Kowalski ester homologation

What is Kowalski ester homologation?

The Kowalski homologation reaction was initially reported in 1985 as a one-carbon extension of the carboxylic acid chain of an ester using methylene dibromide and strong base treatment at low temperatures. It is also known as the Kowalski chain homologation or Kowalski ester homologation.

Kowalski ester homologation - general reaction scheme - Kowalski chain homologation - Kowalski ester homologation
Kowalski ester homologation

= 1º, 2º, and 3º alkyl, aryl, alkenyl, alkynyl, lactone

The original procedure involved the formation of dibromomethyllithium, which reacted with the ester to form a tetrahedral species that could undergo two paths to form α-bromo-α-keto dianions through either dibromoenolate or bromoenolate. The dianion would then rearrange to alkynolate anion, which is quenched by alcohol to yield an ester with one additional carbon.

This reaction has certain advantages over the Arndt-Eistert synthesis, which requires further activation and involves diazomethane and diazoketones. However, the Kowalski homologation has some limitations, such as moderate yield, small scale, and low-temperature requirements.

A modified version of the reaction involves first forming dibromoketone, which is then treated with LHMDS to form bromoenolate or dibromoenolate, followed by an excess amount of butyl lithium to give the alkynolate anion. This modification increases the yield and allows the reaction to be scaled up to larger quantities. The R group of the carboxylic acid in the ester can be a primary, secondary, or tertiary alkyl group or an aryl, alkenyl, or alkynyl group, as well as some lactones, and the stereochemistry is retained during the migration of the R group.

References

Ester homologation via α-bromo α-keto dianion rearrangement
Conrad J. Kowalski, M. Serajul Haque, and Kevin W. Fields
Journal of the American Chemical Society 1985 107 (5), 1429-1430
DOI: 10.1021/ja00291a063

Shares