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的部分饱和氮杂环合成杂种的亲爱的。含氮的杂环在化学的多个领域很重要由于其化学特性，药物，农化学和材料科学生物学意义。这些杂环通常被分组为芳香和非芳香族杂环。芳族杂环广泛可用，并且在各种十字架上的最新进展耦合和C-H激活化学进一步改善了对这些杂环的访问。另一方面，合成非芳族异环的方法通常包含 SP3杂交碳中心的立体源性中心的发达较少。我们的长期目标是开发新的化学转化，这些化学转化将会进行区分，并立体选择性将功能引入杂烯烯，以启用部分合成饱和的氮杂环。部分饱和的杂环是两者的绝佳前体芳族和非芳香族曲霉。例如，二氢吡啶可以是功能化或减少以产生四氢吡啶和哌啶，它们可以被氧化产生吡啶。当前的建议涉及区域性选择性，立体选择性和催化添加亲核者和亲电的杂种，以合成部分饱和的六个成员Azaheterocycles。具体而言，我们提出了由重要的方法支持的方法过渡金属催化的亲爱的尊敬的初步结果和文献先例杂种元素的反应，重点是六元的区域性选择性尊敬含有一个或两个氮原子的杂种。尊敬的方法提出的方法美国包括RH，PD，NI和CU催化硼核菌的添加以及添加有机金属亲核试剂，可激活的N-烷基和N-酰基杂种。除了耦合在亲核试剂中，我们提出了杂含盐盐与电力的亲爱的偶联 Ni-Photoredox系统。控制区域和立体选择性的催化剂设计方法还将探讨加法反应中的。我们描述的方法是创新的，因为它们涉及以前未经探索的方法接近，耦合伙伴和催化剂。从这些研究获得的结果将是显着，因为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品和药品。