Direct asymmetric hydrosilylation of indoles: combined Lewis base and Brønsted acid activation.

While a variety of protocols, including traditional enzymatic or non-enzymatic kinetic resolutions, and organicmoleculeor metal-mediated asymmetric transformations have been described, the direct asymmetric reduction of prochiral indole precursors would be one of the most straightforward ways to make chiral indolines. Thus, a few transition metal/chiral phosphine complexes, including Rh, Ru, and Ir, have been applied by the groups of Kuwano, Feringa, Pfaltz, and others to the asymmetric hydrogenation of indoles, but the methods usually suffer from a limited substrate scope and relatively harsh reaction conditions. A noteworthy breakthrough was made by Zhou, Zhang, and coworkers who reported an elegant palladium-catalyzed enantioselective hydrogenation of unprotected indoles activated by Brønsted acids. In contrast, Rueping et al. presented the chiral Brønsted acid catalyzed transfer hydrogenation of 3Hindoles with Hantzsch dihydropyridine as the hydrogen source. Nevertheless, to the best of our knowledge, there is no successful precedent on the direct asymmetric reduction of 1H-indoles to access chiral indolines under metal-free conditions despite the fantastic progress of organocatalysis over the past decade. Recently we discovered a highly diastereoselective intramolecular direct imino-ene reaction of indoles tethered to an olefinic side chain at C3, in which a Lewis acid promoted enamine–imine isomerization of the indole through C3 protonation was key to its success. We also recognized that, for unprotected indoles, a similar C3 protonation would occur in the presence of suitable Brønsted acids, which would destroy the aromaticity of indoles and result in the formation of electrophilic indolenium ions. We envisioned that the asymmetric reduction of indoles might be realized by utilizing a chiral organocatalytic system that is compatible with a Brønsted acid activation process. Herein we report our endeavors on the first direct enantioselective hydrosilylation of prochiral 1H-indoles by combined Brønsted acid/Lewis base activation (Scheme 2).