Reliable Functionalization of 5,6‐Fused Bicyclic N‐Heterocycles Pyrazolopyrimidines and Imidazopyridazines via Zinc and Magnesium Organometallics

DFT‐calculations allow prediction of the reactivity of uncommon N‐heterocyclic scaffolds of pyrazolo[1,5‐a]pyrimidines and imidazo[1,2‐b]pyridazines and considerably facilitate their functionalization. The derivatization of these N‐heterocycles was realized using Grignard reagents for nucleophilic additions to 5‐chloropyrazolo[1,5‐a]pyrimidines and TMP(2)Zn ⋅ 2 MgCl(2) ⋅ 2 LiCl allowed regioselective zincations. In the case of 6‐chloroimidazo[1,2‐b]pyridazine, bases such as TMP(2)Zn ⋅ MgCl(2) ⋅ 2 LiCl, in the presence or absence of BF(3) ⋅ OEt(2), led to regioselective metalations at positions 3 or 8. Subsequent functionalizations were achieved with TMPMgCl ⋅ LiCl, producing various polysubstituted derivatives (up to penta‐substitution). X‐ray analysis confirmed the regioselectivity for key functional heterocycles.