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

由于在有机分子中引入氟原子(S)有时会显著增强其生物活性，因此开发高效的直接氟化方法变得越来越重要。然而，由于选择性差、氟离子亲核性低、阳极钝化等原因，选择性直接氟化反应迄今进展缓慢。虽然许多杂环化合物具有生物活性，但它们成功的选择性氟化反应的例子还很少。另一方面，我们发现，对于硫化物等多种杂原子化合物的选择性直接氟化，阳极法是一种非常有效的方法。从这些观点出发，我们发展了高效、安全的各种杂环选择性部分氟化的生物配位活性的方法。1)氟化支持电解质的发展及其电化学性质的澄清：自Fluor…更多的IDE盐作为支持电解液对阳极氟化有很大的影响，我们开发了全新的含氟支持电解液，并阐明了它们的电化学性质，如电位窗口等。2)含硫杂环的选择性阳极单氟化：为了建立高效的阳极氟化方法，优化了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-2-酮的阳极单氟化反应条件。3)含氮杂环的阳极单氟化反应：采用不同的阳极材料和氟化物支持电解液，优化了含氮杂环氧吲哚、四氢异喹啉等含氮杂环阳极单氟化的电解条件。4)用催化量的三芳胺中间体成功地实现了β-苯基亚硫基-β-内酰胺的间接阳极单氟脱硫反应。5)对阳离子含氟杂环化合物的生物活性进行了筛选，发现含氟硫杂环酮类化合物具有较强的PLA2抑制活性，从而证明了我们所开发的电解氟化方法具有广泛的适用性，应该是一种制备各种生物活性杂环化合物的通用工艺。较少

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