Novel Synthesis of 4-Fluoropyridines Based on 2-Fluoroallylic Alcohols by Succeeding Ireland-Claisen and Aza-Cope Rearrangements as Key Steps

Abstract

A novel synthetic pathway leads to 4-fluoropyridines bearing aryl substituents in positions 2 and 6 and possibly an additional alkyl group in position 3. 2-Fluoroallylic alcohols were esterified with N-benzoylalanine or N-aroylphenylglycines and the resulting esters were transformed to give 4-(2-fluoroallyl)oxazol-5(4H)-ones in a Steglich-type, Ireland-Claisen rearrangement. The latter compounds gave either N-aroyl-substituted 2-amino-4-fluoro-2-methyl- or 2-amino-4-fluoro-2-phenylalk-4-enoic acids in excellent yields by hydrolysis or substituted 2-aryl-4-fluoro-6-phenylpyridines in a cascade reaction initiated by an aza-Cope rearrangement to form thermally unstable 2-(2-fluoroallyl)oxazol-5(2H)-ones. Succeeding extrusion of carbon dioxide, intramolecular cyclopropanation of the fluorinated double bond with the formed carbene, ring-opening with formation of a fluorinated dihydropyridine, and final oxidative aromatization gave the title compounds in moderate yields.