Copper-Catalyzed Asymmetric Conjugate Addition Of Grignard Reagents To Trifluorocrotonate

As we all know, the introduction of the trifluoromethyl group into organic molecules can greatly change its physical properties, chemical properties and consequently biological features, such as enhanced binding selectivity, higher lipophilicity, and increased metabolic stability and so on. Therefore, trifluoromethylated compounds have played an important role in agricultural and medicinal chemistry. So far, even though a lot of methods for the synthesis of optically active trifluoromethylated compounds have been reported, the development of general catalytic methods for the prepartion of stereogenic tertiary carbon centers bearing a trifluoromethyl group without any heteroatom substituent still remains rare. Developing simple and effective methods to synthesize these compounds is a challenge for organic chemists. The common strategies employed include the transition-metal or organocatalyst catalyzed asymmetric conjugated additions (ACA) of α, β-enones and their derivatives for the synthesis of molecules containing trifluoromethyl group substituted chiral center. However, there are many limitations for these reactions, such as narrow substrates scope or the use of expensive and sensitive transition-metal catalysts etc. These all imply that the studies of synthesis of trifluoromethylated compounds with enantioenrich carbon center via C-C bond formation are very important.This work explored the metal copper and S-TOL-BINAP combined system catalyzed enantioselective1,4-conjugate addition of methyl4,4,4-trifluorocrotonate with aliphatic Grignard reagents to access highly enantioselective compounds which includ a trifluoromethyl group. The major topics of this article are as follows:1) We summarized the literatures about the copper catalyzed conjugate addition reactions of α,β-unsaturated ketone, unsaturated ester, unsaturated nitroalkene and unsaturated compounds with the trifluoromethyl group.2) Different temperatures, copper catalysts, the ratios of copper and chiral phosphine ligand, solvents et. al were tested to find the optimized conditions to get the best enantioselective of the conjugate addition products. With the optimized condition, we examined different aliphatic Grignard reagents to react with the trifluorocrotonate. All of the reactions could get good results, the enantioselectivity of the product could reach top to94%. This reaction realized the copper catalyzed highly enantioselective conjugated addition of aliphatic Grignard reagents to4,4,4-trifluorocrotonate under mild reaction conditions. This study provides a direct and simple method for the synthesis of useful enantioenriched trifluoromethyl-substituted compounds with a tertiary carbon center.