Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

Abstract

N-alkylanilines are ubiquitous motifs in the pharmaceutical and agrochemical industries. 1 In particular, N-methylanilines are found in a range of biologically active compounds such as diazepam, flobetapir, triafamone, and broflanilide (Figure 1). 2 Nalkylation reactions are common and essential transformations for the synthesis of pharmaceuticals and fine chemicals. 3 However, selective mono-N-alkylation of primary alkyl and aryl amines remains a challenging transformation due to the greater nucleophilicity of secondary amines compared to primary amines. 4 The synthesis of N-methylanilines is particularly challenging and the use of classical approaches for N-alkylation via reaction with alkyl halides or by reductive amination often results in the formation of mixtures of secondary and tertiary anilines. 4,5 Often, lab-scale syntheses of N-methylanilines require multistep sequences involving the incorporation and removal of protecting groups or the installation and exhaustive reduction of a carbamate. 6 The difficulty associated with the selective N-monomethylation of primary anilines is often reflected in the price of N-methylanilines versus their primary aniline analogs. A 50-to 100-fold increase in the price per gram is not unusual for this seemingly simple functionalization.The development of robust and selective methods for the selective N-monomethylation of primary anilines would greatly simplify the synthesis of N-methylanilines and several approaches have been reported. On the industrial scale, Nmonomethylation of primary anilines is accomplished via reaction with methanol in the vapor phase using heterogeneous

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

“…First, in the presence of DBU, 4‐chloroaniline reacts with DMC to form the carbamate 205 , which further reacts with DMC to afford the methylated carbamate 206 by the release of MeOH and CO 2 (g). The intermediate 206 in the reaction mixture decomposes on heating to afford the monomethylated product 207 …”

“…The continuous‐flow regime with short reaction times (5–20 min) safely induces monomethylation in the superheated solvent (NMP, 250 °C) at high pressure. The method was applicable to a broad range of primary aniline substrates including ortho ‐, meta ‐, and para ‐substituted anilines, and electron‐rich or electron‐deficient anilines (Table ) …”

“…The intermediate 206 in the reactionm ixture decomposes on heatingt oa fford the monomethylated product 207. [147] Recently,i onic liquids have been used as solvents to promote methylation with DMC. Quan et al reportedaconvenient and efficient S-methylation of mercaptans or thiophenols in room temperature ionicl iquids (RTILs), [148] such as 1-butyl-3methylimidazolium chloride ([Bmim]Cl).…”

“…The methodw as applicable to ab road range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, ande lectron-rich or electron-deficient anilines (Table 29). [147]…”

A New World for Chemical Synthesis?

“…The benefits are recognised in multiple reviews [1c,87] and book chapters. [88] Recent research articles exploit these opportunities to execute solvent-free H 2 reduction, [89] hydrogen-borrowing alcohol amination, [90] thermal Boc deprotection, [10e,91] Diels-Alder reactions, [92] N-monomethylation transformations [93] and air oxidation reactions [94] among many others.…”