Synthesis 2006(13): 2085-2096  
DOI: 10.1055/s-2006-942411
PAPER
© Georg Thieme Verlag Stuttgart · New York

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

Ulrich Wittmann, Frank Tranel, Roland Fröhlich, Günter Haufe*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany
Fax: +49(251)8339772; e-Mail: haufe@uni-muenster.de;
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Publikationsverlauf

Received 18 April 2006
Publikationsdatum:
08. Juni 2006 (online)

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.

2

See reference 1d, pages 129-142.

21

Sheldrick, G. M. SHELXL-97, Programm for crystal structure analysis, Universität Göttingen, 1997.

22

Keller, E. SCHAKAL, Program for the graphical representation of molecular and solid-state structure models. Universität Freiburg, 1997.