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

具有一个或两个氟原子的有机氟化合物有望具有独特的生物学性质，其合成方法的开发仍然是有机氟化学的一个重要课题。目前，构建块策略已成为合成有机氟化合物最方便的方法之一，并且在合成方法的发展方面已经投入了大量的努力。二氟环丙烷衍生物与亲核试剂的开环反应已被报道，并应用于合成各种有机氟化合物，如24,24-二氟-25-羟基维生素D_3。在本研究中，我们利用羰基氧与硅基自由基的反应诱导二氟环丙基醛和酮的开环反应，开发了新的有机氟化合物的合成方法。根据文献资料，以乙酸肉桂酯为原料合成2,2-二氟-3-苯基环丙基乙醛（1a）。以丙烯醛为原料，通过三步法制备相应的肉桂酰乙酸酯，合成了更多具有取代苯的二氟环丙二醛（4-Cl, 4-OMe, 4-CF_3: 1b-1d）。丙烯醛与对取代的碘苯通过Heck反应合成相应的肉桂酰醛，再用NaBH_4还原成醇。这些醇与乙酸酐乙酰化，得到醋酸肉桂酸酯。2,2-二氟-3-苯基环丙基乙醛（1a）与三（三甲基硅基）硅烷在四氢呋喃自由基条件下反应，得到硅基烯醇醚（3a），收率较高。在THF中加入1a和三甲基硅烷（三甲基硅基）（1 a = 1.5）的溶液中，加入AIBN作为自由基引发剂，在100℃下加热8h。每2h加入AIBN，共加入0.3等量的AIBN至3a。开环反应由硅基自由基与羰基氧反应引发，生成二氟环丙基o -硅基烷基，环丙烷只发生C1-C3键断裂。C1-C2键裂解产物未得到。在2,2-二氟-3-苯基环丙基乙醛（1b -1d）中进行开环反应，得到相应的3b-3d，产率较高。出乎意料的是，在自由基条件下，1a与三丁基氢化锡的开环反应没有进行，1a几乎被定量地回收。近年来，自由基反应已成为有机合成，特别是有机氟化合物合成的有力工具。本科研资助项目所开发的自由基反应是在中性和温和的条件下进行的，有望成为合成二氟化有机化合物的一种有前途的方法，特别是从环保的角度来看。少

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