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Downloaded 10/4/2021 1:16:42 PM ORGANIC CHEMISTRY FRONTIERS View Article Online REVIEW View Journal | View Issue Recent advances in metal catalyzed or mediated cyclization/functionalization of alkynes to Cite this: Org. Chem. Front., 2020, 7, 2325 construct isoxazoles Jianxiao Li, * Zidong Lin, Wanqing Wu and Huanfeng Jiang * Isoxazoles and their derivatives represent privileged heteroaromatic motifs, which exhibit remarkable bio- logical and pharmaceutical activities. Notably, metal catalyzed or mediated cyclization/functionalization of alkynes such as alkynone oxime ethers, acetylinic oximes, propargylic amino ethers, alkynyl nitrile oxides, and propargylic alcohols has recently attracted much attention from synthetic organic chemists because of their high efficiency in the assembly of structurally diverse isoxazole architectures under mild conditions with exceptional chemo-, stereo- and regioselectivities. In this review, a wide array of metal Received 19th May 2020, catalysts, such as palladium, copper, iron, gold, silver, and other metals, have been summarized and dis- Accepted 19th June 2020 cussed in detail. Moreover, we also highlight some representative synthetic strategies along with reaction DOI: 10.1039/d0qo00609b mechanisms involved during the reaction. And, the literature has been surveyed from 2010 until the rsc.li/frontiers-organic beginning of 2020. 1 Introduction chemistry.1 As one of the important five-membered heteroaro- matic ring scaffolds, isoxazoles exhibit significant biological Among the vibrant classes of aromatic heterocyclic com- and pharmaceutical activities in natural products, pharma- pounds, isoxazoles, discovered by Claisen in 1888, have always ceutical agents and preclinical candidates, including anti- been considered as a privileged class of molecules in organic cancer, antimicrobial, antibiotic, and anti-inflammatory activi- ties (Fig. 1).2 For example, valdecoxib has been established as 3 4 Published on 22 June 2020. Downloaded 10/4/2021 1:16:42 PM. a COX-2 inhibitor. Oxacillin is used as a β-lactam antibiotic. Key Laboratory of Functional Molecular Engineering of Guangdong Province, School NVP-AUY922 is an experimental drug candidate developed by of Chemistry and Chemical Engineering, South China University of Technology, Vernalis for treating cancer.5 Moreover, the drug ring system Guangzhou 510640, China. E-mail: [email protected], [email protected] Jianxiao Li received his B.Sc. Zidong Lin was born (1996) in degree (2008) from Fuyang Guangdong Province, China. He Normal University. He earned obtained his B.Sc. degree from his M.Sc. under the supervision Jiangnan University in 2019. And of Prof. Zhao-Yang Wang at then, he pursued his M.Sc. South China Normal University degree under the supervision of in 2011. He completed his Ph.D. Associate Prof. Jianxiao Li at the in 2014 under the direction of School of Chemistry and Prof. Huanfeng Jiang at the Chemical Engineering, South South China University of China University of Technology. Technology. From 2014 to 2017, His research focuses on tran- he worked as a postdoctoral sition metal-catalyzed coupling Jianxiao Li fellow with Prof. Huanfeng Jiang. Zidong Lin reactions. He has now joined the School of Chemistry and Chemical Engineering at the South China University of Technology as an associate professor. His current research interests include transition metal-catalyzed coupling reac- tions and green chemistry. This journal is © the Partner Organisations 2020 Org. Chem. Front.,2020,7,2325–2348 | 2325 View Article Online Review Organic Chemistry Frontiers sition metal-catalyzed C–H functionalization of isoxazoles rep- resents the most straightforward and rapid synthetic approaches for the construction of these structural motifs with high regioselectivities.10 Nevertheless, the substrate scope of these protocols is more limited. Alternatively, condensation reactions from β-dicarbonyls with hydroxylamine also rep- resented one of the most important synthetic methods for the assembly of these functionalized heterocycles.11 Despite these significant advances, these developments suffer from relatively harsh reaction conditions and lower regioselectivities. In recent years, metal-catalyzed cycloisomerizations have emerged as fascinating and flourishing synthetic method- Fig. 1 Representative examples of isoxazoles with pharmacological ologies for the construction of various high value-added isoxa- activities. zoles in a step- and atom-economical manner. There are two reviews on the synthesis of isoxazoles that have been published in recent years.12 Szostak and co-workers reviewed the recent analysis shows that the isoxazole ring ranks 33rd among the developments in the synthesis and reactivity of isoxazoles from 351 ring systems found in marketed drugs.6 Besides, isoxa- 2005 to 2014.13 Reactions of [3 + 2] cycloadditions, metal-free zoles can serve as synthetically versatile intermediates for the cycloisomerization reactions, condensation reactions, and highly efficient assembly of polyfunctionalized organic small functionalization of isoxazoles were discussed. However, the molecules and functional materials.7 Therefore, the develop- plausible reaction mechanisms were not addressed in detail. ment of expeditious and practical synthetic methodologies for In 2018, Nakamura’s group reviewed the synthetic approaches the rapid and direct assembly of structurally diverse polyfunc- to functionalized isoxazoles, with particular focus on 1,3- tionalized isoxazoles is more appealing. dipolar cycloaddition, condensation, cycloisomerization, and Owing to their unique chemical and biological character- direct functionalization.12b However, this review considers the istics, the development of efficient and practical synthetic limited aspects of the chemistry of isoxazoles and does not methodologies for the construction of functionalized isoxazole address the advances that have taken place in the past years. building blocks has continued to capture the interest of syn- Nevertheless, the majority of such reviews reported thus far thetic organic chemists in the fields of heterocyclic chemistry have been restricted to selected metals or selected strategies. and medicinal chemistry over the past few decades.8 To the best of our knowledge, there are no reports wherein Traditionally, the classical [3 + 2] cycloaddition reactions of metal-catalyzed cyclization/functionalization of alkynes was alkynes with nitrile oxides displayed the direct and efficient reviewed in particular along with recent achievements (mainly synthetic strategies for the preparation of highly substituted from 2018 to 2020) for the construction of highly functiona- Published on 22 June 2020. Downloaded 10/4/2021 1:16:42 PM. isoxazole frameworks.9 However, most of these synthetic lized isoxazole heteroaromatic motifs. Combining this with approaches required functionalized precursors, harsh con- our interest in palladium-catalyzed chemical transformations ditions, and/or limited substrate scope. Undoubtedly, tran- of alkynes,14 we summarized the application of the ionic Prof. Wanqing Wu received her Prof. Huanfeng Jiang received his PhD from Peking University with PhD from the Shanghai Institute Professors Zhen Yang and Chi- of Organic Chemistry (SIOC) Sing Lee in 2010. And then she with Professor Xiyan Lu in 1993. joined Professor Huanfeng And then he joined the Jiang’s group as a postdoctoral Guangzhou Institute of researcher at the South China Chemistry as a research fellow. University of Technology (SCUT). In 2003, he moved to the South In 2014, she was promoted to China University of Technology Professor and her research inter- (SCUT) as the Leading Professor ests include the development and of Chemistry. He received a applications of new synthetic Chinese Chemical Society-BASF Wanqing Wu methods. Huanfeng Jiang Young Investigator’s Award in 2002 and National Natural Science Funds for Distinguished Young Scholar in 2006. His research interests focus on synthetic methodologies and green and sustainable chemistry. 2326 | Org. Chem. Front.,2020,7,2325–2348 This journal is © the Partner Organisations 2020 View Article Online Organic Chemistry Frontiers Review liquids as the green solvent for palladium-catalyzed coupling this reaction, giving the corresponding trisubstituted isoxa- reactions of alkynes and/or alkenes for the preparation of zoles in moderate to good yields. Moreover, under the opti- diverse heterocyclic frameworks in 2016.15 Recently, in 2019, mized conditions, a wide variety of functional groups such as we also elucidated the palladium-catalyzed cascade cyclization/ ether, nitrile, ketone, aldehyde, ester, and amide groups are alkynylation reactions for the synthesis of structurally diverse compatible with the reaction conditions. However, the elec- monocyclic, bicyclic, fused polycyclic, and spirocyclic skel- tron-rich alkene such as vinyl acetate was not amenable to this etons with excellent chemoselectivities.16 In this review, we protocol. In addition, this protocol also provides a straight- will present a comprehensive summary of the most recent forward synthetic pathway for the preparation of polycyclic advancements (from 2010 until the beginning of 2020) in this naphtho[1,2-c] isoxazole (4) through palladium-catalyzed cycli- rapidly developing area of synthesis of more elaborated isoxa- zation–alkenylation-Heck cascade process.19 zole derivatives by metal catalyzed or metal mediated cross- After this, the same group reported two regioselective syn- coupling from alkynes, including our recent contributions.
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