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Synthesis of Partially Saturated Nitrogen Heterocycles Through Stereo- And Regioselective Dearomatization of Heteroarenes

通过杂芳烃的立体和区域选择性脱芳构化合成部分饱和氮杂环

基本信息

批准号：
10672398
负责人：
Rashad Karimov
金额：
$ 37.41万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-06-30
项目状态：
未结题

项目摘要

Synthesis of partially saturated nitrogen heterocycles through stereo- and regioselective dearomatization of heteroarenes. Nitrogen-containing heterocycles are important in multiple areas of chemistry including pharmaceutical, agrochemical and materials science due to their chemical properties and biological significance. These heterocycles are often grouped as aromatic and non-aromatic heterocycles. Aromatic heterocycles are widely available and recent advances in various cross coupling and C-H activation chemistry have further improved the access to these heterocycles. On the other hand, methods for the synthesis of non-aromatic heterocycles which often contain stereogenic centers at sp3 hybridized carbon centers are less developed. Our long-term goal is to develop new chemical transformations that will regio-, and stereoselectively introduce functionality into the heteroarenes to enable synthesis of partially saturated nitrogen heterocycles. Partially saturated heterocycles are excellent precursors to both aromatic and non-aromatic azaheterocycles. For example, dihydropyridines can be functionalization or reduced to yield tetrahydropyridines and piperidines and they can be oxidized to yield pyridines. The current proposal addresses the regioselective, stereoselective and catalytic addition of nucleophiles and electrophiles to the heteroarenes for the synthesis of partially saturated six- membered azaheterocycles. Specifically, we propose methodologies supported by significant preliminary results and literature precedents for the transition metal catalyzed dearomatization reactions of heteroarenes focusing on the regioselective dearomatization of six-membered heteroarenes containing one or two nitrogen atoms. Dearomatization approaches proposed by us include Rh, Pd, Ni and Cu catalyzed addition of boron nucleophiles as well as addition of organometallic nucleophiles to activated N-alkyl and N-acyl heteroarenes. In addition to coupling of nucleophiles, we propose dearomative coupling of heteroarenium salts with electrophiles using Ni-photoredox system. Catalyst design approaches for controlling the regio- and stereoselectivity of the addition reactions will also be explored. Methods described by us are innovative as they involve previously unexplored approaches, coupling partners and catalysts. The results obtained from these studies will be significant as the saturated and partially saturated heterocycles are common structural motifs in bioactive natural products and pharmaceuticals.

通过立体和区域选择性合成部分饱和氮杂环杂芳烃的脱芳构化。含氮杂环在化学的多个领域都很重要，包括制药、农业化学和材料科学由于其化学性质和生物学意义。这些杂环通常分为芳香族和非芳香族杂环。芳香杂环化合物广泛存在，并且在各种交叉领域取得了最新进展偶联和C-H活化化学进一步改善了这些杂环的获取。另一方面，通常含有非芳香杂环的合成方法 sp3杂化碳中心的立体中心不太发达。我们的长期目标是开发新的化学转化，以区域和立体选择性地将功能引入杂芳烃中，以实现部分合成饱和氮杂环。部分饱和杂环是两者的优良前体芳香族和非芳香族氮杂环。例如，二氢吡啶可以是官能化或还原生成四氢吡啶和哌啶，它们可以被氧化产生吡啶。目前的提案涉及区域选择性、立体选择性和催化加成亲核试剂和亲电试剂与杂芳烃的合成，用于合成部分饱和的六- 成员氮杂杂环。具体来说，我们提出了由重要支持的方法论过渡金属催化脱芳构化的初步结果和文献先例杂芳烃反应重点关注六元化合物的区域选择性脱芳构化含有一个或两个氮原子的杂芳烃。提出的脱芳构化方法我们包括 Rh、Pd、Ni 和 Cu 催化硼亲核试剂的加成以及有机金属亲核试剂活化的 N-烷基和 N-酰基杂芳烃。除了耦合之外对于亲核试剂，我们提出使用以下方法将杂芳鎓盐与亲电子试剂进行脱芳香偶联： Ni-光氧化还原系统。控制区域选择性和立体选择性的催化剂设计方法还将探讨加成反应。我们描述的方法具有创新性，因为它们涉及以前未探索过的方法、耦合伙伴和催化剂。从这些研究中获得的结果将是重要的是饱和和部分饱和的杂环是常见的结构基序生物活性天然产物和药物。