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α-Halo Amides as Competent Latent Enolates: Direct Catalytic Asymmetric Mannich-Type Reaction

Sun, Bo, Balaji, Pandur Venkatesan, Kumagai, Naoya, Shibasaki, Masakatsu
Journal of the American Chemical Society 2017 v.139 no.24 pp. 8295-8301
amides, carbonyl compounds, chemical bonding, dehalogenation, diastereoselectivity, enantioselectivity, imines, models, moieties, stereochemistry
α-Halogenated carbonyl compounds are susceptible to dehalogenation and thus largely neglected as enolate precursors in catalytic enantioselective C–C bond-forming reactions. By merging the increased stability of the α-C–halogen bond of amides and the direct enolization methodology of the designed amide, we explored a direct catalytic asymmetric Mannich-type reaction of α-halo 7-azaindoline amides with N-carbamoyl imines. All α-halo substituents, α-F, -Cl, -Br, -I amides, were tolerated to provide the Mannich-adducts in a highly stereoselective manner without undesirable dehalogenation. The diastereoselectivity switched intriguingly depending on the substitution pattern of the aromatic imines, which is ascribed to stereochemical differentiation based on the open transition-state model. Functional group interconversion of the 7-azaindoline amide moiety of the Mannich-adducts and further elaboration into a diamide without dehalogenation highlight the synthetic utility of the present protocol for accessing enantioenriched halogenated chemical entities.