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 arom atic 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) complexe s as the catalyst. A series of chiral bisoxazoline-copper(II) complexes hav e been tested as catalysts for the reaction with N,N-dimethylaniline and it has been found that a highly regio- and enantioselective Friedel-Crafts re action takes place in the presence of especially tert-butyl bisoxazoline-co pper(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 in vestigated for N,N-dimethylaniline under different reaction conditions and has been developed to be a catalytic highly enantioselective reaction for m eta-substituted N,N-dimethylanilines, containing either electron-withdrawin g or electron-donating substituents, The catalytic enantioselective Friedel -Crafts reaction also proceeds well for cyclic aromatic amines such as N-me thylindoline, N-methyltetrahydroquinoline, and julolidine, where up to 91% yield and 93% ee are obtained. For polyaromatic amines high yields, but mod erate ee values, of the Friedel-Crafts products are obtained. To enhance th e 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 v ariety of other substituents on the aromatic nucleus. The catalytic enantio selective reaction also proceeds for heteroaromatic compounds such as 2-sub stituted furans which react with glyoxylate as well as trifluoropyruvates, giving up to 89% ee of the Friedel-Crafts products. Furthermore, ethyl trif luoropyruvate reacts in a highly enantioselective reaction with m-methoxyan isole to give the corresponding Friedel-Crafts product in good yield. On th e basis of the experimental results and the absolute configuration of the p roducts, the mechanism for this catalytic highly enantioselective Friedel-C rafts reaction is presented.