Development of Practical Electrolytic Partial Fluorination Processes of Heterocyclic Compounds Towards Biological Activities

杂环化合物实用电解部分氟化工艺的开发以实现生物活性

• 批准号: 07555278
• 负责人: FUCHIGAMI Toshio
• 金额: $ 3.33万
• 依托单位: Tokyo Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07555278/
• 关键词: Biologically active compounds; Fluorinated heterocycles; Electrolytic partial fluorination; Anodic oxidation; Fluoride salts; Electrode process; Fluorodesulfurization

Since introduction of fluorine atom (s) into organic molecules sometimes enhances markedly their biological activities, the development of efficient direct fluorination methods has been becoming increasingly important. However, selective direct fluorination has been underdeveloped so far owing to lack of selectivity, the low nucleophilicity of fluoride ions, and passivation of the anode. Although many heterocyclic compounds possess biological activities, there have been few examples of their successful selective fluorinations. On the other hand, we have shown that an anodic method is a quite powerful for the selective direct fluorination of various heteroatom compounds such as sulfides.From these view points, we have developed highly efficient and safe methods for selective anodic partial fluorination of various heterocycles towards bioligical activities as follows. 1) Development of Fluorinated Supporting Electrolytes and Clarification of Their Electrochemical Properties : Since fluor … More ide salts as a supporting electrolyte greatly affect anodic fluorination, we developed entirely new types of fluorinated supporing electrolytes and clarified their electrochemical properties such as potential windows. 2) Selective Anodic Monofluorination of Sulfur-containing Heterocycles : Electroplyutic conditions for anodic monofluorination of various sulfur-containing heterocycles such as thiolanones, oxathiolanones, dithiolanones, and 3H-1,4-benzooxathian-2-ones were optimized using various supporting fluoride salts in order to establish the highly efficient anodic fluorination method. 3) Direct Anodic Monofluorination of Nitrogen-containing Heterocycles : Electrolytic conditions for anodic monofluorination of various nitorgen-containing heterocycles such as oxindoles and tetrahydroisoquinolines were optimized using various anode materials and fluoride supporting electrolytes. 4) Indirect anodic monofluorodesulfurization of beta-phenylsulfenyl beta-lactams was successfully performed by using a catalytic amount of triarylamine mediators. 5) Screening test of biological activities of anodically fluorinated heterocycles was done and fluorothiolanones were found to show strong PLA2 inhibitory activity.Thus, we have demonstrated that our develped electrolytic fluorination can be widely applicable and should be a versatile process for manufacturing various types of biologically active heterocyclic compounds. Less

由于将氟原子引入有机分子有时会显着增强其生物活性，因此开发有效的直接氟化方法变得越来越重要。然而，由于缺乏选择性、氟离子亲核性低以及阳极钝化，选择性直接氟化迄今为止尚未得到发展。尽管许多杂环化合物具有生物活性，但其成功选择性氟化的例子很少。另一方面，我们已经证明，阳极方法对于硫化物等各种杂原子化合物的选择性直接氟化是一种非常有效的方法。从这些角度来看，我们开发了多种杂环化合物选择性阳极部分氟化以实现生物活性的高效且安全的方法，如下所示。 1) 氟化支持电解质的开发及其电化学性能的阐明：由于氟离子盐作为支持电解质对阳极氟化影响很大，因此我们开发了全新类型的氟化支持电解质，并阐明了其电位窗口等电化学性能。 2) 含硫杂环的选择性阳极单氟化：使用各种支持氟化物盐优化各种含硫杂环如硫杂环酮、氧硫杂环酮、二硫杂环酮和3H-1,4-苯并氧杂环己烷-2-酮的阳极单氟化的电解条件，以建立高效的阳极氟化 方法。 3）含氮杂环的直接阳极单氟化：使用各种阳极材料和氟化物支持电解质，优化各种含氮杂环（例如羟吲哚和四氢异喹啉）的阳极单氟化的电解条件。 4)通过使用催化量的三芳胺介体成功地进行了β-苯基硫基β-内酰胺的间接阳极单氟脱硫。 5）对阳极氟化杂环化合物的生物活性进行了筛选试验，发现氟硫杂环酮类化合物具有很强的PLA2抑制活性。因此，我们证明了我们开发的电解氟化方法具有广泛的适用性，并且应该是生产各种类型的生物活性杂环化合物的通用工艺。较少的

项目成果

T.Fuchigami: "Electroorganic Synthesis Using Halogen as a Key Element" DENKI KAGAKU. 65, No.8 (in press). (1997)

T.Fuchigami：“使用卤素作为关键元素的有机电合成”电气化学。

A.W.Erian: "A Novel Synthesis of Fluorothieno [2,3-b] pyridines Using Anodic Fluorination of Heterocyclic Sulfides as a Key Step" The Journal of Organic Chemistry. 60. 7654-7659 (1995)

A.W.Erian：“以杂环硫化物的阳极氟化为关键步骤，新型合成氟噻吩并[2,3-b]吡啶”有机化学杂志。

成塚智: "Electrosyrthesis of 4,4-Dimethyl-2-ethoxycarbonyl-5-flucro-3-thiolanones : Highly Potent Human Type II PLAZ Innibitors" Bioorganic & Medicinal Chemistry Lelfers. 5. 1293-1294 (1995)

Satoshi Naruzuka：“4,4-二甲基-2-乙氧基羰基-5-氟-3-硫杂环酮的电合成：高效人类 II 型 PLAZ 抑制剂”生物有机与药物化学 Lelfers 5. 1293-1294 (1995)。

Ayman W.Eriar: "A Novel Synthesis of Fluorothieno [2,3-b] pyridines Using Anodic Fluorination of Heteroyclic Sulfides as a Key Step" The Journal of Organic Chemistry. 60. 7654-7659 (1995)

Ayman W.Eriar：“以杂环硫化物阳极氟化为关键步骤，新型合成氟噻吩基 [2,3-b] 吡啶”《有机化学杂志》。

淵上寿雄: "有機化合物の選択的電解フッ素化" 有機合成化学協会誌. 55・4(印刷中). (1997)

Hisao Fuchigami：“有机化合物的选择性电解氟化”有机合成化学学会杂志 55, 4（出版中）。