Ti-Catalyzed Oxidative Amination Reactions

Ti 催化的氧化胺化反应

基本信息

批准号：
10624236
负责人：
Ian Albert Tonks
金额：
$ 39.32万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2026-05-31
项目状态：
未结题

项目摘要

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.

项目摘要该提案的目的是设计新的Ti催化氧化反应以组装吡唑衍生物并扩散炔烃。开发TI催化的理由是Ti是土壤丰富的，并且通常是无毒的，这消除了精细化学合成中有效去除和恢复的有效催化剂的需求。早期过渡金属可以访问不同的结构和基本反应步骤，而不是晚过渡金属，导致形成与现有技术互补或正交的债券形成策略。首先，拟议的研究涉及为[2+2+1]合成新的双重催化策略吡唑唑。使用在化学计量学诱导的N-N还原性的实验室中获得的初步数据消除反应，我们将探索氧化剂更新的单电子催化和光催化策略。开发用于n-n偶联等电负键耦合的催化策略，最终将导致轻度和一般的双催化剂系统，用于快速，模块化的高价值生物活性吡唑和还开放了推进催化中其他具有挑战性的键耦合反应的途径。此外，我们将设计有选择的炔烃碳水化合物反应，以初步结果为基础反应类别。炔烃碳水化的反应会导致亚米诺cl豆豆植物和不饱和丙糖，每种其中是有价值的杂环构建块。我们选择性反应设计的策略将是使用ISPCA，我们开发了一种新的统计分析方法，有助于确定反应中的关键控制因素。 ISPCA以及碳水化催化的同时完善将产生合成的实用性反应，以及其他催化研究人员在设计选择性反应时遵循的工具和路线图。最后，我们将利用Ti氧化还原催化的机械洞察力来设计新的多组分目标氧化反应。这项工作的重点是制定策略，将更多的杂原子纳入这些产品使用我们在双重催化和N-N还原性消除方面的初步发现。这些反应将导致催化方法快速产生富含功能群的碳支架。与公共卫生有关。氮杂环构成了最普遍的功能类 FDA批准的小分子药物中的组：在所有独特的小分子药物中，有59％至少含有一个N- 杂环。吡唑是该组中的重要阶级，并且具有广泛的生物活性。虽然很多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夹层，并具有良好的区域选择性限制。吡唑的一般合成，使这些限制是未满足的挑战。通过将方法设计到吡唑，更一般地催化弱键的形成如N-N键，合成化学家将具有快速而收敛的访问权限和新颖的分子体系结构。这些构建块将有助于开发新的小分子药物 - 就像生物医学界的体系结构一样。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cp2Ti(II) Mediated Rearrangement of Cyclopropyl Imines.

DOI：
10.1021/acs.organomet.3c00032
发表时间：
2023-03
期刊：
Organometallics
影响因子：
2.8
作者：
Jaekwan Kim;Dominic T. Egger;C. Frye;Evan P. Beaumier;Ian A. Tonks
通讯作者：
Jaekwan Kim;Dominic T. Egger;C. Frye;Evan P. Beaumier;Ian A. Tonks

Synthesis of Ti Complexes Supported by an ortho-terphenoxide Ligand and their Applications in Alkyne Hydroamination Catalysis.

邻三苯酚配体负载的钛配合物的合成及其在炔烃氢氨化催化中的应用。

DOI：
10.1021/acs.organomet.2c00593
发表时间：
2023
期刊：
Organometallics
影响因子：
2.8
作者：
Butler,StevenK;Ashbrook,EthanP;Tonks,IanA
通讯作者：
Tonks,IanA

Iterative Supervised Principal Component Analysis Driven Ligand Design for Regioselective Ti-Catalyzed Pyrrole Synthesis.

DOI：
10.1021/acscatal.0c03939
发表时间：
2020-11-20
期刊：
ACS catalysis
影响因子：
12.9
作者：
See XY;Wen X;Wheeler TA;Klein CK;Goodpaster JD;Reiner BR;Tonks IA
通讯作者：
Tonks IA

Ti-catalyzed ring-opening oxidative amination of methylenecyclopropanes with diazenes.

DOI：
10.1039/d0sc01998d
发表时间：
2020-06-23
期刊：
Chemical science
影响因子：
8.4
作者：
Beaumier EP;Ott AA;Wen X;Davis-Gilbert ZW;Wheeler TA;Topczewski JJ;Goodpaster JD;Tonks IA
通讯作者：
Tonks IA

Multicomponent syntheses of 5- and 6-membered aromatic heterocycles using group 4-8 transition metal catalysts.