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Arndt-Eistert Synthesis
Synthesis of esters

Kowalski Ester Homologation

The method reported by Kowalski allows the formation of homologated esters by reaction of esters with preformed dibromomethyllithium, followed by organolithium base induced elimination, halogen metal exchange, and a rearrangement. Quenching the resulting alkynolates with acidic ethanol provides the desired esters.

Mechanism of the Kowalski Ester Homologation

According to a mechanistic discussion provided by Kowalski (Org. Synth. 1993, 71, 146. DOI: 10.15227/orgsyn.071.0146), addition of dibromomethyllithium to the ester produces a tetrahedral intermediate.

In the next step, the hindered lithium hexamethyldisilazide base induces an elimination to form a mixture of enolates. Addition of s-BuLi effects the key metal-halogen exchange/rearrangement of the more reactive dibromide at -78°C.

The reaction of the less reactive intermediate can be induced at higher temperatures with n-BuLi. Addition of n-BuLi regenerates LiTMP, which is able to deprotonate the remaining side product.

In earlier examples of the Kowalski Ester Homologation - besides LiTMP in the formation of the dibromomethyllithium - only n-BuLi was used. However, this base is more nucleophilic and leads to formation of a small amount of alkylated side products.

Quenching the resulting alkynolate with acidic ethanol then provides the desired ester.

Recent Literature

Ester homologation via α-bromo α-keto dianion rearrangement
C. J. Kowalski, M. S. Haque, K. W. Fields, J. Am. Chem. Soc., 1985, 107, 1429-1430.

Kowalski Ester Homologation. Application to the Synthesis of β-Amino Esters
D. Gray, C. Concellón, T. Gallagher, J. Org. Chem., 2004, 69, 4849-4851.