Copper-Catalyzed N-Methylation of Amides and O-Methylation of Carboxylic Acids by Using Peroxides as the Methylating Reagents

Abstract

The copper-catalyzed N-methylation of amides and O-methylation of carboxylic acids by using peroxides as the methylating reagent are described. Various amides and carboxylic acids were methylated affording N-substituted amides and esters. Tentative mechanistic studies suggest that this reaction is likely to involve a radical process.

Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid

“…20 While practically the use of air is advantageous, it is noteworthy that the successful reaction observed with tBuOOtBu parallels previous non-aerobic Cu-catalyzed Chan-Lam alkylations.…”

Alkylsilyl Peroxides as Alkylating Agents in the Copper‐Catalyzed Selective Mono‐N‐Alkylation of Primary Amides and Arylamines

“…Initially, we examined the metal‐catalyzed N ‐alkylation of primary amides using acyclic alkylsilyl peroxides 1 (Table ) . When the reaction between benzamide 2 and diethylphenyl‐substituted peroxide 1 a was conducted at 100 °C in the presence of copper iodide, N ‐ethyl benzamide ( 3 a ) was obtained in 63 % yield (entry ).…”

“…[3a] Since then, dialkyl peroxides have frequently been used for various methylation reactions, such as the direct methylation of aryl CÀHb onds, the methylation/cyclization of N-arylacrylamides, and the N-methylation of amides. [3][4][5][6] The weak peroxide (OÀO) bond in dialkyl peroxides can easily undergo ab ond fission initiated by thermal treatment, optionally in the presence of metal reagents, to give an alkoxyr adical. As ubsequent b-scission of the alkoxyr adical generates am ethyl radical with concomitantf ormation of ak etone (Scheme1a).…”

Copper‐Catalyzed Cyanomethylation of Allylic Alcohols with Concomitant 1,2‐Aryl Migration: Efficient Synthesis of Functionalized Ketones Containing an α‐Quaternary Center

“…Finally, the Cu I species could be oxidized to regenerate the Cu II salt. [22][23][24] The fact that a variable amount of 4-oxo-4-phenylbutanenitrile (6) was produced when the reaction of 1 a and acetonitrile was performed in air was indicative of the presence of the radical intermediate F. [25] When the reaction of 1 b was performed in MeCN in the presence of TEMPO (2.0 equiv) under otherwise identical conditions, 2-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]acetonitrile (7) and 1-methoxy-2,2,6,6-tetramethylpiperidine (8) were obtained in yields of 14 and 7 %, respectively (exp. 1, Scheme 5).…”