A Co-operative Bimetallic Approach for the Transformation of Lithiation

锂化转化的合作双金属方法

• 批准号: EP/K001183/1
• 负责人: Robert Mulvey
• 金额: $ 39.91万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FK001183%2F1
• 关键词: Co; operative; Bimetallic; Approach; Transformation

Lithiation is one of best tools for building molecules big and small. Its application transcends chemistry and crosses over to other disciplines such as biochemistry and materials science. It offers an efficient direct way of breaking inert C-H bonds (ubiquitous in organic compounds) and transforming them into reactive C-Li bonds which in turn can be used to make a myriad of molecules, that mankind needs to sustain the quality of our daily lives. Organolithium tools find employment in academic laboratories worldwide and in the manufacture of many fine chemicals, in particular pharmaceuticals (it has been estimated that 95% of manufactured pharmaceuticals involve an organolithium tool in their preparation). The best known organolithium tool, butyllithium is near ubiquitous in synthetic chemistry, and its importance continues to escalate as evidenced by the fact that the chemical company FMC recently opened new butyllithium plants in Hyderabad (India) and Zhangjiagang (China) to service the rapidly expanding pharmaceutical business in the emerging BRIC (Brazil-Russia-India-China) economies. Because butyllithium can break numerous carbon-hydrogen bonds as well as performing other bond-breaking, bond-making tasks, it is widely used in drug development. Organolithium tools are also used to prepare other specialty chemicals such as agrochemicals, biochemicals, catalysts, dyes and perfumes. How to perfect C-H bond activation is one of the World's most pressing scientific grand challenges as new innovative ways must be found for converting cheap and abundant raw materials such as alkanes into precious functionalised organic compounds given the rapid depleting of fossil fuels. Despite its vast utility, lithiation, a direct form of C-H bond activation, suffers from severe limitations. A major limitation which puts a question mark against its long term sustainability is that it is exclusively a stoichiometric process. For example one mole of the organolithium tool is needed to make one mole of the target product. Moreover, lithiation often requires energy wasteful cryogenic conditions as well as ethereal solvents which are expensive and hazardous on a large scale. It also has many intrinsic chemical limitations including a poor tolerance of functional groups, a failure to react with weakly acidic C-H bonds, and incompatibility with subsequent transition metal catalysed bond-forming reactions.To transform lithiation into a substoichiometric process, ultimately developing it to a catalytic process is the ambitious goal of this project. For example, to use as little as 0.1 mole or less of the organolithium tool to make one mole of the target product. To reach this goal, the project will develop a new concept in bimetallic chemistry, synergistic stepwise metal - metal' co-operativity (basically two metals working one after the other in separate molecules) building on the successful, but wholly distinct foundation of synergic synchronised metal - metal' co-operativity (basically two metals working side-by-side in the same molecule) that the PI has recently pioneered. Initially a lithium-zinc co-operativity will be screened. Developing catalytic lithiation will be groundbreaking with direct chemical and economic benefits as well as indirect societal benefits given the long list of applications mentioned above. A library of interesting, useful new chemistry not currently possible in lithiation will emerge on the journey to achieving catalytic lithiation, including improved methods for direct C-H bond activation, new combined lithiation - Negishi coupling and other combined lithiation - transition metal bond forming strategies, reactions with high functional group tolerance, and "greener" processes using more environmentally friendly solvents and milder reaction conditions. Bonds impossible to break with existing organolithium tools will also be broken using new potassium based tools.

锂化是构建大小分子的最佳工具之一。它的应用超越了化学，并跨越到其他学科，如生物化学和材料科学。它提供了一种有效的直接方法来破坏惰性碳氢键（在有机化合物中无处不在），并将其转化为活性碳-锂键，而碳-锂键又可以用来制造无数分子，人类需要这些分子来维持我们的日常生活质量。有机锂工具在世界各地的学术实验室和许多精细化学品的生产中都有使用，特别是药品（据估计，95%的制药业在制备过程中使用有机锂工具）。作为最著名的有机锂工具，丁基锂在合成化学中几乎无处不在，而且其重要性还在不断提升，这一点可以从化学公司FMC最近在印度海得拉巴和中国张家港开设的新丁基锂工厂得到证明，以服务于新兴金砖四国（巴西-俄罗斯-印度-中国）经济中迅速扩张的制药业务。由于丁基锂可以破坏许多碳氢键，也可以执行其他断键、成键任务，因此被广泛用于药物开发。有机锂工具也用于制备其他特种化学品，如农用化学品、生物化学品、催化剂、染料和香水。如何完善C-H键活化是世界上最紧迫的科学挑战之一，因为必须找到新的创新方法，将廉价而丰富的原料（如烷烃）转化为珍贵的功能化有机化合物，因为化石燃料正在迅速枯竭。尽管用途广泛，但作为C-H键激活的一种直接形式，锂化受到了严重的限制。对其长期可持续性打上问号的一个主要限制是，它完全是一个化学计量过程。例如，需要一摩尔的有机锂工具来制造一摩尔的目标产品。此外，锂化通常需要能源浪费的低温条件以及昂贵且危险的大规模溶剂。它也有许多内在的化学限制，包括对官能团的耐受性差，不能与弱酸性的C-H键反应，以及与随后的过渡金属催化成键反应不相容。将锂化转变为亚化学计量过程，最终将其发展为催化过程是该项目的雄心勃勃的目标。例如，使用少至0.1摩尔或更少的有机锂工具来制造1摩尔的目标产品。为了实现这一目标，该项目将在PI最近开创的成功但完全不同的协同同步金属-金属合作（基本上是两种金属在同一个分子中并排工作）的基础上，开发双金属化学的新概念，即协同分步金属-金属合作（基本上是两种金属在同一个分子中并排工作）。最初将筛选锂锌合作项目。考虑到上面提到的一长串应用，开发催化锂化将具有直接的化学效益和经济效益，以及间接的社会效益。在实现催化锂化的过程中，将会出现一个有趣、有用的新化学库，包括直接激活C-H键的改进方法，新的组合锂化-根岸偶联和其他组合锂化-过渡金属键形成策略，具有高官能团耐受性的反应，以及使用更环保溶剂和更温和反应条件的“绿色”工艺。用现有的有机锂工具无法打破的化学键也可以用新的钾基工具打破。

项目成果

Silver-Free Palladium-Catalyzed C(sp3)-H Arylation of Saturated Bicyclic Amine Scaffolds.

• DOI: 10.1021/acs.joc.7b02665
• 发表时间: 2017-12
• 期刊: The Journal of organic chemistry
• 作者: C. Coomber;L. Benhamou;Dejan-Krešimir Bučar;Peter D. Smith;M. Porter;T. Sheppard

TMP (2,2,6,6-tetramethylpiperidide)-aluminate bases: lithium-mediated alumination or lithiation-alkylaluminium-trapping reagents?

• DOI: 10.1039/c4sc01108b
• 发表时间: 2014-01-01
• 期刊: CHEMICAL SCIENCE
• 影响因子: 8.4
• 作者: Armstrong, David R.;Crosbie, Elaine;Robertson, Stuart D.
• 通讯作者: Robertson, Stuart D.

Modifying Alkylzinc Reactivity with 2,2'-Dipyridylamide: Activation of t Bu?Zn Bonds for para -Alkylation of Benzophenone

用 2,2-联吡啶酰胺修饰烷基锌反应性：激活 t Bu?Zn 键以实现二苯甲酮的对位烷基化

• DOI: 10.1002/ange.201302426
• 发表时间: 2013
• 期刊: Angewandte Chemie
• 作者: Armstrong D

Revealing the remarkable structural diversity of the alkali metal transfer agents of the trans-calix[2]benzene[2]pyrrolide ligand.

揭示反式杯[2]苯[2]吡咯配体的碱金属转移剂的显着结构多样性。

• DOI: 10.1039/c6cc07240b
• 发表时间: 2016
• 期刊: Chemical communications (Cambridge, England)
• 作者: Fuentes MÁ

Modifying alkylzinc reactivity with 2,2'-dipyridylamide: activation of tBu-Zn bonds for para-alkylation of benzophenone.

• DOI: 10.1002/anie.201302426
• 发表时间: 2013-07-08
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Armstrong, David R.;Garden, Jennifer A.;Kennedy, Alan R.;Mulvey, Robert E.;Robertson, Stuart D.
• 通讯作者: Robertson, Stuart D.