Metal-free couplings for molecules, materials and bioactive targets

合成化学在许多方面推动了科学进步，因为分子和材料对世界各地数百万科学家的工作至关重要：如果我们不能制造我们需要的分子系统，我们就不能推进科学，对社会的好处也将失去。特别是，芳香族和杂芳族体系中碳-碳键的选择性形成是合成中最重要的目标之一，因为芳香族支架构成了许多药物、农用化学品和材料的结构基础。人们开发了一系列金属催化的交叉偶联过程--现在全世界的每一位执业化学家都很熟悉--来解决这些特殊碳-碳键的形成问题，由此产生的社会效益是显著的。作为表彰，2010年诺贝尔化学奖被联合授予Heck、Negishi和Suzuki，以表彰他们在有机合成中的钯催化交叉偶联。最近，已经开发了通过取代C-H键而不是卤化物来在芳环上的位置形成碳-碳键的方法(所谓的C-H活化)。这些“经典”和“尖端”的交叉耦合过程大多有一个共同点：它们是由昂贵的后过渡金属(如Ru、Rh、Pd和Pd)介导的。不幸的是，这些金属的供应面临风险，未来它们的使用将变得不可持续。因此，一门重要的课程涉及到不涉及使用金属的偶联反应的发展。这种方法还有其他好处，因为金属催化工艺产生的产品中的微量金属污染是工业中的一个主要问题，特别是制药和有机电子行业。在我的研究员项目期间，我将开发无金属工艺，对现有的金属催化交叉耦合技术进行补充，并最终可能导致它们的替代。易于获得的芳香族和杂芳族体系将用于与富含电子的碳基伙伴的无金属交叉偶联。我们的策略将使用芳环上的亚硫醚导向基团来协调相邻位置的碳-碳键的形成：硫磺将在将进入的碳偶联伙伴传递到芳环之前将其捕获。因此，容易的碳-硫键形成事件将被用来触发更具挑战性的碳-碳键的形成，芳环上的氢被取代(所谓的C-H取代)。芳香族和杂芳族亚硫醚的起始原料很容易通过氧化各种商业上可用的硫化物来制造。重要的是，我们方法中的硫磺导向基团可以被视为一个“安全捕获”导向基团：起始材料中的硫磺处于休眠状态，只有在氧化成亚硫氧化物时，衬底才会“开启”，并接受无金属的交叉偶联。在偶联过程中，硫磺导向基团被减少，导向效应被关闭。这种“安全保护”特性带来了许多优点：例如，基材不可能过早反应或过度还原。无金属联轴器的产品本身就具有很高的价值，而且操作也很成熟。例如，无金属转化为工业上重要的苯并噻吩类基元是可能的。为了说明我们的无金属交叉偶联方法的巨大潜力，我们将把这项技术应用于功能分子、有机材料和生物活性靶标的合成和修饰：通常使用供应风险后过渡金属进行的合成。

Synthetic chemistry powers scientific advances on many fronts as molecules and materials are vital to the work of millions of scientists around the world: if we can't make the molecular systems we need, we can't advance science and benefits for society will be lost. In particular, the selective formation of carbon-carbon bonds in aromatic and heteroaromatic systems is one of the most important goals in synthesis as aromatic scaffolds form the structural basis of many pharmaceuticals, agrochemicals and materials.A range of metal-catalyzed cross-coupling processes - now familiar to every practising chemist worldwide - have been developed to address the formation of these particular carbon-carbon bonds and the resultant benefits for society have been remarkable. In recognition, the 2010 Nobel Prize in Chemistry was awarded jointly to Heck, Negishi and Suzuki "for palladium-catalyzed cross couplings in organic synthesis". More recently, methods for the formation of carbon-carbon bonds to sites on an aromatic ring with substitution of a C-H bond, rather than a halide (so called "C-H activation") have been developed. Such processes are highly desirable as the starting materials are often more available, inexpensive and processes usually generate less waste.The majority of these 'classical' and 'cutting-edge' cross-coupling processes have one thing in common: they are mediated by expensive late transition metals (e.g. ruthenium, rhodium, palladium and platinum). Unfortunately, the supply of these metals is at risk and their use will become unsustainable in the future. An important course, therefore, involves the development of coupling reactions that do not involve the use of a metal. Such an approach has additional benefits, as trace metal contamination in products arising from metal-catalyzed processes is a major problem in industry - particularly the pharmaceutical and organic electronic industries.During my Fellowship project I will develop metal-free processes that complement existing metal-catalyzed cross-coupling technologies and could eventually lead to their replacement. Readily-accessible aromatic and heteroaromatic systems will be used in metal-free cross-couplings with electron-rich carbon-based partners. Our strategy will use a sulfoxide directing group on the aromatic ring to orchestrate carbon-carbon bond formation at the position next door: sulfur will catch the incoming carbon coupling partner before passing it to the aromatic ring. Thus, an easy carbon-sulfur bond forming event will be used to trigger the formation of a more-challenging carbon-carbon bond, with substitution of a hydrogen on the aromatic ring (so called "C-H substitution"). The aromatic and heteroaromatic sulfoxide starting materials are very easy to make by oxidation of a wide-range of commercially available sulfides. Importantly, the sulfur directing group in our approach can be viewed as a 'safety-catch' directing group: the sulfur in the starting material lies dormant and only upon oxidation to the sulfoxide is the substrate 'switched on' and becomes receptive to metal-free cross-coupling. During the coupling, the sulfur directing group is reduced and the directing effect is 'switched-off'. This 'safety-catch' feature leads to many advantages: for example, premature reaction or over reduction of the substrate is impossible.The products of the metal-free couplings are of high value in their own right and are also ripe for manipulation. For example, metal-free conversion to industrially-important benzothiophene motifs is possible. To illustrate the great potential of our metal-free approach to cross-coupling we will apply the technology in the synthesis and modification of functional molecules, organic materials and bioactive targets: syntheses that would usually be carried out using supply-risk late transition metals.