R. Gataullin, T. V. Kazhanova, V. A. Davydova
May 1, 1999
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Pharmaceutical Chemistry Journal
Abstract
3,4-Difluoroaniline (I) is a convenient initial reagent for the synthesis of many biologically active compounds [1, 2]. In continuing our investigation into the biological activity of alkenylarylamines, we have synthesized a series of aminoacetic acid difluoroanilides and analogous derivatives of 2-cyclopentenyl-4,5-difluoroaniline and studied their local anesthetic properties. The interaction of difluoroaniline I with chloroacetyl chloride led to chloroacetic acid difluoroanilide (II). Cyclopentenylation of difluoroaniline I with the formation of an aromatic nucleus was effected by the method described in [3], involving the interaction of amine ! with 1-chloro-2-cyclopentene. It was established that the main product of this reaction under the conditions studied was 2-cyclopentenyl4,5-difluoroaniline (III) obtained at a yield of 60%. In addition, the reaction mixture contained a small amount (1.9%) of 2-cyclopentenyl-3,4-difluoroaniline (IV). The structures of compounds lIl and IV were unambiguously established on the basis of lR and ~H NMR data and the results of elemental analyses. The IR spectra show characteristic absorption bands of the NH2 group in the region of 3500 cm ~ [4]. The "aromatic" region of the IH NMR spectrum of compound III contains signals of the H-3 and H-6 protons as a double doublet at 6 = 6.45 and 6.83 ppm with the spin-spin coupling constants J= 11.91, 7.04 and 11,79, 8.88 Hz, respectively. Protons of a double bond of the cyclopentenyl fragment are manifested by the multiplet signals at 6 = 5.76 and 6.02 ppm. In the IH NMR spectrum of compound IV, the signal from the aromatic proton H-6 at 6 = 6.29 exhibits splitting both on the fluorine nuclei and on the neighboring proton with J = 8.84, 4.10, and 1.91 Hz; the H-5 proton signal at 6 = 6.80 ppm has a similar shape with J = 8.84, 9.71, and 11.82 Hz. A single-proton multiplet signal of H-I' in the spectrum of IV was observed in a weaker field (8 = 4.40 ppm) as compared to the signal from the analogous pro-