Intermolecular hydroamination of alkenes Strain-release hydroamination & Cope-type hydroamination

Abstract

The development of efficient routes to nitrogen-containing molecules from olefin feedstocks is of paramount importance to the life science, bulk chemical and fine chemical sectors. The hydroamination reaction, the addition of an N-H bond across an unsaturated C-C bond, is therefore one of the simplest and most desirable transformation for which no general solution exists. This thesis describes the development of conceptually new metal-free intermolecular hydroamination methods designed to address key limitations in this field. The first part of the thesis describes the use of photoinduced strain-release activation to enable 1,4-additions and hydroamination reactions of azoles with cyclolkenones and cycloalkenes, respectively. This is the first time that nitrogen nucleophiles more basic than aniline have undergone an efficient acid-catalyzed hydroamination reaction with unactivated alkenes. The second part of this work describes the development of thermal intermolecular hydroamination reactions of hydroxylamines with strained alkenes, terminal vinylarenes, alkynes and allenes. These transformations give cheap one-step access to nitrogen-containing compounds such as N-alkylhydroxylamines, | N,N-dialkylhydroxylamines, oximes and ketonitrones. Analogous reactivity of hydrazines with alkynes gives hydrazones with complementary regioselectivity. Density functional theory studies shed light on the importance of the proton transfer step during the reaction. Taken together, these reactions are among the most operationally and conceptually simple hydroamination methods. The last section describes early work aimed at the development of an organocatalytic directed Cope-type hydroamination reaction, as well as a hydroamination/Cope-elimination tandem sequence designed to enable endergonic hydroamination reactions.