A Practical Oxone®-Mediated,High-Throughput, Solution-Phase Synthesis of Benzimidazolesfrom 1,2-Phenylenediamines and Aldehydes and its Application toPreparative Scale Synthesis

Abstract

Addition of oxone ® to a mixture of a 1,2-phenylenediamine and an aldehyde in wet DMF at room temperature results in rapid formation of benzimidazoles under very mild conditions. The reaction is applicable to a wide range of substrates including aliphatic, aromatic and heteroaromatic aldehydes, and is not significantly affected by steric or electronic effects. In most cases, crude products are isolated in good to excellent yields (59-95%) and homogeneities (86-99%) by simple precipitation or extraction from the reaction mixture and do not require additional purification. Limitations to the scope of this methodology were encountered in cases where aldehydes were sensitive to oxone ® under the acidic reaction conditions. The features of this methodology make it particularly well suited for the high-throughput, solution-phase synthesis of benzimidazole libraries. The low cost and simplicity of this procedure makes it equally attractive for preparative-scale syntheses where safety and environmental issues are of greater concern. Scheme 1 Table 1 1,2-Phenylenediamine Starting Materials 1 Starting material R 2 NH 2 Yield (%) Yield (%) 98 99 5 100 98 6 99 70 7 98 95 8

Simple, Mild, and Highly Efficient Synthesis of 2-Substituted Benzimidazoles and Bisbenzimidazoles

“…Considering the reaction times, a significant effect of the substituents on either aldehydes or o-phenylenediamines were not observed. A methyl substitution on nitrogen atom of o-phenylenediamine decreased the rate, possibly because of steric hindrance (entries [25][26][27][28][29][30][31][32]. The reactions with N-methyl o-phenylenediamine were completed in longer times with lower yields compared with their unsubstituted analogues (entries 1, 4, 7, 10, 13, 16, 19, and 22).…”

“…The other method is condensation of o-phenylenediamines with aldehydes under oxidative conditions. 15,21 Various reagents such as I 2 /KI, 22 In(OTf) 3 , 23 nitrobenzene, 24 benzoquinone, 25 Oxone, 26 Fe(HSO 4 ) 3 27 and atmospheric air 28 are used for this purpose. Nevertheless, some of these reported methods have limitations such as low yields, high reaction temperatures, long reaction times, harsh reaction conditions, purification difficulties, and formation of by-products.…”

Trimethylsilyl Chloride Catalyzed Synthesis of Substituted Benzimidazoles Using Two Phase System Under Microwave Conditions, and Their Antimicrobial Studies

“…Methods of benzimidazole synthesis include the condensation of 1,2-phenylenediamine with carboxylic acids or their derivatives in the presence of strong acids such as poly phosphoric acids 6 . In another method, benzimidazole has been prepared by classical cyclocondensation of 1,2-phenylenediamine with the corresponding aldehydes under oxidative conditions [7][8] . Recent publications have shown synthesis of substituted benzimidazole via tosylation of N-aryl amidoxime 9 , synthesis of benzimidazole using air as an oxidant 10 and using microwave irradiation 11 .…”

Silica Supported Fluoroboric Acid: An Efficient and Reusable Heterogeneous Catalyst for Facile Synthesis of 2-Aliphatic Benzothiazoles, Benzoxazoles, Benzimidazoles and Imidazo[4,5-b]pyridines

“…1,2 These heterocycles have achieved significance in pharmacology as antibacterial, 3 antiviral, 4 antifungal, 5 anticancer, 6 anticonvulsant 7 and immunosuppressant agents. 8 Quite a plethora of methods have been developed for the preparation of these heterocycles including the condensation of carboxylic acids, 9 acid chlorides, 10,11 orthoesters, [12][13][14] esters, 15 and aldehydes [16][17][18][19][20][21] with o-aminophenols, o-aminothiophenols and o-phenylenediamines, dehydration of o-acylaminophenols, 22 the reaction of o-quinones with amines 23 and Beckmann rearrangement of o-acylphenoloximes. 24 However all of these procedures suffer from one or more of the following drawbacks such as long reaction time, low yield of the products, harsh reaction conditions, use of excess amount of reagents, tedious work up procedures and co-occurrence of several side reactions.…”