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 ZnCl(2).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.

Ligand-activated lithium-mediated zincation of N-phenylpyrrole.

Metalation of N-phenylpyrrole by using an in situ mixture of ZnCl(2)TMEDA (0.5 equiv; TMEDA=N,N,N',N'-tetramethylethylenediamine) and LiTMP (1.5 equiv; TMP=2,2,6,6-tetramethylpiperidino) was optimized. The reaction carried out at room temperature in THF resulted in incomplete metalation (56 % conversion) and selectivity (mixture of 2-iodo and 2,2'-diiodo derivatives in an 86:14 ratio after trapping with iodine). By using diethyl ether (DEE), toluene, or hexane instead of THF, low conversions of 17, 38, or 23 % were observed, respectively, but the formation of the diiodide was avoided. When hexane was used as solvent, strong lithium-complexing ligands such as [12]crown-4 and N,N'-dimethylpropylideneurea (DMPU) inhibited the reaction whereas more (hemi)labile ligands (TMEDA>THF approximately DME) favored it. This result shows that a temporary accessibility of lithium to interact with the rest of the base and/or the substrate is a prerequisite for an efficient metalation. A 75 % yield of 2-iodo-N-phenylpyrrole was obtained after reaction with the base in the presence of five equivalents of TMEDA for two hours at room temperature, and subsequent trapping with iodine. We were able to successfully replace the spare TMP with a less expensive butyl group.

Lithium-mediated zincation of pyrazine, pyridazine, pyrimidine, and quinoxaline.

Deprotonation of pyrazine, pyridazine, pyrimidine, and quinoxaline using an in situ mixture of ZnCl2.TMEDA (0.5 equiv) and LiTMP (1.5 equiv) was studied. Pyrazine and pyrimidine were deprotonated in THF at room temperature, a result evidenced by trapping with I2. The competitive formation of dimer observed in net hexane was reduced by using cosolvents (TMEDA or THF). Starting from quinoxaline, the dimer formation took place in THF also, and mixtures of mono- and diiodides were obtained whatever the solvent and conditions used. A similar competitive formation of a diiodide was noted with pyridazine; the use of THF at reflux temperature nevertheless afforded the 3-iodo derivative in good yield.