Water-Compatible Hydrogen-Bond Activation: A Scalable and Organocatalytic Model for the Stereoselective Multicomponent Aza-Henry.

Abstract

In this communication we described the development and implementation of the first example of a hydrogen bond based organocatalytic multicomponent manifold operating “in the presence of water” conditions. The manifold performs a multicomponent and stereoselective version of the organocatalyzed aza-Henry reaction and it utilizes aniline, aromatic or aliphatic aldehydes, primary or secondary nitroalkanes, N,N-dimethylcyclohexylamine as the catalytic base and a chiral thiourea or squaramide catalyst as the chiral source to afford the corresponding -disubstituted -nitroamine derivatives. The reaction does not require a large excess of nitroalkane (two equivalents are enough) to afford the corresponding product in good yield and high stereoselectivity (up to ≥99.5:0.5 e.r. and ≥99.5:0.5 d.r., anti-adduct). The catalysis is performed through H-bond interactions between the nitroalkane and the chiral catalyst in the presence of interfacial water. Importantly, each family of catalysts delivers the -nitroamine product with complementary enantioselectivity, allowing for the selective access to the two enantiomeric series of these building blocks in an efficient, instrumentally simple and scalable manner.