Asymmetric Synthesis Of α-fluoromethylated α-propargylamines Induced By (S)-tert-butanesulfinamide

In recent years, N-tert-butanesulfinamide as a chiral auxiliary has attracted much attention in the asymmetric synthesis of fluorine-containing amines. The 1,2-addition of organolithium reagents to N-tert-butanesulfinyl ketimines or aldimines which synthesized from N-tert-butanesulfinamide and ketones or aldehydes can achieve the asymmetric synthesis of fluorine-containing amines.Part I:Stereoselective approach for preparation of a-difluoromethylated a-propargylamines has been developed. Firstly, (S)-N-tert-butanesulfinamide was used as the starting material and reacted with difluoroacetyl derivatives 1. The condensation reaction underwent smoothly when using THF as solvent and Ti(OEt)4 as Lewis acid.1,2-Addition of Lithium acetylides to diverse chiral difluoromethylated (S)-N-tert-butanesulfinyl ketimines by using Ti(O'Pr)4 as catalyst and THF as solvent afforded N-tert-butanesulfinamides in good to excellent yields (51-93%) and good diastereoselectivities (dr.85:15 to 93:7). The N-tert-butanesulfinyl group can be readily cleaved under mild acidic condition (4 M HC1 in dioxane) to provide the corresponding a-difluoromethylated a-propargylamine in excellent yields (90-95%). In this addition reaction, the Lewis acid Ti(OiPr)4 has played a key role on the increase of reaction yield, meanwhile, difluoromethyl group enhanced the reactivity of imines and diastereoselectivity of the addition reaction compared to non-fluorine containing analogues.PartⅡ:According to the method established as above, asymmetric synthesis of a-monofluoromethylated a-propargylamines is attempted. Firstly, monofluorinated acetophenones 6 were prepared by direct fluorination of aryl (alkyl) acetophenone with Selectfluor under microwave condition. Then monofluoromethylated (S)-N-tert-butanesulfinyl ketimines were synthesized and isolated prior to the next nucleophilic addition with Lithium acetylides. However, the desired a-monofluoromethylated a-propargylamines have not been achieved under several reaction conditions such as using different solvents and Lewis acids (Ti(OEt)4/THF, BF3·Et2O/THF and Ti(OEt)4/n-Hexane).