The synthesis of carboxylic esters is one of the most fundamental and important processes for producing useful compounds in organic chemistry. The classical esterification reaction is condensation of a carboxylic acid and an alcohol under acidic conditions. This is an equilibrium reaction, and in order to effectively generate the ester, the equilibrium need to be shift toward the ester. To achieve this equilibrium shift requires adding one of the substrates in large excess and the removal of the generated water by distillation. However, when both carboxylic acid and alcohol are expensive and not easily available, it is not economical to use one of the substrates in large excess. Thus the classical esterification method is not the best method to use in such a case. Furthermore, when the substrate is unstable to heat, the classical method does not always yield the desired results.
Since esterification is a basic reaction that is applied to many different types of substrates, there is a need for alternative methods which proceed under mild conditions without the need for using large excess of one of the substrates. Over the years, there has been much research done by many chemists, and many useful methods have been reported.
Recently, Shiina and co-workers have reported a method using 2-methyl-6-nitrobenzoic anhydride 1. This esterification procedure is quite simple. Triethylamine, a catalytic amount of 4-dimethylaminopyridine, and 1 were dissolved in a solvent. The carboxylic acid was added and stirred, and finally a nearly equimolar amount of alcohol was added and the reaction stirred under room temperature. Through this reaction process, the desired ester (ester A) is obtained in high yields. The nitro group on the condensation reagent 1 promotes and facilitates the esterification under room temperature. The introduction of substituents at the two ortho positions of benzene ring controls the generation of byproduct (ester B). These two effects synergistically act to produce the desired ester in excellent yield and high purity. This reaction can also be applied to intramolecular esterification, and can afford lactones in high yields.
Literature
2) I. Shiina, M. Kubota, R. Ibuka, Tetrahedron Lett., 2002, 43, 7535 [DOI].
3) J. Tian, N. Yamagiwa, S. Matsunaga, M. Shibasaki, Org. Lett., 2003, 5, 3021 [DOI].
4) I. Shiina, H. Oshiumi, M. Hashizume, Y. Yamai, R. Ibuka, Tetrahedron Lett., 2004, 45, 543 [DOI].
5) I. Shiina, M. Kubota, H. Oshiumi, M. Hashizume, J. Org. Chem., 2004, 69, 1822 [DOI].
6) I. Shiina, Chem. Rev., 2007, 107, 239 [DOI]; Tokyo Kasei Kogyo, Jpn. Kokai Tokkyo Koho 2003 335731, 2003.
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