基于1,3-共轭烯炔参与的串联环化及官能化反应构建含氟杂环

Heterocycles, such as pyrroles, pyrazoles, pyridines, and furans are well-recognized as privileged scaffolds， which are usually present in a broad range of biologically active natural products and drug molecules. It is well-known that the replacement of hydrogen by fluorine in organic molecules frequently leads to dramatic changes of their properties, such as solubility, metabolic stability, and bioavailability. Fluorine-containing heterocycles have been extensively used as versatile building blocks in synthetic organic and medicinal chemistry. Therefore, the development of efficient methods for the synthesis of these fluorine-containing heterocycles has attracted great attention. Activated or functionalized 1,3-enynes are important synthetic precursors for diverse heterocycles formation. This project will focus on the development of novel tandem reactions for the synthesis of some multi-substituted fluorine-containing heterocycles, such as pyrrole, pyrazole, pyran, furan, pyridine, and thiophene derivatives. Our study involves two parts: (1) Tandem cyclization/functionalization of activated 1,3-enynes with nucleophiles (such as: amines, hydrazines, hydroxylamines, alcohols, thiols, and etc) and fluorine-containing reagents; (2) Tandem intramolecular cyclization/functionalization of functionalizated 1,3-enynes (such as 1-en-3-yn-1-yl esters, 1-en-3-yn-1-yl ethers, 1-en-3-yn-1-yl thioethers, 1-en-3-yn-1-yl amines, and 1-en-3-yn-1-yl ketones). We will expect to obtain some fluorinated, trifluoromethylated, and trifluoromethylthiolated heterocycles, to promote the development of new pharmaceuticals, pesticides, materials, daily chemicals, and etc.

吡咯、吡唑、吡啶和呋喃等杂环被公认为优势骨架，广泛存在于具有生物活性的天然产物和药物分子中。有机分子中的氢原子被氟取代后通常会导致其溶解度、代谢稳定性和生物药效率等性质发生戏剧性变化。因此,含氟杂环在有机合成和药物化学中被广泛用作为多功能合成砌块, 发展高效合成含氟杂环的方法也就倍受青睐。另一方面，活化或官能化1,3-烯炔是合成众多杂环的重要前体。本项目拟利用串联反应策略基于该类前体发展若干多取代的含氟杂环(如：吡咯、吡唑、吡喃、呋喃、吡啶和噻吩等衍生物)。具体涉及：(1) 基于活化的1,3-共轭烯炔与亲核试剂(胺、肼、羟胺、醇和硫醇等)和含氟试剂的串联加成环化及官能化反应；(2) 基于官能化1,3-烯炔(1,3-烯炔基甲酸酯、醚、硫醚、胺和酮)与含氟试剂的串联分子内环化及官能化反应。预期将获得若干氟化、三氟甲基化和三氟甲硫基化的杂环，以满足新型医药、农药、材料、日用化学品等研发需求。

吡咯、吡啶和呋喃等杂环被公认为优势骨架，广泛存在于具有生物活性的天然产物和药物分子中。有机分子中的氢原子被氟取代后通常会导致其溶解度、代谢稳定性和生物药效率等性质发生戏剧性变化。因此,含氟杂环在有机合成和药物化学中被广泛用作为多功能合成砌块, 发展高效合成含氟杂环的方法也就倍受青睐。另一方面，活化或官能化1,3-烯炔是合成众多杂环的重要前体。本项目利用串联反应策略基于该类前体发展了多种官能化的多取代的杂环(如：吡咯、呋喃、吡喃酮、色满酮和吡啶等衍生物)。具体涉及：(1) 基于硝基活化的1,3-共轭烯炔与胺和含氟试剂（Togni’s试剂、selectfluor）的串联加成环化及官能化反应，合成三氟甲基或氟化的吡咯衍生物；(2) 基于硝基活化的1,3-共轭烯炔、胺与芳基亚磺酸钠、TMSN3合成芳基亚磺酰基取代异恶唑或叠氮基取代的吡咯衍生物；（3）基于硝基活化的1,3-共轭烯炔、胺在钯催化作用下合成亚硝基取代的吡咯衍生物；（4）基于酰基活化的1,3-烯炔与三氟甲硫基银发生串联环化反应，合成三氟甲硫基取代的呋喃衍生物；（5）基于1,3-烯炔酯，与N-三氟甲硫基苯胺和N-芳基硫取代的丁二酰亚胺，合成三氟甲硫基化（芳基硫醚化）的2-吡喃酮衍生物；（6）基于1,3-共轭烯炔叠氮化合物在钯催化作用下与三氟甲硫基银反应合成5-三氟甲硫基吡啶类衍生物；（7）基于过渡金属催化的碳氢键活化反应合成各种官能化的2-芳基苯并噻唑衍生物；（8）基于多组分串联环化反应合成具有潜在生物活性的喹啉、菲啶等衍生物。至今已在Org. Lett., J. Org. Chem., Org. Chem. Front., Synthesis, Tetrahedron等期刊上发表标注该项目基金编号的文章19篇，还有若干工作正处于投稿发表中。相关研究成果将在新型医药、农药、材料、日用化学品等研发方面具有潜在应用价值。

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