An enantioselective approach to 2,3-disubstituted indolines through consecutive Brønsted acid/Pd-complex-promoted tandem reactions.

Tandem reactions and consecutive catalysis (or relay catalysis) have been receiving considerable attention in organic synthesis due to their abilities of constructing multiple new chemical bonds to build complex chiral molecules in a single operation. Transition-metal-catalyzed asymmetric hydrogenation is one of the most widely used and reliable catalytic methods for preparation of chiral molecules. The combination of Brønsted acid/transition-metal-catalyzed tandem reactions involving asymmetric hydrogenation as key step remains rare, although Krische and co-workers reported the C C bond formation with metal hydride as the catalytic species. Chiral 2,3-disubstituted indolines are significant building blocks in biologically active natural products and pharmaceutically active compounds. Generally, these compounds are synthesized from either dynamic resolution or multiplestep reactions. The most straightforward and atom economic means towards chiral indolines may be the asymmetric hydrogenation of substituted indole derivatives. Recently, some significant progress has been achieved by us and other groups for the highly enantioselective hydrogenation of substituted indoles using chiral Pd, Rh, Ru, and Ir complexes as catalysts. Very recently, we developed a facile approach to chiral 2,3-disubstituted indolines through dehydration-triggered asymmetric hydrogenation of 3-(a-hydroxyalkyl)indoles. Despite these contributions, the tedious procedure for the preparation of the substrates limits its synthetic applications. So, the search for a rapid, simple, and divergent method for synthesizing chiral 2,3-disubstituted indolines is still highly desirable. Considering reductive alkylation (Friedel–Crafts/dehydration/reduction) of 2-substituted indoles and aldehydes can rapidly lead to 2,3-disubstituted indoles, we envisioned that combination of reductive alkylation of 2-substituted indoles and asymmetric hydrogenation of 2,3-disubstituted indoles can lead to a rapid and divergent approach to chiral 2,3-disubstituted indolines (Scheme 1). Herein, we describe the enantioselective access to chiral 2,3-disubstituted indolines through consecutive Brønsted acid/Pd-complex-