Regiocontrolled Intermolecular Hydroamination of Olefins

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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.