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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.

立体选择性和区域选择性合成部分饱和氮杂环化合物杂芳烃的脱芳构化。含氮杂环在多个化学领域中是重要的，包括由于其化学性质，生物学意义这些杂环通常分为芳族和非芳族杂环芳香杂环化合物是广泛存在的，并且各种杂环化合物的最新研究进展偶联和C-H活化化学进一步改善了对这些杂环的利用。另一方面，用于合成非芳族杂环的方法通常包含： sp3杂交碳中心的立体中心较不发达。我们的长期目标是开发新的化学转化，立体选择性地将官能团引入杂芳烃中，以能够合成部分的饱和氮杂环。部分饱和的杂环是这两种化合物的优良前体。芳族和非芳族氮杂杂环。例如，二氢吡啶可以是官能化或还原以产生四氢吡啶和哌啶，并且它们可以被氧化以产生吡啶。目前的建议涉及区域选择性，立体选择性和催化加成亲核试剂和亲电试剂与杂芳烃反应合成部分饱和的六元- 元氮杂杂环。具体而言，我们提出了由重要的过渡金属催化脱芳烃反应的初步结果和文献先例杂芳烃的反应，重点是六元环的区域选择性脱芳构化，含有一个或两个氮原子的杂芳烃。提出的脱芳方法包括Rh、Pd、Ni和Cu催化的硼亲核试剂的加成以及有机金属亲核试剂转化为活化的N-烷基和N-酰基杂芳烃。除了耦合的亲核试剂，我们提出了杂芳烃盐与亲电试剂的脱芳偶联， Ni光氧化还原体系控制区域和立体选择性的催化剂设计方法也将探讨加成反应。我们所描述的方法是创新的，因为它们涉及以前未探索的方法、耦合伙伴和催化剂。这些研究的结果将重要的是，饱和和部分饱和的杂环是生物活性天然产物和药物。