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English Pages 579 [580] Year 2023
György Keglevich and Bubun Banerjee Non-Conventional Synthesis Green Bioactive Heterocycles
De Gruyter Series in Green Bioactive Heterocycles Volume György Keglevich and Bubun Banerjee (Eds.) Non-Conventional Synthesis, ISBN ----, e-ISBN ----
Volume Asit K. Chakraborti, Bubun Banerjee (Eds.) Aqueous-Mediated Synthesis, ISBN ----, e-ISBN ----
Volume Yunfei Du, Bubun Banerjee (Eds.) Non-Metal Catalyzed Synthesis, ISBN ----, e-ISBN ----
Volume Sreekantha B. Jonnalagadda, Bubun Banerjee (Eds.) Solvent-Free Synthesis, ISBN ----, e-ISBN ----
Volume Basudeb Basu, Bubun Banerjee (Eds.) Multicomponent Synthesis, ISBN ----, e-ISBN ----
Green Bioactive Heterocycles
Edited by Bubun Banerjee
Volume 1
Non-Conventional Synthesis Bioactive Heterocycles Edited by György Keglevich and Bubun Banerjee
Editors Prof. Dr. György Keglevich Department of Organic Chemistry and Technology Budapest University of Technology and Economics Műegyetem rkp. 3. 1111 Budapest Hungary [email protected] Dr. Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India [email protected]
ISBN 978-3-11-099226-7 e-ISBN (PDF) 978-3-11-098018-9 e-ISBN (EPUB) 978-3-11-098027-1 ISSN 2752-1338 Library of Congress Control Number: 2023939273 Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the internet at http://dnb.dnb.de. © 2023 Walter de Gruyter GmbH, Berlin/Boston Cover image: Back Image: IkonStudio/iStock/Getty Images Plus Front Image: demaerre/iStock/Getty Images Plus Typesetting: Integra Software Services Pvt. Ltd. Printing and binding: CPI books GmbH, Leck www.degruyter.com
Preface The creation of the book “Non-conventional synthesis: Bioactive heterocycles” was a great challenge. Within the huge discipline of different heterocycles, we focused on the bioactive derivatives. The book comprises promising or really bioactive N-, O-, Sor P-heterocycles with different ring size, and in not less cases with more heteroatoms. Excellent scientists were invited from all over the World. Biorelevant heterocycles are important from the point of view pharmaceutical industry and plant protecting agents. The main stress was placed on showing up-to-date methods and techniques for the syntheses. Perhaps the most important techniques applied in the preparations are microwave and sonochemical irradiation making use of local overheating and cavitation, respectively, allowing fast and efficient syntheses. Electrolysis, photochemical irradiation, and the use of ball-mill reactors also represent modern approaches in accord with the 12 principals (laws) of green chemistry. A few techniques allow solvent-free accomplishments and involve the use of green solvents, such as ionic liquids. Different kinds of catalysis, like enantioselective metal catalysis and nanocatalysis also represent novel techniques, not speaking about the application of flow reactors making possible safe accomplishments and good productivities. This book may be of interest for researchers working in academia, and specialists developing industrial processes. Beside chemists, chemical engineers, PhD students and students may make use of the valuable subject matter collected in this book. Prof. György Keglevich Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary Dr. Bubun Banarjee Department of Chemistry, Akal University, Talwandi Sabo, Bathinda, Punjab, India
https://doi.org/10.1515/9783110980189-202
Foreword ‘Non-Conventional Synthesis–Bioactive Heterocycles’, edited by Dr. Bubun Banerjee and Professor (Dr.) György Keglevich is an admirable compilation of seventeen chapters showcasing developments inthe nonconventional synthesis of bioactive heterocyclic compounds and related drug design and discovery. The narrative of the book is built on sustainable chemistry leading to efficient synthesis of a wide range of heterocyclic systems. All the chapters are written with a lot of acumen and with a global perspective based on the contributions made by a number of researchersinvolved in developing alternate ways for the synthesis of bioactive heterocyclic compounds. This book is indeed a pleasure to read, in part because it gives a concise but clear description of various nonconventional recent strategies and methodologies for the synthesis of a variety of bioactive heterocycles together with other aspects germane to the development of drug design and development. Historically, the synthesis of heterocyclic compounds is of critical importance in thedevelopment of bioactive molecules, materials and a variety of industries. Further, the ever increasing presence of different types of heterocyclic units in drugs and pharmaceuticals has given much impetus to synthetic chemists for discovering and designing more and more efficient ways of synthesizing heterocyclic compounds, and for which numerous synthetic strategies and protocols have been developed over the years. In recent years, however, considering the detrimental effects on the Earth’s environment due to excessive use of chemicals and release of chemical wastes from various chemical operations,feverish attempts have been made by the chemists, resulting into numerous successful endeavours of discovering, developing and promoting alternate ways of synthesizing chemical compounds, also including the heterocycles.The focus has been on replacing the conventional synthetic methods with alternate, efficient and environment-safe chemical reactions and processes, and technologies for scale-up production of chemical compounds for various needs.It is in these contexts, this book bears much significance. This book comprises seventeen chapters. The first three chapters of the book showcase synthesis of various types of heterocycles under microwave irradiation conditions. In the 1st Chapter entitled ‘Microwave-Assisted Catalyst-Free Synthesis of Bioactive Heterocycles’, Ali Bodaghi, Ali Ramazani, and Zeinab Rafiee, review microwave-assisted synthesis of several five-, six- and seven-membered bioactive heterocycles in the absence of any catalyst under various reaction conditions. The chapter begins with an introductory remark highlighting some drugs and bioactive compounds containing heterocyclic rings. Subsequently the authors describe synthesis of a variety of heterocyclic compounds containing nitrogen, oxygen and sulfur atoms, combined heterocycles, and further other heterocycles such as 3-hydroxy-2-oxidoles, and 3-functionalized 4-hydroxycoumarins, etc. In Chapter 2 entitled ‘Microwave-Assisted Synthesis of N-Heterocycles”, Chetna Ameta, Dharmendra, Yogeshwari Vyas, Purnima Chaubisa, Abhilasha Jain, and Suresh C. Ameta summarize recent developments in the microwave-assisted synthesis of biohttps://doi.org/10.1515/9783110980189-203
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logically promising nitrogen-containing heterocycles using one-pot, multi-component techniques. The chapter uncovers synthesis of different types of five and six-membered heterocycles with one and two N-atoms, synthesis of triazole and tetrazole derivatives, and a few fused heterocyclic compounds containing N-atoms, etc. In Chapter 3 entitled ‘Microwave-Assisted Synthesis of O,S-Heterocycles’, Rajib Sarkar and Chhanda Mukhopadhyay address several aspects of the synthesis of O,Sheterocyclic molecules under microwave irradiation. Presented in three parts, the first part uncovers the microwave protocols by using metal catalysts, the second part emphasizes the synthetic protocols utilizing non-metal catalysts, while the third part includes the catalyst-free microwave assisted protocols. The contents of the above mentioned three chapters are adequate enough not only inproviding a good understanding of required reaction conditions under microwave irradiation for the synthesis of different types of heterocycles, but arealso useful in providing information needed for further development ofmicrowave-assisted synthetic protocols for the synthesis of bioactive heterocycles. The next three chapters are about the ultrasound-assisted synthesis of heterocycles. Thus, in Chapter 4, Yadavalli Venkata Durga Nageswar, Katla Ramesh and Katla Rakhi in the article entitled ‘Ultrasound-Assisted Synthesis of N-Heterocycles’highlight recent research findings in the application of ultrasonic irradiation in thesynthesis of a broad range of nitrogen-containing heterocyclic systems. In chapter 5,GarimaAmetaa, Rakshit Ametab, Seema Kothari and Suresh C. Ameta in their article entitled “Ultrasound-Assisted Synthesis of O,S-Heterocycles’ catalogue sonochemical synthesis of oxygen- and sulfur-atoms containing heterocycles, also including the chromenes, flavones, and a variety of other heterocyclic compounds comprising both the oxygen and sulfur atoms. In the next chapter 6 concerning ultrasound-assisted synthesis, Bubun Banerjee, Aditi Sharma, Anu Priya, Manmeet Kaur and Arvind Singh in their article entitled ‘Ultrasound-Assisted Synthesis of Bioactive 1,2,3-Triazoles via Click Reactions’summarize some of the recent advances inultrasound-assisted synthesis of structurally diverse and biologically promising 1,2,3-triazoles via the click chemistry between various azides and alkynes. The examples of synthetic reactions uncovered in the abovementioned three chapters on ultrasound-assisted methods highlight the efficiency of the sonochemical methods for the synthesis of bioactive heterocyclic molecules of medicinal importance, and useful as scaffolds in different pharmaceuticals. The information provided in these chapters will be quite useful in enhancing the applications of sonochemical methods for the synthesis of bioactive heterocycles, which is expected to grow in the coming days. In Chapter 7 entitled ‘Photoirradiated Synthesis of Bioactive Heterocycles’, Prabhakar Chettia, Vipin Kumar and V. Jayathirtha Rao present an informative account of UV-Vis light-mediated synthesis of different heterocycles containing N/O/S/O,N/N,S atoms. Also are included select named reactions useful in building heterocyclic frame-
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works. The light-mediated synthetic routes are quite promising inproviding relatively more greener and sustainable ways of synthesizing bioactive heterocycles. However, theseprocesses need more attention, in particular with regard to achieving light-induced transformations as cleanly and in as high chemical yield as is the case in ground-state chemistry, and further developing a clear understanding of the light-mediated functional group manipulations and, more importantly, of mechanisms of such processes. This chapter can serve as a basis and reference guide for researchers interested in designing and developing light-induced synthesis of bioactive heterocycles endowed with various useful properties. In Chapter 8 entitled ‘Synthesis of Heterocycles through Electrolysis’, Poulami Hota, Prasenjit Das, Rajjakfur Rahaman, and Dilip K. Maiti provide an assessment of the recent reports on the electrochemical synthesis of heterocycles.The authors showcase several electrochemical syntheses of a diverse group of heterocyclic compounds achieved through intra- and inter-molecular cyclizations involving oxidative / reductive formation of >C-CC-O / >C-N< bonds, utilizing various electronically appropriate functional groups and reactive species. The chapter provides a good understanding of electrochemical synthesis of heterocyclic compounds, and will be helpful in designing and developing electrochemical routes to various bioactive heterocyclic systems. In Chapter 9 entitled ‘Flow Synthesis of Oxygen and Nitrogen Heterocycles’, Moumita Saha, and Asish. R. Das discuss the merits and applications of continuous flow technique for synthesis. This emergent methodology allows sequential combinativesynthesis through which a diverse class of compounds can be obtained serially via application of single flow reactor containing flow switch, and is of much interest in industrial sectors, as well as in pharmaceutical research field, especially in the area of active pharmaceutical molecules. Besides giving a brief introduction of the Flow technique, the authors describe several examples of the synthesis of different kinds of bioactive heterocyclic compounds.The utility, versatility and productivity of flow technique for synthesis is expected to only further grow with the accessibility of novel microprocessor control chips. Sabir Ahammed, Sandipan Ghosal and Brindaban C. Ranu in Chapter 10 entitled ‘Ball-Milling Promoted Synthesis of Bioactive Heterocycles’ present an accomplished and useful overview of the mechanochemically-induced synthesis of a range of heterocyclic molecules of much pharmaceutical importance. Under ball-milling condition, the reactions can be achieved at ambient temperature, and desirably avoiding toxic organic solvents and ligands. Attributes like solvent-free reaction, easy workup, and purification by crystallization avoiding chromatography, fast reaction and high yields of the products in mechanochemically-induced reactions make this approach quite useful for efficient synthesis of bioactive heterocycles. Authors Sabbasani Rajasekhara Reddy, Neelima D. Tangellamudi, Bhulakshmi Sathi, Sridhar P, and Adinarayana Doddi, in Chapter 11 entitled ‘Synthesis of Bioactive Heterocycles via click Reaction’explore the efficacy of the well-known click chemistry towards synthesis of various scaffolds of bioactive heterocyclic compounds. Among
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several other aspects of heterocyclic compounds, the chapter provides a brief but adequate account of the applications of click reactions for diversity-oriented synthesisof various groups of bioactive heterocyclic systems, also including modifications of alkaloids.Indeed, the click chemistry has made significant progress in recent years. It offers a high potential reaction for identifying and optimizing the lead candidates in drug discovery and development and generating compound libraries, and further developing novel bioactive scaffolds for use in medicinal chemistry. Prasenjit Das, PoulamiHota, Rajjakfur Rahaman and Dilip K. Maiti in Chapter 12 entitled ‘Synthesis of Bioactive Heterocycles by Nanocatalysis’ review the use and merits of nanocatalysts in the synthesis of heterocyclic compounds. Desirably, the chapter begins by outlining the basic aspects of nanocatalysts and nanocatalysis, which is followed by a brief survey of nanocatalysts in the synthesis of bioactive heterocycles. Several examples of nanocatalysts-mediated synthesis of heterocyclic systems containing N/O/S atoms in four, five, six and seven membered ring frameworks are presented. In the coming days, the nanocatalysis-mediated synthesis of bioactive heterocyclic compounds is expected to increase in research laboratories,industries and businesses. Helene Pellissierin Chapter 13 entitled ‘Enantioselective Metal-Catalyzed Domino Reactions in the Total Synthesis of Bioactive Heterocycles’ highlight developments in the total synthesis of a variety bioactive chiral heterocycles based on asymmetric metal-catalyzed domino reactions as the key step. The chapter comprises four parts, dealing successively with the syntheses employing bisphosphine ligands, bisoxazoline ligands, P,N-ligands and a few other ligands. Such one-pot catalytic processes mediated by palladium and copper coordinated with different types of chiral ligands allow much complex bioactive heterocyclic architectures to be achieved from simple starting reagents. The asymmetric metal-promoted domino processes are expected to continue to attract attention of synthetic chemists for the total synthesis of bioactive heterocyclic molecules. In Chapter 14, entitled ‘Synthesis of Pharmacologically Significant Pentathiepins: A Journey from Harsh to Mild Conditions’, Lukas M. Jacobsen, Roberto Tallarita, Siva S. M. Bandaru, and Carola Schulzke present a rich account of the synthesis of a special class of cyclic polysulfides – the Pentathiepins, which bear interesting pharmacological significance. The authors showcase synthesis of various pentathiepins achieved via metal-free approaches, and also viaapproaches utilizing metals like Tin, Titanium, and Molybdenum. Further, different reactions of pentathiepins, including thermal decomposition, reduction, oxidation, nucleophilic behaviour, ring contraction, and many other heterocyclic systems are also uncovered. Structural and physical characteristics of pentathiepins as seen under X-ray crystallography and various spectroscopic measurements, some recent DFT calculations results, and a brief discussion of biological activity and applications of different pentathiepinsand their analogues are also described. The focus of Chapter 15 is on the synthesis of ring phosphine oxides, wherein in the article entitled ‘Development in the Synthesis of Ring Phosphine Oxides’, György
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Keglevich presents a nice survey of results published in the last 5 years. The author records newer developments in the synthetic strategies for the cyclic phosphine oxides, such as 5- and 6-ring P-heterocycles, as well as large P-ring compounds and bridged derivatives. Among several other aspects, the new developments of phosphole oxides, phospholene oxides, oxaphospholenes, dihydrophosphinine oxides, tetrahydrophosphinine oxides, hexahydrophosphinine oxides, along with oxaphosphinine and azaphosphinine derivatives are discussed. In Chapter 16, SabbasaniRajasekhara Reddy, Sathi Bhulakshmi and Sanjivani Pal in the article entitled ‘Total Synthesis of Bioactive Heterocyclic Scaffolds via Pauson Khand Reaction’ nicely uncover the efficiency of Pauson Khand Reaction (PKR), wellknown for its ability to incorporate so much of molecular complexity in a single step. The chapter begins with an introduction to the PKR, which is followed by several examples of itsapplications in the construction of different types of terpenoids, alkaloids, and steroids, which in their cyclic structure contain N/O as hetero-atoms. Further highlighted are the possibilities of advancements in developing PKR-based sustainable synthetic methodologies using photocatalytic, aqueous mediated reactions, metal catalysts- based on cost effective and naturally abundant metals, etc. The penultimate Chapter 17 entitled ‘Nonconventional Approaches in Drug Discovery’ is devoted to various aspects of rational drug discovery. Authors Shashi Kiran Misra and Kamla Pathak present an informative account of how nonconventional approaches for drug discovery drive parallel data generation, low volume bioassay and virtual screening in a cost effective manner.The authors rightly point out that these approaches enable researchers to design chemical libraries and facilitate more refined processes in reduced timelines. Due to minimum reagent and chemical consumption in nonconventional approaches, lead compound optimization and validation steps are economically chased. Further on, the authors underline the need for studies of phenotypic screening, predictive validation, biochemical interactions, suitable animal models and other bioassays for opting non-conventional approaches. The learned authors have compiled recent developments in nonconventional synthesis of bioactive heterocycles and aspects of drug discovery together with an insightful analysis and thoughts regarding present-day scenarios and future prospects. In doing so, the authors have discussed ideas and observations of many researchers. Moreover, the book is written and presented in an easy and reader-friendly manner. The authors have discussed the matter in reasonable detail and various aspects of the subject are illustrated by suitable examples of reactions and synthetic transformations together with figures and mechanisms, where appropriate and necessary. At the end of each chapter, authors have included pertinent references on the scientific matters discussed. This will facilitate easy access to a lot of relevant recent references and will prove to be of considerable value to students, teachers and researchers alike. Surely, the topics discussed in the book will sensitize and promote new thinking among researchers with interest in designing and developing environment-safe and sustainable chemical synthesis and technologies for bioactive heterocycles and re-
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lated drug-worthy molecules. With the kind of research advancements made in recent years as evident from the material discussed in this book, it can be safely said that the coming years are destined to witness further development of this area with much greater stride and novelty. More and more new imperatives for the synthesis of bioactive heterocyclic compounds are expected to be discovered and developed, which is pivotal to further develop drugs, pharmaceuticals and many other chemical products. For this, the editors and the authors deserve the heartfelt thanks of the community of students, teachers and researchers in chemical- and allied-sciences, for their commendable efforts of making available this volume on a subject of much interest. I congratulate the editors and the authors and convey my best wishes to them and all the readers. Professor Anil K. Singh Formerly Professor, Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai – 400 076, India Email: [email protected]
A brief professional profile of Prof. Anil Kumar Singh A former Professor of Chemistry in the highest administrative grade at the Indian Institute of Technology Bombay (IIT-B), Prof. Anil Kumar Singh embodies a great wealth of expertise and experience in chemical and allied sciences education and research, policy formulation and administration. During a career spanning over four decades, Prof. Singh has worked in several senior key capacities at IIT-B and participated in drawing up and developing academic policies and programs of education and research, as well as expansion of collaborations both in India and abroad. He has also been associated in multiple capacities with other national and international educational institutions, R&D organizations, government bodies, prestigious science academies and societies, and policy-making entities to drive organizational excellence. He has held the position of Director, CSIR-Regional Research Laboratory, Jorhat, India, and Vice-Chancellor of two major universities, the Bundelkhand University (Jhansi, India) and the University of Allahabad (a central university in Prayagraj, India). Recently, Prof. Singh has also shouldered the responsibility as Independent Director of the Rashtriya Chemicals and Fertilizers Ltd., Mumbai (a public sector undertaking of the Ministry of Chemicals and Fertilizers, Government of India). Prof. Singh’s research interests are multidisciplinary, broadly spanning the areas of organic and bioorganic chemistry, photochemistry and photobiology, with a focus on developing molecular understanding of photocontrol of the structure and functions of photoreceptor proteins involved in sensory (e.g., vision) and energy (e.g., ion transport) transductions; excited state chemistry of linear polyenes and other organic molecules; sustainable approaches towards design and development of novel organic molecules and speciality chemicals; fluorescent probes; radioprotectants/anticancer compounds; nanoparticles of low-molecular-weight organic molecules; bio-inspired smart synthetic photoswitches, phototriggers, and molecular cages for spatially and temporally-controlled delivery of bioactive compounds; etc. Prof. Singh is widely traveled and delivered a large number of talks in prestigious gatherings of academicians and scientists in conferences, and in teaching and research centers of higher learning in India and abroad. His endeavors and contributions have been duly recognized by the academic and research organizations, government and corporate bodies, prestigious science academies, and professional societies with awards and honors.
https://doi.org/10.1515/9783110980189-204
Contents Preface Foreword
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A brief professional profile of Prof. Anil Kumar Singh List of contributors
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Ali Bodaghi, Ali Ramazani, and Zeinab Rafiee Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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Chetna Ameta Dharmendra, Yogeshwari Vyas, Purnima Chaubisa, Abhilasha Jain, and Suresh C. Ameta Chapter 2 Microwave-assisted synthesis of N-heterocycles 33 Rajib Sarkar and Chhanda Mukhopadhyay Chapter 3 Microwave-assisted synthesis of O,S-heterocycles
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Yadavalli Venkata Durga Nageswar, Katla Ramesh, and Katla Rakhi Chapter 4 Ultrasound-assisted synthesis of N-heterocycles 95 Garima Ameta, Rakshit Ameta, Seema Kothari, and Suresh C. Ameta Chapter 5 Ultrasound-assisted synthesis of O,S-heterocycles 129 Bubun Banerjee, Aditi Sharma, Anu Priya, Manmeet Kaur, and Arvind Singh Chapter 6 Ultrasound-assisted synthesis of bioactive 1,2,3-triazoles via click reactions 151 Prabhakar Chetti, Vipin Kumar, and V. Jayathirtha Rao Chapter 7 Photoirradiated synthesis of bioactive heterocycles
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Poulami Hota, Prasenjit Das, Rajjakfur Rahaman, and Dilip K. Maiti Chapter 8 Synthesis of heterocycles through electrolysis 209 Moumita Saha and Asish R. Das Chapter 9 Flow synthesis of oxygen and nitrogen heterocycles
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Sabir Ahammed, Sandipan Ghosal, and Brindaban C. Ranu Chapter 10 Ball-milling-promoted synthesis of bioactive heterocycles
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Sabbasani Rajasekhara Reddy, Neelima D. Tangellamudi, Bhulakshmi Sathi, Sridhar P., and Adinarayana Doddi Chapter 11 Synthesis of bioactive heterocycles via click reaction 307 Prasenjit Das, Poulami Hota, Rajjakfur Rahaman, and Dilip K. Maiti Chapter 12 Synthesis of bioactive heterocycles by nanocatalysis 337 Hélène Pellissier Chapter 13 Enantioselective metal-catalyzed domino reactions in the total synthesis of bioactive heterocycles 375 Lukas M. Jacobsen, Roberto Tallarita, Siva S. M. Bandaru, and Carola Schulzke Chapter 14 Synthesis of pharmacologically significant pentathiepins: a journey from harsh to mild conditions 403 György Keglevich Chapter 15 Developments in the synthesis of ring phosphine oxides
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Sabbasani Rajasekhara Reddy, Sathi Bhulakshmi, and Sanjivani pal Chapter 16 Total synthesis of bioactive heterocyclic scaffolds via Pauson Khand reaction 489
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Shashi Kiran Misra and Kamla Pathak Chapter 17 Nonconventional approaches in drug discovery Index
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List of contributors Chapter 1 Ali Bodaghi Department of Chemistry Tuyserkan Branch Islamic Azad University Tuyserkan, Iran Ali Ramazani Department of Chemistry Faculty of Science University of Zanjan Zanjan 45371-38791, Iran e-Mail: [email protected] Zeinab Rafiee Department of Chemistry Malayer University Malayer, Iran Chapter 2 Chetna Ameta Dharmendra Department of Chemistry University College of Science M. L. Sukhadia University Udaipur 313001, Rajasthan, India
Suresh C. Ameta Department of Chemistry PAHER University Udaipur, Rajasthan, India [email protected] Chapter 3 Rajib Sarkar Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India and Department of Chemistry Prabhu Jagatbandhu College Jhorehat, Andul-Mouri Howrah 711302, West Bengal, India Chhanda Mukhopadhyay Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India [email protected]
Yogeshwari Vyas Department of Chemistry University College of Science M. L. Sukhadia University Udaipur 313001, Rajasthan, India
Chapter 4 Yadavalli Venkata Durga Nageswar Retired Chief Scientist Indian Institute of Chemical Technology-IICT Tarnaka, Hyderabad, Telangana, India [email protected]
Purnima Chaubisa Department of Chemistry University College of Science M. L. Sukhadia University Udaipur 313001, Rajasthan, India
Katla Ramesh Organic Chemistry Laboratory-4 School of Chemistry and Food Federal University of Rio Grande-FURG Rio Grande, RS-Brazil
Abhilasha Jain Department of Chemistry St. Xavier’s College Mumbai 400001, Maharashtra, India
Katla Rakhi Organic Chemistry Laboratory-4 School of Chemistry and Food Federal University of Rio Grande-FURG Rio Grande, RS-Brazil
https://doi.org/10.1515/9783110980189-206
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Chapter 5 Garima Ameta Department of Chemistry University College of Science M. L. Sukhadia University Udaipur 313002, Rajasthan, India Rakshit Ameta Department of Chemistry J. R. N. Rajasthan Vidhyapeeth (Deemed to be University) Udaipur 313001, Rajasthan, India Seema Kothari Department of Chemistry PAHER University Udaipur 313003, Rajasthan, India
Arvind Singh Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab, India Chapter 7 Prabhakar Chetti Department of Chemistry National Institute of Technology Kurukshetra 136119, Haryana, India Vipin Kumar Department of Chemistry National Institute of Technology Kurukshetra 136119, Haryana, India
Suresh C. Ameta Department of Chemistry PAHER University Udaipur 313003, Rajasthan, India [email protected]
V. Jayathirtha Rao Natural Products and Medicinal Chemistry Department and AcSIR-Ghaziabad CSIR-Indian Institute of Chemical Technology Uppal Road Tarnaka Hyderabad 500007, Telangana, India [email protected]
Chapter 6 Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab, India [email protected]
Chapter 8 Poulami Hota Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India
Aditi Sharma Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab, India Anu Priya Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab, India Manmeet Kaur Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab, India
Prasenjit Das Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India Rajjakfur Rahaman Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India Dilip K. Maiti Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India [email protected]
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Chapter 9 Moumita Saha Department of Chemistry University of Calcutta Kolkata 700009, West Bengal, India
Bhulakshmi Sathi Department of Chemistry School of Advanced Sciences Vellore Institute of Technology (VIT) Vellore 632014, Tamil Nadu, India
Asish R. Das Department of Chemistry University of Calcutta Kolkata 700009, West Bengal, India [email protected]
Sridhar P. Department of Chemistry School of Advanced Sciences Vellore Institute of Technology (VIT) Vellore 632014, Tamil Nadu, India
Chapter 10 Sabir Ahammed Department of Chemistry Bankura Sammilani College Kenduadihi, Bankura 722102 West Bengal, India
Adinarayana Doddi Department of Chemical Sciences Indian Institute of Science Education and Research (IISER) Berhampur, Transit Campus, Industrial Training Institute (ITI) Ganjam 760010 Odisha, India
Sandipan Ghosal Department of Chemistry Bankura Sammilani College Kenduadihi, Bankura 722102 West Bengal, India Brindaban C. Ranu School of Chemical Sciences Indian Association for the Cultivation of Science Jadavpur Kolkata 700032, West Bengal, India [email protected] Chapter 11 Sabbasani Rajasekhara Reddy Department of Chemistry School of Advanced Sciences Vellore Institute of Technology (VIT) Vellore 632014, Tamil Nadu, India [email protected] Neelima D. Tangellamudi Swarnandhra College of Engineering and Technology JNTU Kakinada West Godavari 534280 Andhra Pradesh, India
Chapter 12 Prasenjit Das Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India Poulami Hota Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India Rajjakfur Rahaman Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India Dilip K. Maiti Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009, West Bengal, India [email protected]
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Chapter 13 Hélène Pellissier Aix Marseille Univ, CNRS, Centrale Marseille, iSm2 Marseille, France [email protected] Chapter 14 Lukas M. Jacobsen Institute of Biochemistry, Bioinorganic Chemistry University of Greifswald Felix-Hausdorff-Str. 4 17489 Greifswald, Germany Roberto Tallarita Institute of Biochemistry, Bioinorganic Chemistry University of Greifswald Felix-Hausdorff-Str. 4 17489 Greifswald, Germany Siva S. M. Bandaru Institute of Biochemistry, Bioinorganic Chemistry University of Greifswald Felix-Hausdorff-Str. 4 17489 Greifswald, Germany Carola Schulzke Institute of Biochemistry, Bioinorganic Chemistry University of Greifswald Felix-Hausdorff-Str. 4 17489 Greifswald, Germany [email protected] Chapter 15 György Keglevich Department of Organic Chemistry and Technology Budapest University of Technology and Economics Műegyetem rkp. 3. 1111 Budapest Hungary [email protected]
Chapter 16 Sabbasani Rajasekhara Reddy Department of Chemistry School of Advanced Sciences Vellore Institute of Technology (VIT) Vellore 632014, Tamil Nadu, India [email protected] or [email protected] Sathi Bhulakshmi Department of Chemistry, School of Advanced Sciences Vellore Institute of Technology (VIT) Vellore 632014, Tamil Nadu, India Sanjivani Pal School of Advanced Sciences Department of Chemistry Vellore Institute of Technology (VIT) Vellore 632014, Tamil Nadu, India Chapter 17 Shashi Kiran Misra School of Pharmaceutical Sciences CSJM University Kanpur Kanpur 208024 Uttar Pradesh, India Kamla Pathak Faculty of Pharmacy Uttar Pradesh University of Medical Sciences Saifai Etawah 206130 Uttar Pradesh, India [email protected]
Ali Bodaghi, Ali Ramazani✶, and Zeinab Rafiee
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles 1.1 Introduction Heterocycles are ring structures containing at least one heteroatom, such as N, O, and S, as a member of the ring in addition to carbon atoms [1, 2]. Heterocyclic compounds are at the forefront of almost every developing field, especially in the synthesis of biologically active molecules, pharmaceuticals, and a variety of industries. Many naturally occurring bioactive compounds possess heterocyclic skeletons as the main structural unit. All of the nucleic acids, hemoglobin, cellulose, majority of the drug molecules, hormones, vitamins, dyes and pigments, ligands in metal catalysis and many useful organic materials consist of heterocyclic skeletons. Heterocyclic compounds are regarded as very useful starting materials in a variety of industries such as plastics, cosmetics, agriculture, and other industries [3–7]. Over 95% of pharmaceuticals consist of at least one heterocyclic fragment. Among many others, N-based heterocycles are very common in vitamins, hormones, commercially available drug molecules, and many bioactive compounds that play vital roles in human and animal life [1, 8, 9]. Moreover, these compounds possess immense biological activities. In recent years, the synthesis of various heterocyclic compounds involving microwave irradiation as the heating source and in the absence of any catalyst under various reaction conditions has gained huge attention. Since the late 1980s, microwave-assisted synthesis has been gaining significant importance due to its several advantages over conventional methods, such as facile operating conditions, reduction of reaction time, spectacular accelerations in reactions, reduction in the activation energy of reactions, precise temperature control, low cost, high yields, fewer steps, lower quantities of side products, the high selectivity of the products, homogeneous energy distribution, rapid heat generation, selective heating, generation of heat within the material itself, decrease of CO2 emission, energy saving, environmental friendliness, and improved atom economy [20–23]. Microwave irradiation is considered as a useful tool in green chemistry, especially to carry out reactions under solvent- as well as catalyst-free conditions. Compounds with high dielectric constant show a greater tendency to absorb microwaves in comparison with polar materials and crystals. Furthermore, microwave radiation can improve the regio✶
Corresponding author: Ali Ramazani, Department of Chemistry, Faculty of Science, University of Zanjan, Zanjan 45371-38791, Iran, e-mail: [email protected] Ali Bodaghi, Department of Chemistry, Tuyserkan Branch, Islamic Azad University, Tuyserkan, Iran Zeinab Rafiee, Department of Chemistry, Malayer University, Malayer, Iran https://doi.org/10.1515/9783110980189-001
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selectivity, chemoselectivity, and stereoselectivity in synthesizing bioactive heterocycles. Owing to such properties, this method has emerged as a green and useful tool in synthetic organic chemistry. However, the microwave-assisted method suffers from several disadvantages and limitations, such as the high costs of the equipment, infeasibility of reaction monitoring, and unsuitable for large-scale synthesis and commercial utilization [24, 25]. Microwave irradiation contains electric and magnetic fields, which cause molecules to collide with each other and thereby cleave the covalent bond. Microwave synthesis has been widely developed, and can be run in the presence or absence of any catalyst under various reaction conditions [26]. In recent years, numerous efforts have been devoted to the synthesis of bioactive heterocycles utilizing microwave-assisted method without using any catalyst. The catalyst-free conditions provide some advantages relative to using various catalysts. The catalyst-free reactions have been rapidly developed and widely used because they are straightforward, simple way and low-cost strategies, easy of separation and purification of products and also efficient in preventing environmental pollution, less hazardous, and waste free [27, 28]. In this chapter, the recent advances in the microwave-assisted catalyst-free synthesis of bioactive heterocycles including S-, O-, and N-heteroatoms have been summarized in Table 1.1. Table 1.1: Some drugs and bioactive compounds containing heterocyclic rings. S. no. Name
Structure
Application
Reference
Cefatrizine
Antibiotic
[]
Nitrofurantoin
Antibiotic for urinary tract infections
[]
Lipitor (atorvastatin)
Cholesterol/ triglyceride regulator
[]
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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Table 1.1 (continued) S. no. Name
Structure
Application
Reference
Isatoribine
Agonist of TLR
[]
Thiochromeno [,-d]thiazol-ones I
Antitumor
[]
Seroquel (quetiapine)
Antipsychotic
[]
Singulair (Montelukast)
Antiasthmatic
[]
Oxycontin (Oxycodone)
Analgesic
[]
Lamivudine
Anti-HIV
[]
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Table 1.1 (continued) S. no. Name
Structure
Application
Reference
Risperidone
Antipsychotic
[]
Fluorouracil
Anticancer
[]
Tecarfarin
Anticoagulant
[]
Tadalafil
Pulmonary arterial hypertension
[]
Acyclovir (Zovirax)
Antiviral agent
[]
1.2 Synthesis of N-heterocycles Five-, six-, and seven-membered rings containing nitrogen heteroatoms are very long known due to their potent biological properties and are common in bioactive materials such as anticancer drugs, anti-inflammatory agents, antibacterialdrugs, antioxidant agents, alkaloids, and pharmaceutical product precursor to various natural products such as porphyrins (heme and chlorophylls) [29–34]. Some of the five-, six-, and seven-membered rings of N-containing heteroatoms are shown in Figure 1.1 [35].
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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Figure 1.1: Some common heterocycles with one or more N-heteroatom.
1.2.1 Synthesis of pyrrolo[1,10]-phenanthrolines Padmini and coworkers [36] prepared pyrrolo[1, 10]-phenanthrolines (5) in excellent yields from the four-component reaction of substituted aldehydes (1), phenanthroline (2), malononitrile (3), and isocyanides (4) with microwave-assisted without any catalyst in ethanol solvent (Figure 1.2).
Figure 1.2: Synthesis of pyrrolo[1,10]-phenanthrolines.
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1.2.2 Synthesis of pyrrolidinyl spirooxindoles Bhandari et al. [37] reported the construction of pyrrolidinyl spirooxindoles (9) utilizing the isatin (6), amino acids (7), and 3-alkenyloxindole (8) by employing microwaveassisted multicomponent reactions in ethanol as solvent. The 1,3-dipolar cycloaddition synthetic strategy reveals a greener and high cost-effective approach. The enhancement in the yield from 69% to 84% and the reduction of the reaction time from 18 h to 12 min are some of the benefits of this work (Figure 1.3).
Figure 1.3: Synthesis of pyrrolidinyl spirooxindoles.
1.2.3 Synthesis of N-substituted 2-methyl-1H-pyrrole-3carboxylate derivatives Kan et al. [38] designed a new protocol for the synthesis of N-substituted 2- methyl-1Hpyrrole-3-carboxylate derivatives (13) using microwave-assisted one-pot three-component reaction utilizing α-bromoacetophenone (10), various amines (11), and ethyl acetoacetate (12), under the optimized reaction conditions without any catalyst and solvent in good yields (Figure 1.4). This study revealed the efficiency of the microwave-assisted protocol with a notable decrease in reaction time from 18 h to 12 min and a considerable increase in the product yields from 76% to 88%.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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Figure 1.4: Synthesis of N-substituted 2-methyl-1H-pyrrole-3-carboxylate derivatives.
1.2.4 Synthesis of substituted 1,2,3-triazoles Roshandel et al. [39] in 2018 reported the synthesis of substituted 1,2,3-triazoles (16) without using any catalyst and solvent under microwave-assisted neat conditions. In this method, trimethylsilylazide (CH3SiN3) (14) easily reacted with acetylene derivatives (15) via cycloaddition reaction, and the corresponding products were obtained in moderate to excellent yields in 0.5–7 h (Figure 1.5).
Figure 1.5: Synthesis of substituted 1,2,3-triazoles.
1.2.5 Synthesis of benzimidazole derivatives An effective and novel microwave-assisted ABB-type three-component reaction was designed without any catalyst for the synthesis of 2-(3 or 4-(bis(1H-indol-3-yl) methyl) phenyl)-1H-benzimidazole derivatives and 1-{3- or 4-[bis(1H-indol-3-yl)methyl]benzyl}2-{3- or 4-[bis(1H-indol-3-yl)methyl]phenyl}-1H-benzimidazole derivatives (19) through the chemical reaction between one or two equivalents of 4-(bis(1H-indol-3-yl)methyl)benzaldehyde derivatives (17) and o-phenylenediamine (18) (Figure 1.6). The short reaction times, excellent yield, avoidance of injurious examination procedures, potential biologi-
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cal activity, broad substrate scope, and high efficiency of reaction are some advantages of this approach [40].
Figure 1.6: Synthesis of benzimidazole derivatives.
1.2.6 Synthesis of ferrocenylimidazolo[2,1-b]-1,3,4-thiadiazoles Liu et al. [41] developed a microwave-assisted catalyst-free protocol for the synthesis of ferrocenylimidazolo[2,1-b]-1,3,4-thiadiazoles (22) from the reactions of 2-amino-5substituted-1,3,4-thiadiazole (20) and α-bromoacetylferrocene (21) (Figure 1.7). The antibacterial and antifungal activities of synthesized compounds were studied using the agar cup-plate method which showed that these compounds can have significant biological activities. Based on the results of the in vitro studies, aryl substituents with electron-withdrawing groups were more active compared to other Ar and R substituent groups.
Figure 1.7: Synthesis of ferrocenylimidazolo[2,1-b]-1,3,4-thiadiazoles.
1.2.7 Synthesis of 5-substituted 1H-tetrazole Jasim et al. [42] used TAIm[I] ionic liquid as a suitable medium for the synthesis of a variety of 5-substituted 1H-tetazoles (23) under microwave-assisted catalyst-free condi-
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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tions. In this work, a variety of aldehydes and aryl nitrile substrates were irradiated under the microwave (150 W) at 60 °C for less than 1 h (Figure 1.8). The 1,1′,1″-(1,3,5triazine-2,4,6-triyl) tris(3-methyl-1H-imidazol-3-ium) iodide was synthesized in two steps from cyanuric chloride reaction with NaI and then with 1-methylimidazole. TAIm[I] IL is readily converted to TAIm[N3] IL in the presence of NaN3, which behaves as an active solvent as well as reagent, with high efficiency and compatibility with various substrates.
Figure 1.8: Synthesis of 5-substituted 1H-tetrazole.
1.2.8 Synthesis of quinoxalinones Kristoffersen et al. [43] achieved the synthesis of quinoxalinones (26) by combining aryldiazoacetates (24) and 1,2-diamines (25) via one-pot reaction by employing a rapid microwave-assisted reaction without the use of catalysts in 67–96% yields (Figure 1.9). This method can be used for the synthesis of symmetrical and unsymmetrical substituted quinoxalines. The aim of this approach is the development of rapid, simple, clean, eco-friendly, and practical routes for generating these heterocycles.
Figure 1.9: Synthesis of quinoxalinones.
1.2.9 Synthesis of 1,4-dihydropyridines The one-pot three-component reaction between a β-ketoester (27), an aldehyde (28), and ammonium bicarbonate (29) as the source of nitrogen was performed via the Hantzsch method for the synthesis of 1,4-dihydropyridines (30) and their derivatives through solvent-free and catalyst-free by employing microwave irradiation (Figure 1.10) [44].
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Figure 1.10: Synthesis of quinoxalinones.
1.2.10 Synthesis of hydroxylated 2,4,6-trisubstituted pyridines Yin et al. [45] reported a facile catalyst-free method under microwave irradiation for the synthesis of hydroxylated 2,4,6-trisubstituted pyridine derivatives (34) (Figure 1.11). The various products were obtained in the one-pot three-component reaction of 4-hydroxybenzaldehydes (31), acetophenones (32), and ammonium acetate (33) in good yield with microwave power of 400 W at 120 °C for 30 min.
Figure 1.11: Synthesis of hydroxylated 2,4,6-trisubstituted pyridines.
1.2.11 Synthesis of complex fused pyrazole-pyrazines The post-Ugi cascade cyclization reaction was used for the synthesis of densely substituted and complex fused pyrazole-pyrazines (35) without any catalyst in one-pot reaction. The influence of different solvents such as tetrahydrofuran (THF), 2,2,2-trifluoroethanol (TFE), acetonitrile (MeCN), ethanol (EtOH), and dimethylformamide (DMF), increasing temperature from 80 to 110 °C at two different reaction times (10 and 20 min), was studied. The optimized reaction conditions are as follows: the microwave heating for 20 min at 110 °C in DMF solvent leads to the pyrazole-pyrazine product in 95% yield. The studies of this research group reveal that this compound can be applied for the treatment of human colon cancer (Figure 1.12) [46].
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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Figure 1.12: Synthesis of complex fused pyrazole-pyrazines.
1.2.12 Synthesis of 1,2,4-triazole-1,4-dihydropyridine derivatives Fagan and coworkers [47] reported a facile and highly efficient green chemistry approach for the synthesis of 1,4-dihydropyridine analogs under microwave irradiation without using any catalysts. Avoiding hazardous reagents, short reaction time, green solvent (water), excellent yields, mild reaction conditions, and simple workup process are noteworthy other advantages of this novel protocol. The novel 1,4-dihydropyridines (40) were synthesized with excellent selectivity from the one-pot four-component reaction of 3-amino-1,2,4-triazole (36) acetylenedicarboxylate (37) aldehydes having different functional groups (electron-deficient and electron-rich) (38) and malononitrile (39) at room temperature in less than 12 min (Figure 1.13).
1.2.13 Synthesis of indeno[1,2-b][1,6]naphthyridine-1,10(2H)-dione Li et al. [48] presented one-pot three-component strategy for the preparation of indeno[1,2-b][1,6]naphthyridine-1,10(2H)-dione derivatives (44) from the reaction of 4-aminopyridin-2(1H)-ones (41), various aldehydes (42), and 1H-indene-1,3(2H)-dione (43) in water (Figure 1.14). The presented method under microwave-assisted and catalyst-free conditions has several benefits such as rapid reaction, good-to-excellent
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Figure 1.13: Synthesis of 1,2,4-triazole-1,4-dihydropyridine derivatives.
yields, readily accessible aldehydes, green solvent, wide-ranging substrate, low temperature and experimental simplicity, and ease of separation and purification.
Figure 1.14: Synthesis of indeno[1,2-b][1,6]naphthyridine-1,10(2H)-dione.
1.2.14 Synthesis of tetrahydropyridine-3-carboxamides Khumalo et al. [49] presented a green protocol for the synthesis of a series of new tetrahydropyridine-3-carboxamides (49) under microwave-assisted and catalyst-free conditions. Figure 1.15 shows the route to fabricate them from a one-pot multicomponent reaction of various aromatic aldehydes (45), ethylcyanoacetate (46), acetoacetanilide (47), and ammonium acetate (48) in ethanol solvent. In addition to excellent yields, easy workup, simple purification, short reaction time, mild conditions, and low toxicity are the notable benefits of this procedure.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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Figure 1.15: Synthesis of tetrahydropyridine-3-carboxamides.
1.2.15 Synthesis of tryptanthrin derivatives Kaishap et al. [50] in 2021 synthesized tryptanthrin derivatives (52) via microwaveassisted, catalyst-free, and solvent-free conditions. A mixture of isatoic anhydride (51) and isatin (50) was irradiated under microwave reactor (700 W) at 120 °C for 15 min to afford tryptanthrins in good yields. They evaluated the anticancer activity of the synthesized tryptanthrins on prostate cancer cells. The in vitro cytotoxicity tests revealed that the synthesized compounds are highly effective against aggressive prostate cancer cells (Figure 1.16).
Figure 1.16: Synthesis of tryptanthrin derivatives.
1.2.16 Synthesis of substituted benzo[b][1,4]diazepines As Figure 1.17 shows, Vaddula et al. [51] demonstrated a microwave-assisted catalystfree method for the synthesis of H-, Me-, and Et-substituted benzo[b][1,4]diazepines (55) starting from various acetyl acetones (53) and phenyl-1,2-diamine (54) at 120 °C with excellent yields. This construction for the synthesis of the fused pyrazoles and diazepines are known as a rapid, chemoselective, or regioselective procedure which involves other advantages such as short reaction time and simple purification by silica gel column using 20% EtOAc/hexane eluent.
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Figure 1.17: Synthesis of substituted benzo[b][1,4]diazepines.
1.3 Synthesis of O-heterocycles Oxygen-containing heterocyclic scaffolds covered an important structural component as the building block units for numerous bioactive drugs, pharmaceuticals, and agrochemicals, such as alkaloids, flavonoids, and tocopherols [52, 53]. Because of the importance of heterocycles consisting of oxygen atoms, in recent years, convenient and practical various methods especially using microwave-assisted method under different conditions for the synthesis of these compounds have attracted considerable attention. Some common four-, five-, six-, and seven-membered rings of O-containing heteroatom have been shown in Figure 1.18 [35].
Figure 1.18: Some common heterocycles with one or more O-heteroatoms.
1.3.1 Synthesis of 9H-[1,3]dioxolo[4,5f]chromene derivatives Chromiums represent a class of oxygen heterocycles in many important natural and unnatural analogues. They have different medicinal properties such as spasmolytic, diuretic, anticoagulant, anticancer, and antianaphylactic activities. Dioxolochromene derivatives are biologically active and recently exhibited strong cytotoxicity in the NCI60 human tumor cell line anticancer drug screen. SharathBabu and Raghavendar Avula [54] reported a new one-pot three-component reaction under microwave irradiation for the synthesis of 9H-[1,3]dioxolo[4,5f]chromene derivatives (59) without catalysis and sol-
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
15
vent conditions (Figure 1.19). The reaction was carried out between sesamol (56), benzaldehyde (57), and (E)-N-methyl-1-(methylthio)-2-nitro-ethenamine (NMSM) (58) under neat reaction conditions. This method is a benefit and high-efficient strategy due to neat reaction conditions, short reaction time, eco-friendly, and simple purification without column chromatography.
Figure 1.19: Synthesis of 9H-[1,3]dioxolo[4,5f]chromene derivatives.
1.3.2 Synthesis of O-heteroacenes Konstantin Amsharov and his research group [55] have reported a new catalyst-free approach to five-, six-, and seven-membered rings of O-heteroacenes (61) via “ladderization” of fluorinated oligophenylenes (60) without oxygen-containing precursor which relies on an outside oxygen source that potassium tert-butoxide serves as an O2 synthon. C(aryl)-F bond appears to be a potential functionality in contrast to other C-Hal bonds, and remains intact during conventional Pd-catalyzed C-(aryl)–C(aryl) couplings. So, the direct transformation of the C–F bond into C–O functionality appears to be a highly attractive approach to O-heteroacenes (Figure 1.20).
1.3.3 Synthesis of tetrahydrobenzo[b] pyrans Hajra and coworkers [56] have developed an environmentally benign one-pot strategy for the synthesis of tetrahydrobenzo[b] pyrans (65), certain three-component condensation of aldehyde (62), malononitrile (63), and 1,3-cyclic diketone (64) with a green and highly efficient method via microwave irradiation without using any catalyst and solvent in high yields. The reaction conditions were optimized using benzaldehyde (1 mmol), malononitrile (1 mmol), and dimedone (1 mmol) at 80 °C under microwave irradiation for 7 min (Figure 1.21). Also, compatibility with various functional groups and nonchromatographic purification techniques are notable advantages of this procedure.
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Figure 1.20: Synthesis of O-heteroacenes.
Figure 1.21: Synthesis of tetrahydrobenzo[b] pyrans.
1.3.4 Synthesis of coumarin and pyrone-fused pyrans Mishra and Choudhury [57] used microwave-assisted multicomponent reactions involving arylglyoxal monohydrate (66), malononitrile (67), 4-hydroxyl coumarins (68), and cyclic 1,3-dicarbonyls such as 4-hydroxy-6-methyl-2H-pyran-2-one (69) for the synthesis of coumarin and pyrone-fused pyrans (70 and 71). These bioactive alkaloids
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
17
showed pharmacological activities such as psychotropic, anti-inflammatory, antiallergic, and estrogenic activities (Figure 1.22).
Figure 1.22: Synthesis of fused and functionalized pyrans.
1.3.5 Synthesis of 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7, 8-hexahydrocoumarin Coumarin and its derivatives are widely used in pharmacology for the treatment of schizophrenia, angiopathic wounds, and microcirculation disorders. Green synthesis under microwave irradiation is a topic that is planning much recent research interest. Feng and coworkers [58] reported microwave irradiation without any catalyst protocol for the synthesis of hexahydrocoumarin (75) from aromatic aldehydes (72), dimedone (73), and meldrum’s acid (74) (Figure 1.23).
Figure 1.23: Synthesis of hexahydrocoumarin.
1.3.6 Benzylation of naphthols and coumarins One of the fundamental and key reactions in organic synthesis is carbon–carbon bond formation, for example, nucleophilic substitution of benzylic alcohols (76) by
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various nucleophiles such as naphthols (77) or coumarins (78). In general, the reaction of benzylic alcohols makes a good leaving group that activated the hydroxyl group with the use of excess of sulfuric acid or phosphoric acid and stoichiometric amounts of Lewis acids. Benzylation of naphthols and 4-hydroxycoumarin has been reported under catalyst-free and solvent-free conditions by Srinivasarao Yaragorla et al. (Figure 1.24) [59].
Figure 1.24: Benzylation of naphthols and coumarins.
1.3.7 Synthesis of functionalized 2-amino-2H-chromene-3carboxylates 2H-Chromenes are important heterocycles that are found in many natural materials with biological activities, antibacterial, anti-HIV, including antifungal, antitumor, antioxidant, and antiviral activities. Molecules inclusive of these skeletons are also used as cyanide anion receptors, precursors to flavylium dyes, chromogenic and fluorogenic probes, and photochromic materials. Xia et al. [60] reported the synthesis of diversely functionalized 2-amino-2H-chromene-3-carboxylates (81) via green and efficient microwave-assisted and catalyst-free method from salicylaldehydes (79) and β-aminoacrylates (80) (Figure 1.25).
Figure 1.25: Synthesis of functionalized 2-amino-2H-chromene-3-carboxylates.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
19
1.3.8 Synthesis of 2H-pyrans 2H-Pyrans are an important number of natural products. The molecules deport 2Hpyrans to have a variety of fascinating biological activities and medicinal applications. A green approach with high yields and short reaction times for 16 compounds of 2H-pyrans (84) used microwave irradiation of domino Knoevenagel/6π-electrocyclic under solventand catalyst-free conditions by additional reaction between cyclic 1,3-dicarbonyls (82) with α,β-unsaturated aldehydes (83) (Figure 1.26) [61].
Figure 1.26: Synthesis of 2H-pyrans.
1.3.9 Synthesis of methyl-7-amino-4-oxo-5-phenyl-2- thioxo2,3,4,5-tetrahydro-1H-pyrano[2,3-d] pyrimidine-6carboxylates Dongre et al. [62] used benzaldehyde derivatives (85), methyl cyanoacetate (86) and thiobarbituric acid (87) in water as a green solvent for the synthesis of new methyl-7-amino4-oxo-5-phenyl-2-thioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d] pyrimidine-6-carboxylates (88) which has potent in vitro antibacterial and antifungal activities (Figure 1.27).
1.3.10 Synthesis of novel 1,4-pyranonaphthoquinone derivatives A conversion without solvents and catalyst for the four-component synthesis of novel 1,4-pyranonaphthoquinones (93) that consist of two Michael additions, aldol condensation, and annulation reactions was reported by Subbu Perumal and coworkers [63]. One-pot sequential reactions of 2-hydroxynaphthalene-1,4-dione (89), diethyl acetylenedicarboxylate (90), substituted anilines (91), and benzaldehydes (92) under microwave irradiation were accomplished for 3–6 min at 100 °C (Figure 1.28).
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Figure 1.27: Synthesis of methyl-7-amino-4-oxo-5-phenyl-2-thioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d] pyrimidine-6-carboxylates.
Figure 1.28: Synthesis of novel 1,4-pyranonaphthoquinones.
1.3.11 Synthesis of a series of 1,4-pyranonaphthoquinones As shown in Figure 1.29, Shu-Jiang Tu and coworkers [64] reported an efficient and simple method for the preparation of 1,4-pyranonaphthoquinone (96) derivatives, involving both pyran ring and 1,4-naphthoquinone skeleton by the reaction of arylidene malononitrile (94) and 2-hydroxynaphthalene-1,4-dione (95) in the mixed solvent of N, N-dimethylformamide and glacial acetic acid(VDMF/VHOAc; 2:1) using microwave-assisted method without any catalyst at 100 °C for 2–3 min.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
21
Figure 1.29: Synthesis of a series of 1,4-pyranonaphthoquinones.
1.4 Synthesis of S-heterocycles Sulfur-containing heterocyclic compounds are important structural motifs in numerous drug molecules, pharmaceutical products, and agrochemical products [65]. The importance of S-containing heterocyclic compounds has attracted increasing attention for further development of efficient and versatile methods for the synthesis of these compounds. In Figure 1.30, the most important heterocycles with one S-heteroatom have been shown [35]. The following sections illustrate the synthesis of some S-containing heterocycles by employing microwave-assisted method without any catalyst.
Figure 1.30: Some common heterocycles with one S-heteroatom.
1.4.1 Synthesis of 2-(N-carbamoylacetamide)-substituted 2,3-dihydrothiophenes Kordnezhadian et al. [66] reported the synthesis of dihydrothiophene derivatives via microwave-accelerated and diastereoselective one-pot four-component reaction without any catalyst in glycerol solvent with more than 85% in yield. The synthesis of 2-(Ncarbamoylacetamide)-substituted 2,3-dihydrothiophenes (101) was performed by a reaction between aromatic aldehydes (97), malononitrile (98), 1,3-thiazolidinedione (99), and various aromatic and aliphatic amines (100) for about 10 min at 90 °C (Figure 1.31).
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Figure 1.31: Synthesis of indeno[1,2-b][1,6]naphthyridine-1,10(2H)-dione.
Glycerol was well known as a green solvent because it is eco-friendly, safe, nonflammable, and nonvolatile and is also cheap, commercially available, and reusable.
1.5 Synthesis of combined heterocycles Heterocycles with various ring sizes and containing two or more heteroatoms (N, O, and S) at different positions in the ring present a fascinating combination of heteroatom types. These compounds are potent and competent candidates for various applications, especially in drug formulations and bioactive molecules. In Figure 1.32, the number of these types of heterocycles has been shown [35].
Figure 1.32: Some common heterocycles with two or more heteroatoms.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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1.5.1 Synthesis of thiazol-2(3H)-ones In 2021, an expeditious heteroannulation multicomponent process was reported for the synthesis of functionalized thiazol-2(3H)-ones (104) by the reaction of isothiocyanates (102) and 2-bromoketones (103) in different solvents under microwave irradiation without any catalyst. The obtained results disclosed that among used solvents such as isopropyl alcohol, CH3CN, and H2O, ethanol has a critical role in this process. Subsequent studies showed that these bioactive molecules can act as putative acetylcholinesterase inhibitors (Figure 1.33) [67].
Figure 1.33: Synthesis of indeno[1,2-b][1,6]naphthyridine-1,10(2H)-dione.
1.5.2 Synthesis of trisubstituted 1,3-thiazoles Karamthulla et al. [68] demonstrated a clean and highly efficient three-component domino reaction for the synthesis of trisubstituted 1,3-thiazole derivatives (108) via microwave-assisted and catalyst-free conditions in aqueous media within 15 min. As shown in Figure 1.34, a mixture of arylglyoxals (105), 1,3-dicarbonyl (106), and thioamides (107) in H2O was irradiated (200 W) for 15 min. In this domino reaction, initially, a Knoevenagel condensation between arylglyoxal monohydrate and 1,3-dicarbonyl derivatives takes place to form an alkene intermediate. Then, the thioamide derivative undergoes a Michael addition with alkene, and finally, cyclization occurs by the loss of H2O to form 1,3-thiazoles.
1.5.3 Synthesis of 4-hydroxy-3-arylthiazolidine-2-thiones 1,4-Dithiane-2,5-diol (109) is an effective, versatile, powerful, and inexpensive starting material, and this platform has been widely used in organic synthesis [69]. This compound was used for the synthesis of 4-hydroxy-3-arylthiazolidine-2-thiones (111) via
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Figure 1.34: Synthesis of trisubstituted 1,3-thiazoles.
domino reactions of aryl isothiocyanates (110) under catalyst-free microwave-assisted irradiation in good yields (Figure 1.35) [70].
Figure 1.35: Synthesis of 4-hydroxy-3-arylthiazolidine-2-thiones.
1.5.4 Synthesis of hydrazinylthiazole derivatives Chinnaraja and Rajalakshmi [71] reported the synthesis of hydrazinylthiazoles under catalyst-free conditions. The synthesis of a novel series of hydrazinylthiazole derivatives (115) was done through microwave-assisted one-pot three-component reactions of α-bromoketones (112), aryl ketones (113), and thiosemicarbazide (114) within less than 1 min with yields (60–80%) (Figure 1.36).
1.5.5 Synthesis of 2-substituted benzothiazoles Chakraborti et al. [72] described a convenient, clean, and efficient synthesis of 2substituted benzothiazoles (116) and 2-substituted thiazolines in the absence of any acid or base catalyst. In a one-pot reaction, aromatic, aliphatic, heteroaromatic, or
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
25
Figure 1.36: Synthesis of hydrazinylthiazole derivatives.
styryl aldehydes (117) were reacted with 2-aminothiophenol (118) under heating for 5 min in the microwave oven. This reaction is chemoselective, and no substitution of the halogen atoms or the nitro group, O-dealkylation/debenzoylation, or reduction of the nitro group without any thia-Michael addition took place. The procedure is simple workup and purification, noninflammable, nontoxic, high yields, and a green synthetic protocol (Figure 1.37).
Figure 1.37: Synthesis of 2-substituted benzothiazoles.
1.5.6 Synthesis of oxazolo[5,4-b]indoles Diastereo-enriched oxazolo[5,4-b]indoles (122) with good yield were synthesized by microwave-assisted irradiation in environmentally compatible EtOH under catalyst-free conditions. This multicomponent bicyclization reaction occurred with readily available arylglyoxals (119), cyclic enaminones (120), and amino acids (121) in a 1:2:1 mole ratio of substrates, respectively (Figure 1.38). This bicyclization reaction includes C−C, C–N, and C−O bond formation. The functionalized oxazolo[5,4-b]indoles with high diastereoselectivity (up to >99:1) were obtained. This new approach is eco-friendly, economical, and easy to operate, and using β-alanine amino acid gives single diastereoisomer products whereas using glycine gives mixed diastereoisomer products [73].
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Figure 1.38: Synthesis of oxazolo[5,4-b]indoles.
1.5.7 Synthesis of 2-(2-oxoalkylidene)-1,3-oxazolidine derivatives Oxazolidine derivatives are one of the most important classes of heterocyclic compounds that can be used as synthetic intermediates for the construction of biologically active molecules such as antibacterial, antiviral, and anticancer, due to the high reactive sites [74]. As shown in Figure 1.39, the 2-(2-oxoalkylidene)-1,3-oxazolidine derivatives (125) were successfully prepared in high yields (65–97%) by microwave-assisted irradiation through the catalyst-free electrophilic ring opening of N-unprotected aziridines (123) and the thermal Wolff rearrangement of ketene carbonyl group of 2-diazo -1,3-diketones (124) [75].
Figure 1.39: Synthesis of 2-(2-oxoalkylidene)-1,3-oxazolidine derivatives.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
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1.6 Synthesis of other heterocycles 1.6.1 Synthesis of 3-hydroxy-2-oxidoles The synthesis of 3-hydroxy-2-oxindole (128) was described by Meshram et al. under microwave irradiation via condensation of a variety of isatins (126) with acetophenone (127) (Figure 1.40). The presented procedure exhibits some advantages such as the catalyst-free and mild reaction condition, rapid reaction, good yield, use of an aqueous medium and avoidance of organic solvents, and eco-friendly approach [76].
Figure 1.40: Synthesis of 3-hydroxy-2-oxidoles.
1.6.2 Synthesis of 3-functionalized 4-hydroxycoumarin Various coumarin derivatives, for example, substituted 4-hydroxycoumarin derivatives exist in many natural products and are of much importance because they exhibit a wide range of biological activities. Also, Guo-Ning Zhang et al. [77] reported the synthesis of (132) under catalyst-free conditions. For this purpose, 4-hydroxycoumarin (129), phenylglyoxal (130), and 3-arylaminocyclopent-2-enone (131) were reacted using microwave irradiation under catalyst-free condition in ethanol solvent (Figure 1.41).
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Figure 1.41: Synthesis of 3-functionalized 4-hydroxycoumarin.
1.7 Conclusions In this chapter, we have summarized microwave-assisted synthesis of several five-, six-, and seven-membered bioactive heterocycles in the absence of any catalyst under various reaction conditions. Microwave-assisted methods are attractive because of certain advantages such as high yields in lesser reaction times, mild reaction conditions, less hazardous, cost-effective, and reduction of the chances of the formation of side products. Thus, this approach is useful and supportable for the preparation of a wide range of organic compounds in modern synthetic organic chemistry.
References [1] [2] [3]
[4] [5] [6] [7]
Bacolini, G. Topics heterocycle. Syst Synth React Prop 1996, 1, 103. Li, JJ, editor. Heterocyclic chemistry in drug discovery. John Wiley & Sons, 2013 Apr 26. Banerjee, B, Hu, YL, Xing, R. Highly efficient and convenient supported ionic liquid TiCl5-DMIL@ SiO2@ Fe3O4-catalyzed cycloaddition of CO2 and epoxides to cyclic carbonates. ChemSelect 2017, 2, 8362–8376. https://doi.org/10.1002/slct.201701700. Banerjee, B. Bismuth (III) triflate: An efficient catalyst for the synthesis of diverse biologically relevant heterocycles. ChemSelect 2017, 2(23), 6744–6757. https://doi.org/10.1002/slct.201701441. Reichart, B, Kappe, CO. High-temperature continuous flow synthesis of 1, 3, 4-oxadiazoles via N-acylation of 5-substituted tetrazoles. Tetrahedron Lett 2012, 53(8), 952–955. Molnár, Á. Microwave-assisted CN formation reactions. Green Sustain Process Chem Environ Eng Sci 2021, 51–203. https://doi.org/10.1016/B978-0-12-819848-3.00002-5. Brahmachari, G. Green synthetic approaches for biologically relevant 2-amino-4H-pyrans and 2-amino-4H-pyran-annulated heterocycles in aqueous media. In: Green synthetic approaches for biologically relevant heterocycles. Elsevier, 2015, 185–208.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
[8]
[9] [10] [11] [12] [13]
[14]
[15] [16] [17] [18] [19]
[20]
[21]
[22] [23] [24] [25] [26] [27] [28]
29
Vitaku, E, Smith, DT, Njardarson, JT. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals: Miniperspective J Med Chem 2014, 57(24), 10257–10274. DOI: 10.1021/jm501100b. PMID 25255204. Balaban, AT, Oniciu, DC, Katritzky, AR. Aromaticity as a cornerstone of heterocyclic chemistry. Chem Rev 2004, 104(5), 2777–2812. Neu, HC, Fu, KP. Cefatrizine activity compared with that of other cephalosporins. Antimicrob Agents Chemother 1979, 15(2), 209–212. Clark, JS. Heterocyclic chemistry. Organic Chemistry II 2010, 136–155. Müller, M. Chemoenzymatic synthesis of building blocks for statin side chains. Angew Chem Int Ed 2005, 44(3), 362–365. Horsmans, Y, Berg, T, Desager, JP, Mueller, T, Schott, E, Fletcher, SP, Steffy, KR, Bauman, LA, Kerr, BM, Averett, DR. Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology 2005, 42(3), 724–731. Atamanyuk, D, Zimenkovsky, B, Atamanyuk, V, Nektegayev, I, Lesyk, R. Synthesis and biological activity of new thiopyrano [2, 3-d] thiazoles containing a naphthoquinone moiety. Sci Pharm 2013, 81(2), 423–436. Gevorgyan, V. Chemistry of heterocyclic compounds: A renaissance. Chem Heterocycl Compd 2012, 48(1), 1–1. Sahu, M, Siddiqui, NA. A review on biological importance of pyrimidines in the new era. Int J Pharm Pharm Sci 2016, 8(5), 8–21. Costa, M, Dias, TA, Brito, A, Proença, F. Biological importance of structurally diversified chromenes. Eur J Med Chem 2016, 123, 487–507. Heravi, MM, Zadsirjan, V. Prescribed drugs containing nitrogen heterocycles: An overview. RSC Adv 2020, 10(72), 44247–44311. Schaeffer, H, Beauchamp, L, de Miranda, PA, Elion, GB, Bauer, DJ, Collins, P. 9-(2hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature 1978, 272(5654), 583–585. Bielenica, A, Szulczyk, D, Olejarz, W, Madeddu, S, Giliberti, G, Materek, IB, Koziol, AE, Struga, M. 1H-Tetrazol-5-amine and 1, 3-thiazolidin-4-one derivatives containing 3-(trifluoromethyl) phenyl scaffold: Synthesis, cytotoxic and anti-HIV studies. Biomed Pharm 2017, 1(94), 804–812. http://dx.doi. org/10.1016/j.biopha.2017.07.152. Palma, V, Barba, D, Cortese, M, Martino, M, Renda, S, Meloni, E. Microwaves and heterogeneous catalysis: A review on selected catalytic processes. Catalysts 2020, 10(2), 246, 2–58. https://doi.org/ 10.3390/catal10020246. Shang, H, Zhang, H, Du, W, Liu, Z. Development of microwave assisted oxidative desulfurization of petroleum oils: A review. J IndEngChem 2013, 19(5), 1426–1432. Horikoshi, S, Serpone, N. Role of microwaves in heterogeneous catalytic systems. CatalSciTechnol 2014, 4(5), 1197–1210. Surati, MA, Jauhari, S, Desai, KR. A brief review: Microwave assisted organic reaction. Arch App Sci Res 2012, 4(1), 645–661. Priecel, P, Lopez-Sanchez, JA. Advantages and limitations of microwave reactors: From chemical synthesis to the catalytic valorization of biobased chemicals. ACS Sustain Chem Eng 2018, 7(1), 3–21. Kappe, CO, Dallinger, D. Controlled microwave heating in modern organic synthesis: Highlights from the 2004–2008 literature. Mol Diversity 2009, 13(2), 71–193. Jin, C. Catalyst-free organic synthesis. Green Process Synth 2018, 7(2), 180–180. Banerjee, B, Kaur, G. Microwave assisted catalyst-free synthesis of bioactive heterocycles. Curr Microw Chem 2020, 7, 5–22. https://doi.org/10.1515/gps-2017-0184.
30
Ali Bodaghi, Ali Ramazani, and Zeinab Rafiee
[29] Cocco, MT, Congiu, C, Onnis, V. Synthesis and in vitro antitumoral activity of new N-phenyl-3pyrrolecarbothioamides. Bioorg Med Chem 2003, 11(4), 495–503. http://dx.doi.org/10.1016/S09680896(02)00465-0 PMID: 12538014. [30] Carson, JR, Carmosin, RJ, Pitis, PM, Vaught, JL, Almond, HR, Stables, JP, Wolf, HH, Swinyard, EA, White, HS. Aroyl (aminoacyl) pyrroles, a new class of anticonvulsant agents. J Med Chem 1997, 40(11), 1578–1584. http://dx.doi.org/10.1021/jm9606655 PMID: 9171868. [31] Bürli, RW, McMinn, D, Kaizerman, JA, Hu, W, Ge, Y, Pack, Q, Jiang, V, Gross, M, Garcia, M, Tanaka, R, Moser, HE. DNA binding ligands targeting drug-resistant Gram-positive bacteria. Part 1: Internal benzimidazole derivatives. Bioorg Med Chem Lett 2004, 14(5), 1253–1257. http://dx.doi.org/10.1016/j. bmcl.2003.12.042 PMID: 14980676. [32] Kadish, KM, Guilard, R, Smith, KM, editors. Handbook of Porphyrin Science: With applications to chemistry, physics, materials science, engineering. Biol Med World Scientific 2010, 6, 10. [33] Aydogan, F, Basarir, M, Yolacan, C, Demir, AS. New and clean synthesis of N-substituted pyrroles under microwave irradiation. Tetrahedron 2007, 63(39), 9746–9750. [34] Gulati, S, John, SE, Shankaraiah, N. Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects. Beilstein J Org Chem 2021, 17(1), 819–865. https://doi.org/10. 3762/bjoc.17.71. [35] Aljamali, NA. Review paper in heterocyclic compounds. J PlastPolymTechnol (JPPT) 2015, 1(1), 49–64. [36] Dhinakaran, I, Padmini, V, Ganesan, K, Selvarasu, K. A‐one pot four component and microwave‐ assisted synthesis of pyrrolo [1, 10] phenanthrolines. Chem Select 2017, 2(21), 6154–6158. DOI: 10.1002/slct.201700819. [37] Bhandari, S, Sana, S, Sridhar, B, Shankaraiah, N. Microwave‐assisted one‐pot [3+ 2] cycloaddition of azomethine ylides and 3‐alkenyl oxindoles: A facile approach to pyrrolidine‐fused bis‐ spirooxindoles. ChemSelect 2019, 4(5), 1727–1730. DOI: 10.1002/slct.201802847. [38] Kan, W, Jing, T, Zhang, XH. Microwave-assisted one pot synthesis of N-substituted 2-methyl-1Hpyrrole-3-carboxylate derivatives without catalyst and solvent. Heterocycles 2015, 91(12), 2367–2376. [39] Roshandel, S, Suri, SC, Marcischak, JC, Rasul, G, Prakash, GS. Catalyst and solvent free microwaveassisted synthesis of substituted 1, 2, 3-triazoles. Green Chem 2018, 20(16), 3700–3704. https://doi. org/10.1039/c8gc01516c. [40] Luna-Mora, RA, Álvarez-Toledano, C, Rios-Guerra, H, Ortega-Jiménez, F, López-Cortés, JG, PérezFlores, J, Torres-Reyes, Á, Moreno-González, L, Zaldívar, AM, Barrera-Téllez, F, Penieres-Carrillo, JG. Microwave-assisted synthesis of novel 1-{[(diindolyl) methyl] benzyl}-2-{[(diindolyl) methyl] phenyl}1H-benzimidazole scaffold via two-consecutive multicomponent reactions. Arkivoc 2021, 242–252. https://doi.org/10.24820/ark.5550190.p011.450. [41] Liu, Y, Yang, L, Yin, D. Ferrocenylimidazolo [2, 1-b]-1, 3, 4-thiadiazoles: A microwave-assisted catalystfree synthesis, characterization, and biological activities. J Chem Res 2021, 45(5–6), 422–742. DOI: 10.1177/1747519820939906. [42] Jasim, SA, Tanjung, FA, Sharma, S, Mahmoud, MZ, Kadhim, SB, Kazemnejadi, M. Ultrasound and microwave irradiated sustainable synthesis of 5-and 1-substituted tetrazoles in TAIm [I] ionic liquid. Res Chem Intermed 2022, 48(8), 3547–3566. https://doi.org/10.1007/s11164-022-04756-z. [43] Kristoffersen, T, Elumalai, V, Starck, E, Cousin, É, Wagner, LJ, Hansen, SR, Hansen, JH. Microwave‐ assisted synthesis of heterocycles from aryldiazoacetates. Eur J Org Chem 2020, 2020(45), 7069–7078. [44] Vijayakumar, B. Microwave induced solvent-free and catalyst-free synthesis of 1, 4-dihydropyridine derivatives using ammonium bicarbonate. Indian J Adv Chem Sci 2013, 1(2), 77–83. [45] Yin, G, Liu, Q, Ma, J, She, N. Solvent-and catalyst-free synthesis of new hydroxylated trisubstituted pyridines under microwave irradiation. Green Chem 2012, 14(6), 1796–1798. http://dx.doi.org/10. 1039/c2gc35243e.
Chapter 1 Microwave-assisted catalyst-free synthesis of bioactive heterocycles
31
[46] Xu, J, Tan, HB, Zhang, YJ, Tang, DY, Zhan, F, Li, HY, Chen, ZZ, Xu, ZG. catalyst-free one-pot synthesis of densely substituted pyrazole-pyrazines as anti-colorectal cancer agents. Sci Rep 2020, 10(1), 1–13. https://doi.org/10.1038/s41598-020-66137-z. [47] Fagan, A, Bartkowski, M, Giordani, S. Spiropyran-based drug delivery systems. Front Chem 2021, 9, 720087. DOI: 10.3389/fchem.2021.6388323.2.7. [48] Li, C, Zhang, F, Li, T, Liu, Z, Shen, Z. A Facile Three‐component catalyst‐free strategy: Synthesis of indeno [1, 2‐b][1, 6] naphthyridine‐1, 10 (2H)‐dione derivatives in water. Asian J Org Chem 2022, 11(6), e202200145. [49] Khumalo, M, Maddila, SN, Maddila, S, Jonnalagadda, SB. Green catalyst-free one-pot synthesis of novel tetrahydropyridine-3-carboxamides by microwave-assisted approach. J Chem Sci 2020, 132(1), 1–6. [50] Kaishap, PP, Duarah, G, Pal, M. Microwave-assisted, catalyst and solvent free synthesis of tryptanthrin derivatives and their in-vitro cytotoxic activity on prostate DU145 cancer cell lines. Synth Commun 2021, 51(24), 3740–3747. https://doi.org/10.1080/00397911.2021.1989598. [51] Vaddula, BR, Varma, RS, Leazer, J. Mixing with microwaves: Solvent-free and catalyst-free synthesis of pyrazoles and diazepines. Tetrahedron Lett 2013, 54(12), 1538–1541. [52] Nagawade, RR, Shinde, DB. Synthesis and anti‐bacterial activity of new series of 4‐(substituted biphenyl‐4‐yl)‐6‐methyl‐2‐oxo/thioxo‐1, 2, 3, 4‐tetrahydro‐pyrimidine‐5‐carboxylic acid ethyl ester. J Heterocycl Chem 2010, 47(1), 33–39. [53] Chaudhary, A. Recent development in the synthesis of heterocycles by 2-naphthol-based multicomponent reactions. Mol Diversity 2021, 25(2), 1211–1245. https://doi.org/10.1007/s11030-02010076-4. [54] SharathBabu, H, Avula, R. Microwave assisted one-pot, catalyst-free synthesis of novel 9H-[1, 3] dioxolo [4, 5-F] chromene derivatives. Social Sci Res Net 2022, 3, 1–14. https://dx.doi.org/10.2139/ ssrn.4155299. [55] Feofanov, M, Akhmetov, V, Takayama, R, Amsharov, K. Catalyst‐free synthesis of o‐heteroacenes by ladderization of fluorinated oligophenylenes. Angew Chem 2021, 133(10), 5259–5263. https://doi. org/10.1002/ange.202007427. [56] Santra, S, Rahman, M, Roy, A, Majee, A, Hajra, A. Microwave-assisted three-component “catalyst and solvent-free” green protocol: A highly efficient and clean one-pot synthesis of tetrahydrobenzo [b] pyrans. Org Chem Int 2014, http://dx.doi.org/10.1155/2014/851924. [57] Mishra, R, Choudhury, LH. Catalyst-free microwave-assisted arylglyoxal-based multicomponent reactions for the synthesis of fused pyrans. RSC Adv 2016, 6(29), 24464–24469. https://doi.org/10. 1039/C5RA25536H. [58] Tu, SJ, Zhou, JF, Cai, PJ, Wang, H, Feng, JC. A convenient synthesis of 4-aryl-7, 7-dimethyl-5-oxo-3, 4, 5, 6, 7, 8-hexahydrocoumarin under microwave irradiation without catalyst. Synth Commun 2001, 31(24), 3729–3733. DOI: 10.1081/SCC-100108221. [59] Dada, R, Singh, G, Pareek, A, Kausar, S, Yaragorla, S. Microwave assisted benzylation of naphthols and 4-hydroxycoumarin under catalyst& solvent free conditions. Tetrahedron Lett 2016, 57(33), 3739–3742. https://doi.org/10.1016/j.tetlet.2016.07.010. [60] Xia, L, Cai, H, Lee, YR. Microwave-assisted catalyst-free synthesis of diversely functionalized 2-amino2H-chromene-3-carboxylates. Tetrahedron 2015, 71(38), 6894–6900. https://doi.org/10.1016/j.tet. 2015.07.013. [61] Edayadulla, N, Lee, YR. Microwave-assisted solvent and catalyst free synthesis of 2H-pyrans. Bull Korean Chem Soc 2013, 34(10), 2963–2967. http://dx.doi.org/10.5012/bkcs.2013.34.10.2963. [62] Bhat, AR, Shalla, AH, Dongre, RS. Microwave-assisted one-pot catalyst-free green synthesis of new methyl-7-amino-4-oxo-5-phenyl-2-thioxo-2, 3, 4, 5-tetrahydro-1H-pyrano [2, 3-d] pyrimidine-6carboxylates as potent in vitro antibacterial and antifungal activity. J Adv Res 2015, 6(6), 941–948. http://dx.doi.org/10.1016/j.jare.2014.10.007.
32
Ali Bodaghi, Ali Ramazani, and Zeinab Rafiee
[63] Bala, BD, Rajesh, SM, Perumal, S. An eco-friendly sequential catalyst-and solvent-free fourcomponent stereoselective synthesis of novel 1, 4-pyranonaphthoquinones. Green Chem 2012, 14(9), 2484–2490. DOI: 10.1039/c2gc35930h. [64] Wang, XH, Zhang, XH, Tu, SJ, Shi, F, Zou, X, Yan, S, Han, ZG, Hao, WJ, Cao, XD, Wu, SS. A facile route to the synthesis of 1, 4‐pyranonaphthoquinone derivatives under microwave irradiation without catalyst. J Heterocycl Chem 2009, 46(5), 832–836. [65] Pathania, S, Narang, RK, Rawal, RK. Role of sulphur-heterocycles in medicinal chemistry: An update. Eur J Med Chem 2019, 180, 486–508. [66] Kordnezhadian, R, Shekouhy, M, Khalafi-Nezhad, A. Microwave-accelerated diastereoselective catalyst-free one-pot four-component synthesis of 2-(N-carbamoylacetamide)-substituted 2, 3-dihydrothiophenes in glycerol. Mol Diversity 2020, 24(3), 737–751. https://doi.org/10.1007/s11030019-09985-w. [67] Kumar, M, Jaiswal, A, Nand Singh, K. Microwave‐assisted diversity‐oriented synthesis of thiazol-2 (3H)-ones and its interaction with biomacromolecules. Asian J Org Chem 2022, 11(2), e202100389. https://doi.org/10.1002/ajoc.202100389. [68] Karamthulla, S, Pal, S, Khan, MN, Choudhury, LH. “On-water” synthesis of novel trisubstituted 1, 3-thiazoles via microwave-assisted catalyst-free domino reactions. RSC Adv 2014, 4(71), 37889–37899. DOI: 10.1039/c4ra06239f. [69] Jin, H, Siddiqui, MA, Evans, CA, Tse, HA, Mansour, TS, Goodyear, MD, Ravenscroft, P, Beels, CD. Diastereoselective synthesis of the potent antiviral agent (-)-2ʹ-deoxy-3ʹ-thiacytidine and its enantiomer. J Org Chem 1995, 60(8), 2621–2623. http://dx.doi.org/10.1016/j.tetlet.2014.05.062. [70] Zamberlan, F, Fantinati, A, Trapella, C. 1, 4‐Dithiane‐2, 5‐diol: An attractive platform for the synthesis of sulfur‐containing functionalized heterocycles. Eur J Org Chem 2018, 6(25), 3248–3264. DOI: 10.1002/ejoc.201701785. [71] Chinnaraja, D, Rajalakshmi, R. A facile, solvent and catalyst free, microwave assisted one pot synthesis of hydrazinylthiazole derivatives. J Saudi Chem Soc 2015, 19(2), 200–206. [72] Chakraborti, AK, Rudrawar, S, Jadhav, KB, Kaur, G, Chankeshwara, SV. “On water” organic synthesis: A highly efficient and clean synthesis of 2-aryl/heteroaryl/styrylbenzothiazoles and 2-alkyl/aryl alkyl benzothiazolines. Green Chem 2007, 9(12), 1335–1340. DOI: 10.1039/b710414f. [73] Wang, L, Shi, LX, Liu, L, Li, ZX, Xu, T, Hao, WJ, Li, G, Tu, SJ, Jiang, B. Synthesis of diastereo-enriched oxazolo [5, 4-b] indoles via catalyst-free multicomponent bicyclizations. J Org Chem 2017, 82(7), 3605–3611. DOI: 10.1021/acs.joc.7b00129. [74] Gonçalves, RS, Kaiser, CR, Lourenço, MC, De Souza, MV, Wardell, JL, Wardell, SM, Da Silva, AD. Synthesis and antitubercular activity of new mefloquine-oxazolidine derivatives. Eur J Med Chem 2010, 45(12), 6095–6100. [75] Chen, X, Huang, Z, Xu, J. Catalyst‐free electrophilic ring expansion of N‐unprotected aziridines with α‐oxoketenes to efficient access 2‐alkylidene‐1, 3‐oxazolidines. Adv Synth Catal 2021, 363(12), 3098–3108. DOI: 10.1002/adsc.202100320. [76] Meshram, HM, Rao, NN, Rao, LC, Kumar, NS. Microwave assisted catalyst-free synthesis of aza arene-substituted 3-hydroxy-2-oxindoles by the functionalization of sp3 C–H bond in methyl pyridine. Tetrahedron Lett 2012, 53(31), 3963–3966. http://dx.doi.org/10.1016/j.tetlet.2012.05.077. [77] Gao, Y, Zhang, GN, Wang, J, Bai, X, Li, Y, Wang, Y. One-pot synthesis of 3-Functionalized 4hydroxycoumarin under catalyst-free conditions. Molecules 2018, 23(1), 235. https://doi.org/10.3390/ molecules23010235.
Chetna Ameta Dharmendra, Yogeshwari Vyas, Purnima Chaubisa, Abhilasha Jain, and Suresh C. Ameta✶
Chapter 2 Microwave-assisted synthesis of N-heterocycles 2.1 Introduction A specific position was reserved for heterocyclic compounds among the synthetic and natural molecules that are essential for pharmaceutical industry. Because their scaffolds are present in natural products, like hormones, vitamins, antibiotics, alkaloids, herbicides, and nucleic acids (DNA and RNA), nitrogen-based compounds are abundant in nature and these are of vital significance to life. Given the widespread use of Nheterocycles, it is essential to create techniques that will improve their synthesis efficiency and study of their modifications that would affect their biological efficacy. There are numerous time-consuming procedures available for the synthesis of N-heterocyclic compounds and there has been a continual effort to create more effective synthetic processes, since organic synthesis has begun to adhere to green principles as a result of the continuously changing environment calling for sensible and sustainable chemistry. As a part of that, traditional heating method was substituted with microwave (MW) radiation [1–4]. In recent years, medical chemists have used MW-assisted organic synthesis (MAOS) to accelerate the synthesis of complicated heterocyclic structures. The usage of MW energy has rapidly increased due to novel and creative applications in the fields of organic and peptide synthesis, polymer chemistry, material sciences, nanotechnology, and biological processes. Dielectric volumetric heating is used in MAOS to generate heat. Because of the homogeneous heat distribution, this method produces faster and more selective reactions. This “superman heat vision” effect is based on temperature rise caused by dielectric heating, which happens via two mechanisms: (i) dipolar polarization and (ii) ionic conduction. The advantages of using MW irradiation in organic synthesis are: – efficient source of heating, – uniform heating, – selective heating, – reproducibility,
✶
Corresponding author: Suresh C. Ameta, Department of Chemistry, PAHER University Udaipur, Rajasthan, India, e-mail: [email protected] Chetna Ameta Dharmendra, Yogeshwari Vyas, Purnima Chaubisa, Department of Chemistry, University College of Science, M. L. Sukhadia University, Udaipur 313001, Rajasthan, India Abhilasha Jain, Department of Chemistry, St. Xavier’s College, Mumbai 400001, Maharashtra, India https://doi.org/10.1515/9783110980189-002
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increased rate of reaction, high yields, and eco-friendly chemistry.
Shorter reaction times, higher yields, milder reaction conditions, neat reactions, solvent free reactions, that worked well under MW, higher purity of the products formed, and a reduction in the rate of by-product formation are the main benefits of using MW heating over conventional heating techniques. All of these characteristics get MW-assisted reactions closer to an environmentally friendly and green method [5–8]. Here, in this chapter, the developments in the MW-assisted synthesis of some nitrogen-based heterocyclic compounds and their derivatives have been summarized.
2.2 Microwave-assisted synthesis of five-membered heterocycles with one N-atom 2.2.1 Synthesis of pyrrole and its derivatives Mir et al. [9] reported a simple and extremely effective approach for the synthesis of substituted pyrrole-3-methanols (3) using iminonitriles (1) and succinaldehyde (2) under MW irradiation (Figure 2.1). The direct Mannich reaction, cyclization, and dehydrocyanation, followed by the NaBH4 reduction sequence, were carried out using onepot approach with high (up to 75%) yields. The quick synthesis of polycyclic heterocycles, like pyrrolo-dihydrochromene and pyrrolo-dihydroquinoline molecules (4), serves as representative examples.
Figure 2.1: Synthesis of substituted pyrrole-3-methanols.
Feller and Imhof [10] studied the four-component reaction of an α,β-unsaturated aldehyde (5) and a primary amine (6) with carbon monoxide (7) and ethylene (8) under MW irradiation in the presence of Ru3(CO)12 as a precatalyst, giving mixtures of chiral γ-lactams (9) and substituted pyrrole derivatives (10) (Figure 2.2). Monitoring of the substrates, intermediates, and products during the synthetic process became possible due to the ability to take samples of the reaction mixture, while maintaining the ap-
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plied pressure of gas phase. MW irradiation significantly reduces reaction durations as compared to conventional thermal reactions; moreover, it requires lower carbon monoxide and ethylene partial pressures, and involves less precatalyst loading.
Figure 2.2: Synthesis of substituted pyrrole derivatives.
Hassani et al. [11] revealed that chitosan can be used as a green and reusable catalyst for solvent-free synthesis of substituted pyrroles (15) in high yields. This four-component reaction was completed using aldehydes (11), amines (13), 1,3-dicarbonyl compounds (12), and nitromethane (14). When the reaction was investigated under MW irradiation, the yield of the reaction was maximum (91%), and the reaction time was dramatically reduced from several hours to 4–7 min (Figure 2.3).
Figure 2.3: Synthesis of polysubstituted pyrroles catalyzed by chitosan under MW irradiation.
Mishra et al. [12] developed the reaction of phenylglyoxal monohydrate (16), 4hydroxycoumarin (17), and 7-amino-4-methylcoumarin (18) in the weakly acidic medium under MW conditions, which provided the corresponding regioselective fused pyrroles (19) having hydroxycoumarin and aryl moieties. The maximum yield (88%) was observed in acetic acid as the reaction medium under MW exposure at 130 °C for 30 min (Figure 2.4). Jad et al. [13] reported solid-phase multicomponent synthesis of peptide-pyrrole derivatives (22) using amino acid lysine (21) as a nitrogen donor, β-nitrostyrenes (20), 1,3-dicarbonyl compounds (12), and FeCl3 as an easily accessible catalyst under MW
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irradiation. The reaction was carried out in the presence of FeCl3 (0.5 equiv.) as a catalyst in DMF at 100 °C under MW irradiation for 10 min (Figure 2.5).
Figure 2.4: Three-component synthesis of coumarin-fused pyrroles.
Figure 2.5: Synthesis of peptide-pyrrole derivatives.
Manta et al. [14] synthesized novel pyrrole derivatives (26) under MW irradiation via one-step multicomponent reaction of sodium diethyl oxalacetate (24) with an equimolar amount of various aromatic aldehydes (23) and primary amines (25) in ethanol. It was observed that as-synthesized compounds showed noteworthy activity against leukemia and antiviral activities in various cell culture lines. MW irradiation (100 W) at 110 °C for 20 min was selected as the optimum condition for the reaction (Figure 2.6).
Figure 2.6: Synthesis of substituted pyrrole derivatives under MW irradiation.
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Mondal et al. [15] reported DABCO (1,4-diazabicyclo[2.2.2]octane)-based amphoteric ionic liquid-supported TiO2 nanoparticles (NPs) as a reusable, quasi-heterogeneous catalyst for MW-assisted solvent-free synthesis. TiO2-[DABCOC2COOH]+[Br]-has both acidic and basic catalytic sites and can produce maximum yields of the desired products (95%) within a shorter reaction time. The penta-substituted pyrrole synthesized (29) from βcarbonyl ester (11), phenyl glyoxal (16), cyclic 1,3-dione (28), and amines (27) catalyzed by TiO2-[DABCOC2COOH]+[Br]– and N-substituted pyrrole derivatives were prepared from dialkyl acetylene dicarboxylate, phenyl glyoxal, cyclic 1,3-dione, and amines (Figure 2.7). A diverse series of pyrrole derivatives (31) was synthesized using dialkyl acetylene dicarboxylate (30) instead of β-keto ester (Figure 2.8). They reported that MW irradiation in TiO2-[DABCOC2COOH]+[Br]– at 60 °C for 10 min was the most favorable condition for this reaction.
Figure 2.7: Synthesis of polysubstituted pyrroles with β-keto ester.
Figure 2.8: Synthesis of polysubstituted pyrroles with dialkyl but-2-ynedioate.
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Georgescu et al. [16] reported a one-pot, three-component MW-assisted synthesis of a library of novel pyrrolo[1,2-c]quinazoline derivatives (35) using quinazolines (32), 2-bromoacetyl derivatives (33), and electron-deficient alkynes (34) in 1,2-epoxybutane via 1,3-dipolar cycloaddition of quinazolinium N-ylides. This route provides an easy and quick access to a wide variety of pyrrolo[1,2-c]quinazoline derivatives (Figure 2.9).
Figure 2.9: Synthesis of pyrrolo[1,2-c]quinazoline derivatives.
A novel method for the multicomponent synthesis of substituted 2H-chromene-fused pyrrole derivatives was reported by Baral et al. [17]. An array of 3-nitro-2H-chromenes (36), aniline (37), and acetylacetone (12) was used to produce a variety of chromenebased pyrroles (38) in toluene under MW irradiation (Figure 2.10). The synthesis of 2Hchromene-fused pyrrole motifs using FeCl3 as a prompt catalyst and MW irradiation significantly shortened the reaction time and led to good yields (83–95%).
Figure 2.10: Synthesis of chromene-based pyrroles in toluene under microwave irradiation.
Khan et al. [18] developed a cross-metathesis between N-allylamines (39) and α, βunsaturated carbonyl compounds (40) for the fast synthesis of various pyrrole derivatives (41) with moderate-to-good yields (Figure 2.11). This approach is simple, quick, and high yielding. The MW irradiation conditions were around 10 times more favorable than conventional heating for the interconversion of ruthenacyclobutane (RuG to RuH) as evident from computational analysis. Kamel et al. [19] reported the synthesis of pyrrolo[2,3-b]pyrrole derivatives (42–47) under MW irradiation (Figure 2.12).
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Figure 2.11: Synthesis of N-substituted pyrrole derivatives.
Figure 2.12: Synthesis of pyrrolo[2,3-b]pyrrole derivatives under MW irradiation.
Venkatesan et al. [20] studied the effective and simple production of functionalized pyrroles (48) utilizing a UO2(NO3)2.6H2O catalyst under MW irradiation. The synthesis of pyrrole using the uranyl nitrate hexahydrate catalyst provides several benefits, including quick activity, good yields, and a shortening of reaction durations in ethanol media (Figure 2.13).
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Figure 2.13: Synthesis of functionalized pyrrole derivatives under MW irradiation.
2.2.2 Synthesis of pyrrolidines and pyrrolidinones Khaligh et al. [21] carried out MW-assisted synthesis of pyrrolidinones (50) catalyzed by 1,1ʹ-butylene-bis(3-sulfo-3H-imidazol-1-ium) chloride as a sulfonic acid-functionalized ionic liquid in ethylene glycol as a green solvent. A mixture of aryl aldehyde (49), arylamine derivatives (13), diethyl acetylenedicarboxylate (30), and [BBSI]Cl catalyst was stirred in ethylene glycol. The reaction mixture was subjected to MW irradiation of 100 W at room temperature for 5 min (Figure 2.14). The effect of electron-withdrawing and electron-donating groups on aniline derivatives was studied under conventional heating and also on MW irradiation.
Figure 2.14: Microwave-assisted synthesis of pyrrolidinone derivatives.
Hegde et al. [22] reported a one-pot four-component tandem reaction for the synthesis of regioselective dispiropyrrolidine analogues (51) in the presence of magnesium silicate NPs in ethanol under MW irradiation. The reaction proceeds quickly, and it can be finished in 60–90 min (Figure 2.15). This approach has several important benefits, including high yields, mild catalyst, and ease of use. Nayak et al. [23] synthesized diverse spiroindenoquinoxaline pyrrolidine-fused nitrochromene derivatives (55 and 57) via one-pot three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the condensation of indenoquinoxalone (52) and α-amino acids (L-proline (53) and L-phenyl alanine (56)) with 3-nitrochromenes (54) as dipolarophile under classical as well as MW irradiation (Figure 2.16). They also studied versatile protocol for the synthesis of spiroindanone pyrrolidine/piperidine-fused nitrochromene derivatives (59) through a one-pot, three-component
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Figure 2.15: Microwave-assisted synthesis of regioselective dispiropyrrolidine analogues.
Figure 2.16: Synthesis of diverse spiroindenoquinoxaline-pyrrolidine-fused nitrochromene derivatives.
1,3-dipolar cycloaddition reaction of 2-phenyl-nitrochromene dipolarophile derivatives (58) with azomethine ylides, generated in situ from decarboxylative condensation of indane1,3-dione (56) with proline (57) under conventional heating as well as under MW irradiation (Figure 2.17). It was found that the cycloaddition process was highly regiospecific and diasterospecific [24].
Figure 2.17: Synthesis of spiroindanone pyrrolidine/piperidine-fused nitrochromene derivatives.
Sreekanth and Jha [25] synthesized 1-acetyl-2-benzylpyrrolidine-2-carboxylic acid (61) and its derivatives in four steps using 2-benzyl-tert-butylpyrrolidine-1,2-dicarboxylate as initial compound (60) under MW irradiation with better yields (Figure 2.18).
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Figure 2.18: Synthesis of 1-acetyl-2-benzylpyrrolidine-2-carboxylic acid and its derivatives.
2.2.3 Synthesis of indole and its derivatives Lin et al. [26] used MW-assisted environmentally benign protocols for the regioselective synthesis of 3-functionalized indole derivatives (64) through a three-component reaction of anilines (62), arylglyoxal monohydrates (16), and cyclic 1,3-dicarbonyl compounds (63). The favorable reaction conditions were 1:1 (v/v) ethanol/water at 90 °C for 40 min under MW irradiation catalyzed by TFA (Figure 2.19).
Figure 2.19: Microwave-assisted synthesis of 3-functionalized indole derivatives.
Baharfar et al. [27] reported an eco-friendly synthesis of indole-based 4,5-dihydrofurans (68) via a reaction of 3-cyanoacetyl indoles (65) with various aldehydes (66) and Nphenacylpyridinium bromides (67) in the presence of potassium carbonate as an inex-
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pensive and nontoxic base in water. The products were obtained in 85–98% yields in 4–20 min (Figure 2.20).
Figure 2.20: MW-assisted diastereoselective synthesis of indole-based 4,5-dihydrofurans.
Patel et al. [28] carried out the synthesis of 3-(3-oxoaryl) indole derivatives (71) using the efficient Lewis acid catalyst ZrCl4. The desired compounds were synthesized by the Michael addition of 2-phenylindole (69) with chalcones (70) under MW-assisted and solvent-free conditions (Figure 2.21).
Figure 2.21: MW-assisted synthesis of 3-(3-oxoaryl) indole derivatives.
Rathod et al. [29] reported one-pot, solvent-free, and green Betti’s reaction for the synthesis of isoniazid derivatives (77–79) by the reaction of various indole-3-carbaldehydes (72), phenols (74–76), and isoniazid (73). The same compounds were also obtained using a conventional method. The proposed approach is attractive due to the shorter reaction time and high yields (Figure 2.22). Bellavita et al. [30] developed a convenient method for producing a variety of 2methyl-1H-indole-3-carboxylate derivatives (81) from commercially available anilines (80) by various electron-withdrawing and electron-donating groups through an intramolecular palladium-catalyzed oxidative coupling (Figure 2.23). By exposing the pure mixture of reactants to MW irradiation, the conversion of a series of enamines into the relevant indole was optimized, resulting in the required products with high yields and regioselectivities.
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Figure 2.22: MW-assisted synthesis of isoniazid derivatives.
Figure 2.23: Synthesis of functionalized 2-methyl-1H-indole-3-carboxylate derivatives.
2.3 Synthesis of five-membered heterocyclic compounds with two N-atoms 2.3.1 Synthesis of imidazole derivatives Hanoon et al. [31] used 8-hydroxy-7-iodoquinoline-5-sulfonic acid (HISA) as the catalyst for a multicomponent condensation of benzil (82), aromatic aldehydes (83), and ammonium acetate (84) under MW irradiation in ethanol as solvent for the synthesis of 2,4,5triarylsubstituted imidazole derivatives (85) obtained in 61–97% yields (Figure 2.24).
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Figure 2.24: MW-assisted synthesis of 2,4,5-triarylsubstituted imidazole derivatives.
Bai et al. [32] synthesized N-[1-(imidazole-1-yl)alkyl]amides using MW-assisted one-pot multicomponent reaction between imidazole (86), substituted benzaldehydes (87), and substituted benzamides (88) to the synthesis of N-[1-(imidazole-1-yl)alkyl]amides (89). These imidazoles act as indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors (Figure 2.25). The desired product displayed IC50 values of 0.82 μΜ. The in vivo assessment indicated that the desired compound reduced the kynurenine levels in plasma by 42.3% in 4 h, indicating that the compound could act as a promising lead compound for further investigations.
Figure 2.25: Synthesis of N-[1-(imidazole-1-yl)alkyl]amides using MW irradiation.
Cheldavi and Mohammadi [33] synthesized phenanthro[9,10-d]imidazole derivatives (92) with the combinations of phenanthroquinone (90) and benzaldehyde derivatives
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(91) in the presence of ammonium acetate (84). This protocol was investigated under MW irradiation (400 W) at 80 °C for 2 min (Figure 2.26).
Figure 2.26: Synthesis of phenanthro[9,10-d]imidazole derivatives.
A one-step reaction was carried out between aromatic aldehydes and 2,3-diaminomaleonitrile (93) by Kalhor et al. [34] for the synthesis of 2-aryl-4,5-dicarbonitrile imidazole derivatives (94) using HNO3 as a metal-free catalyst and a strong oxidizing agent under the effect of MWs (Figure 2.27).
Figure 2.27: Synthesis of 2-aryl-4,5-dicarbonitrile imidazole derivatives.
Tambe et al. [35] developed fresh heterogeneous catalyst pumice (a porous rock-like structure)-supported sulfonic acid (pumice@SO3H) through natural pumice by straightforward agitation with chlorosulfonic acid. It was reported that this catalyst was utilized for the synthesis of 2,4,5-triaryl imidazoles (95) and acridine-1,8-diones under the MW-assisted solvent-free condition (Figure 2.28). The pumice@SO3H showed an excellent Bronsted acidic nature and it was found stable. The recyclability of the catalyst, the
Figure 2.28: Synthesis of 2,4,5-triaryl imidazoles and acridine-1,8-diones under microwave.
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solvent-free method, good to exceptional yields, and ease of use are the favorable characteristic features noted with this methodology.
2.3.2 Synthesis of pyrazole derivatives An MW-irradiated green protocol for the synthesis of 4,5-dihydro-1H-pyrazole-1carbothioamides (98) from aryl aldehydes (23), acetophenones (96), and thiosemicarbazide (97) using water as a solvent in the presence of tetrabutylammonium hydroxide was reported by Farmani et al. [36] (Figure 2.29).
Figure 2.29: Synthesis of 4,5-dihydro-1H-pyrazole-1-carbothioamides under MW irradiation.
Yazdani-E-Abadi et al. [37] synthesized novel spirooxindole-furo[2,3-c]pyrazole derivatives (101) from hydrazine (99), β-keto ester (12), isatin derivatives (100), and pyridinium ylide (67) in ethanol under MW irradiation at 70 °C, through one-pot two-step four-component reaction catalyzed by triethylamine (Figure 2.30).
Figure 2.30: Synthesis of novel spirooxindole-furo[2,3-c]pyrazole derivatives under MW irradiation.
Bayannavar et al. [38] carried out L-proline-catalyzed MW-assisted synthesis of pyrazolyl-tetrahydroindazolones (105) in polyethylene glycol-400 (PEG-400) via a three-
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component domino reaction of arylhydrazine (102), dimedone (103), and pyrazole aldehyde (104) (Figure 2.31).
Figure 2.31: L-Proline-catalyzed MW-assisted synthesis of pyrazolyl-tetrahydroindazolones.
Sood et al. [39] synthesized pyrazole-4-carbonitriles (106) by condensation of pyrazole-4-carbaldehydes with hydroxylamine hydrochloride, followed by a reaction of the resulting oximes with the Vilsmeier–Haack reagent prepared from phthaloyl dichloride and dimethylformamide under MW irradiation (Figure 2.32).
Figure 2.32: Synthesis of pyrazole-4-carbonitriles.
A series of novel pyrazole-oxopyrrolidine derivatives (107) was synthesized by Jassem et al. [40] through a one-pot multicomponent Ugi reaction under MW in a solvent-free manner (Figure 2.33).
Figure 2.33: Synthesis of pyrazole-oxopyrrolidine derivatives.
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Dhibi et al. [41] used MW irradiation to synthesize a novel series of 5-amino-1Hpyrazole derivatives (112–114) with 2-furoyl moieties from 2-cyano-3-ethoxyacrylonitrile or ethyl-2-cyano-3-ethoxyacrylate (108) and different furan-2-carbohydrazide compounds (109–111) in good yields (Figure 2.34).
Figure 2.34: Synthesis of series of 5-amino-1H-pyrazole derivatives with 2-furoyl moieties.
2.4 Synthesis of triazole derivatives Mahmoud et al. [42] synthesized novel hydrosoluble and air-stable Cu(I)-DAPTA complexes by reacting Cu(I) halide (bromide or iodide) with 3,7-diacetyl-1,3,7-triaza-5phosphabicyclo [3.3.1]nonane (DAPTA) under mild conditions using an MW-assisted three-component azide–alkyne cycloaddition click reaction. This catalyst is applied to the synthesis of disubstituted triazoles (118) from the Huisgen cycloaddition reaction of a terminal alkyne (115), organic halide (116), and NaN3 (47) in an aqueous medium (Figure 2.35).
Figure 2.35: One-pot multicomponent synthesis of 1,2,3-triazoles.
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Carreiro et al. [43] synthesized novel (1,4-disubstituted 1,2,3-triazole)-dihydropyrimidinone (1,2,3-trzl-DHPM)-type hybrids via multicomponent 1,3-dipolar cycloaddition (click)– Biginelli reactions. These hybrids are divided into two types: (i) Hybrid A: It contains dihydropyrimidinone heterocyclic ring decorated with a 1,4-disubstituted 1,2,3-triazole in the C-5 position (123). These derivatives were synthesized by copper(I)-catalyzed azide–alkyne Huisgen 1,3-dipolar cycloaddition (CuAAC) reaction of 1-azidopropan-2-one (119), phenylacetylene (122), benzaldehyde (121), and urea (120) with 39–57% yields. (ii) Hybrid B: It contains two 1,2,3-triazole moieties (124) in the C-5 and C-6 methyl positions of the DHPM. Hybrid B (excellent yields up to 99%) prepared by multistep sequence reaction included bromination, azidation, and CuAAC with functionalization of the C-6 methyl group of hybrid A. A few species from the family of hybrid A and hybrid B were evaluated for their antiproliferative activity against different cancer cell lines such as A549 and SW1573 (nonsmall-cell lung), HBL-100, T-47D (breast), HeLa (cervix), and WiDr (colon). It was found that three of these hybrids are potent cell proliferation inhibitors of non-smallcell lung cancer, colon cancer, breast cancer, and cervix cancer (Figure 2.36).
Figure 2.36: Synthesis of novel (1,4-disubstituted 1,2,3-triazole) dihydropyrimidinone (1,2,3-trzl-DHPM)type hybrids.
Mokariya et al. [44] prepared 3-formyl-indole-clubbed 1,4-disubstituted-1,2,3-triazole derivatives (125) with the aid of CuI catalyst under acceleration of simultaneous ultrasound
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and MW irradiation in a very short reaction time using an eco-friendly, high yielding, and promising one-pot protocol (Figure 2.37).
Figure 2.37: Synthesis of 3-formyl-indole-clubbed 1,4-disubstituted-1,2,3-triazole derivatives.
2.5 Synthesis of tetrazole derivatives Akbarzadeh et al. [45] developed the synthesis of 5-substituted-1H-tetrazoles (128) through multicomponent 1,3-dipolar cycloaddition reaction between aromatic aldehydes (126), malononitrile (127), and sodium azide (116) using Fe3O4 magnetic NPs under solvent-free conditions and MW irradiation (Figure 2.38).
Figure 2.38: Synthesis of 5-substituted-1H-tetrazoles under MW irradiation.
Jasim et al. [46] developed an eco-friendly synthesis of 1-substituted-1H-1,2,3,4-tetrazoles, as well as 5-substituted-1H-tetrazoles (120) using TAIm[I] ionic liquid as a suitable medium. Here, N3– ion was present, and TAIm[N3] active species were responsible for accelerating the processes under both MW and ultrasonic irradiation (Figure 2.39).
Figure 2.39: Synthesis of 5-substituted-1H-tetrazoles under MW irradiation.
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Padmaja and Chanda [47] synthesized 5-substituted-1H-tetrazoles (130) under MW irradiation using a unique and strong ionic liquid-supported copper(II) catalyst. The catalyst assisted by an ionic liquid made it easier to isolate high-purity tetrazole compounds with minimal effort using an organic solvent (Figure 2.40).
Figure 2.40: Synthesis of 5-substituted-1H-tetrazoles under microwave irradiation.
2.6 Synthesis of six-membered heterocyclic compounds with one N-atom 2.6.1 Synthesis of pyridine derivatives Maddila et al. [48] developed a green catalyst-free MW-assisted synthesis of polyfunctionalized 1,4-dihydropyridine derivatives (131) through a one-pot multicomponent reaction in EtOH solvent (Figure 2.41). The advantages of this approach are: no column chromatography is needed, the reaction times are short (97% ee), which was further converted into (+)-agelastatin A through four additional steps. The first one comprised a copper-promoted aziridination of the domino product into a tetracyclic aziridine, which was subsequently treated with In(OTf)3 to provide a tricyclic α-amino
Figure 13.5: Synthesis of (+)-agelastatin A.
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ketone. In the presence of Cs2CO3, the latter subsequently reacted with methyl isocyanate to produce the corresponding tetracyclic product. A final SmI2-mediated radical reduction furnished deprotected (+)-agelastatin A. It is noted that this result could also be mentioned in Section 13.4 dealing with P,N-ligands. In 2012, an asymmetric copper-catalyzed domino-reductive Michael/aldol cyclization reaction was developed by Riant et al. [55] to be applied as a key step in a total synthesis of naturally occurring diterpene marrubiin, which is an antinociceptive and expectorant agent (Figure 13.6). The one-pot reaction took place through enantioselec-
Figure 13.6: Formal synthesis of marrubiin.
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tive reductive Michael addition of a diketoester with phenylsilane promoted by a chiral copper complex of a chiral Taniaphos ligand, resulting in the formation of the corresponding bicyclic product as a single cis-diastereomer in 80% yield and 95% ee. Then, the latter was dehydrated through successive treatments with TFA, TMSCH2N2, and SOCl2 to yield a nonconjugated cyclohexenone. Methylation of this product in the presence of methyl iodide and LDA afforded the desired bicyclic ester, which represented a key intermediate in a total synthesis of marrubiin [56]. Natural product (+)-lycorine is known to have promising biological activities, such as antibacterial, antiviral, or anti-inflammatory properties. In 2015, Lete et al. [57] disclosed a novel route to the core of this alkaloid, which was based on an asymmetric intramolecular domino double Heck process of N-benzyl-2,3-dialkenylpyrroles (Figure 13.7). This reaction was promoted by a combination of Pd(OAc)2 with (R)BINAP in the presence of a base, such as 1,2,2,6,6-pentamethylpiperidine (PMP), which afforded the corresponding pyrrolophenanthridines in 38–68% yield and 7–72% ee.
Figure 13.7: Synthesis of the framework of (+)-lycorine.
The development of efficient methods to synthesize chiral oxindoles is challenging related to their numerous biological activities [58–60]. In 2019, Hu et al. [61] investigated the asymmetric reaction of N-(2-iodophenyl)-N-alkyl-acrylamides exhibiting a branched homoallylic alcohol under CO pressure promoted by a chiral bisphosphine palladium catalyst in toluene as the solvent (Figure 13.8). The latter was in situ generated from Pd2
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(dba)3 and an achiral bisphosphine ligand. An intramolecular carbopalladation performed in the presence of K2CO3 as the base followed by a carbonylative lactonization occurred to give the corresponding chiral spirooxindole δ- or γ-lactones with moderate to high yields (51–93%) and high enantioselectivities (91–96% ee). This novel and highly enantioselective domino palladium-catalyzed Heck/carbonylative lactonization reaction was applied in the total synthesis of natural anticancer product coixspirolactam A. Indeed, one domino product (R1 = R2 = H, R3 = PMB, n = 0) obtained with 76% yield was subjected to deprotection by treatment with TFA to afford expected coixspirolactam A with 92% yield and 99% ee (Figure 13.8).
Figure 13.8: Synthesis of coixspirolactam A.
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In addition to chiral spirooxindole γ- and δ-lactones, their lactam analogs could also be synthesized by extending the same methodology to related substrates bearing an intramolecular nitrogen nucleophile instead of an alcohol group (Figure 13.9). Indeed, the related enantioselective domino palladium-catalyzed Heck/carbonylative lactamization reaction of these amines afforded the corresponding chiral spirooxindole
Figure 13.9: Synthesis of receptor antagonist CRTH2.
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γ- and δ-lactones/lactams with good to quantitative yields (69–99%) and moderate to excellent enantioselectivities (67–99% ee), as presented in Figure 13.9. The utility of this methodology was applied to a total synthesis of receptor antagonist CRTH2. As detailed in Figure 13.9, one domino product (R1 = Cl, R2 = H, R3 = PMB, R4 = p-MeOC6H4) could be converted into the expected almost enantiopure bioactive species (98% ee) through four following steps including benzylation, deprotection of the PMB group, alkylation, and hydrolysis. The precedent domino reactions (Figures 13.8 and 13.9) involved the putative mechanism depicted in Figure 13.10. After oxidative addition, the terminal alkene chelated to the Pd(II) center coordinated to the bidentate chiral bisphosphine ligand in “A,” according to an orientation with the side-chain stretching to the open area away from the ligand. Subsequently, a migratory insertion of the alkenyl moiety to Ar-Pd(II) generated the quaternary carbon center, and an alkyl Pd(II) species “B” then underwent CO insertion and nucleophilic cyclization to provide the final domino products.
Figure 13.10: Mechanism for domino Heck/carbonylative lactonization/lactamization reactions.
13.3 Bisoxazoline ligands Chiral bisoxazolines are among the most widely employed chiral ligands in asymmetric metal catalysis [62, 63]. In 2006, Tietze et al. [64] employed this type of ligands in combination with Pd(TFA)2 to catalyze an enantioselective domino Wacker/Heck reaction between methyl vinyl ketone and a benzyl-protected phenol, constituting the key step of a novel total synthesis of vitamin E (Figure 13.11). Indeed, this one-pot process occurred at room temperature in dichloromethane as solvent in the presence of Pd
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(TFA)2 and (S,S)-Bn-BOXAX along with p-benzoquinone as reoxidant, which produced the corresponding chiral chroman in 84% yield and 97% ee. The conversion of this product into desired vitamin E was achieved through six additional steps, the first of which comprised a hydrogenation on PtO2. The boron enolate of the thus-formed hydrogenated product was obtained in the presence of c-Hex2BCl and DIPEA as base. The latter species then underwent aldol reaction with a chiral aldehyde to yield an enone after treatment with p-toluenesulfonic acid. Further treatment of the latter intermediate with methyl lithium led to a tertiary alcohol, which was transformed into a diene through
Figure 13.11: Synthesis of vitamin E.
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elimination mediated by p-toluenesulfonic acid. This product was finally simultaneously deprotected and hydrogenated over Pd/C to provide the expected vitamin E. In another context, a total synthesis of dopamine D1 agonist A-86929 was described in 2011 by Hajra and Bar [65] on the basis of an asymmetric copper-catalyzed domino aziridination/Friedel−Crafts cyclization reaction (Figure 13.12). This reaction occurred at −25 °C between a functionalized styrene and PhINNs under catalysis with a combination of Cu(OTf)2 and a chiral bisoxazoline ligand in dichloromethane as solvent, which resulted in the formation of the corresponding chiral bicyclic domino product as single trans-diastereomer (>98% de) in 82% yield and 95% ee. This key intermediate was converted into desired A-86929 through four additional steps, beginning with the reaction of its sodium salt generated in the presence of MOMCl and NaH, which led to a methoxy methyl ether. Then, the latter species was subjected to a Pictet−Spengler-type cyclization in the presence of TMSOTf to give a tetracyclic product, which was further deprotected in the presence of K2CO3 and p-methoxythiophenol to provide the corresponding secondary amine. Subsequent demethylation of this amine by treatment with BBr3 afforded expected A-86929. Later in 2016, a formal total synthesis of natural bioactive chroman (−)-siccanin was reported by Tietze et al. [66] (Figure 13.13). The key step of this procedure dealt with an enantioselective three-component reaction between an alkenyl phenol, methanol, and CO (1 atm) promoted by a chiral palladium catalyst in situ generated from Pd(TFA)2 and chiral bisoxazoline ligand (R,R)-Bn-BOXAX. In the presence of p-benzoquinone as oxidant, the domino Wacker/carbonylation reaction afforded a chroman in 71% yield and 93% ee, which could be converted into the expected (−)-siccanin through eight additional steps. The first one dealt with the reduction of the domino product by treatment with diisobutylaluminum hydride to give an aldehyde. Then, the latter was subjected to aldol condensation with a trimethylsilyl enol ether catalyzed by BF3(Et2O) yielding the aldol product. Treated with the Burgess reagent, the latter led to an enone as a major diastereomer, which was subsequently hydrogenated on Pd/C into a cyclohexanone. In the following step, a Peterson olefination afforded a methylene cyclohexane, which upon Sharpless dihydroxylation yielded the corresponding diol. The latter is a key intermediate in the total synthesis of (−)-siccanin described in 2003 by Trost et al. [67]. The key enantioselective domino Wacker/carbonylation reaction in the synthesis of (−)-siccanin can follow the mechanism depicted in Figure 13.14, beginning with the addition through the Si-face of the external C=C double bond of a palladium catalyst, which afforded the corresponding palladium intermediate. Then, the final product was obtained via successive CO insertion and methoxylation.
Chapter 13 Enantioselective metal-catalyzed domino reactions
Figure 13.12: Synthesis of A-86929.
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Figure 13.13: Synthesis of (−)-siccanin.
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Figure 13.14: Mechanism for the domino Wacker/carbonylation reaction.
13.4 P,N-ligands A total synthesis of toxic alkaloid (S)-(+)-coniine responsible of curare-type paralysis was reported by Knochel and coworkers [68] in 2006. The key step of this methodology dealt with an enantioselective copper-catalyzed three-component process between trimethylsilylacetylene, dibenzylamine, and butyraldehyde promoted by a combination of CuBr with (R)-QUINAP as P,N-ligand (Figure 13.15). This domino reaction led to the corresponding chiral propargylamine in 90% yield and 90% ee. This product was further transformed into the expected (S)-(+)-coniine through six additional steps. In the first one, desilylation in the presence of TBAF led to an alkyne, which was further deproto-
Figure 13.15: Synthesis of (+)-coniine.
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nated by treatment with n-BuLi and then alkylated in the presence of ethylene oxide. The resulting alcohol was silylated by treatment with TIPSCl, and then the formed ether was hydrogenated on Pd/C, desilylated with TBAF, and finally subjected to an intramolecular Mitsunobu reaction to deliver (S)-(+)-coniine. In 2015, Zhu and coworkers [69] reported a total synthesis of (+)-esermethole, which is a naturally occurring powerful inhibitor of acetyl-cholinesterase. The key step of this synthesis comprised in an unprecedented enantioselective palladiumcatalyzed domino Heck/intermolecular arylation reaction producing a chiral oxindole/azole bis-heterocyclic species as the key intermediate (Figure 13.16). This domino reaction occurred at 80 °C between N-aryl acrylamides and oxadiazoles in acetonitrile as the solvent in the presence of a combination of PdCl2(MeCN)2 and a chiral P, N-ligand as the catalyst system along with N,N,N,N-tetramethylguanidine as the base. This method allowed the synthesis of chiral bicyclic products with a quaternary stereogenic center in moderate to high yields (55–94%) and high enantioselectivities
Figure 13.16: Synthesis of (+)-esermethole.
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(85–99% ee). One product (R1 = R2 = Me, R3 = H, R4 = Ph) obtained with 94% ee and 71% yield was transformed into the desired (+)-esermethole through five additional steps. The first one involved the reduction of the oxindole with LiAlH4, giving a pyrroloindoline, which was further reacted with SmI2 resulting in the reductive cleavage of the hydrazine. Then, N-methylation by treatment with NaBH(OAc)3 and formaldehyde produced the N-methylated product. Finally, this compound was transformed into (+)-esermethole through successive regioselective bromination in the presence of NBS, and methoxylation of the resulting bromide was promoted by CuI.
13.5 Other ligands In 2004, a BINOL-derived sulfoxide chiral ligand was combined with Et2AlCl by Shibasaki ad coworkers [70] to promote an enantioselective aluminum-catalyzed three-component reaction between a pyridine derivative, a carbonyl chloride, and TMSCN. This domino reaction performed in dichloromethane as the solvent at −60 °C resulted in the formation of a chiral cyanide in 98% yield and 91% ee, as illustrated in Figure 13.17. The latter was used in a formal synthesis of CP-293019, which is a dopamine D4 receptor-selective antagonist. Indeed, this domino product was transformed into an important primary alcohol intermediate in the synthesis of CP-293019 through nine steps. This began with the hydrogenation of the domino product followed by a protection/deprotection sequence, affording a tetrahydropyridine. Reduction of the latter with NaBH3CN furnished a major diastereomer, which was further subjected to annulations producing a bicyclic diamine. Three additional steps afforded the key primary alcohol intermediate [71]. Later in 2010, Hashimoto and coworkers [72] described a total synthesis of a natural product exhibiting blood circulation properties on the basis of an enantioselective rhodium-catalyzed domino carbonyl ylide formation/1,3-dipolar cycloaddition reaction (Figure 13.18). The carbonyl ylide was generated from the corresponding diazo compound, which underwent asymmetric 1,3-dipolar cycloaddition with 4-hydroxy-3methoxyphenylacetylene. Promoted by chiral preformed dirhodium catalyst Rh2(STCPTTL)4, the reaction gave the cycloadduct with good yield (73%) and excellent enantioselectivity (95% ee). This product was converted into the desired natural product through eight additional steps. In the first time, the phenolic ester group of the cycloadduct was protected as a tert-butyldiphenyl silylether, which was further reacted with NaHMDS. Then, the subsequent addition of PhNTf2 followed by palladium-catalyzed reduction of the formed enol triflate afforded a 1,4-diene. Reduction of this compound with LiAlH4 followed by silylation afforded a diether, which underwent an allylic oxidation in the presence of SeO2, providing an allylic alcohol as a single diastereomer. Then, oxidation in the presence of MnO2 led to an enone, which was finally transformed into the expected natural product after deprotection by treatment with TBAF.
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Figure 13.17: Synthesis of CP-293019.
Using the enantiomeric catalyst Rh2(R-TCPTTL)4, the same domino reaction afforded the corresponding enantiomeric cycloadduct in 77% yield and 95% ee [73]. This product was also applied in the synthesis of another natural bioactive product descurainin through 12 subsequent steps (Figure 13.19). The first step involved hydrogenation of the domino product on Pd/C to give a single diastereomer of the corresponding saturated bicyclic product, which was then converted into an o-quinone by treatment with (KSO3)2NO in the presence of KH2PO4. In the presence of Na2S2O4, this compound was directly transformed into a catechol, which was further reacted with methyl iodide in the presence of K2CO3 resulting in the formation of a per-methylated product. The latter was then treated with NaHMDS, PhNTf2 followed by palladium-catalyzed reduction of the resulting enol triflate, which produced an alkene. The subsequent reduction of this compound with LiAlH4 furnished an alcohol, which was further regioselectively demethylated by treatment with NbCl5 into the corresponding phenol. Then, the two hydroxyl groups of this phenol were protected with TBDPSCl, thus producing a diether, which was then subjected to allylic oxidation in the presence of SeO2, followed by oxida-
Chapter 13 Enantioselective metal-catalyzed domino reactions
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Figure 13.18: Synthesis of a bioactive natural product.
tion in the presence of MnO2 to afford an enone. Subsequent deprotection of this enone by treatment with TBAF afforded final descurainin (Figure 13.19). In 2020, novel enantioselective domino Heck/carbonylative Suzuki reactions between N-aryl acrylamides, various nucleophiles, such as alcohols and CO were developed by Guan and coworkers [74] in the presence of a novel chiral monodentate
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Figure 13.19: Synthesis of descurainin.
Chapter 13 Enantioselective metal-catalyzed domino reactions
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phosphoramidite ligand (Figure 13.20). Promoted by a combination of this chiral ligand with Pd(TFA)2 in the presence of CsF or Cs2CO3 as base, the three-component domino Heck carbonylative/Suzuki reaction between N-aryl acryl-amides, alcohols, and CO performed at 45 or −10 °C in mesitylene as solvent afforded the corresponding chiral oxindoles exhibiting a β-carbonyl-substituted all-carbon quaternary stereocenter in good yields (62–89%) and excellent ee values (91–96% ee). It must be noted that these results represented the first enantioselective palladium-catalyzed domino Heck carbonylation reactions in the presence of CO promoted by a chiral monodentate ligand. The utility of this novel methodology was illustrated in the synthesis of three bioactive alkaloids such as (+)-folicanthine, (+)-physovenine, and (+)-physostigmine. Starting from one domino product (R1 = H, R2 = Me, R3 = N-methylindole) obtained with 71% yield and 90% ee, the synthesis of (+)-folicanthine was achieved through five steps, which are detailed in Figure 13.20. This domino product was then oxidized and alkylated with an α-bromoester to give an intermediate. Then, the latter underwent an ester/amide exchange reaction followed by a reductive amidation generating an intermediate. Finally, amide reduction of this intermediate with bis(2-methoxyethoxy) aluminum hydride (Red-Al) afforded expected (+)-folicanthine in 10% overall yield from starting N-aryl acrylamide. Two other bioactive alkaloids, such as (+) physovenine and (+)-physostigmine, could also be synthesized starting from another domino product (R1 = OMe, R2 = Bn, R3 = Me) produced with 85% yield and 91% ee (Figure 13.21). For the synthesis of (+)physovenine, the domino product was subjected to reduction with LiAlH4 which afforded the corresponding chiral tricyclic product. Then, the latter species was deprotected in the presence of BBr3 to give the corresponding phenol. This phenol subsequently reacted with methylisocyanate in the presence of sodium to give the final (+)-physovenine. Concerning the synthesis of (+)-physostigmine, the same domino product was converted into the corresponding amide by treatment with methylamine. The latter species was subsequently reduced with LiAlH4 into esermethole. Then, deprotection of the methyl ether with BBr3 followed by reaction of the formed phenol with methylisocyanate in the presence of sodium led to the desired (+)physostigmine.
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Figure 13.20: Synthesis of (+)-folicanthine.
Chapter 13 Enantioselective metal-catalyzed domino reactions
Figure 13.21: Synthesis of (+)-physovenine and (+)-physostigmine.
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13.6 Conclusions This chapter highlights the total synthesis of a variety of bioactive chiral heterocycles based on asymmetric metal-catalyzed domino reactions as the key steps. It demonstrated that these one-pot processes have allowed much complex bioactive heterocyclic architectures to be achieved from simple starting reagents. Among metals, the most employed are palladium and copper coordinated to different types of chiral ligands including bisphosphines, bisoxazolines, P,N-ligands, and phosphoramidates. Especially, a number of chiral palladium catalysts have been employed as promoters of enantioselective Heck-initiated domino reactions with enantioselectivities of up to 99% ee, which were applied as key steps in the total syntheses of different biologically active heterocycles, such as (+)-halenaquinone, (−)-xestoquinone, (−)-physostigmine, coixspirolactam A, (+)-esermethole, (+)-folicanthine, (+)-physovenine, and (+)-physostigmine. Moreover, palladium-catalyzed enantioselective Wacker-initiated domino reactions achieved with up to 96% ee have been employed in total syntheses of (−)-siccanin and vitamin E. Another type of palladium-catalyzed domino reaction based on a double allylic alkylation and performed with >97% ee was applied in the total synthesis of (+)agelastatin. Along with palladium, a greener metal, such as copper, was also successfully applied to promote different types of enantioselective domino reactions employed as key steps in total syntheses of important bioactive heterocycles. For example, a copper-catalyzed Michael-initiated domino reaction achieved with up to 98% ee has allowed the synthesis of marrubiin. Moreover, the total syntheses of (S)(+)-coniine and A-86929 have been developed on the basis of other asymmetric domino processes including multicomponent transformations with enantioselectivities of up to 95% ee. In addition to copper and palladium chiral catalysts, rhodium chiral complexes have been successfully employed to promote different types of domino reactions with up to 91% ee constituting the key steps in the total synthesis of CP293019. The field of asymmetric metal-promoted domino reactions will undoubtedly continue to be expanded as well as their applications in the total synthesis of biologically important heterocyclic products.
Abbreviations Ar BINAP BINOL Bn Boc BOXAX CAN dba
Aryl 2,2ʹ-Bis(diphenylphosphino)-1,1ʹ-binaphthyl 1,1ʹ-Bi-2-naphthol Benzyl tert-Butoxycarbonyl 2,2ʹ-Bis(oxazolyl)-1,1ʹ-binaphthyl Ceric ammonium nitrate (E,E)-Dibenzylideneacetone
Chapter 13 Enantioselective metal-catalyzed domino reactions
DDQ de DEAD DIBAL (DIBAL-H) DIFLUORPHOS DIPEA DMAP DMF DMSO ee Hex HMDS L LDA MOM Naph NBS NMI Ms M.S. NBS Ns Piv PMB PMP QUINAP Red-Al: r.t. Taniaphos TBAF TBDPS TCPTTL TEA Tf TFA THF TIPS TMG TMS Tol Ts
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2,3-Dichloro-5,6-dicyano-p-benzoquinone Diastereomeric excess Diethyl azodicarboxylate Diisobutylaluminium hydride 5,5ʹ-Bis(diphenylphosphino)-2,2,2ʹ,2ʹ-tetrafluoro-4,4ʹ-bi-1,3-benzodioxole Diisopropylethylamine 4-(Dimethylamino)pyridine N,N-Dimethylformamide Dimethylsulfoxide Enantiomeric excess Hexyl Hexamethyldisilazide Ligand Lithium diisopropylamide Methoxymethyl Naphthyl N-Bromosuccinimide N-Methylimidazole Mesyl Molecular sieves N-Bromosuccinimide Nosyl (4-nitrobenzene sulfonyl) Pivaloyl para-Methoxybenzyl 1,2,2,6,6-Pentamethylpiperidine 1-(2-Diphenylphosphino-1-naphthyl)isoquinoline Bis(2-methoxyethoxy)aluminum hydride Room temperature [2-Diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl) methane Tetrabutylammonium fluoride tert-Butyldiphenylsilyl N-Tetrachlorophthaloyl-tert-leucinate Triethylamine Trifluoromethanesulfonyl Trifluoroacetic acid Tetrahydrofuran Triisopropylsilyl 1,1,3,3-Tetramethylguanidine Trimethylsilyl Tolyl 4-Toluenesulfonyl (tosyl)
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References [1] [2]
[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]
Tietze, LF. Domino reactions in organic synthesis. Chem Rev 1996, 96, 115–136. Parsons, PJ, Penkett, CS, Shell, AJ. Tandem reactions in organic synthesis: Novel strategies for natural product elaboration and the development of new synthetic methodology. Chem Rev 1996, 96, 195–206. Tietze, LF, Rackelmann, N. Domino reactions in the synthesis of heterocyclic natural products and analogs. Pure Appl Chem 2004, 76, 1967–1983. Zhu, J, Bienaymé, H. Multicomponent reactions. Wiley-VCH: Weinheim, 2005. Tietze, LF, Brasche, G, Gericke, K. Domino reactions in organic synthesis. Wiley-VCH: Weinheim, 2006. Nicolaou, KC, Edmonds, DJ, Bulger, PG. Cascade reactions in total synthesis. Angew Chem Int Ed 2006, 45, 7134–7186. Padwa, A, Bur, SK. The domino way to heterocycles. Tetrahedron 2007, 63, 5341–5378. Touré, BB, Hall, DG. Natural product synthesis using multicomponent reaction strategies. Chem Rev 2009, 109, 4439–4486. Sorensen, EJ, Davies, HML. Special issue on rapid formation of molecular complexity in organic synthesis. Chem Soc Rev 2009, 38. Nicolaou, KC, Chen, JS. The art of total synthesis through cascade reactions. Chem Soc Rev 2009, 38, 2993–3009. Orru, RVA, Ruijter, E. Synthesis of heterocycles via multicomponent reactions, topics in heterocyclic chemistry, Vol. I and II. Springer: Berlin, 2010. Tietze, LF. Domino reactions – concepts for efficient organic synthesis. Wiley-VCH: Weinheim, 2014. Zhu, J, Wang, Q, Wang, M. Multicomponent reactions in organic synthesis. Wiley: Weinheim, 2014. Pellissier, H, Clavier, H. Enantioselective cobalt-catalyzed transformations. Chem Rev 2014, 114, 2775–2823. Herrera, RP, Marques-Lopez, E. Multicomponent reactions: Concepts and applications for design and synthesis. Wiley: Weinheim, 2015. Snyder, SA. Science of synthesis. Applications of domino transformations in organic synthesis. Thieme: Stuttgart Verlag, 2016, Vols. 1–2. Pellissier, H. Green copper catalysis in enantioselective domino reactions. Curr Org Chem 2018, 22, 2752–2779. Pellissier, H. The use of domino reactions for the synthesis of chiral rings. Synthesis 2020, 52, 3837–3854. Noyori, R. Asymmetric catalysts in organic synthesis. Wiley-VCH: New York, 1994. Beller, M, Bolm, C. Transition metals for organic synthesis. Wiley-VCH: Weinheim, 1998, Vol. I and II. Ojima, I. Catalytic asymmetric synthesis, second ed. Wiley-VCH: New York, 2000. Beller, M, Bolm, C. Metals for organic synthesis, second ed. Wiley-VCH: Weinheim, 2004. Tietze, LF, Hiriyakkanavar, I, Bell, HP. Enantioselective palladium-catalyzed transformations. Chem Rev 2004, 104, 3453–3516. Ramon, DJ, Yus, M. In the arena of enantioselective synthesis, titanium complexes wear the laurel wreath. Chem Rev 2006, 106, 2126–2208. Pellissier, H. Recent advances in enantioselective vanadium-catalyzed transformations. Coord Chem Rev 2015, 93–110. Pellissier, H. Enantioselective nickel-catalysed transformations. The Royal Society of Chemistry: Cambridge, 2016. Pellissier, H. Enantioselective titanium-catalysed transformations. Imperial College Press: London, 2016. Pellissier, H. Enantioselective silver-catalyzed transformations. Chem Rev 2016, 116, 14868–14917. Pellissier, H. Enantioselective magnesium-catalyzed transformations. Org Biomol Chem 2017, 15, 4750–4782.
Chapter 13 Enantioselective metal-catalyzed domino reactions
401
[30] Pellissier, H. Recent developments in enantioselective cobalt-catalyzed transformations. Coord Chem Rev 2018, 360, 122–168. [31] Pellissier, H. Recent developments in enantioselective vanadium-catalyzed transformations. Coord Chem Rev 2020, 418, 213395. [32] Pellissier, H. Enantioselective indium-catalyzed transformations. Synthesis 2021, 53, 1379–1395. [33] Ramon, DJ, Yus, M. Asymmetric Multicomponent Reactions (AMCRs): The new frontier. Angew Chem Int Ed 2005, 44, 1602–1634. [34] Pellissier, H. Asymmetric domino reactions. Part B: Reactions based on the use of chiral catalysts and biocatalysts. Tetrahedron 2006, 62, 2143–2173. [35] Pellissier, H. Asymmetric domino reactions. Part A: Reactions based on the use of chiral auxiliaries. Tetrahedron 2006, 62, 1619–1665. [36] Enders, D, Grondal, C, Hüttl, MRM. Asymmetric organocatalytic domino reactions. Angew Chem Int Ed 2007, 46, 1570–1581. [37] Chapman, CJ, Frost, CG. Tandem and domino catalytic strategies for enantioselective synthesis. Synthesis 2007, 1–21. [38] De Graaff, C, Ruijter, E, Orru, RVA. Recent developments in asymmetric multicomponent reactions. Chem Soc Rev 2012, 41, 3969–4009. [39] Clavier, H, Pellissier, H. Recent developments in enantioselective metal-catalyzed domino reactions. Adv Synth Catal 2012, 354, 3347–3403. [40] Pellissier, H. Stereocontrolled domino reactions. Chem Rev 2013, 113, 442–524. [41] Pellissier, H. Asymmetric domino reactions. The Royal Society of Chemistry: Cambridge, 2013. [42] Pellissier, H. Recent developments in enantioselective metal-catalyzed domino reactions. Adv Synth Catal 2016, 358, 2194–2259. [43] Chanda, T, Zhao, JC-G. Recent progress in organocatalytic asymmetric domino transformations. Adv Synth Catal 2018, 360, 2–79. [44] Pellissier, H. Recentdevelopments in enantioselective metal-catalyzed domino reactions. Adv Synth Catal 2019, 361, 1733–1755. [45] Pellissier, H. Asymmetric metal catalysis in enantioselective domino reactions. Wiley: Weinheim, 2019. [46] Pellissier, H. Syntheses of natural and biologically relevant products through asymmetric metalcatalyzed domino reactions. A review. Org Prep Proc Int 2019, 51, 311–344. [47] Shu, T, Cossy, J. Asymmetric desymmetrization of alkene-, alkyne- and allene-tethered cyclohexadienones using transition metal catalysis. Chem Soc Rev 2021, 50, 658–666. [48] Harris, GD, Herr, RJ, Weinreb, SM. Synthesis of bicyclic nitrogen compounds via tandem intramolecular Heck cyclization and subsequent trapping of intermediate π-allylpalladium complexes. J Org Chem 1993, 58, 5452–5464. [49] Meyer, FE, Ang, KH, Steinig, AG, De Meijere, A. Sequential Heck and Diels-Alder reactions: Facile construction of bicyclic systems in a single synthetic operation. Synlett 1994, 191–193. [50] Maddaford, SP, Andersen, NG, Cristofoli, WA, Keay, BA. Total synthesis of (+)-xestoquinone using an asymmetric palladium-catalyzed polyene cyclization. J Am Chem Soc 1996, 118, 10766–10773. [51] Kojima, A, Takemoto, T, Sodeoka, M, Shibasaki, M. Catalytic asymmetric synthesis of halenaquinone and halenaquinol. J Org Chem 1996, 61, 4876–4877. [52] Kojima, A, Takemoto, T, Sodeoka, M, Shibasaki, M. Catalytic asymmetric synthesis of halenaquinone and halenaquinol. Synthesis 1998, 581–589. [53] Pinto, A, Jia, Y, Neuville, L, Zhu, J. Palladium-catalyzed enantioselective domino Heck-cyanation sequence: Development and application to the total synthesis of esermethole and physostigmine. Chem Eur J 2007, 13, 961–967. [54] Trost, BM, Dong, G. A stereodivergent strategy to both product enantiomers from the same enantiomer of a stereoinducing catalyst: Agelastatin A. Chem Eur J 2009, 15, 6910–6919.
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Hélène Pellissier
[55] Deschamp, J, Hermant, T, Riant, O. An easy route toward enantio-enriched polycyclic derivatives via an asymmetric domino conjugate reduction-aldol cyclization catalyzed by a chiral Cu(I) complex. Tetrahedron 2012, 68, 3457–3467. [56] Mangoni, L, Adinolfi, M, Laonigro, G, Caputo, R. Synthesis of marrubiin. Tetrahedron 1972, 28, 611–621. [57] Coya, E, Sotomayor, N, Lete, E. Enantioselective palladium-catalyzed Heck-Heck cascade reactions: Ready access to the tetracyclic core of lycorane alkaloids. Adv Synth Catal 2015, 357, 3206–3214. [58] Dalpozzo, R. Recent catalytic asymmetric syntheses of 3,3-disubstituted indolin-2-ones and 2,2disubstituted indolin-3-ones. Adv Synth Catal 2017, 359, 1772–1810. [59] Pellissier, H. Synthesis of chiral 3-substituted-3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines. Beilstein J Org Chem 2018, 14, 1349–1369. [60] Pellissier, H. Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic Domino and Tandem reactions. Synthesis 2019, 51, 1311–1318. [61] Hu, H, Teng, F, Liu, J, Hu, W, Luo, S, Zhu, Q. Enantioselective synthesis of 2-oxindole spirofused lactones and lactams by Heck/Carbonylative cyclization sequences: Method development and applications. Angew Chem Int Ed 2019, 50, 9225–9229. [62] Stanley, L, Sibi, MP. Privileged chiral ligands and catalysts. Wiley: Weinheim, 2011, 171–219. [63] Desimoni, G, Faita, G, Jørgensen, KA. Update 1 of: C2-symmetric chiral bis(oxazoline) ligands in asymmetric catalysis. Chem Rev 2011, 111, R284–PR437. [64] Tietze, LF, Stecker, F, Zinngrebe, J, Sommer, KM. Enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction. Chem Eur J 2006, 12, 8770–8776. [65] Hajra, S, Bar, S. Catalytic enantioselective synthesis of A-86929, a dopamine D1 agonist. Chem Commun 2011, 3981–3982. [66] Tietze, LF, Jackenroll, S, Ganapathy, D, Reiner, JR. Formal synthesis of (−)-siccanin using an enantioselective domino Wacker/carbonylation/methoxylation reaction. Synlett 2016, 27, 96–100. [67] Trost, BM, Shen, HC, Surivet, JP. An enantioselective biomimetic total synthesis of (−)-siccanin. Angew Chem Int Ed 2003, 42, 3943–3947. [68] Gommermann, N, Knochel, P. Practical highly enantioselective synthesis of propargylamines through a copper-catalyzed one-pot three-component condensation reaction. Chem Eur J 2006, 12, 4380–4392. [69] Kong, W, Wang, Q, Zhu, J. Palladium-catalyzed enantioselective Domino Heck/Intermolecular C–H bond functionalization: Development and application to the synthesis of (+)-esermethole. J Am Chem Soc 2015, 137, 16028–16031. [70] Ichikawa, E, Suzuki, M, Yabu, K, Albert, M, Kanai, M, Shibasaki, M. New entries in Lewis acid-Lewis base bifunctional asymmetric catalyst: Catalytic enantioselective Reissert reaction of pyridine derivatives. J Am Chem Soc 2004, 126, 11808–11809. [71] Sanner, MA, Chappie, TA, Dunaiskis, AR, Fliri, AF, Desai, KA, Zorn, SH, Jackson, ER, Johnson, CG, Morrone, JM, Seymour, PA, Majchrzak, MJ, Faraci, WS, Collins, JL, Duignan, DB, Di Prete, CC, Lee, JS, Trozzi, A. Synthesis, SAR and pharmacology of CP-293019: A potent, selective dopamine D4 receptor antagonist. Bioorg Med Chem Lett 1998, 8, 725–730. [72] Shimada, N, Hanari, T, Kurosaki, Y, Takeda, K, Anada, M, Nambu, H, Shiro, M, Hashimoto, S. Catalytic asymmetric synthesis of the endo-6-Aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural product from ligusticumchuanxing via 1,3-dipolar cycloaddition of a formyl-derived carbonyl ylide using Rh2(STCPTTL)4. J Org Chem 2010, 75, 6039–6042. [73] Shimada, N, Hanari, T, Kurosaki, Y, Anada, M, Nambu, H, Hashimoto, S. Catalytic asymmetric synthesis of descurainin via 1,3-dipolar cycloaddition of a carbonyl ylide using Rh2(R-TCPTTL)4. Tetrahedron Lett 2010, 51, 6572–6575. [74] Chen, M, Wang, X, Yang, P, Kou, X, Ren, ZH, Guan, ZH. Palladium-catalyzed enantioselective Heck carbonylation with a monodentate phosphoramidite ligand: Asymmetric synthesis of (+)Physostigmine, (+)-Physovenine, and (+)-Folicanthine. Angew Chem Int Ed 2020, 59, 12199–12205.
Lukas M. Jacobsen§, Roberto Tallarita§, Siva S.M. Bandaru, and Carola Schulzke✶
Chapter 14 Synthesis of pharmacologically significant pentathiepins: a journey from harsh to mild conditions 14.1 Introduction Sulfur, after the elements oxygen, phosphorus, and nitrogen, is the most common heteroatom found in biomolecules. Its significance stands out in biological redox processes and in its functionality for an extensive range of vitally important small molecules, proteins, and enzymes [1, 2]. Figure 14.1 depicts a selection of biologically relevant redox active thiol, disulfide, and polysulfide species including heterocyclic ones. Notably, the binding energy of a S–S bond is approximately 265 kJ/mol, and it is thereby the third strongest homo-nuclear single bond after a C–C bond (ca. 330 kJ/ mol) and the H–H bond (435 kJ/mol), which stabilizes the respective compounds to quite some extent [3, 4].
14.1.1 Pentathiepins: a special class of cyclic polysulfides Among the polysulfur compounds the pentathiepins constitute a particularly notable family with regard to structures and (re-)activities. Polysulfides (R-S(n =2-6)-RI; R, RI = saturated or unsaturated alkyl, or aryl group) generally possess the ability to instigate unusual pro-drug activation mechanisms including redox transformations. Pentathiepins, which are cyclic polysulfides bearing a chain of five sulfur atoms and a C =C double bond or aromatic linker between its ends, as isolated from the Lissoclinum genus of Far-Eastern ascidians (varacin [5] and lissoclinotoxin-A [6]) and Polycitor sp. (varacins A-C [7]) have indeed displayed superior therapeutic potential over other analogues investigated (Figure 14.2).
§
These authors have contributed equally.
✶
Corresponding author: Carola Schulzke, University of Greifswald, Institute of Biochemistry, Bioinorganic Chemistry, Felix-Hausdorff-Str. 4, Greifswald 17489, Germany, e-mail: [email protected] Lukas M. Jacobsen, Roberto Tallarita, Siva S. M. Bandaru, University of Greifswald, Institute of Biochemistry, Bioinorganic Chemistry, Felix-Hausdorff-Str. 4, Greifswald 17489, Germany https://doi.org/10.1515/9783110980189-014
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Figure 14.1: Examples of biologically relevant thiols, disulfides, and cyclic polysulfanes.
Figure 14.2: Examples for naturally occurring pentathiepins.
Figure 14.2 presents examples of compounds with the pentathiepin moiety having been isolated from nature. Applying the Hantzsch–Widman nomenclature method, they are specifically referred to as 1,2,3,4,5-pentathiepins [8]. Fehér, between 1967 and 1971, had already synthesized both unsaturated and saturated derivatives (1,2,3,4,5pentathiepans) thereof [9, 10]. However, it was not until the discovery of naturally occurring varacin in 1991 (Figure 14.2) [11], that pentathiepins have received far more attention from the chemical (and biological/pharmaceutical/medicinal) community owing to their potential drug applications; inter alia for some of them being highly cytotoxic [12]. This chapter portrays the current state-of-the-art of 1,2,3,4,5-pentathiepin chemistry. The account of this unusual scaffold and its chemistry starts with a focal description of respective syntheses: from well-established hazardous chemistry to new and environmentally friendly procedures, as well as from targeted synthesis development
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to serendipitous findings. The discussion then also covers pentathiepin-reactivity, e.g., as excellent starting materials in the organic synthesis of sulfur-bearing derivatives, while considering informative analytical methods, in particular those, which offer species specific signals. It ends with a thorough description of their notable and significant biological activity, and a brief view on other (potential) applications in material science. The notable behavior and characteristics of this truly unusual and intriguing class of very sulfur-rich molecules have been emphasized throughout.
14.2 Synthesis 14.2.1 Metal-free approaches 14.2.1.1 Synthesis of benzopentathiepins With regard to pentathiepin synthesis, researchers have been working intensely on effective synthetic methodologies for a better reaction control, and for increasing the yields and broadening the chemical space of artificial and natural pentathiepin products. Naturally occurring biologically active pentathiepins, such as varacin, and lissoclinotoxins A and B are benzopentathiepins. While varacin and other compounds were isolated from marine sources and identified not before 1991, Fehér and co-workers were the first to report pentathiepin syntheses as early as 1967 including that of benzopentathiepin [9, 10]. The reaction of benzene ortho-dithiol (1), trans-cyclohexane-1,2dithiol or cis-dimercaptoethylenes with dichloro trisulfane (S3Cl2) resulted in moderate to good yields of the corresponding pentathiepins (2, 3, 4, and 5; Figure 14.3). Later, mostly for convenience, S3Cl2 was replaced by stable and commercially available disulfur dichloride (S2Cl2).
Figure 14.3: Synthesis of benzopentathiepins from ortho-dithiols and dichlorotrisulfane.
For instance, Ariyan et al. used S2Cl2 with triethylamine (NEt3) in toluene to synthesize pentathiepin 7 from 2-(inden-1-ylidene)-1,3-dithiolan (6), and the structure of the final product was confirmed later via X-ray single crystal diffraction by Bernal and coworkers (Figure 14.4) [13–15]. The comparably stable pentathiepinis are the major
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products of this synthetic approach. However, a scarcity of bismercapto starting materials and their poor stability prevented this method to be more commonly applied. Chenard and Miller, a little later, used benzothiazoles 8a-e as their starting materials to synthesize the respective set of benzopentathiepins [16].
Figure 14.4: Reaction conditions (A) and reaction mechanism (B) of the double electrophilic addition of S2Cl2 to an endocyclic olefin yielding the respective pentathiepin [13, 15]. The shown structure (to the right of A) was drawn from deposited crystallographic data; CSD ref code: BOMZOS.
The benzothiazoles were thermolyzed with elemental sulfur (S8) in the presence of 1,4diazabicyclo[2.2.2]octane (DABCO) giving a set of benzopentathiepins including several new ones (2, 9b-e) [16]. Under these conditions, various benzene ring substituents were well tolerated, and the procedure resulted in moderate yields (Figure 14.5A). Considering that the 7-substituted benzothiazole (8e) was found to be unreactive, it is likely that steric bulk close to the benzothiazole’s sulfur atom impairs the attack of activated sulfur species (in situ). According to the authors, the presence of DABCO increased yields by approximately 30%. Presumably, DABCO facilitates an ionic mechanism (Figure 14.5B) for the activation of S8, while decreasing the degradation of the benzopentathiepin product at the operating reaction temperatures [16]. In the process of developing new and improved synthetic approaches for cyclic polysulfides, Sato and co-workers introduced an approach to the synthesis of benzopentathiepins, which avoided heating; they reacted 5-substituted 1,2-benzodithiol-2-thiones 10a-d with S8 in liquid ammonia (NH3(l)), i.e. at low temperatures (Figure 14.6A). Improved yields were achieved applying six equivalents of sulfur and carrying out the reaction with benzene as co-solvent. However, this protocol failed to synthesize 7-NO2benzopentathiepin [17]. Interestingly, the addition of 1,3-dinitrobenzene during work-up
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Figure 14.5: Synthesis of benzopentathiepins from benzothiazoles and S8 in the presence of DABCO (A), and a plausible mechanism for the DABCO mediated reaction (B).
enhanced the product yields even further by ca. 20%. This was explained in terms of electron transfer effects of in situ formed dithiolate anions. Also analogues of bisdithiolothione 12a-d were reacted under the same conditions and interestingly yielded only the monotrithiolo-monopentathiepins 13a-d in excellent yields (Figure 14.6B). The absence of alkoxy groups, albeit, resulted in the formation of unidentified polymers, rather than the desired pentathiepins. Continuing their investigations, Sato et al. [18] later described syntheses with gaseous NH3 in dichloromethane yielding several benzopentathiepins 2, 11d, 15c-j, 6,7dimethoxybenzopentathiepin (15g), and 6-(2-aminoethyl)benzopentathiepin (7) (R1 = CH2CH2NH2; R2 = H), as well as partial structures of varacin from the corresponding 1,2benzenedithiols 14a-14j (Figure 14.7A). Trithioles were commonly observed as byproducts, with heavily crowded benzenedithiols (ortho-disubstituted), but pentathiepins constituted usually the thermodynamically preferred products [18]. Furthermore, the obtained side product trithiole 16 was also successfully transformed to pentathiepin 17 upon treatment with sulfur in liquid NH3 in good yields (Figure 14.7B) [19]. In a rather unexpected transformation observed in the context of investigations on trithiadiazepine chemistry, tetrasulfurtetranitride (S4N4) was reacted with 3,3-dimethyl-1(2-carboxyphenyl)triazene (18) under refluxing conditions in xylene, which resulted in benzopentathiepin (2) in 29% yield [20]. Presumably, the benzyne precursor, formed in situ from 3,3-dimethyl-1-(2-carboxyphenyl)triazene, was consumed by S4N4 to give the benzopentathiepin (Figure 14.8). It was also demonstrated that toluene-3,4-dithiol (19) reacted with S4N4 in boiling xylene to predominantly produce 7-methylbenzopentathiepin (20, 59%) along with other polysulfide polymers [20].
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Figure 14.6: The synthesis of 5-substituted benzopentathiepins 2 and 11b-d from 10a-d (A) and the synthesis of 13a-d from 12a-d in S8 and liquid ammonia (B).
Figure 14.7: The syntheses of 2, 11d, and 15c-j from di-substituted dithiols 14a-j in the presence of S8 and gaseous NH3 (A) and the conversion of trithiole 16 into pentathiepin 17 (B).
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Figure 14.8: Synthesis of benzopentathiepins 2 and 20 employing tetrasulfurtetranitride (S4N4).
Francois and co-workers developed a comparably convenient approach specifically towards varacin and isolissoclinotoxin A derivatives by reacting the two di-S-tBubenzenedithiols 21a and 12b with an excess of disulfurdichloride in tetrahydrofuran solvent at room temperature (Figure 14.9) [21]. The corresponding starting materials, the di-S-tBu-benzenedithiols, were synthesized from 2,3-dibromovanillin and n-alkyl cuprous mercaptides. Diacetyl isolissoclinotoxin A (22a) and N-carbobenzoxyvaracin (22b) were isolated through this approach in 52% and 42% yield, respectively (Figure 14.9).
Figure 14.9: Syntheses of benzopentathiepins from 21a-b with S2Cl2 in THF at room temperature.
Later, Sato and co-workers also synthesized benzopentathiepin 24 from di-S-iPrbenzenedithiol 23 via reduction of the thioether functional groups in the presence of Na/NH3 followed by S8/NH3 treatment in 33% yield (Figure 14.10) [22]. However, under
Figure 14.10: Synthesis of benzopentathiepin 24 from di-S-iPr-benzenedithiol 23 via reduction by sodium followed by sulfuration with S8, both carried out in NH3.
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the same reaction conditions 1,2,4,5-tetrathiolo-3,6-bis(isopropyloxy)benzene gave unidentified polymers, and the majority of the tested reactions led to poor yields. In 1993, a total synthesis of the natural pentathiepin varacin (29a) and its analogue varacinium trifluoroacetate (29b) was reported by Behar and Danishefsky [23]. In this procedure, several complex protection and deprotection steps are performed. Essentially, benzyne synthon 25ʹ was prepared separately, and reacted with carbon disulfide to produce a 1,2-dithiol synthon 25ʹ’, and then with alcohols to yield compounds 26a-c (Figure 14.11). From these species, upon reactions with S2Cl2, pentathiepin moieties were formed. Eventually, the desired product was isolated in 46% yield as trifluoroacetate salt 29b; the free NH2 species (varacin) is unstable in solution [23]. Considering the scarcity of 1,2-benzenedithiol starting materials, Toste and Still adopted a new synthetic strategy to synthesize benzopentathiepins and specifically varacin analogues from monothiols [24]. In the course of this procedure an ortho-dithiol dianion intermediate was generated in situ from p-toluenethiol by lithiation. The dilithiated intermediate is converted to the tert-butyl dithiol derivative by treatment with ditert-butyl disulfide (Figure 14.12). A subsequent reaction with S8 and S2Cl2 gave, after purification by chromatography, the desired benzopentathiepin in 59% and 86% yield, respectively. Furthermore, the protocol was proven efficient in the total synthesis of the varacin triflate analogue, which was isolated also in 59% yield after six reaction steps from a benzothiocyanate (Figure 14.13) [24].
14.2.1.2 Synthesis of heterocycle fused pentathiepins While the saturated pentathiepins were synthesized, mostly in lower yields, exploiting olefinic C=C bond activation with S8 at high temperatures, such type of reactivity was not observed with benzene precursors in the absence of ortho-dithiol substitution, which apparently is necessary to facilitate pentathiepin ring formation for aromatic scaffolds. However, with heterocycles carbon-carbon or olefinic C–H bond activations could be realized, resulting in different heterocycle fused pentathiepins. For example, N-methylhexahydroazepine heated with S8 in HMPA (hexamethylphosphoramide) gave pentathiepino pyrrolidine 37 in low yield (5%) along with other polysulfide by-products (Figure 14.14) [25]. Even though the yields were low, the isolation and characterization of these products inspired researchers to optimize the reaction conditions in order to provide novel pentathiepin platforms. Following this, Bergman and co-workers introduced milder and more efficient routes to indole derived pentathiepins. They prepared 2-lithiated 1-methyl indoles from indoles 38a-b via nBu-Li lithiation, followed by reaction with 20 equivalents of S8 giving the 6-methylpentathiepino[6,7-b]indoles 39a-b together with a tetrathioindole (Figure 14.14) [26].
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Figure 14.11: Total syntheses of varacin 29a and the varacinium trifluoroacetate salt 29b.
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Figure 14.12: Synthesis of benzopentathiepin 20 from p-toulenedithiol via a dithiolate anion intermediate.
Figure 14.13: Total synthesis of the varacin triflate salt analogue 35.
Alternatively, anionic thienol produced from indoline-2-thiones 40a-b with sodium hydride in THF was reacted with sulfur to yield indole pentathiepins 39a-b in moderate yields [27]. Notably, the extension of similar reaction conditions to benzo[b]thiophene (41) gave analogous benzothiophenopentathiepin 42 (28%), while the benzo[b]furan 43 gave only a bisbenzofuranotetrathiocine (44) (Figure 14.14) [27]. Heterocycle fused pentathiepins were also synthesized using S2Cl2 as sulfuration reagent on dithiolate salts and nucleophilic heterocycles, such as pyrroles, thiophenes, and their reduced tetrahydro derivatives. The isothiazolopentathiepins 46, 49, and thiophenepentathiepin 52 were synthesized in moderate to excellent yields from the cor-
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Figure 14.14: Syntheses of heterocycle fused pentathiepins and one tetrathioindole by activation of carbon-carbon or (olefinic) carbon-hydrogen bonds with S8.
responding ortho-dithiolate salts (45, 48, and 51) in reactions with S2Cl2 (Figure 14.15) [28–30]. Konstantinova et al. treated nucleophilic heterocycles such as pyrroles, thiophenes and their tetrahydro derivatives with S2Cl2 and DABCO (1,4-diazabicyclo[2.2.2] octane) in chloroform at ambient temperature to synthesize heterocyclic fused pentathiepins [31, 32]. This approach resembles procedures which were already explored in the case of benzopentathiepin synthesis (vide supra). The one-pot reactions of Nisopropylpyrrolidines 53a-b with S2Cl2 (5 equiv.) and DABCO (5 equiv.) in chloroform under inert conditions at room temperature for three days gave fused bispentathiepinopyrrole 55 (31%) along with yellow crystals of pyrrolo monopentathiepins 54a-b (Figure 14.16). In the case of N-methylpyrrole, improved yields of dichloropentathiepinopyrrole 54a were noticed when a base was added, such as pyridine, NEt3 or DABCO. Additionally, under similar reaction conditions 1-methylindole 38b, thiophene 56, and tetrahydrothiophene 58 resulted in the corresponding heterocyclic fused pentathiepins in moderate to good yields (Figure 14.16) [31]. Interestingly, premixing S2Cl2 and DABCO in chloroform enhanced the regioselectivity of the reactions in the case of N-alkylated pyrrolidines and N-alkylated indoles. Additionally, the dehalogenated pyrrolopentathiepin and indolepentathiepins are formed as major fractions and the formation of dechlorinated pyrrolomono-pentathiepin and bispentathiepino-pyrrole byproducts
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Figure 14.15: Syntheses of S/N-heterocyclic-fused pentathiepins from ortho-dithiolate salts with S2Cl2.
were minimized. The authors suggested that a complex formed between a 1:2 mixture of S2Cl2 and DABCO at 0 °C under premixed conditions potentially acts as an electrophilic sulfurating agent rather than a chlorinating agent on the substrates [32]. A respective tentative reaction mechanism is shown in Figure 14.17. When S2Cl2 and DABCO were premixed in chloroform at 0 °C for 48 h, followed by the addition of NEt3 and heating of the mixture, more strange and unexpected reactions occurred. The thienopentathiepin and heptathiocane were synthesized together; their polysulfur rings had the expected chair and crown conformations, respectively. Presumably, the thiophene ring was formed from two ethyl groups, with a new C–C bond formed between two formally inactivated methyl groups; a pentathiepin ring was fused onto the thiophene as in the preceding transformations. The same reactions occurred in lower yields with other tertiary N-ethylamines. Despite the low yields, the reactions have the advantage that the products are made in a single pot from inexpensive raw materials (Figure 14.18) [32].
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Figure 14.16: Syntheses of heterocycle fused pentathiepins from nucleophilic heterocycles with S2Cl2 or S2Cl2 plus DABCO.
Figure 14.17: Effect of S2Cl2 and DABCO premixing on the regioselectivity of five-ring heteroaromatic pentathiepin formation. Thiophene 58 is shown as example [32].
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Figure 14.18: Synthesis of thiophenepentathiepin 59 from the cheap starting materials NEt3 and S2Cl2 with DABCO in chloroform.
14.2.2 Metal mediated syntheses In the strategies discussed in the following, metal complexes play the role of a mediator by generating a reactive source of sulfur that will be transferred to the organic synthon. No truly catalytic reactions have been developed by now for the pentathiepin ring formation. Thus, it must be emphasized, metal complexes are used in quantitative or in half equivalent amounts compared to the starting materials. Many reactions towards polysulfides by -Sn- transfer have been developed, while in the following paragraphs only the ones related to pentathiepin ring synthesis are considered.
14.2.2.1 Synthesis mediated by tin An ene-dithiastannole complex has proven an effective type of precursor for the synthesis of 1,2,3,4,5-pentathiepinoferrocene in high yield [33]. Even though this strategy has not been applied to many other scaffolds as of yet, there is no issue known, which would suggest extending the approach to other precursors would be unsuccessful. However, respective suitable substrates should possess a stability toward bases, such as metal hydrides and the electrophile sulfur source S2Cl2 (Figure 14.19) [34].
Figure 14.19: General pentathiepin synthesis mediated by tin.
The use of the tin complex dwells on the possibility of isolating and, therefore, applying a more manageable version of the inherently unstable 1,2-dithiolferrocene [35] and, by extension, opening up a possibility to utilize all highly reactive 1,2-dithiols.
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The chosen starting material in this proof of concept study was a ferrocenesulfonyl chloride (61), which was converted to the N,N-dimethylsulfonamide (62) by a SNAc mechanism, then to a 2,2ʹ-bis(N,N-dimethylaminosulfonylferrocenyl)-1,1ʹ-disulfide (63) by exposing the ortho-lithium derivative to S8 (Figure 14.20) [33]. The synthesis of the tin complex is achieved by reduction of the disulfide bond and of the sulfonamide with LiAlH4 in THF, exposing the 1,2-dithiolate group to be reacted with dichlorodimethylstannane (Me2SnCl2). Treatment of complex 64 with S2Cl2 at 0 °C gave the respective pentathiepin with a high yield. Using an excess of S2Cl2 only decreased the yield. Compared to other synthetic methods involving S2Cl2, in this case, no 1,2,3-trithiepin formation was detected.
Figure 14.20: Total synthesis of ferrocenopentathiepin 65 mediated by an intermediate tin complex 64.
14.2.2.2 Synthesis mediated by titanium Steudel developed a whole chemical research area with different -Sn- polysulfidotitanocene complexes, all able to transfer their -Sn- moiety to activated electrophile recipients yielding open chain, as well as cyclic polysulfanes [8]. In the example depicted here (Figure 14.21), the complex trisulfidodi(bis(methylcyclopentadienyl) chlorotitanocene) ((Cp2I TiCl)2S3;CpI = η-C5H5Me; 66), is used as a -S3- transfer agent to a 1,2-disulfenylchloride derivative to obtain the pentathiepin.
Figure 14.21: General pentathiepin synthesis mediated by titanium.
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Complex 66 is obtained by treating [Cp'Ti(μ-S2)]2 (67) [36] in CS2 with a toluene solution of phosgene but only a low conversion of the starting materials was observed (Figure 14.22). Compound 66, as compared to other polysulfide complexes, and despite the use of rather coarse reagents in the synthesis, can be easily purified by filtration of the resulting crystals, which are air stable and unusually well soluble in different solvents.
Figure 14.22: Synthesis of titanium complex 66 constituting a source of -S3.
The simple benzopentathiepin 2 is obtained by reacting 1,2-benzendithiol (1) with elemental chlorine in tetrachloromethane (Figure 14.23). Sulfenylchloride 68 is then treated in CS2 at –78 °C with a quantitative amount of titanium complex 66. The recovery of the product in this case is tricky due to the difficult removal of the side product dichlorobis(methylcyclopentadienyl)titanocene (CpI2TiCl2) (69) (Figure 14.23).
Figure 14.23: Total synthesis of benzopentathiepin 2 via titanium mediated complex reaction with sulfenylchloride 68.
14.2.2.3 Synthesis mediated by molybdenum The latest and most promising milestone in preparing heteroaromatic pentathiepins was found serendipitously and is a case of molybdenum mediated synthesis [37]. It comprises one of the mildest and most user-friendly methods for the synthesis of pentathiepin compounds (Figure 14.24). As presented by now, all recipes require the application of one or a combination of distinct harsh conditions: high or very low temperatures or pressures, chemicals difficult to handle, such as S2Cl2, phosgene, liquid or gaseous NH3, highly reactive bases, or unstable metal complexes. The yields are rarely satisfactory, and in most
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Figure 14.24: General pentathiepin synthesis mediated by molybdenum(IV) complex 70.
cases undesired products in form of differently shaped cyclic polysulfides are obtained in significant amounts. Products that can be targeted are limited to a full carbon or few heterocyclic backbones. The potentially desirable functional groups that can be attached to the starting materials need to be resilient enough to sustain the reaction conditions for pentathiepin synthesis. Considering the protocols described above, there are not many which can survive such procedures. The molybdenum-mediated synthetic pathway employs a oxo-bis-(tetrasulfido) molybdate complex (Et4N)2[Mo(S4)2O] as a sulfur activation agent and presumably the eventual source of the -S5- chain (70; Figure 14.25). This complex is easy to prepare, may be obtained in high yields at room temperature, even without an inert atmosphere, and without the need for particularly hazardous and/or difficult to handle chemicals [38]. The starting material is the ammonium heptamolybdate salt 71, which is dissolved in water and, at room temperature, mixed with an ammoniumpolysulfide solution ((NH4)2Sx) for 30 min. The solution is filtered, and complex 70 is precipitated by replacing the smaller ammonium cation via the addition of tetraethylammonium chloride.
Figure 14.25: Synthesis of oxo-bis-(tetrasulfido)molybdate complex 70 from the ammonium salt precursor 71.
The organic synthon for the pentathiepin synthesis (e.g., pyrazine 74) is an azine decorated with a 3,3-diethoxypropargylaldehyde (73) in α-position to the nitrogen, which may be obtained by a Sonogashira coupling reaction [39]. To date, various kinds of general recipes and small tricks to reach the desired alkyne coupled product have been described, and, by optimizing a few parameters, it is most often possible to derive satisfying yields. In the example shown below, mostly standard Sonogashira conditions were adopted (Figure 14.26).
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Figure 14.26: Example for a Sonogashira coupling reaction for pentathiepin precursor 74.
The presence of the diethoxy moiety, in this protocol, goes back to the need of generating a very electron-poor alkyne [40], when attempting to synthesize a molybdenum dithiolene complex as a simplified prototype of oxidoreductase enzymes [41], which accidentally ended up in pentathiepin synthesis. Replacing the diethoxyacetal
Figure 14.27: Heterocyclic pentathiepins synthesized via molybdenum-mediated sulfuration. Only diethoxyacetal derivatives like 74 and 76a-c have been successfully used as starting materials for the reaction under discussion.
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functional group by, for instance, propargyl alcohol has been tried without success as of yet, emphasizing the importance of the former for this type of synthetic procedure (Figure 14.27). The optimized synthetic conditions require an alkynylazine as the starting material, one equivalent of S8, and half an equivalent of molybdenum complex 70. Depending on the specific starting material, yields may be increased by raising the sulfur amount or switching from dimethylformamide (DMF) to acetonitrile (MeCN). The mechanism of the transformation, as well as the exact role of molybdenum (i.e., its interactions with the reactants) still needs to be deciphered, though. However, it is tentatively suggested that the complex reacts with the elemental sulfur and generates the -S5- unit, which then interacts with the C≡C triple bond. No evidence for complex formation between molybdenum and the organic alkyne precursor has been found so far. The reaction does not occur with the sole presence of sulfur or complex; both are required for product generation. A plausible mechanism via an ethoxonium intermediate, taking into consideration the need for the presence of the diethoxyacetal functional group, was tentatively proposed and is shown in Figure 14.28 [37].
Figure 14.28: Plausible mechanism for the molybdenum-mediated synthesis of 75 [37].
Any pentathiepin obtained with this method will be decorated by one ethoxy group (–OEt) on the pyrrole ring. As will be shown in a following subchapter (14.4.2 NMR spec-
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troscopy), this constitutes a signature functional group, as the methylene -CH2- protons give a specific signal in the 1H-NMR spectra, hence confirming, beyond any doubt, the formation of the pentathiepin. A collection of pentathiepins with various substitutions synthesized through the molybdenum method discussed above are currently under study for their pharmacological and biological activities (see Figure 14.29 for some examples) [42]. The versatility in the backbone of the substrates, which can be achieved, is quite notable.
Figure 14.29: Examples of various pentathiepins with different backbones (emphasizing the versatility of the molybdenum-mediated synthetic method).
14.3 Reactions of pentathiepins The five-membered sulfur chain tethered to the ene-moiety is susceptible to cleavage, often associated with the loss of a -S2- or a -S3- unit, and then, in the latter case, acts like a dithiol synthon leading to more common and stable polysulfide rings. Characteristic behavior comprises lability at high temperatures in basic conditions and in the presence of nucleophiles, and a notable stability towards Brønsted acids and electrophiles. As a consequence of the higher sensitivity of polysulfides observed throughout the last decades, reactions involving the sulfur chain have been explored more thoroughly than the ones possibly occurring on the backbone scaffolds.
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14.3.1 Reactions involving the pentathiepin ring 14.3.1.1 Thermal decomposition Heat may easily induce a shrinking from a five- to a three-membered sulfur ring or to polysulfide dimers by freeing sulfur fragments, which eventually end up as S8. That type of reactivity has no useful scope, since the desulfurization products can be easily obtained in more sophisticated ways, and the behavior of the starting material is not entirely predictable. The following examples (Figure 14.30) should be, hence, taken as an advice to control the temperature, when dealing with pentathiepins, rather than as actual chemical recipes [28, 43].
Figure 14.30: Thermal decompositions of pentathiepins giving unpredictable products.
14.3.1.2 Reduction Reactivity towards a few reducing systems may be dictated by the substantial chalcogenophilic nature of the utilized transition metals (Figure 14.31). In the presence of Raney nickel, for instance, it is possible to reach a complete desulfurization of the pentathiepin as demonstrated by the benzofulvene derivative 7 [13]. Switching to hydride sources, such as sodium borohydride, the 1,2-dithiol 84 and trithiols (e.g., 16) were synthesized [44]. Using a single source of hydride, such as lithium aluminium (tri-tert-butoxy)hydride [45] followed by quenching of the reaction with methyliodide thioether 85 is made (Figure 14.31). When a milder source of hydride is used, the reactivity of the sulfur chain is lost, and other functional groups might be addressed in a more constructive type of chemistry transforming the backbone structure.
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Figure 14.31: Treatment of pentathiepins with different reducing agents being active in the polysulfide chain from the strongest (top) to the weakest (bottom).
While the sulfur ring has proven stable under mild reducing conditions, it was indeed possible to functionalize the amino -NH2 group of a benzopentathiepin employing the relatively mild sodium cyanoborohydride (Na(CN)BH3), whereby a chemical modification of the back bone could be achieved under retention of the pentathiepin functional group (Figure 14.32) [46].
Figure 14.32: Resistance of the polysulfur chain against reducing agents, which do transform the backbone functional groups.
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14.3.1.3 Oxidation The pentasulfur chain appears inert to various oxidizing reagents including mild organic peroxides [47] up to even the highly reactive mercury acetate Hg(OAc)2 [48]. Since three of the five sulfur atoms of the chain are in their formal oxidation state 0 and the other two in formal oxidation state -1, this is to some extent surprising. Where the oxidation is accompanied by the actual implementation of an oxygen functional atom, these take place on moieties other than the pentathiepin ring (Figure 14.33).
Figure 14.33: Pentathiepin moieties with inert behavior towards oxidants and backbone structures transformed by oxidation including oxygen transfer.
14.3.1.4 Nucleophilic attack The pentasulfur chain is well known to be cleaved by nucleophiles generating a dithiol derivative with the two sulfur atoms at the chain’s ends (vide supra). The notable affinity to sulfur-based nucleophiles was shown in detail by the work of Chatterij et al. [49] who tested pentathiepins with thiols under various conditions. The respective behavior of pentathiepins in an intracellular environment, where thiols are present, is of particular interest since pentathiepins may be developed towards medicinal application. Pentathiepin abundance was monitored while adding different amounts of 2-mercaptoethanol (RSH, where R =CH2CH2OH). The exposition to three equivalents of RSH results in a complicated mixture of 1,2-dithiolethers and open di-, tri-, or tetrasulfide chains. When a large excess of thiol is used (100 equiv.), the ring is completely cleaved to a 1,2-dithiol while six equivalents of RSH are oxidized to the corresponding disulfide and one equivalent of H2S is released (Figure 14.34) [49].
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Figure 14.34: Disintegration of the pentasulfur moiety by thiols yielding various thioether and polysulfide products.
Reactions with strong nucleophiles, such as a Grignard’s reagent, with the help of a desulfurizing agent, for instance triphenylphospine, leads to ortho-thiolthioethers (e.g., 93), which are not easily addressable by other chemical procedures (Figure 14.35) [50].
Figure 14.35: An example for the synthesis of ortho-thiolthioethers (93) from pentathiepins reacting with Grignard’s reagents.
Molecules of pharmaceutical interest often bear acetylated moieties. It is, hence, desirable to also facilitate the introduction of such moieties through pentathiepin chemistry. Starting from a pentathiepin, a reaction sequence can be induced, which consists of poly-
Figure 14.36: In situ access to a corresponding dithiol employing the strong nucleophile DMAP with pentathiepin precursor 29a and its subsequent transition to the product, here, via acetylation to yield 94.
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sulfide cleavage with the help of N,N-dimethylaminopyridine (DMAP) followed by acetylation of the intermediate dithiol and the amine functional groups (Figure 14.36) [11].
14.3.1.5 Ring contraction to 1,2,3-trithiol Trithiols can be generated in multiple ways and, as mentioned above, appear to be the most common side products of all reactions involving pentathiepins. Chenard [44] and Houk [51] in their research tried to give an explanation for this behavior independently. It was noticed that in methanol 6-trifluoromethylbenzopentathiepin (95a) spontaneously becomes decomposed to the corresponding 1,2,3-trithiol 96a and S8 (Figure 14.37).
Figure 14.37: Examples of observed pentathiepinring contractions from S5 to S3.
Monitoring the reaction mixture composition with the HPLC and/or GC/MS methods when 96a was formed from 95a, this transformation was found to be a first order equilibrium reaction (Figure 14.38) [44].
Figure 14.38: The ring contraction transformation from S5 to S3 established to be a first order equilibrium reaction for the compound with a trifluoromethyl group at position 6 [44].
It was realized that the reaction does not depend on the potentially acidic MeOH proton, a contribution of which to a potential kinetic isotope effect (KIE) was excluded upon testing with deuterated methanol [44]. The authors suggested that it might be rather a nucleophilic intervention of the free electron pairs of the solvent’s oxygen atom (i.e., Lewis/Brønsted basicity) than a protic contribution. They corroborated
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their assessment using hexane as the solvent, in which the reaction took place only, when the base diethylamine was added. The same reaction, under the same conditions was also monitored for the 6-bromobenzopentathiepin (95b), the 6-dimethylamino (95c), and 6-methyl (95d) derivatives, with divergent results [44]. When R=Br (less bulky [52] and with a lower inductive –I effect as compared to the -CF3 group) the transformation took also place as an equilibration reaction, but not according to the first order. A few (non-characterized) side products were also formed. Interestingly, species 96b may be converted back easily to pentathiepin 95b upon addition of S8. When R=Me, with an even lesser extent of steric bulk as compared to the –CF3 and –Br substituents and with an inductive +I effect, no equilibration but merely the decomposition of the starting material was detected. The same phenomenon was observed, when R=NMe2, i.e. the one with the least rotational bulk of all and with a weak –I inductive effect, essentially lying between the methyl and bromine substituents (Figure 14.39).
Figure 14.39: Varied observed outcomes of reactions upon decreasing the electron withdrawing strength (i.e., the –I inductive effect) of the substituents or introducing electron donation ability from first order equilibration (left) to decomposition (right) [44].
In conclusion, these experiments imply that the reactivity of the pentathiepin starting materials rather depends on their electronic structure, than on steric bulk at least where substitutions in ortho-position are concerned (Figure 14.40).
14.3.1.6 Sulfur replacement by carbon The treatment of two pyrazol pentathiepin derivatives with simple acetone in presence of ammonium sulfide led to the replacement of one of the five pentathiepin sulfur atoms by a -C(Me2)- moiety and to three possible isomers of the product (Figure 14.41) [53]. The reaction likely occurs due to an initial nucleophilic attack of the sulfide S2– anion, which opens up the polysulfide ring. Even though no mechanistic studies were performed, it can be concluded from the arbitrary yields of the different isomers that the regioselectivity does not determine the outcome.
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Figure 14.40: Trends in the efficiency of 1,2,3-trithiol formation from pentathiepins compared to rotational steric bulk [52] and the inductive +/–I effects of the ortho-substituents tested.
Figure 14.41: Sulfur replacement by a carbon moiety derived from acetone as reactant.
In another study employing a benzylic phosphonium salt reactant (which is the immediate precursor to an in situ ylide) led to two different products with different yields [54]. One product was a 1,2,4,5-tetrathiepin and the other a 1,2,4-trithiin with a decreased ring size (Figure 14.42). The preference for one or the other most likely goes back to the electron withdrawing or donating ability of the substituent in the paraposition of the phenyl ring [54].
Figure 14.42: Sulfur replacement by carbon moiety transfer from a phosphonium salt, or rather in situ formed ylide (R = H, Me, Cl, OMe, NO2).
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The formation of the trithiin seems not to be affected substantially by the substituent, while it clearly has an impact on the tetrathiepin derivative (Table 14.1). If the phenyl species to be transferred is electron-rich due to the presence of the strongly donating methoxy group, the yield of the isolated product 102d increased to 45%. In contrast, no conversion took place (the yield of 102b was 0%), when a nitro group was installed. With the methyl derivative, which has only an inductive +I effect and no +M effect (the latter of which the methoxy substituent has), an intermediate yield was isolated. Table 14.1: Yields of para-substituted 1,2,3,4-tetrathiepin and 1,2,4-trithiin products obtained from benzopentathiepin with phosphonium cations/ylides.
H, a NO, b Me, c OMe, d Cl, e
a, % b, % c, % d, % e, %
a, % b, % c, % d, % e, %
Even two sulfur atoms are replaced by two carbon atoms, when benzopentathiepin (2) is treated with the boron trifluoride-ethylether complex ([BF3OEt2]), which releases the Lewis acid BF3 in solution [55]. The open polysulfur chain reacts as a 1,5-dipole (Figure 14.43) with the C=C double bond of alkenes yielding the di-substituted ethane moiety. Different (linear or cyclic) alkenes may be used, and the reactions result in high yields.
Figure 14.43: Two sulfur atom replacement by two carbon atoms from alkenes.
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14.3.1.7 Dimerization to tetrathiocines A common reactivity in presence of elemental sulfur is displayed by five-ring heteroaromatic benzo-condensed derivatives, such as indole, N-methylindole and benzofuran: they form the eight-ring sulfur-heterocycles 1,2,3,4-tetrathiocines in addition to pentathiepins. Such reaction is essentially a dimerization upon which the product bears a tetrasulfur ring and it apparently competes with the formation of pentathiepin [26]. A plausible explanation is the high reactivity of position 3 (or β from the view of the heteroatom), which is both, susceptible to deprotonation and to electrophilic substitution. Under certain reaction conditions for the syntheses of pentathiepins, the 1,2,3,4-tetrathiocines form in comparable amounts (Figure 14.44) [26]. In cases, where the reaction is left for a longer time before quenching, 1,2,3,4-tetrathiocines outcompete the pentathiepins with regard to their yields. This suggests that the first one is the thermodynamic product, while the second species is formed more quickly and therefore the kinetic product. It should, hence, be possible to control the outcome of the reactions applying higher or lower reaction times and temperatures.
Figure 14.44: 1,2,3,4-Tetrathiocines and pentathiepins as competitive products derived from benzocondensed five-ring heteroaromatic starting materials.
Accordingly, the N-methylindole 39b is converted into 107b in the presence of NEt3 in ethanol in a high yield (Figure 14.45). This reaction supports the higher thermodynamic stability of the indole-derived tetrathiocines over their related pentathiepins [26]. Treatment of pentathiepins with PPh3 or sodium cyanide results in 1,2,5,6tetrathiocine isomers, which are also eight-ring heterocycles, but distinctly arranged ones (Figure 14.46) [35]. Treatment of species 65 with 2 equivalents of PPh3 in toluene under reflux for 3 h, for instance, afforded product 108 in a moderate (33%) yield [35]. Increasing the amount of PPh3 up to 10 equivalents resulted in a higher yield of 76% of the isolated product (Figure 14.46). No formation of other commonly observed polysulfides was detected. As suggested by Kostantinova et al. [56], the 1,2,5,6-tetrathiocine isomer is likely the product of a zwitterionic intermediate generated after the extrusion of -S3- from
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Figure 14.45: Conversion of the N-methylindole pentathiepin into the bis-N-methylindoletetrathiocine.
Figure 14.46: 1,2,4,5-Tetrathiocine synthesis mediated by PPh3 [35].
the pentathiepin ring, which may be stabilized by a polar aprotic solvent, such as acetonitrile (Figure 14.47).
Figure 14.47: Generation of the plausible dipolar intermediate in the pentathiepin to 1,2,5,6-tetrathiocine transformation as proposed by Konstantinova et al. [56].
Such desulfurization process is quite adaptable to different heteroaromatic scaffolds derived from pyrroles and thiophenes. Asymmetrically substituted starting materials do not show any regioselectivity, but generate an essentially equimolar mixture of the possible isomers in moderate to good yields (Figure 14.48) [56].
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Figure 14.48: 1,2,4,5-Tetrathiocine synthesis mediated by NaCN.
Generally, the reactivity of the pentathiepino-pyrrole synthons in this context is unpredictable, and this phenomenon is not well understood. In cases, where the pyrrole is decorated with an alkyl substituent on the nitrogen and bears protons in α-positions (e.g., 114) the reaction proceeds with a high yield [56]. However, if the starting material’s α-positions are substituted with methyl or phenyl (i.e., 116), the reaction does not even take place. If the pentatiepino-ring includes the carbon atoms in positions 2 and 3 of the pyrrole, the starting material (116) merely becomes decomposed, and no product is detected (Figure 14.49) [56]. An explanation for these observations is, as of yet, unavailable in the literature.
14.3.1.8 1,2,4-trithiins Treating pentathiepins with phosphorus benzyl ylides 101ʹ (direct products of the phosphonium salts 101 discussed above) does not only lead to 1,2,4,5-tetrathiocinederivatives, but also 1,2,4-trithiins 103 can be obtained (Figure 14.50 and Table 14.2). Sato with his group investigated the respective reactivity in detail and showed that in presence of activated methylene compounds, the pentasulfur chain is cleaved and downsized in an unsymmetrical fashion. They also provided a plausible mechanism (Figure 14.50) [57].
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Figure 14.49: The unpredictable behavior of pyrrole in sodium cyanide mediated 1,2,4,5-tetrathiocin formation and decomposition of the pentathiepin, the sulfur ring of which is fused to positions 2 and 3.
Figure 14.50: Plausible mechanism proposed for 1,2,4-trithiin formation from phosphorus ylides.
The first step of the reaction is a nucleophilic attack of the ylide carbon on the sulfur adjacent to the benzene ring. A subsequent chain shortening is followed by a cyclisation with extrusion of triphenylphosphine and a disulfide species, which eventually form PPh3=S being the second product identified. Ylides are obtained in situ in a standard way by treating the corresponding phosphonium halide with bases like hydrides or alkoxides in THF and are then directly added to a solution of pentathiepin in benzene [57]. In case of asymmetric ylides, enantiomer formation of the final product should be taken into consideration, but was not studied in detail in the course of this investigation [57]. In a similar approach, an activated methylene group may be provided by the αhalogen ester 117 [58]. The proton bonded by the carbon bearing both the halogen and the carboxylic group is so acidic that even NEt3 is basic enough to induce the α-Helimination as the initiating step (Figure 14.51).
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Table 14.2: A summary of different 1,2,4-trithiins obtained from the corresponding pentathiepins with phosphorous ylides.
a, %
f, %
g, %
h, %
Figure 14.51: Plausible mechanism proposed for 1,2,4-trithiin formation from an α-halogenester [58].
14.3.1.9 1,4-Thianthrenes Compound 2 reacts as a formal 1,4-dication to give thianthrene 119 in moderate yields in a reaction which may be considered a double aromatic electrophilic substitution (SEAr) (Figure 14.52) [59]. As in a classic Friedel–Crafts reaction [60], the starting mate-
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rial is dissolved in the corresponding arene, and aluminium trichloride (AlCl3) is added under inert atmosphere (Table 14.3).
Figure 14.52: Pentathiepin 2 employed as an electrophile synthon for 1,4-thianthrenes.
Table 14.3: Examples for the arene to 1,4-thianthrene conversion. Arene
Temp (°C)
Product
Yield (%)
rt
14.3.1.10 1,4-dithiins and 1,4-dithians A pentathiepin may act as a 1,5-dipole synthon with unsaturated dipolarophilic compounds to give 1,4-dithiins and 1,4-dithians. This is consistent with the hypothesis of Konstantinova et al. [56] for the 1,2,5,6-tetrathiocine intermediates (Figure 14.47). Switching between alkynes and alkenes, products with a lower and higher degree of saturation in the heterocyclic backbone were obtained, respectively (Figure 14.53). Two
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strategies can be applied to produce the required reactive dipole: (i) using a desulfurizing agent, such as PPh3 or NaCN, and (ii) using a simple base, such as NEt3 [59, 61]. With these methods it was possible to use also activated methylenes, such as malonitrile 125b as reactants. In species 126b, one of the two nitrile groups is transformed into an amino group. Among all reactions discussed here, this is one of the most versatile ones, and it even results in high yields as shown in Table 14.4.
Figure 14.53: Pentathiepins as 1,2-dipole synthon precursors for the synthesis of 1,4-dithiins and 1,4dithians.
Table 14.4: Examples of pentathiepin to 1,4-dithiin or 1,4-dithian conversion. Pentathiepin
Dipolarophile
Product
Conditions
Yield (%)
NaCN in MeCN or PPh in CHCl
PPh in CHCl
PPh in CHCl or NEt in DMF
(PPh) (NEt)
NEt in CHCl
NEt in CHCl
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Table 14.4 (continued) Pentathiepin
Dipolarophile
Product
Conditions
Yield (%)
NEt in DMF
NEt in DMF
14.3.2 Reactions involving (hetero)aromatic backbone Considering the three-step conversion of a nitrile group to a carbomethoxy function, the superior stability of pentathiepins against different electrophilic species has to be emphasized (Figure 14.54) [44].
Figure 14.54: Multistep reaction sequence comprising only electrophilic attacks on the pentathiepin’s (46) backbone.
In the last step of this total synthesis of a ceramide derivative with potential anticancer activity [62], an SNAc reaction takes place resulting in a moderate yield (21%), as expected considering the activated carboxylic moiety with a para-nitrophenol-derived leaving group (Figure 14.55). The acylation of amines can be easily realized both with the use of anhydrides and with acyl chlorides as shown for the following examples of derivatives being pharmaceutically interesting as antimicrobial drugs (Figure 14.56, Table 14.5) [12, 63].
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Figure 14.55: Synthesis of a pharmacologically interesting ceramide containing a pentathiepin moiety.
Figure 14.56: Acylation of the pentathiepin’s amino group using acyl chlorides or anhydrides as the reactants. Table 14.5: Products of acylation reactions on the pentathiepin’s amino group. Synthon Acylchloride
R
Yield (%)
Anhydride
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14.4 Physical and theoretical properties of pentathiepins This section describes analytical experiments and theoretical or computational methods for the characterization of pentathiepins, of their biological activities, and for further applications. Only single crystal X-ray diffraction structural analysis provides direct and almost always entirely unambiguous evidence for the presence of the polysulfur chain of the pentathiepin moiety; other commonly applied techniques mostly gave indirect information in this regard. The aim of this part of the chapter is to guide the reader through the application of all those methods, and provide an idea of what can be concluded at what level of certainty from the respective analysis.
14.4.1 X-ray crystallography X-ray crystallography is nowadays a standard method for the structural elucidation of crystalline organic compounds, and it is particularly crucial for the characterization of pentathiepins, because it provides a definite prove for the presence of the fivemembered sulfur chain. Various structures of pentathiepins, mainly benzopentathiepins and pentathiepins with heterocyclic backbones have been already published [44, 64–67]. Four of those structures are shown as examples below (Figures 14.57–14.60). We focus here on the conformation and configuration of the sulfur ring; for a detailed crystallographic analysis of their metrical parameters and symmetries, the respective literature should be consulted. It has been shown by now that in all published pentathiepin molecular structures they prefer to have their sulfur chain in the thermodynamically more stable chairlike conformation [11, 31, 64, 66]. The average S–S bond lengths in the sulfur ring units (S1 to S5) of the structures are in the range of 2.04–2.06 Å, and are nearly equivalent to the typical bond length of a canonical S–S bond in S8 (2.051 Å) [64, 69]. Chenard et al. [44] observed this consistency for various benzopentathiepins. The carbon sulfur bond lengths with a range of 1.73 to 1.77 Å lie between the sp2 hybridized C–S single bond (1.81 Å) and a C=S double bond length (1.6 Å). Strikingly, the two sulfur atoms bonded to the carbon atoms of the benzene or heterocyclic moiety are almost coplanar to the aromatic moiety. In contrast, the sulfur atoms at positions 2 and 4 are located outside of this plane [37]. Last but not least, regarding the three S–S–S bond angles with values in a narrow range of 103–105°, and the S–S–C bond angles of 124–128°, there is an agreement between the pentathiepin structures evaluated here and those described in the literature [69]. Overall, the structural features of the five-membered sulfur moiety of the pentathiepins are nearly identical, regardless of whether this moiety is tethered to a five-
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Figure 14.57: Molecular structure of 8-(trifluoromethyl)benzo[f][1,2,3,4,5]pentathiepin-6-amine (the trifluoromethyl group is disordered; only the major occupancy is shown); thermal ellipsoids are drawn at 50% probability; space group P21/c, a = 10.214(1) Å, b = 10.838(1) Å, c = 10.488(1) Å, β = 94.665(4) °. Drawn from data submitted to the CSD; ref code: CIVZAL [65, 68].
Figure 14.58: Molecular structure of TEOC-protected varacin; space group P21/c, cell: a = 15.908(12)Å, b = 17.328(13)Å, c = 8.784(3)Å, β = 96.45(5)°. Drawn from isotropic data submitted to the CSD; ref code: WILKEH [67].
or a six-ring, which is an aromatic or a hetero-aromatic species. This strongly suggests a notable stability of this conformation over others, at least in the solid crystalline state.
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Figure 14.59: Molecular structure of ferroceno[1,2f]-[1,2,3,45,]pentathiepin; thermal ellipsoids are drawn at 50% probability; space group P21, a = 8.6743 Å, b = 7.5798 Å, c = 10.4960 Å, β = 110,762 °. Drawn from data submitted to the CSD; ref code: XONDEJ [33, 35].
Figure 14.60: Molecular structure of pentathiepino-pyrrolo[1,2-a]quinoxaline; thermal ellipsoids are drawn at 50% probability; space group P21/n, a = 8.1317 Å, b = 20.856 Å, c = 8.7162 Å, β = 101.63 °. Drawn from our own data also available at the CSD; ref code: FEWMAX [37].
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14.4.2 NMR spectroscopy NMR spectroscopy is a routine method for the structural characterization of organic molecules. Concerning pentathiepins, it is even possible with 1H-NMR spectra to indirectly confirm the presence of the five-membered sulfur ring for a specific family of these compounds. This section gives examples for the most characteristic signals in the NMR spectra of pentathiepins, as observed with various types of these compounds. The first example is varacin (29a), which Davidson and Ford characterized for the first time using NMR spectroscopy [5]. Their study showed that the side chain’s methylene protons exhibited unexpectedly complex NMR signals. NMR experiments at variable temperatures showed that at higher degrees these signals became sharper as expected for an increased mobility. However, even under these conditions distinct diastereotopic signals with an ABXY (or ABX3) pattern, instead of the more common AA´XX´ pattern were observed for the methylene protons with a geminal scalar coupling above 10 Hz. These results can only be explained by the presence of an asymmetry in the molecule, suggesting that varacin and its analogues are chiral. The origin of the chirality of varacin is best explained by the exceedingly slow inversion of the sulfur ring due to an exceptionally high thermodynamic barrier (about 29 kcal mol–1). The same observation was also made by Searle et al. [6] for lissoclinotoxin A. A more recent NMR spectroscopic confirmation of the asymmetric environment, which is felt by the methylene group in α-position of a chiral pentathiepin was provided for N-heterocyclic species [37]. Their unique structural and spectroscopic properties allowed the 1H NMR spectrum to prove indirectly whether or not the fivemembered sulfur ring is present, i.e., they have an actual “fingerprint” signal. The pyrrolo-quinoxaline-fused pentathiepin 135 carries the typical ethoxy substituent, when pentathiepins are obtained by the molybdenum-mediated synthesis and it exhibits a particular splitting pattern in the 1H NMR spectrum (Figure 14.61) [70]. As for the varacin analogue, considering the molecular structure, the normally expected signal for the methylene protons would be a quartet. Due to the chair conformation of the polysulfur ring, the molecule is not planar. As a result, the methylene protons in close proximity of the chair experience the asymmetry and become diastereotopic. This gives rise to a complex multiplet with integrals of 2H at 4.50–4.70 ppm with an ABX3 splitting pattern. Pentathiepins synthesized via the method by Zubair et al. [37], regardless of the heterocyclic backbone, always bear the ethoxy group; the characteristic 1H-NMR-multiplet for these can, hence, be taken as an immediate proof for their formation, since in the absence of the five-sulfur chain in chair conformation, the NMR-behavior is entirely different. An example of a non-chiral member of the pentathiepin family is ferrocenopentathiepin 65, which was studied by NMR spectroscopy by Muraoka et al. [35] and has a mirror plane dividing the molecule in half. Methylene protons are absent, and the spectra look quite different from those discussed above. The 1H NMR spectrum gave a doublet and a triplet signal for the α- and β-cyclopentadienyl ring protons at 4.53 and
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Figure 14.61: 1H NMR splitting pattern for the CH2-protons of the ethoxy functional group of the pentathiepin [70].
4.42 ppm, respectively. A singlet at 4.32 ppm can be assigned to the five cyclopentadienyl protons of the five-ring, which does not bear the -S5- chain. In the 13C NMR spectrum, resonances at 70.0, 71.1, and 75.4 ppm were visible for the unsubstituted carbon atoms. The ipso-cyclopentadienyl carbon atoms attached to the sulfur ring showed a downfield shift of 93.3 ppm, likely due to the deshielding effect of the sulfur atoms.
14.4.3 Mass spectrometry The fragmentation patterns of most benzopentathiepins and a few heterocyclic pentathiepins are comparable, making mass spectrometry a suitable technique for pentathiepin detection. Electron ionization (EI) is most commonly used [11, 64]. In the work of Behnisch-Cornwell et al., Wolff et al. and Zubair et al. the characterization was carried out by atmospheric pressure chemical ionization (APCI) mass spectrometry [37, 70, 71]. Generally, only a low intensity (0.6–25%) of the molecular ion was observed, and the base ion peak at 100% could often be assigned to a fragment with a loss of S2. Cleavage of one sulfur atom only, S1, is not described, though. The heterocyclic pentathiepins, according to Zubair et al., represent an exception. In the corresponding APCI mass spectrum, mostly the molecular ion (without any loss of fragments) corresponds to the base ion peak with an intensity of 100%. However, the previously discussed fragment ions also occur where S2 or S3 have been cleaved off. Figure 14.62 shows an APCI mass spectrum for the pyrrolo-quinoxaline-fused pentathiepin 135. The molecular ion could be detected with 385.44 m/z [M+H]+ as the base ion peak. Furthermore, the fragment with m/z = 321.35 corresponds to the [M-S2] mass [20, 26, 27, 37, 48, 70–73].
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Figure 14.62: APCI mass spectrum of pyrrolo-quinoxaline-fused pentathiepin 135 [70].
14.4.4 Vibrational spectroscopy The infrared (IR) spectra of pentathiepins generally show absorption bands of the S–S vibrations in the range of 460–485 cm–1 [11, 64]. Apart from this, the method is not particularly informative with regard to the chemical pentathiepin structure. Raman spectroscopy, in contrast, is quite suitable for studying sulfur-containing compounds (Figure 14.63) [44]. The valence electrons in the sulfur-sulfur bonds are highly polarizable and give rise to intense Raman bands. Care must be taken to ensure that the sample does not become decomposed. It is known that sulfur-containing compounds are photosensitive and homolytic cleavages of the S–S bonds may occur. A number of Raman spectra of heterocyclic and benzopentathiepins were reported and discussed (Figure 14.63) [44]. As in the IR spectra, the S–S stretching vibrations are generally observed in the 400–500 cm–1 range, typically with the strongest absorption at 490±5 cm–1. Benzopentathiepins also show two additional characteristic absorption bands at 425±5 cm–1 and for very low energy excitation at 180±5 cm–1 [11, 44, 64, 69].
14.4.5 UV-Vis spectroscopy The usefulness of UV-Vis absorption spectroscopy of a pentathiepin depends on the compound’s structure. Most pentathiepins exhibit a notable intense band at a wavelength of ~210 nm (ɛ = 25,000–32,000). Differences of this band and others in this high energy region can be observed for pentathiepins based on the electronic structures of their backbones. The most simple unsubstituted pentathiepin (C2S5) has comparably weak and merely diffuse signals at 206 nm (ɛ = 9,730 M–1 cm–1), 253 nm (ɛ = 3,440 M–1 cm–1), and 315 nm (ɛ = 1,510 M–1 cm–1). Pentathiepins with a heterocyclic backbone, such as pyrrole, pyrazole, or thiophene show absorption maxima at
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Figure 14.63: Raman spectra of heterocyclic and benzopentathiepins in the range from 500 to 100 cm–1. Reprinted with permission from: Chenard, BL, Harlow, RL, Johnson, AL, Vladuchick, SA. Synthesis, structure, and properties of pentathiepins. J Am Chem Soc, 1985, 107(13), 3871–3879. Copyright 1985 American Chemical Society [44].
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230–240 nm [44]. Another specific example is TEOC-protected varacin, which has a broad absorption maximum at 209 nm with a strong shoulder at 245 nm [67]. Lissoclinotoxins A and B show absorption bands at 246 nm [6, 73]. This suggests that heteroatoms other than sulfur have a significant influence on the energies required to bring the electrons from their ground- to an excited state and, hence, on the composition of their frontier molecular orbitals.
14.4.6 Conformation and chirality As already mentioned above, the polysulfur unit of the pentathiepins is exclusively present in the characteristic chair conformation for all compounds evaluated in this regard. The chair conformation has a notably high inversion barrier of ca. 29 kcal· mol–1. The rigidity of this ring plus unsymmetrical substitution patterns on the backbone are the reasons, why most pentathiepins are chiral. The high inversion barrier for the pentathiepins was explained by Searle et al. [6] with the help of a computational investigation. They found that a thermodynamically unfavorable eclipse position of the 3sp3 lone pair orbitals arises during the ring inversion in the half-chair transition state. Figure 14.64 illustrates this using lissoclinotoxin A as an example [6].
Figure 14.64: A strained transition state (b) requires eclipsed sulfur lone pairs in order to invert the chair conformation [6].
Compared to cyclohexane, the inversion barrier of pentathiepins is really high. For cyclohexane, the conformational changes during a ring flip occur in several steps with the highest energy transition state lying at 10.8 kcal mol–1 above the initial/final chair conformation [74]. Brzostowska et al. [75] provided an even more exhaustive study of the pentathiepins’ geometry preferences utilizing DFT-calculations (B3LYP/6-31 G(d)). They calculated the computational stabilities of ortho-fused heterocycles o-C6H4Sx bearing a varied number of sulfur atoms (x = 1 to 8). Lone pair electron interactions in polysulfur chains had been discussed before and it was known that those interactions direct the preferences for the final conformations. This was indeed confirmed for the pentathiepins investigated. For o-C6H4Sx with x=3, 5, or 7 stable gauche interactions of the 3p orbitals (out of plane) were observed, while for x=2, 4, 6, 8 the compounds pre-
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ferred eclipse interactions [75]. As a consequence of those geometrical interactions odd-membered rings are more stable in chair conformation than even-membered rings are (Figure 14.65). Also, as mentioned before, a noticeably unfavorable eclipse position of the lone pair containing orbitals needs to be surpassed during an inversion for odd numbered sulfur rings.
Figure 14.65: Illustration of ortho-fused heterocycles o-C6H4S5 2 (left) and o-C6H4S6 136 (right) [75].
Considering the high energy barrier for the sulfur ring inversion of a pentathiepin, it should be possible to detect the two different diastereoisomers, and a characteristic signal in the 1H-NMR spectrum should be a suitable probe. This crucial experiment was carried out by Sato et al. in 2008 with an atropoisomeric pentathiepin holding a biphenyl scaffold 138 [34]. The atropoisomerism, induced by the backbone, is used to distinguish the two diasteroisomers. The compound was made via tin-mediated synthesis, which directly provided the two diastereomers of interest, in which the methyl substituent of the backbone is used as a sensor (Figure 14.66).
Figure 14.66: Synthesis of atropoisomeric pentathiepin 138 [34].
In the 1H NMR spectrum, the methyl protons appeared as two singlets at 1.99 and 2.17 ppm, and in the 13C NMR spectrum the methyl carbon also appeared twice at 20.26 and 20.86 ppm (Figure 14.67). Both diastereomers were always in equilibrium in solution, which is why the isolation of the diastereomer as an optically active form was practically impossible. The sulfur ring inversion is either so slow (or does not take
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Figure 14.67: 1H (left) and 13C (right) NMR peaks of the methyl group of the two diastereomers of 138. Reused with permission from: Sato, R, Alam, A, Ohta, H, Mori, K-e, Sato, Y, Okawa, M, Tada, M, Nakajo, S, Ogawa, S, Yamamoto, T. Novel chiral cyclic polysulfides with a biphenyl backbone: investigation of atropisomerism and pentathiepin ring inversion. Tetrahedron, 2008, 64(17), 3751–3759 [34].
place at all) that the methyl group is consistently and continuously affected by the two different chair conformations.
14.4.7 DFT calculations A DFT study by Greer published in 2001 provided new insights into the origin of the cytotoxicity of the naturally occurring pentathiepin varacin (29a) [76]. The calculations were performed by exchange-correlation of B3LYP together with the 6–31 G✶, 6 311+G✶, or 6–311 G✶✶ basis sets [77]. The computations predicted a conversion of the polysulfurring to an open-chain polysulfur ion intermediate upon decomposition of the pentathiepin was initiated (Figure 14.68) [76]. The attack of the nucleophile (HS–) was investigated and it occurs, at least theoretically, preferably at the S1 atom, rather than the S2 position. It is then more likely that an S3 fragment dissociates unimolecularly (Figure 14.68A) based on a long and weak S–S bond, while no support for a breakdown of the polysulfur ion intermediate under S2 cleavage was observed (Figure 14.68B). The most energetically favorable decomposition process of all scenarios tested was unambiguously the one, which involves S3 splitting (Figure 14.68A) [76]. Brzostowska et al. [78] provided the first computational evidence that the natural pentathiepins’ terminal amino groups on their backbones can interact with the polysulfur ring and thereby promote self-degradation. They carried out DFT (performed by exchange-correlation of B3LYP together with the 6–31 G(d) basis set [77]) and experimental studies on the role of the –NH2 group of naturally occurring varacin and lissoclinotoxin A or truncated versions or derivatives thereof, which was built on the previously published DFT study by Greer [76].
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Figure 14.68: Computational prediction of the most energetically favorable decomposition processes of the pentathiepin ring with A being far more favorable than B [76].
The results showed that primary (or secondary) amines might interact with the sulfur ring in an intramolecular fashion leading to the same decomposition sequences, as calculated previously for the reaction with HS–(Figure 14.69). The attack of the nitrogen occurs at the directly adjacent electron-deficient S1 sulfur atom. Tertiary amines in contrast may add only reversibly to the S1 sulfur atom because the nitrogen cannot be deprotonated and the reaction cannot proceed without releasing one proton [78]. The DFT calculations results indicated an energetically preferred process corresponding to the loss of the -S3- fragment triggered by the nucleophilic activation through a primary or secondary amine. Overall, the study provided new mechanistic insights into the self-activated bioactivity of pentathiepins. However, considering the abundance of available heteroatom functional groups in the biological environment this will most certainly not be the dominant or even single mechanism of action. Computational studies gave also insights into the chirality and conformational changes of pentathiepins (vide supra). Specifically, the natural pentathiepins varacin (29a) and lissoclinotoxin A possess planar chirality due to their energy barrier for ring inversion being high (ca. 29 kcal ·mol–1), which may be relevant for their biological activity in particular with enzymes. Typically the naturally occurring pentathie-
Figure 14.69: Postulated mechanism for the intramolecular interaction of the amine with the polysulfur ring [78].
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pins were isolated only as their racemates, and not in an enantiomerically pure form. Brzostowska et al. [79] in 2007 with a DFT calculation (B3LYP/6-31 G(d)) identified a low-energy pathway for the racemization of pentathiepins in the presence of a nucleophile (HS–; as an example of a biologically occurring one). This suggests that the planar chirality may be lost in a biological environment concomitant with an increased instability of the pentathiepin’s chemical and spatial structure. Consequently, experimental studies of the mode of action of the two distinct pentathiepin enantiomers are generally challenging. For example, it cannot be determined whether one enantiomer might have a higher potency with regard to biologically toxic properties, than the other. The calculations further confirmed high-energy barriers for the conversion of the pentathiepin enantiomers via chair-chair flipping, which is not lowered by an intramolecular attack of amine nucleophiles, i.e., the presence of an amine on the pentathiepin backbone does not induce racemization [79].
14.5 Biological activity and applications of pentathiepins The biological activities of naturally occurring and synthetic pentathiepins from the initial biological studies to the most current research results are summarized in the following. The (potential) applications range from anticancer to antimicrobial to antifungal activities and others, while the pentathiepins apparently have an impact on various different biomolecules.
14.5.1 Naturally occurring pentathiepins With the discovery of varacin (29a) isolated from the marine ascidian Lissoclinum vareau, interest in the research field of pentathiepins surged. This is mostly because it was found that varacin possesses versatile biological properties. Besides its antifungal activity against Candida albicans, varacin exhibits considerably high cytotoxicity against the human colon cancer cell line HCT116 with an IC90 value of 0.05 μg/mL [5]. It, thus, outperforms the activity of 5-fluorouracil in this assay by a factor of 100 [5]. Compagnone et al. [45] in 1994, first described the isolation of natural varacin analogues which are potent inhibitors of protein kinase C (PKC). These were N,N-dimethyl-5-(methylthio)varacin (IC50 = 3.0 μg/mL) from the Palauan ascidian Lissoclinum japonicum and 3,4-desmethyl varacin (IC50 = 0.5 μg/mL) from Eudistoma sp. of Pohnpei [45]. The same year, lissoclinotoxin A and lissoclinotoxin B, were isolated from the tunicate Lissoclinum perforatum and their notable biological activity could be established soon [6, 73, 80]. These pentathiepins were, for instance, found to be potent antibiotics with an activity comparable to cefotaxime. Lissoclinotoxin A showed anti-
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biotic activity against diverse Gram(+) and Gram(-) strains, including Staphylococcus aureus, with MIC (minimum inhibitory concentration) values ranging from 0.08 to 10 μg/mL. Lissoclinotoxin B showed comparable activity against ichthyopathogenic strains, such as Aeromonas salmonicida and Vibrio angularium.
14.5.2 Benzopentathiepin analogues Following the discovery and characterization of the naturally occurring pentathiepins, synthetic analogues were more frequently tested for their biological activity. The “DuPont compound” 8-cyanoisothiazolo pentathiepin (46), synthesized as early as 1977, exhibited a versatile spectrum of anti-fungal properties, such as against a wide range of plant diseases (Figure 14.70) [44, 81]. Sato et al. synthesized new benzopentathiepins 13 g, 15 g, and 140 (Figure 14.70), which showed considerable cytotoxicity against HeLa S3 cells (IC50 values of 0.26–6.12 μg/mL) [18]. The extent to which the presence of the five-membered sulfur ring was related to cytotoxicity was investigated in addition for the first time in this study. Notably, the benzendithiol derivative 141 (Figure 14.70) of pentathiepin 140 showed a tenfold lower cytotoxicity than the corresponding pentathiepin emphasizing the significance of the seven-membered ring for biological activity [18]. Chatterji et al. [82] in a mechanistic investigation showed for the first time that the simple varacin analogue 7-methylbenzopentathiepin (20, Figure 14.70), can cleave DNA under physiologically relevant conditions. More specifically, this was identified as a thiol-dependent DNA-cleaving activity since pentathiepin 20, in the presence of
Figure 14.70: Benzopentathiepin analogues tested for biological antifungal, cytotoxic, and DNA cleavage activities.
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thiols, allowed efficient conversion of super coiled DNA to the nicked form [82]. On the basis of this study, Lee et al. [83] in 2002 proved that varacin itself can exhibit the same DNA-cleaving activity in the presence of thiols. In addition, the study found that a low pH environment can accelerate the process. In 2014, Xu et al. identified a new potent inhibitor of the tyrosine phosphatase STEP (striatal-enriched protein tyrosine phosphatase) [84]. STEP regulates the N-methyl-Daspartate receptor (NMDAR) and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity, among others. STEP is known to be present at higher concentrations and overactive in several neurodegenerative and neuropsychiatric diseases, such as Alzheimer’s and schizophrenia. High concentrations of STEP cause dephosphorylation of proteins (glutamate receptors and kinases), which inactivates them and ultimately disrupts memory consolidation [84]. The group identified the benzopentathiepin derivative 8-(trifluoromethyl)-1,2,3,4,5benzopentathiepin-6-amine hydrochloride (142; known as TC-2153) as a potent STEP inhibitor with an IC50 value of 24.6 nM. The inhibition mechanism is based on an interaction with polysulfide molecules and catalytic cysteine in STEP. The activity of TC-2153 was demonstrated in vitro and in vivo (using a mouse model of Alzheimer’s disease). Among many other results of this study, it was rather notable that cognitive deficits were significantly improved in the mice, but this was not accompanied by changes in typical pathological symptoms, such as β-amyloid and phospho-tau levels [84]. Building on this study, Baguley et al. synthesized and investigated novel TC-2153 analogues to identify the structural features, which are essential for inhibiting STEP [46]. STEP inhibitory activity assays were performed in both the presence and the absence of 1 mM glutathione (GSH). TC-2153 (IC50 = 24.6±0.8 nM) remains one of the most potent inhibitors together with the aniline hydrochloride salts 143 (IC50 = 25±7 nM) and 144 (IC50 = 32±3 nM). Pentathiepin 134b with a trifluoroacetamide group also showed good potency (IC50 =24±1 nM); in contrast, pentathiepin 134a with the acetamide functionalization had a twofold lower inhibitory activity (IC50 =49±2 nM). Derivatives with alkylated amino groups (pentathiepins 145 and 146) were even less active. Overall, the ones decorated with the trifluoromethyl group, acetamide functionalities and/or hydrochloride salts inhibited STEP quite efficiently, whereas those with an alkylated secondary amino group did not (Figure 14.71) [46]. This suggests that the interaction with the solvent in an aqueous medium might have an influence as well. Around the same time, additional TC-2153 analogues were synthesized by Zakharenko et al. in order to identify novel tyrosyl DNA phosphodiesterase-1 (TDP1) inhibitors [63]. TDP1 is a promising target for anticancer therapy, because it induces type I topoisomerases (Top1) poison-mediated DNA damage. Based on molecular modeling and considering the active site of TDP1, the analogues were modified at the amino group of TC-2153 (Figure 14.72). In Figure 14.72 the IC50 values are provided along the chemical structures of the tested substituents. They lie in the range of 0.2–6.0 µM. The analogue with the dibutyl amine group 134 showed the most potent inhibitory activity; molecular modeling suggests a better binding for this side chain as compared to
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Figure 14.71: A collection of compounds, such as TC-2153 and analogues, tested for STEP inhibition [46, 84].
the other cyclic and thereby less flexible derivatives. All compounds caused apoptotic cell death in MCF-7 and Hep-G2 cells. The compounds with neither the sulfur moiety nor the trifluoromethyl group (147a, 147b) showed strong activity losses emphasizing the importance of these substituents [63]. Later Khomenko et al. studied the antimicrobial activity of TC-2153 and its analogues (Figure 14.72) [12]. TC-2153 and pentathiepins 134a-d proved highly active against, among others, the multiresistant strain S. aureus (MRSA) with a MIC of around 4 µg/ml. The most active derivatives were the ones possessing the acetamide functional group 134a and trifluoroacetamide 134b; in fact, a fourfold activity increase was achieved as compared to the reference antibiotic amoxicillin. These substances also showed the most remarkable efficacy with MICs of 1–2 µg/ml against the fungus C. albicans. Of particular interest was the use of the 1,3-dithiolan-2-one or 1,3dithiolan compounds, which do not have the polysulfur ring. This resulted in the most notable disappearance of any antimicrobial activity [12]. This milestone study has, hence, confirmed that the biological activity of pentathiepins is absolutely dependent on the pentathiepin moiety itself. In 2017 Sinyakova et al. studied the effects of the potential antidepressant 8trifluoromethyl-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) and the well-known fluoxetine on the behavior of Danio rerio fish in the “novel tank” test [85]. The tests showed that neither compound altered any brain levels of serotonin, dopamine, or norepinephrine. Interestingly, however, the brain levels of the significant serotonin metabolite 5-hydroxy indole acetic acid were decreased by fluoxetine but not by TC-2153. The combination of both compounds produced the most successful results with regard to the antidepressant activity [85].
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Figure 14.72: Pentathiepin compounds tested for TDP1 inhibition and their respective inhibitory activities [63].
Mahendran et al. published a ceramide-benzopolysulfane conjugate of varacin (132), which showed potent anti-proliferative properties against diverse human cancer cell lines (MDA-MB 231 (breast), DU145 (prostate), MIA PaCa-2 (pancreas), HeLa (cervix), and U251 (glioblastoma) [62]. IC50 values of 10 to >20 µM were observed, while total cell killing was achieved at 12.5 mM for MDA-MB-231 and at 20 mM for DU145 and HeLa cells. The respective IC50 values are 1.8- and 4.0-fold lower than those for the related PEGylated benzopolysulfane, N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl) benzo[f][1,2,3,4,5]-pentathiepin-7-carboxamide (148). In comparison, simple benzenedithiol o-C6H4(SH)2 exhibits an IC50 value of >30 mM with little effect on MDA-MB-231 and DU145 cells. This is again strong evidence for the polysulfur moiety being essential for activity (Figure 14.73) [62, 86].
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Figure 14.73: The PEG-benzopentathiepin 148 and the ceramide-benzopentathiepin conjugate of varacin 132 [62, 86].
14.5.3 Pentathiepins with a heterocyclic backbone Various pentathiepins with heterocyclic backbones are known today, and in addition to their unique structural properties they have also gained importance with regard to their biological activities. Asquith et al. investigated thiophene-, pyrrole-, and indolefused pentathiepins as inhibitors of the feline immunodeficiency virus (FIV) which is a model for HIV infection [87]. This is possible because FIV shows a significant homology with HIV-1/2 in essential protein domains. The nucleic acid-binding nucleocapsid protein (NCp), which has a conserved double zinc finger peptide unit, was chosen as antiviral target. A proposed, yet not unambiguously proven, mechanism comprises a direct interaction of the pentathiepin ring with the zinc finger structure causing zinc ejection. The authors thereby describe for the first time an alternative mechanism to simple DNA cleavage [87]. In another study, Asquith et al. examined heterocyclic-fused pentathiepins (Figure 14.74) for their inhibitory activity against Sporothrix brasiliensis [81]. It is Brazil’s notorious causative agent of zoonotic sporotrichosis with a truly extreme virulence.
Figure 14.74: Standard drug itraconazole 149 against Sporothrix brasiliensis (left); tested heterocyclic fused pentathiepins (right) [81].
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A series of symmetrical derivatives were tested against eight isolates of skin lesions infected with S. brasiliensis. Compounds 150, 151, and 152 were proven ineffective. Compounds 54a and 54b, in contrast, showed a moderately low activity. Furthermore, a trend was observed with increasing electron-withdrawing properties of the substituents resulting in improved antifungal activity. The unsymmetrical pentathiepins 154 and 39b showed an improved activity compared to the symmetrical ones. In fact, they even outperformed the current standard drug itraconazole [81]. With a rather comprehensive study Behnisch-Cornwall et al. investigated for the first time the biological activity of the heterocyclic-fused pentathiepins prepared by the molybdenum-mediated synthetic route [37, 70]. In general, it was found that the heterocyclic class of pentathiepins (in addition to their unique structural properties) are also biologically very significant as they showed strong and diverse effects on cellular systems of a greater extent than previously thought. Known indole-based pentathiepins were compared with the (at that time new) class of pyrrolo[1,2-a]quinoxaline pentathiepin derivatives (Figure 14.75), and all were found to be novel inhibitors of glutathione peroxidase 1 [70].
Figure 14.75: Most potent established inhibitor of the GPx MSA 155 (left); tested heterocyclic fused pentathiepins (right) [37, 70].
Glutathione peroxidase was chosen as a target because it protects healthy as well as cancer cells against oxidative stress. Cancer cells, however, have a high cell division rate and metabolism, which makes them particularly vulnerable to oxidative stress. The hypothesis was, hence, that inhibiting glutathione peroxidase would have a more substantial cytotoxic effect on cancer cells than on healthy cells. All the pentathiepins tested proved to be very potent inhibitors of glutathione peroxidase (tested was bovine erythrocyte GPx), because they did so at concentrations lower than the most potent inhibitor to date, 2-mercaptosuccinic acid (MSA; 155). Both the most potent pentathiepin 158 with an IC50 value of 0.40 µM and the weakest pentathiepin 77b, with an IC50 value of 2.44 µM, were more active than 155 (IC50 = 5.86 µM). Pentathie-
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pins from the class of the pyrrolo[1,2-a]quinoxalines showed more pronounced selectivity in terms of GPx1 inhibition than the indole-based pentathiepins. Furthermore, all these pentathiepins possess considerable cytotoxicity against diverse human cancer cell lines with IC50 values ranging from low micromolar to sub micromolar concentrations. Overall, it was shown that pentathiepins trigger oxidative stress, DNA strand breaks and apoptosis (or rather apopentathiepinosis) [37, 70]. Building on this study, six new pentathiepins 160–165 (Figure 14.76) were then tested by Wolff et al. against 14 human cancer cell lines and shown to have similar IC50 values in the low micromolar range [71].
Figure 14.76: N-heterocyclic pentathiepins with potent cytotoxic activities against various cancer cell lines [71].
High cytotoxic and antiproliferative activities as well as GPx1 inhibition were observed. A correlation between the ability to induce oxidative stress and DNA damage (single and double-strand breaks) was demonstrated for the first time. Pentathiepins 161–164 generated intracellular oxidative stress with the highest resultant DNA damage. Numerous experiments investigating the activity and mode of action of these heterocyclic pentathiepins were performed and discussed in much detail [71]. However, a comprehensive picture of the actions of pentathiepins on the molecular level in a biological environment is still elusive. Convincing and unambiguous structure-activity relationships still need to be deciphered. It is now established that pentathiepins affect various biomolecules directly or indirectly and a targeted approach to their backbone structures might aid in the development of derivatives which can be applied in a more controlled manner.
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14.6 Other applications of pentathiepins A few different pentathiepin applications in the material sciences have been investigated, widely ranging from polymers to energy storage to photography and to metal sensing devices. None is particularly well developed as of yet, or has relevance beyond niche applications. The norbornene-based pentathiepins were suggested to serve as vulcanization accelerators for the generation of diene rubber [88]. The initiated patenting process, however, was not completed. Benzo- and cyclohexapentathiepins have been tested and proposed as components in photographic applications to reduce the fogging, for instance, or otherwise improve the used materials [11, 64]. A modified poly-(N-methyl pyrrole) bearing pentathiepino rings (S-PMPy; 166) was tested as a positive active material for the lithium secondary cell for batteries (Figure 14.77) [89]. This has not come into common use either, though.
Figure 14.77: Poly-(N-methyl pyrrole) with the pentathiepino ring (166) investigated as additive in lithium secondary cell batteries.
More recently, naphtho[2,3 f ][1,2,3,4,5]pentathiepin-6-ol was shown to have a stable conformation, which is suitable for metal coordination. Two molecules of this pentathiepin derivative could form a complexing cage around a Co2+ ion resulting in complex 167 in the form of a burger rather than a sandwich though it was described as the latter [90]. The good spatial match between binding pocket and metal ion size enabled selective Co2+ ion recognition in aqueous solution (Figure 14.78).
Figure 14.78: Complex of naphtho[2,3 f ][1,2,3,4,5]pentathiepin6-ol with the cobalt(II) ion.
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14.7 Conclusions The chemistry of pentathiepins is often surprising with regard to essentially all aspects. This is a blessing as well as a curse. Sometimes, they are made quite unexpectedly; sometimes they react unpredictably and they bear immense potential for biological, or more precisely: medicinal applications. Here again, they can show cytotoxic and/or antimicrobial activity and much more. How they interact with biological materials on the molecular level is not well understood to date, even though specific biomolecules have been shown to be influenced by the presence of pentathiepins, such as DNA or redoxactive enzymes. All this leaves much room for very exciting ongoing and future research. There is certainly the possibility that scientists working in this field may provide humanity with a solution to one or more of the many urgent problems it faces. In our view, overcoming the resistance of multiresistant bacteria is a likely candidate, and directing specific efforts to this field would be well justified. The structural potential of the pentathiepins’ backbone appears essentially endless, while exploiting it to the highest possible level is anything but an easy task. We are looking forward to continuing monitoring this field, as well as to further contributing to it in the near future.
References [1]
Jacob, C. A scent of therapy: Pharmacological implications of natural products containing redoxactive sulfur atoms Nat Prod Rep 2006, 23(6), 851–863. [2] Giles, GI, Jacob, C. Reactive sulfur species: An emerging concept in oxidative stress Biol Chem 2002, 383(3–4), 375–388. [3] Steudel, R. Properties of sulfur-sulfur bonds Angew Chem Int Ed 1975, 14(10), 655–664. [4] Benson, SW. Thermochemistry and kinetics of sulfur-containing molecules and radicals Chem Rev 1978, 78(1), 23–35. [5] Davidson, BS, Molinski, TF, Barrows, LR, Ireland, CM. Varacin: A novel benzopentathiepin from Lissoclinum vareau that is cytotoxic toward a human colon tumor J Am Chem Soc 1991, 113(12), 4709–4710. [6] Searle, PA, Molinski, TF. Five new alkaloids from the tropical ascidian, Lissoclinum sp. lissoclinotoxin A is chiral J Org Chem 1994, 59(22), 6600–6605. [7] Makarieva, TN, Stonik, VA, Dmitrenok, AS, Grebnev, BB, Isakov, VV, Rebachyk, NM, Rashkes, YW. Varacin and three new marine antimicrobial polysulfides from the far-eastern ascidian polycitorsp J Nat Prod 1995, 58(2), 254–258. [8] Steudel, R. The Chemistry of organic polysulfanes R−Sn−R (n > 2) Chem Rev 2002, 102(11), 3905–3946. [9] Fehér, F, Degen, B. Neue schwefelhaltige ringverbindungen Angew Chem Int Ed 1967, 79(15), 689–690. [10] Fehér, F, Langer, M. Contribution to the chemistry of sulfur, no. 104 Synthesis of pentathiepin and benzopentathiepin Tetrahedron Lett 1971, 12(24), 2125–2126. [11] Konstantinova, LS, Rakitin, OA, Rees, CW. Pentathiepins Chem Rev 2004, 104(5), 2617–2630. [12] Khomenko, TM, Korchagina, DV, Baev, DS, Vassiliev, PM, Volcho, KP, Salakhutdinov, NF. Antimicrobial activity of substituted benzopentathiepin-6-amines J Antibiot 2019, 72(8), 590–599.
Chapter 14 Synthesis of pharmacologically significant pentathiepins
[13]
[14] [15]
[16] [17]
[18] [19]
[20] [21]
[22] [23] [24] [25]
[26]
[27] [28]
[29] [30] [31] [32]
461
Ariyan, ZS, Courduvelis, CI, O’Brien, JT, Spall, WD. 10-(1,3-Dithiolan-2-ylidene)-10H-indeno[1,2-f] pentathiepin, a product from 2-(inden-1-ylidene)-1,3-Dithiolan and disulphur dichloride. J Chem SocPerkin Trans 1974, 1, 447. Korp, JD, Bernal, I. The stereochemistry of organosulfur compounds. J Mol Struct 1982, 19, 459–462. Korp, JD, Bernal, I, Watkins, SF, Fronczek, FR. The stereochemistry of organosulfur compounds. XIX. The crystal and molecular structure of 10-(1,3-dithiolan-2-ylidene)-10H-indeno[1,2-f]-1,2,3,4,5pentathiepin J Heterocycl Chem 1982, 19(3), 459–462. Chenard, BL, Miller, TJ. Benzopentathiepins: Synthesis via thermolysis of benzothiadiazoles with sulfur J Org Chem 1984, 49(7), 1221–1224. Sato, R, Saito, S, Chiba, H, Goto, T, Saito, M. Synthesis of cyclic polysulfides. Reactions of dithiols and related compounds with elemental sulfur in liquid ammonia Bull Chem Soc Jpn 1988, 61(5), 1647–1651. Sato, R, Ohyama, T, Ogawa, S. Efficient synthesis and biological properties of new benzopentathiepins Heterocycles 1995, 41(5), 893. Sato, R, Kimura, T, Goto, T, Saito, M, Kabuto, C. First direct synthesis of 4,8-dialkylbenzo[1,2-d;4,5-d′] bis[1,2,3]trithioles and 6,10-dialkyl[1,2,3]trithiolo[5,4-h]benzopentathiepins from 1,4-dialkyl-2,3,5,6tetrabromobenzenes Tetrahedron Lett 1989, 30(26), 3453–3456. Morris, JL, Rees, CW. Organic heterocyclothiazenes. Part 3. Synthesis and structure of 1,3,5,2,4trithiadiazepines. J Chem Soc-Perkin Trans 1987, 1(0), 211–215. Trigalo, F, Bijamane, A, Guyot, M, Frappier, F. A convenient approach to benzopentathiepins. Application to the synthesis of varacin and isolissoclinotoxin a derivatives Nat Prod Lett 1994, 4(2), 101–106. Sato, R, Ohyama, T, Kawagoe, T, Baba, M, Nakajo, S, Kimura, T, Ogawa, S. Synthesis and characterization of functionalized benzopentathiepins Heterocycles 2001, 55(1), 145–154. Behar, V, Danishefsky, SJ. Total synthesis of the novel benzopentathiepin varacinium trifluoroacetate: The viability of “varacin-free base” J Am Chem Soc 1993, 115(15), 7017–7018. Toste, FD, Still, IWJ, New, A. Route to the synthesis of the naturally occurring benzopentathiepin varacin J Am Chem Soc 1995, 117(27), 7261–7262. Perregaard, J, Scheibye, S, Meyer, HJ, Thomsen, I, Lawesson, S-O. Studies on organophosphorus compounds XVIII. Oxidation of tertiary alicyclic amines with elemental sulfur in Hexamethylphosphoric Triamide (HMPA). Oxidative rearrangements of hexahydroazepines and octahydroazocines to Bis(3-Pyrrolyl)polysulfides Bull Soc Chim Belg 1977, 86(9), 679–691. Rewcastle, GW, Janosik, T, Bergman, J. Reactions of 2-lithiated indoles with elemental sulfur. Formation of pentathiepino[6,7-b]indoles and indoline-2-thiones Tetrahedron 2001, 57(33), 7185–7189. Janosik, T, Stensland, B, Bergman, J. Sulfur-Rich Heterocycles from 2-metalated Benzo[b]thiophene and Benzo[b]furan: Synthesis and structure J Org Chem 2002, 67(17), 6220–6223. Vladuchick, SA, Fukunaga, T, Simmons, HE, Webster, OW. Thiacyanocarbons. 6. 1,4-Dithiino[2,3-c;6,5c’]diisothiazole-3,7-dicarbonitrile, isothiazole[3,4-f][1,2,3,4,5]pentathiepine-8-carbonitrille, and disodium 5-cyanoisothiazoledithiolate J Org Chem 1980, 45(25), 5122–5130. Macho, S, Rodríguez, T, Torroba, T, Rees, CW. A novel oxime to pentathiepin cascade reaction. Chem Commun 2001, 5, 403–404. Earle, MJ, Massey, AG, Al-Soudani, AR, Zaidi, T. The synthesis of some new thiophene derivatives Polyhedron 1989, 8(23), 2817–2821. Konstantinova, LS, Rakitin, OA, Rees, CW. A one-step synthesis of fused pentathiepins. Chem Commun 2002, 11, 1204–1205. Konstantinova, LS, Rakitin, OA, Rees, CW, Amelichev, SA. Regioselective synthesis of pentathiepinofused pyrroles and indoles Mendeleev Commun 2004, 14(3), 91–92.
462
Lukas M. Jacobsen et al.
[33] Nagahora, N, Ogawa, S, Kawai, Y, Sato, R. First synthesis and structure of sulfur-containing heterocycles fused to ferrocene Tetrahedron Lett 2002, 43(33), 5825–5828. [34] Sato, R, Alam, A, Ohta, H, Mori, K-E, Sato, Y, Okawa, M, Tada, M, Nakajo, S, Ogawa, S, Yamamoto, T. Novel chiral cyclic polysulfides with a biphenyl backbone: Investigation of atropisomerism and pentathiepin ring inversion Tetrahedron 2008, 64(17), 3751–3759. [35] Muraoka, H, Ogawa, S, Nagahora, N, Kawai, Y, Sato, R. Synthesis of new pentathiepin and dithiatriselenepin fused to ferrocene via dithiametallacycles Bull Chem Soc Jpn 2005, 78(11), 2026–2036. [36] Giolando, DM, Rauchfuss, TB, Rheingold, AL, Wilson, SR. Chemistry of (RC5H4)2TiE5 (E = S, Se). New information on its reactions with nucleophiles, syntheses and reactions of 1,4-[(RC5H4)2Ti]2E4, and a second isomer of (RC5H4)2TiS2C2(CO2Me)2. Organometallics 1987, 6(3), 667–675. [37] Zubair, M, Ghosh, AC, Schulzke, C. The unexpected and facile molybdenum mediated formation of tri- and tetracyclic pentathiepins from pyrazine-alkynes and sulfur Chem Commun 2013, 49(39), 4343–4345. [38] Draganjac, M, Simhon, E, Chan, LT, Kanatzidis, M, Baenziger, NC, Coucouvanis, D. Synthesis, interconversions, and structural characterization of the molybdenum sulfide anions, [(S4)2MoS]2-, [(S4)2MoO]2-, (Mo2S10)2- and (Mo2S12)2 Inorg Chem 1982, 21(9), 3321–3332. [39] Chinchilla, R, Nájera, C. The sonogashira reaction: A booming methodology in synthetic organic chemistry Chem Rev 2007, 107(3), 874–922. [40] Donahue, JP, Goldsmith, CR, Nadiminti, U, Holm, RH. Synthesis, structures, and reactivity of Bis (dithiolene)molybdenum(IV,VI) complexes related to the active sites of molybdoenzymes J Am Chem Soc 1998, 120(49), 12869–12881. [41] Schulzke, C. Molybdenum and tungsten oxidoreductase models Eur J Inorg Chem 2011, 2011(8), 1189–1199. [42] Bandaru, SSM Molybdenum mediated synthesis of pentathiepins ‒ Potent cytotoxic and antimicrobial agents and discovery of novel Pd/PTABS catalyst for the synthesis of pharmaceutically relevant drug molecules via C‒N, −O, and−S cross-coupling. Greifswald, 2020. [43] Tokitoh, N, Ishizuka, H, Ando, W. 1,2,3-Trithiole, 1,2,3-Triselenole, and 1,2,5-Thiadiselenole. Novel ring systems derived from sterically protected 1,2,3-Selenadiazole Chem Lett 1988, 17(4), 657–660. [44] Chenard, BL, Harlow, RL, Johnson, AL, Vladuchick, SA. Synthesis, structure, and properties of pentathiepins J Am Chem Soc 1985, 107(13), 3871–3879. [45] Compagnone, RS, Faulkner, DJ, Carté, BK, Chan, G, Freyer, A, Hemling, ME, Hofmann, GA, Mattern, MR. Pentathiepins and trithianes from two Lissoclinum species and a Eudistoma sp.: Inhibitors of protein kinase C Tetrahedron 1994, 50(45), 12785–12792. [46] Baguley, TD, Nairn, AC, Lombroso, PJ, Ellman, JA. Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP Bioorg Med Chem Lett 2015, 25(5), 1044–1046. [47] Kimura, T, Hanzawa, M, Horn, E, Kawai, Y, Ogawa, S, Sato, R. Preparation and conformational analysis of 6,10-disubstituted [1,2,3]trithiolo[h]benzopentathiepin monooxides Tetrahedron Lett 1997, 38(9), 1607–1610. [48] Galloway, CP, Doxsee, DD, Fenske, D, Rauchfuss, TB, Wilson, SR, Yang, X. Binary carbon sulfides based on the a-C3S5 subunit and related C-S-O, C-S-Cl, and C-S-N compounds Inorg Chem 1994, 33(20), 4537–4544. [49] Chatterji, T, Gates, KS. Reaction of Thiols with 7-Methylbenzopentathiepin Bioorg Med Chem Lett 2003, 13(7), 1349–1352. [50] Sato, RI, Saito Minoru, K. Synthesis of 2-alkyl- and 2-arylthiobenzenethiols. Reactions of benzopentathiepin with Grignard reagents in the presence of triphenylphosphine Sulfur Lett 1990, 12(1–2), 61–66. [51] Houk, J, Whitesides, GM. Characterization and stability of cyclic disulfides and cyclic dimeric bis (disulfides) Tetrahedron 1989, 45(1), 91–102.
Chapter 14 Synthesis of pharmacologically significant pentathiepins
463
[52] Belot, V, Farran, D, Jean, M, Albalat, M, Vanthuyne, N, Roussel, C. Steric scale of common substituents from rotational barriers of N-(o-Substituted aryl)thiazoline-2-thione Atropisomers J Org Chem 2017, 82(19), 10188–10200. [53] Chenard, BL, Dixon, DA, Harlow, RL, Roe, DC, Fukunaga, T. Synthesis, structures, and conformation dynamics of pyrazolotetrathiepins and related compounds studied by x-ray crystallography, dynamic NMR, and molecular orbital calculations J Org Chem 1987, 52(12), 2411–2420. [54] Ogawa, S, Wagatsuma, M, Sato, R. New sulfur-carbon displacement reaction and systematic desulfurization in multi-sulfur linkages of benzopentathiepin. Heterocycles 1997, 44, 187–196. [55] Sato, R, Onodera, A, Goto, T, Saito, M. Novel formations of unsymmetrical 1,2,5-Benzotrithiepins from Olefins and Benzopentathiepin in the presence of lewis acid. Benzopentathiepin as a Novel 1,5Dipole synthon Chem Lett 1989, 18(12), 2111–2114. [56] Konstantinova, LS, Amelichev, SA, Rakitin, OA. Synthesis of 1,2,5,6-tetrathiocines from fused 1,2,3,4,5pentathiepines Russ Chem Bull 2007, 56(8), 1540–1543. [57] Sato, R, Chino, K. Convenient synthesis of 1,2,4-benzotrithiins from benzopentathiepin with phosphorus ylide Tetrahedron Lett 1991, 32(44), 6345–6346. [58] Sato, R, Kanazawa, Y, Akutsu, Y, Saito, M. Chemistry on benzopentathiepin. Reactions of benzopentathiepin with active methylene compounds in the presence of base Heterocycles 1989, 29(11), 2097–2100. [59] Sato, R, Onodera, A, Goto, T, Saito, M. Chemistry on benzopentathiepin. reactios of benzopentathiepin with aromatic compounds in the presence of lewis acid Heterocycles 1988, 27(11), 2563. [60] Rueping, M, Nachtsheim, BJ. A review of new developments in the Friedel-Crafts alkylation – From green chemistry to asymmetric catalysis. Beilstein J Org Chem 2010, 6, 6. [61] Sato, R, Chino, K, Saito, M. Chemistry of benzopentathiepin. Formation of 1, 4-benzodithianes and 1, 4-benzodithiins by reaction with unsaturated compounds under basic conditions. Sulfur Lett 1990, 10, 233. [62] Mahendran, A, Ghogare, AA, Bittman, R, Arthur, G, Greer, A. Synthesis and antiproliferative properties of a new ceramide analog of varacin. Chem Phys Lipids 2016, 194, 165–170. [63] Zakharenko, A, Khomenko, T, Zhukova, S, Koval, O, Zakharova, O, Anarbaev, R, Lebedeva, N, Korchagina, D, Komarova, N, Vasiliev, V, Reynisson, J, Volcho, K, Salakhutdinov, N, Lavrik, O. Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety Bioorg Med Chem 2015, 23(9), 2044–2052. [64] Konstantinova, LS, Amelichev, SA, Rakitin, OA. 1,2,3,4,5-Pentathiepines and 1,2,3,4,5-pentathiepanes Russ Chem Rev 2007, 76(3), 195–211. [65] Rybalova, TV, Rogachev, AD, Khomenko, TM, Volcho, KP, Salakhutdinov, NF. Molecular and supramolecular structure of 8-(Trifluoromethyl)Benzo[f][1,2,3,4,5] Pentathiepin-6-Amine – A representative of condensed arene pentathiepines J Struct Chem 2018, 59(7), 1753–1758. [66] Konstantinova, LS, Rakitin, OA, Rees, CW, Souvorova, LI, Golovanov, DG, Lyssenko, KA. Unprecedented conversion of triethylamine and disulfur dichloride into a thienopentathiepin and a heptathiocane Org Lett 2003, 5(11), 1939–1942. [67] Ford, PW, Narbut, MR, Belli, J, Davidson, BS. Synthesis and structural properties of the benzopentathiepins varacin and isolissoclinotoxin A J Org Chem 1994, 59(20), 5955–5960. [68] Rybalova, TV, Rogachev, AD, Khomenko, TM, Volcho, KP, Salakhutdinov, NF. 8-(trifluoromethyl)1,2,3,4,5-benzopentathiepin-6-amine. Zh Strukt Khim (Russ) 2018, 59, 1811–1815. [69] Steudel, R. The chemistry of organic polysulfanes R-S(n)-R (n > 2) Chem Rev 2002, 102(11), 3905–3945. [70] Behnisch-Cornwell, S, Bandaru, SSM, Napierkowski, M, Wolff, L, Zubair, M, Urbainsky, C, Lillig, C, Schulzke, C, Bednarski, PJ. Pentathiepins: A Novel Class of Glutathione Peroxidase 1 Inhibitors that Induce Oxidative Stress, Loss of Mitochondrial Membrane Potential and Apoptosis in Human Cancer Cells ChemMedChem 2020, 15(16), 1515–1528.
464
[71]
[72] [73]
[74] [75] [76]
[77]
[78] [79]
[80] [81]
[82] [83] [84]
[85]
[86]
[87]
Lukas M. Jacobsen et al.
Wolff, L, Bandaru, SSM, Eger, E, Lam, HN, Napierkowski, M, Baecker, D, Schulzke, C, Bednarski, PJ. Comprehensive evaluation of biological effects of pentathiepins on various human cancer cell lines and insights into their mode of action. Int J Mol Sci 2021, 22, 14. Tokitoh, N, Ishizuka, H, Yabe, A, Ando, W. Competitive photochemical decarcogenation of 1,2,5thiadiselenole Tetrahedron Lett 1989, 30(22), 2955–2958. Litaudon, M, Trigalo, F, Martin, M-T, Frappier, F, Guyot, M. Lissoclinotoxins: Antibiotic polysulfur derivatives from the tunicate Lissoclinum perforatum. Revised structure of lissoclinotoxin A Tetrahedron 1994, 50(18), 5323–5334. Hendrickson, JB, Pitzer, KS. Transition state in the inversion of cyclohexane Nature 1966, 212(5063), 749–749. Brzostowska, EM, Greer, A. Polysulfane antitumor agents from o-benzyne. An Odd−Even alternation found in the stability of products o-C6H4Sx (x = 1−8) J Org Chem 2004, 69(16), 5483–5485. Greer, A. On the origin of cytotoxicity of the natural product varacin. A novel example of a pentathiepin reaction that provides evidence for a triatomic sulfur intermediate J Am Chem Soc 2001, 123(42), 10379–10386. Frisch, MJ, Gwt, HB, Schlegel, PM, Gill, W, Johnson, BG, Robb, MA, Cheeseman, JR, Keith, TA, Petersson, GA, Montgomery, JA, Raghavachari, J,K, Al-Laham, MA, Zakrzewski, VG, Ortiz, JV, Foresman, JB, Cioslowski, J, Stefanov, BB, Nanayakkara, A, Challacombe, M, Peng, CY, Ayala, PY, Chen, W, Wong, MW, Andres, JL, Replogle, ES, Gomperts, R, Martin, RL, Fox, DJ, Binkley, JS, Defrees, DJ, Baker, J, Stewart, JP, Head-Gordon, M, Gonzalez, C, Pople, JA. Gaussian 94 Gaussian, Inc. Pittsburgh, PA, 1995. Brzostowska, EM, Greer, A. The role of amine in the mechanism of pentathiepin (Polysulfur) antitumor agents J Am Chem Soc 2002, 125(2), 396–404. Brzostowska, EM, Paulynice, M, Bentley, R, Greer, A. Planar chirality due to a polysulfur ring in natural pentathiepin cytotoxins. Implications of planar chirality for enantiospecific biosynthesis and toxicity Chem Res Toxicol 2007, 20(7), 1046–1052. Guyot, M. Bioactive metabolites from marine invertebrates Pure Appl Chem 1994, 66(10–11), 2223–2226. Asquith, CRM, Machado, ACS, De Miranda, LHM, Konstantinova, LS, Almeida-Paes, R, Rakitin, OA, Pereira, SA. Synthesis and identification of pentathiepin-based inhibitors of sporothrix brasiliensis. Antibiotics-Basel 2019, 8(4). Chatterji, T, Gates, KS. DNA cleavage by 7-methylbenzopentathiepin: A simple analog of the antitumor antibiotic varacin Bioorg Med Chem Lett 1998, 8(5), 535–538. Lee, AH, Chan, AS, Li, T. Acid-accelerated DNA-cleaving activities of antitumor antibiotic varacin. Chem Commun 2002, 18, 2112–2113. Xu, J, Chatterjee, M, Baguley, TD, Brouillette, J, Kurup, P, Ghosh, D, Kanyo, J, Zhang, Y, Seyb, K, Ononenyi, C, Foscue, E, Anderson, GM, Gresack, J, Cuny, GD, Glicksman, MA, Greengard, P, Lam, TT, Tautz, L, Nairn, AC, Ellman, JA, Lombroso, PJ. Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of alzheimer’s disease PLoS Biol 2014, 12(8), e1001923. Sinyakova, NA, Kulikova, EA, Englevskii, NA, Kulikov, AV. Effects of Fluoxetine and Potential Antidepressant 8-Trifluoromethyl 1,2,3,4,5-Benzopentathiepin-6-Amine Hydrochloride (TC-2153) on Behavior of Danio rerio Fish in the Novel Tank Test and Brain Content of Biogenic Amines and Their Metabolites Bull Exp Biol Med 2018, 164(5), 620–623. Mahendran, A, Vuong, A, Aebisher, D, Gong, Y, Bittman, R, Arthur, G, Kawamura, A, Greer, A. Synthesis, characterization, mechanism of decomposition, and antiproliferative activity of a class of PEGylated benzopolysulfanes structurally similar to the natural product varacin J Org Chem 2010, 75(16), 5549–5557. Asquith, CRM, Laitinen, T, Konstantinova, LS, Tizzard, G, Poso, A, Rakitin, OA, Hofmann-Lehmann, R, Hilton, ST. Investigation of the Pentathiepin Functionality as an Inhibitor of Feline
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Immunodeficiency Virus (FIV) via a Potential Zinc Ejection Mechanism, as a Model for HIV Infection ChemMedChem 2019, 14(4), 454–461. [88] Nakata, Y, Ishikawa, K Vulcanization accelerators based on reaction products of norbornene or its derivatives and sulfur for diene rubbers. DE10114025, 2001. [89] Tsutsumi, H, Higashiyama, H, Onimura, K, Oishi, T. Preparation of poly(N-methylpyrrole) modified with pentathiepin rings and its application to positive active material for lithium secondary J Power Sources 2005, 146(1–2), 345–348. [90] Arora, H, Sahoo, PR, Kumar, A, Kumar, R, Kumar, S. The direct synthesis of a substituted naphthopentathiepin for selective Co2+ ion recognition in aqueous solution J Incl Phenom Macrocycl Chem 2019, 95(1), 135–145.
György Keglevich✶
Chapter 15 Developments in the synthesis of ring phosphine oxides 15.1 Introduction Organophosphorus chemistry is a special part within organic chemistry [1, 2]. PHeterocyclic chemistry is a subdiscipline both within the organophosphorus and the heterocyclic pool [3, 4]. The author of this chapter has had significant results in the field of five-membered P-heterocycles (phosphole derivatives) [5, 6], six-ring products (phosphinine derivatives) [7–10]. Microwave (MW) assistance is a robust tool also in organophosphorus chemistry and in the field of P-heterocycles [11–14]. Another green chemical device is the application of ionic liquids as solvents or as additives/catalysts [15, 16]. In this chapter, the focus is on the synthesis of ring phosphine oxides. The relevant results published in the last 5 years have been collected and are presented.
15.2 Synthesis of five-membered P-heterocycles Let us first survey the preparation of five-membered P-heterocycles by different cyclizations. A difuran bridged by a PhP(O) unit (3) was prepared by the bismetallation of a suitable bis(bromofuran) (1) followed by cyclization with phenylphosphonous dichloride, and then by oxidation. The phosphole obtained after deoxygenation of the intermediate phosphine oxide (2) was quaternized (Figure 15.1) [17]. A Pd-catalyzed dehydrobrominative synthesis was developed to prepare the corresponding dibenzophosphole oxide derivative (5) by the intramolecular cyclization of bis (2-methylphenyl-)(2-bromophenyl)phosphine oxide (4). Moreover, in the presence of an optically active P-ligand, the reaction was enantioselective (Figure 15.2) [18].
Acknowledgment: This project was supported by the National Research, Development and Innovation Office (K134318). ✶ Corresponding author: György Keglevich, Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, 1521 Budapest, Hungary, e-mail: [email protected]
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Figure 15.1: Synthesis of a bis-furane-fused phosphole oxide (2).
Figure 15.2: A dibenzooxaphosphole (5) by dehydrobrominative intramolecular cyclization.
An efficient method was elaborated for the synthesis of dibenzophospholes (7) by the Tf2O-mediated intramolecular phospha-Friedel–Crafts-type reaction of biaryl-phenylphosphine oxides (6) (Figure 15.3) [19]. No mechanistic details were provided.
Figure 15.3: A ring closing approach to dibenzooxaphosphole oxides (7).
A similar reaction was achieved electrochemically to prepare dibenzo-P-cycles. The formation of a variety of dibenzophosphole oxides (7) from biaryl-phenylphosphine oxides (6) took place via intramolecular dehydrogenerative phosphinoylation (Figure 15.4) [20].
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Figure 15.4: A dehydrogenative intramolecular cyclization providing dibenzooxaphosphole derivatives (7).
Benzophosphole oxide derivatives (8) were prepared by the MW-assisted addition of secondary phosphine oxides to acetylenes followed by oxidative cyclization. A representative example is demonstrated in Figure 15.5 [21].
Figure 15.5: A simple access to benzophosphole oxides (8).
A cyclization cascade starting with diarylphosphine oxides (9) and diphenylacetylene furnished benzophospholes. Depending on the substitution pattern, a single isomer (10) or two isomers (11-1 and 11-2) were formed (Figure 15.6) [22]. The substantiated intermediate is a phosphirenium cation that is transformed into a vinylphosphenium species, which then undergoes a phospha-Friedel–Crafts reaction with the aromatic ring. Budnikova surveyed the possible ways for the synthesis of 1-benzophosphole oxides from diarylphosphine oxides and disubstituted acetylenes (Figure 15.7). The oxidative or dehydrogenative ring closure following the primary addition was performed using Mn(OAc)3, Ag2O, AgOAc or K2S2O8, or even on green LED light. Their own electrosynthetic method was also presented [23, 24]. The addition of secondary phosphine oxides to acetylenic derivatives was investigated in detail. Arylvinylphosphine oxides (14) were obtained by the cobaloximecatalyzed addition of diarylphosphine oxides to the triple bond of diarylacetylenes. In case of suitable model compounds, the addition step was followed by a dehydrogenative cyclization to afford the corresponding benzophosphole oxides (10) (Figure 15.8) [25].
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Figure 15.6: The synthesis of benzophosphole oxides (10 and 11) involving a phospha-Friedel–Crafts cyclization.
Figure 15.7: Different accomplishments for the synthesis of benzophosphole oxides (12 and 13) from diarylphosphine oxides and acetylenes.
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Figure 15.8: A two-step procedure to benzophosphole oxides (10).
Starting from ortho-arylalkynylanilines and diarylphosphine oxides, a series of cascade reactions formed tribenzo[b,e,g]phosphindole oxides (15) as valuable products. The synthesis is exemplified starting from ortho-phenylalkynylaniline (Figure 15.9) [26].
Figure 15.9: Synthesis of pentacyclic phosphole derivatives 15.
Zhao et al. [27] described the Cu-catalyzed radical addition/cyclization of cycloalkanes with diaryl(arylethynyl)phosphine oxides to afford benzo[b]phosphole oxides (e.g., 16). The new protocol is exemplified by a selected example (Figure 15.10). Mainly Z-alkenylphosphine oxides (18) and benzophospholene oxides (19-1 and 19-2) were obtained by the intramolecular transformation of diphenylphosphinoarylacetylenes (17) (Figure 15.11) [28]. In certain cases, E-phosphinoylarylalkenes (20) were the by-products.
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Figure 15.10: Another variation for the preparation of a benzophosphole oxide (16).
Figure 15.11: Substituent–dependent reaction of (diphenylphosphinoyl)arylacetylenes.
An elegant method was elaborated for the synthesis of an optically active benzodihydrooxaphosphole oxide (23✶). Methylphosphonous dichloride was disubstituted, and the phosphine so obtained oxidized. Then, the P–Me group was converted to a P–CH2–I function, and an intramolecular ring closure afforded the dihydrobenzoxaphosphole oxide (23) in a racemic form. After reaction with (+)-menthyl chloroformate, one of the diastereomers crystallized out, and was hydrolyzed to furnish the target molecule in an optically active form (23✶) (Figure 15.12) [29]. A tandem reaction of an N-nitroso-α-aminophosphine oxide (25), initiated by the generation of a diazonium cation (26), and followed by a cycloetherification ended up with a benzo-dihydrooxaphosphole oxide (27) (Figure 15.13) [30]. Allenephosphonic dichlorides (28) were converted to the corresponding dimethylphosphine oxides (29) that were cyclized to oxaphospholene derivatives (30) in reaction with a few electrophilic reagents (Figure 15.14) [31].
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Figure 15.12: Synthesis of an optically active benzo-dihydrooxaphosphole oxide (23✶).
Figure 15.13: An alternative possibility for the preparation of benzo-dihydrooxaphosphole oxides (27).
Figure 15.14: The synthesis of oxaphospholene derivatives (30).
The reaction of allenylphosphine oxides (31) with PhSeCl or SO2Cl2 led to a mixture of 1,2-oxaphospholium salts (32) and phosphinoyl-dihydrofuranones (33) (Figure 15.15) [32]. Starting from phosphinoylallenes (34), a Chinese group elaborated an approach to 3-alkenyl-benzo[b]dihydrophosphole oxides (35) that took place via an intramolecular cyclization involving an unexpected C–O cleavage followed by a direct C–H alkenylation (Figure 15.16) [33].
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Figure 15.15: Allenephosphine oxide (31) → oxaphospholene (32/33) conversions.
Figure 15.16: The conversion of phosphinoy allenes (34) to benzo-dihydrophosphole oxides (35).
Phosphonium salts with bicyclic structures (36) were obtained as intermediates by the photocatalytic cycloaddition of triarylphosphines and alkynes, and were utilized in a Wittig olefination providing triarylphosphine oxides with an ortho-unsaturated chain (37). Representative examples are shown in Figure 15.17 [34].
Figure 15.17: Wittig reaction with a cyclic phosphonium salt (36).
The next example shows a possible modification of five-ring P-cycles. The rhodiumcatalyzed asymmetric arylation of 2,5-dihydro-1H-phosphole oxides (38) afforded the corresponding aryl-2,3,4,5-tetrahydrophosphole oxides (39) in ee values of up to 99% (Figure 15.18) [35]. Finally, a ring-opening and an optical resolution, this latter elaborated by Pietrusiewicz, are discussed. Surprisingly, the interaction of benzophosphol-3-yl triflates
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Figure 15.18: Asymmetric arylation of 3-phospholene oxides (38).
(40) with Grignard reagents afforded 2-ethynylphenyl-diarylphosphine oxides (41). The unusual ring opening was brought about by the nucleophilic attack of the ArMgBr reagent on the P-atom of the heterocycle. A few representative examples are shown in Figure 15.19 [36].
Figure 15.19: Surprising ring opening of benzophosphole oxides (40).
1-Phenyl-2-phospholene (43) obtained from the corresponding P-oxide (42) by deoxygenation was efficiently resolved via quaternization with L-menthyl bromoacetate after crystallizations and acidic hydrolysis (Figure 15.20) [37].
15.3 Synthesis of six-membered P-heterocycles Valuable biphenyl-phenyl-alkynylphosphine oxides (47) were prepared from phenylphosphonous dichloride in three steps that were converted by the use of ICl to provide a mixture of six- and seven-membered phosphacycles (48 and 49, respectively) (Figure 15.21) [38]. PhPCl2 was transformed to a useful diaryl-phenylphosphine oxide intermediate (51) by consecutive arylations with zinc, lithium organic and Grignard reagents. Benefiting from the 2-dithiolanyl moiety, the phosphine oxide (51) could be converted to the corre-
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Figure 15.20: Optical resolution of 1-phenyl-2-phospholene oxide (42).
Figure 15.21: Cyclization of (biphenyl-phenylphosphinoyl)acetylenes (47) to P-heterocycles (48 and 49).
sponding phosphaxanthene isomers (54–1 and 54–2) in three steps. The key intermediate was an ortho-phosphinoylbenzaldehyde derivative (52). (Figure 15.22) [39].
Chapter 15 Developments in the synthesis of ring phosphine oxides
Figure 15.22: Multistep synthesis of phosphaxanthenes (54).
Figure 15.23: (Benzyl-phenylphosphinoyl)acetylenes (55) as intermediates for isophosphinoline oxides (56).
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Phenyl-H-phosphinic acid was converted to (benzyl-phenylphosphinoyl)acetylenes (55) in three steps (Figure 15.23/(1)). These electron-poor alkynes were suitable starting materials for isophosphinoline 2-oxides (56) via an intramolecular cyclization using a PPh3AuCl precatalyst in combination with triflic acid under MW irradiation (Figure 15.23/(2)) [40]. The Trofimov group developed a P-halide-free synthesis of 1,2,3,4-tetrahydroisophosphinoline 2-oxides (59). The key step is a Pudovik reaction followed by intramolecular Friedel–Crafts alkylation, that is, a cyclization (Figure 15.24) [41].
Figure 15.24: P-Chloride-free preparation of tetrahydroisophosphinoline oxides (59).
Enantioselective intramolecular hydroetherification of alkynes with a P-stereogenic center (60) containing two prochiral phenolic units in the presence of an optically active gold catalyst afforded benzo-1,4-dihydrooxaphosphinine oxides (61), as shown by a representative example (Figure 15.25) [42]. Dibenzo-fused dihydro-4,1-azaphosphinine oxide derivatives (63) were synthesized by the dehydrogenative cyclization of suitable diarylaminophenyl-phenylphosphine oxides (62) (Figure 15.26) [43]. The MW-assisted annulation of dibenzooxazepines (65) as cyclic imines with (diazoarylmethyl)-diarylphosphine oxides (64) furnished pentacyclic benzo-δ-phospholactams (66). A typical example is shown in Figure 15.27 [44].
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Figure 15.25: Intramolecular cyclization of a diaryl-alkynylphosphine oxide (60) to a 1,4dihydrooxaphosphinine oxide (61).
were
Figure 15.26: Dehydrogenative cyclization to dihydro-azaphosphinine oxides (63).
Figure 15.27: Synthesis of a 5-ring dihydro-azaphosphinine oxide (66).
Finally, let us see interesting modifications and reactions of P-heterocycles. Arylvinylphosphine oxides (69) were made available by the four-step reaction of a phosphacoumarin (67) with Grignard reagents (Figure 15.28) [45].
Figure 15.28: Ring-opening reaction of a phosphacoumarin (67).
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A dibenzooxaphosphorine oxide (71) obtained by hydrolysis of the corresponding P-chloro compound (70) was converted to biphenyl-derived secondary phosphine oxides (72) with a 2ʹ-hydroxy group that may be valuable intermediates (Figure 15.29) [46].
Figure 15.29: Ring opening of a dibenzooxaphosphole oxide (71).
Within the chemistry of fluorophores, P=O-bridged rhodamines (73) were converted selectively to rhodols (74-1) and fluoresceins (74-2) (Figure 15.30) [47].
Figure 15.30: Modification of fluorophores.
Depending on the substitution pattern and conditions, the intramolecular cyclization of β-hydroxyalkylphosphine oxides (75) resulted in the formation of a benzodihydrophosphole oxide (77) or benzotetrahydrophosphinine oxides (76, 78, 79). The formation of the six-ring products is not trivial (Figure 15.31) [48]. Hydrofluorination of unsaturated (allyl- or propargyl)phosphine oxides (80, 82, 85) led to adducts (81 or 83) and/or P-ring (84 or 86) products. The latter species were formed by cyclization (Figure 15.32). The HF/SbF5 superacid reactions may have involved phosphonium-carbenium intermediates [49].
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Figure 15.31: β-Hydroxyphosphine oxides (75A and 75B), as starting materials for P-heterocycles (76–79).
Figure 15.32: Diverse hydrofluorination reactions leading to different products (81, 83, 84 and 86).
15.4 Special cases: large P-heterocycles and bridged derivatives Cyclic phosphonium anhydrides (88) were obtained from bis(phosphine oxides) (87), as shown in Figure 15.33, that could be utilized in dehydrative glycosylations [50].
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Figure 15.33: The preparation of cyclic phosphonium anhydrides (88).
Figure 15.34: Cyclic phosphine oxides (91 and 93) with disiloxane moieties.
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Cyclic phosphine oxides (91 and 93) incorporating a disiloxane moiety were synthesized by the reaction of bromonaphthyl-diphenylphosphine oxides (89) and dimethyl-chlorosilane or diphenyl-chlorosilane via bislithiation (Figure 15.34) [51]. New chiral crown ethers (96) comprising a phosphine oxide moiety were synthesized by the ring closure method shown in Figure 15.35 [52].
Figure 15.35: Preparation of P-containing crown ethers (96).
An interesting intramolecular hydroarylation cascade catalyzed by a phosphine-gold complex afforded bridgehead methanophosphocines (98). The novel transformation is illustrated on the unsubstituted case (Figure 15.36) [53].
Figure 15.36: Example for the synthesis of a methanophosphocine (98).
Interesting dibenzobarrelene derivatives (99) incorporating a 1-phosphinoxido- or 1thiophosphino-1,3-butadiene unit were described, and their photophysical properties studied (Figure 15.37) [54].
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Figure 15.37: Examples for exotic dibenzobarrelene derivatives (99).
15.5 Conclusions This survey presented the results on cyclic phosphine oxides, such as five- and sixring P-heterocycles, as well as large P-ring compounds and bridged derivatives. Among others, the new developments of phosphole oxides, phospholene oxides, oxaphospholenes, dihydrophosphinine oxides, tetrahydrophosphinine oxides, hexahydrophosphinine oxides, along with oxaphosphinine and azaphosphinine derivatives were discussed. Mostly, new synthetic methods were introduced.
References [1] [2] [3] [4]
Quin, LD. A guide to organophosphorus chemistry. New York: Wiley & Sons, 2000. Keglevich, G, editor. Organophosphorus chemistry – novel developments. Berlin: De Gruyter, 2018. Quin, LD. The heterocyclic chemistry of phosphorus. Wiley, 1981. Mathey, F, editor. Phosphorus-carbon heterocyclic chemistry: The rise of a new domain. Pergamon, Amsterdam, 2001. [5] Keglevich, G. 1-(2,4,6-Trialkylphenyl)-1H-phospholes with a flattened P-pyramid: Synthesis and reactivity. In: Gupta, RR, editor. Topics in heterocyclic chemistry. Heidelberg: Bansal RK, Springer, 2010, Vol. 21, 149–173. [6] Keglevich, G. Synthesis and reactivity of 1-(2,4,6-trialkylphenyl)phospholes having a flattened Ppyramid. In: Attanasi, OA, Spinelli, D, editors. Targets in heterocyclic systems. Rome: Italian Society of Chemistry, 2002, Vol. 6, 245–269. [7] Keglevich, G. Phosphinine derivatives and their use as versatile intermediates in P-heterocyclic chemistry. In: Gupta, RR, editor. Topics in heterocyclic chemistry. Vol Ed Dordrecht: Bansal RK, Springer, 2009, Vol. 20, 65–98. [8] Keglevich, G. 6-Membered P-heterocycles: 1,2-Dihydro-, 1,2,3,6-tetrahydro- and 1,2,3,4,5,6hexahydrophosphinine 1-oxides. Curr Org Chem 2006, 10, 93–111. [9] Keglevich, G. Synthesis of 6- and 7-membered P-heterocycles by ring enlargement. Synthesis 1993, 931–942. [10] Ábrányi-Balogh, P, Keglevich, G. A theoretical study on the conformation of 5- and 6-membered Pheterocycles: 1-substituted 2,3,4,5-tetrahydro-1H-phosphole 1-oxides and 1,2,3,4,5,6hexahydrophosphinine 1-oxides. Curr Org Chem 2017, 21, 2216–2228.
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[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
[22] [23]
[24]
[25]
[26] [27]
[28] [29]
[30]
[31]
485
Guénin, E, Meziane, D. Microwave assisted phosphorus organic chemistry: A review. Curr Org Chem 2011, 15, 3465–3485. Keglevich, G, Grün, A, Bálint, E, Kiss, NZ, Jablonkai, E. Microwave-assisted organophosphorus synthesis. Curr Org Chem 2013, 17, 545–554. Keglevich, G, Kiss, NZ, Mucsi, Z, Körtvélyesi, T. Insights into a surprising reaction: The microwaveassisted direct esterification of phosphinic acids. Org Biomol Chem 2012, 10, 2011–2018. Kiss, NZ, Böttger, É, Drahos, L, Keglevich, G. Microwave-assisted direct esterification of cyclic phosphinic acids. Heteroatom Chem 2013, 24, 283–288. Rádai, Z, Kiss, NZ, Keglevich, G. An overview of the applications of ionic liquids as catalysts and additives in organic chemical reactions. Curr Org Chem 2018, 22, 533–556. Kiss, NZ, Keglevich, G. Microwave-assisted direct esterification of cyclic phosphinic acids in the presence of ionic liquids. Tetrahedron Lett 2016, 57, 971–974. Cao, H, Brettell-Adams, IA, Qu, F, Rupar, PA. Bridged difurans: Stabilizing furan with p-block elements. Organometallics 2017, 36, 2565–2572. Lin, Y, Ma, WY, Sun, QY, Cui, YM, Xu, LW. Catalytic synthesis of chiral phosphole oxides via desymmetric C-H arylation of o-bromoaryl phosphine oxides. Synlett 2017, 28, 1432–1436. Nishimura, K, Hirano, K, Miura, M. Synthesis of dibenzophospholes by Tf2O-mediated intramolecular phospha-Friedel-Crafts-type reaction. Org Lett 2019, 21, 1467–1470. Kurimoto, Y, Yamashita, J, Mitsudo, K, Sato, E, Suga, S. Electrosynthesis of phosphacycles via dehydrogenative C-P bond formation using DABCO as a mediator. Org Lett 2021, 23, 3120–3124. Tajti, Á, Kovács, BD, Popovics-Tóth, N, Perdih, F, Bálint, E. Microwave-assisted synthesis of benzo[b] phosphole oxide derivatives by oxidative addition of acetylenes and secondary phosphine oxides or alkyl phenyl-H-phosphinates. Tetrahedron 2021, 102, 132527. Nishimura, K, Unoh, Y, Hirano, K, Miura, M. Phosphenium-cation-mediated formal cycloaddition approach to benzophospholes. Chem Eur J 2018, 24, 13089–13092. Budnikova, YH. Transition metal-promoted reactions of diarylphosphine oxides as a synthetic method for organophosphorus heterocyclic compounds. Chem Heterocycl Compd 2018, 54, 269–279. Khrizanforova, VV, Kholin, KV, Khrizanforov, MN, Kadirov, MK, Budnikova, YH. Electrooxidative CH/ PH functionalization as a novel way to synthesize benzo[b]phosphole oxides mediated by catalytic amounts of silver acetate. New J Chem 2018, 42, 930–935. Liu, W-Q, Lei, T, Zhou, S, Yang, X-L, Li, J, Chen, B, Sivaguru, J, Tung, C-H, Wu, L-Z. Cobaloxime catalysis: Selective synthesis of alkenylphosphine oxides under visible light. J Am Chem Soc 2019, 141, 13941–13947. Li, J, Zhang, -W-W, Wei, X-J, Hao, W-J, Li, G, Tu, S-J, Jiang, B. Synthesis of tribenzo[b,e,g]phosphindole oxides via radical bicyclization cascades of o-arylalkynylanilines. Org Lett 2017, 19, 4512–4515. Ma, D, Pan, J, Yin, L, Xu, P, Gao, Y, Yin, Y, Zhao, Y. Copper-catalyzed direct oxidative C–H functionalization of unactivated cycloalkanes into cycloalkyl benzo[b]phosphole oxides. Org Lett 2018, 20, 3455–3459. Song, Y, Wang, L, Duan, Z, Mathey, F. Divergent intramolecular reactions between phosphines and alkynes. Chinese Chem Lett 2020, 31, 329–332. Li, G, Wang, X-J, Zhang, Y, Tan, Z, DeCroos, P, Lorenz, JC, Wei, X, Grinberg, N, Yee, NK, Senanayake, CH. Synthesis of P-chiral dihydrobenzooxaphosphole core for BI ligands in asymmetric transformations. J Org Chem 2017, 82, 5456–5460. Li, S-G, Han, ZS, Viereck, P, Lee, H, Kurouski, D, Senanayake, CH, Tsantrizos, YS. Metal-free cycloetherification by in situ generated P-stereogenic α-diazanium intermediates: A convergent synthesis of enantiomerically pure dihydrobenzooxaphospholes. Org Lett 2017, 19, 894–897. Enchev, DD. Allenephosphonic phosphine oxides in reactions with electrophilic reagents. Acta Sci Nat 2018, 5, 17–23.
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[32] Ismailov, IE, Ivanov, IK, Christov, V. Trifunctionalized allenes. Part III. Electrophilic cyclization and cycloisomerization of 4-phosphorylated 5- hydroxypenta-2,3-dienoates: An expedient synthetic method to construct 2,5-dihydro-1,2-oxaphospholes, furan- 2(5H)-ones and 2,5-dihydrofurans. Phosphorus Sulfur Silicon 2020, 195, 314–323. [33] Liu, T, Sun, X, Wu, L. Palladium-catalyzed cascade C-O cleavage and C-H alkenylation of phosphinyl allenes: An expeditious approach to 3-alkenyl benzo[b]phosphole oxides. Adv Synth Catal 2018, 360, 2005. [34] Yusuke, M, Daichi, I, Masahiro, M. Photocatalytic cycloaddition reaction of triarylphosphines with alkynes forming cyclic phosphonium salts. Chem Lett 2021, 50, 1691–1694. [35] Lim, KM-H, Hayashi, T. Dynamic kinetic resolution in rhodium-catalyzed asymmetric arylation of phospholene oxides. J Am Chem Soc 2017, 139, 8122–8125. [36] Ponikiewski, L, Sowa, S. Ring opening of triflates derived from benzophospholan-3-one oxides by aryl Grignard reagents as a route to 2-ethynylphenyl(diaryl)phosphine oxides. J Org Chem 2021, 86, 14928–14941. [37] Pietrusiewicz, KM, Koprowski, M, Drzazga, Z, Parcheta, R, Łastawiecka, E, Demchuk, OM, Justyniak, I. Efficient oxidative resolution of 1-phenylphosphol-2-ene and Diels-Alder synthesis of enantiopure bicyclic and tricyclic P-stereogenic C-P heterocycles. Symmetry 2020, 12, 346. [38] Wu, D, Hu, C, Qiu, L, Duan, Z, Mathey, F. Iodocarbocyclization to access six- and seven-membered phosphacycles from phosphoryl-linked alkynes. Eur J Org Chem 2019, 6369–6376. [39] Fukazawa, A, Usuba, J, Adler, RA, Yamaguchi, S. Synthesis of seminaphtho-phospha-fluorescein dyes based on the consecutive arylation of aryldichlorophosphines. Chem Commun 2017, 53, 8565–8568. [40] Hariri, M, Darvish, F, Mengue Me Ndong, K-P, Sechet, N, Chacktas, G, Boosaliki, H, Tran Do, ML, Mwande-Maguene, G, Lebibi, J, Burilov, AR, Ayad, T, Virieux, D, Pirat, J-L. Gold-catalyzed access to isophosphinoline 2-oxides. J Org Chem 2021, 86, 7813–7824. [41] Malysheva, SF, Gusarova, NK, Belogorlova, NA, Sutyrina, AO, Albanov, AI, Sukhov, BG, Kuimov, VA, Litvintsev, YI, Trofimov, BA. Phosphorus halide free synthesis of 1,2,3,4-tetrahydroisophosphinoline 2-oxides. Mendeleev Commun 2018, 28, 29–30. [42] Zheng, Y, Guo, L, Zi, W. Enantioselective and regioselective hydroetherification of alkynes by goldcatalyzed desymmetrization of prochiral phenols with P-stereogenic centers. Org Lett 2018, 20, 7039–7043. [43] Ye, W, Li, X, Ding, B, Wang, C, Shrestha, M, Ma, X, Chen, Y, Tian, H. Facile synthesis of nitrogencontaining six-membered benzofuzed phenophosphazinine oxides and studies of the photophysical properties. J Org Chem 2020, 85, 3879–3886. [44] Luo, Y, Xu, J. Annulation of diaryl(aryl)phosphenes and cyclic imines to access benzo-δphospholactams. Org Lett 2020, 22, 7780–7785. [45] Tatarinov, DA, Kuznetsov, DM, Fayzullin, RR, Mironov, VF. Synthesis of racemic P-chiral phosphine oxides and phosphonium salts by stepwise reaction of phosphacoumarins with organomagnesium compounds. J Organomet Chem 2020, 918, 121313. [46] Li, Z-C, Zhang, Y, Yan, B-X, Wang, X-N, Zhai, D-H, Li, Q, Zheng, H-X, Zhao, C-Q. The conversion of ether bonds to hydroxyl via a base-promoted rearrangement of cyclic phosphine oxides. Org Chem Front 2021, 8, 5693–5698. [47] Grzybowski, M, Taki, M, Yamaguchi, S. Selective conversion of P=O-bridged rhodamines into P=Orhodols: Solvatochromic near-infrared fluorophores. Chem Eur J 2017, 23, 13028–13032. [48] Włodarczyk, K, Borowski, P, Drach, M, Stankevič, M. Cyclization of β-hydroxyalkylphosphine oxides – Mechanism elucidation using experimental and DFT methods. Tetrahedron 2017, 73, 239–251. [49] Castelli, U, Lohier, J-F, Drukenmüller, I, Mingot, A, Bachman, C, Alayrac, C, Marrot, J, Stierstorfer, K, Kornath, A, Gaumont, A-C, Thibaudeau, S. Evidence of phosphonium-carbenium dication formation in a superacid: Precursor to fluorinated phosphine oxides. Angew Chem Int Ed 2019, 58, 1355–1360.
Chapter 15 Developments in the synthesis of ring phosphine oxides
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[50] Dyapa, R, Dockery, LT, Walczak, MA. Dehydrative glycosylation with cyclic phosphonium anhydrides. Org Biomol Chem 2017, 15, 51–55. [51] Delouche, T, Caytan, E, Quinton, C, Roisnel, T, Cordier, M, Dorcet, V, Hissler, M, Bouit, P-A. Taking advantage of ortho- and peri-substitution to design nine-membered P,O,Si-heterocycles. Chem Eur J 2021, 27, 11391–11397. [52] Szabó-Szentjóbi, H, Majoros, I, Márton, A, Leveles, I, Vértessy, BG, Dékány, M, Tóth, T, Huszthy, P. Synthesis of new chiral crown ethers containing phosphine or secondary phosphine oxide units. Synthesis 2020, 52, 2870–2882. [53] Babouri, R, Traore, L, Bekro, Y-A, Matveeva, VI, Sadykova, YM, Voronina, JK, Burilov, AR, Ayad, T, Volle, J-N, Virieux, D, Pirat, J-L. Golden face of phosphine: Cascade reaction to bridgehead methanophosphocines by intramolecular double hydroarylation. Org Lett 2019, 21, 45–49. [54] Ishii, A, Kikushima, C, Hayashi, Y, Ohtsuka, N, Nakata, N, Muranaka, A, Tanaka, Y, Uchiyama, M. 1-Phosphino-1,3-butadiene derivatives incorporated with dibenzobarrelene skeleton: Synthesis and photophysical properties. Bull Chem Soc Japan 2020, 93, 1430–1442.
Sabbasani Rajasekhara Reddy✶, Sathi Bhulakshmi, and Sanjivani Pal
Chapter 16 Total synthesis of bioactive heterocyclic scaffolds via Pauson Khand reaction 16.1 Introduction The field of synthetic organic chemistry is constantly working to find direct and efficient ways to construct intricate yet adaptable molecular frameworks [1]. In this context, the development of metal-mediated transformations has significantly broadened the range of molecular structures available for organic synthesis, frequently resulting in the simplification of synthetic pathways with greater heights of efficiency. A promising metal-mediated technique for producing molecular complexity in a single step is the Pauson Khand reaction (PKR; Figure 16.1).
Figure 16.1: One-step, three-component Pauson Khand reaction (PKR).
The first reports of this reaction appeared in the 1970s. At first, the reaction was carried out in extreme heat circumstances, which led to findings that were comparatively ineffective. Alkene, alkyne, and carbon monoxide are all included in the one-step, making it a three-component Pauson–Khand (PK) cycloaddition reaction that yields cyclopentanones. Schore et al. [2] described the first intramolecular PK cycloadditions in 1981. Synthesis of fused bicyclic systems was made possible by this process (Figure 16.2).
Acknowledgments: The authors would like to deeply express their gratefulness to everyone who supported them personally and professionally during the completion of the chapter. We would also like to express our gratitude to VIT, Vellore, Tamil Nadu, India, for granting the “VIT SEED GRANT-(RGEMS)SG20230119” and “SPARC GRANT 1905, GOVT, India” for providing the financial assistant which helped us accomplish this task. ✶
Corresponding author: Sabbasani Rajasekhara Reddy, School of Advanced Sciences, Department of Chemistry, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India, e-mails: [email protected]; [email protected] Sathi Bhulakshmi, Sanjivani Pal, School of Advanced Sciences, Department of Chemistry, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India https://doi.org/10.1515/9783110980189-016
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Figure 16.2: Intramolecular Pauson Khand reaction (IMPKR).
Dicobalt octacarbonyl was the only cluster utilized to mediate the reaction up to the mid-1990s. Transition metal complexes, such as titanium, zirconium, iron, molybdenum, tungsten, nickel, rhodium, ruthenium, and palladium complexes, have recently been used to mediate the PKR. Despite its adaptability and tolerance to a wide range of functional groups, the reaction faced a number of constraints due to inherent issues with reaction parameters. High (up to 120 °C) temperature, long reaction times (up to 4 days), and low yields were among them [3]. Because of its tremendous synthetic transformation ability, the requirement for extreme conditions was initially overlooked. Studies have shown that, in addition to the metal catalyst, adding promoters and additives can improve the reaction. Although, with the exception of propynoic acid derivatives, only strained olefins and alkynes efficiently reacted under the traditional experimental conditions, there was still a significant need for substrate scope expansion [4]. Concerning regioselectivity, the cyclopentenone product presents a larger alkyne substituent next to the carbonyl group. Regioisomeric mixtures were produced using asymmetric olefins, and studies found that the regioselectivity of alkynes could be predicted. This demonstrated a disadvantage of the intramolecular PKR (IMPKR), as well as the necessity for the asymmetric PKR. This issue, however, was not observed in the IMPKR. Fox et al. [5] extended the substrate scope to cyclopropanes in 2005, which aided in the design of all carbon quaternary frameworks with diastereoselective chiral centers. Under mild conditions, the cyclopropane ring was cleaved with high regioselectivity. This methodology was used in the synthesis of natural products, as it allows direct access to the formation of cyclopentenones by releasing cyclopropene ring strain. In order to maximize the utility of PKR, four areas needed to be explored [6]: 1) Increasing substrate scope 2) Finding efficient catalytic process 3) Developing asymmetric PKR 4) Application to natural products Bioactive natural compounds are those that are synthesized by plants, animals, or microbes and have potential biological applications, such as antiviral and antitumor. The majority of natural products have complex structures, making their synthesis difficult. Most natural products may be classified as alkaloids, terpenoids, and steroids, which have a wide range of applications. Most natural products contain a cyclopentane ring. Because of its simple approach as well as the ease of functionalization of adduct, the
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Figure 16.3: Representative instances of natural products synthesized using the Pauson Khand reaction (PKR).
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use of PKR is increasing in the synthesis of natural compounds. Herein, we represent some of the significant natural products synthesized using PKR (Figure 16.3).
16.2 Terpenes 16.2.1 Monoterpenoids 16.2.1.1 Synthesis of iridoids Iridoids are a class of monoterpenoids that offer a wide range of biological properties ranging from anti-inflammatory to antiviral and antitumor activities. Additionally, they were discovered to show defensive mechanisms against particular species and to have the ability to serve as sex pheromones. These well-known applications and distinctive cis-fused restricted bicyclic structure prompted the deployment of innovative synthetic techniques. The cyclopenta[c]pyran scaffold that makes up the iridoid framework can be constructed using IMPKR. The precursor for PKR was synthesized from accessible starting material solketal 1. Further, cobalt-catalyzed cyclization at −15 °C gave a 68% yield with cis:trans ratio of 9:1 (Figure 16.4).
Figure 16.4: PKR in the synthesis of iridoid framework.
Multiple iridoids with a similar structural makeup were produced from this cyclized product by diverse reactions (Figure 16.5). These include the synthesis of isoboonein 2, patriscabrol 3, boschnialactone 4, teucriumlactone 5, iridomyrmecin 6, scholarein A 7, and scabrol A 8 [7].
16.2.2 Sesquiterpenes 16.2.2.1 Synthesis of (2R)-hydroxynorneomajucin (2R)–Hydroxynorneomajucin biological potency in support with its highly oxidized structure has provoked the interest of synthetic chemists. The neurotrophic properties of these molecules play a significant role in treating neurogenetic diseases, like
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Figure 16.5: Synthesis of multiple iridoid class of compounds.
Alzheimer’s and Parkinson’s. The first ever attempt to synthesize this natural product was only done in 2016 by Gademann et al. [8]. The first asymmetric total synthesis of (2 R)-hydroxynorneomajucin is reported by Charles et al. [9]. Through retrosynthetic analysis, ketoester and isoprene monoxide were used as starting materials. The starting materials in subsequent reactions undergoing Tsuji−Trost allylic alkylation, Pummerer rearrangement, and Seyfarth-Gilbert homologation gave product 9 suitable to undergo PKR. Due to the failure of optimized conditions of PK with free diol, it was silylated by tert-buytldimethylsilyl trifluromethanesulfonate. Cobalt-catalyzed PKR of the silylated product gave 61% yield and 88% after de-
Figure 16.6: PKR in the synthesis of (2R)-hydroxynorneomajucin.
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silylation of PKR product. Further on, a total of 17 steps lead to the synthesis of (2R)hydroxynorneomajucin 10 with a final yield of 64% diastereoselectively (Figure 16.6).
16.2.2.2 Synthesis of 2-epi-a-cedren-3-one The most challenging task of synthesizing the target molecule was the tricyclic core system. PKR used to produce similar structures of α-, β-cedrene [10] and bicyclic core systems like spiro-oxindole scaffolds and astellatol. In this study, a similar approach was used to synthesize a target molecule in the presence of cobalt catalyst in substoichiometrically optimized amounts. Precursors 11 for PKR were synthesized from olefinated product in two steps. An astonishing 83% of yield was obtained when butyl methyl sulfide as promoter with stoichiometric quantity of cobalt catalyst was used (Figure 16.7). However, it took about 40 min for completion of the reaction. Use of tributylphosphine sulfide, TMTU (tetramethyl thiourea) and microwave-assisted technologies were chosen as three alternative methodologies. These procedures used sub stoichiometric quantities of cobalt catalyst. Hence, when these methods were employed, both the employment of TMTU and tributylphosphine sulfide showed disappointing results, while microwave assisting strategy gave about 69% yield. Beyond the less yield obtained using TMTU and tributylphosphine sulfide, these methods also demanded usage of gaseous carbon monoxide hence; microwave irradiation strategy was considered a better and safe option. This methodology gave a yield of 69% in just 10 min. Using BuSMe as an additive increased the yield to 85%. In this way, the total synthesis of 2-epi-a-cedren-3-one 12 was established in 17 steps with microwave irradiation involving 20 mol% cobalt catalyst as an important step [11].
Figure 16.7: PKR in synthesis of 2-epi-A-cedren-3-one.
16.2.2.3 Synthesis of sinodielide A The root of Sinodielsia yunnanensis contains sinodielide A (SA). It is a naturally occurring guaianolide. Traditional Chinese medicine employs this root, as an antipyretic, analgesic, and diaphoretic agent [12].
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Linalool served as the starting compound for Hu et al. [13] entire synthesis of sinodielide A (Figure 16.8). They believed that a PKR could quickly create the cyclopentane ring system, and that the nucleophilic terminal prenyl group could be used to establish a seven-membered ring. By deprotonating (–)-linalool and with further reactions, ester 13 was created from (–)-linalool. Dicobalt octacarbonyl was used to perform a smooth PKR on this substance, which produced strained bicyclic lactone 14 with overall yield of 65% with 5:2 dr. It then underwent reduction using DIBAL to produce triol 15. It was discovered that the main isomer produced by the PKR had unique cis-connection between the C1 proton and the C10 methyl group compared to most guaianolides.
Figure 16.8: The PKR in the synthesis of sinodielide A.
16.2.3 Diterpenoids 16.2.3.1 Synthesis of waihoensene Waihoensene is another intriguing instance comprising a cis-fused tetracyclic core that is densely crowded and with six contiguous stereogenic centers, with an overall yield of 3.8%. Qu et al. [14] demonstrated an asymmetric complete synthesis of (+)Waihoensene in 15 stages (Figure 16.9). They built the crucial intermediates in a highly diastereoselective way thanks to the realization of structural and stereochemical aspects among the reactants and their respective products. The total synthesis includes the following crucial steps: (1) an asymmetric conjugate addition with Cu catalyst; (2) a conia-ene-type reaction; (3) an intramolecular PKR; and (4) a Ni-catalyzed alkylation. The triquinane core highlighted with four quaternary stereogenic centers was also constructed enantioselectively.
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A combination of the conia-ene-type reaction of diyne 16 and the Co2(CO)8-mediated intramolecular PKR of enyne 17 was used to diastereoselectively synthesize two necessary quaternary stereogenic centers in 18. They discovered that when the reaction was performed in the presence of N-oxide (N2O) in dichloroethane (DCE) for 20 h at 80 °C, the PKR product could be obtained in 59% yield.
Figure 16.9: The PKR in the synthesis of waihoensene.
16.2.3.2 Synthesis of marrubin Marrubium family belongs to the class of labdane diterpene lactones that have high therapeutic potency. There has not been much research on their synthesis despite their potential biological activity due to the challenge of synthesis in a stereo-controlled manner. Nakamura et al. [15] resolved the problem with PKR as the key component to synthesize trans-decalin trans-moiety. However, this path was not smooth either, as when the PKR was employed with cobalt complex in CH2Cl2 and further heating with acetonitrile reflux, it failed to produce the desired PKR products. This was assumed to be due to decomplexation of the dicobalt complex intermediate 19 formed. With the use of CyNH2 (Cy = cyclohexyl) as a promoter, 97% yield was obtained (Figure 16.10). Despite many failures [16], a one-pot synthesis with cobalt complex in CH2Cl2 and further heating and reflux upon addition of CyNH2 afforded 20, as anticipated. From the synthesized core structure of marrubin, many other natural products, like cyllenine C21, marrubasch F22, marrulanic acid 23, marrulactone 24, desertine 25 of the Marrubium family were synthesized through multiple steps (Figure 16.11).
Chapter 16 Total synthesis of bioactive heterocyclic scaffolds via Pauson Khand reaction
Figure 16.10: PKR in the synthesis of marrubin.
Figure 16.11: Marrubium family synthesized from PKR product.
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16.2.3.3 Synthesis of crinipellin A Crinipellin A is a diterpenoid that contains a unique tetraquinane core. It was originally believed that the biological effects of crinipellin A and crinipellin B were similar to those of antibiotics. At a dosage of 5 g/mL, crinipellin A acetate fully prevented the generation of DNA, RNA, and proteins in Ehrlich cancer cells [17]. Crinipellin A and B are promising irreversible substrates for chemical biology and drug development because of the methylene ketone motif. Tetramethyl thiourea (TMTU) was proved to be an excellent ligand in the Co- and Pd-catalyzed PKR, according to Huang et al. [18]. This discovery is related to the development of the PKR as a potent tool in synthesis of natural products. (–)-Crinipellin A 27 and (–)-crinipellin B 28 were successfully synthesized from the readily accessible phenol 26, in 17 and 18 steps, respectively (Figure 16.12). The application of the newly invented thiourea/Pd-catalyzed IMPKR for diastereoselective production of the tetraquinane core of crinipellins was one of the key steps of the synthesis.
Figure 16.12: PKR in the synthesis of crinipellins.
16.2.3.4 Synthesis of 5-epi-cyanthiwigin Cyanthiwigins are biologically active molecules with cyclohepta[e]-indene core that show cytotoxic activity against tumor cells. IC50 values of 3.1 mg/mL and 4 mg/mL against primary cancerous cells and A549 lung cancer cells of human were observed.
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They are structurally modified cyathane-type diterpenoids, unique in having cisoriented stereogenic centers. Synthesis of such diterpenoids, especially cyanthiwigins, has been reported by Phillips et al. [19], Stoltz et al. [20] and Gao et al. [21]. These methodologies used ring opening and closing metathesis as the main steps of the synthesis. Currently, synthesis of same molecule using PK approach has been successful. The PKR has been applied to the intermediate product 29 obtained from Sonagashira coupling. Indene core was synthesized using the PKR as the key step (Figure 16.13). While Co2(CO)8 in 0.5 equivalents and [Rh(CO)2Cl2] in 1.2 equivalents with TMTU as additive did not give the desired product, further optimization conditions led to expected products. Co2(CO)8 (1.2 equiv) without any additive gave a mixture of diastereomers 30, 31. However, using NMO as an additive at 110 °C gave 30 in 70% yield. IMPKR was used for the synthesis of Indene core with unique cis-oriented chiral centers at C6 and C9. This entire synthesis was performed in 17 steps enabling easier pathway of synthesis [22].
Figure 16.13: PKR in the synthesis of cyanthiwigins.
16.2.3.5 Synthesis of 4-desmethyl rippertenol and 7-epi-rippertenol Challenging task of synthesizing 4-desmethyl rippertenol and 7-epi-rippertenol is the tetracyclic core consisting of strained cycloheptanoid ring along with a tetrasubstituted double bond. The absence of functionality increases the need for structural modification and high stereocentral control, in addition to the intrinsic difficulties in developing polycyclic framework. The first total synthesis was reported in 2011 by Synder et al. [23]. Precursor tricyclic system core 32 can be obtained through IMPKR (Figure 16.14). Cobalt-promoted reaction with toluene at 110 °C gave the product with high regioselectivity. Finally, the target molecules were synthesized in a concise 15 steps [24].
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Figure 16.14: PKR in the synthesis of rippertenol and 4-desmethyl rippertenol.
16.2.4 Sesterterpenoids 16.2.4.1 Synthesis of astellatol The highly complicated structure of trans-hydrindane sesterpenoids explains the unraveled knot of synthesis of these molecules. Astellatol belongs to this rare class of sesterpenoids. It is extremely challenging, as it consists of unique right and left scaffolds. These include the isopropyl trans-hydrindane moiety with unique pentacyclic core attached to a bicyclosystem containing 10 stereocenters and an exo-methylene group. Intramolecular PK was employed to obtain trans-hydrindane scaffold. Cobalt-catalyzed
Figure 16.15: PKR in total synthesis of astellatol.
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reaction with PhMe as an additive gave 66% cyclized product 33 (Figure 16.15). Crossing over this hurdle, total synthesis of astellatol 34 with other significant methods employed was completed in 25 steps with an overall yield of 0.63% [25].
16.2.4.2 Synthesis of retigeranic acid Retigeranic acid A is a pentacyclic sesterterpene consisting of eight stereocenters. Because of the potential biological properties and the enticing structure, it is very desirable to establish a complementary approach to (–)-retigeranic acid A and its analogues for both drug development and academic study. Wang et al. [26] succeeded in synthesizing (–)-retigeranic acid in good yields along with good control over the stereogenic centers. Two IMPKRs were utilized as the essential stages in the synthetic investigation of (–)-retigeranic acid A in order to create the complicated pentacyclic core and the bridged quaternary carbons with high diastereoselectivity. IMPKRs were used to build D,E and A,B rings consecutively to construct triquinane subunit, and to install required C6a quaternary center in a diastereoselective manner (Figure 16.16). The success of this method also depends on the Eschenmoser–Tanabe fragmentation, the configuration inversion at C5b, and the diastereoselective 1,4-reduction/methylation sequence. For the initial IMPKR, various scenarios were tested. Enyne 35 was treated with stoichiometric Co2(CO)8 and NMO in a CO environment, and the outcome was the creation of the fused tricyclic compound 36 as a single diastereomer in 72% yield. However, Co2(CO)8 is pricey, and this reaction needed NMO of a high caliber. The reaction’s effi-
Figure 16.16: PKR in the synthesis of retigeranic acid.
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ciency was significantly reduced, when hygroscopic NMO was used. As an alternative, treatment with air- and moisture-inert CoBr2 with zinc dust (2 equiv) in the presence of tetramethyl thiourea, product 36 was produced in an 80% yield.
16.2.5 Triterpenoid 16.2.5.1 Synthesis of haperforin G Haperforin G has attracted the interest of the biomedical community due to its effective inhibiting activity of human 11β-hydroxysteroid dehydrogenase type 1, and it emerged as an effective novel compound for the management of a various metabolic disorder-related diseases, along with Alzheimer’s. It belongs to limonoid tetranortriterpenoid class with unique structure containing six stereogenic centers, lactones and furan rings. By the analysis of retro synthesis of haperforin G, it was observed that enantioselective inclusion of fragments was the most difficult component. Having known the enone and iodide involved in synthesis of haperforin G have stereogenic centers, a convergent strategy was developed to synthesize these in efficient enantioselective pathway. Intramolecular PK was involved in the synthesis of enone. Through Ley’s oxidation of diol, which can be synthesized by IMPKR of enyne, a seven-membered lactone ring of enone was created. For 86% yield of the anticipated dienenone 38 production, enyne 37 had to be exposed to a catalytic quantity of Co2(CO)8 (20 mol%) under CO atmosphere at 110 °C temperature for about 36 h (Figure 16.17). Through a series of important reactions, complex structure (+)-haperforin G is effectively synthesized in 20 steps with a final yield of 50% [27].
Figure 16.17: PKR in the synthesis of haperforin G.
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16.2.6 Special class of terpenoids 16.2.6.1 Synthesis of spirochensilide A Yang et al. [28] demonstrated on the asymmetric construction of spirochensilide A, due to its unique structure containing vicinal chiral centers with all quaternary carbons and a spiroketal ring system. Potential medicinal properties and effective application especially in anti-cancer activity and probe studies made this study more important. Major challenges addressed were (1) enantioselective preparation of enyne, (2) stereoselective synthesis of aldehyde, and (3) synthesis of cyclopentenone motif. The selectivity was obtained through by application of cationic cyclization by epoxide and sequential bromination reaction. Further reactions followed by semi-pinacol rearrangement of resulted in single diastereomer, when treated with BF3 · Et2O. PKR played a role in the synthesis of cyclopentenone framework. However, due to the rigidity and low reactivity of enyne, the optimization of protocol conditions was difficult. With the idea of increasing the reactivity by introducing electron withdrawing groups, chloroenyne was synthesized. Chlorine facilitates polarization and lowers the activation barrier of the process by acting as an electron-withdrawing group. Unlike the failure of formation of annulated product 39, when Co mediated PKR was used with enyne structure, chloroenyne in the presence of rhodium catalyst resulted in the formation of desired annulation product. [Rh(CO)2Cl2] catalyst under different conditions formed different annulated products 40 and 41 in 33% and 67% yield respectively (Figure 16.18). However, due to unsatisfied results, Yang et al. [29] reviewed the total synthesis in a different approach. With the knowledge of using cyclopropane-based cobaltcatalyzed reaction for PK, an aldehyde 41 was synthesized as precursor. This precursor further underwent reactions to give TMS substituted cyclopropene which was found to be more stable. Enyne 42 was subjected to undergo cyclization with [Rh(CO)2Cl]2and Co2(CO)8 under different optimized conditions, but was found to give disappointing results. The reason was presumed to be the instability of the naked cyclopropene ring. Changing the catalysts to iridium and ruthenium complexes also did not show any effect. With further struggle with optimization and exploration, molybdenum complex Mo(CO)3(DMF)3 with other additives gave 43, 44, 45 in 28%, 54% and 3% yield, respectively (Figure 16.19). Using tungsten complex, W (CO)3(MeCN)3 46 and 47 were obtained in 61% overall yield. This improvised methodology for synthesis of CD ring was employed further with other modifications in total synthesis of spirochensilide A (Figure 16.20).
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Figure 16.18: The PKR under various conditions in earlier attempts of synthesis of spirochensilide A.
16.2.6.2 Synthesis of caribenol A The uncommon terpene, caribenol A was discovered in 2007 by Rodriguez and colleagues [30]. It has been demonstrated to have a considerable inhibitory effect on Mycobacterium tuberculosis (H37Rv) [31]. More than 3 million people die from tuberculosis each year worldwide, which is primarily caused by this harmful bacterium. The intramolecular Diels–Alder method and biomimetic oxidation were crucial processes that the Yang group [32] used in 2010 to elaborate the primary total synthesis of caribenol A. The crucial 7-5 ring system of (–)-caribenol A could be constructed through the intramolecular PKR of enyne 48 (Figure 16.21). Wang et al. [33] proceeded to construct the 7-5 ring system using the crucial cyclization precursor 48. Co2(CO)8 as catalyst, toluene, at 110 °C, the typical PKR conditions, produced a single product 49 with a yield of 54%. Using the PKR, a bicyclooctane bridging ring product with the formula [5.2.1] was created. Attempts to create caribenol A from 49 are under process. This reaction is designated as a type-II IMPKR since it results in the formation of the bridging 8/5 ring product. The most popular PKR used to produce fused 6/5 or 7/5 rings is a type-I PKR.
Chapter 16 Total synthesis of bioactive heterocyclic scaffolds via Pauson Khand reaction
Figure 16.19: Molybdenum-based PKR in the synthesis of spirochensilide A.
Figure 16.20: Tungsten-based PKR in the synthesis of spirochensilide A.
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Figure 16.21: PKR in the synthesis of caribenol A.
16.3 Alkaloids 16.3.1 C19 diterpenoid alkaloids One of the greatest obstacles in the total synthesis of the biologically intriguing and architecturally complicated C19-diterpenoid alkaloids is the construction of the [7-5-6] BCD ring structure, the bridged all-carbon tricyclic core. As the paradigm for the BCD ring system of leucostine B, Yang et al. [34] outlined the synthetic process leading to tricyclo[7.2.1.09,10] dodecandiol employing a strong IMPKR and an exclusive 1,2-migration rearrangement as the important stages. A potent method for assembling highly substituted polycyclic carbon skeletons is the IMPKR. Over the years, Wagner–Meerwein-type rearrangement, radical- conjugated addition and cyclopentene-induced ring expansion methodologies were used. However, a unique and easy synthesis of diterpene alkaloids with a hydroxy group insertion at C-12 using PKR was established. IMPKR substrate 51 was prepared from species 50 to start the synthesis (Figure 16.22). The subsequent IMPKR was carried out under a marginally altered Dixon’s condition by treating compound 51 with dicobalt octacarbonyl, and then the resulting cobalt–alkyne complex was exposed to NMO in dichloroethane at a temperature of 40 °C, leading to required cis-isomer in moderate yield of 56% along with trans-isomer in trace amounts.
16.3.2 Synthesis of (–)-daphlongamine H and (–)-isodaphlongamine H The Daphniphyllum species yields the triterpenoid Daphniphyllum alkaloids, which have a peculiar-fused hexacyclic ring topology. These chemical substances have a variety of biological uses and great promise for medical applications [35].
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Figure 16.22: PKR in the synthesis of C19 diterpenoid alkaloid.
The first thorough synthetic procedure of the complicated hexacyclic Daphniphyllum alkaloid (–)-daphlongamine H was accomplished by Cedric et al. [36]. The effectiveness of the technique depends on the assembly of the tricyclic core having four continuous stereocenters, which is made possible by a complexity-boosting Mannich reaction, strategic cyclizations, and hydrogenation with high diastereoselectivity. The hydro-indene substructure was created via the PKR, and the natural product was created by endgame redox manipulations. The fact that the synthetic experiments also made (–)-isodaphlongamine H available, and changed the previously described structure of deoxyisocalyciphylline is notable. Treating 53 with an excess of methyllithium led to the production of respective tertiary alcohol (around 20:1 d.r.). Enyne diol was created as a result, and it underwent PKR to create pentacyclic enone 54 with necessary 10-Hα orientation. Once all eight stereogenic centers had been formed, the last redox changes were carried out (Figure 16.23).
16.3.3 Synthesis of lycopoclavamine-A Lycopodium alkaloids are quinolizine, or pyridine- and α-pyridone-type alkaloids. Few of them are powerful acetylcholinesterase inhibitors (AChE). Huperzine A (HupA) has been shown to enhance memorizing ability in rats, and also act as potential treatment Alzheimer’s disease (AD) [37]. Aneurisms, constipation, fevers, and chronic lung and bronchial illnesses are all treated with it in homoeopathy. Additionally, it eases digestion, lessens gastric inflammation, and aids in the treatment of long-term kidney problems. Studies have shown that Lycopodium clavatum has analgesic, antioxidant, anticancer, an-
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Figure 16.23: PKR in the synthesis of Daphniphyllum alkaloids.
tibacterial, anti-inflammatory, neuroprotective, immunomodulatory, and hepatoprotective properties. Also, it can lessen exhaustion and chronic fatigue. Native Americans frequently employ the spores of Lycopodium clavatum to alleviate nosebleeds and to mend wounds [38]. There are roughly 120 different alkaloids in this class, and lycopoclavamine-A, a unique Lycopodium alkaloid discovered in Lycopodium clavatum by Katakawa et al. [39] in 2011, has structural similarities to fawcettimine. Kaneko et al. [40] described an asymmetric total synthesis of this alkaloid from commercially available crotonamide (Figure 16.24). PKR was used to create the pente-
Figure 16.24: PKR in the synthesis of lycopoclavamine A.
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none moiety in the necessary intermediate formation and a stereoselective conjugate addition led quaternary carbon center at C-12. The IMPKR proceeded with cobalt catalyst generated the necessary bicyclic enone 55, which further gave enedione 56 upon oxidation with AZADOL, for the subsequent conjugate addition. Enedione 56 was then subjected to various reactions to synthesize the required molecule lycopoclavamine-A.
16.3.4 Synthesis of hybridaphniphylline B Zhang et al. [41] reported the total synthesis of hybridaphniphylline B for the first time featuring intermolecular Diels–Alder reaction, Claisen rearrangement, and PKR. The Daphniphyllum alkaloids are a family of more than 320 naturally occurring triterpenoids that were derived from the Daphniphyllum plant genus. They have the potential to be effective therapeutic molecules against cancer and the human immunodeficiency virus, thanks to their numerous continuous stereogenic centers, unusual hexacyclic ring-fused structure, and many stereogenic centers. Due to their unique structures, fantastic learning opportunities for synthetic chemists, and intriguing bioactivities, these compounds are of interest to both chemists and biologists [42]. They realized that the Diels–Alder reaction, that yields hybridaphniphylline B needed a reliable route which called for a P K/C = C bond migration method. In forward synthesis, PK substrate 57 was synthesized using 1,5-diene. In work under PK conditions, MeCN was discovered to be an effective promoter for the conversion of the necessary products from the alkyne dicobalt complex [made from 57 and Co2(CO)8]; 58 and 59 were obtained in 73% yield at a ratio of around 2.4:1. With an important intermediate in hand, further reactions were performed to provide over 100 mg of the required compound (Figure 16.25).
Figure 16.25: PKR in the synthesis of hybridaphniphylline B.
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16.3.5 Total synthesis of (–)-allosecurinine The first instance of a hetero-PKR (HPK) mediated by tungsten is reported by Chirkin et al. [43]. The most prevalent derivative, securinine, was first recognized as GABA (gamma-aminobutyric acid) antagonist and utilized as a CNS (central nervous system) agent. In investigations using mice xenografts, securinine was found to have an in vivo activity and to enhance differentiation of HL60 leukemic cells [44]. Furthermore, only a very small number of semisynthetic analogues created by this alkaloid family have been reported in systematic structure–activity relationship (SAR) studies. In this alkaloid family, HPK strategies have been attempted before but failed. Novel, more potent transition-metal catalysts and promoters have been developed as a result of the improvements made to the HPK approach during the past few years. This idea inspired them to reexamine how the HPK technique could be used to synthesize securinega alkaloids. A good candidate for this reaction was W(CO)6. In just 30 min, they performed the cyclization in 30% yield for the construction of BCD core (Figure 16.26). The crucial HPK cyclization was planned to be the final step after the production of compound 60, a bicyclic molecule with both ketone and Z-enyne functions. The reactant 60 and W(CO)6 complex were combined in a mixture of toluene and dimethyl formamide (DMF) under a CO atmosphere for about 30 min at 140 °C temperature to implement the “one-pot” process. After chromatography, allosecurinine was recovered, but with a poor yield (12%). The same outcome (14%) was attained, when molybdenum hexacarbonyl was utilized as the promoter.
Figure 16.26: PKR in the synthesis of allosecurinine.
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16.3.6 Synthesis of streptazone A Wormer et al. [45] elaborated the first syntheses of streptazone B1/B2, streptazone A, abikoviromycin, and dihydroabikoviromycin in 7, 8, and 9 stages, respectively, using an allene-tethered ynamide substrate. A unique intramolecular PK cycloaddition that yields a bicyclo[4.3.0] core was also found. The streptazones are a subclass of piperidine alkaloids that have a variety of biological functions, and share an intriguing [4.3.0] bicyclic core. Streptazone A, a novel compound with an enaminone, a Michael acceptor, and a bis-allylic epoxide, has been shown to significantly inhibit proliferation of liver cancer cells. It can behave as a naturally occurring cysteine-reactive molecule, and may also be able to encourage cross-linking, according to a biological perspective. It is hoped that further research on this group of natural compounds would shed light on this extremely uncommon reaction. Initially, [Rh(CO)2Cl]2 was used to test the intramolecular allene–ynamide PK cyclization on three ynamides (61a–61c), while regioselectively favoring the allene’s distal pi-bond -in the cyclization (Figure 16.27). Separate chamber protocol system created by Skrydstrup and colleagues was used to safely handle CO gas [46]. All three substrates were successfully cyclized, establishing ynamides as useful antecedents for PK cyclization with rhodium to produce [4.3.0] frameworks. Previously, to make available [3.3.0] scaffolds with an intramolecular allene–ynamide cyclization, only molybdenum was in use. After testing a number of distal selective catalysts, it was determined that [Rh(CO) Cl-(dppp)]2 was appropriate for a suitable synthesis.
Figure 16.27: PKR in the synthesis of streptazones.
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16.4 Steroids 16.4.1 Synthesis of bufospirostenin A The study on the synthesis of complicated steroid natural products has so long been a hot topic and frontier in synthetic chemistry. Bufospirostenin A 65 was discovered in the venom of the Bufo gargarizans, a traditional Chinese drug. It is a unique bioactive spirostanol with A/B ring rearrangement. It has been proven to enhance blood circulation and have a cardioactive effect by inducing a 43% inhibition of Na/K ATPase (NKA) at 25 μM with just 1.9 mg (0.004 mmol) available [47]. Cheng et al. [48] used a 20-step linear procedure to create bufospirostenin A, beginning with the readily available chemical 62. Notably, a novel intramolecular PKR successfully produced the challenging-to-synthesize [5-7-6-5] tetracyclic ring structure found in species 65 and other similar organic compounds. The synthesis of a natural product using an IMPKR involving an alkoxyallene–yne is demonstrated for the first time in this study. Furthermore, 10 of the 11 stereocenters in compound 65 were synthesized using diastereoselective synthesis. This research involved the IMPKR of compound 63 (1.4 g scale) with 5 mol% of rhodium catalyst [RhCl(CO)2]2. The reaction was performed at 110 °C with a balloon pressure of CO in PhMe producing 64 with the required [5-7-6-5] tetracyclic core with a total conversion of 85% (Figure 16.28). Through the intramolecular PKR, the highly functionalized [5-7-6-5] tetracyclic framework in species 64 was effectively synthesized through linear series of reactions from starting material 62. The valuable intermediate 64 can also be employed to manufacture other natural products.
Figure 16.28: PKR in the synthesis of bufospirostenin A.
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16.5 Conclusions The PKR is one of the rare organic reactions that can add so much molecular complexity in a single step. One of the most alluring synthetic methods for obtaining a variety of ring-structured skeletons is cycloaddition. The PKR proved to be highly efficient, along with easy-to-handle reaction conditions. There is a possibility of both intra- and intermolecular PKRs that allows formation of substituted cyclopentenone motifs required in many important molecules. With further advancements, there is a huge development in this reaction by employing the use of different transition metal catalyst. Both type I and II PKR give rise to 6/5, 7/5 and 8/5 fused ring systems, respectively, paves way for synthesis of several biologically important natural products bearing variable pharmacological and medicinal effects. Being addition reaction, it is intended that the waste materials produced would be kept minimum, giving favorable environmental properties. Syntheses of various natural product showing important biological activities were discussed, which employed the PKR for the formation of cyclopentenone moiety, shedding light on the wide application of this reaction in organic and medicinal chemistry. Application of the PKR to the synthesis of terpenes and alkaloids has been well explored in comparison with steroids and other natural products. With the major use of Co, Rh, W, and Mo complexes in catalysis, there are still possibilities for further advancements in developing sustainable methodologies; for instance, use of cost-effective and naturally abundant metals, and photocatalytic and aqueousmediated reactions.
References [1]
[2] [3] [4]
[5] [6] [7]
Ichake, SS, Villuri, BK, Reddy, SR, Kavala, V, Yao, CF. A synthetic strategy for the construction of functionalized triphenylene frameworks via palladium catalyzed intramolecular annulation/ decyanogenative C–H bond alkenylation. Org Lett 2019, 21, 2256–2260. Schore, NE, Croudace, MC. Preparation of bicyclo [3.3. 0] oct-1-en-3-one and bicyclo [4.3.0] non-1 (9)en-8-one via intramolecular cyclization of. Alpha, omega.-enynes. J Org Chem 1981, 46, 5436–5438. Chung, YK. Transition metal alkyne complexes: The PKR. Coord Chem Rev 1999, 188, 297–341. Bandi, V, Kavala, V, Konala, A, Hsu, CH, Villuri, BK, Reddy, SR, Lin, L, Kuo, CW, Yao, CF. Synthesis of polysubstituted cyclopentene and cyclopenta [b] carbazole analogues from unsymmetrical 4-Arylidene-3, 6-diarylhex-2-en-5-ynal and indole derivatives via an iodine mediated electrocyclization reaction. J Org Chem 2018, 84, 3036–3044. Pallerla, MK, Fox, JM. Diastereoselective intermolecular Pauson−Khand reactions of chiral cyclopropenes. Org Lett 2005, 7, 3593–3595. Blanco-Urgoiti, J, Añorbe, L, Pérez-Serrano, L, Domínguez, G, Pérez-Castells, J. The PKR, a powerful synthetic tool for the synthesis of complex molecules. Chem Soc Rev 2004, 33, 32–42. Salam, A, Ray, S, Zaid, MA, Kumar, D, Khan, T. Total syntheses of several iridolactones and the putative structure of noriridoid scholarein A: An intramolecular PKR based one-stop synthetic solution. Org Biomol Chem 2019, 17, 6831–6842.
514
[8]
[9] [10]
[11] [12]
[13] [14] [15] [16] [17]
[18] [19] [20] [21] [22] [23] [24]
[25] [26] [27] [28]
Sabbasani Rajasekhara Reddy, Sathi Bhulakshmi, and Sanjivani Pal
Gomes, J, Daeppen, C, Liffert, R, Roesslein, J, Kaufmann, E, Heikinheimo, A, Neuburger, M, Gademann, K. Formal total synthesis of (−)-Jiadifenolide and synthetic studies toward secoprezizaane-type sesquiterpenes. J Org Chem 2016, 81, 11017–11034. Dooley III, CJ, Rychnovsky, SD. Asymmetric total synthesis of (2 R)-hydroxynorneomajucin, a norsesquiterpene from illicium jiadifengpi. Org Lett 2022. Crawford, JJ, Kerr, WJ, McLaughlin, M, Morrison, AJ, Pauson, PL, Thurston, GJ. Use of a highly effective intramolecular Pauson–Khand cyclisation for the formal total synthesis of (±)-α-and βcedrene by preparation of cedrone. Tetrahedron 2006, 62, 11360–11370. Kerr, WJ, McLaughlin, M, Paterson, LC, Pearson, CM. Total synthesis 2-epi-α-cedren-3-one via a cobalt-catalysed PKR. Tetrahedron 2018, 74, 5062–5068. Hatashita, M, Taniguchi, M, Baba, K, Koshiba, K, Sato, T, Jujo, Y, Suzuki, R, Hayashi, S. Sinodielide A exerts thermosensitizing effects and induces apoptosis and G2/M cell cycle arrest in DU145 human prostate cancer cells via the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Int J Mol Med 2014, 33, 406–414. Hu, X, Musacchio, AJ, Shen, X, Tao, Y, Maimone, TJ. Allylative approaches to the synthesis of complex guaianolide sesquiterpenes from apiaceae and asteraceae. J Am Chem Soc 2019, 141, 14904–14915. Qu, Y, Wang, Z, Zhang, Z, Zhang, W, Huang, J, Yang, Z. Asymmetric total synthesis of (+)waihoensene. J Am Chem Soc 2020, 142, 6511–6515. Sakagami, Y, Kondo, N, Sawayama, Y, Yamakoshi, H, Nakamura, S. Total syntheses of marrubiin and related labdane diterpene lactones. Molecules 2020, 25, 1610. Krafft, ME, Bonaga, LV, Hirosawa, C. Practical cobalt carbonyl catalysis in the thermal pauson− khand reaction: Efficiency enhancement using lewis bases. J Org Chem 2001, 66, 3004–3020. Shinohara, C, Chikanishi, T, Nakashima, S, Hashimoto, A, Hamanaka, A, Endo, A, Hasumi, K. Enhancement of fibrinolytic activity of vascular endothelial cells by chaetoglobosin A, crinipellin B, geodin and triticone B. J Antibiot 2000, 53, 262–268. Huang, Z, Huang, J, Qu, Y, Zhang, W, Gong, J, Yang, Z. Total syntheses of crinipellins enabled by cobalt-mediated and palladium‐catalyzed intramolecular PKRs. Angew Chem 2018, 130, 8880–8884. Pfeiffer, MW, Phillips, AJ. Conversion of cyanthiwigin U to related cyanthiwigins: Total syntheses of cyanthiwigin W and cyanthiwigin Z. Tetrahedron Lett 2008, 49, 6860–6861. Enquist, JA, Jr, Stoltz, BM. The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation. Nature 2008, 453, 1228–1231. Gaikwad, D. Unprecedented total synthesis of bruceolline D, E, and H. Synth Commun 2020, 50, 3158–3164. Chang, Y, Shi, L, Huang, J, Shi, L, Zhang, Z, Hao, HD, Gong, J, Yang, Z. Stereoselective total synthesis of (±)-5-epi-cyanthiwigin I via an intramolecular PKR as the key step. Org Lett 2018, 20, 2876–2879. Li, Z, Zhang, L, Qiu, FG. A concise stereocontrolled total synthesis of (±)‐stemoamide. Asian J Org Chem 2014, 3, 52–54. Zhang, ZC, Zhao, DD, Zhang, ZC, Tan, XY, Gong, JX, Fu, JK, Yang, Z. Synthesis of 4-DesmethylRippertenol and 7-Epi-Rippertenol via photoinduced cyclization of dienones. CCS Chem 2021, 3, 2074–2083. Zhao, N, Yin, S, Xie, S, Yan, H, Ren, P, Chen, G, Chen, F, Xu, J. Total synthesis of astellatol. Angew Chem Internat Edit 2018, 57, 3386–3390. Wang, X, Li, D, Zhang, J, Gong, J, Fu, J, Yang, Z. A synthetic route to the core structure of (−)Retigeranic acid A. Org Lett 2021, 23, 5092–5097. Zhang, W, Zhang, Z, Tang, JC, Che, JT, Zhang, HY, Chen, JH, Yang, Z. Total synthesis of (+)-haperforin G. J Am Chem Soc 2020, 142, 19487–19492. Liang, XT, Chen, JH, Yang, Z. Asymmetric total synthesis of (−)-Spirochensilide A. J Am Chem Soc 2020, 142, 8116–8121.
Chapter 16 Total synthesis of bioactive heterocyclic scaffolds via Pauson Khand reaction
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[29] Liang, XT, Sun, BC, Zhang, N, Zhang, ZC, Li, YH, Xu, QQ, Liu, C, Chen, JH, Yang, Z. Asymmetric total synthesis of (−)-Spirochensilide A, Part 2: The final phase and completion. J Org Chem 2021, 86, 2158–2172. [30] Wei, X, Rodriguez, II, Rodriguez, AD, Barnes, CL. Caribenols A and B, sea whip derived norditerpenes with novel tricarbocyclic skeletons. J Org Chem 2007, 72, 7386–7389. [31] Bloom, BR, Murray, CJ. Tuberculosis: Commentary on a reemergent killer. Science 1992, 257, 1055–1064. [32] Wang, Y, Liu, K, Yu, ZX, Jia, Y. Type-II PKR of 1, 8-enyne in the attempt of building 7/5 ring of (−)caribenol A and DFT understanding. Tetrahedron Lett 2019, 60, 151001. [33] Wang, Y, Liu, K, Yu, ZX, Jia, Y. Type-II Pauson-Khand reaction of 1, 8-enyne in the attempt of building 7/5 ring of (−)-caribenol A and DFT understanding. Tetrahedron Lett 2019, 60, 151001. [34] Yang, G, Zhu, M, Zhao, X, Lei, J, Xu, L. A new route to BCD tricyclic fragment of C19-diterpenoid alkaloids via intramolecular PKR followed by anionic 1, 2-migration rearrangement. Tetrahedron Lett 2021, 69, 152975. [35] Zhong, J, Wang, H, Zhang, Q, Gao, S. The chemistry of Daphniphyllum alkaloids. Alkaloids Chem Biol 2021, 85, 113–176. [36] Hugelshofer, CL, Palani, V, Sarpong, R. Calyciphylline B-type alkaloids: Total syntheses of (−)daphlongamine H and (−)-isodaphlongamine H. J Am Chem Soc 2019, 141, 8431–8435. [37] Ayer, WA, Fukazawa, Y, Singer, PP, Altenkirk, B. Lycoflexine, a new type of lycopodium alkaloid. Tetrahedron Lett 1973, 14, 5045–5048. [38] Bhardwaj, A, Misra, K. Homeopathic remedies. Manag High Altitude Pathophysiol 2018, 217–229. [39] Katakawa, K, Mito, H, Kogure, N, Kitajima, M, Wongseripipatana, S, Arisawa, M, Takayama, H. Ten new fawcettimine-related alkaloids from three species of Lycopodium. Tetrahedron 2011, 67, 6561–6567. [40] Kaneko, H, Takahashi, S, Kogure, N, Kitajima, M, Takayama, H. Asymmetric total synthesis of fawcettimine-type Lycopodium alkaloid, lycopoclavamine-A. J Org Chem 2019, 84, 5645–5654. [41] Zhang, W, Ding, M, Li, J, Guo, Z, Lu, M, Chen, Y, Liu, L, Shen, YH, Li, A. Total synthesis of hybridaphniphylline B. J Am Chem Soc 2018, 140, 4227–4231. [42] Zhong, J, Wang, H, Zhang, Q, Gao, S. The chemistry of daphniphyllum alkaloids. Alkaloids Chem Biol 2021, 85, 113–176. [43] Chirkin, E, Bouzidi, C, Poree, FH. Tungsten-promoted hetero-Pauson–Khand cycloaddition: Application to the total synthesis of (–)-Allosecurinine. Synthesis 2019, 51, 2001–2006. [44] Rana, S, Gupta, K, Gomez, J, Matsuyama, S, Chakrabarti, A, Agarwal, ML, Agarwal, A, Agarwal, MK, Wald, DN. Securinine induces p73‐dependent apoptosis preferentially in p53‐deficient colon cancer cells. FASEB J 2010, 24, 2126–2134. [45] Wørmer, GJ, Villadsen, NL, Nørby, P. Poulsen TB.Concise asymmetric syntheses of streptazone A and abikoviromycin. Angew Chem Internat Edit 2021, 60, 10521–10525. [46] Hermange, P, Lindhardt, AT, Taaning, RH, Bjerglund, K, Lupp, D, Skrydstrup, T. Ex situ generation of stoichiometric and substoichiometric 12CO and 13CO and its efficient incorporation in palladium catalyzed aminocarbonylations. J Am Chem Soc 2011, 133, 6061–6071. [47] Tian, HY, Ruan, LJ, Yu, T, Zheng, QF, Chen, NH, Wu, RB, Zhang, XQ, Wang, L, Jiang, RW, Ye, WC. Bufospirostenin A and Bufogargarizin C, steroids with rearranged skeletons from the toad Bufo bufo gargarizans. J Nat Prod 2017, 80, 1182–1186. [48] Cheng, MJ, Zhong, LP, Gu, CC, Zhu, XJ, Chen, B, Liu, JS, Wang, L, Ye, WC, Li, CC. Asymmetric total synthesis of bufospirostenin A. J Am Chem Soc 2020, 142, 12602–12607.
Shashi Kiran Misra and Kamla Pathak✶
Chapter 17 Nonconventional approaches in drug discovery 17.1 Introduction Drug discovery is a vast and complex process that utilizes immense capital and time. Development of new drug and its market setup comprises myriad academic and clinical research, follows different regulatory guidelines, and performs extensive market surveillances. Drug discovery via traditional system, very first an idea is processed in research domain, compilation of outcomes/findings creates a hypothesis, which is reliant on therapeutic action against a disease. Subsequently, selection of a target, validation of target (genetic, cellular), chemical screening (high-throughput screening (HTS), library screening), secondary assay, ex vivo/in vivo, and preclinical studies for the estimation of safety, efficacy, and toxicity are performed as displayed in Figure 17.1. Lead discovery is exhaustive research that proposes new bioactive/therapeutic agent and faces clinical study (phases 1–4) before launching in market. Diverse approaches, such as trial and error, random screening, and serendipity methods, are usually employed for discovery of new lead compound via traditional way. Secondary metabolites (natural products) have been considered as potential sources while discovering lead compound. Our planet is full of natural resources containing myriad chemical constituents with distinct pharmacological actions [1]. Till date only 10% lead compounds have been evaluated for potential bioactivity and there are still huge opportunities to disclose many more [2]. However, their access is challenging and need exhaustive research and advanced tools and technology. Conventional medicine practices are widely utilized for the discovery of most of the early pharmacophores. This is also known as forward pharmacology or phenotype screening. In this series, well-known aspirin (acetylsalicylic acid) is developed by the natural component “salicin.” This active component is extracted and isolated from willow tree bark, that is, Salix alba. Similarly in the year 1803, myriad benzylisoquinoline alkaloids, such as codeine, morphine, and sanguinarine, have been discovered from the naturally occurring Papaver somniferum and are frequently used in the pharmaceutical industries for manufacturing of several dosages [3]. Table 17.1 lists out few therapeutic agents isolated from natural sources.
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Corresponding author: Kamla Pathak, Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences Saifai, Etawah 206130, Uttar Pradesh, India, e-mail: [email protected] Shashi Kiran Misra, School of Pharmaceutical Sciences, CSJM University Kanpur, Uttar Pradesh 208024, India https://doi.org/10.1515/9783110980189-017
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Figure 17.1: Steps involved in drug discovery via traditional or conventional approach.
Table 17.1: Some pharmacologically active lead compounds isolated from natural resources. Therapeutic agent and category
FDA approval
Chemical structure
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Pilocarpine to treat dry mouth xerostomia
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Penicillin treatment of infections
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(continued)
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Quinine for treatment of malaria
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Therapeutic agent and category
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Chemical structure
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Vancomycin antimicrobial
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Table 17.1 (continued)
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Paclitaxel (Taxol, anticancer)
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Artemisinin (antimalarial)
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(continued)
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Amrubicin hydrochloride (anticancer)
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Therapeutic agent and category
FDA approval
Chemical structure
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Ziconotide a peptide for pain relieving
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Table 17.1 (continued)
[] Sorafenib (kinase inhibitor)
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Innovation and development of novel drugs is carried out by HTS, through which potential action of drugs is decided. The major issue with this conventional approach is enormous time consumption. The finding of desired pharmacophore and its identification takes approximately 15 years with more than 800 million dollars expenses that includes clinical trial and FDA approval for marketing [13]. A study conducted on November 2018 on new drug development in United States assessed scientific significance and estimated cost involved in the drug development during 2015–2016. The reports suggested that most of the lead compounds or pharmacophores become failed in different phases of performed clinical trials and could not get FDA market approval. Only 59 new drugs were approved that included median cost of 19 million dollars [14]. Traditional method initially identifies the phenotype activity of experimental hits via applying diverse cellular/animal models, and physiological actions are determined. Thereafter, lead compounds are identified and purified. Further on, selected leads are subjected for binding capacities with targets (receptors and proteins) through biological screenings or assays, and thus most lead compounds are identified for the target. Overall, this method requires extensive research that takes long time and patience to report a novel drug. Next, the approach moves toward preclinical and in vitro/in vivo studies for the identification of mechanism of action, selectivity for specific receptor, and other associated pharmacokinetic and pharmacodynamic parameters [15]. Hence, the traditional method aims at enhanced physiological effect of the discovered lead compound. However, accurate mechanism action, precise dose response, and possible secondary effects are not clearly estimated by this method. Hence, the chances of failure, extensive time, and money limit traditional approach of drug discovery and suggest implementation of more efficient, cost-effective, nontedious, and broad-spectrum technologies as an alternative [16].
17.2 Reverse pharmacology or rational drug design Ethnopharmacology and conventional herbal remedy have been origin of wide array of modern therapeutics. Enormous phytoconstituents displaying different pharmacological actions are reported in international pharmacopoeia. Ayurvedic traditional practices encourage researchers to find the starting point and pave the path from clinic to laboratory. Although very few of them have been precisely projected and evaluated for their safety and efficacy. Further on, modern scientific tools and technologies are required to collect their well-organized database depicting specific therapeutic potential against specific disease [17]. Earlier, folk remedies incidentally identified countless therapeutics from their natural sources and these accidental discoveries are well known as serendipity. Literatures envisaged many plant constituents and medicinal valued components that
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have been highlighted serendipitous and remained basis of new drug development. Advancements in combinatorial chemistry, biotechnology, and system biology facilitated modern pathway of drug development that are easier, cost-effective less-riskier, and safe to use. Moreover, the modern approaches minimize the issue of post marketing failure of drug that is prime concern of pharma industries [18]. Although classical pharmacology method of drug screening is somehow tedious, inefficient, and time taking, hence scientists move toward opposite pathways for drug discovery via utilizing advanced proteomics, genomics, and metabolomics technologies. Reverse pharmacology is much faster and more competent (