Deprotometalation of substituted pyridines and regioselectivity-computed CH acidity relationships

A series of methoxy- and fluoro-pyridines have been deprotometalated in tetrahydrofuran at room temperature by using a mixed lithium zinc combination obtained from ZnCl2 center dot TMEDA (TMEDA=N,N,N',N'-tetramethylethylenediamine) and LiTMP (TMP=2,2,6,6-tetramethylpiperidino) in a 1:3 ratio, and the metalated species intercepted by iodine. Efficient functionalization at the 3 position was observed from 4-methoxy, 2-methoxy, 2,6-dimethoxy, 2-fluoro and 2,6-difluoropyridine, and at the 4 position from 3-methoxy and 2,3-dimethoxypyridine. Interestingly, clean dideprotonation was noted from 3-fluoropyridine (at C2 and C4) and 2,6-difluoropyridine (at C3 and C5). The obtained regioselectivities have been discussed in light of the CH acidities of the substrates, determined both in the gas phase (DFT B3LYP and G3MP2B3 levels) and in THE solution. In the case of methoxypyridines, the pK(a) values have also been calculated for complexes with LiCI and LiTMP. (C) 2016 Elsevier Ltd. All rights reserved.