Li Zhi group, Shanghai University of science and technology: redox chain opening reaction of quinone and lactone -- Preparation of quinone carboxylic acid derivatives

Introduction quinone derivatives widely exist in nature Many quinone compounds have been used in the field of medicine due to their unique structural and functional characteristics, such as coenzyme Q10, seratrodast and idebenone, which have been on the market for a long time In addition, the redox properties of quinones make them show potential application value in organic synthesis and redox battery materials (Figure 1) Therefore, the synthesis of quinone based drug molecules and functional materials has always been the goal of chemists Recently, Li Zhi group of Shanghai University of science and technology successfully realized ring opening reaction of quinone and five to eight membered cyclic ester by using redox chain reaction mechanism, and prepared a series of quinone carboxylic acid derivatives with various structures Relevant research results are published online in the Journal of organic letters of American Chemical Society (org Lett 2019, 21, 5078) Figure 1 Introduction of Assistant Professor Li Zhi's research group on the application of quinone derivatives the research group has been committed to the design and synthesis of new Lewis acid catalysts and their application in the transformation of renewable resources There are many esters and ethers containing C-O bond in biomass The research group continues to explore new catalytic methods, trying to activate the C-O bond in renewable resource biomass, so as to transform it into high value-added chemical products or drug molecules, and promote the development of chemical industry towards green and sustainable direction Introduction to Assistant Professor Li Zhi, assistant professor He received his bachelor's degree from China University of science and technology in 2006, his doctor's degree in organic chemistry from the University of Chicago in 2011 (supervisor Hisashi Yamamoto), and his postdoctoral research was conducted in Tobin J marks research group, Department of chemistry, Northwestern University from 2011 to 2014 In March 2015, he joined the school of material science and technology of Shanghai University of science and technology as an assistant professor In 2015, he was selected into the 11th batch of "thousand talents plan" youth project of the central organization department and won the thiemechemistry Journal Award in 2018 Leading scientific research achievements: the redox chain opening reaction of quinone and lactone - the direct C-H functionalization of quinone derivatives has been paid more and more attention by chemists In 2011, Baran et al Took the lead in the development of C-H bond functionalization of quinone and borate (j.am.chem.soc 2011, 133, 3292-3295), but could not realize the direct benzylation of quinone When Li Zhi's group studied the [4 + 2] cycloaddition reaction of p-benzoquinone and isopentenyl acetate, the alkylation product of quinone was unexpectedly observed Further research found that the reaction was carried out through a rare redox chain reaction mechanism By adding a small amount of reduction initiator Hantzsch ester to the reaction system, the repeatability and yield of the reaction were significantly improved, and finally the direct C-H functional reaction of quinone, allyl ester and benzyl ester was realized (angel Chem Int ed 2017, 56, 8196-8200; synlett 2018 , 29 , 1807-1813 ）。 After that, the author tried to use the reaction to synthesize the antiasthmatic drug seratrodast, but only the ethyl ester or methyl ester of seratrodast was synthesized at last The simple condition screening did not succeed in hydrolyzing it to get the corresponding drug molecules Therefore, the author speculates whether benzyllactone can also participate in the redox chain reaction of benzoquinone as electrophilic reagent, and introduce carboxyl side chain into quinones directly while constructing new C-C bond After repeated experimental optimization, the ring opening reaction of quinone and five to eight membered cyclic esters was successfully realized, and quinone carboxylic acid derivatives with various structures were prepared The reaction conditions are mild, with redox economy and 100% atom economy (Fig 2) Fig 2 The redox chain reaction of quinone and lactone (org Lett.) by 2, The ring opening reaction of 6-dimethylp-benzoquinone and γ - phenyl - γ - butyrolactone was studied Through a large number of optimization of reaction conditions, it was found that the quinone carboxylic acid product was successfully obtained by stirring reaction at 70 ℃ for 6 hours under the catalysis of 4 mol% HF (OTF) 4 and 4 mol% reduction initiator Hantzsch ester with trifluoromethyl as solvent and 73% separation yield After that, taking 2,6-dimethylp-benzoquinone as the representative quinone, the author investigated the substrate range of the five membered cyclic ester containing different functional groups, and found that the reaction requires that there must be an aryl, heteroaryl or alkenyl functional group conjugated with the reaction site at the γ position of the five membered cyclic ester, and the simple γ - alkyllactone can not achieve C-O bond breaking under the catalysis of HF (OTF) 4 The reaction is compatible with heteroatom (F, Cl, BR), methoxy, methylthio, borate ester and alkenyl When there are strong electron absorbing groups (ester group, cyano group) on the γ - aryl group of cyclic ester, it is impossible to carry out ring opening chain reaction with benzoquinone After that, the author found that both six membered and seven membered cyclic esters can participate in the redox chain reaction of benzoquinone In order to demonstrate the practicability of this method, the author synthesized the antiasthmatic agent seratrodast Eight membered cycloester 8-phenyloxocan-2-one was synthesized in 44% of the total yield in four steps, and then reacted with trimethyl-p-benzoquinone to synthesize seratrodast successfully in 67% yield Then the author studies the range of quinones containing different substituents Most of the substituted benzoquinones react with different five membered cyclic esters and give good yields; p-benzoquinone with one methyl or tert-butyl group can selectively be monofunctionalized at position 5; the substituted naphthoquinone is also a good nucleophilic reagent (Fig 3) Fig 3 After the study of the representative substrate range, the author tried the reaction of 2,6-dimethylp-benzoquinone and γ - alkenyl γ - lactone Due to the steric hindrance, the reaction site was transferred from γ - position to the end position of alkenyl group The NMR noe experiment showed that the product was dominated by e-configuration When γ - alkenyl - γ - methyl - γ - lactone is used, the product of lactone structure preservation is always separated by the author NMR monitoring shows that the intermediate a of ring opening product can be cyclized slowly in the reaction system If the equivalent BF 3 ＜ et 2O is used as the catalyst for this reaction, a higher yield can be obtained (Fig 4) Fig 4 Redox chain reaction of quinone and γ - alkenyl γ - lactone (source: org Lett.) in order to further elaborate the nature of redox chain reaction, the author has conducted in-depth study on the reaction mechanism (Fig 5) When using 0.5 equivalent Ag 2O instead of reduction initiator Hantzsch ester in the reaction system, the target product could not be obtained The experimental results show that the strong oxidation environment will consume the active intermediate hydroquinone and inhibit the key Friedel crafts alkylation reaction Under the standard reaction conditions, the author used five membered cyclic esters with higher EE (31,79% ee and 32,90% ee) and 2, 6-dimethylp-benzoquinone was oxidized and reduced to form quinone carboxylic acid with lower EE value The results showed that lactone produced complete carbocation intermediate or tight ion pair intermediate in the ring opening reaction, which may depend on the resonance effect of aromatic group Figure 5 Study on the mechanism of oxidation-reduction chain reaction (source: org Lett.) in summary, the author developed an efficient, atom economical, oxidation-reduction economical C-H functional reaction of quinone and polycyclic ester, This reaction has experienced a unique redox chain reaction mechanism, and a large number of quinone carboxylic acid derivatives have been synthesized, which has opened up a new direction for the research of quinone based pharmaceutical chemistry and materials This research work was independently completed by Xu Xiaolong, doctoral student of Shanghai University of science and technology The project was supported by general program of National Natural Science Foundation of China (Project No.: 21673141), scientific research start-up fund of Shanghai University of science and technology and start-up fund of "young thousand talents" program Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.