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

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.