One-Pot Hydrogen Peroxide and Hydrohalic Acid Induced Ring Closure and Selective Aromatic Halogenation To Give New Ring-Fused Benzimidazoles

Abstract

ABSTRACT:A new series of selectively dichlorinated and dibrominated five to eight-membered ring [1,2-a] fused benzimidazoles and [1,4]oxazino [4,3-a]benzimidazoles are synthesized in mostly high yields of >80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl is also capable of a one-pot ring-closure and chlorination.The combination of hydrogen peroxide and hydrohalic acid (HX, where X = Cl, Br) is a source of electrophilic chlorine and bromine that can be used for facile aromatic halogenations.

Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones

“…26 Most recently, H 2 O 2 in combination with hydrochloric or hydrobromic acid mediated the cyclization of ocyclic amine substituted anilines to give respectively dichlorinated and dibrominated ring-fused benzimidazoles in high yields of >80%. 27 From a green chemistry and commercial perspective, there are significant advantages to using the low molar mass ubiquitous oxidant H 2 O 2 in synthesis since the only effluent is water, and its cost is lower than conceivable alternatives. Hydrogen peroxide (50% w/v) in water has a pH 4.…”

“…30 It was envisaged that the weak acidic property of H 2 O 2 would negate the requirement for carrying out the cyclization in organic and mineral acids, as described in literature procedures. 3,[23][24][25][26][27][28] Recently the preparation of alicyclic ring-fused benzimidazoles in formic acid was reported at high temperatures using an iodinemediated cyclization of o-nitro-t-anilines, where corrosive HI was generated in situ. 28 Ethyl acetate is classified as a preferred solvent by Pfizer, 31 while GSK give ethyl acetate high ratings for environmental impact, health and reactivity / stability.…”

Polycyclic Benzimidazole: Synthesis and Photophysical Properties

“…This oxidative cyclization is very sensitive towards molar ratio of H 2 O 2 /HX. At higher concentration of H 2 O 2 with respect to HX, benzimidazoquinone is obtained via normal 4‐electron oxidative cyclization process …”

One-Pot Synthesis of Dihalogenated Ring-Fused Benzimidazolequinones from 3,6-Dimethoxy-2-(cycloamino)anilines Using Hydrogen Peroxide and Hydrohalic Acid

“…10 In comparison, the H2O2/HX system is relatively underutilized in the synthesis of heterocycles with H2O2/HBr used to catalyze the aziridination of alkenes with chloramine T. 11 One-pot H2O2/HXmediated oxidative cyclization of o-cyclic amine substituted anilines with selective dichlorination and dibromination gave a series of five to eight-membered ring-fused benzimidazoles, generally in >80% yield (Scheme 2a). 8…”