The effect of hydrogen bond donors in asymmetric organocatalytic conjugate additions

A series of primary amine organocatalysts with various hydrogen bond donors were prepared and examined in the conjugate addition of isobutyraldehyde and acetone to trans-β-nitrostyrene and (E)-methyl 2-oxo-4-phenylbut-3-enoate. The effect of N–H acidity and hydrogen-bonding modes of the catalysts on the catalytic activity and enantioselectivity was studied. The experimental results did not support a general correlation of N–H acidity and hydrogen-bonding modes with catalytic activity and enantioselectivity. The catalysts with double hydrogen-bonding interactions provided better catalytic activities and enantioselectivities than the catalysts with single hydrogen-bonding interactions for the reaction of trans-β-nitrostyrene. The catalyst with the most acidic N–H bond showed the best catalytic activity and enantioselectivity for the reaction of (E)-methyl 2-oxo-4-phenylbut-3-enoate. These results suggest that the effect of hydrogen bond donors in organocatalytic reactions may be highly dependent on the substrates and the reaction conditions.

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N-((1R,2R)-2-Aminocyclohexyl)-1,1,1-trifluoro-methanesulfonamideC7H13F3N2O2S[α]D20=-7.2 (1.06, CH3OH)Source of chirality: (1R,2R)-cyclohexane-1,2-diamineAbsolute configuration: (1R,2R)

N-((1R,2R)-2-Aminocyclohexyl)benzamideC13H18N2O[α]D20=-49.0 (c 1.0, CH3OH)Source of chirality: (1R,2R)-cyclohexane-1,2-diamineAbsolute configuration: (1R,2R)

Methyl 3,3-dimethyl-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-6-carboxylateC15H16O4Ee 76%[α]D20=-19.2 (c 1.04, CHCl3)Source of chirality: asymmetric synthesis