Hydrogen Transfer Reactions of Amines

制药、农用化学品和精细化学品行业正面临越来越大的经济、生态和监管压力，以开发制备其所需化合物的方法，这些方法需要更少的步骤，产生最小的废物并且不利用（或产生）有毒分子。含氮分子（例如多取代胺、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，但它们的制备通常使用多步程序，并且经常使用有毒和/或危险试剂，以及产生有毒废物流。在这个项目中，我们将开发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，该技术产生很少（或没有）副产物，避免了危险试剂，并使用容易获得的良性胺作为起始原料。该项目的化学基础涉及用金属催化剂从胺中除去氢（铱和钌络合物）/该过程形成氧化物质（亚胺），其可经历起始胺不可用的化学反应，从而产生新分子。有几个主题，我们将探讨的基础上，从胺氢去除的基本概念，每个地址的一个新的方法来建设的有机分子在化学工业中的重大意义。在这项工作的第一个主题中，从胺中提取氢形成亚胺，然后与第二个胺反应;当氢通过催化剂返回时，这将使两个胺偶联在一起，得到新的胺产物（整个过程是氢借用）。这将应用于药物分子的合成，如偏头痛治疗药物舒马曲坦和抗组胺药苯那君。与这些想法相关的是与该过程相反的反应：即胺分裂成两种组分，以及胺转化为醇的变体。这两个反应基本上是前所未有的，并可能应用于一系列的合成问题，如吗啡转化为半合成阿片类衍生的止痛药。在第二个主题中，我们将开发的方法，使氢从胺不可逆的去除，通过使金属催化剂捐赠氢（从胺提取）到一个合适的受体或释放它作为氢气。当在该初始步骤中形成的亚胺现在与合适的配偶体反应时，产生的中间体现在不能接受回氢/相反，可以发生进一步的化学反应（包括第二次夺氢氧化）。例如，在水的存在下，亚胺将与水反应，然后进行进一步的氧化，以提供合成酰胺的新方法。酰胺是许多药物分子的非常重要的特征;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来制备的。因此，这种新方法具有环境效益。在最后一个主要主题中，从胺中氧化除去氢将应用于杂环（含有杂原子如氧和氮的环状结构）的合成，这些杂环广泛存在于重要的化学产品中/例如约一半的新药分子含有至少一个杂环。有几种类型的杂环将成为使用金属催化的氢的去除可访问的，我们将通过开发在药物中发现的杂环的路线来验证这种化学，如妥拉唑啉，奥沙普秦，羟苯环利明和替马昔布，这些药物用于广泛的治疗领域。

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.