可见光诱导的自由基构建C-P键反应研究

Phosphorus-containing compounds have enormous significance in the pharmaceutical, biological, agrochemical, synthetic organic, and materials sciences because of their broad and desirable physical, chemical, and biological properties. The reactions for the formation of carbon-phosphorus (C-P) bonds are important strategies to synthesis the Phosphorus-containing compounds. Visible light-induced free radical reactions could play important roles in the formation of C-P bonds. This research proposal is aimed at applying the visible light-induced free radical reactions to the formation of C-P bonds and synthesis of several classes of phosphorus-containing compounds. This proposal is composed of following parts: (1) Difunctionalization of alkenes through visible light-induced radical phosphinylation and functionalization are introduced. These transformations could allow the direct phosphinylation of the α-H of carbonyl ketones and synthesis of the β-ketophosphonates; (2) Phosphinylation of α,α-diaryl allylic alcohols via aryl migration of an aryl group are described, these reactions could be performed to afford a variety of α-aryl-β-phosphinylated carbonyl ketones via 1,2-aryl migration. Moreover, the visible light-induced radical protocols for the concurrent incorporation of phosphinylation and functionalization of alkene and remote C-H via stable radical intermediate triggered by phosphinylation of alkene via 1,5-H radical shift could be developed; (3) Based on aforementioned studies, more information about the reaction process through various methods such as radical trap, and “radical bell” experiment could be obtained, which would be beneficial to illuminate the reaction mechanism; (4) Explore application prospect of the novel research methods in fields of organic synthesis and drug modification. This research proposal could develop several novel methodologies to form C-P bonds.

有机膦化物广泛应用于医药、生物、农业、材料科学、有机合成等领域。碳磷键（C-P）的构建是合成有机膦化合物的重要方法。可见光诱导的自由基成键反应，为C-P键的构建提供了高效的方法学。本项目基于发展可见光诱导的自由基反应构建C-P键的新方法，并用于有机膦化物的合成。主要开展：（1）可见光诱导的膦化串联反应可以实现烯键的双官能团化，这种方法可用于羰基α-H的膦化反应，合成β-羰基膦化物；（2）可见光条件下，α,α-二芳基烯丙醇可发生膦化-芳基迁移反应，得到α-芳基-β-膦化羰基产物；膦自由基加成到烯键，还可能发生1,5-氢迁移反应，实现“远程”官能团化；（3）在上述工作的基础上，通过自由基捕获、“自由基钟”实验等方法可以获取更多的反应过程的信息，阐明反应机理；（4）将研究成果应用到有机合成、药物修饰等领域，探索新方法学的合成应用价值。本项目可发展出若干种高效构建C-P键的新方法。

本项目以自由基构建碳磷键、碳碳键和过渡金属活化C-H键构建碳碳键、碳氮键为研究内容，主要取得了以下几方面的研究成果：（1）研究了铜催化的N-甲基芳胺的氧化反应：发展了铜催化N-甲基芳胺氧化膦化反应、铜催化N-甲基芳胺连续N-去烷基化/N-甲基氧化反应，为α-氨基磷酸酯、磷酰胺、N-芳基甲酰胺类产物的合成提供了新策略；（2）对非键作用条件下碳自由基的串联成键反应进行了探讨：发展了DMF促进ICF2CO2Et和烯醇乙酸酯经氟烷基化和可控C-F键活化生成β-氟烯酮和β-烯胺酮；利用可见光下碘化物/有机膦诱导酰亚胺活性酯和N-芳基丙烯酰胺的脱羧/加成/环化反应高效合成3,3-二取代吲哚酮和异喹啉-1,3-二酮衍生物，该体系也可诱导Togni试剂和1,6-烯炔经连续的分子间自由基加成/环化/碘化合成高取代吡咯烷及苯并呋喃；发展了碱促进ICF2CO2Et生成二氟烷基自由基，进而和1,6-烯炔经串联的二氟烷基化/环化/碘化反应生成吡咯烷及苯并呋喃类产物的新方法；研究了碱诱导ICF2CO2Et和N-芳基丙烯酰胺类底物经连续二氟烷基化/环化生成3-二氟烷基取代的吲哚酮类产物的反应；K2CO3和B2pin2体系也促进ICF2CO2Et 和ICnF2n+1加成到炔键，实现炔类的氟烷基化/碘化反应；（3）探讨了过渡金属催化C-H活化构建碳碳键、碳氮键的反应：采用硫酰胺基团导向策略，[Cp*RhCl2]2和[Cp*IrCl2]2可分别催化硫酰胺二茂铁和取代三甲氧基硅烷试剂高效合成乙烯基二茂铁和芳化二茂铁产物；硫酰胺作为导向基，芳基硼酸作芳化试剂，[IrCl(cod)]2和[Cp*RhCl2]2皆可高效催化硫酰胺二茂铁的芳化反应，这些反应为多官能团化二茂铁化合物的合成提供了新途径；无氧化剂、无配体条件下，钯可催化氯代亚胺底物经连续的氮氯键断裂/N-芳化反应生成3-取代喹喔啉酮类产物，该方法已获得专利授权；（4）发展了碳化钙做炔源，铜催化2-溴-N-芳基苯甲酰胺类底物经连续Sonogashira 偶联和亲核加成环化生成3-亚甲基-2-芳基异吲哚酮化合物的新方法。通过本项目的研究，拓展了自由基串联成键和过渡金属活化C-H键构键反应在合成中的应用，发展了多种合成含磷、含氟、含氮化合物的新策略。