One-Carbon Chain Extension of Esters to α-Chloroketones:  A Safer Route without Diazomethane

Abstract

The reaction of a variety of methyl esters with dimethylsulfoxonium methylide at 0-25 degrees C affords the chain-extended beta-keto dimethylsulfoxonium ylides. Subsequent treatment with hydrogen chloride in THF proceeds with loss of DMSO to afford the corresponding alpha-chloroketones. This sequence has been utilized to convert the methyl esters of CBZ-protected alanine and valine to the anti N-protected alpha-amino epoxides, which are important pharmaceutical intermediates. When the same protocol is applied to BOC-protected phenylalanine methyl ester, epimerization occurs so that the use of a more reactive aryl ester is required. This chemistry provides a practical route to alpha-chloroketones that avoids the use of toxic and explosive diazomethane.

Unusual Reactivity of Dimethylsulfoxonium Methylide with Esters

“…As a first attempt, we chose to perform the reaction using triolein (6). Adjusting the stoichiometry of the reaction for the three ester functional groups in the starting material, triolein was allowed to heat at reflux with 7 equiv.…”

“…[6] Here, a series of aliphatic methyl esters and three amino acid methyl esters were treated with 3 equiv. of dimethylsulfoxonium methylide, obtained from trimethylsulfoxonium chloride and the base sodium tert-butoxide.…”

“…An example of the reactivity of dimethylsulfoxonium methylide reported in the literature. [6] conditions for complete conversion of the starting substrate. In particular, methyl 4-chlorobenzoate required a longer reaction time (more than 48 h) and a greater excess amount of the ylide (5 equiv.).…”

“…The protected amino acid was treated under the reported conditions [6] using dimethylsulfoxonium methylide prepared from the commercially available trimethylsulfoxonium chloride and sodium tert-butoxide. The reaction was completed with a hydrolytic treatment and extraction by an organic solvent.…”

Dimethylsulfoxonium Methylide (DSM): A Versatile Reagent

“…5 (E) Diolefination of Cycloalkanones: Terminal/exocyclic 1,3-dienes are widely used in synthetic organic chemistry. Very recently, Butova and co-workers have synthesized exocyclic 1,3-dienes by a one-pot diolefination of cyclic ketones employing DSM and excess of a base at 130°C.…”