二氟卡宾的产生与反应研究

Difluorocarbene has found widespread application in a variety of organic transformations, but the chemistry of difluorocarbene needs to be further explored. The research program will focus on this chemistry by broadening the utilities of difluorocarbene. Firstly, efficient and mild difluorocarbene reagents will be developed. Many known reagents suffer from high volatility or hygroscopicity, and/or basic or harsh reaction conditions to generate difluorocarbene. The reagents which can release difluorocarbene by decarboxylation under warming conditions will be designed and synthesized. Secondly, new reaction classes will be spawned. The area of the transformation of difluorocarbene is now bottlenecked by the limited reaction classes. The transition-metal-catalyzed transfer of difluorocarbene may lead to an explosive growth of difluorocarbene’s application in organic reactions. Thirdly, the protocols for trifluoromethylthiolation and trifluoromethoxylation with difluorocarbene will be explored. The realization of trifluoromethylthiolation and trifluoromethoxylation by using the [:CF2]/[F-] system will provides convenient and straightforward strategy for the installation of [18F]CF3X (X = S, O) moiety. Lastly, the [4+1] cyclization of 1,3-diene or [2+2+1] cyclization of olefins with difluorocarbene will be investigated. These cyclization reactions remains significant challenges in the chemistry of difluorocarbene. They should be able to be successfully achieved by the selection of suitable substrates and reaction conditions. We plan to move the chemistry of difluorocarbene forward by accomplishing the above work.

作为一种重要的活泼中间体，二氟卡宾在有机反应中已有广泛应用，但是二氟卡宾化学还有待深入研究。申请人拟在以下几方面展开工作：(1) 开发二氟卡宾试剂。设计合成受热后即可脱羧释放二氟卡宾的试剂，解决目前试剂中存在的挥发性或吸水性强、需要在碱性或高温等条件下使用的问题。(2) 发展二氟卡宾的反应类型。二氟卡宾反应类型的发展已经遇到瓶颈。以过渡金属催化二氟卡宾转移的方式可对其有效拓展。(3) 以二氟卡宾实现三氟甲硫/氧基化。由[:CF2]与[F-]组合实现三氟甲硫/氧基化，为有效构建 [18F]CF3X (X = S, O)基团提供重要的方法。(4) 实现二氟卡宾与二烯的[4+1]或[2+2+1]环化反应。此两类环化反应一直是二氟卡宾化学的难题，需要合理设计底物和反应条件才可实现。通过以上几项内容的研究，进一步推动二氟卡宾化学的发展。

主要研究了二氟卡宾化学以及与此相关的鏻盐化学和其它含氟卡宾化学。以课题组发展的鏻盐Ph3P+CF2CO2-(简称PDFA)为二氟卡宾试剂，发现二氟卡宾能与合适的氧源、硫源或氮源反应，分别产生氟光气、硫代氟光气和氰根离子。我们成功地将这些转化方法应用到一些挑战性反应中，如18O-标记的三氟甲氧基化、18F-标记的三氟甲硫基化、氰基二氟甲基化等。对PDFA应用性研究过程中，意外发现R3P/ICH2CH2I体系能够迅速产生碘化鏻盐R3P+-I I-，该鏻盐能够有效活化羰基和羟基，因此以R3P/ICH2CH2I体系实现了醛或醇的脱氧卤化、取代等反应。除了二氟卡宾之外，也探索了其它含氟卡宾，发展了温和有效的三氟甲基卡宾试剂和二氟甲基卡宾试剂，并实现了过渡金属催化的含氟卡宾转移。