Enantioselective Henry and Aza‐Henry Reaction in the Synthesis of (R)‐Tembamide Using Efficient, Recyclable Polymeric CuII Complexes as Catalyst

Abstract

AbstractChiral copper(II) polymeric [H4]salen (salen=bis[(salicylidene)ethylenediaminato]) complexes CuII‐1–3 were generated in situ and used as efficient catalysts in the asymmetric Henry and aza‐Henry reaction of various aromatic and aliphatic aldehydes and N‐tosylimines in the presence of various nitroalkanes at room temperature (27±2 °C) for 20 hours. This group of polymeric [H4]salen complexes demonstrated excellent performance (product yield and enantiomeric excess ee up to 98 %) in the formation of β‐nitroalcohol by using nitromethane with low catalyst loading of 1 mol % (with respect to the monomeric salen unit) and high enantioinduction (ee 94 %) in the aza‐Henry product; β‐nitroamines were obtained with moderate yield (78 %). This catalytic system also worked well with nitroethane and 1‐nitropropane in the case of Henry reaction, to furnish the corresponding products in high yields and enantioselectivities for syn diastereomers. The CuII‐2 complex retained its performance at the gram level and was expediently recycled eight times with no significant loss in its performance. The kinetic study with CuII‐2 complex for the enantioselective aza‐Henry reaction of N‐Ts‐benzylimine (Ts=tosyl) revealed a first‐order dependence on catalyst and nitromethane concentration and was zero order with respect to the substrate. The product obtained was transformed straightforwardly to the pharmaceutically important enantiomerically pure (R)‐tembamide (β‐adrenergic agonist) drug in good yield by the asymmetric nitroaldol reaction of 4‐methoxybenzaldehyde in three successive steps.