铁钴催化的有机钛试剂协同型偶联反应的研究

The facile cooperative cross-coupling by virtue of the bridge action between transition-metal catalyst and organometallic is currently one of most challenging topics in the area of catalytic coupling reactions. Organotitanium proves to be one of ideal organometallic candidates because of its low price, non-toxicity and environmentally benign character. In contrast to the common main group organometallics such as RLi,RMgX, etc,the central titanium atom can coordinate with a large number of diverse types of ligands,and thus organotitanium can be presented in various forms. Accordingly, the reactivities of R moiety can be regulated flexibly by varying lignds and thereby shows high chemo-, regio and stereoselectivity. It is noteworthy that the cooperativity in the coupling reactions using organotitanium as a nucleophile can be achieved more easily than those using main group organometallics. Due to the strong coordination ability of central titanium atom, the desired bridge action for cooperative couplings occurs easily either through its coordination with the ligands of catalyst or the leaving group or through the coordination of catalyst metal with titanium's ligands. This project will focus on the cooperative cross-couplings of various organotitaniums using low-price, low-toxicity iron and cobalt metal as a catalyst by taking advantage of the above-mentioned merits of organotitanium. To this end, the planned cooperative cross-couplings will be achieved via the cooperative bridge action of organotitanium, catalyst and leaving group by altering the types of ligands of organotitanium or catalyst, the species of organotitanium and leaving groups. This project will investigate the scope of iron or cobalt-catalyzed cooperative couplings of various organotitanium and identify the highly selective reactions which are otherwise difficult to be achieved, including the couplings through the cleavage of C-F or C-H bonds, and oxidative couplings of organometallics. The highly regio- and stereoselectiv couplings will also be explored. Finally, novel and enviromentally benign total syntheis of bioactive compounds will be investigated using these cooperative couplings. Obviously, this project will significantly expand the scope and types of the couplings of organotitanium, the couplings catalyzed by iron or cobalt and the cooperative couplings.

利用催化金属与被催化金属之间的"桥联"等作用进行协同型偶联反应，是当前催化偶联领域中颇具挑战性的课题之一。钛廉价，低毒，配位能力强(中心原子配位数目大，配体种类多)，所以有机钛试剂可呈现多种形态，特别是在被其他金属催化时，钛原子很易凭借强的络合力，通过与配体、离去基或待偶联的烃基等络合而产生"桥联"作用,形成双金属协同偶联反应。本课题将利用钛试剂的这些突出特点，采用价格低，毒性小的铁和钴作为催化金属，通过对钛试剂种类及形态、催化剂与配体及离去基团的调整等；建立"桥联"机制，实施铁―钛或钴―钛协同型反应，实现条件温和、适用范围广的铁钴催化偶联反应。项目将实现多种钛试剂参与的碳氢与碳氟键的偶联反应、交叉型氧化偶联和高选择性不对称偶联，并完善它们的应用。显然，课题将突破当前铁钴催化反应的局限，拓展钛试剂偶联反应的类型与范围，对丰富与发展钛试剂、铁钴催化反应和协同效应都有着重要的理论与实际意义。

过渡金属催化偶联反应已成为有机化学中非常重要的合成手段，但这类偶联一直存在着一个突出的问题，即不可持续性；具体表现在两个方面：（1）为了提高化学选择性，往往要将较活泼的格氏试剂或锂试剂转为硼、锌、锡等试剂，从而带来大量（有毒）废料；（2）一直以来，主要使用的过渡金属为钯与镍；钯为贵金属，价格高，而镍毒性大，加之使用中需要添加结构复杂的膦配体，使得这两类催化剂不具可持续性。本项目就是基于这一出发点，拟通过廉价、低毒的铁钴为催化过渡元素，采用另一个廉价、低毒的钛元素替代锌、锡等元素，利用铁钛或钴钛协同催化，建立广谱型条件温和、选择性强且环境友好型偶联反应。.本项目的研究很好地实现了以上目标，建立了以下铁钛、钴钛和钯钛协同型偶联反应（1）钴钛协同型芳芳型偶联反应，丰富了钴催化反应和官能团耐受型偶联反应；（2）铁钛协同型氧化偶联反应，反应无需膦或NHC配体，以氧气为氧化剂，为一种典型的环境友好型反应，很大程度上拓展了氧化偶联及铁催化偶联反应的范围；（3）钴钛协同型氧化偶联反应，同样也较大程度地拓展了氧化偶联及钴催化偶联反应的范围；（4）钴钛协同型C-F活化反应，在无需膦或NHC配体以及底物活化基的条件下，C-F强键被活化并发生偶联，为强化学键的活化提供了指导；（5）配体调控型钯钛协同催化的区域选择性偶联反应，丰富了区域选择性偶联反应。此外，在配体合成中，本研究还建立一种新的2,2ꞌ-联吡啶类配体的合成方法。.本项目的部分成果已在国际重要期刊 Org. Lett.、Chem. Commun.、J. Org. Chem.、Org. Biomol. Chem等期刊上发表，共计7篇。其中有三篇文章被 Synfact 期刊作为亮点文章报道，一篇 J. Org. Chem.文章被刊登为封面文章。此外，还有一个发明专利也获得了授权。