Green-Bond Forming Reactions. Volume 1: Carbon-Carbon and Carbon-Heteroatom [1] 9783110759495

Table of contents :
Cover
Half Title
Also of Interest
Green-Bond Forming Reactions: Carbon-Carbon and Carbon-Heteroatom
Copyright
Preface
Contents
List of contributing authors
1. Recent developments in C–C bond formation catalyzed by solid supported palladium: a greener perspective
1.1 Introduction
1.2 Palladium supported on carbon black
1.3 Palladium supported on carbon nanotubes
1.4 Palladium supported on graphene and graphene oxide
1.5 Palladium supported on organic supports
1.6 Conclusions
References
2. Visible-light-mediated metal-free C–Si bond formation reactions
2.1 Introduction
2.2 C–Si bond formation of alkenes
2.3 C–Si bond formation of alkynes
2.4 C–Si bond formation of allene
2.5 Silylation of arenes and heteroarenes
2.6 Silylation of dienes
2.7 Synthetic application
2.8 Conclusions
References
3. Synthesis of antiviral drugs by using carbon–carbon and carbon–heteroatom bond formation under greener conditions
3.1 Introduction
3.1.1 Synthesis of antiviral compounds by using green chemistry
3.1.2 Contribution of organic electrolysis synthesis to green chemistry
3.2 Conclusions
References
4. Green synthesis of triazolo-nucleoside conjugates via azide–alkyne C–N bond formation
4.1 Introduction
4.2 Synthesis
4.2.1 Synthesis of C-1′ triazolo-nucleosides
4.2.2 Synthesis of C-2′-triazolo-nucleosides
4.2.3 Synthesis of C-3′-triazolo-nucleosides
4.2.4 Synthesis of C-4′-triazolo-nucleosides
4.2.5 Synthesis of C-5′-triazolo-nucleosides
4.3 Conclusions
References
5. An overview of quinoxaline synthesis by green methods: recent reports
5.1 Introduction
5.2 Reactions conducted in aqueous medium
5.3 Reactions conducted at room temperature
5.4 Reactions conducted under microwave energy
5.5 Solvent-free reactions
5.6 Light initiated synthesis
5.7 Application of ultrasonication
5.8 Reactions employing recyclable catalysts
5.9 Reactions conducted at above room temperatures
5.10 Conclusions
References
6. Green protocols for Tsuji–Trost allylation: an overview
6.1 Introduction
6.2 Eco-friendly approaches towards Tsuji–Trost allylation
6.2.1 Synthesis of benzylated and allylated moieties
6.2.2 Synthesis of N-allylated moieties
6.2.3 Synthesis of S-allylated moieties
6.2.4 Synthesis of O-allylated moieties
6.2.5 Other approaches: versatility of the catalyst
6.3 Conclusions
References
7. Recyclable magnetically retrievable nanocatalysts for C–heteroatom bond formation reactions
7.1 Introduction
7.2 Fabrication of magnetic nanoparticles for the designing of magnetically recyclable nanocatalysts
7.2.1 Iron oxides
7.2.2 Mixed spinels (CoFe2O4 NPs, CuFe2O4 NPs, NiFe2O4 NPs, MnFe2O4 NPs, ZnFe2O4 NPs)
7.3 Strategies of imparting durability to the magnetic nanoparticles
7.3.1 Coating
7.3.2 Functionalization
7.4 Applications of magnetic nanocatalysts in C–heterobond formation reactions
7.4.1 C–N bond formation
7.4.2 C–O coupling
7.4.3 C–S coupling
7.4.4 Miscellaneous reactions
7.5 Conclusion and future perspectives
References
8. Carbocatalysis: a metal free green avenue towards carbon–carbon/heteroatom bond construction
8.1 Introduction
8.2 Catalysis
8.3 Carbocatalysis
8.3.1 Graphene oxide (GO)
8.3.2 Graphitic carbon nitride (g-C3N4)
8.3.3 Carbon quantum dots (CQDs)
8.4 Conclusions
References
9. Use of heterogeneous catalysis in sustainable biofuel production
9.1 Introduction
9.2 Viability of heterocatalysts for biodiesel generation
9.3 Production of liquid fuels with conventional catalysts
9.4 Natural materials-based catalysis system for biofuel production
9.5 The importance of heterogeneous catalytic activity towards aqueous ethanol in biofuel production
9.6 The future of energy and the environment with the use of aqueous heterogeneous catalysis
9.7 Conclusions
References
10. Catalytic applications of graphene oxide towards the synthesis of bioactive scaffolds through the formation of carbon–carbon and carbon–heteroatom bonds
10.1 Introduction
10.2 Chemical method for the preparation of graphene oxide (GO)
10.3 Structural analysis of GO
10.4 Graphene oxide (GO) as an effective metal-free catalyst in organic transformation
10.4.1 Graphene-based catalyst towards the formation of C–C and C–heteroatom bond
10.4.1.1 Freidel-Crafts-type reaction
10.4.1.2 Aldol-type reaction
10.4.1.3 Multicomponent reactions
10.4.1.4 Michael addition
10.4.1.5 Miscellaneous reactions
10.5 Conclusions
References
11. Dicarbonyl compounds in the synthesis of heterocycles under green conditions
11.1 Introduction
11.2 Green solvents in organic synthesis
11.3 Solvent-free conditions
11.4 Green catalytic systems
11.5 Heterogeneous catalysis
11.6 Organocatalyzed reactions
11.7 Catalyst-free conditions
11.8 Photochemical activation
11.9 Sonochemistry in the synthesis of heterocycles
11.10 Microwave-assisted synthesis of heterocycles
11.11 Electrochemical redox reactions
11.12 Conclusions
References
12. Polyaniline mediated heterogeneous catalysis in the preparation of heterocyclic derivatives through carbon–heteroatom bond formations
12.1 Introduction
12.2 Applications of polyaniline mediated heterogeneous catalysis for the synthesis of various heterocyclic derivatives
12.2.1 Synthesis of dihydropyrimidinones
12.2.2 Synthesis of 7-membered diazepines and 5-membered benzimidazoles
12.2.3 Synthesis of spiro compounds and procedure for making PANI nanorods
12.2.4 Synthesis of PANI nanorods
12.2.5 Synthesis of pyran derivatives
12.2.6 Triazole derivatives
12.2.7 Quinoxalines
12.2.8 Tetrahydroquinolines
12.2.9 Carbon–nitrogen coupling
12.2.10 Substituted indoles
12.2.11 Formylations
12.2.12 Indolo-chromenes, bisindoles and chromenes
12.2.13 Chromene derivatives
12.3 Addition of nitrogen to open chain compounds
12.3.1 Synthesis of β-aminocarbonyl compounds
12.3.2 Synthesis of β-aminocarbonyl compounds by direct addition
12.4 Conclusions
References
Index

Citation preview

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

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

Green-Bond Forming Reactions Carbon-Carbon and Carbon-Heteroatom Edited by Rakesh Kumar Sharma and Bubun Banerjee

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

ISBN 978-3-11-075949-5 e-ISBN (PDF) 978-3-11-075954-9 e-ISBN (EPUB) 978-3-11-075959-4 Library of Congress Control Number: 2022939565 Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the internet at http://dnb.dnb.de. © 2022 Walter de Gruyter GmbH, Berlin/Boston Cover image: Artfully79/iStock/Getty Images Plus Typesetting: TNQ Technologies Pvt. Ltd. Printing and binding: CPI books GmbH, Leck www.degruyter.com

Preface Carbon-carbon (C-C) and carbon-heteroatom (C-X; X = O, N, S, Si, etc.) bond-forming reactions are regarded as the backbone of synthetic organic chemistry. A huge number of structurally diverse organic compounds have been synthesized almost every day through the C-C and C-X bond formations. In the earlier reports, use of harsh reaction conditions, toxic solvents, non-reusable catalysts were very common for the formation of these types of bonds. During past two decades, continuous efforts have been made to carry out carbon-carbon and carbon-heteroatom bond forming reactions under greener and environmentally benign conditions. This book entitled ‘Green bond forming reactions: Carbon-carbon and carbon-heteroatom’ compiles a huge literature related to the carbon-carbon and carbon-heteroatom bonds that have been accomplished under the umbrella of Green Chemistry. This book contains 12 chapters, contributed by established scientists of high calibers. In chapter 1, Saha and Mukhopadhyay have explored the recent developments in carbon-carbon bond forming reactions by utilizing solid supported palladium as catalyst under environmentally benign conditions. Organosilicon derivatives are acquiring immense attention because of their significant applications in synthetic, medicinal and material chemistry. In chapter 2, Ghosh and Hajra have demonstrated the recent developments on the visible-light mediated metal-free silylation of C‒C multiple bonds which includes alkenes, heteroarenes, alkynes, allenes, enynes and dienes. Viral infections exact several severe human diseases, accounting for remarkably high mortality rates. In chapter 3, Prof. Sreekanth B. Jonnalagadda and his group have summarized the recent developments on the synthesis of antiviral drugs through carbon-carbon and carbon-hetero bond formation under diverse reaction conditions. It was found that incorporation of triazole ring in nucleosides enhances their therapeutic value and various photophysical properties. In chapter 4, Prof. Ashok K. Prasad and his group have compiled the literature related to the synthetic methodologies being employed to synthesize various sugar modified triazolyl nucleosides. In this chapter they have also discussed their therapeutic importance and various other applications of triazolyl nucleosides. Quinoxalines are found to possess a wide range of biological and pharmaceutical efficacies. In chapter 5, Nageswar and Katla have summarized the recent advancements in the synthesis of quinoxaline derivatives through carbon-nitrogen bond formation under environmentally benign conditions. Tsuji–Trost allylation reactions have been extensively used for the development of various greener and sustainable protocols, especially for C-C and C-heteroatom bonds formation. In chapter 6, Bhattacharya and Basu have assimilated and pondered upon https://doi.org/10.1515/9783110759549-201

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Preface

all the recent developments on this unique reaction protocol focusing on the newly designed catalytic systems with high efficiency, the use of eco–friendly solvents or solvent–free conditions, low or room temperature conditions and waste management, along with future outlook. Our group (Prof. Rakesh K. Sharma) has described the use of recyclable magnetically retrievable nanocatalysts that have emerged as sustainable catalysts for carbonheteroatom bond formation reactions in chapter 7. In chapter 8, Dandia et al. have highlighted the recent developments perceived in “C-C, C-N, C-S or C-O” bond construction especially emphasizing greener perspectives utilizing various carbocatalysts such as carbon quantum dots, graphene oxide, graphite carbon nitride etc. Saleh and Hassan have demonstrated the use of heterogeneous catalysis in sustainable biofuel production in chapter 9. Singha et al., in the chapter 10, have explored the catalytic applications of graphene oxide towards the synthesis of various bioactive scaffolds through the formation of carbon-carbon and carbon-heteroatom bond formation under diverse reaction conditions. In chapter 11, Prof. Eder Joao Lenardao and his group have demonstrated the use of dicarbonyl compounds as starting material for the synthesis of structurally diverse biologically promising heterocyclic scaffolds under greener conditions. The last chapter by Rao and Nageswar summarized the recent applications of polyaniline mediated heterogeneous catalysts for the synthesis of various biologically promising heterocycles through the formation of carbon-heteroatom bonds. The editors of this book express their gratitude to all the authors for contributing such good chapters. The contribution of Ms. Stella Muller and Ms. Christene Smith has been tremendous. This book would not have been completed without the timely support from the authors, Ms. Muller and Ms. Smith. We hope that this book on green bond forming reactions will be used extensively by the scientific community. Thank you ALL. Prof. Rakesh Kumar Sharma and Dr. Bubun Banerjee

Contents Preface V List of contributing authors

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Debasree Saha and Chhanda Mukhopadhyay 1 Recent developments in C–C bond formation catalyzed by solid supported 1 palladium: a greener perspective 1 1.1 Introduction 2 1.2 Palladium supported on carbon black 3 1.3 Palladium supported on carbon nanotubes 6 1.4 Palladium supported on graphene and graphene oxide 8 1.5 Palladium supported on organic supports 14 1.6 Conclusions 14 References Sumit Ghosh and Alakananda Hajra 2 Visible-light-mediated metal-free C–Si bond formation reactions 17 2.1 Introduction 19 2.2 C–Si bond formation of alkenes 26 2.3 C–Si bond formation of alkynes 28 2.4 C–Si bond formation of allene 29 2.5 Silylation of arenes and heteroarenes 31 2.6 Silylation of dienes 32 2.7 Synthetic application 33 2.8 Conclusions 33 References

17

Tejeswara Rao Allaka, Naresh Kumar Katari and Sreekanth Babu Jonnalagadda 3 Synthesis of antiviral drugs by using carbon–carbon and carbon–heteroatom 37 bond formation under greener conditions 37 3.1 Introduction 44 3.1.1 Synthesis of antiviral compounds by using green chemistry 49 3.1.2 Contribution of organic electrolysis synthesis to green chemistry 55 3.2 Conclusions 55 References Rajesh Kumar, Jyotirmoy Maity, Divya Mathur, Abhishek Verma, Neha Rana, Manish Kumar, Sandeep Kumar and Ashok K. Prasad 4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne C–N 61 bond formation 61 4.1 Introduction

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4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.3

Contents

Synthesis 63 Synthesis of C-1′ triazolo-nucleosides Synthesis of C-2′-triazolo-nucleosides Synthesis of C-3′-triazolo-nucleosides Synthesis of C-4′-triazolo-nucleosides Synthesis of C-5′-triazolo-nucleosides 99 Conclusions 99 References

63 84 86 95 95

Yadavalli Venkata Durga Nageswar and Ramesh Katla 5 An overview of quinoxaline synthesis by green methods: recent 105 reports 105 5.1 Introduction 106 5.2 Reactions conducted in aqueous medium 115 5.3 Reactions conducted at room temperature 131 5.4 Reactions conducted under microwave energy 137 5.5 Solvent-free reactions 142 5.6 Light initiated synthesis 144 5.7 Application of ultrasonication 145 5.8 Reactions employing recyclable catalysts 150 5.9 Reactions conducted at above room temperatures 166 5.10 Conclusions 168 References Suchandra Bhattacharya and Basudeb Basu 175 6 Green protocols for Tsuji–Trost allylation: an overview 175 6.1 Introduction 177 6.2 Eco-friendly approaches towards Tsuji–Trost allylation 177 6.2.1 Synthesis of benzylated and allylated moieties 178 6.2.2 Synthesis of N-allylated moieties 179 6.2.3 Synthesis of S-allylated moieties 180 6.2.4 Synthesis of O-allylated moieties 181 6.2.5 Other approaches: versatility of the catalyst 183 6.3 Conclusions 183 References Sriparna Dutta, Prashant Kumar, Sneha Yadav, Ranjana Dixit, and Rakesh Kumar Sharma 7 Recyclable magnetically retrievable nanocatalysts for C–heteroatom bond 189 formation reactions 190 7.1 Introduction

Contents

7.2 7.2.1 7.2.2 7.3 7.3.1 7.3.2 7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.5

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Fabrication of magnetic nanoparticles for the designing of magnetically 191 recyclable nanocatalysts 191 Iron oxides Mixed spinels (CoFe2O4 NPs, CuFe2O4 NPs, NiFe2O4 NPs, MnFe2O4 NPs, 195 ZnFe2O4 NPs) 198 Strategies of imparting durability to the magnetic nanoparticles 198 Coating 200 Functionalization Applications of magnetic nanocatalysts in C–heterobond formation 200 reactions 201 C–N bond formation 208 C–O coupling 211 C–S coupling 216 Miscellaneous reactions 217 Conclusion and future perspectives 218 References

Anshu Dandia, Sonam Parihar, Krishan Kumar, Surendra Saini, and Vijay Parewa 8 Carbocatalysis: a metal free green avenue towards carbon–carbon/ 225 heteroatom bond construction 225 8.1 Introduction 228 8.2 Catalysis 228 8.3 Carbocatalysis 229 8.3.1 Graphene oxide (GO) 242 8.3.2 Graphitic carbon nitride (g-C3N4) 245 8.3.3 Carbon quantum dots (CQDs) 253 8.4 Conclusions 254 References Hosam M. Saleh and Amal I. Hassan 257 9 Use of heterogeneous catalysis in sustainable biofuel production 257 9.1 Introduction 259 9.2 Viability of heterocatalysts for biodiesel generation 262 9.3 Production of liquid fuels with conventional catalysts 264 9.4 Natural materials-based catalysis system for biofuel production 9.5 The importance of heterogeneous catalytic activity towards aqueous ethanol 267 in biofuel production 9.6 The future of energy and the environment with the use of aqueous 270 heterogeneous catalysis 271 9.7 Conclusions 272 References

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Rabindranath Singha, Puja Basak and Pranab Ghosh 10 Catalytic applications of graphene oxide towards the synthesis of bioactive scaffolds through the formation of carbon–carbon and carbon–heteroatom 279 bonds 279 10.1 Introduction 282 Scope of this review 282 10.2 Chemical method for the preparation of graphene oxide (GO) 283 10.3 Structural analysis of GO 10.4 Graphene oxide (GO) as an effective metal-free catalyst in organic 283 transformation 10.4.1 Graphene-based catalyst towards the formation of C–C and 283 C–heteroatom bond 296 10.5 Conclusions 296 References Daniela Hartwig, Liane K. Soares, Luiz H. Dapper, José E. R. Nascimento, and Eder João Lenardão 11 Dicarbonyl compounds in the synthesis of heterocycles under green 303 conditions 303 11.1 Introduction 304 11.2 Green solvents in organic synthesis 307 11.3 Solvent-free conditions 313 11.4 Green catalytic systems 321 11.5 Heterogeneous catalysis 325 11.6 Organocatalyzed reactions 328 11.7 Catalyst-free conditions 334 11.8 Photochemical activation 338 11.9 Sonochemistry in the synthesis of heterocycles 341 11.10 Microwave-assisted synthesis of heterocycles 344 11.11 Electrochemical redox reactions 345 11.12 Conclusions 346 References Jayathirtha Rao Vaidya and Yadavalli Venkata Durga Nageswar 12 Polyaniline mediated heterogeneous catalysis in the preparation of heterocyclic derivatives through carbon–heteroatom bond 353 formations 353 12.1 Introduction 12.2 Applications of polyaniline mediated heterogeneous catalysis for the 354 synthesis of various heterocyclic derivatives 354 12.2.1 Synthesis of dihydropyrimidinones

Contents

12.2.2 12.2.3 12.2.4 12.2.5 12.2.6 12.2.7 12.2.8 12.2.9 12.2.10 12.2.11 12.2.12 12.2.13 12.3 12.3.1 12.3.2 12.4

Index

Synthesis of 7-membered diazepines and 5-membered 355 benzimidazoles Synthesis of spiro compounds and procedure for making PANI 356 nanorods 357 Synthesis of PANI nanorods 358 Synthesis of pyran derivatives 358 Triazole derivatives 359 Quinoxalines 361 Tetrahydroquinolines 361 Carbon–nitrogen coupling 362 Substituted indoles 363 Formylations 364 Indolo-chromenes, bisindoles and chromenes 365 Chromene derivatives 367 Addition of nitrogen to open chain compounds 367 Synthesis of β-aminocarbonyl compounds 368 Synthesis of β-aminocarbonyl compounds by direct addition 368 Conclusions 369 References 373

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List of contributing authors Tejeswara Rao Allaka Centre for Chemical Sciences and Technology Institute of Science and Technology Jawaharlal Nehru Technological University Hyderabad Kukatpally Hyderabad Telangana 500085 India Puja Basak Department of Chemistry University of North Bengal Dist-Darjeeling West Bengal India Basudeb Basu Department of Chemistry Cotton University Guwahati 781003 India E-mail: [email protected] Suchandra Bhattacharya Department of Chemistry ABN Seal College Cooch Behar 736101 India E-mail: [email protected] Anshu Dandia Centre of Advanced Studies Department of Chemistry University of Rajasthan Jaipur India E-mail: [email protected] Luiz H. Dapper Laboratório de Síntese Orgânica Limpa –LASOL CCQFA Universidade Federal de Pelotas – UFPel P.O. Box 354 96010-900 Pelotas RS Brazil E-mail: [email protected]

https://doi.org/10.1515/9783110759549-202

Ranjana Dixit Ramjas College Department of Chemistry University of Delhi Delhi-110007 India Sriparna Dutta Green Chemistry Network Centre Department of Chemistry University of Delhi Delhi-110007 India and Hindu College Department of Chemistry University of Delhi Delhi-110007 India Pranab Ghosh Department of Chemistry University of North Bengal Dist-Darjeeling West Bengal India E-mail: [email protected] Sumit Ghosh Department of Chemistry Visva-Bharati (A Central University) Santiniketan 731235 India E-mail: [email protected] Alakananda Hajra Department of Chemistry Visva-Bharati (A Central University) Santiniketan 731235 India E-mail: [email protected]

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List of contributing authors

Daniela Hartwig Laboratório de Síntese Orgânica Limpa – LASOL CCQFA Universidade Federal de Pelotas – UFPel P.O. Box 354 96010-900 Pelotas RS Brazil E-mail: [email protected] Amal I. Hassan Radioisotope Department Nuclear Research Center Egyptian Atomic Energy Authority Cairo Egypt Sreekanth Babu Jonnalagadda School of Chemistry & Physics College of Agriculture Engineering & Science Westville Campus University of KwaZulu-Natal P Bag X 54001 Durban 4000 South Africa E-mail: [email protected] Eder João Lenardão Laboratório de Síntese Orgânica Limpa – LASOL CCQFA Universidade Federal de Pelotas – UFPel P.O. Box 354 96010-900 Pelotas RS Brazil E-mail: [email protected] José E. R. Nascimento Laboratório de Síntese Orgânica Limpa –LASOL CCQFA Universidade Federal de Pelotas – UFPel P.O. Box 354 96010-900 Pelotas RS Brazil E-mail: [email protected]

Naresh Kumar Katari Department of Chemistry School of Science GITAM deemed to be University Hyderabad Telangana 502 329 India and School of Chemistry & Physics College of Agriculture Engineering & Science Westville Campus University of KwaZulu-Natal P Bag X 54001 Durban 4000 South Africa E-mail: [email protected] Ramesh Katla Organic Chemistry Laboratory-4 School of Chemistry and Food Federal University of Rio Grande-FURG Rio Grande RS Brazil Krishan Kumar Centre of Advanced Studies Department of Chemistry University of Rajasthan Jaipur India Manish Kumar Department of Chemistry Bioorganic Laboratory University of Delhi Delhi India Prashant Kumar Department of Chemistry SRM University Delhi-NCR Sonepat Haryana India

List of contributing authors

Rajesh Kumar Department of Chemistry R.D.S. College B.R.A. Bihar University Muzaffarpur India Sandeep Kumar Department of Chemistry Bioorganic Laboratory University of Delhi Delhi India Jyotirmoy Maity Department of Chemistry St. Stephen’s College University of Delhi Delhi India Divya Mathur Department of Chemistry Daulat Ram College University of Delhi Delhi India Chhanda Mukhopadhyay Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India E-mail: [email protected] Yadavalli Venkata Durga Nageswar CSIR-Indian Institute of Chemical Technology Uppal Road Tarnaka Hyderabad-500007 Telangana India and Indian Institute of Chemical Technology-IICT Tarnaka Hyderabad India E-mail: [email protected]

Vijay Parewa Centre of Advanced Studies Department of Chemistry University of Rajasthan Jaipur India E-mail: [email protected] Sonam Parihar Centre of Advanced Studies Department of Chemistry University of Rajasthan Jaipur India Ashok K. Prasad Department of Chemistry Bioorganic Laboratory University of Delhi Delhi India E-mail: [email protected] Neha Rana Department of Chemistry Bioorganic Laboratory University of Delhi Delhi India Debasree Saha Department of Chemistry Raidighi College 24 Parganas (South) Raidighi West Bengal 743383 India Surendra Saini Centre of Advanced Studies Department of Chemistry University of Rajasthan Jaipur India

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Hosam M. Saleh Radioisotope Department Nuclear Research Center Egyptian Atomic Energy Authority Cairo Egypt E-mail: [email protected] [email protected] Rakesh Kumar Sharma Green Chemistry Network Centre Department of Chemistry University of Delhi Delhi-110007 India E-mail: [email protected] Rabindranath Singha Department of Chemistry University of North Bengal Dist-Darjeeling West Bengal India Liane K. Soares Laboratório de Síntese Orgânica Limpa –LASOL CCQFA Universidade Federal de Pelotas – UFPel P.O. Box 354 96010-900 Pelotas RS Brazil E-mail: [email protected]

Jayathirtha Rao Vaidya Fluoro Agro Chemicals Department and AcSIRGhaziabad CSIR-Indian Institute of Chemical Technology Uppal Road Tarnaka Hyderabad-500007 Telangana India E-mail: [email protected] Abhishek Verma Department of Chemistry Bioorganic Laboratory University of Delhi Delhi India Sneha Yadav Green Chemistry Network Centre Department of Chemistry University of Delhi Delhi-110007 India

Debasree Saha and Chhanda Mukhopadhyay*

1 Recent developments in C–C bond formation catalyzed by solid supported palladium: a greener perspective Abstract: The world today is struggling to achieve sustainable means for synthetic processes. Standing at this juncture, we need to develop and implement greener and reusable approaches towards organic synthesis. Transition metals especially palladium is a wonder element which has the ability to catalyze a range of useful organic syntheses. However, the expensive nature of palladium has urged synthetic chemists to search for protocols where a single palladium source may be used repeatedly in successive reactions, thus making the overall process cost effective. Palladium when anchored to solid supports leads to catalytic systems which can be easily separated from the organic phase post reaction and can be reused in successive cycles. Not only does this make the process economically viable but also ensures that no metal contaminates the purity of the final organic product. In this review we will highlight the recent developments in C–C bond formation (which is by far the most fundamental mode of bond making in organic synthesis) via the use of solid supported palladium catalytic systems. We will use this opportunity to illustrate the synthetic processes from a greener sustainable point of view which we feel is of utmost relevance in the current scientific scenario. Keywords: environment friendly; Palladium; reusability; solid support.

1.1 Introduction C–C bond formation is the most vital mode of bond making in organic synthesis and serves as the mainstay of carbon chemistry. With the advent of transition metal catalysis in C–C bond formation, this fundamental mode of bond making has reached unimaginable heights via the development of Suzuki, Heck, Sonogashira, Stille, Negishi, Hiyama and other such coupling reactions [1–9]. Palladium has served as the main catalyst in most of these reactions. However, the expensive nature of palladium and its salts has hindered the cost effectiveness of the protocols. Thus, search for newer reusable palladium sources have gained immense attention. Solid supported palladium catalysts have been explored as a means to increase the economic viability by

*Corresponding author: Chhanda Mukhopadhyay, Department of Chemistry, University of Calcutta, Kolkata 700009, West Bengal, India, E-mail: [email protected] Debasree Saha, Department of Chemistry, Raidighi College, 24 Parganas (South), Raidighi, West Bengal 743383, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: D. Saha and C. Mukhopadhyay “Recent developments in C–C bond formation catalyzed by solid supported palladium: a greener perspective” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0081 | https://doi.org/10.1515/ 9783110759549-001

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1 Recent developments in C-C bond formation with solid supported palladium

exploiting the reusability factor of these catalysts. Another major advantage of these supported palladium catalysts is the fact that these processes lead to environmentally benign pathways as the supported catalysts can be easily removed from the organic system thus minimizing the chances of metal contaminants in the products. A few reviews have already been published on supported palladium catalyzed reactions [9, 10]. However, there is scope of incorporating more recent reported protocols in this field. Moreover, the environmentally benign aspect needs to be highlighted as we need sustainable synthetic methods in today’s world. Thus, in this review we have aimed for the study of comparatively recent reported (ranging between 2007 and 2021) methodologies from a greener sustainable viewpoint. Supported palladium catalysts can be broadly classified based on the support systems. The most common solid supports for palladium are carbon black, carbon nanotubes, graphene and graphene oxide. Other sustainable supports include several organic systems. For better understanding we have dealt with each category under separate subheadings.

1.2 Palladium supported on carbon black Palladium supported on charcoal (Pd/C) has gained immense popularity as a heterogeneous catalyst due to its easy availability and handling as well as reusability [9, 11]. Pd/C catalyst was successfully used for Suzuki, Sonogashira and other coupling reactions. Recently, a few groups have used either ligand free Pd/C catalyst or an aqueous medium for conveniently carrying out the coupling reactions in environmentally benign fashion. In 2007, Sajiki and his group reported a mild ligand free methodology for the development of Suzuki reaction using Pd/C [12]. Both aryl bromides and aryl triflates (1) participated in the reaction with boronic acids (2) to produce respective biphenyl derivatives (3) in moderately high yields at room temperature (Figure 1.1(a)). Aryl vinyl boronic acids (5) also partook in the reaction resulting in only the corresponding trans stilbene product (6) in a highly stereoselective manner (Figure 1.1(b)). The catalyst was found to undergo negligible leaching in solution and could be reused successfully with almost equal efficiency as the first run. A new kind of Pd/C catalyst prepared from palladium nitrate and charcoal known as UC-Pd was developed by Lipshutz and his coworkers [13]. The UC-Pd catalyst was compared with conventional Pd/C catalysts and was found to be more effective in catalyzing Sonogashira reaction of aryl bromides and alkynes. The catalyst was studied extensively via TEM, XRD, XPS, and CO-TPD analyses. The catalyst was successfully used to catalyze copper free Sonogashira coupling reaction between diversely substituted aryl bromides (7) and substituted acetylenes (8)

1.3 Palladium supported on carbon nanotubes

3

a 1

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Figure 1.1: Suzuki Miyaura reaction of aryl halides and aryl/vinyl boronic acids using Pd/C. (a) Suzuki Miyaura reaction of aryl bromides and triflates using Pd/C. (b) Suzuki Miyaura reaction of aryl bromides with aryl vinyl boronic acids using Pd/C.

(Figure 1.2(a)), of which the most striking example was the reaction of bromoacetophenone (10) with acetylene attached to cholesterol residue (11) (Figure 1.2(b)). Li et al. implemented a bimetallic catalyst of Fe and Pd supported on carbon for the Suzuki reaction of aryl halides (13) with phenyl boronic acids (14) in aqueous medium (Figure 1.3) [14]. In addition to the aqueous medium, the other sustainable feature of the methodology involved easy separation of the catalyst from the reaction mixture by using an external magnetic field. The catalyst showed long term stability and could be recycled upto 5 runs with significant yields.

1.3 Palladium supported on carbon nanotubes Carbon nanotubes (CNTs) serve as potential choices for being used as supports for palladium nanoparticles due to their high surface to volume ratio, thermal and mechanical stability and absence of microporosity. Pd nanoparticles supported on CNTs have been effectively employed as catalysts for C–C bond forming coupling reactions. Keeping the environmental aspect in mind we will discuss a few recent such protocols

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1 Recent developments in C-C bond formation with solid supported palladium

a 9

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Figure 1.2: Sonogashira reaction catalyzed by UC-Pd. (a) Sonogashira reaction of aryl bromides with acetylenes using UC-Pd. (b) UC-Pd catalyzed Sonogashira reaction of 4-bromoacetophenone with acetylene having cholesterol residue.

13

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Figure 1.3: Suzuki Miyaura reaction of aryl halides with phenyl boronic acid catalyzed by Fe@Pd/C catalyst.

that have been used as greener alternatives to the conventional methodologies for C–C bond formation. Palladium nanoparticles supported on single walled (Pd/SWCNT) and multi walled (Pd/MWCNT) were developed via a mild solventless ball milling method by Gupton and his group [15]. Both Pd/SWCNT and Pd/MWCNT served as effective catalysts for C–C bond formation via ligand free Suzuki reaction, though the multiwalled variety showed slightly better results in terms of reactivity and recyclability as is evident from a higher turnover number. The protocol involved environmentally benign approach by employing ethanol/ water as solvent system under microwave irradiation. Several diversely substituted aryl

1.3 Palladium supported on carbon nanotubes

16

17

5

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Figure 1.4: Suzuki Miyaura reaction of aryl bromides with phenyl boronic acids catalyzed by Pd/ MWCNT under microwave.

bromides (16) participated in the reaction with substituted boronic acids (17) to yield the corresponding biphenyl derivatives (18) in high yield (Figure 1.4). Ghorbani-Vaghei et al. synthesized a hybrid catalytic system that composed of Pd nanoparticles supported on diethylenetriamine modified single walled carbon nano tube (SWCNT-DETA/Pd). The catalytic system was characterized by XRD, FTIR, SEM, TGA, and TEM analyses. This system served as an efficient and novel catalyst for Suzuki cross coupling reaction between aryl halides (19) and phenyl boronic acid (20) to yield the corresponding biphenyl derivatives (21) (Figure 1.5) [16]. The reactions were carried out in aqueous medium (H2O/ EtOH) in presence of a mild base like potassium carbonate under ambient temperature of 60 °C. The catalyst was recycled upto 7th run with no significant loss in the product yield. Thus, the catalytic system served as an economically viable as well as environmentally mild process for C–C bond formation. In 2017 a novel magnetically separable heterogeneous Pd catalyst was synthesized by Khalili and his coworkers where Pd nanoparticles are supported on amino-vinyl silica functionalized magnetic carbon nanotube [17]. The catalytic system is mainly 8 of CNT@Fe3O4@SiO2-Pd without the involvement of phosphine which makes the system environment friendly. The authors employed this catalyst system for catalyzing Suzuki Miyaura (Figure 1.6(a)) and Heck Mizoroki coupling reactions (Figure 1.6(b)) leading to the desired

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Figure 1.5: Suzuki Miyaura reaction of aryl halides with phenyl boronic acid catalyzed by SWCNT-DETA/Pd2+ under aqueous condition.

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1 Recent developments in C-C bond formation with solid supported palladium

a 22

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Figure 1.6: C–C bond formation catalyzed by CNT@Fe3O4@SiO2-Pd catalyst. (a) Suzuki Miyaura reaction of aryl electrophiles with phenyl boronic acid catalyzed by CNT@Fe3O4@SiO2-Pd catalyst. (b) Heck Mizoroki reaction of aryl halides catalyzed by CNT@Fe3O4@SiO2-Pd catalyst.

products (24) and (27) respectively, in significant yields. The catalyst could easily be separated using an external magnet and could be reused quite successfully for six runs.

1.4 Palladium supported on graphene and graphene oxide Graphene/graphene oxide has become a popular choice as a support for metal nanoparticles especially palladium because of the high specific surface area, excellent dispersibility, extraordinary electrical and thermal conductivities, good mechanical and chemical stabilities and strong thermal resistance. Herein we will deal with a few methodologies leading to C–C bond formation catalyzed by graphene/graphene oxide supported palladium catalysts that involve greener modes of synthesis. Qu and his group used calf thymus DNA as a mediator for graphene based Pd catalyst. DNA is a natural biodegradable material having a well-defined structure [18]. The nucleobases in DNA can stabilize graphene system by interacting with π–π stacking in graphene. Palladium nanoparticles were anchored onto DNA modified graphene sheets resulting in an efficient, stable and recyclable catalyst (DNA-G-Pd) that was employed in catalyzing Suzuki reaction of iodobenzene (28) and phenyl

1.4 Palladium supported on graphene and graphene oxide

28

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Figure 1.7: Suzuki Miyaura reaction of iodobenzene with phenyl boronic acid catalyzed by DNA-G-Pd under aqueous condition.

boronic acid (29) under aqueous, aerobic condition (Figure 1.7). The catalyst could be easily separated post reaction and reused for at least seven cycles with reasonable performance. Palladium nanoparticles were anchored on ionic polymer doped graphene nanocomposite crystals by Kim and his co-workers in 2017 [19]. The resultant catalytic system (Pd-IPG) served as an efficient heterogeneous catalyst for C–C bond formation via Suzuki cross coupling reaction (Figure 1.8). Both aryl iodides and bromides (31) participated in the Suzuki reaction with aryl boronic acids (32), though the yields of the corresponding products with aryl iodides were significantly higher. The reaction was carried out in a benign ethanol water solvent system and the catalyst could be reused effectively for ten cycles thus making the process environmentally and economically feasible. The authors carried out hot filtration test and STEM-EDX analyses on reused catalyst to explore the mechanism of the reaction. The results showed that there is very negligible leaching of Pd nanoparticles from Pd-IPG catalytic system during Suzuki reaction which is the reason behind excellent recyclability of the catalyst. Wang et al. synthesized a three dimensional amine terminated ionic liquid functionalized graphene/Pd catalytic system (3D IL-rGO/Pd) and utilized it for green environmentally friendly synthesis of C–C bond formation via Suzuki Miyaura cross coupling reaction in aqueous ethanolic medium (Figure 1.9) [20]. The protocol combines the advantages of high yields, easy and efficient recyclability, low cost and durability of catalyst which together makes it very relevant and

31

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Figure 1.8: Suzuki Miyaura reaction of aryl halides with aryl boronic acids catalyzed by Pd-IPG catalyst.

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1 Recent developments in C-C bond formation with solid supported palladium

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Figure 1.9: 3D IL-rGO/Pd catalyzed Suzuki reaction of aryl halides and phenyl boronic acid.

useful methodology in today’s synthetic world where we are constantly in search of newer environmentally benign and economically viable procedures. Heydari and his group employed 2,6-diaminopyridine (DAP)-amidoxime (AO) palladium complex supported on magnetic reduced graphene oxide (MRGO@DAP-AOPdll) as efficient catalyst for C–H arylation of imidazole derivatives with aryl bromides in K2CO3/glycerol medium (Figure 1.10) [21]. Several substituted imidazoles (37) and aryl bromides (38) participated in the reaction leading to the formation of arylated imidazole derivatives (39). The catalyst could be recycled upto seven runs with no significant loss in catalytic activity. The advantages of this methodology include low catalyst loading, high yield of product, easy magnetic separation of the supported catalyst and green environment friendly solvent system.

1.5 Palladium supported on organic supports Several inorganic and organic polymeric materials have assisted in C–C bond formation by serving as suitable support systems for palladium metal. Inorganic supports are inexpensive but they do not often offer ease of handling or efficient recyclability. Naturally occurring organic supports, on the other hand, are inexpensive and biodegradable and offer a greener pathway for anchoring palladium and resulting in environment friendly C–C bond formation methods. We will highlight a few recent

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Figure 1.10: C–H arylation of imidazoles with aryl bromides catalyzed by MRGO@DAP-AO-Pd(II).

1.5 Palladium supported on organic supports

9

protocols involving palladium supported on organic polymers that successfully catalyze C–C bond formation under sustainable conditions. Varma and his group developed a green method for the synthesis of palladium nanoparticles via the use of Vitamin B1 (thiamine) as reducing agent in aqueous medium [22]. No separate capping agent was added as Vitamin B1 played out that part as well. The shape of the palladium nanoparticles was dependent on the concentration of the palladium salt precursor used. The authors employed this catalyst for C–C bond formation via Suzuki, Heck and Sonogashira coupling reactions under microwave irradiation (Figure 1.11). Both aryl iodides and bromides (40) participated in the coupling reactions. Even heterocyclic halide like 2-iodothiophene underwent Suzuki and Sonogashira reaction to produce the corresponding products in significant yields. Chitosan (47) is a linear polysaccharide in which D-glucosamine is linked to N-acetyl-D-ghucosamine via ß-(1,4) glycosidic bond (Figure 1.12(a)). It is obtained by treating chitin shells of shrimp and other crustaceans with alkali metal hydroxides.

a 40

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Figure 1.11: C–C bond formation catalyzed by Pd-vit B1 catalyst. (a) Suzuki reaction of aryl halides with aryl boronic acid catalyzed by Pd-vit B1 catalyst under microwave irradiation. (b) Heck reaction of aryl halides with alkyl acrylates catalyzed Pd-vit B1 catalyst under microwave irradiation. (c) Sonogashira reaction of aryl halides with phenyl acetylene catalyzed Pd-vit B1 catalyst under microwave irradiation.

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1 Recent developments in C-C bond formation with solid supported palladium

Ondruschka and his co-workers employed palladium supported on chitosan catalysts for successfully catalyzing Suzuki cross coupling reaction in aqueous medium [23]. Four different methods were used to prepare four varieties of modified chitosan supported palladium catalysts. The catalysts were shown to carry out Suzuki reaction of bromobenzenes (48) (namely 4-bromoacetophenone and 4-bromophenol) with phenyl boronic acid (49) in aqueous medium under microwave irradiation to produce the respective products (50) in significant yields (Figure 1.12(b)). The catalysts were shown to be recycled. The catalysts were found to catalyze Heck and Sonogashira reaction as well though only in non-aqueous organic solvent medium. Gelatin is derived from collagen and is useful as a support for transition metals due to its adhesiveness, flexibility and inexpensive nature. Palladium nanoparticles supported on gelatin were used successfully for the C–C bond formation via Sonogashira Hagihara reaction and dimerization of phenyl acetylenes by Firouzabadi and co-workers (Figure 1.13(a)) [24]. Gelatin served both as reducing agent and as a support for the nano palladium. To illustrate the versatility of the protocol, along with aryl bromides, the authors also used trans-β-bromostyrene (54) as a substrate for coupling with phenyl acetylene (55) to produce the corresponding trans-enyne product (56) (Figure 1.13(b)). The catalyst could be reused three times with loss in catalytic activity due to 31% leaching in molten TBAB after the third run as confirmed by ICP analysis. Agarose is a polysaccharide extracted from agar-bearing marine algae. It is a natural polymer composed of alternating ß-D-galactose and 3,6-anhydro-L-galactose units of agarobiose. Agarose has free hydroxyl groups and can form gel like network in water. In 2011 Firouzabadi and co-workers employed agarose hydrogel supported

a

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Figure 1.12: Suzuki reaction catalyzed by Pd-Chitosan catalyst. (a) Structure of chitosan. (b) Pd chitosan catalyzed Suzuki reaction of aryl bromides and phenyl boronic acid under microwave irradiation.

1.5 Palladium supported on organic supports

11

a 53

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Figure 1.13: Sonogashira Hagihara reaction catalyzed by gelatin supported Pd nanoparticles. (a) Sonogashira Hagihara reaction of aryl halides with acetylenes catalyzed by gelatin supported Pd nanoparticles. (b) Sonogashira Hagihara reaction of β-bromostyrene with phenyl acetylene catalyzed by gelatin supported Pd nanoparticles.

palladium nanoparticles for catalyzing Suzuki Miyaura cross coupling reaction in aqueous medium (Figure 1.14) [25]. Several diversely substituted aryl heteroaryl halides (even chlorides) participated in the reaction. The catalyst could be reused for six runs without appreciable loss in catalytic activity. The methodology provides a cheap, nontoxic and green pathway for C–C bond formation. Cacchi et al. used alginate/gellan beads to stabilize palladium nanoparticles and employed this supported palladium catalyst for Suzuki Miyaura cross coupling reaction of arenediazonium tetrafluoroborates (60) with potassium aryltrifluoroborates (61) [26]. Alginate (63) is composed of linear chain structures of 1–4 linked mannuronic acid and l-guluronic acid (Figure 1.15(a)). It is usually extracted from brown algae (Phaeophyceae). Gellan gum (64) consists of two residues of D-glucose and one residue each of L-rhamnose and D-glucuronic acid (Figure 1.15(b)). The authors utilized the idea of synergic interactions between biopolymers and employed a mixture of alginate and

57

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Figure 1.14: Suzuki Miyaura reaction of aryl halides with phenyl boronic acid catalyzed by agarose supported Pd catalyst.

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1 Recent developments in C-C bond formation with solid supported palladium

a

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Figure 1.15: Suzuki Miyaura reaction catalyzed by Alginate-gellan supported Pd catalyst. (a) Structure of alginate. (b) Structure of gellan. (c) Suzuki Miyaura cross coupling reaction of arenediazonium tetrafluoroborates with potassium aryltrifluoroborites catalyzed by A-G supported Pd catalyst.

gellan polymers as a support for palladium nanoparticles. The resultant catalyst performed quite efficiently in catalyzing Suzuki Miyaura reaction under aqueous, aerobic, base free and phosphine free condition (Figure 1.15(c)). The catalyst could be reused for several cycles without significant loss in activity. Overall, the protocol provides an environmentally benign method for C–C bond formation via Suzuki cross coupling. Kalbasi and his group synthesized palladium nanoparticles supported on poly(N-vinyl-2-pyrrolidone)/mesoporous carbon nanocage (CKT-3) and used this polymer-organic hybrid catalyst for Heck reaction of aryl halides (65) with styrene (66) (Figure 1.16) [27]. The reactions were carried out under sustainable aqueous aerobic condition. The catalyst was shown to be reused 10 times without any loss of catalytic activity. Sayahi and co-workers carried out immobilization of palladium on terpyridine functionalized superparamagnetic iron oxide nanoparticles and employed this as catalyst for C–C bond formation via Suzuki and Heck cross coupling reactions [28]. The

1.5 Palladium supported on organic supports

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Figure 1.16: Heck Mizoroki reaction of aryl halides with styrene catalyzed by Pd-PVP/CKT catalyst.

a 68

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Figure 1.17: C–C bond formation catalyzed by Pd@terPy@SPION catalyst. (a) Suzuki Miyaura reaction of aryl halides with phenyl boronic acid catalysed by Pd@terPy@SPION catalyst. (b) Mizoroki Heck reaction catalyzed by Pd@terPy@SPION catalyst.

catalyst (Pd@terPy@SPION) was characterized by SEM, DLS, FTIR, ICP and VSM analysis. Several diversely substituted aryl halides (68) participated in Suzuki reaction with phenyl boronic acid (69) and Heck reaction with styrene (71) and butyl acrylate (73) under aqueous condition at room temperature (Figure 1.17), which makes the protocol quite sustainable. The catalyst was reused for five cycles without appreciable loss in activity.

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1 Recent developments in C-C bond formation with solid supported palladium

1.6 Conclusions This is a short collage of solid supported palladium catalyzed C–C bond formation via sustainable pathways. We have tried to portray the recent developments in this field from an environmentally viable perspective. Almost all the catalytic systems covered in this review are reusable and most of the protocols involve aqueous medium which make the methodologies environmentally as well as economically sustainable. The world today requires greener reusable protocols for synthesis of organic molecules and thus keeping the need of the hour in mind, we combined C–C bond formation, supported palladium catalysts and sustainable conditions in one platform. We hope that this review will benefit and inspire future work on sustainable methods of molecular synthesis.

References 1. Bej A, Ghosh K, Sarkar A, Knight DW. Palladium nanoparticles in the catalysis of coupling reactions. RSC Adv 2016;6:11446–53. 2. Taladriz-Blanco P, Hervés P, Pérez-Juste J. Supported Pd nanoparticles for carbon-carbon coupling reactions. Top Catal 2013;56:1154–70. 3. García-Suárez EJ, Lara P, García AB, Philippot K. Carbon-supported palladium and ruthenium nanoparticles: application as catalysts in alcohol oxidation, cross-coupling and hydrogenation reactions. Recent Pat Nanotechnol 2013;7:247–64. 4. Molnár Á. Palladium-Catalyzed Coupling Reactions: Practical Aspects, Future Developments. Weinheim: Wiley VCH; 2013. 5. Jana R, Pathak TP, Sigman MS. Advances in transition metal (Pd, Ni, Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem Rev 2011;111:1417–92. 6. Fihri A, Bouhrara M, Nekoueishahraki B, Basset J-M, Polshettiwar V. Nanocatalysts for Suzuki cross-coupling reactions. Chem Soc Rev 2011;40:5181–203. 7. Lamblin M, Nassar-Hardy L, Hierso JC, Fouquet E, Felpin FX. Recyclable heterogeneous palladium catalysts in pure water: sustainable developments in Suzuki, Heck, Sonogashira and Tsuji–Trost reactions. Adv Synth Catal 2010;352:33–79. 8. Zolfigol MA, Khakyzadeh V, Mossavi-Zare AR, Rostami A, Zare A, Iranpoor N, et al. Green Chem 2013;15:2132–40. 9. Gholinejad M, Naghshbandi Z, Nájera C. Carbon-derived supports for palladium nanoparticles as catalysts for carbon-carbon bonds formation. ChemCatChem 2019;11:1792–823. 10. Ghaderia A, Gholinejad M, Firouzabadi H. Palladium deposited on naturally occurring supports as a powerful catalyst for carbon-carbon bond formation reactions. Curr Org Chem 2016;20:327–48. 11. Felpin F-X, Ayad T, Mitra S. Pd/C: an old catalyst for new applications – its use for the Suzuki– Miyaura reaction. Eur J Org Chem 2006:2679–90, https://doi.org/10.1002/ejoc.200501004. 12. Maegawa T, Kitamura Y, Sako S, Udzu T, Sakurai A, Tanaka A, et al. Heterogeneous Pd/C-catalyzed ligand-free, room-temperature Suzuki–Miyaura coupling reactions in aqueous media. Chem Eur J 2007;13:5937–43. 13. Duplais C, Forman AJ, Baker BA, Lipshutz BH. UC Pd: a new form of Pd/C for Sonogashira couplings. Chem Eur J 2010;16:3366–71.

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14. Tang W, Li J, Jin X, Sun J, Huang J, Li R. Magnetically recyclable Fe@Pd/C as a highly active catalyst for Suzuki coupling reaction in aqueous solution. Catal Commun 2014;43:75–8. 15. Siamaki AR, Lin Y, Woodberry K, Connell JW, Gupton BF. Palladium nanoparticles supported on carbon nanotubes from solventless preparations: versatile catalysts for ligand-free Suzuki cross coupling reactions. J Mater Chem 2013;1:12909–18. 16. Ghorbani-Vaghei R, Hemmati S, Hashemi M, Veisi H. Diethylenetriamine-functionalized singlewalled carbon nanotubes (SWCNTs) to immobilization palladium as a novel recyclable heterogeneous nanocatalyst for the Suzuki–Miyaura coupling reaction in aqueous media. Compt Rendus Chem 2015;18:636–43. 17. Khalili D, Banazadeh AR, Etemadi-Davan E. Palladium stabilized by amino-vinyl silica functionalized magnetic carbon nanotube: application in Suzuki–Miyaura and Heck–Mizoroki coupling reactions. Catal Lett 2017;147:2674–87. 18. Qu K, Wu L, Ren J, Qu X. Natural DNA-modified graphene/Pd nanoparticles as highly active catalyst for formic acid electro-oxidation and for the Suzuki Reaction. Appl Mater Interfaces 2012;4: 5001–9. 19. Kwon TH, Cho KY, Baek K -Y, Yoon HY, Moon Kim B. Recyclable palladium–graphene nanocomposite catalysts containing ionic polymers: efficient Suzuki coupling reactions. RSC Adv 2017;7:11684–90. 20. Huang Y, Wei Q, Wang Y, Dai L. Three-dimensional amine-terminated ionic liquid functionalized graphene/Pd composite aerogel as highly efficient and recyclable catalyst for the Suzuki crosscoupling reactions. Carbon 2018;136:150–9. 21. Shariatipour, M, Salamatmanesh, A, Jadidinejad, Mand Heydari, A Imidazole-aryl coupling reaction via C–H bond activation catalyzed by palladium supported on modified magnetic reduced graphene oxide in alkaline deep eutectic solvent. Catal Commun 2020;135:105890. 22. Nadagouda MN, Polshettiwar V, Varma RS. Self-assembly of palladium nanoparticles: synthesis of nanobelts, nanoplates and nanotrees using vitamin B1, and their application in carbon–carbon coupling reactions. J Mater Chem 2009;19:2026–31. 23. Leonhardt SES, Stolle A, Ondruschka B, Cravotto G, Leo CD, Jandt KD, et al. Chitosan as a support for heterogeneous Pd catalysts in liquid phase catalysis. Appl Catal Gen 2010;379:30–7. 24. Firouzabadi H, Iranpoor N, Ghaderi A. Gelatin as a bioorganic reductant, ligand and support for palladium nanoparticles. Application as a catalyst for ligand- and amine-free Sonogashira– Hagihara reaction. Org Biomol Chem 2011;9:865–71. 25. Firouzabadi H, Iranpoor N, Gholinejad M, Kazemi F. Agarose hydrogel as an effective bioorganic ligand and support for the stabilization of palladium nanoparticles. Application as a recyclable catalyst for Suzuki–Miyaura reaction in aqueous media. RSC Adv 2011;1:1013–9. 26. Cacchi S, Caponetti E, Casadei MA, Giulio AD, Fabrizi G, Forte G, et al. Suzuki-Miyaura crosscoupling of arenediazonium salts catalyzed by alginate/gellan-stabilized palladium nanoparticles under aerobic conditions in water. Green Chem. 2012;14:317–20. 27. Kalbasi RJ, Mosaddegh N, Abbaspourrad A Palladium nanoparticles supported on a poly(N-vinyl2-pyrrolidone)-modified mesoporous carbon nanocage as a novel heterogeneous catalyst for the Heck reaction in water. Tetrahedron Lett 2012;53:3763–6. 28. Baloutaki BA, Sayahi MH, Nikpassand M, Kefayati H. Palladium supported terpyridine modified magnetic nanoparticles as an efficient catalyst for carbon–carbon bond formation. J Organomet Chem 2021;935:121682–8.

Sumit Ghosh and Alakananda Hajra*

2 Visible-light-mediated metal-free C–Si bond formation reactions Abstract: Conserving the environment is one of the most imperative goals in recent days among the chemists throughout the world. Swiftly increasing the environmental awareness also increases the demand to build new approaches for synthesizing the same active molecules with zero-waste and pollution. In this background, visible-lightmediated synthesis and functionalization of diverse organic compounds has been established as a tremendously successful topic and has achieved a remarkable stage of superiority and efficiency in the last 20 years. Alternatively, organosilicon derivatives are gradually aspiring leaves among chemists because of their significant application on synthetic, medicinal, and material chemistry. In this scenario, the addition of Si–H group to carbon−carbon multiple bonds (alkenes, hetero-arenes, alkynes, allenes, carboxylic acids, enynes, and dienes) provides an extremely step- and atom-efficient method to obtain silicon-containing compounds. Several attempts for the development of mild, robust, and efficient green protocol were taken in the last two decades. In spite of substantial advancement/research on C–Si bond formation using transition metal catalysis, a green and metal-free approach is highly essential considering its application in the field of medicine and with respect to environmental aspects as well. In this article, we will summarize the reports considering suitable visible-light-mediated metal-free silylation of C–C multiple bonds that includes alkenes, hetero-arenes, alkynes, allenes, enynes, and dienes. Keywords: C–Si bond-forming reaction; metal-free; organophotocatalysis; silylation; synthesis of organosilicon compounds; visible-light.

2.1 Introduction Organosilicon compounds are becoming one of the hot topics in organic chemistry due to their versatile applications in synthetic chemistry, agrochemical chemistry, material chemistry, and medicinal chemistry [1–7]. They are widely used in various crucial building blocks [8–10], drug delivery systems [11], polymers [12–14], etc., because of

*Corresponding author: Alakananda Hajra, Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India, E-mail: [email protected]. https:// orcid.org/0000-0001-6141-0343 Sumit Ghosh, Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India, E-mail: [email protected] As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. Ghosh and A. Hajra “Visible-light-mediated metal-free C–Si bond formation reactions” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0087 | https://doi.org/10.1515/9783110759549-002

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2 Metal-free C–Si bond formation reactions

Figure 2.1: Some examples of drugs containing C–Si bond.

their distinctive chemical, physical, and bioactive properties. In addition, several organosilicon compounds are working as promising drugs [15] (Figure 2.1). Generally, these compounds are manufactured by (i) substitution reactions of silyl halides with nucleophiles such as Grignard- or organolithium reagents [16], (ii) crosscoupling reactions using various transition metals [17–20], and (iii) peroxide-mediated radical silylation methodology [21–23]. However, harsh reaction conditions, employment of poisonous reagents and catalysts, unnecessary by-products, poor atom economy, and selectivity are known to be responsible for hindrance to show utmost efficiency. Hence, a new sustainable C–Si bond formation methodology is highly needed at this time in organic chemistry. In this context, visible light photocatalysis is becoming a powerful and efficient synthetic strategy in modern synthetic chemistry [24–32]. Therefore, visible-light-induced C–Si bond formation (Figure 2.2) is definitely a good choice in this conventional wisdom. The general mechanism is initiated by the formation of silyl radical (i), followed by attacking the unsaturated bond of the substrate (1) to afford another radical intermediate (ii). The single electron transfer (SET) of ii, followed by proton abstraction, furnishes the silylated product (4) (Figure 2.3). In spite of such ubiquitous significance and the presence of a bunch of published literature reports, no direct-review article on photo-induced C–Si bond formation methodology is presented so far in chemical literature. However, in February 2021, we have published a review article on visible-light-mediated silylation methodologies [33].

Figure 2.2: Metal-free visible-light-induced C–Si bond formation methodology.

2.2 C–Si bond formation of alkenes

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Figure 2.3: Common mechanistic pathway for metal-free visible-light-induced C–Si bond formation.

The article mostly described metal-photocatalyzed silylation along with limited discussion on organocatalyzed silylation. Moreover, O–Si and C–Si bond-forming reactions were not discussed in an orderly manner. Therefore, a systematic review on environment-benign metal-free visible-light-induced C–Si bond formation methodologies is highly necessary at this time among the chemical community. Our group also reported several visible-light-induced synthesis and functionalization methodologies [34–47]. In continuation of our efforts on C–Si bond formation methodology [33, 48], we herein wish to report a review on metal-free visible-light-mediated C–Si formation methods. This perspective assembles all the related articles that are published till January 2022.

2.2 C–Si bond formation of alkenes In 2000, Ito et al. [49] first reported the photoinduced C–Si of alkenes (5) without using any catalyst, base, or additive. In this method, bis(dialkylamino)organosilylborane 6 was used as a silylating agent, and ultraviolet light was utilized as an energy source for the reaction. The expected products (7) containing C–Si bond formed to obtain 56% yield within 2 h (Figure 2.4). The authors noticed that UV light absorption of the reaction depended on the size of alkyl group and borane of silylboranes. 1-Octene, cyclohexene, methyl methacrylate, and benzyl methacrylate were important substrates that could be easily silylated by this method and achieved corresponding silyl products. Moreover, they demonstrated that internal alkanes (8) could also be suitable substrates (Figure 2.5).

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Figure 2.4: Visible-light-induced catalyst-free C–Si bond formation of terminal alkenes (Ito method) [49].

Figure 2.5: Visible-light-mediated catalyst-free C–Si bond formation internal alkenes (Ito method) [49].

In addition to that, dienes 11 underwent organosilylative cyclization with organosilylborane to afford 5-exo-cyclized products 12 (Figure 2.6). The reaction went through radical generation, as proved by the radical trapping experiment. In 2017, Wu group [50] developed a metal-free C–Si bond formation technology of alkenes using visible light irradiation. According to this methodology, electron-poor alkenes 13 reacted with silanes 2 in the presence of 3 mol% of 4CzIPN and 10 mol% of quinuclidine-3-yl acetate as the photocatalyst and the hydrogen atom transfer (HAT)

Figure 2.6: Visible-light-induced catalyst-free C–Si bond formation of dienes (Ito method) [49].

2.2 C–Si bond formation of alkenes

21

catalyst, respectively, in acetonitrile solvent under the irradiation of blue light. The desired products (14) containing C–Si bond were achieved with 94% yield within 24 h (Figure 2.7). The use of other organocatalysts, such as 9-mesityl-10-methylacridinium perchlorate and eosin Y, and metal photocatalysts, such as Ir(ppy)3, Ir(ppy)2(dtbpy)3PF6, and Ru(bpy)3Cl2, did not give the desired products when the remaining factors were kept unchanged. A bunch of electron-deficient alkenes responded to the reaction and generated the corresponding silyl products, as shown in Figure 2.7. The authors observed that their methodology could also be applicable for electron-rich alkenes. However, triisopropylsilanethiol and N,N-diisopropylethylamine should be used to

Figure 2.7: Photoinduced metal-free C–Si bond formation of electron-poor alkenes (Wu method) [50].

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Figure 2.8: Photoinduced metal-free C–Si bond formation of electron-rich alkenes (Wu method) [50].

work as HAT catalyst and base, respectively (Figure 2.8). This method also proceeded through radical formation as confirmed by radical trapping experiments and Stern– Volmer quenching studies. In 2018, Wu group [51] again devised a visible-light-induced C–Si and C–C bond formation methodology of alkenes 15 without using any metal catalyst. According to this silacarboxylation process, silanes 2 and CO2 were used as the source of silyl and carboxylic groups. Similar to their previous method, this method also used 4CzIPN and quinuclidine-3-yl acetate as the photocatalyst and the HAT catalyst, respectively. However, this method required a higher concentration of HAT catalyst in comparison with their previous methodology. The desired silacarboxyl products 17 were achieved with 76% yield within 4 h at room temperature (rt) (Figure 2.9). A series of alkenes containing both electron-withdrawing and electron-donating groups straightforwardly participated in the reaction and led to the corresponding silacarboxyl products under the same optimized reaction conditions. Moreover, variation on silane was also tolerated by this method. The gram-scale synthesis signified the practical applicability of this methodology. Moreover, the authors applied their methodology for late-stage synthetic elaboration of biologically relevant complex molecules, such as tryptamine and estrone. Mild conditions, superior step- and redox economy, external oxidant-free, easy scale-up through continuous-flow technology, and wide substrate scopes were vital profits for this process. This reaction also followed radical mechanism. At around the same time, another metal-free protocol for photo-induced C–Si formation of alkene was reported by Wang, Yao, and his coworkers [52]. As per the report of this article, alkenes 18 (1.2 equiv.) interacted with silanes 2 (1 equiv.) in the presence of eosin Y (1 mol%) as a catalyst, triisopropylsilanethiol (5 mol%) as an additive, and K2CO3 (5 mol%) as a base under the irradiation of 5 W white light. Dioxane/H2O (50/1) worked as the most suitable solvent for this method. The desired

2.2 C–Si bond formation of alkenes

23

Figure 2.9: Metal-free visible-light-induced C–C and C–Si bond formation of alkenes (Wu method) [51].

hydrosilylated products 19 were afforded at 36–38 °C (Figure 2.10). Electron-rich alkenes such as vinyl phosphine, vinyl sulfane, vinyl acetate, and vinyl ethers easily responded to the reaction methodology and afforded 91% yield of the corresponding hydrosilylated products. Moreover, internal alkenes as well as cyclic and heterocyclic alkenes also followed this methodology. However, cyclic alkenes required more time to complete the reaction. Furthermore, dienes were also a good substrate for this methodology. Most interestingly, steroidal drugs, stigmasterol, and pregnenolone acetate underwent hydrosilylation on the unsaturated bond of the ring, and other functional groups stayed unchanged (Figure 2.11). Therefore, several silicon-containing medicinally relevant molecules could be synthesized rapidly by this late-stage hydrosilylation methodology. In 2020, Zhou and Wu et al. [53] enlisted a regioselective visible-light-induced C–Si bond formation strategy using organic photocatalyst. No metal was used in this method. According to this methodology, methylene-malononitriles 21 was treated with disilanes 20 in the presence of 2.5 mol% of Mes-Acr+ as organophotocatalyst in DCE/ MeOH (4:1 V/V) mixture solvent under the irradiation of blue light for 12–36 h. The reaction was done at rt, and the desired silylated products 22 were achieved with up to 83% yield (Figure 2.12). The authors observed that organophotocatalyst, such as 2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate, and metal-photocatalysts, such as

24

2 Metal-free C–Si bond formation reactions

Figure 2.10: Metal-free eosin Y-catalyzed visible-light-induced C–Si bond formation of alkenes (Yao method) [52].

Ru(bpy)3Cl2·6H2O Ir(dFppy)2(dtbpy)PF6 and Ir[dF(CF3)ppy]2(dtbpy)PF6, were completely ineffective or produced inferior yields of desired products when the remaining factors were unchanged. The substrate scope study suggested that benzylidenemalononitrile having electron-donating groups (–Me and –OMe) and electronwithdrawing substituents (–Cl, –CN, –CF3) in the aryl group easily took part in the reaction under standard reaction conditions. Moreover, hexamethyldisilane and 1,2-bis(2-methoxyphenyl)-1,1,2,2-tetramethyldisilane acted as the source of silicon. The mechanistic studies suggested a photoredox-mediated radical cation fragmentation for the production of silyl radicals.

2.2 C–Si bond formation of alkenes

Figure 2.11: Visible-light-induced metal-free radical silylation of steroid drugs [52].

Figure 2.12: Visible-light-mediated metal-free C–Si bond formation of methylene malononitriles (Zhou and Wu method) [53].

25

26

2 Metal-free C–Si bond formation reactions

Figure 2.13: Visible-light-induced metal-free decarboxylative C–Si bond formation of alkenes (Wang and Uchiyama method) [54].

In 2020, Wang and Uchiyama et al. [54] developed an organophotocatalyzed decarboxylative C–Si bond formation methodology of alkenes (18) using silacarboxylic acids (3) as the Si source. About 5 mol% of 4CzIPN was used as the organophotocatalyst for the reaction. The reaction was carried out under irradiation of blue light at rt for 12 h. The desired silylated products 19 were obtained with 88% yield (Figure 2.13). However, an inert atmosphere (argon) was needed for the reaction, and no silylated product was achieved in air. The authors observed that metal photocatalysts, such as Ir(pFppy)3, [Ir(ppy)2(bpy)]PF6, and Ir[dF(t-Bu)ppy]3, were inefficient. Both aliphatic and aromatic alkenes responded to the reaction under standard reaction conditions. Moreover, alkenes having electron-withdrawing and electron-releasing groups smoothly took part in the reaction, affording corresponding silylated products with moderate to good yields. Besides, styrenes having different substituents at the phenyl group were also tolerated. In addition, heterocyclic alkenes were also suitable substrates for the reaction. This method was applicable for the gram-scale synthesis of silylated products. Control experiments confirmed that the reaction proceeds through a radical mechanism.

2.3 C–Si bond formation of alkynes In 2014, Bolm group [55] developed a photomediated C–Si bond formation using Brook rearrangements. According to this silylacylation reaction methodology, 1 equiv. of acylsilanes (23) interacted with 2 equiv. of electron-deficient alkynes (24) under blue

2.3 C–Si bond formation of alkynes

27

Figure 2.14: Visible-light-induced metal-free C–Si bond formation of electron-poor alkynes (Bolm method) [55].

light in dichloromethane (DCM) solvent to afford the desired silylacylated products (25) (Figure 2.14). The reaction did not require any catalyst, additive, and base. However, the method was very sluggish (3 days to finish). On studying the substrate scope, an extensive range of aromatic substituents on acylsilane aryl group easily responded to the reaction giving a bunch of functionalized enonyl silane derivatives with 94% yields. However, the use of massive ester groups (containing tert-butyl and isopropyl group) afforded lower yields due to steric effects. Most interestingly, the reaction failed when electron-rich alkenes were used. Moreover, terminal alkynes were also inactive in this method. In 2018, another visible-light-induced organocatalyzed C–Si bond formation strategy for both internal and terminal alkynes (24) through hydrosilylation was reported by Yao group (Figure 2.15) [56]. Tris(trimethylsilyl)silane (TTMS) (26), eosin Y, and dioxane/H2O were used as the silylating agent, catalyst, and solvent, respectively. The method was completed at rt under an inert atmosphere. The catalyst was so active that 1 mol% of eosin Y alone generated 99% of the desired alkenylsilane products (27) within just 4 h. However, triisopropylsilanethiol was required to work as a radical quencher. The authors observed that electron-neutral, electron-rich, and electrondeficient systems smoothly responded to the reaction under standard conditions. Readily obtainable chemicals, extensive substrate scope, high selectivity, and high

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2 Metal-free C–Si bond formation reactions

Figure 2.15: Metal-free radical C–Si bond formation of alkynes using eosin Y catalyst (Yao method) [56].

yields were important advantages for this methodology. The authors suggested a photoredox pathway in which radical initiation through SET process occurred.

2.4 C–Si bond formation of allene Only one article is available on metal-free visible-light-mediated C–Si bond formation methodology of allene, which was from Wang collaborator [57] in 2019. In this hydrosilylation method, a mixture of allene (28) (1 equiv.), TTMS (1.2 equiv.), eosin Y (1 mol%), and triisopropylsilanethiol (1.2 equiv.) in dioxane/H2O was irradiated under blue light for 4 h at 36 °C. The reaction was carried out under an inert atmosphere. The desired products 29 containing C–Si bond were formed with 75% yield (Figure 2.16). The reaction possibility was then studied further based on this optimized reaction condition. The reaction tolerated a diverse range of functional groups, such as alcohol, carboxylic acid, ester, acetoxy, and methanesulfonate. It was found that monosubstituted nonarylated allenes smoothly underwent the reaction to afford linear Eallylsilanes, whereas allenes containing 1,3-disubstitutions of electron-deficient groups generated E-alkenylsilanes. On the basis of some control experiments and previous related articles, the authors suggested a radical mechanism for this regio-, chemo-, and stereoselective silylation methodology.

2.5 Silylation of arenes and heteroarenes

29

Figure 2.16: Metal-free photoinduced C–Si bond formation of allenes (Yao method) [57].

2.5 Silylation of arenes and heteroarenes In 2018, Jiang and coworkers [58] enlisted a photomediated radical silylation approach of biarylhydrosilanes (31) for the preparation of a library of dibenzosiloles through dehydrogenative cyclization reaction without using any metal catalyst. This method used 5 mol% rose bengal as the organophotocatalyst, tertbutyl hydroperoxide (TBHP) as the oxidant, KOH as the base, and DCE/H2O as the solvent. The process was completed at rt within 36 h under irradiation with two 25 W CFL. The desired dibenzosiloles (32) were achieved up to 86% yield (Figure 2.17). This reaction did not require any external silylating agent. The use of other organophotocatalysts, such as acridine, fluorescein, methylene blue, and eosin Y, led to inferior yields of desired products. Similarly, the authors checked the efficiency of Ru-photocatalysts, such as Ru(bpy)3Cl2 and Ru(bpy)3PF6, and found that these were not as efficient as rose bengal. KOH worked as the most suitable base among Cs2CO3, 2,4-lutidine, tBuOLi, CsOAc, and KOH. The reaction methodology endured an extensive series of functional groups and hence showed excellent substrate scope. Based on control experiments, earlier literature reports, and quantum yield measurements, the authors confirmed that the reaction mechanism followed a photocatalytic pathway rather than a radical chain process. In 2021, Liu and Sun group [59] accounted a photoinduced metal-free direct C–Si bond formation methodology of quinoxalinones (33). Tertiary silanes (2) were used as a

30

2 Metal-free C–Si bond formation reactions

Figure 2.17: Visible-light-induced metal-free C–Si bond formation of biarylhydrosilanes via dehydrogenative cyclization (Jiang method) [58].

silylating reagent. The reaction needed 4CzIPN (2.5 mol%), quinuclidine (40 mol%), and pyridine that worked as the organophotocatalyst, HAT catalyst, and base, respectively. DMSO/MeCN (3:1) was the most suitable solvent for the reaction. The reaction was carried out in the open air beneath the blue light illumination for 24 h. The corresponding products (34) containing C–Si bond were obtained up to 77% yield (Figure 2.18). A bunch of quinoxalines-2(1H)-ones having N-protected groups, such as cyclopropylmethyl, n-butyl, allyl, propargyl, ester group, aryl, benzyl etc., were welltolerated by this method under optimized reaction conditions. Besides, electrondeficient heteroarenes like benzothiazole, pyridazine, coumarin, [1,2-b]pyridazine,

2.6 Silylation of dienes

31

Figure 2.18: Visible-light-mediated metal-free C–Si bond formation of quinoxalinones (Liu method) [59].

benzoxazinone, imidazoethyl isonicotinate, isoquinoline-4-carbonitrile, and quinoline-4-carbonitrile were also suitable substrates for this reaction affording corresponding silylated products. Various silanes such as triethylsilane and triisopropylsilane responded to the reaction under standard reaction conditions. However, mono-, di-, and triphenylsilane remained unreactive. This method was applied for large-scale synthesis. On the basis of some control experiments and previous literature reports, the authors suggested that the in-situ produced silyl radical regioselectively interacted with the quinoxalinones to afford silylated products.

2.6 Silylation of dienes In the year 2019, Yao group [60] enlisted a photoinduced radical silylative cyclization methodology of aza-1,6-dienes (35) using diphenyl silane (2) as the silylative agent and eosin Y as the organophotocatalyst to synthesize a library of silicon-containing piperidine products (36) with 76% yield (Figure 2.19). However, triisopropylsilanethiol and potassium carbonate were required to generate the highest yields and worked as a radical initiator and base, respectively. The organophotocatalyst rose bengal and rhodamine B although worked, produced lower yields of desired products. Therefore, the authors explored the scope of the substrate for this methodology based on the optimized reaction conditions and observed that an acrylate or acrylonitrile moiety should be present with one of the alkene part. Various substitutions on the other alkene part were well-tolerated by the reaction. Moreover, the smaller size of the silyl group was preferable for the radical 6-exo-trig cyclization reaction. The authors mentioned that dienes having a trisubstituted electron-neutral olefin showing excellent

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2 Metal-free C–Si bond formation reactions

Figure 2.19: Visible-light-mediated metal-free C–Si and C–C bond formation of aza-1,6-dienes (Yao method) [60].

diastereoselectivity. Based on control experiments, DFT calculations, and earlier literature reports, the authors confirmed that 6-exo-trig cyclization proceeded through radical mechanism.

2.7 Synthetic application The visible-light-mediated C–Si bond formation methodology could be applied for various drugs. For instance, an approach for silylation of camptothecin toward the

Figure 2.20: An approach for the synthesis of anticancer drug, DB-67, using metal-free C–Si bond formation methodology.

References

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synthesis of DB-67, an anticancer drug, could be possible by using this metal-free visible-light-induced C–Si bond formation process (Figure 2.20).

2.8 Conclusions Therefore, this article represents an overview on the latest findings and advances in the emerging area of metal-free photo-induced C–Si bond formation reaction. From the discussion of these articles, it is obvious that the light-driven C–Si bond formation methodology is slowly becoming a significant tool in organic chemistry for the synthesis and functionalization of organic molecules with medicinal and industrial importance within a short time in an easier manner. The prodigious features of this elegant strategy include mild and environment-benign reaction conditions, simple operation mode, high synthetic efficiency, and high selectivity. However, some preventive issues such as use of precious reactants, need for stoichiometric amount additive, lower yield formation, generation of side products, and deficiency of proper knowledge on mechanism are known for the limitation of this appealing approach. Most of the research groups employed 4CzIPN and eosin Y as organophotocatalysts, although plenty of organophotocatalysts are known. Therefore, creating new metalfree photoinduced C–Si bond formation methods is very challenging and fascinating. In this circumstance, creating an innovative approach will be extremely welcomed. The employment of only sunlight as an energy source will be very helpful as the external electrical energy will not be required. Moreover, the use of modern methods such as continuous flow processes, batch-reactor, and microreactor technologies could be revolutionary as it could solve long reaction time as well as low percentage yield. In addition, the reaction mechanism should be carefully evaluated. We hope this article will draw attention of young synthetic chemists.

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Tejeswara Rao Allaka, Naresh Kumar Katari and Sreekanth Babu Jonnalagadda*

3 Synthesis of antiviral drugs by using carbon–carbon and carbon–heteroatom bond formation under greener conditions Abstract: Antiviral medications are a branch of medicines notably used to treat that cause many significant diseases in humans and animals. This monograph mainly focuses on recent developments and synthesis of antiviral drugs using carbon-carbon and carbon–hetero bond cross-coupling chemistry. Viral infections exact several severe human diseases, accounting for remarkably high mortality rates. In this sense, academia and the pharmaceutical industry continuously search for novel compounds with better antiviral activity. The researchers face the challenge of developing greener and economical ways to synthesize these compounds and make significant progress. Keywords: antiviral drugs; C–C & C–heteroatom formations; chiral molecules; COVID-19; green chemistry; nucleic acid synthesis.

3.1 Introduction Viruses especially, RNA viruses effective the World Health Organisation (WHO) in current list of 10 global health threats. The list includes AIDS caused by the human immunological disorder virus (HIV), dengue virus, a worldwide contagious disease pandemic and viral infections caused by the haemorrhagic fevers and Ebola virus, Nipah virus, Zika virus, severe acute respiratory syndrome corona virus, Middle Eastern respiratory syndrome corona virus and disease X [1]. These days illness X is definitely COVID-19, caused by SARS-CoV-2, a corona virus closely associated with SARS-CoV-1 that almost evidently emerged as an animal disease from horseshoe bats in China [2]. The SARS-CoV-2/COVID-19 pandemic has more disclose the lack of antiviral

*Corresponding author: Sreekanth Babu Jonnalagadda, School of Chemistry & Physics, College of Agriculture, Engineering & Science, Westville Campus, University of KwaZulu-Natal, P Bag X 54001, Durban 4000, South Africa, E-mail: [email protected]. https://orcid.org/0000-0001-6501-8875 Tejeswara Rao Allaka, Centre for Chemical Sciences and Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500085, India Naresh Kumar Katari, Department of Chemistry, School of Science, GITAM deemed to be University, Hyderabad, Telangana 502 329, India; and School of Chemistry & Physics, College of Agriculture, Engineering & Science, Westville Campus, University of KwaZulu-Natal, P Bag X 54001, Durban 4000, South Africa, E-mail: [email protected] As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: T. R. Allaka, N. K. Katari and S. B. Jonnalagadda “Synthesis of antiviral drugs by using carbon–carbon and carbon–heteroatom bond formation under greener conditions” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0089 | https:// doi.org/10.1515/9783110759549-003

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scaffolds that may be quickly mobilized and deployed for the treatment of re-emerging or rising viral diseases [3]. Here, this status of antiviral therapies, highlighting methods for combatting EBOV inflicting unwellness and COVID-19, targets for antiviral discovery and discuss the challenges, solutions and choices to accelerate antiviral drug revelation efforts. Most current antiviral targets like purine and pyrimidine derivatives reverse polymerase inhibition to dam the transcription of HIV RNA genome to deoxyribonucleic acid and hence preventing synthesis of viral microorganism ribonucleic acid and proteins (Figure 3.1) [4]. OC43, HKU1, 229 E and NL63, four corona viruses primarily linked with common cold-like symptoms, are endemic in humans, whereas three highly pathogenic zoonotic corona viruses arose in the last two decades, causing epidemics and a pandemic. The severe acute respiratory syndrome corona virus (SARS-CoV) was found in China’s Guangdong province in 2002 and spread to five continents via air transport routes, infecting 8000 individuals and killing 0.8k people before disappearing in 2004 [5, 6]. The novel Corona virus sickness is an epidemic disease that appeared at the end of 2019 with a dramatic increase in number and became known as a pandemic disease caused by a viral infection, prompting most governments to conduct an urgent search for new anti-SARS-COV vaccines and treatments. A variety of clinical trials are currently underway around the world on several medications that use distinct mechanisms of action, such as hydroxychloroquine, favipiravir, and remedisvir. Favipiravir will be

Figure 3.1: Important plot of action on current antiviral agents.

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one of the developed, potentially authoritative pharmaceuticals that will provide benefits to humanity with large-scale manufacture to fulfill the demands of the current pandemic Covid-19 and future epidemic outbreaks [7]. For the first time, researchers used electron microscopy to map the 3D shape of spike proteins that are parts of intact SARS-CoV-2 particles such as ACE2, which are used to gain entry to cells. The spike glycoprotein of the corona virus mediates entry into host cells and is made up of two functional subunits that mediate attachment to host receptors (subunit S1) and membrane fusion (subunit S2) [8]. The S homotrimer is a focus of therapeutic and vaccine design efforts because it is prominently exposed at the viral surface and is the major target of neutralising antibodies [9, 10]. Green chemistry prefers those routes that in addition provides waste reduction, nontoxic reagents high safety standards, solvents, and systematic use of energy and resources (Figure 3.2) [11]. The improvement of C–C bond and C–heteroatom (C–N, C–O and C–P) condensed and coupling reactions could be a field of great interest and has received historic attention in modern organic as well as medicinal chemistry [12]. These reactions are exploited within the synthesis of agrochemicals, prescribed drugs and molecules of interest in materials science. With the increasing awareness of worldwide warming and also the use of renewable energies, it’s of overriding importance to scale back the usage of precarious chemicals in each academic, industrial analysis and to realize healthier surroundings through greenish practices. Green chemistry could be a rapidly promising technique that shows a path for the property future development of science and technologies. Specific conditions for aqueous transformations are reviewed for Hiyama’s, Mizoroki–Heck, Stille’s, Suzuki–Miyaura, Negishi’s and

Figure 3.2: The key merits of green synthesis.

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Sonogashira–Hagihara reaction etc., It emphasizes the exceptional practices and major advances achieved exploitation various inexperienced tools like microwave irradiation (MW), ultrasound irradiation, and high-speed ball milling (HSBM) techniques, and a range of green solvents and reusable catalysts with attention to water. Many HIV-1 protease inhibitor medication are created accessible within the human clinical use of Nelfinavir and CoVs was found to powerful inhibit the replication of SARS-CoV [13–15]. Antiviral agents (lopinavir, ritonavir and ribavirin), type I interferon, steroids and proteins are referred to as immunoglobulins, and convalescent plasma are utilized in the clinical helpful of Middle East respiratory syndrome corona virus (MERS) and severe acute respiratory syndrome (SARS) patients. Many metabolites were isolated from the plant organ of G. Sinnense was construct that 20-hydroxylucidenic acid N, 20(21)-dehydro lucidenic acid N and ganoderic acid GS-2 showed a high potential of HIV-1 proteolytic enzyme activity [16]. Various scaffolds reveal a inhibitory activity against HIV-1 protease enzyme have been identified from Ganoderma lucidum as well as 3β-5α-dihydroxy-6β-methoxyergosta-7,22-diene, ganolucidicacid A, ganodericacid β, gano dermanontriol and ganodermanondiol [17]. Moreover, adenosine has isolated from golden cordycep, and Ganomycin B isolated from G. colosum, ganomycin I and colossolactones have displayed anti HIV-1 protease inhibitor activity [18]. Notably, heliantriol F extracts from lignosus rhinoceros and exhibited restrictive activity against HIV-1 proteolytic enzyme activity [19] (Figure 3.3). Chiral molecules are a very important role in developing new drugs as individual stereo isomers could exhibit marked variations in toxicological, pharmacokinetic and pharmacodynamic properties [20]. Thus, there is significant interest in absolutely characterizing and examining of latest drug development within the pharmaceutical industries and develop de novo enantiomeric pure compounds with their mechanism

Figure 3.3: Compounds against HIV-1 protease inhibitory activity.

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of action (Figure 3.4) [21, 22]. Most approved antiviral drug targets are plays an essential role in RNA or DNA polymerase inhibitors and can be divided into nucleoside analogues and non-nucleoside allosteric inhibitors. All osteric inhibitors bind the enzyme however not at the chemical action situation; inflicting conformational changes that impair enzyme perform. Examples represent the HIV non-nucleoside reverse transcriptase inhibitors (doravirine), anti-HIV nucleoside reverse transcriptase inhibitor (thymidine analogue), acyclic guanosine analogue (acyclovir), RNA-dependent RNA-polymerase antiviral drug (remdesivir), and COVID-19 treatment antiviral inhibitor (ribavirin) [23]. Ribavirin and favipiravir against HCV, saquinavir as HIV protease inhibitors and coumarin scaffold. Tipranavir is used in treating papain like protease and chymotrypsin like proteases (Figure 3.5) [24]. Some of the important entries of antiviral agents that non-enzymatic viral processes such as an antagonist of the host cell co-receptor CCR5 (Maraviroc), biomimetic peptide that inhibits fusion (Enfuvirtide), and a nonimmunosuppressive humanized monoclonal antibody (Ibalizumab) that performs as a post attachment constraint that secure the host CD4 primary receptors [25]. SARS-CoV-2 entry needs the S super molecule, that acknowledges the host cell ACE2 receptor and is primed by host cell protease providing a multiple potential antiviral methods including a clinically proven TMPRSS2µ substance, A1AT etc. [26]. Xiuhai Gan and co-team discovered the chalcone derivatives and evaluated in vivo antiviral activity against TMV, whereas compounds 1, 2, 3 and 4 exhibited superior curative activity with EC50 29.2, 32.8, 29.6 and 38.4 µg/mL values, respectively

Figure 3.4: Some of the selected chiral antiviral drugs.

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Figure 3.5: Some of examples of polymerase and protease inhibitors.

(Figure 3.6) [27]. Among the broad variety of heterocyclic compounds containing benzothiazole or 2-pyridones have attracted a great attention in medicinal and pharmaceutical industry due to their large number of biological active molecules. Some of the natural compounds containing a 2-pyridone ring have incontestable efficiency as antiviral and antitumor agents like camptothecin (CTP) and fredericamycin A, whereas compound ABT-719 exhibited a broad spectrum of antibacterial activity against Gram-(−ve) and Gram-(+ve) microorganisms including methicillin resistant staphylococcus aureus (MRSA) [28, 29]. The productive clinical medicine containing the benzothiazole nucleus, like riluzole, frentizole, ethoxzolomide, thioflavin T and zopolrestat are measure utilized in the treatment of varied diseases and disorders [30]. Further investing of novel synthesized benzo [d]thiazolyl-2-pyridones were tested in vitro antiviral activity opposed to DNA, RNA virus, such as adenovirus type 7 (HAdV7), Coxsackie virus B4 (CBV4), hepatitis A virus (HAV) HM175, herpes simplex virus type 1 (HSV-1) and HCV cc genotype 4. Sharma et al. [31], prepared final scaffolds 5, 6 and 7 reveals promising antiviral activity against DNA, RNA viruses with mean of reduction 16.7–26.7%, 16.7–23.3% and 23.3–50.0%, respectively (Figure 3.6). Corona virus is encompassing form of RNA viruses widespread in humans, birds and different mammals. Numerous pharmaceutical firms and researchers are measure specializing in the event of vaccines and medicines to conflict this deadly virus. Goktas

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Figure 3.6: Some of the important synthesised antiviral compounds.

and co-team [32] improved a synthesis novel sequence of 4-azaspiro [4.5]decan4-carboxamide scaffolds by microwave irradiate technique and biological studies in MDCK cell cultures towards influenza A and influenza B virus (H3N2 and H1N1) and from screening results that compound 10 demonstrated interesting antiviral activity towards influenza A virus [EC50 = 1.4 μM]. Chen and co-team [33] explained a novel class of one-pot protocol of 4-thiazolidinones by using microwave method and evaluated antiviral activity against HIV-1 reverse transcriptase and thiazolidinones (E)-2-(1,3-dichlorobuta-1,3-dien2-yl)-3-(4-ethyl-3,5-dimethylphenyl)thiazolidin-4-one 8, 2-(2-chloro-6-fluorophenyl)-3(4-ethyl-3,5-dimethyl phenyl)thiazolidin-4-one 9, exhibited good antiviral activity inhibition with IC50 0.26 and 0.23 μM, respectively. Sriram and co-authors [34] have been prepared novel series of diaryl-4-thiazolidinones via microwave induced techniques and the synthesized scaffolds (Z)-2-(but-2-en-1-yl)-3-(4-fluorophenyl) thiazolidin-4-one 11 exhibited potent anti-YFV activity with EC50 value 6.9 μM (Figure 3.7). Moreover, the importance of heterocyclic derivatives with their antiviral activity, Roberta L and co-team [35] recently established N-1,3-diphenyl-pyrazolyl methyl aniline derivatives are active against human respiratory syncytial virus (RSV). Whereas the prepared scaffolds 4-bromo-N-((3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methyl)aniline 12, 4-chloro-N((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methyl)aniline 13, N-((3-(4-chlorophenyl)1-phenyl-1H-pyrazol-4-yl)methyl)-4-methylanilines 14 exhibited highest antiviral activity against DENV-2 [EC50 = 23.0 ± 6.0, 14.5 ± 3.5, 11.1 ± 1.6 µM] and WNV viruses [EC50 = 80.0 ± 8.5, 57.5 ± 0.5, 39.0 ± 1.0 µM, respectively] (Figure 3.7).

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Figure 3.7: Thiazolidinone, pyrazole derivatives and their antiviral activity.

3.1.1 Synthesis of antiviral compounds by using green chemistry Mechanochemistry synthesis of C–C bond is associate atom economic, time efficient, energy efficient and sensitive synthesis of C–C bond is usually desired. The solvent free mechanomilling methodology also can be a very important alternative to replace traditional hand grinding strategies with improved energy and time potency. During this section a number of the most important C–C bond forming reactions and their advantages are discussed [36]. Raston and Scott co-authors [37] was reported aldol condensation for the preparation of α,β-unsaturated ketones by using veratraldehyde, 4-phenylcyclohexanone and 1-indanone within the presence of NaOH in oscillate ball mill as shown in Figure 3.8. However, Guillena and co-workers [38] was reported the asymmetric synthesis of aldol condensation between different carbonyl compounds (ketones & aldehydes) under solvent free conditions were performed employing a combination of (S)-binam-L-Proline, (S, S)-dipeptide and benzoic acid as organo catalyst (Figure 3.8). Whereas Wang and co-workers [39] have been reported the first synthesis of α, ß-unsaturated ketones from a Michael reaction between 1,3-dicarbonyls 19, 20 and chalcones, azachalcones using the mild base K2CO3 at high speed vibration mill (HSVM) (Figure 3.8). Moreover, Bolm and co-workers [40] reported (S)-benzyl-3-(1(tert-butyl)piperidin-3-yl)thiourea based on organo catalytic asymmetric version 23 for α-nitro cyclo hexanone 21 and nitro alkenes 22 could undergo a Michael addition reaction under planetary milling conditions to desired product (Figure 3.8). The Morita– Baylis–Hillman reaction engages electrophile aldehydes, olefins, and tertiary amines to give multifunctional products. The reaction between methyl acrylate 24 and different substituted aryl aldehydes 25 in the presence of catalyst 1,4-diazabicyclo [2.2.2]octane (DABCO) at 0.5–5 h to provide MBH product 26 in 98% yield (Figure 3.8) [41]. Pecharsky and co-workers [42] reported the free solvent Wittig reaction (entry 27) of aldehydes or ketones with organo halides, phosphonium salts and phosphorus halides

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Figure 3.8: Formation of C–C bond reactions.

from triphenylphosphine in the presence of K2CO3 (Figure 3.9) Furthermore, Peter and co-authors [43] have described the Pd catalyzed Suzuki coupling reaction (entry 28) between aryl halide, phenyl boronic acid, K2CO3 and Pd(PPh3)4 under ball-milling conditions with 96% yield and NaCl was used an additive to construct the reaction mixture sufficiently stable product (Figure 3.9). Li and co-workers [44] was expanded a liquid assisted grinding technique for Suzuki–Miyaura coupling reaction by aryl chlorides, boronic acids to getting the biaryls in quantitative yield (entry 29). Under the optimized conditions of 4 mol% of PCy3·HBF4, 2 mol% Pd(OAc)2 and excess of K2CO3– MeOH for 1.5 h to get biaryls with excellent yield (90–97%) (Figure 3.9). Frejd and coteam [45] have been reported the mechanochemically Heck reaction expressed that (E)-stilbene scaffolds 30 was prepared by the coupling reaction between styrenes and aryl halides in the presence of Pd(OAc)2, K2CO3 (Figure 3.9).

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Figure 3.9: Synthesis of C–C bond reactions from different conditions.

Stolle et al. [46] was reported a Sonogashira coupling reaction under ball milling processes in the absence of Cu or Pd(OAc)2 or Pd(PPh3)4, or 1,4-diazabicyclo [2.2.2] octane, different aryl halides and acetylenes to obtained the product 31 (Figure 3.9). Moreover Su and co-workers [47] was reported a copper catalyzed mechanochemical dehydrogenative coupling reaction between tetra hydro isoquinolines, alkynes and indoles under the efficient oxidants DDQ, SiO2 respectively (entry 32a, b) (Figure 3.9). Bayat and co-team [48] described an efficient synthesis of 2,2′-arylmethylene bis3-hydroxy-5,5-dimethyl-2-cyclohexene-1-ones (entry 33) from dimedone and various

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aromatic aldehydes in water conditions (Figure 3.10). Meanwhile, Li and co-authors [49] describes a direct C–C coupling reaction via nucleophilic substitutions of indoles and 1,4-benzoquinones gives 3-indolyl-1,4-benzoquinones (entry 34) and bis-indolyl1,4-benzoquinones (entry 35) at rt (96–99%) (Figure 3.10). Meshram and Thakur [50] explained “on water” C–C coupling reactions involving the nucleophilic additions of thiazolidinones or oxindole with isatin and the novel diastereoselective synthesis of 3-thiazolidinones or 3-hydroxy-2-oxindoles (entry 36 & 37) without the aid of catalyst (Figure 3.10). Kaldas and co-authors [51] had reported a light mediated process for the preparation of organo free radicals from unactivated bromo alkanes/arenes and Au(I) photo catalyst under the MeCN conditions to obtained different substituted indoles (entry 38) (Figure 3.10).

Figure 3.10: Synthesis of indole linked to thiazolidinone compounds.

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An efficiently catalyzed reactions of p-dodecyl benzenesulfonic acid (DBSA) with cyclic ketene dithioacetals and substituted secondary alcohols in water conditions for overnight to obtained corresponding Friedel–Crafts alkylated derivatives 39 (Figure 3.11(a)) [52]. Several methods are notable in the literature for the conventional three-component Mannich reactions, whereas Kobayashi and co-team [53] employed DBSA for the synthesis of Mannich adduct by using aldehydes, amines, ketones and water at ambient temperature (entry 40) (Figure 3.11(b)). The same as the above reaction

a

b

c

d

e

f

Figure 3.11: Formation of C–C bond under greener conditions.

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have been derived by p-toluene sulfonic acid as catalyst didn’t give absolute product, whereas the synthesis of another type of Mannich base 41 in the presence of DBSA conditions and silylenolates instead of ketones representing in Figure 3.11(c) [54]. Moreover Jin et al. [55] also support and move the same reactions of 1,3-cyclohexanedione with dimedone using same catalyst, which is provided the corresponding xanthene compounds (42) under water conditions (Figure 3.11(d)). This group also prepared bis1,8-dioxo-octahydroxanthenes (43) from one equivalent of terephthal aldehyde and four equivalents of 1,3-cyclohexanedione or dimedone bearing of p-dodecyl benzenesulfonic acid in water conditions (Figure 3.11(e)) [56]. The catalytic applications of p-dodecyl benzenesulfonic acid was further investigated by Jin and co-group [57], one-pot three components preparation of 6-amino-5-cyano-1,4-dihydropyrano [2,3-c]pyrazole (44) by using malononitrile, aromatic aldehydes, and methyl phenyl-pyrazolinone in aqueous medium (Figure 3.11(f)). From these mild reaction conditions, use of green solvent, metal free catalyst and high atom economy are the mainly advantages of this succeeded protocol. The benefits of chiral auxiliaries is another concept for considered in particularly when the ion attached prolinol have been found to get the enantio selective alkylation of aldehydes and organometallic compounds in ionic liquids present in Figure 3.12. In the same manner, it was denoted that many 4-acyloxyproline scaffolds (46) are the direct asymmetric aldol condensation between benzaldehyde and cyclic ketones were taken in water and to be recycled (Figure 3.12) [58]. Moreover the synthesis of diterpenes from an enantiomerically pure diketone which is a cheap starting material [59]. Whereas, Ultrasounds have been infrequently used, but a numerous of reports are available varying from the acceleration of a Knoevenagel condensation [60] to the production of lanthanide complexes are able to promote the nucleophile addition reaction as shown in Figure 3.12 [61]. Different physical properties like electrochemistry and photochemistry have a insignificant role, and also distinguished by the vary mild conditions in particularly in the former case and did not have any thermal counterpart. Furthermore, we reported the synthesis of 5- and 6-membered scaffolds by using Kolbe electrolysis and the photochemical formation of cyclo butanes (50) through environmental friendly radical cyclizations (Figure 3.12) [62, 63].

3.1.2 Contribution of organic electrolysis synthesis to green chemistry Electrolysis offered a C–C bond formations and functional group inter conversions (FGIs) for all the compounds are electroactive or can react with electro generated reagents. This chapter shows a short overview about the principles, synthesis of C–C bond and C–heteroatom coupling reactions employed in aqueous medium. Aromatic compounds could be a coupled intermolecular or intramolecular at the anode and exhibited the oxidation reactions towards cation radical. Radical coupling with

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Figure 3.12: Examples for enantio selectivity of green synthesis.

following deprotonation shows to biaryls and losses of electron create the benzyl cation, which is react with aromatic compound to obtained diphenylmethane 52 (Figure 3.13) [64]. Another one example for anodic coupling reaction for the compounds 1,3,5-trimethylbenzene 53 and 1,2,4,5-tetramethylbenzene 54 present in Figure 3.14 [65]. Moreover, one-pot cross coupling reactions of 4-methylguajacol and aryl ethers to offered unsymmetrical biaryls without using activating auxiliaries (entry 55) (Figure 3.15) [66]. Indirect electrolysis is way of the reduction or oxidation with stoichiometric amounts of valuable chemical targets becomes more or less catalyst, improves the ecology and economy of the conversion. Applications of indirect electrolysis are the oxidation of 4-methoxy toluene with Ce4+ mediator to give 4-methoxy benzaldehyde 56 (Figure 3.16) [67]. Further investigation, Ni(III) oxide electrode is useful mediator in alkaline medium and a wide variety of indirect oxidations and does not release nickel ions into solution [68]. Moreover, Ni(0) metal complexes are formed from cathodic reduction of nickel(II) salts and used as mediators for the formation of aryloxy

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Figure 3.13: Formation of biaryls and/or diphenylmethanes by using intermolecular coupling reaction.

Figure 3.14: Anodic coupling reactions for 1,3,5-trimethylbenzene and 1,2,4,5-tetramethylbenzene.

Figure 3.15: One-pot anodic coupling reaction without any activating auxiliaries.

carboxylic acid 58, which was reaction between aromatic substituted halides and CO2 (Figure 3.16) [69]. A great number of researchers have been worked on the development, efficient syntheses, and biological activities of acridone core and Ullmann synthesis [70]. This reaction involves the thermal condensation of ortho-halo benzoic acid with substituted aniline to desired substituted phenyl anthranilic acid by using Cu-acetate, potassium acetate, Et 3N and 2-propanol in water. Further the cyclization of substituted anthranilic acid under acid conditions, copper, K2CO3 in dimethyl formamide and the reaction carried out under reflux conditions for 2 h (entry 59) (Figure 3.17). Moreover, Taraporewala et al. [71] designed, synthesis of marine pyrido

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Figure 3.16: Indirect anodic oxidations and cathodic reductions.

thiazolo [5,4-b]acridine 60 as antitumor, antiviral agents and was obtained from 2,3-diaminoacridone and excess of cyanogen bromide (Figure 3.18). To the continues for the preparation of 1,3-dihydroxy acridone derivatives 61 which displayed important antiviral properties and the reaction was performed an equimolar of orthoaminobenzoic acid, phloroglucinol in the presence of ZnCl2 and n-butyl alcohol (Figure 3.19) [72]. The synthesis of fused heterocyclic aglycons was retrieved from 4,6-dichloro pyrimidine, (TMP)2Zn·2MgCl2·2LiCl were coupled with corresponding iodo heterocycles i.e., Negishi cross-coupling reaction to desire 4,6-dichloro-5-hetarylpyrimidine. In addition the reaction between 4,6-dichloro pyrimidine and 2- or 3-iodofuran in THF by Pd(PPh3)4 to obtained furan substituted pyrimidines followed by lithiation/NaN3 to

Figure 3.17: Synthesis of acridone ring by using Ullmann reaction.

Figure 3.18: Synthesis of tetracylic derivatives.

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Figure 3.19: Preparation of 1,3-dihydroacridone derivatives.

give the corresponding pyrrole, furan analogues (Figure 3.20) [73]. The pyrrolyl azides was efficiently cyclized with 1,4-dibromobenzene under reflux conditions for 5 min to affording desired pyrrolo pyrimidines in good yields, whereas furan analogue is utilizing UV cyclization in TFA degradation of starting material. Pyrrolo pyrimidines are treatment with 1 eq. TMSOTf at 80 °C for 1.5 h allowed to prepare final benzoylated fusedpyrrole 7-deazapurine nucleosides 62 and 63 as pure ß-anomers (Figure 3.20) [74]. Rohloff and co-workers [69] was discussed the total synthesis of phosphate salts with (−)-Oseltamivir is mainly depends on two natural products, (−)-Shikimic acid and (−)-Quinic acid which is difficult to be employing in industrial scale quickly and cheaply. The key intermediate 3,4-pentyline ketal was taken in pentyl ether to form a epoxide, further it was converted to azido alcohol, and formation of aziridine and finally azide was diminishes to amine and Oseltamivir. H3PO4 was isolated (Figure 3.21). Pierce et al. [70] reported an enantio selective synthesis of Efavirenz, this reaction involves the addition of cyclopropyl acetylide, trifluoromethyl ketone in the presence of amino alcohol, (1R, 2S)-N-pyrrolidinylnorephedrine, then the reaction was converted into benzoxazinone and deprotection takes place by ceric ammonium nitrate

Figure 3.20: Synthesis and antiviral and cytotoxic profile of 7-deazapurine ribonucleosides.

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Figure 3.21: Synthesis of (−)-Oseltamivir with phosphate salt.

allow Efavirenz (72%) (Figure 3.22). Chandler and co-workers [71] synthesis of antiviral drug Zanamivir by using acetylneuraminic acid, which was converted into methyl ester and acetylation of hydroxy groups. Meanwhile, the acetylated protecting group was removed by sodium methoxide, following hydrolysis of methyl ester with aq. TEA to desire the triethylammonium salt, and it again hydrogenated in presence of Lindlar catalyst to obtained zanamivir in good yields (Figure 3.23). In 2021, Gannedi and coteam [72] derived a one-pot synthesis of remdesivir from the stereo isomeric of phosphorus compounds via employing an imidazolyl derived catalyst, p-TSA and methanol was employed at rt to afford diastereoisomer (73%) (Figure 3.24).

Figure 3.22: Preparation of Efavirenz.

Figure 3.23: Synthesis of antiviral drug zanamivir.

References

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Figure 3.24: Synthesis of remdesivir by imidazolyl catalyst.

3.2 Conclusions Carbon–carbon, carbon–heteroatom forms the “backbone” of each organic molecule, and is essentially thought to be the key transformation in organic synthesis to line up the carbon backbone of organic particles. It is unnecessary to say that the C–C bond formation is always one of the most useful for fundamental reactions within the development of organic and medicinal chemistry. Viral infections cause several serious human diseases, being manages for remarkable high mortality rates. During this sense each the academy and the pharmaceutical trade area incessantly looking for new compounds with their antiviral activity, in addition face the challenge of evolving greener and most efficient methods to preparing of these targets. In this book chapter, we have summarized the development in asymmetric, chiral, normal synthetic methods of anti-virals root on green conditions and especially dominant for the developing countries, authorizing local drugs manufacture with the result of improving effusion to medicines. Acknowledgments: One of the authors (TR Allaka) is thankful to CCST, IST, JNTUH University, and Hyderabad for providing laboratory facilities and financial support.

References 1. Friedrich MJ. WHO’s Top Health Threats for 2019. JAMA, J Am Med Assoc 2019;321:1041. 2. Boni MF, Lemey P, Jiang X, Lam TTY, Perry B, Castoe T, et al. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat Med 2020;5:1408–7. 3. Andersen PI, Ianevski A, Lysvand H, Vitkauskiene A, Oksenych V, Bjoras M, et al. Discovery and development of safe-in-man broad-spectrum antiviral agents. Int J Infect Dis 2020;93:268–76. 4. Safrin S, Chambers HF. Basic & Clinical Pharmacology, 7th ed. Katzung BG, editor. Stamford, Connecticut: Appleton & Lang; 1998:788–802 pp. 5. Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003;348:1967–76.

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Rajesh Kumar, Jyotirmoy Maity, Divya Mathur, Abhishek Verma, Neha Rana, Manish Kumar, Sandeep Kumar and Ashok K. Prasad*

4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne C–N bond formation Abstract: Modified nucleosides are the core precursors for the synthesis of artificial nucleic acids, and are important in the field of synthetic and medicinal chemistry. In order to synthesize various triazolo-compounds, copper and ruthenium catalysed azide–alkyne 1,3-dipolar cycloaddition reactions also known as click reaction have emerged as a facile and efficient tool due to its simplicity and convenient conditions. Introduction of a triazole ring in nucleosides enhances their therapeutic value and various photophysical properties. This review primarily focuses on the plethora of synthetic methodologies being employed to synthesize sugar modified triazolyl nucleosides, their therapeutic importance and various other applications. Keywords: anticancer activity; antiviral; azide-alkyne; click chemistry; Triazolo-nucleoside.

4.1 Introduction Nucleosides are the building block of DNA and RNA and it has a long and rich history in the field of drug discovery [1]. During the past few decades, numerous modified and carbocyclic nucleosides had been synthesised and plenty of these molecules demonstrated various pharmacological properties namely antiviral, antibacterial and anticancer, etc. [2]. Presently, more than 30 nucleoside/nucleotide analogue drug candidates are available in the market and are being efficiently used for treating viral, parasitic, fungal and bacterial infections. Many candidates of this class are currently at the stage of clinical and preclinical trials of drug discovery and development [1, 3]. In search for new clinically useful nucleoside analogous, introduction of a triazole

*Corresponding author: Ashok K. Prasad, Department of Chemistry, Bioorganic Laboratory, University of Delhi, Delhi, India, E-mail: [email protected]. https://orcid.org/0000-0003-2350-4984 Rajesh Kumar, Department of Chemistry, R.D.S. College, B.R.A. Bihar University, Muzaffarpur, India Jyotirmoy Maity, Department of Chemistry, St. Stephen’s College, University of Delhi, Delhi, India Divya Mathur, Department of Chemistry, Daulat Ram College, University of Delhi, Delhi, India Abhishek Verma, Neha Rana, Manish Kumar and Sandeep Kumar, Department of Chemistry, Bioorganic Laboratory, University of Delhi, Delhi, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: R. Kumar, J. Maity, D. Mathur, A. Verma, N. Rana, M. Kumar, S. Kumar and A. K. Prasad “Green synthesis of triazolo-nucleoside conjugates via azide–alkyne C–N bond formation” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0090 | https://doi.org/10.1515/9783110759549-004

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Figure 4.1: Ribavirin A and Zidovudine B are antiviral drugs.

moiety into nucleosides to expand their medicinal impact for drug design [4]. Ribavirin (A) (Figure 4.1) is the first FDA approved triazole based nucleoside drug, which is used against HCV and the progress of azidothymidine (AZT, B) (Figure 4.1) is used as HIV [5]. These results revealed that triazole moiety when attached on various positions of nucleoside analogues such as nucleobase and carbohydrate ring [6], are known to be highly potential and possess biological activities such as antifungal [7], antibacterial [8], antiviral [9], and anticancer [10], activities. Besides this, various triazolyl nucleoside analogues were found to show photophysical properties and other applications [11, 12]. Certainly, triazolyl nucleosides and their derivatives would be a promising candidate for future drug development. In 1960s, Huisgen et al. [13] synthesized triazole rings via 1,3-dipolar cycloaddition reaction between azides and alkynes under thermal conditions. The concept of synthesizing triazole heterocyclic ring via copper-catalyzed azides-alkynes cycloaddition (CuAAC), which is also known as “click chemistry” was established first by Medal and then by Sharpless [14]. It offers a simple and regioselective 1,4-isomeric product under mild reaction conditions. Afterwards, Jia group also developed regioisomer 1,5-disubstituted triazolyl product via ruthenium catalysed azide–alkyne cycloaddition (RuAAC) [15]. It is important to understand that the evolution of click chemistry has provided a golden platform in drug discovery and development [4a, 16, 17] such as lead discovery through target-templated in vitro chemistry, combinatorial chemistry, and bio-conjugation process. Owing to the unprecedented application of triazolyl nucleosides in pharmacological applications, in this article, we have elaborated and discussed the various synthesis routes for facile and efficient synthesis of these molecules as well as biological applications of modified/artificial nucleosides with triazole moiety attached to the carbohydrate portion such as at C-1′, C-2′, C-3′, C-4′ and C-5′ positions of the nucleoside.

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63

Figure 4.2: Synthesis of various 1,2,3-triazolyl nucleosides.

4.2 Synthesis 4.2.1 Synthesis of C-1′ triazolo-nucleosides Click reaction is a very significant and efficient tool for the preparation of desired heterocyclic triazole nucleosides. Earland et al. [18] synthesized triazole nucleosides 3 and 4 (Figure 4.2) from easily available starting material methyl 4-hydroxy-2-butynoate (1) and benzoyl protected ribofuranosylazide (2) with little or no solvent at 50–70 °C by stirring them for 5–7 days. However, when methanol to the reaction mixture, the predominant isomer was 3 in 60% crystalline yield. Further, 8-aza-3-deazaguanosine 5 was synthesized from nucleoside 3 in six steps (Figure 4.2). Naturally occurring guanosine analogues exhibit biological and chemotherapeutic activities [19] and therefore, Panzica research group [20] synthesized β-D-ribofuranosyl triazolo nucleoside 7 from compound 3 in two steps. The synthesized analogue, nucleoside 7 was good resistant to catabolism by nucleoside phosphorylase. In vitro, nucleoside 7 was evaluated for growth inhibitory activity against B16 melanoma cells and murine L1210 leukemia and it showed ID50 > 50 μg/mL towards both cell line. In 1999, Panzica research group [21] synthesized 2′-deoxy-2,8-diaza-3-deazainosine (8) and

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Figure 4.3: Synthesis of triazolo linked carbanucleosides.

2′,3′-dideoxy-2,8-diaza-3-deazainosine (9) starting from β-D-ribofuranosyltriazolonucleoside (7) in several steps (Figure 4.2). Further, 2′,3′-dideoxynucleoside (9) was evaluated against HIV-1 grown in CEM-SS cells and was not cytotoxic from 6.00 × 10−8 to 2.00 × 10−4 in concentration. Saito et al. [22] synthesized the triazolo linked carbanucleoside analogues of ribavirin and evaluated against hepatitis C virus (HCV). The synthesis of desired ribavirin analogue nucleosides 12–14, 19, 21 and 23 (Figures 4.3 and 4.4) was started from epoxide (10). The opening of the epoxide ring of compound 10 was carried out by NaN3, which gave compound 11 in 79% yield, followed by reaction with methylpropiolate under 1,3-dipolar cyclo addition reaction to afford nucleoside 12 in 66% yield. Reaction of 2-cyanoacetamide with azido compound 11, gave corresponding compound 14 in 97% yield. Ammonolysis of compound 12 afforded the amide analogue 13 in 97% yield (Figure 4.3). For the synthesis of the phosphono carbanucleosides 19, 21 and 23 (Figure 4.4), epoxide (10) was treated with tosyl chloride and the subsequent activation with sodium iodide afforded compound 15 in 77% yield. It was reacted further in THF solvent with lithium salt to produce the corresponding phosphonoepoxide (16) in excellent (90%) yield. Compound 16 with sodium azide aqueous methanol produced the azide 17 in good yield, which when reacted with methyl

Figure 4.4: Synthesis of triazole linked phosphonocarbanucleosides.

4.2 Synthesis

65

propiolate and 2-cyanoacetamide yielded the nucleoside 18 and 22, respectively. Finally unmasking of nucleosides 18 and 22 in dichloromethane with bromo trimethylsilane afforded the corresponding free phosphonic acid desired compounds 19 and 23 in approximately 98% yield (Figure 4.4). Ammonolysis of 18 and its subsequent deprotection gave amide analogue 20, which could also be produced directly from 19 in 94% yield with methanolic ammonia solution. The synthesized compounds 12–14, 19, 21 and 23 were tested in vitro for their antiviral activities. Out of the tested nucleoside analogues, only compounds 14 and the phosphonate 22 were observed to show moderate anti-HIV activity. Further, nucleosides 14 and 22 exhibited no cytotoxicity against PBM, CEM or VERO cells. Joubert et al. [23] described the synthesis of triazolo-3′-deoxycarbanucleosides and their analogues and developed Sonogashira reaction using transition metal Pd(0) to achieve cyclic products. The azido compound 24 was achieved from a malonic synthesis [24] and through cycloaddition reaction using the 2-cyanoacetamide and followed by peracylation nucleoside (25) was obtained in good yield (Figure 4.5). On changing, C-5 position of triazole moiety in 25 into an iodine group, it was converted into 26, by using isoamyl nitrite in diiodomethane. Consequently, Sonogashira reaction was applied on 26 to achieve C-5-alkynated nucleosides 27a–i in 44–77% yields. Further, deacetylation using sodium methoxide in methanol at room temperature afforded the corresponding desired nucleosides 28a–i. 8-Aza-3-deazapurine analogue 29h was structurally related to the group of 3-deazapurine family, which exhibited antiviral, antitumor, or antibacterial activities [25]. Ring closure and deacetylation was consequently applied on nucleosides 27a–i with aqueous dimethylamine and ethanol at 80 °C to furnish the nucleosides 29a–h in 56–72% yields (Figure 4.5). When the desired nucleosides were checked in human PBM cells infected with HIV-1LAI [26], 28h was the only one that exhibited moderate anti-HIV activity, with an EC50 = 41.9 μM. Further, the nucleosides did not show any considerable toxicity in CEM, PBM and Vero cells up to 100 μM concentration [27].

Figure 4.5: Synthesis of biologically active 1,2,3-triazolo-3′-deoxycarbanucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Figure 4.6: Synthesis of microwave-assisted α- and β-2′-deoxy-triazolyl-nucleosides.

Guezguez et al. [28] described the synthesis of α- and β-2′-deoxy-triazolylnucleosides under solvent free via microwave approached in high yield. The azido2-deoxyribose (31) was obtained from compound 30 [29] at 0 °C in the presence of TMSN3, and BF3–Et2O in dichloromethane solvent with good (87%) yield as a mixture of α and β anomers (Figure 4.6). It was observed that amalgamation of transition metal Cu(I) and microwave condition used in the reaction with various alkynes in the presence of solid support as a silica gel, gave nucleosides 32a–j (α/β) in 91–98% yields. Further, deprotection of 32a (α/β) in the basic medium gave the corresponding dihydroxynucleoside 33a (α/β) in good yields (Figure 4.6). Azido derivative 34 and various alkynes under Cu(I) catalyst cycloaddition reaction gave triazolyl carbanucleosides 35a–d (Figure 4.7) [30]. During optimization of reaction conditions, three different copper(I) catalysts were tried i.e. Cu(0)/ CuSO4(II), imidazoline(mesythyl)copper bromide (ImesCuBr), and ([Cu(CH3CN)4]PF6), under microwave conditions. It was concluded that the catalytic efficiency is comparable for Cu(0)/CuSO4(II) and [Cu(CH3CN)4]PF6 in term of percentage of conversion. The reaction times were found to be commonly higher with the catalyst [Cu(CH3CN)4]PF6. A very high percentage of conversion with increased reaction times was found in case of Imes CuBr. It was also found that under microwave condition reduce the reaction time period and increase the conversion rates as compared to the thermal conditions.

Figure 4.7: Synthesis of 1,2,3-triazolo-3′-deoxycarbanucleosides by the CuAAC.

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67

During optimization, it was found that reaction with polar alkynes is easier in comparison to non-polar alkynes. Pradere et al. [31] used CuAAC and RuAAC route for the synthesis of desired 1,4and 1,5-disubstituted-1,2,3-triazolylnucleosides, respectively (Figure 4.8) starting from various alkynes on protected β-azido-ribose (2). The synthesis of 1,4-disubstituted1,2,3-triazolyl-nucleosides 36a–h (Figure 4.8) was achieved using catalyst as Cu(0)/ CuSO4 in 63–93% yields. Azido compound 2 was treated with different alkynes and 5 mol% Cp*RuCl(PPh3)2 catalyst in tetrahydrofuran solvent at 50 °C for 6 h to afford the 1,5-disubstituted triazolo compounds 37a–h in good to high yields. Microwave condition [32] was applied on azido sugar 2 with various alkynes under Ru-catalytic conditions to produce nucleosides 37a–h in high yields. Deacylation furnished the corresponding trihydroxy nucleosides 38a–h and 39a–h in high yields (Figure 4.8). Finally, utility of this methodology was applied on azido sugar 40 with hexyne under microwave condition with 5 mol% RuAAC catalyst, to produce 39e in 95% yield (Figure 4.8). Further, the synthesized triazoles compounds were evaluated against HCV in a replicon system using Huh-7 cells but these compounds did not demonstrate any marked activity or toxicity. Ribavirin analogues such as 4-substituted triazolo carba-nucleosides have been prepared and further evaluated against antiviral agents [33] of 3-Azido-4-iodoalcohol (41) was obtained from commercially available cyclopent-3-enyl methanol and was further treated with excess methyl propiolate at 50 °C to afford a mixture of 4- and 5-substituted triazoles 42 and 43 in 79 and 14% yields, respectively (Figure 4.9). Reaction of 42 with ammonium hydroxide gave the corresponding product 44 in 71% yield (Figure 4.9). The desired 4-aryl-1,2,3-triazolyl dideoxyiodocarba nucleosides (46a–56a, Figure 4.10) was obtained by the reaction of azides 41 and 45 with various alkynes in the

Figure 4.8: Synthesis of ribavirin analogues nucleosides by CuAAC and RuAAC reaction.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Figure 4.9: Synthesis of 1,2,3-triazolo-2′,3′-dideoxy-2′-iodocarbanucleosides.

presence of catalyst as CuI and base DIPEA in tetrahydrofuran solvent but along with side product, 46b–56b. However, when cycloaddition reaction was carried out using CuI and DIPEA, the sole products were 46a–56a in good yields. Refluxing the carba nucleosides 46a and 48a–55a with DABCO in benzene solvent gave the corresponding regioisomers products 57–64 in good yields (Figure 4.10). Compounds 46a–50a, 47b and 60 were evaluated for cytomegalovirus (CMV Davis strain) and varicella-zoster virus inhibition in human embryonic lung cells and compounds 48b, 51a–53a, 51b–53b, 55a, 56a, 61, 63 and 64 evaluated for feline corona virus and feline herpes virus inhibition in Crandell–Rees feline kidney cells. However, majority of the nucleosides did not demonstrate any significant results. Akri et al. [34] described the synthesis and biological importance of 4-substituted triazolyl-nucleosides. The 1-azido-ribose (65) and an array of terminal alkynes were reacted via 1,3-dipolar cycloaddition using Brønsted acid via microwave activation and copper(I) catalyst to achieve triazoyl nucleosides 66a–i in quantitative yields (Figure 4.11). Deprotecting acetyl group, afforded trihydroxy nucleosides 67a–i and these compounds were evaluated against tumor cell lines. On the basis of structure– activity relationship study, it concluded that nucleosides 67c and 67g, possessing a

Figure 4.10: Synthesis of 4-aryl-1,2,3-triazolo-2′,3′-dideoxy-2′,3′-didehydrocarbanucleosides.

4.2 Synthesis

69

Figure 4.11: Synthesis of 4-substituted triazolyl-nucleosides.

larger alkyl chain and an aromatic aryl donor group were the most significant active compounds in the series. Broggi et al. [35] synthesized 1,4-disubstituted triazolo-carbanucleosides 69a–f via microwave-assisted using click reaction (Figure 4.12). The azido-sugar 68 was synthesized from D-ribose in multiple step synthesis, and subsequently silyl group was deprotected in the presence of TBAF in THF to yield trihydroxy polar carbanucleosides 70a–f in high yields (Figure 4.12). In continuation to 1,4-disubstituted carbanucleosides, Broggi tried to synthesize 1,4,5-trisubstituted carbanucleosides (71) using conventional method and found that yield was very low. Synthesized triazolo nucleosides did not demonstrate any kind of cytotoxicity or marked antiviral property on infected vaccinia virus cells.

Figure 4.12: Synthesis of 1,4-disubstituted and 1,4,5-trisubstituted triazolo-carbanucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Figure 4.13: Synthesis of one pot three component triazolyl-nucleosides.

Malnuit et al. [36] synthesized triazolo nucleosides via One-potin high yields (Figure 4.13). The azide–alkyne cycloaddition methodology was highly fruitful. The desired disubstituted triazolyl-nucleosides were achieved through trapping of the intermediate (triazolyl-copper) by electrophiles during the reaction process (Figure 4.13) [37]. It was observed that when the concentration of electrophile was enhanced, conversion of triazolyl-nucleosides 72 increased and reduction of the concentration of electrophile yielded higher conversion of 5H-triazole 73 (Figure 4.13). β-1,2,3-Triazolyl-nucleosides were procured as nicotinamide riboside mimics via two different synthetic approach [38]. The fully deprotected A series of nucleoside pyridine mimics 82a–c were easily achieved in three steps from easily available β-azide 75, which in turn was synthesized from compound 74 via substitution of acetyl group with azide using lewis acid. In the first step, deprotection of benzoyl group from the compound 75 with methanolic solution of sodium methoxide followed by acetonide protection furnished the compound 76. Triazole compounds 77a–c were achieved by the treatment of 76 with n-ethynylpyridine under CuAAc method and further, acetonide group was removed with aqueous TFA to accomplish the corresponding 82a–c in good yields (Figure 4.14). Triazole compounds 81a–c was obtained directly from compound 75 by using n-ethynylpyridine and CuAAc reaction conditions. Further, phosphorylation and nucleotides 79a–b were synthesized via chlorodiethylphosphite/tBuOOH combination. The palladium-catalyzed hydrogenation chemistry was applied on 77a–c and 81b, which showed that only pyridine ring was hydrogenated and gave the corresponding compounds 78a–c and partially protected 84b. Similarly, unmasking of acetonide group of compounds 78a–c with aqueous TFA gave the trihydroxy compounds 83a–c. Deprotection of phosphate trimesters 79a–b gave the corresponding

4.2 Synthesis

71

Figure 4.14: Synthesis of 1,2,3-triazolide adducts containing pyridine and piperidine ring.

compounds 80a–b. Docking experiments predicted that the piperidine derivatives compounds would bind generally at the C-pocket of yHst2, however, none of the synthesized triazoles offered any kind of significant level of enzyme inhibition. Pe´ rez-Castro et al. [39] synthesized 4-aryl-1,2,3-triazolocarbanucleosides via click chemistry in excellent yields and further checked their antiviral activity in comparison to antiviral drug, ribavirin. Azido compounds 85 and 89 were synthesized from cyclopentene [33, 40] and desired 4-aryl-1,2,3-triazole moiety was achieved by copper catalysed cycloaddition reaction (Figure 4.15) and this approach gave the only

Figure 4.15: Synthesis of 4-aryl-1,2,3-triazolocarbanucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

one of the two possible regioisomers products (±)-86a–c/(±)-87a–c and (±)-90a–c/ (±)-91a–c. Further, deprotection of the silyl group gave the corresponding compounds (±)-88a–c/(±)-92a–c in 74–99% yields. Nucleosides ((±)-92a–c, (±)-88a–c), (±)-86a–c and (±)-87a/c, were examined for their inhibitory activities against different types of viruses and also compared with well-known drugs, like gancyclovir, acyclovir, (S)-DPHA, brivudin and ribavirin. In all the cases, these compounds did not show any antiviral effects but hopeful results were produced in case of silylated compounds (±)-86a–c and (±)-87a/c in human embryonic lung cells against varicella-zoster virus. Kolganova et al. [41] synthesized an aminomethyl-triazolyl nucleoside phosphoramidite (Figure 4.16). Azido sugar 94 was obtained from chloro sugar 93 in presence of LiN3 in DMF at 0 °C in 85% yield. Further, unmasking of protecting group under basic medium afforded the dihydroxyazido compound 95. The cycloaddition reaction was performed via Fmoc-protected propargyl amine and azido sugar 95 in the presence of base and CuBr to yield triazolyl nucleoside 96. The phosphoramidite derivative 98 was obtained in two steps starting from 96, where in the first step, primary hydroxyl group was protected with DMTrCl in pyridine followed by treatment of 97 with phosphoramidite group in the presence of pyridiniumtetrazolide which afforded the desired phosphoramidite compound 98 in good yield (Figure 4.16). Consequently, hybridization and thermal denaturation studies of the 5′-modified oligonucleotides

Figure 4.16: Stereoselective synthesis of 4-(aminomethyl)-1,2,3-triazolyl nucleoside phosphoramidite.

Figure 4.17: Synthesis of triazolo pyrimidine nucleosides.

4.2 Synthesis

73

showed that the modification had no role on the duplex stability when compared to oligonucleotide with a 5′-aminohexyl group. Parmenopoulou et al. [42] described the preparation of triazolo pyrimidine nucleosides starting from azido sugar 99 and various propargylated nucleobases 100a–e in the presence of copper catalysed cycloaddition reaction (101a–e, Figure 4.17). Consequently, the deacetylated nucleosides 102a–e were obtained in 74– 83% yields. Further, their inhibitory action against ribonuclease A were studied and it was found that these triazolo nucleosides were potent competitive inhibitors of RNase A with low l M inhibition constant (Ki) values and the molecules having a triazole linkage were more significant than the ones without them. The most significant compound is 102a with Ki = 1.6 μM. Elayadi et al. [43] synthesized triazolo ribonucleosides starting from azido-sugar 2 and propargylated compounds 103a–h using catalyst as Na2CuP2O7 and sodium ascorbate (Figure 4.18). The advantage of this procedure was the easy work-up and shorter reaction times which made it a fruitful technique for the synthesis of triazolo-nucleosides in comparison to thermal cycloaddition reaction [44] resulting in a mixture of regioisomers. Further, all triazole-compounds were evaluated for their anti-HCV activity in vitro, and none of the nucleosides were observed to inhibit HCV replication in vitro. Elayadi et al. [44a] reported the triazolyl nucleosides which were analogs of potential anti-influenza A virus agents. Montmorillonite K10 impregnated with CuCl2 and KI was used as novel catalyst for the cycloaddition of azide 2 and various propargylated nucleobases 103a–h to give the corresponding triazoles 106a–h in high yields (Figure 4.19). CuCl2/KI/K10 also served as a greener, reactive and environmentally friendly heterogeneous catalyst.

Figure 4.18: Synthesis of 1,2,3-triazolo ribonucleosides.

Figure 4.19: Synthesis of 1,2,3-triazolyl nucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Bag et al. [44b] reported unnatural triazolyl nucleoside which was utilized in oligonucleotide synthesis. For the synthesis of triazolyl nucleoside, authors started from azido sugar 94 which in turn was synthesized from chloro sugar 93 with CsN3 in presence of DMSO. Further, azido sugar 94 was reacted with 9-phennanthrene acetylene under [3 + 2] cycloaddition reaction and followed by unmasking of protected group gave the corresponding dihydroxy nucleoside 107 in good yield. Furthermore, 5′-hydroxyl group was protected with DMTrCl in pyridine and consequently, phosphoramidite chemistry was applied on 3′-hydroxyl group to afford the corresponding nucleoside 108 (Figure 4.20). Compound 108 was used in oligonucleotide synthesis and found to highly stabilization of the duplex, which is comparable to that of an adenine–thymine (A–T) pair. The large surface area, strong stacking property and polarizability played a significant impact in contribution high duplex stabilization. Bag et al. [45] also synthesized unnatural triazolyl nucleosides/oligonucleotides and compared duplex stability with natural A–T pair. Azido compound 94 was treated with donor/acceptor alkynes under click chemistry (Do/Ac, a–d) produced the corresponding nucleosides 109a–d followed by unmasking with base which afforded 110a–d in very good yields (Figure 4.21). It was found that the synthesised unnatural

Figure 4.20: Synthesis of unnatural triazolyl nucleoside and its phosphoramidite.

Figure 4.21: Synthesis of donor/acceptor unnatural triazolyl nucleosides.

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75

Figure 4.22: Synthesis of 1H-1,2,3-triazole nucleosides.

donor/acceptor triazolyl nucleosides offer a good stabilization of the heteropair/ self-pair duplexes i.e. comparable to that of a natural adenine-thymine pair. Ferreira et al. [46] reported the preparation of triazole nucleoside analogs of ribavirin and further examined their antiviral activity. For the synthesis of desired nucleosides 115a–c (Figure 4.22), authors started from easily available material chloromethylbenzene (111), which on reacting with sodium azide gave the azido compound 112 and further it was reacted with terminal alkynes under click chemistry condition to yield triazoles 113a–c. For the synthesis of triazoles 114a–c, 113a–c were reacted with Pd(OH)2/C under hydrogen atmosphere produced the debenzylated products 114a–c in good yields. Finally, triazole moiety was inserted on protected β-D-ribofuranose with coupling reagent which furnished the compounds 115a–c in high yields. Consequently, these compounds were evaluated against influenza A and herpes simplex virus replication as well as reverse transcriptase (RT) from human immunodeficiency virus type 1. Nucleoside 115b was the most potent having IC50 values 14 and 3.8 µM for influenza A and HIV-1RT, respectively.

Figure 4.23: Synthesis of triazolo-spirocyclic nucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Dell’Isola et al. [47] synthesized triazolo-oxazine compounds and this was synthesized from furanosyl azido sugar 116, which was synthesized from β-D-psicofuranose [48]. Alkylation of primary hydroxyl group of 116 with various substituted propargyl bromides and followed by 1,3-dipolar intramolecular cyclo-addition produced spirocyclic adducts 118a–k in 36–59% overall yields (Figure 4.23). Deacylation of the spiro-derivatives 118a–k, using ammonia solution followed by hydrolysis of the isopropylidene ring in acidic medium (Dowex 50 W) produced the corresponding anomeric spiro-nucleosides 119-k in 47–80% yields. These spiro compounds were evaluated for their antiviral activity using mouse hepatitis virus (MHV) and it was found that compound 119f showed the most significant activity and tolerability. Reddy et al. [49] produced the 1,2,3-triazolyl C-nucleoside 121a–c, 123a–c, 125a–c, and 127 analogues using Huisgen ‘click’ chemistry, in 58–78% yields (Figure 4.24) and further evaluated anti-fungal and anti-bacterial activity in vitro. Adamantane conjugate triazolyl C-nucleosides 125c and 127 showed sublime activity against S. aureus and K. pneumoniae while compounds 121c, and 123a–c demonstrated moderate anti-fungal activity. Elayadi et al. [50] developed a simple and atom economic procedure for the synthesis of 1,4-disubstituted-1,2,3-triazolo-nucleosides 128a–c (Figure 4.25) using

Figure 4.24: Synthesis of tetrahydrofuranyl triazolyl C-nucleoside analogues.

Figure 4.25: Synthesis of 1,4-disubstituted-1,2,3-triazolo-nucleosides.

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Figure 4.26: Synthesis of ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates.

azido sugar 2 and various alkynes via easily available catalyst CuSO4 and KI in good yields. Ouahrouch et al. [51] prepared a triazolyl nucleosides by click chemistry. Compounds 130a–j were synthesised in high yields using the Kabachnik–Fields reaction starting from compound 129 (Figure 4.26). Unmasking of the trimethylsilyl group occurred under catalyst asTBAF in THF produced the terminal alkynes 131a–j. Consequently, the alkynes 131a–j and azido sugar were coupled via the CuI in basic medium under microwave irradiation to afford the nucleosides 132a–j in high yields. Finally, benzoyl group was removed under basic condition to afford the corresponding triazolo nucleosides 133a–j in 95–99% yields (Figure 4.26). Further, Their activity were checked against various strains of DNA and RNA viruses, nucleosides 132b and 132c exhibited a modest inhibitory activity against respiratory syncytial

Figure 4.27: Synthesis of triazolylphenanthrene nucleoside.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

virus (RSV) and compound 132h showed normal inhibitory activity against coxsackie virus B4. Bag et al. [52] synthesised triazolyl fused unnatural phenanthrene nucleosides which showed attractive photophysical property with chrysene type emission. The intermediate compound 138 was prepared from 2-bromoaniline (134) in four steps (Figure 4.27). The other intermediate compound 94 was synthesized from a chlorosugar [53]. Finally, Cu(I)-catalysed cycloaddition reaction was performed between β-azidosugar 94 and 2-ethynyl-1,1″-biphenyl (139) produced the corresponding 5-iodo-4-biphenyl triazolyl nucleoside which upon treatment with Pd(OAc)2 generated the desired fused triazolylphenanthrene nucleoside 140 in 68% yield. Lastly, toluoyl groups were removed using sodium methoxide in methanol which produced the nucleoside 141 in high (82%) yield (Figure 4.27). Bag et al. [54] synthesised unnatural triazolyl donor–acceptor nucleosides 146a–k (Figure 4.28) via azide–alkyne cycloaddition reaction and their photophysical properties in various organic solvents have been evaluated. Azido sugar 94 was synthesised from Hoffer’s chloro-sugar 93, which in turn was synthesised from 2-deoxyribose sugar. Chloro-sugar 93 reacted with CsN3 in DMSO to produce an azido sugar as a mixture of α/β-anomers in good yields. Thus, both the epimeric sugars i.e. 94 and 144 were treated with different donor/acceptor alkynes (a–k) using click chemistry at 80 °C to produce the corresponding triazolyl donor/acceptor nucleosides 142a–k and 145a–k in 80–90% yields. Finally, unmasking of the toluoyl groups produced the triazolyl compounds 143a–k and 146a–k in excellent yields (Figure 4.28).

Figure 4.28: Synthesis of unnatural triazolyl nucleosides.

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79

Alaoui et al. [55] described the synthesis of sulfonamides 4-substituted-triazolyl nucleosides via click chemistry and further checked their anti-cancer activities. β-Azidoglycoside (65) was obtained from tetraacetate sugar 147 in good yield and propargyl-sulfonamides derivatives 149a–k were obtained from two steps. Firstly, sulfonyl chlorides were treated in aqueous medium with primary amines using Na2CO3 as base to afford the mono-substituted sulfonamides 148a–k in 40–90% yields and in the second step, addition of propargyl bromide to sulfonamides 148a–k in the presence of K2CO3, produced the corresponding sulfonamides 149a–k in 34–95% yields. Further, cycloaddition of the azidoglycoside 65 and alkyne sulfonamides 149a–k was carried out in aquous butanol system using CuI and sodium ascorbate which afforded the corresponding nucleosides 150a–k in moderate to excellent yields (Figure 4.29). Lastly, deprotection of acetyl group was performed with base Na2CO3 in methanol to give the trihydroxy nucleosides 151a–k in good yields. All triazolyl nucleosides have been checked activity against two tumor cell lines, RCC4 and MDA-MB-231. Out of them, nucleoside analogue 150i was observed 19 to 66-fold more active than anticancer agent AICAR (5-aminoimidazole carboxamideribosyl).

Figure 4.29: Synthesis of sulphonamides 4-substituted-triazolyl nucleosides.

Figure 4.30: Synthesis of Ir(III)-triazolyl nucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Passays et al. [56] described the synthesis and photophysical properties of triazolyl Ir(III)-nucleosides 153a–c in Figure 4.30. Iridium (III) complexes received an emergent attention for the development of photo-reactants and sensors for biochemical applications. The key precursors were ethynyl functional group on one of the ligand chelated onto the iridium 152a–c center, which was treated with azido sugar 95 under cycloaddition condition to produce the corresponding nucleosides 153a–c in good yields (Figure 4.30). Further, they established the structure of Ir(III) complexes on nucleoside via triazole linkers without changing the properties of complexes and thus providing a novel method for the study of DNA-charge transfer processes. Liu et al. [57] synthesised triazolo nucleosides containing fluorine atom at 2′ position, which were evaluated against hepatitis B virus (HBV). Bromo sugar 154 was treated with sodium azide to produce the corresponding β-azide 155 and their epimer. Further, azido sugar 155 reacted with methyl propiolate via Cu(I)-catalyzed click reaction to afford the corresponding triazolo nucleoside 156 in 95% yield (Figure 4.31).

Figure 4.31: Synthesis of 1,2,3-triazolo-2′-deoxy-2′-fluoro-4′azidonucleosides.

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81

Further, unmasking of 156 with saturated methanolic ammonia to furnish the dihydroxy nucleoside 157 in good yield. Furthermore, selective iodination of 157 at C-5′ position with I2/Ph3P/imidazole in dichloromethane followed by deiodination of 158, produced alkene 159 in 71% yield. Reaction of 159 with reagent ICl/NaN3 in regio- and stereoselective fashion in THF solvent furnished 160 in 78% yield. Protection of hydroxy group of 160 with benzoyl chloride followed by removal of iodine 161 using m-chloroperbenzoic acid (m-CPBA) produced the key compound 162 from which the nucleosides 164a–f were synthesised. Conversion of cyano group of 162 into amide group 163 occurred with nickel reagent in acidic medium followed by unmasking with methanolic ammonia to achieve corresponding compounds 164a, 164c and 164d (Figure 4.31). Treatment of 164d with HCl furnished the ester 164e, followed by reduction with NaBH4 that produced 164f in overall yield of 52%. The tetrazolyl triazole nucleoside 164b was achieved by cycloaddition of 162 with sodium azide followed by unmasking of protecting group in methanolic ammonia solution (Figure 4.31). The synthesis of compound 164g was achieved (Figure 4.32), where click reaction of 155 with cyclopropyl acetylene led to the formation of 166 as described in (Figure 4.31), which finally afforded the desired nucleoside 164g in good yield (Figure 4.32). All synthesised nucleosides were screened for anti-HBV activity in vitro and all the nucleosides display activities comparable to that of the positive control, lamivudine at 20 µM concentration. The amide-substituted analogue 164a exhibited the most significant anti-HBV activity and low cytotoxicity. Moreover, it retained excellent activity against lamivudine-resistant HBV mutants. Andreeva et al. [58] reported a novel series of triazolyl nucleosides using click reaction of N1-alkynyl nucleobases 175a–j, quinazolin-2,4-dione 178a–b and acetylated azido β-D-ribofuranose 65 (Figure 4.33). The azido compound 65 (Figure 4.33) was obtained from commercially available sugar 173 in three steps and N1-alkynylated nucleobases 175a–j and quinazolin-2,4-dione 178a–b were synthesised from known procedure [59]. The click reaction was achieved in aqueous tertiary butanol to afford the corresponding nucleosides 176a–j and 179a–b in high yields. Finally, unmasking

Figure 4.32: Synthesis of 1,2,3-triazolo-2′-deoxy-2′-fluoro-4′-azidonucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Figure 4.33: Synthesis of novel 1,2,3-triazolyl nucleosides.

of O-acetyl groups of 176a–j and 179a–b with methanolic sodium methoxide mediated solution furnished the targeted 177a–j and 180a–b in quantitative yields (Figure 4.33). Further, these nucleosides were checked for their cytotoxicity in vitro and found that these nucleosides are noncytotoxic in normal human cell line and a diploid human cell strain. Ingale et al. [60] synthesised pyrene functionalized triazolyl-nucleoside using ‘click’ chemistry and further investigated their duplex stability. The CuAAC reaction was applied to toluoyl protected β-azide 94 and 1-ethynylpyrene (181) produced the corresponding pyrene conjugate nucleoside 182 in high yield. Subsequently, unmasking of the toluoyl groups with base in methanol produced the 3′,5′-hydroxylated nucleoside 183 in 90% yield (Figure 4.34). Further, protection of C-5′-hydroxyl group with DMTrCl in pyridine, followed by phosphoramidite chemistry on C-3′-hydroxyl group gave the phosphoramidite compound 185 in good yield. Further, duplex stability and fluorescence properties have been checked and it was concluded that short linkers decreases

4.2 Synthesis

83

Figure 4.34: Synthesis of pyrene functionalised triazolylnucleoside and phosphoramidite.

the stability, while the larger linkers have a constructive stabilizing capacity and provides liberty of motion to the pyrene group. Maikhuri et al. [61] synthesised a series coumarin conjugated triazole ring via click reaction between azido sugar 2 and with different 4-ethynylcoumarins 186a–h followed by unmasking of benzoyl group resulting in the desired compounds 188a–h in overall yields of 71–89 (Figure 4.35). Srivastava et al. [62] synthesised a series of coumarin linkage triazoles 191a–d and 194a–d via click reaction starting from azido compound 2 and various alkynylated coumarins 189a–d/192a–d. It was followed by unmasking of benzoyl group with

Figure 4.35: Synthesis of coumarinyl conjugate triazolylnucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Figure 4.36: Synthesis of coumarinyl-triazolyl nucleosides.

methanolic solution of sodium methoxide resulting in 190a–d and 193a–d in high yields (Figure 4.36). Further, these triazoles were evaluated for their anti-tubercular activity in vitro against Mycobacterium tuberculosis. It was found that most of the triazoles were 7–420 times more active than all reported four first line anti-tubercular drugs against multidrug resistant clinical isolate 591.

4.2.2 Synthesis of C-2′-triazolo-nucleosides O’Mahony et al. [63] synthesized a series of 2′-(1,2,3-triazol-1-yl)-2′-deoxyadenosine nucleosides starting from vidarabine 195 (Figure 4.37). Nucleoside 195 was treated with tetraisopropyldisilyl chloride in pyridine followed by mesyl chloride in DCM and sodium azide in DMF which produced nucleoside 196. Triazolylation reaction of nucleoside 196 was carried out by sodium ascorbate and CuSO4.5H2O in 50% aqueous

Figure 4.37: Synthesis of 2′-(1,2,3-triazol-1-yl)-2′-deoxyadenosine nucleosides.

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85

Figure 4.38: Synthesis of C-2′-triazolyl nucleosides.

BuOH in presence of various alkynes, which gave the nucleosides 197a–i in high yields. Lastly, unmasking of silyl group in methanol mediated ammoniumfluoride solution produced the corresponding dihydroxy nucleosides 198a–i (Figure 4.37). Mathur et al. [64] synthesized thirty two 2′-triazolyl nucleosides with various C-4 substitution on the triazolyl ring by Cu(I) catalyzed condensation of corresponding 2′-azido nucleosides 201a–b and different alkynes 202a–c and aryl propargyl ethers 205a–t in high yields (Figure 4.38). Authors started with uridine (199a) and 5-methyluridine (199b) which were converted into corresponding anhydro nucleosides 200a and 200b using diphenyl carbonate with sodium bicarbonate in DMF respectively. Azidation of the nucleosides were carried out with sodium azide in DMF to get nucleoside 201a and 201b. Reaction of nucleoside 201a with alkynes 202a–b produced 4-triazolo-substituted 2′-triazolyl uridines (203a–b), whereas nucleoside 201b reacted with alkynes 202a,c to produce 4-triazolo substituted 2′-triazolyl 5-methyluridine nucleosides (204a–b). Another series of nucleosides were synthesized by reaction of nucleoside 201a and 202a with aryl propargyl ethers 205a–q and 205a–h and r–t, respectively to get nucleosides 206a–q and 207a–h and r–t (Figure 4.38), respectively. t

Figure 4.39: Synthesis of C-2′-triazolyl nucleosides.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Kumar et al. [65] reported a synthetic strategy for production of 2′-triazolyl nucleosides starting from uridine nucleoside 199a (Figure 4.39) and by reactions of diphenyl carbonate, sodium azide and 15-crown-ether in anhydrous solvent DMF, which afforded our key intermediate nucleoside 201a. Next, when azido nucleoside 201a was treated with propargyl ethers of phenols 208a–f using sodium ascorbate and copper sulphate in aqueous tert-butanol, it afforded nucleosides 209a–f in good yields (Figure 4.39).

4.2.3 Synthesis of C-3′-triazolo-nucleosides Herdewijn and his research group [66] reported a series of nucleosides with 1,2,3-triazole-1-yl substituent in the 3′-position of 3′-azido-3′-deoxythymidine by a cycloaddition reaction between different acetylenic compounds and the nucleosides (Figure 4.40). Reaction of 3′-azido-3′-deoxythymidine (210) with trimethylsilylacetylene (211a) in dichloromethane at 120 °C for 48 h produced desired triazolyl derivative 212a together with the desilylated compound 212b. However, refluxing of nucleoside 212a in presence of 1.5 equivalent of Bu4NF (TBAF) yielded exclusively nucleoside 212b.

Figure 4.40: Synthesis of C-3′-1,2,3-triazole-1-yl nucleosides.

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87

Reaction between nucleoside 210 and the propergyl alcohol 211b produced a mixture of nucleosides 212c and 212d (ratio 1:2). However, when acylated nucleoside 213 reacted with 211b under same reaction condition, a mixture of nucleosides 214a and 214b (ratio 3:5) was produced. Reaction of nucleosides 214a and 214b when treated with diethyl amino sulfurtrifluoride in DCM, nucleosides 214c and 214d were produced. Complete deacylation of 214c and 214d produced 212e and 212f, respectively. Reaction of 214a and 214b with carbon tetrachloride and triphenylphosphine in DMF produced 214e and 214f. Treatment of 214a with methyl triphenoxyphosphonium iodide produced unstable nucleoside derivative 214g, which was converted into 214h by hydrogenation and 212j by deacylation. Reaction of thymidine (210) with 211c yielded 212k, which was desilylated to afford nucleoside 212i. Reaction of nucleoside 210 with ethylpropionate 211e and phenylacetylene 211f produced nucleosides 212m and 212n, respectively. Nucleoside 214i was obtained when nucleoside 213 was heated with ethoxyacetylene (211g). Deprotection of 214i with ammonia in methanol produced 212o. When nucleoside 210 was treated with excess of 1-morpholino-2-nitromethene in toluene for one week, it produced nucleoside 212p (Figure 4.40). However, all these triazolyl nucleosides were found to be inactive against HIV. Zhou et al. [67] reported a series of 1,2,3-triazole functionalized thymidines by using sodium ascorbate and CuSO4 system as catalyst (Figure 4.41). Compounds 215– 222 were synthesized with high yields and with 100% regioselectivity towards the 4-substituted triazolo moiety starting from azidothymidine 210 and various alkynes (Figure 4.41). All these compounds were evaluated but were found to be inactive against various virous such as parainfluenza type 3, reo type 1, Sindbis, Coxsackie B4, herpes simplex, Human innunodeficiency virus etc. Coumarin nucleoside conjugates were designed and synthesised using click chemistry by Kosiova et al. [11a] (Figure 4.42). First, five functionalized coumarin

Figure 4.41: Synthesis of 3′-deoxy-3′-(4-substituted triazol-1-yl) thymidines.

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4 Green synthesis of triazolo-nucleoside conjugates via azide–alkyne

Figure 4.42: Synthesis of coumarin conjugate triazolyl nucleosides.

derivatives 224a–e were synthesized starting from the corresponding coumarin alcohols 223a–b or coumarin carboxylic acids 223c–e by treatment of propargyl bromide with base potassium carbonate (in case of 223a–b) or HOBt and dicyclohexylcarbonate (DCC) (in case of 223c–e). When these five alkynes 224a–e reacted with AZT 210 under reaction conditions of CuSO4 and sodium ascorbate in t-BuOH and water, triazolyl nucleosides 225a–e were furnished in good yields (Figure 4.42). A series of 3′-deoxy-3′-triazolyl thymidine 227a–m (Figure 4.43) were obtained and their biological activity against human and Ureaplasma parvem thymidine kinase was evaluated by Lin et al. [68] AZT 210 was dissolved in aqueous tertiary butanol solvent followed by addition of Cu(0), CuSO4 and corresponding substituted alkyne 226a–m, which was heated at 125 °C for 10 min under microwave irradiation (or treatment of AZT and corresponding alkyne in the same solvent mixture, catalyzed by sodium ascorbate and CuSO4) to afford the 3′-deoxy-3′-triazolylthymidine 227a–m (Figure 4.43). Further, these nucleosides were checked with UpTK and human cytosolic thymidine kinase (hTK1) and these compounds exhibited higher proficiencies (Km/Vmax values) in all cases with UpTK than with hTK1.

Figure 4.43: Synthesis of 3′-deoxy-3′-triazolylthymidine.

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89

Figure 4.44: Synthesis of 3′-deoxy-3′-triazolylthymidine.

A series of 3′-deoxy-3′-triazolylthymidine nucleosides analogues 229a–j (Figure 4.44) were obtained starting from AZT 210 [69]. When 210 was treated with alkynes 228a–h in presence of copper sulfate and sodium ascorbate, nucleosides 229a–h were produced. However, reaction between AZT 210 and alkynes 228i, j in presence of Cp*RuClP(Ph3)2 afforded isomeric nucleosides i.e. 5-substituted 1,2,3-triazol-1-ylthymidines 229i, j in good yields (Figure 4.44). Another interesting and important 3′-substituted 1,2,3-triazolo-2′,3′-dideoxypyrimidine nucleosides of AZT was synthesised by Roy et al. [70] Triazole analogues were prepared using compound 230a, 230b and sodium ascorbate/CuSO4 in a equimolar solvent mixture of water and t-BuOH at room temperature, to produce a total of six nucleoside analogues 231a–b (where n = 1, 2, 3; Figure 4.45). The hydroxyl group present in these nucleosides were converted into corresponding azido group to afford nucleosides 232a–b, which were deprotected at the 5′-position to afford 233c–d (where n = 1, 2, 3). The C-4 keto group of these nucleosides were converted into corresponding amine group to afford 234a–b (where n = 1, 2, 3), followed by reaction with saturated

Figure 4.45: Synthesis of 3′-substituted 1,2,3-triazolo-2′,3′-dideoxypyrimidine nucleosides.

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Figure 4.46: Synthesis of triazolo-fused cyclic nucleosides.

methanolic ammonia to produce the corresponding nucleosides 235c–d. When nucleoside 230a–b were treated with 3-(trimethylsilyl)propargyl alcohol at 110 °C, it produced triazolyl nucleosides 236a–b. The hydroxyl group present in these nucleosides were converted into azido group 237a–b, followed by a reaction with saturated methanolic ammonia to produce the corresponding nucleosides 238c–d in good yields (Figure 4.45). Synthesis of triazolo-fused cyclic nucleoside analogues have been described using an intramolecular cycloaddition reaction by Sun et al. [71] (Figure 4.46). Authors started with 3′-azido-3′-deoxythymidine (210) which was propargylated at C-5′ position to afford nucleoside 239, which under refluxing condition of toluene produced triazolo-fused 3′,5′-cyclic nucleoside 240. Next, the reaction of nucleoside 240 with 1,2,4-triazole, base triethylamine and POCl3 in MeCN, followed by reacted with ammonium hydroxide in dioxane produced cytosine analogue 241. With an aim to synthesize another analogue of this series, the hydroxyl group present in 5′-O-trityl2′-deoxythymidine (242) was inverted to afford 3′-azido-nucleoside 243. Unmasking of the trityl group, followed by propargylation and refluxing with toluene produced triazolo-fused 3′,5′-cyclic nucleoside 246. The nucleobase of nucleoside 246 was converted into 5-methylcytosine following the same reaction sequence to get nucleoside 247 in good yield (Figure 4.46). Peiyuan et al. [72] synthesized 1,2,3-triazole based oligoconjugates 248–253 starting from azido thymidine 210 and using various alkynes using sodium ascorbate and CuSO4.5H2O as catalyst (Figure 4.47). The initial in vitro bioassay study showed that only nucleoside 252 considerably inhibited the growth of cervix cancer HeLa cells and was also found to be much better than azido thymidine 210.

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Figure 4.47: Synthesis of triazole fused oligoconjugate based nucleosides.

Figure 4.48: Synthesis of triazolo-fused 2′,3′-cyclic nucleosides.

An intramolecular regiospecific and stereospecific cycloaddition chemistry of nucleoside using azide–alkyne was explored by Wu and his co-workers [73] to synthesize triazolo-fused cyclic nucleoside analogues. 5′-O-Tritylated anhydronucleoside

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254 was treated with NaN3 to get azido nucleoside 255, which was propargylated under ultrasound irradiation reaction condition with NaH in THF to produce triazolo-fused 2′,3′-cyclic nucleoside 257 in good yield (Figure 4.48). Further, nucleobase of compound 257 was converted into cytosine by treatment of 1,2,4-triazole and POCl3, followed by aqueous ammonia in dioxane to afford nucleoside 258. On detritylation with 80% acetic acid solution, nucleosides 257 and 258 afforded nucleosides 259 and 260, respectively. Nucleoside 261 was treated with NaN3 in DMF to get a mixture of nucleosides 262 and 263. Firstly, inversion at the C-3′ hydroxyl position of nucleoside 263 into desired nucleoside 265 was carried out in two steps. Next, the similar reaction sequences were applied on compound 266 to produce nucleosides 267 and 268 in good yields. Further, unmasking of trityl group furnished the nucleosides 269 and 270, respectively. Nucleoside 263 was treated with the following similar reaction sequence, which provided nucleosides 271–274. Similar reaction conditions was also applied on nucleoside 262 to produce the corresponding nucleosides 275–278 in good yields (Figure 4.48). Sirivolu et al. [74] described the synthesis of different substituted triazolothymidine nucleosides. A series of 4-substituted 1,2,3-triazolo-thymidine nucleosides

Figure 4.49: Synthesis of 1,2,3-triazolo-thymidine nucleosides.

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280a–n were synthesized by reaction of AZT 210 with aryl alkynes 279a–n using sodium ascorbate and CuSO4.5H2O in equimolar solvent mixture water and THF. The other series i.e. 5-substituted 1,2,3-triazolo-thymidine nucleosides 281a–n were prepared by the catalyst Cp*RuCl(PPh3)2 in THF solvent (Figure 4.49). A series of propargyl aryl ethers 282a, d, e, h, o–q were synthesized starting from corresponding phenols and propargyl bromides in presence of K2CO3 in good yields and these alkynes were used for the triazolylation reaction. The cycloaddition reaction between AZT 210 and the propargyl aryl ethers 282a, d, e, h, o–q in presence of sodium ascorbate, CuSO4·5H2O in THF and water produced the 4-substituted 1,2,3-triazolo-thymidine nucleosides 283a, d, e, h, o–q in good yields. However, in presence of Ru-catalyst, 5-substituted 1,2,3-triazolo-thymidine nucleosides 284a, d, e, h, o–q were produced (Figure 4.49). Further, these novel compounds evaluated against HIV were found to be inactive against HIV or any other viruses. Arya et al. [75] reported the synthesis of 3′-deoxy-3′-trizolomethyluridine following a chemo-enzymatic pathway (Figure 4.50). The synthetic methodology started with D-xylose (285), which was converted into dihydroxy sugar 286 in two steps in overall yield of 90%. Enzymatic reaction with lipase Novozyme 435 in THF with vinyl benzoate as benzoylating agent to produce monobenzylated furanosylsugar 287, which was converted into nucleoside 292 by treatment of 287 with triflic anhydride in pyridine and DCM, followed by azidation, coupling of nucleobase thymine and deacylation using K2CO3 in methanol. The 1,2,3-triazolyl nucleosides 294a–i were synthesized in 76–92% yield by reaction between azido nucleoside 292 and substituted acetylenes 293a–i catalyzed using Cu(I) catalyst under cycloaddition reaction in an ethanol, water and THF solvent system (Figure 4.50). A series of 3′-deoxy-3′-substituted triazolothymidine nucleosides were synthesized by Vernekar et al. [76] (Figure 4.51). The nucleosides were silylated at the 5′-position with variety of silyl protection groups and were tested against dengue virus and West Nile virus. A series of triazolo nucleosides 296a–i and 299a–i, were synthesized using click

Figure 4.50: Synthesis of 3′-deoxy-3′-triazolo-methyluridinenucleosides.

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Figure 4.51: Synthesis of 3′-deoxy-3′-(4-substituted/5-substituted-triazol-1-yl)-thymidine nucleosides.

reaction between AZT 210 and 5′-TBS-AZT 298 with alkynes 295a–i using CuSO4 and sodium ascorbate in a equimolar solvent mixture of THF and water in high to moderate yields. When nucleosides 210 and 298 were treated with aromatic alkynes 295e, j, k and 295a, d, respectively, with Cp*RuCl(PPh3)2 in THF, 5-substituted-triazolyl nucleosides 297e, j, k and 300a, d were obtained in moderate to low yields. Nucleoside analogue 297a was protected with a variety of protection groups by using corresponding reagents 301a–h to afford 5′-protected 3′-deoxy-3′-((6-methoxynaphtha2-yl)-triazol-1-yl)-thyidine nucleosides 302a–h in good yields (Figure 4.51). 5′-silylated AZT-derived 3′-triazolo nucleoside scaffolds effectively inhibited dengue virus and West Nile virus without preventing HIV or any other kind of tested viruses. Further, structure activity relationship revealed that both the C-5′ silyl protected group and the

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95

Figure 4.52: Synthesis of 4′-(1,2,3-triazol-1-yl)-2′-deoxy-2′-fluoro-β-D-arabinofuranosylcytosine nucleosides.

3′-bulky groups were important part for antiviral activity against dengue virus and West Nile virus.

4.2.4 Synthesis of C-4′-triazolo-nucleosides A series of 4′-triazolo-2′-deoxy-2′-fluoro-β-D-arabinofuranosylcytosine nucleoside (305a) and its 4-substituted triazolo analogues (305b–i) were synthesized via Cu(I) mediated click reaction of compound 303 with suitably substituted alkynes 304a–i in moderate to good yields by Wu et al. [9] (Figure 4.52).

4.2.5 Synthesis of C-5′-triazolo-nucleosides Kosiova et al. [65] synthesized coumarin conjugated 5′-deoxy-5′-substitutedtriazolothymidine nucleosides 308a–e and 310a–e (Figure 4.53). The substituted alkynes were reacted with 5′-azido-5′-deoxyuridine (306) and 5′-azido-5′-deoxythymidine (309) under CuAAC reaction conditions using CuSO4 and sodium ascorbate to afford nucleosides 308a–e and 310a–e, respectively (Figure 4.53).

Figure 4.53: Synthesis of coumarin conjugated 5′-deoxy-5′-substituted triazolo-thymidine nucleosides.

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Figure 4.54: Synthesis of 5′-deoxy-5′-substituted triazolo-uridine nucleosides.

Chaudhary et al. [77] explored new click reaction mediated modified nucleosides as potential chitin synthase inhibitors. Uridine (199a) was converted to the precursor molecule 5′-azido-5′-deoxyuridine (311) in three steps. In the first step, nucleoside 199a was treated with dimethoxy propane in acetone in presence of para-toluenesulfonic acid, followed by TsCl in pyridine and sodium azide and DMF in second and third steps, respectively to afford nucleoside 311 (Figure 4.54). Nucleoside 311 reacted with various alkynes 312a–g and 314a–g, using sodium ascorbate and copper sulphate in an equimolar solvent mixture of t-BuOH and water. It produced two series of nucleosides i.e. 313a–g and 315a–g, respectively. Nucleoside 313d, 313e, 313f and 315f were known to be the most potent chitin synthase inhibitors in comparison to nikkomycin.

Figure 4.55: Synthesis of 2′,3′-diethanethio-5′-triazolonucleosides.

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Nucleosides 313a–d and 315a–b were found to possess better antifungal property against human and plant pathogens. Yu et al. [78] described a series of 2′,3′-diethanethio-5′-triazolonucleosides starting from furanoside 316. The furanoside was tosylated at 5′-hydroxyl position in DCM, followed by reacted with sodium azide in polar DMF solvent to get azidonucleoside 317 (Figure 4.55). Click chemistry between furanoside 317 and substituted alkynes 318a–i in presence of Cu and CuSO4 in an equimolar solvent mixture of n-butanol and water afforded 5′-triazolo-furanosides 319a–i. Treatment of triazolofuranosides with silylatednucleobases of uracil, thymine and N4-benzol-cytosine produced nucleosides 320a–i, 321a–e, h–i and 322a in good yields, respectively (Figure 4.55). Further, antitumor activity was evaluated for these compounds and was found that owing to the conjugation effects of aromatic rings, the compounds demonstrated significant activity towards wide range of tumor cell lines as compared to others. Therefore, these outcomes proposed that on the triazole moiety with the aromatic ring was an essential for bioactivity. Bodnar et al. [79] synthesized triazolyl conjugated 2′-deoxynucleosides of 13α-estrone by application of copper catalyzed alkyne-azide click reaction (CuAAC) (Figure 4.56). Authors started with nucleosides 5′-O-DMTr-2′-deoxynucleosides 323a–c, which were acetylated at the 3′-position followed by deprotection of DMTr from 5′-hydroxyl group and then protection with tosyl group by using tosyl chloride in pyridine to get nucleosides 324a–c. Azido nucleosides 325a–c were obtained by reaction of tosylated nucleosides 324a–c with sodium azide in presence of lithium bromide. Click chemistry between 5′-azido-2′,5′-dideoxynucleosides 325a–c and 3-O-propergyl-13α-estrone (326) were carried out in toluene or THF with CuI and DIPEA at 50 °C. This was followed by deacylation in the presence of methanolic ammonia to get nucleosides 328a–c (Figure 4.56). All the synthesised compounds exhibited

Figure 4.56: Synthesis of triazolyl 13α-estrone–nucleoside.

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moderate to considerable antiproliferative property against HeLa, MCF-7 and A2780 human adherent cell lines. Ruddarraju et al. [80] designed a series of theophylline containing 5′-triazolo nucleosides and screened them against anticancer and antimicrobial activities with in silico analysis. To synthesize the desired analogues, uridine (199a) was protected by acetonide. It was followed by mesylation at the C-5′ hydroxyl and azidation by sodium azide in DMF, which produced nucleoside 311 (Figure 4.57). Next, N-3 of nucleobase uridine was protected by ethyl group using ethyl iodide in DMF with base sodium hydride to give the corresponding nucleoside 330. Finally, treatment of nucleoside 330 with TFA in an equimolar solvent mixture of THF and water followed by methylation of 331 afforded nucleoside 332 in good yield (Figure 4.57). Nucleoside 311 was reacted with alkynes 333a–f, h in presence of CuSO4 and sodium ascorbate in an equimolar solvent mixture of ethanol and water to afford nucleosides 334a–f, h. Similarly, nucleosides 331 and 332 were treated under similar reaction conditions with alkynes 333c, g–i and 333c, h, respectively, to produce the corresponding nucleosides 335c, g–i and 336c, h, respectively (Figure 4.57). Thenucleosides 335c and 335h exhibited considerable cytotoxic effect on all four cancer cells such as colon (HT-29), lung (A549), melanoma (A375) and breast (MCF-7). Nucleosides 334b and 334h exhibited considerable

Figure 4.57: Synthesis of C-5′-triazole with variant nucleoside derivatives.

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antimicrobial activity with minimum inhibitory concentrations (MIC) against Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus cereus, and Escherichia coli.

4.3 Conclusions Recent studies have shown that triazolyl nucleosides have immense potential in the field of chemistry and biochemistry as possible drug candidates, in photophysical utility and also have various other applications. They have drawn considerable attention of researchers over the years are mainly used for the installation of triazole ring on sugar or carbocyclic moiety of nucleosides, mainly copper and ruthenium catalysed azide–alkyne cycloaddition reactions and related modified methodology have been used under various reaction conditions in good to excellent yields. Modified triazole nucleosides have shown broad biological applications such as antiviral, anticancer, antimicrobial, antifungal, antitumor and anti-proliferative activities. Besides biological activities, numerous other applications of these sugar-triazolo compounds have been discussed in this review. The intention of this article is to provide latest developments in the area of triazole modified nucleosides analogues and inspire further research to develop new analogues and chemical approaches to afford biologically active triazole nucleosides. Acknowledgements: Sandeep Kumar thanks CSIR, New Delhi for award of SPM Research Fellowship [File No. 09/045(0269)/2018-EMR-1].

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Yadavalli Venkata Durga Nageswar* and Ramesh Katla

5 An overview of quinoxaline synthesis by green methods: recent reports Abstract: Quinoxalines and their derivatives belong to an important class of bicyclic aromatic heterocyclic system, also known as benzopyrazines, containing a benzene ring and a pyrazine ring. They have attracted considerable attention over the years due to their potential biological and pharmaceutical properties. A wide range of synthetic strategies is reported in this significant area of research. The present review showcases recent research advances in the synthesis of quinoxaline derivatives following environmentally benign approaches. Keywords: aldehydes; benzimidazoles; heterocyclic compounds; orthophenylenediamine; quinoxalines.

5.1 Introduction Promoting sustainable green synthetic processes has become a global necessity due to several regulating and environmental issues. The green chemistry area evolved from the paradigm shift to alternate or eco-friendly reactions from classical organic chemical reactions. The principles of green chemistry cover and consist of factors reducing the pollution load on the environment and thereby contributing to the sustainability of Mother Nature. These broadly include reducing energy requirements for the reactions, avoiding toxic and volatile organic solvents, designing safer biodegradable chemicals, preventing and minimizing hazardous products/by-products, and utilizing safer, recyclable and higher-yielding catalysts [1]. Green chemistry protocols consist of microwave-assisted, ultrasound promoted, solid-state, and grinding reactions. Additionally, reactions catalyzed by biocatalysts, aqueous phase reactions, reactions performed at ambient/moderate temperatures, and reactions conducted under the influence of recyclable catalysts also can be categorized under green chemistry [2–6]. Based on these broad lines, the present review is classified into different sections for the reader’s convenience. Among heterocyclic nitrogen systems, quinoxalines occupy a prominent place as they exhibit a wide range of biological activities such as antiviral, antibacterial, anti-fungal, anthelmintic, insecticidal and anti-cancer properties [7].

*Corresponding author: Yadavalli Venkata Durga Nageswar, Indian Institute of Chemical TechnologyIICT, Tarnaka, Hyderabad, India, E-mail: [email protected] Ramesh Katla, Organic Chemistry Laboratory-4, School of Chemistry and Food, Federal University of Rio Grande-FURG, Rio Grande, RS, Brazil As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: Y. V. D. Nageswar and R. Katla “An overview of quinoxaline synthesis by green methods: recent reports” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0086 | https://doi.org/10.1515/9783110759549-005

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Quinoxalines are also essential building blocks for dyes, electroluminescent materials and organic semiconductors [8]. These scaffolds also serve as platforms for diversity-oriented synthesis in the solid phase [9, 10]. The quinoxaline structural units play a crucial role in chemically controllable switches and macrocyclic receptors for molecular recognition [11–13]. These moieties are also associated with different applications in organic semiconductors [8, 14], dyes [15], dehydroannulenes [16] and cavitands [17, 18]. In general, quinoxaline derivatives can be prepared by the cyclo condensation of 1,2-dicarbonyl compounds and 1,2-diamines [19, 20], 1,4-addition of 1,2-diamines to diazenyl butenes [21], cyclization-oxidation of phenacyl bromides with 1,2-diamines by HClO4.SiO2 [22], oxidative cyclization of α-hydroxy ketones with 1,2-diamines [23] and oxidative coupling of epoxides with ene-1,2-diamines [24]. Even though many synthetic approaches are available, the design and development of facile and eco-friendly protocols are always desirable to achieve sustainable organic synthetic processes. The present review attempts briefly to showcase recent research studies towards synthesizing quinoxaline derivatives by varied green methodologies.

5.2 Reactions conducted in aqueous medium Kumar and co-authors [25] exhaustively assessed the scope and limitations of several surfactant micelles as microreactors in the synthesis of different quinoxaline derivatives (3) in the water medium, using variously substituted 1,2-diamines (1) and 1,2-diketones (2) as reactants. The authors concluded that the catalytic potential of these surfactants followed the order non-ionic surfactants > anionic surfactants > Bronsted acid surfactants > cationic surfactants. Moreover, Tween-40 proved to be the best catalyst among all. The advantages of the protocol are (a) universally acceptable water as medium, (b) room temperature reaction, (c) short reaction times, (d) no waste generation, (e) no other reagents are required, (f) higher yields, (g) ease of product isolation and (h) use of cost-effective, readily available, nontoxic, catalyst Tween 40; Authors also compared the efficiency of other reported Lewis/Bronsted acid-catalyzed methodologies with the reactions catalyzed by Tween 40 (Figure 5.1).

Figure 5.1: General representation of the reactions catalyzed by Tween 40.

5.2 Reactions conducted in aqueous medium

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Chakrabarti and co-authors [26] unveiled a new facile protocol for the synthesis of a diverse library of N-heterocyclic moieties such as benzimidazoles (4), quinazolines (5) and quinoxalines (6) utilizing a wide range of vicinal diamines as well as 2-nitroaniline derivatives, 2-aminobenzyl amines (1) bio-renewable alcohols, symmetrical and unsymmetrical diols (7) as reactants in a water medium. Authors established scalable preparation of different pharmaceutically active quinoxaline and other N-heterocyclic scaffolds. During investigations, authors screened several Ir-precursors and Ir (III) complexes for catalytic efficiency and reported that 2-hydroxy pyridine based Ir (III) complex offered the best results (Figure 5.2). Bardajee et al. [27] successfully employed iron (III) trichloride as a catalyst in the synthesis of pyrazine based polycyclic aromatic compounds such as pyrazine (8a, b), pyridopyrazine (8c–g) and quinoxaline (9a–d) derivatives by the condensation of various aromatic 1,2-diamines (1) and 1,2-dicarbonyl compounds (2) in a water medium. The authors examined the effect of different solvents, such as EtOH, MeOH, DMF, DMSO and H2O in their study (Figure 5.3).

(a)

(b)

(c)

Figure 5.2: Ir (III) complex promoted synthesis of heterocyclic derivatives in water medium.

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Figure 5.3: Representative pyrazine/quinoxaline scaffolds prepared using iron (III) trichloride.

Kumar and co-researchers [28] investigated into a novel, tandem one-pot procedure for obtaining diversely substituted quinoxalines (10) in water. The strategy involves insitu formation of α-halo-β-ketones/α-halo-β-keto esters from β-diketones/β-keto esters (2a) by the reaction of NBS (11) followed by the cyclocondensation of α-halo-β-ketones, α-halo-β-keto esters with o-phenylene diamines (1) in water at 70 °C (Figure 5.4). Initially, the authors evaluated the effect of different solvents and temperatures for carrying out the model reaction. Diversely substituted quinoxaline (12) and 2,3-dihydro pyrazine (13) derivatives were prepared by Camilla Delpivo et al. by the simple addition of 1,2-dicarbonyl compounds (2), and 1,2-diamines (1, 1a) in an aqueous medium at room temperature (Figure 5.5) [29]. Kamal and co-authors [30] investigated into a facile, environmentally benign procedure to make a small library of functionalized quinoxaline-sulphonamide (14)

Figure 5.4: Formation of quinoxaline derivatives via insitu formation of α-halo-β-ketones/α-haloβ-keto esters.

5.2 Reactions conducted in aqueous medium

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(a)

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Figure 5.5: Preparation of 2,3-dihydro pyrazine and substituted quinoxaline derivatives.

conjugates mediated by L-proline in the water medium obtained by the condensation of 1,2-diamines (1) and variously substituted hydroxy ketones (2b) (Figure 5.6). Ghafuri [31] developed a simple, efficient, eco-friendly and catalyst-free preparation of several quinoxaline moieties (15a–e) from different aromatic 1,2-diketones (2) and 1,2-diamines (1) in water medium (Figure 5.7). Edayadulla and Lee [32] prepared a large library of highly substituted novel quinoxalin-2-amine (16) and 3,4-dihydro quinoxalin-2-amine derivatives (17) from 1,2-diamines (1) and various substituted aldehydes (18) and ketones (2a) in the presence of isocyanides (19) using water as a medium via CeO2 nanoparticles catalyzed one-pot three-component methodology. Initially, authors examined the efficacy of InCl3, (NH4)2Ce(NO3)6, CCl3·7H2O, and CeO2 NPS as catalysts and observed that best results could be obtained from CeO2 NPS. Several solvents like toluene, EtOH, CH3CN and water were tested for their suitability. Finally, CeO2 NPS in water at 80 °C was selected at the end of optimization studies (Figure 5.8).

Figure 5.6: L-proline catalyzed synthesis of quinoxaline derivatives.

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Figure 5.7: Catalyst-free preparation of quinoxaline derivatives in water.

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Figure 5.8: CeO2 NPS catalyzed preparation of quinoxalines derivatives.

Bhattacharya et al. [33] employed 4-amino thiophenol self-assembled nano layer-coated gold nanoparticles (Au NPs) (20) as a reusable catalyst for the preparation of different quinoxaline compounds (21) in water medium via insitu oxidation of α-hydroxy ketones (2b), followed by the condensation reaction with aryl-1,2-diamines (1). The effect of various bases and catalysts, as well as their loadings, was studied by

5.2 Reactions conducted in aqueous medium

111

the authors during optimization studies. The scope of the protocol was expanded to include diversely substituted aryl/heterocyclic α-hydroxy ketones (2b) (Figure 5.9). Mulik et al. [34] discussed an efficient and ecofriendly water medium preparation of phthalazine trione (22) and quinoxaline scaffolds (23a, b, c) obtained by the condensation of 1,2-diamines (1) and 1,2-diketone (2) compounds in the presence of biodegradable, less toxic, reusable ionic liquid catalyst (C8dabco)Br. Substrate scope and different reaction parameters were evaluated by the authors during the study (Figure 5.10).

Figure 5.9: AuNPS/H2O aided preparation of quinoxalines.

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Figure 5.10: (C8dabco)Br catalyzed synthesis of heterocyclic compounds.

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Kumar et al. [35] carried out a catalyst-free and additive-free one-pot green protocol affording a broad range of quinoxaline (24) scaffolds in an aqueous medium. The target compounds were formed by the cyclo-condensation of 1,2-diamines (1) with phenacyl bromides (25) (Figure 5.11). Kamal and co-authors [36] have developed a simple, efficient, environmentally benign approach for 4,5-dihydro pyrrolo-[1,2-a]quinoxalines (26), obtained by the condensation of 1-(2-amino phenyl) pyrrole (27) and various aryl aldehydes (18a). Different 1,3-diaryl pyrazole carboxaldehydes (29) were also reacted to afford 4-(1,3-diphenyl-1H-pyrazol-4-yl)4,5-dihydro pyrrolo [1,2-a] quinoxaline (30) scaffolds. In this methodology, authors successfully employed recyclable, solid acid, heterogeneous catalyst-sulfamic acid-H2NSO3H-SA (28). In this operationally simple method, water was used as a solvent. During optimization studies, authors evaluated the effect of various solvents and temperature conditions (Figure 5.12). These compounds were screened for cytotoxic potential against two human cancer cells. The authors discussed the role of H2NSO3H. H. M. Bachhav et al. [37] prepared a large library of quinoxalines (31), benzoxazoles (32) and benzimidazoles (33) by a catalyst-free mild method from variously substituted suitable substrates using glycerol/water medium at 90 °C (Figure 5.13). De Andrade and de Mattos [38] utilized DABCO in a simple method for the preparation of thiazole (34) and quinoxaline compounds (35) in MeCN/water medium. The target compounds are obtained from the reaction of α-mono halogenated intermediates of β-keto esters (2a) with thiourea (36)/o-phenylene diamines (1). Tribromo isocyanuric acid (37) is used for bromination. The scope and generality of the reactions were studied by extending the protocol to various suitable reactants (Figure 5.14). Liu and co-researchers [39] in their paper explained the application of α-amino acids (38) for a concise and practical transition metal-free approach affording pyrrolo [1,2-a]quinoxalines (39, 39a, 39b), with a broader substrate scope and functional group tolerance. The protocol proceeds via the formation of new C–C and C–N bonds. A broad range of target molecules was synthesized using substituted 2-(1H-pyrrol-1-yl) anilines (27, 27a, b) and short as well as long-chain amino acids (38, 38a), following (NH4)2S2O8 mediated oxidative, decarboxylative coupling of primary α-amino acids (38) with

Figure 5.11: Catalyst-free additive-free protocol for quinoxalines.

5.2 Reactions conducted in aqueous medium

(a)

(b)

Figure 5.12: H2NSO3H catalyzed synthesis of dihydroquinoxaline derivatives in water medium.

(a)

(b)

(c)

Figure 5.13: Preparation of different heterocyclic scaffolds using glycerol/water medium.

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5 An overview of quinoxaline synthesis by green methods

(a)

(b)

Figure 5.14: DABCO mediated preparation of thiazole and quinoxaline derivatives.

pyrrolyl anilines (27). During optimization studies, various solvents and catalysts were screened for suitability and consistent results. (NH4)2S2O8 and DCE/H2O provided the best results (Figure 5.15). Brust and Cuny [40] successfully converted a range of disaccharides into a matrix of quinoxalines (40) via 1,2-dicarbonyl intermediates (2b). Isomaltulose (Palatinose R) (41), a naturally occurring disaccharide, and ideal cheap industrial feedstock raw material, was transformed by the authors into different N-heterocycles via isomaltosone formation. The protocol allows the preparation of side-chain hydroxylated quinoxalines (42), pyrazolo [3,4-b] quinoxalines (43), pyrazines (44) and 1,2,4-triazines (45) having a diverse glycosylation pattern, using reducing disaccharides and monosaccharides (Figure 5.16). Kolla and Lee [41] prepared 3,4-dihydro quinoxaline-2-amine derivatives (46) by the reaction of o-phenylenediamines (1), different carbonyl compounds (2c) and isocyanides (19) in water assisted by EDTA, in an eco-friendly one-pot threecomponent approach (Figure 5.17). During the optimization, authors investigated the effect of different Bronsted acid and base catalysts on the model reaction and observed that best results were obtained with 20 mol% of EDTA in water. EDTA is assumed, to act as a Bronsted acid and base catalysts. It was claimed that the protocol was useful for scale up preparations. Murthy and co-authors [42] unveiled an efficient environmentally benign, and expeditious approach for 3-substituted quinoxalin-2-one derivatives (47), obtained by the reaction of substituted 1,2-diamines (1) with different α-keto esters (2a) at 50 °C in

5.3 Reactions conducted at room temperature

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(a)

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(c)

Figure 5.15: (NH4)2S2O8 mediated preparation of pyrrolo [1,2-a] quinoxalines.

water medium under catalyst-free conditions. The reactions were observed to be instantaneous and the end products were separated by simple filtration techniques (Figure 5.18).

5.3 Reactions conducted at room temperature Lassagne et al. [43] successfully conducted studies on ammonium bifluoride catalyzed regioselective synthesis of a library of pyrazolo[2,3-b]pyrazines (48) and quinoxaline derivatives, obtained by the cyclo-condensation of 1,2-dicarbonyl compounds (2) with 1,2-arylene diamines (1b) in methanol/water medium at room temperature. During optimization studies, authors evaluated the influence of different catalysts, solvents and reaction times. To extend the scope of the protocol, the authors applied the strategy to include diversely substituted symmetrical and unsymmetrical 1,2-arylene diamines

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5 An overview of quinoxaline synthesis by green methods

Figure 5.16: Preparation of N-heterocycles from isomaltulose.

and 1,2-dicarbonyl compounds. The authors examined the recyclability of ABF filtrate for successive reactions (Figure 5.19). Dhakshinamoorthy and co-authors [44] presented a straightforward, efficient, eco-friendly protocol for benzimidazole (49) and quinoxaline scaffolds (50). The target compounds were obtained by the reaction of carbonyl compounds (2) and o-phenylene diamines (1) in water medium at room temperature, mediated by water-tolerant recyclable solid acid – Lewis acid catalyst – Zinc chloride exchanged K10-montmorillonite (Clayzic) (Figure 5.20). During optimization studies, the authors examined the effects of different catalysts and solvents for this protocol. To generalize the versatility and scope of this approach,

5.3 Reactions conducted at room temperature

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Figure 5.17: EDTA-assisted preparation of 3,4-dihydroquinoxalin-2-amines.

Figure 5.18: Catalyst-free synthesis of 3-substituted quinoxalinone derivatives.

Figure 5.19: ABF promoted regioselective preparation of pyrazolo[2,3-b]pyrazines and quinoxalines.

differentially substituted aryl/heteroaryl aldehydes (18a) and aliphatic/aromatic dicarbonyl compounds (18a) were used successfully. The role of K10-ZN+2 was explained by the authors. An eco-friendly synthesis of a library of highly functionalized quinoxaline (51) and benzimidazole scaffolds (52) was accomplished by Ghosh and Mandal [45] in an aqueous medium at room temperature, supported by resin-bound hexafluoro phosphate ion (Figure 5.21).

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Figure 5.20: Clayzic mediated synthesis of benzimidazoles and quinoxalines.

(a)

(b)

Figure 5.21: PHP assisted synthesis of quinoxaline and benzimidazole molecules in water medium.

The authors evaluated the effects of different solvents and other reaction parameters. The scope of this straightforward protocol was expanded to include a large number of functionalized substrates. Hexafluorophosphate ion was proved to be bound to Amberlite 900 resin and catalyze all the reactions effectively. The method was compatible with a variety of substituents. Pawar et al. [46] established successfully the efficacy of thiamine hydrochloride, an inexpensive, nontoxic metal ion free catalyst, in the condensation reaction of variously substituted 1,2-diketone compounds (2) and 1,2-diamines (1) at ambient temperatures resulting in quinoxaline compounds (53). During the optimization studies, the authors examined different parameters, such as the effect of various solvents and catalysts on the reactions (Figure 5.22).

5.3 Reactions conducted at room temperature

119

Figure 5.22: Thiamine hydrochloride aided preparation of quinoxalines.

Jafarpour and co-researchers [47] developed a new, green, recyclable Lewis acid catalytic system, zirconium IV oxide chloride octahydrate (ZrOCl2·8H2O), for preparing quinoxaline scaffolds (54) from 1,2-diamines (1) and 1,2-dicarbonyl compounds (2) in ethanol medium at room temperature (Figure 5.23). The reactions were carried out using ethylenediamine and 2,3-butane diones as substrates under identical reaction conditions. Lassagne and co-authors [48] employed saccharin as a cost-effective organic catalyst for the cyclo-condensation of various 1,2-dicarbonyl compounds (2) with several 1,2-arylene diamines (1) affording pyrido[2,3-b]pyrazines (55) and quinoxalines (56) in methanol at room temperature. The authors screened several solvents of different polarities for the reaction and presented results that were compared with the known literature results, where different catalysts and solvents were used (Figure 5.24). Mohammadi et al. [49] has unveiled the application of different metalloporphyrins as new catalytic systems for developing a simple, highly efficient, environmentally benign regioselective protocol for functionalized quinoxaline scaffolds (57, 57a, 57b) by the condensation of alkyl/aryl 1,2-diamines (1, 1a) with α-diketones (2, 2a). In this study, the authors examined the effects of the metal core as well as the substituents on the tetraphenyl porphyrin skeleton. It was observed that the variation of central metal in porphyrin controlled the yield of quinoxalines. It was mentioned that trivalent

Figure 5.23: ZrOCl2·8H2O assisted synthesis of quinoxalines.

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Figure 5.24: Saccharin promoted quinoxaline and pyrido[2,3-b]pyrazine synthesis.

metalloporphyrins like Cr+3, Mn+3, Fe+3, and Co+3 afforded better yields than divalent metalloporphyrins such as Co+2, Ni+2, Cu+2 and Zn+2. Among solvent systems, H2O/EtOH (3:1 V/V) appeared to be the best and Co (TpOMePP)Cl was the most efficient catalyst. The authors discussed the role of metalloporphyrins (Figure 5.25).

(a)

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Figure 5.25: Metalloporphyrin assisted synthesis of quinoxaline derivatives.

5.3 Reactions conducted at room temperature

121

Ghorbani–Vaghei and co-researchers [50] worked on a convenient one-pot threecomponent approach for monoacid bis N-cyclohexyl-3-alkyl (aryl)quinoxaline-2-amines (58, 58a) by Ugi reaction of aromatic amines (1, 1b), aliphatic/aromatic aldehydes (18) and cyclohexyl isocyanide (19a), catalyzed by N,N,N1,N1-tetrabromo benzene1,3-disulfonamide (TBBDA) or poly (N-bromo-N-ethylbenzene-1,3-disulfonamide) (PBBS). The authors evaluated the influence of different solvents on the reaction. The scope of the protocol was expanded to include widely substituted aliphatic and aromatic/heterocyclic aldehydes (Figure 5.26). Kadam et al. [51] described a cost-effective, environmentally benign simple method for preparing a library of quinoxaline molecules (59, 59a–d) by the double condensation of phenanthrene-9,10-dione (2d), substituted benzils (2a), benzoin (2b), and isatin (2c) with aliphatic/aromatic diamines (1) in ethanol at room temperature using heterogeneous, abundantly available reusable graphite as a catalyst (Figure 5.27). Elumalai and Hansen [52] established a catalyst-free, ecofriendly 1 min preparation of a library of quinoxaline derivatives (60) by the cyclo-condensation of aliphatic and aromatic/heterocyclyl dicarbonyl compounds (2) and aryl diamines (1) in methanol at ambient temperatures. During optimization, authors worked on different solvents. A broad range of substrates was used in this protocol (Figure 5.28). Han and co-researchers [53] disclosed an atom economical, green approach for getting vicinal tricarbonyl intermediates (2e) from variously substituted dicarbonyl

(a)

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Figure 5.26: TBBDA/PBBS catalyzed synthesis of quinoxalines and bisquinoxalines.

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Figure 5.27: Graphite promoted quinoxaline synthesis.

compounds (2a) by mild aerobic oxidation in the presence of Cu(II)salts, followed by the condensation with o-phenylene diamines (1) affording diversely functionalized quinoxalines (61, 61a) (Figure 5.29).

5.3 Reactions conducted at room temperature

123

Figure 5.28: Preparation of quinoxaline scaffolds at room temperature.

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Figure 5.29: Cu(NO3)2 aided preparation of quinoxalines.

During optimization, the authors evaluated the effect of different solvents and catalysts on the reaction. A large number of substituted substrates were used in the protocol. Yang and co-authors [54] presented NCS promoted thiocyanation and selenocyanation approaches affording 1-thiocyanato pyrrolo [1,2-a] quinoxalines (62, 62a–c) and 1-selenocyanato pyrrolo[1,2-a] quinoxalines (62d), using several functionalized pyrrolo [1,2-a] quinoxalines (65, 65a, 65b), potassium thiocyanate (63), ammonium thiocyanate or potassium selenocyanate (64, 64a). The authors screened several oxidants and solvents for the protocol (Figure 5.30). Gopalaiah and co-authors [55] investigated a practically simple copper-catalyzed aerobic oxidative coupling of 2-aryl/heteroaryl ethyl amines (1c) with o-phenylenediamines, substituted phenylenediamines and 2,3-diamino pyridine (1, 1a, 1b) leading to a

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Figure 5.30: NCS promoted pyrrolo [1,2-a] quinoxalines preparation.

wide range of quinoxaline and pyridopyrazine scaffolds (66, 66a, 66b) utilizing molecular oxygen as an oxidant. The protocol was enlarged to include a broad spectrum of substrates having functional group tolerance. Various copper salts and solvents are screened to have the best results (Figure 5.31). Catalyst role was discussed by the authors. Harsha and Rangappa [56] unveiled the preparation of an extensive library of highly functionalized quinoxaline scaffolds (67, 67a–d), following an easy and efficient propyl phosphonic anhydride (T3P/DMSO) or T3P mediated oxidative condensation method. In this versatile methodology broad range of substituted 1,2-diketones or α-hydroxy or α-halo ketones, (2, 2a) and o-phenylene diamines (1, 1a) are used as substrates. The effect of different parameters, including solvents, are examined to obtain the best possible results (Figure 5.32).

5.3 Reactions conducted at room temperature

125

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Figure 5.31: Copper-catalyzed aerobic oxidative coupling.

The role of T3P catalyst was discussed by the authors. A series of diversely fused [1,2,4] triazolo [3,4-c] quinoxalines (68a–c) was reported by Yang et al. [57]. The target molecules were obtained via KI/TBHP promoted [3 + 2] cycloaddition of N-aryl sulfonyl hydrazones (69) and pyrrolo [1,2-a] quinoxalines (65) in DCE medium at room temperature. During optimization, authors screened several catalysts, oxidants, and solvents. A broad range of substituted N-tosyl hydrazones (69, 69a–c) and pyrrolo [1,2-a] quinoxalines (65) were employed in this scalable mild protocol. The role of KI and TBHP was accounted by the authors (Figure 5.33). An et al. [58] accomplished a simple, straightforward methodology for producing variously substituted pyrrolo [1,2-a] quinoxaline scaffolds (71, 71a, b) from the reaction of 1-(2-aminophenyl) pyrroles (27a–c) with cyclic/linear ethers (70, 70a, b) employing FeCl3 as a catalyst and readily accessible substrates at room temperature. Initially, the efficacy of several transition metal catalysts, oxidants, and solvents was examined and evaluated. The scope of the protocol was exhaustively studied to include broadly substituted reactants (Figure 5.34). The authors confirmed that reaction did not progress without oxidant or iron catalyst. Optimization conditions include 20 mol% FeCl3; 70% TBHP; 10 mol% CF3SO3H. A novel cascade approach was unveiled by Reddy and co-researchers [59], to synthesize a wide range of highly functionalized poly cyclic molecules, which include

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5 An overview of quinoxaline synthesis by green methods

(a)

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(e)

Figure 5.32: T3P promoted preparation of highly functionalized quinoxaline scaffolds.

(a) polyhydroxylated tetrahydro indolo [1,2-a] pyrrolo [2,1-c] quinoxalines (72) (b) tetrahdrodipyrrolo [1,2-a, 21, 11-c] quinoxalines (72a), (c) hexa hydro-1H-indolizino [8,7,-b] indoles (73), (d) hexahydrobenzo [6,7] pyrrolo [11,21: 1, 2] azepino [3,4-b] indoles (73a), (e) tetrahyddrobenzo [4,5] imidazol [1,2-c] pyrrolo [1,2-a] quinazolines (74) and (f) tetrahydro pyrrolo [1,2-a] tetrazolo [1,5,-c] quinazolines (75). The methodology involves

5.3 Reactions conducted at room temperature

127

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Figure 5.33: TBHP-KI mediated preparation of fused [1,2,4] triazolo [3,4-c] quinoxalines.

efficient lactamization/N-acyliminium Pictet-Spengler domino strategy. The efficacy of acid catalysts such as TFA, InCl3, FeCl3, AlCl3, p-TsOH, Yb(OTf)3, Sc(OTf)3, BF3.OEt2 was evaluated and observed that BF3.OEt2/DCM gave better results, at ambient temperatures (Figure 5.35). Lin and co-authors [60] prepared a library of 2,3-diaryl quinoxaline derivatives (76) obtained by a one-pot facile condensation of benzene 1,2-diamines (1) and benzils (2a) (Figure 5.36).

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Figure 5.34: FeCl3 catalyzed preparation of pyrrolo [1,2-a] quinoxaline scaffolds.

Figure 5.35: Representative polycyclic scaffolds.

The strategy involves tandem N-heterocyclic carbene (NHC) promoted umpolung of aryl/heterocyclyl aldehydes (18)/oxidation of benzoins to benzils. Bases like Na2CO3, K2CO3, NaOH, Et3N, NaHCO3 and DBU, as well as solvents such as DMF, THF,

5.3 Reactions conducted at room temperature

129

Figure 5.36: NHC mediated tandem reactions.

MeCN, CH2Cl2, DMSO and MeOH were examined for the standardization of the reaction. DBU was selected as a better base. Imidazolium salt derived carbene was obtained by the deprotonation of thiazolium salt in the presence of the base. The role of NHC was explained by the authors. A series of pyrido [2,3-b] pyrazines (77) and quinoxalines (78, 78a) were synthesized in an eco-friendly way by Kumbhar and co-researchers [61] by applying newly developed recyclable Bronsted acid hydrotrope combined catalyst (BAHC) – 5 mol% P-toluene sulfonic acid combined with 40% aqueous sodium P-toluene sulfonate (PTSA + NaPTS) at room temperature. Initial optimization studies proved that PTSA was more effective when compared to sodium xylene sulfonate (NaXS) or sodium benzene sulfonate (NaBS) to work with NaPTS. Out of different concentrations, 40% aq. NaPTS along with 5% PTSA afforded desired higher yields. The protocol was extended to include widely substituted diketones (2, 2a), aryl/heterocyclyl 1,2-diamines (1, 1a). Reaction of tetra amines resulted in the formation of 2,3,2,3, tetraaryl (6,6) biquinoxalinyl derivatives (78b) (Figure 5.37). The authors discussed the active role of BAHC. Bhutia and co-authors [62] established an environmentally benign, catalyst-free, cost-effective and mechanosynthesis of various quinoxaline derivatives (79) by a simple liquid assisted hand grinding (LAH) of aromatic/heteroaromatic diamines (1) with several 1,2-dicarbonyl compounds (2) in an agate mortar-pestle. Authors observed the effect of solvents such as water, CHCl3, CH3CN, EtOH, as well as conditions such as neat and the presence of silica gel or basic alumina (Al2O3) as solid reaction media (Figure 5.38). A short environmentally benign mild methodology for pyrazin-coumarin hybrid compounds (80) was disclosed by Khalyambadzha and co-researchers [63]. The strategy involved the nucleophilic substitution of hydrogen in quinoxalones (81) and pteridinones (82) by the reaction of 5,7-dihydroxycoumarins (83) and m-hydroxy benzene derivatives (84). TFA or BF3.Et2O was used as a catalyst in the addition step of C–C coupling. Chloranil or DDQ was used as an oxidant. The reaction occurs at the C-8 position of both chromone/coumarin (85) systems. Reactions were performed at milder temperatures (Figure 5.39).

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(b)

(c)

Figure 5.37: BAHC supported preparation of pyrido [2,3-b] pyrazines and quinoxalines.

Figure 5.38: Quinoxaline preparation by liquid assisted hand grinding method.

5.4 Reactions conducted under microwave energy

131

Figure 5.39: Representative quinoxaline/pteridine hybrid molecules.

Preetam and Nath [64] disclosed an eco-friendly convenient Pictet–Spengler strategy for a library of biologically potent diversely substituted pyrrolo (86)- and indolo [1,2-a] quinoxaline (87a, b) scaffolds obtained by the reaction of 1-(2-amino phenyl)-pyrrole- or 1-(2-aminophenyl) indoles (27a) with a broad range of aromatic aldehydes (18), acetophenones (2d) or isatins (2c) at ambient temperatures using ethanol as solvent medium and employing Bronsted acid surfactant-P-dodecyl benzene sulfonic acid (P-DBSA) as a catalyst. During optimization studies, authors screened different catalysts, solvents, and other conditions for the reaction (Figure 5.40).

5.4 Reactions conducted under microwave energy A straightforward, practical approach for a novel series of 3-(6-phenylimidazo[2,1-b] thiazol-5-yl) quinoxalin-2(1H)-one (88) derivatives by MW assisted synthesis was achieved by Mukherjee et al. [65]. These products were made via Hinsberg reaction of

Figure 5.40a: P-DBSA assisted synthesis of 4-arylpyrrolo[1,2-a]quinoxalines/6-aryl-indolo[1,2-a] quinoxalines, 7-methyl-6-(pyridine-4-yl)indolo[1,2-a]quinoxalines.

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5 An overview of quinoxaline synthesis by green methods

Figure 5.40b: Preparation of 4-methyl-4-aryl-4,5-dihydro pyrrolo[1,2-a]quinoxalines.

Figure 5.40c: Synthesis of 51H-spiro[indolin-31,41-pyrrolo31,61-indolo[1,2-a] quinoxalin]-2-ones; 7-methyl-51H-spiro[indolin-31,61-indolo[1,2-a]quinoxalin]-2-ones.

ethyl-2-oxo-2-(6-phenyl imidazo[2,1,-b]thiazol-5-yl-)acetates (89) with diversely substituted o-phenylene diamines (1) in acetonitrile medium under microwave irradiation conditions. Thiazol-2-amine (90) was reacted with different 2-bromo1-phenylethanones (25) affording 6-phenyl imidazo[2,1,-b] thiazoles (91), which in turn reacted with ethyl chloroacetate (92) in refluxing 1,4-dioxane to produce 2-oxo-2(6-phenyl imidazo[2,1,-b]thiazol-5-yl)acetates (89) (Figure 5.41). A series of substituted 2-phenyl quinoxalines (94) and 7-bromo-3-(4-ethyl phenyl) pyrido[2,3,-b]pyrazines (95) were prepared by Jadhav and co-authors [66] by an expeditious one-pot multicomponent environmentally benign approach in water-PEG, water/ethanol employing acetophenones (96), succinimide (97) aromatic amines (1a), and iodine (98). The protocol proceeds via insitu generation of α-iodoacetophenone, under microwave irradiation conditions. Several solvents were tested initially for suitability (Figure 5.42). Maiti et al. [67] described the synthesis of a wide range of variously substituted scaffolds of symmetrical and unsymmetrical bis(triazolylmethyl)quinoxalines (99) obtained in the presence of Cu (II) catalyst/sodium ascorbate as well as Ir (I) and CuO nanoparticles under microwave conditions (Figure 5.43). Initially a slurry of 1,4-dibromo-2,3-dione and o-phenylenediamine (1) made in ethanolic solution in silica gel was heated in microwave to afford bis(bromomethyl)quinoxaline derivatives (101),

5.4 Reactions conducted under microwave energy

133

Figure 5.41: Preparation of 3-(6-phenyl imidazo[2,1,-b] thiazol-5yl)quinoxalin-2(1H)-one molecules by MW irradiation.

Figure 5.42: Microwave irradiated preparation of 2-phenyl quinoxalines and pyrido[2,3-b] pyazines.

Figure 5.43: MW assisted preparation of bis (triazolyl methyl) quinoxalines.

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which were again converted to azido compounds (101a). These undergo click reaction with phenyl acetylenes (103) in the presence of CuSO4/sodium ascorbate to yield title compounds. During optimization, the authors examined the efficacy of several catalysts, additives as well as solvents and other conditions for the present protocol. Target molecules were investigated for their cytotoxicity, biomolecular interactions and biocompatibilities. An efficient ecofriendly microwave-assisted one-pot four-component cascade approach for a library of highly functionalized indeno[1,2-b]quinoxaline-11,31-pyrrolizine scaffolds (104) was investigated successfully by Akondi and co-authors [68]. The condensation of phenylenediamine (1), ninhydrin (105), proline (106) and nitrostyrene (107) derivatives in ethanol medium afforded the target molecules, which were screened for AChE inhibitory activity. A comparative study of the present results was presented with compounds obtained by both classical and MW irradiated conditions. The reactions proceed via 1,3-dipolar cycloaddition of azomethine ylides (108) with trans-β-nitrostyrene derivatives (107a) (Figure 5.44). Initially, the authors examined the effect of solvents such as MeOH, EtOH, CH3CN, toluene and water and observed that ethanol suited well for the reaction. The authors also observed that MW conditions led to increased reaction rates as well as yields of the products. The protocol was extended to include several substituted β-nitro styrenes (107). Reactions proceeded positively irrespective of electronic, steric properties as well as the position of substituents on the aromatic ring of β-nitrostyrene. Jeena and Robinson [69] presented a cost-effective, eco-friendly, solvent-free, MW assisted one-pot tandem oxidation process for quinoxaline derivatives (109, 109a–c) employing silica gel as a catalyst at 70 °C. In this methodology, aliphatic/aromatic 1,2-diamines (1, 1c) and α-hydroxy ketones (2b, 2c, 2d) were used as substrates. During optimization, several microwave conditions were checked, and the efficacy of different solvents was assessed (Figure 5.45). Chatterjee and co-researchers [70] utilized basic alumina as reusable solid support and Cu(Phen)(PPh3)Br as a catalyst in MW assisted approach for simple green synthesis of a series of triazolobenzoxazines (110), triazoloquinoxalines

Figure 5.44: MW assisted preparation of indeno[1,2-b]quinoxaline-11,31-pyrrolizine scaffolds.

5.4 Reactions conducted under microwave energy

135

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Figure 5.45: Silica gel supported, MW assisted preparation of quinoxalines.

(111), triazolobenzodiazepines (112), triazolobenzoxazepines (113), and triazolobenzothiazines (114) obtained by the reaction of diversely substituted azido alkynes (115) and aryl imidazol-1yl-sulfonates (116) which acted as oxygenated electrophilic compounds. Basic alumina acted as both support and base. Systematic investigations were carried out to establish the efficacy of various solid supports such as TiO2, MgO, basic alumina and also different copper catalysts. It was observed that Cu(Phen)PPh3Br played dual role in the cycloaddition reaction as well as in the activation of C–H bond. The authors conducted a comparative study between conventional and microwave methods. The scope of the protocol was extended to include a large base of substrates (Figure 5.46). A rapid, simple, solvent-free and MW assisted preparation of quinoxalines (117) was carried out by Padmavathi et al. [71]. The method starts with ketones (2a) which are condensed with 1,2-diamino benzenes (1) via α-hydroxyl imino-ketone (118) stage. The authors studied the condensation step in three conditions (a) neat conditions, (b) as a paste in PEG 400 (c) as an acetic acid paste. It was observed that the best results were obtained under neat conditions. This protocol was also investigated both in single-stage one-pot mode as well as in a two-step process (Figure 5.47).

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5 An overview of quinoxaline synthesis by green methods

Figure 5.46: Basic alumina promoted MW assisted synthesis of different heterocyclic derivatives.

Figure 5.47: MW assisted preparation of quinoxalines.

Zhang and co-researchers [72] established a rapid and efficient methodology for synthesizing quinoxalines (121, 121a) by the condensation reaction of 1,2-dicarbonyl compounds (2) and 1,2-diamines (1) by CEM focused microwave-assisted synthesis using PEG-400 at 120 °C. The authors examined the effect of different catalysts, temperature and power on the yields of the reaction. Results obtained by following both conventional and MW methods were compared (Figure 5.48).

(a)

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Figure 5.48: MW assisted preparation of quinoxalines using PEG as an alternate medium.

5.5 Solvent-free reactions

137

5.5 Solvent-free reactions Nikumbh and co-authors [73] disclosed an environmentally benign methodology towards double hetero arylation of N, O, and S nucleophiles leading to the synthesis of a library of polynuclear fused N-heteroarenes containing indole ring fused with furo, pyrrolo and thieno [2,3-b] quinoxaline moieties (122) by the ring closure reaction employing reactants (123), and (125). Initially, the authors examined several catalysts, bases, solvents and other conditions during optimization trials. Interestingly the reaction proceeded well in the absence of any base catalyst or solvent. The generality and scope of the approach were exhaustively studied, employing a range of substrates (Figure 5.49). Shamsi-Sani et al. [74] described a simple, fast solvent-free protocol for quinoxalines (126) and benzimidazoles (127), obtained by the condensation of various aryl aldehydes (18) and 1,2-dicarbonyl compounds (2a) with substituted o-phenylene diamines (1), in the presence of eco-friendly recyclable sulfonated rice husk ash (RHA-SO3H). The authors extended the protocol to include a broad range of substrates (Figure 5.50). The authors compared the efficacy of the present catalyst with other literature reported catalysts. The protocol was extended to include different substrates. Kamal and co-authors [75] employed amberlite IR-120H as an efficient, costeffective, reusable solid-phase catalyst for the preparation of a series of diversely substituted quinoxaline compounds (128) in a solvent-free protocol. During optimization, different reaction parameters were thoroughly examined (Figure 5.51). Kamal and co-authors [76] developed a simple, eco-friendly solvent-free approach for pyrrolo[1,2-a]quinoxalines (129, 130) and 51H-spiro[indoline-3,41-pyrrolo[1,2-a]

Figure 5.49: Solvent-free synthesis of indole fused pyrrolo-, furo-, and thieno[2,3-b]quinoxalines derivatives.

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Figure 5.50: RHA-SO3H assisted solvent-free preparation of quinoxaline/benzimidazole scaffolds.

Figure 5.51: Amberlite IR-120H promoted solvent-free synthesis of quinoxalines.

quinoxaline]-2-ones (131) at room temperature conditions. In this methodology, the authors successfully used inexpensive, recyclable amberlite IR-120H resin as a catalyst. During optimization, the effect of different solvents, temperature conditions, as well as catalyst loadings were investigated for consistent and best results. In the research study 1-(2-amino phenyl)pyrrole (27), various aryl aldehydes (18), some 1,3-diaryl pyrazole carboxaldehydes (29) and isatin compounds (2c) were utilized as substrates. The reactions of different isatin derivatives with 1-(2-aminophenyl)pyrrole afforded 51H-spiro [indoline-3,41-pyrrolo[1,2-a]quinoxaline]-2-ones (131) (Figure 5.52).

5.5 Solvent-free reactions

139

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Figure 5.52: Amberlite IR-120H promoted solvent-free approach for pyrrolo[1,2-a]quinoxalines and 51H-spiro[indoline-3,41-pyrrolo[1,2-a]quinoxaline]-2-ones.

Das and co-researchers [77] developed a facile sustainable approach for a wide range of quinoxaline (132), pyrazine (133), benzothiazole (134) and quinoline derivatives (135) catalyzed by a phosphine free Mn(I) complex via dehydrogenative C–C and C–heteroatom bond formation. Authors carried out the reactions between diversely substituted 1,2-diamines (1c) and vicinal diols (7) affording pyrazines and quinoxalines. Dehydrogenative coupling of 2-aminothiophenol with primary alcohols yielded benzothiazole derivatives. Various quinolines were synthesized by the dehydrogenation and condensation reactions between secondary alcohols (7a) and 2-aminobenzyl alcohols (136) via the concurrent formation of C–C and C–N bonds. Different solvents, bases and catalysts were screened during standardization (Figure 5.53). Roy et al. [78] prepared a library of quinoxaline scaffolds (137) directly from 2-nitro anilines (1e) by the initial reduction with hydrazine hydrate (138) followed by one-pot tandem reaction with 1,2-dicarbonyl compounds or with α-hydroxy ketones (2b) under solvent-free conditions. In this metal-free synthesis, recyclable graphene oxide (GO) or reduced graphene oxide (rGO) was employed as catalyst. The protocol was enlarged to include a broad range of nitro anilines and benzils (Figure 5.54).

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5 An overview of quinoxaline synthesis by green methods

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Figure 5.53: Mn(I) complex supported synthesis of heterocyclic derivatives.

An operationally simple, eco-friendly, solid-phase synthesis of quinoxaline derivatives (140, 140a, 140b) was disclosed by Paul and Basu [79]. The authors obtained these products by the reaction of 1,2-diketones (2a)/α-hydroxy ketones (2b) and substituted 1,2-diamines (1) utilizing KF/alumina. The process involves tandem oxidation–condensation reactions. The efficacy of various solid supports such as silica gel, alumina and KF-alumina, as well as neat conditions, was explored. The protocol was enlarged to include diversely substituted condensing partners (Figure 5.55).

5.5 Solvent-free reactions

141

Figure 5.54: GO/rGO catalyzed preparation of quinoxaline compounds.

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Figure 5.55: KF/alumina promoted solvent-free preparation of quinoxaline compounds.

Nandi et al. [80] reported a simple, efficient, non-chromatographic, solvent-free synthetic approach for the preparation of quinoxaline derivatives (141, 141a) obtained from differently substituted 1,2-diamines (1) and aliphatic (2c) as well as aromatic 1,2-diketones (2) catalyzed by silica gel under grinding conditions at room temperature (Figure 5.56).

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Figure 5.56: General representation of silica gel assisted preparation of quinoxaline, and fused derivatives.

5.6 Light initiated synthesis Sagadevan and co-researchers [81] unveiled one-pot visible light initiated simple, mild, green aerobic direct C–N coupling between terminal acetylenes (103) and o-phenylene diamines (1), mediated by CuCl affording 3-phenyl-2-hydroxy-quinoxalines (142,142a). A broad range of phenyl acetylenes (103) and o-phenylene diamines (1) were used in the study. During the optimization stage, the effect of different copper catalysts, bases, and solvents was investigated (Figure 5.57).

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Figure 5.57: Visible light initiated quinoxaline synthesis in the presence of CuCl.

5.6 Light initiated synthesis

143

A facile visible-light-induced copper-catalyzed controlled aerobic oxidation of terminal alkynes (103) to α-keto esters (2a) followed by quinoxaline/naphthoquinone (143) preparation was presented by Das and co-authors [82]. The process involves phenyl glyoxal (2a) formation as stable intermediates. Molecular O2 was used as a sustainable oxidant. Widely substituted electron-rich and electron-poor aromatic alkynes (103) as well as aliphatic (1°, 2°, 3°) alcohols (7a) were examined for their participation in this simple scalable environmentally benign protocol, wherein strong oxidants, expensive catalysts and elevated temperatures are not used (Figure 5.58). Sarma and co-authors [83] disclosed an eco-friendly and straightforward visible light promoted approach for quinoxalines (145) and quinazolinones (145a) in a water medium in the presence of TBHP, an oxidizing agent in the absence of any catalysts. Authors claim that the driving force is the enhanced rate of decomposition of TBHP in the presence of visible light, facilitating the generation of free radicals. Followed by the optimized conditions, the scope of the reaction was extended to include a wide range of primary alcohols with both electron-withdrawing and donating functional groups in the phenyl ring of the alcohols. Aliphatic alcohols were not suitable for the reaction. Heteroatom containing primary alcohols such as 2-pyridine methanol, 2-thiophene methanol and furfuryl alcohols coupled well with 2-amino benzimidazole (146) and 5-Cl2-amino benzamide (147) (Figure 5.59). The approach was further studied to prepare quinoxalines (145) from α-hydroxy ketones (2b) by the sequential oxidation and condensation with aryl 1,2-diamine (1) in the presence of TBHP, in the water medium, assisted by visible light. Both electronwithdrawing and electron-donating groups on the aromatic ring are compatible with the reaction.

Figure 5.58: Visible light-induced quinoxaline synthesis.

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(a)

(b)

Figure 5.59: Visible light promoted TBHP supported preparation of quinoxalines and quinazolinones.

5.7 Application of ultrasonication Carbon doped MoO3-TiO2 was utilized by Lande et al. [84] as an efficient, green, recyclable heterogeneous catalyst in the preparation of differently substituted quinoxaline derivatives (148), obtained by the condensation of benzil (2a) and 1,2-diamines (1), under ultrasonication method in EtOH–H2O (3:1). Initially, authors prepared a series of carbon-doped MoO3–TiO2 (CMT) by sol–gel method, from ammonium heptamolybdate, titanium butoxide, finely powdered carbon and cetyl trimethyl ammonium bromide (CTAB). During optimization, authors worked on several parameters like solvent systems, catalysts compositions/loadings and reaction times. A comparative study of the reactions in conventional mode as well as at sonication conditions was presented (Figure 5.60). Shahinshavali et al. [85] explored a convenient and environmentally benign ultrasound-assisted synthesis of 3-alkynyl substituted-2-chloroquinoxaline derivatives (149), obtained by the coupling of 2,3-dichloroquinoxaline (101a) with terminal

Figure 5.60: CMT catalyzed quinoxalines.

5.8 Reactions employing recyclable catalysts

145

alkynes (103) in the presence of CuI, PPh3 and K2CO3 in PEG-400. Initially, the effect of several catalysts, bases and solvents on the reaction was analyzed. The authors discussed the role of CuI in the coupling reaction. In silico assessment of these compounds as potential ligands for N-protein of SARS-COV-2 was presented (Figure 5.61).

5.8 Reactions employing recyclable catalysts Sarmah and Srivastava [86] evaluated nanocrystalline ZSM-5 and β-zeolites as catalysts for an environmentally benign protocol, which affords a wide range of five, six and seven-membered heterocyclic derivatives (150, 152, 153, 154, 155), bearing nitrogen and sulfur; Authors explained the role of catalysts and concluded that nanocrystalline ZSM-5 exhibited excellent catalytic efficiency and also selectivity. These catalysts were reused (Figure 5.62). Lahouti and Naeimi [87] carried out an efficient, highly versatile one-pot four-component approach for diversely substituted 5-phenylspiro[diindenopyridinopyridine-indeno quinoxaline]diones (156) catalyzed by magnetically retrievable and reusable heterogeneous organocatalyst-MnFe2O4@Cs–Bu–SO3H MNPs. The catalyst was prepared from MNFe2O4NPs and chitosan. The target compounds were produced by the reaction of ninhydrin (105), 1,2-diamino benzene (1), 1,3-indane dione (105a), and aniline (1i) in acetonitrile at 75 °C (Figure 5.63). A facile synthesis of furo [2,3-b] quinoxalines (157) via A3-coupling followed by 5-endo-dig cyclization by the participation of ethyl glyoxalate (2d), o-phenylenediamines (1), and phenyl acetylenes (103) was described by Reddy and co-authors [88]. Here in novel Cu(OTf)2, loaded protonated trititanate nanotubes were employed as reusable heterogeneous catalysts after the initial study of different catalysts for the reaction. Initially, the authors screened various solvents for the reaction. Substrate scope was expanded to include variously substituted o-phenylenediamines (1) and terminal alkynes (103) (Figure 5.64). A series of new spiro[indeno(1,2-b)quinoxaline-[(11, 21)-thiazolidine]4-ones] (158), were prepared by Singh and co-authors [89], via a multicomponent reaction of indeno [1,2-b] quinoxalinone (159), α-mercapto carboxylic acids (154) and diversely

Figure 5.61: Ultrasound-assisted preparation of 3-alkynyl substituted 2-chloroquinoxalines.

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(a)

(b)

(c)

Figure 5.62: Synthesis of various heterocyclic scaffolds supported by ZSM-5.

Figure 5.63: MnFe2O4@Cs–Bu–SO3H catalyzed synthesis of spiro[diindenopyridino-pyridine-indeno quinoxaline]diones.

5.8 Reactions employing recyclable catalysts

147

Figure 5.64: Cu(OTf)2/HTNT-5 mediated preparation of quinoxaline derivatives.

substituted amines (1i) employing urea-choline chloride (155) as an ecofriendly deep eutectic solvent and carbon-SO3H as a heterogeneous solid acid catalyst (Figure 5.65). The authors successfully quantitatively recovered both solvent and catalyst and reused them, during the investigations. Several acid catalysts such as ACOH, InCl3, ZnCl2, P-TSA, boric acid and carbon-SO3H were checked for efficiency, and authors observed the great superiority of glycerol-based carbon-sulfuric acid. Influence of several solvents and temperature ranges were also examined. Andriamitantsoa and co-authors [90] prepared and studied the catalytic efficiency of novel metal-organic frameworks (MOFs)-derived Bronsted acid heterogeneous catalyst MIL-101-Cr-NH-RSO3H, obtained from 1,3-propanesultone (160) and MIL-101-Cr-NH2. The authors applied this in the preparation of quinoxaline (161) derivatives. Authors established ease of recovery and reuse of the catalyst (Figure 5.66).

Figure 5.65: Reusable urea-choline chloride/carbon-SO3H-system promoted preparation of spiro [indeno[1,2-b]quinoxaline-[11,21]-thiazolidine]-4-ones.

Figure 5.66: MIL-101-Cr-NH-RSO3H catalyzed synthesis of quinoxaline derivatives.

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Huang and co-authors [91] employed silica sulfuric acid (SSA)/polyethylene glycol (PEG) as an efficient, recyclable system for the preparation of pyrazines (162) and quinoxalines (163, 163a–b, 164) obtained by the condensation of differently substituted 1,2-diamines (1, 1f) and α-hydroxy ketones (2b, 2e) (Figure 5.67). A series of structurally diverse novel spiro pyrrolo quinoxaline grafted indole heterocyclic hybrids (165) containing spiropyrrolidine, indenoquinoxaline, and indole structural moieties were synthesized by Arumugam and co-authors [92] following an efficient and environmentally benign one-pot multicomponent approach involving 1,3-dipolar cycloaddition as a critical step. The target compounds are achieved under complete diastereomeric control from o-phenylenediamine (1), variously substituted β-nitro styrenes (107), L-tryptophan (166) and ninhydrin (105c) (Figure 5.68). Formation of azomethine ylide from L-tryptophan and indenoquinoxaline insitu is an important step. The products are evaluated for their anti-mycobacterium tuberculosis activity, employing recoverable and reusable ionic liquid (bmim)Br.

Figure 5.67: SSA/PEG promoted preparation of pyrazines/quinoxalines.

5.8 Reactions employing recyclable catalysts

149

Figure 5.68: Ionic liquid (bmim)Br promoted synthesis of spiropyrroloquinoxaline grafted indole hybrids.

Jeganathan et al. [93] successfully employed K10-montmorillonite as a recyclable heterogeneous catalyst for developing a one-pot facile green method for 2-substituted quinoxalines (167) from the condensation reaction of 1,2-diamines (1) with phenacyl bromides (25), conducted in acetonitrile medium at 50 °C. Dehydration, dehydrohalogenation-cyclization sequence led to the formation of target molecules. Several solvents were screened during initial studies for getting the best results. The approach was compatible with both electron-rich and electron-deficient functionalities on the substrate molecules. The role of K10 clay was discussed. Present results were compared with those of earlier reported procedures (Figure 5.69). Palaniappan et al. [94] described the one-pot synthesis of biologically important quinoxaline derivatives (168) in the presence of stable, inexpensive, eco-friendly and recyclable polyaniline-sulfate salt as a mild polymer-based solid acid catalyst at room

Figure 5.69: Recyclable K-10-montmorillonite promoted quinoxalines formation.

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5 An overview of quinoxaline synthesis by green methods

Figure 5.70: Polyaniline-sulfate salt catalyzed quinoxaline derivatives.

temperature (Figure 5.70). Several 1,2-dicarbonyl compounds (2) were successfully reacted with aromatic 1,2-diamines (1) in 1,2-dichloro ethane and obtained the desired products in excellent yields in a short reaction time. Furthermore, authors also reported some of the new quinoxaline derivatives using ethyl pyruvate, ninhydrin and 1,2-diamino anthraquinone as starting materials. In addition to this, diamines containing electron-donating groups enhanced the product yields as compared to those with electron-withdrawing groups. However, 1,2-diketones containing electron-withdrawing groups enhanced the product yields as compared to compounds containing electron-donating groups.

5.9 Reactions conducted at above room temperatures Series of bioactive spiroindenoquinoxaline pyrrolizines (169), potent anti-cancer and anti-oxidant agents were synthesized by Mani and co-researchers [95]. These novel heterocyclic frameworks contain three important pharmacophoric cores such as quinoline, indeno quinoxaline as well as pyrrolizine skeletons (170). These were made by a one-pot four-component strategy involving ninhydrin, L-proline, quinolinyl chalcones and o-phenylene diamines (1) in methanol via [3 + 2] cyclo-addition. FeCl3 and morpholine have been assessed by Song et al. [96] as co-catalysts for an ecofriendly, facile one-step preparation of a series of quinoxaline derivatives (171), obtained by the condensation of 1,2-diamines (1) and α-hydroxy ketones (2b) in ethanol medium. The authors conducted a systematic study on the efficacy of different catalysts and their molar ratios for the protocol. The scope of the reaction was enlarged to include a broad range of substituted substrates for the research study (Figure 5.71).

5.9 Reactions conducted at above room temperatures

151

Figure 5.71: FeCl3-morpholine mediated quinoxalines.

Deivasigamani and Rajukrishnan [97] developed a practical, atom-economical one-pot sequential five-component approach for highly functionalized pyrazolo-Nmethyl piperidine (172) grafted spiroindenoquinoxaline pyrrolidine scaffolds (173) via [3 + 2] cycloaddition of azomethine ylides (108) as an essential step. The title compounds are obtained by the reaction involving a dipolarophile-3,5-bis-arylmethylidene-N-mehylpiperidine-4-ones (174), ninhydrin (105c), o-phenylenediamine (1), sarcosine (154a), and hydrazinehydrate (138) in refluxing methanol. The sequence of steps includes heterocyclization of 1,2-diamine with ninhydrin affording indenoquinoxaline-11-one, which condenses with sarcosine resulting in azomethine ylide-a dipole which in turn undergoes cycloaddition with dipolarophile. Lastly this cycloaddition product condenses with hydrazine hydrate yielding title products. It was claimed that such a complex structural moiety was assembled in a simple operation with high regioselectivity under mild reaction conditions. Various solvents were screened for suitability during optimization and it was observed that the best results were obtained in refluxing methanol (Figure 5.72).

Figure 5.72: Protocol for pyrazolo-N-methylpiperidine grafted spiro indeno quinoxaline pyrrolidine scaffolds.

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Mani and co-authors [98] reported an enantioselective one-pot four-component strategy for anti-oxidant and antiproliferative novel spiro-indeno[1,2-b]quinoxaline pyrrolo thiazole scaffolds (175) via 1,3-dipolar cycloaddition reactions of aromatic ylides generated insitu from thiazolidine-2-carboxylic acid (176) and indenoquinoxalines (177). The target compounds were made from quinoxaline chalcones (178), ninhydrin (105), o-phenylene diamine (1) and thiazolidine-2-carboxylic acid (176). Solvents like toluene, 1,4-dioxane, acetonitrile, ethanol and methanol were tested, and it was observed that methanol reflux provided the best results (Figure 5.73). Lima and Porto [99] described a mild facile approach for quinoxaline molecules (179, 179a, b) from ethyl gallate (180) as one of the substrates in ethanol medium at 65 °C (Figure 5.74). A series of benzene centered novel carbazole quinoxaline hydrids (181, 181a–c) was synthesized by Reddy et al. [100] by classic Ullmann and Pd/Cu catalyzed Sonogashira coupling reaction. The target compounds were investigated for photophysical, thermal, and electrochemical properties. They are observed as potential host materials for phosphorescent OLEDS. End products were made from 1,2-dicarbonyl key intermediates (2) and o-phenylenediamines (1) in refluxing CHCl3 in the presence of PTSA (Figure 5.75). Issa and co-authors [101] designed and developed a simple approach for various substituted 1,2,4-triazolo (182) and 1,2,4-triazino[4,3-a]quinoxaline derivatives (183) and assessed their antimicrobial and anti-cancer activities (Figure 5.76). Dengke Li et al. [102] explained an efficient one-pot protocol for a library of diversified [1,2,3]triazolo[1,5-a]quinoxaline scaffolds (186, 186a–c), obtained by the reaction of terminal acetylenes (103) or substituted acetaldehydes (18b) with 1-azido-2-isocyanoarenes (115a) at mild temperatures, following cascade annulation approach (Figure 5.77). Moreover, highly functionalized quinoxaline hybrids were prepared employing rhodium (Rh2(esp)2) catalyzed NH/OH insertions to the carbenoid intermediates.

Figure 5.73: Representative structures of spiro-indeno[1,2-b]quinoxaline pyrrolo-thiazole molecules.

5.9 Reactions conducted at above room temperatures

153

Figure 5.74: Quinoxalines preparation from ethyl gallate.

Xia and co-authors [103] reported the new antibacterial and antiviral molecules containing quinoxaline core moiety (188) with penta-1,4-dien-3-one oxime ether linkage. The title compounds were prepared by a mild eco-friendly procedure in which 2-hydroxy quinoxalines (189)/2-hydroxy-6-chloro quinoxalines (190) were used as substrates. Oxime-ether linkage was established by heating both the intermediates in acetonitrile/K2CO3 at 80 °C (Figure 5.78). A simple one-step method for preparing a wide range of pyrrolo[1,2-a]quinoxaline derivatives (191) was unveiled by Cui and co-authors [104]. Annulation [5 + 1] of substituted 1-(2-amino phenyl) pyrroles (27a) with α-carbonyl sulfoxonium ylides (108a) catalyzed by ruthenium reagent afforded the title compounds. The effect of different solvents and catalysts on the reaction was investigated during optimization studies. The reaction scope was enlarged to include a broad spectrum of substrates to assess functional group tolerance. The role of ruthenium catalyst and additive was explained by the authors (Figure 5.79). Additives such as AgSbF6, AgNTf2, AgBF4, AgOTf and Zn(OAc)2 were examined for efficacy. Triloknadh et al. [105] described and carried out the synthesis of a broad range of novel anti-oxidant quinoxaline hydrazide hydrazone-1,2,3-triazole hybrid molecules

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5 An overview of quinoxaline synthesis by green methods

Figure 5.75: Representative carbazole-quinoxaline hybrid frameworks.

Figure 5.76: Representative 1,2,4-triazolo and 1,2,4-triazino[4,3-a]quinoxaline scaffolds.

5.9 Reactions conducted at above room temperatures

155

(a)

(b)

Figure 5.77: [1,2,3]Triazolo[1,5,-a]quinoxalines by cascade annulation approach.

Figure 5.78: Quinoxaline compounds with oxime-ether linkage.

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5 An overview of quinoxaline synthesis by green methods

Figure 5.79: Protocol for pyrrolo[1,2-a]quinoxaline derivatives by ruthenium catalyzed [5 + 1] annulation approach.

(192, 192a, 192b). The target compounds were made by the condensation of triazole linked benzaldehydes (18c) with quinoxaline hydrazides (193) in the presence of EtOH/ AcOH at reflux conditions. Acetic acid was added in a catalytic amount to ethanol (Figure 5.80). Shahrestani and co-authors [106] carried out the preparation of a library of novel enantiomerically pure spiro-indenoquinoxaline pyrrolidine (194) and spiroindenoquinoxaline pyrrolizidines (195) by a simple, one-pot, four-component approach with a high regio, diastereo (up to 96 dr) and enantioselectivity (upto 99% ee). The eco-friendly strategy involves a 1,3-dipolar cycloaddition reaction of azomethine ylides (108) and optically active cinnamoyl-crotonyl oxazolidinone (196), conducted in aqueous ethanol in the absence of Lewis acid catalysts. Azomethine ylides (108) were prepared from 1,2-phenylene diamines (1), ninhydrin (105) and Lproline (106) (Figure 5.81). Xie et al. [107] described an efficient green and novel approach for the preparation of N-heterocyclic fused quinoxalines (197, 197a), employing dimethyl sulfoxide as a reactant (198) as well as solvent. After initial experiments, reaction parameters are fixed. The scope of the reaction of 2(1H-pyrrol-1-yl) aniline derivatives (27, 27a) was evaluated. It was observed that compounds with electron-withdrawing groups gave better yields than those with electron-donating groups. Authors examined and extended the studies to synthesize pyrrolo[1,2-a]quinoxalines (199), indolo[1,2-a] quinoxalines (200), 1-H-pyrrolo[3,2-c]quinolines and benzo [4,5]-imidazo[1,2-c]quinazolines (201) (Figure 5.82). Nikumbh and co-authors [108] explained a cascade reaction resulting in the direct synthesis of a new series of indolofuroquinoxalines (202, 202a) in a one-pot reaction obtained from methyl-2-(2-chloro-1H-indole-3-yl)-2-oxoacetate or its N-alkyl derivatives (203) in an eco-friendly way. During the optimization studies, the authors examined the efficacy of a range of acid catalysts and the effect of solvents such as EtOH and toluene. While examining the scope of the reaction, a series of chloro compounds were used as starting materials (Figure 5.83).

5.9 Reactions conducted at above room temperatures

157

Figure 5.80: Representative quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids.

Figure 5.81: Representative spiro-indenoquinoxaline pyrrolidines/pyrrolizidine scaffolds.

Chang and co-researchers [109] reported the synthesis of a wide range of tricyclic/ tetracyclic quinoxalines (204, 204a, 204b) by the cyclocondensation of 1,2-diamino compounds (1) such as 1,2-diamino benzene (1), 3,4-diamino pyridine (1a) and

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5 An overview of quinoxaline synthesis by green methods

(a)

(b)

27

Figure 5.82: Preparation of heterocyclic derivatives using dimethyl sulfoxide as the reactant.

(a)

(b)

Figure 5.83: Synthesis of indolo[31,21:4,5]furo[2,3-b]quinoxalines.

3,31-diamino benzidine (1c) with diversely substituted α-bromo ketones (25a), obtained by the α-bromination of cyclic ketones (2a) (Figure 5.84). Zhang et al. [110] described an efficient metal-free eco-friendly I2-catalyzed cascade coupling protocol for imidazo[1,5-a]quinoxalines (206) and pyrrolo[1,2-a]quinoxalines (205) via SP3 and SP2 C–H cross dehydrogenative coupling. DMSO was used as an

5.9 Reactions conducted at above room temperatures

159

(a)

(b)

(c)

Figure 5.84: Synthesis tricyclic pyrido quinoxalines and bis quinoxalines.

oxidant. The authors investigated the effect of different solvents and additives, as well as broader substrate scope (Figure 5.85). Lu and co-researchers [111] developed a new catalyst-free domino synthesis of quinoxalines (207) from 1,2-diamino arenes (1) and phenacyl halides (25) in the presence of NaHCO3 and DMSO. The authors also discussed the successful reaction of phenacyl bromide (25) with substituted o-phenylene diamines (1) having 4-Cl, 4-Br, 4-CF3, 4-NO2, 4-OMe or 4,5(Me)2 functional groups (Figure 5.86). Zhang et al. [112] discussed an efficient, green one-pot two-step approach for quinoxalines (208) from 1,2-diaryl-2-hydroxy ethanone (2b) and 1,2-diamino benzenes (1) using readily available oxidant DMSO and p-toluene sulfonic acid (PTSA) as a catalyst. During optimization, several solvents were screened, and different sulfonic acids were assessed for their efficiency (Figure 5.87). Saha et al. [113] developed an unconventional strategy for preparing quinoxaline derivatives (209) from sodium azide (102) and 2-iodo benzoic acid (210) catalyzed by organo Cu(II) catalyst by a one-pot multi-component approach. Initially, Cu(II) catalyst was prepared from 3,5-dinitro benzoic acid (210b), Cu(NO3)2·3H2O and melamine. The authors screened different nitrogenous sources and observed that NH4OH was best for

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5 An overview of quinoxaline synthesis by green methods

(a)

(b)

Figure 5.85: Preparation of imidazo[1,5-a]quinoxalines and pyrrolo[1,2-a]quinoxalines catalyzed by iodine.

Figure 5.86: Catalyst free domino synthesis of quinoxalines.

Figure 5.87: PTSA promoted preparation of quinoxalines.

5.9 Reactions conducted at above room temperatures

161

the protocol. The reaction proceeds via Schmidt reaction and nucleophilic substitution. Researchers compared and proved the efficacy of the catalyst with other metal salts under same optimized conditions (Figure 5.88). Xie et al. [114] described an efficient, metal-free one-pot domino protocol for pyrrolo[1,2-a]quinoxaline derivatives (211, 211a) via imine formation (212), SEAr reaction followed by C–C bond cleavage, catalyzed by Bronsted acid. The influence of several Bronsted acids such as pir OH, AcOH, CF3CO2H, CH3SO3H and TsOH·H2O were studied, and among these, TsOH·H2O was observed to give desirable results. Among several solvents examined, DMSO gave better yields. After standardization, the scope of the protocol was enlarged to include variously substituted reactants, β-diketones and β-keto esters (2a) (Figure 5.89).

Figure 5.88: Organo Cu(II) catalyst promoted preparation of quinoxalines.

(a)

(b)

Figure 5.89: TsOH·H2O/DMSO assisted synthesis of pyrrolo[1,2-a]quinoxaline derivatives.

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5 An overview of quinoxaline synthesis by green methods

Glycerin and CeCl3·7H2O were reported as a new, efficient, eco-friendly recyclable reaction system by Narsaiah and Kumar [115] for affording a range of quinoxaline derivatives (213, 213a–e) via the coupling of diketo compounds (2, 2f) and o-phenylene diamines (1) and other 1,2-diamino compounds (1a, b). Initially, researchers studied different reaction parameters such as temperature, catalyst loadings and time (Figure 5.90).

(a)

(b)

(c)

(d)

(e)

(f)

Figure 5.90: Glycerin/CeCl3·7H2O supported synthesis of quinoxaline derivatives.

5.9 Reactions conducted at above room temperatures

163

An operationally simple environmentally benign route to pyrrolo[1,2-a]quinoxalines (214) employing oxygen as oxidant was revealed by Wang et al. [116]. In this methodology, different 1-(2-amino phenyl) pyrroles (27) were reacted with various aliphatic/aromatic/heterocyclic aldehydes (18) in o-xylene at 140 °C (Figure 5.91). Hajishaabanha and Shaabani [117] described an efficient catalyst-free one-pot three-component approach for a series of oxazepin-quinoxaline bis-heterocyclic scaffolds (215) employing 6-hydroxy benzo [f] quinoxaline-2,3-dicarbonitrile (216), 2-(2-formylphenoxy) acetic acid (18c) and amines (1i) in refluxing toluene. Initially authors assessed the influence of different solvents and reaction temperatures on the reaction (Figure 5.92). Chen et al. [118] disclosed I2 mediated, scalable synthesis of benzo [4,5]imidazol [1,2-c]quinoxaline derivatives (217) from readily available 2-(benzoimidazol-1-yl) amine substrates (27b) in the presence of sodium acetate in toluene, via SP3 C–H amination approach.

Figure 5.91: Oxygen as an oxidant in the preparation of pyrrolo[1,2-a]quinoxalines.

Figure 5.92: Catalyst-free synthesis of oxazepin-quinoxaline bis-heterocyclic scaffolds.

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5 An overview of quinoxaline synthesis by green methods

Figure 5.93: I2 assisted preparation of benzo[4,5]imidazo[1,2-c]quinoxalines compounds.

During optimization studies, the authors evaluated the efficacy of different bases and solvents for this methodology (Figure 5.93). Wang et al. [119] developed a novel versatile and efficient protocol for the synthesis of a library of pyrrolo[1,2-a]quinoxalines (218) as well as indolo[1,2-a]quinoxalines (218b) via FeCl3 promoted SP3 CH-activation and oxidative cyclization strategy in the presence of oxidant TBHP. In this approach S-methyl group of DMSO, N-methyl group of amines and O-methyl group of ethers can be utilized as the carbon source (219). This versatile protocol was applicable to multiple types of solvents having terminal methyl groups (Figure 5.94).

Figure 5.94: FeCl3 promoted pyrrolo[1,2-a]quinoxalines and indolo[1,2-a]quinoxalines.

5.9 Reactions conducted at above room temperatures

165

An atom economical preparation of quinoxalines (220, 220a), quinolines (221) and 2-alkylaminoquinolines (221a) was developed by Shee et al. [120] by employing a new air and moisture-stable Co (NNN) complex. Authors selected dehydrogenative coupling of 1,2-propanediol (7b) with o-phenylenediamine (1) as a model reaction to come out with good optimized conditions. It was reported that CsOH·H2O delivered the best results in the presence of toluene as a medium (Figure 5.95). Aichhorn et al. [121] successfully employed stannic chloride or indium (III) chloride in the synthesis of quinoxalines or quinoline-8-amines (222) starting from N-propargyl aniline compounds (1j) under acidic conditions in refluxing isopropanol (Figure 5.96). Vadagaonkar and co-authors [122] established an efficient one-pot atom-economic metal-free I2-catalyzed tandem approach for the preparation of a series of quinoxalines (223) via SP3-SP2 and SP C–H functionalization; starting from readily available,

(a)

(b)

(c)

Figure 5.95: Co (NNN) complex catalyzed synthesis of quinoxalines, quinolines, and 2-alkylaminoquinolines.

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5 An overview of quinoxaline synthesis by green methods

Figure 5.96: Preparation of quinoxalines starting from N-propargyl anilines.

Figure 5.97: Preparation of quinoxaline derivatives using I2/TBHP/DMSO.

variously substituted diverse range of ethyl arenes (103a), ethylene arenes (103b), ethyne arenes (103) followed by the condensation with o-phenylenediamines (1). The authors successfully employed I2/TBHP/DMSO system for this functional group tolerant protocol. During optimization, authors screened various conditions for this methodology (Figure 5.97). Tert.Butyl hydroperoxide was used as an oxidant. The authors explained the reaction mechanism involving TBHP as an oxidant and DMSO as a solvent as well as co-oxidant, involving the formation of α-iodoacetophenone (96), followed by phenyl glyoxal (2f) and subsequent cyclization with o-phenylenediamine (1). A sulfur mediated preparation of a series of benzofuroquinoxalines (224), benzothienoquinoxalines (225), and indolo quinoxalines (226) obtained by the annulation of 1,2-phenylenediamines/1,2-diamines (1, 1c) in the presence of DABCO/ DMSO was reported by Tran et al. [123]. The authors evaluated the efficiency of different bases, varied amounts of sulfur and solvents during optimization studies (Figure 5.98).

5.10 Conclusions Recent years have witnessed significant growth in organic chemistry research in achieving varied eco-friendly methodologies for the synthesis of a wide range of heterocyclic scaffolds. The design and development of quinoxaline derivatives following greener protocols affording higher yields at reduced times and energies will further ensure the rapid growth of this active area of research resulting in a broader spectrum

5.10 Conclusions

167

(a)

(b)

(c)

(d)

Figure 5.98: S8/DABCO/DMSO system supported synthesis of benzofuroquinoxalines/ benzothienoquinoxalines/indolo quinoxalines.

of biologically active quinoxaline compounds. The authors of this review sincerely appreciate and acknowledge the research groups of the publications cited herein for enriching the green chemistry and heterocyclic chemistry domains. All the figures are redrawn and are representative. The scholars/readers are advised to go through the original research articles for detailed information and learning.

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5 An overview of quinoxaline synthesis by green methods

Acknowledgments: Ramesh Katla (Foreign Visiting Professor-Edital N.03/2020) thanks to the PROPESP/FURG, Rio Grande-RS for Visiting Professorship.

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Suchandra Bhattacharya and Basudeb Basu*

6 Green protocols for Tsuji–Trost allylation: an overview Abstract: Since its inception in 1960s, the Tsuji–Trost reaction, an allylic substitution reaction with diverse nucleophiles such as phenols, amines, thiols, and active methylene compounds, has remained as one of the most useful and widely used organic reactions for the construction of C–C and C–heteroatom bonds. Allylic compounds such as allylic acetates, alcohols, halides, and carbonates undergo this transformation which plays an important role in the total synthesis of various natural products. The competence to incorporate synthetically demanding allylic functionalities makes it a beneficial tool for the synthesis of complex molecules. Over the last two decades, major advancements for this unique and facile Tsuji–Trost allylation reaction have been made with special emphasis to develop greener and sustainable protocols. This chapter presents an update on the significant progress focusing on the newly designed catalytic systems with high efficiency, the use of eco-friendly solvents or solvent-free conditions, low or room temperature conditions and waste management, along with future outlook. Keywords: allylation; carbon–carbon bond formation; carbon–heteroatom bond formation; green protocols; nucleophilic substitution; Tsuji–Trost reaction.

6.1 Introduction The Tsuji–Trost reaction is an allylation reaction that involves the reaction of an allylic substrate bearing a leaving group with oxygen, nitrogen, carbon, or sulfur-based nucleophiles to generate an active metal-allyl species [1]. A vast array of nucleophiles and allylic substrates has already been investigated throughout the last few decades which significantly contribute to the formation of C–C, C–O, C–N, and C–S bonds [2–7]. Nucleophiles like amines [8–10], enolates [11–13], sulfides [14–17], sulfinates [18–20], and leaving groups in the allylic substrate like halides, acetate, carbonate, alcoholic OH group are some promising targets in this field [10, 21–23]. This reaction has emerged in the field of synthetic organic chemistry as a powerful tool owing to its pivotal role in the synthesis of various natural products [24], biologically active

*Corresponding author: Basudeb Basu, Department of Chemistry, Cotton University, Guwahati 781003, India, E-mail: [email protected]. https://orcid.org/0000-0002-7993-2964 Suchandra Bhattacharya, Department of Chemistry, ABN Seal College, Cooch Behar 736101, India, E-mail: [email protected]. https://orcid.org/0000-0002-2291-5952 As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. Bhattacharya and B. Basu “Green protocols for Tsuji–Trost allylation: an overview” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0100 | https://doi.org/10.1515/9783110759549-006

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compounds [3], heterocyclic compounds of medicinal and agrochemical importance [25–28], β, γ-unsaturated amides [29], allylic sulfones [30], detection of trace Pd in flasks and reagent [31], cyclization reactions [32, 33], etc. Based on the mechanistic consideration, the reaction may take place with hard or soft nucleophiles, good regioselectivity, high diastereo- and enantioselectivity [2, 34–41]. Although conventional Pd catalysts like Pd(OAc)2, PdCl2, Pd2(dba)3 along with various ligands show more reactivity and selectivity. Several transition metal complexes have been reported for regio-, stereo- and enantioselective allylic substitution reactions [2, 5, 6]. Besides the major uses of several Pd catalysts [7, 10, 23, 42–50], both in homo- and heterogeneous forms, other transition metals like Cu [7, 51], Ru [1, 52–54], Ir [1, 7, 55], Ni [7, 41], Fe [56], Pt [7, 57], Mo [1, 58] and Zr [7, 59] catalysts have been also explored in Tsuji‒Trost allylation reactions. In addition to that, there are few examples of metalfree Tsuji–Trost allylation [60] and rare allylic azidation [61]. A general mechanistic path of Tsuji–Trost allylation is depicted in the Figure 6.1 [1]. In a conventional mechanistic path, the allylic compound (1) is activated by an organometallic species [MLn] to form an active intermediate (2) that undergoes subsequent attack by a nucleophile to produce the new allylic compound (3 and/or 4) with the expulsion of the leaving group. The leaving group X is removed as X− and the nucleophile can now attack any of the carbons as shown in the Figure 6.1. Though an impressive progress has been noted over the last few decades in Tsuji–Trost allylation process, many of the conventional protocols include use of toxic solvents, harsh reaction conditions etc. Hence, the development of eco-friendly and greener protocols is important and highly desirable. In general, greener methods in synthetic chemistry include the use of environment-friendly solvents or solvent-free reactions, avoidance or use of non-toxic metals, low loading of catalysts and their recyclability, energy sustainable reaction conditions, low or no waste production etc. During the last two decades, there has been a surge towards developing new greener protocols for the Tsuji–Trost allylation reaction [62–70]. In this chapter, a succinct review has been presented on the development of various eco-friendly and sustainable protocols for the Tsuji–Trost allylation process during the last decade along with critical analysis and an outlook.

R

X 1

[MLn] -

( X)

Nu

R 2 [MLn]

Nu = Nucleophile X = Leaving group

Figure 6.1: General mechanism of Tsuji–Trost reaction.

R

Nu 3

+

H R

Nu 4

177

6.2 Eco-friendly approaches towards Tsuji–Trost allylation

6.2 Eco-friendly approaches towards Tsuji–Trost allylation Though a plethora of methodologies can be found in the literature, depicting the emerging research area involving allylic substitution reactions, only a few of them can be considered as greener and environment friendly attempts. This area of research can be categorized in terms of nature of catalysts and its loading, type of bonds formed, solvent used or solvent-free conditions etc. Depending upon the nature of the leaving group the approaches can also vary, e.g. previously the expulsion of allylic OH groups was done through its activation, while with time various developing methodologies arose to surpass this limitation [7, 21, 48]. As mentioned above, even though the Pd catalysts were mostly preferred here like other coupling reactions but several other metal catalysts also served this purpose successfully [7]. On the other hand, if we consider the type of solvent used, it is evident that water is the most suitable choice [71, 72]. Also the influential role of water as solvent is evident in some Pd(0) catalyzed allylation reactions [48]. Another excellent greener solvent can be the room temperature ionic liquids (RTIL) [72] which reported to act as the reaction medium in allylation reaction [73]. Moreover, various advanced methodologies have been developed till date which can avoid the formation of undesired by products and henceforth provide more economic and environmentally benign procedures for the synthesis of target molecules.

6.2.1 Synthesis of benzylated and allylated moieties Cao and Zhang reported an environmentally benign, atom- and step economic pathway of coupling between allylic alcohols and malonates via Tsuji–Trost reaction [74]. The use of carbonate solvent which subsequently activates the C–O bond of the alcohol played a pivotal role here (Figure 6.2). OH O + R 5

O

O

O

Pd(OAc)2 / dppp Cs2CO3, DMC

O

O O

O

o

120 C, 24 h

6

R = 2-OCH3, 3-OCH3, 4-OCH3, 4-O(CH2)4CH3, 4CH3, 3-NH2, 3-CF3, 4-CN, 4-CO2CH3, 2,5-di OCH3 and 1-naphthyl, cinnamyl, allyl, 9-anthracenyl systems Figure 6.2: An atom- and step economic Tsuji–Trost reaction with Pd(OAc)2

7 R Yield 64-96 %

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6 Protocols for Tsuji–Trost allylation

O

O

O

R

O

R2

+

O

Pd/Fe3O4/PEI/rGO

O

R1

O

8

9

R

water, 100 oC 0.5 - 4 h

R = CH3, C6H5, OCH3, OCH2CH3 R1 = H, CH3 R2 = CH3, CH2CH3, CH(CH3)2, (CH3)3, CH2CH(CH3)2, CH2CH2OCH3 and cyclic 1,3-dicarbonyls

O R1

O R2 +

O

O

R

O

10

R2

11

Yield 81- 99 %

Figure 6.3: Pd/Fe3O4/PEI/rGO mediated Tsuji–Trost reaction in water.

O +

Pd2(dba)3, L base, IL, rt

O O

O

OAc 12

O

O

O

O

14 13 K2CO3 : 66-96 % KOAc/BSA : 44-97 %

Figure 6.4: An enantioselective Tsuji–Trost allylation of 1,3-dicarbonyl compounds utilizing ionic liquids (ILs).

Pd NPs immobilized on 2D Fe3O4 graphene nanosheets mediated Tsuji–Trost reaction using ethyl acetoacetate and allyl carbonate in water and air was achieved by Wang et al. [75]. This Pd catalyst (Pd/Fe3O4/PEI/rGO) showed synergistic effect as well as a high turnover frequency and excellent recyclability without compromising the yield. Ease of separation was an added advantage in this protocol (Figure 6.3). Gathergood et al. reported an enantioselective Tsuji–Trost allylation of 1,3-dicarbonyl compounds utilizing allyl acetates under ‘green’ alternative of many organic solvent viz ionic liquid (IL) [76]. The Pd2(dba)3 along with a ligand was the main catalyst here to carry out this C-allylation (Figure 6.4). A selective mono and bis allylation of 1,3-dicarbonyl compounds using MMZNiY catalyst was reported by Kumarraja et al. at room temperature [77]. Yield of the products were reported to be good to excellent (mono allylated: 77–96%, bis allylated: 80–94%). In this ligand free approach, there are certain advantages like no requirement of pyridine, inert atmosphere, longer reaction time, harsh conditions (Figure 6.5).

6.2.2 Synthesis of N-allylated moieties Nagamine et al. showed polymer-supported terpyridine palladium(II) complex mediated Tsuji–Trost reactions under aerobic conditions in water with a high to excellent yield [61]. The catalyst is reusable without much compromising the yield in the allylic azidation of allyl esters with sodium azide (Figure 6.6).

179

6.2 Eco-friendly approaches towards Tsuji–Trost allylation

O

O

R

R'

+ R1

Br 16

15

O

MMZNiY

R'

R

ACN, rt, 6 h

R = CH3, C6H5, OCH2CH3 R' = OCH2CH3, OCH3, CH3, C6H5, OCH2CH3 and dimedone systems R1 = H, C6H5

O

R1

O

+ R

R1

17

O R'

R1

18

Figure 6.5: Allylation of 1,3-dicarbonyl compounds using MMZNiY catalyst at room temperature.

R 19

R'

+ NaN3

OAc

20

PS-PEG-terpyridine-Pd 70 oC, 24 h, water

R

R' 21

R = H, C6H5 R' = C6H5, 4-CH3C6H4, 4-CF3C6H4

N3

18 - 78 %

Figure 6.6: A polymer-supported terpyridine palladium(II) complex catalyzed Tsuji–Trost reaction with azide. O nO

Pd-catalyst, phosphane O

22

+

Et2NH 23

water, rt

nOH

+ CO2

+

NEt2 24

Figure 6.7: A cyclodextrin based miceller system in the Pd-mediated allylation.

Monflier et al. reported Pd catalyzed allylation of amines using allyl carbonates exploring the role of cyclodextrin (CD), CD-based micellar systems, CD-based Pickering emulsions, CD dimers and polymers in the Tsuji–Trost reaction [78]. At the aqueous– organic interface they work to make better contacts between organic phase containing substrate and aqueous phase containing catalyst (Figure 6.7). The aforesaid work does not include any % yield of the product. In the Tsuji–Trost allylic amination reaction, Chanda and coworkers depicted various Pd nanostructures catalyzed C–N bond formation of aniline in water [45]. Nanocubes, octahedra and cuboctahedra produced different ratios of monoallylaniline and diallylaniline under the same conditions (Figure 6.8).

6.2.3 Synthesis of S-allylated moieties Ma et al. reported an extra activator free, mild synthetic pathway towards allylic sulfones using allyl alcohols and sulfinic acids [30]. Easily accessible catalyst viz Pd(PPh3)4 performed its role in water as a solvent and showed good functional group tolerance under this reaction condition (Figure 6.9).

180

6 Protocols for Tsuji–Trost allylation

NH2 Br

+ 25

HN

Pd nanocubes K2CO3 65 oC, water, 1-1.5 h

R

R 27 79-95 %

26

R = H, 4-CH3, 2-CH2CH3, 4-OCH3, 4-CH(CH3)2, 4-C(CH3)3, 2-F, 3,4-diOCH3

Figure 6.8: Pd nanocubes mediated N-allylation of anilines.

R

OH

R2SO2H

+

Pd(PPh3)4 (5 mol %)

or OH

O

R

Water, 40 oC N2, 12 h

S

R1

R2 O

30

1

R R 28

29

56-98 %

R = H, n-C3H7, C6H5, 2-OMe-C6H4, 3-Cl-C6H4, 4-G-C6H4 (G = F, Cl, CF3), 1-naphthyl, 2-thiophenyl R1 = H, CH3 R2 = cyclopropyl, n-Bu, Bn, C6H5, 2-F-C6H4, 2-Cl-C6H4, 4-G-C6H4 (G = F, Cl, CH3, CN), 2-naphthyl, 2-thiophenyl

Figure 6.9: Synthesis of allylic sulfones via Pd-catalyzed Tsuji–Trost reaction.

OH R

PdII-PS-ala

OAc + R' 31

R

P

O

O N

Water, reflux, 16 h

32

R = H, C6H5, 2-OCH3-C6H4, 4-OCH3-C6H4, 4-CH3-C6H4, 4-Br-C6H4 R' = 4-OCH3-C6H4, 4-CH3-C6H4, 4-Br-C6H4, 4-F-C6H4, 4CH2CN-C6H4, 4-CH=CHCOC6H5, Heterocycle

33

R'

OAc

O Pd

OAc

Pd O N

81-94 % O

P

PdII-PS-ala

Figure 6.10: Polymeric β-alanine incarcerated Pd(II) catalyst in the O-allylation in water.

6.2.4 Synthesis of O-allylated moieties An air and moisture stable polystyrene-based polymeric species β-alanine (PS-ala) incarcerated Pd(II) catalyst was developed (designated as PdII-PS-ala). Chloromethylated polystyrene and β-alanine produced the polynmeric imine and subsequent incorporation of Pd(II) furnished the abovementioned catalyst, and applied successfully in the Tsuji–Trost allylic etherification reaction in water by Islam et al. [79]. Several advantages of this methodology like stereospecificity, use of green solvent,

181

6.2 Eco-friendly approaches towards Tsuji–Trost allylation

Figure 6.11: Fe3O4@SiO2Pd – a magnetically recoverable catalyst in Tsuji–Trost allylation.

simple work up etc. are notable for this newly designed heterogeneous catalytic Tsuji–Trost allylation (Figure 6.10). Baig and Varma showed a magnetically separable silica supported Pd catalyzed allylation of phenolic-OH by various allylic acetates in water [80]. The catalyst can be separated by means of an external magnet without any filtration (Figure 6.11).

6.2.5 Other approaches: versatility of the catalyst Meier et al. showed the synthesis of poly(vinylpyrrolidone) stabilized Pd NPs and investigated its catalysis in the Tsuji–Trost allylation in water [43]. The di-allylation of active methylene compounds and the mono allylation of bio-based phenols were performed in presence of a phosphine ligand in high yield with very high turnover numbers of the catalyst (Figure 6.12). O O

O

R

R'

O

+

37

O

PdNP@PVP PPh3

O or

O

O

R

R'

+

R

R'

H2O

O O

R = CH3, OCH2CH3 R' = OCH3

O

40

39

38

HO

O

O

O O

O

O O

O O

O-allylated products (85-96 %)

Figure 6.12: Pd NPs supported on PVP catalyzed C- and O-allylation via Tsuji–Trost reaction.

182

6 Protocols for Tsuji–Trost allylation

Pd/C PPh3, Nucleophile C4-Azo-PEG (CMC)

R OAc

R'

R

R'

Nu

Water, 70 oC, 3h 42

41

36-97 % R = H, C6H5, (CH2)3 R' = C6H5 Nu = p-TsNa, morpholine, Bn2NH, acetylacetone, phenol

Figure 6.13: Pd mediated miceller catalysis in Tsuji–Trost reaction utilizing a photochromic surfactant.

O O

NaOtBu +

Nu

Nu

water, 50 oC, 24 h

43 Nu = acetylacetone, phenol, NaN3, imidazole, propargylamine, (CH3)2CHNH2, BnNH2, cyclopentylamine, CH3CH2NH, morpholine, CH3OH, CH3CH2OH, CH3CH2CH2CH2OH, (CH3)2CHOH

44 42 - 87 %

Figure 6.14: Role of water in transition metal free allylic alkylation.

Billamboz and coworkers furnished a photochromic micellar media under conventional heating and microwave irradiation where a synthetic photochromic surfactant was found to be a versatile, recyclable and efficient in the Pd catalyzed Tsuji–Trost reaction [46]. An overall study showed some excellent properties of the catalyst along with a short coming that it deactivated soon (Figure 6.13). Eppinger et al. provided a transition metal free greener approach for allylic alkylation, amination and O-allylation shedding light on the role of water and the base [81]. The mechanism has been studied thoroughly which is in good agreement with the fact that water and pH has prominent roles in this protocol (Figure 6.14). In the era of heterogeneous catalysis in conventional organic synthesis, Len et al. reported a Pd/C catalyzed Tsuji–Trost allylation under continuous flow system [42]. With a flow rate ranging from 0.5 to 1 mL/min, the yield of the products reported was 5–98%. An affordable catalyst, stability under reaction condition, wide substrate scope, and good to excellent yield make this protocol noticeable among the conventional approaches (Figure 6.15).

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183

Figure 6.15: Pd/C catalyzed Tsuji–Trost allylation of various nucleophiles under continuous flow method.

6.3 Conclusions Metal catalyzed allylic substitutions revealed a whole new direction to design tricky and complex structures that made many transformations feasible which were previously difficult to achieve. Since a plethora of reports of Tsuji–Trost allylations are already there in the literature in the last decade, it appears that there are very limited unexplored avenues that are yet to be deciphered. But contrary to that, in reality, there are many dimensions of Tsuji–Trost allylations that still remain an open field of research, which include the exploration for other metal catalysts and establishment of far more environmentally benign reaction conditions. The incorporation of new methodologies into the synthetic toolbox continues to enrich the field of organic synthesis. With the knowledge of developed methodologies in hand, future scientists will explore new advancements, overcoming the constraints in the Tsuji–Trost allylations in its orthodox form.

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50. Lee NR, Moghadam FA, Braga FC, Lippincott DJ, Zhu B, Gallou F, et al. Sustainable palladiumcatalyzed Tsuji–Trost reactions enabled by aqueous micellar catalysis. Org Lett 2020;22:4949–54. 51. Yoshikai N, Miura K, Nakamura E. Enantioselective copper-catalyzed allylic substitution with aminohydroxyphosphine ligand. Adv Synth Catal 2009;351:1014–8. 52. van Rijn JA, van Stapele E, Bouwman E, Drent E. Remarkable activity of the isomerization catalyst [RuCp(PPh3)2](OTs) in O-allylation of phenol with allyl alcohol. J Catal 2010;272:220–6. 53. Sahli Z, Derrien N, Pascal S, Demerseman B, Roisnel T, Barrière F, et al. Preparation of chiral ruthenium(iv) complexes and applications in regio- and enantioselective allylation of phenols. Dalton Trans 2011;40:5625–30. 54. van Rijn JA, Siegler MA, Spek AL, Bouwman E. Ruthenium-diphosphine-catalyzed allylation of phenols: a gem-dialkyl-type effect induces high selectivity toward O-allylation. Organometallics 2009;28:7006–14. 55. Nakagawa H, Hirabayashi T, Sakaguchi S, Ishii Y. Allylation of alcohols and carboxylic acids with allyl acetate catalyzed by [Ir(cod)2]+BF4− complex. J Org Chem 2004;69:3474–7. 56. Wang DY, Peng XM, Wang GZ. Iron-catalyzed synthesis of amines and thioethers directly from allylic alcohols. Asian J Org Chem 2018;7:875–8. 57. Utsunomiya M, Miyamoto Y, Ipposhi J, Ohshima T, Mashima K. Direct use of allylic alcohols for platinum-catalyzed monoallylation of amines. Org Lett 2007;9:3371–4. 58. Trost BM. Pd- and Mo-catalyzed asymmetric allylic alkylation. Org Process Res Dev 2012;16: 185–94. 59. Lalic G, Blum SA, Bergman RG. Zirconium-mediated SN2’ substitution of allylic ethers: regio- and stereospecific formation of protected allylic amines. J Am Chem Soc 2005;127:16790–1. 60. Chevrin C, Bras JL, Hénin F, Muzart J. Water-mediated transition-metal-free Tsuji–Trost-type reaction. Tetrahedron Lett 2003;44:8099–102. 61. Suzuka T, Kimura K, Nagamine T. Reusable polymer-supported terpyridine palladium complex for Suzuki–Miyaura, Mizoroki–Heck, Sonogashira, and Tsuji–Trost reaction in water. Polymers 2011; 3:621–39. 62. Sharma V, De D, Saha R, Chattaraj PK, Bharadwaj PK. Flexibility induced encapsulation of ultrafine palladium nanoparticles into organic cages for Tsuji–Trost allylation. ACS Appl Mater Interfaces 2020;12:8539–46. 63. Vittoz P-F, Siblani HE, Bruma A, Rigaud B, Sauvage X, Fernandez C, et al. Insight in the alginate Pd-ionogels-application to the Tsuji–Trost reaction. ACS Sustainable Chem Eng 2018;6:5192–7. 64. Li Y-L, Zhang P-C, Wu H-H, Zhang J. Palladium-catalyzed asymmetric tandem denitrogenative Heck/Tsuji–Trost of benzotriazoles with 1,3-dienes. J Am Chem Soc 2021;143:13010–5. 65. Liu J, Hu G, Yang Y, Zhang H, Zuo W, Liu W, Wang B, Rational synthesis of Pd nanoparticleembedded reduced graphene oxide frameworks with enhanced selective catalysis in water. Nanoscale 2016;8:2787–94. 66. Hikawa H, Yokoyama Y. Palladium-catalyzed mono-N-allylation of unprotected amino acids with 1,1-dimethylallyl alcohol in water. Org Biomol Chem 2011;9:4044–50. 67. Li S, Qiu J, Li B, Sun Z, Xie P, Loh T-P. Practical allylation with unactivated allylic alcohols under mild conditions. Org Chem Front 2021;8:3354–9. 68. Zhang G, Zhang H, Wang B, Wang J. Boron-catalyzed dehydrative allylation of 1,3-diketones and β-ketone esters with 1,3-diarylallyl alcohols in water. RSC Adv 2021;11:17025–31. 69. Lee69 Y, Shabbir69 S, Lee69 S, Ahn69 H, Rhee69 H. Catalytic allylic arylation of cinnamyl carbonates over palladium nanoparticles supported on a thermoresponsive polymer in water. Green Chem 2015;17:3579–83. 70. Jérôme F, Ferreira M, Bricout H, Menuel S, Monflier E, Tilloy S. Low melting mixtures based on β-cyclodextrin derivatives and N,N′-dimethylurea as solvents for sustainable catalytic processes. Green Chem 2014;16:3876–80.

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Sriparna Dutta, Prashant Kumar, Sneha Yadav, Ranjana Dixit and Rakesh Kumar Sharma*

7 Recyclable magnetically retrievable nanocatalysts for C–heteroatom bond formation reactions Abstract: During recent years, magnetic separation has proven to be a highly indispensable and sustainable tool for facile separation of catalysts from the reaction medium with the aid of only an external magnetic force that precludes the requirement of energy intensive, solvent based centrifugation or filtration techniques. Extensive research in the area of catalysis has clearly divulged that while designing any catalyst, the foremost features that need to be paid due attention to include high activity, ready recoverability and good reusability. Fortunately, the magnetic nanocatalysts involving a superparamagnetic core material that could comprise of iron oxides such as magnetite, maghemite or hematite or mixed ferrites (CoFe2O4, CuFe2O4) have offered bright prospects of designing the ideal catalysts by proving their efficacy as strong support material that could be further engineered with various tools of nanotechnology and efficiently catalyze various C–heterobond formation reactions. This chapter provides succinct overview of all the approaches utilized for fabricating different types of magnetic nanoparticles and strategies adopted for imparting them durability. The prime forte however remains to exclusively showcase the applications of the various types of magnetic nanocatalysts in C–O, C–N, C–S and miscellaneous (C–Se, C–Te) bond formation reactions which are anticipated to benefit the synthetic community on a broad spectrum by helping them rationalize and analyze the key features that need to be taken into account, while developing these magical nanostructured catalytic systems for boosting the green bond formation reactions/transformations. Keywords: green bond formation reactions; magnetic nanocatalysts; superparamagnetic core.

*Corresponding author: Rakesh Kumar Sharma, Green Chemistry Network Centre, Department of Chemistry, University of Delhi, Delhi-110007, India, E-mail: [email protected] Sriparna Dutta, Green Chemistry Network Centre, Department of Chemistry, University of Delhi, Delhi110007, India; and Hindu College, Department of Chemistry, University of Delhi, Delhi-110007, India Prashant Kumar, Department of Chemistry, SRM University Delhi-NCR, Sonepat, Haryana, India Sneha Yadav, Green Chemistry Network Centre, Department of Chemistry, University of Delhi, Delhi110007, India Ranjana Dixit, Ramjas College, Department of Chemistry, University of Delhi, Delhi-110007, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: S. Dutta, P. Kumar, S. Yadav, R. Dixit and R. K. Sharma “Recyclable magnetically retrievable nanocatalysts for C–heteroatom bond formation reactions” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0101 | https://doi.org/10.1515/ 9783110759549-007

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7.1 Introduction In the preceding chapters, we have seen how green chemistry has completely transformed the outlook of the researchers and paved the pathway for sustainability, especially in the area of organic synthesis. In the list of some of the key green organic transformations that have played an incredible role in reforming the age-old chemical practices adopted by industries, the coupling reactions leading to the formation of C–hetero bond formations have especially left a deep mark with the superlative benefits offered in the form of high atom economy and minimal waste generation [1]. It is really interesting to embark upon the fact that this field has witnessed a rapid surge with the introduction of novel catalytic systems that have proven beneficial on both economic as well as environmental fronts. The past decade particularly saw rise in the use of diverse transition metal catalysts that enabled the formation of diverse C–heterobonds (C–S, C–O, C–N etc.) under milder reaction conditions, often precluding the use of auxiliaries [2, 3]. However, the urge to replace the conventional transition metal based homogeneous catalysts that undeniably suffer from recovery issues or the heterogeneous ones that are incapable to show promising activity has given birth to the advent of absolutely magical heterogenized catalytic systems. The heterogenized catalysts which are also referred as the surface engineered catalysts usually have metal complexes/metal NPs tethered onto a solid support material by means of either covalent forces or other forces of attraction [4, 5]. However, they show interesting prospects of amalgamating the key benefits of both the types of catalytic systems which is the reason behind their compounded utility. Amongst several prospective candidates of solid support, magnetic nanoparticles (ferrites and mixed ferrites) have particularly spread a radical revolution

Figure 7.1: Magnetic nanocatalysts intricately bridge the gap between homogeneous and heterogeneous catalysts.

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with their phenomenal traits of imperishable magnetism that aids in rapid separation of the catalysts along with other advantages such as ready availability, less toxicity, economic viability etc. (Figure 7.1) [6–8]. As compared to the conventional catalysts that are usually isolated using traditional centrifugation and filtration techniques, the magnetic nanocatalysts can be separated from the reaction mixture by using an external magnet which saves time, energy, solvents as well as prevents catalyst loss [9, 10]. Thus, the use of the magnetically retrievable nanocatalysts has further contributed towards sustainable greener synthesis. In this chapter, we have thrown light on different types of magnetic nanoparticles being used currently, along with the preparative methods (the latest innovations in this area). Also, the prime thrust is the application of these riveting magnetically responsive catalytic systems in boosting a number of C–hetero bond formation reactions including C–N, C–S, C–O and miscellaneous (C–P, C–Se, C–Te etc.). The intension remains to motivate/enthuse the readers to transition towards green catalysis with the help of these types of magnetic nanomaterials that aid in the synthesis of compounds (comprising of heterobonds) that are vital for diverse industries.

7.2 Fabrication of magnetic nanoparticles for the designing of magnetically recyclable nanocatalysts 7.2.1 Iron oxides 7.2.1.1 Hematite Magnetic iron oxide nanoparticles can be further classified into hematite (α-Fe2O3), maghemite (γ-Fe2O3). Amongst several iron oxide nanoparticles, hematite an n-type semiconductor having 2.1 eV band gaps which crystallizes in rhombohedral system space group R-3c is considered to be the most stable form under acidic and ambient conditions. Furthermore, its high abundance, non-toxicity, biodegradability, resistance to corrosion are the notable advantages that have prompted researchers to utilize them in diverse fields such as catalysis, waste water treatment, gas sensors, electrodes, solar cells, water splitting and so on. It is a well-known fact that size and morphology of these nanoparticles greatly influences its physico-chemical properties and thus numerous preparative techniques such as co-precipitation, hydrothermal, sonochemical, microemulsion, thermal decomposition, etc. have been reported so far for their effective synthesis. Microemulsion is one such technique that permits synthesis of monodispersed α-Fe2O3 nanoparticles having controllable size and narrow particle size distribution. Within this context, Wei and co-workers reported a low temperature microemulsion approach for synthesizing α-Fe2O3 nanoparticles from ferrihydrite precursor salt and trace Fe(II) as catalysts in presence of hexadecyl trimethyl

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ammonium bromide, n-butanol and n-octane as surfactant, co-surfactant and oil phase respectively [11]. Authors further illustrated that the size of hematite nanoparticles could be controlled by varying the ω value which is the weight ratio of surfactant to n-octane and it was found that increase in ω value increased the size of nanoparticles. Lian and research group explored the possibility of fabricating various morphologies of hematite such as microcubes, nanorods, mesoporous hollow microspheres through an ionic liquid assisted hydrothermal approach [12]. Working on similar lines, Diao et al. explored the possibility of synthesizing α-Fe2O3 nanoparticles through a simple hydrothermal approach wherein PVP and sodium acetate were employed as surfactant and precipitation agent respectively [13]. The formation mechanism of α-Fe2O3 nanoparticles was deeply studied by regulating the precursor concentration, precipitation agent, reaction time and stabilizing agent. Likewise, another publication reported onestep hydrothermal preparation of spherical hematite nanoparticles having an average particle size of 8 nm [14]. Studies conducted by Tadic and research group revealed the fabrication of three forms of α-Fe2O3 nanoparticles comprising of irregular nanoparticles (approx. 50 nm), nanoplates (thickness of 10 nm and diameter 50–80 nm) and microsized ellipsoid structures (length–3.5 mm and diameter–1.5 μm) when synthesized using a hydrothermal technique [15]. The fabrication of hematite nanocubes and nanoparticles has also been reported through a facile hydrolysis of iron (II) acetate. Besides acting as an iron source, the iron (II) salt also provides an etchant (CH3COOH) [16]. The synthesized nanoparticles revealed fascinating shape dependent optical properties and the protocol being simple and low cost could pave the way for large scale industrial applications. Hosny and co-workers reported a solid state synthesis of hexagonal hematite nanoparticles, wherein thermal decomposition of Fe doped poly o-aminophenol (POAP) was performed at 800 °C in a muffle furnace with a rate of 50 °C/min in air [17]. Mantilaka and co-workers employed a novel and economical route for fabricating hematite nanoparticles from iron rich laterites as a natural resource [18]. The synthetic protocol consists of two steps namely hydrolysis and calcination. Laterites rich in Fe and Al were digested using hydrochloric acid to leach the iron into the solution as Fe3+ ions which were further mixed with urea and heated under reflux conditions. The decomposition of urea generates OH ions upon heating which is finally calcined to produce hematite nanoparticles. 7.2.1.2 Maghemite Maghemite (γ-Fe2O3) nanoparticles (oxidized form of magnetite-Fe3O4) possessing superior chemical stability and biocompatibility have garnered immense attention of the scientific community. Though maghemite NPs offers several benefits yet their aggregation behavior is the main concern of the researchers which can be easily overcome through surface coating and functionalization techniques. Physical and chemical properties of maghemite nanoparticles are highly dependent on their nanometric dimensions which remarkably alter their catalytic attributes. A

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significant work in this direction was carried out by Hasanpour and co-workers wherein they synthesized maghemite (γ-Fe2O3) nanoparticles supported onto carboxymethyl cellulose matrix through co-precipitation approach which was subsequently removed with calcination [19]. Microscopic analysis revealed the synthesized nanoparticles to be spherical in shape with narrow size distribution. In another report, a solid state approach was employed to synthesize magnetic iron oxide nanoparticles in an O2 free environment for the removal of methylene blue from aqueous solutions [20]. For accomplishing the desired synthesis, the precursor ferric citrate was heated at 350 °C for 2 h and then after cooling it was grounded for 1 min. On similar grounds, another research group synthesized maghemite nanoparticles through a combined combustion and sonochemical approach which were thereafter immobilized with Pt and Pd nanoparticles to generate effectual catalytic system for the hydrogenation of 2,4-dinitrotoluene to 2,4-toluenediamine [21]. In order to fabricate the desired material, iron citrate was dispersed in polyethylene glycol (PEG 400) through ultrasonication. The iron oxyhydride species so formed were then converted into maghemite nanoparticles via dehydration/dehydroxylation that occurred during combustion process. A significant work in this direction was done by Bansal et al. wherein authors synthesized high quality iron oxide nanoparticles [22]. For accomplishing the desired synthesis, amine coated magnetite nanoparticles were prepared using triethylamine as an amphiphilic hydrolyzing agent which were subsequently oxidized and transformed into maghemite nanoparticles in O2 rich atmosphere. A remarkable attempt was made by Gavilán and co-workers wherein authors fabricated maghemite nanoparticles possessing single-core and multicore morphologies i.e. hollow spheres and nanoflowers [23]. The protocol involves the use of sodium acetate which was found to regulate the nucleation and overall assembly process. Authors also proposed a suitable mechanism highlighting the formation pathway of maghemite nanoparticles. These nanoparticles were formed by burst nucleation and growth process wherein the initial phase of the reaction presents a lepidocrocite (γ-FeOOH) structure which after undergoing quick dehydroxylation converted to an intermediate probably partly dehydroxylated lepidocrocite which after incubation and subsequent crystallization got evolved to maghemite nanoflowers whose size was ranging around 60 nm. An eco-friendly route for synthesizing maghemite nanoparticles was adopted by Yang et al. in which they utilized green vitriol- (a byproduct formed after, leaching ilmenite (FeO-TiO2)) and pyrite as feedstocks [24]. A solid-phase reduction-oxidation reaction was employed wherein magnetite nanoparticles formed initially after the reduction of green vitriol with pyrite in N2 atmosphere at 550 °C were consequently oxidized to maghemite nanoparticles in air at 350 °C. The resulting maghemite nanoparticles having cubic structure and average diameter of 35 nm were found to have surface area and pore volume of 14.63 m2 g−1 and 0.068 cm3 g−1 respectively which were further investigated for the arsenite adsorption. Likewise, maghemite nanoparticles ranging between 2 and 6 nm were fabricated through thermal decomposition of Fe

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(acac)3 at temperatures ranging between 100 and 120 °C for 4 h [25]. The protocol represents a great combination of waste management and green chemistry as it utilizes polysaccharide-apple pectin as stabilizing agent, NaBH4 as the reducing agent and water as the solvent. The activity of obtained maghemite nanoparticles was further evaluated for carrying out the microbial studies of different bacterial strains. 7.2.1.3 Magnetite Magnetite nanoparticles are colloidal Fe3O4 that demonstrate superparamagnetic properties at ambient temperatures. Magnetite nanosheets possessing good magnetochromatic property have been synthesized by Zhuang and co-workers through a two-step solvothermal approach [16]. The solvent diethyleneglycol (DEG) was found to significantly affect the formation of sheet shaped Fe3O4 nanostructures. It was observed that Fe3O4 nanospheres were readily transformed into nanosheets when DEG/EG ratio was 40/0. Another publication reported the fabrication of magnetic Fe3O4 nanoparticles through varying concentrations of poly (vinyl)pyrrolidone [26]. Magnetic nanoparticles having an average particle size of 50–90 nm were facilely prepared through solvothermal approach. Authors further delineated that higher concentration of PVP decreases the particle size of magnetite nanoparticles. A significant work in this direction was carried out by Castaneda-Ovando et al. wherein they synthesized magnetite nanoparticles with size of 14 nm through a combined microwave-solvothermal approach [27]. For this, authors reported a Box-Behnken design (BBD) to optimize the synthesis parameters including temperature, reaction times (gradient and holding) for fabrication, coating and modification of magnetite nanoparticles which can be further exploited in diverse applications such as sorbents for extraction, determination of analytes (heavy metals or organic contaminants). In another publication, fabrication of magnetic Fe3O4 nanostructures possessing different morphologies (cube, octahedron and sphere) has been successfully reported using a modified solvothermal approach in presence of KOH/NH4Ac as capping agent (Figure 7.2) [28]. Cubic and octahedron nanostructures were obtained from ferric sulphate as iron precursor and KOH as capping agent while spheres were readily formed using ferric chloride and NH4Ac as iron precursor and capping agent respectively. Further, it was observed that on increasing the KOH concentration, OH− ions becomes higher which favors the faster growth rate along [111] plane than that of [100] plane thereby resulting in the formation of octahedron. Garg and co-workers utilized an economical and biogenic green synthetic route for preparing magnetite nanoparticles loaded sawdust carbon (Fe3O4/SC) and EDTA modified Fe3O4/SC nanocomposites (Figure 7.3) [29]. The desired nanocomposite was synthesized from ferric nitrate as iron precursor, saw dust as reducing agent and EDTA as functionalizing agent which were subsequently explored for the removal of Cd(II) from aqueous medium in batch mode.

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Figure 7.2: SEM images of Fe3O4 nanoparticles at varying KOH concentrations from FeSO4.7H2O as iron precursor (a and b) 0.5 M, (c and d) 1 M, (e and f) 1.5 M and (g and h) 5 M. Reproduced with permission from ref. [28]. Copyright 2018, Royal Society of Chemistry.

7.2.2 Mixed spinels (CoFe2O4 NPs, CuFe2O4 NPs, NiFe2O4 NPs, MnFe2O4 NPs, ZnFe2O4 NPs) Spinel ferrites having general formula MFe2O4, crystallize in the face centered cubic (fcc) spinel structure which consists of cubic close-packed oxygen lattice, in which an

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Figure 7.3: Illustration depicting synthesis of Fe3O4/SC and EDTA@Fe3O4/SC. Reproduced with permission from ref. [29]. Copyright 2018, Elsevier B.V.

eighth of the tetrahedral and half of the octahedral voids are occupied by metal ions. These inverse spinels have M2+ ions located at the octahedral sites, leading to half the Fe3+ ions to occupy tetrahedral sites. Spinel ferrites demonstrate ferrimagnetic ordering with magnetic moments of the atoms at the tetrahedral sites aligning antiparallel relative to the magnetic moments of atoms at the octahedral sites. Spinels in which M is a divalent cation exhibit superior catalytic, electronic, optical property in comparison to the single component metal oxides. Although, Fe3O4 and Fe2O3 have been extensively employed as catalysts, yet their reactive nature limits their practical applicability in acidic and oxidative conditions. In contrast to them, spinel nanoparticles such as CoFe2O4 or NiFe2O4 offer noteworthy chemical and thermal stability in diverse applications [30–33]. Within this context, Cao and co-workers reported the fabrication of CoFe2O4 nanoparticles via a solution combustion method wherein ferric nitrate, cobalt nitrate and glycine were utilized as precursors [34]. Solution combustion method is actually an exothermal redox reaction between fuels and oxidizers wherein the energy produced through exothermal reactions is used to sustain the reaction system. For this, ferric nitrate, cobalt nitrate and glycine were heated in air using an electrical furnace at 150 °C for 10–15 min. Microscopic analysis revealed that when fuel/ferric nitrate ratio was 0.8, CoFe2O4 nanoparticles were known to have a two-dimensional flocculent structure of approximately 25 nm. The synthesized nanoparticles were found to have a saturation magnetization value of 77.3 emu/g which was 95.7% higher in comparison to bulk materials that are produced at room temperature. Likewise, Pal and co-workers have also reported a low-temperature (approx. 600 °C) solution combustion route for the synthesis of CoFe2O4, NiFe2O4 and Co0.5Ni0.5Fe2O4 nanoparticles possessing cubic spinel structure and size lying in the range of 12–64 nm [35]. For the oxidant (nitrate)/reductant (glycine) ratio of six; phase pure nanoparticles were synthesized. The synthesis approach involves annealing in air

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atmosphere at 600 °C for 2 h with heating ramp of 2 °C/min. In another report, magnetic MnFe2O4, CoFe2O4, NiFe2O4 and ZnFe2O4 nanoparticles were synthesized through co-precipitation of iron and transition-metal hydroxides from aqueous solutions of metals with subsequent hydrothermal treatment at high pressure and temperature [36]. Monodisperse CuFe2O4 nanoparticles with average particle size of 19.9 nm and improved heating efficiency have also been successfully synthesized via solvothermal approach in which triethylene glycol served as a reductant and stabilizing agent in addition to being a solvent [37]. Cubical spinel ferrite nanoparticles of MnFe2O4 and CoFe2O4 possessing diameter in the range of 20–80 nm were synthesized through a coprecipitation approach which was further utilized as magnetic adsorbents for the removal of zinc ions [38]. Another report by Marschall and co-workers highlighted the fabrication of MnFe2O4 nanoparticles having specific surface area of 145 m2 g−1 through a microwave-assisted non-aqueous sol-gel route [39]. The methodology involves mixing Mn (acac)3 and Fe (acac)3 in rac-1-phenylethanol under ultrasonication which was subsequently transferred to borosilicate glass vessel and heated in a microwave reactor at 250 °C. The same research group also fabricated nanocrystalline magnetic spinel NiFe2O4 nanoparticles through fast and energy saving microwave assisted methodology [40]. Garg and co-workers presented a chemical sol-gel polymerization route for synthesizing nanosized NiFe2O4 nanoparticles [41]. For this, aqueous solution of nickel nitrate and ferric nitrate along with citric acid were dissolved in ethylene glycol and heated at 80 °C to form a homogenous mixture. After the formation of gel, temperature was increased to 250 °C and finally calcined at 600 °C for 72 h to yield NiFe2O4 nanoparticles. Similarly, another research group utilized sol-gel approach for preparing nanocrystalline NiFe2O4 nanoparticles wherein PVP, EDTA and CTAB were employed as surfactants [42]. The effect of various surfactants was further investigated towards synthesizing nanoparticles of varying sizes. It was observed that nanoparticles synthesized through EDTA and CTAB were comparatively smaller in size in comparison to those synthesized via PVP. The size of nanoparticles so formed noticeably affects the dielectric and magnetic properties which finds significant potential applications in microwave devices, transformers and cores of inductors. In another report, a coprecipitation approach coupled with hydrothermal aging was employed to fabricate NiFe2O4 nanoparticles in water without the need of any additive [43]. The so-formed NiFe2O4 nanoparticles with sizes below 12 nm demonstrated remarkable catalytic performance in the selective oxidation of benzyl alcohol and substituted ones with TBHP as an oxidant at 60 °C. Working on similar lines, Das et al. delineated the synthesis of magnetic ZnFe2O4 nanoparticles via co-precipitation approach [44]. For this, ZnCl2 and FeCl3 were separately dissolved in distilled water followed by the addition of NaOH to FeCl3 solution to adjust the pH of the solution to 10. The resulting solution was added to ZnCl2 solution and heated at 80 °C for 3 h to obtain a brown precipitate which was

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Figure 7.4: Synthetic approaches most frequently employed for fabricating magnetic iron oxide based nanoparticles.

consequently annealed at 75 °C for 24 h followed by calcination at 500 °C for 5 h to yield desired ZnFe2O4 nanoparticles. Figure 7.4 summarizes the general methodologies utilized for fabricating magnetic iron oxide based nanoparticles.

7.3 Strategies of imparting durability to the magnetic nanoparticles Quite evidently, MNPs have emerged as excellent solid support material for the immobilization of active catalytic species. However, naked MNPs show propensity to undergo aggregation due to strong magnetic interactions which diminishes their catalytic capability [45]. It has been observed that often, under oxidative conditions or in presence of strong chemical environment, their original structure gets disrupted. Surface modification, thus acquires a great prominence in the design of stable MNPs based catalysts as the ultimate aim is to amalgamate/integrate activity, selectivity, reusability and robustness in a single platform.

7.3.1 Coating Thankfully, several protection techniques have been developed for enhancing their applicability which includes coating with different polymers, metals, metal oxides, etc. (Figure 7.5) [46].

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Figure 7.5: General coating approach for protecting MNPs.

The formation of passive coats of inert materials on the surface of the magnetic nanoparticles has shown great success in imparting overall stability. Table 7.1 demonstrates diverse coating agents that have been utilized till date for this purpose. Amongst all these enlisted techniques, silica has proven its efficacy by lowering the isoelectric point of MNPs from pH seven to three via the formation of a thin layer of silica shell which has in turn helped in increasing stability [47]. Another strong reason that supports its extensive use is that it excludes the possibility of desorption of covalently bound silica shells, quite contrary to the phenomenon observed in case of coating accomplished with the aid of monomeric surfactants like steric acid or oleic acid. Apart from the conventional Stober sol-gel process and silicic acid method, other approaches that have been extensively put to use include aerosol pyrolysis, laser Table .: Diverse coating strategies for protecting the MNPs. S. Coating no. strategies

Approaches used

Temperature Precursors

Advantages

.

Silica coating

Sol gel, microemulsion and use of silicic acid solutions

– °C

TEOS, sodium silicate

.

Carbon coating

Hydrothermal, sonochemical, flame spray pyrolysis

– °C

Glucose, cellulose

.

Polymer coating

Inversion microemulsion, oxidative polymerization

– °C

.

Metal coating

– °C

.

Metal hydroxide coating

Microemulsion, redox transmetalation, iterative hydroxylamine seeding Deposition-precipitation, sonochemical

Polyesters, polyaniline, polyethylene glycol, etc. Metal salts

Improves stability and provides sites for covalent attachment of functional groups High chemical and thermal stability as well as excellent compatibility Enhances colloidal stability of MNPs

– °C

Metal salts

Allows linkage of functional ligands besides imparting stability Imparts stability to MNPs

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pyrolysis, arc discharge method and microemulsion method. Currently, sonochemical technique has also been exploited for the preparation of SiO2@Fe3O4 NPs. Impressed by the fascinating attributes of silica as the protecting agent, Sharma et al. designed several silica coated magnetite NPs and utilized these as support for the grafting of several metal complexes which were further employed in expediting a wide array of organic transformations [48, 49].

7.3.2 Functionalization To further expand the utility of the coated MNPs, these are functionalized using appropriate linkers (functionalizing agents) to ultimately aid in the design of advanced catalytic systems more suited for targeted applications. Phosphonates [50], carboxylates [51], alkoxyorganosilanes [52], and sulphonates [53] are some of the most frequently adopted functionalizing groups for surface modification of MNPs. Amongst these, silane based reagents such as 3-aminopropyltriethoxysilane (APTES) and mercaptopropyl triethoxysilane (MPTES) have been considered as potential candidates for modifying the surface of MNPs [54, 55]. Usually, two approaches aid in the accomplishment of the linkers on the MNPs surface:- (i) Non-covalent adsorption of surfactants/linkers, (ii) Covalent grafting/ anchoring technique wherein stable covalent bonds are formed between the linker and the hydroxyl groups present on the surface of bare MNPs/coated MNPs. The second approach remains favorable as it leads to the synthesis of durable catalysts wherein metal leaching problems are minimized to a greater extent. This was proven by Sharma et al. as the research team got engaged in the development of APTES functionalized silica coated MNPs and using the covalent grafting method, they could further modify the catalytic surface which was readily achievable due to availability of surface functional groups (Figure 7.6) [56]. Ultimately, the catalyst worked as excellent robust nanocatalyst with high turnover number (TON) by expediting the reductive amination of ketones and showing recyclability upto eight runs.

7.4 Applications of magnetic nanocatalysts in C–heterobond formation reactions Magnetic nanocatalysts have shown remarkable catalytic performance as heterogenized catalysts in expediting a diverse array of C–heterobond formation reactions owing to their inherent advantages highlighted earlier [57]. Ensuing sections include detailed discussion on the applications of these phenomenal catalytic systems.

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Figure 7.6: Covalent immobilization methodology adopted for the synthesis of magnetic nanocatalyst. Reproduced with permission from ref. [56]. Copyright 2016, Royal Society of Chemistry.

7.4.1 C–N bond formation C–N bond formation acquires a special significance in the realm of synthetic organic chemistry as it opens up new avenues for the construction of nitrogen based molecules that have prevalence in functional materials, natural products and pharmaceutical drugs [58]. Thus, chemists have been actively engaged in exploring novel protocols that allow the ready/facile synthesis of molecules comprising of C–N bonds. Albeit, several competent strategies have been innovated so far that includes transition metals as catalysts, the methods require pre-functionalization, generate stoichiometric amounts of waste by-product and also energy intensive. To circumvent the conventional drawbacks, Ali Reza Sardarian and co-workers fabricated a Cu(II) based catalyst comprising polyvinyl alcohol (PVA) immobilized on Fe3O4@SiO2 nanoparticles [Fe3O4@SiO2-TCT-PVA-Cu(II)] through a multistep approach [59]. The synthetic protocol started with the preparation of Fe3O4@SiO2 nanoparticles according to Stӧber method which subsequently reacted with (3-chloropropyl)trimethoxysilane to produce Fe3O4@SiO2-Cl (1). Afterwards, these nanoparticles were treated with 3-(3-hydroxy-propylamino)-propan-1-ol to generate Fe3O4@SiO2-N(CH2CH2CH2OH)2 (2) nanoparticles. Then, the reaction of Fe3O4@SiO2-N(CH2CH2CH2OH)2 NPs with 2,4,6-trichoro-1,3,5-triazine (TCT) resulted in Fe3O4@SiO2-TCT-PVA-Cu(II)] nanoparticles (3). Finally, Fe3O4@SiO2TCT-PVA-Cu(II) NPs catalyst (4) was obtained by treating Fe3O4@SiO2-TCT-PVA-Cu(II)] with polyvinyl alcohol (PVA) in DMF followed by reaction with copper acetate

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(Cu(OAc)2) in THF (Figure 7.7a). The synthesis of catalyst was confirmed using various analytical techniques such as FT-IR, XRD, TEM, FE-SEM, DLS, UV–Vis, XPS, EDX, TGA, VSM, NMR, ICP and elemental analysis. The developed heterogenized nanocatalyst was efficaciously used in Ullman type N-arylation reaction of five as well as six membered N-heterocyclic compounds (such as imidazole, benzimidazole, indoles, pyrroles, piperazine and phenylpiperazine), and alkylamines using aryl halides (Figure 7.7b). All the substrates resulted good yields of products revealing the efficiency of the designed nanocatalyst. After successful application of catalyst in N-arylation, it’s efficiency was also explored for the synthesis of 5-substitiuted-1Htetrazoles using various aldehydes, hydroxylamine hydrochloride and azide as reaction partners (Figure 7.7c). A catalytic activity comparison between Fe3O4@SiO2-TCT-PVACu(II) NPs catalyst with those of other literature reported catalysts revealed that this nanocatalyst resulted in the higher product yield of N-phenyl imidazole as well as 5-phenyl-1H-tetrazole at lower temperature and in shorter reaction time. The catalyst recovery and reusability test showed that the catalyst could be recovered using an external magnetic field and could be reused upto seven successive times without effective decline in catalytic activity. The demand for developing an appropriate catalyst system for carrying out Pd-catalyzed Buchwald-Hartwig C–N cross coupling reactions using heterogeneous conditions because of speedy recovery and reusability of expensive Pd metal based heterogeneous catalyst and industrial interest to deliver the non-contaminated products urged the Hemmati et al. to develop Pd(II) immobilized ferrite nanoparticles (Fe3O4@PDA@Pd(II)) [60]. Initially, Fe3O4 NPs were prepared using co-precipitation technique and then in situ functionalized by polydopamine by polymerizing dopamine in tris-buffer solution of pH 8.5. Finally, palladium ions were absorbed on PDA layers by reacting Fe3O4@PDA with PdCl2 in acetonitrile which resulted desirable nanocatalyst Fe3O4@PDA@Pd(II) (Figure 7.8a). Various analytical techniques such as FTIR, TGA, ICP, AAS, XPS, FESEM, HR-TEM and EDX were used to characterize the catalyst. AAS (atomic absorption spectroscopy) study revealed the 0.33 0.001 mmol g−1 nanocomposite of Pd(II). The Fe3O4@PDA@Pd(II) NPs catalyst could be effectively used in Buchwald-Hartwig C–N cross coupling reactions between aryl halides and N-heterocyclic molecules (Figure 7.8b). The reaction outcomes established the reactivity order of used halides as R-I > R-Br > R-Cl and also showed that both electron-withdrawing as well as electron releasing groups were well tolerated on aryl halides under applied conditions and resulted high product yields. Also, various amine compounds such as morpholine, piperidine, indole, imidazole, aniline and pyrrolidine could be coupled effectively for N-arylation of aryl halides. The Fe3O4@PDA@Pd(II) could be recovered readily with the aid of a magnet and subsequently reused continually for about six runs. On similar grounds, Allahresani et al. developed a Cu–Co bimetallic magnetic (Fe3O4@PEG@Cu–Co) nanocatalyst wherein imidazolium moiety and PEG chain were anchored on Fe3O4 NPs [61]. The synthetic strategy for the preparation of magnetic

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Figure 7.7: Fabrication of Fe3O4@SiO2-TCT-PVA-Cu(II) NPs and their application in Ulmann type Narylation reactions. (a) Schematic representation of catalyst preparation; (b) C–N coupling between N-heterocyclic compounds and aryl halides using Fe3O4@SiO2-TCT-PVA-Cu(II) NPs. Reproduced with permission from ref. [59]. Copyright 2018, John Wiley & Sons.

Cu–Co bimetallic nanocatalyst has been illustrated in Figure 7.9a. Using this catalyst, C–N cross coupling reactions of N-heterocyclic compounds with aryl halides as well as with phenyl boronic acid were carried out and the resulted N-arylated compounds could be obtained in good yields (Figure 7.9b). Moreover, phenylboronic acid has a

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(a)

(b)

Figure 7.8: Fabrication of Fe3O4@PDA@Pd(II) based nanocatalyst and its application in BuchwaldHartwig C–N cross coupling reaction. (a) Preparation of Fe3O4@PDA@Pd(II) catalyst; (b) C–N coupling reactions between N-heterocyclic compounds and aryl halides using Fe3O4@PDA@Pd(II) catalyst.

dramatic impact in the anticipated output of the reaction compared with aryl halide derivatives. However, p-substituted aryl halides gave satisfactory yield compared to their corresponding o-substituted derivatives that may be attributed to the steric hindrance effect in case of o-substituted aryl halides. Subsequently, Zahra Khorsandi and co-workers synthesized a novel and sustainable cobalt based heterogeneous Co-MTL@MNPs catalyst comprising readily available and safer ligand mannitol [62]. Initially, magnetic nanoparticles were prepared by simple co-precipitation method and then coated with mannitol to form MTL@MNPs. Finally, cobalt species were immobilized onto MTL@MNPs to generate magnetically separable Co-MTL@MNPs catalyst (Figure 7.10a). Various instrumental techniques (TGA, XRD, XPS, FE-SEM and TEM, etc.) were used to investigate the stability, number of organic moieties in catalyst, oxidation state of cobalt metal and surface morphology. The versatility and generality of the catalyst in C–N bond formation was explored for

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Figure 7.9: Scheme depicting fabrication of Fe3O4@PEG@Cu-Co NPs and their application in C–N coupling reaction. (a) Systematic catalyst preparation; (b) Fe3O4@PEG@Cu–Co NPs catalyzed C–N coupling reactions between N-heterocyclic compounds and aryl halides/phenyl boronic acids. Reproduced with permission from ref. [61]. Copyright 2020, Royal Society of Chemistry.

the synthesis of various amino derivatives by coupling aryl halides with several amines which includes N-heterocyclic (indole, imidazole) amine, diphenylamine as well as aliphatic amines (Figure 7.10b). It was observed that the electronic nature of substituents had no significant effect on reaction outcomes. Moreover, the catalyst could also be applied effectively in the synthesis of FDA approved antitumor agents fedratinib and abemaciclib in overall acceptable yields (Figure 7.10c). To further exploit the prospects of magnetically retrievable catalysts in expediting C–N bond formation reactions, Satya Paul et al. fabricated nickel and iron based mono (Ni@Fe3O4–NDCs) and bimetallic (Ni@Fe–Fe3O4–NDCs) magnetic nanocatalyst for Chan-Lam cross coupling reactions of amines with phenyl boronic acid [63]. During the catalyst preparation firstly, nitrogen doped carbons (NDCs) were synthesized and then

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(a)

(b)

(c)

Figure 7.10: Synthesis of Co-MTL@MNPs based nanocatalyst and its application in C–N bond formation reactions. (a) Schematic representation of catalyst preparation; (b) Co-MTL@MNPs catalyzed C–N bond formation; (c) Co-MTL@MNPs catalyzed preparation of fedratinib and abemaciclib.

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magnetically modified to form magnetite nanoparticles on NDCs i.e. Fe3O4–NDCs. Lastly, Ni and Fe metal NPs were immobilized onto Fe3O4–NDCs to get two monometallic, two bi-metallic and one alloy nanocatalyst (Figure 7.11a). Out of the synthesized magnetic nanoparticles based catalyst one mono-metallic (Ni@Fe3O4–NDCs) and one bimetallic (Ni@Fe–Fe3O4–NDCs) catalyst exhibited good activity. The morphological difference detected by SEM images, enlarged surface area in BET and observation of output of the other techniques like HRTEM, XRD and XPS explained the unexpected improved catalytic behavior of Ni@Fe3O4–NDCs over Ni@Fe–Fe3O4–NDCs. Therefore, the scope of Chan–Lam C–N cross coupling reaction to synthesize several diarylamine derivatives was explored using magnetically separable catalyst Ni@Fe3O4–NDCs by coupling different aryl amines, alkyl amines and imidazole with phenyl boronic acids (Figure 7.11b). In case of arylamines, the availability of electron-withdrawing groups or electron-releasing groups at para-Position resulted clean conversion leading to good product yields, however meta-Substituted arylamines took longer time for the reaction

Figure 7.11: Scheme depicting synthesis of Ni@Fe–Fe3O4–NDCs based nanocatalyst and its application in Chan-Lam cross coupling reactions. (a) Ni@Fe–Fe3O4–NDCs NPs synthesis; (b) Ni@Fe– Fe3O4–NDCs catalyzed cross coupling reactions between anilines and phenyl boronic acids. Reproduced with permission from ref. [63]. Copyright 2021, Elsevier B.V.

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completion. Moreover, ortho-Substituted aryl amines were less reactive which implies that the steric hindrance in the vicinity of the amino group had remarkable effect on C–N coupling reaction. On the other hand all phenyl boronic acids reacted smoothly to give the products in good yields. Imidazole delivered the good yield of desired products whereas poor results were found with alkylamines.

7.4.2 C–O coupling Over the past decades cross-coupling reactions are considered as a powerful tool in organic synthesis for the construction of C–O bonds [64]. In this perspective, transitionmetal-catalyzed reactions have appeared to be highly versatile synthetic methodology for the preparation of numerous biologically, pharmaceutically and biochemically important molecules through C–O cross-coupling [65–69]. However, significant achievements have been made through transition-metal-catalyzed C–O bond formation reaction but the toxic effects of catalysts, high costs of metal catalysts, generation of catalytic waste impelled the scientists to develop more efficient and environmentally benign protocols for C–O bond formation. This quest brought the scientific community to develop cheaper, more sustainable and magnetically recoverable heterogeneous metal catalysts immobilized onto a support. In this context, Manoj B. Gawande et al. prepared recyclable magnetic Fe3O4-Co3O4 nanocatalyst for O-arylation of phenol by coupling with 5-nitro-iodobenzene [70]. The preparation of Fe3O4-Co3O4 nanocatalyst started with the synthesis of Fe3O4 NPs by co-precipitation method followed by it’s reaction with CoCl2.6H2O (Figure 7.12a). During Fe3O4-Co3O4 MNPs catalyzed O-arylation of phenols, various diversely substituted phenols were coupled with 5-nitroiodobenzene and corresponding products were obtained in good to excellent yields

(a)

(b)

Figure 7.12: Illustration showing preparative route to Fe3O4-Co3O4 NPs based catalyst and its application in catalyzing C–O bond formation reactions. (a) Fe3O4-Co3O4 MNPs synthesis; (b) Fe3O4Co3O4 MNPs catalyzed C–O bond formation.

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(Figure 7.12b). Lower reaction conversion was observed in case of phenols bearing electron-withdrawing groups at para-Position. Likewise, Batool Akhlaghinia et al. reported MOFs based magnetically retrievable CoII immobilized heterogeneous nanocatalyst (Fe3O4@AMCA-MIL53(Al)NH2-CoII) for efficient C–O cross coupling reactions under solvent free conditions [71]. The stepwise systematic preparation of catalyst is depicted in figure 7.13a, which get started with the thermal synthesis of NH2-MIL53(Al) framework. This NH2-MIL53(Al) is then reacted with citric acid to obtain AMCA-MIL53(Al) which subsequently converted into Fe3O4@AMCA-MIL53(Al) NPs. By refluxing a mixture of Fe3O4@AMCAMIL53(Al) NPs and 2-chloroethylphosphonic acid resulted Fe3O4@ AMCA-MIL53(Al)Ethephon. Then, these NPs was reacted with amino guanidine nitrate to obtain Fe3O4@AMCA-MIL53(Al)-NH2 NPs. Finally, CoII was immobilized onto the surface of aforesaid NPs by treating with CoCl2.6H2O to achieve the desired MOFs, Fe3O4@AMCA-MIL53(Al)-NH2-CoII. To confirm the chemical structure, phase purity, crystalline nature, morphology, elements, thermal stability and magnetic properties various characterization techniques were used. After confirmation of the desired MOFs formation, Fe3O4@AMCA-MIL53(Al)-NH2-CoII was employed to explore it’s importance in C–O cross-coupling reactions. For this purpose various aryl halides were coupled with several phenols, naphthols, benzylic, allylic and aliphatic alcohols derivatives, and corresponding products could be obtained in moderate to excellent yields (Figure 7.13b). Moreover, during the recovery and recyclability experiment it was observed that catalyst can be used for this C–O coupling reaction upto six cycle without any noticeable loss of activity. However, a decrease in activity in seventh cycle could be the result of blocking of some pores of catalyst by organic segments and negligible leaching of cobalt during recycling process. Another Ullmann type O-arylation cross-coupling reactions for C–O bond formations was recently reported by Shiri et al. wherein they reacted various phenols with innocuous aryl tosylate in presence of Fe3O4@Starch-Au catalyst on water [72]. The fabrication of gold complex-functionalized magnetic Fe3O4@Starch-Au NPs started with the synthesis of Fe3O4 NPs by reacting a mixture of FeCl3.6H2O and FeCl2.4H2O in presence of ammonia followed by starch and gold nanoparticles coating (Figure 7.14a). The prepared gold based NPs were characterized by various techniques such as FTIR, TEM, SEM, XRD, TGA, EDX and VSM. The scope of Fe3O4@Starch-Au NPs in C–O coupling reactions was checked by reacting phenols with aryl tosylates (Figure 7.14b). Both electron-releasing and electron-withdrawing groups were well tolerated on phenols as well as aryl tosylates and resulted excellent yields of O-arylated phenols. The magnetic nanocatalyst could be separated from the reaction mixture using an external magnetic and recycled six times without any substantial loss in catalytic performance.

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Figure 7.13: Scheme depicting fabrication of Fe3O4@AMCA-MIL53(Al)-NH2-CoII nanocatalyst and its application in C–O cross coupling reactions. (a) Illustration of catalyst preparation and; (b) Oarylation of alcohols using aryl halides via C–O bond formation. Reproduced with permission from ref. [71]. Copyright 2020, Elsevier B.V.

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Figure 7.14: Fabrication of Fe3O4@Starch-Au catalyst and its application in Ulmann type O-arylation reactions. (a) Fe3O4@Starch-Au catalyst synthesis; (b) Fe3O4@Starch-Au catalyzed diphenyl ether synthesis via C–O bond formation. Reproduced with permission from ref. [72]. Copyright 2021, John Wiley & Sons.

7.4.3 C–S coupling The conversion of C–X bond (X = H, halogen etc.) to C–heteroatom bond is considered a highly important transformation in organic synthesis and enormous efforts have been made by chemist for such reactions. Among the various C–heteroatom bonds, C–S bond has it’s unique identification since aryl sulfides are key moieties of various pharmaceutically active compounds [73, 74] and also sulfides can be easily oxidized to corresponding sulfoxides and sulfone, which acts as building blocks for some medicine [75, 76]. Therefore, significant efforts have been made for the formation of C–S bond which includes the use of volatile, expensive and foul smelling thiols, use of homogeneous catalysts which causes the product contamination by transition metal. To overcome these difficulties heterogeneous catalyst based strategies were used. In continuation of use of heterogeneous catalysts for C–S bond formations, Moghaddam et al. in 2017 developed a magnetically separable cobalt ferrite (CoFe2O4) nanoparticles catalyst for C–S cross coupling reaction between nitroarenes and alkyl halides using thiourea as sulfur source [77]. The catalyst was prepared by co-precipitation method by mixing the solution of iron nitrate and cobalt nitrate in presence of NaOH (pH = 12) followed by addition of oleic acid as surfactant to prevent aggregation and agglomeration of the NPs. Afterwards, the catalytic performance of cobalt ferrite (CoFe2O4) nanoparticles was evaluated during the investigation of C–S coupling reaction of nitrobenzene with benzyl halides (Figure 7.15). Nitrobenzene bearing electron-donating groups delivered high product yield in comparison to the nitrobenzenes containing electron-donating groups. Moreover, benzyl iodides and benzyl bromides reacted more smoothly resulting in high product yields than benzyl chlorides. Reusability and

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Figure 7.15: CoFe2O4 catalyzed C–S coupling reactions.

recoverability studies of the catalyst revealed that it could be separated from the reaction mixture using an external magnetic rod and reused upto 10 cycles without any considerable loss in activity. Later in 2018, Bahareh Atashkar and co-workers synthesized another bimetallic mixed ferrite (NiFe2O4) nanocatalyst for the construction of odourless C–S bond via non-thiolic thio-etherification of phenolic esters by breaking C–O bond [78]. The NiFe2O4 MNPs were prepared by co-precipitation method and their scope in C–S coupling reactions was explored by reacting various phenolic esters (acetates, triflates, tosylates) with arylboronic acids or triphenyltin chloride in presence of S8 to synthesize unsymmetrical and symmetrical thioethers (Figure 7.16a). Phenolic ethers bearing electron-donating groups reacted slower and required more time for the synthesis of corresponding products in good yields than those containing electron-withdrawing groups. Moreover, acetates, triflates, tosylates of naphthalene and pyridine could also react effectively delivering high yields of their respective products. Further, triphenyltin chlorides could also react promptly with phenolic esters in presence of magnetically recoverable NiFe2O4 nano-catalyst and good to excellent yield of products could be obtained (Figure 7.16b). The symmetric diaryl sulfides was obtained by treating phenolic esters with S8 using catalytic amount of NiFe2O4 MNPs in inert atmosphere (Figure 7.16c). The recovery and recyclability experiment showed that NiFe2O4 MNPs can be used as catalyst for five successive runs without significant deterioration in catalytic performance. Working on similar lines, Peng et al. immobilized trisaminomethane-cobalt (TrisCo) complex on the surface of Fe3O4 to synthesize magnetically separable Fe3O4@PTMS-Tris-Co MNPs [79]. The process for the preparation of catalyst started with the synthesis of Fe3O4 MNPs through co-precipitation method followed by immobilization of 3-chloropropyltrimethoxysilane (CPTMS) on the surface of Fe3O4 MNPs to yield Fe3O4@CPTMS MNPs. Then, Tris was embedded on Fe3O4@CPTMS MNPs under N2 atmosphere which lead to Fe3O4@PTMS-Tris MNPs. To finish the preparation of desirable nanocatalyst, alcoholic solution of Fe3O4@PTMS-Tris MNPs was stirred with Co(NO3)2.6H2O for 24 h at reflux temperature (Figure 7.17a). To ensure the synthesis of nanocatalyst and to study the surface morphology, stability and magnetism various

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(a)

(b)

(c)

Figure 7.16: Illustration depicting NiFe2O4 catalyzed construction of C–S bonds. (a) NiFe2O4 MNPs catalyzed C–S bond formation reactions between aryl halides and, (a) phenyl boronic acid; (b) triphenyltin chloride and; (c) using S8.

analytical techniques such as FTIR, SEM, TEM, X-ray mapping, EDS, ICP, XRD, BET and VSM, were used. Afterwards, Fe3O4@PTMS-Tris-Co MNPs were employed in C–S arylation reactions of aryl halides with thiourea (Figure 7.17b). The reactions resulted moderate to good yields of diaryl sulfide products. It was observed that p-substituted aryl halides reacted more smoothly in comparison of o- and m-substituted aryl halides. Metal-organic frameworks (MOFs) are highly-ordered frameworks comprising of spatially assembled inorganic metal centers and organic linkers and, have emerged as an ultimate class of crystalline materials owing to their high surface area, tunable structural features and well defined pore architectures. The fascinating properties of metal-organic frameworks such as presence of co-ordinatively unsaturated metal centers, sites for metals loading within the pores, functionalized ligands, etc. makes them catalytically active. Regardless of these innumerable advantages, MOFs suffers with a few limitations like stability in acid, basic or moist conditions and challenging separation from the reaction mixture prompt Akhlaghinia et al. to investigate magnetically separable heterogeneous catalysts Fe3O4@AMCA-MIL53(Al)-NH2-CoII for cross-coupling reactions [80]. The Fe3O4@AMCA-MIL53(Al)-NH2-CoII nanocomposites

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(a)

(b)

Figure 7.17: Fabrication of Fe3O4@PTMS-Tris-Co nanocatalysts and their applicability in C–S coupling reactions. (a) Fe3O4@PTMS-tris-Co catalyst preparation; (b) C–S bond formation reactions using thiourea and aryl halides.

were developed via the functionalization of Fe3O4@AMCA-MIL53(Al) NPs by 2-chloroethylphosphonic acid (Ethephon) and then reacting with amino guanidine nitrate, which resulted in Fe3O4@AMCA-MIL53(Al)-NH2. Lastly, boiling of ethanolic solution of Fe3O4@AMCA-MIL53(Al)-NH2 with CoCl2.6H2O resulted black powdered magnetically recoverable Fe3O4@AMCA-MIL53(Al)-NH2-CoII nanocomposites (Figure 7.18a). After successful formation of Fe3O4@AMCA-MIL53(Al)NH2-CoII MNPs, the catalytic activity was explored in C–N and C–S coupling reactions. During C–S coupling reactions various aryl halides and thiols were examined under optimized reaction conditions. As illustrated by the results of reactions, aryl iodides reacted faster than aryl bromides followed by aryl chlorides (Figure 7.18b). Furthermore, electron-rich aromatic iodides reacted more smoothly than electron-deficient aryl iodides. Recently, Xiaoqing Xu and co-workers fabricated palladium based magnetic Fe3O4@SiO2/2-aminopyridine-Pd(II) nanoparticles through immobilization of Pd(II) complex on the surface of Fe3O4@SiO2 followed by modification with 2-aminopyridine ligand [81]. The preparation of catalyst was accomplished by initial vigorous stirring of an aqueous solution of Fe(II) and Fe(III) salts followed by addition of NH3 solution and heating the reaction mixture at 80 °C. To the black precipitate of Fe3O4, tetraethyl orthosilicate (TEOS) was added along with PEG and ammonia solution, and continually stirred for 36 h at room temperature. The product, Fe3O4@SiO2 was separated with external magnet and washed with ethanol and water. Then Fe3O4@SiO2 NPs reacted with CPTMS under N2 atmosphere to get Fe3O4@SiO2-CPTMS NPs. Aforesaid MNPs

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Figure 7.18: Synthetic route to Fe3O4@AMCA-MIL53(Al)-NH2-CoII nanocatalysts and their application in C–S bond formation reactions. (a) Schematic representation of catalyst preparation; (b) C–S coupling reactions of aryl halides and thiols in presence of Fe3O4@AMCA-MIL53(Al)-NH2-CoII.

treated with 2-aminopyridine followed by PdCl2 to synthesize Fe3O4@SiO2/ 2-aminopyridine-Pd(II) catalyst (Figure 7.19a). Finally, the scope of catalyst was examined in C–S bond formation by coupling several electronically diversified aryl halides with diaryl disulfides and the desired products could be obtained in moderate to

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(a)

(b)

Figure 7.19: Illustration showing fabrication of Fe3O4@SiO2/2-aminopyridine-Pd(II) based nanocatalyst and its application in C–S bond formation reactions. (a) Preparation of Fe3O4@SiO2/ 2-aminopyridine-Pd(II) nanoparticles; (b) Fe3O4@SiO2/2-aminopyridine-Pd(II) nanoparticles catalyzed C–S coupling between aryl halides and diaryl disulfides.

excellent yields (Figure 7.19b). Recyclability test showed that catalyst can be used upto seven runs without any substantial loss in activity. The substrate scope also exposed that C–Se bond coupling could also be achieved efficiently using Fe3O4@SiO2/ 2-aminopyridine-Pd(II) catalyst (Figure 7.19c).

7.4.4 Miscellaneous reactions In recent years, magnetic nanoparticles based catalysts have also been efficiently utilized for other C–heteroatom bond formations such as C–Se, C–Te, etc. [82, 83]. It is worth mentioning here that Ranu and co-workers reported magnetically separable CuFe2O4 nanoparticles for the synthesis of organotellurides and selenides through coupling of boronic acid with ditellurides and diselenides in PEG-400 in presence of DMSO as the additive (Figure 7.20) [84]. The developed protocol could be effectively used for accessing a wide spectrum of chalcogenides including diaryl, aryl-heteroaryl, aryl-styrenyl, aryl-alkenyl, aryl-allyl, aryl-alkyl and aryl-alkynyl motifs. It was found that a diverse range of substituted organoboronic acids having electron withdrawing and electron donating groups smoothly reacted with diphenyl ditelluride and diphenyl diselenide to furnish corresponding products in high yields. Further, the catalyst was found to show recyclability up to eight cycles without any appreciable loss in its catalytic activity. Arylphosphonates are considered to be highly valuable motifs in synthetic organic chemistry and medicinal chemistry. Additionally, these moieties find numerous

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Figure 7.20: CuFe2O4 nanoparticles catalyzed coupling of boronic acids with aryl diselenides and ditellurides.

Figure 7.21: Pd-imino-Py-γ-Fe2O3 catalyzed synthesis of arylphosphonates through Csp2-P coupling reaction.

applications in polymer chemistry, designing of fuel cell membranes and solar cells and as ligands in diverse catalytic reactions. Considering the high significance of these moieties, Sobhani and co-workers developed a palladium-Schiff base complex covalently anchored onto γ-Fe2O3 (Pd-imino-Py-γ-Fe2O3-γ-) as an effectual catalyst for the synthesis of arylphosphonates in pure water without any additive (Figure 7.21) [85]. The synthesis of catalyst initiated with the reaction of chloro-functionalized γ-Fe2O3 with iminopyridine followed by treatment with Pd(OAc)2 in dry acetone to yield Pd-Schiff base complex supported on γ-Fe2O3. The catalyst was successfully characterized using various physico-chemical characterization techniques such as XRD, TEM, SEM, TGA, ICP, XPS, VSM and elemental analysis. The synthesized catalyst was used for arylphosphinates through Csp2-P coupling reactions. It was found that electrophilic benzenes were successfully coupled with triethylphosphite to form desired products in good to excellent yields in water as the solvent. Further, the catalyst could be facilely retrieved via external magnet and reused for eight consecutive runs without showing any appreciable loss in its catalytic activity.

7.5 Conclusion and future perspectives Recent research on the potential nanomaterials as candidates for ideal green catalysts has wondrously introduced us to a new class of highly promising nanocatalyst, known as the magnetically retrievable nanocatalysts that have spread their essence ideally in all sorts of industrially significant organic transformations, particularly reactions

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involving C–heterobond formations. Owing to their striking superparamagnetic properties, ease of preparation, non-toxicity, economic viability, commendable recyclability (often observed upto 10 cycles), these catalysts involving either iron oxides or mixed ferrites as support are here to stay and rule the field of catalysis as they contribute largely to the development of sustainable and green processes. Also, notably the magnetic nanoparticles offer a tremendous scope of improvement in terms of stability via the profitable utilization of diverse coating and functionalization techniques. Further efforts are on way to improvise their large scale utility via efficient manipulation of their morphological attributes and developing techniques for synthesizing identical nanostructures. Mechanistic studies are also being emphasized upon to comprehend the mechanisms occurring at nanoscale dimensions, so that further work can be done in this area. Fruitful collaborations between academicians and industrialists that can establish strong foundations for extracting the minute details pertaining to these captivating catalysts can help in overcoming some of the current challenges faced while scaling up for industrial purposes.

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Supplementary Material: The online version of this article offers supplementary material (https://doi. org/10.1515/psr-2021-0101).

Anshu Dandia*, Sonam Parihar, Krishan Kumar, Surendra Saini and Vijay Parewa

8 Carbocatalysis: a metal free green avenue towards carbon–carbon/heteroatom bond construction Abstract: Indeed, all the heterocycles comprises of either “C–C, C–N, C–S or C–O” bonds in their skeleton and construction of these bonds has laid the foundation stone of organic chemistry. The present researchers are continually attempting to develop new strategies for synthesizing miscellaneous structurally divergent molecular entities and these bond forming reactions are the fundamental tools. As a consequence, a colossal upheaval is witnessed in development of benign and sustainable synthetic routes for green bond-forming reactions envisaging carbon–carbon/heteroatom. This chapter is aimed towards highlighting the recent developments perceived in “C–C, C–N, C–S or C–O” bondconstruction especially emphasising greener perspectives i.e. carbocatalysis. Keywords: carbocatalysis; carbon quantum dots (CQDs); graphene oxide (GO); graphitic carbon nitride (g-C3N4); green reactions.

8.1 Introduction Heterocycles have witnessed extensive widespread in biologically prominent natural as well as synthetic moieties. Thus, are of immense significance pharmaceutically and industrially. Heterocycles are the structural sub unit scaffolds that are invariable components in vitamins, amino acids, hormones, alkaloids, drugs, cosmetics, agrochemicals, polymers, dyes etc. In fact, naturally available drugs viz. morphine, quinine, atropine, reserpine, papaverine, procaine, theophylline, codeine, emetine cocaine, codeine, digitoxin, pilocarpine and synthetically available drugs viz. barbiturates, diazepam, captopril, isoniazid, metronidazole, methotrexate, azidothymidine, antipyrine and chlorpromazine are heterocyclic in nature [1]. Besides, heterocycles are a vital source of active ingredients in therapeutic agents. Moreover, synthetic heterocycles tends to possess pharmacological properties. As a matter of fact, all the *Corresponding author: Anshu Dandia, Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur, India, E-mail: [email protected] Sonam Parihar, Krishan Kumar, Surendra Saini and Vijay Parewa, Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur, India, E-mail: [email protected] (V. Parewa) As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: A. Dandia, S. Parihar, K. Kumar, S. Saini and V. Parewa “Carbocatalysis: a metal free green avenue towards carbon–carbon/ heteroatom bond construction” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2022-0004 | https://doi.org/ 10.1515/9783110759549-008

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Figure 8.1: Ubiquitous application of heterocycles.

heterocycles comprises of either “C–C, C–N, C–S or C–O” bonds in their skeleton [2–4] (Figure 8.1). Since time immemorial, extensive efforts have been made by organic chemists for formulating novel and benign synthetic transformations. In this domain, “C–C, C–N, C–S or C–O” bond construction via “transition metal catalysis” are considered the most enticing methodologies amongst the conventional fundamental transformations [5–11]. Indeed these methodologies have greatly influenced the synthetic routes as they are time and energy efficient. But, as overviewed, these strategies have pre-requisites such as a metal catalyst and pre-functionalization of coupling partners which are actually disadvantageous. The metal catalysts are toxic and expensive while prefunctionalization of reactants increase the number of steps in the synthetic strategy, thus, hampering the practical applicability of these coupling reactions. Moreover, these traditional approaches displays low atom economy, by products formation, employs volatile organic solvents and toxic transition metals which are hazardous for

8.1 Introduction

227

Figure 8.2: Drawbacks of traditional methodologies.

the environment (Figure 8.2). Undoubtedly, the insight for formulating benign chemical synthesis for “C–C, C–N, C–S or C–O” bond forming reactions witnessed great progress during recent times [12]. Times are gone when chemistry was considered hazardous to the environment. The arsenal of chemist has no dearth of opportunities. With the advent of concept of green chemistry [13], these reactions epitomized a paradigm shift towards the sustainable protocols. Sustainability and green chemistry are two parallel terms which go hand in hand. They focus on the concept of designing the processes that have low environmental impact and based on renewable resources. The “C–C, C–N, C–S or C–O” bond construction has laid the foundation stone of organic chemistry. The present researchers are continually attempting to develop new strategies for synthesizing miscellaneous structurally divergent molecular entities and these bond forming reactions are the fundamental tools. On the contrary, to dispose of the environmental contamination related with the synthetic organic transformations,

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researchers are consistently heading towards economical and sustainable chemical transformations.

8.2 Catalysis As a matter of fact, catalysis is of extraordinary noteworthiness in research arsenal, industrial sector & daily life within the field of nanotechnology. Catalysis is the scientific innovation that influences the pace of chemical reaction, without itself being actually involved in the reaction. Conventional homogeneous catalytic systems are profoundly effective in light of the fact that they are all precise on a molecular level and promptly solvable in the reaction medium, guaranteeing adequate contact between the catalyst and the reactants. Nevertheless, expensive and tiresome purification strategies have to be employed to avoid contamination of catalyst with target product. Remarkably, due to sustainable demands and strict environmental needs, the retrieval and reuse of catalysts is significant. The heterogeneous catalysts have been deliberately developed out of inspiration to provide superior catalysis [14].

8.3 Carbocatalysis Nanotechnology has unlocked new frontiers in materials science by advancement through state-of-the-art heterogeneous catalysts. Carbon is an age old catalytic material, often been used as catalyst support in heterogeneous catalysis owing to the various potential advantages viz. tailorable surface and porous structure, acid–base resistance, stable high temperature range and reasonably priced [15]. The advent of carbonaceous materials offers an exceptional substitute to conventional catalysts [16–19]. The surface chemistry, structure and defects are responsible for providing catalytic attributes in carbon materials. The unmatched controllability towards altering chemical and physical properties of carbon compels it as efficient candidate for heterogeneous catalyst. Considering the fact that the development of the new catalyst and new process goes in parallel to each other, a lot of attention has been devoted to investigating new metal free heterogeneous catalysts employing carbon based materials which is now popularly termed as carbocatalysis. Specifically, carbon nanomaterials have been exhibited as novel array of "mysterious" metal free catalysts, which are successful catalyst, yet can likewise be used as impetus support. They are guaranteed metal free substitutes on account of their ubiquitous nature, environmental tolerability, corrosion endurance and unique external properties. In the impending “Carbon Age”, carbon-based catalysts are copiously established in various catalysis domains. “Carbon nanotubes (CNTs), nano-diamonds, fullerenes, graphite, graphene, graphene oxide (GO), reduced graphene oxide (rGO), graphitic

8.3 Carbocatalysis

229

Figure 8.3: Structural elucidation of graphene oxide (GO).

carbon nitride (g-C3N4) and carbon quantum dots (CQDs)” are the various allotropic forms of carbon which have been explored for their catalytical activities. In this chapter, the various organic transformations deploying “ graphene oxide (GO), graphitic carbon nitride (g-C3N4) and carbon quantum dots (CQDs)” as metal free carbocatalyst have been documented.

8.3.1 Graphene oxide (GO) Graphene oxide contains hexagonal layered structural lattice of carbon atoms bearing sp3/sp2 hybridisation. The basal plane is mainly hydrophilic owing to occurrence of oxygen bearing functional entities such as –OH, C=O, –COOH and epoxy moieties. Moreover, these groups render it acidic properties, thus can serve as Lewis acid. Additionally, they provide surface tunability besides, providing better surface for support for any other nanoparticle fabrication (Figure 8.3). Graphene oxide has now attracted enormous attention owing to its catalytic efficiency due to a copious number of acidic sites, abundant oxygen functionalities, unpaired electrons on edge sites, high surface to volume ratio, high turn-over number, and easy recoverability. The easy synthetic procedure and splendid functional and structural features encouraged employing GO as heterogeneous catalyst in various organic transformations. Various diverse synthetic procedures have been documented by the virtue of the potentialities of graphene oxide as a versatile carbocatalyst. They involve: Chaurasia et al. [20] investigated graphene oxide catalysed straightforward, metal-free and economical procedure for preparing tri-substituted 1,3,5-triazine derivatives (3). The triazines (3) were formed by the reaction of benzyl alcohols (1) and N,N-dimethyl biguanide (2) under the optimised conditions and catalysed by GO. No substantial catalytic activity loss was observed up to six reaction runs. Substituents at the benzyl alcohol influenced the yields (Figure 8.4).

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Figure 8.4: GO catalysed formation of diverse tri-substituted 1,3,5-triazine scaffolds.

Dandia et al. [21] elucidated oxidative coupling of methylarenes (4) and anilines (5) using graphene oxide ascarbocatalysts, TBHP as co-oxidant at room temperature under aqueous condition affording substituted benzamides (6). Also, the oxidative coupling of methylarenes (4) and 2-aminopyridine (7) afforded the heteroaromatic benzamide (8). Moreover, this protocol was further applied for preparation of benzimidazole derivatives (10) through reaction of methylarenes (4) and o-phenylene diamines (9) (Figure 8.5). Hada et al. [22] formulated an ecological and competent methodology for the construction of 3-substituted quinazolinone (13) from the one-pot reaction of isatoic anhydride (11), substituted benzylamine (12) employing DMSO/water solvent system in presence of graphene oxide (Figure 8.6). Liu et al. [23] presented an efficient methodology for synthesis of 3,3′-bisindolylmethane derivatives (16) via cross dehydrogenative coupling reaction between cyclic ether (15) and various indole scaffolds (14) occurring through Friedel-Craft alkylationemploying graphene oxide (Figure 8.7). Wu et al. [24] illustrated metal free “cross-dehydrogenative coupling” reaction of one equivalent of oxindoles (17) with arenes (18) and thiophenols (19) in the presence of graphene oxide affording 3-aryloxindoles (20) and 3-sulfonylated oxindoles (21), respectively (Figure 8.8). Kour et al. [25] explicated a swift, benign and solvent free protocol employing GO as an incredible heterogeneous catalyst, chalcones (22) and 2-aminopyridines (7) as prototypes for synthesizing substituted imidazopyridine scaffolds (23) (Figure 8.9). Bodhak et al. [26] efficiently deployed graphene oxide (GO) as a metal free carbocatalysts for synthesizing iso-indolo[2,1-a]quinazolines (26) and substituted iso-pyridoquinazolines (27) under solvent free conditions employing 2-carboxybenzaldehyde (24) and 2-aminobenzohydrazides/2-aminobenzamides (25) as prototypes for domino condensation (Figure 8.10).

8.3 Carbocatalysis

Figure 8.5: GO catalysed C–H activation of methylarenes.

Figure 8.6: GO catalysed formation of diverse 3-substituted quinazolinone scaffolds.

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Figure 8.7: GO catalysed formation of diverse 3,3′-bisindolylmethane scaffolds.

Figure 8.8: GO catalysed dehydrogenative coupling of oxindole.

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Figure 8.9: GO catalysed formation of diverse imidazopyridine scaffolds.

Figure 8.10: GO catalysed formation of diverse iso-indolo[2,1-a]quinazoline scaffolds.

Fang et al. [27] investigated graphene oxide as a competent carbocatalyst for the explicit dehydrogenative coupling reactions of substituted benzene analogues viz. arenes(18) and naphthenes (29) affording biphenyls (28), binaphthyls (30) and benzylnaphthenes (31). This strategy provided good yields for homo-coupling and cross coupling reactions (Figure 8.11). Gao et al. [28] elucidated the exploration of graphene oxide (GO) towards C–H arylation of benzene ring(18). This protocol formed the biaryl compounds (28) with aryl halides (32) as coupling partners in presence of t-BuOK (Figure 8.12).

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Figure 8.11: GO catalysed homo- and cross coupling.

Dhopte et al. [29] deployed GO for synthesizing benzimidazole/benzothiazole scaffolds (10, 35) in methanol under ultrasound irradiation via reaction of different substituted aromatic/aliphatic aldehydes (33) with 1,2-diaminobenzene (o-phenylenediamine) (9)/o-aminothiophenol (34) (Figure 8.13). Dandia et al. [30] formulated a highly efficient and green protocol encompassing metal free approach towards synthesising array of benzamide derivatives (6)exploiting the surface functionalities of carbocatalyst graphene oxide to trigger the oxidative amidation sequence of aromatic aldehydes (33) with anilines (5) in aqueous environment aided by microwave irradiations (Figure 8.14).

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Figure 8.12: GO catalysed C–H arylation of benzene.

Figure 8.13: GO catalysed formation of diverse benzimidazole/benzothiazole scaffolds.

Bhattacharya et al. [31] elaborated the efficient deployment of GO for preparation of functionalised 1,4-benzothiazines (37) by reaction of 2-aminothiophenol (34) and 1,3-diketo compound (36) (Figure 8.15). Khalili et al. [32] employed GO as competent carbocatalysts for preparing 2-amino3-cyanopyridines (41) in aqueous medium at 80 °C via the reaction of ketones (38), aldehydes (33), malononitrile (39) and ammonium acetate (40) (Figure 8.16). Gupta et al. [33] elaborated the formation of 1-amidoalkyl-2-naphthol (45), 1,2-dihydro-1-arylnaphth[1,2-e]-[1,3]oxazin-3-one (46) and 1-pyrrolidinone-2-naphthol (47) catalysed by graphene oxide under neat conditions at 120 °C. 2-naphthol (42), aryl/hetero-aryl aldehydes (33) and amide (6) or urea (43) or pyrrolidin2-one (44) were efficiently used reactant prototypes for the multicomponent reaction (Figure 8.17). The dibenzo [1,4]diazepine derivatives (49) were efficiently prepared by the reaction of o-phenylenediamine (9), dimedone (48) and various substituted aldehydes and ketones (33, 38) catalysed the graphene oxide under aqueous conditions as reported by Kausar et al. (Figure 8.18) [34].

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Figure 8.14: GO catalysed oxidative amidation sequence of aromatic aldehydes with anilines.

Gómez-Martínez et al. [35] employed GO and carboxylated GO (GO–COOH) for the nucleophilic substitution of allylic alcohols (50) by various nucleophiles (51) viz. N,N-dimethylaniline, phenol and ß-ketoesters in microwave irradiation afforded the substituted product (52). Moreover, the scope of the protocol revealed its application to the “pinacol rearrangement” of 1,2-diols (53) into ketonic moiety (54) (Figure 8.19). Khalili et al. [36] employed GO as an efficient carbocatalyst for the direct thiocyanation of phenols (57), aromatic amines (5, 55), indoles (14) and carbonyl

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Figure 8.15: GO catalysed formation of diverse 1,4-benzothiazine scaffolds.

Figure 8.16: GO catalysed formation of diverse 2-amino-3-cyanopyridine scaffolds.

compounds (38, 60) with pre-requisite presence of a-hydrogen in the moiety. The reaction proceeded in the presence of H2O2 and KSCN afforded the thio-cyanated products (56, 58, 59, 61) (Figure 8.20). Zarabi et al. [37] devised a sonochemical approach for formulating benzo[a]pyrano [2,3-c]phenazines (63) by employing “multisulfonic acid hyperbranched polyglycerol functionalized graphene oxide” i.e. GO@HBPG@SO3H as a robust catalyst for the reaction between o-phenylene diamine (9), benzaldehydes (33), malononitrile (39), and 4-hydroxy-[1,4]naphthoquinone (62) (Figure 8.21). Basak et al. [38] elucidated an exceptional methodology for the preparation of functionalised pyrano-pyrazoles (67) and isoxazoles (65) utilising sulfonated graphene oxide (SGO) as heterogeneous carbocatalysts. The SGO catalysed the reaction between hydroxylamine hydrochloride (64), ethyl acetoacetate (36) and substituted benzaldehyde (33) for the formation of isoxazole scaffolds (65). While the SGO catalysed the reaction between hydrazine (66), ethyl acetoacetate (36), malononitrile (39), and substituted benzaldehydes (33) for the formation pyranopyrazole (67) (Figure 8.22).

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Figure 8.17: GO catalysed formation of diverse 1,2-dihydro-1-arylnaphth[1,2-e]-[1,3]oxazin-3-one and 1-amidoalkyl-2-naphthol scaffolds.

Figure 8.18: GO catalysed formation of diverse dibenzo [1,4]diazepine scaffolds.

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Figure 8.19: GO catalysed nucleophilic substitution of allylic alcohol and pinacol rearrangement.

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Figure 8.20: GO catalysed thio-cyanation.

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Figure 8.21: Functionalised GO catalysed formation of benzo[a]-pyrano[2,3-c]phenazine scaffolds.

Figure 8.22: Sulphonated GO catalysed formation of pyrano-pyrazoles and isoxazoles scaffolds.

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Figure 8.23: GO catalysed formation of a-amino-phosphonates and 3,4-dihydropyrimidin-2-one scaffolds.

Tamalika et al. [39] elucidated synergistically efficient protocol deploying graphene oxide as carbocatalyst and ultrasonic irradiation as energy input for synthesizing a-amino-phosphonates (71) and 3,4-dihydropyrimidin-2-one (72) scaffolds. The a-amino-phosphonates were formedthrough reaction of aryl/heteroaryl aldehydes (33, 68) with amines (5, 69) and diethyl phosphite (70) while 3,4-dihydropyrimidin2-ones were prepared by the reaction of arylaldehyde (33) with ethyl acetoacetate (36) and urea (43) (Figure 8.23).

8.3.2 Graphitic carbon nitride (g-C3N4) The graphitic carbon nitride skeletal comprises of primarily carbon and nitrogen elements in abundance while hydrogen element in meagre amounts. It comprises of abundant π-conjugated systems with certain limited surface functionalities. The H-element signifies a moderately condensed infrastructure besides certain structural imperfections. The lone pairs available on N elements renders copious number of basic sites which portrays g-C3N4 as a prominent Lewis base prototype (Figure 8.24). Thus, abundant availability of paired electrons on edge sites, high surface to volume ratio, high turnover number, robustness, proficient surface functionalization and easy retrievability bestows it with significant application as “metal free heterogeneous catalyst” in various organic transformations. Numerous diverse synthetic procedures have been documented by the virtue of the potentialities of g-C3N4 and functionalised g-C3N4 as a versatile carbocatalyst. They involve:

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243

Figure 8.24: Surface structural moieties of graphitic carbon nitride (g-C3N4).

Ansari et al. [40] synthesised high nitrogen content comprising mesoporous carbon nitride (MCN) and efficiently deployed the MCN for the “Knoevenagel condensation” of aromatic aldehydes (33) with ethyl cyanoacetate (73) under microwave irradiation affording the ethyl-α-cyano-cinnamate derivatives (74) (Figure 8.25). Bahuguna et al. [41] developed a nanocomposite by fabricating reduced graphene oxide (RGO) with potassium-functionalized graphitic carbon nitride (KGCN). This nanocomposite was probed for the formation of arylidene derivatives (74, 75) by “Knoevenagel condensation” of aromatic aldehydes (33, 68) with ethyl cyanoacetate (73)/malononitrile (39) and green formation of aryl substituted chromenes(76) by the reaction of arylidene derivatives (74, 75) with dimedones (48) (Figure 8.26). Bahuguna et al. [42] made further modification in graphitic carbon nitride (GCN) nanosheets by fabricating with polyaniline (PGCN) and doping with ammonia (NPGCN) and elucidated its applicability in catalysing the reaction between substituted salicylaldehyde (77), ethyl cyanoacetate/malononitrile (73, 39) and substituted indoles (14) for the formation of indole-substituted 4H-chromenes (78) in aqueous medium. Furthermore, substituted salicylaldehyde (77) were reacted with with malononitrile/ ethyl cyanoacetate (39, 73) for the formation of substituted 2-(2-amino-3-cyano-4Hchromen-4-yl) malononitrile (79) scaffolds (Figure 8.27). Cai et al. [43] deployed g-C3N4/rGO nanocomposite for the visible light irradiated direct arylation of heteroaromatics (81) with diazonium salts (80) at room temperature affording the 2-arylated heteroaromatic product (82) (Figure 8.28). Ghafuri et al. [44] synthesised sulfonated graphitic carbon nitride (Sg-C3N4) and exploited the acidic nature for condensation reaction resulting in N-bearing heterocyclic moieties. The Sg-C3N4 catalysed the condensation reaction between benzil (83), aldehyde (33) and ammonium acetate (40) affording the imidazole derivatives (84). Also, it catalysed the condensation of benzil (83) and 1,2-diamine (9) affording the quinoxaline derivatives (85) (Figure 8.29). Priti et al. [45] elucidated the deployment of g-C3N4, a basic carbocatalyst for the “Knoevenagel condensations” of benzaldehydes (33) with toluenes (4)/benzylcynide

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Figure 8.25: MCN catalysed Knoevenagel condensation.

(86) affording substituted stilbene (87) in crown-ether as a phase transfer catalyst (Figure 8.30). Shcherban et al. [46] synthesised g-C3N4 from melamine and explored its catalytic supremacy in the “Knoevenagel condensation” between benzaldehyde (33) and ethylcyanoacetate (73) affording the ethyl-α-cyano-cinnamate derivatives (74) in comparison to g-C3N4 prepared from other sources (Figure 8.31). Zhong et al. [47] synthesised a novel bifunctional nanocatalyst i.e. acid functionalized mesoporous carbon nitride (MCN) for the de-acetalization-Knoevenagel reaction

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Figure 8.26: KGCN-RGO catalysed Knoevenagel condensation.

of dimethylacetal (88) and malononitrile (39) affording the arylidene derivative (75) (Figure 8.32). Su et al. [48] deployed mesoporous graphite carbon nitride (mpg-C3N4) as proficient photocatalyst for aerobic oxidation of primary amines (12, 89) into imines (90). Moreover, the efficacy was interrogated towards aerobic coupling of primary amines (12) with o-phenylenediamine (9) and 2-aminothiophenol (34) affording the benzoxazoles (91), benzimidazoles (10) and benzothiazoles (35) (Figure 8.33). Woźnica et al. [49] deployed mesoporous graphitic carbon nitride (mpg-C3N4) as efficient photocatalyst. The mpg-C3N4promoted radical cyclization of 2-bromo1,3-dicarbonyl compounds (92) affording the corresponding cyclopentane derivatives (93, 94) (Figure 8.34).

8.3.3 Carbon quantum dots (CQDs) The carbon quantum dots possess carbon atoms in either sp2 or sp3 hybridisation and appear as a typical spherical structural motif with size ≤10 nms. A copious number of surface defects due to polymeric aggregates and oxygen/nitrogen fostered functionalities are observed. The oxidised edge surface moieties containing –OH, –COOH,

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Figure 8.27: NPGCN catalysed formation of indole-substituted 4H-chromenes.

Figure 8.28: g-C3N4/rGOphotocatalysed arylation of heteroaromatics.

epoxy and amino groups stabilises the nanomaterials besides providing it semiconductor traits and fluorescence (Figure 8.35). Moreover, these functionalities provide better solubility in polar and non-polar solvents. Besides, they aid in better surface functionalization towards tunability of the catalytic activity. Thus, owing to easy surface fabrication, inertness towards chemicals and light degradation, ready availability of bio-based raw source materials, nontoxicity and enhanced solubility encouraged deployment of CQDs and fabricated CQDs as a promising heterogeneous catalyst in organic transformations.

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Figure 8.29: Sg-C3N4 catalysed formation of imidazole and quinoxaline derivatives.

Figure 8.30: g-C3N4 catalysed Knoevenagel condensations.

Figure 8.31: Melamine derived g-C3N4 catalysed Knoevenagel condensations.

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Figure 8.32: Acidified MCN catalysed de-acetalization-Knoevenagel reaction.

Figure 8.33: mpg-C3N4 photocatalyzed aerobic oxidation of primary amines.

Figure 8.34: mpg-C3N4 photocatalyzed formation of cyclopentane derivatives.

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Figure 8.35: Structural elucidation of carbon quantum dots (CQDs).

However, the CQDs are yet to be fully explored towards their synthetic utility in organic transformations. Nevertheless, a handful of diverse synthetic procedures have been documented by the virtue of the potentialities of CQDs and functionalized CQDsas a versatile carbocatalyst. They involve: Han et al. [50] elucidated the deployment of CQDs towards empowering Aldol condensation of aromatic aldehydes (33) and a-H moiety bearing carbonyl compound (95) for the formation of α,β-unsaturated aldehyde scaffolds (96) aided by visible light irradiation (Figure 8.36). Jeon et al. [51] modulated the graphene quantum dots (GQDs) by doping with heteroatoms (nitrogen and sulphur) for tuning the photocatalytic efficacy of GQDs. The as prepared nitrogen and sulphur doped GQDs referred to as NS-GQDs was deployed for oxidative homo/hetero-coupling of various primary amines (12, 89) in visible light irradiation under aerobic conditions for the formation of N-substituted imines (90) at room temperature (Figure 8.37). Biju et al. [52] successfully exploited the surface acidity of carbon nanodots (CNDs) in cyclo-condensation of aldehydes (33, 68) with 2-aminobenzamide (97) affording 2,3-dihydroquinazolinon-4(1H)-one scaffolds (98). Further the carbocatalyst was deployed for catalysing reaction between amines (99) and α,β-olefins (100) for the formation of aza-Michael adducts (101) (Figure 8.38). Mayank et al. [53] elaborated the mutual collaboration of ionic liquids (ILs) fabricated carbon-quantum dots (CQDs) as competent catalytic assemble affording 4H-chromene derivatives (103, 104) via condensation of aldehydes (33, 68), naphthols (42, 102) and malononitrile (39) under ultrasonic irradiations (Figure 8.39).

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Figure 8.36: CQDs catalysed photocatalytic aldol condensation.

Figure 8.37: NS-GQD catalysed photocatalytic oxidative coupling.

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Figure 8.38: CNDs catalysed formation of spiro/glyco-quinazolinones and aza-Michael adducts.

Figure 8.39: CQDs-CRS catalysed formation of 4H-chromene derivatives.

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Figure 8.40: Carbon dots catalysed formation of amido-alkyl-naphthols (AAN).

Divya et al. [54] synthesised the porous coconut shell char extracted sulphonated carbon dots and exploited the acidic efficacy for the condensation of aldehydes (33), ß-naphthols (42) & amides (6, 6a, 43) for the formation of amido-alkyl-naphthols (AAN) (105) (Figure 8.40). Daisy et al. [55] elucidated deployment of sulphuric acid moieties fabricated carbon dots as proficient photocatalyst towards dehydrogenative cross coupling under visible light irradiations. The xanthenes/thioxanthenes (106) were cross coupled with either cyclic ketones (107) or acyclic ketones (108) or 1,3-dicarbonyls (36) affording the corresponding 1-(9-xanthyl)-substituted ketones (109, 110, 111). Dual catalytic role was played by sulphonated carbon dots in photo-oxidation followed by coupling (Figure 8.41).

Figure 8.41: Acidified carbon dot assisted photocatalytic dehydrogenative cross coupling.

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Xianjun et al. [56] effectively functionalised the surface of graphene quantum dots imparting it conspicuous photocatalytic property and exceptional CO2-switchable phase transfer property. The photocatalytic efficacy was exploited for the oxidative coupling of primary amines (12, 89) affording N-substituted imines (90) (Figure 8.42).

Figure 8.42: GQDs catalysed photocatalytic oxidative coupling of primary amines.

8.4 Conclusions “Carbon–carbon/heteroatom bond” construction has been the spine of the organic chemistry. Heterocyclic scaffolds tend to possess ubiquitous biological activities. As a consequence, the millennial year witnessed tremendous outburst in designing of greener protocols for synthesis of value added heterocyclic moieties. Thus, employment of carbocatalysts as efficient heterogenous catalyst has gained tremendous attention owing to their tailorable surface and porous structure, acid–base resistance, stable high temperature range and reasonably priced which makes them an exceptional substitute to conventional catalysts. The surface chemistry, structure and defects are responsible for providing catalytic attributes in carbon materials. The unmatched controllability towards altering chemical & physical properties of carbon compels it as efficient candidate for heterogeneous catalyst. The potentiality of these carbon materials has not been extensively analysed and applied in organic transformation, thus providing evident room for the researchers for exploration in future. This article summarises the facile application of nanocarbons as efficient carbocatalyst in promoting the synthesis of structurally divergent scaffolds. The focal point is encompassing the research articles involving the synthesis of heterocyclic scaffolds via “Carbon–carbon/heteroatom bond” construction along with the tangible objective of providing an exhaustive understanding to researchers of catalytic aspects of carbonbased materials in synthetic organic chemistry and encouraging their further exploration in bond forming reactions.

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39. Bhattacharya T, Majumdar B, Dey D, Sarma TK. Ultrasound mediated synthesis of α-aminophosphonates and 3, 4-dihydropyrimidin-2-ones using graphene oxide as a recyclable catalyst under solvent-free conditions. RSC Adv 2014;4:45831–7. 40. Ansari MB, Jin H, Parvin MN, Park SE. Mesoporous carbon nitride as a metal-free base catalyst in the microwave assisted Knoevenagel condensation of ethylcyanoacetate with aromatic aldehydes. Catal Today 2012;185:211–6. 41. Bahuguna A, Kumar A, Chhabra T, Kumar A, Krishnan V. Potassium functionalized graphitic carbon nitride supported on reduced graphene oxide as a sustainable catalyst for Knoevenagel condensation. ACS Appl Nano Mater 2018;1:6711–23. 42. Bahuguna A, Choudhary P, Chhabra T, Krishnan V. Ammonia-doped polyaniline-graphitic carbon nitride nanocomposite as a heterogeneous green catalyst for synthesis of indole-substituted 4H-chromenes. ACS Omega 2018;3:12163–78. 43. Cai X, Liu H, Zhi L, Wen H, Yu A, Li L, et al. A g-C3N4/rGO nanocomposite as a highly efficient metalfree photocatalyst for direct C–H arylation under visible light irradiation. RSC Adv 2017;7:46132–8. 44. Ghafuri H, Hanifehnejad P, Rezazadeh Z, Rashidizadeh A. Sulfonated graphitic carbon nitride (SgC3N4): a highly efficient heterogeneous organo-catalyst for condensation reactions. Multidiscip Digit Publ Inst Proc 2019;41:14–7. 45. Sharma P, Sasson Y. Highly active g-C3N4 as a solid base catalyst for Knoevenagel condensation reaction under phase transfer conditions. RSC Adv 2017;7:25589–96. 46. Shcherban ND, Mäki-Arvela P, Aho A, Sergiienko SA, Yaremov PS, Eränen K, et al. Melaminederived graphitic carbon nitride as a new effective metal-free catalyst for Knoevenagel condensation of benzaldehyde with ethylcyanoacetate. Catal Sci Technol 2018;8:2928–37. 47. Zhong L, Anand C, Lakhi KS, Lawrence G, Vinu A. Bifunctional mesoporous carbon nitride: highly efficient enzyme like catalyst for one pot deacetalization-Knoevenagel reaction. Sci Rep 2015;5:1–18. 48. Su F, Mathew SC, Möhlmann L, Antonietti M, Wang X, Blechert S. Aerobic oxidative coupling of amines by carbon nitride photocatalysis with visible light. Angew Chem 2011;123:683–6. 49. Woźnica M, Chaoui N, Taabache S, Blechert S. THF: an efficient electron donor in continuous flow radical cyclization photocatalyzed by graphitic carbon nitride. Chem Eur J 2014;20:14624–8. 50. Han Y, Huang H, Zhang H, Liu Y, Han X, Liu R, et al. Carbon quantum dots Carbon quantum dots with photoenhanced hydrogen-bond catalytic activity in aldol condensations. ACS Catal 2014;4:781–7. 51. Jeon SJ, Kang TW, Ju JM, Kim MJ, Park JH, Raza F, et al. Modulating the photocatalytic activity of graphene quantum dots via atomic tailoring for highly enhanced photocatalysis under visible light. Adv Funct Mater 2016;26:8211–9. 52. Majumdar B, Mandani S, Bhattacharya T, Sarma D, Sarma TK. Probing carbocatalytic activity of carbon nanodots for the synthesis of biologically active dihydro/spiro/glyco quinazolinones and aza-michael adducts. J Org Chem 2017;82:2097–106. 53. Singh A, Kaur N, Singh N, Jang DO. A carbon quantum dot-encapsulated micellar reactor for the synthesis of chromene derivatives in water. Mol Catal 2017;439:100–7. 54. Narayanan DP, Cherikallinmel SK, Sankaran S, Narayanan BN. Functionalized carbon dot adorned coconut shell char derived green catalysts for the rapid synthesis of amidoalkylnaphthols. J Colloid Interface Sci 2018;520:70–80. 55. Sarma D, Majumdar B, Sarma TK. Visible-light induced enhancement in the multi- catalytic activity of sulfated carbon dots for aerobic carbon-carbon bond formation. Green Chem 2019;21:6717–26. 56. Tu X, Wang Q, Zhang F, Lan F, Liu H, Li R. CO2-triggered reversible phase transfer of graphene quantum dots for visible light-promoted amine oxidation. Nanoscale 2020;12:4410–7.

Hosam M. Saleh* and Amal I. Hassan

9 Use of heterogeneous catalysis in sustainable biofuel production Abstract: Biofuel is a sustainable energy source that may use to replace fossil-based carbon dioxide and mitigate the adverse effects of exhaust emissions. Nowadays, we need to replace petroleum fuels with alternatives from environmentally sustainable sources of increasing importance. Biofuels derived from biomass have gained considerable attention, and thus most of the traditional methods that harm the environment and humans have retreated. Developing an active and stable heterogeneous catalyst is a step of utmost importance in the renewable liquid fuel technology. Thus, there is a great interest in developing methods for producing liquid fuels from nonedible sources. It may also be from dry plant tissues such as agricultural waste. Lignocellulosic biomass can be a sustainable source for producing renewable fuels and chemicals, as well as the replacement of petroleum products. Hence, the researchers aspired to synthesize new catalysts using a cheap technology developed to hydrolyze cellulose and then produce bioethanol without needing expensive enzymes, which may ultimately lead to a lower fuel price. In this paper, we will focus on the recent technologies used to produce sustainable biofuels through inexpensive incentives and innocuous to the environment. Keywords: bioethanol; biofuels; heterogeneous catalyst; sustainable sources; waste.

9.1 Introduction Sustainability has essentially turned into an emblem for a neoteric society, with developed and growing countries and multinational corporations supporting international research programs on sustainable food, energy, materials, and even urban planning that do not jeopardize future generations [1]. Figure 9.1 depicts the worldwide energy consumption by fuel source in 2019. There is a straightjacket between satisfying increasing energy demands and the need to limit existing emissions of CO2 and hence climate change, forecast to rise globally by 50% by 2040. The cement industry is one of the most energy-consuming industries and at the same time largest CO2 emissions, however, enormous innovative *Corresponding author: Hosam M. Saleh, Radioisotope Department, Nuclear Research Center, Egyptian Atomic Energy Authority, Cairo, Egypt, E-mail: [email protected], [email protected]. https://orcid.org/0000-0002-5889-3548 Amal I. Hassan, Radioisotope Department, Nuclear Research Center, Egyptian Atomic Energy Authority, Cairo, Egypt As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: H. M. Saleh and A. I. Hassan “Use of heterogeneous catalysis in sustainable biofuel production” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2022-0041 | https://doi.org/10.1515/9783110759549-009

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Figure 9.1: Global fuel consumption in 2019. Modified from ref. [2].

studies have been introduced to find alternatives that reduce the great amounts of consumed cement for environmental protection and restoration [3], such as polymers [4–7], natural clay [8, 9], cellulosic fibres [10] and nanomaterials [11, 12]. Foodstuffs can interact chemically to produce vegetable products and the first generation of edible oil fuels, such as palm oil, sunflower oil, and soya oil [13], while aquatic plants have potential applications in wastewater treatment [14, 15]. There are multiple varieties of catalytic materials, which can be manufactured using various methods and processes. It can be applied in variance applications, including environmental and sustainable catalysis, biomass recovery, renewable fuel generation, CO2 recycling, synthetic chemistry, gas storage/capture, pharmaceutical delivery, catalysis, photocatalysis, chemical sensing, and more. Hybrid materials composites of organic and inorganic constituents, which are defined by unique properties because of the synergetic effects of their organic and inorganic components, are worth noting among the various catalytic materials researched [16]. Another significant type of catalytic material is metalfree hybrids that convert CO2 and epoxides into cyclic carbonate and have potential applications in aprotic polar liquids, battery electrical electrolytes, reactive polymers, synthetic raw materials, and medicinal precursors [17]. Additionally, bio-alcohols, biogas, and biodiesel are all viable choices for sustainability. Biodiesel is one of these alternative fuels that is recommended as a supplemental fuel for diesel engines. The mono-alkyl esters of long-chain fatty acids generated from vegetable oil are used to make biodiesel. It is renewable, non-toxic, biodegradable, and ecologically friendly— and because of its changeable physical and chemical characteristics, it may be utilized in compression-ignition (diesel) engines with little or no modification. It also has a lower combustion emission profile than petroleum-based diesel fuel, releasing significantly less carbon monoxide, sulfur dioxide, and unburned hydrocarbons. The

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use of a suitable catalyst by the nature of the oil is one of the primary difficulties confronting the biodiesel manufacturing path [18]. The constitution and qualities of biofuels are determined by the design of catalytic processes, whereas fuel requirements are determined by engine operating conditions. The functional efficiency and side effects of catalysts during transesterification have been a topic of concern, attracting much research. The transesterification or alcoholysis process, which is aided by acids, bases, enzymes, and other types and forms of catalysts, is used to make biodiesel [19]. As the reactants, the catalysts can be in either a homogeneous or heterogeneous phase. The homogeneous catalyst is one in which the catalyst stays in the same phase (typically liquid) as the reactants throughout alcoholysis. The heterogeneous catalyst is in a different phase (typically non-liquid) than the reactants [19]. The proper catalyst is determined by various criteria, including the proportion of free fatty acids (FFAs) in the oil and the water content [20]. This paper includes a thorough explanation of the benefits and viability of heterocatalysts for biodiesel generation, which are both ecologically and economically feasible when compared to conventional homogeneous catalysts. Natural materials-based catalysis systems for biofuel generation, as is the future of energy and the environment with the utilization of heterogeneous catalysis are also highlighted.

9.2 Viability of heterocatalysts for biodiesel generation The presence of a catalyst accelerates the reaction, increasing the yield of the product. Various catalysts are employed in the biodiesel transesterification process. The catalysts utilized in the transesterification reaction may be categorized into four basic categories: homogeneous catalysts, heterogeneous catalysts, biocatalysts, and nanocatalysts [21]. The homogeneous catalysts are used in the transesterification process divided into two types of basic catalysts like NaOH and KOH and acidic catalysts like sulfuric, hydrofluoric, and hydrochloric acids. Homogeneously catalyzed processes are often quicker and need less loading than heterogeneously catalyzed ones. The homogeneous acid catalysts may directly create biodiesel from low-cost lipid feedstocks with high free fatty acid (FFA) concentrations (low-cost feedstocks, such as used waste cooking oil and greases, commonly have FFAs levels >1%) [22]. A homogeneous acid catalyst has a lower reaction rate than a homogeneous base catalyst, and these reactions need excessive amounts of alcohol and a high temperature. Liquid acids create environmental problems like corrosion. The efficiency of alkali-catalyzed transesterification is about four thousand times faster than the rate of acid-catalyzed transesterification.

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Salts of the base and glycerol are formed as byproducts of transesterification processes catalyzed by homogenous bases or acids. After purification, glycerol is commonly employed in the pharmaceutical business, and the excess KOH catalyst is used to produce potassium fertilizer by neutralizing with H3PO4 [23]. One significant drawback of homogeneous catalysts is that separating these catalysts from the medium is complicated and generally uneconomical; hence, reuse is frequently inappropriate. Aside from that, multiple washing stages related to the elimination of the catalyst from the product result in the use of water, typically deionized and extensive wastewater formation [24]. As a result, heterogeneous catalysts have emerged as a feasible option for homogeneous catalysts to address the difficulties outlined above [24]. Heterogeneous catalysts were offered as a cost-effective alternative to acidic and alkaline homogeneous catalysts [25]. That heterogeneous catalysts are noncorrosive, can be regenerated, reused, lack sensitivity to free fatty acids, and have an easy separation of the resulting product are the key reasons for their popularity. The heterogeneous catalytic method that produces a simple purification process is an expected worthy low-cost biodiesel production technique. In terms of catalyst regeneration and the ability to be reused in continuous processes, heterogeneous catalysts reduce the issues associated with homogeneous catalysis [26]. Many heterogeneous biodiesel-suitable catalysts were created and assessed in biodiesel synthesis procedures from original oils. However, until a highly efficient, solid catalyst can be created, many challenges remain, and many research projects for this purpose are conducted [27]. Nearly all commercial biodiesel facilities employ uniform alkaline catalysts, but they cannot be recycled and have significant disadvantages [28]. Recently, heterogeneous biodiesel-free catalysts were used in the industry, and mixed oxides of zinc and aluminum were used as the catalyst [29]. The adaptability of the catalyst depends on physical surface parameters such as surface area, pores size, the concentration of the active site, and limited mass transfer [30]. Fewer works on heterogeneous acid catalysts have been reported than on heterogeneous base catalysts (Table 9.1). Solid acid catalysts employed in transesterification and esterification processes include sulfonated saccharides, tungsten oxides, sulfonated zirconia, and Nafionl resins, as shown in Table 9.2. Muthu et al. [31] showed that using sulfated zirconia as a solid acid heterogeneous catalyst for biodiesel generation from neem oil resulted in a 95% biodiesel output while maintaining a 9:1 methanol to oil ratio. Shu et al. [32] used a carbon-dependent solid acid catalyst to produce 94.8 percent biodiesel from waste vegetable oil. Using a heterogeneous acid catalyst-like titanium-doped amorphous zirconia, Brucato et al. [33] discovered a 65 percent biodiesel output from rapeseed with a 40:1 methanol to oil ratio. Metal hydroxides [42], metal complexes [43], metal oxides such as calcium oxide [44], magnesium oxide [45], zirconium oxide [46], zeolites, hydrotalcite, and supported catalysts are examples of heterogeneous catalyst chemistry [47]. These catalysts have been explored as solid catalysts that address some of the disadvantages of using

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Table .: Catalysts (acidic solids) for the transesterification process. Catalyst

Feedstock

SO−/TiO – SiO

Acidified cottonseed oil Cerberra SO −/ZrO odollam SO−/SnO− – SiO Jatropha curcas SO−/SnO− – SiO Moringa oleifera SO−/SnO− – SiO Croton megalocarpus Jatropha curcas ZrO-AlO KSF-clay amberlyst Jatropha curcas Sulfated zirconia (SZ) Neem oil A carbon-based solid Waste acid catalyst vegetable oil

Temp

Time

Methanol/ Catalyst Oil Amount

Biodiesel Reference Yield

 °C  h

:  wt%

%

[]

 °C  h

:  wt%

%

[]

:  wt% :  wt% :  wt%

% % %

[] [] []

.% % % .%

[] [] [] []

Flash Point

Density (kg/L)

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

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

 °C  h  °C . h  °C  h  °C  °C  °C  °C

h h h . h

: : : .:

. wt%  wt%  wt% . wt%

Table .: Vegetable oil characteristics []. Vegetable oil

Com Cottonseed Crambe Linseed Peanut Rapeseed Safflower Sesame Soya bean Sunflower Palm Babassu Diesel

Heating Kinematic Cetane no ( value MJ/kg viscosity at  °C (mm/s) . . . . . . . . . . . . .

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

. . . . . . . . . . – – .

Cloud Pour point °C point °C −. . . . . −. . −. −. . . . –

−. −. −. −. −. −. −. −. −. −. – – −

homogeneous catalysts. The heterogeneous catalysts include mesoporous silicates and zeolites. Zeolites are employed in oils and create linear and cyclic carboxylic acids, olefins, ketones, aldehydes, and paraffin. Using cracking as an increase in value-added products for triglycerides presents several inconveniences since it creates a wide range of chemicals and helps to create coke [48]. However, the downside of creating CO2 residues is often the hydrocarbon cracking of zeolitic catalysts. Microporous zeolites, like ZSM-5, are often employed as a catalyst for the production of products that include

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a vaster amount of petrol-octane [49]. Through a significant number of active sites located at the crystal’s edge, nanoscale metal oxides offer an excellent catalytic activity for the methanolysis of vegetable oils. Nanocrystalline CaO achieves a conversion efficiency of 100% in 6 h at room temperature using methanol on vegetable oil and poultry fat [26]. In a two-stage process, nanosized CaO is an excellent trans-esterifying catalyst for jatropha oil, yielding up to 98.54% biodiesel [50]. Catalysts have renewability of about nine cycles, and up to six cycles with a 95.8% output are stable. The yield of the biodiesel was 94 and 96% for its catalytic activity in the transesterification of calcium-nitrate nanostructured (CaO/CaN) and snail shells (CaO/ss) [50]. A Li-doped CaO nano catalyst generated a high biodiesel production of 12:1 methanol/oil molar ratio with a 5-wt percentage catalyst and a reaction temperature of 65 °C for 2 h. At 98.95%, the biodiesel yields of nanostructured mixed-metal oxides of CaO–MgO outperformed those of nanoCaO alone. With a 96% yield, the impregnation technique creates KF/CaO in Chinese tallow oil. Another CaO-based nanocatalyst, Ca/Fe3O4SiO2, has found favor in producing biodiesel. Because of Fe3O4, an external magnetic field can easily separate a catalyst supported by magnetic material and maintain it active for multiple cycles [51]. The primary reusable catalyst for creating biodiesel was magnetic nanoparticles (MNPs) with guanidine-functioning Fe3O4 and Fe3O4@SiO2. The Fe3O4–TBD (1,5,7-triazabicyclo [4, 4, 0] dec-5-ene]) showed good catalysis in the 1st cycle, with biodiesel conversion reaching 96%. K2O/μ-Al2O3, the nanosolid base catalyst, is converted into rape oil by 94%. In the transesterification, additionally, KOH impregnated with alumina and calcium aluminate was utilized. Zirconium bitartrate solid base nanocatalyst was also used in the synthesis of biodiesel [51].

9.3 Production of liquid fuels with conventional catalysts Conventional energy sources are currently depleting while the demand for transport fuels is expanding. Many academics focus on developing alternative and renewable sources of liquid fuels which replace commercial petroleum products with new energy resources and are also environment-friendly [52]. The charcoal can be converted into liquid fuels in two ways; directly and indirectly coal liquefaction (DCL and ICL). In both circumstances, the challenge is to increase the end product’s hydrogen/carbon (H/C) ratio while maintaining reasonable total costs and boiling temperatures [53]. Both technologies are in different stages of development. The ultimate products include transport fuels with properties similar to diesel, gasoline, and other fluid chemical compounds such as methanol and dimethyl ether (DME). The DCL process involves dissolving coal in a solvent mixture [53]. Thermal cracking follows, which adds hydrogen as a donor solvent. Two main DCL processes

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are available: (a) the liquidation process of a single-stage process offers either primary reactor distillates or series reactor trains, maybe a hydro reactor for upgrading primary distillates. For single-step direct liquefaction, the best operating temperature shall be around 450 °C, with a molar ratio of around 2:1 between carbon and solvent. The twostage liquefaction process produces distillates in two stages: the first dissolve coal (with or without a low-activity catalyst), and the second offers distillate hydrotreatment in the presence of high-activity catalysts. DCL technology is presently the most efficient method for manufacturing liquids from coal. Liquid yields of 60–70% (by weight) of dry coal have been reported. The product is difficult to refine because of the significant aromatic components and nitrogen. ICL process begins with creating a synthetic gas (syngas) consisting primarily of CO and H2. The reaction occurred in an oxygen-depleted environment with high temperatures (800–1800 °C) and high pressure (10–100 bar). The syngas is subsequently regenerated via the water/gas shift reaction, which involves the combination of H2O and CO to produce CO2 and H2. Sulfur is extracted, and CO2 can be separated and stored by purified syngas. The syngas is a feedstock, which produces several potential advantages; operational flexibility, potential liquid fuels, power polygeneration, cleanliness of products (no sulfur and aromatic materials), and subsequent storage of CO2 [54]. The catalytic process in liquid fuels and chemical intermediates of biomassderived feedstock is difficult and costly. Conversion processes are necessary, including a restricted number of reactions, separation, and purification steps. The combination of catalytic processes can lead to novel ones developed and the overall economy, which helps and improves to convert biomass [55]. Molecular, functional coupling can develop new catalytic materials to replace homogeneous catalysts. Active location coupling in the same reactor can help to minimize operating costs by mixing sequence processes in a single reactor [56]. Exploitation and use of high-quality liquid fuels will aid in the rapid development of related sectors, provide national energy security, alleviate the energy crisis, and improve the social and environmental settings for long-term development [57]. Some 8% of the total oil products are hydrocarbons. Significant emissions of CO2 and environmental consequences can lead to significant jet fuel usage. In this context, the interest is increasingly paid to sustainable biomass jet fuel [58]. Carbohydrates (e.g., xylose and glucose) convert lignocellulosic biomass into an acid or enzymatic hydrolyze, which is then turned into liquid fuels like biocarbon and jet fuel in an aqueous phase of catalytic processing. The alkane products are hydrophobic since the reaction occurs in an aqueous phase and may be automatically separated from the aqueous phase. In terms of energy saving, this brings considerable advantages [59]. If biogas is used as the primary fuel, there is no need for a gasification phase. Rather, through the steam reform process, gas has been turned into syngas, and syngas forms the basis for future synthetic fuels production. To make diesel and gasoline, two procedures are used: the first one is the Fischer–Tropsch synthesis (FT), which generates both primary diesel and gasoline, and the second is incorporating methanol,

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which produces gasoline as the main product fuel [60]. Chemical processes in the FT process convert carbon monoxide and hydrogen into liquid hydrocarbons. At 150–300 °C (302–572 °F) and pressures ranging from one to many tens of atmospheres, these reactions occur in the presence of metal catalysts [61]. Carbon monoxide and hydrogen, the feedstocks for FT, are created by gasification from coal, natural gas, or biomass [62]. These gases are subsequently converted into synthetic lubricants and synthetic fuels using the FT process. As a source of low-sulfur diesel fuel and to address the supply or cost of oil-derived hydrocarbons, the FT process has gained infrequent interest. In FT synthesis, catalysts play a decisive role. By using a heterogeneous catalytic process, FT synthesis transforms syngas into several hydrocarbons [63]. The FT process consists of four steps including dissociation of CO and H2, formation of surface CHx (x = 0–3) species, coupling of CHx species for the C−C bond formation, and dehydrogenation or hydrogenation of CnHm intermediates to produce olefins or paraffin. Methane is produced as a byproduct of the hydrogenation of CHx. Intermediate CnHm is hydrogenated after being dehydrogenated from an alkane or alkene Long-chain n-alkanes are the predominant outcome of this process due to the plentiful availability of H2, and the carbon distribution of the product follows the Anderson– Schulz–Flory (ASF) distributions law. According to the ASF distribution guidelines, the highest product selection is constrained to C2– C4 58%, C5–C11 48%, C8–C16 41%, and C10–C20 40%. Many researchers are keen to develop a catalyst that can overcome the ASF products’ selectivity limitations. Catalysts made of Co, Fe, and Ru dominated the conventional FT reaction. Fe-based calculators are FT catalysts that have been around for a while. It is high in response, has a low price, and has limited methane selectivity, while secondary hydrogenation is not straightforward [63].

9.4 Natural materials-based catalysis system for biofuel production Biodiesel is a liquid fuel generated from modified vegetable oil that is becoming increasingly popular [64]. There are a variety of methods for producing vegetable oil, including combining the oil with conventional diesel, micro-emulsion, and thermal breakdown (pyrolysis). Transesterification is becoming increasingly common among these methods [65]. According to the fuel qualities of vegetable oils mentioned in Table 9.2, the kinematics viscosity of vegetable oils ranges between 30 and 40 mm2/s at 38 °C [41]. The high viscosity of these oils is owing to their massive molecular mass, which is approximately 20 times more than that of diesel fuel. Vegetable oils have a very high flashpoint (over 200 °C). In comparison to diesel fuels (45 MJ/kg), the volumetric heating values are in the range of 39–40 MJ/kg. Vegetable oils’ heating properties are reduced by roughly 10% due to the presence of chemically bonded oxygen. The cetane numbers are in the 32–40 range.

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One of the most promising and risk-free solutions to the environmental problem is to replace conventional diesel with biodiesel made from edible and non-edible plant oils or animal fats. Vegetable oil (triglycerides) reacts with primary alcohol in the presence of a catalyst to make biodiesel (fatty acid alkyl esters) in transesterification, and glycerol is produced as a byproduct during this procedure [66]. Transesterification includes reversible sequential stages, the first stage, triglycerides are converted into diglycerides, and diglycerides are converted into monoglycerides and glycerol. Each of these molecules produces one methyl ester. The reaction is predominantly supported by a catalytic external system [67]. Chemical and biological catalysts are being used, and each has its own set of benefits and drawbacks [68]. Recently, nanocatalysts with high efficiency have been explored. In biological catalysts, nanoparticles are used as solid carriers for lipase immobilization. Lipase immobilized on magnetic nanoparticles has been shown is a flexible biocatalyst in the generation of biodiesel [68]. The plant cell wall is a natural nanoscale network structure consisting of polysaccharides such as cellulose, hemicellulose, pectin, and lignin. The polysaccharides of plant cell walls have been recognized as an extraordinarily source of fermentable sugars that might be used for manufacturing bioethanol and other renewable liquid transport fuels [69]. Lignin has the same magnitude synthesis and is an abundant highenergy macromolecule as a huge polymer of phenylpropanoid residues. One significant role of these cell wall components in plants, nonetheless, is to provide severe tensile and compressive stresses, which permit plants to withstand gravity forces and a wide range of other mechanical forces [70]. The major constituents of food crop residues, specialist biofuel crops, and other plant residues used as biomass sources for biofuel production are cellulose and lignin. Through changes to lignocelluloses, biomass pretreatments, improved enzymes, and other fermenting microorganisms, it has made significant progress in overcoming the resistance of lignocellulosic feedstock to the biofuels industry [70]. Plant biomass may be produced in great amounts, at a cheap cost, and in a variety of environments. Multiple estimates have been made of the global annual output of the primary components of various biomass sources; plants’ ability to capture and turn solar energy into chemical energy aided this production [71]. A hundred billion tonnes of terrestrial biomass and 50 billion tonnes of aquatic biomass per annum have been computed [69]. Two percent is used in biofuel production and is not used in photosynthesis in the case of carbohydrates split into plant biomass [72]. Cellulose is usually included in a matrix of lignin, and the two wall macromolecules provide significant tensile and compressive resistance to the plant structure. The duration of the tree decomposing on the forest floor to be fully decayed is ready to see this resistance to deterioration and is called ‘recalcitrance’ in the biofuel sector, but the advantages of using recalcitrance tactics are huge [73].

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The data showed that lignocellulosic ethanol had a breakeven cost of 0.60 $/L at the cost of feedstock 0.20 $/L, 0.09 $/L, and 0.29 $/L non-enzyme conversion costs [74]. Those biomasses must be produced in an abundance, inexpensive manner and require little treatment to reduce investment costs at all production stages to be competitive in lignocellulosic biomass ethanol production. The presence of lignin prevents enzymes from accessing cellulose, reducing hydrolysis rate and efficiency, and making cellulose highly resistant to enzyme breakdown [75]. Cellulose, an energy dense non-food substance, was chosen for bioethanol production; however, it cannot be turned into bioethanol without first being hydrolyzed into a single component, glucose. The abundance of cellulose offsets the compromise between the input and energy costs of degrading it into ethanol. The most abundant terrestrial natural biopolymer is cellulose, which is made up of β-1,4-linked glucosyl residues [76]. Actual estimates reveal that the breakdown into the form which is fermentable in bioethanol of lignocellulosic biomass, is double the cost of maize starch depolymerization, for ethanol production correspondingly $0.39 and $0.21 [77]. The higher price for the transformation of lignocellulose biomass into monosaccharides is because of the costs of feedstock availability and biomass processing, which are between $30–140/MT per average [69]. But most of the expenses for conversion of lignocellulose are because of expensive processing techniques that need biomass degradation in monosaccharides [78]. For example, with a cellulase dose of 15 filter paper units, the predicted commercial cost for FPU/g cellulose is expected to be around 30 g of enzyme loading per liter of Ethanol produced [79]. However, the costs of saccharification and fermentation of corn Stover appear to be very low in techno-economic modelling, with substantially higher real costs of ethanol of $0.18–0.39/L. As a result, the cost of cell wall degrading enzymes must be below $2/kg protein to achieve economically efficient enzyme hydrolysis in large-scale productions [80]. For successive hydrolyses, recycling enzymes can be one way of reducing the costs of the enzyme. One study showed, for example, that five pretreated batches of maize fiber were hydrolyzed successfully using reclaimed enzyme preparations [81]. While enzyme recycling is advantageous, biological or technological progress ideally reduces or eliminates the necessity for the use of exogenous enzymes. Consolidated bioprocessing is another emerging topic of study that has the potential to reduce biomass processing costs (CBP) [82]. The manufacture of lignocellulose-based bioethanol has a widespread belief that the method is marginal in terms of mass energy balance. The estimates of prospective ethanol yields are mostly based on bench work data (gram scale), which was then extrapolated for large-scale (tone scale) production, assuming linear scalability. For validating these assumptions, more information is required because of the relatively high amount of oxygen in the molecule about its carbon content. A multifaceted approach to the conversion of hemicellulose biofuels is needed to become a commercial reality. Many advances have been made in process engineering used both biochemical and thermochemical approaches to transform biomass into biofuel [69].

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Some studied biological techniques by changing the composition of the cellular membrane or the polysaccharide structure of a specified feedstock to lower costs of enzyme dosage. For instance, 141 and 172% greater glucose and xyloses yields were produced in transgenic maize tissue (TMT) expressing cell wall deteriorating enzymes compared to the control plants after enzymatic hydrolysis. The endoglucanase and xylanase in TMT resulted in an equal % increase in ethanol yields to a reduction in exogenous loads as 50% [83]. In some crop species, progress has also been made in lowering biomass lignin and non-cellulosic polysaccharide content to facilitate cellulose availability for fermentation, which has boosted saccharification effectiveness [69]. Promising findings have been reported in the engineering of low line switchgrass; decreasing the lignin content of this material is stable in the field and has no negative impact on disease susceptibility [84]. The use of a non-GM strategy for the improvement of recalcitrance has come from the employment of a non-GM technique for the finding of poplar lines with relatively low lignin content. During anaerobic fermentation, other components of the cell wall may block the conversion process. Endolytic enzyme cleavage sites, for example, can prevent acetate replacements from being used on pectic polysaccharides, noncellulosic polysaccharides, and lignin [85]. Furthermore, significant amounts of undissociated acetic acid can be harmful to bacteria and inhibit cell growth rates. Furfural (C4H3O-CHO) at a concentration of 4 g/L decreased S. cerevisiae growth and alcohol production by 80 and 97%, respectively. High cell concentrations in the culture media can assist reduce fermentation time while also increasing cell resistance to [86]. However, the substrate is xylose, the inhibition is significantly lower (1.5 g/L), which limits cell growth by 15%, hence reducing ethanol yields by 50% [87]. If thermochemical techniques are used over typical anaerobic fermentation for the manufacture of biofuels based on hydrocarbons, the complexity of the polymers is less important. Despite the current recession in international crude oil prices, the continued volatility and political manipulation of these markets for fossil fuels, and the rapid rise of electrical technologies in automobiles, trucks, and home heating, the global introduction of renewable liquids remains one of our top priorities for the Earth’s future. Finally, one of the most important objectives in the conversion of plant cell wall wastes to sustainable liquid transport biofuels is the rapid development of more generic conversion methods that can handle a wide range of feedstocks without requiring costly or time-consuming modifications [88].

9.5 The importance of heterogeneous catalytic activity towards aqueous ethanol in biofuel production Biodiesel is a potential alternative energy source that can be made in a variety of ways from renewable and low-grade sources. One process that can occur in the presence of

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an appropriate catalyst is alcoholysis or transesterification [19]. The catalyst could be uniform or homogeneous. Biodiesel generation via homogeneous and heterogeneous catalysis has received a lot of attention, and new heterogeneous catalysts are constantly being developed. Homogeneous catalysts may often convert single-origin biodiesel with low free fatty acid (FFA) and water content. Heterogeneous catalysts outperform homogeneous catalysts in terms of activity, selectivity range, FFA, and water adaptability. These qualities are determined by the number and strength of active acid or basic sites. By modifying heterogeneous catalysts like zirconia and zeolite-based catalysts, they can act as both basic and acidic catalysts [89]. Heterogeneous catalysts made from waste and biocatalysts are critical for achieving a sustainable biodiesel production alternative to typical homogeneous catalysts. Nanocatalysts have recently attracted attention due to their excellent catalytic efficiency under benign operating conditions [51]. The desire for environmentally benign technology stimulates research towards renewable, biodegradable, nontoxic, and carbon-neutral energy sources [90]. Fossil fuels have always been a vital component of meeting global energy demand. The diesel engine was invented in 1892 by Rudolf Diesel, is used as the Powertrain for heavy-duty and commercial vehicles, and this position is continuously expanding. Diesel fuel is the most efficient internal combustion engine in the economy [91] because it emits the least amount of carbon dioxide (CO2). Diesel engines surpass all other power generators in terms of performance, torque, and overall drivability, but they emit more pollutants [92]. Biodiesel is a sustainable fuel that can be used to replace fossil fuels while reducing diesel emissions [93]. Diesel is generated from crude petroleum oil, which is a mixture of pure hydrocarbon molecules (no oxygen atoms), ranging from 8 to 21 carbon atoms. Biodiesel is composed of long-chain hydrocarbons containing an ester functional group (–COOR) [94]. TAGs, also known as triglycerides, are mono-alkyl esters of long-chain fatty acids generated from a variety of feedstocks, including plant oils, animal fats, and other lipids. Biodiesel is made by the transesterification or alcoholysis process, which is aided by acids, bases, enzymes, and other types and forms of catalysts. Catalysts, like reactants, can be in a homogeneous or heterogeneous phase. During alcoholysis, the homogeneous catalyst remains in the same phase (usually liquid) as the reactants [50]. A heterogeneous catalyst is one in which the catalyst is in a different phase than the reactants (usually nonliquid) [19]. Separating the product from the reactant mixture is also difficult because the catalyst is relatively miscible in biodiesel and miscible in glycerol [95]. Heterogeneous catalysts have a lot of active acid or basic sites; hence they have a lot of activity, selectivity, and water adaptability. There have previously of several reviews on catalysts, notably heterogeneous catalysts [96, 97]. However, research efforts using bioethanol in the production of biodiesel are currently insufficient since bioethanol has some technological and economic restrictions. The

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quantity of water in crude bioethanol generated by fermentation can be as high as 8%, which is a serious concern when using bioethanol for biodiesel generation. The presence of water has been cited in most literature as a significant component that has a detrimental impact on the biodiesel synthesis process. The base catalyst would saponify the fatty acid, lowering its catalytic activity for creating biodiesel, because water triggers a further breakdown of triglycerides into fatty acids. To compensate for the detrimental effects of water on biodiesel synthesis, crude bioethanol is frequently filtered and dried before use in manufacturing, resulting in a high cost [98]. Because fractional distillation produces a minimum-boiling azeotrope at 78.2 °C, a second dehydration process is required to remove the leftover water, resulting in ethanol (>99%) at a higher cost. Dehydration of bioethanol is a costly and energy-intensive process that requires 9.21–18.84 MJ/kg to produce anhydrous ethanol. Furthermore, because more alcohol is needed for the reversible transesterification phase, any leftover bioethanol is usually recycled for industrial use. Because of continuous ethanol consumption in reaction cycles, the water content in bioethanol would rise, causing energy-intensive post-purification operations such as distillation to remove the moistures before returning to the reactor for the later sequence of reactions. A catalyst that is compatible with the water in ethanol is required to lower bioethanol purification costs and, as a result, FAEE production expenses. Microwave-assisted hydrothermal synthesis of a variety of transition metal glycerolates in powder form was accomplished in a study. Water in crude bioethanol is widely recognized as a stumbling block to biodiesel manufacturing. Because water molecules absorb on the catalyst surface, one of the fundamental causes of heterogeneous catalyst inhibition is the interaction between the catalytic surface and water molecules. As a result, reactants could not reach the catalyst, slowing down the reaction. In addition, surface boundary water may trigger triglyceride hydrolysis into fatty acids that limit biodiesel generation. As a result, bioethanol dehydration and purification, a time-consuming and complex process with a high production cost, is a procedure for using biodiesel [99]. For biodiesel synthesis, bioethanol is preferable to fossil-derived methanol since the raw materials can be renewable [100]. As heterogeneous biodiesel catalysts, several metal glycerolates were studied, with Manganese glycerolate (MnGly) appearing as the most promising catalyst for aqueous ethanol and crude Jatropha oil. MnGly has an excellent water tolerance, allowing it to withstand the presence of 80 wt% water in ethanol for above 90% conversion over a lengthy reaction period. When 95-wt% aqueous ethanol was used under ideal reaction conditions and an overall converting of 99.7% was accomplished in 6 h [101]. Commercially accessible crude bioethanol containing only 14.1% ethanol and 10% glucose was also tested and shown to convert over 90% for 24 hours [102]. As a result, difficult and energy-intensive bioethanol purification phases for biodiesel applications would most likely be simplified, resulting in a more sustainable process.

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9.6 The future of energy and the environment with the use of aqueous heterogeneous catalysis Biomass is an opportunistic renewable resource that may be turned, in the short term, into liquid transport fuels including agricultural residues, forest resources, energy crops, garbage, or algae [103]. Algae are a promising alternative source to the conventional feedstocks for third-generation biofuel production. Microalgae continue to gain attention among renewable biomass resources for advanced biofuels because of their potential for fast growth, high oil yield, the use of non-arable soil for algal cultivation, growth in various water sources, and the benefits of large-scale CO2 [104]. Figure 9.2 depicts a process for producing biodiesel from microalgae. Waste materials have recently been used as catalysts in chemical reactions. In the development of a long-term biodiesel process, low-cost solid-waste sources have shown promise. The most common mineral wastes used in concrete and mortar are quartz, calcite, sodium/calcium aluminosilicates, albite, and portlandite [105]. Because of its mineral matrix, cement has an alkaline pH. Calcium carbonate is abundant in eggshells, which can be transformed to CaO by calcination at 900 °C. In the transesterification process, it showed high catalytic activity and yielded up to 93.5% biodiesel [106]. Plantain peels, wood, coconut shells, palm trunks, and sugarcane bagasse are just a few examples of organic waste-based solid catalysts that have been successfully developed and used. Potassium and sodium oxides have been transformed into equivalent oxides in banana shells [107].

Figure 9.2: Production of conventional biodiesel from microalgae. Modified from ref. [25].

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By drying the peel for 48 h at 80 °C and then calcining it for 4 h at 700 °C, a banana peel catalyst was developed [108]. It was employed in the transesterification of neem oil in two steps. Tucum palm peels, which contain a lot of K, P, Ca, and Mg ions and are calcined at 800 °C, worked well as catalytic materials [108]. The waste shells of Cyrtopleuracostata (angel wing clam) provided 84.11% biodiesel under optimal reaction conditions and could be reused three times with >65% biodiesel production. Calcined animal bone was used as a catalyst in a single-step process to make biodiesel from jatropha oil, yielding 96.1% at 70 °C. Cao supported by waste fly ash converted palm oil to 94.5% biodiesel under optimal reaction conditions [109]. Cinder was used to help CaO/KF create a solid base catalyst for soybean oil transesterification. Cinder is a solid-waste product of the coal-burning industry. Because of the high acid sites and large surface area, a catalyst made from rice husks produced a significant amount of biodiesel (>90%). The coffee residue was used to construct a caprylic acid esterification catalyst based on sulfonated carbon that converted 71.5% in 4 h. As heterogeneous catalysts, birchbark ash and fly ash from a biomass-based power plant were calcined at 800 °C [110]. When utilized as a solid acid catalyst, sulfonated coconut shells generated 88.03%. Biodiesel has been produced using oil palm trunks and sugarcane bagasse– derived heterogeneous acid catalysts, with yields of 88.8 and 96%, respectively [111]. Future energy supply will rely on hydrogen as a sustainable energy source. Hydrogen can be produced using fossil fuels, water electrolysis, or biomass splitting. However, they are inextricably linked to the clean generation of fossil fuel hydrogen (e.g., natural gas, coal propane, methane, gasoline, light diesel), dry bio-biomass, and liquid-based biomass (e.g., methanol and biodiesel), as well as water [112]. Only if carbon dioxide is secreted safely and affordably will such a hydrogen generation route succeed. The development of nanomaterials such as catalysts for a water gas change reaction and inorganic membranes for hydrogen/CO2 separation is the key to the costeffective conversion of coal into hydrogen and carbon capture. Hydrogen will be the primary combustion in the future and transformed into power in fuel cells.

9.7 Conclusions Heterogeneous catalysts have a long history of enabling selective energy-efficient conversions, and they are used in “90%” of chemical processes and 20% of all industrial products. To boost catalytic activity and selectivity, we need more efficient catalytic techniques. Designing catalytic materials with the desired structures and active site dispersion can improve both qualities. Nanocatalysts serve as a bridge between homogeneous and heterogeneous catalysts, allowing for the production of solid acid or solid base catalysts. Conventional filtering and centrifuging because of small particles are not enough to recover the components following synthesis. A magnetic field may most likely be used to recover magnetic nanoparticle-supported catalysts. Increased utilization of waste and low-

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grade oil sources causes rapid deactivation instream, posing a problem for heterogeneous catalysts. Chemists with expertise in catalysis, chemical engineers, and molecular simulation experts must investigate to benefit from breakthrough reactor designs and design catalysts and reactors together to optimize and boost future biofuel supply and demand processes. For biofuel to be a prominent participant in the renewable energy industry, technical breakthroughs are necessary for materials and reactor engineering.

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Rabindranath Singha, Puja Basak and Pranab Ghosh*

10 Catalytic applications of graphene oxide towards the synthesis of bioactive scaffolds through the formation of carbon– carbon and carbon–heteroatom bonds Abstract: During the past several decades, metal-based catalysis is one of the major and direct approaches for the synthesis of organic molecules. Nowadays, materials containing predominantly carbon element which are termed as carbocatalysts, become the most promising area of research to replace transition metal catalysts. In this context of carbocatalysis, the use of graphene oxide (GO) and GO-based materials are under spotlight due to their sustainability, environmental benignity and large scale-availability. The presence of oxygen containing functional groups in GO makes it benign oxidant and slightly acidic catalyst. This chapter provides a broad discussion on graphene oxide (GO) as well as its preparation, properties and vast area of application. The catalytic activity of GO has been explored in different organic transformations and it has been recognized as an oxidation catalyst for various organic reactions. Keywords: carbon-carbon bond; carbocatalyst; carbon-heteroatom bond; graphene; graphene oxide.

10.1 Introduction Nowadays, development of greener and sustainable synthetic methods attracted huge attention for industrial fine manufacturing and commodity chemicals. The four parameters namely catalytic activity, catalytic selectivity, step-selectivity and atomeconomy by which the ideality of the organic reaction is characterized towards the sustainable and economic development of large scale synthesis. By these four parameters, the development of highly selective and catalytically active system has found profound role as its provides an alternative pathway by reducing the activation energy of an organic reaction [1]. The term catalysis was proposed by Jöns Jakob Berzelius in 1800s [2], where the majority of reactions have been taken place based on metal

*Corresponding author: Pranab Ghosh, Department of Chemistry, University of North Bengal, Dist-Darjeeling, West Bengal, India, E-mail: [email protected] Rabindranath Singha and Puja Basak, Department of Chemistry, University of North Bengal, Dist-Darjeeling, West Bengal, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: R. Singha, P. Basak and P. Ghosh “Catalytic applications of graphene oxide towards the synthesis of bioactive scaffolds through the formation of carbon–carbon and carbon–heteroatom bonds” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0096 | https://doi.org/10.1515/9783110759549-010

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catalysts. Recently, transition occurring in catalytic chemistry and as a consequence organocatalysts such as N-heterocyclic carbenes and proline have been developed. These organocatalytic systems have often attracted attention of organic chemists towards the synthesis of biologically active molecules through an environmental friendly facile reaction course [3]. Whenever carbon compounds were used as catalyst then it is termed as carbocatalysts. Carbocatalyst is the heterogeneous version of organocatalyst. Because of their high abundance and environmentally friendliness, the carbocatalysts are most attractive towards the organic synthesis. Initially, carbocatalysts are applied for the oxidation and esterification reactions [4, 5]. However many carbocatalyst are widely used for the contraction of carbon–carbon and carbon–hetero bonds, which are the basic reaction in the synthesis of heterocyclic compounds used in medicinal, pharmaceutical [6], agrochemicals purpose [7] and also in case of fine chemicals and many others [8, 9]. In the early 20th century, organometallic chemistry was the most popular topic and became an efficient and simple invention in synthetic organic chemistry [8]. Transition metal (TM) based catalysis is the content of discussion recently, either in the form of free ions, cluster, coordination complexes or nanoparticles [10–15]. However, the TM catalysed reaction suffers several limitations such as TM catalysts are normally costly, toxic and sometimes it is very tough to take out TM catalyst from the product which is problematic in the field of electronic devices and pharmaceuticals [16–18]. TM catalysts are very sensitive towards moisture as well as oxygen and hence most of TM requires some special conditions. Sometimes addition of co-catalysts/ additives is required in order to initiate the reaction and increase the product selectivity [19–25]. Therefore, alternative pathway is required to eliminate the demerits of TM catalyzed reaction for the construction of carbon–carbon (C–C) and C–hetero bond. Among the metal-free green catalysts organocatalysts and carbocatalysts are more convenient, simple and less toxic than inorganic catalysts. Carbocatalyst are catalyst where carbon materials are used as catalyst for organic reactions. In 1925, Rideal, used charcoal as a carbocatalyst for the oxidation of oxalic acid [26]. In the absence of carbon materials, no conversion of the desired product was observed [27]. The reaction started with the aerobic oxidation of germinal diols bound to the surface of oxalic acid. Successively, in presence of ambient amount of oxygen, peroxide intermediate is formed and resulted in the final product carbon dioxide and water (Figure 10.1) [28].

Figure 10.1: Aerobic oxidation of oxalic acid by charcoal.

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In 1980s, L. E. Cadus and co-worker carried out oxidative dehydrogenation (ODH) of ethylbenzene to styrene by using carbon as catalyst [29]. Ritter, carried out the oxidative cleavage of 4- chlorophenol by using graphite as catalyst which was yielded CO2, H2O and HCl [30]. Though many of the scientists used this carbocatalyst at the time when it did not attract much attention because of its slower catalytic activity than the metal-based catalysts. To check the efficiency of carbocatalyst in organic reaction, in 2010, Bielawski and his co-workers reported graphene oxide (GO) as an efficient carbocatalyst. Various benzylic hydrocarbons undergo aerobic oxidation in presence of GO catalyst [30]. After this year, graphene-based materials have been successively used as carbocatalyst in wide range of organic transformation reactions such as oxidation reaction [31–33], reduction reaction [34–36] and many other reactions [37–39]. Graphene, an important single layer, carbon allotrope which contains generally twodimensional honeycomb carbon network [40, 41]. Nowadays, the most important graphene derivative, GO has drawn much consideration of researchers for organic synthesis. GO is a two dimensional nanomaterial, consisting of several oxygen containing functional groups such epoxide, carbonyl, alcohol and carboxylic acid groups. In the year of 1855, graphite oxide which is a bulk form of graphene oxide, was synthesized by Brodie. He used graphite powder as the starting material and applied strong oxidizing agents such as KMnO4, NaNO3, KClO3 and H2SO4 [41]. As because of the hydrophobic nature and higher interlayer distance, GO can rapidly be exfoliated through ultrasonication in water and other organic solvents. GO with its single and multi-layer sheets disperse well in protic solvents [42]. GO has acidic property and its acidic property can be determined by several methods [43, 44]. Due to the presence of oxygen functionalities on the edges and basal plane of GO, it shows moderate acidity (Figure 10.2). Dimied et al. suggested structure formula of graphene oxide which clearly explained the acidic properties in aqueous medium [45]. In the mid-19th century, Hummers method was extensively used for the GO synthesis. Klinowski and his co-workers demonstrated the structure of GO which explained different chemical connectivity, although its exact structure is unpredictable. GO is formed with C containing honeycomb like graphite planes and -OH and -COOH groups are present at the edges of the layers as shown in Figure 10.2. The nature of these

Figure 10.2: Structure of graphene oxide (GO).

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carbocatalyst nanomaterials is like heterogeneous catalyst and it acts like homogeneous catalyst on the basis of catalytic activity and catalytic selectivity [46]. Nowadays, GO is an attractive research area because of the large surface area, high thermal stability, high catalytic activity and easy to recovery from the reaction [47–51]. The carbocatalyst (GO) has been used in various type of multicomponent reactions (MCRs), such as Diels-Alder reaction, Fridel-craft alkylation, condensation, selective hydrogen transfer, hydration, oxidation, reduction and many other reactions [30, 52–68]. This heterogeneous carbocatalyst GO has been utilized to synthesize biologically important heterocyclic moieties which has wide range of application in pharmaceutical and medicinal chemistry.

Scope of this review In this chapter we have mainly emphasized on C−C bond and C-hetero bond forming reactions (up to 2021) catalyzed by graphene-based materials as carbocatalyst. The purpose of this chapter is to reveal the recent improvement and probabilities of graphene oxide as an effective catalyst to enhance the productivity and sustainability of organic reactions [69].

10.2 Chemical method for the preparation of graphene oxide (GO) In 1859, Brodie reported GO for the first time. A mixture of potassium chlorate (KClO3) and fuming nitric acid was added to the graphite slurry to prepare GO in this method [70]. But the abovementioned process involved time consuming multiple steps and also evolved hazardous gases. However, Brodie’s method was modified by Staudenmeir in 1898. He prepared GO with higher level of oxidation in a single step by using concentrated H2SO4 to graphite powder along with KClO3 and fuming HNO3 [71]. In 1958, Hummers reported a method for the preparation of GO. In this method oxidation of carried out the by the use of NaNO3, conc. H2SO4 and KMnO4. This method have been widely used for the preparation of GO. However, this method evolved some toxic gases NO2/N2O4 during synthesis of GO and dissolves Na+ and NO3− ions in waste water after the reaction. This problem was solved by Tour and his co-workers, they increased the amount of KMnO4 followed by the introduction of H2SO4/H3PO4 (9:1 vol ratio) for prolonged time instead the use of NaNO3. Different chemical methods have been shown in (Figure 10.3) for the synthesis of GO. This method is also known to synthesize heavily oxidized GO and well known as modified Hummers method.

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Figure 10.3: Different chemical oxidation process for graphene oxide (GO) synthesis.

10.3 Structural analysis of GO Over the past years, there was considerable debate to determine the exact chemical structure of GO and even today no structural model fully anticipate the precise chemical structure of GO. There were several reason behind this such as complexity of material varied form sample to sample due to the amorphous nature, nonstoichiometric atomic composition (berthollide character), deficiency of exact characterization techniques of such materials. Despite of these obstacles, in order to understand the structure of GO, the earlier structural models of GO contains lattice structure with discrete repeated units [72, 73]. The electron microscopic structure of graphene oxide which has been prepared by Hummers method showed a hexagonal symmetry with unmodified graphene-sheet. It clearly shows that GO is indistinguishable from graphene and having in plane C-C spacing 0.1421 ± 0.0007 nm. It was obvious from the diffraction pattern that the basal carbon-lattice exhibits a hexagonal symmetry on the length scale of coherence of electron-beam (few nm). Atomic resolution HR-TEM shows C-lattice with crystalline order greater than 10 nm on the scale of length and SEAD pattern depicts the long-range orientation of the entire GO-sheet [74]. The Powder XRD spectra of GO displays a single peak at 2Ɵ = 12.7° with the d spacing 6.90 Ǻ [75].

10.4 Graphene oxide (GO) as an effective metal-free catalyst in organic transformation 10.4.1 Graphene-based catalyst towards the formation of C–C and C–heteroatom bond In recent years, green chemistry has been emerging as a new tool in acid–base catalysis to synthesize target molecules in organic synthesis [76]. Chemists use homogeneous

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catalysts for various organic transformations for the production of fine chemicals and others [77, 78]. But the difficulty during the use of highly efficient traditional homogeneous catalysts is to recycle after the reaction. On the other hand, the easy separation procedure of solid catalysts, make them superior than the homogeneous catalyst [79]. There were several solid acid catalysts which have been developed as mesoporous materials [80, 81], silica-alumina [82] and zeolites [83]. Carbon materials bearing metal-organic frame works [14, 84, 85] and acid moieties [86, 87] have also been developed. There are also several base catalysts such as alkaline Earth oxides, alkali metals on supports, zeolites, modified zeolites, KNH2 on alumina, KF on alumina, oxynitrides and hydrotalcite [88–90]. The common problem during the reaction and separation is chemical absorption (chemisorption) of H2O molecules on the catalyst active surface which further hampers the lifetime of catalyst. To erase these drawbacks, solid acid catalysts with high performing water resistance capacity are in demand [91]. Due to the hydrophobicity, high stability and tunability, graphene-based nanomaterials are supposed to resolve the problem during synthesis. 10.4.1.1 Freidel-Crafts-type reaction Transition metal (TM) catalyzed alkylation of arenes is most common reaction for the synthesis of wide variety of pharmaceutical ingredients and fine chemicals. Nowadays, graphene-based materials were also utilized Friedel-Crafts alkylation of arenes with alcohols and styrene [92]. In 2011, Kumar and Rao reported GO catalyzed reaction of indoles (1) with α, β-unsaturated ketones/nitrostyrene (2) through Friedel-Crafts-type addition reaction (Figure 10.4). A wide range of indole (3) derivatives have been synthesized with the help of GO catalyst. The heterogeneous graphene oxide recycled up to 5th run without losing the catalytic activity [93].

Figure 10.4: GO catalyzed Friedel-Crafts addition reaction.

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Dutta utilized furan derivative (5, 6, 7, 8, 9) derived from biomass for C−C bond forming reaction in presence of high oxygen content GO as a catalyst (Figure 10.5) [94]. The highly oxidized GO showed higher catalytic activity compared to zeolites which are used conventionally in reaction. The catalytic activity of GO decreases significantly after successive fourth run. Wang et al. developed an efficient, environment friendly and cost efficient graphene oxide -catalyzed Friedel-Crafts alkylation type reaction for the synthesis of bis(indolyl)methanes (12) from Benzaldehyde (10) with indoles (11). Water was used as reaction medium. This protocol gives the expected products in good to excellent yields and it has a wide range of substrate scope (Figure 10.6) [95]. In 2014, Guerra reported metal-free GO catalyzed high efficient regio- and enantioselective ring opening reactions of aromatic epoxides (13) with indoles (11) under the solvent-free condition (Figure 10.7) [96]. The product was found with complete inversion of stereochemistry which indicates the occurrence of SN2-type reaction by the GO catalyst. This type of reaction was generally reported by TM catalyst such as nanocrystalline Fe3O4, or CuFe2O4 [97] TiO2 [98].

Figure 10.5: GO catalysed C-C bond formation reaction under neat condition.

Figure 10.6: GO catalyzed reaction for the synthesis of bis(indolyl)methanes.

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Figure 10.7: GO catalyzed ring opening reaction.

Recently, Hu and his co-workers demonstrated a GO catalyzed Friedel-Crafts alkylation reaction using unactivated olefins (18) and alcohols (15). (Figure 10.8) [99]. Both the coupling partners were activated on the surface of GO due to aromatic functional groups and successfully transformed the desired product (17, 19). The reaction has wide range scope with tolerance of various substituents and halides. Favarettoand his co-workers demonstrated reaction of thiophenes (20) with allylic alcohols (21) in presence of GO (Figure 10.9) [100]. It was found that GO acting as a Brønsted acid in this reaction. This reaction protocol required low GO loading and mild reaction conditions that enabled to isolate a wide variety of functionalized thienyl and bithienyl compounds with medium to high yields of the desired product.

Figure 10.8: Alkylation of arenes catalyzed by GO.

Figure 10.9: Alkylation of thiophene by GO catalyst.

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10.4.1.2 Aldol-type reaction The aldol reaction is most advantageous method for the formation of carbon–carbon bonds. The resultant chalcone derivatives are widely used as a precursor for flavonoids and isoflavonoids biosynthesis [101]. Bielawski and his co-worker reported the synthesis of chalcones (25) from alkynes (23) or alcohols (24) through one-pot strategy by using GO which acting as a catalyst and with this method a wide variety of substituted chalcones have been synthesized in good to excellent yields (Figure 10.10) [102]. Acocella et al. utilized GO as an effective carbocatalyst for aldol type coupling reaction between 2-(trimethylsilyloxy)furan (26) and aldehyde (27) (Figure 10.11) [103]. However, on application of this catalytic system it has been found that the anti-diastereoisomer (28, 29) was achieved with high diastereoselectivity in comparison to the conventional catalysts. The reaction exerted the best result under solvent free condition. The authors supposed that carboxylic acid (-COOH) and hydroxy (-OH) functional groups present on the surface of GO are involved to show the catalytic activity of GO. The aliphatic aldehyde showed less reactivity under the same condition.

Figure 10.10: GO catalyzed synthesis of chalcones.

Figure 10.11: Mukaiyama aldol type coupling reaction.

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10.4.1.3 Multicomponent reactions The multicomponent reactions (MCR) have a great significance to synthesize polyfunctionalized heterocyclic compounds via eco-benign pathway [104, 105]. Several levels of structural diversity and high bond forming efficiency can be achieved with MCR as it is time and effort savings [106–108]. GO has been widely utilized as an efficient catalyst for the synthesis of biologically active heterocycles using MCRs. Kapoor demonstrated a solvent-free GO-catalyzed reaction for the synthesis of 1-amidoalkyl-2-naphthols (36, 37)and 1,2-dihydro-1-arylnaphth[1,2-e][1,3]oxazin3-ones (35) (Figure 10.12) [109]. There were several advantages on using GO as catalyst such as short reaction time, high yields of the desired product, ease to separate and environmentally benign protocol. In 2013, Shaabani et al. reported a solid acid heterogeneous GO or sulfated graphene catalysts for one-pot three-component condensation reaction of an aldehyde (38) with a 1,3-diketone (39) and 1-naphthol (40) or 2-naphthol for the synthesis of xanthenes (43) and benzoxanthenes (42, 44). A various type of aldehydes and 1,3-diketones have been used in this reaction. (Figure 10.13) [110]. Different types of solvent have been investigated but among the other solvent water solvent gave the best yield of the expected product. The catalyst can easily be recovered after the reaction by simple filtration method. Khalili reported a four-component reaction for the synthesis of 2-amino3-cyanopyridines (49) from an aldehyde (45), ketone (46), malononitrile (48) and ammonium acetate (47) by using GO as a carbocatalyst in water medium (Figure 10.14) [111]. In order to optimize the reaction condition, acetophenone, ammonium acetate,

Figure 10.12: GO catalyzed synthesis of 1-amidoalkyl-2-naphthols and 1-arylnaphth[1,2-e][1,3] oxazin-3-ones.

10.4 Graphene oxide (GO) as an effective metal-free catalyst

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Figure 10.13: Sulfonated GO catalysed one-pot three-component condensation reaction.

Figure 10.14: GO-catalyzed synthesis of 2-amino-3-cyanopyridines.

4-methylbenzaldehyde and malononitrile were taken as model reaction. Different type of aldehydes or the ketone components have been used in this reaction. Aromatic aldehydes having both electron-donating and withdrawing substituent easily gave the corresponding products. Different types of ketones have also been used, such as aromatic ketones with 4-OMe, 4-Cl, 4-Ph substituents, cyclic ketones and aliphatic ketones. The authors supposed that -COOH groups of graphene oxide play key role in this reaction. The catalyst can easily be recovered after reaction and reused up to six times without significant loss of catalytic activity. Karami demonstrated a one-pot and three-component synthesis of pyranocoumarins (53) using 4- hydroxycoumarin (50), aryl glyoxal (51), and malononitrile (52) in presence of GO as highly efficient metal-free catalyst (Figure 10.15) [112]. The catalyst was reused up to forth run. Suresh developed a simple nitrogen-doped GO (NGO) catalyzed tandem reaction for the synthesis of pyranopyrazoles (58) from various types of aldehydes (55) and ethyl acetoacetate (54) by simple grinding under the neat condition. No chromatographic

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Figure 10.15: GO catalyzed multicomponent condensation reaction for the synthesis of pyranocoumarins.

purifications have been required for this one-pot reaction protocol (Figure 10.16) [113]. The presence various nitrogen sites on the basal plane of GO considerably increase catalytic activity of NGO for the reaction. This carbonaceous catalysed reaction covers a wide range of pyranopyrazoles derivatives. After the reaction the catalyst was simply recovered and reused up to eight consecutive runs. The NGO catalyst provides an alternative way for the development of environmentally benign, sustainable nitrogen-based carbocatalyst multicomponent reaction for the synthesis of several bioactive compounds. Singha et al. demonstrated one-pot synthesis of 5-aryl-pyrimido quinoline 2,4-diones (62) from aromatic amines (60), aldehydes (59) and barbituric acid (61) using GO as a solid acid catalyst. They started their investigation with 4-methoxy benzaldehyde, 4-methyl aniline and barbituric acid as model reaction by utilizing GO at 100 oC in water (Figure 10.17) [114]. They also examine the different type of solvents such as DMF, DMSO, toluene, ethanol, although, best result was obtained in presence of water. In absence of catalyst no yield of the product was seen. With increasing temperature the product yield increases gradually, and the best result is obtained at the refluxing condition. However, below at 100 oC the yield product was quite low. Electron donating group containing anilines exerted high yield of the desired product. Contrarily, substituted aromatic aldehydes gave expected product in good yields and with the aliphatic aldehydes the yield of the desired product was very low. The GO could be recycled upto 5th run.

Figure 10.16: Multicomponent reaction for the synthesis of pyranopyrazole with NGO.

10.4 Graphene oxide (GO) as an effective metal-free catalyst

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Figure 10.17: Graphene oxide catalyzed synthesis of pyrimidoquinoline.

Eskandari et al. demonstrated another three-component coupling reaction between 4-hydroxycoumarin (65), barbituric acids (63) with a range of aryl aldehydes (64) for the synthesis of novel benzylbarbiturocoumarins by using GO nanosheets (0.005 g) in H2O/EtOH (1:1)at 80 oC (Figure 10.18) [115]. Starting materials were successfully condensed by graphene oxide nanosheets via three C–C bond formation. This method was metal-free, efficient and environmentally safe. The desired products were obtained with high selectivities. Pranab developed a one-pot heterogeneous sulfonated GO (SGO) catalyzed reaction protocol for the synthesis of pharmaceutically promising substituted isoxazole derivatives (70) form aldehyde (67) in water medium (Figure 10.19) [116]. The reaction protocol was very smooth and yielded product good to excellent. The catalyst was easily recovered from the reaction mixture and can be used up to 5th cycle with the loss of small catalytic activity [116]. Khalili reported the sequential aldol coupling/aza-Michael addition reaction of aromatic amines to chalcones using GO in presence of surfactant tetra n-butyl ammonium bromide (TBAB) (Figure 10.20) [117]. Benzaldehydes (73) and acetophenone (71) were coupled through the subsequent aza-Michael addition to produce their corresponding chalcones under neat reaction condition.

Figure 10.18: Metal-free GO catalyzed the synthesis of novel benzylbarbiturocoumarins.

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Figure 10.19: Functionalized GO-catalyzed one-pot reaction for the synthesis of isoxazoles derivatives.

Figure 10.20: GO-catalyzed reaction of amines for the synthesis of chalcones.

10.4.1.4 Michael addition The generation of new carbon–carbon bonds through the Michael addition is one of the most important transformations in organic chemistry [118, 119]. Acocella et al. carried out GO catalyzed reaction of 2-(trimethylsiloxy)furan (75) with β-nitroalkenes (76) and anti-diastereoisomer (77, 78) was obtained with high diastereoselectivity [120]. They proposed that van der Waals interaction and π-stacking interactions occurs between catalyst hydrophobic portion and the trimethylsilyl group, and π-domain of the catalyst and β-nitrostyrene respectively, due to this high antidiastereoselectivity was achieved (Figure 10.21). Lee and co-worker demonstrated a simple and green method to produce Michael adducts and derivatives using GO as an effective phase transfer catalyst (PTC) in presence of KOH base. GO can be easily recovered after the reaction and also reused in

Figure 10.21: GO-catalyst Mukaiyama–Michael coupling reaction.

10.4 Graphene oxide (GO) as an effective metal-free catalyst

293

multiple cycles without significant loss of catalytic of GO. They assumed that the migration of potassium ion from aqueous phase to organic phase occurs through the oxygen containing functional groups of GO. They also assumed that the catalytic activity of GO is due to the presence of various oxygenated functional groups such as carbonyl, carboxyl, especially epoxy and hydroxyl groups (Figure 10.22) [121]. 10.4.1.5 Miscellaneous reactions Karthik et al. reported a green carbocatalyst GO catalyzed reaction of arylboronic acids (82) for the synthesis of phenols via ipso-Hydroxylation in water medium (Figure 10.23) [122]. Several solvents have been employed in this method but GO showed the best activity in water. This is because water acting as a good dispersion medium of GO. There were several oxidant such as t-butyl hydroperoxide, TEMPO, H2O2 have been used to examine the role of oxidant in the reaction. Among this various oxidant GO showed more amicable with H2O2. When the same reaction carried out with both oxidant-free and catalyst-free condition, the reaction did not occur. In the application of graphite powder as well as activated charcoal the yield of product was not so better. This implies that the oxygen functionalities of GO, especially carboxylic groups in

Figure 10.22: Micheal addition using GO as a phase transfer catalyst.

Figure 10.23: ipso-hydroxylation of boronic acids by graphene oxide catalyst.

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played an important role for acting catalytic activity during the reaction. Boronic acid containing both the electron-donating and withdrawing substituents does not influence the yield of the expected product. In 2016, Gao et al. reported an inexpensive, green graphene oxide catalyzed carbon–carbon bond formation reaction through the activation of C-H bond [123]. The reaction of aryl halides (84) was carried out with graphene oxide catalyst in presence of tert-BuOK at 120 oC. Aryl iodides with electron-donating group are more reactive as compared to aryl iodides. Aryl iodides having substituted at ortho position show lower reactivity because of the streic hindrance. In the case of aryl chlorides and arylbromides show low reactivity and results the low yields of the desired products. Steric hindrance and electronic effect slower the rate of reaction and the yield of the products (Figure 10.24). In 2018, Wu et al. developed a C–C coupling pathway using GO as catalyst for the reaction of xanthenes and thioxanthene (90, 91) with arenes (Figure 10.25) [124]. Initially they started with the coupling reaction between xanthenes and 1,2-dimethoxybenzene under aerobic condition by using graphene oxide as catalyst. When the reaction was carried out under solvent-free condition at 100 oC in air the desired product was yielded in 46% yield and xanthenone (90) was obtained as major by product. In order to

Figure 10.24: GO catalyzed carbon–carbon bond formation reaction.

Figure 10.25: GO catalyzed C–C coupling reaction.

10.4 Graphene oxide (GO) as an effective metal-free catalyst

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suppress the side product formation various co-catalysts like different organic acids were used with GO but with TsOH.H2O, graphene oxide obtained the best result. The reaction protocol exhibits the wide range of functional group tolerance (Figure 10.25). Chaurasia et al. have been reported a GO (carbocatalyst) catalyzed reaction with biguanides and alcohol for the synthesis of 2, 4-diamino-1,3,5-triazines (94) in toluene solvent (Figure 10.26) [125]. They began their examination by taking benzyl alcohol (92), biguanide (93) with base at 130 oC temperature and the corresponding product was obtained up to 60%. However, when the same reaction was carried out by using GO as catalyst, the yield of desired product was increased upto 91%. This indicates that the GO catalyst plays an excellent catalytic role during the reaction. They examined several solvents such as DMSO, DMF, polyethylene glycol, toluene, water in this reaction but the best suited solvent was toluene. When the same reaction was carried out in water medium the reaction did not take place under the same condition. They also examine the effect of temperature on the model reaction and it showed that on increasing the temperature the yield of the desired product increases and obtaining highest yield at 110 oC and on further increase or decrease in temperature the yield of the decreases. The presence of both electron donating as well as electron withdrawing groups with the benzyl alcohol does not influence the reaction. Benzyl alcohol (92) having ortho substituted decrease in the yield of the product. Su et al. developed a cross-dehydrogenative coupling (CDC) reaction of oxindoles (95) with thiophenols and or arenes by using GO as a catalyst for the direct synthesis of 3-sulfenylated oxindoles (97) and 3-aryloxindoles (98) (Figure 10.27) [126]. To simulate the active site of GO they were utilized small molecules like anthraquinone, tetracene, DDQ and 9,10-phenanthrenequinone. The best yield was obtained using DDQ in presence of GO catalyst.

Figure 10.26: GO catalyzed reaction between biguanides and alcohol for the synthesis of 1, 3, 5-triazines.

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Figure 10.27: GO-catalyzed synthesis of 3-sulfenylated oxindoles and 3-aryloxindoles via CDC of oxindoles with arenes or thiophenols.

10.5 Conclusions In this chapter, we have presented an overview of C-C and C-heteroatom bond formation reaction with graphene oxide catalyst. As demonstrated in this chapter, graphene oxide has potential applications in the field of metal-free catalysis. The methodologies reported here offer GO as a benign carbocatalyst, cocatalyst or phase transfer catalyst for organic transformations. Since, C–C and C–hetero bond formation reactions are the fundamental reactions in the organic synthesis such as synthesis of fine chemicals, medicinal compounds, biologically active compounds etc. This book chapter has been expressed the recent progress of GO- catalysed reactions as well as the catalytic activity of this carbocatalyst. The major advantages to use GO as carbocatalyst for C–C and C–heteroatom bond formation depend on good sustainability, reusability, abundance, easy preparation as well as the presence of diverse functional groups in graphene oxide. Acknowledgment: R. S. is highly gratified to UGC, New Delhi, India for providing National fellowship (RGNF).

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Daniela Hartwig*, Liane K. Soares, Luiz H. Dapper, José E. R. Nascimento and Eder João Lenardão*

11 Dicarbonyl compounds in the synthesis of heterocycles under green conditions Abstract: Carbon–carbon and carbon-heteroatom bond forming reactions are strategically employed for the generation of a variety of heterocyclic systems. This class of compounds represents the most general structural unit, present in many natural compounds. They are recognized for their valuable biologically properties and wide range of applications in medicinal, pharmaceutical, and other related fields of chemistry. This is an updated review on the use of dicarbonyl compounds under environmentally friendly conditions to access a series of heterocyclic structures, e.g., quinoxaline, quinazolinones, benzochalcogenazoles, indoles, among others. Synthetic protocols involving copper-catalyzed, multicomponent and cascade reactions, decarboxylative cyclization, recycling of CO2, and electrochemical approaches are presented and discussed. Keywords: alternative energy sources; alternative solvents; catalysis; dicarbonyl compounds; green synthesis; heterocycles.

11.1 Introduction Heterocyclic compounds have had a central role in medicinal chemistry. Many important cyclic systems can be found in nature, like in nucleic acids, vitamins, and antibiotics, for example. Moreover, the modern society is dependent on synthetic heterocycles for use as drugs, pesticides, dyes, and plastics [1,2]. Thus, organic synthesis has established its position as an important tool to access many new classes of therapeutic compounds, like the synthetic routes to Sofosbuvir, Dolutegravir, among others [2,3]. Besides, over the last decades the chemical industry has been subjected to increasing pressure for a change of attitude, in order to minimizing or, preferably, eliminating the waste [4,5]. In this sense, the green chemistry has offered good practice

*Corresponding authors: Daniela Hartwig and Eder João Lenardão, Laboratório de Síntese Orgânica Limpa – LASOL, CCQFA, Universidade Federal de Pelotas - UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil, E-mail: [email protected] (D. Hartwig) and [email protected] (E.J. Lenardão). https://orcid.org/0000-0001-7920-3289, Liane K. Soares, Luiz H. Dapper and José E. R. Nascimento, Laboratório de Síntese Orgânica Limpa – LASOL, CCQFA, Universidade Federal de Pelotas - UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil, E-mail: [email protected] (L.K. Soares), [email protected] (L.H. Dapper), [email protected] (J.E.R. Nascimento) As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: D. Hartwig, L. K. Soares, L. H. Dapper, J. E. R. Nascimento and E. J. Lenardão “Dicarbonyl compounds in the synthesis of heterocycles under green conditions” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-2021-0095 | https://doi.org/ 10.1515/9783110759549-011

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alternatives to overcome these problems by recommending the use of renewable raw materials, avoiding the use of toxic and hazardous reagents and solvents in the manufacture and application of chemicals, by using cleaner catalytic alternatives, and environmentally benign solvents or solvent-free and catalyst-free conditions [6–8]. According to the literature, the synthesis of heterocycles under green conditions has been widely explored over the past few years, and a review on this subject contributes to a significant change in behavior of both industry and academia toward new greener processes. Thereby, this review provides a comprehensive overview of 69 works on the synthesis of heterocyclic systems starting from dicarbonyl compounds, covering from 2016 to 2021. The use of dicarbonyl compounds in the synthesis of O-heterocycles by classical synthetic methodologies, as well the Lewis acid-promoted addition reactions to α,β-unsaturated dicarbonyl compounds were recently revised [9,10]. However, no concerns were given to the discussion of the green aspects of such synthetic protocols. For a better discussion of the collection of the selected procedures, this review was divided according to the green characteristic of the reaction: 1. Green solvents in organic synthesis, 2. solvent-free conditions, 3. green catalytic systems, 4. heterogeneous catalysis, 5. organocatalyzed reactions, 6. catalyst-free conditions, 7. photochemical activation, 8. sonochemistry in the synthesis of heterocycles, 9. microwave-assisted synthesis of heterocycles, and 10. electrochemical redox reactions.

11.2 Green solvents in organic synthesis Choosing the best solvent is a crucial issue in organic synthesis. Although the solvent is not directly incorporated into the final product, its nature and the used amount have a total influence in the formation of the product [11]. In this context, in addition to the chemical point of view, the environmental issue should also be considered when choosing the solvent [12]. Therefore, green solvents emerge as an alternative to highly flammable, toxic, and harmful volatile organic compounds, generating less toxic waste and as a consequence, polluting less the environment [13]. In this sense, in 2017, Xu and co-workers [14] proposed a methodology for the catalytic reductive amination of levulinic acid 1a into pyrrolidinones 2 (Figure 11.1). This methodology employs levulinic acid 1a and primary amines 3 as starting materials in water, a selective iridium complex I catalyst, and H2 as the hydrogen source due to its high atom economy. Nine derivatives of pyrrolidinones 2 were obtained in yields ranging from good to excellent (63–95% yield). In the same year, a close-related work was described by Wang and his group [15], on the catalytic reductive amination of levulinic acid 1a into pyrrolidones 2 in the presence of water and the iridium catalyst II. A total of twenty N-substituted 5-methyl2-pyrrolidones 2 were synthetized in 53–97% yield employing dicarbonyl compound 1a and aromatic, aliphatic and benzylic amines 3 with H2 (5 bar) as the hydrogen source (Figure 11.1). The method was expanded to the synthesis of N-substituted isoindolinones

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Figure 11.1: Synthesis of pyrrolidinone derivatives 2.

Figure 11.2: Synthesis of N-substituted isoindolinones 4.

4, which were obtained in yields ranging from good to excellent (80–98%) from 2-formylbenzoic 5a and primary amines 3, under the same green conditions (Figure 11.2). Levulinic acid 1a was used by Wang and co-workers [16] in a hydrogen-transfer reaction, using renewable sources of hydrogen donors, such as glycerol, ethanol, and isopropanol. By this protocol, γ-valerolactone 6a was prepared in quantitative yield (>99%) with a water-soluble iridium N-heterocyclic carbine complex III as a catalyst, at 150 °C for 2 h (Figure 11.3). Hasaninejad and co-workers [17] proposed a protocol for the synthesis of spirooxindole 7, spiroacenaphthylene 8 and bis-benzo[b]pyran derivatives 9. The products were formed in yields ranging from very good to excellent (84–98%) and the proposed procedure occurs via a one-pot multicomponent reaction by the

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Figure 11.3: Transfer hydrogenation of levulinic acid 1a to γ-valerolactone 6a.

condensation between isatin 10, acenaphthenequinones 11 or terephtalaldehydes/ isophtalaldehydes 12 with malono derivatives 13, and C–H activated carbonyl compounds 14 by using two different solvents (water or ethanol/water), both under reflux conditions. 1,4-Diazabicyclo[2.2.2]octan (DABCO) was used as an ecofriendly, cheap, nontoxic, and reactive catalyst in this reaction (Figure 11.4). Very recently in this year, Azimzadeh–Sadeghi and co-workers [18] developed a sustainable approach for the synthesis of pyran and chromene derivatives 15 from aryl

Figure 11.4: Synthesis of spirooxindole 7, spiroacenaphtylene 8, and bis-benzo[b]pyran derivatives 9 under green conditions.

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Figure 11.5: Eco-friendly synthesis of tetrahydro-4H-chromene derivatives 15.

or alkyl aldehydes 12, malono derivatives 13, and 1,3-dicarbonyl compounds 16 (Figure 11.5). In this protocol, a new and green deep eutectic solvent (DES) was previously produced, choline chloride/pentaerythritol (ChCl/PE), which also acts as an organocatalyst. By using this ecofriendly method, a variety of tetrahydro-4H-chromenes 15 were synthetized at 80 °C for 1 h, in 80–95% yield.

11.3 Solvent-free conditions Solvent-free reactions have received tremendous attention in recent times in green synthesis, due to the reduction of waste or by-products originated from the use of conventional volatile organic solvents [19]. Thus, in the development of sustainable methods to synthesizing potentially bioactive heterocyclic structures, some solventfree protocols have stood out [20]. In this sense, in 2017, Wu and co-workers [21] related the solvent-free reductive amination/cyclization of keto acids using phenylsilane to afford pyrrolidones 2 or pyrrolidines 17 by switching the catalyst from AlCl3 to RuCl3 respectively, under mild conditions (Figure 11.6). To access the pyrrolidones 2, the reactions were performed from aryl, alkyl, and benzyl amines 3 and keto acids 1 in the presence of 3 equiv of phenylsilane and 5 mol% of AlCl3·6H2O, at 30 °C for 12 h. The pyrrolidines 17, in turn, were synthetized from aryl and benzyl amines 3 and keto acids 1 in the presence of 4 equiv of phenylsilane and 1 mol% of RuCl3·3H2O at 45 °C for 24 h. In both methods, lower yields of products 2 (40%) and 17 (50%) were obtained starting from 4-(trifluoromethyl)aniline 3a, after 24 h of reaction, probably due to the strong electronwithdrawing effect of the substituent. In the same year, they described the use of triethoxysilane as a reducing agent and [Bmim][Lac] (1-butyl-3-methylimidazolium lactate) as a catalyst for the preparation of pyrrolidones 2 by the reaction of keto acids 1 with various amines 3 (Figure 11.6) [22]. A typical procedure involves the use of triethoxysilane (2 equiv), [Bmim][Lac] (20 mol%)

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Figure 11.6: Synthesis of pyrrolidones 2 and pyrrolidines 17 catalyzed by AlCl3·6H2O or RuCl3·3H2O [21] or using triethoxysilane to access pyrrolidones 2 [22].

at 80 °C for up 3 h of reaction. The corresponding products 2 were isolated in 30–93% yield. Sharma and co-workers [23] reported the synthesis of novel thiophene-based 1,4-dihydropyridines derivatives 18 through the solvent-free multicomponent reaction (MCR) of 5-bromothiophen-2-carboxaldehyde 19, 1,3-diones 16, and ammonium acetate using ceric ammonium nitrate [CAN, (NH4)2Ce(NO3)6] as the catalyst for 1–3 h at room temperature (Figure 11.7). By this procedure, seven dihydropyridine derivatives 18 were obtained in 35–75% yield, some of them demonstrated antibacterial and antifungal activities in vitro. The products were purified by treatment of the crude with hexane followed by recrystallization using ethanol and charcoal treatment. In 2019, two strategies to accessing 1,2,3,4-tetrasubstituted pyrroles 20 were reported, both using N-methyl-2-pyrrolidonium methyl sulfonate, [NMPH]CH3SO3, as a catalyst under metal- and solvent-free conditions [24]. The first one is the MCR between

Figure 11.7: MCR strategy to prepare 1,4-dihydropyridine derivatives 18.

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Figure 11.8: Synthesis of pyrroles 20 catalyzed by [NMPH]CH3SO3.

1,3-dicarbonyl compound 16, aryl, alkyl, and benzyl amines 3, and β-nitrostyrene 21 at 75 °C for 30 min, to access 10 different pyrrole compounds 20 (36–92% yield, Figure 11.8). When a nitroalkene was employed, e.g., (E )-1-nitrohex-1-ene 21a, the reaction required a longer reaction time (2 h, 44% yield). The second method is a fourcomponent reaction between aldehyde 12, nitromethane 22a, acetylacetone 16a, and aryl and alkyl amines 3 at 75 °C for 30 min, affording the expected pyrroles 20 in 69– 87% yield (Figure 11.8). It is interesting to point out that a full factorial design was applied to obtain a more robust and statistically correct optimum condition. A series of solvent-free and green catalyzed methods have been reported as promising environmentally friendly strategies to access valuable molecules. For instance, Louroubi and co-workers [25] prepared various pyrroles 20 through domino MCR of aldehydes 12, amines 3, 1,3-dicarbonyl compounds 16, and nitromethane derivatives 22. In this case, natural hydroxyapatite (HAp) in a molar ratio (S/C) = 60, was used as a cheap, natural, and nontoxic catalyst (Figure 11.9). The reactions were performed at 60 °C for 24 h, yielding the corresponding products 20 in 29–90%. To complete the study, it was shown that some of the prepared pyrroles presented good inhibition efficiency for S300 steel in the presence of 1 M hydrochloric acid, which could be applied in the control and reduction of metal corrosion in aqueous environments.

Figure 11.9: Synthesis of pyrroles 20 using natural hydroxyapatite.

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Mohamadpour and co-workers [26–28] have developed different green conditions to prepare 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 23 through Knoevenagel–Michael cyclocondensation of phthalic anhydride 24a, hydrazine monohydrate 25a, aromatic aldehydes 12 and malononitrile 13a. In 2016, they reported the synthesis of 15 differently substituted phthalazine derivatives 23 in 73–89% yield using copper(II) acetate monohydrate (20 mol%) as a catalyst, at 80 °C for 3–5 h (Figure 11.10, method A) [26]. Good results were obtained using aryl aldehydes containing neutral, electron-donating, and electron-deficient groups, while thiophene-2-carbaldehyde gave the corresponding phthalazine derivative 23a in 78% yield after 5 h. Few years later, a similar strategy was applied using carboxymethyl cellulose (CMC, 25 mol%) as a recyclable green and biodegradable catalyst, at 80 °C, during 60– 95 min to access phthalazine derivatives 23 in 77–94% yield (Figure 11.10, method B) [27]. The green aspects of this protocol include direct work-up without column chromatography separation, and the reuse of the CMC catalyst at least five times, with no considerable reduction in its activity (82–89% yield). Aldehyde containing thienyl group also was a good substrate for this reaction, yielding the desired phthalazine 23a in 87% yield in just 75 min of reaction. A third protocol developed by the same group involved the use of theophylline as a non-toxic and biodegradable catalyst under solvent-free conditions at 70 °C for 2–4 h [26]. Aryl and thienyl aldehydes were successfully applied to generate 23 different heterocyclic products 23 in 75–93% yield (Figure 11.10). In 2019, Mohamadpour and co-workers described the one-pot synthesis of polysubstituted quinolines 26, spiro[4H-pyran] derivatives, 12-aryl-tetrahydrobenzo[α] xanthene-11-ones 27, and 14-aryl-14H-dibenzo[α,j]xanthenes in the presence of catalytic amounts of citric acid under solvent-free conditions [29]. The synthesis of compounds 26 (isolated in 87–94% yield) involved the reaction of 2-aminobenzophenone 28a with the dicarbonyl compound 16 in the presence of citric acid (15 mol%) at 90 °C for 10–15 min (Figure 11.11). Spiro derivatives were obtained in 35–60% yield (12 examples) through the reaction between isatins or acetonaphthoquinone, malononitrile, and dicarbonyl compound using citric acid (20 mol%) at 80 °C for 35–60 min. The

Figure 11.10: Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 23 [26–28].

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Figure 11.11: Synthesis of polysubstituted quinolines 26.

Figure 11.12: Synthesis of 12-aryl-tetrahydrobenzo[α]xanthene-11-ones 27.

12-aryl-tetrahydrobenzo[α]xanthene-11-ones 27 were prepared in 84–96% yield by the reaction of β-naphthol 29a, aryl aldehydes 12, and dicarbonyl compounds 16 in the presence of citric acid (20 mol%) at 80 °C for 10–25 min (Figure 11.12). In all the reactions, the products were isolated by filtration and then recrystallized from ethanol. Some very simple and efficient solvent- and catalyst-free methods have been developed to the synthesis of new heterocyclic compounds [30,31]. For instance, Lu and co-workers [30] reacted substituted hydrazine 25 and phthalaldehydic acid or 2-acyl-benzoic acid 30 to obtain 18 examples of phthalazinones 31 in excellent yields

Figure 11.13: Synthesis of substituted phthalazinones 31.

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(86–99%) and short reaction times (up to 1 h) at 100 or 150 °C (Figure 11.13). For the reactions performed at 100 °C, the products were directly obtained when the reaction was complete, and for the ones performed at 150 °C, the compounds 31 were crystallized from ethanol. Gupta and Khurana [31] developed two multicomponent strategies to access 5-hydroxy-chromeno[2,3-b]pyridines 32 from 3-formylchromone 33, malononitrile 13a, and aromatic amines 3 (Figure 11.14). The first method (Method A, Figure 11.14) consists of simply stirring a mixture of the starting materials at room temperature for 10–20 min, while the second one (Method B, Figure 11.14) involves grinding the starting materials in a mortar with a pestle at room temperature for up to 10 min. After the appropriate time, the products were obtained in 90–96% yield by filtration followed by washing with ethanol, without the need for chromatography column. A plausible reaction mechanism for the formation of chromeno[2,3-b]pyridines 32 was proposed by the authors (Figure 11.15). The first step involves the condensation between malononitrile 13a and 3-formylchromone 33 to give the intermediate I, which undergoes Michael-type addition with aromatic amine 3 to afford the intermediate II.

Figure 11.14: Synthesis of 1-aryl-5-hydroxy-2-imino-2,10a-dihydro-1H-chromeno[2,3-b]pyridine3-carbonitrile 32.

Figure 11.15: Proposed mechanism for the synthesis of 32.

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Finally, the intermediate II undergoes an intramolecular cyclization leading to compound 32.

11.4 Green catalytic systems Catalysis is one of the most powerful tools in organic synthesis and the development of greener reaction media is an important focus in the promotion of green chemistry. In this context, the use of green catalysis is an important strategy to access new efficient and environmentally friendly synthetic strategies, aiming the sustainability of chemical processes [32]. The sustainable catalysts used in organic chemistry include biocatalysts, organocatalysts, metal-catalysts, homogeneous and heterogeneous catalysts, among others [33]. In 2018, Gajengi and co-workers [34] reported the synthesis of substituted pyrroles 20 in the presence of Cu2O/Ag nanocomposite (NPs) as catalyst (Figure 11.16). The Cu2O/ Ag NPs were easily prepared using ethylene glycol under microwave irradiation within a short reaction time. This catalyst presented excellent catalytic activity (0.005 g/mmol of aldehyde) in the one-pot four-component reaction of aldehyde 12, amine 3, 1,3‐ dicarbonyl compounds 16, and nitromethane 22a at room temperature. The catalytic system provides good yields (up to 90%) of products 20 for a wide range of substrates. Also, the catalyst could be reused up to four consecutive cycles without loss of its activity (90–98% yield). In 2019, Alishahi and co-workers [35] studied an efficient methodology to the synthesis of several polysubstituted pyridines 34 through a four-component reaction using of calixarene-based ionic liquid ([Cmim]HSO4) as an efficient catalyst. The optimal condition involves stirring a mixture of diverse aldehydes 12, malononitrile 13a, 1,3‐dicarbonyl compounds 16, and aryl amines 3 in the presence of 6 mol% of [Cmim]HSO4 in water at 40 °C for 2–4 h (Figure 11.17). The efficiency of the catalytic system was demonstrated by the synthesis of symmetric and non symmetric polysubstituted pyridines, which were obtained in high yields (83–98%). In addition, the reactions

Figure 11.16: One-pot synthesis of pyrroles 20 catalyzed by Cu2O/Ag NPs.

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Figure 11.17: Synthesis of polysubstituted pyridines 34 catalyzed by [Cmim]HSO4.

occurred under mild conditions, short reaction times, and the catalyst could be reused five times without considerable loss in its activity (89–99% yield). In 2017, Tayade and Dalal [36] described a green method for the synthesis of fifteen 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 23 catalyzed by the supramolecular, biodegradable and reusable catalyst β-cyclodextrin (β-CD). This one-pot threecomponent reaction between aldehydes 12, malononitrile 13a, and phthalhydrazide 31a was performed using 20 mol% of β-CD, in a mixture H2O-ethanol (4:1) as the solvent at 100 °C (Figure 11.18). This method is environmentally benign [low E-factor (0.13) and high atom-economy (AE = 91%)], mild neutral reaction conditions, and good to excellent yields of products (82–93%). Additionally, the catalyst could be recovered and reused for four consecutive cycles without appreciable loss in the catalytic activity (85–93% yield).

Figure 11.18: Synthesis of 1H-pyrazolo[1,2-b]phthalazine5,10-diones 23 in the presence of β-CD.

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Recently, fulvic acid was applied as a catalyst in the one-pot four-component domino synthesis of benzo[a]phenazine annulated heterocycles 35 and 36 in aqueous medium (Figure 11.19) [37]. A mixture containing 2-hydroxy-1,4-naphthalenedione 37a, 2-phenylenediamine 3b, aromatic aldehydes 12, and malononitrile 13a or 1,3-dicarbonyl compounds 16 was reacted in the presence of water and fulvic acid (20 mol%) as catalyst at 60 °C. By this protocol, a total of 27 differently substituted products 35 and 36 were prepared in 83–96% yield. The reaction was performed under mild conditions, and the catalytic system worked well up to five catalytic runs (85–96% yield). Panshina and co-workers [38] studied the reaction of N,N′-dimethylurea 38a with glyoxal 39a in water using etidronic acid [1-hydroxyethane-1,1-diylbis(phosphonic acid), HEDP] as a green catalyst to obtain tetramethylglycoluril 40a in 62% yield (Figure 11.20). In 2017, Javanshir and co-workers [39] studied the use of Caspian isinglass (IG) as a versatile and sustainable biocatalyst for the domino synthesis of spirooxindoles 41 and

Figure 11.19: Preparation of benzo[a]phenazine annulated heterocycles 35 and 36 in the presence of fulvic acid.

Figure 11.20: Synthesis of tetramethylglycoluril 40a using HEDP.

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Figure 11.21: One-pot synthesis of spirooxindoles 41 and spiroacenaphthylenes 42.

spiroacenaphthylenes 42 in water (Figure 11.21). Isinglass, derived from swim bladders of Caspian Sea fish consists predominantly of protein collagen. The authors demonstrated a one-pot three-component synthesis route involving isatin 10 or acenaphthenequinone 11a, activated methylene nitrile derivatives 13, and 1,3-dicarbonyl compounds 16 in the presence of Caspian (IG) as a biocatalyst in water. The respective spiro derivatives 41 were obtained in good to excellent yields (70–97%) in very short reaction times. The authors studied the reuse of the biocatalyst, and it could be used at least four times without significant loss of activity (80–96% yield). Another application of sustainable biocatalysts in organic syntheses was reported by Willis and co-workers in 2016 [40]. The enantioselective synthesis of a pharmaceutically important chiral fluorolactam derivative 43 was performed by a selective direct fluorination via hydrolase-promoted amidation strategy (Figure 11.22). The reaction

Figure 11.22: Synthesis of fluorolactam 43 from 44.

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proceeded in the presence of CAL-B 10,000 as biocatalyst, a recombinant Candida antarctica Lipase B that is commercially available from Fermase. In a typical procedure, the salt 44 was reacted in the presence of CAL-B 10,000 in aqueous phosphate buffer (pH 7.3) at 20 °C for 8 h. The desired enantiopure fluorolactam 43 was generated in 43% yield with 99% of ee. It was observed no loss of CAL-B activity, even after 3 consecutive reactions. A green protocol was developed for the synthesis of 2-amino-3-cyano-4H-pyrane derivatives 15 by the multicomponent reaction of aryl aldehydes 12, malononitrile 13a, and ethyl or methyl acetoacetate 16 [41]. The MCR occurred in the presence of 0.01 g of a novel, previously prepared magnetic nanocomposite polyethylene oxide-coated ferrite-sulfonic acid (Fe3O4/PEO/SO3H) in ethanol as solvent at room temperature. Under these conditions, 12 different 2-amino-4H-pyran derivatives 15 were prepared in 83–95% yield in short reaction times (Figure 11.23). In the end of the reaction, the catalyst was easily removed (the superparamagnetic nanocatalyst) and reused at least for six times with good activity (87–95% yield). In 2017, Maleki and Azadegan [42] described a similar method for the synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives 15. The authors used nano Fe3O4@SiO2 (0.005 g/mmol of aldehyde) as an efficient heterogeneous nanocatalyst in a one-pot three-component condensation of various aromatic aldehydes 12, malononitrile 13a, and 1,3-dicarbonyl compounds 16 in ethanol as solvent at room temperature. The reactions proceeded with a good performance in the presence of an environmentally friendly, reusable (up five times), and easily prepared superparamagnetic nanocatalyst. A total of 16 differently substituted 2-amino-4Hchromene-3-carbonitriles were obtained in good to excellent yields (82–97%) (Figure 11.24). Another versatile and interesting strategy employing magnetic nanoparticles was developed by Asadi and co-workers [43]. In this work, the authors prepared unsymmetrical 1,2,5,6-tetrahydropyridine-3-carboxylate 45 by a one-pot three-component reaction of aryl aldehydes 12, aryl amines 3, and ethyl acetoacetate 16d using Fe3O4@TDSN-Bi(III) [containing 8 mol% Bi(III)/mmol of ethyl acetoacetate] as an efficient heterogeneous catalyst. Several substituted unsymmetrical 1,2,5,6-tetrahydropyridine-3-carboxylates 45 were

Figure 11.23: Synthesis of 2-amino-4H-pyran derivatives 15 using Fe3O4@PEO-SO3H nanocatalyst.

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Figure 11.24: Synthesis of 2-amino-4H-chromene-3-carbonitriles 15 using nano-Fe3O4@SiO2.

Figure 11.25: Fe3O4@TDSN-Bi(III)- and nano-Al2O3/BF3/Fe3O4-catalyzed multicomponent synthesis of 1,2,5,6-tetrahydropyridine-3-carboxylates 45.

prepared in 93–99% yield at room temperature after 1–3 h of reaction. The recovered catalyst can be run at least six times under the optimal conditions, without noticeable loss in the catalytic activity and product yields (98–96%) (Figure 11.25). In 2018, Babaei and Mirjalili [44] described a one-pot synthesis of 5-substituted tetrahydropyridines (THPs) 45 using nano-Al2O3/BF3/Fe3O4 as a highly efficient nano-

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catalyst (Figure 11.25). In this work, the authors prepared 14 differently substituted THPs 45 (75–85% yield) starting from aldehydes 12, 4-substituted anilines 3, and ethyl acetoacetate 16d under solvent-free conditions at 80 °C for 3 to 4 h. Although an increase in reaction time and reducing in product yields compared with the work of Asadi [43], the catalyst could be recycled four times (40–65% yield, 8–13 h of reaction). Additionally, this catalyst does not need special preparation and it can be easily removed from the reaction medium by an external magnet. In 2016, Abadi and co-workers [45] related the obtention of functionalized benzo[a] pyrano[2,3-c]phenazine derivatives 35 by a one-pot, two-step procedure involving the condensation of 2-hydroxynaphthalene-1,4-dione 37a, 4-phenylenediamine 3b, aryl aldehydes 12, and malononitrile 13a in the presence of 1,3,7-trimethylpurine-2,6-dione (caffeine) as an expedient and reusable solid base catalyst (Figure 11.26). By this protocol, 14 pyrano phenazine derivatives 35 were synthetized in 85–96% yield under conventional heating (75 °C; 0.5–2.0 h) or under microwave (MW) irradiation at 180 W power (7–12 min). A reuse study of the caffeine catalyst was performed for the reaction between 2-hydroxynaphthalene-1,4-dione 37a, 4-phenylenediamine 3b, 2,4-dichlorobenzaldehyde 12a, and malononitrile 13a using MW at 180 W during 7 min, or conventional heating at 75 °C for 30 min. The authors observed that the recovered catalyst works with the same performance up to two runs, while in the 3rd and 4th ones the product yield is slightly reduced, indicating probably some weight loss of catalyst during each reuse process. The use of ZrO2 nanoparticles as catalyst was demonstrated in the synthesis of a series of multi-functionalized 2,3-disubstituted isoindolin-1-ones 46. These compounds were obtained in good to excellent yields (78–95%) via a one-pot three-component condensation of 2-carboxybenzaldehyde 5a, aliphatic amines 3, and different nucleophiles: enamines 14, 6-amino 1,3-dimethyluracil 16a 1,3-cyclohexadiones 16, and indole 47a (Figure 11.27) [46]. A total of 33, 2,3-disubstituted isoindolin-1-ones 46 were prepared under solvent-free conditions at 70–75 °C for 1–2 h. ZrO2 NPs (0.25 g/mmol of 5a) acted as a dual acid–base solid support and could be reused by five cycles with good performance under the optimized reaction conditions (83–88% yield).

Figure 11.26: Synthesis of 3-amino-2-cyano-1-aryl-1H-benzo[a]pyrano[2,3-c]phenazine derivatives 35.

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Figure 11.27: Synthesis of multi-functionalized isoindolin-1-one derivatives 46.

Recently, Amirmahani and co-workers [47] used tetrabutyl phosphonium sulfate {[TBP]2SO4} as a both a novel IL and as an efficient catalyst in MCR to prepare pyridazino[1,2-a]indazole, indazolo[2,1-b]phthalazine 48 and pyrazolo[1,2-b]phthalazine 49. By stirring a mixture of aromatic aldehydes 12, succinic or phthalic anhydride 24, hydrazine hydrate 25a, and 1,3-diketones 16 under solvent-free at room temperature for 10–45 min, various substituted products 48 and 49 were prepared in good to excellent yields. The catalyst could be easily recovered and reused up to four times with good activity (85–91% yield) (Figure 11.28).

Figure 11.28: Synthesis of 48 and 49 derivatives in the presence of [TBP]2SO4.

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11.5 Heterogeneous catalysis The adoption of the green chemistry principles aims to reduce the environmental damage caused by chemical activity [48,49]. A great ally in the promotion of green organic synthesis is the heterogeneous catalysis, which contemplates three of the 12 fundamental principles of green chemistry: the atom economy, use of reusable catalysts and the minimization of waste [50]. Therefore, heterogeneous catalysts, which can be easily recycled and reused, have been used more and more, promoting high catalytic activity and reactive efficiency [51]. In this line, Gajenji and co-workers [52] developed in 2016 an unprecedented methodology for the synthesis of substituted pyrroles 20 using NiO NPs as a heterogeneous and robust catalyst under solvent-free conditions. The synthesis of the desired product 20 was achieved through the four-component coupling between primary amines 3, nitromethane 22a, aromatic aldehydes 12, and 1,3-dicarbonyl compounds 16 at room temperature for 4 h under nitrogen atmosphere (Figure 11.29). Thereby, a range of substituted pyrroles 20 were obtained in 35–88% yield under mild conditions. The nanoparticulated catalyst was reused in up to four catalytic cycles without a significative loss of its catalytic activity (72–85% yield). In the same year, Zhang and co-workers [53] described the Pd-catalyzed sequential hydrogenation-amination of levulinic acid 1a to prepare pyrrolidones 2. In this solventfree procedure, levulinic acid 1a and primary amines 3 were reacted with H2 in the presence of a heterogeneous palladium nanocatalyst. The desired pyrrolidones 2 were obtained in 80–94% yield (Figure 11.30). After a series of catalytic activity tests,

Figure 11.29: Synthesis of substituted pyrroles 20 catalyzed by NiO NPs.

Figure 11.30: Pd-catalyzed hydrogenation-amination of levulinic acid 1a to pyrrolidones 2.

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ZrO2-supported Pd was chosen as the best catalytic system for the reaction due to the high chemoselectivity, stability and reuse. Regarding the recyclability of the system, it was observed an excellent conversion rate of levulinic acid, even after the six runs. In 2016, Jafarpour and co-workers [54] reported a protocol for the synthesis of a new, efficient, and reusable heterogeneous catalyst, a zirconium Schiff base complex anchored on magnetic nanoparticles. This catalyst, that demonstrated high activity and stability, was prepared to catalyze the condensation reaction between aryl 1,2-diamines 3 or 50 with 1,2-dicarbonyls 51 in ethanol. As a result of this procedure, a range of quinoxalines and pyrido pyrazine 52 were obtained in good to excellent yields (73–97%) at 60 °C after up to 100 min of reaction (Figure 11.31). Furthermore, it is noteworthy that the catalyst can be recovered by decantation followed by washing with ethyl acetate and ethanol, being efficiently reused in up to four catalytic cycles without a significant drop in the catalytic activity. One year later, Naemi and co-workers [55] reported a simple one-pot multicomponent procedure for the synthesis of a range of pyrido[2,3-d:6,5-d′]dipyrimidines 53 in good to excellent yields (85–98%), as shown in Figure 11.32. The methodology for the formation of the desired product uses aromatic aldehydes 12, 2 equiv of 2-thiobarburic acid 54a, and ammonium acetate 55a as starting materials, in the presence of CuFe2O4 magnetic nanoparticles as the heterogeneous catalyst in water. This protocol is very interesting from an environmental point of view due to the high atom economy, the use

Figure 11.31: Synthesis of quinoxalines and pyrido pyrazines 52 catalyzed by ZrOL2@SM NPs.

Figure 11.32: Synthesis of pyrido[2,3-d]pyrimidine derivatives 53.

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of water as a solvent, the absence of harmful substances, and the catalyst recyclability (up to four consecutive catalytic cycles, 97–98% yield). In 2018, Maleki and co-workers [56] used CuFe2O4 magnetic nanoparticles in the synthesis of a magnetic bionanocomposite, CuFe2O4/chitosan. This material was characterized by different techniques and was used as a heterogeneous catalyst that could be easily retrieved and reused in up to seven cycles with some stability in yields. They promoted the one-pot multicomponent synthesis of diverse 2-amino-4H-pyrans and 2-amino-4H-chromens 15 and polyhydroquinoline derivatives 34 and 56, under mild conditions using this new catalyst (0.01 g/mmol of aldehyde) (Figure 11.33). Thus, for the synthesis of each compound, different aromatic aldehydes were used in the reaction with malononitrile 13a, ethyl acetoacetate 16d or dimedone 16, and ammonium acetate 55a. Therefore, a range of substrates were synthetized in good to excellent yields (79–97%) with no need of column chromatography in the purification step. Patil and his group [57] proposed in 2019 a one-pot multicomponent and solventfree reaction between 2,3-dihydrophthalazine-1,4-dione 31a, malononitrile 13a, and aromatic aldehydes 12 to promote the synthesis of diverse 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 23 in 86–94% yield (Figure 11.34). In this methodology,

Figure 11.33: One-pot multicomponent synthesis of diverse 2-amino-4H-pyrans, 2-amino-4Hchromens 15 and polyhydroquinoline derivatives 34 or 56.

Figure 11.34: Synthesis of different 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 23 catalyzed by CuO NPs.

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previously prepared CuO nanoparticles were used as a heterogeneous catalyst, presenting a good recyclability, being used five times in sequence during the catalytic cycles without a significant loss in yields (86–92%). In the proposed mechanism for this synthesis, firstly the basic oxygen of the heterogeneous catalyst promotes the activation of the C-H bond of the malononitrile 13a which attacks the carbonyl group of the aromatic aldehyde 12 activated under the catalytic effect of the CuO nanoparticles sites that act as Lewis acids, promoting a Knoevenagel condensation and forming intermediate I. This generated Knoevenagel adduct I undergoes a Michael-type addition reaction with n-phthalhydrazide 31a to form the iminomethylene intermediate II. Afterwards, this intermediate II undergoes a step of intramolecular cyclization and tautomerization in the presence of CuO nanoparticles, forming the 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 23 (Figure 11.35). Also in 2019, Xie and co-workers [58] prepared functional porous TiO2 nanosheetssupported Pt nanoparticles (Pt/P-TiO2), an efficient heterogeneous catalyst for organic transformations, which could be recovered from the reaction medium by centrifugation, followed by washing with methanol and ethyl ether. Posteriorly, it was reused in up to four reactions, and the product yield only decreased slightly after the fourth recycle, probably due to some catalyst loss on each recovery. This catalyst was used to promote a reductive amination of levulinic acid and 4‐acetylbutyric acid and its esters 1 in the presence of primary amines 3 and H2, affording a range of N-substituted pyrrolidones or N-alkyl-2-piperidinones 2 in methanol as solvent (Figure 11.36). Thirty-five

Figure 11.35: Proposed mechanism for the synthesis of 23.

Figure 11.36: Synthesis of N-substituted pyrrolidones and N-alkyl-2-piperidinones 2.

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examples of the respective products 2 were obtained in excellent yields (up to 99% yield), of which only the derivatives of 4-iodoaniline and 4-bromoaniline were exceptions (45% and 72% yield, respectively). In addition, by the reductive amination of 2-acetylbenzoic acid and 2-carboxybenzaldehyde under the same reaction conditions, the corresponding N-arylisoindolinones were synthetized in 95% and 96% yield, after 24 and 5 h, respectively. This catalytic system was also used in the catalysis of the reductive amination of levulinic acid with 25% by weight of aqueous ammonia (85% yield) and ammonia (gas) (89% yield). Both products were formed after 72 h of reaction.

11.6 Organocatalyzed reactions Due to the constant environmental concerns of the chemical industry, more precisely in organic chemistry, the organocatalysis represents a sustainable alternative that employs organic molecules to catalyze chemical transformations [59]. Consequently, this recyclable, selective, easily obtainable, and nontoxic catalytic method allows the substitution of metal catalysts, most of them are extremely harmful to the environment [60,61]. In this context, Mohebat and co-workers [62] developed in 2016 an eco-friendly procedure for the one-pot and multicomponent synthesis of 16-(aryl)benzo[a]indeno [2′,1′:5,6]pyrano[2,3c]phenazin-15(16H)-one derivatives 36. The first step of this approach involves reacting 2-hydrozynaphthalene-1,4-dione 37a and benzene1,2-diamine 3b in a fast, catalyst- and solvent-free reaction, forming the intermediary benzo[a]phenazin-5-ol 57, which requires no separation or purification before use. Subsequently, aromatic aldehydes 12 and 1,3-indandione 24a were added to the system, with oxalic acid as an organocatalyst in a mixture ethanol/water (1:1). After refluxing for 2.0–2.5 h, this inexpensive, fast, green, and organocatalytic protocol afforded a range of 16-(aryl)benzo[a]indeno[2′,1′:5,6]pyrano[2,3c]phenazin-15(16H)one derivatives 36 in 85–92% yield (Figure 11.37). In the same year, Gupta and co-workers [63] reported a one-pot and multicomponent procedure for the synthesis of novel 5-hydroxy pyrazolo[1,2-a][1,2,4] triazoles 58 and their dehydration to novel pyrazolo[1,2-a][1,2,4]triazole derivatives 59 (Figure 11.38). This protocol involves reacting alkyl acetoacetates 16, aromatic aldehydes 12 and 4-phenylurazole 60 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an organocatalyst, forming the respective 5-hydroxy pyrazolo[1,2a][1,2,4] triazoles 58 in good yields (70–78%) under mild conditions. In the next step, after addition of sulfuric acid (10 mol%) in the presence of ethanol under reflux conditions, the dehydration reaction was realized. By this method, a total of nine dehydrated pyrazolo[1,2-a][1,2,4]triazole derivatives 59 were synthetized in 75–98% yield. In the proposed mechanism for these syntheses, initially there is a Knoevenagel condensation between methyl or ethyl acetoacetate 16 with an aromatic aldehyde 12 producing the Michael receptor I. Posteriorly, the 4-phenylurazole 60 promotes a

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Figure 11.37: Synthesis of 16-(aryl)benzo[a]indeno[2′,1′:5,6]pyrano[2,3-c]phenazin-15(16H)-one derivatives 36 using oxalic acid as an organocatalyst.

Figure 11.38: Synthesis of 5-hydroxy pyrazolo[1,2-a][1,2,4] triazoles 58 and pyrazolo[1,2-a][1,2,4] triazole derivatives 59.

Michael addition at I to afford the intermediate II, which undergoes an intramolecular cyclization to give the 5-hydroxy pyrazolo[1,2-a][1,2,4] triazoles 58. The dehydrated products 59 were formed using H2SO4 under absolute ethanol reflux (Figure 11.39). Also in 2016, Kumari and co-workers [64] proposed a methodology for the synthesis of triazolyl spirocyclic oxindole derivatives 61 via a sustainable approach. These molecules were produced by a one-pot five-component reaction between acetylacetone 16e, aromatic azides 62, aromatic aldehydes 12, L-proline 63a, and isatin 10a by using DBU as an organocatalyst and PEG-400 as solvent. Several triazolyl spirocyclic oxindole derivatives 61 were synthetized in 86–93% yield (Figure 11.40). In addition, the authors assessed the recyclability potential of the DBU/PEG-400 system, testing it for six successive cycles. The reaction product was easily separated by a simple filtration

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Figure 11.39: Proposed mechanism for the synthesis of 58 and 59.

Figure 11.40: Synthesis of triazolyl spirocyclic oxindole derivatives 61 via a sustainable approach.

and the tested substrates were changed from one cycle to another. The reactions in these tests were conducted between 40 and 65 min and the products were obtained in 81–93%, which proved a great recyclability of the reaction medium. In 2018, Hassani and co-workers [65] developed a multicomponent protocol with different amines 3, 1,3-dicarbonyl compounds 16, aldehydes 12, and nitromethane 22a under microwave irradiation for the synthesis of diverse substituted pyrroles 20 in yields that ranged from good to very good (76–91%) (Figure 11.41). Chitosan was used as a

Figure 11.41: Synthesis of different substituted pyrroles 20 under green conditions.

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recyclable and reusable organocatalyst since it can be used in several catalytic cycles without significant loss of effectiveness. In addition, this methodology has other green features, such as the solvent-free condition and the use of microwave as an alternative energy source, replacing the use of the high energy consuming thermal heating. Posteriorly, in 2020, Fallah–Mehrjardi and his group [66] described a one-pot three-component synthesis of diverse 2-amino-3-cyano-4H-pyrans 15. The sustainable methodology proposed by them involved the reaction between 1,3-dicarbonyl compounds 16, aromatic aldehydes 12, and malononitrile 13a employing MNP@PEG-ImOH as catalyst. This is a thermally stable, recyclable and easily recovered nanomagnetitesupported basic phase-transfer organocatalyst. This procedure was conducted in aqueous media at room temperature for 20–60 min, and the desired products 15 were obtained in good to excellent yields (80–95%) (Figure 11.42).

11.7 Catalyst-free conditions Conventional chemical transformations need new alternatives to avoid the use of substances that are harmful to the environment and to the human health. These include a series of additives often used in organic reactions, like catalysts [67,68]. Based on this, catalyst-free reactions stand out for allowing this minimization of chemical pollution, by excluding the use of many catalysts that are expensive and potentially toxic. In this line, Saroha and co-workers [69] described a one-pot three component procedure to obtain a range of new 5-substituted 6-phenyl pyrrolo[2,3-d]pyrimidine

Figure 11.42: Green synthesis of diverse 2-amino-3-cyano-4H-pyrans 15.

11.7 Catalyst-free conditions

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Figure 11.43: Green synthesis of 5-substituted 6-phenyl pyrrolo[2,3-d]pyrimidine derivatives 64, 65, and 66.

derivatives 64, 65 and 66 (Figure 11.43). The green methodology proposed by them was catalyst-free and proceed in refluxing ethanol. The starting materials of this condensation reaction were phenylglyoxal 67a, 6-amino-1,3-dimethyluracil 68a, and indoles 47/1H-pyrazol-5(4H)-one 69/activated C-H acids 14. By this protocol, a range of different 5-substituted 6-phenyl pyrrolo[2,3-d]pyrimidine derivatives 64 (5 examples, 78–85% yield), 65 (3 examples, 86–90% yield), and 66 (8 examples, 82– 89% yield) were obtained. In 2017, Kon and co-workers [70] developed a catalyst-free green methodology for the synthesis of spiro[dihydroquinolinenaphthofuranone] compounds 70 from substituted isatins 10, 2-naphthols 29 and 1,3-dicarbonyl compounds 16 (Figure 11.44). This ring-opening annulation reaction promoted by hydrogen bonds led to the products 70 in 80–94% yield, using 10 wt% of an aqueous solution of the anionic surfactant sodium dodecyl sulfate (SDS) under solvent-free conditions. In addition, the authors improved their study by analyzing the recyclability potential of the reaction medium

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Figure 11.44: Synthesis of spiro[dihydroquinolinenaphthofuranone] compounds 70.

(scaling up the reaction to 10 mmol), which can be filtered and reused five consecutive times without a significant change in yield (about 90% yield). Among the benefits of this protocol are the recyclable reaction medium, inexpensive reagents, possibility of gram-scale operation, and absence of organic solvents. Brahmachari and co-workers [71] proposed a new protocol for the synthesis of a range of pyrido[2,3-d:6,5-d′]dipyrimidines 53 and 71 under ecofriendly conditions, as catalyst-free, water-mediation, room temperature, and no need of column chromatography purification (Figure 11.45). The reaction was conducted via a one-pot multicomponent reaction between barbituric, N,N-dimethylbarbituric or 2-thiobarbituric acids 54 and 72, substituted amines 3, and aldehydes 12. The corresponding product 53 or 71, was purified by a simple filtration followed by washing with cold aqueous ethanol and were obtained in yields ranging from moderate to very good (57–93%). Afterward, the same research group [72] used a similar methodology to describe the catalyst-free, one-pot, and room temperature approach for the synthesis of variously functionalized 1H-benzo [6,7]-chromeno[2,3-d]pyrimidines 73 (Figure 11.46). The expected products 73 were obtained in yields ranging from very good to excellent (87–99%) after 12–22 h through the reaction between different substituted barbituric acids 54 or 72, aldehydes 12 and 2-hydroxy-1,4-napthoquinone 37a in the presence of a mixture ethanol/water (1:1 v/v). The products were isolated by a simple filtration

Figure 11.45: Synthesis of functionalized pyrido[2,3-d:6,5-d′]dipyrimidines 53 and 71.

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Figure 11.46: Synthesis of functionalized 1H-benzo[6,7]-chromeno[2,3-d]pyrimidines 73.

followed by washing with cold aqueous ethanol, without the need of column chromatography. In the proposed reaction mechanism, initially occurs the enolization step with the barbituric acid 54 or 72, producing I. Afterwards, the aldehyde II protonated under acidic conditions promotes a Claisen–Schmidtt condensation with the compound I, forming the aldol(β-hydroxyketone) III, which after the removal of water, gives the chalcone intermediate IV. Next, occurs a nucleophilic attack under acidic conditions from the third starting material, the 2-hydroxy-1,4-naphtho-quinone 37a, forming a new C-C bond and producing the nucleophilic adduct V. This intermediate V promotes an intramolecular ring-closure in a 6-exo-trig process which form a new C–O bond and therefore, the formation of the cycloadduct VI that, after water removal, generates the desired product 73 (Figure 11.47). Meena and co-workers [73] proposed a condensation reaction between phenylglyoxal 67a, cyclic enolizable dicarbonyl compounds 16 and 2-aminobenzothiazole 74 to synthetize diverse benzo[d]imidazo[2,1-b]thiazoles 75 (Figure 11.48). Two different conditions were used in this procedure: conventional heating or grinding using mortar

Figure 11.47: Proposed mechanism for the synthesis of 73.

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Figure 11.48: Eco-friendly synthesis of benzo[d]imidazo[2,1-b]thiazoles 75.

and pestle, both under a catalyst-free medium and in glycerol. Consequently, several benzo[d]imidazo[2,1-b]thiazoles 75 were produced in 87–93% yield in short reaction times. Cao and co-workers [74] developed in 2020 the catalyst-free halocyclization of olefinic 1,3-dicarbonyls 16, aiming to prepare highly functionalized 2,3-dihydrofurans 76. The reaction was performed in aqueous media at room temperature, in the absence of base or oxidants. In a typical procedure, olefinic 1,3-dicarbonyls 16 were reacted with N-iodosuccinimide 77a in the presence of DMSO/H2O as the reaction medium, in an open flask (Figure 11.49). The valuable 2,3-dihydrofurans 76 were obtained in good to excellent yields (73–96%) after 8 h of reaction. In 2021, Zhao and co-workers [75] proposed the catalyst-free reductive amination followed by a cyclization of biomass-based keto acids 1 and amines 3 into lactams 2 under eco-friendly conditions (Figure 11.50). In this work, the authors reported for first-

Figure 11.49: Synthesis of 2,3-dihydrofurans 76.

Figure 11.50: Synthesis of N-substituted lactams 2.

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time the use of borane ammonia (NH3-BH3) as a proton donor without the need of using any additives. The different synthesized N-substituted lactams 2 were quantified by 1H NMR using mesitylene as the internal standard, and after, isolated. The yields of the isolated product 2 ranged from acceptable to excellent (21–96%). In 2021, Jiang and his group [76] developed a sustainable and solvothermal approach for the synthesis of diverse dihydropyrimidinone derivatives containing benzene 78 or a pyrrole 79 ring. The protocol involves the reaction of 1,3-dicarbonyl compounds 16, urea 38a/thiourea 80a, and different aldehydes 12 or 81 in a catalystfree reaction under a lactic acid media (Figure 11.51). A range of dihydropyrimidinone derivatives were obtained in 70–84% yield, and the synthesized substrates were screened for inhibition of Eg5 motor protein, with good outcomes. Elumalai and co-workers [77] proposed an ecofriendly protocol for the synthesis of quinoxaline derivatives 52 via a fast condensation (1 min) between aryldiamines 3 and 1,2-dicarbonyl compounds 51 (Figure 11.52). This methodology works without the need of catalyst, using methanol as solvent. The desired products were formed in acceptable to excellent yields (29–99%) in only 1 min, in an open flask. Besides, the authors performed five large-scale reactions and three compounds were synthesized in yields ranging from good to excellent (80–94%) at 1 g scale using the same reaction conditions. Additionally, two reactions were performed up to 10 g scale, using ethyl acetate as a solvent, and the corresponding products were obtained in 85% and 90% yield.

Figure 11.51: Route for solvothermal synthesis of dihydropyrimidinones containing a benzene 78 or a pyrrole 79 ring.

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Figure 11.52: Synthesis of quinoxaline derivatives 52.

11.8 Photochemical activation Visible light has received increasing attention of synthetic organic chemists because of their unique properties such as sustainability, cost efficiency and attractive environmental performance [78]. One advantage of photochemical activation consists of promoting chemical reactions involving electron transfer, besides the fact that the reaction rate can be easily controlled by switching light sources on or off [79,80]. Dutta and co-workers [81] related the synthesis of a variety of pharmaceutically important pyran-based heterocyclic scaffolds 15 through a one-pot catalyst-free protocol. 1,3-Diketones 16 were reacted with aromatic aldehydes 12 and malononitrile 13a under ultraviolet irradiation (UV365) in water/ethanol (1:1) medium at room temperature by 45–60 min. When 16 = dimedone (16a) or cyclohexane-1,3-dione (16c), eight pyran based heterocyclic scaffolds 15 were isolated in 89–97% yield (Figure 11.53). The authors also reported the use of isatin and substituted isatins instead of aromatic aldehydes, which also gave three different spiro compounds in 93%, 94%, and 98% yield after 45–60 min at room temperature. Moreover, in vitro studies of the prepared pyran derivatives showed antimicrobial activity. Similarly, Tiwari and co-workers [82] described the synthesis of 4H-chromenes 82a, 82b and pyrano[2,3-d]pyrimidinone 82c by using a household compact fluorescent lamp (CFL 20 W) under solvent-free and catalyst-free conditions (Figure 11.53). The onepot reactions were performed between aromatic aldehydes 12, malononitrile 13a and dimedone 16a/cyclohexane-1,3-dione 16c/barbituric acid 72a under visible light activation at room temperature by 1.5–1.8 h. In a typical experiment, the reaction was quenched with water resulting in the formation of a solid precipitate, which was filtered and dried to obtain the crude product to subsequent purification by recrystallization in methanol. The work includes the use of 4-hydroxy coumarin and ethyl 2-cyanoacetate as starting materials.

11.8 Photochemical activation

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Figure 11.53: Synthesis of pyran based heterocyclic scaffolds 15 and 4H-chromenes 82a, 82b, and pyrano[2,3-d]pyrimidinone 82c.

In 2019, an efficient light on-off one-pot method for the synthesis of 3-styryl coumarins 83 was described by Kong and co-workers [83]. The method consists in the irradiation of a mixture of aryl alkynoates 84, diethyl bromomalonate 16f, [Ir(ppy) 2(dtbbpy)][PF6] (5 mol%) and cesium acetate (2 equiv), in DMF with 3 W blue LEDs (λmax = 450–465 nm) at room temperature for 14 h. After, the catalyst (cat, 5 mol%), styrene 85 and sodium carbonate were added, and the mixture was stirred at 100 °C for additional 12 h. By this sequential photocatalytic and thermocatalytic processes, twenty-four 3-styryl-4-arylcoumarins 83 could be isolated in 42–82% yield (Figure 11.54). The results about absorption, emission and fluorescence quantum yields properties of the prepared compounds indicated that the substituents at 4-position of 3-styryl coumarins might be disadvantageous to improve the molecular fluorescence quantum yields. Nongthombam and co-workers [84] used aromatic amines 3, barbituric acid 72a, and aryl aldehyde 12 to synthesize biologically important pyrimido[4,5-b]quinolinone2,4-diones 86. The protocol involves irradiation of the mixture with UV365 light in a

Figure 11.54: Scope of the one-pot reaction to prepare 83.

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11 Synthesis of heterocycles under green conditions

Figure 11.55: Synthesis of pyrimido[4,5-b]quinoline-2,4-dione derivatives 86 under UV365 irradiation.

mixture H2O/glycerol (1:1) as solvent at room temperature for 1.0–1.5 h, in the absence of photocatalyst (Figure 11.55). The protocol was general and furnished several pyrimido[4,5-b]quinolinone-2,4-dione derivatives 86 in good to excellent yields (85– 98%), which were isolated by simple filtration, followed by washing with warm Millipore water and drying, without any additional purification. In 2019, Zhang and co-workers [85] described a visible-light-initiated, catalyst-free transformation via a one-pot, three-component reaction of aldehydes or isatins 10, malononitrile 13a, and α-cyano ketones 87 to construct functionalized 2-amino-4Hpyran-3,5-dicarbonitrile derivatives 88. The reactions occurred at room temperature, in 5 h, using ethanol/H2O system as solvent under light irradiation (18 W, wavelength in the range of 390–750 nm). Under these conditions, a variety of aldehydes were effectively employed to give twenty-six 2-amino-4H-pyran-3,5-dicarbonitriles, while isatins 10 afforded twenty-seven spirooxindole 2-amino-4H-pyran-3,5-dicarbonitriles 88 in good to excellent yields (75–94%, Figure 11.56). Still, the products could be isolated by precipitation using water followed by filtration and purification by recrystallization from ethanol. Recently, it was demonstrated by Mohamadpou [86] a catalyst-free, visible lightpromoted Knoevenagel–Michael cyclocondensation for the synthesis of spiroacenaphthylenes 89 and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 90 in aqueous ethyl lactate. The optimal conditions involved the irradiation with CFL (compact fluorescent lamp, 23 W) of a mixture of acenaphthequinone 11a, malononitrile 13a, and

Figure 11.56: Synthesis of spirooxindole 2-amino-4H-pyran-3,5-dicarbonitriles 88 from isatins 10.

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Figure 11.57: Catalyst-free synthesis of spiroacenaphthylenes 89.

1,3-diketones 16 or barbituric acid derivatives 72 under catalyst-free at room temperature. By this procedure, seven different spiroacenaphthylenes 89 were obtained after 4.0–6.5 h in 88–94% yield (Figure 11.57). Before in 2016, the same group reported the solvent-free synthesis of spiroacenaphthylenes 89 using CuOAc.H2O catalysis (15 mol%). By stirring a mixture of the reagents for 4–7 h at 80 °C, six different products 89 were obtained in 78–87% yield [27]. In the same work published in 2021 [86], it was reported the catalyst-free synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 23 from the reaction of phthalhydrazide 31a, benzaldehydes containing either electron-withdrawing or electron-donating groups 12, and malononitrile 13a. The reaction mixture was irradiated with visible light (CFL, 23 W) at room temperature for 2.5–5.0 h, giving eighteen phthalazine derivatives 23 in 83–94% yield, by a column-free work up condition (Figure 11.58). Shaikh and co-workers [87] used [Bu3NH][HSO4] as a catalyst in the one-pot synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 23 (13 examples, 85–94%). In this

Figure 11.58: Catalyst-free synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 23.

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case, aryl aldehydes 12 were reacted with malononitrile 13a and phthalhydrazide 31a in the presence of 20 mol% of [Bu3NH][HSO4], without solvent, at 80 °C for 9–20 min. Moreover, 2H-indazolo[2,1-b]phthalazine-triones could also be obtained in 83–95% yield using dimedone 16a instead malononitrile 13a under the same conditions, after 12–30 min of reaction.

11.9 Sonochemistry in the synthesis of heterocycles In recent years, sonochemistry has been employed more frequently in organic synthesis, and has gained popularity as a versatile tool in a variety of applications [88–91]. Ultrasound-promoted (US) reactions have advantages over the traditional thermal methods in terms of reaction rate, yields, purity of the products, product selectivity, among others [92]. In addition, chemical process under ultrasound irradiation can be considered environmentally benign, being less energy intensive and generating reduced quantities of side products [90–92]. An example in this sense is the work developed by Brahmachari and co-workers [93], which described an US-assisted method for synthesis of functionalized 7-aryl/ heteroarylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones 91 (Figure 11.59). The authors demonstrated a three-component tandem reaction between 4-hydroxy coumarin 92a, substituted aromatic aldehydes 12 and 2-aminopyridines 50 in the presence of sulfamic acid (20 mol%) as an ecofriendly solid acid-catalyst in aqueous ethanol at ambient conditions. The expected products 91 were obtained in good to very good yields of 70–97%, and in short reaction times. The calculated green chemistry metrics, effective mass yield (EMY, 86.73%), atom economy (AE, 91.89%), atom efficiency (AE, 87.98%), and carbon efficiency (CE) (72.0–96.0%) are good indicatives of the greenness of this protocol.

Figure 11.59: Synthesis of diversely substituted 7-aryl/heteroarylchromeno[4,3-d]pyrido[1,2-a] pyrimidin-6(7H)-ones 91.

11.9 Sonochemistry in the synthesis of heterocycles

339

In 2017, Costa and co-workers [94] described the use of sonochemistry in the organocatalytic enamine-azide [3+2] cycloaddition between aryl azidophenyl selenides 93 and 1,3-dicarbonyl compounds 16 in the presence of diethylamine (1 mol%) as organocatalyst (Figure 11.60). This US-promoted reaction was suitable to a range of 1,3-dicarbonyl compounds 16 and aryl azidophenyl selenides 93, providing access to novel selenium-containing 1,2,3-triazole compounds 94 in moderate to excellent yields (56–93%), in a few minutes at room temperature. Additionally, the authors extended this protocol to α-cyano ketones and two examples of selanyltriazoyl carbonitriles were synthesized in 80–97% yield under the established reaction condition. In the same year, a similar method was described by Xavier and co-workers [95]. The authors described the use of US as an alternative energy source in the organocatalytic enamine-azide [3+2] cycloaddition reaction. Using diethylamine as organocatalyst, azidobenzene 62 efficiently reacted with electron-neutral and different electron-deficient β-oxo amides 95 under US irradiation (40% of amplitude) at room temperature for 15 min. A total of eighteen N-aryl-1,2,3-triazoyl carboxamides 96 were prepared in 72–95% yield (Figure 11.61). In 2016, Penteado and co-workers [96] described a method to prepare 2-arylbenzothiazoles 97 and 3-aryl-2H-benzo[b][1,4]benzoxazin-2-ones 98 by the reaction of α-arylglyoxylic acid 39 with 2-aminothiophenol 99 or 2-aminophenol 100,

Figure 11.60: Synthesis of [(arylselanyl)phenyl-1H-1,2,3-triazol-4-yl]ketones 94.

Figure 11.61: Synthesis of N-aryl-1,2,3-triazoyl carboxamides 96.

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11 Synthesis of heterocycles under green conditions

Figure 11.62: Synthesis of 2-arylbenzothiazoles 97 and 3-aryl-2H-benzo[b][1,4]benzoxazin-2-ones 98.

using ammonium niobium oxalate (ANO), NH4[NbO(C2O4)2(H2O)x]·nH2O (10 mol%) as the catalyst and PEG-400 as the solvent. The reactions were performed under conventional heating at 100 °C or under US, leading to 2-arylbenzothiazoles 97 and 3-aryl 2H-benzo[b][1,4]benzoxazin-2-ones 98 in good to excellent yields (Figure 11.62). Plausible reaction mechanisms for the formation of 2-arylbenzothiazoles 97 and 3-aryl-2H-benzo[b][1,4]benzoxazin-2-ones 98 were proposed by the authors (Figures 11.63 and 11.64). The first step involves the condensation of 2-aminothiophenol 99 and α-arylglyoxylic acid 39, which is catalyzed by ANO, leading to the formation of the intermediate zwitterion I. In the next step occurs elimination of water to give the iminium II, followed by an intramolecular attack of SH group to generate the intermediate III. The last step is a decarboxylation and after a N-Csp3 bond oxidation, the product 97 is obtained (Figure 11.63). In parallel, in the synthesis of the 3-phenyl benzoxazine-2-one 98 (Figure 11.64) the first step involves an ANO catalyzed esterification reaction between the 2-aminophenol 100 and α-arylglyoxylic acid 39, following by water elimination, leading to the intermediate II. After that, an ANO-catalyzed cyclization by attack of the remaining NH2 group leads to the cyclic intermediate III, which after water elimination is converted to the product 98.

Figure 11.63: Proposed mechanism for the synthesis of 97.

11.10 Microwave-assisted synthesis of heterocycles

341

Figure 11.64: Proposed mechanism for the synthesis of 98.

Figure 11.65: Synthesis of 1H-dibenzo[b,e][1,4]diazepin-1-one derivatives 101 catalyzed by meglumine.

Nongrum and co-workers [97], demonstrated the catalytic ability of meglumine (Nmethyl-D-glucamine), a nontoxic and biodegradable amino sugar, as organocatalyst in aqueous ethanol for the synthesis of some 1H-dibenzo[b,e][1,4]diazepin-1-ones 101 (Figure 11.65). The three-component reaction of 1,2-phenylenediamine 3a, dimedone 16a and different aldehydes 12, in the presence of 5 mol% of meglumine under US irradiation bath or by stirring at room temperature, afforded the expected products 101 in 82–92% after 20–30 min. It was observed that the ultrasonic irradiation reduced the reaction time from hours to minutes and increased the yield of product 101 from 55–68% to 82–92%. In the sequence of the study, the protocol was extended to the reaction of 1,2-diketone 51 with diamines 3 in the presence of 8 mol% of meglumine, under US irradiation or conventional heating at 50 °C (Figure 11.66). A high regioselectivity to quinoxalines derivatives 52 was observed, which were obtained 80–90% yield after 25–35 min under sonication.

11.10 Microwave-assisted synthesis of heterocycles Microwave-assisted organic synthesis (MAOS) exploits the dielectric volumetric heating as an alternative heat source, which results in faster and more selective reactions

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11 Synthesis of heterocycles under green conditions

Figure 11.66: Synthesis of quinoxaline derivatives 52 catalyzed by meglumine.

due to the uniform heat distribution [98]. Thus, the application of microwave (MW) irradiation in organic synthesis has become more promising in resource-friendly and ecofriendly processes [99]. In particular, the use of MW technology in the chemistry has been reported for the synthesis of heterocyclic compounds that contain nitrogen [98], sulfur and oxygen [100], in carbon–carbon and carbon-heteroatom bond formation via multicomponent reactions [99], in cross-coupling reactions [101], and in the synthesis of covalent organic frameworks [102]. In 2016, Kuraitheerthakumaran and co-workers described the use of MW to prepare 3,4-dihydropyrimidin-2(1H)-ones 102 and their corresponding 2(1H)-thiones 103. By using a microwave oven (320 W) and lanthanum oxide (10 mol%) as a catalyst under solvent-free conditions, they developed a multicomponent Biginelli reaction using aromatic aldehydes 12, ethyl acetoacetate 16d, and urea 38b or thiourea 80a (Figure 11.67) [103]. The authors synthesized 10 examples from urea and 10 from thiourea, in 90–98% yield and within up 60 s. However, although the catalyst is separable by filtration, the study of reuse was not carried out. Aliphatic aldehydes were not evaluated. Naeimi and co-workers reported the use of MW irradiation to promote a multicomponent condensation reaction, as showed in Figure 11.68 [104]. Aryl and heteroaryl aldehydes 12, 2-thiobarbituric acid 54a and ammonium acetate 55a reacted in the presence of CuFe2O4 NPs (10 mol%) as a reusable catalyst in water to afford a series of

Figure 11.67: Synthesis of 3,4-dihydropyrimidinones 102/thiones 103 catalyzed by La2O3 under microwave irradiation.

11.10 Microwave-assisted synthesis of heterocycles

343

pyrido-dipyrimidines 53 in 90–98% yield after 1–2 min. The reuse of the catalyst was evaluated through the reaction between 4-chlorobenzaldehyde 12b, 2-thiobarbituric acid 54a, and ammonium acetate 55a under the optimized conditions. After filtered off, the catalyst was washed with acetone, ethanol, distilled water, and dried in an oven at 70 °C overnight. It could be used in four consecutive runs, without a significant loss in yield and catalytic activity (corresponding product 53a was obtained in 97–98% yield). In 2019, Ma and co-workers [105] reported a one-pot synthesis of tetrahydropyrrolobenzodiazepines 104 and tetrahydro-pyrrolobenzodiazepinones 105 by a sequential 1,3-dipolar cycloaddition/N-alkylation (N-acylation)/Staudinger/aza-Wittig reactions (Figure 11.69). To access the benzodiazepines 104, 2-azidobenzaldehyde 106 was reacted with L-alanine ethyl ester hydrochloride 107 and N-ethylmaleimide 77 in the presence of 1.5 equiv of triethylamine and acetonitrile as a solvent under microwave heating at 125 °C for 30 min. In the sequence, the N-alkylation was promoted by addition of ketone 108 and potassium carbonate (2.0 equiv) at 120 °C under regular heating for 2 h (condition A); and then the Staudinger/aza-Wittig reaction occurred in the presence of Ph3P (1.2 equiv) at 105 °C for 6 h. For the synthesis of benzodiazepinones 105, condition A has been replaced by condition B: benzoic acid 109a was added in

Figure 11.68: Synthesis of pyrido[2,3-d:6,5-d′]dipyrimidine derivatives 53 under microwave irradiation.

Figure 11.69: One-pot synthesis of tetrahydro-pyrrolobenzodiazepines and tetrahydropyrrolobenzodiazepinons 104 e 105.

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11 Synthesis of heterocycles under green conditions

triethylamine (1.0 equiv) at 25 °C by 30 min. By this protocol, sixteen different tetrahydro-pyrrolobenzodiazepines 104 were prepared in 63–88% yield, while the examples of tetrahydro-pyrrolobenzodiazepinones 105 were reported in 62–85% yield. It should be noted that green chemistry metrics analysis (e.g.,: mass productivity, atom efficiency, carbon efficiency, etc.) of the one-pot synthesis were compared with the stepwise reaction process and a better performance for the one-step reaction was demonstrated.

11.11 Electrochemical redox reactions In recent years, electrochemical synthesis has been stood out as a sustainable and environmentally benign tool in synthetic organic chemistry [106]. This is due to generation of highly reactive radical and radical ion intermediates, which is superior to the classical chemical process, in a controlled fashion and under mild conditions [107], what have led to the development of various electrochemical methodologies for the preparation of valuable compounds [108]. In 2019, Guan and co-workers described a tandem electrochemical oxidative cyclization of olefinic carbonyls with diselenides to access a series of selanyl-dihydrofurans 110 and selanyl-oxazolines in the absence of metal catalysts and external oxidants [109]. Selanyl-dihydrofurans were obtained by the reaction between symmetric and unsymmetric olefinic carbonyls 111 with diphenyl diselenide 112a in the presence of tetrabutylammonium tetrafluoroborate, acetic acid or acetonitrile as the solvent, by using a C anode and a Pt cathode. The undivided cell containing the reaction mixture was electrolyzed at a constant current of 10 mA at 0 °C for 2.5 h under N2 atmosphere to give new selenium-containing compounds 110 in 26–93% yield (Figure 11.70). The authors observed some steric hindrance influence on the

Figure 11.70: Scope of electrochemical oxidative cyclization of olefinic carbonyls 111 with diselenides 112a.

11.12 Conclusions

345

Figure 11.71: One-pot synthesis of pyrimidin-2(1H)-ones 102.

transformation, however the reaction is compatible with different functional groups. When a gram scale reaction was carried out, a reaction time of 25 h was necessary to form the desired product in 60% yield. In Figure 11.70 three of the obtained examples are highlighted. In the same year, a solvent-free and oxidant-free electrochemical method was employed to synthetize pyrimidin-2(1H)-ones 102 via a three-component cyclization [110]. Firstly, dicarbonyl compounds 16, aryl aldehydes 12 and urea 38b were initially reacted under 105 °C for 9 h to give the Biginelli product (thermal method). Then, the electrochemical dehydrogenation reaction was carried out at a constant current density of 3 mA/cm2 in C|Pt undivided cell using a mixture of TBAPF6 and ethanol as electrolyte solution, at room temperature for 10 h, without the separation of the Biginelli intermediate. By this electrochemical off–on method, a series of oxidation product 102 were isolated in 12–76% yield (Figure 11.71). The protocol worked well using different dicarbonyl compounds 16 and aryl aldehydes 12, however aliphatic aldehyde, such as N-formylpiperidine, was incompatible with the one-pot reaction conditions, and only a trace amount of the expected product was detected. β-Alkyl diketone bearing CF3 group also led to only traces of the desired product 102.

11.12 Conclusions Considering the diversity of reactions presented in this review, it is possible to point out that there is a considerable number of research groups interested in the development of new and alternative protocols to the synthesis of heterocycles from dicarbonyl compounds under greener conditions. Catalyst- and solvent-free procedures, the use of green solvents and green catalysts, alternative energy sources, such as ultrasound and microwave irradiation, and the recent use of photochemistry and electrochemistry, are among the new approaches recently developed. All these results show that green protocols and technologies remain in constant development and point to a gradual and uninterrupted change of practices in academia and industry to access molecules with great synthetic and pharmacological potential with less environmental cost.

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Jayathirtha Rao Vaidya* and Yadavalli Venkata Durga Nageswar

12 Polyaniline mediated heterogeneous catalysis in the preparation of heterocyclic derivatives through carbon–heteroatom bond formations Abstract: Green-bond forming reactions in organic chemistry are very much essential for the sustainability and it is a continuous evolutionary process. Polyaniline (PANI) is one of the catalysts can offer a green-bond forming chemistry. The present chapter is designed to explain PANI mediated reactions leading to the synthesis of heterocycles. PANI and PANI-doped catalyst preparation methods and together with characterization of PANI catalyst using modern analytical tools is explained. Several heterocycles were prepared using PANI or doped-PANI catalyst in a one pot reaction conditions or sometimes multicomponent reaction conditions. Ease of PANI preparation, simple reaction conditions, PANI recovery and reusability and quick-way of product isolation or workup procedure are the highlights of this chapter. Keywords: functionalisation of heterocycles; heterocycles via PANI; multicomponent reactions; PANI and doped PANI catalysts; recovery and reusability.

12.1 Introduction Conducting polymers, composed of monomer units with conjugated chemical bonds are organic polymers capable of conducting electricity. These polymers are useful in the production of materials for various applications such as organic solar cells, printed electronic circuits, super capacitors, chemical sensors, biosensors, and organic light emitting diodes. Polyaniline a promising member of conducting polymers, was first reported by Light Foot during the studies on the oxidation of aniline. It has got good environmental stability and can be made by simple methods. The variation of colours associated with polyaniline at different oxidation states is useful in the making of sensors and electronic devices. It is formed in three oxidation states – leucoemeraldine, emeraldine, and pernigraniline. It has emerged as the intensely researched and well studied arena in the last few decades. Aniline can be polymerized to make polyaniline either by electrochemical or chemical methods. Aniline can be converted to polyaniline employing aqueous solutions containing

*Corresponding author: Jayathirtha Rao Vaidya, Fluoro Agro Chemicals Department and AcSIRGhaziabad, CSIR-Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad-500007, Telangana, India, E-mail: [email protected]. https://orcid.org/0000-0002-6173-3617 Yadavalli Venkata Durga Nageswar, CSIR-Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad-500007, Telangana, India As per De Gruyter’s policy this article has previously been published in the journal Physical Sciences Reviews. Please cite as: J. R. Vaidya and Y. V. Durga Nageswar “Polyaniline mediated heterogeneous catalysis in the preparation of heterocyclic derivatives through carbon–heteroatom bond formations” Physical Sciences Reviews [Online] 2022. DOI: 10.1515/psr-20220040 | https://doi.org/10.1515/9783110759549-012

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electrolytes [1] where polymerization occurs on an electrode prepared from an inert conducting material. Electro-chemically made composite materials based on PANI can be used in rechargeable batteries [1–3] and organic field effect transistors [4, 5]. However, advantageously aniline can be polymerised easily by chemical methods in the presence of different oxidants in excellent yields providing conducting polymers having varied supra molecular structures and physicochemical properties. Oxidants like K2Cr2O7, FeCl3, CuCl2, KMnO4, Fe+3/H2O2, Cu2+/O2, ammonium per-sulphate, urea/H2O2, and chloroauric acid are some of the examples employed for aniline polymerisation. Templates are broadly divided into two categories: (i) soft templates (surfactants, surfactant micelles or polymers) and (ii) hard templates (graphite, carbon nano tubes and inorganic materials like oxides). In addition to employing macromolecular entities such as poly acids polyelectrolytes and polymers [6–8] are being increasingly used as polymeric templates. PANI’s adopt different morphologies and properties depending on the types of dopants as well as polymers. PANI and PANI-doped catalysts have been used for making various heterocyclic compounds. The following narrations illustrate the preparation and utility of PANI and PANI-doped catalysts in making heterocyclics and their functionalized compounds.

12.2 Applications of polyaniline mediated heterogeneous catalysis for the synthesis of various heterocyclic derivatives 12.2.1 Synthesis of dihydropyrimidinones PANI-bismoclite catalyst was prepared by Gangadasu et al. [9] and it`s application was tested in synthesizing dihydropyrimidinones (4) by following Biginelli reaction. PANI was prepared in a standard way of oxidative polymerization of aniline using persulfate. The prepared PANI was treated with NaOH to get PANI-base. The PANI-base was mixed with BiCl3 to make PANI-bismoclite complex catalyst (PANI-BiOCl). A three-component reaction, involving aldehydes (1), ethyl acetoacetate (2), and urea (3) or thiourea (3a), using PANI-BiOCl catalyst was carried out to generate dihydropyrimidinones (4) (Figure 12.1) in very good yields. Fourteen examples are cited, by varying the aldehyde (1)

Figure 12.1: PANI-BiOCl catalyzed synthesis of dihydropyrimidinones in ethanol.

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component. The developed protocol has many advantages like simple, high yielding, ease of product isolation etc. The PANI-BiOCl catalyst was recovered and recycled. There was another report on the synthesis of dihydropyrimidinones (4), using PANI [5].

12.2.2 Synthesis of 7-membered diazepines and 5-membered benzimidazoles Srinivas et al. [10] reported the preparation of PANI sulphate catalyst and its use in making benzodiazepines (7) and benzimidazoles (9). Sodium lauryl sulphate aqueous solution, benzoyl peroxide in acetone was taken together and was mixed with aniline in aqueous sulphuric acid in a controlled way by maintaining the reaction temperature. This gave over 82% yield of PANI-sulphate as precipitate, which was washed, dried, and characterized. Utilizing this synthesized material as catalyst they prepared a series of benzodiazepines (7) as well as benzimidazole (9) in excellent yields. o-Phenylenediamine (5) reacts with two equivalents of α-hydrogen containing acyclic (6) or cyclic (7) ketones to form benzodiazepines (8) involving C–N bond and C–C bond formation catalyzed by PANI-sulfate, whereas o-phenylenediamine (5) reacts with aldehydes (1) to provide benzimidazole (9) by forming C–N bonds (Figure 12.2). o-Phenylenediamine and the ketone taken in dichloroethane was heated in the presence of PANI-sulphate as a catalyst to make benzodiazepines (8) (Figure 12.2) in very good yields. The ketone was replaced with aldehyde (1) to synthesize benzimidazoles

Figure 12.2: PANI-sulphate catalyzed synthesis of diazepines and benzimidazoles.

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(9) (Figure 12.2). The second molecule of ketone enters the reaction pathway to form benzodiazepines. The catalyst was recovered and recycled to conduct reactions. Abdollahi-Alibeik and Moosavifard [11] reported Fe3+ doped PANI nanoparticles catalyzed the synthesis of benzimidazoles (9). PANI and PANI-Fe3+ doped catalysts were prepared by adopting the reported procedure [12]. The prepared catalyst was characterized by several techniques, particularly SEM, XRD and FT-IR to understand the morphology of the solid catalyst and the content of Fe3+. Catalyst loaded with 19% of Fe3+ was selected because it performs better organic transformations. Aldehyde (1) and o-phenylenediamine (5) were taken in alcohol and treated with PANI-Fe3+ Nano catalyst with stirring. After completion of the reaction, ammonia was added, the solid product was filtered, and the remaining worked up to get benzimidazole in excellent yields (Figure 12.3). The precipitate obtained was washed with copious amounts of water and recycled 5 times without much change in reactivity. Several aldehydes were selected to react with o-phenylenediamine for the synthesis of benzimidazoles and a total of 16 examples registered.

12.2.3 Synthesis of spiro compounds and procedure for making PANI nanorods PANI-Fe3O4-CNT was prepared [13–15] accordingly. Carbon nanotubes (CNT) were oxidized by nitric acid, sonicated, stirred, filtered, and dried to get oxidized CNT. Ethyl acetoacetate (2), hydrazines (10), malononitrile (11)/ethyl 2-cyanoacetate (12) and isatin (13) or acenaphthylene-1,2-dione (14) starting materials with PANI-Ferroso-ferricoxide-CNT composite catalyst, is a four-component reaction entwined with complexity leading to spiro-indoline derivatives (15 and 16) (Figure 12.4), involving several C–N, C–O and C–C bond formations. Ferrous chloride, ferric chloride and ammonia were treated together in deionized water and the precipitate was isolated by applying an external magnet to make iron magnetic nanoparticles. PANI-Fe3O4-CNT nanocomposite was prepared by polymerizing the aniline in the presence of oxidized carbon nano tubes and iron nanomagnetic particles, with the help of persulfate. The prepared composite catalyst PANI-Fe3O4-CNT was characterized using various techniques, including TEM and XRD. The obtained composite catalyst PANI-Fe3O4-CNT was applied for the synthesis of heterocycles by

Figure 12.3: Synthesis of benzimidazoles.

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Figure 12.4: Synthesis of spiroindoline derivatives.

Hojati et al. [16]. Four component chemical transformations were conducted to synthesize spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives (15 and 16) (Figure 12.4). Primarily the authors worked on establishing right experimental conditions and then reported the synthesis of heterocycles spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives with several examples. The mechanism involving the four components is also proposed by the authors. PANI-Fe3O4-CNT composite catalyst was found to be effective for over 5 times reuse/recycling. Further, the authors applied the method using acenaphthylene dione system and synthesized the corresponding spiro[acenaphthylene-1,4′-pyrano[2,3-c]pyrazole] derivatives in excellent yields. The method was compared with the other reported procedures and noted the advantages.

12.2.4 Synthesis of PANI nanorods A typical procedure for making PANI-nanorods is given below. Polyanilinedinitrosalicylic acid-nanorods (PANI-DNSA-NR) were synthesized [17] by following a modified procedure reported by Janošević et al. [18]. Aniline and dinitro salicylic acid were taken in water and treated with ammonium persulfate to get PANI-DNSA-NR. These nano structures were characterized by spectroscopic tools particularly TEM, XRD, and Raman spectrum. The authors further conducted carbonization of PANI-DNSA-NR at ∼800 °C to get a product showing better conducting properties. Composite PANI-DNSA-NR catalyst can be used for organic transformations.

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12.2.5 Synthesis of pyran derivatives A three-component reaction involving aldehyde (1), malononitrile (11), and dimedone (17) with PANI-SiO2 as the catalyst afforded substituted fused pyran derivatives (18) (Figure 12.5). It is interesting to note that here two active methylene groups react with an aldehyde to form the corresponding fused pyran compounds. Yelwade et al. [19] reported polyaniline/SiO2 (PANI/SiO2) composite catalyst preparation using a typical procedure. Aniline in water with sulphuric acid was taken and then treated successively with ammonium persulfate and solid porous silica, the obtained precipitate was washed and dried to get the composite catalyst PANI/SiO2. The catalyst was characterized by using various spectral means. The solid porous silica was prepared by adopting sol–gel process. Tetraethyl-ortho-silicate was dissolved in aqueous ammonia; the resulted precipitate was collected by centrifugation, dried and finally calcined at ∼500 °C to obtain solid porous silica material. The stability of the prepared PANI/SiO2 composite catalyst was tested in different organic solvents and was found to be stable. Yelwade et al. [19] utilized PANI/SiO2 composite as a catalyst for synthesizing heterocycles. A threecomponent reaction involving aldehyde (1), malononitrile (11), and dimedone (17), using composite catalyst PANI/SiO2 was performed to synthesize tetrahydro-benzo[b]pyran derivatives (18) (Figure 12.5). The reaction conditions were standardized by varying the several reaction parameters, conducting several runs and to arrive at best reaction conditions leading to higher yields of tetrahydro-benzo[b]pyran derivatives (18). Effect of PANI/SiO2 composite catalyst weight percentage and the amount of catalyst variation on the tricomponent heterocycle synthesis was studied. A 10% weight composite catalyst is effective in making the reaction operative at room temperature with excellent yields. Eight examples of tetrahydro-benzo[b]pyran derivatives (18) are reported with over 90% yields.

12.2.6 Triazole derivatives A three-component reaction with benzyl bromide (19) or phenacyl bromide (23), sodium azide (20), and acetylene derivative (21), where benzyl azide or phenacyl azide were prepared in situ and these were allowed to react with phenylacetylene to form triazoles (22) and (24), in a click reaction fashion catalyzed by PANI@CuI-NP.

Figure 12.5: Synthesis of substituted fused pyran derivatives.

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Figure 12.6: Synthesis of triazoles via click reaction.

Synthesis of nano size of CuI incorporated polyaniline composite catalyst (PANI@CuI-NPs) is reported by Sadat et al. [20]. Polyaniline was prepared by adopting a standard route [21] and the same was used to make PANI@CuI-NPs. PANI was taken in ethanol with CuI and was refluxed for 12 h. The PANI@CuI-NPs catalyst was filtered off, washed, and dried. The SEM picture of PANI@CuI-NPs composite catalyst indicated that the CuI was homogeneously distributed on the surface. PANI@CuI-NPs composite catalyst was used to synthesize various triazole derivatives. The 1,3-dipolar Huisgen reaction using azide, benzyl bromide/α-bromoketone, and acetylene provides 1,2,3-triazole moiety (22) and (24) (Figure 12.6). Reaction conditions were explored to define the best optimal experimental conditions. There are 12 examples cited for the synthesis of 1,2,3-triazole derivatives (22) and (24). The chemistry reported is a threecomponent one pot reaction conducted in water as the reaction medium. The recyclability and reusability of PANI@CuI-NP composite catalyst is found to be good. Authors proposed a possible mechanism for the formation of 1,2,3-triazole [20].

12.2.7 Quinoxalines 1,2-Dione and 1,2-diamine condensation catalyzed by PANI-sulfate gave quinoxalines (28) (Figure 12.7). Another independent study involved the use of 1,2-dione and

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Figure 12.7: PANI-sulfate catalyzed synthesis of quinoxalines.

Figure 12.8: PANI-SiO2 catalyzed synthesis of quinoxalines.

1,2-diamine but the catalyst was PANI-SiO2 leading to several quinoxaline derivatives (30) in a quick fashion (Figure 12.8). Srinivas et al. [22] reported the preparation of PANI-sulfate and its utility to make efficiently quinoxaline derivatives. Aniline was taken in water containing sulfuric acid and to this was added the required amount of sodium persulfate. The precipitated PANI was filtered, washed with copious amounts of water, and characterized by routine techniques. The prepared PANI-sulfate was used as catalyst for making quinoxaline derivatives (Figure 12.7). Diamine (5) and di-carbonyl (25) compounds were taken in water and added 5% wt of PANI-Sulfate to affect the reaction leading various quinoxalines (Figure 12.7). In some runs, diamine, di-carbonyl compounds were treated in the presence of PANI-Sulfate together with sodium lauryl sulfate. In some examples lauryl sulfate helped to improve the yields. The reaction temperature was ambient except in two cases it was refluxing condition and the time of reaction was also convenient. Yields are found to be excellent with easy and simple isolation procedure. There are 16 examples (Figure 12.7) cited by authors. The PANI-SiO2 catalyst was prepared by mixing porous silica and PANI and isolating it by filtration followed by washings. Porous silica was prepared using sol–gel process. The PANI-SiO2 catalyst was characterized using various techniques like, SEM, TEM, TG-DTA, XRD, FT-IR, and EDS. Ajeet et al. [23] reported the synthesis of quinoxalines (26) in excellent yields from the reactions of 1,2-diketones (25) and 1,2-diamines (5) using PANI-SiO2 as catalyst in ethanol at room temperature (Figure 12.8). There are 8 examples (Figure 12.8) presented by varying diamine and diketone structures.

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12.2.8 Tetrahydroquinolines Substituted aniline (27) reacts with two equivalents of N-vinylpyrrolidone (28) and Nvinyl caprolactam (29) in the presence of PANI-I2 used as catalyst to form the corresponding tetrahydroquinolines (27) and (30). This is an interesting reaction in terms of mechanism of formation of tetrahydroquinolines. Although the authors did not elaborate further on the mechanism. Rajender and Palaniappan [24] reported iodine doped PANI and used the same catalyst in making stereoselective tetrahydroquinoline (29 and 31) derivatives. PANI was prepared as per the earlier established procedure [25] and further used for making PANI-I2 by mixing it with iodine in acetonitrile solvent with stirring at room temperature. The precipitate was filtered, washed with acetonitrile until it is colorless, and dried. The catalyst PANI-I2 was characterized using techniques like SEM, FT-IR, XRD and EDAX. Aromatic amine, N-vinyl lactam and PANI-I2 were stirred without any solvent. The product was isolated/separated when the reaction mixture was extracted with ethyl acetate and the residue PANI-I2 catalyst was washed, dried, and recycled. Ethyl acetate layer gave the required product tetrahydroquinoline derivative with diastereo selectivity (Figure 12.9). N-Vinylpyrrolidone and N-vinyl caprolactam substrates employed along with aromatic amine to make corresponding sixteen tetrahydroquinoline derivatives (29 and 31) (Figure 12.9). PANI-I2 catalyst can be recycled by doping with iodine again with the isolated PANI from the reaction mixture.

12.2.9 Carbon–nitrogen coupling Coupling of aryl halides (32) with imidazole (33) to form C–N bond is facilitated by PANI-Cu+ catalyst in the presence of a base like cesium carbonate leading to N-arylated

Figure 12.9: Synthesis of tetrahydro quinoline derivatives.

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12 PANI mediated carbon-heteroatom bond formations

Figure 12.10: Synthesis of N-arylated heterocycles.

imidazoles (34) (Figure 12.10). Under the same optimized conditions other primary or secondary amines like benzimidazole, pyrazole, benzylamine, 4-Me-benzylamine, 4-OMe-benzylamine, and dibenzylamine underwent the reaction smoothly and afforded the corresponding desired products in excellent yields. Preparation of Cu(I) doped PANI catalyst was carried out by Lakshmikantam et al. [26], further its use in conducting organic transformations was also highlighted. PANI was prepared according to the earlier published procedure [27] and was used for making Cu+ doped PANI catalyst. PANI and CuI were mixed in acetonitrile under nitrogen and stirred for 48 h. The solid was filtered, washed with acetonitrile and acetone, and dried to get PANI-Cu+ catalyst. The authors predicted the structure of catalyst as a co-ordination complex between PANI nitrogen atoms and Cu+ ion. The synthesized catalyst was characterized by using several techniques like FTIR, XPS, ICP-AES, SEM, and EDAX. Later it was, during 2015 [20], shown that PANI-Cu+ catalyst is of nano size nature. PANI-Cu+ catalyst was employed in effecting N-Arylation reactions. Best reaction conditions were tuned and established to conduct smooth and high yielding N-arylations (Figure 12.10). It was observed that, by lowering the amount of catalyst, yields were reduced. N-Arylation is effective with iodoarenes and bromoarenes. The PANI-Cu+ catalyst activity was compared with other catalysts to find its superiority. The authors cited 18 examples for N-arylation method development. Iodoarene was replaced with aryl boronic acid for N-arylations to improve the method. Reaction time, mild conditions and higher yields are realized for N-Arylations using aryl boronic acids, but the use of aryl boronic acid is restricted because of their expensive nature.

12.2.10 Substituted indoles Devi et al. [28] used PANI-HBF4 catalyst for conducting multi-component one pot reaction leading to 3-substituted amino methyl indoles. Substituted indoles (35), substituted benzaldehydes (1) and N-methylaniline (36) together to form substituted amino methyl indoles (37) via one pot three component reactions catalyzed by PANI-BF4. The product formed between substituted benzaldehyde and N-methylaniline are getting linked at 3-postion of indole moiety (Figure 12.11).

12.2 Applications of polyaniline mediated heterogeneous catalysis

363

Figure 12.11: Synthesis of amino methyl indoles.

The catalyst PANI-HBF4 was prepared by emulsion polymerization pathway as given in earlier procedure by Palaniappan and John [29]. Multicomponent one pot reaction involved components like substituted indole, substituted benzaldehyde/ pyridine aldehyde and N-methylaniline (Figure 12.11) leading to 13 examples. The three component reaction catalyzed by PANI-HBF4, provided 3-substituted amino methyl indoles (37), in very good yields under solvent free conditions. Optimized reaction conditions were developed first, and then other examples were conducted. After the reaction the catalyst was filtered, washed dried and reused for 5 times, without much change in reactivity.

12.2.11 Formylations Palladium – Auricum – PANI – CNT, a bimetallic composite catalyst designed and used for preferably N-formylations of secondary amines (41). Primary amines were sluggish to provide N-formylations. Inter metallic interactions and nano size carbon of the catalyst favors towards formylations (Figure 12.12). Ju et al. [30] reported a bimetallic composite PANI catalyst Pd–Au/PANI-CNTs (carbon nano tubes) preparation. Marx and Baiker [31] also reported the preparation of Pd–Au/PANI-CNTs for the purpose of oxidation of various benzyl alcohols. The synthesis of Pd−Au/PANI-CNT was achieved by taking HAuCl4, H2PdCl4 in polyvinyl alcohol at 0 °C for 30 min, then adding an aqueous solution of NaBH4 to get the colored solution and then adding PANI-CNT. The insoluble portion of Au–Pd/PANI-CNT was filtered, dried, reactivated at 200 °C in H2 atmosphere and characterized using XRD,

Figure 12.12: N-formylations of amines.

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12 PANI mediated carbon-heteroatom bond formations

TEM, XPS, HADDF-STEM and other techniques also. N-Formylation chemistry was conducted using the prepared catalyst, Pd–Au/PANI-CNT. A small autoclave taken with catalyst Pd–Au/PANI-CNT, 1,4-dioxane solvent, amine substrate (38), gases like CO2 (39) and H2 (40) were maintained at their optimum pressure in the autoclave to get the reaction going at 125 °C for 48 h (Figure 12.12). Pyrrolidine was used to define and optimize the reaction conditions for formylation (Figure 12.12). Various substrates like, primary amines, secondary amines, aliphatic amines, cyclic secondary amine, aniline, and benzylamine were selected for N-formylation. The authors mention that bimetallic nano composite catalyst exhibited very efficient stabilization effect of the support, which is reflected in exemplary performance in N-formylations of amines selected. It was indicated that Pd-sites are acting as hydrogenation reaction sites and Pd–Au sites can be together for N-formylation. The improved catalytic activity of Pd–Au/PANI-CNT bimetallic catalyst was primarily due to improved inter-metallic beneficial interactions at nano size, and this led to changed electronic properties of alloyed bimetallic catalyst.

12.2.12 Indolo-chromenes, bisindoles and chromenes Nanosheets of PANI-Graphitic Carbon Nitride (N-PANI-GCN) were designed and synthesized to conduct multi component one pot reactions leading to indolo-chromenes (44), bisindoles (45), and chromenes (46) (Figure 12.13). Active 3-position of indole is

Figure 12.13: Synthesis of substituted indolo-chromenes, bisindoles and chromenes.

12.2 Applications of polyaniline mediated heterogeneous catalysis

365

evident in forming C–C bond formation in indolo-chromenes and bisindoles. Chromenes were the products when the participation of indole in the reaction was eliminated. Control experiments conducted by changing the mole ratios and changing starting material provided different products 44, 45, and 46. Polyaniline-graphitic carbon nitride nano composite (PGCN) catalyst was introduced by Bahuguna et al. [32] for making indole substituted chromenes. The authors adopted a well-known method for making graphitic carbon nitride [33, 34]. Dicyandiamide was incinerated at appropriate temperature to get yellow colored GCN. Persulfate mediated oxidative polymerization of aniline was conducted in the presence of graphitic carbon nitride to get PANI-GCN. Similarly, by changing the GCN ratio, other combinations like PANI:2GCN and PANI:4GCN catalysts were prepared. Thus, prepared PANI-GCN was allowed to react with ammonia to obtain nano composite N-PANI-GCN. The catalyst was characterized involving SEM, FT-IR, TEM, XRD, XPS and other techniques. N-PANI-GCN was used for the synthesis of indole substituted chromenes. Over seventeen reaction runs were conducted to explore the right reaction conditions to indole substituted chromenes. The multi-component reaction was conducted using salicylaldehyde, malononitrile, and indole in water medium with the help of N-PANIGCN catalyst, to get indolo-chromenes (44) (Figure 12.13) and twenty examples were cited. Yields recorded were as high as 94%. The product of the reaction using salicylaldehyde, malononitrile, and indole, using PANI-GCN was found to be bisindole derivative (45) (Figure 12.13), and six examples reported. The reaction was conducted using salicylaldehyde and malano nitrile, without indole to give chromene derivative (46) (Figure 12.13) with 9 examples. N-PANI-GCN catalyst was found to be effective providing product yields of ∼85%, even after five recycles. The reported reaction conditions, solvent used, and yields observed show that it falls under the category of green methodology.

12.2.13 Chromene derivatives Cu2+ complex of PANI-Schiff Base was utilized to conduct a three component one pot reaction with aldehyde (47 or 50 or 52), ethyl cyanoacetate (11a), and 4-hydroxycoumarin (48) or 1,3-dihydroxybenzene (54) leading to fused chromenes. Active-methylene group reacts with aldehyde functionality, then the hydroxyl group of coumarin enters reaction domain to complete the formation of fused chromenes (49, 51, 53) (Figure 12.14) and benzochromene derivatives (55) (Figure 12.15). Siddiqui and Siddiqui [35] prepared a polyaniline Schiff base complexed with Cu2+ ion catalyst for synthesizing heterocycles. The polymer based organometallic catalyst was synthesized in a stepwise manner. 1,2-Diaminobenzene was treated with salicylaldehyde to make the corresponding Schiff base. The prepared Schiff base was mixed with copper acetate to get Schiff base-Cu++ complex. PANI was prepared as reported earlier [36] by oxidative polymerization of aniline using persulfate. Further PANI and Schiff base-Cu++ complex was mixed at room temperature to get black solid, which was

366

12 PANI mediated carbon-heteroatom bond formations

Figure 12.14: Synthesis of fused chromene derivatives.

Figure 12.15: Synthesis of benzochromene derivatives.

filtered, washed, dried, and characterized. The catalyst Cu-SB/PANI was characterized using various spectral techniques like FTIR, SEM/EDX, elemental mapping, XRD, TEM, TG, XPS, EPR and ICP-AES. Authors reported a three-component reaction leading

12.3 Addition of nitrogen to open chain compounds

367

to chromene derivative. Aldehyde (47 or 50 or 52), ethyl cyanoacetate (11a), 4hydroxycoumarin (48)/1,3-dihydroxybenzene (54) and polymer based organometallic catalyst Cu-SB/PANI were mixed under solvent free conditions to synthesize fused chromene derivatives (49, 51 and 53) (Figure 12.14). Experimental conditions were initially probed and defined well to achieve excellent yields of final products. Polymer based organometallic catalyst Cu-SB/PANI was compared with various catalysts to prove that it has higher efficiency than all other catalysts for this particular reaction. Catalyst Cu-SB/PANI was recovered after reaction and reused six times to evaluate the recyclable efficiency of more than 90%. The authors claim that a polymer based organometallic, Cu-SB/PANI, efficient catalyst was synthesized and applied for the synthesis of chromene derivatives.

12.3 Addition of nitrogen to open chain compounds 12.3.1 Synthesis of β-aminocarbonyl compounds β-Aminocarbonyl derivatives (57) were synthesized in two different ways. First it was aldol condensation between aldehyde (1) and ketone (56) leading to α,β-unsaturated carbonyl compound, which enters into reaction with the available amines (27) (Figure 12.16) present in the multi component reaction mixture. The catalyst utilized was the PANI-Salt. We [36] reported various polyaniline salts and their utility in conducting Mannich type reactions. PANI was prepared as per the reported procedure [36], like oxidative polymerization using persulfate in acidic medium. Various counter ions exchanged PANIs were generated in acetone medium using the corresponding cations, HCl, H2SO4, HClO4, HBF4, C7H6O6S (SSA), C7H8SO3 (PTSA), ZnI2, and FeCl3. PANI was characterized using techniques like, resistance measurement, pellet density, FT-IR, and X-ray diffraction. The three-component reaction involving substituted anilines (27), aldehyde (1) and ketone (56), led to β-aminocarbonyl derivatives (57) (Figure 12.16).

Figure 12.16: β-Aminocarbonyl compounds – aldol condensation followed by amine addition.

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12 PANI mediated carbon-heteroatom bond formations

Figure 12.17: Direct amine addition to α,β-unsaturated system.

To define best experimental conditions, several reactions were conducted by varying solvent, temperature, catalyst and catalyst concentration. Further the recovery and reusability of the catalyst was also tested. The ease of preparation of catalyst, easy handling, and stability of catalyst, recyclability, reusability and eco-friendly nature are the important conclusions.

12.3.2 Synthesis of β-aminocarbonyl compounds by direct addition Another report was provided by Lakshmikantam et al. [26], wherein the synthesis of β-amino carbonyl derivatives (59) was achieved via C–N Bond formation, by reacting amines (38) with activated α,β-unsaturated systems (58) using PANI-Cu+ catalyst (Figure 12.17). Heterocycles like imidazole and benzimidazole, amines like benzyl amine, piperidine, morpholine and di-N-butylamine were employed and α,β-unsaturated systems like methyl-acrylate, ethyl-acrylate, t-butyl-acrylate, methyl vinylketone and acrylonitrile were employed. Reactions were smooth with less reaction time, high yields and a small amount of bis-adduct observed. PANI-Cu+ catalyst recycled 5 times without much change in activity.

12.4 Conclusions Recent years of published work dealing with PANI mediated heterocycle synthesis is brought in this chapter. Various types of PANI discussed as heterogeneous catalysts. Various methods for the preparations of PANI have also discussed. Particularly PANI doped catalysts were found to be more effective. Various types of heterocycles were synthesized mediated by PANI as catalyst. Multicomponent reactions leading to heterocycles via PANI were also discussed. Yields of the products, ease of isolation of products, simple reaction conditions, recovery and recycle of PANI catalyst make these methods for the possible up-scaling processes. The narration of this chapter will help the reader/researcher to grasp the importance of PANI catalyst in conducting multi component organic transformations. Particularly the brief experimental methods given

References

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in this chapter help the reader/researcher to adopt procedure for making heterocycles of choice. We predict that there may be industrial applications using these PANI catalysts. Acknowledgment: VJR thank CSIR-New Delhi for the Emeritus Scientist Honor.

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Index 1-azido-2-isocyanoarenes 152 1H-benzo[6,7]-chromeno[2,3-d]pyrimidine 330 1H-dibenzo[b,e][1,4]diazepin-1-one 341 1H-pyrazolo[1,2-b]phthalazine-5,10-dione 310, 314, 323, 337 1-(2-amino phenyl)pyrrole 138 1,2-diamines 109 1,2-diamino anthraquinone 150 1,2-dichloro ethane 150 1,2-diketones 109 1,2-propanediol 165 [1,2,3]triazolo[1,5-a]quinoxaline scaffolds 152 1,2,4-triazino[4,3-a]quinoxaline derivatives 152 1,2,5,6-tetrahydropyridine-3-carboxylate 317 1,3-dicarbonyl 327 1,3-diketone 288 1,3-dipolar cycloaddition reaction 62 2-amino-3-cyano-4H-pyrane 317 2-amino-4H-pyran-3,5-dicarbonitrile 336 2-aminopyridine 214 2-aminothiophenol 139 2-arylbenzothiazole 339 2-deoxyribose sugar 78 2H-indazolo[2,1-b]phthalazine-trione 338 2-hydroxy-6-chloro quinoxalines 153 2-pyridine methanol 143 2-thiobarburic acid 322 2(1H-pyrrol-1-yl) aniline 156 2-(2-formylphenoxy) acetic acid 163 2,3-butane diones 119 2,3-diamino pyridine 123 2,3-dichloroquinoxaline 144 2,3-dihydrofuran 332 2,3-dihydrophthalazine-1,4-dione 323 2,3-disubstituted isoindolin-1-one 319 3-chloropropyltrimethoxysilane (CPTMS) 212 3-phenyl benzoxazine-2-one 340 3-styryl coumarin 335 [3 + 2] cyclo-addition 150 3,4-dihydropyrimidin-2(1H)-one 342 3,5-dinitro benzoic acid 159 4-amino thiophenol 110 4H-chromene 334 5′-aminohexyl group. 73 5′-azido-5′-deoxythymidine 95 5-hydroxy-chromeno[2,3-b]pyridine 312 5′-hydroxyl group 74 https://doi.org/10.1515/9783110759549-013

5-methylcytosine 90 5-substitiuted-1H-tetrazoles 202 6-membered scaffolds 49 15-crown-ether 86 16-(aryl)benzo[a]indeno[2′,1′:5,6]pyrano[2,3c] phenazin-15(16H)-one 325 α/β-anomers 78 β-amino carbonyl derivatives (59) 368 β-aminocarbonyl derivatives (57) 367, 368 β-azidoglycoside 79 β-d-ribofuranose 75 β-nitrostyrene 134 β-zeolites 145 AAS (atomic absorption spectroscopy) 202 abemaciclib 205 acetophenones 131 AChE inhibitory activity 134 acid catalysts 260 acidic catalysts 259 acridone core 51 activated charcoal 293 aerobic 7, 12, 15 against HIV 93 aggregation 198 alcohols 287 alcoholysis 268 aldehyde 287 aldol condensation 44, 49 algae 270 alkaline catalysts 260 alkenes 35, 36 allylation 49, 175, 177, 181, 183 allylic 178, 179, 182 alternative energy 345 alternative energy source 328 alternative protocol 345 amberlite 900 118 amberlite IR-120H 137 amination 179, 304 amino guanidine nitrate 209 amino methyl indoles (37) 362 ammonium bifluoride 115 ammoniumfluoride 85 ammonium thiocyanate 123 amorphous 283 Anderson–Schulz–Flory 264 anhydronucleoside 91

374

Index

anilines 290 annealed 198 annulation 329 anodic coupling reaction 50 antagonist 41 anti– anti-bacterial 76 – anticancer 98 – anti-fungal 76 – anti-HBV 81 – anti-HBV activity 81 – anti-HCV 73 – anti-HIV 65 – anti-influenza 73 – antiproliferative property 98 – anti-tubercular 84 – antitumor 52 – antitumor agents 205 – antiviral 69, 75 – antiviral activity 71 aqueous 2, 3, 5, 7, 9–15 aqueous media 328 aryl sulfides 211 arylphosphonates 216 asymmetric 44, 49, 55 atom economy 321, 322 Au NPs 110 Au–Pd/PANI-CNT 363 auxiliaries 49, 50 aza-michael addition 291 azidation 85 azide 326 azide–alkyne 70 azide–alkyne cycloaddition reactions 99 azides and alkynes 62 azido alkynes 135 azido compounds 134 azido nucleoside 93 azido sugar 72, 77, 80 azidobenzene 339 azidothymidine 87 aziridine 53 azomethine ylides 134, 156 AZT 88 α-amino acids 112 α-bromination 158 α-bromo ketones 158 α-carbonyl sulfoxonium ylides 153 α-halo-β-keto esters 108

α-halo-β-ketones 108 α-hydroxy ketones 110 α-iodoacetophenone 132 α-keto esters 114 α-mercapto carboxylic acids 145 BAHC 129 ball-milling 45 barbituric acid 290, 335 basic alumina 129 benzils 121 benzimidazoles 112, 355 benzo [4,5]-imidazo[1,2-c]quinazolines 156 benzo[a]phenazine 315 benzo[a]pyrano[2,3-c]phenazine 319 benzochromene derivatives (55) 365 benzodiazepine 343 benzodiazepines:benzodiazepines 355 benzo[d]imidazo[2,1-b]thiazole 331 benzoin 121 benzothienoquinoxalines 166 benzoxazoles 112 benzyl alcohol 295 biaryls 45, 50 biginelli 345 biguanide 295 bimetallic mixed ferrite (NiFe) 212 bio– bioactive 307 – biocatalyst 313, 316 – biocatalysts 268 – biocompatibility 192 – bio-conjugation process 62 – biodegradable 6, 8, 105, 111, 268, 310 – biodiesel 258 – biodiesel applications 269 – bioethanol 266 – biofuel 257, 272 – biofuel crops 265 – biogas 263 – biogenic 194 – biological catalysts 265 – biologically 335 – biomass-based 332 – biomass lignin 267 – biomimetic 41 – bionanocomposite 323 bis-benzo[b]pyran 305 bisindole derivative (45) 365 bisindoles (45) 365

Index

(bmim)Br 148 boronic acid 294 brønsted acid 68 bromo sugar 80 bronsted acid 114 Buchwald-Hartwig C–N cross coupling 202 C-5′ silyl protected 94 (C8dabco)Br 111 calcination 198 calixarene 313 capping agent 194 carbenoid intermediates 152 carbocatalysis 225, 228, 279 carbon doped MoO3-TiO2 144 carbon efficiency 344 carbonaceous materials 228, 253 caspian isinglass 315 catalysis 1, 191, 258 catalyst 178, 257, 307 catalyst-free 328 catalyst-free conditions 115 catalytic activity 279 catalyzed 179 C–C bond formation 49, 55 C–C coupling 47 cellulose 310 CEM 136 CeO2 nanoparticles 109 cervix cancer 90 chalcone derivatives 41 chalcones 287 Chan–Lam C–N cross coupling reaction 207 chemical sol-gel polymerization 197 chemical stability 192 chemisorption 284 chemoselectivity 322 chemotherapeutic activities 63 C–heterobond formation 189 chiral molecules 37, 40 chitosan 145 chloranil 129 chromene 306 chromene derivative 367 cinnamoyl-crotonyl oxazolidinone 156 Claisen-Schmidtt condensation 331 clayzic 116 click chemistry 62, 71 click reaction 96, 134 climate change 257

375

C-N bond 361 C–N bond formation 201 Co (NNN) complex 165 coating 198 cocatalyst 296 combined microwave-solvothermal approach 194 commendable recyclability 218 compact fluorescent lamp 334 composite materials:composite materials 354 Co-MTL@MNPs 204 condensation 319 construction of C–O bonds 208 conventional method 69 co-ordinatively unsaturated metal centers 213 copper catalysed cycloaddition reaction 71 cost-effective 260 coumarin 83 coumarin nucleoside 87 coumarin scaffold 41 coupling 1–3, 5, 7, 9–15 coupling reactions 39,47, 49 covalent grafting/anchoring 200 COVID 37 coxsackie virus 78 Crandell–Rees feline kidney cells 68 cross coupling reactions 50 cross-coupling 342 cross-dehydrogenative coupling 295 crystalline materials 213 C–Se, C–Te, 216 CsOH·H2O 165 Csp2-P coupling 217 CTAB 144 CuAAC and RuAAC 67 Cubic 194 CuCl 142 Cu(I) doped PANI 362 Cu(I) mediated click 95 Cu(I)-catalyzed click reaction 80 Cu(Phen)(PPh3)Br 134 Cu-SB/PANI 366, 367 cyclic/linear ethers 125 cyclization 51, 53 cycloaddition 79, 80 cyclocondensation 310, 336 cyclohexyl isocyanide 121 cytosolic 88 cytotoxicity 65, 69, 81 DDQ 129

376

Index

deacylation 67 deep eutectic solvent 147 dehydration 269 dehydration reaction 325 dehydrogenation 345 dengue 37 deoxyribonucleic acid 38 deprotonation 50 diastereoisomer 54, 287 diastereoselective synthesis 47 dicarbonyl 303 dicarbonyl compound 345 dideoxyiodocarba nucleosides 67 diesel engines 268 dihydropyrimidinone 333, 354, 355 dihydroxyazido 72 diketo compounds 162 dimedone 338 DIPEA 68 disaccharides 114 diseases 37, 38, 42, 55 diselenide 344 disorders 42 dispersion 293 DMTrC 72 DNA and RNA 61 doped-PANI 353 double hetero arylation 137 dowex 50 W 76 d-ribose 69 drug discovery 62 duplex stability 82 duplexes 75 d-xylose 93 ebola 37 EC50 41, 43 eco-friendly 176 ecologically friendly 258 economic restrictions 268 economic viability 218 edible and non-edible plant 265 EDTA 114 efavirenz 53 Eg5 333 electrochemical 344 electrochemistry 49 electrolysis 49 electronic effect 294 emeraldine 353

enantio selective synthesis 53 enantioselective 316 endemic in humans 38 enolization 331 environmental 304 enzymatic hydrolysis 267 enzyme inhibition 71 esterification 260, 340 ethyl chloroacetate 132 ethyl gallate 152 ethyl pyruvate 150 ethylene arenes 166 eutectic 307 exothermal redox reaction 196 face centered cubic (fcc) 195 favipiravir, 38 Fe@ AMCA-MIL53(Al)-Ethephon 209 Fe3+ doped 356 Fe3O4@AMCA-MIL53(Al)-NH2-CoII 209, 213 Fe3O4-CNT nanocomposite 356 Fe@AMCA-MIL53(Al) 209 fedratinib 205 Fe@PEG@Cu–Co 202 Fe@PTMS-Tris-Co MNPs 212 fermentable sugars 265 fermentation 266 Fe@SiO2/2-aminopyridine-Pd(II) nanoparticles 214 Fe@Starch-Au catalyst 209 filtration 330 fischer-tropsch synthesis 263 flow 182 fluorescence 82 fluorolactam 316 foodstuffs 258 four-component 313 free fatty acid 259 friedel-craft alkylation 230, 285 fuel cells 271 functional group inter conversions 49 furan 285 furan analogue 53 furanoside 97 furfural 267 furfuryl alcohols 143 fused chromene derivatives (49, 51 and 53) 367 fused chromenes 365 fused heterocyclic aglycons 52 genotype 42

Index

glycerol 332 glycerol/water medium 112 glyoxal 315 good yields 202 gram-scale 330 gram-(−ve) 42 gram-(+ve) 42 graphene 281 graphene oxide 139, 225, 229, 281 graphite 121 graphitic carbon nitride 225, 242 green chemistry 39, 105, 190, 321 green reactions 225 green solvent 49 greener 176, 177, 304 greener condition 345 grinding 312 grinding strategies 44 guangdong province 38 halocyclization 332 HBV mutants 81 HCV 73 heck reaction 45 hematite 191 hemicellulose biofuels 266 hepatitis c virus 64 heteroarenes 36 heterocyclic 303 heterogeneous 73, 181, 182, 282 heterogeneous catalyst 228–230, 242, 246, 253, 260, 271 heterogeneous nanocatalyst 317 heterogenized catalysts 190 hexafluoro phosphate ion 117 high-energy macromolecule 265 high speed vibration mill 44 high turnover number (TON) 200 high yields 216 hinsberg reaction 131 HIV 87, 94 hiyama’s 39 homogeneous 282 homogeneous catalytic systems 228 host receptors 39 huh-7 cells 67 huisgen ‘click’ chemistry 76 human cell 82 human health 328 human respiratory syncytial virus 43

hydrazine 311 hydrolysis 54 hydrothermal aging 197 hydrothermal synthesis 269 hydroxychloroquine 38 I2/TBHP/DMSO system 166 IC50 43 imidazo[1,5-a]quinoxalines 158 imine formation 161 imperishable magnetism 191 in vivo 41 indazolo[2,1-b]phthalazine 320 indenoquinoxaline 148 indirect electrolysis 50 indium (III) chloride 165 indole 284 indole substituted chromenes 365 indolo[31,21:4,5]furo[2,3-b]quinoxaline derivatives 166 indolo-chromenes (44) 365 indolofuroquinoxalines 156 inert materials 199 influenza – influenza A 75 – influenza A virus 43 – influenza B virus 43 intermediate zwitterion 340 intramolecular 91 intramolecular cyclization 313 iodine 132 iodine doped PANI 361 ionic liquid 313 ipso-hydroxylation 293 Ir (III) complexes 107 iron catalyst 125 iron (III) trichloride 107 isatin 121, 131, 329 isoelectric point 199 isomaltosone 114 isomaltulose 114 isoxazole 291 jatropha oil 271 K10 clay 149 K10-montmorillonite 149 ketone 288 KF-alumina 140 KI/TBHP 125 knoevenagel condensation 243, 244, 325 knoevenagel-michael 310

377

378

Index

kolbe electrolysis 49 lactam 332 lactamization 127 leucoemeraldine 353 levulinic 304 lewis acid 116 lignocelluloses 265 lignocellulosic biomass 263 lipase 265 liquefaction 262 liquid assisted hand grinding 129 liquid fuel 264 l-proline 109 l-tryptophan 148 maghemite 191 magnetic nanoparticle 189, 262, 271, 317 magnetite (Fe) 191 magnetochromatic property 194 malononitrile 288, 312, 323, 337 mannich base 49 mannich reactions 48 mannich type reactions 367 materials 304 MCR 309 mechanochemistry 44 mechanosynthesis 129 medicinal 303 meglumine 341 melamine 159 melanoma 98 mesoporous 284 metal glycerolates 269 metal ion free catalyst 118 metal-free 176 metalloporphyrins 119 metal-organic frameworks (MOFs) 213 methanolysis 262 methyl 2-(2-chloro-1H-indol-3yl)-2-oxoacetate 166 methyl-2-(2-chloro-1H-indole-3-yl)-2oxoacetate 156 micellar 182 michael addition reaction 44 michael receptor 325 microalgae 270 micro-emulsion 264 microporous 261 microscopic 283 microwave 66, 341 microwave induced techniques 43

microwave irradiate technique 43 microwave irradiation 313, 327 microwave-assisted 69 middle east respiratory syndrome corona virus 40 MIL-101-Cr-NH2 147 mild condition 325 mineral wastes 270 mizoroki–Heck 39 MnFe2O4@Cs–Bu–SO3H 145 modified/artificial nucleosides 62 modified oligonucleotides 72 monosaccharides 266 morita–baylis–hillman reaction 44 morphological attributes 218 mortality rates 37, 55 mouse hepatitis virus 76 multicomponent 308 multicomponent reactions 282 MW assisted synthesis 131 N1-alkynylated nucleobases 81 N-alkyl-2-piperidinone 324 nanocatalyst 259, 271, 319 nanocrystalline CaO 262 nanomagnetite-supported 328 nanomaterial 258, 271 nanometric dimensions 192 nanoparticles 3–12, 14–16 nanoscale metal oxides 262 nanosheets-supported 324 nano-solid base catalyst 262 nanostructured 189 naphthoquinone 143 n-aryl sulfonyl hydrazones 125 n-arylated imidazoles (34) 362 n-arylation reactions 362 natural gas 271 negishi cross-coupling reaction 52 negishi’s 39 N-formylation 364 NH2-MIL53(Al) framework 209 n-heteroarenes 137 n-heterocyclic carbene 128 n-heterocyclic compounds 203 nicotinamide riboside 70 Ni@Fe–FeNDCs 205 Ni@FeNDCs 205 ninhydrin 145 N-iodosuccinimide 332 nipah 37

Index

nitro anilines 139 nitromethane 309 non-chromatographic 141 non-covalent adsorption 200 non-nucleoside reverse transcriptase inhibitors 41 non-thiolic thio-etherification 212 nontoxic 309 novozyme 435 93 N-PANI-GCN 365 N-propargyl aniline 165 N-tosyl hydrazones 125 nucleation 193 nucleobase 62 nucleophile addition reaction 49 nucleophiles 175 nucleoside analogue 65, 94 nucleoside pyridine mimics 70 nucleoside/nucleotide 61 nucleosides 61 octahedron 194 olefins 286 oleic acid 211 oligoconjugates 90 one-pot 43, 49, 50, 54 o-phenylenediamines 114 organic transformation 284 organo Cu(II) catalyst 159 organoboronic acids 216 organocatalysis 325 organocatalysts 280 organosilicon 34 organotellurides 216 oseltamivir 53 oxazepin-quinoxaline bis-heterocyclic scaffolds 163 oxidation 49 oxidative dehydrogenation 281 oxindoles 295 o-xylene 163 PANI – PANI 353–365, 367, 368 – PANI mediated 353 – PANI:2GCN 365 – PANI:4GCN 365 – PANI-BF4. 362 – PANI-bismoclite complex 354 – PANI-bismoclite 354 – PANICu+ 361, 362

379

– PANI-Cu+ catalyst 368 – PANI@CuI-NP 358, 359 – PANI@CuI-NPs 359 – PANI-DNSA-NR catalyst 357 – PANI-Fe3+ doped 356 – PANI-Fe3O4-CNT composite 357 – PANI-Fe3O4-CNT 356 – PANI-ferroso-ferricoxide-CNT 356 – PANI-GCN 365 – PANI-HBF4 362, 363 – PANI-I2 361 – PANI-nanorods 357 – PANI/SiO2 358, 360 – PANI/SiO2 composite 358 – PANI-sulfate 355, 359, 360 – PANI-sulphate 355 PBBS 121 Pd–Au/PANI-CNT 363, 364 Pd-imino-PyFe2O3 217 Pd(OAc)2 45, 46 P-dodecyl benzene sulfonic acid 131 Pd(OH)2/C 75 Pd(PPh3)4 45, 46, 52 PEG 400 135 penta-1,4-dien-3-one oxime ether linkage 153 pernigraniline 353 pharmaceutical 280 phase transfer catalyst 292 phenacyl bromide 112, 159 phenacyl halides 159 phenanthrene nucleosides 78 phenanthrene-9,10-dione 121 phenyl acetylenes 142 phenyl boronic acid 45 phenyl glyoxal 143 phloroglucinol 52 phosphine free Mn(I) complex 139 phosphono carbanucleosides 64 phosphoramidite 72 phosphorescent OLEDS 152 photochemical 334 photochemical formation 49 photo-reactants 80 phthalaldehydic acid 311 phthalazine 310 phthalazine trione 111 phthalazinone 311 phthalhydrazide 337 pictet-spengler domino strategy 127

380

Index

piperidine 71 planetary milling conditions 44 plant pathogens 97 polar alkynes 67 poly cyclic molecules 125 polyaniline 353 polyaniline salts 367 polyaniline-sulfate 149 polyethylene glycol 148 polymerase 38, 41 polymers 258, 267 polysaccharides 265 positive control 81 potassium selenocyanate 123 potential 73 power polygeneration 263 propargyl bromides 76 propargylated nucleobases 73 propyl phosphonic anhydride 124 protease inhibitor 40, 41 protein 333 P-toluene sulfonic acid 129 purine 38 pyrano[2,3-d]pyrimidinone 334 pyranocoumarins 289 pyranopyrazoles 289 pyrazin-coumarin hybrid 129 pyrazole carboxaldehydes 112 pyrazolo[1,2-b]phthalazine 320 pyrazolo[2,3-b]pyrazines 115 pyridazino[1,2-a]indazole 320 pyrido pyrazine 322 pyrido[2,3-d:6,5-d′]dipyrimidine 330 pyrido-dipyrimidine 343 pyridopyrazine scaffolds 124 pyrimidin-2(1H)-one 345 pyrimidine 38 pyrimidine nucleosides 73 pyrimidines 52 pyrimido[4,5-b]quinolinone-2,4-dione 335 pyrrole 53, 309, 321 pyrrolidine 307 pyrrolidone 304, 307, 324 pyrrolo pyrimidines 53 pyrrolo[1,2-a]quinoxalines 112 quinoline 310 quinolinyl chalcones 150 quinoxaline 322, 333, 341 quinoxaline chalcones 152

quinoxaline derivatives 360 quinoxaline hydrazides 156 quinoxalines 106 quinoxalines (28) 359 quinoxaline-sulphonamide 108 radical coupling 49 recyclability 4, 7, 8, 323, 329 recyclable 182 recyclable magnetic fenanocatalyst 208 remdesivir 38, 41, 54 renewable 305 renewable energy 272 renewable fuel 258 respiratory 77 reusability 2 reusable 178 reusable ionic liquid 148 reverse transcriptase 75 RHA-SO3H 137 ribavirin 41, 62 ribavirin analogues 67 ribonuclease 73 ribonucleic acid 38 rNase 73 ru-catalyst 93 ruthenium reagent 153 saccharin 119 sarcosine 151 SARS 37 selanyl-dihydrofuran 344 selanyltriazoyl carbonitrile 339 selectivity 279 selenide 216, 339 selenium-containing 1,2,3-triazole 339 selenocyanation 123 seven runs 216 severe acute respiratory syndrome 37, 40 shikimic acid 53 silica sulfuric acid 148 silicic acid method 199 silylation 35, 36 sodium acetate 163 sodium ascorbate 73, 86, 132 sodium azide 75 sodium methoxide 70 sodium xylene sulfonate 129 solid acid 260 solid-phase reduction-oxidation reaction 193 solution combustion method 196

Index

solvent-free 177, 307, 319 solvothermal approach 197 sonochemistry 338 sonogashira 1, 2, 9, 10, 14, 15 sonogashira coupling reaction 46, 152 sonogashira reaction 65 sonogashira–Hagihara reaction 40 SP C–H functionalization 165 SP3 C–H amination approach. 163 SP3 CH-activation 164 spike proteins 39 spinel ferrites 195 spiroacenaphthylene 305 spiro[acenaphthylene-1,4′-pyrano[2,3-c] pyrazole] 357 spirocyclic 76 spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] 357 spirooxindole 305, 336 spiropyrrolidine 148 stannic chloride 165 staudinger/aza-wittig 343 stereo isomers 40 stereoselective tetrahydroquinoline (29 and 31) 361 stereospecific 91 stille’s 39 stober sol-gel process 199 substitution 177, 183 succinimide 132 sugar 341 sulfamic acid 112 sulfated graphene catalysts 288 sulfonated rice husk ash 137 sulfurtrifluoride 87 superparamagnetic 317 surface modification 198 surfactant 106, 211, 291 sustainability 190 sustainable 2, 3, 9, 12–14, 176, 306, 325 sustainable energy 271 sustainable greener synthesis 191 sustainable source 257 suzuki 1–15 suzuki coupling reaction 45 suzuki–miyaura 39 suzuki–miyaura coupling reaction 45 switchgrass 267 synergistic 178 synthetic organic chemistry 201

381

TBBDA 121 tBuOH 85 terrestrial biomass 265 tetrahydro-benzo[b]pyran derivatives 358 tetrahydrofuran 67 tetrahydropyridine 318 tetrahydro-pyrrolobenzodiazepine 343 tetrahydro-pyrrolobenzodiazepinon 343 tetrahydroquinolines (27) and (30) 361 tetramethylglycoluril 315 tetraphenyl porphyrin skeleton 119 theophylline 310 thermal 73 thermal conditions 66 thermal cracking 262 thiamine hydrochloride 118 thiazolidine-2-carboxylic acid 152 thiocyanation 123 thiophene 286, 308 thiourea 112 thymidines 87 tosylated nucleosides 97 transesterification 259, 260 transformation 55 transition metal 280 triazole 75, 325 triazole moiety (22) and (24) 359 triazole nucleosides 63 triazolo-3′-deoxycarbanucleosides 65 triazolofuranosides 97 triazolo-fused 90 triazoloquinoxalines 134 triazolo-thymidine nucleosides. 92 triazolyl nucleosides 62, 77, 90 triazolyl spirocyclic oxindole 326 triazolylation reaction 84 triazolyl-copper 70 triazolyl-nucleosides 70 triazolylphenanthrene 78 tribromo isocyanuric acid 112 tricyclic/tetracyclic quinoxalines 157 triethoxysilane 307 triethylamine 90 trimethylsilylacetylene 86 trisaminomethane-cobalt (Tris-Co) complex 212 TsOH·H2O 161 tsuji–trost 175–180, 182, 183 tumor cell 68 tween 40 106

382

Index

ugi reaction 121 ullman typearylation reaction 202 ullmann synthesis 51 ullmann type O-arylation cross-coupling 209 ultrasonication method 144 ultrasounds 49 ultraviolet irradiation 334 unmasking 74, 78 unnatural 74 unsymmetrical 317 unsymmetrical biaryls 50 urea-choline chloride 147 uS irradiation 339 vaccines 38, 42 vaccinia virus cells 69 varicella-zoster virus 72 vicinal diols 139

vicinal tricarbonyl intermediates 121 viral infections 37, 55 viruses 37 visible light 334 visible light promoted approach 143 visible-light-initiated 336 wittig reaction 44 xanthenes 294 xanthenone 294 x-ray mapping 213 zanamivir 54 zeolite-based catalysts 268 zeolitic catalysts 261 zika 37 zirconium 322 zirconium IV oxide chloride 119 ZSM-5 145