Catalytic enantioselective Friedel-Crafts reactions of aromatic compounds with glyoxylate: A simple procedure for the synthesis of optically active aromatic mandelic acid esters

The first catalytic highly enantioselective Friedel-Crafts reaction of aromatic compounds with glyoxylate catalyzed by chiral Lewis acids is presented. The reaction has been developed for mainly aromatic amines reacting with ethyl glyoxylate in the presence of chiral bisoxazoline-copper(II) complexes as the catalyst. A series of chiral bisoxazoline-copper(II) complexes have been tested as catalysts for the reaction with N,N-dimethylaniline and it has been found that a highly regio- and enantioselective Friedel-Crafts reaction takes place in the presence of especially tert-butyl bisoxazoline-copper(II). This reaction proceeds with the formation of exclusively the para-substituted isomer in up to 95% yield and 94% ee. The reaction has been investigated for N,N-dimethylaniline under different reaction conditions and has been developed to be a catalytic highly enantioselective reaction for meta-substituted N,N-dimethylanilines, containing either electron-withdrawing or electron-donating substituents, The catalytic enantioselective Friedel-Crafts reaction also proceeds well for cyclic aromatic amines such as N-methylindoline, N-methyltetrahydroquinoline, and julolidine, where up to 91% yield and 93% ee are obtained. For polyaromatic amines high yields, but moderate ee values, of the Friedel-Crafts products are obtained. To enhance the potential of the reaction the N,N-dimethyl- and N-methyl substituents can be removed successfully leading to either the mono-N-methyl product or the free amine. The latter class of products allow for the introduction of a variety of other substituents on the aromatic nucleus. The catalytic enantioselective reaction also proceeds for heteroaromatic compounds such as 2-substituted furans which react with glyoxylate as well as trifluoropyruvates, giving up to 89% ee of the Friedel-Crafts products. Furthermore, ethyl trifluoropyruvate reacts in a highly enantioselective reaction with m-methoxyanisole to give the corresponding Friedel-Crafts product in good yield. On the basis of the experimental results and the absolute configuration of the products, the mechanism for this catalytic highly enantioselective Friedel-Crafts reaction is presented.