Atropisomeric compounds due to rotational restriction around an N-C bond have received much attention recently as novel chiral molecules. However, catalytic enantioselective synthesis of such N-C axially chiral compounds has not so far been reported. We succeeded in the highly enantioselective syntheses of atropisomeric ortho-tert-butyl anilides, lactams and indoles having an N-C chiral axis through chiral palladium-catalyzed N-C bond forming reactions.
That is, in the presence of (R)-DTBM-SEGPHOS-Pd(OAc)₂ catalyst, N-arylation (Buchwald-Hartwig amination) of achiral ortho-tert-butylanilides with p-iodonitrobenzene proceeded in a highly enantioselective manner (88−96% ee) to give atropisomeric N-(p-nitrophenyl)anilides in good yields. The application of the present catalytic enantioselective N-arylation to an intramolecular version gave atropisomeric lactam derivatives with high optical purity (92−98% ee). The α-alkylation with the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides proceeded with high diastereoselectivity (diastereomer ratio=31:1-80:1).
On the other hand, 5-endo-hydroaminocyclization of achiral ortho-alkynylanilines using (R)-SEGPHOS-PdCl₂ catalyst afforded optically active atropisomeric indole derivatives (up to 83% ee) in good yields.