Deprotometalation of substituted pyridines and regioselectivity-computed CH acidity relationships

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• 作者：Madani Hedidi^a ; ^b ; Ghenia Bentabed-Ababsa^b ; ^{badri_sofi@yahoo.fr" class="auth_mail" title="E-mail the corresponding author} ; Aï ; cha Derdour^b ; Yury S. Halauko^c ; ^{hys@tut.by" class="auth_mail" title="E-mail the corresponding author} ; Oleg A. Ivashkevich^c ; Vadim E. Matulis^d ; Floris Chevallier^a ; Thierry Roisnel^e ; Vincent Dorcet^e ; Florence Mongin^a ; ^{florence.mongin@univ-rennes1.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CH acidity ; Pyridine ; Mixed lithium&ndash ; zinc base ; Substituent effect
• 刊名：Tetrahedron
• 出版年：2016
• 出版时间：28 April 2016
• 年：2016
• 卷：72
• 期：17
• 页码：2196-2205
• 全文大小：938 K

文摘

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 pK_a values have also been calculated for complexes with LiCl and LiTMP.