Deprotonative Metalation of Five-Membered Aromatic Heterocycles Using Mixed Lithium−Zinc Species

Deprotonation of benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc-protected indole
and pyrrole, and N-phenylpyrazole using an in situ mixture of ZnCl2·TMEDA (0.5 equiv) and lithium
2,2,6,6-tetramethylpiperidide (1.5 equiv) in THF at room temperature is described. The reaction was
evidenced by trapping with iodine, regioselectively giving the expected functionalized derivatives in
52−73% yields. A mixture of mono- and disubstituted derivatives was obtained starting from thiazole.
Cross-coupling reactions of 2-metalated benzo[b]thiophene and benzo[b]furan with heteroaromatic chlorides
proved possible under palladium catalysis. A reaction pathway where the lithium amide and zinc diamide
present in solution behave synergically was proposed for the deprotonation reaction, taking account of
NMR and DFT studies carried out on the basic mixture.