Continuous Flow Synthesis of N-Phenylphenylglycine By Dehydration and Electrochemical Carboxylation

Abstract

α-Amino acids and their derivatives are important and essential resources for human life such as foods, medical drugs, cosmetics and so on. The classical Strecker α-amino acids synthesis is a longstanding method although this classical method requires highly toxic cyanide reagents as the carbon source and these regents are unfavorable from the viewpoint of green chemistry. Carbon dioxide, on the other hand, would also be an abundant and favorable carbon source. There are several examples of synthesis of α-amino acids by direct carboxylation of imines with carbon dioxide. Because of chemical stability of carbon dioxide, this direct carboxylation requires stoichiometric quantities of hard to handle reagents such as magnesium metal and organotins under severe or harsh reaction conditions.In this context, electrochemical carboxylation represents an attractive alternative to conventional chemical carboxylation methods because it is possible to readily generate highly reactive carbon nucleophiles that immediately react with carbon dioxide without handling sensitive, expensive, and toxic reagent. However, metal ions derived from sacrificial anode such as magnesium and aluminium anodes are generally required to stabilize the unstable carboxylate ions.A flow microreactor enables fast generation and consumption of the unstable species. Therefore, it is attractive reaction system for electrochemical carboxylation involving unstable carboxylate ions without sacrificial anodes. Moreover, the electrochemical synthesis with a flow microreactor offers operational advantages over batch processes.Under these backgrounds, we have demonstrated the electrochemical carboxylation of in situ generated imines in a continuous flow system. The present method enables an efficient synthesis for N-phenylphenylglycine derivatives using easily available aldehydes, amines, and CO2 without the use of toxic metal reagents and sacrificial anode.As shown in Figure 1, the imine was smoothly generated from aldehyde and amine by dehydration using MS4A desiccant in a flow operation, and then reacted with carbon dioxide in the electrochemical flow microreactor to afford N-phenylphenylglycine derivatives with high to moderate yields. Figure 1