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Effects of the Pyridine 3‐Substituent on Regioselectivity in the Nucleophilic Aromatic Substitution Reaction of 3‐Substituted 2,6‐Dichloropyridines with 1‐Methylpiperazine Studied by a Chemical Design Strategy
Author(s) -
Bach Peter,
Marczynke Michaela,
Giordanetto Fabrizio
Publication year - 2012
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201200978
Subject(s) - chemistry , regioselectivity , substituent , pyridine , steric effects , medicinal chemistry , nucleophile , stereochemistry , organic chemistry , catalysis
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 ( σ 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 α – 0.59417 β – 0.46169π* ( R 2 = 0.95, p = 1.9 × 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 β parameter. Thus, the 16:1 regioselectivity for the 2‐isomer in DCM ( β = 0.10) could be switched to a 2:1 selectivity for the 6‐isomer in DMSO ( β = 0.76).