Photoreactivity of monofluorinated 2-azidobenzimidazoles towards carboxylic acids

Abstract

Aiming at the development of new photolabeling agents, the synthesis and photoreactivity of all monofluorinated derivatives of 2-azido-1-methylbenzimidazole are described. In the case of 4-, 5-, or 7-fluorination, irradiation in the presence of carboxylic acids (300 nm, Rayonet) afforded the monofluorinated 2-amino-6-acyloxybenzimidazoles in a regioselective manner, presumably after conversion of the initially formed nitrene to the N-cyanodiazaxylylene. Incorporation of chloride was also possible, and yields were comparable to those observed for the non-fluorinated parent compound. When blocking the reactive 6-position by a fluoro substituent, the title reaction was not possible. The analysis of the 19F NMR chemical shifts of the 5- and 7-monofluorinated products allowed the distinction between carboxylates and other nucleophiles.

Di‐ and Trifluorinated 2‐Azidobenzimidazole Derivatives: Synthesis, Photooxygenation, and 19F NMR Prediction

“…Assignment of the trifluoro adducts exploited the fact that the 3 J FF coupling constant is largest, followed by 4 J FF and 5 J FF . As we had observed for the corresponding monofluorinated 2-amino-6acyloxybenzimidazole derivatives, [3] there is only small 19 F NMR dispersion among entries of the same fluorination series. The largest 19 F NMR chemical shift differences are observed within the series of 4,7-and 5,7-difluorinated photo adducts.…”

“…We could show that N‐protected amino acids and certain peptides reacted chemoselectively with their carboxy termini, even in the presence of water [2] . In a pilot study, we extended our reaction to 4‐, 5‐, and 7‐monofluoro derivatives of 2‐azidobenzimidazole [3] . We hoped to be able to conclude on the structure of adducts and other irradiation products by 19 F NMR spectroscopy even in complex mixtures.…”

“…In a second series of experiments, we irradiated our 6fluorinated 2-azidobenzimidazole derivatives in acetic acid (Scheme 5). Monofluorinated compound 48 [3] afforded a mixture containing 6,7-diacetoxylated 2-aminobenzimidazole 49 and the 5-acetoxy-6-fluoro derivative 50 in equal amounts (25-30 %) as major products. Quantum chemical calculation (ωB97XD/TApr-cc-pVDZ, vide infra) predicts the 19 F NMR chem-ical shift of 50 (δ exp À 140.7, δ calc À 140.5).…”

“…Depending on substituents X and Y, a second acetate could attack at C5, C7, or both (X=Y=H), leading to the fluorinated diacetoxy intermediates C or D, respectively. A 6,7-difluorinated intermediate C could undergo [3,3] sigmatropic acetate migration to 59, followed by loss of HF, affording the product. If intermediate C is 4,6-difluorinated or 6-monofluorinated, loss of HF would happen directly without prior acetate migration to product 60 and 50, respectively.…”

“…[2] In a pilot study, we extended our reaction to 4-, 5-, and 7-monofluoro derivatives of 2-azidobenzimidazole. [3] We hoped to be able to conclude on the structure of adducts and other irradiation products by 19 F NMR spectroscopy even in complex mixtures. Encouragingly, the 19 F NMR signal of the fluorine substituent could be used to distinguish between carboxylates as a group, chloride, bromide, and hydrogen placed in the reactive 6-position.…”