Ti-Catalyzed Oxidative Amination Reactions

项目摘要 这项建议的目标是设计新的钛催化的氧化反应，以模块组装吡唑 衍生物和去功能化的炔烃。发展钛催化剂的基本原理是，钛是富含稀土的 通常无毒，在精细化学合成中不需要有效地移除和回收催化剂。 早过渡金属可以访问与晚过渡金属不同的结构和基本反应步骤， 从而形成与现有技术互补或正交的成键策略。 首先，拟议的研究涉及开发新的双催化策略来合成[2+2+1] 吡唑类药物。利用我们实验室获得的化学计量氧化诱导N-N还原的初步数据 在消除反应中，我们将探索单电子催化和光催化的氧化剂周转策略。 开发一种用于电负键偶联的催化策略，如N-N偶联，最终将导致 温和和通用的双催化剂系统，用于快速、模块化地构建高价值生物活性吡唑，以及 也为在催化中推进其他具有挑战性的键偶联反应开辟了道路。 此外，我们将设计选择性的炔碳胺化反应，建立在初步结果的基础上 反应课。炔碳胺化反应可生成亚氨基环丙烷和不饱和亚胺。 其中有价值的杂环构筑基团。我们的选择性反应设计策略将是使用ISPCA， 我们开发了一种新的统计分析方法，它有助于确定反应中的关键控制因素。 同时精制ISPCA和碳胺化催化将产生两者的综合实用 以及其他催化研究人员在设计选择性反应时可遵循的工具和路线图。 最后，我们将利用我们对钛氧化还原催化的机理洞察来设计新的多组份炔烃。 氧化反应。这项工作的一个关键重点将是开发将更多杂原子纳入到 产品，利用我们在双重催化和N-N还原消除方面的初步发现。这些反应 这将导致催化法快速生产富含官能团的碳支架。 与公共卫生的相关性。氮杂环构成了一类最普遍的官能团 FDA批准的小分子药物中的组：59%的独特小分子药物至少含有一种N- 杂环。吡唑类化合物是这类化合物中的重要一类，具有广泛的生物活性。虽然很多人 存在形成吡唑的反应，它们的合成通常依赖于使用潜在的有毒和爆炸性的联氨， 并具有公认的地区选择性限制。一种克服这些缺陷的吡唑类化合物的一般合成 限制是一个没有得到满足的挑战。通过设计方法将吡唑类化合物，以及更一般的催化类化合物 形成像N-N键这样的弱键，合成化学家将有机会快速和收敛地获得各种 和新颖的分子结构。这些积木将有助于开发新的小分子药物-- 就像生物医学社区的建筑一样。

Project Summary The goal of this proposal is to design new Ti-catalyzed oxidation reactions to modularly assemble pyrazole derivatives and difunctionalize alkynes. The rationale for developing Ti catalysis is that Ti is earth-abundant and generally nontoxic, which obviates the need for efficient catalyst removal and recovery in fine chemical synthesis. Early transition metals can access different structures and elementary reaction steps than late transition metals, resulting in bond forming strategies that are complementary or orthogonal to existing technology. First, the proposed research concerns developing new dual catalytic strategies for the [2+2+1] synthesis of pyrazoles. Using preliminary data gained in our laboratory on stoichiometric oxidation-induced N-N reductive elimination reactions, we will explore single-electron catalytic and photocatalytic strategies for oxidant turnover. Development of a catalytic strategy for electronegative bond couplings like N-N coupling will ultimately lead to mild and general dual catalyst systems for the rapid, modular construction of high-value bioactive pyrazoles, and also open avenues for advancing other challenging bond coupling reactions in catalysis. Further, we will design selective alkyne carboamination reactions, building off of preliminary results into this reaction class. Alkyne carboamination reactions can lead to iminocyclopropanes and unsaturated imines, each of which are valuable heterocycle building blocks. Our strategy for selective reaction design will be to use ISPCA, a new statistical analysis method we have developed that aids in determination of key control factors in a reaction. Concurrent refinement of ISPCA along with carboamination catalysis will yield both synthetically practical reactions, as well as a tool and roadmap for other catalysis researchers to follow in designing selective reactions. Finally, we will use our mechanistic insight of Ti redox catalysis to design new multicomponent alkyne oxidation reactions. A key focus of this work will be to develop strategies that incorporate more heteroatoms into the products, using our preliminary discoveries in dual catalysis and N-N reductive elimination. These reactions will result in catalytic methods to rapidly produce functional-group rich carbon scaffolds. Relevance to public health. Nitrogen heterocycles constitute the single most prevalent class of functional groups in FDA-approved small-molecule drugs: 59% of all unique small molecule drugs contain at least one N- heterocycle. Pyrazoles are an important class within this group, and have broad bioactivity. Although many reactions to form pyrazoles exist, their synthesis often relies on using potentially toxic and explosive hydrazines, and have well-established regioselectivity limitations. A general synthesis of pyrazoles that overcomes these limitations is an unmet challenge. By designing methods to pyrazoles, and more generally to the catalytic formation of weak bonds like N-N bonds, synthetic chemists will have rapid and convergent access to diverse and novel molecular architectures. These building blocks will aid in the development of new small molecule drug- like architectures for the biomedical community.