Asymmetric Mannich reactions of (S)- N- tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

Abstract

In the present work, arylethynes were studied as new C-nucleophiles in the asymmetric Mannich addition reactions with (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine. The reactions were conducted under operationally convenient conditions affording the corresponding Mannich adducts with up to 87% yield and 70:30 diastereoselectivity. The isomeric products can be separated using regular column chromatography to afford diastereomerically pure compounds. The purified Mannich addition products were deprotected to give the target enantiomerically pure trifluoromethylpropargylamines. A mechanistic rationale for the observed stereochemical outcome is discussed.

Keywords: C-nucleophile; CF3-aldimine; arylethynes; asymmetric Mannich reaction; fluorinated propargylamine.

Figure 1

Anti-HIV compound containing a trifluoromethylpropargylamine moiety.

Scheme 1

Literature-known methods (a and b) and the here reported (c) approach for the synthesis of α-trifluoromethylated α-propargylamines.

Scheme 2

Substrate scope study. Reaction conditions: arylethyne 2 (0.39 mmol), imine 1 (0.3 mmol), LiHMDS (0.51 mmol), CH₂Cl₂ (3 mL), −78 °C, under nitrogen, 2.5 h. Isolated yields of mixture of isomers. Diastereoselectivities were determined by ¹⁹F NMR.

Figure 2

ORTEP diagram showing of the minor product of 3a.

Figure 3

Mode of nucleophilic attacks A and B.

Scheme 3

Large-scale application of the reaction.

Scheme 4

Removal of the chiral auxiliary.