The Development of a Dual Pd/Cu Catalysed System for Effective Desulflinative Cross-Electrophile Biaryl Couplings

该项目属于EPSRC合成有机化学研究领域。联芳基基序在医学相关分子中普遍存在，其合成主要依赖于钯催化的交叉偶联反应。Suzuki-Miyaura反应是C(sp2)-C（sp2）键形成的最广泛的变体，由于使用无毒硼试剂和温和的反应条件而受到青睐。这种方法已经取得了很大的成功，然而，由于2-吡啶基硼试剂对原deboronation的敏感性，对于具有2-取代吡啶的支架来说，这被证明是有问题的。为了克服这一限制，建立了一种脱硫交叉偶联机制，在反应中使用杂环亚硫酸盐代替硼偶联伙伴。虽然该工艺的成功和范围已经确定，但金属亚硫酸盐难以提纯，并且对多步精化不稳定。与辉瑞公司合作，该小组最近开发了碱活化潜伏n -杂环亚硫酸盐的使用，其中活性亚硫酸盐通过E1cb消除释放。-腈和-酯砜已被证明是与芳基卤化物最有效的偶联剂，这种反应现在在辉瑞的实验室中经常使用。由于亚硫酸盐试剂主要由相应的卤化物合成，因此吡啶卤化物是交叉偶联过程的有吸引力的起始材料，直接与反应中的第二卤化物一起使用。反应通过在其中一个芳基卤化物上安装掩膜亚硫酸盐进行，然后将其去掩膜以与另一个卤化物进行脱硫偶联。这不仅缩短了联芳基合成到一个简单的一锅过程，而且还利用了卤化物起始材料的大量商业可用性。该小组最近证明了脱硫的交叉亲电偶联（方案1）的成功，产率为30%，为一般反应开创了令人兴奋的先例。本项目旨在通过探索不同的配体和转移试剂，进一步提高反应收率，开发和优化交叉亲电偶联反应。人们认为，该反应受到亚硫酸盐对卤化物的SNAr的限制，因此未来的计划还旨在探索使用钯和铜的共催化系统，以催化这一限制步骤。这也将允许非snar活性卤化物转化为潜在的亚硫酸盐。该小组先前已经表明，SMOPS试剂在化学计量量的碘化铜存在下与吡啶卤化物进行了高产偶联，这为铜催化体系提供了潜力。该共催化系统将首先使用铜催化将亚硫酸盐转移试剂与碘化芳基偶联，然后通过碱介导的亚硫酸盐掩膜，最终允许钯催化的脱硫偶联发生并提供所需的联芳基（方案2）。这种方法的成功将依赖于底物与催化剂的匹配，以及开发互补的催化系统。

This project falls within the EPSRC Synthetic Organic Chemistry research area. Biaryl motifs are ubiquitous in medicinally relevant molecules, and predominantly rely on palladium catalysed cross-coupling reactions in their syntheses. The Suzuki-Miyaura reaction is the most widespread variant for C(sp2)-C(sp2) bond formation, which is favoured due to the use of non-toxic boron reagents and mild reaction conditions. This approach has enjoyed much success, however proves problematic for scaffolds featuring 2-substituted pyridines, due to the susceptibility of 2-pyridyl boron reagents to protodeboronation. To circumvent this limitation, a desulfinative cross-coupling mechanism has been established, using heterocyclic sulfinates in place of the boronic coupling partners in the reaction. Although the success and scope of this process has been well established, the metal sulfinates are difficult to purify and are not stable to multi-step elaboration. In collaboration with Pfizer, the group has recently developed the use of base-activated latent N-heterocyclic sulfinates, where the active sulfinate species is released via E1cb elimination. Beta-nitrile and Beta-ester sulfones have shown to be the most effective coupling agents with aryl halides, and such reactions are now routinely used in Pfizer's laboratories. As the sulfinate reagents are primarily synthesised from the corresponding halide, it follows that the pyridyl halides are attractive starting materials for the cross-coupling procedure, employed directly with a second halide in the reaction. The reaction proceeds via the installation of a masked sulfinate on one of the aryl halides, which is then de-masked to undergo desulfinative coupling with the other halide. Not only does this shorten the biaryl synthesis to a simplistic one-pot process, but additionally exploits the vast commercial availability of the halide starting materials. The group have recently proven the success of the desulfinative cross-electrophile coupling (Scheme 1), with a yield of 30% setting exciting precedent for a general reaction. This project aims to develop and optimise the cross-electrophile coupling, by exploring different ligands and transfer reagents to improve the reaction yield further. It is thought that the reaction is limited by the SNAr of the sulfinate to the halide, so future plans also aim to probe a co-catalytic system employing both palladium and copper, in order to catalyse this limiting step. This would also allow non-SNAr active halides to undergo conversion to the latent sulfinates. The group has previously shown that the SMOPS reagent undergoes high-yielding coupling with pyridyl halides in the presence of stoichiometric copper iodide, which provides potential for a copper-catalysed system. The co-catalytic system would proceed by firstly coupling the sulfinate transfer reagent with an aryl iodide using copper catalysis, followed by the base mediated demasking of the sulfinate, to finally allow the palladium-catalysed desulfinative coupling to occur and provide the desired biaryl (Scheme 2). The success of this approach will rely on the matching of substrates to the catalyst, and developing complementary catalytic systems.