Selective Biocatalytic <i>N</i> ‐Methylation of Unsaturated Heterocycles

Methods for regioselective N-methylation and -alkylation of unsaturated heterocycles with “off the shelf” reagents are highly sought-after. This reaction could drastically simplify synthesis privileged bioactive molecules. Here we report engineered natural methyltransferases challenging N-(m)ethylation heterocycles, including benzimidazoles, benzotriazoles, imidazoles indazoles. The reactions performed through a cyclic enzyme cascade that consists two using only iodoalkanes or methyl tosylate as simple reagents. method enables selective important molecules otherwise difficult to access, proceeds high regioselectivity (r.r. up >99 %), yield (up 99 on preparative scale, nearly equimolar concentrations starting materials.