Enantioselective Sulfur-Michael Addition Catalyzed By Chiral Thiourea Catalysts

Asymmetric sulfur-Michael addition (SMA) represents a fundamental chiral carbon-sulfur bond forming reaction and provides an effective method to the synthesis of sulfur-centered optically active compounds. Various catalytic asymmetric SMAs employing alkyl or aryl thiols as sulfur nucleophiles have been developed over the past few decades, while reactions using thioacetic acid have less been explored and the only reported substrates are α,β-unsaturated ketones or nitroalkenes, thus extension of the catalytic systems and the substract scope are highly in demand.Chiral thioureas have been proved to be efficient catalysts for various asymmetric reactions and developed rapidly in recent years. Three types of amine-thiourea catalysts bearing different chiral skeletons were synthesized from (R,R)-1,2-cyclohexanediamine, L-amino acids or quinine, and L-amino acids derived thioureas are relatively new catalysts. After screening of various sulfur nucleophiles and Michael acceptors, new types of SMA were developed.Enantioselective sulfur-Michael addition of thioacetic acid to nitroalkenes catalyzed by a novel leucine-derived bifunctional amine-thiourea was developed with high yields, broad substrate scope and moderate enantioselectivities. The thiourea-ammonium salt formed in the reaction is identified as the active catalysts and the multiple hydrogen bonding system is responsible for the stereocontrol.An organocatalytic enantioselective sulfur-Michael addition of thioacetic acid to arylmethylidenemalonates was developed with high yields and moderate to excellent enantioselectivities (up to 97% ee). Both enantiomers of the products were accessible with two different organocatalysts. The current method provides a practical and convenient preparation of enantiomerically enriched sulfur containing malonate derivatives.A series of aminophenols were selectively alkylated on their hydroxyl group via benzaldehyde protection of the amino group, subsequent alkylation, and hydrolysis; or on their amino group via imination and subsequent reduction. Good to excellent yields were achieved and the current strategy is an economic and practical route for selective alkylation of aminophenols. The resulting O-or N-alkylated derivatives of aminophenols are important synthetic intermediates in organic synthesis.