VOLUME 64 : 2016

Among the known organocatalyst manifolds, the organocatalytic utility of 2-pyridylimidazolines has been less explored. In this study, a collection of chiral 2-pyridyl-2-imidazolines (picolinylimidazolines) were screened for organocatalytic activity towards enantioselective direct Aldol reaction. The chiral imidazolines (1a-1d) were prepared through conventional iodine-promoted oxidative condensation and cyclization of 2-picolinaldehydes 2 (and/or 2,6-pyridine dicarbaldehyde) with chiral 1,2-diamine derivatives 3 in excellent yields (>96% isolated yields). Organocatalytic parameters were optimized to determine the best Aldol reaction conditions that would induce enantioselectivity such as catalyst loading, temperature, reaction time and solvent. Thus, using a C₂-symmetric cyclohexane-based 2-pyridyl-2-imidazoline organocatalyst 1c, the best conditions that gave excellent enantioinduction of up to 99:1 enantiomeric ratio (er) and yield were observed with brine as the solvent, a 1-h reaction period at room temperature and 10 mol% as the minimum catalyst load. The reaction conditions were also amenable to a variety of benzaldehyde substrates with electron-donating and electron-withdrawing substituents. Our study demonstrates for the first time the asymmetric construction of b-hydroxy carbonyl structures using chiral C₂-symmetric 2-pyridyl-2-imidazolines as organocatalysts.

Keywords: Aldol reaction, organocatalysis, picolinylimidazoline, Beta-hydroxy carbonyl, asymmetric synthesis