Stereoselective nucleophilic addition to imines catalyzed by chiral bifunctional thiourea organocatalysts

A new and easy synthesis of chiral bifunctional organic catalysts obtained by the combination of (S)-t-leucine-derivatives with (1R,2R)-trans-1,2-diamino-cyclohexane was developed. A few compounds, representatives of a class of organocatalysts containing a thiourea group and a tertiary amino group connected through a chiral backbone, have been successfully synthesized. The catalytic behaviour of such bifunctional chiral molecules, either neutral or protonated species, was investigated in the addition of acetylacetone to β-nitrostyrene as a model reaction. Using the best conditions, high yields and enantioselectivities of up to 85% were obtained. The same metal free catalysts were then employed in the addition of activated nucleophiles to imines: in the reaction of 1,3-diketones with N-CBz imines, the products were isolated in up to 61% ee, while in the reaction with diethyl malonate enantioselectivities up to 71% were reached.

Graphical abstractBifunctional organic catalysts obtained by combination of (S)-t-leucine-derivatives with (1R,2R)-trans-1,2-diamino-cyclohexane were able to promote the addition of acetylacetone to β-nitrostyrene in 85% ee and the reaction between N-CBz imines and diethyl malonate in up to 71% ee.Figure optionsDownload full-size imageDownload as PowerPoint slide

2-[3-(2-Dimethylamino-cyclohexyl)-thioureido]-3,3,N,N-tetramethyl-butyramideC17H34N4OSEe = 99%[α]23 = +9.5 (c 1.31, CHCl3)

2-[3-(2-Dimethylamino-cyclohexyl)-thioureido]-3,3,N-trimethyl-butyramideC16H32N4OSEe = 99%[α]23 = +1.5 (c 1.01, CHCl3)

N-Benzyl-2-[3-(2-dimethylamino-cyclohexyl)-thioureido]-3,3-dimethyl-butyramideC22H36N4OSEe = 99%[α]23 = −6.5 (c 1.06, CHCl3)