Ortho-selectivity in the nucleophilic aromatic substitution (SNAr) reactions of 3-substituted, 2,6-dichloropyridines with alkali metal alkoxides |
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Authors: | Jeremy L. YapKellie Hom Steven Fletcher |
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Affiliation: | Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA |
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Abstract: | 3-Substituted, 2,6-dichloropyridines have featured in the syntheses of small molecule inhibitors of a wide variety of biological targets. Hence, the regioselective displacement of the chlorines is of significant interest. Through conducting an extensive solvent study, we have found that non-polar, aprotic solvents of low hydrogen bond basicities favour substitution of the chlorine ortho to the 3-substituent by alkali metal alkoxides. We present convincing evidence that coordination of the alkali metal counter-ion to the 3-substituent (nitro, ester, amide) is the origin of the ortho-selectivity to give a cyclic, six-membered transition state. Excellent ortho-selectivities (?98:2) for secondary and tertiary alkoxides were realized with the sodium counter-ion, whereas the more reactive primary alkoxides required the harder, more Lewis acidic lithium counter-ion. |
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Keywords: | Ortho Regioselective Nucleophilic aromatic substitution (SNAr) 2,6-Dichloro-3-nitropyridine Coordination |
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