Multicomponent Synthesis: Bioactive Heterocycles [5] 9783110997330

Table of contents :
Cover
Half Title
De Gruyter Series in Green Bioactive Heterocycles
Green Bioactive Heterocycles: Volume 5
Multicomponent Synthesis: Bioactive Heterocycles
Copyright
Preface
Foreword
A brief professional profile of Prof. Eric F.V. Scriven
Contents
List of contributing authors
1. Synthesis of aza-heterocycles via one-pot domino multicomponent reaction approach
1.1 Introduction
1.2 Synthesis of aza-heterocycles via one-pot domino MCR
1.2.1 Synthesis of nonfused aza-heterocycles
1.2.1.1 Pyrrole and its analogs
1.2.1.2 Pyrazole and its analogs
1.2.1.3 Imidazole and its analogs
1.2.1.4 Tetrazole and its analogs
1.2.1.5 Isoxazole and its analogs
1.2.1.6 Thiazolidine derivatives
1.2.1.7 Pyridine and its analogs
1.2.1.8 Pyrimidine and its analogs
1.2.2 Fused aza-heterocycles
1.2.2.1 Indole and its analogs
1.2.2.2 Pyrrole fused aza-heterocycles
1.2.2.3 Pyrazole-fused aza-heterocycles
1.2.2.4 Imidazole-fused aza-heterocycles
1.2.2.4.1 Benzimidazoles
1.2.2.4.2 Imidazopyridines
1.2.2.5 Quinoline and its analogs
1.2.2.6 Quinazoline and its analogs
References
2. One-pot three-component selective annulation strategies for the synthesis of bioactive β-lactam, pyrrole, and pyridine scaffolds
2.1 Introduction
2.2 Three-component synthesis of β-lactams
2.2.1 Using Ugi reaction
2.2.2 Using Kinugasa reaction
2.2.3 Using Staudinger reaction
2.3 Three-component synthesis of pyrroles
2.3.1 From 1,3-dicarbonyl compounds
2.3.2 From alkynes
2.3.3 From carbonyl compounds
2.3.4 From α,β-unsaturated carbonyls (α,β-UC)
2.3.5 Miscellaneous
2.4 Three-component synthesis of pyridine
References
3. One-pot three-component synthesis of quinolines and some other selective six-membered heterocycles with biological importance
3.1 Introduction
3.2 Nitrogen-containing heterocycles
3.2.1 Quinoline derivatives
3.2.1.1 Synthesis of 3-arylsulfonylquinolines via cascade oxidative coupling
3.2.1.2 Synthesis of 3-arylquinolines via [3+1+1+1] annulation
3.2.1.3 Regioselective synthesis of substituted quinolines
3.2.1.4 Metal-free synthesis of 4-arylquinolines
3.2.1.5 An iron(III)-catalyzed synthesis of 2-pyridones
3.2.1.6 Solid-state synthesis of chromenopyridinones
3.2.1.7 Ball-milling approach of pyridocoumarin synthesis
3.2.2 Pyrimidines and quinazolines
3.2.2.1 Microwave-assisted synthesis of quinazolino[4,3-b]quinazolin-8-ones
3.2.2.2 I2/CuCl2 copromoted synthesis of 2-acyl-4-aminoquinazolines
3.2.2.3 Synthesis of 2,4-substituted quinazolines
3.2.2.4 Synthesis of 5H-chromeno[2,3-d]pyrimidin-5-one derivatives
3.2.2.5 Synthesis of 2,4,6-trisubstituted pyrimidines
3.2.2.6 Synthesis of imidazo[1,2-a]pyrimidines
3.2.3 1,4-Dihydropyridines (DHPs)
3.2.3.1 Metal-free synthesis of Hantzsch 1,4-dihydropyridines
3.2.3.2 Divergent synthesis of dual 1,4-dihydropyridines
3.2.4 Naphthyridines
3.2.4.1 Synthesis of substituted benzo[c]pyrazolo[2,7]naphthyridines
3.2.4.2 Ultrasonic-promoted synthesis of 1,6-naphthyridine
3.2.5 Spiro-heterocycles
3.2.5.1 Synthesis of indol-fused dispiro-heterocycles
3.2.5.2 Synthesis of spirooxindoles fused pyrazolo-tetrahydropyridinone and coumarin-dihydropyridine-pyrazole
3.3 Oxygen and sulfur-containing heterocycles
3.3.1 Pyran
3.3.1.1 Synthesis of pyrano[3,2-c]quinolone derivatives
3.3.1.2 Synthesis of tetrahydrobenzo[b]pyrans and pyrano[2,3-d]pyrimidinones
3.3.2 Oxazines
3.3.2.1 Synthesis of 1,3,5-oxadiazines
3.3.2.2 Synthesis of coumarin fused bis-oxazines
3.3.3 Thiazine
3.3.3.2 Synthesis of naphtho[1,2-e]/benzo[e][1,3]thiazine derivatives
3.3.3.1 Synthesis of 1,3-thiazine-4-ones
3.4 Conclusion
References
4. Multicomponent synthesis of biologically prominent tetrahydrobenzoxanthenone derivatives
4.1 Introduction
4.2 Homogeneous catalyst reported for benzoxanthenone derivative synthesis
4.2.1 Reported biological studies
4.3 Heterogeneous catalyzed reactions
4.3.1 Reported biological activities
4.4 Conclusions
Abbreviations
References
5. One-pot five/four-component synthesis of structurally diverse bioactive quinoxaline-annulated spiroheterocycles through the in situ formation of 11H-indeno[1,2-b]quinoxalin-11-ones
5.1 Introduction
5.2 Five-component synthesis of quinoxaline annulated spiroheterocycles
5.2.1 Five-component synthesis of spiro-pyrrolidines
5.2.2 Five-component synthesis of dispiro-pyrrolidines
5.3 Four-component synthesis of quinoxaline annulated spiroheterocycles
5.3.1 Four-component synthesis of spiro-pyrrolidine
5.3.2 Four-component synthesis of ferrocene-embedded spiropyrrolidine
5.3.3 Four-component synthesis of dispiro-indenoquinoxalines
5.3.4 Four-component synthesis of spiro-indenoquinoxalines
5.3.5 Four-component synthesis of spiropyrans–indenoquinoxalines
5.3.6 Four-component synthesis of spirofuran–indenoquinoxalines
5.4 Conclusions
References
6. Multicomponent synthesis of biologically active quinazolinone derivatives
6.1 Introduction
6.2 Biological applications
6.3 Chemical synthesis of quinazolinone derivatives
6.4 Conclusion
Abbreviations
References
7. Recent approaches toward the synthesis of 1,2,3-triazoles using multicomponent techniques
7.1 Introduction
7.2 The 1,2,3-triazole synthesis by three-component reaction
7.2.1 Three-component coupling among alkyl halide, terminal alkyne, and sodium azide
7.2.2 Three-component coupling among alkyl or aryl boronic acid, terminal alkyne or alkynyl carboxylic acid, and sodium azide
7.2.3 Three-component coupling among α-keto acetal, tosyl hydrazine, and primary amine
7.2.4 Three-component coupling among N-propargyl ortho-bromo benzamide, alkyl halide, and alkyl azide
7.2.5 Three-component coupling among aldehyde, nitroalkene, or nitroalkane and sodium azide
7.2.6 Three-component coupling among o-phenylenediamine, 2-azidobenzaldehyde, and arylchalcogenyl alkynes
7.2.7 Three-component coupling among epoxide, terminal alkyne, and sodium azide
7.2.8 Three-component coupling reaction among isatin Schiff base, sulfonamide, and aromatic aldehyde
7.2.9 Three-component coupling reaction of 2H-azirine, terminal alkyne, and sodium azide
7.2.10 Three-component coupling reaction of diazomethane sulfonamides, primary aliphatic amines, and aromatic aldehydes
7.2.11 Three-component coupling reaction of α-CF3 carbonyls (both ketone and ester), aryl azides, and amines
7.3 Four-component coupling reaction for triazole synthesis
7.3.1 Four-component coupling reaction 2-azidobenzenamines, aldehydes, propiolic acids, and isocyanides
7.3.2 Four-component coupling reaction among terminal alkyne, urea, α-azido ketone, and aromatic aldehyde
7.3.3 Four-component coupling reaction among acid chloride, TIPS-protected 1,3-butadiyne, hydrazine, and alkyl azide
7.4 Five-component coupling reaction for triazole synthesis
7.4.1 Five-component coupling reaction among indole, aromatic aldehyde, propargyl bromide, alkyl halide, and NaN3
7.4.2 Five-component coupling reaction via Ugi-4CR approach
7.4.3 Five-component coupling reaction of N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides, and sodium azide
7.5 Conclusion
List of abbreviation
References
8. Synthesis of various bioactive tetrazoles via one-pot multicomponent click reactions
8.1 Introduction
8.2 Recent literature reports
8.3 Conclusions
References
9. L-Proline and its derivatives catalyzed one-pot multicomponent synthesis of biologically promising N- and O-heterocycles
9.1 Introduction
9.2 Why proline prefers as a good organocatalysts among other natural
9.3 L-Proline-catalyzed synthesis of N-heterocycles
9.3.1 L-proline derivative-catalyzed N-heterocycle synthesis
9.3.2 Synthesis of N-heterocycle by using L-proline-supported catalysts
9.3.3 L-Proline-catalyzed synthesis of O-heterocycles
9.3.4 Proline derivatives catalyzed synthesis of O-heterocycle
9.3.5 Proline-supported catalyzed O-heterocycle synthesis
9.4 Conclusion
Abbreviations
References
10. Microwave-assisted solvent-free multicomponent synthesis of bioactive heterocycles
10.1 Introduction
10.2 Multicomponent reactions
10.3 Microwave-assisted synthesis of solvent-free multicomponent synthesis of heterocycles
10.3.1 Acridone derivatives
10.3.2 Pyrimidine derivatives
10.3.3 Imidazole and fused imidazole derivatives
10.3.4 Pyrrole and fused pyrrole derivatives
10.3.5 Pyridine derivatives
10.3.6 Nitrogen–sulfur heterocycles
10.3.7 Oxygen heterocycles
10.3.8 Spiroheterocycles
10.3.9 Fused bicyclic heterocycles
10.3.10 MW-assisted solvent-free MCR synthesis of heterocycles using catalyst
10.4 Conclusions
References
11. Deep eutectic mixture (DEM)-assisted multicomponent synthesis of heterocycles
11.1 Introduction
11.2 Deep eutectic mixtures (DEMs) as reaction media-cum-catalyst in multicomponent synthesis of heterocycles
11.2.1 Synthesis of spirooxindole and pyrano [2,3-c] pyrazole derivatives
11.2.2 Synthesis of chromene, pyrrole, and α-acyloxyamide derivatives
11.2.3 Synthesis of quinoline, imidazo pyridine, pyrazole, and Betti base derivatives
11.2.4 Synthesis of chromyl phosphate, dihydropyrimidinone, pyrazolopyridine, and pyrazolophthalazine
11.2.5 Synthesis of spirooxindolopyran, spirooxindoloxanthenes, aminobenzochromene, decahydroacridine, chromenopyridine, tetrahydrobenzopyran, and hexahydroxenthene -dione derivatives
11.2.6 Synthesis of pyranopyrimidinone, dihydropyridopyrimidine, and alkylidienethiazolone derivatives
11.3 Deep eutectic mixtures (DEMs) as catalyst with conventional reaction media in multicomponent synthesis of heterocycles
11.3.1 Synthesis of spirodioxoloquinolinepyrimidine, spiropyrazoloquinolinepyrimidine, and pyrazolopyrimidoquinoline derivatives
11.3.2 Synthesis of tetrahydrodipyrazolo pyridine, pyrrole, β-amino ketones, 2-aminochromene, and pyranocoumarin derivatives
11.4 Deep eutectic mixture (DEM)-compatible metallic catalysts in multicomponent synthesis of heterocycles
11.4.1 Synthesis of 3-aminobenzofuran, β-aminoketones, and imidazole derivatives
11.4.2 Synthesis of thieno indoles, aryl ether, and aryl amine derivatives
11.5 Conclusions
References
Index

Citation preview

Basudeb Basu and Bubun Banerjee (Eds.) Multicomponent Synthesis Green Bioactive Heterocycles

De Gruyter Series in Green Bioactive Heterocycles Volume  György Keglevich and Bubun Banerjee (Eds.) Non-Conventional Synthesis,  ISBN ----, e-ISBN ----

Volume  Asit K. Chakraborti, Bubun Banerjee (Eds.) Aqueous-Mediated Synthesis,  ISBN ----, e-ISBN ----

Volume  Yunfei Du, Bubun Banerjee (Eds.) Non-Metal Catalyzed Synthesis,  ISBN ----, e-ISBN ----

Volume  Sreekantha B. Jonnalagadda, Bubun Banerjee (Eds.) Solvent-Free Synthesis,  ISBN ----, e-ISBN ----

Volume  Basudeb Basu, Bubun Banerjee (Eds.) Multicomponent Synthesis,  ISBN ----, e-ISBN ----

Green Bioactive Heterocycles

Series Editor Bubun Banerjee

Volume 5

Multicomponent Synthesis Bioactive Heterocycles Edited by Basudeb Basu and Bubun Banerjee

Editors Prof. Basudeb Basu Department of Chemistry North Bengal University P.O. North Bengal University Darjeeling 734013 West Bengal India [email protected] Dr. Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India [email protected]

ISBN 978-3-11-099733-0 e-ISBN (PDF) 978-3-11-098531-3 e-ISBN (EPUB) 978-3-11-098611-2 ISSN 2752-1338 Library of Congress Control Number: 2023949913 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. © 2024 Walter de Gruyter GmbH, Berlin/Boston Cover image: Back Image: IkonStudio/iStock/Getty Images Plus Front Image: Shaiith/iStock/Getty Images Plus Typesetting: Integra Software Services Pvt. Ltd. Printing and binding: CPI books GmbH, Leck www.degruyter.com

Preface Heterocyclic compounds are ubiquitous and find numerous significant applications in biological, agricultural and material sciences. Bio-active heterocycles are often used as potential drugs, such as antifungal, anti-bacterial, antiviral, antipyretics, anti-allergic, anti-hypertensive, anti-cancer are a few among the myriads. In view of their potential applications as drugs to combat with various diseases, chemists and biologists are deeply concerned with developing new synthetic procedures that are eco-friendly, cost-effective as well as new drug molecules bearing more efficient pharmaceutical activities. Biologists play the important role to evaluate the biological activities, assay their toxicity and effective doses. Multi-component reaction (MCR) represents one of the highly efficient and sustainable methods for the synthesis of heterocyclic compounds. In MCR, the target molecule is synthesized in one-pot convergent approaches using three or more chemical entities. The expediency of MCR can be recognized with many-fold advantages that are usually not possible by conventional multi-step sequential assembly. The present volume is a part of the book series entitled ‘Green Bioactive Heterocycles’ and has been intended primarily to focus on various multi-component reactions that have been developed over the last few decades towards the synthesis of various bioactive heterocyclic molecules. This volume has contained eleven chapters, each having its unique characteristics on the MCRs leading to heterocycles having one or more N, O or S atoms as well as focusing the importance and advantages of non-conventional energy sources, deep eutectic reaction media etc. The first chapter presents a glimpse on the formation of different N-based heterocyclic small molecules by one-pot domino MCR approach. The domino process in general provides several advantages like minimizing the number of steps involved in the process, avoiding the need of isolation, purification in each step and thus becomes a speedy process. The domino strategies towards the construction of heterocyclic molecules would stimulate further development in this direction. Next two chapters delineate three-component MCR strategies leading to the construction of bioactive scaffolds such as β-lactam, pyrrole, pyridine, pyrimidine, naphthyridines, quinazolines, quinolines, pyran, oxazine, thiazine and spiro-heterocyclic moieties as well as their biological significance, mechanistic interpretations etc. The chapter 4 describes various MCR strategies for the synthesis of tetrahydrobenzo[α]xanthene-11-one derivatives. Benzoxanthenes, xanthenes, and benzoxanthenones represent an important class of O-based heterocycles and often find applications in pharmaceuticals, agrochemicals, and material sciences. Chapters 5 and 6 include 4/5-component based MCRs for the synthesis of structurally diverse quinoxaline-annulated spiroheterocycles and quinazolinone derivatives respectively, whereas chapters 7 and 8 present an update on triazoles and tetrazoles respectively via multi-component reactions. L-Proline is the only secondary amine found in the natural amino acids and is often used as a catalyst in various organic transformations. The chapter 9 gives an account on MCRs https://doi.org/10.1515/9783110985313-202

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Preface

catalyzed by L-proline and its derivatives leading to the synthesis of various bioactive N- and O-heterocyles along with an outlook and current trends in this area. Microwave-assisted solvent-free multi-component synthesis of bioactive heterocycles has been summarized in the chapter 10 and the last chapter presents an overview on the applications of deep eutectic mixture (DEM)-promoted multi-component synthesis of various heterocyclic scaffolds used in making drug molecules. Overall, the present book has been attempted to cover the utility and diversity of MCRs for the synthesis of different bioactive heterocyclic compounds. Recent updates on several aspects, the mechanistic considerations and future directions could offer guidance to synthetic chemists for designing new reactions and new heterocyclic chemical entities involving MCRs. Furthermore, this book is expected to provide huge interests to the pharmaceutical chemists both in academia and industries in the years to come. Prof. Basudeb Basu & Dr. Bubun Banerjee

Foreword Principles of green chemistry are a paramount consideration when designing targetdriven synthetic organic chemistry processes today. Consequently, MCR (multicomponent reaction) options are often the first place investigators look especially when the target is a complex molecule. MCRs have been defined as convergent multistep reactions which involve three or more components to give a single product in one pot. Such processes have advantages of high efficiency and atom economy over linear processes. The first example of an MCR was synthesis of an aminonitrile reported by Strecker in 1850. The first involving obtention of a heterocycle was the Hantzsch dihydropyridine synthesis (1881). Much later a four-component example was described by Ugi (1960). Seminal reviews and publications by Posner, Tietze, Padwa, T.J.J. Mueller and others not only described published work but emphasized the potential for MCRs to effect diversity-oriented synthesis, lead to high product yields, minimize waste, and result in less energy consumption. This has led to the plethora of work reviewed in Green Bioheterocycles. The book series ‘Green Bioactive Heterocycles’, edited by Dr. Bubun Banerjee, presents the current state of the art in diversity-oriented synthesis applied to formation of complex products of importance in medicinal and bio-organic chemistry and production of functional molecules. I believe from my experience in academic and industrial chemistry that this work will provide a powerful tool in the hands of practitioners in both areas. This volume ‘Multicomponent Synthesis: Bioactive Heterocycles’, edited by Prof. Basudeb Basu and Dr. Bubun Banerjee, contains 11 chapters which comprise a very valuable treatment of the latest work on MCRs for those working in the field. The first seven chapters are divided by major heterocyclic systems to bring focus to target oriented synthetic work. The subsequent four chapters are more concerned with current and new techniques being used for discovery and development work. The first chapter looks broadly at options and highlights in particular domino MCR strategy for aza-heterocyclic synthesis. Chapter 2 covers ways to make Beta-lactams, pyrroles, and pyridines with a nice treatment of the mechanistic side. Advances in the synthesis of complex six-membered heterocycles of biological importance, often featuring the Ugi and Passerini reactions, are reported in Chapter 3. Chapter 4 deals with biologically important benzoxanthenes, xanthenes, and derivatives. In Chapter 5, recent work on one pot five/four-component synthesis of structurally diverse bioactive quinoxaline-annulated spiroheterocycles is discussed. Chapter 6 concentrates on multicomponent synthesis of bioactive quinazolone derivatives. Recent approaches to the multicomponent synthesis of 1,2,3-triazoles is the topic of Chapter 7. Chapter 8 considers the contribution of multicomponent click reactions to the synthesis of tetrazoles. The role of L-proline and its derivatives as catalysts is examined in Chapter 9. Chapter 10 contains a review of the contribution of MW-assisted solvent

https://doi.org/10.1515/9783110985313-203

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free MCRs for formation of bioheterocycles. The potential for Deep Eutectic Mixture (DEM) assisted MCR synthesis is described in Chapter 11. Dr. Eric F.V. Scriven Publishing Editor Arkivoc President, ARKAT USA, Inc. Gainesville, Florida, USA Email: [email protected] Formerly Head of Research & Development Reilly Industries, Inc., Indianapolis, USA

A brief professional profile of Prof. Eric F.V. Scriven Eric Scriven is a native of Wales, UK. After working at BISRA and ESSO, he attended the University of Salford, graduated in 1965. He received his M.Sc. University of Guelph, 1967 (M.J. Nye) and PhD, University of East Anglia, 1969 (A. R. Katritzky). After postdoctoral years at the University of Alabama (R.A. Abramovitch) and University College London (J.H. Ridd), he was appointed Lecturer in Organic Chemistry at the University of Salford. At Salford his research concentrated on the reactivity of azides and nitrenes applied to heterocyclic synthesis and photoaffinity labeling. He joined Reilly Industries in 1979 and became Head of Research and Development. There he was the leader of discovery and development programs in pyridine chemistry. Currently, he is at the University of Florida. He has edited two books, Azides & Nitrenes (1984) and Pyridines: from Lab to production (2013). He with Professor H. Suschitzky were founding editors of Progress in Heterocyclic Chemistry which has been published from 1989 to the present. He collaborated with Professors Alan Katritzky and Charles Rees on Comprehensive Heterocyclic Chemistry II (1996) and CHEC III (2008) with Professors Katritzky, Ramsden, and Taylor. He has been editor/coeditor (with C.A. Ramsden) of Advances in Heterocyclic Chemistry since 2014, vol.114 to 145 et seq. Currently, he is the Publishing Editor of Arkivoc, an online journal of organic chemistry that is free to readers, authors, and their institutions, founded by Professor Alan Katritzky in 2000.

https://doi.org/10.1515/9783110985313-204

Contents Preface Foreword

V VII

A brief professional profile of Prof. Eric F.V. Scriven List of contributing authors

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Nirjhar Saha, Soumili Biswas, Maulikkumar D. Vaja, Anirban Sarkar, Asit K. Chakraborti 1 Synthesis of aza-heterocycles via one-pot domino multicomponent reaction approach 1 Bijoy P Mathew, Jagmeet Singh, Mahendra Nath 2 One-pot three-component selective annulation strategies for the synthesis of bioactive β-lactam, pyrrole, and pyridine scaffolds

55

Samiran Dhara, Saiful Islam, Asish R. Das 3 One-pot three-component synthesis of quinolines and some other selective six-membered heterocycles with biological importance

117

Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath 4 Multicomponent synthesis of biologically prominent tetrahydrobenzoxanthenone derivatives 157 Bubun Banerjee, Aditi Sharma, Manmeet Kaur, Arvind Singh, Anu Priya 5 One-pot five/four-component synthesis of structurally diverse bioactive quinoxaline-annulated spiroheterocycles through the in situ formation of 11H-indeno[1,2-b]quinoxalin-11-ones 181 Kantharaju Kamanna, Radhika Mane, Yamanappagouda Amaregouda, Aravind Kamath 6 Multicomponent synthesis of biologically active quinazolinone derivatives 221 Sujit Ghosh, Basudeb Basu 7 Recent approaches toward the synthesis of 1,2,3-triazoles using multicomponent techniques 253

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Yadavalli Venkata Durga Nageswar, Katla Ramesh, Katla Rakhi 8 Synthesis of various bioactive tetrazoles via one-pot multicomponent click reactions 305 Kantharaju Kamanna, Yamanappagouda Amaregouda 9 L-Proline and its derivatives catalyzed one-pot multicomponent synthesis of biologically promising N- and O-heterocycles 337 CH. N. S. Sai Pavan Kumar, Vaidya Jayathirtha Rao 10 Microwave-assisted solvent-free multicomponent synthesis of bioactive heterocycles 373 Divyang M. Patel, Hitendra M. Patel 11 Deep eutectic mixture (DEM)-assisted multicomponent synthesis of heterocycles 399 Index

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List of contributing authors Samiran Dhara Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India Saiful Islam Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India Asish R. Das Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India Email: [email protected] Yadavalli Venkata Durga Nageswar Retired Chief Scientist Indian Institute of Chemical Technology – IICT Tarnaka, Hyderabad India Email: [email protected] Katla Ramesh Organic Chemistry Laboratory-4 School of Chemistry and Food Federal University of Rio Grande-FURG Rio Grande RS-Brazil Katla Rakhi Organic Chemistry Laboratory-4 School of Chemistry and Food Federal University of Rio Grande-FURG Rio Grande RS-Brazil

https://doi.org/10.1515/9783110985313-206

Bijoy P Mathew Department of Chemistry Vimala College (Autonomous) Thrissur 680 009, Kerala India Jagmeet Singh Department of Chemistry Faculty of Science University of Delhi Delhi 110 007 India Mahendra Nath Department of Chemistry Faculty of Science University of Delhi Delhi 110 007 India Divyang M. Patel Department of Chemistry Sankalchand Patel University Visnagar 384315, Gujarat India Hitendra M. Patel Department of Chemistry Sardar Patel University Vallabh Vidyanagar 388120, Gujarat India Email: [email protected] CH. N. S. Sai Pavan Kumar Associate Professor Department of Chemistry, School of Applied Sciences and Humanities Vignan’s Foundation for Science, Technology and Research (VFSTR) Vignan University Vadlamudi, Guntur 522 213, Andhra Pradesh India Email: [email protected]

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List of contributing authors

Vaidya Jayathirtha Rao Emeritus Scientist-CSIR & Honorary Professor AcSIR Natural Products and Medicinal Chemistry (NPMC) Department and AcSIR-Ghaziabad CSIR – Indian Institute of Chemical Technology Uppal Road Tarnaka, Hyderabad 500007, Telangana India Email: [email protected] Kantharaju Kamanna School of Basic Sciences Department of Chemistry Rani Channamma University Vidyasangama, P-B, NH-4, Belagavi 591156 Karnataka Email: [email protected] Yamanappagouda Amaregouda School of Basic Sciences Department of Chemistry Rani Channamma University Vidyasangama, P-B, NH-4, Belagavi 591156 Karnataka Aravind Kamath School of Basic Sciences Department of Chemistry Rani Channamma University Vidyasangama, P-B, NH-4, Belagavi 591156 Karnataka Sujit Ghosh Department of Chemistry Raiganj Surendranath Mahavidyalaya Raiganj, West Bengal India Basudeb Basu Formerly Department of Chemistry North Bengal University Darjeeling, West Bengal India Email: [email protected]

Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda, Punjab 151302 India Email: [email protected] Aditi Sharma Department of Chemistry Akal University Talwandi Sabo, Bathinda, Punjab 151302 India Manmeet Kaur Department of Chemistry Akal University Talwandi Sabo, Bathinda, Punjab 151302 India Arvind Singh Department of Chemistry Akal University Talwandi Sabo, Bathinda, Punjab 151302 India Anu Priya Department of Chemistry Akal University Talwandi Sabo, Bathinda, Punjab 151302 India Radhika Mane Department of Chemistry School of Basic Sciences Rani Channamma University Vidyasangama, P-B, NH-4, Belagavi 591156 Karnataka Nirjhar Saha School of Chemical Sciences Indian Association for the Cultivation of Science (IACS) Jadavpur, Kolkata 700 032, West Bengal India

List of contributing authors

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Soumili Biswas School of Biological Sciences Indian Association for the Cultivation of Science (IACS) Jadavpur, Kolkata 700 032, West Bengal India.

Anirban Sarkar Department of Chemistry Vidyasagar College for Women 39 Sankar Ghosh Lane, Kolkata 700006, West Bengal India

Maulikkumar D. Vaja Department of Pharmaceutical Chemistry Saraswati Institute of Pharmaceutical Sciences Dhanap, Gandhinagar 382355, Gujarat India

Asit K. Chakraborti School of Chemical Sciences Indian Association for the Cultivation of Science (IACS) Jadavpur, Kolkata 700 032, West Bengal India E-mail: [email protected]; [email protected]

Nirjhar Saha, Soumili Biswas, Maulikkumar D. Vaja, Anirban Sarkar, Asit K. Chakraborti✶

1 Synthesis of aza-heterocycles via one-pot domino multicomponent reaction approach 1.1 Introduction Multicomponent reaction (MCR) is a convergent reaction in which three or more molecules/reactants combine through a cascade of reactions in one pot to form a product in which usually the structural features of each and every component (reacting molecule) are incorporated [1]. Sometimes MCRs are referred to as a “multicomponent assembly process” (MCAP). The first MCR, three-component reaction (3-MCR) involving aldehyde, ammonia, and potassium cyanide, was reported in 1850 known as Strecker synthesis generating α-amino nitrile/cyanide from which α-amino acid was obtained by hydrolysis of the nitrile group [2]. The MCR strategy is used in various organic syntheses such as total synthesis, synthesis of natural products, complex molecules, functional materials, sequence-controlled polymers, macrocyclic peptides, and easing out the complexity in asymmetric synthesis [3–10]. For the construction of diverse heterocyclic ring systems the MCR strategy has been recognized as an important tool to synthetic organic/medicinal chemists [11–16]. The MCRs allow simple, spontaneous, and high-throughput production of small organic molecule. The MCRs have inherent atom economy with advantages of selectivity and synthetic convergence and are considered as advanced tools of sustainable organic synthesis [17]. The MCR strategy is increasingly finding attention in drug discovery with immense opportunities in pharmaceutical industry [18–20]. On the other hand, aza-heterocyclic framework (cyclic system with at least one Natom present in the ring) has been recognized as the privileged pharmacophoric fea-

Acknowledgment: AKC and NS thank the Department of Atomic Energy, Mumbai, India, for the award of Raja Ramanna Fellowship and Research Associateship, respectively. ✶ Corresponding author: Asit K. Chakraborti, School of Chemical Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700 032, West Bengal, India, e-mails: [email protected], [email protected] Nirjhar Saha, School of Chemical Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700 032, West Bengal, India Soumili Biswas, School of Biological Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700 032, West Bengal, India Maulikkumar D. Vaja, Department of Pharmaceutical Chemistry, Saraswati Institute of Pharmaceutical Sciences, Dhanap, Gandhinagar 382355, Gujarat, India Anirban Sarkar, Department of Chemistry, Vidyasagar College for Women, 39 Sankar Ghosh Lane, Kolkata 700006, West Bengal, India

https://doi.org/10.1515/9783110985313-001

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ture (structural component) to medicinal chemists in the perspective of drug discovery due to the prevalence of aza-heterocyclic ring systems in the preparation of drug candidate molecules, clinical drug candidates, US-FDA-approved drugs and pharmaceuticals, and essential medicines [21–27]. A few representative examples of drugs and bioactive molecules containing diverse aza-heterocyclic ring systems are provided in Figure 1.1. Our group had been involved in the development and use of various MCR strategies and one-pot cascade/domino process that find applications in the construction of various aza-heterocyclic ring systems, for the synthesis of drug molecules, and identification of novel anti-Leishmanial and anti-TB scaffolds for new lead candidates [28–45]. This chapter intends to provide the readers a glimpse on the formation of various aza-heterocyclic ring systems by one-pot domino MCR approach.

1.2 Synthesis of aza-heterocycles via one-pot domino MCR 1.2.1 Synthesis of nonfused aza-heterocycles 1.2.1.1 Pyrrole and its analogs The MCR strategy is the most convenient and explored route for the construction of pyrrole ring [46]. The one-pot three-component domino reaction approach involving arylglyoxal monohydrates (1), acyclic 1,1-enediamines (2), and coumarins (3) in EtOH under reflux for the synthesis of 2-amino-4-coumarinyl-5-arylpyrrole (4) derivatives was explored. The nature of the 1,1-enediamine substrate and the solvent showed influence on the product formation. The use of cyclic 1,1-enediamines (2) and performing the reaction in 1,4-dioxane under reflux in open air leads to the formation of 2-amino-4coumarinyl-5-aryl-6-hydroxylpyrroles (5) (Figure 1.2). The reaction has wide scope with different substituted reagents except nitro-substituted 1,1-enediamines that did not produce the desired product. The six-membered 1,1-enediamines gave higher product yield as compared with five-membered 1,1-enediamines. The mechanism course of the reaction was studied using HPLC-high-resolution mass spectrometry (HRMS) study. It involves the following sequence of reactions: (i) 1,2-addition, (ii) dehydration, (iii) 1,4Michael addition, (iv) imine-enamine tautomerism, (v) 1,2-addition, (vi) dehydration, (vii) keto-enol tautomerism, (viii) abstraction of proton, and (ix) single electron transfer (SET). The SET mechanism was confirmed by using 2,2,6,6-tetramethyl-1-piperidinyloxy as a radical scavenger [47]. Kamalraja and coworkers [48] reported a new approach for the synthesis of polysubstituted pyrrole and fused chromenopyrrole frameworks (9) by a transition metal-free

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Figure 1.1: Drug and bioactive molecules with aza-heterocyclic scaffolds.

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Figure 1.2: Synthesis of pyrrole derivatives by MCR process – influence of active methylene group and solvent on product formation.

one-pot domino reaction. The main advantage of this reaction is regioselectivity and broad application (Figure 1.3). The MCR involving the α-zido ketones (6), 3-formylchromones (7), and the active methylene compounds (8) in aqueous medium in the presence of 10 mol% of piperidine afforded chromenoindolylpyrrole/chomenophenylpyrrole, chromenopiperido/morpholinopyrroles, chromenopyridoiminopyrrole, chromenopyrrole, and chromenopyrrolopyrrole derivatives (Figure 1.3). The reaction proceeds via two different paths generating different products depending upon the nature of active methylene compounds. The non-cyano-based active methylene substrates formed the fused chromenopyrrole scaffolds. On the other hand, the use of cyano-based active methylene compounds afforded the tetrasubstituted pyrroles in two regioisomers forms based on the mechanistic course of the reaction, that is, whether the cyano-based active methylene compound undergoes reaction at the nitrile group or the carbonyl group. The preference for reaction at the nitrile has been observed where the carbonyl has aryl moiety. This MCR proceeds through domino Knoevenagel, Michael addition, cyclization, and rearrangement pathway as the commonly operative mechanistic pathway. The formation of phosphorus containing γ-lactam derivatives (13) was accomplished [49] by a phosphoric acid and binol-derived Bronsted acid-promoted MCR of pyruvate derivatives (10), amines (11), and aldehydes (12) (Figure 1.4). The reaction proceeds by an initial formation of the imine resulting from the condensation between the aldehyde carbonyl and the amine nitrogen promoted by MgSO4 [50]. This is followed by aza-aldol-type reaction by nucleophilic attack by the enol form of the active methylene group of 10 and intramolecular nucleophilic substitution at the ester carbonyl of 10 by the generated amide anion. Depending on the substitution at the five-membered ring het-

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Figure 1.3: Piperidine-catalyzed 3-MCR for the synthesis of polysubstituted pyrroles.

erocycle, the products were obtained in the form of 3-hydroxy-1,5-dihydro-2H-pyrrol-2one or their enamine derivatives (resulting from the nucleophilic substitution of the OH group of the enol form of the pyrrolidone by the amine reactant) wherein there is no substituent at C-5 of the pyrrolidone ring or pyruvate substrate does not contain any substitution in the phospheneoxide moiety. Employing substituted BINOL-derived phosphoric acids as the organocatalyst, certain examples of the enantioselective variant of the procedure were also reported. Additionally, 3-amino 1,5-dihydro-2H-pyrrol-2-one derivatives have demonstrated effective synthetic intermediates in a number of diastereoselective transformations, using the chiral carbon present in the γ-lactam scaffold [49].

Figure 1.4: Bronsted acid-catalyzed 3-MCR for the synthesis of pyrrolinones.

Under catalyst-free conditions, a new MCR for the synthesis of polysubstituted pyrrolidine derivatives (18) was reported. Carbon disulfide (14), secondary amines (15), aliphatic/alicyclic isocyanides (16), and gem-dicyano olefins (17) were used in a one-pot, four-component condensation procedure at room temperature for diastereoselective synthesis of polysubstituted pyrrolidines in 56–96% yields (Figure 1.5). It has been proposed that the overall process includes an intramolecular cyclization that produces

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the basic structure of pyrrolidine after a Mumm-type rearrangement with dithiocarbamates. The 4-MCR involving a domino reaction generates five new bonds in the desired product: one carbon–sulfur, two carbon–nitrogen, and two carbon–carbon [51].

Figure 1.5: 4-MCR for the synthesis of pyrrolidines.

Through the effective one-pot condensation of 1,3-dicarbonyl compounds (19), acrylates (20), and ammonium salts (21) with Cu(OAc)2H2O in HFIP as solvent, Huang and coworkers [52] have generated a series of 2,3,5-trisubstituted pyrroles (22) (Figure 1.6). The reaction results in the creation of carbon–carbon and carbon–nitrogen bonds and offers a quick way to obtain highly functionalized pyrroles without the need for additional raw material processing. The target products are produced using this approach in moderate-to-good yields and are compatible with a wide range of functional groups. The reaction proceeds via the sequence: enamine formation, Michael addition, reductive elimination, and oxidation that has been demonstrated by some control experiment studies taking preformed enaminone of the β-diketone (that gave the desired product) versus preformed Michael adduct of the β-diketone and the acrylate ester that failed to produce the desired product and mass spectrometric identification of the dihydroproduct [52]. The role of Cu(OAc)2 has been proposed to activate the acrylate ester via π-coordination with the acrylate for the Michael addition with the enamine (formed from NH4OAc and the β-diketone) and in the final step to oxidize the dihydroproduct. The solvent HFIP also plays an important role as no product formation took place in MeCN or DCM. Though the specific role of HFIP has not been proposed it is likely that HFIP assists in the formation of the enaminone via converting the β-diketone to its enol form through hydrogen bond (HB)-assisted keto-enol tautomerism and thereafter activating the β-hydroxy enone (the enol form) for azaMichael-type addition due to the strong HB donor property of HFIP [53] and the feasibility of promoting hetero (aza/thia)-Michael addition by imidazolium-based ionic liquids (ILs) as well as water that are capable to activate enone carbonyl group via HB formation [54–56]. The synthesis of substituted pyrroles tethered to pyrazole scaffold (25) using a one-pot, four-component sequential process was designed using an effective green sonochemical method under bronsted acid catalysis. Under ultrasonic irradiation, this reaction was conducted utilizing a variety of 5-amino-pyrazoles (23), aldehydes (12),

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Figure 1.6: Synthesis of trisubstituted pyrroles.

aliphatic/alicyclic isocyanides (16), and dialkyl acetylenedicarboxylates (24) in the presence of p-TsOH (5 mol%) leading to chemoselective formation of functionalized pyrroles (25) in good to excellent yields (Figure 1.7). By forming two five-member heterocycles that are joined in a single step and four new bonds (two carbon–nitrogen and two carbon–carbon bonds), this waste-free (–H2O) reaction demonstrated a high atom economy. The synthesized 1-(pyrazol-5-yl)pyrrole derivatives exhibit intriguing fluorescence characteristics. This four-component domino process mechanism comprised successive processes including imination, dipolar cyclization, and [1,5]-H shift [57].

Figure 1.7: Ultrasound-assisted one-pot domino 4-MCR for the synthesis of pyrazole-linked pyrroles.

By performing the multicomponent tandem [2 + 2 + 1] annulation reaction using an aldehyde (12), glycine ester hydrochloride (26), and benzoylacetonitrile (8), functionalized 2pyrrolines (27) have been generated (Figure 1.8). The sequential one-pot annulation reaction offered a highly stereoselective way to create fully substituted 2-pyrrolines with two contiguous stereocenters from imino esters with benzoylacetonitriles in good yields under benign conditions in the presence of a catalytic amount of bifunctional chiral squaramide. The reaction had a moderate overall yield, but given that it produced two new carbon–nitrogen bonds and one carbon–carbon bond, it was nevertheless surprisingly efficient. Contrarily, chiral 2-pyrrolines were successfully synthesized from aldehyde and glycine ester hydrochloride using a Schiff base imino ester through individual organocatalytic asymmetric domino annulation reactions, followed by a one-pot sequential process, yielding essentially only 2-pyrrolines (2S,3S) with er values as high as 94:6 and dr ratios >20:1 [58].

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Figure 1.8: Synthesis of polysubstituted pyrrolines.

1.2.1.2 Pyrazole and its analogs The bis(pyrazol-5-ol) derivatives (30) were generated through one-pot three-component domino reaction of various aromatic aldehydes (12), ethyl acetoacetate (EAA) (28), and hydrazine hydrate/phenyl hydrazine (29) in the presence of guanidine hydrochloride. The condensation reaction between EAA and hydrazine, followed by the cyclization process, built up the pyrazole scaffold. In the final step, the aldol-type condensation furnishes the desired bis(pyrazol-5-ol) derivatives (Figure 1.9) [59]. The formation of pyrazole ring from the reaction of EAA and hydrazine may also occur through simultaneous double nucleophilic attack by the hydrazine that acts as bis-nucleophilic agent on two carbonyl groups of EAA (acting as bis-electrophile). This usually occurs during the reaction of 1,2-diamines (e.g., o-phenylenediamine) with 1,2-dicarbonyls (e.g., ethyl glyoxalate) to form quinoxalin-2(1H)-one ring system [60]. The reaction of pyrazole with the aldehyde in a 2:1 molar ratio may also proceed analogous to the well-known bis-indolylmethane formation process [61].

1.2.1.3 Imidazole and its analogs Our group invented two solid-supported protic acids as heterogeneous catalysts systems namely HClO4–SiO2 (230–400) and HBF4–SiO2 (230–400) [62–64] that were found to be versatile in catalytic potential [65–72] and attracted attention of other researchers globally for applications in organic synthesis. Using the heterogeneous catalyst HBF4–SiO2 (230–400), one-pot three-component and four-component reactions were

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Figure 1.9: Guanidine-catalyzed one-pot MCR for the synthesis of bis-pyrazole derivatives.

carried out by our research group for the synthesis of trisubstituted (32) and tetrasubstituted imidazoles respectively (34). This heterogeneous catalyst was recycled and reused up to five times without any loss in its catalytic potential. The MCR of benzil derivatives (31), aromatic aldehydes (12), and ammonium acetates (21) constructed the tri-aryl substituted imidazoles (32) while the MCR of 31, 12, benzyl amines (33), and NH4OAc (21) selectively provided the N-benzylated imidazoles (34) using HBF4– SiO2 catalyst. This was the first literature report which addressed the selective formation of the tetrasubstituted imidazoles within the competitive formation of the both tri- and tetrasubstituted imidazoles based on the effect of the catalyst. Detailed reaction condition optimization study suggested that the LiBF4 was also the efficient catalyst with higher amount of catalyst loading for the synthesis of trisubstituted imidazoles under homogeneous reaction condition. In case of tetrasubstituted imidazole synthesis, Zn(BF4)2 with higher amount of catalyst loading was efficient in catalyzing the 4-MCR. Both of the LiBF4 and Zn(BF4)2 work under homogeneous condition, and there is no scope of recyclability. In contrast, HBF4–SiO2 catalytic system was recycled and reused in the MCR (Figure 1.10) [73]. The efficient synthesis of tetrasubstituted imidazoles (39) was carried out through one-pot, four-component domino reaction of hydroxylamine (35), cyclic-1,3-diketones (36), benzyl/arylcyanide (37), and arylglyoxals (38) in ethanol under reflux condition (Figure 1.11). Reaction starts with the nucleophilic addition of hydroxylamine to nitrile derivatives for in situ generation of amidine intermediate. In a simultaneous cascade, the Claisen–Schmidt-type condensation between the 1,3-dicarbonyl compound and glyoxal furnishes the corresponding enones. The aza-Michael addition of amidine intermediate to the β-carbon of enones, followed by cyclocondensation forms the desired imidazole derivatives. The notable advantages of this reported methodology are metal-free reaction condition, easy work-up process, higher yield of the product, and shorter reaction time [74]. The Pd-catalyzed one-pot 3-MCR involving methyl α-isocyanoacetates (40), primary aromatic amines (11), and sulfonyl azides (41) yielded the tetrasubstituted imidazolone derivatives (42) via formation of the sulfonyl guanidine and Pd-nitrene intermediates (Figure 1.12). This methodology offers a broad substrate scope, low amount of catalyst, and ligand loading [75].

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Figure 1.10: Heterogeneous catalyst HBF4–SiO2 (230–400)-catalyzed one-pot MCR for the synthesis of triand tetrasubstituted imidazoles.

Figure 1.11: Catalyst-free four-component synthesis of imidazoles.

Figure 1.12: Multicomponent synthesis of imidaolones.

The preformed amidine (43), synthesized by the reaction of amine and nitrile derivatives, was treated with aromatic amine (11) and glyoxal (38) in the presence of catalytic amount of disodium phosphate (Na2HPO4) to synthesize another set of tetrasubstituted imidazoles (44) through one-pot, three-component domino reaction (Figure 1.13). Ini-

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tially, the condensation reaction between the glyoxal derivatives and aromatic amines in situ generated the imine intermediate which undergoes nucleophilic addition with the amidines. Finally, the intramolecular cyclocondensation process accomplishes the formation of tetrasubstituted imidazoles [76].

Figure 1.13: Disodium phosphate-catalyzed synthesis of imidazoles.

1.2.1.4 Tetrazole and its analogs Tetrazole scaffold is a biorelevant privileged structural feature found in various bioactive molecules [77, 78] and the one-pot multicomponent domino reaction is a popular strategy for construction of this bioactive scaffold [79]. The Zn(II)-catalyzed Ugi-type MCR was explored for the synthesis of tetrazole derivatives. The MCR of isocyanides (16), sulfonamides (45), aldehydes (12), and sodium azide (46) in the presence of Zn(II) catalysis formed the desired tetrazoles (47) (Figure 1.14). Metal Lewis acid-assisted electrophile activation of aldehydes initiates the imine formation between the aldehydes and sulfonamides. In the next step, the ZnCl2-promoted imine activation favors the nucleophilic addition of isocyanides to the imine center. The nucleophilic addition of the azide to the nitrilium moiety and subsequent sigmatropic rearrangement constructs the desired tetrazoles [80].

Figure 1.14: Metal Lewis acid-catalyzed 4-MCR for the synthesis of tetrazoles.

Asymmetric synthesis of tetrazole compounds (50) bearing the chiral center was carried out through one-pot MCR of isocyanides (16), silyl azides (48), and alkylidene malonate derivatives (49) in the presence of chiral Mg(II)-N,Nʹ-dioxide as the catalyst (Figure 1.15) [81].

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Figure 1.15: Synthesis of chiral tetrazole derivatives.

1.2.1.5 Isoxazole and its analogs The cobalt acetylacetonate-catalyzed 4-MCR of perfluoroalkyl reagent/Togni’s reagent (51/55), styrenes (52), azides (46), and TBHP (53) furnished the one-pot domino synthesis of isoxazole derivatives (54/56) via radical pathway (Figure 1.16). The reaction proceeds through the Co(II)-assisted C–I bond cleavage followed by the addition of styrene via radical mediated C–C bond formation. C–O bond formation was achieved through radical coupling with TBHP. In the next step, the DABCO-catalyzed Kornblum−DeLaMare rearrangement followed by dehalogenative aza-Michael addition reaction and intramolecular cyclization via N–O bond formation provided the desired isoxazole derivatives through one-pot MCR approach. Togni’s reagent was also used as trifluoromethyl source for the synthesis of isoxazole azides [82].

Figure 1.16: Co-catalyzed synthesis of isoxazoles via 4-MCR.

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A synthetic enzyme (synzyme) was explored as the catalyst to promote the one-pot 3MCR process for synthesis of isoxazol-5(4H)-one derivatives (57) involving the reaction of aromatic aldehydes (12), EAA (28), and hydroxylamine (41) (Figure 1.17). The synzyme acts as the organocatalyst and structurally, it is the hybrid of polyethylene imine (PEI) and imidazolium IL. This synzyme is entitled as “PEI-IL.” IL is a well-established organocatalyst in the field of organic synthesis [30, 54, 55, 61, 83–87]. In the course of the reaction, the IL component activates the electrophilic carbonyl group through the hydrogen bonding by its C-2 hydrogen. This activation promotes the oxime formation by the reaction of β-ketoesters and hydroxylamines. The imine-enamine tautomerism and subsequent cyclization constructs the isoxazolone scaffold. In the final step, the PEI-IL-promoted aldol-type condensation between aldehydes and isoxazolone furnished the desired product. The catalytic system could be reused up to 15 times without any notable loss of its activity. The detailed mechanistic course of the reaction was established by performing the ESI-MS study. The antimicrobial abilities of all synthesized derivatives against Gram-positive and Gram-negative strains were also evaluated in this work [88].

Figure 1.17: Synzyme-catalyzed construction of isoxazoles.

1.2.1.6 Thiazolidine derivatives The synthesis of 2,3-disubstituted thiazolidinones was achieved by our group through a 3-MCR process catalyzed by protic acids adsorbed on solid supports (Figure 1.18) [89]. The scope and limitations of various protic acids was assessed and the relative catalytic efficiency followed the order TfOH > HClO4 > H2SO4 ~ p-TsOH > MsOH ~ HBF4 > TFA ~ AcOH and is in accordance with the relative acid strength. The catalytic power of the protic acid increased significantly when adsorbed on solid supports for which silica gel of different mesh sizes (60–120, 100–200, 230–400), different varieties of chromatography grade alumina (acidic, basic, neutral), montmorrilonite clays (K-10, KSF), zeolites [Y, K/L (SAR 6.8), ZSM (SAR 6.8), NH4-Y], and amberlite were used. Silica gel (230–400) was the most effective solid support offering the relative catalytic efficiency of various protic acids adsorbed on it as HClO4–SiO2 > TfOH–SiO2 ≫ H2SO4–SiO2 > p-TsOH–SiO2 > MsOH– SiO2 ~ HBF4–SiO2 > TFA–SiO2 ~ HOAc–SiO2. The role of silica gel to enhance the catalytic power of the protic acid was proposed due to its ability to undergo complex formation

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Figure 1.18: 3-MCR strategy for construction of thiazolidinone heterocycle catalyzed by solid-supported protic acid.

with the protic acid through the Si center (Figure 1.19) that accounts for the better catalytic power of HClO4–SiO2 compared to TfOH–SiO2 though TfOH is a stronger protic acid. Due to strong electron withdrawing ability of the F3C group the S = O groups in TfOH coordinates with Si less effectively. On the other hand, due to the presence of three oxygen atoms in HClO4 versus only two such oxygen atoms in TfOH, the HClO4 undergoes more effective coordination with the Si of SiO2 [89].

Figure 1.19: The role of silica gel in enhancing the catalytic power of the protic acids.

The catalyst of HClO4–SiO2 could be recycled for five consecutive reactions.

1.2.1.7 Pyridine and its analogs The MCR strategy has been found to be the popular approach for the construction of pyridine scaffold [90, 91]. The one-pot three-component domino reaction of aromatic aldehydes (12), aliphatic/aromatic amines (11), and the EAA (28) was performed by our research group in aqueous medium for the stereoselective synthesis of tetrahydropyridine derivatives (60) (Figure 1.20) [36]. In view of the necessity of a solubility enhancer to enable reaction in aqueous medium of the water immiscible reactants and our earlier results in the beneficial effect of the surfactant SDS during benzothiazepine synthesis in aqueous medium [92] and of SDOSS for benzothiazole synthesis in aqueous medium at room temperature [93] rather than under reflux [94], though the specific role of SDOSS was proved to be dioxygen activator in addition to being the solubility enhancer [93],

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various surfactants (anionic, cationic, and neutral) were tried for the 3-MCR process to synthesize the tetrahydropyridine derivatives (60) in aqueous medium. In this MCR, the use of SDOSS was the most effective. The systematic study of the reaction in the presence of other anionic surfactants, nonionic surfactants, cationic surfactants, and nonaqueous reaction media suggested that the combination of SDOSS in H2O works best for the synthesis of tetrahydropyridine derivatives. A detailed mechanistic investigation was made to understand whether the reaction proceeds following the Knoevenagel condensation-aza-Diels–Alder reaction (ADR) sequence (Path A) or the tandem inter- and intramolecular Mannich reaction route (Path B). Based on the experimental results of the mechanistic investigation the SDOSS-catalyzed reaction has been proposed to proceed via tandem inter- and intramolecular Mannich-type reactions (Path B) involving the enaminone and imine formation by the reaction of aniline/β-ketoester and aniline–aldehyde, respectively. The nucleophilic addition of enaminones to the imine and subsequently condensation/cyclization step stereoselectively formed the tetrahydropyridines [36].

Figure 1.20: Aqueous SDOSS as catalyst for the stereoselective synthesis of tetrahydropyridines.

Persubstituted 1,4-dihydropyridine derivatives (62) were obtained by the microwaveassisted one-pot four-component reaction of anilines (11), malononitriles (61), aromatic aldehydes (12), and dimethylacetylene dicarboxylate (24) in ethanol at room temperature (Figure 1.21). The reaction pathway is initiated with the Knoevenagel condensation between the malononitriles and aromatic aldehydes for in situ formation of the α,β-unsaturated nitrile derivatives. In the ongoing parallel cascade reaction, the nucleophilic addition of amines to the electron deficient alkynes furnishes the corresponding enaminones intermediate. The in situ generated α,β-unsaturated nitrile and the enaminones undergo Michael addition reaction followed by the cyclization procedure to synthesize the desired dihydropyridine derivatives in good to excellent yield. The distinct benefits of this reaction methodology are the wide substrate scope, nontoxic substrates and reagents, shorter reaction time, higher yield of the products, no

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chromatographic purification, operated at room temperature, and environmentalfriendly reaction conditions [95].

Figure 1.21: Microwave-assisted one-pot 4-MCR for the synthesis of 1,4-dihydropyridine derivatives.

Metal-organic framework (MOF) was applied as heterogeneous catalyst with sulfonic acid moiety as Bronsted acid functionality to carry out the one-pot three-component reaction of aromatic aldehydes (12), 1,3-diketo compounds (19), and ammonium acetate (21) as nitrogen source for the synthesis of 1,4-dihydropyridines (63) via Hantzsch reaction. The MOF termed as MIL-101-SO3H plays the role of heterogeneous Bronsted acid to activate the electrophilic carbonyl groups. The MOF-catalyzed activation of carbonyl groups of 1,3-diketo derivatives promotes its participation in both the Knoevenagel condensation with the aldehydes and the enaminones synthesis with the ammonium salts (Figure 1.22). The enaminones undergo Michael addition reaction with the Knoevenagel product and subsequently the SO3H-promoted cyclocondensation step provided the desired 1,4-dihydropyridine derivatives. The heterogeneous catalyst was recovered and recycled upto eight times without any loss in the catalytic potential. The structural characteristics of the heterogeneous catalyst were confirmed by the FTIR, PXRD, and SEM analyses [96].

Figure 1.22: MOF catalysis in the construction of 1,4-dihydropyridines.

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Chemoselective synthesis of two different types of pyridines (64,65) (persubstituted and tetrasubstituted pyridines) were reported by Du et al. [97] One-pot three-component reaction of 1,3-diketones (19), α,β-unsaturated nitro derivatives (2), and aromatic aldehydes (12) under solvent-free condition or in propylene carbonate provided the nonfused pyridines in good to excellent yields (Figure 1.23). In the reaction mechanistic course, both the reactions follow the identical pathway upto the stage of the formation of 1,4-dihydropyridines. In the final step of the pyridine formation, the chemoselectivity of the reaction determined the fate of the product formation. The base-promoted Knoevenagel condensation between 1,3-dicarbonyl compounds and aromatic aldehydes in situ generates the α,β-unsaturated carbonyl derivatives which further participates in the Michael addition reaction with α,β-unsaturated nitro derivatives. The intramolecular cyclization and dehydration process under heating forms the 1,4-dihydropyridines. In the final stage of the reaction pathway for the aromatization of 1,4-dihydropyridines, the base-promoted denitration of 1,4-dihydropyridines furnished the tetrasubstituted pyridines while the air-mediated dehydrogenative oxidation of 1,4-dihydropyridines provided the persubstituted pyridines. This protocol is effective for rapid parallel synthesis of both persubstituted pyridines and tetrasubstituted pyridines at the same time [97].

Figure 1.23: Synthesis of trifluoromethylated pyridine derivatives via MCR approach.

Deng and coworkers [98] reported the transition-metal-free one-pot three-component reaction of aromatic aldehydes (12), aryl methyl ketones (66), and ammonium iodide/ acetate (67/21) (nitrogen source). The MCR gave different products based on the nitrogen source and oxidant used. Pyridine (68) ring formation took place with ammonium iodide as the nitrogen source and DMSO as oxidant. There is change of product selectivity toward pyrimidine (69) ring formation when NaIO4 was used as the oxidant and ammonium acetate as the nitrogen source (Figure 1.24) [98]. Four different types of pyridin-2-ones (71–74) were synthesized by the one-pot MCRs of 2-cyanoacetamides (70), aromatic aldehydes/acetone, and acetone in the presence of piperidine as base (Figure 1.25). Piperidine promoted the aldol condensation between the 2-cyanoacetamides and acetone followed by dehydration to synthesize

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Figure 1.24: The MCR synthesis of pyridines and pyrimidines.

Figure 1.25: Regioselective synthesis of piperidine derivatives.

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the α-cyano enone moiety which further participates in the Michael addition reaction with the enol form of acetone. The intramolecular cyclization of the Michael adduct completes the piperidine ring construction. Depending upon the regioselectivity of dehydration step, two types of pyridinone formation are possible. The vicinal dehydration process creates the endocyclic olefins, while the geminal dehydration produces the exocyclic olefins in the structure of pyridinones [99]. The one-pot three-component reaction of the amine 11, ethyl acetylene dicarboxylate 24, and diethyl ethoxymethylenemalonate 75 under solvent-free conditions afforded two different types of pyridone derivatives such as pyridine-2-one (76) and pyridine-4-one (77) (Figure 1.26). This base-promoted chemoselective pyridone synthesis proceeds through the Michael addition/ethanol elimination/intermolecular cyclization cascade. The substitution pattern at the aniline derivatives controls the chemoselectivity and type of pyridone formation. Particularly, the presence of halogen group at the ortho position of the aniline leads to the formation of pyridine-4-one derivatives [100].

Figure 1.26: Chemoselective pyridone synthesis via 3-MCR approach.

The MCR of 2-diphenylphosphoryloxy-1,3-dienes (78), aldehydes, and sulfonylated amines carried out in the presence of boron trifluoride enabled the construction of tetrahydropyridine derivatives (79) (Figure 1.27). The reaction proceeds via the ADRs between the in situ-generated imines and 2-diphenylphosphoryloxy-1,3-dienes. The chemical stability of the dienes permits this MCR to take place without any special precautions [101].

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Figure 1.27: Synthesis of tetrahydropyridine derivatives through aza-Diels–Alder reaction.

Wang resin-supported sulfonic acid was utilized as heterogeneous Bronsted acid catalyst for the construction of tetrasubstituted pyridine derivatives (80) through one-pot four-component reaction of aromatic amines (11), aldehydes (12), acetophenone derivatives (66), and malonitrile derivatives (61) under ultrasound irradiation (Figure 1.28). Water was opted as the green solvent to carry out the synthesis under aerobic condition. The reaction process initiates with the ultrasound-assisted Knoevenagel condensation between the malononitriles (61) and aldehydes (12) to in situ form the α,βunsaturated nitrile derivatives which undergo Bronsted acid-catalyzed Michael addition reaction with the enol form of acetophenone derivatives. The nucleophilic addition of aniline derivatives to the nitrile moiety of the Michael adduct, followed by Bronsted acid-promoted cyclocondensation reaction furnishes the 1,4-dihydropyridine derivatives. In the final step, the aerobic oxidation of 1,4-dihydropyridines accomplished the aromatization process and resulted desired pyridine derivatives 113. The Wang resin-bound sulfonic acid catalyst was recycled and reused upto four times without any significant loss in the catalytic activity. These synthesized pyridine derivatives were subjected to in vitro biological evaluation against SIRT1 suggesting the bioactive nature of the synthesized compounds [102].

Figure 1.28: Ultrasound-promoted synthesis of pyridines through 4-MCR approach.

Another one-pot MCR of aromatic aldehydes (12), aniline derivatives (11), and EAA derivatives (28) were carried out in the presence of immobilized lipase enzyme which is adsorbed on the magnetic halloysite nanotubes (Figure 1.29). This magnetic biocatalyst included certain advantages such as higher catalytic efficiency, ease of recyclability of the heterogeneous catalyst through magnetic separation, and use of nontoxic biocata-

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lyst for the synthesis. The magnetic field susceptible catalyst was recovered through magnetic separation and reused for six cycles without any significant loss in the product yield. This synthetic methodology was also scaled up to gram scale to check the feasibility of the protocol at industrial scale [103].

Figure 1.29: One-pot 3-MCR approach for the synthesis of tetrahydropyridine-3-carboxylates.

The one-pot, 4-MCR of diarylethanones (81), aryl methyl ketones (66), aromatic aldehydes (12), and ammonium acetate under solvent-free condition has been reported to form 2,3,4,6-tetraaryl pyridines (82) (Figure 1.30).

Figure 1.30: The 4-MCR for synthesis of tetraaryl pyridines.

Though broad functional group tolerability, aerial solvent-free reaction condition, and the feasibility of the synthesis of multiarylsubstituted pyridines from readily available substrates are some notable features of this protocol, the product yield is poor with ortho-substituted aryl aldehydes (e.g., the reaction with 2-methyl benzaldehyde gave 17% yield of 82 and no desired product formation took place with 2-methoxy benzaldehyde) [104]. It has been demonstrated that the product formation takes place through Knoevenagel condensation involving the diaryl ethenone 81 and the aldehyde 12 followed by Michael addition to this in situ generated 1,3-diarylpropenone with the enamine formed by the reaction of the aryl methyl ketone 66 and ammonia (generated

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from NH4OAc on heating). The resultant Michael adduct undergoes cyclodehydration via intramolecular nucleophilic attack by the nitrogen electron lone pair on the ketone carbonyl to form the corresponding tetraaryl dihydropyridine which on dehydrogenative/oxidative aromatization affords the tetraarylpyridines 82 [104]. The development of a multicomponent domino reaction is an encouraging step toward the greater goal of sustainable synthesis. The GaI3-catalyzed high-yielding, solvent-free, multicomponent domino synthesis of functionalized pyridines (85) was reported by our research group [37] performing the one-pot three-component reaction of (E)-3-(dimethylamino)-1-aryl/heteroaryl-prop-2-en-1-ones (83), 1,3-dicarbonyl compounds (84), and ammonium acetate (21) as nitrogen precursor (Figure 1.31). The required starting material (E)-3-(dimethylamino)-1-aryl/heteroaryl-prop-2-en-1-ones (83) could be conveniently synthesized by organocatalytic procedures developed by us [105, 106]. This MCR was explored in the various metal Lewis acid salts such as metal perchlorates, triflates, halides, and tetrafluoroborates, and this exploration study suggested GaI3 as optimum catalyst to carry out the reaction. The different possible reaction pathways were envisioned and investigated through GC-MS study by identifying the crucial intermediates of the reaction pathway. The mechanistic course of most plausible pathway could be outlined as the intermediate formation of imine or iminium salt by the reaction of the 1,3-dicarbonyl compound with ammonia which participates in the domino nucleophilic Michael reaction to the (2E)-3-(dimethylamino) prop-2-en-1-one by its active methylene carbon through its enamine form followed by intramolecular cyclization and aromatization. The role of different ammonium salts as a nitrogen source was explored and NH4OAc was found to be the best one. Further, the effect of acetate anion on the progress of reaction was studied and its role in cyclization and subsequent aromatization was established. [37].

Figure 1.31: GaI3-catalyzed solvent-free, multicomponent domino synthesis of functionalized pyridines.

1.2.1.8 Pyrimidine and its analogs The Biginelli reaction of aldehydes (12), 1,3-dicarbonyl compounds (84), and urea/thiourea (86) was performed in the presence of catalytic amount of 1-butyl-3-methylimidazolium (bmim) cation containing ILs under solvent-free condition at 100 °C to generate the dihydropyrimidine/thiopyrimidines 87 (Figure 1.32) [30]. The investigation of the reaction in

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the presence of various other bmim cation-based ILs with varying associated counter anion indicated that the [bmim][MeSO4] is the most-efficient organocatalyst for this purpose. The presence of the C-2 hydrogen of the imidazolium moiety in the IL is essential as it participates in the H-bonding to activate the electrophile and simultaneously the counter anion part activates the nucleophile. This simultaneous dual activation of the nucleophile and electrophile facilitates the reaction progression. In order to establish the crucial role of C-2 hydrogen in this Biginelli reaction, various [bmim]-based ILs lacking the C-2 hydrogen (by having a methyl group at C-2 position of the corresponding imidazolium cation moiety and denoted as bmim cation) was utilized to perform this Biginelli reaction. The inferior yields of the product indicated the crucial role of C-2 hydrogen in catalyzing the Biginelli reaction. The reaction proceeds through the imine formation involving the reaction of aldehyde and (thio) urea which might not require any catalytic assistance by the IL. In the next step, the IL catalyzed the nucleophilic addition of the imine to the β-carbonyl compounds followed by cyclocondensation resulting in the dihydropyrimidinone formation (87). The IL was recycled and reused for next five Biginelli reactions. This synthetic methodology was also extended for the synthesis of bioactive dihydropyrimidinones such as monastrol and enastron [30].

Figure 1.32: Ionic liquid-catalyzed Biginelli synthesis of pyrimidinones.

Heterogeneous Bronsted acid catalysis was explored for the multicomponent Biginelli reaction of aldehydes (12), EAA (28), and urea/thiourea (80) to synthesize the substituted dihydropyrimidinones (88) in good–to-excellent yield under solvent-free condition (Figure 1.33). The heterogeneous Cr-based MOF catalyst added the advantage in terms of catalyst recyclability and enhanced catalytic efficacy. The investigation of mechanistic pathway of the reaction revealed the engagement of both the Lewis and Brønsted acid sites of the MOF in the activation of the electrophilic centers during the course of the reaction [107].

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Figure 1.33: MOF-promoted Biginelli synthesis of pyrimidinones.

1.2.2 Fused aza-heterocycles 1.2.2.1 Indole and its analogs The organocatalytic MCR of 1,2,3-tricarbonyl compounds (89), aromatic amines (11), and cyclic-1,3-diketone (36) was performed to synthesize the N-aryl indoles (90). Initially, cyclic mono enaminones, formed in situ by the reaction of anilines and 1,3cyclohexanedione, react with the β-ketoesters through its nucleophilic α-carbon of enone moiety to generate the carbinol intermediate (Figure 1.34). In the next step, the intramolecular cyclization and subsequent elimination of water provide the desired indoles. The unprecedented features of this methodology are application of secondgeneration chiral spirocyclic phosphoric acid as organocatalyst, improved enantioselectivity and wide substrate scope [108].

Figure 1.34: Synthesis of indole derivatives via 3-MCR approach.

Rh(III)-catalyzed one-pot three-component synthesis of isoindolinone derivatives (92) were carried out by performing the reaction of aromatic aldehydes (12), 2aminopyridines (91), and ethyl acrylate (20). In the presence of copper acetate as oxidant, the Rh(III)-catalyzed dehydrogenative amide formation was occurred by the reaction of 2-aminopyridines and aromatic aldehydes (Figure 1.35). The amine group of amide functionality acts as the potential directing group for the metal-catalyzed ortho C–H bond activation. The C–H bond activation favors the alkene insertion step by the

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reaction of rhodacycle and the acrylates. In the final step, the aza-Michael addition completes the annulation process to build up the isoindolinone scaffold. This mild, operationally multicomponent process transforms a wide variety of commercially available aldehydes into the corresponding γ-lactams in good yields. Notably, the anxiolytic drugs pagoclone and pazinaclone can be directly prepared by utilizing this methodology [109].

Figure 1.35: Rh-catalyzed isoindolinone derivatives via 3-MCR.

The 4-oxo-tetrahydroindoles (94) were obtained by the Bronsted acid-catalyzed onepot three-component reaction of the cyclic 1,3-diketone dimedone (36), amines (11), and α-haloketones (93) under ball milling conditions (Figure 1.36). The present protocol for the preparation of 4-oxotetrahydroindoles offers several advantages such as mild reaction conditions, improved selectivity, higher yields of the product, solvent-free reaction conditions, catalyst (sulfamic acid) recycling successfully for the next five cycles, and the use of ball milling as nonconventional energy source [110].

Figure 1.36: Sulfamic acid-catalyzed 3-MCR for the synthesis of tetrahydroindoles under ball milling.

Tetracyclic benzodiazepine-fused isoindolinone scaffold (97) was constructed by the one-pot three-component MCR of 2-formylbenzoic acid (95), aryl methyl ketones (66), and o-phenylenediamine (96) in the presence of mesoporous silica nanoparticles (MSNs) as catalyst (Figure 1.37). The reaction starts with imine formation between opheylenediamine and 2-formylbenzoic acid. The intramolecular cyclization of the imine intermediate by nucleophilic addition of the carboxylic OH to the imine bond generates the hemi-aminal which undergoes nucleophilic attack via the enol form of the aryl methyl ketone to form the lactone and liberates the o-pheylenediamine. The nucleophilic addition of one of the NH2 groups of o-pheylenediamine on the side chain carbonyl group of the lactone intermediate forming the corresponding imine and that

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facilitates intramolecular nucleophilic attack on the lactone carbonyl group by the remaining NH2 group of the o-phenylenediamine followed by elimination of water molecule forms the desired product. Though wide substrate scope, recyclability of the catalyst, and applicability in gram-scale synthesis are few attractive features of this protocol, it requires high reaction temperature and prolonged reaction period [111].

Figure 1.37: Mesoporous silica nanoparticle-catalyzed 3-MCR for the synthesis of fused indoles.

1.2.2.2 Pyrrole fused aza-heterocycles The synthesis of pyrimidine tethered naphthoquinone-fused pyrroles (101) was accomplished by the author using iodine-mediated multicomponent processes. The relating three-component hybrid molecules with naphthoquinone-fused pyrroles tethered with a barbituric acid moiety are generated when aryl methyl ketones (66) or terminal aryl alkynes (98) react with molecular iodine in DMSO, followed by the successive addition of barbituric acids (99) and 2-amino-1,4-naphthoquinone (100). This three-component reaction forms three new bonds (two carbon–carbon and one carbon–nitrogen) in onepot via metal-free C-H oxidation and multicomponent cyclization (Figure 1.38) [112]. Similarly, the similar molecules can be made by reacting arylglyoxals (1), 99 and 100 in refluxing methanol in the presence of catalytic amounts of iodine. These techniques stand out for their one-pot metal-free approach, high yields, adaptability to a variety of acetophenones, phenylacetylenes, and arylglyoxals, simplicity of product purification, and incorporation of naphthoquinone, pyrrole, and pyrimidine moieties. A pseudo-5-MCR process involving double decarboxylative 1,3-dipolar cycloaddition of azomethine ylides and olefinic oxyindoles during the reaction of the aldehyde 12, glycine (102), and alkylidene oxyindoles (103) constitute the diastereoselective synthesis of bispiro[oxindole-pyrrolidine]s (104). The primary diastereomers are distinct compounds having a plane of symmetry and a butterfly shape. To accelerate the reaction, reusable zeolite HY acid was used as the catalyst (Figure 1.39). It is a successive double [3 + 2] cycloaddition that involves two azomethine ylides that are not stabilized. The bulk of the reactants is contained in the product structure for mass efficiency, intermediate purification is not required to reduce waste, and only 1 equiv. of

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Figure 1.38: Synthesis of naphthoquinone-fused pyrroles via 3-MCR approach.

CO2 and 2 equiv. of H2O are produced as byproducts are the major positive aspects of this reaction [113].

Figure 1.39: Spirocyclization of oxyindoles for the construction of fused pyrolidines.

Yan and co-workers [114] have reported the 3-MCR involving various types of arylglyoxal monohydrates (1), ethyl 2-(pyridin-2-yl)acetates (105), and different heterocyclic ketene aminals (106) in ethanol to generate 4-(pyridin-2-ylmethyl)-2-aminopyrroles (107) containing the fused pyrrole ring system (Figure 1.40). In this reaction two new carbon–carbon and one carbon–nitrogen bonds are formed. Thirty-four compounds with different substitutions on the ethyl 2-(pyridin-2-yl) acetates (105) and arylglyoxal (1) were synthesized with good yield. The reaction was also carried out using water or

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mixture of water with ethanol as the solvents but the product was obtained in poor yield. The detailed reaction mechanism was studied using HRMS.

Figure 1.40: Synthesis of fused pyrroles via multicomponent reaction approach.

1.2.2.3 Pyrazole-fused aza-heterocycles The 3-MCR of aryl aldehyde (12), dimedone (36), and 5-amino-3-methyl-1-phenylpyrazole (108) produced the new pyrazolo-[3,4-b]-quinoline scaffold (109) (Figure 1.41). The pyrazolo-[3,4-b]-quinolines (151) were synthesized using the catalyst-free microwave-assisted one pot multicomponent reaction performed at room temperature in aqueous ethanol affording excellent yields (91–98%). The protocol’s distinctive features include operational simplicity, ease of handling, a one-step simple workup method, mild reaction conditions, short reaction time, good selectivity, and no by-product generation [115].

Figure 1.41: Synthesis of pyrazole-fused dihydropyridines under microwave irradiation.

The chemo- and diastereoselective construction of pyrazole-fused tetrahydropyridines (113) was achieved through the one-pot 3-MCR of aminopyrazole derivatives (110), salicylaldehyde derivatives (111), and styrenesulfonyl or cinnamoyl chloride (112) in water that proceeds via intramolecular ADR (Figure 1.42). The aminopyrazoles (110) reacts with the in situ generated O-sulfonylated intermediate 111a to generate the corresponding imine intermediate (110a). In the final step, the intramolecular ADR accomplished the tetrahyhydropyridine ring formation in 113 [116].

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Figure 1.42: Synthesis of pyrazole-fused piperidines through multicomponent reaction.

The synthesis of pyrano[2,3-c]-pyrazoles (114) was achieved via the one pot fourcomponent domino reaction of substituted aldehydes (12), malononitrile (61), hydrazine hydrate (29), and EAA (28) promoted by the MOF catalyst MIL-53(Fe) in ethanol at room temperature (Figure 1.43). The Lewis acidic character of MIL-53(Fe) promotes its strong coordination with the carbonyl group of aromatic aldehydes to activate the electrophilic carbon favoring the Knoevenagel reaction between the aromatic aldehydes and malonitrile to furnish the α,β-unsaturated nitrile derivatives. In a parallel set of reaction in the same pot, the cyclocondensation reaction between EAA and hydrazine generates, in situ, the pyrazolone derivative. The MOF assisted Michael addition reaction between the pyrazolone and the α,β-unsaturated nitrile, followed by cyclization led to the desired fused pyrazole derivatives. The MOF MIL‐53(Fe) was recycled for six times without any significant loss in its catalytic potential. The notable features of the present protocol are the short reaction times, simple workup, high yields, no chromatographic purification, and recoverability of the catalyst [117].

Figure 1.43: MOF-catalyzed room temperature synthesis of pyrazole fused pyrans via 4-MCR.

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The similar type of reaction was also explored in the presence of sulfonated carboxymethylcellulose (SCMC) as heterogeneous organocatalyst. The one-pot four-component synthesis of pyrano[2,3-c]pyrazole (114) was carried out by the reaction of substituted aldehydes (12), malononitrile (61), hydrazine hydrate (29), and EAA (28) in ethanol (Figure 1.44). The synthesized SCMC catalyst was well characterized using FT-IR spectroscopy, energy-dispersive X-ray (EDX) analysis, X-ray diffraction (XRD) pattern, scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The sulfonic acid moiety of SCMC forms hydrogen bonding with the carbonyl groups and nitrile groups to enhance the electrophilicity of these electrophiles. The key features of this methodology are operational simplicity, use of a stable, recoverable, and nontoxic catalyst, easy purification of the product by nonchromatographic methods, high yields, environmentfriendly reaction, and utilization of green solvent as reaction media [118].

Figure 1.44: SCMC-catalyzed 4-MCR for the synthesis of pyrazole-fused pyrans.

1.2.2.4 Imidazole-fused aza-heterocycles 1.2.2.4.1 Benzimidazoles The benzimidazole represents the widely used/found imidazole-fused aza-heterocyclic system. The most convenient way to construct the benzimidazole scaffold is the dehydrative cyclo-condensation of o-phenylenediamines (96) with aldehydes (12) (Figure 1.45).

Figure 1.45: Construction of benzimidazole ring system.

While the reaction of o-phenylenediamine (96) with an aldehyde (12) to form the benzimidazole (115) ideally would involve one molecule of each of the reactants and may not qualify as a MCR process in reality this cyclo-condensation process is inherently multicomponent and may give rise to the formation of the corresponding benz-

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imidazole (115) and 1,2-disubstituted benzimidazole (116) (Figure 1.46). The formation of 115 is a two-component reaction but the formation of 116 is 3-MCR.

Figure 1.46: Two- versus three-component process during benzimidazole formation.

The competitive formation of the 1.2-disubstituted benzimidazole 116 generally occurs [relative amounts may vary with the reactivity of the substrates (o-phenylenediamine and the aldehyde) based on electronic and steric factors, and reaction condition used, for example, nature of catalyst, reaction temperature, solvent, etc.] even when the starting o-phenylenediamine (96) and the aldehyde (12) are taken in 1:1 molar ratio. Thus, this strategy would be associated with the product selectivity, an issue that remained unaddressed till our group deliberated on this aspect [119]. In this context, an efficient catalytic process for 3-MCR involving the reaction of o-phenylenediamines (96) and aldehydes (12) used in 1:2 molar ratio was discovered by our group (Figure 1.47).

Figure 1.47: Supported protic acid-catalyzed 3-MCR for selective formation of 1,2-disubstituted benzimidazoles.

The selectivity of formation of 2-substituted benzimidazole and 1,2-disubstituted benzimidazole was studied in details using various heterogeneous catalysts such as perchloric acid adsorbed on different solid supports, for example, chromatographic silica gels (60–120, 100–200, and 340–400 mesh sizes), chromatographic alumina (acidic, basic, neutral), other protic acids, for example, TfOH, TFA, p-TsOH, MsOH, HBr, and H2SO4 adsorbed on silica gel (340–400), different varieties of zeolites, clays as well as the various grades of silica gels out of which most effective catalyst system was found to be perchloric acid adsorbed on silica gel of 340–400 referred as HClO4–SiO2 that was earlier invented by our group though for other application [62, 64].

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To understand and resolve the issue on the selectivity of formation of 2-substituted benzimidazoles versus 1,2-disubstituted benzimidazoles the mechanistic course of the reaction was studied in depth by GC-MS and various chemical transformations [119]. The formation of 2-substituted and 1,2-disubstituted benzimidazoles during the condensation of o-phenylenediamines with aldehydes was visualized by two different pathways (Figure 1.48).

Figure 1.48: Mechanistic pathways of formation of 2-substituted and 1,2-disubstituted benzimidazoles during condensation of o-phenylenediamines with aldehydes.

The progress of the reaction via “Path I” leads to the formation of the 2-substituted benzimidazole via initial formation of the mono-imine Ia that may exist as ring chain tautomer Ib formed by intramolecular nucleophilic attack by the NH2 nitrogen on the iminic carbon followed by 1,3 (N to N) proton shift. Dehydrogenation/aromatization of the imidazoline Ib results in the formation of 2-substituted benzimidazole 115. In “Path II,” that gives rise to the 1,2-disubstituted benzimidazole 116, both of the NH2 groups of the o-phenylenediamine 96 undergo condensation with the aldehyde 12 to form the bis-imine formation IIb that undergoes rearrangement involving the sequence of elementary reactions such as intramolecular nucleophilic attack by the nitrogen of one of the iminic group on the C=N group of the other imine moiety to form the ionic species IIb, rearrangement via 1,3 (C–C) proton shift in IIb to finally generate the 1,2-disubstituted benzimidazole 116. The GC-MS and NMR analysis of the reaction mixture during the progress of the reaction, experimental proof on the bis-imine formation (by isolating the N,N′bisbenzylated derivative of the o-phenylenediamines by treating the reaction mixture of o-phenylenediamine and 2 equiv. of benzaldehyde with NaBH4), and formationof α,αbis deuterated N-benzylated 1,2-dibenzylated benzimidazole during the reaction of ophenylenediamine with deuterated benzaldehyde established the involvement/operational feasibility of “Path I” and “Path II.” The formation of 1,2-disubstituted benzimidazole via the initial formation of the bis-imine intermediate followed by its rearrangement was demonstrated in carrying out the reaction of o-phenylenediamine (96) with 2 equiv. of deuterated benzaldehyde

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(12a-d) in EtOH at rt under the catalytic influence of HClO4–SiO2 that gave 2-phenyl-1α-d2-methylphenyl-1H-benzimidazole (115a-d2) (Figure 1.49).

Figure 1.49: Mechanistic evidence of formation of 1,2-disubstituted benzimidazoles by rearrangement of the corresponding bis-imine formed during condensation of o-phenylenediamines with deuterated aldehydes.

It has been demonstrated that the issue of 2-substituted benzimidazole versus 1,2disubstituted benzimidazole formation selectivity depends on the possibility of bis-imine formation and the product selectivity switch would be dependent on several factors: electronic and steric effect of the aldehyde carbonyl, electronic effect of the amino groups in o-phenylenediamine as well as the electrophilic activation ability of the catalyst employed. Thus, the treatment of 2 equiv. of sterically hindered 2,4,6-trimethylbenzaldehyde (12b) with o-phenylenediamine (96) afforded only the 2-substituted benzimidazole 116a. That in this case, the corresponding bis-imine formation does not take place due to steric crowding was demonstrated by isolation of the mono-N-benzylated product 117 after treating the reaction mixture with NaBH4 (Figure 1.50) [119]. The influence of electronic factor was also demonstrated in performing the reaction of 4-nitro-o-phenylenediamine (96a) with 2 equiv. of the aldehydes (12) with varying substituents that would reflect variable electrophilicity of the carbonyl carbon. In all of these cases only 2-substituted benzimidazoles (115) were formed. As the NH2 group para to the NO2 group in 96a is significantly less nucleophilic the bis-imine formation does not take place and is supported by the formation of the mono-Nbenzylated-4-nitro-o-phenylenediamine (118) by subjecting the HClO4–SiO2-catalyzed reaction mixture of 4-nitro-o-phenylenediamine (96a) and benzaldehyde with NaBH4 (Figure 1.51) [119]. A metal and acid-free 3-MCR process was devised by our group for the formation of 1,2-disubstituted benzimidazoles (116) by dehydrative cyclo-condensation of o-phenylenediamines (96) with 2 equiv. of aldehydes (12) promoted by the fluorinated alcohols trifluoroethanol (TFE) and hexafluoro-isopropanol (Figure 1.52) [53]. Detailed NMR analysis of aliquot portions of the reaction mixture during the progress of the reaction, formation of 2-phenyl-1-α-d2-methylphenyl-1H-benzimidazole (115a-d2) during the reaction of o-phenylenediamines (96) with 2 equiv. of deuterated benzaldehyde (12-d), and quenching the reaction mixture by treatment of NaBH4 and identifying the formation of the N,N-bis-benzylated derivative of o-phenylenediamine confirmed the formation of the 1,2-disubstituted benzimidazole formation to proceed through the bis-imine intermediate (Figure 1.53).

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Figure 1.50: Influence of the steric effect in the formation of 2-substituted and 1,2-disubstituted benzimidazoles during condensation of o-phenylenediamines with aldehydes.

Figure 1.51: Influence of electronic effect in controlling the formation of 2-substituted and 1,2disubstituted benzimidazoles during condensation of o-phenylenediamines with aldehydes.

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Figure 1.52: Fluorinated alcohol-catalyzed 3-MCR for selective formation of 1,2-disubstituted benzimidazoles.

Figure 1.53: Influence of steric effect in controlling the formation of 2-substituted and 1,2-disubstituted benzimidazoles during TFE-promoted condensation of o-phenylenediamines with aldehydes.

It has been demonstrated that during the TFE/HFIP promoted reaction of equimolar amounts of o-phenylenediamine and benzaldehyde the 1,2-disubstituted and 2-disubstituted benzimidazoles are formed in 40:5/40:7 ratio (based on isolated yields) at RT for 60 min and the ratio becomes 36:27/41:16 (based on isolated yields) at −40 °C for 60 min [53]. As TFE/HFIP exhibit catalytic effect through HB they are very mild electrophilic activating agents. Therefore, the formation of the 1,2-disubstituted benzimidazole irrespective of the molar ratio of the reactants implies that the 2-substituted versus 1,2-disubstituted benzimidazole product selectivity is not much dependent on the catalyst/protocol used but on the reactivity of the substrates. However, the construction of the 1,2-disubstituted benzimidazole scaffold via the dehydrative cyclo-condensation route has two distinct limitations: (i) the nature of the substituents at 1 and 2 are derived from the aldehyde structure and there is no scope of diversity of the substitution pattern at these two positions and (ii) reactions involving unsymmetrical o-phenylenediamines would generate regioisomeric 1,2-disubstituted benzimidazoles (Figure 1.54). It is difficult to distinguish these regioisomers that control their selectivity of formation.

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Figure 1.54: The issue of regioselectivity of 1,2-disubstituted benzimidazole formation by 3-MCR involving unsymmetrical o-phenylenediamine and aldehyde.

For the synthesis of diversely substituted 1,2-disubstituted benzmidazole in regiodefined fashion avoiding the above mentioned regioselectivity issue our group have developed novel “all water” chemistries of tandem N-alkylation-nitro reduction-dehydrative cyclocondensation strategy for one-pot synthesis of 1-arylmethyl-2-substituted benzimidazoles from o-nitroanilines (121), benzyl bromides (122), and aldehydes (12) [32] (Figure 1.55).

Figure 1.55: Regiospecific synthesis of 1-aryl methyl-2-substituted benzimidazoles by one-pot tandem reaction involving o-nitroanilines, benzyl bromides, and aldehydes.

The intermediacy of the N-benzylated o-nitroanilines (123) and mono-N-benzylated ophenylenediamines (124) has been demonstrated by separately carrying out the Nalkylation of o-nitroanilines (121) with the benzyl bromides (122) in water to isolate 123 which on treatment with In in aq HCl formed 124 [32]. The final dehydrative and dehydrogenative cyclo-condensation of 124 with the aldehydes (12) proceeds via initial condensation of the NH2 group of 124 with the carbonyl group of the aldehyde (12) forming the imine 124-a (established by subjecting the reaction mixture to treatment with NaBH4 and isolating the corresponding N,N-dibenzylated o-phenylenediamine 124-c) followed by intramolecular nucleophilic attack by the NH nitrogen on the imine group to form the benzimidazoline intermediate 124-b which on dehydrogenation/aromatization produces the final 1,2-disubstituted benzimidazoles 125 (Figure 1.56). For further diversity generation at the benzimidazole scaffold our group has developed novel “all water” chemistries of tandem aromatic nucleophilic substitution (N-arylation-nitro reduction-dehydrative cyclo-condensation strategy for one-pot synthesis of 1-aryl/alkyl-2-substituted benzimidazoles from o-fluoronitrobenzene (126), aryl/alkyl amines (11), and aldehydes (12) [33] (Figure 1.57). The significant aspect of the protocol is base and catalyst-free aromatic nucleophilic substitution to form the ortho-N-arylated/alkylated nitrobenzenes 127 where water

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Figure 1.56: Progress of dehydrative and dehydrogenative cyclo-condensation of mono-N-benzylated ophenylenediamines (124) with the aldehydes (12).

Figure 1.57: Regiospecific synthesis of 1-aryl/alkyl-2-substituted benzimidazoles by one-pot tandem reaction involving o-fluoronitrobenzene, aryl/alkyl amines, and aldehydes.

plays a crucial role for HB-assisted electrophilic activation of the o-fluoronitrobenzene 126 as lesser yields are obtained with ortho-chloro/bromonitrobenzenes (orthoiodonitrobenzene being totally ineffective) due to their week HB formation ability with water molecule. The HB-assistance rendered by water in promoting the nucleophilic substitution and the final cyclo-condensation process was demonstrated by observing deuterium kinetic isotope effect while comparing the reaction rate in water versus D2O for the steps [33]. 1.2.2.4.2 Imidazopyridines Acetic acid-catalyzed one-pot three-component domino reaction of cinnamaldehydes (130), ethylenediamines (131), and 1,3-dicarbonyl compounds (19) was performed for the synthesis of tetrasubstituted hexahydroimidazo[1,2-a]pyridines (132) (Figure 1.58). The reaction proceeds through the Bronsted acid-catalyzed imine formation in two successive steps followed by intramolecular cyclization to complete the annulation process leading to the desired fused pyridine derivatives. X-ray crystallographic study revealed the trans isomer as the major product [120]. The microwave-promoted one-pot multicomponent domino reactions of arylglyoxal monohydrates (1), aromatic amines (11), and 2-aminopyridines (91) were carried out in the presence of catalytic amount of iodine for the synthesis of 3-amino-imidazo[1,2-a]

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Figure 1.58: Bronsted acid-catalyzed one-pot MCR for synthesis of hexahydroimidazo[1,2-a]pyridines.

pyridines (133). In the progress of the reaction, iodine promotes imine formation involving condensation of arylglyoxal monohydrate and the aromatic amine (Figure 1.59). Nucleophilic addition through pyridine ring nitrogen to the imine intermediate followed by cyclocondensation produced the desired 3-amino-imidazo[1,2-a]pyridine (133). The exploration of the reaction under both classical (oil bath) heating and microwave heating suggested that microwave heating is more efficient to carry out the synthesis in shorter reaction time. Replacement of molecular iodine with Lewis acid catalyst or Bronsted acid catalyst or organocatalyst didn’t improve the reaction efficiency [121].

Figure 1.59: Microwave-assisted synthesis of imidazo[1,2-a]pyridines via MCR approach.

The one-pot, three-component synthesis of imidazo[1,2-a]pyridine (135) was achieved by the reaction of 2-aminopyridines (91), aryl methyl ketones (66), and dimethyl sulfoxide (134) as a methylene donor. The potassium persulfate-promoted deoxygenative nucleophilic addition reaction between the 2-aminopyridines (91) and sulfenium ions followed by the thiomethyl elimination generates the 2-iminium pyridine cation. The enolate-mediated nucleophilic coupling of aryl methyl ketones with the iminium ion generates the β-aminoketones which is further iodinated at the α-position by iodine. In the final step, the intramolecular nucleophilic substitution through pyridine nitrogen and oxidative aromatization process provides the desired imidazo[1,2-a]pyridines (Figure 1.60) [122].

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Figure 1.60: Iodine-catalyzed synthesis of imidazopyridines.

1.2.2.5 Quinoline and its analogs Our group developed a new protocol for the synthesis of 2-styrylquinolines for onepot tandem Friedländer annulation-Knoevenagel condensation catalyzed by In(OTf)3 [123]. The treatment of ortho-aminobenzophenones (136) with alkyl acetoacetates (28) at 100 °C under neat condition for 15 min in the presence of In(OTf)3 (10 mol%) followed by treatment with aromatic aldehydes (12) at 100 °C for 2–4 h under solventfree condition led to the formation of 2-styrylquinolines (137) (Figure 1.61).

Figure 1.61: In(OTf)3-catalyzed one-pot solvent-free tandem 3-MCR for the construction of 2-styryl quinoline ring system.

The reaction proceeds via the intermediate formation of the 2-methyl quinolines (137a), as determined by GC-MS studies during the progress of the reaction and based on earlier report from our group [124]. Various alkali, alkaline, transition, and rare earth metal halides, acetates, tetrafluoroborate, perchlorates, and triflates were tested for their catalytic potential to promote the reaction and best efficiency was observed with In(OTf)3. The In(OTf)3 was recovered and reused for next four cycles. In a microwave-assisted MCR that involves the use of 2-iodoanilines (138), terminal alkynes (98), and oxalic acid dihydrate [(CO2H)2·2H2O] (139) under the catalytic influence of polystyrene-supported palladium (Pd@PS) nanoparticles led to the synthesis of 3-aryl/alkyl-2-quinolones (140). For the carbonylation process (CO2H)2·2H2O served as a stable and solid carbon monoxide (CO) source. This was the first time that a heterogeneous palladium catalyst was investigated for such transformation. A wide range of functional groups were tolerated, and the reaction showed good regioselectivity and substrate diversity with respect to 2-iodoanilines and alkynes (Figure 1.62). The notable benefits of the approach are the use of a recyclable heterogeneous catalyst, bench-

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stable CO surrogate, microwave irradiations, simple reaction handling, and regioselectivity of the products [125].

Figure 1.62: Microwave-assisted synthesis of quinolones.

A series of structurally intriguing new pyrrolo[3,2-c]quinolinone (144) heterocyclic hybrids have been synthesized via a one-pot multicomponent domino reaction sequence that involves a 1,3-dipolar cycloaddition and subsequent intramolecular lactonization and lactamization steps (Figure 1.63). Baylis–Hillman adducts (141) derived from various substituted benzaldehyde and methyl acrylate in the presence of DABCO were used as dipolarophiles, while the 1,3-dipole components were azomethine ylides, formed in situ from isatin derivatives (142) and L-phenylalanine (143). The reaction generated five new bonds, three new rings, and four contiguous stereocenters, which were created with full diastereomeric control [126]. This regioselecive domino process generates five bonds and three rings in a single synthetic operation. It also leads to the fully diastereoselective creation of four adjacent stereocenters, two of which are quaternary and one is an all-carbon stereocenter.

Figure 1.63: Multicomponent synthesis of pyrroloquinolinone derivatives.

A library of 2-arylquinolines (146) has been synthesized by the one-pot three-component domino reaction of aldehydes (12), anilines (11), and nitroalkanes (145) using a catalytic amount of Fe(III) chloride (Figure 1.64). The reaction most likely occurs via a sequential aza-Henry reaction/cyclization/denitration. Readily available chemicals as starting materials, an inexpensive metal catalyst, aerobic reaction conditions, tolerance of a wide

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range of functional groups, and operational simplicity are the notable advantages of this present approach [127].

Figure 1.64: Fe(III)-catalyzed 3-MCR for the synthesis of C-2-arylated quinoline derivatives.

The 3-MCR involving anilines (11), alkynes (98), and paraldehyde (147) under microwave irradiation in the presence of (±)-camphor-10-sulfonic acid (CSA) represents a Povarov-type multicomponent synthesis of 4-aryl quinolines (148). Without the need of a metal catalyst, this reaction proceeds via the [4 + 2] cycloaddition of alkynes and imines (generated in situ from aniline and paraldehyde) (Figure 1.65). The role of CSA has been proposed to activate the imine to prevent the production of Troger’s base and promote the cycloaddition of imines with alkynes [128].

Figure 1.65: Camphor sulfonic acid-catalyzed MCR for the synthesis of quinoline derivatives.

The [3 + 2 + 1] cycloaddition of enaminones (116), aryl methyl ketones (66), and aryl amines (11) was used to synthesize 2,3-diaroyl quinolines (149) (Figure 1.66). A scaffold made of 1,4-dicarbonyl can be produced successfully by this process. Additionally, the 2,3diaroyl quinoline produced that has two active electrophilic sites which can be utilized for further reaction to produce pyridazino[4,5-b]quinolines. The variety of 1,4-dicarbonyl compounds produced by the Povarov reaction was expanded by this MCR [129].

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Figure 1.66: Iodine-catalyzed synthesis of 2,3-diketo quinolines via 3-MCR approach.

1.2.2.6 Quinazoline and its analogs Our group reported a catalyst and solvent-free 3-MCR for the construction of quinazolinone ring system [130]. The treatment of isatoic anhydrides (150), anilines (11), and triethyl orthoacetate (151) either under classical heating at 120 °C for 5 h or microwave irradiation at 140 °C (150 W) for 20–30 min formed the 2,3-disubstituted quinazolin-4(3H)-ones (152) (Figure 1.67).

Figure 1.67: Solvent and catalyst-free 3-MCR for the synthesis of 2,3-disubstituted quinazolin-4(3H)-ones.

The use of ammonium acetate in place of the aromatic amine formed the corresponding 2-substituted quinazolines that is devoid of the N-aryl group. On the other hand, the use of trialkyl orthoformate afforded the quinazolinone that is devoid of the C-2 substitution. The concept was extended toward the 4-MCR for the construction of 2-styryl quinazolinone ring system [130]. The treatment of isatoic anhydrides (150), anilines (11), and triethyl orthoacetate (151) either under classical heating at 120 °C for 4 h or microwave irradiation at 140 °C (150 W) for 20 min followed by further treatment under similar condition with aromatic aldehydes formed the 2-styrylquinazolin-4(3H)-ones (153) (Figure 1.68). Using these methodologies various central nervous system drugs such as methaqualone, mebroqualone, mecloqualone, piriquialone, and diproqualone were synthesized [130].

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Figure 1.68: Solvent and catalyst-free 4-MCR for the synthesis of 2-styryl quinazolin-4(3H)-ones.

The inexpensive CuBr-catalyzed one-pot domino MCR of methyl-2‐bromobenzoate (154), alkyl/arylisothiocyanate derivatives (155), and sodium azide (46) was carried out in the presence of L-proline as ligand to the metal catalyst (Figure 1.69). The reaction proceeds through the metal catalyst-assisted carbonyl group activation of methyl-2‐bromobenzoate to favor the SNAr reaction with sodium azide. The azidation in the phenyl ring and subsequent denitrogenation generates the methyl anthranilate intermediate. The nucleophilic addition reaction of phenyl isothiocyanate with the anthranilates produces the thiourea intermediate which further cyclizes with the elimination of methanol to form the desired quinazolinones (156) [131].

Figure 1.69: Cu-catalyzed MCR for the synthesis of N-alkyl/arylquinazolones.

Dimethyl sulfoxide (134) acts as one carbon source (substrate) and solvent for the onepot domino MCR involving isatoic anhydride (150), arylmethylamines (157) in the presence of graphene oxide (GO) as catalyst (Figure 1.70). The GO stimulates the formation of sulfenium ion and the hydrolysis of it in situ generates the formaldehyde intermediate which actually acts as the C-2 carbon source of quinazolinones. The decarboxylative nucleophilic addition of benzylamines to the isatoic anhydride synthesizes the corresponding amide intermediate which further undergoes condensation reaction with the formaldehyde intermediate to complete the annulation process. The GO-assisted aerial oxidation of the dihydroquinazolinone furnished the desired N-benzylated quinazolinones (158). The crucial role of GO in the course of the reaction was established through performing the reaction under catalyst-free condition which gives no product formation. However, authors have not performed the reaction in the absence of DMSO or in the presence of other solvent to ensure the fact that DMSO is acting as C-2 carbon syn-

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thon in the course of the reaction. The synthesized GO was totally characterized by SEM, XRD, EDX, XPS, and TGA [132].

Figure 1.70: DMSO as C-2 carbon source for the synthesis of quinazolinones via 3-MCR approach.

The metal-catalyzed oxidative one-pot MCR of aryl amine (11), alkyl amines (11a), and formaldehyde (159) was reported for the synthesis of quinazolinones (160) under oxygen. The quinazolinone ring construction takes place via formation of consecutive C−N and C−C bonds, followed by oxidative dehydrogenation and oxidation process (Figure 1.71). After the formation of imine intermediate through the condensation of amine and aldehyde, the reaction may proceed through two different reaction pathways such as the [4 + 2] cycloaddition pathway/isomerization cascade or through the Fridel-crafts alkylation pathway. Both of these pathways lead to the formation of the common intermediate tetrahydroquinazoline which is further oxidized to the dihydroquinazolines via copper-promoted oxidation process under oxygen ballooning. In the final step, the metalcatalyzed benzylic oxidation synthesized the desired quinazolinone derivative [133].

Figure 1.71: Cu-catalyzed synthesis of quinazolinone derivatives.

The I2-catalyzed 4-MCR process involving aryl methyl ketones (66), two molecules of aryl amine (11), and one molecule of DMSO (134) led to the formation of quinazolinones 161 (Figure 1.72). During the progress of the reaction, the iodination/Kornblum oxidation sequence in situ generates the aryl glyoxals from the aryl methyl ketones (66) which subsequently forms the bis imine upon reacting with the amine (11). The intramolecular cyclization of this bisimine intermediate followed by ring expansion provides the tricyclic di-aza-heterocycles. The sulfenium ion produced from the DMSO participates in the bridge formation between two nitrogen atoms of the di-aza-heterocycles to construct

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the bicyclic intermediate. In the final step, the oxidative C–N bond cleavage synthesized the desired quinazolinone derivatives (161) [134].

Figure 1.72: Iodine-catalyzed MCR of methyl ketone, anilines, and DMSO for the formation of quinazolinones.

The catalyst-free one-pot multicomponent Staudinger/aza-Wittig reaction involving the dialkyl acetylenedicarboxylates (24), isocyanides (16), and 2-azidobenzoic acid (162) led to the formation of the quinazolinone derivatives (163) (Figure 1.73). The reaction proceeds through the nucleophilic addition of isocyanides to the dialkyl acetylenedicarboxylates through Michael addition and subsequent hydrolysis generates the amide intermediate. The coupling between the 2-azidobenzoic acid and the amide intermediate furnishes the bis amide bond containing intermediate which further undergoes tandem Staudinger/aza-Wittig reactions to obtain the desired quinazolinone derivatives [135].

Figure 1.73: One-pot multicomponent Staudinger/aza-Wittig reaction for the synthesis of quinazolinones.

The catalyst-free one-pot domino MCR of 2-(2-aminophenyl)-2-oxoacetamide derivatives (164), aldehydes (12), and ammonium acetate (21) was reported to form the quanzolines (165) (Figure 1.74). The aldehydes and ammonium acetate are the synthetic equivalent of C-2 carbon and N3 nitrogen, respectively, of the quinazoline ring. The reaction proceeds through the non-Friedlander pathway of annulation. The condensation reaction between the ammonium acetate and aldehydes generates the corresponding imine intermediate which further reacts with the 2-(2-aminophenyl)-2oxoacetamide under Bronsted acid catalysis to furnish another imine intermediate. The acetic acid-promoted deammoniative intramolecular cyclization accomplishes the

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dihydroquinazoline formation. The aerobic oxidation of dihydroquinazoline synthesized the desired 4-keto quinazolinones (165) [136].

Figure 1.74: Catalyst-free synthesis of quinazolines through 3-MCR approach.

Selectfluor was used as the fluorinating agent in the one-pot multicomponent domino reaction of 2-aminoacetophenones (166), iso(thio)cyanates (155), selectfluor, and water for synthesis of 4-difluoromethyl and 4-fluoromethyl quinazolin(thi)ones (167). It has been proposed that the reaction proceeds through nucleophilic addition/dehydrative cyclization reaction between the ortho-amino acetophenones and iso(thio)cyanates to form the 4-methylene quinazolin(thi)ones derivatives (Figure 1.75). In the next step, selectfluor-mediated electrophilic fluorination generated the iminium intermediate which further determines the fate of difluorinated or monofluorinated product formation. The direct nucleophilic addition of water molecule at the iminic center directly gives rise to the monofluorinated quinazolinone. The tautomeric stabilization of the iminium cation furnishes the 4-methylene quinazolin(thi)ones which further undergo electrophilic fluorination in the presence of selectfluor to provide the gemdifluorinated quinazolin(thi)ones [137].

Figure 1.75: Selectfluor as the fluorinating agent in the synthesis of quinazolinones.

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1.3 Conclusion The aza-heterocycles are important class of compounds that are finding applications in diverse fields such as from organic material, metal complex forming ligands, and more importantly constitute the essential structural components of approved drugs, clinical drug candidates, and in drug discovery medicinal chemistry. While all these necessitate the availability of effective methods of synthesis of diverse aza-heterocycles at the same time it is important to construct the core heterocyclic frame with the shortest possible pathways for effective and speedy supply of the desired target molecules. In this context, a domino MCR toward the construction of the aza-heterocyclic ring systems would minimize the steps involved for their synthesis avoiding the need for isolation and purification at each step, thereby reducing the time, extra cost, and the waste. The present chapter would provide the readers the literature status on the domino MCR strategy for aza-heterocycle synthesis and stimulate further research interests on the development of newer chemistries on this topic.

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Bijoy P Mathew, Jagmeet Singh, Mahendra Nath✶

2 One-pot three-component selective annulation strategies for the synthesis of bioactive β-lactam, pyrrole, and pyridine scaffolds 2.1 Introduction Multicomponent reaction (MCR) strategies differ from traditional synthetic procedures and often involve a combination of three or more smartly functionalized building blocks to produce a customized product in one-pot using the majority of atoms present in the substrates/reagents (remarkable atom economy), ultimately producing good-toexcellent isolated yields, and thereby saving time and energy [1, 2]. MCR protocols have become efficient and effective synthetic techniques for the synthesis of diverse complex scaffolds in a single step. Besides, this concept has been proven effective in a number of areas, including materials science, combinatorial chemistry, drug discovery, and biological probes [3, 4]. Moreover, MCRs are distinguished by time effectiveness, high product yield, production of minimum waste, and less energy consumption. In light of these advantages, synthetic organic chemists became interested to design efficient environmentally friendly synthetic strategies using MCRs [5]. Heterocycles which make up the majority of all-known organic substances constitutes the magnificent kinds of chemicals having tremendous biological actions [6, 7]. Very specifically, N- and O-heterocycles represent a privileged structural subunit that is widely distributed in compounds that occur naturally with incredible biological activities, including anticancer, anti-HIV, antimalarial, antiinflammatory, antimicrobial, and antihyperglycemic, as well as antineurodegenerative disorders like Alzheimer’s, Parkinson disease, Huntington’s disease, and many more [7, 8]. In spite of the enormity of applications, the synthesis of these heterocycles often depends on conventional transformations due to its dependability, robustness, and affordability. It is also true that several of these reactions produce significant volumes of waste by-products. Nonetheless, organic chemists have

Acknowledgments: MN is thankful to the IoE, University of Delhi, India, for providing the FRP grant. JS is grateful to CSIR, New Delhi, India, for the award of senior research fellowship. BPM acknowledges DSTFIST and DBT-STAR College Scheme for the financial assistance. ✶

Corresponding author: Mahendra Nath, Department of Chemistry, Faculty of Science, University of Delhi, Delhi 110007, India Bijoy P Mathew, Department of Chemistry, Vimala College (Autonomous), Thrissur 680009, Kerala, India Jagmeet Singh, Department of Chemistry, Faculty of Science, University of Delhi, Delhi 110007, India https://doi.org/10.1515/9783110985313-002

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shown significant interest in developing novel and affordable MCR synthetic strategies under one-pot operation. In this regard, one-pot three-component reaction is emerging as a useful technique for creating a wide range of molecular entities. Designing one-pot MCRs methodologies that are less hazardous and eco-friendly is a continuing effort in both academia and industry. This chapter emphasizes primarily the formation of three major N-heterocycles – β-lactams, pyrroles, and pyridines via one-pot three-component annulation reactions reported since 2011.

2.2 Three-component synthesis of β-lactams Among the various cyclic amides, β-lactams (2-azetidinones) are unique in terms of bioactivity profile and wide range of occurrence in natural products. The discovery of penicillin was regarded as a milestone in medical history, leaving many researchers inspired to study and utilize β-lactams. Their derivatives developed during the past decades have shown potent antibacterial and antimicrobial properties. However, βlactamase is an enzyme that catalyzes the hydrolysis of the lactam ring in the antibiotic which not only liberate it from the binding site but also deactivate it [9]. And this capability advances in bacterial strains leading to antibacterial resistance and hence demands generation of more number of diverse β-lactam scaffolds. In addition to their antibacterial properties, β-lactams have also shown anticancer, antiviral, antihyperglycemic, and other biological properties [10–16]. Thus, economical and convenient newer protocols to access β-lactams are highly worthwhile. Several reviews have come up regarding the synthesis of β-lactams since 2011 [16–21]. In this section, we have included only the three-component annulation strategies to β-lactams.

2.2.1 Using Ugi reaction Among the various reported multicomponent reactions, four-center three-component Ugi (4C-3C-Ugi) reactions are worth mentioning first [22]. After the introduction of these novel reactions in 1995 by Kehagi and Ugi [23, 24] many reports were published related to the β-lactam syntheses. In fact, these protocols are the modified version of the four-component Ugi-type reaction which involves only three components and one of the components is bifunctional such as amino acids, oxoacids, an isocyanoaldehyde, or isocyanoacid. A typical 4C-3C-Ugi for β-lactams involves a reaction between an β-amino acid, an aldehyde, and an isocyanide (Figure 2.1). The reaction mechanism involved an initial iminium ion formation (2), which in turn attacked by isonitrile as nucleophile leading to oxazepinone-type intermediate (4) from intramolecular addition in intermediate (3), of the carboxylate to the nitrilium ion. This intermediate

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undergoes rearrangement to form β-lactam ring (1). The whole reaction is proposed to be auto-catalyzed via protonation of imine by carboxylic acid group.

Figure 2.1: A typical four-center three-component Ugi (4C-3C-Ugi) reaction.

Focusing only on the reports since 2011, Sureshbabu and coworkers [25] synthesized βlactam-linked peptidomimetics (8a–e) by utilizing this method. In this reaction, chiral Nβ-Fmoc amino alkyl isonitriles (6) were employed with L-aspartic acid α-methylpeptide ester (comprising di/tripeptides) and commercially available organic aldehydes (7) to obtain the requisite β-lactams (8). These reactions were carried out in methanol as solvent at room temperature and products were obtained in moderate yields with good diastereoselectivity (Figure 2.2). Similarly, Blackie et al. [26] synthesized three series of diversely substituted βlactams (Figure 2.3) and evaluated all the compounds for an in vitro assay against the chloroquine sensitive D10 strain of Plasmodium falciparum. All the compounds showed low to moderate level of activity with compounds 9a, 9b, and 9c (from series 1); 9d (from series 2); and 9e (from series 3) showed better 50% inhibitory concentration of 27, 35, and 48; 16; and 15 µM, respectively. The structure-activity relationship wasn’t very clear in the study though broadly aromatic substitution at para with electron-withdrawing group in series 1, terminal methylbenzylamine in series 2 as well as benzotriazole compound in series 3 were cited for improved efficacy. Recently, Rainoldi et al. [27] developed 4C-3C-Ugi using a rare example where ketone has been used as the carbonyl component. In this protocol, β-amino acid (12) as usual was reacted with isocyanide (11) and isatin (10, ketonic counterpart) in an acidic solvent, trifluoroethanol (Figure 2.4). This gave a variety of oxoindole-based β-lactams (13), having a peptidomimetic backbone. Promisingly, enantiomerically pure β-amino acids ((S)-3-amino-3-phenylpropanoic acid and (S)-3-amino-4-methoxy-4-oxobutanoic acid) afforded compounds 13o and 13p, respectively, with moderate diastereoselectively, but both the enantiomers were separable in their pure form. All the compounds (13a–p) were subjected to physico-chemical analysis and were found to exhibit drug-

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Figure 2.2: Synthesis of β-lactam-linked peptidomimetics (8a–e) using 4C-3C-Ugi strategy.

Figure 2.3: Representative β-lactam derivatives with their antimalarial activity against Plasmodium falciparum.

like character according to Lipinski’s rule of five [28]. Further a preliminary in vitro antibacterial assay demonstrated compound (13e, i.e., R1 = Me) to possess inhibition of Streptococcus mutan at a concentration of 0.81 mM.

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Figure 2.4: 4C-3C-Ugi reaction with ketone (isatin, 10) as the third component.

2.2.2 Using Kinugasa reaction Kinugasa reaction involving a [3 + 2] cycloaddition between nitrone and a copper acetylide represents another approach to β-lactam synthesis. For quiet sometimes the reaction suffered from a drawback of no catalytic and highly enantioselective strategy. Toward this end, Miura et al. [29] reported the first enantioselective reaction between phenyl acetylene and α,N-diphenylnitrone with catalyst (CuI), ligand (i-Pr BOX) and base [(–)-sparteine] leading to marginal yield and enantioselectivity. Thereafter several chiral ligands [30–33] have been used for giving enantioselective β-lactam products. In 2014, Safaei-Ghomi et al. [34] have developed chiral catalyst using chiral cyclohexadiamine supported on Fe3O4/ZnO core/MNPs for producing diastereoselective β-lactams via Kinugasa reaction. The reaction involves a catalytic in situ generation and reaction between Cu (I)-acetylides and nitrones via one-pot three-component reaction of aryl aldehyde (14), N-arylhydroxylamine (15), and terminal acetylene (16) using the chiral MNPs in polyethylene glycol (PEG) as solvent and at room temperature (Figure 2.5). In this, Cu(II) is used as a catalyst as opposed to Cu(I) in classical Kinugasa reaction. The mechanism involves usual [3 + 2] cycloaddition with arylacetylide attaching the nitrone from the Si face in the transition state (18), leading to an isooxazoline intermediate (19). This intermediate is thereafter converted to enolate (20) and intercepted with a proton to yield a major diastereoselective cis-β-lactams (17). Qi et al. [35] in 2020 developed for the first time a perfect one-pot three-component Kinugasa reaction between terminal alkynes (21) and nitrones (22) interrupted by a sulfur electrophile (23 or 24) to form an enantioenriched α-thiofunctional chiral β-lactams (25

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Figure 2.5: One-pot three-component enantioselective Kinugasa annulation reaction to β-lactams.

Figure 2.6: Synthesis of α-thiofunctional chiral β-lactams (25 or 26) via interrupted Kinugasa reaction.

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Figure 2.7: Synthesis of stereocontrolled α-quatenary β-lactams (33) via interrupted Kinugasa allylic alkylation.

or 26) (Figure 2.6). Mechanistically, a regular four-member enolate Cu(I)-intermediate (29) in a Kinugasa reaction is intercepted by a sulfur electrophile leading to an unusual introduction of sulfur moiety on a β-lactam ring system, 25 or 26. This is indirectly proved by the failed reaction between the Kinugasa products with PhSO2SCH3. Same group developed a similar interrupted Kinugasa reaction where the regular β-lactam formation is intercepted by allylic alkylation through allylic palladium intermediate (32A) [36]. This involves a three-component reaction between alkyne (30), nitrones (31), and protected allyl compound (32) in presence of bimetallic Cu–Pd catalytic system catalyzing Kinugasa reaction and Tsuji-Trost allylic alkylation, respectively (Figure 2.7). In Figure 2.8, a conceivable catalytic cycle is put forth. The crucial four-membered enolate copper(I) intermediate (33A) is provided by the usual cycloaddition between Cu(I)-acetylide (30A) and nitrones (31). An interim allylic palladium intermediate (32A) is concomitantly generated by activation of allylic electrophile (32) using palladium catalyst. The reactive intermediate 33A and 32A created by the simultaneous catalytic cycles undergo stereo-controlled interrupted Kinugasa allylic alkylation to form the intended α-quaternary chiral βlactams via an intermediate, 33B.

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Figure 2.8: Plausible bimetallic mechanism for Cu/Pd-catalyzed interrupted Kinugasa allylic alkylation.

2.2.3 Using Staudinger reaction Of the various methods available for β-lactam synthesis, Staudinger reaction is the most versatile method, in which ketenes (or its synthetic equivalents) are added to imines in a formal [2 + 2] cycloaddition reaction [37, 38]. In 2014, Mandler et al. [39] gave the first onepot three-component synthesis of β-lactams using phenyldiazoacetate (34), azide (35), and enonediazoacetate (36) with Rh catalyst at 40 °C to give excellent yield and diastereoselectivity (Figure 2.9). The article describes the optimization of Rh-catalyzed imine formation (37) from reaction between compounds 34 and 35. It also suggests the possible Wolff rearrangement of compound (36) to form ketene intermediate (36A) in the presence of Rh catalyst. So the discussed one-pot three-component synthesis will plausibly involve [2 + 2] cycloaddition between intermediate (36A) and imine, 37. In spite of projected versatile application, there is limited substrate scope reported in this paper. In another report, Mozaffari et al. [40] synthesized β-lactams via a one-pot sequential three-component Staudinger coupling between imine and ketene generated in situ from aldehyde (40) with primary amines (39) and an acid chloride (generated from reaction between Ar2OCH2CO2H with p-toluene sulfonyl chloride), respectively (Figure 2.10). In addition to being simple to operate, the protocol has the advantages of short reaction time, convenient workup, good yields, applicability to a wide range of substrates (19 new β-lactams, 42a–s), and a low risk of exposure to humans or the environment. Krasavin and coworkers [41] developed another sequential metal-free threecomponent reaction involving in situ-generated imine, 46A (from amine (44) and aldehyde (43)) followed by reaction with α-acyl-α-diazoacetate, 45 (Figure 2.11). The β-lactams (49) obtained showed promising yield and remarkable diastereoselectivity. Except for

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Figure 2.9: One-pot three-component synthesis of β-lactams via Rh-catalyzed Staudinger reaction.

enolizable α-C–H imines (such as N-(cyclohexylmethylene)-1-phenylmethanamine), other imine did give the requisite β-lactam. This reaction proceeded via a Wolff rearrangement of diazo compound (45) to form ketene (45A) and subsequent trapping of the ketene by imine (46A) through Staudinger cyclization. The mechanism involves formation of stable oxazinone intermediate (47) which on ring-opening (RO; forms betaine intermediate, 48) followed by cyclization give the final product, 49. The same group also reported a similar metal-free sequential three-component strategy using readily available dialkyl diazomalonates (50) [42]. Though the method used two equivalents of 50, but gave an extremely rare type of β-lactam, 3-alkoxy-3-alkoxycarbonyl-2-azetidinones, 51 (Figure 2.12). Chen et al. [43] developed a three-component β-lactam synthesis via reaction between N-hydroxyanilines (52), enynones (53), and diazo compounds (54) using a metalorgano relay catalysis giving highly functionalized β-lactams (55) with two quaternary carbon centers and excellent diastereoselectivities (Figure 2.13). A plausible sequential three catalytic cycle was proposed involving Rh-catalyzed Wolff rearrangement as well as imine formation and an Umpolung Staudinger cyclization. The whole reaction is plausibly initiated by the formation of reactive 2-furyl carbene (53A) from enynones (53a), which in turn combine with amphiphilic nucleophile N-hydroxyaniline (52a), to generate two ylides (IA and IB). These ylides on subsequent migration, rearrangement, and loss of H2O yield imine (IIIA). The synergistic Rh-catalyzed Wolff rearrangement gave ketene (54B), which on nucleophilic attack by organo-base (L2) generate an enolate (54C), which acts as a nucleophile and attack the imine (IIIA) forming the required βlactam (55a) via umpolung Staudinger cyclization (Figure 2.14). An analogous three-

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Figure 2.10: Metal-free one-pot sequential three-component Staudinger coupling to diastereoselective β-lactams.

component synthesis involving Staudinger cyclization was developed with more moderate condition (Figure 2.15) by the same group [44]. The reaction involved a one-pot reaction of N-hydroxyaniline (56) and diazo compounds 57 and 58 to synthesize dual quaternary substituted β-lactams (59) with excellent diastereoselectivity. Minuto et al. [45] recently developed a new ketene three-component Staudinger reaction to synthesize β-lactams. This reaction involves visible light induced coupling of diazoketones (60), primary amines (61) and carbonyl compounds (62) all at once in a one-pot (Figure 2.16) giving trans-products (63) with moderate substrate scope (nine examples). This reaction is first of its kind and an imine is formed in situ as opposed

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Figure 2.11: Synthesis of lactams via sequential metal-free three-component reaction involving concomitant Wolff rearrangement and Staudinger cyclization.

Figure 2.12: Synthesis of a rare type of β-lactam, 3-alkoxy-3-alkoxycarbonyl-2-azetidinones, 51.

to its sequential generation and then, Staudinger cyclization with the ketene. Another one-pot three-component reaction involves tandem imine formation and Staudinger cyclization using substrates N-hydroxyanilines (64), diazo compounds (65), and cyclobutenones (66) (Figure 2.17) [46]. The possible mechanism comprises Rh-catalyzed imine generation (65A) from N-hydroxyaniline (64) and diazo compound (65); this is followed by reaction with ketene (66A), from cyclobutenones (66) at high temperature, to form zwitterionic intermediates (67A). Then, the intermediates (67A) undergo possible [2 + 2] cyclization to produce highly functionalized four-membered β-lactams with excellent diastereoselectivity. The reaction showed good substrate scope and better tolerance to functional groups.

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Figure 2.13: Diastereoselective synthesis of highly functionalized β-lactams (55).

Figure 2.14: A plausible sequential tricatalytic cycle.

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Figure 2.15: Synthesis of β-lactams via Rh-catalyzed C–N bond formation.

Figure 2.16: Photoinduced three-component Staudinger reaction.

Figure 2.17: Diastereoselective synthesis of highly functionalized β-lactams.

2.3 Three-component synthesis of pyrroles Pyrrole constitutes a well-known and almost ubiquitous five-membered heteroaromatic compound. They form the key structural motifs in porphyrin-based biomolecules ranging vitamin B12, chlorophyll pigments, heme as well as enzyme cofactors (cytochrome P450) [47, 48]. In addition, pyrrole ring commonly exists in marine natural products [49, 50], lead drugs [51, 52], synthons [53, 54], and optoelectronic materials [48], and has significant

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applications in medicinal chemistry owing to their broad range of bioactivities [52, 55]. Due to these many applications in bioactivity and drug applications, as intermediates in natural products synthesis and application in materials have caused interest in the development of pyrroles synthesis which include traditional routes, such as the Hantzsch pyrrole synthesis [56], Knorr [57, 58], Paal–Knorr pyrrole [59, 60] synthesis to nonclassical one [61, 62], and many new synthons have been developed. Again focusing on reports since 2011, we discussed in this section only reactions related to one-pot threecomponent synthesis of pyrroles. There are several substrate combinations is reported in literature [63–66]. We have classified the various reports based on common substrates involved among the three-component synthetic protocol.

2.3.1 From 1,3-dicarbonyl compounds Korotaev et al. [67] synthesized novel β-(trifluoromethyl)pyrroles (71) via one-pot, three-component Grob cyclization [68] of 1,1,1-trifluoro-3-nitrobut-2-ene (68) with 1,3dicarbonyls (69) and ammonia or primary aliphatic amines (70) in ethanol as a solvent under reflux (Figure 2.18). A plausible pathway involves an initial formation of intermediate aminoenones (72). This intermediate then undergoes nucleophilic addition to conjugated nitroalkene to form intermediates A and B, which on cyclization give the required compound (71) as outlined in Figure 2.18. This new synthesis of β(trifluoromethyl)pyrroles proceeds under mild conditions and the starting materials are readily available. Several reports of pyrroles synthesized using similar nitroolefins with primary amines and 1,3-dicarbonyl substrates were reported using catalyst such as nano-CoFe2O4-supported antimony(III) [69], an acidic ionic liquid (IL) 3-methyl-2(1-sulfobutyl)-1H-imidazolium hydrogensulfate, [BSO3HMIm]HSO4 [70], or N-methyl-2pyrrolidonium methyl sulfonate ([NMPH]CH3SO3) [71]. In another report, analog substrates nitrostyrenes, amines, and 1,3-dicarbonyls were reacted in refluxing ethanol in the presence of catalytic amounts of iodobenzene and oxone as oxidant to make pyrroles with similar mechanism as illustrated in Figure 2.18 [72]. Significant improvement was reported by Li et al. [73] and they have used gold(I) catalyst and achieved the reaction in ethanol at room temperature. Very recently Akbaslar et al. [74] have used lactic acid as recyclable organic catalyst-cum-reaction medium for obtaining the pyrroles in moderate to excellent yield without using any chromatographic separations. Intermediate βaminoenones (A, Figure 2.19) are also formed in a one-pot three-component reaction catalysed by Yb(OTf)3. In this protocol, Reddy et al. [75] reacted amines (73), an acetyl acetone, and phenacyl bromide (74a) in a single pot in the presence of a reusable Yb(OTf)3 as a catalyst to form new 1,2,3,4-tetrasubstituted pyrroles (75) (Figure 2.19). In vitro studies were also conducted on these compounds to determine their ability to inhibit the PDE4B enzyme. Inhibitors of PDE4 are known to be effective in treating asthma and chronic obstructive pulmonary disease. In the present study, compounds 75a and 75b inhibited PDE4B significantly (57.89% and 66.13% inhibition, respectively), suggesting that the pres-

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ent class of pyrroles may be useful in the development of drugs. When tested at concentrations of 1, 5, 10, 30, and 100 mM, compound (75b) inhibited PDE4B by 20, 40, 61, 69, and 75%, respectively. Docking studies were also reported in this paper. A modified approach with 3-(bromoacetyl)coumarin (74b) as analogous substrate to phenacyl bromide (74a) was carried using an economic, environmentally benign, and mild catalyst alum in water–PEG 400 binary solvent system producing 3-(1-aryl-4-acetyl-5-methyl-1H-pyrrol-2yl)-2H-chromen-2-ones (76), a new heterocyclic scaffold containing synergistic biological benefits of coumarin and pyrrole nuclei in a single molecule [76]. The expected mechanism involved the condensation of β-dicarbonyl(acetyl acetone) and amine derivatives (73) to generate β-enaminone (A) first. It should be noted that the active Al3+ site in alum increases the electrophilicity of the β-dicarbonyl(acetyl acetone), preventing amine nucleophiles from attacking the activated α-C of (bromoacetyl)coumarin (74b) prematurely. Following that, the intermediate β-enaminone (A) experienced alum-catalyzed nucleophilic attack at the α-C (Al3+ polarizes the Br atom) of (bromoacetyl)coumarin (74b) to yield a new intermediate (B), which then undergoes sequential intramolecular cyclization followed by dehydration to yield the target molecule (76). Magar et al. [77] developed a mild, efficient, three-component synthesis of diverse N-protected tetrasubstituted pyrroles (79) in good-to-excellent yields from nitroallylicacetates (77), amines (78), and ethyl acetoacetate mediated by ceric ammonium nitrate (CAN) in MeOH. Possibly β-enaminones (A) formed in situ are thought to engage the nitroallylic acetates (77) to give the pyrroles (79) by an interesting SN2 reaction to form intermediate B and C and aromatization process (of cyclic intermediate C) (Figure 2.20).

Figure 2.18: Synthesis of novel β-(trifluoromethyl)pyrroles 71.

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Figure 2.19: Synthesis of differently substituted pyrroles via alum- or Yb(OTf)3-catalyzed reactions.

Figure 2.20: CAN-mediated one-pot synthesis of N-protected tetrasubstituted pyrroles.

In another report, benzoin derivatives (80), 1,3-dicarbonyls (81), and ammonium acetate were reacted in the presence of an efficient and reusable solid acid catalyst, molybdate sulfuric acid (MSA), to form new 2,3,4,5-tetrasubstituted pyrroles (82) via a novel [2 + 2 + 1] strategy under solvent-free conditions (Figure 2.21) [78]. The plausible mechanism involves initial chemoselective formation of imine intermediate (81A), fol-

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lowed by nucleophilic attack on the MSA-activated benzoin (80A) to form 80B. Then, this undergoes intramolecular cyclization to form a cyclic intermediate, 82A (via dehydration of 80C) and elimination of water produces the corresponding tetrasubstituted pyrroles (82). Using the similar substrates, Niknam et al. [79] have synthesized tetrasubstituted pyrroles using acidic Al2O3 as an efficient and reusable heterogeneous catalyst in refluxing ethanol in high yields. A solvent-free and catalyst-free approach using similar substrates was also reported by Bhat and Trivedi [80].

Figure 2.21: MSA-catalyzed synthesis of tetrasubstituted pyrroles.

Manasa et al. [81] reported a reaction of toluene sulfonyl methyl isocyanide (TosMIC) with aldehydes (83) and 1,3-dicarbonyls (84) to make 3,4-disubstituted pyrroles (86) in one-pot under metal-free conditions (Figure 2.22). The plausible mechanism involves the Knoevenagel condensation between aldehydes (83) and 1,3-dicarbonyls (84) in the presence of base piperidinium acetate resulting in α,β-unsaturated dicarbonyl intermediate (85). Thereafter, TosMIC undergoes base (DBU)-assisted Michael addition on to intermediate (85) giving intermediate (85A), which further undergoes intramolecular cyclisation (forming 85B) followed by a loss of tosylate anion to give intermediate (86A), which finally undergoes base-assisted aromatization to form the final product (86). Huang et al. [82] developed a new [1 + 2 + 2] route for making pharmaceutically significant core scaffold, N-(hetero)aryl-4,5-unsubstituted pyrroles (90), using substrates (hetero)arylamines (87), 1,3-dicarbonyl compounds (88), and α-bromo-acetaldehyde acetal (89) by using aluminum(III) chloride as a Lewis acid catalyst (Figure 2.23). Using the optimized conditions, three pharmaceutically active N-heterocyclic pyrrole derivatives (90a–c) were synthesized, among which N-pyridylpyrroles 90a and 90b are very important intermediates in the synthesis of the activator of soluble guanylyl cyclase (sGC). Plausible mechanism proposed involved the formation of a trivial enamine intermediate (88A) from 87 and 88. Meanwhile, carbocation intermediate (89A) is formed by the activa-

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Figure 2.22: Synthesis of 3,4-disubstituted pyrroles from aldehydes, 1,3-diketones, and TosMIC under metal-free conditions.

Figure 2.23: Synthesis of N-(hetero)aryl-4,5-unsubstituted pyrroles via [1 + 2 + 2] annulation.

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tion of 89 with AlCl3, which in turn was trapped by the enamine intermediate (88A) to generate imine intermediate (89B). Subsequently, 89B underwent an intramolecular electrophilic substitution and a spontaneous aromatization to afford the pyrrole product (90).

2.3.2 From alkynes Alkynes are another important substrate involved in the annulation to pyrrole moiety. Nagarapu et al. [83] reported the use of alkyne substrate, dialkylacetylene dicarboxylates (93), when reacted with phenacyl bromides (91) and primary amines (92) in a one-pot three-component synthesis in an inexpensive, nontoxic, and recyclable PEG gave the tetrasubstituted-pyrroles (94) in good-to-excellent yields. The reaction conditions were moderate and proceeded under catalyst-free conditions at an ambient temperature for 10 h (Figure 2.24). The same reaction was performed using simple, rapid, efficient, and environmentally benign procedure under solvent-free conditions using reusable nanorod ZnO catalyst [84]. In another report, using same substrates, Soltani et al. [85] developed an efficient and mild protocol for the synthesis of polysubstituted pyrroles using heteropoly acids, H3PW12O40 as a commercially available, inexpensive, environmentally friendly, noncorrosive, and reusable catalyst under solvent-free and ambient reaction conditions. Zhao et al. [86] developed a new simple strategy for constructing pharmaceutically significant penta-substituted pyrroles (98) from α-nitroepoxides (95) via RO reaction with primary amines (96) and acetylene dicarboxylates (97). This method needs no additives and is operationally simple. The plausible mechanism (Figure 2.25) involves a nucleophilic RO reaction at the electron-rich center on the α-nitro epoxides (95) to form intermediate (95A). Then, this forms intermediate (95B) via HNO2 elimination owing to the excellent leaving ability of nitro group. Thereafter, an intermolecular nucleophilic attack of N-center of 95B on the acetylene dicarboxylates (97) leads to intermediate 97A and 98A. Finally, an intramolecular condensation of 98A leads to final penta-substituted pyrrole (98).

Figure 2.24: Synthesis of tetrasubstituted pyrrole in PEG-400.

In another study, penta-substituted pyrrole derivatives (102a–h) were produced in excellent yields by a reaction between a primary amine (100), ethyl 2-chloroacetoacetate (99), and activated acetylenic compounds (101), all of which were reacted in the presence of magnetic Fe3O4 nanoparticles (Figure 2.26) [87]. The advantages of the current approach include a clean reaction, a quick reaction time, a high yield, simple purification, and an

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Figure 2.25: Synthesis of penta-substituted pyrrole via ring-opening reaction of α-nitroepoxides (95).

Figure 2.26: Penta-substituted pyrroles from unsymmetrical alkynes.

affordable catalyst. In this protocol unsymmetrically substituted alkynes were used, thus affording pyrroles with diversified substitution. Qiu et al. [88] used propargyl carbonates (103) along with isocyanides (104) and alcohols (105) in the presence of a catalytic amount of Pd(OAc)2 and a stoichiometric amount of tert-butylamine afforded a penta-substituted aminopyrroles (106) in good yields (Figure 2.27). A possible mechanism involves addition of in situ produced isocyanide-coordinated Pd(0) species from Pd(OAc)2 to 103 would result in the production of (σ-allenyl)palladium(II) species A and CO2 at the same time. The latter would be trapped by tBuNH2 to afford carbamate anion B. A triple isocyanide inser-

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Figure 2.27: Polysubstituted pyrroles using propargyl carbonates (103) as alkyne substrate.

tion to the hypothetic (σ-allenyl)palladium(II) intermediate A results in nitrilium D. This is intercepted by carbamate anion B to afford E. Further, 1,4-addition of an alcohol onto conjugated imine E, followed by an intramolecular cyclization to form aminopyrrole F, which on nucleophilic reaction with second molecule of alcohol provided penta-substituted pyrrole (106). Singh et al. [89] used β-cyclodextrin as an efficient supramolecular catalyst in the one-pot three-component reaction involving anilines (107), DEAD/DMAD(diethylacetylenedicarboxylate/dimethylacetylenedicarboxylate) (108) and glyoxal (109) in aqueous media to give polyfunctionalized pyrrole derivatives (110) in high yield (Figure 2.28). The protocol is environmentally benign and the catalyst used is recycled without much loss in catalytic activity. This reaction was previously reported using catalyst DABCO and in organic solvent under ambient temperature [90, 91]. In another green protocol, imidazolium bronsted acidic ionic liquid (BAIL) was used by Atar et al. [92] as a catalyst and solvent in a three-component one-pot coupling reaction of amines (112), dialkylacetylenedicarboxylate (113), and β-nitrostyrene (111) for the production of tetrasubstituted pyrrole derivatives (114a) (Figure 2.29). This protocol showed a clean reaction, a method free of transition metals and solvents, readily available reactants, and ecologically friendly reaction conditions. Mechanistically, amine (112) and alkyne (113) are in situ activated by BAIL, leading to enamine A, which in turn attach β-nitrostyrene (111) to form an intermediate B. Thereafter, intermediate B cyclizes to give an intermediate C, which then on further oxidation-cum-aromatization lead to

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product, 114a. Surineni et al. [93, 94] using similar substrates conducted a one-pot three-component condensation of 2-nitrovinylcarbazoles (111b) with aryl or alkyl amines and DMAD to make novel carbazole-tethered pyrrole derivatives (114b) using FeCl3 as a Lewis acid catalyst. With a MIC of 3.13 µg/ mL, 114b (R = Me & R1 = p-F-Ph) was found to be the most active of the 24 novel carbazole-tethered pyrrole derivatives tested for in vitro antimycobacterial activity against Mycobacterium TB H37Rv. It also showed low cytotoxicity. Khalilpour et al. [95] developed a unique three-component reaction using dialkylacetylenedicarboxylates (116a–b) and alkyl isocyanides (115a–b) with dihydropyrimidones (117a–c) as NH acids to create 10 new dihydropyrimidones substituted pyrrole

Figure 2.28: Tetrasubstituted pyrroles using supramolecular catalysis.

Figure 2.29: BAIL or FeCl3-catalyzed one-pot annulation for the synthesis of tetrasubstituted pyrroles derivatives (114a or 114b).

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heterocycles (118). Comparing the various produced compounds to doxorubicin (IC50 = 3.42 ± 0.20 μM) after 48 h revealed that compounds 118a and 118b with chlorine substituents had larger cytotoxic effects (IC50 = 10.36 ± 0.60 μM, 9.90 ± 0.20 μM, respectively) than the other examined compounds. Additionally, antioxidant testing of the produced products revealed that the presence of substituents (electron-withdrawing or electron-donating) on the aromatic ring might significantly influence its antioxidant activity. This reaction is rationalized mechanistically in Figure 2.30. The initial event, according to the well-known chemistry of isocyanides, is the nucleophilic addition of alkyl isocyanide (115) to the acetylenic ester (116) to produce zwitterion A [96, 97]. Protonation of A by NH-acid (117) results in Aʹ. The positively charged ion Aʹ is

Figure 2.30: Synthesis of novel 3,4-dihydropyrimidin-1(2H)-yl-1H-pyrrole derivatives as anticancer agents.

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then attacked by conjugated base 117ʹ, resulting in compound B. To create compound C, an additional alkyl isocyanide performs a Michael addition on molecule B. Then, compound C proceeds through a cyclization reaction and a subsequent [1,3]-proton transfer to create compound (118). Pharmaceutically important trifluoromethyl-substituted pyrrole (123) was synthesized using a sequential one-pot three-component reaction between substituted ω-bromoacetophenones (119), anilines (120), and methyl perfluoroalk-2-ynoates (122) by Sun et al. [98]. The reaction is transition metal-free and uses readily available substrates. Based on the results of the experiments presented in the paper, it was proposed that the sequential transformation involved the following steps: (i) a nucleophilic substitution of 119 with aniline (120) to produce compound (121); (ii) a subsequent Michael addition of 121 and 122 to give intermediate A; (iii) an intramolecular cyclization that is sparked by the electron-rich amino group of A; and (iv) the dehydration of B, followed by deprotonation and aromatization to give 2-trifluoromethyl pyrrole (123) (Figure 2.31).

Figure 2.31: Synthesis of 2-(perfluoroalkyl)pyrroles using methyl perfluoroalk-2-ynoates.

Shan et al. [99] developed another efficient route for the synthesis of polysubstituted pyrrole derivatives via a copper-catalyzed three-component reaction between alkynyl ketones (124), amines (125) and isocyanoacetates (126) (Figure 2.32). Easily available starting materials, mild conditions, and a wide substrate scope make this approach potentially useful. This reaction involve [3 + 2] cycloaddition between intermediate A (formed by insertion of copper species with isocyanoacetate (126), followed by basepromoted deprotonation) and alkynyl imine B (generated from the condensation of alkynylketone 124 and amine 125) to form cyclic intermediate C. Thereafter, intermediate C undergoes reductive elimination and aromatization to give the final product (127).

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Figure 2.32: Synthesis of polysubstituted pyrrole via [3 + 2] cycloaddition.

Using benzoin (128) instead of isonitrile, Vanga et al. [100] developed an efficient catalyst-free one-pot three-component synthesis of pentasubstituted pyrroles via reaction with anilines (129) and DEAD (130) in acetic acid in good to excellent yields (78%– 93%). The plausible reaction mechanism for one-pot synthesis of penta-substituted pyrroles is shown in Figure 2.33. The initial reaction of benzoin with aniline in the presence of acetic acid gave the α-aminoketone, A, by dehydration. The resulting αaminoketone (A) reacted in situ with DEAD (130), and the nitrogen atom of the αaminoketone experienced Michael addition with the latter, which in turn underwent intramolecular cyclization by combining with the keto carbon. The resulting intermediate B underwent aromatization by the removal of a water molecule in order to produce the penta-substituted pyrrole (131).

Figure 2.33: Synthesis of densely functionalized pyrrole derivatives using benzoin substrates.

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Zhou et al. [101] reported a variety of the synthesis of multiple substituted pyrroles (135) through zirconocene-mediated coupling of two alkynes (132a and b) and an azide (134) in the presence of CuCl (Figure 2.34). The study involving the use of symmetrically and unsymmetrically substituted monocyclic as well as bicyclic zirconacyclopentadienes (133) bearing alkyl and aryl groups resulted in the formation of pyrroles in high yield in most cases. In terms of the mechanism, the dialkenylcopper intermediate A is initially created by transmetalation of zirconacyclopentadiene 133 with CuCl. Then, azide (134) coordinates to two copper metals from the dialkenylcopper to produce intermediate B, which then experiences a nucleophilic attack from alkenylcopper to azide nitrogen to form intermediate C. The coordination of the −N ≡ N group to another copper species may aid in alkenylcopper’s nucleophilic assault on azide nitrogen and denitrogenation to produce intermediate C. In the end, product (135) is synthesized along with the elimination of copper metal by a ring-closure coupling process between the N–Cu and C–Cu moieties of intermediate C.

Figure 2.34: Zr-mediated coupling reaction of two alkynes and azide to afford pyrroles in the presence of CuCl.

Recently, Zhang et al. [102] developed a new, efficient, and versatile Pd(II)-catalyzed oxidative three-component cascade reaction of diverse amines (136), alkyne esters (137), and alkenes (138) and disclosed for the direct synthesis of diverse 2,3,4-trisubstituted pyrroles (139) with broad functional group tolerance and in good to excellent yields (Figure 2.35). This transformation is supposed to proceed through the cascade formation of C(sp2)−C(sp2) (formation of intermediate C) and C(sp2)−N bonds (formation of intermediate F) via Pd(II)-catalyzed regioselective alkene migratory insertion (formation of intermediate C via insertion of Pd-alkene intermediate B into enamine A), intramolecular radical addition (cyclization of D to E), and oxidation sequential processes (conversion of F to final product 139).

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Figure 2.35: Transition-metal-catalyzed C−H oxidative annulations of enamines for the synthesis of pyrroles.

2.3.3 From carbonyl compounds Apart from using β-dicarbonyl or alkyne-based substrates, researchers have also used simple aldehydes/ketones as substrates for pyrrole annulation reactions. Dang et al. [103] developed an efficient copper-N-heterocyclic carbene complex (Cu-NHC) catalyzed synthesis of 1,2-, 1,2,3-, 1,2,3,5-, and fully substituted pyrroles (143) via three-component coupling methods through suitable choice of ketone (141), primary amine (140), and diol (142). In this reaction, they have used a combination of CuBr and ligand, L to generate an in situ Cu-NHC as an efficient non-noble metal catalyst (Figure 2.36). Previously, the same reaction was carried out in the presence of a [Ru(p-cymene)Cl2]2/Xantphos/tBuOK catalyst system [104]. Another synthesis involving carbonyl substrates was developed by Kalmode et al. [105] using a three-component coupled domino reaction of aldehydes (145), ketones (144), and alkyl isocyanoacetates (146) (Figure 2.37). This transformation proceeds through [3 + 2] cycloaddition reaction of chalcone (A, via aldol condensation) with α-cuprioisocyanide (B, via reaction of 146 with CuI), leading to a cyclic organocopper intermediate (C), which on copper–hydrogen exchange followed by oxidation exclusively offers 2,3,4-trisubstituted-1H-pyrrole (147). To efficiently access polysubstituted pyrroles (151), Zheng et al. [106] created an organocatalyzed three-component synthesis using 1,2-diones (148), aldehydes (150), and arylamines (149). Numerous 1,2-diones, arylamines, and aldehydes smoothly reacted with 4-methylbenzenesulfonic acid monohydrate (TsOH.H2O) to produce the

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Figure 2.36: Efficient Cu-NHC-catalyzed synthesis of pyrroles.

Figure 2.37: Synthesis of 2,3,4-trisubstituted-1H-pyrroles via [3 + 2] cycloaddition reaction.

respective polysubstituted pyrroles in acceptable to good yields under relaxed reaction conditions. Based on the research presented in the paper, the multicomponent domino reaction operates according to the mechanism depicted in Figure 2.38. The first step is the nucleophilic addition of the enamine intermediate A produced by the reaction of compounds 148 and 149 to the in situ-generated iminium B from compounds 149 and 150, followed by the intramolecular nucleophilic assault by the C amine to produce the aminoalcohol intermediate D with the help of an acid catalyst. After acid-catalyzed tautormerization of the imine form aminoalcohol D to the equivalent enamine form E, the protonated aminoalcohol E loses a molecule of water to obtain the comparatively stable conjugate iminium ion (F), and then a proton is removed to produce the pyrrole nucleus (151). Su et al. [107] constructed 2,3,4,5-tetrasubstituted pyrroles (155) via one-pot threecomponent (3 + 2) annulation reaction from donor–acceptor cyclopropanes (152), salicylaldehydes (153), and ammonium acetate (154) (Figure 2.39). This reaction involves a

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Figure 2.38: Organocatalyzed three-component reactions for the synthesis of pyrroles.

domino sequence involving the RO of donor–acceptor cyclopropanes, [3 + 2] annulation, and aromatization as the key step (Figure 2.40). This reaction is thought to occur by the base-promoted elimination of the α-H with respect to the carbonyl in the compound (152) to form intermediate (A). After, keto/enol tautomerism, intermediate (A) experiences cyclopropane RO, which is aided by triethylamine, to produce anion (B). Then, the intermediate 2-(iminomethyl)phenol (C) produced from salicylaldehyde (153) and ammonium acetate (154) is attacked by the intermediate (B) to form the amide intermediate (D), which then undergoes two intramolecular nucleophilic additions at the respective carbonyl groups (Ar2-C = O and EtO-C = O, respectively) to form the bicyclic intermediate, 3cyanotetrahydro-2H-furo[2,3-b]pyrrol-2-olate (E). In the presence of a base, a 1,3-hydrogen shift produces conjugated styrene intermediate (F). Furan ring opening converts intermediate (F) into 3-(cyanomethylene)pyrrolidin-2-yl carbonate (G). When the carbonate is removed, 4-(cyanomethylene)-3,4-dihydro-2H-pyrrol-1-ium (H) is produced. This compound then undergoes a 1,3-hydrogen shift to become 4-(cyanomethyl)-2H-pyrrol-1-ium (I). Finally, the deprotonation of 4-(cyanomethyl)-2H-pyrrol-1-ium (I) under basic conditions enabled for the production of the highly substituted pyrroles (155). This elegant methodology readily afforded functionalized pyrroles under mild reaction conditions and with a wide substrate scope. Martin-Santos et al. [108] strategized new organo-catalytic method for the synthesis of 3,4-disubstituted pyrroles (159) by reaction of aldehydes 156 with bromonitroalkenes (157) to form intermediate A (via enamine catalysis), which upon treatment with amines (158) trigger the one-pot domino reaction giving good yields of the product at room temperature (Figure 2.41). In another report, unactivated carbohydrates (160), oxoacetonitriles (161), and ammonium acetate were used to produce densely functionalized pyrroles (162) in yields ranging from 75% to 96% (Figure 2.42) [109]. Novel pyrrolo-glycosides were produced via disaccharides. The exclusive chemo-, regio-, and stereoselectivity of this metal-free, Et3N-catalyzed cascade reaction was

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Figure 2.39: Synthesis of 2-(2,4,5-trisubstituted-pyrrol-3-yl)acetonitriles.

Figure 2.40: Plausible mechanism for the formation of pyrroles from cyclopropane derivatives.

carried out with great atom economy and a broad substrate range. Recently, a threecomponent procedure was established by Chang et al. [110] to produce multiarylsubstituted pyrrole derivatives from arylketones (163), amines (164), and nitrovinylarenes (165) without the use of metals. The proposed mechanism involves amine (164) and arylketone (163) forming imine intermediate A, which is then isomerized into B. Following that, the nucleophilic addition of B to nitrovinylarenes (165) yields intermediate C, which is then tautomerized and cyclized to yield the target product (166) (Figure 2.43).

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Figure 2.41: Organocatalytic synthesis of 3,4-disubstituted pyrroles by a one-pot domino reaction.

Figure 2.42: Synthesis of densely functionalized pyrroles via a three-component cascade reaction.

Figure 2.43: A metal-free synthesis of homologous 1,2,4-triaryl-substituted pyrrole.

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2.3.4 From α,β-unsaturated carbonyls (α,β-UC) Another substrate that is commonly encountered in three-component pyrrole annulation reaction involves α,β-unsaturated carbonyls (α,β-UC). Keiko et al. [111] developed a reaction of 2-alkyl thio-substituted 3-aryl(hetaryl)propenals (167) (α,β-UC) in a one-pot three-component reaction with primary amines (168) and nitroethane to form a highly functionalized pyrroles in 36–80% yields (Figure 2.44). It is observed that the reaction occurs by the synthesis of the intermediate imine (169) of the starting enal (167), which then undergoes 1,2-addition by nitroethane to generate the kinetically regulated 2alkylthio-3-alkylamino-1-aryl(hetaryl)-4-nitro-pentene (170). This adduct can be converted to the thermodynamically regulated 1,4-adduct (171) under either heating or microwave irradiation conditions. The later was cyclized intramolecularly to produce desired tetra-substituted pyrroles (172). The scope of the reaction and the product yields are strongly influenced by the reaction circumstances as well as the substrate structure.

Figure 2.44: Synthesis of new tetrasubstituted pyrroles by coupling reaction of 2-functionally substituted 2-alkenals, amines, and nitroethane.

Shekarrao et al. [112] created a novel multicomponent reaction involving 2-ethynyl pyridine (175), aliphatic amines (174), and β-bromovinyl aldehydes (173) (α,β-UC) that produced 2-alkylated pyridine substituted pyrroles (176) in excellent yields (Figure 2.45). This reaction involved cascade imination, Sonogashira coupling, exo-dig cyclization, and hydride transfer. This palladium-catalyzed procedure establishes C–N, C–C, and C–O bonds all at once, making it simple to generate functionalized pyrroles with a wide range of substituents. According to the proposed mechanism, imino alkyne intermediate A is produced first by the Sonogashira coupling reaction between the imine derivative of βbromovinyl aldehyde (173) and alkyne (175) in the presence of the Pd(OAc)2 catalyst [113]. The ammonium salt intermediate B is then produced via π-coordination of the carboncarbon triple bond of A with the Pd(II) species, followed by exo-dig cyclization. The exodig cyclization in this reaction is most likely caused by the chelation of the pyridine nitro-

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gen atom to the Pd(II) center. The catalyst is regenerated by the following protonation of B by internally produced HBr/AcOH, which results in the ammonium salt intermediate C. The desired product (176) is finally obtained by adding the hydride ion produced by the reaction of dimethylformamide and K2CO3 in the presence of Pd catalyst [114, 115]. Another report, in order to create 3-(1H-pyrrol-3-yl)indolin-2-ones (180) from widely available starting materials, Vivekanand et al. [116] established an effective, ecologically friendly, and atom-economical process (Figure 2.46). The products were produced in high yields through an enamine formation, Michael-addition and an intramolecular cyclization sequence in this one-pot, three-component reaction between primary amines (178), 1,3dicarbonyl compounds (179), and Michael acceptors (177) (α,β-UC) obtained from isatin. Due to the fact that the methodology forgoes the use of catalysts, solvents, and column chromatography, the reaction was conducted in ideal green circumstances. Some environmentally friendly solvents, including water, PEG-200, and glycerol, were also successful in providing the products (180) in high yields for a variety of substrates. Two molecules of water were the only byproduct of this straightforward approach, which enabled the production of two C–N bonds and one C–C bond in a single step. The synthesized compounds (180) also demonstrated significant in vitro cytotoxicity against Ehrlich’s ascites carcinoma tumor cells.

Figure 2.45: Synthesis of alkylated pyridine-substituted pyrroles.

Kumar et al. [117] used (E)-3-(dimethylamino)-1-arylprop-2-en-1-ones (181) as α,β-UC along with anilines (182), and β-nitrostyrenes (183) in a three-component domino reaction in acetic acid to successfully synthesize 1,3,4-trisubstituted pyrroles (184) in excellent yields. One C–C and two C–N bonds form in a single synthetic operation during this one-pot, three-component transformation, which is thought to proceed via an addition-elimination/Michael addition/intramolecular annulation/elimination domino chain of events (Figure 2.47). The authors using this approach have also carried out

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Figure 2.46: Synthesis of 3-(1H-pyrrol-3-yl)indolin-2-ones.

the formal synthesis of an antifungal agent [118]. Wang et al. [119] devised a threecomponent reaction in CH3CN using 2-isocyanoethylindoles (185), gem-diactivated olefins (186) (α,β-UC), and secondary amines (187) to yield polysubstituted pyrroles (188, in moderate yields). Contrary to dibenzyl amine, which produced the desired compounds in subpar yields of 22%, cyclic secondary amines such as morpholine, piperidine, and 1,2,3,4-tetrahydroisoquinoline generated the desired products in moderate yields (34%–46%). A potential reaction mechanism (Figure 2.48) begins with the gemdiactivated olefin (186) being added by isocyanide (185) via a nucleophilic reaction, resulting in the intermediate A. The intermediate A is next subjected to a nucleophilic attack by the amine (187) to produce the intermediate B. In the subsequent process, the

Figure 2.47: Synthesis of 1,3,4-trisubstituted pyrroles via three-component domino reactions.

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Figure 2.48: Polysubstituted pyrroles via the domino reaction of 2-isocyanoethylindoles.

nitrile of intermediate B is nucleophilically attacked by the nitrogen atom, resulting in polysubstituted pyrroles (188). Dawande et al. [120] have designed a highly efficient multicomponent reaction of diazoenals (189) (α,β-UC), amines (190), and aryl aldehydes (191) cooperatively catalyzed by rhodium(II) carboxylate and BINOL-phosphoric acid for the first direct synthesis of valuable α-(3-pyrrolyl)benzylamines (192) with a new stereogenic center (Figure 2.49). The reaction is proposed to involve formation of a transient protic ammonium ylide (B) from the rhodium enal carbenoid (A), a regioselective Mannich reaction (between intermediates B and C) leading to Mannich product D and a intramolecular cyclocondensation cascade in intermediate D leading to final product, 192.

2.3.5 Miscellaneous Other types of pyrrole annulation reactions involving substrates reported only few numbers of times have been included in this section. Peng et al. [121] developed the synthesis of polysubstituted 3-amino pyrroles (196) via palladium-catalyzed three-component tandem reaction of aryl halides (193), Ntosylhydrazones (194), and isocyanides (195) (Figure 2.50). The procedure constructs various polysubstituted 3-amino pyrroles with moderate to excellent yields under mild reaction conditions, assembly efficiency, readily available starting materials, and good functional group tolerance. The mechanism involves formation of a Pd carbene

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Figure 2.49: Direct synthesis of α‑pyrrolylbenzylamines.

complex A (in turn generated from (i) double isocyanides (195) insertion to palladium aryl intermediate generated from oxidative addition of Pd(0) to 193; (ii) followed by trapping of this intermediate by a diazo compound produced from 194). Migratory insertion of imino group in Pd carbene complex gave intermediate B and this under reductive elimination followed by cyclization leading to the formation of 3-aminopolysubstituted pyrroles (196).

Figure 2.50: Synthesis of polysubstituted 3-amino pyrroles via palladium-catalyzed three-component tandem reaction.

Ge et al. [122] designed a novel route to make bioactive trifluoromethyl-substituted pyrroles (200) via a three-component cascade reaction of 1,3-enynes (197), anilines (198), and Togni-II reagent (199) with high regioselectivity under mild conditions. Togni-II reagent is

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utilized as a precursor for the CF3 radical in the presence of Cu(OAc)2 · H2O and a catalytic amount of [Cp*RhCl2]2. The proposed mechanism (Figure 2.51) begins with the azaMichael addition of 1,3-enynes (197) and amine (198), which results in the creation of intermediate A, with the help of molecular sieves acting as Lewis acid and Ca(OH)2 acting as base. Second, a CF3 radical is produced when Togni-II reagent (199) interacts with copper(II), which then reacts with intermediate A to produce intermediate B. Then, intermediate B can be trapped by Cu(II) to produce intermediate C, which then undergoes a transmetallation reaction with Rh(III) to produce rhodacyclic intermediate D. The desired product (200) is produced after intermediate D is finally subjected to reductive elimination cum oxidation, along with a Rh(I) species that engages in a redox reaction with Cu (III) to regenerate the Rh(III) species.

Figure 2.51: One-pot synthesis of fully substituted trifluoromethyl pyrroles using Togni-II reagent.

Mohammadi et al. [123] presented a novel and efficient solvent-free synthesis of 3-amino -4-cyano-5-phenyl-1H-pyrrole-2-carboxamides (204) using a simple three-component reaction involving arylidenmalonononitrile (201), malononononitrile (202), and hydroxylamine hydrochloride (203). The key benefits of this approach include quick reaction times, good to exceptional product yields, affordable and easily accessible starting materials, and, time and energy savings. A potential reaction mechanism (Figure 2.52) calls for the Michael addition of hydroxylamine (203) to arylidenmalononitrile (201) in the first step to create 2-((hydroxyamino)(aryl)methyl)malononitrile A. The intermediate B is produced in the following step by adding malononitrile (202). The intermediate B is then cyclized by adding an oxygen atom to the nitrile group, producing oxazepin-imine, C. In the intermediate C, a nitrogen atom undergoes an intramolecular SN2-like reaction, and the CN atom is eliminated, yielding 7-oxa-1-azabicyclo[3.2.0]heptane (D). After the [1,3] H-shift, D undergoes the electrocyclic RO reaction, followed by the [1,5] H-shift to produce the 3amino-4-cyano-5-phenyl-1H-pyrrole-2-carboxamides (204).

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Figure 2.52: Three-component synthesis of 3-amino-4-cyano-5-phenyl-1H-pyrrole-2-carboxamides (204).

Farahi et al. [124] used a one-pot synthesis of α-hydroxyketones (205), malononitrile (207), and ammonium acetate (206) in the presence of tungstate sulfuric acid (TSA) under mild reaction conditions to create novel tetrasubstituted pyrroles (208) (Figure 2.53). The technique worked well with both electron-rich and electron-poor α-hydroxyketones. This approach is appealing for the synthesis of these valuable heterocycles because of the high catalyst recyclability, solvent-free conditions, ease of use, appropriate reaction durations, and decent yields. In another variant approach, Liu et al. [125] have used an important building block nitroepoxide (209), which has unique chemical properties with two adjacent electrophilic centers, as substrates along with amines (210) and malononitrile (211) under mild conditions (Figure 2.54). This approach is notable for its functional group tolerance, non-transition metal catalyst, and mild reaction conditions. The ring opening of nitroepoxide (209) with amine (210) to produce the intermediate A may be the trigger for the reaction. The produced intermediate A was then converted to aminoketone B by getting rid of one nitrous acid molecule. Additionally, by removing one molecule of H2O, the reaction between aminoketone B and malononitrile (211) would result in intermediate C. Finally, the desired product (212) is obtained by an intramolecular nucleophilic addition of the cyano group followed by tautomerization. Li et al. [126] used a three-component bicyclization/RO/oxidative coupling reaction using β-ketothioamides (KTAs) (213), arylglyoxals (214), and 2-cyanoacetates (215) to rapidly produce disulfides tethered pyrroles (216) in DABCO/air (Figure 2.55). In total, nine chemical bonds and two new pyrrole rings were created through the sequential reactions of Knoevenagel condensation, Michael addition, N-cyclization, O-cyclization, RO, double tautomerization, and oxidative coupling. The method created allows for the creation of disulfides tethered pyrroles with a high atom economy and high formation efficiency. It also has fascinating features such a quick reaction time, mild reaction conditions, no need for transition metals, and simple purification. Unquestionably, this synthetic approach offers a practical method for creating pyrroles with disulfides attached. In contrast to the typical imine condensation, the atypical Ag-catalyzed reaction described by

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Figure 2.53: TSA-catalyzed one-pot synthesis of tetrasubstituted pyrroles 208.

Figure 2.54: Synthesis of N-substituted 2-amino-3-cyanopyrroles via ring-opening of nitroepoxides.

Liao et al. [127] begins with a simple aza-Michael addition (Figure 2.56). This interesting three-component reaction involved 3-formylchromones (217), amines (218), and isocyanoacetates (219) and was catalyzed by affordable silver salt and triphenylphosphine in a straightforward manner to produce polysubstituted pyrroles (220). Ding and coworkers [128] reported on the synthesis of a completely substituted azido pyrrole (224) from 1,3enynes (221), amines (222), and TMSN3 (223) utilizing a Cu and Mn co-mediated aerobic oxidative cyclization and azidation (Figure 2.57). The initial mechanism entails a sequential aza-Michael addition, intramolecular cyclization mediated by copper, radical azidation with a single electron catalyst mediated by manganese, and oxidative aromatization in an air atmosphere at ambient temperature. High regioselectivity, a broad substrate range, and benign reaction conditions are all features of the reaction. Chaudhary et al. [129] developed a three-component domino reactions of arylglyoxal monohydrate (226), (E)-N-methyl-1-(methylthio)-2-nitroethenamine (227), and 1,3-dimethyl barbituric acid/barbituric acid (225) in aqueous media allowed for the chemoselective synthesis of a series of new 5-(1-methyl-5-(methylthio)-4-nitro-2-aryl-1H-pyrrol-3-yl)pyrimidine-triones (228) (Figure 2.58). The reaction had very high green credentials as analyzed by green metrics computations done for the newly designed molecules via one-pot synthetic protocol’s green chemistry metrics were assessed. Atom economy (AE, 86–89%),

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Figure 2.55: Synthesis of disulfide-tethered pyrroles from β-ketothioamides.

Figure 2.56: Pyrrole formation initiated by an unexpected aza-Michael addition.

Figure 2.57: Regioselective synthesis of fully substituted azido pyrroles from 1,3-enynes.

atom efficiency (AEf, 77–81%), carbon efficiency (CE, 87–93%), reaction mass efficiency (RME, 76–81%), optimum efficiency (OE, 70–93%), and process mass intensity (PMI, 27.96– 34.76 g/g), E-factor (3.93–5.20 g/g), solvent intensity (SI, 3.67–4.64 g/g), and water intensity (WI, 29.11–23.02 g/g) were found to be almost at their ideal values, thereby demonstrating a method with excellent green credentials. Liu et al. [130] designed a base-promoted three-component cascade reaction of α-hydroxy ketones (229), malonodinitrile (230), and alcohols (231) that offers a quick and straightforward way to a variety of structurally dif-

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ferent and valuable 2-alkyloxy-1H-pyrrole-3-carbonitrile derivatives (232 or 233) (Figure 2.59). The reaction featured the construction of three distinct bonds (C–C, C–O, and C–N) in a single step, and the structure of the α-hydroxy ketones used determined the reaction’s regioselectivity. Liu et al. [131] have reported another three-component domino reaction, promoted by Brønsted acid to polyfunctionalized fully substituted pyrroles (238 and 239) from enaminones (234), arylglyoxal monohydrates (235), and benzenethiol (236) or indoles (237). Simple mixing of three common reactants in acetic acid with microwave heating is all that is required to carry out the reaction. The reaction moves along quickly and can be completed in 26 min (Figure 2.60). The workup is very practical.

Figure 2.58: Synthesis of series of new 5-(1-methyl-5-(methylthio)-4-nitro-2-aryl-1H pyrrol-3-yl)pyrimidinetriones (228).

Figure 2.59: Construction of pyrroles from α-hydroxy ketones and nitriles.

Figure 2.60: New indolation and thiolation-based three-component domino reactions.

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2.4 Three-component synthesis of pyridine Pyridine is one of the simplest and important heterocycles having structure like benzene with one methine group replaced with nitrogen atom. Pyridine-containing compounds have shown biological importance by showing antitumor [132], anticancer [133], antiproliferative [134], anti-arenavirus [135], antituberculosis [136], and antiinflammatory activity [137] activities. Further, pyridine scaffold is found to be in many commercially available drugs [138] such as piroxicam for arthritis, bromazepam for severe anxiety, phenazopyridine for pain reliever caused by urinary tract infections, abiraterone for prostate cancer, delavirdine as an antiviral against HIV/AIDS, omeprazole for ulcers, and enpiroline for malaria (Figure 2.61). Many of medicinally important natural products [138, 139] contain the pyridine ring such as collismycin, streptonigrin, and nikkomycin (Figure 2.62). Due to biological and medicinal significance, newer approaches are highly worthwhile. So, in this section we have included the three component annulation strategies discovered in the last decade.

Figure 2.61: Some commercially available drugs containing the pyridine scaffold.

Figure 2.62: Medicinally important natural products containing pyridine moiety.

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Dong et al. [140] reported a simple and effective solvent-controlled regioselective synthesis of multisubstituted 4- and 6-amino-2-iminopyridines under extremely mild circumstances by three-component reaction of sulfonyl azides (241), 2-[(amino)methylene] malononitriles (240), and alkynes (242). The 6-amino-2-iminopyridines (243) are predominantly produced in DMF at 50 °C under N2 while the 4-amino-2-iminopyridines (244) are synthesized in good yield in THF at room temperature (Figure 2.63).

Figure 2.63: Synthesis of multisubstituted 4 and 6-amino-2-iminopyridines (243–244).

Several research groups have reported the synthesis of highly substituted pyridines (248) by the one-pot three-component condensation of aldehydes (245), alcohols/thiols (246), and malononitrile (247) under diverse reaction conditions via carbon–carbon and carbon–heteroatom bond formation as shown in Table 2.1. The use of nanoparticles as catalysts increases the selectivity, reactivity, and product yields due to high surfaceto-volume ratio resulting in more active sites per unit area. In this context, Mehrabi and colleagues [141] have reported the synthesis of pyridines in water–ethanol at refluxing temperature utilizing calcium oxide nanoparticle as a catalyst in 70–90% yields (Table 2.1, entry 1). This method provides a mild and green access to synthesize the pyridine motif in shorter reaction times. In continuation, nano copper-ferrite catalyst was also used to synthesize the polyfunctioned pyridine moieties by Douglas and coworkers [142] (Table 2.1, entry 2). This methodology is ecologically friendly with lower catalyst loading, shorter reaction times, higher yields, magnetic recoverability, and the catalyst recyclability. Using nanocrystalline magnesium oxide as a base catalyst, Sheibani and coworkers [143] has developed an effective and ecologically friendly technique for the production of polysubstituted pyridine derivatives (Table 2.1, entry 3). Kidwai and Chauhan [144] have also employed potassium carbonate and PEG (PEG-400) for the mild and green synthesis of pyridine derivatives (Table 2.1, entry 4).

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The recovered PEG-400 phase produced reliable results for up to four cycles. Deep eutectic solvent and IL have also been utilized as these provide milder and environmentally benign methodologies. In this context, Azizi and Haghayegh [145] catalyzed the reaction in choline chloride (ChCl) and urea while Khandebharad et al. [146] employed choline hydroxide (ChOH) as IL catalyst with water at refluxing temperature to synthesize the desired pyridine moieties in good yields. No significant loss in the activity of the catalyst was observed up to four cycles in both the catalyst. Last, Nazeruddin [147] reported microwave-assisted synthesis of pyridine by using sodium acetate as a catalyst. Table 2.1: One-pot synthesis of pyridines by the one-pot three-component condensation of aldehydes, thiols/alcohols, and malononitrile.

S. no.

Conditions

      

Nano-CaO, HO/EtOH, reflux,  min Nano-copper ferrite, EtOH, reflux Nano-MgO, EtOH,  °C, – h  mol% KCO, PEG-,  °C, – h Urea-ChCl,  °C, – h HO/ChOH, reflux AcONa, MW

Yield (%)

Reference

– – – – – – –

[] [] [] [] [] [] []

The plausible mechanism for the entries (1–3) in Table 2.1 involves Knoevenagel condensation between malononitrile and aldehydes followed by annulation reactions with alcohols/thiols leading dihydropyridines, which in turn result in the formation of pyridines via an aromatization reaction. A typical example using metal oxide nanoparticles is given in Figure 2.64. The process commences by the Knoevenagel condensation of aldehyde (245) and malononitrile (247) in the presence of metal oxide, producing cinnamonitrile (249). Cinnamonitrile then combines with another molecule of malononitrile (247) which was subsequently reacted with alcohols/thiols (246) to produce a dihydropyridine intermediate (250). Removal of hydride is facilitated by the oxide ion to convert the dihydropyridine into pyridine. The synthesis of 2,4,6-triarylpyridines (253) by using a one-pot three-component condensation of aromatic aldehydes (245), substituted acetophenones (251), and ammonium acetate (252) under various conditions is depicted in Table 2.2. Reddy et al. [148] developed an efficient methodology for synthesis of 2,4,6-triarylpyridines by using tetrabutylammonium hydrogen sulfate (TBAHS) as a phase transfer catalyst at 120 °C

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Figure 2.64: Plausible mechanism for the synthesis of pyridine (248) using metal-oxide nanoparticle.

temperature in solvent-free conditions (Table 2.2, entry 1). Also, barium chloride dispersed on silica gel nanoparticles (BaCl2-nano-SiO2) were used as a catalyst by Shafiee and Moloudi [149] for the synthesis of trisubstituted pyridine under solvent-free reaction conditions at 120 °C (Table 2.2, entry 2). Further, Li et al. [150], by using diphenylammonium triflate (DPAT) as a catalyst, also reported the synthesis of substituted pyridine under solvent-free reaction conditions at 120 °C (Table 2.2, entry 3). However, Wang and group [151] developed an efficient and environment benign methodology for the synthesis of 2,4,6-triarylpyridines at 130 °C temperature under solvent-free reaction conditions without using any catalyst (Table 2.2, entry 4). With nanocrystalline MgAl2O4 as a heterogeneous catalyst, Safari et al. [152] also developed an efficient and green synthetic protocol for the synthesis of trisubstituted pyridine moieties at 120 °C under solvent free conditions (Table 2.2, entry 5). The catalyst can be used up to five consecutive runs without any significant loss in activity. In continuation, oxozirconium(IV) chloride (ZrOCl2) were used by Zare and coworkers [153] as catalyst for the synthesis of trisubstituted pyridines under solvent-free conditions at 100 °C (Table 2.2, entry 6). The catalyst works efficiently upto four consecutively runs. Further, Amoozadeh [154] also used the heterogeneous catalyst in the form of nanotitania-supported sulfonic acid (n-TSA) for the environmental friendly synthesis of pyridines (Table 2.2, entry 7). The catalyst shows excellent catalytical activity up to six consecutive cycles. Further, in this regard, Kamali and Smith [155] also reported the synthesis of trisubstituted pyridine by using cobalt(II) chloride hexahydrate as a catalyst under solvent-free conditions at 110 °C (Table 2.2, entry 8). The catalyst promotes the condensation reaction through modified Chichibabin pyridine synthesis conditions and works well up to four consecutive runs without any significant loss in the activity. Maleki and Firouzi-Hazi [156] also developed a green synthesis of pyridine derivatives by using the same starting materials in the presence of heterogeneous nanocatalyst LPSF (Fe3O4/SiO2/propyltriethoxysilane/Lproline nanoparticles) at 60 °C (Table 2.2, entry 9). The catalyst is magnetically separable and works well upto seven cycle without any significant loss in the yield of product. Ma and coworkers [157] reported a three-component Cu-catalyzed reaction involving N-sulfonyl-1-aza-1,3-butadienes (254), terminal alkynes (255), and sulfonyl azides (256) in presence of cesium carbonate that provides access to highly functionalized 1,4-dihydropyridine molecules (259A), which serve as a precursor for the produc-

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Table 2.2: Synthesis of 2,4,6-triarylpyridines by using a one-pot three-component condensation of aldehydes, acetophenones, and ammonium acetate.

S. no.

Conditions

        

TBAHS,  °C, – h BaCl-nano-SiO,  °C, – min DPAT,  °C, – h✶  °C, – h Nano-MgAlO,  °C,  h  mol% ZrOCl,  °C n-TSA (. g),  °C CoCl·HO,  °C,  h LPSF (. g),  °C,  h

Yield (%)

Reference

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

[] [] [] [] [] [] [] [] []

✶

NH4HCO3 is used as a nitrogen source

tion of pyridine (257) (Figure 2.65). The [4 + 2] addition reaction is facilitated by the electron-deficient nature of cesium cation for the formation of 1,4-dihydropyridine molecule. The tandem reaction between the terminal alkyne (255) and azide (256) in the presence of stoichiometric quantities of Cs2CO3 was initiated by Cu(I) to produce the cesium ynamidate (258) which is then cyclized with the 1-azadiene (254) to produce [4 + 2] cycloadduct intermediate (259) as shown in Figure 2.66. The cesium cation plays an important role by acting as a Lewis acid to facilitate the formation of intermediate (259). The protonation of intermediate (259) results in the formation of dihydropyridine derivative (259A) which upon aromatization produces the desired pyridine product (257).

Figure 2.65: Synthesis of multisubstituted pyridines (257).

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In the presence of an eco-friendly heterogeneous catalyst K-10, Hanashalshahaby and Unaleroglu [158] reported a simple three-component, one-pot water-mediated reaction using an enolizable ketone (260), Mannich base (261), and ammonium acetate at 80 °C temperature for the synthesis of trisubstituted pyridine moieties (262) (Figure 2.67).

Figure 2.66: Plausible mechanism for the copper(I)-catalyzed synthesis of tetrasubstituted pyridines (257).

Figure 2.67: K-10-catalyzed synthesis of trisubstituted pyridines (262).

Initially, ketone reacts with ammonia to produce enamine (263). Further, enone (264) was also formed in situ from Mannich base (261) as shown in Figure 2.68. The Michael addition reaction of enone (264) with enamine (263) produces intermediate (265) in the next step, followed by intramolecular cyclization to produce intermediate (266) and aromatization to produce 2,3,6-trisubstituted pyridine (262). Lee and Khanal [159] designed the synthesis of trisubstituted pyridines (271–273) by conducting three-component L-proline-catalyzed reaction of easily accessible ketones with α,β-unsaturated aldehydes (267) and ammonium acetate (252). This methodology provides an alternative pathway by avoiding the synthesis of necessary functional groups, such as oximes, imines, or azides through formation of C–C and C–N bonds in a single operation (Figure 2.69). The synthesized pyridine molecules show antibacterial activities and can be used for detection of Cu2+ in solutions. L-Proline enables the enol form (274) to attack the iminium ion (275), which was generated from α,β-unsaturated aldehydes (267) to produce the intermediate (276) as shown in Figure 2.70. Another iminium ion intermediate (277) is produced by deprotonation of intermediate (276), which then underwent proton migration and intramolec-

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Figure 2.68: Plausible mechanism for the K-10-catalyzed synthesis of trisubstituted pyridines (262).

Figure 2.69: L-Proline-catalyzed synthesis of substituted pyridines (271–273).

ular nucleophilic attack to produce intermediate (278). Finally, the aromatization of intermediate (278) produces the desired pyridine molecule (271–273) and L-proline was also recovered. Wan and coworkers [160] reported the synthesis of tetrasubstituted pyridines by [3 + 2 + 1] cycloaddition reaction of diverse enaminones (279 and 280) and aldehydes (245) by using a catalytical system consisting of copper iodide and potassium bisulfate (Figure 2.71). The synthesis is based on highly selective gatherings of NH2 enaminones (279), N,N-disubstituted enaminones (280), and aryl aldehydes (245).

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Figure 2.70: Plausible mechanism for the L-proline-catalyzed synthesis of trisubstituted pyridines (271–273).

Figure 2.71: Synthesis of tetrasubstituted pyridines (281).

Initially, protonic acid facilitates the formation of imine intermediate (282) through the condensation of aromatic aldehyde (245) and enaminone (279) (Figure 2.72). Further, enaminone (280) reacts with intermediate (282) in nucleophilic addition manner to produce the intermediate (283). After tautomerism, intermediate (284) underwent intramolecular 1,4-addition reaction facilitated by the copper(I) results in formation of intermediate (285). Subsequently, replacement of Cu+ by a proton and eliminating the dimethyl molecule from intermediate (286) results in the formation of dihydropyridine intermediate (287) which on aromatization by oxidation with copper(II) produces the desired pyridine moiety (281). Further, Wang et al. [161] employed nitriles (288) and alkynes (289) to synthesize the penta-functionalized pyridines (292) via [2 + 2 + 2] cycloaddition reaction using iron(II) and cobalt(II) co-catalyst (290 and 291). The reaction was carried out in toluene at 50 °C temperature for 20 h. Also, an efficient and regioselective synthesis of tetrasubstituted pyridine (294) was carried out by using copper(I)-catalyzed [2 + 2 + 2] cycloaddition reaction of nitriles (288) and alkynes (289) with vinyl iodonium salts (293) in DCE at 130 °C by Chen and coworkers [162] (Figure 2.73).

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Figure 2.72: Plausible mechanism for the CuI and KHSO4-catalyzed synthesis of tetrasubstituted pyridines (281).

Figure 2.73: Synthesis of tetra-/pentasubstituted pyridines (292 and 294).

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The reaction proceeds through an aza-butadienylium intermediate which was subsequently formed by the vinylation of nitriles with vinyl-tolyl iodonium salts. First, copper(I) bromide and vinyl iodonium salt (293) reacts to generate electrophilic vinyl-CuIII intermediate (295) as shown in Figure 2.74. Intermediate (295) is coordinated with nitriles (288) to afford intermediate (296) which on reductive elimination provide azabutadienyl cation intermediate (297). The [4 + 2] cycloaddition reaction of alkyne (289) with intermediate (297) provides a cyclized cationic intermediate (298) which on aromatization via a loss of proton produce the desired pyridines (294).

Figure 2.74: Plausible mechanism for the copper-catalyzed synthesis of tetrasubstituted pyridines (294).

However, Deng et al. [163] reported an efficient and metal-free synthesis of polyfunctioned pyridines by using ammonium iodide (302). Whereas a stoichiometric amount of ammonium iodide (302) aided the three-component reaction of oxime acetates (299), 1,3-dicarbonyls (300) and benzaldehydes (301) operate effectively, the condensation of oximes (299) and acroleins (304) were facilitated by utilizing a catalytic initiator to produce substituted pyridines. Ammonium iodide (302) served a dual purpose in the transformation by reducing the oxime N–O bond and subsequently assisted the condensation reaction (Figure 2.75). Initially, the N–O bond of oxime acetate (299) is efficiently reduced by ammonium iodide (302) to produce imine intermediate (306) by losing acetic acid and elemental iodine (Figure 2.76). Then, the tautomeric form (308) reacts with α,β-unsaturated carbonyl (304) in 1,4-addition manner producing the enamine intermediate (309) which further give dihydropyridine intermediate (310) through intramolecular condensation reaction. Last, aromatization of dihydropyridine (310) via oxidation by I2 provides the desired pyridine product (305). Ma et al. [164] employed Selectflour (312) as an oxidant for the efficient α-methylenation of 1,3-diketones (311) by using DMSO as a carbon source to produce the corresponding methylene-bridged bis-1,3-dicarbonyl compounds (322) which subsequently condensed with ammonium salt to provide the polysubstituted pyridines (314). Modi-

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Figure 2.75: Synthesis of multisubstituted pyridines from oximes (303 and 305).

Figure 2.76: Plausible mechanism for the synthesis of tetrasubstituted pyridines (305).

fied conditions were developed by Nurkenov and group [165] via the formation of 1,4dihydropyridine (323) by using three-component condensation reaction of acetoacetic ester (311), ammonium acetate (252) and urotropine (313) in ethanol at refluxing temperature. Subsequently, 1,4-dihydropyridine derivative was converted into pyridine moiety by using sodium nitrite in acetic acid at room temperature. Another, alternate reagents involved a three-component cyclo-condensation reaction of 1,3-dicarbonyl compounds (311), DMSO, and ammonium salt (252) in the presence of trifluoroacetic acid, a highly convergent one-pot synthesis of Hantzsch-type pyridine [166]. DMSO served as a carbon source for the α-methylation of dicarbonyl compounds (311), as a solvent, and also as an oxidant to convert the 1,4-dihydropyridine derivative (323) into pyridine moieties (314) (Figure 2.77). The plausible mechanism proposed by Yongmin and co-workers (Figure 2.78) involves five steps. Initially, Selectfluor reacts with DMSO to generate a fluorinated intermediate (317) which on a nucleophilic reaction with enolic form of diketone (318)

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Figure 2.77: Synthesis of multisubstituted pyridines from oximes (314–316).

results in formation of intermediate (319). Further, the intermediate (319) reacts with another molecule of diketone to generate a key intermediate (322) which on intramolecular cyclization in presence of ammonium acetate affords dihydropyridine (323). Finally, the intermediate (323) oxidized in the presence of Selectfluor and DMSO to form desired tetra-substituted pyridines (314). During the course of reaction Selectfluor plays a dual role by providing F+ ions in the first step and also acts as an oxidant in final aromatization step to generate desired pyridine molecules.

2.5 Conclusions The needs for new bioactive heterocycles in health care, combined with the urge to generate these molecules quickly and in an environmentally friendly manner, provide considerable challenges to the synthetic chemical community. Numerous techniques have been developed over the years to produce different heterocyclic moieties, but MCRs are the most desired because of their cost and environmental benefits. Currently, the research concerning the three-component annulation of N-heterocycles (β-lactam, pyrroles, and pyridine) is limited in terms of readily available substrates and in terms for diversity of the three components used. As a result, in spite of many reports, there is still lot many developments needed here for making protocol with better substrate scope. In this chapter, we have elaborated a wide variety of three-component annulation strategies for making these N-heterocyclic compounds during the past decade and have also included the mechanistic pathways in most cases.

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Figure 2.78: Plausible mechanism for the synthesis of tetrasubstituted pyridines (314).

Conflict of interest statement: The authors declare no conflicts of interest regarding this chapter.

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Samiran Dhara, Saiful Islam, Asish R. Das✶

3 One-pot three-component synthesis of quinolines and some other selective six-membered heterocycles with biological importance 3.1 Introduction Drug development and design significantly affected by the discovery of novel heterocyclic scaffolds which has an enormous effect in human lifestyle. Results from multicomponent reactions (MCR) can be thought of as the synthetic pivot for an enormous variety of innovative heterocyclic scaffolds. MCRs are typically defined as reactions in which three or more reactants combine to form novel product in a single operation [1–6]. This procedure has a number of benefits because it manages to combine some basic organic reactions that occur under different circumstances, also offering a vivid solution for a single-step, one-flask procedure that exhibits extraordinary atom economy and superior selectivity towards the heterocyclic skeleton [7–10]. Generally, MCRs are composed of simple techniques for the fabrication of various complex molecules in a straightforward manner and have achieved outstanding success in terms of synthetic efficacy and reaction design [11–14]. Till date, a range of MCR reaction protocols have been developed, for example, the Ugi and Passerini reactions are the preamble examples of MCRs [15]. Due to inherent potency of these techniques significant applications have been developed for the novel and efficient synthesis of complex heterocyclic scaffolds. The countless convergence of MCR offers a rapid, effective, and affordable uncommon to the present direct synthesis. A low-yielding MCR is less expensive than a similar multistep process. The majority of MCRs has a wide range of substrates that they can tolerate in addition to reactive centers with different functionalities. MCR products may be prepared in the way of subsequent cascade transformations. Furthermore, the high yield, one-pot, single-step procedure, extraordinary bond forming

Acknowledgements: We acknowledge the financial support from the University of Calcutta, India. S. D. thanks the UGC, New Delhi, India, for his Senior Research Fellowship [UGC Ref. No. 282/(SC) (CSIRUGC NET DEC.2016)]. ✶ Corresponding author: Asish R. Das, Department of Chemistry, University of Calcutta, Kolkata 700009, West Bengal, India, e-mail: [email protected] Samiran Dhara, Saiful Islam, Department of Chemistry, University of Calcutta, Kolkata 700009, India

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Figure 3.1: Advantages of one-pot MCR reactions.

index, high atom economy, and extremely confluent leads to simple upgrade protocols make the MCR chemistry an almost ideal methodology to construct array of diverse compounds to benefit manhood (Figure 3.1). These factors combined with the enormous scaffold diversity make the MCR chemistry an extremely efficient method. Considering this background, we are discussing nearly current advancements in the onepot synthesis of heterocyclicsegments that are usually accepted by pharmacology and academic circles.

3.2 Nitrogen-containing heterocycles Pyridine, quinolines, pyrimidines, quinazolines, dihydropyridines (DHPs), naphthyridines, and spiro-heterocycles are just a few examples of the heterocyclic moiety that are commonly used in clinical evaluation. Due to the immense biological importance, there are plenty of methodologies reported in the literature on how to carry out the synthesis of these biologically significant compounds.

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3.2.1 Quinoline derivatives The pyridine and quinoline nucleus are the essential core piece of a variety of physiologically and pharmaceutically active compounds with features including antimalarial, antibacterial, antiasthmatic, anticancer, antiinflammatory, and antidiabetic [16–30]. They are also helpful for the synthesis of different significant ligands in coordination chemistry and are utilized as alkali reagents or additives in a variety of organic reactions [31–33]. They serve as a helpful recourse in the synthesis of numerous significant nitrogen-containing heterocycles [34]. Consequently, superior attention has been given to constructing pyridine and quinoline molecules in the course of the last few years.

3.2.1.1 Synthesis of 3-arylsulfonylquinolines via cascade oxidative coupling In 2022, Mal et al. [35] reported a three-component coupling reaction between Npropargylamine (1), diazonium tetrafluoroborate (2), and DABCO. (SO2)2 (DABSO) (3) under argon atmosphere in dichloroethane as a solvent. At room temperature, DABSO used as the sulfone source and an oxidant in this particular radical-medicated cascade reaction. This methodology offered a wide range of substrate scope, mild reaction condition and decent to outstanding yields of anticipated products (4) (Figure 3.2).

Figure 3.2: Synthesis of 3-arylsulfonylquinolines.

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Mechanistic study and previous literature suggest that aryl diazonium tetrafluoroborate (2) and DABSO (3) react to each other to generate an aryl sulfonyl radical (B) in situ. Aryl sulfonyl radical undergoes addition reaction to the 3-propargyal amine (1) to generate an intermediate (C). The intermediate immediately goes through intramolecular cyclization (D), re-aromatization followed by oxidation to produce the desired 3-arylsulfonylquinolines (4) (Figure 3.3).

Figure 3.3: Plausible mechanism for the synthesis of 3-arylsulfonylquinolines.

3.2.1.2 Synthesis of 3-arylquinolines via [3+1+1+1] annulation In 2022 Li and coworkers [36] synthesized a diverse range of quinolines (8) through [3+1+1+1] annulation of arylamines (5), arylaldehydes (6), and dimethyl sulfoxide (DMSO) (7) in the presence of stoichiometric amount base (t-BuOK) and oxidant (K2S2O8). In this protocol DMSO (7) provides two nonadjacent methines (=CH–) to the pyridine ring in quinolines core (Figure 3.4). This annulation offers a straightforward method for producing 3-arylquinolines (8) from easily accessible substrates with good to outstanding yields.

3.2.1.3 Regioselective synthesis of substituted quinolines In 2021, Li and coworkers [37] demonstrated a straightforward regiospecific methodology for the synthesis of highly substituted quinolines (10 and 10′) from 2-aminobenzyl alcohols (9), benzaldehyde (6), and DMSO (7) in the presence of KOH. In this annulation reaction, DMSO (7) acts as one carbon source to the quinoline ring (Figure 3.5). Here, the key step of annulation is the [4 + 2] cycloaddition reaction (Figure 3.6).

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Figure 3.4: Synthesis of 3-arylquinolines.

Figure 3.5: Synthesis of 3-arylquinolines.

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Figure 3.6: Plausible mechanism for the synthesis of 3-arylquinolines.

3.2.1.4 Metal-free synthesis of 4-arylquinolines In 2018, Tiwari and coworkers [38] developed an effective and transition metal-free method to synthesize 4-arylquinolines (12) from easily available anilines (5) and alkynes (11) in the presence of K2S2O8 and DMSO (7). The one-pot cascade method offers a broad substrate range, readily accessible raw ingredients, and good to exceptional yield of the desired quinolies (12). The [4 + 2] oxidative annulation method uses DMSO as one carbon source (Figure 3.7).

3.2.1.5 An iron(III)-catalyzed synthesis of 2-pyridones In 2022, Lee and coworkers [39] discovered a highly effective iron(III) catalyzed threecomponent heteroannulation reaction between 3-formylchromones (13), phenylpropiolamides (14), and water (15) for the synthesis of various multifunctionalized 2-

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Figure 3.7: Synthesis of 4-arylquinolines.

pyridones (16) (Figure 3.8). The key characteristics of this procedure include a cheap catalytic source, short reaction time, ease of operation, and high yield. Water molecule acts as an oxygen resource. The key characteristics of this procedure include a cheap catalytic source, short reaction times, ease of operation, and high yield. Water molecule acts as an oxygen resource (Figure 3.9).

3.2.1.6 Solid-state synthesis of chromenopyridinones In 2015, Lee et al. [40] synthesized highly functionalized and diverse chromenopyridinones (19) using three-component reactions between different 4-hydroxycoumarins (17) with ammonium acetate (18) and 3-formylchromones (13) under L-proline-catalyzed solvent-free conditions (Figure 3.10). The benefit of this protocol includes the employment of low-cost organocatalyst, short reaction time, various functional group tolerance, anticipation of toxic organic solvents, environmental-friendly conditions, solid-state reaction, and excellent yield.

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Figure 3.8: Synthesis of 2-pyridones.

3.2.1.7 Ball-milling approach of pyridocoumarin synthesis In 2017, Das and coworkers [41] developed CuI-Zn(OAc)2 combo-catalyzed solvent-free protocol for the synthesis of functionalized pyridocoumarin framework (21). In this particular reaction an aryl aldehyde (6), terminal alkyne (10), and 3-aminocoumarin (20) couple together to form desired skeleton though a ball-milling process under mild condition (Figure 3.11). Reaction mechanism involves uncommon CuI–CuIII switching combo-catalysis through the formation of a flexible propargylic amine intermediate (C), which results in a quick C(sp2)-H activation for cyclization involving transient CuIII species. The UV-vis study of the reaction mixture proves the existence of transient CuIII species (Figure 3.12).

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Figure 3.9: Proposed mechanism for the synthesis of 2-pyridones.

Figure 3.10: Synthesis of chromenopyridinones.

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Figure 3.11: Synthesis of functionalized pyridocoumarins.

Figure 3.12: Plausible mechanism for the synthesis of functionalized pyridocoumarins.

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3.2.2 Pyrimidines and quinazolines The importance of pyrimidine and quinazoline derivatives has been skillfully acknowledged. A variety of bioactive compounds with diverse biological properties, such as antidepressant, antipyretic, analgesic, anticonvulsant, anti-inflammatory, anti-HIV, antiviral, antitumor, and antibacterial capabilities, all have the pyrimidine and quinazoline motif as its fundamental core component [42–51]. In addition to these uses, heterocyclic scaffolds are similarly utilized, antiplatelet aggregation inhibitors, as serotonin 5-HT6 receptor antagonists, arrhythmic medicines, anti-Parkinsonian drugs, to treat leukemia, anemia, lower cholesterol levels, etc. [52–55]. Due to such pharmaceutical importance, the attention in mounting novel synthetic schemes hase improved for the construction of pyrimidine and quinazoline scaffolds.

3.2.2.1 Microwave-assisted synthesis of quinazolino[4,3-b]quinazolin-8-ones In 2022, Nanduri and coworkers [56] reported a novel microwave-assisted Cu(I) catalyzed one-pot multicomponent synthesis of linearly fused quinazolines (25) (Figure 3.13). This protocol’s synthetic applicability increased by the short reaction time, ligand-free approach, use of environmentally benign PEG-400 as a solvent, and wide substrate scope. Here, one of the diheteroatomic quinazoline ring nitrogen was supplied by TMSN3. In the presence of CuI C–N bond formation takes place at first to give free NH2. Then it reacts with aldehyde with one molecule of water elimination followed by annulation to the desired product (25).

3.2.2.2 I2/CuCl2 copromoted synthesis of 2-acyl-4-aminoquinazolines In 2021, Wu and coworkers [57] discovered I2/CuCl2 co-catalyzed [4 + 1 + 1] cyclization of 2-aminobenzonitraile (26), methyl ketones (27), and ammonium acetates (18) to access 2-acyl-4-aminoquinazolines (28) (Figure 3.14). Cheap metal source, use of iodine as reagent, mild reaction condition, operational simplicity, easily available substrates, and wide range of functional group tolerance make this protocol more relevant. A mechanistic assessment reveals that CuCl2 acts as a Lewis acid to assist in the final cyclization (Figure 3.15).

3.2.2.3 Synthesis of 2,4-substituted quinazolines In 2020, Wang and coworkers [58] reported a useful and mild synthetic route for the construction of 2,4-substituted quinazolines (30) from functionalized 2-aminobenzophenones (29) with numerous benzaldehydes (6) by catalyzed TMSOTf and hexamethyldisi-

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Figure 3.13: Synthesis of quinazolino[4,3-b]quinazolin-8-ones.

lazane (HMDS) under metal and solvent-free and microwave irradiation condition (Figure 3.16). According to the previous literature, in this protocol TMSOTf and HMDS interact with each other to produce gaseous ammonia in situ which acts as a nitrogen source in quinazoline ring formation. This synthetic protocol provided the desired quinazolines with a broad substrate scope, good to excellent yields, short reaction time.

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Figure 3.14: Synthesis of 2-acyl-4-aminoquinazolines.

3.2.2.4 Synthesis of 5H-chromeno[2,3-d]pyrimidin-5-one derivatives In 2021, Zhai and coworkers [59] proposed a microwave-irradiated multicomponent reaction between 3-formylchromones (13), amines (5), and paraformaldehyde (31) for the synthesis of chromenopyrimidine derivatives (32) under solvent free condition (Figure 3.17). In this multicomponent annulation reaction paraformaldehyde (31) acts as C1 building block to construct pyrimidine ring. This catalyst-freemicrowave-assisted protocol provides higher yield under shorter reaction time. Both aromatic and aliphatic amines (5) react to the process. Possible mechanisms show amine attacks to the βposition to the 3-formylchromones (13), followed by ring opening providing the key intermediate (B). Then the intermediate (B) undergoes condensation (C) and annulation, respectively, to generate pyrimidine-fused chroman-4-one (32) (Figure 3.18).

3.2.2.5 Synthesis of 2,4,6-trisubstituted pyrimidines In 2021, Huang and coworkers [60] reported a base-mediated multicomponent reaction between amidine hydrochlorides (33), aldehydes (6), and acetylacetone (34) to

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Figure 3.15: Proposed mechanism for the synthesis of 2-acyl-4- aminoquinazolines.

Figure 3.16: Synthesis of 2,4-substituted quinazolines.

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Figure 3.17: Synthesis of 5H-chromeno[2,3-d]pyrimidin-5-ones.

Figure 3.18: Proposed mechanism for the synthesis of 5H-chromeno[2,3-d]pyrimidin-5-ones.

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achieve 2,4,6-trisubstituted pyrimidines (34). Readily accessible starting materials, numerous functional group tolerance, and metal-free condition are the core features of this protocol (Figure 3.19).

Figure 3.19: Synthesis of 2,4,6-trisubstituted pyrimidines.

3.2.2.6 Synthesis of imidazo[1,2-a]pyrimidines In 2015, Jeong and coworkers [61] demonstrated a green, highly effective one-pot multicomponent protocol for the synthesis of imidazo[1,2-a]pyrimidines (37) scaffolds from 1H-benzo[d]imidazol-2-amine (36), aldehydes (6), and alkyne (11) via intramolecular C–N bond formation and 6-endo-dig cycloisomerization at 85 °C under solventfree conditions (Figure 3.20). Under solvent-free conditions, molybdate sulfuric acid used as an environment-friendly and reusable catalyst to produce good to exceptional yields. In this annulation reaction three new bonds are formed. Eco-friendly benign protocol, use of inexpensive heterogenous catalyst, short reaction time, widely variable function group tolerance, high atom economy, and ease of the reaction are the remarkable feature of this annulation.

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Figure 3.20: Synthesis of imidazo[1,2-a]pyrimidines.

3.2.3 1,4-Dihydropyridines (DHPs) Many cardiovascular disorders are treated clinically with several DHPs. DHPs effectively inhibit calcium (Ca2+) currents through voltage-dependent L-type channels [62]. The therapy of cardiovascular disorders would greatly benefit from derivatives that can function as dual cardioselective calcium channel agonists and smooth muscleselective calcium channel antagonists [63]. Many DHP-containing natural and synthetic products exhibit attractive pharmacological profiles, including anti-inflammatory, antitubercular, anticonvulsant, HIV protease inhibitory, analgesic, antithrombotic, radio and neuroprotectant, and platelet antiaggregatory activities [64–73]. Numerous methods have been developed to synthesize 1,4-DHPs because of their relevant significance in the field of pharmacology.

3.2.3.1 Metal-free synthesis of Hantzsch 1,4-dihydropyridines In 2018, Ranjbar and coworkers [74] reported a novel metal-freeoxidative C–C coupling procedure to synthesize Hantzsch 1,4-dihydropyrimidines (40). Ammonium hydroxide (39), 1,3-dicarbonyl compounds (38), and benzylic alcohols (23) react in the

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presence of HBr in DMSO to produce DHP in high yields. This protocol’s primary characteristics are short reaction time and modest temperature requirement (Figure 3.21).

Figure 3.21: Synthesis of 1,4-dihydropyridines.

Bromodimethylsulfonium bromide is generated in situ from HBr and DMSO, which interact with benzylic alcohol (23) forms an alkoxysulfonium ion that undergoes nucleophilic addition with enaminone under the reaction condition. Basically, in this procedure, the Hantzsch reaction is modified by using benzyl alcohols rather of aldehydes.

3.2.3.2 Divergent synthesis of dual 1,4-dihydropyridines In 2017, Chaturbhuj and coworkers [75] developed a four-component DHPs (40) synthesis from various aldehydes (6), β-ketoesters (38), and ammonium carbonate (41) catalyzed by sulfated polyborate under solvent-free condition. High yields, shorter reaction time, solvent-free conditions, simple workup, reusability of the catalyst, and the ability to tolerate a variety of functional groups are the main advantages of the

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current approach, which has positive effects on both the economy and the environment (Figure 3.22).

Figure 3.22: Synthesis of 1,4-dihydropyridines.

3.2.4 Naphthyridines Naphthyridine derivatives, [6,6] fused heterocycles, are a significant class of “privileged structure” in drug discovery [76]. Among them, the 1,6-naphthyridine derivatives exhibited unique bioactivities in human disease, such as HIV-1, cancer, and Alzheimer [77–81]. On this context, designing a decent synthetic pathway for the synthesis of naphthyridines for chemists and biologists is of utmost importance.

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3.2.4.1 Synthesis of substituted benzo[c]pyrazolo[2,7]naphthyridines In 2020, Yaqub and coworkers [82] reported a concise, environmentally benign, and regioselective multicomponent “on-water” protocol of naphthyridine (45) synthesis from 3-aminopyrazole (43), isatin (42), and malononitrile (44) (Figure 3.23).

Figure 3.23: Synthesis of benzo[c]pyrazolo[2,7]naphthyridines.

Here one-pot base-mediated protocol involves the formation of arylidene as a cause of Knoevenagel condensation of isatin (42) with malononitrile (44), which afterward undergoes Michael addition with 3-aminopyrazole (43) trailed hydrolysis, annulation, decarboxylation, and aromatization to give the desired naphthyridines (45) in excellent yields (Figure 3.24). Water as a green solvent, broad substrate scope, transition metal-free annulation, and short reaction time are the attractive features of this protocol.

3.2.4.2 Ultrasonic-promoted synthesis of 1,6-naphthyridine In 2020, Zhang and coworkers [83] established a straightforward synthesis of polysubstituted 1,6-naphthyridine (48) derivatives from easily accessible 4-aminopyridinone (46), aromatic aldehyde (6), and 1,3-cyclohexanedione (47) as substrates. This approach is very appealing since it uses inexpensive and easily accessible starting ingredients, environmentally friendly ultrasonic irradiation in water, recyclable heterogeneous

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Figure 3.24: Proposed mechanism for the synthesis of benzo[c]pyrazolo[2,7]naphthyridines.

solid acid catalyst, a wide range of substrates, and a straightforward one-pot operation (Figure 3.25).

3.2.5 Spiro-heterocycles Numerous biological and pharmacological features of heterocyclic compounds with the indole nucleus have been described in literature [84, 85]. There are numerous natural alkaloids, and pharmaceutical drugs are the spirofused indole systems [86–91]. These spiro-heterocycles have a variety of therapeutic and biological activities, including anticancer, antimicrobial, and antibiotic [84, 85]. Due to their pharmacological importance, there has been an increase in research work into their synthesis.

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Figure 3.25: Synthesis of poly-substituted 1,6-naphthyridine.

3.2.5.1 Synthesis of indol-fused dispiro-heterocycles In 2020, Kumar and coworkers [92] discovered a pseudo-four component reaction of 6aminouracil/6-amino-2-thiouracil (49), p-toluidine (5), and isatins (42) in an ethanol–water to access Spiro-heterocyclic scaffolds (50). This domino synthetic protocol using β-CD functionalized nanostructured Fe3O4 as heterogeneous catalyst (Figure 3.26). The nanocatalystcharacterized by scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy. Low catalyst loading, high atom economy, green solvent, use of magnetically separable, and reusable heterogeneous catalysts are key features of this technique.

3.2.5.2 Synthesis of spirooxindoles fused pyrazolo-tetrahydropyridinone and coumarin-dihydropyridine-pyrazole In 2018, Choudhury and coworkers [93] reported a microwave-assisted three-component reaction involving isatin (42), 4-hydroxycoumarin (17), and aminopyrazole (43) for the synthesis of fused spirooxindoles (51 and 51′) (Figure 3.27). This methodology’s key features are solvent-dependent reaction path switching properties, the ability to produce two different types of products from the same raw materials, metal-free reaction conditions, a broad substrate range, and good yields. Spirooxindoles (51′) were produced by the ring opening of the hydroxycoumarin moiety during the reactions of isatin (42), aminopyrazole (17), and 4-hydroxycoumarins

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Figure 3.26: Synthesis of fused dispiro-heterocycles.

(43) under microwave irradiations in an acetonitrile medium. On the other hand, in the presence of acetic acid, tetracyclic coumarin-DHP-pyrazolemoiety spirofused with oxindoles (51) were observed (Figure 3.28).

3.3 Oxygen and sulfur-containing heterocycles Pyran, oxazine, and thiazine are the important class heterocyclic compounds that feature in several pharmaceutical drugs and natural products of medicinal interest. A study of the literature reveals various described processes for producing such bioactive molecules.

3.3.1 Pyran Pyrans is a significant heterocycle that exhibits a variety of biological activities and contains many natural compounds in its structure [94–96]. Pyran derivatives are frequently

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Figure 3.27: Synthesis of fused spirooxindoles.

utilized in the chemistry of cosmetics, pigments, and medications [97, 98]. Additionally, pyran and its derivatives are widely employed as the primary component of photochromic materials and play a significant role in the chemical and biological activities [99]. Due to their biological and therapeutic qualities, such as their antibacterial, antimicrobial, antiallergic, antirheumatism, and anticancer capabilities, these chemicals have been regarded as beneficial [99–104]. Also pyrans are utilized as memory boosters to treat neurological conditions like Down syndrome, Parkinson’s, Huntington’s, and Alzheimer’s

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Figure 3.28: Proposed mechanism for the synthesis of fused spirooxindoles.

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[105–107]. Due to their huge biological relevance, there are numerous strategies for synthesizing pyran derivatives that have been documented in the literature.

3.3.1.1 Synthesis of pyrano[3,2-c]quinolone derivatives In 2022, Guleria and coworkers [108] discovered a green method for the synthesis of pyrano[3,2-c]quinolone derivatives (54 and 54’). In the presence of taurine as catalyst in water a three-component MCR takes place between malononitrile (44)/ethylcyanoacetate (53), aldehydes (6), and 4-hydroxy-1-methyl-2(1H)-quinolone (52) to achieve pyranoquinolone derivatives (54 and 54’). Taurine basically 2-aminoethane sulfonic acid is considered as a water-soluble β-amino acid. Taurine exists in zwitterionic form in water and literature studies show that due to that reason taurine is able to carry out the Knoevenagel−Michael cascade reaction effectively (Figure 3.29).

Figure 3.29: Synthesis of pyrano[3,2-c]quinolone.

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Excellent product yields, short time span, cost-effectiveness, atom economy, and a straightforward workup approach without the need for additional purification methods are all benefits of this methodology.

3.3.1.2 Synthesis of tetrahydrobenzo[b]pyrans and pyrano[2,3-d]pyrimidinones In 2022, Kamble and coworkers [109] proposed a novel, gentle, and straightforward one-pot multicomponent synthesis of tetrahydrobenzopyran (56) and pyranopyrimidine (56′) under microwave-assisted condition. Aldehyde (6), malononitrile (44), and 1,3-dicrbonyl compounds (47 and 55) react in aqueous medium in the presence of chitosan-zinc oxide (CS-ZnO) to achieve the target molecules (Figure 3.30). Chitosan-zinc oxide (CS-ZnO) is hybrid nanocatalyst where nanoparticle zinc oxide (ZnO) embedded in polysaccharide is composed by β-linked (1–4) D-glucosamine (Figure 3.31). This technique addresses the use of modified polymeric substrates in organic synthesis while also providing ease of operation, simple set-up, and increased yields (90–95%).

3.3.2 Oxazines Numerous oxazine derivatives, which constitute a large class of both natural and synthetic compounds, have significant biological features like analgesic, anti-inflammatory, antimalarial, anticancer, antitubercular, and antibacterial effects [110–115]. There are many strategies published in the literature for carrying out the synthesis of oxazine motifs because of enormous biological value.

3.3.2.1 Synthesis of 1,3,5-oxadiazines Ma and coworkers [116] achieved the first selective and feasible synthesis of diaryl 1,3,5-oxadiazines (58) in 2021 using cheap and easily accessible amidines (57) in wet DMSO (7 and 15). Control experiments show water molecule acts as the source of oxygen atom which is necessary to form the oxadiazine ring, and DMSO (7) served as the dual carbon synthon. In this particular transformation, among several copper salts, Cu(OTf)2 gave the best outcomes (Figure 3.32).

3.3.2.2 Synthesis of coumarin fused bis-oxazines In 2019, Khurana and coworkers [117] reported a catalyst-free eco-friendly one-pot protocol for the synthesis of pharmacologically relevant coumarin-fused oxazine (60)

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Figure 3.30: Synthesis of tetrahydrobenzo[b]pyrans and pyrano[2,3-d]pyrimidinones.

from 5,7-dihydroxy-4-methyl-2H-chromen-2-one (59), substituted aromatic amines (5), and formaldehyde (31) at room temperature (Figure 3.33). This approach has the benefits of mild reaction conditions, ease of product separation, avoidance of column chromatography, affordable starting reactants, and operational simplicity (Figure 3.34).

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Figure 3.31: Plausible mechanism for the synthesis of tetrahydrobenzo[b]pyrans or pyrano[2,3-d] pyrimidinones.

Figure 3.32: Synthesis of 1,3,5-oxadiazines.

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Figure 3.33: Synthesis of coumarin-fused bis-oxazines.

3.3.3 Thiazine The bioactivesulfur-containing six-membered heterocyclic molecules known as thiazinones have a wide range of pharmacological properties, including anticonvulsant, antifungal, anticancer, antituberculosis, antidiabetic, antiarrhythmic, antimalarial, and anti-HIV activity [118–125]. Additionally, 1,3-thiazine core moieties are employed as reaction intermediates in numerous organic syntheses and transformations, and they also exhibit substantial potential as antiradiation agents and cell growth inhibitors [126–128]. Because of their tremendous biological relevance, numerous methods for synthesizing thiazine motifs have been documented in the literature.

3.3.3.1 Synthesis of 1,3-thiazine-4-ones In 2019, Sharma and coworkers [129] discovered a regioselective catalyst-free multicomponent click reaction between phenylisothiocyanates (61), hydrazine monohy-

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Figure 3.34: Plausible mechanism for the synthesis of coumarin-fused bis-oxazines.

drate (62), and diethyl but-2-ynedioate or dimethyl but-2-ynedioate (63) to achieve 1,3thiazine-4-one derivatives (64) at room temperature (Figure 3.35). This protocol is a prominent replacement for previously reported methods due to factors like prefunctionalized starting materials, expensive reagents, poor atom economy, time-consuming workup, complex purification protocols, nonbeneficial solvents, requirement of inert atmosphere, and nonambient temperature.

3.3.3.2 Synthesis of naphtho[1,2-e]/benzo[e][1,3]thiazine derivatives In 2018, Khurana and coworkers [130] reported a straightforward and environment friendly multicomponent reaction involving thionaphthol/thiophenol (65), aromatic amines (5), and formaldehyde (31) for the synthesis of naphtho[1,2-e]/benzo[e][1,3]thiazines derivatives (66). Formaldehyde acts as a two-carbon source to the thiazine ring

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Figure 3.35: Synthesis of 1,3-thiazine-4-ones.

Figure 3.36: Synthesis of naphtho[1,2-e]/benzo[e][1,3]thiazine.

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in the presence tetra-n-butyl ammonium bromide as a catalyst under solvent-free condition (Figure 3.36). Based on previous literature at first condensation of formaldehyde and aniline with water loss produces imine. The imine is subjected to 2-thionaphthol’s nucleophilic attack, followed by aromatization and condensation with formaldehyde to produce an intermediate, which is then subjected to cyclization to produce the product (Figure 3.37).

Figure 3.37: Proposed mechanism for the synthesis of naphtho[1,2-e]/benzo[e][1,3]thiazine.

3.4 Conclusion Due to its high regioselectivity and atom efficiency, one-pot multicomponent reactions are crucial in the synthesis of organic compounds. The recent advancement of onestep multicomponent synthesis of several heteroatoms holding six-membered heterocycles, such as pyridines, pyrimidines naphthyridines, DHPs, quinazolines, quinolines and spiro-heterocyclic compounds, pyran, oxazine, and thiazine is the focus of this review. Explanation regarding biological significance, mechanistic interpretations, and the adaptability of numerous scaffolds to form the heterocycles are provided. This review will be supportive in the future to develop unique strategies for synthesizing novel bioactive heterocycles.

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[118] Matysiak J, Juszczak M, Karpinska MM, Langner E, Walczak K, Lemieszek MK, Skrzypek A, Niewiadomy A, Rzeski W. Synthesis of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-ones, their lipophilicity and anticancer activity in vitro. Mol Divers, 2015, 19, 725–736. [119] Anand SSA, Loganathan C, Thomas NS, Saravanan K, Alphonsa AT, Kabilan S. Synthesis, structure prediction, pharmacokinetic properties, molecular docking and antitumor activities of some novel thiazinone derivatives. New J Chem, 2015, 39, 7120–71299. [120] Mahato K, Bagdi PR, Khan AT. Yb(OTf)3 catalysed regioselective synthesis of unusual di- and trisubstituted 3,4-dihydrothiochromeno[3,2-e][1,3]thiazin-5(2H)-one derivatives through a pseudo four-component hetero-Diels–Alder reaction. RSC Adv, 2015, 5, 48104–48111. [121] Dandia A, Singh R, Arya K. Phosphorus, microwave induced dry-media synthesis of spiro[indolethiazolidinones/thiazinones] as potential antifungal and antitubercular agents and study of their reactions. Sulfur Silicon Relat Elem, 2004, 179, 551–564. [122] Gutschow M, Schlenk M, Gab J, Paskaleva M, Alnouri MW, Scolari S, Iqbal J, Muller CE. Benzothiazinones: A novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives. J Med Chem, 2012, 55, 3331–3341. [123] Matysiak J, Juszczak M, Karpinska MM, Longner E, Walczak K, Lemieszek M, Skrzypek A, Rzeski W, Niewiadomy A. Synthesis, characterization, and pharmacological evaluation of novel azolo- and azinothiazinones containing 2,4-dihydroxyphenyl substituent as anticancer agents. MonatshChem, 2015, 146, 1315–1327. [124] Salama MA, Almotabacani LA. Synthesis and chemistry of some new 2-mercaptoimidazole derivatives of possible antimicrobial activity. PhophrusSulfur Silicon Relat Elem, 2004, 179, 305–319. [125] Bonzsing D, Sohar P, Giggler G, Kovacs G. Synthesis and pharmacological study of new 3,4-dihydro2H,6H-pyrimido-[2,1-b][1,3]thiazines. Eur J Med Chem, 1996, 31, 663–668. [126] Hossaini Z, Nematpour M, Yavari I. Ph3P-mediated one-pot synthesis of functionalized 3,4-dihydro2H-1,3-thiazines from N,N′-dialkylthioureas and activated acetylenes in water. Monatsh Chem, 2010, 141, 229. [127] Rai VK, Yadav BS, Yadav LDS. The first ionic liquid-promoted one-pot diastereoselective synthesis of 2,5-diamino-/2-amino-5-mercapto-1,3-thiazin-4-ones using masked amino/mercapto acids. Tetrahedron, 2009, 65, 1306–1315. [128] Fodor L, Szabó J, Bernáth G, Sohár P, Maclean DB, Smith RW, Ninomiya I, Naito T. Synthesis of 6H,8H-isoquino[2,3-c][1,3]benzothiazin-8-ones. J HeterocyclChem, 1989, 26, 333–337. [129] Hussen AS, Monga A, Sharma A. Regioselective synthesis of functionalized 1,3-Thiazine-4-ones via multicomponent click reaction approach. ChemistrySelect, 2019, 4, 650–654. [130] Saroha M, Khanna G, Khurana JM. Green synthesis of novel naphtho[1,2-e]/ benzo[e][1,3] thiazine derivatives via one-pot three-component reaction using tetra n-butyl ammonium bromide. ChemistrySelect, 2018, 3, 12560–12562.

Kantharaju Kamanna✶, Yamanappagouda Amaregouda, Aravind Kamath

4 Multicomponent synthesis of biologically prominent tetrahydrobenzoxanthenone derivatives 4.1 Introduction Multicomponent reactions (MCRs) have emerged as an extremely powerful tool in combinatorial chemistry and drug discovery, since they offer significant advantages over conventional multistep syntheses, in terms of improved organic reactions, promoting new reactions, and developing a straightforward synthetic route for bioactive heterocycle synthesis [1]. Among various heterocycles, xanthene skeletons are the most common structural motifs abundant in several natural and synthetic bioactive compounds. Xanthenes (i), benzoxanthenes (ii) and benzoxanthenones (iii) (Figure 4.1) form a distinct class of compounds having diverse applications in fluorescent agents [2], dyes [3], and laser technologies [4], which is the most important class of bioactive heterocycles in the field of medicinal chemistry owing to their broad spectrum of pharmacological activities such as antibacterial, analgesic, anti-inflammatory and antiviral (Figure 4.2) [5]. Some of the xanthene-based compounds have found application in antagonists for paralyzing the action of zolamine and in photodynamic therapy [6]. In addition, their derivatives can be used in dyes, pH-sensitive fluorescent materials for the visualization of biomolecular assemblies, and in laser technologies [7].

Figure 4.1: Different xanthene skeletons abundant in nature.

✶

Corresponding author: Kantharaju Kamanna, Department of Chemistry, School of Basic Sciences, Rani Channamma University, Vidyasangama, P-B, NH-4, Belagavi 591156, Karnataka, India, e-mail: [email protected] Yamanappagouda Amaregouda, Aravind Kamath, Department of Chemistry, School of Basic Sciences, Rani Channamma University, Vidyasangama, P-B, NH-4, Belagavi 591156, Karnataka https://doi.org/10.1515/9783110985313-004

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Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath

Figure 4.2: Various reported applications of benzoxanthene derivatives.

Among benzoxanthene-based derivatives, tetrahydrobenzo[α]xanthene-11-one has emerged as an important skeleton, due to its distinctive structure pattern and simple construction route (Figure 4.3) [8].

Figure 4.3: Structure and numbering of tetrahydrobenzo[a]xanthene-11one.

As it is an interesting skeleton, numerous applications of benzoxanthenone attract chemists in developing a wide range of synthetic methods for the tetrahydrobenzo[α]xanthene11-one, but the multicomponent one-pot condensation route has emerged a promising route and the construction is well documented [9]. One of the best acceptable routes that chemists have explored is the three-component one-pot synthesis of tetrahydrobenzo[a] xanthene-11-one from the reaction of β-naphthol, dimedone, and substituted aromatic aldehydes promoted using various catalysts (Figure 4.4 and Table 4.1) [10].

Figure 4.4: General one-pot synthesis of tetrahydrobenzo[a]xanthene-11-one.

159

4 Multicomponent synthesis of biologically prominent

Table 4.1: List of various aromatic aldehydes employed for the synthesis of tetrahydrobenzo[a]xanthene11-one. O

O

H

H

O

H

O

H

O

Cl

V

IV

O H

O

O

H

O

H

OH

OH X

XIII

XII

O

H

CH OHC CH CH

OH

OMe

ON

Br

XI

Me

OEt XV

XIV

XVI

H

O

OH O

O

H

O

H

Br Br

H

XX

XIX

O

O

F

O

H

XVIII

XVII

OMe H

IX

VIII

H

OH

OH

OH

O

H

Cl

VII

VI

H O

Cl Cl

OMe

III

II

H

H

OMe

NO

NO

O O

H

O NO

I

O

H

O

H

Cl

XXI

XXII

XXIV

XXIII

XXVI

XXV

XXVII O

CHO

H

O

H

O

H

HN

CH H C

Me CHO

C H

Br XXVIII

O

XXIX

XXXI

XXX

CHO

XXXII

O

H

O

H O

O

O O

XXXIX

O O

SCH

Br XLVI

H Cl

XLVII

Cl XLVIII

XXXV

H

O

H

XXXVI O

H

N

Me

Me

XLIII

XLII

CH

OCH

Me

XLIV

XLV

H

H

OH

XXXIV

OCH

Me

N XLI

XL

H

H

OH

CHO

Cl

XXXVIII

OME O

XXXIII

H

O

XXXVII

OMe

C CHO H MeO

H

H

O

O

O

F NO

H H C C

O

O

SMe

OMe

MeO

L

LI

O

LII

H

O Me

O HC

OMe XLIX

O

H

O

F

Cl

Me LIII

H

LIV

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Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath

Table 4.1 (continued) CHO O

O

H

O

H

CHO

CHO

H

OH OH

S

O

Me LV

LVI

CHO

CHO

OH

OMe

H

HC

LVII

LVIII

HC

LIX

O

C LX

H C C CH CH LXI

H O

OMe

CHO

H OMe

HC

CH

H C C CH CH

LX O

OMe H C

OMe

LXI

LXII

LXVII

LXIV

CH

LXVIII

H CHO O OMe

CF

OH LXX O LXXVII

LXXI

H

N LXXV

LXXVI

O LXXVIII

4.2 Homogeneous catalyst reported for benzoxanthenone derivative synthesis Homogeneous catalysis contributes about 17–30% of the total organic molecule synthesis in fine chemical industries and pharmaceuticals. In recent years progress in the homogeneous catalysis has increased significantly, particularly in the polymer and pharmaceutical industries. Homogeneous catalysis takes place in the same phase as other reactants, and it may be derived from the simple ions or molecules of base, metal ions, acid, and complexes of organometallic, macrocyclic, and large enzymes. Homogeneous catalysis is an excellent approach in synthetic chemistry; due to its interesting mechanism, isolation, and kinetics, it also provides opportunities to know the molecular causes of the reactivity. In this chapter various homogeneous catalytic approaches reported for the synthesis of benzoxanthenone derivatives are discussed [11, 12]. Homogeneous catalyst-catalyzed one-pot synthesis of tetrahydrobenzo[a]xanthene-11-one derivatives (4) achieved by three-component condensation of aryl aldehyde (1), β-naphthol (2), and cyclic 1,3-dicarbonyl compounds (3) under solvent-free conditions isolated high yields of the products (Figure 4.5). In Figure 4.6, a mechanistic explanation of the likely course of the events is presented. The ortho-quinone methides intermediate, which was created by the homogeneous catalyst-catalyzed nucleophilic addition of 2-naphthol to aldehyde, is used to carry out the reaction. On

4 Multicomponent synthesis of biologically prominent

161

dehydration, cyclic hemiketal is produced by following Michael addition with cyclic 1,3-dicarbonyl on the o-QM and adding phenolic hydroxyl moiety to the carbonyl of the ketone gave the desired product [12, 13].

Figure 4.5: One-pot synthesis of tetrahydro-benzo[a]xanthen-11-one by homogeneous catalyzed reaction.

Figure 4.6: Tentative mechanism of tetrahydrobenzo[a]xanthene-11-one formation.

Numerous researchers across the globe have reported homogeneous catalyzed synthesis of tetrahydrobenzo[a]xanthene-11-one derivatives via three-component condensation of substituted aldehyde, naphthol, and cyclic 1,3-dicarbonyl compounds under various reaction conditions presented in the Table 4.2.

4.2.1 Reported biological studies Soliman and Khatab [60] reported (Table 4.2, s. no. 48) the evaluation of antibacterial activity of the prepared tetrahydrobenzo-[a]xanthen-11-one; the authors also described Aurora kinase inhibitors, a new class of antimitotic agents and molecular docking studies, and compared them with pentacyclic AKI-001, a novel class of Aurora inhibitors

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Table 4.2: Homogeneous catalyzed one-pot reaction of naphthol, aldehyde, and 1,3-dicarbonyl gave tetrahydrobenzoxanthenone derivatives under various conditions. S. no. Aldehydes

Catalyst

Conditions

Time (min)

Yield (%)

Reference



I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII

InCl₃/PO

Grinding

–/–

–/–

[]



I, III, X, V, VII, VIII, XIX, XX

(NH₄)₂[Ce(NO₃)₆]

Ultrasonication, –  °C

–

[]



I, II, III, IV, V, CH(CH)N(Br) VII, VIII, X, XVI, (CH) XX, XXI, XXII, XXIII, XXIV, XXV

RT

–

–

[]



I, II, III, V, VII, VIII, IX, X, XVI, XXXVIII, XXXIX

I/HOAc

MWI

–

–

[]



I, II, III, V, VI, VII, VIII, X, XVI, XXII

BNBTS

Solvent-free/in solution

–/– –/–

[]



I, II, V, VII, VIII, X, XVI, XXXVIII, XXXIX

I/HOAc

Reflux

–

–

[]



I, II, V, VII, VIII, IX, X, XVI, XXXVI, XXXIX, XLV

I/HOAc

Conventional/ MWI

–/–

–/–

[]



I, II, III, IV, V, VII, VIII, IX, XI, XIV, XVI, XXI, XXII, XXVIII, XXXI, XL, XLII, XLV

CHCH(OH)COOH

Solvent-free

–

–

[]



I, II, III, V, VII, VIII, IX, X, XIV, XVI, XVIII, XLV, XLVII

RuCl·nHO

MWI

–

–

[]



I, II, VII, XVI, XVII, XXI

NHCl

Solvent-free

–

–

[]

4 Multicomponent synthesis of biologically prominent

163

Table 4.2 (continued) S. no. Aldehydes

Catalyst

Conditions

Time (min)

Yield (%)

Reference



I, III, VI, VII, XX, Succinimide-NXXI, XXVII, sulfonic acid XXVIII, XL, XLI, XLIV, XLV, LVIII, LXXIII

Solvent-free

–

–

[]



I, II, III, V, VII, X, XVI, XXII

I

Solvent-free

–

–

[]



I, II, III, V, VII, VIII, X, XVI, XXIV, XXVIII, XXXIII, XXXVIII, XL, LVII, LVIII

-Aminophenol

Solvent-free

–

–

[]



I, II, III, IV, V, VII, X, XVI, XVIII, XXII, LVI, LXXVIII

TPPMS/CBr

Solvent-free

–

–

[]



I, II, III, VII, X, XVI, XXI, XXII, XLI, XLII, XLIV, LXXIII

Rice husk

Stirred,  °C

–

–

[]



I, II, III, V, VII, IX, XI, XXII, XXVI, XXVII, XXVIII, XXXI, XLVIII, LVI

Trityl chloride (TrCl)

Solvent-free

–

–

[]



I, II, III, V, VI, Succinic acid VII, VIII, X, XVI, XXI, XXII, XXVII, XXVIII, XLV, LVI, LXVI

Solvent-free

–

–

[]



I, VIII, XVI, XXVII, XXVIII, LVII

Solvent-free

–

–

[]



I, II, III, IV, V, Manganese VII, VIII, X, XI, perchlorate XVI, XXII, XXVII, LXIII

Ultrasonication

–

–

[]

Formic acid

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Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath

Table 4.2 (continued) S. no. Aldehydes

Catalyst

Conditions

Time (min)

Yield (%)

Reference



I, II, III, V, VII, X, XVI, XIX, XXI, XXII, XXVII, LXIII, LXIX

Cyanuric chloride

Solvent-free

–

–

[]



I, II, III, V, VII, Tartaric acid VIII, X, XVI, XXI, XXII, XXVIII, LVIII

Solvent-free

–

–

[]



II, III, IV, V, VII, [Yb(PFO)] X, XI, XVI, XX, XXIV, XXV, LXVI, LXXV, LXXVI

Solvent-free

–

–

[]



V, VII, XII, XIV, XVI, XXII, XVII

Guanidine hydrochloride

Solvent-free

–

–

[]



I, III, V, VII, XXIV, XXXII, LX, LXII

Strontium triflate

Reflux

–

–

[]



I, II, V, VII, VIII, X, XVI, XIX, XXI, XXII, XXVII, XXXIII, XXXV, L, LXIII

Solvent-free Tungstophosphoric acid

–

–

[]



I, IV, V, VII, X, XVI, XXI, XXII

Baker’s yeast

RT

–

–

[]



II, V, VII, XXI, XXII, XLIV

Sulfamic acid

Solvent-free

–

–

[]



I, V, VII, XXI, XXIV

Cerium(III) chloride

MeOH,  °C

–

–

[]



V, VI, X, XXVI, Glucose sulfonic XXVIII, XLI, acid XLIX, LIII, LVII, LXIV, LXV, LXVI, LXVII

Reflux, water,  °C

–

–

[]



I, II, III, IV, V, TBAHS VI, VII, VIII, X, XVI, XX, XXI, XXII, XXIII, XXIV

HO,  °C, stirring

–

–

[]

4 Multicomponent synthesis of biologically prominent

165

Table 4.2 (continued) S. no. Aldehydes

Catalyst

Conditions

Time (min)

Yield (%)



I, II, III, V, VI, VII, VIII, IX, X, XIV, XVI, XXVII, XXXVI, LXIII

DBSA

Ultrasonication

–

–

[]



I, II, III, V, VII, XVI, XX, XXXII, XXXIII, LIV, LV, LVIII

Zr(HSO)

Solvent-free

–

–

[]



I, II, IV, V, VII, VIII, IX, X, XVI, XXI, XXII, XXVIII, LVI, LVII, LVIII, LXVIII

Imidazole/ isoquinoline

Solvent-free

–/ –

–/–

[]



I, V, VII, XVI, XXI, XXII

KHSO

Solvent-free

–

–

[]



I, II, V, VII, VIII, IX, X, XVI, XIX, XLV

Pyrrolidine

RT

–

–

[]



I, II, III, V, VII, VIII, X, XVI, XXII, XXXII, XXXIII

Bronsted ionic liquids

Solvent-free

–

–

[]



I, II, V, VII, XVI, XL

DSTMG

Solvent-free

–

–

[]



I, III, IV, VIII, SAFIS IX, XI, XXVII, XLVIII, XXVI, XXVIII, LVII, LVI

Solvent-free

–

–

[]



I, II, III, V, VII, DSIMHS VIII, X, XVI, XXI, XXII, XXVIII, XLI, XLIV

Solvent-free

–

–

[]



I, II, III, V, VII, XVI, XXI, XXII, XL, XLIV, XLV

Solvent-free

–

–

[]

Acidic ionic liquid [NMP]HPO

Reference

166

Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath

Table 4.2 (continued) S. no. Aldehydes

Catalyst

Conditions

Time (min)

Yield (%)

Reference

MWI

–

–

[]



I, II, III, V, VIII, Ionic liquid X, XVI, XXI, XXII, XXX, XXXII, LV, LXXIV



I, III, V, VII, XLIV

[DBU][EDSS]

Solvent-free

–

–

[]



I, II, III, V, VII, VIII, X, XI, XX, XXII, XXXII, L

[BDMAP][OH]

HO,  °C

–

–

[]



I, II, III, V, VII, IX, XI, XXII, XXVII, XXVIII, XXXI, XVVIII, LVI

IL, [Pyridine–SOH] Solvent-free Cl

–

–

[]



I, II, III, V, VII, VIII, IX, X, XI, XVI, XXIV, XXVII, XL

bmim[HSO]

Reflux

–

–

[]



I, II, III, IV, V, [BiPy](HSO)Cl VII, VIII, XXII, XXVIII, XL, LVIII

RT

–

–

[]



I, II, III, V, VI, VII, VIII, X, XXI, XXII, XXVII, XXVIII

Solvent-free

–

–

[]



I, II, V, VII, XVI, SiCl (TCS) XXII, XXIII, XXVII, XXXVI, XXXVII, XXXVIII, LXIV

RT

–

–

[]



I, II, V, VI, VII, XVI, XIX, XXIV, XXVI, XXVII, XXVIII, XXXVIII, XLII

[bmim]BF

pTSA

–

–

[]



I, III, XXVII, LVIII, LVI, XXVIII, XIV, XLII, XLVIII

NaOAc

MWI

–

–/–

[]

[TMXH]FeCl

4 Multicomponent synthesis of biologically prominent

167

Table 4.2 (continued) S. no. Aldehydes

Catalyst

Conditions

Time (min)

Yield (%)

Reference



I, III, V, VII, VIII, X, XXXVI

LPCAS

Solvent-free

–

–

[]



I, V, VII, VIII, XVI, XIX, XXI, XXVIII, LVIII, LXX

Lawesson’s reagent

Reflux

–

–

[]



I, III, VII, X, XI, XVII, XXIV, L, LVII, LX

Proline triflate

Reflux

–

–

[]

based on a tetracyclic xanthene scaffold. Khurana et al. [61] reported (Table 4.2, s. no. 49) synthesized derivatives screened for in vitro antifungal activity against Rhizoctonia bataticola, Sclerotium rolfsii, Fusarium oxysporum, and Alternaria porii, and showed moderate to good activity against the pathogens tested. The insecticidal activity of selected derivatives against Spodoptera litura was comparable with the commercial pyrethroid insecticide, cypermethrin, and urease inhibitory activity was also studied. Godse et al. [63] investigated (Table 4.2, s. no. 51) the binding mode of tetrahydrobenzoxanthene-ones at the active site of enzyme topoisomerase II DNA gyrase. Sethukumar et al. [64] tested (Table 4.2, s. no. 52) tetrahydrobenzo-xanthene-ones for antibacterial activity and noticed comparable activities for some of the derivatives .

4.3 Heterogeneous catalyzed reactions A wide range of organic transformation take place by the use of variety of catalytic materials developed; when the physical state of the catalysts is different from that of the product and reactants, it is referred to as heterogeneous catalysis. Metal–organic frameworks (MOFs) are a class of materials containing metal ions or clusters coordinated to organic ligands to form one-, two-, or three-dimensional structures. MOFs have been used to catalyze a variety of organic transformations, including redox and acid–base reactions [66]. Designing organic molecules for the desired and particular catalytic applications is now achievable, thanks to the simple tuning of the pore size, shape, and surface functionality of the organic transformation. Heterogeneous catalysis is a welldemonstrated application in organic synthesis, and offers several benefits like high efficiency, selectivity, controllability, and moderate reaction condition as well as facile post-reaction separation, catalyst reusability, and high stability. The ability to synthesize organic molecules specifically tailored for the catalytic difficulties is demonstrated by

168

Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath

the potential organization of the active centers such as metallic nodes, organic linkers, and their chemical synthetic functionalization on the nanoscale. Heterogeneous catalyzed one-pot synthesis of tetrahydrobenzo[a]xanthene-11-one derivatives (4) achieved by three-component condensation of aryl aldehyde (1), β-naphthol (2), and cyclic 1,3-dicarbonyl (3) isolated high yields of the product (Figure 4.7). Further, the mechanistic plausible route of the formation of product is presented in Figure 4.8. The o-quinonemethide (o-QM) intermediate created by the heterogeneous catalyst involved nucleophilic addition of 2-naphthol to aldehyde; on dehydration, cyclic hemiketal produced by following Michael addition of cyclic 1,3dicarbonyl on o-QM gave product 4 [67].

Figure 4.7: Heterogeneous catalyzed synthesis of tetrahydro-benzo[a]xanthen-11-one.

Figure 4.8: Plausible mechanism of formation of tetrahydrobenzo[a]xanthene-11-one.

Various researchers across the globe have reported heterogeneous catalysts, which can be easily prepared from commercially available starting materials, and showed efficient catalysis for the synthesis of tetrahydrobenzo[a]xanthene-11-one derivatives via condensation of various substituted aldehydes, β-naphthol, and 1,3-dicarbonyl compounds under various reaction conditions. The authors noticed that the devel-

4 Multicomponent synthesis of biologically prominent

169

oped methods have added advantages such as low cost, recyclability, inexpensive catalyst, and applicability for use in the large-scale production (Table 4.3).

4.3.1 Reported biological activities Akbari and Hosseini-Nia [69] demonstrated (Table 4.3, s. no. 3) one of the simple methods for syntheses of tetrahydrobenzo-[a]xanthen-11-one derivatives screened for antibacterial activity against Pseudomonas syringae, Xanthomonas citri, and Pectobacterium carotovorum. Rao et al. [70] reported (Table 4.3, s. no. 4) the synthesis of 12-aryl -8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives and evaluated them for Src kinase activity and anticancer activity.

4.4 Conclusions Benzoxanthenes, xanthenes, and benzoxanthenones belong to one family of bioactive important heterocyclic scaffolds that showed numerous pharmacological applications in antiviral, analgesic, anti-inflammatory, and antibacterial properties. They were also found to be potent CCR1 receptor antagonists and nonpeptidic inhibitors of recombinant human calpain I. Hence, chemists are more focused on synthetic strategies, which make target molecules eco-friendly, inexpensive, recyclable, efficient, and allow for direct isolation of the pure product free from the chromatographic separation. The best literature reported revealed the synthesis of tetrahydrobenzo[a]xanthene-11-one via MCRs of aryl/heterocyclic aldehyde, 2-naphthol, and 5,5-dimethyl-1,3cyclohexanedione (dimedone). Numerous catalysts, both homogeneous and heterogeneous catalyzed reaction, for the synthesis of benzoxanthenone are well documented. In this book chapter, literature compiled so far reported on benzoxanthenone derivatives synthesis via MCRs and biological activity studies performed by numerous research groups across the globe have been discussed. In this chapter more than 100 reported articles have been discussed and related and obviously important skeletons are cited, which play a promising role in various applications in medicine, agrochemicals, pharmaceuticals, and material sciences.

170

Table 4.3: Heterogeneous catalyst-catalyzed condensation of naphthol, aldehyde, and 1,3-dicarbonyl gave tetrahydrobenzoxanthenone derivatives under various conditions. Catalyst

Condition

Time (min)

Yield (%)

Reference



I, II, III, IV, V, VI, VII, VIII, XVI, XXVII, XXXI, LVI, LVIII

NbCl

Reflux

–

–

[]



I, II, III, IV, V, VII, VIII, XVI, XXII, XL

Silica sulfuric acid

Solvent-free

–

–

[]



I, II, III, V, VII, X, XXII, XXVIII, XLIV, LIX

BF.SiO

Solvent-free

–

–

[]

 

I, II, III, V, VII, XVI, XVII, LVIII Sc(OTf) I, II, III, V, VI, VII, IX, XVI, XXI, XXII, XLI, XLIV, LI, LVI, LXIX ZnO NPs

MWI Solvent-free

– –

– –

[] []



I, II, III, V, VII, VIII, XVI, XX, XXI, XXII, XXIV, XXVIII, XXIX

Ce(SO)·HO

Solvent-free

–

–

[]



I, II, III, V, VII, VIII, IX, X, XXII

Perlite NPs@IL/ZrCl

Solvent-free

–

–

[]



II, III, V, VIII, IX, X, LVII, LVIII, LXIX

MWCNTs-SOH

reflux

–

–

[]



I, II, III, IV, V, VII, VIII, X, XVI, XXVII, XXVIII, XXIX, XXX

HPMoO¯ (HPMo)

Solvent-free

–

–

[]



I, II, III, V, VII, VIII, X, XVI, XXII, XXVIII, XXXI

FeO/CS-Ag NPs

HO,  °C

–

–

[]



I, II, III, V, VII, VIII, XVI, XXI, XXII, XXVIII

TiO/AlO/FeO

Solvent-free

–/–/– –/–/–

[]



I, II, III, V, VII, VIII, X, XVI, XXI, XXII, XXVII, XXVIII, XL, XLI

Orange peel

Solvent-free

–

–

[]



I, II, III, V, VII, X, XXII, XXVIII, XLIV

Nano-TiCl/SiO

Reflux

–

–

[]



I, II, III, V, VII, XVI, XXI, XXII, XXVIII

ZrSA

Solvent-free

–

–

[]

Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath

S. no. Aldehydes

V, VII, XIV, XVI, XXII, XVVI

Zr-MCM-

Solvent-free

–

–

[]



I, V, VI, VII, VIII, XVI

FeO/SiO/PPA

Reflux

–

–

[]



I, II, III, IV, VII, VIII, IX, X, XVI, XXII

Starch sulfate

Solvent-free

–

–

[]



I, II, III, IV, VII

FeO@SiO–SOH

Solvent-free

–

–

[]



I, II, III, V, VII, IX, X, XVI, XIX

NO−FePc

Reflux

–

–

[]



I, II, III, IV, V, VI, VII, VIII, XXI, XXII, XXVII, XXVIII, XXXI, XL

NSPVPC

Solvent-free

–

–

[]



I, II, III, IV, V, VI, VII, VIII, IX, XVI, XXI

Trichloroacetic acid

Solvent-free

–

–

[]



I, II, IV, VII, IX, X, XVII, XIX, XXVI, XXXII, XL, LXXI, LXXII

NaHSO·SiO

Reflux

–

–

[]



I, II, V, VIII, XVI, XLII, XLV, XLIX, LX

[B(HSO)]

Solvent-free

–

–

[]



I, II, V, VII

FeO@SiO-SnCl

Ultrasonic irradiation

–

–

[]



I, II, III, V, VII, VIII, X, XVI

Cu/SiO

Solvent-free

–

–

[]



I, X

LaCl/ClCHCOOH

Solvent-free

–

–

[]



I, II, III, V, VI, VII, VIII, X, XVI, XXI, XXII, LVII

Co/Mn/nano-ZnO

Solvent-free

–

–

[]



I, II, III, IV, V, VII, VIII, X, XVI, XXII

CA-SiO

Solvent-free

–

–

[]



I, II, III, V, VII, X, XXII, XXVIII

Nano-SPA

Solvent free

–

–

[]



I, II, III, V, VII, VIII, X, XVI

Cobalt hydrogen sulfate

Solvent-free

–

–

[]

4 Multicomponent synthesis of biologically prominent



(continued)

171

172

Table 4.3 (continued) Catalyst

Condition

Time (min)

Yield (%)



I, II, III, V, VII, IX, XI, XXII, XXVI, XXVII, XXXI, XLVIII, LVI

SBISAC

Solvent-free

–

–

[]



I, II, III, V, VII, XXVII, XLV, LI

Ru@SH-MWCNTs

Reflux

–

–

[]



I, III, V, VII, X, XVI, XXII, XXXI, XXXVIII, XLI, LXIII

CoFeO/OCMC/Cu (BDC)

Ultrasonic irradiation

–

–

[]



I, II, III, V, VII, VIII, X, XVI, XXI, XXII, XXVII, XXVIII, XL, XLI, Cu(II)/FeO@APTMS- Solvent-free XLII, XLIII DFX

–

–

[]



I, II, V, VII, XVI, LX

–

–

[]

HBF/SiO

Solvent-free

Reference Kantharaju Kamanna, Yamanappagouda Amaregouda, Aravind Kamath

S. no. Aldehydes

4 Multicomponent synthesis of biologically prominent

173

Abbreviations APTS [BDMAP][OH] BF3·SiO2 [BiPy](HSO3)2Cl2 BNBTS Ce(SO4)2.4H2O DBSA [DBU]2[EDS] DSIMHS DSTMG Fe3O4@SiO2–SO3H H2PMo12O4¯ (H2PMo) LPCAS MCRs MWCNTs-SO3H MWI NaHSO4·SiO2 NaOAc NbCl5 NO2−FePc NSPVPC Perlite NPs@IL/ZrCl4 [Pyridine–SO3H]Cl SAFIS Sc(OTf)3 TBAHS TCS TCT [TMXH]FeCl4 TPPMS TrCl TTAB Yb(PFO)3 ZnO NPs ZrSA

3‐Aminopropyltriethoxysilane 1-Butyl-(4-dimethylamino)pyridiniumhydroxide Silica-supported boron trifluoride 1,10-disulfo-[2,20-bipyridine]-1,10-diium chloride N,N′-Dibromo-N,N′-1,2-ethanediylbis(p-toluene sulfonamide) Cerium(IV) sulfate tetrahydrate p-dodecyl benzene sulfonic acid Bis-2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepinnium-ethyl disulfate 1,3-disulfonic acid imidazolium hydrogen sulfate N,N-disulfo-1,1,3,3-tetramethyl guanidinium carboxylate ionic liquids Nano-Fe3O4 encapsulated-silica particles-bearing sulfonic acid groups Schiff base (SB)-functionalized graphene oxide (GO) nanosheets containing phosphomolybdic counter‐anion L-Pyrrolidine-2-carboxylic acid sulfate Multicomponent reactions Sulfonated multiwalled carbon nanotubes Microwave irradiation Silica-supported sodium hydrogen sulfate Sodium acetate Niobium pentachloride Fe(III) Tetranitrophthalo cyanine immobilized on activated carbon N-sulfonic acid poly(4-vinylpyridinium) chloride Perlite nanoparticle modified Lewis acid ionic liquid Sulfonic acid-functionalized pyridinium chloride Sulfonic acid-functionalized imidazolium salts Scandium(III) trifluoromethanesulfonate Tetrabutylammonium hydrogensulfate Tetrachlorosilane 2,4,6-Trichloro-1,3,5-triazine Nano-sized cube-shaped magnetic ionic liquid based on caffeine Triphenylphosphine-m-sulfonate Trityl chloride Tetradecyltrimethylammonium bromide Ytterbium perfluorooctanoate Zinc oxide nanoparticles Zirconia sulfuric acid

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Bubun Banerjee✶, Aditi Sharma, Manmeet Kaur, Arvind Singh, Anu Priya

5 One-pot five/four-component synthesis of structurally diverse bioactive quinoxaline-annulated spiroheterocycles through the in situ formation of 11Hindeno[1,2-b]quinoxalin-11-ones 5.1 Introduction Quinoxaline-containing skeletons are very common in naturally occurring bioactive compounds such as echinomycin (I) and triostin A (II) (Figure 5.1) [1, 2]. Quinoxaline and its relevant skeletons play an important role in many commercially available drug molecules [3–7]. Figure 5.2 represents a glimpse of quinoxaline-containing commercially available drug molecules viz., varenicline (III) (used for the smoking cessation) [3], Brimonidine (IV) (used to treat glaucoma) [4], quinacillin (V) (antibiotic) [5], chlorosulfaquinoxaline (VI) (antitumor agent) [6], and R-(+)-XK469 (5) (anticancer agent) [7]. Along with naturally occurring compounds, a huge number of synthetic quinoxaline derivatives also showed significant biological efficacies [8–13]. Among many other quinoxaline derivatives, in recent times, 11H-indeno[1,2-b]quinoxalin-11-ones have gained special attention as they can be used as a precursor to many structurally diverse bioactive spiroheterocycles having potent biological efficacies including anticancer, antimycobacterial, antibacterial, anti-Alzheimer, antimicrobial, antioxidant, antifungal, etc. activities (Figure 5.3) [14–21]. As a result, a large number of atom-efficient reaction protocols have been developed to construct many structurally diverse bioactive heterocyclic scaffolds by following one-pot multicomponent strategies involving 11H-indeno[1,2-b]quinoxalin11-one as an important starting component. On many occasions 11H-indeno[1,2-b]quinoxalin-11-one was formed in situ in the reaction medium from the reactions between ninhydrin and o-phenylenediamine, which then took part in the reactions with the other added components and afforded the desired products. Multicomponent synthesis approaches are regarded as one of the precious tools for synthesizing various structurally diverse organic transformations [22–26]. Among other convincing domains of green chemistry, multicomponent strategy is always a fascinating tool as it has immense benefits. Multicomponent strategies to synthesize ✶

Corresponding author: Bubun Banerjee, Department of Chemistry, Akal University, Talwandi Sabo, Bathinda 151302, Punjab, India, e-mail: [email protected] Aditi Sharma, Manmeet Kaur, Arvind Singh, Anu Priya, Department of Chemistry, Akal University, Talwandi Sabo, Bathinda 151302, Punjab, India https://doi.org/10.1515/9783110985313-005

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heterocyclic compounds offer a number of advantages such as reduction of purification processes, operational simplicity, energy efficiency, atom economy, etc. [27–29].

Figure 5.1: Naturally occurring quinoxaline-bearing bioactive compounds.

Figure 5.2: Commercially available drug molecules with quinoxaline skeleton.

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Figure 5.3: 11H-Indeno[1,2-b]quinoxalin-11-one can be used as a precursor of many synthetic bioactive heterocyclic scaffolds.

5.2 Five-component synthesis of quinoxalineannulated spiroheterocycles 5.2.1 Five-component synthesis of spiro-pyrrolidines In 2011, Ming et al. [30] synthesized a series of spiro-pyrrolidines, viz., (2′S,4′R)-1′methyl-4′-arylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′,3′-dicarbonitriles (7) and (2′S,3′S,4′R)-ethyl 3′-cyano-1′-methyl-4′-phenylspiro[indeno[1,2-b]quinoxaline11,2′-pyrrolidine]-3′-carboxylates (8) via one-pot five-component reactions of ninhydrin (1), o-phenylenediamine (2), sarcosine (3), aromatic aldehydes (4), and malononitrile (5) or ethyl cyanoacetate (6), respectively, in ethanol at 100 °C (Figure 5.4). The desired products (7, 8) were isolated in good yields (62–90%) under conventional stirring at 100 °C for 1–8 h. It was proposed that in this reaction sarcosine (3)

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played dual role, i.e., both as catalyst as well as substrate. In the first step, ninhydrin (1) and o-phenylenediamine (2) reacted to form 11H-indeno[1,2-b]quinoxalin-11-one (A) in situ, which further reacted with sarcosine (3), aromatic aldehydes (4), and malononitrile (5)/ethyl cyanoacetate (6) to afford the desired products.

Figure 5.4: One-pot five-component synthesis of spiro-pyrrolidine derivatives.

In 2018, Wen and his group [31] developed an efficient one-pot five-component method for the synthesis of (2′S)-3′-(indole-3-carbonyl)-1′-methyl-4′-arylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-carbonitrile derivatives (11) in good yields (55–68%) via 1,3-dipolar cycloaddition reactions of ninhydrin (1), o-phenylenediamine (2), 3-cyanoacetyl indole (3), aryl aldehydes (4), and sarcosine (3) in ethanol under refluxed conditions (Figure 5.5). It was believed that in the first step, reactions of ninhydrin (1) and o-phenylenediamine (2) formed 11H-indeno[1,2-b]quinoxalin-11-one (A) in situ, which further reacts with 3cyanoacetyl indole (9), aryl aldehydes (4), and sarcosine (3) to afford the desired products (11). Stereochemistries of the products were confirmed by using detailed spectroscopic and X-ray crystallographic studies. The proposed mechanism of this reaction is shown in Figure 5.6. Under the same reaction conditions they were also able to synthesize (3'S)-2'-(indole-3-carbonyl)-1′-aryl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b] quinoxaline-11,3′-pyrrolizine]-2′-carbonitriles (12) in excellent yields (69–93%) by using L-proline (10) instead of sarcosine (3) (Figure 5.5). In 2015, Velikorodov et al. [32] synthesized 4-{3′,3′-dicyano(or 3′-ethoxycarbonyl -3′-cyano)-1′-methylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidin]-4′-yl}phenyl-N-phenylcarbamates (14) in 75–78% yields via one-pot five-component condensation reactions of

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Figure 5.5: One-pot five-component synthesis of (2′S)-3′-(indole-3-carbonyl)-1′-methyl-4′-arylspiro[indeno [1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-carbonitriles.

ninhydrin (1), o-phenylenediamine (2), sarcosine (3), 4-formylphenyl N-phenylcarbamate (13), and malononitrile (5) or ethyl cyanoacetate (6) through the formation of 11H-indeno [1,2-b]quinoxalin-11-one (A) in situ in the presence of a catalytic amount of ionic liquid [bmim]Br in ethanol under refluxed conditions (Figure 5.7).

5.2.2 Five-component synthesis of dispiro-pyrrolidines In 2014, Liu et al. [33] reported a simple, efficient and one-pot five-component cascade reaction for the synthesis of highly substituted dispiroindenoquinoxaline pyrrolidine derivatives (16) from the reactions of ninhydrin (1), o-phenylenediamine (2), sarcosine (3), 1,3-indanedione, (15) and various aromatic aldehydes (4) through the in situ formation of 11H-indeno[1,2-b]quinoxalin-11-one (A) in ethanol under refluxed conditions (Figure 5.8). All the reactions were completed within 3 h and afforded excellent yields (80–92%). All the products were isolated pure just by simple recrystallization with ethanol. The authors proposed a mechanism of this transformation, which is shown in Figure 5.9. In the same year, Gavaskar et al. [34] designed a one-pot five-component reaction strategy for the synthesis of a series of pyrazolo-functionalized pyrrolidine-based spiroindenoquinoxaline derivatives (19) in good yields (80–88%) from the reactions of ninhydrin (1), o-phenylenediamine (2), sarcosine (3), hydrate hydrazine (17), and 2,6-bisarylmethylidene-cyclohexanone or 2,5-bis-arylmethylidene-cyclopentanone derivatives

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Figure 5.6: Plausible mechanism for the synthesis of (2′S)-3′-(indole-3-carbonyl)-1′-methyl-4′-arylspiro [indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-carbonitriles.

Figure 5.7: One-pot five-component synthesis of 4-{3′,3′-dicyano(or 3′-ethoxycarbonyl-3′-cyano)-1′methylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidin]-4′-yl}phenyl N-phenylcarbamates.

(18) in methanol under refluxed conditions (Figure 5.10). It was proposed that the reactions of ninhydrin (1) and o-phenylenediamine (2) formed 11H-indeno[1,2-b]quinoxalin11-one (A) in situ which reacts with sarcosine (3) to form the corresponding azomethine ylides (20). Now the azomethine ylides (20) underwent [3+2]-cycloaddition with 2,6bis-arylmethylidene-cyclohexanone or 2,5-bis-arylmethylidene-cyclopentanones (18)

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Figure 5.8: One-pot five-component synthesis of (2′R,4′R)-1′-methyl-4′-arylspiro-[2.11′]-indeno[1,2-b] quinoxaline-spiro-[3.2′]indane-1′,3′-dione-pyrrolidine derivatives.

Figure 5.9: Plausible mechanism for the one-pot five-component synthesis of (2′R,4′R)-1′-methyl-4′arylspiro-[2.11′]-indeno[1,2-b]quinoxaline-spiro-[3.2′]indane-1′,3′-dione-pyrrolidines.

to form the corresponding intermediate (21), which further reacted with hydrate hydrazine (17) to form the targeted products (Figure 5.11).

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Figure 5.10: One-pot five-component synthesis of pyrazolo-functionalized pyrrolidine-based spiroindenoquinoxaline derivatives.

Figure 5.11: Plausible mechanism for the synthesis of pyrazolo-functionalized pyrrolidine-based spiroindenoquinoxaline derivatives.

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5.3 Four-component synthesis of quinoxalineannulated spiroheterocycles 5.3.1 Four-component synthesis of spiro-pyrrolidine In 2020, Arumugam et al. [15] synthesized a series of spiro-pyrrolidine-fused indenoquinoxaline derivatives from one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), L-phenylalanine (22), and β-nitrostyrene (23) in ionic liquid [bmim]Br at 100 °C (Figure 5.12). In the beginning 11H-indeno[1,2-b]quinoxalin-11-one (A) was formed in situ from the reactions of ninhydrin (1) and o-phenylenediamine (2). The plausible mechanism of this transformation along with the role of ionic liquid is shown in Figure 5.13. Structures and the stereochemistry of the synthesized compounds were confirmed by using 2D NMR (heteronuclear multiple bond correlation, HMBC) and crystallographic analyses. All the reactions were completed within 1 h and afforded the desired pure products in good yields. Antitubercular activity of the synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv. Among all, compound 24a containing nitro group on a phenyl ring showed similar activity to standard drug ethambutol with MIC (minimum inhibitory concentration) value 1.56 μg/mL.

Figure 5.12: One-pot four-component synthesis of spiro-pyrrolidine-fused indenoquinoxaline derivatives.

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Figure 5.13: Plausible mechanism for the synthesis of spiro-pyrrolidine-fused indenoquinoxaline derivatives.

In 2009, Mohammadizadeh and his group [35] developed a catalyst-free stereoselective method for the synthesis of spiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizidine] derivatives (27) in good yields (75–82%) from the one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), L-proline (10), and various chalcones (26) in ethanol under refluxed conditions (Figure 5.14). All the reactions were completed within 2 h. It was proposed that 11H-indeno[1,2-b]quinoxalin-11-one (A) formed in situ reacts with Lproline (10) to form the corresponding azomethine ylides (28), which afforded the desired products via the 1,3-dipolar cycloaddition with chalcones (26) (Figure 5.15). In 2017, Akondi et al. [36] designed a simple, efficient and stereoselective approach for the synthesis of a series of spiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine] derivatives (29) from one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), L-proline (10), and β-nitrostyrene (23) in absence of any catalyst in ethanol under microwave-irradiated conditions (150 W) at 80 °C (Figure 5.16). All the reactions were completed within just 7–8 min and afforded good yields (86–96%). The same reaction required longer times (4–5.5 h) under refluxed conditions in ethanol as solvent. All the synthesized compounds were evaluated for AChE inhibitory activity. Compound 29a (IC50 value 0.05 μM) showed 20 times better inhibition activity against acetylcholinester-

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Figure 5.14: One-pot four-component synthesis of spiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizidine] derivatives.

Figure 5.15: Plausible mechanism for the synthesis of spiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizidine] derivatives.

ase (AChE) than the potent standard drug galantamine (IC50 value 0.97 μM). The plausible mechanism of this transformation is shown in Figure 5.17. In 2020, Arumugam et al. [37] reported a facile protocol for the regio and diastereoselective synthesis of spiropyrrolo-fused indenoquinoxaline derivatives (31) in good yields (79–88%) from one-pot four-component synthesis of ninhydrin (1), o-phenylenediamine (2), L-tryptophan (30), and β-nitrostyrene (23) in ionic liquid [bmim]Br at 100 °C (Figure 5.18). All the reactions were completed within 45 min. The proposed mechanism of this reaction and the role of ionic liquids are shown in Figure 5.19. Stereochemistry of the synthesized compounds was confirmed by HMBC analysis and X-ray crystallographic studies. All the synthesized compounds were screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. Among all, compound 31a showed comparable efficacies to standard drug ethambutol with MIC value 1.56 μg/mL.

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Figure 5.16: One-pot four-component synthesis of stereoselective spiro[indeno[1,2-b]quinoxaline-11,3′pyrrolizine] derivatives.

Figure 5.17: Plausible mechanism for the synthesis of spiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine] derivatives.

In 2018, Reddy et al. [38] demonstrated a simple, facile, and catalyst-free diastereoselective approach for the synthesis of a series of spiro-pyrrolidinyl-fused indenoquinoxaline derivatives (34) in good yields (70–92%) via one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), isoxazoles (32), and substituted benzyl amines (33) in methanol under refluxed conditions (Figure 5.20). The reaction proceeded via the

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Figure 5.18: One-pot four-component synthesis of spiropyrrolo-fused indenoquinoxaline derivatives.

Figure 5.19: Plausible mechanism for the synthesis of spiropyrrolo-fused indenoquinoxaline derivatives in ionic liquids.

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Figure 5.20: One-pot four-component catalyst-free synthesis of spiropyrrolidinyl-fused indenoquinoxaline derivatives.

Figure 5.21: Plausible mechanism for the synthesis of spiropyrrolidinyl-fused indenoquinoxaline derivatives.

formation of azomethine ylides in situ, which further underwent 1,3-dipolar [3 + 2]cycloaddition reaction to afford the desired products (Figure 5.21). Shahrestani et al. [39] demonstrated a simple, efficient, and catalyst-free method for the synthesis of a series of novel spiroindenoquinoxaline-fused pyrrolidines (37) and spiro-indenoquinoxaline-fused pyrrolizidines (38) via one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), cinnamoyl-crotonoyl oxazolidinone (35), and L-proline derivatives (10, 36) or sarcosine (3), respectively, in ethanol under refluxed conditions (Figure 5.22).

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Figure 5.22: One-pot four-component synthesis of spiro-indenoquinoxaline-fused pyrrolidine and spiroindenoquinoxaline-fused pyrrolizidine derivatives.

Figure 5.23: One-pot four-component synthesis of imidazole-annulated spiro-pyrrolidine derivatives.

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Figure 5.24: Plausible mechanism for the synthesis of imidazole-annulated spiro-pyrrolidine derivatives.

In 2019, Almansoura et al. [17] developed an efficient ionic liquid ([bmim]Br)-mediated protocol for the synthesis of a new class of imidazole-annulated spiro-pyrrolidine derivatives (40) in good yields (80–87%) via one-pot four component 1,3-dipolar cycloaddition reactions of ninhydrin (1), o-phenylenediamine (2), L-histidine (39), and β-nitrostyrene (23) at 100 °C (Figure 5.23). All the reactions were accomplished within 1 h. The plausible mechanism and the role of ionic liquid are shown in Figure 5.24. Screening of anticholinesterase activity revealed that compound 40a is active against AChE enzyme with IC50 value 2.05 μM and interestingly the activity of compound 40b against butyrylcholinesterase (BChE) enzyme (IC50 value 12.40 μM) is almost comparable to the standard drug galantamine. In the same year, Gupta and Khurana [40] reported a facile and straightforward catalyst-free approach for the synthesis of functionalized spiroindeno[1,2-b]quinoxaline-11,3′-pyrrolizines (41) via one-pot four-component cascade reactions of ninhydrin (1), o-phenylenediamine (2), L-proline (10)/L-thioproline (10a), and 3-methyl-4-nitro-5styrylisoxazoles (32) in methanol under refluxed conditions (Figure 5.25).

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Figure 5.25: One-pot four-component catalyst-free synthesis of functionalized spiroindeno[1,2-b] quinoxaline-11,3′-pyrrolizines.

Mani et al. [14] demonstrated a general method for the synthesis of a series of biologically active spiro-indenoquinoxaline pyrrolizine derivatives (43) through one-pot fourcomponent reactions of ninhydrin (1), o-phenylenediamine (2), (E)-3-(2-chloroquinolin-3yl)-1-phenylprop-2-en-1-ones (42), and L-proline (10) in methanol under refluxed conditions (Figure 5.26). All the reactions were completed within 3 h and afforded the desired products in good yields (75–92%). All the synthesized compounds were evaluated for their in vitro antioxidant as well as cytotoxic activities. Among all, the compound 43a

Figure 5.26: One-pot four-component synthesis of bioactive spiro-indenoquinoxaline pyrrolizine derivatives.

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showed better antioxidant efficacies than the standard drug BHT against DPPH, nitric oxide and superoxide with IC50 values 2.96, 1.34, and 4.01 μg/mL, respectively. Interestingly, as compared to the standard drug doxorubicin, the same compound (43a) also showed similar anticancer activity against the cancer cell lines MCF-7 and A-549 with IC50 values 15 μM and 16 μM, respectively. By using different amino acid, i.e., Lthioproline (10a) under the same reaction conditions, the same group also synthesized a series of biologically promising spiro-indenoquinoxaline pyrrolothiazoles derivatives (44) in good yields (70–91%) (Figure 5.26) [41]. As before, all the synthesized compounds were evaluated for their antioxidant and cytotoxic activities and compound 44a showed highest antioxidant as well as anticancer efficacies.

5.3.2 Four-component synthesis of ferrocene-embedded spiropyrrolidine In 2020, Arumugam et al. [42] reported a simple method for the efficient synthesis of biologically promising ferrocene-containing hybrid spiro-pyrrolidine derivatives (46) via one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), Lphenylalanine (22), and ferrocenyl chalcone (45) in ionic liquid [bmim]Br at 100 °C (Figure 5.27). At first indenoquinoxaline (A) was formed in situ from the reactions of ninhydrin (1) and o-phenylenediamine (2). Then L-phenylalanine (22) reacts with indenoquinoxaline (A) to form the corresponding azomethine ylide intermediate, which further undergoes cycloaddition reaction with various ferrocenyl chalcones (45) to afford the desired products in excellent yields within 1 h (Figure 5.28). The structure and stereochemistry of the synthesized compounds were determined by HMBC analysis and X-ray crystallographic studies.

Figure 5.27: One-pot four-component regioselective synthesis of ferrocene-containing hybrid spiropyrrolidine derivatives.

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Figure 5.28: Plausible mechanism for the synthesis of ferrocene-containing hybrid spiro-pyrrolidine derivatives.

In 2013, Babu et al. [43] developed a simple, facile, and ultrasound-assisted protocol for the synthesis of a series of structurally diverse ferrocene-functionalized spiroindenoquinoxaline pyrrolidines (51–55) in good yields (80–90%) via one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), sarcosine (3), and various ferrocenyl chalcone derivatives (45, 47–50) in methanol (Figure 5.29). All the reactions were completed within 1.5 h. The same group also synthesized a series of ferrocene functionalized spiro-indenoquinoxaline pyrrolizidine derivatives (58–62) via one-pot four-component from ninhydrin (1), o-phenylenediamine (2), L-proline (10), and various ferrocenyl chalcone derivatives (50, 47, 49, 56, 57) in methanol under conventional refluxed conditions (Figure 5.30) [44]. The reaction underwent in situ formation of azomethine ylides followed by [3 + 2]-cycloaddition with ferrocenyl chalcone derivatives (50, 47, 49, 56, 57). The proposed mechanism for the synthesis of compounds 58 is shown is Figure 5.31.

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Figure 5.29: Ultrasound-assisted one-pot four-component synthesis of structurally diverse ferrocenefunctionalized spiro-indenoquinoxaline pyrrolidine derivatives.

Gavaskar et al. [45] demonstrated an ionic liquid (N-(1-acroloyl)-N-(4-cyclopentyl)piperazinium phosphate)-mediated protocol for the synthesis of a wide range of structurally diverse ferrocene-functionalized spiro-indenoquinoxaline tetrahydro-1H-pyrrolo [1,2-c][1,3]-thiazoles (63–66) via one-pot four-component reactions of ninhydrin (1), ophenylenediamine (2), (R)-thiazolidine-4-carboxylic acid (10a), and various ferrocenyl chalcone derivatives (50, 47, 45, 56) at 140 °C (Figure 5.32). All the reactions were completed within 2.4 h and the desired products obtained in excellent yields (87–94%).

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Figure 5.30: One-pot four-component synthesis of structurally diverse ferrocene-functionalized spiroindenoquinoxaline pyrrolizidine derivatives.

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Figure 5.31: Plausible mechanism for the synthesis of structurally diverse ferrocene-functionalized spiroindenoquinoxaline pyrrolizidine derivatives.

5.3.3 Four-component synthesis of dispiro-indenoquinoxalines By using the same ionic liquid (N-(1-acroloyl)-N-(4-cyclopentyl)-piperazinium phosphate), Gavaskar et al. [46] reported another one-pot four-component method for the synthesis of steroidal annulated dispiro-pyrrolidine derivatives (68) via the reactions of ninhydrin (1), o-phenylenediamine (2), (Z)-16-benzylideneestrone (67) and sarcosine (3) at 120 °C (Figure 5.33). The proposed mechanism of this reaction is depicted in Figure 5.34. Babu and Ragunathan [47] reported an efficient method for one-pot four-component synthesis of a wide variety of dispiroindenoquinoxaline pyrrolizidine derivatives (73–76) from the reactions of ninhydrin (1), o-phenylenediamine (2), L-proline (10), and various aryl eneones such as 2-arylidene-1,3-indanediones (69), (E)-2-arylidenetetrahydronaphthalene-1-ones (70), (E)-3-arylidene-4-chromanones (71), and (E)-2oxoindolino-3-ylidene acetophenones (72), in the presence of a catalytic amount of heteropolyacid{H4[Si(W3O10)3]}-silica as a catalyst in acetonitrile under refluxed conditions (Figure 5.35). Rajesh et al. [48] synthesized a series of novel 1-methyl-4-arylpyrrolo-(spiro[2.11′]11H-indeno[1,2-b]quinoxaline)-spiro[3.3″]-1″methyl/benzyl-5″-(arylmethylidene)piperidin-4″-one derivatives (78) via one-pot four-component reactions of ninhydrin (1), o-phe-

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Figure 5.32: Ionic liquid-mediated one-pot four-component synthesis of ferrocene-functionalized spiroindenoquinoxaline tetrahydro-1H-pyrrolo[1,2-c][1,3]-thiazole derivatives.

Figure 5.33: One-pot four-component synthesis of steroidal embedded dispiro-pyrrolidine derivatives.

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Figure 5.34: Plausible mechanism for the synthesis of steroidal embedded dispiro-pyrrolidine derivatives.

nylenediamine (2), sarcosine (3), and 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4 (1H)-pyridinones (77) in ionic liquid [bmim]Br at 100 °C (Figure 5.36). The structure and the exact stereochemistry of the synthesized compounds were determined by using HMBC analysis and X-ray crystallography studies. The proposed mechanism of this transformation is shown in Figure 5.37. Malathi et al. [49] carried out one-pot four-component reactions between ninhydrin (1), o-phenylenediamine (2), (E)-3-arylidene-1-methylpiperidin-4-ones (79), and 1,3-thiazolane -4-carboxylic acid (10a) or sarcosine (3) in methanol under refluxed conditions, which afforded the corresponding dispiro-piperidone–indenoquinoxaline-pyrrolothiazoles (80) or dispiro-piperidone–indenoquinoxaline-pyrrolopyrrolidine derivatives (81), respectively (Figure 5.38). Interestingly, under these conditions L-proline failed to produce the desired products. Arumugam et al. [50] synthesized a series of dispiropyrrolidinyl-piperidone-annulated indeno[1,2-b]quinoxaline derivatives (82) via one-pot four-component 1,3-dipolar cycloaddition reactions between ninhydrin (1), o-phenylenediamine (2), bis-arylidene piperidone (77), and L-tryptophan (30) in ionic liquid [bmimBr] at 100 °C (Figure 5.39). All the reactions

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Figure 5.35: Silica-mediated heteropolyacid-catalyzed one-pot four-component synthesis of structurally diverse dispiroindenoquinoxaline pyrrolizidine derivatives.

were completed within 1 h. All the synthesized compounds were screened for their in vitro BChE and AChE inhibitory activities. Among all, compound 82a showed better cholinesterase inhibitory activity than standard drug galantamine with IC50 values 2.01 and 10.45 μM, respectively. A simple, efficient, and catalyst-free one-pot four-component method was reported by Ren et al. [19] for the synthesis of a series of structurally diverse spiroindoleindenoquinoxaline derivatives (84–86) from the reactions of ninhydrin (1), o-phenylenediamine (2), 3-ylideneoxicndoles (83), and various α-amino acids (3, 10, 10a) in ethanol under refluxed conditions (Figure 5.40). TrpRS (tryptophanyl-tRNA synthetase) inhibitory activity studies of the synthesized compounds revealed that compound 85a is most active against human mitochondrial TrpRS (hmTrpRS) and Escherichia

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Figure 5.36: Ionic liquid-mediated one-pot four-component synthesis of 1-methyl-4-arylpyrrolo-(spiro [2.11′]-11H-indeno[1,2-b]quinoxaline)-spiro[3.3″]-1″-methyl/benzyl-5″-(arylmethylidene) piperidin-4″-ones.

Figure 5.37: Plausible mechanism for the synthesis of 1-methyl-4-arylpyrrolo-(spiro[2.11′]-11H-indeno[1,2b]quinoxaline)-spiro[3.3″']-1″-methyl/benzyl-5″-(arylmethylidene)piperidin-4″-ones.

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Figure 5.38: One-pot four-component synthesis of dispiro-piperidone–indenoquinoxaline-pyrrolothiazole or pyrrolidine derivatives.

Figure 5.39: One-pot four-component synthesis of dispiropyrrolidinyl-piperidone-annulated indeno[1,2-b] quinoxalin-11-one derivatives.

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coli TrpRS (ecTrpRS) with IC50 values of 225 and 74 μM, respectively. Interestingly, the same compound (85a) also showed comparable antibacterial activity with the standard drug indolmycin against Staphylococcus aureus (ATCC29213) with MIC90 (minimum inhibitory concentration) value 4 μg/mL. Moreover, the same compound (85a) was also found efficient in suppressing proliferation of cell line DLBCL (diffuse large B-cell lymphoma) with IC50 value 2.9–4.8 μM.

Figure 5.40: Catalyst-free one-pot four-component synthesis of spiroindole-indenoquinoxaline derivatives.

Almansour et al. [51] synthesized a series of highly substituted novel dispiropyrrolidinyl-Nstyrylpiperidone-indeno[1,2-b]quinoxaline derivatives (89) in moderate to good yields (48–64%) from one-pot four-component reactions between 1 equivalent of ninhydrin (1), 1 equivalent of o-phenylenediamine (2), 1 equivalent of 3,5-dibenzylidenepiperidin-4-ones

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(77), and 2 equivalents of L-phenylalanine (22) in ionic liquid [bmimBr] at 100 °C (Figure 5.41). It was proposed that the final products were obtained from the reactions of intermediate 90 and phenyl acetaldehyde (88) generated in situ (Figure 5.42). In this reaction the ionic liquid [bmimBr] behaved as both solvent as well as catalyst. All the synthesized compounds possess moderate to good antimicrobial and antifungal activities. Combinations of compound 89a with streptomycin and vancomycin showed promising synergistic activity against E. coli (ATCC 25922).

Figure 5.41: One-pot domino four-component synthesis of dispiropyrrolidinyl-N-styrylpiperidone-indeno [1,2-b]quinoxaline derivatives.

Babu and Ragunathan [52] reported a facile protocol for the regioselective synthesis of 1N-methyl-spiro[2.11′]indeno-[1,2-b]-quinoxaline-spiro[3.3′′]oxindole-4-benzoyl-pyrrolidines (91) in good yields (82–90%) through the formation of azomethine ylide via one-pot four-component 1,3-dipolar cycloaddition reactions of ninhydrin (1), ophenylenediamine (2), sarcosine (3), and 2-oxoindolino-3-ylidene acetophenones (72) in methanol under refluxed conditions (Figure 5.43).

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Figure 5.42: Plausible mechanism for the one-pot domino four-component synthesis of dispiropyrrolidinyl-N-styrylpiperidone-indeno[1,2-b]quinoxaline derivatives.

Figure 5.43: One-pot four-component synthesis of 1N-methyl-spiro[2.11′]indeno-[1,2-b]-quinoxaline-spiro [3.3″]oxindole-4-benzoyl-pyrrolidine derivatives.

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5.3.4 Four-component synthesis of spiro-indenoquinoxalines In 2017, Maryamabadi et al. [53] reported a simple, convenient, and catalyst-free approach for the synthesis a series of novel spiro-indenoquinoxaline derivatives (93) via one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), malononitrile (5), and N,N′-substituted-2-nitroethene-1,1-diamines (92) in PEG-400 as solvent at 130 °C (Figure 5.44). Although, the reactions required longer times (10–14 h), the desired products were afforded in excellent yields (74–81%). In vitro and in silico studies revealed that all the synthesized compounds possess moderate level of antiAChE and anti-BChE inhibitory activities.

Figure 5.44: One-pot four-component catalyst-free synthesis of novel spiro-indenoquinoxaline derivatives.

Figure 5.45: One-pot four-component catalyst-free synthesis of dihydrothiophenone-fused dispiroindenoquinoxaline-pyrrolidines or pyrrolothiazole derivatives.

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A simple, efficient, straightforward, and catalyst-free method was developed by Rani et al. [54] for the synthesis of dihydrothiophenone-fused dispiroindenoquinoxalinepyrrolidines (95) or pyrrolothiazole derivatives (96) via one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), (2Z,4Z)-2,4-bis(arylidene)dihydrothiophen-3(2H)-ones (94), and sarcosine (3) or L-thioproline (10a), respectively, by using 1,4-dioxane and methanol (1:4 v/v) mixture as solvent under refluxed conditions (Figure 5.45).

5.3.5 Four-component synthesis of spiropyrans–indenoquinoxalines Hasaninejad et al. [55] demonstrated a novel method for the efficient synthesis of a series of structurally diverse 2′-aminospiro[indeno[1,2-b]quinoxaline-11,4′-[4′H]pyran] derivatives (98) via one-pot four-component reactions of ninhydrin (1), o-phenylenediamine (2), several C–H-activated acids (97), and malononitrile (5) or alkyl malonates (6,6a) in the presence of a catalytic amount of ammonium acetate (20 mol%) in ethanol under refluxed conditions (Figure 5.46). The same group [56] also carried out the same batch of reactions in the presence of a catalytic amount of 15 mol% InCl3 in acetonitrile under refluxed conditions (Figure 5.47). Recently, in 2020, Hojati et al. [57] employed a freshly prepared magnetic nanocatalyst [poly(Py-co-Ani)@GOFe3O4] to carry out the same batch of reactions in ethanol under refluxed conditions (Figure 5.48). They prepared this magnetic nanocatalyst by functionalizing Fe3O4 nanoparticles on graphene oxide sheets covered with aniline-pyrrole copolymer. The proposed mechanism of this transformation is shown in

Figure 5.46: Ammonium acetate-catalyzed one-pot four-component synthesis of 2′-aminospiro[indeno [1,2-b]quinoxaline-11,4′-[4′H]pyran] derivatives.

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Figure 5.47: InCl3-catalyzed one-pot four-component synthesis of 2′-aminospiro[indeno[1,2-b]quinoxaline11,4′-[4′H]pyran] derivatives.

Figure 5.48: One-pot four-component synthesis of 2′-aminospiro[indeno[1,2-b]quinoxaline-11,4′-[4′H] pyran] derivatives in the presence of a magnetic nanocatalyst.

Figure 5.49. After completion of the reaction the magnetic nanocatalysts were recovered successively by using a bar magnet and were recycled for several runs without any significant loss in its catalytic activities.

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Figure 5.49: Plausible mechanism for the one-pot four-component synthesis of 2′-aminospiro[indeno[1,2b]quinoxaline-11,4′-[4′H]pyran] derivatives.

5.3.6 Four-component synthesis of spirofuran–indenoquinoxalines In 2015, Sabouri and group [58] reported a simple, catalyst-free, one-pot four-component method for the synthesis of a series of spirofuran-indenoquoxaline (Z)-dialkyl-5-(alkylimino)-5H-spiro[furan-2,11′-indeno[1,2-b]quinoxaline]-3,4-dicarboxylates (101) from the reactions of ninhydrin (1), o-phenylenediamine (2), dialkyl acetylenedicarboxylates (99), and isocyanides (100) in dichloromethane as solvent at room temperature (Figure 5.50). The reactions afforded excellent yields of the desired products after 8 h of stirring. The plausible mechanism of this transformation is shown in Figure 5.51.

5 One-pot five/four-component synthesis of structurally

Figure 5.50: Catalyst-free synthesis of (Z)-dialkyl-5-(alkylimino)-5H-spiro[furan-2,11′-indeno[1,2-b] quinoxaline]-3,4-dicarboxylate derivatives.

Figure 5.51: Plausible mechanism for the catalyst-free synthesis of (Z)-dialkyl-5-(alkylimino)-5H-spiro [furan-2,11′-indeno[1,2-b]quinoxaline]-3,4-dicarboxylate derivatives.

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5.4 Conclusions Quinoxaline skeleton is very common in natural products, commercially available drugs, and synthetic bioactive compounds. Among many other quinoxaline derivatives, 11H-indeno[1,2-b]quinoxalin-11-ones have gained special attention as they can be used as building blocks for many structurally diverse bioactive spiroheterocyclic compounds with potent biological efficacies including anticancer, antimycobacterial, antibacterial, anti-Alzheimer, antimicrobial, antioxidant, antifungal, etc. activities. In this chapter, we have summarized all the recent advances in one-pot five/four-component synthesis of structurally diverse bioactive quinoxaline-annulated spiroheterocycles through the in situ formation of 11H-indeno[1,2-b]quinoxalin-11-ones.

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Kantharaju Kamanna✶, Radhika Mane, Yamanappagouda Amaregouda, Aravind Kamath

6 Multicomponent synthesis of biologically active quinazolinone derivatives 6.1 Introduction Heterocycles are cyclic organic compounds containing at least one heteroatom (N, O, S, etc.) other than carbon in their ring skeleton [1, 2]. The nitrogen-containing heterocycles are found to have highest share in pharmaceutical drugs, natural products, synthetic compounds, veterinary, and agrochemicals [3]. Among them, quinazolinone heterocycle containing nitrogen atom in the ring, derived from natural and synthetic sources showed ubiquitous biological activity [4, 5]. Quinazolinone, obtained by the fusion of 2pyrimidinone with benzene ring, shows three isomeric forms, based on the presence of the keto group, and are named quinazolin-4(3H)-one (I), quinazolin-2(1H)-one (II), and quinazolin-2,4-(1H,3H)-dione (III), and quinazoline (IV). Among the natural and synthetic sources, quinazolin-4(3H)-one (I) skeleton has emerged as an important scaffold and is majorly found among other isomers. They are well documented in the pharmacological and material science applications (Figure 6.1). Quinazolinone skeleton, containing molecules, emerged as a promising heterocyclic scaffold and finds broad applications in the area of pharmaceuticals, as depicted in Figure 6.2.

Figure 6.1: Different isomeric structures of quinazolinone.

Acknowledgments: Authors are thankful to UGC for the award of Major Research Project, VGST, Govt. of Karnataka, for the SMYSR award, and RCUB-IRP-2022-23 for the financial support to KK. ✶

Corresponding author: Kantharaju Kamanna, Department of Chemistry, School of Basic Sciences, Rani Channamma University, Vidyasangama, P-B, NH-4, Belagavi 591156, Karnataka, e-mail: [email protected] Radhika Mane, Yamanappagouda Amaregouda, Aravind Kamath, Department of Chemistry, School of Basic Sciences, Rani Channamma University, Vidyasangama, P-B, NH-4, Belagavi 591156, Karnataka https://doi.org/10.1515/9783110985313-006

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Figure 6.2: Pharmacological application of quinazolinone derivatives.

6.2 Biological applications Quinazolinone is regarded as a noteworthy starting material for the synthesis of numerous derivatives with pharmacological importance. About 150 naturally occurring alkaloids containing quinazolinone skeleton showed a wide spectrum of biological activities [6], and have attracted great deal of interest owing, to their various important biological properties [7]. The SAR studies reported in the literature find three sites affecting the properties of the quinazoline derivatives: (i) pyrimidine ring conjugation, (ii) type of substituents present, and (iii) existence of a substituent, either on the benzene ring or on the pyrimidine ring. Due to its wide spectrum of application in pharmacological and material science research, quinazolinone synthetic protocol has received tremendous attention from organic chemists. The simple route encountered via MCRs of isatoic anhydride, combined with nitrogen nucleophile, gives a wide range of quinazolinone derivatives [8]. Numerous quinazolinone derivatives have exceled as drug candidates for various diseases treatment, such as doxazosin and prazosin employed in post-traumatic stress disorder and prostatic hyperplasia treatment, and both gefitinib and erlotinib are used in pancreatic and lung cancers treatment. Various quinazolinone-based drugs, like Fenquizone, exhibit a broad spectrum of antitumor, cytotoxic, and antifungal activities. Lapatinib displays effective anti-breast cancer activity in combination therapy. 2,3dihydroquinazolinone has received a lot of biological interest because of its range of pharmacological properties, such as monoamine oxidase (MAO)-B inhibitor activity and

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acetylcholinesterase (AChE) inhibitor activity [9], antitumor activity [10–12], antimicrobial activity [13–17], anti-inflammatory activity [18], anti-influenza activity [19], antioxidant activity [20], anticonvulsant activity [21], antihypertensive activity [22], anti-obesity activity [23], antipsychotic activity [24], antidiabetic activity [25], antimalarial activity [26], antibacterial activity [27, 28], anticancer activity [29, 30], etc. The first quinazolinone alkaloid (V) discovered was febrifuge, which could be obtained from the Chinese plant asur (Dichroa febrifuga Lour), and showed antimalarial properties (Figure 6.3) [31].

Figure 6.3: The natural derivative of quinazolinone found in febrifugine.

The quinazoline is structurally related to 2- and 4-quinazolinone isomers, which exhibit chemical behavior similar to their pyrimidine counterpart. However, due to its electrophilic nature, quinazoline is found to be more basic [32]. According to reports, 3,4-dihydroquinazolin-2(1H)-one derivatives and 3-substituted quinazolin-4(3H)-one have a broad spectrum of antitumor action toward various cell types (Figure 6.4) [33]. A few quinazolinone Schiff bases (VIII–X) were synthesized, which showed antiviral activities (Figure 6.4) [34]. Compounds (XI–XIII) are the quinazolinones extracted from Luotonin a shrub, and are natural poisons, according to traditional Chinese medicine (Figure 6.4). Compound XI was initially isolated in 1997. It is currently used in clinical trials as an anticancer agent and also shows moderate human topoisomeraseI inhibitor activity (Figure 6.4) [35]. Bouchardatine, a 2-substituted quinazolinone alkaloid 2-(piperazin-1-yl-methyl) exhibits strong anticancer action (XII, R = acetyl, propionyl) [36], and 2-substituted quinazolinone Bouchardatine alkaloid, derived from Bouchardatia neurococca (Rutaceae), shows anticancer properties (XIII) [37]. Quinazolinone derivatives, such as spiro(2H,3H)-quinazoline-2,10-cyclohexan-4(1H)one (XIV, XV) shows strong anti-inflammatory and analgesic activities, with better GIT safety (Figure 6.5) [38]. Hemalatha et al. [39] prepared 2,3-dihydroquinazolin-4(1H)-one (XVI), which is more effective drug than the diclofenac sodium, and prevents the denaturation of the bovine serum albumin (BSA) (Figure 6.5). Manivannan and Chaturvedi [40] synthesized a new quinazolinone derivative (XVII) and tested it for cyclooxygenase inhibition using rat paw edema, induced by carrageenan and ovine COX. The edema inhibition was observed to be 49 ± 1.16%, 45 ± 0.82%, 46 ± 1.36%, and 54 ± 1.83%, using indomethacin as reference. The prepared compound demonstrated strong anti-inflammatory action (Figure 6.5).

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Figure 6.4: Bioactive quinazolinone derivatives.

Figure 6.5: Quinazolinone derivatives with anti-inflammatory properties.

El-Azab and Eltahir [41] synthesized a group of 2,3,8-trisubstituted-4(3H)-quinazolinone derivatives (XVIII) and tested their ability to prevent electrically (MES) and chemically (PTZ, picrotoxin, and strychnine) produced seizures. The results were compared with two most commonly used anticonvulsants, methaqualone and sodium valproate (Figure 6.6). Researcher have described that for maximum electroshock-induced seizure,

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the subcutaneous pentylenetetrazol(6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)one) analogues (XIX) exhibit good anticonvulsant action (Figure 6.6) [42]. Jatav et al. [43] have reported novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl] compounds (XX and XXI), which are variants of the 2-styryl quinazoline-4(3H)-one, show anticonvulsant action in both MES and scPTZ test models (Figure 6.6).

Figure 6.6: Anticonvulsant activity of substituted quinazolinone derivatives.

Vani et al. [44] reported a number of conjugated quinazolin-4(3H)-one and triazole derivatives (XXII–XXIV), and demonstrated their antimicrobial properties (Figure 6.7). Zhu et al. [45] studied the effect of quinazolinones on malarial parasite Plasmodium species causing malaria in many parts of the Asia, Africa, and South America. The majority of the available antimalarial drugs are no longer effective against these parasites, due to drug resistance and mutation. Hence, researchers are encouraged to create new antimalarial-containing quinazolinone skeletons that show high antimalarial potency and fewer side effects.

Figure 6.7: Antimicrobial activity of quinazolin-4(3H)-one-triazole hybrids.

Febrifugine (XXV) was extracted from Dichroa febrifuga, a Chinese traditional herb (Figure 6.8), and in vivo animal studies showed 50–100 times potent antimalarial effects. In 2015, Birhan et al. [46] reported synthetic Febrifugine analogues WR090212(XXVI) as potent antimalarial agents (Figure 6.8), and synthesized 3-aryl-2-(substituted styryl)-4 (3H)-quinazolinone derivative (XXVII), which also showed potent antimalarial activity (Figure 6.8).

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Figure 6.8: Natural extract containing quinazolinone antimalarial agents.

6.3 Chemical synthesis of quinazolinone derivatives He et al. [47] reported the first synthesis of quinozolinone by Niementowski, and named it as Niementowski quinazolinone synthesis. The most popular technique used for making 4(3H)-quinazolinone (3), based on the Niementowski reaction, involved fusing anthranilic acid (1) analogues with amides (2) at 130–150 °C before going via an o-amidobenzamide intermediate (I) (Figure 6.9).

Figure 6.9: Niementowski reaction of quinazolinone synthesis: (a) MW (60 W), 20 min and (b) 130–150 °C, 6 h.

Song et al. [48] described that a one-pot, three-component condensation of isatoic anhydride (7), aryl aldehyde (4), and ammonium compounds (6) or primary amine (8) gave a variety of mono- and di-substituted 2,3-dihydroquinazolin-4(1H)-one (3), respectively in the presence of methane sulfonated aluminum in ethanol–water system. The author claimed that the method allowed isolation of an excellent product; it was a simple operation and enabled recycling of the catalysts several times (Figure 6.10). In 2018, Ziarani et al. [49] reported the synthesis of quinazolinone derivatives (3) catalyzed by sulfonic acid and functionalized by mesoporous silica (SBA-Pr-SO3H) in a one-pot three-component reaction with aromatic aldehyde (4), isatoic anhydride (7), and urea (5) (Figure 6.11). The authors noticed that the synthetic route is simple, isolated an excellent yield, and the catalysts could be recycled many times, which are the benefits of this reported method. Dabiri et al. [50] in 2010 reported the production of 4(3-substituted)-quinazolinone using the three-components reaction in a single pot, starting with simple reactants available in the market in the presence of molecular iodine catalyzed reaction of isatoic

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Figure 6.10: Synthesis of mono/disubstituted 2,3-dihydroquinazolin-4(1H)-one.

Figure 6.11: Synthesis of 2,3-dihydroquinazolin-4(1H)-one.

anhydride (7) with either ammonium acetate (6) or primary amine (8), and aryl aldehyde (4), and isolated an excellent yield of C2- and N3-substituted quinazolinone derivatives (Figure 6.12).

Figure 6.12: One-pot three-component route to 4(3H)-quinazolinone synthesis.

Wang et al. [51], in 2011, reported a condensation reaction of isatoic anhydride (7) and aldehyde (4) with ammonium salts (6) or primary amine (8) in the presence of strontium chloride in aqueous ethanol under reflux condition. A broad variety of monoand di-substituted 2,3-dihydroquinazolin-4(1H)-one (3) was produced in high yield. When compared to conventional synthesis, one-pot three-component reaction is an appealing and atom-efficient technique to build the DHQ framework. A plausible mechanism for the production of quinazolinone (3) via three-component reaction is

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depicted in Figure 6.13. The catalyst first activates isatoic anhydride (7). Then, the amine group attacks the carbonyl through nucleophile to give the intermediate (I). Next, decarboxylation takes place, producing 2-amino-N-substituted benzamide (II). The catalyst significantly contributes to increase in the electrophilic nature of the aldehyde (4) by acting as a Lewis acid. Activated aldehyde then reacts with II to give the intermediate III, which undergoes an intramolecular cyclization, resulting in product IV, and it undergoes 1,5proton transfer to give substituted 2,3-dihydro-4(1H)-quinazolinone derivative (3).

Figure 6.13: Plausible mechanism for the formation of DHQs.

Brown et al. [52] in 2018 reported the synthesis of the corresponding quinazolinone derivatives by the reaction of isatoic anhydride (7), primary amine (8), and aldehyde (4), catalyzed by CSA/DMSO or CSA/ethanol to give 2- and 3-substituted quinazolinone analogues. The authors demonstrated the mechanistic pathways of quinazolinone involved in the inhibition of Toxoplasma gondii tachyzoite reproduction in an established infection. Two of the quinazolinones were found to be potent (IC50 = 6–7 mM) against T. gondii tachyzoites of the apicomplexan parasite inhibition (Figure 6.14). Mehta et al. [53] reported L-proline-catalyzed MCRs to create a new series of quinazolin-4(3H)-one (10) derivative, containing 1,3-diphenyl-1H-pyrazol-4-yl core substituent at the 2-position, and aromatic or heteroaromatic substituents at the 3-position by a one-pot reaction of aromatic amine (8), isatoic anhydride (7), and 1-phenyl-3-aryl-1H-pyrazole-4carbaldehyde (9). Further, the authors screened the synthesized derivatives for their antibacterial, antifungal, and antitubercular activities. According to the results of the SAR in-

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Figure 6.14: MCRs of quinazolin-4(1H)-one derivative synthesis.

vestigation, it was noticed that the potency was significantly impacted by the substitution at the phenyl ring, next to the pyrazole ring (Figure 6.15). Chen et al. [54] published a onepot three-component condensation reaction of isatoic anhydride (7), aromatic aldehyde (4), and amine (8), catalyzed by dodecyl benzenesulfonic acid (DBSA) under ultrasound irradiation. This process produced 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-one derivatives (3) in 80–92% yields at 40–42 °C in 1–2 h aqueous medium. The authors claimed that the method used a gentle reaction condition, avoided organic solvent, isolated a high yield, and was environmentally friendly (Figure 6.15). Lobo et al. [55] reported acidcatalyzed MCRs of isatoic anhydride (7), aldehyde (4), and aromatic amines (8) in methanol gave quinazolin-4(1H)-one derivative (3). The authors claimed that the catalyst produced a better outcome of the product than several other reported catalysts. The authors claimed that the benefit of the catalysts were a deep eutectic inexpensive mixture of choline chloride and malonic acid, and recyclable, nontoxic, and biodegradable catalysts. Further, by this method, phenyl and heterocyclic substitution were effectively incorporated at 2,3-position of the quinazolinone (3). Zhang et al. [56] demonstrated the CeO2 nanoparticle-catalyzed MCRs of quinazolinone derivatives by the reaction of isatoic anhydride (7), benzaldehyde (4), and benzhydrazide (11). Further, the authors studied the minimum inhibitory concentration (MIC) used to investigate antifungal activity by quinazolinone derivatives, bearing acylamino motif against four phytopathogenic fungi (12) and showed dramatic impacts of the substituents on the antifungal activity. The possible antifungal mechanism of quinazolinone derivative as chitinase inhibitors was confirmed and the significance of the amide moiety was investigated. As a result, the presence of OH, 3-OCH3, 4-OH, 4-CH (CH3)2, 4N(CH3)2, styryl, 4-CHO, and iPr group sensitivity against P. capsici, C. gloeosporioides, and V. mali increased, but the activity against pyrimidine ring decreased. Notably, the addition of the hydroxy group and the 3-OCH3, 4-OH substituent had significantly increased the efficacy against P. capsici. The addition of 4-OCH3, 4-CHO, 3-pyridyl, and styryl also significantly improved the effectiveness against the R1 ring. Similar incidents involving the insertion of styryl or CH(CH3)3 to the fourth site on the ring R1 was reported against V. mali, and the authors also established docking studies (Figure 6.15). In 2021, Tamilselvi et al. [57] reported synthesis of new series of 2-(1H-indol -3-yl)-3-phenylquinazolin-4(3H)-ones (14) in methanol, catalyzed by p-TSA under reflux condition via condensation of isatoic anhydride (7), indole-3-carboxaldehyde (13), and amine (8). The Authors explained that the benefits of the approach include ease of the reaction set up, good yield, faster reaction rate, inexpensive, and not requiring any chro-

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matographic purification (Figure 6.15). Desai et al. [58] introduced a low transition temperature catalytic mixture (LTTM) made of SnCl2 and L-proline. The direct one-pot three-component cyclocondensation of isatoic anhydride (7), ammonium acetate (6), and aldehyde (4) gave 2,3-dihydroquinazolin-4(1H)-one (3) product isolation. The authors claimed that the prepared LTTM is inexpensive, green solvent, nontoxic, offered a high yield, and is recyclable (Figure 6.15). Maleki et al. [59] described an environment friendly magnetic silica-based nanocomposite (Fe3O4/SBA-15)-catalyzed three-component reaction of isotoic anhydride (7), amine derivative (8) or ammonium acetate (6), and aldehyde (4), which gave the title product (3) (Figure 6.15). Kumari et al. [60] reported in 2012 the L-proline-catalyzed one-pot synthesis of 2,3-dihydroquinazolin-4 (1H)-one (3), employing isatoic anhydride (7), ammonium acetate (6), and various substituted aldehydes (4), to give excellent product (3) isolation under mild reaction conditions (Figure 6.15). Shaterian et al. [61] described a three-component cyclocondensation of isatoic anhydride (7), primary amine (8) or ammonium salts (6), and aldehyde (4)-catalyzed Al(H2PO4)3. The authors claimed that the method developed used an efficient, affordable, solvent-free, and heterogeneous reaction to produce the corresponding quinazolinone derivatives (3) in excellent yields. This solid acidic catalyst could be easily recycled for at least three cycles without losing any reported activity (Figure 6.15). Another well documented and most frequently used synthetic route to make DHQs is employing anthranilamide (5) and an aldehyde(4) derivative via cyclocondensation to give the title product. Selected recent protocols are: Zhang et al. [62] described that the reaction of 2-aminobenzamide (5) and 4ʹ-bromoacetophenone (15) in the presence of molecular iodine in tetrahydrofuran solvent at 323 K for 6 h gave the title product in excellent yield. The authors also reported that a solid structure of the compound 2-(4-bromophenyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one (17) in slowly evaporating DMF solution resulted in a crystal appropriate for X-ray diffraction (Figure 6.16). Watson et al. [63] in 2011 described the successful employment of rutheniumcatalyzed hydrogen transfer reaction to convert alcohols (18) and anthranilamide (5) into 2,3-dihydroquinazolinone (3) (Figure 6.16). Narasimhamurthy et al. [64] reported that the reaction of 2-aminobenzamide (5) with gem-dibromomethylarene (19) in the presence of t-BuOK and pyridine-DMF reflux condition gave 2,3-dihydroquinazolin-4 (1H)-one (3) (Figure 6.16). Obaiah et al. [65] described cyclocondensation of 2-amino benzamide (5) with an aldehyde (4), which yielded 2,3-dihydroquinazoline-4(1H)-one (3) in basic ionic liquid. Desai et al. [58] reported a one-pot two-component cyclocondensation of anthranilamide (5) and substituted aldehyde (4) in the presence of low transition temperature mixture (LTTM, SnCl2, and L-proline) to give 2,3-dihydroquinazolin-4(1H)ones (3) in high yield (Figure 6.16). Zhang et al. [66] described microwave-assisted ironcatalyzed cyclization with or without ligand in water (methods A and B) or DMF offered a faster, efficient, and environmentally friendly way to make quinazolinone derivatives from substituted 2-halobenzoic acids (21) and amidines (20). The authors claimed that this was the first report on the iron-catalyzed C–N coupling role in the synthesis of

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Figure 6.15: MCRs of quinazolinone derivative synthesis by various catalysts.

N-heterocyclic compounds in aqueous condition, which gave moderate to high yield of the desired products (Figure 6.16). Starting with nitro derivatives, Dou et al. [67] reported facile synthesis of a series of quinazolinone derivatives, such as imidazole[1,2-c]quinazolin-5-amine (25), benzimidazole[1,2-c]quinazolin-5-amine (27) and 2-thioxoquinazolinones (29). The reaction involved a crucial cyclization process catalyzed by TiCl4/Zn via the reaction of 2-(2nitrophenyl) benzimidazole (26) and isothiocyanate (22) in anhydrous THF, leading to moderate to good yields of benzimidazo[1,2-c] quinazolin-5-amine (27). The reaction of (23) and 2-(2-nitrophenyl)-imidazole (24) under the same optimized reaction conditions gave imidazole[1,2-c]quinazolin-5-amine (25), and the reaction of N-(3-chloro-4methylphenyl)-2-nitrobenzamide (28) and (p-methyl)phenyl isothiocyanate (23) gave 2-thioxoquinazolinone (29) in the presence of titanium catalyst at 60 °C (Figure 6.17). Murthy et al. [68] in 2016 reported a straightforward procedure for the synthesis of tetracyclic quinazolinone derivatives (31) from isatoic anhydride (7), amine (8), and ninhydrin (30) in dioxane in the presence of a mineral acid at 90–100 °C (Figure 6.18).

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Figure 6.16: Synthesis of DHQ using anthranilamide and another substrate.

Puligoundla et al. [69] reported the synthesis of numerous quinazolinone derivatives, such as 3,3-dimethyl-12-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin-1 (2H)-ones (34) or 3,3-dimethyl-12-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin-1(2H)-ones (36) via the condensation reaction between aromatic aldehydes (4), dimedone (33), and 3-amino-1,2,4-triazole (32) or 2-aminobenzimidazole (35), respectively under reflux conditions in the presence of 10 mol% molecular iodine in acetonitrile (Figure 6.19). Gajaganti et al. [70] described a solvent-free method for the synthesis of benzimidazolo/benzothiazolo quinazolinone derivatives (39) by the one-pot reaction of 2-aminobenzimidazole/2-aminobenzothiazole (37), aromatic aldehyde (4), and 1,3-diketone (38)catalyzed scandium triflate under microwave irradiation. The authors claimed the protocol offers many advantages, including excellent yield isolation, faster reaction time, and simple method, and was environmentally friendly (Figure 6.20). Hakimelahi and Mousazadeh [71] reported the direct application of zinc oxide nanotube as a recyclable catalyst for the condensation of isatoic anhydride (7), ammonium acetate (6), and aryl aldehyde (4) to give 2,3-dihydroquinazolin-4(1H)-one deriv-

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Figure 6.17: Synthesis of quinazolinone derivatives.

Figure 6.18: Fused quinazoline-based tetracyclic compound synthesis.

atives (3). The authors claimed the advantages of this method to be simple, recycling of the catalyst, efficient and straightforward procedure to isolate unbeatable yields of the 2,3-dihydroquinazolin-4(1H)-one derivatives (Figure 6.21).

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Figure 6.19: One-pot synthesis of quinazolinone derivatives, 34 and 36.

Figure 6.20: Synthesis of benzimidazolo/benzothiazolo quinazolinone.

Figure 6.21: MCRs of ZnO nanotube-catalyzed reaction.

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Mousavi and Maghsoodlou [72] reported the one-pot cyclocondensation of aromatic aldehyde (4) and dimedone (33) with 3-amino-1,2,4-triazole (32) or 2-aminobenzimidazole (34) in the presence of nano-SiO2 in acetonitrile at room temperature to give a high yield of the product (34 & 36). The authors highlighted that the nano-SiO2 employed in this process is reusable and environmentally friendly, and the reaction is easy to set up (Figure 6.22).

Figure 6.22: NanoSiO2-catalyzed triazoloquinazolinone and benzimidazoquinazolinone derivatives.

Liu et al. [73] reported the reaction of substituted isatin (40) and 2-bromopyridine derivative (37) enabled faster formation of the 1H-pyrido[2,1-b]quinazolin-11-one (41)catalyzed Cu(OAc)2·H2O at high temperature. Further, the authors employed the same condition for the reaction of 2-amino-5-methylbenzoic acid (38) with 2-bromopyridine derivative (37) to give pyrido-fused quinazolinone derivative (39) and noticed that one-pot C–N/C–C bond cleavage and two C–N bond construction take place in the construction of the molecule (Figure 6.23). Elkholy et al. [74] studied the reaction of 2-(6-iodo-4-oxo-4H-benzo[d][1,3]oxazin-2-yl) benzoic acid (43) with an organic base such as p-aminoacetophenone (44), p-anisidine (46), glycine (48), and hydrazine hydrate (50) at 65 °C for 15 min to give four quinazolinone derivatives (45, 47, 49, and 51). The authors confirmed these derivatives by spectroscopic analysis and studied the application to enhance the resistance of lubricating oils to wear and oil oxidation. Lubricating oils are crucial for preserving the overall performance of the automobile industries and ensuring smooth operation of engine components. Such oils consist of a base oil made primarily from crude oil and certain boosting

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Figure 6.23: Pyrido-fused quinazolinone derivative synthesis.

additives, including antioxidants and wear additives. The authors further elucidated the tribological and antioxidation performance of the developed compounds by molecular dynamic simulations to mimic the adsorption orientations of these compounds (Figure 6.24).

Figure 6.24: Synthesis of quinazolinone derivatives for oil antioxidation agents.

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Angulwar et al. [75] demonstrated an efficient synthesis of thiadiazolo[2,3-b]quinazolinone derivatives in a single-pot reaction of 5-aryl-1,3,4-thiadiazolo-2amine (52), dimedone (33), and substituted aromatic aldehyde (4) in the presence of molecular iodine (10 mol%). The authors claimed that the protocol is simple to operate and isolated excellent yield. Further, the authors tested the antibacterial activity of these derivatives and showed a comparable activity (Figure 6.25).

Figure 6.25: MCRs of thiadiazolo[2,3-b]quinazoline-6-(7H)-one synthesis.

Lan et al. [76] described the functionalized quinazolinone derivatives (55, 56, and 57) through tandem hydrolysis, decarboxylation, cyclization, and transesterification reaction with a variety of 2-aminobenzamide (5) and dicarbonyl compounds (54) to achieve a new biocatalyzed technique. The authors claimed strong catalytic activity, excellent yields, exceptional chemoselectivity, and wide range of substrate tolerance by this method. Most importantly, it provides fresh illustration of easy, practical, and sustainable synthetic techniques using enzyme catalysis in organic synthesis (Figure 6.26). Dige et al. [77] in 2019 reported the synthesis of new 4-oxoquinazolin-3(4H)-yl) furan-2-carboxamide derivatives (59) by the reaction of isatoic anhydride (7), 2-furoic hydrazide (58), and substituted salicylaldehyde (4) in ethanol–water (5:5 v/v) solvent system using p-TSA as a catalyst, under ultrasound irradiation at room temperature. The authors explained that the use of ultrasound enables an easy and straightforward reaction to be carried out at room temperature, and that it isolated high yield of the oxoquinazolin-3(4H)-yl) furan-2-carboxamide (59). The authors tested synthesized compounds against tyrosinase enzyme, and all of them showed powerful inhibitors, with IC50 being lower than the reference kojic acid (16.832–1.162 M) of 0.028–0.016 to 1.775–0.947 M. Lineweaver-Burk plots were used to study the kinetics of the compound and results showed that the compound inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. Additionally, the capacity of the derivative (59) to scavenge DPPH-free radicals was examined by both in vitro and in silico analysis, which are consistent with one another, with the ligands posing an acceptable binding energy (kcal/mol) (Figure 6.27). Hassankhani [78] in 2018 reported the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivative (3), employing improved MCRs under solvent-free reaction of isatoic anhydride (4), aromatic aldehyde (2), and ammonium acetate (5) in SnCl2 dihydrate at 110 °C. The authors claimed this method has a number of benefits, including being inexpensive,

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Figure 6.26: Enzymatic route for producing functionalized quinazolinone derivatives.

Figure 6.27: Synthesis of new 4-oxoquinazolin-3(4H)-yl) furan-2-carboxamides.

simple, created a mild reaction condition, showed a faster reaction rate, offered excellent yields, and resulted in a wide range of substituted products (Figure 6.28). Ziarani et al. [79] in 2017 demonstrated a simple sol–gel autocombustion, created by nanomagnetic SrFe12O19, and examined various techniques for its characterization. Further, the authors demonstrated catalytic activity, used the modified Niementowski reaction for the first time, and showed an efficient and environmentally friendly reaction, with an excellent yield of quinazolinone product (60) isolation by the reaction of isotoic anhydride (7), phenylhydrazine (11) and 2-nitrobenzaldehyde (4). The authors reported that by using an external magnet, the nanomagnetic catalyst was separated

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Figure 6.28: Preparation of 2,3-dihydroquinazolin-4(1H)-ones.

from the reaction mixture and the catalysts were reusable; these are the noticeable benefits of this method (Figure 6.29).

Figure 6.29: Nanomagnetic-catalyzed quinazolinone derivative synthesis.

Tajbakhsh et al. [80] in 2013 reported a one-pot three-component reaction of isatoic anhydride (7), cyclic ketone (62), and hydrazide (61) in the presence of a catalytic quantity (20 mol%) of H3PO3 in ethanol, and isolated numerous spiroquinazolinone derivatives (63). The authors claimed the benefits of the protocol include mild reaction condition, high atom economy, operational simplicity, and isolation in excellent yield (Figure 6.30).

Figure 6.30: Preparation of spiroquinazolines.

Chate et al. [81] in 2019 reported a facile and efficient one-pot preparation of spiro oxindole dihydro quinazolinone derivatives, 3ʹ-phenyl-1ʹH-spiro[indoline-3,2ʹ-quinazoline]2,4ʹ(3ʹH)-diones (64) and N-(4-oxo-2-phenyl-1,2-dihydroquinazolin-3(4H)-yl)isonicotinamide derivatives (66) by the reaction of isatoic anhydride (7), isoniazid (65), and isatine (40) or substituted aldehyde (4), catalyzed by 2-aminoethanesulfonic acid (taurine). The authors claimed that the benefits of this organocatalyzed reaction were that it gives ex-

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cellent yield, is easy to operate, and is environmental friendly. Water serves as an environmentally friendly solvent, nontoxic catalysts can be reused effectively, and the final product does not require column chromatographic purification – these are the noteworthy features noticed by the authors (Figure 6.31).

Figure 6.31: Synthesis of spirooxindole dihydroquinazolinone derivatives.

Palaniraja and Roopan [82] in 2015 reported the synthesis of some unknown imidazolo-quninazolinone derivatives (69) via MCRs of 2-fluorobenzonitrile (67) and hydrazine (50) refluxed for 30 min in ethanol, followed by the addition of benzaldehyde (4), and diketone (68) in the presence of iodine (20% in acetonitrile), to isolate 7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (69) (Figure 6.32).

Figure 6.32: Iodine-catalyzed indazolo-quinazolinone synthesis.

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Giri et al. [83] in 2010 described small library of 2-thiazole-5-yl-3H-quinazolin-4-one derivatives (75) by the reaction of thiourea derivative (71) with an appropriate 2-chloromethyl-3-aryl-3H-quinazolin-4-one (70) in acetonitrile, agitated at 75–80 °C. The authors created small-molecule multipathway inhibitors that could be used to treat cancerous condition, factors known to play a crucial role in the onset and development of cancer. The synthetic compounds were tested as inhibitors of NF-kB and AP-1-mediated transcriptional activation and eIF-4E-mediated translational activation. The study findings point to the 2-thiazole-5-yl-3H-quinazolin-4-one (75) scaffold as a useful building block for the development of new multi-pathway inhibitors that can be tested as anticancer drugs (Figure 6.33).

Figure 6.33: Synthesis of 2-thiazole-5-yl-3H-quinazolin-4-one derivatives with mechanism.

Sawant et al. [84] in 2012 produced the crucially important purine quinazolinone scaffold (81 and 82) using a multicomponent microwave-assisted one-pot synthetic method. At 0 °C, the reaction between 2-chloroacetyl chloride (77) and 6-methyl-2-amino benzoic acid (76) produced 2-(2-chloroacetamido)-6-methylbenzoic acid as a crystalline product (78). To this, 2-methyl aniline (79) was added, in the presence of PCl3 as a cyclizing agent, to create an intermediate product, 2-(chloromethyl)-5-methyl-3-o-tolylquinazolin4(3H)-one (80). Finally, this intermediate (80) was condensed with adenine in basic condition under MWI to isolate the target products. The authors compared these derivatives with structural analogues of the PI3K-d inhibitors, IC-87114 and CAL-101, which are being tested in clinical trials for chronic lymphocytic leukemia (Figure 6.34). Bakhshali-Dehkordi et al. [85] in 2020 reported one-pot multicomponent reactions of 3-amino-1,2,4-triazole or 2-aminobenzimidazole (32), dimedone (33), and aromatic aldehyde (4) in the presence of TiO2@ILs as an effective nanocatalyst, and isolated

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Figure 6.34: Microwave irradiation synthesis of purine quinazolinone derivatives.

3,3-dimethyl-12-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin-1(2H)ones (34) and 3-dimethyl-12-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin-1(2H)-ones (36). Additionally, beetroot juice extract was used to make the TiO2 NPs, and they were functionalized utilizing ILs, based on imidazole. Additionally, this ionic liquid demonstrated its potential as a reliable nanocatalyst activator and protector (Figure 6.35).

Figure 6.35: Nano-TiO2@IL-catalyzed synthesis of triazoloquinazolinone and benzimidazoquinazolinone derivatives.

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Kumar et al. [86] in 2023 demonstrated the efficient synthesis of substituted quinazolinone and spiroquinazolinone heterocycles via mixed surfactant-mediated organocatalyzed (L-proline) method by the reaction of isatin (40) and aldehyde (4) with aniline (8) and isatoicanhydride (7). The authors claimed that the procedure developed is extremely efficient and environmentally benign, with water as a medium, room temperature reaction, high yield, and simplicity of purification (Figure 6.36).

Figure 6.36: MCRs of quinazolinone (3) and spiroquinazolinone (64) synthesis.

Xu et al. [87] in 2022 described Ugi four-component reaction (Ugi-4CR)-based protocols used to quickly synthesize various substituted polycyclic quinazolinones. The first protocol involved an ammonia-Ugi-4CR, followed by a palladium-catalyzed annulation. The second method involved a novel use of cyanimide as an amine component in Ugi-4CR and an AIBN/tributyltin hydride-induced radical reaction in MeOH/H2O (3:1) at room temperature for 12 h. The reactions of 2-bromobenzoic acid (84) or benzoic acid (88), 2-cyanobenzaldehyde (83) or 2-idobenzaldehyde (89), cyclohexyl isocyanide (86), and NH4Cl (85) gave the product (87) (Figure 6.37).

Figure 6.37: Synthesis of polycyclic quinazolinones.

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Dawoud [88] in 2012 reported the synthesis of 8-(substituted arylidene)-4-(substituted phenyl) quinazoline-2-(1H)-one (92) using a Biginelli one-pot three-component reaction of cyclohexanone (90), aromatic/or heterocyclic aldehyde (4), and urea or thiourea or guanidine HCl (91) under MWI. The authors claimed that the method developed has operational simplicity, faster reaction rate, and environmental friendliness as the benefits (Figure 6.38).

Figure 6.38: Synthesis of quinazolin-2(1H)-one derivative.

Zeydi and Ghorbani [89] in 2020 reported the solvent-free reaction of 2-aminobenzimidazole (35), benzaldehydes (4), and dimedone (33) catalyzed by γ-Fe2O3@KSF gave tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one (36). The authors prepared a magnetic catalyst by covering a γ-Fe2O3 layer on a KSF core, and demonstrated application in tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one synthesis, and isolated 94% yield. The authors claimed that the benefits of this method were solvent-free reaction, faster reaction rate, excellent yield, and reuse of catalysts using an external magnet four times, without seeing a significant decrease in activity (Figure 6.39).

Figure 6.39: Tetrahydrobenzimidazo[2,1-b]quinazolin-1(2H)-one synthesis.

Beerappa et al. [90] reported via cascade oxidation, Knoevenagel condensation, and Michael addition, followed by cyclization and dehydration, a highly efficient one-pot method to create triazolo/benzimidazolo quinazolinone (95) in the presence of trimethyl amine N-oxide in ethanol by readily accessible benzyl halide (94), 2-amino benzimidazole/3-amino-1,2,4-triazole (35), and 1,3-dicarbonyl compound (93). The author claimed that this is the first instance of the direct synthesis of triazolo/benzimidazolo quinazolinone (95) from benzyl halide (94) in a single pot. The appealing aspects

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of this approach are its straightforward process, environmental friendliness, mild reaction condition, and good yield (Figure 6.40).

Figure 6.40: Synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone.

Rai et al. [91] reported the reaction of 2-(2-halophenyl)benzaimidazole (96), aldehyde (4), and sodium azide (97) as nitrogen source in the presence of copper-mediated aerobic oxidative multicomponent synthesis of benzimidazo[1,2-c]quinazoline (98). The authors noticed that in this protocol three C–N bonds are formed by first azidating haloaryl with sodium azide and then converting azide in-situ into arylamine. It was then condensed with benzaldehyde and subjected to oxidative cyclization to give benzimidazo[1,2-c]quinazoline in excellent yield (Figure 6.41).

Figure 6.41: MCRs of benzimidazo-fused quinazoline synthesis.

Potuganti et al. [92] reported starting with 2-(2-bromophenyl)quinazolin-4(3H)-one (99), aryl aldehyde (4) and different nitrogen sources (97 or 100) under aerobic conditions in one-pot isolated quinazolino[4,3-b]quinazoline derivatives (101). The authors explained that the mechanistic amination of 2-(2-bromophenyl)quinazolin-4(3H)one condensation with the aldehyde and oxidative cyclization, mediated by copper(I) salt, produced the target product in good yield (Figure 6.42).

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Figure 6.42: Multicomponent synthesis of tetracyclic quinazolino[4,3-b]quinazolines.

6.4 Conclusion Quinazolinone is a privileged skeleton extensively found in various pharmacological applications. The scaffold is capable of binding with high affinity at multiple sites on the target site, which facilitates more rapid discovery of medicinally active quinazolinone derivatives. Hydrochloride salts of prazosin, alfuzosine, and terazosine, and doxazosine mesylate-containing quinazolinone are medically approved drugs in the market. Erlotinib and Gefitinib (Iressa®) are derivatives of quinazolinone available in the market as anticancer agents. Researcher reported SARs studies of quinazolinone ring substituents at positions 2 and 3, existence of halogen atom at 6 and 8 positions, and substituents mainly amine or substituted amines at the fourth position which can improve antimicrobial activities. Also, the presence of substituted aromatic ring at position 3 and methyl or thiol group at position 2 are essential for antimicrobial activities. The examples provided above illustrate how innovative synthetic techniques such as MCRs and microwave-assisted synthesis are constantly being developed and are employed to create various quinazolinone analogues. A variety of quinazolinone derivatives showed promising cytotoxic activity of cell lines such as HT29, and HeLa, L1210. Across the globe, numerous research groups have proposed anticancer mechanistic pathways by quinazolinone derivatives, which include: (1) inhibition of EGFR, (2), DNA repair enzyme inhibition system, (3) tubulin polymerase inhibitory effects, and (4) thymidylate enzyme inhibition. There is strong hope in the future investigation of quinazolinone-conjugated bioactive molecules and other modifications to yield some more encouraging results in the field of medicinal chemistry. Researchers have revealed numerous examples of various substituents at different positions having different activities. The different structural alterations surrounding the fused ring of quinazolinone are then assessed for their applicability in the management of various disease conditions. Since quinazolinone is the pharmacophore’s main structural component, it can accommodate various substituents. It has a wide range of therapeutic efficacy, based on its different physicochemical properties. Therefore, this skeleton has promising scope in pharmaceutical, clinical research, and diagnostic treatments, in the present and in the future. This chapter has focused on the recent MCRs developed on quinazolinone derivatives. Around 35 schemes reported by researchers

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across the globe are discussed and the importance of quinazolinone skeleton towards pharmacological and other applications is outlined.

Abbreviations % ℃ δ )))) µL µg DES DHQ Fe3O4 DMSO DPPH EtOH h MWI min MTT MCF MCRs RT SAR scPTZ TLC Ts [Bmim]BF4 [bmim]OH

Percentage Degree Celsius Delta Ultrasound Microliter Microgram Deep eutectic solvents. 2,3-Dihydroquinazolinone. Iron(III) oxide Deuterated dimethyl sulfoxide Diphenylpicrylhydrazyl Ethanol Hour Microwave irradiation Minute (3-(4,5-Dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) Michigan Cancer Foundation Multicomponent reactions Room temperature Structure–activity relationship Subcutaneous pentylenetetrazole Thin-layer chromatography Tosyl Butyl-3-methylimidazolium tetrafluoroborate Butyl-3-methylimidazolium hydroxide

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Sujit Ghosh, Basudeb Basu✶

7 Recent approaches toward the synthesis of 1,2,3-triazoles using multicomponent techniques 7.1 Introduction Triazoles are the five-membered heterocyclic compounds with three nitrogen and two carbon atoms in the ring having molecular formula C2N3H3. The atomic percentage of nitrogen in 1,2,3-triazole is about 60%, indicating the importance of hetero scaffold in the field of organic chemistry. Depending upon the position of nitrogen atoms in the ring they are divided into two isomers: (i) 1,2,3-triazole and (ii) 1,2,4-triaozle [1]. When three N atoms placed in successive position then it is called 1,2,3-triazole or 1H-1,2,3triazole. Again disubstituted 1,2,3-triazoles have three isomers (i) 1,4-, (ii) 1,5-, (iii) 4,5-; and trisubstituted triazoles have only one isomer, that is, 1,4,5 (Figure 7.1). In this chapter, we have discussed the recent literature on the synthetic approaches toward 1,2,3triazoles using multicomponent techniques, their mechanistic insights, and outlook.

R

4

3N

5R 1

4

NH

3N

N 2

(4,5)

N

Triazole (m.f. C2N3H3)

5R 1

R

N R

3N

5 1

4

N

N R

Disubstituted isomer

2

2

(1,5)

(1,4) R

5

4

R 1

3N

N

N R

Trisubstituted isomer

3N

4

5 1

4

N

NH

2

1,2,3-triazole

5 1

N 3

N

NH

2

1,2,4-triazole

2

(1,4,5)

Figure 7.1: Triazole and its various isomers.

The 1,3-dipolar cycloaddition [2], between alkyne and azide, is known as azide–alkyne cycloaddition, commonly called AAC reaction [3]. In 1910, the German chemists, Otto Dim-

✶

Corresponding author: Basudeb Basu, Former Professor, Department of Chemistry, North Bengal University, Darjeeling, West Bengal, India, e-mail: [email protected] Sujit Ghosh, Department of Chemistry, Raiganj Surendranath Mahavidyalaya, Raiganj, West Bengal, India https://doi.org/10.1515/9783110985313-007

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roth and Gustav Fester first synthesized 1H-1,2,3-triazole by heating a mixture of alcoholic solution of hydrazoic acid (HN3) and acetone solution of acetylene at 100 °C for 70 h [4]. The same compound was synthesized later with NaN3 in acid solution instead of taking HN3 (Figure 7.2) [5]. Based on this basic reaction route, the terminal alkyne reacts with alkyl azide resulting in the formation of two possible regioisomers, viz. 1,4-disubstituted 1,2,3-triazole and 1,5-disubstituted 1,2,3-triazole (Figure 7.2). Again, when an internal alkyne (both symmetrical or unsymmetrical) reacts with alkyl azide, a single isomer of 1,4,5-trisubstituted triazole is obtained. On the other hand, the use of HN3 instead of alkyl azide affords only 4,5-disubstituted 1,2,3-triazole derivative (Figure 7.3). 1,3-dipolar cycloaddition 3

H + H

N N N

4

H

N N2

5

H

Hydrazoic acid

N1 H

1H-1,2-3-triazole

+ H

N N N Na

Sodium azide

Figure 7.2: First synthesis of 1H-1,2,3-triazole by cycloaddition reaction with HN3 or NaN3.

Figure 7.3: Synthesis of various disubstituted and trisubstituted 1,2,3-triazoles.

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The American chemist K. B. Sharpless has been awarded his second time Nobel prize in Chemistry in 2022 [5], together with Carolyn Bertozzi and Morten Meldal, for their achievement in “click chemistry” along with bio-orthogonal chemistry [6]. This click reaction was a benchmark and unparallel achievement in the field of triazole synthesis. It is unescapable to mention also that he had received first Nobel Prize earlier in 2002 for another breakthrough, that is, chiral oxidation of alcohol [7]. The term “click” is however not limited to only triazole synthesis, and there are plenty of different click reactions also well documented in the literature [8]. An access toward the synthesis of various derivatives of 1,2,3-triazole by “click protocol” comprehensively exposed the field of pharmaceutical chemistry in last two decades. The term “click” was also first coined by K. Barry Sharpless, in 1998. Later it was described by Sharpless, Hartmuth C. Kolb, and M.G. Finn of the Scripps Research Institute in 2001 [9–11]. Essentially, it is a set of methods for constructing chemical compounds from small molecule, the pioneer work was first started in 2002 where both scientists (Sharpless and Meldal) independently developed copper(I)-catalyzed AAC (CuAAC) reaction. While the CuAAC produces triazoles of 1,4-regiosomer, the other transition metal (ruthenium)-based catalysts gives rise to the selective formation of 1,5-regioisomers, often called as RuAAC reaction procedure [1, 12–16]. Two types of mechanism had already been established for the AAC reaction: (i) via five-member metal-triazolyl ring intermediate; (ii) via both six- as well as five-membered ring intermediate. Both of these mechanisms have been highlighted in this chapter. The 1,2,3-triazoles find their diverse applications not only in pharmaceutical field but also in numerous other fields. Promisingly bioactive and recently synthesized a few triazole scaffolds are depicted in Figure 7.4 [17–20]. In every research or review literatures or in many books or book chapters related to triazole or AAC reaction, countless applications are already crusted. Still the researchers are trying to design structurally diverse many triazole conjugates and/or triazole-tethered heterocyclic molecules with the aim to tuning their bioactivity and applications to new medicinal fields. At present, any synthetic attempt without concerning environmental fates or sustainable development [21] will not be tolerable according to the green chemistry point of view. It is therefore very imperative to design a chemical reaction without using hazardous or explosive substrates. Organyl azides are potentially explosive in nature [22] and not safe for handling. They are better stored at low temperature (−18 °C) and in the dark. Additionally, small molecules containing the azido functionality tend to decompose violently which may result in injury if proper safety precautions are not maintained [22]. Therefore, twocomponent approach of 1,2,3-triazole synthesis via AAC reaction is not a good choice, but in situ generation of organic azide from any of its precursor and NaN3 represents a more viable process. Therefore, multicomponent approach particularly avoiding the direct use of alkyl azide is considered as a green technique toward the formation of triazole derivatives.

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Cl

NH2

N N N

H N

S

O

N

O COOH MeO

N N H

antibacterial agent

anticancer agent

Cl H N N O

O O

N

N N N OH

anti-TB agent

Me

O

HOOC

N N

N

N

NH2

Me

antiinfluenza activity

Figure 7.4: Some representative examples of bioactive 1,2,3-triazoles.

A multicomponent reaction (or MCR) [23], or alternatively called “multicomponent assembly process” (or MCAP), is a chemical reaction where three or more components in one-pot react to form a single product. MCRs have attained considerable interests owing to offering greater potentials in synthetic strategies minimizing time, effort, work-up steps, and waste generation. Because of these factors MCRs are often applied in drug discovery and drug designing. The exact nature of this type of reaction is often difficult to assess as there is much less probability for the interaction among three or more different molecules resulting in a low reaction rate. It is believed that the reactions are more likely to involve consecutive bimolecular reactions where two reactants combine in a sequential manner to give highly selective products that retain majority of the atoms of the starting material. It is thus a step-economic process, which does not require unnecessary separation, isolation, and purification process. Multicomponent reactions have been known for more than 100 years. The first MCR was reported by Laurent and Gerhardt in 1838 [24], and the first documented MCR was the Strecker synthesis of α-amino nitrile in 1850 from which α-amino acids was derived [25]. A few common and widely used examples of MCRs are Biginelli, Mannich, Hantzsch, A3coupling, isocyanide-based MCRs like three-component Passerini, four-component Ugi reaction, etc. [26–28] Other MCRs include (i) free-radical-initiated MCRs, (ii) MCRs based on organoboron compounds, and (iii) metal-catalyzed MCRs [29–32]. Since last two decades adequate number of 1,2,3-triazoles were synthesized by click or AAC process involving copper and other metal catalyst (Rh, Ru, Ir, Zn, Ag, Au) both via two-component [33–40] and three-component approaches [41–50]. In this chapter, we have focused on some recent protocols of triazole synthesis by various multicomponent approaches (mostly covering during the last five years).

7 Recent approaches toward the synthesis of 1,2,3-triazoles

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Methodologies described herein include both click reaction (with Cu, Ni, Zn Mn, Ru metal-based homogeneous, and heterogeneous catalyst) and some non-click reactions (both 3CR and 4CR) under metal, metal-free, and mostly by green shell. In many reports almost similar strategies were taken to synthesize triazole compounds. As the click reaction is more commonly attempted by the researchers to check the efficiency of many newly synthesized or as-prepared catalysts, we have searched out some divergent reactions that give the access of many triazole derivatives. Special emphasis is given on the various types of catalyst preparation and detailed mechanistic interpretation. Some fascinating AAC reactions [51–55] (not shown here) are also found in the literature, while preparing for this chapter. Some renewable and eco-friendly resources are also used as the catalyst for the triazole synthesis viz., fish bone waste, graphene oxide, nano-biocatalyst, etc. [56–59].

7.2 The 1,2,3-triazole synthesis by three-component reaction The 1,2,3-triazoles are best constructed by click reaction as discussed earlier in the introduction. Though the click reaction involves alkyl azide as the reacting partner, its explosive nature prefers in situ preparation from the reaction between alkyl halide and sodium azide. That is why the click reaction by three-component approach is not only a step economy method but also it circumvents direct use of handling hazardous alkyl azide. Apart from the click reaction there are some other multicomponent approaches (both three-component and four-component) in the literature, which have been reported in last few years [76–95].

7.2.1 Three-component coupling among alkyl halide, terminal alkyne, and sodium azide One of the most common approaches for the synthesis of substituted 1,2,3-triazole derivatives is the multicomponent click reaction among alkyl halide or mostly aralkyl halide, terminal alkyne and sodium azide. There are many review articles and book chapters that have shown triazole synthesis. A few among them have showed two-component approach, which is direct AAC reaction between alkyl azide and alkyne. Here, we have discussed the multicomponent approach mostly disclosed in 2017 onward and noticed that some metals like nickel, manganese, ruthenium salts, or complexes have been used as the catalyst in addition to frequently used copper catalyst (Figure 7.5). Magnetic NiFe2O4-supported glutamate-copper(0) catalyst (Figure 7.6) has been found to be a very effective heterogeneous catalyst for the synthesis of a wide variety of 1,4-disubstituted-1,2,3-triazoles via one-pot three-component click reactions of substituted

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Mn catalyst

1,2,3-triazole synthesis (Recent past)

Cu catalyst

Ni catalyst

Ru catalyst

Zn catalyst

Figure 7.5: Involvement of various metal catalysts in the synthesis of 1,2,3-triazoles under this chapter.

benzyl chloride, terminal alkyne, and sodium azide (Figure 7.7) [60]. 1,4-Disubstituted 1,2,3-triazoles were obtained with good-to-excellent yield. More importantly the coupling took place under ambient condition in water. Due to magnetic nature the heterogeneous catalyst it was easily separated simply by using an external magnet and recycled even up to 10th cycle with a very slight decrease in product yield (run 1: 96% vs run 10: 88%). Cu NH2 O

HO

O O

O

O

O

O

O

OH NH2 Cu

HO Cu

O NH2 NiFe2O4-glutamate-Cu(0)

Figure 7.6: Structure of magnetic NiFe2O4-supported glutamate-copper(0) catalyst.

R

Cl +

(1 equiv.) R = 4-Me, 4-Br

R' (1 equiv.)

+ NaN3

NiFe2O4-glutamate-Cu (1 mol%)

(1.1 equiv.)

H2O, RT, 4-8.5 h

R

N N N

R'

50-90%

R' = Ph, p-Tol, 4-Br-C6H4

Figure 7.7: Synthesis of 1,2,3-triazole by three-component coupling among benzyl chloride, terminal alkyne, and sodium azide catalyzed by NiFe2O4-glutamate-Cu(0).

Another example of heterogeneous copper catalyst is Cu2O@ARF (Figure 7.8) as prepared from our laboratory in 2017 and applied for multicomponent click reaction (Figure 7.9) by green procedure under aqueous and aerobic conditions [61]. We had successfully immobilized stabilized Cu2O nanoparticles (NPs) on amberlite resin formate (ARF) [62] under its polyionic polar environment. The oxidation state of metal, that is, Cu(I), in the catalyst

7 Recent approaches toward the synthesis of 1,2,3-triazoles

259

composite [Cu2O@ARF] was ascertained by FT-IR, XRD, XPS, and HR-TEM and metal content (10.8 mg copper per gram of the resin composite) in the catalyst matrix was determined by ICP-AES. The formate counterion (HCOO−) was responsible to reduce the precursor Cu(II) ion to Cu(I) and stabilize Cu2O NPs. The significantly high TOF (219 h−1) and recyclability (up to fourth run) of the catalyst corroborates for the high catalytic activity of Cu2O@ARF. The proposed mechanism of the reaction (Figure 7.10) was believed to pass through the (i) formation of alkynyl copper intermediate from alkyne in presence of Cu(I)system of Cu2O@ARF, (ii) cycloaddition with alkyl azide (formed in situ from alkyl halide and sodium azide) to form the intermediate Cu-triazole intermediate, and (iii) finally protonation of C–Cu bond to afford the triazole product.

Cu2O NPs m

n

O

NMe3

Cu2O@ARF

H O

Figure 7.8: Schematic structure of Cu2O@ARF.

R

X

+

H R' (1.2 mmol)

(1 mmol)

R = aryl, styrenyl, vinyl

NaN3

+

(1.5 mmol)

R' = aryl, alkyl

Cu2O@ARF (25 mg), SDS (0.1 mmol) H2O, RT, 1-8 h

R

N N N

R'

68-91 %

X = Cl, Br, I

Figure 7.9: Synthesis of 1,2,3-triazole by using Cu2O@ARF.

Cu2O@ARF R'

R'

H

H

R'

Cu2O@ARF R

N N N

R H

H2O

N N N

Cu

Cu

RCH2N3

RCH2X + NaN3

Figure 7.10: Proposed mechanism of the three-component click reaction using Cu2O@ARF.

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Sujit Ghosh, Basudeb Basu

Another example of multicomponent click reaction by Cu2O NPs was reported by Peddiahgari and coworkers [63], where the stabilizing agent was hydrogen tritinate nanotube (HTNT). The Cu2O-doped HTNTs were synthesized by impregnation method taking HTNTs and Cu(NO3)2·3H2O. Hydrogen trititanate nanotubes were prepared via a hydrothermal reaction method taking TiO2 and NaOH solution. This catalyst thus prepared was abbreviated as Cu2O/HTNT-7 (here 7 indicates that 7 wt% Cu loaded in the Cu2O/HTNT-7) indicates 7% Cu loaded which worked well under aqueous environment under ambient reaction condition. They used both alkyl halide as well alkyl sulfonate as azide precursor to synthesize 1,2,3-triazole derivatives (Figure 7.11).

Figure 7.11: Multicomponent click reaction catalyzed by Cu2O/HTNT-7.

Rai et al. [64] in 2019 also synthesized Cu2O NPs from Cu(II) salts by employing rice (Oryza sativa) as a cheap and ready source of reducing as well as stabilizing agent (Figure 7.12). Initially acidic hydrolysis of starch results aldohexose sugar (glucose) which reduces Cu2+ ion to produce Cu2O NPs of approximately 10 nm size. The formed NPs do not get agglomerated in the presence of rice and thus it become stable to carry out organic reaction, under aqueous environment. AAC reaction was thus successful under base free condition via one-pot multicomponent click reaction to yield mono-, bis-, and tris-1,2,3-triazoles in good-to-excellent yields (Figure 7.13). The substrate variation has also extended to terminal alkyne compounds, both 1,2- and 1,3-isomers of diethynylbenzene (Figure 7.14).

Starch (Rice)

100 oC +

H3O

CuSO4.5H2O Monosachharide Cu2O NPs + Sodium gluconate (Glucose, Mannose) aq. NaOH

Figure 7.12: Synthesis of Cu2O NPs from starch.

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7 Recent approaches toward the synthesis of 1,2,3-triazoles

Figure 7.13: Synthesis of mono-, bis-, and tris-1,2,3-triazole derivatives by multicomponent click reaction catalyzed by Cu2O NPs.

N + R' (1,2 & 1,3 isomer)

X + NaN3

N

N

R' N +

N

R' N

N N N R'

75-91 %

75-84 %

(R' = Ph, 2-NO2-C6H4, 4-NO2-C6H4, 3-pyridyl) Condition for monotriazole: Alkyne: Alkyl halide: NaN3 = 1.2 : 1: 1.2; 30 min,Cu2O NPs (5 mg), H2O, 100 oC Condition for bistriazole: Alkyne: Alkyl halide: NaN3 = 0.5 : 1.2: 1.2; 60 min, Cu2O NPs (5 mg), H2O, 100 oC

Figure 7.14: Synthesis of mono- and bis-1,2,3-triazole derivatives from 1,3-diethynylbenzene and 1,2diethynylbenzene by Cu2O NPs.

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Sujit Ghosh, Basudeb Basu

Saha et al. [65] prepared a homogeneous copper catalyst from CuI and 1,3-bis(4fluorophenylthio)-propane ligand in acetonitrile to prepare the 1D polymeric coordination complex having formula ([(CuI)2{ArS(CH2)3SAr}2]n, Ar = 4 F-C6H4) and applied this catalyst in the synthesis of 1,2,3-triazole (Figure 7.15). The catalyst was well characterized by 1H NMR, 13C NMR, and single-crystal X-ray diffraction techniques. R2 2 X + R

R1

(1.1 equiv.)

Cu-catalyst (0.1 mol%)

H + NaN3

(1 equiv.)

MeCN: Water (1:1), 50 oC R1

(1.2 equiv.)

N

N

N

76-97 %

1

2

R = Ph, nC7H15, PhCH=CH, CH2=CH

R =

(R = 4-Me, 2-Br, 4-NO2), R CH2CH2CH2Cl, C(Me)(Ph)OH, CH2CO2Me

X = Cl, Br, I

Figure 7.15: Synthesis of 1,2,3-triazole derivatives by CuI 1D polymeric coordination complex catalyst.

While suggesting the mechanism, it was assumed that the reaction was initiated by the metalation of phenylacetylene in the presence of the 1D-CuI dithioether polymeric complexes giving copper acetylide (Figure 7.16). In the subsequent step, alkyl azide was formed in situ by the corresponding halide and sodium azide. The polymeric copper acetylide moiety reacted with alkyl azide via 1,3-dipolar cycloaddition followed by elimination of the complex catalyst give rise to the desired 1,4-disubstituted 1,2,3triazoles as the main product.

H

I

S Cu

R2 I

S Cu S

S

S

S Cu S

I Cu-catalyst

Cu

H+ S

I

R2

R

N N N R2

I

S

1

Cu S

R1 H+

N N N

I

S

R2 S

S Cu S

I

S Cu

Cu I

S

R1

X+ NaN3

(in situ formation of RN3)

Figure 7.16: Mechanism of the multicomponent click reaction using 1D-CuI dithioether polymeric complex.

7 Recent approaches toward the synthesis of 1,2,3-triazoles

263

Synthesis of catalyst involving ball-milling technology is a good green process. By applying mechanochemical approach, a green tool, Tourani et al. [66] synthesized Cu2(BDC)2 (DABCO) catalyst which was a nanoporous metal-organic framework [Cu(II)MOF] (Figure 7.17) and found it as suitable catalyst for the synthesis of 1,2,3-triazole derivatives (Figure 7.18). (BDC: benzene-1,4-dicarboxylic acid; DABCO: 1,4-diazabicyclo [2.2.2]octane). Additionally, the Cu content was found to be 23 wt.% by ICP technique. In the presence of sodium ascorbate as reducing agent the catalyst showed good conversion rate with desired product yielding 98% while in the absence of NaASC due to formation of Glaser homocoupled product between terminal alkyne yields of the desired product became only 68%.

Figure 7.17: Synthesis of Cu2(BDC)2 (DABCO).

R (1 equiv.)

+ R' X (1 equiv.)

R = Aryl, alkyl

+

NaN3

Cu2(BDC)2(DABCO), NaASC (20 mol%)

(1.2 equiv.)

R' = vinyl, aryl, phenacyl, CO2Et

EtOH, 60 oC, 0.75-1.5 h

R N

N

N

R' 87-98 %

X = Cl, Br

Figure 7.18: Synthesis of 1,2,3-triazole derivatives by multicomponent click reaction using Cu2(BDC)2 (DABCO).

The proposed mechanism given by the author is however slightly different from other reports (Figure 7.19). Initially, the copper atom coordinated the triple bond and subsequently, the acetylenic hydrogen was exchanged with the second copper atom to produce copper acetylide followed by coordination with in situ-generated organic azide. 1,3-Dipolar cycloaddition then affords the Cu-MOF-containing triazole, which on protonolysis eventually produced triazole derivatives. Negligible catalyst leaching was agreed by hot-filtration test during recycling experiment of the catalyst taking both types of substituted (EDG as well as EWG) phenyl acetylene. Polyaniline (PANI) could also act as matrix for heterogeneous catalyst, which can bind both Cu(I) and Cu(II) ion as reported by Sarma and his co-workers [67]. Cu/PANI is such type of catalyst that could catalyze the multicomponent click reaction (Figure 7.20). The two types of catalyst mainly differ in the oxidation state of copper ion. During its

264

Sujit Ghosh, Basudeb Basu

R

Cu(II)MOF

N

N

N

Na-ascorbate (NaASC)

R'

R

Cu(I)MOF

H

H+ R N

H+ CuMOF

N

N

Cu

R'

R

H

R' Cu(I)MOF

N N Cu N

R' R'

N3

X + NaN3

Cu Figure 7.19: Mechanism for the synthesis of 1,2,3-triazole using Cu(II) MOF.

preparation by interfacial polymerization method from aniline solution and CuCl2·2H2O/ Na2S2O8 if NaBH4 was used under N2, Cu(I)/PANI catalyst was formed but when there no reducing agent was added, then both Cu(I) as well as Cu(II) remained in the catalyst surface. For the latter case ascorbic acid was used as reducing agent. The reaction passed through the formation of active π-complex followed by the copper acetylide complex as shown in Figure 7.21. Solid-supported catalysts offer numerous opportunities to recover and reuse catalysts from the reaction media. These characteristics of heterogeneous catalysts lead to better process economy and environment compatibility to industrial-scale manufacturing. Silica is one of such cheap stakeholders to prepare such heterogeneous catalyst owing to their good thermal and chemical stability, high surface area, and exceptional porosity. Due to the reactive silanol groups (Si–OH group) in silica surface, different ligand functionality can be strongly anchored onto it. An example of such magnetically separable catalyst is the silica-coated heterogeneous catalyst, copper nanomagnetite (NHC-benzimi@Cu) [68]. Almost similar approach was adopted to prepare the catalyst as done by other researchers (Figure 7.22). This complex used in the multicomponent click reaction via Huisgen 1,3-dipolar cycloaddition reaction of alkyl or aryl halide, sodium azide, and terminal alkyne, which afforded various 1,4-disubstituted 1,2,3-triazoles (Figure 7.23). The catalyst can be easily separated by external bar magnet and recyclable up to 10th cycle. The mechanism of reaction is shown in Figure 7.24. The reaction goes through the successive formation of copper triazolyl, copper triazolyl-acetylide, and six-membered ketenimine ring intermediate, which is converted to five-membered rings intermediate, and after the removal of Cu(I) the desired product is obtained. Very recently benzimidazole-based ionic liquid-tagged Schiff base heterogeneous copper catalyst Cu@ILSB was applied by Biswas and coworkers (Figure 7.25) [69]. The

265

7 Recent approaches toward the synthesis of 1,2,3-triazoles

HN

δ N

N

NH

NH

NH structure of Copper (I) /PANI catalyst

Cu(I)

HN

N

HN

N

δ

N

NH

NH

NH

δ N

NH

NH

NH structure of Copper (II) /PANI catalyst

Cu(II) & Cu(I)

HN

N

X

+ R'

δ

N

NH

(1 equiv.) R = H, NO2, Br X = Cl, Br

NH

Copper (I) /PANI (1.22 mol%) or Copper (I)/(II) (0.82 mol%) & R' Ascorbic acid + NaN3 N H O:EG (1:1), RT, 2-6 h 2

R

NH

(1.2 equiv.) (1.5 equiv.)

R N

N

50-90 %

R' = Ph, CH2SPh, CH2CO2Ph

OMe

Figure 7.20: Synthesis of 1,2,3-triazoles by Cu/PANI heterogeneous catalyst by multicomponent click reaction.

catalyst compatible well under aqueous environment and the triazoles are obtained in excellent yield by multicomponent click reaction (Figure 7.26) but the reaction time was longer (12 h). Aldimine that act as Schiff’s base probably binds the copper ion which may be in + 1 oxidation state as the reaction does not require any additional reducing agent. According to the report of author synthesized copper complex (Cu@ILSB) did not yield single crystals after several attempts and hence the exact structure of the complex

266

Sujit Ghosh, Basudeb Basu

N

N Cu(I)/PANI N

N

R'

R

N

Nδ

Nδ

H

NH

NH

N

N

N

R'

R

Cu (I)

P A N I

[Cu]

R' H R'

N

N

R'

R N [Cu]

P A N I N R'

N

P A N I

[Cu]

R N RN3 (let assume)

P A N I

[Cu]

X + NaN3

R

Figure 7.21: Mechanism of 1,2,3-triazole synthesis by Cu/PANI heterogeneous catalyst.

I Cu Nano magnet

Nano magnet

nanomagnetic-NHC-Benzimi@Cu

O O Si O

N

NH

(EtO)4Si (TEOS: Tetraethylorthosilicate) CuI, THF NaOtBu

N Nano magnet

Xylene, 110 oC (EtO)3Si

Nano magnet

O O Si O

Cl

Cl

Figure 7.22: Synthesis of NHC-Benzimi@Cu complex.

N H DMF, 80 oC, 72 h

Nano magnet

O O Si O

N

NH

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7 Recent approaches toward the synthesis of 1,2,3-triazoles

R

X +

(1 equiv.)

NHC-Benzimi@Cu (10 mol%) NaASC

R'

+ NaN3

R

N

N

N

EtOH, 80 oC, 20-40 min R' 81-94 %

(1 equiv.) (1.1 equiv.)

R = Ph, 2-OMe-C6H4, R' = 4-OMe-C6H4, 3-pyridyl 4-F-C6H4, C6H13, p-Tol, 4-F-C6H4, 4-CN-C6H4, EtOCH2CO X = Cl, Br Figure 7.23: Synthesis of 1,2,3-triazole derivatives by NHC-Benzimi@Cu complex.

N N N

R'

I Cu

R

R'

O O Si O

Nano magnet

R

N N N

N

NH

R

X + NaN3

Cu Nano magnet

O O Si O

N

R

NH

N R

Nano magnet

O O Si O

N N N

N

N

R' Nano magnet

Cu N

NH

N

R'

ketenimine intermediate Nano magnet

O O Si O

N

N Cu

O O Si O

N

N3

N Cu

R

NH

R

NH

R'

copper azido intermediate

copper azido-acetylide intermediate Figure 7.24: Mechanism of 1,2,3-triazole formation by NHC-Benzimi@Cu complex.

could not be assigned. But the p-XRD data revealed that Cu2O NPs may be speeded over the surface network of the catalyst. Probable mechanism for this multicomponent AAC reaction was proposed by the author as shown in Figure 7.27. It was assumed that the preliminary step was initiated by the formation of copper acetylide by metallation of terminal alkynes in the presence

268

Sujit Ghosh, Basudeb Basu

N

Br

N

N H

KOH, MeCN, Reflux, 5 h

N

Br

NH2. HBr

MeOH, Reflux, 12 h N

N

NH2 H

O OH

H2O

OH Cu(OAc)2, MeOH Cu@ILSB

OH

20 h, Reflux

(exact morphology not known)

N

N

N

OH

Figure 7.25: Synthesis of Cu@ILSB.

R

X + R'

(1 mmol)

Cu@ILSB (10 mg), SDS (10 mol%)

H + NaN3

(1.2 mmol) (1.2 mmol)

R = Ph, 4-i-Pr-C6H4, 3-Br-C6H4, 3-I-C6H4, 3-NO2-C6H4, 1-Naphthyl, 4-Cl-C6H4-CO, allyl

R

H2O, 90 oC, 12 h

N N N

R'

79-94 %

R' = Ph, p-Tol, 4-Br-C6H4, 4-NO2-C6H4, 4-OMe-C6H4 X = Cl, Br, I

Ph Figure 7.26: Synthesis of 1,4-disubstituted 1,2,3-triazoles via multicomponent click reaction among alkyl halide, terminal alkyne, and sodium azide by Cu@ILSB catalyst.

of Cu@ILSB catalyst. In the subsequent step, alkyl azide (which was formed by the substitution reaction between an alkyl halide and sodium azide) reacted with the active copper acetylide moiety via cycloaddition reaction to form Cu-triazole intermediate which is followed by the elimination of the copper catalyst forming 1,4-disubstituted 1,2,3-triazoles as the main product. Other than homogeneous and heterogeneous copper catalysts, other metals such as Mn, Ni, and Ru were also found to catalyze the triazole synthesis. Like copper, nickel metal was also searched and applied for multicomponent click reaction which is known as NiAAC. A very few reports have been found in literature that can produce 1,2,3-triazole derivatives. Initially Raney Ni was used which produce both the regioisomers (1,4 and 1,5) [70]. While in 2017 Cp2Ni-Xantphos was applied, both terminal and internal alkyne reacted under this reaction condition [71]. With the terminal alkyne, the 1,5-disubstituted triazoles were obtained as the regioselective product. Another heterogeneous Ni catalyst is triazole-linked organic polymer (Ni-TLOP), which acts as a photocatalyst in solar AAC [72]. However, in all these examples alkyl azide has been directly employed as one of the coupling partners. In 2021, Choudhury et al.

269

7 Recent approaches toward the synthesis of 1,2,3-triazoles

R N

N

H

N R'

R'

H

Cu@ILSB R N BSLI@Cu

N

N

protonolysis Cu@ILSB

R'

R' R'

Cu@ILSB N N R

R

N3

R

X + NaN3

Figure 7.27: Mechanism of multicomponent click reaction by Cu@ILSB.

[73] prepared a ternary composite, Ni-rGO-Zeolite, as an efficient and sustainable catalyst for the AAC reaction. The reaction sequence was essentially an MCR approach avoiding direct use of alkyl azide (Figure 7.28). The catalyst was synthesized sequentially by the following steps: (i) preparation of GO-Zeolite hybrid material composite by the reaction between aqueous dispersion of GO with NaY zeolite in water; (ii) reaction of the GO-zeolite hybrid composite with Ni(II) salt under reducing environment. The resulting ternary nanocomposite Ni-rGO-zeolite is then produced with Ni(0) oxidation state, where highly dispersed Ni-NPs get impregnated over rGO (reduced graphene oxide) surface, as seen from HRTEM images and other analytical data. This heterogeneous catalyst worked well under aqueous environment at 90 °C for the onepot multicomponent click reaction. Unlike copper, the mechanism did not proceed through Cu-acetylide intermediate as the initial step of reaction (Figure 7.29). Rather, Ni(0) NPs from rGO-zeolite surface invite both alkyne and in situ formed alkyl azide via coordination interaction and force them to interact under close vicinity. Alkyne dipolarophile then undergoes regioselective 1,3dipolar cycloaddition with coordinated alkyne and afforded the triazole product.

R

X +

(1 mmol)

R'

H + NaN3

(1.2 mmol) (1.5 mmol)

R = Ph, 4-i-Pr-C6H4, 3-Br-C6H4, 3-I-C6H4, 3-NO2-C6H4, 1-Naphthyl, 4-Cl-C6H4-CO, allyl

Ni-rGO-Zeolite (30 mg) (1.6 mol%) o

H2O, 90 C, 4-6 h

R

N N N

R'

79-94 % R' = Ph, p-Tol, 4-Br-C6H4, 4-NO2-C6H4, 4-OMe-C6H4 X = Cl, Br, I

Ph Figure 7.28: Synthesis of 1,4-disubstituted 1,2,3-triazoles via multicomponent click reaction among alkyl halide, terminal alkyne, and sodium azide by Ni-rGO-Zeolite catalyst.

270

Sujit Ghosh, Basudeb Basu

Ni

Ni

Ni

Ni Ni

Ni Ni

Ni

Ni

Ni Ni

Ni Ni

Ni Ni

Ni

Ni-rGO-Zeolite

Schematic picture of Ni-rGO-Zeolite

R

Ni Ni R

H

R

H

Ni Ni

H

X + NaN3

R'

R'

Ni Ni

Ni

N3

Ni

Ni Ni

R N N

N

Ni Ni

1,3-dipolar cycloaddition on R' Ni-rGO-zeolite surface

N N N

R'

Figure 7.29: Mechanism of triazole formation using Ni-rGO-Zeolite catalyst.

Apart from nickel, manganese was found to catalyze 1,2,3-triazole synthesis [74]. In this method, the metal–organic/inorganic hybrid composite frameworks were applied in click chemistry under green protocol (Figure 7.30). The author performed the reaction at 50 °C. The catalyst was synthesized incorporating manganese on the magnetic Co2Fe2O4 in the presence of terephthalic acid or benzene 1,4-dicarboxylic acid by in situ solvothermal approach (Figure 7.31). The synthesized catalyst was formulated as CoFe2O4/Mn-BDC. Due to excellent magnetic properties of the catalyst, it can be efficiently separated after the reaction using external magnet and was shown to reuse for five consecutive cycles. Though most of the substrate undergo good conversion rate within 2 h (68–100%), very poor conversion was also observed in few cases. For example: (i) only 9% (4-methoxy phenylacetylene, benzyl bromide, NaN3); (ii) 24% (tolylacetylene, benzyl bromide, NaN3); and (iii) 31% (phenylacetylene, n-butylbromide, NaN3).

R (1 equiv.)

+

R' X + (1 equiv.)

NaN3 (1 equiv.)

CoFe2O4/ Mn-BDC

R'

H2O, 50 oC, 2-3 h

N

N

N R

R = Ph, 4-Me-C6H4, R' = Ph, 4-F-C6H4, 4-NO2-C6H4, nPr 4-OMe-C6H4, 4-t-Bu-C6H4 X = Cl, Br

9 to 100 conversion rate

Figure 7.30: Synthesis of 1,4-substituted 1,2,3-triazole by CoFe2O4/Mn-BDC hybrid MOF as catalyst.

7 Recent approaches toward the synthesis of 1,2,3-triazoles

271

CoCl2. 6H2O Mn-BDC = Manganese benzene-1,4-dicarboxylate/ + manganese terephthalate FeCl3.6H2O + NaOAc + PEG-6000 160 oC, 16 h

OH

COOH

OH

CoFe2O4 NPs

COOH MnCl2.4H2O DMF, MeOH, 120 oC, 24 h

microflakes of CoFe2O4/ Mn-BDC hybrid composite (Magnetic nanoparticles)

Figure 7.31: Synthesis of CoFe2O4/Mn-BDC hybrid MOF.

A tentative mechanism (Figure 7.32) illustrating the role of the hybrid MOF was almost similar as seen in case of Ni-catalyzed click reaction. Here no acetylide intermediate was formed initially and role of Mn-BDC was to activate both alkyne and alkyl azide from hybrid MOF surface. Initially, a manganese-coordinated acetylene complex was formed which act as a better dienophile than acetylene itself. After that, in situgenerated alkyl azide interacted with acetylenic complex to form another complex. In the penultimate step, the click reaction on the MOF surface produced another complex, which was basically a triazole-metal complex. Finally, regeneration of CoFe2O4/ Mn-BDC catalyst from the triazole-metal complex liberated the desired heterocycle. Zn also recognized itself as the enlisted metal for click reaction [75]. A novel polymer supported heterogeneous Zn(II) catalyst was prepared by supporting ZnCl2 NPs onto modified SMA [poly(styrene-co-maleic anhydride)] alternating polymer surface. The SMA surface was then converted to SMI [poly(styrene-co-maleimide)] by reaction with 3-aminopyridine to obtain the corresponding immobilized heterogeneous active catalyst as Zn(II)SMI (Figure 7.33). Multicomponent click reaction with this catalyst was reported by Sarmastib groups (Figure 7.34). Lower reaction time along with good recyclable and mild reaction conditions are the notable features of this nanocatalyst. The mechanism of the reaction is depicted in Figure 7.35 which pass through both six as well as five membered intermediate. Another metal that suitably catalyzed the AAC reaction is ruthenium and such reaction is known as RuAAC. In almost all literature reports, it was found that RuCuAAC produce 1,5-substituted derivative of 1,2,3-triazole but Sharma et al. [76] synthesized another regioisomer (1,4) from triazole-based Ru-catalyst. In their research work they used click reaction both in catalyst preparation (Figure 7.36) as well as in the synthesis of 1,2,3-triazoles (Figure 7.37). The formed catalyst SBA-15-Tz-Ru(II)TPP

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Sujit Ghosh, Basudeb Basu

N R

N

N

N

R' N Mn

H

R

H

R

H

R' N

R

R'

Mn

Mn

N N N R

R' + X NaN3

H R'

Mn

N3

Figure 7.32: Mechanism of click reaction by CoFe2O4/Mn-BDC.

alternating co-polymer O H CH2 C

O

O O H2 H C C

O

O

NH2 +

DMF (dry), N2, 35 oC, Ac2O, NaOAc, Et3N, 75 oC

N

SMI

3-amino pyridine SMA poly(styrene-co-maleic anhydride) stryene-maleic anhydride alternating co-polymer

Zn(II)

H2 HC C Ph O

ZnCl2 Ultrasound n

N

O

= SMI polymeric unit SMI/ZnCl2 7.61 % Zn (w/w)

N

O

N poly(styrene-co-maleimide)

alternating co-polymer H2 HC C Ph O

n

DMF (dry), N2, Reflux

N ZnCl2

Figure 7.33: Preparation of polymer-supported heterogeneous Zn(II)SMI catalyst.

273

7 Recent approaches toward the synthesis of 1,2,3-triazoles

X R' (1 equiv.)

+ NaN3 Zn(II)-SMI catalyst (0.05 g/mmol) + R H2O, Reflux, 25 to 100 min (1 equiv.) (1.1 equiv.)

N

R'

N

N R

85-98 %

(phenacyl, R = Ph, p-Tol alkyl, benzyl) X = Cl, Br, I Figure 7.34: Zn-catalyzed multicomponent click reaction to synthesis 1,2,3-triazole.

X + NaN3

R' Zn(II)

R'

H

R R N

H N

Zn

R

N

N R'

N

N3

Zn

R

N

R

[Zn(II)SMI]

R

Zn ring N N contraction N R' from 6 to 5

N N N

R'

R'

Figure 7.35: Mechanism of 1,2,3-triazole synthesis by Zn(II)SMI catalyst.

was recyclable up to five times, and in each step, the catalyst was removed by simple centrifugation, washed (CH2Cl2 or EtOH, 80 °C), and dried overnight under oven before applying in next cycle, and thus this heterogeneous catalyst was recycled up to five times with good efficiency.

(MeO)3Si

Cl

NaN3, TBAB CH3CN

(MeO)3Si

OH

NaN3 Toluene 95 oC, N2

OH OH SBA-15

O

O [RuCl2(PPh3)3]

O Si

DMF, 12 h

N

N

H2N

N

O SBA-15-Tz

NH2

DMF, DIPEA CuI, 50 oC

O Si O SBA-15-N3

O O Si

N

O SBA-15-Tz

N N

Cl PPh3 Ru PPh 3 NH Cl

Figure 7.36: Synthesis of Ru-triazole-based heterogeneous catalyst [SBA-15-Tz-Ru(II)TPP].

N3

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Sujit Ghosh, Basudeb Basu

R' SBA-15-Tz-Ru(II)TPP (0.445 nol%)

R' Br + NaN3 (1.2 equiv.) (1.2 equiv.)

+

R (1 equiv.)

N

N

N

o

H2O, 90 C, 12 h

R = Ph, 4-Me-C6H4, 4-OMe-C6H4, 4-COMe-C6H4, 4-NO2-C6H4, 4-C5H11, 2-OMe-C6H4, 4-O-C5H11, 1-Naphthyl, 2-Pyridyl, nC8H17

R 70-92%

R' = Ph, 4-OMe-C6H4, nPr Figure 7.37: Synthesis of 1,4-disubstituted 1,2,3-triazole by SBA-15-Tz-Ru(II)TPP.

The formation of 1,4-regiosomer was supported by controlled experiments done by the research groups. The plausible mechanism for the regioselective formation of 1,4-disubstituted triazole is shown in Figure 7.38. O N

O Si

N

O

R' N N N

N

SBA-15-Tz R' R

Br HN N N

R

PPh3

Cl PPh Ru PPh3 3 NH Cl

R R

Cl

H Ru N Ph3P N N Cl

R

Ru

Ph3P

H2O

N3 R Cl

Cl Ph3P Ru HN

Ph3P

R N

Ru HN N N

N Cl Ph3P Ru HN

R N

N

Figure 7.38: Synthesis of 1,4-disubstituted 1,2,3-triazole catalyzed by SBA-15-Tz-Ru(II)TPP catalyst.

7.2.2 Three-component coupling among alkyl or aryl boronic acid, terminal alkyne or alkynyl carboxylic acid, and sodium azide Apart from alkyl halide, aryl or heteroaryl boronic acid was also exploited for 1,2,3triazole synthesis, which undergo coupling with alkyne or its surrogates alkynyl carboxylic acid in presence of sodium azide. The previously discussed NiFe2O4-glutamate-Cu(0)

7 Recent approaches toward the synthesis of 1,2,3-triazoles

275

catalyst (Figure 7.6), as used in multicomponent click reaction (Figure 7.7), also worked successfully with aryl boronic acid, terminal alkyne, and NaN3 (Figure 7.39) [60].

Ar B(OH)2 + R'

+

NaN3

NiFe2O4-glutamate-Cu (1 mol%)

Ar

N R' N N 65-95 %

H2O, RT, 3-5 h

(1 equiv.)

(1 equiv.)

(1.1 equiv.)

Ar = Ph, p-Tol

R' = Aryl, 2-thienyl, nC3H7

Figure 7.39: Synthesis of 1,2,3-triazole by three-component coupling among aryl boronic acid, terminal alkyne, and sodium azide catalyzed by NiFe2O4-glutamate-Cu(0).

Another silica-supported heterogeneous catalyst is the Cu-NHC@SiO2 [77], which was prepared starting from 3-chloropropyl trimethoxy silane (CPTMS) as reported by Garg et al. (Figure 7.40). Within the catalyst framework NHC binds the active copper center which is in +2 oxidation state and it was used for 1,2,3-triazole synthesis. Besides direct azide–alkyne coupling triazole unit was also prepared by multicomponent method. The MCR approach involves coupling among arylboronic, alkyne, and NaN3 (Figure 7.41) to produce synthesis of many triazole derivatives.

O Si O O

SiO2 80 oC Dry Toluene

I Cu

Cl SiO2

CPTMS (3-chloropropyl trimethoxy silane)

O O Si O

N

N

Cu-NHC@SiO2 CuI, KOtBu THF, RT

SiO2

O O Si O

N Cl

N

, 6h

(under same condition)

CPTMS@SiO2

SiO2

O O Si O

N

N

Imidazole-CPTMS@SiO2

Figure 7.40: Synthesis of Cu-NHC@SiO2 catalyst.

Vile et al. [78] synthesized a homogeneous Cu-catalyst as single atom crystal for threecomponent regioselective click reaction under base-free conditions. The catalysts were prepared via tricyanomethane polymerization to create a combine an electronic structure. The copper ion gets stabilized by the mesoporous graphitic carbon nitride (C3N4) carrier which acts as a ligand. The catalysts were employed in the synthesis of 1,2,3-triazoles employing azide–alkyne click reaction.

276

Sujit Ghosh, Basudeb Basu

Figure 7.41: Synthesis of 1,4-substituted 1,2,3-triazole from aryl boronic acid, terminal alkyne, and sodium azide by Cu-NHC@SiO2.

Very recently Pharande et al. [79], another heterogeneous catalyst Cell-ThP-Cu(II) (cellulose-supported Schiff base Cu(II) catalyst) was prepared (Figure 7.42) and applied to synthesize 1,2,3-triazoles from aryl boronic acid (Figure 7.43). The reaction proceeded via Chan-Lam coupling and Huisgen 1,3 cycloaddition reaction (Chan-Lam coupling is the cross-coupling reaction between alkyl/aryl boronic acids with N- or O-nucleophile). In the mechanism of the reaction tuning of the catalyst was very interesting; in the first half of the reaction it played the role of aryl azide formation from precursor aryl boronic acid via Cu(II)/Cu(0) redox system. Again in the second half of the reaction it formed product (by click reaction between formed aryl azide with terminal alkyne by Huisgen cycloaddition) via Cu(II)/Cu(I) redox system (Figure 7.44). While reviewing the entry list it was found that 4-fluoro phenylacetylene did not form any triazole product with 4-formyl phenyl boronic acid, 4-bromophenyl boronic acid, and 2-thienyl boronic acid (reported yield 0, in all these cases). Besides recyclability (up to fifth run) excellent TON and TOF as well as biodegradable nature of this heterogeneous catalyst made it prevalent in terms of sustainable development. Another method for the construction of 1,2,3 triazole is the decarboxylative coupling of propiolic acid, aryl boronic acid, and NaN3. Alkynyl carboxylates are wellknown alkyne surrogates because of activated spC–COOH group that immediately get triggered prior to cycloaddition with azide ion (Figure 7.45). This has been reported by Li and group [80]. The mechanistic details are shown in the Figure 7.46 which follow four steps: step I: formation of the copper(I) acetylide from the decarboxylation of propiolic acid (in the presence of copper salt and MeOLi); step II: [3 + 2] cycloaddition of copper(I) acetylide with the azide to form triazolyl-copper intermediate; step III: transmetalation with borate complex (formed by the reaction between phenylboronic acid and MeOLi under O2); and step IV: reductive elimination to produce the desired product with the release of the copper(I) species.

7 Recent approaches toward the synthesis of 1,2,3-triazoles

277

H2N O Si O O (APTES) (3-Aminopropyl)triethoxysilane

Cellulose

O O Si O

AcO

Cellulose

NH2

OAc Cu(II) S

O O Si O

N

Cell-ThP-Cu(II) APTES Toluene /Reflux, 24 h

Cellulose

O O Si O

O

S Cu(OAc)2, EtOH Reflux, 24 h

H Thiophene-2carbaldehyde (ThP) NH2

H

Cellulose

EtOH

S

O O Si O

N H

Cell-NH2

Cell-ThP (imine functionality)

Figure 7.42: Synthesis of cellulose-ThP-Cu(II) heterogeneous catalyst.

R Cell-ThP-Cu(II) (0.072 mol%)

Het/Ar B(OH)2 + R (1 equiv.)

H + NaN3 (1.2 equiv.)

H2O, RT, 6h

(1.5 equiv.)

Het/Ar

Ar/Het = 3-NO2-C6H4, 4-Br-C6H4, 4-CHO-C6H4, 4-OMe-C6H4, 2-thienyl (R = H, Me, F)

N

N N 85-97 %

Figure 7.43: Synthesis of 1,2,3-triazoles by cellulose-ThP-Cu(II) via MCR approach.

7.2.3 Three-component coupling among α-keto acetal, tosyl hydrazine, and primary amine Another set of coupling partners that can provide substituted 1,2,3-triazole are 1° amine, tosylhydrazine, and acetophenone/α-keto acetal (Figure 7.47) [81]. Zehender method is little milder process and (a wide variety of functional groups such as ester, nitriles and carbamates were well tolerated) applicable for alkylamine, heteroarylamine in addition to aryl amine. While acetophenone was used only aryl amine gave the reaction. Initially the reaction is carried out at room temperature between α-keto

278

Sujit Ghosh, Basudeb Basu

1/2H2O

1/2O2

Cell-ThP-Cu(II)

RB(OH)2 Transmetallation

Chan-Lam coupling

B(OH)2

Cell-ThP-Cu(0)

Cell-ThP-Cu(II) R'N3

R

N3

Reductive elimination

Cell-ThP-Cu(II) R

R'

N

N

in situ reduction

N

R'

N

N

Cell-PTh(I)Cu

R Cell-ThP-Cu(II) R

H R (Product)

Consider: Ar/Het = R'

Ligand NaN3 substitution

=R

H

Cell-ThP-Cu(I) H N R R'

Cell-PTh

R Huisgen cycloaddtion

N Cu

N

Cu(I)-ThP-Cell

R'N3 N R

N N N R Cu(I)-ThP-Cell

R'

Figure 7.44: Mechanism of 1,2,3-triazole formation by cellulose-ThP-Cu(II) catalyst involving both ChanLam coupling as well as Huisgen cycloaddition.

Cu(OAc)2 (15 mol%) DMBPy (30 mol%) R COOH + R' N3 + R'' B(OH)2 (1 equiv.) (1.5 equiv.) (2.5 equiv.) R = H, alkyl, aryl

N

N

N R'

MeOLi (2.5 equiv.), CH3CN R R'' O2, 12h, 60 oC 55-73 % R'' = alkyl, aryl

R' = Bn, CH2CO2Me CH2CH2Ph, nBu, nHex, C5H9, CH2CO2Et, CH2CH2OH, CH2SiMe3

Figure 7.45: Synthesis of triazole by three- component coupling among propiolic acid, sodium azide, and alkyl boronic acid.

acetal and tosylhydrazine followed by 80 °C when amine is added in the same pot. The work, however, did not discuss about any plausible mechanistic route or incorporate any evidential studies.

7 Recent approaches toward the synthesis of 1,2,3-triazoles

279

Step-I Cu(II) catalyst, MeOLi R

COOH

R Step-II R' N3

CO2

N

N

N

R'

Step-IV

N

N

N

reductive R'' elimination R

R +

R'

Cu(I)

Step-III transmetalation

Cu(III)

N R

R''

[3+2] cycloaddition N

N

R'

Cu(I)

O2

Cu(I) LiB(OMe)4-n(OH)n

R''B(OH)2 + MeOLi

[R''B(OMe)3-n(OH)n]Li

Figure 7.46: Mechanism of the 1,2,3-triazole formation from propiolic acid, sodium azide, and alkyl boronic acid.

O

1. RT, DMSO

OMe + TsNHNH2 + R2NH2 R 2. 80 oC 3 OMe R (1 equiv.) (1 equiv.) (1.054 equiv.) 1

R1, R3 = H, Me

R1

N

N N R2 45-91 %

R3

R2 = alkyl, aryl, heteroaryl

Figure 7.47: Synthesis of 1,2,3-triazole from α-keto acetal, tosyl hydrazine, and primary amine.

7.2.4 Three-component coupling among N-propargyl ortho-bromo benzamide, alkyl halide, and alkyl azide The 1,2,3-triazole synthesized from alkyne with other functional group was less common in the literature. Ether and amide-linked 1,2,3-triazolyl scaffolds act as antiproliferative agents and these difunctional compounds were synthesized attempting click reaction on N-propargyl ortho-bromo benzamide via MCR approach using sodium ascorbate and CuSO4 at 150 °C (Figure 7.48) [82]. 2-Bromo-N-(prop-2-yn-1-yl)benzamide (i.e., N-propargyl ortho-bromo benzamide) was separately synthesized from the reaction of 2-bromobenzoic acid and propargylamine via amidation reaction.

280

Sujit Ghosh, Basudeb Basu

Figure 7.48: One-pot synthesis of N-(1-aryl-1H-1,2,3-triazol-4-yl)methyl)-2-(aryloxymethyl)benzamide derivatives.

7.2.5 Three-component coupling among aldehyde, nitroalkene, or nitroalkane and sodium azide A different coupling setup to synthesize 1,2,3-triazoles is the coupling among aldehyde, nitroalkene/nitroalkane, and NaN3 [83]. An example of such coupling was the synthesis of triazolochromenes by sequential one-pot three-component reaction. The intermediate compound 3-nitro-2H-chromenes was (Figure 7.49) produced from salicylaldehyde, nitroalkene, and sodium azide. In case of solid salicylaldehydes, yields of products are very low; in that case, the author has developed a two-step mechanochemical approach which gave higher yield. Though the mechanism of the reaction was not proposed by the author, perhaps the double bonds of dihydro pyran ring get activated via removal of NO2 group which undergo cycloaddition with azide ion. Post-functionalization of these compounds results in the formation of many biologically relevant chemical entities. These chromenes are ubiquitous in the nature and important structural motifs for medicinal applications. A metal-free approach under microwave irradiation technique in PEG-400 solvent was reported by Garg et al. [77, 84] for the synthesis of 4-aryl-NH-1,2,3-triazoles. They had chosen aromatic aldehyde, nitromethane, and NaN3 (Figure 7.50) in this threecomponent reaction. The reaction proceeds through the formation of α,β-unsaturated nitrocompound, also called β-nitrostyrene, the Henry reaction product, that is, the aldol condensation product between aromatic aldehyde and nitromethane (Figure 7.51). The activated styrene is then attacked by the N3̶ ion and catalyzed by anthranilic acid, owing to its H-bonding effect in proximity by both NH2 and COOH group, encouraging the formation of five-member ring, via HNO2 elimination and protonation to afford the monosubstituted 4-aryl 1,2,3-triazole. As previously discussed, the Cu-NHC@SiO2 [77] also acts as a suitable catalyst with similar kind of reacting partners (Figure 7.52) to afford 4-aryl-NH-1,2,3-triazoles with diverse benzaldehydes. Under the 1,2,3-triazole family, the NH-1,2,3-triazole represents

7 Recent approaches toward the synthesis of 1,2,3-triazoles

281

Figure 7.49: Synthesis of triazolochromenes from salicylaldehyde and nitroalkene and sodium azide.

an important class of compound from which post alkylation or arylation on NH-1,2,3triazole may lead to the formation of many desirable N2-substituted 1,2,3-triazoles. H2N HO

O Het/Ar H (1 equiv.)

+

O

O N

O Anthranilic acid (10 mol%) CH3

(1.5 equiv.)

+

NaN3 (2 equiv.)

PEG-400

Ar/Het N N N 74-94 %

R Ar =

(R = H, 2-Cl, 2-NO2, 2-OH, 4-Cl, 4-Br, 4-CN, 4-OMe, 3-NO2, 2,4-di-Cl e.t.c)

Het = 2-furyl Reaction condition: constant microwave irradiation 100w (upto 130 °C), 5 min or conventional heating at 130 oC for 2-3 hr. Figure 7.50: Metal-free synthesis of 4-aryl-NH-1,2,3-triazoles by three-component reaction among nitromethane, aldehyde, and NaN3 catalyzed by anthranilic acid.

The above reaction almost under similar reaction condition was reported using ZnO NPs by Phukan et al. [85], except in the proportion of the substrates taken. The ratio

282

Sujit Ghosh, Basudeb Basu

Figure 7.51: Anthranilic acid catalyzed mechanism for the synthesis of 4-aryl-NH-1,2,3-triazoles from nitromethane, aldehyde, and NaN3.

R CHO (1 equiv.)

+

CH3NO2 + NaN3 (1.5 equiv.) (2 equiv.)

Cu-NHC@SiO2 (1.5 mol%) PEG-400, 100 oC, 1.5-3 h

R = 3-furyl, 3-thienyl, 4-Br-C6H4, 4-OMe-C6H4, 4-OH-C6H4, 4-F-C6H4, 2-Cl-C6H4, 3-NO2-C6H4, 2-NO2-C6H4, 2-Cl & 6-F-C6H3

H N N N R (4-substitutedN1-H 1,2-3-triazole) 76-95 %

Figure 7.52: Synthesis of 4-substituted 1,2,3-triazole from aldehyde, nitromethane, and sodium azide by Cu-NHC@SiO2.

they had taken for aromatic aldehyde, nitroalkane, and sodium azide was 1:2:3 to get the optimum yield (98%). The PEG-capped ZnO NPs (15–25 nm) worked efficiently with the tolerance of a wide range of electronically diverse benzaldehydes leading to the synthesize 4-aryl-NH-1,2,3-triazoles.

7.2.6 Three-component coupling among o-phenylenediamine, 2-azidobenzaldehyde, and arylchalcogenyl alkynes Jacob and coworkers [86] synthesized (arylselanyl)- or (arylsulfenyl)-alkyl-1,2,3-triazolo1,3,6-triazonines in moderate-to-excellent yields via the reaction of o-phenylenediamine, 2-azidobenzaldehyde, and different arylchalcogenyl alkynes using a copper-catalyzed MCR approach (Figure 7.53). These reactions tolerate a range of substituents on the arylchalcogenyl alkynes and found to be an efficient methodology for combinatorial synthesis of new selenium- or sulfur-containing triazonines.

7 Recent approaches toward the synthesis of 1,2,3-triazoles

283

O N

NH2

H

NH2 (1 equiv.)

CuI (10 mol%) Et3N ( 2equiv.)

N3 (1 equiv.)

+

1,4-dioxane, 100 C, 24 h, N2

H n

R

N

Z

N

n

R

(R = 4-F, 4-Cl, 4-OMe, 4-Me, 3-CF3, 2,4,6-Me3)

Z

HN

N

o

45-84%

(Z = S, Se)

(1 equiv.)

Figure 7.53: Synthesis of 1,2,3-triazolo-1,3,6-triazonines from arylchalcogenyl alkynes o-phenylenediamine and 2-azidobenzaldehyde.

The mechanism of the reaction has shown in Figure 7.54, which was initiated by the copper acetylide and imine formation via condensation of o-phenylenediamine with 2-azidobenzaldehyde mechanism followed by azidation on copper ion. In the next step, the acetylide–copper complex interacted with the azide intermediate to give Csp2-Cu triazolyl intermediate. In the further step, an intramolecular Ullmann-type coupling of afforded the 10-membered cyclic intermediate, which by reductive elimination produced desired (arylchalcogenyl)-alkyl-1,2,3-triazolo-1,3,6-triazonine, regenerating the copper(I) catalyst. N

HN

N

Z

N

N R

n

R Z

O H2N

H + Et3N

n

H +

Cu(I)

H2O

N3 R Z

N

H

N Cu Z R

N N N

N H

NH2

N

n

H N

Et3N

Cu(I) + Et3NH

n

+

Et3NH

NH2

N N N

NH2 Cu N N N

N3

NH2

Z R Z

Cu

n

n

Figure 7.54: Mechanism for the synthesis of arylchalkogenyl-alkyl-1,2,3-triazolo-1,3,6-triazonines.

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Sujit Ghosh, Basudeb Basu

7.2.7 Three-component coupling among epoxide, terminal alkyne, and sodium azide Magnetic NiFe2O4-supported glutamate-copper (0) catalyst (Figure 7.6) was further employed as effective catalyst for the synthesis of a wide variety of 1,4-disubstituted-1,2,3triazoles via one-pot three-component coupling among epoxide, alkyne, and NaN3 (Figure 7.55). Hydroxymethylated 1,2,3-triazoles were obtained from epoxide substrate which may have scope to be further functionalized to build up many other triazole derivatives. An interesting compound bis(triazoles) was obtained using epichlorohydrin which first gives epoxytriazoles followed by repetition of same step affords the hydroxyl-bis-triazole (Figure 7.56).

O +

R

H (1 equiv.)

R'

+

NaN3

R'

H2O, RT, 2-6 h (1 equiv.)

N N

NiFe2O4-glutamate-Cu (5 mol%)

OH N

H

R 62-95 %

(1.1 equiv.)

R1 = CH2Cl, Me, CH2OCH2CH=CH2,CH2OCnC4H9, CH2OPh, CH2O-p-Tol, CH2O-o-Tol, 4-Cl-C6H4, 4-Br-C6H4, 4-Me-C6H4, Ph (including cyclohexene oxide & cyclopeneteneoxide) R = 4-R''-C6H4 (R'' = 4-OMe, 3-Me, 3-F, 4-F, 4-Cl, 4-C6H13), 2-pyridyl, nC4H9, nC5H12, nPr Figure 7.55: Synthesis of 1,2,3-triazole by three-component coupling among epoxide, terminal alkyne, and sodium azide catalyzed by NiFe2O4-glutamate-Cu.

O Cl +

Ph + NaN3

N N

N

Ph

Ph O + + NaN3

N Ph

N

N N

N

N

OH

Ph

hydroxy bis(triazole)

Figure 7.56: Synthesis of the hydroxy bis triazole.

7.2.8 Three-component coupling reaction among isatin Schiff base, sulfonamide, and aromatic aldehyde The 1,4,5-trisubstituted triazoles were prepared by a completely different coupling set up. The multicomponent coupling among isatin Schiff bases, benzaldehydes, and tosylhydrazine which afforded many structurally diverse 1,4,5-trisubstituted-1,2,3-triazoles. More interestingly, the reaction is metal- and azide-free and promoted under sunlight in the presence of Cs2CO3 as base (Figure 7.57) [87].

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7 Recent approaches toward the synthesis of 1,2,3-triazoles

1

N

R O

NHNH2 O S O +

+

N H (1 equiv.)

H G 2

R Me

R1

O

Cs2CO3 (1 equiv.),

N

N

N R2

DMF, Sunlight, 100 oC 6-8 h

(1 equiv.)

(1 equiv.)

NH2

G

75-90 %

R1 = H, Me, OMe, CN, F, Cl, Br, NO2 R2 = H, 4-Me, 4-OMe, 4-NO2, 4-CN, 4-F, 4-Cl, 3-OMe, 3-NO2, 3,4-(OMe)2 G = CH, N Figure 7.57: 1,4,5-Trisubstituted-1,2,3-triazoles by multicomponent coupling reaction among isatin Schiff base, sulfonalide, and aromatic aldehyde.

The author suggested plausible reaction mechanism (Figure 7.58) and explained with evidence based on various experimental reaction results. The first step was the formation of hydrazone derivative by reaction between aldehyde and tosyl hydrazine. The imine then undergoes deprotonation in the presence of base and the conjugate base thus formed undergoes resonance to form diazo intermediate followed by radical formation in the presence of sunlight under atmospheric oxygen. Here O2 acts as an oxidant and it oxidizes the anion to the radical. In the next step, the radical attacks to the imine bond of isatin ring, with the elimination of Ts radical and a spirocyclic intermediate is formed. The amide bond gets radically hydrolyzed by H2O to produce NH2 and COOH group. Finally, decarboxylation and dehydrogenation occur to afford the desired 1,2,4-trisubstituted 1,2,3-triazole as the final product.

7.2.9 Three-component coupling reaction of 2H-azirine, terminal alkyne, and sodium azide Few researchers emphasize more on the mechanistic investigation rather than the usual formation of triazole by following most common multicomponent route. Zhao and co-workers. [88] explained the formation of 1,2,3-triazole ring formation from 2Hazirines azirine, terminal alkyne, and sodium azide (Figure 7.59) by their theoretical rationalization. They investigated density functional theory (DFT) and MC-AFIR (multicomponent artificial force-induced reaction) (MC-AFIR) and established the mechanistic route involving copper(I)-catalyzed synthesis of 5-enamine-trisubstituted-1,2,3triazole synthesis via C–N cross-coupling and ring opening of 2H-azirines. According to their experimental findings the reaction steps involve (i) dicoppercatalyzed ring opening of 2H-azirines, (ii) alkyne hydrogen atom transfer, (iii) [3 + 2] cycloaddition, and (iv) C–N bond formation through reductive elimination (Figure 7.60). The possibility of as usual mononuclear-Cu(III) intermediate was ruled out in terms of its higher energy

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Figure 7.58: Radical mechanism for the synthesis of 1,4,5-trisubstituted-1,2,3-triazoles.

barrier, AIM analysis, and trapping experiments. DFT outcomes indicate that the transmetalation process is the slow step of the reaction. Their MC-AFIR survey on the prereactant complexes suggested that both the dicopper-catalyzed 2H-azirine RO and activation of spC–H are both thermodynamically viable by a singlet/triplet crossing point. This is attributed by the fact that Et3N play critical for AHT ahead of cycloaddition step. Consequently, this is the main reason for the absence of CuAAC products in this entire interrupted click process.

R'

H +

R N N N

N +

Ph

CuI (10 mol%), DIEA

N

DCM, RT, 12 h R'

N

N RPh

N H upto 97%

N DIEA = N,N-Diisopropylethylamine (Hünig's base) Figure 7.59: 1,4,5-Trisubstituted 1,2,3-triazole formation by multicomponent reaction among from 2H-azirines azirine, terminal alkyne, and sodium azide by Cu-NHC@SiO2.

7 Recent approaches toward the synthesis of 1,2,3-triazoles

Ring opening of azirine

Cu

Cu

hydrogen atom transfer (HAT)

N

N Ph

N

Cu

Ph

R'

R N N N N

R'

N

N R Cu H N Ph

N RPh N H

Dis-Cu R'

Cu HN

Cu

N

Ph

Cu R'

287

Cu

N

R'

N

N

N

N R

N H Cu C-N bond formation

N R N Cu H

Figure 7.60: Mechanism of 1,4,5-trisubstituted 1,2,3-triazole synthesis involving ring opening of azirine and HAT (hydrogen atom transfer).

7.2.10 Three-component coupling reaction of diazomethane sulfonamides, primary aliphatic amines, and aromatic aldehydes Another motivating metal-free three-component synthesis of 1,5-disubstituted 1,2,3triazoles from α-acetyl-α-diazomethane sulfonamides, primary aliphatic amines, and aromatic aldehydes was reported by Krasavin and coworkers [89]. The 1,2,3-triazoline-4sulfonamides were isolated as reported by their immediate former work [90], which endured aromatization via the elimination of sulfur(IV) oxide and amine to afford 1,5isomer (Figure 7.61). In the other variant, both chemical transformations take place in a single step conducted at room temperature. A brilliant modification in the above protocol was done by Malkova et al. [91], taking 2-azido benzaldehyde and propargylamine considering further a tandem [3 + 2] cyloaddition. When these duos were subjected to react with α-acetyl-α-diazomethane sulfonamide structurally intriguing bistriazolo-diazepine and bistriazolo-diazocine were obtained at room temperature (Figure 7.62). When but-3-yn-1-amine hydrochloride reacted, the temperature was increased to 120 °C to get the corresponding bis triazol product. After the formation of monotriazole unit by previous process the free azido end then reacts with triple bond of the propargylamine via intramolecular AAC reaction. They also showed the variation in the propargylamine part taking both internal and terminal alkyne. Few azido compounds such as 2-azidoquinoline-3-carbaldehyde, 2-azido-1-methyl-1H-indole-3-carbaldehyde, and 2-azido-5-nitrobenzaldehyde (Figure 7.63)

288

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Molecular sieve O O O MeOH S Ph O Base N + + R'NH2 RT, 18 h N2 Boc R H

O

Ph H N Boc

S R O H N N R' N

R R'

N

N N 45-90 %

Figure 7.61: Metal-free synthesis of 1,5 disubstituted 1,2,3-triazol by three-component reaction among α-acetyl-α-diazomethane sulfonamides, primary amine and aryl aldehyde.

fail to give the desired reaction. The as-synthesized different types of bis(triazole) compounds were found noncytotoxic and tested against lung cancer cell lines A549 and NCIH460 and found very low level of cell proliferation.

Figure 7.62: Synthesis of bis(1,2,3-triazolo) diazepine and diazocine compounds.

CHO

O O2N

CHO H

N3

N3 N Me

N

N3

Figure 7.63: Structure of inactivated aromatic azide.

7.2.11 Three-component coupling reaction of α-CF3 carbonyls (both ketone and ester), aryl azides, and amines Another metal-free three-component coupling to afford 1,2,4-trisubstituted 1,2,3-triazole was explored by Gao et al. [92], and the coupling partners were α-CF3 carbonyls (both

7 Recent approaches toward the synthesis of 1,2,3-triazoles

289

ketone and ester), aryl azides, and amines. When the enolizable α-CF3 ketones were applied in aqueous reaction medium various substituted 4-amido 1,2,3-triazoles were obtained (Figure 7.64). Control experiment taking 18O-labeling isotope revealed that the in situ-generated β-oxo amide was the key compound for the formal oxygen-shift and the subsequent [3 + 2] cycloaddition reaction, with amine as both the catalyst and reactant. In the case of nonenolizable α-CF3 esters, the densely functionalized 5-amino-1,2,3-triazoles were achieved exclusively. O R1 O 1

R 1

CF3

+

ArN3

R = aryl, alkyl, o-alkyl

+

R2 N H R2

N when R1 = aryl, alkyl Ar N N when R1 = O-alkyl

R2 R N

N R2

R2

O

2

R1

Ar N N N Figure 7.64: Synthesis of 1,2,4-trisubstituted 1,2,3-triazoles from three-component coupling of α-CF3 carbonyls (both ketone and ester), aryl azides, and amines.

Spirostanic 1,4,5-trisubstituted 1,2,3-triazoles were synthesized by the three-component reaction of (25R)-6-azidospirostan-3,5-diols with acetophenones and aryl aldehydes. In this one-pot two-step process, reaction proceeded through the in situ formation of (E)chalcones [93], followed by copper-catalyzed click reaction with organic azides in DMF medium. Products of miscellaneous diversity were achieved by varying the aldehyde and acetophenone nature as well as by changing the stereochemistry of spirostanic azide. Synthesized molecules showed antiproliferative activity against MCF-7, glioblastoma (SNB-19, T98G, A-172), and neuroblastoma (IMR-32, SH-SYSY) (HCT116) cell lines (GI50 in the single-digit micromolar range).

7.3 Four-component coupling reaction for triazole synthesis Four-component MCRs are relatively less common in the literature as compared to three-component coupling routes. One possible reason for this may be that the probability of four body collision is likely to be less than three body collision. But successive bimolecular reaction can lead to the ultimate product. There are however few reports in the literature depicting four-component synthesis of 1,2,3-triazoles or triazoletethered and potentially useful heterocyclic molecules [94–101].

290

Sujit Ghosh, Basudeb Basu

7.3.1 Four-component coupling reaction 2-azidobenzenamines, aldehydes, propiolic acids, and isocyanides The one-pot four-component alkyne–azide cycloaddition reaction (4CR/AAC) involving Ugi reaction is another process for the triazole synthesis. This domino sequence approach affords [1,2,3]triazolo[1,5-a]quinoxalin-4(5H) under metal-free condition as outlined in Figure 7.65. Initially the reaction of 2-azidobenzenamines, aldehydes, propiolic acids, and isocyanides produced the Ugi adducts, which were transformed to the [1,2,3] triazolo[1,5-a]quinoxalin-4(5H)-ones in moderate to good yields via alkyne–azide cycloaddition reaction. 4-Nitrobenzaldehyde and butanal do not undergo this reaction under this for component approach [94].

R3

COOH + R4 N C NH2

R1

+ R2 CHO

N3 (1 equiv. each compound)

R2 Ugi-4CR MeOH, RT, 12-24 h

CONHR4 N

O

R1 N3 R3

R1 = H, 4-Me, 4-Cl, R2 = 4-Cl-C6H4, Ph, 4-Br, 4,6-Me2 2-Cl-C6H4, nPr, p-Tol, 2-furyl, R3 = Ph, Me 2-thienyl 4 R = t-Bu, Cy

IAAC DMF, 90 oC

R2 IAAC: Intramolecular azide-alkyne cycloaddition

CONHR4 N

O

R1 N N N

R3

50-92 % Figure 7.65: One-pot synthesis of [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones by Ugi-4CR/AAC reaction.

7.3.2 Four-component coupling reaction among terminal alkyne, urea, α-azido ketone, and aromatic aldehyde One-pot sequential click-Biginelli reaction afford some important 1,4-disubstituted 1,2,3-triazole-dihydropyrimidinone compounds (1,2,3-trzl-DHPM) [95]. In the sequential series the first step of the reaction involves AAC and the resulting triazole then undergoes Biginelli reaction with various substituted aromatic aldehyde in presence of urea (Figure 7.66). Further bromination on C-6 methyl group of pyrimidine ring followed by azidation and click reaction afforded another class of 1,4-disubstituted 1,2,3-bistriazole dihydropyrimidinone (Figure 7.67). These hybrid compounds are good anti-

291

7 Recent approaches toward the synthesis of 1,2,3-triazoles

proliferative agents. Burke and coworkers have found good in vitro antiproliferative activity [GI50 (growth inhibition of 50%) values are less than 20 μm) in six different human cancer cell lines: A549 and SW1573 (non-small-cell lung), HBL-100 and T-47D (breast), HeLa (cervix), and WiDr (colon)].

+ N3

Ph O H2N

CuI (5 mol%), DIPEA (4 mol%), HOAc (4 mol%) MW, 24 h, 90 oC

O

+ R

R

MeCN

NH2

N N N

Ph

R = H, Cl, OBn R'' R'' = H, Br, OMe

O

R'' NH N H

Aldehyde: Alkyne: Azide: Urea = 1:1:1:1.2

O

39-53 %

Figure 7.66: Synthesis of triazole from terminal alkyne, urea, α-azido ketone, and aromatic aldehyde.

R

R

R

Ph

N N N

R'' TBABr3 (1.5 equiv) Ph NH DCM, RT, 2 h N H

NaN3 (1.5 equiv), DMF Ph 60 °C, NH MW, 30 min

N N N

R''

O Br

(1 equiv.) R''' = Ph, cyclopropyl, 4-Br-C6H4,

N H

O

R'''

Ph

N

N N N

N N

N3

R'''

N O

HN

N N N

R

(1 equiv)

90 °C, MW, DMF

NH O

O

R''

35-97 %

Figure 7.67: Synthesis of 1,4-disubstituted 1,2,3-bis triazole dihydropyrimidinone 1,4-disubstituted 1,2,3-triazole-dihydropyrimidinone by sequential bromination, azidation, and AAC reaction.

R'' NH N H

O

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Sujit Ghosh, Basudeb Basu

7.3.3 Four-component coupling reaction among acid chloride, TIPS-protected 1,3-butadiyne, hydrazine, and alkyl azide Pyrazolyl-tethered-1,2,3-triazole is an important binuclear heteroscaffold and an essential bioactive ingredient. The synthetic route behind the generation of such duo-hetero unit was the four-component coupling among TIPS-protected 1,3-butadiyne, hydrazine, and alkyl azide (Figure 7.68) [96]. Basically, the reaction follows Pd-Cu-catalyzed alkynylation-cyclocondensation-desilylation-CuAAC process, also referred to as ACDC reaction. The mechanistic insight pointed out the pentadiynone intermediate as suggested the following sequential approach (Figure 7.69) via retrosynthestic study. The first step was the Pd-catalyzed Sonogashira coupling which finally ended by CuAAC.

Figure 7.68: Pyrazolyl-tethered-1,2,3-triazoles by four-component coupling among acid chloride, TIPS-protected 1,3-butadiyne, hydrazine, and alkyl azide.

O 1

R

+ Cl

R2 N N R1

TIPS

R3 N N N

Step-I

Step-II H2N

Sonogashira 1 R pentadiynone Alkynylation R2 N N

Step-IV CuAAC

O

R1

H

TIPS Cyclo condensation R2 N N

Step-II Desilylatin

R NH

R1

Figure 7.69: Mechanism toward the synthesis of pyrazolyl-tethered-1,2,3-triazoles.

TIPS

7 Recent approaches toward the synthesis of 1,2,3-triazoles

293

7.4 Five-component coupling reaction for triazole synthesis Five-component approaches toward the synthesis of triazole are rarely found in the triazole or MCR literature [97–100]. Here we have assembled some examples where four-component approach initially produce heteroscaffold leaving azido or alkyne residue to be further triazolized by 1,3-dipolar cycloaddition with corresponding acetylenic dipolarophile or alkyl azide.

7.4.1 Five-component coupling reaction among indole, aromatic aldehyde, propargyl bromide, alkyl halide, and NaN3 The five-component approach was developed by Saehlim et al. [97] to synthesize the indole-triazole hetero-pair scaffold. They used I2 and H2SO4−SiO2 as catalyst in their sequential one-pot three-step procedure. The serial route walked over Friedel-Crafts reactions of indole with aromatic aldehyde followed by N-propargylation and finally CuAAC. The reaction proceeded smoothly yielding a series of bis-indole triazoles hetero duo scaffold at room temperature in a very short reaction (Figure 7.70). A variety of aldehyde derivatives O

H

1

R

+

+

Br

N (1equiv) H

NaN3

R2 (2.2 equiv.) R2 = H, F, Cl, OMe, NO2

R1 = H, F, OMe

One pot synthesis of indole triazoles

+ R3 X +

R3 = alkyl, benzyl, glycosyl

Step-I: H2SO4 -SiO2, I2 (15 mol%), CH3CN, RT, 15 min Step-II: KOH (9.5 equiv.), Propargyl bromide(3 equiv), 1h Step-III: R3X & NaN3 or R3N3 (3 equiv), CuI (30 mol%), Et3N (1.1 equiv), RT, DMF, 1h R2

R1

R1 N

N

R3 N N R3 N N 10-98 % N N Figure 7.70: One-pot synthesis of bis-indole triazole scaffold by five-component approach.

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bearing both electron-donating groups and electron-withdrawing groups were experienced for the reaction, though 4-nitrobenzaldehyde was extremely uncreative (product yield only 17%) under the reaction condition. With the variation in the indole moiety (5-hydroxyindole) or aldehyde component (terephthalaldehyde) bis-indole tetra-triazoles as well as tetra-indole tetra-triazole derivatives were also fruitfully synthesized (Figure 7.71).

Figure 7.71: Synthesis of bis-indole tetra-triazole and tetra-indole tetra-triazole.

7.4.2 Five-component coupling reaction via Ugi-4CR approach Ugi reaction is one of the established multicomponent reactions while scrutinizing MCR techniques. Combination of Ugi and click reaction affords 1,2,3-triazole with another heterocyclic counterpart. An example of such was the combination of UgiCuAAC reaction, strategically in this one-pot procedure, the first step was the fourcomponent synthesis of tetrazole hereto unit leaving a reactive terminal alkynyl chain for to be further cyclized by click protocol. Subsequent steps with organic azide finally via CuAAC result tetrazolo triazole heterocyclic (Figure 7.72) compound [98].

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7 Recent approaches toward the synthesis of 1,2,3-triazoles

One-pot N3 NH2

R2 N C O

+

Ugi rexn

H

N N N N R2 NH

R1

4

5

CuAAC Condition B

Condition A

Si N3

Tetrazole unit 3 N N2 N N R2

R3

1

NH

R1

R1

4

5

N

N

3

R1 = H, 2-X (X = F, Cl, Br); 4-Y (Y = F, Br, OMe); 2,4,5-tri Me R2 = Cy, t-Bu R3 = 4-Z (Z = CN, Cl, NHCOMe)

Triazole unit

N2

1

R3

45-80 %

Condition A: Solvent-free, RT, t-BuOH:H2O (1:1) Condition B: t-BuOH:H2O (1:1), CuSO4 (5 mol%), NaASC (10 mol%)

Figure 7.72: Synthesis of tetrazole-linked 1,2,3-triazole by five-component Ugi-CuAAC approach.

The final product 1,4-disubstituted triazole is also the 1,5-substituted isomer while numbering with respect to tetrazole ring. Such 1,5-DST (disubstituted tetrazole) linked with 1,2,3-triazole moiety are the potent medicinal compounds. Further extension by Knoevenagel condensation of Ugi-CuAAC product produces 3triazolyl-quinolin-2-(1H)-ones as shown by Qian et al. [99], These research groups prepared a variety of novel 3-triazolyl-quinolin-2-(1H)-ones by one-pot, five-component condensation. The first step proceeded via four-component Ugi approach among o-acyl

O

O

O

O Ugi 4CC

NH2 N3 HO

+

NC

MeOH 20 oC,16 h

Ph

O O N3

N O HN

O

CuAAC

N O

Ph 20 oC, 16 h Cu(OAc)2.H2O TEA, NaASC

α -acylamino amides

N N N

HN

Ph N N N N

O O

60 oC, 16 h

HN

3-triazolyl-quinolin-2-(1H)-ones

Figure 7.73: Synthesis of 3-triazolyl-quinolin-2-(1H)-ones via five-component Ugi-CuAAC-Knoevenagel approach.

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aniline, aldehyde, isocyanide, and 2-azido acetic acid to provide α-acylamino amides with azido functionality. In the second step, the azido end of α-acylamino-amides is converted to triazole unit by CuAAC. Intramolecular Knoevenagel condensation finally cyclized the triazole-linked α-acylamino-amides to 3-triazolyl-quinolin-2-(1H)-ones (Figure 7.73).

7.4.3 Five-component coupling reaction of N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides, and sodium azide Spirochromeno carbazole-tethered 1,2,3-triazoles, which are potential anticancer drugs, were synthesized by MCR approach (Figure 7.74) using CuI NPs [100]. Chavana et al. [100] employed this five-component approach among N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides, and sodium azide using cellulose-supported CuI NPs (cell-CuI NPs) as the heterogeneous catalyst to prepare triazole-linked important scaffolds. These compounds showed selective activity toward specific cancer cells but nontoxic toward normal cells.

Figure 7.74: Synthesis of spirochromeno carbazole-tethered 1,2,3-triazoles.

7 Recent approaches toward the synthesis of 1,2,3-triazoles

297

7.5 Conclusion The synthesis of 1,2,3-trizole moiety via MCR represents an extremely important and promising tool. Over the last two decades, this technique has been diversely applied in the field of pharmaceutical chemistry, drug delivery research, etc. The CuAAc has not only redesigned as a multicomponent approach but also there are several new coupling partners have been found to be active in this MCR for the final synthesis of 1,2,3-triazoles. As such, apart from the commonly used alkyl halide, terminal acetylene, NaN3 in the “click” protocols, several other components like aryl boronic acide, aldehyde, 2-azido benzaldehyde, diazo compound, α-keto acetal, tosyl hydrazine and primary amine, N-propargyl ortho-bromo benzamide, N-propargyl isatins, malononitrile, 4-hydroxycarbazole, sulfonamide, amine, o-phenylenediamine, arylchalcogenyl alkynes, urea, α-azido ketone, propiolic acid, isocyanide, o-acyl aniline, and diyne have been successfully employed. Similarly, in addition to new versions of Cu-based catalysts, other metal salts/complexes based on Zn, Mn, Ru, Ni, etc., both as homogeneous and heterogeneous forms, have been investigated and some successful results are observed toward triazole synthesis. Attempts have also been made toward developing and maintaining greener aspects such as use of water as solvent, energy, and waste minimization procedures. Besides, three- and four-component MCRs, the fivecomponent approaches for the synthesis of triazoles have also been investigated. However, it is envisioned that there could be a significant turn of this multicomponent click protocol to synthesize 1,2,3-triazole scaffolds using completely metal catalyst-free conditions.

List of abbreviation AAC ARF BDC BHT CPTMS DABCO DFT DST EDG EWG HAT IAAC ICP−AES MC−AFIR MCAP MCR

Azide–alkyne cycloaddition Amberlite resin formate Benzene-1,4-dicarboxylic acid Butylated hydroxytolune 3-Chloropropyl trimethoxysilane 1,4-Diazabicyclo [2.2.2]octane Density functional theory Disubstituted tetrazole Electron-donating group Electron-withdrawing group Hydrogen atom transfer Intramolecular azide-alkyne cycloaddition Inductively coupled plasma-atomic emission spectroscopy Multicomponent artificial force-induced reaction Multicomponent assembly process Multicomponent reaction

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MOF NaASC NPs rGO TIPS TLOP TPP trzl-DHPM Ts

Molecular organic framework Sodium ascorbate Nanoparticles Reduced graphene oxide Tris-isopropylsilyl Triazole-linked organic polymer Tris-triphenylphosphine Triazole-dihydropyrimidinone Tosyl group

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Yadavalli Venkata Durga Nageswar✶, Katla Ramesh, Katla Rakhi

8 Synthesis of various bioactive tetrazoles via one-pot multicomponent click reactions 8.1 Introduction Tetrazoles containing a five-membered ring with four nitrogen atoms and one carbon atom are nitrogen-rich, aromatic, and stable to several oxidizing or reducing agents. They can be of four types: (a) simple unsubstituted tetrazoles; (b) mono-substituted tetrazoles like 1-, 2-, or 5-substituted, (c) di-substituted tetrazoles such as 1,5- or 2,5disubstituted, and (d) tri-substituted tetrazolium salts such as 1,3,5-, 1,4,5-, or 2,3,5- trisubstituted. Tetrazole chemistry, particularly 5-substituted 1H-tetrazole derivatives have been extensively studied. Bladin first reported the preparation of tetrazoles in 1885 [1, 2]. They play a significant role as valuable pharmacophores in the design and development of drug molecules. Many tetrazole-containing compounds exhibit activities like antibacterial, antifungal, antiviral, analgesic, anti-inflammatory, anti-ulcer, anticonvulsant, and anti-allergic activities [3–9]. Moreover, the tetrazole derivatives have also found applications in the areas like material science [10–14], photography, agriculture as plant growth regulators, herbicides, and fungicides [15, 16], organocatalysis, and coordination chemistry [16]. Valsartan, irbesartan, losartan, and candesartan are a few examples of antihypertensive drugs with tetrazole scaffolds. Some of the important scaffolds with tetrazole skeleton are presented in Figure 8.1. Hantzsch and Vagt [17] in 1901 reported the synthesis of 5-amino-1H-tetrazole from cyanamide and hydrazoic acid involving the [3+2] cycloaddition, which has become a classical method for 5-substituted 1H-tetrazoles. As this method suffered from various drawbacks like hazardous reactants, moisture-sensitive reaction conditions, and the use of strong Lewis acids increased efforts were required towards modifying the methods for the synthesis of 5-substituted 1H-tetrazoles. In 1958, Finnegan et al. [18] improved the procedure from nitriles (1) using sodium azide (2) and ammonium chloride in DMF (Figure 8.2).

Acknowledgment: Ramesh Katla (Foreign Visiting Professor: Edital No. 03/2020) thanks the PROPESP/ FURG, Rio Grande-RS, for visiting professorship. ✶

Corresponding author: Yadavalli Venkata Durga Nageswar, Retired Chief Scientist, Indian Institute of Chemical Technology – IICT, Tarnaka, Hyderabad, India, e-mail: [email protected] Katla Ramesh, Katla Rakhi, Organic Chemistry Laboratory-4, School of Chemistry and Food, Federal University of Rio Grande-FURG, Rio Grande, RS-Brazil https://doi.org/10.1515/9783110985313-008

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Figure 8.1: Biologically active molecules containing tetrazole ring.

Figure 8.2: Synthesis of 5-substituted 1H-tetrazoles from nitriles using sodium azide and ammonium chloride.

[3+2] Cycloadditions between nitriles and an azide constitute an efficient and common route for the synthesis of 5-substituted 1H-tetrazoles. Apart from sodium azide (NaN3) (2), other azides, like benzenesulfonylazide, p-toluenesulfonyl azide, trimethylsilylazide (TMSA), diphenylphosphorylazide (DPPA), tributyltinazide (TBSnA), tetrabutylammoniumazide (TBAA), and organoaluminiumazides have also been employed. Lewis acids, copper salts, iron salts, zinc salts, amine salts, and heterogeneous catalysts, have been used to activate the azide–nitrile cycloaddition reaction. These synthetic methods use

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expensive reagents, toxic metals, high boiling solvents, high temperatures, and long reaction hours. In 2001, Demko and Sharpless [19] reported a cycloaddition reaction between nitriles and sodium azide in water in the presence of ZnBr2 as a catalyst to generate 5substituted 1H-tetrazoles. Since then many methods have been described for the preparation of 5-substituted 1H-tetrazole derivatives. Some of these include the use of – NaN3, CoY, DMF, 120 °C [20]; NaN3,CuFe2O4, DMF, 120 °C [21]; NaN3, K-10-M (M = Fe, Zn, Cu, Ni), DMF, reflux [22]; NaN3, zeolite and zirconia, DMF and H2O, reflux [23]; NaN3, InCl3, DMF, microwave heating [24]; NaN3, TMSCl-NMP, microwave irradiation [25]; NaN3, AcOH, NMP-H2O, microwave irradiation [26]; NaN3, montmorillonite K-10, microwave heating [27]; NaN3, MBA-ZnO, DMSO, 120–130 °C [28]; NaN3, ionic liquids, AcOH, microwave irradiation [29] and nano-powder, DMF,90 °C [30]. Patil et al. [31] have reported a method for the synthesis of 5-substituted 1H-tetrazoles by the reaction of organic oximes with sodium azide in the presence of 25 mol% of copper acetate in DMF. Direct conversion of arylboronic acids to tetrazoles catalyzed by an ONO pincertype Pd(II) complex was reported by Vignesh et al. [32]. Ishihara et al. [33] prepared tetrazoles from amides and diphenylphosphorazidate or bis(p-nitrophenyl) phosphorazidate, which act as both azide source as well as the activator of amide–oxygen for elimination. Various amides were converted into 1,5-disubstituted and 5-substituted 1H-tetrazole derivatives in good yields without employing any toxic or explosive reagents. Ishihara et al. [34, 35] also effectively synthesized 5-substituted 1H-tetrazoles from different aldoximes and diphenylphosphorazidate (DPPA). Patil et al. [36] prepared a library of highly substituted 5-(hydrazinomethyl)-1-methyl-1H-tetrazoles using N-Boc-protected hydrazine in the Ugi tetrazole reaction. Pathare et al. [37] prepared aminotetrazoles from aryl azides, isocyanides, and TMSN3 utilizing a Pd-catalyzed azide–isocyanide denitrogenative coupling to provide an unsymmetric carbodiimide, which reacts with TMSN3 in the presence of FeCl3 in a single pot. Sridhar et al. [38] established a simple one-step bismuth(III) triflate-catalyzed approach for the synthesis of 5-substituted 1H-tetrazoles directly from aldehydes by the reaction of acetohydroxamic acid and sodium azide. Mohammad Abdollahi-Alibeika and Moaddeli [39] applied copper-modified molecular sieves with MCM-41 nano structured heterogeneous recyclable catalyst in the novel multicomponent one-pot preparation of 5substituted 1H-tetrazoles from aldehyde, hydroxylamine, and sodium azide. The heterocyclization reaction of primary amines (4), orthoesters (5), and azides (2) leads to the preparation of tetrazole (6) and its 1-mono- and 1,5-disubstituted derivatives (7) (Figure 8.3) [40]. The term “click chemistry” was coined by Demko and Sharpless [41] when they reported (3+2) cycloaddition reaction conducted between an azide and nitrile moieties resulting in tetrazole formation. Copper(I) as a catalyst [42–45] facilitates a remarkable enhancement of reactivity and regioselectivity, in the case of terminal alkynes acting as the dipolarophile. A metal-free approach was developed by Amantini et al. [46] using tet-

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Figure 8.3: Synthesis of 1,5-substituted tetrazoles.

rabutyl ammonium fluoride (TBAF) as catalyst in the reaction between nitrile compounds and trimethylsilylazide (TMSN3). Due to the mild reaction conditions required and high selectivity, click chemistry has been widely used in material sciences, bioconjugation, and biolabeling. It is also applied in pharmaceutical and biotech industries. Click reactions can be classified into three categories: (1) Cu(I)-catalyzed azide–alkyne click chemistry reaction (CuAAC) (2) Strain-promoted azide–alkyne click chemistry reaction (SPAAC) (3) Ligation between tetrazine and alkene (trans-cyclooctene) The classic copper-catalyzed azide–alkyne cycloaddition is a rapid and effective click reaction for bioconjugation. But it is not suitable for use in live cells due to the toxicity of Cu(I) ions. Due to the oxidative damage caused by reactive oxygen species produced by the copper catalysts this is not suitable for use in live cells. Copper complexes also induce changes in cellular metabolism. Strain-promoted alkyne–azide cycloaddition (SPAAC) has been promoted as a modification to Cu-free click chemistry as a bioorthogonal reaction. Copper-free click chemistry as a bioorthogonal reaction was first developed by Carolyn Bertozzi as a variant of an azide–alkyne Huisgen cycloaddition, based on the work by Karl Barry Sharpless et al. The term “bioorthogonal chemistry” was coined by Carolyn R. Bertozzi in 2003. It refers to any chemical reaction that can occur inside the living systems without interfering with native biochemical processes. The Nobel Prize in Chemistry in 2022 was awarded to Bertozzi [47] for her contribution to the development of click chemistry and bioorthogonal chemistry. This review presents some of the recent research findings in the synthesis of tetrazoles by click chemistry.

8.2 Recent literature reports Chermahini et al. [48] successfully utilized montmorillonite K-10 or Kaolin clays as an efficient eco-friendly and recyclable catalyst in the synthesis of 5-substituted-1Htetrazoles (8) by the reaction of a series of aromatic/heterocyclic nitriles (1a) with sodium azide (2) in water/DMF. Both conventional heating and ultrasonic irradiation were used for the protocol. Compared to the conventional method, ultrasound irradia-

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tion reduced the reaction times with enhanced catalytic efficiency. The protocol was examined for a wider spectrum of nitrile derivatives. Nitrile (1a) compounds with electron-withdrawing groups provided higher yields (Figure 8.4).

Figure 8.4: Synthesis of 5-substituted 1H-tetrazoles catalyzed by clay.

During the initial optimization studies, the authors assessed the influence of different catalytic loadings, nitrile (1)/azide(2) ratios, reaction times, and solvent types. Between water and DMF, DMF provided better yields due to the higher boiling point and conversion was also faster for both K-10 and Kaolin. The catalyst was recycled for three runs consecutively. Linda I. Nilsson et al. [49] described highly selective CuI-catalyzed alkyne cycloaddition with electron-deficient azides (9) via tetrazolo[1,5-a]pyrimidines (10) generating new 41-substituted-2-(11,21,31-triazol-11-yl)pyrimidines (11). It was observed that the alkyne (12) substituent influences the rate of reaction. The influence of the nature of the solvent was also realized by changing from alcohol to toluene, which brought about rapid reaction in the copper-catalyzed azide–alkyne cycloaddition (CuAAc) (Figure 8.5). The scope of the method was established by subjecting 2-azopyrimidines to CuAAc with a broad range of terminal alkynes to explore both steric and electronic effects. Herawi et al. [50] reported a practical, one-pot three-component protocol for the synthesis of 5-substituted-1H-tetrazole (14) derivatives obtained by the reaction of diversely substituted aryl aldehydes (15), hydroxylamine (16), and [bmim]N3 (17). Only traces of the product were obtained when acetaldehyde (15a) was used. In the optimization studies, the authors examined the suitability of the solvents like H2O, DMF, MeCN, as well as solvent-free conditions. Cu(OAc)2 (20 mol%) was observed to be ideal for the reaction. When compared to the electron-withdrawing substituents, electrondonating substituents provided better yields (Figure 8.6a–b). Saiprathima and coauthors [51] developed an efficient, on-water, one-pot, ecofriendly synthesis of quaternary centerd 3-hydroxy-3-(1H-tetrazol-5-yl)indoline-2-ones (18) and 3-(phenylamino)-3-(1H-tetrazol-5-yl)indolin-2-ones (19) via metal-free azide–nitrile

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Figure 8.5: Synthesis of tetrazolopyrimidines.

Figure 8.6: (a) 1-Butyl-3-methyl imidazoliumazide-[bmim]N3. (b) Synthesis of 5-substituted tetrazoles.

(2/1b) (3+2) cycloaddition reaction (Figure 8.7a,b). During the initial studies, the authors examined the efficacy of many catalysts. Patil et al. [52] established an eco-friendly highly efficient β-cyclodextrin-mediated synthesis of 5-substituted-1H-tetrazoles (21) via [2+3] cycloaddition reaction involving vari-

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Figure 8.7: (a) Synthesis of 3-hydroxy-3-(1H-tetrazol-5yl)indoline-2-one derivatives on water. (b) Preparation of 3-(phenylamino)-3-(1H-tetrazole-5yl)indolin-2-one compounds.

ously substituted structurally divergent nitrile (1a) compounds and NaN3(2) in the presence of ammonium chloride in DMF at 120 °C. β-cyclodextrin was recovered and reused three times without significant loss of activity. It was found that β-CD not only improves the yield but also accelerates the reaction. Initially, Li and Ni salts were also studied for their azide ion-releasing capability. β-CD is known as an inexpensive, nontoxic, biodegradable, easily accessible, and reusable catalyst. Desired products were obtained in a simple clean work-up without any column purification (Figure 8.8). A simple, highly effective, regioselective approach for azole-substituted imidazo[1,2a]pyridines (22/23) was unveiled by Kaswan et al. [53]. The protocol follows a ligand-free copper-catalyzed Ullman-type CN cross-coupling of 2-(2-bromophenyl)-imidazo[1,2-a]pyridines (24) with in situ generated 1,2,3-triazoles (25) and variously substituted azoles (25a). It was observed that 20 mol% of CuI and 2 eq. K2CO3 provided encouraging results. The scope and generality of the protocol was expanded to include a series of structurally different azoles such as 1H-benzimidazole, 2-methyl-1H-imidazole, and 4-methyl-1Himidazole. The substrate scope was investigated for the synthesis of 1,2,3-triazole based imidazol[1,2-a]pyridines employing widely substituted phenylacetylenes and aliphatic

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Figure 8.8: β-CD-catalyzed preparation of 5-substituted 1H-tetrazoles.

terminal alkynes (12) (Figure 8.9). Furthermore, functionalization of halo-substituted, azole-substituted imidazo[1,2-a]pyridines was carried out via Suzuki–Miyaura crosscoupling.

Figure 8.9: Synthesis of azole-substituted imidazo[1,2-a]pyridine derivatives.

Cardenes-Galindo et al. [54] synthesized a new series of 2-tetrazolyl methyl-2,3,4,9tetrahydro-1H-β-carbolines(27) following a microwave-assisted, metal-free, one-pot Ugi-azide–Pictet-Spengler process. The authors carried out conventional or microwave-assisted methods as well as one-pot process to obtain the corresponding series of these novel products. In both Ugi-azide and Pictet-Spengler steps methanol was used as solvent (Figure 8.10). Iqbal et al. [55] disclosed the synthesis of nontoxic quinolone-based ionic liquids (30) via N-alkylation (31) followed by anion exchange with fluoride ions (32). The structures were established with advanced spectroscopic techniques. These new ionic liquids were later employed as catalysts for click chemistry and the synthesis of 1H-

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Figure 8.10: Preparation of 2-tetrazolyl methyl-2,3,4,9-tetrahydro-1H-β-carbolines.

tetrazoles (34); 1,2,5,6-tetrahydronicotinonitrile derivative (35), and pyrazole derivatives (36) (Figure 8.11a–d).

Figure 8.11: (a) Synthesis of quinolone-based ionic liquids (QuF). (b) Synthesis of phenyl ring-substituted 1H-tetrazoles by click reaction. (c) Synthesis of 3,5-dimethyl-1-(p-methoxy phenyl)-1H-pyrazole. (d) Solvent-free one-pot Knoevenagel condensation product.

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Figure 8.11 (continued)

Afraj et al. [56] established an efficient, cost effective, two-step, operationally simple method for a new series of (5S, 10R)-10-aryl-5,5a,6,7,8,10-hexahydro pyrrolo [1,2-a]tetrazolo[1,5-d]pyrazines (38/39/40) via a catalyst-free, three-component Strecker reaction followed by an intramolecular [3+2] cycloaddition. The Strecker reaction was performed between diversely substituted aliphatic/aromatic/heterocyclic aldehydes (15) and (S)-2-(azidomethyl)pyrrolidine (41) in the presence of KCN/H2O. In the next step the products underwent intramolecular [3+2] cycloaddition. The products were obtained with good diastereoselectivities. During the optimization, the authors studied the influence of different solvents like H2O, DMSO, DMF, MeOH, CH3CN, DCM, dioxane, and toluene on the reaction (Figure 8.12a, b). A new heterogeneous and recyclable polyvinyl alcohol immobilized Cu(II) Schiff base complex-[PVA@Cu(II)Schiff base complex] was prepared by Milad Kazemnejadi and Sardarian [57]. They successfully applied this catalyst for an eco-friendly, highly efficient, aqueous-phase, one-pot, three-component synthesis of 5-substituted-1H-tetrazole derivatives (42). The method follows click reaction between aliphatic/aromatic aldehydes (15), hydroxylaminehydrochloride (16a), and azide (2) at room temperature in short reaction times. Among the solvents examined – EtOH, MeOH, DMF, CH3CN, Et2O and H2O – water proved to be the best medium. The catalyst was characterized before the application. It was recovered and reused in up to four consecutive runs without significant loss of activity (Figure 8.13).

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Figure 8.12: (a) Strecker reaction followed by intramolecular [3+2] cycloaddition. (b) Representative structures.

Figure 8.13: Synthesis of 5-substituted 1H-tetrazole derivatives promoted by PVA @ Cu(II) Schiff base complex.

An environmentally benign, simple, and cost-effective protocol was revealed by Rad et al. [58] for generating a new series of 5-substituted-1H-tetrazoles (43) having a broad substrate scope, through [3+2] cycloaddition reaction between alkyl nitriles (RCN) (1) and NaN3 (2) promoted by Cu/aminoclay/reduced graphene oxide nano hybrid (Cu/Ac/r-GO). The reactions were performed in water/iPrOH (50:50 v/v). Initially, the authors tested the suitability of various solvents like H2O; H2O/iprOH; H2O/Me2CO; H2O/DMF; H2O/DMSO; H2O/THF; H2O/HMPA; H2O/NMP; H2O/toluene; DMSO, DMF, THF,

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i

PrOH, EtOH, PEG-200, and PEG-400.The authors also examined other parameters like various reaction times and temperatures (Figure 8.14). It was found that H2O/i-prOH at reflux conditions for 4 h provided the best yields with Cu/Ac/r-GO nanohybrid catalyst on the model reaction. The catalytic efficiency of the present nanohybrid was compared with the earlier literature reports, involving various other catalysts. The improved performance of the nanohybrid was observed to be due to the potential π–π✶ interactions of electron enriched r-GO as poly nuclear aromatic sheet with electron-deficient N-heterocyclic cores tethered to α- or β-carbon of the nitrile compounds. In this work, different diversely substituted alkyl nitriles (1) are prepared as substrates by the alkylation of a broad spectrum of bioactive N-heterocyclic cores. It was claimed that Cu/Ac/r-GO nanohybrid was recycled and reused for many consecutive times without significant loss of activity. The amount of leached copper from Cu/Ac/r-GO nanohybrid was observed to be highly negligible (0.008%) even after five runs.

Figure 8.14: Synthesis of novel 5-substituted 1H-tetrazole compounds catalyzed by Cu/Ac/r-GO nanohybrid.

Wright et al. [59] presented the preparation of α-hydroxy-β-azidotetrazoles (45–50) from α,β-epoxy nitriles (1d) in a single step. These were later used for sequential CuAAC reactions leading to a large library of triazolomers by the click process. A total of 11 α-hydroxy-β-triazolotetrazoles and 11 1,1-ethynyl triazoles, and 7 1,1-bitriazoles were generated following the standardized protocols. The authors successfully demonstrated the usefulness of α-hydroxy-β-azidotetrazole moiety as a carbon stapler for varied orthogonal CuAAC reactions (Figure 8.15a, b). Ghumro et al. [60] established the preparation of new N,N-dimethyl pyridin-4-amine (DMAP) (51) based ionic ligands and applied these successfully as efficient, stable catalysts in the solvent-free, eco-friendly synthesis of indole (52) ( via Fischer indole approach) and 1H-tetrazole derivatives (via click reaction) with iminium catalyst. The ILs were subjected to thermal studies (TGA, DSC, and DTG) and molecular dynamic simulations to get the information about their structural and transport properties (Figure 8.16a–c). Pharande et al. [61] unveiled an improved ultrasound-assisted eco-friendly preparation of 1-substituted-1H-1,2,3,4-tetrazoles (55) via a novel isocyanide(28a)-based multicomponent click reaction under solvent, catalyst, and column-free mild reaction

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Figure 8.15: (a) Easily accessible α-hydroxy-β-azido-tetrazoles used for sequential CuAAC reactions. (b) Structures of α-hydroxy-β-azidotetrazoles used for sequential CuAAC reactions.

Figure 8.16: (a) Synthesis of DMAP-based ionic fluoride salts. (b) Fischer indole synthesis-model-reaction. (c) Synthesis of 1H-tetrazoles.

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conditions. The present isocyanide-based multicomponent click reaction (IMCCR) protocol provided products in 71–97% yields (Figure 8.17).

Figure 8.17: Synthesis of 1-STS via IMCCR.

Mehraban et al. [62] developed an efficient, solvent-free, catalyst-free, and eco-friendly protocol for 5-substituted-1H-tetrazole (57) compounds employing choline azide (2c) as an azidation agent, involving the reaction of aromatic/heterocyclic nitrile (1a) derivatives with choline azide at 80–120 °C in about 3–6 h. The products are obtained in the 75–95% range (Figure 8.18).

Figure 8.18: Choline azide-supported synthesis of 5-substituted tetrazole derivatives.

Sardarian et al. [63] reported the synthesis of reusable copper(II) complex supported on Fe3O4@SiO2 coated by polyvinyl alcohol [Fe3O4@SiO2-TCT-PVA-CuII] and the structural and other characteristics were established with the help of FT-IR, XRD, FE-SEM, UV-Vis, DLS, TEM, EDX, TGA, VSM, XPS, NMR, ICP as well as elemental analysis techniques. Later the catalyst was successfully applied to the one-pot three-component, eco-friendly synthesis of 5-substituted tetrazoles (58) via click reaction of aliphatic/aromatic aldehydes (15) with hydroxyl amine hydrochloride (16a) and azides(2). The catalyst was also

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successfully applied to the N-arylation of nitrogen heterocyclic compounds (59) and alkyl amines (4d) with aryl halides (31b) in the absence of external ligands or additives as promoters. The catalyst was reused for seven runs without any significant loss of activity. The authors investigated into various reaction parameters like catalyst loadings, solvents, reaction temperatures, as well as the bases. Among various bases tested t BuONa, K2CO3, NaOH, CS2CO3, NaOAc, and K3PO4, the best results were obtained with t BuONa in DMF with 0.6 mol% catalyst concentration. About 23 diversified N-arylated heterocycles were generated in the range of 83–96% (Figure 8.19a, b).

Figure 8.19: (a) N-Arylation of N-heterocyclic compounds. (b) Synthesis of 5-substituted tetrazoles.

Ajay Gupta et al. [64] prepared a dual synergistic recyclable catalyst Pd-Cu@rGO and after characterization employing XRD, FT-IR, Raman, and X-ray photoelectron spectroscopy as well as analytical techniques, it was applied to the synthesis of triazole (60) and tetrazole(61)-containing biaryls(62) and stilbenes(63) via click reaction. The catalyst was reusable up to seven consecutive runs without significant loss of activity. The authors accomplished the incorporation of Cu on to GO by literature procedure involving the addition of NaBH4 into ultrasonicated mixture of CuCl2 and GO. Finally Pd-Cu@rGO was obtained by the pyrolysis of Pd(OAc)2 in the presence of Cu@rGO in toluene. The authors also applied the catalyst to the synthesis of biaryls with triazole/ tetrazole scaffolds and also carried out scalability studies (Figure 8.20a–d). Goud et al. [65] developed a novel route for the synthesis of highly potent 1Htetrazole derivatives (66) from (Z)-ethyl-3-(1H-indol-3yl)-(1H-tetrazol-5-yl)acrylates (67) and various alkylating agents (31). The starting tetrazolyl acrylates (68) are produced by the Knoevenagel reaction between indole-3-carbaldehydes (15b) and ethyl cyanoacetates (69) catalyzed by L-proline at room temperature and further reaction of the

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Figure 8.20: (a) Pd–Cu @rGO-catalyzed Suzuki reaction. (b) Heck reaction catalyzed by Pd-Cu @ rGO. (c) Preparation of tetrazoles. (d) Preparation of triazoles.

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products with NaN3 (2) in the presence of CuSO4/DMF. During the initial investigation, the authors worked on various reaction parameters to standardize the protocol (Figure 8.21).

Figure 8.21: Synthesis of tetrazole compounds.

Khalili and Rezaee [66] presented the synthesis of an efficient, recyclable, magnetic catalyst-impregnated copper ferrite on mesoporous graphitic carbon nitride-[CuFe2O4/g-C3N4 hybrids]. The structural and morphological characterization of the hybrids were carried out followed by the application to a ligand-free, facile click synthesis of diverse 1,2,3triazoles (70/71/72) and tetrazoles (73), involving aqueous-phase one-pot azide–alkyne (12a) cycloaddition reaction employing alkyl halides (31) and epoxides (74) as azide(2) precursors. During initial optimization studies, the authors assessed the efficacy of Cu(OAc)2·H2O, CuO, Cu, CuFe3O4, and CuF2O4/g-C3N4 and observed the superior capability of CuFe2O4/g-C3N4. The authors also prepared macrocycles possessing the triazole moiety. The catalyst was reused up to six runs (Figure 8.22a–c). Rahini and Ghandi [67] carried out the synthesis of a new series of symmetrical tetrazol-based carbazole compounds (75) from 3,6-diformyl-N-alkyl carbazoles(15d) via a one-pot Ugi-azide reaction of 3,6-diformyl-9-alkyl carbazoles (15d), aromatic amines (4b), trimethylsilylazide (TMSN3) (2a), and isocyanides (28) in methanol medium. In the initial studies, the suitability of several solvents like CH2Cl2, EtOH, H2O,

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Figure 8.22: (a) Click synthesis of diverse 1,2,3-triazoles. (b) Multicomponent synthesis of β-OH-1,2,3triazoles from epoxides. (c) Synthesis of 5-substituted tetrazole derivatives.

MeOH, and THF for the reaction was examined. The efficacy of NaN3 (2) and TMSN3 (2a) was explored as azide (2) source (Figure 8.23a,b). An and Lin [68] produced a panel of sterically shielded tetrazoles (77/78) with different N-aryl groups and evaluated them` for photo-induced tetrazol-alkene cycloaddition reaction. The authors assessed the effect of N-aryl groups on product fluorescence (Figure 8.24a–c). Hajizadeh et al. [69] immobilized Cu(I) on Fe3O4@HNTS-tetrazole (CFHT) nano composite and characterized using physiochemical techniques like CHNS analysis, FT-

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Figure 8.23: (a) Preparation of 3,6-diformyl-9-alkyl-carbazoles. (b) Preparation of novel bis-tetrazole-based carbazoles.

Figure 8.24: (a) Synthesis of the sterically shielded tetrazoles. (b) Cycloadditon of tetrazoles with spiro[2.3]hex-1-ene. (c) Sterically shielded tetrazoles.

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Figure 8.24 (continued)

IR, SEM, TEM, XRD, VSM, TGA, and EDX. Furthermore, the catalyst was applied successfully in the synthesis of 5-substituted 1H-tetrazole derivatives (84) via multicomponent reactions involving malononitrile (1e), diversely substituted aromatic aldehydes (15), and NaN3(2). The catalyst was reused up to five cycles. Catalyst recoverability, high productivity (90–97%), and short reaction times (30–40 min) are notable features of this approach. The catalyst also exhibited remarkable antibacterial activity against E. coli and S. aureus (Figure 8.25). Yao et al. [70] revealed the preparation of 5-substituted-1H-tetrazole compounds (85) by a simple, novel, metal-free approach by the (2+3) cycloaddition of boron azides and nitriles (1a). By shifting NaN3(2) to boron azides (2e) like LiB(N3)4, C2H5N B(N3)3, (N3)3B.N.C4H4, N.B(N3)3, and C9H7N.B(N3)3 an improvement in the yields was observed by the authors. When a catalytic amount of heteropolyacids or amine salts like NH4OAc, NH4Cl, H3PW12O40, and H3PMO12O40 were added to the medium the yields were further

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Figure 8.25: Preparation of 5-substituted 1H-tetrazole derivatives.

increased. H2O, THF, DMF, toluene, and DMF/MeOH were screened as solvents. Conducting the reaction with LiB(N3)4 in DMF/MeOH (9:1) along with 10 mol% NH4OAc proved to be ideal for the approach. Various substituted nitriles (1b) were examined as substrates in the method (Figure 8.26).

Figure 8.26: Formation of 5-phenyl-tetrazole compounds.

Hameed et al. [71] described a one-pot, solvent-free synthesis of 1H-tetrazole derivatives-linked 1,2,5,6-tetrahydronicotino nitriles (86), by the reaction of acetophenones (87) and malononitrile (1e) followed by the addition of azide (2) in the presence of tetra-n-butyl ammonium fluoride trihydrate as solvent and catalyst. The products were screened for cholinesterase inhibition (Figure 8.27). Xue et al. [72] designed and developed an eco-friendly sustainable synthesis of CuNPs decorated on pectin-modified Fe3O4 nanocomposite promoted by Mentha pulegium flower extract as a natural stabilizing/ and reducing agent. The authors characterized the nanocomposite by employing a wide range of physiochemical techniques consisting of FT-IR, elemental mapping, VSM, XRD, IC-OES analysis, FESEM, TEM, and EDX. The catalytic efficiency was assessed by applying it in the synthesis of broadly substituted 1H-tetrazoles (88) via a solvent-free three-component reaction. The nanocomposite was also subjected to reusability, leaching studies, hot filtration, and biological assays (anticancer). From the various studies conducted by the authors, a

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Figure 8.27: One-pot synthesis of tetrazole-1,2,5,6-tetrahydronicotino nitriles.

promising future was expected for the nanocomposite in cancer management. The catalyst was efficient up to nine consecutive runs (Figure 8.28).

Figure 8.28: Cu/pectin@Fe3O4-promoted synthesis of 1-substituted 1H-tetrazoles.

Krištafor et al. [73] reported a one-pot, multistep, microwave-assisted synthesis of 1,2,3triazole (89)-embedded unsaturated Uracil derivatives and the hybrids of 1,5- and 2,5disubstituted tetrazoles and pyrimidines (90/91) employing Cu(I)-catalyzed click chemistry. The compounds are investigated for antiproliferative activity (Figure 8.29a, b). Tamoradi et al. [74] successfully synthesized a magnetic CoFe2O4 centered (95) as paragine-functionalized noble metal (M = Cu, Ni)-anchored nanocomposite. These heterogeneous catalytic materials are characterized by elemental mapping, XRD, SEM, EDX, FT-IR, and VSM. These reusable materials are effectively applied as catalysts in the preparation of diarylthioethers (100) by the C–S cross coupling and azide–alkyne cycloaddition by click reaction affording 5-substituted 1H-tetrazoles (102). Simplicity, high output, magnetic separability, and recyclability of the catalyst are the advantages. Different solvents and bases are examined for suitability in the initial investigations. The catalyst was successfully used for seven runs (Figure 8.30a–c). A high-order, one-pot six-component protocol for 1,5-disubstituted tetrazol-1,2,3triazol hybrid molecules (103) with structural diversity under mild reaction conditions was described by Ceria M. Aguilar-Morales et al. [75]. The present high atom-economy

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Figure 8.29: (a) One-pot, three-step reactions generating 1,2,3-triazole-containing uracil derivatives. (b) Synthesis of 1,5/2,5-disubstituted tetrazol-pyrimidine hybrids.

cascade approach contains three sequential reactions: Ugi-azide, bimolecular nucleophilic substitution (SN2), and copper-catalyzed alkyne–azide reaction (CuAAC) involving the formation of six new bonds (1C-C and 4C-N and 1N-N). The authors evaluated the new molecules for antitumor potential by conducting antiproliferative studies against breast cancer derived cell line MCF-7. These compounds proved to be potential drug candidates against breast cancer (Figure 8.31). Khalili et al. [76] established the catalytic efficiency of a series of copper (I) complexes containing dihydrobis(2-mercapto-benzimidazolyl)borate (Bb) (104) and phosphine co-ligands by applying them in the preparation of nitrogen heterocyclic compounds like 5-substituted tetrazoles (105) and 2H-indazoles (106). The reactions were performed with low catalyst loadings in short reaction timings with operational simplicity. Solvents like DMF, DMSO, H2O, EtOH, Toluene, THF, and PEG-200 were examined for best results. Among 21 compounds, 4 compounds were obtained in trace yields (Figure 8.32a–c).

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Figure 8.30: (a) CoFe2O4@L-asparagine-Cu/Ni nanocatalyst-promoted synthesis of 5-substituted 1H-tetrazoles. (b) Preparation of aryl thioethers. (c) Preparation of the catalyst.

8 Synthesis of various bioactive tetrazoles via one-pot multicomponent click reactions

Figure 8.31: One-pot six-component approach for 1,5-disubstituted tetrazole-1,2,3-triazole hybrids.

Figure 8.32: (a) Synthesis of Cu(II) catalyst complexes. (b) One-pot three-component synthesis of 2H-indazoles. (c) Cu (Bb) (PCy3)-catalyzed synthesis of 5-substituted 1H-tetrazoles.

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Figure 8.32 (continued)

8.3 Conclusions The last few decades have witnessed remarkable growth in click chemistry research and wider scope can be visualized for the development of new strategies towards building tetrazole derivatives. This review is an attempt to bring out the recent advances in tetrazole chemistry. Scholars are advised to go through the original research papers for proper understanding of the chemistry represented here. All the structures are redrawn from these research communications. We acknowledge and appreciate all the original contributors of the research papers and also their publishers cited herein. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

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Kantharaju Kamanna✶, Yamanappagouda Amaregouda

9 L-Proline and its derivatives catalyzed one-pot multicomponent synthesis of biologically promising N- and O-heterocycles 9.1 Introduction Organocatalysis, by definition, uses a simple organic molecule to facilitate organic reactions; it is a reasonably novel as well as a most excited area discovered under the scope of enantioselective (chiral) molecule construction [1]. Although, the idea behind organocatalysis was documented in the last century, it became popular as a discipline of organocatalysis in the late 1990s. Since a small number of reference articles have been reported, it has inspired researchers to explore more in this field. The statistics of organocatalysis manuscripts reported between 1998 and 2008 showed a little more than 1,500 published articles in 130 or more discrete reaction types [2]. Recently, organocatalysis research areas received recognition rewarded due to the significant works of David MacMillan and Benjamin List in this field, who received 2021 the Nobel Prize in Chemistry for their outstanding contribution toward the development of organocatalysts, more precisely a new tool for molecular construction [3]. Currently, the concept of organocatalysts is widely accepted and is considered as one of the important principal divisions of chiral molecule preparation, in addition to the existing and accepted previous organometallic and enzymatic methods. MacMillan explained three important things were essential for the unexpected birth and faster expansion of organocatalysis. They are: conceptualization, wide selection and advantages of the generic mode of activation reactivity, and induction [4]. Yain Shi and coworkers [5], Scott Denmark et al. [6], and Dan Yang et al. [7] reported the use of the chiral ketone to catalyze epoxidation of alkene with enantioselectivity. Following this concept reported, Jacobsen et al. [8] demonstrated first example of asymmetric Strecker reaction via hydrogen-bonding organocatalysts. Corey et al. [9] described chiral bicyclic guanidine as an catalyst in the enantioselective synthesis of -amino nitriles. Miller et al. [10] reported alcohol dervivatives can be resolved kinetically by tripeptide oraganocatalysts. Until 2000, the field of organocatalysts did not take off as expected; however, the field of organocatalysis was effectively relaunched by the simultaneous publication of ✶

Corresponding author: Kantharaju Kamanna, Department of Chemistry, School of Basic Sciences, Rani Channamma University, Vidyasangama, P-B, NH-4, Belagavi 591156, Karnataka, e-mail: [email protected] Yamanappagouda Amaregouda, Department of Chemistry, School of Basic Sciences, Rani Channamma University, Vidyasangama, P-B, NH-4, Belagavi 591156, Karnataka https://doi.org/10.1515/9783110985313-009

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two articles by Benjamin List and MacMillan and their coworkers [10] on enamine and iminium catalysis, respectively. The research work of List et al. explained the underlying mechanism of Hajas–Parrish reaction and it extended to a broader transformation, specifically the intermolecular Aldol reactions [11]. Similar to this work demonstrated use of a small organic molecule could catalyze reaction on that of bigger enzyme molecules and is comparable catalytic activities. Later researcher explained another iminium catalysis pathways involved three crucial concepts conceived focusing on how organocatalysts offered economic, scientific as well as environmental outline advantages broadly activated strategies could use with a wide range of reaction types [12, 13]. The community of chemical synthesis recognized that organocatalysis offered inherent benefits such as simplicity and low cost in completing a reaction. The advantages of organocatalysts, especially amino acids-derived, brought the prospects of a complementary mode of catalysts, with the objectives of cost reduction, energy, time, easier experiments set up, and chemical waste reduction [14–18]. Other properties, like unaffected by atmospheric moisture and oxygen, gave wide scope to select environmentally friendly and nontoxic compound [19]. For the first time, List et al. [20] described the use of L-proline amino acid-catalyzed highly enantioselective intermolecular variants of Hajas-Parrish-Eder-Sauer-Wiechart reaction. Subsequently, this discovery provided insights to various research groups to explore and design more efficient organocatalysts, majorly reported in the asymmetric organic synthesis, and employed more than one functionality in the catalytic mechanism, either through covalent or noncovalent interactions [21]. Researchers revealed the strongest technique to establish carbon–carbon (C–C) bonds by an asymmetric aldol reaction in a chiral manner [22]. The most important improvement mode in organocatalyzed Aldol reaction by developing catalyst with proline skeleton containing various H-doner and acceptor functionalities derivatives has been well documented and discovered [23].

9.2 Why proline prefers as a good organocatalysts among other natural amino acids? The only secondary amine functionality containing natural amino acid that exists is Proline. It showed better nucleophilicity and it raises the pKa value, compared to other amino acids. It can act as a Michael acceptor (enamines) or as a nucleophile to carbonyl groups (iminium intermediate). It can be regarded as a dual functional catalyst. The high stereoselectivity achieved is possibly due to its formation of organized transition states with many hydrogen bonding frameworks. Proline is not the only molecule that promotes catalysis, but it still seems to be one of the best molecules involved in diverse organic transformations [24, 25]. Multicomponent reactions (MCRs) emerged as a valuable and efficient methodology in the section of synthetic chemistry due to the advantages of one-pot procedure,

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atom economy, time-saving, and chemical waste reduction, and gained much attention in synthetic organic chemistry. Even though the concept of MCR synthesis for diverse organic molecules has been well known for over a century, it has only recently got more attention and increasing number of publications, emphasizing biologically relevant organic molecules synthesis via this approach [26]. In the reported literature, synthesized heterocycles via MCRs are subjected to various biological activity screening. It was noticed most of such screening focused on anti-inflammatory, antileihsmanial, ROCK inhibitors, antifibrotic agents, bromodomain inhibitors, neuroprotective agents, human toll-like receptor 8-active, anti-HIV, acetylcholinesterase inhibitors, antioxidant, antimycobacterial, antimicrobial, and anticancer activities [27]. Numerous MCR procedures applied to the construction of organic molecules clearly showed that MCR-based approaches are exceptionally promising in drug discovery and screening processes in medicinal chemistry and in drug discovery programs due to their operational simplicity, high atom-economy, time/cost efficiency, and generation of diverse structural multifunctional substrates [28]. The corresponding nitrogen- and oxygen-containing heterocycles developed via MCRs approaches catalyzed by L-proline (Figure 9.1) and its derivatives that are recently reported in literature are discussed in this chapter.

Figure 9.1: The structure of L-proline amino acid.

9.3 L-Proline-catalyzed synthesis of N-heterocycles Chemistry of nitrogen-based heterocyclic is an important and special class among the applied branches of organic chemistry, with a promising number of research establishments working on the development of novel molecules and composites. These heterocycles received increasing attention over the past two decades, and contributed to the development of numerous organic synthetic routes, catalyzed by a wide range of homogeneous and heterogeneous catalysts. These derivatives showed a vast range of pharmacological applications in pharmaceuticals, agrochemicals, and insecticides [29, 30]. Some of the recently reported L-proline-catalyzed MCRs are discussed in the following section. Parvin and coworkers [31] reported the one-pot synthesis of 1,4-dihydrobenzo[b] [1,8]-naphthyridine (4) by the reaction of 6-aminouracil derivative (R=H, Me, 1) with a substituted quinoline aldehyde (R1=6-Me, 6-OMe) (2) and dimedone (3) in the presence of OCP-1 in ethanol under reflux condition (Figure 9.2). The authors demonstrated aminopyrimidine, regarded as a potential MCR substrates, for the synthesis of various heterocycles, and tested it for its biological activities in addition to this one, and they showed strong antimicrobial and biofilm inhibitory capabilities.

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Figure 9.2: Synthesis of functionalized 1,4-dihydrobenzo[b][1,8]-naphthpyridines.

Li and Zhao [32] reported the successful isolation of pyrazolo[3,4-b]quinoline derivatives (9) using a 4-CR of phenylhydrazine (7), 3-aminocrotononitrile (6), substituted benzaldehyde (8), and 2-hydroxynaphthalene-1,4-dione (5) catalyzed by OCP-1 “on water” (Figure 9.3). The authors explained that the mechanistic pathway of the reaction involved unattached hydroxyl groups of water to be interacted with organic reactants, which led to transition state activation energy lowering, enabling the reaction rate, and increasing the yields in the water-mediated processes.

Figure 9.3: Preparation of pyrazolo[3,4-b]quinoline.

Bonne et al. [33] described unsymmetrical 1,4-DHPs (13) in a three-component OCP-1 catalyzed process, which involved the condensation of a chiral aldehyde derivative (11), 1,3-diketone (12), and a chiral substrate, provided by an enaminoester (10), and gave a product high yield (Figure 9.4). The authors claimed the developed method was atom economic, one-pot, and had mild and minimal waste. Kamalraja et al. described a three-component domino reaction, integrating azido ketone (14), p-tolualdehyde (15), and 3-cyanoacetylindole (16) in the presence of OCP-1. It gave highly substituted and functionalized indolyl pyrrole derivatives (17). Although the authors picked piperidine as their favorite catalyst, they later discovered OCP-1 (25 mol%) in water as an effective catalyst, which gave 75% of the product in 80 °C condition (Figure 9.5) [34].

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Figure 9.4: Unsymmetrical 1,4-DHP synthesis.

Figure 9.5: Synthesis of tetrasubstituted pyrrole via OCP-1 catalysis.

Qi and coworkers [35] reported tetrahydro-4H-indol-4-one derivative (20) by the reaction of cyclohexane-1,3-dione (3), amine (18), and nitroolefin (19), catalyzed OCP-1 in aqueous medium. The authors screened various catalysts (acetic acid, Et3N, DMAP, pyrrolidine, N-methyl morpholine (NMM), K2CO3, and D,L-alanine), and L-proline emerged superior to all other tested catalysts. Further, the authors also examined suitable solvents and found water medium to be better, but protic solvent methanol and 2-propanol also gave high yields. A variety of arylamines and nitroolefins were used in water at 60 °C, which revealed scope and generality of the reaction, and gave excellent product isolation (Figure 9.6).

Figure 9.6: Synthesis of tetrahydro-4H-indol-4-one.

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Zare and Nikpassand [36] reported Hantzsch 1,4-DHPs (23) synthesis by the reaction of aryl aldehyde (21), dimedone(3), and ammonium acetate (22) in water reflux condition in the presence of OCP-1. It gave hexahydroacridine derivative (23) (Figure 9.7). The author also observed that the reaction still took place without proline, albeit in a slow rate, and gave a low yield. Furthermore, they claimed that N-substituted derivatives of (39) synthesized in aqueous ethanol, utilizing aryl and benzyl amines instead of ammonium acetate (38), gave excellent yield, compared to camphor sulphonic acid-catalyzed.

Figure 9.7: Hantzsch dihydropyridine synthesis.

Kumar and Maurya [37] reported a four-component unsymmetrical Hantzsch condensation of aryl aldehyde (21), dimedone (3), acyclicdicarbonyl (24), and ammonium acetate (22) in water medium under room temperature gave hexahydroquinoline (25). The authors screened a number of catalysts, including L-proline, trans-4-hydroxy-L-proline, L-thioproline, D/L-phenylglycine, and (–)-cinchonidine during optimization. But, L-Procatalyzed reaction gave product isolation in high yields. Also, the authors observed that EtOH, H2O, and solvent-free condition for this reaction gave consistent findings, and the procedure worked well for the aromatic aldehyde, in electron-withdrawing or -releasing groups (Figure 9.8). The authors also studied comparable transformation, starting from ethyl acetoacetate, 1,3-indanedione, and ammonium acetate, for the synthesis of unsymmetrically fused 1,4-DHP-catalyzed L-Pro in water under reflux condition. Khazaei and Panahi [38] reported that a reaction of arylamine (26), aryl aldehyde (21), and malononitrile (27) gave 2-amino-4-arylquinoline-3-carbonitrile (28) in water reflux condition (Figure 9.9). Further, the authors extended the procedure to generate spiro-pyrimido[4,5b]quinolinedione frameworks by using cyclohexanone as the carbonyl-starting material. The authors claimed that minimizing the number of reaction steps and using straightforward, reasonably priced starting materials enable the costeffective synthesis of a variety of complicated chiral molecules. Tabassum et al. [39] demonstrated that a water reaction involving four components for the reaction of aryl aldehyde (29), malononitrile (27), acetylene dicarboxylate (31), and arylamine (30) yielded polysubstituted-1,4-DHPs (32) in another variant of the Hantzsch DHP synthesis. The best results were obtained by CuI, according to the authors’ testing of a variety of catalysts, including InCl3, CuO, CuI, CuCN, CuBr, DBU, and piperidine. During

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Figure 9.8: Synthesis of hexahydroquinoline via Hantzsch reaction.

Figure 9.9: Synthesis of 2-aminoquinoline.

these optimization investigations, it was shown that L-proline (20 mol%) could accelerate the reaction to produce the product (32) in 30 min at room temperature – 50% yield was obtained from benzofurane-2-carbaldehyde (29), aniline (30), dimethylacetylene dicarboxylate (31), and malononitrile (27) (Figure 9.10).

Figure 9.10: Ultrasound-promoted synthesis of 1,4-dihydropyridines.

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Sarkar and Mukhopadhyay [40] developed a simple three-component reaction, starting with cyclic 1,3-diketone (33), primary amine (34), and dialkyl acetylene dicarboxylate (35) in water using OCP-1. It gave fused N-substituted-2-pyridone derivatives (36) (Figure 9.11). The authors screened a wide range of catalysts, including SiO2, alumina, MgSO4, p-TsOH, InCl3, glycine, L-proline, pyrrolidine, TiO2, and nano TiO2, but tests revealed that L-Pro showed superior performance to other catalysts. Additionally, the authors also examined the solvent system for the reaction, such as acetonitrile, ethanol, toluene, DMF, DMSO, and water as solvents, and concluded that 10% OCP-1 with 10% SDS as a surfactant in water at 100 °C produced excellent yields. The authors claimed tolerance of the reaction for various substituted substrates such as alkynes, primary aryl or alkyl amines, and various cyclic 1,3-diketones.

Figure 9.11: Substituted 2-pyridone derivative synthesis.

Kumari et al. [41] reported the synthesis of 2,3-dihydroquinazolin-4(1H)-ones (38) by the reaction of isatoic anhydride (37), aryl aldehydes (21), primary amines (34), or ammonium acetate (22) in a single step under MW irradiation in water medium catalyzed OCP-1. The authors screened several amino acids, including glycine, L-alanine, L-proline, and L-valine, and solvent systems, including water, ethanol, methanol, and acetonitrile, but finally the authors noticed that L-proline/water system was more effective and gave the desired products in high yields (Figure 9.12).

Figure 9.12: Dihydroquinazolinone derivative synthesis.

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Shanthi and Perumal [42] reported that a OCP-1-catalyzed reaction of indole (39), salicylaldehyde (40), and malononitrile (27) in water produced indolylchromene derivatives (41). The authors tested several different substituents present in both salicylaldehyde (40) and indole (39) and observed that they gave exceptional yields (Figure 9.13). The authors examined in vitro antioxidant activity of the isolated product. Further, the authors altered the nucleophile to dimedone (3) and synthesized the product 42 under aqueous micellar conditions (Figure 9.13). The authors screened catalysts, which include anhydrous FeCl3, CeCl3.7H2O, ZnCl2, glycine, piperidine, and pyruvic acid, but L-proline emerged as better catalyst; it gave a high yield and product selectivity, and the addition of 8 mol% SDS, an anionic surfactant, increased the reagent’s solubility, leading to excellent yield in water (77–95%). The authors claimed both indole and salicylaldehyde substituted high substrate tolerance.

Figure 9.13: Indolylchromenes and 9 (1H-indol-3-yl)-xanthen-4-(9H)-one synthesis.

Perumal and coworkers [43] reported that a four-component domino reaction in water for the reaction of 1,3-dcarbonyl (43), phenyl hydrazine (44), malononitriles (45), and dialkylacetylene dicarboxylate (35) gave 4H-pyrano[2,3-c]pyrazol-6-amines (46) (Figure 9.14). The authors claimed the developed method minimized the number of reaction steps and was straightforward, with accessible starting materials, enabling the cost-effective synthesis of a variety of complicated chiral molecules. Prasanna et al. [44] described that the formation of two rings and five new bonds (two C–C, one C–N, one C–O, and one C=N) in a single step make this reaction incredible for the alkyl 3,3-bis(5-hydroxy-1H-pyrazol-4-yl) propanoates (48) synthesis. The authors claimed that a one-pot reaction was able to produce excellent yield (up to 97%) – the reaction involved dicarbonyl compounds (43), hydrazine (44), nitrile (45), and alkyl acetylene dicarboxylate (47) in water under reflux condition (Figure 9.15). Dabiri et al. [45] reported that 3-CRs of isatins (49), tetronic acid (51), and 1,3diaryl-1H-pyrazole-5-amines (50) gave pyrazole-fused spiro compounds (52) (Fig-

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Figure 9.14: Synthesis of highly functionalized pyrano[2,3-c] pyrazoles.

Figure 9.15: Dialkyl acetylene dicarboxylate synthesis.

ure 9.16). The reaction took place in the presence of 10% L-proline in water under reflux condition. The authors observed substrate tolerance and reacted with isatin (49), acenaphthylene-1,2-dione (51), and 2-hydroxynaphthalene-1,4-dione.

Figure 9.16: Synthesis of pyrazole-fused spiro compounds using 3-CRs.

Yu et al. [46] demonstrated that a reaction of hydrazine derivative (54), 1,3-dicarbonyl compound (55), isatin (53), and malononitrile (27) in the presence of L-proline-catalyzed

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4-CRs via in situ formation of a pyrazolone intermediate gave structurally diverse spiro compounds (56) in high yields (Figure 9.17). The authors investigated different catalysts (NaOH, Et3N, TBAF, p-TSA, CAN, FeCl3·6H2O, and ZnCl2) and solvents (ethanol, acetonitrile, DMF, ethyl acetate, DMSO, and water) at varied temperatures (RT, 40–100 °C) for the reaction, and determined that the optimized condition of 10 mol% L-proline in water at 80 °C gave excellent product isolation.

Figure 9.17: Spiro[indoline-3,4ʹ-pyrano[2,3-c]pyrazole] synthesis.

Deka et al. [47] reported that water-mediated MCRs, catalyzed by proline, produced intricate heterocyclic structures with a spirocentre at the barbituric acid’s C-5 position. The authors revealed a high-yielding, operationally simple method for producing pyrido[2,3d]pyrimidin-2-amine-6,5′-pyrimidines (60, 61) in water using 2,6-diaminopyrimidin-4-one (57), aldehydes (58), and barbituric acids (59). The authors noticed that the reaction frequently resulted in the mixers of the two diastereomers (60) and (61), and preferred a geometry of 2,4-cis (Figure 9.18). Dommaraju et al. [48] reported that a pseudo-five component reaction, started with 3-aminocrotonitrile (62), hydroxylamine hydrochloride (63), aromatic aldehydes (64) and barbituric acids (65), refluxing water, created spiro(isoxazolo[5,4-b]pyridine5,5′-pyrimidine) ring system (66) (Figure 9.19). The C-2 and C-4 stereocenters in this scenario are positioned relative to one another. The authors explained that the current approach gave high yields, mild reaction condition, and isolated a pure product. Ghosh and Das [49] demonstrated that a green method for the 3-CRs of 4-hydroxycoumarin (67), aryl aldehyde (68), and cyclic secondary amine (69) gave product 70 in watercatalyzed L-proline at room temperature (Figure 9.20). The derivatives tested by the authors showed promising antibacterial action. Srinivas and Bhandari [50] reported that the synthesis of 3-methylisoxazol-5-amine in the presence of an L-proline-catalyzed reaction of ketone (71) with an unsubstituted

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Figure 9.18: 3-CRs of spiro[pyrido[2,3-d] synthesis.

Figure 9.19: Synthesis of spiro-indoline-3,4ʹ-pyrano[2,3-c]pyrazole.

Figure 9.20: OCP-1-catalyzed Mannich reaction.

azole (72) gave Mannich products (73 & 74) (Figure 9.21). The variety of ketones tested and used by the authors in this reaction gave excellent product yields. Javahershenas and Khalafy [51] reported that a reaction of arylglyoxal (75) and 1,3dimethyl-6-aminouracil (76), combined with 4-hydroxycoumarin (67), gave pyrrolo[2,3d]pyrimidine derivatives (77), when catalyzed by L-proline in acetic acid medium (Figure 9.22). The authors monitored the reaction using TLC [mobile phase: EtOAc/hex-

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Figure 9.21: Proline-catalyzed cyclic ketone in the Mannich reaction.

anes (3:1)]. After the reaction, the precipitate obtained was filtered, cleaned with acetic acid and cold water, dried, and recrystallized from ethanol, to isolate the pure title product.

Figure 9.22: Preparation of pyrrolo[3,2-d]pyrimidine derivatives.

Pons and coworkers [52] reported that a reaction of diazide (79) and cyclohexanone (78) gave the product triazole (80), which when heated in an oil bath at 80 °C under stirring condition gave 63% yield. The production of (80) via a different mechanism corroborated chemoselectivity (Figure 9.23). The authors monitored the reaction using TLC and flash chromatography on silica gel for the purification reported.

Figure 9.23: Chemoselectivity synthesis of triazole derivatives.

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He et al. [53] reported that greener one-pot MCRs of indole (81), malononitrile (27), and aryl aldehyde (34), in the presence of OCP-1, isolated excellent yield of the product, 3-indole derivative (82) (Figure 9.24). The authors claimed that the developed method has added advantages of eco-friendliness, simple protocol, easy availability of catalysts, and mild reaction condition. Further, the authors screened a wide range of organic and inorganic catalysts and organic solvent for the reaction, and noticed that a solvent in the presence of ethanol and the catalyst L-proline (10 mol%) gave excellent product isolation.

Figure 9.24: MCRs of 3-alkylated indole synthesis.

Brahmachari and Das [54] described that a one-pot efficient and direct synthesis of a series of bio active gem-(β-dicarbonyl) arylmethane (83, 84, 85, 90, and 91) prepared via a three-component reaction of indoles, aryl aldehyde, and C–H-activated acids in a grinding method under solvent-free catalyzed (10 mol%) L-proline, isolated an excellent product (Figure 9.25). The authors claimed that the developed method gave high yields, was eco-friendly, showed high atom economy, and demonstrated mild reaction condition requirement, which are the visible benefits of this method. The authors reacted five series of C–H-activated acids. 4-hydroxycoumarin (67), 4–hydroxy-6-methoxy-2H– pyran-2-one (86), dimedone (3), 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (88), N, Ndimethyl barbituric acid, and Meldrum’s acid (89) were tested for this protocol, and they successfully achieved the target heterocycles.

Figure 9.25: Three-component one-pot synthesis of gem-(β-dicarbonyl)arylmethanes.

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Shi et al. [55] described that the one-pot synthesis of spirooxindole derivative, by the reaction of isatins (92), 1, 3-dicarbonyl (51), and malononitrile (cyanoacetic ester) (93), and catalyzed by L-proline under aqueous medium gave excellent product (94) isolation (Figure 9.26). The authors revealed that the advantages of this method are greener, short reactions times, high yields, inexpensive catalysts, and simple operations.

Figure 9.26: Synthesis of spirooxindole derivatives in water medium.

Muhiebes et al. [56] reported that MCRs of aniline (30), methylacetoacetate (95), and aryl aldehydes (34), catalyzed by L-proline in ethanol solvent under reflux condition, gave highly functionalized tetrahydropyridine derivatives (96) in excellent yield (Figure 9.27). The authors revealed that method used a green solvent, was eco-friendly, cost less, required a mild reaction condition, and offered high yield isolation, which are some of the noticeable benefits of this method.

Figure 9.27: Synthesis of functionalized tetrahydropyridine derivatives.

9.3.1 L-proline derivative-catalyzed N-heterocycle synthesis Belkheira et al. [57] reported the synthesis of 1-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1Hbenzo[d][1,2,3]triazole (98) by the reaction of cyclohexanone (78), and p-methoxyphenylazide (97) in the presence of catalysts in the presence of dichloromethane at 80 °C in a sealed tube (Figure 9.28). The authors optimized the reaction by increasing the ratio of ketone to azide from 1:1 to 2:1, and noticed an improved yield, up to 92%. The naturally occurring proline amino acid emerged as a blockbuster entity in organocatalysts for a

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wide range of asymmetric organic transformations. Hence, researchers were excited to explore its derivative for the organic reaction.

Figure 9.28: Synthesis of triazole derivatives.

The same authors investigated the reaction of cyclohexanone (78) and arylazide (99), which gave triazole derivative (100). The authors tested the tolerance of the reaction, and observed that the electron-donating groups gave excellent yield, but electron withdrawing groups, like the nitro group, resulted in less yield of the arylazide (Figure 9.29). The intended triazole synthesis gave a high yield and was quantifiable.

Figure 9.29: Synthesis of triazole derivatives using L-proline as catalyst.

Pratap et al. [58] demonstrated that a number of chiral bifunctional organocatalysts used to study the Michael/hemiketalization of ketoester (101), reacted with 2-hydroxy1,4-naphthoquinone (5) and gave 2-hydroxy-1,4-naphthoquinone (102); it converted in the presence of ammonium acetate, resulting in oxindoleketoester (103) (Figure 9.30). This approach provides an elegant synthetic pathway to oxindole derivative at room temperature in dichloromethane with organocatalysts (5 mol%). Oliveira da et al. [59] demonstrated several proline-based organocatalysts, developed to improve the enantio- and diastereo-selectivity of the aldol reaction. The direct asymmetric aldol reaction between aromatic aldehyde (104) and cyclohexanone (78) was carried out using a functionalized o-phenylenediamine prolineamide organocatalyst (Figure 9.31). Further, prolinamide catalytic activity was enhanced to give an excel-

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Figure 9.30: Enantioselective synthesis of spirooxindole naphthoquinone.

lent yield of (R)-2-((S)-hydroxy(phenyl)methyl)cyclohexanone (105) and (3R,7aS)-2-(2(benzylamino)phenyl)-3-phenyl-hexahydropyrrolo[1,2-e]imidazol-1-one (106) in good diastereo- and enantioselectivity.

Figure 9.31: Direct asymmetric aldol reaction.

Wang et al. [60] used bifunctional organocatalytic Michael/intramolecular cascade reaction to establish an asymmetric three-component reaction of indole (107), aldehyde (108), and aniline (109)] to give spirooctahydroacridine-3,3′-oxindoles (110) in an enantiospecific manner (Figure 9.32). Furthermore, this technique was easily altered to preferentially pick an alternate major diastereomer of spirocyclic oxindoles, and it could be used to synthesize natural products and potentially important compounds. The authors claimed exceptional tolerance of this method for a variety of substrates, producing five stereogenic centers containing products in high yield, and with diastereo and enantioselectivities. Zhou et al. [61] reported a combination of bifunctional quinine-based thiourea and diphenyl prolinol silyl ether (d or e) to effectively catalyze a cascading Michael/Michael/aldol addition (Figure 9.33) by the reaction of N-substituted oxindole (112), nitrostyrene (113), and trans-unsaturated aldehyde (114) in a 3-CR-created series of spirooxindole carbocyclic derivatives (111 and 115) with adaptable molecular complexity and enantioselectivity.

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Figure 9.32: Three-component Michael/intermolecular cascade reaction.

Figure 9.33: Michael/aldol cascade reaction.

Xie et al. [62] described that the Michael–Henry cascade reaction went smoothly when the third element of the unsaturated aldehyde (117), substituted with nitroolefin (116), gave a complex polycyclic oxindole backbone (118) with eight contiguous stereocenters and significant stereoselectivity (Figure 9.34). The authors claimed that the method minimizes the number of reaction steps, was inexpensive, and that these methods enable the cost-effective synthesis of a variety of optically pure and possibly bioactive molecules, accomplished through the organocatalytic cascade/tandem route. Zea et al. [63] reported the reactions of unsaturated aldehyde (120) with unsubstituted 2-oxoindolin (119), used in the relay Michael–Michael–aldol reaction (Figure 9.35). The secondary amine Cat. 6 and benzoic acid catalyzed the reaction in the toluene solvent, and isolated the end product, spirocyclohexene-based oxindole skeleton (121), in high yields and in stereo control. Further, the authors demonstrated the synthesis of more novel heterocycles that are used for bioactivity.

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Figure 9.34: Preparation of spirocyclic hydroindaneoxindole via the Michael–Henry cascade reaction.

Figure 9.35: Synthesis of cyclohexene-fused spirooxindole compounds.

Chatterjee and coworkers [64] reported a vinylogous organocatalytic triple cascade reaction of Michael-1,6-addition-vinylogous aldol (125), employing an aldehyde (123), linear 2,4-dienals (124), and methylene indolinone derivatives (122) (Figure 9.36). The authors revealed that the optimized 20 mol% amino catalyst gave high yield and excellent enantioselectivity and diastereomeric control to achieve the desired spirooxindoliccyclohexanes.

9.3.2 Synthesis of N-heterocycle by using L-proline-supported catalysts Arya and coworkers [65] reported L-proline trapped in a faujasite (FAU) zeoliteenabled pyrimidine-fused spirooxindole (129) synthesis in a single pot. The authors employed a three-part Mannich type procedure for the reaction of indolin-2-ones (126) (with 2,3-dihydro-1H-inden-1-one, 1,3-dihydro-2H-inden-2-one, and thiazolidin-4-

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Figure 9.36: Synthesis of complex spirooxindoliccyclohexane bearing six stereocenters.

one serving as alternating substrates), formaldehyde (127), and arylamines (128). The authors studied the FAU zeolite’s catalytic activity in various solvent systems like DMSO, THF, acetonitrile, water, and methanol. In water, it demonstrated a suitable reaction condition and gave excellent product isolation, and recycled up to five times without significantly losing its effectiveness (Figure 9.37).

Figure 9.37: Preparation of spiroheterocycle through Mannich reaction.

Sivamurugan et al. [66] developed a novel one-pot three component solvent free synthesis of 1,5-benzodiazepine (132) in an exceptional yield by the reaction of o-phenylenediamine (130) and two molecules of ketone (131) under solvent-free conditions, with Zn(L-proline)2 as the catalyst, under microwave heating (Figure 9.38). The authors tested both traditional and microwave-irradiation methods to evaluate the effectiveness of the catalysts, and found that the microwave-irradiated product 1,5-benzodiazepine gave moderate to high

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yield (up to 93%) in a shorter time. Further, the authors tested the recycling of the catalyst and observed that it can be used for up to five cycles without a significant loss in its effectiveness.

Figure 9.38: Synthesis of 1, 5-benzodiazepine.

Esfandiary and Heydari [67] reported a novel magnetic core–shell Fe2O3@[proline]CuMgAl-layered double hydroxide, which emerged as an efficient bifunctional catalyst for the reaction of aldehyde (133) and aniline (134); it gave quinolines and 2Hindazoles (135). The authors explained the catalyst construction as a coupling of Cu(II) with Mg and Al in LDH structure, and intercalating L-proline between the layers. The authors claimed that the reaction condition was greener, offered a high yield, was a faster reaction at low temperatures, which were the advantages of this method; the catalyst was reused five times, without a significant loss in its activity being reported (Figure 9.39).

Figure 9.39: One-pot synthesis of quinoline.

Maleki and Firouzi-Haji [68] demonstrated a simple one-pot synthesis of 2,4,6-triarylpyridines (138) by the reaction of acetophenones (136), aromatic aldehydes (137), and NH4OAc (22) in the presence of Fe3O4–SiO2 propyl triethoxysilane L-proline nanoparticle. The authors claimed that the catalyst used was new, efficient, and environmentally friendly in the chemical synthesis of 2,4,6-triarylpyridines (138) (Figure 9.40). Maleki and Firouzi-Haji [69] reported an efficient synthesis of 3-amino imidazo[1,2-a] pyridine derivatives (141) by the reaction of aromatic aldehyde (104), 2-aminopyridine (139), and trimethylsilyl cyanide (TMSCN) (140) in ethanol at room temperature, catalyzed by L-proline-functionalized magnetic nanocatalysts (Fe3O4@L-proline) (Figure 9.41). The authors claimed that the solid nanocatalyst is easily recoverable and was reusable for several cycles, without any loss in its activity.

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Figure 9.40: Synthesis of 2,4,6-triarylpyridines.

Figure 9.41: Preparation of 3-aminoimidazo[1,2-a]pyridines.

9.3.3 L-Proline-catalyzed synthesis of O-heterocycles Oxygen-containing heterocycles emerged as an important class of heterocycles, and is present in drugs (oxazole and coumarin), fragrances, and flavors (lactones) [70]. The fusions of benzene ring with oxygen-heterocycle drastically changes the electron density on the fused ring, thereby altering the chemical/physical/biological properties. These heterocycles are found to be important class of heterocycles in organic chemistry due to their natural abundance and diverse biological functions. Semisynthetic and natural oxygen heterocycles, such as digoxin (CHF treatment), taxol (anticancer), lovastatin (hypolipidemic) and cyclosporine-A (immunosuppressant), are well-known drugs [71]. Rodriguez and coworkers [72] demonstrated an enamine composed of L-Pro and enone, which functions as dienes (141) in a concerted [4+2] cycloaddition, using intermediates made of 1,3-dicarbonyl-derived arylidenes (89) as a complement to the dienophile nature of Knoevenagel adducts. The authors discovered L-Pro-catalyzed threecomponent asymmetric domino-Knoevenagel hetero-Diels Alder reactions of easily accessible enones (142,89), aryl aldehydes (143,144), and 1,3-indanedione (145), enabling the production of highly substituted spiro-[cyclohexane-1,2 indane]1, 3, and 4-trione (146). The process was highly diastereoselective and gave good yields, up to 71% ee product (Figure 9.42).

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Figure 9.42: Three-component asymmetric domino-Knoevenagel hetero-Diels-Alder reactions.

The same author demonstrated that the one-pot synthesis of spiro(pyrrolidine-3,3′indolinones) by the condensation of indolin-2-one (7), Meldrum’s acid (2), and various N-protected aldehyde (8), catalyzed by OCP-1, is well-known Yonemitsu condensation that gave functionalized tetrahydro carbazoles. The last step in the synthesis of chiral 2′,3′-pyranone(pyrrolidinone)-fused tryptamine (149) is a diastereoselective trimolecular condensation of indole (147), Meldrum’s acid (89), and Garner’s aldehyde (148) (Figure 9.43).

Figure 9.43: One-pot synthesis of spiro-pyrrolidine-3,3′-indolinones.

List [73] described the synthesis of alkylidene derivatives and enamines (152) in an in situ one-pot reaction of ketone (150), aldehyde (151), and Meldrum’s acid (89), catalyzed by OCP-1, by a direct Michael addition of unmodified ketone to unsaturated carbonyl. The authors were able to avoid using prefabricated enolate equivalents in this technique, but reported that the result lacked enantioselectivity (Figure 9.44). Abdolmohammadi and Balalaie [74] reported 3,4-dihydropyrano[c]chromene derivatives (154) synthesis from 4-hydroxycoumarin (153), aryl aldehydes (21), and malononitrile (27) in aqueous ethanol, catalyzed by diammonium hydrogen phosphate or L-proline. The authors tested the tolerance of the method for a wide range of aryl aldehydes substitutes such as chloro, methyl, bromo, hydroxyl, cyano, nitro, and dichloro (Figure 9.45). Mofakham et al. [75] demonstrated that two families of fused pyrimidine-2,4diones, namely benzo[g]- (159) and dihydro (158), are produced by starting with cyclic

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Figure 9.44: Carba-acetalization of p-nitrobenzaldehyde.

Figure 9.45: Synthesis of 3,4-dihydropyrano[3,2-c] chromene.

1,3-dicarbonyl compounds (33), aryl aldehyde (155), 2,5-dihydroxy-1,4-benzoquinone (156), or 2-hydroxy-1,4-naphthoquinone (157) in the presence of a catalytic quantity of OCP-1 (Figure 9.46). The authors also tested 3,4-dehydro-L-proline and 4-hydroxy-Lproline as a catalyst for the reaction, although they noticed a less yield. In order to access the structurally diverse frameworks, a wide variety of cyclic 1,3-dicarbonyl compounds, such as Meldrum’s acid and barbituric acid, and aryl aldehydes were employed in the synthesis. Zhu et al. [76] reported pyrano[3,2-c]quinolin-2,5-dione (162) synthesis with a modest (45%) yield, from the reaction of 4-hydroxy-1-methylquinolin-2(1H)-one (160), p-anisaldehyde (161), and Meldrum’s acid (89), in refluxing water with 10 mol% L-proline (Figure 9.47). The authors claimed that the method resulted in high yields, and required mild reaction conditions and ease setup, which are the benefits of this technique. In addition, the authors also described that more biomedical screening work is being done in light of the possible biological actions of these reported compounds. Shi and coworkers [77] demonstrated the environmentally friendly synthesis of a library of spiroxindole derivatives (164) via isatin (163), nitrile (93), and cyclic 1,3dicarbonyl compounds (33), with L-proline (10 mol%) as a catalyst in a 3-CR in water at 80 °C (Figure 9.48). A library of (164) derivatives were successfully synthesized, em-

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Figure 9.46: Fused pyrimidine-2,4-dione benzo[g]- and dihydropyrano[2,3g] chromene synthesis.

Figure 9.47: Pyrano[3,2-c]quinoline-2,5-dionesynthesis.

ploying isatin derivatives (163), nitrile derivative (93), and 1,3-dicarbonyl compounds (33), in excellent yields. Daloee and Behbahani [78] reported that a simple access to 2-amino-5,10-dioxo-4aryl-5,10-dihydro-4H-benzo[g] in an environmentally friendly method by the reaction of aldehyde (8), 4-naphthoquinone (5), and malononitrile (27), catalyzed by L-proline under a reflux condition in ethanol gave chromene-3-carbonitrile (165) (Figure 9.49). The authors claimed that new unidentified 2-amino-5,10-dioxo-4-aryl-5,10-dihydro-4Hbenzo[g]chromene-3-carbonitrile (165) were prepared and demonstrated a chemical shift of NH2, identified in D2O and without D2O, using the 1H-NMR technique. Bodke and coworkers [79] reported that MCRs via Knoevenagel condensation reactions of substituted aldehydes (8), 4-hydroxylcoumarin (67), and 2-mercaptobenzothiazole (166) catalyzed (10 mol%) by L-proline in ethanol solvent isolated 3-[(1,3-benzothiazol-2-4/

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Figure 9.48: Proline-catalyzed three-component synthesis of spiroxindole.

Figure 9.49: Synthesis of chromene-3-carbonitrile derivatives.

sulfanyl(phenyl)methyl]-2H-chromen-4-ol derivative (167) in good yield (Figure 9.50). Further, the authors tested the prepared derivatives for their antimycobacterial, antioxidant, anticancer, and molecular docking studies, and these derivatives showed comparable activity with standard drugs, as reported.

Figure 9.50: Synthesis of 2H-chromene derivatives.

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9.3.4 Proline derivatives catalyzed synthesis of O-heterocycle Li et al. [80] reported structurally varied benzoxanthenes(169) derivatives, catalyzed by proline-triflate, in a three-component reaction in aqueous medium under reflux of β-naphthol (168), aromatic aldehyde (21), and 1,3-dicarbonyl compound (33) (Figure 9.51). The reaction had strong substituent tolerance and scalability, and it produced the required products in high yields.

Figure 9.51: Three-component synthesis of benzo[f]xanthene.

The same authors described that the reaction employing β-naphthol (168), aldehyde (170), and 1,3-dicarbonyl compound (33) gave regioisomeric-fused oxygen heterocycles (171) and (172) respectively, in water medium and under reflux condition, gave desired derivatives in good yields (Figure 9.52).

Figure 9.52: Synthesis of benzo[c]xanthene and benzo[h]cyclopenta[b]chromene.

Kuan et al. established the reaction of aldehyde (174) and two molecules of 2-arylideneindane-1,3-diones (173), organocatalyzed by the Michael–Michael–aldol reaction. This process produced an entirely substituted chiral dispirocyclohexane (175) with two indanone moieties attached (Figure 9.53) [81]. Three C–C bonds were formed in a single pot

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using this [2+2+2] annulation process, catalyzed by L-diphenylprolinoltrimethylsilyl ether. Among the tested basic additive i.e., DMAP, DABCO, and imidazole, DABCO gave high yields. Highest enantioselectivity was obtained by using DMF as solvent and at low temperature (−20 °C) condition.

Figure 9.53: [2+2+2] Annulation reaction for substituted dispirocyclohexane synthesis.

Nazari and Keshavarz [82] described the effect of Amberlite supported by L-prolinate (2–15 mol%) in the reaction of benzaldehyde (176), malononitrile (27), and 3-methyl-1phenyl-4,5-dihydro-1H-pyrazol-5-one (177), when examined under various conditions. The results demonstrated unequivocally that the reaction under reflux in ethanol with 10 mol% [Amb]-L-prolinate gave a high yield of 6-amino-3-methyl-1,4-diphenyl1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (178) (Figure 9.54). The yield grew gradually with the catalyst load up to 10%, but using more catalyst (15%) did not show an enhanced yield, and reducing the quantity of the catalyst resulted in a lower yield isolation.

Figure 9.54: Preparation of 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5carbonitrile.

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9.3.5 Proline-supported catalyzed O-heterocycle synthesis Kidwai and Jain [83] described that the reaction of aldehyde (179) and dimedone (3), condensed in water, in the presence of 2 mol% Zn(L-proline) gave xanthenedione (180) (Figure 9.55). The authors claimed that the method was rapid, showed mild and increased selectivity, required a simple set up, and was environmentally friendly. By avoiding the use of volatile organic media and reusing the catalyst, improved the yields, and offered a cleaner reaction profile, which are the key characteristics of this protocol.

Figure 9.55: Synthesis of xanthenediones.

Siddiqui and Farooq [84] demonstrated a one-pot green synthesis of 3-(aryl/heteroarylaminomethylene)-2-hydroxy-chroman-4-ones (183) ithat occurs when 3-formylchromone (181) and aryl/heteroaryl amine (182) reacts in water under the catalysis of 10% Zn(Lproline)2 (Figure 9.56). The authors explained the mechanistic pathways involved in the reaction – three electron-deficient locations on 3-formylchromone, attacked by compounds with nucleophilicity. The three locations are a formyl carbonyl group at position 3, an active electrophilic essential at C-2, and the unsaturated keto function present.

Figure 9.56: Preparation of 3-(aryl/heteroarylaminomethylene)-2-hydroxy-chroman-4-ones.

Khalafy [85] described a broad variety of 4-aroyl-4H-benzo[g]chromene derivatives (186) that were achieved in high yields in a one-pot synthesis of arylglyoxals (184), 2-hydroxy-1,4-naphtoquinone (185), and malononitrile (27) in H2O/EtOH (1:1), catalyzed by Zn(L-proline)2 at 50 °C (Figure 9.57). The authors claimed that method developed has benefits of recycled catalyst, faster reaction, high yields, use of a green solvent, and mild reaction condition. Safaei-Ghomi and Zahedi [86] discovered an asymmetric Mannich reaction, catalyzed by a magnetic organocatalyst Fe3O4-L-proline NPs. The authors investigated the

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Figure 9.57: Synthesis of 4-aryl-4H-benzo[g]chromene.

catalytic systems to demonstrate the asymmetric synthesis of isoxazolidine (190) with good diastereoselectivity from the reaction of N-arylhydroxylamine (187), arylaldehydes (188), and unsaturated aldehyde (189) (Figure 9.58). As a magnetic organocatalyst, L-proline-functionalized Fe3O4 nanoparticles developed isoxazolidine compounds in high yields as a single isomer with an endo-configuration. Short reaction durations, good to exceptional yields, and a heterogeneous catalyst that can be recycled several times without significantly losing were all noteworthy characteristics of this approach.

Figure 9.58: Asymmetric isoxazolidine synthesis.

9.4 Conclusion L-Proline

is a natural abundant and genetically coded amino acid, containing secondary amine embedded in pyrrolidine ring system. It is nontoxic, of low cost, and it is widely accessible in both enantiomeric pure D- and L-isomer. Due to its dual functionality, it behaves both as an acid and a base, is and involved in imine intermediate formation, led streospecifically by one type of product formation. It was one of the highly extensively studied amino acid in the organocatalysts research field. Researchers studied the mechanistic pathway involved in proline for enantioselective synthesis that is involved in iminium or enamine intermediates, which is characteristic of covalent organocatalysis. A vast number of organic reactions, both asymmetric and MCRs, catalyzed by L-proline is well documented in the literature. Further, researchers have explored the extension of proline and its derivatives of small molecule, which can be the choice for the selected alternatives for organic transformations and MCRs. Recent trends look for-

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ward to the use organic synthesis, carried out in aqueous medium. It is of utmost priority due to the environmental concerns and global warmings, which are crucial, since it is necessary to reduce the production of waste, and avoid the use of volatile organic solvents. Hence, MCRs play a pivotal role in efficient synthetic pathways in the section of synthetic chemistry, due to its advantages of one-pot procedure, atom economy, time-saving, and chemical waste reduction. Even though the concept of MCR synthesis for diverse organic molecules has been well known over a century, it has only recently got more attention and increasing number of publications, emphasizing the biologically relevant organic molecules synthesis via this approach. In combination with MCRs, organocatalsyts reaction make the synthetic route eco-friendlier and isolate more product. Its safety for various biological activity studies is well documented. In this chapter, we provided a critical overview of proline and its derivatives, employed as an organocatalysts for MCRs to produce synthetically and biologically relevant heterocycles, particularly nitrogen and oxygen containing heterocycles, which are playing vital role in medicinal chemistry and pharmaceuticals, as well in agrochemicals and pesticides fields. Recent literature reported by researchers across the globe of more than 50 plus reaction schemes are covered in this chapter for the preparation of heterocycles, influenced by proline and its derivatives.

Abbreviations BINOL Boc DHP DMF DMSO ee EDG EtOAc EWG HClO4 HOMO IPP i-Bu i-Pr NaBH4 OTMS Ph PMP p-Tol PMB t-Bu TBABr

1,1′-Bis(2-naphthol) tert-Butyloxycarbonyl 1,4-Dihydropyridine Dimethylformamide Dimethyl sulfoxide Enantiomeric excess Electron-donating group Ethyl acetate Electron-withdrawing group Perchloric acid Highest occupied molecular orbital Isopentenyl pyrophosphate iso-Butyl iso-propyl Sodium borohydride o-Trimethoxysilane Phenyl p-Methoxyphenyl p-Tolyl p-Methoxybenzene tert-Butyl Tetrabutylammonium bromide

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CH. N. S. Sai Pavan Kumar, Vaidya Jayathirtha Rao✶

10 Microwave-assisted solvent-free multicomponent synthesis of bioactive heterocycles 10.1 Introduction Microwave (MW) technique is being extensively used for conducting organic chemical reactions for the past three or four decades [1, 2]. The MW technique is a nonconventional way of exercising organic synthesis. It helps us conduct almost all kinds of organic chemical reactions. Organic reactions assisted by MWs follow many principles laid down in green chemistry [3, 4]. MW-assisted chemistry has high relevance in pharma industry in making active pharma ingredients and drug intermediates [5, 6]. Chemical processes developed involving MW avoid using solvents and reduce waste generation and these have bearing on pollution creation [7]. Many MW-assisted chemical reactions will be completed in minutes and some are even completed in seconds. MW-assisted organic reactions are cost-effective because of no solvent requirement, time of reaction, heat energy supplied (superheating) in the form of MW, higher yields, and product isolation and purification becomes more effective. Recently, these MW organic reactions are being conducted using MW-flow reactors [7–12]. Percy Spensor (US electrical engineer) was the first to notice the melting of a candy bar/chocolate induced by MW in 1946 confirming the role of MWs as heating aid. This MW-induced heating observation provided entry for present-day MW ovens. MWs use the frequency/wavelength range of 300 MHz to 300 GHz and most of the MW ovens operate in the range of ~2.45 GHz (~12.2 cm λ). These MWs have the ability to pass through/penetrate into fog and clouds and are used for detection leading to the development of Radiation Detection and Ranging (RADAR). Organic molecules display molecular rotations and these molecular rotations play an important role in absorbing the MW radiation [1, 2]. The propagating MW possesses an oscillating electric and magnetic vector and these vectors interact with rotational levels of organic moleAcknowledgment: VJR thanks AcSIR-Ghaziabad for Honorary Professorship and CSIR-New Delhi for Emeritus Scientist Honor. ✶ Corresponding author: Vaidya Jayathirtha Rao, Emeritus Scientist-CSIR and Honorary Professor AcSIR, Natural Products and Medicinal Chemistry (NPMC) Department and AcSIR-Ghaziabad, CSIR – Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad 500007, Telangana, India, e-mail: [email protected] CH. N. S. Sai Pavan Kumar, Department of Chemistry, School of Applied Sciences and Humanities, Vignan’s Foundation for Science, Technology and Research (VFSTR), Vignan University, Vadlamudi, Guntur 522 213, Andhra Pradesh, India, e-mail: [email protected]

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cules leading to the absorption of MWs [13]. The net interaction is the MW energy absorption by the molecule leading to heating of the system [14–16].

10.2 Multicomponent reactions Three or more starting compounds combining to form a product in a one-pot system is known as a multicomponent reaction (MCR). Generally, these MCRs involve elimination of water or small molecules and also adopt condensation type chemistry. The MCRs are known as convergent reactions. Most of the times, the number of atoms present in the starting materials will be incorporated into the final product, providing a decent atom economy. Many times these MCRs involve reactive aldehyde or carbonyl functionalities and their derivatives. MCRs provide higher yield and purity of a product compared to the two-component stepwise reaction. The reduction in number of reaction steps, simplicity in conducting the reaction, diversity, and complexity of outcomes in the resultant products of these MCRs are noteworthy. The sequence in the MCRs maybe: two components react to form a product, which reacts with third component present in the reaction medium leading to a three-component product and further this three-component product will be ready to react with fourth component and so on. The reduction in impurities, less or no side reactions, improved yields, and reproducibility of the chemistry makes these MCRs more attractive for practical applications in research and industry. This chapter provides a compilation of multicomponent organic reactions assisted by MWs and without using any solvent. The precise and quick information coded in the figures of this chapter further help the reader to consider them for the possible development of green chemical processes of importance using continuous flow reactor technology.

10.3 Microwave-assisted synthesis of solvent-free multicomponent synthesis of heterocycles 10.3.1 Acridone derivatives Vetrivel Nadaraj et al. [17] reported synthesis of acridine derivatives (4) by adopting multicomponent single-pot reaction involving benzaldehyde (1), 1-naphthylamine (2), and dimedone (3), without any solvent and with the help of MWs. The authors reported seven examples with yields ranging 92–96% (Figure 10.1). MWs with 160 W power were used for irradiation of the tricomponent mixture (Figure 10.1) to get a yellow-colored solid within 5 min of time in high yields. 1-Naphthylamine reacts with dimedone to form a

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Schiff base, which reacts with aldehyde to form a C–C bond and then it forms another C–C bond at 2-position of naphthylamine leading to acridine derivatives. Thus, synthesized acridine derivatives (4) were taken for antimicrobial studies. Several bacteria and fungi were employed to understand the effect of the prepared acridone derivatives. Ofloxacin and clotrimazole were the standards used to normalize the antimicrobial activity. Quite a few compounds exhibited very good IC50 numbers ranging from 3.9–7.8 μg.

Figure 10.1: Synthesis of 7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one (4) derivatives.

Another study by Tu Ju et al. [18] developed a method for making acridone (6) derivatives (Figure 10.2). Aldehyde (1), dimedone (3), and ammonium carbonate (5) were mixed (without solvent) and microwaved for about 4–7 min to get acridone derivatives (6). The authors provided crystal structure for a compound synthesized. The thermal method, upon mixing all the three components and refluxing, was found to be a low-yielding reaction and also adopts higher reaction time.

Figure 10.2: Synthesis of 9-aryl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-diones-6.

10.3.2 Pyrimidine derivatives Dihydro-pyrimidines (DHPMs) synthesis was first reported by Pietro Bigenelli [19] in 1893. Later, during these years many researchers got interested and showed several publications; in particular, Oliver Kappe [20] came up with a short review [21] on

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these DHPMs via Biginelli reaction, because of several biological activities of DHPMs, like calcium channel modulators [22, 23], adrenergic receptor antagonists [24], mitotic kinesin inhibitors [25], antiviral [26], antibacterial activity [27], anticancer activity [28], cardiotonic activity [29], anti-inflammatory activity [30], and fungicidal activity [31, 32]. Other reports are given on the synthesis of DHPMs, which involved mixing of three components in the presence of acid or catalyst and a suitable solvent [27, 33–35]. Choudhury et al. [36] reported a procedure for making pyrimidines involving a threecomponent reaction – aldehyde (1), urea (7), and ethyl acetoacetate (8) using a catalyst, assisted by MW and without any solvent (Figure 10.3). The authors employed several catalysts to test their activity [36] and the catalysts are supported over montmorillonite or Si-MCM-41 or no support. There are other reports also, using MW and or catalyst and without any solvent, to make pyrimidinones via Biginelli reaction [37–40].

Figure 10.3: Synthesis of pyrimidines (7) via MW and catalyst-assisted solvent-free Biginelli reaction.

Abdulkadir ShubeHussen et al. [41] designed a methodology for making quinazolin4(3H)-imines (Figure 10.4). Substituted 2-aminobenzonitrile (10), substituted aniline (11), and triethylorthoformate (12) were mixed with NH4Cl and MW irradiated to obtain quinazolin-4(3H)-imines (13) (Figure 10.4). Aniline reacts with triethylorthoformate to form an imine intermediate, which reacts with the amino group of 2-aminobenzonitrile to form a C–N bond; then it forms another C–N bond with the nitrile group leading to cyclization to form quinazolineimine compounds. Scaled-up preparative reaction is also reported and compared with thermal conditions, where the yields and reaction times are more favorable for MW-mediated synthesis. Fifteen examples (Figure 10.7) are cited by changing the substitution on the aniline (11) residue and also on the 2-aminobenzonitrile (10) compound. Quinazoline derivatives are potential candidates for the various biological activities [42]. Virsodia et al. [43] demonstrated synthesis of thiazolopyrimidine and pyrimidothiazine (18) compounds (Figure 10.5) in very nice way. Pyrimidine formation followed by the final product (18) involves no solvent and no catalyst and the reaction is assisted by only MW irradiation (Figure 10.5). The first step is a tricomponent Biginelli

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Figure 10.4: Synthesis of quinazolin-4(3H)-imines(13).

reaction, involving aldehyde (1), thiourea (8), and aceto-acetanilide (14), which were MW (400 W) irradiated at 140 °C without any solvent and catalyst. Subsequently, the pyrimidine derivate (15) was allowed to react with 1,2-dibromopropane (16) or 1,3dibromopropane (17) without any solvent and catalyst to afford thiazolo-pyrimidine or pyrimido-thiazine (18) (Figure 10.10). Interestingly, these pyrimidine-based compounds exhibit various biological activities [44–47].

Figure 10.5: Synthesis of thiazolo-pyrimidine and pyrimido-thiazine (18).

10.3.3 Imidazole and fused imidazole derivatives Jiang et al. [48] synthesized various trisubstituted imidazoles (21) (Figure 10.6) via MW activation of MCR. Arylnitrile (19), aldehyde – 2 mol (1) and ammonium acetate (20) were mixed (solvent-free) and microwaved for 15–34 min to make various trisubstituted imidazoles (21) (Figure 10.6). The 25 examples reported indicate the scope of the substrate structure and yields obtained in the MW-mediated multicomponent imidazole synthesis. Interestingly the reaction mechanism suggested informs about the umpolung

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nature (Figure 10.6). Based on the aforementioned findings, potential processes for the production of trisubstituted 2-(20-azaaryl)imidazole derivatives and 1,2-diarylethylbenzamides, respectively, have been postulated. In the first case, ring-closure cascade events such initial condensation, nucleophilic addition, umpolung (from A to B), intramolecular nucleophilic addition (from B to C), and dehydration are involved as depicted in Figure 10.6.

Figure 10.6: Synthesis of trisubstituted imidazoles (21).

Cheldavi and Mohammadi [49] reported synthesis of phenanthro-fused imidazoles (23) (Figure 10.7). This is a three-component reaction involving 9,10-phenanthrodione (22), aldehyde (1), and NH4OAc (20) under MW irradiation conditions. Chemical transformation involves insertion of two nitrogen atoms coming from NH4OAc (20) (Figure 10.7). Variation in the substrate aldehyde structure provided 10 examples with very good yields. Imidazole derivatives have applications in pharma [50] and in organic materials [51, 52].

10.3.4 Pyrrole and fused pyrrole derivatives Ranu and Hajra [53] synthesized substituted pyrroles (Figure 10.14) via a threecomponent, solid support assisted and mediated by MW irradiation. α,β-unsaturated ke-

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Figure 10.7: Synthesis of phenanthro[9,10-d]imidazole (23) derivatives.

tone (24), amine (11), and nitroalkane (25) were loaded on to the surface of silica gel and then irradiated with MW to realize the tetrasubstituted pyrrole products (26) (scheme 1 – Figure 10.8). The second scheme involved with α,β-unsaturated nitro compound (27), amine (11), and aldehyde (28) were loaded on to the surface of alumina, then irradiated using MWs to make trisubstituted pyrroles (29). The third scheme uses α,β-unsaturated nitro compound (27), amine (11), and 5/6/7-membered cyclic ketones (30) were loaded on to the surface of alumina, then irradiated using MWs to make 2,3-fused bicyclic pyrroles (31). All the three schemes covered enough number of examples to understand the effect of structural features on the yields and ease of performing the chemistry. Silica gel is found to serve better in making the tetrasubstituted pyrroles (Figure 10.8: scheme 1), whereas alumina is favored in conducting schemes 2 and 3 in making the corresponding pyrroles (Figure 10.8: schemes 2 and 3) in terms of yields and other advantages. However, the authors provided a few limitations to this procedure: (i) the absence of substituent at α-position of the nitroalkene leads to different products other than providing pyrroles; (ii) open chain ketones in the place of aldehydes also gives different products; and (iii) nitromethane is not effective, whereas nitroethane and nitropropane are very effective in making substituted pyrroles.

10.3.5 Pyridine derivatives Pyridones and aminopyridines were synthesized by Kibou et al. [54] using MW irradiation and without catalyst and solvent (Figure 10.9). The intermediate enaminone was also prepared by adopting MW irradiation, without catalyst and in solvent free conditions (Figure 10.9). Ethyl acetoacetate (7) and 1,1-dimethoxy-N,N-dimethylamethanamine (DMF-DMA) (33) were mixed and irradiated for 5 min using MWs to obtain corresponding enaminone (34) in 90% yield. The obtained enaminone (34) was mixed with amine (11) and ethyl cyanoacetate (35) and microwaved for 2 min to make corresponding pyridones (36). In another experiment, the authors replaced the ethyl cyanoacetate (35) with malononitrile (37), which afforded tetrasubstituted aminopyridines (38).

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Figure 10.8: Synthesis of substituted pyrroles – 26, 29, and 32 using tricomponent surface-coated silica gel and alumina with microwave irradiation.

These chemical transformations do not use catalyst or solvent. The authors have provided a possible mechanism of formation for the formation of these (36 and 38) products. Pyridones are known to act as phosphodiesterase (PDE) enzyme [55] inhibitors, having a role in heart attack problems.

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Figure 10.9: Enaminone, pyridone, and aminopyridines (36 and 38) synthesis via MW irradiation.

10.3.6 Nitrogen–sulfur heterocycles Shubhodam et al. [56] displayed a procedure that aminothiazole (39) reacts with phenacyl-bromide derivatives (40), along with hydrazine (41) under MW conditions without any solvent to give 6-(4-substituted-phenyl)-3-methylimidazo[2,1-b]thiazole2-carbohydrazide derivatives (42) in good yields (Figure 10.10). The authors inform that this is a green method that does not involve any catalyst or solvent. Further, the authors evaluated biological activities of some hydrazides and hydrazones, which are different from Figure 10.3 and are listed in reference [57]. Preparation of starting compound amino thiazole method is also given (Figure 10.10).

10.3.7 Oxygen heterocycles Synthesis of tetrahydrobenzo[b]pyrans and fused tetrahydrobenzo[b]pyrans 43 to 60 were reported by Sougata Santra et al. [58] as a tricomponent, MW-mediated, and solvent-free process. Aldehyde (1), malononitrile (37), and 1,3-cyclohexanedione (3) were mixed and microwaved for ~7 min at 80 °C to obtain various benzopyran derivatives (Figure 10.11) in very good yields. Various tetrahydrobezopyran derivatives synthe-

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Figure 10.10: Synthesis of 6-(4-substituted-phenyl)-3-methyl imidazo[2,1-b] thiazole-2-carbohydrazide derivatives (42).

sized (43–60) are given in Figure 10.11. Interestingly, the pyran derivatives synthesized (43–60) are multifunctional compounds. Particularly, there are several bond-forming reactions involved that make the mechanism of formation of these products interesting. Fardood et al. [59] developed a methodology for the synthesis of amino-chromene derivatives (62, 64) (Figure 10.12). This is a three-component reaction with α-naphthol (61) or β-naphthol (63), aldehyde (1), malanonitrile (37), and a catalyst FeTiO3–MNPs, and MW irradiation under solvent-free conditions afforded 2-amino-4H-chromene derivatives (62 and 64) in very good yields (Figure 10.12). The catalyst, FeTiO3-MNPs were recovered and reused five times without losing catalytic activity. Chromene products (62 and 64) isolated indicated the regioselectivity observed in these conversions. 2-Aminochromene derivatives are found to possess biological activities such as anticancer, anti-allergic, antiproliferative, antiviral, antibacterial and apoptosis inducers [60–62]. Torres-Hernández et al. [63] synthesized epoxy-isoindolinones assisted by MWs and followed by Ugi-4CR/intramolecular-Diels–Alder reaction (Figure 10.13). This is an example of a four-component reaction accelerated by MW irradiation. Furfural (65), amine (11), cyclohexylisocyanide (66), and half ester of diacid (67) were mixed and microwaved for 30 min to get the products (69, 70, 71). The authors predicted the mechanism by showing an intermediate (68) formed from all the four components of the reaction, which undergoes final Diels–Alder [4 + 2] cycloaddition leading to the products (69, 70, 71) mentioned in the Figure 10.13. The main advantages are the reaction time and yields, when compared to the conventional heating method. The chemical transformations reported are free of catalyst and solvent. It is interesting note that the complex structures carrying manipulative functional groups for further chemical transformations can be easily generated through this multicomponent-one pot-MW technique without using catalyst and solvent.

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Figure 10.11: Synthesis of tetrahydrobenzo[b]pyrans and fused tetrahydrobenzo[b]pyrans (43–60).

10.3.8 Spiroheterocycles Dandia et al. [64] synthesized spiroheterocycles (75) (Figure 10.14) to evaluate antifungal activity. The methodology involves a tricomponent reaction assisted by MW and without any organic solvent. Substituted indole-2,3-dione (72), aminoheterocycle (73), and thioacid (74) were microwaved at 135 °C for about 4–7 min to afford the spirocyclic compounds (75) (Figure 14). Substitutions on the isatin (72) ring, heterocyclic

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Figure 10.12: Synthesis of 2-amino-4H-chromene (62 and 64) derivatives.

Figure 10.13: Synthesis of epoxy-isoindolinones (69, 70, 71) – Ugi-4CR/intramolecular-Diels–Alder reaction.

amine (73), and thioacids (74) were changed to understand the role of the structure on the antifungal activity. The authors reported crystal structure for one of the compounds synthesized. Fungal strains employed for testing are Rhizoctonia solani, Fusar-

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Figure 10.14: Synthesis of substituted spiroheterocycles (75) for antifungal activity.

ium oxysporum, and Collectotrichum capsica, where synthesized compounds exhibited very good activity compared to the standards like baynate and thiram. Moghaddam et al. [65] synthesized dispiropyrrolidineoxindole derivatives (79) (Figure 10.15) via a three-component MW-assisted reaction. Oxindole (76), N-methylglycine (77), and 6-methoxy-2-(3-substituted-benzylidene)benzofuran-3(2H)-one (78) were mixed and microwaved for 8–15 min at 100 °C to isolate dispiropyrrolidineoxindole derivatives (79). The authors reported the advantages with MW conditions, upon comparing with thermal conditions. Variations in the substituent attached with the benzylidene–benzofuran derivative (78) introduced 11 examples with excellent yields (Figure 10.15). The structure of one of the dispiro product (79) was established by X-ray diffraction analysis and also by H- and C-NMR data. The synthesized compounds were subjected to docking studies to understand their binding behavior with respect to cyclin-dependent kinase (CDK5) enzyme. Several dispiro compounds (79) exhibited acceptable interactions with the enzyme CDK5.

Figure 10.15: Synthesis of dispiropyrrolidineoxindole derivatives (79).

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Debajyothi Bhuyan et al. [66, 67] reported the synthesis of spiro-indeno-tetrahydropyridine derivatives (81) (Figure 10.16) through an MCR, without catalyst and solvent, using MW irradiation, following Knoevenagel condensation and aza Diels–Alder reaction. Indane dione (80), aldehyde (1), and ammonium acetate (20) were mixed together and microwaved for 7 min to make spiro-indeno-tetrahydropyridine derivatives (Figure 10.16). Variations in the substituent attached with aldehyde structure provided 14 examples in excellent yields (Figure 10.16). Indane dione (80) reacts with aldehyde (1) to form a Knoevenagel condensation product; then it reacts with ammonium acetate (20) to convert one of the carbonyls of the Knoevenagel condensation product to imine. Then a [4 + 2] cycloaddition occurs between imine product and Knoevenagel condensation product leading to the spiro-indeno-tetrahydropyridine (81) derivative.

Figure 10.16: Synthesis of spiro-indeno-tetrahydropyridine (81) derivatives.

10.3.9 Fused bicyclic heterocycles Yadav and Singh [68] provided a method to make fused thiazolo-pyran moieties (86) with very high diastereomeric excess (Figure 10.17), adopting an MCR under MW irradiations and solvent-free conditions. Acetic anhydride (82), glycine (83), and 5-arylidenerhodanine (84) were mixed without any solvent and microwaved to get annulated pyrano-thiazoles (86) with very high diastereo selectivity (>96%) (Figure 15). Glycine (83) reacts with acetic anhydride (82) to form azlactone, which adds to 5-arylidenerhodanine (84) in a Michael addition fashion to generate an intermediate 85 with high diasteroselectivity (>96%). The intermediate 85 further undergoes cyclization and ring-opening to form pyrano-thiazole. Indeed, the authors have isolated the intermediate 85 upon reducing the time of MW irradiation to ~5 min and also microwaved it (85) to observe the product pyarano-thiazole (86) compound (Figure 10.17). The selectivity observed in these MW-induced transformations is indeed a very high (>96%) compared to thermal reaction (>57%). High diastero selectivity (>96%) observed in the formation of compounds, intermediate 85, and product-fused thiazolo-pyran 86 go to explain that MW irradiations produce more polar struc-

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tures and this may be the reason for the observed selectivity. Pyrano-thiazoles are known to exhibit anticancer activities [69]. In favor of the cis (syn) isomers, the production of Michael adducts 85 and their ring modification to 86 were highly diastereoselective. Prior to purification, the diastereomeric ratios of the crude products were verified by 1HNMR spectroscopy to establish that real and correct diastereomeric ratios are presented. By using 1HNMR spectroscopy, it was discovered that the diastereomeric ratio in the case of MW irradiation was >96:4 and that in the case of oil bath heating was >57:43. If the activated complex that forms the cis (syn) isomers is more dipolar than the activated complex that forms the trans (anti) isomers, then the high diastereoselectivity (>96%) in favor of the cis (syn) isomers under MW radiation may be explained as MW radiation promotes the reactions transpiring via more dipolar activated complex.

Figure 10.17: Synthesis of fused pyrano-thiazoles (86) using solvent-free tricomponent reaction under MW irradiation with high de of >96%.

Yadav et al. [70] reported a methodology to make fused thiazolo-s-triazine moieties, adopting solvent-free tricomponent reaction assisted by MW irradiation with notable diastereomeric excess (de) of > 93% (Figure 10.18). Aryl-substituted thiazolo-2-amine Schiff base formed using arylaldehyde (87), ammonium acetate (20), and aldehyde (1) were mixed and microwaved for 6–12 min under solvent-free conditions to afford thiazolo-s-triazine derivatives (88) (Figure 10.18). The yields, purity, and de of MWassisted MCR were compared with thermal reaction and the superiority of MWenhanced MCR over thermal reaction was found. The authors suggested two possible

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mechanisms (Figure 10.18): one route adopts polar addition mechanism and another route is about [4+2] cycloaddition (Figure 10.18). Triazines and its derivatives do possess various biological activities [71–75].

Figure 10.18: Synthesis of fused thiazolo-s-triazinenes(88) using solvent-free tricomponent reaction under MW irradiation with high de of >93%.

Das and Mukhopadhyay [76] developed a procedure to synthesize 1,6-naphthyridines (91) via multicomponent MW-assisted reaction under solvent-free and catalyst-free conditions (Figure 10.19). Acetophenone (89), malononitrile (37), and morpholine (90) were mixed and microwaved at 100 °C for 10 min to make 1,6-naphthyridines (91) (Figure 10.19). The authors reported several 1,6-naphthyridine compounds (Figure 10.19) by varying the structure of starting materials. A comparison was made between thermal conditions and MW reaction conditions to prove the superiority of the MW method. The chemical transformation is found to be interesting in that this reaction involves Knoevenagel condensation, Michael addition, ring closure – cyclization and aromatization cascade, with several C–C and C–N bond-forming processes occurring. The authors provided a reasonably possible complex mechanism of formation of product 1,6-naphthyridines.

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Figure 10.19: Synthesis of various 1,6-naphthyridines (91–106).

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10.3.10 MW-assisted solvent-free MCR synthesis of heterocycles using catalyst Devi and Bhuyan [77] developed a method to synthesize fused pyran derivatives (108) using a three-component, solvent-free, NaBr-catalyzed and MW-assisted cyclocondensation process (Figure 10.20). Aldehyde (1), nitrile (107), and dimedone (3) were mixed with NaBr (catalyst) and microwaved for ~15 min to make highly functionalized, fused pyran derivatives (108) (Figure 10.20). The pyran derivatives have a wide range of biological activities [78].

Figure 10.20: Synthesis of fused pyran derivatives (108).

Parmar et al. [79] conducted an MCR assisted by MW and in the presence of ionic liquid to make fused pyrazolo-pyrans (114, 115, 116) (Figure 10.21). 2-Chloro-8-methylquinoline -3-carbaldehyde (109), pyrazalone (110), and electron-rich olefin (111, 112, 113) were mixed with triethylammonium acetate (TEAA) ionic liquid and microwaved for about 8–12 min to afford pyrazolo-pyran derivative (114, 115, 116) (Figure 10.21). In another reaction, 3-chloroindole-2-carbaldehyde (117) was employed with other starting materials being the same, to make corresponding pyrazolo-pyran (118, 119, 120) derivatives (Figure 10.21). Optimized reaction conditions developed by the authors indicate the upper hand of MW reaction conditions. The ionic liquid, TEAA reacts with activemethylene group of pyrazalone (110) to generate carbanion, which reacts with aldehyde to form corresponding α,β-unsaturated ketone and this enone undergoes [4 + 2] cycloaddition with the electron-rich olefin to provide pyrazolo-pyran derivatives (114, 115, 116, 118, 119, 120) (Figure 10.21). The ionic liquid TEAA is easily recovered by removing water from it and can be reused. Jian-Ming Zhang et al. [80] conducted quinoline derivatives synthesis (Figure 10.22), adopting a tricomponent reaction with catalyst and assisted by MW irradiation. Pentafluorobenzaldehyde (121), substituted aniline (11), and acetylene derivative (122) were mixed with catalyst CuBr/montmorrilonite and microwaved to get quinolines synthesized (123) (Figure 10.22). Aldehyde (121) reacts with aniline to provide Schiff`s base, which reacts with Cu-activated acetylene in situ to generate quinolines (Figure 10.22). The authors report that increasing concentration of acetylene (122) compound fourfold improves the yields of the quinolines.

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Figure 10.21: Synthesis of pyrano-pyrazoles and fused pyrano-pyrazoles.

Figure 10.22: Synthesis of quinoline derivatives (123).

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Banik and coworkers [81] synthesized biologically important 1,4-dihydropyridine (124) (Figure 10.23) compounds via a three-component, MW-assisted and Bi(NO3)3-catalyzed reaction without any solvent. Aldehyde (1), 1,3-dione (7), and ammonium acetate (20) or amine (11) were mixed with catalyst Bi(NO3)3 without solvent, microwaved for about 1–3 min to make 1,4-dihydropyridine (124) derivatives (Figure 10.23). Optimized experimental conditions show the role of catalyst, no solvent, temperature, time of reaction, and product yields. Variation in the structure of starting materials provided 25 examples with very good to excellent yields (Figure 10.23). The catalyst Bi(NO3)3 played a role in decreasing the reaction time and also improved the product yields. These dihydropyridine derivatives are marketed as medicines such as nifedipine, felodipine, nicardipine, and amlodipine, and are used to treat blood pressure and anxiety. Further these 1,4-dihydropyridines are known for their anticancer [82], antimicrobial [83], antidiabetic [84], neurotropic [85], and other activities [86].

Figure 10.23: Synthesis of dihydropyridine derivatives (124).

Alireza Samzadeh-Kermani [87] reported an interesting conversion for making 2nitroalkylidene-1,3-oxathiolane (128) derivatives (Figure 10.24) via a tri-component reaction catalyzed by triethylamine and assisted by microwaves. Epoxide (125), nitromethane (126), and carbon disulfide (127) were mixed with (20% mol) of triethylamine as catalyst and microwaved for 60 min to synthesize 2-nitroalkylidene-1,3-oxathiolane (128) derivatives (Figure 10.24). Cyclopentene epoxide and cyclooctene epoxide were found to be inactive and did not yield any product. Interestingly the MCR assisted by MW exhibited regioselectivity.

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Figure 10.24: Synthesis of 2-nitroalkylidene-1,3-oxathiolane derivatives.

10.4 Conclusions Synthesis of organic molecules via MW irradiation, under MCR and without solvent provides a route for practical applications for a greener and cleaner organic synthesis and it is popular among researchers. There are several advantages with the MCR without solvent when assisted by MWs, such as reaction time, ease of conducting the chemical reaction, ease of workup, simple isolation and purification, several multiple bonds formed or cleaved (C–C, C–N, and C–O bonds) in one-go, and making complex structures in a very simple-way leading to a variety of heterocycles that have potential bio-activity. The present chapter covered all the above facts dealing with the MWassisted solvent-free MCRs and the narration provides confidence to researchers to go for practical applications. Conflict of interest: There is no conflict of interest.

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Divyang M. Patel, Hitendra M. Patel✶

11 Deep eutectic mixture (DEM)-assisted multicomponent synthesis of heterocycles 11.1 Introduction The development of structurally diverse small bioactive heterocycles using environmentally sustainable and energy-efficient strategies has become a growing interest in the field of synthetic organic chemistry [1–5] and drug discovery research [6–9]. Significantly, multicomponent reactions (MCRs), obeying the principles of green chemistry [10–13], offer exceptional synthetic efficiency, high atom economy, and multiple bond formation in one-pot operation, without changing the reaction parameters and without isolating the intermediates [14–19]. Ionic liquids (ILs) have received a lot of attention in the past as eco-friendly solvents and catalyst systems [20–25]. However, ILs, based on imidazolium cations and fluorinated anions, do have drawbacks, including poor eco-compatibility, toxicity, nonbiodegradability, and lower cost-effectiveness [26]. Significantly, green and sustainable advances have greatly benefited from the use of deep eutectic mixtures (DEMs) in organic synthesis [27–30]. Moreover, DEMs are advantageous due to their low cost, reduced toxicity, and good biodegradability [31–35]. DEMs function by forming hydrogen bonds between the salt and the hydrogen bond donor [36–42]. DEMs are classified into the following four types (Figure 11.1) [43]. Some examples of the DEMs are shown in Table 11.1. Type 1: DEMs derived from quaternary ammonium salt derivatives (RN+4X–) and metal chloride (MCln) [44]. Type 2: DEMs derived from quaternary ammonium salt derivatives (RN+4X–) and metal chloride hydrate (MCln·mH2O) [45]. Type 3: DEMs derived from quaternary ammonium salt derivatives (RN+4X–) and hydrogen bond donors (HBDs) [46]. Type 4: DEMs prepared using metal chloride hydrates (MCln·mH2O) and hydrogen bond donors (HBDs) [47].

Acknowledgment: Dr. Divyang M. Patel is grateful to the Department of Chemistry, Faculty of Science, Sankalchand Patel University, Visnagar, Gujarat, India, for the support in research. ✶

Corresponding author: Hitendra M. Patel, Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, India, e-mail: [email protected] Divyang M. Patel, Department of Chemistry, Sankalchand Patel University, Visnagar 384315, Gujarat, India https://doi.org/10.1515/9783110985313-011

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Figure 11.1: Classification of deep eutectic mixtures (DEMs).

Table 11.1: Examples of DEMs. DEM types

Constituents of DEM

DEM examples

Type I Type II Type III Type IV

Quaternary ammonium salt/metal chloride Quaternary ammonium salt/metal chloride hydrate Quaternary ammonium salt/hydrogen bond donor Metal chloride hydrate/hydrogen bond donor

ChCl:CoCl ChCl:CoCl·HO ChCl:urea ZnCl:urea

DEM has been the subject of extensive study in recent years, and interest in it is continually expanding [48]. In a variety of sectors, including synthetic organic chemistry, biocatalysis, polymerization processes, biomass transformation, and separation techniques, they have found use as solvent/catalysts [31]. Particularly, DEMs outperform conventional catalysts and solvents in multicomponent processes, in terms of durability and reusability, without a noticeable deteriorating catalytic activity. Their applications in multicomponent processes, nonetheless, have not been thoroughly and critically examined. In this chapter, we have attempted to provide an overview of the use of DEMs as a solvent and/or catalyst in several MCRs involving Knoevenagel condensation, isocyanide attack on carbonyl compounds, addition of nucleophilic to enamine or imine derivatives, and associated processes.

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11.2 Deep eutectic mixtures (DEMs) as reaction media-cum-catalyst in multicomponent synthesis of heterocycles 11.2.1 Synthesis of spirooxindole and pyrano [2,3-c] pyrazole derivatives DEMs, which were first discovered by Abbott’s team in 2003, have received a great deal of attention among researchers across the world [49]. This is evident from the steady stream of new scientific publications that are being published in the literature [50–81]. DEMs exhibit dual or triple properties, such as solvent, catalyst, and/or reactant in organic synthesis. In 2014, Azizi et al. [50] used a ChCl:urea-based eutectic combination as the solvent and catalyst in a multicomponent synthesis to synthesize the spirooxindole derivatives (6–8) from isatin (1) and cyanoacetic esters or malononitrile 2(a–c), dimedone (3)/1-naphthol (4)/4-hydroxycoumarin (5). According to experiment results, a range of spiro oxindole derivatives were synthesized in the reaction, with different 1,3-diketones, namely methyl acetoacetate and dimedone, in excellent to moderate yields (Figure 11.2). All reactions proceed smoothly, producing the necessary products with a decent to moderate yield. This technique stands out for its straightfor-

Figure 11.2: Synthesis of spirooxindoles (6–8).

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ward purification procedure, friendly reaction procedure, good yield, short reaction span, simplicity of operation, and no use of column chromatography. Significantly, the authors proposed a conceivable mechanism, showing the role of ChCl:urea DEM, for the successful reaction transformation. In this case, the weak acidic property of DEM promotes the Knoevenagel condensation reaction between malononitrile and isatin, which leads to the formation of an adduct. Next, nucleophilic attack by an enolizable-1,3-dicarbonyl compound gives an adduct, and the subsequent cyclization gives the spiro compound (6) (Figure 11.3).

Figure 11.3: Proposed mechanism for ChCl:urea DEM promoted synthesis of the spiro oxindole derivatives (6).

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Rangappa and coworkers [51] used room temperature DEMs to synthesize pyrano[2,3c]pyrazole (12)(75–95% yield) and (13) (62–70% yield) by MCR of aldehydes (10), hydrazines (11), malononitrile (2a), and 1,3-diones 9(a, b) in 10–30 min. Initially, they simply heated choline chloride and urea (in 1:2 molar ratio) to create this unique eutectic combination. It has been observed that this approach worked well with a variety of aryl aldehydes, including those with electron-donating and -withdrawing groups, as well as heterocyclic aldehydes, which afforded the required products, 12 or 13, in acceptable yield (Figure 11.4).

Figure 11.4: Synthesis of 4H-pyrano[2,3-c]pyrazole (12) and (13).

Afterwards, Rajawat et al. [52] developed a range of spirooxindoles (18–21) by treating indoline-1,3-dione (17), hydrazine hydrate (14), phthalic anhydride (15), and cyclodiones (3, 4 and 16, 17) with a DEM of choline chloride: urea (1:2). They utilized cyclic diketones or diamides and various indoline-2,3-dione derivatives to establish the reaction’s scope and found that these worked well in this process to provide a better yield (83–93%) in a short period. By evaporating water, DEM was easily extracted from the filtrate and successfully employed four times (Figure 11.5).

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Figure 11.5: Synthesis of spiro oxindoles (18–21).

11.2.2 Synthesis of chromene, pyrrole, and α-acyloxyamide derivatives Next, Azizi et al. [53] reported a reaction of malononitrile (2a), salicylaldehyde 22(a–c), thiol (23), or amine (25), as well as the use of different nucleophiles (24) to synthesize chromene derivatives (26–28) from the choline chloride: urea eutectic combination (Figure 11.6). Using column chromatography or recrystallization, the reaction’s crude products were purified after completion. The authors used 3-methoxysalicyldehyde 22(a) and 5-bromosalicyldehyde 22(b) to achieve an excellent yield of 65–98%. In addition to various aldehydes, several nucleophiles (such as amines, thiols, and cyanides) were tested to check the reaction’s feasibility. The outcomes demonstrated that cyanide and

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Figure 11.6: Synthesis of chromenes (26–28).

amine-based nucleophiles produced lower yields than thiol nucleophiles. Thiols show quick transformation than other nucleophiles. Rokade et al. [54] synthesized annulated pyrrole derivative (31) (84–94% yield) using ChCl/urea as DEMs by MCRs involving different 1,3-dicarbonyl (9), aromatic amines (30), and sugars (29). To perform the reaction, all reactants were added in ChCl/urea DEM (10 mL). Then, the reaction mixture was agitated for 30–45 min at room temperature. After the reaction was complete, the crude product was extracted using EtOAc. This product was then purified using column chromatography with n-hexane/EtOAc (3:7) mobile phase. This product was acylated by continuous agitation in 5 mL of dichloromethane for half-an-hour at ambient temperature. The authors examined the substrate scope with a number of amines, dicarbonyls, and sugars such as aldohexose, and achieved good results (Figure 11.7).

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Figure 11.7: Synthesis of sugar-fused pyrroles (31).

Using MCR of amines with acyclic 1,3-diones (9), aryl or alkyl aldehyde (10), and nitromethane (32), Hu et al. [55] produced functionalized pyrroles (34) (52–91% yield) using ChCl/malonic acid DEM. No matter what substituents were on them, a range of aromatic and aliphatic amines responded favorably to the procedure. Alkyl aldehydes produced a variety of compounds that were challenging to identify, but aromatic aldehydes produced good results. Aliphatic aldehydes cannot be employed using this approach, for this reason. ChCl/malonic acid-based DEMs function both as reaction media and as catalysts (Figure 11.8).

Figure 11.8: Synthesis of substituted pyrroles (34).

Using reusable urea:choline chloride-based DES, Shaabani and colleagues [56] produced α-acyloxyamides (37) (65–94% yield) in a short span, according to the type of substituents present in substrates. In contrast to aliphatic aldehydes, aromatic aldehydes exhibit improved yield. The resulting product was obtained in a pure form by recrystallization from ethanol or ethyl acetate. Additionally, DEM demonstrated improved potential activity at milder circumstances, avoiding various challenges related to handling, safety, laborious work-up, and catalyst recovery (Figure 11.9).

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Figure 11.9: Synthesis of α-acyloxyamides (37).

11.2.3 Synthesis of quinoline, imidazo pyridine, pyrazole, and Betti base derivatives Shahabi and Tavakol [57] reported on the synthesis of trisubstituted quinoline derivatives (39) (54–96% yield), utilizing SnCl2/ChCl (DEM). Here, aromatic amines (30) were combined with aromatic aldehydes (10) and enolizable aldehydes (38) at 60 °C for 2–4 h to get the desired compounds. Following that, the products underwent column chromatography or recrystallization in ethanol for additional purification. The authors have investigated a variety of aromatic aldehydes, aromatic amines, and enolizable aldehydes to show how flexible reactions can be (Figure 11.10).

Figure 11.10: Synthesis of trisubstituted quinolines (39).

Azizi and Dezfooli [58] described urea/chlorofluorocarbon DEM as a catalyst and solvent to produce imidazo[1,2-a]pyridine derivatives (42) from a one-pot reaction of cyclohexyl isocyanide (40), aldehydes (10), and 2-amino pyridine (41) at 80 °C for 2–6 h (Figure 11.11). After completion of the reaction, the resulting product obtained was pure in form by recrystallization from ethanol or ethyl acetate. Imidazo pyridines with hydroxyl, methoxy, methyl, and chloro functionality at the aromatic ring were

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effectively accessible. Furthermore, when 4-(dimethylamino)-benzaldehyde is used, no successful reaction transformations have been observed.

Figure 11.11: Synthesis of [1,2-a] pyridine derivatives (42).

Aryan et al. [59] reported a reaction of aldehydes (10), hydrazine (11), and malononitrile 2(a) to produce pyrazole-4-carbonitrile (43) (83–92% yield) at room temperature. Researchers demonstrated that glucose-urea-based DEM can be reused up to four times, with only a little influence on the reaction’s proficiency. Apart from the recyclability of the DEM, this approach has other advantages, such as a shorter processing time and the absence of a metal-based catalyst (Figure 11.12).

Figure 11.12: Synthesis of pyrazole-4-carbonitrile (43).

Azizi and Edrisi [60] further demonstrated the use of a ChCl:urea-based eutectic combination for the synthesis of 1-aminoalkyl-2-naphthol (Betti base) (45) (72–96% yield) using three-component reaction of secondary amines (25) with aldehydes (10) and 2naphthol (44) (Figure 11.13). The authors first prepared the ChCl:urea-based DEM by simply heating a mixture of choline chloride and urea (1:2) until a clear liquid was obtained. Then, they dissolved 1 mmol of the reactants in 1 mL of it and stirred it for 1–3 h at 60 °C. After the experiment was completed, the crude mass was filtered and a pure form was obtained by recrystallization from ethanol. The DEM can be recycled and reused, without substantial change in its catalytic activity.

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Figure 11.13: Synthesis of 1-aminoalkyl-2-naphthols (Betti bases) (45).

11.2.4 Synthesis of chromyl phosphate, dihydropyrimidinone, pyrazolopyridine, and pyrazolophthalazine Krishnammagari et al. [61] synthesized 4H-chrome-4-yl phosphates (47) by combining malononitrile 2(a) with dialkylphosphites (46) and salicylaldehyde derivatives (22) in ChCl:urea DEM (1:2) (Figure 11.14). The authors also tested non-choline chloride-based DEMs during reaction condition optimization, though low activity was observed with non-choline chloride-based DEMs. To test the scope of the reaction, the authors used different functionalized salicylaldehydes. This approach is industrially helpful for generating essential phosphorus-containing compounds because of its simple set up, moderate reaction procedure, and short reaction span.

Figure 11.14: Synthesis of 2-amino-4H-chrome-4-yl phosphates (47).

Momeni and colleagues [62] synthesized dihydropyrimidinone moieties (49 or 50) (70–95% and 89–92% yield) in a ChCl:chloroacetic acid eutectic mixture by reacting urea (48) with ethyl acetoacetate (9) and aldehydes (10) (Figure 11.15). Aldehydes, with electron-withdrawing functionalities, finished the reaction faster than those with electron-donating functionalities. The authors found that the recycled catalyst

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could be used up to four subsequent runs, with a significant loss in activity after the third time. The authors also reported the synthesis of dimedone-fused dihydropyrimidinones (50) under identical reaction parameters.

Figure 11.15: Synthesis of dihydropyrimidinone derivatives (49 and 50).

Vanegas et al. [63] described a multicomponent technique for the synthesis of pyrazolopyridine analogues (52) in a choline chloride and urea-based DEM by the reaction of ethyl acetoacetate (9), ammonium acetate (51), aldehyde (10), and hydrazine (11). The reaction mixture was refluxed at 110 °C for 30 min to produce the desired product in good to excellent (65–96%) yield. This method shows excellent substrate compatibility with a wide range of aromatic and aliphatic aldehydes (Figure 11.16).

Figure 11.16: Synthesis of pyrazolopyridine analogues (52).

Patil et al. [64] efficiently prepared pyrazolo[1,2-b]phthalazinetriones (54) and (55) by reacting different aldehydes (10), 4-hydroxylcoumarin (4) dimedone (3) and dihydro phthalazinedione (53) at refluxing temperature for 30 min using an equimolar proline: oxalic acid dihydrate-based DEM (Figure 11.17). After the reaction was finished, 5 mL of water was added, and the product was filtered to ensure it was pure enough for characterization. This protocol offers good reaction yields, with aldehydes (10) having substitutions like hydroxyl, fluoro, chloro, bromo, iodo, methoxy, nitro, and methyl. Fur-

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Figure 11.17: Synthesis of pyrazolo[1,2-b]phthalazinetriones (54 and 55).

thermore, the DEM was recycled up to five runs with no substantial deterioration in catalytic activity.

11.2.5 Synthesis of spirooxindolopyran, spirooxindoloxanthenes, aminobenzochromene, decahydroacridine, chromenopyridine, tetrahydrobenzopyran, and hexahydroxenthene -dione derivatives Nishtala and Basavoju [65] developed an MCR-based synthesis of xanthenes and spirooxindolopyrans (56–59) in a DEM of ZnCl2:urea (1:3.5) (Figure 11.18). The DEM used in this case could be recycled and utilized multiple times without deterioration in its activity. Using a one-flask reaction, the spirooxindolopyrans (56–59) synthesized in 28–50 min at 80 °C in acceptable yields (82–95%) from isatin (1), barbituric acid (16), 4-hydroxycoumarin (4), and 1,3-indandione (17). Spirooxindolo xanthenes (59) were synthesized in acceptable yield using isatin and dimedone in 30–37 min. Fekri et al. [66] described a single-step reaction of α- or β-naphthol (5 or 44), aldehydes (10), and malononitrile (2a) in choline chloride/oxalic acid (1:1) DEM at 80 °C in 15 to 25 min to produce chromene derivatives (60, 61) (Figure 11.19). Here, electron-releasing and -donating functionality-bearing aldehydes, like m-hydroxybenzaldehyde, o-methoxybenzaldehyde, p-methoxybenzaldehyde, p-nitrobenzaldehyde, o-chlorobenzaldehyde, and p-chlorobenzaldehyde were employed

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Figure 11.18: Synthesis of spirooxindolopyrans and spirooxindoloxanthenes (56–59).

to explore the substrate scope of the reaction and show good reaction transformations (91–97% yield). Bhosle et al. [67] developed an efficient approach for synthesizing sulfonyl decahydroacridine (63) in 30 min, utilizing a one-flask reaction of dimedone (3), aryl amine (30), and aryl aldehyde (62) in a ChCl:ZnCl2 (1:2) DEM. Here, DEM serves both as a catalyst and a solvent for the reaction. Here, the title reaction could not show successful reaction transformation at ambient temperature condition. Nevertheless, when the temperature increased, the product yield began to increase, but no significant change in product yield was seen above 80 °C (Figure 11.20). Using a choline chloride:oxalic acid (1:2) DEM as catalyst cum solvent, Sayahi et al. [68] demonstrated an effective protocol for the synthesis of chromeno[4,3-b]pyridine-2,5(1H)-

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Figure 11.19: Synthesis of chromenes (60–61).

Figure 11.20: Synthesis of sulfonyl decahydroacridine (63).

dione (65) (Figure 11.21), tetrahydrobenzopyran derivatives (66) (Figure 11.22), and hexahydro-1H-xanthene-1,8(2H)-dione (67) (Figure 11.23). The authors used aldehyde (10), dimedone (3), 4-hydroxycoumarin (4), and ammonia (64) to synthesize product 65, while aldehyde, malononitrile, and dimedone were used to produce product 66. Moreover, 67 was synthesized by reacting aldehyde and dimedone in a 1:2 molar ratio.

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Figure 11.21: Synthesis of chromeno[4,3-b]pyridine-2,5(1H)-dione (65).

Figure 11.22: Synthesis of tetrahydrobenzopyran derivatives (66).

Figure 11.23: Synthesis of hexahydro-1H-xanthene-1,8(2H)-dione (67).

11.2.6 Synthesis of pyranopyrimidinone, dihydropyridopyrimidine, and alkylidienethiazolone derivatives Biglari et al. [69] developed a simple one-pot process for producing tetrahydro benzopyran derivatives (66) and pyrano[2,3-d]pyrimidinone derivatives (68) (Figure 11.24). Here, the authors prepared a DEM using choline chloride, urea, and thiourea in 1:1:1 molar proportion for the reaction of propane dinitrile with enolizable C–H acids and aldehydes. This method tolerates a wide range of substituents present on aromatic

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aldehydes, including nitro, chloro, hydroxy, fluoro, and methoxy. Significantly, the DEM was recycled up to four runs without any substantial loss in its catalytic activity.

Figure 11.24: Synthesis of tetrahydro benzopyran (66) and pyrano[2,3-d]pyrimidinone (68).

A novel microwave-assisted method for synthesizing 2,3-dihydropyrido[3,2-d]pyrimidin-4 (1H)-one scaffolds (70) from the reaction of amines (30), aldehydes (10), and pyridoisatoic anhydride (69) with urea:CuCl2 DEM at 100 °C temperature was described by Riadi [70] (Figure 11.25). In the absence of DEM, a very low yield of product (70) was produced. Moreover, this process was performed using just urea, and a similar yield, albeit a lower yield of product, was achieved. These findings demonstrated that both urea and CuCl2 are required for the formation of product (70). Following the synthesis of several 2,3dihydropyrido[3,2-d]pyrimidin-4(1H)-one derivatives (70), their pharmacological activity was tested against several bacterial strains, and the findings were promising.

Figure 11.25: Synthesis of 2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one (70).

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Azizi et al. [71] reported a three-component reaction of rhodanine (71), aldehyde (10), and amine (51) using a choline chloride:glycerin-based DEM for the synthesis of 5alkylidiene thiazolone(72) at 70 °C with constant stirring (Figure 11.26). After the completion of the reaction, water was added to the crude product, which was purified using EtOAc or ethanol to get 5-alkylidiene thiazolone derivatives (72) (53–97% yield). The authors investigated a wide range of substrates by employing various amines and carboxaldehyde derivatives with electron-releasing and -withdrawing substituents. The authors achieved good reaction yields (56–79%) of the desired product (72) in this experiment.

Figure 11.26: Synthesis of 5-alkylidiene thiazolones (72).

11.3 Deep eutectic mixtures (DEMs) as catalyst with conventional reaction media in multicomponent synthesis of heterocycles 11.3.1 Synthesis of spirodioxoloquinolinepyrimidine, spiropyrazoloquinolinepyrimidine, and pyrazolopyrimidoquinoline derivatives Sustainable catalyst design and manufacture are gaining popularity among academic and industry specialists from several fields. This pursuit is especially beneficial for chemists, since catalysis is fundamental in solving green chemistry concerns. DEMs have been used as potential catalysts for numerous transformations in chemistry and related disciplines. This section displays an overview of the most impressive achievements of DEMs as unique sustainable catalysts or catalytic medium in organic reactions.

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Patel and Patel [72] used a trimethyl glycine betaine-oxalic acid DEM to develop a diastereoselective and sustainable method for spiro [[1,3] dioxolo[4,5-g] quinoline-7,5′pyrimidine] scaffold (74). A pseudo-four-substrate reaction comprising 3,4-methylenedioxyaniline (73), aryl/heteroaryl aldehyde (10), and N,N-dimethyl barbituric acid (16) is used in this method (Figure 11.27). With a molar ratio (1:2:1) of 3,4-methylenedioxyaniline (73), aldehyde (10), and dimethyl barbituric acid (16), the reaction proceeds smoothly. The TMGB-oxalic acid DEM outperforms all other DEMs tested, in terms of chemical transformations. Most spirocyclic derivatives with high diastereoselectivities (dr > 50:1) were produced here.

Figure 11.27: Synthesis of spiro [[1,3]dioxolo[4,5g]quinoline-7,5′-pyrimidine] (74).

Significantly, the authors proposed a conceivable mechanism showing the role of TMGB: oxalic acid in the promotion of the one-pot reaction of 3,4-methylene-dioxyaniline (73), aryl/heteroaryl aldehyde (10), and N,N-dimethyl barbituric acid (16). Initially, acidic DEM supports the formation of the Knoevenagel adduct through the reaction of aldehyde and dimethyl barbituric acid. This undergoes a reaction with aniline and generates an active intermediate with a free amino group. Next, this active free amino group reacts with the second equivalent of aldehyde and generates a Schiff’s base. In the presence of DEM, this undergoes a subsequent intramolecular cyclization reaction and generates spiro derivatives (74) (Figure 11.28). Patel et al. [73] then tested the effects of substrates, specifically barbituric acid 16(a) and N,N-dimethyl barbituric acid 16(b), with 5-aminoindazole (75) and aldehyde (10) in ethanol, at reflux temperature, using TMGB:oxalic acid DEM. Using N,N-dimethyl barbituric acid in the title multicomponent process results in diastereoselective (dr > 20:1)

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Figure 11.28: Proposed mechanism for TMGB:oxalic acid DEM-promoted synthesis of spiro [[1,3]dioxolo[4,5g]quinoline-7,5′-pyrimidine] (74).

spiro[pyrazolo[4,3f]quinoline-8,5ʹ-pyrimidine] scaffolds (75), whereas barbituric acid results in pyrazolo[4,3f]pyrimido[4,5-b]quinolines (76). This method tolerates electrondonating and electron-withdrawing functions well and yields spiro derivatives up to 91% (Figure 11.29).

11.3.2 Synthesis of tetrahydrodipyrazolo pyridine, pyrrole, βamino ketones, 2-aminochromene, and pyranocoumarin derivatives Tamaddon and Khorram [74] employed a multicomponent protocol for the development of tetrahydrodipyrazolo pyridine(52) (78–95% yield) and pyrrole derivatives (77) using CoCl2:ChCl DEM in water (Figure 11.30). This DEM was developed by heating the ChCl (20 mmol) and CoCl2·6H2O (5 mmol) mixtures for 60 min at 100 °C. To synthesize the product (52), the authors used a DEM-promoted reaction of aldehyde, ethyl acetoacetate, ammonium acetate, and hydrazine in a (1:2:1:2) ratio, while product (34)

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Figure 11.29: Synthesis of spiro[pyrazolo[4,3f]quinoline-8,5ʹ-pyrimidine] (75) and pyrazolo-[4,3f]pyrimido[4,5-b]quinolines (76).

Figure 11.30: Synthesis of tetrahydrodipyrazolo pyridines (52).

is synthesized using the reactions of aldehyde, ethyl acetoacetate, nitromethane, and aromatic amine derivatives in (2:2:1:2) molar proportion (Figure 11.31). Keshavarzipour and Tavakol [75] used the Mannich reaction of aldehydes (10), enolizable ketones (77), and aromatic bases (30) in water at room temperature to produce ChCl:ZnCl2 DEM-assisted β-amino ketones (78) (52–98% yield) (Figure 11.32). It was observed that aldehydes, with an electron-donating group, offered a larger yield compared to the others, although ketones had a minimal effect on the reaction. Nevertheless, amines containing electron-withdrawing substituents lowered the product yield. Further-

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Figure 11.31: Synthesis of tetrasubstituted pyrrole (34).

more, the use of aliphatic aldehyde derivatives shows parallel side reactions, indicating that the suggested technique is ineffective in the case of aliphatic aldehyde. Afterward, as the reaction completes, the DEM was easily recovered and reused four times, with no discernible change in catalytic activity.

Figure 11.32: Synthesis of β-amino ketones (78).

Chaskar [76] developed a one-pot reaction of aryl aldehyde (10), malononitrile (2a), and dimedone (3) in aqueous media, involving ChCl:urea DEM, to synthesize 2amino-4H-chromenes(66). The author significantly explored pyranocoumarin (79) using 4-hydroxycoumarin (4) under identical reaction parameters. The author employed different CH acids and aryl aldehydes for the generalization of the reaction and found that procedure works efficiently with various CH acids, like ethyl cyanoacetate (2c), malononitrile (2a), and aryl aldehydes (10), including benzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-methoxybenzaldehyde, p-methylbenzaldehyde, and o,p-dihydroxybenzaldehyde to form the desired products, 66 and 79, in excellent yields (81–96%) and a shorter reaction time (Figure 11.33).

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Figure 11.33: Synthesis of 2-amino-4H-chromenes (66) and pyranocoumarins (79).

11.4 Deep eutectic mixture (DEM)-compatible metallic catalysts in multicomponent synthesis of heterocycles 11.4.1 Synthesis of 3-aminobenzofuran, β-aminoketones, and imidazole derivatives Several organic reactions have profited from the adaptability of DEMs, which provide an excellent reaction medium, catalyst, or co-catalyst for a wide range of chemical transformations. A summary of various multicomponent processes in organic synthesis that involve DEMs and compatible metallic catalysts in the synthesis of heterocycles has been provided. Abtahi and Hossein [77] reported a MCR of aryl alkyne (80), amine (81), and salicylaldehyde (22), promoted by ChCl:ethylene glycol (1:2) DEM and copper iodide (a compatible metallic catalyst), for the synthesis of 3-aminobenzofurans (82) (70–91% yield). After the completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated and evaporated. A pure product was obtained by the chromatography technique. The authors observed the temperature dependence of the product from the reaction screening experiments. Significantly, the desired products were formed at 80 °C temperature using copper iodide and ChCl:ethylene glycol (1:2) DEM (Figure 11.34). Azizi and coworkers [78] developed a SBA-15-supported HMPCl:ZnCl2 catalyst using N-methyl-2-pyrrolidone hydrochloride (HMPCl) and ZnCl2

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(Figure 11.36). The authors investigated the catalytic efficiency of this catalyst by synthesizing β-amino ketones (78) in a one-pot, three-component reaction of aldehydes (10), ketones (77), and amines (30). Significantly, under optimum reaction parameters, this protocol offers excellent reaction conversion (68–95% yield) under mild reaction conditions. Here, successful reaction transformation was achieved using functionalized aromatic aldehydes; however, no response has been observed with aliphatic aldehydes. In catalyst recycling experiments, the catalyst can be reused up to four subsequent reactions, with a small deterioration in its catalytic efficiency.

Figure 11.34: Synthesis of 3-aminobenzofurans (82).

In a plausible mechanism, the formation of an iminium ion from the chemical reaction of salicylaldehyde and secondary amine, with the removal of water molecules, is the feasible method for the synthesis of functionalized benzo furans employing CuI along with DES. The organometallic precursor (consisting of a C–Cu bond) is formed by stimulating the C–H bond, which results from the reaction of acetylene with CuI. Following that, Cu-acetylide strikes the iminium ion to form an amine as a second intermediate. An oxygen atom then targets sp-carbon as a nucleophile and generates a 5-membered ring via an intermolecular interaction. Finally, it is believed that isomerization would result in the final product (82) (Figure 11.35). Aziizi et al. [79] developed ChCl:urea DEM-stabilized iron oxide nanoparticles for the one-pot synthesis of tetrasubstituted imidazole derivative (80) using 1,2-diphenylethane1,2-dione (79), ammonium acetate (51), aldehyde (10), and amines (30). The reaction proceeds smoothly at refluxing temperature (60 °C) using these reactants to form desired imidazole derivatives (80) in acceptable yields (60–90%) (Figure 11.37).

11.4.2 Synthesis of thieno indoles, aryl ether, and aryl amine derivatives Nguyen and Tran [80] investigated a one-pot multicomponent protocol for the synthesis of thieno[2,3-b]indole derivatives (83) in magnetic nanoparticles, supported by ChCl:urea DEM media, using acetophenone (77), sulphur (82), and indole (81). By varying acetophenone and indole derivatives, the authors created functionalized

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Figure 11.35: Proposed mechanism for the synthesis of 3-aminobenzofurans (82) using DEM and CuI.

Figure 11.36: Synthesis of β-aminoketones (78).

thieno[2,3-b]indole derivatives (83) (Figure 11.38). Significantly, in catalyst recycling experiments, nanoparticle-supported ChCl:DEM was reused for up to five consecutive runs without a substantial loss in catalytic activity. Zamani et al. [81] investigated a reusable catalyst composed of a DEM of choline chloride and p-toluene sulfonic acid (p-TSA), immobilized on magnetic nanoparticles (MNPs) for chemoselective direct ipso etherification and amination of naphthol derivatives (85) (Figure 11.39).

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Figure 11.37: Synthesis of tetrasubstituted imidazoles (80).

Figure 11.38: Synthesis of thieno[2,3-b]indoles (83).

The functionalized magnetic nanoparticle catalyst exhibited an average yield of 84% for 16 investigated etherification processes and 77% for 5 tested aminations process. The yield was greater than 70% for all 23 processes evaluated, and the p-TSA loading was just 0.45 mol%. Strong DES-support contacts, hydrogen donor species interactions with naphthol, and nanoparticle dispersion may all have contributed to the catalytic performance.

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Figure 11.39: Synthesis of aryl ethers/aryl amines (85).

11.5 Conclusions It has been a primary goal for the scientific and manufacturing communities to replace traditional solvents with those that are less hazardous and have a lesser impact on the environment because of demands for sustainable technology. As DEMs are typically reusable, inexpensive starting ingredients may be used to make them, and many of them are fully biodegradable; they can be conceived of as beneficial alternatives. DEMs can be employed in a variety of fields as valuable alternatives for traditional organic solvents to avoid frequent hassles in the separation or extraction of high-value natural products, as well as reaction media in a variety of chemical transformations involving green and sustainable synthesis of bioactive heterocycles. It might be claimed that using DEMs as solvent-cum-catalyst in multicomponent processes is a step in the right direction, particularly when those mixes are made of natural materials and renewable resources. The literature reveals an exponential increase in works that use DEMs, indicating they are capable of being considered a viable resource in green chemistry. In this chapter, we provided a review of a couple of key MCRs for the synthesis of heterocycles of biological importance, where DEMs are now being used, and where they have bright future.

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Index (±)-camphor-10-sulfonic acid 41 (arylchalcogenyl)-alkyl-1,2,3-triazolo-1,3,6triazonine 283 . β-cyclodextrin 311 [3 + 2] cycloaddition 26 [Fe3O4@SiO2-TCT-PVA-CuII] 318 1H-1,2,3-triazole 254 2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one 415 2,3-dihydroquinazolin-4(1H)-one 230 2-amino-4-coumarinyl-5-arylpyrrole 2 2-amino-4H-chromenes 420 2H-indazoles 329 2-thiazole-5-yl-3H-quinazolin-4-one 241 3,4-dihydroquinazolin-2(1H)-one derivatives 223 3-aminobenzofurans 421 3-substituted quinazolin-4(3H)-one 223 4H-chrome-4-yl phosphates 409 5-alkylidiene thiazolone 416 alkyne dipolarophile 269 amidation reaction 279 amlodipine 392 annulation 120, 122, 127, 129, 132, 136 anthranilamide 230 atom economy 117–118, 132, 138, 143, 147 aza-Diels–Alder reaction 15 aza-Diels–Alder reactions 19 azide 257–258, 263, 268, 275–277, 279–280, 282–283, 285–286, 289, 293, 295–296 azide–alkyne click reaction 275 azide–alkyne cycloaddition 267 Baylis–Hillman adducts 40 benzoxanthenes 157 benzoxanthenone 158 benzoxanthenones 157 Betti base 408 Biginelli 256 Biginelli reaction 23, 376 bioactive 127, 139, 146, 149 bioactivities 135 bioconjugation 308 biolabeling 308 bioorthogonal chemistry 308 bismuth(III) triflate 307 bis(pyrazol-5-ol) derivatives 8 bis-tetrazole 323 https://doi.org/10.1515/9783110985313-012

catalyst free 143 catalyst-free 129, 146 choline azide 318 chromene 411 chromene derivatives 404 chromeno[4,3-b]pyridine-2,5(1H)-dione 413 Claisen–Schmidt-type condensation 9 click chemistry 308 click-Biginelli reaction 290 CoFe2O4@L-asparagine-Cu/Ni nanocatalyst 328 Cu/Ac/r-GO nanohybrid 316 Cu/pectin@Fe3O4 326 CuFe2O4/g-C3N4 321 Cu-free click chemistry 308 cycloaddition 59, 61–62, 78–79, 81–82, 102–103 C–H sulfonylation process 127 de nitrogenative coupling 307 decahydroacridine 412 dihydropyrimidinone 409 dispiropyrrolidineoxindole 385 DMAP-based ionic fluoride 317 domino Knoevenagel 4 domino-Knoevenagel hetero-Diels Alder reactions 358 enaminone 69, 103 environmental-friendly 123 examples of the DEMs 399 Fe3O4@HNTS-tetrazole 322 Febrifugine analogues WR090212 225 felodipine 392 Fenquizone 222 Friedländer annulation-Knoevenagel condensation 39 functionalized pyrroles 406 graphene oxide 43 green chemical 374 green chemistry 373 green method 381 green solvent 136, 138 greener 393 Hajas-Parrish-Eder-Sauer-Wiechart reaction 338 Hajas–Parrish reaction 338

432

Index

Hantzsch 256 Hantzsch reaction 16 Heck reaction 320 heterocycles 383, 386, 390, 393 heterocyclic 117–118, 137, 139, 146, 149 heteropolyacids 324 high yield 117, 123 Huisgen 1,3-dipolar cycloaddition reaction 264 IMCCR. 318 imidazo[1,2-a]pyridine 407 imidazole 422 imine 57, 62–64, 70, 73, 75, 78, 82, 84, 86, 91–92, 103, 105 indomethacin 223 inexpensive 132, 136 inexpensive catalyst 169 intermolecular Aldol reactions 338 intra-molecular Mannich reaction 15 intramolecular-Diels–Alder reaction 382 isatoic anhydride 228, 232 Knoevenagel condensation 17, 295, 313, 386, 388 Knoevenagel condensations reactions 361 Knoevenagel reaction 29 Kornblum−DeLaMare rearrangement 12 L-phenylalanine

189 319, 347, 351 L-thioproline 198 L-proline

Mannich 89, 101, 256 Mannich products 348 Mannich reaction 365, 419 MCR 117, 142 MCRs 55–56, 107, 117, 157, 169, 173 mesoporous graphitic carbon nitride-[CuFe2O4/ g-C3N4 hybrids] 321 metal-free 132–133, 136 metal-organic framework 16 Michael addition 4, 15, 71, 78–79, 87, 91–92, 94, 101 Michael adduct 20 Michael–Henry cascade reaction 354 Michael–Michael–aldol reaction 354, 363 microwave technique 373 mild synthetic route 127 monoamine oxidase 222 montmorillonite K-10 308 multicomponent assembly process 1

multicomponent reaction 86, 89, 256, 374, 377, 386 multicomponent reactions 55, 149, 374 multicomponent reactions (MCRs) 55 multicomponent synthesis 399 nano 68, 97, 99–100 nanocatalyst 138, 143 naphthol derivative 423 N-Arylation 319 nicardipine 392 Niementowski quinazolinone synthesis 226 nifedipine 392 ninhydrin 181, 183–185, 189–192, 194, 196–200, 202, 204–205, 208–209, 211–212, 214 one-pot 117, 127, 132, 136–137, 143, 149 one-step 149 Passerini 256 Pd–Cu @rGO 320 pharmaceutical 127, 137, 139 pharmacological 133, 137, 146 PVA @ Cu(II) Schiff base complex. 315 pyrano[2,3-c]pyrazole 403 pyrano[2,3-d]pyrimidinone 414 pyranocoumarin 420 pyrano-thiazoles 387 pyrazole-4-carbonitrile 408 pyrazolo-[3,4-b]-quinolines 28 pyrazolo[4,3f]pyrimido[4,5-b]quinoline 418 pyrazolopyridine 410 pyrrole 418 pyrrole derivative 405 quinazolinone 221 quinoline 407 quinoline-based ionic liquids 313 quinoxaline 181 recyclability 169 regioselectivity 90, 93, 95 regiospecific 120 ruthenium-catalyzed 230 sarcosine 183–185, 194, 199, 202, 204, 209, 212 short reaction time 123, 127–128, 132, 134, 136 single-step 117 small bioactive heterocycles 399

Index

solvent free 379, 387, 390, 393 solvent-free 381–382, 386 Sonogashira coupling 292 spiro [[1,3] dioxolo[4,5-g] quinoline-7,5′-pyrimidine] 417 spiro-indenoquinoxaline derivatives 211 spiro-indeno-tetrahydropyridine 386 spirooxindole derivatives 401 spirooxindole dihydroquinazolinone 239–240 spirooxindoles 403 spiro-oxindoliccyclohexanes 355 spirooxindolopyrans 411 spiro[pyrazolo[4,3f]quinoline-8,5ʹ-pyrimidine] 418 spiro-pyrrolidines 183 sterically shielded tetrazoles 322 Strecker reaction 314 Suzuki reaction 320 Suzuki–Miyaura cross coupling 312 tetrahydro benzopyran 414 tetrahydro-1H-β-carbolines 312 tetrahydrobenzo[a]xanthene-11-one 158 tetrahydrobenzo[a]xanthene-11-one derivatives 160 tetrahydrobenzo[b]pyrans 381 tetrahydrobenzopyran 413 tetrahydrodipyrazolopyridine 418 tetrahydronicotinonitriles 326

tetrazole-1,2,3-triazole hybrids. 329 tetrazolopyrimidines 310 tetrazol-pyrimidine hybrids 327 tetrhydrobenzo[a]xanthene-11-one 168 thiazolo-s-triazine 387 thieno[2,3-b]indole 422 Ugi reaction 256, 294 Ugi tetrazole reaction 307 Ugi-azide–Pictet-Spengler process 312 Ullman-type CN cross-coupling 311 uracil derivatives 327 Wolff rearrangement 62–63, 65 Xanthenes 157, 411 Yonemitsu condensation 359 Zn(L-proline)2 365 zolamine 157 α-acyloxyamides 406 α-hydroxy-β-azidotetrazoles 316 β-amino ketone 419 β-amino ketones 422 γ-lactam 4

433