Abstract

Background: In the field of asymmetric aminocatalysis, chiral catalysts derived from azoles (five-membered heterocycles containing exclusively N atoms) play an important role. Surprisingly, all the catalysts used for enamine and/or iminium ion activation derive from pyrrole or imidazole. We decided to test if other reduced azole derivatives could be used as organocatalysts and particularly in aminocatalysis via iminium ion activation. The azole derivatives that came naturally to mind are the 3,5-disubstituted 2-pyrazolines (also called 4,5-dihydro-1H-pyrazoles).

Methods: We synthesized racemic 3,5-diphenyl-2-pyrazoline, separated both enantiomers by chiral-HPLC on a Lux-Cellulose-4 column (heptane/ethanol 70:30 as mobile phase), determined the absolute configuration of their hydrochloride salts (pyrazolinium) by the combined use of experimental rotatory power and B3LYP/6-311++G(d,p) theoretical calculations and use one the enantiomers, the R, as the catalyst.

Results: We have demonstrated that the enantiopure (R)-3,5-diphenyl-2-pyrazoline is able to catalyze the Michael addition of 1-(4-nitrophenyl)propan-2-one to cinnamaldehyde and crotonaldehyde via iminium activation.

Conclusion: This is the first example of activation of both types of enals, aliphatic and aromatic, via pyrazolinium salts and opens new possibilities to the design of other type of chiral organocatalysts than the traditional pyrrole and imidazole derivatives.

Keywords: Absolute configuration, DFT calculations, 4, 5-dihydro-1H-pyrazoles, Michael addition, organocatalysis, Pyrazolines.

Graphical Abstract