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.

项目摘要 拟议的研究的主要目标是使用碳 - 氢气开发新的和有用的转换 键功能反应。使用C-H键作为可转换的官能团是有利的，因为 这些键通常是有机分子中最丰富的功能，也是大多数起始材料 在大规模上可用，仅包含碳碳和碳氢键。直接转换 这些与所需功能的键缩短了合成途径，可节省试剂，解决方案和劳动。 但是，明显的问题，例如烷烃SP3 C-H键的反应性低，难以达到 这些键的调节选择性功能化已阻止使用C-H功能化的宽度 方法论。我们的努力是针对在药物的背景下解决这些问题的 相关转换。特别是，该项目将重点放在辅助指导的Alkane C-H债券上 功能化和第11组金属催化的SP3 C-H键通过卡宾中间体功能化。我们 有大量的初步数据，显示拟议的化学是可行的，可能导致 有用的方法。 我们将开发用于SP3 C-H键功能化的第二代辅助设备，以取代 氨基喹啉指导小组并应对其剩余的挑战。具体而言，单次元素1- 氨基吡啶和吡唑衍生物将用于指导SP3 C-H键功能化。钥匙 与第一代辅助机构的差异更容易去除，缺乏或抑制产品，配体的可能性 加速催化，同时匹配氨基喹啉的出色指导能力和能力 在胺衍生物中官能化β-位。这些研究将具有重要的影响，并且已经 导致辅助辅助物用于SP3 C-H键的芳基化。 C-H键激活产生的反应 将完成当前C-C和C- Heteroatom键形成的方法，并将具有很大的 对合成方法的影响。 我们获得了初步结果，表明非导向组11金属催化的SP3 C-H键 用烷基重氮和氟化重氮化合物的功能化是可行的。这些独特的转换 使用其他方法可以轻松实现。新的催化剂应允许前所未有的晚期 药物相关分子的阶段功能。 研究的具体目的如下：1。定向C-H的新辅助和反应开发 功能化，2。对映选择性C-H键功能化，3。组11金属催化的C-H 通过卡宾类中间体的功能化。