基于单电子转移过程的新型羰基化有机硼试剂的交叉偶联反应研究

Three-component coupling reaction of arylboronic acid, carbon monoxide, and aryl halides/pseudo-halide, generally known as classical carbonylative Suzuki reaction, has become a powerful tool in organic synthesis due to its numerous advantageous features: (1) readily available, and thermally-, air- and water-stable reactants; (2) high regio- and stereoselectivity; (3) wide functional group compatibility. However, there are still some challenges such as lack of innovation in reaction mechanism, alkyl halide having a difficulty in oxidative addition to Pd0, problem of β-H elimination, narrow scope of substrates, and dependence on expensive and toxic palladium catalyst, which hinder its advancements and widespread use. The project investigates novel single-electron transfer-induced carbonylative cross-coupling reactions of organoboranes, including iron-catalyzed carbonylations of unsaturated organohalides, aryl diazonium salts, and alkyl carboxylic acids with unsaturated organoboranes; transition metal-free carbonylations of alkyl chlorides with organoboranes; and visible-light photocatalyed carbonylations of alkylating reagents with organoboranes. And explorations of the application of these protocols by gram-scale experiments, late-stage functionalizations, and synthesis of pharmaceuticals, natural products, and other biologically active compounds, demonstrate their practical utility. The aim of the project is to employ new catalytic approaches toward innovation of mechanism of carbonylative cross-coupling of organoboranes. It is not only to offer a new way to tackling the challenging problems of classical palladium-catalyzed carbonylative reactions of organoboranes, but also to lay a solid foundation for creation of new approaches to substance transformations and invention of new carbonylation reactions.

经典羰基化硼试剂的交叉偶联反应是钯催化的羰基化Suzuki反应，它是有机合成的重要工具，其构造的羰基官能团是有机转化的中心基团。然而，该反应存在诸多亟待解决的问题：反应过程单一、烷基卤代物氧化加成难、β-H消除的副反应、反应底物范围窄、以及依赖贵金属催化剂钯。本项目通过铁催化、无过渡金属催化和可见光催化的新方法，确立新型的单电子转移的羰基化有机硼试剂的交叉偶联反应过程：实现铁催化的不饱和有机卤代物、芳基重氮盐、烷基羧酸与不饱和有机硼试剂的自由基羰基化反应；实现无过渡金属催化的烷基氯代物与有机硼试剂的自由基羰基化反应；实现可见光催化的烷基试剂与有机硼化合物的自由基羰基化反应，并将这些反应用于药物分子、天然产品和生物活性分子的合成。本项目旨在利用新的催化方法实现新的催化机制，为解决经典钯催化羰基偶联反应中存在的一系列挑战性问题提供新的策略，更为实现新的物质转化途径和发展新的羰基化反应奠定基础。

发展环境友好的合成方法是合成化学发展的重要趋势。基于单电子转移过程的新型羰基化有机硼试剂的交叉偶联反应研究，确立了新型的单电子转移的羰基化有机硼试剂的交叉偶联反应过程，解决了对贵金属钯的依赖问题，具有环境友好、经济和可持续性的优势，有利于广泛推广和大规模应用。发展的新方法可以用于合成商品化的抗血脂药物非诺贝特和非诺贝特酸，以及抗癌活性分子Naphthylphenstatin和羰基碳-13标记的分子。本项目的研究是对经典的钯催化羰基化反应过程的创新，不仅丰富羰基合成化学，更为实现新的物质转化途径和发展新的羰基化反应提供理论指导。基于单电子转移过程的研究，进一步拓展研究了铁催化自由基新反应，实现了苄基碳-氢和芳碳-氢的直接高选择性氧化，解决了该领域长期以来的挑战性问题，为研究原子经济性、步骤经济性和环境友好的合成方法奠定了重要基础。.以上研究的重要结果独立发表在Science, Nature Commun., Green Chem., Chem. Commun.等SCI源学术期刊上，计14篇，并授权中国发明专利2件。