An efficient synthesis of 4(5)-benzyl- L -histidines employing catalytic transfer hydrogenolysis at elevated temperatures

An efficient two-step synthesis of 4(5)-benzyl-l-histidine from l-histidine was developed. A Pictet-Spengler reaction between l-histidine and benzaldehyde in the presence of excess strong base yielded 4-l-phenylspinacine within one hour. Catalytic transfer hydrogenolysis in methanol at reflux using ammonium formate rapidly converted 4-l-phenylspinacine to 4(5)-benzyl-l-histidine within five minutes. No racemization of the final product 4(5)-benzyl-l-histidine was observed using the Marfey reagent. To show the utility of this method, a series of fluorinated benzylhistidines were prepared.