A practical synthesis of benzyl esters and related derivatives

The benzyl ester is one of the earliest and best known of the carboxyl protecting groups. Its advantages over the corresponding methyl or ethyl ester derivatives lie in its ease of removal under very mild conditions, such as catalytic hydrogenation. The classical Fischer esterification of carboxylic acids in benzyl alcohol is not as easy as the analogous reaction in methanol or ethanol, due to the higher degree of steric hindrance imposed by the bulkier benzyl group and the difficulties encountered in evaporating the excess of high boiling benzyl alcohol at temperatures that could lead to decomposition of the products. Alternative routes such as the substitution of the silver or sodium salts with benzyl bromide, or the use of phenyldiazomethane have been described, but these are not always suitable, and the last method is inapropriate on large scale because of the explosive nature of the reagent. Klemm, Hintze and Gercken have also proposed a milder method adapted from earlier work by Vowinkel which involves the use of N,N'- dicyclohexyl-O-benzylisourea (DBI), itself obtained from N,N'-dicyclohexyl- carbodiimide (DCC) and benzyl alcohol. Another original route to benzyl esters is based on the thermal decomposition of benzyldimethylanilinium salts of carboxylic acids in refluxing toluene. This method needed modification for the preparation of acid sensitive tryptophan benzyl ester. More recently, benzyl trichloroacetimidate was found to convert carboxylic acids into the corresponding benzyl esters under catalysis by a Lewis acid such as boron trifluoride. As a complement to these earlier procedures, we now describe a mild, efficient, and practical benzylation method based on some new aspects of the chemistry of xanthates.