Rational Design of Sterically and Electronically Easily Tunable Chiral Bisimidazolines and Their Applications in Dual Lewis Acid/Brønsted Base Catalysis for Highly Enantioselective Nitroaldol (Henry) Reactions

Abstract

A new addition to the rational design of sterically and electrically easily tunable chiral bis(imidazoline) ligands from chiral amino alcohols has been developed. Vast structural variation of chiral bis(imidazoline) ligands can be simply achieved by the choice of both the 1,2-amino alcohol and its N-1 R1 substituent. A small library of chiral bisimidazolines (1 a-h) has been constructed. The method has provided an easy and simplified route to a diverse set of air-stable and water-tolerant chiral bis(imidazoline) ligands on 10 g scales. The dual Lewis Acid/Brønsted base catalytic system generated from the (S)-1 a/Cu(OTf)2 complex and Et3N was able to catalyze Henry reactions between aldehydes and nitromethane effectively at room temperature, and also to tolerate a wide scope of aldehydes with excellent enantiomeric excesses. Not only aromatic aldehydes but also aliphatic aldehydes afforded the nitroalcohol products, with enantiomeric excesses in the 93-98% range. This dual catalytic system is among the most effective systems so far reported for the asymmetric parent Henry reactions. This work also represents the first members of the class of chiral bisimidazolines to have been demonstrated to achieve excellent enantioselectivities.