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中的一些。然而，它们的使用仍然存在限制，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、稳定性差和困难。事实上，辉瑞的药物化学家关于未满足的合成需求的内部调查将某些杂环硼酸酯（特别是2-吡啶基硼酸酯）的不稳定性列为头号合成挑战。Willis小组和格罗顿的发现化学家（Rocke、Blakemore、Mascitti）之间的合作一直在探索偶联过程中杂环硼酸的替代品，最近确定吡啶亚磺酸酯是钯催化的芳基和杂芳基卤化物偶联反应中的优秀偶联伴侣（方案1b）。最近的化学已被证明可以扩展到使用替代的杂环，成功的亚磺酸酯底物的基础上嘧啶，吡嗪，哒嗪，咪唑，吡唑和吲唑核心现在已经成功地合成和耦合。这些杂环亚磺酸酯的使用解决了相应硼酸的许多限制;它们通过许多方法直接制备，它们对储存和使用稳定，并且它们提供高效的反应。杂芳基亚磺酸酯在与芳基和杂芳基卤化物偶联中的显著效用表明，该化学可以扩展以解决与杂环官能化相关的几个剩余挑战，特别是制备具有小（环状）烷基取代基的杂环核，并引入不同的基于N和O的亲核偶联配偶体。这两个调查领域涵盖了建议的范围。第一个目的是扩展已经开发的化学，包括sp2-sp3偶联过程（方案2）。这些无疑是具有挑战性的反应，但与杂环衍生的亚磺酸酯相关的稳定性和效率，以及它们在sp2-sp2偶联中的成功，表明化学是可行的。待研究的偶联反应的实例以及初始评估的基础示于方案2中。从杂环核实现sp2-sp3键的替代方法是采用共轭加成型化学。这种方法也应该是可行的，使用杂环衍生的亚磺酸酯，和基于金属催化的直接加成到贫电子烯烃（Rh-催化）的方法，以及基于光氧化还原的方法将被研究。该提议的第二个主要方面是探索杂环衍生的亚磺酸酯在Chan-Lam型偶联中的使用。这些反应通常在氧化条件下使用Cu（II）催化剂，并补充基于钯方法（如Buchwald-Hartwig）的方法。这些反应的传统形式依赖于硼酸衍生物作为偶联配偶体之一，并且由于反应性和稳定性差的问题，因此当使用杂环变体时受到限制。我们建议开发这种化学的变体，其利用杂环衍生的亚磺酸酯在这些反应中的反应性和稳定性。方案3说明了我们将调查的目标，以及初步调查的基础。该化学的一个特定目标是将联合收割机杂环衍生的亚磺酸酯与氨基和羟基取代的杂环化合物结合。本项目属于EPSRC合成有机化学研究领域的福尔斯。

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.