Ligand-Activated Lithium-Mediated Zincation of N-Phenylpyrrole

Metalation of N‐phenylpyrrole by using an in situ mixture of ZnCl2⋅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≈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. Accessibility of lithium is a prerequisite for efficient metalation: The effect of solvents and lithium ligands on the outcome of zincation reactions was examined and the reaction pathway and mechanism were discussed on the basis of theoretical calculations (see picture).