Continuous-Flow Regioselective Reductive Alkylation of Oxindole with Alcohols and Aldehydes in a Fast and Economical Manner

Oxindole is a widely used scaffold in drug discovery, which can be found in several marketed drugs, among them sunitinib and ziprasidone. Thus, the derivatization of oxindole is of considerable current interest. The extreme reaction conditions (high temperature, high pressure) described in the literature for the batchwise regioselective multistep 3-alkylation of oxindole with alcohols in the presence of Raney nickel motivated us to develop a robust, time-and cost-efficient continuous-flow variant for this reaction. In addition, the continuous flow technology was also extended to the reductive 3-alkylation of oxindole with aldehydes. The elaborated methodology allows the safe use of Raney nickel, an inexpensive and widely applied, albeit pyrophoric catalyst. Under the optimized reaction conditions, 10 oxindole derivatives were synthesized ranging from simple 3-alkyl to 3-aralkyl derivatives including two (trifluoromethyl)benzyl congeners. The technology is considerably robust and the catalyst showed a long-term usability. The model reaction between oxindole and acetaldehyde could be run for 16 hours uninterruptedly, rendering possible the efficient ethylation of about 20 g of oxindole utilizing only approximately 800 mg of Raney nickel.