New Methods for Direct Carbon-Hydrogen Bond Functionalization

直接碳氢键功能化的新方法

• 批准号: 9376480
• 负责人: Olafs Daugulis
• 金额: $ 29.94万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-05 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9376480
• 关键词: Address; Alkanes; Alkylation; Amination; Amines; Aminopyridines; Aminoquinolines; Carbon; Catalysis; Chemistry; Complement; Data; Development; Excision; Generations; Goals; Hydrogen Bonding; Lead; Ligands; Medicine; Metals; Methodology; Methods; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Production; Pyrazoles; Reaction; Reagent; Research; Savings; Solvents; Testing; Transition Elements; analog; base; carbene; catalyst; cost; design; diazo compound; drug synthesis; functional group; prevent

PROJECT SUMMARY The main goal of the proposed research is to develop new and useful transformations using carbon-hydrogen bond functionalization reactions. Use of C-H bonds as a transformable functional group is advantageous since these bonds are typically the most abundant functionality in organic molecules, and most starting materials that are available on large scale contain only carbon-carbon and carbon-hydrogen bonds. Direct conversion of these bonds to the desired functionality shortens synthetic pathways saving reagents, solvents, and labor. However, obvious problems, such as low reactivity of alkane sp3 C-H bonds and difficulty to attain regioselective functionalization of these bonds, have prevented widespread use of C-H functionalization methodology. Our efforts are directed towards addressing these issues in the context of pharmaceutically relevant transformations. Specifically, the project will focus on the auxiliary-directed alkane C-H bond functionalization and group 11 metal-catalyzed sp3 C-H bond functionalization via carbene intermediates. We have a substantial amount of preliminary data showing that proposed chemistry is viable and may lead to useful methodology. We will develop second-generation auxiliaries for sp3 C-H bond functionalization that will replace aminoquinoline directing group and address its remaining challenges. Specifically, monodentate 1- aminopyridine and pyrazole derivatives will be used to direct sp3 C-H bond functionalization. The key difference from first-generation auxiliaries is easier removal, lack or product inhibition, possibility of ligand- accelerated catalysis while matching the outstanding directing abilities of aminoquinoline, and ability to functionalize β-positions in amine derivatives. These studies will have important implications, and have already resulted in superior auxiliaries for arylation of sp3 C-H bonds. The reactions arising from C-H bond activation will complement the current methods for C-C and C-heteroatom bond formation and will have a substantial impact on synthetic methodology. We have obtained preliminary results showing that non-directed group 11 metal-catalyzed sp3 C-H bond functionalization with alkyl diazo and fluorinated diazo compounds is feasible. These unique transformations cannot be easily achieved by using other methodology. The new catalysts should allow for unprecedented late- stage functionalization of medicinally relevant molecules. The specific aims of the research are as follows: 1. New auxiliary and reaction development for directed C-H functionalization, 2. Enantioselective C-H bond functionalization, 3. Group 11 metal-catalyzed C-H functionalization via carbenoid intermediates.

项目概要 拟议研究的主要目标是利用碳氢开发新的有用的转化 使用C-H键作为可转化官能团是有利的，因为 这些键通常是有机分子中最丰富的官能团，也是大多数起始材料 可以大规模地仅含有碳-碳和碳-氢键的直接转化。 这些与所需功能的键合缩短了合成途径，节省了试剂、溶剂和劳动力。 但烷烃sp3 C-H键反应活性低、难以获得等明显问题 这些键的区域选择性功能化阻碍了 C-H 功能化的广泛使用 我们的努力旨在在药学背景下解决这些问题。 具体来说，该项目将重点关注辅助定向烷烃C-H键。 通过卡宾中间体进行官能化和 11 族金属催化的 sp3 C-H 键官能化。 有大量初步数据表明所提出的化学方法是可行的并且可能导致 有用的方法论。 我们将开发用于 sp3 C-H 键功能化的第二代助剂，以取代 氨基喹啉指导基团并解决其剩余的挑战，特别是单齿 1-。 氨基吡啶和吡唑衍生物将成为直接sp3 C-H键功能化的关键。 与第一代助剂的区别是更容易去除、缺乏或产物抑制、配体-的可能性 加速催化，同时与氨基喹啉出色的定向能力相匹配，并且能够 这些研究将具有重要意义，并且已经产生了作用。 产生了用于 sp3 C-H 键芳基化的优异助剂，由 C-H 键活化引起的反应。 将补充目前的 C-C 和 C-杂原子键形成方法，并将具有实质性 对合成方法的影响。 我们获得的初步结果表明非定向11族金属催化的sp3 C-H键 用烷基重氮化合物和氟化重氮化合物进行官能化是可行的。 使用其他方法无法轻松实现，新的催化剂应该允许前所未有的后期。 医学相关分子的阶段功能化。 具体研究目标如下： 1. 定向C-H新助剂及反应开发 功能化，2. 对映选择性 C-H 键功能化，3. 第 11 族金属催化的 C-H 通过类胡萝卜素中间体进行功能化。