Exploiting sulfinate coupling partners for the preparation of diversely functionalized heterocycles

芳基硼酸和相关的硼酸盐是合成化学家可用的最通用和最广泛使用的试剂之一。然而，它们的使用仍然存在局限性，最重要的是从发现化学的角度来看，许多杂环衍生的硼酸的制备效率低、稳定性差、制备困难。事实上，辉瑞药用化学家关于未满足的合成需求的内部调查将一些杂环硼酸盐(特别是2-吡啶基硼酸酯)的不稳定性列为头号合成挑战。Willis小组和Groton(Rocke，Blakemore，Mascitti)的发现化学家合作，一直在探索偶合过程中杂环硼酸的替代品，最近确定了吡啶亚磺酸盐在钯催化的与芳基和杂芳基卤化物的偶联反应中是很好的偶联伙伴(方案1b)。最近，化学已经被证明扩展到替代杂环的使用，并且成功地合成了以嘧啶、吡嗪、哒嗪、咪唑、吡唑和吲唑为核心的亚磺酸盐底物。这些杂环亚硫酸酯的使用解决了相应的硼酸的许多局限性；它们可以通过多种方法直接制备，它们对储存和使用都很稳定，并且它们提供了高效的反应。杂芳基亚硫酸盐在与芳基和杂芳基卤化物偶联方面的显著作用表明，该化学可以扩展到解决与杂环官能化有关的几个剩余挑战，特别是阐述具有小(环)烷基取代基的杂环核心，并引入不同的N和O基亲核偶联伙伴。这两个调查领域涵盖了提案的范围。其中第一个目的是扩展已经开发的化学，以包括sp2-sp3耦合过程(方案2)。这些反应无疑具有挑战性，但杂环亚磺酸盐的稳定性和效率，以及它们在sp2-sp2偶联中的成功，表明这种化学是可行的。要研究的偶联反应的例子以及初步评估的基础如方案2所示。从杂环核心实现sp2-sp3键的另一种方法是使用共轭加成类型的化学。使用杂环衍生的超硫酸盐，这种方法也应该是可行的，并将研究基于金属催化的贫电子烯烃直接加成(Rh催化)的方法，以及基于光氧化还原的方法。这项建议的第二个主要方面是探索杂环衍生的亚硫酸盐在Chan-Lam类型联轴器中的使用。这些反应通常使用氧化条件下的铜(II)催化剂，以及基于钯方法的补充方法(如Buchwald-Hartwig)。这些反应的传统版本依赖于硼酸衍生物作为偶联伙伴之一，因此当使用杂环变体时，由于反应性和稳定性较差的问题，这些反应受到限制。我们建议开发一种这种化学的变体，在这些反应中利用杂环衍生的硫化物的反应性和稳定性。方案3说明了我们将调查的目标，以及初步调查的基础。这一化学的一个特殊目标是将杂环衍生的亚硫酸盐与氨基和羟基取代的杂环结合起来。该项目属于EPSRC合成有机化学研究领域。

Aryl boronic acids, and related boronates, are some of the most versatile and widely used reagents available to synthetic chemists. However, limitations with their use remain, most importantly from a discovery chemistry perspective, the low efficiency, poor stability and difficulty in preparation of many heterocycle-derived boronic acids. Indeed, an internal survey of Pfizer's medicinal chemists regarding unmet synthetic needs ranked the instability of some heterocyclic boronates (in particular the 2-pyridyl boronate) as the number one synthetic challenge. A collaboration between the Willis group and discovery chemists at Groton (Rocke, Blakemore, Mascitti), has been exploring alternatives to heterocyclic boronic acids in coupling processes, and has recently established that pyridine sulfinates are excellent coupling partners in palladium-catalyzed coupling reactions with aryl and heteroaryl halides (Scheme 1b). Recently the chemistry has been shown to extend to the use of alternative heterocycles, and successful sulfinate substrates based on pyrimidine, pyrazine, pyridazine, imidazole, pyrazole and indazole cores have now been successfully synthesised and coupled. The use of these heterocycle sufinates addresses many of the limitations of the corresponding boronic acids; they are straightforward to prepare via a number of methods, they are stable to storage and use, and they deliver highly efficient reactions. The remarkable utility of heteroaryl sulfinates in coupling with aryl and heteroaryl halides suggests that the chemistry could be extended to tackle several remaining challenges associated with heterocycle functionalization, specifically elaborating heterocycle cores with small (cyclic)alkyl substituents, and introducing diverse N- and O-based nucleophile coupling partners. These two areas of investigation encompass the scope of the proposal. The first of these aims to extend the chemistry already developed to include sp2-sp3 coupling processes (Scheme 2). These are undoubtedly challenging reactions, but the stability and efficiency associated with heterocycle-derived sulfinates, together with their success in sp2-sp2 coupling, suggests the chemistry is viable. Examples of the coupling reactions to be investigated, together with the basis of an initial evaluation are shown in Scheme 2. An alternative approach to achieve an sp2-sp3 linkage from a heterocycle core is to employ conjugate-addition type chemistry. This approach should also be viable using heterocycle-derived sufinates, and approaches based on metal-catalyzed direct addition to electron-poor alkenes (Rh-catalysis), as well as photoredox based approaches will be investigated. The second major aspect of this proposal is to explore the use of heterocycle-derived sufinates in Chan-Lam type couplings. These reactions typically employ Cu(II) catalysts under oxidative conditions, and complement approaches based on palladium methods (such as Buchwald-Hartwig). Traditional versions of these reactions rely on boronic acid derivatives as one the of the coupling partners, and as such are limited when heterocyclic variants are employed, due to issues of poor reactivity and stability. We propose to develop a variant of this chemistry that exploits the reactivity and stability of heterocycle-derived sufinates in these reactions. Scheme 3 provides an illustration of the targets we will investigate, together with the basis of an initial investigation. A particular goal of this chemistry will be to combine heterocycle-derived sulfinates with amino- and hydroxyl-substituted heterocycles. This project falls within the EPSRC synthetic organic chemisty research area.