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

以二氟环丙烷为关键中间体的环保合成方法开发

• 批准号: 14540547
• 负责人: YOSHIDA Masato
• 金额: $ 2.18万
• 依托单位: Shimane University (School of Medicine) (2003)Tokyo Metropolitan University (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14540547/
• 关键词: fluorine; cyclopropane; radical reaction; environment

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

含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。积木策略现已成为有机氟化合物合成最便捷的方法之一，人们在合成方法的开发上投入了大量的精力。二氟环丙烷衍生物与亲核试剂的开环反应已有报道，并应用于24,24-二氟-25-羟基维生素D_3等多种有机氟化合物的合成。在本研究中，我们利用羰基氧与硅基自由基反应引发的二氟环丙醛和酮的开环反应开发了有机氟化合物的新合成方法。2,2-二氟-3-苯基环丙基甲醛(1a)是由乙酸肉桂酯合成的。 文学。类似地，也由相应的乙酸肉桂酯合成了具有取代苯（4-Cl，4-OMe，4-CF_3：1b-1d）的二氟环丙甲醛，其由丙烯醛通过以下三步制备。通过丙烯醛与对位取代碘苯的Heck反应合成了相应的肉桂醛，并用NaBH_4还原为醇。将醇用乙酸酐乙酰化，得到乙酸肉桂酯。当2,2-二氟-3-苯基环丙基甲醛(1a)在THF中在自由基条件下用三(三甲基甲硅烷基)硅烷处理时，以良好的收率获得甲硅烷基烯醇醚(3a)。向1a和三(三甲基甲硅烷基)硅烷(1.5当量至1a)的THF溶液中添加AIBN作为自由基引发剂，并将所得溶液在100℃下加热8h。每2小时添加一次AIBN，0.3当量。 3a中完全添加了AIBN。开环反应是由甲硅烷基自由基与羰基氧反应生成二氟环丙基O-甲硅烷基羰基引发的，并且仅发生环丙烷的C1-C3键断裂。没有得到C1-C2键断裂的产物。在2,2-二氟-3-苯基环丙基甲醛(1b -1d)中进行开环反应，以良好的收率得到相应的3b-3d。出乎意料的是，1a与氢化三丁基锡在自由基条件下的开环反应并未进行，并且几乎定量地回收了1a。自由基反应近年来已成为有机合成中的有力工具，特别是在有机氟化合物的合成中。本次科研资助中开发的自由基反应在中性和温和的条件下进行，预计将成为合成二氟化有机化合物的一种有前途的方法，特别是从环境保护的角度来看。较少的

项目成果

M.Yoshida, M.Ohkoshi, H.Matsuyame, M.Iyoda: "Oxygenative Perfluoroalkylation of Olefinic Compounds Using Perfluoroalkyl Iodide in the Presence of Oxygen"Bull.Chem.Soc.Jpn.. 75. 1833-1842 (2002)

M.Yoshida、M.Ohkoshi、H.Matsuyame、M.Iyoda：“在氧气存在下使用全氟烷基碘化物对烯烃化合物进行氧化全氟烷基化”Bull.Chem.Soc.Jpn.. 75. 1833-1842 (2002)

M.Ohkoshi, T.Horino, M.Yoshida, M.Iyoda: "Synthesis and Inclusion Properties of a Novel Macrocyclic Hexaketone Monohydrate with a Hemiactal Structure"J.Chem.Soc., Chem.Commun.. 2582-2586 (2003)

M.Ohkoshi、T.Horino、M.Yoshida、M.Iyoda：“具有半缩醛结构的新型大环六酮一水合物的合成和包合性质”J.Chem.Soc.、Chem.Commun.. 2582-2586 (2003)

M.Ohkoshi, T.Horino, M.Yoshida, M.Iyoda: "Synthesis and Inclusion Properties of a Novel Macrocyclic Hexaketone Monohydrate with a Hemiactal Structure"J.Chem.Soc., Chem.Commun.. 2585-2586 (2003)

M.Ohkoshi、T.Horino、M.Yoshida、M.Iyoda：“具有半缩醛结构的新型大环六酮一水合物的合成和包合性质”J.Chem.Soc.、Chem.Commun.. 2585-2586 (2003)

伊与田正彦, 山村公明, 森田 昇, 吉田正人: "基礎からの有機化学"朝倉書店. 154 (2003)

Masahiko Iyoda、Kimiaki Yamamura、Noboru Morita、Masato Yoshida：“有机化学从基础开始”Asakura Shoten 154 (2003)。

M.Ohkoshi, T.Horino, M.Yoshida, M.Iyoda: "Synthesis and Inclusion Properties of a Novel Macrocyclic Hexaketone Monohydrate with a Hemiactal Structure"J.Chem.Soc., Chem.Commun. 2585-2586 (2003)

M.Ohkoshi、T.Horino、M.Yoshida、M.Iyoda：“具有半乳结构的新型大环六酮一水合物的合成和包合性质”J.Chem.Soc.，Chem.Commun。