Development of Environmentally Friendly Synthetic Method Using Difluorocyclopropane as an Key Intermediate

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Organofluorine compounds possessing one or two fluorine atoms are expected to have unique biological properties, and the exploitation of the synthetic methods is still an important subject in organofluorine chemistry. The building-block strategy has now become one of the most convenient approaches for the synthesis of organofluorine compounds, and considerable efforts have been devoted to the development of the synthetic methods. Ring-opening reactions of difluorocyclopropane derivatives with nucleophiles have been already reported, and applied to the syntheses of various organofluorine compounds such as 24,24-difluoro-25-hydroxyvitamin D_3. In this study, we have developed the novel synthesis of organofluorine compounds using ring opening reactions of difluorocyclopropyl aldehydes and ketones induced by the reaction of the carbonyl oxygen with silyl radicals.2,2-Difluoro-3-phenylcyclopropylcarbaldehyde (1a) was synthesized from cinnamyl acetate according to the literature. Similarly, … More difluorocyclopropancarbaldehydes possessing substituted benzenes (4-Cl, 4-OMe, 4-CF_3 : 1b-1d) were also synthesized from corresponding cinnamyl acetates, which were prepared from acrolein in the following three-steps. The corresponding cinnamyl aldehydes were synthesized by Heck reaction of acrolein with p-substituted iodobenzenes, and reduced to alcohols by NaBH_4. The alcohols were acetylated with acetic anhydride to give the cinnarriyl acetates. When 2,2-Difluoro-3-phenylcyclopropylcarbaldehyde, (1a) was treated with tris(trimethylsilyl)silane in THF under radical conditions, silyl enol ether (3a) was obtained in good yield. To the solution of 1 a and tris(trimethylsilyl)silane (1.5 equiv. to 1a) in THF, AIBN was added as a radical initiator, and the resulting solution was heated at 100℃ for 8h. AIBN was added every 2h, and 0.3 equiv. of AIBN to 3a was totally added. The ring-opening reaction was initiated by the reaction of silyl radical to the carbonyl oxygen to produce the difluorocyclopropyl O-silyl ketyl, and the C1-C3 bond cleavage of the cyclopropane occurred exclusively. The products by C1-C2 bond cleavage were not obtained. The ring-opening reactions in 2,2-difluoro-3-phenylcyclopropylcarbaldehydes (1b -1d) proceeded to give corresponding 3b-3d in good yields. Unexpectedly the ring-opening reaction of 1a with tributyltin hydride under radical conditions did not proceed, and 1a was recovered almost quantitatively.Free radical reactions have recently emerged as a powerful tool in organic synthesis, especially in the synthesis of organofluorine compounds. The radical reaction developed in this Grant-in-Aid for Scientific Research proceeded under neutral and mild conditions, and is expected to be a promising method for the synthesis of difluorinated organic compounds, especially also from view of environmental protection. Less