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

用于有效脱硫交叉亲电联芳基偶联的双 Pd/Cu 催化体系的开发

• 批准号: 2604923
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2604923
• 关键词: Development; Dual; Pd; Cu; Catalysed

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.

该项目属于EPSRC合成有机化学研究领域的福尔斯。联芳基基序在医学相关分子中普遍存在，并且在其合成中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，由于使用无毒的硼试剂和温和的反应条件，这是有利的。这种方法已经取得了很大的成功，然而，由于2-吡啶基硼试剂对脱硼的敏感性，证明了具有2-取代吡啶的支架的问题。为了避免这种限制，已经建立了一种双取代交叉偶联机制，在反应中使用杂环亚磺酸酯代替硼酸偶联配偶体。虽然该方法的成功和范围已经得到很好的确立，但金属亚磺酸盐难以纯化，并且对于多步精制不稳定。在与辉瑞公司的合作中，该小组最近开发了碱活化潜在N-杂环亚磺酸盐的使用，其中活性亚磺酸盐物质通过E1 cb消除释放。β-腈和β-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常规使用。由于亚磺酸酯试剂主要由相应的卤化物合成，因此吡啶基卤化物是用于交叉偶联程序的有吸引力的起始材料，在反应中直接与第二卤化物一起使用。该反应通过在芳基卤化物之一上安装掩蔽的亚磺酸酯来进行，然后将其去掩蔽以与另一个卤化物进行缩合偶联。这不仅将联芳基合成缩短为简单的一锅法，而且还利用了卤化物起始材料的大量商业可用性。该小组最近证明了反式交叉亲电偶联的成功（方案1），产率为30%，为一般反应创造了令人兴奋的先例。本项目旨在开发和优化交叉亲电偶联，通过探索不同的配体和转移试剂，以进一步提高反应产率。据认为，该反应受到亚磺酸盐到卤化物的SNAr的限制，因此未来的计划还旨在探索使用钯和铜的助催化体系，以催化该限制步骤。这也将允许非SNAr活性卤化物转化为潜在的亚磺酸盐。该小组先前已经表明，SMOPS试剂在化学计量碘化铜的存在下与吡啶基卤化物进行高产率偶联，这为铜催化体系提供了潜力。助催化体系将通过以下进行：首先使用铜催化将亚磺酸酯转移试剂与芳基碘偶联，随后碱介导的亚磺酸酯解蔽，以最终允许发生钯催化的双加成偶联并提供所需的联芳基（方案2）。这种方法的成功将依赖于基质与催化剂的匹配，以及开发互补的催化系统。