Preparation of benzimidazole N-oxides by a two-step continuous flow process

One-Pot Two-Step Synthesis of 2-Aryl benzimidazole N-oxides Using Microwave Heating as a Tool

“…Our starting point for developing our methodology was to build on the previously reported two-step route [29,35]. Our objective was to use ethanol as the solvent for the S N Ar reaction between o -nitrochlorobenzene derivatives ( 1a-c ) and a range of different aryl amines ( 2a-n ) (Scheme 1).…”

“…This proved to be the most challenging aspect of the study. We initially followed a literature protocol [29]. This consisted of an initial liquid-liquid extraction with ethyl acetate in order to remove any unreacted aniline, 3 , since this is preferentially soluble in the organic layer.…”

“…The deprotonation of 3 is proposed as the first step of the cyclization mechanism, and thus, reducing the propensity for this impacts the efficacy of the reaction [22,37]. Moving to the amine component, while we have previously shown that the reaction can be performed using alkylamines [29], product isolation using our new approach proved challenging.…”

“…Both steps employ solvents such as 1,4-dioxane and dimethylformamide (DMF), which are undesirable from a sustainability viewpoint [23,24,25,26,27,28]. In our research, we have attempted to address this drawback by developing a continuous-flow process using ethanol, 2-propanol, and water as solvents [29]. This procedure works well with substrates bearing short-chain alkyl substituents, but shows some drawbacks when more non-polar substituents, due to precipitation of the 2-nitroaniline intermediates with concommitant clogging of the flow reactor.…”

Medium effect (water versus MeCN) on reactivity and reaction pathways for the SNAr reaction of 1-aryloxy-2,4-dinitrobenzenes with cyclic secondary amines

“…Even a cursory look at the literature shows the versatility of S N Ar reactions, which have been employed recently in at least one step of the reported syntheses of: fluorescent teraaza [8]circulenes, 8 2-amino-and 2-arylazoanulenes, 9 aromatic ring substituted porphyrins, 10 substituted amidoazopyridines from perfluorinated pyridine, 11 various potentially therapeutic substituted pyrimidines 12,13 and dipyridylazepines, 14 and benzimidazole N-oxides. 15 The reactions of water-soluble polymers end-group substituted with electron-deficient aromatics have been studied 16,17 and in post-polymerization functionalization, poly(acrylamide) bearing pendant 3,5-dichloro-2,4,6-triazinyl groups can react via S N Ar reaction to yield a wide range of modified poly(acrylamide)s. 18 Some significant potential environmental remediation protocols also rely on nucleophilic aromatic displacement. [19][20][21]…”