Nitric Acid → 1,1,1-Trichloroethane

Participants

Reaction Steps

4-Acetylamino-2-methylbenzoic acid (Peltier) is converted into the 5-nitro compound by treatment with cold fuming nitric acid. The reaction mix was poured into crushed ice and the solid product collected by filtration and purified by recrystallization from DMF/water or by silica chromatography. The acetamide is removed by alkaline hydrolysis with 1-10% NaOH solution in 90% ethanol. The reaction mixture was added to excess dilute HCl and the solvent evaporated. The crude acid is esterified with satd. methanolic HCl at room temperature for several days. After removal of solvent the product is partitioned between ethyl acetate and satd. sodium bicarbonate. After washing with water the organic phase is evaporated and the residue purified by silica chromatography. The nitro group is reduced to the amino using hydrogen and palladium on carbon in ethanol or DMF. After filtration through celite and evaporation, the crude diamine is converted to the methyl 2-amino-6-methylbenzimidazole-5-carboxylate using cyanogen bromide in methanol at reflux. The mixture is cooled and poured into satd. aq. sodium bicarbonate and the solid product filtered and purified by recrystallization. The exocyclic amino group is acylated by refluxing with phthaloyl dichloride in pyridine followed by reaction of the diazepine with pyrazole in refluxing acetonitrile according to the method of Katritzky. The compound is reacted with either bromine or N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin either neat or in carbon tetrachloride or chloroform or 1,1,1-trichloroethane with the aid of a high intensity sun lamp and/or benzoyl peroxide, to provide the benzylic bromide. It is possible to acylate the diazepine further with isobutryl chloride in pyridine to produce a triply acylated benzimidazole species. This is normally done prior to the bromination.

Provenance & Evidence