Asymmetric organocatalytic benzylation of α,β-unsaturated aldehydes with toluenes

The direct organocatalytic enantioselective benzylation by using toluenes and α,β-unsaturated aldehydes is presented. The reaction is catalyzed by tert-butyldimethylsilyl-protected diphenylprolinol in the presence of a mild organic base and proceeds with excellent yields and enantioselectivities up to >99 % ee. This reactivity is based on a synergistic effect between the iminium ion intermediate and the base-activated toluene. Toluene derivatives having various electron-withdrawing substituents were also applied in this unprecedented transformation. The synthetic potential is demonstrated by manipulations of the products to, for example, biologically active phenylbenzazepines. The synergy of an organocatalyst and an organic base allows the use of simple toluenes for the direct benzylation of α,β- unsaturated aldehydes. The concept is developed for a series of different toluenes to provide optically active benzylated products in excellent yields with up to >99 % ee. The application of this concept for the synthesis of the chiral structural motif of benzazepines is shown.