Asymmetric benzaldehyde methylation with titanium TADDOLate complexes

• Titanium TADDOLate complexes catalyze the methylation of benzaldehyde.
• Complete conversion and high enantiomeric excess (ee) is observed.
• 4-Chlorobenzaldehyde is methylated with 96% enantiomeric excess.
• Chlorinated TADDOL ligands enhance selectivity with unsubstituted benzaldehyde.
• We report 100% conversion of benzaldehyde to (S)-1-phenylethanol with up to 97% ee.

The Lewis acid catalyst derived from Ti(OiPr)4 and (4R,5R)-(−)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol, (R,R)-TADDOL, [1], in the presence of Me2Zn, mediates the complete conversion of 4-chlorobenzaldehyde to (S)-1-(4-chlorophenyl)ethanol with 96% enantiomeric excess. With unsubstituted benzaldehyde, the maximum enantiomeric excess observed under the same conditions is 91%. Application of chlorinated (R,R)-TADDOL derivatives to the methylation of unsubstituted benzaldehyde reveals that addition of chloro substituents to the ligand also induces the result of increasing the enantioselectivity of the catalysis. The reaction of (−)-dimethyl 2,3-O-isopropylidene-l-tartrate with 3,4-dichlorophenyl magnesium bromide or 3,5-dichlorophenyl magnesium bromide yields the octachlorinated (R,R)-TADDOL derivatives (4R,5R)-(−)-2,2-dimethyl-α,α,α′,α′-tetra-3,4-dichlorophenyl-1,3-dioxolane-4,5-dimethanol, 3,4-[1] and (4R,5R)-(−)-2,2-dimethyl-α,α,α′,α′-tetra-3,5-dichlorophenyl-1,3-dioxolane-4,5-dimethanol, 3,5-[1]. Catalysis screenings showed that 3,4-[1], in conjunction with Ti(OiPr)4 and Me2Zn, forms a Lewis acid titanium TADDOLate catalyst capable of converting benzaldehyde to (S)-1-phenylethanol with >99% conversion and >96% enantiomeric excess.

Chlorinated (R,R)-TADDOLate titanium complexes moderate the methylation of benzaldehyde with dimethyl zinc to produce (S)-1-phenylethanol with complete conversion >96% ee.Figure optionsDownload as PowerPoint slide