Designing new alpha,beta-unsaturated thioesters for the catalytic, enantioselective Friedel-Crafts alkylation of indoles

A new class of alpha,beta-unsaturated S-(1,3-benzoxazol-2-yl) thioesters of type 2 have been synthesized and effectively employed as electrophiles in the stereoselective alkylation of indoles. The combination of electronic as well as steric properties of such Michael acceptors allowed us to carry out Friedel-Crafts alkylations of various substituted indoles in the presence of a catalytic amount (20 mol-%) of chiral cationic [Pd-11(Tol-binap)] complexes. With the optimized catalytic system (PdCl2(MeCN)(2)/Tol-binap/AgSbF6), the desired beta-indolyl-substituted thioderivatives 4 were obtained in good yield, with an enantiomeric excess (ee) of up to 86%. The remarkable versatility of the enantiomerically enriched thioesters 4 was demonstrated by quantitatively transforming them into optically active beta-indolyl esters and amides under mild conditions. With this stereoselective, catalytic Friedel-Crafts reaction, we open up the way towards new alpha,beta-unsaturated compounds that could be suitable candidates for the preparation of a number of optically active beta-substituted carboxylic compounds.