Deprotometalation of substituted pyridines and regioselectivity-computed CH acidity relationships. Issue 17 (28th April 2016)

• Record Type: Journal Article
• Authors: Hedidi, Madani; Bentabed-Ababsa, Ghenia; Derdour, Aïcha; Halauko, Yury S.; Ivashkevich, Oleg A.; Matulis, Vadim E.; Chevallier, Floris; Roisnel, Thierry; Dorcet, Vincent; Mongin, Florence
• Is Part Of: Tetrahedron. Volume 72:Issue 17(2016)
• Page Start: 2196
• Page End: 2205
• Publication Date: 2016-04-28
• Subjects: CH acidity -- Pyridine -- Mixed lithium–zinc base -- Substituent effect; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2016.03.022
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: 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 ·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 THF solution. In the case of methoxypyridines, the p K a values have also been calculated for complexes with LiCl and LiTMP. Graphical abstract: