Heterogeneous catalysis in the nitro-mannich reaction

Abstract

A simple, efficient, and environmentally friendly method was devised for the nitro Mannich reaction guided by the concept of green chemistry and its twelve principles. A heterogeneous catalyst, Amberlyst A-21-supported copper(!) iodide (Cul.A-21), with a low loading of 5 mol %, was successfully used to catalyse a multicomponent nitro Mannich reaction for the synthesis of P-nitroamines, which are versatile intermediates for the access of valuable bioactive natural products and pharmaceuticals. The Cul.A-21 catalyst was determined to be advantageous in terms of green chemistry due to being relatively cheap, requiring a simple two-step process for preparation, showing high activity since 'it was reusable for at least eight cycles with consistent results and exhibiting high stability, with only 1 % copper leached into solution after eight cycles. Optimisation of the reaction between aldehydes, amines and nitroalkanes at mild reaction conditions, including a solvent-free medium, insensitivity to air or to anhydrous conditions, and an industrially acceptable temperature of 100°C resulted in the synthesis of P-nitroamines, in relatively short times of between 1.5 to 10 h and high yields. Examination of the scope of the reaction, both at room temperature and the optimised 100°C temperature, gave similar results for each product, in terms of isolated yield, despite longer reaction times under the former condition. A wide versatility was observed with 38 products being synthesised, including more than 25 novel P nitroamine products. Reaction times and isolated yields were affected by steric and electronic effects, as well as lone pair availability for the imine nitrogen activation by the bifunctional catalyst. Aromatic aldehydes and amines were highly reactive and resulted in moderate to excellent yields, greater than 90% in some cases. Aliphatic aldehydes were less reactive, furnishing poorer yields whilst aliphatic amines were unreactive. Nitroalkanes, other than nitromethane, resulted in lower yields. The multicomponent reaction was shown to exhibit a green protocol with a 93% atom economy and an E-factor of 1.26.