Organocatalytic Fluorinations with Fluoride Salts

氟是元素周期表中的一种独特元素，对社会产生了巨大影响，因为许多药物、农用化学品和麻醉剂的重要特性都归功于其结构中氟原子的存在。例如，小而电负性高的氟原子在药物化学中起着显著的作用。选择性地将氟安装到治疗或诊断小分子候选物中可以增强分子特性，如改善代谢稳定性和增强膜渗透。氟替代作为一种增加候选药物与靶蛋白结合亲和力的策略也已在许多案例中得到证实。与这些化合物的发现和生产相关的挑战之一是高效和成本效益的碳氟（C-F）键形成的催化方法的可用性。迄今为止，世界各地的许多化学家都积极致力于这一领域的研究，并为此目的开发了一系列工艺，但迄今为止发现的反应使用了来自F2的昂贵氟源，F2是一种黄色气体，具有很强的反应性和腐蚀性。这些过程中只有一小部分使用较便宜的氟化物盐，但这些过程需要昂贵的过渡金属催化剂，并且受底物范围狭窄的影响。在这个项目中，我们建议开发和研究一种新的碳氟键形成的催化反应，这种反应受益于使用具有成本效益的氟化物盐和由纯有机材料制成的具有成本效益的催化剂，不含过渡金属离子。我们系统的设计允许容易的化学改性，因此简单的粗或微调催化剂的结构和反应性。我们为氟化物活化设计的催化过程在机械上是前所未有的，并将应用于制备重要的氟化分子，立即应用于药物化学。因此，这些新的催化氟化和这些反应的产物对工业界和学术界的化学家都具有很大的价值，并且有可能通过改善健康和生活质量对社会产生广泛的影响。

Fluorine is a unique element of the periodic table that impacts hugely on society because many pharmaceuticals, agrochemicals and anaesthetics owe their important properties to the presence of fluorine atoms within their structures. For example, the small and highly electronegative fluorine atom plays a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance molecular properties such as improved metabolic stability and enhanced membrane permeation. Fluorine substitution as a strategy to increase binding affinity of drug candidates to target protein has also been documented in a number of cases. One of the challenges associated with the discovery and production of these compounds is the availability of highly efficient and cost effective catalytic methods for carbon-fluorine (C-F) bond formation. To date, many chemists worldwide have actively worked in this area of research, and developed a range of processes for this purpose, but the reactions discovered to date employ expensive fluorine source derived from F2, a gas yellow in colour that is highly reactive and corrosive. Only a minority of these processes make use of cheaper fluoride salts, but these then require expensive transition metal catalysts, and suffer from narrow substrate scope.With this project, we propose to develop and study a novel catalytic reaction for carbon-fluorine bond formation, that benefits from the use of cost effective fluoride salts and cost effective catalysts made of purely organic materials and free from transition metal ions. The design of our system allows for easy chemical modification and hence simple coarse or fine-tuning of the catalysts structure and reactivity profile. The catalytic process that we have designed for fluoride activation is mechanistically unprecedented, and will be applied to the preparation of important fluorinated molecules for immediate application in medicinal chemistry. Accordingly these new catalytic fluorination and the products of these reactions will be of great value to chemists in industry and academia alike, and have the potential to impact widely on society by improving health and quality of life.