Regiodivergent Metalation of Pyridines Using Mixed TMP-Titanate and TMP-Fe-Titanate Bases

Functionalization of pyridine rings via direct metalation remains challenging because of issues pertaining to functional group compatibility under mild conditions, regiodivergence and coupling reactions of 2-pyridyl organometallics. Here we report two novel, practical and readily available TMP-based metallic reagents: Ti-1⋅2(TMPMgCl⋅LiCl) [A] and Ti-1⋅FeCl _{2 ⋅2(TMPMgCl⋅LiCl) [B], which enabled the rapid metalation of various unactivated and functionalized pyridines with high functional group tolerance and regioselectivity at room temperature. Notably, these two reagents exhibited unprecedented regiodivergence; A selectively metalated 2- or 3-functionalized pyridines at C6 position irrespective of the classic ortho direction of 2- and 3-position functional groups, whereas B promoted the metalations ortho to the functional groups. Moreover, under the mediation of A, the regiodivergent Pd and Fe-catalyzed deprotonative cross couplings of pyridines were easily achieved using simple catalyst (i.e., Pd(dba) 2 /PPh 3 and FeCl 3 /TMEDA) and without transmetalation, thereby providing a solution to the cross-coupling problem of 2-pyridyl organometallics. Preliminary DFT calculations suggest that the metalation using A should involve magnesiation while that using B may involve ferration promoted by Fe/Ti synergism. These findings not only provide a powerful tool for the direct functionalization of pyridines, but also allow the late-stage diversification of natural products and drugs, as demonstrated for nicotine and boscalid.}