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

含一个或两个氟原子的有机氟化合物具有独特的生物活性，其合成方法的探索一直是有机氟化学研究的重要课题。积木式合成法是合成有机氟化合物最方便的方法之一，人们在这方面做了大量的工作。二氟环丙烷衍生物与亲核试剂的开环反应已有报道，并已应用于24，24-二氟-25-羟基维生素D_3等多种有机氟化合物的合成。本研究以乙酸肉桂酯为原料，通过羰基氧与硅自由基反应，引发二氟环丙基醛和酮的开环反应，合成了2，2-二氟-3-苯基环丙基甲醛（1a）。同样地， ...更多信息 以丙烯醛为原料，经三步反应制得相应的肉桂醇乙酸酯，再经三步反应制得含取代苯的二氟环丙烷甲醛（4-Cl，4-OMe，4-CF_3：1b-1d）。以丙烯醛和对取代碘苯为原料，经Heck反应合成了相应的肉桂醛，再用硼氢化钠还原为醇。用乙酸酐将醇乙酰化，得到乙酸肉桂酯。2，2-二氟-3-苯基环丙基甲醛（1a）在自由基条件下与三（三甲基硅基）硅烷在THF中反应，得到硅烯醇醚（3a）。向Ia和三（三甲基甲硅烷基）硅烷（1.5当量）的溶液中加入三（三甲基甲硅烷基）硅烷（1.5当量）。向1a）的THF溶液中加入AIBN作为自由基引发剂，并将所得溶液在100℃下加热8小时。每2小时添加AIBN，并且添加0.3equiv. AIBN完全加入3a。开环反应是由硅自由基与羰基氧反应生成二氟环丙基O-硅烷基酮基引发的，而环丙烷的C1-C3键仅发生断裂。没有得到C1-C2键断裂的产物。2，2-二氟-3-苯基环丙基甲醛（1b-1d）的开环反应以良好的产率得到相应的3b-3d。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，并且1a几乎定量地被回收。在该科学研究补助金中开发的自由基反应在中性和温和的条件下进行，特别是从环境保护的角度来看，预计是合成二氟有机化合物的有前途的方法。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