Transition Metal Catalyzed Routes to N-Heterocycles

过渡金属催化制备 N-杂环化合物的路线

• 批准号: 8887343
• 负责人: JANIS LOUIE
• 金额: $ 26.82万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887343
• 关键词: Address; Alkynes; Area; Azocines; Biological Factors; Carbon; Chemistry; Cods; Coupling; Cyanamide; Development; Dust; FDA approved; Felis catus; Future; Health; Heterocyclic Compounds; Mediating; Methods; One-Step dentin bonding system; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Protocols documentation; Pyrimidine; Pyrimidines; Reaction; Research; Route; Side; System; Transition Elements; azetidinone; base; carbonyl group; catalyst; cycloaddition; pharmacophore; piperidine; programs; pyridine; rapid technique; small molecule

DESCRIPTION (provided by applicant): N-Heterocycles serve as a core to a many of biologically active pharmacophores. O f t h e 181 small molecule drugs that were approved by the FDA in the last 10 years, 51% i n c o r p o r a t e a 6 - m e m b e r e d N - h e t e r o c y cl e s t r u c t u r e. Of these 92 compounds, 25% comprise a pyridine, 22% comprise a pyrimidine, and 20% comprise a piperidine. Clearly, new and efficient methods to prepare N-heterocycles would have an enormous impact on the synthesis of current and future pharmaceuticals. To address the challenges of N-heterocycle synthesis, we chose to build a research program centered around the development of a general Ni-based cycloaddition catalyst system because 1) cycloaddition of unsaturated compounds, a reaction that provides an ideal, atom- efficient entry to ring systems, 2) mechanistically, heteroatom incorporation and concurrent inhibition of side product formation seemed more tangible for the Ni system; and 2) stoichiometric oxidative coupling reactions suggested that Ni may have a higher reactivity (and therefore more generality) than the traditional Co and existing Rh and Ru systems. We have since expanded our focus to include the development of new Fe based cycloaddition catalysts, which we have found to have complimentary reactivities compared to current catalytic systems. This proposal outlines our continuing efforts and encompasses the preparation N-heterocyclic compounds, not previously synthesized through cycloaddition chemistry, from environmentally friendly and readily available starting materials. Specifically, we seek 1) to expand Ni-catalyzed cycloadditions of azacyclobutanones, 2) develop new Fe cycloaddition catalysts for the preparation of pyrimidines, and 3) develop toolbox of catalysts that regioselectively couple alkynes and cyanamides to afford pyridines.

描述（由申请人提供）：N-杂环是许多生物活性药理的核心。在过去的10年中，FDA批准的181个小分子药物，51％i n c o r p o r p o r a t e a 6 -m e m e r e r e d n -h e d n -h e t e r o c y c y c y c y c y c y c y c y c y c y c y c y c y s t r c t u c t u r e r e。在这92种化合物中，有25％的化合物包括吡啶，22％构成嘧啶，而20％构成哌啶。显然，制备N型型物体的新的有效方法将对当前和未来药物的合成产生巨大影响。为了应对N-杂环合成的挑战，我们选择建立一个围绕开发基于Ni的Cycloadition Catalyst系统的研究计划，因为1）对不饱和化合物的环加成，这种反应提供了一种理想的，有效地对环系统的原子，2）机械，杂质融合和侧面的构成系统的构成，是更多的构成的构成。 2）化学计量氧化耦合反应表明，与传统的CO和现有的RH和RU系统相比，Ni的反应性可能更高（因此更通用性）。从那以后，我们将重点扩大到包括新的基于FE的环加成催化剂的开发，我们发现与当前的催​​化系统相比，我们发现它们具有免费反应性。该提案概述了我们的持续努力，并涵盖了从环保且易于使用的起始材料中的制备N-异环化合物，以前未通过环加成化学合成。具体而言，我们寻求1）扩大偶氮周期素的Ni催化环加成，2）开发新的Fe Cycloclatition催化剂来制备嘧啶，3）开发催化剂的工具箱，这些催化剂的工具箱可在区域选择性上对炔烃和Cyanamides夫妇和Cyanamides进行pyridines的负担。