Non-Metal Catalyzed Synthesis: Green Bioactive Heterocycles [3] 9783110997286

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Yunfei Du and Bubun Banerjee (Eds.) Non-Metal Catalyzed Synthesis Green Bioactive Heterocycles

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

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

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

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

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

Green Bioactive Heterocycles

Edited by Bubun Banerjee

Volume 3

Non-Metal Catalyzed Synthesis Bioactive Heterocycles Edited by Yunfei Du and Bubun Banerjee

Editors Prof. Yunfei Du School of Pharmaceutical Science and Technology (SPST) Tianjin University Room A208, Building 24 92 Weijin Road 300072 Tianjin China [email protected] Dr. Bubun Banerjee Department of Chemistry Akal University Talwandi Sabo, Bathinda 151302 Punjab India [email protected]

ISBN 978-3-11-099728-6 e-ISBN (PDF) 978-3-11-098547-4 e-ISBN (EPUB) 978-3-11-098616-7 ISSN 2752-1338 Library of Congress Control Number: 2023941764 Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the internet at http://dnb.dnb.de. © 2024 Walter de Gruyter GmbH, Berlin/Boston Cover image: theasis/E+/Getty Images Typesetting: Integra Software Services Pvt. Ltd. Printing and binding: CPI books GmbH, Leck www.degruyter.com

Preface This book is a part of the book series entitled ‘Green Bioactive Heterocycles’ and mainly focuses on non-metal catalyzed synthesis of biologically relevant heterocyclic compounds. In recent decades, green chemistry has gained increasing attention from chemists in both academia and industry. Improving the atomic availability and reducing the generation of by-products during the reaction has been the target that the chemists are striving for. Therefore, we hope that this new book titled ‘Non-Metal Catalyzed Synthesis: Green Bioactive Heterocycles’ could provide an emphasis and reference value for upper-level college students, instructors, and professional chemists to further explore this field. This volume (Volume 3) generally contains 11 chapters written by experts from different countries. In the first chapter, Pellissier presented the vital role of organocatalytic dynamic kinetic resolution in synthesizing bioactive heterocyclic rings. Chapter 2 is related to the synthesis of heterocyclic compounds catalyzed by organophotoredox, introduced by Maiti and co-researchers. Das's group described the synthesis of imidazo [1,2-a]pyridines and indazoles without metal catalysis in Chapter 3. In Chapter 4, Paixao and co-researchers reviewed the synthesis of bioactive heterocycles catalyzed by microwave-assisted metal-free solid support. In Chapter 5, Hussain's group described that Graphene oxide (GO), an efficient and recyclable catalyst, can be utilized to synthesize bioactive heterocyclic compounds. And Rehman and colleagues summarized methods for synthesizing N-heterocyclic compounds catalyzed by amino acids in Chapter 6. We focused more on iodine catalysis since Chapter 7, especially the application of hypervalent iodine reagents in synthesizing heterocyclic compounds.Among them, Rao's group summarized the construction of N-containing heterocyclic compounds mediated by iodine molecules in Chapter 7, while Chapters 8-11 discussed numerous applications of hypervalent iodine reagents, including synthesis of bioactive heterocycles mediated by in situ-generated hypervalent iodine species studied by Du's group, hypervalent iodines-enabled dearomatization discussed by Singh et al., construction of biologically important nitrogen- and oxygen-containing heterocycles catalyzed by hypervalent iodines reviewed by Singh et. al., and synthesizing bioactive heterocycles mediated by hypervalent iodine reagents introduced by Maiti’s group. Finally, we would like to thank all the worthy contributors and appreciate all the constructive comments given by peer-reviewers. Prof. Yunfei Du & Dr. Bubun Banerjee

https://doi.org/10.1515/9783110985474-202

Foreword The synthesis of biorelevant N-and O-heterocycles embraces practically all kinds of chemical transformations applied in synthetic organic chemistry. The principles of green chemistry may be applied well within the discipline under discussion. A key issue is the use of catalysts to achieve chemo-, regio-, diastereo- and enatioselective transformations and to decrease the need for energy. The application of different metal- or metal salt catalysts is widespred in chemical syntheses. Let us just mention the heterogeneous and homogeneous transformations exemplified by oxidations/ hydrogenations and hydroformylations/ hydrogenations, respectively. Different C-C coupling rections also involve the use of metals, e.g. palladium. These days, it became a hot topic to replace metal catalysts by environmentally more favorable organocatalysts, or to develop catalyst-free accomplishments. This is justified by the depleting sources of metals, and by the metal contamination from large-scale industrial processes applying metal catalysts. The excellent book “Non-metal catalyzedsynthesis – Green bioactive heterocycles” edited by Prof. Yunfei Du and Dr. Bubun Banarjee is a good summary of the possible green tools and techniques to make heterocyclic syntheses more environmentally friendly. Optical resolution is an important tool in syntheses related to optically active ligands, or different preparations of intermediates or agents in the pharmaceutical industry. Chapter 1 presents, as a new approach, organocatalytic dinamic kinetic resolutions useful in the synthesis of biologically active heterocycles. Photoredoxcatalysis is another up-todate method. Chapter 2 shows how to apply this approach in the synthesis of biorelevant heterocycles. Chapter 3 is on the ”green” (metal-free) preparation of two special groups of compounds, imidazopyridines and indazole. It is a recent observation that microwave irradiation may substitute catalysts comprising metal-catalysts in certain chemical transformations. The application of this tool in the synthesis of bioactive heterocycles is discussed via case studies. Recyclable catalysts and one-pot accomplishments are attractive in green chemistry (Chapter 4). Chapter 5 elucidates how to apply graphene oxide in the synthesis of heterocycles with potential bioactivity. Optically active catalysts and additives may be important actors in stereoselective preparations. Chapter 6 is on the application of L-proline as an enentioselective catalyst. Iodine has found many applications in a variety of syntheses. There are different possibilities for this. The simplest version involves the use of molecular iodine (Chapter 7). A more sophisticated variation is the utilization of hypervalent iodine species. The latter is exemplified via diverse applications in the preparation of a wide range of N- and O-containing heterocycles (Chapters 8-11). Prof. György Keglevich Professor of Chemistry, DSc, Dr Habil. PhD Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, HUNGARY

https://doi.org/10.1515/9783110985474-203

About Prof. György Keglevich György Keglevich graduated from the Technical University of Budapest (TUB) in 1981. He got PhD (1984), DSc (1994) and Dr Habil(1995) degrees. He has been the Head of Department of Organic Chemistry and Technology for 22 years (1999– 2021). He developed P-heterocyclic research in the subject of 6- and 7membered, as well as bridged P-heterocycles. Additional research interests include the modification of the P-functions, and mechanisms. He also deals with environmentally friendly (green) chemistry embracing MW chemistry,ionic liquids, new catalysts and selective syntheses. He took also part in pharmaceutical industrial projects marked by 3 patents. He is the author or co-author of 670 papers including 42 review articles, 3 books and 52 bookchapters. His h-index is 46. 21 PhD degrees were born with his supervision, 3 degrees are in process. He is the Editor-in Chief of Curr. Org. Chem., founder E-I-C of Curr. Green Chem., and the Section-E-I-C of the “Chemical Section” of Symmetry. He is Associate Editor for Curr. Org. Synth., Lett. in Org. Chem., Lett. in Drug Design and Discovery and Heteroatom Chem. He is Editorial Board Member for Molecules, Green Processing and Synthesis and Phosphorus, Sulfur, Silicon. He is the member of the Steering Committee of International Conference of Phosphorus Chem. (ICPC). The 22nd ICPC was arranged in Budapest/Hungary in 2018 under his chairmanship. Presently he is the “Trustee of the Rector” on sustainable affairs.

https://doi.org/10.1515/9783110985474-204

Contents Preface Foreword

V VII

About Prof. György Keglevich List of Contributors

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Hélène Pellissier Chapter 1 Organocatalytic dynamic kinetic resolution in the total synthesis of bioactive heterocycles 1 Rajjakfur Rahaman, Prasenjit Das, Poulami Hota, and Dilip K. Maiti Chapter 2 Organophotoredox-catalyzed synthesis of bioactive heterocycles

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Rahul Dev Mandal, Moumita Saha, and Asish R. Das Chapter 3 Synthesis of imidazo[1,2-a]pyridines and indazole under metal-free conditions 47 Akbar Ali, Huma Masood, Muhammad Ibrahim, Tahir Maqbool, Nadia Akram, and Marcio Weber Paixao Chapter 4 Microwave-assisted metal-free solid-support-catalyzed synthesis of bioactive heterocycles 81 Akbar Ali, Zill-e-Rehman Abbas, Muhammad Ibrahim, Atta Ul Haq, Nadia Akram, and Amjad Hussain Chapter 5 Graphene oxide (GO): an efficient and recyclable catalyst for one-pot synthesis of bioactive heterocycles 103

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Tahir Farooq, Razia Noreen, Bushra Parveen, Kulsoom Ghulam Ali, Muhammad Abdul Qayyum, Arruje Hameed, Tanzeela Khalid, Sahar Ilyas, and Touseef Ur Rehman Chapter 6 L-Proline-catalyzed green synthesis of functional N-heterocycles 131 Chebolu Naga Sesha Sai Pavan Kumar and Vaidya Jayathirtha Rao Chapter 7 Molecular iodine-catalyzed synthesis of N-heterocycles and some important organic transformations 163 Xiangyu Zhan and Yunfei Du Chapter 8 The aryl iodine-catalyzed synthesis of bioactive heterocycles via hypervalent iodine species generated in situ 189 Gana R. J., Kokila Sakthivel, Ritu Mamgain, and Fateh V. Singh Chapter 9 Hypervalent iodine-mediated synthesis of biologically important heterocycles via dearomatization of phenols 239 Sathish Kumar J., Anindya Borah, Ritu Mamgain, and Fateh V. Singh Chapter 10 Hypervalent iodine-mediated synthesis of biologically important nitrogenand oxygen-containing heterocycles 285 Rajarshi Sarkar, Dripta De Joarder, and Dilip K. Maiti Chapter 11 Synthesis of bioactive heterocycles involving λ3-hypervalent iodine Index

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List of Contributors Hélène Pellissier Aix-Marseille Université CNRS Centrale Marseille iSm2 Marseille France Email: [email protected] Chebolu Naga Sesha Sai Pavan Kumar Department of Chemistry Vignan’s Foundation for Science, Technology and Research (Deemed to be University) Vadlamudi Guntur 522 213 Andhra Pradesh India and Department of Chemistry Vignan Degree and P.G. College Palakaluru Road Guntur 520 009 Andhra Pradesh India Vaidya Jayathirtha Rao Emeritus Scientist – IICT Honorary Professor – AcSIR Organic Synthesis and Process Chemistry Department and AcSIR-Ghaziabad CSIR-Indian Institute of Chemical Technology Uppal Road Tarnaka Hyderabad 500007 Telangana India Email:[email protected], [email protected] Rajjakfur Rahaman Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009 West Bengal India

https://doi.org/10.1515/9783110985474-206

Prasenjit Das Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009 West Bengal India Poulami Hota Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009 West Bengal India Dilip K. Maiti Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009 West Bengal India Email: [email protected] Rajjakfur Rahaman Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009 West Bengal India Prasenjit Das Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009 West Bengal India

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Poulami Hota Department of Chemistry University of Calcutta 92, A. P. C. Road Kolkata 700009 West Bengal India

Ritu Mamgain Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai Chennai 600 127 Tamil Nadu India

Rajarshi Sarkar Department of Chemistry VIT-AP University Amaravati Andhra Pradesh India

Fateh V. Singh Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai Chennai 600 127 Tamil Nadu India Email: [email protected]

Dripta De Joarder Department of Chemistry VIT-AP University Amaravati Andhra Pradesh India Dilip K. Maiti Department of Chemistry University of Calcutta 92 APC Road Kolkata 700009 West Bengal India Gana R. J. Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai Chennai 600 127 Tamil Nadu India Kokila Sakthivel Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai Chennai 600 127 Tamil Nadu India

Sathish Kumar J. Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai 600 127 Tamil Nadu India Anindya Borah Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai 600 127 Tamil Nadu India Ritu Mamgain Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai 600 127 Tamil Nadu India Fateh V. Singh Chemistry Division School of Advanced Sciences (SAS) Vellore Institute of Technology Chennai 600 127 Tamil Nadu India Email: [email protected]

List of Contributors

Rahul Dev Mandal Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India Moumita Saha Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India Asish R. Das Department of Chemistry University of Calcutta Kolkata 700009 West Bengal India Email: [email protected] Akbar Ali Department of Chemistry Government College University Faisalabad Faisalabad 38000 Pakistan Email: [email protected] Huma Masood Department of Chemistry Government College University Faisalabad Faisalabad 38000 Pakistan Muhammad Ibrahim Department of Applied Chemistry Government College University Faisalabad Faisalabad 38000 Pakistan Tahir Maqbool Department of Chemistry Government College University Faisalabad Faisalabad 38000 Pakistan

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Nadia Akram Department of Chemistry Government College University Faisalabad Faisalabad 38000 Pakistan Marcio Weber Paixao Department of Chemistry Universidade Federal de Sa˜o Carlos (UFSCar) Sao Carlos Sao Paulo Brazil Xiangyu Zhan Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency School of Pharmaceutical Science and Technology Tianjin University Tianjin 300072 China Yunfei Du Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency School of Pharmaceutical Science and Technology Tianjin University Tianjin 300072 China Email: [email protected] Zill-e-Rehman Abbas Department of Chemistry Government College University Faisalabad Faisalabad 38000 Pakistan Atta Ul Haq Department of Chemistry Government College University Faisalabad Faisalabad 38000 Pakistan

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Amjad Hussain Department of Chemistry University of Okara Okara Punjab 56300 Pakistan

Muhammad Abdul Qayyum Department of Chemistry Division of Science and Technology University of Education Lahore Pakistan

Tahir Farooq Department of Applied Chemistry Government College University Faisalabad Pakistan

Arruje Hameed Department of Biochemistry Government College University Faisalabad Pakistan Email: [email protected]

Razia Noreen Department of Biochemistry Government College University Faisalabad Pakistan Bushra Parveen Department of Chemistry Government College University Faisalabad Pakistan Kulsoom Ghulam Ali Department of Chemistry Government College University Faisalabad Pakistan

Tanzeela Khalid Department of Applied Chemistry Government College University Faisalabad Pakistan Sahar Ilyas Department of Applied Chemistry Government College University Faisalabad Pakistan Touseefur Rehman Department of Applied Chemistry Government College University Faisalabad Pakistan

Hélène Pellissier✶

Chapter 1 Organocatalytic dynamic kinetic resolution in the total synthesis of bioactive heterocycles 1.1 Introduction In spite of the impressive development of asymmetric synthesis and catalysis, the resolution of racemates still represents the most employed methodology to reach chiral products in industry. In a simple kinetic resolution, one enantiomer (SR) of a racemic mixture is more rapidly transformed into the corresponding chiral product (PR) while the other (SS) is recovered unchanged [1–4] (Figure 1.1).

Figure 1.1: Simple kinetic resolution.

However, this simple methodology presents a major drawback related to the limitation of its yield to 50%. In order to overcome this limitation, organic chemists have developed the concept of dynamic kinetic resolution, allowing the production of one of the enantiomers of the product to be achieved with up to quantitative yield. Actually, dynamic kinetic resolution is based on the combination of the resolution step of a kinetic resolution with an in situ equilibration or racemization of the chirally labile substrate (Figure 1.2). The two enantiomers of a racemic mixture are induced to equilibrate at a rate that is faster than that of the slow-reacting enantiomer in reaction with the chiral reagent (Curtin–Hammett kinetics). If the enantioselectivity is sufficient, then isolation of a highly enantioenriched product is possible with a theoretical yield of 100% based on the racemic substrate. In order to gain the complete set of advantages of dynamic kinetic resolution, special requirements have to be fulfilled, such as the irreversibility of the resolution step and the fact that no product racemization should occur under the reaction conditions. To achieve highly enantioenriched products, the selectivity (kfast/kslow) of the resolution step should be at least 20. Moreover,

✶

Corresponding author: Hélène Pellissier, Aix-Marseille Université, CNRS, Centrale Marseille, iSm2, Marseille, France, e-mail: [email protected]

https://doi.org/10.1515/9783110985474-001

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Hélène Pellissier

Figure 1.2: Dynamic kinetic resolution.

the rate constant for the racemization process (kinv) should be faster than the rate constant of the resolution step (kfast); otherwise, a very high selectivity has to be ensured. Under dynamic kinetic resolution conditions, the two enantiomers of the racemic mixture can be ideally converted into a single enantiopure product with 100% theoretical yield. The required racemization of the substrate can be performed either biocatalytically, chemically, or even spontaneously. Importantly, the reaction conditions must be chosen in order to avoid the racemization of the formed chiral product. This powerful concept has been applied to either enzymatic [5–10] or nonenzymatic reactions [11–30]. Along with metal catalysts [31–49] and enzymes, organocatalysts present considerable advantages in addition to be environmentally compatible since they are robust, nontoxic, cheap, and often readily available [50–64]. Their use in the synthesis of drugs is highly appreciated since the final products do not include any trace of hazardous metals. These green catalysts have been applied to develop the first examples of organocatalyzed dynamic kinetic resolutions in the last two decades, allowing an impressive extension of the synthetic scope of the dynamic kinetic resolution methodology. This short chapter collects rare developments in the total synthesis of bioactive heterocycles based on the use of organocatalytic dynamic kinetic resolution. It is divided into three sections, dealing successively with total syntheses employing N-heterocyclic carbene (NHC) catalysts, (dialkylamino)pyridine catalysts, and other organocatalysts.

1.2 N-Heterocyclic carbene catalysts In the last decades, NHCs have become one of the most employed organocatalysts in asymmetric C−C bond formations [65–68]. Especially, the utility of these catalysts in asymmetric domino reactions has received a great attention in the past decade [69–94]. They can react with aldehydes to give catalytically competent (homo)enolate equivalents, which can be trapped with electrophiles of various types. Organocatalytic reactions catalyzed by stable carbenes are dominated not only by imidazolium- or thiazolium-derived carbenes but also by triazolylidene carbenes [95, 96], which are readily prepared from chiral amino acid precursors. Generally, the active carbene species are in situ generated through deprotonation of the precursor salts of the corresponding NHCs by using a base. Although significant progress has been achieved in this area of organocatalysis, examples

Chapter 1 Organocatalytic dynamic kinetic resolution

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of NHC-catalyzed dynamic kinetic resolutions remain rare and even more in their applications to the total synthesis of bioactive products [97, 98]. A rare example was described in 2015 by Scheidt and coworkers [99], dealing with a total synthesis of a benzopyran estrogen receptor β-agonist (Figure 1.3). The key step of this novel synthesis consisted in an intramolecular domino aldol/acylation reaction of α-substituted-β-ketoester 1 into the corresponding chiral bicyclic lactone 2 performed at 23 °C in DCE as solvent in the presence of 7 mol% of chiral NHC catalyst 3. Lactone 2 underwent an unusual β-lactone decarboxylation at room temperature to give the corresponding chiral cyclopentene product 4 in 86% yield and 92% ee. This chiral product was further converted into expected estrogen receptor β-agonist in four additional steps. The first step consisted in the hydrogenation of 4 on Pd/C to give the corresponding cyclopentane 5 with 48% yield and 90% de. Then, this methyl ester was subsequently converted into the corresponding Weinreb amide 6 with 90% yield by treatment with a Grignard reagent. Then, this amide was used to prepare chiral aryl ketone 7 through its reaction with the appropriate aryllithium reagent. Subsequent deprotection and cyclization of 7 afforded the final desired bioactive product in one-pot with 45% overall yield by successive treatment with TsOH in methanol, followed by the addition of NaBH3CN in the presence of HCl. In 2019, Fang and coworkers [100] employed closely related chiral NHC catalyst 8 to promote the intramolecular benzoin reaction of a variety of ketoaldehydes evolving through dynamic kinetic resolution. The process was performed at −20 or 0 °C in THF as solvent in the presence of 20 mol% of this organocatalyst or its enantiomer. As depicted in Figure 1.4, the benzoin reaction of substrate 9a promoted at −20 °C by organocatalyst 8 resulted in the formation of natural and bioactive chiral rotenoid cisfused tetrahydrochromeno[3,4-b]chromene-12a-hydroxymunduserone in 58% yield and 86% ee. The enantiomeric organocatalyst ent-8 could be applied to the synthesis of three other bioactive natural heterocycles, such as tephrosin, milletosin, and 12ahydroxyrotenone, starting from three types of substrates exhibiting different electronic properties. Indeed, the benzoin reaction of ketoaldehyde 9b organocatalyzed at 0 °C with 20 mol% of ent-8 led to natural biologically relevant rotenoid natural product tephrosin with 61% yield and 73% ee. Furthermore, the synthesis of another important bioactive heterocycle, such as milletosin, was achieved through the related reaction of ketoaldehyde 9c performed at −20 °C in the presence of the same catalyst. The expected natural product was obtained with 60% yield and 89% ee. In addition, the same catalyst system was applied at 0 °C to the benzoin reaction of ketoaldehyde 9d which delivered naturally occurring bioactive 12a-hydroxyrotenone with 47% yield and 98% ee albeit as a mixture of diastereomers (0% de).

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Figure 1.3: Synthesis of a benzopyran estrogen receptor β-agonist.

Chapter 1 Organocatalytic dynamic kinetic resolution

Figure 1.4: Synthesis of 12a-hydroxymunduserone, tephrosin, milletosin, and 12a-hydroxyrotenone.

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1.3 (Dialkylamino)pyridine catalysts Early used as promoters of esterifications and related reactions in the late 1960s [101– 105], 4-(dialkylamino)pyridine catalysts have become key organocatalysts [106, 107]. In 1996, Vedejs and Chen [108] introduced the first chiral 4-(dialkylamino)pyridine catalysts to be applied in asymmetric catalysis. Ever since, many other chiral organocatalysts of this type have been developed and successfully employed to promote many types of asymmetric transformations [109–112]. Their chiral environment and nucleophilicity can be tuned using a variety of scaffold designs. For example, chiral 4-(dialkylamino)pyridine organocatalysts have allowed the synthesis of a number of chiral molecules to be achieved. The difficulty in designing a useful enantioselective catalyst of this type is to introduce an effective chiral environment without eroding the nucleophilicity of the organocatalyst. The high reactivity of 4-(dialkylamino)pyridine catalysts is related to the capacity of the lone pair of the dialkylamino group to donate to the nitrogen atom of the pyridine moiety. Some of these catalysts have encountered remarkable success in dynamic kinetic resolution methodologies. For example, Salan and Piotrowski [113, 114] in 2017 developed an enantioselective three-component reaction between tetrazole 10a, acetaldehyde 11, and isobutyric anhydride 12 catalyzed by only 3 mol% of chiral 4-(dialkylamino)pyridine 13. This regioselective domino reaction was performed at 0 °C in MTBE as solvent in the presence of TEA as base, leading to the corresponding chiral tetrazole-derived hemiaminal 14 in quantitative yield and 94% ee (Figure 1.5). The latter constituted a key intermediate in a total synthesis of an inhibitor of proprotein convertase subtilisin/kexin-type 9 (PCSK9). Indeed, domino product 14 was further converted into desired PCSK9 inhibitor through four additional steps, involving successive magnetization, transmetalation, Negishi coupling, and N-Boc deprotection. The first step consisted in magnetization of chiral tetrazole 14 performed at −45 °C by treatment with i-PrMgCl in THF. Then, transmetalation to the corresponding organozinc derivative was accomplished by the addition of ZnCl2. Subsequently, a Negishi coupling occurred when bromide 15 along with [XantPhosPd (allyl)]Cl was added at 45 °C to the reaction mixture to give intermediate 16. A final N-Boc deprotection was achieved in the presence of HCl, thus delivering the expected chiral bioactive heterocycle with 89% yield. In 2022, the key step of this total synthesis was reinvestigated by Xie et al. [115] by using another type of organocatalyst, such as 4-aryl-pyridine-N-oxide 17. In this case, the three-component reaction between tetrazole 10a, isobutyric anhydride 12, and acetaldehyde 11 was performed in the presence of 5 mol% of this organocatalyst and Na2CO3 as base in mesitylene as solvent (Figure 1.6). The dynamic kinetic resolution occurred at −20 °C to give regioselectively (>20:1 regioisomeric ratio) the corresponding chiral tetrazole-derived hemiaminal 14 with 89% yield and 88% ee. The methodology was applicable to the same total synthesis of the PCSK9 inhibitor, but its scope was also extended to other N-heteroaromatic substrates, including substituted pyra-

Chapter 1 Organocatalytic dynamic kinetic resolution

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Figure 1.5: Synthesis of a PCSK9 inhibitor.

zole, imidazole, purine, benzimidazole, and benzotriazole, allowing the synthesis of a wide diversity of chiral heterocyclic hemiaminals with up to 99% ee.

1.4 Other organocatalysts In 2008, Guercio et al. [116] disclosed a total synthesis of NK-1 antagonist GW597599 employed against central nervous system disorders and emesis. While the early synthesis of this bioactive heterocyclic product was based on a classical resolution step of a ketopiperazine obtained in 38% yield through a classical fractional crystallization using L-mandelic acid in ethyl acetate, the novel synthesis developed by these authors involved a dynamic kinetic resolution methodology performed in the presence of L-mandelic acid. As illustrated in Figure 1.7, racemic ketopiperazine 18 could form an iminium derivative with an aldehyde, such as dichlorosalicylaldehyde 19, increasing the acidity of the benzylic proton. The thus-formed compound could easily racemize, allowing the desired (S)-enantiomer to precipitate out as its mandelate salt, leaving the unwanted enantiomer 20 in solution ready to be further racemized. Using this

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Hélène Pellissier

Figure 1.6: Modified synthesis of a PCSK9 inhibitor.

methodology, enantiopure (S)-ketopiperazine 18 was isolated in 90% yield. The latter constituted a key intermediate for the total synthesis of NK-1 antagonist GW597599. It was first reduced with 81% yield into the corresponding cyclic diamine 21 through four steps, involving successive treatments with TBAB in THF, NaBH4, BF3·Et2O, and then HCl in methanol [117]. Then, product 21 was regioselectively protected with Boc2O and the thus-formed N-Boc protected amine was subsequently coupled with carbamoyl chloride 22 in the presence of TEA as base to give intermediate 23 [118]. The latter was subjected to deprotection by treatment with MeSO3H to finally afford expected NK-1 antagonist GW597599 with 85% overall yield from compound 21. Chiral Brønsted acids constitute one of the most used organocatalysts in asymmetric catalysis [119–125]. Between Brønsted acids, chiral phosphoric acids, among which many are derived from axially chiral backbones such as BINOL, have attracted great attention related to their ability to act as bifunctional catalysts. Indeed, the acid unit of these catalysts captures electrophilic reagents when the phosphoryl oxygen acts as a Lewis base activation center and the bulky 3,3′-position extends stereoselectivity [126–131]. In the last

Chapter 1 Organocatalytic dynamic kinetic resolution

Figure 1.7: Synthesis of NK-1 antagonist GW597599.

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decade, a wide variety of versatile chiral phosphoric acids have been applied in many types of asymmetric transformations including dynamic kinetic resolutions performed in most cases under mild reaction conditions. In 2016, Wang and coworkers [132] described an enantioselective two-component Ugi-type reaction between isonitriles 24 and 3-(arylamino)isobenzofuran-1(3H)-ones 25 carried out at 0 °C in the presence of 10 mol% of chiral phosphoric acid catalyst 26 in DCE as solvent (Figure 1.8). The dynamic kinetic resolution allowed the corresponding chiral 3-oxo-2-arylisoindoline-1-carboxamides 27 to be synthesized in both good to high yields (74–99%) and enantioselectivities (82–96% ee). These heterocyclic molecules are important products in medicinal chemistry. For example, they constitute the structural motif in many bioactive products, such as anxiolytic and analgesic drugs (R)-pazinaclone and (S)-(+)-lennoxamine (Figure 1.8).

Figure 1.8: Synthesis of the skeleton of (S)-(+)-lennoxamine and (R)-pazinaclone.

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1.5 Conclusions This chapter highlights rare developments in the application of organocatalytic dynamic kinetic resolution in the total synthesis of bioactive heterocycles. The key steps of these syntheses were based on various types of transformations evolving through dynamic kinetic resolution promoted with different types of chiral organocatalysts, such as NHCs, (dialkylamino)pyridines, phosphoric acids, and α-hydroxy acids. For example, an NHC has been successfully applied to catalyze a domino aldol/acylation reaction achieved with 92% ee which allowed the total synthesis of an estrogen receptor β-agonist. Other organocatalysts of this family were applied to promote benzoin reactions with up to 98% ee as key steps in the total synthesis of four bioactive products, such as 12a-hydroxymunduserone, tephrosin, milletosin, and 12a-hydroxyrotenone. On the other hand, chiral (dialkylamino)pyridines were successfully employed to catalyze a three-component reaction based on a dynamic kinetic resolution to give a key intermediate with 94% ee which was used in a total synthesis of a PCSK9 inhibitor. Other types of organocatalysts, such as a phosphoric acid, allowed the formal synthesis of drugs (S)-(+)-lennoxamine and (R)-pazinaclone, the key step of which was an Ugi-type reaction achieved with 96% ee. In addition, L-mandelic acid was used in a total synthesis of NK-1 antagonist GW597-599. In accordance with the huge advent of asymmetric organocatalysis and that of dynamic kinetic resolution, more organocatalytic dynamic kinetic resolutions were undoubtedly applied as key economic steps in the total synthesis of other bioactive heterocycles in the near future.

Abbreviations Ar BINOL Boc Cy DCE de ee MOM Naph MS MTBE NHC PCSK TBAF TEA THF Ts Xantphos

Aryl 1,1ʹ-Bi-2-naphthol tert-Butoxycarbonyl Cyclohexyl 1,2-Dichloroethane Diastereomeric excess Enantiomeric excess Methoxymethyl Naphthyl Molecular sieves Methyl tert-butyl ether N-Heterocyclic carbene Proprotein convertase subtilisin/kexin tetra-Butylammonium fluoride Triethylamine Tetrahydrofuran 4-Toluenesulfonyl (tosyl) 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

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Rajjakfur Rahaman, Prasenjit Das, Poulami Hota, and Dilip K. Maiti✶

Chapter 2 Organophotoredox-catalyzed synthesis of bioactive heterocycles 2.1 Introduction 2.1.1 Background and importance The restoration of radical chemistry in synthetic organic chemistry over the last few years has introduced renaissance in the attention of photochemistry. Most of the renewed concern has come owing to the reactivity that can be retrieved through the intermediate reactive open-shell species, which is challenging or tough through the meaning of chemical catalysis. Reactivity in radical chemistry frequently suggests a complementarily to double-electron manifolds. Photoredox catalysis is possibly one of the greatest fastgrowing regions of radical chemistry in organic synthesis. A lot of synthetic chemistry researchers ranging from materials science and biomedical chemistry are rapidly accepting and using photocatalysis as a mild and novel alternative of attaining exclusive chemical reactivity. In this chapter, we will highlight the developments from the previous few years that have placed the footing for present advances in photocatalysis as well as deliver readers with the simple tools to plan and application of photocatalysis in synthetic organic chemistry. Significantly, this chapter will be mainly focused in organophotocatalyst systems for the synthesis of heterocyclic compounds and will discuss the advances and drawbacks for using organophotoredox catalysts over the other metal photocatalysts. We expect that it is just the beginning of what potentials a productive area of research for decade to come.

Acknowledgments: Funding from Ministry of Mines (Project Met4-14/19/2021) and postdoctoral research fellowship (R.R.) from D.S. Kothari [F.4-2/2006 (BSR)/CH/19-20/0183], UGC Govt. of India, are gratefully acknowledged. ✶

Corresponding author: Dilip K. Maiti, Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700009, West Bengal, India, e-mail: [email protected] Rajjakfur Rahaman, Prasenjit Das, Poulami Hota, Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700009, India https://doi.org/10.1515/9783110985474-002

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2.1.2 Why organophotoredox catalysis? Current developments on the photocatalysis have focused mostly on the transitionmetal chromophores [1−7] such as complexes of iridium and ruthenium polypyridyl stand at the leading class, and well-described usefulness in organosynthesis has gathered specific appreciation of late. In spite of that, organo-chromophores were extensively recognized for the capacity to take part in photoinduced electron transfer (PET) reactions rather than the catalytic use in synthetic organic chemistry. Various areas in organophotoredox catalysis were studied earlier [8−17] but suffer in substrate scope or predate present significant advances in progress of catalyst and the finding of novel reactivity. An inclusive study of the collected works that include the number of organic photoredox programs and deliver some past background for new advances of organophotoredox catalysis is still absent. Still, compared to transition-metal photocatalysis, one might ask what organophotoredox catalysis offer? We expect that the answer will be clear as we discuss the properties and reaction behavior of organosubstrates usually used in organic synthesis as photocatalysts. Precisely, we desire to highlight that organophotoredox catalysis proposed far away more than substitutes to metal-mediated examples; specifically, the effective reactivity delivered by numerous organocatalysts permits access to exclusive understandings and a wide range of compounds that are not reactive in maximum synthesis. Additionally, the variety of these organosubstrate molecules presents a group that promises to be valuable in the finding and optimized procedures in new synthesis.

2.2 Photophysical and electrochemical considerations A periodic subject in this chapter is that the photophysical properties of a molecule get excited electronically eventually to govern its photochemical reactivity. Consequently, both the states (ground and excited) are crucial properties of a photocatalyst to effect its reactivity. The current flow of novel synthesis for molecules absorbing light was led by an era of electrochemical and photophysical studies of ion radicals and organic molecules. With direct or indirect methods, these hard works to describe the activities of excited state organic molecules form the origin for their fruitful distribution as photocatalysts. Additionally, the mechanistic study of the photocatalytic processes often relies on the similar setup and methods for examining the mechanism of the reactions and determining the growth of additional active catalysts in organic synthesis. Given the vital role of photophysical insight in this recursive connectivity among excited states and reactive photochemical properties, we have faith in it which is essential to lead our

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chapter of synthetic methods described in the previous reports with a conversation of the photophysical and electrochemical basics of organic photocatalysis.

2.2.1 Photophysical methods The high-value photochemistry accompanying with organic compounds instigates in a series of excited states and the rate of reaction which manages their photophysical methods. The basic energy-level diagrams depicted in Figure 2.1 are used to frame the model, and from that we know the reactivity of a photocatalyst. The ensuing discussion from this paradigm and of photophysical processes attracts greatly from the article in photoredox chemistry by Turro [18]. When a molecule absorbed light, it gives an electronically excited organic molecule. Usually, an electron is promoted from a singlet ground state (S0) to a high-energy excited singlet state. Electromagnetic radiation helps a series of excited singlet states in separate vibrational energy levels within a very short period of time, likely picoseconds, and other high energy states relax to the bottom energy level, which is called the vibrationally first excited singlet state (S1). The photophysical method of higher energy excited state in separation, the place of S1 is equally governed by radiative and nonradiative processes: through the radiative process, the molecule goes to low energy states by releasing the absorbed light; on the other hand, in the nonradiative process, the energy dissipated is lost as heat. The first excited state singlet molecule (S1) returns to the ground state by fluorescence or internal conversion (IC), or through intersystem crossing, a spin-forbidden process goes to T1. The T1 states have highest time lived process, the T1 → S0 is a spinforbidden process, called phosphorescence, while the nonradiative process leads under normal environments. Both the states S1 and T1 are most likely to take part in bimolecular process, and they can go through energy and electron transfer (ET) meth-

Figure 2.1: Photocatalysts: photophysical and electrochemical processes.

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ods. Light-emitting diodes have emerged as an important tool in photoredox catalysis, as they possess a relatively narrow emission band enabling selective excitation of chromophore and constitute an energy-efficient, high-intensity light source [19−21]. We have accumulated some related properties for the photocatalysts considered in this chapter (Figure 2.2). Moreover, we discuss how these values are important for selecting an appropriate photocatalyst when examining new reactivity, alongside with how the upper properties effect photocatalytic reactions.

Figure 2.2: Common organic photoredox catalysts.

2.3 Common mechanisms in photoredox catalysis Most of the photocatalytic methods go through one of the two mechanisms, and it is represented in Figure 2.3. The cycles start with the excitation of the photocatalyst from the ground state to the excited state photocatalyst (PC✶) by irradiation with a

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visible light (Figure 2.3). When the reaction follows through an oxidative quenching cycle, the excited state photocatalyst PC✶ formed earlier is oxidized by giving an electron to the substrate molecule or the presence of oxidizing agent in reaction medium; on the other hand, in a reducing cycle (Figure 2.3), the excited state photocatalyst (PC✶) is reduced by taking an electron from the substrate molecule or the reducing agent present in the reaction mixture. The photocatalyst regeneration process comprises reduction of the oxidized form of the photocatalyst PC•+ in the oxidizing process and the photocatalyst PC•− (reduced form) is oxidized in the reductive process. In both the cases, the substrate molecule is an outside reagent or an intermediate which is formed in the reaction medium, and they were responsible for the photocatalyst regeneration, irrespective of whether the reactant goes through an ET reaction in the PET step or the catalyst regeneration process. In every quenching cycle, three common redox results are possible for the substrate molecule. The processes are net reductive, net oxidative, and net redox-neutral. Figure 2.4 describes the three processes along with taking a common specimen for each complete reaction. When the whole reaction process goes through an oxidative pathway, it needed an outside oxidative agent that can take up the electrons in both photoinduced and the catalyst regeneration steps. Similarly, when the reaction is overall net reductive, it contains an outer

Figure 2.3: The quenching cycles (oxidative and reductive) of a photocatalyst.

Figure 2.4: Redox results for photocatalysis methods.

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reducing agent which can donate electrons in PET or catalyst regeneration steps. The more complicated process is when the whole reaction process is redox-neutral, it frequently needs to return ET with oxidizing or reducing catalyst, sometimes a cocatalyst that is redox-active in nature.

2.4 Arene- and cyanoarene-containing organophotocatalyst 2.4.1 Photoredox-catalyzed arylation reactions Pandey group developed an elegant method for the synthesis of heterocyclic compound (+)-2,7-dideoxy-pancratistatin (4) via an interesting key step depicted in Figure 2.5 [22]. They start with (−)-quinic acid (1), which is extended to form the crucial intermediate silylenol ether 2 for the oxidative cyclization process. With the same type of conditions, they [23] developed a synthetic method for the preparation of heterocycle tetrahydroisoquinoline from 2 irradiated by visible light, and the catalyst DCN that used 2.4 mol% under air afforded the desired single diastereomeric product as 68% yield.

Figure 2.5: Photoredox-catalyzed formation of (+)-2,7-dideoxypancratistatin.

The mechanism proposed for these methods includes a single-electron oxidizing process by the catalyst which takes up the proton from the substrate molecule silyl enol ether (5) (Figure 2.6), and then by cyclization to provide a distonic radical cation 6. In the next step, the trimethylsilyl cation loses a proton and forms the cyclohexadienyl cation 7, which again lose a proton to deliver the final ketonic product (8). The photocatalyst DCN is regenerated through a one-electron oxidizing process by molecular oxygen, which forms the hydrogen peroxide in the later step.

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Figure 2.6: Proposed mechanistic pathway for the synthesis of (+)-2,7-dideoxypancratistatin.

2.4.2 Photoredox-catalyzed [3 + 2]-cycloaddition reactions This novel methodology is proposed for the synthesis of heterocyclic compound pyrrolidines by a unique substitute azomethine ylide. Starting from α,α-disilylamines (9) and then the intermediate azomethine ylides can be formed, which coupled with dipolarophiles (10) to produce the cyclic product pyrrolidine with good yields (11) (Figure 2.7) [24]. Through one-electron oxidation process from the starting compound α,α-disilylamines and then the silyl cation removed subsequently in the next two steps to form the final compound pyrrolidine 11. Also noted that after TMS is removed in the second step, the nonstabilized azomethine ylide is formed, which react with the dipolarophiles (10) and cyclize to form the product (11). Various olefins were examined, and the reaction process is high-degree functional group tolerance to form the respective products with 55–83% yield, and the geometry of the final products is same as the starting olefin. Arnold and Albini [25] reported a transformation for the synthesis of highly substituted tetrahydrofuran by an oxidative [3 + 2]-cycloaddition reaction via photoredoxcatalyzed process using epoxides and acrylonitrile in the presence of photocatalyst of DCN. Stilbene oxide (17) substituted as cis- and trans- easily react with the alkene (16) to form the respective products (18–19) with good yield (Figure 2.8). It is noted that the stereochemistry of the starting compounds is retained in the product molecules. From these observations, previous reports, and fluorescence quenching studies, they proposed a reaction mechanism for this process that is depicted in Figure 2.8. The photocatalyst DCN was excited by the visible light and takes up one electron to form the radical cation (22) of the

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Figure 2.7: Synthesis of pyrrolidine adducts by [3 + 2]-oxidative cycloaddition reactions.

starting compound. Then the radical cation (22) forms the carbonyl ylide (23) by opening the ring. The major product is 18 compared to 19 because of the 1,3-steric interactions of the phenyl ring in the intermediate formed after breaking of the C–C bond. The intermediates EE-23 and EZ-23 take up one electron from the catalyst to form the corresponding carbonyl ylides (24), which undergo through cyclization to afford the final product with stereochemistry same as the starting compounds. Mattay and coworkers [26−29] developed a photoinduced synthesis of 2,4-imidazolophanes from a variety of azirines and acetylene dicarboxylates (Figure 2.9). The photocatalyst DCN is used as sub-stoichiometric quantities to react azirines (25) with alkynes (26) to give the desired product pyrrolidine (27) with good-to-moderate yield. When the coupling partner was imines (29) instead of alkynes, imidazoles (30) were formed as the product with moderate yields (Figure 2.9). Mattay group reveals the detailed mechanistic investigations depicted in Figure 2.10 and found an aza-allenyl radical cation (32) as an important intermediate, which is formed via an oxidizing process of the starting substrate azirine (31) by the excited catalyst DCN✶. The author gives an explanation for the formation of this intermediate by trapping experiments of the radical. In the next step, the radical cation intermediate

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Figure 2.8: Formation of tetrahydrofuran by an oxidative [3 + 2]-cycloaddition reaction using epoxides and acrylonitrile.

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Figure 2.9: Photoinduced synthesis of 2,4-imidazolophanes from azirines and acetylene dicarboxylates.

Figure 2.10: Proposed mechanism for the synthesis of 2,4-imidazolophanes.

reacts with the imine to form the intermediate 33 and loss of proton in the next step formed the cycloaddition product imidazole (34) and regenerates the photocatalyst.

2.4.3 Anti-Markovnikov olefin hydrofunctionalization Gassman [30] in 1991 first reported a photocatalytic synthesis of anti-Markovnikov olefin hydrolactonization of acid-containing alkene 35 to give the product lactone 36 and a small amount of side product 37 (Figure 2.11). By examining various substrates with the standard process, the product is formed with good-to-excellent yield without any difficulties. If the reduction potential of the excited state cyanoarene decreased, the

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percentage of the formation of the antiproduct (36) increased. Notably, only catalytic amount of 40 (15 mol%) was used in combination with 15 mol% Ph-Phto to provide the lactonization product.

Figure 2.11: Photocatalytic synthesis of anti-Markovnikov olefin hydrolactonization.

A common mechanism for the anti-Markovnikov hydrofunctionalization reaction by single electron oxidation of alkene is depicted in Figure 2.12. The excited photooxidant (Ox✶) is reacted with the olefin that gives rise to an alkene radical cation (42). The addition of the various nucleophiles such as water, carboxylic acids, amines, alcohols, and cyanide forms the corresponding intermediate radicals 43 and 44. To control the reaction process toward the anti-Markovnikov pathway, the formation of the regioselective compounds of this reaction is where the addition occurs between the nucleophile and the olefinic compounds, which is likely the regiospecific reaction and it depends on the initial radicals (43 vs. 44) formed in the reaction [31]. In the next step,

Figure 2.12: Plausible reaction mechanism for olefin hydrofunctionalization.

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depending on the substitution present on the alkene molecule, two ways are possible to form the final product. When the reaction follows the pathway A, 44 is reduced by Ox•−and then the hydrogen transfer forms the final product (46) and regenerates the oxidative photocatalyst cyanoarene.

2.5 Benzophenones and quinones 2.5.1 Conjugate addition reactions of radical Recently, conjugate addition of a radical was the fruitful result of a work to use the solar light in synthetic methods by applying in reactor equipped with a mirror to concentrate the sunlight irradiation. The reaction between alcohol and acetal 52 with different unsaturated keto-substrates with aqueous soluble derivatives of benzophenone such as BPSS usually moderately yielded cycloaddition products 53–56 (Figure 2.13) [32]. If isopropanol is a radical precursor, it reacted with the substrate to form lactols 53 and lactones 54 and 55.

Figure 2.13: Sunlight-irradiated synthesis of lactols and lactones.

To prove the mechanism depicted in Figure 2.14, the authors did several control and quenching experiments. The mechanism begins with the removal of hydrogen atom from isopropanol (or acetal 52) by the excited photocatalyst BPSS✶. The addition of the radical 57 to the olefin 58 (or alkyne) and then the subsequent radical addition intermediate 59 to go through RHAT with ketyl radical formed earlier. Then the photocatalyst BPSS is regenerated, delivering the product 60. Subsequently, the cyclization reaction provides the final products 53–56 if i-PrOH is employed as a reactant.

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Figure 2.14: Plausible mechanism for the synthesis of lactols and lactones.

2.6 Pyryliums and thiapyryliums 2.6.1 Radical cation Diels–Alder reaction In 1999, Blechert and Steckhan [33] disclosed several 1,3-dienes that reacted and have described using TPT and p-methoxy-TPT as one-electron photoredox catalyst for the cyclic additions as shown in Figure 2.15. Different distinctive dienes such as 62, 64, and 66, all coupled with indoles (61) to furnish the indoline products 63, 65, and 67 in good yields. Notably, when the substrates 62 and 66 were used, these afforded a single-region isomeric compounds 63 and 67. Using PET for the imino-Diels–Alder process, various research groups reported using pyrylium salts as photocatalyst (Figure 2.16) [34–36]. Generally, electron-donating olefins are needed for the conversion where different coupling partners such as N-vinylcarbazole (68), N-vinylpyrrolidinone (71), and p-OMe-β-methylstyrene (74) reacted with the imines such as N-aryl benzaldehyde to give the tetra-hydroquinoline as the final product. Thiobenzophenone compounds also used the same type of reaction processes where pyrylium and thiapyrylium salts were used as photocatalysts [37, 38]. Miranda’s group has established the mechanistic pathway for the 4-heterocycle -substituted tetra-hydroquinoline derivatives. They used several experiments and DFT calculations for the reaction establishment. It was found that the mechanistic pathway is involved in one-electron oxidizing process of olefin since 77 was identified by the absorption spectrum (Figure 2.17). DFT calculations indicate that the imine reacted in an extremely asynchronous fashion which gives the intermediate 78. A 1,3-hydrogen shift succeeds to form the intermediate 79, and in the regeneration step of the catalyst, the final product (76) was formed.

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Figure 2.15: Diels–Alder reaction between indoles and exocyclic 1,3-dienes through the formation of radical cation.

Figure 2.16: Photocatalyzed Diels–Alder reaction: synthesis of 4-heterocycle-substituted tetrahydroquinoline derivatives.

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Figure 2.17: Plausible mechanism for the synthesis of tetra-hydroquinoline derivatives.

2.7 Acridiniums 2.7.1 Formation of heterocycles by oxygenation and oxidizing reactions Baeyer–Villiger oxidation reaction of cyclobutanones (80) catalyzed by photoredox catalyst Acr-Me+ was reported by Feng’s group [39] to deliver γ-lactones (81) as the final product in high-to-excellent yields, where 1.2 equiv of H2O2 was used (Figure 2.18). The highest yield of the products was found with important background reactivity: the authors performed the reaction in dark (the photocatalyst acridinium is used in the reaction medium) and gave moderate yield of the products 82–86 at ambient conditions, whereas at 80 °C, they observed 82% yield of the product formation.

Figure 2.18: 10-Methylacridinium-catalyzed Baeyer–Villiger oxidation of cyclobutanones.

2.7.2 Organophotocatalytic arene C–H functionalization Gonzalez-Gomez’s group has developed a dehydrogenation and lactonization of 2-benzoic acids (87) forming aroyloxy radicals catalyzed by Mes-Acr-Me+ via oxidative photoredox activity (Figure 2.19) [40]. With this developed method, the authors synthesized a huge

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number of substituted benzo-3,4-coumarins 88 in excellent yields, employing oxidizing agent (NH4)2S2O8. They were observed in variable degrees of regioselectivity when the substrate was substituted with 2-aryl group at 3-position (such as lactone 90). The mechanism proposed by the group gives the comparatively prolonged aroyloxy radical 92, fetching in a radical cyclized process on the neighboring phenyl ring to form an intermediate cyclohexadienyl radical 93. In the next step, the formation of the aromatic product was said to occur by consecutive one-electron oxidizing step and removal of proton or by hydrogen atom transfer (HAT) from 93. SO4•− is probably generated via the cleavage of S2O82−, and the photocatalyst is regenerated through the turnover step.

Figure 2.19: Organophotocatalytic dehydrogenative lactonization of 2-arylbenzoic acids.

2.7.3 Olefin hydrofunctionalization Alcohols such as allylic and propargylic that take part in the cyclization reaction (Figure 2.20, method 1) [41] formed cyclic ethers 99–104 (Figure 2.21) in a moderateto-good yield. An equivalent amount of PMN was needed in this reaction; however, extending the process to propiolic and acrylic acids (Figure 2.20, method 2) [42] needs a catalytic amount of 2,6-lutidine and disulfide or thiol as additives formed the corresponding products such as 105–107 (Figure 2.21) with good yields. The visible light PRCC method was also useful for the preparation of substituted γ-butyrolactam and pyrrolidine compounds such as 108–111 (Figure 2.21) with nucleophiles such as amide and amine (Figure 2.20, method 3) [43]. Last, o-benzyloxime acids could be coupled with alkenes in a photocatalytic PRCC to afford α-(benzyloxy)-amino-γ-butyrolactones (Figure 2.20, method 4) [44]. The photoredox catalyst Mes-Acr-Me+ was given a satisfactory result for high-catalytic performance, and HAT catalyst is diphenyl disulfide, which is

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optimal, giving the final products 112–115 (Figure 2.21) good-to-high yields and with variable diastereoselectivities (Figure 2.21, method 4).

Figure 2.20: Photocatalytic synthesis of heterocycles by anti-Markovnikov alkene hydrofunctionalization.

The Mes-Acr-Me+ and HAT catalysts allowed the intramolecular cyclized process of allylic amide substrate molecules (116) to the oxazoline compounds 117 (Figure 2.22) [45]. Especially, with this method, different oxazoline compounds were synthesized [46]. The photocatalytic method needs (PhS)2 as HAT catalyst and delivers the product with good to high yields. This reaction is supposed to be mechanistically same as hydrofunctionalization of the alkene which is discussed earlier. The amide oxygen attacks to the electrophilic center and subsequent transformation of the oxazoline molecule occurs by HAT. Thioamides 120 equally take part in the intramolecular cyclic process to form the respective products 121 with moderate-to-high yields, but the process seems to go together with a change in the mechanistic pathway.

2.7.4 Visible-light-induced formal [3 + 2]-cycloaddition reactions In 2014, Xuan et al. [47] reported the preparation of pyrroles 128 by the reaction between 2H-azirines 127 and alkynes 126 catalyzed by Mes-Acr-Me+ (Figure 2.23). This transformation gives 98% of the product yield that is not achieved with other photoredox catalysts other than Mes-Acr-Me+ such as Ru(bpy)32+ or Ir(ppy)2(dtbbpy), which highlighted the ability of the catalyst Mes-Acr-Me+✶ to oxidize the substrate molecules with higher potentials [Eox(127•+/127) = +1.65 V vs. Ag/AgNO3]. Using different substituents such as activated alkynyl compounds 126 and azirine 127 gives diversely substituted products in high-to-excellent yields.

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Figure 2.21: Synthesis of differently substituted heterocycles by alkene hydrofunctionalization.

Figure 2.22: Efficient oxidative synthesis of thioamide and 2-oxazolines.

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Figure 2.23: Visible-light-induced formal [3 + 2]-cycloaddition for pyrrole synthesis.

Recently, a double-step synthetic method has been reported for [3 + 2]-cycloaddition of oxazoles 142 using a photoredox-mediated process of 2H-azirines 141 with aldehydes 140 (Figure 2.24) [48]. The mechanistic pathway postulated started with the formation of aza-allenyl radical cation from the aldehyde 140 through the oxygen of the aldehyde. In the next step, the cation radical 149 is cyclized and reduced by Mes-Acr-Me• to form 151 and this is oxidatively aromatized by DDQ to deliver the final product 2,5dihydrooxazoles 152.

Figure 2.24: [3 + 2]-Cycloaddition/oxidative aromatization sequence via photoredox catalysis: one-pot synthesis of oxazoles.

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2.8 Xanthenes dyes: fluoresceins and rhodamines 2.8.1 Visible-light-initiated oxidations and oxygenations Wang’s group reported that arylsulfinyl radicals are formed from sulfinic acids and the radicals react with alkynes 154 (Figure 2.25) [49] to produce a vinyl radical intermediate 160 and subsequently a cyclization reaction to an alkyne. The oxidative aromatization of the radical intermediate finally leads to the formation of final product coumarin 155 with a good yield. The authors proposed a mechanistic pathway initiated by the formation of t-BuO• via oxidizing quenching process of excited eosin Y [EY]✶, followed by a HAT from the sulfinic acid 153. Regeneration of the photocatalyst might happen by taking up one electron from the excited radical catalyst of a cyclo-hexadienyl radical intermediate 161.

Figure 2.25: Visible-light-induced cyclization of phenyl propiolates with sulfinic acids to form the coumarin.

In 2015, Zhang and coworkers [50] described that α-amino radicals can start a cascade cyclization process with maleimides 163 to form a hexagonal ring 164 (Figure 2.26) similar to a Povarov reaction. The photocatalyst eosin Y was used by group under the aerobic conditions with good yields of the final product tetra-hydroquinolines 164. The authors found that the reaction of dimethylanilines 162 with a number of N-aryl or N-methyl maleimides 163 gives the products with good yields. The mechanism was established, and it proceeds via the radical cascade cyclization depicted in Figure 2.26. It subsequently forms the cyclohexadienyl radical intermediate 171. Finally, the desired product is formed by an oxidative step and in the aromatization step which is proceeded through the O2•− to abstract a hydrogen atom. In 2014, Rueping and coworkers [51] reported an organophotoredox-catalyzed process where maleimides are used as a coupling partner in a cyclized process of tertiary alkylamines: the desired product pyrrolo-isoquinolines 174 is prepared from

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Figure 2.26: Visible-light-initiated oxidative cyclization of N,N-dimethylanilines with maleimides for the synthesis of a hexagonal ring containing heterocycles.

tetra-hydroisoquinolines in a double-step process (Figure 2.27). In the first step, the photoredox catalyst rose Bengal mediated the cyclization process, and in the next step, the NBS was added to give the final heterocyclic compounds such as 175–177. It was noted that the reaction proceeds via the intermediate 179, which is formed from the intermediate 178.

Figure 2.27: Visible-light photoredox-catalyzed synthesis of pyrrolo-isoquinolines through organocatalytic [3 + 2]-cycloaddition reaction.

Xiao et al. [52] recently described an organophotoredox-catalyzed method where sodium salt of eosin Y-catalyzed methodology and hydrazines 181 were used as the

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C-centered radical precursors by a visible-light-mediated aerial oxidative cyclization of 2-isocyanobiphenyls (Figure 2.28)].

Figure 2.28: Oxidative cyclization of 2-isocyanobiphenyls for the synthesis of phenanthridines.

The conditions of aerial oxidative process of cyclization of 2-isocyanobiphenyls shown in Figure 2.29 are catalyzed by eosin Y (EY-TBA2) and proposed a comparatively mild synthesis of benzoxazoles (194–198). The substrate scope of this reaction is very high, and imines are also used as the coupling partner to form the corresponding products. In 2015, Yadav’s group [53] disclosed an effective synthetic methodology of 1,3,4oxadiazoles where eosin Y was used as the organophotocatalyst for the cyclization process of semicarbazones 199 to 1,3,4-oxadiazoles 200 (Figure 2.30). This process essentially needs CBr4 and light, although they used a catalytic amount of eosin Y (1 mol%) to give maximum yields of the desired product and atmospheric O2 as the oxidizing agent. The preparation of one more class of heterocyclic compounds was supported by eosin Y as organophotocatalyst. 1,2,4-Thiadiazole 208 heterocyclic compounds could be synthesized from thioamide 207 as the precursor under atmospheric conditions using O2 as the sole oxidant (Figure 2.31) [54]. This oxidization process delivered the heterocyclic compound 1,2,4-thiadiazoles 209–211 as the final product in high yield

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Figure 2.29: Eosin Y-catalyzed oxidative cyclized process for the preparation of 2-isocyanobiphenyls.

Figure 2.30: Photocatalytic oxidative cyclization of semi-carbazones for the synthesis of 1,3,4-oxadiazoles.

with symmetrically substituted alkyl, aryl, or heteroaryl group. Yadav group suggested that a photoredox-catalyzed oxidative process of thioamide 207 by [EY]✶ yields a thione-centered cation radical, deprotonation following a dimer formation of the compound 213 to form the product with an S–-N bond. In an extra step oxidizing and deprotonating the intermediate give the thiyl radical 215, oxidization by the aerial oxygen, most probably a superoxide molecule. The loss of “SO22−” in the last step formed by the heterocyclic ring. Yadav’s group [55] in 2015 reported a visible-light-induced difunctionalization of arenes for the synthesis of 5-aryl-2-imino-1,3-oxathiolanes (Figure 2.32). By the photocatalyst eosin Y, a thiocyanate radical SCN• was formed by PET, and addition of this

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Figure 2.31: Visible-light-induced oxidative-cyclized process for the synthesis of 1,2,4-thiadiazoles catalyzed by eosin Y.

Figure 2.32: Preparation of 5-aryl-2-imino-1,3-oxathiolanes by a light-induced functionalization of styrenes.

molecule to alkene in the next step and the desired product 2-imino-1,3-oxathiolanes are formed. Compared to the photocatalyst, Rose Bengal (72% yield) and eosin Y gave higher yield (92% yield) under the same reaction conditions.

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In 2015, Leonori group [56] described a visible-light-induced formation of N-centered radical hydro-imination and imino-hydroxylation cyclization where eosin Y is used as the organophotocatalyst (Figure 2.33). The N-centered radicals of iminyl are hardly formed but a very useful intermediate is established by Leonori group.

Figure 2.33: Visible-light-induced N-centered radicals that mediate hydro-imination and iminohydroxylation cyclization reactions.

Konig group [57] reported a visible light photocatalytic process for the preparation of benzothiophenes, a mechanistically related transformation using eosin Y as an organophotocatalyst (Figure 2.34), where the salts of 2-methylthioaryldiazonium 136 reacted with alkynes 137 to generate benzothiophenes 138. With this methodology, various substituted benzothiophenes were formed with high yields from different 2methylthioaryldiazonium salts with alkynes or alkyl butynedioates.

2.9 Conclusions In this chapter, we have attempted to summarize the organophotoredox-catalyzed synthesis of heterocyclic compounds delivered by synthetic organic chemists with the newly designed tools to spread over to the diverse fields in organic chemistry. The amazing group of reaction activity including C–H functionalizations, cycloadditions, and atom transfer cyclic reactions, hydrofunctionalization of alkene and bond-breaking reactions hold potential for effectiveness in organosynthetic chemistry. Significantly, using the organophotocatalyst, the overall reaction conditions are mild in nature which enable tolerance for various complex functional groups. In spite of the important advances in the last few decades in this field, there remain many scopes for further investigations and developments. Regarding the development of organophotoredox catalyst,

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Figure 2.34: Visible-light-initiated photocatalytic synthesis of benzothiophenes from aryldiazonium salts and alkynes.

clearly there is a scarcity of highly reducing catalyststhat exist, and to identify more novel organophotocatalysts is always in demand. Moreover, even there are numerous reports on C−H functionalization employing organophotoredox catalysis, and many challenges still remain, such as site-specific reaction and C−H bond functionalizations that are very strong in nature. Methodologies that control the enantioselectivity of the molecules are rare and remain as new challenges for the research scientists. The applications of natural product synthesis using organophotoredox catalysts have just started, which will be fascinating to watch how these procedures are applied in the field of complex natural product synthesis. Finally, how the organophotoredox catalysts will use the other fields such as material and biological science remain to be seen. All these scientific fields become sure to convey the fascinating and significant science for years to come.

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[24] Pandey, G, Lakshmaiah, G, Kumaraswamy, G. A new and efficient strategy for non-stabilized azomethine ylide via photoinduced electron transfer (PET) initiated sequential double desilylation. J Chem Soc Chem Commun 1992, 1313–1314. [25] Albini, A, Arnold, DR. Radical ions in photochemistry. 6. The photosensitized (electron transfer) ring opening of aryloxiranes. Can J Chem 1978, 56, 2985–2993. [26] Muller, F, Mattay, J. [3 + 2] Cycloadditions with azirine radical cations: A new synthesis of N-substituted imidazoles. Angew Chem Int Ed Engl 1991, 30, 1336–1337. [27] Muller, F, Mattay, J. A new synthesis for imidazolo- and pyrrolophanes by [3+2] cycloaddition with azaallenyl radical cations. Angew Chem Int Ed Engl 1992, 31, 209–210. [28] Mueller, F, Mattay, J, Steenken, S. Radical ions and photochemical charge-transfer phenomena. 39. Cycloadditions. 42. Radical cation [3 + 2] cycloadditions of 2H-azirines. Mechanistic studies concerning the intermediate radical cation. J Org Chem 1993, 58, 4462–4464. [29] Albrecht, E, Averdung, J, Bischof, EW, Heidbreder, A, Kirschberg, T, Muller, F, Mattay, J. Photoinduced electron transfer (PET) in organic synthesis. [3 + 2]-Type cycloaddition, cyclization and C-C bond cleavage reactions. J Photochem Photobiol A 1994, 82, 219–232. [30] Gassman, PG, De Silva, SA. Use of sterically hindered sensitizers for improved photoinduced electron-transfer reactions. J Am Chem Soc 1991, 113, 9870–9872. [31] Arnold, DR, Chan, MS, McManus, KA. Photochemical nucleophile-olefin combination, aromatic substitution (photo- NOCAS) reaction, Part 12. Factors controlling the regiochemistry of the reaction with alcohol as the nucleophile. Can J Chem 1996, 74, 2143–2166. [32] Dondi, D, Protti, S, Albini, A, Carpio, SM, Fagnoni, M. Synthesis of γ-lactols, γ-lactones and 1,4monoprotected succinaldehydes under moderately concentrated sunlight. Green Chem 2009, 11, 1653–1659. [33] Peglow, T, Blechert, S, Steckhan, E. Radical cation Diels−Alder reaction between indoles and exocyclic 1,3-dienes with incorporated intentional cleaving points. Chem Commun 1999, 5, 433–434. [34] Zhang, W, Jia, X, Yang, L, Liu, ZL. Photosensitized Diels−Alder reactions of N-arylimines: Synthesis of tetrahydroquinoline derivatives. Tetrahedron Lett 2002, 43, 9433–9436. [35] Zhang, W, Guo, Y, Liu, Z, Jin, X, Yang, L, Liu, ZL. Photochemically catalyzed Diels−Alder reaction of arylimines with N-vinylpyrrolidinone and N-vinylcarbazole by 2,4,6-triphenylpyrylium salt: Synthesis of 4-heterocycle-substituted tetrahydroquinoline derivatives. Tetrahedron 2005, 61, 1325–1333. [36] Perez-Ruiz, R, Domingo, LR, Jimenez, MC, Miranda, MA. Experimental and theoretical studies on the radical-cation-mediated imino-Diels-Alder reaction. Org Lett 2011, 13, 5116–5119. [37] Arguello, JE, Perez-Ruiz, R, Miranda, MA. Novel [4+2] cycloaddition between thiobenzophenone and aryl-substituted alkenes via photoinduced electron transfer. Org Lett 2007, 9, 3587–3590. [38] Domingo, LR, Perez-Ruiz, R, Arguello, JE, Miranda, MA. DFT study on the molecular mechanism of the [4 + 2] cycloaddition between thiobenzophenone and arylalkenes via radical cations. J Phys Chem A 2009, 113, 5718–5722. [39] Xu, HJ, Zhu, FF, Shen, YY, Wan, X, Feng, YS. Baeyer-Villiger oxidation of cyclobutanones with 10-methylacridinium as an efficient organocatalyst. Tetrahedron 2012, 68, 4145–4151. [40] Ramirez, NP, Bosque, I, Gonzalez-Gomez, JC. Photocatalytic dehydrogenative lactonization of 2-arylbenzoic acids. Org Lett 2015, 17, 4550–4553. [41] Grandjean, JMM, Nicewicz, DA. Synthesis of highly substituted tetrahydrofurans by catalytic polarradical-crossover cycloadditions of alkenes and alkenols. Angew Chem Int Ed 2013, 52, 3967–3971. [42] Zeller, MA, Riener, M, Nicewicz, DA. Butyrolactone synthesis via polar radical crossover cycloaddition reactions: Diastereoselective syntheses of methylenolactocin and protolichesterinic acid. Org Lett 2014, 16, 4810–4813. [43] Gesmund, NJ, Grandjean, JMM, Nicewicz, DA. Amide and amine nucleophiles in polar radical crossover cycloadditions: Synthesis of γ-lactams and pyrrolidines. Org Lett 2015, 17, 1316–1319.

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[44] Cavanaugh, CL, Nicewicz, DA. Synthesis of α-benzyloxyamino-γ-butyrolactones via a polar radical crossover cycloaddition reaction. Org Lett 2015, 17, 6082–6085. [45] Morse, PD, Nicewicz, DA. Divergent regioselectivity in photoredox-catalyzed hydrofunctionalization reactions of unsaturated amides and thioamides. Chem Sci 2015, 6, 270–274. [46] Schwekendiek, K, Glorius, F. Efficient oxidative synthesis of 2-oxazolines. Synthesis 2006, 2006, 2996–3002. [47] Xuan, J, Xia, XD, Zeng, TT, Feng, ZJ, Chen, JR, Lu, LQ, Xiao, WJ. Visible-light-induced formal [3+2] cycloaddition for pyrrole synthesis under metal-free conditions. Angew Chem Int Ed 2014, 53, 5653–5656. [48] Zeng, TT, Xuan, J, Ding, W, Wang, K, Lu, LQ, Xiao, WJ. [3 + 2] Cycloaddition/oxidative aromatization sequence via photoredox catalysis: One-pot synthesis of oxazoles from 2H-azirines and aldehydes. Org Lett 2015, 17, 4070–4073. [49] Yang, W, Yang, S, Li, P, Wang, L. Visible-light initiated oxidative cyclization of phenyl propiolates with sulfinic acids to coumarin derivatives under metal-free conditions. Chem Commun 2015, 51, 7520–7523. [50] Liang, Z, Xu, S, Tian, W, Zhang, R. Eosin Y-catalyzed visible-light-mediated aerobic oxidative cyclization of N,N-dimethylanilines with maleimides. Beilstein J Org Chem 2015, 11, 425–430. [51] Vila, C, Lau, J, Rueping, M. Visible-light photoredox catalyzed synthesis of pyrroloisoquinolines via organocatalytic oxidation/[3+2] cycloaddition/oxidative aromatization reaction cascade with rose bengal. Beilstein J Org Chem 2014, 10, 1233–1238. [52] Xiao, T, Li, L, Lin, G, Wang, Q, Zhang, P, Mao, Z, Zhou, L. Synthesis of 6-substituted phenanthridines by metal-free, visible-light induced aerobic oxidative cyclization of 2-isocyanobiphenyls with hydrazines. Green Chem 2014, 16, 2418–2421. [53] Kapoorr, R, Singh, S, Tripathi, S, Yadav, L. Photocatalytic oxidative heterocyclization of semicarbazones: An efficient approach for the synthesis of 1,3,4-oxadiazoles. Synlett 2015, 26, 1201–1206. [54] Srivastava, V, Yadav, A, Yadav, L, Eosin, Y. catalyzed visible-light-driven aerobic oxidative cyclization of thioamides to 1,2,4-thiadiazoles. Synlett 2013, 24, 465–470. [55] Yadav, AK, Yadav, LDS. Visible-light-mediated difunctionalization of styrenes: An unprecedented approach to 5- aryl-2-Imino-1,3-oxathiolanes. Green Chem 2015, 17, 3515–3520. [56] Davies, J, Booth, SG, Essafi, S, Dryfe, RAW, Leonori, D. Visible-light-mediated generation of nitrogencentered radicals: Metal-free hydroimination and iminohydroxylation cyclization reactions. Angew Chem 2015, 127, 14223–14227. [57] Hari, DP, Hering, T, Konig, B. Visible light photocatalytic synthesis of benzothiophenes. Org Lett 2012, 14, 5334–5337.

Rahul Dev Mandal, Moumita Saha, and Asish R. Das✶

Chapter 3 Synthesis of imidazo[1,2-a]pyridines and indazole under metal-free conditions 3.1 Introduction Nitrogenous heterocycles are one of the most important and widely explored motifs due to their biological, medicinal and pharmacological importance. Because of their numerous uses in biomedical field, the N-heterocyclic compounds bearing indazole and imidazopyridine motifs are both significantly fused bicyclic 5–6 heterocyclic compounds known as “drug prejudice” scaffolds. Imidazopyridine and indazole both are displaying a broad area in pharmacological action such as anti-inflammatory, antitumor, antifungal, antiviral, antibacterial, antiprotozoal, analgesic, antipyretic, hypnoselective, antiapoptotic, and anxioselective activities [1–12]. A variety of drugs containing imidazole and indazole moieties such as zolpidem (1) [13], alpidem (2) [14], olprinone (3) [15], Riociguat (4), CCR1 antagonists (5), and lonidamine (6) [16–19] are widely available in the market (Figure 3.1). Since today, these two classes of heterocycles are widely studied, and various methods have been reported to synthesize them. But among the reported methods metal-free synthetic route has wide advantages over metal-catalyzed synthesis and for this reason metal-free procedure grabbed the attention of many researchers. This method is inexpensive, nontoxic, requires comparatively less complex and benign reaction conditions, and more eco-friendly as it does not produce any caustic wastes. Due to this importance of the described nitrogenous heterocycles and the nonmetal synthetic protocol, we collect the recent important advances related to this, which will be helpful to the readers working in this field. In this chapter, we present an overview of the many methods used to synthesize the imidazo[1,2-a]pyridineandindazole.

Acknowledgments: We acknowledge the financial support from University of Calcutta, India. R. D. M. thanks the CSIR, New Delhi, India, for his Senior Research Fellowship (file no.: 09/028(1056)/2018-EMR-I). ✶

Corresponding author: Asish R. Das, Department of Chemistry, University of Calcutta, Kolkata 700009, India, e-mail: [email protected] Rahul Dev Mandal, Moumita Saha, Department of Chemistry, University of Calcutta, Kolkata 700009, India https://doi.org/10.1515/9783110985474-003

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Figure 3.1: Imidazopyridine and indazole-based drugs.

3.2 Established techniques to synthesize imidazopyridines Because of the significance of imidazopyridines in drug design, several publications on their synthetic route have been emerged. Herein, we try to provide an organized literature of several procedures for the making of imidazo[1,2-a]pyridineunder metalfree conditions involving multicomponent reactions, cyclization reactions, microwave-assisted reactions, condensation reactions, and photocatalytic reactions.

3.2.1 Synthesis of imidazo[1,2-a]pyridine derivatives through multicomponent reactions Multicomponent reactions have emerged in the present years as one of the most effective methods in synthesizing biologically important N-heterocyclic compounds. The key characteristics of these reactions are high atom economy, ease to use, time and energysaving, eco-friendliness, and finally goal-oriented coupled with variety-concerned synthetic output [20]. In several research areas, including biomedical field and pharmaceutical chemistry, these reactions have received a lot of interest during organic product generation [21, 22].

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Molecular iodine efficiently acts as a mediator during the synthesis of several heterocycles in the present time due to its significant function in the construction of C–N, C–-C, and C-hetero bonds during oxidative coupling reactions [23, 24]. Due to nontoxicity, ready accessibility, and cost-effectiveness in comparison to transition metal, molecular iodine has widely employed for the synthesis of various types of heterocyclic compound and biologically active molecules [25]. In 2018, Kour et al. [26] reported an easy and effective way to synthesize 2-aroyl3-aryl imidazo[1,2-a]pyridines (9) through the iodine-NH4OAc enhanced one-pot multicomponent reaction by using iodine as a key reagent under metal-free condition from the various types of 1,3-diaryl-prop-2-en-1-ones (8) and various derivatives of 2aminopyridine (7). Mechanistically, iodonium intermediate A is developed through the reaction between 1,3-diaryl-prop-2-en-1-ones (8) and molecular iodine. Then to create intermediate C through Ortoleva-King-type intermediate B, the attack by the endocyclic pyridine nitrogen on the beta-center of the intermediate A has taken place. After that, intermediate D has formed through the cyclization of intermediate C. Finally, the desired product (9) is formed through the aerial oxidation of intermediate D (Figure 3.2). A difficult challenge in the area of organic synthesis is the preparation of C3-functionalized imidazopyridines. However, multicomponent processes haven’t yet been investigated for the synthesis procedure of 3-substituted imidazo[1,2-a]pyridines. However, using a productive one-pot multicomponent technique followed by the involvement of organosulfur chemistry [27, 28], the C3-functionalization of imidazo[1,2-a]pyridines became viable. In 2019, Reddy et al. [29] reported a synthetic pathway for the construction of 3sulfenylimidazo[1,2-a]pyridines(13) via multicomponent reaction of α-bromomethyl ketones (10), 2-aminopyridine derivatives (7) and thiosulfonates (12). Upon application of sodium halides, K2S2O8 produces C3-halogenated imidazo[1,2-a]pyridines(14). The process includes the formation of pyridinium salt A by the help of nucleophilic substitution reaction of (7) and (10) in the presence of NaHCO3 which undergoes elimination and intramolecular condensation reaction to provide the synthesis of imidazo [1,2-a]pyridines (11). The bromine radical attack at the C3 position of 11 to produce the intermediate C. After that intermediate D produce via oxidation procedure with the help of sulfur radical. Deprotonation of the D results in the creation of product 14. Molecular iodine reacts with the thiosulfonate (12) to form the electrophilic species PhSI. Imidazolinium intermediate C′ produces through the regioselective sulfenylation (PhS +) at the C3-position of 11. After that proton migration of sulfenylated product C′ to give intermediate D′. Finally the sulfenylimidazo[1,2-a]pyridine(14) is synthesized through the deprotonation of D′ (Figure 3.3). Ramezanpour et al. [30] in 2017 synthesized 3-iminosaccharin scaffolds through the multicomponent-type reaction. In 2020, they have expanded on this research with the help of 2-aminopyridine (7). They constructed a route for the synthesis of imidazo [1,2-a]pyridine derivatives (19) with the help of benzaldehydes (15), cyanides (16),

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Figure 3.2: Synthesis of imidazopyridine with the help of three components.

2-aminopyridine 7 and utilizing an organocatalyst like saccharine (18) [31]. Mechanistically, the lone pair of the NH2 group of 2-aminopyridine (7) attacks to the electrophilic site of benzaldehyde derivatives (15) to produce imine A. After that this imine A under the acid catalyst saccharine results in the formation of intermediate B which undergoes intramolecular interaction, followed by the tautomerism to produce target imidazopyridine (19) (Figure 3.4).

3.2.2 Synthesis of imidazopyridine derivatives through cyclization reactions The metal-free cyclization process has been extensively studied for the production of biologically important N-heterocycle derivatives [32]. It is anticipated that an intramo-

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Figure 3.3: Synthesis of imidazopyridine by the multicomponent approach.

lecular cyclization process will produce imidazo[1,2-a]pyridines with a higher yield [33, 34]. Nowadays significant progress has been achieved in the preparation of imidazo[1,2-a]pyridines via cyclization processes. Halogen-containing imidazo[1,2-a]pyridines are biologically significant N-heterocyclic compound due to a wide range of applications in materials science and pharmaceutical chemistry [35–37]. Adimurthy and coworkers [38] reported a traditionally halogenation process for the preparation of halo-containing imidazopyridines. To synthesize halogen-containing imidazopyridine such as 3-bromo-imidazo[1,2-a] pyridines(21) using an atom-efficient techniques, in 2019, Liu et al. [39] develop an I2/ TBHP-mediated one-pot tandem cyclization process by the reaction between 2-aminopyridine derivatives 7 and α-bromoketones (20) with the outstanding yield under the metalfree condition. In this reaction, I2 helps the oxidative cyclization and TBHP (tertbutyl hydrogenperoxide) act as a catalyst. [40] Mechanistically, initially, pyridinium salt A is produced by the help of displacement of halo group of α-bromoketones by the nitrogen

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Figure 3.4: Synthesis of different types of imidazopyridine by the multicomponent approach.

of pyridine moiety, after that intermediate B is formed through the ring-closing procedure of pyridinium salt A. By the oxidation process of TBHP, the released HBr is converted into Br. Finally, the required product 21 was produced by the bromination of intermediate B (Figure 3.5). In 2019, Chen et al. [41] established a straightforward, environmentally friendly, and one-pot method for producing different imidazo[1,2-a]pyridines (23) with the ethyl acetate and water combination as a solvent under the metal-free condition with the excellent yields. N-bromosuccinimide (NBS) (22) is served as both a source of bromine and an oxidant. In this reaction a catalytic amount of AIBN is used. This methodology offers an efficient, quick, and ecologically responsible method for the preparation of biologically important imidazo[1,2-a]pyridinesderivatives (Figure 3.6).

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Figure 3.5: Synthesis of various imidazo[1,2-a]pyridines with the α-bromoketones via cyclization process.

The imidazo[1,2-a]pyridine and 1,2,3-triazole cores both are attentive in biological and pharmaceutical field. To create a novel hybrid framework by combining several scaffolds in order to produce a pharmacologically active compound, in 2020, Ashok et al. [42] developed a synthetic pathway for the construction of imidazo[1,2-a]pyridines(26) via structural combination of 1,2,3-triazole. In the presence of NH4OAc as a mild base and iodine as a catalyst, using aromatic ketones (24) and commercially available 2aminopyridine derivatives (25), they conveyed a number of novel 2-(5-methyl-1-aryl1H-1,2,3-triazol-4-yl) imidazo[1,2-a]pyridine (26) derivatives with good to excellent yield (Figure 3.7). The bioactivity was increased by changing the C3 position of the imidazo[1,2-a] pyridine ring [43, 44]. In 2021 Vuillermet et al. [45] approached the synthesis of complicated imidazo[1,2-a]pyridines. They report a route for the synthesis of imidazo[1,2a]pyridines (29) in yields ranging from fair to outstanding using 2H-azirines (27) and 2-chloropyridines 28. Mechanistically, first 2H-azirines (27) are activated by Tf2O in the presence of 2-chloropyridines (28) to form intermediate A. Stable pyridinium salts B are produced when the A is combined with 2-chloropyridine (28). The intermediate B can go in either of two directions. Direction I, bicyclic salt D, is produced via the rearrangement of intermediate B, after that bicyclic salt D is neutralized in the presence of base and give the intermediate E. According to direction II, to create zwitterionic intermediate C, intermediate B goes through ring-opening reaction in the

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Figure 3.6: Synthesis of various imidazo[1,2-a]pyridines by the cyclization process.

presence of base and then through intramolecular SNAr to create E. The required product (29) is produced by the elimination of N-triflate group from the E with concurrent rearrangement (Figure 3.8).

3.2.3 Synthesis of imidazopyridine derivatives through microwave-assisted reactions For the past 10 years, synthetic organic researchers have continuously focused on microwave-assisted reactions. It has been considered as a potent instrument for the synthesis of organic compound. Advancements of microwave-assisted reactions for the

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Figure 3.7: Synthesis of a hybrid of imidazo[1,2-a]pyridines with 1,2,3-triazole.

organic synthesis are (a) increase the reaction time, (b) good to excellent product yield and (c) several types of carbon-heteroatom bond formation [46]. In comparison to traditional heating procedure, microwave irradiation approach is better due to high yield and mild reaction condition as well as speeds up the rate of reaction in the preparation of organic compounds. With the help of a solvent like water, organic synthesis using microwave has received a lot of interest due to the nonflammability and nontoxicity of water [47, 48]. In 2018, Rao et al. [49] reported a synthetic method for the synthesis of imidazo [1,2-a]pyridines (31) with the good to excellent yield in H2O-IPA (isopropyl alcohol) as the reaction medium under greener conditions. The authors proposed a heteroannulation reaction between 2-aminopyridines (7) and α-bromoketones (30) under the metal-free condition to produce the target molecule. Mechanistically, N-alkylated adduct A is formed through the nucleophilic substitution reaction of 2-aminopyridines 7 and phenacyl bromides (30) to give intermediate B followed by removing HBr. The intermediate C is formed with the help of intramolecular cyclization of amine with the carbonyl group of ketones and subsequently a proton exchange. Then water is eliminated from the intermediate C to produce the target imidazo[1,2-a]pyridine derivatives (31) (Figure 3.9).

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Figure 3.8: Synthesis of imidazo[1,2-a]pyridines with 2H-azirines and 2-chloropyridines.

The imidazo[1,2-a] pyridine 3-carbaldehydes are frequently utilized as a scaffold to incorporate different heterocycles into a wide range of bioactive structure [50]. The several ways for the synthesizing imidazo[1,2-a] pyridine 3-carbaldehydes have been described. There are a lot of problems for the synthesizing of imidazo[1,2-a] pyridine 3-carbaldehydes including (a) lengthy reaction times, (b) expensive metal catalyst, (c) high reaction temperature and (d) producing side product [51]. Kusy et al. [52] in 2019 synthesized 3-formyl imidazo[1,2-a]pyridines (33) through the microwave-assisted protocol under metal-free condition. In this process, 2-aminopyridine (7) and bromomalonaldehyde (32) were used to synthesize 3-formyl imidazo[1,2-a] pyridines (33). Mechanistically, at first 2-aminopyridine attacks on the bromomalonaldehyde (32); after that the water is removed, and an intermediate imine A and an enamine B are formed. By intramolecular cyclization and removing the bromide anion from intermediate B, the product 33 was produced (Figure 3.10). The most effective method for producing an imidazo[1,2-a]pyridine moiety is the multicomponent Groebke-Blackburn Bienayme reaction (GBBR) [53]. In the

Chapter 3 Synthesis of imidazo[1,2-a]pyridines and indazole under metal-free conditions

Figure 3.9: Synthesis of imidazo[1,2-a]pyridines via microwave irradiation process.

Figure 3.10: Synthesis of imidazo[1,2-a]pyridines via microwave irradiation process.

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modern years, nongreen methods have also been used to synthesize chromone and imidazo[1,2-a]pyridine [54]. To create a sustainable approach, in 2020, Zarate-Hernández et al. [55] developed a productive microwave-assisted way for the synthesis of a series of imidazo[1,2-a] pyridinchromones (36) under metal-free condition with short reaction time as well as good to excellent yields. Utilizing ethanol as a solvent, the imidazo[1,2-a]pyridinchromones (36) were prepared from the 3-formyl-chromone (34), 2 aminopyridines (7), and isocyanides (35) (Figure 3.11).

Figure 3.11: Synthesis of imidazo[1,2-a]pyridines with 3-formyl-chromone via microwave-assisted approach.

For the preparation of imidazo[1,2-a]pyridine analogues with a variety of side chain, including the modification of the physicochemical characteristics, their function, and applicability, the production of far more effective fluorophores and bioactive chemicals is a subject of significant new attention [56–58].

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In 2020, Rodríguez et al. [59] described a new microwave irradiation-aided method for the synthesis of imidazo[1,2-a]pyridines(38) from 2-aminopyridine 7 and phenacyl bromide (37) with good to outstanding yields. Microwave irradiation is used to produce phenacyl bromide derivatives (37) from the bromination process of acetophenones (Figure 3.12).

Figure 3.12: Synthesis of imidazo[1,2-a]pyridines with phenacyl bromide via microwave-assisted approach.

3.2.4 Synthesis of imidazopyridine derivatives through condensation reactions A crucial procedure in synthetic organic chemistry is the condensation process, which produce a variety of organic compounds. Many researchers have recently used these methods to synthesize heterocyclic compounds [60]. In 2020, Bhutia et al. [61] created a straightforward, environmentally friendly synthetic methodology. They revealed that I2 promoted a unique, ecologically friendly, and effective method for synthesizing 2-arylimidazo[1,2-a]-pyridine derivatives (42) at room temperature in aqueous media. The target product is produced by the condensation of different types of aryl methyl ketones (39/40) derivatives and 2-aminopyridine

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derivatives (41) with the gentle heating in micellar medium with good to outstanding yields. The researchers also developed the procedure using NH4Cl in moderately acidic circumstances at room temperature. Initially, acetophenone 39 reacts with the 2-aminopyridine (41) and formation of Schiff’s base A. Iodine enhances tautomerization by acting as a Lewis acid to form a partial bond with imine. The cyclic intermediate D is developed by the attacking of enamine into the pyridyl nitrogen. The final product, 2-arylimidazo[1,2-a]-pyridine (42), is produced by oxidative aromatization, which is aided by the dissolved oxygen in water (Figure 3.13).

Figure 3.13: Synthesis of imidazo[1,2-a]pyridines with acetophenone via condensation process.

In the pharmaceutical industry, it is still extremely desirable to create more efficient, environmentally friendly, and sustainable synthetic processes that can eliminate or significantly reduce the use of hazardous solvents and catalysts for making imidazo[1,2-a]pyridines. Grindstone chemistry has become a potential sustainable method for conducting solvent-free solid-state reactions in a variety of chemical domains [62–67] by the help of mortar and pestle for grinding all the solid reactants. In keeping with this focus in employing grind stone technology to create solventfree solid-state processes, Godugu et al. in 2021 [68] described a synthetic route for the production of 2-substituted imidazo[1,2-a]pyridines(45) from the reaction between

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bromomethyl ketones (44) and 2-aminopyridine derivatives (43) under the solvent and transition metal-free condition utilizing a grindstone method for 3–5 min at 25–30 °C (Figure 3.14).

Figure 3.14: Synthesis of imidazo[1,2-a]pyridines via condensation process.

3.2.5 Synthesis of imidazopyridine derivatives through photocatalytic reactions To eliminate the usage of expensive costly transition metal catalysts or other hazardous dyes, the scientists have concentrated on photochemical processes [69]. There are various types of difficulties to synthesize heterocyclic compounds using heat-promoted multicomponent processes including (i) deficiency of specificity, (ii) high thermal energy, and (iii) the development of unstable intermediates. Various research group developed that in the photocatalytic methodology, the photocatalyst abstract a single proton from the Ncentre of amine [70, 71]. In 2016, Yadav et al. [72] proposed an environmentally efficient, transition metalfree, one-pot visible light-catalyzed technology for exceptionally regioselective synthesis of 2-nitro-3-arylimidazo[1,2-a]pyridines (47) with the 2-aminopyridine derivatives (7) and nitroalkene (46). In this methodology the researchers used atmospheric oxygen as an oxidant and eosin Y (EY) as a photoredox catalyst. Mechanistically, at first, Michael adduct A developed with the help of Michael addition between endocyclic ni-

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trogen of 2-aminopyridine and β-nitrostyrene (46). The catalyst EY is activated to a singlet state by the absorption of visible light (EY✶), which transforms into a more stable triplet state (EY✶). After that, radical cation B is formed by the single electron transfer (SET) process of triplet state (EY✶) and then intermediate C is developed followed by the removal of H2O2. An additional EY proceeds via SET to produce a radical cation D, which further goes through intramolecular cyclization and oxidation to produce the desired product 47 by removing H2O2 (Figure 3.15). Many synthetic researchers have paid close attention to organic synthesis triggered by visible light [73, 74]. Compared to UV light, visible light is safer [75]. Because of this, visible light is more investigated by the researchers for the suitable method to initiate various types of organic transformations. In, 2018 Shivhare et al.’s [76] construct a multicomponent reactions using visible light methodology to produce 3-amino imidazofused heterocycle (50). In this methodology the researchers used various types of derivatives of 2-aminopyridine (7), aldehydes (48), and isocyanides (49) via the GBBR. For this synthesis, readily accessible source of energy was used to initiate the reaction. The imine intermediate A is produced by the help of reaction between 2-aminopyridine (7) and benzaldehyde (48); after that intermediate B is formed by the attacking of isocyanide (49) into intermediate A. Free-radical C is generated by the photochemical activation of B with the visible light. In the last step imidazo-fused product (50) is produced by the help of cyclization of C followed by a [1,3]-H shift (Figure 3.16). In situ halogenation has received a lot of interest recently when it comes to the development of N-heterocyclic ring scaffolds. Previously, the researchers reported a technique where environmentally hazardous halogenating agents like CBr4, CBrCl3, NBS, or PhI(OAc)2 [77–79] are used. Considering these restrictions, Roslan et al. [80] in 2019 described a protocol for the synthesis of imidazo[1,2-a]pyridines (52) under visible light by combining 1,3-dicarbonyls (51) and 2-aminopyridine derivatives (7) with the photocatalyst erythrosine B(EB) and using KBr as a halogenating agent. Mechanistically, in the presence of visible light irradiation to promote the photoredox catalyst, erythrosine B(EB), to its excited state (EB✶). The Br. radical and the radical anion EB.– are generated by SET from the bromide ion to EB✶. Enamine A and tautomer A’ are produced through a condensation reaction between 1,3dicarbonyl (51) and 2-aminopyridine (7). Afterward, the α-bromo intermediate B is produced by the addition of Br˙ and proton abstraction by O2–. HO2– anion is developed via electron transfer to HO2˙. After that, the final product (52) is produced followed by the formation of intermediate C with the attacking of B in nucleophilic manner (Figure 3.17). To eliminate the usage of harmful transition metals or hazardous organic dyes, visible light-promoted photoredox catalyst-free synthetic organic reactions have recently attracted a lot of attention [81]. In 2020, Das and Thomas [82] describe a onepot photochemical protocol for the synthesis of imidazo[1,2-a]pyridines (54) from the 2-aminopyridine (7) and alkenes (53) under the metal catalyst-free condition. This method works by forming α-bromoketones when acetonitrile and water are exposed to UV LED fluorescent black light (380–390 nm) (Figure 3.18).

Chapter 3 Synthesis of imidazo[1,2-a]pyridines and indazole under metal-free conditions

Figure 3.15: Synthesis of imidazo[1,2-a]pyridines with nitroalkene via photochemical method.

63

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Figure 3.16: Synthesis of imidazo[1,2-a]pyridines with aldehyde via photochemical method.

3.3 Synthesis of indazole derivatives through the various types of reactions Indazoles are much more important N-heterocyclic compound in medicinal chemistry, which are importance compounds with an N–N bond [83–85]. The two main forms of indazole derivatives, 1H- and 2H-indazoles, are produced via tautomerization process [86]. Indazoles displayed a wide variety of pharmacological and biological effects [87, 88] and fluorophoric properties [89, 90]. Due to the different biological characteristics of indazoles core researchers are more interested to synthesize various types of indazole derivatives. For the synthesis of indazole core derivatives metal-free condition is the more feasible route due to mild reaction condition as well as nontoxicity. In this portion, we present an organized chapter of few methods for the synthesis of indazole core derivatives under metal-free conditions.

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Figure 3.17: Synthesis of imidazo[1,2-a]pyridines via photochemical method.

3.3.1 Synthesis of N-substituted-2H-indazol-2-amines through reductive cyclization process In 2017, Nazaré and coworkers [91] proposed a reaction pathway beginning from readily available materials such as various types of 2-nitrobenzaldehydes (55) and hydrazines derivatives (56), a two-step, one-pot method to produce 2-H indazol-2-amines (57) in good to excellent yield through the reductive cyclization with an organophosphorus reagent. Additionally, heteroaryl analogues were tolerable and provided the required

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Figure 3.18: Synthesis of imidazo[1,2-a]pyridines with alkene via photochemical method.

indazole (57) in good to outstanding yield. The reaction between 1-aminoindole and 1aminoipiperidine goes through the moderate efficiency (Figure 3.19).

3.3.2 Synthesis of 2H-indazoles using an organophosphorus-silane system Using the commonly accessible 2-nitrobenzaldehydes and amines as starting materials, an effective and economically straightforward one-step, one-pot technique would easily allow accessibility to a broad and wide variety of 2-H indazoles. In 2018, Nazaré and his group [92] showed how to build the privileged 2H-indazole (61) and (63) scaffold in a straightforward and easy-to-follow manner. To obtain 2Hindazoles, the newly proposed one-pot method is used for the formation of N–N bond with the help of phospholene (60). They synthesized substituted 2H-indazoles (61) and (63) with the reaction between various 2-nitrobenzaldehydes derivatives (58) and primary amines (59) and (62) in the presence of phospholeneoxide (60) with the outstanding yield that are readily accessible in market. For understanding the mechanism the author carried out an online NMR experiment at 110 °C. Mechanistically, 2-nitrobenzal-

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Figure 3.19: Synthesis of indazole with hydrazine via reductive cyclization process.

dehyde is reacted with the primary amines to get intermediate A. The initial deoxygenation of A is carried out by the phospholene B and release D followed by intermediate C. Then the nitrene intermediate F is produced by the subsequent deoxygenation process of compound D. Finally, the targeted products are produced by the formation of N–N bond followed by reductive cyclization (Figures 3.20 and 3.21).

3.3.3 Synthesis of 2H-indazoles via mills reaction through the cyclization process Due to the great usefulness of N-heterocyclic compounds like indazoles, significant effort has been made to develop innovative and effective synthetic methods in organic synthesis. Several outstanding publications on the one-pot synthesis of 2H-indazoles have recently been published. The synthesis consists of various types of reaction like cadogan-reductive cyclization with the help of organophosphorus reagents [93, 94], tandem palladium-catalyzed cross-coupling and cyclization [95], metal catalyzed multicomponent reaction [96, 97]. In 2019, Kondo et al. [98] described a mills reaction utilizing 2-aminobenzyl alcohols (64) and nitrosobenzenes (65) in one-pot for synthesizing 2H-indazoles (67) in

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Figure 3.20: Synthesis of indazole with primary amine using an organophosphorus-silane system.

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Figure 3.21: Mechanistic pathway for the synthesis of indazole with primary amine using an organophosphorus-silane system.

room temperature under the metal-free condition. In this methodology the researchers utilized brominating substances like PBr3 or SOBr2 in acetic acid medium. Mechanistically, in the initial step SOBr2 is reacted with the OH group of (66) followed by the releasing of HBr and form the intermediate A which is protonated by the acetic acid to the formation of intermediate B. Then the intermediate C is produced with the help of intramolecular SN2 cyclization of intermediate B by the removal of HBr and SO2. At the last step it deprotonates the intermediate C and dearomatization of the benzene ring in the presence of acetic anion and acquires the indazole compound 67 (Figure 3.22).

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Figure 3.22: Synthesis of indazolevia mills reaction.

3.3.4 Synthesis of indazole through the diazo activation with the help of diazonium salts Over the past few decades, diazo substances have garnered a lot of attention on carbene precursors [99–103]. This fascinating diazenium technique offers a novel way to accomplish complicated nitrogen-containing heterocycle synthesis under friendly circumstances [104–107]. Motivated by these concepts Li et al. [108] in 2020 disclosed a metal-free pathway for the synthesis of substituted indazole derivatives (70) where the diazonium salts activate the donor/acceptor diazo compounds via the diazenium intermediate. In this process the various types of biological active indazole derivatives are produced followed by the diazenium intermediate in good to outstanding yield. From these synthetic transformations the authors proved that aryl diazonium salts with electron-withdrawing substituents were acceptable for producing indazole derivatives good to outstanding yields. On the other hand, electron-withdrawing groups are failed to deliver the expected results. To investigate the reaction mechanism, they use in-operando infrared spectroscopic analysis to observe and check the progress of the reaction (Figure 3.23).

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Figure 3.23: Synthesis of indazole through the diazo activation with the help of diazonium salts.

3.3.5 Synthesis of indazole through the visible-light-driven photocyclization process Researchers were able to conduct the necessary experiments to investigate the strong affinity of nitrene intermediates in photocatalyst-free circumstances due to the invention of photochemical techniques. Over the past 10 years, in synthetic organic chemistry visible light-mediated reaction is more valuable due to plentiful source of energy, nontoxic and renewable [109–111]. In 2021, Wang and coworkers [112] describe a visible light-mediated synthetic route to access 2H-indazole-3-carboxamides (72) through an effective photocyclization process of aryl azides (71) using photocatalyst-free and external additive-free circumstances. This approach is an environmentally friendly and long-lasting method, contains some benefits, wide range of substrates, step- and atom-economy, mild reaction conditions, and environmentally friendly circumstances. Mechanistically, initially, the ni-

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Figure 3.24: Synthesis of indazole through the visible-light-driven photocyclization process.

trene intermediate A was produced by the photolysis of aryl azides (71) when exposed to visible light followed by the release of N2. A coordinated nitrene insertion process changed transition state B into intermediate C which was additional aromatization to change into the target product (72) (Figure 3.24).

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3.4 Conclusions The most recent advancements in the synthesis of imidazopyridines and indazole derivatives from different types of substrates under metal-free condition are summarized in this chapter. Notable advancements have been achieved in the synthesis of imidazopyridines and indazole during the past five years employing a variety of photocatalysts, acids, bases, as well as greener protocols and traditional methods. Different synthetic methods under the metal-free condition have also been highlighted in this chapter. The commonly accessible substrate 2-aminopyridine has been used in the majority for the synthesis of imidazo[1,2-a]pyridine. In order to achieve a higher production for the target product in a shorter amount of time, future research should focus on the synthesis of imidazo[1,2-a]pyridines and indazole using a simple, feasible, metal-free, environmentally friendly procedure. Imidazo[1,2-a]pyridines and indazoles are the fundamental building blocks in many natural and unnatural bioactive N-heterocyclic compounds and various commercially available drugs. The synthesis of this N-heterocyclic compound has to be thoroughly studied because of the continuous significance of this core in the scientific community. This chapter will contribute to the provision of adequate and current knowledge on various approaches for the synthesis of different substituted imidazo[1,2-a]pyridine and indazole moieties which is helpful for the drug modification and its usage by the scientific community in many different fields.

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Akbar Ali✶, Huma Masood, Muhammad Ibrahim, Tahir Maqbool, Nadia Akram, and Marcio Weber Paixao

Chapter 4 Microwave-assisted metal-free solid-supportcatalyzed synthesis of bioactive heterocycles 4.1 Introduction Green chemistry has emerged as a major scientific discipline over the past few decades [1]. With several new technologies introduced each year, trends toward greener alternatives have prompted the development of more benign and cleaner chemical processes [2]. In the present era, synthetic chemists in industry and academia are continuously improving their chemical processes to make them more environmentally beneficial for the production of the required targeted compounds [3, 4]. To demonstrate the benefits of greener alternatives, the construction of biologically significant heterocyclic compounds in a synthetically efficient and eco-friendly manner is one of the prime goals of contemporary organic synthesis [5–8]. In that context, microwaveassisted nonmetal solid-support-catalyzed synthesis of bioactive heterocycles has been proved as an effective and green approach [9]. Microwave technology has been employed as an alternate energy source to heat chemical processes since the late 1970s [10]. Unlike traditional heating methods, microwave irradiation can manage selective and instant heating of materials, resulting in quicker reaction rates, enhanced yields, and better chemical transformations [11]. The microwave irradiation technology was mostly used in the area of synthetic inorganic chemistry [12]. In 1986, Gedye et al. [13–15] published the utility of microwave technology to the organic chemistry community. Since then, direct heating of chemical reactions using microwave technology has become the most common technique in organic synthesis. With the advent of microwave technology, chemical transformations can now be performed up to 1,240 times faster than conventional techniques [16–19]. Correspondingly, catalysis plays an essential role in the design, development, and implementation of green chemistry [20]. Over the last decade, metal-catalyzed approaches ✶

Corresponding author: Akbar Ali, Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan, e-mail: [email protected] Huma Masood, Tahir Maqbool, Nadia Akram, Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan Muhammad Ibrahim, Department of Applied Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan Marcio Weber Paixao, Department of Chemistry, Universidade Federal de São Carlos (UFSCar), São Carlos, São Paulo, Brazil https://doi.org/10.1515/9783110985474-004

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like the Ullmann reaction and Buchwald–Hartwig cross-coupling have gained prominence due to the disadvantages of conventional synthetic methods, viz., harsh conditions, prolonged reaction times, and narrow substrate scope [21, 22]. However, despite the considerable efficiency of metal-catalyzed reactions, the difficulty of removing metal residues resulting from the metal catalysts has greatly limited their use in industry and chemical biology [23]. Furthermore, most of these metal-catalyzed reactions need heavy metals, which are not only valuable and rare but can also pollute the environment if they are not disposed of appropriately [24]. In this scenario, nonmetal solid-supported catalysts have been proven to be a relatively benign approach for the construction of bioactive heterocycles [25]. In chemistry, a catalyst support is the material sometimes called a carrier, upon which a catalyst is dispersed as the minor component [26]. It is often solid with a large surface range. Even though the support is catalytically inert, it can add to total catalytic activity [27]. Increased effective surface area, reactivity, selectivity, ease of handling, facile catalyst detachment, and recycling, lengthy catalytic life, and thermal stability are the important points that make solid-supported reagents an exciting field in synthetic organic chemistry [28]. The use of microwave irradiation combined with solid supported reagents has become an intriguing and widespread concept in organic chemistry [29]. This chapter will emphasize the importance of microwave-assisted nonmetal solid-support-catalyzed synthesis of bioactive heterocyclic compounds since they are crucial in any modern society. This is evident by the fact that heterocycles constitute almost 60% of all medicinal substances [30]. They are also important as dyes, agrochemicals, organic optoelectronics, novel materials, and synthons in the production of more complex compounds [31]. The topics in this chapter have been organized in accordance with the heteroatoms, present in the heterocyclic rings constructed through the microwave-assisted solid-supportcatalyzed technology.

4.2 Nitrogen-containing heterocycles Among bioactive heterocycles, nitrogen-containing heterocyclic compounds have shown great medicinal importance [32]. They are found in a diverse range of natural products including hormones, alkaloids, and vitamins, in addition to medicines, dyes, herbicides, and various other compounds [33, 34]. Given the immense importance of N-heterocycles, the preparation of these compounds has emerged as a major field of research in synthetic organic chemistry [35]. Vast number of biologically relevant N-heterocycles has been synthesized using microwave irradiation with supported reagents.

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4.2.1 Aziridines Aziridines are well-recognized heterocyclic compounds with numerous biological activities, predominantly antitumor and antibacterial ones, and they also serve as important reactive intermediates for the synthesis of azomethine ylides, chiral amino alcohols, and amino acid derivatives [36–41]. As part of an investigation into the viability of accelerating organic reactions with supported reagents under MW irradiation, Saoudi et al. [42] introduced a unique process for the production of strained three-membered nitrogen-containing aziridine rings by condensing primary amines (1) with dihaloalkanes (2) (Figure 4.1). The reaction was catalyzed by environmentally benign bentonite clay under microwave irradiation. Bentonite is a swelling clay primarily composed of montmorillonite (a smectite) and is used as a solid support in acid catalysis [43]. Under microwave irradiation, as compared to traditional heating using the same conditions, it was observed that desorption predominates over Michael addition.

Figure 4.1: Synthesis of aziridine rings by condensing primary amines with dihaloalkanes.

4.2.2 Pyrroles Pyrroles are significant heterocycles found in an extensive variety of bioactive compounds and pharmaceuticals [44–47]. Abid et al. [51] have described a Paal-Knorr [48– 50]-type approach for synthesizing pyrrole derivatives (7 and 9) by the condensation of sulfonamides (6) and primary amines (8) with 2,5-dimethoxytetrahydrofuran (5) on montmorillonite clay K-10 in the presence of microwave irradiation and solvent less conditions (Figure 4.2). K-10 montmorillonite, a synthetic clay, is a recognized and frequently used solid-support catalyst in organic chemistry [52]. Because of its great stability, large surface area, and strong acidity, K-10 clay is an excellent catalyst both for bifunctional and acid catalysis. Several nitrogen-substituted pyrroles can be prepared within 3–6 min under solvent-free reaction conditions. This procedure has several benefits, including high yield, moderate reaction conditions, selectivity, and convenience of product separation. Substituents seemed to have no noticeable impact on the rate or selectivity of the cyclization process.

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Figure 4.2: Synthesis of pyrrole derivatives by the condensation of sulfonamides and primary amines with 2,5-dimethoxytetrahydrofuran.

Tejedor et al. [53] designated a novel diversity-oriented approach for the formation of tetrasubstituted pyrrole derivatives (12) through an SiO2-supported coupled domino reaction of primary amines (8) and alkynoates (10) (Figure 4.3). A wide variety of tetrasubstituted pyrrole derivatives can be prepared in a one-pot manner. Under microwave-assisted metal-free conditions, the reaction takes place in only 8 min, even though it requires months to complete at ambient temperature and hours using traditional heating methods. In the overall process, 1,3-oxazolidine (11) is formed as an intermediate, which then rearranges intramolecularly to yield tetrasubstituted pyrrole derivatives (12) in a solvent-free domino reaction.

Figure 4.3: Synthesis of tetrasubstituted pyrrole derivatives through a SiO2-supported coupled domino reaction of primary amines and alkynoates.

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4.2.3 Cyclic imides and bisimides Cyclic imides and their N-derivatives containing bisimide linkages belong to an essential class of bioactive compounds. They have shown wide chemical applications, particularly in synthetic, biological, and polymer chemistry [54–59]. Habibi and Marvi [60] reported the synthesis of some cyclic bisimides (14) and (3aR,7aS)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-diones (15) on montmorillonite K-10 clay irradiated in a microwave oven in solvent-free conditions using diverse aliphatic and aromatic amines and diamines (Figure 4.4).

Figure 4.4: Synthesis of some cyclic bisimides and (3aR,7aS)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)diones.

Robert Bruce Merrifield invented Merrifield resin, a lightly cross-linked polystyrene resin (16) (Figure 4.5). Chandrasekhar et al. [61] described a unique procedure for the microwave-induced, solvent-free synthesis of N-phthalimide derivatives (18) using anhydrides (13) on a solid-support (Merrifield resin) (Figure 4.6). It is used as a polymer support for solid-phase synthesis as well as for immobilizing catalysts and reagents [62–66]. In this method, two insoluble supports, specifically silica gel and Merrifield resin, were used in a one-pot reaction and were easily detached physically through different types of mesh filters. The 4-aminobutanoic acid (17), esterified using Merrifield resin (16), was reacted with anhydride and silica-supported Lewis’s acid (TaCl5– SiO2) and exposed to microwave irradiation after mixing thoroughly. After washing with a suitable solvent, the resin-bound imide was separated from the polymer support by treating with 1,1,1-trifluoroacetic acid to form acid derivatives in a 60–65% yield. Habibi and Marvi [67] demonstrated an eco-friendly and effective route to synthesize biologically active bisphthalimides and bismaleimides (21) through the condensation reaction of a suitable mixture of phthalic and maleic anhydrides (19) with various diamines (20). Montmorillonite clays (K-10 and KSF) [68–70] were used as solid-support catalysts under microwave irradiation in solvent-less conditions to attain high yields

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Figure 4.5: Structure of Merrifield resin.

Figure 4.6: Synthesis of N-phthalimide derivatives using anhydrides on a solid support.

(61–86%) in a short time period (Figure 4.7) [71]. It was observed that the products formed with KSF clay had a higher yield than those formed with K-10 clay, whereas the reaction durations with K-10 clay were shorter. It could be associated with the more acidic character of the KSF clay and the larger surface area of the K-10 clay, respectively. The use of aromatic diamines produces higher yields than aliphatic diamines, which could be related to product stability differences.

Figure 4.7: Synthesis of biologically active bisphthalimides and bismaleimides through the condensation reaction of a suitable mixture of phthalic and maleic anhydrides with various diamines.

4.2.4 Imidazoles The imidazole molecule is a key component of many biologically active compounds, including histidine, histamine, nitrosoimidazole, metronidazole, and megazol. These compounds exhibit potential therapeutic activities, including anti-inflammatory, antihypertensive, antimicrobial, anticancer, and other biological activities [72–76]. Usyatinsky and Khmelnitsky [77] reported a microwave-assisted solid-supportcatalyzed synthesis of tri- and tetrasubstituted imidazoles in a solvent-free environ-

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ment. In the synthetic process, 1,2-dicarbonyl compounds (23) are combined with aldehydes (22) or aldehydes (22) and amines (8) to form 2,4,5-trisubstituted imidazoles (24) or 1,2,4,5-tetrasubstituted imidazoles (25), respectively. The reaction’s ammonia source is ammonium acetate (Figure 4.8). An evaluation of various solid supports revealed that acidic alumina was the best choice for the construction of the desired imidazoles. Without heating or in the absence of catalyst support, no progress of reaction was observed.

Figure 4.8: Synthesis of tri- and tetrasubstituted imidazoles in a solvent-free environment.

Villemin et al. [78] have described the synthesis of benzimidazoles (28) by the condensation of orthoesters (26) with ortho-substituted aminoaromatics (27) supported on the montmorillonite clay KSF using either traditional heating in toluene or microwave irradiation without solvent. Under focused microwave radiation, the dry synthesis of benzimidazoles catalyzed with clay was quick and easy. The reaction was simple and led to pure benzimidazoles (28) (Figure 4.9).

Figure 4.9: Synthesis of benzimidazoles by the condensation of ortho esters with ortho-substituted aminoaromatics.

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4.2.5 Pyridines Pyridines are always an interesting target for synthetic chemists because of their diversity and biological activity in pharmaceuticals and natural products [79–81]. Penieres et al. [82] have designated a novel synthetic method for the formation of pyridines through a modified Hantzsch method catalyzed by the NH4NO3/bentonite system under microwave irradiation in a dry medium (Figure 4.10). In general, pyridines are obtained by oxidizing 1,4-dihydropyridines. And the most common method of producing 1,4-dihydropyridines is the Hantzsch synthesis, which involves the condensation of β-ketoester (29), aldehyde (22), and ammonia in a 2:1:1 ratio. This was the first time that the Hantzsch method was used for synthesizing pyridines in a simple and direct one-pot process. It was assumed that, due to microwave irradiation and the acidity of bentonite clay, ammonium nitrate decomposes into nitric acid and ammonia, causing the reaction. The ammonia produced serves as the nitrogen source in the first step of the reaction producing 1,4-dihydropyridines (30 or 31). The in situ bentonite/HNO3 system then causes the oxidation of 1,4-dihydropyridine to pyridine in the following step. However, alkyl aldehydes were required to achieve C4-substituted pyridine derivatives (30) in high yields. For instance, when benzaldehyde was used, just 5% of the 4phenyl pyridine derivative was formed, whereas C4-unsubstituted pyridine (31) was formed in good yield (75%). Later, the reaction scope was widened by Cotterill et al. [83] to make it accessible for combinatorial synthesis.

Figure 4.10: Synthesis of pyridines through a modified Hantzsch method catalyzed by the NH4NO3/ bentonite system under microwave irradiation in a dry medium.

Sharma et al. [84] demonstrated the condensation of cyanomethylenes (33) with βformyl enamides (32) catalyzed by basic alumina under microwave irradiation to synthesize annelated pyridines(36) (Figure 4.11). The β-formylenamide and cyanomethylene were thoroughly mixed in the presence basic alumina before being exposed to irradiation for 8–10 min in a household microwave oven. It was observed that microwave irradiation of reactants without using silica gel or basic alumina resulted in the condensation product (34). The required product (36), on the other hand, is predicted to be formed through a mechanism involving Knoevenagel condensation of reactants

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Figure 4.11: Synthesis of the annelated pyridines through the condensation of cyanomethylenes with β-formyl enamides catalyzed by basic alumina under microwave irradiation.

(32) and (33) into an intermediate (34), followed by alumina-catalyzed intramolecular cyclization (35).

4.3 Oxygen-containing heterocycles Oxygen-containing heterocycles are biologically important structures existing in a broad range of natural or synthetic alkaloids. The great relevance of O-heterocycles in biomedicine [85–87] has motivated researchers to develop novel effective and economical synthetic approaches for obtaining these compounds. Here we will discuss the synthesis of some important bioactive O-heterocycles using solid-supported catalysts and microwave irradiation.

4.3.1 Benzofurans Benzofurans have gained substantial interest because of their diverse pharmacological activities and occurrence in a wide range of natural products [88–90]. Using microwave irradiation and KF-Al2O3, Varma and Liesen [94] described an expeditious solvent-free synthesis of benzofuran-3-yl(phenyl)methanone derivatives (39) from readily available α-tosyloxyketones (37) and salicylaldehydes (38) (Figure 4.12). The reaction involves the mixing of reagents onto mineral oxides as solid supports, for instance, basic alumina or its doped version with KF, and then the mixture is exposed to irradiation in a domestic microwave oven for 2.5–3.5 min. Maximum yields were attained under basic conditions using potassium fluoride (KF) doped on alumina. The

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generality of this method was demonstrated by the use of several substituted αtosyloxyketones and salicylaldehydes, which tolerates a wide variety of functional groups.

Figure 4.12: Synthesis of benzofuran-3-yl(phenyl)methanone derivatives from readily available salicylaldehydes and α-tosyloxyketones.

Wang et al. [91] have developed a one-pot synthetic method for the construction of functionalized benzofurans (42) through O-alkylation, C–C cyclization/coupling, and olefination/dehydration tandem reactions of phenylacyl bromide (41) with phenols (40) (Figure 4.13). Ether was formed as a side product. These reactions occur in the presence of microwave irradiation and are catalyzed by mineral-supported inorganic bases. The best selectivity for preparing benzofuran was accomplished with Na2CO3 as a base. This novel synthesis involves the assembly of one ring system and three new bonds in one step.

Figure 4.13: Synthesis of functionalized benzofurans from phenylacyl bromide and phenols.

A simple and efficient process for the production of hydroxyl iminodihydrobenzofuran derivatives (45) in the presence of acidic silica gel and microwave irradiation was reported by Barange et al. [92]. The procedure involves the Michael addition of nitro-olefines (43) to cyclic 1,3-dicarbonyl compounds (44) accompanied by an intramolecular cyclization to form a mixture of E and Z isomers of hydroxyl iminodihydrobenzofuran derivatives (45) (Figure 4.14).

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Figure 4.14: Synthesis of hydroxyl iminodihydrobenzofuran derivatives from nitroolefines and cyclic 1,3-dicarbonyl compounds.

4.3.2 Dioxolanes Dioxolanes have shown excellent antifungal and antibacterial activities [93–95]. The best procedure for dioxolanes (51) formation was believed to be the interchange with 2,2-dimethyl-1,3-dioxolane (DMD) (50) on K-10 clay under exposure to irradiation for 10–30 min (Figure 4.15) [96]. Even though this is a two-step procedure (DMD synthesis followed by interchange), it generates higher yields of product without the need of a solvent than previous approaches that used benzene or toluene. By employing the Synthwave 1000 apparatus, the preparation of protected carbonyl compounds on a 2 mol scale in an open-vessel and solvent-less conditions using high-boiling glycols and montmorillonite clay K-10 has been investigated. It was observed that the workup

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for large-scale (2 mol) experiments was simpler than small-scale (10 mmol) experiments due to the probability of eliminating the alcohol formed (10% MeOH) by constant distillation under microwave irradiation. The conditions (time, temperature) remained same as the scale goes from 10 mmol to 2 mol.

Figure 4.15: Synthesis of dioxolanes through the interchange with 2,2-dimethyl-1,3-dioxolane (DMD).

The ketones and aldehydes (52) were successfully protected as dioxolanes and acetals (54) by utilizing orthoformates, 2,2-dimethyl-1,3-dioxolane or 1,2-ethanedithiol (53) (Figure 4.16) [97]. Under dry conditions, the reaction can be catalyzed by either KSF clay or p-toluenesulfonic acid. Microwave heating produced significantly higher yields than conventional heating methods. It may be concluded that the exchange method is the best one to form dioxolanes with better yields in a short period of time (10– 30 min), with montmorillonite clay (KSF) being the best catalyst choice.

Figure 4.16: Protection of ketones and aldehydes as dioxolanes and acetals.

4.4 Sulfur-containing heterocycles Sulfur-containing heterocyclic compounds has long been acknowledged as an essential component of pharmaceutically active compounds and FDA approved drugs. Thus, various efforts have been made to prepare a wide range of novel sulfur containing compounds [98,99].

4.4.1 Thiophenes Thiophenes belong to an essential class of medicinally relevant chemical compounds [100–102]. The most efficient and well-known traditional process to synthesize thiophen-2-amine derivatives is Gewald’s method, involving a multicomponent reaction of an elemental sulfur (57), a ketone (55), and activated nitrile (56) catalyzed by morpho-

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line. Sridhar et al. [103] used aluminadoped with KF as a solid support catalyst to prepare thiophen-2-amine derivatives (58) by a microwave-enhanced multi-component reaction (Figure 4.17). This procedure is a convenient and effective modification of Gewald’s method because it can be done in a relatively short amount of time when exposed to microwaves.

Figure 4.17: Synthesis of thiophen-2-amine derivatives by a microwave-enhanced multi-component reaction.

Acosta et al. [104] have designated an improved synthesis of sulfur-containing heterocyclic quinones (63) using K-10 clay and microwave irradiation (Figure 4.18). In dry media, various 2-(thiophene-2-carbonyl)benzoic acids (62) are cyclized to yield sulfurcontaining fused quinones (63). Some clays were investigated, and montmorillonite

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Figure 4.18: Synthesis of sulfur-containing heterocyclic quinones via the cyclization of various 2-(thiophene-2-carbonyl) benzoic acids.

clay K-10, devoid of feldspar and quartz, proved to be an efficient catalyst producing desired sulfur-containing heterocycles in good yields.

4.4.2 Thiadiazepine Thiadiazepinesare well-known heterocyclic compounds exhibiting diverse therapeutical properties like antiviral, anticancer, antimicrobial, and antiproliferative [105–109]. Dandia et al. [110] disclosed a simple, dry media process for the production of a series of thiadiazines containing fused benzopyranotriazole rings (67) through the Michael addition-condensation reaction between 3-arylidene flavanones (64) and 4amino-5-alkyl 3-mercapto-1,2,4-triazoles (65) at 145 °C using basic alumina as a solid support catalyst (Figure 4.19). The exposure to microwave irradiation lowered reaction times from hours (60–65 h) to minutes (3–5 min) with enhanced yield as compared to classical heating methods, indicating the versatility of the procedure. Furthermore, the technique described was free of danger associated with solventphase reactions. The antifungal activity of the synthesized compounds was screened in vitro against Collectotrichum capsici, Rhizoctonia solani, and Fusarium oxysporum. The majority of these compounds have demonstrated potential activity against these pathogens. The same authors developed a facile microwave-enhanced cycloaddition method to synthesize fluorine-containing benzothiazepine fused β-lactam derivatives (71) in the presence of potassium carbonate (Figure 4.20) [111]. A microwave-assisted metalfree improved synthesis of the required starting material, 1,5-benzothiazepine derivatives (70), was also achieved using KSFclay. The reaction was also performed classically in a basic medium, and after a prolonged reaction period, the product was formed with a lower yield. Most of the prepared compounds possess antifungal activity against Collectotrichum capsici, Rhizoctonia solani, and Fusarium oxysporum. Using microwave irradiation and montmorillonite clay K-10 as solid support, new classes of pyrazolo(4,3-c)(1,5)-benzothiazepines (77) have been synthesized in a solventless dry medium (Figure 4.21) [112]. Irradiation of aminothiophenol (75) with (E)-5benzylidene-1,5-dihydro-4H-pyrazol-4-ones (74) resulted in the construction of pyrazolo (4,3-c)(1,5)-benzothiazepines (77) rather than the other possible isomer, pyrazolo(3,4-b)

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Figure 4.19: Synthesis of a series of thiadiazines containing fused benzopyranotriazole rings.

Figure 4.20: Synthesis of fluorine-containing benzothiazepine fused β-lactam derivatives.

(1,5)-benzothiazepine. The most adaptable support was montmorillonite clay K-10, as it gave greater yield in a short period of time. The reaction mechanism includes the generation of Michael adduct as an intermediate (76) through nucleophilic attack of the sulfhydryl group on the β-carbon of the double bond of benzylidene-pyrazolinones (74), which is turned electrophilic via the carbonyl-vinyl conjugation. This is consistent with the previously reported observations that in the presence of substituted α,β-unsaturated ketone, the nucleophilic attack of the mercapto group occurs only on the β-carbon, followed by

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condensation reaction of primary aromatic amine with a carbonyl group to furnish a seven-membered ring system. Promising antifungal activity of the formed compounds was observed.

Figure 4.21: Synthesis of some new classes of pyrazolo(4,3-c)(1,5)-benzothiazepines.

4.5 Conclusions This chapter necessarily demonstrates the importance of microwave-assisted metalfree solid-support-catalyzed synthesis of bioactive heterocycles. The preparation of various pharmaceutically important heterocyclic compounds has been described in a relatively benign manner, as in most of the cases the environment is solvent-free. Microwave irradiation combined with a solid-supported catalyst is a unique and rapidly emerging process in the field of green chemistry, as the synthesis of numerous organic compounds of diverse structural complexity has been reported. This protocol will find a wide range of applications and will continue to garner much attention in synthetic organic chemistry.

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Akbar Ali✶, Zill-e-Rehman Abbas, Muhammad Ibrahim, Atta Ul Haq, Nadia Akram, and Amjad Hussain

Chapter 5 Graphene oxide (GO): an efficient and recyclable catalyst for one-pot synthesis of bioactive heterocycles 5.1 Introduction to graphene The carbon community was familiar with graphic (3D) carbon allotropes (diamond and graphite), linear (1D) carbon nanotubes (CNTs), and zero-dimensional (0D) fullerenes. By 2004, the argument over the presence of depthless and two-dimensional (2D) allotropes of carbon lingered. A paper by Andre Geim and Konstantin Novoselov [1] reports the fruitful segregation of a 2D monolayer of graphite (graphene). Graphene, a 2D monoatomic thick constituent of a carbon allotrope, has emerged as a twentyfirst-century exotic material, acquiring worldwide interest due to its exceptional mechanical, optical, thermal, and charge transport properties. Nearly every research and engineering field is actively seeking graphene and its analogues. Graphene is the most auspicious and versatile nanostructured material addressing “nontoxic, hygienic, and effective energy.” Recent research has shown that components based on graphene may have a significant impact on energy storage, nanotechnology, chemical sensors, electrical and ophthalmic devices, and other areas. This is because of its unique properties like being extremely strong (its tensile strength is over 130 GPa) and having high electrical and thermal conductivity. Graphene provides novel solutions to the current industrial problems related to energy production and storage. In order to progress toward the desired technologies necessary for commercial interest, graphene-based systems for energy generation (photovoltaics, fuel cells, etc.), energy storage (supercapacitors, batteries, etc.), and hydrogen storage will be technologically upgraded [2].

✶ Corresponding author: Akbar Ali, Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan, e-mail: [email protected] Zill-e-Rehman Abbas, Atta Ul Haq, Nadia Akram, Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan Muhammad Ibrahim, Department of Applied Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan Amjad Hussain, Department of Chemistry, University of Okara, Okara 56300, Punjab, Pakistan

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5.1.1 Methods of preparation of graphene There are diverse methods for the preparation of various types of graphene material. The first method, published in 2004, was the machine-driven exfoliation of tiny patches of extremely organized pyrolytic graphite [3]. Furthermore, electrophoretic deposition is one of the stimulating methods for manufacturing a nano-sheet of graphene (Figure 5.1). By utilizing microwave plasma-enhanced chemical vapor deposition approach, the nitrogen-doped graphene could be synthesized [4].

Figure 5.1: Tracks elaborating on the formation of graphene sheets [5].

5.1.2 Characteristics of graphene 1. 2.

3.

Graphene is a zero bandgap material [6]. The opening of graphene’s bandgap is the requirement for its use in electronics or ophthalmic devices. Pristine graphene is insoluble, intractable, and disintegrates after earlier melting [7]. Thus, the classical material processing methods are ineffective for reforming it into the desired structures. Free-standing graphene sheets tend to fold or stack together due to hydrophobic and π–π interactions. As a result, only solid-type materials can materially stabilize graphene sheets [8, 9].

Chapter 5 Graphene oxide (GO)

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Pristine graphene typically has poor catalytic performance and weak interactions with other tiny molecules or polymers [10], limiting its scope in catalysis, composites, and sensors.

5.1.3 Application of graphene

Figure 5.2: An overview of applications of graphene [2].

5.2 Graphene oxide Graphene oxide (GO) is a depthless 2D carbon sheet with oxygen-containing functionality (hydroxyl, carboxyl, and epoxy) on the basal pinacoid at the boundaries and displays enhanced dispersibility in some solvents than graphene. GO changes the size, shape, and comparative portion of the sp2-hybridized regions, making it an auspicious substance for the biological system [11].

5.2.1 Synthesis of GO Hummers’ method (NaNO3, H2SO4, and KMnO4) is most frequently used for the formation of GO because of its extraordinary productivity and reaction safety. However, it has the following two limitations:

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The oxidation routed is charged poisonous gases, for example, N2O4 and NO2. The residual Na+ and NO3⁻ ions in the leftover water, which are generated during the production and purification of GO, are hard to detach.

5.2.2 Improved synthesis of GO Tour and his colleagues [17] upgraded the Hummers technique by adding more KMnO4, removing NaNO3, and utilizing the 1:9 (by volume) ratio of H3PO4/H2SO4 solution. This variation significantly increased the reaction yield and reduced the poisonous gas evolution; however, it consumed twice the amount of KMnO4 and 5.2 times the volume of H2SO4 as required for Hummer’s approach, in addition to introducing a new H3PO4 module into the reaction mechanisms. Other improved synthetic technique are given below (Table 5.1). Table 5.1: Synthesis of graphene oxide by employing the following techniques. Carbon origin

Oxidant

Temperature Time Characteristics (°C) period for graphite oxide

Graphite powder (CBG mining)

HSO, KMnO



 min

Graphite

HSO, NaNO, KMnO

/

 h/ min Superior performance and improved controllability

[]

Graphite –  mesh

HSO, NaNO, KMnO

Ambient temperature

h

Effective use in supercapacitors

[]

Graphite –  micro

HSO, HPO, KMnO

 h

High efficiency and high performance of electrochemical that maintain safety and reduce the temperature of an exothermic reaction

[]

Graphite –  micro

HSO

Ambient temperature