Aqueous-Mediated Synthesis: Bioactive Heterocycles [2] 9783110997262

Table of contents :
Cover
Half Title
De Gruyter Series in Green Bioactive Heterocycles
Green Bioactive Heterocycles: Volume 2
Aqueous-Mediated Synthesis: Bioactive Heterocycles
Copyright
Foreword
A brief professional profile of Prof. John C. Warner
Preface
Contents
List of contributors
1. Construction of benzazoles in aqueous medium: a sustainable approach
1.1 Introduction
1.2 Sustainable approaches for organic synthesis and the construction of benzazole scaffolds
1.2.1 Sustainable reaction media
1.2.1.1 Neat condition
1.2.1.2 Polyethylene glycol (PEG)
1.2.1.3 Eutectic solvent and supercritical fluid
1.2.1.4 Ionic liquids
1.2.1.5 Biomass-derived solvents
1.2.1.6 Alcohols
1.2.1.7 Fluorinated alcohols
1.2.1.8 Ethanol and water (EtOH:H2O) mixture
1.2.1.9 Water
1.2.2 Nonconventional energy sources
1.2.3 Sustainable reaction approaches/strategies
1.2.4 Sustainable catalysis
1.3 Synthesis of benzimidazoles in aqueous media
1.3.1 Water as reaction medium
1.3.2 Water–surfactant mixture as reaction media
1.4 Sustainable synthesis of benzoxazole derivatives
1.4.1 Water as reaction media
1.5 Sustainable synthesis of benzothiazole derivatives
1.5.1 Water as reaction medium
1.5.2 Water–surfactant mixture as reaction medium
1.6 Common sustainable synthesis of benzimidazole, benzothiazole, and benzoxazoles in aqueous medium
1.6.1 Water as the reaction medium
1.6.2 Aqueous suspension of SDS as reaction medium
1.7 Conclusions
References
2. Catalyst-free synthesis of bioactive heterocycles in aqueous media
2.1 Introduction
2.2 Synthesis of bioactive heterocycles in aqueous media
2.2.1 Rhodanines
2.2.2 1,2,3-Triazole synthesis
2.2.3 Chromone synthesis
2.2.4 Synthesis of complex indolizine rings
2.2.5 Synthesis of spirooxindole-fused pyrrolidines
2.2.6 Synthesis of densely functionalized pyridine rings
2.2.7 Furan ring synthesis
2.2.8 Synthesis of pyran rings
2.2.9 Synthesis of [1,6]naphthyridines
2.2.10 Imidazo- and benzimidazo-fused polyheterocycle synthesis
2.2.11 Synthesis of 2-benzazepine derivatives
2.2.12 Synthesis of quinolone-2-thiones
2.2.13 Synthesis of isoquinolones
2.2.14 Synthesis of 1,4-dihydropyridines and polyhydroquinolines
2.3 Conclusions
References
3. Aqueous-mediated sustainable catalytic methods for the synthesis of bioactive N-heterocycles
3.1 Introduction
3.2 Synthesis of nitrogen heterocycles
3.3 Conclusions
References
4. Catalyst-free synthesis of monocyclic heterocycles in aqueous medium: a sustainable approach
4.1 Introduction
4.2 Classification of monocyclic heterocycles
4.3 Classical/traditional methods for the synthesis of monocyclic heterocycles
4.3.1 Robinson–Gabriel synthesis of oxazole
4.3.2 Biginelli reaction
4.3.3 Hantzsch dihydropyridine synthesis
4.3.4 Pyridine synthesis
4.4 Sustainable approaches for synthesis of monocyclic heterocycles
4.5 Synthesis of monocyclic heterocycles in aqueous media
4.5.1 Four-membered heterocycles
4.5.2 Five-membered heterocycles
4.5.3 Six-membered heterocycles
4.5.4 Seven-membered heterocycles
4.6 Conclusions
References
5. Water as benign reaction medium for the synthesis of quinoxalines
5.1 Introduction
5.2 Water as reaction medium for organic synthesis
5.3 Recent developments in the synthesis of quinoxalines in aqueous m
5.3.1 Synthesis of quinoxalines in aqueous medium in the presence of catalyst
5.3.2 Quinoxaline synthesis in water in the presence of surfactant
5.3.3 Water as reaction media
5.4 Conclusions
References
6. Synthesis in water: a sustainable tool for the construction of quinoline derivatives
6.1 Introduction
6.2 Recent developments in the synthesis of quinolines in aqueous media
6.2.1 Catalyst-based approaches for synthesis of quinoline derivatives in aqueous medium
6.2.2 Quinoline synthesis in aqueous medium using surfactants
6.3 Conclusions
References
7. Aqueous-mediated synthesis of bioactive O-heterocycles
7.1 Introduction
7.2 Aqueous-mediated synthesis of bioactive O-heterocycles under catalyzed conditions
7.3 Aqueous-mediated protocols under catalyst-free conditions
7.4 Conclusions
References
8. Aqueous-mediated synthesis of bioactive S-heterocycles
8.1 Introduction
8.2 Recent research work
8.2.1 Sodium fluoride catalysis
8.2.2 NBS-promoted synthesis
8.2.3 Erucin derivatization
8.2.4 β-CD-mediated synthesis
8.2.5 K2S2O8-mediated oxidative condensation
8.2.6 Nafion-H-promoted synthesis
8.2.7 (NH4)2HPO4 or 10% DABCO-assisted preparation
8.2.8 Microwave/ultrasound-assisted/conventional synthesis
8.2.9 Cu(II)–DiAm–Sar/SBA-15-catalyzed synthesis
8.2.10 Copper salt-assisted synthesis
8.2.11 CTAB-catalyzed synthesis
8.2.12 Sm(OTf)3-catalyzed preparation
8.2.13 Fe(III)–Schiff base/SBA-15-supported synthesis
8.2.14 Iron salt-catalyzed S-arylation
8.2.15 CuCl2–phen-catalyzed synthesis
8.2.16 Catalyst-free domino synthesis
8.2.17 FeCl3/1,10-phen-catalyzed preparation
8.2.18 Quaternary ammonium salt-catalyzed synthesis
8.2.19 Ionogel-catalyzed preparation
8.2.20 Brønsted acid–surfactant-combined ionic liquid [BAILs]-catalyzed synthesis
8.2.21 Synthesis in pyridine/water system
8.3 Conclusion
References
9. Aqueous-mediated synthesis of bioactive spirooxindoles
9.1 Introduction
9.1.1 Spirocyclic compounds
9.1.2 Spirooxindoles
9.2 Aqueous-mediated synthesis of spirooxindoles
9.2.1 One-pot synthesis of spirooxindoles in aqueous media
9.2.2 Nanocatalyzed green synthesis of spirooxindoles in aqueous media
9.2.3 Green synthesis of spirooxindoles in aqueous media
9.2.4 Microwave-assisted synthesis of spirooxindoles in aqueous media
9.3 Conclusions
References
10. Sodium dodecyl sulfate in water: A valuable combination for the synthesis of various bioactive heterocycles
10.1 Introduction
10.2 Synthesis of bioactive heterocycles
10.2.1 Synthesis of bioactive N-heterocycles
10.2.1.1 Synthesis of pyrroles
10.2.1.2 Synthesis of N-aryl-1,8-dioxo decahydroacridines
10.2.1.3 Aza-Diels–Alder reaction
10.2.1.4 Synthesis of 1,2-disubstituted benzimidazoles
10.2.1.5 Synthesis of quinoxaline derivatives
10.2.1.6 Synthesis of pyrrolo-quinoxalines
10.2.1.7 Synthesis of imidazopyridines
10.2.1.8 Synthesis of phthalazines
10.2.1.9 Synthesis of tetrahydropyrazolopyridine-6-ones
10.2.2 Synthesis of bioactive O-heterocycles using sodium dodecyl sulfate
10.2.2.1 Synthesis of benzo[b]furans
10.2.2.2 Synthesis of 3,4-dihydropyrano[c]chromene
10.2.2.3 Synthesis of 2-amino-3-cyano-tetrahydrobenzo[b]pyrans
10.2.3 Synthesis of bioactive N,O-heterocycles using sodium lauryl sulfate
10.2.3.1 Synthesis of functionalized pyrimidine
10.2.4 Synthesis of bioactive N,S-heterocycles using sodium dodecyl sulfate
10.2.4.1 Synthesis of 2-phenylbenzothiazole
10.2.4.2 Synthesis of 2,3-dihydro-1,5-benzothiazepines
10.3 Conclusions
References
11. Synthesis of bioactive heterocycles involving heterogeneous catalysis in water
11.1 Introduction
11.2 Synthesis of three-membered ring
11.3 Synthesis of five-membered ring
11.3.1 Synthesis of polysubstituted pyrroles
11.3.2 Fabrication of hydroindeno[1,2-b]indoles
11.3.3 Preparation of trisubstituted furans and pyrroles
11.3.4 Synthesis of tetrasubstituted pyrroles
11.3.5 Construction of substituted indoles
11.3.6 Synthesis of functionalized trifluoromethylated oxindoles
11.3.7 Preparation of disubstituted isoxazolines and isoxazoles
11.3.8 Synthetic strategy toward 3,5-disubstituted isoxazoles
11.3.9 Strategy toward disubstituted isoxazolines
11.3.10 One-pot preparation of dihydrospiro furo[2,3-c]pyrazole
11.3.11 Construction of imidazo[1,2-a]pyridines
11.3.12 Preparation of differently substituted triazole derivatives
11.3.13 Synthesis of substituted benzothiazoles
11.3.14 Preparation of thiazolidinone-linked triazoles
11.4 Synthesis of six-membered ring
11.4.1 Synthesis of hexahydroquinolines
11.4.2 Preparation of hexahydroacridine derivatives
11.4.3 Preparation of hexahydroacridine derivatives
11.4.4 Fabrication of pyrazolo[3,4-b]pyridine
11.4.5 Fabrication of pyridopyrimidine derivatives
11.4.6 Strategy toward pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines derivatives
11.4.7 Synthesis of imidazopyrimidine scaffolds
11.4.8 Fabrication of pyrrolo[1,2-a]pyrazine moeties
11.4.9 Preparation of isoquinoline and isoquinolone derivatives
11.4.10 Synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes derivatives
11.4.11 Construction of dihydropyrano[c] chromene scaffolds
11.4.12 Preparation of 2-amino-4H chromenes
11.4.13 Preparation of 4H-pyrans
11.4.14 One-pot strategy for the preparation of various pyranopyrazole moieties
11.4.15 One-pot strategy for the preparation of various pyranopyrazole moieties
11.4.16 Fabrication of 3,4-dihydropyrimidin-2(1H)-one scaffolds
11.4.17 Synthesis of 2-substituted quinazolinone
11.4.18 Synthesis of spirooxindolepyrimidines and spirooxindole
11.4.19 Fabrication of tetrahydrobenzoxanthene and 1,6-dioxooctahydroxanthene scaffolds
11.4.20 Preparation of benzopyrano-chromene and pyrano-chromene moieties
11.4.21 Preparation of xanthenediones
11.4.22 Strategies toward variety of 3-aryl-3,4-dihydro-2H- naphtho[2,1-e][1,3]oxazine scaffolds
11.5 Synthesis of seven-membered ring
11.5.1 Preparation of 4,5,6,7-tetrahydro-1H-1,4-diazepine- 5-carboxamide
11.6 Miscellaneous
11.6.1 Mn-catalyzed dehydrogenative conversion of alcohols into acids
11.6.2 Fabrication of β-quinoline allylic sulfones
11.6.3 Synthesis of aminophosphonate derivatives
11.6.4 Preparation of 2-sulfonylquinoline derivatives
11.7 Conclusions
References
12. Microwave-assisted aqueous-mediated synthesis of bioactive heterocycles
12.1 Introduction
12.2 Thermal versus nonthermal effects
12.3 Principles of microwave activation
12.4 Role of solvents in organic synthesis
12.5 Water as solvent
12.6 Comparison of microwave and conventional heating
12.7 Microwave-assisted synthesis of bioactive heterocycles
12.7.1 Synthesis of biaryl derivatives by Suzuki coupling reaction
12.7.2 Synthesis of triazones
12.7.3 Synthesis of triaza-benzo[b]fluoren-6-one derivatives
12.7.4 Synthesis of pyrazole and pyridazine derivatives
12.7.5 Synthesis of pyranopyrazoles
12.7.6 Synthesis of substituted acridine derivatives
12.7.7 Synthesis of diketopiperazines
12.7.8 Synthesis of 2-aminochromenes
12.7.9 Synthesis of dioxane-functionalized compounds
12.7.10 Synthesis of benzoxazines
12.7.11 Synthesis of bis-coumarin derivatives
12.7.12 Synthesis of rhodanine derivatives
12.7.13 Synthesis of terpyridines and fused pyridines
12.7.14 Synthesis of tricyclic β-lactam ring compounds
12.7.15 Synthesis of disubstituted 1,2,3-triazoles
12.7.16 Synthesis of 1,4-dihydropyridines
12.7.17 Synthesis of aryl-4(3H)-quinazolinone derivatives by deamination protocol
12.7.18 Synthesis of benzimidazole derivatives
12.7.19 Synthesis of pyranopyrazoles
12.7.20 Synthesis of indenoquinoline derivatives
12.7.21 Synthesis of 10H-phenothiazines
12.7.22 Fischer indole synthesis from phenylhydrazine
12.7.23 Synthesis of podophyllotoxin derivatives
12.7.24 Synthesis of benzo[f]azulenones
12.7.25 Synthesis of azaspiro cyclic compounds
12.7.26 Synthesis of azacyclic and isoindole derivatives
12.7.27 Synthesis of thiazolopyrimidine derivatives
12.7.28 Synthesis of quinazolinone derivatives
12.7.29 Synthesis of indole derivatives
12.7.30 Synthesis of N-aryl pyrrolidines
12.7.31 Synthesis of sugar-based pyrazole derivatives
12.8 Limitation
12.9 Conclusions
References
13. Ultrasound-assisted aqueous-mediated synthesis of bioactive heterocycles
13.1 Introduction
13.2 Five-membered heterocyclic compounds
13.2.1 Furan
13.2.2 Thiophene
13.2.3 Isoxazole
13.2.4 Pyrazole
13.2.5 Thiadiazole
13.2.6 Tetrazoles
13.3 Six-membered heterocyclic compounds
13.3.1 Pyran
13.3.2 Pyrimidine
13.3.3 Thiazine
13.4 Seven-membered heterocyclic compounds
13.4.1 Thiazepines
13.5 Fused heterocyclic compounds
13.5.1 Indole
13.5.2 Isoindolin
13.5.3 Benzothiazole
13.5.4 Benzopyrans
13.5.5 Quinoline
13.5.6 Pyridotriazole
13.6 Conclusions
References
Index

Citation preview

Asit K. Chakraborti and Bubun Banerjee (Eds.) Aqueous-Mediated Synthesis

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 ----

www.degruyter.com

Green Bioactive Heterocycles

Edited by Bubun Banerjee

Volume 2

Aqueous-Mediated Synthesis Bioactive Heterocycles Edited by Asit K. Chakraborti and Bubun Banerjee

Editors Prof. Asit K. Chakraborti School of Chemical Sciences Indian Association for the Cultivation of Science (IACS) 2A & 2B Raja S. C. Mullick Road Jadavpur 700032 West Bengal India [email protected] Dr. Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India [email protected]

ISBN 978-3-11-099726-2 e-ISBN (PDF) 978-3-11-098562-7 e-ISBN (EPUB) 978-3-11-098609-9 ISSN 2752-1338 Library of Congress Control Number: 2023947822 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 Back Image: IkonStudio/iStock/Getty Images Plus Front Image: anusorn nakdee/iStock/Getty Images Plus Typesetting: Integra Software Services Pvt. Ltd. Printing and binding: CPI books GmbH, Leck www.degruyter.com

Foreword In chemistry we spend a great deal of time imagining the shape of molecules. In turn, we have sought to understand the shape of the electronic orbitals that control these geometries. The development of quantum mechanics has allowed us to quantify the probability of finding electrons somewhat precisely in specific regions surrounding atoms and within molecular bonds. Knowledge of this geometry is important because all chemical reactions occur by constant movement and subsequent collisions of reactive species. By understanding these electronic geometries one can choreograph the molecular trajectories that define reaction coordinates. Chemists dissolve molecules in solvents to facilitate these collisions. We heat things up and put them under pressure to increase the frequency of collisions. Interestingly, we often DO NOT actually promote the precise collision necessary to form the reaction product, we increase the frequency of ALL collisions. Throughout the history of chemistry this has enabled the vast library of chemical reactions to be invented, optimized, and deployed in a myriad of chemical syntheses. Obviously, the solvent choice must be compatible with the chemistry being carried out. If the solvent creates an unwanted side reaction, then the chemical reaction cannot occur properly. Water has historically been a “forbidden” solvent. Because the protons act as Lewis acids and the electron pairs on oxygen act as Lewis bases, most of the traditional chemical reactions not only could not use water as a solvent, but chemists had to go through extraordinary measures to avoid the presence of even trace amounts of water in aprotic solvents. Water was “the enemy.” From a sustainability perspective, water is a very desirable material. Traditional organic solvents do not regularly exist in nature. The emission of organic solvents into the environment (air, water bodies, and soils) and into biological organisms creates countless negative impacts – leading to toxicity and environmental destruction. Because all of life and the earth’s living ecosystem are built on aqueous-based cellular systems, water is commonplace and ever present. Chemists have historically had to cope with the drawbacks of using traditional organic solvents and spend a lot of time, effort, and money into ensuring that the solvents did not escape into the environment. The wonderful thing about science and research is that many things that couldn’t be done yesterday, with human creativity and ingenuity, can be done today and tomorrow. This book is a testament to the amazing authors of chapters within this book and the authors cited within each of the chapters. One might argue that the synthesis of heterocyclic materials, of all the many types of chemistry, can be most problematic in aqueous environments. The polarity of the heteroatom-carbon bond is most susceptible to unwanted hydrolytic reactions. Here we have this book on Aqueous-Mediated Synthesis: Bioactive Heterocycles, edited by Asit K. Chakraborti and Bubun Banerjee, with 13 chapters describing techniques and syntheses that was the stuff of science fiction just a few years ago! I have marveled at the accomplishments described in this volume. I could not have imagined when I was a chemistry student in the 1980s carryhttps://doi.org/10.1515/9783110985627-202

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Foreword

ing out all my synthetic heterocyclic reactions in traditional organic solvents, that this type of chemistry would be possible. And yet, here it is! Enjoy! John C. Warner Distinguished Professor of Green Chemistry, Monash University, Melbourne, Australia President and CEO, Technology Greenhouse, LLC, Woburn, MA, USA

A brief professional profile of Prof. John C. Warner John Warner is one of the founders of the field of Green Chemistry. He wrote a book, with Paul Anastas in 1998, which provides the definition and 12 principles of Green Chemistry. As an industrial chemist, he has over 350 patents and has worked with hundreds of companies worldwide. He received the Perkin Medal in 2014 from the Society of Industrial Chemistry. As an academic, he was a tenured full professor of chemistry and a tenured full professor of plastics engineering at the University of Massachusetts where he started the world’s first PhD program in Green Chemistry. He has over 120 publications in synthetic methodologies, noncovalent derivatization, polymer photochemistry, metal oxide semiconductors, and Green Chemistry. In 2022 he received the August Wilhelm von Hofmann Medal from the German Chemical Society and in 2004 the Presidential Award for excellence in science mentoring (PAESMEM) from the US National Science Foundation (NSF) and President George W. Bush. As an inventor, John’s inventions have led to the founding of many companies in the fields of photovoltaics, neurochemistry, construction materials, cosmetics, and water technologies. In 2016 he received the Lemelson Invention Ambassadorship from the Lemelson Foundation and the American Association for the Advancement of the Sciences (AAAS). John is a member of the Club of Rome, Distinguished Professor of Green Chemistry at Monash University in Australia, Distinguished Professor of Chemistry at Chulalongkorn University in Thailand, and Honorary Professor of Chemistry at the Technical University of Berlin where they have named the “John Warner Center for Start Ups in Green Chemistry.” John currently serves as President and CEO of The Technology Greenhouse.

Preface Heterocyclic compounds are ubiquitous and find wide applications in biological, medicinal, agricultural, and material sciences. Heterocyclic scaffolds are the common structural feature in the naturally occurring bioactive compounds and have tremendous role in drug discovery and design. Various heterocyclic moieties are the critical pharmacophoric components in many commercially available drug molecules. In view of their potential applications, chemists are deeply involved to develop ecofriendly and cost-effective new synthetic strategies for generating structurally diverse biologically important heterocyclic compounds. Conventionally, the synthesis of heterocyclic compounds involves performing the desired organic reactions in commonly used volatile organic solvents (VOSs). However, in general, these VOSs have incomplete recovery efficiency and gets into the environment (admixed with air, water, and living systems) causing negative impact due to the toxicity. This has driven chemists to search for eco-friendly and safe alternative to the VOSs. Thus, solvent management becomes the critical issue in a typical chemical manufacturing process that has compelled the pharma industries to create solvent selection guides in which water, the solvent of the Nature, tops the list of the preferred solvents. Toward the endeavor of finding environmentally benign reaction media water drew the attention as it is safe for use being nontoxic, nonflammable, cheap, and abundantly available. Moreover, on many occasions, the use of water offers distinct advantages in terms of rate acceleration and modulating selectivity of the organic reaction. The ability of water to play the hydrogen-bond-assisted dual role to activate both the electrophile and nucleophilic reacting partners in the transition state offers rational of its selection to obtain the desired products. Incidentally, the very first organic synthesis performed in 1828 (Wohler’s synthesis of urea from ammonium cyanate) happens to fulfill the two important aspects of green synthesis: atom economy and use of water as solvent. Although water suffers from certain limitations, in particular due to the low solubility of organic reactants in aqueous medium but due to the high surface tension and hydrophobic nature of water (leading to beneficial enforced hydrophobic interaction), in some cases the organic reactants in water are bound to form aggregates in order to decrease the exposed organic surface area, which eventually increases the rate of the reaction. However, the adverse impact on the reaction rate due to the poor aqueous solubility of organics may also be circumvented by the proper choice of surfactants (as the solubility enhancer). The first chapter presents a glimpse on the synthesis of various benzazole derivatives in aqueous medium. On few occasions, the actual role of water toward the formation of the desired products is also explained in this chapter. Chapter 2 deals with the catalyst-free synthesis of bioactive heterocycles using water as the green solvent. Various aqueous-mediated protocols for the sustainable synthesis of structurally diverse bioactive N-heterocycles are discussed in Chapter 3. Chapter 4 describes the role of aqueous medium for the catalyst-free synthesis of various monocyclic heterocycles. https://doi.org/10.1515/9783110985627-203

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Chapters 5 and 6 are related to the synthesis of various quinoxalines and quinoline derivatives, respectively, in aqueous medium. The next two chapters summarize various water-mediated synthetic methods for the preparation of biologically relevant Oheterocycles and S-heterocycles, respectively. Chapter 9 relates to the synthesis of various bioactive spirooxindoles in water. The catalytic role of sodium dodecyl sulfate in water for the synthesis of various bioactive heterocycles is discussed in Chapter 10. Chapter 11 describes the role of different reusable heterogeneous catalysts for the synthesis of various biologically promising heterocycles in water. Chapters 12 and 13 summarize the aqueous-mediated synthetic methods for the preparation of structurally diverse bioactive heterocycles under the influence of microwave and ultrasound irradiation, respectively. The benefits of these nonconventional approaches over the conventional heating methods are also discussed in these chapters. Overall, the present volume of the book series titled “Green Bioactive Heterocycles” has attempted to cover the utility of water as solvent for the synthesis of various bioactive heterocyclic compounds. Recent updates on the catalytic role of various catalysts in water, nonconventional approaches in water, mechanistic considerations, and future directions in the aqueous-mediated reactions could offer guidance to the synthetic chemists for designing new strategies toward the synthesis of new biologically promising heterocyclic entities in water as the greenest solvent. Furthermore, we believe this book will be useful to the pharmaceutical chemists both in academia and industries and would create considerable interest in the years to come. Prof. Asit K. Chakraborti & Dr. Bubun Banerjee

Contents Foreword Preface

V IX

List of contributors

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Nirjhar Saha, Asim Kumar, Soumili Biswas, Anirban Sarkar, and Asit K. Chakraborti Chapter 1 Construction of benzazoles in aqueous medium: a sustainable approach Dwaipayan Das, Moumita Saha, and Asish R. Das Chapter 2 Catalyst-free synthesis of bioactive heterocycles in aqueous media

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59

Sabbasani Rajasekhara Reddy and Pooja Garg Chapter 3 Aqueous-mediated sustainable catalytic methods for the synthesis of bioactive N-heterocycles 85 Asim Kumar, Nirjhar Saha, Soumili Biswas, and Asit K. Chakraborti Chapter 4 Catalyst-free synthesis of monocyclic heterocycles in aqueous medium: a sustainable approach 101 Babita Tanwar, Asim Kumar, Nirjhar Saha, and Asit K. Chakraborti Chapter 5 Water as benign reaction medium for the synthesis of quinoxalines Nirjhar Saha, Kshitij I. Patel, Antarlina Maulik, and Asit K. Chakraborti Chapter 6 Synthesis in water: a sustainable tool for the construction of quinoline derivatives 183 Rajib Sarkar and Chhanda Mukhopadhyay Chapter 7 Aqueous-mediated synthesis of bioactive O-heterocycles

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Yadavalli Venkata Durga Nageswar, Katla Ramesh, and Katla Rakhi Chapter 8 Aqueous-mediated synthesis of bioactive S-heterocycles 227 Razia Noreen, Arruje Hameed, Tanzeela Khalid, Shaheera Batool, and Tahir Farooq Chapter 9 Aqueous-mediated synthesis of bioactive spirooxindoles 255 Bubun Banerjee, Anu Priya, Aditi Sharma, Manmeet Kaur, and Arvind Singh Chapter 10 Sodium dodecyl sulfate in water: A valuable combination for the synthesis of various bioactive heterocycles 283 Dripta De Joarder, Rajarshi Sarkar, and Dilip K. Maiti Chapter 11 Synthesis of bioactive heterocycles involving heterogeneous catalysis in water 307 Chebolu Naga Sesha Sai Pavan Kumar and Vaidya Jayathirtha Rao Chapter 12 Microwave-assisted aqueous-mediated synthesis of bioactive heterocycles 353 Seema Kothari, Khushbu Sharma, Rakshit Ameta, and Suresh C. Ameta Chapter 13 Ultrasound-assisted aqueous-mediated synthesis of bioactive heterocycles 385 Index

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List of contributors Yadavalli Venkata Durga Nageswar Retired Chief Scientist Indian Institute of Chemical Technology (IICT) Tarnaka, Hyderabad Telangana 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 Rajib Sarkar Department of Chemistry University of Calcutta 92 APC Road Kolkata 700009 West Bengal India And Department of Chemistry Prabhu Jagatbandhu College Jhorehat, Andul-Mouri Howrah 711302 West Bengal India Chhanda Mukhopadhyay Department of Chemistry University of Calcutta 92 APC Road Kolkata 700009 West Bengal India email: [email protected]

https://doi.org/10.1515/9783110985627-205

Sabbasani Rajasekhara Reddy Department of Chemistry School of Advanced Sciences Vellore Institute of Technology (VIT) Vellore 632014 Tamil Nadu India email: [email protected] Pooja Garg Department of Chemistry School of Advanced Science Vellore Institute of Technology (VIT) Vellore 632014 Tamil Nadu India Dripta De Joarder Department of Chemistry School of Advanced Sciences VIT-AP University Andhra Pradesh India Rajarshi Sarkar Department of Chemistry School of Advanced Sciences VIT-AP University Andhra Pradesh India Dilip K. Maiti Department of Chemistry University of Calcutta 92 APC Road Kolkata 700009 West Bengal India

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Chebolu Naga Sesha Sai Pavan Kumar Department of Chemistry School of Applied Sciences and Humanities Vignan’s Foundation for Science Technology & Research (Deemed to be University) Vadlamudi, Guntur 522213 Andhra Pradesh India And Department of Chemistry Vignan Degree & P.G. College Palakaluru Road, Guntur 520009 Andhra Pradesh India Vaidya Jayathirtha Rao Emeritus Scientist, IICT Honorary Professor, AcSIR Organic Syntheis & Process Chemistry Department and AcSIR – Ghaziabad CSIR – Indian Institute of Chemical Technology Uppal Road Tarnaka, Hyderabad 500007 Telangana India email: [email protected] Dwaipayan Das Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India Moumita Saha 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]; [email protected]

Seema Kothari Department of Chemistry PAHER University Udaipur 313003 Rajasthan India Khushbu Sharma Department of Chemistry Bhupal Nobles’ University Udaipur 313001 Rajasthan India Rakshit Ameta Department of Chemistry J.R.N. Rajasthan Vidhyapeeth (Deemed to be University) Udaipur 313001 Rajasthan India Suresh C. Ameta Department of Chemistry PAHER University Udaipur 313003 Rajasthan India email: [email protected] Asim Kumar Amity Institute of Pharmacy Amity University Haryana Manesar 122413 Haryana India Nirjhar Saha School of Chemical Sciences Indian Association for the Cultivation of Science (IACS) Jadavpur, Kolkata 700032 West Bengal India

List of contributors

Soumili Biswas School of Biological Sciences Indian Association for the Cultivation of Science (IACS) Jadavpur, Kolkata 700032 West Bengal India

Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India email: [email protected]

Asit K. Chakraborti School of Chemical Sciences Indian Association for the Cultivation of Science (IACS) Jadavpur, Kolkata 700032 West Bengal India email: [email protected]

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

Razia Noreen Department of Biochemistry Government College University Faisalabad Faisalabad Pakistan Arruje Hameed Department of Biochemistry Government College University Faisalabad Faisalabad Pakistan Tanzeela Khalid Department of Applied Chemistry Government College University Faisalabad Faisalabad Pakistan Shaheera Batool Department of Biochemistry CMH Institute of Medical Sciences Multan Multan Pakistan Tahir Farooq Department of Applied Chemistry Government College University Faisalabad Faisalabad Pakistan email: [email protected]

Aditi Sharma Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India Manmeet Kaur Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India Arvind Singh Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India email: [email protected] Anirban Sarkar Department of Chemistry Vidyasagar College for Women 39 Sankar Ghosh Lane, Kolkata 700006 West Bengal India

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Kshitij I. Patel Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research S.A.S. Nagar 160062 Punjab India Antarlina Maulik Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research S.A.S. Nagar 160062 Punjab India

Babita Tanwar Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research (NIPER) S.A.S. Nagar 160062 Punjab India

Nirjhar Saha, Asim Kumar, Soumili Biswas, Anirban Sarkar, and Asit K. Chakraborti✶

Chapter 1 Construction of benzazoles in aqueous medium: a sustainable approach 1.1 Introduction Benzazoles (benzimidazoles, benzoxazoles, and benzothiazoles) are biorelevant heterocycles and well-recognized privileged pharmacophores ubiquitously found in various drugs, clinical and preclinical candidates. The benzazole scaffold is a frequently observed ring system in US FDA-approved drugs and pharmaceuticals, list of essential medicines, in US clinical trial compounds, and fragment-based leads [1–7]. The benzazole ring systems can be classified into different categories depending on the number and type of heteroatoms present in the structure (e.g., benzimidazole, benzothiazole, benzoxazole, benzotriazole indole, and indazole) or the type of the heterocycles fused to each other (e.g., imidazopyridine and carbazole) (Figure 1.1). Figures 1.2–1.4 provide some representative examples of benzazole-containing drugs and bioactive molecules. The extensive prevalence of benzazoles as therapeutic agents/leads is observed in antimicrobial/bacterial agents and in proton pump inhibitors (PPIs). Apart from pharmaceutical applications, the benzazole moiety is the structural backbone of various ionic liquids (ILs) and N-heterocyclic carbenes, which are used as organocatalysts and ligands in various organic transformations [8–10]. The benzazole scaffolds have been recognized as privileged pharmacophores and continue to attract the attention of medicinal chemists in the design of new therapeutic agents [11–16]. The prevalence of the benzazole ring systems in bioactive molecules, natural products, and their applications as organocatalysts/ligands inspired synthetic medicinal/organic Acknowledgments: 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 700032, West Bengal, India, email: [email protected]; [email protected] Nirjhar Saha, School of Chemical Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700032, West Bengal, India Asim Kumar, Amity Institute of Pharmacy, Amity University Haryana, Manesar 122413, India Soumili Biswas, School of Biological Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700032, West Bengal, India Anirban Sarkar, Department of Chemistry, Vidyasagar College for Women, 39 Sankar Ghosh Lane, Kolkata 700006, West Bengal, India

https://doi.org/10.1515/9783110985627-001

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Figure 1.1: Classification of benzazoles.

chemists to search for various efficient reaction methodologies for construction of the benzazole ring systems. The adverse impact of chemicals on the environment and human health is the matter of concern after the establishment of various potential toxic effects of chemicals [17–21]. To minimize/avoid the detrimental effects of a chemical process on the environment, the globally recognized Environment Protection Agency mandated the pharma industry to adopt the triple bottom line philosophy of green chemistry that has witnessed an increasing influence of green chemistry in chemical manufacturing processes in chemistry research based organizations as it provides a framework for sustainable future [22–31]. This prompted academia and industry to thrive for sustainable chemical processes [32–37]. In the context of the green/sustainable chemistry and potential adverse impact on the environment and the index of sustainability of the adopted/developed procedures reported for the construction of benzazole scaffolds, some of these reactions may be considered as greener approaches, while the others may not comply with the sustainability/green index of chemical synthesis. In view of the importance of benzazoles in new drug discovery and their applications in organic synthesis and material sciences, this chapter focuses on various approaches/protocols for construction of the benzazole scaffolds (benzimidazole, benzoxazole, and benzothiazole) reported in the literature that aim to attain sustainable synthesis.

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Figure 1.2: Benzimidazole-containing drugs and bioactive molecules.

1.2 Sustainable approaches for organic synthesis and the construction of benzazole scaffolds The green chemistry approaches [38–40] for organic synthesis are the essential components for attaining sustainability in chemical processes. Pharmaceutical industries identified the key areas for sustainable development [41, 42]. In the broader perspectives, sustainability in organic synthesis can be achieved by adopting various approaches: (A) improvement of reaction medium [43–48] as a safer alternative to the classical volatile organic solvents (VOSs); (B) adopting newer technologies as nonconventional energy sources such as (i) microwave and ultrasound irradiation [49–53], (ii) mechanochemistry [54–57], (iii) visible light [58–60], and (iv) electrochemical pro-

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Figure 1.3: Benzoxazole-containing drugs and bioactive molecules.

cess [61]; (C) alternate synthetic strategies [62] such as waste minimization can be attained in devising atom economic synthesis [62–65] and multicomponent reaction (MCR) strategy [66–71] which, in particular, provides convenient way for the synthesis of heterocyclic compounds [72–77]. In this context, following some of the above approaches, over the past two decades, our research group has been actively engaged in the development of sustainable chemistries for the construction [78–90] and functionalization [91–97] of benzazole

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Figure 1.4: Benzothiazole-containing drugs and bioactive molecules.

ring systems for sustainable synthetic processes of drug molecule [98], and generation of new therapeutic leads [99–105]. The various approaches toward the sustainable synthesis of benzazoles are summarized in Figure 1.5. Since the selection of the reaction medium plays a critical role [43–48] in the sustainable development of chemical processes, sustainable synthesis of benzazoles has been explored in various reaction media presumably as greener alternatives to the traditional VOSs (Figure 1.6). The traditional way of heating the reaction mixture to cross the desired energy barrier is generally achieved through water bath or oil bath heating that are not energy efficient due to longer time period required for completion of the reaction. The nonconventional approaches [microwave irradiation, ultrasound irradiation, visible light, ball milling (mechanochemical energy), and electrochemical method] enable to achieve the desired activation energy in shorter time period to carry out the organic transformations and have been extended toward benzazole synthesis (Figure 1.7).

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Figure 1.5: Various approaches for sustainable synthesis of benzazoles.

While the most commonly adopted chemistry for the construction of the benzazole ring systems have been the cyclocondensation of aldehydes, carboxylic acids/esters, and acid halides with ortho-phenylenediamines, ortho-aminophenols, and ortho-aminothiophenols, alternative eco-friendly synthetic strategies involving MCR and C–H activation have been reported for the construction of benzazole ring systems (Figure 1.8) that are discussed in detail in the following sections. Sustainable synthesis of benzazoles have also been achieved by using various catalytic procedures such as the use of organocatalysts, heterogeneous catalysts, biocatalysts, and photocatalysts (Figure 1.9).

1.2.1 Sustainable reaction media 1.2.1.1 Neat condition The potential toxicity and hazards associated with the commonly used VOSs would suggest solvent-free reaction conditions which are perhaps the best way to avoid the reaction media related hazards [106]. However, non-homogeneity and difficulty in the product isolation in the workup procedures make it problematic to pursue. 2-Aminoaniline/ thiophenol/phenol (1/2/3) reacted with substituted aldehydes under neat condition to produce the corresponding benzazoles [107–110]. o-Phenylenediamines (1) were treated with various electrophiles separately (e.g., orthoacetates, ammonium thio-

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cyanate, formic acid, and urea analogues) under neat condition for the synthesis of C-2substituted benzimidazoles (Figure 1.6) [107, 108, 111].

1.2.1.2 Polyethylene glycol (PEG) Polyethylene glycol (PEG), considered as a green solvent for sustainable organic synthesis [112], has used widely for the synthesis of N-heterocycles [113]. 2-Aminoaniline/thiophenol/phenol (1/2/3) were subjected to cyclocondensation reaction with the carbonyl derivatives in PEG (used as reaction medium) to carry out the synthesis of C-2-substituted benzimidazoles/benzothiazoles in good to excellent yield (Figure 1.6) [114–116].

1.2.1.3 Eutectic solvent and supercritical fluid The deep eutectic mixture has emerged as new generation of designer green solvents popularly termed as deep eutectic solvents (DESs) [117–120]. Ultrasoundassisted synthesis of C-2-substituted benzoxazoles was achieved by the nucleophilic substitution–cyclocondensation reaction between 2-aminophenol (3) and ester compounds in deep eutectic mixture of urea and glycine-derived IL [121]. In another procedure, carbonyl compounds undergo cyclocondensation reaction with o-phenylenediamines in deep eutectic mixture to furnish the desired benzimidazoles (Figure 1.6) [122–124]. Supercritical fluids (SCFs) have distinct advantages over the parent liquid/gas with adjustable/improved solubility and are used as alternatives to common organic solvents in industrial and laboratory chemical processes. Though most common examples of SCFs are carbon dioxide and water, the supercritical MeOH was used both as the reaction media and C-2 carbon source in the synthesis of benzimidazoles. 2-Nitroaniline or 2-aminoaniline reacted with supercritical MeOH in the presence of copper-doped porous metal oxides as the catalyst to synthesize the desired benzimidazoles (Figure 1.6) [125].

1.2.1.4 Ionic liquids ILs are often touted as future green solvents [126–128] and have been used as an alternative to the conventional organic solvents as the reaction medium in performing various organic reactions [129–131], including the synthesis of heterocycles [66, 132]. However, the green solvent image of ILs is under critical assessment [133–139], and as the onus of green solvent appears to be shifting onto DES [140, 141], it warranted finding a new strategy to utilize the unmatched ability of ILs to promote organic reac-

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tions. In this regard, we delved into the non-solvent uses of imidazolium cation-based ILs for various organic reactions, including the construction of heterocycles, and unraveled the molecular basis of the role of ILs as “ambiphilic dual activation” organocatalyst through “cooperative hydrogen bond (HB) and charge–charge interaction” that represents some early examples of supramolecular organocatalysis through demonstration of the HB formation by time-dependent IR and 1H NMR experiments and cation identification of the respective supramolecular species by ESI and MALDI mass spectrometric ion fishing [142–147]. The HB-assisted catalysis by ILs gained popularity for applications in organic synthesis [148, 149]. Benzimidazoles/benzothiazoles were produced by one-pot MCR of the reaction of 2-aminoaniline/thiophenol (1/2) derivatives, carbon dioxide, and hydrosilane in the presence of IL. In this reaction protocol, IL holds the title of “multifunctional catalyst” as it works as reaction media, nucleophile–electrophile activating catalyst, and auxiliary substrate for in situ generation of formoxysilane intermediate (surrogate of C-2 carbon) [150]. Further, the 2-aminoaniline/thiophenol/phenol (1/2/3) was treated with orthoacetates in IL that acts both as reaction medium and electrophile activating agent to synthesize the desired benzazoles (Figure 1.6) [151–153].

1.2.1.5 Biomass-derived solvents Biomass-derived solvents are considered as green solvents due to their nonhazardous nature to the environment and uninterrupted supply from the renewable sources. The biomass-derived solvent dimethyl carbonate (DMC) was used as green solvent for the synthesis of benzimidazole and benzoxazole. The one-pot MCR of o-phenylenediamine, benzyl alcohol, and 2,6-difluorobenzyl bromide was performed in the presence of Mn catalyst in DMC under aerobic conditions [154]. For the synthesis of benzoxazoles, the heterogeneous manganese-catalyzed intramolecular cyclization of phenolic imines was achieved in DMC as green solvent [155]. The C-2-substituted benzimidazoles were obtained by Pd/C-catalyzed reaction of o-phenylenediamine and tertiary amine under microwave irradiation in γ-valerolactone as the green solvent (Figure 1.6) [156].

1.2.1.6 Alcohols Alcohols such as EtOH, iPrOH, nPrOH, MeOH, nBuOH, and tBuOH are considered as preferred/green solvents according to the solvent selection guide of Pfizer [23]. Various alcoholic solvents such as ethanol, isopropanol, and tert-butanol were used as reaction media for synthesis of various types of benzazoles. For example, 2-nitroaniline was subjected to in situ nitro reduction by Fe powder, followed by cyclocondensation with formic acid to synthesize benzimidazoles in isopropanol/tert-butanol as green solvent [157]. The synthesis of benzimidazoles was achieved by the reaction of o-phenylenediamine with

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triethyl orthoacetates in EtOH, and benzothiazoles were formed from the reaction of 2aminothiophenols with aldehydes in EtOH (Figure 1.6) [158].

1.2.1.7 Fluorinated alcohols Fluorinated alcohols such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) have gained popularity as reaction media for various organic reactions [159–163], and HFIP is considered the solvent of choice for C–H activation reactions [164, 165]. The magical influence of the fluorinated alcohols in promoting organic reactions has been presumed to be due to their better higher H-bond-donating ability compared to their non-fluorinated analogs. However, a molecular-level interaction of TFE/HFIP with the reactants that had been lacking has been addressed by our group by devising a nonsolvent use of TFE/HFIP for the construction of benzimidazole ring systems [166]. During the formation of 1,2-disubstituted benzimidazole by cyclocondensation reaction of o-phenylenediamines and aromatic aldehydes in the presence of 3 molar equivalents of TFE/HFIP, the role of TFE/HFIP has been demonstrated to activate both the nucleophile and electrophile through hydrogen bonding due to strong HB formation ability of the fluorinated alcohols. In these reactions, fluorinated alcohols act as both reaction media and promoter (organocatalyst) in the form of HB donor (Figure 1.6) [166]. In the nucleophilic addition reaction of 2-aminoaniline/thiophenol/phenol (1/2/3) with isocyanides, HFIP acts as the proton transporter through hydrogen bonding framework [167]. Benzimidazoles were synthesized by the reaction of o-phenylenediamine and orthoesters in the presence of HFIP used as solvent [168].

1.2.1.8 Ethanol and water (EtOH:H2O) mixture As most of the organic compounds (substrates and/or products) are insoluble in water, ethanol is usually added to the water to increase the solubility of the substrates retaining the sustainability parameters of the solvent. Ethanol is rated as the third best in the list of green/preferred solvents of pharma industry [23]. The ethanol–water mixture was applied in the cyclocondensation reaction of aldehydes and 2-aminoaniline/thiophenol (1/2) to synthesize benzimidazoles/benzothiazoles in good to excellent yield (Figure 1.6) [169].

1.2.1.9 Water The solvent selection guide of pharma industry rates water as the most preferred reaction medium for sustainable organic synthesis [23]. Accordingly, there had been upsurge in performing organic reactions in aqueous medium [170–175]. Realizing the distinct advantages in terms of acceleration of reaction rate and improvement of

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product selectivity (wherever applicable) in using water as the reaction medium in place of classical VOSs, several theories such as “on water,” “in water,” and “in the presence of water” [176–181] have been proposed to rationalize these distinct differences/advantages. However, a molecular-level understanding on the interaction of water molecules with the reactants largely remained inadequately addressed. In the earlier days, a general and obvious discouragement toward the development of aqueous organic synthesis persisted, as it was assumed that the insolubility or sparingly solubility of organic substrates in water may be detrimental to the reaction efficiency. However, the Breslow hydrophobic effect [182–184] in the form of “enforced hydrophobic interaction” offered some reason for the enhanced reaction rate though related to only Diels–Alder-type reactions and encouraged toward a few practical syntheses using water as the reaction medium and kept the interest on aqueous organic synthesis alive [181]. A better understanding on the “on water” reaction rate acceleration was realized through hydrogen bonding effect involving the dangling OH groups of water molecules at the water–organic interface [185, 186], discounting any significant contribution of hydrodynamic effects [187]. The molecular origin of the rate acceleration and change in product selectivity could be realized through the original proposal [82, 188, 189] on “electrophile–nucleophile dual activation” by a water molecule through a “cooperative HB network” involving the reactants (electrophile and nucleophile) and water molecule(s). It rationalizes gas-phase radical-molecule reaction catalyzed by a single water molecule [190] and the preferential construction of six-membered tetrahydropyran (THP) oxacycle over the five-membered THF ring formation via epoxide ring opening cascade promoted by marine water [191]. The concept/ proposal of HB-mediated “synergistic electrophile–nucleophile dual activation” by water provides scope for rational selection of aqueous medium to perform organic reactions and led to some novel “all water” chemistries for the synthesis of novel class antianginal drug ranolazine in its racemic and enantiopure forms [192], protecting group-free synthesis of the drug (RS)/(S)-lubeluzole with a shorter route [98], representing a step-economic synthesis [99], and increasing the sustainability credentials, and to devise a tandem Nalkylation–reduction–condensation route for regiospecific one-pot synthesis of diverse N-aryl/arylmethyl-2-substituted benzimidazoles [86, 88] (an elaboration on this will follow in a later section of this chapter). The distinct advantage of the HB-assisted activation by water also enabled to extract the double benefit of aqueous medium and Pd nanoparticle for the construction of a versatile pharmacophoric unit toward the synthesis of several drugs belonging to different therapeutic areas [193]. The syntheses of various types of benzazoles have been reported through different reaction pathways in water as the reaction medium (Figure 1.6) [82, 194–197]. In most of these reactions, water either activates the electrophile and nucleophile simultaneously or it provides the suitable hydrophobic environment for the substrates favoring the progress of the reaction. In this chapter, the water-assisted benzazole synthesis has been discussed in detail in some later sections.

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1.2.2 Nonconventional energy sources Nonconventional sources of heating the reaction mixture were introduced in the replacement of conventional heating processes with certain advantages such as shorter reaction period, higher yield of the product, less hazardous to the laboratory personnel, less prone to laboratory accidents, less consumption of energy, milder reaction conditions, and ease of operation. This sustainable approach was also explored widely in the synthesis of benzazoles (Figure 1.7). 2-Aminoaniline/thiophenol/phenol (1/2/3) was subjected to the Zn-catalyzed nucleophilic addition reaction with various carbodiimide derivatives under microwave irradiation to synthesize the desired benzazoles [198]. Similar type of Zn catalysis under microwave irradiation was applied for the synthesis of benzimidazoles from o-phenylenediamines and β-ketoesters [199]. The synthesis of benzimidazoles from o-phenylenediamines through cyclocondensation approach was also investigated under microwave irradiation (Figure 1.7) [200, 201] and ultrasonic irradiation [202, 203]. Ball milling is a technique that converts the mechanochemical energy into the reaction energy and has been explored in organic synthesis [54–57], which has been extended for the synthesis of benzimidazole [204]. One-pot domino reaction of anilines with carbon disulfide, followed by addition of 2-aminothiophenol/phenol (2/3), furnishes the desired 2-aminobenzothiazole/benzoxazole derivatives under ball milling condition [205]. A sustainable reaction protocol for the synthesis of benzazoles was developed under ball milling conditions. 2-Aminoaniline/thiophenol/phenol (1/2/3) was subjected to ZnO–nanoparticle-catalyzed cyclocondensation reaction with the aldehydes under neat and ball milling condition to furnish the desired benzazoles in excellent yields (Figure 1.7) [206]. This methodology offers sustainability in terms of recyclable catalyst, solvent-free reaction condition, ball milling as reaction energy source, and room temperature operation. Another alternative sustainable reaction energy source that has been adopted in organic synthesis is the energy obtained from the visible light. Benzazoles were synthesized by the heterogeneous photocatalyzed cyclocondensation reaction of 2aminoaniline/thiophenol/phenol (1/2/3) with in situ generated aldehydes from the oxidation of alcohols or toluene [207]. Similar cyclocondensation reactions were also tried under visible light for the synthesis of benzazoles [208–210]. The Ru2+-catalyzed photocatalytic single electron transfer enables sp2 C–H bond activation and subsequently intramolecular cyclization via C–O bond formation for the synthesis of desired 2-aminobenzoxazoles under visible light irradiation [211]. In the synthesis of benzimidazoles, TiO2-assisted simultaneous redox processes promote the cyclocondensation of in situ generated o-phenylenediamines and aldehydes from 2-nitroaniline and alcohols, respectively. The catalyst participates in the simultaneous reduction of nitro group to amine group and oxidation of alcohol to corresponding aldehydes (Figure 1.7) [212].

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1.2.3 Sustainable reaction approaches/strategies MCRs are considered as more sustainable than the multistep reaction methodologies due to higher atom economy, less waste generation, shorter time period required to obtain the final product, and ease of operation. The MCR strategies are most suitable and widely used in the synthesis of N-heterocycles [66, 71–77, 213]. Benzimidazoles were constructed through the one-pot MCR approaches (Figure 1.8) [214–216]. The C(sp3)–H activation strategy was applied in the synthesis of benzazoles by the heterogeneous photocatalyzed cyclocondensation reaction of 2-aminoaniline/thiophenol/phenol (1/2/3) with in situ generated aldehydes from the oxidation of alcohols or toluene [207]. Nickel-catalyzed C(sp2)–H bond activation facilitates the intramolecular C–S bond formation to synthesize 2-aminobenzothiazoles (Figure 1.8) [208]. In the context of sustainable chemistry, metal-free reaction protocols are preferred over the metal-catalyzed methods due to the reduction in total costs, less number of steps in the isolation/purification of the final compound, less risk of contamination of the final product with metallic impurities, and subsequently less risk of error in the bioassays (enzymatic in particular). The metal-free protocols have been reported for the construction of benzimidazole-fused N-heterocycles including benzimidazoles [209, 210]. Metal-free syntheses of benzazoles were achieved by one-pot reaction of 2aminoaniline/thiophenol/phenol (1/2/3), carbon dioxide, and hydrosilanes. The mixture of carbon dioxide and hydrosilanes acts as the surrogate of silyl formates which is the source of C-2 carbon of benzazoles [211]. Various metal-free approaches were also adopted for the synthesis of benzimidazoles from o-phenylenediamines (Figure 1.8) [212–215]. Higher atom-economical reactions indicate the higher incorporation of the substrate molecules into the desired final compound and possibility of less waste generation. The MCRs exhibit higher atom economy than the multistep processes. The cyclocondensation of o-phenylenediamines with carbonyl compounds (commercially available or in situ generated) represents a sustainable protocol due to the higher atom economy and environment friendly characteristics (Figure 1.8) [216].

1.2.4 Sustainable catalysis The organic transformations require the catalyst to reduce the activation energy barrier gap. Thus, the use of a catalyst for organic synthesis is inherently a sustainable approach in a chemical process as it is associated with the lesser energy consumption compared to the non-catalytic mode of operation of the same chemical transformation. The Lewis acid/base catalysis and transition metal catalysis in the form of homogeneous catalysis were explored widely in the synthetic organic chemistry for the synthesis of various types of heterocycles [77, 217–220]. However, transition-metalcatalyzed (which generally forms a homogeneous reaction mixture) synthesis is often

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recognized to suffer from certain drawbacks such as increment in the synthetic cost, nonrecyclability of the catalyst, requirements of additional steps of isolation, risk of metal contamination in the final product, and increased probability in the metal contamination in the bioassays (enzymatic in particular). The use of organocatalysis, bioenzymatic catalysis, and heterogeneous catalysis (because of ease of catalyst recovery in catalysis and less likelihood of contaminating the product) mitigates these drawbacks favoring the reaction to proceed in more sustainable ways. In the synthesis of benzimidazoles/benzothiazoles, various organocatalysts such as L-proline and urea derivatives act as HB forming agents with the substrate molecule or transition states/intermediates [221, 222]. Quaternary ammonium compounds act as organocatalyst in the synthesis of 2-aminobenzoxazoles (Figure 1.9) [223]. Iodine (generated in situ by oxidation of tetrabutylammonium iodide with hydrogen peroxide) catalyzed the cyclodesulfurization of phenolic thioureas to form 2-aminobenzoxazoles [224]. Various bioorganic molecules such as enzymes, vitamins, and enzyme cofactors are applied in the biocatalytic transformations of 2-aminoaniline/thiophenol/phenol (1/2/3) into benzazoles. The cyclocondensation reaction of 2-aminoaniline/thiophenol (1/2) with aldehydes was catalyzed by the enzyme catalase in the presence of water as sustainable reaction media. The graphene oxide-supported vitamin B1 was incorporated as the catalyst in the synthesis of C-2-substituted benzoimidazoles by the cyclocondensation reaction of o-phenylenediamines with aromatic aldehydes [225]. Vitamin B12-catalyzed cyclocondensation of primary amine with in situ generated carbonyl compound from catechols synthesizes the desired benzoxazolidines, which further undergoes aerial oxidation to furnish the desired C-2-substituted benzoxazoles [226]. Bioenzymatic catalysis produced the desired benzimidazoles by the cyclocondensation of o-phenylenediamine with aldehydes (commercially available or in situ generated) (Figure 1.9) [227–230]. Heterogeneous catalysis is expectedly the preferred choice over the homogeneous counterpart due to the scope of recyclability and repurposing of the catalyst, and presumably better catalytic performance due to higher surface area accessibility. Heterogeneous catalyst Cu@U-g-C3N4 was utilized for the in situ formation of boron formate derivatives that further participate in the nucleophilic addition reaction with o-phenylenediamine for its formylation. The intramolecular cyclization of Nformyl-o-phenylenediamine produced the desired benzimidazoles [231]. Polymersupported zinc catalyst has been used for synthesis of benzimidazoles and organic carbamates through CO2 fixation [232]. Benzazole ring systems were also constructed by the reaction of 2-aminoaniline/ thiophenol/phenol (1/2/3) with either aldehydes or its parental compound orthoesters in the presence of various types of heterogeneous catalysts [233–237]. Silica gelsupported salicylic acid was treated as supported heterogeneous catalyst in the synthesis of benzimidazoles. The imine derivative, formed in situ oxidation of benzyl amines, reacts with o-phenylenediamine in the presence of silica-supported salicylic acid as a heterogeneous catalyst to furnish the C-2-substituted benzimidazoles in good

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Figure 1.6: Synthesis of benzazoles in sustainable reaction media.

Chapter 1 Construction of benzazoles in aqueous medium: a sustainable approach

Figure 1.7: Synthesis of benzazoles under nonconventional heating.

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Figure 1.8: Synthesis of benzazoles through sustainable reaction approaches/strategies.

Chapter 1 Construction of benzazoles in aqueous medium: a sustainable approach

Figure 1.9: Synthesis of benzazoles by sustainable catalysis.

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to excellent yield [238]. Nitrogen-doped MnO2, the heterogeneous catalyst, promoted the in situ oxidation of benzyl alcohol to provide the corresponding benzaldehyde which further participates in cyclocondensation with 2-aminophenol derivatives to synthesize the C-2-substituted benzoxazoles (Figure 1.9) [239].

1.3 Synthesis of benzimidazoles in aqueous media Solvents, the crucial component of organic reactions, are involved in various steps of organic synthesis such as in the solubility of the reaction components to maintain homogeneity of the reaction mixture, in product isolation (workup) and purification steps, and in the spectrometric analysis of the final compound. The impact of solvents on the environment, biodiversity, and human health is crucial along with its importance in the organic reactions. The term “green solvent” indicates the extent of nonhazardous, sustainable impact of the solvent to the environment, biodiversity, and human health. In the context of sustainable synthesis using green solvent, water, the nature’s solvent, has gradually found its position in the friendship zone of the organic chemists from once considered enemy in performing the organic transformations in water [170–175]. Thus, benzazoles were also synthesized in different aqueous media such as water or water–surfactant aqueous suspension, with or without the presence of metal/Brønsted/ Lewis catalyst. In most of these reactions, water provides assistance in the progress of the reaction, either the H-bonding-mediated electrophile–nucleophile dual/synergistic activation or creating the suitable environment through micelle formation for the favorable enforced hydrophobic interaction between the hydrophobic starting materials [176–181]. Benzimidazole synthesis involving these types of reaction conditions is discussed in detail in the following sections.

1.3.1 Water as reaction medium The most convenient and popular approach for the construction of the benzimidazole ring system appears to be the cyclocondensation of o-phenylenediamines with aldehydes. However, this route has the potential to lead to a mixture containing the 2-substituted benzimidazoles and the 1,2-disubstituted benzimidazoles (Figure 1.10), an issue that remained mostly unattended/unnoticed and was delved into by our group to tune up catalytic conditions that would selectively form the 1,2-disubstituted benzimidazoles [87]. It was realized that the regioselectivity issue would become more complex when unsymmetrically substituted o-phenylenediamines are used for the reaction with aldehydes as in addition to the selectivity issue involving the formation of 2-substituted benzimidazole versus 1,2-disubstituted benzimidazole. There will be

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Figure 1.10: The selectivity issue during the synthesis of benzazoles by cyclocondensation of o-phenylenediamines with aldehydes.

further issue on the formation of regioisomers of 1,2-disubstituted benzimidazoles. This warranted methods for regiocontrolled construction of 1,2-disubstituted benzimidazoles. The issue was delved into by our group by devising a novel “all-water” chemistry for tandem N-alkylation–reduction–condensation that led to a one-pot synthesis of diverse N-arylmethyl-2-substituted benzimidazoles in excellent yields (82–90%) (Figure 1.11) [86].

Figure 1.11: “All-water” tandem N-alkylation–reduction–condensation for one-pot synthesis of N-arylmethyl-2-substituted benzimidazoles.

The overall transformation proceeds through the intermediate formation of the monoN-alkylated derivative of the starting nitroaniline and that subsequently gets converted to the corresponding mono-N-alkylated o-phenylenediamine derivative that has been demonstrated by isolation of these intermediates. The beneficial effect of water as the reaction medium has been demonstrated by separately carrying out N-alkylation of the nitroaniline with benzyl bromide in water as well as various organic solvents that established the superiority of water as the reaction medium. The condensation of the isolated mono-N-alkylated o-phenylenediamine derivative with an aldehyde was performed in water as well as in various organic solvents to reveal the beneficial effect of water as the reaction medium for the cyclocondensation to form the corresponding 1,2-disubstituted benzimidazole. The crucial role of water in promoting the initial N-alkylation of the nitroaniline and in the final step involving the cyclocondensation of the mono-N-alkylated o-phenylenediamine derivative with the aldehyde has been visualized due to the ability of water to act both as HB acceptor and HB donor for the necessary HB-mediated dual activation of the electrophile and the nucleophile presumably through the formation of the supramolecular assemblies I (Figure 1.12) and IIa/IIb (Figure 1.13).

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Figure 1.12: Dual activation role of water in promoting the N-alkylation of o-nitroanilines with benzyl bromides.

Figure 1.13: Dual activation role of water in promoting the cyclocondensation of mono-N-alkylated o-phenylenediamines with aldehydes.

The cyclocondensation of mono-N-alkylated o-phenylenediamines with aldehyde could proceed either via the formation of the imine intermediate (A) or the immonium intermediate (B) (Figure 1.13). The possibility of the involvement of the immonium pathway was ruled out by subjecting the reaction of mono-N-benzylated o-phenylenediamine with benzaldehyde treatment with NaBH4 that led to the formation of N,N ′-dibenzylated o-phenylenediamine (C) (Figure 1.13). Apart from using water as the reaction medium, another distinct advantage of this tandem N-alkylation–reduction–condensation strategy is that it provides the scope of diversity generation with respect to installation of different aryl/alkyl moieties at 1 and 2 positions of the benzimidazole scaffold. On the other hand, the classical route of cyclocondensation of o-phenylenediamines with aromatic aldehyde is restricted to the formation of 1,2-disubstituted benzimidazoles bearing the same aryl group at 1 and 2 positions apart from the issue on competing formation of 2-substituted and 1,2-disubstituted benzimidazoles. A more diversification of the construction of the 1,2-disubstituted benzimidazole scaffold was also achieved by our group through the design of novel “all water” chemistry, utilizing the HB-driven “synergistic electrophile–nucleophile dual activation” role by water for one-pot synthesis of diversely substituted 1,2-disubstituted benzimidazoles in excellent yield (80–89%) (Figure 1.14) [88].

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Figure 1.14: Hydrogen bond-driven “synergistic electrophile–nucleophile dual activation” role by water for “all-water” one-pot diverse synthesis of 1,2-disubstituted benzimidazoles.

The “all-water” one-pot construction of the N-aryl/alkyl-2-substituted benzimidazole scaffold proceeds via the formation of the N-aryl/alkyl-o-nitroaniline (formed by waterassisted aromatic nucleophilic substitution of o-fluoronitrobenzene by the aryl/alkyl amine) and its subsequent reduction product mono-N-aryl/alkyl-o-phenylenediamines that have been isolated during separate reactions of o-fluoronitrobenzene with aryl/ alkyl amine in water and the treatment of N-phenyl-o-nitroaniline with In metal in aqueous HCl. It has been demonstrated that water plays a beneficial role as the reaction medium compared to the commonly used organic solvents during the first step of conversion of o-fluoronitrobenzenes to the corresponding N-aryl/alkyl-o-nitroanilines, and in the final step of cyclocondensation involving N-aryl/alkyl-o-phenylenediamines and aldehydes [88]. The critical role played by water has been visualized as HB-driven “synergistic electrophile–nucleophile dual activation” through the formation of supramolecular assemblies such as III/IIIa (Figure 1.15). The importance of HB assistance was revealed by the fact that o-chloro-, o-bromo-, and o-iodo-nitrobenzenes gave no/poor yields (15/24%, 0%, and 0%) when reacted with benzylamine/aniline in water. In contrast, 94/90% yields were obtained in the reaction of o-fluoronitrobenzene with amine/ aniline under similar conditions. The reason is that the fluorine is capable to undergo HB formation with water molecule and makes the feasibility of formation of the hydrogen bonded supramolecular assemblies III/IIIa (Figure 1.15) for the reaction to proceed.

Figure 1.15: Hydrogen bond-driven “synergistic electrophile–nucleophile dual activation” role by water for aromatic nucleophilic substitution of o-fluoronitrobenzene by aryl/alkyl amine to form N-aryl/alkyl-onitroanilines.

Further, the importance of HB-assisted acceleration of the reaction rates during the initial aromatic nucleophilic substitution (to form the N-aryl/alkyl-o-nitroanilines) step and the cyclocondensation of the mono-N-aryl/alkyl-o-phenylenediamines with aldehydes to form the desired 1,2-disubstituted benzimidazoles in the final step was

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demonstrated through a distinct decrease in product yields for the reaction of ofluoronitrobenzene with aniline and mono-N-phenyl-o-phenylenediamine with benzaldehyde when performed in D2O compared to that obtained in water in a timedependent manner [88]. The one-pot “all-water” tandem N-alkylation–reduction–condensation [86] and tandem N-arylation–reduction–condensation [88] strategies for the diversified synthesis of N-aryl/alkyl/arylmethyl-2-substituted benzimidazoles exemplify the implementation of the principles/concept of pot economy and one-pot synthesis of target molecules [240]. The aqueous reaction of aldehyde (49) with o-phenylenediamine (43) was performed in the presence of TMSCl as an imine activator for the synthesis of 1,2disubstituted benzimidazoles (50) (Figure 1.16). In the bis-imine (43a) formation step, water plays the role of simultaneous activation of both nucleophile and electrophile through H-bonding catalysis. The imine nitrogen interacts with the Si atom of TMSCl (43b) to facilitate the cyclization process. In the next step, the desilylation process promotes the 1,3-hydride migration (43c) to furnish the 1,2-disubstituted benzimidazoles. The 1,3-hydride migration step was confirmed by performing the isotope labeling experiment [241].

Figure 1.16: TMSCl-promoted synthesis of 1,2-disubstituted benzimidazoles in water.

2-Phenylbenzimidazole (46) derivatives were synthesized by the intramolecular aromatic nucleophilic substitution of the amidine derivatives (51) in the presence of K2CO3 as base and water as the reaction medium (Figure 1.17). Base-promoted amidine tautomerism favors the NH center (51a) to undergo the nucleophilic substitution of the aryl halide to construct the five-membered ring (51b). The base-assisted dehydrohalogenation and aromatization finally construct the benzimidazole scaffold. Although the wide substrate scope and usage of water as reaction medium are advantages of this protocol, it requires prolonged (30 h) heating [242].

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Figure 1.17: Base-assisted dehalogenative C–N bond formation in water.

The synthesis of 2-phenylbenzimidazoles (46) using water as solvent was reported by Hikawa et al. (Figure 1.18). The nucleophilic addition of 43 with benzoyl methyl phosphates (52) generates the corresponding N-substituted benzamide (52a) which further undergoes HB-assisted cyclocondensation reaction to form 46. In this reaction protocol, 52 acts as biomimetic acylating agents and as an acid catalyst precursor. However, the protocol requires long reaction time under heating [243].

Figure 1.18: Synthesis of C-2-substituted benzimidazoles in water.

o-Phenylenediamine (43) reacted with α-aroylketene dithioacetals (53) in water in the presence of HOAc as catalyst to synthesize 2-arylbenzimidazoles (46). The reaction

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may proceed through either aza-Michael addition pathway to form benzodiazepines or through imine formation pathway to form 2-arylbenzimidazoles. The exclusive formation of 2-arylbenzimidazoles confirms that the reaction follows the imine formation (53b) pathway. The condensation reaction of diamine and keto groups produces the imine (53b), which further undergoes the cyclization–aromatization cascade to furnish the desired 2-arylbenzimidazoles in good to excellent yield. The reaction was performed under both thermal heating and microwave irradiation, resulting in similar yield of the particular product (Figure 1.19) [244]. Some of the advantages are metal catalyst-free condition, high product yield, use of eco-friendly solvent, and short (2 h) reaction time.

Figure 1.19: HOAc-promoted synthesis of benzimidazoles in water.

In another approach of catalyst-free benzimidazole synthesis, the condensation partner of 1,2-phenylenediamine (43) changed from carbonyl compounds to arylidene ma-

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lononitriles (54). The aza-Michael addition of 43 to the β-carbon (54a) followed by cyclization and removal of malonitrile anions constitute the benzimidazole precursor benzimidazolidine moiety (54b). In the final step of the reaction, arylidene malononitriles (54c) assisted dehydrogenation of benzimidazolidines to furnish the desired benzimidazoles in good to excellent yield (Figure 1.20). The notable disadvantages of this reaction methodology are the low atom economy, requirement of more than the stoichiometric amounts of substrate, difficulty in product isolation, and generation of reduced form of arylidene malononitriles as waste [245].

Figure 1.20: Catalyst-free synthesis of benzimidazoles in water.

1,2-Biarylbenzimidazole (56) synthesis was reported by the cyclocondensation of benzoic anhydride (55) and o-phenylenediamines (43) using a high-pressure and hightemperature water microflow chemical process (Figure 1.21). The reaction proceeds through the amide formation and subsequent cyclocondensation of it. The notable features of this reaction protocol are rapid production of various benzimidazoles in

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Figure 1.21: Synthesis of benzimidazoles using a high-pressure and high-temperature (HPHT) water microflow chemical process.

very high yields, tolerance to a wide range of functional groups, non-requirement of additional catalysts like acid or base for the dehydration step, ease of workup, and ease of scale-up [246]. Benzo-heterocycle-fused benzimidazoles (58 and 60) were synthesized by the cyclocondensation reaction of o-phenylenediamines (43) and o-alkynyl aldehyde (57, 59) in water as the reaction medium (Figure 1.22). The benzimidazolidine ring (57b) is constructed through cyclization of imine derivative (57a). The aerial oxidation of benzimidazolidine furnishes the benzimidazole scaffold (57c). The intramolecular nucleophilic addition of benzimidazole amine moiety to the alkyne functionality completes the cyclization step to form the pyridine moiety (58). The plausible roles of water in the reaction are the nucleophile–electrophile activation for imine formation and source of proton for the vinylic anion. The advantages of this simple and benign methodology are high yield of product, catalyst-free approach, higher atom economy, and less waste generation [247]. A catalyst-free convenient reaction methodology for the synthesis of 1,2-disubstituted (50) and 2-substituted benzimidazoles (46) with high to excellent yields has been developed (Figure 1.23). The reactions of o-phenylenediamines (43) with aromatic aldehydes (49) were carried out in the aqueous medium while bubbling air into the reaction mixture to synthesize mono- and di-substituted benzimidazoles. In the presence of aerial oxygen, the aromatic aldehyde (49) is converted to the benzoic acid (49a). The reaction can proceed through either benzoic acid- independent or -dependent pathway. The involvement of benzoic acid in the reaction process leads to the formation of 1,2-disubstituted benzimidazoles, while the nonparticipation of the benzoic acid leads to the synthesis of 2-substituted benzimidazoles. The condensation reactions of o-phenylenediamines and aromatic aldehydes form the Schiff base (49c), which further cyclizes to furnish benzimidazolidine. The aerial oxygen-promoted dehydrogenation of benzimidazolidine provides the C-2-substituted benzimidazoles (46) in the benzoic acid nondependent pathway. On the other hand, the free amino group of the Schiff base (49c) condenses with the second molecule of aromatic aldehyde for the in situ generation of the bis-imine derivative (49d). In situ generated benzoic acid acts as Brønsted acid to activate the imine carbon through protonation at the imine nitrogen center (49e). This electrophilic activation favors the in-

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Figure 1.22: Catalyst-free synthesis of fused benzimidazoles in water.

tramolecular cyclization of the bis-imine derivative to form 1,2-disubstituted benzimidazolidines (49f), which undergo carboxylate anion-assisted intramolecular 1,3-hydride shift to gain aromaticity for the formation of 1,2-disubstituted benzimidazoles (50). The reaction methodology was scaled up to gram-scale synthesis with good yield of the 1,2disubstituted benzimidazoles [248]. The photocatalytic metal-free synthesis of bioactive 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles (62) was achieved by conducting the one-pot MCR of 1,2-phenylenediamines (43), aromatic aldehydes (49), and 2-mercaptoacetic acid (61) in aqueous ethanol at room temperature (Figure 1.24). The imine (61a), generated from the reaction of diamines and aldehyde, undergoes nucleophilic addition by the thiol group of 2-mercaptoacetic acid (61). In the subsequent steps, the photocatalytic radical coupling (61c and 61d) and cyclocondensation reactions generate the thiazolidine fused benzimidazoles (62) in good

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Figure 1.23: Catalyst-free synthesis of benzimidazoles in water under air bubbling.

to excellent yield. This high yielding photocatalytic synthesis of benzimidazoles has certain advantages over other reported methodologies such as low cost of operation, higher atom economy, broad substrate scope, reaction operation simplicity, functional groups tolerance, shorter reaction time, and ambient reaction temperature under mild reaction conditions [249].

1.3.2 Water–surfactant mixture as reaction media The major bottleneck in carrying out organic reaction/synthesis in aqueous medium has been the immiscibility of organic compounds with water and to sidestep this issue resulted in the advent of using surfactants that contain lipophilic moiety to partition organic compounds [250]. Use of acidic surfactant was reported for the synthesis of C-2-substituted benzimidazoles (46). The reaction of o-phenylenediamines (43) with

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Figure 1.24: Photocatalytic metal-free synthesis of bioactive benzimidazoles.

benzaldehyde (49) was performed in the presence of DBSA as surfactant and iodine as coactivator (Figure 1.25). The role of DBSA could be to assist imine (A) formation and also in the incorporation of the substrates into the hydrophobic cavity through the micellar formation of the hydrophobic substrates. The reaction proceeds through the DBSA-promoted imine formation (A) followed by activation of imine (B) by iodine coordination. The intramolecular nucleophilic addition and subsequent aerial oxidation of benzimidazolidine (C) furnish the desired benzimidazoles (46). High yield of product, higher chemoselectivity, and operational simplicity are some of the advantages of this reaction [251]. The aqueous extract of Acacia concinna pods acts as acidic surfactant and was utilized as catalyst for the synthesis of 1,2-disubstituted benzimidazole (50) derivatives in water (Figure 1.26). The surfactant saponin present in the aqueous pod extract forms the micelle to engulf the hydrophobic substrates into the hydrophobic core of the micelle. This type of micelle catalysis enhances the reaction rate by reducing the intermolecular distances. The condensation reaction of aromatic aldehyde (49) and o-phenylenediamine (43) proceeds through the bis-imine (D) formation, which was further activated by the acidic surfactant catalysis (E). Activation of the imine (E)

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Figure 1.25: DBSA-promoted cyclocondensation of o-phenylenediamines with benzaldehydes.

promotes the intramolecular cyclization and subsequent aromatization of F to form the desired 1,2-disubstituted benzimidazoles (50) in good to excellent yield. The notable features of this reaction protocol are use of water as green reaction medium, easy workup process, shorter reaction time, biocompatible catalyst, and mild reaction conditions [252].

Chapter 1 Construction of benzazoles in aqueous medium: a sustainable approach

Figure 1.26: Synthesis of 1,2-disubstituted benzimidazoles in water–surfactant mixture.

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1.4 Sustainable synthesis of benzoxazole derivatives 1.4.1 Water as reaction media 2-Arylbenzoxazoles (47) were synthesized from the autoredox reaction of 2-nitrophenols (64) and amino acids (63) by the efficient C–N bond formation in the presence of base and TEMPO (Figure 1.27). Amino acids act as the benzylamine source while 64 behaves as 2-aminophenol surrogates during the reaction process. The base plays a crucial role for both the decarboxylation of the amino acids to generate the benzylamine anion and reducing agent to convert the nitro functionality to imine moiety. The reaction is initiated with the base-assisted proton abstraction from both the substrates and subsequent nitro reduction and coupling with benzylamine anion generates the o-imino phenoxide anion (64c). In the next step, the TEMPO-promoted single electron transfer from the phenoxide anion generates the corresponding phenol radical (64d), which undergoes radical cyclization to furnish the benzoxazolidine radical (64e). In the final step, TEMPO promoted another radical generation at C-2 carbon which completes the aromatization to produce the desired benzoxazoles. This reaction protocol utilizes 2-nitrophenols instead of widely explored 2-aminophenols as the synthetic equivalent of benzoxazoles. However, although the protocol is metal free, it requires higher reaction temperature and longer reaction time [253].

Figure 1.27: Synthesis of benzoxazoles from α-amino acids.

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1.5 Sustainable synthesis of benzothiazole derivatives 1.5.1 Water as reaction medium The ability of water to promote organic reaction through cooperatively formed HBassisted electrophile–nucleophile dual activation had been demonstrated by our group by performing two different types of organic reactions in water without the presence of any catalyst: (i) thia-Michael addition to enones [188] and (ii) N-t-Boc formation of amines with Boc2O [189]. These represent the two earliest examples on the electrophile–nucleophile dual activation catalysis by water. In this context, the generality of this molecular-level involvement of water to accelerate organic reaction was demonstrated in developing a green protocol for the synthesis of benzothiazoles by the treatment of aldehydes with o-aminothiophenols in water under heating [82] (Figure 1.28).

Figure 1.28: Synthesis of benzothiazoles in water.

Detailed GCMS (Gass chromatography-mass spectrometry) studies revealed that the reaction proceeds via the initial cyclocondensation of o-aminothiophenol and aldehyde to form thiazoline A which subsequently undergoes dehydrogenation/aromatization to form the desired benzothiazoles. The distinct advantages of water as the reaction medium with respect to reaction rate acceleration and selectivity (benzothiazoline vs benzothiazole formation/accumulation) were established by comparing the reaction outcome in water with various organic solvents. Here the reaction was completed in shorter time in water with complete conversion to the desired benzothiazole, whereas the reactions performed in organic solvents took longer time for complete consumption of the starting materials and led to a mixture of benzothiazoline and benzothiazole. The ability of water in chemoselective formation of the benzothiazole had been revealed to be associated with the presence of dissolved oxygen that facilitates dehydrogenation/oxidation of the intermediately formed benzothiazoline to the benzothiazoles as demonstrated by performing the reaction in degassed water. Here, benzothiazoline was the sole product and was further supported by the clean formation of benzothiazole at much shorter time when oxygen gas was bubbled into the reaction mixture. The role of water had been proposed as depicted in Figure 1.29 [82].

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Figure 1.29: HB-assisted dual activation role of water in the construction of benzothiazole ring.

Though the cyclocondensation of o-aminothiophenol with aldehyde to form the benzothiazoline A could proceed via Path a and/or Path b, the involvement of Path b had been considered to be less likely by demonstrating that under the experimental condition imine formation did not take place when 3,4-dimethoxybenzaldehyde was treated with 4-aminothiophenol. The molecular basis of acceleration of the reaction rate in water had been visualized as HB-mediated dual activation through the supramolecular assembly I accounting for the faster reaction rate in water compared to the organic solvents. One-pot MCRs of elemental sulfur, o-iodoaniline (65), and quaternary ammonium salt (66) were performed in aqueous medium to synthesize the C-2-substituted benzothiazoles (48a and 48b) (Figure 1.30). The quaternary ammonium salt plays the role of both alkylating agent and phase transfer catalyst. In the presence of sulfur powder, the alkylating agent is transferred into the disulfide intermediate which reacts with 2-iodoanilines to form the S-alkylated 2-aminobenzenethiols. Thus, the alkylating agent acts as the source of C-2 carbon of the benzothiazoles. The intramolecular cyclization of substituted benzenethiols furnishes the desired product [254]. Although this

Figure 1.30: Quaternary ammonium compounds as phase transfer catalyst and alkylating agent in the synthesis of benzothiazoles.

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is metal catalyst-free methodology under aqueous reaction media, the reaction conditions are harsh (requires prolonged heating at high temperature). In spite of various reported efforts for increasing the reaction efficiency through micellar solubilization, the synthesis of 2-arylbenzothiazoles (48) was carried out through inclusion complexation catalysis in the presence of β-cyclodextrin as the catalyst and air as an oxidant (Figure 1.31). In the aqueous solution of β-cyclodextrin, the substrates are inoculated into the inner hydrophobic cavity of β-cyclodextrin, and it forms the inclusion complexes through H-bonding with the OH group of β-cyclodextrin (44a and 49a). Thus, the OH group activates both the electrophile and nucleophile to enhance the reaction efficiency. The condensation reaction between aldehyde (49) and 2-aminothiophenol (44) generates the Schiff base (44b), which further cyclizes to benzothiazolidine intermediate (44c). The aerial oxygen-promoted dehydrogenation of benzothiazolidine furnishes the desired 2-arylbenzothiazole in excellent yield. In this methodology, water merely acts as the reaction medium. The role of β-cyclodextrin is a solubility enhancer of the organic substrates in aqueous medium and H-bonding catalysis. The catalyst is recovered and reused up to six times without any alteration in the catalytic efficiency [255].

Figure 1.31: β-Cyclodextrin-catalyzed synthesis of benzothiazoles.

Photocatalytic synthesis of 48 by the reaction of 49 and 44 in water as the reaction medium has been achieved under visible light (Figure 1.32). 2-Aminothiophenol reacts with the aldehyde to generate the imine intermediate which further undergoes intramolecular nucleophilic addition by thiol group to construct the benzothiazoline heterocycle (44c). 2-Aminothiophenol in situ generates the photosensitizer disulfide (44d) which photosensitized the molecular oxygen to generate singlet oxygen and reactive oxygen species. The dehydrogenation process for converting the benzothiazoline intermediate to benzothiazole is accomplished by both reactive oxygen species and singlet oxygen [256]. The characteristic features of this methodology are the mild reaction conditions,

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Figure 1.32: Photocatalytic synthesis of 2-arylbenzothiazoles.

application of naturally available resources, and non-requirement of external additives such as oxidants and photosensitizers.

1.5.2 Water–surfactant mixture as reaction medium The immiscibility of organic substances in water is often considered as the detrimental effect to perform organic reactions in aqueous medium due to which perhaps the reactions need to be carried out at high temperature. To address this issue, surfactants have been introduced for aquatic organic synthesis. Our group has earlier reported the use of the anionic surfactant SDS in the synthesis of heterocyclic compounds in water [257]. The Brønsted acidic surfactant DBSA was also used in heterocyclic ring construction in water [258]. It has been proposed that the surfactants create micellar assemblies that

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serve the purpose of microreactors in encapsulating the water-immiscible reactants which under such confinement undergo chemical reaction. In view of the fact that the benzothiazole synthesis in aqueous medium reported by us [82] required heating further made attempt to improve the protocol to make it energy efficient so as to perform the reaction at room temperature. Being influenced by the traditional apprehension on water immiscibility and the reason for the requirement of higher temperature, various surfactants (anionic, cationic, and neutral) were used that identified the anionic surfactant SDOSS as the most effective catalyst (SDS being the next best catalyst) in enabling the benzothiazole synthesis in aqueous medium at room temperature [84] (Figure 1.33). However, the influence of SDOSS to promote the reaction had been realized to be beyond its role as a solubility enhancer of the water-immiscible organic substrates in aqueous medium. The specific role of SDOSS had been demonstrated as its ability to convert the intermediately formed benzothiazoline A to the final product benzothiazoles 48 (Figure 1.33). That the role of SDOSS in promoting the benzothiazole formation at room temperature is not related solely to its ability to solubilize the reactants in aqueous medium was demonstrated in performing a model reaction in various organic solvents in the presence of catalytic amount of SDOSS that did not provide good conversion to benzothiazole 48, and the major product was benzothiazoline A though the reaction mixtures were homogeneous.

Figure 1.33: SDOSS-promoted synthesis of benzothiazoles in water at room temperature.

Both water (as the reaction medium) and the dissolved oxygen in water were crucial for clean conversion to 48 as no significant amount of 48 was formed in water in the absence of SDOSS or in degassed water in the presence of SDOSS. This protocol provided a novel approach of aerobic oxidation of benzothiazolidine intermediate with the help of surfactant-mediated oxygen reuptake from air to water (Figure 1.33). The relative ability of various surfactants used in the reaction had been correlated well with their relative oxygen uptake ability [84]. This concept provides a novel avenue to the applications of surfactants in organic chemistry. The surfactant SDOSS captures the air oxygen and delivers it into the aqueous reaction mixture favoring the dehydrogenative oxidation of benzothiazolidine. This has been demonstrated by identifying the supramolecular adducts involving the surfactant (SDOSS/SDS), molecular oxygen, and water molecule through rigorous mass spectrometric (ESI-MS) studies [84]. Our research group also reported the chemoselective and regioselective formation of benzothiazole-2-carboxylates (69) by the water–surfactant-mediated reaction of 2-

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aminothiophenols (67) with 1,2-dicarbonyl compounds (68) that occur through 5-endotrig process contrary to Baldwin’s rule (Figure 1.34). On the other hand, the reaction of 2-aminophenols/anilines with 1,2-dicarbonyl compounds formed benzazine-3-ones or benzazine-2,3-diones (70) via 6-exo-trig process in accordance with Baldwin’s rule. The benzothiazole-2-carboxylates versus benzazine-3-ones/benzazine-2,3-diones product formation selectivity was rationalized with the help of hard–soft acid–base principles, orbital interaction, and quantum chemical calculation studies. In the first step, nucleophilic addition of 2-aminophenol/thiophenol/aniline to ethyl glyoxalate generates the corresponding amide derivative (67a and 67b). In case of the reaction involving 2-aminothiophenol, in-

Figure 1.34: SDOSS-promoted chemoselective synthesis of benzothiazoles.

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tramolecular HB involving the SH hydrogen and the amide carbonyl group in 67d facilitates the intramolecular transfer of hydrogen to the amide carbonyl to form the corresponding enol tautomer. In the next step, the intramolecular nucleophilic attack by the sulfur atom on C=N forms the cyclocondensation product, the benzothiazoline 67e, which on elimination of water molecule gives benzothiazole-2-carboxylates (69). Using quantum chemical calculation studies, it has been demonstrated that the role of water is to decrease the activation energy barrier of the cyclocondensation reaction [89].

1.6 Common sustainable synthesis of benzimidazole, benzothiazole, and benzoxazoles in aqueous medium The sustainable synthesis of benzazoles in aqueous medium described above is applicable to a particular class of benzazole, that is, either benzothiazole or benzimidazole or benzoxazole. However, there are a few reports wherein sustainable protocols that have been developed are applicable to the synthesis of more than one class of benzazoles. The methodologies reported for such purposes are discussed herein.

1.6.1 Water as the reaction medium A bienzymatic catalysis was applied in the synthesis of both 2-arylbenzothiazoles and 2-arylbenzoxazoles. The reactions of aldehydes (49) and 2-aminothiophenol/2-amiophenol (67) were performed in the presence of cooperative biocatalysis of glucose oxidase (GOX)–chloroperoxidase (CPO) catalytic system under oxygen atmosphere to synthesize the C-2-substituted benzothiazoles/benzoxazoles (72) (Figure 1.35). The reaction of 67 with

Figure 1.35: Bienzymatic catalysis in the synthesis of benzazoles.

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49 proceeds by initial formation of the Schiff base followed by intramolecular cyclization to form benzothiazolidine/benzoxazolidine (70). The GOX-catalyzed formation of hydrogen peroxide from glucose (71) is utilized for the CPO-assisted dehydrogenation of 68 to furnish benzothiazoles/benzoxazoles (72) in good to excellent yield. The distinctive features of the methodology are the biocatalyzed oxidation of the benzthiazolidine/benzoxazolidine intermediate with the help of the renewable source of oxygen (i.e., glucose) and cooperative tandem catalysis by the two bioenzymes [259]. An electrosynthesis of 2-aminobenzoxazoles (47) and 2-aminobenzothiazoles (48) was carried out by utilizing inexpensive mediators in catalytic amounts (Figure 1.36). The electrochemical reaction of 2-aminophenols (45) with isothiocyanates (73) was carried out in the presence of catalytic amount of NaI and NaCl in aqueous ethanol to synthesize 2-aminobenzoxazoles (47). The anodic oxidation of iodide anion in situ generates iodine as the oxidizing species. In the cathode section, water is reduced to hydroxide anion which acts as base in the reaction cascade. The nucleophilic addition of amine to the electrophilic carbon of isothiocyanate produces the corresponding thiourea derivative (73a), which is oxidized by iodine to 73b. The intramolecular nucleophilic addition followed by desulfurization–aromatization cascade produces 2-aminobenzoxazoles (47). The identical reaction protocol and mechanism was also applied for the synthesis of 2-aminobenzothiazoles (48) [260]. The notable advantages of this reaction protocol are the uses of inexpensive catalysts, transition metal-free reaction protocol, easy scale-up, less waste generation, and mild reaction conditions.

1.6.2 Aqueous suspension of SDS as reaction medium The synthesis of 1,2-disubstituted benzimidazoles (50) in aqueous medium was carried out by performing the reaction between o-phenylenediamines (43) (1 equiv.) and aldehyde (49) (2 equiv.) in the presence of surfactant SDS (Figure 1.37). SDS forms the micelle to provide the inner hydrophobic space and outer hydrophilic layer. As benzaldehyde (49) and o-phenylenediamines (43) are hydrophobic in nature, both of the substrates accommodate themselves inside the hydrophobic core of SDS micelle favoring the faster condensation reaction between the electrophile and nucleophile. The reaction proceeds through the simultaneous formation of bisimine derivative (D, Figure 1.26), which further undergoes intramolecular cyclization/aromatization/1,3-hydride shift cascade (E, F, Figure 1.26) to form the 1,2-disubstituted benzimidazoles (50). The similar SDS-mediated aqueous reaction of o-phenylenediamines/2-aminothiophenols(75) (1 equiv.) and aldehyde (49) (1 equiv.) was performed in the presence of ammonium persulfate as an oxidizing agent to synthesize the 2-substituted benzimidazoles/benzothiazoles (76). The reaction proceeds through the monoimine (G) formation which further cyclizes to benzimidazolidine (H). The ammonium persulfate-promoted dehydrogenation of benzimidazolidine furnishes the 2-substituted benzimidazoles [261]. This reaction protocol is

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Figure 1.36: Electrochemical synthesis of 2-aminobenzazoles.

environmentally benign, and the notable advantages are higher chemoselectivity, higher yield of the product, and operational simplicity. Similar type of SDS-mediated aqueous reaction in the presence of potassium persulfate as the oxidizing agent and Cu(II) salt as catalyst to synthesize the benzazoles (78) was also reported (Figure 1.38). Oxidative condensation of 77 with 49 synthesized the bioactive 2-substituted benzimidazoles in good to excellent yield. The condensa-

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Figure 1.37: SDS-catalyzed synthesis of benzazoles.

tion between aldehyde and amine generates the imine (77a), which coordinates with the Cu(II) salt to facile the intramolecular nucleophilic addition step at iminic carbon. The potassium persulfate–CuSO4-assisted dehydrogenation of benzimidazolidine (77b) furnishes the 2-substituted benzimidazoles (78). The same reaction protocol was also explored using 2-aminothiophenols, 2-aminophenols, and anthranilamide as substrate to synthesize benzothiazoles, benzoxazoles, and quinazolin-4(3H)-ones, respectively,

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Figure 1.38: Synthesis of benzazoles in the water–SDS mixture.

in good to excellent yield [262]. Compared to those in organic solvents, higher yields were observed in aqueous micelles. This simple, cheap, and high-yielding methodology has advantages of excellent chemoselectivity, environmental friendliness, shorter reaction time, and large-scale synthesis.

1.7 Conclusions Benzazoles are important class of scaffolds present as crucial pharmacophores in various bioactive molecules and approved drugs. The medicinal importance of benzazoles inspired synthetic organic/medicinal chemists for designing new protocols for their synthesis. However, often these are not in compliance with the green chemistry principles and are potentially detrimental to the environment. These drawbacks of the existing methodologies usher in the regulation of sustainable practices in the synthesis of benzazoles. Thus, the objective of this chapter is to dig into the literatures for sustainable approaches toward the synthesis of benzazoles. Among various sustainable approaches, the reactions performed using water as the reaction medium opened up vast scope for developing greener synthesis of benzazoles. Although the solubility problems of the starting materials and sticky nature of the reaction mixture might create operational issues, the synthetic methodologies with water as the reaction medium are still preferred by chemists due to certain advantages such as precipitation of the final compound in water thereby easing out the product isolation and purification, use of sustainable eco-friendly reaction media that does not pose any environmental threat, and activation of the substrates (both the nucleophile and electrophile) through water-mediated H-bonding that accelerates the reaction rate which often is not achievable by conventional organic solvents. The participation of water through

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H-bonding network catalyzes the reaction and lowers the energy barrier. The industrial scale-up of some of these methodologies was also reported, indicating the utilization of water as reaction medium in large-scale synthesis. The applications of these water-assisted synthetic protocols for the manufacturing of benzazole-containing drug candidate molecules and approved drugs will be the novel tool for the pharmaceutical industries. Toward these objectives, this chapter provides the readers impetus to delve into developing new chemistries for sustainable synthesis of benzazoles.

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

Chapter 2 Catalyst-free synthesis of bioactive heterocycles in aqueous media 2.1 Introduction The impact of human activity and growth of the modern society on the environment is a well-discussed topic nowadays, and sustainability has materialized as the prime endeavor in every aspects of human livelihood. The chemical industry plays a major role in the development of humankind, and consequently an immense responsibility resides on the chemists to design sustainable processes. In these circumstances, the concept of green chemistry has been developed, where the design of chemical substances and processes reduces or eliminates the generation/use of hazardous materials following the established guidelines [1]. In a reaction setup, usually the solvent use constitutes the share of maximum percentage of the total mass, and it is the major source of waste in a representative procedure [2]. Therefore, the use of traditional organic solvents has enough chances to create various hazardous issues like toxicity, pollution, and waste management. Hence, solvent-free/neat conditions would be ideal to carry out a reaction. However, performing a reaction in an appropriate solvent offers several advantages such as optimum mass and heat transfer, facile reaction rate, and controlling chemo- and regioselectivities [3]. Thus, a continuous process for the development of alternative sustainable solvents is a prime issue in synthetic organic chemistry. In this context, various eco-friendly solvents like 2-methyltetrahydrofuran, cyclopentyl methylether, polyethylene glycol, supercritical fluids (SCFs), and ionic liquids (ILs) have emerged as the substitute for the volatile commonly used organic solvents [4]. Although these alternative solvents are environmentally benign but are not easily available and economical. For the SCFs and ILs, sophisticated and tedious techniques are required to prepare them. Considering these facts, water flourishes as an ideal green solvent since it is one of the most abundant compounds in the Earth’s crust. It also offers several distinct chemical and physical properties that enable solvation or other molecular assembly formation in reacting substrates, allowing them to react effectively [5]. The unassailable stability of water as a reaction medium under various conditions, like ambient temperature (both conven-

✶

Corresponding author: Asish R. Das, Department of Chemistry, University of Calcutta, Kolkata 700009, West Bengal, India, emails: [email protected], [email protected] Dwaipayan Das, Moumita Saha, Department of Chemistry, University of Calcutta, Kolkata 700009, India https://doi.org/10.1515/9783110985627-002

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tional and microwave heating), pressure, and ultrasonication in the absence or presence of homogeneous and heterogeneous catalysts, is increasing the implementation of it in diverse reactions. Some unique properties of water, such as high polarity, viscosity, and immiscibility with organic compounds, allow the easy extractive workup and purification of products [6, 7]. Due to these inimitable features, water-mediated organic reactions are receiving phenomenal attention nowadays. Heterocyclic scaffolds hold a significant share in the framework of bioactive natural and synthetic products [8–12]. They are also the leading candidates found in agrochemicals, dyes, cosmetics, and material science [13–16]. Hence, the design and development of new synthetic procedures for heterocyclic compounds are highly demanding area in synthetic organic/medicinal chemistry during the last decade. With this background, this chapter emphasizes on the recent advancements in the titular field.

2.2 Synthesis of bioactive heterocycles in aqueous media In this part, various important water-mediated protocols for the synthesis of the heterocyclic scaffolds are highlighted.

2.2.1 Rhodanines Rhodanine scaffolds are very useful in therapeutic purpose. In particular, they possess excellent inhibitory activity against HCV NS3 protease and β-lactamase [17, 18]. Hence, the synthesis of rhodanines is of great importance in the field of biology and pharmacology. In 2011, Rostamnia and Lamei [19] developed a greener procedure for the synthesis of rhodanine moieties in aqueous medium under ultrasonication from amines (1), CS2 (2), and acetylene diesters (3) (Figure 2.1). Interestingly, these rhodanine scaffolds contain an exocyclic carbon–carbon double bond.

2.2.2 1,2,3-Triazole synthesis The 1,2,3-triazole moieties are highly privileged scaffolds in both synthetic organic chemistry and medicinal chemistry [20–22]. These triazole scaffolds have broad application in the synthesis of biologically active molecules and application-oriented organic materials [23–27]. Due to their chelating ability with transition metal, these scaffolds have emerged as an important building block in metal-catalyzed reactions [28–31]. In this context, in 2018, Wan and coworkers [32] designed a water-mediated

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Figure 2.1: Three-component synthesis of rhodanines in aqueous medium under ultrasonication.

Figure 2.2: Water-mediated synthesis of 4-acyl-NH-1,2,3-triazoles.

rapid cycloaddition reaction between N,N-dimethyl enaminones (5) and tosylazide (6), where 4-acyl-NH-1,2,3-triazoles (7) were obtained as exclusive products (Figure 2.2).

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Figure 2.3: Plausible mechanism for the water-mediated synthesis of 4-acyl-NH-1,2,3-triazoles.

This protocol features excellent sustainability since it requires water as the sole reaction medium, nominal thermal energy, and is devoid of external catalyst (Figure 2.3).

2.2.3 Chromone synthesis Structurally chromones are the benzene-fused γ-pyrones which can be found in many naturally occurring compounds. The molecules comprising chromone skeleton are medicinally very important as they have various promising biological activities, namely, phosphatidylinositol-3-kinase inhibitors, antifungal, antiallergic, antiviral, antitubilin, antihypertensive, and anticancer agents [33]. Organothiocyanate compounds are also the vital structural cores present in vast range of natural products, lead drugs, and other biologically active molecules [34]. Additionally, thiocyanates are utilized as synthetic precursors of many sulfur-containing biologically active compounds and organosulfur compounds such as thiols, sulfides, and thioesters [35–38]. In 2019, Yang et al. [39] reported a metal-free protocol for the synthesis of 3-thiocyanochromone and 3-selenocyanochromone (10) from (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one (8) and KSCN/KSeCN (9) in the presence of iodobenzene diacetate (PIDA) (Figure 2.4 and 2.5). The use of water as the solvent at room temperature and the metal-free approach of this protocol offer great sustainability. This protocol requires a very short time (only 1 h) to achieve the desired result.

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Figure 2.4: Synthesis of 3-thiocyanochromone and 3-selenocyanochromone.

Figure 2.5: Plausible mechanism for the synthesis of 3-thiocyanochromone.

2.2.4 Synthesis of complex indolizine rings Indolizine moieties are extremely important heterocyclic scaffolds in pharmaceuticals due to their promising biological activities [40, 41]. The available reports have described the potential of indolizine derivatives as histamine H3 receptor antagonists [42], antimicrobacterial agents [43], leukotriene synthesis inhibitors [44], calcium entry blockers [45], and inhibitors of 15-lipooxygenase [46, 47]. In 2011, Boruah and coworkers [48] have reported a multicomponent reaction (MCR) protocol to synthesize the indolizine-fused tricyclic heteroaromatic compound, known as cycl[3.2.2.]azine that have gained keen attention due to their remarkable physical and chemical properties. The protocol involves three reacting components: alkylpyridines (11), α-bromo carbonyl compounds (12), and activated alkynes (13) (Figure 2.6). The application of water as the solvent under the unconventional energy source, microwave, increases the significance of this protocol due to the environmentally sustainable setup.

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Figure 2.6: Synthesis of cycl[3.2.2.]azine derivatives.

This reaction is composed of two steps: at first, alkylpyridine reacts with α-bromo carbonyl to generate the Chichibabin indolizines. Next, a [8+2]π-cycloaddition reaction takes place between the alkyne and in situ-generated indolizines to produce the desired product (14) (Figure 2.7).

Figure 2.7: Plausible mechanism for the synthesis of cycl[3.2.2.]azine derivatives.

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2.2.5 Synthesis of spirooxindole-fused pyrrolidines The spirooxindoles are privileged structural frameworks often found in synthetic drug molecules and bioactive natural products. They are extremely important in pharmaceuticals due to their various biological activities like antimicrobial and antitumor [49–51] as well as inhibitors of the human NKI receptor. The spirooxindolefused pyrrolidine scaffolds are used as local anesthetics [52]. In 2016, Meshram and coworkers [53] reported a water-mediated protocol to prepare spirooxindole-fused pyrrolidine under microwave irradiation. This MCR protocol involves isatin derivatives (15), β-nitrostyrenes (16), and an amine source (17) as the reacting partners (Figure 2.8). Here, the used amine sources are benzyl amines and α-amino acids.

Figure 2.8: Water-mediated MCR protocol to synthesize spirooxindoles under microwave irradiation.

2.2.6 Synthesis of densely functionalized pyridine rings In 2022, Chandra and coworkers [54] developed a catalyst-free tandem Knoevenagel reaction procedure to synthesize densely functionalized pyridine rings from 4-oxo-4Hchromene-3-carbaldehyde (19), malononitrile (20), and ammonium acetate (21) (Figure 2.9). This reaction is highly sustainable in terms of green chemistry as it is

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Figure 2.9: Synthesis of densely functionalized pyridine rings in aqueous medium.

carried out in aqueous medium (Figure 2.10). The short reaction time under microwave condition adds to the sustainability to further extent. Interestingly, molecular docking and other in silico studies predicted the compound 22e as a potential MK-2 protein inhibitor.

Figure 2.10: Plausible reaction mechanism for the synthesis of 22a.

2.2.7 Furan ring synthesis Furan scaffolds are present in core structure of several natural products, such as kailolides and combranolides [55, 56]. Additionally, these heterocycles can be found in many industrial products like pharmaceuticals, fragrances, and synthetic dyes [57, 58]. The MCRs are very efficient tools for synthesizing furans as they offer a straight-

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forward one-pot reaction sequence with minimum waste generation. Performing MCRs in water is more significant as it offers economic and environmental benefits. In 2019, Anary-Abbasinejad and coworkers [59] reported a protocol for the synthesis of 5-(furan-3-yl)barbiturate and 5-(furan-3-yl)thiobarbiturate (26) derivatives via a one-pot three-component reaction using easily available starting materials arylglyoxals (23), barbituric acid or thiobarbituric acid (25), and acetylacetone (24) in aqueous medium (Figure 2.11). Under the gentle heating conditions, fully functionalized furan cores emerge as the main product.

Figure 2.11: Synthesis of 5-(furan-3-yl)barbiturate and 5-(furan-3-yl)thiobarbiturate derivatives.

In 2014, Ramasastry and coworkers [60] developed an expeditious procedure to synthesize pyran-fused dihydrofurans (29) from suitably functionalized pyran rings (27) and different 1,3-diketo compounds (28) in aqueous medium (Figure 2.12).

2.2.8 Synthesis of pyran rings The synthesis of densely functionalized pyran molecules is also very appealing to the scientists due to their versatile application in agrochemicals, cosmetics, food additives, and pharmaceuticals. A wide range of biological activities shown by the pyran ring are anticancer [61], anti-HIV [62], antifungal [63], antiviral [64], anti-inflammatory [65], anti-

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Figure 2.12: Synthesis of pyran-fused dihydrofurans.

malarial [66], antioxidant [67], and antimicrobial [68]. The MCR protocols are also very effective in the synthesis of pyran heterocycles. In 2019, Jonnalagadda and coworkers [69] reported a procedure to prepare tetrahydrobenzo[b]pyrans from readily available aromatic aldehydes (30), cyclohexan-1, 3-dione (32), and cyanoacetic esters (31). They used microwave irradiation as a heating source and water as the solvent. These unconventional reaction conditions promote the sustainability of this protocol (Figure 2.13).

Figure 2.13: Synthesis of tetrahydrobenzo[b]pyran derivatives.

In 2013, Khalili and coworkers [70] developed an ultrasonication-mediated reaction procedure for the synthesis of kojic acid (34)-fused pyran systems. The reaction proceeded smoothly in aqueous medium (Figure 2.14).

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Figure 2.14: Synthesis of kojic acid-fused pyran systems.

2.2.9 Synthesis of [1,6]naphthyridines 1,6-Naphthyridines have emerged as an attractive target of research in medicinal and synthetic chemistry [71–76]. They are used for the treatment of Alzheimer’s disease and have antiproliferative effect against various human cancer cells [77–80]. In 2022, Shen et al. [81] designed a three-component domino reaction protocol to prepare [1,6]naphthyridine cores from 6-methyl-1-phenyl-4-(phenylamino)pyridin-2(1H)-one (38), benzaldehyde (39), and 1H-indene-1,3(2H)-dione (40) (Figure 2.15).

Figure 2.15: Synthesis of substituted 1,6-naphthyridine derivatives.

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Figure 2.16: Plausible mechanism for the synthesis of 1,6-naphthyridine derivatives.

The approach is very useful in terms of sustainability as it proceeds in water, is devoid of requirement of any catalyst or additive, and the reaction proceeds in a very facile manner under microwave irradiation (Figure 2.16).

2.2.10 Imidazo- and benzimidazo-fused polyheterocycle synthesis Imidazo- and benzimidazo-fused polyheterocycles have emerged as a highly significant scaffold due to their immense biological properties. In this class of polyheterocycles, imidazo[1,2-a]pyridines, imidazo[2,1-b][1,3]thiazole, benzimidazo[1,2-a]isoquinoline, and so on are very important due to their antimicrobial [82, 83], anthelmintic [84], antiinflammatory [85], anticonvulsant [86], anxiolytic [87], hypnotic [88], antiulcer [89], and antitumor agents [90–92], and cardiotonic activities [93, 94]. Hence, the synthesis of these polyheterocycles is very attractive to the synthetic organic chemists. In 2006, Mirzaei and coworkers [95] described a protocol for the synthesis of 3-aminoimidazo[1,2-a]pyridines and 5-aminoimidazo[2,1-b][1,3]thiazoles (45a–d) via a three-component MCR between 2-aminopyridines or 2-aminothiazoles (44), aldehydes (43), and isocyanides (42) in water under mild heating condition (Figure 2.17). In 2016, Mishra and Verma [96] developed an environmentally benign protocol for the synthesis of diversely functionalized benzimidazo-fused polyheterocycles under a catalyst-free condition in aqueous medium. This tandem approach has furnished a wide range of functionalized benzimidazole-fused benzofuro[3,2-c]pyridines (48), benzofuro/thieno[2,3-c]pyridines (51), and γ-carbolines (49) in good to excellent yield (Figure 2.17–19). During the progress of the reaction, initially two new C–N bond is formed between the starting materials through successive inter- and intramolecular nucleophilic addition. Finally, a 6-endo-dig ring closure step generates the desired product (Figure 2.20).

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Figure 2.17: Synthesis of 3-aminoimidazo[1,2-a]pyridines and 5-aminoimidazo[2,1-b][1,3]thiazoles.

Figure 2.18: Synthesis of benzimidazo-fused heterocycles from 46.

2.2.11 Synthesis of 2-benzazepine derivatives Benzazepine is the benzene ring-fused seven-membered N-heterocyclic moiety present in several biologically active products [97–99] and naturally occurring alkaloids like aphanorphine, lennoxamine, and cephalotaxine. Due to the unique structural fea-

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Figure 2.19: Synthesis of benzimidazo-fused heterocycles from 50.

Figure 2.20: Plausible mechanism for the synthesis of benzimidazo-fused polyheterocycles.

ture and biological importance, benzazepine systems are highly tempting scaffolds to be explored. In 2010, Anil Kumar and coworkers [100] developed a unique protocol, which afforded benzazepine (54) scaffolds from coumarin moieties (52). The reaction proceeds under catalyst-free conditions in aqueous medium which exalts the sustainability of this protocol (Figure 2.21).

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Figure 2.21: Synthesis of 2-benzazepines from 4-chloro-3-formyl coumarin.

2.2.12 Synthesis of quinolone-2-thiones Quinoline-2-thiones are known for their large array of biological activities, and can be found in different natural products and synthetic pharmaceuticals. Several representative molecules of this category are known to possess wide range of pharmacological activities like antitumor [101] and antiproliferative [102], inhibitors of inositol 5-phosphatases [103], prostate apoptosis response-4 secretagogue [104], and human A3 adenosine receptor antagonists [105]. Due to these reasons, the development of new and efficient synthetic procedures of these heterocycles is a constant source of attraction to synthetic organic chemists. In 2020, Yu and coworkers [106] developed a microwave-assisted synthesis of polyheterocycle-fused quinoline-2-thiones (57) in water (Figure 2.22). The reported procedure features several advantages such as catalyst-free set up, short reaction tenure, usage of recyclable and green solvent system, and column chromatography free facile purification/isolation of product using simple filtration technique. These salient features shape this protocol operationally very simple and highly environmentally benign. Initially, the amine (55) is transformed to isothiocyanate (II), and then a 6πelectrocyclization takes place between heterocycles and isothiocyanate (II) to form quinoline-2-thiones (57) (Figure 2.23).

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Figure 2.22: Microwave-assisted synthesis of polyheterocycle-fused quinoline-2-thiones in water.

Figure 2.23: Plausible mechanism.

2.2.13 Synthesis of isoquinolones Polyheterocycle-fused isoquinoline frameworks are present in many natural products, synthetic drugs, and organoelectronics. The most important application of these frameworks is found in medicinal chemistry as they have a potential role in treating hemoglobinopathies and cancer, and peripheral benzodiazepine receptor ligand, controlling the potassium ion flux [107–110]. Due to such important benefits, the synthesis of frameworks is highly desirable in the domain of organic chemistry. In 2022, Yu and coworkers [111] reported a PIDA (60)-mediated visible-lightinduced decarboxylative radical cyclization procedure at room temperature for the

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Figure 2.24: Synthesis of benzimidazo and indolo[2,1-a]isoquinolinone derivatives.

synthesis of densely functionalized benzimidazo and indolo[2,1-a]isoquinolinones (61). The mild catalyst-free reaction conditions and use of water as a green solvent elevate the sustainability of this protocol. The proposed mechanism suggests the (Figure 2.24) generation of benzoyl or tertbutyl radicals from α-oxocarboxylic acids (59) in the presence of PIDA (60) and visible light, and the addition of this radical with the starting material drives the reaction to the final product (Figure 2.25).

2.2.14 Synthesis of 1,4-dihydropyridines and polyhydroquinolines 1,4-Dihydropyridines (DHPs) are important class of N-heterocyclic scaffolds as they play a vital role in medicinal field. These unique skeletons have shown immense activity in the treatment of angina pectoris [112], blood pressure, and hypertension [113]. Due to their partially reduced structure, they can mimic the natural redox system NAD/NADH+ and have emerged as the H-transfer reagents in biomimetic reductions [114, 115]. Very recently, these molecules have been used as the alkyl and keto aryl radical sources in different reaction protocols [116, 117]. In 2013, Das and coworkers [118] have reported a visible-light-induced, catalyst-free synthesis of DHPs (65) and polyhydroquinolines (67) in an aqueous solution of ethyl-Llactate from different 1,3-diketo compounds (62, 66), aldehydes (63), and ammonium formate (64) (Figure 2.26 and 2.27). Here, ammonium formate (64) acts as the nitrogen

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Figure 2.25: Plausible mechanism.

Figure 2.26: Synthesis of 1,4-DHPs.

source. The reaction follows an MCR pathway. Interestingly, they have also synthesized two bioactive 1, 4-DHPs, nitrendipine (65d), and nemadipine B (65c) in excellent yields using this protocol.

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Figure 2.27: Synthesis of polyhydroquinolines.

2.3 Conclusions Synthetic organic chemists were skeptic for a long time about the feasibility of water as a practical medium for organic transformations. But with the recent development in green and sustainable chemistry, water-compatible synthetic procedures have gained tremendous momentum. Water, as solvent, offers several advantages: not only the sustainability but also it can deliver improved reactivities and selectivities, simpler workup and purification process, and mild reaction conditions. The stability of water under different conventional and unconventional reaction conditions promotes the reactions even under catalyst-free conditions. The reusability of water as a reaction medium is also very advantageous in terms of economic aspect. Due to these reasons, water is complementing the typical organic solvents in the synthesis of diverse range of bioactive heterocyclic scaffolds. This chapter covers and discusses on the recently developed catalyst-free water-mediated alternative procedure which will assist different research groups in designing new techniques in this field.

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[98] Thum S, Kokornaczyk AK, Seki T, De Maria M, Zacarias NV, de Vries H, Weiss C, Koch M, Schepmann D, Kitamura M, Tschammer N. Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold. Eur J Med Chem 2017, 135, 401–413. [99] Brewer MD, Burgess MN, Dorgan RJ, Elliott RL, Mamalis P, Manger BR, Webster RA. Synthesis and anthelmintic activity of a series of pyrazino [2, 1-a][2] benzazepine derivatives. J Med Chem 1989, 32, 2058–2062. [100] Prasad JV, Prabhakar M, Manjulatha K, Rambabu D, Solomon KA, Krishna GG, Kumar KA. Efficient catalyst-free Domino approach for the synthesis of novel 2-benzazepine derivatives in water. Tetrahedron Lett 2010, 51, 3109–3111. [101] Lu J, Xin S, Meng H, Veldman M, Schoenfeld D, Che C, Yan R, Zhong H, Li S, Lin S. A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay. PLoS One 2013, 8, e53317. [102] Clement B, Girreser U, Steinhauer TN, Meier C, Marko D, Aichinger G, Kaltefleiter I, Stenzel L, Heber D, Weide M, Wolschendorf U. 11‐Substituted Benzo [c] phenanthridines: New structures and insight into their mode of antiproliferative action. ChemMedChem 2016, 11, 2155–2170. [103] Pirruccello M, Nandez R, Idevall-Hagren O, Alcazar-Roman A, Abriola L, Berwick SA, Lucast L, Morel D, De Camilli P. Identification of inhibitors of inositol 5-phosphatases through multiple screening strategies. ACS Chem Biol 2014, 9, 1359–1368. [104] Burikhanov R, Sviripa VM, Hebbar N, Zhang W, Layton WJ, Hamza A, Zhan CG, Watt DS, Liu C, Rangnekar VM. Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis. Nat Chem Biol 2014, 10, 924–926. [105] Baraldi PG, Tabrizi MA, Preti D, Bovero A, Fruttarolo F, Romagnoli R, Zaid NA, Moorman AR, Varani K, Borea PA. New 2-arylpyrazolo [4, 3-c] quinoline derivatives as potent and selective human A3 adenosine receptor antagonists. J Med Chem 2005, 48, 5001–5008. [106] Li XY, Liu Y, Chen XL, Lu XY, Liang XX, Zhu SS, Wei CW, Qu LB, Yu B. 6π-Electrocyclization in water: Microwave-assisted synthesis of polyheterocyclic-fused quinoline-2-thiones. Green Chem 2020, 22, 4445–4449. [107] Kochanowska-Karamyan AJ, Hamann MT. Marine indole alkaloids: Potential new drug leads for the control of depression and anxiety. Chem Rev 2010, 110, 4489–4497. [108] Khan AY, Suresh Kumar G. Natural isoquinoline alkaloids: Binding aspects to functional proteins, serum albumins, hemoglobin, and lysozyme. Biophys Rev 2015, 7, 407–420. [109] Bressy C, Alberico D, Lautens M. A route to annulated indoles via a palladium-catalyzed tandem alkylation/direct arylation reaction. J Am Chem Soc 2005, 127, 13148–13149. [110] Szkotak AJ, Murthy M, MacVinish LJ, Duszyk M, Cuthbert AW. 4‐Chloro‐benzo [F] isoquinoline (CBIQ) activates CFTR chloride channels and KCNN4 potassium channels in Calu‐3 human airway epithelial cells. Br J Pharmacol 2004, 142, 531–542. [111] Tang L, Ouyang Y, Sun K, Yu B. Visible-light-promoted decarboxylative radical cascade cyclization to acylated benzimidazo/indolo [2, 1-a] isoquinolin-6 (5 H)-ones in water. RSC Adv 2022, 12, 19736–19740. [112] Siragy HM, Bedigian M. Mechanism of action of angiotensin-receptor blocking agents. Curr Hypertens Rep 1999, 1, 289. [113] De Gasparo M. AT (1) and AT (2) angiotensin II receptors: Key features. Drugs 2002, 62, 1. [114] Hilgeroth A. Dimeric 4-Aryl-1, 4-dihydropyridines: Development of a third class of nonpeptidic HIV-1 protease inhibitors. Mini-Rev Med Chem 2002, 2, 235. [115] Hilgeroth A, Lilie H. Structure-activity relationships of first bishydroxymethyl-substituted cage dimeric 4-aryl-1, 4-dihydropyridines as HIV-1 protease inhibitors. Eur J Med Chem 2003, 38, 495.

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Sabbasani Rajasekhara Reddy✶ and Pooja Garg

Chapter 3 Aqueous-mediated sustainable catalytic methods for the synthesis of bioactive N-heterocycles 3.1 Introduction Water is the most abundant liquid on the Earth. Water, known as a versatile universal solvent, plays an essential role in chemical synthesis [1]. It is a good alternate to conventional organic solvents as it is readily available, cost-effective, nonflammable, and nontoxic. Water can act as a solvent or cosolvent in organic reactions. It can either be produced or consumed during a chemical reaction. Aqueous-mediated reactions are a component of green chemistry. The use of water as a reaction medium for organic transformations has various benefits for the environment and economy. The use of water speeds up the reaction rate in comparison to organic solvents [2]. Numerous reasons including the hydrophilic effect, density of water, stabilization of the transition state via hydrogen bonding, and cohesive energy have contributed this rise in reaction rate [3]. A few specific properties of water have been described in Figure 3.1. Water-mediated reactions also show certain unique advantages, such as salting in and salting out, control over exothermic and endothermic reactions, and control over the pH variation range. The use of water as a reaction medium complies with the green chemistry principles. It demonstrates that using water is an environmentally friendly method. Many studies have recently reported that the use of water in chemical reactions is a milestone in organic synthesis [4]. Despite this, the low solubility of organic compounds in water makes it as a reaction medium and is a significant challenge for organic chemists. Water interacts with organic compounds in multiple ways: hydrogen bonding, hydrophobic interactions, and dipole–dipole interactions, and so on [5]. Numerous reactions such as aldol condensation, Mannich reaction, Michael reaction, desymmetrization of epoxides, Pauson–Khand reac-

Acknowledgments: S. R. Reddy gratefully greets the VIT seed grant (RGEMS)-SG20230119 for providing financial support for research at Vellore Institute of Technology (VIT), Vellore, India. The authors are grateful to the SPARC/2019-2020/P1905/SL, GOVT, India, and GOVT of India for giving financial support for the book chapter work. ✶

Corresponding author: Sabbasani Rajasekhara Reddy, Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India, email: [email protected] Pooja Garg, Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Vellore 632014, India https://doi.org/10.1515/9783110985627-003

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Figure 3.1: Properties of water.

tion, and Knoevenagel reaction have been reported in aqueous medium [6]. That is why this study focused on aqueous-mediated synthesis of organic compounds. Organic compounds with heteroatoms like nitrogen, oxygen, and sulfur in the rings have been synthesized and evaluated for their biological properties. Majorly, nitrogencontaining compounds have been designed, synthesized, and studied for their biological importance. N-Heterocycles have been categorized in various types depending on the number of nitrogen and carbon atoms in the ring, aromaticity, number of rings, and the presence of other heteroatoms [7]. Pyrrole, pyridine, pyrimidine, pyrazole, quinoline, quinazoline, imidazole, thiazole, thiazolidine, isoxazole , and so on are some examples of different ring structures of nitrogen-containing compounds [8]. The N-heterocyclic compounds are the most abundant organic moieties with versatile biological properties. Some pharmaceutical applications of N-heterocyclics are their use as antacids, antidiabetic, antibacterial, antiviral, anticancer, antifungal, antitubercular, anti-inflammatory, and antioxidant agents [9–11]. Some of the commercially used drugs containing Nheterocycles are depicted in Figure 3.2. These compounds constitute various large biomolecules or their subparts such as enzymes, vitamins, and hormones. There are several reports on the synthesis of N-heterocycles in organic solvent via conventional methods but very few reports are there for their synthesis using green reaction conditions. Since there is increasing concern toward environment, efforts are being made to synthesize organic compounds by adopting green methodology. Some significant reports have been compiled in this study, which cover the synthesis of N-heterocycles in aqueous medium in accordance with principles of green chemistry. Various recyclable catalytic systems such as organocatalysts, metal complexes, nanoparticles (NPs), and ionic liquids have been used for the synthesis of N-heterocycles.

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Figure 3.2: Examples of bioactive N-heterocycles.

Mostly organocatalysts such as acetic acid, p-toluenesulfonic acid (PTSA), p-dodecylbenzenesulfonic acid (DBSA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), polyphosphoric acid (PPA), meglumine, and DABCO are used in the synthesis [12, 13]. These catalysts are readily soluble in water and easily available. Metal catalysts such as copper, ruthenium, manganese, palladium, and many more have been in use for the synthesis of annulated heterocycles [14]. This study discusses the synthesis of N-heterocyclic compounds in aqueous medium under different catalytic conditions.

3.2 Synthesis of nitrogen heterocycles Kumar and Maurya [15] synthesized Hantzsch esters or 1,4-dihydropyridine (4) and polyhydroquinoline derivatives (7) in aqueous micelles with PTSA as catalyst via Hantzsch pyridine synthesis. Figure 3.3 depicts a one-pot multicomponent reaction (MCR) involving β-keto ester like ethyl acetoacetate, an aldehyde like formaldehyde, and a nitrogen donor like ammonium acetate or ammonia. Here, ultrasonic radiations are used, which produced more yield in less time than that of the traditional way. Fewer side products, excellent yields, shorter reaction times, and milder reaction conditions are some significant advantages of this approach. Furthermore, no column purification was necessary. Using a straightforward and efficient method, Kidwai et al. [16] produced a library of coumarin-fused isoxazoles, pyrazoles, and pyrimidine derivatives. Under microwave irradiation, aryl aldehydes were first condensed with 4-hydroxycoumarin in aqueous medium to produce 3-arylidene chromane-diones (9). In the second step, cyclocondensation of (9) with the nucleophiles (NH2-G) such as urea, hydrazine, hydroxylamine hydrochloride, and thiourea took place to yield dihydrochromeno isoxazol-4-ones (10), pyrazol-4-

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Figure 3.3: Synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives.

ones (11), and 4-substituted-tetrahydro-benzopyranopyrimidine-2,5-diones (12) (Figure 3.4). Under an environmentally friendly solvent system and mild reactions with very few or no side products, all the produced derivatives were obtained in excellent yield.

Figure 3.4: Synthesis of coumarin-fused pyrazoles, isoxazoles, and pyrimidine derivatives.

Fan et al. [17] developed a practical and green strategy for the preparation of pyranopyridone and pyranopyran derivatives (14). Figure 3.5 depicts a one-pot three-component reaction of aldehyde, 4-hydroxy-pyridinone or 4-hydroxy-pyranone (13), and malononitrile

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mediated by an ionic liquid. The reaction proceeded via Knoevenagel condensation and Michael addition reaction processes. A series of pyrimidine nucleoside with 2-pyranone or pyridinone hybrids have been obtained, and their in silico evaluation as potential antiviral and antileishmanial agents was done.

Figure 3.5: Preparation of pyridinone or 2-pyranone hybrids.

Vaccaro and coworkers [18] carried out the aza-Diels–Alder reaction of N-benzylidene aniline (15) and Danishefsky’s diene (16) in the presence of a catalytic amount of copper(II) triflate-sodium dodecyl sulfate [Cu(OTf)2-SDS] in acidic aqueous medium. This Lewis acid–surfactant-combined catalyst worked well in aqueous medium at pH 4.0. All the derivatives of compound (17) were obtained in good yields, 84–95% (Figure 3.6). The catalyst was recovered from the reaction mixture after usual workup and reused further with no loss in efficacy.

Figure 3.6: Synthesis of diphenyl-2,3-dihydro-4-pyridones.

Das and coworkers [19] developed an efficient, mild, and product-specific MCR protocol in aqueous medium catalyzed by glacial acetic acid under reflux conditions (Figure 3.7). The benzylpyrazolyl coumarin derivatives (18) were obtained in excellent yields without tedious purification procedure. Zonouz et al. [20] designed a mild, efficient, and eco-friendly MCR for the synthesis of dihydropyrano[2,3-c]pyrazole carboxylates (20) in aqueous medium under catalyst-free conditions. In this strategy, one-pot MCR of dimethyl acetylenedicarboxylate

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Figure 3.7: Preparation of benzylpyrazolyl coumarins.

Figure 3.8: Preparation of dihydropyranopyrazole-3-carboxylates.

(19), hydrazine hydrate, malononitrile, and aromatic aldehydes was carried out in water to afford the target compound (Figure 3.8). This method is atom-economic, high yielding, and does not require column chromatography purification. Das et al. [21] synthesized a library of trisubstituted imidazoles (22) by the reaction of benzil (21) with ammonium acetate and aldehydes in aqueous media in the presence of DBSA as the catalyst under reflux conditions as depicted in Figure 3.9. 1,2,4,5-Tetrasubstituted imidazoles (24) were also synthesized by the same reaction by using an additional amine. All the derivatives were obtained in excellent yields. Good yields were obtained with aromatic aldehydes with the corresponding imidazole; however, with aliphatic aldehydes lesser yields were obtained. Figure 3.10 shows the mechanistic pathway for the formation of trisubstituted and tetrasubstituted imidazole, where aryl aldehyde first reacts with ammonium acetate to form diamine which further under condensation with benzil (diketone) gives the imidazoles. Babazadeh and his group [22] reported a versatile and eco-friendly multicomponent synthesis of benzoxazepine (25) and malonamide derivatives (24) using nanohybrid catalyst. A highly efficient, recyclable, nontoxic, and magnetic inorganic–organic nanohybrid catalyst (HPA/N‐[3‐(triethoxysilyl)propyl]isonicotinamide (TPI)–Fe3O4 NPs) was designed. This nanohybrid catalyst was prepared by the surface modification of Fe3O4 NPs by the chemical anchoring of H6P2W18O62 with the help of TPI as linker. This catalyst was recovered easily by magnets and recycled ten times with no loss of efficacy (Figure 3.11).

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Figure 3.9: Preparation of trisubstituted and tetrasubstituted imidazoles.

Figure 3.10: Plausible mechanism for the synthesis of trisubstituted and tetrasubstituted imidazoles.

Figure 3.11: Preparation of malonamide and tetrahydrobenzo[1,4]oxazepane.

An aqueous-mediated metal-free TEMPO-catalyzed cycloaddition of organic azides with electron-deficient internal olefins was developed by Elangovan and coworkers [23]. This is a simple strategy (Figure 3.12) for the preparation of disubstituted and trisubstituted triazoles (26). Among all the reaction conditions and solvent systems used, the best oxidant is TEMPO, co-oxidant is O2, and solvent is water. This method is compatible with open-chain olefins as well as with cyclic olefins. It is a metal-free watermediated reaction that worked well with aryl, aliphatic, and benzyl azides.

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Figure 3.12: Preparation of substituted triazoles.

Pardeshi et al. [24] investigated the use of manganese(II) chloride as an effective catalyst for the synthesis of indolyl-diphenylpropan-1-ones (29) in good yields using aqueous reaction medium under microwave radiations. Manganese chloride (MnCl2·4H2O) is an easily available, cost-effective Lewis acid which is easy to handle and insensitive to air and moisture. This catalyst promoted water-mediated reaction of various chalcones (28) with indole (27), yielding the desired product in excellent yields (Figure 3.13). This strategy avoids the use of highly toxic organic solvents, and the developed method was simple and cost-effective.

Figure 3.13: Preparation of 3-indolyl-diphenylpropan-1-ones.

Polystyrene-supported DABCO ionic liquid ([P-DABCO]Cl) was used as green catalyst by Xu and his group [25] for the preparation of spiro[2-amino-4H-pyrans] via one-pot MCR. As shown in Figure 3.14, isatin (30), malononitrile, and dimedone were reacted at ambient conditions in 25 min for the synthesis of final product (31). Two consecutive reactions such as Knoevenagel condensation and Michael addition reactions took place to give the final product in good yield (Figure 3.15). This method is very simple, and no chromatographic purification was required. Shankar and his group [26] described an eco-friendly approach for the preparation of iodo-triazoles (33), iodo-imidazopyridines (34), and iodo-benzoimidazothiazoles (35) in water catalyzed by CuI/β-CD (β-cyclodextrin) as shown in Figure 3.16. High regioselectivity and in situ generation of 1-iodoalkyne and alkyl/aryl azide under mild reaction conditions are some significant characteristics of this methodology. Molecular docking

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Figure 3.14: Synthesis of spiro[2-amino-4H-pyrans].

Figure 3.15: Stepwise mechanism showing synthesis of spiro[2-amino-4H-pyrans].

studies showed the role of β-CDs in the reaction. CuI/β-CD catalytic system is best suited in aqueous-mediated reaction. A green and eco-friendly one-pot cascade approach of dihydropyrimidine-thione derivatives (36) was accomplished by Thriveni and coworkers [27] in excellent yields. Figure 3.17 shows that DBU catalyzed the reaction of aromatic ketone, aromatic aldehydes, and thiourea in aqueous ethanol to form the desired products in excellent yields. Figure 3.18 shows the mechanism of the reaction in which DBU is catalyzing the reaction through generation of nucleophilic center in aryl ketones. Nucleophilic

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Figure 3.16: Schematic representation of synthesis of iodobenzoimidazole derivatives.

ketones further undergo nucleophilic addition reaction with aryl aldehydes and produce intermediate A. This intermediate reacts with activated thiourea via 1,4-addition reaction to give the final product. All the derivatives were characterized by various spectrometric techniques like FTIR and NMR.

Figure 3.17: Synthesis of dihydropyrimidine-thione.

Larijani and coworkers [28] prepared a novel series of dihydropyranoquinoline derivatives (39) and examined them for their in vitro inhibitory potential for α-glucosidase. The systematic route to achieve the desired derivatives is outlined in Figure 3.19. Initially, benzoquinolinone (38) was obtained by reacting naphthyl amine (37) and malonic acid in the presence of catalytic amount of PPA. Then the resulted derivative was treated with malononitrile and aryl aldehydes using L-proline in ethanol to produce the final products in excellent yields (80–90%). All the synthesized derivatives have shown good antidiabetic inhibitory activity; however, chloro- and fluoro-derivatives have been found to show maximum activity. Cytotoxicity studies done on breast cancer cell lines showed no toxic effects on cells. Jadhav et al. [29] designed and synthesized a library of azlactones or 4-arylidene-2phenyl-5(4H)-oxazolones (41) in an eco-friendly way. This reaction was catalyzed by acetic anhydride and base under reflux condition. Reaction of hippuric acid (40) with

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Figure 3.18: Catalytic pathway for the preparation of dihydropyrimidine-thione.

Figure 3.19: Preparation of dihydropyrano[3,2-c]quinoline.

various aldehydes catalyzed by sodium acetate and catalytic amount of acetic anhydride in a combination of water and ethanol as green solvent gave good yields of the products (Figure 3.20). Aromatic aldehydes without substitution and with electronwithdrawing group gave excellent yield in comparison to other aldehydes containing electron-donating groups. Figure 3.21 depicted the stepwise mechanism of the formation of arylidene-oxazolones.

Figure 3.20: Synthesis of a series of arylidene-oxazolones.

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Figure 3.21: The proposed mechanism for synthesis of arylidene-oxazolones.

A group of N-heterocycles like substituted quinolines (42), acridines (43), and 1,8naphthyridines (44) was prepared by Kundu and coworkers [30] via water-mediated reaction. Ortho-Amino benzylalcohols reacted with other alcohols in the presence of water-soluble iridium complex as the catalyst (Figure 3.22).

Figure 3.22: Synthesis of N-heterocyclic-substituted quinolines, acridines, and naphthyridines.

Siddiqui and coworkers [31] introduced a simple and highly feasible method for this one-pot multicomponent synthesis of polysubstituted aminopyrroles (45). Figure 3.23 shows that glyoxal monohydrate derivative on reacting with anilines, coumarin derivatives, and malononitrile in the presence of meglumine as catalyst at 65 °C gave the designed product. Meglumine is a biodegradable and inexpensive recyclable catalyst. Meglumine is a sugar alcohol derived from sorbitol with amino group. It possesses many primary and secondary hydroxyl groups that can activate the electrophilic as

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well as nucleophilic components of the substrate either by hydrogen bonding or donation of lone pair of electrons. Use of green solvent, cost-effectiveness, and easy workup are the main features of reported strategy. Figure 3.24 shows the role of meglumine in the formation of polysubstituted-2-aminopyrroles.

Figure 3.23: Synthesis of polysubstituted 2-aminopyrroles.

Figure 3.24: Proposed mechanism for the preparation of polysubstituted 2-aminopyrroles.

A library of eight new spiro-dihydro‐indolone‐amino‐4‐tetrahydro‐quinazoline‐diones (46) was developed by Abdolmohammadi et al. [32] through MCRs of isatin, guanidine nitrate, and cyclohexanediones. His group used Kit‐6 mesoporous silica-coated Fe3O4 NPs (Fe3O4@SiO2@KIT‐6) as a nanocatalyst in aqueous media at 60 °C. Short reaction time, magnetically separable catalyst, easy workup procedure, use of recyclable catalyst, and high yield of products are some eco-friendly features of this developed methodology (Figure 3.25). A library of dihydropyrano[2,3-c]pyrazol-6-amines (47) was developed by Pasha and his group [33] via single-pot four-component reaction in aqueous medium. NaHSO4 catalyzed the reaction of aryl aldehyde, ethylacetoacetate, phenylacetonitrile, and hydrazine hydrate in ethanol–water system under reflux and gave the final products in good yield as depicted in Figure 3.26.

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Figure 3.25: Synthesis of spiro-tetrahydro-quinazoline-diones.

Figure 3.26: Preparation of dihydropyranopyrazol-6-amines.

3.3 Conclusions Nitrogen-heterocyclic compounds have played a major role in pharmaceutical industry. The major part of organic chemistry is occupied by N-heterocycles. There are numerous reports on biological properties of naturally derived N-heterocycles. These heterocyclic compounds have been synthesized in various ways through various strategies. A plethora of reports are there on synthesis of N-heterocyclic compounds, and their bioactivity is evaluated through in silico and in vitro studies. Most synthetic strategies are based on the use of organic solvents, metal catalysts, and strong bases or acids, for long time duration and at high temperature. Some more drawbacks of these reactions are tedious separation and purification procedures, more by-product formation, less atom economy, and so on. To overcome these adversaries’ reaction conditions based on principles of green chemistry has been developed such as the use of aqueous media, recyclable catalyst, and easy workup. In this report, data is compiled on aqueous-mediated synthesis of N-heterocyclic compounds under green conditions. One-pot MCR, microwave-assisted reaction, click reaction, and cycloaddition reaction are the methods reported in this study to synthesize the target compounds. Microwave-assisted reactions are observed to be more efficient and faster in the synthesis of N-heterocycles as compared to conventional methods.

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[20] Zonouz AM, Eskandari I, Khavasi HR. A green and convenient approach for the synthesis of methyl 6-amino-5-cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates via a one-pot, multicomponent reaction in water. Tetrahedron Lett 2012, 53, 5519–5522. [21] Das B, Kashanna J, Kumar RA, Jangili P. Synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles in water using p-dodecylbenzenesulfonic acid as catalyst. Monatsh Chem 2013, 144, 223–226. [22] Vessally E, Hosseinzadeh-Khanmiri R, Babazadeh M, Ghorbani-Kalhor E, Edjlali L. Environmentally friendly and highly efficient synthesis of benzoxazepine and malonamide derivatives using HPA/TPI‐ Fe3O4 nanoparticles as recoverable catalyst in aqueous media. Appl Organometal Chem 2016, 31(5), e3603. [23] Gangaprasad D, Raj JP, Kiranmye T, Karthikeyan K, Elangovan J. A new example of organo click reactions: Tempo-promoted oxidative azide-olefin cycloaddition for the synthesis of 1,2,3-triazoles in water. Eur J Org Chem 2016, 34, 5642–5646. [24] Jadhav SA, Mane DV, Shinde DB, Pardeshi RK. Manganese chloride catalysed synthesis of 3-(1h-indol-3yl)-1,3-diphenylpropan-1-ones in water under microwave irradiation method. Heterocycl Lett 2016, 6(2), 383–388. [25] Huang L-S, Hu X, Yu Y-Q, Xu D-Z. Highly efficient heterogeneous catalytic synthesis of densely functionalized 2-amino-4h-pyrans under mild condition in aqueous media. ChemistrySelect 2017, 2, 11790–11794. [26] Dheer D, Rawal RK, Singh V, Sangwan PL, Das P, Shankar R. β-CD/CuI catalysed regioselective synthesis of iodo substituted 1,2,3-triazoles, imidazo[1,2-a]-pyridines and benzoimidazo[2,1-b] thiazoles in water and their functionalization. Tetrahedron 2017, 73, 4295–4306. [27] Sekhar T, Thriveni P, Harikrishna M, Murali K. One-pot synthesis of 3,4-dihydropyrimidine-2(1h)thione derivatives using DBU as green and recyclable catalyst. Asian J Chem 2018, 30(6), 1243–1246. [28] Nikookar H, Mohammadi-Khanaposhtani M, Imanparast S, Faramarzi MA, Ranjbar PR, Mahdavi M, Larijani B. Design, synthesis and in vitro α-glucosidase inhibition of novel dihydropyrano[3,2-c] quinoline derivatives as potential anti-diabetic agents. Bioorg Chem 2018, 77, 280–286. [29] Jadhav SA, Mazahar F, Pardeshi RK. An ecofriendly synthesis of biologically active 4-arylidene-2phenyl-oxazolones at conventional method. Int J Univers Print 2018, 4(2), 100–106. [30] Maji M, Chakrabarti K, Panja D, Kundu S. Sustainable synthesis of N-heterocycles in water using alcohols following the double dehydrogenation strategy. J Catal 2019, 373, 93–102. [31] Yadav VB, Yadav N, Rai P, Ansari MD, Kumar A, Verma A, Siddiqui IR. Meglumine promoted strategy: Environmentally benign protocol towards the synthesis of polysubstituted 2-aminopyrroles in aqueous condition. ChemistrySelect 2019, 4, 5376–5380. [32] Abdolmohammadi S, Shariati S, Fard NE, Samani A. Aqueous‐mediated green synthesis of novel spiro[indole-quinazoline] derivatives using kit‐6 mesoporous silica coated Fe3O4 nanoparticles as catalyst. J Heterocycl Chem 2020, 57(7), 2729–2737. [33] Azzam SHS, Siddekha A, Pasha MA. Green, rapid, simple, and an effective one-pot multicomponent strategy for synthesis of novel dihydropyrano[2,3-c]pyrazol-6-amines in aqueous medium. Univers J Pharm Res 2020, 5(2), 16–22.

Asim Kumar, Nirjhar Saha, Soumili Biswas, and Asit K. Chakraborti✶

Chapter 4 Catalyst-free synthesis of monocyclic heterocycles in aqueous medium: a sustainable approach 4.1 Introduction Heterocyclic compounds and their derivatives have versatile applications in various fields of science, and in particular in the practice of drug design and discovery [1]. Monocyclic heterocyclic systems (e.g., azirine, oxirene, pyrrole, pyridine, furan, pyran, azoles, thiophene, and diazepines) are integral structural components of several bioactive molecules such as anticancer [2], antimicrobial [3–5], antihyperlipidemic [6], antihypertensive [7], anti-inflammatory [8, 9], and antifungal [10] agents, and kinase inhibitors [11] (Figure 4.1). Therefore, synthesis of these heterocycles is a perpetually evolving domain of research to synthetic organic/medicinal chemists, owing to their diverse properties and applications [12, 13]. The burgeoning issue of the twenty-first century is to devise synthetic strategies that are greener, atom economical, less polluting, and sustainable both in the context of economy and environmental aspects. Therefore, it is highly imperative to work upon environmentally benign approaches toward the synthesis of these heterocycles. Watermediated organic reactions have shown lots of promise in attaining some of the goals toward achieving sustainability. It offers several advantages, owing to its innocuous nature and favorable physicochemical properties. Water fits well in the category of green solvent and is largely regarded as nature’s reaction media. The ease of separation of the product from the reaction media is one of the distinct advantages offered by water. Various literature reports established that apart from being a sustainable reaction media, water also accelerates the rate of chemical reactions and modulates their selectivity [14]. Different research groups across the globe propounded various theories regarding water-mediated synthetic transformations such as “on water” [15–18], “in water” [19], and “both on water Acknowledgments: 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 700032, West Bengal, India, emails: [email protected], [email protected] Asim Kumar, Amity Institute of Pharmacy, Amity University Haryana, Manesar 122413, India Nirjhar Saha, School of Chemical Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700032, West Bengal, India Soumili Biswas, School of Biological Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700032, West Bengal, India https://doi.org/10.1515/9783110985627-004

Figure 4.1: Drug molecules containing monocyclic heterocycles.

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and in water” [20]. Toward this objective, our research group has delved into the understanding of molecular-level interaction of the substrates with water that would further rationally promote the use of water as reaction medium and has proposed some unique supramolecular assemblies involving the reactants and water molecules for water-promoted organic reactions. We have envisaged “electrophile–nucleophile dual activation” via a cooperative hydrogen bond (HB) network [21–23] and “cooperative HB-assisted ambiphilic (electrophile–nucleophile) activation by water” [24–27] that formed the basis of devising novel “all-water” chemistries [24–26] for the synthesis of bioactive heterocyclic scaffolds [24, 25] and total synthesis of drugs [26, 27]. The immiscibility (lack of solubility) of organic compounds in water is often considered as a detrimental factor in carrying out organic reactions in aqueous medium. To circumvent this problem, the use of surfactants has been invoked and is a common practice in performing organic synthesis in water. In this context, surfactant-assisted synthesis of bioactive heterocycles in aqueous medium has been achieved by our group [28]. However, the role of surfactant in aquatic organic synthesis may not be limited to a mere solubility enhancer and it has been proposed by our group to look beyond through invoking new role of the surfactant such as transition metalfree nonheme model of dioxygen activation for green oxidation under aerobic condition in aqueous medium [29]. The importance of water-mediated synthetic transformations particularly for the synthesis of heterocycles could be well realized by the growing number of research publications pertaining to this topic. This chapter focuses on and summarizes some of the notable literature reports on water-mediated synthesis of monocyclic heterocycles.

4.2 Classification of monocyclic heterocycles The monocyclic heterocycles can be classified according to their ring sizes such as three-, four-, five-, six-, seven-, eight-, and nine-membered heterocycles wherein the heteroatom(s) is(are) present in a single ring. The representative examples of each class are provided in Figure 4.2. These can further be categorized as saturated/nonaromatic and unsaturated/heteroaromatic monocyclic heterocycles. Besides these classifications, depending upon the number of heteroatoms present in the ring, the monocyclic heterocycles can be grouped into mono-, bis-, tri-, and multi-heteroatomic monocyclic heterocycles.

4.3 Classical/traditional methods for the synthesis of monocyclic heterocycles The most common method of synthesis of some of the heterocycles such as substituted furan (4), pyrrole (3), and thiophene (2) is Paal–Knorr synthesis [30]. This reaction is

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well explored, and various literatures have been produced pertaining to their modifications over the years [31]. Mechanistic details of Paal–Knorr synthesis are depicted in Figure 4.3. It involves intramolecular condensation reaction involving a 1,4-dicarbonyl compound (1) with an excess of nucleophilic source such as amine (for pyrrole) and thiols or Lawesson’s reagent (for thiophene). The synthesis of furan involves acidcatalyzed cyclocondensation process. Commercial preparation of furan, on the other hand, could be carried out by heating a pentose derivative (5) generating furfural intermediate which on further heating with copper oxide in the presence of oxygen generates the furan ring. Synthesis of imidazole (9) involves a condensation reaction between glyoxal (6), aldehyde (7), and ammonia (8). Synthesis of oxazole (12) occurs by the reaction of α-hydroxyketone (10) with amide (11). However, these synthetic strategies involve metal catalysts, Lewis acid, which require large amount of organic solvents and are associated with the generation of wastes that are detrimental to the environment. Therefore, greener and atom-economical methodologies that would have reduced adverse impact on the environment need to be developed and are in high demand.

4.3.1 Robinson–Gabriel synthesis of oxazole One of the widely used procedures of intramolecular cyclocondensation of α-acylamino ketone (13) to construct the oxazole ring (12) is known as Robinson–Gabriel synthesis [32, 33]. This reaction is particularly used for the synthesis of 2,5-diaryloxazoles. The keto-enol tautomerism can facilitate the nucleophilic addition of oxygen to the amide carbonyl, followed by dehydration to form the oxazoles (12) (Path a). In another pathway, the amide iminol tautomerism favors the nucleophilic addition of amidic oxygen anion to the electrophilic ketone carbonyl group, followed by dehydration to form the desired oxazoles (12) (Path b) (Figure 4.4). The reactions performed with O18-labeled substrates suggest the mechanistic operation via Path b [34].

4.3.2 Biginelli reaction The multicomponent reaction (MCR) strategy [35–40] is the most prevalent synthetic route for the construction of diverse heterocycles [41–43] and acyclic compounds that exhibit biological activities [44–46]. The Biginelli reaction is one of the most popular methods for the construction of six-membered N-heterocyclic system having two ring nitrogen in 1,3-position known as pyrimidine core. The dihydropyrimidinones/thiones (16) were synthesized using the Biginelli reaction approach which is one-pot domino MCR of aldehydes (7), 1,3-diketones (14) and ureas/thioureas (15). Various metal-catalyzed [47, 48], metal-free [49–51], metal and solvent-free [52, 53], homogeneous [54, 55] and heterogeneous [56–58] catalysis approaches have been reported. The reaction starts with the imine formation (15a) by the reaction of one of

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Figure 4.2: Classification and examples of monocyclic heterocyclic systems.

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Figure 4.3: Classical/traditional approaches for the synthesis of five-membered heterocycles.

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Figure 4.4: Robinson–Gabriel synthesis of oxazole.

the amino groups of urea/thiourea (15) with the aldehydes (7), and the subsequent reaction of 15a with the 1,3-diketo compounds (14) furnishes the enaminone intermediate (15b). The imine–enamine tautomerism makes the α-carbon more nucleophilic favoring the cyclization step to form 16 (Figure 4.5).

Figure 4.5: Biginelli reaction.

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4.3.3 Hantzsch dihydropyridine synthesis The MCR of aldehyde (7) and a β-ketoester (17) in an aqueous ammonium hydroxide solution (ammonia source) (18) was carried out to synthesize the dialkyl 1,4-dihydro -2,6-dimethylpyridine-3,5-dicarboxylates (19) for the first time in 1882 (Figure 4.6) by Hantzsch [59]. During the progress of the reaction, initially, the aldehyde (7) reacts with the β-ketoester (17) via Knoevenagel condensation like approach to form the corresponding carbinol intermediate (17a). In a parallel route, the reaction between the ammonia (18) and the β-ketoester generates the enaminone (17b). In the final step, the condensation between the enaminone and the carbinol intermediate followed by cyclization produces the desired 1,4-DHP (19) (Figure 4.6).

4.3.4 Pyridine synthesis In 1957, Bohlmann and Rahtz [60] reported for the first time a two-step synthesis of trisubstituted pyridines (22) by performing the reaction of enamines (20) with ethynyl

Figure 4.6: Hantzsch dihydropyridine synthesis.

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ketones (21) or with aldehydes. Regioselective condensation of 1-phenyl-2-propyn-1one or propargylic aldehyde (21) with ethyl β-aminocrotonate or β-aminocrotonitrile or 2-amino-2-penten-4-one (20) furnishes the desired pyridine esters (22). The reaction proceeds via Michael addition of 20b to ynones generating the intermediate 20d which is separated and purified (Figure 4.7). The diene E/Z isomerization is facilitated by heating the intermediate to 120–170 °C and finally spontaneous cyclodehydration results in the formation of 2,3,6-trisubstituted pyridines (22) in very good yields (Figure 4.7).

Figure 4.7: Bohlmann–Rahtz pyridine synthesis.

The pioneering work of Bohlmann and Rahtz opened the doors for various approaches for the construction of the pyridine heterocycle, and the recent past has witnessed efforts directed toward the construction of pyridine ring system. In this context, our group reported the domino MCR strategy and understood the detailed catalytic pathways for constructing the pyridine core [61] from easy-to-access intermediates [62–64].

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4.4 Sustainable approaches for synthesis of monocyclic heterocycles Most of the classical/conventional heterocycle synthesis appear to be non-environment friendly and are not sustainable processes as these are often associated with the use of toxic and hazardous solvents [65–71], higher reaction temperature (requirement of more energy) [71, 72], utilization of costly and rare earth metal catalysts [73–80], longer reaction time [81–84], lower atom economy [85, 86], and large amount of waste production [87–90]. In order to avoid the detrimental effects of academia and industrial research activities on the environment and public health, the necessity for sustainable practices of organic synthesis has been realized and is mandated by the regulatory authority such as the United States Environmental Protection Agency (US EPA). During organic synthesis, the sustainability can be implemented in the designing reaction protocols by (i) application of heterogeneous catalysis instead of homogeneous catalysis as the recycling of the heterogeneous catalysts is more feasible, (ii) performing the reactions promoted by organocatalysts in place of metal catalysts, (iii) utilizing nonconventional energy sources, (iv) modifying the synthetic reaction approaches such as adopting the MCR strategy which require less reaction steps, supporting higher atom economy, and (v) utilizing environmentally benign reaction media in place of toxic solvents. Organic solvents are needed as reaction media to solubilize all the reaction components in single phase. Volatile organic compounds and cytotoxic solvents are the potential threats to the environment as well as human health. In order to address the hazardous effects of the toxic and volatile solvents, the benign reaction media was picked up as a sustainable tool for the synthesis of heterocycles. The popular approach to avoid/minimize the hazardous effects of the solvents is to carry out the reactions under neat condition either by classical heating, which was chosen as a sustainable approach for the synthesis of heterocycles [91–95]. However, this approach suffers from practical disadvantages such as discontinuation of magnetic stirring due to the nonhomogeneity of the reaction mixture and transfer of the crude product from one vial to another without dissolving it with organic solvents. Therefore, various green solvents such as ethanol [96, 97], polyethylene glycol [98–100], isopropanol [101], fluorinated alcohols (TFE and HFIP) [102–105], biomass-derived solvents [106–108], supercritical fluids [109], deep eutectic mixtures [110–113], water [114, 115], and ionic liquids (ILs) [116–119] were opted for the sustainable synthesis of various heterocycles (Figure 4.8). With the growing interest and compelling need for sustainable and greener approaches that utilize environmentally benign principles, it was being felt to devise greener and more efficient catalyst system for various organic reactions. In this context, heterogeneous catalysis is preferred over homogeneous catalysis. Heterogeneous catalysts can be recycled by filtration or magnetic separation for reuse in the next cycles of reactions [120]. Clays, zeolites, and silica are popular heterogeneous catalysts introduced for green catalytic procedures and find applications in promoting organic reactions including those involved in the

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synthesis of pharmaceuticals [121–124]. In pursuit of sustainable organic synthesis, our group has invented two highly efficient and easy to prepare heterogeneous catalysts namely HClO4–SiO2 [125] and HBF4–SiO2 [126, 127] that find applications to promote various organic reactions [128–133] as well as in the synthesis of prodrugs [134, 135] and heterocycles [136, 137], and have drawn attention of other research groups globally for uses of these catalysts in organic synthesis. Catalysis by metal nanoparticles has emerged as a new addition to the sustainable synthetic chemistry toolbox as it offers the benefits of the homogeneous and heterogeneous catalysts with additional synergistic effect in case of bimetallic nanoparticles and find applications in various organic reactions that include the construction and functionalization of heterocycle, preparation of pharmaceuticals, and generation of new therapeutic agents [138–144]. Metal nanoparticle-catalyzed reactions [145–149], solid phase synthesis [150–153] and catalyst (metal and/or organocatalyst) supported on solid template through a linker moiety [154–156] belong to heterogeneous catalysis approach for the synthesis of monocyclic heterocycles (Figure 4.8). Transition metal and alkali metal salts were vigorously explored by the synthetic chemists to activate the electrophilic or nucleophilic moiety of the reactants for the synthesis of monocyclic heterocycles [62, 157–165]. Presence of trace amount of metal in the purified product may alter the bioactivity results due to the chelation of the metal with the amino acids of the target enzyme. Hence, in the practice of synthesizing bioactive heterocycles, metal-catalyzed reactions are replaced with organocatalyst-promoted synthesis of heterocycles. Being capable of interacting with the reactants through H-bonding, various amino acids (e.g., proline) [166–168] and urea analogues (e.g., urea, thiourea, and guanidine) [169–171] act as organocatalysts in the synthesis of monocyclic heterocycles. Enzymes can also catalyze the organic reactions through its active site (Figure 4.8) [172–175]. Organocatalysts contribute to sustainable development as they can be designed as electrophile activator or electrophile–nucleophile dual activator to promote various organic reactions [176–179] and can also be used in MCR process for the synthesis of heterocycles [180]. In this context, the supramolecular organocatalysis through HB and charge–charge-assisted electrophile–nucleophile dual activation opens up new horizon for sustainable organic synthesis using ILs, popular as alternative nonconventional reaction media, as it promotes the non-solvent uses of ILs [181–184] and avoid the potential drawbacks associated with their uses in large quantities. Organocatalysis by ILs can be utilized for heterocyclic synthesis via MCR approach [185]. The HB-assisted acceleration of reaction rates also leads to design non-solvent applications of the fluorous alcohols (TFE and HFIP) in the regiocontrolled synthesis of heterocycles [186]. Most of the organic syntheses are performed under conventional heating such as oil or water bath heating. Reactions performed under nonconventional energy sources (e.g., microwave irradiation [187, 188], ultrasonic irradiation [189–192], ultraviolet irradiation [193], visible light [194–196], and ball milling [197–199]) have distinct advantages over conventional heating as follows: (i) these reactions require shorter reaction time, lower reaction temperature, less amount of solvents, lower catalyst loading, or catalyst-

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free conditions and less consumption of energy; and (ii) these reactions are more atomeconomical process with higher yield of the product. These mentioned advantages add sustainable features to the synthesis. The microwave-assisted acceleration of organic reactions is an effective tool for sustainable organic synthesis and is in practice in performing various organic reactions and heterocycle synthesis [200–206]. Discovery of an efficient and sustainable approach to carry out organic synthesis is a significant aspect on the scientific skill of synthetic organic chemists, which is required for conversion of a nonsustainable methodology to sustainable methodology. For example, multicomponent and one-pot reaction protocols for heterocycle synthesis [207–209] are more sustainable than multistep reactions due to requirement of less time, less consumption of energy, and less workup purification steps. Metal-free approaches always receive the distinct attention in the sustainable heterocycle synthesis [210–213]. The C–H activation strategy is the sustainable alternative to the classical cross-coupling reactions as it does not require pre-functionalization of the reactant and increases the atom economy of the process. Various C–H activation approaches were adopted for the synthesis of heterocycles (Figure 4.8) [214, 215]. Flow chemistry, an emerging field in sustainable organic synthesis, plays a key role in the synthesis of heterocycles and also in drug discovery [216, 217]. This sustainable technology is more advantageous than the conventional synthetic operations in terms of high selectivity, greater mass and energy transfer, higher yield of the products, and reduced energy consumption. Till now, the synthesis of monocyclic heterocycles has been reported in aqueous medium in the presence of catalyst [218–222], in water–surfactant media [223–230], and exclusively in water [231–234]. In the quest of sustainable approaches for the synthesis of monocyclic heterocycles, this chapter focuses on the literature reports on the use of water as benign reaction media for the purpose and underlines the role of water.

4.5 Synthesis of monocyclic heterocycles in aqueous media 4.5.1 Four-membered heterocycles The N-substituted azetidines (24) were synthesized via microwave-assisted cyclization of 3-(ammonio)propyl sulfates (23) in water (used as solvent). The starting compound 23 was obtained by the reaction of primary amines with the cyclic sulfate of 1,3-propanediol (Figure 4.9) [235]. Application of microwave irradiation as energy source, use of water as the reaction medium, and shorter reaction time demonstrate the sustainability of this synthetic protocol compared to other methodologies of azetidine synthesis.

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Figure 4.8: Sustainable approaches for synthesis of monocyclic heterocycles.

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Figure 4.9: Microwave-assisted synthesis of N-substituted azetidines (24) in water.

4.5.2 Five-membered heterocycles The five-membered heterocycles such as oxazole, thiazole, imidazole, and pyrazole are present in various bioactive heterocycles. For example, furan, pyrrole, and thiophene are very unique in the sense that they exhibit aromaticity which imparts stability. In each of these heteroaromatic compounds, at least one pair of lone electrons undergoes resonance with the π-electrons of the ring thereby producing the aromatic sextet of electrons. At the same time, this makes the heteroatom to adopt sp2 hybridization. The aromatic character makes these heterocycles reactive toward electrophilic substitution reaction. The dipole moments for pyrrole, furan, and thiophene are 1.8 D, 0.7 D, and 0.5 D, respectively. The observed rate of reactivity toward electrophilic substitution reaction follows the order pyrrole ≫ furan > thiophene > benzene. Figure 4.10 outlines the resonating structures of five-membered heterocycles [236].

Figure 4.10: Resonating structures of some five-membered heterocycles.

The synthesis of five-membered heterocycles has been an attractive and important topic of research for the synthetic medicinal/organic chemists [237, 238]. The major bottlenecks associated with the classical synthetic strategies are the use of environmentally detrimental solvents, generation of hazardous wastes, requirement of large amount of energy, and lack of atom economy. Therefore, it is imperative to devise greener and environmentally benign approaches for the synthesis of five-membered heterocycles. Organic synthesis using water as the reaction medium is regarded as a greener approach as water is nontoxic, cheapest, and readily available.

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4.5.2.1 Synthesis of substituted pyrroles Duan et al. [239] devised a β-cyclodextrin (β-CD)-promoted synthesis of N-substituted pyrroles (3) by the Paal–Knorr reaction of γ-diketones (1) with amines (8) in aqueous medium. In this reaction, β-CD that acts as a supramolecular catalyst [240] was recovered after the reactions and reused subsequently with the catalytic activity largely being retained. Use of water as an innocuous reaction medium, recyclable β-cyclodextrin as the catalyst, high atom economy, and no generation of harmful waste are some of the greener aspects of the protocol. The proposed mechanism involves electrophilic activation of the carbonyl groups of 1 by β-CD through HB formation. Subsequently, the activated γ-diketones (1r) reacts with 8 to form the imine 1s, followed by intramolecular nucleophilic addition leading to cyclization–elimination process (via 1t and 1u) to form the desired N-substituted pyrroles (3) (Figure 4.11).

Figure 4.11: β-Cyclodextrin (β-CD)-promoted synthesis of pyrrole in aqueous medium.

Sharma et al. have reported a novel biobased material gluconic acid aqueous solution (GAAS) (23) that mediated Paal–Knorr synthesis of substituted pyrrole (3) (Figure 4.12). “GAAS” is a relatively greener, reusable, less toxic, and environmentally benign reaction medium. The protocol was utilized for the synthesis of various N-substituted 2,5dimethyl-pyrrole derivatives both under ultrasonication and without ultrasonication at room temperature with yield ranging from 87% to 97%. The reusability of GAAS as the reaction medium, its cost-effectiveness, excellent ability to promote the reaction, bio-based protocol, reaction at room temperature, and reaction rate acceleration via ultrasonication are some of the sustainable aspects [241].

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Figure 4.12: Bio-based GAAS-assisted Paal–Knorr synthesis of pyrrole in aqueous medium.

4.5.2.2 Synthesis of substituted pyrazole Savant et al. [242] developed a methodology for the preparation of trisubstituted pyrazole derivative (26) by a tandem condensation of the acylketene dithioacetals (24) with hydrazine hydrate (25) (Figure 4.13).

Figure 4.13: Synthesis of trisubstituted pyrazole under aqueous condition.

Marković and Joksović [243] devised a reaction methodology for the synthesis of substituted pyrazole derivative (29) from 4-aryl/hetaryl/alkyl-2,4-diketoesters (27) by condensation with semicarbazide hydrochloride (28) in water as reaction media (Figure 4.14).

Figure 4.14: Synthesis of substituted pyrazole under aqueous condition.

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4.5.2.3 Synthesis of substituted isoxazole Chary et al. have developed an aqueous polyethylene glycol-promoted 1,3-dipolar cycloaddition reaction for the synthesis of isoxazoles (31) and isoxazolines (32). The strategy involves the reaction between benzoylnitromethane/ethyl 2-nitroacetate (30) with terminal alkyne and alkenes (Figure 4.15). The greener aspects of the reaction are catalyst (base/acid)-free condition and the use of nonhazardous solvent [244].

Figure 4.15: Aqueous PEG-promoted synthesis of isoxazole via 1,3-dipolar cycloaddition.

Patil et al. devised a novel neoteric micellar medium prepared from the fruit extract of Averrhoa bilimbi and used for metal-free synthesis of isoxazol-5(4H)-one derivatives (35). The most important aspect of the reaction is the use of a greener natural acidic medium, that is, Averrhoa bilimbi extract (ABE). This ABE offers various advantages such as being nontoxic in nature, plant-based renewable origin, recyclability, nonhazardous in nature, minimum waste generation, economic viability, and ease of product isolation and purification without requirement of chromatographic separation. The critical micellar concentration was determined via DLS technique. Figure 4.16 enumerates the standardized reaction methodology [245].

Figure 4.16: Synthesis of isoxazole derivative using ABE-based neoteric micellar solution.

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4.5.2.4 Synthesis of other five-membered heterocycles Chanu et al. developed a methodology for the synthesis of ketene aminal or imidazolidine derivative (38). The reaction involves the treatment of electron-withdrawing group (EWG)-substituted ketene-S,S-acetals (36) with ethane 1,2-diamine (37). Various diamines and ketene-S,S-acetals containing diverse EWGs were tested but the best result occurs with the reaction of dicyano S,S-acetal with ethane 1,2-daimine (Figure 4.17) [246].

Figure 4.17: Synthesis of tetrahydroimidazole derivatives by the reaction of ketene-S,S-acetals with ethane-1,2-diamine in water.

Kumar et al. carried out the reaction of α-tosyloxy ketones (39) with amidines (40) for the synthesis of diaryl imidazoles (41) using water as the solvent (Figure 4.18). The protocol offers various advantages such as the use of water as sustainable reaction media, no use of any metal catalyst and corrosive organic solvents, and good product yields [247].

Figure 4.18: α-Tosyloxy-mediated synthesis of diaryl imidazole using water as solvent.

Ren et al. developed a novel method for the synthesis of trisubstituted furan derivatives (44). The protocol involves a tandem oxidative radical-mediated cycloaddition reaction of enynones (42) with arylsulfinic acids (43) in water under open air (that serves as an oxidant) to generate sulfonyl substituted furan derivative (Figure 4.19). The main advantages of the reaction are the use of water as innocuous reaction medium, air as oxidant, broad substrate versatility, and higher yield of the products. It was hypothesized that in the presence of air, a sulfinyl anion forms first followed by formation of sulfonyl radical. The sulfonyl radical attacks on enynones to generate

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Figure 4.19: Synthesis of trisubstituted furan via the reaction of enynones with aryl sulfinic acids in aqueous medium.

an enolate/(enol ether) radical, which undergoes an intramolecular cyclization by radical addition to generate trisubstituted furan (44). HRMS and EPR studies identified some of the radical species that have been proposed to be formed (Figure 4.20) [248].

Figure 4.20: Proposed radical pathway mechanism.

4.5.3 Six-membered heterocycles Ultrasound-assisted synthesis of substituted pyridine (47) was carried out in the presence of sodium chloride as an additive under aqueous condition. This MCR approach involves the reaction of aromatic aldehydes (33), malononitriles (45), and aromatic thiols (46) to construct the pyridine ring (47) [249]. The specific role of sodium chloride can be realized

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through chloride anion-assisted abstracts of the methylenic proton of malononitrile and makes it more nucleophilic favoring its addition to the aromatic aldehydes (the sodium cation, though less coordinating in nature, might also assist in activating the aldehyde). Condensation between 33a and 45a generates the α, β-unsaturated nitrile derivative (33b), which might form HB with water through the nitrogen atoms of the nitrile groups and in the process can be activated for Michael addition with the chloride anion-assisted deprotonated malononitrile anion 45a leading to 33c. The H-bonding with water and the nitrile groups activates the β-position of 33c and the chloride anion also might assist in abstraction of the SH proton of 46 facilitating the nucleophilic addition of thiols to the nitrile carbon followed by cyclization to furnish 33d. In the final step, oxidation/(dehydrogenative aromatization) of 33d generates 47 (Figure 4.21).

Figure 4.21: Ultrasound-assisted synthesis of pyridines in water.

Ferrocene-tethered pyridine (50) was synthesized by water-assisted MCR of aromatic aldehydes (33), nitriles (48), ferrocenyl ketones (49), and ammonium acetate [250]. The important role of water may be realized as follows. Initially, water activates the

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carbonyl group of 33 to favor the aldol-type condensation between 33 and 48 to form the acrylonitrile derivative 33f. In a parallel reaction, the imine (49a) or its tautomeric form (49b) is generated in situ by the reaction of 49 with ammonia (liberated from ammonium acetate). This is followed by Michael addition reaction between 33f and 49a that might be water promoted via activation of the Michael acceptor 33f (at βcarbon) for generation of the intermediate 33i. Finally, the intramolecular nucleophilic addition leading to cyclization of 33i followed by dehydrogenation generates the desired pyridine derivatives (50) (Figure 4.22).

Figure 4.22: One-pot MCR approach for the synthesis of pyridines in water.

Photocatalytic MCR of aldehydes (33), α-ketonitriles (51), and malononitriles (45) was achieved under LED light in aqueous medium for the synthesis of pyran derivatives (52) [251]. Photochemical abstraction of the methylenic proton of 45 via free radical mechanism in situ generates the corresponding ketimine intermediate 45a, which undergoes Knoevenagel condensation with aldehydes to furnish the α,β-unsaturated nitrile derivative 33k. LED light-promoted homolytic cleavage of the nitrile bond of 33k produces the iminic diradical 33l. In another simultaneous reaction, 51 is converted to its radical 51b via photocatalytic abstraction of H-radical from α-position by malononitrile radical. The radical coupling involving 51b and 33m in Michael-type addition fashion leads to the corresponding 33n intermediate. Tautomeric form of 33n undergoes cyclization to form the substituted pyrans 52 (Figure 4.23). Base-assisted MCR of aromatic aldehydes (33), malononitriles (45), and β-ketoesters (14) was performed under aqueous condition [252]. Base-catalyzed aldol-type reaction

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Figure 4.23: Photochemical MCR approach for the synthesis of pyrans in aqueous media.

between malononitrile anion and HB-activated aromatic aldehydes (33) generates the α, β-unsaturated nitrile derivative 45c, which interacts with water through H-bonding to escalate the electrophilicity of the β-carbon of the olefin. The deprotonated β-ketoester (14b) undergoes Michael addition reaction with 45d (the activated alkene) to generate the intermediate 14c, which cyclizes through its enolic form to afford the substituted pyrans 53 (Figure 4.24).

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Figure 4.24: Base-promoted synthesis of pyran derivatives in water.

The chemoselective and regioselective 4H-pyran (55) synthesis was achieved by performing the one-pot MCR of aldehydes (33), malononitrile (45), and ethyl acetoacetate (14) [253]. In the presence of sodium hydroxide used as base, the Knoevenagel condensation between aldehydes and malononitrile produces the α-cyanocinnamyl nitrile which further undergoes Michael addition reaction with ethyl acetoacetate (through its nucleophilic α-carbon) to generate the pre-cyclization intermediate 33q. Keto-enol tautomerism of 33q facilitates the nucleophilic cyclization through acetyl carbonyl oxygen to construct the desired 4H-pyrans. Replacement of water with alcohols leads to the corresponding pyridine derivative of pyran. It signifies that water has a role in the chemoselective pyran formation. In the case of alcohol, used as solvent [254], the nucleophilic addition of alcohol to the nitrile group and subsequent cyclization via nucleophilic addition of iminic nitrogen, generated from the nitrile, on the ester group generates the pyridine scaffold. In contrast, in the presence of water as solvent,

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the predominance of the enol form in water encourages the intramolecular nucleophilic addition by carbonyl oxygen of the enol on the nitrile group that is activated via HB with water, to furnish the pyran scaffold (Figure 4.25).

Figure 4.25: One-pot MCR approach for the synthesis of pyrans in water.

Ultrasound-promoted aqueous phase MCR involving kojic acid (56), malononitrile (45), and aromatic aldehyde (33) constructs the pyran moiety of 2-amino-4,8-dihydropyrano [3,2-b]pyran-3-carbonitrile (57) [255]. Though the original article does not divulge the mechanistic details, this MCR may proceed through two pathways depending upon the order of the reactants reacting initially. In pathway A, the aldol condensation between kojic acid and HB-activated aromatic aldehyde followed by Michael addition of malononitrile generates the intermediate 56b, which further undergoes intramolecular nucleophilic addition to the HB-activated nitrile group to afford the pyranopyran derivatives 57. In pathway B, the aldol-type condensation between malononitrile and HB-activated aromatic aldehyde followed by Michael addition of kojic acid furnishes the intermediate 33t (the keto form of 56b). The nitrile group of 33t undergoes electrophilic activation by Hbonding with water for the subsequent intramolecular nucleophilic attack by one of the carbonyl oxygens of the ortho-quinone moiety to the activated nitrile group (Figure 4.26). The advantages of this methodology are environmental friendliness, excellent yields, and no necessity of external base or metal Lewis acid. In the presence of water, the γ-keto quaternary ammonium chloride (58) was subjected to de-dimethyl amination reaction to synthesize the enones 58a via retro-azaMichael process (Figure 4.27). Water-assisted HB with the carbonyl oxygen makes β-carbon of the alkene more electrophilic. The bis-aza-Michael addition of the primary amine (8) to the β-carbon of two molecules of the in situ generated enones 58a generates the di-keto intermediate 58b, which undergoes cyclization through the liberated dimethyl amine-assisted enolization to form the 4-hydroxy piperidines (59) [256].

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Figure 4.26: Ultrasound-promoted MCR approach for construction of pyran moiety in water.

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Figure 4.27: Synthesis of pyran derivatives from quaternary amines in water.

Thiomorpholine-1,1-dioxide (61) was synthesized from the reaction of diethyl 2,2ʹsulfonyldiacetate (60), aromatic aldehydes (33), and ammonium acetate (as ammonia surrogate) [257]. The reaction is initiated with the water-assisted electrophile activation of the aldehyde which facilitates the reaction with ammonia for the corresponding imine (33x) formation. The iminic carbon in turn is also activated through H-bonding by water. The water-assisted keto-enol tautomerism of 60 makes the α-position more nucleophilic to react with the HB-activated imine 33x to generate the amine intermediate 60a. The primary amine group of 60a reacts with the activated aldehydes to provide the corresponding imines 60c, which undergo intramolecular nucleophilic addition by the α-carbon to form the desired product 61 (Figure 4.28). The one-pot tandem MCR between amines (8), carbon disulfide, arylglyoxals (62), and malononitrile (45) was carried out in aqueous ethanol as solvent at room temperature to synthesize thiazines (63) in good to excellent yields [258]. The reaction sequence starts with the nucleophilic addition of the amine 8 to carbon disulfide for in situ generation of the dithiocarbamate, which subsequently undergoes thia-Michael addition to the α-carbon (α to keto group) of the H-bonding activated arylidene malononitrile (62a) (generated in situ by the Knoevenagel condensation of phenylglyoxal with malononi-

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Figure 4.28: Synthesis of thiomorpholine-1,1-dioxide (61) in water.

trile) to form 62b. In the next step, the intramolecular nucleophilic addition of the amine group of 62b to one of the electrophilic nitrile carbon completes the cyclization process to furnish 62c. Finally, 1,3 C to N hydrogen shift of 62c furnishes the desired product 63 (Figure 4.29). Various metal-free Biginelli reactions in water were reported for the synthesis of dihydropyrimidinone/thiones (16) (Figure 4.30). The water-mediated one-pot domino MCRs of aldehydes, 1,3-diketo carbonyl compounds, and ureas/thioureas were carried out in the presence of Bronsted acids (methods A and B) [259, 260], microwave irradiation (method A) [259], hypervalent iodine reagent (method C) [261], oxones (method D) [262], recyclable catalyst Amberlyst-70 (method E) [263], bio-organic catalyst known as taurine-(2-aminoethanesulfonic acid) (method F) [264], and ILs (method G) [265]. Apart from the role of the electrophile activator (Bronsted acid, IL, heterogeneous catalyst, etc.), there is a possibility of participation of water in the mechanistic pathways of Biginelli reaction. Water acts as HB donor to the carbonyl group for its activation and simultaneously it acts as HB acceptor to the amino group of urea/thiourea for activation of the nucleophile. This nucleophile–electrophile activation dual characteristics of water helps in the condensation of aldehyde (33) and urea/thiourea (15) to generate the corresponding imine (15c). Further, water-assisted activation (as HB donor) of the 1,3-diketones favors the condensation of the imine intermediate with

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Figure 4.29: One-pot MCR approach for the aqueous phase synthesis of thiazines.

1,3-diketones to furnish the imine–enaminone intermediate (15d), which further cyclizes to the desired dihydropyrimidinone derivatives. The HB assistance by water speeds up the reaction rate. A few reactions were also performed using water as the reaction medium in the presence of metal catalysts; however, the proposed mechanism did not anticipate any significant role of water in the mechanistic pathway [266–269]. Microwave-assisted one-pot domino MCR was performed to synthesize the pyrimidines and its oxo derivatives (Figure 4.31). Base-promoted one-pot domino reaction of aromatic aldehydes (33), ethyl cyanoacetate (64), and amidines (65) in the presence of water (used as green reaction media) leads to the pyrimidinone derivative (66) under microwave irradiation [269]. Two reaction pathways were proposed depending on the order of the reactants reacting initially with each other. In pathway A, 33 and 64 initially undergo Knoevenagel condensation to furnish the intermediate 33z. Amidine undergoes aza-Michael addition to the intermediate 33z to produce the adduct 33ab, which subsequently undergoes cyclization followed by dehydrogenation to produce the desired pyrimidinone scaffold 66. In pathway B, 33 and 65 initially react to form the

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Figure 4.30: Biginelli reactions in aqueous media.

corresponding imine intermediate 33ac, which undergoes nucleophilic attack by 64 to produce the anionic intermediate 33ad. In the final step, the 33ad undergoes intramolecular nucleophilic addition on the ester carbonyl to form 33ae which on dehydrogenation leads to the formation of the desired pyrimidinone scaffold 66. The same methodology was extended for the synthesis of corresponding amino pyrimidine derivatives (67) (Figure 4.32) [269]. The microwave-assisted one-pot domino MCR of the aromatic aldehydes (33), malononitrile (45), and amidines (65) in water (used as green reaction media) was performed to synthesize the amino pyrimidines 67. Microwave-assisted synthesis of hexahydropyrimidine (69) was achieved by performing the condensation reaction of N-acyl-propanediamine (68) and formaldehyde in water (Figure 4.33) [270]. Water interacts with formaldehyde through H-bonding (H-bond donor) with carbonyl group to increase its electrophilicity. Water acts as a Hbond acceptor to the amine groups of 68 to increase the nucleophilicity of the amines favoring the condensation reaction with the activated formaldehydes. In this way, water acts as a dual nucleophile–electrophile activator. The scope of water-assisted synthesis of substituted THPs was explored by our group [271]. Various aryl aldehydes were treated with various amines and 1,3-dicarbonyl compounds to get the functionalized THPs via one-pot MCR approach (Figure 4.34). The

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Figure 4.31: Microwave-assisted one-pot domino MCR for synthesis of pyrimidinones in water.

Figure 4.32: Microwave-assisted one-pot domino MCR for synthesis of pyrimidines in water.

Figure 4.33: Microwave-assisted synthesis of hexahydropyrimidine in water.

reaction initiates with the in situ formation of the enaminone intermediate from the reaction of amine and 1,3-diketo compound. The enaminone further reacts with the aromatic aldehydes to synthesize the cinnamate ester. In a parallel reaction, the condensa-

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tion between amine and aldehyde produces the imine intermediate which in turn reacts with the cinnamate ester intermediate to furnish the desired THPs. Water may play its crucial role in the imine, enaminone, and cinnamate ester formation steps by activating both the amines (nucleophile) and aldehydes (electrophile) simultaneously through H-bonding.

Figure 4.34: Synthesis of THPs in aqueous media.

Substituted dihydropyrazine (72) was synthesized by the reaction of vicinal diamines (71) and 1,2-di-keto compounds (62) in the presence of water as reaction media at room temperature (Figure 4.35) [272]. Besides the role of water as benign reaction media, water activates the electrophilic centers (keto groups) through hydrogen bonding with the carbonyl oxygen. It facilitates the nucleophilic addition of amines to the carbonyl carbon to furnish the carbinol intermediates 71a, which further undergoes dehydration to synthesize the desired product. Our group developed a sustainable method of cyclocondensation of ortho-phenylene diamines or 1,2-diamines with benzils or 1,2-diketones in aqueous medium under micellar catalysis to form quinoxalines (73) or dihydropyrazines (72) [273]. The catalytic potential of several cationic, anionic, and neutral surfactants was tested, and the neutral surfactant Tween 40 was most effective. Various 1,2-diaryl/dialkyl/aryl-alkyl diketones and 1,2dilakyl/cycloalkyl diamines and o-phenylenediamines diamines were used as the reactants (Figure 4.36). Room temperature operation, high product yields, and feasibility of reuse of the reaction medium (spent water) containing the catalyst, recovery/reuse of the catalyst mark some of the distinct advantages and support the sustainability of the pro-

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Figure 4.35: Synthesis of dihydropyrazines in water.

cess. The role of the surfactant has been proposed to form microreactors at the water interface to encapsulate the reactants that undergo nucleophile–electrophile dual activation through HB formation with water molecules to promote the cyclocondensation. The superiority of the surfactant (Tween 40) has been demonstrated by comparison with several reported catalysts under identical reaction conditions.

Figure 4.36: Synthesis of quinoxaline and dihydropyrazines in water.

Though the condensation of o-phenylenediamines diamines with 1,2-diketones appears to be a straightforward approach toward the construction of the quinoxaline heterocyclic system it, however, suffers from the regioselectivity issue when unsymmetrical o-phenylenediamines diamines or 1,2-diketones are used as coupling partners (Figure 4.37).

Figure 4.37: The issue of regioselectivity during quinoxaline ring construction.

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In this context, our group devised and implemented a novel “all-water” tandem N-alkylation–nitro reduction–cyclocondensation strategy for regiocontrolled synthesis of 2-aryl quinoxalines (Figure 4.38) [274].

Figure 4.38: “All-water” chemistry for regiocontrolled construction of 2-aryl quinoxalines.

4.5.4 Seven-membered heterocycles Microwave-assisted synthesis of perhydro-1,3-diazepines (77) was achieved by performing the condensation reaction of N-acyl-butanediamine (76) and formaldehyde in water as reaction medium (Figure 4.39) [270]. The critical role of water could be nucleophile–electrophile dual activator as realized for the formation of 69 (Figure 4.33).

Figure 4.39: Microwave-assisted synthesis of perhydro-1,3-diazepines (77) in water.

The nucleophilic substitution reaction between sodium 2,2-dicyanoethene-1,1-bis(thiolate) (78) and 2-chloroethylamine hydrochloride (79) in water as solvent, followed by intramolecular aza-Michael addition reaction afforded the novel (Z)-5-amino-7-thioxo -2,3,4,7-tetrahydro-1,4-thiazepine-6-carbonitrile (80) (Figure 4.40) [275]. The 3D geometry of the most stable tautomeric form was investigated using density functional theory calculations.

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Figure 4.40: Synthesis of tetrahydrothiazepines in water.

The substituted flavone derivatives (81) were treated with ethylenediamines (82) in aqueous medium under refluxed for 15 min to furnish the 1,4-diazepines (83). The reaction is initiated through the aza-Michael addition of 70 to the β-carbon of the enone moiety of flavones (81) to furnish 81a. Subsequently, intramolecular condensation between amine and carbonyl groups of 81a synthesizes the desired 1,4-diazepine derivatives in good to excellent yield (Figure 4.41) [276].

Figure 4.41: Synthesis of 1,4-diazepines under aqueous phase.

4.6 Conclusions Monocyclic heterocycles and their derivatives continue to be attractive synthetic targets to organic chemists, owing to their unique physicochemical and biological properties and being well-recognized pharmacophore enjoy the status of privileged scaffold in the fields of medicinal chemistry in the context of drug design. Therefore, there is a pressing need to design and develop environmentally benign synthetic approaches to access these bioactive heterocycles. In view of sustainability, any synthetic methodology utilizing innocuous solvents, metal-free reagents, water as reaction medium, use of alternative source of energy, bio-based extracts as catalyst, reusable catalysts, and devoid of the generation of waste would be greener and most preferred approach. Therefore, it is in this pursuit, this chapter enlists and put to the attention some of the notable works pertaining to monocyclic heterocycle synthesis under aqueous medium. This might inspire synthetic organic/medicinal chemists to further put efforts to enrich their synthetic toolbox for sustainable and greener synthetic transformations.

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Babita Tanwar, Asim Kumar, Nirjhar Saha, and Asit K. Chakraborti✶

Chapter 5 Water as benign reaction medium for the synthesis of quinoxalines 5.1 Introduction The quinoxaline heterocycle is present in various FDA-approved drugs, essential medicines, and bioactive natural products [1–4]. A few representative examples are shown in Figure 5.1. Thus, the quinoxaline ring system has been recognized as a privileged scaffold in the quest of discovering new leads in diverse therapeutic areas [5]. Preclinical compounds with quinoxaline scaffolds are the privileged drug-like candidates active against various pathophysiological conditions [5–15]. Apart from the applications in the fields of pharmaceutical sciences, the quinoxaline ring finds its uses in organic synthesis as directing group and coordinating ligands for metals for C–H bond functionalization [16, 17], the essential structural component of dyes [18], and ion sensors [19]. Thus, there have been perpetual efforts to devise various newer synthetic strategies [20, 21]. Some of the recent literature reports on the development of new methods for the synthesis of quinoxalines adopting various approaches based on the starting materials as the essential components to construct the quinoxaline ring core are summarized in Figure 5.2 [22–35].

5.2 Water as reaction medium for organic synthesis Though the development of newer methods of organic synthesis is an important metrics of advancement of chemical research, the chemical processes often have the potential to adversely affect the environment and the ecosystem [36–38] and do not make such processes/development sustainable. This led the Environmental Protection Acknowledgments: 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 700032, West Bengal, India, emails: [email protected], [email protected] Babita Tanwar, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India Asim Kumar, Amity Institute of Pharmacy, Amity University Haryana, Manesar 122413, India Nirjhar Saha, School of Chemical Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700032, West Bengal, India https://doi.org/10.1515/9783110985627-005

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Agency to impose regulations in the uses and manufacturing of chemicals, insisting on the implementation of the green chemistry principles toward the development of sustainable chemical processes [39, 40]. Thus, over the past couple of decades, the academia and pharmaceutical industries have been thriving for inculcating green chemistry practices in chemical research so as to avoid the use of toxic reagents, utilize renewable energy and feedstock, reduce the overall energy consumption, use organocatalyst in place of metal-derived catalysts, use of alternate reaction media or biomass-derived solvents, and so on [41–49]. Thus, for the advancement of chemical research for a sustainable future, it is necessary that organic chemists put into practice the green chemistry principles in devising new innovative reactions by proper selection of chemicals, reactions, and processes that would not only be cost-effective but be energy efficient and with no/minimal adverse effect on the environment and the ecosystem [50–56]. Expectedly, there has been influence of green chemistry culture in the efforts to develop newer synthetic methods of quinoxalines [57–59]. In the pursuit of achieving sustainability in chemical synthesis, the pharmaceutical industries have identified a few key green chemistry areas [60, 61], and keeping in view of the fact that the major contributors for environmental damage of any chemical process are the commonly used volatile organic solvents [62, 63], consider the use of safer alternatives [64–70] as the effective and most obvious way toward the design of a greener process. Selection of appropriate sustainable reaction media is the crucial step in the development of novel synthetic methodologies, and the solvent-selection guide of pharma industry puts water at the top of the list [40]. Therefore, synthetic organic/medicinal chemists in industrial and academic research and development organizations have been motivated to use water as the alternate and environment-friendly reaction medium for organic synthesis [71–77]. The various organic reactions that have been performed in water as the reaction medium are C–C bond-forming reactions [78] that include Diels–Alder reaction [79, 80], diverse cross-coupling reactions such as Sonogashira, Heck, Suzuki [81–84], asymmetric synthesis [85–87], and the C–H activation reactions [88–92]. The adventure of organic reaction in water has been extended towards the synthesis of heterocycles as well [93–95]. In view of the distinct advantages of acceleration of reaction rates and modulation of product selectivity for organic reactions carried out using water as the reaction medium over those observed in organic solvents, efforts were made to understand the beneficial role of water in promoting organic reactions. The hydrophobic effect [96–98] theory could be used for the enhanced reaction rate in aqueous medium but confined to the Diels–Alder-type reactions. The proposal on the hydrogen bonding effect of the dangling OH groups of water molecules at the water–organic interface [99, 100] appeared to gain popularity and discounted any significant contribution of hydrodynamic effects [101]. Subsequently to understand the reasons behind the efficiency of water as the reaction medium to assist organic reactions, several proposals namely “on water,” “in water,” and “in the presence of water” have been put forward [102–107]. However, these do not delineate the molecular-level

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Figure 5.1: Quinoxaline-containing drugs and bioactive molecules.

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Figure 5.2: Some recently reported various approaches for the construction of the quinoxaline scaffold. (A) Silica gel, MWI [22]; (B) NBS [23]; (C) IBN, Ac2O [24]; (D) vitamin B1@carbon nitride, neat, 100 °C [25]; (E) Ni@Co3O4 nanocages, ethanol, room temperature [26]; (F) Ir-based catalyst, base, DMA, N2, visible light, room temperature, 24 h [27]; (G) R-SH, Xe lamp [28]; (H) DTP/SiO2 [29]; (I) Co@NCP, PhMe, 140 °C, 12 h [30]; (J) PIFA, THF [31]; (K) TMAH (IL), ethylene glycol [32]; (L) NaOH, toluene, reflux [33]. (M) Ni catalyst, CsOH·H2O, toluene, reflux [34]; and (N) Fe-based catalyst, Me3NO, toluene, reflux [35].

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interaction that might occur involving the reactants and the water molecule(s) and would provide a rationale for selection of water as the reaction medium in performing organic reactions. Toward this objective, we envisaged the role of water in promoting organic reactions due to its ability to act as “electrophile–nucleophile dual activation” agent via “cooperative hydrogen bond (HB) network” formed with the reactants [108–110]. Such a model rationalizes single water molecule catalysis in the gas-phase radical–molecule reaction [111] and explains the selective cascade epoxide ring promoted by marine water toward the formation of the six-membered oxacycle (tetrahydropyran), the essential structural unit of the marine toxins, over the five-membered ring, that is, tetrahydrofuran [112]. The concept on the ability of water in promoting organic reactions by HB-mediated “electrophile–nucleophile synergistic dual activation” is the key feature for rational design of novel “all-water” chemistries that had been used for green synthesis of drugs [113, 114] and for double advantage of aqueous medium and Pd-derived nanocatalysis in the construction of the essential pharmacophoric moiety leading to the synthesis of drugs used for the treatment of diverse therapeutic conditions [115]. In this chapter, we focused on the synthesis of quinoxalines in aqueous medium.

5.3 Recent developments in the synthesis of quinoxalines in aqueous medium The recognition of water as the environment-friendly reaction medium [40, 64–70] that encouraged aquatic organic synthesis [71–77] motivated organic chemists to perform various organic reactions that had earlier been carried out in organic solvents, in aqueous medium [78–92], including the synthesis of heterocycles [93–95]. Therefore, efforts have been made to develop new methods of synthesis of quinoxalines in aqueous medium, and various literature reports for this purpose can be classified in the following three categories: quinoxaline synthesis in aqueous medium in the presence of catalyst, quinoxaline synthesis in aqueous medium in the presence of surfactant, and catalystfree quinoxaline synthesis in aqueous medium. These are summarized below.

5.3.1 Synthesis of quinoxalines in aqueous medium in the presence of catalyst The various literature reports on the synthesis of quinoxalines in aqueous medium that involves the use of metal-derived Lewis or Brønsted acid as catalyst are presented in this section. The Ag(I)-catalyzed diverse synthesis of fused quinoxalines (3) from o-alkynylaldehydes (1) and amines (2) in water as solvent was reported by Rustagi et al. (Figure 5.3). The reaction proceeds through the Ag(I)-catalyzed imine (1a) formation followed by Ag(I)-

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catalyzed intramolecular cyclization for the construction of dihydroquinoxaline moiety (1b) [116]. In the final step, the metal-catalyzed intramolecular addition to alkyne forms the fused quinoxalines. In this reaction protocol, the authors have not envisaged any specific role of water other than being used as the reaction medium.

Figure 5.3: Tandem synthesis of fused quinoxalines and benzimidazoles.

The Brønsted acid hydrotrope catalysis in water was explored in the acid-catalyzed synthesis of quinoxalines at ambient temperature (Figure 5.4). The reaction proceeds with the convenient cyclocondensation reaction between the amines (4) and the 1,2diketo keto groups in the benzils (5) to furnish 2,3-diaryl substituted quinoxalines (6) [117]. The water molecules reduce the electrostatic interaction between the hydrotrope groups through incorporation between them. As a result, the two head groups of hydrotrope were separated from each other favoring the hydrophobic interactions

Figure 5.4: Synthesis of quinoxalines promoted by Brønsted acid hydrotrope catalysis in aqueous medium.

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and facile interactions of diamine with diketone to generate the quinoxaline moiety. In the course of the reaction, the eliminated water molecules were easily absorbed by the hydrophilic head groups of the hydrotrope. The less toxic and biodegradable ionic liquid (IL) [C8dabco]Br (9) was utilized for the synthesis of quinoxalines (6) from o-phenylenediamines (4) and the benzil derivatives (5) in water as reaction media (Figure 5.5) [118]. The notable advantages of this reaction protocol are recyclability of the catalyst, high yields, water as benign reaction media, ease of product purification, and higher atom economy.

Figure 5.5: Synthesis of quinoxaline using [C8dabco]Br.

The nanocatalysis has emerged as a new green chemistry tool for organic synthesis [119–125] and finds applications in the construction [126, 127] and late-stage functionalization [128, 129] of heterocycles. The main advantages of nanocatalysts as green chemistry tool are associated with the easy recyclability, larger surface, and higher catalytic efficiency. The condensation reactions between 4 and 5 were carried out in the presence of Fe3O4@SiO2/Schiff base complex of Co(II) as catalyst in aqueous medium at room temperature (Figure 5.6). The heterogeneous nanocatalyst was recovered through external magnetic field and recycled for five times without any significant change in the yield [130].

Figure 5.6: Synthesis of quinoxaline using magnetic nanocatalyst.

In another approach of nanocatalyst-assisted quinoxaline (11) synthesis, Cu-doped CdS nanoparticles (NPs) were explored as catalysts to carry out the reaction between

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isatin derivatives (10) and 1,2-diamines (4) under microwave irradiation (MWI, Figure 5.7). The heterogeneous catalyst makes coordination complex with the keto group of 10 to activate the electrophile and consequently further promotes the condensation reaction of it with 4. The nanocatalyst was recycled up to five times without any significant reduction in the product yield. The catalytic efficiency of Cu-doped CdS NPs was higher in case of MWI with respect to the conventional heating. The Cu-doped CdS NPs exhibit a dual role acting as both catalyst and susceptor (of the MW energy). The notable advantages of this reaction methodology are the easy workup, mild reaction conditions, cost-effectiveness, and the catalyst recyclability [131].

Figure 5.7: Chemoselective synthesis of indolo[2,3-b]quinoxaline derivatives.

The CeO2 NP-catalyzed multicomponent reaction of o-phenylenediamines (4), aldehydes (12) or ketones (13), and isocyanides (14) were performed in water as reaction media for the syntheses of quinoxaline (15) or dihydroquinoxaline (16) derivatives [132] (Figure 5.8). The Lewis acidic character of Ce(IV) activates the carbonyl group for condensation reaction, followed by nucleophilic addition of isocyanide to the activated imine. In the next step, intramolecular nucleophilic addition to the nitrilium ion and subsequent aromatization completes the quinoxaline ring formation. In this reaction protocol, the CeO2 NPs act as the electrophile activator, but no specific role of water has been invoked apart from the role of reaction media.

Figure 5.8: Chemoselective synthesis of indolo[2,3-b]quinoxaline derivatives.

The research group of Namboothiri et al. reported gold NPs and carbon nanotube hybrid (AuCNT) as the catalyst for in situ oxidation of either α-hydroxyketones (17) or

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1,2-diols (18) into the corresponding carbonyl groups for cyclocondensation reaction with o-phenylenediamines (4) to form quinoxalines (19) in good to excellent yield [133] (Figure 5.9). The heterogeneous AuCNT catalyst was recycled for four times without any significant loss in its catalytic activity.

Figure 5.9: AuCNT-catalyzed reaction of α-hydroxy ketones or 1,2-diols with o-phenylenediamines in PhMe–water for the synthesis of quinoxalines.

The iron-catalyzed condensation reaction of o-phenylenediamines (4) and α-diazo-βketoesters (20) in water as reaction medium was reported for the construction of polyfunctionalized quinoxalines (21) in good to excellent yield [134]. The reaction proceeds through in situ generation of the metal carbenoid species which reacts with o-phenylenediamine to complete the annulation process, and subsequently the oxidative aromatization resulted in the formation of quinoxalines (Figure 5.10). The notable advantages of this methodology are wide substrate scope, utilization of earth-abundant metal-derived catalyst, and green reaction medium.

Figure 5.10: Construction of polyfunctionalized quinoxalines.

The one-pot multicomponent reaction of acetophenone (22), succinimide (23), and o-phenylenediamines (4) was carried out in the presence of iodine as catalyst and silver iodide as additive under MWI in PEG–water for the synthesis of substituted 2-phenylquinoxaline (24) [135] derivatives (Figure 5.11). The in situ generation of Niodosuccinimide by the reaction of 23 and iodine further reacts with acetophenone to form α-iodoacetophenone in situ. The reaction of α-iodoacetophenone with ophenylenediamines (4) via tandem N-alkylation–intramolecular imine formation– dehydrogenation sequence leads to the formation of 24. In this reaction protocol, water not only acts as the reaction media but also activates the carbonyl group of α-iodoacetophenone through hydrogen bonding [108–115] to assist the tandem nucleophilic substitution–cyclocondensation reaction between α-iodoacetophenone

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and o-phenylenediamines to form the C-2-substituted quinoxalines. The notable features of this reaction methodology are the wide substrate scope, greener reaction media, shorter reaction time, and less waste generation.

Figure 5.11: Synthesis of quinoxaline derivatives.

It has been established that o-phenylenediamines (4) undergo cyclocondensation reaction with 1,2-dicarbonyl compounds (5) to form the 2,3-disubstituted quinoxalines (6). Thus, the presence of reducing agent in the reaction protocol may reduce the quinoxaline to tetrahydroquinoxaline. This approach was attempted by Liu et al. for the synthesis of tetrahydroquinoxalines (26) [136] from commercially available 2-amino(nitro)anilines (4/25) and 1,2-dicarbonyl compounds (5) in the presence of diboronic acid–water as reducing agent under metal-free conditions (Figure 5.12). In this synthetic methodology, water acts as both solvent and hydrogen donor for the nitro reduction. The reaction proceeds through in situ generation of o-phenylenediamine (4) through reduction of 2-nitroanilines (25) by the diboronic acid–water reducing agent. In the next step, the condensation between 4 and 5 forms the quinoxaline moiety (6), which was further reduced to tetrahydroquinoxaline (26) scaffold through diboronic acid-assisted hydrogen transfer from water. The reaction was also carried out in D2O to establish that water is essential for the hydrogen atom transfer in the reduction of quinoxalines. The authors have also explored the synthesis of tetrahydroquinoxalines from 1,2-dinitrobenzene using higher amounts of diboronic acid (10 equiv.) as reducing agent. The metal-free biocatalyst gum arabic was used for the synthesis of substituted quinoxalines (6) by the condensation reaction of o-phenylenediamines (4) and 1,2-dicarbonyl compounds (5) at room temperature in aqueous reaction medium (Figure 5.13) [137]. In another approach, in situ generation of o-phenylenediamines from the reduction of 2-nitroanilines was attempted with the help of recyclable iron catalyst. The condensation reaction of 2-nitroanilines (25) and the benzil derivatives (5) was carried out in the presence of reusable Fe–SiCN nanocomposite as catalyst which participates in the in situ reduction of the nitro group in 25 to amino group [138]. The in situgenerated o-phenylenediamines undergo cyclocondensation reaction with the benzil derivatives to furnish the quinoxaline moiety (Figure 5.14). Although the reaction was carried out under heterogeneous catalysis, this reaction protocol required higher reaction temperature, longer reaction time, and special efforts and reagents for the preparation of the catalyst.

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Figure 5.12: B2(OH)4-mediated synthesis of quinoxaline derivatives.

Figure 5.13: Synthesis of quinoxaline derivatives in the presence of GA.

Figure 5.14: Selective synthesis of substituted quinoxalines.

Iridium-complex (27)-catalyzed dehydrogenative coupling of 1,2-diamines/2-nitroanilines (4/25) with 1,2-diols in water as the reaction medium has been reported [139] to form variously substituted quinoxalines (6) (Figure 5.15). In case of 2-nitroaniline derivatives (25), the reaction could presumably proceed through in situ generation of the corresponding o-phenylenediamines by Ir-catalyzed reduction of the nitro group in 25, which undergoes

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imine formation with the 1,2-diketone, generated in situ via the Ir-catalyzed dehydrogenation of the vicinal diols 18. The imine formation involving both the amine and ketone groups in the in situ generated o-phenylenediamines and the 1,2-diketones would result in the cyclocondensation to construct the quinoxaline ring in 6. However, no ophenylenediamine formation was detected (though its formation could not be totally ruled out) during the progress of the reaction, suggesting the reaction might proceed by the alternative pathway as speculated via initial imine formation of the amine group in 25 with the ketone group of the in situ generated α-hydroxyketone (or one of the ketone groups of the in situ generated 1,2-diketone) followed by nitro reduction to generate the amine group that further undergoes intramolecular imine formation leading to the formation of 6.

Figure 5.15: Iridium-complex-catalyzed synthesis of various quinoxalines from diamines and nitroanilines in aqueous medium.

The biomimetic organocatalyst polydopamine was applied in the aqueous medium for the synthesis of quinoxalines (29) from the reaction of 2-phenylethylamines (28) and o-phenylenediamines (4) [140] (Figure 5.16). The reaction proceeds through the oxidative transamination of 28, followed by in situ formation of imine derivative and intramolecular cyclization to obtain the quinoxalines. The notable advantages of this reaction protocol are the metal-free reaction condition in the presence of biomimetic organocatalyst, wide substrate scope, utilization of oxygen as green oxidant, and the recyclability of the organocatalyst. Xu et al. reported Ir-complex-catalyzed reaction of o-phenylenediamines (4) with sulfoxonium ylides (30) in water as the reaction medium to provide the synthesis of C-2-substituted quinoxalines (31). The interaction between Ir catalyst and sulfoxonium ylide in situ generates the iridium-containing organometallic intermediate which further undergoes nucleophilic addition with the o-phenylenediamines for the C–N bond formation step. Finally, the release of the Ir catalyst followed by cyclocondensation reaction generates the desired quinoxaline derivatives (Figure 5.17) [141].

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Figure 5.16: Synthesis of various quinoxalines using polydopamine.

Figure 5.17: Synthesis of diverse quinoxalines from o-phenylenediamines and various sulfoxonium ylides catalyzed by Ir complex in water.

Itaconic acid was used as a recyclable acidic promoter for the synthesis of structurally diverse quinoxalines (6) from the cyclocondensation reaction of o-phenylenediamines (4) and benzil derivatives (5) (Figure 5.18). In this reaction protocol, itaconic acid acts as the HB donor to activate the carbonyl group of benzil to increase the electrophilic character of the carbonyl carbon and favors the cyclocondensation process [142].

Figure 5.18: Itaconic acid-catalyzed synthesis of quinoxaline derivatives in aqueous medium.

The bifunctional and recyclable acidic IL 34 was used as an organocatalyst in the decarboxylative cyclization of 2-arylanilines/2-heteroarylanilines (32) with α-oxocarboxylic acids (33) in water to form the fused quinoxalines (35) (Figure 5.19) [143]. Initially, the reaction proceeds through the imine formation involving the reaction of aniline functionality of 32 and keto group of 33. In the next step, the sulfonic acid group of the IL activates the iminic carbon through H-bonding and subsequently promotes the aryl/heteroaryl ring-assisted intramolecular cyclization process. The imidazolium moiety of the IL 34 interacts with the carboxylic carbonyl group through ionic interaction to favor the

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Figure 5.19: Decarboxylative cyclocondensation of α-oxocarboxylic acids with o-phenylenediamines to form fused quinoxalines in aqueous medium.

decarboxylative process. The IL-assisted decarboxylation process finally provides the fused quinoxalines (35). The catalyst 34 could be recycled.

5.3.2 Quinoxaline synthesis in water in the presence of surfactant The organic substrates in general have poor solubility in water due to their hydrophobic nature and require ambiphilic substances such as surfactant for their better solubilization into the polar reaction medium such as water. The ability of surfactants to promote organic reactions in aqueous medium has been correlated with their ability to form micelles in aqueous medium [144]. The beneficial effect of the use of surfactant in the synthesis of heterocyclic compounds can be demonstrated in the tandem thiaMichael addition–cyclocondensation for the “on water” construction of heterocyclic scaffold promoted by the anionic surfactant SDS as reported by us [145]. Though the surfactants presumably encapsulate the reactants inside the micellar assemblies that act as microreactors to enable the progress of the reaction under confinement, the role of surfactant may not be merely to act as solubility enhancers of organic substances in aqueous medium. Often, the use of surfactants in aqueous environment might be associated with generating new chemistries as is the case on the findings on surfactant-based transition-metal-free dioxygen activation in aqueous medium for a room temperature aquatic aerobic oxidation during the construction of some heterocyclic scaffold [146]. Thus, surfactants not only enhance the solubilization of the hydrophobic organic substrates into the water but also may act as a catalyst in the organic transformations. The potential of DBSA was explored as both surfactant and Brønsted acid catalyst in the synthesis of quinoxaline derivatives (6) for the reaction of 1,2-dicarbonyl compounds (5) and o-phenylenediamines (4) at room temperature (Figure 5.20). In this reaction protocol, DBSA acts as Brønsted acid catalyst for activation of the electrophile 5 and promotes the cyclocondensation reaction with 4 [147]. Apart from the role of solubility enhancer, the surfactants create a microreactor environment at the oil–water interface and the applications of such microreactor in performing the organic synthesis has been explored widely [148–150]. Based on the chemical structures and properties, the various surfactants are classified into four distinct broad categories: neutral, anionic, Brønsted acid, and cationic surfactants. In order to develop

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Figure 5.20: DBSA-catalyzed synthesis of quinoxalines in aqueous medium.

an efficient method for quinoxaline synthesis in aqueous medium, the scope and limitations of these four classes of surfactants were assessed for the cyclocondensation reaction of o-phenylenediamines (4a) and benzil derivatives (5a) in aqueous suspension of various types of surfactants to form the disubstituted quinoxalines (6a) [151] (Figure 5.21). Initial results on the screening of various types of surfactants indicated the nonionic surfactants to be efficient in promoting the quinoxaline synthesis in comparison to the other types of surfactants. Within the set of anionic surfactants, sodium dodecylsulfate (SDS) and sodium dioctylsulfosuccinate (SDOSS) were found to be most efficient. To find out the most effective surfactant from the set of the effective surfactants (e.g., SDS, SDOSS, Triton X 100, Triton X 110, Triton X 114, Triton SP 135, Triton SP 190, Tween 20, Tween 40, Tween 60, and Tween 80), the reaction of electron-deficient and less nucleophilic 4-nitro-ophenylenediamine 4b with 5a was performed in the presence of the above mentioned surfactants in water at room temperature for different time intervals (Figure 5.21a). The results of these studies revealed that Triton SP 135, Triton SP 190, and Tween 20 are the most effective catalysts among all the four types of surfactants explored. These three surfactants along with SDS and SDOSS were further used for the reaction of 4b with the less electrophilic benzyl 5b to synthesize 6c (Figure 5.21a). These detailed studies revealed Tween 40 (used in 10 mol%) as the most efficient catalyst to carry out the synthesis of 6a–c. The absence of surfactant gave lower yield of the product (6a) when the reaction of 4a and 5a was carried out in water at room temperature. The replacement of water as solvent by the classical organic solvents gave inferior yield of the product in the presence of the surfactant. These observations established the crucial role of both the Tween 40 as surfactant and water as the reaction medium during the course of the reaction. The role of surfactant (Tween 40) is not only to enhance the solubility of the hydrophobic organic substrates in water but also to provide the suitable microreactor environment for smooth proceeding of the cyclocondensation reaction. The influence of any trace metal ion impurities (that might be present in water) for the cyclocondensation was ruled out in performing the reaction of 4a and 5a in the presence of Tween 40 as catalyst in tap water, ultrapure water, double glass distilled water, and degassed water separately that led to the formation of the desired product without any significant change in the yield in each case. The optimal water/surfactant

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Figure 5.21: Tween 40-catalyzed quinoxaline synthesis in aqueous medium.

ratio ranges from 1:0.03 (w/w) to 1:0.25 (w/w). The catalyst (Tween 40) could be recovered and recycled up to fourth cycle without significant loss in the yield of the product. The Tween 40-catalyzed cyclocondenation of 1,2-dimines (4) with 1,2-diketones (5) for the synthesis of substituted quinoxalines (6) exhibited wide substrate scope (Figure 5.21b). The catalytic efficiency of Tween 40 for the aqueous synthesis of quinoxalines was compared with the catalytic efficiency of water-tolerant catalysts and earlier reported catalysts for quinoxaline synthesis, revealing that Tween 40 to be either better or comparable in catalytic efficiency for quinoxaline synthesis. The reaction pathway for the formation of quinoxaline has been depicted as shown in Figure 5.22, invoking the monoimine intermediate (II) generated in situ by the condensation reaction of 4a and 5a. The crucial role of water has been proposed through the involvement of two molecules of water in H-bonding to generate the supramolecular assembly (I) during imine formation, wherein one water molecule acts as HB donor for electrophilic activation of the 1,2-diketone through bifurcated H-bonding. The other water molecule activates the nucleophile through H-bonding (HB acceptor), and at the same time being engaged in H-bonding with the other water molecule. Such HB donor–acceptor role of water in the assembly I promotes the condensation via dual ac-

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tivation of nucleophile and electrophile to form the imine intermediate II, which further undergoes the intramolecular cyclocondensation process to form the desired quinoxaline derivatives (6a). The inferior results with the classical organic solvents may be attributed to the lack of H-bonding capability. The surfactant provides the necessary microenvironment to encapsulate the reactant for the required HB formation with the water molecule(s).

Figure 5.22: Role of water in Tween 40-catalyzed quinoxaline synthesis in aqueous medium.

The one-pot multicomponent reaction between o-phenylenediamines (4), β-ketoesters (38), and sulfonyl azides (39) in the presence of cooperative biocatalysis of lipasehemoglobin (dual protein catalysis) provided the synthesis of quinoxalines (40) in water–surfactant reaction medium [152] (Figure 5.23). In this reaction protocol, Triton X-100 only acts as the surfactant to bring the three components of the reaction into the same phase of the reaction media, perhaps through micelle formation. The histidine molecule present in the lipase enzyme acts as the base for proton abstraction from β-ketoesters to generate the corresponding enolates, which subsequently undergo diazo transformation reaction to form the diazoesters. The heme moiety of hemoglobin facilitates the N2 elimination from diazoesters followed by the formation of iron carbenoid species between β-ketoesters and heme group. The iron carbenoid species reacts with o-phenylenediamines initially via nucleophilic addition, and this is followed by cyclocondensation to produce the desired quinoxaline esters 40.

Figure 5.23: Lipase–hemoglobin system for the synthesis of quinoxalines.

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5.3.3 Water as reaction media In the previous sections, the synthesis of quinoxalines in aqueous medium has been summarized in performing the reactions using water as the reaction medium in the presence of either metal salts or surfactants as the catalyst to promote the cyclocondensation of 1,2-diamines with 1,2-diketones. The focus of this section is on the synthesis of catalyst-free quinoxaline in aqueous medium. The tandem one-pot synthesis of quinoxalines (42) was carried out in two steps from the 1,3-diketo derivatives (38). In the first step, the in situ formation of α-halo-βketo derivatives (41) was carried out by treating the 1,3-diketo compounds (38) with N-bromosuccinimide (NBS). In the next step, the o-phenylenediamines (4) were added in the same pot to react with the α-halo-β-keto compounds. The nucleophilic substitution and further cyclocondensation reaction between o-phenylenediamines and αhalo-β-keto derivatives synthesized the desired quinoxalines (Figure 5.24) [153]. The notable advantages of this reported methodology are wide substrate scope, catalystfree reaction condition, one-pot reaction, and shorter reaction time.

Figure 5.24: Synthesis of highly substituted quinoxalines.

The catalyst-free cyclocondensation reaction of o-phenylenediamines (4) and 1,2diketones (5) has been reported using water as the reaction medium for the synthesis of 2,3-disubstituted quinoxalines (6) [154] (Figure 5.25). The reactions occurred at room temperature for a short period of time but poor yields (10–30%) are obtained in case of benzils, which are used as the 1,2-diketone reacting partner. Regioisomeric product mixtures were formed for reactions involving unsymmetrical substrates (X = Cl, R1 ≠ R2). However, halogenated solvent has been used during workup procedure for product isolation that undermines the benefit of using water as the reaction medium. Though it appears that the construction of the quinoxaline ring system could be a straightforward approach involving the cyclocondensation of 1,2-dicarbonyl compounds with 1,2-diamines, this route has the potential of generating regioisomeric product mixture (Figure 5.26) while using unsymmetrical substrate(s) as the reacting partner(s).

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Figure 5.25: Catalyst-free synthesis of 2,3-diarylquinoxalines in water.

Figure 5.26: Regioselectivity issue in the synthesis of quinoxalines.

In the literature reports discussed thus far, the aspect of regioselectivity might have been arisen due to the use of symmetrical substrates or might have been overlooked (though in some cases the formation of regioisomeric product mixture has been mentioned). The issue of such regioselectivity has been highlighted and addressed by our research group through the development of one-pot tandem N-aroylmethylation–nitro reduction–cyclocondensation reaction for the synthesis of 2-aryl quinoxalines (44) utilizing the “all-water” strategy (Figure 5.27). While the reaction is performed using water as the reaction medium, 2-nitroanilines (25) undergo N-alkylation reaction with αbromoketone (43) derivatives to form 2-[(2-nitrophenyl)amino]-1-phenylethanone (43b)

Figure 5.27: Regio-controlled synthesis of quinoxalines in water.

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as an intermediate, which was further subjected to nitro reduction–cyclocondensation cascade in the same pot to synthesize the desired quinoxaline derivatives [155]. The concept of “all-water” chemistries developed earlier by our research group for regio-controlled construction of benzazoles [156, 157] that finds applications in sustainable synthesis of drugs [113, 114] and generation of new anti-TB therapeutic leads [158, 159] forms the basis of the development of this protocol for regioselective synthesis of quinoxaline in aqueous medium. The role of water has been demonstrated to be crucial for the overall progress of the reaction. Water forms the HB acceptor with NH2 hydrogen of 25 (nucleophilic activation). Another molecule of water from the dimer framework acts as HB donor to the Br atom of 43 (electrophilic activation) and brings the bromomethylene carbon in the close proximity to the NH2 nitrogen of 25 in the H-bonded supramolecular species 43b (Figure 5.28). Further, the carbonyl group of 43 undergoes HB formation with one of the water molecules of the water dimer, whereas the other water molecule of the water dimer forms HB with the remaining NH hydrogen of 25. This array of HB network gives stability to the supramolecular assembly. This H-bonded network in the supramolecular assembly (43b) facilitates the “ambiphilic nucleophilic–electrophilic dual activation” to synthesize the desired quinoxalines.

Figure 5.28: The envisaged role of water in promoting N-aroylmethylation of 25 with 43 to form 43b.

During the synthesis of quinoxaline (47) derivatives in aqueous medium, the o-alkynylbenzoates (46) were subjected to oxidation reaction with NBS in DCE–water (1,2-dichloroethane) to generate in situ the benzil-o-carboxylates (46a) which were subsequently treated with the o-phenylenediamine 4 in the same pot for cyclocondensation to provide the desired quinoxaline derivatives (Figure 5.29) [160]. In this synthetic process, apart from being the reaction medium, water plays the role of substrate/reactant to form the 1,2-diketo moiety in the intermediate 46a. Zhang et al. [161] also reported catalyst-free synthesis of quinoxalines from the reaction of 1,2-diamines and phenacyl derivatives, to form quinoxalines (49) from α-azido ketones (48) and o-phenylenediamines (4) in water as reaction medium (Figure 5.30). Initially, heating of α-azido ketones at 90 °C promotes the elimination of N2 and generates the corresponding α-ketoimine derivatives presumably via nitrogen exchange involving nitrene and one of the NH2 groups in 4. Water acts as the HB donor for both the

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Figure 5.29: Reaction of benzil-o-carboxylate with 1,2-diamine.

carbonyl and imine functionalities to activate the electrophilic centers, and it also acts as the HB acceptor for 1,2-diamines to activate the nucleophilic center. This dual activation of electrophile and nucleophile favors the cyclocondensation reaction, and subsequent elimination of ammonia molecule furnished the desired quinoxalines.

Figure 5.30: Synthesis of polyfunctionalized quinoxalines.

Visible-light-promoted one-pot multicomponent reactions of o-phenylenediamines (4), ketones (13), and isocyanides (14) were reported in aqueous medium under catalyst-free condition to synthesize the dihydroquinoxalines (50) (Figure 5.31). In the mechanistic pathway, the imine intermediate (13a), generated in situ from the reaction of o-phenylenediamine (4) and 13, undergoes nucleophilic addition with the third component isocyanide (14). In the next step, the visible-light-promoted photochemical activation of N–H bond and nitrilium moiety enables the intramolecular radical coupling of NH2 group and nitrilium group to complete the annulation process. In the final step, the 1,3-H shift furnishes dihydroquinoxalines [162]. The notable advantages of this synthetic protocol are the wide substrate scope, less generation of waste, one-pot multicomponent reaction protocol, catalyst- and additive-free synthetic methodology, shorter reaction time with higher yield of the product, and use of water as green reaction medium. An ultrasound-assisted catalyst-free synthesis of fused quinoxaline derivatives (52) was performed by the reaction of ninhydrin (51) with o-phenylenediamine (4) in water at room temperature (Figure 5.32) [163]. UV fluorescent light-assisted tandem one-pot synthesis of quinoxalines (54) was developed through the reaction of alkynes (53) with o-phenylenediamines (4) under cata-

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Figure 5.31: Synthesis of 4-dihydroquinoxalin-2-amine derivatives.

Figure 5.32: Ultrasound-assisted synthesis of quinoxaline derivatives in aqueous medium.

lyst-free condition in the aqueous reaction media [164] (Figure 5.33). As there is no electrophilic center present in the alkynes, the first job was to convert it into α-halo-ketones (43), which possess dual functionality for reaction with o-phenylenediamines (4). In the presence of N-bromosuccinamide, the alkynes were transformed into 43, which are further subjected to react with o-phenylenediamines via nucleophilic substitution/cyclocondensation to furnish the desired quinoxalines. In this reaction process, water may activate the keto group of 43 through HB donation (electrophilic activation) and simultaneously may act as the HB acceptor for the amino group of o-phenylenediamines to activate the nucleophilic partners. This dual role of water facilitates the cyclocondensation step to proceed under catalyst-free condition. The notable features of this synthetic

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Figure 5.33: Catalyst-free oxidative cyclization of diamines and phenacyl bromide to access quinoxalines.

protocol are the wide substrate scope, one-pot synthetic protocol, catalyst-free reaction condition, and application of UV light as nonconventional energy source.

5.4 Conclusions Quinoxalines, the privileged scaffold in the pharmaceutically active ingredients, were synthesized by utilizing both nonsustainable and sustainable approaches. The drawbacks associated with the nonsustainable approaches such as health and environmental hazards influenced to adopt the sustainable approaches for the synthesis of quinoxa-

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lines. Within the various sustainable approaches of quinoxaline synthesis, the reactions carried out using water as reaction medium were widely explored. In this chapter, the representative examples of quinoxaline synthesis in aqueous medium are discussed in detail with the plausible mechanistic explanation on the role of water in the course of the reaction.

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Nirjhar Saha, Kshitij I. Patel, Antarlina Maulik, and Asit K. Chakraborti✶

Chapter 6 Synthesis in water: a sustainable tool for the construction of quinoline derivatives 6.1 Introduction The presence of the quinoline ring in various US FDA-approved drugs and essential medicines [1–7] has made this nitrogen heterocycle a privileged pharmacophoric feature in the context of drug design. Some representative drug molecules and bioactive natural products containing the quinoline ring and quinoline-fused ring systems are shown in Figures 6.1 and 6.2. Apart from the importance in the pharmaceutical field, the quinoline compounds find applications in material sciences such as being the structural backbone of various dyes [8, 9], luminescent metal–organic frameworks [10, 11], third-generation photovoltaics [12], fluorescent probes [13–15], and chemosensors [16, 17]. In synthetic organic chemistry, the quinoline ring is used as the directing group for C–H functionalization [18–24], coordinating ligand for various metals [25–27], and precursors for organic transformations [28]. The broad spectrum of biological activities, wide applications in organic and material chemistry, makes the quinoline moiety an important N-heterocyclic scaffold. Thus there has been perpetual interest and efforts to develop newer synthetic methods for the preparation of this privileged class of compounds. The synthesis of quinolines can be achieved by adopting the traditional named reaction chemistries such as the Friedländer [29–31], Doebner–von Miller [32], Combes [33], and Skraup [34] synthesis, as well as Heck [35], and Pfitzinger [36] reactions. The newer approaches for quinoline synthesis include the use of radical reactions [37, 38], single atom catalysis [39], C–H activation reactions [40], and multicomponent reactions (MCRs) [41]. The adverse effects of chemicals on the environment and ecosystem [42–44] have induced a paradigm shift in the culture in chemical research advocating green and sustainable manufacturing processes [45, 46]. This has been reflected in the research publications over the last two Acknowledgments: 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 700032, West Bengal, India, emails: [email protected], [email protected] Nirjhar Saha, School of Chemical Sciences, Indian Association for the Cultivation of Science (IACS), Jadavpur, Kolkata 700032, West Bengal, India Kshitij I. Patel, Antarlina Maulik, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar 160062, Punjab, India

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decades, emphasizing on the applications of green chemistry principles in organic synthesis (e.g., avoidance of toxic reagents, utilization of renewable energy and material sources, reduction in the net energy consumption, applications of organocatalysis, and use of biomass-derived solvents) [47–55]. These imply that an organic chemist should adopt the green practices in reaction design and innovation through appropriate selection of chemicals, reactions, and processes that would lead to future [56–62]. The rapid growth of green chemistry applications encouraged the researchers to develop greener routes for quinoline synthesis [63–65], which includes the metal-free reactions [66–68], nanocatalysis [69], utilization of heterogeneous catalysts [70, 71], applications of microwave irradiation [72], and using deep eutectic solvents [73]. The pressing need for sustainable development led pharmaceutical industries to identify key areas for attaining greener process [74, 75], and the adverse impact of the classical volatile organic solvents on the environment [76, 77] advocates the use of safer alternatives [78–84]. Though the projection of ionic liquids (ILs) as future green solvents couple of decades ago [85–87] generated sparks to use ILs as alternative reaction medium in the synthesis of heterocycles [88, 89], there is apprehension on the green image of ILs [90–96]. However, to benefit from the ability of ILs to promote and change the course of organic reactions that remained unmatched by any other conventional reaction media, the non-solvent applications drew attention. Thus, in the quest for non-solvent applications of imidazolium cation-based ILs in promoting organic reactions, including synthesis of heterocycles, we unraveled the organocatalytic role of ILs as “ambiphilic dual activators” acting through “cooperative hydrogen bond (HB) and charge–charge interaction.” These findings are the early examples of supramolecular organocatalysis for which the HB formation has been demonstrated by time-dependent infrared and 1H NMR experiments, and the involvement of the respective supramolecular species was established by ESI and MALDI mass spectrometric ion fishing [97–102] and triggered interests on HB-assisted catalysis by ILs in organic synthesis [103, 104]. As water occupies the top position in the list of preferred solvents of the solvent selection guide of pharma industry [46], organic synthesis in aqueous medium gained popularity [105–111]. Though proposals such as “on water,” “in water,” and “in the presence of water” have emerged [112–117] to account for the beneficial role of water, the proposal depicting the molecular-level interaction with the reactants remained to be addressed. Our original proposals [118–120] on “electrophile–nucleophile dual activation” through a “cooperative HB network” involving the reactants and water molecule(s) had been of use to rationalize radical–molecule reaction catalyzed by a single water molecule in the gas phase [121] and accounting for selective formation of the sixmembered THP oxacycle in competition with the five-membered THF ring via epoxide ring-opening cascade promoted by marine water [122]. The HB-mediated “synergistic electrophile–nucleophile dual activation” by water in promoting organic reactions represents a conceptual advancement and provides scope for rational use of water in performing organic reactions and enabled to design some novel “allwater” chemistries for the synthesis of drugs [123, 124] and regio-defined synthesis

Figure 6.1: Quinoline-containing drug molecules.

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Figure 6.2: Drug molecules and natural products having quinoline-fused ring system.

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of diverse N-aryl/arylmethyl-2-substituted benzimidazoles [125, 126] via one-pot tandem N-alkylation–reduction–condensation route. The HB-assisted electrophile/nucleophile activation by water also enabled to utilize simultaneously the benefit of aqueous medium and Pd-derived nanocatalysis for the synthesis of drugs in different therapeutic areas [127]. Keeping in view of the versatile applications of quinoline-based heterocyclic compounds [1–28, 128, 129] that encourage the development of new methods of construction of the quinoline ring system and the necessity for adopting sustainability in chemical reactions/processes, in this chapter, we have highlighted literature reports on the quinoline synthesis performed in aqueous medium.

6.2 Recent developments in the synthesis of quinolines in aqueous media The literature reports on quinoline synthesis in aqueous medium can be classified into three protocols wherein the reactions are performed by employing catalysts, utilizing surfactants to enhance the solubility of the substrates in aqueous medium, and under catalyst-free conditions. These are discussed individually in the following sections.

6.2.1 Catalyst-based approaches for synthesis of quinoline derivatives in aqueous medium The catalyst-based aquatic synthesis of quinoline compounds involves the use of water as the reaction medium in the presence of catalysts to facilitate the formation of quinoline ring. These methods have gained attention due to the adoption of green chemistry principles, mild reaction conditions, and functional group compatibility. In these protocols, various catalysts have been employed, including metal-derived catalysts, organocatalysts, photocatalysts, and biocatalysts. The choice of catalyst depends on the particular reaction and desired quinoline derivatives. The examples mentioned below provide a glimpse of the diverse range of quinoline synthesis in aqueous medium performed in the presence of a catalyst. IL was employed as organocatalyst in the Friedlander annulation reaction of 2aminobenzophenone derivatives (1) with the α-methylene group containing ketone derivatives (2) to synthesize the desired substituted quinoline derivatives (3) (Figure 6.3) [130]. The IL behaves as organocatalyst through C-2 hydrogen-mediated hydrogen bonding with the electrophiles and the counter anion-mediated nucleophile activation. This dual nucleophile–electrophile activation facilitates the Friedlander annulation process. The reaction was also explored in the absence of water, and no product was formed. It

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indicates the role of water in the course of the reaction. In this reaction, water promotes the precipitation of nonpolar-type quinoline derivatives during the ongoing reaction, favoring the forward step of the quinoline synthesis. Additionally, the presence of water helps to separate the final compound and recycling of the IL. The commercially available ILs are costly or have to be prepared in the laboratory prior to the synthesis. Hence, its recycling reduces the cost of synthesis for a group of molecules. The ILs were recycled up to fifth cycle without any significant loss in the catalytic efficiency.

Figure 6.3: Ionic liquid-catalyzed Friedlander synthesis of quinolines.

Reddy et al. [131] reported a multicomponent domino process catalyzed by montmorillonite K-10 in water to synthesize 2-substituted quinolines (7) by the one-pot reaction of anilines (4), aldehydes (5), and ethyl acetate derivatives (6) (Figure 6.4). During the progress of the reaction, initially, under mild acidic conditions, aniline 4 reacts with aldehyde 5 to generate imine 4a. Simultaneously, ethyl 3,3-diethoxypropanoate 6 undergoes hydrolysis by liberating the aldehyde functionality and is converted to its tautomeric form ethyl β-hydroxy acrylate (8). The imines 4a and 8 then participate in a Mannich reaction, followed by an intramolecular cyclization, leading to the formation of 1,2dihydroquinoline 4c intermediate. Subsequent oxidation of 4c in the presence of air/oxygen results in the formation of the desired product 7. The involvement of air/ oxygen is further supported by the isolation of ethyl 2-(3,4-difluorophenyl)-6,7dimethoxy-1,2-dihydroquinoline-3-carboxylate 4c when the MCR involving 4, 5, and 6 was carried out under inert atmospheric conditions while keeping the other conditions consistent. The Rh(II) acetate/TPPTS-catalyzed synthesis of disubstituted quinolines (10) from the reaction of allylic alcohols (9) and aniline derivatives (4) has been performed in water [132]. Though the Rh-based catalyst was expensive, the recyclability of Rh(II) acetate/TPPTS up to five times compensates the cost-related disadvantage of the reaction methodology. In situ oxidation of the allylic alcohols to the ketone derivatives followed by homo aldol condensation between the carbonyl compounds furnished the corresponding enones, which further undergo aza-Michael addition reaction with the

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Figure 6.4: Montmorillonite K-10-catalyzed one-pot synthesis of substituted quinolines 7.

anilines. In the final step, the ring assisted cyclocondensation reaction followed by aromatization process generated the desired quinolines (Figure 6.5).

Figure 6.5: Rhodium-catalyzed synthesis of quinolines.

The base-promoted synthesis of indolo[2,3-b]quinoline-11-carboxylic acid 13 was carried out by the reaction between 3-acetyl-2-ethoxyindole 11 and isatins 12 in aqueous medium under reflux condition (Figure 6.6) [133]. This strategy also highlights the potential for the creation of more complex indolo[2,3-b]quinoline alkaloid derivatives. The presence of the carboxyl functional group on the indolo[2,3-b]quinoline ring is significant as it positions these molecules as promising building blocks for the development of novel neocryptolepine alkaloid derivatives. The plausible reaction mechanism suggests the ring opening of 12 by KOH to form 2-(2-aminophenyl)-2-oxoacetate 12a. This intermedi-

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ate then undergoes a condensation reaction with 3-acetyl-2-ethoxylindole 11, leading to the formation of fused indolo[2,3b][1]benzazocine-5-carboxylate 12b. Subsequently, a base-mediated tautomerization occurs, generating the enol form 12d. In the proposed mechanism, it is hypothesized that the generated enol form undergoes an intramolecular electrocyclic reaction, facilitated by ambient light. It is suggested that the substituent present in the molecule may positively influence the rate of the subsequent thermal pericyclic reaction. The polycyclic-fused system 12e possesses inherent ring strain, making it prone to strain-releasing reactions at the refluxing temperature. This leads to the cleavage of the cyclobutanone ring and the unexpected formation of indolo[2,3-b]quino-

Figure 6.6: Synthesis of derivatives of indolo[2,3-b]quinoline 13 with polycyclic fusion.

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line moiety 13. The overall reaction has been proposed to proceed through a tandem electrocyclic reaction/thermal ring cleavage sequence (Figure 6.6). The synthesis of C-2-substituted quinolines (16) was achieved [134] by carrying out the reaction of secondary alcohols (14) with 2-aminobenzyl alcohols (15) in the presence of heterogeneous recyclable copper catalyst using water as reaction medium (Figure 6.7). The reaction proceeds through the in situ oxidation of both the 2-aminobenzyl alcohols (15) and the secondary alcohols (14) to the corresponding ketones, and the remaining reaction sequences follow the Friedlander reaction pathway to construct quinolines 16 (Figure 6.7). Apart from the use of water as green reaction medium, the recyclability of the catalyst up to five times adds to the sustainability of the process.

Figure 6.7: Heterogeneous catalysis for the synthesis of quinolines.

Elias and coworkers developed the synthesis of N-containing heterocyclic compounds by adopting the eco-friendly approach to carbon–carbon bond formation using alcohols as alkylating agents. The authors disclosed the synthesis of a water-soluble catalyst based on ruthenium(II) consisting of 8-aminoquinoline and p-cymene ligand (Figure 6.8). This catalyst was utilized in the reaction of secondary alcohols or ketones (14) and 2-aminobenzyl alcohols (15) to construct the quinoline scaffold (16) in water as a sustainable reaction medium [135]. A wide range of 2-aminobenzyl alcohols, including those with electron-donating (methyl and methoxy), electron-withdrawing (e.g., CF3), and halo (fluoro and bromo) groups, on the aryl ring exhibited successful reactivity with the secondary alcohols 14. The catalyst was sufficiently effective for the synthesis of quinolines through a sequential process involving acceptor dehydrogenation and cyclization (Figure 6.9).

Figure 6.8: Ruthenium-based catalyst for the synthesis of quinolines.

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Figure 6.9: Quinoline 16 synthesis using 2-methyl benzyl alcohol 14 and 2-aminobenzyl alcohols 15.

Figure 6.10 depicts the plausible mechanistic pathways for the progress of the reaction through various stages. The catalyst [Ru]-1 reacts with the base KtOBu, generating an active species denoted as [Ru]-1a. This species “[Ru]-1a” then reacts with primary or secondary alcohols, leading to the formation of alkoxy intermediates 14a and 15a. These intermediates undergo a β-hydride elimination reaction, resulting in the conversion of intermediates 14a and 15a into aldehyde 14aa and ketone 15aa, respectively. Simultaneously, a ruthenium hydride complex intermediate 14b is formed. The in situ generated aldehyde 15aa and ketone 14aa undergo a cross-aldol condensation reaction under basic conditions, resulting in the formation of α,β-unsaturated carbonyl compound 15b. The ruthenium hydride intermediate 14b selectively reduces the double bond into the saturated carbonyl compound 15c, resulting in the formation of the αalkylated ketone. In the synthesis of quinoline 16, the formation of α-alkylated ketone 15c is followed by a further step, including imination and cyclization [135].

6.2.2 Quinoline synthesis in aqueous medium using surfactants While many organic transformations can take place in water, the lack of solubility of the reactants often limits the scope of the reaction. As a workaround, the “on-water” strategy has emerged, which uses surfactants to enable the progress of the reaction promoted by micelle in aqueous medium [136]. The anionic surfactant sodium dodecyl sulfate (SDS) and Brønsted acidic surfactant p-dodecylbenzenesulfonic acid (DBSA) promoted the synthesis of heterocyclic compounds in aqueous medium and this has been reported by us [137, 138]. The role of the surfactants has been presumed to be the formation of micellar assemblies as microreactors to encapsulate the reactants so that under such confinement, they take part in chemical reaction. The solubility of hydrophobic substances in water is greatly enhanced by the addition of surfactants and detergents. They could even be able to stabilize and orient substrates in ways that change their reactivity. However, the role of surfactant may not necessarily be limited to its ability to enhance the solubility of organic substances in water as sometimes there remains a possibility to derive new chemistries such as transition-metalfree dioxygen activation, leading to aquatic aerobic oxidation at room temperature [139].

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Figure 6.10: Plausible mechanism of formation of the α-alkylated ketone and quinolines 16.

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The strategy of surfactant-assisted organic reaction in aqueous medium has been successfully utilized for the synthesis of various functionalized quinolines. The Friedlander annulation process for the synthesis of substituted quinolines (3) was carried out by the reaction of 2-aminobenzophenone derivatives (1) with the α-methylene group containing ketones (2) in the presence of dodecylphosphonic acid that acts as both surfactant and catalyst in water as reaction medium (Figure 6.11) [140].

Figure 6.11: Dodecylphosphonic acid-catalyzed synthesis of quinolines.

Earlier, our research group reported the construction of the quinoline scaffolds via Friedländer annulation under the influence of In(III)-derived Lewis acid catalyst [141, 142]. Though these methodologies were performed under neat conditions to extend the chemistry toward a metal-free process, it was planned to use a Brønsted acid that would facilitate the Friedländer annulation in place of a metal catalyst and would also be compatible with water so as to devise a sustainable methodology for quinoline synthesis in water as green reaction media. The Friedlander synthesis of bioactive quinolines (3) has been achieved in the presence of DBSA that acts as both surfactant and catalyst in water as reaction medium [143]. The Friedlander annulation reaction between 2-amino-aromatic aldehydes/ketones (1) and α-methylene group-containing carbonyl derivatives (2) was carried out at moderate temperature (Figure 6.12). The notable advantages of this reported methodology are the wide substrate scope, easy purification of the final compound, shorter reaction time, and the requirement of low amount of surfactant. The quinoline esters and the amides derivatized from those esters were subjected to in vitro evaluation of antitubercular (TB) activity to identify new therapeutic lead as anti-TB agent.

Figure 6.12: Synthesis of quinolines in the presence of DBSA.

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An environment-friendly alternative to the conventional Pfitzinger reaction for the synthesis of quinoline-4-carboxylic acids 18 was explored. The traditional Pfitzinger process involves the reaction of isatin (12) with ketone (17), catalyzed by strong bases like NaOH and KOH. However, these bases are challenging to recycle, and the reaction leads to the formation of highly basic waste. To address these issues, a recyclable and water-soluble basic catalyst was sought for to facilitate the reaction of generally waterinsoluble substrates. The ring opening of isatin by the basic CTAOH followed by cyclocondensation with ketone derivatives afforded the desired quinolines in the presence of water as reaction media under ultrasound irradiation (Figure 6.13). Among various bases tested, CTAOH emerged as both the most effective catalyst and an efficient surfactant to solubilize the hydrophobic substrates into the water. This alternative approach not only

Figure 6.13: CTAOH-mediated synthesis of quinoline-4-carboxylic acid derivatives 18.

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provides more sustainable method but also overcomes the challenges associated with waste disposal and catalyst recyclability. In the progress of the reaction (Figure 6.13), CTAOH converts isatin to isatoic acid 12g, which further interacts with ketone to form the corresponding imine derivative (12h). The imine–enamine tautomerism favors the cyclocondensation reaction to complete the annulation process (12i). In the final step, the surfactant promoted elimination of water by producing the desired quinoline-4-carboxylic acids. When the products were separated, the aqueous layer, which included CTAOH, was recycled without additional purification. The surfactant was successfully recycled for two times without significant change in the yield of the product [144].

Figure 6.14: One-pot synthesis of polysubstituted quinolines 21.

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An efficient method for synthesizing highly substituted quinolines (21) was reported from the reaction of α-amino ketones (19) with substituted alkynes (20) in aqueous suspension of the surfactants [145]. The reaction was carried out in the presence of molecular iodine as a halogenating agent and K2CO3 as a base, along with the surfactants tetrabutyl ammonium bromide and SDS (Figure 6.14). The use of these surfactants created a micellar system that improved the solubility of the reactants, enabling the facile synthesis of quinoline under mild reaction conditions. The progress of the reaction toward quinoline formation involves several stages (Figure 6.14). The reaction initiates with the deprotonation of α-amino ketone 19 by K2CO3, generating 19a, which then reacts with I2 to form the iodinated species 19b. The next step involves the elimination of HI from 19b, resulting in the formation of an imine intermediate 19c. In the presence of iodine and phenyl alkyne, 20 and 19c undergo an intermolecular cyclization process, leading to the formation of a tetrahydroquinoline species 19d. Subsequently, a proton shift occurs, resulting in the formation of species 19e. Finally, under aerobic conditions, 19e undergoes dehydrogenation/oxidation to form the highly substituted quinoline derivative 21. The reaction protocol was extended for the synthesis of bioactive azalignans (22).

6.3 Conclusions The wide applications of quinoline derivatives in chemical, pharmaceutical, and material sciences provoked the synthetic organic/medicinal chemists to develop novel synthetic methodologies for the construction of quinoline ring. While there has been plethora of methods for this purpose, the harsh reaction conditions, utilization of costly metal catalysts or additives, requirement of non-environmental-friendly solvents, and use of toxic substrates urged for sustainable methods for quinoline synthesis. The use of aqueous medium in performing organic reaction/synthesis has recognized a sustainable tool in pharmaceutical research. In view of this, water was chosen as green solvent by various research groups for the sustainable synthesis of quinoline derivatives. In this chapter, such representative examples are discussed elaborately. As quinoline is a recognized pharmacophoric feature found in various crucial drugs such as bedaquiline and hydroxychloroquine, water-mediated synthetic protocols for quinoline synthesis could be the new addition to the armory of pharmaceutical chemists for sustainable synthesis of quinolines.

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Rajib Sarkar and Chhanda Mukhopadhyay✶

Chapter 7 Aqueous-mediated synthesis of bioactive O-heterocycles 7.1 Introduction Water is the most unique universal eco-friendly safe solvent found in nature and plays a key role as solvent in chemical as well as biochemical reactions in living organisms. The use of water as reaction medium is also helpful to promote a range of reactions in the presence or absence of catalysts, featuring the operational feasibilities under ambient temperature, pressure, microwave and ultrasonic irradiation, and so on [1–8]. This thought to take benefits of aqueous medium resulted in to modify the reaction environment in organic syntheses. Remarkably, the applications of these aqueous-mediated protocols introduce numerous convenient and straightforward ways of developing diverse variety of heterocyclic scaffolds having biological importance. In this perspective, the synthesis of bioactive O-heterocycles by employing the ubiquitous water as the solvent has also been intensely studied. Till date, researchers in the area of aqueous-mediated strategies have projected many efficient catalytic processes under aqueous conditions [9, 10]. Despite the considerable development of aqueous-mediated protocols, at present the literature does not have any systematic review on aqueous-mediated synthesis of bioactive O-heterocycles. This chapter addresses several aspects of synthesis of bioactive O-heterocycles in aqueous medium reported in recent past years. The key aim of this chapter is to appraise the aqueous-mediated protocols and applications to synthesize O-heterocyclic molecules. We suppose that this critical evaluation will provide the key information to develop the future aqueous-mediated protocols. The discussion in the first part covers the catalyzed protocols (Cu-based nanoparticles (NPs)) in aqueous medium. The second portion covers the aqueous-mediated catalyst-free protocols.

Acknowledgments: The first author thanks Prabhu Jagatbandhu College for the kind support. The authors are also thankful to CAS-V (UGC), Department of Chemistry, University of Calcutta. ✶

Corresponding author: Chhanda Mukhopadhyay, Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, West Bengal, India, email: [email protected] Rajib Sarkar, Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India; Department of Chemistry, Prabhu Jagatbandhu College, Jhorehat, Andul-Mouri, Howrah 711302, India https://doi.org/10.1515/9783110985627-007

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7.2 Aqueous-mediated synthesis of bioactive O-heterocycles under catalyzed conditions In 2007, Polshettiwar and Varma [11] established an efficient eco-friendly method for the synthesis of bioactive 1,3-dioxanes (3) through bis-aldol reaction between the ketone (1) and paraformaldehyde (2) catalyzed by polymer-supported commercially available inexpensive Polymer-supported polystyrenesulfonic acid (PSSA) (Figure 7.1). The reaction is carried out in water at 120 °C under microwave irradiation for 20–35 min to produce excellent yield of the product.

Figure 7.1: Microwave-assisted synthesis of 1,3-dioxanes (3) in water.

In 2008, Dabiri et al. [12] developed an efficient method for the preparation of 14Hdibenzo[a,j]xanthenes (6) by the reaction between 2 equivalents of beta-naphthol (4) and 1 equivalent of aliphatic or aromatic aldehydes (5) catalyzed by alum in water at 100 °C (Figure 7.2). A total of 12 various aromatic and aliphatic aldehydes was used to obtain diverse 14H-dibenzo[a,j]xanthenes in good to excellent yields in short time period.

Figure 7.2: Aqueous-mediated synthesis of 14H-dibenzo [a,j]xanthenes (6) catalyzed by alum.

In 2009, Hajra and coworkers [13] also reported another method for the synthesis of 14H-dibenzo[a,j]xanthenes (6) to form beta-naphthol (4) and aldehydes (5) catalyzed by indium(III) triflate in water under reflux (Figure 7.3). Here, 14 aromatic and aliphatic aldehydes were considered to obtain various 14H-dibenzo [a,j]xanthenes in good to excellent yields in 5–15 h.

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Figure 7.3: Aqueous-mediated synthesis of 14H-dibenzo [a,j]xanthenes (6) catalyzed by In(OTf)3.

In 2009, Barbero et al. [14] reported the synthesis of xanthones (8) through remarkable displacement of bromine by a nucleophilic aromatic substitution protocol involving 2-halobenzophenone (7) in the presence of KOH (2.0 equiv.) or NaOtBu (1.0 equiv.) in water at 80–120 °C (Figure 7.4).

Figure 7.4: Aqueous-mediated synthesis of 14H-dibenzo [a,j]xanthenes (8).

In the same year, Khurana and Kumar [15] constructed a simple eco-friendly protocol to synthesize 3,4-dihydropyrano[c]chromenes (11) by the reaction of 4-hydroxycoumarin (9) and aldehydes (5) with malononitrile (10) catalyzed by tetrabutylammonium bromide (TBAB) in water at 100 °C (Figure 7.5). This protocol features numerous advantages, including short reaction time period and excellent yields under environmentally benign reaction conditions.

Figure 7.5: TBAB-catalyzed synthesis of 3,4-dihydropyrano[c]chromenes under aqueous conditions (11).

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Heravi et al. [16] demonstrated a proficient synthesis of 2-(cyclohexylamino)-3-arylindeno[1,2-b]furan-4-one derivatives (14) through a three-component reaction between aldehydes (5), cyclohexylisocyanide (13), and 1,3-indandione (12) in water under reflux (Figure 7.6). Good to excellent yields of 2-(cyclohexylamino)-3-arylindeno[1,2-b]furan-4-ones (14) were obtained in 5 h using the environmentally favorable solvent water.

Figure 7.6: Aqueous-mediated synthesis of 2-(cyclohexylamino)-3-aryl-indeno[1,2-b]furan-4-ones (14).

In 2010, Yao and coworkers [17] established a useful method for the synthesis of tricyclic chromeno-isoxazolines (17) and chromeno-isoxazole (18) from the oxime (15 and 16) catalyzed through [hydroxy(tosyloxy) iodo]benzene in water (Figures 7.7 and 7.8). A total of 18 isoxazolines (17) and 5 isoxazoles (18) was derived in good to excellent yields in 45 min at room temperature.

Figure 7.7: Aqueous-mediated synthesis of tricyclic isoxazolines (17).

Figure 7.8: Aqueous-mediated synthesis of tricyclic isoxazole (18).

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In the same year, Ahadi et al. [18] have studied the piperidine-catalyzed preparation of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitriles (22) in good to excellent yields through a multicomponent protocol involving β-ketoesters (19), hydrazine hydrate (20), and substituted isatins (21) with malononitrile (10) in aqueous media at room temperature for 5 h (Figure 7.9).

Figure 7.9: Piperidine-catalyzed synthesis of spiroindoline-pyranopyrazole derivatives (22) in water.

In 2012, Shingare and coworkers [19] developed an efficient green multicomponent cyclocondensation reaction between ethyl acetoacetate (19), hydrazine hydrate (20), aldehydes (5), and malononitrile (10) for the synthesis of pyrano[2,3-c]pyrazoles (23) (Figure 7.10). The reaction has been promoted by silica in water at room temperature and offers many advantages regarding the reaction time period and yield of the pyrano[2,3-c]pyrazoles (23) including sustainability of the reaction.

Figure 7.10: Aqueous-mediated synthesis of pyrano[2,3-c]pyrazoles (23).

In 2013, Ghahremanzadeh and coworkers [20] established a three-component ecofriendly protocol involving isatins (21), cylohexane-1,3-diones (24), along with active cyanomethanes (10), catalyzed by copper ferrite NPs in refluxing water (Figure 7.11). This is the synthesis of fused spirooxindole heterocycles (25) catalyzed by magnetically retrievable and recyclable copper ferrite NPs under mild conditions. The broad substrate scope has been achieved through the synthesis of various oxindoles (25) in high yields with purity. The copper ferrite NP catalyst of 35 nm was also prepared from aqueous sodium hydroxide by coprecipitation of Cu(NO3)2 and Fe(NO3)2. The op-

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Figure 7.11: Copper ferrite NP-catalyzed synthesis of spirooxindoles (25).

erational simplicity and easy workup with ease of recyclability of magnetically separated nanocatalyst make the protocol more attractive. Patel and coworkers in 2014 [21] developed the synthetic route of benzoxazoles (27) and o-hydroxyanilides (28) from o-haloanilides (26) by using CuO nanocatalyst under refluxing water (Figure 7.12). The inorganic base Cs2CO3 is used as the promoter in the formation of benzoxazoles (27) as one of the product, while the use of organic base N,N, N′,N′-tetramethylethane-1,2-diamine (TMEDA) facilitates the selective synthesis of ohydroxyanilides (28). A wide range of o-halophenylalkylamide derivatives selectively furnish either benzoxazoles (27) or o-hydroxylated amides (28) depending on the base used along with CuO NPs. The reaction is highly versatile with broad substrate scope, and the CuO nanocatalyst is recyclable up to five times with similar catalytic activity.

Figure 7.12: CuO-NP-catalyzed synthesis of benzoxazoles (27).

In 2015, Brahmachari [22] developed a green Knoevenagel reaction of substituted salicylaldehydes (29) with Meldrums acid (30) for the preparation of coumarin-3-carboxylic acids (31) in water at room temperature for 20 h (Figure 7.13). Use of potassium carbonate as an inexpensive and less toxic catalyst provides good to excellent yields of 2-oxo2H-1-benzopyran. The coumarin scaffold is an important pharmacophore and possesses a broad range of medicinal as well as agrochemical uses and applications in optic materials. The present method is environmentally benign featuring no column chromatographic purification of the synthesized coumarin derivatives, and applicable for gram-scale synthesis.

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Figure 7.13: Aqueous-mediated synthesis of coumarin-3-carboxylic acid (31).

In the same year, Liu and his group [23] developed a heterocyclic ionic liquid (32)promoted intramolecular annulation of 5-(aryloxy)-1H-pyrazole-4-carbaldehydes (33) to chromeno[2,3-c]pyrazol-4(1H)-ones (34) (Figure 7.14). This is an oxidative coupling between the aromatic C–H bond and the aldehyde C–H bond in water at 120 °C under metal-free conditions. The heterocyclic ionic liquid has been successfully recycled without losing its activity.

Figure 7.14: Aqueous-mediated synthesis of chromeno[2,3-c]pyrazol-4(1H)-ones (34).

Muthusamy and Ramkumar [24] successfully carried out a rhodium(II)-promoted diastereoselective synthesis of spiro-indolooxiranes (36) and spiroindolodioxolanes (37) (Figure 7.15). The spirocyclic oxindole framework is found to exhibit various medicinal properties; for instance, diuretics, anticonvulsants, sleep potentiators, and transaminase inhibitor. The reaction is carried out between diazoamides (35) and aromatic aldehydes (5) at room temperature to provide moderate to good yields of the products. Most importantly, the method avoids the use of toxic organic solvents and is performed under mild conditions. Subsequently, Liju et al. [25] established an efficient ultrasound-assisted L-prolinecatalyzed multicomponent synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] (39) in 1:1 water/ethanol (v/v) at room temperature in 2015 (Figure 7.16). The reaction has been carried out between dialkyl acetylenedicarboxylate (38), substituted phenylhydrazine (20), substituted isatin (21), and malononitrile (10) to produce spiro[indoline-3,4′-pyrano [2,3-c]pyrazole] molecules (39) in good to excellent yields in aqueous medium under ultrasound irradiation.

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Figure 7.15: Aqueous-mediated synthesis of spiro-indolooxiranes (36) and spiroindolodioxolanes (37) catalyzed by rhodium(II).

Figure 7.16: Aqueous-mediated synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] (39) molecules.

Dam et al. [26], in 2015, have also reported a nano-Fe3O4–DOPA–L-proline-catalyzed fourcomponent protocol to synthesize 12 diversely substituted pyrano[2,3-c]pyrazole (23) derivatives in water (Figure 7.17). The reaction was carried out involving ethyl acetoacetate (19), substituted phenylhydrazine (20), and aromatic aldehyde (5) with malononitrile (10) to produce good to excellent yields of pyrano[2,3-c]pyrazoles (23) at room temperature under aqueous-mediated ultrasound environment for 2–10 min.

Figure 7.17: Preparation of pyrano-pyrazolone derivatives (23).

In 2015, Tabassum et al. [27] also reported an ultrasound-promoted multicomponent synthesis of biologically relevant 2-amino-3-cyano-4H-pyran (40) derivatives in water at room temperature (Figure 7.18). This ultrasound-promoted cyclocondensation involved

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the reactions of compounds having active methylene group (19), aromatic aldehydes (5), and malononitrile (10) catalyzed by iodine in water at room temperature for 10 min to produce excellent yields of the substituted pyrans (40).

Figure 7.18: Preparation of 2-amino-3-cyano-4H-pyrans (40).

At the same time, Safari and Javadian [28] synthesized a series of diversely substituted 2-amino-4H-chromenes (42) in water at 50 °C catalyzed by magnetically separable Fe3O4–chitosan NPs in water (Figure 7.19). The condensation reaction involved various aldehydes (5) with resorcinol (41) and malononitrile (10) under ultrasound environment for 15–25 min to afford excellent yields of the products.

Figure 7.19: Synthesis of 2-amino-4H-chromenes (42) catalyzed by magnetically separable Fe3O4–chitosan nanoparticles in water.

In 2016, Jafari and Ghadami [29] developed a synthetic procedure to form a series of 2-amino-3-cyano-4,5-dihydropyrano[3,2-c]chromenes (44) in water. This is a room temperature protocol involving 4-hydroxycoumarin (43), aromatic aldehydes (5), and malononitrile (10) catalyzed by cetyltrimethyl ammonium bromide (CTAB) (Figure 7.20). The pyrano[3,2-c]chromenes are a class of O-heterocycles showing broad biological properties. Operational simplicity, mild reaction conditions, and good to excellent yields of diverse 2-amino-3-cyano-4,5-dihydropyrano[3,2-c]chromenes (44) including gram-scale synthesis are the main features of this reaction. In 2016, Yazdani-Elah-Abadia et al. [30] developed an L-proline-catalyzed microwaveassisted sustainable synthesis of diverse benzo[a]pyrano[2,3-c]phenazines (48) and benzo [a]chromeno[2,3-c]phenazines (49) through the reaction involving 2-hydroxynaphthalene

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Figure 7.20: Aqueous-mediated synthesis of diverse 2-amino-3-cyano-pyrano[3,2-c]chromen-5(4H)-ones (44) catalyzed by CTAB.

-1,4-dione (45), o-phenylenediamine (46), aromatic aldehydes (5), and 1,3-indandione (47) or 2-hydroxynaphthalene-1,4-dione (22) in water (Figures 7.21 and 7.22). Benzo[a]phenazine-annulated heterocyclic moieties are significant molecular structures bearing phenazine, chromene, and pyran scaffolds within them. The main advantages of this method are operational simplicity, short reaction time, simple workup, excellent yields, and reuse of the organocatalyst without any loss of its activity.

Figure 7.21: Microwave-assisted L-proline-catalyzed aqueous-mediated synthesis of benzo[a]phenazineannulated heterocycles (48).

Figure 7.22: Microwave-assisted L-proline-catalyzed aqueous-mediated synthesis of benzo[a]phenazineannulated heterocycles (49).

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In 2017, Golchin et al. [31] developed diastereoselective synthesis of biologically relevant functionalized benzofurans (52) through the domino reaction between phenacyl bromides (50) with cyclic 1,3-dicarbonyls (51) and aldehydes (5) in the presence of DABCO (1,4-diazabicyclo[2.2.2]octane) as an economically easily accessible catalyst in water under reflux conditions (Figure 7.23). Benzofurans are oxygen-containing heterocycles commonly found in several bioactive natural products as well as widely used in pharmaceuticals. Here, the benzofurans are obtained within short reaction time without chromatographic purification in good to excellent yields under green environment.

Figure 7.23: DABCO-catalyzed aqueous-mediated synthesis of polyfunctionalized benzofurans (52).

Rahimzadeh et al. [32] have also developed a green method to construct substituted oxazoles through the Van Leusen reaction involving tosylmethyl isocyanide (53) and benzaldehyde (5), in 2017 (Figure 7.24). The reaction was carried out in the presence of inexpensive Et3N with β-cyclodextrin (β-CD) as catalyst at 50 °C in water at short reaction time period also.

Figure 7.24: Green method for the Van Leusen synthesis of oxazoles (54).

In 2019, a proficient regioselective oxidative 6-endo-dig oxy-cyclization protocol involving 2-alkynylbenzamide or 2-trimethylsilylethynylbenzamide has been reported by Wang et al. [33] (Figures 7.25 and 7.26). Diverse isocoumarin-1-imines (57) and 3-metheneisobenzofuran-1-imine (58) were prepared, respectively, in good to excellent yields by using 50 mol% TBAB with potassium carbonate and 2 equivalents of oxone in water/THF (1:1, v/v) mixture at 80 °C for overnight.

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Figure 7.25: Aqueous-mediated synthesis of isocoumarin-1-imines (57) via 6-endo-dig oxy-cyclization 2-alkynylbenzamide catalyzed by TBAB.

Figure 7.26: Aqueous-mediated synthesis of 3- metheneisobenzofuran-1-imine (58) catalyzed by TBAB.

In 2019, Maddila et al. [34] developed a Mn-doped zirconia-catalyzed four-component synthetic method to generate a series of diversely substituted pyrano[2,3-c]pyrazole derivatives in water/ethanol mixture (1:1, v/v) at room temperature (Figures 7.27 and 7.28). The reaction was carried out involving ethyl acetoacetate (19) or dimethyl acetylene dicarboxylate (38) with phenylhydrazine (20), aromatic aldehyde (5), and malononitrile (10) to achieve good to excellent yields of pyrano[2,3-c]pyrazoles 23a and 23b, respectively, under aqueous-mediated ultrasound environment for 10–15 min.

Figure 7.27: Aqueous-mediated synthesis of pyrano[2,3-c]pyrazole-3-carboxylate (23a).

Khare et al. [35] also developed a sonochemical method to synthesize 10 diverse 1,2,3triazolyl pyrano[2,3-c]pyrazoles (61) in excellent yields in water at 30 °C for 5–7 min catalyzed by NaHCO3, in 2019 (Figure 7.29).

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Figure 7.28: Aqueous-mediated synthesis of pyrano[2,3-c]pyrazole-3-carboxylate (23b).

Figure 7.29: Aqueous-mediated synthesis of 1,2,3-triazolyl pyranopyrazoles (61).

Abdolmohammadi et al. [36] in 2019 also proposed reported a multicomponent ultrasound-assisted protocol for the synthesis of 12 various substituted chromeno[b]pyridine (63) in water at room temperature (Figure 7.30). The reaction involving 4-aminocoumarin (62), aromatic aldehydes (5), and malononitrile (10) furnished 93–96% yields of the products within 20 min under optimized reaction conditions.

Figure 7.30: Aqueous-mediated ultrasound-assisted synthesis of chromeno[b]pyridines (63).

A ring-closing metathesis reaction of oxygen-bearing dienes (64) with 2 mol% ruthenium as catalyst in H2O at room temperature for 3 h was demonstrated by Kaur [37] in 2019 (Figure 7.31). This method introduces a superior platform to synthesize dihydrofuran (65) in very good yields.

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Figure 7.31: Aqueous-mediated synthesis of dihydrofuran (65).

In 2020, Auria-Luna et al. [38] established a simple ultrasound-assisted multicomponent method to synthesize variously substituted 4H-pyran derivatives (67) catalyzed by Et3N as a readily available catalyst in water at room temperature (Figure 7.32). This is an extremely appealing methodology featuring short reaction times, clean purification, and isolation of the products in excellent yields under aqueous medium for the synthesis of potentially biologically active 4H-pyran scaffolds (67).

Figure 7.32: NEt3-catalyzed aqueous-mediated synthesis of substituted 4H-pyrans (67).

In 2020, a number of diversely substituted pyrazolopyranopyrimidines (69) were prepared in water under ultrasound irradiation at 50 °C by Akolkar et al. (Figure 7.33) [39]. This is a four-component reaction involving ethyl acetoacetate (19), hydrazine (20), and aromatic aldehydes (5) with barbituric acid (68) catalyzed by β-CD. By this methodology, 21 differently substituted triheterocyclic pyrazolopyranopyrimidine derivatives (69) were prepared in good to excellent yields.

Figure 7.33: Aqueous-mediated preparation of pyrazolopyranopyrimidines (69) under ultrasound irradiation.

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Manisha Mishra et al. [40] also reported an expeditious method for the synthesis of 14 different pyrano[2,3-c]pyrazoles (23) in water catalyzed by 18-crown-[6]-ether (Figure 7.34). This is also a multicomponent reaction involving ethyl acetoacetate (19) with substituted phenylhydrazine (20), aromatic aldehyde (5), and malononitrile (10) to achieve excellent yields of pyrano[2,3-c]pyrazoles (23) under aqueousmediated ultrasound environment within 10 min.

Figure 7.34: Aqueous-mediated ultrasound-assisted synthesis of pyrano[2,3-c]pyrazoles (23) catalyzed by 18-crown-[6]-ether.

Polyhydroxyalkyl furans (71) were also synthesized by lipase-catalyzed Knoevenageltype reaction between malononitrile (10) and reducing sugars (70) in water at 60 °C (Figure 7.35) [41]. Among various lipases, the Novozyme-435 provides the best catalytic activity to achieve the product polyhydroxyalkyl furans (71) in very good yield in 6 h.

Figure 7.35: Aqueous-mediated synthesis of polyhydroxyalkyl furans (71) catalyzed by lipase.

7.3 Aqueous-mediated protocols under catalyst-free conditions In 2009, Kumaravel and Vasuki [42] synthesized a library of diverse 2-amino-4-(5-hydroxy -3-methyl-1H-pyrazol-4-yl)-4H-chromene-3-carbonitriles (73) by the reaction between ethyl acetoacetate (19), hydrazine (20), and substituted 2-hydroxybenzaldehydes (72) with malononitrile (10) in water at room temperature under catalyst-free condition (Figure 7.36). A simple process for the synthesis of coumarins (75) was developed by Rehanaanjum, in 2012. The reaction was carried out with β-keto ester (19) and phenolic sub-

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Figure 7.36: Synthesis of 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-4Hchromene-3-carbonitriles (73) in water.

strate (74) in water at room temperature for 12–15 min (Figure 7.37) [43]. The reaction takes place spontaneously at room temperature and was accomplished within 12–15 min to afford up to 89% yields.

Figure 7.37: Aqueous-mediated ultrasound-assisted synthesis of coumarins (75).

In 2012, a green and efficient one-pot, four-component synthesis of methyl-6-amino-5cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates (23) in water is reported by Adeleh et al. (Figure 7.38) [44]. The method is catalyst-free and atom-economical, and does not involve tedious workup or purification affording the target compounds in good yields.

Figure 7.38: Synthesis of methyl-6-amino-5-cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates (23).

In 2013, Bihani et al. [45] developed a green and superior method for the preparation of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole carbonitriles (23) by a

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multicomponent reaction among aldehyde (5), malononitrile (10), ethyl acetoacetate (19), and hydrazine hydrate (20) under refluxing water (Figure 7.39). This is a catalystfree protocol furnishing good to high yield of the biologically active library of products under environmentally benign conditions.

Figure 7.39: Aqueous-mediated synthesis of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c] pyrazolecarbonitriles (23).

In 2015, Shabalala et al. [46] also developed a multicomponent protocol for the synthesis of eight various pyranopyrazoles (23) in water under ultrasound at 50 °C (Figure 7.40). Employment of ultrasound requires 0.5–1.5 h to build the pyranopyrazoles in good to excellent yields, and no chromatographic purification was needed.

Figure 7.40: Synthesis of pyranopyrazoles (23) in water under ultrasound environment.

In 2017, Deb et al. [47] established a catalyst-free multicomponent green reaction between aldehydes (5), naphthols (76), and tetrahydroisoquinolines (77) to synthesize 1,3oxazines (78) (Figure 7.41). The reaction was carried out under aqueous medium in the presence of molecular O2 (1 atm) at 100 °C for 12–20 h. This is a catalyst-free green protocol. Initially, formation of 1-aminoalkyl-2-naphthols takes place and is followed by cyclization to the desired product in moderate yields. Aromatic aldehydes with methyl, fluoro, bromo, chloro, iodo, methoxy, and nitro functional groups are well compatible to furnish the desired products. Interestingly, the para-substituted aromatic aldehydes produce better yield as compared to ortho- and meta-substituted aldehydes. Furthermore, the heterocyclic aldehydes are also able to produce the products in moderate yields. However, the aliphatic aldehydes did not react under the same optimized reaction condition. The same reaction leads to moderate yields of the products, when carried out under open air.

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Figure 7.41: Aqueous-mediated synthesis of 1,3-oxazines (78).

In 2017, the group of Xiao [48] studied the formation of spiro-tetrahydroquinolines (81) under water at room temperature (Figure 7.42). Here the C(sp3)–H bond functionalization is an “on-water” process involving 2-(pyrrolidin-1-yl)benzaldehydes (79) with 4-hydroxycoumarins (80). The reactions were carried out for 25 h to acquire the spiro-tetrahydroquinolines in good to excellent yields.

Figure 7.42: Aqueous-mediated synthesis of spiro tetrahydroquinolines (81).

In 2017, Lee and Sanford [49] developed a regioselective C(sp3)–H oxygenation, where the protonated 1°, 2°, and 3° aliphatic amines were successfully hydroxylated under aqueous medium (Figure 7.43). Here, potassium persulfate was used as the oxidant to promote the desired reaction in water at 80 °C. Most significantly, this reaction has been applied to the synthesis of bioactive molecules, including Alzheimer’s drug memantine. The selective oxygenation at the tertiary C(sp3)–H of the epilepsy drug pregabalin (82) takes place to produce the heterocyclic lactone A (83). In 2019, a straightforward three-component protocol involving aryl-glyoxalmonohydrates (84) and acetylacetone (85) with barbituric or thiobarbituric acid (86) furnished the polyfunctionalized 5-(furan-3-yl)barbiturates or 5-(furan-3-yl)thiobarbiturate derivatives (87) in good yields (Figure 7.44) [50]. This method deals with readily accessible starting materials in water at 60 °C for 10 h, under catalyst-free environmentally benign conditions.

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Figure 7.43: Aqueous-mediated synthesis of heterocyclic lactone A (83).

Figure 7.44: Synthesis of 5-(furan-3-yl)barbiturate/thiobarbiturates (87) in water.

7.4 Conclusions Aqueous-mediated protocols are found to be very effective for the synthesis of a variety of differently substituted bioactive heterocyclic molecules. As a result, the last decade has seen tremendous outburst to design new protocols for the synthesis of various bioactive heterocyclic molecules under aqueous reaction conditions. Using aqueous reaction conditions, the synthesis of O-heterocycles also has gained significant attention. This chapter summarizes the applications of aqueous-mediated synthesis of various bioactive O-heterocyclic molecules such as spirooxindoles, benzoxazoles, coumarin-3-carboxylic acid, chromeno[2,3-c]pyrazol-4(1H)-ones, spiro-indolooxiranes, spiroindolodioxolanes, 2amino-3-cyano-pyrano[3,2-c]chromen-5(4H)-ones, benzo[a]phenazine-annulated heterocycles, polyfunctionalized benzofurans, substituted 4H-pyrans, 6-amino-4-aryl-3-methyl -2,4-dihydropyrano[2,3-c]pyrazole carbonitriles, 1,3-oxazines, spiro–tetrahydroquinolines, and heterocyclic lactone under green environment. All the catalyzed and catalyst-free protocols were highlighted in this chapter. We expect that this review will draw more attention and contributions in the field of aqueous-mediated reactions. The concepts of green chemistry have always gained much attention, and the innovation of more efficient and greener reaction conditions in aqueous medium is highly appreciated.

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[44] Adeleh MZ, Issa E, Hamid RK. A green and convenient approach for the synthesis of methyl 6-amino -5-cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates via a one–pot, multi–component reaction in water. Tetrahedron Lett 2012, 53, 5519–5522. [45] Bihani M, Bora PP, Bez G. J Chem 2013, 2013, 1–8. [46] Shabalala NG, Pagadala R, Jonnalagadda SB. Ultrasonic-accelerated rapid protocol for the improved synthesis of pyrazoles. Ultrason Sonochem 2015, 27, 423–429. [47] Deb ML, Pegu CD, Borpatra PJ, Saikia PJ, Baruah K, K P. Catalyst-free multi-component cascade C-Hfunctionalization in water using molecular oxygen: An approach to 1,3-oxazines. Green Chem 2017, 19, 4036–4042. [48] Zhu S, Chen C, Xiao M, Yu L, Wang L, Xiao J. Construction of the tetrahydroquinoline spiro skeleton via cascade [1,5]-hydride transfer-involved C(sp3)-H functionalization “on water”. Green Chem 2017, 19, 5653–5658. [49] Lee M, Sanford MS. Remote C(sp3)-H Oxygenation of protonated aliphatic amines with potassium persulfate. Org Lett 2017, 19, 572–575. [50] Dehghanzadeh F, Shahrokhabadi F, Anary-Abbasinejad M. A simple route for synthesis of 5-(furan-3yl) barbiturate/thiobarbiturate derivatives via a multi-component reaction between arylglyoxals, acetylacetone and barbituric/thiobarbituric acid. Arkivoc 2019, part v, 133–141.

Yadavalli Venkata Durga Nageswar✶, Katla Ramesh, and Katla Rakhi

Chapter 8 Aqueous-mediated synthesis of bioactive S-heterocycles 8.1 Introduction Heterocyclic chemistry deals with the synthesis, properties, and reactions of heterocyclic compounds encompassing about 65% of organic chemistry literature [1]. Heterocyclic compounds belong to a major class of cyclic organic compounds containing at least one atom of an element other than carbon in the ring. Structurally, these can be viewed as derivatives of carbocyclic analogues by substitution of one or more ring carbons with heteroatoms such as nitrogen, oxygen, or sulfur. Heterocycles can be classified based on their electronic structures as well as the ring size. These are widely distributed in nature and play a significant role in many biological processes (Figure 8.1). Moreover, with their diversified richness in structural, pharmaceutical, biological, and other properties as well as versatile applications, these compounds continue to influence regular human life. Among these, sulfur-containing heterocyclic compounds are common constituents of petroleum and liquids derived from coal. These are also present in many microorganisms and plants as well as they are pharmaceutically important molecules. Paul Anastas and John Warner postulated the 12 principles of green chemistry in the 1990s, for the development of new chemical processes and analytical techniques, and to reduce the pollution burden on the environment [2, 3]. In general, these include avoiding toxic and volatile organic solvents, reducing energy requirements for the reactions, preventing/minimizing formation of hazardous products/by-products, designing safer biodegradable chemicals, and utilizing safer, recyclable, and higher yielding catalysts. Presently, one of the most active and important areas of research and development in both basic and industrial domains is “green chemistry.” Organic reactions and processes generally involve the use of solvents, which are inflammable and hazardous. In turn, the use of solvent in various lab and industrial processes causes chemical pollution, health hazards, and burden on environment disturbing the ecological balance. A Acknowledgments: The author Ramesh Katla (Foreign Visiting Professor-Edital N. 03/2020) thanks the PROPESP/FURG, Rio Grande-RS, for visiting professorship. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. ✶

Corresponding author: Yadavalli Venkata Durga Nageswar, Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, Telangana, India, email: [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/10.1515/9783110985627-008

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Figure 8.1: Some important bioactive S-heterocycles.

search and application of an alternate medium for the chemical reactions is desirable and need of the hour. Among alternate media, naturally abundant, economically viable, nontoxic universal solvent water occupies the prime position. In view of the advantages derived by the use of water as a solvent, there is an increasing trend to perform organic reactions in water [4–9]. Development of operationally simple, economically viable, and environmentally benign strategies for the synthesis of varied chemical libraries of biologically important scaffolds is a promising area of research [10–19]. This review addresses the recent research works employing water as the reaction medium in the synthesis of sulfur-containing heterocyclic compounds.

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8.2 Recent research work 8.2.1 Sodium fluoride catalysis Banothu et al. [20] described the synthesis of 2,4-disubstituted-1,3-thiazoles (1) and selenazoles (2) by the reaction of phenacyl bromides (3)/3-(2-bromoacetyl)-2H-chromen2-one (3a) and thiourea (4)/phenylthiourea (4a)/selenourea (4b) in aqueous methanol at ambient temperatures employing sodium fluoride as a mild and efficient catalyst. The authors compared the catalytic efficiencies of different metal halides such as KF, NaF, CuCl2, AlCl3, SnCl2, Bacl2, PCl5, CuPy2Cl2, and CoPy2Cl2 and observed the superior activity of NaF for this reaction (Figure 8.2).

Figure 8.2: Synthesis of 2,4-disubstituted-1,3-thiazoles and selenazoles.

8.2.2 NBS-promoted synthesis Shinde and Kshirsagar [21] unveiled N-bromosuccinimide (NBS)-promoted one-pot ecofriendly synthesis of substituted imidazopyridines (5) and thiazoles (6) from commercially available styrenes (7) via the formation of α-bromoketones (3) followed by the reaction with suitable nucleophiles like 2-aminopyridines (8) or thioamides (9) in water medium at 80 °C. During the optimization studies, the authors examined the efficiencies of different halide sources, oxidants, and suitability of several solvents. It was observed that there was no need of co-oxidant for the successful conduct of the reaction. 1,2Dichloroethane (DCE), dimethyl sulfoxide (DMSO), CH3CN/H2O, DMSO/H2O, H2O/dioxane, H2O/acetone, and H2O were tried as solvents. I2, NIS, NBS, KI, NCS, tetrabutyl ammonium bromide (TBAB), and Br2 were assessed for the best results (Figure 8.3). Liang Chen et al. [22] unveiled a facile, eco-friendly one-pot synthesis of imidazoles (10–13) and thiazoles (14–17) promoted by NBS in water medium from ethyl arenes (18) via in situ formation of α-bromoketone (3) under metal-free conditions. In the initial screening studies, the authors investigated the suitability of various reaction parameters such as solvents, oxidants, reaction temperature, and effects of different bases on the methodology. The authors also checked the influence of several bromine

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Figure 8.3: Preparation of substituted imidazopyridines and thiazoles.

sources on the reaction and conducted the scalability studies. The protocol was extended to the preparation of gastroprotective drug Zolimidine (11) (Figure 8.4a–c). Wagare et al. [23] developed facile aqueous-phase one-pot protocol for the preparation of 4-aryl-2-aminothiazoles (20) obtained by the reaction of aromatic ketones (21) and thioureas (4) assisted by NBS (22) in polyethylene glycol (PEG)-400 under microwave irradiation at 80 °C. The method avoids the use of lachrymatory α-haloketones. The authors determined the suitability of different solvents like toluene, CH2Cl2, EtOH, [Bmim]PF6, H2O, and PEG + H2O. Electronic effects of the functional groups situated on acetophenone ring exhibited only small effects on the yields of the products (Figure 8.5).

8.2.3 Erucin derivatization Sharma et al. [24] developed an efficient metal-free and green protocol for the synthesis of benzazole (23/24) and thiourea (25/26) analogues of erucin in aqueous medium in the absence of any base from naturally occurring erucin. In the initial screening, various solvents such as EtOH, PhCH3, CH3CHOHCH3, H2O, and EtOH/H2O were studied for the suitability. The protocol tolerates many sensitive functional groups, affording a diverse range of azoles (23/24) and thiourea (25/26) bearing entities (Figure 8.6a –d).

Chapter 8 Aqueous-mediated synthesis of bioactive S-heterocycles

(a)

(b)

(c)

Figure 8.4: (a) Preparation of imidazo[1,2-a]pyridines; (b) synthesis of Zolimidine; and (c) highly substituted imidazoles and thiazoles.

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Figure 8.5: Synthesis of 4-aryl-2-aminothiazoles assisted by NBS.

Figure 8.6: Synthesis of (a) benzazole and thiourea analogues of erucin; (b) benzazole analogues; (c) thiourea analogues of erucin by the reaction with primary amines; and (d) thiourea analogues of erucin by the reaction with secondary amines.

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Figure 8.6 (continued)

8.2.4 β-CD-mediated synthesis Bandaru Madhav et al. [25] developed a first-ever tandem mild one-pot aqueousphase synthetic protocol for thiazole (29)/selenazole (30) derivatives in the presence of β-cyclodextrin (β-CD) by employing a three-component reaction involving alkynes (31), thiourea (4)/selenourea (4b), and NBS (22). The reaction proceeded through the in situ formation of 2,2-dibromo-1-phenylethanone (32) from NBS (22) and alkyne (31), which further reacted with thiourea (4)/selenourea (4b) resulting in the title compounds. The scope of the methodology was expanded by using various substituted thiourea (4)/selenourea (4b) derivatives as well as different phenyl acetylenes (31) (Figure 8.7a and b).

Figure 8.7: β-CD-mediated preparation of (a) thiazole derivatives and (b) selenazoles.

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Figure 8.7 (continued)

Ramesh Katla et al. [26] demonstrated an efficient, environmentally benign aqueous phase synthesis of benzothiazoles (33)/benzimidazoles (34), assisted by β-CD, and obtained by the reaction of aromatic aldehydes (35) with 2-aminothiophenol (27a)/ophenylene diamine (27b). β-CD was recycled up to four runs (Figure 8.8).

Figure 8.8: Synthesis of benzothiazoles/benzimidazoles assisted by β-cyclodextrin.

8.2.5 K2S2O8-mediated oxidative condensation Yang et al. [27] reported nontransitional metal-involved preparation of 2-aryl benzothiazoles (36/37) by the oxidative condensation of benzothiazoles (38) with arylaldehydes (35) mediated by K2S2O8, in the presence of DMSO and water mixture at 100 °C (Figure 8.9a and b).

Figure 8.9: Preparation of (a) 2-arylbenzothiazoles and (b) benzothiazole derivatives from glyoxalic acids.

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Figure 8.9 (continued)

8.2.6 Nafion-H-promoted synthesis Kidwai et al. [28] presented a simple, efficient, and ecofriendly method for 2aminothiazoles (40) from α-bromoketones (3) and thioureas (4) employing NafionH as a reusable solid-supported catalyst in PEG–water system. Several solvents like EtOH, CH3CN, THF, toluene, ethylene glycol, PEG 400, and PEG/H2O were studied for suitability and successful results (Figure 8.10).

Figure 8.10: Preparation of 2-aminothiazoles assisted by Nafion-H.

8.2.7 (NH4)2HPO4 or 10% DABCO-assisted preparation Saeed Balalaie et al. [29] described a simple and efficient aqueous-phase synthetic protocol for 2-aminothiazole (41) and 2-iminothiazolidine (42) derivatives, from the reaction of phenacylbromide (3) with thiourea (4) derivatives employing economical, watersoluble, and nontoxic salt 10% diammonium hydrogen phosphate–(NH4)2HPO4 or 10% DABCO at room temperature. Iminothiazolidine derivatives (42) were prepared by the

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reaction of phenacyl bromide (3) with N,N-disubstituted thioureas (4c), which were obtained from primary amines (8a) and phenyl isothiocyanate (28a) (Figure 8.11).

Figure 8.11: Preparation of 2-aminothiazole and 2-iminothiazolidine derivatives.

8.2.8 Microwave/ultrasound-assisted/conventional synthesis Dandia et al. [30] brought out a simple one-pot three-component condensation reaction of 2-aminobenzothiazole (43), malononitrile (44)/ethylcyanoacetate (44a), and carbonyl compounds (45) affording pyrimido[2,1-b]benzothiazole (46) derivatives involving Knoevenagel condensation followed by Michael addition and cyclization in water medium. Various reaction conditions were examined before finalizing the reaction parameters. The protocol was tried under both conventional and microwave heating as well as under the influence of ultrasound (Figure 8.12).

Figure 8.12: Synthesis of [2,1-b]pyrimidobenzothiazole derivatives.

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8.2.9 Cu(II)–DiAm–Sar/SBA-15-catalyzed synthesis Mohammadi et al. [31] prepared a novel environmentally benign recyclable heterogeneous and highly active catalyst Cu(II)–DiAm–Sar/SBA-15 by anchoring Cu(II)–DiAmsar complex on the mesoporous SAB-15 support (47). The catalyst was later applied successfully in the synthesis of benzothiazole derivatives (48) from 2-aminothiophenol (27a) and substituted aryl aldehydes (35) in water medium. The catalyst was characterized by using various physicochemical techniques such as X-ray diffraction, transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), and Brunauer–Emmett–Teller to assess the pore dimensions, morphology, catalyst loadings, and functional group analysis. The authors successfully demonstrated the functionalization of silica with diamine-sarcophagus and subsequent complexation with copper(II) (Figure 8.13a and b). (a)

(b)

Figure 8.13: (a) Synthesis of benzothiazole-based heterocyclic derivatives catalyzed by Cu(II)–DiAMsar/ SBA-15 in water and (b) catalyst structure.

8.2.10 Copper salt-assisted synthesis Nilufa Khatun et al. [32] narrated a straightforward, efficient, and sustainable method for the aqueous-phase synthesis of 2-aminobenzothiazoles (49–56) from the in situgenerated α-halothioureas (4) and various substituted isothiocyanates (28b) promoted by CuI (5 mol%) at 90–100 °C. It was reported that aromatic isothiocyanates (28b) having electron-donating substituents such as 4-Me, 4-OMe, and 2,6-(CH3)2 showed most effective coupling. Substrates

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with electron-withdrawing groups such as 4-Br, 3-NO2, 2-Cl, 4-CF3, and 4-CN required longer reaction times. Unusual demethoxylation of o-methoxy-2-iodo-arylthiourea was observed. In the case of 1-(2-iodo-1-methyl-phenyl)-3-(2-methoxyphenyl)thiourea, demethoxylation followed by methylation was observed (Figure 8.14a –f). (a)

(b)

(c)

Figure 8.14: Synthesis of (a) 2-aminobenzothiazoles from 2-iodoaniline and different isothiocyanates; (b) 2-aminobenzothiazole derivatives from 4-methyl-2-iodoaniline and various isothiocyanates; (c) 2aminobenzothiazoles from secondary amines with 2-iodophenyl isothiocyanates; (d) 2aminobenzothiazoles from 2-bromo/2-chloroanilines; (e) CuI-catalyzed 2-aminobenzothiazoles; and (f) 2aminobenzothiazoles catalyzed by CuI in aqueous medium.

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(d)

(e)

(f)

Figure 8.14 (continued)

Sahoo et al. [33] unveiled a mild, environmentally benign Cu(II) salt-catalyzed chemoselective oxidative transformation of unsymmetrical thioureas (4) to thioamidoguanidine (60/61) at room temperature via oxidative dimerization followed by an imine disulfide rearrangement. 2-Aminobenzothiazole (62) derivatives were obtained at 80 °C via dehalogenation route. Reactive halogens (–Br, –I) on thioureas provide 2-aminobenzothiazoles (62) at room temperature only (Figure 8.15a –c). Xia et al. [34] achieved an efficient and rapid green synthesis of Nebularine (64) and vidarabine (65) via dehydrazination of a wide range of heteroaromatics (66) in aqueous medium in the presence of CuSO4 as the catalyst. In the initial studies, the authors worked on 9-benzyl-6-hydrazinopurine as a model substrate for finalizing the reaction conditions. During the course of study, various catalysts like AgNO3, Mn(OAc)3, FeSO4, K3Fe(CN)6, and CuSO4 were examined for their efficiencies. It is reported that the catalytic system could tolerate different functional groups, including F, Cl, NH2, alkyl, allyl, ribosyl, deoxyribosyl, and arabinofuranosyl groups (Figure 8.16).

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(a)

(b)

(c)

Figure 8.15: Synthesis of (a) thioamidoguanidine compounds from aryl isothiocyanates and secondary amines; (b) thioamidoguanidines from aryl isothiocyanates and secondary amines; and (c) 2-aminobenzothiazoles from 2-haloaryl isothiocyanates and secondary amines.

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Figure 8.16: Dehydrazination of heteroaromatic substrates.

8.2.11 CTAB-catalyzed synthesis Yang et al. [35] communicated an eco-friendly aqueous-phase one-pot synthesis of 2substituted benzothiazoles (67–69) obtained by the condensation of 2-aminothiophenol (27a) and aldehydes (alkyl, aryl, heteroaryl, and 2-aryl formyl) (35) by employing cetyl-

Figure 8.17: Preparation of 2-substituted benzothiazole derivatives promoted by CTAB.

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trimethylammonium bromide (CTAB) without the requirement of any additional oxidants or solvents (Figure 8.17).

8.2.12 Sm(OTf)3-catalyzed preparation Gorepatil et al. [36] demonstrated the efficiency and recyclability of samarium(III) triflate as a catalyst in the environmentally benign methodology for benzoxazole (71) and benzothiazole compounds (72) obtained by the reaction of o-aminophenols and oaminothiophenols (27/27a) with aliphatic/aromatic aldehydes (35) in water medium. During the initial investigations, the authors examined the efficiencies of various catalysts like ZnO, In2O3, and Sm(OTf)3 as well as solvents such as toluene, dioxane, MeCN, EtOH, and EtOH/H2O. It was observed that electron-deficient aldehydes (35) provided better yields in shorter reaction times than electron-rich aldehydes (Figure 8.18).

Figure 8.18: Sm(OTf)3-catalyzed preparation of 2-substituted benzoxazoles and benzothiazole derivatives.

8.2.13 Fe(III)–Schiff base/SBA-15-supported synthesis A simple, efficient, and green methodology for benzoxazole (73)/benzothiazole (74)/ benzimidazole (75) compounds was reported by Bardajee et al. [37] for the condensation reaction between aldehydes (35) and o-aminophenol (27)/o-aminothiophenol (27a)/ o-phenylenediamines (27b) in water medium promoted by Fe(III)–Schiff base/SBA-15. The structure and morphology of the prepared Fe(III)–Schiff base-functionalized SBA-15 (76) were assessed by the authors before applying this heterogeneous nanocatalyst for improving the yields. Toluene, DMF, EtOH, and H2O were tested for their suitability as solvents. The catalyst was reused for six runs. Both electron-rich and electrondeficient substrates provided good yields in the case of o-aminothiophenol (27a) and o-aminophenol (27). However, with o-phenylenediamine (27b), the products were obtained in lesser yields, and the reaction appeared to be controlled by the effects of the reacting aldehydes (Figure 8.19a and b).

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(b)

Figure 8.19: (a) Synthesis of heterocycles catalyzed by Fe(III)–Schiff base/SBA-15 and (b) catalyst: Fe(III)– Schiff base–SBA-15.

8.2.14 Iron salt-catalyzed S-arylation A simple route for accessing the aryl-(2-aminoaryl)-sulfides (77) by S-arylation of benzothiazole (43a) compounds with various aryl/heteroaryl iodides (18b) in water medium assisted by iron(III) chloride in the presence of diamine ligand was presented by Lee et al. [38]. In the initial screening, the authors examined the superior efficiency

Figure 8.20: Iron-catalyzed S-arylation of benzothiazole with aryl iodides.

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of trans-1,2-diaminocyclohexane, dimethylethylenediamine, and 1,10-phen as ligands and noted that trans-1,2-diaminocyclohexane provided the best results. NaOH, KOH, and NaOBut were tested as bases and observed that NaOH afforded excellent yields (Figure 8.20).

8.2.15 CuCl2–phen-catalyzed synthesis Hang Deng et al. [39] disclosed an efficient, simple, eco-friendly one-pot threecomponent reaction of o-iodoaniline (8c), aldehydes (35), and sulfur powder (78) affording benzothiazoles (79–81), assisted by 10 mol% CuCl2–phen/K2CO3 system in water medium at 100 °C. In the preliminary investigations, the authors assessed the efficiency of different copper catalysts like CuI, CuSO 4·5H 2O, CuCl 2·2H 2O, Cu 2O, Cu(OAc)2·H2O and concluded that 10 mol% CuCl2 provided the best results. Among the ligands examined, 1,10-phenanthroline exhibited highest catalytic capability for the present protocol. Among various bases that were tested, K2CO3 has shown better suitability. The authors claimed that the protocol exhibited tolerance toward diverse range of functional groups, making this an attractive strategy (Figure 8.21a–c). (a)

(b)

Figure 8.21: Catalytic three-component reaction using different (a) aldehydes and (b) 2-iodoanilines. (c) Synthesis of PMX-610 – an antitumor agent.

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Figure 8.21 (continued)

8.2.16 Catalyst-free domino synthesis Shaik Karamthulla et al. [40] carried out a clean, efficient, and catalyst-free on-water multicomponent domino reaction of cyclic-1,3-dicarbonyls (82), aryl glyoxals (83), and thioamides (9), under microwave conditions affording a diverse range of novel trisubstituted-1,3-thiazoles (84) in short reaction times. During the optimization studies, the authors investigated the suitability of various solvents like DMF, CH3CN, THF, toluene, EtOH, EtOH/H2O, and water and noted that the methodology worked well in the water medium in the absence of any catalyst. The scope of the protocol was widened by extending to include various cyclic-1,3dicarbonyls (82), thiobenzamides (9a), diversely substituted aliphatic thioamides (9), and aryl glyoxals (83). Aryl glyoxals (83) and 1,3-dicarbonyl compounds (82) reacted in a Knoevenagel-type process forming alkene on which thia-Michael addition of thioamide took place affording an intermediate, which subsequently cyclized losing water molecule resulting in the title compounds (Figure 8.22).

Figure 8.22: Domino synthesis of 1,3-thiazoles.

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8.2.17 FeCl3/1,10-phen-catalyzed preparation Qiuping Ding et al [41] presented an eco-friendly simple method involving FeCl3catalyzed tandem reaction of 2-iodoaniline (8c) with isothiocyanate (28a) in water, affording 2-aminobenzothiazole (85/86) derivatives with broad substrate scope in the presence of octadecyl trimethyl ammonium chloride as phase transfer catalyst. The authors reused the reaction media without significant loss of activity. In the preliminary screening studies, the effects of different phase transfer catalysts such as TBAB, sodium dodecyl benzosulfonate, hexadecyl dimethyl benzyl ammonium chloride, and octadecyl trimethyl ammonium chloride were examined for the best results. The authors also investigated the suitability of several ligands like PPh3, β-cyclodextrin (β-CD), proline, and 1,10-phenanthroline. Apart from these, various catalysts such as FeCl3, K3Fe(CN)6, Fe(NO3)3, Fe2O3, and Fe2(SO4)3·FeSO4 were assessed for their efficiencies. Bases like DABCO, Et3N, DBU, NaOH, K3PO4, K2CO3, Cs2CO3, NaHCO3, and Na2CO3 were screened for encouraging results (Figure 8.23a and b). (a)

(b)

Figure 8.23: FeCl3-catalyzed tandem reaction of (a) 2-iodoaniline with isothiocyanates and (b) different 2iodoanilines with isothiocyanates.

8.2.18 Quaternary ammonium salt-catalyzed synthesis Lei Pan et al. [42] prepared substituted benzothiazoles (87–90) by a metal and catalystfree aqueous-phase three-component protocol involving the reaction of o-iodoaniline (8c) and sulfur powder (78) in the presence of quaternary ammonium salts as alkylating

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agents and KOH as the base, at 140 °C in 14 h. Different bases like K2CO3, Cs2CO3, KOH, NaOH, NH3·H2O, Et3N, pyridine, and KOH were checked for their suitability. The influences of various quaternary ammonium salts on the protocol were also studied. It was noted that long-chain alkyl or benzyl alkyl groups provided best results. A series of 2halogenated anilines (28c) were used as substrates in this methodology. Substrates with electron-donating substituents provided better yields (Figure 8.24a and b). (a)

(b)

Figure 8.24: Synthesis of substituted benzothiazoles (a) with various quaternary ammonium salts and (b) from various anilines and quaternary ammonium salts.

8.2.19 Ionogel-catalyzed preparation Sharma et al. [43], by following a sol–gel process, developed an ionogel by the confinement of 1,3,5-trimethyl pyrazolium chloride (92) as an ionic liquid in silica gel matrix. Later, it was applied as a catalyst in the development of a protocol for benzothiazoles (93/94) from formaldehydes/ketones (21) and 2-aminothiophenol (27a) under solventfree conditions. Ionogel was characterized by scanning electron microscopy, TEM, FTIR, and TGA (Figure 8.25a–c).

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(a)

(b)

(c)

Figure 8.25: (a) Ionogel-catalyzed preparation of benzothiazoles; (b) reaction of 2-aminothiophenol with aryl ketones; and (c) structure of 1,3,5-trimethyl pyrazolium chloride.

8.2.20 Brønsted acid–surfactant-combined ionic liquid [BAILs]-catalyzed synthesis Senapak Warapong et al. [44] described an efficient eco-friendly strategy for a library of 2-alkyl/2-aryl/heterocyclyl benzothiazoles (95) under metal-free conditions, employing aqueous-phase reusable Brønsted acid–surfactant-combined ionic liquid (BAILs) as a catalyst (96). Initially, the authors prepared the catalyst from 1-bromoalkane (18c) and imidazole (97) in K2CO3/CH3CN system. BAILs are very powerful acid catalysts. The alkyl imidazoles (97a) were treated with stoichiometric amount of trifluoromethane sulfonic acid by stirring at room temperature in dichloromethane. To the suspension of 10 mol% BAILs in water, 2-aminothiophenol (27a) and the carbonyl compounds (45) were added in the presence of tert-butyl hydrogen peroxide at room temperature. The authors observed that among different BAILs, [bs dodecim][OTf]

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provided the best results. Other BAILs examined for the current methodology were [bsmim][HSO4], [bsmim][PTSA], [bsmim][OTf], [bsocim][OTf], [bsdecim][OTf], [dodecim][OTf], and [bs tetradecim][OTf] (Figure 8.26a and b). (a)

(b)

Figure 8.26: (a) Preparation of the catalyst BAILs and (b) synthesis of 2-substituted benzothiazoles with various carbonyl compounds.

8.2.21 Synthesis in pyridine/water system Jiang et al. [45] demonstrated a modular multicomponent metal-free strategy for the synthesis of a diverse range of 2,4,5-trisubstituted thiazole derivatives (100–102) from a variety of ketones (21), substrates like aliphatic methyl ketones (21a), aromatic methyl ketones (21), as well as non-methyl ketones (21b), in optimized pyridine/water reaction medium (Figure 8.27a –c).

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(a)

(b)

(c)

Figure 8.27: (a) Preparation of 2,4-diaryl-5-benzyl thiazoles; (b) synthesis of 4-vinyl thiazoles from methyl aliphatic ketones; and (c) formation of trisubstituted thiazoles.

8.3 Conclusion The last few years have witnessed a significant growth in the chemical research, leading to varied eco-friendly methodologies aimed at the synthesis of different sulfur-containing heterocyclic scaffolds. Even though conventional approaches for the preparation of these compounds are in vogue, environmentally benign protocols have been developed with the goal of increasing the yields or reducing reaction times, energies, as well as environmental pollution. Furthermore, research into the greener strategies for the synthesis of sulfur heterocycles will ensure rapid growth of this active and important area of research in heterocyclic chemistry, resulting in the construction of a wider spectrum of biologically important and pharmaceutically promising sulfur-containing molecules. In this review, efforts have been made to appraise and assess aqueous-phase preparation of Sheterocycles from the recently published literature. All figures are redrawn and representative. The readers are advised to go through the original research papers for any detailed information. The authors of this review appreciate and acknowledge the original contributors and publishers of the articles cited here.

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Razia Noreen, Arruje Hameed, Tanzeela Khalid, Shaheera Batool, and Tahir Farooq✶

Chapter 9 Aqueous-mediated synthesis of bioactive spirooxindoles 9.1 Introduction 9.1.1 Spirocyclic compounds The spirocompound is a bicyclic structure having two rings connected through a single common atom. The common atom connecting the two rings differentiates these compounds from bicyclic compounds like biphenyl and from fused rings and bridged compounds. In fact, in bicyclics, the connecting rings have no common atom [1–3]. Two rings are connected by two adjacent atoms in case of fused rings; however, two known adjacent atoms connect two rings in bridge compounds. Mainly the spirocompounds are classified as carbocyclic compounds or heterocyclic spirocompounds (Figure 9.1). In carbocyclic spirocompounds, only carbon and hydrogen atoms are present, whereas in case of heterocycles, atoms other than carbons make the system heterocyclic. Spirocarbocycles as well as heterocycles are frequently present in nature with high potential to serve as scaffolds for the preparation of drugs and bioactive therapeutics. The spiromotif is a unique structural entity in a large number of functional compounds, including dyes, electronically active polymeric materials, and chiral legends (Figure 9.2) [4–6]. The spirocyclic compounds have emerged as leading therapeutic agents owing to their privileged spirocyclic systems [7]. They have shown promising applications as laser dyes, pesticidal agents, pesticides, and fungicides [8–10]. Over the last decade, they have shown a broad spectrum of biological activities, including antibacterial, antimicrobial, antifungal, and antioxidant activities. They have widely been exploited as potent leads for the development of anticancer agents. A number of natural as well as synthetic spirocyclic compounds have received considerable attention for clinical trials [11–13].

✶

Corresponding author: Tahir Farooq, Department of Applied Chemistry, Government College University Faisalabad, Faisalabad, Pakistan, email: [email protected] Razia Noreen, Arruje Hameed, Department of Biochemistry, Government College University Faisalabad, Faisalabad, Pakistan Tanzeela Khalid, Department of Applied Chemistry, Government College University Faisalabad, Faisalabad, Pakistan Shaheera Batool, Department of Biochemistry, CMH Institute of Medical Sciences Multan, Multan, Pakistan https://doi.org/10.1515/9783110985627-009

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Figure 9.1: Some known spiro-carbocyclic compounds.

Figure 9.2: Spirocyclic chiral ligands.

9.1.2 Spirooxindoles The rigidity and 3D geometry have given unique physiochemical attributes of the spirocyclic compounds. In recent years, the spirooxindoles have emerged as promising compounds with a variety of versatile activities. It has a diverse range of analogs originating from C-2 or C-3 indolyl ring with any other heterocycles furnishing a range of potent spiro-skeletons. Among the spirocyclic compounds, the spirooxindoles have received special attention owing to their exceptional therapeutic potential unique spatial architecture [14–16]. The spirooxindole is a privileged scaffold encompassing to substructural units like highly functionalized oxindoles and heterocyclic or cycloalkyl motifs at C-3 of oxindoles (Figure 9.3). Together they control physiochemical properties and liposolubility attributes of spirooxindole skeleton [17–19]. Over the last few decades, natural and synthetic spirooxindoles have established their worth as highly potent spirocycles showing a range of biological activities including antidiabetic, antiviral, antianalgesic, and anti-inflammatory (Figures 9.4 and 9.5) [20–22]. In recent years, they have been well exploded for their exceptional anticancer potential (Figure 9.6) [23, 24].

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Figure 9.3: Generally known approaches for the synthesis of spirooxindole.

Figure 9.4: Potent natural spirooxindoles.

9.2 Aqueous-mediated synthesis of spirooxindoles Over the last two decades, there has been a great interest to find alternative reaction media under the concepts of green chemistry and cleaner production strategy [25–27]. The alternative reaction media are expected to modify the course of reactions avoiding the application of metallic catalysts, chemical additives, and harsh conditions. Over the years, the water has been recognized as an alternative reaction medium for organic synthesis. It has widely been exploded as green reaction media for a variety of organic transformations including pinacol coupling reactions, Claisen rearrangement reactions, and Diels–Alder reactions [28, 29]. The compounds containing indole moiety usually display a broad spectrum of bioactivities, including antiviral, antifungal, antibacterial, and anticancer potentials. A large variety of natural and synthetic compounds with indole found a number of clinical applications. The spiroindoline derivatives exhibit high biological profiles due to the presence of shared indole 3carbon. The natural alkaloids and many other pharmacological agents carry spirooxindole as the main structural motif. Over the last decade, there is a great emphasis to reduce the generation of toxic wastes in synthetic reactions. In this connection, efforts

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Figure 9.5: Examples of bioactive spirooxindoles.

Figure 9.6: Spirooxindoles with anticancer potential.

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have always been made to design new protocols for the synthesis of biologically potent heterocycles. Accordingly, it is encouraged to use environmentally compatible and less toxic materials. The efforts have been made to avoid the use of toxic solvents as reaction media. Alternatively, the synthetic procedures have been designed to employ water as solvent for the reactions. Similarly, efforts are underway to minimize the use of metallic-based catalysts for synthetic transformations. In recent years, the field of organocatalysis has revolutionized the domain of organic synthesis with the introduction of small organic molecules in compassing huge potential to catalyze organic reactions [30, 31]. In this connection, L-proline-catalyzed synthetic reactions gained considerable attention over the last decade. It has widely been exploded as an effective catalyst for Knoevenagel, α-amination, Diels–Alder, Michael, and Mannichtype reactions. It has also shown wide applications in unsymmetric Biginelli reaction and asymmetric aldol reactions. The avoidance of waste generation in organic reactions could also be managed by introducing single-step reaction protocols. Such reaction strategies opened up the possibilities for the construction of highly complex compounds through simple reaction procedure. They allow the savings of reagents and especially the organic solvents, also simplify the isolation and purification steps. Over the last two decades, the three- and four-component reactions as emerging multicomponent reactions (MCRs) have revolutionized the synthetic operations in synthetic chemistry [27, 32, 33]. They have widely been used for the formation of C–C and C–N bonds for the preparation of various functional organic and heterocyclic compounds. Recently, there is a great interest to apply all such environment-friendly reaction strategies for the development of a super green reaction approach, especially for the preparation of highly useful spirooxindole derivatives [34, 35]. The following sections highlight the aqueous-mediated synthesis of spirooxindoles by employing recent synthetic strategies ensuring their green and eco-friendly synthesis. The modern green synthetic approaches include – One-pot multicomponent synthesis – Nanocatalysis in synthesis – Microwave-assisted synthesis – Organocatalysis in synthesis

9.2.1 One-pot synthesis of spirooxindoles in aqueous media Recently, there is a great interest for the synthesis of biologically active heterocycles in aqueous media. There has been a great demand of bioactive molecules containing more than one heterocyclic moiety. Accordingly, a one-pot three-component reaction described an efficient and simple synthesis of biologically potent spirooxindole scaffolds (32). In aqueous media 1,3-dicarbonyl compound (31) reacted with activated methylene reagent (30) and isatin (29) furnishing high yields of the product. The reaction procedure is found to be eco-friendly, simple, and efficient (Figure 9.7) [36].

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Figure 9.7: One-pot three-component synthesis of spirooxindole in aqueous media.

In this connection, back in 2009, an excellent one-pot three-component reaction strategy disclosed an efficient protocol for the facile synthesis of spirooxindole derivatives (34). The three-component including 1,3-dicarbonyl compounds (33), malononitrile, and isatins was reacted using L-proline as catalyst in aqueous media. The simple operational reaction offered several advantages including shorter reaction time, high yield, and low cost. The described reaction protocol met the criteria of eco-friendly reactions due to its one-pot nature, use of water as reaction media, and avoidance of metallic catalyst (Figure 9.8) [37].

Figure 9.8: L-Proline-catalyzed one-pot synthesis of spirooxindoles in aqueous media.

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The pryzole ring is an important structural motif in a number of naturally occurring and synthetic bioactive compounds. The pyrazolopyridines have emerged as promising heterocycles showing a broad range of bioactivities [38–40]. They have shown immense potential as protein kinase inhibitor, HIV reverse transcriptase inhibitors, and cyclin dependent kinase I inhibitors [41–43]. Owing to their usefulness, they have been targeted for the development of various operationally simple synthetic strategies. In 2010, another report described the synthesis of spirooxindole derivatives (36) using water as reaction media. The one-pot three-component reaction was catalyzed by ceric ammonium nitrate affording high yields of a series of spirocompounds. The disclosed reaction protocol furnished important heterocyclic derivatives under mild conditions. The reaction method showed a broad substrate scope with minimum environmental impacts. The straight forwardness of the procedure, avoidance of the organic solvents, and one-pot procedure made this synthetic approach reasonably ecosustainable (Figures 9.9 and 9.10) [44].

Figure 9.9: Efficient one-pot synthesis of novel spirooxindoles in aqueous media.

The fused heterocyclic compounds have shown valuable biological properties and find applications across a variety of scientific disciplines including biological probes, functional materials, and active pharmaceutical agents. The three-component reaction has emerged as eco-friendly approach for the green preparation of functional spirocyclic oxindoles. The protocol designed guaranty the eco-friendliness of the operation providing high yield in minimum reaction time. In 2014, a one-pot MCR describes the efficient synthesis of various spirooxindole derivatives (41, 42, 44, 46). The prepared spirocyclic compounds were tested for the human breast cancer and colorectal cell lines. The antitumor activity of the spirocycles depends on the presence of substituents at C5 and C6

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Figure 9.10: Ceric ammonium nitrate-catalyzed synthesis of a series of spirocompounds.

positions of the pyrane ring, halogen at the C5 of the indole ring, and ester at the C3 of the pyrane ring. The halogen atoms develop hydrogen bonding with the target proteins. The bulkiness of the ester substituents also improves the activity of the title compounds. The structure–activity relationship of the prepared spirocyclic compounds established their worth as promising candidates for antitumor activity (Figure 9.11) [45]. In 2019, a report describes the synthesis of spirooxindoles, employing a simple and easy procedure. The one-pot three-component methodology involved 1,3-dicarbonyl compounds, malononitrile, and isatin under mild reaction conditions. The reaction employed Na2CO3 as a catalyst using different solvents including water; however the best performance was observed when water/methanol (1:1) is used as solvent. Different carbonates were tested as catalysts. The best results were optimized with sodium carbonate as a catalyst at room temperature. The described method offered various advantages, including short reaction time, higher yield, easy product isolation, and purification. The protocol was suggested as economical, easy, and less hazardous (Figure 9.12) [46]. As described earlier, the one-pot tandem reactions exhibit inherent simplicity, environment-friendly nature, and broad substrate scope. The multistep reactions provide complex molecules starting from simpler and easily available reagents avoiding the unnecessary separation of intermediates. Over the last decade, one-pot methodology combined with chemical catalysis has emerged as forefront approach in organic synthesis. In recent times, there is a great emphasis to maximize the green impacts and eco-sustainability of one-pot tandem approach by employing biocatalysts as environ-

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Figure 9.11: Multicomponent synthesis of various spirooxindoles in aqueous media.

mental friendly alternatives. With the recent advancements in biocatalysis, the field of chemical synthesis has gradually transformed in respect of the concepts of green chemistry. The replacement of traditional chemical catalyst with new biocatalysts has improved the eco-friendliness of the much exploded one-pot reaction methodology.

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Figure 9.12: Na2CO3-catalyzed synthesis of spirooxindoles in aqueous media.

The enzyme-catalyzed reactions could help in the synthesis of drugs and pharmaceutical agents avoiding the use of polluting solvents and catalysts. The recent attraction in spirooxindole compounds as pharmaceutical products has highlighted the need for their development through enzyme-catalyzed reaction protocols. In this connection, spirooxindole derivatives (48) were prepared using cyclic ketones (47) employing lipase-catalyzed one-pot tandem approach. The biocatalyzed reaction protocol showed several advantages, including reasonable reaction time, mild conditions, and wide functional group tolerance. The reaction proceeded in green route furnishing moderate to good yield of the title compound (Figure 9.13) [47].

9.2.2 Nanocatalyzed green synthesis of spirooxindoles in aqueous media The chemical processes demand environmentally benign conditions including highly efficient catalyst. Generally homogeneous catalysts are highly efficient than heterogeneous catalysts owing to their reasonably high solubility in reaction media. However, the applications of homogenous catalyst are limited because of their separation and

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Figure 9.13: Lipase-catalyzed one-pot tandem synthesis of spirooxindoles in aqueous media.

recycling issues. Although the heterogeneous catalyst is less efficient, it offers advantages of easy recovery and reusability. Over the last decades, the metallic oxide nanoparticles (NPs) have emerged as promising catalyst support due to high surface area, good stability, and easy preparation protocols. The magnetic NPs have received special attention because their easy and desirous functionalization could bridge the gap between homogenous and heterogeneous catalysis. They can easily be separated and reused without compromising catalytic efficiency. The heterocycles with pyrimidine structural motifs show a wide range of pharmacological activities including anti-inflammatory, antimalarial, and antifungal properties. The asymmetric features of the spirocyclic systems enhance their biological properties. Hence, great attempts are made to develop easy operational strategies for their preparation under eco-friendly conditions. In 2014, coprecipitation method was employed to prepare superparamegnatic manganese ferrite NPs and subsequently the silanization reaction was performed to coat them with 3-aminopropyltriethoxysilane. Further the reaction between aminofunctionalized MnFe2O4 with isatoic anhydride furnished functional manganese ferrite NPs with bidentate ligands. Furthermore, the immobilized nickel complex was re-

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ceived from amino-functionalized NPs after treatment with nickel acetate. The prepared nanosystem was employed as an efficient catalyst for the preparation of spirooxindoles (50) in aqueous media. The nanocatalyst efficiently provided the title compounds in excellent yield. The disclosed protocol offered advantages like short reaction time, easy operation, and high product yield. The prepared nanocatalyst exhibited high reusability with simple recovery process (Figure 9.14) [48].

Figure 9.14: Nanocatalyst-mediated green synthesis of spirooxindoles.

As described earlier, there is a great demand to replace toxic organic solvents with some green reaction media to enhance the eco-sustainability of organic reactions. A lot of research has been done to use water as solvent for organic reactions. The synthetic reactions in aqueous media have received considerable success for large-scale practical applications. However, in some of the cases the solubility of reactants and unavoidable catalysts limits their feasibility in aqueous media. Therefore, efforts have been made to introduce green solvents for organic synthesis to maximize the reaction yield in shorter time. In recent years, polyethylene glycol (PEG) has received attention as a promising green solvent, owing to some notable features like low toxicity, nonvolatility, recoverability, thermal stability, and water solubility. Recently efforts have been made to carry MCRs in PEG as green solvent using NPs as efficient and easily reusable catalysts for the development of environmentally benign synthetic protocols. Another report in 2014 used anilinolactones (51), malononitrile, and isatins for the preparation of spirooxindole derivatives (52). The environmentally benign protocol employed manganese ferrite NPs as easily recoverable and efficiently reusable catalyst. The presented method showed various advantages like simple operations, green solvents, and excellent product yields. The nanocatalyst was tested in various solvents including PEG-400, water, and some ionic liquids (Figure 9.15) [49].

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Figure 9.15: Manganese ferrite NP-catalyzed preparation of spirooxindole derivatives.

Over the last few years, the metallic NPs have emerged as promising catalysts due to unique physiochemical and biological properties. Especially the silver NPs have received significant attention for applications in textile coatings, imaging, drug delivery, and environmental remedial applications. Over the last decade, they have extensively been exploded as catalyst for the preparation of various bioactive compounds including heterocycles. Recently there is a great focus to use Ag-NPs as efficient catalyst in green and environmental friendly synthetic methodologies. In this very connection,

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attempts are being made to employ them in MCRs especially for the preparation of biologically active heterocycles. In 2016, a report described the use of Ferula latisecta leaf extract as a capping and reducing agent for the preparation of Ag-NPs under mild conditions. The prepared NPs were further used as nanocatalyst for the synthesis of various spirooxindoles (53) in aqueous media. The disclosed reaction method exhibited various advantages like simplicity of operation, green conditions and excellent product yield. The one-pot operation utilized easily available and economical starting material (Figure 9.16) [50].

Figure 9.16: Ag NP-catalyzed green synthesis of spirooxindoles.

Over the last decades, the nanocomposites (NCs) with core shell structures have gained attraction due to their some unique physiochemical properties. The magnetic core shell NCs show special applications in selective separations, biosensing, and catalysis in organic synthesis. The CoFe2O4 NPs have emerged as promising magnetic materials with wide scope of applications. However, they often show aggregation, which limits their application especially in the field of catalysis in organic synthesis. In the last few years, a great attention has been diverted for functionalizing the surface of NPs for the introduction of desirous characteristics. They are also coated with different materials, including zeolites, silica, clays, and activated carbons. The silica particles with hydroxal groups are easy to functionalize and they are also show high stability under the redox and acidic conditions. They could be easily coated for the tuning of biocompatibility. SiO2 has emerged as promising shell composites with inner magnetic core due to such fascinating structural characteristics. They are highly useful for catalysis in organic synthesis.

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Recently there is a great interest to functionalize Co-ferrite NPs with easily modifiable silica coatings. In 2019, another report describes the preparation and application of nanocatalyst for the synthesis of spirocyclic compounds (55). A new nanocatalyst CoFe2O4@SiO2 was employed for the coupling reaction of 1,3-dicarbonyl compounds, malononitrile, and various isatins using water as green reaction media. The newly developed catalyst exhibited high reusability and easy recovery through simple operation. The catalyst also exhibited high stability and minimum functional loss even after five successive cycles (Figure 9.17) [51].

Figure 9.17: CoFe2O4@SiO2-catalyzed green synthesis of spirooxindoles.

As described earlier, the metallic NPs have wide spread applications as efficient nanocatalysts in various known synthetic transformations. Among them silver and gold NPs have long list of applications in biosensing, biological assays, and photonics and organic catalysis. Considering their wide scope of applications in catalysis recently efforts are underway to prepare a system incorporating both Au and Ag metals to achieve synergistic effects. These metals can easily develop alloy because they have same lattice spacing and phase center cubic crystal rearrangements. Accordingly, various techniques have been well exploded for the preparation of Au–Ag bimetallic NPs. Further, the bimetallic NPs are immobilized on polymeric matrices to increase their stability and to avoid their aggregation. The metallic NPs are highly susceptible to aggregation leading to reduce catalytic efficiency. Very recently,

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graphene oxide (GO) has emerged as promising solid support for NPs, owing to high carrying mobility, high surface area and unique chemical stability. It has been used for immobilizing monometallic and bimetallic NPs for various applications. In recent years, there is a great interest for the application of GO as solid support for bimetallic NPs for application as catalyst in organic synthesis. In very recent efforts, the GO nanosheets have been used as shell and Fe3O4 as core for the preparation of magnetic-based NCs. Recently, attention has been focused for the application of magnetic NCs as catalysts for the eco-friendly synthesis of heterocycles specially spirocyclic compounds. In 2020, a report successfully described the preparation of Au–Ag NPs immobilized on Fe3O4/GO as novel NCs. Subsequently, the prepared NC was used as an efficient catalyst for the condensation reaction of 6aminouracil, barbituric acid, and isatins in aqueous media. The presented one-pot three-component methodology offered several advantages, including simple operation, mild conditions, and high yields (56). The prepared nanocatalyst exhibited easy separation and high reusability (Figure 9.18) [52].

Figure 9.18: Nanocomposite-catalyzed green synthesis of spirooxindoles.

9.2.3 Green synthesis of spirooxindoles in aqueous media The 1,4-dihydropyridine (1,4-DHP) derivatives are biologically potent compounds showing a broad range of bioactivities. The compounds containing 1,4-DHP as structural motifs are clinically potent for the treatment of hypertension, angina, and other cardiovascular disorders. They are also known as calcium channel blockers. Considering there wide scope of medicinal application, a lot many synthetic strategies have been described in the literature. As described earlier, the heterocycles containing spi-

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rooxindoles have gained interest for drug development. Accordingly, the medicinal chemist has focused the preparation of spirooxindoles containing 1,4-DHPs in a single molecule. At the same time, efforts have been made to synthesize such bioactive compounds through green and eco-friendly synthetic approaches. In 2012, a one-pot pseudo-five-component reaction protocol describes the simple facile and efficient synthesis of spirooxindole-fused 1,4-dihydropyridine derivatives (59). The straight forward reaction procedure utilized economical and easily available reagents and catalyst affording the title compounds in high yield. Advantageously, the condensation reaction was run in aqueous media with simple workup and short reaction time (Figure 9.19) [53]. The supramolecular catalysis has become a forefront approach in synthetic organic chemistry. It involved the host–guest-type interactions. Their interacting radicals, ions, and molecules do not establish covalent bonds. The frequently used β-cyclodextrin is a cyclic oligosaccharide with seven glucose units. Its hydrophobicity and the cavity size could help to encapsulate a range of guest molecules including aromatic compounds. It has widely been exploded in respect of selectivity, reaction rate, and inclusion complexes. It is nontoxic, metabolically safe, and easily recoverable and thus have wide scope of applications in organic catalysis. The β-CD-mediated synthetic transformations are environmentally safe and widely exploded for the synthesis of bioactive heterocycles. The pyranopyrazole derivatives are used in full structural entities showing a range of biological properties including anti-inflammatory, anticancer, and analgesic. Considering the medicinal usefulness of spirooxindoles and pyranopyrazoles, there has always been a demand to put these two structural units together in a compound for promising biological activities. Further, it is of great interest to develop single-step one-pot eco-friendly reaction procedures generating minimum waste. In this connection, in 2015 a remarkable reaction procedure described the synthesis of spirooxindole and pyranopyrazole derivatives (62). The β-CD was used as a biodegradable and highly efficient in one-pot four-component reaction under neutral conditions. The β-ketoesters, malononitrile, hydrazine hydrate (61), isatins, and various aldehydes (60) reacted in aqueous medium furnishing high yield of title compounds. The green reaction methodology offered various advantages like simple and clean workup, short reaction time, and facile recovery of the catalyst. The biodegradable catalyst exhibited high reusability and exceptional efficiency (Figure 9.20) [54]. As described earlier, the spirooxindoles are potent structural motifs showing a broad scope of bioactivities and therapeutic applications. The 3,2′-tetrahydrofuryl spirooxindole moiety is a potent structural unit in a number of bioactive compounds and naturally occurring alkaloids. Among spirooxindoles, the oxindoles with a fivemembered ring fused at C-3 position have received special attention in pharmaceutical perspectives. Accordingly, a number of methodologies have been developed for their facile synthesis. However, the generally known methods require organic solvents, chemical additives, long reaction time, and tedious workup. Few of the re-

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Figure 9.19: One-pot, pseudo-five-component green synthesis of spirooxindoles.

ported methods require three to five steps, complex catalysts, and reagents. Few of the representative methods show limited substrate scope, presynthetic steps, complex workup, and purification processes.

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Figure 9.20: β-Cyclodextrin-catalyzed synthesis of spirooxindole derivatives.

Over the last decade, there is a great interest for the development of green and eco-sustainable methodologies for the green synthesis of 3,2′-tetrahydrofuryl spirooxindoles. In 2017, a metal-free and operationally simple procedure describes the synthesis of oxindole-fused spirotetrahydrofurans (64) in aqueous media. The one-pot approach employed methanesulfonic acid as catalyst without the involvement of any additional chemical additive. This new methodology was highly efficient step- and atom-economical. The reported procedure did not involve any organic solvent or metallic catalyst thus regarded as green route for the preparation of 3,2′-tetrahydrofuryl spirooxindoles (Figure 9.21) [55]. The ZnFe2O4 NPs have received considerable attention owing to its unique physiochemical properties thus show wide applications in photocatalysis, adsorption, and bio-

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Figure 9.21: Metal-free cyclization reaction for the synthesis of spirooxindoles.

sensing. They have also shown promising application in calorimetric detection of glucose and photocatalytic degradation of dyes and colorants. Despite their wide scope of applications, the existing protocols for their synthesis found challenges in the control of structure and morphology. Over the last two decades, their application as catalyst in organic synthesis is much intercepted for the synthesis of complex molecules.

Figure 9.22: ZnFe2O4 NP-catalyzed green synthesis of spirooxindoles.

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In 2018, a report describes the novel synthesis of ZnFe2O4 NPs and subsequently characterized by different spectroscopic techniques. Further, the prepared NPs were used as green nanocatalyst for the facile synthesis of spirooxindole derivatives (32). The one-pot three-component condensation reaction of 1,3-dicarbonyl compounds, malononitrile, and isatin proceeded in aqueous media under mild conditions. The described protocol offered various advantages including simple operation, short reaction time, and higher yields of the title compounds. The prepared catalyst was easy to handle showing high reusability with ease of separation (Figure 9.22) [56].

9.2.4 Microwave-assisted synthesis of spirooxindoles in aqueous media Over the years, the synthetic chemists are trying to develop synthetic methodologies with less number of steps. It saves time, energy, solvents for reaction, isolation, and purification of the product. They aim to increase the eco-friendliness of the synthetic protocols. It also helps to introduce environmentally benign conditions in chemical reactions. In modern times, three or more steps are brought together in MCRs offering significant advantages related to the eco-sustainability of the reactions. Conventionally, the reactions in multiple steps are associated with complex workup, high cost, and low yields. They also require the application of organic solvents at each step, high energy consumptions, and longer reaction time. They generally produce waste at each step and thus are not favorable in respect of green reactions. In the current era, the attentions have been focused for the development of green reaction protocols requiring minimum energy inputs. In this connection, over the last two decades, the applications of microwaves have been well exploded in organic synthesis for the preparation of various functionalized molecules including bioactive heterocycles. These alternative energy sources have offered several advantages including short reaction time, higher yields, operational simplicity, and purity of products. Recently, it has become interesting to develop clean and green methods for the preparation of bioactive heterocycles. Accordingly, great efforts have been made to combine MCRs with microwave irradiation technology using water as green reaction media. All such efforts intend to maximize the eco-friendliness of the reaction protocols. The medicinal chemists are putting their efforts to adopt such green approaches for the synthesis of highly demanded bioactive heterocycles with minimum impacts on ecosystem. In 2016, a microwave-assisted reaction protocol was described for the preparation of functionalized spirooxindole derivatives (68) in good to excellent yield. The reaction involved readily available precursors like α-aminoacids (67), β-nitrostyrenes (66), and isatin (65) in aqueous media. The one-pot three-component eco-friendly reaction furnished title compounds with good diastereoselectivity. The disclosed reaction offered various advantages like low energy consumption, higher yield, and simple workup (Figure 9.23) [57].

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Figure 9.23: Microwave-assisted synthesis of spirooxindoles.

Over the years, a number of synthetic methodologies have been developed for the clean synthesis of spirooxindole derivatives employing various reaction conditions. A number of efforts were directed for designing of environmentally benign protocols. In this connection, various procedures have been developed where MCRs have been adopted as main synthetic strategies. Few other attempts report the application of green reaction media in order to enhance the eco-sustainability of synthetic protocols. Few such attempts have also been reported, where conventional energy sources have been replaced with modern tools like microwave irradiation techniques. At the same time, steps have been taken to introduce organocatalysis as green alternative of conventional metal-based catalysts. Over the years, the introduction of nanomaterials as highly efficient catalysts has revolutionized the synthesis of bioactive N-heterocycles. In recent years, there is a great interest to introduce a highly clean and green synthetic strategy for the synthesis of N-heterocycles especially the highly demanded spirooxindoles. In 2017, a report described the preparation of Fe3O4@SiO2-imid-PMAn magnetic nanocatalyst and its subsequent application for eco-friendly synthesis of spirooxindole

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derivatives (70). The microwave-assisted one-pot reaction between 1,3-dicarbonyl compounds (69), activated methylene, and isatin derivatives was optimized in various solvents and solvent free conditions. The prepared nanocatalyst exhibited excellent catalytic activity in aqueous media. The clean, green, and efficient reaction procedure exhibited some advantages including simplicity, short reaction time, and easy workup. The catalyst showed high thermal stability and efficiency even after several cycles. Advantageously, the nanocatalyst was easily separable showing features of heterogeneous catalyst with high catalytic performance (Figure 9.24) [58].

Figure 9.24: Microwave-assisted nanosphere-catalyzed synthesis of spirooxindoles.

A number of naturally occurring alkaloids carry pyrrolidinyl spirooxindole as potent structural motifs for their potent biological activities [59–61]. Considering their versatile medicinal importance, a number of reaction procedures target their high yielding synthesis. However, most of the reported procedures require harsh conditions, prolonged reaction times, toxic solvents, complex catalysts, and other chemical additives. In recent years, few attempts have been made to introduce one-pot reaction strategies for their synthesis. However, these significant advancements have some scope limitations because they focused only secondary aminoacids as potent precursors. The primary aminoacids have gained special attention in asymmetric synthesis of complex N-heterocycles, owing to their natural and inexpensive availability. As described earlier, the application of MCRs for the synthesis of N-heterocyclic compounds offers some advantages like atom economy, less reaction time, simple operation, and high yield of the target compounds. Therefore, in recent years, it is highly desirous to develop diastereoselective, cost-effective, and green protocols for the formation of C–N and C–C bonds using microwave irradiations as source of energy. In a recent attempt, pyrrolidine-fused bis-spirooxindoles (72) were prepared by employing a one-pot microwave-assisted method. The efficient reaction protocol proceeded by the

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[3 + 2] cycloaddition of 3-alkenyl oxindoles and in situ generated izomethine ylides under catalyst-free conditions. The presented protocol exhibited high atom economy, broad substrate scope, and eco-sustainability. Advantageously, the microwave-assisted methodology provided single diastereomer of bis-spirooxindole skeleton in operationally simple protocol (Figure 9.25) [62].

Figure 9.25: Microwave-assisted synthesis of pyrrolidine-fused bis-spirooxindoles.

Over the years, there is a great interest for the facile preparation of oxindoles functionalized at C-3. Accordingly, a number of reaction protocols and methodologies include arylation of cyclopropans, in situ-generated diazomethane, phinacylbromide and its pyridinium salts, arenes, and α-ketoesters. Recently, a considerable attention has been paid for the synthesis of 3,3′-cyclopropyl spirooxindoles as highly potent bioactive targets. Their synthesis has also been focused from economical precursors under mild reaction conditions. It is highly desirous to introduce operationally simple, clean, and green synthetic procedures for their preparation in higher yield. Very recently, a cascade reaction described the green synthesis of spirocyclopropyl oxindoles (75) in aqueous media. The energy-efficient methodology furnished good to excellent yield of the title compounds. The reaction proceeded with the formation of two chiral centers, exhibiting a broad substrate scope in controlled experiments (Figure 9.26) [63].

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Figure 9.26: Microwave-assisted cascade reaction for the synthesis of spirocyclopropyl oxindoles.

9.3 Conclusions Herein, we have presented the recent examples highlighting the green synthesis of spirooxindoles employing modern synthetic strategies and tools. The presented examples signify the use of water as reaction media, and microwaves as alternative energy source. Further, the applications of organocatalysis highlighted the avoidance of metallic catalysts for the synthesis of potent N-heterocyclic scaffolds like spirooxindoles under green conditions.

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

Chapter 10 Sodium dodecyl sulfate in water: A valuable combination for the synthesis of various bioactive heterocycles 10.1 Introduction In recent times, applications of various metal-free organocatalysts are increasing significantly [1–6]. Among many others, surfactant-type catalysts have gained considerable attention due to their environmental friendliness [7–10]. Surfactants are generally regarded as surface-active agents due to their amphiphilic nature [11, 12] which helps to carry out surfactant-catalyzed organic transformations in aqueous medium. Sodium dodecyl sulfate (SDS) or sodium lauryl sulfate is one of such surfactant-type catalysts which have been extensively used for various organic transformations in aqueous medium [13]. It is a commercially available inexpensive and less toxic substance. It is an anionic surfactant with lower critical micelle concentration (CMC) value [14]. It has also been used in detergent, soap, face wash, tooth pastes, and so on [15]. SDS can easily be synthesized in large scale via Steopan’s process from the reactions of lauryl alcohol and sulfur trioxide followed by neutralization with sodium carbonate [16]. It was hypothesized that the hydrophobic organic compounds accumulate inside the vesicles of the in situ formed micellar droplets of SDS ; this reduces the distance between the reactants, which facilitate the progress of the reaction and rate enhancement [17–20]. By using SDS as catalyst we can carry out various organic transformations in water, the safest solvent. Therefore, the use of SDS as catalyst in water is considered quite safe and does not have any toxic effect. On the other hand, heterocyclic scaffolds, in general, are reported to possess a broad range of biological activities [21–28]. More than half of the commercially available drug molecules consist of various heterocyclic skeletons [29, 30]. In this chapter

Acknowledgments: The authors are thankful to Prof. Gurmail Singh, Vice-Chancellor, Akal University, for his wholehearted encouragement and support. BB is grateful to Akal University and Kalgidhar Trust, Barusahib, India, for the financial assistance. ✶

Corresponding author: Bubun Banerjee, Department of Chemistry, Akal University, Talwandi Sabo, Bathinda 151302, Punjab, India, email: [email protected] Anu Priya, Aditi Sharma, Manmeet Kaur, Arvind Singh, Department of Chemistry, Akal University, Talwandi Sabo, Bathinda 151302, Punjab, India https://doi.org/10.1515/9783110985627-010

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we have highlighted the applications of SDS as an efficient surfactant-type catalyst for the synthesis of various biologically promising heterocyclic scaffolds in water.

10.2 Synthesis of bioactive heterocycles 10.2.1 Synthesis of bioactive N-heterocycles 10.2.1.1 Synthesis of pyrroles Pyrrole skeleton is very common in many biologically active compounds having a wide range of biological efficacies including antioxidant, antiviral, anti-inflammatory, antitumor, antibacterial, and anticancer activities [31–34]. In 2013, Veisi et al. [35] reported an efficient method for the synthesis of a series of pyrrole derivatives (3) starting from substituted anilines (1) and hexane-2,5-dione (2) in the presence of a catalytic amount of SDS in water at room temperature (Figure 10.1). The same group was also able to synthesize N-substituted pyrroles (6) via the condensation of γ-diketones (4) with p-toluenesulfonyl hydrazide (5) using the same catalyst in water at 100 °C (Figure 10.2).

Figure 10.1: SDS-catalyzed synthesis of pyrroles in water at room temperature.

Figure 10.2: SDS-catalyzed synthesis of N-substituted pyrroles in water under refluxed conditions.

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10.2.1.2 Synthesis of N-aryl-1,8-dioxo decahydroacridines N-Aryl-1,8-dioxo decahydroacridines have been considered as potential lead candidates in drug design and discovery. Antimicrobial activities of N-aryl-1,8-dioxo decahydroacridine moieties were reported by Kaya et al. (Figure 10.3) [36]. N-Aryl-1,8-dioxo decahydroacridines were synthesized by using various homogeneous as well as heterogeneous catalysts under diverse reaction conditions [37]. In 2009, Shi et al. [38] reported a facile and aqueous-mediated protocol for the synthesis of a series of N-aryl-1,8-dioxo decahydroacridines (9) in moderate yields via one-pot pseudo-four-component reactions between 2 equivalents of dimedone (7), 1 equivalent of substituted benzaldehydes (8), and 1 equivalent of anilines (1) in the presence of SDS as catalyst at 90 °C (Figure 10.4).

Figure 10.3: Biological activities of N-aryl-1,8-dioxo decahydroacridines.

Figure 10.4: SDS-catalyzed synthesis of N-aryl-1,8-dioxo decahydroacridines in water.

10.2.1.3 Aza-Diels–Alder reaction In 2009, Costantino et al. [39] developed a facile and efficient direct aza-Diels–Alder reaction protocol between 2-cyclohexen-1-one (10) and benzaldimines (11) using a catalytic mixture of layered α-zirconium hydrogen phosphate and SDS in water at 30 °C

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(Figure 10.5). This reaction afforded the corresponding aza-Diels–Alder adducts (12) in a ~1:1 ratio of the endo and exo forms. The aqueous medium containing the catalyst was recovered and recycled for six successive runs with almost equal efficiency. Though the reactions required longer time to complete but afforded the products in excellent yields.

Figure 10.5: Direct aza-Diels–Alder reaction in the presence of sodium dodecyl sulfate and α-zirconium hydrogen phosphate in water.

In 2012, Lanari et al. [40] reported a simple, efficient, and aqueous mediated protocol for the synthesis of 1,2-diaryl-2,3-dihydro-4-pyridones (14) via Aza-Diels–Alder reaction between various N-benzylideneaniline (11) and Danishefsky’s diene (13) in the presence of a mixture of copper(II) triflate–sodium dodecyl sulfate as catalyst under acidic conditions (pH 4) at 30 °C (Figure 10.6). The catalyst containing aqueous medium was recovered and reused for the second time without any significant loss in its catalytic activity.

Figure 10.6: Synthesis of 1,2-diaryl-2,3-dihydro-4-pyridones via aza-Diels–Alder reaction in water.

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10.2.1.4 Synthesis of 1,2-disubstituted benzimidazoles Various benzimidazoles showed a wide range of biological activities, including antiviral, antihypertensive, anticancer, and antifungal. In 2011, Ghosh et al. [41] synthesized a series of 1,2-disubstituted benzimidazoles (16) via one-pot pseudo-three-component reactions between 1 equivalent of substituted o-phenylenediamine (15) and 2 equivalents of aldehydes (8) in the presence of SDS as catalyst in water at room temperature (Figure 10.7). All the reactions were completed within 30 min and afforded the corresponding desired products in excellent yields. Aldehydes with electron-donating as well as electron-withdrawing substituents participated with equal efficiency in the reaction. After the completion of the reaction the catalyst-containing reaction medium was recovered and recycled successfully for the six consecutive runs.

Figure 10.7: SDS-catalyzed synthesis of 1, 2-disubstituted benzimidazoles in water.

10.2.1.5 Synthesis of quinoxaline derivatives Various quinoxaline moieties possess significant pharmacological efficacies, and few of them are used as food flavoring materials (Figure 10.8) [42–45].

Figure 10.8: Some important quinoxaline molecules.

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In 2013, Ghosh et al. [46] synthesized a series of biologically promising structurally diverse quinoxaline derivatives (19–21) from the reactions of α-bromo carbonyl compound (17) and various 1,2-diamines (15, 15a, 18) in the presence of a catalytic amount of SDS as a catalyst in water at room temperature (Figure 10.9). All the reactions afforded excellent yields of the desired products after stirring for 6–7 h. The catalyst containing aqueous medium was recycled further for five successive runs without any significant loss in its catalytic activities. Catalytic activities of other surfactants such as cetylpyridiniumchloride, cetyl trimethyl ammoniumbromide, sodium dodecylbenzenesulfonate, tetra-n-butylammonium bromide, and tetra-n-butylammoniumiodide (TBAI) were also screened in water medium but were found to be less effective. Gram-scale synthesis of the desired product was also achieved. The authors performed the dynamic light scattering measurement study of an 11.57 mM aqueous SDS solution which indicated the presence of micelles with diameter around 322 nm. This data supports that the reactions can occur inside the hydrophilic core of the micelles. Under the same optimized reaction conditions, 2α-bromofriedelin (23) (prepared from friedelin (22) was also reacted smoothly with o-phenylenediamine (15) and afforded the corresponding quinoxaline derivative (24) in good yield (Figure 10.10).

Figure 10.9: SDS-catalyzed synthesis of quinoxaline derivatives in water at room temperature.

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Figure 10.10: Synthesis of quinoxaline derivative starting from 2α-bromofriedelin.

10.2.1.6 Synthesis of pyrrolo-quinoxalines In 2016, Keivanloo et al. [47] reported a facile method for the synthesis of a number of 1,4-disubstituted pyrrolo[1,2-a]quinoxaline derivatives (28) via one-pot three-component reactions of 3-substituted-2-chloroquinoxalines (25), secondary amines (26), and propargyl alcohol (27) in the presence of Pd/Cu as catalyst and SDS as cocatalyst in basic aqueous medium at 80 °C (Figure 10.11). Interestingly, 6 years ago, the same group [48] also synthesized a series of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines (31) from the reactions of N-alkyl-3-chloroquinoxaline-2-amines (29) with various 1-alkynes (30) using the same Pd/Cu combination as catalyst in the presence of SDS as cocatalyst in water (Figure 10.12). Later on, in 2012, the same group [49] also synthesized a variety of 5,6disubstituted-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles (33) from the reaction of 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicarbonitriles (32) with phenylacetylene (30) by following almost similar reaction conditions (Figure 10.13). In all these reactions, the necessity of SDS as the cocatalyst was established by carrying out the same reactions in the absence of SDS which afforded poor yields of the desired products.

10.2.1.7 Synthesis of imidazopyridines Many commercially available drugs such as zolmidine (effective for the treatment of peptic ulcer) [50], miroprofen (analgesic) [51], zolpidem [52], and alpidem (used for the treatment of insomnia) [53] contain imidazopyridine skeleton (Figure 10.14). In 2020, Bhutia et al. [54] synthesized a series of structurally diverse 2-arylimidazo[1,2-a] pyridines (36a–c) in excellent yields from the reaction of 2-aminopyridines (34) and various aryl methyl ketones (35a–c) in the presence of 30 mol% molecular iodine as catalyst and 10 mol% of SDS as cocatalyst in water at 40 °C (Figure 10.15). In the absence of surfactant, the same reaction with only 30 mol% iodine as catalyst afforded poor yield of the desired products. Using this method, they successfully synthesized zolmidine in gram scale. Interestingly, Bakherad et al. [55] synthesized another series of 2-substituted imidazo[1,2-a]pyridines (36d) via Sonogashira reactions of 2-amino-1(2-propynyl)pyridinium bromide (37) and various iodobenzenes (38) using Pd–Cu cat-

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Figure 10.11: Aqueous-mediated synthesis of 1,4-disubstituted pyrrolo[1,2-a]quinoxalines in the presence of SDS as cocatalyst.

Figure 10.12: Aqueous-mediated synthesis of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines in the presence of SDS as cocatalyst.

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Figure 10.13: Aqueous-mediated synthesis of 5,6-disubstituted-5H-pyrrolo[2,3-b]pyrazine-2,3dicarbonitriles in the presence of SDS as cocatalyst.

Figure 10.14: Commercially available drugs with imidazopyridine skeleton.

Figure 10.15: SDS-catalyzed synthesis of 2-arylimidazo[1,2-a]pyridines in water.

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Figure 10.16: Synthesis of 2-substituted imidazo[1,2-a]pyridines via Sonogashira reaction in water.

alytic system in the presence of SDS as the surfactant in water under basic conditions at 60 °C (Figure 10.16). When the other conditions were unaltered, the reactions afforded only 10% of the desired product in the absence of surfactant.

10.2.1.8 Synthesis of phthalazines Phthalazine derivatives showed immense biological efficacies including antimicrobial [56], anti-inflamatory [57], anticonvulsant [58], and antihypertensive [59] activities. Figure 10.17 represents some of the other pharmacologically active phthalazine derivatives [60]. In 2018, Bakherad et al. [61] synthesized a series of 3-aryl-6-chloroimidazo [2,1-a]phthalazines (40) in moderate to good yields via the reactions of 1-chloro-4propargylaminophthalazine (39) and various aryl halides (38,38a) using Pd–Cu catalytic system in the presence of SDS as the surfactant in water under basic conditions at 70 °C (Figure 10.18). Antimicrobial activities of the synthesized compounds were evaluated, and among all compounds 40a–c showed highest biological activities against all the tested strains.

10.2.1.9 Synthesis of tetrahydropyrazolopyridine-6-ones In 2016, Hemmati et al. [62] demonstrated a simple and facile SDS-catalyzed aqueousmediated protocol for the synthesis of 3-methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b] pyridine-6-ones (43) via one-pot three-component reactions of Meldrum’s acid (41) substituted benzaldehydes (8) and 5-methylpyrazol-3-amine (42) at 100 °C (Figure 10.19). It was proposed that SDS form micelles in water which solubilized organic compounds and the reaction proceeded through the pathway shown in Figure 10.20.

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Figure 10.17: Pharmacologically active compounds with phthalazine skeleton.

Figure 10.18: Synthesis of 3-aryl-substituted 6-chloroimidazo[2,1-a]phthalazines via Sonogashira coupling reaction.

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Figure 10.19: Synthesis of 3-methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones in water.

Figure 10.20: Plausible mechanism for the sodium dodecyl sulfate-catalyzed synthesis of 3-methyl-4-aryl2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones in water.

10.2.2 Synthesis of bioactive O-heterocycles using sodium dodecyl sulfate 10.2.2.1 Synthesis of benzo[b]furans A series of substituted benzo[b]furans (45) was synthesized by Prof. Ranu and his group [63] through the Sonogashira coupling reactions followed by 5-endo dig cyclization between 2-iodophenols (44) and arylacetylenes (30) using in situ-generated Pd(0) nanoparticles as catalyst in the presence of a catalytic amount of SDS as the cocatalyst in water under basic conditions (Figure 10.21). The reactions required 12–18 h of stirring to complete at 100 °C. It was proposed that the reaction proceeded through the standard pathway of Sonogashira coupling reaction [64]. At the first step, oxidative addition of 2-iodophenol to Pd(0) occurred, which is followed by transmetallation, re-

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Figure 10.21: Synthesis of benzo[b]furans via Sonogashira coupling–5-endo-dig cyclization.

Figure 10.22: Plausible mechanism for the synthesis of benzo[b]furans via Sonogashira coupling reactions.

ductive elimination, and at last cyclization processes afforded the desired products with regeneration of Pd(0) for the next cycle (Figure 10.22).

10.2.2.2 Synthesis of 3,4-dihydropyrano[c]chromene Several 3,4-dihydropyrano[c]chromene derivatives were reported to possess significant biological efficacies which include anticancer [65], antibacterial [66], and xanthine oxidase inhibitory [67] activities (Figure 10.23). In 2010, Mehrabi and Abusaidi [68] developed a simple and effective protocol for the synthesis of a series of 3,4dihydropyrano[c]chromenes (48) via one-pot three-component reactions of substituted benzaldehydes (8), malononitrile (46), and 4-hydroxycoumarin (47) in the presence of a catalytic amount of SDS in water at 60 °C (Figure 10.24). All the reactions were completed within 3 h and afforded the desired products in excellent yields. After

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Figure 10.23: Glimpse of biologically promising 3,4-dihydropyrano[c]chromene derivatives.

Figure 10.24: SDS-catalyzed synthesis of 3,4-dihydropyrano[c]chromenes in water.

completion of the reaction, the catalyst containing reaction media was recovered and recycled for four successive runs without any significant loss in product yields.

10.2.2.3 Synthesis of 2-amino-3-cyano-tetrahydrobenzo[b]pyrans 2-Amino-3-cyano-tetrahydrobenzo[b]pyran derivatives are reported to possess a wide range of biological activities [69]. Figure 10.25 represents some recently reported

Figure 10.25: Bioactivity of synthetic 2-amino-3-cyano-tetrahydrobenzo[b]pyrans.

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2-amino-3-cyano-tetrahydrobenzo[b]pyran derivatives with potent antibacterial [70], antimicrobial [71], and antifungal [72] activities. Very recently, our group [13] reported a simple, facile, and convenient method for the synthesis of a series of 2-amino-3-cyano-

Figure 10.26: SDS-catalyzed synthesis of 2-amino-3-cyano-tetrahydrobenzo[b]pyrans in water.

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tetrahydrobenzo[b]pyran derivatives (49) via one-pot three-component reactions of dimedone or 1,3-cyclohexanedione (7), aromatic aldehydes (8), and malononitrile (46) using 10 mol% SDS as an efficient surfactant-type catalyst in aqueous medium at room temperature (Figure 10.26). Under the same optimized reaction conditions synthesis of 2-amino-3-cyano-spiropyrans (51,52) was also achieved from the reactions of ninhydrin/ isatins (50), malononitrile (46), and dimedone or 1,3-cyclohexanedione (7). All the reactions were completed within 2.5 h and afforded the desired products in good to excellent yields. It was assumed that SDS in water form micelles which helped to aggregate hydrophobic organic reactants in it and the reaction proceeded through the pathway shown in Figure 10.27.

Figure 10.27: Plausible mechanism for the SDS-catalyzed synthesis of tetrahydrobenzo[b]pyrans.

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10.2.3 Synthesis of bioactive N,O-heterocycles using sodium lauryl sulfate 10.2.3.1 Synthesis of functionalized pyrimidine Various heterocycles with pyrimidine skeletons showed a broad range of biological efficacies which include anti-inflammatory, antihypertensive, antitumor, and antiviral activities [73–76]. In 2018, Pramod K. Sahu [77] synthesized a number of 7-phenylbenzo[4,5] thiazolo[3,2-a]chromeno[4,3-d]pyrimidin-6(7H)-one derivatives (56) via one-pot threecomponent reactions of 4-hydroxycoumarin (47), substituted benzaldehydes (8), and benzo[d]thiazol-2-amines (53) in the presence of 10 mol% of SDS as an surfactant-type catalyst in water at room temperature (Figure 10.28). Following this protocol they were able to synthesize a series of functionalized pyrimidines with excellent yield (Figure 10.28). Instead of using benzo[d]thiazol-2-amines (53), by following the same optimized reaction conditions, they were also able to synthesize 3,4-dihydro-1H-chromeno [4,3-d]pyrimidines (57) and 7-phenyl-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a] pyrimidin-6-one (58) in good yields starting from urea/thiourea (54) and 1H-1,2,4-triazol3-amine (55), respectively (Figure 10.28). The same group also synthesized another series

Figure 10.28: SDS-catalyzed synthesis of various functionalized pyrimidines catalyzed in water.

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Figure 10.29: SDS-catalyzed synthesis of 3,4-dihydro-1H-chromeno[4,3-d]pyrimidines in water.

of 3,4-dihydro-1H-chromeno[4,3-d]pyrimidine derivatives (57) using a catalytic amount of SDS as catalyst in water (Figure 10.29) [78]. During this study the authors observed that the solid reactants, which were initially in the floating conditions in aqueous medium, were converted to a homogeneous mixture upon addition of SDS . They also observed that the resultant mixture further turned into a white turbid emulsion to form colloidal particles. The formation of micelles was confirmed by the optical microscopic studies.

10.2.4 Synthesis of bioactive N,S-heterocycles using sodium dodecyl sulfate 10.2.4.1 Synthesis of 2-phenylbenzothiazole In 2007, Prof. Asit K. Chakraborty and his research group [79] reported a simple, convenient, and clean “on water” method for the efficient synthesis of a series of 2-substituted benzothiazoles from the reactions of various aryl/heteroaryl/styryl aldehydes and 2-aminothiophenol under refluxed conditions at 110 °C. In 2011, the same group [80] achieved the same synthesis at room temperature by using a catalytic amount of sodium dioctyl sulfosuccinate (SDOSS) or SDS as surfactant-type catalyst in water. By using SDS as catalyst, they obtained 2-phenylbenzothiazoline (60a) and 2-phenylbenzothiazole (60b) in 2:98 ratio from the reaction of 2-aminothiophenol (59) and benzaldehyde (8) (Figure 10.30). They also investigated the role of surfactants in this transformation.

Figure 10.30: SDS-catalyzed synthesis of 2-phenylbenzothiazole in water.

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They were able to identify the discrete intermediates through mass spectrometry which confirmed the ability of SDS/SDOSS as a dioxygen activation agent.

10.2.4.2 Synthesis of 2,3-dihydro-1,5-benzothiazepines In 2008, Prof. Chakraborti and his research group [81] further employed SDS as an efficient catalyst in water for the synthesis of a series of 2,4-diaryl-2,3-dihydro-1,5benzothiazepine derivatives (62) from the reactions of 2-aminothiophenol (59) and structurally diverse α,β-unsaturated ketones (61) at 110 °C (Figure 10.31).

Figure 10.31: SDS-catalyzed synthesis of 2,3-dihydro-1,5-benzothiazepines in water.

10.3 Conclusions SDS or sodium lauryl sulfate is a surfactant-type catalyst that has been extensively used for various organic transformations in aqueous medium. It is an environmentfriendly, commercially available, and inexpensive substance. It is an anionic surfactant with lower CMC value. It has many applications including in detergents, soaps, face washes, and tooth pastes. SDS can be synthesized in large scale via Steopan’s process from the reactions of lauryl alcohol and sulfur trioxide followed by neutralization with sodium carbonate. Various organic transformations were catalyzed by SDS in water. In this chapter we have summarized the applications of SDS as an efficient

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surfactant-type catalyst for the synthesis of structurally diverse biologically promising heterocyclic scaffolds in water.

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Paliwal PK, Jetti SR, Jain S. Green approach towards the facile synthesis of dihydropyrano(c)chromene and pyrano[2,3-d]pyrimidine derivatives and their biological evaluation. Med Chem Res 2013, 22, 2984–2990. Vala ND, Jardosh HH, Patel MP. PS-TBD triggered general protocol for the synthesis of 4Hchromene, pyrano[4,3-b]pyran and pyrano[3,2-c]chromene derivatives of 1H-pyrazole and their biological activities. Chin Chem Lett 2016, 27, 168–172. Kappe CO. 100 years of the Biginellidihydropyrimidine synthesis. Tetrahedron 1993, 49, 6937–6963. Atwal KS, Rovnyak GC, O’Reilly BC, Schwartz J. Substituted 1,4-dihydropyrimidines. 3. Synthesis of selectively functionalized 2-hetero-1,4-dihydropyrimidines. J Org Chem 1989, 54, 5898–5907. Atwal KS, Swanson BN, Unger SE, Floyd DM, Moreland S, Hedberg A, O’reilly BC. Dihydropyrimidine calcium channel blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. J Med Chem 1991, 34, 806–811. Rovnyak GC, Atwal KS, Hedberg A, Kimball SD, Moreland S, Gougoutas JZ, O’Reillly BC, Schwartz J, Malley MF. Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1, 4dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents. J Med Chem 1992, 35, 3254–3263. Sahu PK. Role of surfactant and micelle promoted mild, green, highly efficient and sustainable approach for construction of novel fused pyrimidines at room temperature in water. RSC Adv 2016, 6, 67651–67661. Sahu PK, Sahu PK, Kaurav MS, Messali M, Almutairi SM, Sahu PL, Agarwal DD. One-pot facile and mild construction of densely functionalized pyrimidines in water via consecutive C–C and C–S bonds formation. RSC Adv 2018, 8, 33952–33959. Chakraborti AK, Rudrawar S, Jadhav KB, Kaur G, Chankeshwara SV. ‘‘On water’’ organic synthesis: A highly efficient and clean synthesis of 2-aryl/heteroaryl/styryl benzothiazoles and 2-alkyl/aryl alkyl benzothiazolines. Green Chem 2007, 9, 1335–1340. Parikh N, Kumar D, Roy SR, Chakraborti AK. Surfactant mediated oxygen reuptake in water for green aerobic oxidation: Mass-spectrometric determination of discrete intermediates to correlate oxygen uptake with oxidation efficiency. Chem Commun 2011, 47, 1797–1799. Sharma G, Kumar R, Chakraborti AK. ‘On water’ synthesis of 2,4-diaryl-2,3-dihydro-1,5benzothiazepines catalysed by sodium dodecyl sulfate (SDS). Tetrahedron Lett 2008, 49, 4269–4271.

Dripta De Joarder, Rajarshi Sarkar, and Dilip K. Maiti✶

Chapter 11 Synthesis of bioactive heterocycles involving heterogeneous catalysis in water 11.1 Introduction Heterocyclic compounds are ubiquitous in nature and have been a part of our daily life since time immemorial. Predominant ring organic compounds are heterocycles and contain N-, S-, and O-atoms prevalently [1]. Most drugs including antibiotic, antitumor, anti-inflammatory, antimalarial, antidepressant, anti-HIV, antibacterial, antiviral, antidiabetic, antifungal, herbicidal, fungicidal, and insecticidal agents are heterocyclic compounds. Moreover, heterocyclic compounds are also found in vitamins, agrochemicals, DNA, RNA, dyes, enzymes, etc. [2–13]. Scientists have made sincere efforts to synthesize these compounds in laboratory for ages employing stoichiometric reagents. The production of heterocycles has become significantly simpler with time as a result of the development of new and effective catalytic methods. A catalyst is a chemical compound that accelerates the speed of a chemical reaction, but it remains unchanged, which can be separated and reused in other reactions [14]. There are two main types of catalysis viz. homogenous catalysis and heterogeneous catalysis. In homogeneous catalysis, the reactants are in the same phase (solid, liquid, or gas) as the catalyst [15]. On the other hand, in heterogeneous catalysis, catalyst remains in the different phase compared to the starting materials, e.g., solid catalyst that catalyzes the reaction between liquid or gaseous reactants [16]. With the dawn of a new environmentally friendly era, it was realized that traditional method of synthesizing heterocycles is creating too much pollution. Active pharmaceutical ingredients and other chemical components are getting released into the environment during their production, use, and disposal, which in turn contribute to the development of antimicrobial resistance, one of the major emerging threats to mankind nowadays [17]. Paul Anastas and Roger Garrett first proposed the concept of “green chemistry” in 1991 as a means of addressing the problem of chemical contamination of the environment. Afterwards, Joe Breen coined the term “green chemistry

Acknowledgments: The authors gratefully acknowledge the financial assistance from the Ministry of Mines, GOI (Met4-14/19/2021). ✶

Corresponding author: Dilip K. Maiti, Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, West Bengal, India Dripta De Joarder, Rajarshi Sarkar, Department of Chemistry, School of Advanced Sciences, VIT-AP University, Andhra Pradesh, India https://doi.org/10.1515/9783110985627-011

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(GC)” [18]. Since its inception, the field has expanded enormously, and chemical manufacturing houses are attempting to implement GC techniques whenever it is logistically feasible, as fiercely advised by the US Environmental Protection Agency (US EPA). According to a recent report, the global market for GC will reach $98.5 billion by the end of 2020 [19]. Reducing the usage of harmful organic solvents, which account for more than 80% of the total waste materials created, is one of the main objectives of GC. In this respect multiple research areas such as catalytic reactions in water medium, solvent-less reactions, and biphasic reaction media are emerging. Using water as solvent has particularly unique feature as it is cheap, abundant, and green solvent [20]. However, the inherent difficulties in using organic starting materials in water stem from the fact that they are not miscible. In this regard heterogenous catalytic reactions are gaining much importance. This chapter will discuss various catalytic reactions that are heterogeneous in nature, reported in the literature after 2011 for the synthesis of bioactive heterocycles.

11.2 Synthesis of three-membered ring Aziridines represent a crucial structural motif in drugs and natural products [21–23]. Shukla et al. [24] revealed an effective route for the preparation of tosylaziridines (3) from styrene derivatives (1 and 4) by combining I2 and hypervalent iodine (HVI), PhI = NTs(Ntosyliminobenzyliodinane, NTIBI) (2) as a nitrene source and graphene oxide as a watertolerant catalyst. The reaction is supposed to occur through insertion of nitrene into different alkenes (Figure 11.1).

11.3 Synthesis of five-membered ring 11.3.1 Synthesis of polysubstituted pyrroles Pyrrole is an essential heterocyclic nucleus found in a number of natural compounds [25–29]. Its derivatives find many applications in material science [30–32] and display several biological activities [33–43]. Although many synthetic methods have been developed to furnish these valuable motifs [44–64], efficient and green synthetic strategies are still in demand, particularly in the preparation of polysubstituted pyrroles. Muthusubramanian and coworkers [65] furnished a facile and regioselective synthesis of polysubstituted pyrroles (8) from azido chalcones (6) and 1,3-dicarbonyl compounds (7) by an InCl3-catalyzed reaction in water medium under microwave irradiation (Figure 11.2).

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Figure 11.1: Synthesis of N-tosylaziridine and 2-nitro-1-tosylaziridine derivatives using N-tosyliminobenzyliodinane.

Figure 11.2: InCl3-mediated preparation of polysubstituted pyrroles from azidochalcones.

11.3.2 Fabrication of hydroindeno[1,2-b]indoles Rostami-Charati and his group [66] devised a synthesis of highly substituted pyrrole ring utilizing ninhydrin (11) and cycloalkan-1,3-dione (9) in the presence of primary amines (10) in H2O. This methodology was used to furnish various hydroindeno[1,2-b] indoles (12). (Figure 11.3).

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Figure 11.3: Preparation of functionalized N-acyl-2-vinyl-pyrrolidines.

11.3.3 Preparation of trisubstituted furans and pyrroles Using nanoparticle as catalyst in water, acetylenic vicinal diols and amino alcohols (13) was converted to their corresponding furans and pyrroles, (14) respectively. Nanomicelles made up of the designer-surfactant TPGS-750-Menable the gold-catalyzed reactions to take place at room temperatures and in high isolated yields (Figure 11.4) [67].

Figure 11.4: Gold-catalyzed synthesis of substituted furan and pyrrole derivatives.

11.3.4 Synthesis of tetrasubstituted pyrroles Perumal and coworkers [68] illustrated an effective synthetic protocol for the preparation of highly functionalized indolylpyrrole moieties (18) by means of a threecomponent cascade reaction between p-tolualdehyde (16), α-azidoketone (15), and 3cyanoacetylindole (17). Initially, they observed that 25 mol% aqueous solution of Lproline was an efficient catalyst that produced product (18) at 80 °C (Figure 11.5) in an excellent yield of 75%; however, piperidine was preferred as catalyst over L-proline later. The role of proline in this transformation is to promote Knoevenagel condensation between 16 and 17 initially via iminium catalysis. It also played an analogous role in the ensuing Michael addition of building block 15 and served as catalyst for the following steps.

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Figure 11.5: Proline-catalyzed strategies toward tetrasubstituted pyrrole.

11.3.5 Construction of substituted indoles Indoles are common architectural motifs in natural products with biological activity [69, 70]. Ackermann and his group [71, 72] published a report (Figure 11.6) describing oxidative annulation of alkynes (19) employing aniline derivatives (20) catalyzed by cationic ruthenium (II) complex in water. The use of substrates bearing easily removable directing groups is the key feature of the reported protocol.

Figure 11.6: Oxidative annulation of electron-rich anilines constituting a removable protecting group.

11.3.6 Synthesis of functionalized trifluoromethylated oxindoles CF3-substituted oxindoles that contain a quaternary carbon is prevalent in many natural products and biologically active compounds [73–75]. Liang Lipshutz and coworkers [76, 77] developed a feasible and affordable method for producing a range of trifluoromethylated oxindoles with quaternary carbon centers (24) via Cu-catalyzed aryl Csp2–H functionalization (Figure 11.7). Langlois’ reagent (CF3SO2Na) (23) is cheap and was used as the source of CF3 radical in this reaction. Reactions were performed at room temperature in water under air. In addition, this reaction allows for the reuse of the aqueous medium containing the water-soluble copper catalyst.

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Figure 11.7: Preparation of trifluoromethylated oxindoles catalyzed by copper.

11.3.7 Preparation of disubstituted isoxazolines and isoxazoles Isoxazolines and isoxazoles are essential heterocyclic systems that are frequently present in natural products, bioactive substances, and are used as chiral ligands [78–83]. By oxidizing oxime (25) with alkenes or alkynes, respectively, Yoshimura et al. [84] were able to produce isoxazolines (26) and isoxazoles (27) scaffolds in good to excel-

Figure 11.8: Synthesis of disubstituted isoxazolines and isoxazoles.

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lent yields. The oxidation was carried by in situ-generated HVI from substituted iodobenzene with oxone in aqueous hexafluoro isopropanol (Figure 11.8).

11.3.8 Synthetic strategy toward 3,5-disubstituted isoxazoles Meena et al. [85] have described as an effective microwave-assisted fabrication of several isoxazoles in environmentally friendly solvents. As shown in Figure 11.9, the synthesis started with functionalized aromatic aldehydes 28, which was converted to Nhydroxyl imidoyl chlorides. Substituted alkynes 29 were then reacted using 2 mol% of Cu(I) complexes as a catalyst to produce 3,5-disubstituted isoxazoles 30 while being heated by microwaves. The plus points of this unique synthetic procedure include the addition of reagents gradually, one at a time, without any purification following reactions, and a decrease in the number of synthetic processes, which improves operational simplicity.

Figure 11.9: Microwave-assisted strategy toward 3,5-disubstituted isoxazoles.

11.3.9 Strategy toward disubstituted isoxazolines One-pot isooxazoline (33) fabrication was developed by Pal et al. [86] using a variety of aldehydes (31), hydroxylamine hydrochloride, alkenes (32), iodosobenzene, and catalytic amounts of sodium dodecyl sulfate, which acts as an anionic surfactant in water (Figure 11.10).

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Figure 11.10: Preparation of disubstituted isoxazolines employing iodosobenzene.

11.3.10 One-pot preparation of dihydrospiro furo[2,3-c]pyrazole Kale et al. [87] delineated preparation of dihydrospiro furo[2,3-c]pyrazole (36) in 93% yield from pyrazolone (34) and benzaldehyde (35) utilizing oxidative approach using iodoxobenzene diacetate (IBD) in aqueous medium (Figure 11.11)

Figure 11.11: Construction of dihydrospiro furo[2,3-c]pyrazole utilizing IBD.

11.3.11 Construction of imidazo[1,2-a]pyridines Imidazo[1,2-a]pyridine is one of the main structural components of many pharmacological molecules, including zolpidem, olprinone, and minodronic acid to name a few. For the first time, a three-component, Cu–Mn spinel-catalyzed preparation of imidazo[1,2-a] pyridines (39) in aqueous media was described by Vishwakarma and his group [88] (Figure 11.12). The reaction proceeded via coupling of 2-aminopyridines (37) with aldehydes (38) and alkynes (29) and is followed by 5-exo-dig cycloisomerization. This method’s effectiveness is based on the Cu and Mn bimetallic catalyst’s inclusion of Cu and Mn ions in several oxidation states (Cu2+, Mn2+, Mn3+, and Mn4+). In the first optimized

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reaction, 2-amino pyridines, phenyl acetylene, and benzaldehyde are coupled in water at 100 °C for 4 h while being exposed to 10 mol% Cu:Mn (1:0.25). The intended product could be produced in good yields using electronically different 2-aminopyridines (37) and benzaldehydes (38). Both phenyl acetylenes and sterically hindered benzaldehydes actively participated in this process.

Figure 11.12: Cu–Mn spinel oxide mediated coupling toward imidazo[1,2-a]pyridines.

11.3.12 Preparation of differently substituted triazole derivatives Triazole derivatives (42) were produced from aromatic alkynes (29), organic halides (40), and sodium azide (41) in a one-pot, three-component green synthesis that used silica-immobilized NHC-Cu(I) as the catalyst (Figure 11.13). Huisgen [3 + 2] cycloaddition was carried out in water with the catalyst’s 1,4-regioselectivity. The reactants for standardizing the reaction conditions were chosen as sodium azide, phenyl acetylene, and benzoyl chloride. Lower product yields were only produced by aromatic alkyne derivatives possessing electron-rich functional groups. Due to its poor reactivity for Huisgen [3 + 2], p-methoxybenzyl chloride needed a longer (9 h) time [89].

Figure 11.13: One-pot three-component strategy toward triazole derivatives via silica-immobilized NHC–Cu(I) catalysis.

Srivastava and coworkers [90] reported the preparation of 1,4-disubstituted 1,2,3triazoles (42) from the in situ-created aromatic azides and phenylacetylene in the presence of Cu(10%)/Meso-ZSM-5 catalyst in water (Figure 11.14). Surprisingly, neither bromobenzene nor iodobenzene produced the target molecule.

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Figure 11.14: CuNP-decorated mesoporous ZSM-5-mediated preparation of 1,2,3-triazole moieties.

It is well known that 1,2,3- and 1,2,4-triazoles have extraordinary biological features that make them effective anticancer, antiviral, anti-inflammatory, analgesic, antifungal, or antibacterial medicines [91–93]. A multicomponent click reaction of propargyl menthyl ether (43) derived from (–)-menthol was conducted at 70 °C to produce 1,2,3triazole (45) (Figure 11.15) [94].

Figure 11.15: Preparation of 1,2,3-triazole via three-component click reaction utilizing (–)-menthol.

Likewise, 1,2,3-triazole moiety (47) was generated from propargyl ether of racemic methyl lactate (46) (Figure 11.16).

Figure 11.16: Click reaction toward lactic acid-derived 1,2,3-triazole.

1,2,3-Triazole developed from glucose was synthesized from α-D-glucopyranosyl bromide (48) which was in turn prepared from α-D-glucose pentaacetate (Figure 11.17).

Figure 11.17: Preparation of 1,2,3-triazole acquired from glucose.

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11.3.13 Synthesis of substituted benzothiazoles O-iodoaniline (50), aldehydes (52), and sulfur powder (51) were used in a Cu-catalyzed three-component reaction to create substituted benzothiazoles (53) using water as the solvent (Figure 11.18) [95]. 1,10-Phenanthroline (10 mol%) as ligand, CuCl2·2H2O, and K2CO3 in H2O at 100 °C for 24 h constitute the ideal catalytic conditions. With benzaldehydes, no notable substituent effects were noticed. Few heterocyclic aldehydes produced decent yields of the target molecule.

Figure 11.18: Copper-catalyzed reaction involving sulfur toward substituted benzothiazoles.

11.3.14 Preparation of thiazolidinone-linked triazoles Several drugs contain thiazolidinones and 1,2,3-triazoles ring systems [96, 97]. Thiazolidinones in particular show interesting anticancer [98], anti-HIV [99–102], antimalarial [103], tuberculostatic [104], antihistaminic [105], anticonvulsant [106, 107], antibacterial [108], and antiarrhythmic [109] activities. Similarly, various triazole derivatives possess antifungal [110], anticancer [111], antituberculosis [112, 113], and antimicrobial [114] activities. In 2015, Kumar et al. [115] outlined a microwave-assisted synthesis of thiazolidinone-linked triazoles (59) via a four-component sequential reaction catalyzed by copper(II) sulfate. According to the procedure, propargyloxy benzaldehyde 54 and phenyl azides 55 were combined with copper (II) as a catalyst under microwave irradiation to produce an intermediate 56. This intermediate then underwent a one-pot reaction with an array of anilines 57 and thioglycolic acid 58 to produce thiazolidinone-linked triazoles 59, as depicted in Figure 11.19. Although this methodology did not work under classical thermal heating, microwave irradiation allowed the reaction to progress with excellent yield.

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Figure 11.19: Microwave-mediated synthesis of thiazolidinone-linked triazoles.

11.4 Synthesis of six-membered ring 11.4.1 Synthesis of hexahydroquinolines Kumar and Maurya [116] synthesized hexahydroquinolines 63 via a four-component Hantzsch condensation of dimedone 60, arylaldehydes 61, acyclic β-dicarbonyl compounds 62 at ambient temperature, and in the presence of ammonium acetate. The reaction scheme was represented in Figure 11.20. A variety of catalysts were screened to optimize the reaction condition, including L-proline, L-thiaproline, D/L-phenylglycine, (–)-cinchonidine, and trans-4-hydroxy-L-proline. Among those, L-proline was the most efficient catalyst furnishing the products in satisfactory yields. In terms of scope, the method was successful for aromatic aldehydes containing substituents of different electronic nature. An analogous L-proline-catalyzed protocol using ethylacetoacetate and 1,3-indanedione in the presence of ammonium acetate was utilized to construct fused, unsymmetrical 1,4-DHPs in aqueous media under reflux conditions [117]. These reactions were carried out successfully and products were obtained in decent yields by various other alternative methods, such as β-cyclodextrin in deep eutectic solvent of ureacholine chloride [118].

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Figure 11.20: L-Proline-catalyzed Hantzsch synthesis of hexahydroquinolines.

11.4.2 Preparation of hexahydroacridine derivatives 1,4-Dihydropyridines (DHPs) can fine-tune variety of enzymes, receptors, and ion channels selectively and referred as “privileged scaffolds” despite being molecular framework they can also act as ligands [119]. Synthesis of Hantzsch DHP was first developed in 1881 [120] and is considered as one of the efficient protocols to synthesize symmetrically substituted 1,4-DHPs [121–123]. The Hantzsch 1,4-DHP synthesis was carried out by reacting cyclic β-dicarbonyl compound dimedone 60, arylaldehydes 61, ammonium acetate, and in the presence of L-proline under reflux conditions in aqueous medium and the to afford hexahydroacridine derivatives 64, as represented in Figure 11.21. Trial runs demonstrated that the reaction also occurred without proline; however, completion time was longer and yield was lower [124]. Moreover, various Nsubstituted derivatives of 64 were also synthesized by replacing ammonium acetate with aryl and benzylamines in aqueous ethanol media [125]. Thus, obtained yields were comparable to traditional conditions [126].

Figure 11.21: Hantzsch dihydropyridine synthesis in water using L-proline.

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11.4.3 Preparation of hexahydroacridine derivatives Owing to its wide range of biological activities fused-indoles have attracted a lot of attention from research community. These motifs are also present in many natural products and bioactive compounds [127–131]. Tetracyclic indoles, in particular, which have a seven-membered ring, constitute a typical structural motif found in a number of bioactive molecules, including anticancer and antibacterial substances [132, 133]. The corresponding indole derivatives 67 are produced in good yields when β-nitro-o-(alkynyl) styrenes are combined with indoles in water using gold catalyst and TFA (Figure 11.22) [134, 135]. Following an initial Michael addition of the indole to the nitroalkene molecule, the reaction proceeds by cyclizing over the triple bond that is coordinated with gold.

Figure 11.22: Gold-mediated approach toward tetracyclic indole derivatives having a seven-membered ring.

11.4.4 Fabrication of pyrazolo[3,4-b]pyridine Chemists are interested in creating pyrazolo-fused pyridines because of their several desirable biological characteristics. Pyrazo[3,4-b]pyridine (70) derivatives have recently been prepared via a one-pot cyclocondensation method in H2O [136]. The βdiketones 62, 3-methyl-1-phenyl-1H-pyrazolo-5-amine 68, and formaldehyde 69 were heated in a microwave oven with indium chloride as a catalyst to produce the desired heterocyclic scaffold as shown in Figure 11.23. This method has been further developed to produce new nitrogen fused heterocycles at a high yield. Ease of operation, greater yields, insignificant cost, and broad substrate scope compared to conventional methodology are some of the many important feature of this novel environmentally friendly synthetic procedure.

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Figure 11.23: Microwave-mediated creation of pyrazolo[3,4-b]pyridine scaffolds.

11.4.5 Fabrication of pyridopyrimidine derivatives Numerous heterocyclic substances with pyrazolopyridines rings exhibit a variety of pharmacological and biological properties, such as antibacterial, antidepressant, antihyperglycemic, anti-inflammatory, and antitumor [137–146]. In addition to herbicidal and fungicidal properties, pyrazolopyridines exhibit biological activity including a powerful cyclin-dependent kinase 1 (CDK1) inhibitor, HIV reverse transcriptase inhibitors, CCR1 antagonists, protein kinase inhibitors, and cGMP degradation inhibitors. Additionally, pyridoxopyrimidines show promising biological and pharmacological activities, including those that are antifolate, antibacterial, antityrosine kinase inhibitors, antimicrobial,

Figure 11.24: InCl3-promoted fabrication of pyridopyrimidine derivatives.

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anti-inflammatory, analgesic, antileishmanial, antituberculostatic, anticonvulsant, diuretic and potassium-sparing, and antiaggressive activities [147–157]. Three-component combinatorial synthesis of several bioactive pyrimidine and pyrazole derivatives was accomplished by Khurana et al. [158] using water as the solvent and InCl3 as the promoter (Figure 11.24). The derivatives (74) were produced by refluxing aldehyde 71, 1,3-dicarbonyl compound 60, and amino heterocycles rich in electrons such as 3-methyl-1-phenyl-1H-pyrazol-5-amine and 6-amino-1,3-dimethyl uracil (72). A novel family of pyrimidine derivatives, synthesized under the same reaction conditions, was also disclosed. The catalyst could be recycled and the reaction product was simple to separate, making the reactions environmentally benign.

11.4.6 Strategy toward pyrido[2,3-d]pyrimidin-2-amine-6, 5′-pyrimidines derivatives Deka and colleagues [159] established an operationally straightforward, high-yielding process that did not require chromatographic separations for the fabrication of pyrido [2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] from aldehydes 71, 2,6-diaminopyrimidin-4one 75, and barbituric acids 76 in H2O. 2,4-C is geometry was preferred as the reaction typically produced mixture of the two diastereomers 77 and 78 (Figure 11.25).

Figure 11.25: Three-component synthesis of spiro[2,3-d]pyrimidin-2-amine-6,5-pyrimidines] catalyzed by proline.

Due to its conformational constraint, the fabrication of the aza spirocyclic core, which is present in many natural compounds, is of great interest to organic and medicinal chemistry fraternity [160, 161]. Spiropyrimidines and their analogues are among the aza spirocycles which are famous for their potential as antibacterial agents [162–164].

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Dommaraju et al. [165] created spiro motifs spiro(isoxazolo[5,4-b]pyridine-5,5′pyrimidine), 79 by performing a pseudo five-component reaction mediated by proline in refluxing water using barbituric acids 76, 3-aminocrotonitrile 77, aromatic aldehydes 78, and hydroxylaminehydrochloride 80 (Figure 11.26). The C-2 and C-4 stereo centers in this instance are presumed to be cis; however, the authors did not designate the configuration.

Figure 11.26: Preparation of spiro[indoline-3,4ʹ-pyrano[2,3-c]pyrazole] derivative via pseudo fivecomponent assembly.

11.4.7 Synthesis of imidazopyrimidine scaffolds The biological activities of imidazopyrimidines include antioxidant, antibiotic, and antiarrhythmic, anti-inflammatory, antiviral, antimicrobial, antidiabetic, herbicidal, anticancer, calcium anagostic, antineoplastic, antihepatitis, as well as DNA-gyrase inhibitory, and lipid peroxidation inhibitory properties [166–171]. The ecologically friendly synthesis of imidazopyrimidine 83 derivatives from aromatic aldehydes 61, active methylene compounds 81, and 2-aminobenzimidazole 82 was presented by Srivastava and colleagues (Figure 11.27) [172]. This approach uses starch functionalized magnetite nanoparticles (s-Fe3O4) as a catalyst. Compared to aromatic aldehydes having electron-donating groups, those with electron-withdrawing groups quickly produced the desired compound. This approach is advantageous over

Figure 11.27: Green strategy toward preparation of imidazopyrimidine scaffolds (83).

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the previously published method because it has a number of benefits, including simple catalyst and product separation, excellent conversion, applicable to a broad range of substrates, and good atom economy.

11.4.8 Fabrication of pyrrolo[1,2-a]pyrazine moeties A key class of heterocycles in medicinal chemistry are those which contain pyrrole rings in their structure. Moreover, these substances have antitumor, antifungal, antibacterial, and antioxidant effects. Pyrrolopyrazines are one group of pyrrole derivatives and have biological activities such as HIV-1 integrase inhibitors, 5HT2C agonist, selective on competitive mGluR5 antagonists, and vasopress in 1b antagonist [173–181]. A convenient, multicomponent synthetic protocol to obtain pyrrolo[1,2-a]pyrazine (87) motifs was reported by Rostami and Shiri [182]. In order to produce 87, this process involves the reaction of ethylenediamine 84, dialkylacetylenedicarboxylate 85, and β-nitrostyrene derivatives 86 in water at 100 °C for 2 h (Figure 11.28). Pyrolo[1,2-a]pyrazine compounds were produced from variously substituted β-nitrostyrenes in excellent quantities.

Figure 11.28: Fabrication of pyrrolo[1,2-a]pyrazine scaffolds catalyzed by Fe3O4@SiO2-OSO3H.

11.4.9 Preparation of isoquinoline and isoquinolone derivatives Pharmaceuticals like CWJ-a-5, perafensine, moxaverine, and indeno[1,2-c] isoquinolone comprise important N-heterocycles called isoquinoline and isoquinolone derivatives [183–189]. Wu and coworkers [190] delineated a synthetic route to structurally diverse isoquinolines and isoquinolones from substituted nitrile derivatives 88 and arylboronic acids 89 by means of a sequential nucleophilic addition catalyzed by Pd succeeded by a intramolecular cyclization in the presence of Pd(acac)2/bpy or Pd(CF3CO2)2/bpy. Although Pdassisted carbocyanation reaction, commencing from aryl cyanides, is familiar, but the unique facet of transformations reported by the group is that (Figure 11.29) the palla-

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dium-catalyzed carbopalladation takes place onto the nitrile (which is completely different to isonitriles). Finally, the carbonyl group underwent intramolecular addition with in situ-generated palladium ketamine intermediate. A double version of reactions provided substituted isoquinolines and isoquinolones moieties in 40−99% yields (Figure 11.29). This synthetic protocol was successfully utilized to prepare a topoisomerase I inhibitor (CW-j-a-5) [191]. The key step used in the asymmetric syntheses of (−)-zephyranthine, (−)-α-lycorane, and (+)-clivonine is a distinct technique that can be described as a pseudo-domino process [192].

Figure 11.29: Preparation of isoquinolines and isoquinolones.

11.4.10 Synthesis of 2-amino-4-(indol-3-yl)-4H-chromenes derivatives Functionalized chromenes have been increasingly significant in the field of medicinal chemistry in recent years [193]. Particularly, 2-amino-4H-chromenes scaffolds are prevalent in drugs having spasmolitic-, diuretic-, anticoagulant, and antianaphylactic activities [194–196] and as therapeutics for human inflammatory TNFα-mediated diseases [197]. Rawat et al. [198] disclosed ionic liquid tetrabutylammoniumvalinate {[NBu4][Val]} supported on 3-chloropropyltriethoxysilane-grafted superparamagnetic Fe3O4 nanoparticles (VSF). This catalyst was used to obtain (93) via Friedel–Crafts/Knoevenagel/Pinner/ reaction, as depicted in Figure 11.30. This methodology exhibited good functional group tolerance.

Figure 11.30: Fabrication of 2-amino-4-(indol-3-yl)-4H-chromenes.

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11.4.11 Construction of dihydropyrano[c] chromene scaffolds Hosseini et al. [199, 200] used a three-component method to synthesize a chromene derivative. Here, an iron ore pellet was used as catalyst during the reaction of aldehyde (61), 4-hydroxy-2H-chromen-2-one (94), and malononitrile (81), furnishing dihydropyrano[c]chromene derivatives (95) (Figure 11.31). This methodology uses iron ore pellets, which are benign and affordable.

Figure 11.31: Iron ore pellet-catalyzed construction of dihydropyrano[c] chromenes.

11.4.12 Preparation of 2-amino-4H chromenes For the construction of 2-amino-4H chromenes, Behbahani et al. [201] developed a green synthetic method that is catalyzed by copper(II) sulfate (Figure 11.32). Quick completion time and re-usable green catalyst in aqueous media make this reaction highly interesting. To produce 2-amino-4-phenyl-4H-benzo[f], the procedure employed bezaldehyde (61) (1 mmol), malononitrile (81) (1 mmol), α/β-naphthol (96) (1 mmol), water (5 mL), and CuSO4·5H2O (5 mol%). Both 97 and 98 were generated. Aldehydes having different electronic properties produced 2-amino-4H chromenes in modest yields.

Figure 11.32: Construction of 2-amino-4H chromenes catalyzed by Cu(II) sulfate.

11.4.13 Preparation of 4H-pyrans Pyran rings and other pyrene derivatives are present in a wide range of bioactive substances, notably sugars. These scaffolds show a wide range of bioactivities, including

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sedative, antitubercular, antiprotozoal, antibacterial, and antifungal effects [202–205]. Recent years have seen the development of new methods for the synthesis of pyrene derivatives [206, 207]. Peng and Song have published a method describing one-pot synthesis of 4H-pyran moieties using the amino-functionalized ionic liquid [2-aemim] [PF6] (1-methyl-3-(2-aminoethyl)imidazolium hexafluorophosphate). A mixture of aromatic aldehydes 61 with malononitrile (81) and ethyl acetoacetate (99) was treated at 100 °C in water utilizing [2-aemim][PF6], and the microwave-mediated cyclization occurred rapidly (1–4 min) (Figure 11.33). The 4H-pyran derivatives (100) have been isolated in good yields.

Figure 11.33: Formation of 4H-pyrans using a mixture of water and ionic liquid as solvent.

11.4.14 One-pot strategy for the preparation of various pyranopyrazole moieties Even though several strategies have been published for the fabrication of pyranopyrazoles, still simple and eco-friendly approaches are in demand [208]. In this regard, multicomponent reactions (MCRs) offer fascinating edge owing to convenient procedures, atom economy, and convergent characteristics [209–211]. Utility of MCRs in material sciences, drug discovery, ligand synthesis, and natural product synthesis demonstrates the usability of this methodology [212, 213]. A one-pot, four-component strategy toward a variety of pyranopyrazole scaffolds has been developed by employing ZnO nanoparticles as a heterogeneous catalyst and H2O as the solvent. The proposed route quickly produced the necessary compounds in good yields (85–90%) [214]. This procedure is economical and environmentally benign because the ZnO NPs could be recycled and utilized again after the reaction without suffering a substantial loss of activity.

11.4.15 One-pot strategy for the preparation of various pyranopyrazole moieties Pyrano[2,3-c]pyrazoles are medicinally important compounds having a variety of biological and pharmacological uses [215]. In 2013, Tekale et al. [216] illustrated the con-

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Figure 11.34: Synthesis of various pyranopyrazole derivatives by means of a one-pot four-component by using ZnO NPs.

struction of 4H-pyrano[2,3-c]pyrazoles (106) in good yields via an one-pot, fourcomponent coupling reaction of aromatic aldehydes, ethyl acetoacetate, malononitrile, and hydrazine hydrate in H2O (Figure 11.35).

Figure 11.35: One-pot four-component green synthesis of pyranopyrazoles catalyzed by ZnO NPs.

11.4.16 Fabrication of 3,4-dihydropyrimidin-2(1H)-one scaffolds Pyrimidine (six-membered aromatic, heterocyclic compounds whose 1 and 3 positions are occupied by two nitrogen atoms) derivatives are extremely abundant in the biological world. They are found in various building blocks of life including nucleotides, for example, thymine, uracil, cytosine, and natural products such as alloxan and thiamine (vitamin B1). Incidentally, this heterocyclic unit is also present in a number of medications such as zidovudine (anti-HIV) and barbiturates. Other pharmaceutical activities exhibited by this class of heterocycle include antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, anticancer, and antineoplastic activity [217]. Siddiqi et al. [218] communicated an innovative and green method to obtain 3,4-dihydropyrimidin-2(1H)-one derivatives (108) by catalyzing a Biginelli reaction with employing bis[(L)prolinato-N,O]Zn. (Figure 11.36). This significant and beneficial MCR provides a quick and easy technique to produce multifunctionalized 3,4dihydropyrimidin-2(1H)-ones (DHPMs) and related heterocyclic compounds [219].

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DHPMs, among other Biginelli compounds, are effective calcium channel blockers [220]. The straightforward operational process involves a fairly quick reaction times and excellent yields and the catalyst showed no significant reduction in reactivity up to five catalytic cycles.

Figure 11.36: Fabrication of 3,4-dihydropyrimidin-2(1H)-one scaffolds catalyzed by [Zn(L-proline)2].

11.4.17 Synthesis of 2-substituted quinazolinone In 2016, Zhou and coworkers [221] reported the first instance of iron(III)-catalyzed preparation of 2-substituted quinazolinone (110 and 111) via condensation of 2-amino benzamide (108) with both cyclic or acyclic 1,3-diketones 109 and 62. They described why using iron(III) chloride in an H2O-PEG solvent is a superior choice to furnish these heterocyclic motifs. Under oxidant-free conditions, the N-aryl-2-aminobenzamide having groups with different electron demands formed the intended product in a 56–93% yield (Figure 11.37).

Figure 11.37: Iron(III) chloride-catalyzed synthesis of 2-substituted quinazolinone in water.

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11.4.18 Synthesis of spirooxindolepyrimidines and spirooxindole The heterocyclic structural motifs spirooxindoles and pyrimidines, which have a variety of uses in medical chemistry, are present in many natural and manufactured substances [222–232]. In 2012, Liu and his colleagues [233] have established a potent one-pot, three-component reaction using barbituric acids, isatins, and cyclohexane1,3-diones for the direct synthesis of a library of spirooxindole-pyrimidine derivatives catalyzed by nanomagnetically silica-supported dodecyl benzenesulfonic acid in H2O. Coating of silica layer was performed by sonication of γ-Fe2O3 in tetraethylorthosilicate solution forming silicate the red γ-Fe2O3@SiO2 mixture. After that, dodecyl benzene sulfonic acid was added and the reaction mixture was heated to form dodecyl benzenesulfonic acid-impregnated silicate the red magnetic nanoparticles [γFe2O3@SiO2-DDBSA]. 5,5-Dimethylcyclohexane1,3-dione 60, isatin 112, and barbituric acid 76 were refluxed in the aqueous media with the catalyst as depicted in Figure 11.38 to test the catalytic activity. To their surprise, they obtained a 95% yield for spirooxindole pyrimidines 113. Other catalysts, including lithium chloride, silicotungstic acid, trifluoromethane sulfonic acid, cerium ammonium nitrate, and acetic acid, were tested using this protocol to demonstrate their catalytic efficiency, but they only yielded very little of the desired compound. Following the optimization of various solvents, water was identified as the effective solvent.

Figure 11.38: Synthesis of spirooxindolepyrimidines using [Fe2O3@SiO2-DDBSA NPs].

Spirooxindole derivatives are important indole-containing heterocycles with biologically and medicinally significant properties, such as anticancer, antifungal, and antibacterial action, as well as muscarinic serotonin receptor inhibitory and antimicrotubular activity [234–240]. The E3 ubiquitin protein ligase MDM2 is known to be inhibited by spirooxindoles, which also have anticancer, anti-HIV, antitubercular, and progesterone receptor modulating properties [241]. Pal et al. [242] synthesized various spirooxindole moieties 114 by employing a glutathione-grafted nano-organocatalyst (nano-FGT), and they also utilized L-proline as a catalyst to obtain the parent compound in 91% yield (Figure 11.39).

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Figure 11.39: Preparation of spirooxindole in gram scale.

11.4.19 Fabrication of tetrahydrobenzoxanthene and 1, 6-dioxooctahydroxanthene scaffolds Due to antiviral, antibacterial, anti-inflammatory, anticancer, and antitumor properties, xanthenes and benzoxanthenes derivatives have been widely studied [243–246]. Tetrahydrobenzoxanthene and 1,8-dioxooctahydroxanthene moieties have been prepared using an environmentally friendly method [247]. Aromatic aldehydes 61 and cyclic 1,3-diketone 114 using heterogeneous catalyst Fe–Cu/ZSM-5 in H2O at room temperature under ultrasound irradiation gave 1,8-dioxooctahydroxanthene derivatives 116 and 117 (Figure 11.40).

Figure 11.40: Fe–Cu/ZSM-5-catalyzed preparation of tetrahydrobenzoxanthene and 1,6dioxooctahydroxanthene motifs.

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11.4.20 Preparation of benzopyrano-chromene and pyrano-chromene moieties Considering their fascinating chemical and biological utilities of triazole, tetrazole and quinoline derivatives were chosen to construct a diverse library of heterocyclic compounds. Patel and colleagues [248] have recently illustrated the fabrication of benzopyrano-chromene and pyrano-chromene scaffolds 121–124 using a method that involves the reaction of 4-hydroxycoumarin 118, quinoline-3-carbaldehydes 119/120, 6-(un) substituted-2-(aminotriazole/tetrazole) or 4-hydroxy-6-methylpyran 125, nitriles 126, catalyzed by L-proline (Figure 11.41).

11.4.21 Preparation of xanthenediones Xanthenediones are prominent in naturally occurring compounds and important intermediates for synthesizing different organic moieties. Their potential applications include sensitizers in photodynamic therapy and for several other medicinal uses [249, 250]. Jain and coworkers [251] have delineated the synthesis of this family of compounds by the reacting aldehyde derivatives with dimedone in the presence of Zn(L-proline)2 in aqueous media (Figure 11.42). Operational simplicity was achieved by using a recyclable catalyst in a catalytic amount in a water-mediated reaction rather than costly, corrosive chemicals, and hazardous solvents.

11.4.22 Strategies toward variety of 3-aryl-3,4-dihydro-2Hnaphtho[2,1-e][1,3]oxazine scaffolds Thiamine hydrochloride (VB1), a multifinctional biodegradable and reusable catalyst, was used to produce 1,3-oxazine derivatives (128, 129) in an effective, one-pot, and practical three-component condensation of α- or β-naphthol, aniline (127), and formaldehyde (69) in water as the solvent of choice [252] (Figure 11.43).

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Figure 11.41: Preparation of benzopyrano-chromene and pyrano-chromene moieties.

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Figure 11.42: Preparation of xanthenediones by employing dimedone with aldehydes employing Zn(Lpronline)2 catalyst.

Figure 11.43: Strategies toward 3-aryl-3,4-dihydro-2H-naphtho[2,1-e][1,3]oxazine scaffolds.

11.5 Synthesis of seven-membered ring 11.5.1 Preparation of 4,5,6,7-tetrahydro-1H-1,4-diazepine5-carboxamide Tetrahydro-1H-1,5-benzodiazepine-2-carboxamide (Figure 11.44) and 4,5,6,7-tetrahydro1H-1,4-diazepine-5-carboxamide were synthesized by Shaabani et al. [253] utilizing wool-supported Fe3O4 nanoparticles and natural wool sulfonic acid (wool-SO3H) catalysts. Different amines and carbonyl compounds were used during the substrate scope investigation, and it was discovered that these had interacted to produce the target compounds in good to exceptional yields.

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Figure 11.44: Nano-Fe3O4@wool and wool-SO3H-catalyzed fabrication of 4,5,6,7-tetrahydro-1H-1,4diazepine-5-carboxamide.

11.6 Miscellaneous 11.6.1 Mn-catalyzed dehydrogenative conversion of alcohols into acids A wide spectrum of biological actions, including antibacterial, anticancer, antihypertensive, cardiotonic, antiproliferative, vasodilator, antifolate, antimalarial, analgesic, and antifungal activities, are exhibited by pyrido[2,3-d]pyrimidines along with their spiro counterparts [254–263]. Liu and colleagues [264] showed how dehydrogenative coupling of alcohols with hydroxyl groups can produce carboxylate anion. Due to the manganese-pincer complex 134’s catalytic activity at very low catalytic loading (0.2 mol%) and under mild oxidation conditions, this direct oxidation approach is successful (Figure 11.45). The acidic work up of the reaction mixture produced good to excellent yields of the carboxylic acid. Both aliphatic and aromatic alcohols showed excellent functional group tolerance in this reaction; however aliphatic alcohols called for more equivalents of KOH than benzyl alcohols (NaOH). The robust nature and superior functional group tolerance of this Mn-catalyzed transformation exemplified its potential application in

Figure 11.45: Manganese-catalyzed dehydrogenative conversion preparation of acids from alcohols.

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the synthesis of highly functionalized advanced chemicals. To further illustrate the synthetic adequacy of this protocol, several generic pharmaceutical agents such as adapalene, 3-cyclopropoxy-4-(difluoromethoxy)benzoic acid, and etamivan were selected as target molecules. These three drug molecules containing aromatic carboxylic acid units were easily obtained from the corresponding primary alcohols in excellent yield using this synthetic method.

11.6.2 Fabrication of β-quinoline allylic sulfones There are several quinoline derivatives present in natural compounds, bioactive pharmaceuticals, and functional materials [265–270]. Among those common molecular skeletons with substantial bioactivities is 2-alkenylquinoline [271, 272]. Deng and colleagues [273] reported about the fabrication β-quinoline allylic sulfones 140. 2-(3-(Phenylsulfonyl) prop-1-en-2-yl)quinolone was produced in 52% yield by the model reaction of 2-methylquinoline 137 and sodium benzene sulfinate 138 in dimethyl acetamide, which functions as a dual synthon, in the presence of 10 mol% FeCl3 and 3.5 equivalent Of K2S2O8 at 110 °C for 14 h (Figure 11.46).

Figure 11.46: Multicomponent reaction for the fabrication of β-quinoline allylic sulfones.

11.6.3 Synthesis of aminophosphonate derivatives A method was developed by Rostamnia et al. [274] to produce Fe3O4@β-CD nanoparticles with prominent catalytic properties for use as a catalyst in the Kabachnik–Fields MCR (Figure 11.47). Aldehyde 71 and amine 141 were added to the catalyst in water and agitated for two minutes. After that, dimethyl phosphite was introduced, and the reaction was allowed to continue for 1 h to produce the aminophosphonate derivatives 142.

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Figure 11.47: Synthesis of aminophosphonate derivatives catalyzed by Fe3O4@β-CD nanoparticles.

11.6.4 Preparation of 2-sulfonylquinoline derivatives 2-Sulfonylquinolines (145) were prepared using quinoline-1-oxide and sulfonyl chloride in water under ultrasound catalyzed by zinc dust [275] (Figure 11.48). In comparison to the conventional heating method, the ultrasound irradiation increases the efficiency and rate of the process, streamlines scale-up, and decreases other unwanted reactions or the generation of by-products. Using a green procedure and a one-pot synthesis, good product yields (61–91%), high energy efficiency, chemo- and regioselectivity, and an atom economy of 70.7% were achieved.

Figure 11.48: Preparation of 2-sulfonylquinoline moieties in aqueous medium.

11.7 Conclusions This chapter described several synthetic approaches toward biologically active heterocycles in water medium using different heterogeneous catalysts. Although there has been an increase in the number of journal articles in literature reporting catalytic, organic reactions in aqueous media however are far from being perfect. Drawbacks include high catalyst loading, high manufacturing cost of catalyst, long reaction time, requirement of high temperature, necessity of cosolvent, and use of phase transfer reagent. Hence, it necessitates further research in this area.

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[272] Ding D, Dwoskin LP, Crooks PA. Efficient synthesis of cis-2,6-di-(2-quinolylpiperidine). Tetrahedron Lett 2013, 54, 5211–5213. [273] Xiao F, Liu C, Yuan S, Huang H, Deng G,-J. A four-component reaction for the synthesis of βquinoline allylic sulfones under iron catalysis. J Org Chem 2018, 83, 10420–10429. [274] Rostamnia S, Doustkhah E. Synthesis of water-dispersed magnetic nanoparticles (H2O-DMNPs) of βcyclodextrin modified Fe3O4 and its catalytic application in Kabachnik–Fields multicomponent reaction. J Magn Mater 2015, 386, 111–116. [275] Xie L-Y, Li Y-J, Qu J, Duan Y, Hu J, Liu K-J, Cao Z, He W-M. A base-free, ultrasound accelerated one-pot synthesis of 2-sulfonylquinolines in water. Green Chem 2017, 19, 5642–5646.

Chebolu Naga Sesha Sai Pavan Kumar and Vaidya Jayathirtha Rao✶

Chapter 12 Microwave-assisted aqueous-mediated synthesis of bioactive heterocycles 12.1 Introduction Even though fire is no longer utilized in synthetic chemistry, it wasn’t until Robert Bunsen’s invention of the burner in 1855 that this heat source’s energy could be directed specifically at a reaction vessel [1]. Later, the iso-mantle, the oil bath, or the hot plate took the place of the Bunsen burner as a method of heating a chemical reaction. Interestingly, microwave (MW) energy has gained popularity among scientists in recent years as a means of heating and accelerating chemical reactions. Since the 1950s, various technological uses for MW energy have been discovered in the chemical and associated industries, particularly in the food processing, drying, and polymer industries [2]. Percy Spencer first used MW energy for cooking foodstuffs in the 1940s. Other uses include pathology (histo-processing, tissue fixation), biochemistry (protein hydrolysis, sterilization), analytical chemistry (MW digestion, ashing, and extraction), and medical therapies (diathermy). Surprisingly, the use of MW heating in organic synthesis dates only from the middle of the 1980s [3–5]. Richard Gedye et al. [6–8] published the first studies on the use of MW heating to expedite organic chemical reactions (MAOS, MW-assisted organic synthesis) (Figure 12.1). In recent years, the development of a new tool for organic synthesis has emerged as MAOS. The MAOS has aroused as a new “lead” in organic synthesis. The method makes the synthesis of several organic compounds quick, easy, clean, effective, and affordable. This technique has several key advantages, including a substantially accelerated rate of reaction leading to a decrease in reaction time and an improvement in product yield and purity. The MAOS is seen as a key step toward green chemistry because it seems warranted in the present scenario.

Acknowledgments: CHNSSPK thanks VFSTR and VDC, Guntur. VJR thanks AcSIR-Ghaziabad for Honorary Professorship and CSIR-New Delhi for Emeritus Scientist Honor. ✶ Corresponding author: Vaidya Jayathirtha Rao, IICT, AcSIR, Organic Synthesis and Process Chemistry Department and AcSIR-Ghaziabad, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India, email: [email protected] Chebolu Naga Sesha Sai Pavan Kumar, Department of Chemistry, School of Applied Sciences and Humanities, Vignan’s Foundation for Science, Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India; Department of Chemistry, Vignan Degree and P.G. College, Palakaluru Road, Guntur 520009, Andhra Pradesh, India

https://doi.org/10.1515/9783110985627-012

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Figure 12.1: Hydrolysis of benzamide: the first reported reaction of microwave ovens for organic synthesis.

The application of MW radiation to chemical reactions is known as MW chemistry. MW-enhanced chemistry, MW organic reactions enhancement, and other names for the approach gained prominence as these reactions have increased rates under MW radiation due to the heating impact.

Figure 12.2: Pictorial description of MAOS in water.

The domains of screening, combinatorial chemistry, medicinal chemistry, and drug discovery could all be significantly impacted by this technology, which is still under-used in the lab. Conventional methods of organic synthesis generally need extended heating times and laborious setup, which raises the expense of the procedure and causes environmental contamination due to the excessive use of solvents and reagents.

12.2 Thermal versus nonthermal effects Molecules that have been excited by MW radiation align their dipoles with the external field. An intense internal heating results the strong agitation that is produced by the reorientation of molecules in tandem with the electrical field stimulation [9]. By

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comparing the reaction rates in the cases when the reaction is carried out under irradiation versus under normal heating, it is possible to determine whether a nonthermal process is active. In reality, the majority of reactions have not been discovered to have any nonthermal effects, and the acceleration is solely ascribed to super-heating. However, it is evident that nonthermal factors do contribute to some reactions. Green chemistry is gaining popularity and has the ability to significantly reduce waste output, byproducts, and energy expenditures [10]. MW irradiation (MWI) has been utilized to enhance a wide range of organic processes because of its capacity to link directly with the reactants and circumvent thermal conductivity, causing a sharp increase in temperature.

12.3 Principles of microwave activation The interaction of the material with the electromagnetic field, which results in both thermal and nonthermal processes, causes the stimulation of reactions by MWI. Dipolar polarization and ionic conduction are the two basic ways by which the electric component of an electromagnetic field generates heat. The sample’s ions or dipoles align in the applied electric field when exposed to MW radiation [11]. As the applied field oscillates, the dipole or ion field strives to realign itself with the alternating electric field. During the process, energy is diminished as heat due to both molecular friction and dielectric loss. The capacity of the matrix to align with the frequency of the applied field directly correlates with the quantity of heat produced by this process. Such a feature induces rotation and friction of the molecules, which results in internal homogeneous heating. Adding ions to a solution causes a noticeable rise in the rate of dielectric heating due to the ionic conductance. The use of safer solvents or solventfree procedures, selective catalysis, and commonly achieving improved selectivity and yields have all been made possible by selective, volumetric dielectric heating.

12.4 Role of solvents in organic synthesis On both an industrial and laboratory scale, a wide variety of reactions are carried out in solutions in organic synthesis. Solvent use makes it possible for: – obtaining an effective molecular combination of reagents; – bringing the reagents into contact at the proper concentrations to attain the required rate; – controlling the reaction temperature;

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increasing the temperature in endothermic processes while staying within the solvent’s boiling point range; and absorbing excess heat and regulating the temperature through refluxing solvent or by directly chilling the solvent in exothermic processes.

However, using classical organic solvent does have a number of drawbacks and is not an eco-friendly process. The quantity of solvents utilized is 10–100 times greater than the amount of reagents, and the majority of them are volatile [hence are usually referred to as volatile organic components (VOCs)]. In order to achieve the final product, solvents are also utilized in the separation/purification viz., recrystallization, chromatography, and, perhaps, a final separation like decantation, evaporation, distillation, filtration, or centrifugation. Furthermore, due to their volatile character, solvents are the auxiliary products that are most likely the contaminants of the environment. Solvents may be environmentally harmful, hazardous, flammable, explosive, and have other downsides including causing pollution. Solvents may also intensify the greenhouse effect and contribute to the depletion of the ozone layer.

12.5 Water as solvent Water is a manifest replacement for popular organic solvents in green chemistry although it is rarely employed due to the limited solubility of organic compounds at ambient temperature. A new sustainable chemistry has emerged as a result of the discovery of neoteric solvents, supercritical fluids, ionic liquids, and fluorinated solvents. All of these systems have been effectively used in MW-radiated processes. A prime example of a green solvent is water [12–15]. Water is cheap, nontoxic, inflammable, and ubiquitous. The limited solubility of organic compounds has hindered the use of water in organic synthesis, but new methods have been developed to address this issue, such as the use of an organic cosolvent, taking advantage of hydrophobic properties (chemical “on-water”), and using water at high temperatures. MW radiation makes it simple to take advantage of the latter conditions. Water has distinct characteristics that are substantially different from those seen at room temperature when it is heated above the critical point. Typically, MW equipment is tuned at 2.45 GHz. It is well known that solvents’ dielectric constants drop as the temperature rises. For several MW-assisted organic processes, such as hydrolysis and aqueous hydrogen peroxide oxidation reactions, water is the natural, environmentally friendly solvent of choice. It is a universal, readily available, and nontoxic solvent currently being investigated for application in the synthesis of chemical reactions (Figure 12.2). The dielectric constant of water, which is 78 at 25 °C, descends to 20 at 300 °C, making it commensurate to acetone’s dielectric constant at room temperature. As a result, water at high temperatures can substitute for nonenvironmentally be-

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nign organic solvents, acting as a pseudo-organic solvent. Besides this, the product isolation from water is also easier due to the decrease of its solubility during postreaction cooling. Nowadays, water-based MW reactions are widely available in the literature [16– 18]. The additional advantage of the usage of water is, from room temperature to 250 °C, the ionic product of water raises by three orders of magnitude. As a result, water can be utilized as a strong acid/base at this temperature, avoiding the need for neutralization of mineral acids and bases after the reaction is complete.

12.6 Comparison of microwave and conventional heating Conventional heating

Microwave heating

Convection

Energetic coupling

Thermal reaction starts from the surface of material (superficial heating)

Thermal reaction begins uniformly from surface to bulk of the material (interaction at the molecular level)

Slow

Expeditious

Superficial

Volumetric

Independent of the properties of the material, that is, nonselective

Depends on the properties of the material, that is, selective

Necessitates physical contact between the surface of materials and vessel

Physical contact between surface of materials and vessel is not necessary

Heating takes place by electric or thermal source

Heating takes by microwave

More than 3,500 publications have been published in the field of MW-aided organic synthesis since the Gedye and Giguere group’s [6–8, 19] initial studies on the use of MW heating to speed up organic chemical transformations in 1986. It might be predicted that, in a few years, the preponderance of chemists will likely use MW energy to heat chemical reactions on a laboratory scale because of the popularity/advantage in MAOS-related research work published since the late 1990s. Controlled MW heating in sealed vessels has frequently been demonstrated to significantly speed up reaction times, high product yields, and improve product purity by minimizing other side reactions when compared to traditional synthetic processes. The various benefits of this enabling technology have been used in sectors like polymer chemistry, material engineering, nanotechnology, and biochemical processes [20–23] in addition to organic synthesis (MAOS). Furthermore, the utilization of MW radiations led to an increase in multistep synthesis.

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Figure 12.3: Conventional versus microwave heating.

Therefore, MWI offers an alternative to the traditional approach for heating or generating energy into the system in the context of green chemistry. It makes use of the capacity of conducting ions in solids or mobile electric charges present in liquids to convert electromagnetic energy into heat. Fast, efficient, economical, and environmentally benign, MW-assisted processes have been dubbed the “technology of the future. (Figure 12.3)” Green chemistry, also known as sustainable chemistry, is an approach to chemical engineering and research that promotes the development of new products and procedures/processes that reduce the use and production of dangerous compounds. The reactions investigated under MWI in water entail palladiumcatalyzed coupling reactions, synthesis of heterocyclics [24, 25], multicomponent reactions, nucleophilic substitutions, cycloadditions, decarboxylations, hydrolysis, assembly of nanomaterials, and radical reactions. Due to the significance of MAOS in various fields as shown in Figure 12.4, several papers and reviews published in the literature from the past to the present [26–29].

12.7 Microwave-assisted synthesis of bioactive heterocycles Heterocycles have been identified as a pivotal structural feature in medical chemistry [30–32]. They are also frequently present in biomolecules, including enzymes, vitamins, natural products, and biologically active substances, such as insecticidal, antiHIV, anticancer, antiviral, anti-inflammatory, antibacterial, antioxidant, anticonvulsant, and antiallergic agents. Due to the large number of heterocyclic compounds that are utilized in medicinal/pharmacological fields for the treatment of a wide range of diseases, they are gaining popularity tremendously in organic/medicinal chemistry.

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Figure 12.4: Various benefits and applications of microwave-assisted synthesis.

Herein, the summarized report depicts the MAOS for the preparation of some bioactive heterocyclic compounds in water as an environmentally benign solvent/medium.

12.7.1 Synthesis of biaryl derivatives by Suzuki coupling reaction Using MWI, Leadbeater and Marco [33] delineated a Suzuki coupling in water for the synthesis of biaryl compounds (3). Because it improves the solvation of the organic substrate aryl bromide (1) in water and speeds up the coupling reaction by forming a complex with the boronate, the inclusion of TBAB as a phase transfer agent aided the reaction (Figure 12.5). The reaction can be carried out, according to the authors, without the need of a palladium catalyst which may have the ability to use hetero aromatic units as coupling partners [33]. Chloro group attached to aryl part did not yield any phenyboronic acid coupling product. The chemistry indicates that MWs can substitute transition metals widely used as the catalyst.

Figure 12.5: Metal-free microwave-assisted Suzuki coupling reaction in water.

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12.7.2 Synthesis of triazones Synthesis of triazones (7) by the three-component condensation reaction of N,Ndimethylurea (4), formaldehyde (5), and primary amine (6) was reported by Balalaie and Shokrollahi [34] in aqueous medium under MWI at 850 W for 2–5 min (Figure 12.6). Products were easily extracted with CH2Cl2 and purified by distillation.

Figure 12.6: Synthesis of triazones under MW irradiation in aqueous medium.

12.7.3 Synthesis of triaza-benzo[b]fluoren-6-one derivatives Shao et al. [35] delineated the synthesis of triaza-benzo[b]fluoren-6-one derivatives (11) by the condensation of 2-aminobenzimidazole (8), aldehyde (9), and cyclohexane1,3-dione (10) in water using MWI (Figure 12.7). The reaction was completed in a very short reaction time (2–4 min) and the product was obtained after filtration. All the synthesized compounds were screened for biological activity like central nervous system affecting properties and showed very good activity.

Figure 12.7: MW-assisted synthesis of biologically active triaza-benzo[b]fluoren-6-one.

12.7.4 Synthesis of pyrazole and pyridazine derivatives Molteni et al. [36] have demonstrated a simple one-pot method for converting enaminoketones into various heterocycles like fused pyrazole (15) and pyridazine derivatives (16) employing a variety of bis nucleophiles, water as a benign solvent, and MWs as the

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heating source (Figure 12.8). The benefits of this strategy include a shorter reaction time and, in particular, very easy to isolate the product via filtration. 1,3-Dione (10) reacts with dimethylformamide dimethyl acetal (DMFDMA) (12) to generate the enaminoketone in situ that reacts with hydrazine (13) to provide the corresponding pyrazole (15) in good yields, with ease of isolation (Figure 12.8). Under the same reaction conditions, hydrazine was substituted with amidine (14) to afford pyridazines (16).

Figure 12.8: Aqueous-mediated one-pot MW synthesis of pyrazole/pyridazine derivatives.

12.7.5 Synthesis of pyranopyrazoles Under MWI, benzopyrano[4,3-c]pyrazoles (19) were produced by Kidwai et al. [37] via condensation between in situ produced 3-arylidene-2,4-chromanediones (18) with phenylhydrazine (Figure 12.9). This technique is useful for yielding pharmaceutically utile compounds carried out in the water as a solvent [30]. 4-Hydroxycoumarin (17) undergoes condensation with substituted benzaldehyde (9) to provide (18), which further reacts in situ with hydrazine to yield pyrazole compounds (19).

12.7.6 Synthesis of substituted acridine derivatives Hua and coworkers [38] reported a Hantzsch-type synthesis of N-substituted acridine derivatives (21) in a one-pot fashion that involved the condensation of an aldehyde (9), 1,3-cyclohexanedione (10) (2 equiv.), and methylamine (20) in a domestic MW oven (Figure 12.10). Water was used as a solvent when 1,3-cyclohexanedione was used as a dicarbonyl substrate. However, the dimedone reaction could only be carried out in high yields in glycol [31].

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Figure 12.9: Synthesis of benzopyrano[4,3-c]pyrazoles under microwave irradiation in water.

Figure 12.10: Bioactive acridone derivative synthesis using MW under aqueous medium.

12.7.7 Synthesis of diketopiperazines Under both thermal and MW-assisted heating conditions Luthman and his group [39] have described the synthesis of numerous structurally different 2,5-diketopiperazines (23) from dipeptide methyl esters (22) (Figure 12.11). The most effective method of cyclization with acceptable yields and results independent of the amino acid sequence was MWI in an aqueous medium. The crude product only needed to be isolated by filtration after precipitating on its own.

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Figure 12.11: MW-assisted synthesis of 2,5-diketopiperazines in aqueous medium.

12.7.8 Synthesis of 2-aminochromenes 2-Aminochromenes are mostly used in cosmetics and are potent biodegradable agrochemicals. Efficient synthesis of 2-aminochromenes (26)/(27) has been described by Kidwai et al. [40] by treating a mixture of aldehyde (9), malononitrile (20), and resorcinol (24) or β-naphthol (25) in a saturated aqueous solution under MWI for 2–4 min (Figure 12.12). A simple filtration procedure was used to separate the solid product after the reaction mixture had been cooled and triturated by ice water [40]. All these 2-aminochromenes were assayed for antibacterial activity.

Figure 12.12: Green synthesis of 2-aminochromenes by MW irradiation.

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12.7.9 Synthesis of dioxane-functionalized compounds One-pot synthesis of dioxane-functionalized molecules (30) has been accomplished by Polishettiwar and Varma [41] via MW-assisted tandem aldol reaction of ketones (28) with paraformaldehyde (29) (Figure 12.13). These compounds are well known for their therapeutic potential. This chemical process offers a simple and adaptable way to link dioxane arms to different ketones for further extension in drug development. The reaction was carried out in aqueous media and was catalyzed by polystyrene sulfonic acid. Interestingly, these reactions took place in an aqueous medium without the use of a phase-transfer catalyst. The authors used 14 different substrates to show the generality of the reaction [41].

Figure 12.13: Microwave-assisted tandem bis-aldol reaction in water.

12.7.10 Synthesis of benzoxazines Kaval and his group [42] synthesized benzoxazines (32) (Figure 12.14), an important class of bioactive heterocycles under MWIconditions from substituted aldehydes (31). The reaction was carried out in pure water with good yields [42].

Figure 12.14: Green synthesis of benzoxazines in MW under benign water solvent.

12.7.11 Synthesis of bis-coumarin derivatives Coumarin derivatives exhibit a wide range of biological activities and are an important class of heterocycles for the development of novel pharmaceuticals. Gong et al. [43]

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treated 4-hydroxycoumarin (17) with various aromatic aldehydes (9) in a pure water medium to achieve the catalyst-free green synthesis of aryl substituted bis-coumarin derivatives (33) under MWI (Figure 12.15). The reaction was completed in 8–10 min; after cooling the solid product was precipitated out and was isolated by filtration [43].

Figure 12.15: MAOS of bis-coumarin derivatives in aqueous medium.

12.7.12 Synthesis of rhodanine derivatives Rhodanine derivatives are known for their biological properties, which include protease inhibitors for the hepatitis C virus. By using MW-aided cross aldol condensation of aromatic aldehydes (9) with rhodamine (34), catalyzed by tetrabutylammonium bromide (TBAB) in water, a number of benzylidene rhodanine derivatives (36) (Figure 12.15) have been prepared by Zhou et al. [44]. The reactions were performed in less than 10 min, and appreciable yields were obtained upon isolation of the solid product by filtration. According to Lu et al. [38], aldehyde and thiobarbituric acid (35) undergo a similar coupling reaction to attain the benzylidene derivatives (37). Without requiring a catalyst, they carried out the reaction in water under MWI (Figure 12.16) [45].

12.7.13 Synthesis of terpyridines and fused pyridines Tu et al. [46] reported the Krohnke reaction (Figure 12.17) to synthesize 4ʹ-aryl-2,2ʹ:6ʹ,2ʹʹterpyridines (39) using a one-pot reaction of 2-acetylpyridine (38) with aromatic aldehyde 9 and ammonium acetate in water as benign solvent underexposure to MW radiation [39]. In a similar fashion aldehyde (9) was treated with indanone (40) and ammonium acetate in water under MW to synthesize fused pyridine compounds (41) (Figure 12.17).

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Figure 12.16: MW-assisted synthesis of rhodanine derivatives in water.

12.7.14 Synthesis of tricyclic β-lactam ring compounds Yadav et al. [47] reported an aqueous copper-catalyzed intramolecular N-aryl coupling involving β-lactam nitrogen and haloaryl moiety (42) to (43) (Figure 12.18). Under MW conditions, amides, imides, amines, and β-lactams reacted with aryl halides resulted various compounds with N–C coupling [40]. These reactions were conducted in both aqueous media and without the use of any solvent at 85–90 °C. Compared to the solvent-free conditions, reactions in water as solvent afforded better results with respect to yields and reaction time. This methodology was also effectively used for intramolecular N–C coupling leading to fused tricyclic β-lactam ring compounds (43) to (50) (Figure 12.18) in water under MWI conditions [47].

12.7.15 Synthesis of disubstituted 1,2,3-triazoles The independently discovered Cu(I)-catalyzed click-type process in 2002 by Fokin, Sharpless, and Medal groups demonstrates a reliable reaction with an exceptional degree of regioselectivity. In this course, the copper-catalyzed Huisgen reaction was the first to be studied using MWI by Fokin and other coworkers. They depicted that the reaction of an alkyl halide (51) with sodium azide in water, which produces the neces-

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Figure 12.17: Synthesis of terpyridines and fused pyridines under microwave radiation.

sary organic azide in situ, in the presence of various alkynes (52), results in a series of 1,4-disubstituted-1,2,3-triazoles (53–65) in good to excellent yields with exclusive regioselectivity (Figure 12.19). By com-proportioning Cu(0) and Cu(II), the requisite Cu(I) catalyst is produced in situ for these reactions [48]. The advantages claimed include in situ generation of the azide to avoid its isolation and to take care of the stability issue, significant decrease in the reaction time, and formation of easily isolable triazoles (53)–(65) (Figure 12.19) by varying the structure of the acetylene and halide substrates.

12.7.16 Synthesis of 1,4-dihydropyridines 1,4-Dihydropyridines, that contain important pharmacophoric features in the development of new drugs, are synthesized by adopting Hantzsch reaction strategy. The synthesis of substituted 1,4-dihydropyridine-3,5-dicarboxylates (67) utilizing MWI from aldehydes (9) and ketoesters (66) in aqueous ammonium hydroxide has been delineated (Figure 12.20) by Ohberg and Westman [49]. The reaction observed has enhanced reaction rate, considerable product yield, and purity.

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Figure 12.18: Intramolecular N–C coupling leading to fused tricyclic β-lactam ring compound under water and MW irradiation conditions.

12.7.17 Synthesis of aryl-4(3H)-quinazolinone derivatives by deamination protocol Aryl-4(3H)-quinazolinone derivatives (69) were synthesized by deamination protocol using oxidant like KMnO4 in water medium under MW conditions (Figure 12.21), which produced remarkably high yields of the products, than attained in conventional oil bath heating [50]. Another excellent method to convert amines into amides is amino-carbonylation reported by Wu and Larhed [51], who converted a series of amines (71) into the corresponding benzamides (72) in water medium, using Mo(CO)6 under MW heating (Figure 12.22).

12.7.18 Synthesis of benzimidazole derivatives Ferro et al. [52] treated α-hydroxycinnamic acids (73) with 1,2-phenylenediamine (74) in water to produce benzimidazoles (75), which have the ability to block HIV-1 integrase. The best approach for producing the necessary heterocyclic compounds in modest yields was two cycles of irradiation lasting 5 and 3 min at 110 °C (Figure 12.23). Under MW, the reaction time was expectedly shortened compared to normal heating

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Figure 12.19: Synthesis of Cu-catalyzed MW-assisted 1,2,3-triazoles in aqueous medium.

at 120 °C (2 h vs 8 min). With an EC50 of 27 µM, benzimidazole was shown to block HIV-1 IIIB’s cytopathic effect.

12.7.19 Synthesis of pyranopyrazoles Peng et al. [53] presented their research on the 4H-pyrano-[2,3-c]pyrazoles (77) synthesis (Figure 12.24) using combined MW and ultrasonic irradiation (CMUI), as a “proof of concept” of reaction in aqueous environments. In a model reaction of pyran (76) with

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Figure 12.20: Hantzsch synthesis of substituted 1,4-dihydropyridines in water under MW irradiation.

Figure 12.21: Deamination protocol under MW irradiation in water.

Figure 12.22: Conversion of amines to amides under MW radiation.

Figure 12.23: Synthesis of benzimidazoles under MW conditions.

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hydrazine monohydrate and piperazine as catalyst, it was found that the CMUI approach (100%, 1 min) could achieve the extortionate conversion in the very short reaction time, as opposed to MWI alone or the combination of oil bath heating and ultrasound irradiation. This technique is exemplary for the preparation of substituted pyranopyrazoles with respect to time (40–60 s) and yields (89–93%) [53].

Figure 12.24: Synthesis of 4H-pyrano-[2,3-c]pyrazoles under MW-US irradiation.

12.7.20 Synthesis of indenoquinoline derivatives Tu et al. [54] described a method for synthesizing polysubstituted indeno[1,2-b]quinolines (80) as shown in Figure 12.25, using a three-component reaction involving 1,3indanedione (78), (het)-aryl or alkyl aldehydes (9), and substituted enaminones (79), with p-toluenesulfonic acid in water under MW conditions (2–7 min). In addition, some reactions were also carried out at the same temperature using conventional heating, resulting in fairly lower yields and requiring a prolonged reaction time to form the products (2 h) [54].

Figure 12.25: Synthesis of indenoquinolines under MW radiation.

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12.7.21 Synthesis of 10H-phenothiazines Mayer et al. [55] reported a library of 10H-phenothiazines (82). The reaction of sulfur and diarylamines (81) in distilled water at 190 °C took place within 20 min with considerable yields (Figure 12.26). The 10H-phenothiazine compounds instantly precipitated upon cooling and could be separated by filtration due to their hydrophobicity [55]. The cyclized products were alkylated to make target compounds (Figure 12.26).

Figure 12.26: MW-assisted library synthesis of 10H-phenothiazines.

12.7.22 Fischer indole synthesis from phenylhydrazine Complete conversion of phenylhydrazine (93) was achieved by using the conditions for the Fischer indole synthesis delineated by Strauss et al. [56] (Figure 12.27). Requisite 2,3-dimethylindole (95) was obtained in 64% yield after the reaction was carried

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Figure 12.27: Fischer indole synthesis under MW radiation.

out at 270 °C for 30 min; however, about 28% HPLC yield of an unknown by-product was also found.

12.7.23 Synthesis of podophyllotoxin derivatives Derivatives of podophyllotoxin serve as antitumor lignans that prevent microtubule assembly. This skeleton has undergone various structural alterations in order to produce more effective and possible anticancer agents. In this regard, a three-component synthesis involving an aldehyde (9), an aromatic amine (6), and either tetronic acid (96) or 1,3-indanedione (78) was devised by Tu and coworkers [57] to produce 4-azapodophyllotoxin (97) or fused heterocycles (98) in water (Figure 12.28). Higher yields in shorter reaction times were obtained from reactions carried out in water as op-

Figure 12.28: Bioactive podophyllotoxin derivatives by MW irradiation.

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posed to other organic solvents. Cooling the reaction mixture caused the product to precipitate out and was subjected to recrystallization for isolation [57].

12.7.24 Synthesis of benzo[f]azulenones The regioselective synthesis of benzo[f]azulen-1-ones (100) has been developed via a MW-assisted three-component strategy from 1,2-diamines (99), aldehydes (9), and tetronic acid (96). Utilizing easily available and inexpensive substrates, the reaction was carried out in aqueous medium while being MW irradiated (Figure 12.29). Wang et al. [58] demonstrated a wide substrate scope and good overall yields (70–89%). The innovative synthesis demonstrates appealing green chemistry traits such the use of water as the reaction medium, clear one-pot conditions, less reaction times (7–24 min), simple work-up/purification, and minimized waste creation without the use of any acid or metal promoters [58].

Figure 12.29: MW assisted synthesis of benzo[f]azulen-1-ones in water.

12.7.25 Synthesis of azaspiro cyclic compounds In order to produce azaspiro tri- and tetracyclic compounds (104) in aqueous environments at ambient temperature, Santra and Andreana [59] developed a Ugi/Michael/ aza-Michael cascade reaction (Figure 12.30). Good to excellent yields, in terms of stereochemical aspects and regioselectivities with noticeable diastereoselectivity, are the significant features of the method [59]. Benzylamine (101), 4-hydroxybenzaldehyde (9), t-butylisocyanide (102), and half ethylester of fumaric acid (103) in water were irradiated with MW to generate complex structure (104) (Figure 12.30) having three fused rings with spiro bond. Structural variations introduced in the starting compounds generated over 12 new compounds (105)–(116) with the scope to control diastereoselectivity and yields.

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Figure 12.30: Cascade reaction for synthesis of azaspiro compounds in MW radiation.

12.7.26 Synthesis of azacyclic and isoindole derivatives Several biologically active N-substituted 4,5-dihydro-pyrazole (119), 2,3-dihydro-1Hisoindoles 120, pyrazolidine, and 1,2-dihydro-phthalazine derivatives were directly synthesized by Ju and Varma [60, 61] in aqueous medium under MWI by doublealkylation of hydrazines (117) by alkyl dihalides (118) or ditosylates (119) (Figure 12.31); the environmentally friendly chemical transformation took place in a single step and

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did not require the use of expensive metal catalysts to create two C–N bonds [53, 54]. Reactions between hydrazine (117), (118), and (119) lead to the formation of cyclic pyrazoles and diazoles (Figure 12.31) [60, 61]. Isoindoles (137) [54] were synthesized involving amines 6 and dihalides or ditosylates (136) in the presence of potassium carbonate and water as medium (Figure 12.32). Azacycloalkanes (139) were synthesized [54] using amines (138) and dihalides or di-tosylates (118) and (119) in the presence of potassium carbonate in water under MWI (Figure 12.32).

Figure 12.31: MAOS of various heterocycles like 1,2-diazacyclic derivatives in water.

12.7.27 Synthesis of thiazolopyrimidine derivatives Yildirim et al. [62] reported a green method for producing a series of nitrothiazolo[3,2-c] pyrimidines (141) by Mannich reactions under MWI. This process comprised the multicomponent cyclization of formaldehyde (5), different aliphatic or aromatic amines (6), and 2-(nitromethylene)thiazolidine (140) in water (Figure 12.33). With MW activation, product yields were increased and the reaction times on comparison with conventional heating were greatly reduced [62].

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Figure 12.32: MAOS of various heterocycles like iso-indoles and azacyclic derivatives in water.

Figure 12.33: Microwave-mediated Mannich cyclization for synthesis of nitrothiazolo[3,2-c]pyrimidines.

12.7.28 Synthesis of quinazolinone derivatives The first instance of iron-catalyzed C–N coupling reactions in aqueous conditions to produce N-heterocycles has been documented by Zhang et al. [63]. Through MW activation, this method has been used to produce quinazolinone derivatives (144) from 2halobenzoic acids (142) and amidines (143). Iron chloride catalyzes the cyclization reaction in the presence of a ligand in water. Even with inert substrates like guanidines, the desired products were produced with moderate to high yields (Figure 12.34). Several experiments were conducted to define and fine-tune the reactions conditions to achieve best results.

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Figure 12.34: MAOS of quinazolinone derivatives in water.

12.7.29 Synthesis of indole derivatives Through the use of water as a benign solvent and acidic or basic salt as a catalyst, Carpita et al. [64] produced a series of substituted indoles (146) and three azaindole derivatives by MW-aided cycloisomerization of 2-alkynylanilines (145) with both electron-rich as well as electron-poor substrates and a variety of aromatic substituents (Figure 12.35). Three experimental procedures were developed based on the variables selected, and each one is effective in its own way [64].

12.7.30 Synthesis of N-aryl pyrrolidines By reacting aryl amines (6) with 1,4-dimesyloxybutane (166) in the presence of an aqueous potassium carbonate (alkaline medium), Li et al. [65] reported a more environmentally friendly method of producing N-aryl pyrrolidines (167) in a cyclocondensation pathway (Figure 12.36).

12.7.31 Synthesis of sugar-based pyrazole derivatives Du et al. [66] used the aforementioned approach to develop novel sugar-based pyrazole compounds (170) by MW-assisted cyclization of phenyl hydrazide (168) with the diketones (169) in water (Figure 12.37). They screened the synthesized compounds for possible activities and some of the compounds showed very good antitumor activity.

12.8 Limitation One of the limitations of usage of MAOS is the issue of scale-up which is crucial [67]. New advancement in MW scale-up technologies must be warranted in order for MW chemistry to be a useful tool for process chemists and to be both economically and

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Figure 12.35: MW-assisted synthesis of indole and azaindole derivatives.

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Figure 12.36: MW-assisted synthesis of N-arylpyrrolidines in water.

Figure 12.37: Expeditious synthesis of sugar-based pyrazole derivatives under microwave irradiation.

environmentally sustainable when the energy balance is taken into account. Sometimes, usage of closed reaction vessel is dangerous which may explode.

12.9 Conclusions MW synthesis is a practical means of achieving green/sustainable chemistry, and its application in organic synthesis is highly recommended. Some of the aforementioned examples are interesting and practically useful for the synthesis of many heterocycles, small molecules, nanomaterials, and so on. Nowadays, MAOS is becoming more popular throughout the world due to its advantages. An account of the combination between heterocyclic chemistry and MWI has demonstrated the need for special consideration when carrying out MW-assisted reactions. This chapter discussed the synthesis of various biologically active heterocycles using MW conditions in water as solvent medium. We believe the chapter will be beneficial for both academicians and industrial researchers.

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[61] Ju Y, Varma RS. Aqueous N-heterocyclization of primary amines and hydrazines with dihalides: Microwave-assisted syntheses of N-azacycloalkanes, isoindole, pyrazole, pyrazolidine, and phthalazine derivatives. J Org Chem 2006, 71, 135–141. doi:10.1021/jo051878h. [62] Yildirim M, Celikel D, Durust Y, Knight DW, Kariuki BM. A rapid and efficient protocol for the synthesis of novel nitrothiazolo [3,2-c]pyrimidines via microwave-mediated Mannich cyclisation. Tetrahedron 2014, 70, 2122–2128. doi:10.1016/j.tet.2014.02.003. [63] Zhang X, Ye D, Sun H, Guo D, Wang J, Huang H, Zhang X, Jiang H, Liu H. Microwave-assisted synthesis of quinazolinone derivatives by efficient and rapid iron-catalyzed cyclization in water. Green Chem 2009, 11, 1881–1888. doi:10.1039/b916124b. [64] Carpita A, Ribecai A, Stabile P. Microwave-assisted synthesis of indole- and azaindole-derivatives in water via cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by amines or catalytic amounts of neutral or basic salts. Tetrahedron 2010, 66, 7169–7178. doi:10.1016/j. tet.2010.06.083. [65] Li HB, Liang W, Liu L, Chen K, Wu Y. Microwave-assisted convenient synthesis of N-arylpyrrolidines in water. Chin Chem Lett 2011, 22, 276–279. doi:10.1016/j.cclet.2010.09.034. [66] Du K, Xia C, Wei M, Chen X, Zhang P. Microwave-assisted rapid synthesis of sugar-based pyrazole derivatives with anticancer activity in water. RSC Adv 2016, 6, 66803–66806. https://doi.org/10.1039/ C6RA05284C. [67] PriecelP, Lopez-SanchezJA. Advantages and limitations of microwave reactors, from chemical synthesis to the catalytic valorisation of bio-based chemicals. ACS Sustainable Chem Eng2019, 7, 3–21. https://doi.org/10.1021/acssuschemeng.8b03286.

Seema Kothari, Khushbu Sharma, Rakshit Ameta, and Suresh C. Ameta✶

Chapter 13 Ultrasound-assisted aqueous-mediated synthesis of bioactive heterocycles 13.1 Introduction The importance of heterocycles is well established in varied fields of chemical sciences such as organic, inorganic, agricultural, pharmaceutical, bioorganic, and material science. Presently, a majority of reactions for the synthesis of heterocycles are carried out using traditional methods that are not energy-efficient apart from leading to pollution. This can be avoided by using ultrasound as a source of energy, which can produce high temperature and pressure during the collapse of bubbles. Use of ultrasound in organic reactions is due to cavitation, which is a physical process of creating, enlarging, and implosion of cavities (gaseous and vaporous). Organic synthesis under ultrasounds has the potential to offer certain advantages such as: – High yields – High purity of the products – Increased selectively – Reduced energy consumption – Minimum quantity of hazardous solvents – Mild conditions – Green solvents – Higher atom economy and low E-factor – Short reaction time – Reusability of solvents – No column chromatography – High turnover number – Metal-free synthesis – Easy workup procedure ✶ Corresponding author: Suresh C. Ameta, Department of Chemistry, Paher University, Udaipur 313003, Rajasthan, India, email: [email protected] Seema Kothari, Department of Chemistry, Paher University, Udaipur 313003, Rajasthan, India Khushbu Sharma, Department of Chemistry, Bhupal Nobles’ University, Udaipur 313001, Rajasthan, India Rakshit Ameta, Department of Chemistry, J.R.N. Rajasthan Vidhyapeeth (Deemed to be University), Udaipur 313001, Rajasthan, India

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13.2 Five-membered heterocyclic compounds 13.2.1 Furan Hooshmand et al. [1] reported the use of combinatorial construction of some rhodanine-furan bis-heterocyclic scaffolds (7) (yield up to 70%) via one-pot sequential sixcomponent reaction in aqueous medium with 100% atom economy under ultrasound irradiation (Figure 13.1). It is a tandem Michael reaction, followed by domino cycloaddition/zwitterionic adduct formation/Mumm rearrangement/[1 + 4] cycloaddition processes. This reaction involved maleic anhydride (1), dialkylacetylene dicarboxylates (2), carbon disulfide (3), diverse primary amines (4), and different isocyanides (5 and 6). It was revealed that in this process no catalyst is required, but the use of aqueous two-phase (on water) conditions was critical. It was suggested that the as-prepared bis-heterocyclic frameworks formed is useful inhibitors of an enzyme, human aldose reductase.

Figure 13.1: Ultrasound-assisted synthesis of rhodanine-furan bis-heterocyclic scaffolds.

Dige et al. [2] synthesized some 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamide derivatives (11) at room temperature. They used para-toluenesulfonic acid (p-TSA) as the catalyst under ultrasound irradiation (Figure 13.2). The reactants were isatoic anhydride (8), 2-furoic hydrazide (9), and different substituted salicylaldehydes (10) in ethanol:water (5:5 v/v) (solvent). It was observed that oxoquinazolin-3(4H)-yl)furan-2-carboxamides could be obtained with high yields (58–78%) and in short reaction time. As-synthesized compounds were found to be potent inhibitors against tyrosinase enzyme with relatively much lower IC50 value (0.028 ± 0.016 to 1.775 ± 0.947 µM) than that of kojic acid (16.832 ± 1.162 µM) used as the standard. Sadjadi et al. [3] synthesized magnetic hybrid system, which contains Fe2O3 hollow spheres (nanomagnetic), silver nanoparticles, silica shell, and the ionic liquid [pmim]Cl. They prepared silver nanoparticles via biosynthesis using flowers of Achillea millefolium as reducing as well as stabilizing agent. They used this hybrid system as an effec-

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Figure 13.2: Ultrasound-assisted synthesis of 4-oxoquinazolin-3 (4H)-yl) furan-2-carboxamides.

tive and reusable catalyst not only for the synthesis of benzo[b]furan (12) (Figure 13.3) (82–95%) but also for promoting of green ultrasonic-assisted A3 and KA2 coupling reactions. It was found that decoration of the Fe2O3 magnetic core with nonmagnetic moieties reduced maximum saturation magnetization. Even then, catalyst was still superparamagnetic in nature and it could be easily separated from the reaction mixture with the help of an external magnet. The heterogeneous nature of this hybrid system catalyst was also ascertained on the basis of its stability, reusability, and leaching of silver.

Figure 13.3: Ultrasound-assisted synthesis of benzo[b]furans.

13.2.2 Thiophene A series of 5-bromo-thiophenes containing chalcone derivatives (13) (90–95% yields) were synthesized (Figure 13.4) by Panigrahi et al. [4] under ultrasonic irradiation in the presence of lithium hydroxide monohydrate (LiOH·H2O) (catalyst).

Figure 13.4: Ultrasound-assisted synthesis of thiophene chalcone.

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13.2.3 Isoxazole Safari et al. [5] synthesized 3-methyl-4-arylmethylene isoxazole-5(4H)-one derivatives (17) (yield: 95% in aqueous media; 70% in 1:1 ethanol:water) by the reaction of hydroxylamine hydrochloride (15), ethyl acetoacetate (14), and benzaldehyde derivatives (16) through sonication in the presence of imidazole (used as catalyst) in aqueous media (Figure 13.5).

Figure 13.5: Ultrasound (US)-assisted synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-one.

Alaoui et al. [6] synthesized a series of 3,5-disubstituted isoxazoles (18) (yield: 62–95%) via a green “one-pot three-step” methodology. It involves an oxidative 1,3-dipolar cycloaddition in aqueous media under ultrasonic irradiation in the presence of cerium (IV) ammonium nitrate (Figure 13.6).

Figure 13.6: Ultrasound-assisted synthesis of sulfonamide-isoxazoles.

Some sulfonamide–isoxazoline hybrids (yield: 66–86%) were synthesized by Talha et al. [7] via regioselective 1,3-dipolar cycloaddition (Figure 13.7). They used trichloroisocyanuric acid as a green oxidant and chlorinating agent for in situ conversion of aldehydes (16) to nitrile oxides (19) in the presence of hydroxylamine hydrochloride (15) under ultrasound. As-obtained nitrile oxides undergo 1,3-dipolar cycloaddition reactions with various alkenes (20), and as a result, sulfonamides-isoxazolines hybrids

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Figure 13.7: Ultrasound-assisted synthesis of sulfonamides-isoxazolines hybrids.

(21) could be obtained. These were evaluated for their antineoplastic activity against some model leukemia cell lines.

13.2.4 Pyrazole Khare et al. [8] synthesized a series of 1,2,3-triazolyl pyrano[2,3-c]pyrazoles (22) (yield: 92–98%) using sodium bicarbonate under ultrasonic irradiation (Figure 13.8). It was revealed that some of these compounds exhibited excellent antifungal activity and most of compounds displayed potent antioxidant activity too.

Figure 13.8: Ultrasound-assisted synthesis of 1,2,3-triazolyl pyrano[2,3-c]pyrazoles.

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13.2.5 Thiadiazole Chauhan et al. [9] developed a simple, environmentally benign, catalyst-, and metal -free procedure for the synthesis of 1,2,4-thiadiazole derivatives (25) using thioamides (23) and chloranil (24) in water at room temperature under ultrasound irradiation (Figure 13.9). This proposed protocol provided 1,2,4-thiadiazoles in excellent yields (87–95%) in short reaction time via sonochemical approach.

Figure 13.9: Ultrasound-assisted synthesis of 1,2,4-thiadiazole derivatives.

Feng et al. [10] developed an eco-friendly and efficient synthesis of substituted 1,3,4thiadiazole derivatives (26) (yield: 73–90%). It was reported that this aqueous heterogeneous route is smooth and proceeds quickly under both microwave and ultrasound irradiations in the presence of FeCl3 (Figure 13.10).

Figure 13.10: Synthesis of 1,3,4-thiadiazole derivatives under microwave and ultrasound irradiation.

13.2.6 Tetrazoles Atarod et al. [11] reported preparation of 1-aryl-5-amino-1H-tetrazoles (29) (yield: 12–95%) using different N-arylcyanamides (27) and sodium azide (28) in the presence of sono/ nanocatalytic system (Figure 13.11). They used mixed metal oxide nanoparticles (CuO– NiO–ZnO). The effect of the reaction conditions was also evaluated for catalytic activity and on selectivity of mixed metal oxide NPs for the synthesis of aminotetrazole derivatives. It was revealed that regioselective synthesis of 1-aryl-5-amino-1H-tetrazoles could be achieved with high yields, which was attributed to synergistic effect between ultrasound irradiation and the nanocatalyst. The nanocatalyst could be recovered and reused for several times without any significant loss in its selectivity and catalytic activity.

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Figure 13.11: Ultrasound-assisted synthesis of 1-aryl-5-amino-1H-tetrazoles.

Some tetrazole-based pyrimidine (31) and pyrazole derivatives (30) (yield: 73–80%) were synthesized by Dofe et al. [12] using ultrasound irradiation (Figure 13.12). It was reported that five compounds exhibited good activity against the tested strains (Aspergillus niger, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli, Staphylococcus aureus, and Candida albicans) as compared to the standard drugs chloramphenicol and clotrimazole. Reagents and conditions: (i) Acetic anhydride, pyridine, 100 °C, 3–4 h (ii) AlCl3, 150 °C, 3–4 h (iii) 4-Fluorobenzaldehyde, KOH, EtOH, RT, 2–3 h (iv) H2O2, NaOH, 0 °C to RT, 2–3 h

Figure 13.12: Ultrasound-assisted synthesis of tetrazole-based pyrazole and pyrimidine derivatives.

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(v) 2-Chloroacetonitrile, K2CO3, DMF, RT, 3–4 h (vi) Sodium azide, ZnBr2, H2O, reflux, 100 °C, 4–5 h (vii) Hydrazine hydrate, ethanol, ultrasound irradiation, 65 °C, 45–55 min (viii) Thiourea, KOH, ethanol ultrasound irradiation, 65 °C, 15–25 min

13.3 Six-membered heterocyclic compounds 13.3.1 Pyran Naeimi and Lahouti [13] developed one-pot protocol for the preparation of spiro-4Hpyrans (32 and 33) (yield 73%) in aqueous media using sulfonated chitosan-coated Fe3O4 nanoparticles (Fe3O4@CS-SO3H NPs) under ultrasonic irradiation (Figure 13.13). First of all, they prepared Fe3O4@CS NPs from the reaction between chitosan with Fe3O4 NPs. Then, as-prepared Fe3O4@CS NPs were treated with chlorosulfonic acid leading to Fe3O4@CS-SO3H NPs (efficient catalyst).

Figure 13.13: Ultrasound-assisted synthesis of spiro-4H-pyrans.

Auria-Luna et al. [14] synthesized highly substituted 4H-pyran derivatives (34) (yield: 34–92%) using Et3N as catalyst (20 mol%) in water (Figure 13.14). It was revealed that 4H-pyran derivatives behaved preferentially as minor groove binders over major groove or intercalators based on DNA interaction analysis. It was also revealed that pyrans are interesting DNA binders with high binding constants (Kb ranges from 1.53 × 104 to 2.05 × 106 M−1). A novel series of substituted 2-amino-3-cyano-4H-pyran derivatives (38) (yield: 85–97%) was synthesized by Tabassum et al. [15] via one-pot three-component cyclocondensation reaction (Figure 13.15). They used malononitrile (36), heteroaryl aldehydes (35), and active methylene compounds (37) as reactants and iodine as catalyst in aqueous medium under ultrasound irradiation in comparison with conventional methods.

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Figure 13.14: Ultrasound-assisted multicomponent synthesis of 4H-pyrans.

Figure 13.15: Ultrasound-assisted synthesis of 2-amino-3-cyano-4H-pyran derivatives.

The proposed protocol has following advantages: convenient, mild conditions, short reaction time, higher yields, and environmental friendliness. The synergistic effect of sonication and multicomponent reaction provides a simple route for preparing these derivatives. Banitaba et al. [16] reported a green approach for the synthesis of 2-amino-4,8dihydropyrano[3,2-b]pyran-3-carbonitrile scaffolds (40) via three-component reaction (Figure 13.16). Kojic acid (39), malononitrile (36), and aromatic aldehydes (16) were used as components and water (green solvent) under ultrasound irradiation. The advantages of this protocol are good functional group tolerance, short reaction time, simplicity, and selectivity with excellent yields (85 to 98%), but without using any transition metal or base catalyst.

Figure 13.16: Ultrasound-assisted synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile.

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The magnetic nanoparticles were coated with copper (I) iodide (Fe3O4@CQD@CuI) and carbon quantum dot by Najafi et al. [17] and used as heterogeneous Lewis/ Brønsted acid and Cu(I) as eco-friendly nanocatalyst. These nanoparticles were used for the synthesis of kojic acid-based dihydropyrano[3,2-b]pyran derivatives (41) via three-component reaction, which was followed by the synthesis of kojic acid-1,2,3triazole-based dihydropyrano[3,2-b]pyran derivatives (42) (yield: 88–95%) in the presence of this recyclable catalyst in the CuI-catalyzed azide/alkyne cycloaddition reaction (Figure 13.17).

Figure 13.17: Ultrasound-assisted synthesis of kojic acid-based dihydropyrano[3,2-b]pyran derivatives and kojic acid-1,2,3-triazole-based dihydropyrano[3,2-b]pyran derivatives.

Shabalala et al. [18] developed a highly efficient and catalyst-free green procedure for the synthesis of two series of polyfunctionalized pyran derivatives (45 and 46). They used malononitrile (36), aromatic aldehydes (16), and either dimedone (43) or 1,3dimethyl barbituric acid(44) in one-pot reaction using EtOH:H2O (1:1 v/v) as solvent under ultrasound irradiation (Figure 13.18). It was reported that an excellent yield (90–99%) of these pyran derivatives could be obtained in 5 min. Other advantages of such reactions were 95% atom economy and 100% carbon efficiency. One-pot synthesis of imidazopyridine having pyran bis-heterocycles (47) was reported by Thakur et al. [19]. These compounds were synthesized in an aqueous solution of gluconic acid under ultrasound irradiation as well as conventional heating (Figure 13.19). It was found that desired compounds were obtained in good to moderate yields (65–88%) in 20–60 min under ultrasonic irradiation.

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Figure 13.18: Ultrasound-assisted synthesis of poly-functionalized pyran derivatives.

Figure 13.19: Ultrasound-assisted synthesis of imidazopyridine bearing pyran.

Khare et al. [20] developed an efficient ultrasound-assisted one-pot three-component synthesis of a series of new 1,2,3-triazole-linked tetrahydrobenzo[b]pyran derivatives (48) (76–99% yields) using sodium bicarbonate (Figure 13.20).

Figure 13.20: Ultrasound-assisted synthesis of 1,2,3-triazole-linked tetrahydrobenzo[b]pyran derivatives.

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13.3.2 Pyrimidine Abdolmohammadi and Afsharpour [21] reported the synthesis of [1]benzopyranopyrido[d]pyrimidines (49) (yield: 55–91%) over porous graphene/MoO3 under ultrasound radiation (Figure 13.21). The effect of different operational parameters on reaction efficiency was also evaluated such as sonication power, sonication time, and different solvents.

Figure 13.21: Ultrasound-assisted synthesis of [1]benzopyranopyrido[d]pyrimidines.

One-pot multicomponent reaction of barbituric acid (44), ethyl acetoacetate (14), aromatic aldehydes (16), and hydrazine hydrate (50) has been developed by Akolkar et al. [22] for the construction of bioactive heterocyclic moieties under ultrasound irradiation (Figure 13.22). This synthesis of tri-heterocyclic fused pyrazolopyranopyrimidines was found to be promoted by β-cyclodextrin (biomimetic catalyst) using water as a green solvent. It was revealed that this protocol afforded selective synthesis of pyrazolopyranopyrimidine derivatives (51) without any side products with excellent yield (32–91%) in short reaction time. They also confirmed reusability and recyclability of the catalyst. This protocol offers cost-effective catalyst, metal-free synthesis, and easy isolation of products on a gram-scale basis.

Figure 13.22: Ultrasound-assisted synthesis of pyrazolopyranopyrimidines.

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Verma et al. [23] developed an efficient and green one-pot multicomponent synthesis of imidazopyrimidine derivatives (54) (yield: 98%) using aromatic aldehydes (16), 2aminobenzimidazole (52), and active methylene compounds (53 and 43) under ultrasonic irradiation (Figure 13.23). This reaction was catalyzed by starch functionalized magnetite nanoparticles (s-Fe3O4). The reusability of the catalyst was also established.

Figure 13.23: Ultrasound-assisted synthesis of 2-aminobenzimidazole.

An efficient procedure has been reported by Patil et al. [24] for the synthesis of pyrano[2,3-d] pyrimidine diones (56) and 5-benzylidene-1,3-dimethylpyrimidine-2,4,6 (1H,3H,5H)-trione (55) (yield: 80–93%) at room temperature (Figure 13.24). They used L-proline nitrate (ionic liquid) under ultrasonic irradiation for this purpose. The L-proline nitrate can be easily prepared by mixing L-proline and nitric acid and it is a homogeneous and green catalyst possessing excellent catalytic activity under ultrasonic irradiation at room temperature. It was also indicated that this catalyst can be reused for five times without any significant loss in its activity.

Figure 13.24: Ultrasound-assisted synthesis of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)trione and pyrano[2,3-d] pyrimidine diones.

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Brahmachari et al. [25] reported ultrasound-promoted green procedure for the preparation of 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(aryl)methyl)pyrimidine-2,4 (1H,3H)-diones (60 and 61) (Figure 13.25). A three-component tandem reaction was carried out with 4-hydroxycoumarin, substituted aromatic aldehydes (16), and 6aminouracils (58)/6-amino-2-thiouracil (59) as reactants in aqueous ethanol using a sulfamic acid as catalyst (yield: 80–90%).

Figure 13.25: Ultrasound-assisted synthesis of 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(aryl)methyl) pyrimidine-2,4(1H,3H)-diones.

The green chemical synthesis of pyrazolo[1,5-a]pyrimidine derivatives (63 to 66) has been reported by Kaping et al. [26] under ultrasound irradiation in the presence of KHSO4 in aqueous medium (Figure 13.26). First, 3-(4-methoxyphenyl)-3-oxopropanenitrile was treated with hydrazine hydrate in refluxing ethanol to afford 5-(4-methoxyphenyl) -1H-pyrazol-3-amine (62). Then condensation of 3-aminopyrazoles with formylated active proton compounds gave pyrazolopyrimidines with high to excellent yields (96–97%). The protocol avoids use of any harsh reaction conditions. Dharmendra et al. [27] reported an efficient and eco-friendly route for one-pot multicomponent construction of pyrazolopyranopyramidine derivatives (67) (Figure 13.27). They used barbituric acid (44), aromatic aldehydes (16), ethyl acetoacetate (14), and hydrazine hydrate (50) as reactants under ultrasound irradiation using water as a solvent. This reaction was found to be promoted by starch@Fe3O4 at room temperature. Easy separation of catalyst (magnetically) and its reusability was also demonstrated. An eco-friendly and effective ultrasonic strategy was developed by Riadi et al. [28] for the synthesis of S-arylated-pyridopyrimidines (69) (Figure 13.28). The 4halogenopyridopyrimidines or 4-thiol (68) was used as reactants for this purpose under ultrasonic irradiation in water (green solvent). A dihydroxy ionic liquid ([Py-2OH]OAc) (72) prepared from pyridine (70) and 2chloropropane-1,3-diol (71) under ultrasonication [29] (Figure 13.29). Here, sodium acetate was used as an ion exchanger. It was reported that a library of condensed products

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Figure 13.26: Ultrasound-assisted synthesis of pyrazolo [1, 5-a] pyrimidine analogs.

Figure 13.27: Ultrasound-assisted synthesis of pyrazolopyranopyramidine.

can be prepared using DABCO-catalyzed Knoevenagel condensation under ultrasound irradiation and ([Py-2OH]OAc as a promoter. The reusability of the ionic liquid was demonstrated with a yield around 97% for seven consecutive cycles without any significant reduction in its performance. (yield: 94–99%).

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Figure 13.28: Ultrasound-assisted synthesis of S-arylated-pyridopyrimidines.

Figure 13.29: Ultrasound-assisted synthesis of rhodanine.

13.3.3 Thiazine Singh et al. [30] developed ultrasound promoted synthesis of spiro[acenaphthylene thiazine]-diones in aqueous media using three-component reaction of 3-mercaptopropionic, acenaphthalene-1,2-dione, and anilines. They used the polymer supported catalyst (PEGOSOH) that played a dual role as a phase-transfer catalyst as well as Bronsted acid to enhance this multicomponent reaction.

13.4 Seven-membered heterocyclic compounds 13.4.1 Thiazepines Dandia et al. [31] reported catalyst-free multicomponent domino reaction in aqueous medium affording spiro[indole-3,4′-pyrazolo[3,4-e][1,4]thiazepines] (73) under ultrasound with excellent yields in short time (Figure 13.30). This protocol provided a new seven-membered ring system selectively in place of expected five-membered ring system or other possible isomers. In comparison to conventional synthesis the advantages

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Figure 13.30: Ultrasound-assisted synthesis of spiro[indole-3,4′-pyrazolo[3,4-e][1,4]thiazepines].

of this method are: catalyst-free, easy workup water as the solvent, and relatively ecofriendly nature. The representative compounds of this series were screened for the inhibition of the enzyme α-amylase.

13.5 Fused heterocyclic compounds 13.5.1 Indole A simple efficient and green protocol for one-pot synthesis of functionalized 2-oxobenzo[1,4]oxazines (74) has been reported by Jaiswal et al. [32] under ultrasound irradiation in water as compared to conventional methods (Figure 13.31). It was indicated that the protocol avoids steps of purification, chromatography, and afforded target molecules in excellent yields (upto 98%) with no side products. It was also found to be applicable on gram scale. They could also prepare functionalized 2-oxo-quinoxaline analogues (yield: up to 98%), bioactive heterocyclic scaffolds, using this procedure. This protocol was used for the synthesis of an anticancer indole alkaloid, Cephalandole A 35.

Figure 13.31: Ultrasound-assisted synthesis of 2-oxo-benzo[1, 4]oxazines.

Joshi et al. [33] used 1-hexene sulfonic acid sodium salt as catalyst for the synthesis of bis (indol-3-yl)methanes (76), which is eco-friendly in nature (Figure 13.32). The reaction of indole (75) was carried out with different aldehydes (17) in water under ultrasound irradiation at room temperature affording the desired products in good to excellent yields. Simple reaction conditions, isolation, purification, and use of aqueous medium make this procedure very interesting from an economic and environmental point of view.

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Figure 13.32: Ultrasound-assisted synthesis of bis(indol-3-yl)methanes.

Li et al. [34] carried out ultrasound-assisted synthesis of bis(indolyl)methanes (78) by reaction between indole or N-methylindole (77) with aromatic aldehydes (16) using dodecylbenzenesulfonic acid (ABS) as catalyst (Figure 13.33). This protocol provided excellent yields (85–98%) in aqueous media at 23–25 °C.

Figure 13.33: Ultrasound-assisted synthesis of bis(indolyl)methanes.

Amrollahi and Kheilkordi [35] developed a convenient and direct approach for the preparation of bis(indole) derivatives (80) by one-pot four-component synthesis (Figure 13.34). They used condensation of aldehydes (17), indole (75), and active methylene compounds (79) in the presence of 12-tungstophosphoric acid in aqueous media under ultrasound irradiation. The major advantages of this procedure are: simplicity of the experiments, high yields, and short reaction times with the green aspects by avoiding the use of any toxic solvents and catalysts. The reaction of indole (75) with electron-deficient alkenes (81) has been reported by Rahimi et al. [36] in aqueous media. This protocol allowed the synthesis of bis(indole) derivatives (82) in good to high yields (77–94%) at 90 °C under ultrasound irradiation (Figure 13.35). It was reported that high yields of products in short reaction times are the

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Figure 13.34: Ultrasound-assisted synthesis of bis (indol) derivatives.

Figure 13.35: Ultrasound-assisted synthesis of bis indole.

main advantage of this proposed procedure. This reaction was catalyzed by 12tungstophosphoric acid avoiding the use of toxic solvents and other metal-based catalysts. Khorshidi and Tabatabaeian [37] used ferric chloride hexahydrate as a recyclable catalyst (homogeneous) for the synthesis of 3-(indol-3-yl)-3-hydroxyindolin-2-ones (83) in aqueous media under ultrasound irriadiation (Figure 13.36). It was reported that the products could be obtained smoothly in good to excellent yields (85–97%).

Figure 13.36: Ultrasound-assisted synthesis of 3-(indol-3-yl)-3-hydroxyindolin-2-ones.

Dandia et al. [38] reported the synthesis of substituted 2′amino-4′benzoyl-2′-methyl spiro[indole3,5′-[1,3]oxathiolane]-2(1H)-ones (85) in aqueous medium from the reaction of spiro [indole-3,2′-oxiranes] thioacetamide (84) (Figure 13.37). They used LiBr as catalyst for this purpose. The reaction was carried out in the presence of microwaves and ultrasound and results were compared with the traditional method. It was observed that an improvement in rates and yields was observed, when this reaction was carried out under ultrasound as compared to microwave-assisted reaction as well as conventional heating method.

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Figure 13.37: Ultrasound-assisted synthesis of 2′amino-4′benzoyl-2′-methyl spiro[indole3,5′-[1,3] oxathiolane]-2(1H)-ones.

Dandiab et al. [39] developed ultrasound-promoted protocol for the synthesis of spiro [indole-thiazolidinone] (86) libraries in aqueous medium (Figure 13.38). They carried out tandem reaction in the presence of cetyltrimethylammonium bromide as a phase transfer catalyst. This method is more convenient and efficient when compared to multistep conventional processes. It was also revealed that azeotropical removal of water and use of any dehydrating agents and carcinogenic solvents was avoided in this procedure.

Figure 13.38: Ultrasound-assisted synthesis of spiro[indole-thiazolidinone].

An efficient and green method has been developed by Deshmukh et al. [40] for the synthesis of bis(indolyl)methane derivatives (88) in water (Figure 13.39). They used pyruvic acid as a catalyst. It was reported that pyruvic acid catalyzes this reaction of aldehyde (16) with indole (87) and desired products were obtained in good to excellent yields under ultrasound irradiation. The lower temperature is required for sonication (50 °C), while 80 °C for conventional method. The advantages of this protocol are: use of environmental-friendly, biodegradable catalyst, excellent yields, short reaction times, Lewis acid and metal-free mild conditions, and applicable for a wide range of diverse sub-

Figure 13.39: Ultrasound-assisted synthesis of bis(indolyl)methane derivatives.

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strates. It was also revealed that the use of pyruvic acid (catalyst) in water under ultrasound radiation is a better alternative to synthesize bis(indolyl)methane derivatives as compared to some other traditional methods. Ramarao et al. [41] reported the synthesis of 4(3H)-quinazolinone ring (91) under ultrasound irradiation (Figure 13.40). These compounds are potential inhibitors of chorismate mutase (MtbCM), an established target for the identification of antitubercular agents. The approach involved iodine-mediated reaction of 2-aminobenzamides (89) with alcohols (90) in aqueous DMSO in under ultrasound. They prepared a series of 4(3H)-quinazolinone derivatives with substituents like alkyl, aryl, heteroaryl ring, or styryl moiety at the C-2 position of the product. Some quinazolinones were also prepared such as pteridin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives using this sonochemical route. It was observed that a good yield of product was obtained, when arene moiety was present at C-2 position. It was revealed that these compounds exhibited good in vitro activities (>50% inhibition) against MtbCM. The aryl C-2 substituent are beneficial as evident for structure–activity relationship and followed the order: Benzene > Pyridine > Indole ring

Figure 13.40: Ultrasound-assisted synthesis of 4(3H)-quinazolinone.

Dandia et al. [42] synthesized graphitic carbon nitride (g-C3N4) from melamine and it was functionalized by treatment with H2SO4 using ultrasound-assisted approach. The prepared functional carbon nitride (Sg-C3N4) was used as a catalyst for the synthesis of 1,3,5-trisubstituted hexahydro-1,3,5-triazine derivatives (94) using formaldehyde (93) and aryl amines (92) under ultrasound irradiation in aqueous media (Figure 13.41). It was revealed that SO3H functionality of Sg-C3N4 displayed decisive function in a metal-free approach. It was also indicated that Sg-C3N4 exhibited about 21-fold higher catalytic activity under ultrasound irradiation as compared the conventional process. This may be due to a synergistic effect of ultrasound irradiation with catalyst and water in the reaction. It was found that the reactions were clean with easy workup and highly selective.

13.5.2 Isoindolin Mardjan et al. [43] prepared a library of 3-hydroxyisoindolin-1-ones (96) from 3alkylidenephthalides (95) under ultrasonic irradiation (Figure 13.42). The synthetic

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Figure 13.41: Ultrasound-assisted synthesis of 1,3,5-trisubstituted hexahydro-1,3,5-triazine.

Figure 13.42: Ultrasound-assisted synthesis of 3-hydroxyisoindolin-1-ones.

method has certain advantages such as high efficiency, broad functional group tolerance, and yields. This reaction can also be carried out in multigram scale and it was revealed that it can be further extended to obtain motifs of isoindolin-1-ones in one pot. Milovanović et al. [44] prepared a series of benzamide-dioxoisoindoline derivatives (99) (Figure 13.43). They used phthalic anhydride (97) and different benzoyl hydrazides (98) as reactants under ultrasound irradiation in aqueous medium without any catalyst. It was reported that these synthesized phenolic compounds were having good antioxidant properties as determined by DPPH test.

Figure 13.43: Ultrasound-assisted synthesis of benzamide-dioxoisoindoline derivatives.

13.5.3 Benzothiazole Rezki et al. [45] reported the synthesis of N-(benzo[d]thiazol-2-yl)-2-(4-substituted-1H1,2,3-triazol-1-yl)acetamides (101) using different alkynes and 2-azido-N-(benzo[d]thia-

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zol-2-yl)acetamide derivatives (100) via 1,3-dipolar cycloaddition reaction in the presence of ultrasound irradiation (Figure 13.44). They used t-BuOH/H2O (1:1, v/v) as solvent and CuSO4 · 5H2O/sodium ascorbate as the catalyst. The copper catalyst was used to afford regioselective 1,4-disubstituted 1,2,3-triazoles. Significant reductions in reaction times with comparably higher yields were observed, when the reactions were carried out under ultrasound irradiation. It was also revealed that as-prepared compounds were found active against B. subtilis, Streptococcus pneumoniae, and S. aureus, E. coli, Pseudomonas aeuroginosa, Klebsiella pneumonia, C. albicans, and Aspergillus fumigatus with minimum inhibition concentration ranging between of 4 and 16 μg/mL.

Figure 13.44: Ultrasound-assisted synthesis of N-(benzo[d]thiazol-2-yl)-2-(4-substituted-1H-1,2,3-triazol-1yl)acetamides.

13.5.4 Benzopyrans An iron oxide-supported phenylsulfonic acid (Fe3O4@Ph-SO3H) core–shell structure was prepared by Elhamifar et al. [46]. They used efficient nanocatalyst for an eco-friendly synthesis of tetrahydrobenzo[b]pyrans (102) (Figure 13.45) via modification of iron oxide cores (magnetic) with 1,4-bis(triethoxysilyl)benzene, which was followed by sulfonation of aromatic rings. The synthesis of tetrahydrobenzo[b]pyrans was carried out in water (green solvent) under ultrasonic conditions at room temperature. The selectively, recoverability, and reusability of the nanocatalyst were also confirmed.

Figure 13.45: Ultrasound-assisted synthesis of tetrahydrobenzo[b]pyrans.

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13.5.5 Quinoline Litim et al. [47] synthesized a series of α-aminophosphonate (104) derivatives incorporating quinoline, quinolone, coumarylthiazole, or 5-phenylthiazol-2-amine moieties (103) via Kabachnik–Fields reaction under ultrasound irradiation in the presence of an ionic liquid (Figure 13.46). It was reported that the presence of coumarylthiazole moiety and hydroxyl in the quinoline group enhanced inhibitory activity against some microbial pathogens.

Figure 13.46: Ultrasound-assisted synthesis of α-aminophosphonates derivatives bearing substituted quinoline or quinolone and thiazole.

Geesi et al. [48] developed an efficient and green strategy for the synthesis of a series of quinolinthiones (107). The desired derivatives were prepared from the reaction between arylhydrazides (106) and 2-thiocoumarin (105) in refluxing water under ultrasound irradiation (Figure 13.47). All the prepared compounds exhibited antibacterial activity against S. aureus and E. coli, respectively.

Figure 13.47: Ultrasound-assisted synthesis of quinolin-2-thione.

A catalyst-free multicomponent procedure for the condensation of 2-naphthol (110)/ resorcinol (109), malononitrile (36), aldehydes (16), and ammonium acetate (108) for

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the synthesis of dihydroquinolines (111 and 112) at 60 °C was proposed by Pagadala et al. [49] (Figure 13.48). The reaction was carried out in aqueous medium under ultrasound irradiation yielding 90–97% products within a short period (60–90 min).

Figure 13.48: Ultrasound-assisted synthesis of dihydroquinolines.

13.5.6 Pyridotriazole A rapid one-pot four-component economical synthesis of pyrido[2,3-d:6,5-d]dipyrimidines (114) was reported by Naeimi and Didar [50]. They carried out this reaction between aldehyde (16), ammonium acetate (108), and 2-thiobarbituric acid (113) in the presence of magnetically heterogeneous catalyst under ultrasonic irradiation in aqueous medium (Figure 13.49). The proposed synthesis has some advantages such as use of magnetically recoverable and reusable catalyst, high to excellent yields, short reaction periods, convenient one-pot operation, and use of water as a green solvent, and it can be also considered a relatively environmentally benign reaction.

Figure 13.49: Ultrasound-assisted synthesis of pyrido[2,3-d:6,5-d]dipyrimidines.

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13.6 Conclusions An enhancement in the reaction rate of organic reactions in the presence of ultrasound fulfills some of the goals of green chemistry. The use of ultrasound has proved to be a useful tool by minimizing the production of wastes and reduction in requirements of energy. Ultrasound can help us in having cleaner reactions with improved yields and selectivity. This technique takes short reaction times and is environmentally benign. It has been successfully applied for the synthesis of a number of heterocyclic scaffolds. Time is not far off, when use of ultrasound in organic synthesis will play a dominant role in future.

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Index (MAOS) 357, 359 [bs tetradecim][OTf] 249 [bsdecim][OTf] 249 [bsmim][HSO4] 249 [bsmim][OTf] 249 [bsmim][PTSA] 249 [bsocim][OTf] 249 [dodecim][OTf] 249 “on water” reaction 10 1,2,3-triazole 60 1,2,4-thiadiazole derivatives 390 1,2,4-triazoles 316 1,2-disubstituted benzimidazolidines 27 1,2-disubstituted pyrrolo[2,3-b]quinoxalines 289 1,3-oxazines 221 1,8-dioxooctahydroxanthene 331 14H-dibenzo [a,j]xanthenes 206 18-crown-[6]-ether 219 2-amino-3-cyano-4H-pyran 212 2-amino-3-cyano-4H-pyran derivatives 392 2-amino-4H chromenes 326 2-amino-4H-chromenes 213 2-aminobenzothiazole 239 2-aryl quinoxalines 169 2-methyltetrahydrofuran 59 2-oxo-2H-1-benzopyran 210 2-substituted benzimidazoles 18 2-substituted imidazo[1,2-a]pyridines 289 2-substituted quinolines 188 3,4-dihydropyrano[c]chromene 295 3,4-dihydropyrano[c]chromenes 207 6π-electrocyclization 73 adapalene 336 aggregation 269 aldol 364–365 aldol condensation 85, 188 ambiphilic 103 ambiphilic dual activators 184 ambiphilic nucleophilic-electrophilic dual activation 170 anionic surfactants 165 anthelmintic 70 anticancer potential 256 antitubilin 62 anxiolytic 70

https://doi.org/10.1515/9783110985627-014

aphanorphine 71 aqueous heterogeneous catalytic protocols 205 aqueous medium 360, 362, 365, 374–375 aqueous-mediated 259 atom economy 394 Averrhoa bilimbi extract 117 aza-Diels–Alder adducts 286 aza-Michael addition 25 ball milling 11 benzamide-dioxoisoindoline 406 benzimidazole 1 benzimidazoles 9 benzo[b]furan 387 benzo[d]thiazol-2-amines 299 benzothiazole 1 benzotriazole indole 1 benzoxazole 1 bicyclic structure 255 Biginelli compounds 329 Biginelli reaction 104 Biginelli reactions 127 biocompatibility 268 biomass-derived solvent 8 biosensing 268 Breslow hydrophobic effect 10 Brønsted acidic surfactant 36, 192 Bronsted acids 127 Brønsted acid–surfactant-combined ionic liquid 248 calorimetric detection 274 carbazole 1 cardiotonic 70 catalysis 269 catalytic performance 277 cephalotaxine 71 cetyl trimethyl ammoniumbromide 288 cetyltrimethyl ammonium bromide 213 cetyltrimethylammonium bromide 242 chiral centers 278 Claisen rearrangement 257 classical volatile organic solvents 3 cleaner production 257 click reaction 316 Combes 183

416

Index

combranolides 66 coumarin 364 critical micelle concentration 283, 301 C(sp3)–H activation 12 cyclic ketones 264 cycloaddition 278 cyclopentyl methylether 59 Danishefsky’s diene 89, 286 DBSA 29 deep eutectic solvents 7, 184 diastereoselectivity 275 Diels–Alder-type reactions 152 dihydropyrano[3,2-b]pyran derivatives 394 dimethyl carbonate 8 Doebner–von Miller 183 eco-friendly 259 electrophile–nucleophile dual activation 155 electrophile–nucleophile synergistic dual activation 155 Environment Protection Agency 2 etamivan 336 Fokin, Sharpless 366 friedelin 288 Friedländer 183 Friedländer annulation 194 green chemistry 59, 257, 353, 355–356, 358, 374 Hantzsch 361 Hantzsch condensation 318 Hantzsch esters 87 Hantzsch pyridine synthesis 87 Hantzsch reaction 367 Heck 152, 183 hemoglobinopathies 74 heterocycles 358, 360, 364, 377 heterocyclic 358–359, 368, 380 heterocyclic derivatives 261 heterogeneous catalysis 265 histamine H3 receptor antagonists 63 human A3 adenosine receptor antagonists 73 imidazo[1,2-a]pyridine 314 imidazole 86 imidazopyridine 1

iminothiazolidine derivatives 235 indazole 1 indolo[2,3-b]quinoline 191 inositol 5-phosphatases 73 ionic liquids 59 isatins 260 isoxazol-5(4H)-one derivatives 117 isoxazole 86 itaconic acid 163 Kabachnik-Fields multicomponent reaction 336 kailolides 66 Knoevenagel 259 Knoevenagel condensation 92, 236, 310 Knoevenagel reaction 86 kojic acid 124 Krohnke reaction 365 Langlois’ reagent 311 Lawesson’s reagent 104 lennoxamine 71 leukotriene synthesis inhibitors 63 lipase-catalyzed 264 local anesthetics 65 L-proline 260 magnetic nanoparticles 394 maleic anhydride 386 Mannich reaction 85 Mannich reactions 376 Mannich-type reactions 259 MAOS 353, 357–359, 365, 378 MCRs 259 metallic nanoparticles 267 Michael addition 109, 120, 310 Michael addition reactions 92 Michael reaction 85 microwave energy 353, 357 microwave irradiation 355, 358–367, 371, 375 microwave-assisted 277 MK-2 protein inhibitor 66 multicomponent reaction 221, 261 multicomponent reactions 12 Nafion-H 235 nanocatalyst 210, 266 nanosheets 270 N-aryl-1,8-dioxo decahydroacridines 285

Index

nebularine 239 neocryptolepine alkaloid 189 NKI receptor 65 N-substituted azetidines 112 octadecyl trimethyl ammonium chloride 246 on water 300 one-pot 259 o-phenylenediamines 160 organocatalysis 111, 184, 276 organocatalysts 87 oxindoles 256 Paal–Knorr reaction 115 Paal–Knorr synthesis 103, 115 Pauson–Khand reaction 86 Pfitzinger 183 Pfitzinger reaction 195 pharmacological activities 265 phase transfer catalyst 246 phosphatidylinositol-3-kinase (PI3K) inhibitors 62 photocatalytic synthesis 35 phthalazine derivatives 292 polyethylene glycol 59 polyfunctionalized quinoxalines 159 potent leads 255 prostate apoptosis response-4 secretagogue 73 proton pump inhibitors 1 pyrano[2,3-c]pyrazoles 219 pyranopyrazoles 271, 327 pyrazole 86 pyrazolo[1,5-a]pyrimidine 398 pyrazolopyranopyrimidines 218 pyrazolopyridines 261 pyridine 86 pyrido[2,3-d – 6,5-d]dipyrimidines 409 pyrimidine 86 pyrrole 86 pyrrole derivatives 284 pyrrolidinyl 277 quinazoline 86 quinoline 86 quinoline-fused ring systems 183 quinoxalines 152, 156

retro-aza-Michael process 124 reusability 270 rhodanine 60 samarium(III) triflate 242 SDOSS 37 SDS 37 Skraup 183 sodium dioctyl sulfosuccinate 300 sodium dioctylsulfosuccinate 165 sodium dodecyl benzosulfonate 246 sodium dodecyl sulfate 283, 300 sodium dodecylbenzenesulfonate 288 sodium dodecylsulfate 165 sodium lauryl sulfate 283 Sonogashira 152 Sonogashira coupling reactions 294 spatial architecture 256 spiro-4H-pyrans 392 spiro-carbocycles 255 spirocompounds 255 spirocyclopropyl oxindoles 278 spiroindoline 257 spiro-tetrahydroquinolines 222 supercritical fluids 59, 356 superparamegnatic 265 surfactant 167 Suzuki 152 Suzuki coupling 359 synergistic electrophile–nucleophile dual activation 184 TBAB 207 tert-butyl hydrogen peroxide 248 tetrabutyl ammonium bromide 246 tetrahydrobenzoxanthene 331 tetra-n-butylammonium bromide 288 therapeutic agents 255 thermal and nonthermal processes 355 thiazole 86 thiazolidine 86 thiomorpholine-1,1-dioxide 126 Tween 40 166 Ugi/Michael/aza-Michael 374 ultrasonic irradiation 388

417

418

Index

vidarabine 239 visible light irradiation 11 visible-light-promoted 171 volatile organic components (VOCs) 356 water 356, 359, 362, 364, 366, 368, 374, 376, 378 Zolimidine 230, 289

α-D-glucopyranosyl bromide 316 β-cyclodextrin 115, 234, 271 β-ketoesters 271 β-lactamase 60