Development of Rhodium Catalysts for Alkene Hydroamination

描述（由申请人提供）：生物活性分子、活性药物成分及其结构单元中普遍存在胺。烯烃加氢胺化反应，形式上是在不饱和碳-碳键上添加N-H键，代表了从简单烯烃起始原料合成胺的有效、实用和原子经济的方法。在过去的几十年里，在开发该反应方面取得了重大进展;然而，具有广泛官能团耐受性的未活化烯烃的分子间氢胺化的通用且可靠的方法仍然难以捉摸。提出的研究概述了一种策略，对未活化烯烃的氢胺化铑催化剂的发展。具体目标是：1）合成，分离，并表征铑催化剂含有一个？6-与磷或氮供体相连的芳烃。一系列膦基烷基芳烃和吡啶基烷基芳烃配体将被合成并转化为相应的铑配合物，用于随后的氢胺化研究中的评估。2)检测作为具体目标1的一部分制备的催化剂，用于当前系统不催化的分子内和分子间氢化胺化。将被研究的底物包括1，1-和1，2-二取代的氨基烯烃，其在烷基链上缺乏用于分子内氢化胺化的偕二取代，以及用于分子间反应的未活化的烯烃，如1-戊烯。3)揭示目标1的铑配合物催化氢胺化反应的机理信息。很难预测目标1的配合物催化的反应中的限制转化率的步骤是否是对配位烯烃的亲核攻击或烷基铑中间体的质子分解。为了解决这个问题，机理研究将集中在识别和分离的关键alkylrhodium中间体从胺加成到配位烯烃，并研究该中间体对质子酸的反应性。4)发展对映选择性氢胺化反应，这是一个长期的目标。手性铑配合物含有目标1的配合物的结构核心将被调查的对映选择性氢胺化的发展。公共卫生相关性：对于市场上的每一种药物，作为药物发现计划的一部分，合成了数千种化合物。随着用于合成生物活性分子的新颖且有效的方法的发展，将更快地发现用于治疗疾病的新药。

DESCRIPTION (provided by applicant): The presence of amines in biologically active molecules, active pharmaceutical ingredients, and their building blocks is widespread. The alkene hydroamination reaction, formally the addition of an N-H bond across an unsaturated carbon-carbon bond, represents an efficient, practical and atom-economical method for the synthesis of amines from simple alkene starting materials. Significant advances have been made over the past few decades in developing this reaction; however, a general and dependable method for the intermolecular hydroamination of unactivated alkenes with broad functional group tolerance remains elusive. The proposed study outlines a strategy toward the development of rhodium catalysts for the hydroamination of unactivated alkenes. The specific aims are: 1) To synthesize, isolate, and characterize rhodium catalysts containing an ?6-arene tethered to a phosphorus or nitrogen donor. A series of phosphinoalkylarene and pyridylalkylarene ligands will be synthesized and converted to the corresponding rhodium complexes for evaluation in subsequent hydroamination studies. 2) To test the catalysts prepared as part of Specific Aim 1 for intra- and intermolecular hydroaminations that current systems do not catalyze. Substrates that will be investigated include 1,1- and 1,2-disubstituted aminoalkenes that lack gem-disubstitution on the alkyl chain for intramolecular hydroaminations and unactivated olefins, such as 1- pentene, for intermolecular reactions. 3) To reveal mechanistic information about hydroaminations catalyzed by the rhodium complexes of Aim 1. It is difficult to predict whether the turnover-limiting step in reactions catalyzed by complexes of Aim 1 will be nucleophilic attack on the coordinated olefin or protonolysis of the alkylrhodium intermediate. To address this question, mechanistic studies will be focused on the identification and isolation of the key alkylrhodium intermediate from addition of amine to the coordinated olefin, and to study the reactivity of this intermediate toward protic acids. 4) To develop enantioselective hydroaminations, which represents a long-term objective. Chiral rhodium complexes containing the structural core of the complexes of Aim 1 will be investigated for the development of enantioselective hydroaminations. PUBLIC HEALTH RELEVANCE: For every drug on the market, thousands of compounds were synthesized as part of a drug discovery program. With the development of novel and efficient methods for the synthesis of biologically active molecules, new drugs will be discovered more rapidly for the treatment of disease.