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.

项目概要该提案的目标是设计新的钛催化氧化反应来模块化组装吡唑衍生物和双官能化炔烃。开发Ti催化的基本原理是Ti在地球上储量丰富且储量丰富。通常无毒，这消除了精细化学合成中有效去除和回收催化剂的需要。早期过渡金属可以获得与晚期过渡金属不同的结构和基元反应步骤，产生与现有技术互补或正交的键形成策略。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。使用我们实验室获得的化学计量氧化诱导 N-N 还原的初步数据消除反应，我们将探索氧化剂周转的单电子催化和光催化策略。开发 N-N 耦合等电负性键耦合催化策略将最终导致用于快速、模块化构建高价值生物活性吡唑的温和和通用双催化剂系统，以及还为推进催化中其他具有挑战性的键偶联反应开辟了道路。此外，我们将根据初步结果设计选择性炔烃碳胺化反应反应类。炔烃碳胺化反应可产生亚氨基环丙烷和不饱和亚胺，每种其中是有价值的杂环结构单元。我们的选择性反应设计策略是使用 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 与碳胺化催化的同时改进将产生综合实用的结果反应，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，我们将利用对 Ti 氧化还原催化机理的洞察来设计新的多组分炔烃氧化反应。这项工作的一个重点是开发将更多杂原子纳入其中的策略产品，利用我们在双重催化和 N-N 还原消除方面的初步发现。这些反应将产生快速生产富含官能团的碳支架的催化方法。与公共卫生的相关性。氮杂环构成了最普遍的一类官能团 FDA 批准的小分子药物中的组：所有独特小分子药物中 59% 至少含有一种 N- 杂环。吡唑类化合物是该类化合物中的一类重要化合物，具有广泛的生物活性。虽然很多存在形成吡唑的反应，其合成通常依赖于使用具有潜在毒性和爆炸性的肼，并具有明确的区域选择性限制。克服这些问题的吡唑类化合物的通用合成局限性是一个尚未解决的挑战。通过设计吡唑的方法，更一般地说是催化的方法形成像 N-N 键这样的弱键，合成化学家将能够快速、集中地获得不同的和新颖的分子结构。这些构建模块将有助于开发新的小分子药物就像生物医学界的架构一样。

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）

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

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

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

Ti-Catalyzed Multicomponent Oxidative Carboamination of Alkynes with Alkenes and Diazenes.