Science of Synthesis

Irudayanathan, F. M.; Lee, S., Science of Synthesis Knowledge Updates, (2019) 2, 1.

Benzimidazoles are efficiently synthesized in one-pot via three-component reactions of 2-haloanilines in the presence of transition-metal catalysts. Recently, Kim and co-workers reported the copper-catalyzed, three-component coupling of 2-bromo- or 2-iodoanilines ‌1‌ with aldehydes ‌2‌ and sodium azide for the construction of 1H-benzimidazoles ‌3‌ in high yields (‌Scheme 1‌).[‌1‌] Aromatic aldehydes with electron-withdrawing groups, such as chloro or nitro, at the para-position of the aryl ring yield the corresponding benzimidazoles ‌3‌ in moderate to good yields. Aromatic aldehydes with electron-donating groups, such as dimethylamino, methyl, and methoxy, at the para-position of the aryl ring give the corresponding 1H-benzimidazoles ‌3‌ in good to excellent yields. 2-Haloanilines bearing other substituents on the aromatic ring can also be used as substrates, but the reaction is not regiospecific, giving the most stable benzimidazole tautomer and sometimes even a mixture of tautomers. The use of amino(halo)pyridines in place of haloanilines gives imidazo[4,5-b]pyridines in good yields, but also as mixtures of tautomers.

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