Hydrogen Transfer Reactions of Amines

胺的氢转移反应

• 批准号: EP/F037643/1
• 负责人: Stephen Marsden
• 金额: $ 24.06万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF037643%2F1
• 关键词: Hydrogen; Transfer; Reactions; Amines

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.

制药、农用化学品和精细化工行业正面临越来越大的经济、生态和监管压力，需要开发出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，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）在药物、农药和其他特种化学品中无处不在，但它们的制备通常需要多步程序，经常使用有毒和/或危险试剂，并产生有毒废物流。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，这种技术产生很少（或没有）副产物，避免使用有害试剂，并使用现成的和良性的胺作为起始材料。这个项目的化学基础包括用金属催化剂（铱和钌络合物）从胺中去除氢/这个过程形成氧化物质（亚胺），它可以进行化学反应，这是起始胺所不能得到的，从而产生新的分子。基于从胺中脱氢的基本概念，我们将探讨几个主题，每个主题都涉及构建化学工业中具有重要意义的有机分子的新方法。在本工作的第一个主题中，从胺中提取氢形成亚胺，然后与第二胺反应；当氢被催化剂返回时，这将把两种胺偶联在一起，产生新的胺产物（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苯海拉明。与这些想法相关的将是与这一过程相反的反应：即胺分裂成两种组分，以及胺转化为醇的变体。这两种反应基本上都是前所未有的，可用于一系列合成问题，例如将吗啡转化为半合成阿片类衍生止痛药。在第二个主题中，我们将开发使氢从胺中不可逆去除的方法，通过使金属催化剂将氢（从胺中提取）提供给合适的受体或以氢气的形式释放。当在初始步骤中形成的亚胺现在与合适的伙伴反应时，生成的中间体现在不能接受回氢/相反，可以进行进一步的化学反应（包括第二次抽氢氧化）。例如，在有水存在的情况下，亚胺将与水反应，然后进一步氧化，为酰胺的合成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制备的。因此，这种新方法具有环境效益。在最后一个主题中，胺中氢的氧化脱除将应用于杂环的合成（含有杂原子如氧和氮的环结构），这在重要的化学产品中广泛存在/例如大约一半的新药分子含有至少一个杂环。有几种类型的杂环可以通过金属催化脱除氢来获得，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，例如托拉唑啉，奥沙丙嗪，氧苄西林和替马昔布，这些药物用于广泛的治疗领域。

项目成果

Iridium-catalyzed formylation of amines with paraformaldehyde

• DOI: 10.1016/j.tetlet.2010.08.106
• 发表时间: 2010-11
• 期刊: Tetrahedron Letters
• 影响因子: 1.8
• 作者: O. Saidi;M. Bamford;A. Blacker;James Lynch;S. Marsden;P. Plucinski;R. Watson;Jonathan M. J. Williams-Jonathan-M.-J.

Selective Amine Cross-Coupling Using Iridium-Catalyzed "Borrowing Hydrogen" Methodology

• DOI: 10.1002/anie.200904028
• 发表时间: 2009-01-01
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Saidi, Ourida;Blacker, A. John;Williams, Jonathan M. J.
• 通讯作者: Williams, Jonathan M. J.