ORGANIC CHEMISTRY FRONTIERS View Article Online REVIEW View Journal | View Issue Recent developments in 1,6-addition reactions of para-quinone methides (p-QMs) Cite this: Org. Chem. Front., 2020, 7, 1743 Jia-Yin Wang, Wen-Juan Hao,* Shu-Jiang Tu * and Bo Jiang * In recent years, para-quinone methides (p-QMs) have emerged as attractive and versatile synthons in organic synthesis owing to their high reactivity. Consequently, p-QM chemistry has attracted increasing attention and remarkable advances have been achieved. Among the numerous transformations involving p-QMs, catalytic reactions play a pivotal role, and a variety of catalytic systems mediated by Lewis acids, Brønsted acids, bases, transition metals, N-heterocyclic carbenes, and other catalysts have been estab- lished for performing 1,6-conjugate addition reactions. Various molecular scaffolds have been con- Received 30th March 2020, structed using p-QMs to obtain the core structures of numerous natural and synthetic substances of Accepted 28th May 2020 chemical and biomedical relevance. In this review, we provide a comprehensive overview of recent pro- DOI: 10.1039/d0qo00387e gress in this rapidly growing field by summarizing the 1,6-conjugate addition and annulation reactions of rsc.li/frontiers-organic p-QMs with consideration of their mechanisms and applications. 1. Introduction cal processes, such as lignin biosynthesis,2 adrenergic recep- tors,3 enzyme inhibition,4 and DNA alkylation5 and cross- para-Quinone methides (p-QMs; Fig. 1, type A) are ubiquitous linking.6 Owing to their unique structural assembly compris- structural motifs present in a wide variety of biologically active ing reactive carbonyl and olefinic moieties, p-QMs undergo natural products.1 p-QMs also play numerous roles in biologi- resonance between neutral and zwitterionic structures (Fig. 1, type B) and display remarkable chemical reactivity as versatile acceptors for 1,6-addition reactions, including Michael Published on 28 May 2020. Downloaded 10/5/2021 3:33:54 PM. School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic addition and radical addition. As Michael acceptors, p-QMs Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, P. R. China. E-mail: [email protected], [email protected], have been successfully subjected to 1,6-addition or annulation [email protected]; Fax: +8651683500065; Tel: +8651683500065 reactions with carbon-, phosphorus-, and nitrogen-centered Jia-Yin Wang was born in 1993 Wen-Juan Hao was born in 1983 in Jiangsu Province (China). He in Jiangsu province, China. She received his BS in 2016 at received her B.S. in 2006 and M. Xuzhou Institute of Technology. S. in 2009 at Jiangsu Normal He received his MS in 2019 at University under the supervision Jiangsu Normal University under of Prof. Shu-Jiang Tu, Ph.D. in the supervision of Prof. Shu- 2014 at Soochow University with Jiang Tu and Prof. Bo Jiang. Prof. Shu-Jun Ji and then joined Currently, he is pursuing his the School of Chemistry and PhD at Nanjing University under Materials Science at Jiangsu the supervision of Prof. Guigen Normal University as a lecturer Li and Prof. Bo Jiang (JSNU). His and is currently promoted to Jia-Yin Wang research interests include radical Wen-Juan Hao Associate Professor. She was as a triggered bicyclization and asym- Visiting Scholar at Nanyang metric transformation. Technological University from July 2016 to January 2017 in Singapore with Prof. Choon Hong Tan. Her research interest includes synergistic catalysis, heterocyclic syntheses, and radical domino reactions. This journal is © the Partner Organisations 2020 Org. Chem. Front.,2020,7,1743–1778 | 1743 View Article Online Review Organic Chemistry Frontiers Fig. 1 p-QMs and their resonance structures. nucleophiles under various catalytic systems. Interestingly, p-QMs have also been exploited as highly reactive radical acceptors for capturing various carbon- and nitrogen-centered radicals via radical addition/cyclization or radical cross-coup- ling. These transformations provide numerous elegant and Fig. 2 p-QMs and their derivatives. practical methods for the formation of a variety of carbon– carbon and carbon–heteroatom bonds, permitting the syn- thesis of important molecules that are difficult to obtain by tegic design, reaction discovery, and fundamental character- other approaches. Since two pioneering works describing the istics of the 1,6-conjugate addition and annulation reactions of synthesis of diarylmethines from p-QMs via 1,6-conjugate p-QMs with an emphasis on achiral transformations in con- addition were independently reported by Fan7a and sideration with recent asymmetric advances. Jørgensen,7b several reaction modes of p-QMs have been thoroughly explored,8 including [2 + 1], [4 + 1], [3 + 2], [4 + 2], [4 + 3], and double annulations involving various p-QM sub- strates containing different functional groups and substitution 2. Chemistry of p-QMs patterns (Fig. 2, 1a–1h), resulting in new three-, five-, and six- membered and polycyclic systems. In the past years, Li, 2.1. 1,6-Addition of nucleophiles to p-QMs Bernardi, Enders, and Tortosa independently highlighted 2.1.1. Catalyst-free 1,6-addition. Environmentally benign 9 achievements in the asymmetric transformations of p-QMs. and sustainable synthetic approaches to target compounds Undoubtedly, implementing catalytic approaches involving of have attracted increasing attention in recent years, with con- p-QMs is one large research field, which includes both chiral siderable research effort devoted to the development of reac- and achiral aspects. Owing to the increasing attention that tion conditions for green and sustainable chemistry, such as Published on 28 May 2020. Downloaded 10/5/2021 3:33:54 PM. p-QM chemistry has received in recent years, especially with metal-free catalysis,10 catalyst-free synthesis, and the utiliz- respect to non-asymmetric transformations, there is a strong ation of green solvents.11 In this context, Anand and co- demand to summarize these recent advances. Therefore, the workers reported a straightforward strategy for the 1,6-conju- purpose of this review is to provide our perspective on the stra- gate addition of dialkylzinc reagents to p-QMs 1a under con- Shu-Jiang Tu was born in 1957 Bo Jiang was born in 1981 in in Jiangsu (China) and received Jiangsu (China). He received his his B.S. in 1983 at Jiangsu B.S. in 2004 and M.S. in 2007 at Normal University. He was Jiangsu Normal University under appointed as Assistant Professor the supervision of Prof. Shu- at the Xuzhou Normal University Jiang Tu, Ph.D. in 2010 at in 1999 and was promoted to Soochow University with Prof. Full Professor in 2003. His Shu-Jiang Tu and Prof. Guigen current interests are the develop- Li. He joined Jiangsu Normal ment of new synthetic methods, University as a lecturer and was green chemistry, and microwave promoted to Full Professor in multicomponent syntheses. 2019. He was as an Associate Shu-Jiang Tu Bo Jiang Research Professor at Texas Tech University from Aug. 2015 to Feb. 2017 in USA with Prof. Guigen Li. His research interest includes asymmetric catalysis, radical transformations, and the innovation of synthetic methods. 1744 | Org. Chem. Front.,2020,7,1743–1778 This journal is © the Partner Organisations 2020 View Article Online Organic Chemistry Frontiers Review tinuous-flow conditions in a microreactor (Scheme 1).12 Upon injection of a toluene solution of p-QMs 1a and 2.0 equivalents − of dialkylzinc reagent at a flow rate of 5 μL min 1 (residence time in the microreactor = 10 min), the reactants were smoothly transformed into unsymmetrical alkyl diaryl- methanes 2 at room temperature. This protocol was generally applicable to a wide range of p-QMs 1a and dialkylzinc reagents without any catalyst or promoter. In 2017, Kang et al. synthesized diaryl diazaphosphonates 4 via 1,6-hydrophosphonylation of p-QMs 1a with N-heterocyclic phosphine (NHP)-thioureas 3 under catalyst- and additive-free conditions.13 This transformation proceeded smoothly in ff CHCl3 at room temperature over 16 h to a ord 20 examples of Scheme 3 1,6-Addition of sulfonyl hydrazides to p-QMs. the desired product (Scheme 2a). When the 2,6-diisopropyl- phenyl-substituted NHP-thiourea 3 was employed under the optimized reaction conditions, the reaction did not proceed. (Scheme 3a). Various types of sulfonyl hydrazides 8 bearing On the basis of control experiments, the authors proposed a either aryl or alkyl groups were well tolerated in this conjugate plausible reaction pathway (Scheme 2b). The 1,6-conjugate addition reaction, and the authors proposed a plausible addition between the p-QM 1a and the bifunctional NHP- mechanism for this catalyst-free transformation. In the first thiourea 3, which is activated by hydrogen bond formation step, the sulfinyl anion is formed from sulfonyl hydrazide 8 in with the thiourea Brønsted acid, generates the diazaphospho- the presence of water with the release of N . The resonance ff 2 nium intermediate 5. Subsequent proton transfer (PT) a ords structure of the sulfinyl anion, sulfur-centered anion 10, the anionic thiourea intermediate 6, which undergoes intra- undergoes 1,6-conjugate addition to the p-QM 1a to afford molecular nucleophilic substitution to furnish the final intermediate 11. The desired product 9 is formed upon proton product 4 alongside thiazolidine 7. transfer from hydronium ions to the intermediate 11 Subsequently, the Liu group developed a 1,6-conjugate (Scheme 3b).14 The similar unsymmetrical