Metal-free couplings for molecules, materials and bioactive targets

合成化学在许多方面推动着科学进步，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：如果我们不能制造出我们需要的分子系统，我们就不能推进科学，社会的利益也将丧失。特别地，在芳族和杂芳族体系中选择性形成碳-碳键是合成中最重要的目标之一，因为芳族支架形成许多药物的结构基础，已经开发了一系列金属催化的交叉偶联方法-现在为全世界每一位执业化学家所熟悉-以解决这些特定碳的形成，碳键和由此产生的社会效益是显著的。2010年诺贝尔化学奖授予了赫克、根岸和铃木三人，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C-H键取代而不是卤素取代（所谓的“C-H活化”）来形成与芳环上的位点的碳-碳键的方法。这些方法是非常理想的，因为起始材料通常更容易获得，价格便宜，并且通常产生更少的废物。大多数这些“经典”和“尖端”的交叉偶联方法有一个共同点：它们都是由昂贵的后过渡金属（例如钌，铑，钯和铂）介导的。不幸的是，这些金属的供应面临风险，其使用在未来将变得不可持续。因此，一个重要的过程涉及不涉及使用金属的偶联反应的发展。这种方法有额外的好处，因为金属催化过程中产生的产品中的痕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工业。在我的奖学金项目期间，我将开发无金属工艺，以补充现有的金属催化交叉偶联技术，并最终取代它们。容易获得的芳族和杂芳族体系将用于与富电子碳基伙伴的无金属交叉偶联。我们的策略是在芳环上使用一个亚砜导向基团来协调相邻位置的碳-碳键形成：硫将在进入芳环之前捕获进入的碳偶联伙伴。因此，容易的碳-硫键形成事件将用于触发更具挑战性的碳-碳键的形成，其中芳环上的氢被取代（所谓的“C-H取代”）。芳族和杂芳族亚砜起始材料非常容易通过氧化多种市售硫化物来制备。重要的是，我们的方法中的硫导向基团可以被视为“安全捕获”导向基团：起始材料中的硫处于休眠状态，并且只有在氧化成亚砜时，底物才“打开”并接受无金属的交叉偶联。在偶联过程中，硫导向基团被还原，导向作用被“关闭”。这种“安全锁紧”功能带来了许多优点：例如，不可能发生过早反应或过度还原底物。无金属偶合器的产品本身就具有很高的价值，并且也适合操作。例如，无金属转化为工业上重要的苯并噻吩基序是可能的。为了说明我们的无金属交叉偶联方法的巨大潜力，我们将在功能分子，有机材料和生物活性靶标的合成和修饰中应用该技术：通常使用供应风险后过渡金属进行合成。

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.