Scalable catalyst free electrochemical chlorination of aminophenol derivatives enabled by a quasi-divided cell approach

Abstract

Chlorinated 4-aminophenol derivatives are widespread in pharmaceutical ingredients. An electrochemical procedure for the synthesis of these compounds via mono- and dichlorination of the corresponding electron-rich precursors using dichloromethane (DCM) both as the solvent and the chlorine source has been developed. The method is based on the degradation of DCM at the cathode, which releases chloride ions that can be used to generate active chlorine at the anode. Key to the success of this protocol is the utilization of a “quasi-divided” cell with a cathode surface area much smaller than the anode, ensuring that only the solvent and not the molecules in solution are degraded by cathodic reduction. The electrochemical protocol has been demonstrated for a wide range of substrates (25 examples) in moderate to excellent isolated yield (up to 94%). Importantly, the procedure has been translated to a parallel plate flow electrolysis cell. To achieve this goal, a bespoke cell design featuring a PTFE mesh that partially covers the cathode surface has been developed, which provides adequate anode to cathode surface area ratio for quasi-divided cell operation. This is the first example of quasi-divided cell operation in a parallel plate flow electrochemical reactor.