Regiocontrolled Intermolecular Hydroamination of Olefins

描述（由申请人提供）：胺在制药行业中普遍存在。事实上，2010年美国前200名品牌药物中有152种含有胺或酰胺官能团。含胺药物的显著实例包括抗组胺剂扑尔敏和减充血剂麻黄碱和苯丙氨酸。由于胺在治疗中以及在染料、溶剂、农用化学品和商品和精细化学品的生产中的巨大流行，碳-氮键的形成是至关重要的。加氢胺化是一种有吸引力的安装胺官能团的方法，并且可以补充并且甚至可以证明比现有的方法更有用，现有的方法通常产生化学计量的废物，需要剧烈的反应条件，或依赖于昂贵的起始材料。拟议的研究旨在开发一种正式的加氢胺化方法，该方法将允许从容易获得的末端烯烃起始材料获得线性胺。这种转化在历史上一直是具有挑战性的，因为亲核试剂倾向于以马尔可夫尼科夫选择性加成到烯烃中。这种新策略将依赖于一个中继系统，该系统将耦合三个不同的催化循环。此外，使用类似的方法描述了外消旋和对映体富集形式的支链胺的构建。总的来说，提出的正式氢胺化策略应该提供从容易获得的烯烃起始材料构建药用特权胺的替代和简洁的方法。 公共卫生相关性：胺官能团在制药工业中普遍存在，并且可以在治疗各种疾病的药物中发现，包括抗组胺药，镇静剂，减充血剂，精神兴奋剂和抗抑郁药。由于胺在治疗中以及在染料、溶剂、农用化学品和商品和精细化学品的生产中的巨大流行，碳-氮键的形成是至关重要的。为了满足这一需求，提出的研究的目的是开发一种正式的加氢胺化方法，该方法将允许从容易获得的烯烃前体获得线性和立体异构的支链胺。

DESCRIPTION (provided by applicant): Amines are ubiquitous in the pharmaceutical industry. In fact, 152 out of the top 200 brand name drugs in the US in 2010 contain amine or amide functionalities. Notable examples of amine-containing drugs include the antihistamine, chlorpheniramine, and the decongestants, ephedrine and phenylephrine. Due to the enormous prevalence of amines in therapeutics, as well as in the production of dyes, solvents, agrochemicals, and commodity and fine chemicals, the formation of carbon-nitrogen bonds is of paramount importance. Hydroamination is an attractive method to install the amine functionality, and may complement and may even prove more useful than existing methodologies that often produce stoichiometric waste products, require drastic reaction conditions, or rely on expensive starting materials. The proposed research aims to develop a formal hydroamination methodology that would allow access to linear amines from readily available terminal olefin starting materials. This transformation has been historically challenging because of the tendency of nucleophiles to add into olefins with Markovnikov selectivity. This new strategy would rely on a relay system that would couple three different catalytic cycles. Additionally, construction of branched amines in both racemic and enantioenriched form is described using an analogous approach. Overall, the formal hydroamination strategies proposed should offer alternative and concise methods of constructing medicinally privileged amines from readily accessible olefin starting materials. PUBLIC HEALTH RELEVANCE: The amine functional group has a pervasive presence in the pharmaceutical industry, and can be found in drugs that treat a variety of maladies, including antihistamines, tranquilizers, decongestants, psychostimulants, and antidepressants. Due to the enormous prevalence of amines in therapeutics, as well as in the production of dyes, solvents, agrochemicals, and commodity and fine chemicals, the formation of carbon-nitrogen bonds is of paramount importance. In order to address this need, the aim of the proposed research is to develop a formal hydroamination methodology that would allow access to linear and stereogenic, branched amines from readily available olefin precursors.