Hydrogen Transfer Reactions of Amines

制药、农化和精细化工行业正面临越来越大的经济、生态和监管压力，要求它们开发制造所需化合物的方法，这些方法需要更少的步骤，产生最少的废物，并且不利用(或产生)有毒分子。含氮分子(如多取代胺、醇、杂环分子、酰胺等)普遍存在于药物、农药和其他特种化学品中，但它们的制备通常采用多步骤步骤，经常使用有毒和/或危险的试剂，以及产生有毒的废气。在这个项目中，我们将开发一种新的方法来形成这些有价值的分子，使用一种称为氢转移的技术，这种技术产生很少(或不产生)副产品，避免危险的试剂，并使用容易获得的和良性的胺作为起始材料。这个项目的基础化学涉及到用金属催化剂(Ir和Ru络合物)从胺中脱氢/这个过程形成一种被氧化的物种(亚胺)，它可以进行起始胺不能进行的化学反应，从而生成一种新的分子。我们将基于从胺中脱氢的基本概念来探索几个主题，每个主题都解决了构建在化学工业中具有重要意义的有机分子的新方法。在这项工作的第一个主题中，从胺中提取氢形成亚胺，然后亚胺与第二个胺反应；当氢被催化剂返回时，这两个胺将结合在一起得到新的胺产品(整个过程是一个借氢过程)。这将应用于药物分子的合成，如治疗偏头痛的舒马曲坦和抗组胺药物苯那曲。与这些想法相关的是与这一过程相反的反应：即将胺裂解成两个组分，以及将胺转化为酒精的变体。这两个反应基本上都是史无前例的，可以应用于一系列合成问题，如将吗啡转化为半合成阿片衍生止痛药。在第二个主要主题中，我们将开发使胺中氢的去除不可逆的方法，通过使金属催化剂将氢(从胺中提取出来)提供给合适的接受者或将其释放为氢气。当在第一步中形成的亚胺现在与合适的伙伴反应时，产生的中间产物现在不能接受返回的氢/相反，可以发生进一步的化学作用(包括第二次氢提取氧化)。例如，在水存在的情况下，亚胺将与水反应，然后进行进一步的氧化，为合成酰胺提供了一种新的方法。酰胺是许多药物分子的重要特征，通常这些化合物是通过使用浪费的活化剂将胺与羧酸偶联而得到的。因此，这种新方法对环境有好处。在最后一个主要主题中，胺的氧化脱氢将应用于杂环(含有氧和氮等杂原子的环结构)的合成，杂环广泛存在于重要的化学产品/例如大约一半的新药物分子中至少含有一个杂环。有几类杂环可以通过金属催化的脱氢反应来获得，我们将通过开发在药物中发现的杂环的路线来举例说明这种化学，如在广泛的治疗领域中使用的托拉唑啉、恶丙嗪、奥施芬西汀和替马昔布。

The pharmaceutical, agrochemical and fine chemical industries are coming under increasing economic, ecological and regulatory pressure to develop methods of making their desired compounds which require fewer steps, create minimal waste and do not utilise (or generate) toxic molecules. Nitrogen-containing molecules (eg polysubstituted amines, alcohols, heterocyclic molecules, amides etc) are ubiquitous in drugs, pesticides and other specialty chemicals, but their preparation typically uses multi-step procedures and frequently employs toxic and/or hazardous reagents, as well as generating noxious waste streams. In this project, we will develop new methods for the formation of these valuable molecules using a technique called hydrogen transfer which generates few (or no) by-products, avoids hazardous reagents, and uses readily available and benign amines as the starting materials.This chemistry underpinning this project involves the removal of hydrogen from an amine with a metal catalyst (iridium and ruthenium complexes) / this process forms an oxidised species (an imine) which can undergo chemical reactions that are not available to the starting amine, thus generating a new molecule. There are several themes we will explore based on the basic concept of hydrogen removal from amines, and each addresses a new approach to the construction of organic molecules of major significance in the chemicals industry. In the first theme of this work, hydrogen abstraction from the amine forms an imine which then reacts with a second amine; when the hydrogen is returned by the catalyst this will have coupled together the two amines to give a new amine product (the overall process is one of hydrogen borrowing ). This will be applied to the synthesis of drug molecules such as the migraine treatment Sumatriptan and the antihistamine Benadryl. Related to these ideas will be reactions which are the reverse of this process: namely the fragmentation of an amine into two components, and a variant where the amine is converted into an alcohol. Both reactions are essentially unprecedented and may be applied to a range of synthetic problems such as the conversion of morphine into semi-synthetic opioid derived painkillers.In the second major theme, we will develop methods to make the removal of hydrogen from the amine irreversible, by making the metal catalyst donate the hydrogen (abstracted from the amine) to a suitable acceptor or release it as hydrogen gas. When the imines formed in this initial step now react with a suitable partner, the intermediates generated cannot now accept back hydrogen / instead, further chemistry (including a second hydrogen abstraction oxidation) can take place. For example, in the presence of water, the imines will react with the water and then undergo further oxidation to provide a novel approach to the synthesis of amides. Amides are hugely important features of many drug molecules; usually these compounds are prepared by coupling amines with carboxylic acids using wasteful activating agent. This new approach therefore has environmental benefits. In the final major theme, the oxidative removal of hydrogen from amines will be applied to the synthesis of heterocycles (cyclic structures containing heteroatoms such as oxygen and nitrogen) which are widespread in important chemical products / for example about half of new drug molecules contain at least one heterocycle. There are several classes of heterocycle which will become accessible using metal-catalysed removal of hydrogen, and we will exemplify this chemistry by developing routes to heterocycles found in pharmaceuticals such as Tolazoline, Oxaprozin, Oxyphencyclimine and Tilmacoxib, which are used in a wide range of therapeutic areas.