Green-Bond Forming Reactions. Volume 2: Synthesis of Bioactive Scaffolds [2] 9783110797077

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Rakesh Kumar Sharma, Bubun Banerjee (Eds.) Green-Bond Forming Reactions

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Physical Sciences Reviews e-ISSN -X

Green-Bond Forming Reactions Synthesis of Bioactive Scaffolds Edited by Rakesh Kumar Sharma and Bubun Banerjee

Editors Prof. Rakesh Kumar Sharma University of Delhi Department of Chemistry 109, Block B, First Floor North campus Delhi-110007 India [email protected] Dr. Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda Punjab-151302 India [email protected]

ISBN 978-3-11-079707-7 e-ISBN (PDF) 978-3-11-079742-8 e-ISBN (EPUB) 978-3-11-079746-6 Library of Congress Control Number: 2022938837 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. © 2022 Walter de Gruyter GmbH, Berlin/Boston Cover image: Artfully79/iStock/Getty Images Plus Typesetting: TNQ Technologies Pvt. Ltd. Printing and binding: CPI books GmbH, Leck www.degruyter.com

Preface A retrospection over the past few decades clearly reveals that green chemistry has transformed the outlook of the researchers, paving the pathway for sustainability, especially in the area of organic synthesis. Carbon-carbon (C-C) and carbon-heteroatom (C-X; X = O, N, S, Si, etc.) bond-forming reactions have emerged as most efficient toolboxes for enabling the sustainable synthesis of bioactive scaffolds. A huge number of structurally diverse biologically promising organic compounds are being synthesized almost every day through these approaches. Many of these synthesized compounds have indeed shown marvelous biological efficacies. Some are under screening of drug development processes. Perceiving the immense significance, this book entitled ‘Green bond forming reactions: Synthesis of bioactive scaffolds’ compiles a huge literature related to the synthesis of bioactive scaffolds through the formation of carbon-carbon and carbon-heteroatom bonds that have been accomplished under the umbrella of Green Chemistry. This book contains 10 chapters, contributed by established scientists of high calibers. In chapter 1, Sabir Ahammed and Prof. Ranu have explored the synthesis of structurally diverse bioactive scaffolds through the formation of various carbon-nitrogen, carbonoxygen, carbon-sulfur and carbon-selenium bond formation using copper nanoparticles in greener conditions. Quinazolinone and quinazoline derivatives are acquiring immense attention because of their significant pharmacological importance. In chapter 2, Prof. Pooja A. Chawla and her research group have demonstrated the recent developments on the synthesis of structurally diverse quinazolinone and quinazoline derivatives utilizing greener credentials. Prof. Pooja A. Chawla and her group have contributed another chapter and summarized various green synthetic approaches in chapter 3 for the efficient synthesis of various saturated biologically promising S-heterocyclic scaffolds. In Chapter 4, Dr. Reddy and his research group compiled the literature related to the Cu-catalyzed tandem reactions for building biologically promising poly heteroatom containing heterocycles under greener conditions. Cinnolines and phthalazines are found to possess a wide range of biological and pharmaceutical efficacies. In Chapter 5, Prof. Sadek and his research team have summarized the recent advances in the green synthesis of cinnolines and phthalazines. The docking studies and mode of action for some key scaffolds have also discussed in this chapter. In Chapter 6, Prof. Das and his research group have demonstrated the role of quantum dots for the green synthesis structurally diverse biologically relevant scaffolds. https://doi.org/10.1515/9783110797428-201

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Preface

Natural products play a crucial role in the drug development. Chapter 7, by Dr. Majhi, deals with the synthesis of various bioactive natural products and their analogues at room temperature. In Chapter 8, Prof. Kamanna and his research group have highlighted the applications of agro-waste extracted solvent medium for the efficient synthesis of bioactive scaffolds. Our group (Dr. Bubun Banerjee) has summarized one-pot multi-component approaches for the synthesis of diverse bioactive heterocyclic scaffolds involving 6aminouracil or its N-methyl derivatives as a versatile reagent. The last chapter by Prof. Banik and his group has described the conceptual design and cost-efficient environmentally benign synthesis of beta lactams. The editors of this book express their gratitude to all the authors for contributing highly valuable chapters. We want to particularly acknowledge Ms. Stella Muller and Ms. Christene Smith who have extended all possible support for making this a book a reality. Furthermore, this book could not have been completed without the timely support from the authors, Ms. Muller and Ms. Smith. We firmly believe that this book on green bond forming reactions will be used extensively by the scientific community. Thank you ALL. Prof. Rakesh Kumar Sharma and Dr. Bubun Banerjee

Contents Preface V List of contributing authors

XIII

Sabir Ahammed and Brindaban C. Ranu 1 Copper nanoparticles catalyzed carbon–heteroatom bond formation and 1 synthesis of related heterocycles by greener procedures 1 1.1 Introduction 2 1.2 Carbon–heteroatom bond formation 2 1.2.1 C–N bond formation 15 1.2.2 C–O bond formation 18 1.2.3 C–S bond formation 23 1.2.4 C–Se bond formation 26 1.2.5 C–P bond formation 28 1.3 Conclusions 29 References Simranpreet K. Wahan, Sangeeta Sharma and Pooja A. Chawla 2 Synthesis of quinazolinone and quinazoline derivatives using green 33 chemistry approach 33 2.1 Introduction 35 2.2 Use of catalyst for preparing quinazolinone derivatives 41 2.3 Metal-free conditions 42 2.4 Microwave assisted synthesis 45 2.5 Conclusion 45 References Sharma Arvind Virendra, Simranpreet K. Wahan, Chandrakant Sahu and Pooja A. Chawla 3 Green synthesis of various saturated S-heterocyclic scaffolds: an 49 update 49 3.1 Introduction 50 3.2 Principles of green chemistry 51 3.3 Synthesis of sulphur containing heterocyclic compound 52 3.3.1 Synthesis of thiirane 57 3.3.2 Synthesis of thiane 62 3.3.3 Synthesis of thiolane 3.3.4 Miscellaneous synthesis of saturated S-containing heterocycles 69 3.4 Conclusions 69 Abbreviation 70 References

65

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Contents

Sabbasani Rajasekhara Reddy and Jyothylakshmi Jayakumar 4 Cu-Catalysed tandem reactions for building poly hetero atom 75 heterocycles-green chemistry tool 75 4.1 Introduction 77 4.2 Synthesis of heterocycles 78 4.2.1 Synthesis of annulated heterocyclic compounds 82 4.2.2 Synthesis of benzoxazines 4.2.3 Synthesis of fused pyrrolobenzoxazinones and 83 pyrroloquinazolinones 4.2.4 Synthesis of poly heterocyclic compounds using one-pot 85 methodology 86 4.3 Transition metal catalysed isoindolinones synthesis 89 4.4 Synthesis of fluoroalkylated isoxazoles 91 4.5 Fabrication of acid-responsive poly indolones 91 4.6 Cu-catalysed intermolecular cross-coupling 92 4.7 Multicomponent polymerization reactions (MCPs) 4.7.1 Synthesis of iminocoumarin/quinoline-based poly 92 N-sulfonylimines 95 4.8 Cascade synthesis of pyrroles 97 4.9 Conclusions 97 References Ramadan Ahmed Mekheimer, Mohamed Abd-Elmonem, Mohamed Abou Elsebaa, Maiiada Hassan Nazmy, and Kamal Usef Sadek 5 Recent developments in the green synthesis of biologically relevant 101 cinnolines and phthalazines 101 5.1 Introduction 103 5.2 Cinnolines 104 5.2.1 Synthesis of cinnoline derivatives 148 5.3 Phthalazine 148 5.3.1 Synthesis of phthalazine derivatives 176 5.4 Conclusions 177 References Dwaipayan Das, Moumita Saha and Asish. R. Das 6 Synthesis, properties and catalysis of quantum dots in C–C and 187 C-heteroatom bond formations 187 6.1 Introduction 193 6.2 Properties of quantum dot 194 6.2.1 Surface reactivity of quantum dot 195 6.2.2 Optical properties

Contents

6.2.3 6.2.4 6.2.5 6.3 6.4 6.5 6.5.1 6.5.2 6.5.3 6.5.4 6.5.5 6.5.6 6.6 6.6.1 6.6.2 6.6.3 6.6.4 6.6.5 6.6.6 6.6.7 6.6.8 6.6.9

6.6.10 6.6.11 6.6.12 6.7 6.8 6.9

IX

Quantum yield 195 196 Cytotoxicity of QD 197 Recyclability of QD 197 Synthesis of QD 200 Characterization of QD 201 Applications of quantum dot in miscellaneous fields 201 Bio-imaging 202 Photovoltaic devices 202 Photodetectors 203 Light emitting devices 203 Quantum computing 203 As a photocatalyst in organic syntheses Application of QD in C–C and C–X (X = heteroatom) bond 204 formation 204 Synthesis of xanthenes using CuS quantum dots (QDs) catalyst Copper (I) sulfide QD-catalyzed synthesis of 4-phenyl-1H-1,2,3206 triazole Hydrogenation of imines from amines via hydrogen transfer using QD as 210 catalysts 213 C–C bond formation using quantum dot as photoredox catalysts 217 Pd–Ag@CQD nanohybrid for the Suzuki Coupling Graphene quantum dots functionalized Fe3O4 nanoparticles supported 219 PdCu for Sonogashira coupling Piperidine-functionalized Fe3O4 supported graphene quantum dots for 222 the synthesis of 2-aminochromenes 225 CuS QD catalyzed synthesis of DHPMS Synthesis of hydrophobic cellulose aerogel-based graphene quantum dot/Pd as heterogeneous catalyst in oxidation of alcohols and 228 alkenes Iron oxide nanoparticles modified with carbon quantum nanodots for the 231 Suzuki reaction Synthesis of indeno and acenaphtho cores using SnO2 quantum 233 dot Uncapped SnO2 quantum dot catalyzed rapid and green synthesis of 235 pyrano[2,3-c] pyrazole and spiro-2-oxindole derivatives 238 Future aspects of QD 239 Advantages and limitations 240 Conclusion 240 List of abbreviations 242 References

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Contents

Sasadhar Majhi 7 Synthesis of bioactive natural products and their analogs at room 259 temperature – an update 259 7.1 Introduction 7.2 Applications of the total synthesis of bioactive natural products and their 261 analogs at room temperature 261 7.2.1 Antibiotic 262 7.2.2 Polyketide 266 7.2.3 Macrolide 277 7.2.4 Terpene 280 7.2.5 Miscellaneous 282 7.3 Conclusions 283 References Kantharaju Kamanna and Yamanappagouda Amaregouda 8 Synthesis of bioactive scaffolds catalyzed by agro-waste-based solvent 287 medium 288 8.1 Introduction 292 8.2 Multicomponent reactions 8.2.1 Extraction and characterization of agro-waste ash powder or extract 294 solution 8.2.2 Homogeneous agro-waste solvent media used for the organic scaffolds 296 synthesis 314 8.2.3 Heterogeneous agro-waste for organic scaffolds synthesis 320 8.3 Future perspectives and challenges of agro-waste catalyst 320 8.4 Conclusions 321 List of abbreviations 322 References Arvind Singh, Bhupinder Kaur, Aditi Sharma, Anu Priya, Manmeet Kaur, Mussarat Shamim and Bubun Banerjee 9 One-pot multi-component synthesis of diverse bioactive heterocyclic scaffolds involving 6-aminouracil or its N-methyl derivatives as a versatile 331 reagent 331 9.1 Introduction 9.2 Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR 332 in water 332 9.2.1 Synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine-diones 9.2.2 Synthesis of Spiro[pyrimido[4,5-b]quinoline-5,5-pyrrolo[2,3-d]pyrimi332 dine]-pentaones

Contents

9.2.3 9.2.4 9.2.5 9.2.6 9.3 9.3.1 9.3.2 9.3.3 9.3.4 9.3.5 9.4 9.4.1 9.4.2 9.4.3 9.4.4 9.4.5 9.4.6 9.4.7 9.4.8 9.4.9 9.5 9.5.1 9.5.2 9.6

XI

Synthesis of isoxazolo[5,4-b]quinolin-4-yl)pyrimidine-2,4(1H,3H)-diones 334 and isoxazolo[5,4-b]quinolin-4-yl)-1H-pyrazol-5-amines 335 Synthesis of functionalized dihydropyrido[2,3-d]pyrimidines 335 Synthesis of polyfunctionalized pyrido[2,3-d]pyrimidines 337 Synthesis of 5-aryl-pyrimido[4,5-b]quinoline-2,4,6-triones Solvent-free synthesis of heterocycles involving 6-amino-1,3-dimethyl 337 uracil via MCR 338 Synthesis of novel pyrimidinedione derivatives 339 Synthesis of pyrimido[4,5-d]pyrimidine-2,4-diones 339 Synthesis of naphthopyranopyrimidines 340 Synthesis of spiro pyridodipyrimidines 342 Synthesis of pyrido[2,3-d]pyrimidines Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR 342 in alcohol 342 Synthesis of pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones 343 Synthesis of fused pyridines 343 Synthesis of substituted pyrimido[4,5-d]pyrimidones Synthesis of 6-(phenylsulfonyl)-5-(aryl)-6,8a-dihydropyrido[2,3-d]pyrim344 idine-2,4-diones 344 Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines Synthesis of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d] 345 pyrimidines 346 Synthesis of pyrido[2,3-d]pyrimidines Synthesis of 1,4-dihydrobenzo[b][1,8]-naphthyridines and pyrano[2,3-b] 347 quinolines Synthesis of hexahydropyrimido[4,5-b]-1,8-naphthyridine 348 derivatives Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR 349 in acetic acid Synthesis of naphthaquinone and pyrimidine fused 1,4349 dihydropyridines Synthesis of 5-unsubstituted 6-(benzimidazol-2-yl)pyrido[2,3-d]pyr350 imidino-2,4(1H,3H)-diones 351 Conclusions 352 References

Aparna Das, Ram Naresh Yadav and Bimal Krishna Banik 10 Conceptual design and cost-efficient environmentally Benign synthesis of 357 beta-lactams 357 10.1 Introduction 358 10.2 Synthesis of beta-lactams

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10.2.1 10.2.2 10.2.3 10.2.4 10.2.5 10.2.6 10.2.7 10.2.8 10.3

Index

Contents

Results with acid derivatives under different conditions 358 360 Discussions of the results with acid derivatives 365 Indium-catalyzed glycosylation of amino β-lactams 367 Synthesis of pyrrole-substituted β-lactams 369 Azide-alkyne cycloaddition in β-Lactams Cycloaddition with sterically hindered imines: Synthesis of 374 β-Lactams 377 Michael reaction toward polycyclic oxazepenes Synthesis of two isomers of thienamcin side chain via 380 glycosylation 384 Conclusion 384 References 389

List of contributing authors Mohamed Abd-Elmonem Chemistry Department Faculty of Science Minia University Minia 61519 Egypt Sabir Ahammed Department of Chemistry Bankura Sammilani College Kenduadihi Bankura 722 102 West Bengal India E-mail: [email protected] Yamanappagouda Amaregouda School of Basic Sciences Department of Chemistry Rani Channamma University P-B, NH-4 Belagavi 591156 Karnataka India Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo Bathinda Punjab 151302 India E-mail: [email protected] Bimal Krishna Banik Department of Mathematics and Natural Sciences-Core Curriculum Prince Mohammad Bin Fahd University Al Khobar, 31952 Kingdom of Saudi Arabia E-mail: [email protected]

https://doi.org/10.1515/9783110797428-202

Pooja A. Chawla Department of Pharmaceutical Chemistry ISF College of Pharmacy Moga Punjab 142001 India and Department of Pharmaceutical Analysis ISF College of Pharmacy Moga 142001 India E-mail: [email protected] Aparna Das Department of Mathematics and Natural Sciences-Core Curriculum Prince Mohammad Bin Fahd University Al Khobar, 31952 Kingdom of Saudi Arabia Dwaipayan Das Department of Chemistry University of Calcutta Kolkata 700009 India Asish R. Das Department of Chemistry University of Calcutta Kolkata 700009 India E-mail: [email protected] or [email protected] Mohamed Abou Elsebaa Chemistry Department Faculty of Science Minia University Minia 61519 Egypt

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List of contributing authors

Jyothylakshmi Jayakumar Department of Chemistry Vellore Institute of Technology Vellore Tamil Nadu, 632014 India

Maiiada Hassan Nazmy Biochemistry Department Faculty of Pharmacy Minia University Minia 61519 Egypt

Kantharaju Kamanna School of Basic Sciences Department of Chemistry Rani Channamma University P-B, NH-4 Belagavi 591156 Karnataka India E-mail: [email protected]

Anu Priya Department of Chemistry Akal University Talwandi Sabo Bathinda Punjab 151302 India

Bhupinder Kaur Department of Chemistry Akal University Talwandi Sabo Bathinda Punjab 151302 India Manmeet Kaur Department of Chemistry Akal University Talwandi Sabo Bathinda Punjab 151302 India Sasadhar Majhi Department of Chemistry (UG & PG) Triveni Devi Bhalotia College Kazi Nazrul University Raniganj West Bengal 713347 India E-mail: [email protected] Ramadan Ahmed Mekheimer Chemistry Department Faculty of Science Minia University Minia 61519 Egypt

Brindaban C. Ranu School of Chemical Sciences Indian Association for the Cultivation of Science Jadavpur Kolkata 700032 India E-mail: [email protected] Sabbasani Rajasekhara Reddy Department of Chemistry Vellore Institute of Technology Vellore Tamil Nadu, 632014 India E-mail: [email protected] Kamal Usef Sadek Chemistry Department Faculty of Science Minia University Minia 61519 Egypt E-mail: [email protected] Moumita Saha Department of Chemistry University of Calcutta Kolkata 700009 India

List of contributing authors

Chandrakant Sahu Department of Pharmaceutical Chemistry ISF College of Pharmacy Moga Punjab 142001 India

Sharma Arvind Virendra Department of Pharmaceutical Chemistry ISF College of Pharmacy Moga Punjab 142001 India

Mussarat Shamim Department of Chemistry University of Jammu Jammu India

Simranpreet K. Wahan Department of Pharmaceutical Chemistry ISF College of Pharmacy Moga Punjab 142001 India

Aditi Sharma Department of Chemistry Akal University Talwandi Sabo Bathinda Punjab 151302 India Sangeeta Sharma Department of Applied Science & Humanities Shaheed Bhagat Singh State University Ferozepur Punjab 152004 India Arvind Singh Department of Chemistry Akal University Talwandi Sabo Bathinda Punjab 151302 India

Ram Naresh Yadav Department of Chemistry Faculty of Engineering & Technology Veer Bahadur Singh Purvanchal University Jaunpur Uttar Pradesh India

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Sabir Ahammed and Brindaban C. Ranu*

1 Copper nanoparticles catalyzed carbon– heteroatom bond formation and synthesis of related heterocycles by greener procedures Abstract: A variety of procedures for the carbon–nitrogen, carbon–oxygen, carbon– sulfur and carbon–selenium bond formation using copper nanoparticles in greener conditions have been highlighted. The synthesis of several heterocyclic compounds of biological importance has also been reported using these protocols. Keywords: carbon–hetero atom bond formation; cross coupling reaction; Cu nanoparticle; green nanotechnology; transition meal catalysis.

1.1 Introduction The last two decades have witnessed a massive growth in the field of nanoscience and nanotechnology. The easy accessibility to nanoparticles has accelerated investigations on their applications in other areas. The recent reports showed remarkable level of their performance as catalysts in chemical reactions in terms of reactivity, selectivity and yields of products. Thus, efforts have been made to investigate the potential of environmentally benign and inexpensive metal nanoparticles in organic transformations, particularly the functionalization of molecules. The carbon–carbon bond formation by cross coupling reaction catalyzed by transition metals is an important milestone in organic synthesis. Later this approach has been successfully extended to the carbon–heteroatom bond formation too. Copper metal has been found to have wide applications in organic synthesis, particularly carbon–carbon bond formation during last century [1–3]. In recent times copper nanoparticles demonstrated improved efficiency as catalyst for carbon–carbon as well as carbon–heteroatom bond formation and have been used for the synthesis of aryl sulfides, aryl selenides, aryl and vinyl dithiocarbamates, aryl amines by reduction of aromatic nitro compounds and azides and other organic transformations [4–10]. The objective of this article is to highlight the various applications of benign copper nanoparticles for different reactions in organic synthesis and development of green procedures for the synthesis of useful molecules. *Corresponding author: Brindaban C. Ranu, School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India, E-mail: [email protected] Sabir Ahammed, Department of Chemistry, Bankura Sammilani College, Kenduadihi, Bankura 722 102, West Bengal, India, E-mail: [email protected]. https://orcid.org/0000-0002-2555-7054 As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. Ahammed and B. C. Ranu “Copper nanoparticles catalyzed carbon–heteroatom bond formation and synthesis of related heterocycles by greener procedures” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0083 | https://doi.org/ 10.1515/9783110797428-001

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1 Copper NPs catalyzed carbon-heteroatom bond formation

1.2 Carbon–heteroatom bond formation 1.2.1 C–N bond formation The formation of C–N bond is of much significance as it provides a powerful tool for the synthesis of various compounds with biological [11, 12] and material [13] importance. In 2007, Punniyamurthy and co-workers reported a C–N cross coupling reaction of amines with aryl halides catalyzed by CuO nanoparticles (particle size of 33 nm with surface area of 29 m2/g) (Scheme 1.1) [14]. In this reaction, aryl iodide gives slightly better yield than aryl bromides and chlorides. The anilines bearing electron-donating groups exhibit greater reactivity in comparison to those having electron-withdrawing groups. The reaction conditions required a combination of DMSO and KOH as solvent and base respectively. From the mechanistic studies, it is suggested that the reaction might occur via oxidative addition followed by reductive elimination. The catalyst is simple, robust and recyclable without loss of activity. Li reported a solvent-free N-arylations of nitrogen-containing heterocycles with aryl and heteroaryl halides catalyzed by copper(I) oxide nanoparticles [Cu2O] (Scheme 1.2) [15]. Among the various shapes of Cu2O NPs (NPs: nanoparticles) only the cubic form of the nanoparticles is effective for this reaction. Among the N-containing heterocycles, triazoles and indoles showed good reactivity with aryl iodide in the presence of 1,10-phenanthroline ligand to give high yield of the products. The hindered as well as unhindered imidazoles underwent reaction with aryl halides without any difficulty to give good to excellent yield of products. Another work of Cu2O nanoparticles catalyzed C–N cross coupling reaction has been reported by Punniyamurthy et al. (Scheme 1.3) [16]. In this reaction, copper iodide is treated with KOH to form Cu(I) NPs which catalyzes the amidation of aryl iodides. For the preparation of Cu2O nanoparticles, PEG (polyethylene glycol) is used to facilitate the formation and stabilization of NPs. The Cu2O nanoparticles were prepared by treatment of CuI with KOH in the presence of PEG. The coupling reaction using Cu2O NPs provided the best results compared to commercially available Cu2O, CuO nanoparticles, CuSO4·5H2O and CuCl2·2H2O salts. The size of the Cu2O nanoparticles ranges from 7 to 10 nm. After the completion of the cross-coupling reaction, Cu2O nanoparticles were separated by centrifugation and reused for the next reaction. The reaction of aliphatic and aromatic amides with various aryl iodides provided the corresponding products in high yields. Aliphatic amides are found to be more effective for the coupling reaction compared to the aromatic one. Rao and his groups developed an efficient and straight forward ligand free protocol for the cross-coupling of vinyl halides and imidazoles catalyzed by CuO nanoparticle to provide N-vinylimidazoles (Scheme 1.4) [17]. In this reaction, the increase of amount of CuO nanoparticles from 1.0 to 1.5 mol% gave best yield of the product. The reaction

1.2 Carbon–heteroatom bond formation

3

Scheme 1.1: Reaction of aryl and alkyl amines with iodobenzene.

was optimized with several copper salts e.g. Cu(acac)2, CuI etc. for the synthesis of N-vinylimidazoles, and it was observed that the combination of nano CuO with KOH in DMSO offered the best result. Different types of imidazoles and benzimidazoles reacted efficiently with various vinyl iodides to give a broad spectrum of the corresponding products with moderate to excellent yield. On the other hand, the coupling of vinyl bromides with imidazoles was slow. This reaction required longer time and produced lower yield of the desired product compared to its iodo substrate. The reaction did not

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.2: N-arylations of nitrogen-containing heterocycles using Cu NPs.

proceed at all when electron-withdrawing group substituted imidazoles were used. The geometry of double bond of the product remains unchanged during the reaction. The CuO nanoparticles can be filtered, separated and recycled for the next step up to four cycles. Yuan and his group reported the preparation of DMAP (dimethylaminopyridine) stabilized Cu-NPs in monodispersed state in solution [18]. DMAP plays the role of

1.2 Carbon–heteroatom bond formation

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Scheme 1.3: Cu NPs catalyzed N-Arylation of benzamide with aryl iodide.

stabilizing agent and it can also alter the electronic state of copper due to its electron donating nature. The size distribution of the nano particle is in the range of 5–10 nm. DMAP-Cu NPs were prepared by using controlled decomposition of a DMAP-Cu(acac)2carbohydrazide complex in ethanol. Then solvent was evaporated to get the dried DMAP-Cu NPs catalyst. The DMAP-Cu NPs catalyzed the cross-coupling reaction of hexyl amine and substituted imidazole with aryl halide (Scheme 1.5). A high stereoselectivity is observed when an optically active amino alcohol is used in N-arylation reaction. The unique feature in this protocol is the reactivity of substrates having steric hindrance. Bulky pyrazole reacts with aryl halide without any difficulty. The recyclability of the DMAP-Cu NPs catalyst was checked by using the catalyst upto five cycles and a loss of activity to the extent of 10% was observed. The size distribution of the nanoparticle is in the range of 5–10 nm.

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.4: CuO NPs catalyzed cross-coupling reaction of styrenyl halides with imidazole/ benzimidazole.

Rawat et al. reported the synthesis of benzimidazole using CuI nanoparticle as a catalyst (Scheme 1.6) [19]. The traditional method for benzimidazole synthesis involved the condensation of o-phenylenediamine with carboxylic acid/carboxylate ester at high temperature in the presence of a strong acid. Rawat and his group modified the reaction condition by using oxygen as green oxidant. CuI nanoparticle was found to be stable under optimized reaction condition. The catalyst was very effective and could be recycled upto five runs without appreciable loss of product yield. CuI NPs was easily separated from reaction mixture by centrifugation method. Several substituted o-phenylenediamines reacted with a variety of aromatic aldehydes to produce the corresponding products. The aldehydes containing electron withdrawing substituent produced better yield in comparison to those with electron donating substituent. It was observed that para-substituted aryl aldehydes gave higher yield than ortho-substituted ones due to steric hindrance. o-Phenylenediamine derivative produced maximum yield when it has electron donating substituent in the para position.

1.2 Carbon–heteroatom bond formation

Scheme 1.5: DMAP-Cu NPs catalyzed N-arylation of heterocycles/β-amino alcohol.

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.6: Cyclization of substituted O-phenylenediamine with benzaldehyde using Cul NPs.

Gomez and his group demonstrated the preparation of Cu(I) oxide nanoparticle stabilized by poly(vinylpyrrolidine) in glycerol [20]. In this transformation dihydrogen has been used as the reducing agent and copper(II) acetate as copper source. It was observed that Cu/monomer ratio was kept in 1:10 for avoiding the agglomerization of the formed nanoparticles. No reduction of metal was observed in the absence of H2 or PVP. The Cu2O NPs have been successfully applied to the C–N cross coupling reaction (Scheme 1.7). The catalyst was recycled at least ten times keeping its activity and selectivity unaffected. Aryl iodides with electron donating and withdrawing groups were efficiently coupled with different types of primary amines as well as ammonia without any difficulty. Concerning the development of solid-supported nano-materials, Rawat and his group reported the preparation of inexpensive and environment friendly Cu(0) on alumina/silica catalyst and used it for the N-arylation reaction (Scheme 1.8) [21]. The copper nanoparticles on alumina/silica (Cu(0)@Al2O3/SiO2) was prepared from copper nitrate salt impregnated in alumina/silica followed by calcination at high temperature and reduction by applying hydrogenation technique. The catalyst can be used several times for subsequent runs. From ICP-AES analysis, it was observed that no leaching of reused Cu(0)@Al2O3/SiO2 catalyst occurred. The TON and TOF of the catalyst exhibited

1.2 Carbon–heteroatom bond formation

9

Scheme 1.7: Cu2O NPs catalyzed C–N cross coupling of aryl iodide with aliphatic amines.

higher value compared to other Cu(0) NPs catalyst. They further broadened the scope of the impregnated copper nanoparticle catalyst by the coupling of different substituted amines with aryl chlorides, which are usually inert under traditional conditions. In general, the reaction proceeds smoothly to provide moderate to high yield of products. Aryl amines containing electron donating substituent (–Me, –OMe, –iPr) in para position provided excellent yield whereas the presence of –I group (–OMe) in the meta position reduced the yield of the product. A variety of N-arylated products by the reaction of different types of N-heterocycles such as imidazole, benzimidazole and triazole with halo benzene were synthesized. Electron deficient heteroaryl chlorides also produced high yields. In recent years, cross dehydrogenative coupling (CDC) reaction has emerged as a powerful tool in organic synthesis to construct C–C and C-hetero atom bond [22–24]. Cross dehydrogenative coupling (CDC) of 3° amine with terminal alkyne catalyzed by

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.8: Cu(0)@Al2O3/SiO2 catalyzed N-arylation of heterocyclic and secondary amines with aryl chlorides.

Zeolite Y supported Cu nanoparticles was investigated by Moglie and his group (Scheme 1.9) [25]. Cu NPs/ZY catalysts were prepared through impregnation and reduction method by thermal treatment. From TEM analysis, it was clear that size of the spherical monodispersed nanoparticles were 1.7 ± 0.7 nm. It was found that 1.5 mol% of catalyst with TBHP as oxidant at 70 °C is the best (optimized) condition for an efficient reaction. A variety of substituted tertiary amines including benzyl, aryl and alkyl groups were coupled with both aliphatic and aromatic terminal alkynes in the presence of Cu NPs on Zeolite leading to the corresponding propargyl amines in good to excellent yields (Scheme 1.9). The unique feature of the catalyst is that it restricts homo-coupling of

1.2 Carbon–heteroatom bond formation

Scheme 1.9: CDC of tertiary amines and terminal alkynes catalyzed by Cu NPs/ZY.

Scheme 1.10: Cross dehydrogenative coupling of 3° amines and alkynes catalyzed by Cu NPs/ZY.

11

12

1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.11: Cu@Fe2O3 nanoparticle catalyzed synthesis of aminoindolizine.

1.2 Carbon–heteroatom bond formation

13

Scheme 1.12: CuO NPs catalyzed N-Arylation of acyclic, cyclic amides and aryl amines.

terminal alkynes completely (Scheme 1.10). The CDC coupling is highly regioselective towards the attack of N-nucleophile to the terminal position of alkynes. Recently, magnetically separable nano material is of increasing interest as a green and sustainable catalyst as it offers cost-effectiveness, eco-friendliness and easy recoverability by external magnetic bar [26–28]. Rawat and his group demonstrated a green and efficient preparation of CuO and Cu2O mixed oxide nanoparticle supported on hematite (Cu@Fe2O3) and the potential of the catalyst was explored for C–N cross coupling reaction to synthesize aminoindolizines and pyrrolo [1,2-a]quinolines (Scheme 1.11) [29]. The Cu NPs on hematite (Cu@Fe2O3) was synthesized by using onestep hydrothermal method taking FeCl3, CuCl2, urea and aqueous NH3 in the presence

14

1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.13: CuO NPs catalyzed N-Arylation of N-heterocycles.

of glucose at 180 °C for 8 h. A series of diversely substituted aromatic alkynes underwent reactions with various secondary amines e.g. morpholine, N-methylaniline, phenylpiperazine along with the derivative of 2-pyridine carbaldehyde to provide aminoindolizine and pyrrolo [1,2,a]quinoline derivatives. The catalyst was recovered and was recycled upto six times with marginal loss of activity during subsequent runs. Biogenic synthesis of metal oxide nanoparticle is of increasing attention as these protocols are eco-friendly, cost-effective and they use readily available plant extract [30–32]. These methods of preparation are superior due to pH independence, use of no harmful chemicals as reducing agent and avoidance of vigorous reaction condition. Islam and his group reported the biosynthesis of CuO NPs from ocimum sanctum leaf extract at room temperature. The biogenic CuO NPs exhibited higher catalytic activity towards N-arylation of cyclic and acyclic amines with aryl and styryl halides (Scheme 1.12) [33]. This catalyst provides several advantages such as milder reaction condition, high functional group tolerance, excellent yield compared to other methods. This C–N cross coupling was also extended for the synthesis of indole, pyrrole, imidazole, benzimidazole and carbazole derivatives (Scheme 1.13). Ortho substituted

1.2 Carbon–heteroatom bond formation

15

Scheme 1.14: Cu-nanoparticle catalyzed O-arylation of phenols.

(E )- styryl bromides coupled with pyrolidinone smoothly affording enamides with high streoselectivity.

1.2.2 C–O bond formation Diaryl ethers are an important class of organic compounds as they exhibit useful biological activities [34], and are used in polymer industry [35]. The traditional method for the formation of C(aryl)–O bond is Ullmann coupling reaction [36]. Apart from that, Buchwald [37], Hartwig [38], Evans [39] and Chan [40] couplings are also widely utilized for the formation of diaryl ether derivatives. In the last decade, a lot of significant developments have been made by using Cu NPs as a catalyst. Majumdar and co-workers have reported an efficient methodology for the coupling of phenols with aryl halide in the presence of copper nanoparticles (Scheme 1.14) [41]. The Cu NPs catalyst was prepared in an aqueous core of reverse miceller droplet and the

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.15: Cu2O nanocube catalyzed C–O cross coupling reactions.

sizes were in the range of 10–70 nm. The catalyst was recycled and reused for four times. Phenols attached with electron-donating groups afforded better yields compared to those with electron-withdrawing groups. Park et al. reported a unique procedure for the preparation of Cu2O nanocube using poly(vinylpyrrolidone) (PVP) as surfactant and 1,5-pentanediol (PD) as reductant in a solvent (Scheme 1.15) [42]. The SEM and TEM image confirm that the size of the monodispersed cubic Cu2O nanoparticles were in the range between 45.1 ± 3.1 nm. They reported an efficient coupling of phenols with aryl halide in the presence of Cu2O nanocube in THF at 150 °C. The catalyst was separated and reused for at least three times. It was observed that the relative reactivity order of aryl halides was ascertained as: Ar–I > Ar–Br > Ar–Cl. The attachment of electron-withdrawing or electron-donating substituent affects the rate of the reaction.

1.2 Carbon–heteroatom bond formation

17

Scheme 1.16: Cu nanoparticle catalyzed synthesis of arylbenzoxazoles.

Heterocyclic scaffolds are very useful precursor to many biologically active compounds [43]. Kidwai and co-workers have developed the synthesis of benz-fused heterocycles by coupling of 2-aminophenol with aromatic or hetero aromatic aldehyde catalyzed by Cu NPs (Scheme 1.16) [44]. In the first step of the reaction mechanism, 2-aminophenol condensed with aromatic aldehyde in the presence of Cu NPs to form Schiff’s base which further underwent cyclization to give 2-phenylbenzoxazole derivative. The catalyst was recycled and reused for four to five runs. Recently Sun and his group developed a magnetically separable efficient CuFe2O4 nano catalyst for the C–O cross coupling of phenol with aryl halide (Scheme 1.17) [45]. They demonstrated that the presence of iron as a co-catalyst accelerated the rate of cross coupling reaction. The electron deficient aryl iodide and electron rich phenols were the best combination to give excellent yields. The steric hindrance of phenol did not have much effect for this reaction. It was observed that aryl bromide reacts less efficiently than aryl iodide, whereas aryl chlorides remained unreactive under the optimized condition.

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.17: Magnetically separable CuFe2O4 NPs catalyzed O-arylation.

Recently Ahn et al. reported a microporous covalent triazine polymer supported copper nanoparticle (Cu@MCTP-1) and used this material as catalyst for Ullmann coupling reaction to obtain several aryl ethers using a variety of aryl halides and phenols in the absence of any external ligand (Scheme 1.18) [46]. The catalyst was recovered easily by centrifugation and reused up to five times. The progress of the reaction was very slow when the reaction was performed using the homogeneous Cu salt catalysts and the yield of product was relatively low.

1.2.3 C–S bond formation Organic sulphides have attracted considerable interest in recent times because of their biological activity [47], application in organic materials [48] and use as intermediates

1.2 Carbon–heteroatom bond formation

19

Scheme 1.18: Cu@MCTP-1 catalyzed O-arylation of aryl halides with various phenols.

in organic synthesis [49]. Moreover, methodologies have been developed to synthesize important aryl sulphides to treat Alzheimer’s and Perkinson diseases [50], cancer [51] and HIV [52]. The traditional method used for C(aryl)–S bond formation is the crosscoupling reaction of thiols with aryl halides in the presence of copper and ligand under harsh condition. To avoid these drawbacks, ligand free condition using recyclable nano-catalysts has been developed. Ranu and his group reported a new protocol for the synthesis of diaryl sulphides using aryl iodides with thiophenol in the presence of Cu nanoparticles under basic conditions applying microwave irradiation (Scheme 1.19) [53]. The electron-withdrawing as well as electron-donating substituent attached with aryl sulphide and aryl halide participated in this coupling reaction without any difficulty. Steric effect does not have much influence on the C–S coupling. The reaction shows chemo selectivity towards aryl iodide over aryl chloride. 20 mol% of copper nanoparticles were used to obtain the best yield of the product. A comparison was drawn between conventional method and microwave method and it was observed that the reported microwave assisted method

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.19: Cross-coupling reaction of aryl iodides with thiols catalyzed by Cu NPs.

using Cu NPs was superior in terms of reaction time and product yield. The reaction proceeded through a free radical pathway. A single electron transfer from copper catalyst to aryl halide initiates the reaction. In situ formed aryl radical combines with R-SH to provide the desired product. Another green and efficient procedure was developed by Ranu et al. for the synthesis of aryl and vinyl dithiocarbamates catalyzed by copper nanoparticles in water (Scheme 1.20) [54]. This one-pot three component reaction provides high distereoselectivity towards vinyl dithio carbamates also. A variety of substituted aryl halides (I, Br) and styrenyl bromide underwent coupling with dithiocarbamate ion, prepared in situ by the reaction with amine and carbon disulfide to produce the dithiocarbamate derivatives. The catalyst was recycled upto four times without appreciable loss of efficiency in terms of yield of the product. Nageswar and co-worker developed an eco-friendly and highly efficient protocol for the synthesis of aryl sulphides catalyzed by CuO NPs using aryl halides and inexpensive thiourea as sulphur source (Scheme 1.21) [55]. The objective of the use of thiourea is to avoid foul smell of thiols. The standardisation process established that DMF as

1.2 Carbon–heteroatom bond formation

21

Scheme 1.20: Copper nanoparticles catalyzed synthesis of aryl and styrenyl dithiocarbamate.

polar protic solvent and Cs2CO3 as base at 110 °C was the superior combination for this coupling reaction. It was observed that aryl halide attached with free amino group reacted smoothly to form symmetrical diaryl sulfides without any protection of amino group. The CuO nanoparticles were recycled four times without much loss of activity. Synthesis of unsymmetrical aryl sulphides are of much importance because of their biological activities and application as useful materials (Scheme 1.22) [56]. Kakulapati and his group demonstrated a synthesis of unsymmetrical organic sulphides using ethyl potassium xanthogenate and aryl halides catalyzed by CuO nanoparticles under ligand free condition [57]. In this method, hetero-thioethers were also obtained in moderate to high yield when several heteroaryl halides were coupled with various

22

1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.21: Copper nanoparticle catalyzed synthesis of symmetrical aryl sulfides.

thiophenols. Alkyl halides such as n-hexyl, -pentyl, cyclohexyl etc. underwent reaction to produce the unsymmetrical thio ethers without any difficulty. After the completion of reaction, the CuO NPs catalyst was separated, dried and recycled upto five runs. To check the industrial utility of this methodology, a large scale reaction was successfully performed with high product yield. Recently, Ranu et al. reported a magnetically separable copper nanoparticle catalyzed ligand free C–S cross-coupling reaction in water (Scheme 1.23) [58]. A variety of unsymmetrical aryl and heteroaryl sulphides were easily obtained by this method. Generally, sterically hindered sulphides are very difficult to achieve by the traditional coupling methods. They have investigated particularly the reaction of sterically hindered aryl halides with bulky thiols and found that they smoothly reacted to produce high yield of the products. Another unique feature of this protocol is the high stereoselectivity of the product when styrenyl halides coupled with thiols. Different types of mono and di-styrenyl bromide reacted with aryl and heteroaryl sulphides to produce high yield of the corresponding products maintaining the stereoselectivity. The reactions of thiols and dithiols with aryl dihalides were also performed and several acyclic and cyclic bis-sulfides were obtained by this protocol. This method is equally

1.2 Carbon–heteroatom bond formation

23

Scheme 1.22: CuO nanoparticle catalyzed synthesis of thioethers with aryl halides.

efficient for the reaction of heteroaryl halide with heteroaryl thiol to obtain diheteroaryl sulphide. The catalyst was easily recovered by an external magnet and recycled for ten times without any substantial loss of activity.

1.2.4 C–Se bond formation Organo selenium compounds are of much importance as anti-cancer and antioxidant agents [59]. Traditionally, organoselenides are prepared by the reaction of aryl halides with selenol (R-Se-H) or selenoate anion catalyzed by palladium metal [60]. Due to the foul smell and toxicity of selenol, it cannot be considered as green reagent. Thus a number of methods have been developed by using cheap and inexpensive copper catalyst and modified selenium reagent for selenylation. Among these protocols, Ranu and his group developed a green procedure for selenylation of aryl and vinyl halides with diphenyl diselenides catalyzed by copper nanoparticles in water (Scheme 1.24) [61]. Aryl halides attached with electron-donating

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.23: CuFe2O4 catalyzed C–S bond formation in water.

and electron-withdrawing substituent produced moderate to good yield of products. In case of styrenylation, it was observed that (E )-styrenyl halide maintained high streoselectivity as it produced (E )-styrenyl selenides whereas (Z ) isomer produces mixture of (E ) and (Z )-styrenyl selenides. Due to the agglomerisation tendency of Cu NPs, it could not be reused for the coupling reaction after four runs. An efficient C–Se cross coupling reaction of aryl halides/aryl boronic acids and seleno urea catalyzed by copper oxide nanoparticle under ligand-free condition has been developed by Rao et al. (Scheme 1.25) [62]. Using this protocol a variety of symmetrical diaryl selenides have been synthesized in good to excellent yield. The reaction of heteroaryl halides with selenourea went smoothly without any difficulty. Among aryl halides, aryl iodides showed better reactivity compared to bromides and chlorides. The catalyst retained its high level of efficiency even after the fourth cycle.

1.2 Carbon–heteroatom bond formation

25

Scheme 1.24: Phenyl-selenylation of aryl iodides and vinyl bromides using Cu nanoparticles.

Park and his group introduced a new procedure for the preparation of Cu NPs from copper metal-organic framework [Cu3(BTC)2] and immobilization of nanoparticles onto activated charcoal (AC) at room temperature under sonication (Scheme 1.26) [63]. The heterogeneous Cu NPs/AC catalyst has been successfully applied in C–Se cross coupling reaction to give unsymmetrical organo selenides from aryl boronic acids with excellent yield. This protocol was extended to the alkyl/benzyl substrate in addition to aryl selenides. Pinacol ester of alkenyl boronic acid was also coupled with diphenyl diselenides easily to form aryl-alkynyl selenides. Various substituted aryl and heteroaryl boronic acids provided a library of unsymmetrical organoselenides. The Cu NPs/ AC was easily separated by centrifugation and recycled for five times.

26

1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.25: Synthesis of symmetrical diphenyl selenides.

1.2.5 C–P bond formation Organophosphorous compounds have received broad applications in catalysis, organic synthesis and medicinal as well as materials chemistry [64–66]. Thus, the C–P bond formation has drawn considerable interest in recent times. Radivoy and his group demonstrated ZnO supported Cu nanoparticle catalyzed synthesis of β-ketophophonates through C–P cross coupling reaction (Scheme 1.27) [67]. The Cu NPs were synthesized from CuCl2 salt by using fast reduction method. The size of mono dispersed Cu NPs was 6.0 ± 0.5 nm. A number of terminal aromatic and aliphatic alkynes were smoothly reacted with dialkyl phosphites to give the corresponding β-ketophosphonates in good to excellent yield. It was observed that aromatic alkynes produced exclusively β-ketophosphonates, whereas aliphatic alkynes provided inseparable E/Z isomer of vinyl phosphonates.

1.2 Carbon–heteroatom bond formation

27

Scheme 1.26: Synthesis of arylselenides via C–Se cross coupling catalyzed by copper nanoparticles.

As it appears from the discussion on the application of copper and other copper salt nanoparticles for various reactions, nanoparticles catalysts, in general, offer significant improvements in terms of yield, reaction time, selectivity compared to similar reactions using parent metals. Moreover, the catalyst loading of nanoparticles for efficient reactions are much less with respect to the parent metal counterpart. However, because of the tendency of the nanoparticles to agglomeration the nanoparticle catalyst cannot be recycled for more than a few runs. In addition, the Cu nanoparticles often need to be freshly prepared for better efficiency. Thus, the challenges to the chemists working in this area are to find suitable techniques to prevent agglomeration and use of copper nanoparticles for large scale reactions.

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1 Copper NPs catalyzed carbon-heteroatom bond formation

Scheme 1.27: Synthesis of β-ketophosphonates and vinyl phosphonates.

1.3 Conclusions This chapter highlights the recent developments on the copper nanoparticles catalyzed carbon–heteroatom bond formation. Basically, carbon–nitrogen, carbon–oxygen, carbon–sulfur and carbon–selenium bond formations have been discussed. Copper nanoparticles are relatively benign, inexpensive and readily accessible. Many of these reactions have been performed in water or less toxic solvents under ligand free conditions and thus these procedures meet the basic requirements of a green process.

References

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Several useful heterocyclic compounds have been obtained using these protocols. We believe, this article will be of much interest to the practising chemists in academia as well as industry.

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61. Saha A, Saha D, Ranu BC. Copper nano-catalyst: sustainable phenyl-selenylation of aryl iodides and vinyl bromides in water under ligand free conditions. Org Biomol Chem 2009;7:1652–7. 62. Reddy VP, Kumar AV, Rao KR. Unexpected C-Se cross-coupling reaction: copper oxide catalyzed synthesis of symmetrical diaryl selenides via cascade reaction of selenourea with aryl halides/ boronic acids. J Org Chem 2010;75:8720–3. 63. Mohan B, Yoon C, Jang S, Park KH. Copper nanoparticles catalyzed Se(Te)-Se(Te) bond activation: a straightforward route towards unsymmetrical organo-chalcogenides from boronic acids. ChemCatChem 2015;7:405–12. 64. Engel R. Phosphonates as analogues of natural phosphates. Chem Rev 1977;77:349–67. 65. Tang W, Zhang X. New chiral phosphorus ligands for enantioselective hydrogenation. Chem Rev 2003;103:3029–37. 66. Chou HH, Cheng CH. A highly efficient universal bipolar host for blue, green, and red phosphorescent OLEDs. Adv Mater 2010;22:2468–71. 67. Gutierrez V, Mascaro E, Alonso F, Moglie Y, Radivoy G. Direct synthesis of β-ketophosphonates and vinyl phosphonates from alkenes or alkynes catalyzed by Cu NPs/ZnO. RSC Adv 2015;5:65739–44.

Simranpreet K. Wahan, Sangeeta Sharma and Pooja A. Chawla*

2 Synthesis of quinazolinone and quinazoline derivatives using green chemistry approach Abstract: Green chemistry has been most compelling area of research. Green chemistry is vital to long-term sustainability, not only because of its fundamental notion of reducing the use and manufacture of hazardous materials, but also because of its broad applicability as one of the most efficient and problem-solving pathways for the synthesis of new materials. Various chemists have studied a plethora of strategies to lessen the release of hazardous chemical waste, waste material recyclization and reuse. New techniques have been created based on a green chemistry strategy that includes the utilization of catalysts, nanosized materials and composites, such as metal and nonmetal nanoparticles, their oxides and salts, and different heterocyclic rings. Quinazolines and quinazolinones are biologically significant heterocyclic rings with a wide range of characteristics. In a summary, this chapter focuses on recent novel synthesis methods for quinazoline and quinazolinone derivatives, which are vital to humanity. Keywords: heterocycles; metal-free synthesis; microwave assisted synthesis; multicomponent reactions.

2.1 Introduction Green chemistry, coined by scientist Paul T. Anastas, has piqued organic and medicinal chemists’ interest in the synthesis of key heterocyclic rings [1–5]. The 12 principles of green chemistry are centered on minimal waste production, the use of safer chemicals and solvents, the use of catalysts to construct efficient synthesis methods, waste material degradation design and the use of safer chemistry for accident prevention [6–9]. The green chemistry concept encourages the discovery of novel chemical reactivities and reaction conditions that might possibly improve chemical syntheses in terms of resource and energy efficiency, product selectivity, ease of operation and human health and the environment safety [10–13]. Before being released to the environment, the residues created in chemical-pharmaceutical analyses must be pre-treated. Greener

*Corresponding author: Pooja A. Chawla, Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab 142001, India, E-mail: [email protected] Simranpreet K. Wahan, Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab 142001, India Sangeeta Sharma, Department of Applied Science & Humanities, Shaheed Bhagat Singh State University, Ferozepur, Punjab 152004, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. K. Wahan, S. Sharma and P. A. Chawla “Synthesis of quinazolinone and quinazoline derivatives using green chemistry approach” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0223 | https://doi.org/10.1515/9783110797428-002

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strategies have been used to build well-known chemical compounds and novel materials using through more sustainable routes [14]. Earlier developed approaches involved in the synthesis have been modified due to the progress of industrialization, a watershed moment in world economic development. Since the 1940s, social movements have transformed green chemistry, resulting in shifts in industrial roles and sustainable processes, as well as improvements in environmental effect and population awareness [15–17]. Efforts have been made to overlap principles for economic bulk production with principles of green chemistry [18, 19]. A plethora of synthetic approaches have been developed by various scientists that have not only reduced harmful impact on the environment but also helped to maintain the economic efficacy of the reaction process [20, 21]. Figure 2.1 depicts 12 principles of green chemistry. According to the US retail market in 2020–2021, heterocyclic moieties constitute the fundamental skeletons for 80% of commercial medications [22], however, many real synthesis techniques are not sustainable, necessitating eco-friendly tactics [23]. Not only are heterocyclic ring containing compounds found as the backbone in a variety of physiologically active natural items utilised as traditional medicines but some of their synthetic derivatives in various sizes are now prescribed and marketable drugs [24, 25]. Furthermore, N-based heterocycles serve as scaffolds in the majority of

Figure 2.1: Twelve principles of green chemistry.

2.2 Use of catalyst for preparing quinazolinone derivatives

35

vitamins, nucleic acids, enzymes, co-enzymes, hormones, and alkaloids [26]. Many chemical complexes of importance in biology, pharmacology and medicine include heterocycles. Exploring new strategies or procedures for building and functionalizing these molecules has gotten a lot of attention recently, and it’s become one of the key foci of sustainable chemistry. Microwave-assisted synthesis, for example, generates compounds quickly and with high yields while using less energy [27]. Similarly, the use of metal-impregnated nanoparticles in nanoparticle-catalyzed synthesis provides advantages such as catalyst recyclability, high yields, and quick reaction times. Solvent-free synthesis, ionic liquid-supported synthesis, organic synthesis in water, sonochemical synthesis and combinatorial synthesis are some of the other environmentally friendly techniques [28, 29]. The utilization of other energy inputs (mechanochemistry, ultrasound- or microwave irradiation), photochemistry and greener reaction media as applied to the synthesis of organics and nanomaterials are abridged trends in greener and sustainable process development during the last 25 years. Eliminating solvents can reduce toxicity and danger, reduce waste and save time and resources in chemical processes, according to green chemistry principles [30]. Quinazoline and quinazolinones are privileged pharmacophore showing anticancer [31], antibacterial [32], antifungal [33], anticonvulsant [34], anti-inflammatory [35], anti-HIV [36], anti-Parkinsonism [37], analgesic [38] and other range of biological characteristics. The recent green synthesis advances of quinazolinone with a catalyst, metal-free synthesis and microwave aided synthesis are all covered in this chapter.

2.2 Use of catalyst for preparing quinazolinone derivatives Catalysts shorten the time taken for chemical reactions by decreasing the amount of energy required [39, 40]. Catalysts were increasingly used in industrial operations. Solid acids, unlike liquid acids, which have well-defined acid characteristics, can have a range of acid sites [41]. Nanoscience is one of the most important fields of current scientific research. Surface functionalization of mesoporous silica and silica-coated magnetite nanoparticles; in particular, have been extensively utilized as heterogeneous catalysts in the production of important organic and medicinal chemicals [42, 43]. Multi-component reactions (MCR) have been extensively explored because three or more reactants combine to form a single product along with definite characteristics from each reactant. Compared to traditional chemical reactions, MCRs have the benefit of simplicity and synthetic efficiency. Selectivity, synthetic convergency, and atom economy all are benefits of MCRs. Four component reactions were carried out by Balalaie and team to synthesize quinazolinone sulfonamide 5 with 72% yield in presence of heterogenous nano-catalyst using saccharin 3 as sulphur source for sulfonamide moiety (Figure 2.2). The reaction was carried out on solvent-free conditions

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Figure 2.2: Multicomponent reaction to develop quinazolinone sulfonamide.

and resulted in high yield thereby leading to the development of an efficient, simple and selective method as compared to the conventional approach [44]. In another discovery, one-pot synthesis of quinazolinone derivatives was explored. The method involved the study of 1,4-diazabicyclo[2.2.2]octane (DABCO)based ionic liquid catalysts which resulted in easy environment-friendly approach at mild conditions (Figure 2.3). The method involves reaction of aldehyde 6, β-ketones 7 and 2-aminobenzimidazole 7 using [DABCO](HSO3)2(Cl)2 and [DABCO](HSO3)2(HSO4)2 as a catalyst which proved to be a highly economically favourable reaction. In the suggested mechanism (Figure 2.4), knoevenagel condensation takes place between activated aldehyde to form an intermediate. The reaction can now proceed through two routes, in the first route intermediate formed loses water to form α, β-unsaturated carbonyl compound, followed by Michael addition reaction forms another intermediate which undergoes intramolecular cyclization to produce quinazolinone. In the other route, the carbonyl group which gets activated by H to form the ionic liquid which produces an intermediate that undergoes an intramolecular cyclization to produce the desired product [45]. Yu et al. further exploited one-pot synthesis by reacting ammonium formate, 2-nitroacetophenone 10, and aldehyde 11 in a single pot by using active AgPd nanoparticles fused on WO2.72 nanorods as a catalyst (Figure 2.5). The combined composition of AgPd nanoparticles clubbed with WO2.72 resulted as a promising catalyst in dehydrogenation reaction with a high percentage yield under mild conditions [46]. Khandebharad and team developed a newer approach for the synthesis of quinazolinone derivatives 14–16 by using triethanolamine (TEOA) as a catalyst which increased the solubility of reaction hence, increases the rate of reaction (Figure 2.6). The catalyst along with the use of sodium chloride not only controlled the hydrophobic interaction and formation of micelles but also brought about greater selectivity. The probable mechanism for the approach is depicted in Figure 2.7 [47].

Figure 2.3: Synthesis of quinazolinone using DABCO based ionic liquid catalysts.

2.2 Use of catalyst for preparing quinazolinone derivatives

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Figure 2.4: Mechanism of synthesis of quinazolinones using [DABCO](HSO3)2(Cl)2 and [DABCO](HSO3)2(HSO4)2 as a catalyst.

Figure 2.5: AgPd diffused WO2.72 nanorods to synthesize quinazoline derivatives.

Shendy and co-workers developed a green chemistry approach using acidicfunctionalised magnetic silica-based heterogeneous catalyst for preparing quinazolinone derivatives by reaction of diaminoglyoxime with anthranilic acid 18. The magnetic nanoparticles used were synthesized by co-precipitation reaction. Solution of ferric chloride and ferrous chloride was charged with ammonia solution followed by addition of isopropyl alcohol and TEOS (Figure 2.8). The silica-coated magnetite nanoparticles were removed by an external magnet and further treated with (3-aminopropyl)triethoxysilane in toluene. The amino-modified nano-particles were collected and functionalized by the solution of bromoacetic acid in acetonitrile [48]. 2-Aminobenzamide 22 was cyclized in presence of base Cs2CO3 in methanol which acted as both the C1-source and a green solvent (Figure 2.9). This new approach resulted in better yield as compared to earlier methods used. Also, the synthesis cost was highly

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Figure 2.6: Synthesis of quinazolinone derivatives by using triethanolamine.

Figure 2.7: Plausible mechanism of quinazolinone synthesis by using triethanolamine (TEOA) as a catalyst.

reduced as easily available copper catalyst Cu(OAc)2.H2O under atmospheric oxygen in ligand-free condition was used to catalyze the reaction. The mechanism for the reaction was proved in several experiments. In the proposed mechanism (Figure 2.10), methanol is oxidized in the presence of copper catalyst to produce formaldehyde which further reacts with 2-aminobenzamide in presence of Cs2CO3 to form imine intermediate which on intramolecular cyclization results in the formation of dihydro-quinazolinone, on further oxidation yields quinazolinone as a final product [49]. Amino glucose-functionalized silica-coated nanoparticles were developed and utilized by Keyhani et al. for the synthesis of azo-linked 2-aryl quinazolinones. In

2.2 Use of catalyst for preparing quinazolinone derivatives

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Figure 2.8: Magnetic silica based heterogeneous catalyst for preparing quinazolinone derivatives.

Figure 2.9: Synthesis of quinazolinone by use of base Cs2CO3.

Figure 2.10: Proposed mechanism for synthesis of quinazolinone using copper-based catalyst.

the approach azo-linked benzaldehydes 23, isatoic anhydride 24, and glycine 25 are reacted in presence of amino glucose-functionalized silica-coated nanoparticles which considerably reduced the reaction time and also resulted in enhanced product yield (Figure 2.11). The catalyst proved to be highly promising as it was easily isolated after the reaction was complete and recused another six times with no reduction in the activity. In the proposed mechanism, hydrogen bonding between NiFe2O4@SP@GA and carbonyl ester activates the carbonyl ester group, followed by nucleophilic attack by glycine with the removal of carbon dioxide gas. The intermediate formed reacts with aldehyde which on the removal of catalyst results into the final product (Figure 2.12) [50].

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Figure 2.11: Synthesis of azo-linked 2-aryl quinazolinones by using amino glucose-functionalized silica-coated nanoparticles.

The chemoselective approach using biocatalyst for the synthesis of quinazolinone from 2-aminobenzamide 28 and β-dicarbonyl compounds 29 was carried out by Lan and team by hydrolysis, decarboxylation, cyclization followed by transesterification (Figure 2.13). The reaction turned out to be highly promising methodology used which resulted in high yield and did not involve utilization of high temperature or light energy [51].

Figure 2.12: Proposed mechanism for synthesis of azo-linked 2-aryl quinazolinones using silicacoated nanoparticles.

2.3 Metal-free conditions

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Figure 2.13: Synthesis of quinazolinone using biocatalyst.

2.3 Metal-free conditions Heavy metals persist in the environment, pollute food systems and create a variety of health issues. Because of their numerous industrial, household, agricultural, medicinal and technical applications, they have been widely distributed in the environment, raising worries about their possible impacts on human health and the environment [52, 53]. Heavy metal poisoning has shown to be a significant danger, with several health problems connected with it. Heavy metal also acts as pseudo elements their toxic effects persist in a form that is destructive to the human body and its proper functioning [54]. Therefore, numerous scientists have shown their keen interest in exploring green chemistry approaches involving metal-free synthesis [55–59]. Catalyst and metal free electrochemical synthesis of quinazolinone was carried out from substituted alkenes and 2-aminobenzamides via selective anodic oxidative difunctionalization/C–C bond cleavage and oxidation. Suitable amides and aldehydes were reacted with n-Bu4NBF4 using methanol and methyl nitrile mixture as solvent (Figure 2.14). The method emerged out as a highly promising method because of lower method cost, convenient and complete elimination of metal or any catalyst [60]. Various quinazolinone hybrids were synthesized by using (NH4)2S2O8 as oxidant in the reaction. The reaction involved C–H/N–H bond formation through cross dehydrogenative coupling through amide iminium intermediate under mild conditions (Figure 2.15). In the suggested mechanism (Figure 2.16), peroxydisulphate, S2O82− undergoes thermal homolysis to form SO4− radical anion and meditated intramolecular oxidative cyclization. 2-Aminobenzamide undergoes single-electron transfer by SO4− radical anion, followed by generation of an amide iminium intermediate, an intramolecular nucleophilic addition, and oxidation to obtain the final product [61].

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Figure 2.14: Electrochemical synthesis of quinazolinone.

Figure 2.15: Synthesis of quinazolinone by using (NH4)2S2O8.

2.4 Microwave assisted synthesis Microwave radiation has displayed its unique potential to affect chemical processes in recent years. This newer green chemistry synthesis technique uses a novel graphene production method with a short processing time [62, 63]. The starting materials (graphite, amorphous carbon and other carbon sources) are heated to a high temperature in a shorter time using a high-frequency pulse. Microwave radiation, an electromagnetic radiation, is widely used as a source of heating in organic synthesis. The basic mechanisms observed in microwave assisted synthesis are dipolar polarization and conduction [64]. Microwave assisted organic synthesis (MAOS) has emerged as a new “lead” in organic synthesis. Microwave irradiation has several advantages over other conventional methods, including faster and uniform heating, no selective surface heating, energy savings, greater yield and shorter preparation time, reduced processing cost, smaller narrow particle size distribution and outstanding purity [65, 66]. Phosphotungstic acid mediated and microwave assisted green synthesis was explored by Novanna and team to fabricate 2′-spiro and 2, 3-dihydro quinazolinone hybrids under solvent-free conditions. On few minutes of microwave radiations,

2.4 Microwave assisted synthesis

43

Figure 2.16: Suggested mechanism for synthesis of quinazolinone by using (NH4)2S2O8.

various aryl and heteroaryl 2-amino amides on treatment with suitable aldehydes transformed into corresponding 2′-spiro and 2, 3-dihydro quinazolinone hybrids 39, 40 (Figure 2.17). Further derivatives were produced by N-alkylation with various halides [67]. Modified Grimmel’s method was explored using Bmim (1-butyl-3-methylimidazolium tetrafluoroborate)[BF4]-H2O (IL) catalyst to produce 2,3-disubstituted-4(3H)-quinazolinone sulphonamide hybrid molecules 41 through N-heterocyclization under microwave irradiation technique (Figure 2.18). The [Bmim][BF4]-H2O (IL) acted as green solvent and catalyst in the synthesis and two stereoisomers of aldimines were obtained. The method proved to be highly economic as a final product with sufficient yields was developed along with reduced reaction time [68].

Figure 2.17: Phosphotungstic acid mediated and microwave assisted green synthesis of quinazolinone.

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Two microwave assisted quinzolinone synthesis were investigated using eutectic solvents. In the first approach, anthranilic acid 21, methyl orthoformate 42, and corresponding amine 43 are reacted in a microwave reactor to achieve a synthesis of quinazolinone (Figure 2.19). In the second approach, benzoxazinone prepared from anthranilic acid by treatment with acetic anhydride was reacted with substituted with aromatic amines in presence of DES ChCl:U (deep eutectic solvent choline chlorideurea) to series of quinazolinone hybrids. The proposed mechanism (Figure 2.20) involves the attack of amine to carbon atom resulting in the ring opening of benzoxazinone 44, stabilization by eutectic solvent, elimination of water molecule followed by cyclization to form final product [69].

Figure 2.18: Modified Grimmel’s method for synthesis for quinazolinone.

Figure 2.19: Synthesis of quinazolinone derivatives by using eutectic solvents.

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Figure 2.20: Proposed mechanism involved in synthesis of quinazolinone using eutectic solvents.

2.5 Conclusion Greener methodologies have been used to manufacture both well-known chemical compounds and novel materials using more sustainable routes. Greener methods are used to make a variety of nanosized materials and composites, such as metal and nonmetal nanoparticles, their oxides and salts, and various heterocyclic rings. Significant instructional resources have been developed, as well as significant foreign investment, particularly in the area of sustainable development. Curricula are being developed that challenge scientific society to make methods based on sophisticated green chemistry measurements and societal issues. Acknowledgments: The authors are heartily thankful to the management of ISF College of Pharmacy for constant encouragement, support and motivation.

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51. Lan J, Le Z, Li H, Meng J, Gong B, Xie Z. Selective synthesis of functionalized quinazolinone derivatives via biocatalysis. Mol Catal 2020;498:111261. 52. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Mol Clin Environ Toxicol 2012;101:133–64. 53. Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN. Toxicity, mechanism and health effects of some heavy metals. Interdiscipl Toxicol 2014;7:60. 54. Egorova KS, Ananikov VP. Toxicity of metal compounds: knowledge and myths. Organometallics 2017;36:4071–90. 55. Li H, Wang L, Zhang Y, Wang J. Transition‐metal‐free synthesis of pinacol alkylboronates from tosylhydrazones. Angew Chem Int Ed 2012;51:2943–6. 56. Fabry DC, Stodulski M, Hoerner S, Gulder T. Metal‐free synthesis of 3, 3‐disubstituted oxoindoles by iodine (III)‐catalyzed bromocarbocyclizations. Chem Eur J 2012;18:10834–8. 57. Noel-Duchesneau L, Lagadic E, Morlet-Savary F, Lohier JF, Chataigner I, Breugst M, et al. Metal-free synthesis of 6-phosphorylated phenanthridines: synthetic and mechanistic insights. Org Lett 2016;18:5900–3. 58. Khan I, Zaib S, Ibrar A. New frontiers in the transition-metal-free synthesis of heterocycles from alkynoates: an overview and current status. Org Chem Front 2020;7:3734–91. 59. Ali A, Corrêa AG, Alves D, Zukerman-Schpector J, Westermann B, Ferreira MA, et al. An efficient onepot strategy for the highly regioselective metal-free synthesis of 1, 4-disubstituted-1, 2, 3-triazoles. Chem Commun 2014;50:11926–9. 60. Teng QH, Sun Y, Yao Y, Tang HT, Li JR, Pan YM. Metal‐and catalyst‐free electrochemical synthesis of quinazolinones from alkenes and 2‐aminobenzamides. ChemElectroChem 2019;6:3120–4. 61. Xie L, Lu C, Jing D, Ou X, Zheng K. Metal‐free synthesis of polycyclic quinazolinones enabled by a (NH4) 2S2O8‐promoted intramolecular oxidative cyclization. Eur J Org Chem 2019;2019:3649–53. 62. Kappe CO, Dallinger D. The impact of microwave synthesis on drug discovery. Nat Rev Drug Discov 2006;5:51–63. 63. Schanche JS. Microwave synthesis solutions from personal chemistry. Mol Divers 2003;7:293. 64. Nüchter M, Ondruschka B, Bonrath W, Gum A. Microwave assisted synthesis–a critical technology overview. Green Chem 2004;6:128–41. 65. Caddick S, Fitzmaurice R. Microwave enhanced synthesis. Tetrahedron 2009;65:3325–55. 66. de la Hoz A, Díaz-Ortiz A, Prieto P. Microwave-assisted green organic synthesis. Amsterdam: Elsevier; 2016:1–33 pp. 67. Novanna M, Kannadasan S, Shanmugam P. Phosphotungstic acid mediated, microwave assisted solvent-free green synthesis of highly functionalized 2′-spiro and 2, 3-dihydro quinazolinone and 2-methylamino benzamide derivatives from aryl and heteroaryl 2-amino amides. Tetrahedron Lett 2019;60:201–6. 68. Patel TS, Bhatt JD, Dixit RB, Chudasama CJ, Patel BD, Dixit BC. Green synthesis, biological evaluation, molecular docking studies and 3D-QSAR analysis of novel phenylalanine linked quinazoline-4 (3H)-one-sulphonamide hybrid entities distorting the malarial reductase activity in folate pathway. Bioorg Med Chem 2019;27:3574–86. 69. Komar M, Molnar M, Jukić M, Glavaš-Obrovac L, Opačak-Bernardi T. Green chemistry approach to the synthesis of 3-substituted-quinazolin-4 (3 H)-ones and 2-methyl-3-substituted-quinazolin-4 (3 H)-ones and biological evaluation. Green Chem Lett Rev 2020;13:93–101.

Sharma Arvind Virendra, Simranpreet K. Wahan, Chandrakant Sahu and Pooja A. Chawla*

3 Green synthesis of various saturated S-heterocyclic scaffolds: an update Abstract: Development of reliable and eco-friendly novel schemes for the synthesis of organic compounds is an important step in the field of organic and medicinal chemistry. Green chemistry-based strategies involving use of catalysts, green solvents, atom economic reactions etc. play a key role because of their exceptional ability to minimize the toxicity or hazards of the side products and processes. With the use of these green techniques, a number of researchers were able to synthesis a wide range of heterocyclic compounds. This chapter highlights the potential and diverse biological activities of saturated sulphur containing heterocyclic compounds including thiirane, thiane, thiolane and many more. The aim of this chapter is to provide fresh perspective on the various techniques employed for the formation of C–S bond by summarizing all green synthesis from 2016 to 2021. Keywords: green synthesis; sulphur containing heterocyclic; thiane; thiirane; thiolane.

3.1 Introduction Pollution has an adverse influence on human health and biodiversity. Our environment has been poisoned by toxic and hazardous substances over the last few decades [1]. Various chemical reactions utilizing several toxic chemical reagents were employed in the chemical industry. The chemical waste released from laboratories directly mixed with fresh water bodies leads to increasing polluting levels in the environment. Pollution has been a matter of concern for the environment and piqued the interest of numerous experts, resulting in the introduction of a new concept known as green chemistry. Firstly P. T. Anastas used the term “green chemistry” in 1991 [2, 3]. The majority of organic solvents and reactants are dangerous and poisonous, posing a threat to the environment. Solvents play a crucial role in organic synthesis because they provide medium to reaction progress and also required at multiple stages such as separation, extraction, purification and drying of chemical products. Long-term exposure to hazardous solvents causes a variety of illnesses, including *Corresponding author: Pooja A. Chawla, Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab 142001, India; and, Department of Pharmaceutical Analysis, ISF College of Pharmacy, Moga 142001, India, E-mail: [email protected] Sharma Arvind Virendra, Simranpreet K. Wahan and Chandrakant Sahu, Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab 142001, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. A. Virendra, S. K. Wahan, C. Sahu and P. A. Chawla “Green synthesis of various saturated S-heterocyclic scaffolds: an update” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0222 | https://doi.org/10.1515/9783110797428-003

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carcinogenicity, mutagenicity [4]. Therefore, major approach of green chemistry in organic synthesis is to replace hazardous organic solvents and reactants with greener ones, as well as to use synthetic procedure or operation that do not produce toxic side products [5, 6].

3.2 Principles of green chemistry By establishing a new chemical approach based on green chemistry strives to eliminate the dangerous and toxic waste created in the chemical process, as well as to preserve human health and the environment. The 12 green chemistry principles listed below in Figure 3.1 that can help researchers put green chemistry into practice [7]. Heterocyclic compounds are the organic molecules with a ring structure that contains minimum one carbon atom with additional hetero element includes N, O or S. Although carbon remains the major prevalent ring element in heterocyclic compounds, the quantitative change and diversity of heteroatoms in the rings of known or novel compounds has increased over time [8]. Because rings of any size starting from threemembered onwards, having heteroatoms can be obtained in almost any combination from a wide number of elements, the number of potential heterocyclic compounds is basically enormous. There are a great number of heterocyclic bioactive molecules that have been discovered, and the number is constantly increasing [9]. If a carbon atom in a carbocyclic ring is substituted by sulphur, alicyclic or aromatic compounds are obtained. Sulphur containing heterocyclic compounds may have one or more sulphur atoms, which affect the physio-chemical and biological aspects of

Figure 3.1: Twelve principle of green chemistry.

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Figure 3.2: Structures of S-containing heterocyclic compound.

the compounds [10]. The structures of saturated or unsaturated S-containing heterocyclic compound are displayed in Figure 3.2. The simplest smallest S-containing cyclic chemical compound thiirane is also known as ethylene sulfide and generic term for any derivative of the parent ethylene sulfide. The thiirane moiety exhibit various medicinal potential with vital biological functions [11]. Thiirane derivatives have recently received a lot of attention due to their scarcity of pharmacological activities. Cytotoxic effects have also been observed for a variety of substituted thiirane derivatives [12]. When two or more heterocyclic and nonheterocyclic systems are combined, their biological profile is enhanced or altered more compared to the parent nuclei alone. Some compounds with thiirane in their molecular framework are considered [13]. Thiane also called tetrahydro-2H-thiopyran is an organosulphur and heterocyclic compound which possess six-membered ring in saturated manner. In saturated ring of thiane, one sulphur and five carbon atoms are present with sigma bonds [14]. Therefore, thiolane contains saturated five membered rings and one sulphur and four carbons were structured. It is colorless liquid that possess volatility in nature along with extremely unpleasant odor. Thiolane is a soft base that could be help in multiple reaction conditions to synthesize organic compounds [15].

3.3 Synthesis of sulphur containing heterocyclic compound Most common traditional methods for the synthesis of heterocyclic compounds are Paterno–Bü chi reaction, Fischer indole, Huisgen cycloaddition, Paal Knorr syntheses, Nobel Prize winning reaction such as asymmetric epoxidation, cross coupling and

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many more. However, these traditional methods are also associated with non-ecofriendly limitations. Hence in this chapter an emphasis has been given on green chemistry approaches in synthesis of S-containing heterocycles [16].

3.3.1 Synthesis of thiirane 3.3.1.1 Synthesis of thiiranes using chitosan-silica sulphate nano hybrid For organic synthesis, ultrasonic technology is a frequently utilized green technique. It offers a variety of major benefits, including being biodegradable, having a high yield, reducing undesirable side reactions and by-products, requiring less reaction time, being cost effective, and being great in terms of selection and efficiency [17]. Silica sulphuric acid is an environmentally acceptable heterogeneous type of acid catalyst that has been successfully employed in a range of organic reactions. In a green synthesis procedure of thiiranes from epoxides in water, the catalysis exhibited by chitosan-silica sulfphate nano hybrid (CSSNH) (Figure 3.3) was examined [18].

Figure 3.3: Structure of chitosan-silica sulphate nano hybrid (CSSNH).

Synthetic procedure: In 20 mL water, a mixture of epoxide (10 mmol), thiourea (15 mmol), and CSSNH (0.3 g) were taken and transferred into an open-capped cylindrical pyrex-glass. This mixture was put into an ultrasonic apparatus at room temperature and radiation (60 W). On completion of reaction, filtration of catalyst was performed and washed with CHCl3 followed by separation of organic layer. The crude product was purified using column chromatography on silica gel eluting with n-hexane. Also, the effect of several parameters was evaluated on the sample reaction. According to this research, using water at reflux yields the required product in 88% after 5 h whereas using other multiple solvents including MeCN, ethanol, DMF, methanol, DMSO and chloroform yielded the sample product in 62–81% yield. Since temperature has an effect on reaction, the sample was tested in water at various temperatures. After 24 h of performing the sample reaction at room temperature, the sample product was obtained in 63% yield. By raising the reaction temperature, the efficiency of the reaction was found to be enhanced (Figure 3.4) [19].

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Figure 3.4: Conversion of epoxide to thiirane using chitosan-silica sulphate nano hybrid (CSSNH) by using ultrasound approach.

Figure 3.5: Proposed mechanism for synthesis of thiiranes using chitosan-silica sulphate nano hybrid (CSSNH) catalyst.

Behrouz et al. proposed a reaction mechanism shown in Figure 3.5. In which, CSSNH catalyst behaved as a Bronsted acid-base catalyst and first epoxide-CSSNH (I) complex was generated via H-bonding between amine residue and epoxide. The nucleophile thiourea then attacked the complex to produce an intermediate (II). The activation of the hydroxyl moiety (II), which binds to the iminium carbon to generate a cyclic intermediate, then owes to the amine residue (III). The elimination of urea from cyclic intermediate (III) resulted in the end product thiirane (Figure 3.5) [19].

3.3.1.2 Conversion of epoxides to thiiranes using alumina immobilized thiourea Formation of thiiranes from epoxides is a simple O–S replacement reaction involving use of various sulphur S-transferring agent such as thiourea, DMF, thiocyanate and many more with diverse protocols but these conventional reactions have multiple drawbacks that includes unsafe reagents, require high temperature, more reaction time, unwanted by-products etc. Therefore, green chemistry is employed to overcome these drawbacks. In the last few years, immobilized catalysts and reagents on solid supports get a huge attention due to their green advantages such as simple

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Figure 3.6: Synthesis of thiirane using alumina immobilized thiourea.

Figure 3.7: Reaction mechanism for synthesizing thiiranes by using alumina immobilized thiourea.

purification, recyclable, prevention of release of reaction by-product into ecosystem. Therefore, Eisavi et al. designed synthesis of thiiranes from epoxide by using alumina immobilized thiourea with the green approach. Synthetic procedure: At r.t Epoxide (1 mmol) and 0.752 g of alumina immobilized thiourea (25% w/w) without any solvent was grinded in mortar for 2–9 min. TLC was employed for monitoring the reaction progress (n-hexane: EtOAc [5:2]). After completion, the product so obtained was washed with EtOAc and the solvent was evaporation under reduced pressure so as to obtain crude thiirane with 83–98% yield (Figure 3.6) [20]. Although the exact mechanism of formation of thiiranes from epoxides synthetic process is not clear, but Eisavi et al. proposed the mechanism involved in the conversion of epoxides to thiiranes is shown in Figure 3.7. 3.3.1.3 Synthesis of thiiranes by use of magnetically separable nano CuFe2O4 Magnet containing nanoparticle catalyst gained huge attention due to its various advantages such as eco-friendly, air and moisture insensitivity, easily recoverable and separable approach [21]. Eisavi and team designed the synthesis of thiiranes from epoxide using thiourea with the help of magnetic nano CuFe2O4 heterogeneous catalysts. Synthetic procedure: In 3 mL ethanol solution, thiourea (1 mmol) and epoxide (1 mmol) were added and the prepared reaction mixture was attached with a condenser and magnetically stirred followed by addition of nanocatalyst CuFe2O4 (0.05 mmol) into the reaction mixture under the reflux conditions for the period of 34–45 min. After the completion of reaction, ethanol was evaporated and CuFe2O4 nanoparticles were

Figure 3.8: Synthesis of thiiranes using thiourea/nano CuFe2O4 system.

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Figure 3.9: Proposed mechanism for synthesizing thiirane using thiourea/nano CuFe2O4 system.

Figure 3.10: Synthesis of thiirane by employing NiFe2O4 and MFe2O4 (M = Mg, Ni) system.

Figure 3.11: Proposed mechanism for synthesis of thiirane using NiFe2O4 and MFe2O4 (M = Mg, Ni) system.

recovered by using external magnet. The product so obtained was filtered and purified by short column chromatography over silica gel (Figure 3.8) [22]. The proposed possible mechanism of the reaction is presented in Figure 3.9. 3.3.1.4 Synthesis of thiiranes using NiFe2O4 and MgFe2O4 magnetic nano catalysts A mixture of an epoxide (1 mmol), ammonium thiocyanate (1 mmol) and nano-XFe2O4 (0.05 mmol) where X = Mg, Ni, were heated at 60 °C. TLC was used for the monitoring of reaction progress or completion. After completion of reaction, the mixture was cooled at r.t and transferred into H2O with stirring. Furthermore, ethyl acetate employed for the extraction process followed by removal of catalyst with magnet, washing with ethyl acetate and drying under vacuum (Figure 3.10) [23]. The actual mechanism of reaction is not clear at present. However, a possible mechanism is presented in Figure 3.11.

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Figure 3.12: Synthesis of thiirane from thiourea using CuFe2O4/Mg(OH)2 nanocatalyst.

Figure 3.13: Proposed mechanism for synthesis of thiirane by use of CuFe2O4/Mg(OH)2 nano-catalyst.

3.3.1.5 Synthesis of thiiranes by using CuFe2O4/Mg(OH)2 nanocomposite in water Synthetic procedure: CuFe2O4/magnesium hydroxide (0.05 g, 0.17 mmol) was added in 2 mL of water along with epoxide (1 mmol) and thiourea (0.47 g, 3 mmol) taken in round bottom flask attached with magnetic stirrer. This sample mixture was allowed to stand for 1–3.5 h. After washing with ethyl acetate, external magnet was used for the recovery of nanoparticles. Moreover, extraction and drying were proceeded by using CH2Cl2 and anhydrous Na2SO4, respectively Figure 3.12 [24]. The actual mechanism of reaction is not clear at present. However, a possible mechanism is presented in Figure 3.13. 3.3.1.6 Synthesis of thiirane by using two-phase system (DCM/H2O) Kowalski et al. designed and synthesized thiirane by reacting 1,1,1-trifluorodiazoethane with suitable thioketones in a two-phase system (DCM/H2O) at room temperature.

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Figure 3.14: Synthesis of thiirane in a two-phase system (DCM/H2O).

Synthetic procedure: Cycloaliphatic thioketones (1.0 mmol), sodium nitrite (3.0 mmol), and 2,2,2-trifluoroethylamine hydrochloride (2.0 mmol) were added into a mixture of 10 mL of DCM and water (v/v: 10:1) at r.t. under argon gas atmosphere (Figure 3.14) with continuous stirring of mixture. After the color of thioketone faded, product was extracted and dried was adding water to the reaction mixture [25].

3.3.2 Synthesis of thiane 3.3.2.1 Synthesis of ferrocenated thiols and bis-dithianes Despite of the associated costs and risks, metals are commonly utilized in catalysis because they readily undergo reduction/oxidation (redox) reactions by adding or removing electrons from the target molecules. Iodine is the largest, least electronegative, most polarizable of the halogens and heaviest non-radioactive element categorized as a non-metal. Iodine atoms can be used as alternative for metal catalysis, which can help in redox reactions because of its varying oxidation states. Moreover, iodine is one of the amplest elements on the planet with significantly low toxicity, making it an ideal “green” redox element. Ishihara and co-workers discovered that a small amount of a carefully prepared iodine salt with a well specified three-dimensional form can accelerate a crucial organic ring-closing reaction when combined with ecologically benign reagents. The catalyst provides near-complete control over the final product geometry and is a significant step forward in the quest for environmentally friendly chemical processes [26, 27]. In 2020, Srivastava and coworkers synthesized vast array of ferrocenated mono, bis and di-thianes in presence of molecular iodine as catalyst at room temperature, which resulted in high yield of product. In the presence of molecular I2 and chloroform as a solvent, at initial stage of reaction using 2-formyl-1-chlorovinyl ferrocene and 1,2-dithiol in 1:1 ratio (Figure 3.15), a small amount of an orange-colored product was

Figure 3.15: Reaction of ferrocene derivative with 1,2-dithiol.

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Figure 3.16: Reaction of ferrocene derivative with 1,3-dithiol.

Figure 3.17: Reaction of ferrocene derivative with equimolar mixture 1,2-dithiol and 1,3-dithiol.

produced. Furthermore, higher yields of same orange-colored product were obtained when two equivalent of 1,2-dithiol were added to the reaction [28]. Moreover, the specificity of reaction increased to 96% (% yield) when the reaction was carried out with 1,3-dithiol (Figure 3.16). In the next approach, equimolar combination of 1,2-dithiols and 1,3-dithiols were taken and the reaction was carried out with the same reaction conditions as before to investigate their reactivity towards ferrocene, as well as the attainability of synthesis of both the five and six-membered dithianes. The reaction yielded dithiolane-dithiane as major product (74% yield) along with bis-dithiane as a minor product (Figure 3.17). Formation of dithiolane-dithiane as a major product presents the occurrence of biprotection by concomitant attack of di-thiols. Despite the fact that no intermediate was generated throughout the reaction, a feasible mechanism has been postulated and illustrated in Figure 3.18, is been divided into two routes based on the results of the reaction.

Figure 3.18: A feasible reaction mechanism of ferrocene formyl derivative using equimolar mixture 1,2-dithiol and 1,3-dithiol.

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3.3.2.2 Synthesis of thiochromanyl-spirooxindoles conjugates PyBidine, an C2 symmetric Bis(imidazolidine) pyridine ligand is an important class of organocatalyst for selective asymmetric catalysis (Figure 3.19). The PyBidine catalyst smoothly catalyzes the highly endo, as well as exo-selective [3 + 2] cycloaddition reactions [29]. In recent years, catalytic asymmetric 1,3-dipolar cyclization using chiral metal organocatalysts for the stereoselective synthesis of the pyrrolidine ring has been effectively developed. The catalytic asymmetric synthesis of thiochromanylspirooxindoles was described by Arai and colleagues. The process used the (PyBidine)Ni(OAc)2 complex to catalyze the asymmetric Michael/aldol reaction between methyleneindolinone and thiosalicylaldehyde, yielding (2′R,3S,4′R)-thiochromanylspirooxindole [30]. Organocatalyst ligands (IAP and PyBidine) were examined with metal salts of nickel, zinc, copper, and cobalt at various temperatures during the optimization of reaction conditions. The maximum thiane production (99%) was obtained when PyBidine (11 mol%) was combined with the metal salt Ni(OAc)2 (10 mol%) at −40 °C using toluene as reaction medium [31] (Figure 3.20). Figure 3.21 depicts the suggested catalytic cycle for the PyBidine–Ni (OAc)2-Catalyzed Michael/Aldol Reaction. 3.3.2.3 Synthetic approaches of spirooxindoles In(OTf)3 is one of effective the metal salts of triflic acid showing its catalytic activity in several classes of reactions. They are often called “Lewis superacids”. Distinctive

Figure 3.19: Chemical structure of PyBidine ligand.

Figure 3.20: Chemical reaction of methyleneindolinones and thiosalicylaldehydes.

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Figure 3.21: A proposed mechanism of PyBidine-Ni(OAc)2-catalyzed asymmetric synthesis.

applications of triflates include inter and intramolecular C–C, C–O, and C–S bond formation. Metallic triflates have shown a wide range of synthetic applications; depending on specificity of functional groups exist in organic compound. In(OTf)3 was found as the most promising catalyst for the addition of sulphur into olefins or dienes [32, 33]. The structure of In(OTf)3 is depicted in Figure 3.22. Hao et al. reported the facile synthesis of spiro[indoline-3,40-thiopyran]-2-ones with a (tetrahydro)thiopyran skeleton by [3 + 3] annulation of spirocyclopropyl oxindole and 1,4-di-thiane-2,5-diol in the presence of In(OTf)3 as a catalyst (Figure 3.22). The promotetability of [3 + 3] annulation of various triflate catalysts was tested during reaction condition optimization, and only In(OTf)3, Sc(OTf)3 and Ga(OTf)3 were found to

Figure 3.22: Chemical structure of In(OTf)3.

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assist the [3 + 3] annulation. Because it produces high-quality diastereoselective desirable products, In(OTf)3 was chosen for subsequent cycloaddition reactions. Furthermore, the researchers discovered that throughout the condition optimization process, the reaction be quenched in time to avoid undesired epimerization. Spirocyclopropyl oxindoles (0.15 mmol), 1,4-di-thiane-2,5-diol (0.09 mmol) and In(OTf)3 (10 mol%) as catalyst in DCM at room temperature were chosen as the final optimal conditions [34] (Figure 3.23).

Figure 3.23: Synthesis of spiro[indoline-3,40-thiopyran]-2-ones in the presence of In(OTf)3 catalyst.

3.3.2.4 Synthesis of thiochromanyl-spirooxindole derivatives Potassium carbonate (K2CO3) has gained popularity as benign environment friendly catalyst in many organic reactions. Potassium carbonate has been widely employed as a moderate base catalyst in several chemical processes such as in thiolysis of epoxides, synthesis of 2H-chromenes, o-alkylation, monomethylation reactions and Knoevenagel and nitroaldol condensation in the recent years. Potassium carbonate’s special features like solubility in water, mild character, easy availability, eco-friendly and its non-toxic nature proves it as mild basic medium for organic reactions. Also, easy removal by water, which makes K2CO3 a green catalyst [35, 36]. Sun and co-workers developed an effortless method for the synthesis of thiochromanyl-spirooxindoles in the catalytic presence of potassium carbonate as green catalyst. The initial step involved the reaction of (E)-ethyl-2-(1-methyl2-oxoindolin-3-ylidene) acetate and 2-mercapto-benzaldehyde in the presence of one equivalent triethylamine in CH2Cl2 at room temperature, which resulted in 61% yield within 30 min. A quick filtering of various organic and inorganic bases disclosed that K2CO3 was the most sufficient base, which resulted in 85% yield (Figure 3.24) [37].

Figure 3.24: Synthesis of thiochromanyl-spirooxindoles through sulfa-Michael/aldol reaction.

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Figure 3.25: A proposed mechanism of synthesis of thiochromanyl-spirooxindoles through sulfaMichael/aldol reaction.

Possible mechanism of the tandem reaction presented in Figure 3.4 based on prior literatures and experimental data in represented in Figure 3.25.

3.3.3 Synthesis of thiolane 3.3.3.1 Synthesis of five-membered sulphur heterocycles via tin-based catalyst Microwave irradiation produces direct heating at molecular level in reaction mixture by direct coupling of microwave irradiation between ions or dipoles that flows through microwave transparent vessel wall. Microwaves heat any medium containing mobile electric charges, such as polar molecules in a fluid or conducting ions in a solid, by acting as high frequency electric fields. Microwave assisted reactions have several advantages like reductions in reaction durations, greater yields, modified selectivities, enhanced product purity, and simplified work-up processes were detailed, and in most cases, these conditions and outcomes could not be reached by traditional heating [38, 39]. Suzuki and co-workers reported the synthesis of thiolane via annulation of α-mercapto ketones with cyanoalkenes catalyzed by tin alkoxide, using microwave irradiation as a heating source (Figure 3.26). During optimization of reaction under microwave conditions, the reaction was tested in presence as well as absence of various tin enolate providing bases like Sn(Oct)2-2MeOH, Bu3SnOMe and Sn(Oct)2, and it was found that reaction yield was moderate (53–68%). Various organic solvents like MeCN, THF and Et2O were employed in the devised reaction and MeCN was found to be most

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Figure 3.26: Synthesis of thiolane via tin alkoxide catalyst, using microwave irradiation.

efficacious (53–99%) solvent for the synthesis of thiolanes under microwave assisted conditions. Furthermore, the research group also reported that utilizing MeCN as a medium, the production of thiolane progressed even in the absence of a catalyst and a heat source with >99% yield [40]. Figure 3.27 depicts the proposed catalytic cycle for the annulations of mercapto ketone and alkene 3.3.3.2 Synthesis of tetrahydrothiepines using donor-acceptor cyclopropanes Sc(OTf)3 is one of the metal salts of triflic acid acts as an effective catalysts for synthesis organic reactions. They are often called “Lewis superacids”. Distinctive applications of triflates include inter and intramolecular C–C, C–O and C–S bond formation. Metallic

Figure 3.27: A proposed catalytic cycle for the annulations of mercapto ketone and alkene.

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triflates have shown a wide range of synthetic applications depending on specificity of functional groups exist in organic compound. Augustin et al. synthesized a series of thiolane derivatives by (n + 3)-cycloaddition processes of monomeric form of thiochalcone under fine-tuned conditions, resulting in generation of thiolanes as 1,2-addition products. The final devised reaction involved heating mixture (40 °C) of cyclopropane (100 μmol), thiochalcones (180 μmol), and Lewis acid (20 mol%) in 1.5 mL of solvent for 12 h. Further team tested the reaction with variety of solvents (DCM, dioxane, toluene and ethylene oxide) and Lewis acids like Al(OTf)3, TiCl4 and Sc(OTf)3. The team found that combination of Sc(OTf)3 as Lewis acid and ethylene oxide as solvent resulted in highest yield of 63% (Figure 3.28) [41]. Based on the findings, the team drafted the reaction mechanism, shown in Figures 3.28 and 3.29. 3.3.3.3 Synthesis of nuphar sesquiterpene thioalkaloids Rhodium is a rarely found transition metal. Approximately 80% of rhodium produced worldwide is used in catalysis. Rhodium is an excellent catalyst when it comes to redox reactions. In recent years, after the discovery of Wilkinson’s catalyst, rhodium is been extensively explored for various green hydroformation reactions and cyclization reactions [42, 43]. The synthesis of thiolane was carried out by Lu and co-workers using Stevens-type ring expansion of tetrasubstituted thiolanes proceeded by enzymemediated desymmetrization processes. The reaction proceeded in two steps. The initial step was to synthesize thietane, then catalyze the reaction between the synthesized ring and methyl 2-diazo-3-butenoate in the presence of 2% Rh2(OAc)4, 20 h of refluxing resulted in the synthesis of required thiolane product with a yield of 71% was obtained (Figure 3.30) [44].

Figure 3.28: Synthesis of tetrahydrothiepines using donor-acceptor cyclopropanes.

Figure 3.29: Reaction mechanism of synthesis of tetrahydrothiepines using donor-acceptor cyclopropane.

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Figure 3.30: Synthesis of stereoisomers of thiolane based on Stevens-type ring expansion.

3.3.3.4 Synthesis of unsymmetrically/chiral molecules by employing coppercatalyzed thiolane apparatus Microwave irradiation produces direct heating at molecular level in reaction mixture by direct coupling of microwave irradiation between ions or dipoles that flows through microwave transparent vessel wall. Microwaves heat any medium containing mobile electric charges, such as polar molecules in a fluid or conducting ions in a solid, by acting as high frequency electric fields. Microwave assisted reactions have several advantages like reductions in reaction durations, greater yields, modified selectivities, enhanced product purity and simplified work-up processes were detailed, and in most cases, these conditions and outcomes could not be achieved by traditional heating strategy. Steven’s rearrangement of a sulfonium ylide, formed in situ via the coupling of a copper-carbene with a spirocyclic thietane, was used to synthesize core bis-spirocyclic tetrahydrothiophene by Lacharity et al. After testing a variety of catalysts, the researchers discovered that a combination of Cu(hfacac)2 and microwave irradiation was the most effective for thiolane ring synthesis. Under optimal reaction conditions, the thietane ring were microwave-irradiated to 100 °C in the presence of Cu(hfacac)2, which resulted in core thiolane ring with 55% yield (Figure 3.31) [45].

3.3.4 Miscellaneous synthesis of saturated S-containing heterocycles 3.3.4.1 One pot synthesis of Sulphur cycle fused 1.2.3-triazole The protocols of click reaction follows approaches of green chemistry are beneficial for the eco-friendly synthesis of organic compounds with amazing advantages such as

Figure 3.31: Synthesis of bis-spirocyclic tetrahydrothiophene ring derivatives by Steven’s rearrangement.

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3 Green synthesis of various saturated S-heterocyclic scaffolds

simple to process, generate only appropriate by-products that can be separated easily without help of chromatography [46]. Wang et al. synthesized 1,2,3-triazoles containing sulphur using copper(I) catalyst. Synthetic procedure: To a mixture of CuI (0.02 mmol), MeOLi (0.4 mmol) and dioxane (1 mL), phenylacetylene (0.2 mmol) and azide (0.3 mmol) were added. Then this mixture was stirred under N2 atmosphere for 12 h. Celite was employed for the filtration of reaction mixture and evaporation under reduced pressure was performed. Wang et al. picked phenylacetylene and azide as a substrate and 20 mol% copper iodide as catalyst with base whereas LiOtBu used as base. This reaction was investigated under the influence of diversity of solvent such as dioxane, DMSO, DCM, toluene, hexane etc. The results obtained reported maximum yield (71%) by using dioxane as solvent with click product 1,4-disubstituted 1,2,3-triazole. Furthermore, MeOLi give the best yield when it was act as base in the reaction (Figure 3.32) [47]. 3.3.4.2 One pot synthesis of thiazolo[3,2-a] benzimidazole and pyran hybrids One pot synthesis gained much attention because of their ecological and economical approach that includes condensation process of more than two step in one-pot operation. One pot synthesis has achieved huge development to synthesize desired molecular complexity compare with conventional process [48]. Mariappan et al. also proposed one pot synthetic method for preparation thiazolobenzimidazole fused dihydropyran derivatives. Synthetic procedure: In ethanol, mixture of 2-((1Hbenzo[d]imidazol-2-yl)thio)1-phenylethan-1-one (1 mmol), aryl aldehyde (1 mmol), sodium hydroxide (1.5 mmol) and malononitrile (1 mmol) was stirred at room temperature. Pyridine derivatives are formed when RCOCH2R, malanonitrile and arylaldehyde molecules combined in the presence of alcoholic base. However, because the active methylene part in the system contains acidic hydrogen present in the benzimidazole ring, Mariappan et al. expected a distinct cyclization. Desired product, dihydro-4H-benzo [4,5]imidazo[2,1-b]pyrano [2,3-d] thiazole product was obtained (Figure 3.33).

Figure 3.32: One pot synthesis of sulphur cycle fused 1.2.3-triazole.

3.3 Synthesis of sulphur containing heterocyclic compound

67

Figure 3.33: One pot synthesis of thiazolo[3,2-a] benzimidazole and pyran fused poly heterocyclic scaffold.

3.3.4.3 Synthesis of N, S-heterocycles by the cyclothiomethylation of diamides The catalytic cyclothiomethylation of (thio) carbonic acid diamides and dihydrazides employing H2S, sodium sulphide crystallohydrate or bis(dimethylamino)methane has been established as an effective method for producing N, S-heterocycles with (thio)amide fragments. Cs2CO3 (79%) and RbNO3 (80%) were found to be the most effective alkali or alkaline-earth metal catalysts. At a 10: 20: 20: 2 (thio)urea–diamine–H2S–RbNO3 ratio (70 °C, EtOH CHCl3 2: 1, 8 h), the reaction produced 1,3,5-thiazinane-4-thione and 1,3,5-thiazinane-4-one in yields of 80 and 69%, respectively (Figure 3.34) [49]. 3.3.4.4 Synthesis of thiocarbonates by use of lithium tert-butoxide catalyst Atom economy is one of the major concepts that helps in preventing waste at molecular level. It comprehends the efficiency of the reaction and its equation helped to measure how many molecules combined and produced the final desired product [50]. Diebler et al. developed and synthesized the solvent-free synthesis of cyclic dithiocarbonates from CS2 and epoxides. Various alkali metal alkoxides catalyst such as LiOMe, LiOEt, LiOiPr and LiOtBu were used to find out efficiency of various catalyst. About 5 mol% of LiOtBu was analyzed as a responsible catalyst for the synthesis of cyclic dithiocarbonates with highest yield of 95%. The general scheme involved dropwise addition of epoxide or thiirane (1.0 equivalent) into CS2 (2.0 equivalent) and catalyst (0.05 equivalent) in the pressure tube.

Figure 3.34: Synthesis of N, S-heterocycles with (thio)amide fragments.

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3 Green synthesis of various saturated S-heterocyclic scaffolds

This reaction mixture allowed standing for 5 h at 25 °C under continuous stirring. Then all volatility containing compound got removed by vacuo and dissolved in CH2Cl2. After filtration they got thiocarbonates. The mixture was stirred for 5 h at 25 °C. Subsequently all volatiles were removed in vacuo. The residue was dissolved in CH2Cl2 and filtered. After removal of all volatiles in vacuo the thiocarbonates were obtained (Figure 3.35) [51]. 3.3.4.5 Carbonylative cyclization of propargylic alcohols in the presence of 1,8-Diazabicyclo[4.3.0]undec-7-ene (DBU) catalyst Sulphur has been utilized for millennia in various purposes as in medications, fabric bleaching, lamp wick manufacturing, gun powder composition and, more recently, latex vulcanization. Currently, elemental sulphur is obtained as a result of petroleum refining. Thus, the elemental sulphur is available in excess and is quite cheap thereby making utilizing elemental sulphur in large scale not only cost efficient, but also promotes atom economy and waste valorization [52]. Hu et al. developed a DBU-catalyzed carbonylation process comprising of cyclization of propargylic alcohols with elemental sulphur. The reaction was investigated under the influence of diverse bases like DBU, DBN, TBD, etc., and various solvents such as toluene, DMSO and MeCN, which devised optimal reaction conditions of heating of DBU (10 mol%) with propargylic alcohol (0.5 mmol) and elemental sulphur (0.25 mmol) in 2 mL of MeCN and 10 bar carbon monoxide at room temperature for 12 h, with 97% yields (Figure 3.36) [53]. 3.3.4.6 One pot synthesis of lactones by use of InCl3/PhSiH3 as catalyst Sakai and colleagues identified a one-pot synthesis including the direct conversion of lactones to thiolactones with the help of elemental sulphur catalyzed by InCl3/PhSiH3.

Figure 3.35: Synthesis of di- and trithiocarbonates by use of lithium tert-butoxide.

Figure 3.36: 1,8-Diazabicyclo[4.3.0]undec-7-ene (DBU)-catalyzed carbonylative cyclization of propargylic alcohols.

Abbreviation

69

Figure 3.37: One pot synthesis of lactones by use of InCl3/PhSiH3.

The suitable reaction conditions were determined by testing several Lewis acid catalysts like In(OAc)3, InCl3, In(OTf)3, etc. in different solvents such as, o-DCB, PhCl, toluene and 1,2-DCE. The reaction involved heating of γ-phenyl-γ-butyrolactone (0.5 mmol) with elemental sulphur (1.1 equivalent) in the presence of catalyst (5 mol%), hydrosilane (two equivalent) in 0.5 mL of solvent at 80 °C for 24 h. The optimal reaction conditions resulted in good yield of 58% (Figure 3.37) [54].

3.4 Conclusions In this review, we covered all the recent methodologies based on the green chemistry approaches for the synthesis of saturated S-containing heterocyclic compound such thiirane, thiane, thiolane and others. These heterocyclic scaffolds often exhibit interesting biological activities and structures that often generate compounds having significant importance in medicinal chemistry. The therapeutic potential is dependent on their structure. Therefore, several chemists have carried out the synthesis of organic compound on frequently manner that leads to an increased formation of different waste chemicals. That is why in reduction and minimization of generation of hazardous organic substances, green synthetic methods are applied in this manner. These methods are getting more attention since the last couple of decades. Green chemistry methods cover a wide range of methods, including the application of ultrasound and microwaves, one pot synthesis and green solvents, solvent-free synthesis and multicomponent reactions. We have tried to gather all the information that could be useful for the scientific community to synthesize compounds by taking into account the safety of the ecosystem into consideration and reduce plausible negative impact of organic aids on the state of the earth.

Abbreviation (CH3CN)4BF4 Bu3SnOMe CH2Cl2 CHCl3 CS2 Cs2CO3 CSSNH Cu(hfacac)2

Tetrakis(acetonitrile)copper(I) tetrafluoroborate Tributyltin methoxide Dichloromethane Chloroform Carbon disilfide Cesium carbonate Chitosan-silica sulphate nano hybrid bis(hexafluoroacetylacetonato)copper(II)

70

Cu(tfacac)2 DBN DBU DCB DCE DME DMF DMSO IAP K2CO3 LiOEt LiOiPr LiOMe LiOtBu MeCN MeOH MeOLi Mg(OH)2 o-DCB OTf PhCl PTAD RbNO3 Rh2(esp)2 Rh2(OAc)4 SmCl3 Sn(Oct)2 TBD THF TiCl4 TLC

3 Green synthesis of various saturated S-heterocyclic scaffolds

copper(ii) trifluoroacetylacetonate 1,5-Diazabicyclo[4.3.0]non-5-ene 1,8-Diazabicyclo[4.3.0]undec-7-ene 1,4-Dichlorobenzene 1,2-dichloroethane 1,2-dimethoxy-ethane DiMethyl-formamide DiMethyl sulphoxide Imidazoline aminophenol Potassium carbonate Lithium ethoxide Lithium isopropoxide Lithium methoxide Lithium tert-butoxide Acetonitrile Methanol Lithium methoxide Magnesium hydroxide 1,2-Dichlorobenzene Triflate or trifluoromethanesulfonate Chlorobenzene 4-Phenyl-1,2,4-triazole-3,5-dione Rubidium nitrate Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] Rhodium(II) acetate Samarium chloride Tin(II) 2-ethylhexanoate or stannous octate Triazabicyclodecene Tetrahydrofuran Titanium tetrachloride Thin layer chromatography

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Sabbasani Rajasekhara Reddy* and Jyothylakshmi Jayakumar

4 Cu-Catalysed tandem reactions for building poly hetero atom heterocycles-green chemistry tool Abstract: Of late, regio-selective tandem reactions are given much attention due to the formation of several multiple bonds in a single synthetic operation, avoids altering the reaction conditions, isolation of the intermediates during the reaction, reduces the production of toxic waste to the environment and can produce highly complex organic molecules with desired selectivity. Though, it requires the well-built knowledge for optimization of the process, it permits to make the complex organic molecules with least number of steps, and it has eventually made great interest and inspiration to the upcoming organic chemists. Presentation of current book chapter presents the CuCatalysed tandem reactions for building poly hetero atom heterocyclic compounds via green approach. Keywords: heterocyclics; poly heteroatom; regioselective synthesis; sustainable approach; tandem reactions.

4.1 Introduction Heterocyclic compounds with poly hetero atoms are essential because they are found in the majority of natural products, bioactive substances, and therapeutics. For this purpose, several novel methods for the synthesis of these compounds, involving both metal- and non-metal-assisted processes, have recently been investigated. However, these reactions are robust, reliable, and cost-effective, and can be synthesised using both traditional and conventional methods [1a]. The by-products produced by these methods are a major disadvantage, whereas copper-mediated procedures create less waste and are thus environmentally friendly. In recent decades, copper-catalysed cyclization techniques for the creation of heterocycles, have made significant advances in organic chemistry. As a consequence of this significant advantage, copper nanoparticles were utilised as catalysts in a variety of tandem processes. As a result, copper catalysts have proven to be useful in one-pot synthesis [1a]. A tandem reaction is a synthetic process that generates several bonds without changing the reaction *Corresponding author: Sabbasani Rajasekhara Reddy, Department of Chemistry, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India, E-mail: [email protected] Jyothylakshmi Jayakumar, Department of Chemistry, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. R. Reddy and J. Jayakumar “Cu-Catalysed tandem reactions for building poly hetero atom heterocycles-green chemistry tool” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0232 | https://doi.org/10.1515/9783110797428-004

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Figure 4.1: Advantages of tandem reactions.

conditions, separating the reagents, or introducing intermediates. Although it is a beneficial method, it necessitated a high level of process optimization expertise [1b]. Multiple synthetic stages can be completed in a single operation, avoiding the isolation of intermediates, avoiding the production of side products, and reducing the number of purification steps [2a, b]. It also reduces the quantity of toxic waste emitted into the environment and can produce very complex organic molecules with the desired selectivity [3]. The terms tandem and multicomponent were used by Grigg et al. [4a] and Dyker [4b] to express the same meaning for amino acid derivative synthesis and cyclization operations. The approach allows for the simplest imaginable production of complex compounds, and it has sparked the interest of and inspired the next generation of organic chemists. Figure 4.1 presented the tandem and its advantages in detail [5]. Common terms for tandem reactions include sequential, cascade, multi-component, domino, and one-pot reactions [6]. In current scenario, such methods boost the atomeconomy to adhere to green chemistry principles. Poly heterocyclic compounds were synthesised using a tandem technique, which is useful in the creation of therapeutic

4.2 Synthesis of heterocycles

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Figure 4.2: Tandem reactions initiated by copper catalyst.

active molecules in medicinal chemistry [7]. Pericyclic, radical and polar reactions were carried out under mild circumstances employing transition metal catalysis [8]. A tandem reaction has the following advantages: it minimises the number of reaction steps, reduces toxicity, simplifies the workup, reduces reaction time, and reduces the formation of by-products after synthesis [9a]. In addition to these advantages, the use of organic solvents is quite minimal as compared to multistep synthesis [9b, c]. However, some of these reactions are still constrained by green chemistry protocols, such as the usage of additives, volatile organic solvents, costly metal catalysts and toxic reagents. In the bulk of published methods, traditional methodologies are still applied. As a result, the basic processes like tandem reactions are necessary in generating a variety of heterocyclic compounds as depicted in Figure 4.2 [9a]. These reactions can be studied along with green solvents such as ILs and green solvent media to meet the green chemistry principles in tandem reactions, and they are in high demand.

4.2 Synthesis of heterocycles Heterocyclic compounds are structural elements that can be found in a wide range of biomolecules. In bioorganic and pharmaceutical chemistry, small N-heterocyclic rings are crucial. They’re fascinating, and they are seen in diverse natural and as well as biologically active products [10a]. In this context, scientists are working hard to produce new bioactive N-heterocycles. Necopidem, olprinone and saripidem [10b] are

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A

B

C

D

Figure 4.3: Various drug molecules with five-membered heterocyclic frameworks.

examples of pharmaceuticals produced from five-membered heterocyclic core components (Figure 4.3).

4.2.1 Synthesis of annulated heterocyclic compounds In the Ullmann and Goldberg procedures, copper is utilised as a catalyst to prepare C–N coupled product via reaction between aryl halides and N-nucleophiles [11a]. As a result, these reactions have become very prevalent among Cu-catalysed coupling transformations of all kinds. Herein represented some examples where the copper iodide employed as a catalyst [11b] (Figure 4.4). In this procedure, the tandem C–N coupling reaction was used to generate ring expansion of heterocyclic compounds from amino functionalized aryl halides. Here,

Figure 4.4: Sustainable methodology for developing C–N coupling via tandem reaction.

4.2 Synthesis of heterocycles

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Figure 4.5: Designing C–N coupling of substituted indole using green methodology.

β-lactams were used as the starting material, with 5 mol% Copper iodides as the catalyst and 10 mol% N,N′- dimethylenediamine (DMEDA) as the ligand, yielding similar products in 59–96% yields. Using a copper catalyst to form new C–N bonds, for example, the reaction between 2-halo benzyl amino functionalities 1 and nitrogen nucleophiles 2 can yield medium-sized heterocyclic systems 3 in excellent yields (Figure 4.4). Substituted indole 8 was synthesised in the presence of copper iodide as a catalyst [12], using primary amine and O-alkynyl arylhalide 5. The intermediate 9 was also produced in Figure 4.4 via C–N coupling and subsequent cyclization to yield the product 8. The strategy was developed to synthesise a variety of biomolecules such as carbamides or amides by using N,N′-DMEDA to obtain N-acetylindoles 6, then acidic conditions in the presence of TFA to obtain compound 7 (Figure 4.5). Oxygen nucleophiles are less reactive than C–N nucleophiles due to lower oxygen atom valency thus, the reaction initiated by C–O coupling are less reactive than C–N coupling in tandem reaction [13a]. Bao et al. described a copper catalysed C–O tandem coupling reaction using a catalytic amount of Cu2O and Cs2CO3 as the base in which

Figure 4.6: Tandem C–O coupling using sustainable approach.

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4 Cu-Catalysed tandem reactions for building polyheterocycles

Figure 4.7: Plausible mechanism for C–O coupling reactions.

1,10-phenanthroline acts as a ligand in the reaction. The epoxide ring 11 was opened on both sides by O-hydroxy iodo-benzene nucleophile 10, and the major product was formed when the epoxide with the less hindered side 12 was opened (Figure 4.6) [13b]. In the coupling, o-iodophenol 10 would first transform into phenate 10′ in the presence of a base, and then attack electrophilic carbons of styrene oxide C, generating the intermediates (major I & minor II). The copper-oxygen coordination produces intermediates III (major) and IV (minor), which are then oxidatively added to the aryl iodide portion to form intermediates V (major) and VI (minor). In addition, while the catalyst/ligand is being regenerated, a reductive elimination is performed to yield products 12 and 13 (Figure 4.7). In synthetic organic chemistry, C–C coupling reactions are widely considered and employed. The C–C coupling reactions for the synthesis of single heterocyclic systems was developed by Cacchi et al. [14] The methodology described the synthesis of heterocyclic compounds by using o-iodobenzene with N-protected aniline 14 via Sonogashira coupling to obtain the intermediate 15 which gradually undergo cyclization to

4.2 Synthesis of heterocycles

81

Figure 4.8: Developing tandem C–C coupling using sustainable approach.

Figure 4.9: Copper catalysed approach for C–C and C–O coupling reaction.

obtain 16 and de-protection of 16 occurs to obtain the heterocyclic compound 17 in 11–96% yield and the side product with 0–31% yield of 18 (Figure 4.8). Patil et al. [15] used a catalytic quantity of Cu (OTf)2 to treat pent-4-yn-1-ol 18 with 19 at 60 °C to get C3 substituted indoles 20 in good to outstanding yields. In comparison to previous approaches, the suggested methodology was used for large-scale synthesis of substituted indoles using affordable copper triflates. Furthermore, under mild reaction circumstances, electron withdrawing, electron donating and steric hindered groups were successfully transformed into desirable products (Figure 4.9). The first step in the mechanistic pathway would be the complexation of Cu (II) catalysts with the alkyne functional group in 18, resulting in intermediate I (Figure 4.10, cycle A). The cyclization phase can then be completed immediately by attacking the proximal hydroxyl group, yielding vinyl copper intermediate II. The protodemetalation process would be followed by the release of catalyst to form exocyclic enol ether III. The catalyst is meant to act as a Lewis acid once III is produced, and it begins another catalytic cycle (cycle B). The Lewis acid catalyses the production of oxonium ion IV from enol ether III; as a result, the final product 20 is obtained by intermolecular nucleophilic addition of indole 19 to IV followed by re-aromatization and proto-demetalation, with catalyst liberation (Figure 4.10).

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4 Cu-Catalysed tandem reactions for building polyheterocycles

Figure 4.10: Plausible mechanism for C–C and C–O coupling.

4.2.2 Synthesis of benzoxazines Domino reactions are the most efficient synthetic transformations in modern organic synthesis, allowing the synthesis and breakage of many bonds in a single operation. The domino reactions that have been identified so far in modern chemical synthesis are quite promising [16]. However, several of these reactions have shortcomings, such as the need for expensive metal catalysts, toxic reagents and volatile organic solvents and additives [17, 18]. Feng et al. reported a suitable methodology for the synthesis of substituted 1,4 benzoxazines 23 using copper catalyst and 2-halophenols 21 with 2-holoacetamide 22 as a starting material under microwave irradiation at 130 °C to obtain the products in remarkable yields. The approach has been successfully used to invent substituted derivatives, making it particularly appealing to medicinal chemistry and drug development applications in the pharmaceutical industry (Figure 4.11) [19]. It was discovered that copper-metal-catalysed methodologies for the synthesis of pyrrolo-/pyrido[2,1-b] benzo[d][1,3]oxazin-1-ones in ionic liquids were interesting. In continuation of the research efforts, our group reported one-pot tandem processes for the synthesis of highly substituted pyrrolo[1,2-a] benzoxazines 26 from 2-aminobenzyl alcohols 24 with alkyne-containing carboxylic acids 25 with outstanding yields in ionic liquid ([Bmim]OTf) as solvent at 100 °C using catalytic amount of Cu(OAc)2·H2O [20a, b] (Figure 4.12).

4.2 Synthesis of heterocycles

83

Figure 4.11: Synthesis of 1, 4 benzoxazines.

Figure 4.12: Green synthesis of fused heterocycles from 2-aminobenzyl alcohol.

The bulk of the specified techniques for the synthesis of benzoxazines have been started using transition metal catalysts, and the catalytic cycle will be finished with the help of an acid that is either created internally or absorbed as an open form. The mechanistic aspects reveals that Cu(OAc)2.H2O initiates the reaction by coordinating with the alkyne moiety of the reactant 4-pentynoic acid 25, resulting in the formation of vinyl intermediate I with the loss of one acetic acid molecule 27 following the release of Cu (II) catalyst, and then intermediate I was converted to enol-lactone 28 (proto-demetalation). The molecule 24 attacks the 28 which results in tautomerization and undergo cyclization to form 26 (Figure 4.13).

4.2.3 Synthesis of fused pyrrolobenzoxazinones and pyrroloquinazolinones Organic compounds containing benzoxazinones skeleton extensively used as a range of potential agents for a variety of activities including anti-bacterial, and as an inhibitor for protease 29 and lipase inhibitor (Cetilistat) 30 as shown in Figure 4.14 [21]. Whereas quinazolinones including its derivatives were extensively used as anti-tumour agents for example, the antiviral and anticancer compound Cruciferane alkaloid 33 (Figure 4.15)

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Figure 4.13: Proposed reaction mechanism of copper catalysed tandem cyclization.

Figure 4.14: Some important therapeutically active benzoxazinones.

4.2 Synthesis of heterocycles

85

Figure 4.15: Some important therapeutically active quinazolinones.

was isolated from the root of the Isatisindigotica plant [22]. Tryptanthrin 34 (Figure 4.15) is a bioactive alkaloid derivative with antibacterial, antiparasitic and anti-cancer activities [23,24]. Dictyoquinazols A and C (Figure 4.15) 35, 36 are alkaloids isolated from the dictyophoraindusiata fungus and used to treat neurological illness. Methaqualone 37 and Cloroqualone 38 were also proven to have antitussive and anticonvulsant activities (Figure 4.15) [25]. Several synthetic methodologies were reported earlier in connection with the synthesis of therapeutically active benzoxazinones and quinazolinones using transition metal catalyst (Figure 4.16). Liu et al.developed a tandem strategy for synthesising the same using expensive gold catalyst, thereby a new approach was required which could be cost-effective, less toxic and recyclable [26]. Later, Patil et al. [18] described a copper based tandem approach relating to which our group has generated an idea of using ionic liquid as a solvent media for copper catalysed tandem reactions for efficient syntheisis of pyrrolo/pyrrido benzoxazinones and quinazolinones. The heterocycles 40 were prepared through reaction happened between 2-aminobenzoic acid 39 and alkyne acid 25 in presence of [Bmim]BF4 ionic liquid. Using 5 mol% of copper acetate catalyst at a temperature of 120 °C for 12 h, the product was obtained with more than 80% of yields. The reaction follows the same mechanism with 39 as mentioned in Figure 4.17 [20].

4.2.4 Synthesis of poly heterocyclic compounds using one-pot methodology Pericherla et al. described the synthesis of imadazol pyridines using one-pot tandem imine cyclization in the presence of less toxic, in expensive copper catalyst in 48–92% yield. Zolimidine (drug) is used for treating the peptic ulcer, and using this strategy they have achieved the 61% yield [27] (Figure 4.18).

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Figure 4.16: Various synthetic strategies for the synthesis of benzoxazinones.

The production of imidazo[1,2-a] pyridine 43 is thought to be explained by the formation of an imine from the interaction of ketone and 2-aminopyridine, which can equilibrate to enamine I (Figure 4.19). The adduct II is formed when I react with the catalyst which is subjected to intramolecular aerobic oxidative cyclization in order to produce 43.

4.3 Transition metal catalysed isoindolinones synthesis Santra et al. reported a nano copper catalysed synthesis of fused isoindolinones 47 in aqueous medium using 2-formylbenzoic acid 45 as a starting material, as well as

4.3 Transition metal catalysed isoindolinones synthesis

Figure 4.17: Atom economical approach for synthesis of pyrrolo-/pyrido based benzoxazinones

Figure 4.18: Additive free approach for the synthesis of imadazol pyridines.

87

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4 Cu-Catalysed tandem reactions for building polyheterocycles

Figure 4.19: Mechanism for the synthesis of 43.

Figure 4.20: Nano copper catalysed synthesis of polycyclic isoindolinones.

isotonic anhydride 44 and functionalized amine 46 as intermediates. Water plays an important role as an electrophile and a nucleophile by forming a hydrogen bond with the carbonyl group of an isotonic anhydride and the amine functionality [28]. The nano copper oxide was also utilised multiple times without losing its activity. Because no chemical waste is formed during the reaction, thus, this methodology can be considered as an effective green chemistry protocol (Figure 4.20). In this change, water plays a critical role. The first stage of the process is probably accelerated by water molecules. Through hydrogen bonding between the water molecule and the carbonyl group’s oxygen atom, the isatoic anhydride’s carbonyl group’s electrophilicity is multiplied several times. The amine’s nucleophilicity is boosted as a result of the hydrogen bond formed between the oxygen atom of the water molecule and the hydrogen atom of the amine. Transition state gains higher stability as a result of this dual activation, which eventually leads to the production of intermediate I via CO2 and H2O elimination (Step I). Upon that the intermediate I combine with the aldehyde in the presence of nano CuO to generate the quinazolinone intermediate II (Step II), which is then cyclized intramolecularly to yield the product as in step III (Figure 4.21).

4.4 Synthesis of fluoroalkylated isoxazoles

89

Figure 4.21: Plausible reaction mechanism.

4.4 Synthesis of fluoroalkylated isoxazoles Hu et al. developed a facile, scalable, efficient, regio and chemoselective “click synthesis” of fluoroalkylated isoxazoles (FIOs) 48. This one-pot, low-cost approach was used to establish the direct synthesis of FIOs from alkynes and amines. The domino reactions were carried out in the presence of copper(I) as a catalyst and tert-butyl nitrite (TBN) as the reagent between a difluoro-methyl carbene solution dissolved in chloroform or acetonitrile and alkynes (Figure 4.22). The reaction produced lower yields at first but adding zinc salts boosted the yield to 87%. This possibility demonstrated that the reaction requires both copper iodide and zinc bromide [29]. In diverse functional groups, the reaction tolerated ortho, meta, and para substitution in a diverse of functional groups.

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Figure 4.22: Cascade green synthesis of fluoro alkylated isoxazoles.

Cu-carbene initiates the reaction from diazo compounds (generated in situ by FIOs reacting with TBN), followed by transmetalation and migratory insertion, resulting in carbenoid. This carbenoid was captured by the nitrosonium ion from TBN, which undergoes tautomerization to generate an oxime, which is then cyclized to yield isoxazoles (Figure 4.23).

Figure 4.23: Mechanistic pathway for synthesis of isoxazoles.

4.6 Cu-catalysed intermolecular cross-coupling

91

4.5 Fabrication of acid-responsive poly indolones Qi et al. presented a series of one-pot, two-step, three-component polymerizations to produce poly indolones (Figure 4.24). The reaction used a catalyst mixture that included bis(triphenylphosphine)palladium (II) dichloride, copper iodide, and N, N-diisopropylethylamine in the presence of THF in a N2 atmosphere. The general reaction was started with 52, electron-deficient aromatic diyne 53 and diamines as the nucleophile. The reaction between 52 and 53 was carried out for one day at room temperature, after which 54 was formed, onto which the Michael addition took place for 12 h at 60 °C to yield polymer [30].

Figure 4.24: Multicomponent one-pot polymerizations of diynes, and diamines.

The tandem polymerization was able to create 12 poly indolones efficiently and conveniently with diverse and multifaceted structures in high yields under mild reaction conditions via bimetallic-cooperative catalytic approach. Aromatic diynes, primary and secondary aliphatic amines, and aromatic amines are among the monomers that MCTPs can bind. The developed poly indolones shows a distinct acid-triggered fluorescence “turn on” response and selective fluorescence detection due to the quick conversion of enamine to ketone in an acidic medium, as demonstrated by small molecular model reactions.

4.6 Cu-catalysed intermolecular cross-coupling Collins et al. described the copper-catalyst mediated cross-coupling reactions of thiols with bromoalkynes to produce alkynyl sulphides. The catalyst for this reaction is ligand supported commercially available copper complex ligand combination of [Cu (MeCN)4] PF6 and dtbbpy (4,4′-di-tert-butyl-2,2′-dipyridyl). The approach is significant for being the first to efficiently link aryl-, alkyl-, silyl- and peptidic alkynyl coupling partners with ambient reaction temperatures and short reaction periods, yielding almost 80% products. Important features include a wide substrate range, high reactivity, and ease of usage. The chemoselectivity of the approach opens additional options. The alkynyl sulphide functional group can be used in a variety of ways [31] (Figure 4.25).

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Figure 4.25: Synthesis of alkynyl sulfides via intermolecular cross-coupling.

4.7 Multicomponent polymerization reactions (MCPs) 4.7.1 Synthesis of iminocoumarin/quinoline-based poly N-sulfonylimines Tang et al. produced two well-organized MCPs of diynes, sulfonyl azides, and 2-hydroxybenzonitrile or 2-aminobenzonitrile for poly N-sulfonylimines production. It was drawn to the building of iminocoumarin or quinoline structures because the reaction conditions were changed and made gentle. This research demonstrated efficient domino multicomponent polymerizations of the alkynes using triethyl amine as a catalyst and copper chloride as a catalyst under mild conditions at 40 °C, yielding iminocoumarin/aminoquinoline-based poly N-sulfonylimine s with well-defined structures, high molecular weights of 37,700 g/mol, and excellent yields of 96%. N2 is the only by-product. With good thermal stability and solubility, poly-N-sulfonylimines was well-liked. Poly-N-sulfonylimines were used to detect Ru3+ selectively and has antibacterial effects [32] (Figure 4.26).

4.7 Multicomponent polymerization reactions (MCPs)

93

Figure 4.26: MCPs of diynes, disulfonyl azides, and 2-hydroxybenzonitrile.

The terminal alkyne interacts with sulfonyl azide first to form keteneimine I, which is catalysed by CuCl and Et3N in a general plausible mechanism of the MCR processes. Triethylamine deprotonates 2-hydroxybenzonitrile to yield nucleophile II, which then attacks keteneimine I to yield intermediate III. Intramolecular cyclization of III produces anionic species IV, which is subsequently protonated and isomerized to produce amino-substituted iminocoumarin 61 (Figure 4.27). Tang et al. demonstrated that a multi-component polymerisation technique using copper catalyst resulted in the overall synthesis of nitrogen-containing polymers. Ammonium chloride, an inorganic salt, was essayed as the monomer in the polymerization. The fluorene-containing diyne, aromatic disulfonyl azide, and NH4Cl were added in the presence of CH2Cl2 at ambient temperature 25 °C under N2 atmosphere with triethylamine in the form of catalyst, and potassium hydroxide also marked its presence in the reaction [33] (Figure 4.28). At room temperature, the MCPs converted NH4Cl to imine moieties with remarkable atom economy and provided the desired poly sulfonyl

Figure 4.27: General mechanism for MCP reaction.

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Figure 4.28: MCPs of diynes, disulfonyl azides, and NH4Cl.

amidines with distinct specific structures imparting high yields and refractivity, appreciable molecular weights, good solubility and thermal stability, which were accomplished by copper catalyst. Furthermore, the fluorescence nature is induced by the metal coordinating property of poly sulfonyl amidine in combination with other monomer activities. Heterogeneous polymerization in dichloromethane/tetrahydrofuran proceeds smoothly at room temperature, yielding a variety of poly sulfonyl amidines with yields up to 96% and molecular weights up to 47,100 g/mol. Poly sulfonyl amidines may be modified to have unique photophysical characteristics and metal ion detection using monomers or in situ produced products, resulting in selective and sensitive Ru3+ fluorescence sensors. Choi et al. described a tandem three-component reaction for making doubly grafted polymers. In catalytic concentrations of copper bromide, an azide, an alkyne, and amines were subjected to multicomponent coupling (Figure 4.29). An electrondeficient copper bounded triazole moeity is formed via the Cu-catalysed cycloaddition of alkyne macromonomers with sulfonyl azides on the polymer surface [34]. The bond is broken by the immediate discharge of nitrogen, resulting in the formation of a reactive unstable ketene intermediate, that gets converted into doubly grafted polymers by the nucleophilic addition of amine macromonomers. 1H NMR and size

Figure 4.29: Plausible mechanism/reaction for Cu-Catalysed MCG strategy.

4.8 Cascade synthesis of pyrroles

95

exclusion chromatography (SEC) investigations revealed the MCG’s high efficiency and selectivity, with grafting efficiency of 79.99% and narrow-to-moderate dispersities.

4.8 Cascade synthesis of pyrroles Oximes are a versatile family of reagents that are non-toxic, air and moisture stable and operational easy. As shown in Figure 4.30, several pyrrole ring-containing molecules can be produced from oxime-based compounds [35]. Wei et al. demonstrated an effective, operationally scalable copper-assisted annulation/aromatization to produce multi-substituted pyrroles using promptly available oximes and azadienes as basic materials. The gram-scale reaction of 75 with 76 yields 77 with an 88% of yield. With a simple operating strategy, a wide substrate range, and good functional group compatibility, this approach examined the possibility of more than 40 examples of unique and exciting pyrroles. Under basic reaction conditions, the C=NTs group present here gets possibly hydrolysed into a ketone group. Nucleophilic substitution and condensation processes in tandem readily transformed the resulting product 78 to 79 (Figure 4.31). Furthermore, 77 undergoes C–H chlorination proficiently in presence of dimethylsulfoxide and N-chlorosuccinimide (NCS) and produces 80 [35].

Figure 4.30: Some pyrrole-containing bioactive molecules.

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Figure 4.31: Gram scale synthesis of pyrroles.

The mechanistic analyses reveal that in the presence of Cu(I) salt, a Cu (II) species and an iminyl radical I get generated via a single-electron reduction of the oxime N–O link. It is possible that the latter may quickly tautomerize into the -carbon radical II, leading to the radical addition of azadiene and the formation of a radical intermediate with a new radical III. The carbon atom may be added to the intramolecular imine group to produce IV radical species, which the Cu (II) salt could then oxidise to form the spiro-N-heterocycle V. Ring opening and aromatization activities can be combined to create the final product 80 (Figure 4.32).

Figure 4.32: Plausible mechanism for pyrrole synthesis.

References

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4.9 Conclusions The transition metal (TM)-catalysed organic reactions are without a doubt one of the most reliable and tunable synthetic procedures in the synthetic organic chemist’s toolkit, with applications spanning from fine chemistry to materials, pharmaceuticals and agrochemicals. Copper-based catalysts are widely used in a wide range of catalytic processes. Copper is an obvious very versatile, inexpensive, and easily available metal utilised in chemical processes in various oxidation levels Cu (0), Cu(I), Cu (II) and Cu (III). As previously stated, copper catalysed reactions have shown as a useful tool for deriving small-sized heterocyclic compounds. Numerous papers have lately emerged because of the various heteroatom presence in five-membered heterocyclic compounds, which are of crucial importance due to their vast range of biological properties. Click synthesis, annulation, cycloaddition, C–N hetero atom couplings, multicomponent polymerizations (MCPs), microwave assisted processes, and other methods can be used to synthesise heteroatoms. Microwave-assisted processes are thought to be faster and more efficient in the synthesis of contemporary heterocycles. These reactions, when aided by copper, allow for a wider range of substrates, greater tolerance of various functional groups, improved chemo and regioselectivity, and higher yields. While conducting a copper-based reaction, the use of a ligand can be reduced, this is considered even more helpful in this heteroatom creation. Acknowledgments: The authors are grateful to VIT, Vellore, Tamil Nadu, India, for granting the ’VIT SEED GRANT-SG20210267’ that enabled us to complete this book chapter work. Jyothylakshmi expresses her gratitude to the VIT for providing her a fellowship.

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Ramadan Ahmed Mekheimer, Mohamed Abd-Elmonem, Mohamed Abou Elsebaa, Maiiada Hassan Nazmy and Kamal Usef Sadek*

5 Recent developments in the green synthesis of biologically relevant cinnolines and phthalazines Abstract: Both cinnolines and phthalazines are heterocyclic compounds which have a wide range of biological activities and pharmacological profiles. This work represents the recent advances in the green synthesis of cinnolines and phthalazines as 1,2 and 2,3-diazanaphalenes were cited. The docking studies and mode of action for key scaffolds were also reported. Keywords: Cinnolines; Docking; Green Synthesis; Phthalazines

5.1 Introduction The majority of commercial medicines are heterocyclic compounds either mono or fused rings [1]. Such scaffolds are common in natural products as well as synthesized compounds. The pharmaceutical industries have been previously identified as nonenvironmentally friendly technique which is a main source of chemical wastes [2]. In recent years, numbers of alternative chemical procedures have been established to introduce eco-friendly techniques in heterocyclic synthesis to help reduction of toxic and harmful waste [3, 4] Research has been focused on the use of transition metal catalyzed reactions- recently their utility in cross dehydrogenative coupling- which directly utilize the inactive C–H bond to construct C–C and C–heteroatom bonds [5], green solvents, solvent-free and catalyst-free reactions. Moreover, the utility of unconventional protocols (microwave, ultrasonic, ball milling and reactions under reduced pressure) will increase the energy efficiency of the reaction [6, 7]. Cinnoline (A); 1,2-diazanaphthalene and phthalazine (B); 2,3-diazanaphthalene (known also as benzo-ortho diazine) are two isomeric heterocycles [8] resulted in

*Corresponding author: Kamal Usef Sadek, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt, E-mail: [email protected]. https://orcid.org/0000-0003-43425394 Ramadan Ahmed Mekheimer, Mohamed Abd-Elmonem and Mohamed Abou Elsebaa, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt Maiiada Hassan Nazmy, Biochemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: R. A. Mekheimer, M. Abd-Elmonem, M. Abou Elsebaa, M. H. Nazmy and K. U. Sadek “Recent developments in the green synthesis of biologically relevant cinnolines and phthalazines” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr2021-0091 | https://doi.org/10.1515/9783110797428-005

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Figure 5.1: Structure and numbering role of cinnoline and phthalazine.

Figure 5.2: Glimpse of biologically active cinnoline derivatives.

fusion of benzene ring with pyridazine scaffold (Figure 5.1). They are also isomeric with other naphthyridines namely quinazoline and quinoxaline. Cinnoline derivatives have attracted significant attention due to their great spectrum of pharmaceutical and medicinal activities. They show anti-bacterial [9, 10], antiinflammatory [11, 12], anti-allergic [13, 14] and anti-cancer activities [9, 10, 15–20]. Cinnolines are also possess liver x-receptor [21], anti-malarial [22], analgesic [23], DNA intercalators activities [24] and act as agrochemicals [25] and fluorescent agents in cellbased imaging [26]. Examples of biologically active cinnolines are illustrated in Figure 5.2. Phthalazines have gained increasing attention as a privileged motifs in the design of novel drugs owing to their potentiality as anti-diabetic [27], anti-cancer [28, 29], antiinflammatory [30, 31], anti-microbial [32–34], anti-malarial [35] and androgen receptor

5.2 Cinnolines

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Figure 5.3: Glimpse of biologically active phthalazine derivatives.

antagonist [36]. Examples of biologically relevant phthalazine derivatives are illustrated in Figure 5.3. This work will summarize the recent advances for the green synthesis of cinnolines and phthalazines as well as their biological activities.

5.2 Cinnolines Among the benzodiazine isomers, quinazoline has been extensively studied [37–39] while cinnolines and phthalazines have been relatively less investigated. The classical methods for the synthesis of cinnolines focused in two main approaches, i- Via aryl hydrazine/aryl hydrazone intermediates (Neber-Bossel and Barber synthesis); ii- Arene-diazonium salts (Richter synthesis and Widman–Stoermer synthesis). Recently, metal-catalyzed C–N and C–C bond formation have been utilized as a privileged tool for their synthesis. Also, oxidative annulation reactions utilizing alkynes offer an efficient route for the C–N and C–C bond formation. These main approaches were summarized in Figure 5.4.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.4: Classical and advanced methods for the synthesis of cinnolines.

5.2.1 Synthesis of cinnoline derivatives 5.2.1.1 Transition-metal catalyzed synthesis A powerful and growing tool in the chemo selective and atom economical synthesis of complex molecules is the radical cascade cyclization processes [40–43]. In such reactions a free radical species adds to multiple bonds followed by intermolecular cyclization affording the corresponding cyclic molecule [44–46]. An efficient protocol for the synthesis of interesting compounds which is not available via conventional methods has been recently initiated through aryl migration radical cascade cyclization [47, 48]. Wang et al. [49] have reported a novel copper-catalyzed cascade reaction of aryl sulfonyl hydrazones 11 obtained from the reaction of O-alkynyl aryl ketones 9 with hydrazine derivatives 10 and subsequent cyclization to give cinnoline derivatives 12 (Figure 5.5).

5.2 Cinnolines

105

Figure 5.5: Synthesis of cinnoline derivatives 12 via desulfonylation/cyclization of arylsulfonyl hydrazones.

A Plausible mechanism to account for the formation of the reaction product 12a was illustrated in Figure 5.6 [49]. Copper (II) intermediate A activated intramolecular aminocupration of 11a, then formation of vinyl-copper complex B. Subsequently, the homolysis of complex B produced vinyl radical C and copper(I) which could be oxidized to regenerate copper (II) to delivering spirocyclic intermediate D, which underwent a rapid rearomatization with desulfonylation to produce the aminyl radical E, constructing the new C−C bond, which could resonate with C-centered radical F. Oxidation by TBHP occurred to form the benzylic cation G and in the presence of (−OH); hydrolysis of G gave intermediate H. The oxidation of intermediate H by (t-BuO•) onto the OH group afforded O-centered radical I and successive N-C bond homolysis gave diazo radical J followed by an intramolecular cyclization with the aromatic ring formed aryl radical K which was oxidized to generate cationic intermediate L. Finally, cinnoline 12a has been formed by the base-assisted deprotonation.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.6: Proposed mechanism for the synthesis of cinnoline derivatives 12a.

A pioneering method was recently developed by Xu et al. [50] for direct access to cinnoline derivatives 14a-p through aerobic copper catalyzed C–N bond formation which involves selective C–H functionalization and dehydrogenative amination (Figure 5.7).

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Figure 5.7: Synthesis of cinnoline derivatives 14 via aerobic copper catalyzed C–N bond formation.

The authors concluded from their study that with various aryl substituents afforded the corresponding cinnolines smoothly with excellent yields regardless of their electronic and steric properties. A plausible mechanism to rationalize for the formation of the reaction product 14a was depicted in Figure 5.8.

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Figure 5.8: Plausible mechanism for the synthesis of cinnoline derivative 14a.

In recent years, C–C bond formation from transition metal-catalyzed dehydrogenative coupling (CDC) of relatively unreactive (C–H) bonds have received considerable interest in organic chemistry [51–54]. Among them the C–C bond formation from two C–H unreactive bonds utilizing copper catalyst under aerobic oxidation conditions has received an increasing interest. Several advances have been gained utilizing such conditions as high atom economy, and avoidance of toxic by-products upon using oxygen as the sole oxidant [55–58]. A diversity of Csp3–H or Csp2–H bond functionalization have been recently developed [59, 60]. In comparison Copper-catalyzed, CDC coupling of Cp3–carbon atoms adjacent to heteroatom suffers from restricted substrate scope [61–63]. Ge et al. [64] developed an efficient synthesis of 3-substituted cinnoline derivatives 16a–ab via copper-catalyzed cyclization-aromatization of 1-aryl-2-(-1-aryl ethylidene)1-methyl-hydrazine 15 in excellent yields (Figure 5.9). The reaction mechanism proposed for the formation of 16a–ab was illustrated in Figure 5.10. A direct synthesis of cinnoline derivatives 19 has been recently reported through Rh-catalyzed C-N bond formation of the readily available compounds 17 and 18 or analogs which proceeds via redox-neutral annulation under mild conditions [65] (Figure 5.11).

5.2 Cinnolines

Figure 5.9: Synthesis of 3-substituted cinnoline derivatives 16a–ab.

109

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.10: A Proposed reaction mechanism for the synthesis of 16a.

Figure 5.11: Synthesis of cinnoline derivatives 19 via Rh-catalyzed C–N bond formation.

To optimize the reaction conditions, authors examined several azo substrates 17 with R1 = phenyl or t-Bu, there is no reaction product and the starting materials were recovered. The reaction delivered products 19c–e in 41, 37 and 19%, yields, respectively, which indicate the advantage of carboxylate substrates as an appropriate leaving group (Table 5.1). To optimize the catalyst, load the reaction of 17a-e and 18a as a model was examined.

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Table .: Testing of several azo substrates a–e against diazo compound a.

a b c d e

% % % % %

R = Ph R = t-Bu R = COt-Bu R = COEt R = COBn

Table .: Using of several silver salts and co-solvents.

Entry

Catalyst

Solvent (v/v)

Yield (%)

          

[Cp*RhCl]/AgSbF [Cp*RhCl]/AgOAc [Cp*RhCl]/AgCO [Cp*RhCl]/AgSbF [Cp*RhCl]/AgSbF [Cp*RhCl]/AgSbF [Cp*RhCl]/AgSbF [Cp*RhCl]/AgSbF [Cp*RhCl]/AgSbF [Cp*RhCl]/AgSbF [Cp*RhCl]/AgSbF

AcOH/DCE (:) AcOH/DCE (:) AcOH/DCE (:) HCOOH/DCE (:) EtCOOH/DCE (:) PivOH/DCE (:) MSA/DCE (:) PivOH/DCE (:) PivOH/DCE (:) PivOH/DCE (:) DCE

      Trace  Trace  Trace

Several silver salts were tested and AgSbF6 afforded product 19c in 41% yield. An excellent yield (92%) was obtained when using PivOH/DCE as co-solvent in molar ratio 1:20 (Table 5.2). The mechanism to account for the formation of the product was postulated in Figure 5.12.

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Figure 5.12: Plausible mechanism for the synthesis of 19c.

A closely related synthesis of cinnoline derivatives 21a–p has been reported by Zhu et al. in the year 2016 utilizing Rh(III) catalyst [66]. Authors relied on the reaction of 1-alkyl-1-aryl-hydrazines 20 and diazo-β-ketoesters 18a in a redox-neutral coupling partners in the presence of [RhCp*Cl2]2/lithium acetate in methanol at ambient temperature which yielded excellent yields (Figure 5.13). A plausible mechanism was proposed in Figure 5.14. Rhodium(III) salts have received extensive studies for functionalization of aromatic ortho C–H bond and annulation reactions to construct heterocyclic scaffolds involving nitrogen-containing directing groups [67–70]. Early, Heck and his co-authors reported a stoichiometric annulation of cyclometalated azo benzenes with alkynes in nitromethane at 100 °C [71–73] (Figure 5.15).

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Figure 5.13: Synthesis of cinnoline derivatives 21 via Rh(III) catalyst intermolecular cyclization.

Figure 5.14: Proposed mechanism for the synthesis of 21a.

A convenient synthesis of cinnoline derivatives 24 has been recently reported that relied on RhCp*-catalyzed annulation of azo benzenes 6 with alkynes 7 either symmetric or asymmetric with various oxidants. Among oxidants utilized a combination of AgBF4 (1.00 mmol) and Cu(OAc).H2O (1.00 mmol) gave the best yields. Tertiary butyl alcohol (t-BuOH) was found to be the best solvent for the reaction. Other solvents as t-amyl-OH, MeOH, EtOH, 1,2-dichloroethane (DCE), THF and AcOH are less effective

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Figure 5.15: Synthesis of cinnolinium salts 23 via Heck and Rhodium (III) catalyzed synthesis.

giving lower yields of the product. Based on the result above the optimum reaction conditions found to be [(Rhp*Cl2)]2 (1 mmol), Cu(BuF4)2·6H2O (0.50 mmol) and t-BuOH as solvent in air (Figure 5.12). A reasonable mechanism to account for formation of the reaction products was illustrated in Figure 5.16. Cinnoline-3-(2H)-ones are found in several natural products and biologically relevant heterocycles [74, 75]. Kim et al. [76] have developed synthesis of cinnoline-3(2H)-ones 27 and 28 via coupling of azobenzene 6a with either Meldrum’s acid 25 or diethyl-2-diazomalonate 26 (Figure 5.17). However, the reaction requires the use of 3 equivalent of Ruthenium catalyst, which is a disadvantage. Recently, Patel and Borah [77] reported the first Ir(III)-catalyzed alkylation/ annulation of azobenzene 6 with diazotized Meldrum’s acid 25. The reaction shows

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115

Figure 5.16: Reasonable mechanism for the synthesis of cinnolinium salts 23.

Figure 5.17: Synthesis of cinnoline-3-(2H)-ones 27 and 28.

structural dependency on solvent used. In 1,2-dichloroethane, it afforded the corresponding cinnoline-4-carboxylate 29 derivatives, however, in methanol provided the corresponding ester 27 (Figure 5.18). In their study, authors concluded that the presence of In(OTf)3 (10 mol%) as an additive is crucial for reaction completion. A reasonable mechanism was postulated in Figure 5.19. A well-known method for the synthesis of cinnolines is the annulation of alkynylsubstituted aryltriazine. However, Harsh condition (e.g. high temperature or strong acids) are required [78–80]. Palladium annulation of alkynes by ortho-functionally substituted aryl halides has been established as a convenient and versatile methodology for the synthesis of variety of interesting and complicated heterocyclic scaffolds [81–83].

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Figure 5.18: Synthesis of cinnoline-3-(2H)-ones 27 via Ir(III) C–H activation.

Figure 5.19: Proposed mechanism for the synthesis of 27a.

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Table .: Pd-catalyzed reaction of ,-diethyl--(-iodophenyl)triaz--ene  with diphenylacetylene a.

Entry

Catalyst

Solvent

Base

Ligand

Yield (%)

             

Pd(dba) Pd(dba) Pd(dba) Pd(dba) PdCl PdCl PdCl PdCl PdCl PdCl PdCl PdCl PdCl PdCl

DMF CHCN Toluene ,-clioxane DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF

EtN EtN EtN EtN EtN EtN EtN EtN EtN i PrEtN n BuN KCO n BuN n BuN

– – – – PPh P(o-Toly) dppe dppf P(-Furyl) P(o-Toly) P(o-Toly) P(o-Toly) P(o-Toly) P(o-Toly)

      Trace       

A convenient synthesis of 3,4-disubstituted cinnoline derivatives 24 has been developed by Yamane et al. [84] through palladium-catalyzed annulation of 2-iodoaryltriazines 30 with alkynes 7 in the presence of base and promoted by heating under reflux in DMF as a solvent. To determine the role of the base, the reaction was carried out in the absence of the base and the yield was low (∼40%). Among bases examined Bu3N proved to be superior over others [Et3N, Pr2NH and K2CO3]. Moreover, various phosphine ligands were tested and P(o-tolyl)3 afforded higher yields than others. Authors realized that the optimal reaction conditions for the annulation reaction are: DMF in presence of PdCL2 (7.5 mol%), P(o-tolyl)3 (15 mol%) and nBu3N (2 equiv.) stirred at 90 °C (Table 5.3, Figure 5.20). A pioneering research by Gagosz et al. [85] in 2011 on the gold (I)-catalyzed hydroarylation of N-propargyl-N′-arylhydrazines 31 showed a great dependence of the reaction on steric interactions and the nucleophilicity of the phenyl group. Thus, dimethyl 1-phenyl-2-(prop-2-yn-1-yl)hydrazine-1,2-dicarboxylate 31a was chosen as model substrate to establish the reaction conditions. Under previously reported protocol [86] used for the hydroarylation of N-aminophenyl propargyl malonate utilizing gold complex [XPhOSAu(NCCH3)SbF6] 32 in refluxing nitromethane, no formation of the oxo-methylene tetrahydrocinnoline could be detected. This negative result could be rationalized for the possible formation of conformers 33 and 34 among which 34 is the less stable due to steric interactions and/or dipole repletion of the two ester groups.

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Figure 5.20: Synthesis of 3,4-disubstituted cinnoline derivatives 24a–q.

Moreover, the presence of ester group on the nitrogen atom attached to benzene ring reduces the nucleophilicity of such ring let it more inert (Figure 5.21). In order to solve this problem, authors replaced one of the ester groups by another alkyl or phenyl group. Annulation of 31b under optimized reaction conditions afforded cinnolines 35b in good yield (Figure 5.22).

Figure 5.21: Hydroarylation attempt of N-propargyl-N-arylhydrazines 31a with no formation of cinnolines 35a.

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119

Figure 5.22: Synthesis of dihydrocinnoline 35b and isomeric cinnoline 36b.

Thus, treatment of compound 31 with low load of gold (I) (1 mol %) catalyst and heating under reflux in nitromethane did not produce the desired cinnoline derivatives 35. Surprising, upon using higher molar ratio of the catalyst (4 mol %), the desired cinnoline was obtained, in 99% yield, after 1 h heating under reflux. A simple treatment of 35b with p-TsOH in a catalytic amount (5 mol%) yielded the isomeric cinnoline 36b in 76% yield (Figure 5.22). In order to establish the applicability of such methodology to other substrates, author first examined a series of N-alkylated substrates at the nitrogen atom attached to phenyl ring. The results were summarized in Table 5.4 which indicated rapid formation of cinnolines 36c–f in 75–99% yields. The low yield associated with the N-t-butyl derivatives 35f was rationalized as a result of competitive 5-endo nucleophilic addition of t-butylamino group onto the activated alkyne-gold complex 37 which led to unstable dihydropyrazole 38 (Figure 5.23).

Table .: Hydroarylation of N-alkylated substrates at the nitrogen atom attached to phenyl ring.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.23: Possible synthesis of dihydropyrazole 38 in case of t-butylamino group.

Figure 5.24: Hydroarylation with several para-substituted phenylhydrazine derivatives 39a-g.

In a second step, authors turned their attention to perform the annulation process on substrates at para position of the aromatic nucleus 39a–g. Authors concluded from their study that the nature of substituent had no remarkable influence on the reaction efficiency. In all cases, the reaction with the aryl group proceeds equally and smoothly with both electron-donating, electron attracting groups and halogen atoms and afforded good to excellent yields (Figure 5.24), however, with strong electron-withdrawing group (such as NO2) no reaction occur. For m-substituted aromatic nuclei 42a,b; although the reaction could be efficiently proceeds but mixtures of tetrahydro cinnolines 43 and 44a,b were obtained as a result of unselective nucleophilic addition of the aryl moiety to the activated gold-alkyne complex. For the o-substituted derivatives 45a,b; the annulation was found to be more difficult and requires longer reaction times (Figure 5.25). This may be rationalized by a probable unfavorable steric interaction in the cyclization transition state between N-methyl group and substrate at ortho-position. Thus, the annulation of 48a,b was found to be rapid and highly efficient and

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121

Figure 5.25: Hydroarylation of several ortho-and meta-substituted phenylhydrazine derivatives 42a,b and 45a,b.

Figure 5.26: Competitive hydroarylation with diarylhydrazine derivatives 48a–c.

surprisingly less selective. However, 49c showed higher selectivity. Authors concluded that the mechanism of annulation cannot be a simple process involving of electronic and/or steric effects but a more look should be considered (Figure 5.26). A formal three-component [2+2+2] cycloaddition reaction of 2-(trimethylsilyl)aryl triflate 51, tosyl hydrazine 52 and α-bromo acetophenone derivatives 53a–o has been recently developed for efficient synthesis of cinnoline derivatives 54 [86]. Reaction of 51, 52 and 53 in acetonitrile catalyzed by 3 equiv. of CSF at 80 °C for 3 h afforded the corresponding cinnoline derivatives 54a–o. In order to explore the scope of the reaction, authors examined other solvents (dioxane, THF, DCE, Toluene and EtOAC). Acetonitrile was the best choice as no products were obtained with the other solvents.

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The substrate scope of α-bromo ketones 53 was also studied and the authors revealed that the electronic effect of aryl substituent have significant influence on reaction efficiency. With neutral, electron donating and halogen substituents, the reaction proceeds smoothly and products were obtained in moderate to good yields (56–70%). Moreover, β-naphthyl and biphenyl groups afforded the expected products 54l and 54m. However, strong electron withdrawing groups (4-CN, 4-NO2) possess a negative effect on this reaction resulted in low product yield. Also, with heterocyclic substituents (2-benzofuryl) and methyl substituent no products were obtained (54n and 54o) (Figure 5.27).

Figure 5.27: Synthesis of cinnolines 54a–o via α-bromo ketone substrates 53.

5.2 Cinnolines

123

Figure 5.28: Synthesis of Synthesis of cinnolines 54p–w via 2-(trimethylsilyl)aryl triflates 51b–e.

The scope of 2-(trimethylsilyl)aryl triflates 51b–e was also studied, for symmetrically substituted aryne precursor 51b; the corresponding product was achieved in 43% yield. Meanwhile, with unsymmetrically arynes triflate precursor 56d,e; a mixture of two isomers was obtained in good yields. However, aryne 51c afforded sole regio isomers 54q–s (Figure 5.28). Based on cross-over experiments a plausible mechanism account for the formation of the reaction products was depicted in Figure 5.29.

Figure 5.29: A possible mechanism for the synthesis of cinnoline 54a.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Willis et al. [87] have developed a two steps annulation of diethyl diazene-1,2dicarboxylate 56 with various 2-(2-bromo alkenyl)aryl bromides 55 catalyzed by Cu(I) diamine catalyst to afford dihydrocinnoline derivatives 57. Thus, treatment of dibromide 56 with hydrazide diester 55 with a catalyst produced from Cu(I) and N,N`-dimethylethylenediamine using K2CO3 as a base in dioxane as solvent at 90 °C for 18 h afforded the desired diethyldihydrocinnoline-1,2-dicarboxylates 57 in excellent yields. The synthesized scaffolds could be transformed into their aromatic cinnolines 58 counterparts via heating under reflux in aqueous sodium hydroxide in ethanol at 70 °C for 16 h (Figure 5.30).

Figure 5.30: Copper-catalyzed synthesis of dihydrocinnolines 57 and NaOH mediated conversion into cinnolines 58.

5.2 Cinnolines

125

5.2.1.2 Synthesis via diazotization-annulation reactions A general and convenient synthesis of cinnoline derivatives has been achieved through diazotization-annulation of 2-aminoarylketones utilizing several reagents. The synthesized cinnoline were transformed to several polyfunctionally substituted biologically relevant heterocycles. Thus, Sugasawa reaction [88] of 2-chloroaniline 59 with nitriles 60 in the presence of stoichiometric amounts of AlCl3 and BCl3 afforded the corresponding 2-amino-3-chlorobenzophenone 61 which converted to cinnoline derivatives 62–66 as illustrated in Figure 5.31. As CF3 group does not survive the Sugasawa reaction an alternative route to the synthesis of 8-CF3 substituted cinnoline 73 was illustrated in Figure 5.32. Several cinnoline derivatives were prepared and examined for their liver X receptor LXRB binding potency referenced TO-901317 (74) and was found to show a potent LXR

Figure 5.31: Synthesis for series of cinnoline derivatives 62–66. Reagents and conditions: (a) BCl3/AlCl3, 30–60%; (b) NaNO2/H+; (c) 80 °C, 20–80% over all yield for step (b) and (c); (d) POBr3/DMF or POCl3; (e) arylboronic acids, K3PO4, Pd(PPh3)4, dioxane, 30–85%; (f) benzyl amines, NaBH(OAc)3, DMF, 30–90%; (g) benzyl bromides/K2CO3 or benzyl alcohol, DIAD, PPh3; 30–90%.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.32: Synthesis of 8-CF3 substituted cinnoline 73. Reagents and conditions: (a) SOCl2, 84% (b) HNMeOMe; (c) PhCH2CH2MgCl, 81% for step (b) and (c); (d) NH3/DMF, 90%; (e) NaNO2/H+, 34%; (f) POBr3, DMF, 34% for step (e) and (f); (g) K3PO4, Pd(PPh3)4, dioxane, 74%; (h) benzyl bromides, K2CO3, or benzyl alcohol, DIAD, PPh3, 30–90%.

pan agonist (Table 5.5). Authors demonstrated that non-substituted scaffolds 74 and mono-substituted benzyl scaffolds 78 and 79 showed potent binding affinity for LXRB (IC50 < 50 nM), however their subtype binding selectivity was low. With di-substituted analogues 80 a better binding selectivity was shown. Shifting the CF3 from (position 3) to (position 5) 81 dropped the selectivity to 12-fold. Table .: Binding affinities of compounds – for LXR receptor α and β.

Compound

R

R

Ar

L

                      

– – – Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl CF CF CF CF CF CF Cl Cl Cl

– – – Bn Bn Bn Bn Bn Bn Bn Bn Bn Ph Ph Bn Bn Bn Bn Bn Bn Bn Bn Ph

– – – Ph -Cl-Ph -CF-Ph -Cl--CF-Ph -Cl--CF-Ph -CF--Cl-Ph -CF–-F–Ph -Cl–-CF–Ph -CF–-F–Ph -CF–-Cl–Ph -Cl–-CF–Ph -CF–-Cl–Ph -CF–-F–Ph -F–-CF–Ph -Cl–-CF–Ph -Me–-indole -Me–-indole -Me–-indole -Me–-indole -Me–-indole

– – – O O O O O O O NH NH O NH O O O O O O NH NH NH

5.2 Cinnolines

127

hLXRβ IC (nM)

hLXRα IC (nM)

Ratio α/β

                      

           >   >    > > >  

. .  . . .      > . . >    > > >  .

Changing the orientation to 2CF3-5-Cl 82 increases the selectivity to 21-fold, however the LXRB binding affinity decreased from 12 nM for 81–85 nM for compound 82. Compound 83 showed a binding affinity and selectivity similar to 82 (IC50 44 nM and 27-fold). Cinnolines with linker L=NH (84 and 85) showed somehow similar selectivity or binding affinity with those with L= O (80 and 83). However, 3-phenyl substituted cinnolines (86 and 87) (R2 = Ph) exhibit a big loss in binding selectivity and similar LXRB binding affinity. Moreover, all 8-CF3 scaffolds with 2,3 and 2,5-disubstituted phenyl group’s (88–91) showed good binding selectivity for LXRB with indole 93 have the most selectivity (71-fold) and potent binding affinity (IC50 14 nM) in this 8-CF3 series. While the 8-Cl-3-benzyl indole 94 also possess potent and selective potency toward LXRB (IC50 14 nM and 42-fold) the 8-Cl-phenyl analogues 95 was also potent (LXRX, IC50 10 nM) but not selective (6.2 fold). A docking study of the cinnoline 93 into a previously solved in-house-X-ray structure of WAY-254011 was performed which established the best scoring pose of 93 as illustrated in Figure 5.33. Very recently, 4-hydroxycinnolines 99a–d were synthesized via a similar protocol in good yields and subjected to propargylation of the free hydroxyl group followed by click regioselective 1,3-dipolar cycloaddition reaction with azides affording the corresponding cinnoline-1,2,3-triazole derivatives 102a–o, 103a–d (Figure 5.34). The in vitro antibacterial potency of all the synthesized compounds was investigated [89].

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.33: Compound 93 docked into the LXRβ/WAY-254011 pocket (ligand is shown in magenta). Only key residues of the binding site are shown for simplicity. Residue difference, that is, Ile277(β)/ Val263(α) closest to the ligand is highlighted in yellow and distance from Cd of Ile277 to 7-methyl group of indole is shown in magenta. Hydrogen bonds to key residues are shown as dotted cyan line. Reproduced with permission from Ref. [88]; Copyright 2009; Elsevier Ltd.

The synthesized compounds were tested for their in vitro anti-bacterial activity against gram-positive (Bacillus subtilis, Staphylococcus aureus) and gram negative (Pseudomonas aeruginosa, Escherichia coli) bacterial strains at 10 μM/ml using DMSO as a solvent compared to standard drug Norfloxacin. The results revealed that the antibacterial activity was enhanced with scaffolds bearing halogen and electron-donating groups (102d, 102g and 102k). Moreover, products with morpholine side chain (103a–d) have more anti-bacterial potency. The results of compounds with excellent zone of inhibition were given in Table 5.6. A molecular docking study for compound 102d, 103a, 103b and 103c with Elastase of P. aeruginosa was studied and results revealed that compared to antibiotic Norfloxacin, the high docking score and binding affinity are in the range of 110.706– 129.425:135.922. Among them 102a fitted well in the active cite pocket. The best H-bonded conformations of tested compounds were illustrated in Figure 5.35. In a similar manner cinnoline precursors 107–115 were synthesized, as illustrated in Figures 5.36 and 5.37 and utilized for further synthesis of biologically relevant cinnolines [90]. Synthesized cinnoline derivatives were tested as potential PDE10A inhibitors. Three synthesized compounds were found to be potent inhibitors of PDE10A with IC50 values ranging from 1.52 ± 0.18 to 2.68 ± 0.10 µM, the results are illustrated in Table 5.7. A convenient synthesis of 6,7-dimethoxy-4-(pyridin-3-yl)cinnoline derivatives 116a–m has been reported by Hu et al. Specifically authors utilize 1-(2-amino4,5-dimethoxyphenyl)-ethanone 106b as a precursor as illustrated in Figure 5.38 [12].

5.2 Cinnolines

129

Figure 5.34: Synthesis of 4-hydroxycinnoline derivatives 99a–d and the corresponding cinnoline1,2,3-triazole derivatives 102a–o, 103a–d.

In early report, the same principal author, synthesized diversity of cinnoline derivatives with 4-(2-substituted pyridyl) moiety 109d–l and evaluated their PDE10A potency (Table 5.8) [91].

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Table .: Anti-bacterial activity of compounds d,g,k and a–d.* Compound

Gram-positive

Gram-negative

Bacillus subtilis Staphylococcus aureus Pseudomonas aeruginosa Escherichia coli d g k a b c d Norfloxacin

 . . . . . . .

. – . . . . . .

. – – . . . -eth] .

. . – . . . – 

*Zone of inhibition (mm)  mg/mL concentrations.

Figure 5.35: Receptor–ligand hydrogen bonds (green color) and bumps (pink color) of compounds 102d, 103a, 103b, 103c and norfloxacin with active site residues of Elastase of Pseudomonas aeruginosa (PDB: 1U4G). Reproduced with permission from Ref. [89]; Copyright 2020; Taylor & Francis.

Table .: The PDEA inhibition activity (IC nM) of cinnoline analogues.

Compound

R

R

R

R

a b a

OBn OMe OMe

OMe OMe OMe

H CH CH

Pyridn--yl Pyridn--yl -Flouro-pyridin--yl

lC (nM) . ±  . ± . . ± .

5.2 Cinnolines

131

Figure 5.36: Synthesis of cinnoline analogues 110a–c and 111a–c. Reagents and conditions: (a) HNO3, SnCl4, CH2Cl2, −70 °C; (b) Fe, NH4HCO3, toluene, water, reflux; (c) NaNO2, acetic acid, 70%H2SO4, Et3N; (d) POCl3, PCl5; (e) 2-fluoropyridine-5-boronic acid, Pd(PPh3)4, Cs2CO3, diglyme; (f) i. 4-(pyridin-3-yl)piperidin-4-ol or 4-methyl-piperidin-4-ol, K2CO3, DMSO, reflux; or ii. K2CO3, DMSO, reflux, then H2, 10% Pd/C, methanol, 75 psi.

According to the results obtained authors demonstrated that the PDE10A IC50 values ranging from 590 nM with R= Cl to 7.6 nM with R= NHiPr which revealed that nitrogen atom is the optimal linker as carbon and oxygen linker decrease the potency.

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Figure 5.37: Synthesis of cinnoline derivatives with substitution in the pyridine ring. Reagents and conditions: (a) H2 (75 psi), 10% Pd/C, MeOH; (b) 2-(bromomethyl)quinoline or 1-bromo3-fluoropropane, NaH, THF; (c) 2-fluoro-3-methylpyridine-5-boronic acid, Pd(PPh3)4, Cs2CO3, 1,2-dimethoxyethane; (d) 5-bromo-2,3-dichloro-pyridin, K2CO3, DMSO, 110 °C; (e) bis(pinacolato) diboron, KOAc, (1,1′-bis(diphenylphosphino)ferrocene) Pd(II) dichloride, dioxane, 120 °C; (f) piperidinol, K2CO3, DMSO, 100 °C.

Consequently, authors concluded that a small modification in pyridine ring substituents will have a great effect on their PDE10A inhibition potency. Among the different cinnoline derivatives, investigation of structure activity relationship, revealed

5.2 Cinnolines

133

Figure 5.38: Synthesis of 6,7-dimethoxy-4-(pyridin-3-yl)cinnoline derivatives 116a–m. Reagents and conditions (a) NaNO2, HCl, water, 75 °C, 71% yield; (b) POBr3, MeCN, 70 °C, 77% yield; (c) Cs2CO3, Pd(PPh3)4, DME, water; 40–95% yield; (d) amine, K2CO3, DMSO, 90 °C. Table .: SAR of -pyridine analogs.

Compound

R

d e f g h i j k l

Cl H CH CF CN NH NHiPr CHiPr OiPr

PDE IC (nM)  ,   .  . . .

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Table .: Examination of diversity substitution for PDEA activity.

Compound b d e g i c g e m

PDE IC (nM) . . . . . . . . .

Figure 5.39: X-ray co-crystal structure of compound 114f in the catalytic domain of PDE10A enzyme. Reproduced with permission from Ref. [12]; Copyright 2012; Elsevier Ltd.

5.2 Cinnolines

135

that derivatives 114b,d,e,g,I and 116c,e,g,m exhibited the best potent and metabolically stable PDE10A activity (Table 5.9) and convenient for testing in behavioral model the rest of synthesized compounds depicted poor to moderate potential. To assess the potency of the synthesized compounds in a rodent model Schizophrenia an Avoidance Response Condition (CAR), Sprague-Dawley rats were tested 1 h post dosing at 3, 5.6 and 10 mg/kg by oral gavage utilizing compound 114b. It was found that it could suppress the avoidance response (AR) in rats with a MED of 5.6 mg/kg. Using compound 114f, co-crystallization was performed with the human PDE10A catalytic domain which elucidates the key bonding interactions (Figure 5.39). The methoxy groups in the cinnoline scaffold established a hydrogen bonding with the conserved Gln716. The aniline substituents extend to a Shelf-like are in the enzyme consisting of the amino acids Met704, Phe686, Met703, and Ile 701. Cyclization of o-ethynyl substituted aryltriazines 118a–c have been reported to produce either isoindazole or cinnoline derivatives according to reaction conditions [92, 93]. A Richter type cyclization was achieved upon cleavage of triazine moiety with aqueous HCl or HBr, affording the corresponding cinnoline derivative through o-ethynenearyldiazonium salt [94]. It is worth mentioning that the cyclization of orthosubstituted ethynylarenes is well established, however cyclization of β 1,3-diynylβ derivatives has attracted less attention due to their availability and stability. An interesting cyclization of o-(dodeca-1,3-diynyl)arenediazonium salts 118a–c by the action of HCl or HBr has been reported by Balova et al. [79]. They demonstrated that, the nature of

Figure 5.40: Richter cyclization of o of o-(dodeca-1,3-diynyl)arenediazonium salts 118a–c.

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Table .: Comparison between Richter reaction of o-(dodeca-,-diynyl)aryltriazines and the yield of products. Triazine

a a b a b a a c c c

X

H H Br H Br H H H H H

Y

Br Br CH Br CH Br Br COMe COMe COMe

Solvent (time; h)

Acetone () Acetone () Acetone () Acetone () Acetone () Acetone () EtO () Acetone () Acetone () Acetone (.)

HHal (conc.)

HBr ( M) HBrconcd HBrconcd HCl ( M) HClconcd HCl ( M) HBrconcd HBrconcd HClconcd HBrconcd

Products, yield (%) 





         

– – – – – – –   

– – – – – – –  – 

Figure 5.41: Reaction of methyl 4-bromo-3-(dec-1-yn-1-yl)cinnoline-6-carboxylate (119c), 4-bromo-3(dec-1-yn-1-yl)cinnoline (119g) with MeNH2, Na2S and phenylacetylene.

substituent and reaction conditions influences the structure of the reaction product (Figure 5.40, Table 5.10). The main product methyl 4-bromo-3-(dec-1-yn-1-yl)cinnoline-6-carboxylate (119c) was subjected to several transformations to the corresponding cinnoline derivatives 122–124 (Figure 5.41). Human neutrophil elastase (NHE) is a serine protease and contains 218 amino acid residues as well as four disulfide bridges. It plays a crucial role in several physiological

5.2 Cinnolines

137

Figure 5.42: Synthesis of cinnoline derivatives 129a–d and 130. Reagents and conditions: (a) (C2H5O)2CO, anhydrous THF, NaH, reflux, 4h; (b) CF3COOH, 0 °C; rt, 2 h; (c) for 129a: cyclopropancarbonyl chloride, Et3N, anhydrous CH2Cl2, 0 °C, 2 h; rt, 2 h; for 129b: CH3I, anhydrous CH3CN, Na2CO3, reflux 8 h; for 129c: 3-methylbenzyl chloride, K2CO3, anhydrous DMF, 80 °C, 1 h; for 129d: m-toluyl chloride, Et3N, anhydrous CH2Cl2, 0 °C, 2 h; rt, 2 h; (d) NaOH (6N), 100 °C, 5 h.

processes such as inflammation, blood coagulation and apoptosis due to its proteolytic activity, against a diversity of extracellular matrix proteins [95–97]. Recently, (NHE) display activity in fields related to progression of cancer and chronic functional

Figure 5.43: Synthesis of cinnoline derivatives 133a–d. Reagents and conditions: (a) HCl conc., NaNO2 solution, 0 °C, 2 h; rt, 48 h; (b) m-toluyl chloride, Et3N, anhydrous CH2Cl2, 0 °C, 2 h; rt, 2 h; (c) 3,4-dihydro-2H-pyran, (NH4)2Ce(NO3)6, anhydrous CH3CN, rt, 24 h; (d) CF3COOH/CH2Cl2 1:6, rt, 3 h.

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Figure 5.44: Synthesis of cinnoline derivatives 137a–c, 138a–c and 139. Reagents and conditions: (a) 136a,c: NCS or NIS, anhydrous DMF, 60 °C, 3 h; 136b: Br2, CH3COOH, CH3COONa, reflux, 1 h; (b) R-COCl, Et3N, CH2Cl2, 0 °C, 2 h; rt, 2 h; (c) H2, Pd/C, EtOH abs., 30PSI (Parr), 4 h.

Figure 5.45: Synthesis of cinnoline derivatives 141b–d, 143 and 145. Reagents and conditions: (a) m-toluyl chloride, Et3N, anhydrous CH2Cl2, 0 °C, 2 h; rt, 2 h; (b) HCOONH4, Pd/C, EtOH abs., 80 °C, 2 h.

recovery for brain treatment injury [98, 99]. Although, several examples of (NHE) inhibitors have been developed, only two drugs are currently used for clinical treatment [99], namely, Prolastin and Sivelestat. To date Sivelestat is currently under evaluation for bronchiectasis [100] (Figure 5.42).

5.2 Cinnolines

139

In continuation to their efforts to discover a new class of NHE inhibitors [101] Giovannoni and co-worker [102] synthesized a diversity of new cinnoline scaffolds and evaluates their HNE inhibition activity compared to N-benzoylindazoles (Figures 5.43–5.45). The results obtained revealed that the synthesized compound although exhibiting (HNE) inhibitory activity but has lower potency than previously reported N-benzoylindoles. Among the tested compound 133a incorporating 1-(-3-methylbenzoyl)-substituent possess a good balance between chemical stability (t1/2 = 114) and inhibitory activity (IC50= 56 µM). The inhibition constants (Ki) for the two derivatives with highest (HNE) inhibitory activity (133a and 133e) were determined which showed values of 75 and 110 µM respectively. The analyses of reaction kinetics evidence that compounds 133a and 133e act as reversible competitive inhibitors of (HNE). A comparison between chemical stability of 133f (IC50= 0.2 µM) and previously reported N-benzoylimidazoles showed that cinnoline derivatives is more stable with (t1/2 for 133f = 233 min). Molecular docking studies has become an important key and rational approach for drug for drug discovery. It is aiming to give a prediction of the ligand-receptor complex structure using computation methods [103–106]. Molecular docking studies were performed to reveal the mode of binding inside the active pocket of Ser195, His57 and Asp102. Cinnoline with 4(1H)-one and C-4 ester

Figure 5.46: Panel Docking poses of reference compound 129b (dark-green) and compound 133e (blue). Reproduced with permission from Ref. [102]; Copyright 2016; Taylor & Francis.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.47: Synthesis of 6-hydroxycinnolines 149 and 151a–e. Reagents and conditions: (a) HNO3/HCl/90 °C/10 min; (b) methyl cyanoacetate/EtOH/NH4OH/rt/ 10 min; (c) hydrazine hydrate/EtOH/reflux1 h; (d) arylthiol/EtOH/reflux 5 h.

function subjected to nucleophilic attack of Ser195-OH which can be accomplished with by proton transfer from serine OH group through His57 to Asp102. Moreover, a favorable orientation of the side chains for Ser195, His57 and Asp102 was accomplished with this mechanism (Figure 5.46). 5.2.1.3 Synthesis from hydrazone precursors One of the most established approaches for the synthesis of cinnoline derivatives is utilizing arylhydrazones as precursors [107, 108]. Example of earlier reports has been illustrated in Figures 5.47 and 5.48.

5.2 Cinnolines

141

Figure 5.48: Synthesis of cinnoline derivatives 158, 160 and 162. Reagents and conditions: a) MeCOCH2Cl, EtONa, EtOH, reflux, 5 h; 60%. b) N2H4·H2O, EtOH, rt, 12 h; 75%. c) MnO2, THF, rt, 12 h; 86%. d) i). N2H4·H2O, EtOH, rt, 12 h; ii). MnO2, THF, rt, 12 h; 40%. e) BBr3, CH2Cl2, −50 – rt, 12 h; 82%. f) TsCl, pyridine, DMAP, CH2Cl2, reflux, 12 h, 70%. g) THF, reflux 72 h.

Mubark and his co-authors [109] reported the synthesis of relevant biologically active 3-(4-(Substituted)-piperazin-1-yl)cinnolines 167 via intermolecular cyclization of hydrazones 166 (Figure 5.49).

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Figure 5.49: Synthesis of 3-(4-(Substituted)-piperazin-1-yl)cinnolines 167.

The synthesized compounds were screened for their in-vitro antibacterial, antifungal and anti-cancer activities. The results obtained revealed the inactivity of the synthesized compounds against either Gram-negative (Escherechia coli ATCC 8739) or Gram-positive (Staphylococcus aureus ATCC 25923) microorganisms at 25 μM/ml. Moreover, they are also possessing inactivity toward Candida glabrata clinical neonatal isolates 1,2. Compounds 167a–h showed fairly good activity against C. albicans [109] clinical isolates in contrast to their inactivity C. albicans ATCC 10–23′ and C. glabrata ATCC 15126. Compounds 167a–d possess fungicidal activity rather than fungistatic activity against C. glabrata ATCC 15126 strains with minimum inhibitory concentration (MIC) ranging from 0.3–0.5 mg/mL referenced to Nystain with MIC ranging from 0.003– 0.008 mg/mL [109]. Compounds 167e–h showed no antifungal activity against C [109]. Glabrata clinical isolates1, 2 and C. albicans ATCC 10231, however, 167e and 167h have moderate antifungal activity toward C. albicans (ATCC 15126) strains. Moreover, 167e,f,h showed

Figure 5.50: Synthesis of dihydrobenzo[h]cinnoline-5,6-diones 171.

5.2 Cinnolines

143

Figure 5.51: A Proposed mechanism for the synthesis of dihydrobenzo[h]cinnoline-5,6-diones 171.

moderate antifungal activity against C. glabrata ATCC 15126 and ATCC 10231 strains, however 167g is inactive [109]. The anticancer activity of compounds 167a–l was evaluated against breast cancer cells (MCF-7) and leukemia cancer cell lines (K562), at a concentration of 50 μM/ml. The results revealed that compounds 167b, j and l have the highest potency against (MCF-7) cell lines with 167b have the highest IC50=5.56 µM. However, none of compounds 167b,j,l have any activity against K562 [109]. A novel synthesis of functionalized dihydrobenzo[h]cinnoline-5,6-diones 171 was developed by Dang and co-authors [110] via a one pot multi-component reaction of 2-hydroxy-1,4-naphthoquinone (168), methylhydrazine (169) and aromatic aldehydes 170 in refluxing t-BuOH for 2–3 h (Figure 5.50). A plausible mechanism for the formation of the reaction products 171 was depicted in Figure 5.51. The synthesized compounds were evaluated for their cytotoxicity profile. Compounds 171a–o showed moderate cytotoxicity activity against the KB and Hep-G2 cell lines compared to the anticancer reference compound Ellipticine. Among them,

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.52: Synthesis of 3-cinnoline carboxamides derivatives 187a–d, 190a–h and 191a–f.

compounds (171a,b,d,f,h,j,k,m) possess the highest potency with IC50 values below 5 µM against the two-cell line, with 171j displayed the highest potent scaffold with IC50 values of 0.56 and 0.77 µM toward the KB and Hep-G2 cell lines. A pioneering synthesis of 3-cinnoline carboxamides as highly potent and selective ATM inhibitors was developed by Barlaam and co-authors [111] that relied on

5.2 Cinnolines

145

Figure 5.53: Synthesis osazone 193k and cinnoline derivatives 194.

Figure 5.54: Synthesis of cinnoline derivatives 196.

Figure 5.55: Synthesis of 1,4-dihydrocinnolines derivatives 197 from cinnolines 196.

re-esterification/saponification of 1-(2-amino-5-bromophenyl)ethanone 98c and subsequent cyclization to intermediate 181. A diversity of 3-cinnoline carboxamides was synthesized precursors 182 as illustrated in Figure 5.52. The synthesized compounds were evaluated as Ataxia Telangiectasia Mutated kinase inhibitors. Compound 191e was identified as the most potent with IC50 = 0.0028 µM associated with favorable physicochemical and pharmacokinetics properties as well as high selectivity. Combination of 191e with Irinotecan possesses superior regression against tumor in the SW620 colorectal Xenograft model rather than Irinotecan alone.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.56: Synthesis of 1-(3,4-dichlorobenzyl)-3-(3-methylcinnolin-5-yl)urea (200) from reaction of 198 with 199.

An interesting and efficient synthesis of 3-substituted cinnolines utilizing glucose osazone 193 as precursor has been reported by Delvin et al. selected cinnolines 196 were converted to the corresponding 1,4-dihydrocinnoline derivatives 197 in high yields (Figures 5.53–5.55) [112]. Authors stated that the synthesized heterocyclic scaffolds could serve as precursor for future programs concerning medicinal chemistry. 5.2.1.4 Synthesis from cinnoline precursors The synthesis of functionally substituted cinnoline derivatives from cinnoline precursors represents a direct and efficient protocol to provide targeted biologically relevant heterocycles.

Figure 5.57: Synthesis of 4-(piperidin-1-yl)cinnoline (206) and 3-(cinnolin-4-yl(isopropyl)amino)propane-1,2-diol (208).

5.2 Cinnolines

147

A convenient synthesis of 1-(3,4-dichlorobenzyl)-3-(3-methylcinnolin-5-yl)urea (200) has been reported by Gomtsyan et al. [113] starting from commercially available 5-amino 3-methyl-cinnoline (198) via reaction with 3,4-dichlorobenzylamine (199) (Figure 5.56). The in-vitro activity of the synthesized compounds for blocking Capsaicin activation of transient receptor potential Vanilloid 1 (TRPV1) receptor antagonist was examined and showed less activity (IC50 = 189 µM) than isomeric quinazoline (IC50 = 42 µM) and phthalazine (IC50 = 175 µM). Few examples of antibacterial drugs possess cinnoline derivatives are yet known [114, 115]. Several 4-amino cinnoline derivatives were achieved starting from cinnoline-4-one 201 as illustrated in Figure 5.57 [116]. The synthesized amino compounds seem to be of high potency owing to their structural similarity with known drug scaffolds. 5.2.1.5 Synthesis from pyridazine precursors Although, the synthesis of cinnoline derivatives has received great attention utilizing arene precursor, only Sadek et al. [117] have reported novel synthesis of polyfunctionally substituted cinnolines 213 which involves the reaction of ethyl 1-aryl-5-cyano4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate 209 with nitroolefins 211 in dioxane/pip promoted by controlled microwave irradiation (Figure 5.58).

Figure 5.58: Synthesis of polyfunctionally substituted cinnolines 213.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

5.3 Phthalazine The general and most extensively studied synthesis of phthalazines relied on the condensation of o-dicarbonyl arenes with hydrazines. An alternative route which is applicable for some specifically substituted phthalazines including the formation of hydrazones instead of azines, from phthalhydrazide and utility of phthalizinones as precursor for producing functionally substituted phthalazines were also investigated. A pioneering protocol has been developed by our group via the reaction of 4-alkylpyridazines with a diversity of electrophiles.

5.3.1 Synthesis of phthalazine derivatives 5.3.1.1 From hydrazine and its derivatives Substituted phthalazine-1-ol derivatives exhibit a significant anti-cancer [118, 119], cardiotonic and antimicrobial activities [120]. The reaction of hydrazines with o-dicarbonyl arenes or ylidenoisobenzofuran-1-ones allowed the formation of phthalazine-1-one phthalazine-1-ol derivatives which possess a dynamic equilibrium between the two tautomers. Elgendy et al. [121] have developed a convenient green synthesis of phthalazine-1-ol derivatives 217 via the reaction of 3-benzylidene iso-benzofuran-(3H)-one (214) with

Figure 5.59: Synthesis of phthalazine-1-one 216 and phthalazine-1-ol derivatives 217.

Figure 5.60: Synthesis of the functionalized phthalazine-1-ol derivatives 219, 220 and 221.

5.3 Phthalazine

149

Table .: Screening of synthesized phthalazines against human cell lines. In vitro cytotoxicity IC (μM)

Compound

DOX  with tautomer  Pure   

HePG

HCT-

MCF-

. ± . . ± . . ± . . ± . . ± .

. ± . . ± . . ± . . ± . . ± .

 ± . . ± . . ± . . ± . . ± .

Figure 5.61: Synthesis of N-substituted phthalazine derivatives. Reagents and conditions: (a) dioxane, rt, 1 h; (b) NH2NH2, propanol, 2 h (c) POCl3, reflux 70 °C, 2 h; (d) p-phenylenediamine, butanol, 110 °C, 1 h, (e); benzoyl chlorides, acetonitrile, TEA, 6 h; (f) aryl isocyanates, DMF, reflux 8 h; (g) 1a–c, Cs2CO3, acetonitrile, reflux 6 h; (h) piperazines, K2CO3, KI, EtOH, reflux 3 h.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

4-chloro-benzaldehyde (170) and hydrazine hydrate promoted by microwave irradiation at 125 °C (Figure 5.59). Authors demonstrated that utility of MW irradiation favors the predominance of 4-(2-(4-chlorophenyl)-1-phenylvinyl)phthalazin-1-ol (217) over tautomeric product, namely, 4-(2-(4-chlorophenyl)-1-phenylvinyl)phthalazin-1(2H)-one (216). According to TGA-studies, 50.8% mass loss of (214) is related to the first full half reaction at 404 K which outlined the thermal stability of the phthalizine-1-one (50.9) than that approximately produced 4-(2-(4-chlorophenyl)-1-phenylvinyl)phthalazin-1-ol (217) (40%) reflecting the thermal kinetic control stability of 4-(2-(4-chlorophenyl)-1-phenylvinyl) phthalazin-1(2H)-one (216) (13 kcal/mol). However, performing the reaction under microwave irradiation resulted in formation of phthalazine-1-ol (217) at 413 K that stabilized by 36 kcal/mol due to aromaticity. The synthesized phthalazine-1-ol derivative 217 could be functionalized to other derivatives 219 and 221 (Figure 5.60). The synthesized phthalazines 216, 217, 219 and 221 were screened for their cytotoxicity against HePE2, HCT-116 and MCF-7 human cell lines referenced to Doxorubicin (DOX). The results are summarized in Table 5.11. Biarylamides and piperazinyl moieties exhibit privileged biological activities ([122–124]). In order to possess more potent biological activities, Elmeligie and coauthors [125] designed a hybrid 1-biarylamide 231, biarylurea 224, 229 and 232 or N-substituted phthalazine derivatives 231, 229 and 232 respectively, via synthetic protocol depicted in Figure 5.61. Authors explored the anti-proliferative activity of the synthesized compounds of the tested the compounds, (232b,e) were exhibited the most potent inhibition against various cancer cell lines including leukemia, non-small cell lung cancer, melanoma, prostate cancer as well as breast cancer. Compound 232e showed the most potent inhibitory against most of the tested leukemia and melanoma cell lines. Likewise, compound 229b exhibited highly potent inhibitory against leukemia, colon, melanoma and breast cancer meanwhile, 229a showed moderate potency against breast and leukemia cell lines.

Figure 5.62: Examples of commercially therapeutic phthalazine derivatives.

5.3 Phthalazine

151

Figure 5.63: Synthesis of N-substituted phthalazine sulfonamide compounds 237.

Owing to their pronounced pharmacological properties, phthalazines were commonly employed as therapeutic agents. Examples of commercially utilized phthalazine derivatives are illustrated in Figure 5.62 [126, 127]. Sulphonamides are considered essential scaffolds for the synthesis of bacteriostatic antibiotics [128]. Moreover Sulphonamides possess a wide range of biological activities as carbonic anhydrase (CA) enzymes inhibitors [129, 130] anti-hypertensive reagents, treatment of cancer, glaucoma, heart failure, epilepsy and Alzheimer’s disease [131–134]. Recent study on the synthesis of novel N-substituted phthalazine sulphonamides was performed by Türkeş et al. [127] through the reaction of 4-sulphonylamide ester 234 with hydrazine hydrate in ethanol at 70 °C for 24 h (Figure 5.63). The novel synthesized compounds were investigated for their inhibitory activity against the cytosolic HCA I, II and AcHE. In particular, authors reported that IC50 values of tested phthalazine sulphonamides toward HCAI ranging from 12.42 ± 0.23 to 32.80 ± 0.49 µM. Compound 237b with electron withdrawing substituent exhibited the most potent activity (IC50 = 12.42 µM) while electron donating substituent resulted in a lessen HCAI isoenzyme activity. Moreover, the Ki constants for 237a–f were estimated and were found to be ranging from 80 ± 0.10 to 85.91 ± 7.75 µM with 237b showed the most potent activity (Ki 6.8 ± 0.10 µM) compared to acetazolamide (AAZ) 11.91 µM. Moreover, most of compounds 237a–f showed a potent inhibition of HCA II (KIS 6.32 ± 0.06–128.98 ± 23.11 µM), and IC50 of 10.14 ± 0.13 to 28.57 ± 0.05 µM. The results obtained revealed that the synthesized compounds displayed higher inhibition against HCA II compared to HCA I. Authors revealed that the best inhibitor was 237l whereas 237e exhibit the least effect. In silico molecular docking studies have been performed to understand the molecular mechanism underlying inhibitory activities [103]. Docking for compound 237b

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Figure 5.64: Interaction of native ligands with the key amino acids within the binding sites of HCA I, HCA II, and ACHE (A) Docking pose of 2,3,5,6-tetrafluoro-4-piperidin-1-ylbenzene-sulfonamide (3UG) with the active site of HCA I (PDB ID: 4WUQ). (B) Docking pose of N-[(2Z)-1,3-oxazolidin-2-ylidene] sulfuric diamide (OVX) with the active site of HCA II (PDB ID: 4FU5). (C) Docking pose of donepezil (E20) with the active site of ACHE (PDB ID: 4EY7). Reproduced with permission from Ref. [127]; Copyright 2019; Elsevier Ltd.

Figure 5.65: Formation of phthalazine derivatives 240 via Single-Step Catalytic synthesis.

5.3 Phthalazine

153

Figure 5.66: Synthesis of phthalazine 242 via different Photocatalysts A, B and C.

and 237l to account for the obtained biological study results were illustrated in Figure 5.64 [127]. Docking appeared that these derivatives might be of interest for further pharmacologic and medicinal research. A pioneering synthetic protocol of phthalazine derivatives 240 has been developed by Goswami and co-authors [135] via a controlled tandem intermolecular coupling between 1,2-benzenedimethanol derivatives 238 and hydrazine hydrate utilizing Ni(II) complex of 2,6-bis(phenylazo)pyridine 239 under mild and aerobic reaction conditions (Figure 5.65). Carbon-amination and hydro-amination reactions particularly via radical reactions are currently under investigation [136, 137]. A novel synthetic route for the synthesis of phthalazine derivatives 242 was recently developed by a radical hydroamination reaction and subsequent smiles rearrangement of ortho-alkynylsulphonohydrazone derivatives 241 or a one pot two steps synthesis of o-alkenyl aromatic

154

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Figure 5.67: Synthesis of phthalazine derivatives 242a–y via Photocatalysts A.

5.3 Phthalazine

155

Figure 5.68: Plausible mechanism for the synthesis of phthalazine 242 via radical reaction.

aldehydes with sulphonyl hydrazine and subsequent cyclization following up the aforementioned optimized conditions (Figures 5.66 and 5.67) [138]. A proposed mechanism was depicted in Figure 5.68. Despite the numerous reported methods for the synthesis of phthalazines, they usually lack a direct protocol for a wide range of substituted phthalazines. Recently, Wanger et al. [139] reported a convenient and efficient synthesis of polyfunctionally substituted phthalazines 247 via directed ortho-lithiation of aromatic aldehyde utilizing lithium amides 244 to form the corresponding α-amino-alkoxides 245 which on treatment with n-BuLi afforded the anion 246. When subjected to a consecutive reaction with DMF followed by hydrolysis with ammonium chloride and hydrazine hydrate yielded the final isolable product 247 (Figure 5.69). A very important article investigated recently the radical reactivity of phosphonohydrazones which permits the synthesis of a diversity of phthalazine derivatives under mild reaction conditions [140]. Specifically, authors developed a straightforward method to synthesize the functionally substituted phthalazines 252 via Sonogashira cross coupling of o-bromo aromatic aldehydes or ketone derivatives 248 to obtain the

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Figure 5.69: Synthesis of substituted phthalazines 242a–o.

corresponding 2-(arylethynyl)aldehyde/ketone 249 which reacted with phosphonohydrazines 250 to afford hydrazones 251. Finally, cyclization of 251 was performed using Ru(bpy)3(PF6)2, t-BuONa in MeOH promoted by blue LED irradiation for 16 h (Figure 5.70). The reaction mechanism was depicted in Figure 5.71 which confirmed the formation of N-Centered Radical (NCR). 5.3.1.2 Synthesis from phthalazine precursors Phthalazine are frequently utilized as reactive intermediate for the synthesis of 1- and/ or 4-substituted phthalazines [141], specifically, its chlorination afforded the corresponding chloro derivatives which could be further utilized as privileged precursors for phthalazine derivatives.

5.3 Phthalazine

157

Figure 5.70: Synthesis of functionally substituted phthalazines 252 via Sonogashira cross coupling.

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Figure 5.71: Mechanistic proposal for the synthesis of phthalazines 252.

Abouzid et al. [142] have been developed the synthesis of new 1-N-substituted phthalazines 256a–c and 258a–i via chlorination of 4-(4-bromo-phenyl)phthalazinone 253 and subsequent nucleophilic substitution of the formed of 4-chloro derivatives 254 with various nitrogen nucleophiles 255a–c and 2-mercaptobenzothiazole 257a–i (Figure 5.72). The synthesized compounds were evaluated for their human breast cell line MCF-7 anti-proliferative activity. The results revealed that compounds 258a,g,I and 256a–c displayed better activity than reference Doxorubicin (IC50= 2.97) (Table 5.12). A similar protocol has been reported by Behalo and co-authors [143] but explore the reaction of the synthesized 1-cholorophthalazine derivatives 262 to a variety of nucleophiles include carbon, oxygen, sulfur and nitrogen nucleophiles (Figures 5.73–5.78). A convenient mechanism to rationalize for the formation of compound 291 was exemplified in Figure 5.78. The anti-cancer activity of some synthesized compounds (260–263, 283, 284b and 291) against four cancer cell lines (HePG2, MCF-7, PC3, HCT-116) were reported. Of the

5.3 Phthalazine

159

Figure 5.72: Synthesis of 1-N-substituted phthalazines 256a–c and 258a–i.

Table .: Testing of the compounds against human breast cancer cell line (MCF-). Compound Doxorubicin a g i a b c

IC (lM) . . . . . . .

synthesized library compounds 260, 283 and 291 displayed better anti-cancer activities as compared to Doxorubicin (Table 5.13). In addition, investigation of compounds antioxidant activity showed that compound 283 possess the highest activity (Table 5.14). Recently Abouzid research group [125] followed the footprints of previous scientists in the synthesis of a diversity of 1-substituted phthalazine derivatives with N and O linkers as depicted in Figures 5.61, 5.79 and 5.80.

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Figure 5.73: Synthesis of 1-cholorophthalazine derivatives 262.

Figure 5.74: Reaction of 1-cholorophthalazine 262 with active methylene compounds.

Upon evaluation of the anti-proliferative activity of the synthesized compounds authors relied that of compounds series 232b,e; 229b; 296a,c; 299d and 300a exhibit a marked potency against the full national cancer institute (NCI) 60 cell lines panel concerning lung cancer, melanoma, colon, CNS, breast cancer, ovarian, renal and prostate cancer with IC50 values ranging from 0.15 to 841 µM. Regarding the sensitivity toward the tested cell lines, products 229b and 296c showed the highest inhibitory activity against leukemia, colon. Melanoma, breast and renal cancer cell lines with IC50 values for 229b of 0.15–2.81 µM and for 296c of 0.2–2.66 µM respectively. In addition, the cytotoxic activity of compounds 231a,c; 232 a, c, d, f; 229c,d,f; 230b,c,e,j against MCF-7 and HCT-116 cancer cell lines referenced to Doxorubicin was evaluated. The results exhibited significant inhibition for 232a,d against both cell lines (IC50 = 6.2, 6.0 and 3.2, 3.1 µM) compared to (67.6, 91.2 and 67.6, 57.5 Mµ) respectively.

5.3 Phthalazine

161

Figure 5.75: Reaction of 1-cholorophthalazine 262 with nitrogen nucleophiles.

Figure 5.76: Synthesis of phthalazine derivatives 278–283.

Moreover, the inhibition activity of 295b,c and 296c against VEGFR-2 Tyrosine kinase assay revealed IC50 values of 4.4, 2.7and 2.5 µM respectively at a single dose 10 µM. Molecular docking study of the most potent synthesized compounds in the VEGFR-2 kinase active cite was performed using Auto-Dock Vinu [144] to achieve the relative binding affinities and binding interaction with kinase active site. The structure

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Figure 5.77: Synthesis of phthalazine derivatives 284–285.

Figure 5.78: Proposed mechanism for the synthesis of phthalazine derivative 291. Table .: Cytotoxic activity (IC) of some compounds against human tumor cells. In vitro cytotoxicity IC (μg/mL)

Compounds

DOX     b 

HePG

MCF-

PC

HCT-

. ± . . ± . . ± . . ± . . ± . . ± . . ± .

. ± . . ± . . ± . . ± . . ± . . ± . . ± .

. ± . . ± . . ± . . ± . . ± . . ± . . ± .

. ± . . ± . . ± . . ± . . ± . . ± . . ± .

5.3 Phthalazine

163

Table .: Antioxidant assay (ABTS). ABTS Abs (control)_Abs (test)/Abs Method Compound Control of ABTS Ascorbic acid     b 

(control) ×  Absorbance of samples

% Inhibition

. . . . . . . .

 . . . . . . .

of VEGFR-complex with Sorafenib as its inhibitor was utilized to obtain the VEGFR-2 coordinates which illustrate the hydrogen bonding interactions of NH and CO groups of urea moiety with the backbone of ASP1046 and the carboxylic acid moiety of GLU885 as well as H-bond with Cys919 residue of kinase active site. The biaryl derivatives 232c which possess higher inhibitory activity compared to analogs 232a,b revealed the inclusion of H-bonding interaction of GLU885 and ASP1046 with the urea group of 232c besides additional hydrophobic interactions

Figure 5.79: Synthesis of 1-substituted phthalazine derivatives 294–296. Reagents and conditions: (a) NH2NH2 acetic, reflux 3 h (b) POCl3, reflux 110 °C, 1 h (c) p-phenylenediamine, butanol, 110 °C, 1 h, (d) phenyl isocyanates, DMF, reflux 8–10 h, (e) 1a–c, Cs2CO3, acetonitrile, reflux 6–8 h.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.80: Synthesis of 1-substituted phthalazine derivatives 297–300. Reagents and conditions: (a) aniline derivatives, butanol, K2CO3, KI, reflux, 3 h (b) NBS, dibenzoyl chloride, reflux 24 h (c) aniline derivatives, acetone, K2CO3, KI, reflux 6 h (d) phenol derivatives, NaH, acetone, reflux 8 h.

Figure 5.81: The docking pose of 232c as magenta sticks. Reproduced from Ref. [125]; Copyright 2019; Taylor & Francis (there is no required permission).

between the trichloro and trifluromethyl moiety of 232c with the hydrophobic side chain of 11892, Leu1019 and Val1898. However, losing the H-bonding interaction between the terminal amide group of Sorafenib with Cys919 illustrate the lower inhibitory activity of 232c in comparison to Sorafenib (Figure 5.81). Melatonin, a neuro hormone once synthesized inside the body they get incorporated into the central nervous system and regulates several physiological functions via the activation of MT1 and MT2 protein coupled receptors [145, 146]. Melatonin receptors were involved in the regulation of several physiological processes as core body

5.3 Phthalazine

165

Figure 5.82: Synthesis of phthalazine derivatives 307a–c. Reagents and conditions: a) NH2NH2.H2O, EtOH, reflux, 65%; b) POCl3, reflux, 86%; c) Ethyl cyanoacetate, NaH, anhydrous THF, 80%; d) 5M HCl, reflux, 60%; e) H2, Raney Ni, NH3; (g), rt,70%; f) R1COCl, K2CO3, EtOAc/H2O, 40–55%.

temperature and blood hypertension [147], sleep and wakefulness [148] as well as many disorders such as depression, Alzheimer, and Parkinson [149–152]. A new family of melatonin receptors was achieved via the synthesis of phthalazine scaffold carrying an ethyl amide side chain and methoxy group as depicted in Figure 5.82. The biological activity of the synthesized compounds was evaluated and compared with that of Agomelatine bio isosteric analogue; the results obtained revealed that the obtained phthalazine derivatives showed unfavorable effect for the melatonegic

Figure 5.83: Synthesis of phthalazine derivatives 309a–j. Reagents and conditions: (a) triisochlorocyanouricacid, 40–50 °C, 4 h; (b) EtOH, H2NNH2.H2O, reflux 5 h; (c) 1,2,3-trimethylimidazoliummethylsulphate, 50 °C, 1 h.

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affinity. In particular 307a exhibit a significant decrease in affinity for MT1 and MT2 receptors compared to Agomelatine. Replacement of acetamido group in 307a with ethyl or propyl group 307b–d possesses a weak improvement compared to 307a [153]. To overcome the growing resistance against conventional known anti-malarial drugs such as mefloquine, chloroquine, artemisinin, the search of quinolone analogues has been extensively studied. Of the examined heterocycles, several studies have revealed the potent antimalarial activity of several phthalazine derivatives [154, 155]. In 2016, Basappa reported the synthesis of novel phthalazine and evaluated their potential as antimalarial agents [35], the synthetic protocol is a two-step route depicted in Figure 5.83 which involves a selective chlorination of phthalazine 240 by trichloroisocynuric acid which afforded 1-chloroderivatives 227 as major product with minor 1.4-dichloro moiety 293. Compound 227 was treated with excess of hydrazine (99%) in ethanol to afford 1-hydrazino derivative 308, which upon treatment with a diversity of aldehydes utilizing Brønsted acidic ionic liquid (1,2,3-trimethyl-imidazoliummethylsulphate) as a green solvent the final Schiff base derivatives 309a–j obtained in high yield. In silico analysis of the synthesized hydrazine’s was performed to evaluate their binding affinity to plasmodium falciparum dihydroorotate dehydrogenase (DHODH). The analysis showed that the synthesized ligands have similar hydrophobic similarity to the Co-crystallized ligand IDI-6253 with several nitrogen containing aromatic rings [156], in addition five of compounds tested for in vitro validation against P. Falciparum 309c,d,e,g,i display significant inhibitory activity with estimated IC50 less than 20 µM. Moreover, compounds 309c,d,e,g,i were identified as potent inhibitor against 3D7 Parasites with IC50 values of 13.7, 12.1, 3.4, 3.4 and 1.6 µM respectively. In a parallel experiment utilizing chloroquine-resistant K1 strain, these compounds showed IC50 values of 6.6, 5.9, 2.4, 2.2 and 1.6 µM respectively. To establish the cytotoxicity of the same compounds and to estimate their selectivity, authors performed cytotoxic assay of Madin-Draby kidney (MDCK) cell lines. Results indicated that cytotoxicity using concentration up to 200 µM was detectable which apparently clarify that selective inhibition of the malaria parasite was performed by most of synthesized compounds. Molecular modeling of new hydrazines revealed that the presence of electron donating group at gamma position of phthalazine moiety increases the inhibitory

Figure 5.84: Examples of drugs containing phthalazine scaffolds with substitutions at positions 2,4.

5.3 Phthalazine

167

Figure 5.85: Synthesis of 2-(1-(1,4-dioxo-3,4-dihydrophthalazine-2(1H)-yl)isoquinolin-2-(1H)fumarates 312a,b.

Figure 5.86: Plausible mechanism for the synthesis of 312a,b.

activity while electron withdrawing substituent at the same positions reduces the inhibitory activity. As several drugs containing phthalazine scaffolds possess substitution at positions 2,4 efforts have been devoted to their synthesis via simple and efficient protocols. Example of such drugs is illustrated in Figure 5.84. An interesting study dealing with the synthesis of 2-(1-(1,4-dioxo-3,4-dihydrophthalazine-2(1H)-yl)isoquinolin-2-(1H)fumarates 312a,b was described by Bazgir et al. [157]. Specifically, the authors developed a one pot efficient procedure for the synthesis of 312a,b that employed a nucleophilic attack of phthalhydrazide 292 to activated

Figure 5.87: Synthesis of phthalazine derivatives 315.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.88: Synthesis of phthalazine derivatives 316b,c.

Figure 5.89: Synthesis of 2-(7-amino-2,2-dimethyl-4-oxo-5-aryl-4,5dihydropyrano[2,3-d]-[1,3]dioxin6-yl-carbonyl)-2,3-dihydrophthalazine-1,4-diones 319.

acetylenes 310a,b in the presence of isoquinoline 311 in acetone at ambient temperature for 24 h (Figure 5.85). In case of 310c, the targeted phthalazine was obtained in a trace amount. A plausible mechanism was provided in Figure 5.86 which involves the formation of Zwitterion intermediate 313 while was protonated by phthalhydrazide followed by nucleophilic attack by the conjugate base of phthalhydrazide to produce the final isolable products. The reaction was extended to other nitrogen nucleophiles and the results were illustrated in Figures 5.87 and 5.88. Suman et al. [158] reported scheme for efficient and green one-pot synthesis of 2-(7-amino-2,2-dimethyl-4-oxo-5-aryl-4,5dihydropyrano[2,3-d][1,3]dioxin-6-yl-carbonyl)-2, 3- dihydrophthalazine-1,4-diones 319 as depicted in Figure 5.89. They reacted 3-(1,4-dioxo1,2,3,4-tetra-hydrophthalazine-2-yl)-3-oxopropanenitrile 317 with aromatic aldehydes 170 and Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) 318 utilizing L-Proline as catalyst in ethanol at ambient temperature. The products were isolated in moderate to good yields.

5.3 Phthalazine

Figure 5.90: Possible mechanistic reaction for the synthesis of 319.

Figure 5.91: Alternative mechanism for the synthesis of 319.

169

170

5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.92: Synthesis of phthalazine-1-one derivatives 332–338.

Two possible reaction mechanisms were proposed to rationalize for the formation of the reaction products (Figures 5.90 and 5.91). In mechanism 79, a fast formation of intermediate 324 from Knoevenagel condensation of 320 and 317 followed by attack of the carbanion 321 to 323 and cyclization of the acyclic intermediate 327. Concerning alternative mechanism, it involves initial formation of the carbanion 321 by L-Proline abstraction of hydrogen proton from active methylene group of 317 to afford the corresponding carbanion, which attacks the positively charged ylidenic group in 328 to afford 329 via Michael addition and subsequent cyclization affording the final isolable products 319. A diversity of 4-benzyl-2-substituted phthalazine-1-one derivatives 332–338 using 4-benzyl- phthalazine-1-one 331 precursors as illustrated in Figure 5.92 [159]. 4-Benzyl-1-chlorophthalazine 339 was also utilized as a precursor for the synthesis of a diversity of new 1,4-disubstituted phthalazines 340, 341, 343, 345 and 347 as depicted in Figure 5.93. Antimicrobial activities of some synthesized compounds were studied and results revealed promising effect of some of these products against Gram-Positive Bacillus Cereus (ATGG 14579), Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11) and Staphylococcus (MTCC 96), Gram Negative Pseudomonas aeruginosa (MTCC 741), Escherichia coli (NCTC 10410) bacteria and two fungus, Aspergillus ochraceus Wilhelm

5.3 Phthalazine

171

Figure 5.93: Reactions of 4-benzyl-1-chlorophthalazine 339 with amines derivatives.

(AUCC 530). The results obtained revealed promising inhibitory activity of compounds 340a–j, 343, 345 and 347a,b against Gram-Positive, Gram-Negative bacteria and fungi. Hybrid phthalazine new lead inhibitors to fit the estimated Glomerular Filtration Rate (EGFR) hydrophobic sub pocket and cleft region were recently synthesized by Boraei et al. [160] and tested for their anti-proliferative activity against in vivo and in vitro cancer cells. Adversity of hybrid phthalazines were synthesized, as illustrated in Figures 5.94–5.98, starting from ethyl-2-(4-benzyl-1-oxophthalazine-2-(1H)-yl)acetate 336 as precursors.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.94: Synthesis, alkylation, and glycosylation of phthalazino-1,3,4-oxadiazolethione 349.

Figure 5.95: Synthesis of diverse 1,2,4-triazolo-phthalazines.

5.3 Phthalazine

173

Figure 5.96: Alkylation and condensation of 4-amino-1,2,4-triazole-3-thione 360.

Figure 5.97: Reactions of hydrazide 337 with D-glucose, phthalic anhydride, benzoyl chloride, ethyl acetoacetate and phenyl hydrazine.

Authors reported the in vitro activity of synthesized phthalazines against hepatocellular carcinoma (HepG2 cell line) in comparison with that of the standard drug Doxorubicin (IC50 = 4.0 µM). Compounds 354 and 374a were found to be the most

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.98: Coupling of azide 371 with amino acid esters and amines.

Figure 5.99: Compounds 354 red, 374a green, 358 brown, 351b purple, docked in EGFR with key residues involved in ligand binding. Reproduced with permission from Ref. [160]; Copyright 2019; Elsevier Ltd.

potent among synthesized phthalazine hybrids with IC50 7.09 and 5.7 µM respectively. The results of in vivo activity pointed out those compounds pointed out those compounds 351b and 354 exhibit IC50 values 7.25 and 7.5 µM respectively compared to reference Cisplatin (IC50 9.0 µM). Moreover, in silico discovery of the phthalazine derivatives showed a good inhibition toward EGFR. The docking study for the most potent compounds, 354 and 374a was evaluated and revealed that compound 354 docked well in the EGFR active site and the docking pattern allows a hydrogen bonding between side chain hydrazide nitrogen’s and Arg 841 and Asn 842. An additional hydrogen bonding exits between one of the phthalazine

5.3 Phthalazine

175

Figure 5.100: O-acylmethylation of 2-arylphthalazine-1,4-diones 375 with α-carbonyl sulfoxonium 376.

nitrogen’s with Thr 854 and Asp 855. Remaining residues hold the inhibitor tidily to the active site via hydrophobic interactions including Lys 721, Lys 745, Met 766, Leu 777, Leu 788, Thr 790, Leu 799, Asp 800, Leu 844 and Thr 854 (Figure 5.99). An interesting direct ortho-Csp2-H acylmethylation of 2-aryl-2,3-dihydrophthalazine-1,4-diones 375 with α-carbonyl sulfoxonium yielded 376 catalyzed with [RuCl2(p-cymene)]2 (5 mol%) in EtOH at 80 °C for 12 h in N2 atmosphere was reported by Sakhuja and co-authors [161] (Figure 5.100). The mechanism to account for the formation of reaction products was depicted in Figure 5.101.

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5 Green synthesis of biologically relevant cinnolines and phthalazines

Figure 5.101: Proposed mechanism for the synthesis of phthalazine derivatives 377.

Figure 5.102: Synthesis of phthalazine derivatives 384a–c and 385.

5.3.1.3 Synthesis from pyridazine precursor A simple highly efficient synthesis of phthalazine derivatives 384 and 385 have been developed via reaction of alkyl pyridazine carbonitriles 381 with several electrophilic reagents. This is the first reported synthesis of phthalazines from pyridazine precursors (Figure 5.102) [162–166].

5.4 Conclusions Cinnolines and phthalazines as benzo diazine derivatives have gained extensive attention due biological activities and their complement in the field of medicinal

References

177

chemistry as well as organic chemistry. A variety of pharmacological properties were associated with both ring systems as cancer, diabetes, hypertension, microbial infection and depression. This work covered decent advances in the synthesis of cinnolines and phthalazines derivatives as well as their biological activity.

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Dwaipayan Das, Moumita Saha and Asish. R. Das*

6 Synthesis, properties and catalysis of quantum dots in C–C and C-heteroatom bond formations Abstract: Luminescent quantum dots (QDs) represent a new form of carbon nanomaterials which have gained widespread attention in recent years, especially in the area of chemical sensing, bioimaging, nanomedicine, solar cells, light-emitting diode (LED), and electrocatalysis. Their extremely small size renders some unusual properties such as quantum confinement effects, good surface binding properties, high surface‐to‐volume ratios, broad and intense absorption spectra in the visible region, optical and electronic properties different from those of bulk materials. Apart from, during the past few years, QDs offer new and versatile ways to serve as photocatalysts in organic synthesis. Quantum dots (QD) have band gaps that could be nicely controlled by a number of factors in a complicated way, mentioned in the article. Processing, structure, properties and applications are also reviewed for semiconducting quantum dots. Overall, this review aims to summarize the recent innovative applications of QD or its modified nanohybrid as efficient, robust, photoassisted redox catalysts in C–C and C-heteroatom bond forming reactions. The recent structural modifications of QD or its core structure in the development of new synthetic methodologies are also highlighted. Following a primer on the structure, properties, and bio-functionalization of QDs, herein selected examples of QD as a recoverable sustainable nanocatalyst in various green media are embodied for future reference. Keywords: bioimaging; coupling reaction; organo-catalyst; photo-redox catalyst; photoluminescence; quantum dots; semiconducting nanomaterials.

6.1 Introduction Medicinal complications have always been a great concern in nearly all civilization. This has led us to be enough conscious while developing an efficient drug delivery system that the pharmacologically active moieties could act only to the site of action, without affecting the healthy cells and tissues. In recent years, nanostructured materials are experienced an extensive investigation and application in various fields because of their ability to make a bridge between the bulk and molecular stages and

*Corresponding author: Asish. R. Das, Department of Chemistry, University of Calcutta, Kolkata 700009, India, E-mail: [email protected] or [email protected] Dwaipayan Das and Moumita Saha, Department of Chemistry, University of Calcutta, Kolkata 700009, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: D. Das, M. Saha and A. R. Das “Synthesis, properties and catalysis of quantum dots in C–C and C-heteroatom bond formations” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0093 | https://doi.org/10.1515/9783110797428-006

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help to uncover a novel path for utilization of nanomaterials, especially in computer electronics, optical engineering and medicinal field. Due to the sudden expansion of nanotechnology and nanoengineering as a fascinating research front in present scientific advancement, they have been considered as a potential vehicle in nanomedicine and other biomedical fields [1]. Bearing in mind the environmental issues, the application of “Green Chemistry” concept is become mandatory to reduce adverse environmental hazards during synthesis [2]. Modern synthetic developments highlights on designing chemical processes without involving toxic chemicals, drastic reaction conditions along with reduction of waste production and efficient recycling of catalyst. Consequently, chemists are now turning their research aim in exploring heterogeneous catalytic processes [3, 4]. The concept of Quantum dot was first disclosed in 1981 by Alexey Ekimov in a glass matrix and then its existence in colloidal solutions was uncovered by Louis E. BRus in 1985. The term “quantum dot” was first used by Mark. Semiconductor nanoparticles (NPs) in colloidal phase are commonly termed as quantum dots (QDs), recently have been considered as a new type of fluorophore in which inorganic atoms are stabilized by the surrounding organic ligand layer. The reason behind their high demand in medicinal biology and nanotechnology field originates due to their (i) good photo-physical properties, (ii) wide absorption spectra; (iii) poor emission spectra; (iv) lengthy fluorescence lifetime; and, (v) good photostability [5]. The diameter of tiny QD-nanoparticles generally ranges from 2 to 10 nm. However, in a quantum dot with semiconductor properties has roughly a million atoms with equivalent number of electrons and most of these electrons are tightly bound to the nuclei of the QD, providing very poor number of free electrons between one and a few hundred. These electrons have de Broglie wavelength which are very close to the size of the dot, and the electrons reside in discrete quantum levels and thus displays different excitation spectrum [6]. The classification of QD generally done based on their chemical structure and composition and the different types of QD are classified as core type, core–shell, and alloyed quantum dots [7]. Among the developed nanomaterials, QD assisted size-tuned emission spectrum (Figure 6.2) offers potential development in a multicolor optical coding technique. For this reason, researchers have employed QDs for in vivo and in vitro imaging and as a fluorescent marker in a living cell replacing conventional organic dyes [8]. Monodispersed nanoparticles are generally attained by using organic molecules as a capping agent which are chemically attached on the surface of nanoparticle [9]. The advantages of using capping agents in the synthesis of QD are instantaneous formation of colloidal suspension and facile bioconjugation to different biomolecules. To improve the optical properties and passivity of the QDs, the nanomaterial is mainly used as the core material which is further enclosed inside another semiconductor layer with a large spectral band gap [10]. In case of a semiconductor nanomaterial, generally the band gap separates the valence and conduction levels from each other. Upon absorption of a photon, an electron excited to jump to the conduction level from the valence state creating a hole

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in the lower energy valence state (h+). When the electron comes back to the low energy valence shell, ‘Fluorescence’ is emitted. However, in the short time span of photoexcitation, the autonomous movement of electron (e−) and valence band (h+) are restricted due to the Columbic type attraction between each other. The distance between the electron (e−) and the valence band (h+) pair is termed as excitation Bohr radius. When the magnitudes of semiconductors are decreased to nanometer range and becomes less than Bohr radius, it is said to belong in a confinement quantum regimen and then it could be termed as QDs [11, 12]. QDs are generally made of several elements of groups III–V, II–VI, or IV–VI of the periodic table, some examples are CdS, CdSe, CdS@ZnS, CdSe@ZnS, CdSeTe@ZnS and many more [13]. These types of QDs have exceptional fluorescence characteristics and therefore extensively employed in nanosensing, biosensing applications and efficient diagnostic markers in medicinal field. Biocompatible QDs such as SiQDs (Silicon quantum dot), C-dots, and GQDs are generally used in pharmaceutical fields due to their poor toxicity [14]. Till now, various synthetic approaches have been adapted to produce QDs, which can be roughly classified into mainly two approaches (i) top-down and (ii) bottom-up (Figure 6.2). The top-down approach involves the breaking down of bulk carbonaceous materials, such as carbon nanotubes, graphite etc. into nanosized structures [15–19] and the Bottom-up approach involves assembling of nanoscale carbonaceous material from the bottom like atomic and molecular level through utilization of existed physical and chemical forces operating in these nanoparticles to generate a bulk structure. The methods generally adapted for the synthesis of QD involves heating/combustion method, hydrothermal method, microwave/ultrasonic promoted synthesis, electrochemical synthesis, acid oxidation, arc discharge, plasma treatment and laser ablation (Figure 6.4) [18, 20–22]. To date, the colloidal synthesis methods have been widely accepted in order to synthesize QDs, such as, CdSe, CdTe, ZnSe, ZnS and CdS. Additionally, InP, a near infrared (NIR) QDs, and other lead chalcogenides, have also been synthesized by applying colloidal method with hot injection [23, 24]. Post fabrication of QDs needs hydrophilization of QDs since fabricated QDs are generally very water repelling and highly soluble in nonpolar medium. Hydrophilization technique helps to make the QDs biocompatible which are essential for its application in medicinal as well as analytical areas. Hydrophilization comprises three basic steps, in which the first step involves ligand exchange in which the original hydrophobic coating is detached and replaced with a hydrophilic bipolar molecule, such as, mercapto carbonic acids. Where one end of this bifunctional molecule is connected to the QD surface while the other hydrophilic end is set free for conjugation to several biomaterials. The second step involves silanization and the last step involves encapsulation of the water repelling QDs using various carrier agents e.g., amphiphilic polymeric material [25]. The QDs could be easily characterized due to special size and structure and scanning transmission electron microscopy (STEM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering technique (DLS), scattering and conductivity experiments etc. [26].

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Carbon quantum dots (CQDs), [27] a novel carbon containing nanostructures in zerodimension have captivated huge popularity due to their nano size range and robust fluorescence properties. The example of different carbon-based nanomaterials which are extensively studied in various research fields include quantum dots, graphene quantum dots (GQDs), carbon nanodots (CNDs), and polymer dots (PDs). The presence of various polar functional groups such as ether, epoxy, carbonyl, carboxylic acid, hydroxyl group etc. at the surfaces of CQDs imparts high hydrophilicity to C-dots [28]. Although GQDs, CNDs, and PDs have comparable dimensions and photoelectrochemical nature, their internal structure and functionalization at the surface are quite different from each other. To synthesize CQD several methods have been reported for example pyrolysis, laser ablation, ultrasound- and microwavemediated synthesis, wet oxidation, hydrothermal process, and electrochemical etching etc. They are monodispersed spherical shape nanoparticles with a carbon containing framework attached with many polar functional groups at the surface [29]. To study the fluorescent actions of this material, the particle size and nature of functional groups are carefully monitored for the controlling of electronic properties. CQDs not only show good optical properties comparable to the typical semiconductor quantum dots, but also used instead of conventional semiconductors to reduce cytotoxicity, environmental hazards during the reaction. Apart from this, CQDs are also found to be quite water-soluble material and also have high chemical stability, good resistance against photobleaching, easy surface modification and gram-scale synthesis [30]. Although there are several recent reports describing the photoluminescence and electrocatalytic contribution of CQDs, there is no reports that highlights the synthetic utilities of CQDs in organic synthesis field up to date. Among several interesting applications of C-Qdots, the reduction of Pd NPs by CQD and utilization of reduced Pd catalyst in Suzuki and Heck coupling reactions in aqueous condition is one of the alluring examples of organo-catalysis [31]. Again, GQDs, another nano range carbon material, emerged as a superior and universal fluorophore due to their unusual physical and chemical features, including small size, chemical inertness, stable photoluminescence, low cytotoxicity, and good biocompatibility [32–34]. and ease functionalization capability with a variety of biomolecules revealing effectivity in materials science and engineering field [35]. It was also realized that the combining effect of GQD alone and in the metal reinforced GQD could vividly advance the stability and activity of GQD due to its excellent electron carrying ability and excellent stability as well [36]. Previously, some detailed review articles based on syntheses, properties bioimaging, biosensing, drug delivery, and other potentials of GQDs have been informed in literature [37, 38]. Du et al. in 2015 reported a mini review in which recent research progress on doping science of fluorescent carbon dots (DFCD) are summarized [39]. In this review numerous doping categories are described based on the synthetic methods and variations in synthesis methods between the DFCDs and the undoped ones. The review also signified

6.1 Introduction

Authors

Publication Year 2016

Reference

Topic

[39]

Meghdad Pirsaheb, Anvar Asadi, Mika Sillanpä ä , Negin FarhaUdian V Navakoteswara Rao , N Lakshmana Reddy, M Mamatha Kumari , K K Cheralathan et al.

2018

[40]

Recent progress on chemically doped luorescent carbon and graphene quantum dots for bio-imaging, sensor, catalytic and photoelectronic applications Tuneable photocatalytic characteristics of CQDs

2019

[41]

Mohammad Jafar Molaei et al Xiaoli Kou, Shicui Jiang, Soo-Jin Park and Long-Yue Meng

2020

[42]

2020

[43]

2021

[44]

2021

[45]

Yan Du and Shaojun Guo

Maryam Jouyandeh, Seyed Soroush Mousavi Khadem, Sajjad Habibzadeh et al.

Deeptimayee Prusty ,Lekha Paramanik and Kulamani Parida Dan-Yan Wang, Yu-Yun Yin, Chuan-Wei Feng et al.

2021

[46]

Das et al.

2022

This work

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Application of quantum dots in enhanced hydrogen production particularly under visible light irradiation application of QD in different kinds of sensors Preparations and applications of heteroatomdoped CQD Recent advancements in the greener and sustainable synthesis of carbon, graphene and metal-based QDs, and their applications in photocatalytic H2 production, degradation of hazardous pollutants and reduction of CO2 Alloyed Quantum Dots for Photocatalytic Hydrogen Evolution Application of QDs (CdS/CdSe) as homogeneous photocatalysts in various organic reactions Application of various QDs (CdS, CuS, GQD) as homogeneous or heterogenous photocatalysts to obtain diverse heterocyclic scaffolds via C-C and C-X bond formation

Figure 6.1: Comparative study of present review on QD as photocatalyst in organic synthesis with the previously published works.

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about the impact of doping on optical properties of QD s, especially DFCDs doped with N, mostly investigated (Figure 6.1). Meghdad Pirsaheb et al. in 2018 [40] presented a comprehensive review describing the application of CQDs in photocatalytic reactions where organic dyes were generally studied as sample pollutants. Additionally, the role of CQDs in enhancement of photocatalytic activity was also discussed in details. The adjustable photocatalytic features of CQDs were broadly mentioned in the review. Moreover, the outstanding photocatalytic performance of CQDs alone or its blending with photoactive species in the photoassisted degradation of organic contaminants was also emphasized. V Navakoteswara Rao et al. in 2019 [41] described the recent discoveries on various synthetic approaches adapted for the synthesis of quantum dots and their enhanced materials properties causing an improved hydrogen production specially under visible light condition. Additionally, the methods to improve quantum efficiency were also proposed in this perspective. The importance of quantum dots had been highlighted as an efficient photocatalyst to scale up the efficiency of the photocatalysts towards practical applications. Mohammad Jafar Molaei et al. in 2020 [42] represented a detailed review on the introduction, synthetic methods and optical characteristics of QDs. Numerous CQD-derived sensors and biosensors and their reaction pathway were nicely explained in the review. The CQDs in which the carbon core containing oxygen-rich functional groups at the surfaces of QD had shown to exhibit extra advantages as compared to traditional heavy metals comprising semiconductor QDs in view of toxicity and chemical stability. The review article by Kou et al., in 2020 [43] summarizes the conventional approaches for cultivating the fluorescence productivity of QDs doped with several nonmetallic (heteroatom) elements. The authors highlighted three types of heteroatomimpregnated CQDs (1) CQDs doped with a single heteroatom; (2) CQDs doped with two heteroatoms; and (3) CQDs doped with three heteroatoms. The limitations and future traits of doped CQDs in view of producing CQDs for diverse applications and particularly for bioimaging and light emitting diodes, had also portrayed in details. In addition, the different advantages of doped CQDs were also discussed focusing their innovation in bioimaging and LEDs. Very recently, Wang et al. in 2021 [46] summarize the recent application of colloidal phase CdS or CdSe QDs as homogeneous catalysts in several photoassisted organic conversions like C–C coupling or oxidation of benzyl alcohol, photocatalytic annulation of ClCF2COOEt and olefins, photocatalytic synthesis of disulfides with hydrogen etc. and many more (Figure 6.1) [44, 45]. Inspired by the reported review articles, we interested to present a review article describing recent catalytic contributions of various homogeneous and heterogeneous QD nanostructures (Cu2S QD, CdSe QD, CQD, GQD etc.) in carbon-carbon and

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carbon-heteroatom bond construction to achieve diverse biologically important heterocyclic scaffolds with detailed analysis. The catalytic efficiency of QDs is nicely described in this perspective with the recent advancement in developing advanced strategies for creating novel functional QD-based nanomaterials for application as catalyst in myriad of electrocatalytic reactions, including multicomponent (MCR) synthesis of biologically important heterocycles, Suzuki-Miyura cross-coupling for the generation of C–C bonds, Sonogashira coupling, oxidation of alcohols, amines etc. We are optimist that this review definitely provides a comprehensive guide to synthetic practitioners on the structural modifications of QDs with adjustable properties for various synthetic applications.

6.2 Properties of quantum dot Quantum dots (QDs) are nanorange semiconductor particles, whose size are normally ranges from 1–10 nm. Their extremely small size exerts outstanding electronic and optical properties which are quite dissimilar from those of bulk materials. QDs could be prepared from single-element constituents, for example Si, Ge or from mixture of semiconductors, such as CdSe, PbSe, CdTe, and PbS [47]. When the size of metals (Si and Ge), metal chalcogenide, and metal oxides is in the quantum regime, the quantum mechanical coupling effect is prominent which generates a band structure of nanomaterials [11]. Due to the generation of band structures in these quantum sized materials, the optical, magnetic, and electronic properties can be finely controlled by changing their size and shape, for example, super para-magnetism of magnetic QDs, surface plasmon resonance [48]. Majority of the synthesized QDs are able emit light of particular wavelengths on excitation by light or electricity. The electronic characteristics of QDs depends strongly on their size and shape, which further controls the emission wavelengths of QD with the change in size which is evidenced by the existing literature reports (Figure 6.2). Naturally, smaller QDs with an average radius of 2∼3 nm emits shorter wavelengths with the generation of colors like violet, blue or green, while bigger QDs (e.g., radius of 5∼6 nm) emitting lights of longer wavelengths consisting of colors like yellow, orange or red. Their size dependent optical properties revealed them as a fascinating entity with broad application in research and commercial fields like solar cells, LEDs, bioimaging, diode lasers, and transistors and so forth. The examples of various synthesized quantum dots are- CdSe QD, CdS/ZnS QD, CdSe/ZnS QD, ZnSe/ZnS and other functional Quantum Dots etc. The main reason for showing interesting features of different QDs probably due to two reasons. The one reason was assumed to the complete exhaustion of ultra-fine particles by charge carriers and the second reason is the increase of surface-to-bulk ratio due to the decrease in the particle size of nanoparticle. All of these interesting characters make the nanoparticle economical and powerful alternative over the traditional Brønsted and Lewis acid catalysts applied for industrial purpose [49].

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Figure 6.2: Optical properties of QDs as a function of their size.

6.2.1 Surface reactivity of quantum dot Because of remarkable surface-to-volume ratio of nanoparticle as well as its surface defects, the surface states in which electronic quantum states are related with the surface, have substantial impact on the optical responses of Q-dots. For instance, roughly 15% of the whole atoms in a 5 nm size CdS QD could be available on the surface [50]. Owing to such a high area-to-volume ratio permits an increased or decreased transfer percentage of charge carriers which are created upon photo absorption as a result of good density of surface sites. The surface sites may influence the optical properties (photoluminescence excitation– PLE), quantum productivity, luminescent power and spectrum and aging properties [51]. On the whole, this surface state originates from unfulfilled bonds at the restored surface and could be influenced by nonstoichiometry as well as voids. The energies of these surface voids generally lie in the band-gap of the QDs [52]. And for this reason they can behave as charge carriers (electron or hole) and successfully perform the role of reducing (electron) or oxidizing (hole) agents in many chemical transformations.

6.2 Properties of quantum dot

195

6.2.2 Optical properties In case of semiconducting nanoparticle, the existence of inherent band gap is mandatory where the electrons are jumped from the valence state to the conduction state on absorption of light energy, creating a hole in valence state. Then an exciton could be generated after combination of electron and the hole. Then when this exciton reunites a photon with longer wavelength will be released, and the phenomenon is generally termed as ‘Fluorescence’ [53]. However, contrast to the bulk semiconducting materials, QDs could not create the continuous valence and conduction band. Generally, the smaller the size of QD, greater will be the band gap. Since the emission wavelength depends on the QDs size, their fluorescence could be nicely monitored with the help of the size of QD during the synthesis process. QDs could produce the brightness essential for highly sensitive detection and their good photostability is also essential for tracking different dynamic processes, and their multiplexing ability required to clarify complex systems. Additionally, the relative oxidation and reduction potentials of nanoparticle could be effectively tuned up to several hundreds of mV by adjusting the nanoparticle size, making them suitable to exhibit redox properties in a particular photochemical conversion [53–55]. Other interesting characteristics of QDs comprise good quantum yield, good photostability, and appreciable molar extinction coefficients. The emission spectrum of QDs is also narrow and regular at particular wavelengths. Moreover, the literature reports reveals that their fluorescence quantum yield could be improved by creating a “shell” of a longer band gap semiconductor material surrounding their surface [56].

6.2.3 Quantum yield QY denoted to the efficiency to convert absorbed light into emitted light in the form of fluorescence. The fluorescence behaviors of carbon dots could be determined by their sizes, degree of crystallinity and nature of functionalities. Notably, bare quantum dots are usually observed to be less fluorescent, although fluorescence properties could be significantly improved through chemical modifications with a vast range of organic molecules [57]. Consequently, with the aim of achieving carbon dots with appreciable QY, researchers thoroughly studied carbon dots with surface modifications and doping with inorganic materials to produce highly fluorescent carbon dots via a one-step synthesis. The fluorescence QY of naked CDs is observed to be less than 10% [58]. For example, Sun et al. prepared photoluminescent CDs by doping it with ZnO or ZnS to achieve CZnO-Dots or CZnS-Dots, which experienced comparable fluorescent behavior to commercially available CdSe/ZnS QD [59]. To confirm the role of chemical and structural composition of CDs, particularly its impact on nitrogen doping, and its effect on QY, a wide range of starting materials were used for grafting with QD like citric acid, phenyl alanine or their mixture in various

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6 Synthesis, properties and catalysis of quantum dots in C–C

ratios which resulted 65% QY with a peak excitation/emission of 350/413 nm [60]. Ding in 2019 explored carbon dots with a high-fluorescence quantum yield rate which was synthesized from L-cysteine and citric acid under microwave conditions. The obtained carbon dots exhibited a high-fluorescence quantum yield up to 85%, which could be attributed to the amalgamation of amidogens and sulfydryl with carbon dots [60, 61].

6.2.4 Cytotoxicity of QD QDs decorated with several targeting moieties (drugs and other biomolecules), are superior candidates for site-specific clinical diagnosis and drug delivery, especially in cancer diagnosis. However, previous studies indicated that CdSe-core quantum dots are certainly cytotoxic under many conditions. Specifically, after oxidation of surface of QD, it helps in the generation of reduced Cd on the QD surface and increased concentration of free cadmium ions which can cause permanent cell damage. Under primary hepatocytes as the chosen liver model, researcher found that CdSe-core QDs were really highly toxic under particular conditions. Although after coating with CdSe, CdSe-core QDs was found non-toxic and could serve as a biomarker to scrutinize cell migration and reformation in vitro [62]. In addition, upon exposure of CdTe QDs to different cell types, a notable change in cell morphology were observed by researchers. A thorough study with different QD concentrations, different exposure times, and different cell types signified that (i) cadmium-containing QDs, particularly CdTe QDs, were the most lethal to the living cells, particularly QDs containing short ligands; (ii) QDs with multiple shells, e.g. CdSe/ZnS QDs, were however less toxic and thus suitable for experiments with living cells with prolong exposure [63]. However, researchers for several years are trying to address the toxicity issue of QD though wrapping the Cd core by a robust outer layer, impermeable to the QD environment. Particle size also influences their performance in cells for example smaller particles tend to be more toxic than larger ones due to higher permeability [64]. Another proposed mechanism through which QD is assumed to impart toxicity is the generation of transient oxygen species, such as free radicals and generation of singlet oxygen [65]. Generation of such reactive oxygen species can result irreversible impairment to enzymes, nucleic acids, and many cellular organisms like mitochondria, plasma and nuclear membranes. Over the last few decades researcher have dedicated tremendous efforts in order to reduce the toxicity of QD during their synthesis for example, Silicon QDs are a well-studied QDs which has shown excellent biocompatibility with adjustable physical and chemical properties, making them competent material for therapeutic applications [66]. In addition Kim et al. designed an L-cysteine (Cys) capped CdTe QDs which was found less cytotoxic against HeLa cancer cell lines (Kim et al. 2015) [67]. Again, CdTe quantum dots is a highly fluorescent nanoparticle commonly employed as a competent biomarker with poor cytotoxicity [68].

6.3 Synthesis of QD

197

Another pioneering investigation by Chen et al. related to the cytotoxicity of InP/ZnS QDs grafted with various polar functionalities e.g., NH2, COOH, OH against two lung-derived cell lines, resulted that the particle size of InP/ZnS-OH in the water was far greater than the other InP/ZnS-COOH and InP/ZnS-NH2 probably due to aggregation and thus the cellular uptake of InP/ZnS-COOH and InP/ZnS-NH2 were comparatively easier as compared to InP/ZnS-OH [69].

6.2.5 Recyclability of QD The versatility of CdSe QDs for photocatalytic organic synthesis was reported by Weix and co-workers. The authors concluded that single-sized CdSe QDs with grain size of 3.0 ± 0.2 nm, stabilized by trioctylphosphine oxide and oleic acid, could perform the role of an efficient photocatalyst for a range of photoredox reactions including the β-alkylation of aldehydes, the β-aminoalkylation of ketones and the dehalogenation of aryl iodides [70]. Similarly, Xiao and co-workers used CdS in combination with nickel catalysis for C−N and C−O cross-couplings [71]. The authors also showed that heterogeneous photocatalyst could be recycled up to 10 times without significant decrease in product conversion. Walied A.A. Mohamed et al. in 2020 reported the synthesis of three samples of ZnO QD to study their photoluminescence properties and also showed that the prepared ZnO Nps were reusable for 8 times [72].

6.3 Synthesis of QD Many synthesis methods of CDs have been reported which are basically categorized into two main methods, top-down and bottom-up. In top-down approaches, large carbon materials are fragmented into smaller one by using molecular beam epitaxy (MBE), e-beam lithography, ion implantation, and X-ray lithography, arc discharge, acid oxidation, laser ablation, electrochemical exfoliation, or solvothermal synthesis methods (Figure 6.3). Again, in the bottom-up approaches, smaller precursor materials are carbonized through, microwave, hydrothermal and thermal pyrolysis methods [73]. In epitaxial synthesis a rapid injection of semiconductor precursors was subjected into vigorously stirred hot organic solvents containing molecules that are planned to bind to the surface of the advanced QD particles. The lithography-based technique of QD preparation, is generally used to generate QDs by combining the high-resolution electron beam lithography and consequent etching [74, 75]. In arc discharge method, the carbon atoms are subjected to decomposition from the bulk carbon starting material placed in the anodic electrode in a sealed glass reactor in the presence of the gas plasma. The temperature inside the reaction chamber is maintained as high as 4,000 K through electric current to create a high-energy

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6 Synthesis, properties and catalysis of quantum dots in C–C

Serial

Method of

No.

generation

1 Epitaxial growth and/or nanoscale patterning

Reference

Description

Merit and demerit

[73-74]

Epitaxy (oriented overgrowth)

Possibility of direct

is where the crystalline

integration in a high

orientation of the deposited

quality crystalline

ilm is in luenced by the

matrix, which

crystalline orientation of the

provides high optical

substrate material and has

quality essential for

been recognized.

application in optical and electrical devices.

2

[75]

A semiconductor wafer is coated with a photosensitive “resist” material, which is then covered with a stencil and exposed to ultraviolet light, causing hardening of the exposed part. Then a chemical washes away the part of the resist not exposed under UV. The wafer is then etched with a chemical (hydro luoric acid) that attacks the part of semiconductor uncovered by resist.

[76]

Method to reorganize the

Photo Lithographic method

3

carbon atoms decomposed

Arc Discharge

from the bulk carbon precursors in the anodic electrode driven by the gas plasma generated in a sealed reactor. In the cathode the

Precise positioning and size control of the quantum dots but lithographic methods and subsequent processing often induce contamination, defect formation, size non-uniformity, poor interface quality, and even damage to the bulk material. CQDs obtained by this method have good water solubility but large particle size distribution which cause reduction of active catalytic sites in electrocatalytic process

carbon vapor assembly to form CQDs. [77-78]

4 Laser ablation method

A high-energy laser pulse used to irradiate the surface of the target to a thermodynamic state in which high temperature and high pressure are generated causing extremely heating and the material evaporates into a plasma state, and then the vapor crystallizes in nanoparticles

CQDs obtained with narrow size distribution, good water solubility, and luorescence characteristics. However, operation is complicated and expensive.

Figure 6.3: Different methods of QD synthesis with its merits and demerits.

6.3 Synthesis of QD

[79-80]

5

Acidic Oxidation

6

Combustion/ Thermal

[81-83]

Carbon nanoparticles derived from Chinese ink was oxidized by a mixture solution of HNO3, H2SO4, and NaClO3 and further exfoliation and decomposition of bulk carbon into nanoparticles, with instantaneous anchoring of hydrophilic groups, e.g., -OH group or carboxyl group on the surface of QD. The precursor material is generally heated or combusted

Routes

at temperatures ranging from 100 ℃ to 200°C for de ined time span followed by dilution with aqueous solutions. The QDs are further procured by using dialysis method.

Exhibits tunable PL behaviour, higher quantum yield (QY), and longer luorescence lifetime than the pure CQDs

The obtained QDs possessed uniform particle size and rich carboxyl groups on the surface would facilitate the adsorption of water molecules, is bene icial for electrocatalytic process in aqueous solution.

7

Microwave

[84-85]

Synthesize of CQDs by combining poly(ethylene glycol) (PEG200) and a saccharide (glucose, fructose, etc.) in water to form a transparent solution, followed by heating in a microwave oven

Simple, fast and ecofriendly approach for accessing CQDs with oxygen-containing groups, which delivers coordination sites of metal ions in designing carbonbased electrocatalysts.

8

Hydrothermal

[86-87]

Small organic molecules

Reaction setup is simple and the particle size is almost uniform with high QY.

/

and/or polymers dissolved in

Solvothermal Synthesis

form the precursor, which was

water or organic solvent to then transferred to a Te lonlined stainless steel autoclave at very high temperature to form carbon seeding cores and then grow into CQDs with a particle size of less 10 nm [88-89]

9 Electrochemis try Method

Figure 6.3: Continued.

The bare graphite rods are taken as starting material which heated at 1050 °C causing defects in graphene structure. The defect-induced graphite used as anode and cathode and then dipped in the electrolyte solution which is a mixture of citric acid and NaOH in water.

Required normal temperature and pressure conditions and inely tuned particle size and PL.

199

200

6 Synthesis, properties and catalysis of quantum dots in C–C

plasma. The carbon vapor generated under high temperature assembled at the cathode to generate QDs [76]. The laser ablation technique utilizes a high-powered laser pulse for irradiation the surface of the precursor material to a thermodynamic state with the generation of high temperature and pressure causing rapid heating of precursor which then converts to plasma state, and gradually the vapor crystallizes in to nanoparticles. The generated CQDs exhibited adjustable visible photoluminescence (PL) [77, 78]. In Acidic oxidation method a bulk carbon containing precursors are exfoliated and subjected decomposition into nanorange, and various hydrophilic groups, like hydroxyl, carboxyl group are introduced on the surface of synthesized CQDs, which attain improved water solubility and fluorescence phenomenon [79, 80]. Li et al. in 2017 prepared a fluorescent GQDs by combustion or thermal oxidation method of citric acid followed by functionalization with carboxyl groups through conjugation of acetic acid moieties under high temperature. GQDs obtained in current method possessed a uniform particle size of 8.5 nm and polar groups on the surface of GQDs which helps in water absorption, causing its smooth application in electrocatalytic process in water [81–83]. Among the different bottom-up strategies, the microwave pyrolysis method is a very common method owing to rapid synthesis and cost-effectiveness. Zhu et al. described a simple microwave pyrolysis method to generate CQDs through the combination of poly(ethylene glycol) and a saccharide (glucose, fructose, etc.) molecules in clear aqueous solution with subsequent heating under microwave irradiation [84, 85]. Particularly, hydrothermal process is mostly employed strategy for the synthesis of CQDs since the experimental condition is simple and the particle is obtained with uniform size range and appreciable quantum yield [86]. Typically, a solution of small organic polymer samples in water or organic solvents is used as the starting material, which then subjected to a Teflon-coated autoclave reactor. The molecules in starting sample combined together under high thermal condition to form carbon cores which successively have grown into CQDs containing particles less than 10 nm [87]. The electrochemical process of QD synthesis is a straightforward and suitable approach which could be carried out under ambient temperature and pressure. Typically, a bare graphite rod is heated at 1050 °C to create defects in graphene material for the synthesis of CQDs by electrochemistry method [88, 89].

6.4 Characterization of QD Optical characterization of quantum dot is generally performed by UV–VIS and photoluminescence spectroscopy, which are rapid, nondestructive and contactless option. In a report by Hazdra et al. photomodulated reflectance spectroscopy, a rarely used method was employed to investigate the advanced QD structures. This procedure

6.5 Applications of quantum dot in miscellaneous fields

201

delivers information regarding equivalent energy resolution to the observed photoluminescence at low temperatures and could detect critical points with several high order intersystem optical transitions which are important to predict band structure, particularly the wetting layer [90]. Photoconductivity enhancement effect in QD containing nanocomposite could be studied by photoluminescence (PL), optical absorption, photoconductivity spectroscopy, and time-dependent PL. As previously discussed, the optical properties (fluorescence emission) of QDs have found strongly dependent on its size, which is a significant factor in order to predict the spectral position and purity of photoluminescence. The size of QDs is calculated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS) methods [92]. To monitor the size of QDs prepared through epitaxial methods TEM, scanning tunneling microscopy (STM), atomic force microscopy (AFM) etc., are mainly used. Scientists used magneto-tunneling experiments to determine the size of doped QDs’ and the characterization results was found to be very close with the results obtained in AFM and TEM. To investigate the surface of QD several techniques were used for example, X-ray photoelectron spectroscopy, nuclear magnetic resonance spectroscopy, and Rutherford backscattering. In some cases, analytical ultracentrifugation method was also mentioned to characterize the surface property and size calculation of QD [93].

6.5 Applications of quantum dot in miscellaneous fields 6.5.1 Bio-imaging In recent years, Fluorescent QDs experienced a considerable extent of research investigation for long-term multicolor labeling of cellular and molecular activities utilizing their facile bioconjugation with different biomolecules [94]. With this aim, several organic and inorganic dyes have chosen as biological markers for years. Still, use of organic dyes for bioimaging purpose is complicated with major disadvantages of poor quantum yield and low photostability. In this realm, QDs are considered superior in many aspects as compared to conventional organic dyes and consequently explored as an important topic in biological field for some of their exciting properties, including (1) higher extinction coefficients; (2) good quantum yields; (3) poor photobleaching; (4) good tuning of absorptions and emissions with size; (5) broad excitation windows with narrow emission peaks; (6) chance of using many QDs in the same assay with minimal interference of one to another; (7) low toxicity in comparison to organic dyes, and (8) the easy functionalization QDs with diverse biomolecules. More particularly, it has been established that QDs are 20-fold brighter and 100 times more stable with respect to

202

6 Synthesis, properties and catalysis of quantum dots in C–C

Q-dots

Purpose

CdSe/CdS/ SiO2

Imaging of Mouse ibroblast cell Sensing or Biological detection Imaging of Cancer cell lymph nodes Survey of Maltose binding protein

CdSe/ZnS CdTe/CdSe CdSe/ZnS

Imaging techniques In vitro Fluorescence

Emission/ Size of Q-dots 550 nm & 630 nm

References

In vitro Fluorescence

1-4 nm

[96]

In vivo Fluorescence

NIR

[97]

In vitro FRET

560 nm

[98]

[95]

Figure 6.4: Selected in vitro and in vivo bioimaging studies using QDs.

conventional organic dyes [95]. Recently, there are many well-established synthetic methods are available in order to achieve QDs with noticeable brightening properties. In case of application in bioimaging field, the fluorescent probes should be well-distributed and stable in aqueous medium under broad pH and ionic strengths conditions. Up to now, enough research endeavors have been devoted to investigate the bioimaging capability of QDs in vitro and in vivo, which are important in solving many unknown complexities in medicinal field, the mechanism of several biological processed such as embryogenesis, lymphocyte immunology etc. [96, 97]. Additionally, QDs are efficiently applied to investigate intracellular processes, in vivo cell trafficking, tumor directing, cellular imaging and many more at high resolutions. Moreover, Researchers worldwide have also anticipated that quantum dots could deliver as siRNA gene-silencing tool far better to target cells as compared to conventional methods [98, 99] (Figure 6.4).

6.5.2 Photovoltaic devices Because of their good and finely tuned absorption spectrum and good extinction coefficient, QDs are recognized as a promising entity for light harvesting, and also advantageous for developing photovoltaic instruments. QDs also have potential to increase the productivity of silicon photovoltaic cells by reducing costs of the whole process [100].

6.5.3 Photodetectors Photodetectors (QDPs) derived from QDs could be prepared using conventional singlecrystalline semiconductors or solution-process. QDPs prepared by above process was

6.5 Applications of quantum dot in miscellaneous fields

203

found quite effective for the amalgamation of several substrates and application in integrated circuits. These colloidal quantum dots extensively used in spectroscopy, surveillance, and industrial study [101].

6.5.4 Light emitting devices QDs are considered as an useful alternative carbon-based nanomaterials with good emissive properties for the application in lighting and display applications to generate updated light-emitting diodes (LEDs). QDs could be optically and electrically excited, and the generated emissions originates photoluminescence (PL) and electroluminescence (EL), respectively. QDs are competent material for light emitting devices and helps in improving the performance of light-emitting diode (LED), important for the designing of “Quantum Dot light Emitting Diode”. QDs are very useful for display applications considering their unique optical properties and due to their capability of offering visibly more accurate and excellent colors. Moreover, QD-LED displays could produce colors which are more accurate and consume much less power as compared to the traditional displays [102, 103].

6.5.5 Quantum computing Recently, semiconductor based superconducting qubits and silicon-based qubit technology using silicon quantum dots have received great attention and make possible to design powerful ‘supercomputers’ also termed as quantum computers. Quantum computers could function and gather information in the form of quantum bits or ‘qubits’, which can operate in two states as on and off concurrently. This interesting phenomenon helps in improving both the information processing speeds and memory capacity as compared to conventional computers [104].

6.5.6 As a photocatalyst in organic syntheses During the last few decades, the development of photo redox catalysis has paved the field of photoassisted organic synthesis. The preparation of catalyst has been boosted through application of catalysts for solar energy generation. For this purpose, Ruthenium (Ru) and iridium (Ir) containing complexes are generally employed as a main catalyst. In addition to the homogeneous catalysts, the use of photoredox semiconductor material as heterogenous catalysts in organic synthesis is still the subject of intense investigation. Colloidal quantum dots (QDs) with good semiconducting properties have also experienced huge attention for their contribution in diverse area [105, 106]. Considering the ability of intrinsic light reactivity over a broad spectral range and surface reactivity upon photogenerated excitons, QDs could offer promising

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6 Synthesis, properties and catalysis of quantum dots in C–C

activity as photocatalysts in synthetic chemistry field. Bearing in mind the excellent photocatalytic and redox activities of QD, synthetic chemists become interested to design advanced structure of QDs for smart and clean organic transformations [106]. These nanocrystalline catalysts possesses surprising research interest since they contain some interesting features of homogeneous catalysts, for instance large extinction coefficient in visible region, and ability to be separated on applying ultra-filtration or centrifugation from the reaction mixture. Quantum dots can turn light energy into reducing electrons to catalyze reactions. Now they have, for the first time, been shown to be able to catalyze a number of carbon–carbon bond forming reactions [107–111]. The researchers used cadmium– selenium dots with 3 nm in diameter to replace the expensive iridium and ruthenium catalysts in five different bond forming reactions including β-alkylation and β-aminoalkylation. The quantum dots have some added advantages of easy synthesis and finely tuned photophysical and redox properties by changing the dots dimension.

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation 6.6.1 Synthesis of xanthenes using CuS quantum dots (QDs) catalyst Synthesis of xanthenes and its compounds through multicomponent reaction is attained enormous importance in organic and medicinal industry [112, 113]. Xanthene derivatives display broad spectrum of biological activities such as antibacterial, antiviral, anti-inflammatory, photo dynamic activity etc. and consequently frequently applied as laser technology, dyes, and pH sensitive fluorescent materials as diagnostic markers [114, 115]. Till date, several types of catalysts were involved in synthesis of xanthenes which are mostly associated with several drawbacks, such as involvement of high thermal energy, long reaction time, expensive reaction condition, handing of harmful reagents, low yield, hectic work up step [116–118]. Following this, in 2014, Bansal et al. described a relatively mild and simple syntheses of xanthenes derivatives with the aid of CuS quantum dots (QDs) [119]. The preparation of CuS QDs nanoparticle was carried out under microwave condition and include many advantages like low energy requirement, shorter reaction time, less hazardous by-product formation and use of low temperature with high yield with respect to reported procedures [120, 121]. During the optimization experiments to discover the most suitable condition, a large variety of catalysts were scrutinized along with the developed CuS QDs for this particular Biginelli reaction (Figure 6.5). They performed the model reaction using the substrates β-napthol (3) or 1,3-diketones (2) and bezaldehyde (1) in a 2:1 ratio using CuS

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

205

Figure 6.5: Different synthetic routes of QDs.

QDs under neat conditions at 80 °C. It was also observed that increase in catalyst loading from 1 to 6 mg improved the yield of xanthenes although further increase in the catalyst loading was not beneficial to offer any further improvement in the reaction yield. But in case of CuO NPs, 7 mg of the catalyst was essential to get the optimum yield. Therefore, CuS QDs has proven more efficient than the CuO NPs in terms of catalyst loading and reaction yield. The substrate scope for this MCR was also checked by reacting β-naphthol (3) or dimedone (2) with diversely functionalized aromatic aldehydes (1a-h) having both electron withdrawing and electron donating groups (Figure 6.6). After the reaction was over, the resulting solution was diluted with DCM and the catalyst was filtered from the reaction mixture. The separated catalyst was then washed with DCM for three to four times and then dried at oven at 100 °C. The separated catalyst could be used in next four cycles without any significant loss in catalytic activity. Previous reports [122–124] describing the synthesis of xanthene derivatives revealed that in presence of catalyst other than CuS QDs, the reaction need either higher catalyst loading or elongated reaction time. In some cases, where DCM was used as the reaction medium resulted toxic halogenated vapors and by-products as well as O

R1 O

O

O 4

R1

OH

2

O

CuS QD, 80 0C solvent free 6-15 min

CHO R1 1

3 CuS QD, 80 0C solvent free 6-15 min

Figure 6.6: Synthesis of xanthene derivatives using CuS QDs.

O 5

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6 Synthesis, properties and catalysis of quantum dots in C–C

Figure 6.7: Plausible mechanism of synthesis of xanthenes.

makes the work up process difficult. A comparative study of various catalysts with the reported CuS QDs was also performed for the synthesis of xanthenes. The result demonstrated the greater efficiency of CuS QDs as per the reaction yield and time viewpoint [122–124]. The plausible mechanism of formation of Xanthene derivatives (4) and (5) proposed by the authors shown in (Figure 6.7). The presence of Cu center in CuS QDs acted as Lewis acid catalyst due to its high affinity to coordinate with various polar groups like carbonyl (-CO), nitrile (-CN), hydroxyl (-OH), thiol (-SH), etc. Dimedone (2) or aldehyde (1) underwent activation by the interaction with acidic metal centers and became enough electrophilic for nucleophilic attack by enolic moiety of dimedone in the next step, and then after a Cu facilitated intramolecular cyclization and dehydration of 2d furnished the final product. The CuS QDs were released from the cycle and participated in next cycle (Figure 6.7).

6.6.2 Copper (I) sulfide QD-catalyzed synthesis of 4-phenyl-1H1,2,3-triazole During the last few years, light induced metal oxide prompted organic transformations has experienced an explosive progress as a new path of research in which the electrons

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

207

in conduction band are proposed to involve directly into the reaction mechanism. The photocatalytic performance of these metal oxides are mainly responsible to show nonselective free radical reaction mechanism. Some alluring methods are established utilizing the plasmonic effect of Au nanoparticles in presence of visible light, where the gold metal probably acted in the enhancement of electron density of palladium catalyst to stimulate the aryl halides for Suzuki cross-coupling [125–127]. Likewise, photoassisted charge transfer from graphene-based carbon nitride to pd in Suzuki coupling reaction was also informed by Li et al. at room temperature [128]. Others efficient methods of Suzuki reaction were also reported in literature involving different types of catalysts [129–131]. Inspired by the above innovation [132, 133], Nandy et al. in 2016 [134] nicely exploited the photonic effect of copper (I) sulfide QD towards the azide-alkyne cycloaddition reaction to achieve 1,4-substituted regio-isomeric 1,2,3-triazole derivatives (8) (Figure 6.7), commonly known as a ‘Click reaction’, which has vast application in organic synthesis, biological chemistry and materials science [135]. There are numerous efficient methods had been documented in synthetic literature describing Click reaction using a good variety of copper species with base [136–141]. In present work, authors have reported a ‘two-step process’ of preparation of polyaniline grafted copper sulfide nanoparticles in which initially, the Cu (I)-polyaniline composite was prepared and in second step the construction of polymer stabilized photonic Cu2S quantum dots was accomplished. On application of UV-light with high photon energy, the electrons in the conduction band of the Cu2S nanoparticles participated in azide-alkyne cycloaddition reaction and played a pivotal character in controlling the ‘proton abstraction mechanism’ via quenching of the terminal hydrogen of alkyne molecule (Figure 6.7) [134]. The similar type of photonic effect was also exhibited in presence of sunlight (low energy photon) since the copper sulfide is a semiconductor with small band gap. Click reaction in presence of UV-light showed potential advantage in view of environmental sustainability, as in this case the use of harmful base molecule could be avoided. In this report, the valence bond electron transfer of Cu(1) to the conduction band of QD through light excitation acted as a terminal proton quencher of alkyne moiety in presence of azides by delivering 1,4-substituted 1,2,3-triazoles (Figure 6.8). In present cycloaddition reaction, copper (1) species of Cu2S acted as the key catalytic center. The experiments were carried out under the influence of UV-light, daylight and in dark environment and the observations were nicely defined in the article. The synthesis of Cu2S QD were carried out using two step methods, where in the first step Cu(I)-polyaniline composite were formed and in next step the target nanoparticles was prepared using thiourea. A significant advancement of the present UV-light assisted reaction was the fast product generation. Photoassisted generation of conduction band electron catalyzed click reaction has shown faster than the traditional reactions under basic environment. Also, noteworthy to mention that use of base in a Click reaction is generally a major problem for achieving the desired targeted product

208

6 Synthesis, properties and catalysis of quantum dots in C–C

R1 N

N

Cu2S-PANI

+

R2

N

6a-d R1

R2

PhCH2

Ph

(2-Br)PhCH2

Ph

PhCH2

(4-OMe)Ph

7a-c %yield of 8 88c

62d

40e

35f 8g 92c 59d 48e 40f 7g 89c 65d 49e 41f 10g

MeOH (4 mL) 2h

R2

R1 (2-Br)PhCH2 PhCH2 (2-Br)PhCH2

R1 N N N 8 R2

1-hydroxy cyclopentyl 1-hydroxy cyclohexyl 1-hydroxy cyclohexyl

%yield of 8 69c 53d 84c 55d 79c 53d

Reaction Conditions: azide 6(1mmol), alkyne 7(1mmol), MeOH (4 ml), Cu2S(5 mol% of Cu), 2h, c =UV, d = daylight in presence of base, e = daylight without base, f = dark condition in presence of base, g = in dark condition

Figure 6.8: Substrate scope of the click products in day light with base and under base free UV irradiation.

as most of the organic functional groups are reactive to several bases. In view of the above difficulties, present method offered an efficient route without any hindrance of using base sensitive substrates for the desired Click reaction under mild environment. The synergic physical (photonic) and chemical (catalytic) characteristics of the Cu2S had altered the path of original reaction pathway of Click reaction through formation of a different route under light energy sources as described in Figure 6.8. Copper(I) sulfide (Chalcocite) is known to be a p-type semiconductor comprising a direct band gap of 1.8 eV. The prepared polyaniline stabilized Cu2S nanoparticle exhibited an exceptional catalytic performance to promote the azide-alkyne cycloaddition reactions under (UV) condition. A thorough study in comparing the action of daylight and dark conditions were also carried out applying various photonic conditions, for example under simply daylight (DL), daylight with base (DLB), dark condition without base (D) and dark condition with base (DB) under ambient condition. The XRD data of prepared polyaniline stabilized Cu2S quantum dots consisted four intense peaks at 36.90°, 46.20°, 48.50° and 54.80° which were originated due to (102), (110), (103) and (112) lattice planes, which were identical with the reported peaks for chalcocite Cu2S [142]. X-ray photoelectron spectroscopic (XPS) analysis indicated the binding energies of the photoelectron peaks of Cu 2p3/2 and 2p1/2 were found to be 932.5 and 952.5 eV, respectively, which was very close to standard reference of XPS spectrum of Cu 2p in Cu(I). The TEM image confirmed the formation of copper sulfide quantum dots (dark spots) with size distributions in the range of 10–40 nm. A broad variety of diversely functionalized azides and alkynes was verified under both UV irradiation and in the presence of base under daylight condition to explore the versatility of the present click reaction (summarized in Figures 6.8 and 6.9). The glucose and galactose substituted azide molecules were also employed as the substrates and it

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

209

Figure 6.9: Substrate scope of the click products using benzyl bromides, sodium azide and alkyne derivativesa.

was concluded that the functionalized azide molecule successfully reacted with alkynes to form β-D-glucopyranoside and β-D-galactopyranoside containing triazole moieties, respectively, using both ultra-violate light and Cu2S catalyst. The plausible pathway of the present Cu (I) catalyzed cycloaddition reaction of azide (6) with alkyne (7) proposed by the authors is depicted in Figure 6.10. Firstly, the reaction of Cu (I) and the alkyne molecule formed a π-complex, which resulted a decrease of the pKa value of the terminal proton of acetylene [132, 133] promoting the ‘H’ atom abstraction from the terminal C–H bond of alkyne on using triethylamine (Et3N) as a base. Next, the copper-acetylidine complex underwent addition to the azide molecule providing an intermediate complex which subsequently underwent protonation and elimination of the catalyst to form 1,2,3-triazole derivatives (8) and (11). Again, important to mention that, the Cu2S was completed the role of the active catalyst in present transformation and under UV-irradiation without use of any base the reaction delivered optimum amount of cycloaddition adduct. The photon generated from using UV source (deep UV (UV-C)), possess energy approximately 4.43–6.53 eV, which was adequate to reallocate an electron from the valence shell to the conduction end of Cu2S quantum dot. The electron at the conduction level acted as a quencher of the terminal hydrogen atom of the alkyne generating the corresponding copper-acetylidine complex. The authors also checked the impact of ultra-violate and sunlight condition on the reaction yield. It was proposed that the conduction level of Cu2S QD contains higher number of electrons, since the photon energy of the UV-light is much greater than that of daylight, to capture the terminal proton of the alkyne causing

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Figure 6.10: Proposed mechanism of Cu2S catalyzed azide-alkyne cycloaddition in presence of Et3N and under UV or daylight condition.

substantial improvement in the reaction yield. In presence of daylight condition with base causes significant improvement of the product yield as compared to the only daylight condition and the reason behind this observation was possibly due to synergetic effect of electrons at conduction level and lone pair electron of the base as then both efficiently participated in the proton removal mechanism. Important to mention that, the lowering of product yield under UV illumination on using triethylamine was observed as in this case base acted the role of hole-scavenger and coordinated to the Cu(I) to form a complex [143]. This complex could inhibit the electron transfer from valence band to conduction with a substantial decrease in the product yield.

6.6.3 Hydrogenation of imines from amines via hydrogen transfer using QD as catalysts Aliphatic amines are considered as a valuable synthetic precursor in organic synthesis and represent the essential building blocks in numerous natural products, medicines,

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and agrochemicals [144]. Among different synthetic methods, hydrogenation of imines through transfer of hydrogen are the most common and straightforward method which basically rely on using transition metal catalysts [145], organocatalyst [146], and metalorganic cooperative catalyst [147] etc. However, the major shortcomings and limitations of these protocols are increase of cost due to the use of precious metal catalyst, comparatively poor catalytic activity and turnover number due to undesired reaction of the amines with the catalysts, inadequate substrate variety and drastic reaction conditions. It is therefore the responsibility of synthetic chemists to search an alternative robust and mild strategy for the reductive hydrogenation of imines. Recently, study of several visible-light receptive photocatalysts (ruthenium and iridium coordination compounds) organic dyes [148, 149], as visible-light photoredox catalysis have been thoroughly investigated and employed in conducting myriad of radical reactions. After this innovative advancement, Xi and his co-workers in 2018 reported the preparation of CdSe/CdS core–shell quantum dots (QDs) nanocomposite and considered it for application as an active photoredox catalysts in reductive hydrogenation of imines involving (12), amines (14) and thiophenol as a source of hydrogen atom (Figure 6.11) [150]. This method progressed through proton-coupled electron transfer (PCET) from the conduction band of QDs to the protonated imine followed by HAT (Hydrogen atom transfer) from thiophenol to the α-aminoalkyl radical. This interesting conversion could be easily scaled up and performed under metal-free conditions in one step involving aldehyde (13), amine (14), and thiophenol (Figure 6.10). Notably, current protocol features ample substrate variety, good to satisfactory yield of the amine, minute amount of catalyst (0.001 mol %), good turnover number (105), and mild environment with the assistance of sun light or visible light under ambient conditions. Moreover, with respect to the simple-core CdSe and QDs, CdSe/CdS core–shell QDs has high stability as photocatalysts under applied reaction condition for the study of present synthesis (Figure 6.10). The different types of QDs used in present protocol were accessed using the previously reported method by Xi et al. [151, 152] The prepared CdSe and CdSe core in

Figure 6.11: Reduction of imines.

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core/shell QDs have grain size of about 3 nm, which underwent absorption at 550 nm. For choosing a shell material CdS was considered owing to its good optical phenomenon and well-established methods for the preparation of CdSe/CdS core/shell QDs. During optimization experiments a vast range of hydrogen sources were screened in varying amounts. After thorough study the optimum reaction condition was set to CdSe/CdS core/shell QDs containing three monolayers of CdS shell, 4-fluoro thiophenol (7 equiv) under 8 h visible light irradiation which gave the most satisfactory result. Control experiments indicated necessity of both QDs and thiophenol for smooth progress of present transformation. Also, in dark the reaction could not proceed. The scope of aldimines was also explored in detail for this particular reaction (Figure 6.12) which was revealed that almost all aldimines (12) underwent the full conversion within 6–10 h of irradiation. Almost all reactions continued with the reaction yield of greater than 80% yield irrespective the nature of substituents (electron-rich or electron poor (Figures 6.11 and 6.12) present on either of the phenyl rings). Moreover, the number and position of the substituents on the phenyl rings did not influence the reaction yield (Table 6.6, entries 13 and 14). For instance, 4-acetyl substituted aniline provided 79% yield with concomitant decomposition of imine evidenced by GC-MS measurements. Besides comparatively low yield (40%) was obtained for 15t most possibly due to gradual degradation of the imine under standard condition (Figure 6.13). To expand the substrate scope, N,N-dibenzylidene-1,4-phenylenediamine were also tested, and the corresponding diamine was obtained quite satisfactorily indicating smooth reduction of the diamine. Moreover, N-aryl aldimines and N-alkyl aldimines also smoothly responded under optimized conditions, providing the corresponding amines as final products with appreciable conversion. When the reactions of various aryl alkyl ketimines and diaryl was conducted, authors observed that ketimines behaved equally well towards reduction reaction with good isolated yields (Figure 6.12). The effect of sun light was also tested for this reaction. The reaction proceeded fast under sunlight and completed within only 3 h on a clear day to deliver the product 15d in 82% yield.

Figure 6.12: Expansion of substrate scope.

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Figure 6.13: Scope of aldimines in reduction reaction.

The synthesized QDs were exhibited good stability under imposed reaction conditions, confirmed by the excellent colloidal stability during reaction and no substantial change in catalytic performance even after 24 h irradiation. TEM characterization revealed the size and shape of the synthesized QDs which signified no significant alteration after multiple use. On the basis of previous works and control experiments, a probable mechanism for the photoredox hydrogen transfer reaction of amines was depicted in Figure 6.14. At first the CdSe/CdS QDs was assumed to absorb visible light to create an electron−hole couple. Then the transfer of Holes to thiolate and thiophenol from the valence state (route one in Figure 6.14) (route two in Figure 6.14) to provide either the thiyl radical directly or via deprotonation of the thiophenol cation radical. The protonated oleylamine and thiophenol then transfers proton to the imine through electron transfer from the conduction bond of QDs to produce a radical intermediate A (Figure 6.14) [129]. The second thiophenol molecule on Hydrogen atom transfer (HAT) afforded the target product and an additional thiyl radical [153] which after dimerization gives the disulfide product.

6.6.4 C–C bond formation using quantum dot as photoredox catalysts For the last few decades, photoredox catalysis have seen a sudden eruption as an efficient as well as sustainable tool in modern organic synthesis because it enables to designing important molecular frameworks under ambient condition avoiding the use

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Figure 6.14: Mechanism for photoredox catalyzed hydrogen transfer reaction.

of drastic environments [154]. Among the several new types of phtocatalysis, quantum dots (QDs) based semiconductor material are an efficient optimal owing to its inherent photostability, greater photons absorbance per molecule, longer stable excited states, and wide absorption spectra [155]. The QDs can also be considered as much efficient as organic dyes due to good charge transfer ability to organic molecules [156]. Moreover, the relative oxidation and reduction potentials of QDs could be enhanced up to several hundreds of mV by changing the size of nanoparticle [157]. In the present work by Caputo and co-workers, colloidal nanocrystal quantum dot (QDs) nanoparticles have been successfully exploited for the first time as a photoredox catalyst to several carbon–carbon bond forming reactions [158] (Figure 6.15) in some cases replacing various expensive metal catalysts (Ru and Ir etc.). Here authors showed

Figure 6.15: Model reaction of β-alkylation of aldehydes with acceptor olefins.

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215

that nanocrystal quantum dots (QDs) in colloidal phase served as an efficient, metalexempted, photoassisted redox catalysts. A single-sized CdSe quantum dot (3.0 ± 0.2 nm) could serve as an catalyst for five different types of photoredox reactions such as β-alkylation, β-aminoalkylation, dehalogenation, amine arylation, and decarboxylative radical formation (Figure 6.17) replacing several dye catalysts. The CdSe QDs were shown very efficient for the generation of C–C bond formation reactions, even in presence of low catalyst loadings. The photo-physics of CdSe QD is well studied, and the QDs are assumed to possess similar higher energy state reduction potentials to that Ir and Ru based photoredox catalysts (excited-state E1/2 from −1.43 to −1.80 V vs SCE compared to −1.33 V and −1.51 V in Ru and Ir) [133, 157]. A single-sized CdSe QD (3.0 ± 0.2 nm) was employed as catalyst for five different photoredox reactions, including C–C bonds forming reactions, reactions using organic co-catalysts, and metal co-catalysts. After studying the metal−dye catalysts with varied amount for the each of the five reactions, oleate-capped CdSe QDs with 3.0 nm size had proven comparable or superior with respect to native catalysts under identical reaction conditions. The catalysts were also equally active at very low loadings (0.0008 mol %), which was really very poor in magnitude than commonly available values in case of Ir dyes (∼1 mol %) [134, 158]. On a whole, these results signified that a single size CdSe QDs could be used as a competent

Figure 6.16: Mechanism of quantum dot catalyzed photoredox reaction.

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6 Synthesis, properties and catalysis of quantum dots in C–C

substitute with respect to the two commonly applied photoredox catalysts for example Ru(bpy)3X2 and Ir(ppy)2(dtbbpy)X, with the observed turnover numbers and frequencies are already greater in some cases as compared to informed Ir dyes (Figure 6.16). In this present report Caputo et al. began the studies of investigating the classical reaction β-alkylation of aldehydes (16) with acceptor olefins (17) under photocatalytic condition (Figure 6.15). During the optimization study it was observed that the reactions became slower on using larger QDs and delivered poor yield in some cases which was

Figure 6.17: Scope of different photoredox reactions catalyzed by QDs.

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217

quite desirable due to positive reduction potential (−1.52 and −1.42 V vs SCE for 3.4 and 4.5 nm QDs) and, thus proved ineffective for this particular reaction. The reaction smoothly tolerated several potential poisons and ligands (acids, bases, amines, alcohols, carboxylates etc.). It is also important to mention that not only the organic co-catalysts but also the applied transition metal containing co-catalyst was nicely survived. Particularly, a 3.00 nm grain size CdSe QD catalyst could be employed replacing very popular three metal dye catalysts, Ir(ppy)3, Ir(ppy)2(bpy)X and Ru(bpy)3X2.

6.6.5 Pd−Ag@CQD nanohybrid for the Suzuki Coupling Carbon-carbon (C−C) cross-coupling reactions are one of the utmost demanding research subjects in the modern organic synthesis and in this regard, the revolutionary work by Suzuki, Heck, and Negishi for the formation of new C–C bond through palladium-assisted C–C cross-coupling reactions are the standard and widely applied method in organic literature [159]. Till date in order to synthesize the biaryl compounds, Suzuki-Miyura cross-coupling reaction had developed as the benchmark strategy, which have significant potential in the synthesis of natural products, agrochemicals, drugs, and advanced materials [160]. The conventional Suzuki-Miyaura approach generally proceeded with the assistance of homogeneous palladium complexes using different ligands (such as phosphine) as key catalytic combination [161–166]. Although this catalytic system involves high efficiency and selectivity, but the catalyst recovery and reusability is a major concern which restricts their industrial applications. In the current study by Bayan and his co-workers, bimetallic Pd-Ag@CQD catalyst was employed as heterogeneous catalyst in the Suzuki-Miyaura coupling of aryl bromides (19) and aryl chlorides (20) in absence of any ligand under ambient reaction conditions (Figure 6.20) [167]. The synergic activity of the constituents of the nanocatalyst (Pd-Ag@CQD) render rate acceleration of the coupling reaction which was evidenced by short reaction time and satisfactory yields. The Pd−Ag@CQD bimetallic nanocatalyst was prepared through a UV-light-promoted (365 nm) one-step wet chemical method via in-situ reduction of Pd2+ and Ag+ ions by CQDs (shown in Figure 6.18), and applied as a photoredox catalyst in Suzuki−Miyaura coupling for the first time. The physico-chemical behavior of Pd-Ag@CQD nanohybrid was studied by FTIR, X-ray diffraction, UV−vis, TEM and electron dispersive X-ray analyses. The dimensions of nanohybrid were found in the range of 3–5 nm. In current process, CQDs played the dual role of reductants and stabilizing agents as well. As per the previous reports, the polar functional groups e.g., hydroxyl, alkoxyl, epoxy, carbonyl, and carboxylic groups at the surface of CQDs [168] helped Pd2+ and Ag+ ions to CQDs facilitating the reduction to Pd(0) and Ag(0). The dramatic suppression of the characteristic fluorescence emissions of CQD was well established the reduction of Pd2+ and Ag+ ions by CQDs. The heterogeneous nature of the nanohybrid also made the recovery of the catalyst easy from the solution and the recycling process easy up to

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Figure 6.18: Preparation of the Pd-Ag@CQD nanohybrid.

sixth consecutive turns. Up to third run, the catalyst exhibited good reusability without negligible loss of catalytic performance. Although, the catalyst exhibited little agglomeration after fourth but a slight decrease in the reaction yield was noticed. During the study of catalyst screening and substrate scope, it was realized that the reaction time and yield of present Suzuki−Miyaura coupling reaction was increased dramatically on applying Pd-Ag@CQD nanohybrid. To explain the cause of rate and yield enhancement in presence of the developed nanohybrid, the cross-coupling reaction of the aryl boronic acid derivative with aryl chloride was screened using a large variety of related nanomaterials like CQDs, AgNP, PdNPs. This study indicated that the reaction did not proceed only using CQDs. Again, when only PdNPs were employed, the reaction was sluggish delivering poor yield of final product. Thus, these results confirmed the necessity of pd for the progress of the reaction. Again, on using both PdNPs and AgNPs simultaneously, a slightly better yield was obtained (Figure 6.20). This confirmed that AgNPs assisted PdNPs to catalyze the reaction effectively. The result suggested the synergic capability of CQDs and AgNPs in rate acceleration of the cross-coupling reaction. This result also indicated the cause of acceleration in reaction rate and yield on application of Pd−Ag@CQD nanohybrid system. Hence, it can be assumed that both Ag and CQDs played an important role in activating and stabilizing the Pd center in the nanohybrid, by confirming their active presence in the catalytic cycle (Figure 6.21). The combination of Pd with Ag in the nanohybrid amplified catalytic performance of Pd due to the synergic metal-metal interactions, promoting efficient electron redistribution mechanism between them [169]. Additionally, owing to many polar functional groups at the surface of CQDs it could serve as the reaction center for secondary interactions with the reactants though H-bonding, π-π interactions, and so forth, particularly in oxidative addition and transmetalation mechanism (Figure 6.19). Besides, the energy released in the surrounding during electron transfer mechanism helped to progress the reaction [169]. To study the substrate possibility and limitations of the developed procedure, various aryl boronic acid derivatives was reacted with diversely functionalized and

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

219

Figure 6.19: Oxidative addition and transmetalation steps.

Figure 6.20: Substrate scope of the Pd−Ag@CQD-catalyzed Suzuki−Miyaura cross-coupling.

unsubstituted aryl bromides and aryl chlorides under standard conditions. The results of substrate study are presented in Figure 6.20.

6.6.6 Graphene quantum dots functionalized Fe3O4 nanoparticles supported PdCu for Sonogashira coupling The cross-coupling of aryl or vinyl halides with terminal acetylenes in presence of palladium and other transition metal catalyst, commonly referred as Sonogashira crosscoupling reaction which is a very popular and broadly approved sp2–sp2 carbon–carbon bond forming reactions frequently applied in the creation of complex natural products, medicinally active molecules, compounds and polymers and many more [170]. However,

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6 Synthesis, properties and catalysis of quantum dots in C–C

Figure 6.21: Mechanism of reduction and consequent formation of the Pd-Ag@CQD nanohybrid under UV-Light condition.

the addition of copper, although beneficial in terms of increasing the reactivity of the system, have some unavoidable shortcomings such as necessity to avoid oxygen environment to inhibit unwanted side product formation in the coupling of alkyne via a copper-catalyzed Hay/Glaser reaction [171]. With the aim of resolving above issues, an alternative solution was to eliminate the copper catalyst in the Sonogashira reaction. Recently palladium-catalyzed C–C or C–X (X = heteroatom) bond formation become a benchmark in performing numerous transformations [172, 173]. Considering the remarkable toxicity and expensive nature of Pd, in these days numerous modified heterogeneous and reusable palladium catalysts were prepared and employed as a mild alternative in various cross-coupling reactions. Particularly, Graphene quantum dots (GQD) have lately been acknowledged significantly in materials science and engineering field as a consequence of their attractive features like low-toxicity, good photostability, small dimensions, biocompatibility, highly controlled photoluminescence [174]. Gratifyingly, the GQD supported Pd catalyst

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

221

Figure 6.22: Preparations steps of PdCu@GQD@Fe3O4

was firstly employed to perform Sonogashira cross-coupling reported by Gholinejad et al. to generate C–C and C-heteroatom bonds under relatively mild environment. In the year of 2017, Gholinejad et al. [175] disclosed a structural modification of Fe3O4 nanoparticles using graphene quantum dots (GQD) for the first time and engaged this material in stabilizing PdCu nanocomposite. This novel magnetic composite PdCu@GQD@Fe3O4 was characterized with the help of different characterization techniques such as SEM, HRTEM, XPS, XRD, EDS-map, etc. Authors employed this novel nanocomposite to accomplish Sonogashira reaction of alkynes with aryl iodides, bromides and chlorides in toluene or N, N-dimethylacetamide solvent at 60–110 °C on using very low Pd loading (0.3%) (Figure 6.23). The preparation steps of the nanocatalyst are portrayed in (Figure 6.22). In brief, GQD at first were synthesized applying ethylenediaminetetraacetic

Figure 6.23: Substrate study for the PdCu@GQD@Fe3O4 catalyzed Suzuki-Miyaura coupling reaction.

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6 Synthesis, properties and catalysis of quantum dots in C–C

acid (EDTA) mediated direct carbonization of organic precursor under solid phase [152]. The prepared GQD exhibited broad fluorescence spectra in water at 431 nm on excitation at 365 nm [176]. Then to synthesize GQD grafted Fe3O4, GQD was reacted with previously synthesized Fe3O4 NPs in water using the temperature at 60 °C for 2 days. TEM image of GQD decorated Fe3O4 NPs indicated uniform distribution of Fe3O4 NPs on GQD and very fine coating of GQD about the Fe3O4 NPs. In another setup bimetallic PdCu was synthesized from the reaction of CuSO4.5H2O and Pd(OAc)2 and further reaction of the resulting mixture with GQD@Fe3O4 in acetone (Figure 6.22). The atomic absorption spectroscopy showed that the attained PdCu@GQD@Fe3O4 NPs was found to contain 0.12 and 0.14 mmolg−1 Pd and Cu respectively. TEM study of PdCu@GQD@Fe3O4 NPs indicated the existence of small nanoparticles in the composite material. Particle size distribution plot obtained from TEM experiment suggested presence of majority of the nanoparticles in two different size range of 3–4 and 9–25 nm corresponding to the PdCu and GQD@Fe3O4 structures respectively. The obtained SEM image again indicated uniform distribution of PdCu@GQD@Fe3O4 NPs. In order to scrutinize the scope and limitations of the developed protocol, aryl iodides functionalized with both electron-releasing groups such as -Me and -OMe and electron-withdrawing groups (-F, -Cl, and -NO2 etc.) as well as with heteroaryl substituents (2-iodothiophene) was thoroughly reacted with phenylacetylene and gratifyingly, they all delivered the corresponding alkynes in satisfactory yields (Figure 6.23). Also, scrutiny of the activity of different alkynes such as 4-ethynyltoluene was also carried out and, in every case, satisfactory yield was obtained (Figure 6.23). Reactions of poor reactive aryl bromides were also smoothly responded under the standard condition. Recycling study of PdCu@GQD@Fe3O4 was carried out using a model reaction involving the substrates iodobenzene and phenylacetylene. After completion of first run, the catalyst was removed from the reaction mixture using an external magnet and then washed it thoroughly with diethyl ether solvent and then employed in a fresh reaction. After 6th run, the reaction yield was decreased to 90% from 99% and after 9 th turn the yield reached to 77% which was indicated through GC analysis of the reaction mixture. However, the reaction yield lowered dramatically after 9 th run (57%). These experimental results indicated that the designed catalyst could be successfully recycled at least up to six consecutive turns without substantial reduction in reaction yield. TEM image of recycled catalyst showed no significant alteration of the catalyst structure up to 3rd run with very little agglomeration of nanoparticles. Moreover, XPS study indicated the all Pd species in Pd(0) state.

6.6.7 Piperidine-functionalized Fe3O4 supported graphene quantum dots for the synthesis of 2-aminochromenes Chromenes and its fused heterocyclic motifs are recognized to be an ubiquitous heterocyclic motif which are present as the key constituent of severally naturally extracted

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223

compounds like, tocopherols, alkaloids, flavonoids, and anthocyanins etc. [177]. Amid the various chromene structures, 2-amino-4H-chromenes represents an interesting core as they found to present actively in numerous renowned medicinal scaffolds serving as an useful source to realize small-molecule with marked diuretic, spasmolytic, anticoagulant and anti-anaphylactic actions [178]. They have also known to display additional exciting biological activities as an antibacterial [179, 180], anti-viral, anti-fungal [181–184], anti-tumor [185], hypotensive agents [186], and central nervous system (CNS) stimulators [187]. A large variety of catalytic systems, such as InCl3, [188] ZrO2 nanoparticles [189], Mg/Al hydrotalcite [190] K2CO3 under MW condition [191], KF [192] or NaOAc [193], Na2HPO4 [194], DBU in water [195], [bmim] [PF6] ionic liquid [196], ionic liquid [197] etc. have been reported in order to accomplish this exciting heterocyclic scaffold. However, many of the aforesaid methods involves prolong reaction time, stringent reaction conditions, poor yields, and/or uses organic solvents revealing the discovery of an alternative mild protocol. In 2019, Moghanlo et al. [198] reported a piperidine containing 3-piperidino propyltrimethoxysilane and piperidine-anchored nanocatalyst (Fe3O4@GQDs-Pip) as a magnetically recoverable heterogeneous catalyst in the one-pot synthesis of 2-aminochromenes on reacting β-naphthol 3 (1 mmol), malononitrile 23 (1 mmol), aldehyde 1 (1 mmol) (Figure 6.25) under neat conditions utilizing MW energy source. The catalyst was prepared using microwave irradiation technique. Fe3O4@GQDs and Fe3O4@GQDs-Pip were studied using FT-IR, XRD, SEM, VSM, TGA characterization tools. To achieve the desired Lewis basicity, piperidine was attached with Fe3O4@GQDs through the reaction with 1-(3-trimethoxysilylpropyl) piperidine and the new magnetic nanocatalyst (Fe3O4@GQDs-Pip) was attained (Figure 6.24). This modified catalyst was then evaluated to synthesize a series of 2-aminochromenes and the catalyst Fe3O4@GQDs was proved to give better yield as compared to the GQD alone. Catalyst Fe3O4@GQDs-Pip was prepared according to the procedure displayed in Figure 6.24. First, Magnetic Fe3O4 nanoparticles were developed using the reported method and was next coated with graphene under MWI to generate Fe3O4@GQDs catalyst. Then, Fe3O4@GQDs was reacted with 1-(3-trimethoxysilylpropyl) piperidine under reflux conditions to produce Fe3O4@GQDs-Pip. The structure of Fe3O4@GQDs and Fe3O4@GQDs-Pip were characterized through FT-IR, XRD, TGA, SEM and VSM analyses. The appearance of peaks at 562 cm−1 due to Fe-O stretching vibration, at 3422 cm−1 for O-H stretching vibration and O-H deformed vibration at 1636 cm−1 confirmed the existence of magnetite nanoparticles in Fe3O4@GQDs. Again, peaks at 1245 cm−1(C−N) and 2938 cm−1 (C–H) were ascribed to the piperidine anchored Fe3O4@GQDs. The catalytic activity of prepared catalysts was judged by employing it in the three-component reaction of β-naphthol, benzaldehyde and malononitrile to synthesize 2-aminochromene (24). Various catalysts such as poly (4-vinylpyridine), [EMIM] [OH], [bmim][PF6], SiO2-Pr-SO3H were also screened to optimize the reaction yield. Fe3O4@GQDs-Pip was found superior with respect to time and yield. Also, in the

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Figure 6.24: Synthesis of the nanocatalysts: Fe3O4@GQDs and Fe3O4@GQDs-Pip.

presence of Fe3O4@GQDs-Pip, the proposed reaction required lower microwave power. Reactions of various aryl aldehydes with electron-withdrawing or electron-donating substituents were also inspected under Fe3O4@GQDs-Pip catalyst condition applying standardized condition to accomplish a library of substituted chromenes 24a-e (Figure 6.25). The three-component reaction proceeded with high to satisfactory conversion to corresponding chromenes in all cases. The recyclability behavior of catalyst was also explored by separating the catalyst from the reaction mixture applying an

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

225

Figure 6.25: Synthesis of chromene derivatives 24a-k using catalyst Fe3O4@GQDs-Pipa. Entry 1 2

Product

Fe3O4@GQD

Fe3O4@GQDs-Pip

Time (min)

Yield%

Time (min)

Yield%

24a (X= H)

6

85

4

98

24b

5

84

4

98

6

80

5

90

5

86

4

96

6

80

4

99

(X = 2-NO2) 3

24c (X = 3-NO2)

4

24d (X = 4-NO2)

5

24e (X = 4-Cl)

Figure 6.26: Comparison of Fe3O4@GQDs and Fe3O4@GQDs-Pip as a catalyst for the synthesis of chromenes 24a-4e.

external magnetic field. The isolated catalyst was employed in the synthesis of 4a under identical condition. The observation revealed that the catalyst could be efficiently recycled up to five consecutive cycles with minor changes in reaction yield. Synthesis of 2-aminochromenes (24a-e) were also examined using the two different types of catalysts Fe3O4@GQDs and Fe3O4@GQDs-Pip and the experimental consequences were presented in Figure 6.26. It was concluded that Fe3O4@GQDs-Pip promoted the reactions more effectively in comparison with Fe3O4@GQDs and it also proved as one of the best eco-friendly and user-choice catalyst in accessing 2-aminochromenes.

6.6.8 CuS QD catalyzed synthesis of DHPMS Dihydropyrimidinone/thiones impregnated heterocyclic frameworks signifies most important heterocyclic compounds showing an active role in the synthesis of DNA and RNA with additional medicinal activities like calcium channel blockers [199], antihypertensive drugs [200], alpha/a-adrengenic antagonists and neuropeptide mitotic kinesin inhibitor [201], anticancer agent [202] and antibacterial [179, 203] and also vastly explored in the synthesis of modified functional materials for example renewable polymers [204], adhesives [205], fabric dyes [206]. Apart from they are also existed in many marine natural products, including the batzelladine alkaloids, which are

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renowned HIV gp-120-CD4 inhibitors and anti-HIV drugs [207]. In this regard to access this pharmacologically interesting dihydropyrimidinone core, MCR reactions like Biginelli and Hantzsch synthesis are mostly adapted involving a large number of catalysts e.g., lanthanide triflate25 [208], indium triflate [209], iodine [210], strontium (II) triflate [211], zirconium tetrachloride [212], cobaltous chloride [213], Copper catalyst in presence of MWI [214], copper (II)complex [215], Si-MCM41 supported iron chloride [216] Lanthanum chloride [217], Keggin and Dawson type polyoxometalate [218] and many more. Despite potential advancement, the synthetic strategies have several complications e.g., long completion times, tedious work up procedure, harsh reaction environment, use of expensive catalyst/reagents, high catalyst loading. Consequently, encouraged by the environment friendly and recoverable nanocatalyst based organic synthesis in recent times. Chaudhary et al. in 2014 proposed CuS quantum dots (QDs) mediated cost-effective and mild approach of Biginelli reaction involving commercially available aldehyde (1), ethylacetoacetate (25), urea or thiourea (26) as reactants under MW (800 W) source and neat conditions (Figure 6.27) [219]. In present report, CuS QDs contributed as an robust heterogeneous catalyst for the proposed Beginelli reaction with regard to reaction completion time, work up method, and energy requirement. The method has proven highly preferable in terms of cost effectiveness and undesired product formation. The catalyst was prepared using the described procedure [220]. Briefly, in a beaker 100 ml of 0.01 M solution of CuCl2.2H2O was mixed with 100 ml of 0.012 M solution of thioacetamide which was prepared in another beaker. After mixing of both solutions, the resulting mixture was heating using microwave radiation until a black precipitate appeared. The precipitate was then filtered and washed several times with water, dried at normal temperature and applied in the hypothetical Beginilli reaction. The proposed Bignelli reaction were also carried out in the presence of ionic liquid, ethylene glycol anchored Cu NPs and simple Fe3O4 nanocatalyst [221, 222]. Which concluded that, ionic liquid, ethylene glycol protected Cu catalyst provided the desired product after long reaction time as compared to the CuS QD and made the synthesis method complex and costly. The synthesis using Fe3O4, the catalyst was required in large amount and moreover involved long completion time to generate DHPM with lower yield.

Figure 6.27: Synthesis of different DHPM using CuS QDs.

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227

Figure 6.28: Proposed mechanism of formation of DHMP.

The obtained QDs CuS Quantum dots (QDs) contained particle size in the range of 2–3 nm confirmed by the UV-visible spectrophotometer, TEM, XRD, and SAED patterns. The catalyst provided a series of desired DHPMs products (27a-j) in comparatively short reaction time. During substrate study it was observed that aromatic aldehydes bearing electron withdrawing as well as electron donating groups reacted smoothly in the presence of CuS QDs irrespective the nature of substituents (Figure 6.27). A plausible mechanism for the synthesis of DHMP is also depicted in Figure 6.28. Firstly, nucleophilic addition of urea (26) to the benzaldehyde (1) generated N-(1-hydroxybenzyl)-urea (A′). ‘Hemiaminals’ was assumed to participate in rapid dehydration process with the aid of CuS nanoparticle to generate a carbenium ion intermediate which recognized as a highly sensitive N-acyliminium species (B′) (Figure 6.28). If no 1,3-dicarbonyl compounds was used then a second equivalent of urea was added to get the bis-ureides (D′). Moreover, when ethyl acetoacetate (25) was present in the reaction mixture, iminium ion (A′) is generated from the ethyl acetoacetate (25) fragment, probably after formation the enol tautomer, to furnish intermediates (C′), which then cyclize to form the Biginelli compounds (27a) [223, 224]. Recyclability study of the catalyst was evaluated after using it four consecutive cycles. The characterization data of recovered catalyst depicts insignificant decrease in the reaction yield even at 4th recycle.

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6 Synthesis, properties and catalysis of quantum dots in C–C

6.6.9 Synthesis of hydrophobic cellulose aerogel-based graphene quantum dot/Pd as heterogeneous catalyst in oxidation of alcohols and alkenes Catalysts are well-known substances for the useful conversion of alcohols, alkylbenzenes in presence of thermal energy to a myriad of useful products [225]. But, the oxidative transformations are not always adaptable for the purpose of hazard-free industrial applications due to the generation of several unwanted reactive intermediates which further converted to a variety of poisonous side products that often cause the reduction in reaction yield and also hampers environmental hygiene. Thus, it is desirable to develop a more efficient protocol which can control the generation of undesired products as this is an extremely hard to maintain and often increase total cost. Of late, heterogeneous catalysts have recognized as a center of interest in modern chemistry for the oxidation of alcohols, alkylbenzene into carbonyl compounds. Among the various substrates tested in oxidation reactions, aromatic alkanes, such as ethylbenzene are the most commonly used substrate because of their useful oxidation products having enormous contribution in many marketed drugs and functional materials. As an example, the ethylbenzene on oxidation gives acetophenone and 1-phenylethanol which are very useful precursors to synthesize optically active alcohols [225], benzal acetophenones (chalcones) [226, 227], and hydrazones [228] and many more to perform numerous synthetic transformations employing these starting materials. The conventional oxidation method generally relied on using a stoichiometric quantity of oxidants for example permanganates [229, 230], chromium reagents [207–210, 231–234], ruthenium (VIII) oxide [235, 236], activated dimethyl sulfoxide (DMSO) [237] or Dess–Martin periodinane [238], and TPAP/NMO (tetra-N-propylammonium perruthenate/N-methyl-morpholine-N-oxide) [239] etc., and most of these strategies embrace drastic reaction condition like high temperature and or pressure, use of noxious chemicals and generation of equivalent amount of waste metals as halogenated organic solvents [240, 241] which are not desirable in view of environmental sustainability. In 2019, Keshipour et al. synthesized a novel cellulose aerogel (CA) reinforced graphene quantum dots (GQD)/Pd with high hydrophobicity, superior porosity, high catalytic activity and applied it in the oxidation of alcohols (28), ethylbenzene (29), and alkenes (31) (Figure 6.29) as a robust heterogeneous catalyst [242]. The aerogel grafted GQD nanocatalyst was achieved in four steps, in first step the cellulose aerogel was functionalized with CA, second step involves a salinization reaction of citric acid in the presence of TiO2 nanoparticles and MTMS to give polysiloxane/TiO2 nanoparticles supported on CA (ST@CA), in next step the ST@CA was modified with GQD to yield polysiloxane/TiO2 nanoparticles/GQD supported on cellulose aerogel (STG@CA), and in the final step Pd nanoparticles were deposited on STG@CA after reduction with

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

229

Figure 6.29: Oxidation of various substrates with STGP@CA.

sodium borohydride (shown in Figure 6.31). The developed catalyst features good yields, excellent selectivity, mild environment, multiple reusability and biocompatibility and use of cheap green resources for the synthesis of nanocomposite such as cotton and citric acid. Herein, CA was salinized in presence of methyltrimethoxysilane (MTMS and TiO2 NPs) in order to improve the hydrophobicity of the nanocomposite. Synthesis of STGP@CA: The synthesis of STGP@CA involves several steps in which GQDs was first prepared applying the thermal treatment of citric acid which were loaded on the GO via the esterification reaction in presence of N, N-dicyclohexylcarbodiimide (DCC), N, N- and dimethylaminopyridine (DMAP) [243] catalyst. The prepared material based on GQD was enough stable to be retain perfectly on the cellulose-CA support during the catalytic reactions of STGP@CA. The cellulose-CA support (2) was prepared by reacting cellulose aerogel with CA in presence of TiO2 Np and MTMS. Finally, in situ chemical reduction of Pd (II) to Pd (0) was achieved using NaBH4 to form STGP@CA catalyst (Figure 6.31). Chemical reduction of metal ions promotes smooth deposition of the metal NPs on the cellulose-CA-GQD support with a uniform distribution of the catalyst on the support [244]. The structure of the designed catalyst was then thoroughly characterized using FT-IR spectroscopy, X-ray photoelectron spectroscopy (XPS) analysis, Energy dispersive X-ray spectroscopy (EDX), TEM. The wettability of STGP@CA was also determined by the WCA of the aerogel support. The used aerogel confirmed hydrophobicity with a water contact angle of 136.2°. It also showed remarkable capacity of oil/water absorption selectively with an oil uptake of up to 79 g g-1 with 134 g g-1 selectivity. The catalytic activity of STGP@CA was examined in the oxidative conversion of alcohols, ethylbenzene, and alkenes in presence of air as the sole oxidant (bubbling rate of oxygen was kept as 20 ml min−1) (Figure 6.30). The condition of the oxidation reaction was also established by employing the catalyst in varied amount and

230

Entry

6 Synthesis, properties and catalysis of quantum dots in C–C

Substrate

Catalyst

Conversion (%)

1

Benzyl alcohol

STGP@CA

59

2

Ethylbenzene

STGP@CA

67

3

Styrene

STGP@CA

63

4

Benzyl alcohol

STG@CA

0

5

Ethylbenzene

STG@CA

0

6

Styrene

STG@CA

0

7

Benzyl alcohol

STG@CA

47

8

Ethylbenzene

STG@CA

42

9

Styrene

STG@CA

51

10

Benzyl alcohol

STG@CA

54

11

Benzyl alcohol

GP@CA

52

Figure 6.30: Oxidation of benzyl alcohol, ethylbenzene, and styrene with STGP@CA (cellulose supported catalyst), STG@CA, STP@CA, STGP@C, and GP@CA.

thoroughly screen the reaction media for the oxidation of 1-pentanol. The conversion and selectivity of the above oxidation reaction were determined by GC analysis. Turnover number (TON) was also calculated for the oxidation reaction of 1-pentanol. The reaction delivered optimum yield in the presence of 0.036 mmol of the catalyst. Among the various solvents studied, H2O proved to be the best choice in terms of reaction yield and environmental impact . The study of TONs for these reactions found greater than 1-pentanol and 1-octanol which was evidenced by the more facile oxidation of secondary alcohols in comparison to primary alcohols. The oxidation of benzyl alcohol (2 ml) to corresponding benzoic acid was proceeded selectively with 314 TON. Cyclohexene, styrene, 1-hexene were also

Figure 6.31: General protocol for the synthesis of STGP@CA.

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

231

underwent oxidation similarly under identical conditions to generate the corresponding ketones (Figure 6.30). Ethylbenzene (1 ml) was oxidized in a similar manner to afford acetophenone in excellent selectivity with 150 TON. However, 1-hexene and cyclohexene on oxidation afforded moderate conversions revealing less facile oxidation of linear and cyclo-alkenes in comparison to aryl alcohols. The reusability performance of STGP@CA was verified in the oxidation of benzyl alcohol. After completion of the reaction, the catalyst was separated by filtration washed with acetone (2 × 5 ml) for several times, dried in a vacuum oven at 70 °C, and applied for the next turn. A minor decrease in the reaction yield was observed after six cycles which indicated high stability of the catalyst under the imposed conditions and minor change in product yield after using the recovered catalyst during the reaction process.

6.6.10 Iron oxide nanoparticles modified with carbon quantum nanodots for the Suzuki reaction The Suzuki–Miyaura cross-coupling and its contribution in synthetic chemistry has seen an explosive growth through the last few decades, which clearly indicate its high practicability and effectiveness. This method has widely used an efficient synthetic route for the direct formation of carbon–carbon bonds in which Pd-catalyzed Suzuki coupling reactions are very familiar for the formation of C–C and C-heteroatom bonds [245]. However, due to toxicity and expensive nature of Pd catalyst, recently, several research groups become interested in the modification of commonly employed Pd catalysts to make it recoverable and therefore dedicated enough efforts to prepare heterogeneous Pd catalysts [246, 247]. With this motive, different solid materials such as modified silicas [248], polymers [249], mesoporous materials [250, 251], ionic liquids [252], and natural supports [253] have been employed as supports. Consequently, various greener strategies have been developed in presence of heterogeneous Pd catalyst for coupling reaction bypassing the expensive non-recoverable palladium, nickel, gold, ferrites, copper, silver, and cobalt based diverse catalytic systems [254–257]. Inspired by the prevailing achievements, in recent years, C-dots-reduced Pd nanoparticles have been employed as a competent catalyst in Suzuki and Heck coupling reactions in water [258]. After this innovative work, in 2016 Gholinejad et al. [259] described the synthesis of Fe3O4 nanoparticles (NPs) functionalized carbon quantum dots (C-dots) and their characterization and application as a green catalyst in the Suzuki–Miyaura cross-coupling reaction in water for the first-time involving aryl bromides and chlorides (20) with arylboronic acids (19). Optimization experiments revealed that the use of 0.22 mol% of Pd, K2CO3 as the base in water-ethanol mixture was the best reagent combination. The polar carboxylic and hydroxyl functionalities on the C-dots impart good water dispersibility along with biocompatibility to make the

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6 Synthesis, properties and catalysis of quantum dots in C–C

catalyst effective for this particular coupling reaction. Under the optimized reaction conditions, the reactions of structurally different aryl bromides and chlorides with different arylboronic acids were also tested in the presence of the catalyst. The results indicated that aryl bromides containing electron-donating groups, such as 4-OH, 4-OMe, and 4-Me, as well as electron-withdrawing groups, such as 4-NO2, 4-Cl, 4-CN, 4-CHO, and 2-CHO, reacted smoothly with phenylboronic acid (Figure 6.31). Moreover, unsubstituted aryl bromides, such as bromobenzene, bromobiphenyl, and 1-bromonaphthalene also responded smoothly in this particular reaction. However, aryl chlorides could not participate in coupling reaction at room temperature under the optimized conditions but could furnish the desired products quite satisfactorily on increasing the reaction temperature. To check the necessity of C-dots in the activation and stabilization of Pd NPs, a similar catalyst without C-dots was also synthesized and employed as a catalyst in proposed Suzuki reaction. The model reaction was also tested using Pd absorbed on Fe3O4 NPs under standard conditions which provided the desired product with only 14% yield in 24 h. This result indicated an active participation of C-dots in the reduction process and formation of reactive Pd NPs in the catalyst structure. Other importance benefits of using magnetite-NPs-supported catalysts were easy isolation from the reaction mixture and good recycling ability of the catalyst. The recyclability was also confirmed by successful exploitation of the recovered catalyst in the model reaction between 5-bromopyrimidine with phenylboronic acid under optimized conditions up to eight consecutive runs just by decantation with a magnetic bar with minimal decrease in product yield (Figure 6.32). Fe3O4 NPs were prepared through a co-precipitation method according to the reported procedure by Massart which initiates the synthesis from FeCl3·6H2O and FeCl2· 4H2O. C-dots were also prepared using the previous method [260, 261]. Briefly, the mixture of urea and citric acid was subjected to heating in a Teflon lined autoclave at 160 °C for 6 h. Next, the C-dots were treated with Fe3O4 NPs at 60 °C for 24 h to get C-dots@Fe3O4 NPs. Lastly, PdCl2 was dissolved in water under US irradiation. C-dots@Fe3O4 was then added to the above mixture and dissolved in water using sonication, and the resulting mixture was heated at 60 °C for 24 h to get Pd@Cdots@Fe3O4 catalyst. The synthesized catalyzed was then characterized by SEM, TEM, EDX, solid UV spectroscopy, vibrating sample magnetometry, XRD, and X-ray photoelectron spectroscopic techniques. With the designed nanocatalyst the established

Figure 6.32: Pd@C-dots@Fe3O4 NPs catalyzed Suzuki-Miyaura coupling.

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

233

reaction condition for this newly developed Suzuki reaction was finally set to arylboronic acid 19 (1.5 mmol), aryl halide 20 (1 mmol), base (1.5 mmol), catalyst (8 mg that contained 0.22 mol% Pd) and water-ethanol (1:1, 2 mL) mixture at RT or 808 °C(depending on the substitution in aryl halide) under magnetic stirring condition.

6.6.11 Synthesis of indeno and acenaphtho cores using SnO2 quantum dot Indeno[1,2-b]indoles are an vital heterocyclic motif comprising small planar heterocyclic fragments. Because of its abundance in several bio-relevant heterocyclic molecules, indeno[1,2-b]indoles serve as a challenging ADP/guanosine triphosphate-competitive inhibitors of protein kinase (CK2) and act as DNA intercalators and topoisomerase II inhibitors, with substantial cytotoxic activity to cancer cells [262]. Furthermore, coumarin and uracil attached heterocycles are also renowned pharmacophores exhibiting a broad spectrum of medicinal activity. Most of the coumarin fused heterocycles offer antitumor [263], antibacterial [264], antifungal [265], anticoagulant [266], antiinflammatory [267], and antiviral [268] activities. A good number of adenosine receptor agonists and antagonists also received huge interest as highly effective and subtype discriminating ligands [269, 270]. In spite of immense biological applications, syntheses of these heterocyclic molecules are limited with a few existing references in literature [271–273]. Despite enough efficiency, the reported strategies have several complications like low yields of products, long reaction time, multistep synthesis and narrow substrate scope. In 2015, Pradhan et al. described a simple, robust, and mild approach regarding the synthesis of dihydroxy indeno[1,2-b]indolone, acenaphtho[1,2-b]indolone, coumarin and uracil conjugated indeno[1,2-b]pyrrole and acenaphtho[1,2-b]pyrrole motifs using an eco-friendly and competent monodisperse SnO2 QDs catalyst by assembling the commodity based substrates aniline (14), cyclohexane-1,3-dione or dimedone (2) and ninhydrin (32) in aqueous medium (Figure 6.33) [49]. The SnO2 QD was synthesized following the solvothermal method and completely characterized using XRD and TEM and energy-dispersive X-ray spectroscopy (EDX). In

Figure 6.33: Three-component reaction for the synthesis of indeno and acenaphtho cores.

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6 Synthesis, properties and catalysis of quantum dots in C–C

short, a mixture of tin(IV) chloride pentahydrate (SnCl4. 5H2O; 1 mmol) in a mixed solvent (methanol and ethylenediamine) was stirred for 1 h at normal temperature. Then the aqueous solution of Urea (10 mmol) added to the above mixture and the resultant solution was turned in to a white slurry after stirring for 30 min. It was then heated in a Teflon coated stainless steel autoclave at 90 °C for 8 h. After the required time period the mixture was cooled, centrifuged and washed with deionized H2O and ethanol successively for 2–3 times to wash out unwanted impurities and next dried overnight in a vacuum oven to get pure SnO2 QD. A wide variety of catalysts were screened by employing different nano metal oxide catalyst like nanoFe3O4, zinc oxide (ZnO), silicon dioxide (SiO2), aluminum oxide (Al2O3), CuO, nano CuFe2O4, SiO2–OSO3H etc. to achieve the optimum yield. Apart from, SnO2 nano particles with different grain size were also checked and it was observed that reaction rate increases with the reduction in size of SnO2 nano particles because of increase in surface area. Among the various catalyst screened, SnO2 QD with a particle size of 3.9 nm showed best catalytic action. Various polar and nonpolar solvents were also screened (water, dioxane, acetonitrile, DMF, toluene etc.). Polar solvents were found more suitable than the nonpolar ones in terms of reaction yield and water was considered as the best choice for this particular reaction. After a thorough optimization study the optimized reaction condition was finally set as amine (14) (1.0 mmol), 1,3-dicarbonyl compound (2) (1.0 mmol), 1,2-dicarbonyl compounds (32 and 33) (1.0 mmol) and SnO2 QDs (10 mol%), water (5 mL) at 70 °C (Figure 6.33). Through the study of substrate scope for this three-component reaction, aromatic amine derivatives substituted with e-donating functional groups provided comparatively greater yield in comparison with electron withdrawing or unsubstituted aromatic amine derivatives (Figure 6.34). Furthermore, amine derivatives bearing sensitive heterocyclic functionalities, the reaction also proceeded efficiently. The strategy was also equally productive with 1,3-dicarbonyls as substrate (cyclohexane-1,3- dione, dimedone) in water under established conditions (Figure 6.33). After completion of the reaction, water was evaporated from the reaction mixture using rotary evaporator and then to the crude reaction mixture 5 mL of methanol was added and catalyst was separated by simple filtration, leaving the resulting mixture transparent. The separated catalyst washed with methanol for several times and dried at 70 °C for 1 h. After successful recovery of the catalyst, it was then employed in a new reaction with fresh reaction medium and reactants under same conditions.

Figure 6.34: The catalytic cycle for the construction of the product 34.

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

SnO2 nano crystal

Particle Size (nm)

Time (h)

Yield (%)

Uncapped SnO2 QD

3.9

2.5

93

OA capped SnO2

2.6

8

43

400

3

82

235

QDs SnO2 nano lower

Figure 6.35: Evaluation of catalytic activity of uncapped SnO2 QDs, OA capped SnO2 QDs and SnO2 nanoflower for the synthesis of 38.

The recovered catalyst could be successfully engaged in seven consecutive turns without any substantial loss in catalytic performance. The XRD and TEM characterization also indicated minor alteration in crystal composition of the SnO2 QDs after seven runs (Figure 6.35). The proposed mechanism of the present transformations was also illustrated in Figure 6.34. The presence of Lewis acidic Sn4+ center of the SnO2 nanoparticle facilitated the condensation reaction of amine to the 1,3-diketones by increasing the electrophilicity of carbonyl center of the 1,3-diketones to generate the intermediate I (Figure 6.34). The mechanism helped to point out the reason behind the activity of various amines in this particular reaction. In case of the aromatic amines substituted with electrondonating groups, intermediate I was formed favorably as compared to the electronwithdrawing substituents or unsubstituted aromatic amines. SnO2 QDs then facilitated Michael reaction of I and 32/33 (ninhydrin and acenaphthoquinone) to form intermediate II. To end, the Lewis acidic Sn4+ coordinated with intermediate II, which then underwent intramolecular cyclization generating a five membered ring (34). All-over, this method was quite promising in the scenario of sustainable chemistry lookouts.

6.6.12 Uncapped SnO2 quantum dot catalyzed rapid and green synthesis of pyrano[2,3-c] pyrazole and spiro-2-oxindole derivatives 4H-pyran derivatives represent an essential core in a large variety of oxygen rich heterocycles. They have frequently employed as cosmetics, pigments [274], and potential decomposable agrochemicals [275] and active presence in several biologically active entities [276–280]. Apart from, they also found to exhibit outstanding medicinal activities like antibacterial, antimicrobial, anti-tubercular, anticancer, anti-allergic, anti-coagulant, antibiotic, hypolipidemic, and many more [281–288]. In addition, they are also applied as cognitive enhancers in neurodegenerative diseases like Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, AIDS associated dementia and Down’s syndrome, as well as in the treatment of myoclonus and schizophrenia [289].

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6 Synthesis, properties and catalysis of quantum dots in C–C

Considering the huge biological reputation of 4H‐pyran derivatives, numerous efficient approaches have been illustrated using different types of catalysts such as silica‐bonded 1,4‐diazabicyclo[2.2.2]octane [290], SiO2 nanoparticles [291], electro‐ generated base [292], baker’s yeast [293], and amino‐decorated ionic liquid [294], microwaves heating [295], ultrasonic irradiation [296], and involving other additives like hexadecyltrimethylammonium bromide [297], triethylbenzylammonium chloride [298], DABCO [299], (S)‐proline [300], triphenylphosphine [301], PEG-400 [302], β-cyclodextrin [303] etc. Paul et al. in 2014 developed a new strategy describing a sustainable and economical synthesis of substituted pyrano[2,3-c]pyrazole and spiro2-oxindole derivatives through uncapped SnO2 quantum dots (QDs) catalyzed one pot multicomponent reaction using the commercially available phenyl hydrazine (35) (1.0 mmol), ethyl acetoacetate (25) (1.0 mmol), benzaldehyde (1) (1.0 mmol) and malononitrile (23) (1.0 mmol) as precursors in aqueous medium (Figure 6.37) [304]. The present reaction required very low catalyst loadings to perform the desired conversion with good tolerance of diverse functional groups. Among the various catalysts assessed such as nano-ZnO, CuO, SnO2, Fe3O4, SiO2, Al2O3, ZnFe2O4 etc. uncapped SnO2 QDs provided optimum product yield of the desired pyrano[2,3-c]pyrazoles (5a). The catalyst was prepared by solvothermal method (described in Figure 6.36). SnO2 nanoflower, uncapped and capped SnO2 quantum dots (QDs) were thoroughly characterized by X-ray diffraction study, FESEM and TEM. The low-resolution TEM image indicated the particle size of approximately 4 nm ± 10% for the catalyst and the HRTEM image of uncapped SnO2 QDs showed the distance between two nearest lattice planes of (110) of SnO2 QD to be 0.32 nm. The FESEM images of uncapped SnO2 catalyst indicated a flower like morphology of nanoparticle. The model reaction was also screened using a range of commonly used solvents like (Dioxane, DMSO, CH3CN, Toluene, DMF and H2O). The superior product yield was obtained in water as reaction medium. The authors also employed three different types of SnO2-nanoparticles (uncapped SnO2 QDs, OA capped SnO2 QDs, SnO2 nanoflower) in the model reaction in which uncapped SnO2 QDs offered optimum catalytic activity for the synthesis of pyrano[2,3-c] pyrazoles through four component MCR of phenyl hydrazine 35 (1.0 mmol), ethyl acetoacetate 25 (1.0 mmol), benzaldehyde 1 (1.0 mmol) and malononitrile 23 (Figure 6.37). The prepared uncapped SnO2 QDs in nanometer range exhibited good Lewis acidic character due to high surface area and a good number of Sn4+ centers for the activation of carbonyl compounds in the four-component coupling reaction. However, in OA grafted SnO2 QDs, Sn4+ metal ion center of the catalyst could not reach to the reaction center of carbonyl compounds because of oleic acid layer at the surface of SnO2. In addition, SnO2 nanoflower exhibited higher catalytic action most likely due to its flower like structure with high surface area. Above mentioned results confirmed Sn4+ as the key active species of SnO2 nanoflower to achieve the desired transformation (Figure 6.38). During the study of various substrates for the proposed MCR strategy it was experienced that the electron-rich as well as electron deficient aryl aldehydes also

6.6 Application of QD in C–C and C–X (X = heteroatom) bond formation

237

Figure 6.36: Method of synthesis of catalyst capped SnO2 QDs.

Figure 6.37: Synthesis of 3-methyl substituted pyrano[2,3-c]pyrazoles using four-component reaction.

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6 Synthesis, properties and catalysis of quantum dots in C–C

Figure 6.38: The possible mechanism of product formation.

equally effective to produce desired pyrano[2,3-c]pyrazole derivatives with satisfactory amount (Figure 6.37) showing good compatibility of substituents e.g., -OCH3, -Cl, -NO2, -Br, -CH3 present on aromatic skeleton under standard conditions. Moreover, aldehydes with electron-rich substituents were less reactive as compared to electron withdrawing substituents. After the completion of reaction, the catalyst was washed with methanol for two or three times and then dried under vacuum oven at 70 °C for 1 h. Then a new reaction was carried out with the recovered catalyst using fresh solvent and reactants under standard condition. Delightedly, SnO2 QDs catalyst was efficiently recovered and used up to six consecutive turns without any considerable change in product yield. The structural integrity of recovered SnO2 QDs after sixth runs was established through X-ray diffraction (XRD) and TEM analysis which not only explained the excellent recycle capability, but also showed high stability of this magnetic catalyst.

6.7 Future aspects of QD In near future QD material have found enormous applications which is beyond any expectation limits due to their remarkable photophysical and chemical properties. The

6.8 Advantages and limitations

239

quantization size effect allows to show a variety of properties of QD for which it become suitable candidate for numerous modern applications highlighted in current review. QD materials are applicable in the future, especially, in the field of solar cells, bioimaging, biosensors, quantum computers, photodetectors, photocatalysis and many others. Particularly, quantum dots in colloidal state could serve as a competent photocatalysts in a large variety of organic reactions with some exciting outcomes. The added advantages of using Colloidal quantum dots are high yield and good selectivity as in the case of visible light catalysis, and the TON value is greater than that of conventional photocatalysts. The quantum dot size has a strong influence on the reaction rate. However, the use of quantum dots as a homogeneous photocatalyst for organic conversion is still an on-going research topic, with both opportunities and challenges. In spite of enough research endeavors, applications of quantum dots as both homogeneous and heterogeneous catalysts in synthetic chemistry have not been well-explored. Again, recoverability and recyclability of this nanomaterial is quite challenging and need further investigation to improve the TON (turn over number). As shown in different research studies, the synthesis and application of Cd-free quantum dots is highly enviable to biological field. Moreover, to apply QD in the generation of solar energy for organic transformations, the structure, composition, and surface functionalization of quantum dots need to be carefully investigated. In view of above, scientists are adapting enough advancement to solve the problems associated with application of quantum dot, especially in coating QDs surface with protecting and stabilizing layer, to make them a suitable candidate for subsequent bioconjugation with proteins, peptides or other chemical moieties. It was also found that round shape of QDs is preferred particularly for the application in biosensing. Additionally, while the colloidal QDs is mostly preferred in synthetic field, the deposited QDs are generally found application optoelectronic media. Apart from, Future QD displays will provide successful applications or counter intelligence as biomarker against the most common enemy ‘cancer’ to our modern civilization [36].

6.8 Advantages and limitations As compared to conventional dyes, QDs possess remarkable photostability due to their fluorescence intensity and novel composition. While generally sharp emission peaks are obtained in case of organic dyes, QDs exhibits a narrow emission peak and broader excitation spectra [305, 306]. Although several advantages, a well-known complication in biological area of QD is due to large physical size, poor diffusion capability of these nanoparticle across cellular membranes. Solubility in water is a common disadvantage of all types of QDs since for the application in vitro and in vivo imaging involving QD, aqueous solubility is an essential factor. To avoid this problem, use of ligand exchange and polymer wrapping are generally more operative avoiding the generation of QDs in water directly. Another serious problem of using QDs is the leakage of heavy metal ions

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6 Synthesis, properties and catalysis of quantum dots in C–C

from the core of QD on application of several oxidants and light energy [59, 60]. The leakage of transition metal ion from QDs and its long-term presence in body affects the body causing serious problems and the biocompatibility of QD is hampered [62, 63]. For this reason the application of QD may be sometimes harmful for the cell and unsuitable for performing any biological reactions. Their fairly extended lifetime is the main reason to create complications in certain applications where the biodegradation of QDs is required immediately after the reaction has been completed. In spite of these restrictions, QDs are enough efficient in converting short wavelength into longer one with good purity. Apart from that, quantum dots are rather stable and could be easily handled during synthesis. They are available in various morphologies like beads, dust etc. which also makes its space of applications wider [306].

6.9 Conclusion Owing to the initial success of different capped or uncapped QDs-or its modified structure employed as a safe, environment friendly and efficient catalyst in several types of organic reactions, it is quite expected that in future researchers will definitely focus on designing of more advanced QD nanostructures for new type of organic transformations. The gradual increasing in the number of examples of QD catalysis from the year 2010–2020 indicates the increase in demand of QDs in the field of organic chemistry. The predominant role of metal nanoparticles is today threatened by their negative environmental impacts and thus these newly developed organic nanoparticles gradually become familiar as photoredox catalysts due to their comparatively low toxicity, low cost, superior optical properties, easy surface modifications and good recoverability in different reaction conditions used in C–C or C–X bond formation strategies. Furthermore, the wide functionalization range to obtain the desired QDs, leads to a possibility to obtain nanoparticles soluble in all reaction media starting from water to a broad range of organic solvents. Furthermore, the challenges and future prospects of QD-catalyzed transformation turns it into a thriving research field, with a perception toward the ultimate achievement of highly competent and long-standing stable QD-mediated photocatalysis. However, in spite of good number of reports on organocatalysis with luminescence QD, there is still enough scope to discover new kind of QD nanostructure and also investigate their role in modern organic synthesis.

List of abbreviations RT UV eV

room temperature ultraviolet electron volt

List of abbreviations

DAAD DMF MeOH DCM HIV AIDS Si-MCM41 THF PEG DBU NaN3 CuS CuO CuFe2O4 SiO2–OSO3H Al-SBA15 Zn Pd Pt Fe Au Se Si Cd SnO2 KOH AgNO3 ZnCl2 MgO KF Al2O3 FeF3 K3PO4 POCl3 NH4Cl Na2CO3 KMnO4 TBAH Pd (OAc)2 GO RGO [bmim][OH] g h MW MWI min mL

241

Diacetylene di carboxylate Dimethylformamide methanol dichloromethane Human immunodeficiency virus acquired immunodeficiency syndrome (Mobil Composition of Matter No. 41) is a mesoporous material with a hierarchical structure of silicate and aluminosilicate solids Tetrahydrofuran Polyethylene glycol 1,8-Diazabicyclo(5.4.0)undec-7-ene sodium azide Copper(II) sulphide Cupric oxide Copper ferrite Silica Sulfuric Acid Aluminum-doped mesoporous silica Zinc Palladium Platinum Iron Gold selenium silicon cadmium stannic oxide Potassium hydroxide Silver nitrate Zinc chloride Magnesium oxide Potassium fluoride Alumina Iron (III) fluoride Tripotassium phosphate Phosphorus oxychloride Ammonium chloride Sodium carbonate Potassium permanganate Tetrabutylammonium hydroxide Palladium acetate Graphene oxide Reduced graphene oxide 1-butyl-3-methyl imidazolium hydroxide Gram Hour Molecular weight microwave radiation Minute milliliter

242

6 Synthesis, properties and catalysis of quantum dots in C–C

mmol nm μL E.coli. SiO2 ZnO NW ZnO Np H 2O Cu CuCl2 Cu(OAc)2 [RhCp*Cl2]2 TiO2 Al(NO3)3 Zn(NO3)2 K7[PW11CoO40] HClO4-SiO2 MCR ZrOCl2·8H2O ZnO@SiO2 FeNi3 NPs IL TGA VSM EDX SAED

millimole nanometer microliter Escherichia coli Silicon dioxide Zinc oxide nanowire ZnO nanoparticles Water Copper Cupric chloride cupric acetate Pentamethylcyclopentadienyl rhodium(III)chloride dimer Titanium dioxide Aluminium nitrate Zinc nitrate Keggin-type lacunary and transition metal substituted polyoxometalates Silica supported perchloric acid multi-component reactions Zirconyl Chloride Octahydrate silica-coated ZnO nanoparticles Fe–Ni alloy nanoparticles Ionic liquid Thermo gravimetric analysis Vibrating Sample Magnetometer Energy Dispersive X-ray analysis Selected Area Electron Diffraction

Acknowledgments: M.S. thanks U.G.C., New Delhi, India, for the grant of her Research fellowship and D.D thanks C.S.I.R., New Delhi, India, for the grant of his Senior Research fellowship.

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Sasadhar Majhi*

7 Synthesis of bioactive natural products and their analogs at room temperature – an update Abstract: Sustainability is a concept that is employed to distinguish methods and procedures that can ensure the long-term productivity of the environment as it includes environmental, social, and economic dimensions. New generations can live on this planet with less hazardous substances and minimum requirement of energy for chemical transformations as green chemistry is related to creativity and the development of innovative research. Among the 12 principles of this clean chemistry, the sixth principle is devoted to the “design of energy efficiency” which discloses that less or the minimum amount of energy is required to conduct a specific reaction with optimum productivity. The most successful way to save energy is to construct strategies/methodologies that are capable enough to carry out the chemical transformations at ambient temperature and standard pressure. Hence, the present review wishes to cover the synthesis of bioactive natural products and their derivatives at room temperature. Bioactive secondary metabolites play a crucial role in the drug discovery together with drug development process; chiefly anticancer along with antibiotic molecules is noticeably enriched with molecules of natural origin. Natural sources, structures, and biological activities of natural products are highlighted in this review and it is also aimed to offer an overview of the design and synthesis of bioactive natural products and their analogs at room temperature for the first time efficiently. Keywords: bioactive natural products; drug discovery; room temperature; sustainable chemistry and pharmacological properties; total synthesis.

7.1 Introduction Chemistry as well as organic chemistry is mainly connected to our daily life. It has been investigated that organic chemistry has a profound role to produce essential materials such as dyes, polymers, medicines cosmetics, food products, agrochemicals, and other valuable materials [1–3]. Environmental difficulties and unwanted side effects arise due to such type of blossoming because these chemical protocols not only produce the needed products but also huge quantities of unsolicited and hazardous substances are discharged in the form of solids, liquids together with gases and have become the major

*Corresponding author: Sasadhar Majhi, Department of Chemistry (UG & PG), Triveni Devi Bhalotia College, Kazi Nazrul University, Raniganj, West Bengal 713347, India, E-mail: [email protected]. https://orcid.org/0000-0002-3495-0472 As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. Majhi “Synthesis of bioactive natural products and their analogs at room temperature – an update” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0094 | https://doi.org/10.1515/9783110797428-007

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challenge that chemical science has to face. As a result, our environment is continuously polluted owing to the discharge of several toxic substrates; various chemical reactions that are linked to pharmaceutical chemistry mainly are unsafe to living organisms and the environment. The application of hazardous chemicals and volatile solvents makes the situation worse. Environmental pollution touches such levels so that governments put up laws to reduce or eliminate the use or creation of hazardous substances. This situation begins with environment-friendly chemistry as well as green or clean chemistry. Green chemistry aims to protect Mother Nature and human health as sustainable chemistry goes for less toxic materials over more toxic ones along it tries to minimize the use of flammable, explosive, or highly reactive materials. To stop further environmental damage and to save our society, chemists and engineers try to develop greener products and methodologies that should be safer, cheaper, and not harmful to our circumstances and the need for energy should be less to perform a chemical synthesis. Among the 12 principles of sustainable chemistry as well as green chemistry, the sixth principle is devoted to the “design of energy efficiency” which discloses that less or the minimum amount of energy is required to carry out a specific chemical reaction having optimum productivity [1]. The selection of proper substrate, reagent, catalyst, and solvent should be managed in such a manner so that this conversion proceeds at ambient temperature and pressure. The most victorious way to control energy is to create strategies/methodologies that are capable enough to carry out the chemical transformations at room temperature and standard pressure. Hence, this review tries to cover the application of the total synthesis of bioactive natural products and their analogs at room temperature with speed and efficiency. Molecules of natural origin of significant biological activities originate from Mother Nature; secondary metabolites will continue to play a profound role in the drug development and discovery process [4–15]. Natural products together with their analogs structures consists of biologically active pharmacophores, diverse chemical structures, a greater number of stereogenic centers, various proportions of heteroatoms that make them enthusiastically lead structures for contemporary drug discovery and continue to motivate state of the art inventions in chemistry, medicine, and biology [16, 17]. It is interesting to be noted that more than one-third of secondary metabolites and their analogs are approved by all U.S. Food and Drug Administration (FDA) for current molecular entities [18]; mainly anticancer together with antibiotic compounds are remarkably enriched with molecules of natural origin [19]. To my knowledge, there is no review of applications of the total synthesis of bioactive natural products and their analogs at room temperature in extant literature. Hence, the main aim of this overview is to summarize the luminous applications of the total synthesis of molecules of natural origin at room temperature and highlights natural origin, structures, and important biological activities of the valuable organic molecules splendidly, focusing on the involvement of at least one or more steps at room temperature as a green protocol.

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7.2 Applications of the total synthesis of bioactive natural products and their analogs at room temperature In a research laboratory, the total synthesis has profound role in the preparation of the rare bioactive secondary metabolites because various bioactive natural products are originated in minute amounts from natural origin, mainly those from higher plants along with marine organisms [5, 6]. As total synthesis includes a privileged position of trust in supporting the hypothetical complex structures of molecules of natural origin, it has charmed the attention of organic synthetic community. So, this section wishes to deal with applications of the total synthesis of bioactive natural products at room temperature. Hence, this section commences with a concise discussion regarding the type of natural products such as antibiotic, polyketide, macrolide, terpenoid, etc. and next, it was also able to deal with the vivid applications of the total syntheses of secondary metabolites of potential biological interests at room temperature, sources of natural products, structures, and biological properties of important molecules of natural origin gracefully.

7.2.1 Antibiotic Antibiotics are medicines as well as ‘wonder drugs’ that are applied to remedy infections originated by bacteria or to fight microbes. Tetracyclines antibiotics were created in the 1940s, which restrict the synthesis of proteins by restricting the link of aminoacyl-tRNA to the site of the ribosomal acceptor (A) [20]. Antibiotics have a profound role in therapeutic uses along with the majority of antibiotic uses in other industries namely agriculture together with animal husbandry. Increased demand for antimicrobial molecules across various sectors it has permitted the manufacture of millions of metric tons of newer classes of antibiotics. The plenty and irresponsible use of antibiotics has provided extraordinarily to the appearance of resistant strains [21]. So, we require the total synthesis of new antibiotics because antibiotic resistance is one of the major challenges to worldwide health, as well as the emergence of resistance has outpaced the promotion of novel antibiotics. 7.2.1.1 Total synthesis of mangrolide A Natural Source: SNA18 strain of Actinoalloteichus sp. [22] Class of Compounds: Antibiotic Biological Activity: Mangrolide A plays a crucial role against Gram-negative bacteria such as Acinetobacter baumannii with a minimum inhibitory concentration (MIC) value of 0.25 μg mL−1 along with Pseudomonas aeruginosa having a MIC value of 1.0 μg mL−1 [23, 24].

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Both academic communities and the pharmaceutical industry wish to prepare novel antibiotics because of antimicrobial resistance (AMR) which is an increasingly momentous threat to worldwide public health. Although, sustainability along with an appropriate application of existing antimicrobials is demanded but the enhancement of lead structures having new molecular scaffolds as well as mechanisms of action includes a remarkable goal. Hence, Gademann and co-workers [22] accomplished the total synthesis of natural mangrolide A (6) using tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) as an activator under room temperature for the first time in 2018 (Figure 7.1). The structure of bioactive mangrolide A (6) comprises an highly unsaturated 18-membered macrocycle which is decorated by uncommon carbohydrates. The targeted pure E,E isomer (2) was prepared from oxazolidin-2-one (1) over several steps and the desired donor (3) was also synthesized from methyl D-glycoside as a mixture of anomers (α/β 1:1) in quantitative yield. Next, E,E-isomer (2) was treated with the donor (3) in the presence of the TBSOTf at room temperature as a green protocol to furnish β-isomer (4) smoothly in 42% yield with entire selectivity as a key step. The derivative of the mangrolide A tetraol (5) was prepared from azide (4) and the targeted bioactive natural mangrolide A (6) was synthesized from tetraol (5) in one step finally through a convergent and modular strategy [22].

7.2.2 Polyketide Polyketides are precious treasures for mankind since they display manifold functions with clinical uses as well as biological activities such as anticancer, antimicrobial,

Figure 7.1: Total synthesis of mangrolide A at room temperature as key step (s).

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immunosuppressive activities, and a lot more [25]; most of them are medicinal or display toxicity. Polyketides are obtained by various organisms together with filamentous fungi and they were named in the 1890s to refer to a structurally mosaic group of natural products that included several carbonyls and alcohols, generally separated by methylene carbons; manifold polyketides are applied as antibiotics, cancer chemotherapy, worthy cholesterol-lowering agents, and much more [26]. 7.2.2.1 Total syntheses of actinoallolides Natural Source: Actinoallomurus fulvus MK10-036 [27] Class of Compounds: Polyketide Biological Activity: Actinoallolides exhibit potent activity against Trypanosoma protozoan parasites [27, 28]. Interestingly, no toxicity was displayed against the MRC-5 human cell line by actinoallolides suggesting an excellent selectivity index [28]. Chagas disease [29] as well as human African trypanosomiasis (sleeping sickness) [30] is neglected tropical diseases which are produced by protozoan parasites of the genus Trypanosoma. In 2015, the World Health Organization (WHO) accounts that these neglected diseases had joint mortality of around 13,000, and further eight million people are presently infected [31]. Hence, Paterson and co-workers [31] achieved the first total synthesis of natural potent anti-trypanosomal macrolide actinoallolide A (11) along with four congeners actinoallolides B-E (12–15) at room temperature from actinoallolide A (11) in 2020 (Figure 7.2). The actinoallolide A (11) is a family of complex polyketides that is characterized by the uncommon 12-membered macrolactone and it also includes 10 stereocenters along with two trisubstituted E-alkenes. At first, two complex fragments alcohol (8) and acid (10) were prepared from ethyl ketone (7) and (S)-lactic acid (9) respectively for the total syntheses of actinoallolides. At first, bioactive polyketide (+)-actinoallolide A (11) was synthesized with 8% overall yield by the combination of the key intermediates alcohol (8) and acid (10) over several steps applying the extremely stereocontrolled aldol transformations of three chiral ketone building blocks successfully as crucial steps. The investigators also desired to prepare the other four members of the actinoallolide family namely actinoallolides B-E (12–15) at room temperature because they observed conversion of congeners from actinoallolide A (11) during the purification of it (11) by chromatography on alumina. As a result, actinoallolide A (11) provided a separable 1:1 mixture of (+)-actinoallolide C (13) (50%) together with ring expanded isomer (+)-actinoallolide E (15) (48%), indicating that these two congeners may be isolation antiquity. Moreover, actinoallolide A (11) was treated with Et3B and NaBH4 at room temperature as an ecological friendly procedure to deliver actinoallolide B (12) through a Narasaka 1,3-syn reduction of the C21 ketone in 93% yield. Actinoallolide B (12) was transformed into actinoallolide D (14) by treatment with trifluoroacetic acid in DCM at room temperature as another green methodology for 3 min only in 99% yield [31].

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Figure 7.2: Total synthesis of actinoallolides at room temperature as key step (s).

7.2.2.2 Total synthesis of ripostatin B Natural Source: Sorangium cellulosum (Bacteria strain So ce 377) [32] Class of Compounds: Polyketide Biological Activity: 14-Membered macrolide ripostatin B display antibiotic activity against Staphylococcus aureus with a MIC value of fewer than 1 μg mL−1 [33]. Natural products have a significant role in the fields of antibiotics research and cancer treatment which is originated from marine together with terrestrial

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Figure 7.3: Total synthesis of ripostatin B at room temperature as key step (s).

microorganisms, fungi, and plants mainly [34]. From a structural perspective, the polyketide macrolide ripostatin B (24) includes 14-membered macrolactone carrying an important unsaturated side chain. Synthetic chemists were interested in its synthesis due to its attractive structure and biological property [33]. Hence, Altmann et al. [35] completed the total synthesis of bacterial RNA-polymerase Inhibitor (RNAP) ripostatin B (24) at room temperature as crucial steps in 2012 through the longest linear sequence in 21 steps (Figure 7.3). Initially, the building block (17) was constructed from 2-bromopropene (16) at room temperature in 78% yield over several steps through the corresponding Weinreb amide as a key step and another building block (19) was also synthesized from chiral epoxide (18) involving room temperature conditions as green methodologies in excellent yield over several steps (three steps were performed at room

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temperature). Next, the targeted ketone (17) reacted with an aldehyde (19) through aldol reaction under Paterson conditions to afford aldol product (20) in 62% yield. Then, the aldol product (20) underwent Evans–Tishchenko reduction to generate β-hydroxy ester (21) in 93% yield; the ester (21) was treated with TBSCl and imidazole in DMF at room temperature as a green protocol for 20 h to deliver bis(TBS)-protected triol (22) in 94% yield. The targeted carboxylic acid (23) was synthesized from bis(TBS)-protected triol (22) over several steps involving Stille coupling, ring-closure reaction, Dess–Martin oxidation as key steps at room temperature in very good yields (four steps were carried out at room temperature out of five steps). Finally, the desired carboxylic acid (23) was effective to produce natural ripostatin B (24) through cleavage of the two secondary TBS (tertbutyldimethylsilyl) ethers in carboxylic acid (23) with a 3.6% overall yield [35].

7.2.3 Macrolide Macrolides were originated from Streptomyces species and they are applied as antibiotics to treat respiratory, skin, and soft tissue, together with urogenital infections mainly [36]. Macrolides include a large lactone ring that varies in size from 12 to 16 atoms. Erythromycin A was considered as the first macrolide which was able to display antimicrobial property [37]. 7.2.3.1 Total synthesis of amphidinolide B Natural Source: Amphidinium sp. [38, 39] Class of Compounds: Macrolide Biological Activity: Amphidinolides B, G, and H display powerful, nanogram-scale cytotoxicity against several tumor cell lines (against L1210 murine lymphoma as well as KB human epidermoid carcinoma) [38, 39]. Amphidinolides H was also effective to stimulate actin polymerization through covalently bonding to the actin cytoskeleton [40]. The amphidinolides are supreme macrolides bearing complex structures and they were found to show several interesting biological activities on tumor cell lines [38, 39]. The interesting structure and potential biological properties of the amphidinolides have fascinated the attention of synthetic organic chemists as well as the biological group [41]. Structurally, amphidinolides comprise 27- as well as 26-membered macrolide skeletons consisting of allylic epoxide along with s-cis-diene functionalities; they also include nine stereogenic centers as well as five hydroxyl groups make them a considerable challenge to the improvement of effective routes for their synthesis [42]. However, Nishiyama et al. [42] overcome the challenge successfully and completed the total syntheses of amphidinolides B (33), G (35), and H (36) at room temperature as a green protocol in 2012 (Figure 7.4). The total synthesis of bioactive macrolide amphidinolide B (33) was initiated from diol (25) to provide the alkyne (26) at room

7.2 Applications of the total synthesis of bioactive natural products

Figure 7.4: Total syntheses of amphidinolides B, G, H at room temperature as key step (s).

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temperature in 89% yield over several steps using Parikh–Doering oxidation as a key step (six steps at room temperature). Next, the alkyne (26) coupled with the aldehyde (27) to construct the key intermediate (28) at room temperature involving Wittig olefination and Dess–Martin oxidation as crucial steps in 96% yield (two steps at room temperature). The targeted ketone (30) was synthesized from nitrile (29) at room temperature applying Sharpless asymmetric dihydroxylation and PCC oxidation as central steps. Herein, the key aldol reaction occurred between aldehyde (28) and ketone (30) to afford the targeted (S)-31 in 72% yield. The next phase included the formation of the macrocyclic lactone system. For this purpose, the alcohol (32) was produced from (S)-31 at room temperature in the presence of the TBSOTf, 2,6-lutidine, tetra-n-butylammonium fluoride, and acetic acid in 89% yield over two steps. Finally, bioactive natural product amphidinolide B (33) was prepared from the alcohol (32) over several steps at room temperature in 86% yield (four steps at room temperature). Then, the attention of the investigators moved to the total synthesis of amphidinolides G (35) and H (36). The total synthesis of amphidinolide G (35) was executed from the aldehyde (34) at room temperature (four steps at room temperature) and the synthesis of amphidinolides H (36) was conducted from amphidinolide G (35) to follow the protocol of Kobayashi and co-workers [43], under mildly basic conditions. 7.2.3.2 Total syntheses of amphidinolides T1, T3, and T4 Natural Source: Marine dinoflagellates of the genus Amphidinium sp. [38, 39] Class of Compounds: Macrolide Biological Activity: Amphidinolides (T1–T5) show cytotoxic functions against L1210 murine lymphoma cells along with KB human epidermoid carcinoma cells [44]. Challenging structures together with glamorous biological properties of amphidinolides (T1–T5) has attracted broad interest presently [41]. Organic chemists and the biological community are attracted to the total syntheses of amphidinolides (T1–T5) owing to their challenging structures and attractive biological properties [41]. From a structural perspective, amphidinolides of the T subgroup diverge only in their oxygenation pattern along with stereochemistry in the C12–C14 section. The unique feature of the amphidinolide T1 (46) includes a ketone at C12 surrounded by a hydroxy group at C13 and T3–T5 are isomers of the natural amphidinolide T1 (46). Clark and co-workers [45] disclosed total syntheses of macrolides amphidinolides T1 (46), T3 (47), and T4 (48) through an efficient and high-yielding pathway at room temperature as key steps in 2013 (Figure 7.5). The total syntheses were started from the readily available alcohol (37) to generate alkene (38) at room temperature in excellent yield over several steps (at least four steps at room temperature). The carboxylic acid (39) provided ester (40) at room temperature over two steps in a 76% yield. Now the treatment of the alkene (38) with the ester (40) delivered western (C1–C11) fragment (41) as a single diastereomer having the needed configuration at C8. The coupled product (42) was produced from the alcohol (41) over two steps in 68% yield and ester

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Figure 7.5: Total syntheses of amphidinolides T1, T3, and T4 at room temperature as key step (s).

(42) was treated with Me3SiOK in THF and HCl to furnish the seco acid (43) at room temperature as a green protocol in 86% yield. The isomeric Z-vinylsilanes (44) along with (45) in a combined yield of 89% were obtained from the seco acid (43) and the reaction of the (44) using m-CPBA delivered selective epoxidation of the vinylic silane and subsequent Fleming–Tamao oxidation at room temperature yielded the desired amphidinolide T1 (46) in 73% yield and 13-epi-amphidinolide T1 in 7% yield also over

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two steps. Epoxidation of the vinylic silane (45) was also carried out under the same conditions to provide other natural products amphidinolides T3 (47) and T4 (48) in 79% yield as a separable mixture (d.r. = 1.6:1) of diastereomers, completed total syntheses in 17 steps from the commercially available alcohol (37) with the overall yields of amphidinolides T1, T3, T4 6.9%, 5.9%, and 5.5%, respectively-which further demonstrated the utility of this protocol for the preparation of complex secondary metabolites [45]. 7.2.3.3 Total synthesis of bryostatins Natural Source: Marine organism Bugula neritina [46, 47] Class of Compounds: Macrolide Biological Activity: Bryostatins are important modulators of protein kinase C and these macrolides are employed for the therapy of Alzheimer’s disease. In addition, bryostatins are used as HIV/AIDS agents along with as anticancer agents in clinical trials [46–48]. After the initial invention of compounds of the bryostatin family, they remain popular synthetic targets owing to their significant biological properties and their surprising structural motifs. From a structural perspective, cyclic polyketides bryostatins consist of three tetrahydropyran cores together with a common 25-membered macrolactone skeleton [49]. The total synthesis of natural bryostatin 1 (57) was reported by Hale et al. [49] at room temperature as a green protocol in 2011 (Figure 7.6). The investigators started total synthesis of bryostatin 1 (57) from aldehyde (49) to construct the A-ring allylsilane (50) at room temperature over several steps (at least six steps at room temperature). Southern hemisphere enal (52) was produced from isobutylD-lactate (51) over several steps (at least four steps at room temperature). Next, the important alkene (53) was obtained by the reaction between allylsilane (50) and enal (52) over several steps using Prins union as a vital step and alkene (53) was efficient to provide ketone (54) using the AD-mix-α in tBuOH/H2O for 24 h and NaIO4 in THF at room temperature to save energy, phosphate buffer (pH 7) at room temperature for 3 h over two steps in 81% yield. Lactone (55) was prepared from (54) and lactone (55) provided (56) using K2CO3, CH3OH, octadienoic anhydride in DCM together with DMAP for 12 h over two steps in 71% yield at room temperature. Finally, bioactive macrolide bryostatin 1 (57) was obtained from (56) in one step; a synthetic route for the synthesis of the bryostatins will accelerate efforts to build analogues for future neurological drug improvement [49]. 7.2.3.4 Total synthesis of (3R, 4S)-4-hydroxylasiodiplodin Natural Source: Lasiodiplodia theobromae IFO 31059 [50] Class of Compounds: Macrolide

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Figure 7.6: Total synthesis of bryostatin at room temperature as key step (s).

Biological Activity: At a concentration of 10−4 M (3R, 4S)-4-hydroxylasiodiplodin was found to display significant potato micro tuber inducing activity [51]. Lasiodiplodins consist of an influential type of bioactive natural products owing to their miraculous diverse biological along with pharmacological properties including cytotoxic, antimicrobial property, anti-leukemic activity, a Hill reaction inhibitor etc. [52]. From a structural perspective, natural (3R, 4S)-4-hydroxylasiodiplodin (66) comprise an interesting 12-membered macrocyclic skeleton together with C-3 and C-4 positions bear two asymmetric centers. Prasad et al. [51] completed a total synthesis of

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Figure 7.7: Total synthesis of macrolide (3R, 4S)-4-hydroxylasiodiplodin at room temperature as key step (s).

important macrolide (3R, 4S)-4-hydroxylasiodiplodin (66) through the alternative and concise pathway at room temperature from readily available starting materials 6-heptenal (58) and orsellinic acid (61) using ring-closing metathesis (RCM), Sharpless epoxidation and Wittig transformation as central steps in 2020 (Figure 7.7). The aliphatic fragment (60) was successfully prepared from 6-heptenal (58) through the formation of the unsaturated ester (59) at room temperature as a green protocol. The aromatic segment (64) was also synthesized from known orsellinic acid (61) via the construction of the desired aldehyde (62) as well as the hydrolysis of ester (63) at room temperature using LiOH in the presence of THF:MeOH:H2O (3:1:1) for 4 h in an excellent 93% yield. Latter, the authors constructed a macrocyclic framework with the help of the key segments alcohol (60) and acid (64). Finally, the desired natural product (3R, 4S)4-hydroxylasiodiplodin (66) was synthesized in 79% yield from macrolide (65) when macrolide (65) was treated with Pd/C, H2 in EtOAc at room temperature for 2 h through reduction and the deprotection [51]. 7.2.3.5 Total syntheses of multiplolide A together with its diastereoisomer Natural Source: Xylaria multiplex [53] Class of Compounds: Macrolide Biological Activity: Multiplolides A and B display antifungal properties against Candida albicans having a half-maximal inhibitory concentration value (IC50) of 7 and 2 μg mL−1, respectively [54].

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273

Secondary metabolites having ten-membered lactones (also known as decanolides) mainly exhibit a broad range of biological activities including antifungal, antimalarial activities as well as the inhibition of cholesterol biosynthesis [55]. Meshram et al. [54] explored the stereoselective total synthesis of bioactive secondary metabolite multiplolide A (83) and its diastereoisomer (86) from cheap starting materials through the removal of the tBuPh2Si group with Bu4NF at room temperature as a vital step in 2013 (Figure 7.8). At first, the chiral oxirane (67) delivered allylic alcohol

Figure 7.8: Total syntheses of multiplolide A and its diastereoisomer at room temperature as key step (s).

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(68) over two steps in preparing the olefinic alcohol fragment (73). Protected allylic alcohol (69) was prepared from the resulting alcohol (68) in 88% yield at room temperature using pivaloyl chloride in the presence of the tBuPh2SiCl, 1H-imidazole, K2CO3 in MeOH. The key intermediate (73) was synthesized from protected allylic alcohol (69) via the formation of the olefinic diol (71) in 70% yield and ethenyl-1,3-dioxol (72) in 90% yield at room temperature. The preparation of ethenyloxiranes (75) and (78) were executed from unsaturated 1,4-diol (74) through a selective monoprotection of the OH group at room temperature in the presence of the tBuPh2SiCl in DCM in 86% yield as a central step. The synthesis of (76) and (79) was achieved via the deprotection of the t BuPh2Si ether at room temperature in 88% yield for 2 h employing Bu4NF in THF. Then (76) and (79) were subjected to oxidation to yield the required oxiranecarboxylic acids (77) and (80). Latter, bis-olefins (81) as well as (84) were obtained by the combinations of (77) and (73) as well as (80) and (73) respectively during esterifications using the 2,4,6-trichlorobenzoyl chloride, DMAP, and Et3N at room temperature in good yield (80%). Finally, bis-olefins (81) and (84) were able to afford targeted multiplolide A (83) together with a diastereoisomer (86) respectively through the formation of penultimate compounds (82) and (85) when (82) and (85) were reacted with CF3COOH in DCM at room temperature for10 h in 70% yield [54]. 7.2.3.6 Total synthesis of sacrolide A Natural Source: Cyanobacterium Aphanothece sacrum [56] Class of Compounds: Macrolide Biological Activity: Sacrolide A (102) exhibits cytotoxicity against 3Y1 rat fibroblasts having a GI50 of 4.5 μm [56] and it is also a powerful inhibitor for the growth of several species of Gram-positive bacteria, the yeast Saccharomyces cerevisiae together with the fungus Penicillium chrysogenum [57]. Cyanobacteria are microscopic which are continued to be wealthy sources of bioactive natural products [58]. Mohapatra and co-workers [59] described the total synthesis of bioactive sacrolide A (98) in a stereoselective manner at room temperature under Pinnick conditions and intramolecular Nozaki–Hiyama–Kishi (NHK) macrocyclization as crucial steps in 2016 (Figure 7.9). Structurally, sacrolide A (98) includes two unsaturations, a vinylic ketone along with a cis-configured double bond in the side chain and it is decorated with two chiral centers. The synthesis of an acid segment (90) was commenced with 1,9-nonane diol (87) to provide TBS-protected vinyl iodide (88) in 92% yield. Vinyl iodide (88) was treated with DDQ (2,3-dichloro-5,6-dicyano1,4-benzoquinone) in DCM/H2O under the pH 7 buffer solution at room temperature as an eco-friendly method to deliver primary alcohol (89) in 92% yield through the oxidative removal of the PMB group. The resulting alcohol (89) undergoes Swern oxidation to produce the corresponding aldehyde and the aldehyde was subjected to the important oxidation under Pinnick conditions using NaClO2, NaH2PO4, and 2-methyl-2-butene as a scavenger for 2 h at room temperature to generate carboxylic

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275

Figure 7.9: Total synthesis of sacrolide A at room temperature as key step (s).

acid (90) in 77% yield over two steps. Commercially available epichlorohydrin gave protected epoxide (91) initially, which was very effective to produce alcohol fragments (92) in the presence of the TBAF (tetra-n-butylammonium fluoride) in THF for 4 h in excellent yield (90%) as a key step at room temperature. With segments (90) and (92)

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in hand, the investigators desired to construct ester (93) through critical macrocyclization. The ester (93) was treated with DDQ in wet DCM under phosphate buffer solution (pH 7) to generate alcohol (94) at room temperature in 92% yield via the removal of the PMB protecting group. The key aldehyde (95) was obtained from the alcohol (94) and aldehyde (95) undergoes crucial intramolecular NHK macrocyclization at room temperature applying the CrCl2 and NiCl2 in DMSO to afford allylic alcohols (96) in 52% yield over two steps. Allylic alcohol (96) was effective to yield the enone (97) and natural sacrolide A (98) was synthesized from the enone (97) through the desilylation at room temperature with HF pyridine complex in THF for 7 h in 81% yield [59]. 7.2.3.7 Total synthesis of tiacumicin B aglycone Natural Source: Soil bacterium Dactylosporangium aurantiacum [60] Class of Compounds: Macrolide Biological Activity: Tiacumicin B (also known as lipiarmycin A3 or fidaxomicin) is a powerful inhibitor of Mycobacterium tuberculosis [61] and it displays potent antibacterial activity along with an inhibitor of bacterial RNA-polymerase [61]. The biologically potent tiacumicin B (109) was attractive in total synthesis and from a structural perspective; it comprises an 18-membered macrolactone skeleton bearing four chiral centers together with an improved degree of unsaturation [62]. The total synthesis of the tiacumicin B aglycone (108) was achieved by Altmann and co-workers [62] in 2014 through an efficient approach at room temperature as vital steps and the authors provided a basis for structure-activity relationship (SAR) studies that can lead to better variants of tiacumicin B (Figure 7.10). The desired building block (100) was prepared from the known alcohol (99) at room temperature as a central step using the MnO2-mediated allylic oxidation, reduction of the Weinreb amide, application of the Corey-Peterson olefination reaction, and allylation of enal as central steps. The synthesis of another building block (102) was initiated from racemic but-3-en-2-ol (101) at room temperature involving Sharpless kinetic resolution, CuI-catalyzed formal hydroboration as crucial steps. Later, diene (103) was treated with the fragment (100) to afford the desired acid (104) at room temperature as a key step in 69% yield along with TES-deprotected material (105); the latter was transformed readily into acid (104) by treatment with an excess of TESCl at room temperature for 10 min in 84% yield over two steps. Next, the esterification was carried out between acid (104) and alcohol (102) to furnish ester (106) at room temperature in 81% yield for 5.5 h employing the Cl3H2C6COCl, triethyl amine, and DMAP in toluene. The ester (106) was effective to provide the targeted macrocycle (107) in 73% yield at room temperature for 25 min with [Pd(PPh3)4] and TlOEt in THF/H2O (3:1) as a 9.5:1 mixture of E/Z isomers at C4–C5. Finally, tiacumicin B aglycone (108) was obtained from macrocycle (107) in 47% yield after purification by preparative HPLC [62].

7.2 Applications of the total synthesis of bioactive natural products

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Figure 7.10: Tiacumicin B aglycone’s total synthesis at room temperature as key step (s).

7.2.4 Terpene Terpene is an important secondary metabolite having several medical properties as well as biological activities and found in plants, algae, fungi, and animals [63]. Among terpenoids, diterpenoids are responsible to exhibit various biological and pharmacological activities including anticancer, antimicrobial, anti-inflammatory, antiviral, antiparasitic etc. [64].

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7.2.4.1 Diterpene 7.2.4.1.1 Total synthesis of 1-hydroxytaxinine Natural Source: Taxus cuspidate [65] Class of Compounds: Diterpenoid Biological Activity: Taxane diterpenoid 1-hydroxytaxinine is cytotoxic to murine leukemia L1210 cells along with human epidermoid carcinoma KB cells (half-maximal inhibitory concentration (IC50) = 4.6 and 6.9 mg mL−1, respectively) [66]. Taxane diterpenoids include significant biological profiles along with it consists of more than 400 congeners [67]. Taxol is one of the potent bioactive congeners in this family which is applied clinically to medicate several cancers [66, 67]. The intricately fused structure as well as the interesting biological property of diterpenoid 1-hydroxytaxinine (132) commits it to a great challenging synthetic target. From a structural perspective, the bioactive secondary metabolite (132) comprises a 6/8/6-membered carbon framework bearing six oxygen substituted carbon centers, two quaternary carbon centers together with two olefins in its densely oxygenated core makes the synthetic challenge of 1-hydroxytaxinine (132) [66]. In 2019, Inoue and co-workers [66] explored an asymmetric total synthesis of cytotoxic natural 1-hydroxytaxinine (132) at room temperature as key steps (Figure 7.11). The important radical precursor (116) was synthesized from the readily available starting material (110) in nine steps; at least four steps were performed at room temperature through the formation of the vinyl iodide of (112), regio- and enantioselective dihydroxylation, the construction of the methyl ester (115) and saponification of the ester with aqueous LiOH as central steps. Then, the adduct enone (117) was synthesized with the help of the radical coupling between the A-ring segment (116) and C-ring segment 6-oxocyclohex-1-enecarbonitrile as a single C9-isomer in 65% yield. The formation of the substrate (120) was executed at room temperature from enone (117) involving nucleophilic 1,4-addition of MeMgBr and subsequent NaBH4 reduction of the C4-ketone at room temperature, the construction of the α,β-unsaturated nitrile (119) from the alcohol (118) at room temperature also. Now, the stage was set for exploring the chemoselectivity of the secondary C2-OH of tricycle (121) from the substrate (120); the tricycle (121) provided acylated product (122) at room temperature in the presence of the acetic anhydride. The C4-ketone (128) was obtained from the 6/8/6-membered ring system (122) over several steps at room temperature applying the C5- and C13-allylic methylenes of the 6/8/6-membered ring system (122), 1,2-reduction of the hydrazone (124), allylic diazene rearrangement, and olefination as central steps. The targeted natural diterpenoid 1-hydroxytaxinine (132) was synthesized from the C4-ketone (128) over several steps ultimately by utilizing the Burgess reagent along with HF pyridine in THF at room temperature as a key step [66].

7.2 Applications of the total synthesis of bioactive natural products

Figure 7.11: Total synthesis of 1-hydroxytaxinine at room temperature as key step (s).

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Figure 7.11: Continued.

7.2.5 Miscellaneous 7.2.5.1 Total Synthesis of Adunctin B Natural Source: Piper adunctum [68] Class of Compounds: Cinnamoyl-hexahydrodibenzofuran derivative Biological Activity: Adunctin B was reported to show antibacterial activity against Micrococcus luteus at a concentration of 3.5 μg mL−1 [68]. The biggest family of flowering plants is the Piperaceae (pepper family) which comprises nearly 3600 species. The total synthesis of a bioactive adunctin B (143) was completed by Dethe and co-workers in 2018 employing two different strategies at room

7.2 Applications of the total synthesis of bioactive natural products

281

Figure 7.12: Total synthesis of adunctin B at room temperature as key step (s).

temperature as a green protocol in seven and three steps (Figure 7.12). From a structural perspective, natural cinnamoyl derivative adunctin B (143) includes a hexahydrobenzofurane moiety carrying three stereocenters at 1″, 4″, and 6″ positions [68]. The concise racemic total synthesis of adunctin B (143) was initiated by Dethe et al. [69] from the readily available acid (133) and 5-methoxyresorcinol (134) through the construction of the dihydrochalcone (135) in 69% yield as a single regioisomer under protecting group free pathway; the terpenoid carvone (136) was effective to furnish the dihydrocarveol (137) at room temperature via the one-pot regioselective double bond

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reduction in the presence of Adam’s catalyst for 5 h, followed by Luche reduction for 15 min in 81% yield with sodium borohydride. Now the resulting substrates (135) undergoes the key Friedel-Crafts alkylation reaction with dihydrocarveol (137) at room temperature as a crucial step to afford the mixture of compounds (138) and (138a) in 6:1 in 79% yield; silica gel column chromatography was very helpful to separate diastereomers (138) and (138a). Next, epoxide (139) was prepared from (138) over two steps involving acetylation and diastereoselective epoxidation. Later, treatment of epoxide (139) with lithium hydroxide (LiOH) in THF:MeOH:H2O (2:2:1) at room temperature delivered the tricyclic alcohol (140) in 72% yield over two steps for 3 h. Finally, bioactive natural adunctin B (143) was obtained from the tricyclic alcohol (140) over two steps. It was interesting to be noted that adunctin B (143) was also prepared using another strategy from the compound (138) on treatment with Pd(OAc)2 (acts as the olefin activator), MnO and triethylamine in MeCN at room temperature for 3 h as a key step, followed by β-hydride elimination reaction for the construction of the needed double bond [69].

7.3 Conclusions Green chemistry or clean chemistry is associated with creativity and the development of innovative research and it is based on chemical, social, along ecological responsibility. The concept of green chemistry is relevant today as this chemistry is an influential proposal to the design, manufacture, together with the use of novel chemical products to reduce or eliminate chemical hazards. Energy plays a crucial role in most chemical reactions; according to the sixth principle of clean chemistry, the most successful pathway to govern energy is to develop strategies/procedures that are capable enough to conduct the chemical conversion at ambient temperature and standard pressure. So, this overview covered the application of the total synthesis of bioactive natural products and their analogues at room temperature which should mentor sustainable chemical preparation of molecules of natural origin in the future. Hence, the present overview will certainly make some impact in this direction since it inspires the next generation to synthesize natural products as well as new medicines for the community at room temperature to save energy properly. Acknowledgements: S. Majhi is grateful to his mother Sadeswari Majhi and father Tarani Majhi as well as elder brother Sudhir Majhi, and his wife. The author is thankful to the respected principal of Triveni Devi Bhalotia College Dr. A. K. Dey for his kind support and inspiration.

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Kantharaju Kamanna* and Yamanappagouda Amaregouda

8 Synthesis of bioactive scaffolds catalyzed by agro-waste-based solvent medium Abstract: The backbone of synthetic organic chemistry is the formation of carbon– carbon and carbon–heteroatom bonds. Scientists are actively working to develop new methods of bond-forming reactions because it is one of the most useful tools for the development of structurally diverse molecular entities. On the other hand, scientists are constantly discovering chemical processes to make them more sustainable in order to avoid the ever-increasing chemical emission associated with hazards to the environment. Thus, the development of greener catalytic reactions demonstrated a massive uptick in the ability to carry out carbon–carbon and carbon–heteroatom bond-forming reactions under environmentally friendly and simple reaction conditions. Various approaches are demonstrated, namely, solvent-free, microwave irradiation, ionic liquids, ball milling, ultrasound, one-pot, and aqueous-mediated methods under green chemistry protocol. Agro-waste is the postharvest part or agricultural residues derived from various agricultural activities, which has diverse scope and applications. The use of this agro-waste is an eco-friendly and cost-effective process of waste management. Appropriate and optimal utilization of these waste by-products is one of the major challenges in the present days. The recent trend around the globe is to transform waste into wealth concepts to achieve various applications. Agro-waste-derived ashes and extracted medium are successfully studied recently as a heterogeneous- or homogenous-based catalyst in various organic transformations. Agro-waste-derived catalysts are easily available, cost-effective, simple to prepare, nontoxic, easy to handle, biodegradable, and more environmentally benign. This article focuses more on a few instances of agro-waste-based homogeneous and heterogeneous organic synthesis, especially those used in the construction of bioactive molecule synthesis via C–C and C–X bond formation reactions are discussed. The compiled literature in this article is based on keywords used in the search engine on “agro-waste-based catalyst for organic transformations”, and review articles published on this topic, future scope, and summary are discussed. Keywords: agro-waste; green chemistry; homogeneous; organic synthesis; solventfree.

*Corresponding author: Kantharaju Kamanna, School of Basic Sciences, Department of Chemistry, Rani Channamma University, P-B, NH-4, Belagavi 591156, Karnataka, India, E-mail: [email protected] Yamanappagouda Amaregouda, School of Basic Sciences, Department of Chemistry, Rani Channamma University, P-B, NH-4, Belagavi 591156, Karnataka, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: K. Kamanna and Y. Amaregouda “Synthesis of bioactive scaffolds catalyzed by agro-waste-based solvent medium” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0097 | https://doi.org/10.1515/9783110797428-008

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8.1 Introduction A solvent in a chemical transformation is often used because it is essential in various stages of the reaction by acting as a homogeneous heat-transferring agent between the reactants [1]. The solvent also provides a comfortable contact between reactants and intermediates produced during the reaction and guides to choose the appropriate procedure for the workup or in recycling or disposal processes. Thus, the choice of the solvent is an essential aspect, which allows control over the rate of reaction selectivity and conversion factors for various reactions [2]. However, the use of solvent remains questionable due to produce toxicity, environmental concern, and waste management. Thus, there is a huge need of greener solvent that replaces volatile hazardous solvents and the waste by lowering the environment pollution and global warming. To find the alternative substitutes for the classical volatile organic compounds (VOCs), researchers are developing novel green and cleaner nonconventional strategies as an alternative. The use of water in place of volatile solvents is one of the green method initiations described in organic reactions. However, the use of water as a solvent medium has a limitation of solubility of reactants [3]. Therefore, organic solvent is still a choice of the organic chemist due to its easy solubility; it simplifies isolation and recovery of the used solvent by simple evaporation and often prevents decomposition of thermally sensitive products and/or reactants. However, the solvent-concerned serious safety issues of exposure, storage, and often spillage into the surrounding environment lead to the tropospheric ozone formation, pollution to soil and water, and harm to the animal kingdom. The utilization of the solvent leads to produce 80% of the waste chemical during the synthetic procedure encountered [4]. The concern of environmental impact and present green chemistry processes is that there is a constant effort to practice alternative methods, and it minimizes hazards in organic synthesis employing eco-friendly solvents and nontoxic reagents [5]. Although, there are several conventional techniques available for bioactive heterocyclic synthesis, they are still not fully accepted due to the current environmental condition and safety concerns. Thus, the current developments are in the establishment of novel sustainable synthetic approach that emphasizes on the process of rapid and eco-friendly alternative to classical approaches [6]. There is a high demand for the development of sustainable synthetic methods to rediscover the present concern of demand. The green chemistry rules [7] demand organic synthetic processes to be performed by employing a method that maximize the conversion factor of starting reactants into the target product with low waste or by-products, less energy, avoid toxic solvent, hazardous and corrosive solvent, or catalyst usage [8–10]. The serious issue on environmental pollution produced during synthetic processes is that there is a serious revisit to replace volatile, toxic, corrosive, and inflammable chemical solvents into sustainable green chemistry protocol in the synthetic method. The design and establishment of environment-friendly, one-step, and sustainable green organic transformation for numerous bioactive

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289

heterocyclic compounds are the present focus of the chemist. Therefore, the synthetic protocol based on solvent-free or neat condition emerged as an alternative to these issues to make a protocol green, but limited to use in the synthesis [11]. To reduce pollution, scientists and engineers try to design a suitable chemical process that gives less clot on the environment, and organic solvents are replaced by ionic-liquid-based catalysts and solvents [12]. Due to their unique properties, they have been viewed as green solvents and are employed in enzymatic organic synthesis [13], solvent-free organic reactions [2], carbon–carbon cross-coupling reactions [14], and many more chemical synthesis, thus creating a huge challenge to researchers to discover an alternative, sustainable, and eco-friendly approach for the existing organic transformations. Since the last two decades, the green chemistry concept explained the fundamental basic technique focused on environment and human health protection under green chemistry principles [15]. It focused on design, production, chemical use, and processes with no or little hazardous produce with high economic and technological feasibility. Nowadays, agriculture is the backbone of many developing countries; it plays a very vital role in the economic improvement of the countries and fulfills maximum needs of the human kind, such as food, income, and employment to remote populations. It is revealed that about 60% of the country’s GDP is mainly dependent on the agriculture production [16], and further stabilization has been taken place for the effective improvement and economical productivity of the agriculture sector [17]. By introducing modern technology, the crop yield increases tremendously, with the agriculture by-product also more aggregating. After harvesting the main product, the economic part of the crop is called yield and the least important part is called as “agrowaste” [18]. Tremendous number of organic agro-effluents produced from processing industries like juice, chips, confectionary, fruit, rice mills, tea, and sugar cane produced metric tons of agro-waste everyday (Figure 8.1). The agro-waste are employed in recent days for useful purposes like the energy production from mustard, rice hull crop for the combustion of boiler technology plant, situated at Uniara, Tonk, with a capacity of 8 MW, biofuel production from rice bran, and bioethanol from sugar cane waste [19]. Alternatively, the agro-waste materials are also employed in environmental remedies for heavy metal removal in polluted water and preparation of biologically active nanomaterials with more accurate dimensions [20]. Also employed in the preparation of construction of materials by using cotton and paper mill waste in the preparation of thermally stable bricks, the materials prepared by the waste have equal stability that of the standard reference material reported. The sugar cane industry bagasse and other agro-waste constituents are frequently employed as binders in the preparation of structural concrete fiber to make the material become more stable [21]. The agro-wastederived materials are employed in the field of waste management for the purification of water and organic synthesis processes [22–33]. The silica containing saw dust found its application in preparation of the electrical energy storage device materials like silica nanoflakes in lithium battery manufacture. Anu et al. demonstrated that the synthesis

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8 Synthesis of bioactive scaffolds catalyzed by agro-waste

Figure 8.1: Selected agro-waste solvent media source.

of biologically active graphene-tin oxide by using coconut shell derivative gave a round-shaped nanocomposite with higher biological activity, and the synthesis of carbon dots by employing orange fruit peel waste was reported [34]. Apart from this waste to wealth concept, recently, a chemist discovered agro-waste extracts (AWEs) as an alternative green chemistry solvent media surrogate in organic transformations. Recently reported major extract agro-wastes include water extract of banana (WEB) in Suzuki–Miyarura, Dakin reaction, Sonogashira coupling, Henry reaction, and peptide bond formation. Similarly, agro-waste water extract of rice straw ash (WERSA) and water extract of waste papaya bark ash (WEPBA) found good performance for some of the above-mentioned reactions [35].

8.1 Introduction

291

Figure 8.2: Advantages of AWE approach in organic synthesis.

The synthesis of biologically significant heterocyclic scaffolds like coumarin, dihydropyrimidines, and other bioactive heterocyclic molecules are synthesized using AWE. Some of the advantages of the AWEs observed by researchers include AWEs standing as an efficient alternative to hazardous organic or inorganic chemicals or solvent, a reaction catalyzed in mild condition, least toxicity produced, and abundant in nature (Figure 8.2). Thus, all these merits of the AWEs toward organic synthesis inspired us to write a book chapter on the recent development on AWEs as an ecofriendly solvent medium for developing various bioactive molecule transformations. In recent years, rapidly growing research has set its goal in the establishment of a novel type of solvent/catalyst, which is termed as AWEs; it has emerged as an eco-friendly approach catalysis for various named reactions (Figure 8.3). The agro-waste-derived catalysts emerge in current trends as an alternative chemical surrogate and show that sustainable approach can be discovered much more in organic synthesis [36]. The agricultural waste offered an excellent substitute to replace various hazardous and toxic catalysts due to its less toxicity, easy degradability, and the ability to act as an

Figure 8.3: Selected named reaction catalyzed by AWEs.

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8 Synthesis of bioactive scaffolds catalyzed by agro-waste

Table .: Important elemental composition of the AWEs. Source of catalyst (Ash)

Components

Musa balbisiana underground stem M. balbisiana peels Musa paradisiaca peels Banana (Musa Gros Michel) peels Lemna perpusilla Torrey Acacia nilotica tree stem Cocoa pod husk Camphor tree leaf Banana peel Rice straw Papaya bark

SiO, KO, CaO, MgO, PO, AlO, SrO, FeO, NaO K, Ca, Mg, Na O, Mg, P, K, Si, Cl, Al K, Na, Mg, Ca, Mn, Fe, Zn Si, K, Na, C Si, Ca, Mg, Na, K, Al, P K, Mg, O, P, Si Ca, Mg, Al, Na, K K, Na, Cl, CO Na, Li, Ca, Mg, K, Si Mg, Ca, Na, K,

Ref. [] [] [,] [] [] [] [] [] [] [] []

eco-friendly catalytic medium compared to chemical catalysts [37]. High abundance of agro-waste in nature makes them use cost-effective reagents [38]. Agro-waste-derived catalytic medium acting as a dual function in both solvent and/or catalyst is a remarkable alternative system in organic synthesis. These AWEs are generated by agrowaste ash water extraction, which is abundant in nature and produced from numerous food industries. The composition of the major constituents of extract medium found hydroxides and carbonates of K, Na, Li, Si, Mg, Ca, P, etc. The oxides generated from the agro-waste ash are converted in to corresponding hydroxides/carbonates after water treatment and found remarkable catalytic activity in many organic syntheses as a solvent and/or catalyst (Table 8.1).

8.2 Multicomponent reactions Multicomponent reactions (MCRs) are the ones that are known since 150 years. The first reported Strecker synthesis of α-amino cyanides was established in the year 1850 for α-amino acids synthesis. Numerous MCRs exist today; among them, isocyanide-based MCRs are most documented. Among various multicomponent named reactions reported, some of the selected important reactions are represented in Figure 8.4. Due to the flexibility of carbon, it has played a crucial role in the form of numerous structure, which are almost essential to living beings. The complete organic synthesis revolves around the theme of making and breaking of C–C and C–X bonds. The success story of every drug is dependent on the design and synthesis employing readily available starting material with efficiency. In this regard, MCRs are the concurrent transformation, in which three or more substrates reacted to produce a single macromolecule, whose functionality and structure differ from its precursors. Thus, due to the significance of MCRs, there are various synthetic protocols that are target-guided to

8.2 Multicomponent reactions

293

Figure 8.4: Some of the remarkable named MCRs reported.

produce biologically potent scaffolds, natural products, and druglike compounds [51,52]. MCRs emerged as a better technique in synthetic chemistry to achieve various bioactive and metal chelation compounds. MCRs are performed in one-pot, where organic reactants made to combine together become a facile route for many organic chemists because of the ease of operation, efficiency, less by-products, and shorter reaction time (Figure 8.5) [52]. The length of a synthetic protocol is solely dependent on molecular complexity of the product per operation, which is dependent on the number of chemical bond formation involved. Thus, the development of a single-stage reaction in multibond formation avoiding multiple steps is gaining huge attention as well as permanent search for the economic and greener synthesis. MCRs, where many reactants are combined in a single step to produce products by incorporating substantial amount of reactants used in it, comply severe requirements for the ideal organic syntheses [52]. Agro-waste-catalyzed C–C and C–X (heteroatom) bond formation reactions have made significant contributions to pharmaceuticals, fine chemicals, smart materials, natural products, and building blocks synthesis in recent years [53]. To establish the catalytic cross-coupling reaction employing heteroatomic functional groups to form carbon–heteroatom bonds was a milestone in methodology development. The C–C and C–heteroatom (C–O, C–P, and C–N) bond formation reaction

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8 Synthesis of bioactive scaffolds catalyzed by agro-waste

Figure 8.5: Multistep v/s multicomponent strategy.

development is a fascinating topic that got huge attention in recent organic synthesis, especially in MCRs. The synthesis of organic scaffolds via MCRs employed in recent years using these agro-waste solvent media is growing because of global warming, environmental awareness, and renewable energy sources. It is critical to limit the use of toxic chemicals in industrial and academic research, as well as to attain a good environmental system requiring green chemistry practices. This article summarizes the recent developments on bioactive scaffold synthesis using agro-waste-based solvent medium as a green protocol technique for coupling and condensed processes involving carbon–carbon and carbon–heteroatom bond construction in organic transformations.

8.2.1 Extraction and characterization of agro-waste ash powder or extract solution For clarity of understanding AWE processes involved, our recent work reported explains the steps involved in the AWEs, and the characterization of the greener catalytic solvent medium from agro-waste sample is taken as an example in detail [54]. 8.2.1.1 Water extract of orange fruit shell ash preparation Water extract of orange fruit shell ash (WEOFSA) is prepared by a previously reported procedure (Figure 8.6) [54], briefly, orange (Citrus sinensis) fruit peels are locally collected and the peel is washed with water, sunlight dried, and burnt on a Bunsen burner to get ash. The obtained peel ash (10 gm) is soaked in 100 mL of distilled water and stirred for about 2–3 h and then filtered; the obtained filtrate is termed as WEOFSA. The pH of the extracted solution found is 10.12. The basic nature of the extracted solution responsible for elemental contents was analyzed; first, powdered ash was

8.2 Multicomponent reactions

295

Figure 8.6: Schematic representation of WEOFSA preparation.

examined using scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX), and the data revealed rich elements of potassium (9.14), calcium (5.55), and magnesium (0.89) in wt% (Figures 8.7a and 8.8a). Further extended SEM-EDX collection after water extraction to ash powder, surprisingly, observed negligible wt% corresponding to K, Ca, and Mg (Figures 8.7b and 8.8b). The data revealed that, in water, extraction elements are present in oxide/carbonate form causing the solution to turn basic in nature. The surface morphology SEM images of the ash also supported EDX data before and after water extraction of dense whiter element’s honeycomb structure

Figure 8.7: SEM images of ash: (a) before and (b) after extraction.

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8 Synthesis of bioactive scaffolds catalyzed by agro-waste

Figure 8.8: EDX images of the ash: (a) before and (b) after extraction.

due to the presence of carbonate/oxide forms of elements, but the SEM image of after water extraction gave honeycomb structure without the white spot on it. This surface and elemental analysis studies revealed that the ash powder contains active elements and is extracted to the solution. The data are also validated further using flame photometry (FP) analysis of the 10% solution extracted in FP. The FP experiments were carried out by preparing known respective salt solutions of Na, Li, Ca, and K series of concentrations of 40, 60, and 80 ppm range. The final FP of 10% WEOFSA solution outcome showed the presence of 44, 493, and 1921 ppm wt% of Mg, Ca, and K, respectively. These experimental analyses revealed the presence of carbonate and oxide formation of the respective alkali and alkaline earth metals after ash soaked with water, and it contributes to the basic nature [54].

8.2.2 Homogeneous agro-waste solvent media used for the organic scaffolds synthesis 8.2.2.1 Suzuki–Miyaura coupling reactions Suzuki–Miyaura reaction is known for metal-catalyzing, the typical palladium (Pd) was found suitable for this reaction associated with aryl, alkynyl, or vinyl organoborane triflate or halide in the presence of a basic medium. This coupling reaction is exclusively used for C–C bond formation to produce conjugated styrene, biaryl, or alkene compounds. Chemists are examining various combination of organic or inorganic bases employed in reactions; researchers described that a base is critical to activate organoboron and palladium reagents [43]. The base used, on the other hand, frequently competes with functional group resulting in protodeboronation of arylboronic acid electron-deficient spot in many circumstances and is also hazardous to the environment [44,45]. As a result, researchers developed an alternative base derived

297

8.2 Multicomponent reactions

Br R1 1

+ (HO)2B

R2

or R1

Het 2

Br

R1

WEB (3 mL), r.t. 3

4

R2

and

Pd(OAc)2, 5-20 min

Het R1

R2 5

(R1= aryl/heteroaryl and R2= aryl) Figure 8.9: Suzuki–Miyaura cross-coupling reaction-catalyzed Pd(OAc)2 in WEB.

from the agro-waste source as an alternative surrogate, and it is reported to have emerged as a superior solvent medium. Sarma and coworkers described WEB as a dual function base-cum-solvent medium for the Suzuki-Miyaura in the presence of palladium [55] (Figure 8.9). Authors examined various aryl bromides (1) and arylboronic acid functionalities (3) using WEB media and achieved outstanding catalytic efficiency. The authors highlighted WEB as several advantages over previous methods were reported including higher conversion rate, shorter reaction time, and high atom economy. This new approach emerged successful eco-friendly medium to replace base, ligand, or organic solvent. It is worth noting here that the agro-waste extracted media perform very well under the ligand-free reaction condition with low loading of palladium at room temperature (rt) and in the open air. Furthermore, the cross-coupling occurs solely without evidence of any homocoupling by-products, resulting in higher atom economy. Authors also examined other banana peel ash variants for the same reactions, which included: (i) Musa acuminata (Dwarf Cavendish) and (ii) Musa septennium (Chinia Manohar), showing identical catalytic cross-coupling reactions [56]. Authors studied the influence of Pd(OAc)2 on coupling in a comparatively short reaction time with low loading (0.5 mol%), yielding a product up to 99% (4) at rt for both electron donating group (EDG) and electron withdrawing group (EWG) present on aryl bromides (1) and/or arylboronic acids (3). The catalytic medium showed a tolerance to large functional group range tested on aryl bromides including –OMe, –CH3, –NO2, – CN, –CHO, and –COMe. Authors revealed that the agro-waste-based catalyst system produces necessary biaryls with low catalyst loading without the need for any further additives, external bases, ligands, and not-produced unwanted homocoupling products. Authors further examined several heterocyclic bromide (2) systems in Suzuki– Miyaura coupling partners in the developed catalytic system, and isolated product (5) in excellent yield. Sarma and coworkers reported WERSA, another agro-waste derived by Suzuki–Miyaura reaction of arylboronic acids (3) and aryl bromide (1) at an ambient temperature. The Pd(OAc)2-WERSA system emerged as an efficient and eco-friendly reaction giving excellent yield. Bora et al. reported WEPBA in the presence of palladium cross-coupling of aryl bromide (1) and arylboronic acid (3), after successfully

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8 Synthesis of bioactive scaffolds catalyzed by agro-waste

B(OH)2 ArCHO + R2 6

3

Ar

WEB, rt Pd(OAc)2

R2 7

(R2 = aryl)

Figure 8.10: Suzuki–Miyaura crosscoupling catalyzed by Pd(OAc)2 in WEB.

identifying the composition of the WEPBA basicity [57]. It also reduces the undesired side reaction taking place during coupling photodeboronation, but the crude reaction mixtures exhibited trace amount of arene in GC–MS noticed. Boruah and coworkers described a ligand-free cross-coupling of substituted aldehyde (6) and arylboronic acids (3) in the aqueous extract of banana-mediated-palladium acetate. Authors claimed a developed procedure that is facile, efficient, and an inexpensive alternative to the conventional method. Because the extract medium is readily available, this technique has a lot of potential applications in the field of research and industries. Authors described that only Pd(OAc)2 of 0.5 mol % was required to give a high yield product (7). The exact mechanism route of Suzuki–Miyaura reaction in WEB medium is unknown, but authors predicted that the agro-waste peel extract presents sodium and potassium carbonates/hydroxides operating as a base and other salts element promoters in the reaction (Figure 8.10) [58,59]. The importance of cosolvent during the coupling reaction was studied, and the emerged greener ethanol solvent for crosscoupling reaction gave excellent yield [60]. Rosa et al. described cross-reaction of 4-bromoanisole (6) with phenylboronic acid (3) catalyzed Pd/RHA and Pd/BPA optimized reaction condition of Pd (0.5 mol %) at high temperature (100 °C) for 24 h in ethanol [61]. Overall different research labs across the globe reported AWEs for Suzuki– Miyaura coupling reaction, which works as an eco-friendly solvent medium giving the product in high yield. 8.2.2.2 Sonogashira cross-coupling reaction Sonogashira reaction is a cross-coupling between a terminal alkyne with a vinyl or aryl halide in the presence of palladium, cocatalyst copper (I), and a base containing nitrogen employed for the formation of C–C bonds by conventional synthesis. Dewan et al., for the first time, investigated WEB as an eco-friendly system for Sonogashira reaction with Pd(OAc)2 using 4-iodo-nitrobenzene (8) and phenylacetylene (9) model reaction carried out in the absence of ligand, base, or additive. The authors observed a 50% of the cross-coupling product, and they explained that the poor solubility of the reactants in water caused the reduced product yield (10) (Figure 8.11) [62]. As a result, the authors performed reactions in WEB with a series of organic solvent systems (1:1), and ethanol emerged as the best suitable solvent system for the reaction and gave excellent yields. Further, authors easily recovered the catalytic system and recycled up to the fifth cycle. Bora et al. expanded the importance of WEPBA developed in Pd-catalyzed

8.2 Multicomponent reactions

I

WEB, r.t.

+ Pd(OAc)2

O2N 8

299

O2N

9

10

Figure 8.11: Sonogashira cross-coupling reaction-catalyzed Pd(OAc)2 and WEB.

Sonogashira reaction [33]. The reaction was performed under ligand-free, eco-friendly WEPBA-EtOH media, giving an excellent cross-coupling product. Apart from supplying basic condition in the reaction, additionally WEPBA-EtOH combination decreases the Pd(II) catalyst amount required due to the active Pd(0)-nanoparticle formation (particle size 10–20 nm) during the reaction observed. The cross-coupling reaction extended to various substituted aryl iodide with different aliphatic or aryl acetylene was reacted, giving excellent coupling products. The authors examined several test reactions employing electronically different aryl iodides and acetylenes under optimized reaction for better studies of the developed protocol. Authors revealed that aryl halides containing EWG substituents such as the nitro group gave good yields of the product, but meta-substituted electron-rich aryl iodide found no significant variation in the isolated yield. However, the yield of sterically hindered o-nitroiodobenzene was found to be quite low [33]. Researchers extended the utility of WEB in the nitro-Aldol and Henry reaction of nitroalkane (nucleophilic) with a carbonyl (electrophilic) substrate, giving β-nitro alcohols (Figure 8.12). This reaction is a base-mediated Aldol-type carbon–carbon bond formation reaction of an aldehyde (11) or ketone and nitroalkane to synthesize β-nitro alcohols (12) [56]. The reaction does not require the addition of promoters or external base and has a broader substrate scope (60–90% yield) with reusability. Authors studied comparative solvent systems of WERSA and WEB in Henry reaction, and found that the WERSA-catalyzed reaction gave lower yield than WEB-catalyzed reaction due to the low pH of the extract solution. Chia et al. described the reaction of aldehyde (13) and 4-hydroxycoumarin (14), producing a range of bisenol derivatives (15) under an optimal reaction condition using ash-water extract (Figure 8.13). Bisenols were precipitated as a pure compound without further need of column purification, giving excellent product isolation (62–94%). The

R-CHO

CH3NO2 11

OH

WEB

NO2

R 12

(R= aromatic) Figure 8.12: Nitro-aldol reaction in neat WEB catalyst.

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8 Synthesis of bioactive scaffolds catalyzed by agro-waste

R1 O H

R1

OH

R2

Ash-water extract

OH

OH

R2

+ O

O

O O

O

14

13

O

15 1

(R = aromatic and R2 = aryl)

Figure 8.13: Bisenol synthesis in the presence of ash-water extract.

authors claimed many advantages of their method using ash extract, namely, shorter reaction time, EWG yielding excellent yields, no external base or additives in the reaction, and superior catalytic performance [63]. Further, authors successfully extended this protocol to cinnamic acid derivative synthesis by other than salicylaldehyde derivatives with Meldrum’s acid, followed by ring-opening in aqueous media. At first, only condensation product was noticed by the reaction of benzaldehyde (13) with Meldrum’s acid (16) at rt using the aqueous extract of Acacia concinna pods and further reaction performed at 60 °C gave cinnamic acid derivatives (17 and 18) with good yields (Figure 8.14) [64]. Various substituent types inserted into cinnamic acid discovered to have a significant impact on the pharmacological effect of produced cinnamic acid derivatives for in vitro studies and revealed that some of them are more successful than traditional medicine used for treating chronic or infectious disorders. Furthermore, these derivatives showed substantial antituberculosis action, antibacterial action against (Staphylococus aureus) bacteria, with potent antimalarial activity [65].

O O

RT O

O O

H + R

O

R

60 °C

17

Catalyst

O

O 13

O

16

60 °C

OH R 18 (R= aromatic)

Figure 8.14: Synthesis of cinnamic acid derivatives.

8.2 Multicomponent reactions

301

R1 O S

O

NH2 + R

19

O H+

11

or

N

O Onion peel Solvent free, 100 °C

O

S

O N 22

21

or S

NH2

R1 O

20

N S

O N

23 1

(R = aromatic)

Figure 8.15: Onion peel ash extract-catalyzed MCRs.

Chia et al. evaluated the green catalyst onion peel ash for aminothiazole derivative synthesis (22 and 23) by benzaldehyde (11), ethyl acetoacetate (21), and 2-aminothiazole (19) or 2-aminobenzothiazole (20) reaction. The authors examined the tolerance of the reaction for various substituted aldehyde and aminothiazole and revealed aromatic aldehyde with EDG, with ethyl acetoacetate giving moderate to good yields, but aromatic aldehyde with EWG observed high yields (Figure 8.15) [66]. In another work, Gulati et al. reported water extract of onion peel (WEOP)-catalyzed synthesis of bis-indolylmethane (25) by the reaction of substituted aldehyde (6) with indole (24). The authors claimed a developed approach that had several advantages including avoidance of traditional acid or base, reusability of the catalyst, and avoidance of the use of harmful reagents (Figure 8.16) [58]. The same research group reported the synthesis of bis-hydroxycoumarin (26) (Figure 8.17) from substituted aldehyde (6) and 4-hydroxycoumarin (14) in the presence of WEOP, giving a product by heating at 80 °C for a few min, resulting in excellent yield [66]. The conventional Knoevenagel reaction employed catalyst inorganic metal or H N

ArCHO + 6

H N

WEOP

24

Ar 25 (Ar = aryl)

NH

Figure 8.16: Synthesis of bisindolylmethane.

302

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

R2

O

R2

O WEOP

ArCHO + 6

OH

O

OO

OH

14

Ar

O

OH

26 (Ar = aryl and R2 = aromatic)

Figure 8.17: Synthesis of bis-hydroxycoumarin.

CN R CHO + CN 11

27

WEB grinding

CN R

CN 28

(R = aromatic)

Figure 8.18: WEB-catalyzed synthesis of Knoevenagel product.

metal oxides or organic base to achieve the expected product in excellent yield. Recently, Kantharaju et al. developed a more environment-friendly methodology based on “waste to wealth” concept in which the agro-waste extract of orange fruit peel ash (WEOFPA) catalyzed gave excellent product isolation (Figure 8.18) [67]. The importance of the Knoevenagel condensation product was employed in various bioactive molecule syntheses as a precursor, and the researcher discovered a metalfree greener approach synthesis that was found to be superior to earlier approaches. In another work, researchers used water extract of teak leaf (Tectona grandis) ash (WET) as a solvent media in Knoevenagel reaction of substituted aryl aldehyde and malononitrile and claimed that the Knoevenagel condensation product yielded greater yields in less time for aromatic aldehydes with EWG (–NO2, –CN, –Cl, and –Br) compared to EDG (–CH3, –OCH3, and –OH). As a result, the authors revealed that the electronic property of the benzaldehyde has a major impact on the product formation [68]. In another work researcher reported simple grindstone condition at rt preparation of Knoevenagel reaction of substituted aryl aldehyde (11) or heteroaryl aldehydes and malononitrile (27) catalyzed WEB gave excellent yield (28) [69]. The conversion of one functional group into another is common in organic synthesis and challenging. Jin et al. reported water extract of pomegranate peel ash (WEPPA)-mediated conversion of aromatic nitrile (29) into amide derivatives (30) in a special synthetic reactor at the high temperature (150 °C) described. The product isolated was simple and was collected by filtration, thus achieving pure aromatic amide derivatives through silica gel column chromatography (Figure 8.19) [70]. Bora et al. reported WET-catalyzed hydration reaction of nitriles to amides using stoichiometric oxidant hydrogen peroxide [71]. The authors have successfully studied the optimization reaction condition for the conversion of a number of electrically diverse aryl nitriles.

8.2 Multicomponent reactions

303

O CN WEPPA

NH2

150 °C 30

29

CN

NH NH

+

+

13

O

O

CHO

R

Figure 8.19: Synthesis of nitrile derivatives in WEPPA.

CN 27

O 31

NH2 N N

WEMPA, EtOH Microwave

CN

O 32 R (R = aromatic)

Figure 8.20: Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones-catalyzed WEMPA.

Recently, Kantharaju et al. demonstrated that MCRs of malononitrile (27), aldehyde (13), and phthalhydrazide (31) in the presence of water extract of mango peel ash (WEMPA) under microwave irradiation found facile and faster isolation of 1H-pyrazolo [1,2-b] phthalazine-5,10-diones (32) (Figure 8.20) [72]. This developed medium found inexpensive, nontoxic, faster, and environment-friendly are the major advantages of this method [71]. 8.2.2.3 Carbon–heteroatom bond formation reaction-catalyzed agro-waste The C–C and C–X (heteroatom) bond making are fundamental reactions focused in organic chemistry. This reaction is extensively important in achieving pharmacologically significant molecules, valuable compounds, and agrochemicals. Hence, the novel synthesis of eco-friendly and more facile method development always has a demand in organic synthesis. Most of the chemists are rediscovering conventional protocols with presently available techniques and reagents to minimize the environmental pollution and target high-yield product isolation with recycle of catalysts are of more interest in the present organic synthesis. Sarmah et al. reported the use of both AWEs and H2O2 required for achieving dihydric phenols (33) in just 60 min with excellent yield (34). The aqueous extract promotes abstraction of proton from peroxide and provides an aryl format intermediate via migration. Overall, the agro-waste extract approach is benign and facile compared to the existing procedures as it does not produce the side product benzoic acid or benzyl alcohol, and it works robustly than the previous method reported (Figure 8.21) [56]. Dakin reaction involves aryl aldehyde (13) or ketone reacting with the basic H2O2, generating a product phenol (35), which is a major transformation obtained [56]. The

304

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

HOO-

HOOH + B(Base from WEB)

H OH

O

HO

OH

H2O2, WEB 33 HO O H O

34

Hydrolysis O O

OH

H OH

Figure 8.21: Probable mechanism of the WEB–H2O2-catalyzed Dakin reaction.

developed protocol that is able to transform hydroxybenzaldehyde derivatives of various substituted into dihydric phenols in the presence of WEB at rt are described (Figure 8.22). Borah et al. reported WERSA solvent system and compared it with WEB-catalyzed Dakin reaction. The authors observed that the WEB-catalyzed reaction gave high yield when compared to WERSA, and the reaction takes longer time to complete. The lower metal content and basicity may account for the difference in the reaction explained [73]. The most flexible organometallic reagent arylboronic acid is employed to prepare ipso-hydroxylation to phenol derivatives. This transformation is normally carried out in H2O2 and base conditions [74–76]. Bora et al. established an effective protocol for the ipso-hydroxylation (35) of aryl/heteroarylboronic acid (3) in the presence of WERSA– H2O2 medium as an exceptional greener AWEs (Figure 8.23) [73]. Further, authors examined the conversion with a small amount of hydrogen peroxide (0.2 mL) and tolerance variety of electronically different arylboronic acids in a faster method. Furthermore, the WERSA simply separated after the reaction and is reusable up to five cycles without losing its effectiveness. In another work, a researcher reported ipsohydroxylation using WET in the presence of H2O2 environment-friendly oxidant reaction. CHO

OH WEB, r.t.

R

H2O2 13

R 35 (R= aromatic)

Figure 8.22: Dakin reaction in H2O2–WEB system.

8.2 Multicomponent reactions

B(OH)2

305

OH H2O2

R

WERSA, r.t. 5-15 min

R

35

3

(R= aryl) Figure 8.23: ipso-Hydroxylation of phenylboronic acid into phenol.

Kantharaju et al. demonstrated 2-amino-4H-chromenes (37, 39, and 41) synthesis by reaction of aryl aldehyde (13), malononitrile (27), and resorcinol/naphthol (36, 38, and 40) catalyzed by WEPPA as a facile and eco-friendly solvent media (Figure 8.24). The reaction took 3–6 min for completion under microwave irradiation and isolated excellent product by filtration, followed by recrystallization that gave a pure (does not require further chromatographic purification) product [77]. 2-Amino-4H-chromene showed various pharmacological applications with antibacterial, anti-inflammatory,

HO

R1

OH

36

CN

MWI, 300W, 3-5 min HO

WEPPA

NH2 37

OH R2

CHO + R 13

CN

38

CN

MWI, 300W, 4-5 min

27

CN NH2 O

WEPPA OH

39 NH2

40

CN

O

MWI, 300W, 4-6 min WEPPA 41

R3

(R1, R2 and R3 = aryl)

Figure 8.24: WEPPA-catalyzed synthesis of 2-amino-4H-chromenes.

306

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

R1

O

COOH + H2N

N H

Ph

R2 COOMe. HCl

EDC. HCl WEB/EG

N H

Ph

43

42

R1

O

H N O

COOMe 2

R

44 1

(R = alkyl and R2 = aromatic)

Figure 8.25: Peptide bond formation in WEB/EG system.

antimicrobial, antiviral, antidiuretic, anticoagulant, anticancer, and anti-anaphylactic properties.[78]. Sarma et al. described WEB-catalyzed coupling of protected amino acids (42) with methyl ester of amino acid (43) to produce peptides (44) in the presence of the coupling agent and ethylene glycol (EG) at rt (Figure 8.25). The authors reported reaction proceeds to give excellent yield of the product by adding 6% EG as an additive. The greener method of synthesis of peptide gave more advantages and importance due to their clinical research in evaluating physiological and biochemical mechanisms of the peptides [56]. Nag et al. reported aryl aldehyde (6), C–H-activated carbonyl (45), and malononitrile (27) reaction giving 4H-pyrans (46) catalyzed by water extract of Tamarindus indica seed ash (WETSA) at rt. The authors optimized the reaction condition using suitable solvent system and found product isolation excellent (80–95%) (Figure 8.26) [79]. The authors also studied the substrate scope of various aryl aldehydes and substituted 1,3-cyclohexanediones with aromatic aldehydes containing EWG and EDG substituents, thus giving excellent yields. Further, authors extended the utility of the agro-waste prepared for the synthesis of pyranocoumarins (48) in the presence 4-hydroxycoumarin, aryl aldehyde (47), and malononitrile (16) in WETSA: EtOH (2:4) at 60 °C (Figure 8.27). This skeleton-containing molecules showed antibacterial and antifungal properties and have good biological activity [63]. O

O + Ar-CHO + CN

R

CN

O

R 45

Ar CN

WETSA : EtOH O

RR 27

6

NH2

46 (Ar = aryl, R= CH3, H)

Figure 8.26: Synthesis of tetrahydrobenzo[b]pyrans using WETSA.

O CHO + OH O 47

O O 16

COOH

Catalyst RT

O 48

O

Figure 8.27: Synthesis of 3-carboxycoumarins.

307

8.2 Multicomponent reactions

NH2

O

O R1

WEOPA 80°C

O+

N

R1

O 49

O 50

51

Figure 8.28: Synthesis of phthalimide derivative.

(R1= aromatic)

O O

CHO

O OH

O

WEB RT

+

O OH

O

47

O

52

16

Figure 8.29: Synthesis of 3-carboxycoumarins in the presence of WEB.

Chia et al. reported phthalimide derivative (51) synthesis using WEOPA as an agrowaste media for the combination of phthalicanhydride (49) and aromatic amine (50). The authors reported used WEOPA that is capable to recover and be reused for at least five cycle synthesis of the product without loss of the activity (Figure 8.28) [80]. Bendre et al. demonstrated 3-carboxy coumarin derivative (52) synthesis from the reaction of salicylaldehyde (47) and Meldrum’s acid (16) in WEB (Figure 8.29). The authors used cosolvents for better solubility of the reactants and isolated excellent yield [81]. Further extended to variety of commercially available salicylaldehydes, and phenolic monoterpenoids derivatives (eugenol, thymol, and carvacrol) for the synthesis, the developed protocol tolerable and gave excellent product isolation. Patil and coworkers demonstrated a one-pot highly functionalized pyranopyrazoles (58) and benzochromenes (53 and 54) using Agave americana (century plant) leaf ash extract by the reaction of aldehyde (55) and malononitrile (27). Agro-wastederived catalyst showed many advantages and has mild reaction condition, high yield, facile product isolation, is environment-friendly, and does not require chromatographic separation (Figure 8.30) [82]. O

CN

R

NH2 NH2

O

O

CN

O or 53

R 54

naphthol isomers agave leaf ash extract RT

H

R

+ CN 55

O

OC2H5 56 + R1-NHNH2 57 agave leaf ash extract RT

CN

R CN N N R1

O

NH2

58

27

(R, R1 = aryl)

Figure 8.30: Synthesis of pyrano[2,3-c]pyrazoles and benzochromenes.

308

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

R1 CN

R1CHO +

2 + R SH

CN 27

11

WEB/EtOH 65 °C

NC

CN N

H2N

59

SR2

60 1

(R , R2 = aryl)

Figure 8.31: Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines using WEB. Table .: Synthetic methodologies reported for product . Compound

Catalyst

Condition

-amino-,-dicarbonitrile--thio-pyridines

WEB IBX CTAB ZnCl FeCl

RT °C °C MW MW

Time (min)

Yield (%)

Ref.

    

    

[] [] [] [] []

IBX, iodoxybenzoic acid.

Akhlaghinia et al. reported one-pot 2-amino-3,5-dicarbonitrile-6-thio-pyridines synthesis by the reaction of substrates 11, 27, and 59 in the presence of WEB as an agrowaste with the goal of reducing environmental impacts (Figure 8.31) [83]. Authors thought that WEB-accelerated chemical reactions due to the presence of potassium and sodium carbonate resulted basic, and this method is economic and beneficial to the environment. A few selected comparisons of methods employed for the reactions are tabulated in Table 8.2; the data revealed superiority of WEB-catalyzed reaction. Tamuli and coworkers established a greener synthesis of imidazoles (63) and dihyropyrimidinones (67) using pomelo-water-extract-catalyzed reaction of benzil (61), aldehyde derivatives (6), and ammonium acetate (62) at rt. Further, authors extended application of the agro-waste extract for dihydropyrimidinone (67) synthesis via one-pot three-component reaction of aldehyde derivatives (64), 1,3-dicarbonyl (65), and thiourea/urea (66) (Figures 8.32 and 8.33) [84]. Venkateswarlu et al. proposed a mechanism of WEPA-accelerated aromatic/heteroaromatic bromination (69) connected electrophilic brominative to alkynoic acidic proton (68) in NBS and agro-waste extract. The WEPA plays a key role and acts as a O Ph +

Ph

ArCHO + NH4OAc

O 61

6

62

WEP RT

Ar

N Ph

HN Ph 63 (Ar = aryl)

Figure 8.32: Preparation of imidazole derivatives using WEP.

8.2 Multicomponent reactions

O

Ar

O

ArCH2O + H3C

R1

X R1 + H2N

65

64

309

NH2

O

HN

WEP RT

X

66

N H 67 (Ar = aryl)

Figure 8.33: Preparation of dihydropyrimidine derivatives using WEP.

H Ar/ Het

R

Br

NBS R

WEPA- EtOH rt

68

Ar/ Het 69

Figure 8.34: Bromination of (hetero)/aromatics using NBS in WEPA.

(R= NH2, NMe2)

SH

70

S

Solvent T(°C), time

+ 9

71

Figure 8.35: Synthesis of thioether-catalyzed WERSA.

basic medium for the strong reactivity of the aromatic/heteroaromatic bromination reaction (Figure 8.34) [85]. Godoi and coworkers described a reaction of 4-methylbenzenethiol (70) and phenylacetylene (9) in WERSA in an inert atmosphere yielding a high yield of thioether (71) and low stereoselectivity (Figure 8.35) [86]. Researchers reported the reaction of arylidenemalononitrile (72), and 3-methyl-5-pyrazolone (73)-catalyzed WEB produce quantifiable amount of 6-amino-3-methyl-4-phenyl-2,3,3a,4-tetrahydrofuran[2,3-c]pyrazole-5-carbonitrile (74) (Figure 8.36) [58]. The bioactive nature of these derivatives reported in anti-allergic, antifungal, antibacterial, antimicrobial, anticancer, anti-leukemia, and antioxidant pharmacological applications of 6-amino-3-methyl-4-phenyl-2,3,3a,4-tetrahydrofuran[2,3-c]pyrazole-5-carbonitrile derivatives are evaluated. They have caught

CN + CN 72

N N H 73

O

WEB, r.t.

H3C

CN

HN N

O 74

Figure 8.36: Synthesis of carbonitrile derivative using WEB.

NH2

310

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

Table .: Synthetic methodologies reported for carbonitrile derivatives. Compound

Catalyst

Condition Time Yield (%) (min)

-amino--methyl--phenyl-,, a,-tetrahydrofuran[,-c]pyrazole--carbonitrile

WEB DABCO γ-alumina L-proline KF-alumina EtN

rt reflux reflux reflux reflux reflux

     

     

Ref.

[] [] [] [] [] []

the attention of many researchers to explore the synthesis processes to be simple because of their diversity in bioactivity [87]. A few selected comparisons of reported protocols are mentioned in Table 8.3, and it revealed various expensive and tedious catalysts, but WEBcatalyzed reaction showed simple and eco-friendly reaction conditions. Kantharaju et al. reported that the agro-waste-based water extract of muskmelon fruit shell ash (WEMFSA) as a catalyst for one-pot reaction of reactants 13, 27, and 76 gave 2-amino-4H-pyran (75), and the other three-component reaction of 13, 27, and 45 gave tetrahydrobenzo[b]pyran (76) derivatives that were achieved without the use of external base or catalyst/ligand/additives. The authors claim that the developed method has added advantages of efficiency, facileness, and cost-effectiveness (Figure 8.37) [88]. This structural core motif has gotten a lot of attention in recent years because of their intriguing pharmacological applications [89]. The same authors developed the synthesis of benzylidinemalononitrile (80) by the reaction of substrates 13 and 27 and the synthesis of 3-carboxy coumarin (79) in the presence of 77 and 78 using a greener, cost-effective, and environment-friendly WENBA solvent medium. This technique tolerates Knoevenagel reaction of aryl aldehyde or salicylaldehyde and active methylene Meldrum’s acid or malononitrile (Figure 8.38) [90]. To assess their biological effects, a number of novel coumarin3-carboxamide derivatives were developed and synthesized. The compounds had low or no activity against Gram-negative and Gram-positive bacteria, but they showed the O R

O EtO

O CN

EtO H3C

CH3

CHO

76

75

NH2

O CN

+

WEMFSA, EtOH rt O

R

O

R 13

O CN

45

WEMFSA, EtOH CN rt 27

O

NH2

76 (R= aromatic)

Figure 8.37: Synthesis of 2-amino-4H-pyrans and tetrahydrobenzo[b]pyrans using WEMFSA.

8.2 Multicomponent reactions

311

CHO CHO O + OH

R

O + NC

O

R

O

77

78 O

27

13

WENBA

CN

O

R

CN

CN

OH R O

79

80 (R = aryl)

Figure 8.38: Synthesis of coumarin-3-carboxylic acid and arylidenemalononitrile using WENBA.

ability to stop cancer cells from further growth. Furthermore, derivatives showed most powerful HepG2 cancer cell against, and many more broad applications are reported [91]. In another work, the same group reported O-phenylenediamine (81) with various benzoyl chloride derivative (82) reaction using a greener catalyst WEPBA at rt to produce 2-substituted benzimidazoles (83) (Figure 8.39) [92]. The derivatives of benzimidazole skeletons showed extensive pharmacological benefits in antibacterial, antiulcer, anthelmintic, anticancer, antiviral, analgesic, anti-inflammatory, and other inhibitions [93]. The same authors also demonstrated an in-situ synthesis of amide bond (86) by the reaction of aromatic carboxylic acid (84) and primary amines (85) in the presence of coupling agent and agro-waste extract medium. The authors claim the reaction to be efficient, faster, and simple, resulting in pure product separation with excellent yields when employing MWI rather than the traditional heating method reported (Figure 8.40) [94]. In another work, Kantharaju et al. demonstrated agro-waste solvent system for the synthesis of 2-amino-4H-chromene (89). The synthesis consists of a one-pot threecomponent reaction of malononitrile (27), aldehyde (87), and naphthol/resorcinol (88) with a greener catalyst water extract of lemon fruit shell ash (WELFSA). In this synthesis, the authors examined various synthetic methods, but microwave-assisted reaction found faster product formation with high yield (Figure 8.41) [95]. 2-Amino-

H2N

Cl

RT

O 81

N

WEPBA

+

H2N

82

R2 N

R1 83

(R2 = aryl)

Figure 8.39: WEPBA-catalyzed synthesis of 2-aryl-substituted benzimidazole derivatives.

312

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

COOH

NH2

WEB EDC,HCL Ethylene Glycol M,W 300 W

+ OH 84

O N H OH

Figure 8.40: Sterically hindered aromatic carboxylic acid with less nucleophilic amine coupling.

86

85

CHO

( X , Y) OH

NC +

WELFSA MW 300 W 2-8 min

+ CN

(X , Y) 87

27

OH

CN

HO

88

O

NH2

89 (X= Cl, F, Br, OCH3, NO2 and Y= OH, OCH3)

Figure 8.41: 2-amino-4H-chromene synthesis using WELFSA.

4H-chromene derivatives have, in literature, a wide range of biological actions, including anticancer, anticonvulsant, antibacterial, anticholinesterase, antituberculosis, and antidiabetic properties [96]. For a glance, few selected reported synthetic methods for comparison, as mentioned in Table 8.4. The reported earlier method reveled, expensive, harsh reaction condition and tedious isolation compared to the WELFSA noticed. The same authors reported a solvent-free synthesis of coumarin-3-carboxylic acid, and 3,4-dihydropyrimidin-2(1H)ones(thiones) catalyzed agro-waste-derived Lewis acid catalyst RHA-SiO2-BO3H3. The reaction of aryl aldehyde (13), 1,3-diketoester (76), and urea/thiourea (90) under thermal stirring condition and catalyst resulted in DHPM (91) product. Coumarin-3-carboxylic acid was prepared by the Lewis-acid-catalyzed Table .: Comparative table of the previously reported and agro-waste catalyzed for -aminoH-chromene synthesis. Compound

Catalyst

Catalyst loading (mL/mol %)

Condition

-amino-H-chromene

WELFSA POPINO LIPINO NAPINO MAPINO

 mL    

MW reflux reflux reflux reflux

Time (min)

Yield (%)

TON

TOF (h−)

Ref.

    

    

– . . . .

– . .  .

[] [] [] [] []

POPINO, potassium phthalimide-N-oxyl; LIPINO, lithium phthalimide-N-oxyl; NAPINO, sodium phthalimide-N-oxyl; MAPINO, magnesium phthalimide-N-oxyl.

8.2 Multicomponent reactions

CHO R

R

+ 13

X

H2N + O

O

313

O

90

NH2

RHA-SiO2-(NP's)-BO3H3 50 °C 1hr

NH

C2H5O H3C

H3C OC2H5

N H

X

91

76

(R= H, OMe, Br, NO2, Cl, CH3, F, OH and X= O, S)

Figure 8.42: Dihydropyrimidin-2(1H)ones(thiones) synthesis using RHA-SiO2-BO3H3.

X

CHO OH

NC +

+ NC

X 92

27

OH 88

WEB MW

CN HO

O

NH2

93 (X= H, F, Cl, Br, NO2, CH3, OCH3)

Figure 8.43: WEB-catalyzed synthesis of 2-amino-4H-chromene.

reaction of o-hydroxybenzaldehyde and Meldrum’s acid under sonication. Various spectroscopic approaches were used to describe and confirm the isolated products (Figure 8.42) [97]. In another work, the same group established derivatives of 2-amino-4H-chromene (93) synthesis using malononitrile (27), benzaldehyde (92), and naphthol or resorcinol (88) in a one-pot-catalyzed WEB under microwave and grindstone methods, as reported. The reaction proceeds environmentally benign and facile for the separation of the pure product described (Figure 8.43) [98]. Patil et al. demonstrated a natural greener BFE media for one-pot reactions of substrates 13, 27, 38, and 40 to produce 2-amino-4H-chromene derivatives (94 and 95). The authors claimed that the technique provides a gentle, efficient, and inexpensive protocol with an excellent yield and a protocol extended to large-scale production (Figure 8.44) [99]. Deka et al. achieved aza-Michael reaction of amines (96) with α,β-unsaturated ketone (97) under water hyacinth ash as an efficient and reusable catalyst in solventfree rt, thus achieving γ-amino carbonyl/nitrile (98). The protocol showed high application in synthetic organic molecules due to inexpensive catalyst, efficient catalytic activity, simple process, and produce excellent yield of the product in less time (Figure 8.45) [100,101].

314

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

R

OH OH CN O

NH2

CHO

40 BFE, EtOH: H2O

+ R 13

94

38

CN CN

R

CN

BFE, EtOH: H2O O

27

CN

95 (R= aromatic)

Figure 8.44: BFE-catalyzed synthesis of 2-amino-4H-benzochromenes.

O NH2

OMe

+ O

Catalyst rt, neat

N H 98

97

96

OMe

Figure 8.45: aza-Michael reaction of amines with α,β-unsaturated ketone.

8.2.3 Heterogeneous agro-waste for organic scaffolds synthesis 8.2.3.1 Carbon–Carbon bond formation Patil and coworkers reported pomegranate fruit peel ash as a cross-aldol condensation reaction efficient catalyst. For the first time, the authors presented a straightforward and eco-friendly approach for bis-substituted benzylidene cycloalkanones (100) synthesis via a cross-aldol process in aqueous medium utilizing APP as a heterogeneous catalyst (Figure 8.46) [102]. By condensation of cyclic ketones (99) with aryl aldehyde (13) in a strong base, a number of cycloalkanone (100) derivatives were produced. These derivatives discovered to have hypocholesterolemic activity and helped in reducing blood cholesterol levels [103]. Bora et al. reported calcined burned peel ash (CBPA, Musa balbisiana Colla peels) as an environmentally benign, recyclable, and inexpensive solid base catalyst for Knoevenagel reaction. For the first time, the authors studied the catalyst effect on O

O Ash of Pomegranate Peels

H +

R 13

O R

H2O, 0°C 99

100

(R= aromatic)

Figure 8.46: Synthesis of 2-(4-methoxybenzylidene)-1-tetralone.

8.2 Multicomponent reactions

315

O H + NC

R

CN 27

13

CBPA

CN

R

EtOH, 50 °C

CN 80 (R= aryl)

Figure 8.47: Synthesis of BMN derivatives using CBPA.

H X 101

+ NC

O

CN

CN

CBPA EtOH, 50 °C

CN

X

27

102 (X= O, N)

Figure 8.48: Knoevenagel condensation reaction of heterocyclicaldehyde with malononitrile.

Knoevenagel reaction of aryl/hetero-aryl aldehydes (13 and 101) with malononitrile (27) under optimal reaction condition; thus, CBPA demonstrated high selectivity for the synthesis of benzylidenemalononitrile (BMN, 80 and 102) derivatives. The isolated product has high yield, facileness, and is a recycled catalyst for six consecutive cycles, as reported (Figures 8.47 and 8.48) [104]. The BMN derivatives are found to be better inhibitors of tyrosine kinase, and many derivatives that are also used as a precursor to make various pharmacological lead molecules are well-documented [105]. Rokhum et al. reported Henry reaction catalyzed by Musa acuminata peel ash heterogeneous solvent-less reaction of 4-nitrobenzaldehyde (11), and nitromethane (103) produce β-nitroalcohol product (104) at rt. The authors claimed that the reaction took only 15 min, resulting in excellent (98%) product isolation. The authors noticed no dehydrated by-product during the reaction, ensuring that the process was selective. Authors investigated solvent effect on a model reaction and showed that the reaction with no solvent produced high yields (Figure 8.49) [106]. Further, the authors demonstrated a method that can be extended to 50 mmol scale reaction and isolated β-nitroalcohol product yielding practically a quantitative yield (98%). Gohain et al. reported Carica papaya stem ash (CPS) as a heterogeneous catalyst that is environment-friendly, facile, and reusable for biodiesel transesterification OH

O 1

H + R

R 11

103

NO2

MAPA Solvent free, RT

NO2

R R1 104

(R= alkyl, aryl and R1= alkyl, H) Figure 8.49: Henry reactions of aromatic and aliphatic aldehydes with nitromethane.

316

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

O H

CN

+ NC 27

105

Catalyst Solvent, 55 °C

CN CN

106

Figure 8.50: Knoevenagel condensation reaction in the presence of agro-waste CPS. Table .: Comparative synthetic methodologies reported for BMN synthesis. Compound

Catalyst

Condition

BMN

CPS NiCu@MWCNT Sodium azide Sodium saccharin Alanine Aspartic acid

RT °C RT RT RT RT

Time

Yield

     

     

Ref. [] [] [] [] [] []

reactions and creation of BMN (106) using the reaction of 105 and 27 substrates. The GC–MS and NMR tools are used to monitor the conversion and confirmation of spent cooking oil and Scenedesmus obliquus lipid to biodiesel. Under optimal reaction conditions, biodiesel conversions of 93.33 and 95.23% were achieved. The developed catalyst revealed an alternative and inexpensive catalyst for biodiesel conversion and Knoevenagel condensation (Figure 8.50) [107,108]. A few selected comparisons of reported catalysts used for the conversion are tabulated in Table 8.5. Bordoloi et al. investigated that the reaction of benzaldehyde (13) and acetophenone (107) in stoichiometric-catalyzed MMPA in aqueous medium gave chalcone derivatives (108). The authors were delighted to discover an exceptional result, when they performed the reaction solvent-less in 15 mg of MMPA (Figure 8.51) [109]. The authors reported a range of chalcone derivative synthesis using the most optimal and favorable reaction-condition-catalyzed MMPA or MCPA catalysts. Various structurally and electronically distinct acetophenones are reacted with various O CHO

CH3 + R

1

R

107

R Banana peel ash Solvent free RT

1

R

O

13

108 1

(R= aromatic and R = CH3, OCH3, F, Cl, OH, NO2) Figure 8.51: Preparation of chalcone using banana peel ash.

8.2 Multicomponent reactions

317

benzaldehyde derivatives at rt, yielding 2-hydroxylchalcone in 10–24 min [109]. The derivative of 2-hydroxy-chalcones has a wide range of bioactivity with antioxidant, lipoxygenase (LOX) inhibitory, and more pharmacological applications, as reported [107]. 8.2.3.2 Carbon–heteroatom bond formation and miscellaneous reactions Lalitha and coworkers reported a one-pot cyclocondensation of aromatic aldehydes (13), phthalhydrazide (31), and cyanoacetamide (109) in a solvent-less, efficient, and catalyzed fish-scale hydroxyapatite (FS-HAP) for 3-amino-1H-pyrazolo[1,2-b]phthalazine2-carboxamide (110) synthesis. The authors were able to produce impressive product yields in a short time, and the catalyst was recycled (Figure 8.52) [110]. These derivatives showed antibacterial activity against Gram-negative (Serratia marcescens, B) and Grampositive (Bacillus cereus, Bacillus. aryabhattai, Bacillus. megaterium, and Staphylococus aureus) microorganisms. Pseudomonas putida, E. coli, and E. cloacae bacteria were reported. Patil et al. demonstrated waste freshwater mussel shell to design cost-effective and eco-friendly heterogeneous base catalyst to synthesize 4H-pyrans (112) using the substrates 13, 27, and 76 in aqueous medium at rt. The same catalyst was also used to synthesize 2-arylidenemalononitrile (13 and 27), followed by the reaction with 45 giving the product 4H-pyran (111) (Figure 8.53) [111]. The transesterification step decreases the vegetable oil viscosity and makes them suitable for use in conventional diesel engines, in which the triglyceride molecules of oil/fat (113) reaction with alcohol (114) in the presence of Musa acuminata banana trunk ash (MBTA) gave fatty acid methyl esters (115, 116, and 117) as well as glycerol (118) byproducts (Figure 8.54). This transformation can be carried out using a variety of alcohol such as ethanol, methanol, amyl alcohol, and other alcohols. However, the authors revealed methanol to be a more suitable product to achieve in terms of efficiency, eco-friendly metrics, and cost [112]. Further the same authors designed waste banana peel ash biomass-derived heterogeneous catalyst for the transformation of soybean oil into biodiesel. R CHO

O NH + NH

+ R

O 31

O CONH2

13

CN 109

FS-HAP Solvent-free, 110 °C

O

N N O

NH2 NH2

110

(R= aromatic) Figure 8.52: FS-HAP-catalyzed synthesis of pyrazolo-phthalazine derivatives.

318

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

O O

R O

O

CN

111

O

45

NH2

CMS, Water

O

O H

R

R OEt

CN

+ NC

O

76

CN

EtO

CMS, Water

O

27

13

NH2

112

(R= aryl) Figure 8.53: Synthesis of 4H-pyran derivatives using CMS catalyst in aqueous medium. O R1 O O 1

R

O

OMe

115 R3 O

O

2

R

+ MeOH

O

Musa acuminate trunk ash (MBTA)

H2C-OH

O R2 OMe 116

Room temperature

114

+

HC-OH H2C-OH

O

113 3

R

118 OMe

117 1

(R , R2 and R3 = alkyl) Figure 8.54: Synthesis of biodiesel by transesterification of soybean oil using MBTA.

The optimized reaction condition resulted in high biodiesel output isolated up to 98.95%. The catalyst developed lots more advantages of being a bio-waste, inexpensive, biogenic, efficient, and green catalyst for biodiesel synthesis on a large-scale production, as reported [112]. Gohain and coworkers studied M. balbisiana Colla peel ash for eco-friendly and effective solid-base-catalyzed reaction of triglyceride (119) and methanol (120), thus producing biodiesel (fatty acid methyl esters) (121) and glycerol (122) (Figure 8.55) [113]. Rokhum et al. reported the transesterification reaction of glycerol and dimethyl carbonate using MAPA as a heterogeneous catalyst under microwave irradiation

O

O

O

R1 H2 O C O + CHO R2 R3

HO CH2 + HO CH R2 CH2 O HO

H3C 3 H3C OH

Catalyst

R1 O

O H3C

120

O H3C

R3

122

O 119

121

(R1, R2 and R3 = alkyl)

Figure 8.55: Biodiesel produced from biomass-waste-based solid catalysts.

8.2 Multicomponent reactions

319

O O

OH HO

O

OH 123

MAPA 75 °C

+ O H3CO

OH 125 + MeOH 114

OCH3

Figure 8.56: Formation of glycerol carbonate by transesterification of glycerol and DMC.

124

R2

OH 1

Banana peel ash O2 (1 atm)

R

O

R2

O R1

RT

O

125

126

(R1= aromatic, and R2 = aryl)

Figure 8.57: Preparation of chalcone and flavone derivatives via Claisen-Schmidt reaction.

condition. The authors claimed that the developed method has advantages of renewable, sustainable, and environment-friendly heterogeneous catalysts. The reaction performed in a 10 mL microwave tube containing glycerol (123), DMC (124), and MAPA subjected to irradiation gave product 125 (Figure 8.56) [114]. Bordoloi et al. synthesized 2-hydroxylchalcone (125) via cross-Aldol reaction of acetophenone derivatives with aromatic aldehydes in MMPA and MCPA catalytic system with oxygen balloon (1 atm) at rt, thus giving excellent product isolation. The flavone derivatives were easily generated (126) in banana peel ash-O2 unique catalytic system with intermediate chalcone derivatives (125), giving excellent flavone derivative isolation (Figure 8.57) [109]. Recently, Kamble et al. reported most convenient and environment-friendly onepot cycloaddition of aryl aldehyde (13), malononitrile (27), and dimedone/barbituric acid (45/128) in WELPSA, which gave tetrahydrobenzo[b]pyran (128) and pyrano [2,3-d]pyrimidinones (127). Further, the authors studied prepared derivatives for SARS-CoV-2 virus inhibition studies and showed a comparable inhibition activity with the reference drug used (Figure 8.58) [115]. R

O H

O H O

CN

N N H

O 127

NH2

N

N

O

R

H O

CHO

128 WELPSA, H2O MW

O 45

CN

WELPSA, H2O MW

+ R 13

O

CN

27

O CN O

NH2

128

(R= aromatic) Figure 8.58: WELPSA-catalyzed synthesis of pyrans and pyrimidinones.

320

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

8.3 Future perspectives and challenges of agrowaste catalyst Agro-waste-based catalysts in recent years gained much attention of organic chemists as an alternative substitute for many synthetic reagents/catalysts in the organic synthesis, as they fulfill green chemistry principles. In comparison with chemical reagents or catalysts, in agro-waste, the materials are derived from the agricultural activities that produced large quantities as a source of “waste to wealth concept” and are alternative routes that can replace environmentally hazardous catalysts and solvents in terms of being less toxic, biodegradable, noncorrosive, inexpensive, and abundantly large. Recently, a researcher established this dual role agro-waste-based catalytic systems in terms of catalyst as well as a solvent media, gaining a lot more interest of organic chemists as an outstanding alternative tool for eco-friendly organic synthesis. Samples of reaction types including oxidation, multicomponent, deprotection, condensation, hydroxylation, transesterification, cycloaddition, dehydration, and other important C–C and C–X (heteroatom) bond forming reactions have successfully demonstrated both homogeneous and heterogenized agro-waste-derived catalytic medium performed under various reaction conditions. In bulk scale catalytic protocol, the most important accepting factors safety and cost, critical on less turnover limiting and discourage to use in the industrial applications. Because agro-waste-derived solvent catalytic systems are often inexpensive than conventional organic or inorganic reagents used, they can also be employed in larger quantities, and this area needs to be optimized. Moreover, it is widely recommended that manufacturing bulk fine chemicals and active pharmaceuticals that can follow green chemistry principles of eco-friendly protocol can be achieved by using this agro-waste-assisted catalyst. In future, academic research labs and chemical industries can adopt this new approach for bulk production of fine chemicals, which will serve our aim of reducing global warming and environmentally benign process development.

8.4 Conclusions The backbone of synthetic chemistry is the construction of C–C and C–X (heteroatom) bond formations. Organic chemists are striving to develop everyday novel methodologies of bond-making reactions since they played an important role in the development of a variety of structurally diverse substrates. On the other side, organic chemists are constantly innovating alternative chemical processes to make more sustainable and eco-friendly processes in order to avoid the ever-increasing chemical emission and hazardous chemical entering into the environment. Thus, the development of greener catalytic reactions has demonstrated a massive uptick in the ability to construct C–C

List of abbreviations

321

and C–X (heteroatom) bond reactions under green chemistry protocol. In literature, greener sustainable approaches are classified and reported to be solvent-free, ionic liquids, microwave, ball milling, one-pot reactions, ultrasound, and water medium as the major areas covered under green chemistry protocol. Recently agro-waste-based homogeneous and heterogeneous catalytic media emerged as a sustainable greener catalytic solvent media employed for many organic reaction transformations. Agro-waste is the after-harvesting agricultural products that resulted in feedstock (agricultural residues), for which diverse applications have been discovered recently. The chemists also outlined that the added advantages of agrowaste emerged an alternative source for eco-friendly and inexpensive process of waste management. The recent trends around the globe are focused to transform waste into wealth concepts to achieve useful products for various application purposes. Agrowaste-derived ashes and aqueous extracted medium are successfully studied recently as a heterogeneous or homogenous base catalyst in various organic transformations. Agro-waste-derived catalytic medium received more importance due to its high abundance, inexpensive, facileness, nontoxic, easy to handle, biodegradable, and ecofriendly properties. Further, this article will not be exhaustive, focusing instead on a few instances of agro-waste-based homogeneous and heterogeneous importance of organic synthesis, especially used in the construction of bioactive molecule synthesis via carbon–carbon (C–C) and carbon–heteroatom (C–X) bond formation, as discussed.

List of abbreviations AWEs WEB Pd(OAc)2 EtOH WERSA PrOH Rt H2O2 CH3NO2 WEPBA WETSA FS-HAP WEOPA WEPPA APP WEP WEOP WEOFPA NBS WET

Agro-waste extracts Water extract of banana peel ash Palladium(II)acetate Ethanol Water extract of rice straw ash Isopropyl alcohol Room temperature Hydrogen peroxide Nitromethane Water extract of waste papaya bark ash Water extract of Tamarindus indica seed ash Fish-scale hydroxyapatite Water extract of onion peel ash Water extract of pomelo peel ash Ash of pomegranate peels Water extract of pomelo Water extract of onion peel Water extract of orange fruit peel ash N-bromosuccinimide Water extract of teak leaf (Tectona grandis) ash

322

8 Synthesis of bioactive scaffolds catalyzed by agro-waste

MAPA MBTA MMPA MCPA WEMPA WEMFSA WENBA WEPPA EDC. HCl WELFSA DHPM CMS CBPA BFE CPS WHA BMN GC-MS WO SO DMC GC BPA RHA

Musa acuminata (banana) peel ash Musa acuminata banana trunk ash Musa Malbhog peel ash Musa Champa peel ash Water extract of mango peel ash Water extract of muskmelon fruit shell ash Water extract of Nilgiri bark ash (Eucalyptus) Water extract of pomegranate peel ash 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide. Hydrochloride Water extract of lemon fruit shell ash 3,4-dihydropyrimidin-2(1H)ones/(thiones) Calcined mussel shell Calcined burnt peel ash Bael fruit extract Carica papaya stem Water hyacinth ash Benzylidenemalononitrile Gas chromatography-mass spectrometry Waste cooking oil Scenedesmus obliquus Dimethyl carbonate Glycerol carbonate Banana peel ash Rice husk ash

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Arvind Singh, Bhupinder Kaur, Aditi Sharma, Anu Priya, Manmeet Kaur, Mussarat Shamim and Bubun Banerjee*

9 One-pot multi-component synthesis of diverse bioactive heterocyclic scaffolds involving 6-aminouracil or its N-methyl derivatives as a versatile reagent Abstract: The present review summarizes all the multi-component reaction strategies reported during last two decades for the synthesis of diverse bioactive heterocyclic scaffolds involving 6-aminouracil or its N-methyl derivatives. Keywords: 6-amino-1,3-dimethyl uracil; 6-aminouracil; atom efficient; multi-component reactions; one-pot synthesis; sustainable synthesis.

9.1 Introduction Multi-component reaction strategies (MCRs) are regarded as an important tool for synthesizing structurally diverse biologically promising molecular entities. Constant efforts have been made during last two decades to sharpen this tool. One-pot multicomponent reaction strategy fulfilling some of the goals of ‘green and sustainable chemistry’ by offering a number of advantages which include operational simplicity, atom-economic, energy efficient, minimization of the purification processes etc. [1–3]. On the other hand, heterocycles are considered as the backbone of organic compounds [4–10]. Majority of the commercially available drugs are found to consist of different heterocyclic scaffolds. Heterocyclic skeletons are also very common in naturally occurring compounds which showed immense biological activities such as cytotoxic [11], anticancer [12], anti-malarial [13], anti-HIV [14], anti-inflammatory [15], anti-hyperglycemic and anti-dyslipidemic [16], anti-microbial [17], along with antineurodegenerative disorders [18] and many more [19, 20]. As a result, designing new

*Corresponding author: Bubun Banerjee, Department of Chemistry, Akal University, Talwandi Sabo, Bathinda, Punjab 151302, India, E-mail: [email protected] Arvind Singh, Bhupinder Kaur, Aditi Sharma, Anu Priya and Manmeet Kaur, Department of Chemistry, Akal University, Talwandi Sabo, Bathinda, Punjab 151302, India Mussarat Shamim, Department of Chemistry, University of Jammu, Jammu, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: A. Singh, B. Kaur, A. Sharma, A. Priya, M. Kaur, M. Shamim and B. Banerjee “One-pot multi-component synthesis of diverse bioactive heterocyclic scaffolds involving 6-aminouracil or its N-methyl derivatives as a versatile reagent” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0098 | https://doi.org/10.1515/9783110797428-009

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synthetic strategy for the synthesis of bioactive heterocycles is considered one of the thrusting research fields [21–24]. Among many others, 6-aminouracil and its N-methyl derivatives have been used as versatile building blocks for the several bioactive nitrogen containing heterocycles [25, 26]. These are being used as an important starting component for the synthesis of many purine-based drugs, such as theobromine, caffeine, theophylline, and penciclovir [27, 28]. A number of other bioactive heterocyclic skeletons such as pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine-diones, isoxazolo [5,4-b]quinolines, pyrimido[4,5-b]quinolines, 1,4-dihydropyridines, pyrido[2,3-d]pyrimidines, naphthopyranopyrimidines, pyrrolo[2,3-d]pyrimidines, pyrimido[4,5-d] pyrimidones etc. were also synthesized starting from 6-aminouracil or its N-methyl derivatives as one of the important component. Many multi-component atom-economic strategies were designed starting from 6-aminouracil or its N-methyl derivatives [29, 30]. The present review summarizes all the multi-component reaction strategies reported during last two decades for the synthesis of diverse bioactive heterocyclic scaffolds involving 6-aminouracil or its N-methyl derivatives.

9.2 Synthesis of heterocycles involving 6-amino1,3-dimethyl uracil via MCR in water This section deals with the synthesis of various heterocyclic scaffolds utilizing 6-amino-1,3-dimethyl uracil or its derivatives in aqueous medium.

9.2.1 Synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidinediones In 2016, Daraie and Heravi [31] reported a facile and aqueous-mediated one-pot fourcomponent protocol for the efficient synthesis pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine-diones (5) from the reactions of 6-amino-1,3-dimethyl uracil (1), substituted benzaldehydes (2), hydrazine hydrate (3) and ethyl acetoacetate (4) in the presence of a catalytic amount of either L-proline or triethyl amine (TEA) as green catalysts under refluxed conditions (Figure 9.1). Use of metal-free organocatalysts, high atom economy, and aqueous medium are some of the major advantages of this method.

9.2.2 Synthesis of Spiro[pyrimido[4,5-b]quinoline-5,5-pyrrolo [2,3-d]pyrimidine]-pentaones Bazgir and his group [32] reported a simple, environmentally benign, efficient method for the aqueous mediated unconventional synthesis of spiro[pyrimido[4,5-b]quinoline5,5′-pyrrolo[2,3-d]pyrimidine] derivatives (7) via the pseudo three-component reactions

9.2 Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR in water

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Figure 9.1: Four-component synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine-diones.

between two equivalents of 6-amino-uracils (1) and one equivalent of isatin or substituted isatins (6) in the presence of a catalytic amount of p-toluenesulfonic acid under refluxed conditions (Figure 9.2). The mechanism of the formation of the product is shown in Figure 9.3. Anti-bacterial activities of the synthesized compounds were evaluated and some of them showed promising efficacies. Little bit lower products were isolated when they carried out the same reactions in refluxing ethanol [33].

Figure 9.2: Synthesis of spiro[pyrimido[4,5-b]quinoline-5,5-pyrrolo[2,3-d]pyrimidine] derivatives.

Figure 9.3: Plausible mechanism of the formation of spiro[pyrimido[4,5-b]quinoline-5,5-pyrrolo[2,3d]-pyrimidines].

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9.2.3 Synthesis of isoxazolo[5,4-b]quinolin-4-yl)pyrimidine2,4(1H,3H)-diones and isoxazolo[5,4-b]quinolin-4-yl)-1Hpyrazol-5-amines Poomathi et al. [34] developed a simple, facile and aqueous mediated approach for the efficient synthesis of novel isoxazolo[5,4-b]quinolin-4-yl)pyrimidine-2,4(1H,3H)-diones (9) via the one-pot three component reactions of 6-amino-uracils (1), isatin or 5-substituted isatins (6) and 3-phenylisoxazol-5(4H)-one (8) in the presence of a catalytic amount of p-toluenesulphonic acid as catalyst under refluxed conditions (Figure 9.4). It was proposed that the reaction underwent through the cleavage of the isatin C–N bond followed by ring expansion reaction (Figure 9.5). Interestingly, under the same conditions, reactions with 6-amino-uracils (1), N-substituted isatins (6a) and

Figure 9.4: Synthesis of isoxazolo[5,4-b]quinolin-4-yl)pyrimidine-2,4(1H,3H)-diones.

Figure 9.5: Proposed mechanism for the formation of isoxazolo[5,4-b]quinolin-4-yl)pyrimidine2,4(1H,3H)-diones.

9.2 Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR in water

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Figure 9.6: Three-component synthesis of isoxazolo[5,4-b]quinolin-4-yl)-1H-pyrazol-5-amines.

3-phenylisoxazol-5(4H)-one (8) afforded isoxazolo[5,4-b]quinolin-4-yl)-1H-pyrazol5-amines (10) in excellent yields (Figure 9.6). All the reactions were completed within 5 h and the synthesized compounds were isolated pure just by simple filtration. High regioselectivity is one of the major advantages of this developed protocol.

9.2.4 Synthesis of functionalized dihydropyrido[2,3-d]pyrimidines Naidu et al. [35] reported a simple and aqueous mediated protocol for the efficient synthesis of a series of functionalized dihydropyrido[2,3-d]pyrimidine derivatives (12) via one-pot three-component reactions between 6-amino-uracils (1), aromatic aldehydes (2) and 3-cyanoacetyl indole (11) in the presence of a catalytic amount of indium trichloride under refluxed conditions (Figure 9.7). Under the same optimized conditions, 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones (1a) were also underwent smoothly and afforded the desired product in excellent yields.

9.2.5 Synthesis of polyfunctionalized pyrido[2,3-d]pyrimidines Starting from isatins (6), 1,3-dicarbonyl compounds (13) and 6-aminouracil (1), an efficient PEG-OSO3H mediated one-pot three-component domino coupling reaction was developed for the synthesis of a series of spirooxindoline fused pyrido[2,3-d] pyrimidines (14) in water at 70 °C (Figure 9.8) [36]. A number of 1,3-dicarbonyl compounds (13) such as dimedone (13a) cyclohexane-1,3-dione (13b), indane-1,3-dione (13c) and

Figure 9.7: InCl3 catalyzed synthesis of functionalized dihydropyrido[2,3-d]pyrimidines in water.

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Figure 9.8: PEG-OSO3H catalyzed synthesis of spirooxindoline fused pyrido[2,3-d]pyrimidines.

1,3-dimethylbarbituric acid (13d) were employed and interestingly under the same optimized conditions all of them afforded the desired products in good to excellent yields. After completion of the reaction, the catalyst was recovered by the evaporation of water under reduced pressure. The recovered catalyst was washed thoroughly and recycled for six successive runs without any significant loss in its catalytic efficiency. Lu and Cai [37] reported PEG-200 (polyethylene glycol) promoted facile synthesis of spiro[benzo[h]pyrimido[4,5-b]quinoline-7,3′-indoline] derivatives (14a) via the one-pot three-component reactions of isatins (6), 2-hydroxy-1,4-naphthaquinone (13e) and 6-aminouracil (1) in water at 80 °C (Figure 9.9). Under the same catalytic conditions, reactions with aldehydes (2), 1,3-dicarbonyl compounds (13) and 6-aminouracil (1) afforded either

Figure 9.9: PEG-200 promoted catalyzed synthesis of spirooxindoline fused pyrido[2,3-d]pyrimidines.

Figure 9.10: PEG-200 promoted catalyzed synthesis of polyfunctionalized pyrido[2,3-d]pyrimidines.

9.3 Solvent-free synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR

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polyfunctionalized pyrido[2,3-d]pyrimidines (15) or the corresponding uncyclized adducts (16) in excellent yields (Figure 9.10). By using various 1,3-dicarbonyl species (13), Tanifum et al. [38] synthesized another series of structurally diverse polyfunctionalized pyridopyrimidine derivatives in acetic acid medium. They also evaluated the ability of the synthesized compounds to inhibit cyclic nucleotide synthesis in the presence of stable toxin of Escherichia coli and some of the compounds showed promising results. Agarwal et al. [39] prepared another series of dihydropyrido[2,3-d]pyrimidine derivatives in boiling acetic acid. In another study, the same group evaluated in vitro anti-leishmanial activity of a series of dihydropyrido[2,3-d]pyrimidine derivatives in promastigote and amastigote models and found prominent results [40].

9.2.6 Synthesis of 5-aryl-pyrimido[4,5-b]quinoline-2,4,6-triones Using a catalytic amount of indium trichloride as catalyst, a simple and facile one-pot three-component reaction protocol was developed by Khurana et al. [41] for the combinatorial synthesis of biologically promising 5-aryl-pyrimido[4,5-b]quinoline2,4,6-triones (17) from the reactions of aldehydes (2), dimedone (13a) and 6-amino1,3-dimethyl uracil (1) in water under refluxed conditions (Figure 9.11). Authors were able to isolate the intermediate 18. No tedious column chromatographic separation was required as all the synthesized compounds were isolated pure just by simple filtration.

9.3 Solvent-free synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR This section summarizes the literature related to the synthesis of various heterocyclic scaffolds utilizing 6-amino-1,3-dimethyl uracil or its derivatives under solvent-free conditions.

Figure 9.11: Synthesis of 5-aryl-pyrimido[4,5-b]quinoline-2,4,6-triones in water.

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9.3.1 Synthesis of novel pyrimidinedione derivatives In 2013, Abdolmohammadi et al. [42] carried out a series of reactions between aldehydes (2), various 1,3-dicarbonyl compounds (13g, 13c, 13a, 13f) and 6-aminouracil (1) in the presence of a catalytic amount of Zr(HSO4)4 under solvent-free conditions at 80 °C (Figure 9.12). Reactions with aldehydes (5), 6-aminouracil (1) and barbituric acid (13g) or indane-1,3-dione (13c) undergoes cyclization followed by aromatization which afforded the corresponding pyrimidine derivatives i.e., pyrimido[5′,4′:5,6]pyrido[2,3-d] pyrimidines (19) or indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidines (20), respectively, in excellent yields. Interestingly, under the optimized conditions, reactions with dimedone (13a) afforded the corresponding 5-aryl-pyrimido[4,5-b]quinoline-2,4,6-triones (17) whereas 4-hydroxycoumarin (13f ) produced the corresponding uncyclized adducts (16) (Figure 9.12). In 2015, Azev et al. [43] synthesizes 5-alkyl-1,3,7,9-tetramethyl2,4,6,8-tetraoxopyrido[2,3-d][6,5-d’]dipyrimidine derivatives (19a) from the one-pot

Figure 9.12: Zr(HSO4)4 catalyzed synthesis of novel pyrimidinediones under neat conditions.

9.3 Solvent-free synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR

339

Figure 9.13: Formic acid catalyzed synthesis of 5-alkyl-1,3,7,9-tetramethyl-2,4,6,8-tetraoxopyrido [2,3-d][6,5-d’]dipyrimidine derivative.

pseudo three-component reactions of two equivalents of alkanals (butanal or pentanal) (2) and one equivalent of 6-amino-1,3-dimethyluracil (1) using formic acid as catalyst under solvent-free conditions at 50 °C (Figure 9.13).

9.3.2 Synthesis of pyrimido[4,5-d]pyrimidine-2,4-diones In 2008, Dabiri et al. [44] reported facile synthesis of a series of pyrimido[4,5-d]pyrimidine-2,4-(1H,3H,5H,8H)-dione derivatives (22) via a one-pot three-component, condensation reactions between aromatic aldehydes (2), 6-amino-1,3-dimethyluracil (1) and 2-benzylisothiourea hydrochloride (21) under solvent-free conditions at 120 °C (Figure 9.14). Aldehydes with both electron donating as well as withdrawing substituent underwent smoothly and afforded the desired products in excellent yields.

9.3.3 Synthesis of naphthopyranopyrimidines In 2015, Sajadikhah [45] developed a simple and straightforward protocol for the efficient synthesis of a series of 8,10-dimethyl-12-aryl-12H-naphtho[1′,2′:5,6]pyrano[2,3-d] pyrimidine-9,11-diones (24) via one-pot three-component equimolar reactions between aromatic aldehydes (2), 6-amino-1,3-dimethyl uracil (1) and β-naphthol (21) in the

Figure 9.14: p-toluene sulphonic acid catalyzed synthesis of pyrimido[4,5-d]pyrimidine-2,4-diones.

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Figure 9.15: Synthesis of naphthopyranopyrimidines under neat conditions.

presence of a catalytic amount of Al(H2PO4)3 as catalyst under neat conditions at 110 °C (Figure 9.15). All the reactions were completed within just 75 min and the desired products afforded in excellent yields. Three years later, Sadeh et al. [46] also synthesized another series of 8,10-dimethyl-12-aryl-12H-naphtho[1′,2′:5,6]pyrano[2,3-d]pyrimidine-9,11-dione derivatives in excellent yields by using a formic acid as catalyst under solvent-free conditions at 90 °C (Figure 9.15).

9.3.4 Synthesis of spiro pyridodipyrimidines Mohammadizadeh et al. [47] demonstrated a facile, rapid and microwave-assisted one-pot pseudo three-component protocol for the efficient synthesis of spiro [indoline-3,5′-pyrido[2,3-d:4,5-d′]dipyrimidine] derivatives (25) from the reactions of two equivalents of 1,3-di-methyl-6-aminouracil (1) and one equivalent of isatin or substituted isatins (6) under solvent-free conditions (Figure 9.16). The proposed mechanism of this transformation is shown in Figure 9.17. Under the same optimized conditions, ninhydrin (26) and acenaphthoquinone (27) were also underwent smoothly and afforded the corresponding 1′,3′,7′,9′-tetramethyl-1′H-spiro[indene2,5′-pyrido[2,3-d:4,5-d’]dipyrimidine]-1,2′,3,4′,8′,10′(3′H,6′H,7′H,9′H)-hexaone (28) and 1′,3′,7′,9′-tetramethyl-1′H,2H-spiro[acenaphthylene-1,5′-pyrido[2,3-d:4,5-d′]dipyrimidine]2,2′,4′,8′,10′(3′H,6′H,7′H,9′H)-pentaone (29), respectively, in excellent yields (Figure 9.16). Under microwave-irradiated conditions, the reaction was so rapid that all the reactions were completed within just 3 min. The same reactions when carried out under conventional refluxed conditions in ethanol required 4–5 h to complete.

9.3 Solvent-free synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR

Figure 9.16: Synthesis of spiro pyridodipyrimidines under microwave irradiated neat conditions.

Figure 9.17: Proposed mechanism for the synthesis of spiro[indoline-3,5′-pyrido[2,3-d:4,5-d′]dipyrimidine] derivatives.

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Figure 9.18: Microwave-assisted synthesis of 7-amino-5-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles under neat conditions.

9.3.5 Synthesis of pyrido[2,3-d]pyrimidines Synthesis of 7-amino-5-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (31) was achieved from the reactions of 6-aminouracils (1), benzaldehyde (2) and malononitrile (30) under microwave-assisted solvent-free conditions (Figure 9.18) [48].

9.4 Synthesis of heterocycles involving 6-amino1,3-dimethyl uracil via MCR in alcohol This section deals with the alcohol mediated synthesis of various heterocyclic scaffolds utilizing 6-amino-1,3-dimethyl uracil or its derivatives.

9.4.1 Synthesis of pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones Azizian et al. [49] demonstrated an unconventional catalyst-free approach for the efficient synthesis of some novel pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones (32) from the reactions of ninhydrin (26), 6-aminouracils (1) and alkyl cyanoacetate (30a) in ethanol under refluxed conditions (Figure 9.19). Proposed mechanism is shown in Figure 9.20.

Figure 9.19: Synthesis of pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones.

9.4 Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR in alcohol

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Figure 9.20: Proposed mechanism for the catalyst-free synthesis of pyrido[2,3-d]pyrimidine(1H,3H)2,4-diones.

9.4.2 Synthesis of fused pyridines In 2016, Upadhyay et al. [50] reported one-pot three-component synthesis of pyrido[2,3d]pyrimidine derivatives (33) via electrochemically induced condensation of substituted benzaldehydes (2), dimedone (13a) and 6-amino uracil (1) in the presence of NaBr as supporting electrolyte in ethanol (Figure 9.21). The electrolytic reaction was carried out at a constant current of 50 mA. All the reactions were completed within just 30 min and afforded the desired products with excellent yields. Earlier, in 2007, Dabiri et al. [51] carried out the same reactions using p-toluenesulfonic acid as catalyst in ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) as solvent at 100 °C.

9.4.3 Synthesis of substituted pyrimido[4,5-d]pyrimidones Hamama et al. [52] developed a catalyst-free pseudo four component reaction protocol for the efficient synthesis of a series of pyrimido[4,5-d]pyrimidin-2,4-dione derivatives (35) from the reactions of one equivalent of 6-amino-1,3-dimethyluracil (1), one equivalent of aryl amines (34) and two equivalents of various aldehydes (2) in ethanol at 35 °C (Figure 9.22). All the reactions were completed within 2 h.

Figure 9.21: Synthesis of 8,9-dihydro-1,3,8,8-tetramethyl-5-phenylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,7H)-trione.

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Figure 9.22: Catalyst-free synthesis of pyrimido[4,5-d]pyrimidin-2,4-dione derivatives.

9.4.4 Synthesis of 6-(phenylsulfonyl)-5-(aryl)-6,8adihydropyrido[2,3-d]pyrimidine-2,4-diones In 2015, Dommaraju et al. [53] reported an efficient method for the unexpected formation of a series of 6-(phenylsulfonyl)-5-(aryl)-6,8a-dihydropyrido[2,3-d]pyrimidine2,4-diones (37) via one-pot three-component reactions between 6-aminouracil (1), sulfonyl acetonitrile (36) and aromatic aldehydes (2) in the presence of a catalytic amount of triethylamine in ethanol under refluxed conditions (Figure 9.23). Under the same optimized conditions, 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones (1a) were also afforded the desired products. Synthesized compounds were well characterized and the structures were established by using IR, NMR and HRMS analysis. It was proposed that the reaction undergoes through the domino Knoevenagel condensation and then Michael addition followed by cascade cyclization pathway (Figure 9.24).

9.4.5 Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines Rad-Moghadam and Azimi [54] reported a novel and facile one-pot three-component protocol for the efficient synthesis of 5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives (39) in good to excellent yields via the sequential reactions of isatin (6), acetophenone (38) and 6-amino-uracils (1) in ethanol under refluxed conditions (Figure 9.25). Formation of the products was accomplished through

Figure 9.23: Synthesis of 6-(phenylsulfonyl)-5-(aryl)-6,8a-dihydropyrido[2,3-d]pyrimidine-2,4-diones.

9.4 Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR in alcohol

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Figure 9.24: Plausible mechanism for the synthesis of 6-(phenylsulfonyl)-5-(aryl)-6,8adihydropyrido[2,3-d]pyrimidine-2,4-diones.

the sequential tandem manner under two different pH. It was proposed that the first step was catalyzed by piperidine whereas p-toluenesulfonic acid played the catalytic role in the second step to afford the desired product (Figure 9.26). In vitro anti-microbial activity of the synthesized compounds was screened and few of them showed promising efficacies.

9.4.6 Synthesis of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d] pyrimidines Quiroga et al. [55] synthesized a series of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d] pyrimidine derivatives (41) in moderate yields via one-pot three-component reactions of dimedone (13a), arylglyoxal (40) and 6-amino-1,3-dimethyl uracil (1) in the presence of a catalytic amount of acetic acid in ethanol under refluxed conditions (Figure 9.27). Under the same optimized conditions, 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)ones (1a) were also afforded the desired products. Another series of pyrrolo[2,3-d]

Figure 9.25: Synthesis of 2-oxoindolin-3-yl-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-diones.

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Figure 9.26: Proposed mechanism for the synthesis of 2-oxoindolin-3-yl-pyrrolo[2,3-d]pyrimidine2,4(3H,7H)-diones.

pyrimidine derivatives was prepared by Naidu and Bhuyan [56] in acetic acid under microwave-assisted conditions.

9.4.7 Synthesis of pyrido[2,3-d]pyrimidines In 2010, Singh and his research group synthesized a series of pyrido[2,3-d]pyrimidine6-carbodithioates (43) via one-pot, three-component cyclocondensation reactions of β-oxodithioesters (42), aryl aldehydes (2) and 6-amino-1,3-dimethyluracil (1) in the presence of a catalytic amount of silica sulphuric acid as an efficient heterogeneous recyclable catalyst in ethanol under refluxed conditions (Figure 9.28) [57]. Very next year, the same group also reported the synthesis of pyrido[2,3-d]pyrimidine]pyrimidine-6,7-dicarboxylates (45) via another one-pot three-component reactions between 6-amino-1,3-dimethyluracil (1), aldehydes (2), and dialkyl acetylenedicarboxylates (44) using L-proline as catalyst in ethanol under refluxed conditions (Figure 9.29) [58].

Figure 9.27: Synthesis of pyrrolo[2,3-d]pyrimidines under neat conditions.

9.4 Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR in alcohol

347

Figure 9.28: Silica sulfuric acid catalyzed synthesis of pyrido[2,3-d]pyrimidine-6-carbodithioates.

Figure 9.29: Synthesis of pyrido[2,3-d]pyrimidine-6,7-dicarboxylates.

9.4.8 Synthesis of 1,4-dihydrobenzo[b][1,8]-naphthyridines and pyrano[2,3-b]quinolines Catalytic amount of L-proline was also found efficient to catalyze the one-pot three-component regioselective reactions between 6-aminouracils (1), substituted 2-chloroquinoline-3-carbaldehydes (46) and dimedone (13a) which afforded either 1,4-dihydrobenzo[b] [1,8]-naphthyridines (47) or pyrano[2,3-b]quinoline derivatives (48) in good yields in ethanol under refluxed conditions (Figure 9.30) [59]. It was reported that methyl and methoxy substituted 2-chloroquinoline-3-carbaldehydes (46) selectively afforded the corresponding 1,4-dihydrobenzo[b] [1,8]-naphthyridines (47) by following path ‘a’ at the last step where as other 2-chloroquinoline3-carbaldehydes (46) followed the path ‘b’ and thus produced pyrano[2,3-b]

Figure 9.30: Synthesis of benzo[b]pyrimido[5,4-g][1,8]naphthyridines and pyrano[2,3-b]quinolines.

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Figure 9.31: Proposed mechanism for the synthesis of benzo[b]pyrimido[5,4-g][1,8]naphthyridines and pyrano[2,3-b]quinolines.

quinoline derivatives (48) (Figure 9.31). Under the same optimized conditions, reactions of 6-aminouracils (1), 3-methyl-1H-pyrazol-5(4H)-one (49) and substituted 2-chloroquinoline-3-carbaldehydes (46) afforded pyrazolo[4′,3′:5,6]pyrano[2,3-b] quinolin-4-yl)pyrimidines (50) in excellent yields (Figure 9.32).

9.4.9 Synthesis of hexahydropyrimido[4,5-b]-1,8-naphthyridine derivatives Synthesis of some novel biologically promising hexahydropyrimido[4,5-b]-1,8naphthyridine derivatives (52) was achieved via one-pot three-component reactions of 2-cyano-3-(1H-indol-3-yl)-pent-2-enedinitrile (51) or ethyl-2,4-dicyano-3-(1H-indol-

Figure 9.32: Synthesis of pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolin-4-yl)pyrimidines.

9.5 Synthesis of heterocycles involving 6-amino-1,3-dimethyl uracil via MCR in acetic acid

349

Figure 9.33: Synthesis of some novel hexahydropyrimido[4,5-b]-1,8-naphthyridine derivatives.

3-yl)but-2-enoate (51a), 6-amino-1,3-dimethyluracil (1) and aromatic aldehydes (2) (Figure 9.33) [60]. The reaction was catalyzed by triethyl amine in ethanol under refluxed conditions. Initially, the starting compounds 51 and 51a were prepared by using piperidine as catalyst from the reactions of 3-(cyanoacetyl)indoles (11) and malononitrile (32) or ethyl cyanoacetate (32a), respectively.

9.5 Synthesis of heterocycles involving 6-amino1,3-dimethyl uracil via MCR in acetic acid This section summarizes the literature related to the synthesis of various heterocyclic scaffolds utilizing 6-amino-1,3-dimethyl uracil in acetic acid.

9.5.1 Synthesis of naphthaquinone and pyrimidine fused 1,4-dihydropyridines In 2017, Choudhury and his research group [61] designed a facile and rapid microwave assisted protocol for the efficient synthesis of a series of naphthaquinone and pyrimidine fused 1,4-dihydropyridines (53) via one-pot three-component reactions between 2-hydroxy-1,4-naphthaquinone (13e), 6-amino-1,3-dimethyluracil (1) and aromatic aldehydes (2) in acetic acid-water (1:1 v/v) mixture as solvent (Figure 9.34). The same

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Figure 9.34: Synthesis of naphthaquinone and pyrimidine fused 1,4-dihydropyridines.

reactions under conventional refluxed conditions afforded the acyclic products (54). Aliphatic aldehydes, under the same optimized conditions, also produced the corresponding acyclic trisubstituted methane derivatives (54).

9.5.2 Synthesis of 5-unsubstituted 6-(benzimidazol-2-yl)pyrido [2,3-d]pyrimidino-2,4(1H,3H)-diones Dzvinchuk and Lozinskii [62] reported an unconventional approach for the synthesis of a number of 5-unsubstituted 6-(1H-benzimidazol-2-yl)pyrido[2,3-d]pyrimidino2,4(1H,3H)-dione derivatives (56) via one-pot three-component reactions between 2-acylmethyl-1H-benzimidazoles (55), p-(dimethylamino)benzaldehyde (2a) and 6-amino-1,3-dimethyluracil (1) in acetic acid at 120 °C (Figure 9.35). It was proposed that at the initial stage of the reaction, by following Hantzsch reaction pathway, 1,4-dihydropyridine-bearing compounds (57) were formed which underwent

Figure 9.35: Synthesis of 5-unsubstituted 6-(benzimidazol-2-yl)pyrido[2,3-d]pyrimidino-2,4(1H,3H)diones.

9.6 Conclusions

351

Figure 9.36: Plausible mechanism for the synthesis of 5-unsubstituted 6-(benzimidazol-2-yl)pyrido [2,3-d]pyrimidino-2,4(1H,3H)-diones.

aromatization followed by cleavage of N,N-dimethylaniline to afford the desired products (56) (Figure 9.36). In another report, under the same optimized conditions, they further synthesized another series of 5-unsubstituted 6-(hetroaryl)pyrido[2,3-d] pyrimidino-2,4(1H,3H)-dione derivatives (58) in good to excellent yields [63].

9.6 Conclusions Multi-component reaction strategy is an important tool to design versatile bioactive heterocyclic scaffolds under greener conditions. Many multicomponent reaction protocols are being reported almost every day. In this review we have summarized all the multicomponent reaction protocols reported in the recent past involving 6-aminouracil or its N-methyl derivatives as one of the starting component. A number of bioactive heterocyclic skeletons such as pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine-diones, 1,4-dihydropyridines, isoxazolo[5,4-b]quinolins, naphthopyranopyrimidines, pyrido [2,3-d]pyrimidines, pyrimido[4,5-b]quinolines, pyrrolo[2,3-d]pyrimidines, pyrimido [4,5-d]pyrimidones etc. were synthesized by following multicomponent reaction strategy under various reaction conditions starting from 6-aminouracil or its N-methyl derivatives as one of the important component.

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Acknowledgments: Authors are thankful to Prof. Gurmail Singh, Vice-Chancellor, Akal University for his wholehearted encouragement and support. BB is grateful to Akal University and Kalgidhar Trust, Baru Sahib, India, for the financial assistance.

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36. Paul S, Das AR. Dual role of the polymer supported catalyst PEG-OSO3H in aqueous reaction medium: synthesis of highly substituted structurally diversified coumarin and uracil fused spirooxindoles. Tetrahedron Lett 2013;54:1149–54. 37. Lu G-P, Cai C. A one-pot, efficient synthesis of polyfunctionalized pyrido[2,3-d]pyrimidines and uncyclized adducts by aldehydes, 1,3-dicarbonyl compounds, and 6-aminouracils. J Heterocycl Chem 2014;51:1595–602. 38. Tanifum EA, Kots AY, Choi BK, Murad F, Gilbertson SR. Novel pyridopyrimidine derivatives as inhibitors of stable toxin a (STa) induced cGMP synthesis. Bioorg Med Chem Lett 2009;19: 3067–71. 39. Agarwal A, Chauhan PMS. First report on the abnormal dearylation/alkylation reaction in one‐pot hantzch synthesis with 6‐amino‐1,3‐dimethyl uracil. Synth Commun 2004;34:4447–61. 40. Agarwal A, Ramesh A, Goyal N, Chauhan PMS, Gupta S. Dihydropyrido [2, 3-d] pyrimidines as a new class of antileishmanial agents. Bioorg Med Chem 2005;13:6678–84. 41. Khurana JM, Chaudhary A, Nand B, Lumb A. Aqua mediated indium(III) chloride catalyzed synthesis of fused pyrimidines and pyrazoles. Tetrahedron Lett 2012;53:3018–22. 42. Abdolmohammadi S, Balalaie S, Barari M, Rominger F. Three-component green reaction of arylaldehydes, 6-amino-1,3- dimethyluracil and active methylene compounds catalyzed by Zr(HSO4)4 under solvent-free conditions. Comb Chem High Throughput Screen 2013;16:150–9. 43. Azev YA, Ermakova OS, Gibor AM, Ezhikova MA, Kodess MI, Berseneva VS. Unusual reactions of 6-amino-1,3-dimethyluracil with some aliphatic aldehydes. Mendeleev Commun 2015;25:310–1. 44. Dabiri M, Azimi SC, Arvin-Nezhad H, Bazgir A. An efficient three-component, one-pot synthesis of new pyrimido[4,5-d]pyrimidine-2,4-diones. Heterocycles 2008;75:87–93. 45. Sajadikhah SSA. (H2PO4)3 as an efficient and recyclable catalyst for the one-pot synthesis of naphthopyranopyrimidines. RSC Adv 2015;5:28038–43. 46. Sadeh FN, Lashkari M, Hazeri N, Maghsoodlou MT. Synthesis of naphthopyranopyrimidines using formic acid as effective catalyst under solvent-free conditions. Org Chem Res 2018;4:124–30. 47. Mohammadizadeh MR, Azizian J, Teimouri F, Mohammadi AA, Karimi AR, Tamari E. Reaction of 6-aminouracils - a novel and highly efficient procedure for preparation of some new spiro pyridopyrimidines under classical or microwave-assisted solvent-free conditions. Can J Chem 2008;86:925–9. 48. Devi I, Kumar BSD, Bhuyan PJ. A novel three-component one-pot synthesis of pyrano[2,3-d] pyrimidines and pyrido[2,3-d]pyrimidines using microwave heating in the solid state. Tetrahedron Lett 2003;44:8307–10. 49. Azizian J, Mohammadizadeh MR, Mohammadi AA, Karimi AR, Teimouri F. A novel one-pot procedure for preparation of some new condensed pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones. Heteroat Chem 2007;18:16–8. 50. Upadhyay A, Sharma LK, Singh VK, Singh RKP. An efficient one pot three component synthesis of fused pyridines via electrochemical approach. Tetrahedron Lett 2016;57:5599–604. 51. Dabiri M, Arvin-Nezhad H, Khavasi HR, Bazgir A. A novel and efficient synthesis of pyrimido[4,5-d] pyrimidine2,4,7-trione and pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone derivatives. Tetrahedron 2007;63:1770–4. 52. Hamama WS, Ismail MA, Al-Saman HA, Zoorob HH. Facile construction of substituted pyrimido [4,5-d]pyrimidones by transformation of enaminouracil. J Adv Res 2013;4:115–21. 53. Dommaraju Y, Bora S, Prajapati D. A facile approach to the synthesis of structurally diverse 6,8adihydropyrido[2,3-d]pyrimidine derivatives via a three-component domino reaction. Org Biomol Chem 2015;13:9181–5. 54. Rad-Moghadam K, Azimi SC. Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines via a threecomponent sequential tandem reaction. Tetrahedron 2012;68:9706–12.

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Aparna Das, Ram Naresh Yadav and Bimal Krishna Banik*

10 Conceptual design and cost-efficient environmentally Benign synthesis of betalactams Abstract: Stereoselective preparation of diverse trans and cis β-lactams following different experimental conditions are executed. A variety of circumstances are critically analyzed. It has been found that the stereochemistry of the products depends on a number of parameters including the conditions of the procedures, composition of the Schiff bases and acid chlorides or equivalents, method of addition of the reactants, temperature of the process and nature of the media. Using some of the compounds and methods as described herein, a number of useful chemical transformations for the preparation of heterocycles are achieved. These methods include indium-catalyzed glycosylation of amino β-lactams, preparation of pyrrole-substituted β-lactams, cycloaddition with sterically congested Schiff bases towards β-lactams, Michael reaction for the preparation of polycyclic oxazepenes and synthesis of two chiral isomers of the thienamycin side chain. Most of the products are obtained stereospecifically and in optically active forms. Many reactions described here are catalytic and therefore, these are environmentally friendly. Keywords: β-lactams; catalyst; design; organic molecules; stereochemistry; synthesis.

10.1 Introduction β-Lactams are crucial biologically effective compounds. Many groups have reported the its activities against cancer [1], bacteria [2], fungus [3], and cholesterol absorption inhibitor activity [4]. Besides, activities against inflammations [5], hepatitis [6], analgetic [7] and hyperglycaemia [8] were also reported by several groups. Because of a diverse range of medicinal activities of β-lactams, preparation of these types of molecules as racemic and optically active biologically active compounds is very crucial. Several ways are currently known for the synthesis of β-lactams. For example, cycloaddition reaction [9], hydroxamate method [10], condensation reaction of ester *Corresponding author: Bimal Krishna Banik, Department of Mathematics and Natural Sciences-Core Curriculum, Prince Mohammad Bin Fahd University, Al Khobar, 31952, Kingdom of Saudi Arabia, E-mail: [email protected] Aparna Das, Department of Mathematics and Natural Sciences-Core Curriculum, Prince Mohammad Bin Fahd University, Al Khobar, 31952, Kingdom of Saudi Arabia. https://orcid.org/0000-0002-2502-9446 Ram Naresh Yadav, Department of Chemistry, Faculty of Engineering & Technology, Veer Bahadur Singh Purvanchal University, Jaunpur, Uttar Pradesh, India As per De Gruyter's policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: A. Das, R. N. Yadav and B. K. Banik “Conceptual design and cost-efficient environmentally Benign synthesis of beta-lactams” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0088 | https://doi.org/10.1515/9783110797428-010

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enolate-imine [11], isocyanate-alkene procedure [12], the nitrone-alkyne coupling [13], asymmetric preparation [14] and synthesis induced by polymer [15]. Our research group has presented the preparation of many β-lactams by various methods extensively [1, 16–18]. During our synthetic study, it has come to our attention that depending on the beginning substances and conditions of the experiments the relative and absolute stereochemistry of the products can be altered and thus, various proportions of a single stereoisomer (i.e. cis or trans) of β-lactam may result in from a particular reaction. It is known that both the stereoisomers are equally crucial for the pharmaceutical target. For example, cis amido β-lactam is the main part of penicillin and cephalosporin. But trans β-lactam is the main portion of thienamycin and several other antibiotics. Thus, governing diastereoselectivity (trans or cis) of the lactam’s formation is a crucial task during synthesis. This paper has described the stereoselective synthesis of functionalized β-lactams using numerous circumstances through cycloaddition interaction of Schiff bases and acid chlorides. Moreover, the preparation of diverse molecular structures using the stereodivergent route has also been discussed.

10.2 Synthesis of beta-lactams 10.2.1 Results with acid derivatives under different conditions Staudinger cycloaddition reaction for the synthesis of monocyclic β-lactams was investigated extensively. This reaction mainly required a Schiff base, a tertiary base and an acid chloride or equivalent. As shown in Figure 10.1, the interaction of an acid chloride (1) with a Schiff base/imine (2) in the existence of a tertiary base under suitable conditions produced cis (3) and trans (4) isomers of lactams. The yield of the cis (3) and trans (4) isomers varied with reaction conditions. Based on our contribution in this field, we have synthesized these types of molecules following different methods. These procedures have identified numerous possibilities including the mechanism of these processes.

Figure 10.1: Synthesis of β-lactam isomers 3 and 4 under diverse conditions.

10.2 Synthesis of beta-lactams

359

10.2.1.1 Experiment number 1 Heating Schiff base with an acid chloride in benzene formed trans and cis β-lactams in various ratios. Because of the high boiling, lower pKa (7.61) value and good solubility in organic solvents, NMM (N-methylmorpholine) was considered as a base for the chemical reaction in place of commonly used TEA (trimethylamine). A solvent which is non-polar, for example, benzene was preferred as the medium for reaction and temperature of the reaction was held between 45 °C and 50 °C. Later, it was found that the reaction is not accomplished even after 4 min and it raised a mixture of cis 3 (70%) and trans 4 (30%) β-lactams (Figure 10.1). Therefore, this precondition was favorable for the synthesis of cis-lactams, although most of the starting materials were not consumed. The proportions of the trans and cis-isomers were decided from the coupling constants of the C-4 and C-3 protons of the lactam rings. An identical procedure was followed to assign the stereochemistry of the β-lactam rings in the following experiments. 10.2.1.2 Experiment number 2 A relatively higher temperature was also applied for the formation of β-lactams from the solution of Schiff base and acid chloride. To describe the influence of polarity of the media on selectivity, chlorobenzene was chosen. N-methylmorpholine was taken as a base for this interaction and the reaction was conducted at 95 °C–100 °C. The chemical reaction was performed for 300 s. This raised trans (90–95%) and cis (5−10%) isomers. Hence, the circumstance of the reaction was helpful was for the formulation of trans isomer. 10.2.1.3 Experiment number 3 To identify the effects of the solvent for the synthesis of β-lactam, another experiment was performed solventless. The interaction of acid chloride and imine was performed at 95 °C–100 °C in the existence of N-methylmorpholine in a microwave. It was difficult to note the temperature when the interaction was conducted with a small scale (1 mmol). However, it was done when the method was performed with a higher scale (10 mmol). The process was accomplished within 180 s and it created a mixture of cis (lower amounts, 5–10%) and trans (higher amounts, 90–95%) compounds. It seemed that solvent retards the process. A higher dilution of the reaction mixture was responsible for a slower reaction in the presence of a solvent. 10.2.1.4 Experiment number 4 In order to determine the effects of irradiation from the microwave on the stereochemistry and yield of the β-lactam products, a method was adopted with a preheated oil bath. For this purpose, an oil bath was preheated at 90 °C. The reaction of an acid

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10 Conceptual design and cost-efficient synthesis of beta-lactams

chloride with Schiff bases in the presence of chlorobenzene/NMM at 90 °C using the oil bath as the heating source was performed. It was done for 300 s and it created trans (90–95%) and cis (5–10%) β-lactams. 10.2.1.5 Experiment number 5 In a different variation, an oil bath was considered. During the reaction, the temperature was increased in a gradual manner, from room temperature to 90 °C. NMM and chlorobenzene were taken as the base and solvent. The reaction of the Schiff base with acid chloride was completed within 15 min under this condition and it created a mixture of trans (50%) and cis (50%) isomers. 10.2.1.6 Experiment number 6 One more modification of this method was performed following a one-pot approach (Figure 10.2). For example, benzaldehyde 6 and p-anisidine 5 were used as the reactants with clay. N-methylmorpholine, chlorobenzene and acetoxyacetyl chloride were brought together to the reaction. The reaction was conducted for 120 s in a microwave and trans product was only obtained. The reaction produced a varying proportion of the trans and cis isomers without the application of microwave (for example, at room temperature).

Figure 10.2: Reaction between benzaldehyde and p-anisidine.

10.2.2 Discussions of the results with acid derivatives The findings from different experiments and conditions were intriguing since acetoxy β-lactams are important starting materials. Table 10.1 demonstrated the percentages of the trans and cis products during diverse circumstances. The results indicated that experiments 6(a), 2, 3, and 4 were favored for the preparation of trans β-lactams in good yield. Experiments 6(b) and 1were favored for the preparation of cis isomers. In contrast, experiment 5 was fine for the preparation of trans and cis β-lactams in a mixture. A graphical plot of the β-lactam formation under various methods is given in Figures 10.3–10.5.

10.2 Synthesis of beta-lactams

361

Table .: The cis  and trans  lactams ratios under various methods. Experiments Temperature Time (min)       (a)  (b)

 °C– °C  °C– °C  °C– °C  °C RT –  °C  °C– °C  °C–RT

cis/trans ratio (AcOCHCOCl)

cis/trans ratio (PhOCHCOCl)

cis/trans ratio (BnOCHCOCl)

/ / / / / / /

/ / / / / / /

/ / / / / / /

     – Overnight

cis / trans ra o Vs condi ons cis/trans ra o

2.5 2 1.5 1 0.5 0 -0.5 0

1

2

3

4

5

6

7

Condi ons

Figure 10.3: Graphical representation of the β-lactam formation under 1–5 circumstances with AcOCH2COCl.

cis/trans ra o Vs condi ons

cis/trans ra o

10 8 6 4 2 0 -2 0

1

2

3

4

5

6

7

Condi ons

Figure 10.4: Graphical demonstration of the lactam production under 1–5 circumstances with PhOCH2COCl.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

cis/trans ra o Vs condi ons cis/trans ra o

25 20 15 10 5 0 -5 0

1

2

3

4

5

6

7

Condi ons

Figure 10.5: Graphical demonstration of the lactam production under 1–5 circumstances with BnOCH2COCl.

Additionally, it was observed that the cis lactams do not shift to trans isomers by treating them with N-methylmorpholine in chlorobenzene at 90 °C. These experiments confirmed that cis isomerization to thermodynamically much stable trans compound at high temperature did not take place (Figure 10.6).

Figure 10.6: Reaction of cis β-lactam with NMM/chlorobenzene.

10.2 Synthesis of beta-lactams

363

10.2.2.1 Experiment number 7 Benzyloxyacetyl chloride (7) in reaction with Schiff bases 8 in the existence of N-methylmorpholine and dimethyl-formamide produced trans and cis-β-lactam (9 and 10) in different ratios (Figure 10.7).

Figure 10.7: Synthesis of β-lactam isomers 9 and 10.

Table 10.2 indicated cis/trans ratios from this reaction. The data indicated that cis beta-lactams were preferentially made at relatively low temperatures. In contrast, high-temperature reactions favored trans beta-lactams. Table .: The cis and trans beta-lactams ratios with respect to time. Time (min)

Temperature

     

 °C  °C  °C  °C  °C  °C

cis/trans ratio / / / / / /

cis/trans ra o

Figure 10.8 showed the changes in the cis and trans-compounds production with irradiation of microwave up to 300 s at low power. The data showed that cis and trans amount gradually goes down with time and then becomes stable at 4–5 min. 6 5 4 3 2 1 0 0

1

2

3

4

5

6

Time Figure 10.8: Plot of cis and trans ratio of lactam with the progress of time of exposure to radiation.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

10.2.2.2 Experiment number 8 Phthalimido acetic acid 11 and Schiff base 2 in the existence of chlorobenzene and N-methylmorpholine yielded corresponding trans and cis β-lactam (13 and 12) in diverse ratios (Figure 10.9).

a: R1=Ph, R2=p-Anisyl; b: R1=R2=p-Anisyl Figure 10.9: Reaction of activated phthalimido acetic acid with Schiff base.

10.2.2.3 Experiment number 9 Several acid chlorides with imine 14 (obtained from D-glyceraldehyde) using chlorobenzene and TEA yielded only the corresponding cis lactam (15). At the same time, imine 16 (produced from L-glyceraldehyde) with acid chloride (1) yielded cis lactam (17) with inverse absolute configuration in 100% yield under identical reaction conditions (Figure 10.10).

Figure 10.10: Experiments 9 (a) and 9 (b).

10.2 Synthesis of beta-lactams

365

By selecting pre-assigned stereochemistry of sugar derivatives, stereospecific synthesis of cis β-lactams was performed. For example, D-mannitol derived imines on reaction with acid chloride afforded cis β-lactams as the only products. Notably, these chiral cis β-lactams were unable to isomerize to the trans β-lactams by treating them at high temperatures with an organic base. 10.2.2.4 Experiment number 10 It was also observed that trans isomer 4 is obtained in quantitative amount by slow accession of N-methylmorpholine in dichloromethane to a mixture of the Schiff base 2 and the acid chloride (1a) (Figure 10.11).

Figure 10.11: Experiments 10.

10.2.3 Indium-catalyzed glycosylation of amino β-lactams The phthalimido group in β-lactam was deprotected by two reagents. However, N-methyl hydrazine was the best reagent to obtain cis-amino beta-lactam 19a and 19b (Figure 10.12, Table 10.3, Method A and Method B). These methods were highly successful to obtain both stereoisomer (3R, 4S) and (3R, 4R) of optically active betalactams. It is important to note this method was applied to prepare a number of racemic 3-amino β-lactams also.

Figure 10.12: Deprotection of N-phthalimido group: Preparation of 3-amino β-lactams.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

Table .: Deprotection of N-phthalimido group in β-lactams a and b. Entry

Method A Reagent

Solvent Equiv.



Methyl amine (% in HO)

Ethanol

.



Methyl amine (% in EtOH)

Ethanol

.



Methyl amine (% in HO)

THF

.



Methyl amine (% in EtOH)

THF

.

T( C)

 °C – rt

a

Method B Time Yield (h) (%)  a () b ()  a () b () . a () b () . a () b ()

Reagent

Solvent Equiv.

NHNH.HO CHCl

.

NHNH.HO THF

.

NHNH.HO EtOH

.

NHNH.HO MeOH

.

Time Yield (h) (%)a  a () b ()  a () b ()  a () b ()  a () b ()

 °C – rt

isolated yield after column chromatography.

Because of the low nucleophilicity of the amino group, the reaction of the amino β-lactams with unsaturated sugar (glycal) was not possible even in the presence of an acid or an activator. This type of procedure was used extensively with hydroxyl derivatives. It was realized that a highly reactive sugar component is necessary for effective glycosylation of amino β-lactams. On this basis, an epoxide 21 of the sugar by the oxidation of the alkene group of glycal 20 was prepared in an excellent yield (Figure 10.13). Finally, the sugar epoxide 21 was reacted with amino β-lactams 19a and 19b in the presence of indium tribromide as the catalyst. This reaction produced two isomers 22a and 22b (R1 = phenyl) as well as 23a and 23b (R1 = p-anisyl). This was interesting to note that there is no other isomers are formed in this reaction. The amino group in 19 attacked the epoxide ring 21 with retention and inversion of configuration (Figure 10.14).

Figure 10.13: Synthesis of 1,2-anhydrosugar.

10.2 Synthesis of beta-lactams

367

Figure 10.14: Indium salt catalyzed Iminoglycosylation.

10.2.4 Synthesis of pyrrole-substituted β-lactams One-pot synthesis of medicinally useful unique molecules 3-pyrroloazetedin-2-one was prepared using 3-oxo-β-lactams 24. Towards this endeavor, azetidine-2,3-dione was reacted with trans-4-hydroxy L-proline 25a using p-toluenesulfonic acid in ethyl alcohol at room temperature as a model entry. However, no products were formed. Upon heating the reaction mixture at 60–70 °C for 1 h, two distinct new spots appeared. The reaction was then continued for an additional 2 h. The NMR data of the reaction products demonstrated the formation of two compounds. The crude mixture on purification gave two pyrrole-fused optically active cis-β-lactams 28 (78%) and transβ-lactams 29 (22%) at C-3 of the ring (Figure 10.15, Table 10.4). The absolute configuration of 28 and 29 was established by NMR and optical rotation experiments. The cisdiastereomer 28 showed a strong peak at 1746 cm−1 for the ketone group of the β-lactam. In addition, 28 indicated two doublets at δ 5.42 and 5.76 ppm in the NMR spectra for C4-H and C3-H of the ring. The cis-configuration in 28 was confirmed by the coupling constant (5.49 Hz) of the two doublets. The structure was also confirmed by two triplet signals (δ 5.88 and 6.47 ppm) for the methine hydrogens of the pyrrole with a coupling constant of J = 2.07 Hz. These NMR data dictated the formation of the pyrrole ring structure. A peak at δ 167.8 ppm in 13C NMR confirmed the presence of β-lactam

Figure 10.15: Asymmetric synthesis of 3-pyrrole-beta-lactam.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

Table .: Chiral synthesis of -pyrrole-substituted-β-lactams. Entry -Oxo R lactams Racemic- (+/−) ()

R





a

CH

CH

:

a

CH

CH

:

b

c

CH

pMeOCH pMeOCH pMeOCH pMeOCH

:

c

pMeOCH pMeOCH CH

b 

Trans/Cis Yield Absolute ratio [%] Structure C-C

: : :

 a(S,S) a(R,S)  a(R,R) a(S,R)  b(S,S) b(R,S)  b(R,R) b(S,R)  c(S,S) c(R,S)  c(R,R) c(S,R)

Optical Rotation [α]. D +. (c .,CHCl) +. (c .,CHCl) −. (c .,CHCl) −. (c ., CHCl) +.(c.,CHCl) +.(c.,CHCl) −. (c ., CHCl) −. (c ., CHCl) +. (c .,CHCl) +.(c.,CHCl) −. (c ., CHCl) −. (c ., CHCl)

carbonyl group. The slightly acidic nature of the reaction media was unable to rupture the carbon-nitrogen bond of the cyclic system. The minor diastereomer 29 also showed a peak at 1745 cm−1 in IR. Two doublets at δ 4.96 and 5.13 ppm for C4-hydrogen and C3-hydrogen in the NMR of the ring were noted. The trans structure in 29 was confirmed from the coupling constant data of the two hydrogens (J = 2.0 Hz). The pyrrole ring was identified by the presence of two triplets (δ 6.25 and 6.76 ppm) which demonstrate a coupling constant of 2.19 Hz. A major peak at δ 167.8 ppm in the 13C NMR confirmed the carbonyl group of the ring. The reaction of cis-4-hydroxy 25b and 3-oxo-β-lactam 24 was also studied and a similar result was obtained with cis-hydroxy proline. A cis compound 27 (78%) and 26 (22%) as a trans compound was obtained (Figure 10.15 and Table 10.4). The spectral data for 27 and 26 were identical with 28 and 29. However, the optical rotation of these molecules 27 and 26 was opposite in sign with respect to 28 and 29. These values suggested their mirror-image structures. The configurations of the β-lactams 28 and 29 were determined based on the optical rotation value. The specific optical rotation for 28 was [α]20.1D +10.8 (c 2.0, CHCl3) and that of 29 was [α]20.1D +2.08 (c 1.0, CHCl3). It was known that a (S)-stereo configuration at C(4) of a β-lactam ring shows positive optical rotation data. The absolute configuration of 28 and 29 were also deduced by NMR data by comparison with molecules using chiral reagents. The probable reaction mechanism of this reaction is shown in Figure 10.16. The formation of 3-pyrrole-azetidine-2-ones 26, 27, 28 and 29 were explained through a nucleophilic addition process of cis/trans-hydroxyproline 25a/25b with carbonyl group of the α-keto structures 24a-c with TsOH. This produced a spirocyclic intermediate 30 (Figure 10.16). The intermediate amino alcohol reacted with the carboxylic

10.2 Synthesis of beta-lactams

369

Figure 10.16: Proposed reaction mechanism of pyrrole synthesis.

group of hydroxyproline very fast to generate the ring structure 30. The hydroxyamino acid 25a/25b reacted with the C=O group of β-lactam from the back face of the C(4)-group because of steric crowding caused by the group R1. The nucleophilic pathway and subsequent ring closure step at C(3) were crucial. This pathway dictated the absolute structure at C(4) in 30. The intermediate 30 was then converted to azomethine ylide 31 through decarboxylation at high temperature and the ylide was then transformed to 32 through dehydration, due to the conjugation. A proton transfer from 33 was followed to generate compounds 28 and 29 to receive an aromatic structure. The structures in the resonance forms of 33 in the proton relocation process were planar. The minor trans-product 29 was produced through a protonation pathway of the anionic center at C(3) from the front direction. This was possible due to a temperature-dependent isomerization of 33 because the trans-compound was the more stable isomer. An identical mechanism was followed with other compounds for the preparation of compounds 26–29.

10.2.5 Azide-alkyne cycloaddition in β-Lactams We have investigated a facile azide-alkyne cycloaddition in β-lactam for the synthesis of polycyclic compounds. The 3-acetoxy cis β-lactam 34a-b was synthesized from the

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10 Conceptual design and cost-efficient synthesis of beta-lactams

Staudinger [2 + 2] cycloaddition of acteoxyacetyl chloride and chiral Schiff base derived from isopropyldine(R)-glyceraldehyde with aromatic amines [19, 20]. The acetoxy group of 34a-b was removed to the corresponding 3-hydroxy β-lactams 35a-b with 10% lithium hydroxide in THF/H2O (3:1) in quantitative yield. The hydroxyl group was converted to the propargyl ether 37a-f and 38a-f. This was done by treating the ether with a sodium hydride in THF at 0 °C followed by the reaction of the required alkenyl bromides 36a-c in 75–95% yields (Figure 10.17, Table 10.5) [21].

Figure 10.17: Azide-alkyne cycloaddition.

Table .: Polycyclic compounds. Compound

n

Ar

R

Yield [%]

a b c d e f a b c d e f

           

Ph Ph Ph PMP PMP PMP Ph Ph Ph PMP PMP PMP

H Me Et H Me Et H Me Et H Me Et

           

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371

Figure 10.18: Formation of β-lactam diols. Table .: β-lactam diols. Compound

n

Ar

R

Yield [%]

a b c d e f a b c d e f

           

Ph Ph Ph PMP PMP PMP Ph Ph Ph PMP PMP PMP

H Me Et H Me Et H Me Et H Me Et

           

The acetonide group in 37a-f and 38a-f was deprotected to the corresponding diols 39a-f and 40a-f by reaction with ferric chloride in dichloromethane (Figure 10.18, Table 10.6). The dialcohols were used to make the 4-formyl β-lactams 41a-f and 42a-f through oxidation with sodium metaperiodate at 0ºC-RT. The crude products 41a-f and 42a-f were reduced with sodium borohydride in dry methanol. These reactions produced the 4-hydroxymethyl β-lactams 43a-f and 44a-f in 65–80% yields (Figure 10.19, Table 10.7). A three-component metal-free azide-alkyne cyclization reaction in a one-pot method was reported [22–26]. To test the feasibility of the reaction, compound 43a was selected as a model system. The initial test was focused on the identification of the condition of the process. The molecule 45a was reacted with p-toulenesulfonyl chloride (1.0 equiv.) or methanesulfonyl chloride in the presence of triethylamine to get the tosylate or mesylate in excellent yield. Sodium azide was added and the mixture was refluxed at 40–50 °C for 12 h. Surprisingly, there was no desired product formed. A deprotection of the

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10 Conceptual design and cost-efficient synthesis of beta-lactams

Figure 10.19: Synthesis of 4-hydroxymethyl β-lactams.

Table .: -hydroxymethyl β-lactams. Compound

n

Ar

R

Yield [%]

a b c d e f a b c d e f

           

Ph Ph Ph PMP PMP PMP Ph Ph Ph PMP PMP PMP

H Me Et H Me Et H Me Et H Me Et

           

propargyl ether group was seen rather than the cycloaddition reaction. THF, Toluene, Xylene and 1,4-Dioxane also failed to give the product. So, the conditions were altered. The mesylate (or tosylate) of the substituted alkyne was treated with sodium azide at 80–100 °C for 12–24 h. It was gratifying to note that the reaction proceeded smoothly under the condition of a mixture of the solvent system (entry 6, Table 10.8) to give a fused triazolo oxazepine β-lactam 46a. The structure of the product was elucidated by the NMR experiment that led to its identification as compound 47a (Figure 10.20). A sharp singlet peak has appeared at 7.8 Hz in 1H NMR confirmed triazole ring on the preexisting β-lactam system. It is worthy to note that this method failed in dimethylsulfoxide or dimethylformamide even at high temperatures. Under these conditions, decomposition of the starting molecules was observed. Acetonitrile-DMSO (2:1 ratio) was the best solvent for this cycloaddition reaction.

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373

Table .: Screening of best reaction experimental condition using the reaction of a with sodium azide as a model system. Entry

Solvent(s)

     

CHCl CHCl DMF DMF DMSO DMSO:CHCN (:)

NaN [equiv.]

T [°C]

. . . . . .

     

Yield [%]     Trace 

Figure 10.20: Synthesis of compound 47a.

To analyze the scope of this procedure, azide-alkyne reactions of terminal alkynes were repeated with internal alkynes (Figure 10.21, Table 10.9). Many intramolecular azide-alkyne cycloadditions were involved with terminal alkynes. The application of this process with internal alkyne was not well investigated [27, 28]. The intramolecular [2 + 3] cycloaddition was expected to produce a product with a high degree of molecular complexity. The cycloaddition of electron-poor alkynes proceeded. Under this condition, a breakage of the alkenyl chain was observed in some examples.

Figure 10.21: Azide-alkyne cycloaddition reactions of internal alkynes.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

Table .: Scope of intramolecular Azide-Alkyne [ + ] cycloaddition reaction. Compound

Ar

R

Yield [%]

b c a b c

Ph Ph PMP PMP PMP

Me Et H Me Et

    

10.2.6 Cycloaddition with sterically hindered imines: Synthesis of β-Lactams Highly enantioselective synthesis of chiral trans-β-lactams with bulkier multiaromatic group attached to N-(1) position of azetidin-2-ones ring derived from (+)-car-3-ene was investigated. The optically active trans-β-lactams 55a and 55b should exhibit anticancer activity based on our earlier results. The synthesis of optically pure trans-β-lactam 55a and 55b using chiral bicyclic acid 51 were reported. The trans-β-lactams such as 1-N-chryseneyl and 1-N-phenanthrenyl 3-acetoxy-4-aryl-2-azetidinones was synthesized from polyaromatic imines and other imines. The racemic version of trans-1-N-chryseneyl and 1-N-phenanthrenyl derivatives have a strong and selective anticancer power based on the preliminary structure-function investigation. The diastereoselectivity of 2-azetidinone formation with imines that have N-polycyclic aromatic substituents was also reported. It is believed that optically pure trans-1-N-chryseneyl and 1-N-phenanthrenyl 3-acetoxy derivatives of β-lactams would have enhanced anticancer property in comparison to their racemic forms. The synthesis of chiral trans-β-lactams 55a and 55b via a chiral ketene derived from a natural terpenoid was reported. The synthesis of a bicyclic chiral acid 51 derived from readily available and naturally abundant (+)-carene (49) was also studied. The (+)-Car-3-ene (49) was subjected for the bromination reaction with N-bromosuccinimide in presence of ethylene glycol to afford bromoalcohol 50 in moderate yield. Jones oxidation reaction was performed on bromoalcohol 50 to get bicyclic chiral acid 51 in excellent yield (Figure 10.22).

Figure 10.22: Synthesis of bicyclic chiral acid 51.

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375

Figure 10.23: Synthesis of chiral trans-β-lactams.

The Staudinger cycloaddtion of chiral acid 51 with imines 52a and 52b in presence of Et3N, Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide) was reported. The 1H NMR spectra of crude products indicated showed a formation of transβ-lactams 53a and 53b, respectively, in good yield (Figure 10.23). No trace of cisisomer was detected on 1H NMR. The yield of the products was very good. The crude compounds were purified by flash column chromatography to produce trans-β-lactams 53a and 53b, respectively, as white solids. These results are highly unprecedented since the preparation of a chiral trans-β-lactam starting from a chiral ketene component has not been disclosed so far. The stereochemical outcome and structure for 53a were established by IR and 1H NMR spectroscopy. The diastereomer 53a demonstrated a characteristic absorption band at 1766 cm−1 for carbonyl moiety. The proton spectra showed doublets at 4.95 and 5.48 ppm for H-C(4) and H-C(3) of the ring. The coupling constant of the two observed doublets is 1.95 Hz, which confirmed trans-configuration for the β-lactam ring for 53a. The signals in the aliphatic region at 0.67–2.48 ppm indicate the car-3ene group. The signal at δ 166.8 ppm in the 13C NMR spectra confirms the β-lactam carbonyl moiety.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

The cleavage of the chiral carene group was achieved by reacting pure diastereoisomers 53a and 53b with Zn/acid to give corresponding enantiomerically pure 3-hydroxy-β-lactamβ derivatives 54a and 54b, respectively, in excellent yields (Figure 10.23). Their formation of 3-hydroxy-trans-β-lactams 54a and 54b was confirmed by their spectroscopic data (1H and 13C NMR). Further, 3-hydroxy-transβ-lactams 54a and 54b on reaction with AcCl and Et3N gave 3-acetoxy-trans-β-lactams 55a and 55b, respectively, again in excellent yield. The structures 55a and 55b were established by spectroscopic data and analytical data. The absolute structure of β-lactam 55a was identified on the basis of its specific optical rotation and melting point data in comparison with those of an authentic sample of 55a. The optical rotation for 55a was [α]20.1D −39.62 (c 0.12, CHCl3). The absolute configuration of 55a as trans-(3R, 4R) was also fixed by comparison with available trans-β-lactams with respect to optical rotation and proton NMR data. The mechanism behind the formation of β-lactam isomers is shown in Figure 10.24. Acid chloride in the presence of a tertiary base (NMM or TEA) produced a ketene intermediate 56. The formation of the ketene was evidenced by a strong band at 2200 cm−1 in infra-red spectra. The reaction of the ketene 56 with the imine 57 produces an ion (iminium ion) 59. The stability of this ion 59 dictates the stereochemistry of the resulting products. If the ion undergoes reversible equilibrium with 60, mixtures of β-lactams are formed. The relative proportions of these two β-lactams depend on the stability of the ions 59 and 60. More stable 59 favors cis and the reverse is equally true for 60 (more trans). It is understandable that the ion 59 can alter its structure under the conditions or because of the presence of certain specific groups in its structure. It is found that electron-withdrawing aromatic groups at the nitrogen stabilizes the iminium ion and helps to rotate the intermediates to form 60. That results in the isomerization of the intermediates 59 to 60 and eventually in the formation of a trans isomer

Figure 10.24: Mechanism of formation of β-lactam isomers.

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377

61 (nitro aromatics and polayaromatic groups at the nitrogen). Without this type of isomerization, the products become cis 62. High power microwave irradiation and concentrated solution favor the formation of 60 even with imines that have electrondonating groups (e. g. p-anisyl) as can be seen from this study. This stereochemical situation becomes highly complicated if electron-withdrawing functionalities are kept in C-3 of the compound. Clearly, a rapid rise of temperature favors trans β-lactam formation through an isomerization process irrespective of the groups present in nitrogen. Microwave irradiation, polar solvent, concentrated solution and electronwithdrawing groups at C-3 and an aryl group at C-4. Acetoxy and phthalimido groups have superior electron-withdrawing capacity than the benzyloxy group. These groups prefer to form the trans product (for example, the acetoxy/phthalimido and benzyloxy at the C-3). The use of non-polar solvent retards the formation of the β-lactams under similar conditions. For example, the reactions are sluggish in benzene whereas they proceed at a significantly faster rate under neat conditions. The use of benzene lowers the concentration of the reactants and intermediates. However, this explanation is not valid with imines derived from D- and L-glyceraldehydes. The exclusive formation of cis products (single stereoisomer) with these two imines indicates rotation of the iminium ion structure is restricted due to the presence of a ketal group. The function of the ketal group in this process is not established. It can be assumed that the ketal group due to its cyclic structure forces the ion to adopt only one configuration. Inverse addition (the base was added to the reaction mixture) of the base favors trans beta-lactam formation with racemic imines. The proportion of the ketene in the reaction mixture is not sufficient in this type of reaction and thus the intermediate ion prefers to undergo isomerization to the more stable structure at high temperature. Preparation of these beta-lactams following the procedures as described herein is simple and the isomers are separated by chromatography. Perhaps, a significant outcome was observed by performing these reactions within a few minutes with limited amounts of solvents. Clearly, this reaction proceeds in the absence of solvent with complete stereocontrol. The one-pot reaction in the presence of clay is also very interesting since it maintains the stereochemical outcome in a predictable way. The success of this reaction is because of the dehydrating power of the clay which helps to form the imines and stabilizes the iminium ion by stabilizing the system through its surface properties.

10.2.7 Michael reaction toward polycyclic oxazepenes Hetero-Michael’s addition is an attractive method for the preparation of heterocycles natural compounds as well as bioactive molecules. Michael reaction describes a nucleophilic conjugate addition of Oxygen (oxa-Michael), Nitrogen (aza-Michael), and Sulfur (thia-Michael) to the olefinic group [29–32]. The oxa- and aza-molecules are present in numerous alkaloids and medicinally crucial compounds molecules [33, 34].

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10 Conceptual design and cost-efficient synthesis of beta-lactams

Figure 10.25: Examples of drugs having a 1,4-oxazepane system.

1,4-Oxazepane are promising molecules and are present in chemotherapeutically active compounds. These have anti-inflammatory, antithrombotic, antihistaminic, anxiolytics, antipsychotic, anti-aggregating, progesterone agonist epidermal growth factor receptor tyrosine kinase inhibitory, glycosidase inhibitor, and nitric oxide synthase activities [35–40]. Despite biological significance, 1,4-oxazepanes can also serve as a synthon to synthesize and control the bioactivity of many molecules. Clinically active dioxazepane nucleus are present in Microline A analog I (62), Loxapine (63), and Sintamil (64) (Figure 10.25) [41–44]. Many efforts have been paid to synthesize 1,4-oxazepane ring system. It has been examined demonstrated that the amino acid-derived oxazepanes serve as a building block in realizing the preparation of peptides. Some elegant synthesis of 1,4-oxazepane includes intramolecular reductive etherification (Gharpure et al.), aziridine/epoxide ring-opening process (Panda et al.), N-propargylamine-induced method (Esrafili et al.), 7-endo seleno-cyclization reaction (Encabo et al.), solid-phase preparation (Huang et al.), aza-oxy-allyl cation-induced [3 + 4] cycloaddition method (Saha et al.), and ketene-imine-induced Cu(I) catalyzed [3 + 2] cycloaddition [36–40, 45]. Regio-and stereoselective preparation of β-lactamconnected with 14-oxazepane through intramolecular oxa-Michael process without using any metal catalyst was reported by us. In recent years oxa-Michael reaction has been used to execute functionalized oxygenated five (tetrahydrofuran) and six-membered (tetrahydropyran) rings [29, 46]. In contrast, the synthesis of seven-membered heterocyclic molecules via intramolecular oxyMichael reaction has not been investigated much. Our research group has been actively engaged in the synthesis and evaluation of the biological activity of β-lactams as potential anticancer molecules and medicinal chemistry [1, 47–49].

10.2 Synthesis of beta-lactams

379

We used a direct approach in installing the acceptor motif by the base-assisted N-alkylation of 3-amino azetidine-2-one with methyl-(E )-4-bromobut-2-enoate. However, no desired Michael acceptor was produced. To overcome this obstacle, we decided to mask the free amino group by transforming it to its corresponding imine by condensing cis-3-amino-β-lactam with benzaldehyde. The imine was reduced by sodium borohydride into N-benzyl protected β-lactam in 75–80% yield. The secondary amine was then alkylated with the corresponding unsaturated bromo ester using fused potassium carbonate to afford the Michael acceptors 66a-b (70–75%, Ar = Ph, X = OEt) and 67a-b (85–90%, Ar = PMP, X = OMe) (Figure 10.26) [50]. Ferric chloride was a good reagent for deketalization. About 50% of the 3,4-fused 1,4-oxazepane 68a+69a was formed as a mixture of 1:1 diastereomeric ratio in the presence of FeCl3. A one-pot intramolecular oxy-Michael reaction in a single-pot operation was then attempted [51–53]. The reaction proceeded in basic conditions (∼pH 14). Potassium hydroxide (0.5 M in aqueous THF) at 0 °C was found to be the most effective base to activate the oxy-nucleophile to accomplish the 7-exo-trig-cyclization. This method was used to provide the annulated 1,4-oxazepanes 68a+69a as a mixture in a 20% yield (Figure 10.27).

Figure 10.26: Synthesis of Michael acceptors 66 and 67.

Figure 10.27: Synthesis of compounds 70 and 71.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

To derivatize the hydroxyethyl group of the β-lactams, different protecting groups were attempted. The silyl protecting group worked to produce the pure diastereomers. In addition, the mixture of 68a+69a on reaction with TBDMSCl furnished the silylprotected 1,4-oxazepane β-lactam 68a (cis, 25%) and 69a (trans, 22%).

10.2.8 Synthesis of two isomers of thienamcin side chain via glycosylation Tatsuta et al. reported a synthesis of (+)-thienamycin using carbohydrate as chiral auxiliary [54]. Numerous thienamycin analogs are also reported [55–58]. Bismuth triflate-catalyzed method to produce enantiomeric forms of the 1-hydroxyethyl side chain of thienamycin was developed by us. The main reaction involved in a Ferrier rearrangement of racemic β-lactam alcohol and various unsaturated sugars. The glycosylation of alcohols is crucial because of the applications of the method [59]. Several methods were known. But, Ferrier rearrangement is the best for the preparation of glycosides using glycal as the donor [60, 61]. In some instances, Lewis acids and/or acidic supports are used as sugar activators [62, 63]. This reaction gave 2,3-unsaturated glycosides between the oxygen at the anomeric center of the carbohydrate [64]. The stereochemistry of the anomeric bond remained unpredictable as the reaction relies on the protecting groups of the glycals, the nucleophilic power of alcohols, temperature of the process, and nature of the solvents [65]. This reaction yields a mixture of alpha- and beta-glycosides or a pure isomer. A few crucial methods were identified to obtain pure isomer selectively. Indium metal-induced reaction was identified for the stereoselective preparation of glycosides by the reaction of alcohols and bromo sugar derivatives. Stereospecific glycosylation of alcohol through molecular iodine-catalyzed reaction was also reported. Thienamycin, PS-5, and carpetimycin are crucial antibiotics. Some synthetic procedures were known for the preparation of these antibiotics [66]. A chiral 3(1-hydroxyethyl)-4-acetoxy-2-azetidine 74 was necessary for their synthesis. Racemic suitably substituted β-lactam alcohol may act as the precursor for the synthesis of optically active thienamycin side chain [18]. In our previous publications, preparation of all isomers in chiral forms of monocyclic 3-hydroxyl β-lactam was realized through molecular iodine-catalyzed Ferrier glycosylation of D-glycal [67]. Based upon our experience on optically active β-lactam by Ferrier rearrangement, we became interested in synthesizing the hydroxyethyl-containing portion at C-6 position of the thienamycin because racemic cis-3-(1-hydroxyethyl)-2-azetidinone 74 is the key intermediate part of this compound. On this basis, we carried out the reaction of racemic (±)-ethyl-3-hydroxy-butyrate 72 and anisylaldimine 73 [68, 69]. The lithium dianion of ester-enolate condensation reaction produced cis-β-lactam 74 only (Figure 10.28). The stereochemistry of the resulting β-lactams from a reaction depends on the configuration of the Z/E lithium enolate and the imines in the transition state of the

10.2 Synthesis of beta-lactams

381

Figure 10.28: Synthesis of cis-β-lactam 74.

intermediates. The cis product is formed due to the involvement of E-enolate in the activated state of the process [69]. The transition state of the E-enolate forms the cis β-lactam (3R, 4S) 74 (Figure 10.29). This stereochemistry is possible because of a driving force for respective transition state stabilization through a remote hydrogen bonding that occurs between the hydroxyethyl and the ester of butyrate group. The cis-β-lactam 74 was isolated through chromatography. Bismuth triflate-catalyzed glycosylation of cis-3-(1-hydroxyethyl)-azetidinone 74 using D-glucal 75 was conducted (Figure 10.30). Column chromatography of the crude materials gave two products corresponding to compounds 76–77 and 78–79 in 70% yield [70]. On the other hand, bismuth triflate-catalyzed glycosylation of 3, 4, 5-triO-acetyl D-galactal with racemic β-lactam alcohol 74 did not produce desired glycosides. Moreover, tri-O-benzyl D-glucose derivative failed to react with alcohol 74. These results suggested that the protecting group in D-glycals has a tremendous role in Ferrier rearrangement [71].

Figure 10.29: Cis β-lactam 74 formation.

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10 Conceptual design and cost-efficient synthesis of beta-lactams

Figure 10.30: Bismuth triflate-catalyzed glycosylation.

The configuration of the anomeric carbon in the unsaturated sugar derivative is difficult to identify. But it is not difficult to identify it in saturated sugar. Therefore, the unsaturated bond in 76 and 79 was hydrogenated with ammonium formate/Pd-C [72]. Reaction with other hydrogen transfer agents (for example, cyclohexene, hydrazine, formic acid, cyclohexadiene and sodium hypophosphite) was not fruitful. Microwaveassisted hydrogenation in ethylene diol and ammonium formate with 10% Pd-C gave saturated products 82 and 83. A less sterically hindered β-lactam system often produced open-chain amide derivatives 80 and 81 because of the N1-C4 bond rupture. The NMR data of the 2, 3-dideoxy compounds 82 and 83 demonstrated a small coupling constant (approximately 1–2 Hz) for the anomeric proton and this indicates an axial linkage of the anomeric bond. The β-glycoside demonstrates a higher coupling constant (8–10 Hz) due to the axial-axial interactions of the hydrogen (Figure 10.31).

Figure 10.31: Hydrogenation.

10.2 Synthesis of beta-lactams

383

Figure 10.32: Conversion of hydroxy β-lactams to their acetates.

The sugar group was removed with aqueous hydrochloric acid to produce the chiral hydroxy β-lactams 84 and 85. The hydroxy β-lactams were then converted to their acetates 85 and 87. It was important to note that the β-lactam 85 was found to be chiral [67]. This NMR investigation also demonstrated that molecules 85 and 87 are enantiomeric to each other (Figure 10.32). The absolute configuration of these derivatives was determined. The hydroxyβ-lactams 84 and 86 were transformed to the alkenes by mesylation and elimination [73]. The formation of Z-olefin β-lactam indicated the stereochemistry of the alcohol group and the hydrogen at the C3 position of the system (Figure 10.33). The alkene group of the β-lactam was oxidized with an osmium tetraoxide-mediated reaction followed by

Figure 10.33: Conversion of hydroxyl compounds to the alkenes.

384

10 Conceptual design and cost-efficient synthesis of beta-lactams

an oxidative cleavage with NaIO4. This produced the 3-oxo-β-lactam. Then, the keto group was reduced to the cis-hydroxy β-lactam with known absolute stereochemistry as 84. The hydroxy β-lactam 89 was transformed to acetate 90 with a known configuration.

10.3 Conclusion β-Lactams are a group of crucial medicinally important molecules. The anticancer, antibacterial, antifungal, anti-inflammatory, antihepatitis, analgesic and antihyperglycemic activities of numerous azetidinones are extensively investigated. As a result of the wide range of medicinal activities of β-lactams, preparation and derivatization of these types of molecules are studied by many prominent researchers in the World. In recent years, studies are directed to design the synthesis of these types of compounds through concise and economical approaches that can produce compounds following green chemistry. Stereoselective synthesis of β-lactams following diverse conditions is reported in this paper. Many reaction conditions and parameters are considered and successfully analyzed in this study. The relative and absolute configuration of the β-lactam formation reaction is dependent on the nature of the actual experiments, composition and nature of the Schiff bases and acid chlorides (equivalent), the way the reagents are added, reaction temperature and nature of the solvents used. The compounds and methods as described in this paper are useful to perform a number of other related chemical transformations. These methods are indium-mediated glycosylation of amino β-lactams with epoxy sugar, synthesis of optically active pyrrole-substituted β-lactams, cycloaddition with structurally congested imines from natural products towards β-lactams, conjugate addition for the preparation of polycyclic oxazepenes and synthesis of optically active thienamycin side chains. Some of these reactions described here catalytic, economical, environmentally friendly and conceptually new.

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Index (1,2,3-trimethyl-imidazoliummethylsulphate) 166 1-(2-amino-4,5-dimethoxyphenyl)-ethanone 128 1-(2-amino-5-bromophenyl)ethanone 145 1,2-diazanaphthalene 101 1,2-dichloroethane 113 1-(3,4-dichlorobenzyl)-3-(3-methylcinnolin-5-yl) urea 147 1,3-diynyl 135 1-(-3-methylbenzoyl)- 139 1,4-dihydrocinnoline 146 1,4-dioxane 372 1,4-disubstituted phthalazines 170 1,4-oxazepane 378 1,4-oxazepanes 378 1-cholorophthalazine 158 1-hydroxytaxinine 278 1-N-chryseneyl 374 1-N-phenanthrenyl derivatives 374 1-N-substituted phthalazines 158 1-substituted phthalazine 159 12 green chemistry 50 2-(1-(1,4-dioxo-3,4-dihydro-phthalazine-2(1H)-yl) isoquinolin-2-(1H)fumarates 167 2-(2-bromo alkenyl)aryl bromides 124 2,3-diazanaphthalene 101 2,6-bis(phenylazo)pyridine 153 2-amino-3-chlorobenzophenone 125 2-aminoarylketones 125 2-aminobenzyl alcohols 82 2-aryl-2,3-dihydrophthalazine-1,4-diones 175 2-(arylethynyl)aldehyde/ketone 156 2-hydroxy-1,4-naphthoquinone 143 2-iodoaryltriazines 117 2-mercaptobenzothiazole 158 2-phenylbenzoxazole derivative 17 2′-spiro and 2, 3-dihydro quinazolinone hybrids 42 2-(trimethylsilyl)aryl triflate 121 2-(trimethylsilyl)aryl triflates 123 3-(1,4-dioxo-1,2,3,4-tetra-hydrophthalazine-2yl)-3-oxopropanenitrile 168 [3 + 3] annulation 60 3-(4-(Substituted)-piperazin-1-yl)cinnolines 141 3-amino azetidine-2-one 379 3-benzylidene iso-benzofuran-(3H)-one 148 https://doi.org/10.1515/9783110797428-011

3-cinnoline carboxamides 144 3-hydroxy-lactam 376 3-pyrrole-azetidine-2-ones 368 3-pyrroloazetedin-2-one 367 (3R, 4S)-4-hydroxylasiodiplodin 271 4-(2-(4-chlorophenyl)-1-phenylvinyl)phthalazin1-ol 150 4-(2-substituted pyridyl) 129 4-alkylpyridazines 148 4-amino cinnoline 147 4-benzyl- phthalazine-1-one 170 4-Benzyl-1-chlorophthalazine 170 4-hydroxycinnolines 127 4-sulphonylamide ester 151 6-amino-1,3-dimethyl uracil 345 6-aminouracil 332 7-exo-trig-cyclization 379 8-Cl-3-benzyl indole 127 α-amino-alkoxides 155 α-bromo acetophenone 121 β-alkylation 204 β-aminoalkylation 204 β-lactams 79 β-ketoesters 112 acacia concinna pods 300 acetates 383 acetonitrile 372 acetoxyacetyl chloride 360 acetylation 282 acetylenes 168 acid-triggered 91 activation 147 activity 128, 139, 151, 173, 176 acyclic 170 acylmethylation 175 adunctin B 280 advances 108 advantage 110 aerobic 106 aerobic oxidative 86 aeruginosa 170 affinity 166 agglomerization 8 agomelatine 165 AgPd nanoparticles 36 agro-waste 287, 289, 292, 293, 307, 320, 321, 325 AgSbF6 111

390

Index

AIDS associated dementia 235 aldehyde 268 aldol 263 aliphatic and aromatic amides 2 alkenyl bromides 370 alkyl pyridazine 176 alkylation 114 alkyne moiety 83 alkynes 115 alkynyl-substituted 115 alumina immobilized thiourea 54 alzheimer 151, 165, 235 amazing advantages 65 ambient 91 amides 155 amination 106 aminocupration 105 ammonium formate 382 amphidinolide B 266 amphiphilic polymers 189 amyotrophic lateral sclerosis 235 an excellent catalyst 64 analgesic 102 anhydrase 151 anisylaldimine 380 annulation 108, 114, 118, 121, 124 anti– anti-aggregating 378 – anti-allergic 102 – anti-bacterial 83, 102, 127, 128, 142, 300, 305, 309, 312, 317 – antibiotic 128, 151, 261 – anti-cancer 142, 158, 159 – anticonvulsant 85 – antifungal 142 – antihistaminic 378 – anti-inflammatory 102, 378 – anti-malarial 102, 166 – antimicrobial 148, 170 – anti-proliferative 150, 158, 160, 171 – antipsychotic 378 – antithrombotic 378 – anti-tumour 83 – antitussive 85 – antiviral 83 anxiolytics 378 apoptosis 137 approaches 140 arene 147

arene-diazonium 103 aromatic 112, 124 aromaticity 150 aryl 104, 107 – aryl boronic acids 25 – aryl hydrazine 103 – aryl hydrazone 103 – arylhydrazones 140 – aryltriazine 115 – aryltriazines 135 aryne 123 aspergillus 170 ataxia 145 (ATCC 15126) strains 142 ATM inhibitors 144 atom economical synthesis 104 atom economy 93 AWEs 290, 291, 294, 298, 303, 304, 321 aza-michael 377 aza-michael reaction 313, 327 azetidin-2-ones 374 azetidine-2,3-dione 367 azide-alkyne 369 azides 127 azo 110 azobenzene 114 azo-linked 2-aryl quinazolinones 38 bacillus 170 bacteria 261 bacteriostatic 151 barber 103 base-assisted 105 benzaldehyde 360 benzene 359 benzo diazine 176 benzodiazine 103 benzoxazinones 85 benzyloxy 377 benzyloxyacetyl chloride 363 beta-glycosides 380 better yield 37 biarylamides 150 biginelli reaction 204 bimetallic 91 binding 166 bioactive heterocycles 332 biocatalyst 40 bioimaging 190 bio isosteric 165

Index

biological 114, 125, 141, 150, 176 biosensing 189, 190 bismuth triflate 380, 381 blocking 147 blood 137 bohr radius 189 bonds 108 brain 138 breast 143, 158 breast cancer 150 bromoalcohol 374 bronchiectasis 138 bryostatin 1 270 butyrate 381 by-products 77 cancer 143, 160, 177, 357 cancer cell 143 capsaicin 147 carbon 158 – carbanion 170 – carbenoid 90 – carbon nanodots 190 – carbon nanotubes 189 – carbon quantum dots (CQDs) 190 – carbon-amination 153 – carbon-carbon 287, 289, 294, 314, 321, 326 – carbonic 151 – carbonitriles 176 – carbon-nitrogen, carbon-oxygen, carbonsulfur and carbon-selenium bond formation 1 carcinoma 173 cardiotonic 148 C(aryl)–O bond 15 cascade 76, 97–99 catalyst-free 101 catalytic cyclothiomethylation 67 CBPA 314 CBPA 322 C–C and C–X 287, 292, 293, 303, 320 C–C, C–O, and C–S bond formation 63 C-C coupling 80 CdSe/CdS core/shell QDs 211 cell line 143, 158 cells 143 central nervous system (CNS) activity 223 cereus 170 C-H functionalization 106 chagas disease 263

391

charged 170 chemistry 146 chemoselectivity 91 chiral carene 376 chitosan-silica sulfate nano 52 chlorobenzene 359 chloroquine-resistant 166 cinnoline 107, 115, 118, 124, 125, 128, 135, 136, 139, 146, 147, 176 cinnoline-1,2,3-triazole 127 cinnoline-3-(2H)-ones 114 cinnoline-4-carboxylate 115 cis-4-hydroxy 368 cis-amino beta-lactam 365 cis-diastereomer 367 cisplatin 174 click reaction 207 C–N cross coupling 14 coagulation 137 co-crystallization 135 colloidal nanocrystal quantum dot 214 colon 150 complex 105 complexation 81 computation 139 condensation 148, 170 condensation reaction 357 conduction band 188 conformations 128 conjugate base 168 consecutive 155 convenient 113, 117, 125, 128, 147, 155 conventional 104, 166 copper – copper acetate 85 – copper(I) catalyst 66 – copper (II) 105 – copper-catalyzed 104 – copper iodide 66, 79 – copper metal-organic framework 25 – copper nanoparticle catalyst 9 – copper nanoparticles 1 – copper triflates 81 co-solvent 111 cost-effective 85 coupling 101, 108, 112, 114, 153, 155 coupling constant 367 Cp3-carbon 108 cross 155

392

Index

cross-coupling reaction 5 cross-over 123 C–S coupling 19 Cs2CO3 37 Cs2CO3 (79%) and RbNO3 (80%) 67 Cu2O nanocube 16 CuNPs on Zeolite 10 CuO nanoparticles 2 cyclization 75, 104, 120, 135, 141, 155, 156, 170 cyclization of propargylic alcohols 68 cyclization-aromatization 108 cycloaddition 121, 358 cycloaddition reaction 357 cyclohexadiene 382 cyclohexene 382 cyclometalated 112 cytosolic HCA I, II 151 cytotoxic 160 cytotoxic effects 51 cytotoxicity 143, 166 DBU catalyst 68 dehydration 369 dehydrogenase 166 dehydrogenative 101, 106, 108 deketalization 379 depression 177 D-glyceraldehyde 364 diabetes 177 dialcohols 371 diastereoselectivity 358 diazo 112 diazotization-annulation 125 diethyl diazene-1,2-dicarboxylate 124 diethyldihydrocinnoline-1,2-dicarboxylates 124 dihydrobenzo[h]cinnoline-5,6-diones 143 dihydrocinnoline 124 dihydroorotate 166 dimedone 335 dimethyl-formamide 363, 372 dimethylsulfoxide 372 directing 112 diversity 129 D-mannitol 365 DNA intercalators 102 docking 127, 128, 139, 151, 174 domino 76 doubly grafted 94 Down’s syndrome 235 doxorubicin 158, 159, 173

drug discovery 139 drugs 166 dual activation 88 dynamic light scattering technique (DLS) 189 easily recoverable 54 eco-friendly 287, 288, 291, 297, 298, , 305, 310, 314, 317, 318, 320, 321, 323, 326 eco-friendly tactics 34 economically favourable 36 ecosystem into consideration 69 E-enolate 381 effect 121, 122 efficiency 122 efficient 104, 120, 146, 155, 167, 168, 176 elastase 128 electrochemical etching 190 electrochemical synthesis 41 electron-deficient 94 electron-donating groups 128 electron−hole pair 213 electron rich phenols 17 electron withdrawing groups 122 electronic 107, 121, 122, 188 electrophilic 80, 176 electrophilicity 88 embryogenesis 202 enantioselective 278 endo, as well as exo-selective [3 + 2] cycloaddition reactions. 59 energy-dispersive spectroscopy 232 enhanced product purity 62 environment-friendly 36 enzyme 135 enzymes 151 epoxidation 270 escherichia 170 ester enolate-imine 358 ethyl 1-aryl-5-cyano-4-methyl-6-oxo-1,6dihydropyridazine-3-carboxylate 147 ethyl cyanoacetate 349 ethyl-2-(4-benzyl-1-oxophthalazine-2-(1H)-yl) acetate 171 ethylene diol 382 eutectic solvents 44 exocyclic 81 falciparum 166 faster and uniform heating 42 ferric chloride 379 ferrocenated mono, bis, and di-thianes 57

Index

filtration 171 fine chemistry 97 fluorescence 195 fluorophore 188 formic acid 382 free radical 104 friedel-crafts alkylation 282 FS-HAP 317, 321 functionalization 108,112 functionally 148 glomerular 171 glucose 146 glycal 366 glycosylation 380 gold catalyst 85 gold complex 117 gold (I)-catalyzed 117 gram negative 142, 170 gram-positive 170 gram-scale 95 graphene quantum dots (GQDs) 190 great 147 greater selectivity 36 green 101, 148, 166, 168 green advantages 53 green chemistry 76, 98, 188, 287–289 group 110 hazardous 49 H-bonded 128 H-bonding 164 heart failure 151 heavy metals 41 hepatocellular 173 Hep-G2 143 heteroatom 108 heterocycles 114, 146, 166 heterocyclic 75, 98, 101, 122, 146 heterogeneous 94 Hetero-Michael’s 377 high stereoselectivity 22 high-frequency pulse 42 highly 176 highly efficient protocol 20 high-quality diastereoselective 61 house-x-ray structure 127 human 135, 158 huntington’s disease 235 hybrid 171 hydrazide nitrogen’s 174

hydrazine 155, 382 hydrazines 112 hydrazones 104, 141, 148 hydroamination 153 hydro-amination 153 hydroarylation 117 hydrochloric acid 383 hydroformation reactions 64 hydrogen atom transfer (HAT) 213 hydrogen bonding 88, 174 hydrogenation of imines 211 hydrophilization 189 hydrophobic 171, 175, 228 hydrophobic interaction 36 hydrothermal synthesis 190 hydroxamate method 357 hydroxyethyl group 380 hydroxyl derivatives 366 hypertension 165, 177 IC50 128 imadazol 85 imine 359 iminium ion 376 iminocoumarin 92 iminyl radical 96 InCl3/PhSiH3 68 indium tribromide 366 indium trichloride 335 infection 177 inflammation 137 inhibition 128, 150, 174 inhibitor 128, 138, 145, 166, 171, 175 inhibitory 139, 142, 151, 163, 167 inhibitory activity 171 In(OTf)3 60 interaction 120, 163, 175 intermediate 80, 105, 145, 156, 168, 170 intermolecular 86, 104, 105, 141, 153 iodo-benzene 80 ionic liquid 82, 166 Ir(III)-catalyzed 114 irradiation 147, 150, 156 isocyanate-alkene 358 isoenzyme 151 isoindazole 135 isolable 155 isomerization 362 isoquinoline 168 isoxazoles 90

393

394

Index

K2CO3 a green catalyst 61 keteneimine 93 kinase 145 kinetic control 150 kinetics 139 knoevenagel 170 knoevenagel condensation 344 large-scale 81 laser ablation 190 leaving 110 leukemia 143, 150 lewis acid 81, 206, 380 lewis acid catalysts 69 lewis superacids 59 L-glyceraldehyde 364 library 159 ligands 117 linker 131, 159 lithium 155 lithium hydroxide 370 liver X receptor 125 lower method cost, 41 loxapine 378 L-Proline 168 LXRB binding 125, 127 lymphocyte immunology 202 macrolide 261 magnetic nano CuFe2O4 heterogeneous catalysts 54 magnetically separable nano material 13 malaria parasite 166 malononitrile 349 mangrolide A 261 materials 110 MBTA 317, 322 MCRs 292, 294, 303 mechanism 107 medicinal 102, 146, 153, 176 medicinal biology 188 medicinal chemistry 82 melanoma 150 melatonegic 165 melatonin 164 meldrum’s acid 168 mercapto carbonic acids 189 mesylate 371, 372 metabolically 135 metal-catalyzed 108 methanesulfonyl chloride 371

methods 104, 139 methyl 4-bromo-3-(dec-1-yn-1-yl)cinnoline-6carboxylate 136 methyl-(E)-4-bromobut-2-enoate 379 michael addition 91, 170, 344 microbial 177 microline 378 microwave 101, 147, 150, 359 microwave-assisted 97 microwave-assisted synthesis 35 microwave irradiation 62, 82 migratory insertion 90 mild 92 mild conditions 108 modification 132 moieties 150 moiety 135 molecular 128, 139, 151 monocyclic 358 most effective alkali or alkaline-earth metal 67 mother nature 260 mukaiyama’s reagent 375 multi-component 76, 98, 143 – (MCR) synthesis 193 – reaction 204 – reaction strategies 331 multiplolide A 272 multistep synthesis 77 multi-substituted 95 musa acuminate 297 myoclonus 235 N-acetylindoles 79 nano copper oxide 88 nanomedicine 188 nanoparticles 75, 99 nanoscience 35 nanosensing 189 nanosized materials 45 nanostructured materials 187 nanotechnology 188 naphthyridines 102 N– N-arylation reaction 5 – N-arylations of nitrogen-containing heterocycles 2 – N-based heterocycles 34 – N-benzoylimidazoles 139 – N-benzoylindazoles 139 – N-benzoylindoles 139

Index

– N-bromosuccinimide 374 – N-methylmorpholine 359 – N,N′-dimethylethylenediamine 124 – N-nucleophiles 78 – N-polycyclic aromatic 374 – N-propargyl-N′-arylhydrazines 117 – N-substituted isatins 334 Neber-Bossel 103 necopidem 77 nervous 164 neuro 164 neutrophil 136 NHE inhibitors 139 ninhydrin 340 nitrogen 158 nitrone-alkyne 358 nitroolefins 147 norfloxacin 128 novel 143 novel graphene 42 Nozaki–Hiyama–Kishi 274 nucleophiles 158 nucleophili 140 nucleophilic 158, 168 nucleophilic addition 94 nucleophilic substitution 95 nucleophilicity 117, 118, 366 numerous 155 o-alkenyl 153 ochraceus 170 o-dicarbonyl arenes 148 o-ethynenearyldiazonium 135 o-iodophenol 80 olefination 278 olprinone 77 one-pot 75, 85, 99, 143, 167, 168 one pot synthesis 65 optoelectronics 188 organic materials 18 organic synthesis 82 orientation 127 ortho-alkynylsulphonohydrazone 153 ortho-lithiation 155 osazone 146 osmium tetraoxide 383 ovarian 160 oxa-Michael 377 oxidants 113 oxidation 105

395

oximes 95 oxygen 158 oxygen as green oxidant 6 oxy-nucleophile 379 p-anisidine 360 parkinson 165 parkinson’s disease 235 partners 112 Paul T. Anastas 33 PDE10A 128 PDE10A catalytic 135 PDE10A potency 129 Pd(OAc)2 297, 298, 321 PEG-200 336 peptic ulcer 85 pericyclic 77 pharma – pharmaceutical 101, 102 – pharmacokinetics 145 – pharmacologic 153 – pharmacological 151, 177 – pharmacophore 35 phosphine 117 phosphono-hydrazones 155 phosphotungstic acid mediated 42 photophysical 94 phthalazine 147, 151, 153, 155, 156, 165, 166, 171 phthalazines 102, 148, 155, 171, 173, 176 phthalazine-1-one 170 phthalhydrazide 168 phthalimido acetic acid 364 phthalimido group 365 phthalizine-1-one 150 physicochemical 145 physio-chemical 50 physiological 136, 164 piperazinyl 150 piperidine 345 PivOH/DCE 111 plasmodium 166 poly hetero atoms 75 polyfunctionalized pyridopyrimidine 337 polyfunctionally 125, 147, 155 polyketide 261 polymer dots (PDs) 190 polymerisation 93 positively 170 potassium hydroxide 379 potency 125, 132, 135, 139, 147, 160

396

Index

potent 128, 144, 145, 150, 174 potential 128, 135 precursors 128, 145, 146, 170, 176 preventing waste 67 promastigote and amastigote models 337 promising 39 propargyl ether 370 propargylation 127 properties 107 prostate 160 prostate cancer 150 protease 136 protein kinase 233 proteolytic activity 137 protocol 104, 146, 150, 158, 166 protocols 167 protodemetalation 81 proton 140 proton-coupled electron transfer (PCET) 211 proximal 81 pseudo elements 41 pseudomonas 170 PyBidine 59 PyBidine–Ni (OAc)2-catalyzed Michael/Aldol reaction 59 pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidinediones 332 pyridazine 176 pyridine ring 132 quantum computers 203 Quantum dot light emitting diode 203 quantum dots 188 qubits 203 quinazoline 102, 103, 147 quinazolinone sulfonamide 35 quinazolinones 85 quinoxaline 102 radical 153, 155 rate 171 reactivity 155 reagents 176 rearrangement 153 reasonable 114 receptors 164 recyclability 35 recyclable 85 redox-neutral 108, 112 reduced harmful 34 reduced reaction time 43

reduction/oxidation (redox) reactions 57 reductive elimination 80 re-esterification 145 regio isomers 123 regioselectivity 97 resistance 166 RHA-SiO2-BO3H3 312 rh-catalyzed 108 RhCp*-catalyzed 113 rhodium 64 rhodium(III) 112 richter synthesis 103 ring opening 96 ring-closing reaction 57 ripostatin B 265 room temperature 93 ruthenium catalyst 114 sacrolide A 274 salt 135 saponification 145 saripidem 77 scaffold 101, 124, 135, 147 scalable 89 scanning electron microscopy (SEM) 189 scanning transmission electron microscopy (STEM) 189 schiff bases 358 schizophrenia 135, 235 Sc(OTf)3 63 selective 106, 144 selectivities 62 selectivity 76, 126, 127 selenium reagent 23 SEM-EDX 295 separable approach 54 serine 136 serine OH group 140 short processing time 42 significant danger 41 silanization 189 silica sulfuric 52 silica-based heterogeneous 37 silica-coated nanoparticles 38 silico 151 silver salts 111 simple to process 66 simplified work-up 62 single-electron reduction 96 sintamil 378

Index

siRNA 202 societal issues 45 sodium – sodium azide 371 – sodium borohydride 371 – sodium hydride 370 – sodium hypophosphite 382 – sodium metaperiodate 371 solvent media 85 solvent-free 35, 101 solvents 101 sonogashira 80, 155, 290, 298 sonogashira coupling 193 sophisticated green chemistry measurements 45 sorafenib 164 sphaericus 170 spirocyclic 105 spirocyclic intermediate 368 spiro-N-heterocycle 96 stability 150 staphylococcus 170 starting materials 110 state 120 staudinger cycloaddition 358 stereochemistry 359 stereoisomer 358, 365 stereoselective synthesis 59 steric 107, 120, 121 steric hindered 81 stoichiometric 112, 125 strong 122 styrene oxide 80 substituents 107, 122 substitution 158 substrates 110 subtilis (MTCC 441) 170 sugasawa reaction 125 sulfonyl 104 sulfur 158 sulfur s-transferring agent 53 sulphonamides 151 sulphonyl 155 surface plasmon resonance 193 sustainable routes 34 suzuki-miyaura 296, 297, 326 suzuki-miyura cross coupling 193 symmetrical diaryl sulfides 21 symmetrically 123 synthetic 150

397

synthesis 101, 113, 117, 125, 128, 140, 141, 143, 144, 147, 155, 167, 176 synthesis cost was highly reduced 38 tandem 75, 98, 99, 153 tautomerization 83 tautomers 148 telangiectasia 145 terminal alkyne 93 terpenoid 261, 374 tetrahydrocinnoline 117 tetrahydrofuran 378 tetrahydropyran 378 the five and six-membered dithianes 58 therapeutic 151 therapeutically 85 thermal 150 thia-Michael 377 thiazolobenzimidazole fused dihydropyran derivatives 66 thienamycin 380 thiocarbonates 68 three-component 91, 121 tiacumicin B 276 tolerance 97 tolerated 89 toluene 372 tosyl hydrazine 121 tosylate 371 toxic 49 toxicity 77 trans-1-N-chryseneyl 374 transfer 140 transformations 136 transition 108, 120 transition metal 77 transition state 88 transmetalation 90 transmission electron microscopy (TEM) 189 triazine 135 triazole moeity 94 triazole ring 372 tri-chloroisocynuric 166 triethanolamine (TEOA) 36 triethylamine 371 trimethylamine 359 tumor 145 tunable 97 turn on 91 two stereoisomers of aldimines 43

398

Index

ultrasonic 101 ultrasonic technology 52 ultrasound- and microwave-assisted synthesis 190 unreactive 108 unsymmetrical thio ethers 22 unsymmetrically 123 valence band 188 VEGFR-2 kinase 161 via selective anodic oxidative difunctionalization/C–C bond cleavage 41 vinyl intermediate 83 vinyl-copper 105 vital biological functions 51 volatile organic solvents 77 water 88 WEB 290, 297–299, 302, 304, 306–310, 313, 321, 323–327

WELPSA 319 WEOFSA 294, 296 WEOPA 307, 321 WEPBA 290, 297, 298, 311, 321 WEPPA 302, 305, 321, 322 WERSA 290, 297, 299, 304, 309, 321, 325, 326 WET 302, 304, 321 wet oxidation 190 WETSA 306, 321 widman-stoermer synthesis 103 wilhelm 170 xylene 372 ylidenic 170 ylidenoisobenzofuran-1-ones 148 zolimidine 85 zwitterion 168