Research group of Professor Zhang Wanbin of Shanghai Jiaotong University: copper catalyzed synergistic reaction of reductive defluorination of β - trifluoromethylenone and oxidative coupling of Grignard reagent

The author: as a kind of very important fluorine-containing block, Wu Xiaoting's end-site difluorene skeleton has been widely used in fine chemicals, medicine, agricultural chemicals, materials science and organic synthesis Therefore, the introduction of end-site difluorene skeleton into organic molecules is a very important research topic in modern fluorine chemistry On the other hand, the oxidative coupling reaction of Grignard reagent catalyzed by copper has always been a hot topic in organic synthesis Although researchers have developed a variety of methods to realize the efficient construction of csp2-csp2, csp-csp, there are only Severin group (angel Chem., int ed 2013, 52, 630), Zeng infantry group (Synthesis 2013, 45, 518), Shi Yi'an group (org Lett 2014, 16, 6144) and Wei Wenlong group (RSC advantages 2016, 6) for the construction of csp3-csp3 , 86998) Therefore, new reaction systems need to be developed to achieve this kind of reaction The SN2 'reaction of nucleophiles with α - trifluoromethylene is one of the common methods for the preparation of difluorene terminated compounds However, it is difficult to synthesize some functionalized difluoroenes, such as difluoroenone In the SN2 'reaction, the electron is directly used to defluorinate the trifluoromethyl compounds containing π electron system, which can realize the synthesis of functionalized end-point difluorene compounds (chem Rev 2012, 112, 1344) However, due to the difficulty of providing effective electronic sources, so far, there are only a few reports on this kind of electronic reductive defluorination reaction, that is, using electrochemistry to provide electronic sources or using metal magnesium to provide electronic sources, and using photocatalytic excitation to provide electronic methods developed in recent two years (J.Org Chem 2016, 81, 7908; angel Chem Int ed 2017, 56, 15073; Chem Commun 2017, 53, 9478) (Figure 1, previouswork) To solve the problem of electronic source, recently, the research team of Professor Zhang Wanbin of Shanghai Jiaotong University has developed the copper catalytic synergistic reaction of reduction defluorination of β - trifluoromethenone compound and oxidation coupling of Grignard reagent: a pair of electrons released from oxidation self coupling of Grignard reagent catalyzed by copper are used as electronic source to realize the reduction defluorination of trifluoromethyl compounds containing π electron system At the same time, the trifluoromethyl compound containing π electron system, as a new oxidant, realizes the oxidation self coupling reaction of Grignard reagent catalyzed by copper (Figure 1, ourdesign) In these two reactions, the copper catalyst plays a role of "one stone, two eagles" Relevant research work was published in the recent org Lett (org Lett 2018, 20, 1638) Fig 1 The electron reductive defluorination reaction (source: Organic letters) the author chooses β - trifluoromethylenone 1A with π electron system as the reaction substrate The experimental results show that when the catalytic amount of Cu (I) Tc is added, the main products are reduction defluorination product 2a and oxidation couple product 3A (Fig 2, entry 2) When triphenylphosphine was added as the ligand of Cu (I) Tc, the chemical selectivity of the reaction was obviously improved The author determined that 1 mol% Cu (I) TC was the best catalytic condition by optimizing the type of copper salt and the amount of catalyst (Fig 2, entry 7) Figure 2 Optimization of reaction conditions a (source: organicletters) the author investigated the applicability of β - trifluoromethylenone derivatives using the above optimal catalytic reaction conditions (Table 2) R 1 group is suitable for alkyl and aryl groups When R 1 is phenyl, substituted phenyl, naphthyl or heteroaromatic, and R 2 is phenyl or substituted phenyl, the corresponding difluoronene-terminated compound 2 can be obtained with high yield Linear polyconjugated enone 1x also showed very good selectivity and activity None of the above reactions detected conjugated addition products of Grignard reagent to conjugated ketene or 1,2-addition products of p-keto carbonyl Fig 3 Development of β - trifluoromethylenone substrate a (source: organicletters) On the other hand, the author used β - trifluoromethylenone as oxidant to investigate the application range of a series of Grignard reagents in the oxidative coupling reaction under the copper catalytic system (Table 3) No matter for aryl Grignard reagent or phenyl substituted alkenyl Grignard reagent, the reaction can obtain oxidized self coupling dimer products with high yield It is worth noting that alkylgrignard reagent, especially Grignard reagent with β - H, can also obtain oxidative coupling products with high yield, which provides an effective method for the construction of csp3-csp3 Fig 4 Extended a of Grignard reagent (source: organicletters) according to the results of this series of experiments and the relevant literature (chem Rev 2012, 112, 1344; angelw Chem Int.ed 2007, 46, 9093), the author proposed the possible catalytic mechanism of the reaction (Fig 5) Fig 5 Possible reaction mechanism (source: Organic letters) in order to illustrate the versatility of γ, γ - difluoroalkenones synthesized by this catalytic method, the author, with 2A as the representative, has carried out the conversion of various functional groups, and obtained various fluorine-containing compounds with high yield (Fig 6) Figure 6 Transformation of γ, γ - difluoroenenone 2A (source: Organic letters) The research results were published on organic letters Professor Zhang Wanbin and associate professor Xie Fang of Shanghai Jiaotong University were co correspondents, and Wu Xiaoting, doctoral candidate of Shanghai Jiaotong University, was the first author of the paper This work is supported by NSFC Review of previous reports of Professor Zhang Wanbin's research group: research team of Professor Zhang Wanbin of Shanghai Jiaotong University: IR / Cu Bimetallic synergetic catalytic system for the stereodivergent synthesis of unnatural α, α - disubstituted α - amino acids