AN EFFICIENT SYNTHESIS OF α-KETO AMIDES VIA REACTION OF α-(N-METHYLANILINO)-ACETONITRILE WITH ESTERS FOLLOWED BY HYDROLYSIS USING COPPER (II) ACETATE

Abstract

An efficient sequence proposed for the conversion of esters to α-keto amides involves the reaction of α-(N-methylanilino)-acetonitrile with esters to afford β-hydroxy-α-cyanoenamines of which hydrolysis using copper (II) acetate gives the corresponding α-keto amides in good yields.

Recent Developments in General Methodologies for the Synthesis of α-Ketoamides

“…Alkyl groups at the amide nitrogen atom, including bulky isopropyl groups, were suitable, while two phenyl groups produced a considerable drop in the yield of α-ketoamide (28%). The α-ketoamide featuring one methyl and one phenyl group at the nitrogen atom was isolated as a mixture of s- cis and s- trans isomers in 9:1 ratio, which was in agreement with findings by Takahashi et al…”

“…The use of KH-deprotonated cyanomethylamines as C(1) umpolung reagents, originally introduced by Takahashi et al to prepare α-ketoamides by reaction with benzoic ester followed by oxidation with Cu­(OAc) 2 , was revisited by Wang and co-workers 20 years later, providing a great improvement of the procedure. In detail, the safe base NaHMDS was added to a THF solution of cyanomethylamines and methyl esters of aryl carboxylic acids in order to produce the corresponding acylated cyanomethylamine sodium salts, which were directly oxidized by adding 5.25% NaOCl solution (Clorox) at room temperature (Scheme ).…”

“…Alkyl groups at the amide nitrogen atom, including bulky isopropyl groups, were suitable, while two phenyl groups produced a considerable drop in the yield of α-ketoamide (28%). The α-ketoamide featuring one methyl and one phenyl group at the nitrogen atom was isolated as a mixture of s-cis and s-trans isomers in 9:1 ratio, which was in agreement with findings by Takahashi et al 81 A possible mechanism to explain this transformation involved deprotonation at the benzylic position of the starting amide to give the enolate 5 (Scheme 17). Its reaction with molecular oxygen produced the peroxy anion 6, which was eventually transformed to α-ketoamide by α-proton abstraction and hydroxyl anion expulsion.…”

Synthesis of α-Ketoamides from a Carbamoylsilane and Acid Chlorides

“…Due to such interests, numerous methods for the synthesis of α-ketoamides have been reported. Earlier approaches have been summarized, and new methodologies have continued to appear, with the palladium-catalyzed amino (double) carbonylation of organic halides arguably representing the most commercially useful approach . The latter, however, is attendant with drawbacks associated with the use of toxic carbon monoxide, usually employed under elevated temperatures and high pressures .…”

A Strategy for the Synthesis of Aryl α-Ketoamides Based upon the Acylation of Anions Derived from Cyanomethylamines Followed by Oxidative Cleavage

“…Precedent for this approach was provided in 1983 by Takahashi and co-workers, who showed that phenylated α-keto-amides 14 were formed by reacting benzoic ester 11 and cyanomethylamine 12 using KH as the base, followed by oxidation with Cu(II)(OAc) 2 , as summarized in Scheme . However, the process described by Takahashi requires two individual reaction steps with purification of the intermediate 13 , and the oxidation procedure requires elevated temperatures.…”