Catalytic C-H Activation of Aliphatic Amines

脂肪胺的催化 C-H 活化

• 批准号: EP/N031792/1
• 负责人: Matthew Gaunt
• 金额: $ 81.9万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FN031792%2F1
• 关键词: Catalytic; Activation; Aliphatic; Amines

Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods available for the synthesis of this important feature is surprisingly small. Methods such as reductive amination, alkylative tactics, hydroamination and transamination have met the demand for many years, however the development of new straightforward methods for the synthesis of complex systems is essential for the continued advance of synthesis. A systematic method for the synthesis of complex aliphatic amines would be valuable to practitioners of drug discovery, and a streamlined approach to these molecules could involve a catalytic process capable of transforming simple, readily available aliphatic amines into complex variants via selective functionalization of their C-H bonds.Methods that enable the practical and selective functionalization of inert aliphatic C-H bonds have applications in fields that range from fine chemical production to drug discovery. Transition metal catalysis has emerged as a powerful tool to activate these traditionally unreactive C-H bonds. Several classes of functional group can direct C-H activation via a process called cyclometallation; coordination of the metal centre to a proximal Lewis basic atom steers the catalyst into position where the C-H bond can be cleaved. Reaction of the resulting C-metal bond with an external reagent leads to an overall transformation that sees a C-H bond converted into a versatile motif. Cyclometallation has led to a number of useful catalytic C-H functionalization processes that have expanded the chemists toolbox of available reactions; tailoring the electronic properties of directing functionalities has enabled cyclometallation in aliphatic hydrocarbons displaying carboxylic acid, hydroxyl groups, and derivatives of these motifs. Despite these advances, related transformations on aliphatic amines are rare and successful examples require the use of strongly electron withdrawing sulfonyl or bespoke directing groups to modulate the metal coordinating power of the nitrogen atom. As such, their synthetic intractability frequently precludes the wider application of strategic C-H bond activation in aliphatic amine systems.The overarching aim of this proposal is to establish aliphatic amines as viable feedstock molecules for C-H activation using a novel activation strategy. This will provide distinct C-H disconnections that will form part of a C-H activation road map for synthesis. The aliphatic amine motif is so ubiquitous in pharmaceutically relevant molecules that it is considered a 'privileged' feature and so we will investigate how the multi-faceted C-H activation platform can be translated into viable applications that have impact drug discovery and development.

脂肪胺对于许多生物活性分子的功能至关重要，其在大量药剂中的普遍存在就证明了这一点。附加在这些氮原子上的基团在决定胺的物理性质方面至关重要，并且与它与生物靶标的相互作用有关。尽管脂肪胺基序明显简单，但可用于合成这一重要特征的一般方法的数量惊人地少。诸如还原胺化、烷基化策略、氢胺化和转胺化等方法已经满足了多年的需求，然而开发用于合成复杂体系的新的直接方法对于合成的持续进步是必不可少的。合成复杂脂肪胺的系统方法对于药物发现的从业者将是有价值的，并且这些分子的流线型方法可能涉及能够将简单的，本发明提供了能够将惰性脂族C-H键的实际和选择性官能化的方法，氢键在从精细化学品生产到药物发现的各个领域都有应用。过渡金属催化剂已经成为激活这些传统上不反应的C-H键的有力工具。几类官能团可以通过称为环金属化的过程来引导C-H活化;金属中心与邻近的刘易斯碱性原子的配位将催化剂引导到C-H键可以断裂的位置。所得的C-金属键与外部试剂的反应导致整体转化，将C-H键转化为多功能基序。环金属化已经导致了许多有用的催化C-H官能化过程，这些过程已经扩展了化学家可用反应的工具箱;定制定向官能团的电子性质已经使环金属化能够在脂肪烃中显示羧酸、羟基和这些基序的衍生物。尽管有这些进展，脂肪胺上的相关转化是罕见的，并且成功的例子需要使用强吸电子磺酰基或定制的导向基团来调节氮原子的金属配位能力。因此，他们的合成棘手性经常排除了更广泛的应用战略C-H键活化脂肪胺systems.The总体目标的建议是建立脂肪胺作为可行的原料分子C-H活化使用一种新的活化策略。这将提供不同的C-H断开，其将形成用于合成的C-H活化路线图的一部分。脂肪胺基序在药学相关分子中如此普遍，以至于它被认为是一种“特权”特征，因此我们将研究如何将多方面的C-H活化平台转化为影响药物发现和开发的可行应用。

项目成果

Palladium(II)-Catalyzed C(sp3)-H Activation of N,O-Ketals towards a Method for the ß-Functionalization of Ketones

钯 (II) 催化 N,O-缩酮的 C(sp3)-H 活化，用于酮的 α-功能化方法

• DOI: 10.17863/cam.37718
• 发表时间: 2019
• 作者: Gaunt M

Streamlined Synthesis of C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

可见光介导光催化简化富 C(sp3) N-杂螺环的合成

• DOI: 10.17863/cam.43931
• 发表时间: 2019
• 作者: Flodén N

Carboxylate-assisted oxidative addition to aminoalkyl-Pd(II) complexes enables catalyzed C(sp3)-H arylation of alkylamines via distinct Pd(II)/Pd(IV) pathway

氨基烷基-Pd(II) 配合物的羧酸盐辅助氧化加成能够通过不同的 Pd(II)/Pd(IV) 途径催化烷基胺的 C(sp3)-H 芳基化

• DOI: 10.17863/cam.39664
• 发表时间: 2019
• 作者: Gaunt M