N-Heterocycles: Synthesis and Biological Evaluation 9811908311, 9789811908316

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Keshav Lalit Ameta · Ravi Kant · Andrea Penoni · Angelo Maspero · Luca Scapinello   Editors

N-Heterocycles Synthesis and Biological Evaluation

N-Heterocycles

Keshav Lalit Ameta · Ravi Kant · Andrea Penoni · Angelo Maspero · Luca Scapinello Editors

N-Heterocycles Synthesis and Biological Evaluation

Editors Keshav Lalit Ameta Department of Chemistry Mody University of Science and Technology Lakshmangarh, India Andrea Penoni Department of Chemistry University of Insubria Varese, Italy

Ravi Kant Department of Chemistry Shri Ramswaroop Memorial University Lucknow, Uttar Pradesh, India Angelo Maspero Department of Science and High Technology University of Insubria Varese, Italy

Luca Scapinello Department of Science and High Technology University of Insubria Varese, Italy

ISBN 978-981-19-0831-6 ISBN 978-981-19-0832-3 (eBook) https://doi.org/10.1007/978-981-19-0832-3 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

Azaheterocycles always played a vital role in biological processes and are widespread as natural products. Their skeleton is substantially ubiquitous in different classes of bioactive compounds. A brief survey of the most active pharmacophores shows that nitrogen-based heterocycles are the most prevalent form of biologically relevant small molecules. N-heterocycles are well-known scaffolds for compounds that exhibit interesting biological activities: antioxidant, anti-inflammatory, antinociceptive, anticancer. Nitrogen-containing heterocycles are generally diffuse in building blocks and fine chemicals of immense research interest because they are widely found as naturally occurring bioactive compounds. The importance of N-heterocycles is essential to develop new methods to enhance their synthetic efficiencies and investigate the effects of their modifications on biological potential. The fundamental relevance of nitrogen-containing heterocycles in pharmaceuticals cannot be understated, as the presence of such ring systems in compounds such as vitamins, herbicides, antifungal agents, anti-bacterial agents, and anticancer agents. The importance of these applications has created an unprecedented need for more efficient synthetic methodologies. The development of more efficient synthetic procedures in this direction is the need of the day. Total synthesis, asymmetric synthesis, homogeneous and heterogeneous catalysis, multi-component reactions, green synthetic approaches, and benign environmental techniques are only few examples of novel methodologies that were introduced during the decades and that led the organic synthesis to excellent levels of sophistication. This book presents an overview of recent advancements for the synthesis of smalland medium-sized nitrogen-containing heterocycles, including pyrroles, indoles, pyrimidines, pyridines, pyrrolidines, imidazoles, pyrazoles, pyrazolines, lactams, and 1,2,3-triazoles, which are significant scaffolds for compounds with pharmaceu-

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Preface

tical uses. The book also discusses various properties and performance attributes of azaheterocycles including their bioactivity and synthetic strategies. The book can be a valuable reference for beginners, researchers, and professionals interested in organic synthesis and medicinal chemistry. Lakshmangarh, India Lucknow, India Varese, Italy Varese, Italy Varese, Italy

Keshav Lalit Ameta Ravi Kant Andrea Penoni Angelo Maspero Luca Scapinello

Contents

1

2

3

Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis and Biological Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . Kamal Krishna Rajbongshi, Binoyargha Dam, and Bhisma Kumar Patel

1

Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey on Synthetic and Biological Relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . Mirta Gladis Mondino and Roberto da Silva Gomes

51

Lactams, Azetidines, Penicillins, and Cephalosporins: An Overview on the Synthesis and Their Antibacterial Activity . . . . Adilson Beatriz, Mirta Gladis Mondino, and Dênis Pires de Lima

97

4

Synthesis and Biological Importance of Pyrazole, Pyrazoline, and Indazole as Antibacterial, Antifungal, Antitubercular, Anticancer, and Anti-inflammatory Agents . . . . . . . . . . . . . . . . . . . . . . 143 Nisheeth Desai, Dharmpalsinh Jadeja, Harsh Mehta, Ashvinkumar Khasiya, Keyur Shah, and Unnat Pandit

5

An Overview on the Synthesis and Biological Studies of Some Seven Membered Heterocyclic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Vnira R. Akhmetova, Guzel R. Khabibullina, and Askhat G. Ibragimov

6

Various Synthetic Strategies and Therapeutic Potential of Thiadiazole, Oxadiazole, Isoxazole and Isothiazole Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 Kishor R. Desai and Bhavin R. Patel

7

Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles . . . . . . . . . . 275 Vnira R. Akhmetova, Nail S. Akhmadiev, and Askhat G. Ibragimov

8

Synthetic Approach of Quinazolines Candidates . . . . . . . . . . . . . . . . . 313 Vinay Kumar Singh, Anjani Kumar Tiwari, and Mohd. Faheem

vii

viii

9

Contents

An Overview of Cinnolines, Quinazolines and Quinoxalines: Synthesis and Pharmacological Significance . . . . . . . . . . . . . . . . . . . . . 331 Pratibha Saini, Krishan Kumar, Swati Meena, Dinesh Kumar Mahawar, Anshu Dandia, K. L. Ameta, and Vijay Parewa

10 Pharmacological Significance of Triazoles and Tetrazoles in Neurodegenerative Disease: An Overview . . . . . . . . . . . . . . . . . . . . . 355 Pankuri Gupta and Abha Sharma 11 An Insight into the Synthesis and Pharmacological Activities of Indoles, Isoindoles and Carbazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 Surendra Saini, Krishan Kumar, Savita Meena, Anshu Dandia, K. L. Ameta, and Vijay Parewa 12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments and Their Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 Shyam L. Gupta, Surendra Saini, Pratibha Saini, Anshu Dandia, K. L. Ameta, and Vijay Parewa 13 Synthesis of Bioactive Thioxoimidazolidinones, Oxazolidinones, Thioxothiazolidinones, Thiazolidinediones . . . . . . . 443 Esmail Doustkhah and Fatemeh Majidi Arlan

Editors and Contributors

About the Editors Prof. (Dr.) Keshav Lalit Ameta is working as a Professor and Head at the Department of Chemistry, School of Liberal Arts and Sciences, Mody University of Science and Technology, Lakshmangarh, Rajasthan, India. His fields of research are green chemistry and nanotechnology in organic synthesis, heterocyclic and medicinal chemistry. In addition, to this he has keen interests in photocatalysis. Prof. Ameta has published over 80 research articles in the field of synthetic organic chemistry, medicinal chemistry, and material science with publishers of international repute. Moreover, he is honored Fellow of Linnean Society of Chemistry (FLS) UK in 2021 and Fellow of Indian Chemical Society in 2014. He has vast experience of teaching both graduate and postgraduate level students. Apart from this, he is faculty advisor of American Chemical Society (ACS) chapter and Research and Development coordinator at SLAS, Mody University of Science and Technology.

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Editors and Contributors

Dr. Ravi Kant FRSC(UK), FICS, FLS(UK), presently working as Professor of Chemistry, Faculty of Chemical Sciences with an additional Responsibility of Director Research and Consultancy, Shri Ramswaroop Memorial University Lucknow-Deva Road Uttar Pradesh India. From past 21 years, involved in Research in the area of bioorganometallics, material science and metalopharmaceutical chemistry along with teaching of Chemistry/Applied Chemistry/Pharmaceutical and Medicinal Chemistry in undergraduate and post graduate students of engineering, science and pharmaceutical sciences. He is the winner of Rashtriya Shiksha Gaurav Puraskar2015, Young Scientist Award-2018, and Best Faculty Award-2017 along with many more scientific recognition from across the country. He is an active fellow of Royal Society of Chemistry London, Linnean Society of London, Indian Science Congress Association, Uttar Pradesh Academy of Sciences, Indian Chemical Society, Chemical Research Society of India and Centre for Educational Growth and Research. Andrea Penoni is Associate Professor in Organic Chemistry at the Department of Science and High Technology at the University of Insubria in Como, Italy since 2017. He graduated in Chemistry (1996, laurea degree) and received a Ph.D. in Chemical Sciences (2000, doctoral research) at the University Statale of Milano under the supervision of Prof. Sergio Cenini working on a project on amination reaction of olefins and hydrocarbons using transition metal complexes as catalysts. He did his postdoctoral training at the University Statale of Milano, and then joined the research group of Prof. Kenneth M. Nicholas (2000–2001) at the University of Oklahoma, where he studied the annulation reactions between nitro- and nitrosoaromatics with alkynes. Since 2003, he has been Assistant Professor in Organic Chemistry at the University of Insubria and worked in the research group of Prof. Giovanni Palmisano. His research is particularly focused on the synthesis of nitrogen-containing heterocycles, naturally occurring compounds and potentially bioactive molecules. Further, he is involved in research projects on the carbon–nitrogen bond formation mediated by metals and metal complexes and synthesis of biindole compounds as interesting moieties in material science.

Editors and Contributors

xi

Angelo Maspero is Associate Professor in Inorganic Chemistry at the Department of Science and High Technology at the University of Insubria in Como, Italy since 2017. His research interests involve Coordination and Organometallic Chemistry (working on the Synthesis, Reactivity and Spectroscopic characterization), Homogeneous Catalysis studying the Molecular dioxygen reactivity, the Oxidation and oxygenation of organic substrates, Carbon dioxide activation and functionalization, Catalytic formation of C–C, C–N and C–O bonds. He worked even on Organic synthesis assisted by metal centers: Polymerization and olygomerization of alkynes, Cyclopropanation of alkenes. His recent research works in Inorganic Materials (Synthesis and spectroscopic characterization of coordination polymers, Photoluminescent properties of coordination compounds). In the last decade he particularly focused his attention on the preparation, characterization and study of the properties of Metal-Organic Frameworks. Luca Scapinello got his Chemistry BS and M.Sc. in 2017 under the supervision of Prof. Andrea Penoni at the Department of Science and High Technology in University of Insubria and he is currently working as Ph.D. student in the same group. His research topics focus on novel strategies for indole ring synthesis and, in cooperation with prof. T. Benincori, on synthesis of inherently chiral biindoles for applications in materials science. He spent 10 months as visiting Ph.D. student at University of Stuttgart (Germany) in the Polymer Chemistry group headed by Prof. S. Ludwigs.

Contributors Nail S. Akhmadiev Laboratory of Molecular Design and Biological Screening of Candidate Substances for the Pharmaceutical Industry, Institute of Petrochemistry and Catalysis, Russian Academy of Science, Ufa, Russian Federation Vnira R. Akhmetova Laboratory of Heteroatomic Compounds, Institute of Petrochemistry and Catalysis, Russian Academy of Science, Ufa, Russian Federation K. L. Ameta Department of Chemistry, School of Liberal Arts and Sciences, Mody University of Science and Technology, Lakshmangarh, Rajasthan, India

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Editors and Contributors

Fatemeh Majidi Arlan Research Department of Chemistry, Iranian Academic Center for Education, Culture and Research, Urmia, Iran Adilson Beatriz Institute of Chemistry (INQUI), Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil Roberto da Silva Gomes Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA Binoyargha Dam Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam, India Anshu Dandia Department of Chemistry, Centre of Advanced Studies, University of Rajasthan, Jaipur, India Dênis Pires de Lima Institute of Chemistry (INQUI), Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil Nisheeth Desai Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, India Kishor R. Desai Department of Chemistry, Bhagwan Mahavir University-Surat, Surat, Gujarat, India Esmail Doustkhah Koç University Tüpra¸s Energy Center (KUTEM), Department of Chemistry, Koç University, Istanbul, Turkey Mohd. Faheem Department of Chemistry, Dr. Shakuntala Misra National Rehabilitation University, Lucknow, India Pankuri Gupta Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli, India Shyam L. Gupta Government Polytechnic College, Alwar(Raj.), India Askhat G. Ibragimov Laboratory of Heteroatomic Compounds, Institute of Petrochemistry and Catalysis, Russian Academy of Science, Ufa, Russian Federation Dharmpalsinh Jadeja Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, India Guzel R. Khabibullina Laboratory of Heteroatomic Compounds, Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Ufa, Russian Federation Ashvinkumar Khasiya Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, India Krishan Kumar Department of Chemistry, Centre of Advanced Studies, University of Rajasthan, Jaipur, India

Editors and Contributors

xiii

Dinesh Kumar Mahawar Department of Chemistry, Centre of Advanced Studies, University of Rajasthan, Jaipur, India Savita Meena Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur, India Swati Meena Department of Chemistry, Centre of Advanced Studies, University of Rajasthan, Jaipur, India Harsh Mehta Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, India Mirta Gladis Mondino Faculdade Oswaldo Cruz-Faculdade de Ciências Farmacêuticas e Bioquímica Rua Brigadeiro Galvão, São Paulo, SP, Brazil Unnat Pandit Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India Vijay Parewa Department of Chemistry, Centre of Advanced Studies, University of Rajasthan, Jaipur, India Bhavin R. Patel Department of Chemistry, Uka Tarsadia University, Bardoli, Surat, Gujarat, India Bhisma Kumar Patel Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam, India Kamal Krishna Rajbongshi Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam, India; Department of Chemistry, Handique Girls’ College, Guwahati, Assam, India Pratibha Saini Department of Chemistry, Centre of Advanced Studies, University of Rajasthan, Jaipur, India Surendra Saini Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur, India Keyur Shah Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, India Abha Sharma Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli, India Vinay Kumar Singh Department of Chemistry, Dr. Shakuntala Misra National Rehabilitation University, Lucknow, India Anjani Kumar Tiwari Department of Chemistry, Babasaheb Bhimrao Ambedkar University, Lucknow, India

Chapter 1

Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis and Biological Activities Kamal Krishna Rajbongshi, Binoyargha Dam, and Bhisma Kumar Patel

1.1 Pyridine 1.1.1 Introduction Pyridine is a six-membered cyclic molecule that belongs to a significant class of nitrogen heterocycles found in many active pharmaceuticals, natural products, and functional materials. It is a planar molecule that follows Huckel’s criteria for aromaticity. In many respects, it is similar to the most basic aromatic molecule, benzene, with an N-atom replacing one of the C-H groups. Pyridine is a key scaffold in many naturally occurring biologically active compounds and naturally occurring substances such as alkaloids, enzymes, or polypeptides. Niacin 1 and pyridoxine 2 (vitamin B6 ) which play crucial roles in biological systems also are pyridine derivatives. In addition, NADP 3, a coenzyme involved in various oxidation–reduction processes in our body is known as prosthetic pyridine nucleotide as they are derived from niacin. Nicotine 4, Promothiocin A 5 are two significant natural alkaloids having a pyridine core. Some naturally occurring pyridine substructures are shown in Fig. 1.1 (Khan 2021).

K. K. Rajbongshi · B. Dam · B. K. Patel (B) Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India e-mail: [email protected] K. K. Rajbongshi Department of Chemistry, Handique Girls’ College, Guwahati, Assam 781001, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_1

1

2

K. K. Rajbongshi et al. HO O

H

OH

HO

NH2

N Me N

N

N Nicotine (4)

Vitamin B6 (2)

Niacin (1) O O

N

N S

NH HN

N H

NH2 O

N

H2N

O O

O N

N

NH2 NH

O NH

N

NO O

O S

HO

OH

O O O P O P O O O HO

Promothiocin A (5)

O

N

N N

OH

NADP (3)

Fig. 1.1 Some naturally occurring pyridine substructure

1.1.2 Historical Background of Pyridine The term pyridine is an origin of two Greek words where “pyr” means fire and “idine” which is used for heterocyclic aromatic bases containing N-atom. In the year 1846, Thomas Anderson isolated picoline as the first known pyridine from animal bone oil (Anderson 1846). After nearly 25 years its structure was determined by Wilhelm Korner in 1869 and James Dewar in 1871, independently (Dobbin 1934). They formulated that pyridine is a mono-aza-analog of benzene and its structure might be derived by substituting a CH moiety with a nitrogen atom. This brought about a remarkable growth in research in this area. However, there was no method available for the synthesis of pyridine till the latter half of the nineteenth century. Coal tar was the only source of pyridine which served the little commercial demands of that time.

1.1.3 General Approaches to Pyridine Rings It was William Ramsay in 1876, who for the first time developed a synthetic route for pyridine (Ramsay 1876). However, the commercial production of pyridine was based on either the traditional Chichibabin pyridine synthesis, the Bönnemann reaction- a cobalt-catalyzed cyclotrimerization of alkynes and nitriles or from the condensation of aldehydes such as formaldehyde, crotonaldehyde in the presence of ammonia (Scheme 1.1). Owing to their diverse biological activity, scientists world-

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis … Scheme 1.1 Industrial procedures for the synthesis of simple pyridines

3

O + H

HCHO

2

A

+ NH3

N B

+ Me-CN N

H

C

+ HCHO + NH3

O

N

wide have been encouraged to develop newer synthetic methods for the preparation of different substituted pyridines (Henry 2004; Hill 2010). We will discuss few general approaches for the synthesis of pyridine in this chapter as it is beyond the scope to cover all the reported synthetic methodologies.

1.1.3.1

Hantzsch Pyridine Synthesis

It is a well-adopted method for the preparation of pyridines (Hantzsch 1882). The classical Hantzsch pyridine synthesis is a two-step multi-component reaction that involves the cyclo-condensation of an aldehyde, with a 1,3-dicarbonyl compound in the presence of ammonia to form 1,4-dihydropyridines 6 (DHPs), which undergo oxidation to yield the symmetric pyridine derivatives 7 (Scheme 1.2) (Stout and Meyers 1982). Classically oxidation was accomplished with nitric acid or nitrous acid. Later several oxidants like cupric nitrate, CAN, or manganese dioxide on montmorillonite was found to be suitable for this process. Since the first report, there have been numerous developments and applications in the literature. De Paolis et al. reported a one-pot solvent-free synthesis of substituted pyridines under microwave irradiation, using Pd/C/K-10 montmorillonite as catalyst (De Paolis et al. 2008). Aromatic or aliphatic aldehydes, ammonium acetate, and ethyl acetoacetate readily undergo cyclization in the presence of K-10 montmorillonite while palladium on charcoal dehydrogenates the dihydropyridine intermediates to the desired product 8 (Scheme 1.3).

O R1

OR2 O

R

3

O

O

+ NH3 H

EtOH or AcOH Reflux

OR

R3

2

O

O OR

1

R

1

N R H 1,4-DHP(6)

Scheme 1.2 General Hantzsch pyridine synthesis

2

[O]

R3

OR2 R1

O OR2

N (7)

R1

4

K. K. Rajbongshi et al.

Scheme 1.3 MW-assisted Hantzsch synthesis of pyridines

O Me O R1

R1

O 10% Pd/C K-10 montmorillonite EtO OEt MW, neat Me 135 °C, 1.5-2 h + NH4Ac

O

H

O OEt

N

Me

(8)

Unsymmetrical 1,4-dihydropyridines can be formed by directing the Hantzsch synthesis in a modified way, by performing one or more of the condensation steps before the reaction (Robinson et al. 1998). Robinson and his co-workers used αsubstituted acetophenone and a verity of α, β-unsaturated ketones along with ammonium acetate to afford pyridine derivatives 9 as a model for Streptonigrin ring C. Alternatively, condensation of X-substituted enone and substituted ethanones can be used to afford pyridines 10 (Scheme 1.4). Hantzsch synthesis for non-symmetrically substituted pyridine can be performed more efficiently by involving a preformed enaminoester, an intermediate in classical Hantzsch synthesis, in addition to an aromatic aldehyde, a 1,3-dicarbonyl derivative. Following this variation of Hantzsch strategy, Dondoniet al. reported the synthesis of some heterocyclic α-amino acids wherein condensation of oxazolidinyl ketoester, benzaldehyde, and methyl aminocrotonate initially afford the corresponding dihydropyridyl-cycloadduct 11 as a 1.5:1 mixture of diastereoisomers in 85% yield which transformed to the 2-pyridyl-α-alanines 12 in the subsequent steps (Scheme 1.5) (Dondoni et al. 2003).

1.1.3.2

Chichibabin Pyridine Synthesis

In 1906, Chichibabin reported a procedure for the construction of substituted pyridines by thermal cyclo-condensation between ammonia and aldehydes in presence of catalyst such as alumina. This is known as Chichibabin synthesis (Sagitullin et al. 1996). In addition, pyridine derivatives can be synthesized by adding ammonia Scheme 1.4 Pyridine synthesis from enone and acetophenone derivatives

Ph

Ph X Ph

R1

+

R2

O

O

NH4OAc AcOH, O2

Ph

Ph

+ O

N (9)

R2

Ph

Ph X

R1

X

O

R1 NH OAc 4

X

AcOH, O2

Ph

R2

X= NO2, NHAc or CN R1 = H, Me or CN R2 = Ph, Me or 2-furyl

R1 N (10)

R2

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

O RO

O

O

O + O

H

OR

NH2

O

O OR a) AcOH/H O(5/1) 2 RT, 24 h

RO tert-BuOH

N H

4Å MS, 70 °C

b) cat. TEMPO, BAIB, RT, 3h, 60%

NBoc

NBoc O

O R= tert-Bu

5

O

RO

O R N

O

NHBoc OH

Dihydropyridyl-cycloadduct (11)

(12)

Scheme 1.5 Synthesis of 2-pyridyl-α-alanines

gas to acetonitrile or acetylene over a heated contact catalyst. The protocol is also suitable for α,β-unsaturated aldehydes, keto acids, aromatic and aliphatic ketones (Scheme 1.6). Soon after the first report on pyridine synthesis by Chichibabin, a vast number of modifications of this process have been described in literature along with their utilization in the synthesis of several biologically active compounds. An important application of Chichibabin reaction was spotted in the synthesis of 2-amino3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives which are potent IKKβ inhibitors (Murata et al. 2004a, 2004b). The construction of 2-amino-6-aryl3-cyano-4-piperidinylpyridine core 13 can be achieved by the four component one-pot Chichibabin reaction of acetophenone derivative, malononitrile, N-Bocformylpiperidine, and ammonium acetate on heating in 1,4-dioxane at 110 °C. The final product 14 which is known for best IKK-β Inhibitor can be reached after the deprotection step (Scheme 1.7). R O

3R

+ NH3 H

high pressure

R

R

R

R +

N

N

R

Scheme 1.6 General scheme for Chichibabin pyridine synthesis

O

H O

O

H N

Boc N

Boc N 1,4-dioxane 110 °C, 3 h 42% CN

+ CN

OPMB NH4OAc

CN

O N OPMB (13)

Scheme 1.7 Chichibabin-based synthesis of IKK-β Inhibitors

NH2

CN

O N OH (14)

NH2

6

1.1.3.3

K. K. Rajbongshi et al.

The Bohlmann-Rahtz Pyridine Synthesis

Bohlmann and Rahtz pyridine synthesis is a two-step process to generate trisubstituted pyridines reported in 1957. The process involved the conjugate addition of an enamine to an alkynone followed by a thermal cyclodehydration (Scheme 1.8) (Bohlmann and Rahtz 1957). A modified version of Bohlmann-Rahtz pyridine synthesis was reported by Bagley in 2001 (Bagley et al. 2001). In this synthesis, the highly functionalized pyridines 15 were prepared from enamino esters and alkynones in one step using acetic acid or Amberlyst 15 ion exchange resin at 50 °C (Scheme 1.9). Promothiocin A 17 isolated from Streptomycessp. SF2741 belongs to the family of biologically active thiopeptide antibiotics. The use of the traditional BohlmannRahtz procedure for the total synthesis of promothiocin A was explored by Bagley et al. (2000). The key pyridine-oxazolyl core 16 was assembled by the original Bohlmann-Rahtz conditions. It was followed by solvent elimination and heating the residue at 140 °C under vacuum to enable cyclodehydration to the anticipated substituted pyridine 16 in decent yield (83%). It requires another 11 steps to finally achieve Promothiocin A 17 (Scheme 1.10).

1.1.3.4

Kröhnke Pyridine Synthesis

Condensation of A-pyridinium methyl ketone salts with α,β-unsaturated carbonyl compounds via Michael addition in the presence of ammonium acetate and acetic acid to afford 2,4,6-trisubstituted pyridine derivatives in a reaction known as Kröhnke pyridine synthesis named after Dr. Fritz Kröhnke who first reported it in 1961 (Scheme 1.11) (Kröhnke et al. 1962). The Kröhnke pyridine synthesis has been employed for the synthesis of a variety of poly-substituted pyridines on several occasions. A clean aqueous Kröhnke reaction process has been accomplished to access terpyridines 18 which have potential biological activities (Tu et al. 2007). This is achieved via treating 2-acetylpyridine and O R2 H 2N

+ R1 O

ETOH, 50 °C R3

R2 H2N

R3 120-170 °C

R2 R1

R1

N

R3

Scheme 1.8 The general Bohlmann-Rahtz pyridine synthesis

Scheme 1.9 The one-pot Bohlmann-Rahtz pyridine synthesis

R4

R4

R3 + R2

NH2 O

R5

AcOH or Amberlyst 15

R3

PhMe, 50 °C

R2

R6

N (15)

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

7

OBn

OBn

O

EtO2C

EtOH, 50°C

+ H2N

CO2Et

N

140 °C in vacuo 83%

N O

N

NHBoc (16)

O BocHN

11 steps O O

N

N S

NH HN

N H

NH2 O

N O

O N

NH

O NH

N

O

O S Promothiocin A (17)

Scheme 1.10 Total synthesis of Promothiocin A employing a classical Bohlmann-Rahtz reaction

Scheme 1.11 General Kröhnke pyridine synthesis

R2

O O R

R2

R2

N

1

NH4OAc AcOH

Br

R2

R2

aromatic aldehyde with ammonium acetate in a one-pot process under conventional heating or microwave irradiation (Scheme 1.12). Betti et al. reported an elegant route for the SMO antagonist SEN794 20 using Kröhnke reaction (Betti et al. 2012). In this synthesis, the key substituted pyridine 19 was prepared efficiently by the reaction of pyridinium salt with methacrolein and ammonium acetate in refluxing ethanol which in turn afford the desired product 20 in a couple of steps (Scheme 1.13). Scheme 1.12 Kröhnke synthesis of terpyridines

O H

N +

O

NH4OAc H 2O

N

N O

N

(18)

N

8

K. K. Rajbongshi et al. Cl

O N

I

O Cl

N

Cl

H NH4OAc/AcOH

4-steps

N

N

EtOH, reflux 71%

Br (19)

N O SEN794 (20)

N

Scheme 1.13 Synthesis of SMO receptor antagonist SEN794 using Kröhnke reaction

1.1.3.5

Synthesis via Cycloaddition Reactions

Diels–Alder Reaction with Oxazole Kondrat’eva and Huan reported a [4+2] cycloaddition approach for the synthesis of pyridine in 1965 by the addition of acrylic acid as a dienophile to an oxazole (Wang 2010). This protocol gives the target pyridine 21 in good yield (70%) by the subsequent extrusion of the oxazole oxygen (Scheme 1.14). Industrial synthesis of vitamin B6 can be achieved by using the Kondrat’eva approach which is a combination of Diels–Alder reaction with aromatization to access the key intermediate, 5-hydroxy-6-methylpyridine-3,4-dicarboxylic acid diethyl ester 22. Subsequent reduction of the ester moieties in the intermediate followed by isolation technique affords the required product, vitamin B6 23 with an approximate yield of 38–54% (Scheme 1.15) (Dumond and Gum 2003).

Diels–Alder Reactions with Nitriles as Dienophiles Nitriles are also used as formal dienophiles in the [4+2] cycloaddition reactions. Recently, Ogoshi and co-workers demonstrated nickel (0) catalyzed dehydrogenative [4+2] cycloaddition of 1,3-butadienes with nitriles to give variedly substituted pyridine 26 (Scheme1.16) (Ohashi et al. 2011). CO2H O N

CO2H

CO2H

PhH, reflux 70%

O N

Scheme 1.14 Synthesis of pyridine via [4+2] approach

-H2O (21)

N

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis … CO2Et

OEt N

O

HO

OH CO2Et

CO2Et neat, 110°C, 2h

N

9

O (22)

CO2Et

HCl, EtOH 85%

CO2Et

N steps

HO

HO

CO2Et

OH

N

Vitamin B6 (23)

Scheme 1.15 Synthesis of vitamin B6 using the Kondrat’eva method

R2

R1 + N

3

R

R2

10% Ni(cod)2 40% PCy3

R3

PhMe, 130 °C

R4

R1

N R4 (26)

Scheme 1.16 Synthesis of pyridines with nitriles dienophiles

Synthesis of Pyridines via Formal [2+2+2] Cycloaddition Reactions The construction of pyridine derivatives by mixing two equivalents of alkynes (same or different) with one equivalent nitrile using transition metals is a well-established, straightforward and attractive [2+2+2] cycloaddition method (Varela and Saá 2003). The cobalt-catalyzed cyclization of a nitrile and two equivalents of acetylene brings a highly commercially valuable route to substituted pyridines. However, the pyridine formation by the coupling of two different alkynes with nitrile via intermolecular pathway may cause an issue of selectivity. (Scheme 1.17). One interesting approach to solve the regioselectivity is described by Vollhardt and his co-workers. In this strategy α,ω-alkynenitriles and alkynes undergo cyclization to access [b]annelated pyridines 27, 28 with five-, six-, and seven-membered fusedring systems in moderate to excellent yields (Brien et al. 1982). The reaction shows excellent regioselectivities with asymmetric alkynes as the bulky substituent is placed next to the nitrogen (Scheme 1.18). Cycloaddition reaction of the type [2+2+2] for the synthesis of pyridine derivatives using Fe as a catalyst is known in the literature. Recently, Wan et al. reported an R1 R1 R2

R1 R2

M

'M' R2

R1 R2

R1

R2 R CN R 3

1

R

2

R1

R2

+ R1

N

R3

Scheme 1.17 General [2+2+2] cycloaddition for two different alkynes

R3

N

R2

10

K. K. Rajbongshi et al.

Scheme 1.18 Synthesis of pyridine with α, ω-alkynenitriles, and alkynes

C C H (CH2)n

+

C CN n = 3,4,5

Scheme 1.19 An [2+2+2] approach for the synthesis of pyridine derivatives using Fe-catalyst

R1

CpCo(CO)2 h , Heat v

R2

RL

Z

RS

R

R1 N (27)

R2

10% FeI2 20% dppp, 20% Zn

+

Z= C(CO2Me)2, O, NTs, -(CH2)2RL

R1

N (28)

RL R Z

N

THF, rt

N

Z

R2 + (CH2)n

(CH2)n

(30) RS

R Fe

Ln

RL

(Azaferracyclopentadiene (29)

efficient protocol to construct pyridines 30 via the partly intermolecular [2+2+2] cycloaddition of tethered diynes with inactivated nitriles using Fe as catalyst. (Wang et al. 2011). The formation of an intermediate azaferracyclopentadiene 29 explains the high regioselective nature of the reaction. The catalyst is produced in situ from an inorganic iron salt and a diphosphine ligand (Scheme 1.19).

1.1.3.6

Functionalization of Pyridine Ring Systems

Aromatic Nucleophilic Substitution (SN Ar) In an effort for the bulk production of an ORL-1 antagonist 32, the substantial ethyl 2(4-formyl-3-methyl-1H-pyrazol-1-yl)nicotinate 31 was achieved on large scale by an aromatic nucleophilic substitution reaction of methyl 2-chloronicotinate with pyrazole derivative. The use of KI as a catalyst in presence of K2 CO3 in a solution of DMF at elevated temperature gave the best yield for this transformation. (Scheme 1.20) (Debaillie et al. 2015).

Palladium-Catalyzed Reactions Recently, the use of palladium as the catalyst for the synthesis of substituted pyridines is known in the literature. Younis et al. developed a suitable synthetic route for the preparation of 3,5-diaryl-2-aminopyridines 34, a potential antimalarial agent, using Pd catalyst. (Younis et al. 2012). Initially, 3-bromo-5-iodopyridin-2-amine coupled with 4-methylsulfonyl-phenyl boronic acid via Suzuki cross-coupling reaction to

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

11

F F H

Cl N + N

O

CO2Me

O Cl

S

2.0 equiv K2CO3 N N 0.1 equiv KI, O DMF, 100°C, 8h N 72%

N H

N

N

N (32) Ph

(31)

Scheme 1.20 Functionalization of pyridine using SN Ar mechanism

NH2

Scheme 1.21 Pd-catalyzed synthesis of substituted pyridine

NH2 Br

B(OH)2

N + I

5 mol% Pd(PPh3)2Cl2 3 equiv 1M aq K2CO3

Br

N

1,4-dioxane 110 °C, 16h, 58% SO2Me

(33) N F 3C CF3

MeO2S N N

NH2

B(OH)2

SO2Me

7 mol% Pd(PPh3)2Cl2 3 equiv 1 M aq. K2CO3 1,4-dioxane 110 °C, 16h, 65%

(34)

yield substituted 3-bromopyridin-2-amine intermediate 33. This pyridine derivative 33 was allowed to undergo another Suzuki coupling with a variety of pyridinylboronic acids to furnish the target 34 in 65% yield (Scheme 1.21).

1.1.4 Biological Activity Synthetic and natural pyridine derivatives are appreciated for their potent biological activities. The pyridine has some interesting features such as negligible size, water-solubility, basicity, and hydrogen bond-forming capacity due to which these scaffolds are preferable in synthetic drugs. Pyridine-based compounds display a wide various biological activities that include antimalarial, anticancer, antitubercular, antiviral, anti-inflammatory, antileishmanial, antidepressant, antibiotic, antifungal, and many others (Khan 2021). Consequently, widespread research has been focused on designing new bioactive molecules to generate numerous synthetic and semisynthetic pyridine-based pharmacologically important compounds. At present,

12

K. K. Rajbongshi et al.

over 7000 existing drugs contain pyridine in their structure. Omeprazole 35 is a widely used pyridine-based drug to treat acid reflux and ulcers have been dominating the medicinal market since 1998 (Wallmark 1986). Sulfapyridine 36 is a sulfanilamide antibacterial drug prescribed for the treatment of linear IgA disease and use in veterinary medicine (Castle and Witt 1946). Salazosulfapyridine 37 is a blend of sulfapyridine and 5-aminosalicylic acid that is suitable for the treatment of chronic inflammatory bowel diseases (Hilliquinet al. 1992). Atazanavir 38 (Harrison and Scott 2005) and imatinib mesylate 39 (Deininger and Druker 2003) are two important pyridine-based medicines prescribed for human immunodeficiency virus (HIV) and chronic granulocytic leukemia, correspondingly. Ethionamide is a structurally simple drug with pyridine moiety used to treat tuberculosis (Vannelliet al. 2002) (Fig. 1.2).

1.1.4.1

Anticancer Properties

Cancer is a fatal illness responsible for growing death worldwide. There are several naturally occurring, as well as synthetic and semisynthetic, pyridine-based molecules that have been reported to have antitumor activity. Pyrinodemin A 41 is a pyridine N

O N H

NH2

O S N

N OH

O N O N

N N H

S O

HO

SO2

N H

O

Salazosulfapyridine (37)

Sulfapyridine (36) N

Omeprazole (35)

H N

N

N

N

N O MeO

N H

H N O

OH

O N

HN

N H

O

OMe O

Imatinib Mesylate (39) S

Atazanavir (38)

NH2 N Ethionamide (40)

Fig. 1.2 Commercially available medicines containing pyridine rings

HOMs

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

13

O

N

R

HO

F

N O O

OH

O

F

N

O S O HN

R = 3-Me; Pyridine epothilones B (42) R = 4-Me; Pyridine epothilones B (43)

O

N N

(44)

H

O

N N

N N

O

N

N H Pyrinodium A (41)

Fig. 1.3 Natural and synthetic pyridine-based compounds with anticancer activity

alkaloid that is isolated from the marine sponge Amphimedon sp. This natural alkaloid is found to demonstrate strong cytotoxicity against KB epidermoid carcinoma cell sand murine leukemia L-1210 (Tsuda et al. 1999). Nicolaou et al. designed and synthesized some pyridine epothilone B analogs to investigate their cytotoxicity (Nicolaou et al. 2000). On evaluation, it was found that pyridine epothilone B analogs 42, 43 have higher potentials than naturally available epothilone B against a variety of drug-resistant cancer cells. Imidazo[1,2-a]pyridine derivatives 44 are known for excellent dual PI3K/mTOR inhibitors. They demonstrated excellent antitumor activities that might be practiced as lead molecules for anticancer therapy (Yu et al. 2020) (Fig. 1.3). The use of pyridine derivatives as anticancer agents continues to attract interest among the scientific community in the pharmaceutical industry. This effort has recently led to great success. Alpelisib 47, an excellent PI3K inhibitor is accessible in the market as a drug for the treatment of breast cancer since May 2019. Abiraterone acetate 45 is widely used medicine to treat the patient with prostate cancer. Neratinib (INN) 46, is another FDA-approved anticancer medication used to treat breast cancer (Fig. 1.4).

1.1.4.2

Antimicrobial Properties

The pyridine derivatives are found to be effective antimicrobial agents and many research groups are constantly working in this area to discover some efficient antimicrobial agent(s) that lead to promising drug molecules. Recently, Havel et al. synthesized some novel substituted (E)-N’-benzylidene2-(2-ethylpyridin-4-yl)-4-methyl thiazole-5-carbohydrazide derivatives also tested for bacterial and fungal activities. Among all, compounds 48, 49, and 50 exhibited outstanding antibacterial and antifungal activities (Muluk et al. 2019). Fused pyridine derivatives such as 51 and 52

14

K. K. Rajbongshi et al. O

N

N

HN N

H O

H O

C HN

O

O Cl Neratinib (46)

H

Abiraterone acetate (45) H N

N O

N

O

NH2

S

N

N

F

N

F F

Alpelisib (47)

Fig. 1.4 Prominent FDA-approved pyridine-containing drugs

display potent inhibitory against all bacterial strains, particularly against K. pneumoniae with comparable MIC values with the standard. Additionally, these two compounds remained the most potent against the fungi strains, A. ochraceus and A. flavus. (Othman et al. 2020). Ivachtchenko et al. reported the synthesis of some pyrano[2,3-c]pyridine derivatives 53 and investigated for antimicrobial activities. Most of the synthesized compounds exhibited substantial activity against fungal or bacterial strains with the MIC in the range of 12.5–25 μg/mL, which is very near to standard drug (Zhuravel’ et al. 2005). Compounds 54, 55, and 56 that are synthesized by linking aryl pyridine with 4,5-dihydro-2-pyrazolines showed excellent antitubercular activity against the most frequently used Mycobacterium tuberculosis H37Rv strain (MIC value 12.5 μg mL−1 ) (Sowmya et al. 2017) (Fig. 1.5).

1.1.4.3

Antiviral Activity

De Castro et al. synthesized bicyclic heterocyclic systems with γ-sultone moiety and evaluated them for their antiviral activities. Interestingly, compounds 57–59 showed inhibitory toward HIV-1 and might be considered as potential specific anti-HIV1 lead molecules (De Castro et al. 2011). Benzothiazepine derivatives containing pyridine moiety 60 exhibited excellent potential as well as a promising candidate against tobacco mosaic virus (TMV). The measured EC50 value of compound 60 is 352.2 μM, which is better than that of commercially available agent ningnanmycin (Li et al. 2017). Hosono et al. designed a series of histidine-pyridine-histidine (HPH) derivatives and evaluated them for their antiviral activities against herpes simplex virus type 1. Compound HPH-8 (61) showed strong antiviral activity against HSV1 with an EC50 of 15 μM, which is comparable with the standard antiviral drug, acyclovir (Hosono et al. 2008). Oximinopiperidino-piperidine amide SCH 351,125 (62), is found to be a potent inhibitor of HIV-1. It possesses excellent antiviral activities against a panel of primary HIV-1 viral isolates using CCR5 co-receptor (Palani et al. 2001) (Fig. 1.6).

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

15

X

Ph N NH

O

Ph

NH2 CO2H

N

S N

N

N

S N

N

S

N

O

N

(51)

N

NH2 N N

N

N

(52) R1

48, X= 4-Cl 49, X= 3-Br 50, X= 3-Cl

NH

OH

N

O R' N

N H

N

N

O

R

CH3

54, (R= 3,4-F2, R1= 3,4-(OMe)2) 55, (R= 3,4-F2, R1= 2-Cl-6-F) 56, (R= 4-Br, R1= 2-Cl-6-F)

R''

(53)

Fig. 1.5 Synthetic pyridine-based compounds with antimicrobial activities Ph N O R S O O

R

1

S

57, (R=Me, R1= Me) 58, (R= -CO2Me, R1= Me) 59, (R=-CONH2, R1= Me)

Br

O (60) O

S NH (H3C)3CS

S

N

(61)

HN

N

Br

N N N N

SC(CH3)3

Cl

SCH351125 (62)

N

O

O

Fig. 1.6 Synthetic pyridine-based compounds with antiviral activities

1.1.4.4

Antidepressant Activities

Emmitte and his co-workers reported that pyridine derivative 63 is known for its highly selective mGlu3 NAM with DMPK properties that enable its convenient use in rodent models of psychiatric disorders (Engers et al. 2015). Compound with

16

K. K. Rajbongshi et al.

pyrazolo[4,3-c]pyridine nucleus 64 is highly suitable for the treatment of anxiety and depression disorder. It possesses the least toxicity and negligible side effects as compared to standard drugs like Diazepam and Fluoxetine (Zhmurenko et al. 2012). The compound of type 65 with pyridine moiety is found to exhibit excellent antidepressant activity while evaluating using the FST and TST methods (Sowmya et al. 2017) (Fig. 1.7).

1.1.4.5

Antioxidant Potentials

Thiazolo[3,2-a]pyridine derivatives 66 were found to be outstanding scavengers of free radicals and displayed potent antioxidant activity (Shi et al. 2009). Bis(imino) pyridine derivatives, 67–69 were found to have a strong ability for scavenging free radicals like DPPH and ABTS. Two derivatives 67 and 69 proved to be more effective than standard antioxidants (ascorbic acid and Trolox) in all assays (Miloševi´c et al. 2020) (Fig. 1.8).

1.1.4.6

Antipsychotic Activity

Fluorinated imidazo[1,2-a]pyridine derivatives are known for potential novel antipsychotic agents. The compound 70 demonstrated strong antipsychotic-like activity Fig. 1.7 Synthetic pyridine-based compounds with antidepressant activities

O N

N

N Cl

N N

O

(63)

Cl

F HCl HN N

O

F

O

O O F

N

Fig. 1.8 Synthetic pyridine-based compounds with antioxidant activities

N

N NH (65)

(64)

OH NO2 N

H2N

R

CN

NC N

S

O

NO2 OH

(66)

R

67, R= C6H4-4-OH 68, R = 8-OH-2-Qu 69, R = C6H4-4-NMe2

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

17 N

Fig. 1.9 Synthetic pyridine-based compounds with antipsychotic activity

F

N O

(70)

N

which is comparable to the known drug zolpidem while carried out on rats (Marcinkowska et al. 2016) (Fig. 1.9).

1.1.5 Conclusion Several methods for the synthesis of pyridines have been developed since the late nineteenth century due to their various pharmacological activities. Many of these are alterations to prevailing methodologies, whereas others describe novel transformations. Synthesis of pyridine via condensation of amine- and carbonyl-containing fragments area well-established method from the very beginning. However, the current trend involves transition-metal-catalyzed processes, especially Pd-catalyzed crosscoupling reactions that may open a new route to achieve this important class of heterocycles. In addition, most of the mentioned protocols have wide application in the synthesis of some biologically natural products with ease. Although tremendous progress has been made in this area, the construction of extremely substituted, poly-functional pyridine derivatives remains a challenge till now.

1.2 Dihydropyridines 1.2.1 Introduction Dihydropyridines (DHPs) are vital heterocyclic moieties based on the pyridine ring system that is of utmost importance in the biological world. They contain a sixmembered ring that possesses nitrogen at the first position. Theoretically, there are five possible isomers of DHP as shown in Fig. 1.10. But out of those five possible regioismers only 1, 2 (71), and 1,4-isomers (72) were found to have significant importance. The 1,4-DHP scaffold is present in many Fig. 1.10 Various region-isomers of DHP N H

N H

N

N

N

(71)

(72)

(73)

(74)

(75)

18

K. K. Rajbongshi et al.

bestseller drugs such as amlodipine (76) and nifedipine (77) (Huang et al. 2015). 1,4DHP achieved remarkable attention once found its close similarity to nicotinamine adenine dinucleotide (NADH) coenzyme 78, which plays a vital role in the biological redox reaction. Recently, 1,2-dihydropyridines has been utilized countless times for the synthesis of several drugs and important alkaloids. 1,2-DHPs are the precursor for the synthesis of the 2-azabicyclo[2.2.2]octanes (isoquinuclidines) 79 ring system present in alkaloids, ibogaine, and dioscorine. 1,2-DHP is the starting material for the synthesis of oseltamivir phosphate (Tamiflu) 80, anti-influenza drug, (Nakano et al. 2010). In addition, DHPs occur in many compounds exhibiting a wide range of biological activities like anticancer activity (Manna et al. 2018), antihypertensive activity (De Luca et al. 2019), anti-inflammatory activity (Bahekar and Shinde 2002), etc. (Fig. 1.11).

1.2.2 Historical Background of Dihydropyridine Arthur Hantzsch in the year 1882 included the most precious scaffold to the toolbox of medicinal chemists by reporting the preparation of DHP (Hantzsch 1882). This reaction produced DHP as an isolable intermediate which was converted to pyridines by oxidation. The outbreak of research attention in this set of molecules was encouraged by two key discoveries: (a) Separation and establishment of NADH 78 structure in 1950s, its task in biological oxidation–reduction processes, and (b) extensive interest gained by molecules like nifedipine 77 which possess antihypertensive properties in 1970s.

Cl O

O O N H

O O O

Amlodipine (76)

H2N

H O

H

NH2

O

N

N H Nifedipine (77)

HO

O NH2

NO2 O

OH

O O O P O P O OH OH XO

CO2Et R N

Isoquinuclidines (79)

N OH

X= H (NADH); X=PO3H2 (NADPH) (78)

1

R

N O

NH2H3PO4 NHCH2OMe Oseltamivir phosphate (Tamiflu) (80) O

Fig. 1.11 Various DHP moieties having antihypertensive properties

N N

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

19

1.2.3 General Approaches to Achieve DHP Rings 1.2.3.1

Synthesis of 1,2-Dihydropyridine

Reduction of Pyridine Synthesis of 1,2-DHP was achieved by adding hydride sources to N-acylpyridinium salts. Fowler and co-workers in the year 1972 did revolutionary work in this field. In their report, the research group carried out the reduction of N-carboxypyridinium ions formed in situ from chloroformate esters and pyridine with sodium borohydride (Fowler 1972). It was observed that reaction when carried out at 0 °C with THF, a mixture of carbomethoxy-1,2- (81) and 1,4-isomer (82) was obtained with 1,4isomer giving 35–40% of yield. But, when the reaction was set up in the presence of methanol at − 70 °C, the amount of 1,4-isomer got reduced to 2–4% and 1,2-isomer gave a yield of 86–88% (Scheme 1.22). Another fascinating work involving sodium borohydride (reducing agent) to synthesize N-sulphonyl-1,2 and 1,4 DHPs was developed by Knaus et al. (Scheme 1.23) (Knaus and Redda 1977). In their work, they observed that reduction of N-sulphonylpyridinium salts is dependent upon temperature and solvent. It was observed that when the reaction was done with methane sulphonyl chloride and methane sulphonic anhydride, using solvent methanol, at − 65 °C, attack of hydride anion took place exclusively at 2-position of pyridine, affording 1,2-isomer in 32 and 37% yield, respectively. Reaction, when carried with benzene sulphonyl chloride, afforded an isomeric mixture of 1, 2 and 1, 4-isomer in a ratio of 8:1. When pyridine was applied concurrently both as reactant and solvent at 25 °C, 4-position attack was favored affording compounds 83 and 84 in the ratio of 2:1. Scheme 1.22 Sodium borohydride mediated synthesis of DHP

N

ClCOOCH3 + NaBH4 Organic solvents Temperature THF, 0-10 °C

+ N N COOCH3 COOCH3 (81) (82) 60-65%

35-40%

CH3OH, -70 °C 86-88%

Scheme 1.23 Synthesis of DHP by reduction of N-sulphonylpyridinium salts N

O S Cl NaBH R 4 O + or (RSO2)2O

2-4%

+ N SO2 R

R = Me (83) R = Ph R = 4-MeC6H4 R = 4- MeCONHC6H4

N SO2 R (84)

20

K. K. Rajbongshi et al.

Cycloaddition Reaction Another important synthetic approach of 1,2-DHPs is via cycloaddition reactions. Heterodienes underwent [4+2] cycloaddition with high region chemical control. Cycloaddition reaction of electron-deficient 2-azadienes and phosphazene (route a, Scheme 1.24) afforded 1,2-DHPs 86 in 39–72% of yield. Alternatively, when 2-azadienes are reacted with enamines, the reaction went in a regiospecific manner thereby leading to the formation of tetrasubstituted 1,2-DHPs 88 (route b, Scheme 1.24). Following this procedure, 1,2-DHPs can be obtained in the yield ranging from 42 to 62% (Palacios et al. 2001, 1999). Tong research group reported a procedure for the preparation of highly substituted 1,2-DHPs 89, which involved [2+2+2] annulation between N-tosylimines and 1phenylpropynones in the presence of triphenylphosphine as a catalyst (Liu et al. 2010) (Scheme 1.25). Reactions were reported to undergo smoothly leading to the formation of a broad range of 1,2-DHP derivatives in good yields (59–90%). This Scheme 1.24 Azadiene mediated regioselective synthesis of 1,2-DHPs

R3

R3

R4OOC

N + R1 CO2R

R1

N

2

CO2R2 N R1 PPh2R

Route a

Route b LiClO4, Et2O, 25 °C

R= Ph R = Me

R1

Scheme 1.25 Synthesis of 1,2-DHPs via triphenylphosphine mediated [2+2+2] annulation reaction

R3 H

R3

COOR2 N PPh2R CO2R2 (85)

N CO2R2 (87) - HN

H -NHPPh2R

Ph +

CO2R2 (88) COOR2

N

R1 (86)

CO2R2

O O

COOR4

N

R1

R3 N

COOR4

N

[4+2]

NTs PPh (20 mol%) Ph 3 R Toluene, reflux H(D)

O Ph

N Ts (89) R = Ph (75 %) R = 4-MeOC6H4(90 %) R = 4-MeC6H4(59 %) R = 4-ClC6H4(67 %) R = 4-BrC6H4(85 %)

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis … Scheme 1.26 Preparation of 1,2-DHP via triphenylphosphine catalyzed [4+2] annulation reaction

(D) H PPh3

O 3

R

(D) H

NTs

COR1

R1 PPh3

O

D (H) COR1

21

R2

TsN

1) [1,2]-H (D) (D) H 2) [1,5]-H (D) 3) -PPh3

R2 COR1 (90)

COR3 1) Conjugate addition 2) [1,2]-elimination of PPh3 PPh3 3) [1,3]-H (D)

R2 N Ts (91)

R1 = OMe, R2 = Ph, R3= Ph (59 %) R1 = OMe, R2 = 4-MeOC6H4, R3= Ph (96 %) R1 = OMe, R2 = 4-BrC6H4, R3= Ph (86 %) R1 = OMe, R2 = 4-MeOC6H4, R3= 4-MeOC6H4 (59 %) R1 = OMe, R2 = 4-BrC6H4, R3= 4-MeC6H4 (60 %) R1 = OMe, R2 = 4-BrC6H4, R3= 4-MeOC6H4 (50 %) R1 = OBn, R2 = 4-MeOC6H4, R3= Ph (63 %)

study reported that when the reaction was carried out in presence of three equivalents of compounds at high temperature, the desired product was obtained in good yield. The same group also reported [4 + 2] annulations reaction of alkyl propiolates and aryl N-tosylimines (Scheme 1.26) catalyzed by triphenylphosphine. Intermediate 90 was formed through Mannich type reaction of zwitter ion (formed by the reaction of triphenylphosphine and propiolate) with N-tosylimine followed by a coupled proton transfers and [1,5]-elimination of triphenylphosphine. Then it undergoes a Michaeltype addition with another molecule of zwitter ion formed in situ. The desired 1,2DHP 91 was then obtained after consequent conjugate addition, [1,2]-elimination of triphenylphosphine, and [1,3]-proton transfer.

Nucleophilic Addition to Pyridinium Salts Addition of various types of nucleophiles to pyridinium salts has been carried out by many researchers for synthesis of highly functionalized DHP. The capability of an N-acyl substituent to stabilize DHP system led to the application of these intermediates in the addition of organometallic reagents to N-acylpyridinium salts. However, there are some problems in this approach, especially the close electrophilicity of 2-, 4- and 6-positions on N-acylpyridinium salts, leading to non-regioselective additions. Also, to attain desired enantioselectivity, the carbon–nitrogen bond of the N-acylpyridinium intermediate should be fixed in the transition state. However, numerous groups effective/working in this area, have found inventive methods to evade both problems. Comin and his co-workers reported a chiral-auxiliary mediated synthesis of substituted 1,2-DHP (92a, 92b). In this procedure, diastereoselective addition of Grignard’s reagent to chiral N-acylpyridinium salts was carried out

22

K. K. Rajbongshi et al. * O Sn (iPr)3 R X N

Sn (iPr)3

O Cl

1. RMgX, 2. Oxalic acid R silica gel

Cl N COOR*

Xa R* = (-)-8-(4-phenoxyphenyl)menthyl

+ N N R COOR* COOR* (92a) (92b)

Xb R*= (-)-8-phenylmenthyl

Scheme 1.27 Chiral-auxiliary mediated synthesis of 1,2-DHP

(Scheme 1.27) (Comins et al. 1991). Several reactions were performed and a range of products was obtained in higher yields (58–87%). Diastereomeric excess of the products was determined by 1 H NMR and HPLC analyses. Wenkert et al. studied the interaction between indole tethered pyridinium salts with a mixture of ethyl (methylthio) acetate and lithium diisopropylamide (LDA) (Wenkert et al. 1986). They reported that an anionic intermediate 93 thus formed acted as a nucleophile and reacted at the C-6 position of N-alkylpyridinium salts leading to the formation of 1,2-DHP moieties 94. The synthesized 1,2-DHPs then on treatment with one equivalent of base undergoes ring opening to form a conjugate triene derivative 95 (43%) (Scheme 1.28).

Other Methods a.

Vinylogous Iminoaldol Reaction Brunner et al. prepared functionalized 1,2-DHP derivatives 96 by reaction of vinylepoxide with benzhydril protected aldimine in the presence of scandium triflate as the catalyst (Scheme 1.29) (Brunner et al. 2006). The 1,2-DHP derivatives were obtained in moderate yields. Mechanistic studies proved that the reaction proceeded via Lewis acid-mediated epoxide ring opening followed by 1,2-hydride shift and successive enolization. Intermediate formed would then react with aldimine to give (E)-amino-α,β-unsaturated aldehyde, which gets

Scheme 1.28 Addition of nucleophile to indole tathered pyridinium salt

Br

N

NH H

MeS

(93)

Li MeS CO2Et

CO2Et N

(94)

O

O H N N H

NH H O

SMe CO2Et

(95)

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

R2 O

Ph

Ph

R1 + R3

H

THF, MS, 2-3 h, 0-50 °C

R2

N

Ph

Sc(OTf)3 (15 mmol)

Ph

N

23

R3 R1 (96)

R1: EtO2CR3: Aryl, EtO2C, R2: Alkyl-, ArylFuryl

Yield: Upto 63%

Scheme 1.29 Preparation of 1,2-DHP by vinylogous imino-aldol type reaction

R2 CHO NTs R1

R3 23 THF

Li

OH R2 NTs R1

(97)

R

2

R1

RCOCl Pyridine

R2

R

R1

R3

(98)

PtCl2 (10 mlo%)

R

X

R3 N Ts (99) X = O or NH

O/NH

NTs

3

PhMe (0.2 M), 100 °C, 3h

O

O

Scheme 1.30 Platinum (II) catalyzed synthesis of 1,2-DHP

converted to Z-isomer under the influence of scandium (III) triflate. This then undergoes cyclization and leads to the formation of the desired 1,2-DHP through the elimination of water. b.

Cycloisomerization of Aziridinyl Propargylic Esters The 1,2-DHP 97 was also synthesized by Motamed et al. using platinum (II) as the catalyst. In their work, cycloisomerization of aziridinyl propargylic esters 98 was carried out to afford 1,2-DHP moieties 99 (Scheme 1.30) (Motamed et al. 2007). Aziridinyl propargylic esters were synthesized by acylation of aziridine propargylic alcohols 97. Aziridine propargylic alcohols were prepared from aziridinyl aldehyde via diastereoselective 1,2-addition of Grignard’s reagent. Aziridinyl propargylic esters on treatment with PtCl2 (10 mol%), in the presence of 0.2 M toluene at 100 °C afforded 1,2-DHP in good yield after 3 h.

24

1.2.3.2

K. K. Rajbongshi et al.

Synthesis of 1,4-Dihydropyridine

Condensation Reactions Arthur Hantzsch synthesized 1,4-DHP for the first time in the year 1882 (Hantzsch 1882). This synthesis method allows the proficient preparation of 1,4-DHPs 100 by one-pot multi-component reaction of aldehyde, acetoacetic ester, and ammonia under solvent-free conditions (Scheme 1.31). This procedure had been employed for the preparation of several important Hantzsch esters. These Hantzsch esters possess several functionalities attached to the DHP core (Fig. 1.12). Hantzsch esters have found their use as multidrug resistance (MDR) 101 (Nogae et al. 1989), in the treatment of benign prostatic hyperplasia (BPH) 102 (Wong et al. 1998), and as adenosine receptor antagonists 103 (Jiang et al. 1999). Multidrug resistance (MDR) is a problem established in cancer chemotherapy. The Hantzsch ester 101 has been found to overcome MDR. SNAP 5089 (102) is a specific adrenoreceptor that is being used in the treatment of BPH. Benign prostatic hyperplasia (BPH) is a condition characterized by nodular enlargement of prostatic tissue which blocks the urethra. DHP 103 is a Hantzsch ester that is found to have selective adenosine receptor binding activity. Adenosine receptors are prospective R1 ROOC 2 X

+ O

1

R

COOR

ROOC

O H

+ NH3 N H (100)

Scheme 1.31 Synthesis of 1,4-DHP by Hantzsch procedure NO2

S

Ph

Ph

S MeOH2CH2COOC

COOCH2CH2OMe

N COOCH2CH2CH2

MeOOC N H (101)

N H Ph H

EtOOC N H

Fig. 1.12 Various Hantzsch esters

Ph COOCH2

(103)

(102)

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

25

targets for drugs that are used to treat asthma. This particular DHP derivative is found to have selective A3 adenosine receptor antagonist activity. Another one-pot multi-component strategy is reported by J. H. Lee, for efficient synthesis of 1,4-DHP (104/105) using Baker’s yeast as the catalyst under mild conditions (Scheme 1.32) (Lee 2005). In this procedure, a solution of phosphate buffer (pH 7.0), D-glucose, yeast extract was taken and treated at 35 °C. Further, Baker’s yeast was added to it and was stirred for 30 min at 30 °C. Following that 1 mmol of acetoacetic ester and ammonium acetate or 3-aminocrotonitrile was added to it. The reaction was then stirred for 24 h at room temperature and then extracted with diethyl ether. After recrystallization with ether and n-hexane pure product was obtained within yields ranging from 46 to 70%. An inexpensive, efficient, and simple procedure was developed by Yao et al. for the synthesis of 1,4-DHP derivatives 106 using iodine as the catalyst (Ko et al. 2005). Initially, benzaldehyde, 1,3-cyclohexanedione, ammonium acetate, and ethyl acetoacetate were stirred in the presence of ethanol at room temperature (Scheme 1.33). It was observed that after 4 h of stirring only 56% of the product was obtained.

O

NH4OAC

O OR +

R= Et, Me

or NH2

Baker's yeast, D-glucose, ROOC Phospahte buffer (pH 7.0)

COOR N H (104)

CN

ROOC

or R= Et, Me

CN N H (105)

Scheme 1.32 Baker’s yeast catalyzed synthesis of 1,4-DHP

Scheme 1.33 Synthesis of 1,4-DHP catalyzed by iodine

CHO

O +

O

O + NH4OAc +

O

I2, room temperature

O

O O N H (106)

O

26

K. K. Rajbongshi et al.

Other Methods a.

Addition of Grignard and Organo Copper Reagents Comins and Yamaguchi research groups reported the reaction of an alkyl Grignard’s reagent with 1-acetylpyridinium chloride (Comins 1983; Comins and Abdullah 1982; Comins et al. 1983; Comins and Mantlo1983; Yamaguchi et al. 1983). This led to the formation of 1,4-DHP 107 and 1,2-DHP 108. Further, it was noticed that when a catalytic amount of CuI was used in the reaction, exclusively 1,4-isomer was formed. Application of stoichiometric organocopper reagents like R2 CuLi, RCu, etc. also leads to exclusive formation of 1,4-isomer (Scheme 1.34).

b.

Regioselective Addition of Grignard’s Reagent to Nicotinic Acid Ester Another methodology was developed by Wanner et al. for synthesizing 4,4disubstituted 1,4-dihydronicotinates by the addition of Grignard’s reagent to nicotinic acid ester catalyzed by triisopropylsilyl triflate (TIPS-OTf) (Scheme 1.35) (Sperger and Wanner 2009). The reaction proceeded via intermediate 109. Depending on the structure of the organomagnesium reagent varying ratios of 1,2- (110), 1,4- (111), and 1,6- (112) isomers were obtained, but in all the cases 1,4-isomer was found to predominating.

Alkyl Grignard Reagent

COCH3 N Cl

COCH3 N

COCH3 N R

R (107) Yield: 95% Alkyl Grignard Reagent CuI

H3COC N

(108) Yield: 5% R

R = alkyl group

(107) Yield: 37%

R2CuLi or RCu

COCH3 N (107) R Yield: 59%

Scheme 1.34 Organo copper and Grignard’s reagent catalyzed synthesis of 1,4-DHP

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis … Ph

Ph COOEt

N

COOEt

TIPS-OTf

CH2Cl2, room temperature

N Si

OTf

(i) RMgX -78 °C-50°C (ii) Phosphate buffer, pH 7, 1 M

(109)

Ph

R

N Si (110)

27 Ph

Ph COOEt

COOEt

+

+

R

N Si

N Si

(111)

(112)

COOE t R

Scheme 1.35 TIPS-OTf catalyzed synthesis of DHP

1.2.4 Biological Activity Following the first synthesis of DHP in the year 1882, it took many decades to test these compounds for their biological activities. Bossert and Vater for the first time found that 1,4-DHP possess coronary vasodilator activities (Bossert and Vater 1989). Because of the structural resemblance of DHP with NADH, they have found their applications for the treatment of hypertension. DHP has also been found to exhibit various medicinal activities like anti-tumor, antitubercular, anti-inflammatory activities, etc.

1.2.4.1

Antihypertensive Activity

Hypertension is often called a “silent killer” because most often it has no symptoms. Hypertension is the major factor for coronary heart disease (Stamler et al. 1993). Treatment of hypertension is important public health care objective in most countries. Kai Zhou and co-workers reported a group of compounds based on nitrendipine moieties whose antihypertensive activities can be improved by elongating its alkyl chain in 3 or 5th position. Nitrendipine and its seven analogs were synthesized and their antihypertensive activities were studied on spontaneously hypertensive rats (SHR). Compound 113 was found to display noteworthy hypertensive activity (Zhou et al. (2011). Mohajeri and co-workers synthesized a series of DHPs having 1-(4fluorobenzyl)-5-imidazolyl substituent at 4th position 114 and tested for hypotensive activities in male rats. Hypotensive activities of all compounds were found to be less than nifedipine (Mohajeri et al. 2011). Balaev et al. synthesized new 1,4-DHPs containing 3-alkylamino-2,2-dimethylpropyl fragments 115 and found that these compounds showed higher hypotensive activities than nifedipine (Balaev et al. 2010) (Fig. 1.13).

1.2.4.2

Antitubercular Activity

Afshin Fassihi et al. reported the synthesis of 4-substituted imidazolyl-2,6-dimethylN3, N5-bisaryl-1,4-dihydropyridine-3,5-dicarboxamides (Fassihi et al. 2009). These were then tested against Mycobacterium tuberculosis H37Rv as antitubercular

28

K. K. Rajbongshi et al.

Fig. 1.13 DHP core with antihypertensive activity

SR1

NO2 O

O

O

O

O

R2

C7H15

O

O

N H (113)

(114)

N H

NO2 O

F 2 O R

R1 R 2 Me Me Me Et Et Me Et Et

O

O

O

NH2

N H (115)

Fig. 1.14 DHP core with Antitubercular activity

SMe N O Ar

N H

N

O N H

Ar

Ar = 4-Chlorophenyl; 116 Ar = 2-pyridyl; 117

N H (116-117)

agents. Using the agar proportion method minimum inhibitory concentrations (MICs) were determined. Compound 116 was the most effective one among all the tested compounds (Fig. 1.14). It was as powerful as rifampicin against M. tuberculosis H37RV. Compound 114 also showed antitubercular activities with a similar substituent as compound 117 at the 4th position and pyridyl group at the 3rd and 5th positions of the 1,4-DHP ring.

1.2.4.3

Antioxidant Activity

A new series of 1,4-DHPs has been reported by Vijesha and co-workers (Vijesh et al. 2011). These moieties were synthesized by reaction of ammonium acetate and 1,3-dicarbonyl compounds with 3-aryl-1H-pyrazole-4-carbaldehydes. Antioxidant activities of these compounds were studied by measuring DPPH radical scavenging assay. Compounds 118, 119, and 120 were found to exhibit strong antioxidant and antibacterial activities (Fig. 1.15).

1.2.4.4

Anticancer Activities

The development of multidrug resistance is one of the major remedial obstructions in chemotherapy. Circumvention of multidrug obstacles is thus an important step in

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

29

H N N

Ar O Et

O

O

O N H

Et

Ar = 4-Thioanisyl; 118 Ar = Biphenyl; 119 Ar = 4-Chlorophenyl; 120

(118-120)

Fig. 1.15 DHP core with Antioxidant activity

improving cancer chemotherapy. Drugs like nicardipine, verapamil, etc. were found to overcome drug resistance in vitro and in vivo (Kiue et al. 1990). Series of 1,4DHP derivatives containing thiosemicarbazide and semicarbazide was synthesized by Kumar et. al. and were found to exhibit anticancer properties in vivo (Kumar et al.2011). Compound 121 was found to be active against MCF7 (breast) and HepG2 (Liver), whereas compound 122 was found to be active against Hela (cervical). Sirisha and the research group evaluated in vitro anticancer, antibacterial and antitubercular activities of synthesized 1,4-DHPs. Among them, compound 123 was found to exhibit the highest anticancer activity (Sirisha et al. 2010) (Fig. 1.16).

1.2.4.5

Antiulcer Activity

Subudhi and research groups reported a series of DHP derivatives 124 and tested them for antiulcer activities. Antiulcer activity significantly got enhanced on conjugation with sulphanilamide substitution of methoxy group (Subudhi and Bhatta 2009) (Fig. 1.17). H N

H2N O

O

R

O N H

N H

H N

N H 121-122

NH2 R1

R 4-OH-3-OCH3-Ph 4-OH-3-OCH3-Ph

Cl

O Ar

O N H

Ar

N H Ar = 2-Methyl-4-oxo-3H-quinazoline-3-yl 123

Fig. 1.16 DHP core with Anticancer activity

R1 O; 121 S; 122

30

K. K. Rajbongshi et al.

Fig. 1.17 DHP core with Antiulcer activity

Et O O N H2NO2S

O

NH O O Et

1.2.4.6

(124)

Antialzheimer Activity

Alzheimer’s disease is an age-related neurodegenerative process where the decline in language skills, progressive memory loss, and other cognitive impairments take place (Goedert and Spillantini 2006). Rafael and research groups reported the synthesis and medicinal evaluation of a series of newly formed DHPs 125–129 (León et al. 2008). These compounds were found to exhibit potential therapeutic activity against Alzheimer’s disease. Jose Marco-Contelles and co-workers reported synthesis and evaluation of a series of tacrine-DHP hybrids and were found to be potent inhibitors of AChE and showed neuroprotective activity (Marco et al. 2009). Structure 130 shows one of the most important derivatives of this evaluated series (Fig. 1.18).

1.2.5 Conclusion After a thorough review of DHPs, it can be concluded that they are molecules of multifunctional properties. DHP skeleton has revolutionized pharmaceutical research to a greater extent. It is a drug of choice for various treatments. Herein, in this chapter, we have reviewed several methods for syntheses of various DHP moieties and discussed its medicinal activities. However, continuous development in the field of research of Fig. 1.18 DHP core with Antialzheimer activity

X O

NH2

N N H (125-129) 125 126 127 128 129

X C-H C-F C-Me C-OMe N

O

NH2

O Et O N H (130)

N

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

31

DHPs demands more diversity. Therefore, it is one of the vivacious and challenging areas of research.

1.3 Piperidines 1.3.1 Introduction Piperidine is a nitrogen-containing saturated six-membered heterocycle with molecular formula C5 H11 N. Numerous natural products, bioactive agents and many therapeutic alkaloids contain extremely functionalized piperidine scaffolds as a core ring in their skeleton (Shimizu 1984). Morphine 131, Scopolamine 132, quinine 133, and sedamine134 are some of the most prominent natural alkaloids containing a piperidine ring (Fig. 1.19) (Ojima and Iula 1999). Piperidine also has a leading role in the production of various pharmaceuticals which are of substantial interest. In addition, it is widely used to convert ketones to enamines which can further be employed in the Stork enamine alkylation reaction. It is also found to be a suitable base and solvent in many chemical reactions.

1.3.2 Historical Background of Piperidine The name “Piperidine” originates from the genus name Piper, which means pepper in Latin. Thomas Anderson a Scottish chemist was the first to isolate piperidine base NH H Ph O

OH

H HO Morphine (131) (opioid analgesics)

O

N

O

scopolamine (132) (anticholinergic drug)

N

HO

O

HO

OH N

O N Quinine (133) (antimalarial drug)

Sedamine (134) inhibitor of pea seedling amine oxidase

Fig. 1.19 Some natural-occurring piperidine substructure

32

K. K. Rajbongshi et al.

in 1850 (Anderson 1850). However, in the year 1852 Cahours independently isolated piperidine from the alkaloid piperine found in black pepper (Piper nigrum). He isolated piperidine directly by distilling piperine, a crystalline solid (m.p. 129.5 °C), over soda lime (Cahours 1852).

1.3.3 General Approaches to Piperidine Rings Piperidine-based natural products most often have quite complex structures built around the piperidine ring scaffold. Thus, the preparation of these molecules is synthetically quite challenging. This has necessitated attention toward the search for general, effective, and stereoselective means for the synthesis of the piperidine ring. These studies have become more extensive in modern days owing to the development of newer heterocyclic drugs.

1.3.3.1

Reduction of Pyridines

Classically, pyridine was hydrogenated to tetrahydropyridine or piperidine with sodium in the presence of alcohol. However, industrially the compound is produced by catalytic hydrogenation of pyridine over nickel catalyst under the solvent-free condition at 170–200 °C. The unreacted pyridine in trace amounts is removed by azeotropic distillation with water. A variety of metal catalysts like Pd/C, PtO2, or Rh/C have also been reported for the synthesis. Even on the laboratory scale, hydrogenation of pyridine derivatives is the most effective way for the synthesis of piperidine compounds. With substituted pyridines, reduction to piperidine often led diastereomeric mixture in most cases. Optically active Cbz-protected cis-4-phenyl2-pipecolic acid derivative 135 can be achieved by catalytic hydrogenation of 4phenylpicolinic acid (Keenan et al. 1999). The optical resolution was accomplished with L-tyrosine hydrazide to provide 135 in 98% see (Scheme1.36). Scheme 1.36 Catalytic reduction for diastereoselective piperidine

Ph

N

i) H2, PtO2, H2O ii) CbzCl, NaOH ii) optical resolution CO2H

50%, 98% ee

Ph

N CO2H Cbz (135)

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

1.3.3.2

33

Cycloadditions

Aza Diels–Alder Reactions Since the first report on imino-Diels–Alder reaction over six decades ago, it is still of current interest for the versatility of the reaction toward regio- and stereoselective construction of nitrogen heterocycles (Buonoraet al. 2001). Normally, the imine dienophile variant of the imino-Diels–Alder reaction requires the use of activated dienes or imines with electron-withdrawing group substituents. In an attempt for the total synthesis of alkaloid cylindrospermopsin, Weinreb and co-workers described the synthesis of a piperidine A-ring precursor 136 via Imino Diels–Alder reaction of the imine and the diene (Heintzelman et al. 1996). The piperidine ring 136 can be achieved as an only stereoisomer in a single step by treating the diene with imine in the presence of ZnCl2 at room temperature (Scheme 1.37). Maison and Adiwidjaja reported the synthesis of azabicyclooctenes 137 via stereoselective aza-Diels–Alder reaction of 1,3-cyclohexadiene with a chiral imine. Subsequent oxidative cleavage of 137 with suitable reagents afforded enantiomerically pure pipecolic acid derivatives 138 (Scheme 1.38) (Maison and Adiwidjaja 2002). 1-Azadienes as diene are less reactive and seldom used for the synthesis of piperidine heterocycles. 1-Azadiene resulting from Enders’ hydrazines and α,β-unsaturated aldehyde undergoes cycloaddition with cyclic dienophiles to afford a cycloaddition adduct 139 with high facial selectivities. The adducts 139 can be readily transformed into enantiomerically pure epimeric piperidine derivatives 140 and 141 by esterification followed by N–N bond cleavage with zinc in acetic acid and at the end reducing the double bond (Scheme 1.39) (Beaudegnies and Ghosez 1994). Recently, Rovis et al. reported a protocol focusing on [4+2] cycloaddition of 1azadienes with nitro-alkenes in presence of catalyst for synthesis of piperidines 142. CO2Et +

NTs

OCH2Ph

CO2Et

ZnCl2 N

PhMe, rt 58% PhH2CO

Ts

(136)

Scheme 1.37 Synthesis of piperidine A-ring precursor Ph N +

H

BF3.OEt2 TFA, CH2Cl2 CO2Et -80°C-rt 65%

N CO2Et (137)

Ph

i) O3, MeOH, -80°C ii)Me2S, rt iii)NaBH4 78%

HO

Scheme 1.38 Synthesis of enantiomerically pure pipecolic acid derivatives

N

CO2Et OH

(138)

34

K. K. Rajbongshi et al. O N N

O

MeOH CH2N2

X

O

X

N N

OMe X=O, NPh

COOMe

Zn, AcOH

O

COOMe +

N H

OMe (139)

COOMe

N H

COOMe

(141)

(140)

Scheme 1.39 Synthesis of substituted piperidines with 1-azadienes as diene

The cycloaddition is highly regio- and diastereoselective in presence of inexpensive, readily available Zn as catalyst and novel BOPA ligand (F-BOPA). The orthosubstitution in the F-BOPA ligand is responsible for stereo directing the course of the reaction and achieving high enantioselectivities (Scheme 1.40) (Chu et al. 2015).

[3+3] Cycloaddition Construction of the piperidine ring via [3+3] cycloaddition method has been utilized on many occasions and considered one of the most vital strategies for the synthesis of piperidine derivatives (Harrity and Provoost 2005). Functionalized piperidines 143 were synthesized through a [3+3] cycloaddition reaction of aziridines with Pd-trimethylenemethane complexes (Pd-TMM) as the source of dipolar synthon. One important feature of this protocol is the application of this procedure in the total synthesis of the natural alkaloid (–)-pseudoconhydrine 144 (Scheme 1.41) (Hedley et al. 2001).

1.3.3.3

Aza-Michael Addition

Aza-Michael addition reaction proves to be most suitable to build substituted piperidine rings in natural product research areas (Vinogradov et al. 2019). Among several known synthetic instances utilizing intramolecular aza-Michael addition in literature, i. Zn(II), F-BOPA (20mol%)

Ar N

R2 +

R1

ii. ZnCl2, NaCNBH, MeOH NO2

R1 N H

F F-BOPA:

Ar N

O

N

F N

O

R2 NO2

(142) 43-87% upto 92% ee

Bn Bn

Scheme 1.40 Synthesis of Piperidines from 1-azadienes and nitro-alkenes

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

N R

+

AcO

SiMe3

Pd(OAc)2 P(OPr)3, n-BuLi

35

N R (143)

THF, 60°C 63% R: p-methoxybenzenesulfonyl

i. O3, DMS ii. L-Selectride

77%

OH

OH Na-Naphthalenide N H

N R

79%

(144) (–)-pseudoconhydrine

Scheme 1.41 Substituted piperidine via [3+3] cycloaddition

construction of (−)-andrachcinidine, a natural alkaloid isolated from Andrachne Aspera Spreng is one of the best examples reported by Krishna and co-workers (Radha Krishna and Reddy 2013). Starting from homoallylic alcohol, the key product 9-benzyloxy-7-amino-2,3-dehydroketone 145 can be produced in 12 steps. The resultant product 145 then cyclized in an aza-Michael manner to give a Cbzprotected piperidine derivative 146 with high diastereoselectivity. Deprotection of 146 by catalytic hydrogenation finally offered the target (−)-andrachcinidine 147 (Scheme 1.42). An effort was made by Golubev et al. for the synthesis of 4-substituted pipecolic acids, a structural component of the cyclic peptide virginiamycin S1 which possesses antibiotic properties (Golubev et al. 1996). The crucial step of the strategy consists of an intramolecular Michael addition of the enones 148 in presence of BF3 .Et2 O under refluxing benzene to afford protected piperidone 149. The final product 4-OxoL-pipecolic acid 150 was obtained after deprotection in presence of i-PrOH/H2 O at room temperature (Scheme 1.43). Snider et al. employed a double Michael addition in the synthesis of bicyclic piperidine, a model for cylindrospermopsin (Snider and Harvey 1995). The key OBn NHCbz

OH

O

12 steps 3

(145) 60% O

OH 3

N H (147)

H2,Pd/C MeOH 89%

Scheme 1.42 Total synthesis of (−)-andrachcinidine

i. TFA, iPrOH ii. Cbz-Cl, NaHCO3

OBn 3

O N Cbz (146)

36

K. K. Rajbongshi et al. O

O

O

BF3.OEt3 HN F3C O F 3C (148)

O

Benzene reflux

N F3C F3C

i-PrOH/H2O

O

r.t.

O (149)

COOH N H (150)

Scheme 1.43 Synthesis of 4-oxo-L-pipecolic acid using intramolecular aza-MR

O NH3OH, NH4Cl, BocHN

MeOH, 67°C, 16h

O

Me NH

Me

55% (151)

(152)

NHt-Boc

O3SO Me (153)

Me N

NH2

NH

Scheme 1.44 Synthesis of a cylindrospermopsin model

substrate dienone 151 transformed to piperidinone derivative 152 on exposing to ammonia and ammonium via double aza-Michael reaction. The final bicyclic piperidine 153 can be produced in 10 steps which can be used as a precursor of cylindrospermopsin, causative agent of a 1979 outbreak of hepatoentexitis in Australia (Scheme 1.44).

1.3.3.4

Ring-Closing Metathesis

Ring-Closing Metathesis (RCM) is a powerful tool for the construction of carbo- as well as small, medium, and large nitrogen-containing rings. This protocol is particularly suitable for N-allyl and N-butenylamines which effectively cyclize under RCM catalysis to form dehydropiperidines. Sedamine is an alkaloid found in several Sedum species. An asymmetric synthesis of (+)-sedamine with ring-closing metathesis reaction has been reported (Cossy et al. 2002). The synthesis used benzaldehyde as a starting material which was transformed to the protected unsaturated hydroxyamine 154 in eight steps. Protected unsaturated hydroxyamine 154 undergoes RCM to produce the desired of 3,4-dehydropiperidine 155 in high yield on treatment with Grubbs’ catalyst in benzene. Hydrogenation of the double bond followed by removal of both protecting groups afforded (+)-sedamine 156 in 78% yield and with a diastereomeric excess of 98% after crystallization (Scheme 1.45). Vankar et al. reported a synthetic procedure for (R)-coniine starting from a chiral amine 157 obtained from butanal and (R)-α-methylbenzylamine (Pachamuthu and Vankar 2001). Allylation of this chiral amine 157 gave a diastereomeric mixture of dienes 158, 159 which was then subjected to RCM in the presence of Grubbs catalyst to give purely one diastereomeric 2-substituted unsaturated piperidine 160. Finally,

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis … Boc N PMBO

O Ph

8 steps

Ph

154 Grubs' catalyst

94% HO

Me

Ph

N 156

37

i- H2, Pd/C Boc N PMBO ii-DDQ iii-LiAlH4

Ph

Benzene

155

(+)-Sedamine

Scheme 1.45 Synthesis of (+)-Sedamine using RCM

N

N

(157)

N

(158) (159) (Inseparable diastereomers) Grubs' catalyst(10 mol%) CH2Cl2, r.t. isolated one diastreomer with 64%

H2 N H (161)

+

N

Pd-C (10 mol%) 90%

(-)-Coniine

(160)

Scheme 1.46 Synthesis of (R)-coniine using RCM

hydrogenation of the unsaturated piperidine 160 afforded (R)-coniine 161 in 58% overall yield (Scheme 1.46).

1.3.3.5

Hydroamination Reactions/Cyclization

The catalytic intramolecular hydroamination across an inactivated C–C multiple bonds offers a route to nitrogen heterocycles. The protocol is very useful as it involves common functional groups and without any byproduct. Intramolecular hydroamination to form piperidines has been reported with a double bond, triple bond, and allenic systems mediated by different catalysts (Arredondo et al. 1999).

38

K. K. Rajbongshi et al.

A very classic example found in literature is lanthanocene-catalyzed diastereoselective synthesis of 2,6-disubstituted piperidines using intramolecular hydroamination reaction (Molander et al. 2001). In this protocol, the earlier synthesized 2substituted 8-nonen-4-amines 162 cyclized via intramolecular hydroamination reaction in the presence of complex Cp*2 NdCH(TMS)2 to achieve 2,6-disubstituted piperidines 163 with greater than 100:1 selectivity for the formation of the cis isomer. Following this route, a short stereoselective synthesis of pinidinol 164, a natural alkaloid can be achieved (Scheme 1.47). In another interesting example, intramolecular hydroamination reaction of 1-(3aminopropyl)vinylarenes 165 readily cyclized in the presence of readily available [Rh(COD)(DPPB)]BF4 as a catalyst to afford 3-arylpiperidine derivatives 166, which comprise the core structure of known dopamine autoreceptor agonists (Takemiya and Hartwig 2006). Reactions of amino olefins with substituents β to the nitrogen on the alkyl chain were found suitable and produced 3,5-disubstituted piperidines with high diastereomeric excess. The regio-chemistry of this cyclization is very interesting as it follows anti-Markovnikov addition (Scheme 1.48).

1.3.3.6

Mannich Reactions

Highly stereoselective synthesis of polysubstituted piperidines is possible using Mannich reaction which serves as a powerful tool for rapid and efficient product formation. Recently, a three-component reaction between 5-bromopentanal, panisidine, and acetone catalyzed by proline is reported (Chacko and Ramapanicker 2015). This one-pot Mannich reaction proceeded via cyclization leading to the OTBDPS Cp*2NdCH(TMS)2 Benzene, r.t

H2N (162)

OTBDPS=

N H (163)

; Cp NdCH(TMS) = 2 2

O Si

OH

OTBDPS i. KOH, MeOH N H

ii. HCl iii. KOH

(164)

NdCH(TMS)2

Scheme 1.47. Synthesis of substituted piperidines using catalyzed hydroamination reaction

R2 NHMe

Ph R1 (165)

R3

Me N

[Rh(COD)(DPPB)]BF4, 10 mol% THF, 70°C, 48h

R3 R2

Ph R1 (166)

Scheme 1.48 Stereoselective Rh-catalyzed intramolecular hydroamination

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis …

39

synthesis of 2-substituted piperidine derivative 167 in good yield. Triethylamine has a special role in this reaction as without it, the reaction gave a very low yield. This methodology has significant application as it can be further utilized for the short synthesis of natural alkaloids pelletrine 168, and also some others like sedridine, allosedridine, and coniine (Scheme 1.49). The asymmetric synthesis of poly-substituted piperidines from δ-amino β-keto esters and ketones or aldehydes has been reported by Rao and his co-workers (Davis et al. 2001). Treatment of δ-amino β-keto esters 169 with TFA in methanol followed by addition of aldehydes afforded 4-oxypiperidine derivatives 170 via intramolecular Mannich reaction with high diastereoselectivities. Further, decarboxylation leads to 2,6-disubstituted 4-oxopiperidines, an important chiral building block for piperidine alkaloid synthesis (Scheme 1.50).

1.3.4 Biological Activity Piperidine core exists in numerous biologically active natural products and piperidine itself can be isolated from Piper nigrum L.(Piperaceae) plant. One example of wellknown piperidine alkaloid is piperine 171 which is isolated from black pepper (Piper nigrum), possesses plentiful pharmacologically important properties such as inhibition of dopamine p-hydroxylase, the stimulation of the pituitary-adrenal axis, and increase in the permeability of intestinal epitheleal cells in addition to responsible for the spiciness of black pepper (Platel and Srinivasan 2000). (−)-Prosophylline 172 having 2,6-disubstituted-3-piperidinol skeleton was isolated from the leaves, O

O Br + CHO H2N

L-Proline (10 mol%)

O N

Et3N, CH2Cl2 30°C, 3h OMe

N H OMe

(167)

(±)-pelletrine (168)

Scheme 1.49 Synthesis of 2-substituted piperidine using Mannich reaction

O

R1 NH2 O R

i. TFA/MeOH

O OMe

(169)

ii.R1R2C=O DCM iii. aq. NaHCO3

R2

N

H

OH

O OMe

R

N H

CO2Me R1 R2

(170)

Scheme 1.50 Synthesis of poly-substituted piperidine using intramolecular Mannich reaction

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K. K. Rajbongshi et al.

stems, and roots of Prosopis africana possesses notable antibiotic and anesthetic properties (Ande et al. 2018). Lobeline 173 is a pharmaceutically attractive piperidine alkaloid isolated from Indian tobacco (Lobelia inflata). It has a similar action to nicotine on nicotinic cholinergic receptors though is less potent. This alkaloid has a variety of clinical utilities including peripheral vascular disorders, insomnia respiratory disorders, and smoking cessation (Butler 2008). Coniine 174 a poisonous piperidine alkaloid with potent neurotoxin, is isolable from poison hemlock (Conium maculatum). It can cause death by respiratory failure and was often used to execute criminals in ancient Greece (Butler 2008). The piperidine moiety is one of the most common nitrogen heterocycles in many FDA-approved drugs Donepezil 175 and is a widely used piperidine-based drug in the medicinal market since 1996. It is used in the treatment of Alzheimer’s disease (Dooley and Lamb 2000). Paroxetine 176 is one of the finest synthetic drugs prescribed for the treatment of depression and anxiety disorders (Bourinet al. 2001) (Fig. 1.20). Piperidine being a privileged scaffold plays a crucial role in leading drug development and new piperidine derivatives for future drug molecules with high potential are therefore still being searched.

1.3.4.1

Anticancer

Piperidines are known for their excellent antitumor properties and numerous compounds with the piperidine moieties are employed as a drug in the pharmaceutical industry to treat cancer. Ibrutinib 177, sold under the brand name Imbruvica a BTK inhibitor, is prescribed for treating patients with B cell cancers like O O

OH

N

O

OH N H Prosophylline (172)

4

Piperine (171)

O OH

O N

N CH3 H (s)-Coniine (174)

Lobeline (173) O

H N N

MeO

O

O

O

MeO Donepezil (175)

Paroxetine (176)

F

Fig. 1.20 Natural and synthetic biologically active piperidine compounds

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis … N H2N

HN

N O

N

41

N

N

O

N

S

(179)

N

O

N O O

N

N

N

O

R1 R2

S

R3

R5

(177)

NO2

4

R

O

180, (R1, R3, R4, R5 = H);

R2 = Cl

182, (R1, R4, R5 = H; N

O

R2 = Br, R3 = OCH3) O

N H

N N O

(178)

N

N

N

O S

N S N

(181)

Fig. 1.21 Piperidine derivatives with anticancer activities and anticancer drugs

chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, and mantle cell lymphoma (Avendaño and Menéndez 2015). Alectinib 178, a tyrosine kinase receptor inhibitor is an oral drug is suitable for treating non-small-cell lung cancer (NSCLC) (Mckeage 2015). Krasavin et al. discovered 4-(1,2,4-oxadiazol-5-yl)piperidine-1carboxamides as a new class of tubulin inhibitors of which compound 179 (GI50 = 120 μM) is known as the most potent anticancer agent to treat prostate cancer (Krasavin et al. 2014). A new class of imidazolylmethylpiperidine sulfonamides 180–182 has been demonstrated as the most powerful aromatase inhibitors with IC50 values that are comparable to that of standard letrozole and SYN 20,028,567 (Di Matteo et al. 2016) (Fig. 1.21).

1.3.4.2

Antibacterial

Shin et al. designed and synthesized a new series of heterocycle fused oxazolidinone derivatives containing several piperidinyl moieties and assessed for their antibacterial activity against clinically available Gram-positive and Gram-negative strains (Shin et al. 2013). Compound 182 exhibited excellent activities against penicillinresistant Staphylococcus pneumonia and taphylococcus agalactiae which is more effective than the standard linezolid. A few analogs of fluoroquinolone 183 with piperidine rings at the C-7 position are found to demonstrate high in vitro antibacterial activity (Dang et al. 2007). Several of them displayed substantial activities against Gram-positive organisms, which were proved to be more effective than those of linezolid, gemifloxacin, and vancomycin. Kidwai et al. synthesized some Cephalosporin derivatives 184 by coupling Cephalosporin with piperidine that demonstrated notable

42

K. K. Rajbongshi et al. O NC N

N

H O N

NC F (182) H2N

R2ON

S N N S

O

N N

O F N

OH N

N

1

R HN

(183)

S O

N (184)

Fig. 1.22 Biologically active piperidine derivatives with antibacterial activities

antibacterial activity against P. vulgaries, Z. mobilis, and E. herbicola which is comparable to cephlothin acid as a reference drug (Kidwai et al. 2001) (Fig. 1.22).

1.3.4.3

Antimalarial

Several natural piperidines with potent antimalarial activities are reported in the literature. Febrifugine 185, a natural piperidine alkaloid is the most popular antimalarial that has been used for more than 2,000 years (Kuehl et al. 1948). Mefloquine, 186 an orally administered drug that has been marketed since 1990 for both acute treatment of falciparum malaria and malaria prophylaxis (Sweeney 1981). 4-Aminopiperidine analogs 187 and 188 showed excellent antimalarial activity against the causative agent of the deadliest strain of malaria, a multidrug-resistant strain of Plasmodium falciparum (Brinner et al. 2005). Functionalized quinoline analogs, decorated with a modified piperidine-containing side chain were also found to possess antimalarial activity. 4-Aminoquinoline-piperidine derivatives 189–193 demonstrated excellent in vitro antiplasmodial activity against parasite strains NF54 and K1 (Van et al. 2020) (Figs. 1.23 and 1.24).

1.3.4.4

Antiviral

A few new classes of N-phenyl piperidinyl aminopyrimidine scaffold 194, 195 were developed by Tang and his co-workers that exhibited remarkable potency against wild-type HIV-1 and a broad range of clinically significant NNRTI-resistant mutant viruses (Tang et al. 2010). N-(4-Fluoro-benzyl)piperazine analog 196 hydrochloride displayed excellent potency against HIV-1 activity with IC50 at nanomolar similar to that of standard TAK-220 hydrochloride (Dong et al. 2012). In addition, compounds bearing the piperidine moiety exhibit a broad range of biological activities such as antihypertensive, anti-inflammatory, analgesic, antioxidant α1 -AB antagonists, diabetes, and many more (Sajadikhah et al. 2012).

1 Pyridines, Dihydropyridines and Piperidines: An Outline on Synthesis … O

F

OH

F

F

F N

N O

N

(185)

43

F F

H HO

H N

N

(186)

Ph N

(187)

HN

Ph H N

N

Ph N

(188)

Ph

Ph

N N

N

Ph

NH

O

NH

NH R

N R

189, R=H 190, R=Cl

N 191, R=H 192, R=Cl

Cl

(193)

N

Fig. 1.23 Examples of antimalarials agents with piperidine scaffold H N

N

CONH2

N

N

R O

O

R1

CN

O

F

N

N

N

N

1

194, R=H, R =H 195, R=Br, R1=F

Cl

(196)

Fig. 1.24 Examples of antivirals agents with piperidine scaffold

1.3.5 Conclusion Since this privileged pharmacologically active piperidine has moved into preclinical and clinical testing over a couple of years, the development of the new approach for piperidines and their derivatives is a major concern among scientists. Some prominent strategies involved in constructing piperidine rings are ring-closing metathesis, aza Diels–Alder reaction, reduction of pyridines, etc. Although the preparation

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of piperidines has been widely studied, the synthesis of diversely functionalized piperidines remains one of the challenges of organic chemistry and needs special attention.

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Othman IMM, Gad-Elkareem MaM, Anouar EH et al (2020) Novel fused pyridine derivatives containing pyrimidine moiety as prospective tyrosyl-tRNA synthetase inhibitors: design, synthesis, pharmacokinetics and molecular docking studies. J Mol Struct 1219:128651 Pachamuthu K, Vankar YD (2001) Synthesis of (−)-coniine and (−)-pipecoline using ruthenium catalyzed ring closing metathesis. J Organomet Chem 624:359–363 Palacios F, Herrán E, Rubiales G (1999) Reaction of N-vinylic phosphazenes derived from βamino acids with aldehydes. Azadiene-mediated synthesis of dihydropyridines, pyridines, and polycyclic nitrogen derivatives. J Org Chem 64:6239–6246 Palacios F, Alonso C, Rubiales G et al (2001) Cycloaddition reactions of neutral 2-azadienes with enamines− regiospecific synthesis of highly substituted dihydropyridines and pyridines. Eur J Org Chem 2001:2115–2122 Palani A, Shapiro S, Clader JW et al (2001) Discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1‘-[(2,4-dimethyl-3- pyridinyl)carbonyl]-4‘-methyl-1,4‘- bipiperidine NOxide (SCH 351125): an orally bioavailable human CCR5 antagonist for the treatment of HIV infection. J Med Chem 44:3339–3342 Platel K, Srinivasan K (2000) Influence of dietary spices and their active principles on pancreatic digestive enzymes in albino rats. Nahrung 44:42–46 Radha Krishna P, Reddy BK (2013) Total synthesis of the 2,6-disubstituted piperidine alkaloid (−)-andrachcinidine. Tetrahedron: Asymmetry 24:758–763 Ramsay W (1876) XXXIV. On picoline and its derivatives. London. Edinburgh Dublin Philos. Mag. J. Sci. 2:269–281 Robinson JM, Ahmed M, Alaniz NJ et al (1998) Pyridine syntheses. II. Condensation routes toward streptonigrin ring C. J Heterocycl Chem 35:65–69 Sagitullin RS, Shkil GP, Nosonova II et al (1996) Synthesis of pyridine bases by the chichibabin method (review). Chem Heterocycl Compd 32:127–140 Sajadikhah SS, Maghsoodlou MT, Hazeri N et al (2012) One-pot five-component synthesis of highly functionalized piperidines using oxalic acid dihydrate as a homogenous catalyst. Chin Chem Lett 23:569–572 Shi F, Li C, Xia M et al (2009) Green chemoselective synthesis of thiazolo[3,2-a]pyridine derivatives and evaluation of their antioxidant and cytotoxic activities. Bioorg Med Chem Lett 19:5565–5568 Shimizu Y (1984) Alkaloids, volume 1: chemical and biological perspectives. In William Pelletier S (ed) Wiley-Interscience, p 398 Shin H-N, Seo SH, Choo H et al (2013) Synthesis and antibacterial activities of new piperidine substituted (5R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl] oxazolidinones. Bioorg Med Chem Lett 23:1193–1196 Sirisha K, Achaiah G, Reddy VM (2010) Facile synthesis and antibacterial, antitubercular, and anticancer activities of novel 1, 4-dihydropyridines. Arch Pharm 343:342–352 Snider BB, Harvey TC (1995) Synthesis of a bicyclic model for the marine hepatotoxin cylindrospermopsin. Tetrahedron Lett 36:4587–4590 Sowmya PV, Poojary B, Revanasiddappa BC et al (2017) Novel 2-methyl-6-arylpyridines carrying active pharmacophore 4,5-dihydro 2-pyrazolines: synthesis, antidepressant, and anti-tuberculosis evaluation. Res Chem Intermed 43:7399–7422 Sperger CA, Wanner KT (2009) Regioselective addition of organomagnesium reagents to N-silyl activated nicotinic acid esters—a convenient method for the synthesis of 4, 4-disubstituted 1, 4-dihydronicotinates. Tetrahedron 65:5824–5833 Stamler J, Stamler R, Neaton JD (1993) Blood pressure, systolic and diastolic, and cardiovascular risks: US population data. Arch Intern Med 153:598–615 Stout DM, Meyers AI (1982) Recent advances in the chemistry of dihydropyridines. Chem Rev 82:223–243 Subudhi BB, Bhatta P (2009) B B Subudhi, P K Panda and D Bhatta Synthesis and antiulcer activity study of 1,4-dihydropyridines and their mannich bases with sulfanilamide. Ind J Chem (Sec B). NISCAIR 2009; 48(B):725–728). Indian J Chem Sect B 48(B):725–728

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Sweeney TR (1981) The present status of malaria chemotherapy: mefloquine, a novel antimalarial. Med Res Rev 1:281–301 Takemiya A, Hartwig JF (2006) Rhodium-catalyzed Intramolecular, anti-markovnikov hydroamination. Synthesis of 3-arylpiperidines. J Am Chem Soc 128:6042–6043 Tang G, Kertesz DJ, Yang M et al (2010) Exploration of piperidine-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with broad potency against resistant mutant viruses. Bioorg Med Chem Lett 20:6020–6023 Tsuda M, Hirano K, Kubota T et al (1999) Pyrinodemin A, a cytotoxic pyridine alkaloid with an isoxazolidine moiety from sponge Amphimedon sp. Tetrahedron Lett 40:4819–4820 Tu S, Jia R, Jiang B et al (2007) Kröhnke reaction in aqueous media: one-pot clean synthesis of 4 -aryl-2,2 :6 ,2 -terpyridines. Tetrahedron 63:381–388 Vannelli TA, Dykman A, Ortiz De Montellano PR (2002) The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase. J Biol Chem 277:12824–12829 Varela JA, Saá C (2003) Construction of pyridine rings by metal-mediated [2+2+2] cycloaddition. Chem Rev 103:3787–3802 Vijesh A, Isloor AM, Peethambar S et al (2011) Hantzsch reaction: synthesis and characterization of some new 1, 4-dihydropyridine derivatives as potent antimicrobial and antioxidant agents. Eur J Med Chem 46:5591–5597 Vinogradov MG, Turova OV, Zlotin SG (2019) Recent advances in the asymmetric synthesis of pharmacology-relevant nitrogen heterocycles via stereoselective aza-Michael reactions. Org Biomol Chem 17:3670–3708 Van De Walle T, Boone M, Van Puyvelde J et al. (2020) Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents. Eur J Med Chem 198:112330 Wallmark B (1986) Mechanism of action of omeprazole. Scand J Gastroenterol 21:11–16 Wang C, Li X, Wu F et al (2011) A simple and highly efficient iron catalyst for a [2+2+2] cycloaddition to form pyridines. Angew Chem Int Ed 50:7162–7166 Wang Z (2010) Kondrat’eva pyridine synthesis. In: Wang Z (ed) comprehensive organic name reactions and reagents, pp 1668–1671 Wenkert E, Angell EC, Drexler J et al (1986) Carbon-carbon bond-forming additions to 1-alkyl-3acylpyridinium salts. J Org Chem 51:2995–3000 Wong WC, Chiu G, Wetzel JM et al (1998) Identification of a dihydropyridine as a potent α1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate. J Med Chem 41:2643–2650 Yamaguchi R, Nakazono Y, Kawanisi M (1983) On the regioselectivity of the reaction of Nmethoxycarbonylpyridinium chloride with Grignard reagents: highly regioselective synthesis of 2-substituted N-methoxycarbonyl-1, 2-dihydropyridines. Tetrahedron Lett 24:1801–1804 Younis Y, Douelle F, Feng T-S et al (2012) 3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential. J Med Chem 55:3479–3487 Yu YN, Han Y, Zhang F et al (2020) Design, synthesis, and biological evaluation of imidazo[1,2a]pyridine derivatives as novel PI3K/mTOR dual inhibitors. J Med Chem 63:3028–3046 Zhmurenko LA, Molodavkin GM, Voronina TA et al (2012) Synthesis and antidepressant and anxiolytic activity of derivatives of pyrazolo[4,3-c]pyridine and 4-phenylhydrazinonicotinic acids. Pharm Chem J 46:15–19 Zhou K, Wang X-M, Zhao Y-Z et al (2011) Synthesis and antihypertensive activity evaluation in spontaneously hypertensive rats of nitrendipine analogues. Med Chem Res 20:1325–1330 Zhuravel’ IO, Kovalenko SM, Ivachtchenko AV et al (2005) Synthesis and antimicrobial activity of 5-hydroxymethyl- 8-methyl-2-(N-arylimino)-pyrano[2,3-c]pyridine-3-(N-aryl)carboxamides. Bioorg

Chapter 2

Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey on Synthetic and Biological Relevance Mirta Gladis Mondino and Roberto da Silva Gomes

2.1 Imidazole or 1,3-Diazole 2.1.1 Introduction This five-membered aromatic heterocycle is a white solid, melting point 90–91 °C and boiling point 257 °C, soluble in water and other polar solvents such as ethanol, chloroform, and pyridine, with a dipole moment µ = 3.61 D. It is classified as aromatic because it meets the criteria for aromaticity but, comparing levels of aromaticity requires that the conditions under which the data were collected be known. Let me explain, for example, imidazole and 1,2,4-triazole in the solid phase have intermolecular hydrogen bonds (Fig. 2.1), decreasing their aromaticity. The reason may be the increased length of the 1,2 bond induced by the N hydrogen bond N(1)-H(1)…N(3) [1]. Its occurrence can be represented as an equilibrium between two tautomeric structures (Fig. 2.2), in which the hydrogen atom can be bonded to one or the other nitrogen. These two nitrogen give these compounds special characteristics because, depending on where the hydrogen binds, they have different characteristics through their electron pairs. One nitrogen act as pyrrole-type nitrogen, and the other one shows a close resemblance to pyridine-type nitrogen (Fig. 2.3) [1]a . Imidazole is an amphoteric compound because it can be used as an acid or a base. As an acid, the pKa = 14.5 gives it less acidity than phenols and carboxylic acids but more acidic than pyrrole. As a base, pKaH = 6.95 makes it a more basic compound than pyridine and much more basic than pyrrole. Imidazole is more basic M. G. Mondino Faculdade Oswaldo Cruz-Faculdade de Ciências Farmacêuticas e Bioquímica Rua Brigadeiro Galvão, 530- Barra Funda São Paulo-SP-CEP, São Paulo 01151-000, Brazil R. da Silva Gomes (B) Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_2

51

52

M. G. Mondino and R. da Silva Gomes

Fig. 2.1 N-hydrogen bond N(1)-H(1)…N(3)

H

N

N

3

H

Fig. 2.2 Annular tautomerism

N

N1

1

N

H

N

NH

N N

N H

Fig. 2.3 Type of Nitrogen like pyridine nitrogen

N like pyrrole nitrogen

Fig. 2.4 Cation imidazolium

N

H N+

H+

N H

N H

NH

N

+N

H

H

than pyrrole because the imidazolium cation is stabilized by two equivalent resonance structures (Fig. 2.4) without breaking the aromaticity. In contrast, the pyrrolium ion concentrates hydrogen in a single nitrogen [1].

2.1.2 Synthesis of Imidazole Since 1840 there has been reported the existence of imidazole. Still, in 1858, Heinrich Debus proposed a synthesis that uses glyoxal and formaldehyde in the presence of ammonia to form imidazoles (Scheme 2.1). Despite the low yield, it is still used. In recent decades, there have been several strategies for synthesizing imidazole compounds, including van Leusen imidazole synthesis, Debus-Radziszewski imidazole synthesis, Wallach imidazole synthesis, etc. Among these synthetic strategies, R1 O

O

R1

R2

R3 O

+ H

N

+ 2 NH3 - 2 H 2O

Scheme 2.1 Synthesis of imidazole- Debus-reaction

R2

N H

R3

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

53

it is well-known that the van Leusen imidazole synthesis based on TosMICs, which is the cycloaddition reaction, is one of the most convenient and attractive protocols for the preparation of imidazole-based small molecules, due to its excellent advantages like simple manipulation, easily obtained raw materials and a wide range of substrates, which has been developed rapidly in the past decades (Zheng 2020; Geigle 2019) (Scheme 2.2). Shabalin and Camp highlighted in a recent review the most modern regiocontrolled synthesis of substituted imidazoles (Shabalin 2020). The review is organized by sorts of bond disconnections employed to construct the heterocycle (Scheme 2.3). One bond Former: Fang et al. reported a novel protocol for the cyclization of amido-nitriles 1 to form disubstituted imidazoles 2 (Scheme 2.4). The reaction conditions were mild enough to include a variety of functional groups, including aryl halides and aromatic and saturated heterocycles. This reaction is reported to proceed via nickel-catalyzed addition to nitrile 1, which is followed by proto-demetallation, tautomerization, and dehydrative cyclization to afford 2,4disubstituted NH-imidazoles 2 in poor to excellent yield depending on the coupling partners (Fang 2019) (Scheme 2.5). Two-bond Former: A two-bond disconnection for the synthesis of imidazoles has been explored to connect a C2–N3 fragment with an N1–C4–C5 unit. Shi et al. used this concept to form trisubstituted NH-imidazoles 5 from the reaction of benzimidates 4 with 2H-azirines 3 in the presence of zinc (II) chloride (Shi 2018) (Scheme 2.6). Recently, a reaction of triazole 6 and nitriles 7 synthesis afforded protected imidazoles 10 via a BF3 ·Et2 O (Yang 2018) (Scheme 2.7). The proposed mechaScheme 2.2 General van Leusen imidazole synthesis

R2

R3(H) R1 HC

NR 2

Base Tos

R3(H)

NC

N

R2

R2

N R1

N R

R3

N R

2

R

N

R4

R4

2

R3

R3 R2 N

N three bonds R

N

two bonds

one bond

4

R1

N R1

1

R1

N

N

R

3

four bonds R1

R4

Scheme 2.3 Synthetic methodologies (scheme taken from reference 4)

N R4

R3

54

M. G. Mondino and R. da Silva Gomes R2B(OH)2 (2 eq) Ni(PPh3)2Br2 (10mol%) Na2SO4 (3 eq) R2 O

N N

N H

R1

N

10 mol%

N

R1

N

Toluene,120oC,24h 38 examples 13-90%

(1)

H

(2)

Scheme 2.4 Nickel-catalyzed cyclization of amido-nitriles R2B(OH)2 (2 eq) Ni(PPh3)2Br2 (10mol%) Na2SO4 (3 eq)

O R

1

N H

O R

N

1

R2

N H

R1

N

(1)

R1

R2 N

R2

HN O

NH

O

[Ni]

10 mol%

N

N

R2

HN

R1

NH2

N H

(2)

Scheme 2.5 Fang proposed mechanism R2 R2

R1

R

NH

3

N (3)

OEt

N

ZnCl 2 (10mol%) MeCN, 80oC, 12h R3 28 examples 32-87%

(4)

(5)

R1

N H

Scheme 2.6 Shi method overview

Scheme 2.7 Yang reaction overview

R1 N

R1

BF3-Et2O (1 eq)

N N SO2R (6)

2

R3CN (7), reflux 30-200min 23 examples 32-99%

N R3

N SO2R2 (10)

nism proceeded via an initial ring-opening of the triazole 6 to form diazoimine 8. BF3 ·Et2 O promoted the addition of the nitrile affords nitrilium intermediate 9, which subsequently forms the substituted imidazoles 10 by cyclization in good to excellent

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey … R1

R1

N2

N

55 R1

N2

N

F3B

N SO2R2

SO2R2 (6)

N

F3B

-N2

SO2R2

N SO2R2

(9)

(8) R

R1

N

R CN

BF3

N

R3 3

1

N R3

N SO2R2 (10)

Scheme 2.8 Yang proposed mechanism

yield (Scheme 2.8). The products of the reaction are sulphone-protected imidazoles that have substitution at the C-2 and C-4 positions (Yang 2018). The following synthesis (Shabalin 2020) is interesting because it occurs under mild conditions and short microwave reaction time. The reaction to forming NHimidazoles 13 occurred between methyl propiolate 11 and substituted amidoximes 12 (Scheme 2.9). So, when this activated alkyne 11 joins a variety of amidoximes 12 to a two-stage microwave methodology with a catalytic amount of 1,4-diazabicyclo [2.2.2] octane (DABCO) afforded the desired NH-imidazoles 13 in moderate yield. The mechanism proposed for the reaction is shown in Scheme 2.10. DABCO (10mol%) DMF

NH2

CO2Me N

R CO2Me

N

(11)

OH

(12)

wave, 80oC,15 min then 240oC, 2 min 9 examples 6-25%

R

N H (13)

Scheme 2.9 Cyclization method overview

NH2 CO2Me

[3,3]

CO2Me

NH

1,3-H R

R N

(11)

CO2Me

NH2

R OH

N

HN

O

O

(12) HN

CO2Me

CO2Me

CO2Me

N

N

R NH O

Scheme 2.10 Shabalin proposed mechanism

R

N H

OH

R

N H

(13)

56

M. G. Mondino and R. da Silva Gomes

Three bonds Former: A considerable number of strategies for forming imidazole containing 3 new bonds have been reported. Geng et al. found that ketones 14 and 2-amino benzyl alcohols 15 reacted in the presence of iodine, FeCl3 , and toluenesulphonylmethyl isocyanide to afford 1,4-disubstituted imidazoles 16 (Geng 2020) (Scheme 2.11). The reaction is reported to proceed via the initial oxidation of ketone 14 to keto-aldehyde 18. Subsequent condensation of aldehyde 18 with 2-amino benzyl alcohol 15 and reaction with the in situ formed tosylamine 17 afforded imine 19. Intramolecular cyclization of amine 19 followed by elimination of TsH and aromatization via C–O bond cleavage gave 1,4-disubstituted imidazole 16 (Scheme 2.12). Wang et al. (2019) synthesized imidazoles substituted at the C-2, C-4 e C-5 positions using the three-disconnect strategy. Two equivalents of nitrile 21 were used to react with the acetylide generated in situ from alkynes 20 to afford the desired substituted imidazoles 22 on average to excellent yield (Scheme 2.13). In this reaction condition, the t-BuOK reacts as both a base and a nucleophile. The reaction methodology afforded NH-imidazoles with aryl or heteroaryl substituents. The proposed mechanism for the reaction starts with the reaction of in situ formed acetylide of the alkyne 20 with the first equivalent of nitrile 21 to form imine 23. The addition of the second equivalent of nitrile 21 to imine 23 followed by 5-exo-dig cyclization and

O

R1

TosMic, I2 (0.8 eq) FeCl3 (1.0 eq)

NH2

N

R2 R1

OH

Me (14)

DMSO, 110oC, 1h 32 examples 52-76%

N

HO

(15) R2 (16)

Scheme 2.11 Geng method overview

C-

N

Ts

H 2O

NH2

Ts

O

(17) O R

1

O

I2, DMSO Me

O R

-HI, -DMS

FeCl3 R1

(15) O

1

(18)

(14) N (17)

H N

H N

Ts R1

N H N

O (19)

Scheme 2.12 Ferric-chloride/iodine-catalyzed [2+2+1] addition

Ts R1

O

(16)

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

57 R2

t

N

R

R2

1

(21)

(20)

BuOK (2.5 eq) cyclohexane, 110oC, 11h, Ar

then acidic silica gel 30 examples 49-93%

N R2

OtBu N H (22)

R1

Scheme 2.13 Wang method overview

protonation gave heterocycle 24. The addition of tert-butoxide to exocyclic methylene followed by aromatization and protonation when purifying in silica afforded imidazoles 22 (Scheme 2.14). Four bonds Former: One of the most common syntheses of imidazoles is the simultaneous formation of four heterocyclic nucleus bonds. Thus metal-catalyzed or metal-free processes have been reported recently. Maleki et al. (2019) employed derivatized magnetic nano-catalysts in a wide range of synthetic applications due to the fact that they are easily recoverable. For example, a sulfonated Fe3 O4 @PVA superparamagnetic nano-catalyst was used for the synthesis of trisubstituted-NH-imidazoles 27 from the condensation reaction of benzyl 25, an aldehyde 26, and ammonium acetate. The catalyst role is as organic– inorganic Brønsted acid and can be recycled up to ten times without a significant loss of reactivity (Scheme 2.15) [4].

R2

R2

R2

N

(20) t BuOK

N

(21)

N

2

t

BuOH

-tBuO-

N

R1

R1

R1

(23) R

2

R2 N

N t

R

R2 N R

-tBuOH

(21)

2

R2

N

BuOR2

N (24)

R1

OtBu

(22)

N R1

Scheme 2.14 Base-catalyzed [2+2+2] addition protocol

Ph

O

Ph

OH

R-C(O) (26) NH4OAc (4.0 eq) Fe3O4@PVA-SO3H

Ph

OH

EtOH, rt, 25-70 min 14 examples 75-96%

or Ph

O

(25)

Scheme 2.15 Maleki method overview

Ph N R

N H (27)

Ph

58

M. G. Mondino and R. da Silva Gomes O R1

HBr (aq) 10mol% Me

R1

DMSO, 85oC 4-18 h

O

R-C(O) (29) NH 4OAc (5.0 eq)

O

MeOH, rt, 3-24 h 28 examples 23-85%

(28)

R1 N R2

N H (30)

Scheme 2.16 Toledo method overview

Toledo et al. (2019) recently reported that a metal-free, one-pot process could also synthesize imidazoles 30 from ketones 28 via oxidation and subsequent dehydrative coupling with aldehydes 29 and ammonium acetate (Scheme 2.16) [4].

2.1.3 Synthesis of Novel Imidazole Derivatives of 4-Aminoquinoline Using Van Leusen Multicomponent Synthetic Protocol Malaria is an acute febrile infectious disease. According to the WHO, 3.2 billion people are at risk of contracting it worldwide. Between the protozoan parasites (P. falciparum, vivax, ovale, malariae, and knowlesi) of the genus Plasmodium, P. falciparum is the most prevalent, virulent in humans, and more lethal. Among several quinoline-based antimalarials, chloroquine (CQ) is the most effective and widely used drug in malaria chemotherapy because it has a fast action, good tolerability, and low cost. However, these drugs have limitations, so it is necessary to discover new drug candidates to treat the resistance of the parasites to existing drugs. (Kondaparla 2018), continuing the studies in their laboratory of the antimalarial program, reported the following summary. The diethylamine function of chloroquine (CQ) is replaced by a substituted imidazole derivative containing tertiary terminal nitrogen. The synthesis of the substances was via a two-step efficient and straightforward synthetic protocol. Initially, treatment of 4,7-dichloroquinoline 31 with excess of ethylenediamine 32 under solvent-free conditions furnished the corresponding N1 -(7-chloroquinolin-4-yl)ethane-1,2-diamine 33 in quantitative yield. Further, 33 was used as amine input in TosMIC based multicomponent cyclization reaction. Next, condensation of aldehyde with 33 gives aldimine followed by TosMIC induced base (K2 CO3 ) catalyzed cyclization in DMF at 90 °C afforded the target compounds 34–51 in good yield (Scheme 2.17). These compounds exhibited moderate antiplasmodial activity (Kondaparla 2018).

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

59 N N

NH2 H 2N

Cl

HN

(32) N

Cl

HN

NH2

80-130oC, 8h

N

Cl

(31)

TOSMIC/K 2CO3 90oC, overnight

(33)

compound no

compound no

R

(34)

(40)

N H

R

Aldehyde, DMF

compound no

R

N

Cl

(34-51) R

(46)

N

O

(41)

(35)

(47)

O

O

S

(48)

(42)

(36)

F

N H

(37)

CF3

(38) (39)

N

(43)

(49)

O

(44)

CN

(50)

(45)

O

(51)

OH

Scheme 2.17 Synthesis of novel imidazole derivatives of 4-aminoquinoline by utilizing van Leusen protocol

2.1.4 Pharmacological Activities Imidazole and its derivatives are compounds whose peculiar chemical structure presents a series of advantages for biological activity. Due to these characteristics, they combine with several receptors and enzymes in biological systems through weak interactions. Thus, they are the core of many drugs used to treat different illnesses, such as antibacterial, antifungal, anti-inflammatory, antiviral, antiparasitic, anticancer, antihistaminic, and enzyme inhibitor. Some chemical structure and their respective pharmacological actions are given in Fig. 2.5 (Zheng 2020).

2.2 Hydantoins or Imidazolidine-2,4-Diones 2.2.1 Introduction Hydantoin is a particularly interesting heterocyclic compound because of its chemically similar structure to allantoin. It is a glyoxylic acid monoureate, which can be obtained from the hydrogenation of allantoin. This procedure is exactly the one that how Adolph von Baeyer discovered it in 1861. This substance occurs naturally, mainly in marine animals such as sponges and corals and bacteria and fungi.

60

M. G. Mondino and R. da Silva Gomes N O 2N

Cl

N CH 3

N

N

OH

N

F Bifonazole Antifungal

N

O

Cimicoxib Anti-inflammatory

Metronidazole Antibacterial SO 2NH 2

N S

N

N O

NH2

N

O 2N

N

N N

N

Cl

H 2N

O

O Cl

N N

Capravirine Antiviral

O

N H

Dacarbazine Anticancer

Nimorazole Antiparasitic

O CH3 O Ciproxifan Antihistaminic

N N H

N

N

O

Enzime inhibitor NO2

Fig. 2.5 Various pharmacological activities and chemical structures of imidazole-based molecules

Alkaloids extracted from sponges and fungi showed cytotoxic properties (Meusel 2004). On the other hand, many hydantoins and their derivatives exhibit diverse biological and pharmacological activities in medicinal, such as antimicrobial, antiviral, antitumor, antiarrhythmic, anticonvulsant, antihypertensive, antidiabetic, and agrochemical, such as herbicidal and fungicidal, applications (Meusel 2004). This wide range of applications has increased the number of synthesis methods reported in the literature. The classic methods for hydantoin synthesis include the Bucherer-Bergs synthesis and the reaction of urea with carbonyl compounds. In particular, highly substituted hydantoins are synthesized by reacting N-substituted α-amino acids or their esters with isocyanates. But many other more modern syntheses are also being tested. Researchers consider substitution patterns in these syntheses because each leads to different pharmacological properties (Konnert 2017). The classical syntheses are the Urech reaction (6.2.2.1), the Bucherer-Bergs reaction (6.2.2.2), the Read reaction (6.2.2.3), and Biltz synthesis (6.2.2.4). Different strategies for the synthesis of substituted hydantoins used transition metal-catalyzed reactions (6.2.2.5), Ugi reaction (6.2.2.6), the reaction of α,β-unsaturated carboxylic acids with carbodiimide (6.2.2.7), the reaction of α-amino amides with triphosgene (6.2.2.8), ring expansion

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

61

(6.2.2.9), ring contraction (6.2.2.10) and solid-phase synthesis (6.2.2.11). All these methods will be discussed in this chapter.

2.2.2 Hydantoins Syntheses 2.2.2.1

The First Classical Synthesis

The first classical synthetic pathway to hydantoins was found in 1873 when Friedrich Urech published his work on the formation of 5-monosubstituted hydantoins from amino acids and potassium cyanate followed by cyclization of the intermediate hydantoic acid (ureido acid) with hydrochloric acid (Meusel 2004) (Scheme 2.18).

2.2.2.2

Bucherer-Bergs Reaction

The Bucherer-Bergs reaction is one the most practical methods for the preparation of 5-substituted and 5,5-disubstituted hydantoins. This protocol is currently used, and many modifications have been proposed to the classical reaction. This reaction works for aliphatic and aromatic aldehydes or ketones as well as cyclic ketones (Meusel 2004; Kalnik 2021). The Bucherer-Bergs reaction is the reaction of carbonyl compounds or cyanohydrins with ammonium carbonate and potassium cyanide to give hydantoins (Scheme 2.19). The proposed mechanism for this reaction is given in Scheme 2.20. Alternative hydantoin formation via 4-imino-2-oxoimidazolidine ring (Scheme 2.21). Alternative hydantoin formation via disubstituted urea (Scheme 2.22). Spiro hydantoins are present in compounds such as Hydantocidin or Glucopyranosylidene-spiro-hydantoin. The following is an example of compound spiro formation via the Bucherer-Bergs reaction. (Scheme 2.23). R

R OH

H 2N O

1) KOCN 2) HCl

R

HCl

HO NH O H2N

5

O

-H2O O

NH

1

O

N3 H

Scheme 2.18 Urech hydantoin synthesis

Scheme 2.19 Bucherer-Bergs Method overview

R1

KCN O

R

(NH4)2CO3

R1

R 5

O

NH

1

N3 H

O

62

M. G. Mondino and R. da Silva Gomes

R1

KCN

R1

R1

OH

NH3

(NH4)2CO3

R

R

CN

-H2O

R1 N

R HN

R1

H

OH O

N

R1

R

NH

5

NH2

O

NH

R

CN

N=C=O

R

O

O

R

R1

CO2

NH2

O

1

O

O

N3 H

Scheme 2.20 Mechanism of hydantoin formation

R1

NH

R1

O

N

R R

NH2

HN

H

5

O

N H

N

R1

R

H 2O

O

NH

1

O

N3 H

Scheme 2.21 Alternative hydantoin formation

R

R1 NH

R

1

NH2

R CN

CO2

R1

rt

HN

NH2

R R1

R1

R

H 2O

NH

NH

O

NC HN

rt

R

H 2O

O

N R

O

R

O

rt

NH2

1

O

N

NH2

R R1

O

O

Scheme 2.22 Alternative hydantoin formation via disubstituted ureas O O HN

KCN

O

H N O

NH

R

NH (NH4)2CO3

R

O

R

R= tert-butyl R= benzoyloxy

Scheme 2.23 Stereochemistry of spiro products

Atypical Bucherer-Bergs reaction starting from di-O-isopropylidene-pentoses (Scheme 2.24). Sorbinil (also known as CP-45,634), according to the NIH (National Institute of Health), is an aldose reductase inhibitor that was in phase III clinical trials to prevent diabetic retinopathy and neuropathy in patients with insulin-dependent diabetes but this study was discontinued. Its synthesis can be done following the Bucherer-Bergs protocol (Scheme 2.25).

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

O

O

O

O

O

O

O

KCN

CHO O

H

HO

O

or CHO

63

O

HN

O

HN

NH

NH

(NH4)2CO3

O

O

O

Scheme 2.24 Atypical Bucherer-Bergs reaction starting from di-O-isopropylidene-pentoses

O

O O

HN

F

50% aq EtOH, 65oC

O

HN

O

F

KCN, (NH4)2CO3

NH

NH

O

F (-)-brucine O

O

4S-(+)-enantiomer (62%, 40% overall)

racemate (64%)

Scheme 2.25 Synthesis of sorbinil by Bucherer-Bergs reaction Ph NaCN, (NH4)2CO3

NH

Ph

60% aq EtOH, 110oC,48h

O

Ph

O

N H (75%)

O Ph Ph KCN, (NH4)2CO3 acetamide, 110oC, 6h

NH

Ph O

N H

O

(91-96%)

Scheme 2.26 Synthesis of phenytoin via Bucherer-Bergs reaction

Phenytoin is a class of compounds called anticonvulsants. It works by decreasing abnormal electrical activity in the brain. Its synthesis can be done following the Bucherer-Bergs protocol (Scheme 2.26).

2.2.2.3

Read Reactions

The Read reaction (Read 1922) and the Urech reaction (Urech 1873) follow the same protocol. In the case of a Read-type reaction, in addition to amino acids, it uses nitriles. The general reaction takes place between amino acids or nitriles with inorganic isocyanates. This reaction is an advantage when the kinetic product is

64

M. G. Mondino and R. da Silva Gomes O

O O F

PPh2

N Strecker reaction

F

O

F

O 100%, 98% ee 93%, >99% ee after recritalization

NH

HN

O

F

3) HCl, H2O, 100oC

PPh2

HN

NC

TMSCN (1.1 eq) EtCN, -40oC, 83h

O O

1. HCl (conc), 90oC 2. KOCN, H2O, 100oC

(i-PrO)3Gd (1mol%) ligand (2mols%) 2,6-dimethylphenol (1eq)

O Sorbinil (67%)

Scheme 2.27 Synthesis of sorbinil applying the Read-type reaction

desired. For example, sorbinil can be obtained using this method in a 67% overall yield contrarily to the 40% overall yield obtained by classical Bucherer-Bergs reaction (Scheme 2.26). In this case, the catalytic enantioselective Strecker reaction of ketoimines was applied to prepare the intermediate amino compound (Scheme 2.27).

2.2.2.4

Biltz Reactions

Using benzyl (dicarbonyl compound) and urea (or thiourea), base-catalyzed condensation is still the best way to synthesize phenytoin. This is a classical reaction of formation hydantoins proposed by Biltz (Biltz, 1908). Several recent improvements allowed the rapid synthesis of this compound in higher than 80% yields (Scheme 2.28). These compounds can be used to treat epilepsy (Kalnik 2021). X

X Ph NH2

H2N

Ph

HN

NH

NH Ph

Ph DMSO, MW

O

O Ph

X

N H

HN

X:O, S (80%)

O

NH X: O,S (20%)

X

S

Ph

Ph H 2N

NH2

DMSO, MW aq KOH (cat)

Ph O

Ph NH

N H (92%)

Scheme 2.28 Biltz synthesis of phenytoin

S

H 2O 2

Ph

DMF/AcOH, rt

O

NH N H (95%)

O

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

65 OH2

HO Ph

O H2N

O

Ph

Ph

H 2N

NH

Ph

H+

NaOH/EtOH O

Ph

NH

Ph

O

OH N H

pinacol rearrangement

O

N H

HO

intermediate NH Ph -H2O

Ph

Ph

Ph

O

N H

HO

NH

Ph

O HO

NH

Ph HO

O

N H

N H

Ph NH

Ph -H+ O

N H

O

Phenytoin

Scheme 2.29 Mechanism of reaction

The mechanism suggests the formation of a heterocyclic pinacol intermediate which upon acidification yields hydantoin because of a pinacol rearrangement (Scheme 2.29).

2.2.2.5

Metal-Catalyzed Protocol

Zhao et al. synthesized various 5-aryl-hydantoins from methyl arylacetates or β,γunsaturated methyl ester via their copper-catalyzed and di-tert-butyldiaziridinone as nitrogen source (Zhao 2008; Konnert 2017) (Scheme 2.30). O

CuCl-P(nBu)3 (1:1) (5mol%)

O R

Me

R O N

N

O

N

CHCl3, 65oC, 12h

N O

R CH3SO3H-Hexane

(1:10), 65oC, 3.5h

O HN NH O 9 examples 49-79% yield

Scheme 2.30 Copper-catalyzed synthesis of N,N-ditert-butyl-hydantoins

66

M. G. Mondino and R. da Silva Gomes 5CC

MeOH/CO2

R3 R

R1CHO +

R3 N

1

R

1

N

O

R1 O NH

N R2NH2 +

R

2

R3NC O O

O

MeOCO2-

R

methyl carbonic acid

nitrilium ion

NH

2

R2 R1

R1 NH

N R2

O

R3

KOH, MeOH: THF: H2O

R2

O N N

3 days, then HCl conc

carbamate

O

R3 Hydantoin trisubstituted

Scheme 2.31 Multicomponent reaction. Synthesis employing Ugi/De-Boc/cyclization methodology

2.2.2.6

Ugi Reaction in Hydantoin Synthesis-Multicomponent Reaction

The Ugi five-components condensation (5CC) product with base affords hydantoins in good yield (Hulme 2000) (Scheme 2.31). The reaction consists of an aldehyde (or ketone), amine, isonitrile, methanol, and CO2 condensation. The key step is adding methyl carbonic acid (generated from CO2 and methanol) to the intermediate nitrilium ion. Acyl transfer step subsequently drives the reaction to completion, giving the carbamate in good yield. Then treatment of carbamate with a base such KOH in a solvent mixture MeOH:THF:H2 O for three days and then with concentrated HCl produces 1,3,5-trisubstituted hydantoin [9].

2.2.2.7

α,β-Unsaturated Carboxylic Acids with Carbodiimide

α,β-unsaturated carboxylic acids as fumaric acid derivatives containing an electronattracting group in the β position react with carbodiimides under mild conditions (20 °C, dichloromethane) to provide 1,3,5-trisubstituted hydantoins. The reaction occurs through a domino-type regiospecific condensation/aza Michael/N→O acyl migration (Volonterio 2005) (Scheme 2.32).

2.2.2.8

α-Amino Amide with Triphosgene

Zhang et al. developed a method of preparing enantiomerically pure hydantoins from optically pure R-α-amino amides in the presence of triphosgene (Zhang 2006; Konnert 2017) (Scheme 2.33).

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

67 R2

R3 HOOC

R

R4

R1

R1 N=C=N

R4

N

"one pot"

2

O

O

N R3

R1 = EWG, R2 = H, COOEt, CF3, R3 = alkyl or aryl, R4 = alkyl or aryl

Scheme 2.32 Synthesis of 1,3,5-trisubstituted hydantoin

O O R1

1) Triphosgene (0.4 eq) CH2Cl2, Ar atm, 0oC

R2 N H

for 1.5 h then 40oC, 12 h 2) HCl salt of 6g was used

NH2

R1

N

R2

N H

O

entry

R1

R2

product

yield %

ee %

1

PhCH2

CH2CH3

(S)

73

>96

2

PhCH2

(CH2)3CH3

(S)

70

>96

3

PhCH2

CH2Ph

(S)

58

>96

4

PhCH2

(CH2)-p-OMe-Ph

(R)

41

>96

5

(CH2)2CHCH2

CH2Ph

(S)

55

>96

6

TBSOCH2

CH2Ph

(R)

73

>96

7

PhCH2

(S,S)

80

>96

CO2Me

Scheme 2.33 Preparation butyldimethylsilanylloxy)

2.2.2.9

of

hydantoin

from

α-amino

amides.

Note

TBSO

(tert-

Hydantoins Formed by Ring Expansion

Talaty et al. prepared 1,5-disubstituted hydantoins from 1,3-di-tert-butylaziridinone and cyanamide through selective cleavage of the acyl-nitrogen bond (Talaty 1997) (Scheme 2.34).

2.2.2.10

Hydantoins Formed by Ring Contraction

When reacted with a very dilute sodium hydroxide solution, Uracil derivatives cause ring contraction to form hydantoins via the exocyclic methylene intermediate. Lopez

68

M. G. Mondino and R. da Silva Gomes O

O

NH2

reflux, THF NH2CN N

O NH

N-

3h

N N

NH

O

O HNO 2

N tautomerism

NH

N

N NH2

O

Scheme 2.34 Synthesis of 1,5-disubstituted hydantoin

O R

O R

OAc

N

OH

OH O

N

-

OH

OAc O

N

O

N

CH2

HO O2C

H 2C

R N

N

O

R'

R'

R' R

O

N

-CO2 H 3C

N

O

R'

Scheme 2.35 Synthesis of 1,3,5-trisubstituted hydantoins by ring contraction

et al. mentioned in their book that several 5-acetoxy-6-(acetoxymethyl)uracil in basic conditions formed 1,3,5-trisubstituted hydantoins (Lopez 1985) (Scheme 2.35).

2.2.2.11

Solid-Phase Organic Synthesis

The use of solid-phase organic synthesis (SPOS) technique has some advantages over solution synthesis. These include easy reaction workup manipulations (i.e., filtration and solvent washing), ready access to the product with labor efficient procedures, overall yields comparable to one-pot solution-phase protocol but with improved product purity and much simpler product isolation/purification, and the practical ability to use excess reagents to drive solid-phase chemical reactions to completion (Park 1998). Park et al. published the solid-phase synthesis of cyclopropanoid isoxasoloimidazolidinedione (Park 1998). The total reaction took place in several steps, namely O-alkylation of the carboxylate salt of 1 with Merrifield resin and 18-crown6 produced 2. The BOC group in amino ester 2 was cleaved by 50% TFA in CH2 Cl2 , neutralized with triethylamine/CH2 Cl2 give amino ester 3. Then various isocyanates

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey … O

O

O NHBOC

HO

69

O

1) KOH 2)

O

R

R

NCO

(3) O

H N

NH

NH2

DCM

(2)

O O

O

2) Et3N, DMF

Cl

18-cr-6, DMF

(1)

NHBOC 1) TFA,DCM

H N

NH

O

O O N

R

Et3N, THF R

(4) (5)

O

R'

N O

NH H O N R'

= 2% DVB/98% styrene resin = PS

(6)

Scheme 2.36 Cyclopropanoid Isoxasoloimidazolidinediones; solid-phase reactions

were used to provide the urea 4. The transformation from 4 to 5 was diastereoselective, and through 1,3-dipolar cycloaddition, the cyclization occurred mediated by base producing 6 (Park 1998) (Scheme 2.36).

2.2.3 Natural Products Containing a Hydantoin Moiety Hydantoins of natural origin can be found in allantoin, well-known to be the end product of urea metabolism in plants and invertebrates as well as in marine organisms (sponges and corals) and bacteria and fungi. Investigation of the antimicrobial fraction of the organic extract of the Red Sea sponge Hemimycale arabica yielded three hydantoin alkaloids 1–3, including two new ones, Hemimycalins A and B (2 and 3) and compound 1 (Z)-5-(4-hydroxybenzylideneimidazolidine)-2,4-dione. Compounds 1–3 displayed variable antimicrobial activities against E. coli, S. aureus, and C. albicans (Youssef 2015) (Fig. 2.6). Recently, Lee et al. (2019) found thiohydantoin and hydantoin in the roots of Armoracia rusticana (horseradish). Investigation of the potential neuroprotective effect of these compounds are being evaluated (Fig. 2.7). Allantoin is also known to be the end product of the metabolism of urea in plants and invertebrates. It also is known to be the end product of the metabolism of urea. Hydantoins substituted at the 5-position are precursors to optically pure natural and unnatural α-amino acids, which is achieved through their chemical or enzymatic hydrolysis (Scheme 2.37).

70

M. G. Mondino and R. da Silva Gomes O

N

O NH

HN

HO

O

O

(1)

N

N

HO

O

O

(2)

N

HN

HO

(3)

O

O

Fig. 2.6 Alkaloids hydantoins

O

O OH

N

R2

N

N

R1

R

R1 S O O

N

R = O, S

R2 OH OH H

Fig. 2.7 Thiohydantoin and hydantoin

Scheme 2.37 Obtention of optically pure amino acid from hydantoin

5-monosubstitute D-hydantoin R

O

H

O 5-monosubstitute L-hydantoin

O

HN

NH

HN

O

R H

O

R

NH

HN

D-hydontoinase

H

hydantoin racemase

O OH NH2

CO2 + NH3 carbamoylase

O

R H

OH NH2

D-amino acid

Others natural hydantoins (Fig. 2.8).

2.2.4 Pharmacological Drugs Containing a Hydantoin Moiety Hydantoins are a very important substance because they are not only the core of several known biologically active drugs, but they are also intermediate reagents in the formation of products widely used in the food industry as in the manufacture

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey … H N

H 2N

O

HO O HN

O

O

O

71

Br

HN

HN

NH

NH

N H

OH O

HO

O

O O

(+)-Hydantocidin

Allantoin

NH

H N

Mukanadin B

Fig. 2.8 Natural compound containing a hydantoin moiety

of the sweetener aspartame (N-(L-α-aspartyl)-L-phenylalanine, 1-methyl ester) and precursors of optically pure D-amino acids. These amino acids are used to produce certain drugs, such as β-lactam antibiotics (penicillin and amoxicillin) and anticancer agents like goserelin, among others (Konnert 2017) (Fig. 2.9). Et

Ph

O

O

O

N H

Ph NH

Ph

NH

Ph

N

O

O

O

N O

Mephenytoin antiepiletic anticonvulsant

Phenytoin antiepiletic

NH

NH

Ph

O

OH P

OH

O

CF3

Fosphenytoin pro-drug anticonvulsivant

OH

NO2 Nilutamide anticancer

HO NO2

HO O

N H Glucopyranosylidenespiro-hydantoin

O N N

O

NH

OH

O

O

N

N

O O

N H

N O

Dantrolene muscle relaxant

OH

N H

O Nitrofurantoin antibacterial H N

O N

Nifurtoinol anti-infective agents

O

N

O

NO2

N O

NO2

O

N

O

N

N

Cl

O

Azimilide antiarrhytmic

N O

N

O

N N Cl Iprodione fungicide

Fig. 2.9 Drugs containing hydantoin moiety

Cl

72

M. G. Mondino and R. da Silva Gomes

2.3 Thiazole or 1,3-Thiazole 2.3.1 Introduction Thiazoles are aromatic heterocyclic compounds belonging to the family of azoles, such as imidazole and oxazole, containing one sulfur and one nitrogen atom in the 1,3-position. They are planar and have a higher aromatic character than oxazole, with a more significant displacement of π electrons. Another fact that proves its aromatic character is the chemical shift observed by 1 H NMR. Values between 7.27 and 8.77 ppm, indicating a strong diamagnetic current in the ring. Calculation data about π-electron density (Fig. 2.10) reveals that the electron density at C-5 makes it able to receive electrophiles and C-2 more able to be attacked by nucleophiles. The values found are 1.01 and 0.87, respectively. Its PkaH = 2.5 indicates a weaker base than imidazole, but the pKa = 14.4 equal to imidazole suggests no difference in acidity between them (Mondino, 2014). The five- and six-membered heterocyclic compounds are protagonists in biological activity studies because they are available in all living organisms and have a vital contribution to the development of these organisms. Mainly, five-membered heterocyclic rings, especially those containing one nitrogen and one sulfur atom such as thiazoles, are preferred by researchers, both substituted and in hybrid structures. “Hybrid structures are understood as those molecules obtained by combining different chemically reactive groups and biological activity characteristics. The synergetic effects of the nuclei in which the hybrid structures are possessed may add extra features to the structure” (Gumus 2019). Many substances contain thiazole in their structure. Vitamin B1, better known as thiamine, is responsible for the proper functioning of the central nervous system, muscles, and heart. Thiamine pyrophosphate participates in the decarboxylation of α-ketoacids (Mondino 2014). Other drugs such as sulfathiazole, effective against a wide range of gram-positive and gram-negative pathogenic microorganisms; cambendazole, antinematodal agent; niridazole, schistosomicide; bleomycin, anticancer; ritonavir, which is associated with antibiotic, is indicated for the treatment of HIV infected patients, dasatinib, antineoplastic agents and pramipexole indicated for the symptomatic treatment of Parkinson’s disease. It is found in cyanine dyes that are used as photographic sensitizers. Thiazoles are also the core of many natural products, vitamin B1 as described above, thiazole-based peptides alkaloids (TBPs) mainly of marine origin, anabolic steroids, and penicillin. For all these reasons, studies that improve classical syntheses or new syntheses are being developed. The Hantzsch synthesis (1887) Fig. 2.10 Thiazole structure

1.97

S 1.01

5

3

E+

0.96

0.87

1

N

1.19

Nu-

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

73

was the first, and it is the most used method. It consists of the reaction between an α-halocarbonyl compound and thioamides, thioureas or thiocarbamic acid derivatives (6.3.2.1), the reaction of Cook-Heilbron (1947) from α-aminonitrile is another interesting reaction (6.3.2.2), relatively newer methods involve of TosMic to thione derivatives (6.3.2.3), oxidation of thiazoline/thiazolidine ring systems (6.3.2.4), Ugi reaction (6.3.2.5), palladium-mediated coupling processes (6.3.2.6), intramolecular thia-Michael strategy (6.3.2.7). Other strategies aimed at functionalizing the C-2,4positions (6.3.2.8), C-2,5-positions (6.3.2.9), C-4,5-positions (6.3.2.10), C-2,4,5positions (6.3.2.11) and C-2, N-3, C-4,5-positions (6.3.2.12) of the ring thiazole are also important.

2.3.2 Thiazole Synthesis 2.3.2.1

Hantzsch Synthesis

This methodology is based on the condensation of α-halocarbonyl compound with thioamides, thioureas, or thiocarbamic acid derivatives (Mondino 2014; Ali 2020) (Scheme 2.38). Thiazole 3 can be obtained by reaction between α-chloroacetaldehyde 1 and thioformamide in good yield.

2.3.2.2

Cook-Heilbron Synthesis

The synthesis of Cook-Heilbron stands out for its 5-amino substituted thiazole form. The chemical reaction occurs with α-aminonitriles or aminocyanoacetates with dithioacids, carbon disulfide, carbon oxysulfide, or isothiocyanates at room temperature under mild or aqueous conditions. For example, amino malononitrile ptoluene sulfonate 4 and aryl isothiocyanate 5 are used to form 2-arylamino-4-cyano5-aminothiazole in the presence of 1-methyl-2-pyrrolidone- NMP (Scheme 2.39). The following reaction with mechanism is another example applying the CookHeilbron methodology. In the first step, a lone pair on the nitrogen of the αaminonitrile 7 performs a nucleophilic attack on the carbon of carbon disulfide 8. The sulfur atom donates its electron to the nitrile carbon as a Lewis base, forming a sulfur-carbon bond in an intramolecular 5-exo-dig cyclization. This cyclization forms

H

S

H

Cl (1)

H

NH2

O

HO

O

NH S

(2)

Scheme 2.38 Synthesis by Hantzsch methodology

H

N

N

H S

S (3)

74

M. G. Mondino and R. da Silva Gomes + NH3

CN OTs

N

NMP +

CN

Ar-N=C=S

(4)

H2 N

(5)

NHAr

S (6)

Scheme 2.39 Synthesis by Cook-Heilbron methodology

S

H :B

HN S

(8)

N

NH

C N

S (7)

:B

R

C

NH2

N C

H

R

R

S

H+

Lewis base

S

S H+

(9)

R N H 2N

S

SH

(10)

Scheme 2.40 Synthesis and mechanism by Cook-Heilbron methodology

5-imino-2-thionethiazolidine 9 that undergoes a tautomerization with a base, for example, H2 O yielding the final aromatic product 5-amino-2-thiolthiazole derivatives (Scheme 2.40).

2.3.2.3

TosMic to Thione Derivatives

A synthetic route starting from Z-deoxy-3,5-di-O-toluyl-β-D-ribofuranosyl cyanide 11 was reported. The main step is the reduction of the cyano group of compound 11 to a formyl 12 and subsequent condensation with tosylmethyl isocyanide (TosMic) to yield the formamide derivative 13. Cyclization with H2 S followed by removal of the toluoyl group with ammonia gave 5-(2’-deoxy-β-D-ribofuranosyl)thiazole 14 (Bergstrom 1994) (Scheme 2.41).

2.3.2.4

Oxidation of Thiazoline/Thiazolidine Ring Systems

Studies published by Martin (1999) and later by You (2003) indicate that thiazole can be obtained by oxidizing thiazoline with activated MnO2 in dichloromethane. The thiazole amino acids are obtained from the oxidation of their corresponding thiazoline amino acids (Scheme 2.42).

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

TolO

H

O

CN

Raney Ni, NaH2PO2,

TolO

N,N'-diphenylethylene diamine, HOAC-Py-H2O

H TolO (11)

H

PhN O

75

NPh

O PTSA

TolO

H

H

(12) CN OTs

O

TolO

Et3N, POCl3 H

H

O

OTos

H2S, DME

H

DME, -5oC

TolO (13)

TolO

N

N

S

S H

H

TolO

O

BuOH,DME -35 to -30oC

TolO

H

O

CH2Cl2-Ketone

H TolO

HCHN Tosylmethyl isocianide,

TolO

conc NH3/ MeOH HO

O

H

O H

55oC

H

HO

TolO

(14)

Scheme 2.41 Synthesis of thiazole derivatives by TosMic

O

O OAryl

N

OAryl

N

Activated MnO2

FmocHN

FmocHN S

S

CH2Cl2

R

R R: Me, 89%; i-Pr, 91%

Scheme 2.42 Synthesis of thiazole derivatives by oxidation

2.3.2.5

Thiazole via Ugi Reaction

Kazmier and Ackerman report on the application of Ugi reactions for the synthesis of endothiopeptides and their conversion into thiazoles (Kazmaier 2005) (Scheme 2.43). RCOSH O

R1NH2 R R2CHO NC

COOR

R2 N R1

S H3CO

R2

O

NH R

N

N

COOR OCH3 R: Me or Ph

X

Scheme 2.43 Thiazole synthesis via Ugi reaction

R1 R1: Bn

S R2: aliphatic or aromatic

76

M. G. Mondino and R. da Silva Gomes R2

S

N

O R2

NH2

R1

R3

R3

R1 (17) 21 examples 31-91%

K2S2O8 (1.2 eq), NaHCO3 (1.5 eq) DCE, 120oC

(16)

(15)

PdCl2 (10mol%), CuBr2 (10mol%) S

Scheme 2.44 Zheng method overview

2.3.2.6

Palladium-Catalyzed Synthesis of Thiazoles

Zheng et al. report a facile method for synthesizing 2,4-disubstituted and 2,4,5trisubstituted thiazoles 17 using PdCl2 as the catalyst, K2 S2 O8 as a stoichiometric oxidant, and catalytic CuBr2 as the promoter for the C(sp2 )-H bond activation process (Zheng 2014). The thioamides used in the transformation include aryl- and alkylthioamides 15, while the ketones include ketones, diones, and ketoesters or amides 16 (Scheme 2.44).

2.3.2.7

Intramolecular Thia-Michael Strategy

Synthesis of thiazoles via an intramolecular thia-Michael strategy is a general protocol developed by Sasmal et al. to obtain mainly C-2 substituted thiazoles. To achieve this goal, they devised a strategy via an intramolecular thia-Michael reaction (Sasmal 2006) (Scheme 2.45). In the reaction, the thione 18 were treated with silylprotected amines 19 and the results were spontaneous cycloisomerization providing the corresponding thiazoles 22. R2

P

O

S P

R1

N

O

HN

X R (18)

R3

2

R1

(19)

(20)

X: leaving group P: Protecting group R2

N

R2

R3

N

O

O

S R1

R3 S

R3

(21)

Scheme 2.45 Intramolecular thio-Michael strategy

S (22)

R1

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

77

2.3.3 Functionalizing Positions The synthesis of thiazoles and their derivatives to obtain new compounds or even the idea of combining these compounds with another group of molecules with different structures and functions required substitutions. Thus came the idea of presenting reactions with a certain substitution pattern, starting at the C-2 position and then increasing this number to di-, tri-, and tetrasubstituted.

2.3.3.1

Functionalizing C-2 and C-4 Positions

The 2-aminothiazole ring system is useful in medicinal and agricultural chemistry and has found a broad application in drug development to treat allergies, hypertension, inflammation, schizophrenia, and bacterial and HIV infections (Castagnolo 2009). The reaction of propargyl bromide 23 with thiourea 24 at 130 °C in the presence of the stoichiometric amount of K2 CO3 and under microwave irradiation lead in only ten minutes to 2-aminothiazole with a yield of 90% 25 (Scheme 2.46).

2.3.3.2

Functionalizing C-2 and C-5 Positions

This reaction was first described by Gabriel in 1910 when reacted N-(2-oxo-2phenylethyl)acetamide 26 with an equimolecular amount of phosphorus pentasulfide to yield 2-methyl-5-phenylthiazole 27 (Ali 2020) (Scheme 2.47). S

Br H 2N (23)

N

K2CO3, DMF NH2

(24)

NH2

S

MW, 2x5 min 130oC

(25)

90%

Scheme 2.46 Reagents and conditions of reaction for 2,4-disubstituted thiazole NH

N Ph

Ph O

O

OH

HO

(26)

Scheme 2.47 Synthesis of 2,5-disubstituted thiazole

N

P 2S 5 Ph

S (27)

NH

2

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M. G. Mondino and R. da Silva Gomes

2.3.3.3

Functionalizing C-4 and C-5 Positions

When the dithioformic 28 is reacted with α-aminonitrile 29, it forms the 4,5disubstituted thiazole 30 in good yield. These reactions were carried out in an ethereal aqueous solution at room temperature (Ali 2020) (Scheme 2.48).

2.3.3.4

Functionalizing C-2, C-4, and C-5 Positions

Andrade and Mattos used tribromoisocyanuric acid 31 for α-mono-halogenation of β-keto esters 32 in an aqueous medium, thiourea 33, and DABCO to produce 2,4,5-trisubstituted thiazoles 34 with a yield of 87% following a simple and efficient “one-pot” protocol (Andrade 2018) (Scheme 2.49).

2.3.3.5

Functionalizing C-2, N-3, C-4, and C-5 Positions

De Santana et al. synthesized 2,3,4,5-tetrasubstituted thiazoles 39 by the reaction between 4’-trifluoromethyl-benzaldehyde 35 with thiosemicarbazide 36 in acid catalysis and reflux forming the intermediate 37 an arylthiosemicarbazone (De Santana 2018). Then, reacted with acetophenone derivatives 38 and gave thiazole derivatives 39 with 34–90% yield (Scheme 2.50). N

S

H

S

NH2 (29)

(28)

N

NH

SH

H 2N

S

S (30)

Scheme 2.48 Synthesis of 4,5-disubstituted thiazole

O Br N N

O

Br O

Br

N

S Ph

O

N H

(31)

NH2 (33)

N MeCN/H2O (1:1) 70oC, 20 min

O DABCO OEt (32)

Scheme 2.49 Synthesis of 2,4,5-trisubstituted thiazole

EtO2C

S (34) 73%

NHPh

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

79

O H N H 2N

R

F 3C

X

R2

R1

3 (38) R

S

F 3C (37)

(36) R1

R2

CF3

N

R1: H, Me, Ph R2: Ph, 4-NO2Ph, 4-FC6H4, 4-MeC6H4 R3: H, Me, Ph

N R3

H N

N

1

S (35)

O

H N

H N

S

N

(39)

34-90%

Scheme 2.50 Synthesis of 2,3,4,5-tetrasubstituted thiazole

2.3.4 Pharmacological Drugs Containing Thiazole Moiety The biological importance of the thiazole ring in therapy is reflected in the presence of this nucleus in many natural and synthetic substances. Chalabria et al., in a recent review, described and exemplified in detail not only compounds that already exist on the market but also new ones that are being investigated with an extensive range of biological activities. Thus, structures corresponding to substances have a tested and proven function and are already on the market (Chalabria 2016) (Figs. 2.11 and 2.12). Thiazole derivatives under therapeutics investigation (Figs. 2.13 and 2.14). Cl O NH O 2N

S

N HO

N

N

S

S

Fentiazac anti-inflammatory non-steroidal

Niridazole schistosomicide N

N

O

N S

N H Thiabendazole fungicide and chelating agent

Fig. 2.11 Thiazole-based drugs

H 2N

Amiphenazole respiratory stimulant

N H

N

S O2

Sudoxicam antipyretic

N S

OH

O

O Abagungin antifungal

NH2

N HN S

NH N

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M. G. Mondino and R. da Silva Gomes HO2C N

O

H N

NH SO2

S

HO

O O NH

H2 N

S

N H

N

N

N

S O

N

Sulphathiazole antimicrobial agent

Ritonavir antitetroviral (HIV)

S

Cl

N

H N

NH

HO3S

N

S

Azereonam used in patient with penicillin allergies

O O

N Dasatinib anticancer

NH

N N

O

Febuxostat treatment of hyperuricaemia

NC

O

N

OH

HO

S

NH2

N

O

N

N

O

Pramipexazole Parkinson disease

NH2

S

Fig. 2.12 Thiazole-based drugs

anti-cancer

N H

CNS-modulators

OH

N S

O

N N H

HN

CO2CH3

O

HO

O

S

S

N S N N

O O

N

N H

S

N F

Anti-Alzheimer

O

N N H

N

N

S

S

N

Cl

Cl N H

O Anticonvulsant

N

O

H3CO

H N

N

N H

S

Cannabinoid receptor

N

NO2 S

O

N N HN

O S

N

S N

Nicotinic acetylcholine receptor

Fig. 2.13 Thiazole derivatives under therapeutic investigation

Opioid receptor antagonist

S

Cl

N N

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81

COCH3 N

N

O

S O

NH

O

N S S

HO

NH2 S

SO2

S F3C

N

O

F3C

N

Antidiabetics

Anti-tubercular

N

CF3

O

O N HO

Auto-imune diseases

N O

S

N

N N

F3C

Anti-obesity H N

S

N

N Cl

N O S

HO

N

O

H3CO

S

H N

Cl

N

S N

N anti-fungal

N S

S H2 N

O

N H

S

Anti-viral

NH

O S N

N

O

N H

Cl

Antimicrobial

Fig. 2.14 Thiazole derivatives under therapeutic investigation

2.3.5 Natural Compound Containing Thiazole Core Many natural products, especially of marine origin, contain thiazole, oxazole, and reduced form in their structure. These natural compounds are secondary metabolites and demonstrate biological activity against bacteria, fungi, and viruses. Many marine organisms contain the thiazole ring. Some examples from the review by Dahiya et al. are given in Figs. 2.15 and 2.16 (Dahiya 2020).

2.4 Oxazole or 1,3-Oxazole 2.4.1 Introduction Oxazoles belong to the family of azoles, along with imidazole and thiazole. They are formed by oxygen and a nitrogen atom which are the 1,3 positions in a fivemembered ring. Oxazoles are aromatic compounds but less aromatic than thiazoles. Based on Katrizki and Ramsden method (Mondino 2014), aromaticity varies with the state because the molecular environment influences interactions, particularly

82

M. G. Mondino and R. da Silva Gomes

HO N

N N

NH2

S

OH S

N

H O

H O

Thiamin

HN

O O

H

H N O O Penicillin G

N

S N CO2H

N

O O

N

H Apratoxin A cyanobacterial metabolites as promising drugs leads against the Mpro and PLpro of SARS-Cov-2 an in silico analysis

Fig. 2.15 Natural compounds containing thiazole core

asymmetric heterocyclics. Oxazole, without any substituents, is a weak base, the pKa of conjugate acid the pKaH = 0.8, remembering that the pKaH of the imidazole is 6.95 and the pKaH of the thiazole is 2.5 (Fig. 2.17). It is a water-soluble compound with an odor similar to pyridine. Its boiling point is 69 °C and its dipole moment µ = 1.4D. Due to their structural characteristics are used as versatile precursors in obtaining various heterocyclics through ring-opening and later recyclization. Being relatively easy to occur, ring-opening allows amino ketones, amino acids, and dipeptides to be obtained. Oxazoles also serve as synthetic intermediates. They have expressive biological activity mainly in their derivatives, the 5oxazolones, which can act as an antimicrobial, cardiotonic, anti-inflammatory, analgesic, immunomodulator, nitic oxide enzyme inhibitor, and photography. In nature, they are the structural unit of many macrocyclic peptides remarkably of marine origin. Among the various syntheses proposed, the Robinson-Gabriel synthesis (6.4.2.1) is the most popular method. Another widely used strategy is the van Leusen synthesis (6.4.2.2). Other reactions include oxidation of oxazolines (6.4.2.3), ceric ammonium nitrate promoted oxidation of oxazoles (6.4.2.4), cycloisomerization of propargyl amides (6.4.2.5), synthesis of 2,4-disubstituted oxazoles (6.4.2.6), synthesis of 4,5disubstituted oxazoles (6.4.2.7), one-pot synthesis (6.4.2.8), Palladium-catalyzed (6.4.2.9), and others.

2.4.2 Oxazole Synthesis 2.4.2.1

Robinson-Gabriel Synthesis

The Robinson-Gabriel synthesis in which a 2-acylamino ketone reacts intramolecularly followed by dehydration with POCl3 or H2 SO4 to give 2,5-disubstituted oxazole. A dehydrating agent is required to catalyze the reaction. Robinson and Gabriel

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

O S

H O

N

NH NH

N

S

O

S

O

O

N

83

O

N

N

H

N

O

NH

NH

O

N H

O

S

S

NH

O

O

N

HN S N H

O

Haligramide A isolated from the marine sponge Haliclona nigra. Cytotoxic

S

Ulithiacyclamide from ascidiam Lissoclinum patella cytotoxic

O N NH

O O

N HN

N

HN N

S

N

NH O

O N H

S O

O

O

O

O H 2N

O

S

NH

O N

NH

Dolastatin 3 from cyanobacteria inhibition of HIV1 integrase

Mollamide B from the indonesian tunicate Didemnum molle anti-cancer and leishmania donovani

Fig. 2.16 Natural compounds containing thiazole core

Fig. 2.17 Oxazole structure

PkaH = 0.8 N3 5

O1

independently described this process early in the twentieth century and continue to have adjustments, especially regarding dehydrating agents, creating milder conditions for constructing more complex and sensitive oxazoles, particularly those of natural origin. Here will be present the reaction in its classic version (Robinson 1909; Gabriel 1910) (Scheme 2.51).

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M. G. Mondino and R. da Silva Gomes O

R1

R1 H

R3

H2SO4

R2

N H

N O

R3

- H 2O

O

R2

Scheme 2.51 Robinson-Gabriel synthesis

R

2

R1 H

R1

H

H

NH O O

R

HN

+

R

3

H -H2O R3

R1 N

3

R1 H

R2

H

O

3

O

R

H

R1

O O

R2

-H+ + H+

R3

H

R1

N

H O

R2

OH

H

N

-H+ O

N

R2

R3

O

R2

Scheme 2.52 Robinson-Gabriel reaction mechanism

Protonation of amide oxygen moiety is followed by cyclization and dehydration. Although protonation to either ketones or amides can occur in carbonyl oxygens, amides are more basic than ketones, and their conjugate acids are weaker. Thus, the oxygen in the oxazole is the oxygen from the amide (Scheme 2.52).

2.4.2.2

Van Leusen Synthesis

In 1972, van Leusen et al. reported the discovery of a vitally important reagent for the construction of heterocyclic compounds (van Leusen 1972). This reagent was tosyl-methyl isocyanides (TosMICs) which, when reacted with an unsaturated system such as aldehyde, converts it efficiently and in a one-pot reaction into 5substituted oxazoles. This same reaction has already been used to obtain imidazole. The classical reaction is given below (Scheme 2.53). The reaction mechanism suggested by the authors (van Leusen 1972) is given below (Scheme 2.54). Scheme 2.53 Van Leusen method overview

H 2C N C SO2

O K2CO3

N3 5

CH3OH

Ph

O1

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

85 O

H

H C N

H

C

SO2

H C N

K2CO3

C

C:

SO2

N

C:

SO2

CH3OH

O_

Tos

Ph

Tos

N

N

H

N=C

N

+H+

-Tos Ph

O

O

Ph

H

O

Scheme 2.54 Mechanism of van Leusen reaction

2.4.2.3

Oxidation of Oxazolines

Meyers and Tavares synthesized oxazoles from the oxidizing of oxazolines (Meyers 1996). The oxidation of oxazolines and thiazolines containing several 2-alkyl substituents provided the corresponding oxazoles and thiazoles, respectively. They used a mixture of Cu (I) and Cu (II) salts to enhance the oxidation of the intermediate captodative radical. The limitation of this method is linked to the failure of the oxidation when oxazolines/thiazolines lacking the carboalkoxy group at C-4 are used (Meyers 1996) (Scheme 2.55). It is important to highlight that the oxazolines are readily prepared from appropriate nitriles, carboxylic acids, and amino alcohols.

2.4.2.4

Ceric Ammonium Nitrate Promoted Oxidation of Oxazoles

Evans et al. described how ceric ammonium nitrate promotes the oxidation of oxazoles with various substituents forming the corresponding imides in good yields and without restriction to functional groups and substituents on the oxazole moiety (Evans 2006) (Scheme 2.56). R-CN or RCO2H

O R

R1 HO

R2

R1

O

Cu(I)/Cu(II)

2

R N

NH2

Scheme 2.55 Oxazoline oxidation reaction

t

CO2R

BuO2-C(O)-Ph

R1

2

N

CO2R

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M. G. Mondino and R. da Silva Gomes Ph

O

N

O

CAN (3.8 eq) R

Ph

Ph

MeCN, H2O 8:1, rt

O

PhCO2H

R

N H 66-91%

Scheme 2.56 Oxidation of various 4,5-diphenyloxazoles

2.4.2.5

Cycloisomerization of Propargyl Amides

Wipf et al. prepared 2,5-disubstituted (Scheme 2.57) and 2,4,5-trisubstituted (Scheme 2.58) and oxazole-5-yl carbonyl compounds (Scheme 2.59) in good yields and under mild SiO2 -mediated cycloisomerization of propargyl amides (Wipf 2004).

O

RCOCl, Et3N NH2

1. nBuLi (2.2 eq) (1a,b,c,e) or OH LiHMDS (2.2 eq) (1d), THF Ph o -78 C R

NH

CH2Cl2, r t

N H

R

2. PhCHO, -78o to 0oC O

O Dess-Martin oxid.

Ph R

NH CH2Cl2 r.t.

O

Ph

Sílica gel (300% w/w)

O

CH2Cl2, 24h

R N

O a) R= Ph >99%; b) R= vinyl 87%; c) R=tBu >99%; d) R= Et 32%; e) R= OEt no reaction

Scheme 2.57 Silica gel mediated conversion of propargyl amides to 2,5-disubstituted oxazoles

Ph

CHO

1. LiCCSiMe 3, THF, -78oC,81% 2. MsCl, Et3N, CH2Cl2 >99% 3. NaN3, DMF, 90%

H N

Ph

O

Ph

Ph O

2. PhCHO, -78oC r.t. 51%

PhCOCl, Et3N

Ph

CH2Cl2, r.t., 62%

4. SnCl2, MeOH, 85% 5. KF, MeOH, >99% OH 1. LiHMDS (2.2 eq) Ph THF, -78oC

H N

NH2

1. Dess-Martin oxid. CH2Cl2 r.t. 2. Silica gel (3005, w/w) CH2Cl2, 24h, 62%

Ph

O

Ph O

Ph N

Ph

Scheme 2.58 Silica gel mediated conversion of propargyl amides to 2,4,5-trisubstituted oxazoles

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

87 CO2Et

1.TBAF (5 mol%) PhCOCl, THF, r.t.

1. BuLi, THF, -78oC

TMSCl, Et3N NH2 CH2Cl2, r.t. 58%

2. ClCO2Et, -78 a 0oC

N(TMS) 2

CO2Et Sílica gel (300% w/w)

O

EtO

O

2. H+

Ph N

O

CH2Cl2, 72h, 90%

N(TMS) 2

Ph

N H

Scheme 2.59 Silica gel mediated conversion of propargyl amides to oxazole-5-yl acetates

2.4.2.6

Synthesis of 2,4-Disubstituted Oxazoles

Hermitage et al. proposed the synthesis of 2,4-disubstituted oxazoles starting from dichloroacetonitrile 1 to form methyl imidate 2, then methyl imidate 2 condensed with serine methyl ester hydrochloride gave the oxazoline 3 in excellent crude yield (Hermitage 2001). Upon treatment of 3 with sodium methoxide in methanol get if the oxazole 4 (Scheme 2.60) reaches the final product, in the step before aromatization, there is a rearrangement with HCl output (Scheme 2.61). O

Cl

Cl NaOMe (10 mol%),

OMe Cl

CN

o

MeOH, -10 to 0 C

Cl

(1)

HO

OMe

HCl

MeOH

NH2 N (2)

Cl O

O

NaOMe (10 mol%),

Cl

Cl

MeOH, 10oC

N

N

CO2Me

CO2Me (4)

(3)

Scheme 2.60 Synthesis of 2,4-disubstituted oxazole

Cl

Cl O Cl H

O

O

NaOMe (10 mol%),

Cl

MeOH, 10oC

N

N

N CO2Me (3)

Scheme 2.61 Rearrangement with HCl output

CO2Me

CO2Me (4)

88

M. G. Mondino and R. da Silva Gomes

2.4.2.7

Synthesis of 4,5-Disubstituted Oxazoles

Baumann et al. used a multipurpose mesofluidic flow reactor to synthesize 4,5disubstituted oxazoles (Baumann 2006) (Scheme 2.62). The authors used ethyl isocyanoacetate and reacted with acyl chloride.

2.4.2.8

“One-Pot” Synthesis

Merkul and Muller proposed a novel consecutive three-component synthesis of 1-(hetero)-aryl-2-(2-(hetero)aryl-oxazole-5-yl) ethanones starting from propargyl amine and acid chlorides (Merkul 2006) (Scheme 2.63). Mechanistic proposed by authors (Scheme 2.64).

2.4.2.9

Palladium-Catalyzed Sequential C−N/C−O Bond Formations

Zheng et al. (2020) proposed a highly efficient method for the synthesis of oxazole derivatives from simple amides and ketones via a Pd(II)-catalyzed sp2 C−H activation pathway in one step (Scheme 2.65). O R1

R1

Cl

EWG EWG

O

OH

N

R1

N

C

EWG N

C EWG: CO2Et or SO2-Tol

Scheme 2.62 Synthesis of 4,5-disubstituted oxazoles

O R1

Cl O NH2

NH R1

O R2

Cl

Scheme 2.63 Merkul-Muller reaction overview

O

R1

R2

O R2

O N

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

O

NH2

O

Ph

Ph O

Cl

Ph

1.0 eq of NEt3 THF, 0oC to r.t., 1h

89

N

then, 2% PdCl2(PPh 3)2, 4%CuI 1.0 eq PhCOCl Amidation

Cycloisomerization

O R2

O

Cl

O NH

NH Ph

II

I

[Pd , Cu ]

O

Ph

Ph

Coupling

Scheme 2.64 Mechanism of the amidation-coupling-cycloisomerization

O

O NH2

R3 R

PdCl 2 10 mol% CuBr 2 20 mol%

R3 O N

2

K2S2O4 1.2 eq NaHCO 3 1.5 eq DCE, 120oC, 24h

R2

9 examples 54-87%

Scheme 2.65 Pd-Catalyzed Synthesis of Substituted Oxazoles from Benzamide and Ketones

2.5 Synthetic and Natural Oxazoles 2.5.1 Oxazoles Synthetics and Your Pharmacological Activities 2.5.1.1

Compounds with Proven Biological Activity

It is not only the core oxazole that is important, but all its derivatives also including oxazole, isoxazole, oxazolines, oxadiazoles, oxazolidones, benzoxazoles have biological properties and exist as drugs or candidates for the treatment of various types of diseases such as antibacterial, antifungal, antiviral, antitubercular, anticancer, anti-inflammatory and analgesic, antidiabetic, antiparasitic, anti-obesity, anti-neuropathic, antioxidative and others. In Fig. 2.18 below, we have compounds with proven biological activity.

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M. G. Mondino and R. da Silva Gomes F

F

O

N

F

OH

N

H

H N O

O

O

N

OH Ditazole non-steroidal antiinflammatory (NSAID)

S

O HO

O

N N

O (CH2)3 Aleglitazar antidiabetic

N

Mubritinib tyrosine kinase inhibitor

N O O OH Oxaprozin acute or chronic rheumatoid arthritis

Fig. 2.18 Compounds with biological activity

2.5.1.2

Compounds with Potential Therapeutic Activity

Oxazole ring-based molecules are candidates for pharmacological activity (Zheng 2020) (Fig. 2.19). SH

Cl

N O

O HN

O

N

O

N N H

Antitubercular

N O

Anti-inflammatory

Antifungal

Antibacterial

N

O Ph

O

NH

H N

O

N

O NC Antiparasitic

Fig. 2.19 Compounds with potential therapeutic activity

N O Anticancer

OH OH

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey …

91

2.5.2 Natural Oxazoles In a review, Davyt and Serra present structures containing oxazoles extracted from marine animals such as Neopeltolide, Hennoxazole A, Ariakemicins A, Bengazole A, B, and C, Leucascandrolides, diazonamides, and Almazole. Also, oxazoles are isolated from microbes such as Primprinine and Phorboxazoles A-D. In general, these compounds have biological activity, so the elucidation of their structures and synthesis is important to test these properties (Davyt 2010).

2.5.2.1

Neopeltolide

Was isolated from a deep-water sponge of the family Neopeltidae. Is it effective as an anticancer (Fig. 2.20).

2.5.2.2

Hennoxazole

First isolated by Scheuer from the marine sponge Polyfibrospongia, displays antiviral activity against herpes simplex type 1, as well as peripheral analgesic behavior (Smith 2007) (Fig. 2.20).

2.5.2.3

Ariakemicins A

This substance was discovered from the fermentation extract of marine gliding bacterium Rapidithrix sp. (Fig. 2.21).

2.5.2.4

Bengazole A, B, and E

Extract from the sponge Dorypleres splendens. The compounds show growth inhibitory activity in the human cancer cell (Fig. 2.21).

5 9

O 3

MeO

11

O 13

OH O 18 O

N O

OMe 25

MeO

HN

1

O Neopeltolide

O

N

O O

N

O Hennoxazole A

Fig. 2.20 Structures of Neopeltolide and Hennoxazole

O

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M. G. Mondino and R. da Silva Gomes H 2N

O

N

OH

OH

N

N

O

Ariakemicins A

OH

OH

O

O OR O

Bengazole A: R = CO(CH2)12CH3 Bengazole B: R = CO(CH2)11CH(CH2)3 Bengazole E; R = CO(CH2)13CH3

NH O

O

Fig. 2.21 Structure of Ariakemicins and Bengazole A, B, E

H N

O O

O

O N

H

O

O

N

N

O

O

O O

O

Leucascandrolide

N H

Almazole C

Fig. 2.22 Structure of Leucascandrolide and Almazole C

2.5.2.5

Leucascandrolide A and B

Obtained from calcareous sponge Leucascandra caveolata, coral sea New Caledonia (Fig. 2.22).

2.5.2.6

Almazole C

Isolated from the red seaweed Haraldiophylum, Dakar coast (Fig. 2.22).

2.5.2.7

Pimprinine

It is an indole alkaloid extract from Streptomyces sp. (Fig. 2.23).

2.5.2.8

Phorboxazoles

It is isolated recently from an Indian Ocean sponge Phorbas sp. (Fig. 2.23).

2 Imidazole, Hydantoins, Thiazole, and Oxazole: A Journey … 17

HO

O 18

13

N

O N

93

HO O

O

O 24

O

O O HO 31

N

O

H 38

30

N H Pimprimine

3

1

O Phorboxazole A

O

43

H

46

Br

Fig. 2.23 Structure of Pimprinine and Phorboxazole A

References Ali SH, Sayed AR (2020) Review of the synthesis and biological activity of thiazoles. Synthetic Comm 51:670–700 Andrade VSC, Mattos MCS (2018) One-pot telescoped synthesis of thiazole derivatives from b-keto esters and thioureas promoted by tribromoisocyanuric acid. Synthesis 50:4867–4874 Baumann M, Baxendale IR et al (2006) Fully automated continuous flow synthesis of 4,5disubstituted oxazoles. Org Lett 8:5231–5234 Bergstrom D, Zhang P, Zhou J (1994) Synthesis of 2’-Deoxy-β-D-ribofuranosyl Imidazole and thiazole C-Nucleosides. J Chem Soc Perkin Trans I 20:3029–3034 Biltz H (1908) Über die Konstitution der Einwirkungsprodukte von substituierten Harnstoffen auf Benzil und über einige neue Methoden zur Darstellung der 5.5-Diphenyl-hydantoine. Ber Dtsch Chem Ges 41:1379–1393 Castagnolo D, Pagano M et al (2009) Domino alkylation-cyclization reaction of propargyl bromide and thioureas: a new facile synthesis of 2-aminothiazoles and 5-H-thiazolo[3,2a] pyrimidin-5ones. Synlett 13:2093–2096 Chalabria MT, Patel S et al (2016) Thiazole: a review on chemistry, synthesis and therapeutic importance of its derivatives. Curr Top Med Chem 16:2841–2862 Dahiya R et al (2020) Natural bioactive thiazole-based peptides from marine resources: structural and pharmacological aspects. Mar Drugs 18:329 Davyt D, Serra G (2010) Thiazole and Oxazole alkaloids: isolation and synthesis. Mar Drugs 8:2755–2780 De Santana TI, Barbosa MO et al (2018) Synthesis, anticancer activity and mechanism of action of new thiazole derivatives. Eur J Med Chem 144:874–886 Evans DA, Nagorny P, Xu R (2006) Ceric ammonium nitrate promoted oxidation of oxazoles. Org Lett 8:5669–5671 Fang S, Yu X et al (2019) Nickel-catalyzed construction of 2,4-disubstituted imidazoles via C–C coupling and C−N condensation cascade reactions. Adv Synth Catal 361:3312–3317 Gabriel S (1910) Eine synthese von oxazolen und thiazolen. I. Ber. Dtsch. 43:134–138 Geigle SN, Petersen AC, Satz AL (2019) Development of DNA-compatible van leusen threecomponent imidazole synthesis. Org Lett 21:9001–9004 Geng X, Wang C et al (2020) Employing TosMIC as a C1N1 “two-atom synthon” in imidazole synthesis by neighboring group assistance strategy. Org Lett 22:140–144

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Gumus M, Yakan M, Koca I (2019) Recent advances of thiazole hybrids in biological applications. Future Med Chem 11:1979–1998 Hermitage SA, Cardwell KS et al (2001) An efficient, practical approach to the synthesis of 2,4 -disubstituted thiazoles and oxazoles: application to the synthesis of GW475151. Org Process Res Dev 5:37–44 Hulme C, Ma L, Romano J et al (2000) Novel applications of carbon dioxide/MeOH for the synthesis of hydantoins and cyclic ureas via the Ugi reaction. Tetrahedron Lett 41:1889–1893 Kalnik M, Gabko P, Bella M, Koos M (2021) The bucherer-bergs multicomponent synthesis of hydantoins—excellence in simplicity. Molecules 26:4024 Kazmaier U, Ackermann SA (2005) Straightforward approach towards thiazoles and endothiopeptides via Ugi reaction. Org Biomol Chem 3:3184–3187 Kondaparla S, Manhas A, Rao Dola V et al (2018) Design, synthesis and antiplasmodial activity of novel imidazole derivatives based on 7-chloro-4-aminoquinoline. J Bioorg 80:204–211 Konnert L, Lamaty F, Martinez J, Colacino E (2017) Recent advances in the synthesis of hydantoins: the state of the art of a valuable scaffold. Chem Rev 117:13757–13809 Lee TH, Khan Z, Kim SY et al (2019) Thiohydantoin and hydantoin derivatives from the roots of armoracia rusticana and their neurotrophic and anti-neuroinflammatory activities. J Nat Prod 82:3020–3024 López CA, Trigo GG (1985) The chemistry of hydantoins. Adv Heterocycl Chem 38:177–228 Maleki A, Rahimi J, Valadi, K (2019) Sulfonated FeO@PVA superparamagnetic nanostructure: design, in-situ preparation, characterization and application in the synthesis of imidazoles as a highly efficient organic–inorganic Bronsted acid catalyst. Nano-Struc Nano-Obj 18:100264 Martin L, Hu BH (1999) Thiazole and oxazole building blocks for combinatorial synthesis. Tetrahedron Lett 40:7951–7953 Merkul E, Müller TJJ (2006) A new consecutive three-componenet oxazole synthesis by an amidation-coupling-cycloisomerization (ACCI) sequence. Chem Commun 46:4817–4819 Meusel M, Gütschow M (2004) Recent developments in hydantoin chemistry. A Review Org Prep Proced Int 36:391–443 Meyers AI, Tavares FX (1996) Oxidation of oxazolines and thiazolines to oxazoles and thiazoles. Application of the kharasch-sosnovsky reaction. J Org Chem 61:8207–8215 Mondino MG (2014) Compostos heterocíclicos: estudo e aplicações sintéticas. Editora Atheneu, São Paulo, Brazil Park K, Olmstead M, Kurth M (1998) Diastereoselective solid-phase synthesis of novel hydantoinand isoxazoline-containing heterocycles. J Org Chem 63:6579–6585 Read WT (1922) Researches on hydantoins. Synthesis of the soporific, 4,4-phenylethylhydantoin(nirvanol). J Am Chem Soc 44:17461755 Robinson RJ (1909) A new synthesis of oxazole derivatives. J Chem Soc. Trans 95:2167–2174 Sasmal KP, Sridhar S, Iqbal J (2006) Facile synthesis of thiazoles via an intramolecular thia-Michael strategy. Tetrahedron Lett 47:8661–8665 Shabalin DA, Camp JE (2020) Recent advances in the synthesis of imidazoles. Org Biomol Chem 18:3950–3964 Shabalin DA, Dunsford JJ et al (2020) Synthesis of 2,4-disubstituted imidazoles via nucleophilic catalysis. Synlett 31:797–800 Shi S, Xu K et al (2018) ZnCl2 -catalyzed [3+2] cycloaddition of benzimidates and 2H-azirines for the synthesis of imidazoles. J Org Chem 83:14791–14796 Smith TE, Kuo W-S et al (2007) Total synthesis of (−)-hennoxazole. Org Lett 9:1153–1155 Toledo I, Grigolo JM et al (2019) Modular synthesis of Di- and trisubstituted imidazoles from ketones and aldehydes: a route to kinase inhibitors. J Org Chem 84:14187–14201 Urech F (1873) Ueber lacturaminsäure und lactylharnstoff. Liebigs Ann Chem 165:99 van Leusen AM, Hoogenboom BE et al (1972) A novel and efficient synthesis of oxazoles from tosylmethylisocyanide and carbonyl compounds. Tetrahedron Lett 23:2369–2372

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Chapter 3

Lactams, Azetidines, Penicillins, and Cephalosporins: An Overview on the Synthesis and Their Antibacterial Activity Adilson Beatriz, Mirta Gladis Mondino, and Dênis Pires de Lima

3.1 Lactams 3.1.1 Introduction Lactams are cyclic amides, usually categorized by ring size. For example, 3 to 7Member rings are classified α-lactam (2-aziridinones), β-lactam (2-azetidinones), γlactam (2-pyrrolidinones), δ-lactam (2-piperidinones) and ε-lactam (2-azepanones), respectively (Fig. 3.1). Lactams are one of the most praised classes of heterocyclic compounds from a biological and synthetic point of view. These cyclic amides possess a very diversified chemical structure, knowing that the size of the ring can vary from three to dozens of members. Since the beginning of the twentieth century, numerous studies of natural lactams and the synthetic development of new lactam derivatives have been extensively explored in medicinal chemistry. The main reason for the high interest in this class of compounds arises from the fact that the lactam moiety is present in various natural and synthetic compounds that possess a broad spectrum of biological properties, especially those of three to seven members. A few examples of such activity are inhibition of β-lactamase, inhibition of cholesterol absorption, antimicrobial, antifungal, antimalarial, anti-HIV, anticancer, anti-inflammatory, anti-depressive, antiviral, inhibition of DPP-411, and anticonvulsant (Pharande 2021). Although the structural complexity and the synthetic intractability limits their pharmaceutical application, the natural macrolactams have wide application in A. Beatriz (B) · D. P. de Lima Institute of Chemistry (INQUI), Federal University of Mato Grosso do Sul, Av. Senador Filinto Müller, 1555, Campo Grande, MS 79074-460, Brazil e-mail: [email protected] M. G. Mondino Faculdades Oswaldo Cruz, R. Brigadeiro Galvão, 540. Barra Funda, São Paulo, SP 01151-000, Brazil © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_3

97

98

A. Beatriz et al.

O

O

NH

NH

-Lactam

-Lactam

O

O

O

-Lactam

NH

NH

NH

-Lactam

-Lactam

Fig. 3.1 Ring variants of lactam heterocycles

O OH O

OH NH2

HO

Fluvirucin A1 (antiviral)

O OH OH

MeO

O NH

OH

AcO

NH

O O

O

OH

Rifamycin (antibiotic)

Fig. 3.2 Macrolactams fluvirucin A1 and rifampin as examples

the discovery and development of drugs; multiple macrocyclic natural compounds possess an exceptional therapeutic potential and incomparable biological activities. Figure 3.2 depicts two important examples of macrolactams. Fluvirucine A1 is a lactam isolated from the fermentation broth of a species of actinomycetes and displays potent inhibitory activity against the influenza virus A (Pharande 2021). Rifamycin and its derivatives comprise a prominent class of antibacterial agents. The family of antibiotics rifamycin includes rifampicin, rifapentine, rifabutin, and rifaximin. Chemically, this class is composed of a 25-membered macrolactam, possessing a naphthalene aromatic fraction bonded to an aliphatic chain (Yu and Sun 2013).

3.1.2 Synthesis of 2-Azetidinones (β-Lactams) The construction of the β-lactam ring is by far the most studied synthesis of lactams carried out by synthetic organic chemists and medicinal chemists due to its medicinal value. Staudinger synthesized the first derivative of this class of compounds in 1907, which involves the [2+2] cycloaddition of ketenes-amines. Cycloadditions such as alkyne-nitrone, alkyne-imine, alkyne-oxime, ester-enolate-imine, and the alkene-isocyanate or cyclization strategies employing Ugi multicomponent reactions (Pharande 2021), β-amino acids, β-amino esters, and functionalized β-amides are used to make the β-lactam ring (Singh 2003; Singh and Sudheesh 2014) (Fig. 3.3).

3 Lactams, Azetidines, Penicillins, and Cephalosporins … O

Cycloaddition Reactions

.. ..

N

99

.. .

Cyclization Reactions

Ugi MCR -amino acids -amino esters

Staudinger’s Ketene Imine Alkyne nitrone or alkyne-oxime Ester-enolate imine Alkene isocyanate

Fig. 3.3 Main strategies for the formation of the β-lactam ring

Generally, these cycloadditions are variations of the Staudinger reaction, having a ketene as an intermediate in the [2+2] cycloaddition as one of the steps of the process. Other strategies may involve expanding or contracting rings of other heterocycles, such as aziridines, isoxazolidines, and piperazines (Singh and Sudheesh 2014; Singh et al. 2008). Cycloaddition Reactions Staudinger ketene-imine cycloaddition The Staudinger ketene-imine reaction is a versatile method for the synthesis of β-lactam. Although it is called [2+2] cycloaddition, it is not a concerted reaction because it involves a two-step process (Scheme 3.1). The first step is the nucleophilic attack of the imine’s nitrogen into the central electrophilic carbon on the ketene to form a zwitterionic intermediate that undergoes a conrotatory cyclization to produce the cis or trans β-lactam. Stereochemistry is primarily controlled by the electronic effects on the ketene and the imine’s substituents and by the steric hindrance of the N-substituent on the imine (Wang et al. 2006) (Scheme 3.2). There are many chiral versions of the Staudinger reaction reported in the literature. For instance, Zhang et al. (2008) used the chiral N-heterocyclic carbene precursor 3 to catalyze the Staudinger reaction. The pre-chiral catalyst 3 was conveniently prepared from L-pyroglutamic acid, catalyzing the arylalkilketene 1 reactions with various Nterc-butoxycarbonyl arylimines 2 to afford the correspondent cis-β-lactams 4 in good yields (Scheme 3.3), with good diastereoselectivity and excellent enantioselectivity (up to 99% ee). The authors proposed two possible catalytic paths initiated by the addition of NHC to ketene or imine. Hodous and Fu (2002), in turn, demonstrated that the planar-chiral derivative of 4-(pyrrolidin)pyridine 8 is an excellent catalyst for enantioselective Staudinger reactions. A variety of symmetrical or asymmetrical disubstituted ketenes 5 couple to a wide range of imines 7 to afford β-lactams 9 in excellent stereoselectivity and yields. The authors believed that Staudinger reactions catalyzed by 8 proceed via the Scheme 3.1 The formal [2+2] cycloaddition of imines to ketenes forms β-lactams

O . 1

R

N

+ H

R2

R3 H

CH2Cl2, 0 oC

O R1

N

R3

2 H H R

100

A. Beatriz et al. zwitterionic intermediate O . R1

N R2

H

R3

O R1

H

R3

H R2

O R1

N

R3 N

H H

O

H

R1

N

R2

H H

O R1

R2

R3

H

N

R3

H R2

Scheme 3.2 Staudinger’s cycloaddition mechanism

O . Ar

1

R 1

N

+ Ar

2

2

Ph Boc Ph

N

N BF4 N Ph

OTBS (3, 10 mol%)

Cs2CO3 (10 mol%) THF, rt

O R Ar1

N

Boc Ar2

4

Yield: 53-78% ee: up to 99%

Scheme 3.3 Asymmetric Staudinger reaction catalyzed by 3

chiral intermediate 6, shown in Scheme 3.4. This work represented a considerable expansion of the scope for this important approach to preparing β-lactams. In situ formation of ketenes Musio et al. used a microwave reactor to generate primary ketenes 12 in situ by thermal decomposition of α-diazoketones 10, followed by reaction with imines 11 (Musio et al. 2016). The preferential formation of transβ-lactams 13 was observed during Staudinger [2+2] cycloaddition of one gram of ketenes with different imines under controlled reaction conditions (Scheme 3.5). Some insights into the reaction mechanism reported under high temperatures, and a new molecular visualizer based on the web, that benefits from augmented reality technology (AR) are also described for a faster interpretation of computational data. The system’s security and reliability during the scale-up of the reaction were tested, as demonstrated by the continuous multigram preparation of N-benzyl propionamide. Carboxylic acids-Imines cycloadditions Jarrahpour and Zarei (2009, 2010) reported that ethoxy or methoxymethylene-N, N-dimethyliminium salts (16) are efficient reagents for the one-pot synthesis of cis-β-lactams from imines 14 and acetic acid derivatives 15 under mild conditions in good to excellent yields (18–95%)

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

O .

Ts + 1

R

R

N

5

R

toluene, rt 7-7.5 h

R2

H

O

0.1 eq. catalyst

7

101

N 1

R

N

Boc

N

R2

Me Me

9 High stereoselectivity High yield

Catalyst* 8

Fe

Me Me

Me 8

O

R1

Catalyst* R

6

Scheme 3.4 Catalytic enantioselective Staudinger reactions of symmetrical disubstituted ketenes with a range of imines

O

Scheme 3.5 Microwave-assisted Wolff-Staudinger strategy with formation of β-lactams 13 in situ

N2 10 R2 + N

R3

H

H

R1

11

. O 12

R1

O

N

R2

R1 R3 MW (80 W), 165 oC, 13 < 20 bar trans- -Lactams 7 min (up to 85% yield)

(Scheme 3.6). The authors suggested that the reaction proceeds by forming an activated form of the carboxylic acid 17 that undergoes deprotonation and loss of DMF to generate the corresponding ketene 18. Despite the high toxicity of Me2 SO4 , the low cost of DMF/Me2 SO4 (16) and the high yield of the products made DMF/Me2 SO4 an attractive reagent for the synthesis of β-lactams. The same authors reported another mild and efficient procedure for the synthesis of β-lactams from imines and acetic acid derivatives in the presence of the adduct TCT-DMF (Zarei and Jarrhpour 2011) (Scheme 3.7). The efficient conversion of the Schiff bases 21 and carboxylic acid 20 to the respective 2-azetidinones 23 can H R1

N N R2

14

O +

OH

OMe MeSO4

16 Et3N, CH2Cl2 rt

R3 15

O 3

R

Et3N:

N

O H

H 17

OMe -DMF, -Et3NH OMe

R3

. H

18

O

O

N

R1

R2 19 Mainly cis- -lactams (up to 95% yield) R3

Scheme 3.6 Synthesis of 2-azetidinones using the reagent methoxymethylene-N, N-dimethyl iminium salt 16

102

O

A. Beatriz et al.

R

OH +

Y

N

1.2 eq. TCT/DMF 4 eq. Et3N CH2Cl2 rt

Ar 20

21

Y = OAr, NPhth, OMe, Cl, N3 R = Ar, Me, Bn

O Y

N 23

Cl

R

N

Ar

cis- -Lactams (up to 93% yield)

N

N Cl TCT/DMF 4 eq. DMF, rt, 5 min Cl

Scheme 3.7 Synthesis of 2-azetidinones using the cyanuric chloride-DMF complex

PhO O

Ph N 24

PhO O

Ph

S

N 25

CO2Et

Fig. 3.4 β-lactam systems synthesized via 1-methyl-2-halopyridinium salt

be done at room temperature in dichloromethane, using a complex of cyanuric-N, N-dimethylformamide chloride, affording 45–93% yields. The complex is easily prepared by reaction of cyanuric chloride and DMF at room temperature. According to the authors, the reaction mechanism is similar to that reported on the papers using alkoxymethylene-N, N-dimethyliminium salts (Jarrahpour and Zarei 2009, 2010). The carboxylic acids-Imines cycloadditions are a splendid variation of the method reported by Amin et al. (1979) that used Mukaiyama’s reagent (1-methyl2-halopyridinium salts) to develop the synthesis of various substituted β-lactams, including polycyclic β-lactam systems as 24 and 25 (Fig. 3.4). Alkyne-imines, alkyne-nitrones, and alkyne-oximes cycloaddition Recently, oxidative [2+2] cycloaddition of terminal alkynes with imines catalyzed by rhodium to afford β-lactams as products with high trans diastereoselectivity in mild conditions was developed by Kim et al. (2014). In the presence of Rh (I) catalyst and 4-picoline-N-oxide (28), a terminal alkyne (26) is converted to a species of rhodium ketene 29 via oxidation of vinylidene complexes and subsequent [2+2] cycloaddition with an imine (27) to produce the desired β-lactams 30. Mechanistic studies suggest that the reaction proceeds through a metaloketene instead of a free ketene intermediate (Scheme 3.8). Alkyne-nitrones cycloadditions, commonly known as Kinugasa reaction, emerged as a powerful tool for synthesizing various types of β-lactams. Kinugasa reaction is an attractive procedure due to its simplicity and scale-up perspective for synthesis (Stecko et al. 2014). In a short communication, Kinugasa and Hashimoto (1972) reported that the reaction of copper (I) phenylacetylene 31 with nitrone derivatives 32 in dry pyridine promptly afforded the correspondent cis or trans β-lactams 33 in good yields (Scheme 3.9).

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

R1

H

N

+ R2

26

R3

27

O N 28 5 mol % RhCl(PPh3)3 CH3CN, 50 oC

R1

103

. H

O

O

[Rh]

R1

29

N 30

R3 R2

trans- -Lactams 30 examples (up to 96% yield)

Scheme 3.8 Rhodium-catalyzed [2+2] cycloaddition of alkynes with imines

Ar2

Cu +

Ph

N

O Ar1

31

32

O

1. dry pyridine rt, 0.5-1.0 h 2. H+

N

Ar2 Ar1

Ph 33

Scheme 3.9 Kinugasa cycloaddition reaction

Miura et al. provided another significant contribution to the studies about the Kinugasa reaction (Miura et al. 1995). They demonstrated the reaction of several terminal alkynes 34 (aromatic or aliphatic) with nitrones 35, using catalytic amounts of CuI and excess of pyridine to afford β-lactams 36 as the major products. Furthermore, asymmetric induction is observed in the reaction of phenylacetylene with α-N-dephenylnitrone to give 1,2,4-triphenyl-2-azetidinone in the presence of chiral ligands of the kind bisoxazoline (Scheme 3.10). Recently, a new protocol of Kinugasa reaction was developed by Hosseini and Schreiner for the one-pot synthesis of 4-substituted β-lactams using calcium carbide (37) and nitrone derivatives 38. Calcium carbide is activated by TBAF.3H2 O in the presence of CuCl/NMI (Hosseini and Schreiner 2019). The easiness of synthesis and use of cheap chemicals give fast access to reasonable amounts of substituted β-lactams 40, exclusively at position 4 (Scheme 3.11). A modification of the Kinugasa reaction was accomplished by Zhao and Li (2006) using a multicomponent reaction to give β-lactams. In this modification, the necessary

Ar +

R1 34

N 35

O

CuI-pyridine

R2

K2CO3/DMF rt or 80 oC, 2-72 h

O R1

N

Ar R2

36 mainly cis- -Lactams (up to 82% yield)

Scheme 3.10 Reaction of terminal alkynes with nitrones using CuI-pyridine

104

A. Beatriz et al. Ar2

Ca

+

O

N

Ar1

37

38

CuCl-NMI/CaC2 THF/H2O/TBAF -5 oC, 2-72 h

O

N

Ar2 Ar1

40

-Lactams (up to 90% yield)

Scheme 3.11 Kinugasa-based β-lactam synthesis using calcium carbide as acetylide source

nitrone is generated in situ from the correspondent aryl aldehyde and methyl or benzyl hydroxylamine, and subsequent reaction with the alkyne present (41) in the reaction mixture (Scheme 3.12). All these reactions are held under neat conditions, at 70 °C, in the presence of 5 mol% of the complex CuCl/2,2’-bipyridine and sodium acetate (AcONa) as the base. The reactions were highly diastereoselective, producing cis-βlactams 42 as major products. The best ratio cis/trans was 89:11, and the worst was 63:37. McKay et al. studied these Kinugasa multicomponent reactions catalyzed by copper in nanoreactors of SDS in aqueous media. The reactions were carried out in a single “pot” for a series of C, N-diarylnitrones generated in situ with Cu(I) phenylacetylide, affording β-lactams 45 in 45–85% yields (Scheme 3.13). However, the diastereoselectivity of the reaction was low (the ratio cis/trans varied from 1:1 to 2:1). Moreover, in addition to the desired β-lactam products, it was observed the formation of product 46. Therefore, the authors concluded that amide 46 resulted from the decomposition of one of the intermediates from the cascade and not from the final β-lactam (McKay et al. 2009). 5 mol% CuCl, 5 mol% 2,2'-bipyridine

RCHO + MeNHOH.HCl +

41

O

N

Me

R 30 mol% NaOAc, 1 eq. KHCO3 Ph 42 70 oC, neat -Lactams cis/ trans (up to 99% yield)

Scheme 3.12 Coupling of aldehydes with N-methylhydroxylamine and phenylacetylene

CHO

R

+ 43

NHOH

+ 41

44

CuSO4.5H2O sodium ascobate pyridine ethanolamine buffer (pH 10) SDS/H2O 0 oC to rt

O Ar

N

Bn Ph

O +

45 -Lactams cis/ trans 1:1 to 2:1 (yield 45-85%)

Scheme 3.13 Micelle-promoted multicomponent Kinugasa reaction

Ph

NH

Ph

46

yield 10-47%

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

105

CO2Me

R

n

OH N 47 OH N

O 10 mol% CuSO4 dioxane

CO2Me

N

MeO2C 49

R

up to 84% yield up to >99:1 dr

o

120 C, 48 h

48

O

CO2Me

N n

MeO2C 50

Scheme 3.14 Copper-catalyzed β-lactam formation using oximes and methyl propiolate

Scheme 3.15 Ester enolate-imine cycloaddition

O

R1 R2

OR3

O

1. Base 2.

R4

N R5

R1

N

R5

4 R2 R

Another variation of the Kinugasa reaction was recently described by Qi and Wang (McKay et al. 2009), which allows for the construction of β-lactams 49 and spirocyclic β-lactams 50 from the reaction of oximes and methyl propiolate, catalyzed by copper (II) (Scheme 3.14). This protocol provides excellent flexibility of substrate and diastereoselectivity (up to 99:1 dr). In situ FT-IR mechanistic experiments support that species of ketene may be involved in the formation of β-lactams. Ester enolate-imine cycloaddition The cyclo condensation of ester enolate-imine (Scheme 3.15) provides β-lactams in good yields and high stereoselectivity. Many types of esters and imines can be used. The cycloaddition of N-methoxyphenyl aldimines 52 with lithium ynolates 51 was reported by Shindo et al. (2000) to afford β-lactam enolates 53, that react with one more equivalent of imine to produce β-lactams rings in gold yields. N4-Methoxyphenyl imines are inert regarding the lithium ynolates, demonstrating that the methoxy group at position 2 is important as a coordination site for the metal (Scheme 3.16). The authors studied the reaction of several ynolates (51) and N-2-methoxyphenyl imines (52) to obtain the corresponding β-lactams 54a–i in yields in the range of 0–97%. When the aryl aldehyde imines were used, the reaction proceeded smoothly, producing the adducts in good to excellent yields (52–97%). However, the bulky imine 52 (R2 = terc-Bu) did not afford the desired products. The diastereoselectivity cis/trans was between 1:0 and 3:1, depending on the aldimine’s substituent (Scheme 3.16). Boyer et al. reported a study of the parameters that can influence the selective synthesis of β-lactams or β-amino esters during the Reformatsky reaction between

106

A. Beatriz et al. R2

R1

OLi

O

N

+

LiO

THF -78 oC, 2h

MeO

51

N

R1

52

R2

53

OMe

O

OMe 54a, R1 = Bu, R2 = Ph, 79% cis/ trans 1:0 54b, R1 = Bu, R2 = 1-naphthyl, 78% cis/ trans 1:0 54c, R1 = Bu, R2 = 2-naphthyl, 74% cis/ trans 1:0 54d, R1 = C6H11, R2 = Ph, 52% cis/ trans 1:0 54e, R1 = Me, R2 = Ph, 96% cis/ trans 1:1 54f, R1 = Me, R2 = 1-naphthyl, 88% cis/ trans 2:1 54g, R1 = Me, R2 = 2-naphthyl, 93% cis/ trans 3:1 54h, R1 = Me, R2 = tert-Bu, 0% 54i, R1 = Me, R2 = 4-(MeO2C)C6H5, 97% cis/ trans 3:1

N

Li

OMe

2 1 R NH R

R2

R2 R1

N

MeO

Scheme 3.16 Cycloaddition of the lithium ynolate with the N-2-methoxyphenyl aldimine

ethyl bromodifluoroacetate (56) and various imines 55, that were prepared in quantitative yields by condensation of (R)-phenylglycinol and aldehydes (Boyer et al. 2007). (R)-Phenylglycinol was selected for being an efficient chiral auxiliary. The authors demonstrated that when the nature of the imine or the reaction conditions were modified, it was always possible to invert the ratio of β-amino esters/β-lactams. For example, Scheme 3.17 shows two extremes: when the imine 55a is used, the β-lactams 57a is exclusively obtained with high diastereoselectivity (>98%), while the imine 55b only affords the β-amino ester 58b, with high diastereoselectivity, too. Some recent reactions were mediated by other metals, such as rhodium, indium, and diethylzinc (Singh and Sudheesh 2014; Troisi et al. 2010). Alkene-isocyanate cycloaddition The reaction of electron-poor cyanates and electron-rich alkenes is a robust and relatively mild method to synthesize βlactams. However, unlike the Staudinger reaction, this reaction offers less flexibility concerning the functionality of the starting materials, with most of the examples using Ph

O

OH

N

+

R

55a, R = Ph 55b, R = 4-Pyridyl

Br F F

OEt

Zn THF, reflux, 2 h

56

Ph O F

N F

+ R

57a 100% (56% yield) 57b 0% de > 98%

Ph

OH EtO O

OH

HN F F

R

58a 0% 58b 100% (67% yield) de > 98%

Ph N R

OH

Ph HN

O R

Scheme 3.17 Synthesis of gem-difluoro-β-amino esters or gem-difluoro-β-lactams from ethyl bromodifluoroacetate and imines during Reformatsky reaction

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

+

RNCO

O 59

O

100 oC, 20 h

N

R R = Me, Et, n-C4H9 cyclohexyl, (CH3)3C, PhCH2

H

H

800 MPa

107

O 60 (up to 100% yield)

Scheme 3.18 Reaction of several isocyanates with 2,3-dihydrofuran under pressure

activated isocyanates, such as chlorosulfonyl isocyanate (CSI), p-toluenesulfonyl isocyanate, trifluoroacetyl isocyanate, and trichloroacetyl isocyanate (TCAI) (Anant et al. 2020). Although the Staudinger reaction is usually accepted to follow a two-step mechanism, computational studies lead to step-by-step and concerted mechanisms between electron-rich alkenes and electron-deficient isocyanates (Anant et al. 2020). Tagushi et al. reported the [2+2] cycloaddition with 2,3-dihydrofuran (59) under pressure to afford β-lactams 60 in 28–100% yields (Scheme 3.18) (Tagushi et al. 1996). Other similar β-lactams were obtained under high pressure in the reaction of phenyl isocyanate and several vinylic ethers. Whereas the [2+2] cycloaddition of alkyl isocyanates to 2,3-dihydrofuran has been accelerated under high pressure to afford β-lactams in good yields, the reactions of alkyl isocyanates with ethyl vinyl ethers were slow, even under high pressure (Anant et al. 2020). Cyclization Reactions A substantial range of cyclization reactions lead to the β-lactams moiety (MartínTorres and González-Muñiz 2017). In this section, we will present just a few representative examples. The most obvious approach to the preparation of β-lactams would be the use of cyclization reactions of β-amino acids or appropriate derivatives, such as the one made by Nagao et al. (1996) that used the dehydrating agent 3,3 -(phenylphosphoryl)bis-(1,3-thiazolidine-2-thione) (PPTT) to promote the cyclization of many β-amino acids 61, to afford the corresponding β-lactams 62 (Scheme 3.19). This method was used to obtain precursors of monobactams. Salzmann et al. developed a protocol to afford β-lactams that involved the treatment of aspartic acid diester 63 with trimethylsilyl chloride and a magnesium alkyl OH

O H

1

R R 61

NH 2R

3

Ar

PPTT (2 equiv.) i-Pr2NEt (3 equiv.) MeCN, reflux

O H

N R1 R2

Ar R3

62 5 examples 95 to 99% yield

O Ph P

N

S S

2

PPTT

Scheme 3.19 Synthesis of β-lactams by intramolecular dehydration of β-amino acids promoted by PPTT

108

O

A. Beatriz et al. OBn NH2 H CO2Bn 63

OTBDMS CO2R H H NH2 MeO2C 66

TMSCl/TEA t

BuMgCl

BuMgCl

NH CO2Bn

64

O

TMSCl/TEA t

OH

O

HO

O

HH S

N 65

NH2

CO2H

NH CO2R

H 67

Scheme 3.20 Treatment of β-amino esters with Grignard reagents

Scheme 3.21 Base promoted cyclization of β-amino esters

R

OCH3

PMP NH

O

LHMDS dry THF 5 min

68a-d a, R = Me b, R = Et c, R = i-Pr d, R = Ph

O

N

PMP

R 69a-d 88 to 93% yield ee >99%

chloride to afford the 2-azetidinone 64, crucial for the synthesis of carbapenem (+)-thienamycin (65) (Salzmann et al. 1980). This procedure was applied to the synthesis of β-lactams 67 from N-trimethylsilyl derivatives from β-amino esters 66 (Martín-Torres and González-Muñiz 2017) (Scheme 3.20). Vicario et al. reported a cyclization promoted by a base of β-amino esters (68a– d) (Vicario et al. 2001), providing, after flash column chromatography purification, the desired enantiomerically pure β-lactams 69a–d in excellent yields (88–93%) (Scheme 3.21). Ugi Multicomponent Reactions Ugi Multicomponent reactions (MCRs) have been used to build a wide variety of β-lactams from carboxylic acid derivatives, amines, aldehydes, and isocyanide, which is known as isocyanide-based multicomponent reaction (IMCR) (Pharande 2021; Singh and Sudheesh 2014). IMCRs, especially 4-component Ugi (Ugi-4CR) and 3-component Ugi reaction (Ugi-3CR) are perfectly adequate for synthesizing densely functionalized β-lactams. Using a Ugi-4CR/SN i cyclization strategy, Zeng et al. (2014) developed an efficient protocol for the synthesis of β-lactams as 26 in moderate to excellent yields (Scheme 3.22). The authors reacted phenylglyoxal derivatives 70 and bromo carboxylic acid (71) with several amines and isocyanides to afford the intermediate Ugi 72 that, in the presence of Cs2 CO3 , suffers a cyclization reaction, via SN i, providing the desired β-lactams 73. Also, using an Ugi-4CR strategy, Gao et al. (2018) reacted maleic or fumaric acid derivatives 74 with aldehydes, isocyanides, and amines to produce the β-lactams 77

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

CHO

+

Br 71

+ +

Br

O

70 R2 NH2

Base

O

O R1

109

OH

O

Cs2CO3 MeOH, rt, 12 h

3

N

R2

R3

R NC

O

H O

NH

N

3 R2 R NH

S Ni

O

O

R1

R1 73

72

58-93% yield

1

R = 4-Cl, 4-Br, 4-NO2 R2 = t-Bu, n-Pr, 4-ClC6H4, Ph, 4-MeC6H4 R3 = t-Bu, c-Hex

Scheme 3.22 Ugi-4CR/SN i cyclization to obtain β-lactams CO 2H R 1O 2C

+

74

MeOH

+ R 3 CHO

R 1O 2C

R 2 NH 2

+

R 4 NC

55 oC, 10 h

R4

O

O N H

N R3 75

R2

R 1O 2C

O

O

R 4 NH O

H 76

N R2 R3

Michael reaction

N

R 1O 2C HN R4

R2 R3 O

77 61-82% yield

Scheme 3.23 One-pot synthesis of a β-lactams scaffold by a hydrogen bond-controlled UgiMichael cascade

in excellent yields in methanol at 55 °C (Scheme 3.23). According to the authors, this reaction prefers a Michael addition path through the Ugi adduct 76 instead of the aza-Michael path. For a successful reaction, the heterocyclic aldehyde must establish a hydrogen bond with the amide (75) or enolic (76) form of the Ugi adduct. Besides, based on theoretical calculations, the authors observed that the Michael addition step controlled the diastereoselectivity. The advantage of this methodology is its robustness to synthesize medicinally important β-lactams in a single pot under moderated conditions (Pharande 2021). Vishwanatha et al. prepared functionalized β-lactam peptidomimetic 80 via Ugi3CR, employing chiral isocyanides 79, L-Aspartic acid 1-methyl ester 78a, and aldehydes (Vishwanatha et al. 2011). Thirteen Ugi products were prepared in good to moderate yields and with good diastereoselectivity (Scheme 3.24).

3.2 Azetidines 3.2.1 Introduction Azetidine or azacyclobutane is a colorless liquid with a boiling point of 61 °C, soluble in water, pKaH = 11.25, much more basic than aziridine pKaH = 7.98. One of the reasons for these values is the lower tension of the azetidine ring, the calculations of angular stress are 25.2 kcal mol−1 and 26.7 kcal mol−1 , respectively, which would justify the greater availability of the pair of electrons of azetidine, on the other hand,

110

A. Beatriz et al. FmocHN R1 CO2H

H2N

R1

CO2Me 78a

NC

+ FmocHN

+

MeOH

2

R CHO

rt

79

NH

O O

N

R2 O

MeO 80 49 to 78% yield

Scheme 3.24 Synthesis of β-lactam peptidomimetic

increasing the s character of the non-binding orbital of the electron pair in aziridine nitrogen would decrease its basicity. The structure of the molecule is not flat. Its three carbon atoms, when appropriately substituted, can give rise to chiral substances, in addition to cis or trans isomers being possible (Scheme 3.25). 1 H NMR studies prove nitrogen inversion. The lone pair on nitrogen is favored in the pseudoaxial position; however, with an inversion barrier of ~10 kcal mol−1 , inversion at room temperature occurs (Scheme 3.25) (Mondino 2014). The diffraction data of azetidine has been used to calculate the bond lengths and bond angles present in the molecule, shown in Table 3.1 (Bott and West 2012). The 1 H NMR chemical shift data of heterocycles aziridine (81), azetidine (82), and pyrrolidine (83) also shows a much closer resemblance to azetidine (2) to pyrrolidine (3) rather than aziridine (1) (Bott and West 2012). See (Fig. 3.5). H H H

N

N

H

H

H

Scheme 3.25 Inversion barriers

Table 3.1 Geometric parameters of azetidine

Bond length (Å)

Bond angle (degrees)

N–C

CNC

1.48

92

C–C

1.55

CCC

87

C–H

1.11

CCN

86

N–H

1.02

HCH

110

3 Lactams, Azetidines, Penicillins, and Cephalosporins … 1.62 ppm H

2.23 ppm H

N-H

81

Fig. 3.5

1H

3.54 ppm H

111 1.59 ppm H

2.75 ppm H N-H

N-H

83

82

NMR chemical shifts of aziridine (1), azetidine (2), and pyrrolidine (3)

3.2.2 Azetidine Synthesis The reactions of syntheses of four-membered N-heterocyclic rings, despite their biological importance, have always been studied to a lesser extent when compared to reactions for syntheses of five- and six-membered rings. Fortunately, there is a tendency to close this gap. Various creative strategies for preparing azetidines have been reported, including cyclization by nucleophilic substitution, cycloaddition, ring expansion and rearrangement, ring-contraction, and reduction of β-lactams. However, the most widely used method continues with cyclization by nucleophilic substitution, where the use of a good leaving group facilitates its displacement to obtain good yields. Azetidine derivatives are reported to show various antimicrobial, antitubercular, anticonvulsant, anti-inflammatory, antimalarial, anticancer, antiviral, antioxidant, and cardiovascular activities. Next, we will see the most important reactions and the oldest, Gabriel’s synthesis of 1888. Obtaining azetidines by cyclization N–C Gabriel synthesized azetidines from 3-bromopropylamine in 1888. α-Haloalkylamines in the presence of base form azetidines (Scheme 3.26). The yield in these cases is low. The reaction occurs through an intramolecular substitution reaction by attacking the amine’s electron pair, displacing the halogen. When electron-donating substituents are present in the chain and the halide is primary, the yield improves (Mondino 2014). Other attempts to improve the yield were made, and, thus, alkylaminosulfate was reacted in a basic medium (Scheme 3.27). In this reaction, what changes from the previous one is the leaving group (Mondino 2014). Fortunately, the advancement of microwave technology made possible the improvement of the yield of the above-proposed reaction (Scheme 3.27). Burkett Scheme 3.26 The first reported synthesis of the azetidine

NH2

Scheme 3.27 Synthesis of azetidines by cyclization of 3-aminopropyl sulfates in aqueous base

NHR

Br

SO2O-

OH-

NaOH

N H

N R

Br-

H 2O

Na2SO4

H2O

112

A. Beatriz et al. O O S O O

RNH2, MeCN

H H N R

O S O O

O

o

80 C 77-91% 84

85

KOH, H2O w, 150oC 55-84%

N R

86

Scheme 3.28 Synthesis of azetidines using microwave heating

Scheme 3.29 Azetidine synthesis using N,N-bis(toluenesulfonyl)1,3-diaminopropane

NHTs

NaOH aq

NHTs- TsOH

N Ts

Nao, C10H8

-TsOH

N H

70%

et al. have reported the synthesis of a variety of different N-substituted azetidines in good yields by reaction of primary amines with the cyclic sulfate of propanediol (84) (Scheme 3.28). The initial formation of 3-(ammonium)propyl sulfates 85 followed by fifteen minutes of microwave irradiation in basic aqueous media gave rise to analytically pure azetidines 86 in moderate to good yields (Burkett et al. 2009). Another synthesis (Scheme 3.29) uses N, N-bis(toluenesulfonyl)-1,3diaminopropane, and the reaction occurs in two stages. In the first stage, cyclization occurs in the presence of sodium hydroxide and, in the next stage, the tosyl group is removed with metal sodium in naphthalene, a reduction widely used in synthesis (Mehra et al. 2017). A typical procedure is to inject a fair concentration solution of the toluene sulfonate into a stirred tetrahydrofuran solution containing 2–6 equiv (ca. 0.3 M) of sodium naphthalene under nitrogen. Completion of reaction, indicated by the disappearance of the intense green color of the anion radical, usually occurs within a few seconds at room temperature. However, for certain sulfonates, the best yields were obtained by carrying out the reaction at about −80 °C; the reaction is noticeably slower at this temperature. The addition of a small amount of water to convert the alkoxide salt to alcohol completes the process. Another approach was by De Kimpe and coworkers (Stankovi´cS et al. 2011). They have utilized α-chloro-β-amino-sulfinyl imidates 87 for the synthesis of enantiopure trans-2-aryl-3-chloroazetidines 91. The azetidines are precursors for obtaining 3substituted azetidine-2-carboxylic acids. The key step involved the deprotection of α-chloro-β-amino-sulfinyl imidates 87 with 4 N HCl in dioxane to afford the corresponding imidate hydrochloride 88, which underwent hydrolysis at 50 °C to yield ester 89. Reduction of ester 89 using LAH in dry THF at low temperature yielded β-chloro-γ-sulfonylamino alcohol 90, which underwent intramolecular cyclization under Mitsunobu conditions to afford trans-2-aryl-3-chloroazetidines 91 (Scheme 3.30). A versatile asymmetric synthesis of 3-substituted azetidine-2-carboxylic acids and 2-substituted azetidine-3-carboxylic acids via 1,3-amino alcohols with excellent stereoselectivities (de ≥ 96%, ee ≥ 96%) was reported by Enders and Gries (2005). The asymmetric synthesis of the azetidines was carried out as depicted in Scheme 3.31. First, the SAMP hydrazones 92 were hydroxymethylated

3 Lactams, Azetidines, Penicillins, and Cephalosporins … R1

NH

t-Bu S N O

R2

R1

4N,HCl in dioxane

OMe

HCl

NH

R2

Et2O, rt, 1h

Cl

NH

113

R1

H2O, 50oC

OMe

24h

Cl

LHA, THF

R1

0oC, 2,5 h

R

R1

N

Mitsunobu reaction

OH

2

OMe

89

PPh3, DIAD, THF, rt, 24h

NH

O

Cl

88

87

NH

R2

2

R

Cl

90

R1: Tos; R2: C6H5

Cl

91

89-90%

Scheme 3.30 Azetidine synthesis from α-chloro-β-amino-sulfinyl imidates

LDA, THF, 0oC then

N H3CO

N

100oC, SEMCl 66-77%

H

N H3CO

PhLi, CeCl3 N

H R

R

(S)-92

N

NH

H3CO

Si(CH3)3

O

3 stepsa,b

Si(CH3)3

O

(R,S)-93

Ts

HN

58-64%

R

THF, -105oC

Si(CH3)3

O R

(S,R,S)-94

(S,R)-95 a) BH3.THF, THF, reflux, then HCl; b) TsCl, K2CO3, CH2Cl2, reflux Ts

Ts LiBF4, MeCN-H2O

DIAD,PPh3

HN

98:2, Reflux

OH R

(S,R)-96

N

THF, rt 86-94% over 2 steps

R: Me; Et; i-Pr; n-Bu

(S,S)-97

R

Scheme 3.31 Azetidine synthesis from SAMP or RAMP hydrazones

with excellent diastereoselectivities (de ≥ 96%) by α-alkylation with (2trimethylsilylethoxy)methyl chloride (SEMCl) instead of benzyloxymethyl chloride. This alteration meant a change of the O-protecting group from benzyl to TMS-ethyl, thus easily enabling the selective O-deprotection in the presence of the benzylic amine moiety generated in the next step of this synthesis. Next, a phenyl substituent

114

A. Beatriz et al.

1) Tf 2O, Hunig's base ACN, -35oC

HO OH

N

2) Benzhydrylamine

98

99

Scheme 3.32 Azetidine synthesis from (R)-1,3-butanediol

was introduced by a nucleophilic 1,2-addition of a phenylcerium reagent to the C = N double bond of the hydrazones 93. Next, crudehydrazines 94 were directly submitted to a reductive N–N bond cleavage to remove the chiral auxiliary. The corresponding O-protected amino alcohols were subsequently refluxed with tosyl chloride in the presence of K2 CO3 to yield the differently N, O-protected amino alcohols 95 in good yields (58–64% over 3 steps) and excellent diastereomeric and enantiomeric excesses. The initial attempts to remove the TMS-ethyl protecting group employing HF·pyridine gave only moderate yields. Finally, the cleavage was effectively achieved by refluxing 95 and LiBF4 in a 98:2 mixture of MeCN and water. The N-protected amino alcohols 96 were not purified but cyclized under Mitsunobu conditions. The corresponding N-tosylated 2-phenylazetidines 97 were obtained in good yields (86–98%) over two steps (Enders and Gries 2005). Note: (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) or (R)-1-amino2-methoxymethylpyrrolidine (RAMP). Further, (S)-N-(diphenyl methyl)-2methylazetidine (99) are important intermediates in the obtention of azelnidipine. Following preparation via synthesis on the one-pot conditions, best results in terms of yield were obtained via dropwise addition of trifluoromethanesulfonic anhydride (Tf2 O) to a premixed solution of (R)-1,3-butanediol (98) and Hunig’s base, DIPEA ou DIEA (N,N-Diisopropylethylamine) (Scheme 3.32). Treatment of sulfonyl azides 100, phenylacetylenes 101, and benzenethiol Schiff bases 102 in the presence of CuI and Et3 N at 0 °C as depicted in the (Scheme 3.33) originates of disulfide-linked N-sufonylazetidin-2-imines 103. Hu et al. have developed an efficient method to react through a multicomponent reaction (Mehra et al. 2017). The synthesis of azetidines via organocatalysis was performed by Yadav and coworkers using the strategy [2+2] reacting aldehydes with aldimines obtaining azetidine-2-ols stereoselectively (Mehra et al. 2017) (Scheme 3.34). The treatment of aldehyde 104 with pyrrolidine-based catalysts 105 to afford chiral enamine intermediate 106, which upon [2+2] annulation reaction with aldimines 107 in the presence of K2 CO3 resulted in the diastereoselective synthesis of corresponding azetidin-2-ols 108 as depicted in Scheme 3.34. Kaufman and Amongero (2013) developed the enantioselective and organocatalyzed synthesis de 1,2,3-trisubstituted azetidines 115 employing a one-pot synthesis of γ-aminoalcohols 114 followed by microwave cyclization with TsCl-Et3 N. No

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

115 R2

R1O2SN R1

SO2N3

N

R3

100 R2

S

Et2N, THF, 0oC 10h

HS

101

N

R3

CuI (20 mol%)

102

R3

S

N

R1: C6H5; 4-CH3C6H5; 4-Cl-C6H5 R2: C6H5; 4-CH3C6H5; 4-NO2-C6H5

R2

R3: H,4-CH3, 4-OCH3, 4-Br

NSO2R1

103

Scheme 3.33 Synthesis of disulfide-linked N-sulfonylazetidin-2-imines

Ph

H

1

R

O

104

N H

OTMS

105

Ph

Ph N

THF, 30 min

R2

OTMS

K2CO3,THF,5 - 7h, r.t.

R1 2

OH

R1

N R2

108

R3

(79 - 90%)

106 1

R3

107

Ph H

N

3

R : Me, Et, PhCH2; R : Ph, -4-MePh, 4-NO2Ph, 2-MePh; R : Ts, PhSO2, 4-MeOPhSO2

Scheme 3.34 Synthesis of azetidine via organocatalysis

protection groups were used. The γ-aminoalcohols 114 resulted from the tricomponent cross-Mannich synthesis of β-amino aldehydes and their reduction in situ (Scheme 3.35). The substituents in the benzaldehyde and the starting aniline were electron releasing and electron-withdrawing. Azetidines synthesis by [2+2] photocycloaddition-Aza Paternò-Buchi reactions-; via expansion rings; via ring contraction and b-lactam reduction The synthesis of azetidines via [2+2] photocycloaddition-Aza Paternò-Buchi reactions-; via expansion rings; via ring contraction and the β-lactam reduction will be shown in Schemes 3.36–3.39. Mukai group discovered a novel [2+2] photocycloaddition, representing the first example of an oxime undergoing an aza-Paternó-Buchi reaction (Richardson et al. 2020; Mukai et al. 1983) (Scheme 3.36). De Kimpe and coworkers (Stankovi´c et al. 2011) described a synthesis of azetidines 124 through the formation and subsequent ring expansion of aziridines as intermediates derived from N-alkylidene-(2,3-dibromo-2-methylpropyl)amines 119 (R1 = Me) upon treatment with NaBH4 in methanol under reflux through a rare aziridine 121 to azetidine rearrangement. These findings stand in sharp contrast to the

116

A. Beatriz et al. R2 CHO

NH2 N

L-proline (20mol%) R3

H

NMP,MW (70oC, 1h)

R2

R3

110

109

R2

OH

Et2O, 0oC

MW

R1

1

R3

R1

N

TsCl, Et3N

NaBH4, MeOH

R R3

R2

HN 4

-20oC, 24h

111

R2 HN

R1CH2CHO (112), NMP

R

113, R4: CHO

R3

114

115

Scheme 3.35 Synthesis of azetidines 1,2,3-trisubstituted

O

O N

H

N

H R

116

118

117

R: CN, CO2R'

R:CN 75%

6:1 exo/endo R

Scheme 3.36 Synthesis via [2+2] photocycloaddition-aza Paternò-Buchi reactions

known reactivity of the closely related N-alkylidene-(2,3-dibromopropyl)amines 120 (R1 = H), which are easily converted into 2-(bromomethyl)aziridines 128 under the same reaction conditions (Stankovi´c et al. 2011) (Scheme 3.37). a

b Br

Br

H

H+

HN

MeOH R

119 ou 120)

R H

1

a

R

R1: CH3 (119) ou H (120) 122

MeOH,

R

R

1

NaBH4

N

H4 aB N 3 , OH Br Me Br 3N aB H Me 4 OH , b

R

121

N

CH3

Br

Scheme 3.37 Synthesis via expansion rings

OMe N

Br

BrR

123

N

MeOH

N R

N

H OMe

Br

R

124 N

BrR

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

117

O Br N

SO2Ar

CONu

K2CO3(1,5-3-equiv) MeCN:MeOH 9:1

N Nu: ROH, or ArNH2 rt, -60oC, 3-60h 73-98%

125

SO2Ar

126

Scheme 3.38 Synthesis via ring contraction R

R O

N

NaBH4, isopropanol

N

rt 10h R2 R1 R: H, Cl, CH3

R2 R1

127 R1: H, Cl, CH3

R2:

;

128 83-92%

Scheme 3.39 Preparation via β-lactam reduction

Another example of synthesis de azetidines through contraction of larger rings was proposed by Blanc et al. A one-pot nucleophilic addition-ring contraction of α-bromo-N-sulfonylpyrrolidinones 125 with K2 CO3 in the presence of acetonitrile: methanol (9:1) to yield the α-carbonylated N-sulfonylazetidines 126. Various nucleophiles, such as alcohols, phenols, or anilines, have been incorporated into the azetidine derivatives (Kern et al. 2014) (Scheme 3.38). Reduction of β-lactams (azetidin-2-ones) 127 with DIBAL-H and chloroalanes is considered one of the most convenient approaches for the chemoselective synthesis of azetidines 128 (Mehra et al. 2017) (Scheme 3.39).

3.2.3 Azetidines Reactions The ring-opening of azetidines is not as common as it is for lower homolog aziridines. It can be attributed to the greater stability of the azetidine ring in comparison to the aziridine ring. However, some useful ring-opening reactions of azetidines and their applications in heterocyclic synthesis have been published in recent years (Singh 2020) (Scheme 3.40).

118

A. Beatriz et al. HCl

NH3

NH Acid-base R1

R

2

N

Cl

X-

Tetraalkylamonium halide

SO2R3

DCM, BF3.OEt2

R

SN2-Type

R1 N

2

F3B

R2

X R1

SO2R

NH SO2R3

3

99%

R1: Ar, Bn; R2: H, Et, nPr; R3: 4-Me-C6H4, 4-NO2-C6H4; X: Cl, Br, I R

MXn N

R

R: OMe, OBn, Bn MXn: MgCl2.6H2O, LiBr,MgBr2.6H2O, LiI

R1

Bn

KF/ 18-crown-6

O

OTf

Bn

R

10-66%

TMS

N

X

N H

liq. SO2, 80oC 10-63hs

Cbz carbamate-protected Ph

Cbz

H

O

R

N

Ph

R: Ph; R1: Et, Ph, COPh

R1

O

THF, -10oC to r.t. 57-82%

O

Scheme 3.40 Ring open of azetidines reactions

3.2.4 Azetidines Therapeutics Use The following are compounds containing the azetidine nucleus. Some of these substances have proven medicinal uses (Computed by LexiChem 2019) (Scheme 3.41). OCH3

BRD 3444

N HN

9 HO

10

C

H

H

N

H

HO

N

O

O

N

S

Siponimod

F HN

F

N

O

Baricitinib

O I

F

Cobimetinib

O

O N N

N

N

8 N

F F

N

N

O

F

N

N N

C

H

O N

HN O

Ximelagatran Nitrile

Scheme 3.41 Some biologically relevant azetidine compounds

O

OH

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

H N

CO2H

O

Cl

O

O

N

Gelsemoxonine

OH HO HO N H

H

N H

Tebanicline

L-Aze

N O

HO

O

N H

119

Penaresidin A

O

O N

OH

OH

OH N H

OH OH O

Mugineic acid OH

OH

HO

HO N H

Penaresidin B

OH

N H

Penazetidine A

Fig. 3.6 Natural azetidines

3.2.5 Natural Azetidines Natural substances present in marine animals, like penaresidin A and B; the plant’s growth inhibitor (S)-azetidine-2-carboxylic acids (L-aze) and their derivatives, although entirely rarely found in nature, for example, tebanicline (Fig. 3.6). L-Azetidine-2-carboxylic acid (Aze) is a plant non-protein amino acid analog of proline. Aze is found in numerous plants from the bean family Fabaceae and has also been detected in small quantities in table beets, garden beets, and sugar beets. Penaresidin A and B are two novel azetidine-derived alkaloids obtained from the Okinawan marine sponge Penares sp. They exhibited potent actomyosin ATPaseactivating activity. Penazetidine A is an inhibitor of protein kinase C and azetidine produced by Penares sponges. Tebanicline is a drug product or related to the manufacturing of drugs; modified by veterinary, animal, or pet if indicated by source. Mugineic acid is an amino acid excreted by some graminaceous plants under iron deficiency conditions as part of a strategy of solubilizing Fe from the root environment for uptake by the plant. It forms a complex with iron. Gelsemoxonine is part of a large family of monoterpenoid indole alkaloids. It was isolated in 1991 from the leaves of Gelsemium elegans Benth.

3.3 Penicillins Penicillin V is considered one of the molecules that changed the world (Nikolaou and Montagnon 2008). This substance is responsible for the significant revolution in medicine in the twentieth century. It was accidentally discovered by Alexander

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A. Beatriz et al. 1 6 5 S

S O

NH

HN

N

O

2-Azetidinone, Thiazolidine the simplest -lactam ring

O

2

H2N 2

3

Penem 6

Carbapenam

N

O

3

Penam

N

1 5 S

6

O

5 1 N

O

S N 6-APA

CO2H

2

3

Carbapenem

Fig. 3.7 β-lactam, thiazolidine moieties, and structural types related to penicillin

Fleming in 1928 when he noticed that a mold of the family Penicillium had produced a substance that provides a potent antimicrobial activity. In this period, humankind had to deal with the dreadful problem of lethal bacterial infections, and, after that, this matter would be resolved exceptionally. Alexander Fleming and Howard W. Florey were awarded the 1945 Nobel Prize of medicine (Ghosez 2019). Despite its importance and the effort of several chemists during and after World War II, the total synthesis of penicillin V was only announced in 1957 by John C. Sheehan from the Massachusetts Institute of Technology (MIT, USA), putting an end to the extended search for the first rational synthesis of biosynthetic penicillin (Nikolaou and Montagnon 2008). Penicillins belong to the class of drugs known as β-lactams. Chemically speaking, they are 4-membered lactams or azetidin-2-ones fused with a thiazolidine ring, composing the central nucleus of penicillins called aminopenicillanic acid or 6-APA (Fig. 3.7). R. B. Woodward described it as “diabolical concatenation of functional groups”: a massive challenge to a synthetic chemist! (Ghosez 2019). On the one hand, this nucleus is essential to antibiotic activity; on the other, the substituents bonded to the amino group determine its pharmacological properties (Corey et al. 2007). Nomenclature such as penam, penem, carbapenam, carbapenem, etc., are used to describe structure types related to penicillin. For instance, 6-aminopenicillanic acid is an example of a substituted “penam”. The “penem” moiety, in turn, is derived from the penam system by the introduction of a double bond. Carbapenams and carbapenems have a—CH2 unit replacing the sulfur atom of the thiazolidine ring (Fig. 3.7). The production of various natural penicillins became possible when it was discovered that the chemical composition of the fermenting media influences the side chain. For example, the addition of phenylacetic acid or phenoxy acetic acid to the fermenting media of Penicillium chrisogenium results in the production of penicillin G and penicillin V, respectively (Scheme 3.42) (Corey et al. 2007).

3 Lactams, Azetidines, Penicillins, and Cephalosporins … H N

PhO

H

O

S

N

O

CO2H

Phenoxyacetic acid

H2N

Penicillium chrysogenium

O

Penicillin V

H

S

N CO2H

121 Phenylacetic acid

H N

Ph O

Penicillium chrysogenium

O

H

S

N

Penicillin G

6-APA

CO2H

Scheme 3.42 Production of natural penicillin V and G

As previously mentioned, the first total synthesis of penicillin V was concluded in 1975 by John C. Sheenan and Henry-Logan (Corey et al. 2007; Sheehan and HeneryLogan 1957). The condensation of D-penicillamine (2) with tert-butyl phthalimidonaldehydate (1) provided an epimeric mixture (D-α and D-γ isomers), and the compound with the targeted stereochemistry was obtained in 24% yield. The D-γ isomer can be converted to the D-α isomer (3) in high yields, achieving an efficient stereochemical synthesis. Treatment of 3 with hydrazine, followed by acid work-up with aqueous HCl, provided compound 4 in 85% yield. Treatment of 4 with phenoxyacetyl chloride in the presence of triethylamine, followed by tert-butyl cleavage with HCl, dried and recrystallized with acetone–water with one equivalent pyridine, provided the product 5 in 56% yield (both steps). The reaction of 5 and DCC, in the presence of 1 equivalent of KOH in dioxane-water, yielded the potassium salt of penicillin V entirely synthetic (Scheme 3.43) (Sheehan and Henery-Logan 1957).

O

OH

N O

O

CO2H +

O

1

1. NaOAc, EtOH/H2O

NH2.HCl

HS

D and DL-penicillamine hydrochloride (2)

r.t., 24 h, 75%

O H

N

O O

O

S

HN CO2H 3 (D-α, major isomer)

1. N2H4, H2O 2. aq. HCl, 85% Ph 1. KOH (1 eq.) 2. DCC, dioxane/water 25 oC, 20 min, 12%

1. PhOCH2COCl Et3N, DCM, 0 oC, 22 h, 75%

O

O

NH H

HO2C

S

HN 5

CO2H

Ph O

HN O O

H

S

N CO2K

Penicillin V potassium

Scheme 3.43 First total synthesis of penicillin V

2. dry HCl, DCM, 0-5 oC, 30 h, 75%

HCl.H2N

H

O

HN

O

S CO2H

4

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A. Beatriz et al.

The new synthetic methods could not compete economically against the fermentation process established to produce penicillin V and G. However, new syntheses of penicillin were accomplished in Merck’s research laboratories by Sharp and Dohme. Thus, those effective against a wide range of pathogenic bacteria, including penicillinase-producing organisms, could be available to all humankind (Newton 1957). Sheenan and Henry-Logan prepared the aminopenicillanic acid (6-APA) via total synthesis and semi-synthesis (Wright et al. 2014; Sheehan and Henery-Logan 1959, 1962), as described in Scheme 3.44. The intermediate 6 and 7 were accessible by chemical synthesis and semi-synthesis (Sheehan and Henery-Logan 1959, 1962) and were converted to 8 and 9 after treatment with trityl chloride and diethylamine. The treatment of 8 or 9 with N, N  -diisopropyl carbodiimide in dioxane-water (or furanwater) provided the corresponding crystalline compounds 10 and 11in 25% and 28% yield, respectively. The methyl ester 10 was hydrolyzed, preferentially obtaining the corresponding 6-tritilaminopenicillanic acid, that after detritylation, afforded the 6APA acid. 6-APA was also obtained by catalytic hydrogenolysis of 11, followed by acid deprotection (Scheme 3.44). Shortly after, scientists of Beecham Research Laboratories in the United Kingdom reported the isolation of 6-APA from fermentation broths of penicillin (putting forward a patent claim in 1957), and later this intermediate, produced by fermentation, had become the major forerunner for semi-synthetic production of penicillins. Unfortunately, due to the number of steps involved and the global yield, the total synthesis route of penicillins proposed by Sheehan was not competitive whatsoever. However, his pioneering synthetic efforts led to the discovery of 6-APA. Thus, after the large-scale production of 6-APA, it became possible to plan and synthesize plenty of semi-synthetic penicillin derivatives (Scheme 3.45) with enhanced potency and bioavailability that are still not clinically used (Nikolaou and Montagnon 2008; Wright et al. 2014). HCl.H2N O

H HN OH

S

TrCl, Et2NH

TrNH O

CO2R

6, R = Me 7, R = Bn

H

HN OH

S

DIC

TrNH

CO2R

8, R = Me 9, R = Bn

O

H

S

N

CO2R 10, R = Me 11, R = Bn 1. H2, Pd 2. H3O+ (2 eq.)

1. NaOH (1 eq.) 2. H3O* (1eq.) 3. H3O+ (2 eq.) H2N O

H

S

N CO2H 6-APA

Scheme 3.44 Chemical synthesis of semi-synthetic penicillins 6-APA

3 Lactams, Azetidines, Penicillins, and Cephalosporins … Scheme 3.45 Chemical synthesis of semi-synthetic penicillins derived from 6-APA

H2N O

H

S

N

123

Chemical synthesis

R HN

O CO2H

6-APA

R

X

O

O H

S

N

CO2H Semisynthetic penicillins

Penicillin-based drugs are classified into generations (1st, 2nd, 3rd, and 4th generation) according to their antibacterial activities. The natural penicillins produced by the mold Penicillium chrysogenum are of 1st generation. The ones from the 2nd and 4th generations are all semi-synthetic obtained from chemical synthesis starting from 6-APA. Table 3.2 shows the main APIs of antibiotics with their respective chemical structures that were or still are used worldwide (LiverTox 2021). By the late 70s, research concerning the search for new antibiotics of microbial origin and structurally related to penicillins led to the discovery of clavulanic acid (Fig. 3.8). Clavulanic acid has proved to be a potent β-lactamase inhibitor produced by Streptomyces clavuligerus. It has been successfully used in combination with β-lactam antibiotics (for instance, amoxicillin/clavulanic acid) to treat infections caused by pathogens producers of β-lactamase (Corey et al. 2007; Paradkar 2013). Sulbactam is also a β-lactamase inhibitor that was discovered by Pfizer’s researchers (Fig. 3.8). Sulbactam is a semi-synthetic sulfone with a β-lactam ring derived from 6-APA. It is an irreversible inhibitor of a wide range of bacterial βlactamases, noticing that sulbactam has low activity per se. Nevertheless, in combination with certain penicillins, it has synergistic activity against many β-lactamases producing bacteria, broadening the spectra of activity of these antibiotics (Corey et al. 2007; Scholar 2007). In the 1980s, the development of tazobactam (Fig. 3.8) culminated in a β-lactamase inhibitor with significantly low toxicity, a wide range of inhibition, and weak β-lactamases induction (Toomer et al. 1991; Micetich et al. 1987; Gutmann et al. (1986). Tazobactam is combined with the β-lactam antibiotic piperacillin (4th generation antibiotic) of extended spectra for the medication piperacillin/tazobactam, used in infections caused by Pseudomonas aeruginosa. Tazobactam amplifies the spectra of piperacillin, making it efficient against organisms that express β-lactamase and generally would decompose piperacillin (Yang et al. 1999). Tazobactam was patented in 1982 and came into use in medicine in 1992. World Health Organization (WHO) of 2020 warns that the 43 antibiotics, among them eleven β-lactams, are in development. However, they cannot hold back on all the super bacteria described in the global priority pathogens list (global PPL) from WHO. Aside from M. tuberculosis, more than 12 bacteria (Table 3.3) have been used to inform and guide proprietary areas of research and development since 2017 (WHO 2020). The list is divided into three categories based on the urgency of the need for new options of treatment that require, therefore, R&D.

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A. Beatriz et al.

Table 3.2 Chemical structures for 2nd and 4th Generation penicillin Generations 3ª.

2ª.

OMe H N

NH2

H

S N

OMe O

H

H N

S N

O

N

O

N

O NH

O

CO2H

O

CO2H

O

4ª.

Ampicillin

Methicillin

H

H N

S N

O

CO2Na

O Piperacillin OEt H N

NH2

H N

O

CO2H H N

S N

O

HO

CO2H

O

H

H N

S

Ticarcillin O

N

O

NH2

H N

H

O

S

S

Oxacillin

O

O

NH

O

O

O Bacampicillin

CO2H

O S

N

N

O

N

O

N

H

H N

CO2H

O

Amoxicillin

Nafcillin

S N

O

S

CO2H

O

H

O

H

H N

O O

S N

O

CO2H

O Mezlocillin

N

O

NH2

H N

Cl O Cl

H

S

O

Dicloxacillin

N

O

O

S N

O

O O

H

CO2H

Carbenicillin

O

O H N

Cl

H

O

S

N

O

CO2H

Cloxacillin N

Pivampicillin

CO2H

CO2H H N

S N

O

N

O

H

H N

O H N

Cl F

H

O

S

N

O

CO2H

Flucloxacillin

H

O

O

N CO2H

Clavulanic acid

OH O

H O O S

H O O S

N

N

CO2H

Sulbactam

O

N

N

N

CO2H Tazobactam

Fig. 3.8 Chemical structures for the β-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

125

Table 3.3 Prioritization of pathogens to guide discovery, research, and development of new antibiotics for drug-resistant bacterial infections Priority pathogens CRITICAL

HIGH

MEDIUM

Acinetobacter baumannii

Carbapenem-resistant

Pseudomonas aeruginosa

Carbapenem-resistant

Enterobacteriaceae

Carbapenem-resistant, 3rd gen. cephalosporin-resistant

Enterococcus faecium

Vancomycin-resistant

Helicobacter pylori

Clarithromycin-resistant

Salmonella species

Fluoroquinolone-resistant

Staphylococcus aureus

Vancomycin-resistant and methicillin-resistant

Campylobacter species

Fluoroquinolone-resistant

Neisseria gonorrhoeae

3rd gen. cephalosporin-resistant, fluoroquinolone-resistant

Streptococcus pneumoniae

Penicillin-non-susceptible

Haemophilus influenzae

Ampicillin-resistant

Shigella species

Fluoroquinolone-resistant

Semi-synthetic penicillins continue to raise interest in many research groups to discover new antibiotics that may tackle the super bacteria. 6-APA is still the most critical synthetic intermediate that can be included and reused in semi-synthetic antibiotics. Including amoxicillin, ampicillin, and cephalosporin antibiotics cefadroxil and cephalexin, to name a few. The growing incidence of antibiotic resistance raises the demand for semi-synthetic antibiotics, and more than 75% of the current penicillin production is directed at the production of 6-APA. Enzymatic hydrolysis of acylase penicillins offers a milder and more efficient alternative to the semi-synthetic process of 6-APA (Scheme 3.46). Penicillin G acylase (PGA) of Escherichia coli is the chief H N

Ph O

O

H

S

N

Penicillin G

CO2H

H2N

H2O Penicillin G acylase

O

H

CO2H 6-APA

1. Me3SCl 2.PCl5, - 40 oC Ph

N Cl O

H

S

N

S

H2O n-BuOH -40 oC

N

Ph

N BuO

CO2SiMe3

Scheme 3.46 Chemical and enzymatic production of 6-APA

O

H

S

N CO2SiMe3

126

A. Beatriz et al.

industrial biocatalyst for deacylation of benzylpenicillin, producing more than 20,000 tons of 6-APA each year. The protein engineering of PGAs of E. coli and Alcaligenes faecalis was explored until its catalytic activity and stability were enhanced. At the same time, immobilization of the free enzyme PGA or entire cells has been accomplished to make its efficacy possible as an industrial biocatalyst (Sawant et al. 2020; Kallenberg et al. 2005). Structural modification of antibiotics comprises strategies that seek new antibiotics with a wide range of action and low toxicity. For example, Bijev and Hung (2001) prepared 12 new penicillin derivatives for microbiological evaluation by Nacylation of ampicillin and amoxicillin with pyrrole carboxylic acids activated at the beginning of the security by mixed anhydrides, following Schotten-Baumann’s procedure (Scheme 3.47). According to the authors, the introduction of pyrrole-acyl residues to the free amino group, either from ampicillin or amoxicillin, did not increase the antibacterial activity of the initially selected substrates. However, the significant activity observed against gram-positive strains and the low toxicity observed encourage stimuli to keep on with this strategy, focusing on designing new types of pyrrole carboxylic acylating agents (Bijev and Hung 2001). Giacomo et al. synthesized new penicillin derivatives, penicillin sulfone, and sulfoxide, containing a C-alkylidene substituent, designed as β-lactamases inhibitors R2

O

N R

R2

O O R1

Cl

O

OEt

or

O

O

O

O

O

N R

Et3N

O

EtO

OEt

Pyr 12a, R = H, R1 = OH, R2 = OEt 12b, R = H, R1 = OH, R2 = OEt 12c, R = H, R1 = OEt, R2 = OH 12d, R = H, R1 = OEt, R2 = OH 12e, R = H, R1 = OH, R2 = CH3 12f, R = H, R1 = OH, R2 = CH3 12g, R = H, R1 = CH3, R2 = OH 12h, R = H, R1 = CH3, R2 = OH 12i, R = H, R1 = OH, R2 = OMe 12j, R = H, R1 = OH, R2 = OMe 12k, R = CH3, R1 = OH, R2 = CH3 12l, R = CH3, R1 = OH, R2 = CH3

O

N R NH2

1.

O

X

H

H N

R1

13a, R = H, R2 = OEt 13b, R = H, R2 = OEt 13c, R = H, R1 = OEt 13d, R = H, R1 = OEt 13e, R = H, R2 = CH3 13f, R = H, R2 = CH3

13g, R = H, R1 = CH3 13h, R = H, R1 = CH3 13i, R = H, R2 = OMe 13j, R = H, R2 = OMe 13k, R = CH3, R2 = CH3 13l, R = CH3, R2 = CH3

S N

O

CO2H

X = H, ampicillin or X = OH, amoxilin

2. 40% Na-2-ECA in EtOAc

Pyr

X

O NH O

H

H N

S N

O

CO2Na

14a, Pyr (R = H, R2 = OEt), X = H 14b, Pyr (R = H, R2 = OEt), X = OH 14c, Pyr (R = H, R1 = OEt), X = H 14d, Pyr (R = H, R1 = OEt), X = OH 14e, Pyr (R = H, R2 = CH3), X = H 14f, Pyr (R = H, R2 = CH3), X = OH 14g, Pyr (R = H, R1 = CH3), X = H 14h, Pyr (R = H, R1 = CH3), X = OH 14i, Pyr (R = H, R2 = OMe), X = H 14j, Pyr (R = H, R2 = OMe), X = OH 14k, Pyr (R = CH3, R2 = CH3), X = H 14l, Pyr (R = CH3, R2 = CH3), X = OH

Scheme 3.47 Synthesis of pyrrole carboxylic derivatives of ampicillin and amoxicillin

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

127 R2

R1

O

H O S N

17a O O

H

S

N

15

R2

Ph3P=R1R2 O

O O

O

DCM, 0 oC 30 min

rt

R1

O

H

S

R2

N O

O

R2 R2

a

COCH3

CH3

b

CONH2

H

c

R1

O

O

H O O S N

18a-c

Suine liver esterase, H2O/acetone (9:1), phosfate buffer (pH 8), 30 oC, 24 h R1

R1

O

O

16a-c

OH O

OH O

or bistributyltinoxide, Et2O rt, 6 h

H

S

N

19a-c

OH O

-CH2(CH2)3CO-

Scheme 3.48 Synthesis of new penicillin, penicillin sulfone, and sulfoxide derivatives

from the classes A and C. The synthesis route is summarized in Fig. 9.3.9. Ketone 15 was treated with an appropriate triphenylphosphoranylidene derivative, in DCM or THF, at room temperature for about 30 min to obtain the alkylidene derivatives 16a–c. The Wittig reaction provided mainly the isomer Z, easily purified by flash chromatography. The oxidation of 16a–c with 2.5 equiv. of m-chloroperbenzoic acid, followed by hydrolysis, in the presence of porcine liver esterase, in acetone/water, or by bis(tributyltin) (BBTO) cleavage in Et2 O, generated the penicillanic acid derivatives 18a–c. The treatment of 16a with one equiv. of m-CPBA, followed by hydrolysis, afforded the correspondent sulfoxide 17a, with S configuration (see Scheme 3.48). Compounds 18a–c and 19a–c were capable of inhibiting TEM-1 (a class A enzyme from Escherichia coli) or P-99 (a class C enzyme from E. cloacae), or both enzymes, when tested competing experiments using nitrocefin as reporter substrate. Furthermore, a synergistic effect against an S. aureus strain that produces the enzyme PC1 (a class A lactamase) was observed for compound 19a when used in combination with amoxicillin. Thus, the authors concluded that the synthesized compound has a broader range of activity as β-lactamase inhibitors rather than clavulanic acid because they are active towards class A and C enzymes. Nonetheless, the compounds cannot penetrate well in the external membrane of gram-negative bacteria (Giacomo et al. 2002). Boggián and Mata described an interesting solid-phase method for the synthesis of 2β-methyl-substituted- penicillins, using two different polystyrene resins commercially available. The functionalization of the penam moiety bonded to the Merrifield and Wang resin was performed by a penicillin sulfoxide rearrangement, and the products were released from the medium in mild conditions (Scheme 3.49) (Boggián and Mata 2006).

128

Y

A. Beatriz et al.

X H

O

O

HS

S

H

N O

O

S

S N -H2O

Y

S S

X N

O O

N Z

Y

Z S

X N

O O

O

Y

X

Z

S N

O

O

O

Y

O

X H

O

S

Z

N O

O

20a-m

Scheme 3.49 Mechanism for functionalization of the penam moiety by sulfoxide rearrangement

The usefulness of this methodology was demonstrated by synthesizing 15 penicillin analogs (compounds 20a–m, Table 3.4) with several substituents in the positions 1,6 and 2β-methyl, which are analogs of sulbactam and tazobactam. After flash column chromatography, the isolated global yields varied from moderate to good (24–70%). The primary nucleus of penicillins (6-APA) can undergo cleavage to result in acyclic systems or rearranged cyclic derivatives (Brabandt and Kimpe 2005; Alcaide et al. 2007; Dekeukeleire et al. 2009; Alcaide et al. 2011; 2012). The ring strain existing in the β-lactam ring inhibits the resonance happening in an ordinary amide and makes the molecule susceptible to nucleophilic attack in the carbonyl group (Lee and Robinson 1995). Therefore, the cleavage of the β-lactam bond (N4-C7) is very common, and many researchers have been exploring this fact to produce acyclic penicillin derivative compounds. Liu et al. carried out the opening of the β-lactam ring from the methyl ester penicillin V, providing the thiazolidine amides 22a–f (Scheme 3.50) with p-benzylamine, ansidine, thiophenemethylamine, methoxybenzylamine, cyclopropane methylamine, and nonylamine (Liu et al. 2015). The authors also promoted the rearrangement of the β-lactam ring from 6-APA, providing 8-hydroxypenillic acid derivatives with methyl, propyl, benzyl, diethylaminoethyl, and 2-(bromomethyl)benzo [d] thiazole side chains (compounds 24a–d and 25a, b, Scheme 3.51). According to the authors, the compounds were deposited in the NIH Small Molecule Repository. They were selected, and their biological results were deposited in PubChem (PubChem 2021). The biological activity can be found using the identification numbers of the compounds (CID), highlighting the following compounds: 22a—inhibits human tyrosyl-DNA phosphodiesterase 1 (TDP1); 22e—modulates the interaction between C-terminal C-end Rule (CendR) and neuropilin-1 (NRP-1); 22f—inhibits KCNQ2 potassium channels; 24b—enhances the survival of human-induced pluripotent stem cells and

Br

Br

Br

Br

Br

20c

20d

20e

20f

20g

Br

Br

Br

21a

21b

Br

Br

Br

Br

Br

Br

Br

Br

Y

1. 10% TFA in CH2Cl2, r.t., 30 min 2.CH2N2, Et2O.

Br

O

20b

O

Br

O

Z

1. AlCl3, CH2Cl2/NO2Me, 0 °C, 30 min; 2. CH2N2, Et2O OR

X

O

N

S

(O)n

Compound

O

Y

X H

20a

O

N

X H O S Y

Table 3.4 Solid-phase synthesis of penicillin derivatives

O

S

(O)n

O

20a-m, n = 0 21a-b, n = 2

N

X H

O

Y Z

0

0

0

0

0

2

2

0

0

N

S

S

S

S

S

Br

Cl

Br

Cl

Z

N N N N

N

S

N

S

N

O

N

O

Ph

Ph

OEt

(continued)

3 Lactams, Azetidines, Penicillins, and Cephalosporins … 129

Cl

Cl

Cl

Cl

Br

20i

20j

20k

20l

20m

Br

20h

Table 3.4 (continued)

H

H

H

H

H

Br

0

0

0

0

0

0

S

S

S

S

Cl

S

S

N

S

N

S

N

O

N

O

N

Ph

Ph

OEt

130 A. Beatriz et al.

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

131 OPh

H N

PhO O

H

S

O HN H

Primary amines

N

O CO2Me Penicillin V methyl ester

22a, R =

22b, R =

22d, R =

22e, R =

O

CH2Cl2, r.t., 12h 55%-65%

R

S

HN NH

CO2Me

22a-f

S

22c, R = OMe 22f, R =

OMe

Scheme 3.50 Ring-opening of β-lactams of penicillin V methyl ester H2N O

H

S

N 6-APA

CO2H

24a, R = Me 24d, R =

NaO2C

NaHCO3/H2O dry ice, r.t., 24 h lyophilization, 90%

24b, R = N

HN O

RI/Br

S N 23

DMF, r.t., 12 h CO2Na

Et

25b, R =

S

HN

N

CO2R O 24a-d RBr DMF, 45 oC 3h

24c, R =

Et 25a, R =

RO2C

S N

MeO2C R N

S N

CO2Me O 25a-b

Scheme 3.51 Synthesis of 8-hydroxypenillic acid esters from 6-APA

24c—can identify antagonists of the human trace amine-associated receptor 1 (TAAR1). Ashraf et al. adopted the concept of molecular hybridization and synthesized numerous penicillin derivatives by condensation of 6-aminopenicillanic acid (6APA) with nonsteroidal anti-inflammatory drugs as antimicrobial agents Ashraf et al. 2015). Molecular hybridization is a concept in drug design development based on combining a pharmacophoric moiety of many bioactive substances to provide a new hybrid compound with enhanced affinity and efficacy compared to the original drugs (Viegas-Junior et al. 2007). The derivatives of penicillin (26a–h) were synthesized via nucleophilic acyl substitution between the amino group of 6-aminopenicillanic acid and the appropriate acyl chlorides shown in Scheme 3.52. AINEs’ acyl chlorides were prepared in the first step, from their correspondent acids, that were then condensed with 6aminopenicillanic acid (6-APA) to provide the hybrid compounds 26a–h with yields ranging from 51 to 75%.

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A. Beatriz et al. H

H2N

S

N

O

6-APA

26a

S

N

O

26a-h

26b Ibuprofen

H

R

Acetone/2% aq NaHCO3 0 oC, 2-4 h. 51-75%

CO2H

H N

O

(Ar)RCOCl

CO2H

F

26c Flurbiprofen

Dexiibuprofen

O 26e

26d

OMe 26f

Naproxen

Ketoprofen

OMe

Cl 26g

HN

26h Cl Diclofenic

N O

H N

Cl Indomethacin

Mefanamic acid

Scheme 3.52 Synthesis of penicillin derivatives (26a–h)

According to the authors, compounds 26c and 26e displayed excellent antibacterial potential against Escherichia coli, Staphylococcus epidermidus, and Staphylococcus aureus compared to the standard amoxicillin. The most potent among them, the derivative 26e, showed the same activity as the standard amoxicillin against S. aureus. In the enzyme inhibition assay, compound 26e inhibited E. coli MurC with an IC50 value of 12.5 μM. Moreover, the higher antibacterial potential of compounds 26c and 26e was proved through molecular docking scores. These results confirm the importance of the side chain functional groups and the presence of a penam group. Using the strategy mentioned above, De Rosa et al. planned and synthesized a set of new penicillanic acid (6-APA) derivatives containing an additional β-lactam functionalized linked to the 6-APA amino group. Hence, hypothetically the presence of the other 2-azetidinone ring in the structure of 6-APA would increase the compound’s stability, as well as its biological activity (De Rosa et al. 2015). Scheme 3.53 shows the retrosynthetic analysis for target penicillanic acid derivatives. For example, synthesis of 27 could be implemented with a simple strategy, R

R

H N

N R1 R2

O 27a-d

O O

H

HN S

N 1

R

N CO2Na

OH

R2

O 28a-d

+

O

Scheme 3.53 Retrosynthetic analysis of the penicillanic acid derivatives 27a–d

O

H

S

N 6-APA

CO2H

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133

based on the coupling of the 6-APA nucleus with a functionalized 2-azetidinone ring (28) that could be built through [2+2] cycloaddition reaction of ketene with an imine. The carboxylic group in the structure of 28 would link this moiety to the nucleus 6-APA through an amide bond with the amino group in position 6 on 6-APA. This is a structural characteristic common to many natural and semi-synthetic penicillins (De Rosa et al. 2015). The authors prepared the 2-azetidinones 28a–d (Scheme 3.54) using Staudinger [2+2] cycloaddition reaction between appropriately substituted imines and ketene prepared in situ from methyl 3-(chloroformyl) propionate, followed by hydrolysis of the correspondent methyl ester. The necessary imines for the aimed cycloaddition were prepared with good yields (85–96%), through the condensation of the suitably substituted aldehydes and anilines, in ethanol under reflux. As anticipated, Staudinger’s reaction is one of the most widely used methods for preparing the preparation of the β-lactam nucleus because it gives direct access to functionalized 2azetidinones, enabling the adjustment of the stereochemical outcome of the reaction. In the experimental conditions shown in Scheme 3.54, the first step of the reaction, which consisted of [2+2] cycloaddition reaction, provided the trans-5-cycloadducts with moderate yields (45–60%). In the sequential step, the hydrolysis of the methyl ester with LiOH solution yielded the corresponding acids 28a–d in almost quantitative yields. This intermediate was then used directly for the coupling reaction with the 6-amino penicillanic nucleus (De Rosa et al. 2015). With the intermediates 28a–d in hands, the target compounds 27a–d were prepared as described in Scheme 3.55. The attempts of direct coupling between the acids 28a–d and 6-APA failed. Then it used the benzyloxy ester of (+)-6-APA, followed by hydrogenolysis in a mixture of THF and aqueous NaHCO3 to deprotect the benzyl ester, yet directly provide the target compounds 27a–d as sodium salts with high yields. The synthesized compounds had their antimicrobial activities screened in vitro against a panel of gram-positive and gram-negative pathogens and also environmental bacteria. All synthesized compounds were characterized by a strong antimicrobial activity against gram-positive bacteria, emphasizing compound 27a, which presented higher activity. Moreover, 27a was the only compound that displayed low activity R R2

O H R

R2 +

H2N

1

R

EtOH, reflux

N R

R1

O 1.

Cl

O OMe

n-But3N, toluene, reflux 2. LiOH, THF/H2O, r.t.

OH

N R1 R2

O 28a-d

O

28a, R = R1 = R1 28b, R = H, R1 = R2 = CH3 28c, R = R1 = H, R2 = OMe 28d, R = NO2, R1 = H, R2 = OMe

Scheme 3.54 General synthetic route to compounds 28a–d

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A. Beatriz et al. R R H

HN OH

N 1

R

R2

O 28a-d

O

+

S

1. DCC, DCM, rt

N

O

3

CO2R R3 = H, (+)-6-APA 3 R = Bz, (+)-6-APA benzyloxy ester

H N

N 1

R

2. H2, 10% Pd/C, NaHCO3/H2O/THF, rt

O

O

R2

O

27a-d

H

S

N CO2Na

a, R = R1 = R1 b, R = H, R1 = R2 = CH3 c, R = R1 = H, R2 = OMe d, R = NO2, R1 = H, R2 = OMe

Scheme 3.55 Synthesis of compounds 27a–d

against gram-negative bacteria, supporting its better antibacterial capacity (De Rosa et al. 2015).

3.4 Cephalosporins As for penicillins, cephalosporins constitute a class of antibiotics belonging to the β-lactam group, having the 7-aminocephalosporanic acid (7-ACA) as its core. This substance is composed of two rings: a β-lactam ring and a dihydrothiazine ring. The cephalosporins on clinical use are semi-synthetic derivatives of 7-ACA, initially obtained from cephalosporin C, a natural antibiotic (Fig. 3.9), produced by the mold Acremonium chrysogenum. Cephalosporins P and N have been identified; however, only cephalosporin C showed activity against gram-positive and gramnegative bacteria, and it is stable in the presence of β-lactamase (Craig and Andes 2015). Nomenclatures such as cepham, cephem, oxacephem, and carbacephem are also used for the basic structural cores of cephalosporins. Cephem is the basic moiety without substituents of cephalosporins. The 7-ACA is an example of substituted H N

HO2C O

NH2

H N

O

1 H2N 7 6 S

S OAc

O

CO2H

O

N Cephem

S

2 3

4 3' CO2H

OAc

O

N

Cepham

7-ACA

Cephalosporin C S

N

O N O Oxacephem

O

N

Carbacephem

Fig. 3.9 Structural formulas for cephalosporin C, 7-aminocephalosporanic acid (7-ACA), and related moieties

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

135 O

NH2 H N O

H

NH2 H N

S

N

O

O CO2H

Cefalexina (1st generation)

N S H2N

N

O O

H

S

S

N

N CO2

Cefepime (4th generation)

N

O

H2N

N N

N O H N O O

N

S

S

H2N

Cl CO2H

N

H

H

S

N

OAc

CO2H Cefotaxima (3rd generation)

S

N

H N

O O

Cefaclor (2nd generation)

O H N

H

S

S S

N

CO2

Ceftaroline (5th generation)

N

H2N

N N

N OH H N O O

H

S N

N CO2

O

Ceftobiprole (5th generation)

Fig. 3.10 Some examples of 1st and 5th generation semi-synthetic cephalosporins

cephem. Oxacephem, in turn, defines the system of rings in which an atom of oxygen substitutes the atom of sulfur from a cephem ring. Carbacephem is the name of a system where a unit -CH2 substitutes the sulfur (Fig. 3.9) (Brown 1982). This class includes different drugs, usually classified into generations, according to the development order and spectra, as shown in Fig. 3.10. The spectra change is due to changes in the sidechains (N of C-7 and C-3 ) of the basic cephalosporin moiety. First-generation cephalosporins show activity predominantly against gram-positive coccus: Streptococcus and Staphylococcus. The activity and power against a diversity of gram-negative microorganisms, such as Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, increases as generations evolve. However, no class antibiotics show activity against Chlamydia, Legionella (intracellular bacteria), and Mycoplasma (bacteria that lack a cell wall). In addition, 5th generation cephalosporins also lack a spectrum for bacteria of the genus Enterococcus—except Ceftaroline and Ceftobiprole (Fig. 3.10) (Brown 1982). The first total synthesis of cephalosporin C was reported by Woodward et al. in 1966 from L-(+)-cysteine, which has half of its structure as a carbon skeleton and one of the chiral centers of the target molecule (Woodward et al. 1966). L-(+)-cystine was converted into compound 28 in 3 steps. The thiol and amine groups were protected with acetone, followed by treatment with pyridine and t-butyloxycarbonyl chloride, resulting in the correspondent L-(-)-N-t-butyloxycarbonyl-2,2-dimethylthiazolidine4-carboxylic acid, which was converted in the ester 28 by treatment with diazomethane. Next, dimethyl azodicarboxylate was used to undergo an α-oxidation in 28 trans-selective towards the methyl ester. After converting the new hydroxyl group from 30 to an amine (31) in a few steps, the β-lactam 32 was formed by treating the aminoester with triisobutylaluminum. The lactam 32 was then functionalized with a Michael acceptor, resulting in the compound 33 that, after an acid-assisted deprotection, the structure of the cephem nucleus (34) was obtained. Steglich’s esterification of 34 with 35 leads to compound 36 that afforded the cephalosporin C after three more steps (Scheme 3.56). Natural cephalosporins and penicillins were modified to afford semi-synthetic cephalosporins and penicillins, respectively, with enhanced antibacterial activity and resistance to β-lactamases (Gaurav et al. 2007). The 7-aminocephalosporanic acid

136

A. Beatriz et al. O

HS

OH

2. But OCOCl Py 3. CH2N2

NH2 L-(+)-Cysteine

O

H

H2N

NHTroc

S

O

O

TFA

CHO

O 34

O

OHC H

CCl3

O

H N NHTroc

O O 36

H

S

N O

CHO O

CHO

H NBoc

O

HN H S

80 oC

CO2Me NBoc 30 1. MsCl, DIPEA 2. NaN3 3. Al-Hg, MeOH CO2Me

H2N

H NBoc

i-Bu3Al

S

NBoc 31

32

33

DCC,pyr Steglich esterif ication

O

CHO

O

N S

O

O

O

OHC

N

O CCl3

Cl3C

28

Cl3C

+

35

NBoc

S

CO2Me CO2Me HO N HN CO2Me 1. Pb(OAc)4 N MeO2C N 2. NaOAc, MeOH S MeO2C NBoc S 29 CCl3

HO

O

CO2Me

1. Acetone

1. BH3 2. AC2O, pyr 3. Zn, AcOH

CCl3

O

H N

HO NH2

O

O

Cephalosporin C

H

S OAc

N O

OH

Scheme 3.56 Total synthesis of cephalosporin C

(7-ACA) is the key intermediate for the production of semi-synthetic cephalosporins (Gaurav et al. 2007; Zhang and Xu 1993). The chemical method to obtain 7-ACA incorporates several costly steps. First, it demands complicated techniques to undertake the hydrolysis of the most stable amine (in position 7 ) and keep the β-lactam ring untouched. Classical hydrolysis using strong bases would lead to cleavage of the β-lactam, which is necessary for the antimicrobial activity of cephalosporins. Initially, the hydrolysis could be done using acid because the cephem moiety is stable. However, this procedure leads to meagre yields (Gröger et al. 2017). Morin et al. used nitrous acid to obtain an iminolactone (37) from the acyclic amide, which is readily hydrolyzed, but with only 40% yield (Scheme 3.57a) (Morin et al. 1969). Another intramolecular path (Fechting et al. 1968) is the aminolysis between the acyclic amine and the amino group from the sidechain (38), which resulted in a 50% yield for the correspondent benzyl ester of 7-ACA, compound 39 (Scheme 3.57b). Scheme 3.58 shows the strategy considered the most efficient one for cleavage of cephalosporin C’s side chain. It is a conversion of the cyclic amide to an imidoyl chloride. This functional group was then converted to the imido ester 40, followed by its subsequence hydrolytic cleavage with sequential formation of the desired 7-ACA (Gröger et al. 2017). Although the classical method for the synthesis of 7-ACA, shown in Scheme 3.58, is an elegant solution, this method also reveals a series of disadvantages when applied to a bigger scale for the commercial production of 7-ACA, such as several high-cost steps, time-consuming, complicated techniques, and environmental problems. Therefore, most of the 7-ACA currently produced are obtained through enzymatic deacylation of CPC to overcome these deficiencies. Cephalosporin C is directly converted

3 Lactams, Azetidines, Penicillins, and Cephalosporins …

137

a) H N

HO2C O

NH2

H

S

N

O

OAc

OAc

CO2R 7-ACA, R = H 7-ACA benzyl ester, R = Bn (39)

CO2H

O NH

OH

NH H NH2 O 38

S

N

O

OAc

Iminolactone (37)

OH

HO2C

H

H2O

N

O

CO2H

Cefalosporin C b)

O2C

H2N

NH H S

O

OH NH H

S

N

HO2C

OAc

RO2C

NH2 O

S

N

RO2C

CO2H NH2 H

HO2C OAc

NH

S

N

O

RO2C

OAc

Scheme 3.57 Preparation of 7-ACA. a Formation of iminolactone with nitrous acid. b Intramolecular aminolysis of the adjacent amide H N

HO2C NH2

O

O

H

S

N

Cephalosporin C

OAc CO2H

1. TMSCl, DMA CH2Cl2, r.t. 2. PCl5, CH2Cl2, 2.5 h, -55 oC 3. n-BuOH, 2.5 h

N

TMSO2C NHTMS

OR O

H

S

N

MeOH/H2O

7-ACA

OAc CO2TMS

40, R = n-Bu

Scheme 3.58 Classical method for the chemical synthesis of 7-ACA

into 7-ACA by the enzyme cephalosporin C acylase. Furthermore, it was verified that the enzyme could catalyze the acylation of 7-ACA with the corresponding organic acid (Gröger et al. 2017). Thus, there are innumerable advantages to producing 7ACA from the CPC using an enzymatic process compared to chemical synthesis. These include (1) safety (avoiding the use of chemicals such as trimethylsilyl chloride, phosphorus pentachloride, dichloromethane, dimethylaniline); (2) selectivity; (3) lower energy consumption; (4) economy (use of simpler and cheaper equipment) and (5) quality (Pollegioni et al. 2013). β-lactamic products are relatively more unstable due to the ring strain that inhibits resonance in the peptide bond, making the molecule too susceptible to nucleophilic attack on the carbonyl. Hence, reactions must be carried out, preferably, in organic solvents and tolerable temperatures (up to 60 °C). If aqueous systems are used, the processes are confined to a narrow range of pH because extreme pH values cause fast decomposition of the cephem moiety. Besides, β-lactam compounds, most of the time, are amorphous and can be purified only by chromatography, which is a problem since this technique hardly ever reaches the high purity (≥98%) necessary to an API. This problem can usually be solved by recrystallization; however, discovering a crystalline form requires luck and hard work. Success can come in weeks or even in years (Lee and Robinson 1995). Much effort was devoted by researchers towards the chemical transformation of 7-ACA into new cephalosporins. The amine group’s structural modifications are usually made in C-7 and C-3 , keeping the cephem’s moiety untouched. One of

138

A. Beatriz et al.

these researches, conducted by scientists from Shionogi & Co., Ltd, Japan, led to discovering a new siderophore cephalosporin, the cefiderocol (Scheme 3.59). This compound can actively cross the external membrane of the cellular wall of gramnegative bacillus by linkage to the serum iron, using the iron transport system of the bacteria. The antibiotic entrance through the iron transportation system increases and accelerates the influx of cefiderocol into the periplasmic space, allowing the compound to exert its bactericidal activity by inhibiting the cell wall synthesis. This pharmacological property makes cefiderocol active against many clinically relevant MDR gram-negative bacteria, as evidenced by several in vitro and in vivo studies. FDA approved Cefiderocol in the USA, on November 14, 2019, for the treatment of complex infections in the urinary tract. On September 28, 2020, cefiderocol was approved to treat bacterial pneumonia acquired in hospitals and bacterial pneumonia associated with mechanical ventilation (Parsels et al. 2021). Scheme 3.59 shows the synthesis of cefiderocol. It summarizes the synthesis of the cephalosporin moiety (25a–d, 26a–d, 27a, and 27b). First, compounds 41a and 41b were condensed with 42 in C-7 to obtain the corresponding intermediate, which was oxidized with m-CPBA to afford the sulfoxide intermediate 43a or 43b. Then, after the halogen exchange (chlorine for iodine, 43a or 43b), the quaternization between the resultant iodide and the sidechain C-3, followed by reduction of 1-sulfoxide, resulted in the quaternary ammonium salts that were treated with a Lewis acid, such as aluminium trichloride in the presence of anisole, to afford cefiderocol (Aoki et al. 2018). Boc NH H2N O

H

S

N Cl

N

+

CO2R 41a, R= PMB 41b, R = BH

N

N O

HO2C

Boc NH

1.C6H5OP(O)Cl2 NMM, CH2Cl2 -40 oC

S

OH O

S

N N O

2. m-CPBA, CH2Cl2 -40 oC

HO2C

42

H N O O

H

O

CO2R

44

1. NaI, DMA, 10 oC 2. 44, DMA, 10 oC 3. AcCl, KI, DMF, 0 oC 4. ACl3/CH2NO2, anisole, CH2Cl2, -30 oC

H2N

Cl OPMB

S

N

OPMB

N O HO2C

Cl

N

43a, R = PMB 43b, R = BH

N H

O S

H N O O

H

S N

N CO2

Cefiderocol

HN

O Cl OH OH

Scheme 3.59 Synthesis of the new siderophore cephalosporin cefiderocol

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Chapter 4

Synthesis and Biological Importance of Pyrazole, Pyrazoline, and Indazole as Antibacterial, Antifungal, Antitubercular, Anticancer, and Anti-inflammatory Agents Nisheeth Desai, Dharmpalsinh Jadeja, Harsh Mehta, Ashvinkumar Khasiya, Keyur Shah, and Unnat Pandit

4.1 Introduction Nitrogen-based heterocyclic chemistry is a prominent and fascinating class of medical chemistry applications. For many years, these scaffolds have been gaining popularity in the field of drug chemistry. They also improved a variety of natural combination standards and discovered useful applications in medicinal science. Numerous N-heterocyclic compounds are abundant in nature and have physiological and pharmacological qualities, as well as being constituents of various organically relevant atoms, such as numerous nutrients, nucleic acids, medicines, and antimicrobials. Furthermore, they are an important component of a number of pharmacologically active entities. Nitrogen-containing heterocyclic scaffolds, such as purines, pyrimidines, and others, are added to the basic sets of DNA and RNA (guanine, cytosine, adenine, and thymine). In the rapidly expanding disciplines of natural and therapeutic research, as well as medicinal chemistry, these nitrogen-containing heterocyclic atoms with recognizable properties and uses have acquired remarkable quality. Furthermore, the electron-rich nitrogen heterocycle can effectively build up weak interactions in addition to donating and accepting protons. Some of these intermolecular interactions, such as hydrogen holding arrangements, dipole–dipole cooperations, hydrophobic impacts, van der Waals powers, and stacking communications of nitrogen compounds, have increased their significance in the field of N. Desai (B) · D. Jadeja · H. Mehta · A. Khasiya · K. Shah Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364002, India U. Pandit Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_4

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therapeutic science and allow them to tie with a variety of chemicals and receptors in organic focuses with high efficacy due to their improved binding properties. Their derivatives’ underlying highlights are valuable because they exhibited a wide spectrum of bioactivities. The structural significance of nitrogen-based heterocycles in medication design and biological importance in prescription medications were revealed by a quick search of FDA databases. Due to the flexibility of the element of atom to easily tie up with biological targets, N-heterocyclic skeletons have a wide range of therapeutic uses as building blocks for a number of new drug candidates. Pyrazine, pyrazoline, and indazole derivatives, for example, offer a wide range of therapeutic applications in medicinal chemistry. Antineoplastic, anti-HIV, anti-malaria, antitubercular, antimicrobial, and diabetic properties were found in a variety of nitrogen-containing heterocyclic entities. The nearly 97,400 papers on heterocycles that emerged between 2009 and 2020 demonstrate their importance in the strategy of heterocycles. As seen by the list of nitrogencontaining therapeutic medications (Kachaeva et al. 2019; Akhtar et al. 2017; Grover et al. 2020; Gliši´c et al. 2016; Kerru et al. 2020; Ansari et al. 2017; Pałasz and Cie˙z 2015; Ahmed et al. 2019; Shaabani et al. 2019; Reddy et al. 2020; Khan et al. 2019; Turkan et al. 2019; Raut et al. 2020; Zhang et al. 2018; Murugavel et al. 2020) the utility of N-heterocyclic compounds is a burning focus in medicinal chemistry and drug discovery. The three aspirants of N-containing scaffolds pyrazole, pyrazoline, and indazole, as well as their synthesis pathways and biological importance, were reviewed in this chapter (Fig. 4.1).

4.2 Pyrazole Pyrazole is a chemical compound with the formula C3 H4 N2 . It is a heterocyclic molecule with a five-member ring structure. Figure 4.2 depicts pyrazole structures in various forms. Due to its involvement in the core structures of well-known medications such as celecoxib 4 and stanozolol 5, the pyrazole moiety has played a significant role in medicinal chemistry (Fig. 4.3).

4.2.1 General Preparations of Pyrazole From α, β-unsaturated aldehydes α, β-unsaturated aldehydes reacted with hydrazine to form pyrazole (Scheme 4.1). Knorr pyrazole synthesis 1,3-dicarbonyl compound reacted with hydrazine to produce pyrazole (Scheme 4.2).

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline … Cl

H N N NH

Cl N

R

H N

O S

O

NH N

N N

O O N

N

NH2 O

N N H

H

N NH

N+ N

S

NH2

HO

H2N

Cefoselis

N-atom containing active pharmacophoric scaffolds

O

O-

N

Attached to -N atom heterocyclic ring

Het

HO

O

H N

NH N

NH

Crizotinib

S

Sulfaphenazole

HO

N

O

Substituted phenyl ring

H2N

OH HO

2N

Substituted phenyl ring that increase biological activity with electron-withdrawing and elctron-donating groups

Axitinib

N N

O

F

S

O

145

Cl N

Biologically active heterocyclic moiety for better activity of drugs

Pyrazofurin

N Cl

O

Lonodamine

OH

Fig. 4.1 Pyrazole, pyrazoline, and indazole motifs are present in commercially available drugs (Akhtar et al. 2017; Ansari et al. 2017; Cefoselis- Cheng et al. 2020; Lonodamine- Meijer et al. 2018; Sulfaphenazole- Shah and Verma 2018)

N H (1)

N

N (2)

N

N

N

(3)

Fig. 4.2 Structures of pyrazole O S F F

N

NH2

HO

O H

N

F

HN

H N

(4)

H (5)

Fig. 4.3 Pyrazole containing commercially drugs, celecoxib 4 and stanozolol 5

H

146

N. Desai et al. O

NH N

NH2NH2

(6)

(7)

Scheme 4.1 Synthetic pathway of pyrazole (Schmidt and Dreger 2011)

O

O

O NH2NH2

N N H (10)

N NH2 (8)

(9)

Scheme 4.2 Knorr synthesis of pyrazole (Wiley and Hexner 1951)

4.2.2 Synthesis and Antimicrobial Activity of Some Pyrazole Derivatives In 2020, Desai et al. (2020a; b) synthesized hybrid molecules of pyrazole bearing benzodiazepine moiety. Glacial acetic acid and phenylhydrazine 12 were added to a solution of acetophenone 11 in ethanol and warmed for 1 h to get compound 13. Compound 13 then reacted with Vilsmeier-Haack reagent to furnish compound 14. Compound 14 reacted with substituted acetophenone 15 to form chalcone 16 and chalcone 16 further reacted with benzene-1,2-diamine to furnish pyrazole bearing benzodiazepine derivatives 17 (Scheme 4.3 and 4.4). They tested their antimicrobial activity in terms of MIC values against a variety of bacterial and fungal species. Ciprofloxacin was used as a control for antibacterial activity, whereas K. nystatin was used as a control for antifungal activity (Fig. 4.4). Desai et al. (2021) developed hybrid compounds with pyrazole and oxazole moiety for testing their antibacterial efficacy against a variety of bacterial and fungus species. Using 4-fluoroacetophenone 23 as a reactant, compound 22 was synthesized according to Scheme 4.3. The oxazole moiety was produced by cyclizing compound 24 with hydroxylamine hydrochloride at 120 °C for 15 h, yielding pyrazole bearing oxazole molecules 25 (Scheme 4.5 and Fig. 4.5). O NHNH2 O

(11)

EtOH Gla. AcOH

+

(12)

N

H N

H DMF, POCl3 70-80°C Reflux, 5 h

(13)

Scheme 4.3 Synthetic pathway of basic core as 1H-pyrazole-3-carbaldehyde

N

N

(14)

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

147

R O

N

N

H2N

O

H

H N

NH2

O

N

MeOH, KOH Stirring RT, 4 h

+ R

N

Piperidine Acetic acid DMF Ref lux, 8-10 h

N

(15)

(14)

R

(16)

N

N

(17)

Where R= Dif f erent substituents

Scheme 4.4 Synthetic pathway of pyrazole clubbed benzodiazepine derivatives Br NO2

H N

H N

Electron-withdrawing groups responsible f or better antibacterial activity

N N

N

N N

(18)

N (19)

MIC values E. coli. - 12.5 μ /mL P. aeruginosa - 12.5 μg/mL

MIC value S. aureus - 12.5 μg/mL O

Electron-donating group responsible f or better antif ungal activity

N N N

H N

NH N

O N (20)

N

(21)

MIC value A. niger - 12.5 μg/mL

MIC value C. albicans - 12.5 μg/mL

Fig. 4.4 Most active molecules of pyrazole clubbed benzodiazepine derivatives F

R F H

N N

R

F

O

O

N

O

+

R (23)

MeOH, KOH Stirring RT, 4 h

N

NH2OH•HCl N

EtOH, NaOH Ref lux, 15 h

N

O

N

(22) (24)

(25)

Where R = Dif f erent substituents

Scheme 4.5 Synthetic pathway of pyrazole bearing oxazole derivatives

148

N. Desai et al. N

O

NO2

Cl O N Cl

N

N

N N F (26)

MIC value S. pyogenes - 12.5 μg/mL

Electron-withdrawing groups increase antibacterial activity

F

(27)

MIC value S. aureus - 25 μg/mL

Fig. 4.5 Potent molecules of pyrazole clubbed oxazole derivatives O

O S N

R

N N

(28)

(29)

S

H N

N N

Ref lux, 4–6 h

H

O

S H2N

EtOH, AcOH

O

N

N

N S

O

O N H

NH2 +

Br

R (30)

(31)

Where R = Dif f erent substituents

Scheme 4.6 One-pot synthesis of pyrazole clubbed coumarin and benzothiazole hybrids

In 2018, Gondru et al. (2018) synthesized pyrazole-thiazole hybrids and evaluated their antimicrobial activity. Aldehyde of pyrazole bearing coumarin and benzothiazole moiety 28 reacted with thiosemicarbazide 29 and various α-bromoketones 30 to furnish hybrid compounds 31. Aldehyde was prepared by Vilsmeier-Haack reaction of acetyl coumarin and benzothiazole hydrazide (Scheme 4.6 and Fig. 4.6).

4.2.3 Preparation and Antitubercular Activity of Some Pyrazole Hybrids Shingare et al. (2018) produced pyrazole clubbed oxadiazole hybrid compounds in four steps and tested antibacterial and antitubercular properties. Compound 35 was treated with 4-sulfonamido phenylhydrazine hydrochloride in ethanol to yield pyrazole ester 36. The ester interacted with the hydrazine hydrate to produce acid hydrazide 37, which was then cyclized by carbon disulfide to produce pyrazoleoxadiazole hybrid molecules 38–39 (Scheme 4.7 and Fig. 4.7). In 2015, Nayak et al. (2015) have introduced pyrazole pyridine hybrid molecules. Antitubercular and antibacterial activities were performed on hybrid molecules. Acetophenone 42 reacted with semicarbazide hydrochloride to give compound 43, which further reacted with Vilsmeier-Haack reagent to form pyrazole aldehyde 44. Pyrazole aldehyde reacted with isonicotinohydrazide, to form imine 45. Imine on

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

N

N

N

H N

CH3

N S

Electron-donating group most f avarable f or good antibacterial activity

N

S

O

149

(32)

O

MIC value B. subtilis - 1.9 μg/mL M . luteus - 3.9 μg/mL K. planticola - 3.9 μg/mL P. aeruginosa - 3.9 μg/mL N N

N N

S

O

H N

Br

O

N

Electron-withdrawing group showed good antif ungal activity

S

O

O

MIC value B. subtilis - 3.9 μg/mL C. albicans MTCC 227- 3.9 μg/mL

(33)

Fig. 4.6 Lead molecules of pyrazole clubbed thiazole derivatives H2NO2S

SO2NH2

OEt O

O

O

· HCl

HO

Diethyl oxalate F

NHNH2

NaH, Toluene

O

EtOH

F

(36)

(35)

NH2NH2 · H2O EtOH

SO2NH2

SO2NH2

O

O

CO2Et

F

O

(34)

N N

O

SO2NH2

F

F

N

N N

R-X

N

TEA, EtOH O

N N (39)

S R

N N

O SH

CS2, KOH, EtOH Dil. HCl

O

N

F

N

CONHNH2 (37)

(38)

Where R = Dif f erent substituents

Scheme 4.7 Multicomponent synthesis of pyrazole clubbed oxadiazole derivatives

150

N. Desai et al. O S NH 2 O S

O NH 2 S O

N N

O

S F

N N

F

N N

O

(40)

N N

O

O

(41)

MIC value M . tuberculosis H 37R - 50 μ g/ mL

MIC value M . tuberculosis H 37R - 62.5 μg/ mL

Aliphatic alkyl substituent responsible f or better antimycobacterial potential and antibacterial activity

Fig. 4.7 Active molecules of pyrazole clubbed oxadiazole derivatives

reaction with substituted benzoic acids furnished compound 46 (Scheme 4.8 and Fig. 4.8). Jadhav et al. (2018) have synthesized pyrazole hybrids and evaluated antitubercular activity. Substituted acetophenones and phenylhydrazine reacted to produce corresponding imines, which underwent cyclization to produced compound 49 by Vilsmeier-Haack reaction. Compound 49 further on reaction with compounds 50 and 51 yielded final compounds 52 (Scheme 4.9 and Fig. 4.9).

O

O

H2N

N H

N

• HCl NH2

Sodium acetate 80°C, 8 h

R1

R1

O

(42)

N H

NH2

H

POCl3

O N

DMF 80°C, 2 h

R1 (43)

(44) O N H

N O

OH

NH2

O

O N

N

R2

N NH

N N O N H

(46)

EtOH Cat. H2SO4 80°C 4h

R1

R1

N

N H

EDC, HOBt, DMAP Dichloromethane RT, 16 h

N

R2

Where R1, R2 = Dif f erent substituents

Scheme 4.8 Synthetic pathway of pyrazole clubbed pyridine derivatives

N H

(45)

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

151

MIC value M . tuberculosis H 37R - 0.8 μg/mL MIC value M . tuberculosis H 37R - 1.6 μg/mL O

O N

Cl

N

Cl

N N

N N

O

O N

N H

N

Cl

N H Cl

(47)

(48)

Electron-withdrawing groups enhance the antitubercular and antibacterial activity

Fig. 4.8 Most active antitubercular agents of pyrazole clubbed pyridine derivatives R4

F F F O

N

R5 R4

N

O

NaOEt, EtOH

N O

R1 H

+

O N

N

R2

or

O

(51)

N N

S

R1

S

(50)

(49)

N

N S

R3

N N

Ref lux, RT, 12–14 h

R2

R3 (52)

Where R1, R2, R3, R4 = Dif f erent substituents R5 = -CN, -OCF3

Scheme 4.9 Synthetic pathway of pyrazole bearing thiazole and pyrimidine moiety

N N

Electron-donating group responsible f or good antitubercular activity

CH3 N

N N

S N

S

N

N

O N

H3C

O

(53) 2

MIC value M . smegmatis mc 155 - 9 μg/mL M . tuberculosis H 37R - 1.9 μg/mL

(54)

N

MIC value - M . smegmatis mc2 155 - 15 μg/mL

Fig. 4.9 Potent antitubercular agents of pyrazole clubbed thiazolo[3,2-a]pyrimidin-5-one derivatives

4.2.4 A Facile Synthesis of Some Novel Pyrazole Derivatives and Their Anticancer Activity In 2019, Chaudhary et al. (2020) have synthesized some hybrid molecules containing pyrazole and curcumin. The synthetic pathway was started with chalcone 57 formation of substituted benzaldehydes 55 and different acetophenones 56 in presence

152

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of base using ethanol as a solvent. The chalcone was then treated with hydrazine hydrate in presence of formic acid, which formed pyrazole moiety 58 having a free formyl group. Then the pyrazole carbaldehydes 58 were refluxed with curcumin using chloroform as a solvent. By Knoevenagel condensation reaction between pyrazole carbaldehydes and active methylene group of curcumin yielded the hybrid of pyrazole and curcumin 59 (Scheme 4.10 and Fig. 4.10). R

R H

O

O

O

NaOH EtOH

+ R

NH2NH2

O

H

N N

HCOOH

R1 R1

(56)

(55)

R1

(57) (58) O

O O

O

CHCl3

OH

HO

Ref lux

Curcumin O

O O

O N N

HO

R1

(59)

OH

R

Where R, R1 = Dif f erent substituents

Scheme 4.10 Multicomponent reaction of pyrazole clubbed curcumin derivatives

O

O

O O

O HO

N N

OH

O O

O HO

N N Br

Cl

OH

HO (60)

IC50 value - 14.2 g/mL

Electron-withdrawing groups (chloro and bromo) responsible f or anticancer activity

OH

(61)

IC50 value - 18.6 g/mL

Fig. 4.10 Lead molecules of pyrazole clubbed curcumin derivatives

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

153

In 2020, Wang et al. (2020) have synthesized some pyrazole hybrids containing pyrazole and methoxy naphthalene via multicomponent reaction. Initially, deoxybenzoins 64 were synthesized by the condensation reaction of substituted phenylacetic acids 63 and 1-methoxynaphthalene 62 in presence of trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) as a catalyst. The deoxybenzoins were then treated with N, N-dimethylformamide, and dimethylacetal (DMF-DMA) at 80 °C for 24 h which was then resulted in enamine 65 formation. The enamines were further treated with hydrazine hydrate to form pyrazole moiety 6 using IPA as a solvent at room temperature which resulted in the synthetic hybrids of pyrazole and methoxy naphthalene (Scheme 4.11 and Fig. 4.11). In 2020, Kuthyala et al. (2020) have synthesized some pyrazole-based hybrid heteroatomics to evaluate their anticancer activity via multicomponent reaction. The synthetic route started by the reaction of acetylacetone 68 with DMF-DMA and phenylhydrazine which resulted in acylated pyrazole 69 through Michael addition reaction. Acylated pyrazole 69 was then reacted with semicarbazides in presence of sodium acetate using ethanol as a solvent, which formed pyrazole-semicarbazides 70. The compound was reacted with POCl3 in the presence of DMF solvent, yielding substituted pyrazole carbaldehydes 71 via the Vilsmeier-Haack reaction. The aldehyde group of the substituted pyrazole carbaldehydes 71 was subsequently transformed into a dihydropyrimidine 72 by the Biginelli reaction, which was carried out in the presence of ammonium acetate using ethyl acetoacetate/methyl acetoacetate/acetylacetone. Instead of cyclizing into dihydropyrimidine ring, substituted O

O

O O

OH +

O (62)

R

TFAA, TFA

O NH2NH2•HCl

DMF, DMA 80 °C, 24 h

RT, 12 h

(63)

O

Isopropanol RT - 40°C, 1 h

N

R

R

NH N

R (64)

(65)

(66)

Where R = Dif f erent substituents

Scheme 4.11 Synthetic pathway of pyrazole clubbed methoxy naphthalene derivatives

HN

N

Electron-donating group at 4th position at phenyl ring enhanced the anticancer activity O

O (67)

IC50 value - 2.78 ± 0.24 μM

Fig. 4.11 Biologically active molecules of pyrazole clubbed naphthalene

154

N. Desai et al. O

O O O O

H2N

HN H2N

N

N

N H

NH2

H2N

(68)

H

DMF, POCl3

Sodium acetate EtOH, Water Ref lux, 5 h

DMF, DMA Ref lux, 4 h

O

HN N

NH N

N N

(69)

N

Ref lux, 7 h

N

(70)

(71)

Ethyl acetoacetate Methyl acetoacetate Acetylacetone Ammonium acetate EtOH Ref lux, 6 h

H N N

H N N

R

N N

R

N N H

(72)

Where R = Dif f erent substituents

Benzil Ammoniumacetate AcOH Ref lux, 6 h

N

HN

(73)

C6H5

N C6H5

Scheme 4.12 Synthetic pathway of some pyrazole-based hybrid heteroatomics

HN N N N O

Electron-withdrawing group responsible f or good anticancer actvity

O

N O

O

(74)

IC50 value A549 cell lines - 42.79 M

Fig. 4.12 Most active motif of pyrazole clubbed 1,4-dihydropyridine derivatives

pyrazole carbaldehydes 71 may be cyclized into imidazole ring 73 by reacting it with benzil, ammonium acetate, and acetic acid (Scheme 4.12 and Fig. 4.12).

4.2.5 Synthetic Route for the Preparation of Heterocyclic Motifs Appended as Anti-Inflammatory Pyrazole Analogs In 2017, Prabhudeva et al. (2017) have synthesized novel thiophene appended pyrazole analogs to access anti-inflammatory activity. The synthetic procedure has initiated from chalcone formation 77 by the reaction of 5-chloro-2-acetylthiophene 75 with aromatic aldehydes 76 under basic conditions. Then after the cyclocondensation reaction was applied to chalcone 77 to form different pyrazole hybrids 78 using

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

155

phenylhydrazine hydrochlorides in citrus extract medium in the presence of tetrabutylammonium bromide (TBAB) as phase transfer catalyst (PTC). Pyrazole hybrids were formed in good yields (Scheme 4.13 and Fig. 4.13). In 2017, Abdelgawad et al. (2017) have synthesized pyrazole hybrids via multicomponent reaction. Initially, diazotization reaction was performed by different aromatic amines. Diazonium salts of the aromatic amines 81 were treated with malononitrile in the presence of sodium acetate to form hydrazonomalononitriles 82. The resulting hydrazonomalononitriles were treated with substituted phenylhydrazine derivatives using ethanol as a solvent under reflux conditions, which resulted in different pyrazole hybrids 83 (Scheme 4.14 and Fig. 4.14). In 2020, Sivaramakarthikeyan et al. (2020) have synthesized some molecular hybrids integrated with benzimidazole and pyrazole to access anticancer activity. Cl NHNH2•HCl H

O S

O

MeOH, KOH

S

N N

Citrous extract TBAB Ref lux, 5-6 h

+

R

(75)

Cl

R1

RT, 3-4 h Cl

R

S

O

R

(76)

R1 (78)

(77)

Where R, R1 = Dif f erent substituents

Scheme 4.13 Synthetic pathway of thiophene appended pyrazole analogs

Cl

Cl

Electron-withdrawing group responsible for anti-inflammatory activty

S N

N

N N

Cl

S

Cl

Cl

(79)

(80)

IC50 value sPlA2 - 10.2 μM

IC50 value sPlA2 - 11.0 μ M

Fig. 4.13 Most active hybrids of pyrazole clubbed thiophene scaffolds

NHNH2 HCl NH2

R (81)

(i) NaNO2 Con. HCl, 0°C (ii) CH3COONa CH2(CN)2

R

R1 N H

N

CN CN

(82)

EtOH Ref lux, 12 h

R N H

N HN

NH2 N N

(83)

Where R, R1 = Dif f erent substituents

Scheme 4.14 Synthetic pathway of pyrazole derivatives

R1

156

N. Desai et al. NH2 N N

N HN

NH

H2NO2S

CH3

(84)

IC50 value - 0.67 M (COX-2) and 1.92 M (5-LOX) inhibition of carrageenan-induced paw edema - 9.6 NH2 N N

N NH

H2NO2S

Electron-donating group responsible f or 5-LOX inhibition and Electron-withdrawing group responsible f or COX-2 inhibition

HN

Cl

(85)

IC50 value - 0.58 M (COX-2) and 2.31 M (5-LOX) inhibition of carrageenan-induced paw edema - 12.8

Fig. 4.14 Higher potency of pyrazole-hydrazone derivatives R1 R1

O

R2

NH

N

R2

MeOH R3

N N

R3

N H

N

N

N N H (86)

C N

(87)

C N

(88)

Where R1, R2, R3 = Dif f erent substituents Scheme 4.15 Synthetic pathway of pyrazole bearing benzimidazole hybrids

In this multicomponent reaction, Schiff bases of phenylhydrazine and substituted aralkyl ketones were formed by using AcOH as a catalyst. Vilsmeier-Haack reaction of these Schiff bases (POCl3 -DMF) turned into the cyclization of pyrazole carbaldehyde. When pyrazole carbaldehydes 86 reacted with benzimidazolyl acetonitrile 87 in basic media by using piperidine as a catalyst, it formed benzimidazole-tethered pyrazoles 88 (Scheme 4.15 and Fig. 4.15).

4.2.6 Miscellaneous Kenchappa and Bodke (2020) in 2020 have synthesized benzofuran-pyrazole hybrids and evaluated their analgesic activity. To a stirred solution of phenylhydrazine hydrochloride 91 and sodium acetate, 1-(benzofuran-2-yl)ethenone 90 was added and

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

Electron-withdrawing group responsible f or better anti-inf lammatory activity

NO2

N

157

HN NC N

N

% inhibation value - 93.53 % (89) Fig. 4.15 Lead molecules of pyrazole clubbed benzimidazole derivatives

stirred for 2 h at room temperature to yield Schiff base 92. Schiff base 93 then reacted with Vilsmeier-Haack reagent which formed pyrazole derivatives 94. Compound 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one reacted with pyrazole derivatives 94 to furnish final compound 95 (Scheme 4.16 and Fig. 4.16). Novel antioxidant agents of pyrazole derivatives were synthesized by Viveka et al. (2015a; b) in 2015. 4-formylpyrazoles 97 were synthesized by Vilsmeier-Haack from corresponding hydrazones. 4-formylpyrazoles 97 were converted into corresponding dihydropyrimidinone derivatives 98, 1,4-dihydropyridine 99, and 2,4,5-trisubstituted R1

R1 O O

CH3COONa

+

O

EtOH

N N

H

DMF O

POCl3

R1

R

O

HN N

NHNH3 Cl

(93) R

(90)

(91)

R

O O

(92)

CH3OH NaOH

O O R O O

O N N

Where R, R1 = Dif f erent substituents

Scheme 4.16 Synthesis of novel benzofuran-pyrazole hybrids

(94) R1

158

N. Desai et al.

Br

Br

O2N O

O O

O

N

N

N

N O

O

Electron-withdrawing groups showed highest analgesic activity O

(95)

Cl

% of protection - 59.40

O

(96)

% of protection - 60.53

Fig. 4.16 Pyrazole clubbed furan hybrids as potent analgesic agents

imidazoles 100 by Biginelli reaction, classical Hantzsch condensation, and Debus reaction, respectively (Scheme 4.17 and Fig. 4.17). Liu et al. (2016) in 2016 have synthesized 3a,6a-dihydro-1H-pyrrolo[3,4c]pyrazole-4,6-dione 108 and carried out anti-HIV activity. Intermediate 1phenylethyl-pyrrole-2,5-diones 104 were synthesized by maleic anhydride 103 and corresponding phenylethylamines. Other intermediates 107 were obtained by the reaction between substituted aldehydes 105 and corresponding phenylhydrazines 106. Both the intermediates were reacted and furnished final compounds 3a,6aDihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione 108 (Scheme 4.18 and Fig. 4.18).

4.3 Pyrazoline Pyrazoline is an organic compound having molecular formula C3 H6 N2 . This heterocyclic chemical compound is five-member ring. It is partially unsaturated form of pyrazole moiety. Different structures of pyrazoline are shown in Fig. 4.19.

4.3.1 Multicomponent Reaction and Antimicrobial Activity of Some Pyrazoline Hybrids Desai et al. (2017) in 2017 synthesized pyrazole clubbed benzimidazole bioactive molecules to evaluate their antimicrobial activity. Ester 115 was synthesized by reacting α-napthol 114 with ethylchloro acetate in dry acetone. Ester was refluxed with hydrazine hydrate to form acid hydrazide 116 which on further cyclization with 1-(1H-benzo[d]imidazol-2-yl)-3-phenylprop-2-en-1-one furnished compound 117 (Scheme 4.19 and Fig. 4.20).

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

159 H N

O O H2N

HN

R

NH2

Ethylacetoacetate HCl in EtOH Ref lux, 6 h

O

R1

O

R N N

(98) R

R1

R

H N

O

R

O

R

N

NH

N

Ethylacetoacetate Ammonium acetate EtOH Ref lux, 8 h

N

O

R1

(99)

R

(97) R

Benzil Ammonium acetate AcOH Ref lux, 6-7 h

N NH N N (100)

Where R, R1 = Dif f erent substituents Scheme 4.17 Synthesis of various pyrazole analogs

O

O NH N H

N N

O Cl

Electron-withdrawing groups responsible f or good antioxidant activity

Cl (101)

% DPPH scavenging - 89.41 Fig. 4.17 Pyrazole hybrids as antioxidant agents

HN O F

N H

N N

F (102)

% DPPH scavenging - 83.34

160

N. Desai et al. O

O

Phenylethylamines

O

N

NaOAc, (Ac)2O Ref lux, 30 min

O

R1 O

(103)

(104) R

O R

H2N NH

O

N

AcOH

N O

+

R

EtOH, RT, 8 h

EtOH Ref lux, 12-20 h

R2

R2 (106)

(105)

N

N

H N R1

R2 (108)

(107)

Where R, R1, R2 = Dif f erent substituents

Scheme 4.18 Synthesis of 3a,6a-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione

F

CH3

Electron-withdrawing groups reponsible for good anti-HIV 1 activity

O N N HO

N

O N N

F

F

O (109)

O

(110)

EC50 value - 3.98 mM

O

EC50 value - 4.10 mM

N OH O

Fig. 4.18 Anti-HIV agents of pyrazole-pyrrole scaffolds

NH N H (111)

N

N

(112)

N

NH

(113)

Fig. 4.19 Structure of pyrazoline

In 2019, Desai et al. (2020a, b) synthesized pyrazoline hybrids for the evaluation of their antimicrobial activity. Compound 122 was synthesized according to Scheme 4.3 by taking p-chloroacetophenone. Compound 122 reacted with compound 123 to form chalcone 124 which further reacted with isoniazid to furnish pyrazoline hybrids 125 (Scheme 4.20 and Fig. 4.21). Desai et al. (2017) in 2016 worked on a hybrid approach to synthesize pyrazoline clubbed quinoline and pyridine hybrids and carried out their antimicrobial activity. To synthesize final compounds, they have taken quinoline aldehyde 131 and substituted acetophenone 132 which formed from chalcone derivatives 133. Chalcone derivatives 133 on cyclization with isoniazid yielded final compounds 134 (Scheme 4.21 and Fig. 4.22).

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

161

OH

OCH2COOC2H5

ClCH2COOC2H5 K2CO3 (115)

(114)

NH2NH2 EtOH H N

O H N

R

OCH2CONHNH2

N

O

N N

O

AcOH, Ref lux, 10 h

N (116)

R

(117)

Where R = Dif f erent substituents Scheme 4.19 Synthetic pathway of pyrazoline-bearing benzimidazole derivatives

NH

HN

Electron-withdrawing groups responsible f or the better antibacterial activity

N O

N N

N

O

Cl

O

O

N N

(119) (118)

O2N

MIC value E. coli - 50 g/mL P. aeruginosa - 50 g/mL S. pyogenes - 12.5 g/mL

MIC value E. coli - 25 g/mL P. aeruginosa - 12.5 g/mL S. aureus - 50 g/mL S. pyogenes - 25 g/mL

O H3C O

O

O

Electron-donating groups responsible f or the better antif ungal activity

N N

N N

N HN

O

N NH

(120)

MIC value A. clavatus - 25 g/mL A. niger - 50 g/mL

(121)

MIC value A. niger - 50 mg/mL

Fig. 4.20 Pyrazoline clubbed benzimidazole derivatives as antimicrobial agents

162

N. Desai et al. R

N

Cl Cl

CONHNH2

O

O

R

O H +

N N

N

MeOH, KOH Stirring RT, 4 h

R

N

O

N N

Gla. AcOH H2SO4 Ref lux, 28-30 h

N

N

N

Cl

(123)

(125)

(122)

Where R = Dif f erent substituents

(124)

Scheme 4.20 Synthetic pathway of pyrazoline clubbed pyrazole and pyridine moiety N N

N

O

Electron-withdrawing group responsible f or better antibacterial activity

Cl

N

Cl N

N

N

Cl

(127)

Cl

N

N

N

(128)

MIC value E. coli - 12.5 g/mL

O

O

N NO2

N

N

MIC value S. pyogenes - 12.5 g/mL N

Electron-donating gorup responsible f or better antif ungal activity

O N

N

O

N OH N

Cl

N (129)

N

(130)

MIC value C. albicans - 25 g/mL

MIC value C. albicans - 25 g/mL

Fig. 4.21 Higher biological activity of pyridine derivatives containing pyrazoline R Cl N

O

O

H + R

(131)

N CONHNH2

O

MeOH, KOH Stirring RT, 4 h

R N

N

Cl N

Gla. AcOH Ref lux, 15 h

Cl

(132)

N

O

N (134)

(133)

Where R = Dif f erent substituents

Scheme 4.21 Synthetic pathway of pyrazoline clubbed quinoline and pyridine motifs

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

163

Electron-withdrawing group inhibited bacterial and f ungal strians

Cl

F Cl

N

N N

Cl

O

N

N

N N

Cl

O

N

N N

N

O

N

(137)

(135)

MIC value A. clavatus - 12.5 g/mL

(136)

MIC value E. coli - 12.5 g/mL

Cl

MIC value P. aeruginosa - 12.5 g/mL

Fig. 4.22 Potent molecules of pyrazoline clubbed quinoline and pyridine derivatives

4.3.2 Synthesis and Antitubercular Activity of Some Novel Pyrazoline Derivatives In 2020, Pola et al. (2020) have synthesized a novel series of compounds having pyrazole and naphthalene and they have carried out in vitro antitubercular activity. Substituted napthaldehydes 138 reacted with substituted acetophenones 139 to yield chalcone derivatives 140 which on further cyclization with hydrazine hydrate produced pyrazoline hybrids 141 (Scheme 4.22 and Fig. 4.23). Karad et al. (2016) have proposed a synthetic rout to synthesized pyrazolinebearing morpholinoquinoline molecules. They have evaluated antitubercular activity. Morpholinoquinoline carbaldehyde 145 was prepared by the reaction of quinoline aldehyde 143 and morpholine 144. Morpholinoquinoline carbaldehyde 145 reacted with substituted acetophenones 146 to produce chalcone 147. Chalcones reacted with hydrazine hydrate to form pyrazoline derivatives 148. Compound 147 reacted with R1 O

R1 N

O O

H R

(138)

+ R1

NH

NH2NH2•HCl

MeOH, NaOH RT

EtOH R

(139)

R (140)

Scheme 4.22 Synthetic pathway of pyrazoline motif

(141)

Where R, R1 = Dif f erent substituents

164

N. Desai et al.

Electron-withdrawing group at 3rd position with respect to pyrazoline ring enhance antimycobacterial activity

HO

HN N

Br

(142)

MIC value M . tuberculosis H37 R - 6.25 M Fig. 4.23 Biologically active molecules of pyrazoline-bearing naphthalene derivatives

thiosemicarbazide, 4-fluorophenyl hydrazine hydrochlorides, and hydrazine hydrate to form compounds 149, 150, and 151, respectively (Scheme 4.23 and Fig. 4.24). O

O H N

H

DMF

+ N

Cl

K2CO3 Stirring, 90°C, 2 h.

O

(143)

O H

N

+

N O

(144)

R (146)

(145)

Stirring EtOH + NaOH O O N N

NH2NH2

R N

N O

(148)

N H

R

N O (147)

F

S H2N

N

AcOH MW 350 W, 12-15 min

NH2

N H

NaOH MW EtOH 350 W, 5-7 min

NH2

Cl

NH2NH2•H2O

MW 350 W, 15-18 min

EtOH AcOH

DMF MW 350 W, 6-8 min

F O

S H2N

H N N

N N

N

N

N

N

N O

O

O (149)

R

R

R N

N N

(150)

(151)

Where R = Dif f erent substituents

Scheme 4.23 Multicomponent synthesis of pyrazoline-bearing quinoline and morpholinoquinoline derivatives

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

165

F

Electron-withdrawing group responsible f or better antitubercular and Antimalerial activity

N N Br N

N O

(152)

MIC value M . tuberculosis H 37R - 47 M IC50 value - 0.015 M

Fig. 4.24 Potent molecule of pyrazoline clubbed quinoline motifs

In 2016, Harikrishna et al. (2016) have synthesized 1 -(4-chlorophenyl)pyrazole containing 3,5-disubstituted pyrazoline derivatives for the evaluation of antitubercular and antimicrobial activities. Compound 153 was synthesized according to Scheme 4.3 by taking p-chlorophenylhydrazine as starting material. Compound 153 reacted with 5-acetyl-2,3-dihydrobenzofuran, 5-acetyl-2-methylfuran, and monoacetyl biphenyl to produced compounds 154, 156, and 158, respectively. Further compounds 154, 156, and 158 reacted with hydrazine hydrate to furnish final compounds 155, 157, and 159, respectively (Scheme 4.24 and Fig. 4.25).

4.3.3 Conventional Synthetic Route and Anticancer Activity of Some Pyrazoline Hybrids In 2015, Karabacak et al. (2015) have synthesized pyrazoline-thiazole hybrids to access the anticancer activity of the synthesized hybrids via multicomponent reaction. The first step of the multicomponent reaction was chalcone formation by reacting 2-acetyl thiazole 162 and 4-chloro benzaldehyde under basic conditions at room temperature using ethanol as a solvent. The chalcone 163 was further treated with hydrazine hydrate under reflux conditions to form pyrazoline motif 164. The pyrazoline moiety 164 was then treated with chloroacetyl chloride in presence of triethylamine using toluene as a solvent at room temperature to form 1-(Chloroacetyl)-3-(2thienyl)-5-(4-chlorophenyl)-2-pyrazoline 165. The chloroacetyl pyrazoline hybrid was then reacted with different aryl thiols to synthesize the targeted molecule 1[(aryl)thioacetyl]-3-(2-thienyl)-5-(4-chlorophenyl)-2-pyrazolines 166 (Scheme 4.25 and Fig. 4.26). In 2018, Chen et al. (2018) have synthesized some nicotinoyl pyrazoline derivatives to evaluate anticancer activity. The Vilsmeier-Haack reaction of substituted indoles 168 resulted in the synthesis of indole carbaldehydes 169. The hydrogen of the indole’s –NH– group was replaced by a methyl group by CH3 I in the presence of NaH in THF as a solvent. The formyl group of the N-methyl indole 170

166

N. Desai et al. O

Cl

O

O

O

MeOH, NaOH rt, 4 h Cl

NH2NH2

N N

EtOH Reflux, 3 h

N N

Ar

Ar

(154)

(155)

O O

N

HN N

Cl

O

Cl

O

O

MeOH, NaOH rt, 4 h Cl O

N O

Ar

NH2NH2 EtOH Reflux, 3 h

N N (156)

N N Ar

Ar

O HN N (157)

H Cl

(153) O

NH2NH2 MeOH, NaOH rt, 4 h

N Cl

N

Ar

EtOH Reflux, 3 h

N N Ar

HN N (159)

(158)

Where Ar = Different substitution

Scheme 4.24 Synthesis of pyrazoline motifs by chalcone derivatives Cl

Cl

MIC value - M . tuberculosis - 6.25 g/mL N

N

(160)

HN N

N

Electron-donating group responsible f or better antitubercular activity

S

O (161)

MIC value - M . tuberculosis - 1.56 g/mL

Fig. 4.25 Most active molecules of pyrazoline clubbed pyrazole and thiophene motifs

N

NH N

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline … S

S O

(162)

S

S

O Cl

O

NH2NH2

H S

167

N HN

ClCOCH2Cl

EtOH Ref lux, 5 h

10% NaOH EtOH RT, 6-8 h Cl (163)

O

N N

O Ar-SH Acetone S RT, 8 h Ar

TEA, Toluene Cl RT, 1 h Cl (164)

Cl (165)

N N

Cl (166)

Where Ar = Dif f erent substituents

Scheme 4.25 Synthetic pathway of pyrazoline-thiophene hybrids

Fig. 4.26 Potent molecule of pyrazoline clubbed thiophene scaffold

was treated with substituted acetophenones to form various chalcones via ClaisenSchmidt condensation reaction under basic media. Chalcone 171 was then cyclized into pyrazoline moiety by reacting with hydrazine hydrate. Indole-pyrazoline hybrid was then reacted with substituted nicotinic and isonicotinic acids in presence of HOBt and EDC-HCl catalyst to form hybrid structure of three heterocyclic motifcontaining indole, pyrazoline, and pyridine. These hybrids 172 and 173 showed some promising results on anticancer activity (Scheme 4.26 and Fig. 4.27). In 2019, Kuthyala et al. (2019) have synthesized imidazopyridine containing pyrazoline derivatives to access their anticancer study. Substituted 2-amino pyridines 175 were reacted with 3-chloro-2, 4-pentadione using DCM as a solvent, which resulted in acetyl imidazopyridine 176. The acetyl group was then converted into chalcone 177 via Claisen-Schmidt condensation reaction with substituted benzaldehydes chalcone and then cyclized to form pyrazoline through hydrazine hydrate in presence of acetic/propionic/butyric acid as a catalyst. The hybrid molecule containing imidazopyridine and pyrazoline 178 was synthesized in good yields (Scheme 4.27 and Fig. 4.28).

168

Scheme 4.26 Synthetic pathway of pyrazoline clubbed indole derivatives

Fig. 4.27 Most active hybrids of pyrazoline-bearing indole moiety

Scheme 4.27 Synthetic pathway of imidazopyridine-pyrazoline hybrids

N. Desai et al.

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

169

CH3 N

N

H3C

Electron-donating group showed good anticancer activity

H3C N N

N

N

CH3

O

N N

O

CH3 Cl

Cl

H3C

(180)

(179)

IC50 value A549 cellline - 43.56 M

IC50 value A549 cellline - 44.49 M

Fig. 4.28 Molecules of pyrazoline clubbed imidazo[1,2-a]pyridine with higher anticancer score

4.3.4 Facile Synthesis and Anti-inflammatory Activity of Some Novel Pyrazolines In 2017, Lokeshwari et al. (2017) have synthesized triaryl pyrazolines to access their anti-inflammatory activity. The triaryl pyrazolines were synthesized by cyclization of chalcones. Using methanol as a solvent, the reaction of 2,3-dichlorobenzaldehyde 181 and substituted acetophenone derivatives 182 at room temperature under basic conditions produced chalcone 183 in 3–4 h. When chalcone 183 was treated with phenylhydrazine it is resulted in formation of pyrazoline moiety 184 under reflux conditions using methanol as a solvent and glacial acetic acid as a catalyst. The triaryl pyrazolines were characterized by different analytical techniques and evaluated antiinflammatory activity (Scheme 4.28 and Fig. 4.29). In 2018, Prabhudeva et al. (2018) have synthesized pyrazoline-thiazole hybrids using amberlyst-15 catalyst. It was observed that in comparison with the conventional procedure amberlyst-15 reduced reaction time and occurs at room temperature. Initially, 3-methylthiophene-2-carbaldehyde 187 was reacted with substituted acetophenones 188 under basic conditions to form chalcones 189 through R1 R2 O

O R

Cl +

R1

Cl

R3

MeOH, KOH RT, 3-4 h

Cl

R2 (181)

Cl Cl

O

H

NHNH2•HCl

R

(182)

Cl

MeOH AcOH Ref lux 3-4 h

(183)

R2 N N R R3

R1

(184)

Where R, R1, R2, R3 = Dif f erent substituents

Scheme 4.28 Reaction path for the synthesis of 1,3,5-triaryl-2-pyrazolines

170

N. Desai et al. Electron-withdrawing groups responsible f or good anti-inf lammatory activity

N N

F

Cl

Cl

Cl

N N

(185)

Cl

(186)

IC50 value phospholipase A2 - 10.2 M

Cl

IC50 value phospholipase A2 - 11.1 M

Fig. 4.29 Most active molecules of pyrazoline derivatives

Claisen-Schmidt condensation reaction. The chalcones 189 were first reacted with thiosemicarbazide using amberlyst-15 (10%, w/w) in acetonitrile as a solvent and then after the reaction mixture was kept in reflux condition with 30% acetic acid. Pyrazoline-thiazole hybrids 190 were obtained in good yields (Scheme 4.29 and Fig. 4.30). In 2017, Chen et al. (2017) have synthesized new arylpyrazoline-coumarin derivatives for anti-inflammatory activity via multicomponent reaction. The synthetic procedure was initiated by formation of 3-acetyl coumarin 195 through o-hydroxy benzaldehyde 193 and ethyl 3-oxobutanoate 194 under basic conditions at low temperature. The acetyl group of coumarin was converted into chalcone 196 via Claisen-Schmidt condensation reaction by reacting it with 2 or 4-(trifluoromethyl) benzaldehyde under basic conditions using butanol as a solvent. Chalcone 196 was R2 R2 R1

O R H + R1

S

O

R2

(187)

(188)

R

MeOH, KOH O

RT, 3-4 h

(i) Amberlyst-15 Acetonitrile RT, Stirring, 30-60 min (ii) AcOH (30%) Ref lux, 3-4 h S

S (189)

H2N

N H

R1 R N N S

•HCl NH2

NH2 S

(190)

Where R,

R 1,

R2

= Dif f erent substituents

Scheme 4.29 Schematic diagram for the synthesis of thiophene-pyrazoline motifs

Electron-withdrawing groups showed excellent anti-inf lammatory activity

S H2N

S N N

N N

NH2 S

S Cl

F

(192)

(191)

IC50 value sPLAN2 - 10.762 M

IC50 value sPLAN2 - 9.110 M

Fig. 4.30 Lead molecules of pyrazoline clubbed thiophene scaffold

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

171

then cyclized into pyrazoline entity 197 by treating with hydrazine hydrate and BrCH2 COOH, 4-nitrobenzenesulfonyl chloride at 40–60 °C. The halogen group (– Br) was then converted into alkyl group by the reaction of amine or flavone at 40– 50 °C. The aryl pyrazoline coumarin hybrids 198 were synthesized in good yields (Scheme 4.30 and Fig. 4.31).

H

O

OH

+

(193)

O

O

O

O

O

Piperazine

CF3

2 or 4-(trif luoromethyl)benzaldehyde

O

Piperidine,Butanol Ref lux, 14 h

20-30 C 20 min

O

O

O

(195)

(194)

(196)

NH2NH2•H2O BrCH2COOH 4-Nitrobenzenesulf onyl chloride

40-60 C 2h

CF3

CF3 R

N N O

Where R = Dif f erent substituents

O

40-50 C, 4-6 h

O (198)

Br

N

Flavone or amine

N O

O

O (197)

Scheme 4.30 Synthetic pathway of arylpyrazoline-coumarin derivatives

O

O

N

Heterocyclic motif helping to improving good anti-inf lammatory activity

N

CF3

O

O

O

O

O

IC50 value TNF-α - 16.83 M IL-6 - 14.18 M

(199)

Fig. 4.31 Most active molecule of pyrazoline clubbed coumarin derivatives

172

N. Desai et al.

4.3.5 Miscellaneous In 2015, Viveka et al. (2015a; b) developed novel pyrazolyl-pyrazolines analgesics. The Vilsmeier-Haack reaction was used to convert dichloro hydrazones to pyrazole aldehyde 200. Pyrazole aldehyde 200 produced chalcone derivatives when it interacted with substituted acetophenone derivatives 201. Furthermore, chalcone derivatives 202 interacted with appropriate hydrazine hydrates to produce pyrazoline 203, acetyl pyrazoline 205, and phenyl pyrazoline 206 by substituting phenyl hydrazines 204 (Scheme 4.31 and Fig. 4.32). Marella et al. (2015) published a study on pyrimidine nitrilepyrazoline as a novel class of hybrid antimalarial drugs in 2015. Substituted benzaldehydes and substituted acetophenones reacted to furnish chalcone derivatives 208. Substituted aldehydes reacted with thiourea and ethyl cyanoacetate to form dihydropyrimidine derivatives by Biginelli reaction, which was further reacted with hydrazine hydrate to form hydrazide derivatives 209. Chalcone derivatives 208 reacted with hydrazide derivatives 209 to furnish pyrazoline derivatives 210 (Scheme 4.32 and Fig. 4.33). R

Cl Cl

Cl Cl O N N

Cl

O H

KOH

+

NH2NH2•H2O

O N N

Stirring, 12 h

(201)

N NH

AcOH EtOH, Ref lux 1-2 h

R (200)

Cl

(202)

N N

R

NH2NH2•H2O AcOH, HCOOH Propionic acid Ref lux 4-5 h

R2-C6H4-NHNH2 AcOH Ref lux, 8 h R Cl

(203)

R

Cl

Cl

Cl N

N N

N

N N

N

O R1

N R2

(205)

(204)

Where R,

R 1,

R2 =

Dif f erent substituents

Scheme 4.31 Synthetic route for the preparation of pyrazoline containing pyrazole motif

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline … F Cl

173

Electron-withdrawing groups increased analgesic activity

O2N

Cl N N

N

N

N

N N

O

N

Tail f lick latency value - 7.7 (60 min)

Cl Cl

(206)

(207)

Tail f lick latency value - 7.1 (60 min)

Fig. 4.32 Lead molecules of pyrazoline conjugate pyrazole derivatives O NHNH2

NC N

+ R1

R2

NH

O

Alcohol

R3

NH O

R3

(209)

N N N

HCl Ref lux

R2

(208)

R1

CN (210)

Where R1, R2, R3= Dif f erent substituents Scheme 4.32 Synthetic route of pyrazoline scaffold bearing pyrimidine moiety

O NC O

O N

HN N N

O O

Electron-donating groups enhanced antimalerial activity

H2N (211)

IC50 value - 1.63 M

Fig. 4.33 Potent molecule of pyrazoline clubbed pyrimidine moiety

174

N. Desai et al. R1

R2

O O

H

HO

O N

R

R2

EtOH, Piperidine Stirred, 78°C, 5 h

R3

NH2•HCl HN

R1

R2 N

R3 O

N

O

HO

N R

R1

HO

EtOH, AcOH Stirred, 78°C, 5 h

O N

(212)

R (213)

(214)

Where R, R1, R2, R3= Dif f erent substituents

Scheme 4.33 Synthesis of quinolinone–pyrazoline hybrids

O

O

N N

HN

O

O O

OH

Electron-donating groups responsible f or good antioxidant activity

O

N N

O N

HO HO

(215)

DPPH scavenging ability - 86% lipid peroxidation inhibition - 83%

(216)

DPPH scavenging ability - 100% lipid peroxidation inhibition - 79%

Fig. 4.34 Most active molecules of pyrazoline clubbed pyrazole derivatives with high inhibition scores

Kostopoulou et al. (2021) have prepared novel quinolinone–pyrazoline hybrids and evaluated them for their antioxidant activity. Acetyl derivatives of hydroxyquinoline 212 were reacted with substituted benzaldehyde, which yielded into chalcone derivatives 213. Substituted phenyl hydrazines reacted with chalcone derivatives 213 to yield pyrazoline derivatives 214 (Scheme 4.33 and Fig. 4.34).

4.4 Indazole The heterocyclic aromatic compound indazole, commonly known as isoindazole, has the molecular formula C7 H6 N2 . The pyrazole and benzene rings make up this bicyclic ring. The indazole ring is present in the alkaloids nigellicine, nigeglanine, and nigellidine. Indazole derivatives have biological action (Fig. 4.35).

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

175

Fig. 4.35 Structure of indazole

H N

N NH

N

(217)

Scheme 4.34 Synthesis of indazole pathway

(218)

O OH

N N H

NHNH2 (219)

(220)

4.4.1 Indazole Synthesis by Fischer Fischer first prepared indazole 220 by heating o-hydrazine cinnamic acid 219 (Scheme 4.34).

4.4.2 Indazole Hybrids: Synthesis and Antimicrobial Activity In 2017, Angapelly et al. (2017) synthesized indazole bearing thiazolidinone hybrids. They have carried out antimicrobial activity of novel synthesized compounds. Reduction of nitro indazole 221 converted into primary amine 222 with the help of hydrogen palladium catalyst. Further, by one-pot synthesis of amine indazole 222 with substituted aldehydes and thioglycolic acid yielded final compounds 223 (Scheme 4.35 and Fig. 4.36). Ghelani et al. (2017) in 2017 synthesized indazole bearing oxadiazole moiety. They have evaluated their antimicrobial activity. Cyclohexane-1,3-dione 227 reacted with diethyl oxalate 228 to yield indazole ester. Further, it reacted with hydrazine hydrate to produce indazole acid hydrazide 229. Compound 229 refluxed with substituted benzoic acids 230 to furnish indazole bearing oxadiazole hybrids 231 (Scheme 4.36 and Fig. 4.37).

O2N N N H (221)

H2/Pd-C MeOH, 12 h

H2N N N H (222)

VOSO4 (5 mol %) RCHO, Thioglycolic acid MeCN Ultrasonication, 1 h

H N

O

N N

S

R (223)

Where R = Dif f erent substituents

Scheme 4.35 Synthetic pathway of indazole bearing thiazolidinone moiety

176

N. Desai et al.

MIC value K. planticola - 15.6 g/mL O B. subtilis - 31.25 g/mL

H N N N H N

S H N

O

O

N N

(224)

N

F3C

N

S

S F3CO

Electron-withdrawing groups responsible f or good antibacterial activity

CF3 (225)

MIC value K. planticola - 15.6 g/mL M . luteus - 15.6 g/mL S. aureus - 31.25 g/mL

(226)

MIC value K. planticola - 15.6 g/mL M . luteus - 31.25 g/mL

Fig. 4.36 Potent antimicrobial agents of indazole bearing thiazolidinone moiety

O

O

OC2H5

O

OC2H5

+ O (227)

N NH

O O (229)

(i) EtONa, EtOH EtOH RT- 0°C, 6 h (ii) NH2NH2•H2O EtOH Ref lux, 5 h

(228)

O H N

NH2

N NH

OH

POCl3

+

H N

NH2

O

O

(229)

N

H N

Ref lux, 6 h

N N O

R

O

R (230)

(231)

Where R = Dif f erent substituents Scheme 4.36 Synthetic pathway of indazole bearing oxadiazole derivatives

4.4.3 Antitubercular Activity and Facile Synthesis of Some Novel Indazoles In 2017, Vidhyacharan et al. (2017) have proposed one-pot catalyst-free and solventfree synthesis of indazole 238. Reaction of azidobenzaldehyde 236 and anthranilamide 237 was carried out under catalyst-free and solvent-free condition at 110 °C temperature. They have evaluated antitubercular activity of synthesized compounds (Scheme 4.37 and Fig. 4.38). In 2017, Oliviera et al. (2017) synthesized indazole bearing pyridine derivatives to evaluate their antitubercular activity. Aldehyde of indazole 241 reacted with isoniazid

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

177

O

O N

N

Electron-donating groups f avourable against Proteus vulgaris bacterial strain

N

N O

N

O

(232)

O

MIC value P. valgaris - 2.0 μg/mL N

Electron-withdrawing groups resist to Staphylococcus aureus bacterial strian

N O

N

(233)

N

N

N

O

MIC value P. valgaris - 2.1 μg/mL

O

N

O

N O

Br

NO2

O

N N

N

Br (236)

(234)

MIC value S. aureus - 1.2 μg/mL

MIC value S. aureus - 1.7 μg/mL O N

N N

N

O

MIC value S. aureus - 1.7 μg/mL

(235)

Fig. 4.37 Indazole conjugates oxadiazole moiety with higher potency

O

R1

R2 NH

O H

N3

H N R2

+

NH2

(236)

Solvent f ree Catalyst f ree

O R1

N

110°C, 12-15 h

N

(237)

(238)

Where

R 1,

R2

= Dif f erent substituents

Scheme 4.37 Reaction scope of anthranilamides in 2H-indazole

O

O

Electron-donating groups showed promising antitubercular activity

O O NH

O NH O N O

(240)

N N

N

(239)

MIC value M . tuberculosis H 37R - 7.75 M

MIC value M . tuberculosis H37 R - 4.20 M

Fig. 4.38 Lead active molecules of indazole hybrids

178

N. Desai et al. NH2 NH

O N N H

O

p-TSA + N (242)

O (241)

N H

N Vibrating ball mill 50 Hz, 2.0 mm, RT, 2 h

N

N

N H

(243)

Scheme 4.38 Synthetic pathway of indazole clubbed pyridine motif

H N

O

N

N H

N

N

Postion isomers inhibited M ycobacterium tuberculosis

O

HN

N

N

(244)

N H

N

(245)

MIC value - M . tuberculosis H37 R - 0.06 M

MIC value - M . tuberculosis H37 R - 0.03 M

Fig. 4.39 Biologically active indazole clubbed pyridine motif

O

O

O

Ar N N H (246)

N H

EtOH Ref lux

NH2

N HN

O N

O Ar

N H (247)

Where Ar = Dif f erent substituents Scheme 4.39 Synthetic route of hydrazide derivatives of indazole motif

242 using p-TSA as catalytic in vibrating ball mill at room temperature to furnish imines of indazole and pyridine 243 (Scheme 4.38 and Fig. 4.39). Indazole bearing indole derivatives were synthesized by Angelova et al. (2019) in 2019. Antimycobacterial activity of newly synthesized compounds was carried out. They have reacted indazole aldehyde 224 with substituted acid hydrazides which yielded into respective imines 225 (Scheme 4.39 and Fig. 4.40).

4.4.4 Preparation and Anticancer Activity of Some Novel Indazoles In 2019, Abdelsalam et al. (2019) have synthesized some fused indazoles and evaluated their anticancer activity. To synthesize fused indazoles, first 6-methoxy3,4-dihydronaphthalen-1(2H)-one 250 was reacted with ethyl acetoacetate in presence of sodium ethoxide using ethanol as a solvent, this led to the formation of

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

179

N S HN N O N

O

O

Heterocyclic ring enhanced antimycobacterial activity

N H

O N N H (249)

(248)

MIC value M. tuberculosis H37R - 1.32 M IC50 value - 61.6 M

NH N

MIC value M. tuberculosis H37R - 1.66 M IC50 value - 33.9 M

Fig. 4.40 Lead molecules of indazole derivatives with good activity

an acetyl group (–COCH3 ) in the parent molecule. When 2-acetyl- 6-methoxy3,4-dihydronaphthalen-1(2H)-one 251 was reacted with substituted hydrazines (hydrazine hydrate and phenyl hydrazine) fused indazoles were formed. It was observed that when 2-acetyl-6-methoxy-3,4-dihydronaphthalen-1(2H)-one 251 was treated with guanidine hydrochloride instead of indazole, pyrimidine ring structure was formed. It confirms that 2-acetyl- 6-methoxy-3,4-dihydronaphthalen-1(2H)-one 251 possessed both keto 252 and enol 253 forms. Reaction with keto 252 form produced indazole moiety 254 while reaction with enol 253 form gave pyrimidine moiety 255 (Scheme 4.40 and Fig. 4.41). In 2019, Panchangam et al. (2019) have performed one-pot synthetic procedure to form fused indazole and evaluated their anticancer activity. Three components o-bromobenzaldehyde 258, substituted anilines 259, and sodium azide 260 were reacted under reflux condition with Cu2 O nano, and rhombic dodecahedra catalyst using DMSO as a solvent which resulted in fused indazole 261 synthesized in good yields. This synthesis involves C-N and N–N bond formation followed by cyclization which was prominent to inhibit cancer cells (Scheme 4.41 and Fig. 4.42). In 2019, Elsayed et al. (2019) have synthesized some indazole derivatives to access their anticancer activity via multicomponent reaction. Diazotization of 2methyl-4-nitroaniline 263 through sodium nitrite in glacial acetic acid yielded 5nitroindazole 264. Catalytic reduction of 5-nitroindazole 264 through H2 , Pd/C yielded 5-aminoindazole 265. Nucleophilic substitution reaction of 5-aminoindazole 265 and 2,4-dichloropyrimidine obtained a hybrid molecule containing indazole and pyrimidine 266. To this hybrid molecule, treatment with phenyl isocynate in dry THF yielded targeted hybrid 267 entity in good yields (Scheme 4.42 and Fig. 4.43).

180

N. Desai et al. O

O

O

O

O O

EtONa, EtOH

O

(251)

(250)

OH

O

O

OH

3:1 O

O (252)

NH2-NH-R

S H2N

(253)

• HCl NH2

NaOH NH2

R N N

N

O

N

O (254)

(255)

Where R = Dif f erent substituents Scheme 4.40 Synthetic pathway of indazoles derivatives bearing pyrimidine moiety

N H N

Electron-donating group attachment at nitrogen responsible f ot anticancer activity

N N O

O (257)

(256)

IC50 value MCF-7 cell - 7.21 to 21.55 M (rang) Fig. 4.41 Most active molecules of indazole derivative

4.4.5 A Facile Synthesis and Anti-inflammatory Activity of Some Indazoles In 2015, Reddy et al. (2015) have synthesized 1H-pyridin-4-yl-3,5-disubstituted indazoles to access anti-inflammatory activity. 2-cyano-4-chloropyridine 274 and

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline … Br

R1

2 mol% Cu2O nano rhombic dodecahedra

NH2 H +

O (258)

+ R2

(259)

181

NaN3

N

DMSO, 1,10-phen., 80°C 4-8 h, N2 atmosphere

(260)

R2

N R1

(261)

Where

R 1,

R2

= Dif f erent substituents

Scheme 4.41 Synthetic pathway of indazoles derivatives

CH3

N

Electron-donating group increased anticancer activity

N CH3

IC50 value A549 cell - 37.1 M MDA-MB-468 cell - 25 M HCT116 cell - 26.1 M

(262)

Fig. 4.42 Potent molecule of indazole derivatives Cl O

Cl Cl

NH2

NaNO2 Gla. AcOH NO2 (263)

HN

N HN

H2, Pd/C

RT, 72 h NO2

N

N

N N

NH

N

TEA, EtOH NH2 Ref lux, 5 h

Dry THF RT, 24 h

N N O

N NH (266)

(265)

(264)

N

N

N

NH

Cl

10%,MeOH 40°C, 30 psi 3h

C

NH (267)

N N

Isopropenol Ref lux, 3h

Cl R2

H N

H N

X N

N NH R1

N

R1

N

Isocyanates or Isothiocyanate THF or DMF, RT, 24 h

N

(268)

NH R1

N

R1

N (269)

Where X = O, S, R1, R2 = Dif f erent substituents

Scheme 4.42 Synthetic pathway of indazoles clubbed pyrimidine derivative

methyl 1H-indazole-3-carboxylate 273 were reacted in presence of CuI, L-proline, and cesium carbonate using DMSO as a solvent which resulted in the formation of 1-(2-cyanopyridin-4-yl)-1H-indazole-3-carboxylic acid 275. The acidic group was converted into carboxamides through SOCl2 , EDC, and alkylamines and cyano (-CN) group were converted into amide (–CONH2 ) 276 to form targeted hybrid entity 277 (Scheme 4.43 and Fig. 4.44).

182

N. Desai et al. H N

H N N

H N

O

N

CH3

N

O

Cl

Cl

N

H N N

Cl

O

N O

N

N

Electron-withdrawing group at 3rd or 5th position enhanced anticancer activity

O (270)

O (271)

IC50 value - 5.6 M

IC50 value - 5.4 M Cl O H N N

HN O

O

N N O

(272)

N

IC50 value - 5.4 M

O

Fig. 4.43 Lead molecules of indazole bearing quinazoline with higher outcomes O R1

O O

Cl

N NH

+

N CN

R1 (273)

(274)

O OH

CuI, L-Proline Cs2CO3, DMSO 75-80°C 6-12 h

N

N

R2

R1

SOCl2 EDC, Amines (R2)

N N

80-85°C 1h

N

N CN (275)

CN

(276)

Con. H2SO4 NaCl, H2O 40-45°C, 1 h CONH2

R2

N

O

Where R1, R2 = Dif f erent substituents

R1

N

N

(277)

Scheme 4.43 Synthesis of 1H-pyridin-4-yl-indazole-3-carboxylic acids and derivatives

In 2017, Pérez-Villanueva et al. (2017) have synthesized 2-phenyl-2H-indazoles via multicomponent by Cadogan reaction. 2-nitrobenzaldehyde 281 was reacted with substituted aromatic amines to form Schiff bases or imines 282 under reflux conditions. The imines 282 were reduced and cyclocondensation reaction was performed using P(OEt)3 to form 2-phenyl-2H-indazoles 283 in good yields. 2,3-diphenyl2H-indazoles 288 were also synthesized using different reaction conditions as well

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

O

183

H3C

N

N N

O

N

N- substituted hetero cyclic rings and alkyl chain shows anti-inf lammatory activity

N

N N

CN

N

NC O

(278)

N

N (279)

% edema inhibition - 39.42

% edema inhibition - 38.70

N N (280) N

% edema inhibition - 39.42

CN

Fig. 4.44 Most active molecules of indazole with different heterocyclic and alkyl chains

as catalysts. All the synthesized compounds 284–288 were evaluated for antiinflammatory activity, which showed some promising results (Scheme 4.44 and Fig. 4.45). R1 O

N H

NO2

R1C6H5NH2

R2= R3= -H

H

EtOH, Ref lux

NO2 (282)

(281)

(283)

NaOH MeOH Ref lux

BBr3 CH2Cl2 RT, 0°C

R1

N N

150°C

NaIO4, AcOH CH3CN, H2O 80 C

NaIO4, AcOH CH3CN, H2O RT

R3C6H4I

O OH

N N

SOCH3

OH

N N

SO2CH3

N N

R3

N N N N

(284)

(285)

(287)

(286) 1

2

3

(288)

Where R , R , R = Dif f erent substituents

Scheme 4.44 Synthetic pathway of 2-phenyl-2H indazoles derivatives

R2

184

N. Desai et al. O H3C S O

O

N N

O

(289)

% inhibition of COX-2 - 50.01

Electron-withdrawing groups responsible f or better anti-inf lammatory activity

N N

(290)

% inhibition of COX-2 - 44.45 N

N

N

N

O O

(291) O

S

H3C

O

(292)

% inhibition of COX-2 - 41.22

% inhibition of COX-2 - 36.35

Fig. 4.45 Potent anti-inflammatory agents of indazole derivatives

4.4.6 Miscellaneous 1-(2-cyanopyridin-4-yl)-1H-indazole-3-carboxylic acid 275 was prepared by Reddy et al. (2015) and they have carried out their analgesic activity. Compounds were synthesized as shown in Scheme 4.43 and Fig. 4.46. N

N

NC

CN

N

N

N

N

O (298)

N

OH

Mean Response - 5.50 (60 min) N

C-3 position of indazole moiety responsible f or analgesic activity

O (299)

Mean Response - 8.16 (60 min) O

CN

N

H2N N

N

N

O

N N

(300)

Mean Response - 5.50 (60 min)

O

N

O (301)

Mean Response - 5.50 (60 min)

Fig. 4.46 Active molecules of indazole with different heterocyclic and alkyl chain

4 Synthesis and Biological Importance of Pyrazole, Pyrazoline …

Br

NO2

a HO

O

Br

NH2

c HO

(302)

O

O

(303)

N N

e

d

b

185

O

f B(OH)2

Br

h

O

(304)

N N

g

O

Br

H N R

O

(305)

(306)

Reagents and conditions: a) Hydantine, Con. H2SO4, 0°C - RT, 3 h, b) Con. H2SO4, KNO3, - 10-0°C, 1 h, c) Con. H2SO4, MeOH, 70°C, 12 h, d) Zn, NH4Cl, MeOH, H2O, RT, 1.5 h, e) KNO2, AcOH,Water, RT, 4 h, f ) Copper acetate, Pyridine, EDC, 70°C, 12 h, g) LiOH, MeOH, H2O, 65°C, 2 h, h) R-NH2, DIPEA, HATU, DMF, RT, 6-12 h R = Dif f erent Substituents

Scheme 4.45 Synthetic pathway of novel indazole hybrids

Br

N

Br

N N

N

HN

O

Electron-withdrawing amine at C-4 position exhibited better SOR and OH scavenging activity

Br (307)

% SOR activity - 89.37%

HN

O

Cl (308)

% OH activity - 81.95%

Fig. 4.47 Most active molecule of indazole derivative

Sawant et al. (2020) synthesized a novel series of 6-bromo-1-cyclopentyl1-H-indazole-4-carboxylic acid-substituted amide derivatives as antioxidant agents to prominent activity. Among synthesized compounds, 6-bromo-N(4-bromophenyl)-1-cyclopentyl-1H-indazole-4-carboxamide and 6-bromo-N-(4chlorophenyl)-1-cyclopentyl-1H-indazole-4-carboxamide were observed as most active antioxidant agents (Scheme 4.45 and Fig. 4.47).

4.5 Conclusion Different synthesis strategies and biological functions of nitrogen-containing heterocyclic scaffolds, such as pyrazole, pyrazoline, and indazole, have been discussed in this chapter. Different biological activities (antitubercular, antibacterial, anticancer, and anti-inflammatory), as well as some miscellaneous (antimalarial and antioxidant) properties, have been discussed. Many researchers have worked on synthesizing nitrogen-containing heterocycles and evaluating their biological activity in

186

N. Desai et al.

recent years. In addition, researchers have discovered some intriguing results for the development of powerful compounds. Electron-withdrawing and electron-donating functional groups were important in enhancing biological activities. The results of the biological evaluation of synthetic hybrids are discussed in this chapter. It is possible to conclude that creating hybrid molecules of active pharmacophores has a stronger impact on increasing biological activity. The influence of functional groups on different positions of heterocycles has been observed, and it will be very important for the future creation of medications for the treatment of diseases such as antitubercular, antibiotic, anticancer, and anti-inflammatory diseases. In a nutshell, we have chosen heterocyclic moieties that are quite adaptable and will be extremely valuable in the development of nitrogen-containing drugs. Acknowledgements One of the authors Prof. Nisheeth C Desai is thankful to UGC for awarding BSR faculty fellowship-2019 (No. F18-1/2011 (BSR)) and financial assistant. Authors are thankful to the University Grants Commission, New Delhi.

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Chapter 5

An Overview on the Synthesis and Biological Studies of Some Seven Membered Heterocyclic Systems Vnira R. Akhmetova, Guzel R. Khabibullina, and Askhat G. Ibragimov

5.1 Introduction Heterocycles are the structural basis among the important natural and synthetic biologically active substances, which stimulates the development of new synthetic strategies of the intermolecular and intramolecular cyclization (Katritzky and Rees 1984; Quin and Tyrell 2010; Li and Johnson 2010). The seven-membered O, S, Ncontaining heterocycles due to their great contribution to medical and pharmaceutical chemistry are an object of deep research (Xu 2016; Bariwal et al. 2008; Rosowsky 1984). Seven-membered heterocycles with one nitrogen atom—azepines, with two heteroatoms in the cyclic system in combination of the N,N atoms—diazepines, the O,N atoms—oxazepines and the S,N atoms—thiazepines, exhibit different activity. In recent publications (Ram et al. 2019; Muylaert et al. 2016; Kaur et al. 2021), the structural aspects and chemical activity of saturated and unsaturated isolated or benzo-fused seven-membered heterocycles containing one or two heteroatoms in the ring, as well as natural and synthetic analogs in drug development are well described. In addition, the review article presents an analysis of the literature on the synthesis of azepine derivatives by [1,7]-electrocyclization (Nedolya and Trofimov 2013). Nevertheless, there is unflagging interest in the synthesis of seven-membered heterocycles, driven by the desire to expand the methods of organic synthesis, create new libraries of azepines, oxa- and thiazepines, and also reveal previously unknown unique pharmacological properties of these compounds to discover new drugs.

V. R. Akhmetova (B) · G. R. Khabibullina · A. G. Ibragimov Laboratory of Heteroatomic Compounds, Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Octyabrya, Ufa 450075, Russian Federation e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_5

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Fig. 5.1 Design strategy of azepine derivatives by one-pot synthesis

One-pot synthesis Recyclization of carboand heterocycles

Multicomponent reactions (MCR) Diverse azepine, azepane derivatives

This chapter summarizes the literature data on the development of methods for one-pot synthesis of compounds with an azepine scaffold, based on small or middle ring expansion by recyclization reactions and multicomponent heterocyclization reactions (Fig. 5.1).

5.2 Azepines and Diazepines 5.2.1 Synthesis of Isolated Azepines N-Unsubstituted 1H-azepines are rare, the most stable isomer is 3H-azepine, and the least stable isomer is 2H-azepine, although their benzo derivatives are much more stable (Fig. 5.2) (Ram et al. 2019). Fig. 5.2 N-unsubstituted H-azepines

Scheme 5.1 Recyclization azacycles, which lead to azepines

NH

N

N

N

1H-

2H-

3H-

4H-

NH

NH NH

Aza-norkaradiene R N N R

R O N

R R N N

5 An Overview on the Synthesis and Biological Studies … OH N

H-OSO3H

N

193

+ OH2

OH2 N

H

O

O HO

HN

S

O

H

H

O N

O

OSO3H H

N

O

Scheme 5.2 Beckman rearrangement of cyclohexanone oxime to form azepinone

The classical routes for the synthesis of azepines include reactions with the expansion via recyclization of aziridine rings, for example, as in the case of azanorkaradiene, as well as rearrangements of five-membered azacycles (Scheme 5.1) (Barton and Ollis 1983). The stable compounds of this class of interest to researchers are hydrogenated or fully saturated azepinanes, which can be obtained using well-known Beckman rearrangement (Scheme 5.2) (Mokaya and Poliakoff 2005). Novel approach to the construction of an isolated azepine has been proposed by the recyclization of azacyclobutane (Drouillat et al. 2016). For instance, new azepanes, which are of high relevance in medicinal chemistry, were obtained from the tetraatomic azetidines bearing a 3-hydroxypropyl side chain at the C2-position and the methyl substituent at the C4-carbon atom, via intramolecular N-alkylation through the intermediate 1-azonia-bicyclo[3.2.0]heptane and with following action by different nucleophiles (cyanide, azide or acetate anions) (Scheme 5.3). New synthesis of isolated azepines is based on multicomponent heterocyclization of amines with electron-deficient acetylenes and 1,4-dinucleophilic reagents by the (1+2+4)-type cyclization, namely, (N + CC + CCCC) (Mallepalli et al. 2011). This efficient three-component method for the one-pot synthesis of N-substituted azepine derivatives with excellent yields has been carried out under catalyst-free condition by using polyethylene glycol (PEG) (Scheme 5.4). The subject of research is not only synthesis methods for creating a library of novel diverse azepine (Yang et al. 2017), but also the study of the conformational features of molecules for their pharmacological activity (Freitas et al. 2014). Thus, the work (Yamashita et al. 2006) showed the relationship between structure and activity among the possible 5-, 6- and 7-monomethyl-substituted analogs of isolated OH

N

Bn

Nu

1. SOCl2, DCM, reflux then Na2CO3 workup 2) MNu (10 eq.), DMF, 80oC, 2-10h MNu: NaOAc (13%), KCN (26%), NaN3 (60%)

Me

N Bn

Scheme 5.3 Intramolecular recyclization of azetidines with the formation of isolated azepane

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NH2

PEG-400

CO2R

N

+

+

MeO

RO2C

CO2R

60oC, 7h

OMe

O

CO2R

Scheme 5.4 Synthesis of N-substituted azepine derivatives by using the three-component procedure

azepanone in the 5-methyl series, aimed at detecting osteoporosis (Fig. 5.3). Cis-4SDiastereomer (a) has 150 times more inhibitory activity against cathepsin K than its trans-4S-diastereomer (b) (Fig. 5.3). (3R)-3-Aminoazepane derivatives were used as important synthetic building blocks to obtain many compounds with potential biological activity such as fourthgeneration fluoroquinolone antibiotics—besifloxacin and nazartinib (Feng et al. 2017, 2019) exhibiting antitumor activity in the treatment of lung cancer (Cui et al. 2021; Lelais et al. 2016). Novel azepane derivatives based on natural (-)-balanol have been prepared and evaluated for protein kinase B (PKB-R) and protein kinase A (PKA) inhibition (Fig. 5.4) (Breitenlechner et al. 2004, 2005).

a A = Me, B-F = H; O

O

b B = Me, A, C-F=H;

H N

N H O

O

A

B C

c C = Me, A,B,D-F = H;

O

4 5

N 6

7

D E F

S

N

d D= Me, A-C,E,F = H; e E = Me, A-D, F = H;

O

f F = Me, A-E=H

Fig. 5.3 Structures of methyl-substituted 4S-azepanones a–f

N

Cl

O

N

H2N

N

N

O

HN

O

OH

F

N N

N

O

Cl

Nazartinib

Besifloxacin N O O

O

HN

R

N

N

N

NH F HN HO O

O

Balanol derivative

.

NH2 N H

NH

NH2

2 HCl

Hexamethylene amiloride (HMA)

Fig. 5.4 Biologically active azepane representative derivatives

5 An Overview on the Synthesis and Biological Studies …

195

R O

O H N

N OH

CN

O N O

N H

O

Amamistatin A R=OMe Amamistatin B R=H

O

O N

H

N

N

O

OH

N

CH3

Diaryl ether caprolactam

OH

O

O NH O F3C N F

H H N

N N

H N

N

n

O NH

O O

F

Fluorocontaining azepan-2-one

n = 9, 10, 12, 14 3-(Acylamino)azepan-2-on

Fig. 5.5 Biologically active caprolactam representative derivatives

The amiloride-based drugs (Fig. 5.4)–hexamethylene amiloride (HMA) are known to use as selective inhibitors of the human urokinase plasminogen activator in treatment of malignant cancers (Buckley et al. 2018). Natural caprolactams–Amamistatin A, Amamistatin B (Fig. 5.5), and its analogs were isolated from the actinomycete Nocardia asteroides, which showed growth inhibition against human tumor cell lines, were found. Related natural products formobactin, nocobactin and brasilibactin were also isolated from strains of Nocardia, with brasilibactin showing similar anticancer activity (Fennell et al. 2008). Diaryl ether caprolactam has been reported as dual-target cancer chemotherapeutic agents (DeSolms et al. 2003). Ch. S. Burgey et al. reported novel (3R,6S)-3-amino-6-(2,3-difluorophenyl)1-(2,2,2-trifluoroethyl)azepan-2-one of the CGRP receptor antagonist telcagepant (Burgey et al. 2008), which has demonstrated efficacy in treatment of migraine headache clinical trials (Fig. 5.5) (Paone et al. 2007). In addition, similar lactams such as 3-(acylamino)azepan-2-ones (n = 9 (S), 10 (S), 12 (S), 14 (S and R), 16 (S)) have been discovered as stable chemokine inhibitors and anti-inflammatory agents that are resistant to metabolism in vivo (Fox et al. 2005).

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5.2.2 Synthesis of Benzo-Fused Azepines and Diazepines 5.2.2.1

Benzoazepines

Compounds with benzoazepine cores are part of plant metabolites (Fig. 5.6) (Kulandai Raj et al. 2017). Homocryptolepione is a natural product isolated from the Ghanaian plant gryptolepis sanquinolenta. New 5,6,11,12and (±)-9tetrahydropyrrolo[1 ,2 :1,2]azepino[4,5-b]indole-3-carbaldehyde hydroxy-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxamide were isolated from the flowers of Juglans regia (Li et al. 2017a). The extracts of this plant have been used as traditional medicine to treat a wide array of ailments, including cancer (Panth et al. 2016). The synthesized natural benzo[b]azepine-2-carboxamide showed cytotoxic properties (Marepu et al. 2018). Tetrahydrobenzo[b]azepines represent scaffolds, whose can be found in a molecular variety of medicines in the treatment of cardiovascular disease, including evacetrapib, benazepril and tolvaptan (Wang et al. 2020; Cao et al. 2011). The syntheses of benzazepines are successfully carried out on the basis of one-pot reactions with the expansion of benzo-fused carbo- and heterocycles. For example, 9,10-dihydroanthracene and anthracen-9(10H)-one under the action of trimethylsilyltriazide and water in situ form cyclic oximes, which then undergo a rearrangement under the reaction conditions (Scheme 5.5) (Qin et al. 2011). As a result, benzannelated six-membered-hydrocarbon rings were converted by recyclization into seven-membered lactams in 61-72% yields. Another example of the synthesis of benzazepines based on the Au-catalyzed recyclization of azacycle was described in work (Kulandai Raj et al. 2017). The mechanism is shown in Scheme 5.6, in which the target benzoazepine is formed through the intermediate five-membered azacycle A followed by rearrangement leading to carbocatione B. In sum, facile and stereoselective construction of important tetrahydro-benzoazepines occurs by gold-catalyzed reactions between en-propargyl O

O

NH NH

N

N Me

Homocryptolepinone

NH2

N H OH

CHO

Indolo-pyrrolofused azepine

O

Benzoazepinecarboxamide

Fig. 5.6 Plant metobolites with benzoazepine cores

Scheme 5.5 Transformation of 9,10-dihydroanthracene and anthracen-9(10H)-one into seven-membered lactams

FeCl2 (10 mol%) DDQ (2.2 eq.) Me 3SiN 3 (2.0 eq.)

X X = CH2, C=O

H2O (2.0 eq.), HOAc, Ar

O NH

O

5 An Overview on the Synthesis and Biological Studies … Ph

197 Ph

NHOH

.

O

10 mol% IPrAuCl/AgNTf 2

+

O

DCE, 60oC

R

O H

R'

R

N H

Ph

OAuL

Ph

O

AuL

O

R'

O

-AuL

N

N +

R'

R' A

Scheme 5.6 Gold-catalyzed N-hydroxyanilines

R

reactions

B

of

R

allene-containing

propargyl

ethers

with

ethers containing the allene group and N-hydroxyanilines to generate ketone-derived nitrones, further affording benzoazepin-4-ones. The interesting variant of azepine formation by ring expansion reactions of fivemembered heterocyclic systems (eg. oxindoles) occurs by actions of aryne. Taking into account the above, the synthesis of dibenzo-[b,e]azepin-6-one derivatives was carried out in the presence of CsF at 90 °C (Scheme 5.7) (Samineni et al. 2016). The authors have applied this short one-pot method for aryne insertion strategy to synthesize antiulcer darenzepine from substituted oxindole. The reaction at room temperature has proceeded with the retention of the oxindole scaffold. Another method for constructing benzazepane is based on the intermolecular recyclization of aziridines. A simple synthetic route to tetrahydrodibenzo[c,e]imidazo[1,2-a]azepines was invented passing via SN 2type ring-opening of N-activated aziridines with 2-bromobenzylamine followed by a cascade cyclization reaction comprising a cross dehydrogenation catalyzed by CuI and C–N coupling intramolecular reaction (Scheme 5.8) (Ghorai et al. 2014). TMS

Ph CsF, 90oC

R1

N R2

Ph TfO +

12h, AcCN

O

6h, AcCN

O

O R1

Ph

CsF, rt

N R2

R1

N R2

Scheme 5.7 Synthesis of dibenzo-[b,e]azepin-6-ones using ring expansion reactions

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N

Ar2

1) LiClO4 (30%), CH3CN, reflux, 4-6h 2) CuI (10 mol%) L-proline (20 mol%), NaH (2.5 eq), DMF, 90oC, 14h

Br

N

Ar1 N

NH2 Ar1 Ar1 = Ph, 4-MeC6H4, 4-F-C6H4, 4-tBu-C6H4 Ar2 = Ts, 4-tBuC6H4SO2

77-85%

Scheme 5.8 Synthesis of tetrahydrodibenzoimidazoazepines by recyclization of aziridines

5.2.2.2

Benzodiazepines

In the pharmaceutical industry of the twentieth century, benzodiazepines, which are characterized by isomerism of the position of nitrogen atoms in the seven-membered heterocycle (eg. 1,2-, 1,3-, 2,3- or 1,4-diazepines)(Evans et al. 1988; Patchett and Nargund 2000; Sum et al. 2003) have proven themselves well. The first introducing drug into medical practice was diazepam (7-chloro-2-methylamino-5-phenyl-3H1,4-benzodiazepine-4-oxide) intending for the treatment of diseases of the central nervous system (Greenblatt et al. 2020). Later the new generation drugs had been created on the basis of 2,3-benzodiazepines (Horváth et al. 2000). It should be noted that benzodiazepin-2-ones are known as “privileged” structures and were described in review (Horton et al. 2003). Particularly, pyrrolobenzodiazepines have antimicrobial (Gerratana 2010) and antitumor activities (Hartley 2011). In 2004, Nakatani et al. investigated an extract of the fruit bodies of the myxomycete Fuligo candida and isolated cycloanthraniloproline and its derivatives a, b and c (Fig. 5.7). A recent study has shown that Fuligocandin B sensitizes leukemia cells to apoptosis (Nakatani et al. 2004). The synthesis of alkaloids Fuligocandin A and its thioderivative B by expansion reactions of the six-membered ring by action of the amino acid L-proline was realized (Scheme 5.9) (Pettersson et al. 2011).

HO

OH

O

H

HN

N

N O

N H

O H N H

NH2

Pyrrolobenzodiazepine

X = CH3 (a), CH2C(O)OH (b)

N

O

O

H (c)

N H

X

O

Alkaloid

Fig. 5.7 Native compounds with benzodiazepine scaffolds

Scheme 5.9 Synthesis of alkaloids fuligocandins A and B

H N

O

O L-proline

N

O O

DMSO 100oC, 4h

N H

H X X=O

X=S

P; 60oC

5 An Overview on the Synthesis and Biological Studies …

199

The cyclization reactions between hydrazines and 1,5-dicarbonyl compounds, for example, diketones (Kharaneko and Bogza 2013), keto acids and their esters (route A) (Zappalà et al. 2006) or the recyclization of oxacyclanes with hydrazine (route B) are the most common methods for the synthesis of benzo-1,2-diazepines (Scheme 5.10). Another used method for the synthesis of benzo-1,2-diazepines was based on the recyclization of benzo-α-pyrones by hydrazine (Scheme 5.11) (Kibalny et al. 2010). Original method for producing 2,3-benzodiazepinones from benzocyclobutenone and diazo compounds was presented (Scheme 5.12) (Matsuya et al. 2006). In the twenty-first century, new compounds with an azepine scaffold with a wide profile of pharmacological properties (Fryer and Taylor 1991; Horton et al. 2003) were synthesized based on multicomponent reactions, in particular, using the Ugi reaction (Shaabani et al. 2021). In recent review has been discussed the synthesis and

AlkO

O

H2N

2 NH2-NH2 Ar

Route A:

H N

O

Ar

O

Ar

Ar

O

OAlk O

O

Ar

NH2-NH2

NH N

O Ar

Ar

NH N

NH2

Ar

O

Ar

Ar

- NH2-NH2

N

Ar

Route B:

O

Ar

Scheme 5.10 Cyclization of hydrazines with 1,5-dicarbonyl compounds (Rout A) and recyclization of oxacyclanes with hydrazine (Route B)

Me

NH2-NH2

Me

MeO

N

O+ ClO4-

MeO

Et

Et

Et MeO

MeO

Me

MeO

+

N

N

MeO

OMe

OMe

OMe

OMe

OMe

OMe

ClO4NH2

+

Scheme 5.11 Recyclization of benzo-α-pyrones with the participation of hydrazine

+

N2 Li

R = COOEt or (Me)3Si

O

R

O

R

R

THF -78oC

-

-

O-

O R

+

N2

N

N

N.-

N

O

R N NH

Scheme 5.12 Synthesis of 2,3-benzodiazepinones from benzocyclobutenone and diazo compounds

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biological activity of benzodiazepines obtained from cyclic imines by Ugi reaction (Nazeri et al. 2020). The method for the synthesis of 1,5-benzodiazepanes is based on the cyclocondensation of ortho-phenylenediamine with ketones, α,β-unsaturated carbonyl compounds or 1,3-dicarbonyl compounds (Kartsev 1999). One-pot synthesis of diazepine derivatives using 1,2-diamine, a linear or cyclic ketone, and isocyanide was discussed in the books (Gharib 2014; Dandia et al. 2014). In 2018, a methodology of one-pot synthesis of new types of spiro[benzo[b][1,4]diazepine-2,2 -pyrano[3,2-c]chromen]-5 -ones was developed using commercially available 4-hydroxychromen-2-one, o-phenylenediamine and acetone in a 1: 1: 3 ratio of starting reagents under catalyst- and solvent-free conditions (Scheme 5.13) (Zhu et al. 2018). Derivatives of pyrazolyl-dibenzo[b,e][1,4]diazepinones were obtained by the InCl3 -catalyzed (25 mol%) three-component reaction of pyrazole-4-carbaldehydes, cyclic diketones and aromatic diamines in acetonitrile under mild conditions (Scheme 5.14) (Brahmbhatt et al. 2020). It should be added that the compounds were isolated with high purity without liquid chromatographic method and showed antimicrobial, antioxidant, antiproliferative and antitumor [against A549 (lung), HeLa (cervix), SW1573 (lung) T-47D (breast) and WiDr (colon) cell lines] activities. H3C

R OH

+ O

O

O

60oC, 24h

H2N

R

H3C NH O

H2N

3

H N

CH3 CH3

R = H, Me, Cl, NO2

Scheme 5.13 Multicomponent c]chromen]-5 -ones

synthesis

O

O

spiro[benzo[b][1,4]diazepine-2,2 -pyrano[3,2-

of

H

Ph

O O

R2

NH2

N

R

N

X

N

rt, 6h

+

+

N

R1

InCl3, AcCN

3

X

R3

NH2

2

R

O

H N

O

X = O, R1 = H, Me, Cl; R1

N H

X = S, R1 = H, Cl;

R3

R2 = H, COPh

R3

R3 = H, Me

Scheme 5.14 Multicomponent synthesis of pyrazolyl-dibenzo[b,e][1,4]diazepinone R1 R

NH2 O + CH2Y NH2 H3C

a

R

NH2

b

NH

Y

Me a) solvent-free, catalyst-free, rt b) dry EtOH, PMA, ice-salt bath

(N) S CHO R

R1

(N) H N

S Y

R = H, CH3, Br

N H

Me

R1 = H, 3-CH3, 5-CH3, 3-Br, 4-Br, 5-Br Y = CO2Me, CO2Et

Scheme 5.15 Multicomponent synthesis of thiophene containing 1,5-benzodiazepine derivatives

5 An Overview on the Synthesis and Biological Studies …

201

Multicomponent synthesis of novel 1,5-benzodiazepine derivatives was designed by the combination of ortho-phenylenediamine and ester group under solventfree, catalyst-free and room temperature conditions with following addition of thiophene or thiazole carbaldehydes (Scheme 5.15). Library of synthesized 1,5benzodiazepines was evaluated for in vitro antimicrobial activity against C. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus. Most of the 1,5-benzodiazepine derivatives have exhibited considerable potency against all of the tested strains (Wang et al. 2015).

5.3 Oxazepines and Benzoxazepines Oxazepines have various biological activities and some are used in the composition of drugs, in particular, 1,4-oxazepine derivatives exhibit antibacterial, fungicidal and antitumor activity (Goutham et al. 2015; Hanoon 2011). The main approach to the synthesis of 1,3- and 1,4-oxazepines is based on multicomponent reactions (MCRs) (Kwiecie´n et al. 2012), including the Ugi reaction (Hulme and Dietrich 2009). Original approach to the synthesis of 1,3-oxazepine through the ringopening/recyclization reactions was developed. A MCR for N-propargyl/allyl amine, allyl/propargyl ethers, acrolein and β-oxobutenoates was carried out for the synthesis of 1-allyl(propargyl)-6-allyl(propargyl)oxy-1,4,5,6-tetrahydropyridines, with the participation of cerium(IV) ammonium nitrate (CAN), which catalyzed this fourcomponent one-pot reaction (Sridharan et al. 2009). Next, in situ dihydropyridines were transformed into highly functionalized pyrido[2,1-b][1,3]oxazepines by ringclosing metathesis (RCM) or ring-closing enyne metathesis (RCEYM) processes (Scheme 5.16). It was presented a three-component one-pot reaction involving 3alkyl(aryl)imidazo[1,5-a]pyridines, dimethyl acetylenedicarboxylate (DMAD) and N-alkylisatins for the synthesis of 3,10-dihydro-2H-1,3-oxazepino[7,6-b]indoles under mild conditions in 32–43% yields (Sammor et al. 2018) (Scheme 5.17). Rhodium-catalyzed [5+2] cycloadditions between quinolinium ylides A and electron-deficient alkynes have been used to obtain seven-membered 1,4-oxazepines O

O O R3

CAN (1.5 mol%)

R3

CH3CN, rt

O + OH

O

CH3

O

N

CH3

R1 Grubbs RCM (R = H) RCEYM (R1, R2 = H, Alk)

O

N R2

CH3

R

NH2 3

R = OMe, OEt, S-t-Bu R1 1

R

R2

2

R

Scheme 5.16 Synthesis of highly functionalized pyrido[2,1-b][1,3]oxazepines

3

202

V. R. Akhmetova et al.

X

N +

N R1

MeO2C O

O

CO2Me

CH2Cl2

R

O

+

rt, 24h

N

MeO2C

O

R1 = Me, 4-ClC6H4

R2

CO2Me

X

N

1

N

N

R2

2

R = Me, Bn, 4-ClC6H4

Scheme 5.17 Multicomponent synthesis of 3,10-dihydro-2H-1,3-oxazepino[7,6-b]indoles under mild conditions

+

R

R

CO2R1

N2

N

CH2Cl2, rt, Ar

Ar2 +

Ar1

CO2R1

Rh2(OPiv)4 (2 mol%)

CO2R2

Ar1 O

N O

CO2R2

Ar2 R N Ar1

O Ar2

A

Scheme 5.18 Multicomponent synthesis of 1,4-oxazepine compounds

at room temperature (He et al. 2019). This method has provided the synthesis of highly substituted 1,4-oxazepine structures. Pyridium ylides of α-diazoketones could act as active 1,5-dipole intermediates thus inducing [5+2] cycloadditions with alkynes (Scheme 5.18). The next cycle of works involves the use of isocyanide in MCRs, including the Ugi reaction. A. Shaabani et al. have performed the catalyst-free one-pot reaction of 2-aminophenols, Meldrum’s acid and isocyanides under mild conditions to obtain tetrahydrobenzo[b][1,4]oxazepines in the yields of 75–87% (Scheme 5.19) (Shaabani et al. 2010). A simple MCR of unprotected carbohydrates with D-(L)-amino acids and isonitriles was developed. 1,2-Syn configured oxazepines were formed from L-amino acids and 1,2-anti-isomers—from D-amino acids. By applying this Ugi-type reaction to an unprotected disaccharide novel oxazepines with glycopeptide structure have become accessible in yields up to 76% (Voigt et al. 2015) (Scheme 5.20). Ugi four-component reaction of 2-aminophenols, isocyanides and 2(halogen)benzoic acids with aldehydes to form dibenz[b,f][1,4]oxazepines (route I) was carried out (Xing et al. 2006). Later (Shi et al. 2016), consecutive U-4CR and intramolecular Ullmann etherification of U-4CR products were discussed (route II). The experience with the first procedure showed the formation of U-4CR products in R2

O NH2 OH

CN

CH2Cl2

O

+

O R1

rt, 12h

O

R1 = aliphatic and alicyclic; R2 = H, Me, Cl

Scheme 5.19 Synthesis of tetrahydrobenzo[b][1,4]oxazepines

R2

H N O

O O

O

NH R1

5 An Overview on the Synthesis and Biological Studies …

203

R1

OH

O

R2

O

HO2C

OH HO

N H

OH CN

OH

O

CO2Et

MeOH, 80oC, 3h

OH

OH

N R2

DIPEA 10 mol%

+

O

R1

HO

R1

O

OH

NH CO2Et

O

R2

N

+

NH

HO

CO2Et

O

Scheme 5.20 The three-component Ugi reaction of D-ribose with L-amino acids and ethyl isocyanoacetate

30 min at 60–80 °C under microwave irradiation. By the second way, the reaction has occurred under microwave conditions by using 10 mol% CuI or with 30 mol% of N,N-dimethylglycine hydrochloride (DMG•HCl) in the presence of Cs2 CO3 at 150 °C to produce dibenz[b,f][1,4]oxazepines with a lactam-containing ring in high yields (Scheme 5.21). Benzoxazepinone carboxamides were prepared by Ugi 3CC reactions using bifunctional aromatic compounds with aldehyde and carboxylic acid group, isocyanides and primary amines under mild conditions in 56–91% yields (Zhang et al. 1999) (Scheme 5.22). A novel strategy was designed to explore the Ugi one-pot three-component fourcenter reaction with two bifunctional starting materials: 2-(2-formylphenoxy)acetic acid, 2-aminobenzamide and isocyanide through a refluxing solution in ethanol without using any catalyst. In result, the synthesis of biologically important

Cl CHO

route I 1. MeOH, MW 60oC, 30min

OH R1

2. aq K2CO3, MW, 120oC, 10 min

+ NC 4

NH2 R

O

X CO2H

+

O

NO2

N

NH 4 R 17-49%

O

X

X = H, F, Cl, Br

NO2

R1

Cl

Br CHO +

route II o

1. MeOH, 60 C, 48h 2. CuI, DMG*HCl, Cs2CO3, dioxane, MW, 150oC, 30min

O

CO2H

NO2

R1 NO2

N

O

O

4

R NH Br

81-97%

Scheme 5.21 One-pot synthesis of dibenz[b,f][1,4]oxazepine via U-4-CR-SN Ar and post-Ugi transformation R HN

O

R2

2

R CHO

NH2

N

rt, 24h

O

+ O

CO2H

O

CN R4

2

R = (CH2)2NHCOMe, (CH2)2OH, cycle-Hex, Bn, R4 = (CH2)2S(CH2)2COOMe, n-Bu, (CH2)2OMe, (CH2)2Ph

Scheme 5.22 Synthesis of benzoxazepinone carboxamides in one synthetic step

204

V. R. Akhmetova et al. O NH2 CHO O

NH2 +

CO2H

O

N

O N

EtOH reflux, 24h

NC R1 R1 = tert-butyl; 1,1,3,3-tetramethylbutyl; cyclohexyl

HN O R1

Scheme 5.23 Synthesis of oxazepine-quinazolinone fused heterocyclic scaffolds

benzoxazepine-fused quinazolinones has occurred with excellent overall yields (91–98%) (Shaabani et al. 2019b) (Scheme 5.23). 2-(2-Formylphenoxy)acetic acid as a bifunctional building block was also successfully used in one-pot reaction with different amines and nucleophilic reagents, such as 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile without using catalyst for the synthesis 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-5-ylbenzo[f]quinoxaline2,3-dicarbonitrile derivatives with excellent yields (72–96%) (Hajishaabanha and Shaabani 2014) (Scheme 5.24). A universal synthesis of diarene-fused [1,4]oxazepines and [1,4]thiazepines has been proposed, depending on the use of hydroxy or sulfhydryl aromatic carboxylic acids (Scheme 5.25) (Reutskaya et al. 2019). At first, aromatic carboxylic acids were condensed with diamines monoprotected with a Boc group with the formation of amides. Then the interaction between the latter and bis-electrophilic (halogen- and nitro-substituted) aromatic substrates led to the corresponding [1,4]oxazepines and [1,4]thiazepines. H2N

O R

O N R

CHO + O

NC

N

NC

N

OH

toluene reflux, 24h

CO2H

R = Me, n-Pr, i-Pr, n-Hex, s-Bu, Bn 4-MeC6H4CH2, 2-ClC6H4CH2,

NC

N

NC

N

OH

Scheme 5.24 Synthesis of oxazepine-quinoxaline derivatives

CO2H

+ Y

OH (S)

NHBoc

H2N

n

Z

LG

1

R2 W

LG2

LG1=Hal, LG2=NO2

O

1. CDI,DCM or dioxane 2. Hal-,nitro-Ar, K2CO3, DMF, rt-80oC, 5-24h

N R1

Y

n

Z

O W (S)

Y, Z, W = CH, N

Scheme 5.25 Multicomponent synthesis of [1.4]oxazepines and [1.4]thiazepines

NH2

R2

5 An Overview on the Synthesis and Biological Studies …

205

5.4 Isolated and Benso-Fused Thiazepines, Dithiazepines 5.4.1 Synthesis of Thiazepines Thiazepines being compounds from the azepine class can be formed by rearrangement of cyclic systems. Recently, it was found that the ring opening reaction of 2thia-4-azabicyclo[3.2.0]hepta-3,6-dienes has been realized to give seven-membered heterocyclic derivatives (López et al. 2009) (Scheme 5.26). Triaryl-1,3-thiazepine derivatives along with triarylpyridine were obtained in 15–30% yields from the thiopyrylium salts and the polymer-supported azide (Mouradzadegun et al. 2015a) or azide source in ionic solvent (Mouradzadegun et al. 2015b) (Scheme 5.27). Recyclization of 1,3-thiazole with the acetylenic unit containing an alkyl or aryl substituent (R3 ), and carbonylation with the subsequent addition of the hydrogen (CO–H2 , 1:1, 21 atm) have occurred in the presence of zwitterionic rhodium complex and (PhO)3 P to afford pure thiazepin-5-ones in 86–90% yields (Van den HovenG and Alper 2001) (Scheme 5.28). It is known that 1,4-thiazepin-containing compounds exhibit greater antimicrobial activity against A. baumannii than other compounds lacking this cycle (Patil et al. 2021). Pseudo-three component reaction of β, β-disubstituted acroleins [3-methyl-2butenal (1), 3-methyl-2-hexenal (2) and citral (3)] with cysteine at a reagent ratio of X = H, Y = H, NH2

X

disrotatory ring opening S

X

S

X

N

Y

Y X

N

controtatory ring opening X = CO2H, Y = H, NH2

Scheme 5.26 Recycling of 2-thia-4-azabicyclo[3.2.0]hepta-3,6-dienes into the seven-membered 1,3-thiazepine derivatives

-

Ar2

N3

-

N3

N+

N

Ar2

CH3

Ar2

+

N

H3C N

Ar1

+ S Ar1 ClO4-

130oC

N Ar1

S

Ar1

+ Ar1

N

Scheme 5.27 Recycling of thiopyrylium salts to triaryl-1,3-thiazepines by the azides

Ar1

206

V. R. Akhmetova et al.

R2

N

Rh , (PhO)3P

R3 R1

O

H zw

S

21 atm, CO/H2 (1:1) CH2Cl2, 110oC, 18-36h

R2

N

R1

H S

R3

Scheme 5.28 Recyclization of acetylenyl-1,3-thiazole to thiazepin-5-one by sequence actions of CO and H2

+ 2 R

S

O HS

NH2

pH 1

COOH

COOH

R

R = CH3, CH2CH2CH3, (CH2)2-CH=C(CH3)2

R=(CH2)2CHC(CH3)2

NH S

COOH S HN

COOH NH2

OH

Scheme 5.29 Synthesis of hexahydro-1,4-thiazepines by pseudo-three component reaction of β, β-disubstituted acroleins with two moleculars of cysteine

1:2 led to novel hexahydro-1,4-thiazepines in 31–79% yields (Scheme 5.29) (Starkenmann et al. 2005). Compound on the base of citral reacted further to give a new bicyclic compound.

5.4.2 Synthesis of Benzo- and Heterofused Thiazepines Compounds with benzothiazepine scaffold have been used as pharmaceuticals (Zhao et al. 2018; Almassy et al. 2008; Ruiz et al. 2014), for example, cardiovascular modulator (Mukherjee and Biehl 2004) and antiarrythmic–diltiazem, clentiazem, angiotension-converting enzyme (ACE) (Yi and Zora 2018) inhibitors. In addition, thiazepines have exhibited anticancer (Shaik et al. 2020; Gudisela et al. 2017), antimicrobial (Mor et al. 2012) anti-inflammatory (Lokeshwari et al. 2017) and antiviral activities (Boulware et al. 2001; Li et al. 2017b). It should be noted that the multistage synthesis and applications of benzothiazepines were presented in the review (El-Bayouki 2013). Presented here are one-pot methods for the synthesis of benzo-fused thiazepines. Thiopyran-4-one, located at the ortho-position of nitrobenzene, has undergone in situ reduction to aniline with the following recyclization to form benzo-1,4-thiazepines. Intramolecular recyclization products such as ethyl 5,11dihydrodibenzo[b,e][1,4]thiazepin-11-ylacetate were produced in excellent yields (~97%)(Bates and Stannous 2002). A new semipinacol rearrangement has been offered to explain this extensive skeletal rearrangement under reflux in ethanol in the presence SnCl2 . Compound with benzo[1,4]thiazepine scaffold is of interest as potential means for the treatment of type II diabetes mellitus (Pei et al. 2003) (Scheme 5.30).

5 An Overview on the Synthesis and Biological Studies …

207

O RO2C Cycl

SnCl2 (5 equiv),

S

ROH, reflux, 2 h

S

N H

NO2 Cycl: Ar, thiophen

Cycl

R = Me, Et, sec-Bu

Scheme 5.30 Intramolecular cyclization of 2-(2-nitrophenyl)-thiochroman-4-one

SO2R

NH2

N

K2CO3

H N

+

NHSO2R SH

Br

R = Me, Ph, 4-MeC6H4

S

Scheme 5.31 Synthesis of N-(2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl) sulfonamides

Ts N Ar

1) Cu(OTf)2 (30 mol%), CH2Cl2, rt, 3-6h 2) CuI (10 mol%) L-proline (20 mol%), NaH (2.5 eq), DMF, 90oC, 14h

Br +

R

S(O)H R

Ts

N Ar S(O)

Ar = Ph, 4-Cl-C6H4, 4-F-C6H4, 4-Me-C6H4, 4-tBu-C6H4; R = H, F

Scheme 5.32 Synthesis of tetrahydrobenzoxazepine

The reaction of 2-(bromomethyl)aziridines with o-aminobenzenethiol led to N(2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl)sulfonamides in ~80% yield as a result of intramolecular recyclization in the presence of potassium carbonate (Karikomi et al. 2008) (Scheme 5.31). N-Tosylsubstituted tetrahydrobenzo[e][1,4]thiazepine or tetrahydrobenzo[e][1,4]oxazepine derivatives have been synthesized in high yields (80–85%) (Scheme 5.32) through the ring-opening of 2-aryl-N-tosylaziridine by 2-bromobenzyl mercaptan or alcohols, respectively, followed by CuI-catalyzed N-arylation reaction (Ghorai et al. 2014). The next approach for the synthesis of target products includes MCR. Onepot synthesis of benzothiazepines was successfully carried out involving 1,2aminodithiol or 2-aminobenzenethiol (El-Bayouki 2013). MCR with a Sonogashira coupling–isomerization–cyclocondensation sequence of an electron poor halogenbenzene with nitro, cyan group or heterocycle and a terminal propargyl alcohol in the presence of a Pd(PPh3 )2 Cl2 -CuI catalytic system under reaction conditions (reflux, THF) followed by the cyclocondensation with 2-aminothiophenol led to the formation of 2,4-di(hetero)aryl substituted 2,3-dihydro-benzo[b][1,4]thiazepines (Braun and Müller 2004). It turned out that benzothiazepine structures are quite unstable and under basic conditions or upon heating at 120 °C have been transformed to quinoline rings by elimination of the sulfur atom (Scheme 5.33) (Chanteau et al. 2004).

208

V. R. Akhmetova et al. GWE

aryl

EWG n S

n +

Hal OH aryl

N

F H2N

F

S

1

R = p-F-Ph R

OSiR12R2 R F

CF2-RF

2

N

C4F9

N

Ether or dioxane 1. [Pd, Cu] HS reflux THF, NEt3,reflux 2. then 2-amino-thiophenol Y = H, CF 3 HOAc, reflux Y R = alkyl, aryl, sugar residue 1 2 R SiR 2R OH F F F RF F

R

R

Y 1 2 3 RF or or

O F

F RF

3

Scheme 5.33 The three-component synthesis of 1,4-benzothiazepines

H2N

O Cl

R1

+

R2

+ HS

[2% PdCl2(PPh3)2, 4% CuCl] NEt3, THF, rt, 1h,

R2 S

R1 N

then: 2-amino thiophenol CH3COOH, 60oC, MW, 30min

Scheme 5.34 Three-component synthesis of 2,4-disubstituted benzo[b][1,5]thiazepines

A similar three-component reaction between acid chlorides, terminal alkynes and ortho-amino thiophenols as the Sonogashira coupling–Michael addition–cyclocondensation sequence led to the formation of 2,4-di(hetero)aryl substituted unsaturated benzo[b][1,5]thiazepines in good yields (45–77%) (Willy and Müller 2010) (Scheme 5.34). For the purpose of drug design of benzo-1,4-thiazepines, it has been shown that unsaturated dihydro-1,5-benzothiazepines can lead to substituted benzothiazepinefused β-lactams under the reaction conditions indicated in Scheme 5.35 (Xu 2005). p-Toluenesulfonic acid-catalyzed one-pot synthesis of spiro[indoline-3,4 pyrazolo[3,4-e][1,4]thiazepine]dione derivatives has been occurred by MCR of 5-amino-3-methylpyrazole, isatin and thioacid (Scheme 5.36) (Chen and Shi 2011). This three-component condensation of methyl-5-amino-pyrazoles, thioacids and aromatic aldehydes, or isatins was expanded to produce pyrazolosubstituted or spirofused [indoline-3,4’-pyrazolo[3,4-e][1,4]thiazepine]dione derivatives (Scheme 5.37) (Shaabani et al. 2019a). 1,4-Thiazepines can be produced by the Ugi MCR. For instance, the intramolecular Ugi four-component condensation between 6-oxo-4-thiacarboxylic acids, benzylamines and cyclohexyl isocyanide gave hexahydro-1,4-thiazepin-5-ones and 1,4-benzothiazepin-5-ones in good yields (71–88%) (Marcaccini et al. 2003) (Scheme 5.38). When heteroaryl-fused bifunctional 6-oxo-4-thiacarboxylic acids were used, 1,4-thiazepines were formed (Ilyn et al. 2006). So, for instance, a convenient synthesis of novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides and 5-oxo1,4-thiazepine-3-carboxamides was presented using a modification of the Ugi fourcomponent condensation of various heterocycles, containing carboxylic and carbonyl groups, amines and isocyanides (Scheme 5.39).

5 An Overview on the Synthesis and Biological Studies … Scheme 5.35 Approaches to the synthesis of benzothiazepine-fused β-lactams

209 R1

S

O

R2O

NCH2COCl

N

O

N O

ClCH2COCl

S

R2

N

R1

O

R1

S

Cl NEt3

O 1

N

R

S

R2

Cl2CHCOCl

R2

N

Cl Cl

O

R1

S

PhOCH2COCl

R2

N

OPh O

R3

R2 O

+

N N R1

NH2

R2

R4 O

N

+

OH

HS

R3

CH3CN, 80oC p-TSA, 12-24h

O

N S N

N R1

N H

O R4 O

Scheme 5.36 A one-pot synthesis of spiro[indoline-3,4 -pyrazolo[3,4-e][1,4]thiazepine]dione derivatives

5.4.3 Synthesis of Dithiazepines A MCR as intermolecular cyclization of bifunctional S-nucleophiles, in particular 1,2-ethanedithiol, with various N-containing reagents and formaldehyde is a common approach to the synthesis of perhydro dithiazepines. It should be noted that the cyclocondensation can proceed via route a or b to give the target dithiazinanes (Akhmetova and Rakhimova 2014) (Scheme 5.40). The three-component heterocyclization of amino alcohols and amino acids with formaldehyde and 1,2-ethanedithiol proceeds with the selective formation of hydroxy-containing and N- (carboxymethyl) substituted 1,5,3-dithiazepanes (90– 98%) (Khabibullina et al. 2014, 2016); heterocyclization of ammonium salts NH4 X

210

V. R. Akhmetova et al. R2 R2 CHO

S R3

N o

N

NH2

N

N

120 C 3 + R

N O

H

R1

SH R3

1

R

CO2H

N

R3

O

N

O

S O

CH3CN, 80oC p-TSA, 12-24h

R3

N N

N O

H

R1

Scheme 5.37 Synthesis of pyrazolo[3,4-e][1,4]thiazepine]diones

S R1=Me, R2=H

R2

R3-NH2

S

R1

CO2H

O

+

MeOH reflux, 3h

Me

N

c-C6H11NHOC

O

R3 H

S

R1,R2=-(CH2)4-

c-C6H11NC

c-C6H11NHOC

R3 = C6H5CH2, 4-ClC6H4CH2, 3,4-MDB

N

O

R3

cis / tr ans

Scheme 5.38 Synthesis of hexahydro-1,4-thiazepin-5-ones and 1,4-benzothiazepin-5-ones using the Ugi MCR

S

1. R1-NH2

S CO2H

Het

MeOH

+

O

2. R2-NC CH3

Het

=

N

1

R

O

N

O

Het

HN R2 Ph

CH3 N

N

N N

H3C

CH3

Scheme 5.39 Synthesis of heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides

(X = F, Cl, Br, SO4 ) (Khabibullina et al. 2013) or hydrazine (Akhmetova et al. 2012) under these conditions led to bis-1,5,3-dithiazepanes in 67 and 81% yield, respectively (Scheme 5.41). It was revealed that mono- and bis-1,5,3-dithiazepanes exhibit fungistatic or fungicidal activity against Bipolaris sorokiniana, Fusarium

5 An Overview on the Synthesis and Biological Studies …

211

OH S +

Route a: 2 CH2O + HS(CH2)nSH n

RNH2

S S

OH

R

N n S

R N Route b: RNH2 + CH2O

HS(CH2)nSH

RN=CH2 N R

N R

Scheme 5.40 Synthesis of 1,5,3-dithiazepane by MCR of 1,2-ethanedithiol, amines and formaldehyde

S

R-NH2

S

NH4X

N

S

S

20oC, 2:6:3

S

+ X = F, Cl, Br, SO4

S 67%

HS

H

O

S

N

H

20oC, 1:2:1

S 90-98% NH2-NH2

HS

R N

0-70oC, 1:4:2

S

S N N

R = OH (a), (CH2)2OH (b), (CH2)4OH (c), CH2CH(CH3)OH (d), CH2CH(Ph)OH (e), CH2CO2H (f), (CH2)2CO2H (g)

S

S 81%

Scheme 5.41 Synthesis of mono- or bis-1,5,3-dithiazepane using a MCR of 1,2-ethanedithiol with various N-containing reagents and formaldehyde

oxysporium, Aspergillus fumigatus, Aspergillus niger and Paecilomyces variotii (Akhmetova et al. 2014). There are examples of this MCR for the synthesis of 1,5,3-dithiazepanes by using N,N,N ,N -tetramethylmethanediamine instead of formaldehyde. Thus, in (Makhmudiyarova et al. 2013a), heterocyclization of hetarylamines was carried out in the presence of 5 mol% CuCl2 as the catalyst with the selective formation of 3-hetaryl-1,5,3-dithiazepanes in 64–87% yields (Scheme 5.42) (Rakhimova et al. 2013). The synthesis of α,ω-bis-1,5,3-dithiazepanes was carried out by heterocyclization of aliphatic diamines with N,N,N ,N -tetramethylmethanediamine and 1,2ethanedithiol in the presence of 5 mol% SmCl3 :6H2 O as the catalyst (20 °C, 3 h, EtOH–CHCl3 ). The study of the fungicidal activity of bis-1,5,3-dithiazepan-3-ylethane has shown that this compound completely inhibits the development of Botrytis cineria and Rhizoctonia solani. Another route of the three-component reaction of amines with fomaldehyde and ethanedithiol was realized through the formation of N,N-di(methoxymethyl)amine obtained from aromatic amine and formaldehyde in methanol (Scheme 5.43) (Khairullina et al. 2015). In result, by heterocyclization of N,N-di(methoxymethyl)amine with 1,2-ethanedithiol in the presence CuCl (Makhmudiyarova et al. 2013b, 2015) was successfully isolated N-aryl-perhydro-1,5,3-dithiazepines. This reaction in the

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S

N

X

NH2

H2N

S

N

N

[SmCl3.6H2O]

S

S

Het-NH2

X = (CH2)n, n = 2-10; ((CH2)2O)m(CH2)2, m = 1,2; ((CH2)2S)2

S

60oC, CHCl3

20oC

+ HS

N

SH

Het N

[CuCl2]

S

Het = 5-methyl-1,2-oxazol-3-yl (a), 5-nitrothiazol-2-yl (b), pyridin-3-yl (c), pyridin-2-yl (d), 5-brompyridin-2-yl (e), 5-methylpyridin-2-yl (f), (pyridin-4-yl)metyl (g), 5-nitrobenzothiazol-2-yl (h), 2-(indol-3-yl)ethyl (i), 5-methylpyrazol-3-yl (j).

Scheme 5.42 MCR for the tetramethylmethanediamine

synthesis

of

1,5,3-dithiazepanes

using

N,N,N ,N -

Ar

NH2 + CH2O

SH HS

CH3OH -H2O

S Ar

R

N S

R

OMe

[M] Ar

-2 MeOH

R =H, Me

S

HS(CH2)2SH

[M]

N

Ar

N

-2 MeOH OMe

R = H, CH3

S

Ar = Ph, m,p-CH3C6H4, o,m,p-CH3OC6H4,o,m,p-Cl-C6H4, o,m,p-Br-C6H4, o,m,p-FC6H4

Scheme 5.43 Heterocyclization of aromatic amines with CH2 O and dithiols

presence of Sm-based catalysts gave benso-fused 1,5,3-dithiazepines (Scheme 5.43) (Makhmudiyarova et al. 2016). To obtain compounds of this class, triazine recyclization reactions were also used. Thus, the synthesis of 1,5,3-dithiazepane was based on the recyclization reaction of 5-(tert-butyl) perhydro-1,3,5-trithiazin-2-one with 1,2-ethanedithiol in the presence of BF3 · OEt2 (Scheme 5.44) (Wellmar 1998). It was found (Rakhimova et al. 2012) that o- and p-aminophenols or aminothiophenols upon interaction with an equimolar amount of N-tert-butyl-1,5,3-dithiazepane or 1-oxa-3,6-dithiacycloheptane (conditions: 20° C, 3 h, 5 mol% Sm(NO3 )3 :6H2 O, EtOH: CHCl3 ) selectively form 2- and 4-(1,5,3-dithiazepinan-3-yl)(thio)phenols in 30–85% yields (Scheme 5.45). m-Isomers under the developed conditions NH N

O

S

NH

HS

SH

N BF3.OEt2

S

Scheme 5.44 Synthesis of 1,5,3-dithiazepane by triazine recyclization reactions

5 An Overview on the Synthesis and Biological Studies …

R

O

S

O N H

R

N S

N H [M]

213

R' NH2

NH2 R'

X S

S

S N

[Sm], 20oC

S

X = t-BuN, O; [M] = YbF3, SmCl3.6H2O

R = o-OH (a), p-OH (b), p-SH (c)

R = p-C5H4N (a), m-C5H4N (b), o-MeOPh (c), m-MeOPh (d), MeO (e), t-BuO (f)

Scheme 5.45 Synthesis of N-substitued-1,5,3-dithiazepane by recycling of N-tert-butyl-1,5,3dithiazepane or 1-oxa-3,6-dithiacycloheptane

Scheme 5.46 Synthesis of tetrahydro[1,5,3]dithiazepanindoles

R

R HS(CH2)2SH

O

S

BF3.Et2O

N X

N S

HO X R = H, 10-F, 9-NO2, 9-OCH3 X = CH3, C6H5, CH2NHCOCH3

afford poorly soluble compounds. Similarly, transamination of N-tert-butyl-1,5,3dithiazepane, as well as recycling of 1-oxa-3,6-dithiacycloheptane led to N-(1,5,3dithiazepan-3-yl) amides (Scheme 5.45) using carboxylic acid hydrazides in the presence of catalysts (YbF3 , SmCl3 · 6H2 O) (Khairullina et al. 2013). N-Acylsubstituted indoles in situ allowed to synthesize fused tetrahydro[1,5,3] dithiazepanindoles (45–50% yields). The synthesis was carried out by reactions of N-acylindoles with 1,2-ethanedithiol in the presence of BF3 ·Et2 O (Scheme 5.46) (Tsotinis et al. 2007).

5.5 Summary The literature data have been presented in this chapter on the synthesis and biomedical properties of compounds with an azepine scaffold showed that at the moment the interest of researchers in heterocyclic compounds of this class remains due to the emergence of new methodologies for their synthesis and the identification of specific pharmacological properties. The one-pot formation of seven-membered heterocycles is based on the recyclization reactions of three-, four-, five- and six-membered carbo-, oxa- or azacyclanes, as well as reactions of intermolecular heterocyclization of bifunctional substrates, including one-stage synthesis by using multicomponent reactions such as cyclization of acetylenes with carbonyl compounds and N-nucleophiles Ugi and thiomethylation reaction. New data on the versatile biological activity of azepine derivatives indicate that in future, it will be expected the emergence of new polyfunctional drugs, the molecules of which contain azepine fragments.

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Acknowledgements This work was performed within the framework of the Project part of the State Assignment FMRS-2022-0079.

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Chapter 6

Various Synthetic Strategies and Therapeutic Potential of Thiadiazole, Oxadiazole, Isoxazole and Isothiazole Derivatives Kishor R. Desai and Bhavin R. Patel

6.1 Thiadiazole 6.1.1 Introduction Thiadiazole comprises a five-membered ring with three heteroatoms and is widespread in environment and appears in number of therapeutic molecules and natural products (Christoforou et al. 2006; Khazi et al. 2011; Jain et al. 2013; Hu et al. 2014; Haider et al. 2015; Vadivelu et al. 2015). On the basis of their chemical structure, thiadiazoles can be categorized into four groups as shown in Fig. 6.1. The last decade has seen impressive achievements in the thiadiazole synthesis which widely involved the carbon–sulfur and nitrogen-sulfur bond formation from sulphonyl chlorides, disulfides, or sulphonyl hydrazides. One significant advancement was the use of stable and easily accessible elemental sulfide (Adib et al. 2018; Jiang et al. 2018) as sulfur source in the immediate production of thiadiazoles. As a consequence of advent of organic transformation protocols, several new techniques have been implemented in thidiazole synthesis.

K. R. Desai (B) Department of Chemistry, Bhagwan Mahavir University-Surat, Surat, Gujarat, India B. R. Patel Department of Chemistry, Uka Tarsadia University, Bardoli, Surat, Gujarat, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_6

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Fig. 6.1 Isomers of thiadiazole

6.1.2 Synthetic Strategies for Thiadiazole 6.1.2.1

Synthesis of 1,2,3-Thiadiazoles

1,2,3-Thiadiazole is widely found in nature and, due to its use in the materials industry, has gained considerable interest (Chen et al. 2016a, b) and as therapeutically active agents (Balasankar et al. 2005; Cikotiene et al. 2009; Hayat et al. 2010; Wang et al. 2011; Dai et al. 2016; Chen et al. 2017). These moieties can be synthesized conventionally through Hurd–Mori cyclization reaction (Hurd and Mori 1955; Hu et al. 1999; Attanasi et al. 2005), the Wolff rearrangement (Wolff 1904; Caron 1986), and the Pechmann condensation (Sheehan and Izzo 1949). The development of operationally effective, economical, and straightforward approaches to 1,2,3-thiadiazole has received considerable attention. A number of new strategies have been developed which involve azides/diazo compounds, N-tosyl hydrazones, or sulphonyl hydrazines as starting material. Synthesis of 1,2,3-thiadiazoles from Di-azo/Azide Compounds: A solvent-free strategy for disubstituted-1,2,3-thiadiazoles synthesis from α-enolic di-thioesters with tosyl azide at 0 °C in presence of triethyl amine through cycloaddition was demonstrated by Singh and co-workers in 2013 (Scheme 6.1) (Singh et al. 2013). The annulation of cyano-thioamide derivatives with benzene sulphonyl azide at room temperature in presence of pyridine to afford an amino-cyano substituted1,2,3-thiadiazoles was documented by Filmonov VO’s group in 2017 (Scheme 6.2) (Filimonov et al. 2017). Zhang’s group later identified ground-breaking experiment for disubstituted thiadiazole synthesis from α-diazo carbonyl compounds with carbon disulfide (Scheme 6.3) (Zhang et al. 2018a, b). The notable benefits of the approach were

Scheme 6.1 Synthesis of 1,2,3-thiadiazole by the reaction of α-enolic Dithioesters with tosyl azide

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Scheme 6.2 Synthesis of 1,2,3-thiadiazoles by the reaction of 2-cyano ethanethioamides with benzenesulfonyl azide

Scheme 6.3 Synthesis of 1,2,3-thiadiazoles by the reaction of α-diazo carbonyl compounds with carbon disulfide

mild reaction conditions, the usage of cost-efficient and easily accessible carbon disulfide with improved substrate compatibility. Synthesis of 1,2,3-thiadiazoles from Sulfonyl Hydrazines or N-Tosylhydrazones: The convenient approach for 1,2,3-thiadiazole synthesis using ionic liquid was demonstrated by Kumar and co-workers in 2012 (Scheme 6.4) (Kumar et al. 2012). The methyl ketones reacted with sulphonyl hydrazine supported by ionic liquid to afford corresponding hydrazones supported by ionic liquid which upon treatment with SOCl2 converted into 1,2,3-thiadiazoles.

Scheme 6.4 Synthesis of 1,2,3-thiadiazoles by the reaction of ionic liquid-supported hydrazones with ketones and thionyl chloride

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Scheme 6.5 Synthesis of 1,2,3-thiadiazoles by the reaction of N-tosyl hydrazones with elemental sulfur

Scheme 6.6 Synthesis of 1,2,3-thiadiazoles by α-chlorosulfonohydrazides

TBAI catalyzed 1,2,3-thiadiazole synthesis from N-tosyl hydrazone and elemental sulfur was demonstrated by Chen and co-workers in 2016 (Scheme 6.5) (Chen et al. 2016a, b). This was a simple and feasible technique for obtaining 1,2,3-thiadiazole. The protocol represents a significant improvement in the Hurd–Mori approach. Later, 1,2,3-thiadiazole synthesis from N-tosyl hydrazones and sulfur through chemo-selective oxidative ring formation using impressive flavin–iodine-catalyzed system under metal-free conditions was described by Ishikawa and co-workers (Ishikawa et al. 2017). This technique forbids stoichiometric oxidants from being used. A quite equivalent technique that involves the application of electrons as a reagent for redox processes through an electrochemical approach was developed by Mo et al. (2019). A simple synthetic methodology for 4-substituted-1,2,3-thiadiazole from in situ generated azo alkenes and tri sulfur anion, through detosylation process was described by Liu et al. in 2018 (Scheme 6.6) (Liu et al. 2018). A wide variety of chlorosulfonohydrazides comprising different electron-releasing or electronattracting groups effectively endured this reaction to provide the associated 1,2,3thiadiazoles.

6.1.2.2

Synthesis of 1,2,4-Thiadiazoles

Synthesis of 1,2,4-Thiadiazoles From Thioamides or Their Derivatives Many approaches were employed for 1,2,4-thiadiazoles synthesis from thioamide. One efficient route is the oxidative dimerization of primary thioamide (Scheme 6.7) (Shah et al. 2009; Mayhoub et al. 2011; Mayhoub et al. 2012; Sun et al. 2014; Yajima et al. 2014; Mahajan et al. 2015; Yoshimura et al. 2015; Davison and Sperry 2016; Vanajatha and Reddy 2016; Frija et al. 2017; Wang et al. 2017a, b, 2018).

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Scheme 6.7 Synthesis of 1,2,4-thiadiazole derivatives from thioamides

Scheme 6.8 Synthesis of 1,2,4-thiadiazole derivatives from aryl nitriles

Ammonium sulfide catalyzed dimerization of aryl nitrile can also give the target products (Scheme 6.8) (Noei and Khosropour 2013). 1,2,4-thiadiazole was also synthesized by the reaction of nitriles with thioamides or their derivatives (Scheme 6.8) (Chai et al. 2017, 2018; Tumula et al. 2018). Similarly, 1,2,4-thiadiazole moieties were also constructed through effective oxidation and cyclization of amidine hydrochlorides or iso thiocyanates approach. The one-pot reaction of in situ generated imidoyl thiourea from iso thiocyanates and amidine hydrochlorides which was catalyzed by copper to afford 3-substituted-1,2,4thiadiazole-5-amine was reported by Kim and co-workers in 2014 (Scheme 6.9, route a) (Kim et al. 2014). The catalyst Cu was replaced by I2 as sole oxidizing agent in the same reaction by Wang group in 2017 (Scheme 6.9, route b) (Wang et al. 2017a, b). Almost simultaneously, the 1,2,4-thiadiazole synthesis through intramolecular formation of nitrogen-sulfur bond catalyzed by cobalt in water was identified by Yang and co-workers (Scheme 6.9, route c) (Yang et al. 2019). Synthesis of 1,2,4-thiadiazoles from Amidines or 2-aminopyridines:

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Scheme 6.9 Synthesis of 1,2,4-thiadiazoles from amidine hydrochlorides and isothiocyanates

Scheme 6.10 Synthesis of 1,2,4-thiadiazoles from amidines

The synthesis of diaryl-substituted-1,2,4-thiadiazoles from 2-methylquinolines (or benzaldehydes), amidines, and elemental sulfur and under transition-metal-free conditions was described by Xie and co-workers in 2016 (Scheme 6.10) (Xie et al. 2016). After one year, a palladium-catalyzed disubstituted-1,2,4-thiadiazoles were synthesized from aryl methyl ketones, sulfur, and amidine. The approach was designed by Wang and group (Scheme 6.10) (Wang et al. 2017a, b). The multicomponent reaction of elemental sulfur, amidine, and benzylic bromide afforded nonsymmetric diaryl-substituted-1,2,4-thiadiazoles in basic conditions was demonstrated by Zhou et al. in 2017 (Scheme 6.11) (Zhou et al. 2017).

Scheme 6.11 Synthesis of 1,3,4-thiadiazoles by the reaction of benzyl bromides, amidines, and elemental sulfur

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Scheme 6.12 Synthesis of 1,2,4-thiadiazoles by the reaction of aminopyridines/amidines with isothiocyanates

Molecular I2 catalyzed reaction of amidine or 2-amino pyridines with isothiocyanates through formation of nitrogen-sulfur bond afforded fused-1,2,4-thiadiazoles and imino disubstituted-1,2,4-thiadiazoles was developed successfully by Tumula and group in 2017 (Scheme 6.12) (Tumula et al. 2017).

6.1.2.3

Synthesis of 1,3,4-Thiadiazoles

The subsequent condensation and cyclization through oxidation of thiosemicarbazides with aldehydes in presence of I2 were described by Niu et. al. in 2015 (Scheme 6.13, route b) (Niu et al. 2015). The generation of amino-1,3,4-thiadiazoles from thio-semicarbazones through oxidative intramolecular carbon–sulfur bond formation using DDQ as oxidant was demonstrated by Singh and co-workers in 2016 (Scheme 6.13, route a) (Singh et al. 2016). Three-component coupling of elemental sulfur and two different N-tosyl hydrazones in presence of copper afforded the nonsymmetric disubstituted-1,3,4thiadiazole library in moderate yields was developed by Zhou et al. in 2016 (Scheme 6.14) (Zhou et al. 2016). The 1,3,4-thiadiazole synthesis from different carboxylic acids and hydrazines through one-pot protocol using Lawesson’s reagent was given by Zarei in 2017 (Scheme 6.15) (Zarei 2017).

Scheme 6.13 Synthesis of 1,3,4-thiadiazoles from thiosemicarbazones

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Scheme 6.14 Synthesis of 1,3,4-thiadiazoles by the three-component reactions of two different N-tosyl hydrazones with elemental sulfur

Scheme 6.15 Synthesis of 1,3,4-thiadiazoles by the reaction of carboxylic acids and hydrazines

6.1.2.4

Synthesis of 1,2,5-Thiadiazoles

The 1,2,5-thiadiazole structure was developed over a hundred years ago, and these compounds today exhibit wide range of applications in pharmaceutical chemistry, industry, and analytical chemistry (In 2008, Todres 2011, Konstantinova et al. 2014a, b). Recently, 1,2,5-thiadiazole derivatives have been commonly applied in the development of radical anion salts and are considered to be effective electron receptors, which may have anti-ferromagnetic interactions in their spin systems (Gritsan and Zibarev 2011; Woollins and Laitinen 2011). The synthetic route for 1,2,5-thiadiazoles or its oxide from sulfur monochloride and dimethyl glyoxime was demonstrated by Konstantinova group (Scheme 6.16) (Konstantinova et al. 2014a, b, 2015). The synthesis of 1,2,5-thiadiazoles through ring contraction of disubstituted1,2,6-thiadiazine-ketals in thermal condition was described by Kalogirou and coworkers in 2016 (Scheme 6.17) (Kalogirou et al. 2016). The reaction might take place through Wagner–Meerwein rearrangement.

Scheme 6.16 Synthesis of 1,2,5-thiadiazoles by dimethylglyoxime

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Scheme 6.17 Synthesis of 1,2,5-thiadiazoles from 3,5-diaryl-1,2,6-thiadiazine 4,4-catechol ketals

6.1.3 Therapeutic Potential of Thiadiazole Derivatives Thiadiazoles can be used as antidepressants (Jatav et al. 2008; Sharma et al. 2014), anxiolytic (Clerici et al. 2001; Jubie et al. 2015), antimicrobial (Farghaly et al. 2015), antitubercular (Oruç et al. 2004; Kolavi et al. 2006; Barday et al. 2017), antiinflammatory agents (Salgın-Gök¸sen et al. 2007; Chidananda et al. 2012), antihyperglycemic drugs (Lee et al. 2010), anticancer (Kumar et al. 2010; Abdo and Kamel 2015), anti-hypertensive (Hasui et al. 2011), or antifungal drugs (Zoumpoulakis et al. 2012; Rezki et al. 2015) (Fig. 6.2). Because of their wide range of biological activity, 1,3,4-thiadiazole has been considered as a significant class of heterocycles and demonstrated a broad research interest. A variety of 1,3,4-thiadiazole moiety-containing drugs, such as megazole, acetazolamide are available in the market, but the only commercial medication of 1,2,4-thiadiazole is cefuzonam antibiotics. The diversified range of pharmacological significance of 1,3,4-thiadiazole derivatives has been classified into following categories.

Fig. 6.2 Chemical structures of some bioactive thiadiazoles

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Antibacterial and Antifungal Activity

A new sequence of substituted thiadiazole derivatives (1) has been evaluated for in vitro inhibitory potency against different fungal and bacterial organisms (Önkol et al. 2008). Several substituted 1,3,4-thiadiazoles (2) were screened for their potency against several clinical isolates of Candida albicans (Matysiak and Malinski 2007).

N N

N N CH2

nS

O

N N

HO NH R

S OH

NHR

(2)

(1)

The new 1,3,4-thiadiazole derivative (3) synthesized by Abdel-Wahab et al. (2009) exhibited significant potency against C. albicans and E. coli. Verma et al. described distinct antibacterial and antifungal activity for thiadiazole derivative (4) (Verma et al. 2011).

F

O

O

N N

N H

N

N

N N

N

N

NH

S CH3

S

Ar N

S

S

O

O

Ar (3)

6.1.3.2

(4)

Anticancer Activity

Indole substituted thiadiazoles were prepared by Kumar and group (2010). The synthesized compounds were tested for anticancer potency and identified eight compounds as potent agents for cytotoxicity. 1,3,4-thiadiazole derivative (5) was evaluated as the most active compound of the synthesized library. The compound (6) has established a wide spectrum of growth inhibition potency against human tumor cells.

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OMe N

N

N H

Cl N N

S

Br

6.1.3.3

O

OCH2CH2CH2CH3 HO

S

S

Cl (6)

(5)

Anti-helicobacter Pylori

A Gram-negative Helicobacter pylori is microaerophilic bacterium present in the stomach. Feeling like nausea or an acute gastritis with stomach ache may appear due to acute infection of H. pylori. Imidazole substituted thiadiazoles were synthesized by Moshaf et al. (2011) and tested for their bactericidal potency against H. pylori. Compound (7), exhibits a potential anti-H. pyroli activity.

CH3 N N O2N

S

N

H CH3

N N N CH3 (7)

6.1.3.4

Anticonvulsant Activity

Disubstituted 1,3,4-thiadiazoles were prepared by Rajak et al. (2009) and tested for their anti-convulsant potency. Semicarbazone (8) having nitro phenyl substitution was found to be the most potent derivative compared with carbamzepine. 1,3,4thiadiazoles library was developed by Dogan et al. (2002). Compound (9) exhibited 90% potency against generalized convulsions induced by pentylene tetrazole.

N HN

N N

O HN

N N

S

S

OH

O2N (8)

OH

(9)

NH C2H5

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6.1.3.5

Anti-Inflammatory Activity (COX-Inhibitors)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective substances that are pharmacologically active in treating pain, fatigue, acute and chronic inflammation. It has been reported that thiadiazole incorporated in various heterocyclic motifs has potent anti-inflammatory activity. The several synthetic approach for biphenyl derivative of 1,3,4-thiadiazole (10) were documented by Kumar et al. (2008) and these compounds were evaluated for analgesic and anti-inflammatory potency of varying ranges from 27.27 to 63.63%. The 78.02% inhibitory action in rat had shown by 1,3,4-thiadiazole analogs of naproxen carrying a bromo phenyl substitution (11) at second position of thiadiazole ring (Amir et al. 2007).

CH3 N

N N S

O (10)

6.1.3.6

N

Br S

MeO

N H

HN (11)

Br

Antitubercular Activity

The 1,3,4-thiadiazole derivatives containing furan motif were prepared by Foroumadi et al. (2004) and these derivatives were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis H 37 Rv. The compound (12) and (13) were demonstrated good activity among the synthesized compounds.

N N O2N

O

S

N N S

(12)

6.1.3.7

NO2

O2N

O

S

O

S (13)

O

Antiviral Activity

The thiadizaole derivative (14) was constructed by Hamad et al. (2010) and evaluated for in vitro antiviral potency.

6 Various Synthetic Strategies and Therapeutic Potential of Thiadiazole …

N N

H N

O

233

NH S

O (14)

6.1.3.8

Anti-leishmanial Activity

The parasite Leishmania is responsible for Leishmaniasis disease and is transmitted by sandflies to humans (Navarro et al. 2003). A numerous synthetic derivatives of 1,3,4-thiadiazoles have been well reported and tested in anti-leishmanial assays in recent years. The IC50 of 1.11 μM was shown by compound (15) against L. major promastigotes (Alipour et al. 2011). The 1,3,4-thiadiazole ring containing phenylpiperazine functionality at C2 (16) exhibited a highest potency level of inhibitory concentration at 0.1 μM against L. major promastigotes (Foroumadi et al. 2005).

O2N

O2N

N

O

N S

N

O

N S

CH3

N

S O

N (15)

(16)

6.2 Oxadiazoles 6.2.1 Introduction The five-membered heterocyclic ring with an oxygen atom and two nitrogen atoms is known as oxadiazole. Two methylene (=CH) groups of furan when substituted with nitrogen (–N = ) to afford oxadiazole (Nagaraj et al. 2011; Boström et al. 2012). Depending upon the position of nitrogen atom, four types of oxadiazole is shown below in Fig. 6.3. 1,3,4-oxadiazole is a significant moiety among the various heterocyclic compounds for the production and design of new pharmaceutically potent molecules. There is a broad physiological potency of compounds containing 1,3,4-oxadiazole cores. Because of their elite structure, having vast physiological outlook, the ability

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Fig. 6.3 Isomers of oxadiazole

of 1,3,4-oxadiazoles to undergo various chemical transformations has made them crucial for molecular design.

6.2.2 Synthetic Strategies for Oxadiazole Different protocols for the preparation of 1,3,4-oxadiazol have been described in the literature, some of which are as follows. Microwave-assisted rapid and efficient solvent-free approach for disubstituted oxadiazoles synthesis from fatty acid hydrazides have been reported by N. N. Farshori (Scheme 6.18) (Farshori et al. 2017). Silica and sulfuric acid-catalyzed expeditious and eco-friendly methodology for 1,3,4-oxadiazoles synthesis was described by M. Dabiri and co-workers (Scheme 6.19) (Dabiri et al. 2007). One pot efficient and convenient approach for preparation of substituted-1,3,4oxadiazoles has been demonstrated by P. Stabile (Scheme 6.20) (Stabile et al. 2010). The preparation of new library of amino-substituted-1,3,4-oxadiazoles containing benzimidazole core was documented by Kerimov and co-workers. The titled

Scheme 6.18 Synthesis of 2,5-disubstituted -1,3,4-oxadiazoles from fatty acid hydrazides under microwave

Scheme 6.19 Synthesis of 2,5-disubstituted -1,3,4-oxadiazoles using silica and sulfuric acid

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Scheme 6.20 One-pot synthesis of 2-phenyl -5-substituted-1,3,4-oxadiazoles

Scheme 6.21 Synthesis 2-amino-1,3,4-oxadiazoles carrying a benzimidazole moiety

compounds were synthesized by the reaction between phenyl substituted benzimidazole acetohydrazide and cyanogen bromide (Scheme 6.21) (Kerimov et al. 2012). Sauer and co-workers reported a straightforward eco-friendly methodology for 1,2,4-oxadiazoles synthesis from aldoxime and N-protected amino acid in Acetone– Water in high yield in 2019 (Scheme 6.22) (Sauer et al. 2019). The process, which is advantageous in terms of easy work-up procedure, requires a short reaction time with better yield. Amidoxime and esters underwent the condensation in presence of K2 CO3 afforded 1,2,4-oxadiazoles through a conveniently one-step process. This method was found to be very useful in the synthesis of various mono-and bis-oxadiazoles with excellent yields (Scheme 6.23) (Amarasinghe et al. 2006). The reaction of trichoro acetoamidoxime with acyl chlorides (R = methyl ethyl, propyl, Ph, CH2 Cl, CHCl2 , CCl3 ) in toluene for 20 h at 100 °C gives 5-substituted3-trichloromethyl-1,2,4-oxadiazoles conveniently in one step. The protocol was described by Bretanha (Scheme 6.24) (Bretanha et al. 2009). The application of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate, TBTU as an activating agent for carboxylic acid functionality in

Scheme 6.22 Microwave-assisted synthesis of 1,2,4-oxadiazole

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Scheme 6.23 Synthesis of mono- and bis-1,2,4-Oxadiazole

Scheme 6.24 Synthesis of 5-substituted-3-trichloromethyl-1,2,4-oxadiazoles

ortho acylation step for 1,2,4-oxadiazoles synthesis from amidoxime and carboxylic acids was given by Poulain (Scheme 6.25) (Poulain et al. 2001). The library of 1,2,4-oxadiazoles moieties was synthesized by this method. p-toluene sulphonic acid and anhydrous zinc chloride catalyzed reaction of amidoximes with organo-nitriles in dimethyl formamide at 80 °C formed 1,2,4oxadiazoles. In this case, the reaction was completed in 4–8 h. However, the reaction time was considerably decreased (1–2 h) in the same reaction when it was carried out in acetonitrile as solvent (Scheme 6.26) (Augustine et al. 2009). The 1,3-dipolar cycloaddition approach for preparation of trisubstituted 1,2,4oxadiazoles was given by Ajay Kumar and co-workers (Ajay Kumar and Lokanatha Rai 2004). The reaction was carried out by the action of nitrile oxides and imines,

Scheme 6.25 The synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using TBTU

Scheme 6.26 The synthesis of 1,2,4- oxadiazoles from organo nitrile using PTSA

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Scheme 6.27 The synthesis of trisubstituted 1,2,4-oxadiazoles

Scheme 6.28 Synthesis of 1,2,4-oxadiazoles with Vilsmeier reagent as a carboxylic acid group activator

which were generated through chloramine-T induced dehydrogenation of aromatic aldoximes. The adduct products were evaluated for their potency against various bacteria and fungi (Scheme 6.27). In 2018, Zarei M. reported an interesting, one-pot synthetic methodology for disubstituted-1,2,4-oxadiazoles synthesis from carboxylic acids and amidoximes. The activation of –COOH group with Vilsmeier reagent was taken place during the reaction (Scheme 6.28) (Zarei 2018). The advantages of the associated approach in the application of accessible starting materials, the one-pot synthesis strategy, decent to excellent yields (61–93%), and an easy purification protocol. The two-component one-pot synthesis of 3,5-diaryl-substituted-1,2,4-oxadiazole from gem-dibromo methylarenes with amidoximes was reported by Vinaya K. et al. in 2019 (Scheme 6.29) (Vinaya et al. 2019). The availability of different gem-dibromo methylarene derivatives and excellent yields (about 90%) of the product were the key benefits of this method. However, its broad application was diminished by long reaction time and complex purification protocol. The visible light irradiated cycloaddition reaction of nitroso arenes with disubstituted-2H-azirines to give trisubstituted-1,2,4-oxadiazoles was presented and studied by Cai B et al. in 2019 (Scheme 6.30) (Cai et al. 2019). A Green effective synthetic protocol for 1,2,4-oxadiazole synthesis is included in this synthetic strategy. Moderate yields (35–50%) restrict the broad application of this type of transformation despite promising and environmentally friendly circumstances.

Scheme 6.29 Synthesis of 3,5-substituted-1,2,4-oxadiazoles using gem-dibromomethylarenes

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Scheme 6.30 [3+2]-cycloaddition of 2H-azirines and nitrosoarenes

6.2.3 Therapeutic Potential of 1,3,4-Oxadiazole Derivatives The oxadiazole nucleus, which is typical and essential part of variety of natural products and pharmaceutical products, is one of the most important and well-known heterocyclic moiety. In a number of drug domains, such as antimicrobial, antitubercular, anti-inflammatory, anticancer, anticonvulsant, hypoglycemic, molluscide, etc., oxadiazole nucleus is present as a main structural component. They have been classified as pharmaceutically relevant scaffolds due to the large spectrum of physiological potency of oxadiazole and its derivatives.

6.2.3.1

Antimicrobial Activity

The 1,3,4-oxadiazole derivatives (17,18 and 19) synthesized by Hui. et al. through Mannich reaction were screened for growth-inhibitory potency against E.Coli, S.aureus, and B.subtilis. Compound (19) containing phenyl substitution was found most potent candidates of this series (Hui et al. 2002).

O

R1 N O

N

O (17)

N

R2

N O

N

O (18)

N

N R1 R2

O

N

N

O (19)

R

Shah’s group prepared series of 1,3,4-oxadiazole derivatives (20) and evaluated their growth-inhibitory potency against gram-positive bacteria B. megaterium and S. citrus and gram-negative bacteria S. typhi and E.coli. The derivatives containing methoxy and isopropyl substitutions give good results in the antimicrobial studies (Shah et al. 1996).

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NO N

O

N O NH R

(20)

6.2.3.2

Anticancer Activity

Mazumder synthesized 1,3,4-oxadiazole containing benzimidazole and quinoline moieties (21,22). The synthesized derivatives were tested for their anticancer potency on various cell lines/panels. Compound (22) (when R = dimethoxyphenyl) showed high activity on CNS cancer and renal cancer and displayed 95.70 growth percent (GP) and the compound (21) (when R = phenoxymethyl) showed high activity on CNS cancer and displayed 96.86 GP in in vitro testing on cancer cell line (Mazumder and Shaharyar 2015).

N R N

R1

O

N

N N

O N N

N Cl

Cl

(22)

(21)

Holla synthesized some chloro substituted-1,4-bis methyleneoxy phenylene derivatives of 1,3,4-oxadiazole (23) and their in vitro potency as anticancer agents were tested against different human cancer cell line including CNS, colon, melanoma, lung, prostrate, ovarian, renal, leukemia, and breast cancer. The R = chloro substituted phenyl ring exhibited prominent potency against most of the cancer cell line (Holla et al. 2005).

R

Cl

O N N

N N

O

O (23)

O

R

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K. R. Desai and B. R. Patel

Anti-inflammatory Activities

Some newer 1,3,4-oxadiazole containing indole and pyrazoline nucleus (24) had synthesized by Sharma and co-workers. The compounds obtained were evaluated against their anti-inflammatory activity. Compared to phenylbutazone (45.6% inhibition at 50 mg/kg dose), the most active 49 percent inflammation inhibition at same dose was found for the compound with R = p-hydroxy phenyl substitution of this sequence (Sharma et al. 2002).

R

H N N N

N N H

O

O

N

(24)

Khan et al. prepared pyridine substituted-oxadiazole-2-thiol (25) and (26). The anti-inflammatory activity was evaluated for the synthesized compounds. Compared to the standard drug indomethacin, compounds (25 and 26) showed promising results with 40.7 and 39.2% inhibition, respectively (Khan et al. 2004).

N N

N

O S (26)

SH

(25)

6.2.3.4

N N

N

O

O

Antitubercular Activities

In 1999, Kagthara synthesized aryl sulfonamido derivatives of 1,3,4-oxadiazoles (27) and benzoylamino1,3,4-oxadiazoles having benzimidazole core (28). The prepared compounds have been screened for their antiTB potency against M. tuberculosis H37 Rv using BACTEC method (Kagthara et al. 1999).

H N

N N O

H N

S O2

R

H N

N N O

H N

N

N

(27)

(28)

R O

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In 2013, Dighe and colleagues have prepared a novel library of some 1,2,3oxadiazole derivatives containing substituted benzimidazole core to find improved anti-inflammatory and antitubercular potency (29) (Dighe 2013). The antitubercular activity was screened against M. tuberculosis H37 Rv strain. Good antitubercular activity has been shown by the compounds having R = -phenyl, o-hydroxy phenyl, and p-amino phenyl substitution.

S

N N

R O

N N

S R’

(29)

6.2.3.5

Molluscidal Activities

Fused oxadiazole with thiazoline (30) was synthesized by Nizamuddin and Singh. The molluscicidal activity against Lymnaea acuminate was evaluated for the synthesized compound (Singh 2004).

N S

6.2.3.6

N

R

O (30)

Hypoglycemic Activities

Hokfelt synthesized a number of alkyl aryl sulfonamido-l,3,4-oxadiazoles (31), and the synthesized derivatives were tested for their hypoglycemic potency. It was observed that several synthesized compounds showed a powerful hypoglycemic potency. The compound containing 3–5 carbon comprising alkyl group was found to have optimal activity. The p-amino group was found to be a prerequisite for hypoglycemic potency (Hokfelt and Jonsson 1962).

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R O N N S O N O H

R1

(31)

6.2.3.7

Anticonvulsant Activities

Fluoro phenoxy phenyl substituted oxadiazoles (32) were synthesized by Almasirad et al. and their anticonvulsant activity has been screened. Oxadiazole ring having amino substituent on 2nd position has the best anticonvulsant potency in both MES and PTZ models (Almasirad et al. 2004).

NH2 N N

O

F O (32)

A novel semicarbazone derivatives of oxadiazole (33) were synthesized by Rajak et al. and evaluated for their anticonvulsant activity. MES, scPTZ, and scSTY models were used to investigate the anticonvulsant activities of synthesized compounds (Rajak et al. 2013).

R2 O N N O

N NH

R1

O (33)

6.2.3.8

Antiprotozoal Activities

In 1999, Patil and co-workers prepared some novel indole substituted 1,3,4oxadiazole-thione (34) and indole substituted 1,3,4-oxadiazol acetohydrazide (35).

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Their anthelmintic potency was tested against Pheratima posthuma using piperazine citrate as standard (Patil and Biradar 1999).

R

R1 O N H

S

R1

R

O

N NH

N H

N N

S O N H

NH2

(35)

(34)

Maske prepared several oxadiazole having diethyl amino-substituted benzimidazole (36) in 2012. The antiprotozoal activity for the synthesized compound was evaluated against Paramecium caudatum and Vorticella campanula. It was found that para-substituted phenyl group exhibited better potency against P. caudatum (Maske et al. 2012).

N

N S N

R N N (36)

6.2.4 Therapeutic Potential of 1,2,4-Oxadiazole Derivatives A five-member heterocyclic ring 1,2,4-oxadiazole has gained significant interest among the researchers due to its bioisosteric characteristics and an exceptionally wide variety of pharmacological potential. It is therefore providing a great platform for the production of novel drugs. A century after the discovery of 1,2,4-oxadiazole, the unusual potential attracted medical chemists’ interest, leading to the development of a few commercially available medicines incorporating 1,2,4-oxadiazole. It should be noted that curiosity in the biological application of 1,2,4-oxadiazole has increased in the last 15 years. Pharmaceutically potent tests of 1,2,4-oxadiazole derivatives were reported in the early 1940s and 20 years later, and the first-in-class commercial drug-containing 1,2,4-oxadizaole ring oxolamine (Fig. 6.4) was introduced into the pharmaceutical industry as a cough suppressant (Anderson et al. 1942; Catanese and Silvestrini 1964). Over the past 40 years, the 1,2,4-oxadiazole heterocycle has been studied extensively, bearing numerous compounds with various physiological potency, for

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Fig. 6.4 Chemical structures of commercial drugs based on a 1,2,4-oxadiazole scaffold

example, antibacterial, antifungal, anti-inflammatory, anticancer, antiviral, analgesic, anticonvulsant, anti-depressant, antiparasitic, anti-alzheimer, antiangiogenic, antiinsomnia, and anti-edema. Butalamine (vasodilator, Fig. 6.4), Fasiplon (nonbenzodiazepine anxiolytic drug, Fig. 6.4), Ataluren (Duchenne muscular dystrophy treatment drug, Fig. 6.4), Pleconaril (antiviral drug, Fig. 6.4), Oxolamine, Prenoxdiazine (cough suppressant, Fig. 6.4) and Proxazole (a drug for gastrointestinal function) are currently a few commercially available medicines comprising 1,2,4-oxadiazole nucleus (Coupar et al. 1969; Rotbart et al. 2001; McDonald et al. 2017). Only one of the isomers of oxadiazole, the 1,2,4-oxadiazole ring exists in natural product structures. For instance, two indole alkaloids, Phidianidine A & B (Fig. 6.5), were isolated from the Opisthobranch Phidiana militaris sea slug by Carbone et al. (2011). Both Phidianidines have been shown to exhibit in vitro cytotoxic potency against tumor and non-tumor mammalian cell lines (colon adenocarcinoma-CaCo-2,

Fig. 6.5 Chemical structures of naturally occurring 1,2,4-oxadiazole-containing compounds

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245

human cervical-HeLa, rat heart myoblast-H9c2, and mouse embryo-3T3-L1) as well as selective agonist potency against chemokine receptor type 4 and protein-tyrosine phosphatase 1B (Vitale et al. 2013; Zhang et al. 2016). Quisqualic acid (Fig. 6.5), obtained from the seeds of Quisqualis indica, is another example of a naturally occurring compound bearing 1,2,4-oxadiazole. This alanine derivative is associated with metabotropic glutamate receptors type-II and IV, which are ideal molecular targets for treating neurodegenerative disorders, epilepsy, and stroke (Kozikowski et al. 1998; Hermit et al. 2004).

6.2.4.1

Anticancer Agent

The 1,2,4-oxadiazole ring having aniline and tertiary butyl substitution (37) was synthesized by Maftei and group in 2013. The synthesized compound showed moderate potency with inhibitory concentration of approximately 92.4 μM against panel of 11 cancer cell lines “(gastric carcinoma, lung adenocarcinoma, non-small cell lung carcinoma, colon adenocarcinoma, melanoma, ovarian adenocarcinoma, uterus carcinoma, breast cancer-derived from athymic mice’ lung metastatic site, renal cancer, pancreatic cancer, pleuramesothelioma cancer)” (Maftei et al. 2013).

N O

NH2

N (37)

6.2.4.2

Antimicrobial Agent

The preparation of diarylsubstitued-1,2,4-oxadiazole derivatives was documented by Cunha F. S. et al. in 2018. The prepared compounds were evaluated for their antimicrobial potency against E. faecalis, P. aeruginosa, E.coli, P.mirabilis, and S.aureus using agar diffusion method (Cunha et al. 2018). Activity results described that some of the synthesized compounds exhibit good inhibitory activity against the growth of E.coli, E.faecalis, and P.mirabilis. However, no activities were observed against P. aeruginosa and S. aureus. The most active compound was (38) having minimal inhibitory concentration value of 60 μM against E. coli. In addition, antimicrobial activity was decreased by the substitution of -NO2 functionality or -Cl atom attached to aromatic carbon. It turned out that the existence of -NO2 functionality is crucial for activity.

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N O2N

Cl

O N (38)

Inspired by the structure of cinnamic acid as antitubercular agents, Upare and group documented the preparation and physiological screening of novel 1,2,4oxadiazole derivatives in 2019 (Upare et al. 2019). Cinnamic acid and its derivatives have been shown to demonstrate strong biological activity against Mycobacterium tuberculosis, so in order to improve the anti-tuberculosis properties, it thus seemed fitting to add 1,2,4-oxadiazole to cinnamic acid (Cardona 2012). Compounds acquired have been tested against M. tuberculosis (H 37 Ra). The findings suggested that the compound (39) displayed the greatest anti-tuberculosis activity.

N N O O

(39) OH

6.2.4.3

Anti-inflammatory Agent

The preparation of mercaptobenzthiazole-clubbed-1,2,4-oxadiazole was described by Yatam S. et al. The prepared compound were screened for their in vivo and in vitro inflammatory potency (Yatam et al. 2018). Among the derivatives acquired, the compound (40) was the most potent and selective against COX-2 (5.0 μM IC50 value), but its potency was much weaker than the reference compounds celecoxib and indomethacin, widely used NSAIDs (0.36 and 0.038 μM IC50 values, respectively). Interestingly, in vivo experiments of (40) demonstrated higher potency than that of ibuprofen in carrageenan-induced rat paw edema assays (81% of inhibition of inflammation for 34 and 72% of ibuprofen inhibition).

O N O N S S N

N O (40)

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6.2.4.4

247

Anti-allodynic Agents

The synthesis of -phenyl substituted-1,2,4-oxadiazoles was demonstrated by Cao and group in 2019. They tested a series of synthesized compounds as potent anti-allodynic agents having affinity to σ1 and σ2 receptors with poor activity to other CNS receptors at the same time (Cao 2019). The preparation of compound hybrids based on the 1,2,4-oxadiazole structure with pyrimidine and pyridazinone as pharmacophore sixmembered heterocyclic rings resulted in improved activity, based on their previous study (Lan et al. 2014; Cao et al. 2016). The in vitro primary σ1 and σ2 binding assay was evaluated for synthesized compounds using radiolabelled ligands. Compound (41) exhibited the highest affinity and selectivity to σ1 receptor.

N

N O N Cl

6.2.4.5

(41)

Cl

Anticonvulsant Agents

A number of coumarin- and acridone- hybrid 1,2,4-oxadiazoles (41–42) were presented by Mohammadi-Khanaposhtani M. The anticonvulsant activity was tested for the synthesized derivatives PTZ and MES models in mice (MohammadiKhanaposhtani et al. 2015, 2016).

O O N O N N O (41)

O

O

O

N N O

(42)

Cl

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Anti-Alzheimer Agents

The synthesis of coumarin substituted 1,2,4-oxadiazole hybrids was performed by Zhang J. et al. in 2018. The synthesized compounds were evaluated as neuroprotective potency with selective BChE and AChE antagonists (Zhang et al. 2018a; b). Moderate potency toward AChE with inhibitory concentration ranging from 89.7 to 45.6 μM was resulted for all synthesized compounds. The most selective BChE inhibitor exhibiting inhibitory concentration values 8.2 and 77.6 μM against AChE and BChE, respectively, was compound (43).

O

O

O N (43)

HN

N O

6.3 Isoxazole 6.3.1 Introduction In organic chemistry, isoxazoles are significant 5-membered aromatic heterocycles. Many isoxazoles are essential components of tiny chemical entities found in everyday synthetic goods (Grünanger and Vita-Finzi 2009; Grünanger et al. 2009; AlvarezBuilla et al. 2011; Boyd et al. 2014). In recent years, number of exciting advances in isoxazole synthesis and functionalization have been reported. In particular, new transition-metal-catalyzed reactions have resulted the synthesis of attractive and highly efficient synthetic approaches to densely functionalized isoxazoles.

6.3.2 Synthetic Strategies for Isoxazole 6.3.2.1

Synthesis of Isoxazoles via [3+2] Cycloaddition Reactions

In 2014, Oakdale group reported ruthenium (II) catalyzed dipolar addition of 1haloalkynes to afford isoxazoles via [3+2] cycloaddition (Scheme 6.31) (Oakdale et al. 2014). The reaction afforded useful 4-halo-isoxazoles. The product showed outstanding regioselectivity and tolerates a wide range of functional groups, but the electron-withdrawing group must be retained in the reactive alkynes. In this reaction,

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249

Scheme 6.31 Synthesis of 4-haloisoxazoles via Ru(II)-catalyzed 1,3-dipolar cycloaddition of 1haloalkynes

the reduced steric obstruction of the cyclopentadienyl ligand is assumed to play an important role. The efficient tandem Sonogashira coupling of alkynes with acid chlorides produces 4-disubstituted isoxazoles having acyl functionality via a thermallypromoted cycloaddition with nitrile oxides (Scheme 6.32) (Willy and Mueller 2008; Willy et al. 2008). The protocol was documented by Willy in 2008. The authors found that the use of microwave irradiation (90 °C, 30 min) provided ideal cycling conditions for alkynone nitrile oxide. The facile and regioselective dipolar cycloaddition of nitrile oxides with onitrophenyl alkynes to afford trisubstituted isoxazoles in better yields was demonstrated by McIntosh group in 2012 (Scheme 6.33) (McIntosh et al. 2012). The existence of -NO2 substituent is essential to obtain successful cycloaddition.

Scheme 6.32 Synthesis coupling/cycloaddition

of

3,4,5-trisubstituted

isoxazoles

via

two-component

Scheme 6.33 Regioselective synthesis of 3,5-disubstituted and trisubstituted isoxazoles using ortho-nitrophenyl alkynes in [3+2] cycloaddition

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K. R. Desai and B. R. Patel

Catalyst Promoted Cycloaddition

N-heterocyclic carbene (NHC) catalyzed dipolar cycloaddition of alkynes with nitrile oxides was documented by Kankala and group in 2011 (Scheme 6.34) (Kankala et al. 2011). The reaction continues with very high selectivity for cycloaddition of both disubstituted and terminal alkynes. The mild reaction conditions and high functional group tolerance are also noteworthy remember. The preparation of bis-isoxazoles through metal-free click cycloaddition of terminal alkynes with dichloro glyoxime in presence of aq. potassium hydrogen carbonate was reported by Van der Preet in 2013 (Scheme 6.35) (Van der Peet et al. 2013). The preparation of isoxazoles through in situ generations of nitrile oxides from the corresponding oxime in presence of hypervalent iodine was described by Yoshimura and Zhdankin in 2013 (Scheme 6.36) (Yoshimura et al. 2013).

Scheme 6.34 NHC-catalyzed synthesis of isoxazoles via 1,3-dipolar cycloaddition

Scheme 6.35 Synthesis of bis-isoxazoles via metal-free click reaction

Scheme 6.36 Synthesis of isoxazoles via [3 + 2] cycloaddition by generation of nitrile oxides from oximes

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Scheme 6.37 Synthesis of 3,5-disubstituted isoxazoles via hydroamination of 1,3 dialkynes/cycloisomerization

Scheme 6.38 Gold(I)-catalyzed synthesis of 4-fluoro-3,5-disubstituted isoxazoles from alkynyl oxime ethers via cyclo-isomerization/fluorination

6.3.2.3

Metal-Free Cyclodimerizations

The metal-free cyclodimerization of hydroxyl amine with dialkynes under mild conditions to afford, 5-disubstituted isoxazoles was reported by Wang and co-workers in 2012 (Scheme 6.37) (Wang et al. 2012).

6.3.2.4

Metal-Catalyzed Cyclo-Isomerization’s

Gold(I)-catalyzed cyclo-isomerization and fluorination alkynyl oxime afforded disubstituted-4-fluoroisoxazoles. The protocol was reported by Jeong et. al. in 2014 (Scheme 6.38) (Jeong et al. 2014). One of the most prominent features of regioselectivity control in the preparation of isoxazoles by N-alcoxy carbonyl amino ethers and propargylic N-hydroxy carbamates through platinum-catalyzed cyclo-isomerization was reported by Allegretti and group in 2013 (Scheme 6.39) (Allegretti and Ferreira 2013).

6.3.2.5

Synthesis of Isoxazoles via Condensation Reactions

The condensation of α, β—unsaturated carbonyl compound with N-hydroxy-ptoluene-sulphonamide to afford the 3,5-disubstituted isoxazoles was observed by Tang and co-workers in 2009 and 2010 (Scheme 6.40) (Tang et al. 2009, 2010).

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Scheme 6.39 Platinum(II)-catalyzed regioselective synthesis of positional regioisomers of 3,5disubstituted isoxazoles from N-hydroxycarbamates and N-alkoxycarbonyl amino ethers

Scheme 6.40 Regioselective synthesis of 3,5-disubstituted isoxazoles via conjugate addition/condensation

A one-pot synthetic methodology for disubstituted isoxazoles from terminal alkynes, hydroxylamine, and aldehydes was described by Harigae et. al. in 2014 (Scheme 6.41) (Harigae et al. 2014).

Scheme 6.41 Synthesis of 3,5-disubstituted isoxazoles from terminal alkynes

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Scheme 6.42 Synthesis of 3-substituted isoxazole-4-carbaldehydes from 3-oxetanones

Scheme 6.43 Palladium(II)-catalyzed synthesis of 1,2-benzisoxazoles via CH activation

6.3.2.6

Synthesis of Isoxazoles via Miscellaneous Methods

The highly efficient methodology for 3-substituted-isoxazole-4-carboxyaldehyde synthesis through base mediated rearrangement of oxetanes was given by Huang and group in 2011 (Scheme 6.42) (Huang et al.). The first example for benzo-fused isoxazoles synthesis via amide-directed carbonhydrogen bond activation of N-phenoxy acetamides/[4+1] annulation with aldehyde was disclosed by Duan and co-workers in 2014 (Scheme 6.43) (Duan et al. 2014).

6.3.3 Therapeutic Potential of Isoxazoles Among the large variety of heterocycles studied for the development of pharmacologically significant molecules, isoxazoles play a crucial role in the field of medicinal chemistry. Isoxazoles are an important class of heterocycles widely used in pharmaceuticals and therapeutics such as antimicrobials, analgesic agents, anti-inflammatory agents, antioxidants, anticancer agents, anti-tuberculosis agents, etc.

6.3.3.1

Antimicrobial Isoxazoles

In order to obtain strong pharmacological active isoxazole derivatives, Sagar and group, (Sagar et al. 2017) fused the two entities (substituted aromatic aldehyde and ketones) with isoxazole (44) (Fig. 6.6). Isoxazole derivatives exhibited growthinhibitory potency against bacteria, as predicted, in which some compounds are better and some are moderately potent relative to standard drugs studied. Some

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Fig. 6.6 Structures of antimicrobial isoxazoles

gram-positive and gram-negative microorganisms have been screened for inhibitory potency. P. Kumar et. al. synthesized isoxazole derivatives bearing disubstituted phenyl ring and quinoline moiety (45) (Fig. 6.6) (PKumar and Jayaka 2015). The eight compounds prepared were screened for growth-inhibitory potency against escherichia coli, bacillus subtilis, staphylococcus aureus, and pseudomonas aeruginosa bacteria. The compounds were also tested for growth-inhibitory potency against saccharomyces cerevisiae and aspergillus niger fungi. The preparation of novel isoxazoles, cyanopyridine, and pyrimidinthiones (46) (Fig. 6.6) from chalcones having s-triazine nucleus was reported by Anjani S. et al. (Solankee et al. 2013). The various synthesized derivatives were tested against certain bacteria and fungi for their antimicrobial activity. Nearly all the compounds demonstrated antimicrobial activity.

6.3.3.2

Analgesic and Anti-inflammatory Isoxazoles

Joseph and George (2016) developed novel isoxazole series (47) (Fig. 6.7) and tested the synthesized derivatives for their in vivo and in vitro anti-inflammatory potency.

Fig. 6.7 Structures of analgesic and anti-inflammatory isoxazoles

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Seven compounds demonstrate important inhibition potency against inflammation out of 25 synthesized isoxazole derivatives. The synthesis, anti-inflammatory, and antibacterial activity of novel indolylisoxazoles (48) (Fig. 6.7) were demonstrated by Panda et al. (2009). The acute antiinflammatory potency and antibacterial potency were evaluated for the synthesized compound. The design and synthesis of some new diphenylamino Isoxazole derivatives (49) (Fig. 6.7) were stated by Dravyakar et al. (2008). They tested these compounds for anti-inflammatory potency. When compared with ibuprofen as standard antiinflammatory agent, all the synthesized compounds showed better potency.

6.3.3.3

Antioxidant Isoxazoles

The synthesis of a series of styryl substituted isoxazoles (50) was published by Madhavi et al. (2010) with a view to evaluate the impact of nitro substitution on styryl isoxazoles. Good anti-inflammatory activity with better antioxidant properties as well as ulcerogenic potential and are devoid of toxicity was exhibited by the compounds having sterically hindered phenolic groups.

O2 N N O

R (50)

6.3.3.4

Anticancer Isoxazoles

The synthesis and physiological screening of some novel isoxazole derivatives 51a– 51c (Fig. 6.8.) were described by Hamama et al. (2017). The antitumor activity was screened for the newly synthesized compounds compared to 5-fuloro uracil as a well-known cytotoxic agent using ehrlich ascites carcinoma cells. Interestingly, the precisely collected results described that six compounds had elevated antitumor activity compared to 5-fluoro uracil. In 2012, Kalirajan et al. documented a convenient approach toward the synthesis of novel anilinoacridine substituted isoxazole derivatives 52 (Fig. 6.8.) (Kalirajan et al. 2012). The compounds were tested for in vitro antioxidant potency. In the HEp-2 cell line, the cytotoxic potency of the compounds was also studied. All of the compounds’ isoxazole derivatives have important pharmacological potency.

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Fig. 6.8 Structures of isoxazoles exhibits anticancer activity

6.3.3.5

Antitubercular Isoxazoles

Khanage et al. synthesized triazole hybrid new class of isoxazole derivatives (53) in order to satisfy structural prerequisite necessary for growth-inhibitory potency against bacteria and tumor cells (Khanage et al. 2012). In vitro growth-inhibitory potency against bacteria for example e.coli, c. albicans, b. subtillis, and a. niger was screened and minimal inhibitory concentration values were determined for synthesized compound. There was important antibacterial and fungicidal potential in chloro, nitro, methoxy substituted derivatives. The compounds were also screened for in vitro antimycobacterial potency.

R1 N R2

N

R

N N O

(53)

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6.3.3.6

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Miscellaneous Active Isoxazoles

The synthesis of some novel disubstituted, trisubstituted-dihydroisoxazoles (54) (Fig. 6.9.) was demonstrated by Shailaja and group (Shailaja et al. 2011). The growth-inhibitory activity against different bacteria and fungus for the synthesized compounds was evaluated. Moreover, the effect of compounds on the isolated heart of the frog was also reported. The compounds demonstrate stronger sodium-calcium exchange ion inhibition in isolated frog heart tests. The synthesis of fused isoxazole-pyrimidine-6-one and 4-aryl-pyrazolo[3,4d]pyrimidine-6-one derivatives (55) (Fig. 6.9.) was demonstrated by Wageeh and coworkers (2006). The anti-hypertensive activity was screened for all the synthesized compounds. Ikegami et al. prepared an amino acid substituted isoxazole derivative (56) (Fig. 6.9.), through Mitsunobu reaction of isoxazolin-5-one with N-BoC-L-serine tertiary butyl ester and subsequent deprotection of coupling product (Ikegami et al. 2000). The physiological potency was also screened with cloned glutamate receptors and transporters using xenopus oocyte expressing system exhibiting substrate activity on an excitatory amino acid carrier 1 as glutamate transporter.

6.4 Isothiazole 6.4.1 Introduction Isothiazoles are a novel class of heterocyclic compounds with wide variety of medicinal applications, prompting researchers to investigate their synthesis as well as the chemical transformations of their derivatives. Isothiazole is a key motif having electronegative “N” and “S” atoms at the 1,2-position in a five-membered ring. The synthesis of isothiazole and its derivatives has been published using a variety of methods. Isothiazole’s physical and chemical properties have also been thoroughly studied to date. Because of their unusual reactivity, isothiazole motifs have been considered as useful building blocks for synthetic compounds. They are also useful

Fig. 6.9 Structures of miscellaneous active isoxazoles

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in the creation of new molecular structures and the quest for alternative synthetic strategies. Many articles on the chemistry of isothiazoles and their fused derivatives have been reported in the literature (Adams and Slack 1956). The interest in the pharmacological significance of isothiazole derivatives prompted researchers to look into the chemistry of its synthetic versatility. Isothiazoles are aromatic compounds with a delocalized π-electron mechanism.

6.4.2 Synthetic Strategies for Isothiazoles (1) The emergence of new condensation methods; (2) design of metal-catalyzed formal cycloaddition and condensation reactions; (3) implementation of advanced methods for the synthesis of benzoisothiazoles; and (4) synthesis of novel derivatives based on the isothiazole architecture are among the major developments in the synthesis of isothiazoles.

6.4.2.1

Isothiazole Synthesis Through Condensation Reactions

Shukla and co-workers documented an efficient, one-pot, transition-metal-free, synthesis of 3,5-disubstituted and annulated isothiazoles. The reaction was taken place in open air in the presence of ammonium acetate in AcOH which is used as an NH3 source (Scheme 6.44) (Shukla et al. 2016). Condensation reactions caused by conjugate additions have been the subject of recent efforts in the synthesis of isothiazoles. Barton published two separate synthetic routes for 3-amino-5-arylisothiazole from readily available propynenitriles (Scheme 6.45) or 3-chloropropenenitriles (Scheme 6.46) in 2018 (Hackler et al. 1989; Barton 2018). The synthesis of 3,5-disubstituted isothiazoles through a cascade trisulfur radical anion addition to α,β-unsaturated N-Ts imines/detosylation was documented by Liu and co-workers (Scheme 6.47) (Liu et al. 2018). (i) in situ generation of trisulfur radical anion; (ii) incorporation of tri sulfur radical anion to α,β-unsaturated N-Ts

Scheme 6.44 One-pot transition-metal-free synthesis of 3,5-disubstituted and annulated isothiazoles

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Scheme 6.45 Synthesis of 3-amino-5-arylisothiazoles from propynenitriles

Scheme 6.46 Synthesis of 3-amino-5-arylisothiazoles from 3-chloropropenenitriles

Scheme 6.47 Synthesis of 3,5-disubstituted isothiazoles via tri sulfur radical anion addition

imine; (iii) radical isomerization; (iv) cyclization and (v) detosylation are all steps in the reaction. Dwivedi and co-workers published an important isothiazolone synthesis using a stereoselective conjugate incorporation of thiocyanate to α,β-alkynylamides (Scheme 6.48) (Dwivedi et al. 2017). Bezbaruah and colleagues published microwave-assisted synthetic protocol for fused isothiazoles using a one-pot condensation/1,4-addition of β-bromo- α,βunsaturated aldehydes, sodium thiocyanate, and urea (Scheme 6.49) (Bezbaruah et al. 2012). Rovira and colleagues expanded on their previous work using a Thorpe-Zieglertype cyclization to synthesize 4-amino isothiazoles (Scheme 6.50) (Rovira et al. 2017). This protocol quickly produces C5 -unsubstituted 4-amino isothiazoles with amino and carbonyl functionalities, which can then be further derivatized. The Scheme 6.48 Synthesis of isothiazolones via conjugate addition

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Scheme 6.49 Synthesis of fused isothiazoles via conjugate addition

Scheme 6.50 Synthesis of methyl 4-aminoisothiazole-3- carboxylate by Thorpe-Ziegler cyclization

Thorpe-Ziegler reaction is an intramolecular cyclization onto a nitrile that is promoted by a base (Baron et al. 1904).

6.4.2.2

Synthesis of Isothiazoles by Metal- Catalysis

Transition-metal catalysis has made significant progress in the synthesis of isothiazoles. Seo and colleagues published one of the most versatile isothiazole synthesis protocols in 2016, which involves trans annulation of 1,2,3-thiadiazoles with nitriles using an Rh(I)-as transition-metal catalyst (Scheme 6.51) (Seo et al. 2016). Yanagida and co-workers used Cu(I) catalyst to create enantioenriched isothiazoles by forming a cascade of C–C and N–S bonds (Scheme 6.52) (Yanagida et al. 2011).

Scheme 6.51 Rh-catalyzed synthesis of isothiazoles via transannulation of 1,2,3-thiadiazoles with nitriles

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Scheme 6.52 Cu-catalyzed synthesis of enantioenriched bicyclic isothiazoles

6.4.2.3

Synthesis of Benzoisothiazoles

Isothiazoles with benzo groups are a type of biologically active molecule. The majority of benzoisothiazole synthesis protocols use an oxidative N–S bond formation mechanism. Xie and colleagues published a one-pot, transition-metal-free oxidative method for synthesis of amino-substituted-benzisothiazoles from amidines using sulfur in 2018 (Scheme 6.53) (Xie et al. 2018). Using 2-amino-N -aryl-benzohydrazides as starting materials, Anand and colleagues published a one-pot, transition-metal-free synthesis of N-aryl-diazenyl2,1-benzoisothiazoles in 2015 (Scheme 6.54) (Anand et al. 2015). The hydrazide moiety was converted using Lawesson’s reagent, yielding benzothiohydrazide. Willis and co-workers published a transition-metal-free synthesis of 1,2benzothioazoles using a 3+2 cycloaddition between benzynes and 1,2,5-thiadiazoles to produce a variety of 3-substituted benzoisothiazoles (Scheme 6.55) (Chen and Willis 2015).

Scheme 6.53 Oxidative synthesis of 3-amino-benzoisothiazoles

Scheme 6.54 Oxidative synthesis of 2,1-benzoisothiazoles

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Scheme 6.55 Synthesis of 3-substituted benzoisothiazoles from arynes and 1,2,5-thiadiazoles

6.4.2.4

Synthesis of Novel Isothiazole Derivatives

In recent years, the synthesis of novel heterocyclic architectures based on isothiazole has gotten a lot of attention. This project is especially promising in terms of druglike molecule shape diversity generation, which could lead to new drug development opportunities using previously undiscovered privileged scaffolds (Murray and Rees 2009; Erlanson et al. 2016). The synthetic protocol for benzo[c]isothiazole 2-oxides from 2-(Smethylthiomethyl)anilines was published by Lamers and colleagues in 2016 (Scheme 6.56) (Lamers et al. 2016). The researchers discovered that Suzuki crosscoupling and other reactions, such as condensation at the acidic C3 site, could be used to further derivatize these novel heterocycles. Lamers and colleagues then announced the synthesis of tricyclic isothiazole derivatives, tetrahydrobenzo[c]thieno[2,1-e]-isothiazole-4-oxides (Scheme 6.57) (Lamers and Bolm 2018). The accessibility of aniline starting materials is a particularly prominent part of this synthesis, in addition to the unique scaffold generated.

Scheme 6.56 Synthesis of benzo[c]isothiazole 2-oxides

Scheme 6.57 Synthesis of tetrahydrobenzo[c]thieno[2,1-e]isothiazole 4-oxides

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Scheme 6.58 Synthesis simple five-membered isothiazole oxides by (A) intramolecular halocyclization; (B) Hofmann-Löffler-Freytag reaction

Scheme 6.59 Synthesis of fused isothiazoles by Cu-catalyzed nitrene transfer to alkynes

Wang, Zhang and colleagues expanded their approach to the synthesis of novel isothiazole oxides with simple five-membered ring systems (Scheme 6.58) (Wang et al. 2016; Zhang et al. 2017). Two methods were pursued: (i) intramolecular halocyclization of unsaturated sulfoximines using PhI(OAc2 ) as an oxidant (Scheme 6.58a) (Wang et al. 2016); and (ii) an I2 —mediated Hofmann-Löffler-Freytag reaction of sulfoximines (Scheme 6.58b) (Zhang et al. 2017). Rodriguez and colleagues published a novel synthesis of fused isothiazole derivatives using a Cu(I)-catalyzed nitrene transfer (Scheme 6.59) (Rodríguez et al. 2017). The reaction afforded a mixture of sulfinamide and isothiazole products using alkynes and PhI = NTs in the presence of a copper catalyst (TpBr3 Cu(NCMe), TpBr3 = hydrotris (3,4,5-tri-bromo pyrazolyl-borate)).

6.4.3 Therapeutic Potential of Isothiazole Derivatives Isothiazole derivatives structural diversity has made them significant in the pharmaceutical and medical fields. Isothiazole derivatives exhibited extraordinary antiviral, anti-inflammatory, and immunotropic properties. Antipsychotic drugs, Geodon and

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Fig. 6.10 Isothiazole derivatives which act as antiviral, anti-inflammatory, and immunotropic properties

Perispirone, contains benzo fused isothiazole motif in their structure (Howard et al. 1996; Matsushita et al. 2005). In terms of action against gram-positive and gram-negative bacteria, penicillins and cephalosporins with an isothiazole moiety competed successfully with ampicillin (Raap and Micetich 1968). Many isothiazole derivatives have also been found to be effective anti-inflammatory, anticonvulsant, and serine protease inhibitors in the treatment of Alzheimer’s disease. They are also believed to have inhibitors of histone acetyl transferase (Stimson et al. 2005), and carrageenan-induced edema inhibitory activity (Regiec et al. 2006). Isothiazoles are antiviral and anti-inflammatory agents that have a lot of potency. The antiviral, anti-inflammatory, and immunotropic effects of different derivatives of 5-amino-3-methyl-4-isothiazolecarboxylic acid (57) (Fig. 6.10.) were notable (Regiec et al. 2006). The 5-N-benzoyl series of this amino acid (58) (Fig. 6.10.) has been extensive. 5-N-benzoylamino--3-methyl-4-isothiazolecarboxamide (ITF) (59) (Fig. 6.10.) was found to have important anti-inflammatory and antiviral activity among the compounds studied. Lipnicka et al. (2005) tested a few derivatives of 5-substituted 3-methyl4-isothiazolecarboxylic acid (60) (Fig. 6.11) for humoral immune response and screened for delayed form hypersensitivity reaction using sheep red blood cells through in vivo process and found to have promising results. Fig. 6.11 Compound (60) used for humoral immune response and delayed-type hypersensitivity reaction

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Fig. 6.12 The synthesis of the partial GABAA agonist thio-4-PIOL through the usage of different substituents

Krehan et al. (2006) announced the synthesis of the partial GABAA agonist thio4- PIOL (61) (Fig. 6.12) using various substituents, and the effect of each substituent on activity was also investigated and found to be good. Swayze and colleagues (1997) announced the synthetic protocol for 6-methyl9—D-ribofuranosylpurine and imidazo [4,5-d]isothiazole derivatives (62), which inhibited L1210 cell growth moderately (Fig. 6.13). Da Settimo et al. (2005) synthesized acetic acid derivatives of naphtha [1,2d]isothiazole (NiT), and the synthesized derivatives were tested and found to be novel aldose reductase (ALR2) inhibitors. The compound (63) was also shown to be successful in preventing cataract formation in galactosemic rats (Fig. 6.14). Fig. 6.13 The compound which exhibited moderate inhibition of L1210 cell growth

Fig. 6.14 The compound 63 uses as novel aldose reductase (ALR2) inhibitors

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Woollins JD, Laitinen R (2011) Selenium and tellurium chemistry: from small molecules to biomolecules and materials. Springer Science & Business Media Xie H et al (2016) A three-component approach to 3, 5-diaryl-1, 2, 4-thiadiazoles under transitionmetal-free conditions. Org Lett 18(9):2196–2199 Xie H et al (2018) Efficient synthesis of 1, 2-benzisothiazoles from o-haloarylamidines and elemental sulfur via N-S/C–S bond formation under transition-metal-free conditions. Green Chem 20(4):827–831 Yajima K et al (2014) Facile access to 3, 5-symmetrically disubstituted 1, 2, 4-thiadiazoles through phosphovanadomolybdic acid catalyzed aerobic oxidative dimerization of primary thioamides. Chem Commun 50(51):6748–6750 Yanagida Y et al (2011) Asymmetric synthesis of isothiazoles through cu catalysis: direct catalytic asymmetric conjugate addition of allyl cyanide to α, β-unsaturated thioamides. Angew Chem 123(34):8056–8060 Yang L et al (2019) Co-catalyzed intramolecular S-N bond formation in water for 1, 2benzisothiazol-3 (2H)-ones and 1, 2, 4-thiadiazoles synthesis. Eur J Org Chem 2019(6):1281– 1285 Yatam S et al (2018) Focused library design and synthesis of 2-mercapto benzothiazole linked 1, 2, 4-oxadiazoles as COX-2/5-LOX inhibitors. J Mol Struct 1159:193–204 Yoshimura A et al (2013) Hypervalent iodine catalyzed generation of nitrile oxides from oximes and their cycloaddition with alkenes or alkynes. Org Lett 15(15):4010–4013 Yoshimura A et al (2015) Preparation, structure, and versatile reactivity of pseudocyclic benziodoxole triflate, new hypervalent iodine reagent. Chem Commun 51(37):7835–7838 Zarei M (2017) One-pot synthesis of 1, 3, 4-thiadiazoles using Vilsmeier reagent as a versatile cyclodehydration agent. Tetrahedron 73(14):1867–1872 Zarei M (2018) A mild and efficient one-pot preparation of 1, 2, 4-oxadiazoles from nitriles and carboxylic acids using Vilsmeier reagent. ChemistrySelect 3(40):11273–11276 Zhang D et al (2017) An iodine-mediated Hofmann-Löffler-Freytag reaction of sulfoximines leading to dihydroisothiazole oxides. Adv Synth Catal 359(24):4274–4277 Zhang J et al (2018a) Synthesis and evaluation of coumarin/1, 2, 4-oxadiazole hybrids as selective BChE inhibitors with neuroprotective activity. J Asian Nat Products Res Zhang L et al (2016) Design, synthesis and in vitro activity of phidianidine B derivatives as novel PTP1B inhibitors with specific selectivity. Bioorg Med Chem Lett 26(3):778–781 Zhang L et al (2018b) Addition of Diazo compounds ipso-C–H bond to carbon disulfide: synthesis of 1, 2, 3-thiadiazoles under mild conditions. J Org Chem 83(7):4275–4278 Zhou Z et al (2017) Multicomponent reactions (MCRs) of arylmethyl bromides, arylamidines and elemental sulfur toward unsymmetric 3, 5-diaryl 1, 2, 4-thiadiazoles. Tetrahedron Lett 58(26):2571–2573 Zhou Z et al (2016) Multicomponent coupling reactions of two N-tosyl hydrazones and elemental sulfur: selective denitrogenation pathway toward unsymmetric 2, 5-disubstituted 1, 3, 4-thiadiazoles. Org Lett 18(20):5268–5271 Zoumpoulakis P et al (2012) Synthesis of novel sulfonamide-1, 2, 4-triazoles, 1, 3, 4-thiadiazoles and 1, 3, 4-oxadiazoles, as potential antibacterial and antifungal agents. Biological evaluation and conformational analysis studies. Bioorg Med Chem 20(4):1569–1583

Chapter 7

Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles Vnira R. Akhmetova, Nail S. Akhmadiev, and Askhat G. Ibragimov

7.1 Introduction The objects of numerous examples of drug design are derivatives of the fivemembered heterocycles with two nitrogen atoms—diazoles, which are separated into isomers according to the arrangement of heteroatoms in the ring: for instance, pyrazole contains two nitrogen atoms in the 1- and 2-positions, while imidazole has two nitrogen atoms at positions 1 and 3 (Fig. 7.1). The structural diversity of pyrazoles is due to the ability to modify through nucleophilic (at C-3 or C-5 positions) and electrophilic substitution (preferably at N-1, N-2, or C-4 positions) reactions as they have 6π delocalized electrons, which can form pseudo-aromatic system in the rings (Faisal et al. 2019; Secrieru et al. 2020). Pyrazoles, unlike imidazoles, are rarely found in nature. Withasomnine and cinachyrazole A, B, C alkaloids with pyrazole moiety were isolated from indonesian sea sponges (Santos et al. 2020). Its benzo-derivative indazole is part of alkaloids, namely, nigellicine, nigeglanine, and nidellidine (Schmidt et al. 2008). Despite this, the pharmaceutical industry on a large scale produces valuable drugs with a pyrazole scaffold in the molecule or with its reduction product—pyrazoline (Scheme 7.1), and in the case of oxidation—pyrazolone-3 (Mashkovsky 2012). Synthetic pyrazoles and their derivatives are obtained by reactions of intraand intermolecular heterocyclization. The most general approach is based on the interaction between 1,3-dicarbonyl compounds or their analogs and hydrazines. V. R. Akhmetova (B) · A. G. Ibragimov Laboratory of Heteroatomic Compounds, Institute of Petrochemistry and Catalysis, Russian Academy of Science, 141 Prospekt Octyabrya, Ufa 450075, Russian Federation e-mail: [email protected] N. S. Akhmadiev Laboratory of Molecular Design and Biological Screening of Candidate Substances for the Pharmaceutical Industry, Institute of Petrochemistry and Catalysis, Russian Academy of Science, 141 Prospekt Octyabrya, Ufa 450075, Russian Federation © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_7

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V. R. Akhmetova et al. 3

4

4 N

5

3 N

4

4

3

2

2 5

N H 1

Pyrazole

N 5

N H 1

Imidazole

2

N H 1

3

3a

5

N 6

7a 7

Pyrazoline

2

N H 1

Indazole

Fig. 7.1 The family of five-membered azoles

N

H2

NH

[O]

NH 1

3 N H

N H

O

N 2H

Pyrazolone-3

Pyrazoline

Scheme 7.1 The synthetic route for the construction of pyrazoline and pyrazolone structures

To obtain some N-unsubstituted pyrazoles, thiocarbonic acid hydrazides are introduced in the reaction with α-haloketones. Pyrazoles can also be obtained by cyclization of acetylenic hydrazines, electrocyclization of unsaturated diazo compounds, cycloaddition of 1,3-dipolar diazo compounds, and nitrilimides (Fustero et al. 2011). The interest of researchers in the class of diazacyclopentadienes is still high due to the discovery of unique properties and ease of synthesis with the desired molecular modification. Moreover, as seen in Fig. 7.2 the largest number of publications, when asked in the search engines “pyrazole”, “pyrazoline” and “indazole”, in 2020 falls on the pyrazole structure: Web of Science—999 (2021), Sci-Finder®—2710 (2021), Pub Med®—2461 (2021), Scopus—2443 (2021). Pyrazole

Pyrazoline

Indazole

2710 2461

2443

999 647 150 162 WOS

235 Sci-Finder

327 67 PubMed

169

347

Scopus

Fig. 7.2 The number of publications given in the Web of Science, Sci-Finder, PubMed, and Scopus databases in 2020 when specifying the keywords “pyrazole”, “pyrazoline” and “indazole”

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

277

To date, there are a number of sulfur-containing derivatives of pyrazole, pyrazoline, and indazole, which have been successfully commercialized into medications in the pharmaceutical market, for example, axitinib and pazopanib (tyrosine kinase inhibitor), celecoxib, and metamizole sodium (non-steroidal anti-inflammatory drug), sildenafil and udenafil (phosphodiesterase inhibitor 5A1 PDE5), tozasertib (Aurora kinase inhibitors), penthiopyrad (fungicide), indiplon (hypnotic sedative), sulfamazone (antibiotic with antipyretic properties), fipronil (insecticide), pyroxasulfone (pre-emergence herbicide), ibipinabant (selective CB1 receptor antagonist) and as aza dyes, for example, tartrazine (lemon yellow color) (Fig. 7.3). Some compounds have been found in multiple biological activities that are superior to known analogs, for example, in I neuropathic pain treatment (Kim et al. 2016), as II anticancer agent (Akhmetova et al. 2020a), III and IV analgesic, antiinflammatory drag (Yewale et al. 2012; Farag et al. 2015), V metal extractants (Anpilogova et al. 2018), VI antioxidant (Hartwig de Oliveira et al. 2020), VII antiproliferative agent (Dalla Via et al. 2009), VIII DNA gyrase inhibitor (Boehm et al. 2000), IX herbicidal activity (Ma et al. 2010), X RAFT agent (Gardiner et al. 2016), XI 5-HT6 receptor antagonist (Haydar et al. 2010), XII bacteriostatic agent (Johnston et al. 2018), XIII α-amylase inhibitor (Maksimov et al. 2016) (Fig. 7.4). The evolution of approaches to the design of pyrazole and its sulfanylmethyl derivatives is shown in Scheme 7.2 (Knorr 1883; Pechmann 1898; Katritzky and Lam 1989; Mustafa et al. 1944; Poppelsdorf and Holt 1954). Over the past five N

NH O

O

H N

N

N

F

N

N

S

N

N

S N H

S

O

O

Pazopanib

O

NH2

Axitinib F N

I Neuropathic pain treatment H2N

O

S

N N H

N

O

CN

S

S

O

S F

N H

N

H2N

H N

Cl N

N

II Anticancer activity

Cl

N

Fipronil

S

Ph

N

N

Ph

N

F S F

F

N N H

V Metal extractants

N

F

F

VI Antioxidant activity

O

III Analgesic and anti-inf lammatory activities

F N

O

F

Celecoxib

S H2N

N

N

O

F3C

N

N N

O

O

O

N

S

NH2

N

R = CN; R = COOEt

N

O Na

R

IV Analgesic and anti-inf lammatory activities

O Metamizole sodium

N

O

S

X=N

O

N

N H N HN

Sildenaf il (R' = Et)

N

N N

S O

N H

O

O

N

N

HN

S Tozasertib

X

X= HN

N

N R' Udenaf il (R' = n-Pr)

Fig. 7.3 Representative classes of important sulfur-containing azoles scaffolds

O

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V. R. Akhmetova et al. O

O

H N

S

Cl

N

N

N CF3

Cl

NH

N

S

Cl S

O

HN N

N

N

Ph

N O

Ibipinabant

O

Penthiopyrad H3CO

S

O

O

VII Antiproliferative activity VIII DNA gyrase inhibitor O

O

N

N O

N

S

Cl

O

O

S

H2N

CF3

O

N

O CF3

N

N

N

S

IX Herbicidal activity N

N O

O

N

S

N

S

S

N

N O

F

Indiplon

OH

F N

Pyroxasulfone

N

HO

XI 5-HT6 receptor antagonist

O O

Ph

XII Antimicrobial agent

O

Ph

S

O

S

N

NH

O

O NaO

N

ONa S

N

O

S

CN

HN

HO N

S

N

S N

O O

N N

X RAFT agent

N

Sulfamazone

HN N

N

O

S

ONa

S O

XIII a-Amylase inhibitor

N

Tartrazine

NH

Fig. 7.4 Skeletal diversity of pharmacologically active pyrazoles, pyrazolones, and indazoles bearing the sulfanyl or sulfo moiety

years, a number of comprehensive reviews have been published concerning the latest advances in the synthesis of structural motifs (Sapkal and Kamble 2020; Aziz et al. 2020; Mykhailiuk 2021; Sikandar and Zahoor 2021; Gomes et al. 2020; Baiju and Namboothiri 2017), asymmetric synthesis of pyrazoles (Xie et al. 2019), the applicability as chemosensors (Kashyap et al. 2020), colorimetric and fluorescent probes (Tigreros and Portilla 2020), and the use in medicinal chemistry (Zefeng et al. 2019; Verma et al. 2021; Xu et al. 2017; Costa et al. 2021; Ansari et al. 2017; Saleh et al. 2020). Meanwhile, in the scientific literature, there is no information on the systematization of data on different sulfanyl derivatives of pyrazole. This chapter discusses the latest advances in the synthesis, biological activity of sulfur-containing pyrazole scaffolds over the past decade.

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles 1883, Knorr L

279

Knorr pyrazole synthesis Ph

C10H10N2O

NH O

O

N

+ H2N

NH

Ph

Ph

O

OEt

N

N

- C2H5OH

- H2O

OEt

1898, Pechmann Hv

O

Pechmann pyrazole synthesis H N

+

N

N

N

1954, Poppelsdorf F and Holt SJ I N

N

Ph

N

+ R

SH

Na/MeOH

N

N

Ph

O

O

Δ

N SH + CH2O

+ R

S

CH3COOH/H2O

R

N Ph

O 1964, Mustaf a A and et al. O O

S N

+

HN

SH

HN

150oC

R N Ph

N R

Ph

1989, Katritzky AR and Lam JN CH2O, H2O, 42 h

HN

HO

HCl

N

HCl .Cl

N N

N

N

5 mol% NiCl2 . 6H2O, C2H5OH, 60 oC, 4 h

2018, Akhmadiev NS and et al. O

O

R

SH

O

S

N N

N NH

+ N2H4. H2O

2 equiv. Ph EtONa, PhSH, 3 h, rt

H

H

One-pot 4-CR

S R

Scheme 7.2 Evolution of approaches to the design of pyrazole and its sulfanylmethyl derivatives

7.2 Design, Synthesis, and Biological Activities of Sulfur-Containing Pyrazoles Sulfur atoms in biological molecules in the form of sulfide or thiol groups exhibit antioxidant properties, while thiomethyl groups S–CH3 participate in the fixation

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V. R. Akhmetova et al.

Scheme 7.3 The design of S-derivatives of pyrazoles

N

SR N H b

c

a N

N N

N N

N H

er Spac

Pyrazole motif

SR

d

SR Spacer

N

SR

N H

and transport of methyl groups (Pacell 2002). In addition, sulfur atoms provide a subtle process of energy transfer in the cell by accepting an electron from an oxygen molecule to its free orbital. Taking into account these functions, the introduction of sulfanyl substituents into the pyrazole scaffold is quite expedient. The design of S-derivatives of pyrazoles, as a rule, is carried out by replacing hydrogen atoms with an S- atom at the C- or N-reaction centers of the ring (routes a, b) or by introducing sulfur atoms through the spacers (routes c, d), the role of which carry out methylene or ethylene chains, as well as aromatic or heterocyclic ring (Schema 7.3).

7.2.1 Synthesis of Sulfanyl Pyrazole Derivatives The design of C-sulfanylpyrazoles is possible with the participation of malonodinitrile, which, as a CH-acid with ketenodithioacetal, gives the key synthon, namely, Knoevenagel product 2-[bis(alkylsulfanyl)methylidene]malononitrile 1 with a yield of more than 70% (Scheme 7.4). Cyclocondensation of the latter with phenylhydrazine 2 leads to pyrazole 4 with bearing RS-, CN-, and NH2 moieties substituents. A similar reaction with 2-(1,3-dithiolan-2-ylidene)malononitrile 3 gives 3,3 -{disulfandiylbis[(ethane-2,1-diyl)sulfanediyl]}bis-(5-amino-1-phenyl1H-pyrazole-4-carbonitrile) 5 in 87% yield (Lipin et al. 2020). The construction design of the pyrazole ring with phenylsulfanyl substituents at the C(sp2 )-position is realized by nucleophilic substitution of chlorine atoms in 3-chloro-2,4-dicarbonyl substrates 6 with thiophenols 7 followed by cyclization of 3-phenylsulfanyl-2,4-dicarbonyl compounds 8 with hydrazine hydrate (Scheme 7.5, 12 examples) (Kim et al. 2015). The synthesized C-sulfanyl pyrazoles 9 have been studied for their anti-lipolytic effect. It was found that 4-(phenyl)thio-1H-pyrazole can be identified as a novel

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

281

CN CN

CN

RS CN

CN

RS

RS

1

SR

NH

N HN

NH2

NH2

HN

N

NH

EtOH, reflux, 5 h

N

Ph

Ph

2

4 (72%, 82%) N

CN

N

CN

H2N

CN

S

S S

S S

N

Ph

A

Ph

PhHN

RS

NH2

NC

N

N

5 (87%)

S

Ph

3

Scheme 7.4 Synthesis of mono- and bis-sulfanyl pyrazoles using the heterocyclization between phenylhydrazine, malonodinitrile, and ketenodithioacetales

O O

SH

O

+

1 equiv. Piperidine, CH2Cl2-MeOH, 0 oC rt, 6 h

R1

N

O

NH2NH2 . H2O, EtOH, reflux,12 h

R1

NH

R1

S

S Cl

6

7

R2

8

R2

9 12 examples (33 - 91%)

R2

Scheme 7.5 Synthesis of sulfanyl pyrazoles based on the condensation of 3-chloro-2,4-dicarbonyl substrates with thiophenols and hydrazine hydrate

high-throughput GPR109A agonist scaffold that does not contain a carboxylic acid moiety. The activity of the leader compound (EC50 = 45 nM) over a concentration range from 1 nM to 100 μM, in the calcium mobilization assay, was similar to niacin (EC50 = 52 nM) having a nicotinic acid fragment, but its activity at 10 μM in the b-arrestin kit was about 2–5 times weaker than niacin (Kim et al. 2015). A similar methodology for the synthesis of C-sulfanyl pyrazoles was proposed in (Vydzhak et al. 2017) using the heterocyclization reaction of 2-phenyl sulfanylacetoacetic ester 10 with hydrazine hydrate (Scheme 7.6). Further alkylation of 4(phenylthio)-1H-pyrazole-5-ol 11 with methyl bromoacetate gave phenylpyrazolyl sulfide 12, which was hydrolyzed to carboxylic acid under the action of LiOH. A green and efficient MCR protocol has been developed for the synthesis of C-4 sulfanylated pyrazoles 15 by iodine-catalyzed cyclocondensation of 1,3-dicarbonyl compounds 13 at the methylene CH-acid position with thiols 14 and at the carbonyl groups with hydrazines. As a result, two new C-N bonds and one C-S bond are created simultaneously in one step. This method provides a simple and reliable way to create valuable sulfanylated pyrazoles (Scheme 7.7) under metal- and solvent-free

282

V. R. Akhmetova et al. MeOOC H O

O N

N

2

NH2NH2 . H2O

OEt

OH

N Br

N

COOMe COOMe

1 equiv. K2CO3

O

- 2HBr

S S

S

11

10

12 COOMe

3 equiv. LiOH, rt, 24 h

COOH 2 examples

Scheme 7.6 Synthesis of acid and ester substituted sulfanyl pyrazoles

50 mol% I2, 50 mol % HOAc, EtOH, 120 oC, 5 h O R1 = R2 = Me

H2NHN S Ar

O

O + Ph NHNH2

R1

13

10 examples, (47 - 89%)

O

R2

R4 SH 14 5 mol% I2, 3 equiv. DMSO, 70 oC, 24 h, Ar

R4 = Ar

S

R4

R2

27 examples, (56 - 88%)

R1 N Ph

N 15

Ph I2

N O

H

N

+ R4 R2

R1

SI

- H2O - I2 - HI

B

Scheme 7.7 I2 -catalyzed cyclocondensation of 1,3-dicarbonyl compounds with thiols and phenylhydrazine

conditions (Sun et al. 2017a). According to the proposed mechanism, the iodine molecule catalyzes two processes, namely, the cyclocondensation of 1,3-dicarbonyl compounds with phenylhydrazine to form a pyrazole structure and the formation of electrophilic PhSI particles as an intermediate product of the oxidative coupling reaction involving 1,2-diphenyldisulfide (Sun et al. 2017a). Another approach to the synthesis of sulfanyl pyrazolones 15 via iodine-catalyzed sulfanylation reaction was proposed in (Sun et al. 2015), by using sulfonyl hydrazides as a source of sulfur, instead of thiols 14 (Scheme 7.7). The reaction proceeds under

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

283

more hard conditions (120 °C), but in a shorter time interval (5 h) with good yields of target products. Continuing the research, the same group of authors has developed the synthesis of pyrazolo[1,5-a]pyrimidin-4-ium sulfonates 18 based on the iodine-catalyzed pseudothree-component bicyclization reaction between β-ketonitriles 16 and sulfonylhydrazides (Scheme 7.8) (Sun et al. 2016). Subsequent treatment of sulfonate salts with an alkaline solution leads to the formation of pyrazolo[1,5-a]pyrimidines 19, which were subjected to direct disulfanylation at the C(sp2 )-H bonds in the C-3 and C-6 positions by sulfonyl hydrazides, but under more hard conditions (110 °C). The green and efficient method of cross-dehydrogenation upon the formation of the C–S bond in the pyrazole ring is realized in the iodine-catalyzed reaction of substituted pyrazoles 21 with thiols 14 (Scheme 7.9). This is a new, highly efficient, and practical method, in which the starting reagents are readily available (Yang NH2NHPh NH2NHSO2R2 50 mol% I2, CH3CN, 100 oC, 5 h

R2

S H2N

NH2NHSO2R2 20 mol% I2, EtOH, 90 oC, 5 h

O CN

R N Ph

R

R = Ar

NH2 N

N

Ar

16

N

Ar

N H

R2SO3 18 17 examples, (50 - 83%)

17 20 examples, (41 - 84%)

10% NaOH (aq), rt, 30 min NH2

NH2 S

N

N

50 mol% I2, CH3CN, R RSO2NHNH2

N N Ar

Ar

Ar

N

Ar

N R

19 8 examples, (91 - 98%)

S

20 15 examples, (41 - 78%)

Scheme 7.8 Synthesis of sulfanyl pyrazoles and pyrazolo[1,5-a]pyrimidin-4-ium sulfonates from β-ketonitriles and sulfonylhydrazides

R3 N

N

R4

+ HS

R1

R3

10 mol% I2, DMSO, 100 oC, 18 h

N

N

R1

R2

R2 S

21

14

22 R4 31 examples, (62 - 96%)

Scheme 7.9 I2 -catalyzed reaction of substituted pyrazoles with thiols

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V. R. Akhmetova et al. S

H2N CN

NH2

CN

EtOH, 3 h, reflux

CN

S/NaBH4/EtOH, 1 h ice bath Cl

SH N

N

SNa N

N

N

N

Ph

Ph

Ph

23

C Refluxe 2 h, CN Stirring overnight

Cl

CN

NH2

EtONa/EtOH, Δ, 10 min N

CN N

Ph

S

SCH2CN N

N Ph

25 (75%)

24 (85%)

Scheme 7.10 Synthesis of cyano-substituted sulfanylpyrazole and its heterocyclization to thienopyrazole

et al. 2016). The developed method provides a strategy for the design of various C-sulfanyl-substituted pyrazole structures. The original approach to the synthesis of cyano-substituted C-sulfanylpyrazole 24 with subsequent heterocyclization to thienopyrazole 25 has been proposed by using the reductive introduction of the thiol group into chloro-substituted pyrazole 23 with the S/NaBH4 reagent. The cyclization of 24 to the thiophene 25 occurs with the participation of carbonitrile and sulfide groups under the base action (Scheme 7.10) (Zaki et al. 2018). The selective method for the synthesis of thiocyanate derivatives of aminopyrazole 26 was recently proposed based on the C(sp2 )-H thiocyanation reaction of aminopyrazoles 21 with the addition of NH4 SCN and eight-fold excess of 30% hydrogen peroxide solution as an oxidizing agent (Scheme 7.11, conditions 1). The use of water as green solvent, room temperature, and short reaction times (20–30 min) should be noted as significant advantages of this method (Ali et al. 2020). Another method for thiocyanation of substituted pyrazoles 21 (Songsichan et al. 2018) is based on the use of the tandem reagent KSCN—K2 S2 O8 in DMSO at 60 °C (Scheme 7.11, conditions 2). Further transformations of the thiocyanate group under the action of phenylmagnesium bromide give sulfide 27 in 65% yield (Ali et al. 2020), and the use of sodium azide in the presence of an equimolar amount of ZnCl2 by the cycloaddition reaction gives tetrazole 28 in 91% yield (Songsichan et al. 2018) (Scheme 7.11). In additional experiments in order to study a possible mechanism with radical trapping reagents [for example, 2,2,6,6-tetramethylpiperidine-1-oxyl

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles R3 - NH2 30% H2O2, NH4SCN, H2O, 20 - 30 min, rt, 11 examples, (20 - 85%) or

285

1)

R3 R2 N R1

2) R2 = R3 = Ph 1 equiv. K2S2O8, KSCN, DMSO, 2 h, 60 oC 6 examples, (52 - 99%)

N

21

NH2

MgBr Ph

N

R2

NaN3, 1 equiv. ZnCl2, i-PrOH, 50 oC, 3 h

R2 R1

S

(65%)

R3

N

N

THF, N2, rt, 5 h

SCN

N

26

27

NH2 Ph

(82%)

N S N NH N

R2

28

N N

Scheme 7.11 Synthesis of thiocyanate derivatives of aminopyrazole through the C(sp2 )-H thiocyanation reaction of aminopyrazoles

(free radical)], the reaction did not take place, on the basis of which the authors stated the reaction radical mechanism with the formation of the thiocyanate radical ·SCN at the reaction first stage. Heterocyclization of hydrazines with β-ketocyanides was developed in the synthesis of sulfanyl-substituted pyrazole derivatives. The reaction of 3-oxo-3arylpropanenitrile 16 with two moles of arylsulfonylhydrazides was carried out in the presence of N-iodosuccinimide (NIS) as the catalyst (Scheme 7.12, 27 examples). The series of 3-aryl-4-(arylthio)-1H-pyrazole-5-amines 29 were synthesized by successive cyclization and sulfanylation (Wei et al. 2021a). A two-stage method for the synthesis of previously unknown pyrazole-4sulfonylchlorides 30 (Sokolyuk et al. 2015) is based on the heterocyclization reaction of (2-benzylthio)malonaldehyde 33 (or isothiouronium salt 31) with substituted hydrazines, followed by oxidative chlorination of 32 (or 34), which selectively converts dimethylthiocarbamate or benzylthio groups into sulfonyl chloride (Scheme 7.13). The obtained pyrazoline sulfonyl chlorides 30 were selectively reacted with ammonia to obtain the corresponding sulfonamides 35 inmore than 70% yield. Subsequent alkylation of pyrazole 34 with (chloromethyl)cyclopropane

O

+ ArSO2NHNH2

0.5 equiv. NIS, EtOH, 80 oC, 6 h

N

H N NH2

CN Ph

Ph

16

SAr

NIS = O

N I

O

29 27 examples, (57 - 93%)

Scheme 7.12 N-Iodosuccinimide catalyzed heterocyclization of β-ketocyanides with arylsulfonylhydrazides

286

V. R. Akhmetova et al. Br O

Bn

N N

ClO2S

RNHNH2, EtOH, HCl, reflux S

Cl2, CH2Cl2, H2O, 0 - 10 oC

(61 - 83%)

(76 - 89%)

N

S

Bn

S

RNHNH2, S MeOH, reflux

Cl2, CH2Cl2, H2O

(78 - 92%)

(69 - 90%)

N

N

N

O

N N

O

R

N

O

R

30 9 examples

32 2 examples

(79 - 92%)

33

34 9 examples

R

31

O

NH3, 80 oC

Cl

R = H, (89%) NaH, DMF, rt Bn

N

N

H2NO2S

S

N

35 5 examples

N R

36

Scheme 7.13 A two-stage synthesis of pyrazole-4-sulfonylchlorides and their transformation to corresponding sulfonamides

at the N-1 position of the pyrazoline ring made it possible to obtain hardly accessible N-alkyl-substituted pyrazole 36 in 89% yield. The construction design of C-sulfanyl pyrazoles based on iminoacetylenes is carried out in two ways (Yu et al. 2020). A method was developed for the synthesis of 4-chalcogenylated pyrazoles 40 by electrophilic chalcogenation/cyclization of α,βalkyne hydrazones 37 (Scheme 7.14). Cyclization of α,β-alkyne aldehydehydrazones can be induced by either sulfanyl chloride 38 or by S-electrophiles 39 formed in situ by the reaction between NCS and arylthiols. This method has been successfully applied to the synthesis of the celecoxib sulfanyl analog. R3

Cl S

38 1 equiv. AlCl3, MeNO2, 60 oC, 4-6h 10 examples, (43 - 75%) HN

R2 Ph

Ph

N SR3

N N R2 R1

R3 S

37 O

N

1 equiv. AlCl3, CH3CN, 60 oC, O 2-4h 7 examples, (52 - 98%)

39

Scheme 7.14 Iminoacetylenes based design of sulfanyl pyrazoles

R1

40

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles R2

5 mol% DMPA THF : Et3N (5:1), 80 oC

N R1O2S

287 R4

R2

N

N

SO2R1 N R4

R3

DMPA = N

41

R3

N

42 21 examples, (47 - 95%)

Scheme 7.15 Synthesis of propargylsulfonylhydrazones

highly

substituted

4-sulfonyl-1H-pyrazoles

from

N-

The synthesis of highly substituted 4-sulfonyl-1H-pyrazoles 42 (Scheme 7.15) was developed from derivatives of N-propargylsulfonylhydrazones 41 with the formation of 1H-pyrazole with a sulfonyl group at the 4-position (Zhu et al. 2013). In order to introduce the pyrazole ring into the 3-sulfonyl-chromen-4-one molecule, an original method for the synthesis of 2-[5-methyl-4-(toluene-4-sulfonyl)2H-pyrazol-3-yl]-phenol 47 in 90% yield has been offered (Scheme 7.16). Condensation with hydrazine occurs due to the opening of the pyran ring 46 in the course of the (3 + 2)-heterocyclization (Chang et al. 2018). Flynn et al. (2019) has proposed the unusual synthesis of highly functionalized pyrazoles 49 and 50 via thermal dipolar [3 + 2]-cycloaddition between αdiazoacetates 48 and α-thio-β-chloroacrylamides (α-sulfonyl-β-chloroacrylamides). The method allows obtaining C(4)-sulfanyl 49 or sulfonic derivatives of pyrazole 50 by rearranging the sulfide group from the C-3 position of the intermediate pyrazoline to the C-4 position, leading to 3,5-disubstituted pyrazoles. In the presence of an electroacceptor (sulfonic) group in β-chloroacrylamides, the reaction proceeds under milder conditions to give the target pyrazole as the main product (Scheme 7.17). In this case, during heat treatment, the formation of two regioisomeric products of Nsubstituted pyrazoles 49a,b in a minor amount is observed. The authors proposed two Tol O

Tol O

S

OH

+

1.1 equiv. Cu(OAc)2, 1.1 equiv. BOP, O 1 equiv. DMPA, MeNO2, reflux, 3 h

O

O S

Tol S O

80% NH2NH2 (aq), dioxane, 3 h, reflux

O NH

(90%)

N

O

OH

44

O

46

45

N N

BOP =

P N

OH

47

P F6 O N

N N

Scheme 7.16 Synthesis of 2-[5-methyl-4-(toluene-4-sulfonyl)-2H-pyrazol-3-yl]-phenol using sulfonylacetylenes and salicylic acid

288

V. R. Akhmetova et al. O R2

S R1

OR O

X

SR1

O

OR

SR1

O Cl

SR1

Toluene, 100 oC, 24 h

O

R2

+

X

+ N

N

X N

N

X N H

R2

OR

O O RO

O

O RO

49a

Major 49 17 examples, (19 - 71%)

OR

N

R2

O

49b

Minor regioisomer

N2

48

OEt O

O

O

N

O

H N N H

R3

R3

S

O

N H

R1

+

SO2R1

R = Et CH2Cl2, rt

50 7 examples, (9 - 18%)

Cl

Scheme 7.17 [3 + 2]-Dipolar cycloaddition between α-diazoacetates and α-thio(sulfonyl)-βchloroacrylamides in synthesis of sulfone derivatives of pyrazole

possible mechanisms (E1 and E1CB elimination), in which the migration of sulfur proceeds passes through the opening of the episulfonium ion ring. The synthesis of the pyrazole ring by the reaction of 1,3-dicarbonyl compounds with hydrazine was taken as the basis for the design of N-sulfoxide derivatives (Scheme 7.18, 12 examples). The method was developed using the reaction in water of the hydrochloride salt of aromatic sulfonic acid hydrazides 51 with copper(II) acetylacetonate 52 under microwave irradiation, leading to the corresponding pyrazoles in high yields (Venkateswarlu et al. 2018). This protocol forms important N-heterocyclic fragments into final target structures, which makes it possible to use the reaction in medicinal chemistry, especially in targeted modification strategies for creating drugs. A strategy for the synthesis of N-sulfoxide-substituted pyrazoles 56 with simultaneous C-sulfanyl functionalization was proposed on the basis of mononitrile malonic ester 54, for which the key Knevenagel product was previously synthesized using ketendithioacetal (Scheme 7.19) (Thore et al. 2016). Further heterocyclization as O

O S

N H

R

O

NH2

+

O Cu

O

51

O

O

H2O MW (50 W), 5 min, 100 oC

S

N N

R O

52

53 12 examples, (82 - 97%)

Scheme 7.18 Synthesis of N-sulfoxide derivatives of pyrazoles by the reaction of aromatic sulfonic acid hydrazides with copper(II) acetylacetonate

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

289 O

O S

O

R1

H N

R H3CS

NH2

SCH3

K2CO3, DMF, 2 - 3 h, ref lux

N R1

55 (71%, 78%)

O

NH2

K2CO3, DMF, 2 - 3 h, ref lux O

N

S HN O

S

O

N

NH2

CN

O

O

54

NH2

N S R

O

56 (78%, 81%)

Scheme 7.19 Synthesis of N-sulfoxide-substituted pyrazoles on the basis of mononitrile malonic ester

a result of condensation with various hydrazines gives a number of new ethyl 5amino-3-methylthio-1H-pyrazole-4-carboxylates 55, and the reaction with sulfonic acid hydrazides opens the way to N-sulfonic derivatives 56. The synthesized compounds 55 and 56 were in vivo tested for analgesic and anti-inflammatory activity using writhing test in mice caused by acetic acid and the carrageenan-induced paw edema test in rats, respectively. Diclofenac sodium was used as a reference drug for comparison. These compounds showed significant analgesic and anti-inflammatory activity at a dose of 25 mg/kg, at the same time, they were less ulcerogenic, the ulcer index was in the range 0.9–1.12, whereas for diclofenac sodium this index was 3.10 (Thore et al. 2016).

7.2.2 Synthesis of Sulfanylpyrazolones Drugs containing the pyrazolone scaffold are common in medicine (Zefeng et al. 2019). The formation of the C-sulfanylpyrazalone nucleus 60 was carried out by heterocyclization of hydrazines with 2-sulfanyl β-ketoesters 59, which in turn are obtained by efficient cross-Claisen condensation of α-thioacetic acid 57 with acid chlorides 58 inthe presence of bis(trimethylsilyl)lithium amide (LiHMDS) as the catalyst (Scheme 7.20) (Ragavan et al. 2009). A new strategy for direct sulfanylation of 1-arylpyrazolones 61 using aryl thiols 14 is realized at room temperature under the action of N-chlorosuccinimide (NCS) (Scheme 7.21) (Kamani et al. 2017). The protocol turned out to be simple, effective, and without the use of transition metals, which allows products to be obtained with good yields without additional purification. A similar reaction of C-sulfonation of pyrazolones with aryl thiols 14 successfully proceeds under the conditions of metal complex catalysis (Scheme 7.21). The same group of chemists developed a catalyst based on the PdCl2 complex with thiamine (vitamin B1) (Purohit et al. 2016), which proved to be efficient in the regioselective thiolation reaction through the activation of the 4C–H bond in 1-aryl-3-methyl-1Hpyrazole-5(4H)-on 61.

290

V. R. Akhmetova et al. R3 O

O

LiHMDS, - 78 oC, Toluene

O

+

OEt

R3-NHNH2, Ethanol R2

R2

R2

OEt

O

S

57

S

59

R1

58

R1

60 7 examples, (38 - 53%)

SiMe3

Me3Si N Li

LiHMDS = Me3Si

Li

N

SiMe3

N Li

Me3Si

SiMe3

Scheme 7.20 Synthesis of sulfanylpyrazalones from α-thioacetic acid TfO N

N

O

N

TfO

N Et NCS

3 mol% TfO, 5 mol% I2, CH3CN, O2 25 or 40 oC, 13 examples, (71-98%)

O

Cl N

O

O

1.2 equiv. NCS, DCM, rt, 45 - 60 min, 24 examples, (76-87%)

1.2 equiv. NaOH, CH3CN, 60 oC, 2 - 5 h, 21 examples, (77-99%) HO

O

R2

SH 7 examples, (78-97%)

14 N

61

S

20 mol% I2, DMSO, 80 oC, 1.5 h

+ Ar / Het

N

N

Cl

S R1

N

O

Ar / Het R2

N N

62

R3

R3

3 equiv. DMSO, 90 oC, air, 2 - 5 h, 27 examples, (55-99%) Pd(NHC)Cl2

N N

HO

S

N Pd

Cl

NH2 Cl

5 mol% Pd(NHC)Cl2, 1.5 equiv. K2CO3, DMF, 100 oC, 3 - 4 h 15 examples, (79-85%)

Scheme 7.21 C-Sulfanylation of pyrazolones by radical reactions with thiols

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

291

2 mol% DABCO, 1.5 equiv. AgOAc, MeOH, rt or 60 oC, 2-8h 12 examples, (5 - 94%)

R2 O N

+

Ar

S Ar

S

N

R3

20 mol% AgOTF, 1 equiv. AgOAc, toluene, Ar, 100 oC, 16 h 8 examples, (51 - 84%)

63 61

S

O N R3

Ph

20 or 50 mol% I2, DMSO, 60 oC, 2-3h 10 examples, (63 - 95%)

Ar

R2

N

62 Ph

10 mol% I2, 30% H2O2 (aq.), 1,4-dioxane, rt, 24 h 22 examples, (66 - 97%)

Scheme 7.22 C-Functionalization of pyrazolones using disulfides and oxidizing agents

The reactions of pyrazolones with thiols as effective methods of 4C-sulfanylation of CH-acids, which proceed by a radical mechanism, were realized in the presence of activators DMSO (Sun et al. 2017b), NaOH (Liu et al. 2016), TfO (Tanimoto et al. 2019), and I2 (Siddaraju and Prabhu 2017). Disulfides 63 are also used as thiolating reagents. In these cases, oxidizing agents such as silver salts (Ma et al. 2017; Thupyai et al. 2018), iodine (Siddaraju and Prabhu 2017), and hydrogen peroxide (Hao et al. 2017) are suitable for 4C-functionalization of pyrazolones (Scheme 7.22). One-pot thioetherification of pyrazolones 61 to their corresponding derivatives 4-mercaptopyrazolones 62 occurs under the action of elemental sulfur followed by cross-coupling with various aromatic and heteroaromatic iodides 64 under the action of the Pd(OAc)2 /Xantphos (9,9-dimethyl-9H-xanthene-4,5diyl)bis(diphenylphosphine) catalytic system (Scheme 7.23). The binding of these thiol intermediates D with 64 via the SN 2 mechanism. The procedure involves the use of inexpensive starting materials and a short reaction time (Mukherjeem and Das 2017). Thioesters of arylpyrazolone 62 in enol form were synthesized (Scheme 7.24) via I2 -catalyzed cross-coupling of pyrazolones 61 with arylsulfonyl hydrazides in the presence of p-toluenesulfonic acid, which apparently facilitates the in situ decomposition of sulfonyl hydrazides to generate the ArSI intermediate (Zhao et al. 2014). An efficient method for the synthesis of thioesters of pyrazolone 62, as well as thioesters of 2-aryl- and 3-arylbenzofuran, using arylsulfonyl chlorides as sulfonation reagents in the presence of triphenylphosphine has been developed (Scheme 7.25,

292

V. R. Akhmetova et al. Ar

2 mol% Pd(OAc)2/ 2 mol% Xantphos, 1 drop Et3N, 1.2 equiv. Cs2CO3, EtOH, reflux, 40 min DMSO, 130 oC, Ar, 2.5 h

O N

N

+ S8 + Ar

S

O

I

N

64 PPh2

L

N

PPh2

O

Xantphos =

61

R1

R1

62 19 examples, (88 - 98%)

Ph

Ph N

N

N

N

O

O

- Pd0L

Ar S

SH

Pd L

D

Scheme 7.23 Pd-catalyzed one-pot thioetherification of pyrazolones by elemental sulfur and aromatic iodides 5 mol% I2, 0.5 equiv. TsOH, i-PrOH, 120 oC, 1.5 h

O O

R1

+ Ar

N

S

HO S Ar N

R1

NHNH2

N

O

N

R2

R2

62 R1 = Alk 15 examples, (75 - 94%) R1 = Ar 13 examples, (46 - 92%)

61

Scheme 7.24 I2 -catalyzed coupling of pyrazolones with arylsulfonyl hydrazides in the presence of p-toluenesulfonic acid 1) 0.2 equiv. KI, 2 equiv. Ph3P, 1.4-dioxane, 80 oC, 12 h 23 examples, (50 - 96%) or

O O

R1

+

N N

61

Ar

S O

R2

Cl

2) 2 equiv. HBr, 2 equiv. TBAI, PEG-400, 100 oC, 45 min 6 examples, (75 - 87%)

HO S Ar R1

N N

R2

62

Scheme 7.25 Reaction of pyrazolones with arylsulfonyl chlorides in the presence of triphenylphosphine

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

293

condition 1). It was found that potassium iodide facilitates this conversion by in situ forming more reactive sulfonyl iodide from sulfonyl chloride (Zhao et al. 2016). This process also proceeds successfully under the action of the HBr–TBAI system in PEG-400 at 100 °C (Scheme 7.25, condition 2) (Wang et al. 2016). There are isolated examples of trifluoromethylthiolation of pyrazolone 61 using the tandem of trifluoromethanesulfonyl chloride with trimethylphosphine as a reducing agent and a source of the electrophilic SCF3 group (Scheme 7.26), which give the target product in 77% yield (Chachignon et al. 2016), as well as sodium trifluoromethanesulfonate and phosphorus trichloride to afford the target product in 23% yield (Zhao et al. 2017). Panigrahi et al. (2021) succeeded in synthesizing N-triflated pyrazolone derivatives with the formation of a heteroatom-heteroatom (N–S) bond at the imine nitrogen 68, instead of the traditional route of the sulfanylation or sulfonation reactions at the C4 position like in synthesis of compounds 65–67. Langlois reagent (CF3 SO2 Na) and phenyliodine(III) bis(trifluoroacetate) (PIFA) were used in the reaction. It should be noted that the reaction proceeded at room temperature within 5 min to form target products in yields of up to 80%. The thiocyanation of pyrazolin-5-ones at the C-4 position was also carried out at room temperature using the NH4 SCN reagent to form 4-thiocyanated 5-hydroxy1H-pyrazoles 67 in yields of up to 95% (Scheme 7.26) (Mao et al. 2020). When SCF3 HO R2 N R1

N

66 14 examples (70 - 92%) 2 equiv. BiCl3, PhNHSCF3, DCE, 80 oC, 12 h, Ar

SCF3 HO

N Ph

N

65

4.4 equiv. PMe3, CF3SO2Cl, THF, -78 oC, rt, 22 h (77%)

2 equiv. K2S2O8, NH4SCN, MeCN, rt, overnight

O

SCN HO

R2

1.2 equiv. PCl3, R1 CF3SO2Na, CH3CN, 60 oC, 2 h (23%)

N

R2 N

N R1

61 2 equiv PIFA, CF3SO2Na TFE/H2O (3 : 1), rt, 5 min.

O

F3C

N

67 21 examples, (67 - 95%) O

CF3

I O

PIFA =

O

R2 N R1

N SO2CF3

68 23 examples, (16 - 83%)

Scheme 7.26 C-sulfanylation and C-or N-sulfonation reactions of pyrazolones

O

294

V. R. Akhmetova et al. 30 mol% KIO3, 120 oC, 8 h, EtOH 15 examples, (63 - 86%)

O

2 mol% I2, 1 equiv. TBHP, DME, rt, 2-4 h

O

R1

+

N

S Ar

N

ONa

61

O

TBHP =

S Ar R1

N N

R2 OH

O

O

HO

R2

69 24 examples, (44 - 98%)

Scheme 7.27 Iodine-catalyzed sulfonation of pyrazolones by sodium salts of arylsulfonic acids

promoting with 2 molar equivalents of BiCl3 , trifluoromethylthiolated derivatives of 5-hydroxy-1H-pyrazole 66 were obtained via the interaction between pyrazolin-5ones and trifluoromethanesulfenamide as an electrophilic source of CF3 S+ (Liu et al. 2017). Convenient sulfonation of pyrazolones 61 is carried out by reaction with sodium salts of arylsulfonic acids, catalyzed by molecular iodine in the presence of tertbutyl hydroperoxide (TBHP) at room temperature (Scheme 7.27). This methodology makes it possible to synthesize a number of valuable sulfonated pyrazolones 69 in the enol form (Wei et al. 2017). Another efficient method for the synthesis of sulfonated pyrazolones 69 involves the use of the KIO3 catalyst as an oxidizing agent (Daoqing et al. 2019). Fifteen target products were obtained with yields ranging from 63 to 86%. Some of the resulting products 69 showed high inhibitory activity against the fungi Valsa mali and Botrytis cinerea.

7.2.3 Synthesis of Sulfanyl Pyrazoles Linked to the Sulfur Atom Through Spacers A rational way to functionalize pyrazole by introducing sulfur atoms through a methylene spacer is based on multicomponent reactions of 1,3-dicarbonyl compounds 13. Ni-catalyzed one-pot method for the synthesis of sulfanylmethyl-substituted 3,5dimethyl-1H-pyrazoles 71 has been created. There are actually two approaches to the synthesis of these heterocycles: sequential one-pot four-component condensation of 2,4-pentanedione with formaldehyde 70, S-nucleophiles 14, and hydrazine hydrate, or a two-stage way through the preliminary synthesis of sulfanyl derivatives of diketones 72 (Scheme 7.28). According to in vitro experiments, the obtained

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

R

5 mol% NiCl2 . 6H2O, C2H5OH, 60 oC, 4 h

SH 14

O

O

O + H

13

295

71 5 examples, (63 - 87%)

N2H4. H2O 5 mol% NiCl.2 . 6H2O, C2H5OH : CHCl3 1:1, rt, 6 h

Me

O

R 72

N

S

N NH2

N H R2COOH 112 - 116 oC 2-3h

Py R2

73 6 examples, (50 - 81%) +

Me

O

O

R

N2H4. H2O C2H5OH, 60 oC, 2 h

O

S

Via

N

NH

R

R = Alk 71

NH

S R 40 mol% ZnCl2, Δ, MeOH, 16 h

N S

NH

S R

One-pot 4-CR

H

70

N

N2H4. H2O 2 - 3 drops AcOH, C2H5OH, reflux, 6 h

71 3 examples, (91 - 96%) + O OMe N

74

N S

NH

R 71 2 examples, (87%, 73%)

Scheme 7.28 Synthesis of sulfanylmethyl-substituted 3,5-dimethyl-1H-pyrazoles by one-pot or two-stage methods

sulfanylmethylpyrazoles 71 had a fungicidal effect against the phytopathagenic fungus Rhizoctonia solani (Akhmadiev et al. 2018). In the methodology development of the two-stage synthesis at the heterocyclization stage of thiomethylated diketones, new conditions of the reaction medium, catalysts have been proposed and various hydrazines have been involved. It turned out that heterocyclization of 3-[(alkylsulfanyl)-methyl]pentane-2,4-diones 72 with Nnucleophilic reagents (phenylhydrazine, nicotinic hydrazide), when heated in acetic, propanoic, or pentanoic acids, gives a mixture of products—sulfanylmethylpyrazoles 71 and sulfanyl-1-acyl-1H-pyrazoles 73. Heterocyclization in ethanol catalyzed by acetic acid proceeds selectively (Baeva et al. 2018), and catalysis by ZnCl2 is accompanied by the elimination of the methyl ester of nicotinic acid 74 and the formation of sulfanylmethyl-substituted-1H-pyrazoles 71 (Scheme 7.28) (Baeva

296

V. R. Akhmetova et al.

et al. 2020). The synthesized 4-[(hexylsulfanyl)methyl]-3,5-dimethyl-1-phenyl-1Hpyrazole and 4-[(hexylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazole were found to be efficient complexing agents for palladium(II) (Anpilogova et al. 2018, 2020). To obtain compounds with antidiabetic activity by inhibiting the enzyme αamylase, bis-(sulfanyl-3,5-dimethylpyrazoles) have been synthesized. The oriented synthesis of target molecules was realized through a two-component Ni-catalyzed thiomethylation reaction to obtain α,ω-bis-(sulfanyl diketones) 76 followed by condensation with 2 mol of hydrazine hydrate (Akhmetova et al. 2014). Another way is a pseudo-seven-component reaction catalyzed by potassium carbonate, that is one-pot condensation of 1,2-ethanedithiol 75, formaldehyde 70, 2,4-pentanedione 13, and substituted hydrazines in a molar ratio of 1:2:2:2 (Scheme 7.29). Molecular docking of ligands carried out on the model of the pancreatic amylase or Aspergillus niger amylase enzyme indicates a high complementarity of the studied bispyrazoles to the target enzyme. Experimental in vitro studies of the inhibitory activity against aqueous solution of α-amylase produced by Aspergillus oryzae demonstrated that methylsulfanyl-substituted N,N-dimethyl-bis-pyrazole is a competitive inhibitor (Akhmetova et al. 2020b). Acetoacetic ester as 1,3-dicarbonyl CH-acid is successfully involved in the twostage synthesis of 4-{[alkyl(or benzyl)sulfanyl]methyl}-5-methyl-2,4-dihydro-3Hpyrazole-3-ones, through preliminary preparation of 2-[(alkylsulfanyl)methyl]-3oxobutanoates (Baeva et al. 2019). Based on the spectral characteristics data of 2,4-dihydro-3H-pyrazole-3-ones, the authors made an assumption about the existence of four tautomeric forms in solution, among which the keto tautomer A is predominant (Scheme 7.30). O

O

5 mol% NiCl2 . 6H2O MeOH or CHCl3 : C2H5OH, rt, 8 h

13 + H2S

O

O

or

70

H

HS

75

SH

H

70

H

76

O

13

MeOH, 60 oC, 1 h X

O

10 mol% NH2NH R K2CO3, MeOH, One-pot 60 oC, 3 h

S R

O NH2NH2 . H2O

+

O

O

S

Via

X H

X S

O

S

HN

S

N N

R

N NH

N 77 8 examples, (69 - 77%)

S

N N

78 6 examples, (64 - 89%)

Scheme 7.29 Synthesis of bis-(pyrazolylmethylsulfides) by MCR of 2,4-pentanedione with formaldehyde, varies dithiols and hydrazines

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

O

10 mol% 10% NaOH (aq), rt, 2 - 3 h + RSH

O

O

+ OEt

79

H

70

O

O

OEt

HN

NH

N

NH

O

S

S

R

81 R 3 examples, (65 - 71%)

HN

NH

N

N

B

OH

SR

SR

SR

NH

OH

O

O

A

NH2NH2 . H2O, EtOH, rt 30 - 45 min

H

80

N

297

C

SR

D

Scheme 7.30 Two-stage synthesis of 4-{[alkyl(or benzyl)sulfanyl]methyl}-5-methyl-2,4-dihydro3H-pyrazol-3-ones

It is known that nuclei of 1,5-dimethyl-2-phenyl-1H-pyrazole-3(2H)-one 61, which carry the acidic functional group in the C-4 position, are attacked by electrophilic reagents. For the activation of such reactions, catalysis is important, which provides a reduction in the time and temperature of the process, thus reducing the impact on the environment (Beletskaya and Kustov 2010). On the basis of Cthiomethylation of pyrazolone 61, a convenient preparative method for the synthesis of sulfanylmethyl-82 and oxasulfanylmethyl-84 derivatives of medicinal antipyrine was recently developed by the InCl3 -catalyzed reaction with formaldehyde 70 and thiols 14 or α,ω-mercaptoalkanols 83 in water as a green solvent (Scheme 7.31). To determine the anti-inflammatory effect of antipyrine S-derivatives, molecular docking was performed, demonstrating that the presence of the naphthylsulfanylmethyl substituent in the C4-position of the nucleus provides selective inhibition of the competitive type of COX-2 with E bind = − 9.73 kJ/mol (Celecoxib E bind = − 10.27 kJ/mol) (Akhmadiev et al. 2021). The green synthesis of acyclic sulfanylmethyl derivatives of ampyrone (4-amino2,3-dimethyl-1-phenyl-3-pyrazolin-5-one) 85 was carried out by the thiomethylation reaction 85 with formaldehyde 70 and thiols 14 without a catalyst under heating or ultrasonic (microwave) radiation in water (Scheme 7.32). Molecular docking of N,Nbis(sulfanylmethyl)substituted aminoantipyrines 86 for steric complementarity with active centers of cyclooxygenase isoforms (COX-1 and COX-2) has shown that the molecules are selective inhibitors of COX-2 of a competitive type with free binding energy E bind = − 9.36 – − 4.52 kcal/mol in similar calculations had E bind = − 10.27 kcal/mol (Akhmadiev et al. 2020). Carbon disulfide CS2 is used as a thiomethylating agent for the N-functionalization of 3,5-dimethyl pyrazole 21. The reaction proceeds under alkaline conditions (KOH) to obtain potassium pyrazolyl dithiocarbamate 87, which reacts with alkyl chlorides 88 to give esters of pyrazolyl dithiocarbamic acid 89 (Scheme 7.33) (Gardiner et al. 2016).

298

V. R. Akhmetova et al.

R SH 5 mol% InCl3, H2O, 6 h, 80 oC

O

N

N

+

O

H

N

N

O

H 70

61

S R

HO

5 mol% InCl3, H2O, 6 h, 80 oC

SH X 83

82 7 examples, (52 - 88%)

O N

N

N

O

N

S X

O

84 3 examples, (53 - 79%)

Scheme 7.31 In-catalyzed C-thiomethylation of pyrazolone

N

O

N

+ R

+ H

O

SH

Catalyst free H2O or C2H5OH:CHCl3 (1:1), 4 h (rt) or 30 min (80oC) O

H 70

N

N

14

N

NH2 85 S

S R

R 86 7 examples, (67 - 91%)

Scheme 7.32 The green synthesis of sulfanylmethyl derivatives of ampyrone S

1 equiv. KOH, THF, rt, 50 min

NH

+ N

21

N

CS2 N

87, (89%)

S

SK

ClCH2R 88

N

S

N

89 2 examples, (61%, 59%)

Scheme 7.33 N-Functionalization of 3,5-dimethylpyrazole by carbon disulfide

R

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

299

Selective condensation of pyrazolones 61 with isatins 90 in water represents a simple and eco-friendly pathway to the synthesis of various potentially bioactive pyrazolone-substituted indolinones. In particular, the synthesis of C-sulfanylmethylsubstituted pyrazolone derivatives 92 has been realized (Scheme 7.34) (Zhang et al. 2020). Convenient pathway for thiomethylation of pyrazolone was implemented on the basis of the thia-Michael reaction between the 4C-methylidene derivative of pyrazolone 93 and aromatic thiophenols 14 in the presence of Zn(L-Pro2 ) as the catalyst (Scheme 7.35) (Katla et al. 2019). Diastereoselective synthesis of new spiro[tetrahydrothiophene-3,3 -pyrazoles] 96 based on Michael/Michael tandem cascade cyclization of ethyl trans-4mercaptobutenoate 95 with various 4-benzylidene-5-methyl-2-phenylpyrazolones has been implemented in the presence of DABCO as the catalyst in PhMe at 0 °C

O

Ar O

R1

O

N

+

N

20 mol% Imidazole, H2O, 80 oC, 48 h

O

N

+

N R2

O

10 mol% DBSA, H2O, 80 oC, 8 h

N HO

N N

S

O

90

61

O

SH

N H

91, (86%)

N H

14

92, (85%) O

OH S

DBSA =

O

10

Scheme 7.34 Eco-friendly synthesis of various bioactive pyrazolone-substituted indolinones

R1 S SH

R

R

20 mol% Zn(L-Pro)2, EtOH, ref lux, 6 - 8 h

N

+

N

N N

O

O R1

14 93

O

94 12 examples, (57 - 68%) O

Zn(L-Pro)2 =

N

Zn

N

O

O

Scheme 7.35 Thia-Michael reaction between methylidene derivative of pyrazolone and thiophenols

300

V. R. Akhmetova et al.

N

O

+ HN

HS

Ph

Ph

N

S

H H S Ph

O

N

O N

N

O

O

O

O

95

O

10 mol% DABCO, PhMe (abs.), N2, Ph 0 oC, 12 h

Ph

93 N

Ph

E

OEt

96 20 examples, (83 - 99%)

N

Scheme 7.36 Synthesis of new spiro[tetrahydrothiophene-3,3 -pyrazoles] Michael/Michael tandem cascade cyclization

based

on

with a high yield of up to 98% (Scheme 7.36). The authors suggested that the thiol mercapto group can be activated under the action of the DABCO tertiary nitrogen atom, which provides the first stage of intermolecular Michael addition to the double bond and the subsequent intramolecular Michael addition reaction with excellent formation of a diastereoselective cycloadduct (Cai et al. 2016). Biologically active sulfur-containing pyrazoles 103 with an aminomethyl spacer were obtained by a multistage method from diethyl oxalate 97, which was transformed into ether 98 containing the 1,3-dicarbonyl moiety (Scheme 7.37). The formation of pyrazole 99 is carried out in the classical way by the reaction of 1,3dicarbonyl substrates with hydrazines. Further transformations were carried out at the acyl substituent in pyrazole to afford an aminomethyl group, which readily reacts with sulfonic acid chlorides. The combinatorial series of aryl(1,5-disubstituted pyrazole3-yl)methylsulfonamides 103 was obtained in good yields up to 90%. The design of the molecules was based on the structural units of known antiepileptic drugs (Zonisamide, Ethosuximide, Phenytoin), which have (exhibit, possess) inhibitory activity of T-type calcium channels (Kim et al. 2016). The tests of a series of compounds by in vitro and in vivo methods on the model of neuropathic pain (mechanical and cold allodynia) showed that the leader is a O

O O

R1COCH2Cl, NaOEt, EtOH, rt

EtO

O

O

EtO

OEt O

97

O

R2NHNH2, EtOH, 0 oC, rt, EtO R1 2 examples, (85, 87%)

(97%)

N N

98

R2

N

H2N LiAlH4, DCM, 0 oC to rt

N H N

Ph

O

O

N

N

S N

Ph

ArSO2Cl, Et3N

N Ph

86%

99, (86%) R1

OH

NH2OH . HCl, Et3N, DCM, rt

DIBAL-H, DCM, - 78 oC H

Ar

100, (86%) N

N H

N

Ph

(67 - 91%)

(99%)

102, (99%)

101, (97%)

H

DIBAL-H =

103 16 examples, (67 - 89%)

Al

Scheme 7.37 Design of the combinatorial series of aryl(1,5-disubstituted pyrazole-3yl)methylsulfonamides

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

301

H

O

HS

R1 R2

N

N

O NH

HS

+

+

N

R1 2 drops H+, EtOH,

O

reflux, 5 - 6 h

N

N

N

N

R3

13

NH2

NH2

R4

103

R2

N N

R4

R3

104 105 16 examples, (72 - 88%)

Scheme 7.38 Three-component synthesis of mercapto-substituted 4-(benzylideneamino)-5-(3,5dimethyl-1H-pyrazol-1-yl)-triazoles

compound containing phenyl substituents. The leader compound had selective inhibition against T-type channels with IC50 α 1G = 5.65 μM and IC50 α 1H = 5.80 μM (compared to N-type channels and hERG) and a rapid action on mechanical pain, exceeding the activity of the reference drug mibefradil and gabapentin (Kim et al. 2016). There are examples when pyrazoles are linked to sulfur atoms through heterocyclic spacers. A simple three-component one-pot protocol for the synthesis of mercapto-substituted 4-(benzylideneamino)-5-(3,5-dimethyl-1H-pyrazole-1-yl)4H-1,2,4-triazoles was implemented by the reaction of 4-triazole-3-thiol or 4-amino5-hydrazinyl-4H-1,2,4-triazole-3-thiol with acetylacetone and various substituted benzaldehydes (Scheme 7.38) (Jilloju and Vedula 2018). Sulfur-containing pyrazoles 108, linked to a diazepine spacer, have been also synthesized (Scheme 7.39). For this goal, basic pyrazolodiazepine heterocycles 107 were exploited with subsequent functionalization by thiols according to the Michael reaction (Bol’but et al. 2014). Another example of the preparation of benzo- and pyrazolo-fused N,Sheterocycles of medium sizes 111, 112 is described in (Abd El-Aal 2020). The method is based on intramolecular cyclization of sulfanyl pyrazoles with substituents containing ester 109 or carboxylic acid 110 to afford annelated tricyclic ketones when catalyzing by AlCl3 /MeNO2 , TfOH, or polyphosphoric acid (Scheme 7.40).

R1

O

R1

O OEt

NH N

NH2

106

R1

O

NH N

N

OEt

N R

H+

N H

N

R3-SH 14 HCO2H, 12 h 24 h

N N H

R

107

OH

Scheme 7.39 Synthesis of sulfur-containing pyrazolo-fused diazepines

R

N H

108 12 examples, (71- 97%)

SR3

302

V. R. Akhmetova et al. O CO2Et HN

n HN

n 1)

N

S N

N

109

S

N

2) 4 equiv. CF3SO3H, DCE, ref lux, 5 - 10 h

y Ar

Ph

5 equiv. AlCl3, MeNO2, CH2Cl2, rt, 12 - 20 h

Ph

3) 3.3 equiv. Phenylpropanolamine, 160 oC, 4 - 8 h

CO2H

y

111 4 examples, (70 - 84%) R

O

R N

S N

N

Ph

y 110

n

S

N

Ar

112 4 examples, (85 - 7%)

Ph

Scheme 7.40 Synthesis of benzo- and pyrazolo-fused N,S-heterocycles

7.3 Sulfur-Containing Pyrazolines In the literature there are a limited number of publications on methods for the synthesis devoted to sulfur-containing pyrazolines, herewith according to the graph of the total number of publications for all types of azoles in 2020 (Fig. 7.2), the least number of publications falls on the pyrazolines group. Meanwhile, pyrazolines, including sulfur-containing derivatives, were found to possess versatile biological activity (antimicrobial, anti-inflammatory, analgesic, antidepressant, and antitumor) (Shaaban et al. 2012; Matiadis and Sagnou 2020; Bansal and Singh 2020). The domino reaction of N,N-dimethyl enaminone 113 with sulfonyl hydrazines was used to synthesize functionalized pyrazolines 114 (Scheme 7.41) with the formation of new C =N and C–N bonds during consecutive reactions. The reactions proceed according to the (3 + 2)-cyclization type under metell-free conditions using a water— acetic acid mixture acting simultaneously as the promoter and the solvent (Li et al. 2017). O

N 113

+ NH2NHSO2R2

AcOH-H2O (1:3), 65 oC, 1 h - HNMe2

O

N

O N

S R2

NHNHSO2R2 114 19 examples, (57 - 91%)

Scheme 7.41 Heterocyclization reaction of N,N-dimethyl enaminone with sulfonyl hydrazines

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

303

The synthesis of highly functionalized 3-amino-pyrazolines 117 annelated with phthalazine-5,10-diones (Scheme 7.42) is based on a one-pot three-component reaction of aldehydes 104, phthalhydrazide 115, and (phenylsulfonyl) acetonitrile 116 using 2-hydroxyethylammonium acetate catalyst in EtOH as a green solvent (Shi et al. 2018). A selective method was proposed for the synthesis of sulfonyl pyrazolines 121 by the cyclocondensation reaction of the methyl ester of Earylsulfonylethenesulfonylacetic acid 118 with 2-aminoethanethiol 119 in the presence of the promoters of samarium(III) chloride and n-BuLi to obtain 2-(Earylsulfonylethenesulfonylmethyl)-4,5-dihydrothiazoles 120 (Scheme 7.43). Further interaction with diazomethane or nitril imines led to the formation of the target dior tetrasubstituted pyrazolines 121 (Padmaja et al. 2014). To expand this methodology bis-sulfonyl pyrazolines 124 linked by the paraphenylene spacer have been synthesized (Scheme 7.44) via the 1,3-dipolar cycloaddition of nitril imines to the product of the Knoevenagel reaction 123 obtained by condensation of 2-arylsulfonylacetic acid 122 with terephthalaldehyde 104 (Lavanya et al. 2014). Pyrazoline carboxamidine derivative 131, in which the sulfo group is linked to the nucleus through the C=N spacer were found to exhibit pharmacological activity. These compounds are known to be potent 5-HT receptor antagonists (Arnol’d et al. 2015). O

O O H

O

+

O

10 mol% HEAA, EtOH, rt, 12 h

NH

+

R

N S

S N

NH NC

R O

115

104

O

O

116

NH2

O

O

HEAA =

117 13 examples, (61 - 96%)

H3N OH

O

Scheme 7.42 Synthesis of highly functionalized 3-amino-pyrazolines annulated with phthalazine5,10-diones

O Ar

O

O

S S O

118

O

+ SH

H2N 119

1equiv. SmCl3, 2.2 equiv. n-BuLi, OMe Toluene, 0 oC - (20 min) 100 oC (8-10h) Ar

O

O

N

S S

S O

O 120, (70 - 78%)

O

1) CH2N2, Et3N, -20 to -15 oC, 40 - 48 h, R1 = R2 =H

Ar

the

O

O

O

N

S S

2) R1-CH=NNHR2, 1.2 equiv. Chloramine-T 3H2O, MeOH, 18 - 20 h, R1 = Ar'; R2 = Ph

Scheme 7.43 Synthesis of sulfonyl pyrazolines from arylsulfonylethenesulfonylacetic acid and 2-aminoethanethiol

S

R1

methyl

N N

R2

121 6 examples, (71 - 77%)

ester

of

E-

304

V. R. Akhmetova et al.

O

O

Ar

BnNH2, AcOH, ref lux, 6 - 8 h

O

H

O

O

+

S Ar

S O

O

O

OH

H

O

122

S

123 3 examples, (74 - 77%)

104

Ph

Ph

N

N

N

Ar

Ar'-CH=NNHPh, 4 equiv. Chloramine-T 3H2O, MeOH, ref lux, 16 - 18 h

N

Ar'

Ar'

Ar

O

O

S O

S Ar

O 124, 6 examples, (68 - 79%)

Scheme 7.44 Synthesis of bis-sulfonyl pyrazolines linked by the para-phenylene spacer

The essence of their preparation consists in the interaction between the corresponding substituted 4,5-dihydro(1H)-pyrazole 125a,b or its isomer and isothiocyanate 126 to obtain the amide of the substituted 4,5-dihydro-(1H)-pyrazole-1carbothioic acid 127 (Scheme 7.45). The resulting intermediates 127 were affected by CH3 I to give the S-alkylated intermediate 128, the interaction between the latter and the sulfonamide derivative 129 led to target derivatives 130 and 131 (Arnol’d et al. 2015).

DiPEA =

N

N

1 equiv. DiPEA, 30 oC - 1h  10 oC - 2h

NH N

125a

CH3I, MeOH, 45 oC, 2 h

N

CH3CN, Reflux overnight

N N

N

NH2

C

+ S

126

NH

S

O

N H

S

S

O

128 127

N

N N N

O

HN

3 equiv. 1 M HCl, EtOH, 55 oC, 45 h

125b

129

N

O S

S N

NH

N

O

131

NH

O

O H2N

O

N

N H

130

Scheme 7.45 Multistage synthesis of pyrazoline carboxamidine based on 5-dihydro(1H)-pyrazole and isothiocyanate

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

305

7.4 Synthesis of Practically Important Sulfanyl Indazoles Indazole is a very important scaffold in medicinal chemistry. It is commonly found in compounds with diverse biological activities, e.g., antimicrobial and antiinflammatory agents (Zhang et al. 2018). However, only a few examples are presented for the synthesis of sulfonylindazole derivatives. The work (Wei et al. 2018) discusses a multistage method for the synthesis of a structural analog of the antitumor drug Axitinib (Fig. 7.3), an inhibitor of vascular endothelial growth factor receptor tyrosine kinase (VFGFR-1, VEGFR2, and VEGFR-3). The design of the target molecules consisted of the formation of the –N=N-fragment at the C-3 position of the indazole ring 132 and the replacement of the pyridine ring (Axitinib) by benzene and pyrrole fragments (Scheme 7.46). Initial screening of inhibitory activity by in vitro method showed that sulfanyl derivatives containing pyrrole-diazenyl fragments showed strong antiproliferative activity against HUVEC and showed significant inhibitory activity against VEGFR-2 kinase, exceeding the activity of the reference drug Axitinib. N-Functionalization of indazole by introducing sulfur atoms through a paraphenylene spacer was carried out by a multistage method from a starting orthonitrobenzaldehyde 104, which was transformed into an imine 139 under the action of para-amino-thiophenol 138 (Scheme 7.47) (Pérez-Villanueva et al. 2017). Intramolecular heterocyclization of nitroimine 139 to indazole 140 proceeds as (3 + 2)-cyclocondensation under the action of trialkoxyphosphine. Wei and coworkers have presented another example of directed synthesis of low molecular weight anticancer agents containing indazole scaffold 148 (Wei et al. 2021b). The idea of functionalization of the indazole framework 145 was the introduction of the 1,3-dimethoxybenzene fragment at the C-3 position, which imparted hydrophobic properties to the molecule, and the introduction of various hydrophilic groups, including sulfonamide, at the C-6 position through a para-phenylene spacer (Scheme 7.48). However, the introduction of the latter groups did not allow surpassing

SH H N

O

Br

N

N H

+

5 mol% Pd2(dba)3, 10 mol% xantphos, 2 equiv. Cs2CO3, 1.4-dioxane, N2, 80 oC, 12 h

O

H N

S

H N

H N

O

R1

12 M HCl, H2O, 0 oC

H N

N

S

+ R2

N

N

135 or

R3

R4 H2N

132

14

H2N

133, (57%)

N2 Cl

134 N

NaNO2, 12 M HCl, H2O, ice bath O

H N

S

N

N R

N

137 9 examples, (15 - 35%)

Scheme 7.46 Design of biologically active diazo-substituted sulfanylindazoles

H N

R5

136

306

V. R. Akhmetova et al. 68%

S

H

X

X = SO 142

92% EtOH, ref lux

+

140 (61%)

X=S

2.5 equiv. NaIO4, AcOH/CH3CN/H2O rt, 24 h

S

O

X = SO2 141

1 equiv. NaIO4, AcOH/CH3CN/H2O 80 oC, 12 h

3 equiv. P(OEt)3, 150 oC, 0.5 - 2 h H

N

N NO2

104

N

NO2

NH2

138 Ph

139, (92%)

Ph P H

Pd2(dppf )Cl2 . DCM =

Fe

Cl

C6H5I or C6H5Br, 5 mol% Pd(dppf )Cl2 . DCM, 10 mol% PPh3, 1 equiv. Ag2CO3, H2O, 50 oC

. CH2Cl2

Pd H P

Cl Ph

Ph

S

N N

143, (71%)

Scheme 7.47 Functionalization of indazole by introducing sulfur atoms through a para-phenylene spacer 5 mol% Pd2(dppf )Cl2, 1.5 equiv. Cs2CO3, dioxane/H2O (1:4), 100 oC, 8 h

O H N

Br

N

I2, 2 equiv. KOH, DMF, rt, 3 h

H N

Br

N

+

(71%)

(46 - 67%)

Br

O B

132

O

I

145

O O

146

O

N

HN

5 mol% Pd2(dppf )Cl2, R 2 equiv. K2CO3, N dioxane/H2O (1:4), R' 95 oC, N2, 8 h

Ph Ph R

P H

Pd2(dppf )Cl2 =

Fe

N Cl

Ph

O

O B

S

O O

O

Cl Pd

H P

147

O

S

R' O

Ph

O HN

N

148 2 examples, (27%, 31%)

Scheme 7.48 Synthesis of sulfon derivatives of indazole with para-phenylene spacer

the antiproliferative activity in in vitro experiments against several types of cancer (A549, 4T1, HepG2, MCF-7, HCT116).

7 Sulfur-Containing Pyrazoles, Pyrazolines and Indazoles

307

7.5 Conclusion The literature analysis indicates that the most rational pathway for the synthesis of sulfur-containing pyrazoles is based on intra- and intermolecular (3 + 2) coupling (namely, CCC + NN) reactions with tandem C- or N-ring functionalization by sulfanyl or sulfone groups. The low prevalence of sulfur-containing pyrazole derivatives in nature is associated with the limited availability of hydrazines in living systems. The established specific pharmacological properties of this class of compounds stimulate the search for new structures with a pyrazole scaffold and synthetic methodologies for their construction. Due to the ability of sulfur atoms to have different oxidation states, electronegativity close to carbon, to act as an electrophile or nucleophile, an extensive arsenal of S-reagents such as sulfide nucleophiles (RS− H), electrophiles (RS+ Hal) or radicals (RS•), and sulfonating agents (RS+ O2 ) has been developed. As a result, with the help of these S-reagents, the methods of introducing sulfur atoms directly to the pseudo-aromatic ring or through spacers have been realized. Catalysts and other metrics of green chemistry play an important role in the development of these processes. Currently, sulfanyl and sulfonyl-substituted pyrazolones are widely used in medical practice, and pyrazolines and indazoles are still under study. We are confident that promising prospects await researchers in the development of multifunctional drugs based on sulfanylsubstituted compounds with a pyrazole scaffold, in which sulfur atoms impart additional pronounced antioxidant activity to the molecules. Acknowledgements This study was carried out under the research plans of the IPC RAS on the subject “Multicomponent catalytic reactions in the synthesis of cyclic and acyclic heteroatomic compounds”, State Registration no. FMRS-2022-0079 (2022–2024), as well as with financial support from the Stipend of the President of the Russian Federation to young scientists and graduate students (SP-1691.2022.4).

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Chapter 8

Synthetic Approach of Quinazolines Candidates Vinay Kumar Singh, Anjani Kumar Tiwari, and Mohd. Faheem

8.1 Introduction The nitrogen-containing compounds have a promising property in the medicinal field. These compounds are found in many natural systems in the form of alkaloids, nucleic acid, vitamins, and many other natural products. In the heterocyclic world, quinazoline derivatives have versatile properties in the pharmaceuticals industry. The skeleton’s molecular formula represents C8 H6 N2 which is a very interesting aromatic heterocyclic organic skeleton and composed of the fused six-membered aromatic ring and nitrogen atom present at 1,3-position, shown in Fig. 8.1. The containing of two nitrogen atoms the term given as suffix “aza” (Bogert et al. 1900). The Griss reported the first quinazoline derivative in 1869. The skeleton is commonly constructed by using anthranilic acid and cyanogen gas in the presence of an aqueous-alcoholic solution (Bogert et al. 1900). In M. Taylor, Bogert, and A. H. Gotthelf 1900, reported a scheme for the formation of quinazoline synthesis by the reaction in between acetonitrile and anthranilic acid at 220 °C. The positioning and numbering for the nomenclature were suggested by Paal and Busch and the property of quinazoline derivatives are varying concerning substitution on the benzene ring or pyrimidine ring and conjugation. As time going passed away, the syntheses are reported in the favor of green chemistry and microwave radiation.

V. K. Singh (B) · Mohd. Faheem Department of Chemistry, Dr. Shakuntala Misra National Rehabilitation University, Lucknow 226017, India e-mail: [email protected] A. K. Tiwari Department of Chemistry, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_8

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N

N N

N

N

N

quinoxaline

quinazoline

cinnoline

N N phthalazine

Fig. 8.1 Isomeric form of quinazoline

8.2 Synthesis Methods The synthesis methods are classified as classical and modern methods. The modern methods are further divided on the basis of reagents, catalysts, and solvents which are described below.

8.3 Classical Methods Several methods have been published with an excellent yield reported in which a method for the quinazoline moiety (3) was synthesized by Grignard reagent and by Meerwein cyclization using nucleophilic reagent (Bergman et al. 2003) Scheme 8.1. Later in 1993, a unique method had been published for the synthesis of quinazoline derivatives (6) with excellent yield by reacting substituted 2(methoxycarbonyl)benzoic acid (4) or benzoic anhydride in the presence of sodium azide, shown in Scheme 8.2 (Canonne et al. 1993). The synthesized of quinazolines by using anthranilic acid (7) and in this reaction, the two intermediate compounds (8,9) were formed which on cyclization gave cyclized quinazoline Scheme 8.3 (Couture et al. 1991). The common synthesis of quinazoline by using anthranilic acids but in some methods, the carbon dioxide is used for the building block of carbon atom (Wang O

NH CN O N 1 H

MeMgX

H2O

O

R

N

NH N

R

R

3

2

Scheme 8.1 Synthesis of quinazoline by Grignard reagent

X

X COOH

4

COOCH3

NaN3 ClCO2C2H5 / (C2H5)N

NCO

amino acid

COOCH3

H2O-Dioxan

Intermediate 5

H N N O

O R H

CO2H 6

Scheme 8.2 Synthesis of quinazoline by sodium azide and amino acid in water-dioxane

8 Synthetic Approach of Quinazolines Candidates

315 OR'

H N

7

O

O H Cl OH

OR'

O

NH

NH

COOR' NaOH

OH 8

O

H

N H

H

N R N-methylmorpholine

O H

9

DBU

H N

O N

R

10 O

Scheme 8.3 Conversion of anthranilic acid into quinazoline diones

et al. 2011; Fujii et al. 2018) for the formation of the pyrimidine ring in a solvent-free system. Many of the reactions are catalyzed by metal like copper (Omar et al. 2014; Chen et al. 2018a, b), ruthenium (Wang et al. 2016, 2019), and non-metal like iodine (Jin et al. 2016; Saha et al. 2017) gives a high yield.

8.4 Modern Methods The modern methods for quinazoline skeleton are explained in the following categories based on reaction conditions. The reactions are divided into three main categories: 8.4.1. 8.4.2. 8.4.3.

Metal-catalyzed based reaction Reagent-Base-based reaction Microwave-based reaction.

8.4.1 Metal Catalyst-Based Reaction The metal catalyzed reaction is very common for the synthesis of heterocyclic compounds. The many synthetic routes using metal as a catalyst are reported for the synthesis of quinazoline moiety. Here the most important and latest synthetic routes are listed below. Hu et al. (2011) designed a scheme for the synthesis of quinazoline derivatives by using stannous chloride di-hydrate as a reducing agent. In this reaction 2-nitrobenzamides (11) and di-carbonyl compounds (12a, 13a) are reduced using a reducing agent and then cyclized to give the best yield Scheme 8.4. Ju et al. (2012) report a reaction between 2-bromo aromatic aldehyde/ketone (14), aromatic aldehyde (15), and ammonia are coupled to each other to develop a threecomponent scheme for the substituted quinazoline derivatives (17). The reaction proceeded in presence of copper which is used as a catalyst in a one-pot give excellent yield product Scheme 8.5. Xu et al. (2013) reported a scheme by using zinc as a catalyst. This reaction started with compound (18) which was synthesized by ethynyl aniline coupled with N-(iodophenyl)acetamide via Sonogashira reaction. Compounds (18) undergo intramolecular cyclization to form the target compound (19) Scheme 8.6.

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O

O

O

O Cl

NH

H 12a

O

O 12

NH

N H

N H

X

SnCl2.H2O

NH

O N H NO2

Y

R

O

N H

13 SnCl2.H2O

13a

11 yield = 91%

yield = 83%

Scheme 8.4 Synthesis of 1,3-diazanaphthalene by 2-nitrobenzamides and stannous chloride

O

O H

R1

+

Br

14

R2 + 15

NH3

CuCl

N

R1 N

R2

17

16

R = Cl (74%)

Scheme 8.5 Synthesis of 1,3-diazanaphthalene derivatives catalyzed by copper chloride

i

H N

Pr O

ZnBr2

N

N

18 yield = 92% 19

NH2

Scheme 8.6 Synthesis of 1,3-diazanaphthalene derivatives catalyzed by zinc

Omar et al. (2014), also used copper metal as a catalyst for the synthesis of quinazoline derivatives. In the reaction bromophenyl-methanamines (20) and amidinium salt (21) are used and converted into the product via intramolecular nucleophilic substitution reaction in the presence of copper iodide as catalyst, potassium phosphate as a base, and pivalic acid [12] Scheme 8.7. N-substituted quinazoline synthesized by using aminoacetophenone (23) and acetohydroxamic acid (24) in the presence of zinc triflate in the toluene solvent system. The reaction is shown in Scheme 8.8 (Madabhushi et al. 2014). Gao et al. (2014), also design a scheme by using copper salt like copper iodide in 2014 for the construction of quinazoline skeleton. This reaction was preceded with bromo-substituted alkyl/aryl aldehyde (26) derivatives reacting with 5-aminopyrazoles (27) in the presence of copper iodide as catalyst and potassium NH.HCl NH2 Br 20

CuI, K3PO4

H 2N + 21

pivalic acid

N N yield = 90% 22

Scheme 8.7 Synthesis of quinazoline by copper as a catalyst and K3 PO4 as a base

8 Synthetic Approach of Quinazolines Candidates

317 R1

O O R1 + 23

NH2

N H

R2

OH

N

Zn(OTf)2, Toluene

O

R2 N 25 R1 = Me R2 = Me (95%), Et (92%), pro (90%), iso-pro(92%)

24

Scheme 8.8 Lewis acid-catalyzed production of 1,3-diazanaphthalene

CHO Br 26

N

H2 N +

CuI, K2CO3

HN N 27

N 28 N

DMF

yield = 78%

Scheme 8.9 Copper-catalyzed reaction for the synthesis of 1,3-diazanaphthalene

N

R1

N H 29

Br

O + H

Ph

R2

R2

R3 30

CuCl, NH3.H2O DMF

N

N

R1

N

N N 31 H

R3

N H yield = 92% 32

Me

Scheme 8.10 CuCl catalyzed reaction for 1,3-diazanaphthalene derivatives

carbonate as a base in dimethylformamide, formed good yield product of quinazoline derivatives (28) Scheme 8.9. The copper iodide was further used as a catalyst in other reactions shown in Scheme 8.10 in which reaction initiated by aromatic aldehyde (30) in ammonia, water in an inert atmosphere. The aromatic aldehyde condensed with pyrazoles substituted halo-benzene (29) derivative formed quinazoline moiety (32) (Guo et al. 2014). The synthesis of quinazoline derivatives synthesized by nucleophilic aromatic substitution reaction (SNAr) and Niementowski cyclization reaction. The reaction starts with amino-fluoro benzonitrile (33) reacts with amino alcohol (34) to give quinazoline derivative. The reaction is shown in Scheme 8.11 (Hensbergen et al. 2015). In the synthesis of quinazoline, many types of the metal complex are used as the catalyst for obtaining excellent yield in which rhodium (III) complex with silver tetrafluoroborate is used as a catalyst for the obtaining excellent yield product was reported. The reaction initiates with alkyl benzimidate (43) and dioxazolones (44) in [Cp*RhCl2 ]2 complex which acts act as promoting redox reaction and dioxazolones play a role in the formation of cyclic oxidant reaction. The reaction showing in Scheme 8.12 (Wang et al. 2016). In other methods rhodium complex with silver hexafluoroantimonate(V) is used for the synthesis of quinazoline. A reaction is shown in Scheme 8.13 in which

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CN

HO 34

+

NH2

Boc N

NH2

CN NaH

NH2 CN

H N

HO +

H N

O 35

F 33

yield = 71% 36 N

N H

38

O

NH2 CN

NH2

F 33

N

HCOOH H2SO4

37

H2N

NH2

41

40

O

NH2 CN

N O

N

BOP DBU MeCN yield = 89%

39

43b

HCOOH H2SO4

NaH

+ HO

O

BOP DBU MeCN

NaH

F 33

CN

N

HCOOH H2SO4

N N

BOP DBU MeCN

O

NH

yield = 70% 42

Scheme 8.11 Niementowski cyclization reaction

Br

NH OMe

Ph

+

43

O

O

N O 44

[Cp*RhCl2]2 AgBF4

N N

yield = 96%

45 OMe

Scheme 8.12 Rhodium-catalyzed reaction

O O S

H N + 46

NH 47

O [Cp*RhCl2]2 / AgSbF6 CuF2 or CsOAc DCE

N 48 N

Scheme 8.13 Synthesis of 1,3-diazanaphthalene derivatives by rhodium-catalyzed reaction

rhodium complex and silver hexafluoroantimonate are used. In this reaction, Nphenylacetimidamide and benzoylmethylide were used in the DCE solvent which is showing the best yield of quinazoline (48) (Lai et al. 2019). Another reaction was designed by Chen et al. (2018a, b), in which azole derivatives are coupled with starting compound (49, 51) to form quinazoline derivatives. The reaction is completed in the presence of copper salt. In this reaction the substitution of the bromine atom to form a C-H bond and make a quinazoline skeleton (Chen et al. 2018a, b) Scheme 8.14. The reaction in between ortho-fluorobenzamides (53) and fluorine, amide substituted compound (54) in the presence of cesium carbonate to give excellent yield product. This reaction proceeds via SNAr reaction in the presence of a base as the

8 Synthetic Approach of Quinazolines Candidates

319 N

N

NH

N

N N

N H 49

CuCl2 K3PO4

Br

N

50

yield = 96%

NH N

H N

N N 51

N

CuCl2 K3PO4

Br

52

N N yield = 92%

Scheme 8.14 Copper-catalyzed (CuCl2 ) reaction for the production of 1,3-diazanaphthalene NH2

O

O +

O

F Cs2CO3

H 2N

F

DMSO

53

54

NH

F

N yield = 92% 55

Scheme 8.15 Synthesis of quinazoline in the presence of cesium carbonate

promoter and further via cyclization, dehydration process step to complete for the construction of quinazolinone moiety (Iqbal et al. 2019) Scheme 8.15. Ruthenium pincer catalyst is also used for the synthesis of quinazoline moiety. In this reaction, the 2-aminophenyl methanol (56) reacts with alkyl-amide or aryl-amide (57) to form target compounds via oxidation, hydration, and cyclo condensation step (Wan et al. 2019) Scheme 8.16. The Mn(I) complex is also used as the catalyst for the synthesis of quinazoline moiety. The reaction in between 2-aminobenzyl alcohol (59) and substituted aryl nitriles (60) react to each other in the presence of Mn(I) complex catalyst. The reaction is completed by using the oxidation, dehydrogenation annulation, and dehydration step (Das et al. 2019) Scheme 8.17. Nickel complexes are very common and act as catalysts reported for the quinazoline synthesis regarding best yield. In this scheme, using nickel catalyst and reaction starts with 2-aminobenzyl alcohol (62) and substituted benzonitrile (63) was react to each other in the presence of potassium tert-butoxide which is act as a base in N

OH 56

NH2

+ MeO

57

N

Ru-pincer catalyst KOtBu amyl alcohal

N CH3 58

OMe yield = 87%

Scheme 8.16 Rhodium-catalyzed reaction in the presence of tert-potassium butoxide

320

V. K. Singh et al. NC

OH

R1 59

NH2

N

NNS-Mn(I) comples

+

N yield = 86% 61

Xylene -H2 -H2O

60

Scheme 8.17 Manganese (I) catalyzed reaction

toluene to give good yield product (Chakraborty et al. 2019) which is showing in Scheme 8.18. Sikari et al. (2019) also published work in which the same Ni-II complex was used as a catalyst. The product was synthesized by a C–N cross-coupling reaction on nitrogen nucleophile and aryl halide array in the base and in CH3 CN/DMF solvent system to give good yield product Scheme 8.19. Iridium complex in an inert condition is also used for the synthesis of quinazoline and its derivatives. The reaction starts with 2-(aminomethyl) aniline (71) and reacted with benzyl alcohol (72) in the presence of iridium complex as a catalyst in water and argon atmosphere to give an excellent yield product (74) (Chakrabarti et al. 2019) Scheme 8.20.

NH2

H N

N Ni N H

N H2N CN

62

NH2

N

64

OH

KOtBu Toluene

+ 63

+ H2O2 + H2O

N 65

Scheme 8.18 Ni-II complex catalyzed reaction

NH

O

N

NH2

Br +

66

67

Br

Ni-II complex

Ni-II complex

NH2 +

N

CH3CN/DMF

CH3CN/DMF

69

70

68

Scheme 8.19 C–N cross-coupling reaction on nitrogen nucleophile by nickel

HO

NH2 71

NH2

OH +

H2O/Argon 72

2OTf

N Ir N OH2 73

NH2 Br

NH N N 74

Scheme 8.20 Iridium catalyzed reaction for the synthesis of 1,3-diazanaphthalene

8 Synthetic Approach of Quinazolines Candidates

321

8.4.2 Synthesis by Using Reagent or Base Synthesized quinazoline derivatives are also synthesized by using different bases and reagents under many solvent conditions. Modern synthetic and important regarding yield are described in this section. The allylic amine (75) containing electron-withdrawing group condensed with 2aminobenzaldehyde (76) and then reduced nitro group by In-HCl formed compound (78). Compound 78 underwent intermolecular cyclization in the presence of CNBr and NaOMe to convert the target compound (79) (Nag et al. 2008) Scheme 8.21. Srivastava et al. (2009) synthesized targeted quinazolines (83) by using the base. In this reaction, anthranilic acid (80) and aromatic acid chloride (81) react to each other in the presence of base and pyridine in which pyridine is used as solvent Scheme 8.22. Alonso et al. (2010) designed a scheme by using the photochemistry concept which is a good concept in terms of yield. In this reaction 2-amino-acetophenone (84) is condensed with hydroxylamine and benzaldehyde (86) to form an oxime compound (87). Oxime compound (87) was cyclized in mercury lamp through pyrex give target compound (88) Scheme 8.23. The synthesis of quinazoline derivatives (93) by the cyclization of compound 92 gives the high yield targeted product. The intermediate compound is prepared R O EWG

R

EWG

R H

76

NO2

CH2Cl2

In-HCl,THF/H2O 77

O

EWG NH

NO2

NH

+ NH2

75

R

NH

CNBr NH2 NaOMe

N

MeOH

78

N

79

Scheme 8.21 Synthesis of 1,3-diazanaphthalene derivatives by allylic amine

O O OH NH2

80

O

O

Cl 81

O Pyridine

N

NH2NHCONH2.HCl Ethanol

N 82

NHCONH2

N 83

Scheme 8.22 Synthesis of quinazoline through acid chloride and pyridine

O H NH2 O Me 84

86

NH2

H2NOH py

N Me 85

OH

H N

hv/pyrex N

OH

Me 87

Scheme 8.23 2-amino-acetophenone based photochemical reaction

N N yield = 98% Me 88

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V. K. Singh et al.

89

N H NH2

O

O

O

Me

Me

Boc

+

N H NH Boc N O 91

N

HOOC 90

HCl

O

Me N H . HCl CH(OEt)3 NH H N O 92

N Me N O

N

93

yield = 82%

Scheme 8.24 Reaction 2-aminobenzamide acylate with anhydride N-Boc proline OH

O

N

ArCHO p-TsOH

NH2OH.HCl 94

NH2

NaOH

N

NH2

95

96

N H

O

visible light

N

CH3CN

Ar

97

N

Ar

yield = 90%

Scheme 8.25 Synthesis of 1,3-diazanaphthalene by carbon-based catalyst

by using 2-aminobenzamides (89) and N-Boc amino acid (90) in hydrochloric acid gives the high yield product (Iminov et al. 2012) Scheme 8.24. The reaction of 2-aminoacetophenone (94) reacts with hydroxylamine hydrochloride in base, compound 95 was formed. The compound 95 further reacts with different aromatic aldehyde in the presence of p-TsoH which is used as a catalyst the quinazoline moiety (97) was formed (Chen et al. 2013) Scheme 8.25. Condensation is a very common method for the synthesis of quinazoline. Paumo et al. (2016) published their work in which they design a multistep reaction. In this reaction, first aminobenzamide (98) is treated with NBS and NIS then condensed with benzaldehyde derivative (100) in the presence of iodine as a catalyst to give excellent yield product of quinazolines Scheme 8.26. Jin et al. (2016), design a scheme in which iodine is used as a catalyst in ionic liquids. This reaction starts with o-aminobenzohydrazides (102) reacting with formyl benzoic acid (103). In this reaction, the target molecule of quinazoline (104) yield depends upon the electron-withdrawing and electron releasing group which is substituted on the phenyl ring Scheme 8.27. In 2017, the reaction proceeds in acidic or basic conditions and synthesized compound completed by oxidative annulation. The reaction starts with 2-amino O O NH2 98

O

O

NH2

Br

NH2

NBS NIS

99

R

H 100

Br

NH2 I

N

I

H

N 101 yield = 93%

Scheme 8.26 Synthesis of 1,3-diazanaphthalene via NBS and NIS

OMe

8 Synthetic Approach of Quinazolines Candidates

323

O

O COOH

NHNH2

R1 102

NH2

+ 103

I2

N

[PMIm]PF6

CHO

H N

O yield = 89% 104

N H

Scheme 8.27 Iodine catalyzed reaction in ionic liquid

benzophenone (105) and reacts with heteroatom-cyclic containing amine in potassium tert-butoxide condition to form quinazoline skeleton (Pandya et al. 2017) Scheme 8.28. Fujii et al. (2018) designed a unique scheme for the synthesis of quinazoline derivatives by using carbon dioxide. In this reaction ortho-aminobenzonitrile (107) is reacted with carbon dioxide (108) in the presence of an organic base which acts as a catalyst. In this reaction, the organic base, tetrabutylammonium fluoride used as a catalyst which promotes the cyclization reaction and gives the best yield for the quinazoline derivatives (109) Scheme 8.29. Many of the other reagents are also used in which N-diisopropylethylamine is also reported which is responsible for the synthesis of quinazoline moiety. The reaction starts with 1H-azuleno[2,1-b]pyrrole-2,3-dione (110) condensed with 6-hylo-1Hbenzo[d][1,3]oxazine-2,4-dione (111) in the presence of DIPEA in toluene give best yield of 2-hyloazuleno[1 ,2 :4,5]pyrrolo[2,1-b]quinazoline-6,14-dione (112) (Kogawa et al. 2018) Scheme 8.30. Hypervalent iodine compound is also used which is a versatile method for the synthesis of quinazoline derivatives. This reaction was designed in a one-pot reaction by using a hypervalent iodine complex as a catalyst. The reaction starts with carbonyl compounds and is condensed with 2-aminomethyl aniline (114) in the presence of iodine catalyst in DCM as solvent (Saha et al. 2017) Scheme 8.31. Chatterjee et al. (2018), designed a scheme that is eco-friendly and metal-free synthesis. This reaction used many bases with the different solvents used but DABCO F O

O

N R

N

N

KOtBu

NH2 105

N N yield = 80% 106

O

Scheme 8.28 Reaction under the metal-free condition to produce 1,3-diazanaphthalene

NH2 + CN

Cl 107

CO2 108

H N

Bu4NF DMSO

Cl

O NH

109

O

yield = 99%

Scheme 8.29 Synthesis of 1,3-diazanaphthalene by using Bu4 NF as a base

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V. K. Singh et al. O NH +

O

O

110 O

X

O

O DIPEA N

Toluene

N H 111

X

112

N O X = Br yield = 90% I yield = 91%

Scheme 8.30 Synthesis of 1,3-diazanaphthalene in DIPEA

N

O R

113

NH2

+

H

NH2 114

N

PhI(OAc)2

N

DCM

115 yield = 94%

Scheme 8.31 Hypervalent iodine catalyzed reaction for 1,3-diazanaphthalene derivatives

and sodium hydroxide in acetonitrile and water solvent system, respectively give an excellent yield of quinazoline product. The reaction starts with 2-aminobenzylamine (116), trihalotoluenes (117) react to each other and reaction undergoes via nucleophilic substitution reaction in the presence of base and aromatization with molecular oxygen give derivatives product Scheme 8.32. The simple coupling of the ortho C-H bond of aniline (122) and aromatic aldehyde (123) reacts to each other in the presence of ammonium iodide in benzyl chloride is given quinazoline skeleton. The DMSO is used in this reaction as an oxidant in benzyl chloride to give an excellent yield product (Chen et al. 2018a, b) Scheme 8.33. NH2 116

CBr3

MeCN

N yield = 78% 118

117

NH2 119

N

DABCO

+

NH2

CBr3 +

NH2

N

NaOH N

H2O

120

yield = 73% 121

Scheme 8.32 Catalyzed reaction to synthesize 1,3-diazanaphthalenes NH2

CHO N

DMSO +

R 122

+ NH4I 123

PhCl

t

Bu

Ph N

124 Ph yield = 95%

Scheme 8.33 Four component reactions for 1,3-diazanaphthalenes synthesis

8 Synthetic Approach of Quinazolines Candidates

325 Ar O O P OH O CH3 Ar

O

CH3

CF3

+ N 125 H H N 2

127 Phosphoric acid catalyst

126

N

Toluene

NH CF3 128

Scheme 8.34 Phosphoric acid-catalyzed reaction for 1,3-diazanaphthalene derivatives

Phosphoric acid catalysts are also used for the synthesis of quinazoline skeleton in the different solvent systems. This reaction starts with the condensation and amineaddition of fluorinated ketones (126) and 2-(1H-indolyl) anilines (125) in the presence of substituted chiral phosphoric acid. The catalyst gives the best yield in toluene which is the best reaction system for the high yield product (Wang et al. 2019) Scheme 8.34.

8.4.3 Microwave-Based Reaction Bedi et al. (2004) reported a multistep step method in microwave radiation for quinazoline derivative. The first step is that N-aryl benzamidine/guanidines converted into N-imidoyl iminophosphorane (129) then reacts with benzaldehyde derivative (130) give quinazoline moiety by electro-cyclization and aromatization process Scheme 8.35. In 2007, a reaction has been reported for the quinazoline synthesized in hexamethylenetetramine (HMTA) and THF. The reaction starts with ethyl phenyl carbamate (134) which was converted into quinazoline derivatives (135) by intermolecular cyclization process (Chilin et al. 2007) Scheme 8.36. Quinazolines in microwave radiation are synthesized in two ways which are shown in Scheme 8.37. The reaction starts with 4-nitro and 5-nitroanthranilic acid and proceeded to reaction via intermolecular cyclization. In the first route nitroanthranilic acid (136) react with formamide (142) or N, N-dimethylformamidedimethylacetate CH3

CH3 O

+ N

R N 129

PPh3

R1

H 130

N R Electrocyclization HN

Microwave R N 131

N H

N

R Aromatisation CH3

N

H R1 132

R1

Scheme 8.35 Synthesis of 1,3-diazanaphthalene by electrocyclization process

CH3 R1

133

326

V. K. Singh et al. microwave HMTA TFA

NHCOOEt H3 C

N H 3C

134

N yield = 95% 135

Scheme 8.36 1,3-diazanaphthalene synthesized under microwave conditions in the presence of HMTA and THF O O 2N

O 2N

OH 136

+ DMFDMA 137

NH2

CO2Me N 138

O O 2N

141

NH2 139 Me micromawe N AcOH Me

micromawe

OH micromawe + H 2N O NH2 142

N 143

N

N

144

Bn

Bn

N 140

Br

O O 2N

O O 2N

O O 2N

N

NaH, DMF micromawe

Bn

N 145

Scheme 8.37 Synthesis of 1,3-diazanaphthalene moiety under microwave condition through DMFDMA

O H

+

N NH

NH2

N

microwave heaƟng/H2O OH 146 OCH3

147

N N H 148

OH OCH3 yield = 93%

Scheme 8.38 Synthesis of 1,3-diazanaphthalene derivatives under microwave radiation in the presence of water

(DMFDMA) (137) in microwave radiation then quinazoline moiety was formed. This reaction is completed in multistep and via an intermolecular cyclization process (Hédou et al. 2013) Scheme 8.37. The synthesis of quinazoline also proceeded by cyclo condensation in between phenyl-pyrazole substituted aniline (147) and benzaldehyde derivatives (146) in microwave radiation in the presence of water (Kumar et al. 2014). The reaction is shown in Scheme 8.38.

8.5 Conclusion In this chapter, we gave a brief knowledge about the modern synthesis route for the construction of quinazoline derivatives and their reaction in different conditions. We have summarized different synthetic methods for the quinazoline skeleton with

8 Synthetic Approach of Quinazolines Candidates

327

excellent products in the different conditions/catalysts like metal, acid, polyacid, hypervalent iodine, different solvents, base, and other condition by using different reaction mechanisms. The application of quinazoline derivatives used in the pharmaceutical industry and have the property to bind different target sites to discover various immerging drugs structurally by the diverse ligand of quinazoline.

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Hédou D, Guillon R, Lecointe C, Logé C, Chosson E, Besson T (2013) Novel synthesis of angular thiazolo [5, 4-f] and [4, 5-h] quinazolines, preparation of their linear thiazolo [4, 5-g] and [5, 4-g] quinazoline analogs. Tetrahedron 69:3182–3191 Hensbergen AW, Mills VR, Collins I, Jones AM (2015) An expedient synthesis of oxazepino and oxazocino quinazolines. Tetrahedron Lett 56:6478–6483 Hu Y, Wang MM, Chen H, Shi DQ (2011) Efficient and convenient synthesis of spiroindolinonequinazolines induced by stannous chloride. Tetrahedron 67:9342–9346 Iminov RT, Tverdokhlebov AV, Tolmachev AA, Volovenko YM, Shishkina SV, Shishkin OV (2012) Synthesis of condensed tetrahydroimidazo [1, 2-a] quinazoline-1, 5-dione derivatives. Tetrahedron 68:3098–3102 Iqbal MA, Lu L, Mehmood H, Khan DM, Hua R (2019) Quinazolinone synthesis through basepromoted SNAr reaction of ortho-fluorobenzamides with amides followed by cyclization. ACS Omega 4:8207–8213 Jiang B, Shi F, Tu SJ (2010) Microwave-assisted multicomponent reactions in the heterocyclic chemistry. Curr Org Chem 14:357–378 Jin RZ, Zhang WT, Zhou YJ, Wang XS (2016) Iodine-catalyzed synthesis of 5H-phthalazino [1, 2-b] quinazoline and isoindolo [2, 1-a] quinazoline derivatives via a chemoselective reaction of 2-aminobenzohydrazide and 2-formylbenzoic acid in ionic liquids. Tetrahedron Lett 57:2515– 2519 Ju J, Hua R, Su J (2012) Copper-catalyzed three-component one-pot synthesis of quinazolines. Tetrahedron 68:9364–9370 Kogawa C, Fujiwara A, Sekiguchi R, Shoji T, Kawakami J, Okazaki M, Ito S (2018) Synthesis and photophysical properties of azuleno [1 , 2 : 4, 5] pyrrolo [2, 1-b] quinazoline-6, 14-diones: azulene analogs of tryptanthrin. Tetrahedron 74:7018–7029 Kumar D, Kumar R (2014) Microwave-assisted synthesis of pyrazolo [1, 5-c] quinazolines and their derivatives. Tetrahedron Lett 55:2679–2683 Lai R, Wu X, Lv S, Zhang C, He M, Chen Y, Wang Q, Hai L, Wu Y (2019) Correction: synthesis of indoles and quinazolines via additive-controlled selective C–H activation/annulation of Narylamidines and sulfoxonium ylides. ChemComm 55:10027 Madabhushi S, Mallu KK, Jillella R, Kurva S, Singh R (2014) One-step method for synthesis of 2, 4-disubstituted quinazoline 3-oxides by reaction of a 2-aminoaryl ketone with a hydroxamic acid using Zn (OTf) 2 as the catalyst. Tetrahedron Lett 55:1979–1982 Nag S, Mishra A, Batra S (2008) A facile route to the synthesis of pyrimido [2, 1-b] quinazoline core from the primary allyl amines afforded from Baylis-Hillman adducts. Tetrahedron 64:10162– 10171 Omar MA, Conrad J, Beifuss U (2014) Copper-catalyzed domino reaction between 1-(2-halophenyl) methanamines and amidines or imidates for the synthesis of 2-substituted quinazolines. Tetrahedron 70:3061–3072 Pandya AN, Villa EM, North EJ (2017) A simple and efficient approach for the synthesis of 2aminated quinazoline derivatives via metal free oxidative annulation. Tetrahedron Lett 58:1276– 1279 Paumo HK, Mphahlele MJ, Rhyman L, Ramasami P (2016) Synthesis, photophysical properties and DFT study of novel polycarbo-substituted quinazolines derived from the 2-aryl-6-bromo-4chloro-8-iodoquinazolines. Tetrahedron 72:123–133 Saha M, Mukherjee P, Das AR (2017) A facile and versatile protocol for the one-pot PhI(OAc) 2 mediated divergent synthesis of quinazolines from 2-aminobenzylamine. Tetrahedron Lett 58:2044–2049 Sikari R, Sinha S, Chakraborty G, Das S, van Leest NP, Paul ND (2019) C–N Cross-coupling reactions under mild conditions using singlet di-radical nickel (II)-complexes as catalyst: Narylation and quinazoline synthesis. Adv Synth Catal 361:4342–4353 Srivastava V, Srivastava AM, Tiwari AK, Srivastava R, Sharma R, Sharma H, Singh VK (2009) Disubstituted 4 (3H) quinazolones: a novel class of antitumor agents. Chem Biol Drug Des 74:297–301

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Chapter 9

An Overview of Cinnolines, Quinazolines and Quinoxalines: Synthesis and Pharmacological Significance Pratibha Saini, Krishan Kumar, Swati Meena, Dinesh Kumar Mahawar, Anshu Dandia, K. L. Ameta, and Vijay Parewa

9.1 Introduction Heterocycles engage a middle arrangement in synthetic organic chemistry. Over the past two centuries, heterocyclic chemistry has been soundly established due to the agricultural, pharmaceutical and industrial importance of the majority of organicbased value-added chemicals. Heterocyclic entities play an essential position in Natural systems and show a noteworthy involvement in maintaining livelihood (Brahmachari 2015). They are extensively scattered in “Universe” which is crucial for existence such as oxygen transporting pigment “hemoglobin,” photosynthetic pigment “chlorophyll,” plant alkaloids (e.g., Strychnine, Flavones), vitamins (e.g., vitamin B6, vitamin E), enzymes, polysaccharides, anthocyanins, energy carrier (e.g., ATP, ADP), neurotransmitter (e.g., Serotonin, Histamine) and nucleic acid (DNA and RNA) (Shalini et al. 2010; Keri et al. 2014; Afzal et al. 2015; Shinde and Haghi 2020; Hussaini et al. 2019). Furthermore, numerous amino acids, alkaloids (e.g., nicotine and caffeine), carbohydrates, hormones, pheromones, antibiotics, antioxidants, flavorings and perfumes, etc. are also value-added heterocyclic compounds that are important for our life (Berger 2007; Ramsewak et al. 1999; Padwa et al. 1992; Festa et al. 2019; Ameta et al 2014; Lambat et al. (2020); Liu and Fu (2012); Dandia et al. 2011, 2012, 2013a, 2014, 2020a; b) (Fig. 9.1).

P. Saini · K. Kumar · S. Meena · D. K. Mahawar · A. Dandia · V. Parewa (B) Department of Chemistry, Centre of Advanced Studies, University of Rajasthan, Jaipur 302004, India K. L. Ameta Department of Chemistry, School of Liberal Arts and Sciences, Mody University of Science and Technology, Lakshmangarh, Rajasthan 332311, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_9

331

332

P. Saini et al.

Fig. 9.1 Heterocyclic materials at the interface of chemistry and biology

9.1.1 N-Heterocyclic Compounds As life has developed in universe over last centuries, nature has expanded an assortment of valuable heterocyclic compounds that provide as chemical couriers that activate biological feedbacks and regulate biological course of actions, more commonly. N-Heterocyclic compounds have become an imperative contributor of everyday life during last the century and it plays a major role in our environment (Verma 2020). The chemistry of “N-Heterocycles” attracts particular concentration in science basically due to its enormous significance to our everyday life. N-Heterocyclic compounds have diverse uses such as in life saving drugs, optoelectronics, flavoring agents, polymers, herbicides, preservatives, anticorrosive agent, light-emitting diode, fragrances, fabric whiteners, fertilizers, conductivity-based sensors, pesticides, agrochemicals and modifier for rockets propellant fuels (Dandia et al. 2012, 2013c, 2015, 2016, 2017a, b, 2018a, 2019a, 2020a, b, c, 2021a, b, c). Owing to their marvelous impact of N-heterocyclic compounds in our humanity, there are constant demands to decrease unpreserved resources and expenses to have less disadvantageous impact to the atmosphere. The fused N-heterocyclic compounds

9 An Overview of Cinnolines, Quinazolines and Quinoxalines … N N Quinazoline

N N Quinoxaline

N

N

Cinnoline

333 N N Phthalazine

Scheme 9.1 Isomeric form of the fused N-heterocyclic compounds containing two N-atoms in the benzene ring

have an immense significance in therapeutic chemistry (Aher et al. 2014; Mermer et al. 2021; Bhardwaj et al. 2021). One of the most imperative fused scaffolds in medicinal chemistry is cinnolines, quinoxalines and quinazolines (Scheme 9.1). They are well-known heterocycles for their extensive pharmacological properties counting anticancer, anticonvulsant, anti-allergic, anti-inflammatory, antidiabetic, antimalarial, antibacterial, antitumor, antitubercular, antihypertensive, as anti-hypertensive, antihistamine and antihypertensive (Taek et al. 2017). The N-heterocyclic fused ring has drained an enormous deliberation because of their prolonged applications in field of therapeutic chemistry. This chapter assembles the modern work on fused 6-membered N-heterocyclic scaffolds with two N-atoms like quinoxalines, cinnoline and quinazolines reported in literature by researchers (Keneford et al. 1950; Mathew et al. 2017; Mamedov 2016; Chandra et al. 2014). These N-heterocyclic compounds are manufactured from combination of pyrimidine and benzene ring. One benzene ring contains two N-atoms. On the basis of position of the two nitrogen atoms these fused N-heterocyclic compounds are named as cinnoline, quinoxalines and quinazolines (Fig. 9.2).

9.2 Cinnoline 9.2.1 Introduction Cinnoline is an organic N-heterocyclic compound having molecular formula C8 H6 N2 . Cinnoline (1,2-benzodiazine) has fascinated a great covenant of attention owing to their friendship with a variety of pharmaceutical and biological properties (Lewgowd and Stanczak 2007; Abdelrazek et al. 2006; Somei and Ura 1978). It is a fused N-heterocyclic compound in which two N-atoms are present at 1,2 position (benzene and pyrimidine ring). It is an isomeric form of quinoline or isoquinoline and also with phthalazine. As a outcome of widespread range of biological significance’s for example antiinflammatory, analgesic, anxiolytic, antitumor, antimalarial, antifungal and antibacterial activities of cinnoline (1,2-benzodiazine) derivatives, enormous endeavor has been made to construct these bioactive molecules (Fig. 9.3). For that reason, construction of these biologically active N-heterocyclic moieties has increased enormous significance in organic synthesis. The plenty implication of Cinnoline (1,2benzodiazine) derivatives have influence them to meet via the development of various

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P. Saini et al.

Fig. 9.2 Structure of fused N-heterocyclic compounds and its isomers cinnoline, quinoxalines and quinazolines

organic transformations (Alvarado et al. 2006; Tian et al. 2021; Rinderspacher et al. 2021; Kandeel et al. 2018; Bommagani et al. 2020). To date many procedures have been described to access these scaffolds.

9.2.2 Various Approaches for the Preparation of Cinnolines An exceedingly proficient microwave-assisted method to access bioactive molecules of cinnoline derivatives by the reaction of 4-Alkylpyridazine and nitrostyrene in dioxane/piperidine at 100 °C was presented by Hameed et al. (2017) (Scheme 9.2). Feng et al. (Li et al. 2021a) designed a straightforward and palladium-catalyzed sustainable pathway to afford biologically important cinnoline derivatives via one-pot dual C–H activation strategy in AcOH at 80 °C (Scheme 9.3). Mekheimer et al. (Nazmy et al. 2020) described a microwave-induced reaction in dioxane/piperidine to generate densely functionalized cinnolines derivatives at 100 °C. The synthesized cinnolines derivatives show in vitro anticancer biological activity through apoptosis generation (Scheme 9.4). An competent and green Neber Bossel preparation of several cinnolines from diazotization of (2-aminophenyl)-hydroxyacetate under acidic conditions at 0 °C was introduced by Henry et al. (1960) The reaction was followed by intramolecular condensation and aromatization (Scheme 9.5).

9 An Overview of Cinnolines, Quinazolines and Quinoxalines … O

H N

335 H N

OMe

N

N N OMe N

MeO

N

OMe

N

Anti-inflammatory activity (IV)

Antitumor

GABAA receptor modulator R2

R2 R3

O

R1

H N

R1

S

N N

Bu N

N

OMe

Me

N

O

N

CH3 Antifungal agent

F

F CO2Me

N

NH O N

OMe N

N

H3C

O

OCH3 NH2

Anti-tumor activity (V)

Liver X receptor (LXR)

O

O

OH

N

CF3

Bun

N

N

OEt

NH

NH2 N

N N

Anti-Cancer agent (VI) CSF-1R Inhibitor (II)

N

Inhibitor of ulceration (III)

Fig. 9.3 General structures of cinnoline-based biological active compounds Ar'

CH3 CN

EtO2C N

NO2

+ N Ar

Dioxane, Piperidine

CN

HO

100oC, MW 20 min

Ar'

O

O2N

N

N Ar

O

Scheme 9.2 Microwave-assisted method to access bioactive molecules of cinnoline derivatives R R O R1

O

N H N

R

I

Pd(OAc)2 (10 mol%) AgBF4 (2.0 equiv.)

+ R2

AcOH (0.1 M) 80oC, 6 h

O R1

R

N

O N

R2

Scheme 9.3 Palladium-catalyzed sustainable pathway to afford biologically important cinnoline derivatives

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P. Saini et al. Ar' CH3

EtO2C

O2N

CN N

+ CH3NO2 N Ar

Dioxane, Piperidine

+ Ar'CHO

CN

HO

100oC, MW

O

N

N Ar

O

Scheme 9.4 Microwave-induced reaction in dioxane/piperidine to generate densely functionalized cinnolines derivatives OH

OH 1. NaNO2, HCl, 0oC

CO2Na

2. SnCl2, HCl, 0oC

NH2

N H

CO2H NH2

OH

HCl N

N

Scheme 9.5 Neber Bossel synthesis of several cinnoline derivatives

Barber et al. (1961) have been demonstrated catalytic behavior of TiCl4 to afford a library of biologically relevant compounds cinnolines by intramolecular cyclization of phenylhydrazone-linked acid chloride under Friedel–Crafts condition (Scheme 9.6). A proficient pathway for the production biologically important cinnolines utilizing PPA catalyst at 100–120 °C was explained by Mubarak and co-workers (Awad et al. 2012). The cinnoline is formed through hydrazone intermediate. The author observed that the formed cinnoline derivatives show anticancer and antibacterial activity (Scheme 9.7). Cu(I) catalyzed production of various functionalized cinnolines derivatives through tandem C–N bond forming reaction using K2 CO3 and DMEDA in dioxane at 90 °C was described by Willis and co-workers (Ball et al. 2012). The reported method is based on diazotization chemistry (Scheme 9.8). NH2 O

O NC R1 N H

N

N H

R2

TiCl4 or AlCl3 Solvent, Heating

R1

N

N H

N

R2

Scheme 9.6 TiCl4 catalyzed production of biologically relevant scaffolds

O H N

N

N

N

PPA N

X

Ar

100-120oC

X

N N

N

X = H, F, Cl, Br

Scheme 9.7 Production biologically important cinnolines utilizing PPA catalyst

Ar

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MeO MeO

Br

Br

+ EtO2C

N H

H N

CuI DMEDA

MeO

K2CO3 dioxane 90oC

MeO

CO2Et

MeO

NaOH (aq.) NCO2Et

N CO2Et

o

EtOH, 70 C

N

MeO

N

Scheme 9.8 Cu(I) catalyzed production of various functionalized cinnolines derivatives

H R1 N

R2

N H

CuSO4, CuI Pyr., TFA, DMF O2, 110oC

R2 R1 N

N

Scheme 9.9 Cu(II) induced aerobic dehydrogenative cyclization of hydrazine to afford pharmacologically important cinnoline derivatives

Zhang et al. (2012) used Cu(II) as green catalyst for the aerobic dehydrogenative cyclization of hydrazine to afford pharmacologically important cinnoline derivatives followed by the Csp3 -H oxidation, cyclization and aromatization sequence in DMF under air atmosphere at 110 °C (Scheme 9.9). A proficient formal [2 + 2 + 2] cycloaddition of arynes, tosylhydrazine and αbromoketones to access cinnoline derivatives catalyzed by CsF in CH3 CN at 90 °C was developed by Shu co-workers (Shu et al. 2016). In this transition-metal-free reaction, two C-N bond and one C–C bond are formed via one-pot succession (Scheme 9.10). Au(I)-induced hydroarylation of N-propargyl-N’-arylhydrazines has been successfully applied to generate 4-exo-methylene-1,2-dihydrocinnoline derivatives via hydroarylation process in refluxing nitromethane under catalytic acidic conditions were reported by Gagosz et al. (2011) In this reaction [XPhosAu(NCCH3 )SbF6 ] is used as Au complex (Scheme 9.11). O

TMS +

R1 OTf

TsNHNH2

+

R2

CsF Br

CH3CN, 90oC

R2 R1 N

N

R1 = CH3, CH3O R2 = Aryl

Scheme 9.10 [2 + 2 + 2] cycloaddition of arynes, tosylhydrazine and α- bromoketones to access cinnolines catalyzed by CsF

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P. Saini et al. Me

R

[XPhosAu(NCCH3)SbF6] (4 mol%) N CH3NO2, 100oC N CO2Me Me

R

pTsOH (5 mol%) N CHCl3, 60oC CO2Me N Me

R N CO2Me N Me

Scheme 9.11 Au(I)-induced synthesis of cinnolines

9.3 Quinazoline 9.3.1 Introduction Quinazoline is well-known N-containing heterocyclic compounds for their extensive pharmacological properties including anticancer, antifungal, antibacterial, antiulcer, anticonvulsant, antiinflammatory, antidiabetic, antimalarial, antitumor, antitubercular, antihypertensive, antihistamine and antihypertensive (Wang et al. 2013; Kuneš et al. 2000; Ravez et al. 2015; Alafeefy et al. 2010; Marzaro et al. 2012). They are also found in numerous natural products like L-vasicinone, ispinesib, luotonin E, circumdatin F and sclerotingenin and pharmaceutical drugs. Numerous quinazolines are presently in utilized for therapeutic motive owing to their superior pharmaceutical proficiency (Abuelizz et al. 2017; El-Azab et al. 2010). Quinazolinone alkaloids (derivative of quinazoline) are widely present in nature. Quinazolinones have also been provided as constructive synthetic intermediates. Furthermore, these quinazolinone motifs are of attention as COX-2 inhibitors, herbicidal agents, anti-allergic, antipsychotic, melatonin receptor MT1 and agonists (Ahmad et al. 2017; Rehuman et al. 2021; Li et al. 2021b; Zheng et al. 2020; Selvam et al. 2011) (Fig. 9.4). Owing to their remarkable properties, traditionally various synthetic approaches have been the subject of several publications for the production of derivatives of quinazoline.

9.3.2 Various Approaches for the Preparation of quinazolines To date many procedures have been developed to prepare these compounds. t-butylhydroperoxide is used as a competent and efficient catalyst by Asif et al. (2014) to generate quinazoline derivatives from aminobenzophenones and benzylamines in acetonitrile (Scheme 9.12). Pd is used as a competent catalyst by Wang and co-workers (Wang et al. 2011) to synthesize 4-aminoquinazoline derivatives from isonitriles and N-aryl amidines in toluene. This reaction takes place via intramolecular C(sp2 )-H amidination (Scheme 9.13). An exceedingly proficient microwave-promoted synthesis of bioactive molecules of quinazoline derivatives from o-phenyl oximes and aldehydes was presented by

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339

Fig. 9.4 Biological activities of quinazoline-based compounds O R

+

H2N

NH2

Ar

tBuOOH MeCN

Ar

N N R

R = Me, Ph

Scheme 9.12 Ceric ammonium nitrate-t-butylhydroperoxideis catalyzed synthesis of quinazoline derivatives NHR11 R1 N H

+ NH

CN-R11

N

Pd(OAc)2, CS2CO3 Toluene

Scheme 9.13 Pd(OAc)2 catalyzed synthesis of 4-aminoquinazoline derivatives

N

R1

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P. Saini et al. R1

R1 OPh

O +

H

NH2

ZnCl2 R11

N

PF4

N

R11

Scheme 9.14 Microwave-promoted synthesis of bioactive molecules of quinazoline derivatives

Portela-Cubillo and co-workers (Portela-Cubillo et al. 2009). For this microwavepromoted reactions, ZnCl2 is used as efficient catalyst with PF4 (Scheme 9.14). Ferrini et al. (2007) illustrated new microwave-induced cyclization reactions to afford quinazolines through Fries rearrangement reactions of anilides catalyzed by ammonium formate. For this Fries rearrangement reaction, salicylamides are formed by the acylation of o-aminoacyl benzene derivatives (Scheme 9.15). Ligand-free copper has been successfully used as cheap and willingly accessible catalyst to generate 2-phenylquinazolines (quinazoline derivatives) from 2bromophenyl methyl amines and amindes was described by Zhang et al. (2010). In this method, K2 CO3 is used as a mild base (Scheme 9.16). Dandia and co-workers (2019b) envisaged a commercially available Cu(I)catalyzed novel flexible strategy for selective production of quinazolinones utilizing smoothly accessible anthranilonitrile and benzyl bromides. This reaction is complete through N-benzylation/CSp3 -H oxidation/CN hydrolysis/cyclization sequence (Scheme 9.17). Dandia et al. (2018b) designed a new regioselective water-assisted strategy to access substituted quinazolinones from o-aminobenzamides with benzyl alcohols catalyzed by NaCl under microwave irradiation. In this approach, NaCl plays a deceive role for the C–N bond formation through “kosmotropes perturbation” (Scheme 9.18). A novel and environmental friendly visible-light photoredox procedure to access quinazolinones in the presence of Cu decked ZnS nano-photocatalyst in CH3 CN was reported by Dandia et al. (2020d). This reaction completed through amide intermediate (Scheme 9.19). O R11

HCO2NH4 N H R1

R11

N N R1

O

Scheme 9.15 Microwave-induced cyclization reactions to afford quinazolines through fries rearrangement reactions of anilides catalyzed by ammonium formate

NH2 Br

+

Ar

NH2 O

K2CO3 2 PrOH

Ar

N N

Scheme 9.16 Production of quinazolines derivatives using ligand-free copper catalyst

9 An Overview of Cinnolines, Quinazolines and Quinoxalines … O

CN NH2

341

CuI, Cs2CO3

Br

+

NH

TBHP, DMSO 160 oC

N

CN Via

O

N H amide intermediate

Scheme 9.17 Cu(I)-catalyzed novel flexible strategy for selective production of 2-aryl-quinazolin4(3H)-ones derivatives O

O NH2

OH

+

NH2

R

NH NaCl, TBHP H2O, MW

N R

Scheme 9.18 Regioselective water-assisted strategy to access quinazolinones catalyzed by NaCl O

O NH2

Br

+

NH2

NH

Cu doped ZnS NPs N

Visible light

R

R

Scheme 9.19 Visible-light photoredox procedure to access quinazolinones using Cu decked ZnS nano-photocatalyst

Peng et al. (2018) reported a convenient Pd-catalyzed carbonylative cyclization reaction to give 2,3-disubstituted quinazolinones derivatives utilizing Mo metal containing carbonyl complex as a reductant and a CO supplier (Scheme 9.20). Ding et al. (Ren et al. 2018) demonstrated one-pot Pd(PPh3 )4 -initiated crosscoupling of 2-azidobenzamides and isocyanides to prepare biological active quinazolinones derivatives in DMF at room temperature (Scheme 9.21). Trifluoroacetic acid (TFA) has been successfully used as cheap and willingly accessible CF3 source to generate trifluoromethyl substituted quinazolinones by narrative and sensible chronological cascade pathway was introduced by Almeida and co-workers (2018) (Scheme 9.22).

Br

R3

O O

O NH2

O R3

R2NO2

[Pd] Mo(CO)6

N N

R2 R3

Scheme 9.20 Pd-catalyzed carbonylative cyclization reaction to give 2,3-disubstituted quinazolinones

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P. Saini et al. O O O

R1 N3

HN R2

Pd(PPh3)4 DMF, r.t, 1h

R3 NC

N H

R1 N

C

R2

N

R1

R2

N

N H

R3

N R3

Scheme 9.21 Pd(PPh3 )4 -initiated cross-coupling of 2-azidobenzamides and isocyanides to prepare biological active quinazolinones derivatives O

O R2NH2, TFA O Pr P O O O P P O O Pr Pr

OH

R

NH2

N

R N

R2 CF3

T3P

Scheme 9.22 Trifluoroacetic acid (TFA) catalyzed synthesis of quinazolinones

Huang et al. (Lin et al. 2019) developed an environmentally benign electrochemical process to afford substituted 2-aryl-quinazolinones derivatives through cascade cyclization of o-aminobenzamides with alcohols utilizing manganese(II) sulfate as a catalyst in CH3 CN/H2 O medium (Scheme 9.23). Salehi et al. (2005) accomplished a versatile way for the production of disubstituted quinazolinones by the reaction of commercially available reactants utilizing silica sulfuric acid at 80 °C temperature (Scheme 9.24). Alper et al. (Zheng et al. 2008) demonstrated Pd(OAc)2 /PPh3 /CO-catalyzed cyclo-carbonylation of iodoanilines and acid chlorides to generate a series of quinazolinones proceed by in situ construction of an amidine (Scheme 9.25). O

O R1

OH

NH2

R

NH2

Undivided cell, Pt-Pt MnSO4.H2O LiClO4, TFA air, RT

NH

R N

R1

Scheme 9.23 Electrochemical process to afford substituted 2-aryl-quinazolinones derivatives O

O O

R N H

R1 C(OEt)3 O

NH4OH

Silica sulfuric acid 80oC

NH

R

Scheme 9.24 Production of disubstituted quinazolinones utilizing silica sulfuric acid

N

R1

9 An Overview of Cinnolines, Quinazolines and Quinoxalines …

343 O

I

N

R NH2

Cl

R1

Pd(OAc)2/PPh3/CO Et3N, THF

R2

N

R

R1 R2

N

Scheme 9.25 Pd(OAc)2 /PPh3 /CO-catalyzed synthesis of a series of quinazolinones O COOH R NH2

HC(OR)3

Yb(OTf)3

N

R

R1

N

R1 NH2

Scheme 9.26 Lanthanide triflate [Yb(OTf)3 ] catalyzed production of pharmaceutical vital quinazolinones

Lanthanide triflate [Yb(OTf)3 ] catalyzed production of pharmaceutical vital quinazolinones from 2-aminobenzoic acid, ortho-esters and amine was developed by Wang and co-workers (Wang et al. 2003) (Scheme 9.26). A broad and proficient process to synthesized a variety of quinazolinones from the condensation of aldehydes and anthranilamide catalyzed by the complex of Ir metal in aqueous medium was developed by Feng co-workers (Li et al. 2015) (Scheme 9.27). [Cu(Py)4 (OTf)2 ] is found as an competent catalyst by Kapdi et al. (Gholap et al. 2017) to afford substituted quinazolinones derivatives through one-pot sequential way (Scheme 9.28). [Cp*RhCl2 ] is found as competent catalyst by Xiong et al. (2018) to afford substituted quinazolinones derivatives through one-pot successive regioselective orthoC–H amidation and cyclization of N-methoxybenzamide and dioxazolones under nitrogen atmosphere. In this reaction AgSbF6 is used as acid catalyst (Scheme 9.29). Bi-SO3 H-functionalized ionic liquids (ILs) provoked aerobic oxidation approach to afford quinazolinones via solvation-induced proton transfer under air atmosphere described by Yu and co-workers (Yu et al. 2017) (Scheme 9.30). O

O NH2

R

R1 CHO

NH2

H2O

NH

R

[Cp*Ir(H2O)3][OTf]2 Reflux, 1h

N

R1

Scheme 9.27 Synthesis of quinazolinones in the presence of the complex of Ir metal O

O R

N R1

NH2

R2

[Cu(Py)4(OTf )2] DMF,

130oC, air

12h

O N

R N

R1

N

R R2

NH

Scheme 9.28 [Cu(Py)4 (OTf)2 ] catalyzed synthesis of substituted quinazolinones derivatives

R1 R2

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P. Saini et al. O

O Ar

O N H

R2

O Ph

[Cp*RhCl2] O

N

Ar

AgSbF6, 100oC, 12h N2

N

OR Ph

Scheme 9.29 [Cp*RhCl2 ] catalyzed synthesis of substituted quinazolinones derivatives O R

O

NH2 NH2

Ph

CHO

Bi-SO3H-functionalized ILs EtOH, 80oC or PEG-400, 120oC

O NH

R N

Ph

R

NH NH

Ph

major

Scheme 9.30 Bi-SO3 H-functionalized ionic liquids (ILs) provoked aerobic oxidation approach to afford quinazolinones

9.4 Quinoxaline 9.4.1 Introduction Quinoxaline is isomeric form of quinoline or isoquinoline, phthalazine, cinnoline and also with phthalazine. It is also called a benzopyrazine. Quinoxalines are wellknown fused N-containing heterocyclic compounds for their extensive pharmacological properties including anticancer, anticonvulsant, antineoplastic, antitubercular, antiamoebic, anti-HIV agent, antidepressant, antibacterial, antifungal, antimalarial, anti-inflammatory, antileishmanial, herbicidal, antiprotozoal, fungicidal, insecticidal, antioxidant and anti-ebola activities (Ahmed et al. 2018; Loughran et al. 2016; Ibrahim et al. 2017; Achutha et al. 2013; Carta et al. 2001; Shekhar et al. 2014; Ali et al. 2017; Corona et al. 2009). Quinoxaline derivatives also exist in many natural compounds, for example vitamin B2, izumiphenazines A-C, cyclic peptide triostin A, hunanamycin A (Zhang et al. 2014; Abdelfattah et al. 2010; Henriques et al. 2010; Shingare et al. 2013; Hu et al. 2013; Refat et al. 2011) and DNA cleavage agents and functional materials (Dandia et al. 2012, 2013b, 2015, 2016, 2017a, 2020b, 2021a; b) (Aher et al. 2014; Mermer et al. 2021; Bhardwaj et al. 2021; Taek et al. 2017; Keneford et al. 1950; Mathew et al. 2017; Mamedov 2016). They are also important in the fields of technology for example chemical switches, cavitands, fluorescent dying agents, semiconductors and electroluminescent materials (Jaung 2006; Zhang et al. 2008; Thomas et al. 2005; Crossley and Johnston 2002; Dailey et al. 2001; Katoh et al. 2000; Sessler et al. 2002) (Fig. 9.5).

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Fig. 9.5 Biological activities of quinoxaline-based compounds

9.4.2 Various Approaches for the Preparation of Quinoxalines To date many procedures have been developed to prepare these compounds. Kundu and co-workers (Shee et al. 2020) described a straightforward and proficient NiBr2 /1,10-phenanthroline system-promoted approach to generate quinoxalines using cesium carbonate at 150 °C. The used catalytic system is reusable for the next seventh cycle (dehydrogenative coupling reaction) (Scheme 9.31).

NH2 R1

NH2/NO2

HO

R2

HO

R3

+

NIBr2 + Phen. Cs2CO3, Tolune, 150oC

R1

N

R2

N

R3

Scheme 9.31 NiBr2 /1,10-phenanthroline system-promoted approach to generate a series of quinoxalines

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P. Saini et al.

Alumina-supported heteropolyoxometalates (AlMoVP) has been successfully used as cheap and reusable catalyst to generate a series of quinoxalines from 1,2dicarbonyls and 1,2-diamines at 25 °C was introduced by Romanelli and co-workers (Ruiz et al. 2012) (Scheme 9.32). An earth-abundant manganese(I) complex (Mn(CO)5 Br) is demonstrated to be a competent catalyst for the preparation of functionalized quinoxalines and quinazolines by the dehydrogenative annulation reaction described by Balaraman et al. (Mondal et al. 2020). In this dehydrogenative annulation reaction, only H2 O and H2 is formed as side product (Scheme 9.33). Co-phen/C-800 have been successfully used as an innovative, selective, reusable and efficient catalyst to generate a series of quinoxaline derivatives via coupling reaction between diamines and diols at 150 °C was described by Kundu et al. (Panja et al. 2020) (Scheme 9.34). R1

R1 O O

H2N

+

R2

Toluene, 25oC

H2N

R1

R2

N

MoVP Catalyst

N R1

Scheme 9.32 Alumina-supported heteropolyoxometalates (AlMoVP) catalyzed synthesis of a series of quinoxalines

NH2

R1

+

NH2

2H2

HO

N H N

R2

HO

R2

N

NHR

3 mol% 2 mol% Mn(CO)5Br KOtBu, toluene 130oC

N

+ R1

OH N

+

N N

NH2 O

+

R

H2

R

2H2O

Scheme 9.33 Manganese(I) complex (Mn(CO)5 Br) is used as catalyst for the preparation of functionalized quinoxalines and quinazolines

R

NH2 NH2

+

OH OH

R1

Co-phen/C-800 (1.5 mol%)

R2

CsOH.H2O (0.75 equiv,) toluene, 150oC 24 h

N

R1

N

R2

R

Scheme 9.34: Co-phen/C-800 catalyzed synthesis of quinoxaline derivatives

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347

In situ formed alcohols and nitroarenes using tricarbonyl (η4-cyclopentadienone) iron complex have been successfully used as simple and efficient reactant for the Pictet-Spengler-type annulation/oxidation reaction to access the quinoxaline derivatives at 160 °C was developed by Hong et al. (Chun et al. 2020) (Scheme 9.35). Zahouily et al. (Dânoun et al. 2020) depicted eco-friendly synthesis of functionalized quinoxalines via nanostructured Na2 PdP2 O7 catalyzed condensation reaction of aryl 1,2-dicarbonyl and diamines in EtOH at room temperature. The used bifunctional heterogeneous catalyst is reusable for the next five consecutive cycles (Scheme 9.36). Chen et al. (Xie et al. 2016) developed an environmentally benign process to afford quinoxaline derivatives through one-pot domino reaction of 2-pyrrol-1-ylaniline[2(1H-pyrrol-1-yl)phenyl]amine and a variety of β-diketones catalyzed by Brønsted acid (TsOH·H2 O) in DMSO at 110 °C (Scheme 9.37). Gi et al. (Cho and Oh 2006) demonstrated a ruthenium RuCl2 (PPh3 )3 -catalyzed reaction of o-phenylene diamines and vicinal diols to generate a series of quinoxalines in the presence of KOH and diglyme at reflux (Scheme 9.38). Lindsley et al. (Zhao et al. 2004) described a microwave-induced protocol to generate functionalized quinoxaline in 9:1 MeOH-HOAc at160 °C (Scheme 9.39). Magnetically separable Fe3 O4 nanoparticles were found a proficient catalyst to access substituted 2 quinoxalines in water was introduced by Zhang and co-workers (Lü et al., 2010). The used nano-catalyst is reusable (Scheme 9.40).

N

+

HO

NO2

N

Fe Catalyst, TMAO, O2

R

MS, CPME, 160oC

N

R

Scheme 9.35 Pictet-Spengler-type annulation/oxidation reaction to access the quinoxaline derivatives

NH2 NH2

+

O

N

Na2PdP2O7 EtOH, r.t.

O

N

Scheme 9.36 Synthesis of functionalized quinoxalines via nanostructured Na2 PdP2 O7 catalyzed condensation reaction

O

N +

R NH2

R1

O

TsOH . H2O R2

o

120 C or r.t.

N R N

R1

Scheme 9.37 Brønsted acid (TsOH·H2 O) catalyzed synthesis of quinoxaline derivatives

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P. Saini et al. R1

NH2

HO

RuCl2(PPh3)3

+

R1

NH2

HO

R2

diglyme

R1 R1

R2

Scheme 9.38 Ruthenium RuCl2 (PPh3 )3 -induced reaction of o-phenylene diamines and vicinal diols to generate a series of quinoxalines

NH2 R

Ph

O

+ NH2

Ph

O

MeOH : HOAc (9 : 1) 160oC, 5 min Microwave

N

Ph

N

Ph

R

Scheme 9.39 Microwave-induced protocol to generate functionalized quinoxaline

R1

NH2

R3

O

R4

O

+ R2

NH2

Nano-Fe3O4 H2O (r.t.)

R1

N

R3

R2

N

R4

Scheme 9.40 Magnetically separable Fe3 O4 nanoparticles catalyzed synthesis of substituted 2 quinoxalines in water

9.5 Conclusion This chapter emphasizes on effective and miscellaneous biological activities and synthetic methods of the fused N-heterocyclic compounds for example cinnoline, quinoxalines and quinazolines derivatives described in literature. It offers an viewpoint on modern advances of cinnoline, quinoxalines and quinazolines consuming numerous biological activities such as anticonvulsant, antifungal, antibacterial, antiulcer, antiinflammatory, anticancer, antimalarial, antitumor, antitubercular, antihypertensive, antihistamine, antidiabetic and antihypertensive. This chapter could be useful for other scientist to advanced important drugs having these moieties for the treatment of numerous deadly syndromes in future. Cinnoline, quinoxalines and quinazolines derivatives are considered as significant precursor to synthesize numerous biologically important scaffolds. In this chapter, we hope to deliver an overview of the significant common approaches for manufacturing these moieties and current progresses toward their biological activity and exposed the entrance for upcoming research in this field.

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Chapter 10

Pharmacological Significance of Triazoles and Tetrazoles in Neurodegenerative Disease: An Overview Pankuri Gupta and Abha Sharma

10.1 Introduction Azole moieties like triazole and tetrazole are heterogeneous in nature. They are cyclic structures containing three/four nitrogen and one/two carbon atom surrounded by single and double bonds. They were first synthesized by J. A. Bladin in 1885 (Benson 1947). He was a swedish chemist working at University of Upasala. Tetrazoles contain most amount of nitrogen present in a stable heterocyclic system (Wei et al. 2015). Theys emit nitrogen fumes on decomposition. Reaction of these azoles is vigorous on exposure to heat, shock and friction. Presence of free N-H bonds contributes to its acidic character (Varala and Babu 2018). They can react in anionic as well as cationic form. They are not found naturally. Triazoles are found in form of 2 regioisomers, namely 1, 2, 3-triazoles and 1, 2, 4-triazoles. Both these regioisomers have 2 tautomers. 1, 2, 3-triazoles have 1H and 2H tautomers whereas 1, 2, 4-triazoles have 1H and 4H tautomers. In case 1, 2, 3-regiomer, 1H form is majorly present in gaseous phase whereas both 1H and 2H is present in aqueous phase. For 1, 2, 4-triazoles, 1H is majorly present in all phases (Cox et al. 1990). Tetrazole is crystalline solids which show tautomerism. The most common tautomer is 1H form. Other forms that have been found are 2H and 5H (Fig. 10.1). 1H is majorly present in solution form whereas higher percentage of 2H tautomer was found in vapor phase. 5H form has not been experimentally isolated (Kiselev et al. 2011). Bioisosteres are groups that show comparable biological attributes to the chemical compounds on replacing the substituent with them. Triazoles are bioisosteres for amides. It’s also used as a replacement to olefinic bond, ester and carboxylic acids (Malik et al. 2020). Tetrazoles are commonly used as bioisostere for carboxylic P. Gupta · A. Sharma (B) Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_10

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4

H 1 C N HC N NH 3

2

2H

H 3 C N HC N 1 N 2 H 1H 1, 2, 3-Triazole 5

5 4

4

4

H C

3

N CH N NH 2

1

1

2

1H

4H 1, 2,4-Triazole

5

1

N NH N N 3

HC

H 5 3 N CH HC N N

5

4

2

1H

H C

1

N N N NH 3

2

2H

H 4

5

H N N1 N N 3

C

2

5H

Fig. 10.1 Tautomerism in triazoles and tetrazoles

acids and cis-amides. They show similar behavior when parameters are compared. Carboxylates and anionic tetrazoles have nearly same pKa (4.2–4.4 and 4.5–4.9 respectively) (Malik et al. 2014). Main purpose of replacing carboxylic acids with tetrazoles is better stability and penetrating capability of the later one. Tetrazoles have higher metabolic stability than acids as they do not undergo most of phase II metabolic reactions. They also penetrate blood brain barrier (BBB) more efficiently than their counterparts due to their highly lipophilic nature. Replacement of carboxylic acids with tetrazole is necessary to cross BBB in case of BACE-1 inhibitors. They are used to treat Alzheimer’s disease (AD) (Arabi 2017). Both triazoles and tetrazoles and its derivatives exhibit various pharmacological activities. They have shown anticancer, antibacterial, antifungal, antimalarial, antitubercular, antiangiogenic, anti-oxidant, anti-inflammatory, anti-alzheimer activity (Shneine and Alaraji 2016; Zou et al. 2020). They also possess anti-hypertensive (Ronchi et al. 2016), anti-thrombotic (Abrahamsson et al. 2016), anti-hyperglycemic (Kharb et al. 2011; Kattimani et al. 2020), analgesic (Khanage et al. 2013), anticonvulsant (Wang et al. 2019a), anti-depressant (Paudel et al. 2017a) properties. These azoles are highly energetic compounds capable of exploding when heated beyond their melting point. They are used as explosives, catalyst, polymers and corrosion inhibitors (Ostrovskii et al. 2017).

10 Pharmacological Significance of Triazoles and Tetrazoles in Neurodegenerative … O N H

NC

F

O

TMSN3 (1.2 eq) MeOH-H2O (3:1) 25 C, 20h

N H

357 N N N N

F

Scheme 10.1 Synthesis of 1-substituted 1H tetrazole

Scheme 10.2 Synthesis of 5-substituted 1H tetrazole

Cl NC

Cl

NaN3 Cu(NO3)2, DMF 120 C, 16h

N N N NH

5-substituted 1H Tetrazole

10.2 Synthesis of Triazole and Tetrazole Derivatives 10.2.1 Synthesis of 1-Substituted 1H Tetrazole Domling and his coworkers prepared 1-substituted 1H tetrazoles using substituted cyanoacetamides. They were treated with trimethylsilyl azide (1.2 equivalents) and methanol-water mixture was used as solvent. The reaction was carried out at 25 °C for 20 hours to get the finished product (Scheme 10.1). N-(4-fluorobenzyl)-2-(1Htetrazol-1-yl) acetamide was obtained in excellent yield (95%) (Neochoritis et al. 2019).

10.2.2 Synthesis of 5-Substituted 1H Tetrazole Tao et al. prepared tetrazoles using substituted benzonitriles as substrate. 4-chloro benzonitrile (1 mmol) was treated with sodium azide (2 mmol). The reaction followed [3+2] cycloaddition pattern. Cu(NO3 )2 was used as a catalyst, and dimethyl formamide (DMF) was used as solvent (Scheme 10.2). The reaction was carried out at 120°C for 16 hours. Product was obtained in excellent yield (93%) (Tao et al. 2017).

10.2.3 Synthesis of 1, 5-Disubstituted Tetrazoles 5-(4-chlorophenyl)-1H-tetrazole was treated with ethyl bromoacetate in presence of dry acetone. Basic condition was maintained by use of potassium carbonate. Ethyl

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BrCH 2COOEt

N N N NH

Cl

Cl

Cl

K2CO3/Acetone, reflux

NH2NH2, H2O/EtOH

N N

reflux

N N O OEt

N N N N O NHNH 2

Scheme 10.3 Synthesis of 1, 5-disubstituted tetrazole

CF3CO2Ag (1.2 eq)

Me3SiCHN2 N2BF4

Et3N (1.5 eq) CsF (1 eq) THF, -78°C to RT

N N N N

Scheme 10.4 Synthesis of 2-substituted 2H tetrazole

acetate derivative of tetrazole was formed. On further reaction with hydrazine hydrate and ethanol, hydrazide was formed (Scheme 10.3) (Gouda et al. 2020).

10.2.4 Synthesis of 2-Substituted 2H Tetrazoles Phenyl diammonium tetraflouroborate (0.2 equivalents) and trimethylsilyldiazomethane (1.1 equivalents) were taken as reactants. Triflouro salt of silver (1.2 equivalents) was used as catalyst. 1 equivalent of cesium fluoride was used. Triethyl amine (1.5 equivalents) was used as base and THF (−78 °C) was used as solvent (Scheme 10.4). The reaction followed [3+2] cycloaddition. The product was obtained in good yield (75%) (Patouret and Kamenecka 2016).

10.2.5 Synthesis of 2, 5-Disubstituted Tetrazoles 2-bromo phenyl diazonium tetraflouroborate and phenylamidine (1.04 mmol each) were used as substrates. It is a one-pot synthesis. Both reactants and K2 CO3 (5.21 mmol) were mixed with DMSO, and mixture was stirred at room temperature for 1h. Then, I2 (1.25 mmol) and KI (1.56 mmol) were added and mixture was stirred at room temperature for one more hour (Scheme 10.5). The product, 5-(2-bromophenyl)-2phenyl-2H-tetrazole, was obtained in good yield (87%) (Ramanathan et al. 2015).

10 Pharmacological Significance of Triazoles and Tetrazoles in Neurodegenerative …

H 2N

N2BF4 Br

Ph NH

Ph N N N N

359

Br

I2 /KI, DMSO Scheme 10.5 Synthesis of 2, 5-disubstituted tetrazole

CuSO4.5H2O (0.25-2 mol%) R1 N3

R2

sodium ascorbate (5-10 mol%) R2

H

R1 N H2O/ t-BuOH, 2:1 RT, 6-12 h

N N

Scheme 10.6 Synthesis of 1, 2, 3-triazole

10.2.5.1

Synthesis of 1, 2, 3-Triazoles

The copper (I) catalyzed azide-alkyne cycloaddition/click (CuAAC) reaction introduced by Sharpless et al. is the most common way of synthesizing 1, 2,3-triazoles. This method is more selective and leads to formation of 1, 4-disubstitued regioisomer only. Originally used Huisgen cycloaddition requires high temperatures and gives a mixture of both 1, 4 and 1, 5-disubstituted regioisomers. Ruthenium catalyzed cycloaddition, on other hand, gives specifically 1, 5-disubstituted 1, 2, 3-triazoles. In CuAAC reaction, an alkyne and azide react to form triazole in presence of a Cu catalyst and solvents used are mixture of t-buOH and water in 1:2 ratio. Copper sulfate and sodium ascorbate are used to generate in-situ Cu (I) species. The reaction takes place in ambient temperature and it’s completed in 6–12 h with good yields (75–90%) (Himo et al. 2005) (Scheme 10.6).

10.2.6 Synthesis of 1, 2, 4-Triazoles 1, 2, 4-Triazoles can be easily prepared from substituted thiosemicarbazide via base assisted cyclization. Thiosemicarbazide (0.0006 mol) was dissolved in 2M NaOH solution and this mixture was refluxed for 4 h and further acidified to obtain final product which is 5-(4-nitrophenyl)-4-phenyl-4H-1,2,4-triazole-3-thiol (Hashim and Alias 2012) (Scheme 10.7).

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O 2N

SH

H N

H N S

Reflux, 4 h

N

NaOH

N

H

N O 2N

Scheme 10.7 Synthesis of 1, 2, 4-triazoles

10.3 Drugs Containing Triazole and Tetrazole Moiety Azoles are Bioisosteres for various functional groups. This property has been utilized for preparing a lot of drugs. Food and Drug Administration (FDA) has permitted a large number of molecules containing them. They show different pharmacological activities and have been used for treating various diseases and disorders (Mittal and Awasthi 2019). Some marketed drugs are shown in Figs. 10.2 and 10.3.

10.4 Drugs in Clinical Trials Plenty of drugs containing triazole and tetrazole moieties have undergone clinical trials. Some of them are used clinically whereas some have failed them due to various reasons. Some of the drugs are listed below in Table 10.1.

10.5 Alzheimer’s Disease (AD) AD is a neurodegenerative disease which is progressive in nature. It is mainly observed in elderly, usually above 60 years of age. Aβ plaques and Neurofibrillary tangles (NFTs) are biomarkers of this disease. Etiology of the disease is still debatable. Hypotheses given are low levels of Acetylcholine (Ach) enzyme, aggregation of hyper-phosphorylated tau proteins forming NFTs, formation of Aβ plaques, dyshomeostasis of metal ions and oxidative stress. The disease is not curable but symptoms can be treated. Findings of tetrazole derivatives as anti-alzheimer agents have been reported. Some of them are discussed below.

10.5.1 Cholinesterase Inhibitors Acetyl-cholinesterase (AChE) is an enzyme which hydrolyzes Ach specifically. It is classified under carboxylesterases enzyme family. Butylcholinesterase (BuChE) hydrolyzes other choline esters including Ach. It is a non-specific, pseudo enzyme

10 Pharmacological Significance of Triazoles and Tetrazoles in Neurodegenerative … O N N

O

O N

N

N

N

N

N N N

H N

N N

O

N N

O

Cilostazol vasodilator and anti-platelet agent

Alfentanil Opoid analgesic

Corazolum Anti-depressant and convulsant

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Drugs used in Central Nervous System (CNS) Disorders O

O O

O N N

N

N N HN N

N

N S

N N N NH

N Cl Losartan

O

HN O

N HO

O

N H

NH2 S O

Cl

Azosemide

Candesartan

Angiotensin II Blockers (ARBs) O

OH

N N

N N H

N

OH

N N N

O

O N

O

N N

O

H

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S

N

O

S

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H

S

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OH Cefazolin

Cefamandole

Cephalosporin Antibiotics N N HN

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N N O N

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N N

K

+

N H

O O

Pranlukast

Pemirolast

Anti-Histaminic Agents

Fig. 10.2 Marketed drugs containing tetrazole

which is predominant in glial and endothelial cells. AChE is mainly responsible for hydrolysis whereas BuChE serves as an auxillary. In AD, higher expression of these cholinesterases leads to excessive hydrolysis of Ach thereby, reducing its level in the brain. It is also reported that AChE is promoting formation of Aβ plaques (Mushtaq et al. 2018). Kushwaha et al. synthesized a series of benzofuran tetrazoles as selective AChE Inhibitors (Fig. 10.4). They tested AChE inhibitiory activity of these compounds on

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N O O

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F

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F

N

N N

N O N

N

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N N

Itraconazole Antifungal drug

Fluconazole Antifungal Drug

N N

N Cl

N

OH

HO

O

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N HO

Alprazolam Anxiolytic

O

H O O S NH2 O

N N

Ribavirin Antiviral drug

O

OH

N N N

Tazobactum Antibacterial Drug

Fig. 10.3 Marketed drugs containing triazole nucleus

extract of CL4176 strain of C. elegans, a transgenic roundworm. Molecular docking of Compound 1 was also performed with AChE enzyme. Tetrazole ring formed Hbond with OH group of Tyr121 residue present in peripheral anionic site (PAS) site of AChE. This interaction gave compound better binding affinity. The 3d structure in Fig. 10.5 shows various interactions where green dotted lines show hydrogen bonds and yellow cylindrical pattern show π-π stacking. Compound 1 has inhibitory concentration of 0.0085 μM (Kushwaha et al. 2019). Compound 2 also shows good cholinesterase inhibition (Di¸sli et al. 2018). Hameed et al. synthesized series of AChE and BuChE inhibitors which showed potent inhibitory activity. Molecule 3 is an AChE inhibitor whereas 4 selectively inhibits BuChE. R in compound 4 is methoxy group (Hameed et al. 2016). Similarly, Yuttras et al. synthesized compound 5, 6 and 7. Compound 5 was able to inhibit 98.51% inhibition on AChE enzyme whereas 7 showed 51.26% inhibition on BuChE enzyme (Yurtta¸s et al. 2017).

Use/category

Topical Antibacterial drug Treatment for nosocomial pneumonia

Antihypercholesterolemic drug/CETP inhibitor

Thrombin inhibitor

Treatment of acute heart failure/ETA/B receptor antagonist

Treatment of Advanced tumors

Antifungal/CYP51 inhibitor

Antifungal/CYP51 inhibitor

Compound name

Tedazolid phosphate

Evacetrapib (LY2484595)

AZD-8165

Tezosentan

CC-115

Otesecenazole (VT-1161)

Quilseconazole (VT-1129)

Table 10.1 Drugs in clinical trials

Viamet pharmaceuticals

Mycovia pharmaceuticals

Celegene pharmaceuticals

Idorsia pharmaceuticals

Astra Zeneca

Eli Lilly and company

Bayer pharmaceuticals Cubist pharmaceuticals LLC

Company

Phase 1

Phase 3

Phase 1

Phase 3

Phase 1 (terminated)

Phase 3

Phase 3 (completed) Phase 3

Phase/Status

N/A

NCT03840616

NCT01353625

NCT01077297

NCT01150812

NCT02227784

NCT02066402 NCT02019420

NCT No

(Wang et al. 2019b)

(Wang et al. 2019b)

(Beebe and Zhang 2019)

(Khadtare et al. 2017)

(Abrahamsson et al. 2016)

(Zhou et al. 2016)

(Zhou et al. 2016)

References

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H N O

H N

O

N N

N HN N t-Bu

S H1

CH3

H3 H2

F

N N NH CN

NC

N N N

N NH CN

N

N

I

2 IC50= 1.75 M

1 IC50= 0.0085 M

N

N

NC

NH CH3

NH CH3

C H2

C H2

R

F

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R

4 IC50= 0.290 0.130 M R=OMe

3 IC50= 2.01 0.027 M

NO2 N N N N S Ph

N N N N S Ph

NO2

N NH O

N NH O

6 IC50= 42.5 3.54 g/mL

5 IC50= 54.67 0.58 g/mL

OH N N

N NH

N N Ph

S O

7 IC50= 55.2 3.05 g/mL Fig. 10.4 Tetrazole based cholinesterase inhibitors

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Fig. 10.5 Molecular docking of compound 1 with AChE enzyme. Reprinted with permission from ref. Kushwaha et al. (2019). Copywrite (2019) Elsevier

Triazoles are also potent AChE and BuChE inhibitors. Compound 8 shows 49.95 ± 0.95% Inhibition at 10 μM concentration (Jain and Piplani 2020). Compound 9 has IC50 value of 26.93 μM and can also reduce Aβ42 aggregation in-vitro in SHSY5Y cells (De Freitas Silva et al. 2020). Coumarin-triazole derivatives have shown good cholinesterase activity. Some of these derivatives also show inhibition of Aβ aggregation. Compound 10 acts on both AChE and BuChE with IC50 values of 29.35 and 33.12 nM (Sepehri et al. 2020). Compound 11 shows more selectivity toward BuChE and inhibits it with IC50 value of 21.71 μM. It also inhibits self-induced and AChE-induced Aβ aggregation by 32.6 and 29.4% (Karimi Askarani et al. 2020). Compound 12 shows 46.97 ± 1.75% AChE inhibition at 100 μmol L−1 (De Sousa et al. 2021). Compound 13 shows IC50 value of 14.66 ± 2.29 μmol L−1 (Bousada et al. 2020). The structures are shown in Fig. 10.6.

10.5.2 Tau Inhibitors Tau proteins are found to be involved in AD pathology. They are found in neuron and involved in stabilizing microtubules and forming cytoskeleton. Tau proteins are modified post translation. They are phosphorylated and de-phosphorylated in order to achieve micro-tubular stability. When these tau proteins are hyper-phosphorylated, they lead to formation of abnormal neurofibrillary tangles (NFTs) in the brain. NFTs

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O N

N N

N

N

O

S

O N+

N H

O

OH

O N

-

N N

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9 AChE IC50= 26.30 M

8 49.95±0.95% AChE Inhibition at 10 M concentration

F F

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10 AChE IC50= 29.35 nM BuChE IC50= 33.12 nM

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11 BuChE IC50= 21.71 M

O

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O 12 46.97±1.75% AChE inhibition at 100 mmol L-1

HO

N N N O

O

O

13 AChE IC50= 14.66±2.29 mmol L-1

Fig. 10.6 Triazoles as cholinesterase inhibitors

have been associated with neuronal death and cognitive impairment (Medina and Avila 2020). Dual Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) are classified under proline-directed kinase of CMGC group. The acronym is given after members of the enzyme superfamily. The group contains cyclin-dependent kinases (CDK), mitogen-activated protein kinases (MAPK), glycogen synthase kinase (GSK) and CDK-like kinases (CLK). They contain different kinases among which DYRK 1A is majorly involved in tau phosphorylation (Stotani et al. 2016). Darwish et al. has synthesized derivatized thiophenes which show good DYRK 1A inhibition (Fig. 10.7). Compound 14 shows 24.4% inhibition at concentration of 250 nM (Darwish et al. 2018). Compound 15 also has good DYRK 1A inhibition capacity (Zhou et al. 2017). Compound 16 can inhibit 35% tau aggregation at concentration of 1 μM and it does not show cytotoxicity below 100 μM (Lee et al. 2019).

10 Pharmacological Significance of Triazoles and Tetrazoles in Neurodegenerative …

H N

N N N NH

S

O

367

N

N

14 24.4% inhibition at 250 nM concentration H N

N

N N N NH OH 15 IC50= 86 17 nM N N

F N

S

N N N

CH3

16 35% inhibition at 1 M concentration Fig. 10.7 Tetrazole based tau inhibitors

10.5.3 GSK-3β Inhibitors Similar to DYRK, Glycogen Synthase Kinase 3 (GSK-3) enzyme also belongs to serine-threonine kinase family of CMGC group. Out of two known isoforms of GSK3 enzyme (α and β), GSK-3β is most expressed in central nervous system. Imbalance in activity of this enzyme has been linked to both Aβ formation and tau hyperphosphorylation. GSK-3β also plays a role in neuroinflammation and neurogenesis (Lauretti et al. 2020). Monte et al. synthesized a selective GSK-3β inhibitor (17) which lead to 69% enzyme inhibition at concentration of 10 μM (Yadav et al. 2018). Two multi-target inhibitors have also been reported. 18 can inhibit both GSK-3β as well as CDK 5 enzyme. It gave neuroprotection to cells by showing 70% cell viability at concentration of 10μM after treatment with 20 μM Aβ25-35 peptides in MTT assay (Xie

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MeO H N

N N N N

H N O

S N

H N

N

N N N 17 GSK-3 IC50= 0.14 M GSK-3 IC50= 0.13 M

N

S

O

O 18 70% cell viability at 10 M in MTT assay

F

N N N N

N

H N O

N

N H

CH3

19 p38 MAPK IC50= 0.038 M GSK-3 IC50= 0.072 M

Fig. 10.8 Tetrazole based GSK-3β Inhibitors

et al. 2017). On other hand, 19 can inhibit p38-MAP kinase along with GSK-3β. The inhibitory capacities (IC50 ) for p38-MAPK and GSK-3β are 0.038 and 0.072 μM (Fig. 10.8) (Heider et al. 2019). Molecular docking of compound 19 with GSK-3β enzyme is shown in Fig. 10.9. Tetrazole ring forms a π-alkyl interaction with Arg141 residue and a hydrogen bond with Thr138 residue. Triazole based molecules also show good GSK-3β Inhibition. Compound 20 (PF367) has IC50 = 2.1 nM when tested in-vitro against a recombinant GSK-3β assay (Bernard-Gauthier et al. 2019). Redenti et al. developed a dual GSK-3β and CD1δ inhibitor using docking based design approach. The compound 21 shows good inhibition of both enzymes with GSK-3β IC50 = 0.17 μM and CD-1δ IC50 = 0.68 μM (Redenti et al. 2019). The structures are shown in Fig. 10.10

10.5.4 MA/MAO Inhibitors Monoamine oxidases (MAO) are used in regulation of biogenic amines in the body. They degrade monoamines (MA) by process of oxidative deamination. MAO has 2 isoforms, A and B. MAO-A is majorly expressed in lungs and Gastro-intestinal

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Fig. 10.9 Molecular docking of compound 19 with GSK-3β enzyme. Reprinted with permission from ref. Heider et al. (2019). Copywrite (2019) American Chemical Society

O N O

N

N H Cl O

20 GSK 3 IC50= 2.1 nM

H N

N

N N

N

N O

N N NH2

NH2 N

21 GSK 3b IC50= 0.17 M CK-1 IC50= 0.68 M

Fig. 10.10 Triazole based molecules targeting GSK-3β

tract (GIT). MAO-B activity is predominant in Lungs, Platelets and CNS. MAOA is more selective toward 5-hydroxytryptamine (5-HT) and norepinephrine (NE) whereas MAO-B mainly acts on benzylamine and phenylethylamine. Dopamine and tyramine are oxidized by both forms. Inhibition of MAO increases levels of biogenic amines and monoamine neurotransmitters, which increases neuronal transmission (Ramsay and Albreht 2018). Increased levels of enzyme MAO-B have been reported in brain of AD patients. MAO-B has been linked to production of hydrogen peroxide, a free radical generator. Lebreton et al. synthesized a potent MAO-B Inhibitor (22)

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O

N N

N N N N

N N

N

S O

NC 22 IC50= 2 nM

SO2NH2

23 IC50= 0.127 0.005 M

N N N N

N N

24 5-HT IC50= 0.1587 M NE IC50= 0.099 M DA IC50= 0.0975 M

N N N N

N

N N N N

N

NO2

25 5-HT IC50= 0.31 M NE IC50= 2.51 M DA IC50= 6 M

Fig. 10.11 Tetrazole based MAO-B and triple reuptake inhibitors

26 5-HT IC50= 1.24 M NE IC50= 1.35 M DA IC50= 1.98 M

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with IC50 value of 2 nM (Tripathi et al. 2018). As shown in Fig. 10.11, Compound 23 shows 91.57% enzyme inhibition at concentration of 1 mM (Sa˘glık et al. 2020). AD is often characterized by dementia. Some complications from dementia in AD include Depression, sleep disorder, anxiety, hyperactivity etc. Although the link between AD and depression is still unclear, patients suffering from both AD and depression have been found to show higher and rapid cognitive dysfunction (Cassano et al. 2019). “Monoamine Deficiency” has been given as reason for pathogenesis of depression. Molecules present in market elevate monoamines (5-HT, NE) by blocking respective transporters to inhibit their reuptake by neurons. This increases retention of these neurotransmitters in synaptic cleft, which may increase neurotransmission and reduce depression. Triple reuptake inhibitors/SNDRIs (Sertonin, Norepinephrine and Dopamine Reuptake Inhibitors) can be useful for this purpose. They inhibit reuptake of 5-HT, NE and Dopamine (DA) (Subbaiah 2018). Paudel et al. worked for designing these inhibitors containing different heterocyclic compounds. Compound 24 is a potent inhibitor of reuptake of all three monoamines (Paudel et al. 2017a). Compound 25 and 26 show good reuptake inhibition (Fig. 10.12) (Paudel et al. 2017b). Molecular docking of compound 25 with human serotonin transporter (hSERT) is shown in Fig. 10.9. Tetrazole forms hydrogen bonds with Tyr175 and Thr497 residues which enclose ligand binding pocket of hSERT. They give compound higher binding strength. Triazoles have been associated anti-MAO activity. Compound 27 shows 27.51 ± 0.63% MAO-B inhibition at 1 μM concentration (Can et al. 2017) whereas Compound 28 has MAO-B inhibitory capacity of 3.54 μM. It has high selectivity

Fig. 10.12 Molecular docking of compound 25 with hSERT. Reprinted with permission from ref. Paudel et.al. (2017b). Copywrite (2017) Elsevier

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N N

N N N

N H

27 27.51±0.63 % MAO-B inhibition at 1 µM concentration

N 28 MAO-B IC50= 3.54 M

Fig. 10.13 Triazole based molecules showing MAO-B inhibition

with 27.7 times more specificity toward MAO-B instead of MAO-A. The molecules are shown in Fig. 10.13 (Di Pietro et al. 2016).

10.5.5 BACE-1 Inhibitors β-site APP cleaving enzyme (BACE) is an transmembranal protein. BACE has 2 isoforms. Expression of BACE-1 is mainly observed in CNS whereas BACE-2 works outside. BACE-1 is aspartic endopeptidase which cleaves APP at β-site. It cleaves Amyloid Precursor Proteins (APP) at Asp+1 residue of Aβ sequence. This leads to formation of N-terminal of the Aβ peptides. It was found that BACE-1 deficient mice showed small amount of Aβ production in AD mice models (Yan 2016). Thus, BACE-1 is considered as important target in AD. Peptidomimetic BACE-1 Inhibitors like KMI-420 (29) and KMI-429 (30) possess good BACE-1 inhibition and have higher BBB penetrability (Derrick and Lim 2015). KMI-420 shows 99% inhibition at 2 μM concentration. KMI-429 shows 20% decrease in levels of hippocampal sAPPβ in transgenic mice on administering a dose 2.5 nM after 3h. In wild type mice, similar treatment leads to 38 and 31% decrease in levels of Aβ40 and Aβ42 levels. Hamada et al. has contributed a lot in designing of BACE-1 inhibitors. They have designed both peptidic and non-peptidic inhibitors. Compound 31, 32 are active in nanomolar quantities (Fig. 10.14). 32 shows 86% inhibition at 100 μM in the cell (Ghosh and Osswald 2014). Tetrazole moiety forms hydrogen bonds with Arg307, Asp233, Tyr198 and Lys224 residues. KMI-1303 (33) and 34 are non-peptidic molecules which show significant inhibitory activity with 99% inhibition at concentration of 2 μM (Hamada and Usui 2018). Triazoles show weak to moderate BACE-1 activity depending upon the type of molecule. Compound 35 shows weak BACE-1 inhibitory activity with 13.97 ± 12.99% at 10 μM concentration (Najafi et al. 2019). Yazdani et al. synthesized a series of compounds out of which compound 36 has BACE-1 IC50 of 8.55 ± 3.37 μM. These compounds also show metal chelation and anti-oxidant property. Interactions between compound 36 and BACE-1 are shown in Fig. 10.15. It interacts with catalytic dyad, Asp32 and Asp228. Also it interacts with an important residue, Arg235 (Yazdani et al. 2019). Compound 37 also has BACE-1 pIC50 = 7.97 (Oehlrich et al. 2019). Compound 38 can penetrate blood brain Barrier (BBB) and has inhibitory

10 Pharmacological Significance of Triazoles and Tetrazoles in Neurodegenerative …

O O N N N NH

O N H

NH2

O

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N H

OH

N H

O

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O

N N NH

O N H

NH2

O

H N

N H

O

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30 KMI-429 IC50= 3.9 nM

NH2

H N

OH

N NH2

H N

HN N N N

O O

HN

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O

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H N

HN

OH

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29 KMI-420 IC50= 8.2 nM

373

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32 IC50= 5.6 nM

Br

O

H N

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F N

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H N

I

HN N N N

O

H N

N

F N

O

OH

H N

HN N N N

O Ph

O 34 IC50= 10 nM

Fig. 10.14 Peptidomimetic and non-peptidic BACE-1 inhibitors

capacity of 2.2 μM (Iraji et al. 2017). Jiaranaikulwanitch et al. developed a series of multifunctional triazole based molecules. Out of these, bis-tryptoline triazole (39) gave good results with BACE-1 Inhibition capacity of 67.45% at concentration of 25 μM (Fig. 10.16). It also has several pharmalogical properties like inhibition of Aβ aggregation, free radical scavenging, metal chelation and neuroprotective activity (Jiaranaikulwanitch et al. 2017).

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Fig. 10.15 Interactions between compound 36 and BACE-1 enzyme. Reprinted with permission from ref. Yazdani et al. (2019). Copywrite (2019) Elsevier

10.5.6 NMDA Receptor Antagonists N-methyl-D-aspartate (NMDA) Receptor is included in class of Ionotropic Glutamate Receptors (iGluRs) along with kainate and AMPA receptors. Glutamate is an excitatory neurotransmitter in CNS which leads to excitotoxicity on excessive expression. Higher level of toxicity is due to excess influx of Ca2+ ions in neurons. NMDA receptors are highly permeable to calcium ions when compared to other iGluRs. High levels of Ca2+ levels causes decreased synaptic activity and increases death frequency of neuronal cell. It has also been reported that Aβ aggregation leads to activation of NMDA receptors in earlier stages of AD (Liu et al. 2019). NMDA Receptor antagonists have been used to treat moderate and severe AD. Ornstein et al. has worked for development of NMDA receptors containing tetrazole moiety. They synthesized a number of compounds (40–43) which have inhibitory capacity ranging from nanomolar to micromolar concentrations. Derivatives of scaffold 40 show NMDA receptor antagonism with IC50 values ranging between 1.5 and 61.3 μM (Ornstein et al. 1996). Compound 41 is a selective NMDA inhibitor with IC50 value of 100 nM L−1 . Derivatives 42 and 43 contain carbon linkers which have been varied to check effect on activity. IC50 of these compounds ranges between 1 and 10 μmol L−1 (Popova and Trifonov 2015). Lenda et al. made 2-aminoadipic acid derivatives which contain 2, 5-substituted tetrazole (44). These derivatives were able to inhibit 39–76% activity of NMDA receptors at concentration of 150 μM. Some derivatives of this series showed no neurotoxicity (Lenda et al. 2011). (Tetrazol-5-yl) glycine (45) on other hand shows selective NMDA receptor agonism with EC50 value of 0.66±0.18 μM and does not exert effect on other receptors (Jones et al. 1996). It is used as a potent convulsant (Fig. 10.17).

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O O O N N N Cl

HN O

Cl

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35 13.97±12.99 % BACE-1 Inhibition at 10 µM concentration

N

NH2 N

H N

N

O

NH H N O

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36 BACE-1 IC50= 8.55 ± 3.37 µM O

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N H

N

O

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F

N

Br

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N N N

O

37 BACE-1 pIC50= 7.97

38 BACE-1 IC50= 2.2±0.5 µM

H N N N HO

N N HN HN

39 67.45% BACE-1 Inhibition at concentration of 25 µM

Fig. 10.16 Triazole based BACE-1 Inhibitors

10.5.7 Anti-inflammatory Agents Neuroinflammation is reported in neurodegenerative diseases like AD and PD. Cyclooxygenase (COX) enzyme is used for synthesizing prostaglandins from Arachidonic acid. It has 2 forms, namely COX 1 and 2. Elevated levels of Cyclo-oxygenase 2 (COX-2) and prostaglandin 2 (PGE2 ) were found in AD brain. Also, role COX-2 induced inflammatory response has been linked to AD pathogenesis but it is still

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COOH

H N N

NH

NH

N N H

X

N N

COOH

H

40 X= S, NH, NHC(O), CH(Me), CH2 etc. IC50= 1.5-61.3 M

N N N NH

N N N NH

HO

NH3 Cl

O

N

NH2

HOOC

41 IC50= 100 nM L-1

O n

n

NH N

N N N N

NH HOOC

R

43

42

OH

44 R= Alk, Ar, Het. 39-76% Inhibition at concentration of 150 M

n= 1-4 IC50= 1-10 mol L-1

N N N N H

COOH NH2

45 EC50= 0.66 0.18 M

Fig. 10.17 NMDA receptor antagonists and agonist

debated. Evidence shows that COX-2 enzyme is also expressed in microglia, which upregulates levels of inflammatory cytokines like IL-1β, IL-6 and TNF-α, etc. (Wang et al. 2014). 46 shows very potent inflammatory action with IC50 of 1.9 nM (Navidpour et al. 2006). It has high solubility when it is kept in pH greater than 7 and it does not damage mucosal lining in stomach. In rat paw edema test, it shows 40% reduction in paw volume after 3 h at dose of 3 mg/kg (Kaur et al. 2015). 47 is a quinolone tetrazole derivative which shows 21% anti-inflammatory activity at 100 μg/mL concentration (Sribalan et al. 2019). Ganesh et al. synthesized two compounds (48, 49) containing tetrazole rings, both of them showing activity in nanomolar ranges. These are prostaglandin E2 receptors (EP2 ) antagonists which are helpful in controlling inflammation (Ganesh et al. 2018). Lamie et al. worked on designing tetrazole derivatives as COX-2 inhibitors. 50 and 51 both show 71 and 79% inhibition in paw edema after 1h exposure when

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carrageenan-induced rat paw edema assay was performed (Lamie et al. 2017). 52 showed decrease in levels of IL-6 and TNF-α along with COX-2 inhibition (Fig. 10.18) (Lamie and Azmey 2019). Jawabrahal et al. made a range of compounds (53, 54 and 55) which show COX-2 inhibition within micromolar ranges (Jawabrah Al-Hourani et al. 2015, 2016; Murumkar and Chikhale 2018). 56 also shows good inhibition (71.42%) in rat paw edema assay (Sathishkumar and Kavitha 2017). 57 (Kumbar et al. 2018) and 58 (Sureshkumar et al. 2017) also show anti-inflammatory activity (Sureshkumar et al. 2017). 57 was able to inhibit 37% NO production at 1 μM concentration (Kumbar et al. 2018). 59 has shown to inhibit inflammosomes O S

H 3C

O

HN N N N

N

O

N N

CF3

N N

N

N N N N

NH N

N NH

46 COX-2 IC50= 1.9nM

48 TG8-15 EP2 KB= 22.3nM

47 IC50= 0.023 M

N N N N

O

O

N

HN N N N

OMe

N

O

OMe

NH

OMe N

H3CO2S

HN 49 TG8-69 EP2 KB= 48.5 nM

N N N

50 IC50= 0.11 M

N

N

N

N

52 COX-2 IC50= 0.23 IL-6= 73 pg/mL TNF- = 37.6pg/mL

Fig. 10.18 Anti-inflammatory agents

O O

51 IC50= 0.14 M

O N N

N

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NH2 S O

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in the body which produces inflammatory cytokines (Fig. 10.19); ultimately reducing inflammation in brain (Chen et al. 2019). Deoliveria et al. and Cardoso et al. studied compounds (60 and 61) containing tetrazoles (Fig. 10.14). They also made a bioisoteric replacement of pyrazole (LMFQ-21) with triazole (LMFQ-96) ring. Compound 60 was able to show 19.7% inhibition in 1h at dose of 36 mg/Kg (de Oliveira et al.

N N

N N

N N N N

MeO O

S

O NH2

HOH2CH2C 54 COX-2 IC50= 3 M

53 IC50= 1.2 M

N N N N

H 3C S O O

H 3C S O O

H 3C

N N

N

N N

HN

N

N H MeO

N N

N

S

Cl Cl

55 COX-2 IC50= 2 M

57 56 71.42% inhibition at dose of 50mg/Kg 37% inhibition at 1 M concentration

O

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HO N N N N S

O S

HO OH O

CF3 N N N N

N 58 59 QS-15 14% Inhibition at concentration of 1 g 50% Inhibition of TNF- at dose of 4 mg/kg

F

F N N N N H

Br

N N

60 LMFQ-21 19.7% Inhibition in 1h at dose of 36 mg/kg

Fig. 10.19 Tetrazoles as anti-inflammatory agents

N N N N H

N N N

61 LMFQ-96 19.6% Inhibition in 1h at dose of 20mg/kg

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Fig. 10.20 Molecular docking of compound 46 and 58 with COX-2 enzyme. Reprinted with permission from ref. Navidpour et al. (2006) and Sureshkumar et al. (2017). Copywrite (2006 & 2017) Elsevier

2017). Compound 61 reduced levels of TNF-α and PGE2 by 24.4 and 16.5% ay the dose of 20 mg/Kg. In rat paw edema test, it reduced paw volume by 19.6% in 1h at same dose (Cardoso et al. 2020). Docking studies of compound 46 and 58 are shown in Fig. 10.15. Nitrogen atoms in tetrazole of compound 46 form H-bond with Arg513, His90 and Phe518 residues of COX-2 enzyme (Navidpour et al. 2006). Compound 58 forms H-bonds with active site residue Asp107 in binding site of COX-2 enzyme as shown in Fig. 10.20. Triazole also inhibits COX enzyme. Compound 62 inhibits 60.5% of COX-1 enzyme at concentration of 200 μM and IC50 value of 41.88 μM. It is similar to standard drug, naproxen, which inhibits 60% COX-1 at same concentration (Tratrat et al. 2021). Compound 63 has COX-2 IC50 of 3.4 μM (Kumar et al. 2020). Compound 64 inhibits COX-2 with IC50 value of 24.33 μg/mL which is comparable to standard drug, diclofenac sodium (Kadambar et al. 2021). Compound 65 shows high potency with IC50 value of 17.9 nM and high COX-2 selectivity with 1080 times more specificity for COX-2 rather than COX-1. In-vivo studies show that 5 mg/kg compound 65 exhibited better in vivo anti-inflammatory activity and gastric protection compared to 10 mg/kg indomethacin (Li et al. 2020). Compound 66 decreases NO production from 100% to 19.88 ± 1.23% in lipopolysaccharide (LPS) treated cells. It also shows good cell viability (Menghere¸s et al. 2021). The structures are shown in Fig. 10.21.

10.5.8 Anti-oxidants Oxidative stress has been presented as one of the hypotheses for AD. Reactive oxygen species (ROS) and free radical damage occur in neuronal cells due to high oxygen

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O O

O

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N 63 COX-2 IC50= 3.4 M

62 60.5% COX-1 Inhibition at 200 M concentration

O

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N N S

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Cl

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F 65 COX-2 IC50= 17.9 nM

64 COX-2 IC50= 24.33 g/mL

N N

O O

O O O

N

N O

N N

O

66 Decreases NO production to 19.88% in LPS treated cells

Fig. 10.21 Triazoles as anti-inflammatory agents

consumption of these cells. Factors like dyshomeostasis of metals, dysfunctional mitochondrial metabolism and presence of Aβ aggregates contribute to production of oxidative stress. Disturbance in electron transport chain in mitochondria can cause neuronal death rapidly (Sharma et al. 2019). Combating this problem is necessary and anti-oxidants tend to scavenge free radicals, thereby, reducing damage to neurons. Kaushik et al. synthesized 10 pyrazolo-tetrazole derivatives. Out of these, 3.4.5trimethoxy derivative (67) was found to be most active with inhibitory capacity of 13 μM (Kaushik et al. 2016). 68, 69 also showed free radical scavenging activity (ElMekabaty 2015; Shchegol’kov et al. 2017). Anti-oxidant activity is mostly commonly measured by checking DPPH (2, 2-diphenyl-1-picrylhydrazyl) radical scavenging capability. 70, 71 were synthesized by Eftekhar et al. that show good anti-oxidant properties (Eftekhar et al. 2014). Similarly, Ozkan et al. synthesized sulfonamide derivatives with tetrazole ring. Compound 72 was found to possess moderate activity

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(Özkan and Demirci 2019). Srinivas et al. synthesized triazolo-tetrazole compounds and also measured their Iron chelation and H2 O2 capacity along with DPPH activity. Both 73 and 74 had shown better activity as compared to ascorbic which was used as positive control. DPPH activity of compound 1 was very similar to standard taken (ascorbic acid) proving it to be a potent anti-oxidant (Srinivas et al. 2018). Compound 75 gave moderate anti-oxidant capacity with 60 ± 5.9% inhibition at 100 μM concentration. The measurement was done using phospho-molybdenum method (Fig 10.22) (Leal et al. 2017). Triazoles also serve as anti-oxidants and free radical scavengers (Fig. 10.23). Compound 76 has an anti-oxidant inhibitory capacity of 34.38 μg/mL (Kumari et al. 2021). Compound 77 shows trolox equivalent anti-oxidant capacity of 9.51 ± 0.460 mmol L−1 g−1 in DPPH assay (Dias et al. 2021). Brahimi et al. made triazole derivative (78) of castor oil which show anti-oxidant potential (Brahimi et al. 2020). Compound 79 decreased the levels of H2 O2 /ROS levels (Reactive Oxygen Species) induced oxidative stress from 130 to 110% in SH-SY5Y cells (Sooknual et al. 2020). Compound 80 shows good iron chelation activity along with anti-oxidant activity (Fig. 10.23). 80 shows 89.9% radical scavenging activity at 200 mg/L concentration. The iron chelation activity of this compound was found to be 24.7% at concentration of 25 μg/mL (Nural et al. 2020).

10.6 Parkinson’s Disease Parkinson’s disease (PD) is a neurodegenerative disorder in which major hallmark is formation of aggregates of α-synuclein protein, known as lewy bodies. Along with lewy body formation, loss of dopaminergic neurons prominently in pars compacta region of substantia nigra (SNpc) is also observed. Bradykinesia, rigidity, tremors and lack of maintenance of posture are some symptoms of PD (Aziz et al. 2014). Neurodegeneration occurs more rapidly in neurons containing a dark-brown pigment known as Neuromelanin (NM). Neurodenegeration in non-melanized neurons is not consistent and does not occur only in PD. SNpc contains a large number of these melanized neurons, giving it a darker color. NM is synthesized in melanin producing cells called as melanocytes (CarballoCarbajal et al. 2019). This is an enzyme-mediated process. Firstly, L-tyrosine undergoes hydroxylation to form L-DOPA. Then, it’s oxidized to L-Dopaquinone, which is a precursor compound of melanin pigment. Tyrosinase enzyme is used for catalysis of both of these reactions. When tyrosinase is overexpressed, it leads to rapid oxidation of L-DOPA and dopamine to L-dopaquinone. This reduces dopamine levels in brain, causing neurodegenration, causing PD (Li et al. 2018). Choi et al. virtually screened compounds to select a few and also made analogs of these structures. They tested the inhibitory activity against tyrosinase enzyme and also performed molecular docking of most active compounds. 81 and 82 showed potent inhibitory activity. Also 81 was able to chelate the Cu ions present in tyrosinase enzyme (Choi et al. 2016). Molecular docking of 81 is shown below in Fig. 10.24. Tetrazole moiety is

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HN N N

MeO

N N N

H N

N N

MeO OMe

N

N N

COOMe

HO CF3 67 DPPH IC50= 13.19 M

O

S N N

NH

N

N H

N

S

Cl

70 IC50= 32.2 2.4 M

69 75% Inhibition at dose of 1 mg/mL

N N

71 IC50= 31.9 11.1 M

O

O

HS

NO2

N N N N N

N N N N N

N

N Ph

68 IC50= 20.1 1.8 M

HN N N

O HN S O

N N

I

72 IC50= 62.45 M

O

O

N

Cl

N N N

N N

N

N N N

N

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73 DPPH IC50= 79.23 M Iron chelation IC50= 68.05 M H2O2 IC50= 121.11 M

O

S

N

HN N

N

75 60.5% Inhibition at dose of 100 M

Fig. 10.22 Tetrazoles as anti-oxidants

N

74 DPPH IC50= 102.07 M Iron chelation IC50= 75.33 M H2O2 IC50= 102.11 M N N

Cl

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O

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C15H31

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N N

SH

76 Inhibitory capacity= 34.38 g/mL

N

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77 Trolox equivalent antioxidant capacity= 9.51±0.460 mmol L-1 g-1 N N N NH2

OH

SH

78 IC50= 50.15 0.41 g/mL

O

O

NH2

O

O

O

N N N

O

O

79 Decreased ROS levels from 130% to 110%

N H O

N N N

80 89.9% radical scavenging activity at 200 mg/L concentration

Fig. 10.23 Triazole as anti-oxidants HO

N

OH

N HN

N N N N H

81 Ki= 11 ± 1 nM

N HN

N N N N H

82 Ki= 35 ± 3 nM

Reprinted from Choi J, Choi KE, Park SJ, et al (2016) Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors. J Chem Inf Model 56:354–367. Copyright (2016) American Chemical Society.

Fig. 10.24 Tetrazole based tyrosinase inhibitors and molecular docking of compound 81 in binding site of tyrosinase enzyme. Reprinted with permission from ref. Choi et al. (2016). Copywrite (2016) American Chemical Society

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F

N N N O

O

HN S

N N

N H

O

S

Br

83 Tyrosinase Inhibition IC50= 24.6±0.9 mM Free radical scavenging EC50= 39.2±1.1 µM

N NH2

N

84 Reduces aggregation upto 33%

Fig. 10.25 Triazole based compounds targeting Parkinson’s disease

essential as it interacts with histidine 61, 263, 296 residues and copper ions in the enzyme site. Dashed line shows hydrophilic interactions whereas curves are used to show hydrophobic areas. 1, 2, 3-Triazole also inhibits tyrosinase enzyme providing relief in case of Parkinson’s disease. Compound 83 has high tyrosinase inhibition activity with IC50 = 24.6 ± 0.9 μM and free radical scavenging activity with EC50 = 39.2 ± 1.1 μM. (Ranjbar et al. 2020). Triazoles have been reported for inhibiting aggregation of alpha synuclein protein (α-syn). It is a presynaptic protein which controls release of neurotransmitters from synaptic vessels. α-syn is misfolded and aggregates to form lewy bodies, a hallmark for PD. Compound 84, as shown in Fig. 10.25, can reduce the aggregation of these proteins up to a 33% (Vittorio et al. 2020).

10.7 Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease which progresses gradually. It affects motor neurons in cortex, brain and spinal cord. Muscular weakness, atrophy and dysphagia are commonly observed as it develops. It’s found generally in people above 50 years of age but some rare cases of younger people (25 years or above) have been reported. Imbalance in clearance of glutamate excitotoxins, misfolded protein aggregation, oxidative stress and mitochondrial dysfunction, neuroinflammation, genetic and environmental factors are some factors involved in its pathogenesis (Kjældgaard et al. 2018). Neuroinflammation is caused when motor neurons are destroyed. Findings show P2X7 receptors are involved in neuroinflammation due to its activity in CNS. These are ionotropic receptors which are expressed in immunity building cells like lymphocytes, microglial cells, etc.

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Cl N N

Cl

N

N

N

N

N

N N

85 A-438079 pIC50= 6.9

F F

N

F

NH O

S

86 HIgher neuroprotective activity than parent drug Riluzole

Fig. 10.26 Molecules targeting amyotrophic lateral sclerosis

P2X7 is involved in formation of NLR3 inflammosome. This leads to release of proinflammatory cytokines, majorly IL-1β and also IL-18 from microglia and astrocytes in the brain. This causes inflammation which is one of the reasons for neurodegeneration (Zheng et al. 2017). Abott Laboratories prepared a derivative containing tetrazole as heterocyclic ring, A-438079 (85). This molecule had low molecular weight and good pharmacological activity with pIC50 value of 6.9 but its pharmacokinetic properties were not suitable for further proceedings. A-438079 had very less halflife of an hour and its bioavailability was very low when injected intraperitoneally (Fig. 10.26) (Ruiz-Ruiz et al. 2020). Nevertheless, improvement of these characteristics can lead to formation of a potent tetrazole analog for treating neuroinflammation. Compound 86 is a triazole based riluzole derivative which has more neuroprotective effect than riluzole itself. Riluzole is currently used for treating ALS. The molecule gives neuroprotection against kainate induced dendritic loss (Sweeney et al. 2018).

10.8 Conclusion and Future Directions Both triazoles and tetrazoles as a pharmacophore have lot of potential due to ability to show various therapeutic properties and bioisosterism. Drugs like cilostazol, losartan, cefazoline and pemirolast are currently marketed. There has been a lot of advancement in synthetic methods for formation of both these azole derivatives. They have shown anti-alzheimer activity by targeting enzymes like AChE, BuChE, BACE-1, GSK-3β and DYRK. These are involved in formation of Aβ plaques and tau protein hyperphosphorylation, both being hallmarks of AD. They also show inhibition of MAO-B enzyme and prevent reuptake of biogenic amines in neurons making it useful in treatment of AD related depression. Both of them also possess anti-oxidant and anti-inflammatory properties. They can properly fit into binding site of COX-2 enzyme rendering high activity. It can be

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useful in controlling neuroinflammation associated with neurodegenerative diseases. Also, these derivatives have been used to control ROS formation due to mitochondrial dysfunction. Triazoles and tetrazoles can chelate metals like Cu and Fe efficiently due to presence of nitrogen atoms which contributes to its anti-oxidant potential. These azoles, although have been used in targeting PD and ALS, there is still scope for improvement. They show potent tyrosinase inhibition and Cu ion chelating capacity which can be exploited for further usage. Research on this moiety is progressing and it is expected to delve into more aspects in future.

Azole & Its substitution (colour-code)

1H

2H

5- Substituted 1H

2-Substituted 2H

1, 5 –Disubstituted

2, 5- Disubstituted

1, 2, 3-Triazole

1, 2, 4-Triazole

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Chapter 11

An Insight into the Synthesis and Pharmacological Activities of Indoles, Isoindoles and Carbazoles Surendra Saini, Krishan Kumar, Savita Meena, Anshu Dandia, K. L. Ameta, and Vijay Parewa

11.1 Introduction Heterocycles are the most imperative class of organic compounds having a broad collection of significance to human life because various natural products such as alkaloids (e.g. nicotine and caffeine), amino acids, nucleic acid (DNA and RNA), hormones, vitamins (e.g. vitamin B6, vitamin E), and antibiotics as well as dyes, herbicides, agrochemicals, pharmaceuticals, and many other compounds contain heterocyclic scaffolds (Brahmachari 2015; Shalini et al. 2010; Keri et al. 2014; Afzal et al. 2015; Shinde and Haghi 2020; Hussaini et al. 2020; Berger 2007). Over the past two centuries, several heterocyclic compounds have been developed by the researchers which have several biological actions such as antimicrobial, anti-HIV, antitumor, anti-inflammatory, antifungal, antitubercular, antidiabetic, various herbicides, and insecticides agents (Ramsewak et al. 1999; Padwa et al. 1992). On the other hand, heterocycles also play a vital role in polymer, material science, and supramolecular chemistry. In addition, heterocyclic composites show photoelectric properties, such as bio- and chemiluminescence photochromic, and solvatochromic properties. Therefore, “heterocyclic chemistry” is the branch of organic chemistry, which plays an essential role for the synthesis, and biological evaluations (Festa et al. 2019).

S. Saini · K. Kumar · S. Meena · A. Dandia · V. Parewa (B) Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur 302004, India K. L. Ameta Department of Chemistry, School of Liberal Arts and Sciences, Mody University of Science and Technology, Lakshmangarh, Rajasthan 332311, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_11

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N H Indole

NH Isoindole

N H Carbazole

Scheme 11.1 N-heterocyclic compounds containing one N-atom in the pyrrole ring

11.1.1 N-Heterocyclic Compounds N-heterocyclic complexes are ubiquitous structural motifs found in various natural products, nucleic acids, medicine, agrochemicals and various natural and synthetic dyes (Khan et al. 2019; Rostovtsev et al. 2002; El-mekabaty 2014; Brahmachari and Nayek 2017; Chuprakov et al. 2007; Hopkinson et at. 2014). In addition, they are representing an ample variety of ideal synthetic intermediates, chiral axillaries, drugs molecules, metal ligands in synthetic organic chemistry. Moreover, an extensive range of natural drugs such as papaverine, horsfiline, atropine, elacomine and morphine, as well as synthetic drugs like diazepine, metronidazole, barbiturates, antipyrine, methotrexate, etc., bears heterocyclic moiety (Kaur et al. 2020; Kutateladze et al. 2019; Kumar et al. 2019; Nising et al. 2008; Cheng et al. 2004; Toure et al. 2009; Dounay 2003; Kaur 2019). Infect most of the heterocyclic compounds contain nitrogen and oxygen in their scaffold. N-Containing heterocyclic compounds have always attracted attention of researchers because of their widespread interest in synthetic chemistry, biological and pharmaceutical relevance. Indoles, isoindoles and carbazoles possess broad biological activities and numerous uses in pharmaceutical applications (Tianhui et al. 1994; Denya et al. 2018; Barraza et al. 2018; Kaur et al. 2019; Tan et al. 2001; Dandia et al. 2012, 2013, 2015, 2016, 2017a, 2017b, 2021, 2022) (Scheme 11.1). N-heterocyclic moieties exist in an extensive array of pharmaceutically active molecules, alkaloids, vitamins, natural products, anticorrosive agents, biomolecules, and active compounds that illustrate a huge Significance of N-heterocycles in various field as represented in (Fig. 11.1).

11.2 Indole 11.2.1 Introduction Heterocycles are the branch of organic chemistry, which plays a key role in the synthesis, and biological evaluation. Heterocyclic compounds have an extensive variety of applications in the areas of agrochemicals, photochemistry, dyes, drugs design, and so on (Singh et al. 2018). Amongst all, indole represents one of the most N-heterocyclic compounds which have a bicyclic system containing of a benzene

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Fig. 11.1 Significance of nitrogen-containing heterocycles in various fields

ring fused with pyrrole nuclei and molecular formula of indole is C8 H7 N. The indole moiety is the most abundant heterocyclic scaffolds that occur ubiquitously in biologically active natural products, pigments pharmaceuticals, fragrances, agrochemicals as well as optoelectronic functional materials and are relevant substructures in functional materials (Vicente 2011).

11.2.2 Biological Activity Indoles and their derivatives (indolines, oxindoles and isatins) are valuable and versatile structural scaffolds having extensive range of pharmacological activities such as antidiabetic, anticancer, antioxidant, antifungal, antimicrobial, analgesic, anti-HIV, anticonvulsant, anti-inflammatory and plant growth regulator (Sharma et al. 2010) (Fig. 11.2).

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CN

CH2COOH

OCH3

N H

N S

CF3

Thiazolidine-4-one

HOOC

HOOC N

N NO2

N

N H

N H

Ph O

N H

1,2-disubstituted-5methoxyindole

3-(3-indolyl) thiophene

CN

O

C6H5 N CH2C6H5

COCH3

HOOCH2C

3-(4-trifluoromethyl-2nitrophenyl) indole

2-phenyl-3-(2'-carboxyphenyliminomethyl)indole

2-phenyl-3-(2'-carboxyphenyliminomethyl)indole-1-acetic acid

Fig. 11.2 General structures of indole based biological active compounds

11.2.3 Various Methods for the Synthesis of Indole Due to its widespread application in biologically active moiety, many synthetic methodologies were present in the literature using different parameters for the construction of indole and its derivatives. Choi et al. (2016) has been synthesized indole derivatives through reductive cyclization of 2-(2-nitroaryl)-acetonitrile using (Co2 Rh2 /C) nanoparticle as catalyst under very mild condition (Scheme 11.2). Wu et al. (2016) have described a new approach for the production of indole through N-aryl enamines as a starting material using the iridium complex Ir(ppy)3 as a photosensitizer, and cobaloxime catalyst under visible light irradiation at very mild conditions (Scheme 11.3). R2 X R1

CN NO2

Co2Rh2/C (5 mol % ) H2,(1 atm) wet MeOH (3 ml) r.t., 24 h

R2 R1

X N H

R1 = H, Alkyl, Alkoxy, Halogen R2 = H, Alkyl, Aryl, Ester, Halogen X = CH or N

Scheme 11.2 Synthesis of indole through the reductive cyclization CO2Et Ph N H

Ir(ppy)3, Cobaloxime CO2Et

DMF/i-PrOH, r.t. visibe light no oxidant and no base

Scheme 11.3 Iridium catalysed synthesis of indole derivatives

Ph N H

+ H2

11 An Insight into the Synthesis and Pharmacological Activities … Ph

H2 (2.0 MPa) Au/Fe203

H2 (2.0 MPa) Au/Fe203

toluene 60 oC, 1 h

toluene 120 oC, 1 h

NO2

399

Ph N H

Scheme 11.4 One-pot reaction for the construction of indole derivatives R' R' N R

O O

R' +

R'

N H

NH

O +

H2N

NH2

Fe3O4@SiO2@KIT-6

HNO3

R O

H2O, 60 oC, 5-7 h

NH2

NH O N H

O

Scheme 11.5 Fe3 O4@SiO2 @KIT-6 catalysed synthesis of indole derivatives

Yamane et al. (2009) has been synthesized indole through the one-pot hydrogenation/hydroamination reaction of (2-nitroaryl) alkynes catalysed by Au/Fe2 O3 nanoparticles under given conditions (Scheme 11.4). Abdolmohammadi et al. (2020) have described a facial pathway for the production of indole derivatives by the reaction of guanidinium nitrate, isatins, and 1,3cyclohexanediones utilizing Fe3 O4@SiO2 @KIT-6 as a nanocatalyst in water at 60 °C (Scheme 11.5). Xu et al. (2009) have been synthesized indole derivatives via one-pot fisher indole synthesis by reacting phenyl hydrazine with aldehyde utilizing a novel, efficient, and green sulfonate ionic liquid as a catalyst in aqueous at 80 °C (Scheme 11.6). Ye et al. (2009) have been explained the regioselective cyclization of substituted 2-ethynylanilines to give indole-1-carboxamides using Au(I) and Ag(I) as a cocatalyst under MW (microwave) irradiation in aqueous media. These derivatives are beneficial for the treatment of diabetes and inflammatory diseases (Scheme 11.7). The regioselective Michael addition of indole and derivatives with deficient olefins have been explained by Perumal et al. for the construction of 3-alkylindoles in very good yield utilizing tetrabutylammonium hydrogen sulphate (TBAHS) as a catalyst in water at very mild condition. The synthesized compound showed good antibacterial activity (Damodiran M et al. 2009) (Scheme 11.8). O NHNH2

H HO3S

+

3

N

N

SO3 3

H2O, 80 oC, 2h

Scheme 11.6 Sulfonate ionic liquid catalysed synthesis of indole derivatives

N H

400

S. Saini et al. H N

O

O

R1

10% [Au(PPh3)]Cl 10% AgCO3

NH

N

H N

R1

H2O, MW 10 min., 150 oC 40-93%

CH

R1 = Bn,

,

OMe,

CH2 ,

Br, etc.

Scheme 11.7 Cyclization reaction of 2-ethynylanilines

R4 R3 R2 + N R1

R4

EWG

TBAHS ( 50 mol %) H2O, r.t. 1-10 h 76-90%

EWG

R3 R2 N R1

R1, R2 = H, Me; R3 = H, OMe, Br; R4 = H, Ph EWG = NO2, C(O)R

Scheme 11.8 Synthesis of 3-alkylindoles derivatives

11.3 Isoindole 11.3.1 Introduction Isoindoles are most abundant N-heterocyclic compounds present widely in nature and have great biological significance to our life due to their structural subunits (Heugebaert et al. 2012). They are found in lot of dyes, alkaloids, herbicides, phthalocyanines, artificial pharmaceutical as well as synthetic fused heterocycles, isoindoline pigments, etc. (Yu et al. 2016; Ni et al. 2014; Liu et al. 2014). Isoindoles are important 10π aromatic hererocyclic system which are isomers of indoles and their derivatives fewer well studies. These are less stable than indoles, thus the saturated, fused, and 1- or 1,3-dioxo derivatives are utilized in pharmaceutical and organic chemistry (Bhatia 2017). The most efficient methodology for the construction of isoindoles and derivatives consists of “Diels–Alder” cyclization (Duan et al. 2008). Besides, they are additionally synthesized through cyclization reactions beginning from alkynes and nitrogenous compounds which may or may not be catalysed through transition metals.

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11.3.2 Biological Activity The isoindoles and their fused derivatives have great significance to our life as they have got an extensive range of biological evaluations antimicrobial, anxiolytic, antiarrhythmic, anti-inflammatory, and sedative activity (Nannini et al. 1973; Okazaki et al. 1988; Csende et al. 1992; Reyes et al. 2010; Wada et al. 1992; de Wit et al. 2006; Zsoter et al. 1972) (Fig. 11.3). Therefore, a number of studies have been achieved for the synthesis of isoindoles and various biological evaluations of these novel antiviral scaffolds have seen and increased relevance during the last few years. Moreover, isoindole and their associated compounds are interesting skeletons due to their fluorescent, electroluminescent and capacity medicinal values.

Fig. 11.3 Biological activities of isoindole based compounds

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11.3.3 Various Methods for the Synthesis of Isoindole Peng et al. (2008) have been synthesized isoindole derivatives by the reaction of o-acetylenyl substituted phenyl diazoacetates with amines in the presence of CuPF6 (MeCN)4 catalyst using DCM (dichloromethane) as a solvent at very mild condition (Scheme 11.9). Yeom et al. (2009) have been explained a new synthetic pathway for the construction of isoindole and its derivatives starting from geometry dependent ketoximes and nitrogen catalysed by gold complexes at 70 °C temperature (Scheme 11.10). Heugebaert et al. (2009) have been demonstrated two-step synthesis of 1cyanoisoindoles from ethynyl benzaldehyde. This synthesis was originated by the reaction of 2-ethynylbenzaldehyde, trimethyl silylcyanide, and secondary amine in the presence of lithium perchlorate (LiClO4 ) to give aminonitriles at 165 °C. After the addition of gold catalyst 1-cyanoisoindoles was obtained at room temperature (Scheme 11.11). Ding et al. (2007) have been demonstrated palladium-catalysed isoindol-1ylphosphonate derivatives from a-amino (2-alkynylphenyl) methyl phosphonate,

N2

CO2Me CO2Me

RNH2

CuPF6(MeCN)4 CH2Cl2, r.t. 10 min

N R

Scheme 11.9 Copper catalysed sustainable pathway to afford biologically important isoindole derivatives

R1 Bn N+ O

O Au(iPr)OTf (5 mol%) CH3NO2, 70 oC AuOTf (5 mol %), Bu2P(biphenyl) CH3NO2, 70 oC

R1 NBn

R1 = H, Me, n-C4H9, C6H5, 4-MeO-C6H4

Scheme 11.10 Production biologically important isoindole utilizing gold catalyst R4 R3

O H

1. 5 M LiClO4, Et2O 2. 1.1 eq. RNHR' 3. 1 eq.TMSCN

R2 R4

N

1 mol % AuCl3, r.t.

R1

CN

Scheme 11.11 Au(III) catalysed two-step synthesis of 1-cyanoisoindoles

R2 R3 N R1 CN

11 An Insight into the Synthesis and Pharmacological Activities … EtO EtO O P

R2NH2 HP(O)(OEt)2

CHO

403 EtO OEt P O

NHR2

Pd(II)

N R2

FeCl3 R1

R1

R1

Scheme 11.12 Palladium-catalysed synthesis of isoindole derivatives

which were synthesized by the reaction of 2-alkynyl benzaldehyde, diethyl phosphate, and primary amine at very mild condition with good to excellent yields (Scheme 11.12). Kouzehrash et al. (2021) have been synthesized isoindole derivatives through the one-pot multicomponent reaction of 3-phthaldehydic acid, diverse C–H acids and 5substituted 3-aminopyrazoles utilizing PTSA (4-toluene sulphonic acid) in solvent free condition at 80 °C (Scheme 11.13). Claessens et al. (2008) have described a facial synthetic pathway for the development of benzo[f ]isoindole-4,9-diones by the reaction of 2,3-bis(bromomethyl)-1,4dimethoxynaphthalene with amines utilizing diethyl ether as a solvent in the presence of cerium(IV) ammonium nitrate at room temperature (Scheme 11.14). Takahashi et al. (1985) have been provided a synthetic pathway for the construction of substituted isoindoles via “Strecker” reaction utilizing primary amines and o-phthalaldehyde in the existence of sodium hydrogensulfite (Scheme 11.15).

O

O NH2

OH H

R

O

N H

O

O

N N

Solvent free/TsOH 80 oC, 5-8h

N

N

R

O

Scheme 11.13 PTSA catalysed synthesis of biological active isoindole derivatives O

O 7.5 eq. MeS-Na+ MeOH, 12 h, r.t.

O

excess MeNH2 EtOH, 2 days

3 eq. RNH2 diethyl ether 0 oC, 30 min.

O N R

O

N Me O

O Br Br

O

Me

O

O

O

S S

Me

Oxidation O2 from air

N Me O

Scheme 11.14 Cerium(IV) ammonium nitrate catalysed synthesis of isoindole derivatives

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CHO CHO

H i) 2NaHSO3 aq.

CN

CN

N R

N R

ii) RNH2 iii) 2KCN

H

CN

Scheme 11.15 Sodium hydrogensulfite catalysed synthesis of 2-substituted isoindoles

Scheme 11.16 Rh-catalysed synthesis of isoindole derivatives via intramolecular cyclization

N2

COO2R3 COO2R3 R2

R1

Rh2(Oct)4

R1

N H R2

N3

Zhu et al. (2019) have been demonstrated the Rh-catalysed intramolecular cyclization of α-aryldiazoesters with benzyl azides for the synthesis of isoindole derivatives utilizing dichloromethane as a solvent (Scheme 11.16). N-chloroimines were used as effective synthons for direct C–H functionalization by Qi and co-workers. They were synthesized 2H-isoindoles by the reaction of α-diazo-α-phosphonoacetates with N-chloroimines through the dechlorinative/dephosphonative utilizing Rh(III) as a catalyst (Qi et al. 2019) (Scheme 11.17). Hui et al. have been synthesized isoindole derivatives through the intramolecular cycloaddition reaction of azide–alkene. The reaction proceeded easily through the heating of azides at 100 °C utilizing toluene or DMF as solvent (Hui et al. 2009) (Scheme 11.18). Lin et al. were described visible light-induced intermolecular “Diels–Alder” reaction for the construction of isoindole derivatives from maleimides and acetylene dicarboxylate in the presence of air to give diastereoselective bridged ring heterocycles under very mild reaction conditions (Lin et al. 2015) (Scheme 11.19). Ph N

N2

Cl (EtO)2OP

CO2Ph

Ph

Rh(III) NaOAc

N H

-Cl -PO(OEt)2

Ph

Ni(II) Ph3SiH (-CO2Ph)

N H

CO2Ph

Scheme 11.17 Rh(III) catalysed synthesis of 2H-isoindoles

Scheme 11.18 Synthesis of isoindoles through intramolecular cycloaddition reaction

R R''

R'

OMe CO2Et

R i) 1.5 eq. NaN3 DMF, 0 oC, 1 h ii) extractive work-up iii) toluene, 3 h, 100 oC,

R''

R' N H CO2Et

11 An Insight into the Synthesis and Pharmacological Activities …

405 R1 R2

MeO2C R2

N

CO2Me

CO2Me CO2Me

DEC, r.t., air

N R1

6 W blue LED

O N R3

R1 R2

N

O

O N

R3

O

Scheme 11.19 Visible light-induced intramolecular “Diels–Alder” reaction to access isoindole derivatives

Scheme 11.20 Sodium naphthalenide catalysed sustainable pathway to afford isoindole derivatives

NH2

Ph N N Ph

(i) NaNaph, THF (ii) H2O

Ph N

Ph

Bovenkerk et al. (2015) have been designed a novel synthetic pathway for the production of isoindole derivatives through the one-electron reduction of dibenzo[1, 4]diazocines utilizing sodium naphthalenide (NaNaph) at room temperature (Scheme 11.20).

11.4 Carbazole 11.4.1 Introduction Carbazoles are well-known class of aromatic heterocyclic compound. It has a tricyclic system having two 6-membered benzene rings, which are fused on either side onto a pyrrole ring (Bashir et al. 2015). Carbazole and its derivatives are privileged nitrogen heterocyclic compounds that are present in naturally occurring products, optoelectronic materials, functional materials, pharmaceuticals, and artificial dyes (Roy et al. 2012).

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Antirheumatoid arthiritis

Antiepileptic

Antimicrobial

N H Antiproliferative

Anti-inflammatory

Antipsychotic

Fig. 11.4 Biological activity of carbazole based compound

11.4.2 Biological Activity The ubiquity of carbazoles and its derivatives are one of the most imperative heterocyclic system that endowed a huge pharmacological profile having anti-vascular, antiepileptic, antiproliferative, antipsychotic, analgesic, anti-inflammatory, antioxidant, antimicrobial, anti-HIV, anti-rheumatoid arthritis, and anticancer (Sadiq et al. 2017) (Fig. 11.4).

11.4.3 Various Methods for the Synthesis of Carbazole Sridharan et al. (2009) have been designed a novel efficient synthetic pathway for the double bond activation of diarylamines yielded oxygenated carbazoles utilizing microwave irradiation with Pd(OAc)2 as catalyst and copper acetate as a co-oxidant under non-acidic conditions (Scheme 11.21). R4 R3

R4

R2 R1

N H

Pd(OAc)2, Cu(OAc)2 DMF, 130oC

R3 R2 R1

N H

Scheme 11.21 Palladium acetate and copper acetate catalysed synthesis of carbazole derivatives

11 An Insight into the Synthesis and Pharmacological Activities … O B

407

F X

O

NH SO2R

Pd(PPh3)4, K2CO3

R

DME/H2O, MW, 140 oC

R

SO2R

Scheme 11.22 Palladium-catalysed tandem “Suzuki cross-coupling” reaction to access carbazoles derivatives

St Jean et al. (2007) have been designated a novel one-pot pathway for the development of functionalized carbazoles through the tandem “Suzuki crosscoupling” reaction from the aniline-derived boronic ester and substituted dihalide utilizing palladium catalyst under microwave irradiation at 140 °C temperature (Scheme 11.22). Seijas et al. have described microwave-assisted Madelung’s reaction for the development of 9H-Dibenzo[a,c]carbazole from N-[2-(phenylmethyl)phenyl]benzamide using potassium t-BuOK at 160 °C temperature (Nunez-Alvarez et al. 2009) (Scheme 11.23). Abid et al. (2006) have been explained a novel, effective, environmentally benign solid acid and K-10 montmorillonite catalysed Friedel–Crafts cyclization reaction for the development of substituted carbazoles utilizing microwave irradiation under solvent free condition (Scheme 11.24). Cochard et al. (2004) have been synthesized 1,2,3,4-tetrahydrocarbazoles through the one-pot MCR (multicomponent reaction) of indoles, numerous aldehydes and Meldrum’s acid utilizing D, L-proline in benzene under microwave irradiation (Scheme 11.25).

t-BuOK MW, 160 oC HN

N H

N H 30 %

O

Scheme 11.23 Microwave-assisted Dibenzo[a,c]carbazole

Madelung’s

reaction

30 %

for

the

synthesis

of

9H-

O OH or N OH R R = H, CH3, Bu, Ph

O

K-10, MW 90 oC, 160-170 oC

N R

Scheme 11.24 Microwave-induced Friedel–Craft cyclization to access substituted carbazoles

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R1

O

O

CHO

O

N R

O Ar

O

O

D, L-proline Benzene, MW

O

O Ar R1

N R

R = H, CH3, R1 = H, COOEt, Ar, Aryl, OCH3Ar, NO2Ar

Scheme 11.25 Microwave-assisted method to access bioactive molecules of carbazole derivatives

Saravanabhavan et al. (2014) have been explained an effective synthetic pathway for the development of carbazole derivatives through the one-step synthesis of carbazole derivatives with 2-aminoethanol catalysed by P-TsOH under microwave irradiation with good to excellent yield (Scheme 11.26). Wu et al. (2016) have been designed a novel and green methodology for the development of 2,6-disubstituted 9-arylcarbazoles from cyclohexanones and arylureas using the combination of potassium iodide and iodine under metal free condition in oxygen atmosphere (Scheme 11.27). Tsang et al. (2005) have described efficient protocols for the construction of Nacetyl carbazole from 2-acetaminobiphenyl through the direct C–H functionalization and amide arylation utilizing palladium acetate as a precatalyst while copper acetate as a reoxidant in toluene at 120 °C temperature (Scheme 11.28). O CHO N H

NH2

HO

Cl

P-TsOH, MW N H

HN

Scheme 11.26 Microwave-induced carbazoles synthesis utilizing P-TsOH

O R1

Ar

R1

R2

H N

R3 O

KI/I2, P-TsOH Toluene, O2

R1

N Ar

Scheme 11.27 Transition metal free carbazole synthesis

Scheme 11.28 Palladium acetate/Copper acetate catalysed synthesis of N-acetyl carbazole

O N H

Me

Pd(OAc)2 / Cu(OAc)2 toluene, 120 oC

O N Me

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11.5 Conclusion Over the past few decades numerous indole, isoindole and carbazole and their derivatives were developed, synthesized and studied for biological activity. In this chapter we summarized synthetic methodologies and biological activity of fused N-heterocyclic compound such as indole, isoindole and carbazole and its derivatives. It offers a viewpoint on modern advances of indoles, isoindoles and carbazoless consuming several biological activities such as anticancer, antifungal, antibacterial, antiulcer, anticonvulsant, anti-inflammatory, antidiabetic, antimalarial, antitumor, anti-HIV, antitubercular, antihypertensive, antihistamine, antihypertensive and analgesic potencies.

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Sadiq Z, Akbar Hussain E, Naz S (2017) Carbazole derivatives by microwave promoted protocols: a mini review. Mini-Rev Org Chem 14:469–488 Saravanabhavan M, Murugesan V, Sekar MJ (2014) Microwave assisted synthesis of pyrido [2, 3-a] carbazoles; investigation of in vitro DNA binding/cleavage, antioxidant and cytotoxicity studies. Photochem Photobiol B Biol 133:145–152 Shalini K, Sharma PK, Kumar N (2010) Imidazole and its biological activities: a review. Der Chemica Sinica 1:36–47 Sharma V, Kumar P, Pathak D (2010) Biological importance of the indolenucleus in recent years: a comprehensive review. J Heterocycl Chem 47:491–502 Shinde RS, Haghi AK (2020) Design and synthesis of triazine amine derivatives as antibacterial and antifungal agents. In: Shinde RS, Haghi AK (eds) Modern green chemistry and heterocyclic compounds: molecular design, synthesis, and biological evaluation, 1st edn. CRC Press, United State, pp 59–78 Singh TP, Singh OM (2018) Recent progress in biological activities of indoleand indole alkaloids. Mini-Rev Med Chem 18:9–25 Sridharan V, Martín MA, Menéndez JC (2009) Acid-Free synthesis of carbazoles and carbazolequinones by intramolecular Pd-catalyzed, microwave-assisted oxidative biaryl coupling reactions-efficient syntheses of murrayafoline A, 2-methoxy-3-methylcarbazole, and glycozolidine. Eur J Org Chem 4614–4621 St Jean DJ, Poon SF, Schwarzbach JL (2007) A tandem cross-coupling/SNAr approach to functionalized carbazoles. Org Lett 9:4893–4896 Takahashi K, Suenobu K, Ogura K (1985) An efficient method for synthesis of 1-cyano-2substituted-isoindoles by Strecker reaction using o-phthalaldehyde and primary amines. Chem Lett 14:487–1488 Tan KL, Bergman RG, Ellman JA (2001) Annulation of alkenyl-substituted heterocycles via rhodium-catalyzed intramolecular C−H activated coupling reactions. J Am Chem Soc 123:2685– 2686 Tianhui R, Qunji X (1994) A survey on multifunctional oil additives of N-containing heterocyclic compounds and their derivatives. Tribology 14:370–381 Toure BB, Hall DG (2009) Natural product synthesis using multicomponent reaction strategies. Chem Rev 109:4439–4486 Tsang WP, Zheng N, Buchwald SL (2005) Combined C–H functionalization/C–N bond formation route to carbazoles. J Am Chem Soc 127:14560–14561 Vicente R (2011) Recent advances in indole syntheses: new routes for a classic target. Org Biomol Chem 9:6469–6480 Wada T, Fukuda N (1992) Effect of a new anxiolytic, DN-2327, on learning and memory in rats. Pharmacol Biochem Behav 41:573–579 Wu CJ, Meng QY, Lei T et al (2016) An oxidant-free strategy for indole synthesis via intramolecular C-C bond construction under visible light irradiation: cross-coupling hydrogen evolution reaction. ACS Catal 6:4635–4639 Wu J, Xie Y, Chen X et al (2016) Transition metal-free carbazole synthesis from arylureas and cyclohexanones. Adv Synth Catal 358:3206–3211 Xu DQ, Wu J, Luo SP et al (2009) Fischer indole synthesis catalyzed by novel SO 3 H-functionalized ionic liquids in water. Green Chem 11:1239 Yamane Y, Liu X, Hamasaki A et al (2009) One-pot synthesis of indoles and aniline derivatives from nitroarenes under hydrogenation condition with supported gold nanoparticles. Org Lett 11:5162–5165 Ye D, Wang J, Zhang X et al (2009) Gold-catalyzed intramolecular hydroamination of terminal alkynes in aqueous media: efficient and regioselective synthesis of indole-1-carboxamides. Green Chem 11:1201–1208 Yeom HS, Lee Y, Lee JE et al (2009) Geometry-dependent divergence in the gold-catalyzed redox cascade cyclization of o-alkynylaryl ketoximes and nitrones leading to isoindoles. Org Biomol Chem 7:4744–4752

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Chapter 12

Pyrazoles, Indazoles and Pyrazolines: Recent Developments and Their Properties Shyam L. Gupta, Surendra Saini, Pratibha Saini, Anshu Dandia, K. L. Ameta, and Vijay Parewa

12.1 Introduction 12.1.1 Pyrazole Pyrazole and its derivatives are the 5-membered ring heterocyclic composites which contain two N-atoms in its structure. The word pyrazole is given by L. Knorr in the year 1883. Pyrazolylalanine, the first natural pyrazole, was secluded from the watermelon seeds in the year 1959 (Noe and Fowden 1959; Eicher et al. 2013). The structure of pyrazole is given in Fig. 12.1. Nitrogen containing heterocyclic compounds played a very important role in society. Pyrazole and its derivatives are found in medicinal and natural product. Most of the pyrazole derivatives showed anticancer activities (Ahmet et al 1986; Goddard et al. 1987); many natural products like pyrazole carboxylic acid, oxoformycin B, pyrazofurin, formycin B, etc., have pyrazole unit in their structure (Kumar et al. 2013). Many marketable drugs such as celecoxib (Cox-2 inhibitor), apixaban, sildenafil (Keter and Darkwa 2012; Elguero et al. 2002), anti-obesity drug (Rimonabant) (Kaur et al. 2016) and β-enaminoketoesters (Persson et al. 2006) (Fig. 12.2) are constructed from pyrazole moiety. Pyrazoles are biologically important compounds which show many medicinal properties such as anticonvulsant (Amnerkar et al. 2010), antioxidant S. L. Gupta Government Polytechnic College, Near Itarana Fly Over, Kalimori, Alwar(Raj.) 301001, India S. Saini · P. Saini · A. Dandia · V. Parewa (B) Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur 302004, India K. L. Ameta Department of Chemistry, School of Liberal Arts and Sciences, Mody University of Science and Technology, Lakshmangarh, Rajasthan 332311, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_12

415

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S. L. Gupta et al.

N N H Fig. 12.1 Structure of pyrazole

OH

N(CH3)2 HO

(CH2)3

OH

HO

N

N H

N

N NH2

O

N

O

OH

N H

N

N

Allopurinol

O

Benzydamine (Antiinflammatory drug)

Pyrazofurin (Natural product)

O H3 C

O

N NH

NH2

O

N

N N

N N

N Cl

Cl

O

Apixaban (Anticoagulant)

Cl

Rimonabant (Antiobesity drug)

OCH3

Fig. 12.2 Chemical structure of pyrazole containing natural product and drugs

(Rangaswamyet al. 2012), antibacterial (Damljanovi´c et al 2009; Desai et al. 2013), fungicides (Vicentini et al. 2007), antiviral (Park et al. 2005), anti-inflammatory (Ragab et al. 2013), antidepressant (Özdemir et al. 2007), anti-tubercular (Pathak et al. 2012), anticancer (Clapham et al 2009; Lv et al. 2010) and antipyretic (Sener ¸ et al. 2002).

12.1.2 Indazole Indazole and its derivatives are the bicyclic ring heterocyclic compounds which contain one benzene ring, and another is pyrazole ring. Indazole is found in two forms; one is 1H-indazole, and second is 2H-indazole; both are tautomeric form of each other. The structure of indazole is given in Fig. 12.3. Indazoles and its derivatives possess many biological properties which are antitumor (Wan et al. 2018), anti-inflammatory (Wrzeciono et al. 1993), antifungal (Gopalakrishnan et al. 2009), anti-HIV (Se-Ho et al. 2013) and antipyretic (Mosti et al. 1992). Indazoles are found in many drugs which are found in market such

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

417

N

NH

N H

N

1H-indazole

2H-indazole

Fig. 12.3 Structure of indazole

NMe2 N

O

N

N OH

(CH2)3

N

Benzydamine

N

O

N

CONH2

O

Bendazac

Niraparib SO2NH2

N

CH3 HN

H3C N S O

NHCH3

N H

H3C

N

N N

N

N

Pazopanib

CH3

Axitinib

Fig. 12.4 Chemical structure of indazole containing drugs

as bendazac, benzyldamine, lificiguat, axitinib and linifanib (Ghosh et al. 2020) (Fig. 12.4). Another important property of indazoles is that these compounds showed photo-physical properties with -conjugated system and developed light-emitting diodes as OLED devices (Philipp et al 2010; Ghosh et al. 2020).

12.1.3 Pyrazoline Pyrazoline is the five-membered N-containing heterocyclic compounds and used as a synthon in the synthesis of pharmacological active organic compounds. Pyrazolines are found in three tautomeric forms which are known as 1 -pyrazoline, 2 -pyrazoline and 3 -pyrazolines which are shown in Fig. 12.5. Pyrazolines are found in many natural products, alkaloids, pigments, vitamins, etc. (Swathi et al. 2019). Pyrazolines showed many biological activities like antiinflammatory, antimicrobial (Abdel-Wahab et al. 2009), analgesic (Sauzem et al. 2009), anti-amoebic (Budakoti et al. 2009), antioxidant (Padmaja et al. 2011), antinociceptive, anticancer (Shaharyar et al. 2010), antiglaucoma (Kasımo˘gulları

418

S. L. Gupta et al.

N

HN

N N

N H

N H

1

∆ -pyrazoline

2

3

∆ -pyrazoline

∆ -pyrazolines

Fig. 12.5 Three tautomeric forms of pyrazoline

CH3

CH3 H3C

H 3C

N

,

H3C

N N

N HO3S

Me2N

O

O

Metamizole

Phenazone

Aminophenazone

CH3 O

(H2C)3 F3C

N N

N

O

CH3

O

N

NH2

S

N

O

O

Celecoxib

N N

Phenylbutazone

Fig. 12.6 Chemical structure of pyrazoline containing drugs

et al. 2010), antidiabetic (Shaharyar et al. 2010), antidepressant (Lo et al. 2010) activities, etc. Pyrazolines containing drugs which are found in market are phenazone, metamizole, aminophenazone, phenylbutazone, sulfinpyrazone, etc. (Kalyani et al 2020; Bardalai et al. 2012) (Fig. 12.6). Besides pharmacological activities, pyrazolines are also important in industry because they exhibit excellent fluorescence properties (Yang et al 2003; Lu et al. 2000) and due to these fluorescence properties, used as chemosensors, brightening agents, and in electrophotography in the form of OLED devices (Young and Fitzgerald 1995; Sano et al. 1995). Therefore, the advance of new methodology for the synthesis pyrazole, indazole and pyrazoline, developed recently are comprised in this chapter. This chapter focused on the synthetic methods of these compounds and their derivatives and also showed their biological activity.

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

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12.2 Synthetic Protocol of Pyrazoles Tafti et al. (2021) have developed a green and environmentally friendly novel catalyst by the combination of titanium (IV) with eggshell nanoparticles used in the MCR of ethyl acetoacetate 1, malononitrile 2, aldehydes 3 and hydrazine hydrate 4 for the preparation of pyranopyrazoles 5 (Scheme 12.1). Catalyst is characterized by IR, XRD, FESEM, EDX and TGA, and on the basis of FESEM data, morphology of catalyst is found in spherical shape. Komendantova et al. (2020) have synthesized 3,4-dicarbonyl-substituted pyrazoles 8 from 1,3-diketones 6 and thiohydrazides 7 using ethanol as solvent and iodine as a catalyst under thermal condition (Scheme 12.2). This reaction proceeds via heterocyclization with the elimination of sulfur. The most important thing about this reaction is that it is not completed without using iodine. Westermeyer et al. (2020) have synthesized disubstituted pyrazole derivatives 11 by the reaction between N-tosylhydrazones 9 and bromovinyl acetals 10 which is proceeds through diazo compounds generated from N-tosylhydrazones during reaction (Scheme 12.3). Mechanistically, this reaction proceeds through 1,3-dipolar cycloaddition reaction. Beaumont et al. (2019) have synthesized Molybdenum mediated pyrazole derivatives 14 from isoxazoles 12 by the reaction of hydrazines 13 under thermal condition in the presence of 1 M HCl (Scheme 12.4). Further, they used unsymmetrical isoxazoles 15 to check the regioselectivity of the formation of pyrazoles and successfully achieved high regioselectivity between product 16a and 17a with 12:1 and product 16b and 17b with 25:1 (Scheme 12.5). Ar CN

O

O

+ OEt

1

CN Nano-eggshell/Ti(IV)

CN

Solvent free, RT

2

+

N

+ ArCHO

NH2NH2.H2O

4

N H

O

NH2

5

3

Scheme 12.1 Synthesis of pyranopyrazoles

I2 (1.0 eq) TsOH (10 mol%)

S O

O +

R1

6

R2

H 2N

H N

N H

R3

O

O

EtOH, 40 oC

7 O

Scheme 12.2 Synthesis of 3,4-dicarbonyl-substituted pyrazoles

R3 NH

R2

R1

N N H

8

420

S. L. Gupta et al. NHTs

N

N

OR1 H R

OR1

K2CO3 (4.5 eq.)

Br

+

NH

OR1

THF, Reflux

11

10

9

OR1

R R= Me, OMe, Cl, F, Br, I, CF3, CN, NO2 R1 = C2H5,

O O

O

,

O

Scheme 12.3 Synthesis of disubstituted pyrazoles R4 O

R2

N

R1

R4

+

12

N H

NH2

N Catalyst, HCl (aq) THF/H2O, 70oC

13

R3

R2

N

R1

R3

14

R1, R2, R3, R4 = H, Alkyl, Aryl, Heteroaryl

Catalyst = Mo OC CO OC

Scheme 12.4 Mo catalyzed pyrazole synthesis

MeO +

15

O

N

Ar

N H

NH2

Catalyst, HCl (aq) THF/H2O, 70oC

13 13a, Ar = Ph 13b, Ar = 4-CNC6H4

Ar

N N

+ Ar

N N

Ar

Ar

16a 16b

6a/7a = 12:1 6b/7b = 25:1

17a 17b

Scheme 12.5 Regioselectivity in pyrazole derivatives

A convenient approach has been developed by Kumar et al. (2019) for the preparation of ferrocenyl containing pyrazoles 21 catalyzed by iodine and sodium bicarbonate (Scheme 12.6). In this reaction iodine behaves as cyclizing agent in presence of sodium bicarbonate. This reaction was successfully completed by cyclocondensation of acetyl substituted ferrocene 19 with hydrazine 20 followed by cyclization. Further, Kumar and group screened these compounds for antimicrobial and DNA photo-cleavage activity and found very potent.

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

CH3COOH

Fe+2

Fe+2

HCl

421

COCH3 PhNHNH HCl 2. 20

Fe+

I2/NaHCO3

18

N

19

N

R R = H, Ph

21

Scheme 12.6 Synthesis of ferrocenyl substituted pyrazoles

Fe+2

COCH3

CH3COOH

Fe+2

HCl

PhNHNH2.HCl

Fe

N

+

N

I2/NaHCO3 H3COC

22

N

23

N

24

Scheme 12.7 Synthesis of bis-ferrocenyl pyrazoles

Further, bisferrocenyl pyrazole derivatives 24 were also synthesized under same reaction conditions and these compounds were synthesized successfully with excellent yield (Scheme 12.7). Konwar et al. (2019) have synthesized pyrazoles 27 from diketones 25 and hydrazine 26 under room temperature using ionic liquids combination with Fe (III) salt and this catalyst was easily separated from reaction mixture due to its magnetic nature (Scheme 12.8). Mechanistically, electrophilic nature of carbonyl carbon of diketones is increased by attraction between iron and oxygen atom of diketone which facilitated the attack of nitrogen of hydrazine to carbon to furnished the final product. R2

R1

NHNH2 O

R1

O R1

R1 R2

25

N N

[C4mim][FeCl3]

+

RT 26

R3

R1 = CH3, C2H5 R2 = H,Cl, CH3, C2H5, R3 = H, 4-CH3, 4-Br, 4-CF3, 4-CN, 4-Cl, 4-NO2, Ph, 2,4-diNO2, 2-hydrazino pyridine, 2-furoic hydrazide

Scheme 12.8 Ionic liquids mediated pyrazole synthesis

R3

27

422

S. L. Gupta et al. R CH3 O

O

H R1 TBAOH (40 wt% in water)

S +

+

28

R

29

H 2N

R1

MW

NH2

30

N

N

N H R = H, 4-F, 4-Cl, 2,4-Cl2, 2,6-Cl2, 4-Br, 3-Br, H N 2 4-CH3, 4-OCH3, 4-OCH2Ph, 9-Anthracenyl, 2-Thiophenyl, 1-Naphthyl R1 = H, 4-Cl, 4-CH3

31

S

Scheme 12.9 Pyrazole synthesis under MW R O O COOR1 NH +

+

NH

N

Tetrabutylammonium bromide

COOR1

34

33

R

COOR1

R N N

Solvent free, RT

C O

32

R2

R

O HN R2 R = H, NO2 R1 = CH3, C2H5 R2 = Cyclohexyl, (CH3)3

COOR1

35

Scheme 12.10 TBAB mediated pyrazole synthesis

A microwave-assisted methodology for the preparation of pyrazoles 31 has been synthesized by Farmani et al. (2018) using a MCR of acetophenones 28, thiosemicarbazide 29 and aldehydes 30 in aqueous medium catalyzed by tetrabutylammonium hydroxide (Scheme 12.9). Soltanzadeh et al. (2017) have established an environmentally friendly methodology for the preparation of pyrazole derivatives (Scheme 12.10). In this protocol pyrazoles 35 were produced by the reaction of N -benzoylbenzohydrazide 32, dialkyl acetylenedicarboxylate 33 and isocyanides 34 using tetrabutylammonium bromide (TBAB) as ionic salt. All the products were synthesized in excellent yield. Further, they investigated the role of TBAB and found that ammonium ion of TBAB attracts the electrons of oxygen atom of carbonyl group of carboxylates and increased the electrophilic nature of carbonyl carbon which facilitated the Michael addition of isocyanide to furnish the final product. Beyzaei et al. (2017) have been synthesized pyrazoles 39 by the reaction of 2,4-dinitrophenyl hydrazine 36, malononitrile 37 and aldehydes 38 using glycerol/potassium carbonate as eutectic solvent (Scheme 12.11). In this reaction only Schiff base was formed in glycerol which showed the importance of K2 CO3 in this reaction to furnished the final product pyrazole. Further, they tested all the prepared

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

423 NC

R

NHNH2

N

H2N

NO2

Gly/K2CO3/H2O

+ CH2(CN)2 + RCHO 38 37 NO2

N NO2

80oC R = 4-CH3OC6H4, 4-NO2C6H4, 4-CH3CONHC6H4, 2-HO-3-CH3OC6H3, NO2 2,4-Cl2C6H3, 2,6-Cl2C6H3

36

39 Scheme 12.11 Synthesis of pyrazole derivative

compounds for in vitro antimicrobial activity and showed good inhibitory effect different strains of bacteria. Salehzadeh et al. (2016) established an efficient silica-coated catalyst Fe3 O4 magnetite nanoparticles which supported by dioxomolybdenum complex and used in the reaction of pyrazoles 43 synthesis from aldehydes 40, malononitrile 41 and phenylhydrazine 42 at room temperature without using any solvent (Scheme 12.12). This catalyst characterized by different technology such as XRD, SEM, EDX, ICP-AES. Mechanistically, pyrazole derivatives are formed by the Knoevenagel mechanism followed by Michael addition of hydrazine to Knoevenagel adduct.

H

O

H2N

NH2 NH

N

CN +

+

CN

Solvent free, RT

CN

41

42

Mo

Mo

Si O Mo

43 Mo

2

2

SiO

o

M

Si

SiO

Catalyst

R

O 2 Fe3O4 NPs

2

40

R

N Catalyst

M

o

Dioxomolybdenum complex supported on silica-coated magnetite nanoparticles

Scheme 12.12 Fe3 O4 magnetite nanoparticles catalyzed pyrazole synthesis

424

S. L. Gupta et al.

O RNHNH2

O

+

Bakers yeast

R

Phosphate buffer D-glucose, RT

44

45

N N

46

R = H, CH3CO, C6H5, C6H5CO, 4-ClC6H4CO, 2-ClC6H4CO, 2-BrC6H4CO, 3-C5H4NCO, 4-C5H4NCO, 4-NO2C6H5CO, 2,4-NO2C6H3, 3-CH3C6H4OCH2CO,

Scheme 12.13 Pyrazole synthesis catalyzed by biocatalyst

Mane et al. (2015) developed an environmentally benign methodology for the preparation of pyrazoles using fermented Baker’s yeast as a biocatalyst (Scheme 12.13). Pyrazole derivatives 46 were prepared by the cyclo-condensation between hydrazine’s 44 and diketones 45. Baker’s yeast is fermented using phosphate buffer (pH 7) and d-glucose at 32 °C for 12 h. Further, this group analyzed kinetic study of the reaction by gas chromatography and aliquots are collected after a time interval which are analyzed by NMR spectroscopy. The rate of reaction in terms of yield is analyzed and up to 6 min only 16% product is formed which is increased up to 79% after 9 min and 92% after 15 min.

12.3 Synthetic Protocol of Indazoles A copper acetate catalyzed methodology for the preparation of indazole derivatives 50–51 was established by Solomin and co-workers by the reaction of 2formylphenylboronic acids 47 with dialkylazodicarboxylate derivatives 48 followed ring closing catalyzed by acid or base (Scheme 12.14) (Solomin et al. 2021). Firstly, they tried different copper sources such as CuCl and CuI, but in the presence of CuCl no product formation taken place and in the presence of CuI product furnished with good yield. Finally, excellent yield was observed in presence of copper acetate. In

O

Base

O R1O N

O

R

+

47

B(OH)2

Cu(OAc)2

N

R N

OR1 O

48

R1O

49

H N

O

N

R N H

50

OR1 O

N

R Acid

N R 1O

O

51

R1 = Et, i-Pr, Bn, i-Bu, Me, allyl, t-Bu

Scheme 12.14 Acid and base catalysed synthesis of indazole derivatives

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

425

Ar N

MoO2Cl2(DMF)2 (10 mol%) Pinacol (5 eq.)

R

N

100 oC, Sealed vial

52

NO2

R

53

Ar

N

R = H, Cl Ar = C6H5, 4-OMeC6H4, 2,4,6-(OMe)3C6H2, 3,5-(OMe)2C6H3, 2-FC6H4, 2-BrC6H4, 4-IC6H4, 2-Br-4-FC6H3, 2-Br-4-ClC6H3, 2-Br-5-CF3C6H3, 2-Br-4-CF3C6H3, 1-Naphthyl, 2-Naphthyl

Scheme 12.15 Mo(VI)-Catalyzed indazole synthesis

final step, C-N bond formation taken place by acid- or base-catalyzed ring closing but in presence of base, indazoles produced with unprotected N-atom while in presence of acid, N-protected indazoles were produced. Kaldhi et al. (2019) established a Mo(VI)-catalyzed methodology for the preparation of indazoles 53 from the deoxygenation of nitroaromatic compounds 52 using pinacol as reducing agent (Scheme 12.15). A wide variety of indazole derivatives were synthesized with electron donating and withdrawing groups. Shamsabadi et al. (2018) have firstly synthesized 2-hydrazobenzophenones 56 via a benzyne mechanism which is converted into 1H-indazoles 57 and 2H-indazoles 58 (Scheme 12.16). Malapati et al. (2018) have established a methodology for the preparation of indazole derivatives and for this initially, β-acetylphenylhydrazine 59 reacted with hydroxylamine hydrochloride 60, chloral hydrate 61 and hydrochloric acid to furnished N-acetylaminoisonitrosoacetanilide 62 which reacted with H2 SO4 and gave indazole-3-carboxylic acid 63 (Scheme 12.17). Further, indazoles reacted with Br2 in the presence of glacial CH3 COOH to produced 5-bromo derivatives 64 which is reacted with hydroxybenzotriazole 65 and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) 66 to furnished final product, i.e., respective amide derivative of indazoles 67. Further, synthesized indazole derivative were screened for R1 Cleavage of carbamates

R1

O H N R1

N COOR2

54

COOR2

55

N

Dehydrative cyclisation

TMS

OTf

N H

57 O H N

TBAT, 50oC N

R1

COOR2

COOR2

56

1. Alkylation 2. Cleavage of carbamates, Dehydrative cyclisation

Scheme 12.16 1H-indazoles and 2H-indazoles synthesis

N N

58

R3

426

S. L. Gupta et al. O

OH

O

N H

NH2OH.HCl, Cl3CCH (OH)2 60 61

H N

COCH3

Na2SO4, HCl, 3 h, 100°C

H3COC

N

CH

NH

N

62

59

H2SO4, refluxed

N N 63 H

OH

16 h 90°C; 90°C to 5°C

Br2

O

O

DMF, EDCI (66), Br Hydroxybenzotriazole (65)

Br N

N

RT

N H

67

OH

NHR

64

N H

Scheme 12.17 Synthesis of indazole derivatives

the tuberculosis by thermal shift assay and glutamate racemase enzyme inhibition assay and compound 11 and 22 were found most effective against replicating and non-replicating bacteria. Sirven et al. (2015) have synthesized indazole derivatives and in this methodology, firstly, 3-amino-4-methylbenzoic acid 68 reacted with C2 H5 OH in the presence of SOCl2 and converted into ester 69 which is converted into indazole 71 by the reaction of isopentyl nitrite 70 (Ruechardt et al.) in presence of acetic anhydride, potassium acetate and hydrochloric acid (Scheme 12.18). CH3

CH3 SOCl2, EtOH reflux, N2

O

68

N

i) Ac2O, AcOK, NH2 isopentyl nitrite 70, reflux, N2

NH2

NH

ii) HCl, 60°C

71

OH

O

69

OEt

OEt

O LiAlH4, THF,

N

N NH

74

0°C, N2

N NH

EtSH, KOH (1.5 eq)

MsCl, Et3N, EtOAc

reflux, EtOH-THF (1:1), N2

0°C, N2

SEt

73

OMs

Scheme 12.18 Multi-component reaction of indazole synthesis

NH

72

OH

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

427

Further, synthesized indazoles 71 reacted with LiAlH4 to reduced ester group into alcoholic group 72 which reacted with mesityl chloride in the presence of base triethylamine to furnished mesylate product 73. Finally, mesylate group is substituted by nucleophile ethane thiolate generated in situ from ethane thiol and potassium hydroxide and final product 6-(ethylthio)methyl indazole 74 is formed.

12.4 Synthetic Protocol of Pyrazolines Recently, N-acyl pyrazolines 77–79 have been prepared by Asad et al. (2021) by the reaction of chalcones 75 and hydrazine hydrate 76 using aliphatic acids (Scheme 12.19). Further, these pyrazolines were tested for antimicrobial using disk diffusion method and compound 79 was found most prominent against gram-positive and gram-negative bacteria. Compound 77–79 was also studied for inhibitory action against therapeutic agents. Further, this group used Hirshfeld analysis to check the inter- or intramolecular interactions between the molecules in the crystal packing (Spackman et al. 2009). O CH3

O NH2NH2.H2O 76 Br

75

N

N

CH3COOH

H3CO

Br

H3CO

77

O

O

CH3

N

N CH3CH2CH2COOH

75

Br

NO2

78

NH2NH2.H2O Br 76

NO2 O

O

N NH2NH2.H2O 76

H 3C S

CH3

CH3CH2COOH

75

CH3

N

H 3C

NO2

Scheme 12.19 Synthesis of pyrazolines from aliphatic acids

S

CH3

79

NO2

428

S. L. Gupta et al. COCH3

O

O Ar1CHO + 80

Ar2

81

CH3

Ar1

N2H4.H2O gla. CH3COOH Ar2 Ar

82

NH

N

1

83

or Ar1

Ar2

N

N

84

Ar2

Ar1 = S

Cl

Br O

O

Ar2 =

N H

Scheme 12.20 Synthesis of pyrazoline derivatives

Further, same methodology is also used by Mantzanidou et al. (2021) in ethanol using CH3 COOH (Scheme 12.20) and pyrazolines are screened for anti-inflammatory activity. Recently, Sultan et al. (2021) also used earlier methods for the preparation of pyrazolines 89 from α, β-unsaturated carbonyls 87 and hydrazine 88 (Scheme 12.21). α, β-unsaturated carbonyls are prepared form the condensation of acetophenones 85 and furane aldehyde 86 catalyzed by NaOH. All the prepared compounds are tested for antimicrobial assay using agar well-diffusion method (Fatima et al. 2018) and all compounds showed moderate to good activity against pathogens. Revanasiddappa et al. (2020) have synthesized pyrazolines 94 by the reaction of chalcones 92 and semicarbazide 93 using ethanol as solvent (Scheme 12.22). All synthesized compounds are tested for antidepressant activity and all compounds showed good to moderate activity. Antidepressant activity is done in-vivo by tail suspension test (TST) and forced swimming test (FST). Wahyuningsih et al. (2019) have synthesized N-acetyl pyrazolines 99 from α,β-unsaturated carbonyls 97 and hydrazine 98 in the presence of CH3 COOH O

O CHO

+ O

H 2N

85

86

O

NaOH EtOH

87

H2N

EtOH NH2NH2.H2O 88 N

NH O

89 H2N

Scheme 12.21 Synthesis of pyrazoline derivatives of furane aldehyde

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments … R2 R1

CH3 90

+

R2 NaOH

R1

EtOH

OHC

429

91

O

O 92 CH3OH NH2CONHNH2 NaOH 93 R2 R1 N

R1 = 4-Cl, 4-CH3, 4-OH, 4-NO2, 2,4-(Cl)2 R2 = 4-NO2, 4-Cl, 4-F, 2-Cl

94

N NH2

O

Scheme 12.22 Synthesis of pyrazoline derivatives from semicarbazide and chalcones

(Scheme 12.23). These pyrazolines were screened for cytotoxic activity against cancer cell lines and found that chloro-substituent in pyrazoline moiety increased the cytotoxic activity while hydroxy substituent decreased the cytotoxic activity. Jasril et al. (2019) have also synthesized pyrazolines 104 using same methodology, i.e., from chalcones 102 and hydrazine 103 catalyzed by glacial CH3 COOH under MW (Scheme 12.24). Synthesized chalcones tested for toxicity assay (LC50 ) which was determined by Brine Shrimp Lethality Test method and pyrazolines were studied for antioxidant activity by using diphenylpicrylhydrazyl. Compound 105 and 106 OCH3

OCH3 R1

R2

OCH3

+

95

CH3 OHC O

R1

NaOH

96

OCH3

R2

O

97 NH2NH2

AcOH

98

OCH3 R1

R1 = H,Cl, OH R2 = H, OH

OCH3

R2

N N CH3

99 O

Scheme 12.23 Synthesis of N-acyl pyrazoline derivatives

430

S. L. Gupta et al.

R1

R2 CH3 100

NaOH

+

R2

EtOH OHC

O

R1

O

101

102

CH3COOH R3NHNH3 103 EtOH

R1

R2

R1 =R2 =H, OCH3 R3 = H, C6H5

N 104

N R3

Scheme 12.24 Synthesis of pyrazoline derivatives under MW

H3CO

OCH3

H3CO

H3CO

O

O 105

106

N NH 107

Fig. 12.7 Synthesized biologically active compounds

were showed toxicity assay with LC50 while compound 107 showed high antioxidant activity (Fig. 12.7). Another methodology for the synthesis of pyrazoline derivatives 112 using chalcones 110 and hydrazine’s 111 have been developed by Sethiya et al. (2019) in glacial acetic acid under ultrasonic irradiation (Scheme 12.25). Chalcones 110 were prepared form acetanilides 108 and aromatic aldehydes 109 underneath ultrasonication using C2 H5 OH as solvent following Claisen–Schmidt mechanism. Prepared pyrazolines were tested for anti-inflammatory activity via carrageenan-induced rat paw edema inhibition process and all pyrazolines showed remarkable activity. Zhang et al. (2019) have synthesized pyrazoline derivatives 117 from chalcones 115 and hydrazine hydrate 116 underneath reflux condition using acetic acid (Scheme 12.26). Chalcones 115 is synthesized from acetophenones 113 and cuminaldehyde 114 catalyzed by NaOH in ethanol. These synthesized compounds are tested for antifungal activity and pyrazoline 118 (R = 2-F) showed highest antifungal activity.

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments … NHCOCH3

431 R

CHO H N

US

+

2N NaOH

108

O

110 NHNH2

R 109

US Gla. CH3COOH

111 R R = NO2, Cl, F, CH3, OH

N

N

112

Scheme 12.25 Synthesis of pyrazoline derivatives under sonication

CHO

O

COCH3

O

N

NaOH

CH3 +

C2H5OH

R

R

AcOH N2H4.H2O Reflux 116

115

113

R

N

117

R = 2-CH3, 2-Br, 2-Cl, 2-F, 3-CH3, 3-Br, 3-Cl, 3-F, 4-CH3, 4-Br, 4-Cl, 4-F,

114 COCH3 N

F

N

118

Scheme 12.26 Synthesis of pyrazolines in the presence of acetic acid

Novel pyrazolines 121 were synthesized by Kaka et al. (2019) by the reaction of 2,6-dibenzylidenecyclohexanone 119 and thiosemicarbazide 120 in ethanol and DMSO (Scheme 12.27). Annes et al. (2018) have established a methodology for the preparation of pyrazolines 125 from aldehyde 122, styrene 123 and phenylhydrazine 124 mediated by TfOH (Scheme 12.28). Alkaloid 126 is synthesized using this protocol which is found in Euphorbia guyoniana. Kedjadja et al. (2018) have synthesized pyrazolines 131–132 and bis-pyrazolines 135–136 containing quinoline moiety from chalcones 129 and hydrazine hydrate 130 in BF3 . Et2 O or in CH3 COOH (Scheme 12.29 and 12.30). Chalcone 129 of 3acetyl-2-methylquinoline derivatives 127 is prepared from aromatic aldehydes 128 in presence of NaOH using ethanol as solvent (Kotra et al. 2010).

432

S. L. Gupta et al. O N NH

X

X

119

C2H5ONa + DMSO

+

X

S H2N

N H 120

X

121 X = H, Br, N(CH3)2, OCH3, NO2

NH2

Scheme 12.27 Synthesis of novel pyrazolines

CHO R Ph + ArNHNH2

+

122

R

TfOH/MeCN 30 oC

124

N

123 R = H, 4-Me, 4-OMe, 3-OMe, 4-Br, 4-Cl, 4-F, 4-NO2, 2-NO2, 2-OH, Ar = C6H5, 4-MeC6H4

Ar

N

Ar

125

Ph

N Ph

Ph

N

126

Scheme 12.28 TfOH catalyzed pyrazoline synthesis

Fluorinated pyrazolines 139 have been synthesized by Salim et al. (2018) from chalcones 137 and hydrazine’s 138 under reflux condition in ethanol (Scheme 12.31). A microwave-assisted protocol for the preparation of coumarin–pyrazolines 146 have been established by Akhtar et al. (2017) from chalcones 144 and hydrazine 145 in ethanol acetic acid solvent (Scheme 12.32). All compounds were tested for antimalarial and antimicrobial activity. Antimalarial activity is done by schizont maturation inhibition assay and compound 146 (R = 3,4,5-(OCH3 )3 ) showed highest antimalarial and antimicrobial activity. Hegde et al. (2017) have prepared pyrazoline derivatives 155 from chalcones 149 and hydrazine derivative 154 insolvent PEG-400 catalyzed by NaOH (Scheme 12.33). Chalcones 149 are prepared from 2-acetyl thiophene 147 and aromatic aldehyde 148 catalyzed by NaOH using ethanol as solvent and the hydrazine derivative 154 is synthesized by the reaction of ethyl [(5-chloroquinolin-8yl)oxy]acetate 152 and hydrazine 153. All the prepared compounds were experienced

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

433

O

O EtOH, PhCHO (1eq)

R

R

128

127

NaOH (1.1eq)

N

129

N

AcOH, reflux, 6h H2NNH2·H2O (1.1 eq.) 130

DMF, BF3·OEt2 H2NNH2·H2O (1.1 eq.) 130

O

O N

N

N

N

R

R N

N

132

131

Scheme 12.29 Synthesis of pyrazolines containing quinoline moiety

O N

R

O R

EtOH, NaOH (2.2eq)

N

terephthalaldehyde (0.5eq.), r.t

N

R

134

O

133

127

DMF, BF3·OEt2 H2NNH2·H2O (2.2 eq.)

AcOH, reflux, 6h H2NNH2·H2O (2.2 eq.)

HCOOH, Reflux

O

130

O N

N

130

N N

R

N

R

N

R

N

N

136

R

135

N

N

N

N

O

O

Scheme 12.30 Synthesis of bis-pyrazolines containing quinoline moiety O

R

R1

EtOH, Reflux R

137

R1

N

R2NHNH2 138

Scheme 12.31 Synthesis of fluorinated pyrazolines

R2

N

139

434

S. L. Gupta et al. O

R

141

H

140

OH

O

O

Ethylacetoacetate,

O

O

Aldehyde 143

n-BuOH, reflux

Ethanol, piperidine, reflux

142

144

O

O

ethanol:acetic acid (1:1), Hydrazines 145 Microwave O

O

R1 = 3,4-(OCH3)2, 3,4,5-(OCH3)3, 4-CH3, 4-Cl, 3-OCH3 R2 = COCH3, C6H5

R

N

N

146

R1

Scheme 12.32 Synthesis of coumarin–pyrazoline derivatives

O S 147

+ ArCHO CH 148

Ar S

3

Cl

O

NaOH, EtOH 149

PEG-400 NaOH

Cl

Cl

N O

Cl K2CO3, Acetone N OH 150

OEt

Cl O 151

NH2NH2 N

153

N

N

O

O

O

O

Ar S

OEt 152

O

N

155

NHNH2 154

Scheme 12.33 Synthesis of thiophene substituted pyrazoline derivatives

for antibacterial and antioxidant properties but pyrazoline Ar = 4-NO2 C6 H4 showed both antibacterial and antioxidant activities. Cerium chloride heptahydrate-catalyzed methodology for the preparation of pyrazolines 160 has been established by Bhat et al. (2017) from chalcones 158 and hydrazine hydrate 159 in a green solvent ethyl lactate under reflux condition (Scheme 12.34). Mechanistically, Cerium chloride heptahydrate increased the electrophilic nature of carbonyl carbon by binding with oxygen atom and facilitated the nucleophilic attack of hydrazine to chalcones. 1,3,5-Trisubstitued pyrazolines 170 have been synthesized by Liu et al. (2016) form ferrocenyl chalcones 169 and hydrazine derivative of pyrimidine 167 under conventional heating (Scheme 12.35). Compounds 164–168 have been synthesized according to literature (Pavia 2009). Further, this group also recorded fluorescence spectra of synthesized pyrazoline derivatives in tetrahydrofuran, chloroform, and dichloromethane and emission wavelength was found around 422–434 nm.

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments …

435 Ar1

O

O

Ar1

CH3

Ar2CHO

Ethyl lactate (70%), Reflux PhNHNH2 159

Ar1

157

156

Ar2

CeCl3.7H2O (20mol%)

NaOH

N

Ar2

158

N

160

Ph

Ar1 = C6H5, 4-CH3C6H4, 4-OCH3C6H3 Ar2 = 4-CH3C6H4, 4-ClC6H4, 4-(CH3)2NC6H4, 4-MeOC6H4, 4-NO2C6H4, 3-NO2C6H4, 4-CH3C6H4, 3-NO2C6H4, 2-ClC6H4, 3,4-diMeOC6H3, 3-NO2C6H4

Scheme 12.34 CeCl3 .7H2 O catalyzed pyrazoline synthesis

O

O

CHO O

O

+

+

H2N H2N

EtO

162

161

O 163

NH

AlCl3 EtO EtOH, reflux

HNO3

O N H 165

O

N H 164

EtO

O

N

EtO

POCl3

EtOH, reflux

O Ar

N

Fe

N

O

169

O

NH2NH2 167

N N

170

Fe

NaOH, CH3COOH, ArCHO EtOH, reflux

N

EtO N H 168

EtOH, reflux NHNH2

N

EtO N H 166

Cl

Scheme 12.35 Synthesis of trisubstituted pyrazolines

Another important pyrazoline derivatives 179 with the combination of imidazole ring have been synthesized by Ebrahimzadeh et al. (2016) (Scheme 12.36). Initially, this group synthesized imidazole-5-carboxaldehyde derivatives 175 according to literature (Ebrahimzadeh et al. 2004b) which reacted with acetophenones 176 to furnished chalcone derivatives 177. Finally, chalcones 177 reacted with hydrazine derivative 178 to furnished final pyrazoline derivative containing imidazole ring 179. A green and environmentally friendly methodology for the preparation of pyrazolines 182 has been established by Punyapreddiwar et al. (2016) using saccharomyces cerevisiae as biocatalyst at room temperature using methanol as solvent (Scheme 12.37). A new pyrazoline derivative 187–188 of vanillin analog has been synthesized by Karangiya et al. (2016) by the reaction chalcones 185 and hydrazine hydrate 186 (Scheme 12.38). Chalcones were prepared from aldehyde of vanillin analog and acetophenone derivatives. Further, this group check the effect of presence of acetic

436

S. L. Gupta et al.

R1NH2 + HO 171

OH O 172

N

N

KSCN n-BuOH AcOH

HS

OH

OH-

OH

H3CS

DMS

N R1 173

N

COCH3

H3CS

OHN

177

MnO2

CHCl3 176

R2

174

R1

R2

N H3CS

N

CHO

N R1

O

175

R1 R3NHNH2 178 R2

N H3CS

N

N

R1

R3

N 179

Scheme 12.36 Synthesis of pyrazoline derivatives containing imidazole ring R2

NH2NH2.H2O 180

R2

R1

+

Saccharomyces cerevisiae

R1

MeOH, RT O

N

181

182

NH

R1 = H, 4-OH, 2-OH, 3,4-OCH3 R2 = H, 4-NO2, 4-Cl, 4-OCH3, 4-N(CH3)2

Scheme 12.37 Baker’s yeast catalyzed pyrazoline synthesis Cl

Cl

Cl

OCH3 O

183

+ RCOCH3 184

Cl

OCH3 O

20% NaOH

R

185

CHO

O

CH3COOH Cl

NH2NH2.H2O 186

NH2NH2.H2O 186

Cl

Cl

OCH3

Cl

OCH3 O

O

N N

187 O

Scheme 12.38 Synthesis of vanillin analog pyrazolines

188

HN N

12 Pyrazoles, Indazoles and Pyrazolines: Recent Developments … CHO

O CH3 189

CHO

O

N N

NaOH

+ 190

R

C2H5OH

437

HCOOH 191

R

NH2NH2.H2O 192

193

R

Scheme 12.39 Synthesis of pyrazolines in the presence of formic acid

acid and found that N-protected by acetyl group pyrazolines 187 formed in presence of acetic acid while without acetic acid n-unprotected pyrazolines 188 were formed. All synthesized compounds showed good antimicrobial activity against different strains of bacteria such as B. subtilis, S. aureus and P. aeruginosa. Another methodology for the preparation of pyrazolines 193 have been established by Tanwar et al. (2015) from α, β-unsaturated carbonyls 191 and hydrazine 192 catalyzed by formic acid (Scheme 12.39) and α, β-unsaturated carbonyls 191 were prepared from acetophenone 189 and aldehydes 190 in the presence of sodium hydroxide using ethanol as solvent.

12.5 Conclusion Since the synthesis of diversified and medicinal important pyrazoles, indazoles and pyrazolines have attraction from many years and recently, many articles have been published from many authors which show many important biological properties of these compounds. We, trying to summarize recent articles published on these compounds in this chapter but the synthesis of distinctly important pyrazoles, indazoles and pyrazolines relics one of the challenges of organic chemistry and needs attention.

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Rangaswamy J, Kumar HV, Harini ST et al (2012) Synthesis of benzofuran based 1, 3, 5-substituted pyrazole derivatives: as a new class of potent antioxidants and antimicrobials-A novel accost to amend biocompatibility. Bioorganic Med Chem Lett 22:4773–4777 Ragab FA, Gawad NMA, Georgey HH et al (2013) Synthesis of novel 1, 3, 4-trisubstituted pyrazoles as anti-inflammatory and analgesic agents. Eur J Med Chem 63:645–654 Rey M, Beaumont S (2019) Molybdenum-mediated one-pot synthesis of pyrazoles from isoxazoles. Synthesis 51:3796–3804 Rakhtshah J, Salehzadeh S, Gowdini E et al (2016) Synthesis of pyrazole derivatives in the presence of a dioxomolybdenum complex supported on silica-coated magnetite nanoparticles as an efficient and easily recyclable catalyst. RSC Adv 6:104875–104885 Rüchardt C, Hassmann V (1972) Simplification of the Jacobson indazole-synthesis. Synthesis 375 Ruechardt C, Sauer J, Sustmann R (2005) Rolf huisgen: some highlights of his contributions to organic chemistry. Helv Chim Acta 88:1154–1184 Revanasiddappa BC, Kumar MV, Kumar H (2020) Synthesis and antidepressant activity of pyrazoline derivatives. Dhaka Univ. J. Pharm. Sci. 19:179–184 Sener ¸ A, Kasim Sener ¸ M, Bildmci I et al (2002) Studies on the reactions of cyclic oxalyl compounds with hydrazines or hydrazones: Synthesis and reactions of 4-benzoyl-1-(3-nitrophenyl)-5-phenyl1H-pyrazole-3-carboxylic acid. J Heterocycl Chem 39:869–875 Se-Ho K, Benjamin M, Richard T et al (2013) Discovery of a new HIV-1 inhibitor scaffold and synthesis of potential prodrugs of indazoles. Bioorg Med Chem Lett 23:2888–2892 Swathi V, Shine S, Dhanya K et al (2019) A review on the CNS activity of pyrazolines. J Med Sci Clin Res 7:612–618 Sauzem PD, Sant’Anna GDS, Machado P et al (2009) Effect of 5-trifluoromethyl-4, 5-dihydro-1Hpyrazoles on chronic inflammatory pain model in rats. Eur J Pharmacol 616:91–100 Shaharyar M, Abdullah MM, Bakht MA et al (2010) Pyrazoline bearing benzimidazoles: search for anticancer agent. Eur J Med Chem 45:114–119 Sano T, Fujii T, Nishio Y et al (1995) Pyrazoline dimers for hole transport materials in organic electroluminescent devices. Jpn J Appl Phys 34:3124 Soltanzadeh Z, Imanzadeh G, Noroozi-Pesyan N et al (2017) Green synthesis of pyrazole systems under solvent-free conditions. Green Chem Lett Rev 10:148–153 Solomin VV, Seins A, Jirgensons A (2021) Synthesis of indazoles from 2-formylphenylboronic acids. RSC Adv 11:22710–22714 Shamsabadi A, Chudasama V (2018) A facile route to 1 H-and 2 H-indazoles from readily accessible acyl hydrazides by exploiting a novel aryne-based molecular rearrangement. Chem Commun 54:11180–11183 Sirven AM, Stefak R, Rapenne G (2015) Improved synthesis of 6-[(ethylthio) methyl]-1H-indazole. Heterocycl Commun 21:5–8 Spackman MA, Jayatilaka D (2009) Hirshfeld surface analysis. Cryst Eng Comm 11:19–32 Sultan MI, Abdula AM, Faeq RI et al (2021) Synthesis, characterization, and antimicrobial evaluation of new pyrazolines incorporating imine moiety. In J Phy Conf Ser 1853:012043 Sethiya JP, Bhavsar SP, Shahare HV (2019) Synthesis of potential anti-inflammatory pyrazoline derivatives under ultrasonic irradiation. Int J Pharmaceu Sci Res 10:3290–3294 Salim AS, Girgis AS, Basta AH et al (2018) Comparative DFT computational studies with experimental investigations for novel synthesized fluorescent pyrazoline derivatives. J Fluoresc 28:913–931 Tafti AD, Mirjalili BBF, Bamoniri A et al (2021) Rapid four component synthesis of dihydropyrano [2, 3-c] pyrazoles using nano-eggshell/Ti (IV) as a highly compatible natural based catalyst. BMC Chem 15:1–8 Tanwar N, Rana D, Kaur R et al (2015) Synthesis and characterization of Pyrazoline derivatives. J Integr Sci Technol 3:39–41 Vicentini CB, Romagnoli C, Andreotti E et al (2007) Synthetic pyrazole derivatives as growth inhibitors of some phytopathogenic fungi. J Agric Food Chem 55:10331–10338

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Chapter 13

Synthesis of Bioactive Thioxoimidazolidinones, Oxazolidinones, Thioxothiazolidinones, Thiazolidinediones Esmail Doustkhah and Fatemeh Majidi Arlan

13.1 Thiazolidine 13.1.1 Introduction The Thiazolidine family is an important class of five-membered heterocyclic compounds composed of a sulfur atom at position 1, a nitrogen atom at position 3, and various substitutions on 2, 4 and 5 positions responsible for various bioactive compounds properties. Thiazolidine and its derivatives are key motifs of numerous natural products and drugs and are also present in many synthetic bioactive compounds (Manjal et al. 2017a, b; Deep et al. 2016; Jain et al. 2012; Mobinikhaledi et al. 2010; Cunico et al. 2008; Cantello et al. 1994). Thiazolidine 4-one and thiazolidine 2,4-dione (Fig. 13.1) are among the most prominent structures of the thiazolidine family and are considered crucial compounds from a pharmaceutical point of view. Carbonyl groups in positions 2 and 4 create thiazolidinone and thiazolidinediones with wide variety of activities such as anti-tubercular, antiparasitic (Zehetmeyr et al. 2018; Moreira et al. 2012), antimicrobial (Sankar et al. 2017; Deep et al. 2015; Agarwal et al. 2014), anti-inflammatory (Ma et al. 2011; Barros et al. 2010; Geronikaki et al. 2008), anticancer (Osmaniye et al. 2017; Havrylyuk et al. 2013; Zhang et al. 2010; El-Gaby et al. 2009), and as anti-HIV agent (Jiang et al. 2011; Murugesan et al. 2009; Barreca et al. 2002). Figure 13.2 shows the structure of some drugs with thiazolidine core.

E. Doustkhah (B) Koç University Tüpra¸s Energy Center (KUTEM), Department of Chemistry, Koç University, Istanbul 34450, Turkey F. M. Arlan Research Department of Chemistry, Iranian Academic Center for Education, Culture and Research, Urmia, Iran © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 K. L. Ameta et al. (eds.), N-Heterocycles, https://doi.org/10.1007/978-981-19-0832-3_13

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Fig. 13.1 The general structure of thiazolidine 4-one, and thiazolidine 2,4-dione

Fig. 13.2 Some examples of thiazolidine-based drugs

Versatile applications of thiazolidineone scaffolds shed light on the importance of efficient procedures and synthetic routes to access various thiazolidineone derivatives. Condensation reactions of amine and aromatic aldehydes and tioglycolic acid through one-pot or two-step processes are classical procedures reported to synthesize these compounds. In the past few years, various synthetic pathways, including solvent-free reactions, microwave assistance, sonication reactions, nontoxic solvents in the presence of a wide variety of catalysts, have been introduced. Although various homogeneous and heterogeneous catalysts have been employed to synthesize substituted thiazolidinones, designing new greener and cleaner synthetic strategies to access new well-derivatized thiazolidines remains an active field of research. Based on the aforementioned facts and special attention paid to novel multifunctional nanocatalysts as a worth researching topic, this chapter mainly emphasizes much greener approaches toward synthesizing thiazolidine derivatives with nanocatalysts’ role-playing.

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13.1.2 Nanocatalytic Processes to Synthesis of 1,3-Thiazolidine-4-Ones 1,3-Thiazolidine-4-ones are privileged heterocyclic structures present in natural and synthetic pharmaceutical and agricultural compounds which exhibit a wide variety of biological activities (Manjal et al. 2017a, b; Deep et al. 2016; Jain et al. 2012; Mobinikhaledi et al. 2010; Cunico et al. 2008; Cantello et al. 1994). Rosiglitazone (1) and Pioglitazone (3) are essential derivatives of the thiazolidineone family, known as commercial drugs with hypoglycemic action to treat diabetes (Fig. 13.2). Nowadays, the diverse biological activity of thiazolidineones has convinced researchers to conduct innovative novel procedures to synthesize these scaffolds. A novel zeolite-based nanocomposite was synthesized and used as a multifunctional nanocatalyst for the multicomponent synthesis of 3-benzimidazolyl1,3-thiazolidin-4-ones and 3-benzthiazoleyl-1,3-thiazolidin-4-ones (7) A mixture including appropriate amounts of various aryl aldehydes 2-aminobenzimidazole or 2-aminobenzothiazole, and thioglycolic acid and 5% of the nanocatalyst was mixed at ambient temperature to obtain the corresponding thiazolidineones. Nano-Ni/SO3 H@ Zeolite-Y activates the carbonyl group of the aldehyde by SO3 H functional group and nickel ions on the surface of zeolite to produce the related corresponding intermediates final products under mild conditions (Scheme 13.1). Broad substrate scope, reduced reaction time, high yields, operational simplicity, nontoxic nature of the catalyst, and reusability are beneficial features of this methodology (Kalhor and Banibairami 2020). A similar reaction was carried out in the presence of Ni@zeolite-Y. Diverse 1,3-thiazolidine-4-ones were synthesized through a condensation reaction of 2aminobenzimidazole, aromatic aldehydes, and 2-mercaptoacetic acid in the presence of a highly efficient nanoporous catalyst (Scheme 13.2). The mixture of raw materials and 10% W of Ni@ Zeolite-Y as nanocatalyst was stirred in EtOH under mild conditions to afford the corresponding thiazolidineones. The results revealed that aryl aldehydes possessing both electron-rich and electron-deficient substituents reacted efficiently to produce the desired products in good yields; however, by applying aliphatic aldehydes, the yield of the related products did not improve. Mentioned

Scheme 13.1 Synthetic strategy for 1,3-thazolidin-4-one derivatives applying Ni/SO3 H@ ZeoliteY

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Scheme 13.2 Synthetic procedure for thiazolidine4-one derivatives

data may suggest that donor–acceptor interactions between empty d-orbital of Ni ions and the π-electrons of the aromatic ring are key drivers to enhance the process. Short reaction time, simple separation of products, reusable catalyst, and high yields are notable advantages of this methodology (Kalhor et al. 2018). Based on several beneficial aspects of sonochemistry, such as high yields, product selectivity, reduced reaction time, minimized chemical pollution, and mild reaction conditions, special attention has been paid to applying ultrasound waves in chemical processes (Pagadala et al. 2014; Ziarati et al. 2013; Leonelli and Mason 2010). The possibility of conducting multicomponent reactions under ultrasonic irradiation in the presence of a heterogeneous catalyst could improve the procedure’s efficiency from both cost-effectiveness and environmental perspectives (Cunico et al. 2007, 2008; Sivastava et al. 2002). A facile and straightforward ultrasound-mediated catalytic procedure for synthesizing 1,3-thiazolidine-4-ones through multicomponent condensation reaction was developed (Scheme 13.3). A mixture of aldehydes, aromatic amine, thioglycolic acid, and nano-CdZr4 (PO4 )6 ceramics were sonicated at 60w power to afford the desired product. Nano CdZr4 (PO4 )6 ceramics have gained fame due to their unique properties and potential applications (Safaei-Ghomi et al. 2015; Gorodylova et al. 2013), and the results of this study also verified the high efficiency of these nanoceramics. Investigation upon reaction scope showed better yields for aromatic aldehydes with electron-withdrawing groups than those with electron-releasing groups. Environmentally-friendly procedures, reusable catalysts, simple work-up, short reaction times, and the use of ultrasound irradiation as a green and powerful technology are beneficial features of this protocol (Safaei-Ghomi et al. 2016a).

Scheme 13.3 Synthesis of 1,3-thiazolidine4-one derivatives using nano-CdZr4 (PO4 )6

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An efficient and straightforward, pseudo-five component synthesis of bisthiazolidineones (8) from substituted aromatic aldehydes, ethylenediamine, and thioglycolic acid using nano-CdZr4 (PO4 )6 as a robust catalyst was developed (Scheme 13.4). The catalyst may provide the surface to carry out the reaction, and it was observed that little catalyst loading sufficed the process to obtain the corresponding products in good yield (Safaei-Ghomi et al. 2016b). Nano-CoFe2 O4 @SiO2 /PrNH2 was another nanocatalyst employed to synthesize 1,3-thiazolidine-4-one via one-pot reaction of one-pot reaction aniline, substituted benzaldehyde, and thioglycolic acid in different solvents (Scheme 13.5). The catalyst was highly efficient and robust and was reusable for seven progressive cycles. The novel catalytic reaction was carried out using various aromatic aldehydes and aniline. It was observed that aldehydes with electron-donating groups reacted longer than those with electron-withdrawing groups. Reduced reaction time, operational simplicity, and recoverable nanocatalyst merits this methodology (Safaei-Ghomi et al. 2016c). FeNi3 on ionic liquid modified-magnetic nanoparticle was a robust, stable, and inexpensive nanocatalyst introduced to one-pot solvent-free synthesis of 1,3thiazolidin-4-one derivatives (7) from amine, aldehyde, and thioglycolic acid (Scheme 13.6). Ionic liquids supported on FeNi3 nanocatalyst made the process eco-friendly and highly synthetic importance. Neat and mild reaction conditions and applying immobilization techniques are advantageous for this method (Sadeghzadeh and Daneshfar 2014).

Scheme 13.4 Synthesis of bis-thiazolidineones applying nano-CdZr4 (PO4 )6

Scheme 13.5 Synthesis of 1,3-thiazolidine-4-ones using nano-CoFe2 O4 @SiO2 /PrNH2

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Scheme 13.6 Synthesis of 1,3-thiazolidine-4-ones applying FeNi3 -IL MNPs

Scheme 13.7 Synthesis of 1,3-thiazolidine-4-ones applying MNP@SiO2 -IL

Nano-Fe3 O4 @SiO2 -IL was the fourth nanocatalyst employed for the synthesis of substituted thiazolidinones (Scheme 13.7). With a little catalyst loading, the mixture of aryl aldehydes, aniline, and thioglycolic acid was heated at 70°C under neat conditions and resulted in the product. The performance of the catalyst in different solvents was also investigated in this research and the higher efficiency was obtained under solvent-free conditions at 70 °C in the presence of MNPs@SiO2 -IL. Furthermore, the catalyst was reusable for ten runs without considerable loss in the activity (Azgomi and Mokhtary 2015).

13.2 Thiazolidine-2,4-dione 13.2.1 Introduction Hydantoin and thiazolidinedione are assumed as privileged and multifunctional motifs in medicinal chemistry which are mostly core structures of drugs and various bioactive agents and are vital intermediates for the synthesis of anti-HIV and antidiabetic agents (Nanjan et al. 2018). These heterocyclic compounds are essential due to

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their broad therapeutic effects and pharmacological activities. Among thiazolidine2,4-dione derivatives, Rosiglitazone and Pioglitazone are clinically approved antidiabetic drugs. As a consequence of the gravity of these frameworks, the molecular modification and synthesis of diverse derivatives have been paid much attention from a synthetic point of view, and numerous catalytic processes for the synthesis of their derivatives have been developed. However, most of the methodologies suffer from low yields, long reaction times, harsh reaction conditions, tedious work-up procedures, and toxic residues (Chen et al. 2019). Designing economically feasible and environmentally benign recyclable heterogeneous catalysts that could provide mild conditions and minimize waste is of great value. In this regard, during recent years, the nanocatalytic processes have gained significant attention in many organic transformations. Applying environmentally-friendly recoverable catalysts with reduced pollution that work for the target reaction is of great demand. Among novel catalysts, magneticbased nanocatalysts offer unique features such as easy preparation and functionalization, considerable durability, high surface area, low toxicity, and straightforward recovery via external magnet; that affirmed magnetic catalysts as a highly efficient and versatile catalyst.

13.2.2 Nanocatalytic Approaches to Gain Thiazolidinediones Copper has been found as an efficient catalyst for aldolization reaction in high yields, and thus, Fe3 O4 @PABA-Cu MNPs was proposed as a robust and multifunctional nanocatalyst for the synthesis of 5-arylidenthiazolidine-2,4-diones (9) through aldol condensation between substituted aromatic and heteroaromatic aldehydes and hydantoin or thiazolidin-2,4-dione, in ethanol as a green solvent (Scheme 13.8). The recyclability of the copper functionalized nanocatalyst under optimized reaction conditions was investigated, and it was observed that the catalyst is reusable for seven cycles with no efficiency loss. High yields in short reaction time, less toxicity, and operational simplicity are clear merits of this method over conventional catalytic methodologies (Esam et al. 2020).

Scheme 13.8 Synthesis of 5-arylidenthiazolidine-2,4-diones and 5-arylidene-imidazolidine-2,4dione derivatives in the presence of Fe3 O4 @PABA-Cu(II)

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A novel catalytic approach for the diastereoselective synthesis of well-structured hydantoins through hybrid nanocatalyst with high potential and efficiency is developed recently (Ghomi et al. Safaei-Ghomi and Bakhtiari 2019). The nanocatalyst, W (iv)/NNBIA-SBA-15, was synthesized via covalent grafting on chloro-functionalized SBA-15, followed by the anchoring of WCl6 to gain the desired catalyst. Then the efficiency of the synthesized catalyst was assessed through a multicomponent reaction of diverse carbonyl compounds, malononitrile, and hydantoin, to achieve (10) and (11) (Scheme 13.9). The reaction was carried out by applying various aldehydes, and the results disclose that the reaction progressed well with aldehydes bearing both electron-donating and electron-withdrawing groups. Furthermore, the presence of diverse isatin compounds has improved the reaction’s yields and diastereoselectivity. It is worth noting that the two hydrogens connected to the adjacent chiral carbon are trans; however, the multicomponent reaction created a cis fused scaffold. Using isatin, one diastereomer of a racemic mixture of highly strained spirooxindole with a quaternary stereocentre was produced. Analyzing the structure of hydantoin shed light on the plausible role of hydantoin. Hydantoin can play the role of a 1,3-binucleophile by using the (CH2 ) and the (O) of the amide and as well the role of a 1,2-binucleophile while using the (CH2 ) and the adjacent (N.H.) as shown below. Hydantoin also acts as 1,2-binucleophile. Modifying mesoporous SBA-15 with tetradentate ligands, increased active sites, high recyclability, and, more importantly, diastereoselectivity that are notable positive features of the reported method. Fe3 O4 MNPs have gained special attention among diverse heterogeneous catalysts due to eco-friendliness, facile recovery, high efficiency, and biocompatibility (Zhang et al. 2013). A sustainable and high-performance protocol in the presence of Fe3 O4 MNPs for one-pot synthesis of phenytoin derivatives from readily available

Scheme 13.9 Synthesis of spirooxindole-2-azapyrrolizidine and 2-azapyrrolizidine derivatives

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Scheme 13.10 One-pot synthesis of phenytoin derivatives

α-hydroxyketones and urea was developed (Scheme 13.10). The magnetic nanoparticles were reusable for up to five cycles with no special treatment. Reduced reaction time, easily accessible starting materials, and minimized chemical waste are beneficial aspects of this procedure (Li et al. 2018).

13.3 Oxazolidinones 13.3.1 Introduction Oxazolidinones are of significant importance among various bioactive molecules (Naresh et al. 2014). For instance, cytoxazone, a selective immunomodulatory inhibitor, is considered as an essential member of this family that inhibits the signaling pathway of Th2 cells (Reddy et al. 2010). Moreover, oxazolidinones recently have emerged as antibiotics, and Linezolid (Nasibullah et al. 2015), an FDA-approved drug, contains oxazolidinone scaffolds (Fig. 13.3). Indeed, this family is used as chiral auxiliaries and is commonly used to source 1,2 amino alcohols (Heravi and Zadsirjan 2013; Kerr et al. 2012). Generally, a well-established approach for the synthesis of oxazolidinone derivatives is the functionalization of amino alcohols with carbonyl derivatives; however, aziridines or epoxides are further used as substrates in carbonyls’ place (Yang et al. 2012; Watile et al. 2011). Modern catalytic processes have emerged as outstanding and convergent approaches for preparing desired scaffolds. Fig. 13.3 Examples of biologically active oxazolidinones

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13.3.2 Nanocatalytic Synthesis of Oxazolidinones A novel and well-designed catalytic methodology for synthesizing diverse 2oxazolidinones (15) has been reported via the reaction of easily accessible propargyl amines and CO2 in the presence of Pd NPs which were supported on porous organic polymers (POP) (Scheme 13.11). Yamada and co-workers initially reported this caboxylative cyclization of N-propargylamine derivatives applying carbon dioxide to afford the corresponding oxazolidinones (Ren et al. 2014). However, POP’s Pd NPs-loaded porous organic polymer is competitive with the previously reported methods. Initially, microporous polymeric materials of BBA-1 and BBA-2 (benzenebenzylamine), a porous organic polymer, were synthesized through Friedel–Crafts alkylation of benzene and benzylamine by applying formaldehyde dimethyl acetal and anhydrous FeCl3 as a cross-linker and a promoter, respectively. Ultimately, Pd NPs were decorated over BBA-1 and BBA-2 to produce the desired Pd@BBA-1 and Pd@BBA-2. The efficiency of created Pd NPs was assessed through the carboxylative cyclization reaction of both internal and terminal alkynes with atmospheric CO2 in DMSO as solvent at 40–80°C with 30–60 mg catalyst. It was revealed that the newly synthesized nanocatalyst exhibited outstanding catalytic performances for the synthesis of oxazolidinones in the absence of neither organic nor inorganic bases. Furthermore, the novel nanocatalyst Pd@BBA-2 performed extraordinary recycling efficiency, up to five runs, with no noticeable decay in its activity (Ghosh et al. 2020). Recently, the application of solid acids as heterogeneous catalysts in organic transformations due to their unique recoverability and high performance has been drastically increased. In this regard, heteropoly acid compounds based on their strong Bronsted acidity, non-corrosive nature, eco-compatibility, energy-efficiency, and low-environmental impact have emerged as proper substituents to homogeneous acidic catalysts (Meireles et al. 2018; Yuan et al. 2017; Liu et al. 2017). However, some problems such as small surface area and low availability of the active sites for reactants are common applying HPA in bulk type. Further investigations revealed that the stability of the HPA can be improved via immobilization onto suitable supports.

Scheme 13.11 Pd NPs-applied cyclization process for the synthesis of oxazolidinones from CO2 and various unsaturated amines

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Scheme 13.12 Synthesis of 5-benzoyl-4-phenyloxazolidin-2-one MnFe2O4@CS@PTA as nanocatalyst

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derivatives

applying

Recently, Chitosan is used as a support to immobilize the HPA. Magnetic chitosanbased multifunctional nanocatalyst is utilized to synthesize substituted oxazolidine2-ones (16, 17) from α-epoxyketones, urea, or thiourea, in green media at 60 °C (Scheme 13.12). The operational multiplicity of chitosan stems from primary and secondary hydroxyl and amino groups in its scaffold, which enables chitosan to exhibit both electrophilic and nucleophilic behaviors. Therefore, chitosan plays a key role in the efficiency of synthesized MnFe2 O4 @CS@PTA nanoparticles (Mozafari et al. 2019).

13.4 Rhodanine and Thiohydantoin 13.4.1 Introduction Five-membered heterocyclic systems based on the core of 1,3-thiazolidine and imidazolidine have been widely investigated because of a broad spectrum of biological activities (Manjal et al. 2017a, b; Vengurlekar et al. 2012). Derivatives including exocyclic sulfur and oxygen atoms, such as rhodanine or thiohydantoin (Fig. 13.4) based on the presence of double-bonded atoms are of particular interest since such bonds along with functional groups might result in a high density of active binding sites for polar interactions and hydrogen bonds; which are responsible for biological activities (Mendgen et al. 2012). Strong polar and the electron-withdrawing trait are other significant features of such scaffolds that make them appropriate anchoring and electron-accepting groups in preparation of merocyanine dyes for organic dyesensitized solar cells (DSSC) (Sivanadanam et al. 2018; Narayanaswamy et al. 2015; Chang et al. 2013). Fig. 13.4 The general structure of rhodanine and 2-thiohydantoin

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Scheme 13.13 Synthesis of rhodanine and thiazolidine derivatives using Fe3 O4 @SiO2 -NH2 /Cu

13.4.2 Nanocatalytic Transformation for the Synthesis of Rhodanine and Thiohydantoin An efficient and worth-noting condensation reaction for the synthesis of thiazolidinedione derivatives was developed by employing copper functionalized magnetic nanoparticles (Scheme 13.13). A mixture of the proper amount of aliphatic and aromatic aldehydes and rhodanine or thiazolidin-2,4-dione derivatives with catalytic loading of Fe3 O4 @SiO2 -NH2 -Cu MNPs was refluxed in EtOH (Akhavan et al. 2017). The broad substrate scope, high yields, sustainable reaction conditions, and reusable catalysts are beneficial aspects of the mentioned process. The exhibition of a broad spectrum of biological and pharmaceutical activities of sulfur-oxygen-containing heterocycles is critical to developing diverse synthetic methodologies. Acidic reaction conditions are imperative to conduct most reactions. However, considering the disadvantages of homogeneous acid catalysis, such as chemical pollution, tedious separation, and the need for neutralizing to quote only a few, have caused chemists for better alternatives (Tanabe and Holderich 1999). Based on numerous therapeutic applications of thiohydantoin, clean and straightforward one-pot synthesis of thiohydantoin employing mesoporous silica SBA-15 functionalized with 8-hydroxyquinoline-5- sulfonic acid was reported. A mixture of α-aminoesters, and isothiocyanate derivatives with little loading of HQS-SBA-15, was heated at 60°C for 1 h to afford the corresponding product (Scheme 13.14). Then the produced solid precipitate was dissolved in hot ethanol to remove the catalyst via filtration. Applying clean and green protocol and high yields through short reaction time highlights the mentioned procedure (Vavsari et al. 2016). Magnetically separable Fe3 O4 @KCAR nanocomposite was synthesized by reacting Fe3 O4 nanoparticles with natural κ-carrageenan (KCAR) biopolymer. The catalytic efficiency of synthesized nanocomposite without further modification was evaluated via multicomponent reaction of diverse amines, CS2 and DMAD, to afford well-derivatized rhodanines in green media under ambient conditions (Scheme 13.15). The in situ reaction of amine and CS2 gave the corresponding dithiocarbamate, which subsequently underwent reaction with DMAD under the aqueous condition at room temperature. The developed approach is noteworthy for

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Scheme 13.14 Synthesis of 2-thiohydantoin derivatives in the presence of HSQ-SBA-15

Scheme 13.15 Fe3 O4 @KCAR utilized multicomponent synthesis of rhodanine derivatives

the simple work-up procedure, eco-friendliness, high yields within a short reaction time, and reusable catalyst (Rostamnia et al. 2015). Another efficient and high-performance synthetic route for synthesizing biologically active rhodanine derivatives (21) was developed through multicomponent reaction and SBA-15 based nanocatalyst (Rostamnia et al. 2013). Hexafluroisopropanol dispersed catalytically loading of SBA-15(HFIP/SBA-15) with organic substrate exhibited outstanding catalytic efficiency that is competitive with previous reported catalytic transformations. One-pot three-component reaction of amines, carbon disulfide, and electron-deficient acetylenes along with nanoporous SBA-15, afforded the desired alkyl rhodanines under mild conditions within a short reaction time (Scheme 13.16). Work-up simplicity, high yields, and high recovery potential highlight the mentioned catalytic process.

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Scheme 13.16 The synthesis of thioxo-thiophenecaboxylate scaffold via HFIP/SBA-15

13.5 Conclusion This chapter discussed the nanocatalysts’ roles in synthesizing bioactive 1,3thiazolidine and imidazolidine five-membered heterocycles through nanocatalysts, which have been reported so far over the last decade. In conclusion, non-corrosive nature, reusability, eco-compatibility, energy and cost efficiency, reduced chemical waste and reaction time, along with increased yields, have flourished nanocatalysis in the field of organic synthesis pharmaceutical and industrial intermediates. This chapter can provide a clue and update to the researchers of the field toward a better insight into the potential values of nanocatalysis in the synthesis of challenging scaffolds.

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