Exploiting sulfinate coupling partners for the preparation of diversely functionalized heterocycles

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry

Abstract

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.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509711/1 01/10/2016 30/09/2021
1950162 Studentship EP/N509711/1 01/10/2017 30/06/2021 Janette McKnight