Catalysts Bearing Traceless Tethers for Single Step Meta and Para C-H Functionalization

用于单步间位和对位 C-H 官能化的带有无痕系链的催化剂

• 批准号: 9809929
• 负责人: Timothy Brewster
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809929
• 关键词: Acids; Address; Aldehydes; Amines; Anthelmintics; Benzaldehyde; Benzylamines; Communicable Diseases; Complex; Coupling; Development; Docking; Ensure; Hand; Hydrogen Bonding; Individual; Kinetics; Ligands; Methodology; Methods; Molecular Conformation; Nature; One-Step dentin bonding system; Organic Chemistry; Organic Synthesis; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Prevalence; Production; Protocols documentation; Public Health; Reaction; Route; System; Testing; Time; Transition Elements; Waste Products; Water; Work; base; catalyst; combat; cost; cost effective; design; flexibility; functional group; halogenation; improved; new therapeutic target; prospective; reaction rate; salicylanilide; small molecule; tool; wasting

Project Summary/Abstract Rapid development of new target drugs, essential to the improvement of public health, is reliant on the ability to efficiently synthesize a wide range of organic molecules, commonly substituted arenes. Regioselective derivatization of aromatic substrates is most commonly accomplished using cross-coupling reactions. Unfortunately, regioselectivity is attained at the expense of stoichiometric quantities of various, often toxic, waste products. To decrease the need for costly separation associated with current synthetic practices, direct functionalization of C-H bonds provides a promising, atom-economical alternative. However, controlling reaction selectivity becomes challenging due to the large number of energetically similar C-H bonds in any given arene substrate. While “directed activation” strategies are now well-known to provide selective ortho-functionalization of substituted arenes, analogous one-step directed functionalization of arenes at meta- and para- C-H bonds has remained elusive. In this project, catalysts will be developed which allow for direct, one-step, meta- and para- C-H functionalization of benzaldehydes and benzylamines. Developed systems will rely on ligand “tethers” which will dock and orient the substrate molecule in such a way that kinetically favors reaction at the desired C-H bond. In principle, the methodology developed could be used to selectively functionalize ANY C-H bond in ANY molecule that contains an aldehyde or amine functional group. This extremely powerful contribution to the field of synthetic organic chemistry has the potential to revolutionize pharmaceutical synthesis. Three specific aims have been developed to further guide the proposed work. (1) Design and synthesis of tether ligands. Designed ligands must serve to both dock and orient the substrate in the proper manner for regioselective functionalization. Ligands will be designed computationally to ensure that the geometrical parameters for proper orientation are met. (2) Synthesis and stability of organometallic complexes bearing ligand tethers. With ligands in hand, the synthesis of palladium complexes will be undertaken. Eventual catalytic conditions will require the presence of both acid and water. The stability of our prospective catalysts under these conditions will be evaluated. (3) Catalyst testing and substrate scope. Complexes will be evaluated for their ability to facilitate C-H functionalization based on reaction rate and regioselectivity. Functional group tolerance will also be explored. In the long term we will work to extend our “tether” methodology to additional pharmaceutically relevant substrate classes.

项目总结/摘要 新靶向药物的快速开发对改善公众健康至关重要， 有效合成各种有机分子的能力，通常被取代 芳烃。芳香族底物的区域选择性衍生化是最常用的方法 使用交叉偶联反应。不幸的是，区域选择性是以牺牲 化学计量的各种各样的，通常是有毒的废物。为了减少昂贵的 与当前合成实践相关的分离，C-H键的直接官能化 提供了一个有前途的，原子经济的替代方案。然而，控制反应选择性 由于在任何给定的分子中存在大量能量相似的C-H键， 芳烃底物虽然“定向激活”策略现在众所周知提供选择性激活， 取代芳烃的邻位官能化，类似的一步定向官能化， 芳烃的Meta位和帕拉C-H键仍然难以捉摸。在这个项目中，催化剂将 开发了允许直接，一步，Meta位和帕拉- C-H官能化的 苯甲醛和苄胺。已开发的系统将依赖于配体“系链”， 对接并定向底物分子，使其在动力学上有利于在 所需的C-H键原则上，所制定的方法可用于有选择地 使含有醛或胺官能团的任何分子中的任何C-H键官能化 组这对合成有机化学领域的巨大贡献 有可能彻底改变药物合成。 为进一步指导拟议的工作，制定了三个具体目标。(1)设计与 系链配体的合成。设计的配体必须用于对接和定向 以适当的方式在基底上进行区域选择性官能化。配体将被设计为 以确保满足用于适当取向的几何参数。（二） 含配体链的有机金属配合物的合成与稳定性。与配体 在这方面，将进行钯配合物的合成。最终催化条件 将需要酸和水两者的存在。我们未来催化剂的稳定性 将对这些条件进行评估。(3)催化剂测试和底物范围。复合物将 基于反应速率评估它们促进C-H官能化的能力， 区域选择性还将探索官能团耐受性。从长远来看， 将我们的“系链”方法扩展到其他药学相关的底物类别。