Continuous Flow, Highly Enantioselective Michael Additions Catalyzed by a PS-Supported Squaramide

Abstract

A polystyrene (PS) supported bifunctional squaramide organocatalyst promotes fast Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with very high enantioselectivities at low catalyst loadings. The polystyrene supported catalyst can be recycled up to 10 times without any decrease in enantioselectivity (average 96% ee) and adapted to continuous flow operation (24 h). A single flow experiment involving six different nitroalkenes in a sequential manner highlights the applicability of this methodology for rapid access to chemical diversity.

A polystyrene-supported 9-amino(9-deoxy)epi quinine derivative for continuous flow asymmetric Michael reactions

“…At the light of the excellent performance depicted by organocatalysts immobilized onto resins through coppercatalyzed alkyne-azide cycloaddition (CuAAC) reactions, 11 we considered the possibility of using this methodology for the immobilization of cinchona alkaloids. We report in this communication the implementation of this strategy and the use of the resulting functional resins as highly active and enantioselective organocatalysts for a variety of asymmetric Michael additions under batch and flow conditions.…”

“…Bromonitromethane afforded the target Michael adducts with high yield and excellent enantioselectivity by simply increasing catalyst amount to 20 mol% and reaction time (8a-e). Malonitrile (9a-c), phenylsulfonylnitromethane (11) and Meldrum´s acid (12a-b), which had not been previously used in Michael additions mediated by cinchone-derived amines, were also found to be suitable substrates when treated with an excess of the enone. In a similar manner, β-keto acid 6d can be a valuable donor in additions mediated by 1a.…”

Asymmetric Organocatalysis in Continuous Flow: Opportunities for Impacting Industrial Catalysis

“…38 High yields and excellent enantioselectivities were observed for various nitroalkenes 7 bearing electrondonating or -withdrawing substituents when the reactions were performed in batch (Scheme 17a). With this particular catalyst, Only in the case of thienyl derived nitroolefin a lower yield (69% vs 90%) was obtained when the reaction was performed in flow.…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…Unsaturated nitro compounds are good Michael acceptors and this reaction has been adapted for use in flow processes (50)(51)(52). The process can be asymmetric (53).…”