Enantioselective Organocatalytic Addition of Nitromethane to Trifluoromethyl Aryl Ketimines Promoted by Electron-Rich Bifunctional Iminophosphoranes

Thiourea-based iminophosphorane (BIMP) organocatalysts featuring SPhos- or BIDIME phosphine units have been developed and successfully applied in the asymmetric addition of nitromethane to N-Boc-protected trifluoromethyl aryl ketimines. alpha-Trifluoromethyl beta-nitroamines were obtained in 40-82% isolated yields and 80-95% enantioselectivities. A careful evaluation of the catalytic activity of BIMPs indicates that the catalysts derived from the combination via Staudinger reaction of a chiral 1,2-amino alcohol-derived thiourea-organoazide with electron-rich phosphines, promote the aza-Henry reaction on fluorinated ketimines with the highest enantioselectivity, leading to the amine featuring a tetrasubstituted stereocenter in up to 95% ee. The reaction was performed also on gram scale, without loss of enantioselectivity.

Automated summary

Thiourea-based iminophosphorane (BIMP) organocatalysts, featuring SPhos- or BIDIME phosphine units, have been developed and applied successfully in the asymmetric addition reaction. alpha-Trifluoromethyl beta-nitroamines were obtained with high yields (40-82%) and enantioselectivities (80-95%) on N-Boc-protected trifluoromethyl aryl ketimines. The highest enantioselectivity (up to 95% ee) was achieved by using BIMPs derived from the combination of a chiral 1,2-amino alcohol-derived thiourea-organoazide and electron-rich phosphines via Staudinger reaction.