Continuous flow synthesis of xylidines via biphasic nitration of xylenes and nitro-reduction

Herein, we disclose the continuous flow synthesis of xylidines via biphasic nitration of xylenes followed by nitro-reduction in various continuous flow systems, demonstrating that mass transfer greatly influences conversion and product selectivity. An efficient biphasic continuous flow nitration procedure towards various nitrobenzenes in assay yields greater than 90%, with residence times of 6 min or less, was demonstrated by ensuring efficient mixing in the reactors. Nitration scale up was safely performed accompanied by a throughput of 16.6 g/h of nitrobenzene thus demonstrating safe handling of an exothermic reaction in flow. The resultant nitrobenzenes underwent reduction to afford the respective xylidines in assay yields greater than 94% (isolated yield >92%) with a 2.5 min residence time. Due to safety concerns of the nitration procedure, we further demonstrated in situ synthesis and reduction of nitrobenzenes from xylenes in a multi-step continuous flow synthetic procedure with the incorporation of a liquid/liquid separator. This afforded xylidines in assay yields greater than 84.6% (isolated yield more than 80%) via nitro-reduction.