Mechanochemical asymmetric three-component Mannich reaction involving unreactive arylamines.

Abstract

We report here a mechanochemical protocol for an asymmetric three-component Mannich reaction involving unreactive arylamines with simple cyclic ketones and arylaldehydes catalyzed by (S)-proline with a chiral diol. In this mechanochemical protocol, ball milling enables reaction acceleration and enantioselectivity control. The reported asymmetric three-component Mannich reactions usually involve reactive arylamines such as p-anisidine and phenylamine, while the catalytic asymmetric Mannich reactions involving unreactive arylamines in solution did not proceed smoothly or gave low yields and enantioselectivities. However, the use of ball-milling techniques overcomes the deficiency of the batch systems in solution and avoids the use of toxic organic solvents. The desired products were obtained in moderate-to-good yields (49%-80%) with good-to-high enantioselectivities (up to 99% ee). This is the first example of a mechanochemically activated catalytic asymmetric three-component Mannich reaction involving unreactive arylamines.