Full Functionalization of the Imidazole Scaffold by Selective Metalation and Sulfoxide/Magnesium Exchange

A simple, flexible, and straightforward method for the functionalization of all the positions of the imidazole heterocycle through regioselective arylations, allylations, acylations, and additions to aldehydes is disclosed. Starting from the readily available key imidazole 1, highly functionalized imidazole derivatives have been synthesized in a regioselective manner from directed metalations and a sulfoxide/magnesium exchange. Moreover, the selective N3‐alkylation followed by deprotection of N1 (trans‐N‐alkylation) allows the regioselective N‐alkylation of complex imidazoles. The successive regioselective functionalization of the imidazole scaffold can be realized by direct metalation with TMPMgCl⋅LiCl and TMP2Zn⋅2 MgCl⋅2 LiCl as well as by a sulfoxide/magnesium exchange triggered by iPrMgCl⋅LiCl (see scheme, An=4‐methoxy‐3,5‐dimethylphenyl). The corresponding Mg and Zn intermediates have been quenched with a broad range of electrophiles, for example, aryl, alkenyl and allylic halides, acid chlorides, and aldehydes.