Photochemical Arylation of Brønsted Acids with 2‐Azidobenzimidazole

Abstract

Irradiation of N‐benzylated 2‐azidobenzimidazoles at 300 nm in the presence of an excess amount of carboxylic acids results in a novel regioselective synthesis of 2‐amino‐6‐oxybenzimidazoles in isolated yields of 60–70 %. It is also possible to regioselectively introduce 6‐bromo, 6‐chloro, and 6‐triflyloxy groups. Irradiation in dichloromethane in the absence of external nucleophiles revealed that after loss of nitrogen, the benzimidazolylnitrene probably undergoes coarctate ring opening to an N‐cyano diaza‐o‐xylylene intermediate.

Water Compatible Photoarylation of Amino Acids and Peptides

“…Recently, we reported that irradiation of N‐( p ‐fluorobenzyl)‐2‐azidobenzimidazole in AcOH/CH 2 Cl 2 afforded the 2‐amino‐6‐acetoxybenzimidazole in high yield and perfect regioselectivity 10. Probably, the initially formed nitrene intermediate (Scheme ) undergoes ring opening to a non‐symmetrical diazaxylylene which is protonated at the more basic imine nitrogen, followed by nucleophilic attack of acetate at the β‐position of the iminium ion, ring closure to the 2‐iminoimidazole, and rearomatization via proton shift.…”

“…The aliphatic hydroxy group was tolerated. The reaction with Boc‐Tyr‐OH at longer wavelength (370 nm) gave the ester in lower 33 % yield, accompanied by formation of 1‐( p ‐fluorobenzyl)‐2‐aminobenzimidazole (29 %) 10…”

“…[10] Irradiation of doubly Boc-protected cystine (4 equiv, Scheme 5) and quenching with pyrrolidine afforded pyrrolidine carboxamide 17 as major product (27 %). In addition, bis adduct 18 (22 %) was isolated, presumably formed after competing arylation of the disulfide sulfur by intermediate 19, followed by nucleophilic attack of pyrrolidine at the sulfonium salt.…”

“…The reaction with Boc-Tyr-OH at longer wavelength (370 nm) gave the ester in lower 33 % yield, accompanied by formation of 1-(p-fluorobenzyl)-2-aminobenzimidazole (29 %). [10] Chromatography of more polar photoarylation products required the use of protic mobile phases, which led to substantial loss by hydrolysis or methanolysis of the aryl ester with formation of 2-amino-6-hydroxybenzimidazole (11). We found that addition of pyrrolidine (8-12 equiv based on azide 2) to the reaction mixture immediately after irradiation afforded stable carboxamides via acyl transfer after 24-72 h. In the case of Boc-His-OH, quenching with pyrrolidine led to carboxamide 12 (30 %, Scheme 3).…”

“…We had observed earlier that the presence of phosphoric acid leads to incorporation also of neutral nucleophiles such as MeOH. [10] However, the N-methyl analogue 13 [12] (Scheme 4) reacted in the presence of phosphoric acid affording 2-amino-1-methylbenzimidazole (14, 18%), e-lactam 15 (20 %, by intramolecular aminolysis), and adduct 16 (52 %). With Boc-Arg-OH hydrochloride chlorination of the benzimidazole 6-position occurred (56 %) instead of arylester formation, probably because the guanidinium side chain and the carboxy terminus remained protonated, making chloride the best nucleophile in solution.…”