Domino dehydration/intermolecular (enantioselective) ketone-ene reactions catalysed by a simple solid in batch and in flow

Abstract

The intermolecular carbonyl-ene reaction of ketones is still considered a challenge in organic chemistry, particularly with reusable solid catalysts, and implemented in a domino reaction. Herein, we show that the extremely cheap and non-toxic solid salt MgCl₂ catalyzes the reaction of trifluoromethyl pyruvates not only during the conventional carbonyl-ene reaction with various aromatic and alkyl alkenes (in very high yields, up to >99%) but also in a domino reaction with the corresponding alcohols (precursors to the alkenes) in similar good yields. The solid can be reused in both cases without any erosion of the catalytic activity and can be employed in an in-flow process to maximize the reaction throughput. Besides, the reaction can be performed under solventless reaction conditions. Addition of a catalytic amount of chiral binaphthyl hydrogen phosphate allows carrying out the reaction with a reasonable enantiomeric excess (up to >70%) and in flow, in a rare example of enantioselective solid-catalyzed domino carbonyl-ene reaction using a cheap, simple, readily available and physically mixed catalytic solid. The MgCl₂-catalytic system is also active in the industrially relevant citronellal-to-isopulegol carbonyl-ene reaction. These results pave the way to design sustainable domino carbonyl-ene reactions with extremely cheap solid catalysts.