l-Proline amides catalyze direct asymmetric aldol reactions of aldehydes with methylthioacetone and fluoroacetone

Direct aldol reactions of aldehydes with methylthio- and fluoroacetone catalyzed by proline amides have been investigated. l-Prolinamide 5e was found to be the best catalyst. Under the optimized reaction conditions, a series of aromatic and aliphatic aldehydes reacted smoothly with methylthioacetone, to generate 1-methylthio-4-hydroxyketones 3 in good yields and with high regio- and enantioselectivities. Excellent enantioselectivities of up to 98% ee were observed for aromatic aldehydes and even higher enantioselectivities of >99% ee were observed for aliphatic aldehydes. Asymmetric direct aldol reactions of fluoroacetone with aldehydes in the presence of 20 mol % of 5e preferentially occurred at the fluoromethyl group, yielding products with high enantioselectivities (up to 98% ee).

Figure optionsDownload as PowerPoint slide

1-Methylthio-4-hydroxy-4-(4′-nitrophenyl)-butan-2-oneC11H13NSO4Na[α]D = +39.4 (c 0.5, DCM)

1-Methylthio-4-hydroxy-4-(4′-cyanophenyl)-butan-2-oneC12H13N1SO2Na[α]D = +43.2 (c 0.225, DCM)

1-Methylthio-4-hydroxy-4-(4′-trifluoromethyl-phenyl)-butan-2-oneC12H13SO2F3Na[α]D = +40.0 (c 0.5, DCM)

4-(4-Methylthio-1-hydroxy-3-oxo-butyl)-benzoic acid methyl esterC12H13SO2F3Na[α]D = +39.2 (c 0.5, DCM)

1-Methylthio-4-hydroxy-4-(4′-chlorophenyl)-butan-2-oneC11H13CIO2SNa[α]D = +39.8 (c 0.6, DCM)

1-Methylthio-4-hydroxy-4-(2′-fluorophenyl)-butan-2-oneC11H13SO2FNa[α]D = +42.5 (c 0.44, DCM)

1-Methylthio-4-hydroxy-4-(2′-chlorophenyl)-butan-2-oneC11H13SO2CINa[α]D = +69.5 (c 0.5, DCM)

1-Methylthio-4-hydroxy-4-(3′5′-dibromophenyl)-butan-2-oneC11H12Br2SO2Na[α]D = +32.0(c 0.5, DCM)

1-Methylthio-4-hydroxy-4-(3′5′-bis-trifluoromethyl-phenyl)-butan-2-oneC13H12SO2F6Na[α]D = +29.0 (c 0.5, DCM)

1-Methylthio-4-hydroxy-4-(2′6′-dichlorophenyl)-butan-2-oneC11H12Cl2SO2Na[α]D = −23.9 (c 0.64, DCM)

1-Methylthio-4-hydroxy-4-phenyl-butan-2-oneC11H14SO2Na[α]D = +15.2 (c 0.5, DCM)

1-Methylthio-4-hydroxy-5-(5′-dimethyl)-hexan-2-oneC9H18SO2Na[α]D = +59.0 (c 0.71, DCM)

1-Methylthio-4-hydroxy-5-methyl-hexan-2-oneC8H16SO2Na[α]D = +48.9 (c 0.8, DCM)

1-Methylthio-4-(cyclohexyl)-4-hydroxy-2-butanoneC11H20SO2Na[α]D = +42.8 (c 0.5, DCM)