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[摘要]：A chemical design strategy has been used to select 3-substituted 2,6-dichloropyridines for the nucleophilic aromatic substitution reaction with 1-methylpiperazine. The aim was to study the dependency of the regioselectivity in these reactions on the character of the pyridine 3-substituent expressed by their lipophilicity (PI), size (MR), and inductive effect (sigma(p)). Interestingly, the regioselectivity did not correlate with any of these parameters, but in a statistically significant manner with the Verloop steric parameter B1, as indicated by the p value of 0.006 (R-2 = 0.45). This implies that bulky 3-substituents close to the pyridine ring induce regioselectivity towards the 6-position. Useful in practical synthesis is the different regioselectivity obtained with a carboxylic acid 3-substituent and precursors or derivatives thereof. Thus, in acetonitrile as solvent, 3-carboxylate and 3-amide substituents were preferred to obtain the 2-isomer (9:1 ratio of the 6-isomer), whereas the 3-cyano and 3-trifluoromethyl substitutents were preferred to obtain the 6-isomer (9:1 ratio of the 2-isomer). Analysis of the regioselectivity R-sel for the pyridine 2-position in the reaction of 2,6-dichloro-3-(methoxycarbonyl)-pyridine with 1-methylpiperazine in 21 different solvents showed that R-sel could be predicted by the Kamlet-Taft equation: R-sel = 1.28990 + 0.03992 alpha - 0.59417 beta -0.46169 pi* (R-2 = 0.95, p = 1.9 x 10(-10)). R-sel is thus mainly correlated with the ability of the solvent to function as a hydrogen-bond acceptor, as expressed by the solvatochromic beta parameter. Thus, the 16:1 regioselectivity for the 2-isomer in DCM (beta = 0.10) could be switched to a 2:1 selectivity for the 6-isomer in DMSO (beta = 0.76). |
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