Improving the yield of graphene oxide-catalysed N-heterocyclization of amines through fed batch mode

Abstract

The use of graphene oxide, a metal-free, heterogeneous carbocatalyst for a facile, efficient, and simple protocol for N-heterocyclization of aromatic amines with dihaloalkane to give azacycloalkanes and isolindolines was studied. The catalyst displays excellent selectivity and a high yield in a short reaction time under mild reaction conditions of temperature and at atmospheric pressure in the presence of H₂O:EtOH, green solvents. GO with oxygen functionality serves a dual purpose; it provides an anchor site to the reactant and serves as a co-catalyst initiator by aiding base dissociation. The reaction of aromatic amines with dihaloalkanes was optimized for catalyst loading, base, base loading, reaction temperature, and solvents to give 84% yield at 80 °C, in 1 : 2 H₂O : EtOH solvent within 4 h. Yield improvement was observed on performing the reaction in fed-batch mode. The reaction protocol was further modified to employ a fed-batch strategy to maintain low concentration of base and minimize the inactivation of the catalyst. The nominal yield of 40% was improved 2.3-fold employing a fed-batch strategy. The GO catalyst was easily separated by filtration and showed remarkable recyclability up to 5 cycles. Different substituents of amines and dihaloalkanes were studied and characterized by ¹H and ¹³C NMR. The mild reaction conditions and readily re-usable nature of the GO catalyst show immense potential for application of the methodology in synthetic strategies for the production of pharmaceutical intermediates and APIs.