UC Berkeley

ConspectusCatalytic intermolecular hydroamination of alkenes is an atom- and step-economical method for the synthesis of amines, which have important applications as pharmaceuticals, agrochemicals, catalysts, and materials. However, hydroaminations of alkenes in high yield with high selectivity are challenging to achieve because these reactions often lack a thermodynamic driving force and often are accompanied by side reactions, such as alkene isomerization, telomerization, and oxidative amination. Consequently, early examples of hydroamination were generally limited to the additions of N-H bonds to conjugated alkenes or strained alkenes, and the catalytic hydroamination of unactivated alkenes with late transition metals has only been disclosed recently. Many classes of catalysts, including early transition metals, late transition metals, rare-earth metals, acids, and photocatalysts, have been reported for catalytic hydroamination. Among them, late transition-metal complexes possess several advantages, including their relative ease of handling and their high compatibility of substrates containing polar or sensitive functional groups.This Account describes the progression in our laboratory of hydroaminations catalyzed by late transition-metal complexes from the initial additions of N-H bonds to activated alkenes to the more recent additions to unactivated alkenes. Our developments include the Markovnikov and anti-Markovnikov hydroamination of vinylarenes with palladium, rhodium, and ruthenium, the hydroamination of dienes and trienes with nickel and palladium, the hydroanimation of bicyclic strained alkenes with neutral iridium, and the hydroamination of unactivated terminal and internal alkenes with cationic iridium and ruthenium. Enantioselective hydroaminations of these classes of alkenes to form enantioenriched, chiral amines also have been developed.Mechanistic studies have elucidated the elementary steps and the turnover-limiting steps of these catalytic reactions. The hydroamination of conjugated alkenes catalyzed by palladium, rhodium, nickel, and ruthenium occurs by turnover-limiting nucleophilic attack of the amine on a coordinated benzyl, allyl, alkene, or arene ligand. On the other hand, the hydroamination of unconjugated alkenes catalyzed by ruthenium and iridium occurs by turnover-limiting migratory insertion of the alkene into a metal-nitrogen bond. In addition, pathways for the formation of side products, including isomeric alkenes and enamines, have been identified during our studies. During studies on enantioselective hydroamination, the reversibility of the hydroamination has been shown to erode the enantiopurity of the products. Based on our mechanistic understandings, new generations of catalysts that promote catalytic hydroaminations with higher rates, chemoselectivity, and enantioselectivity have been developed. We hope that our discoveries and mechanistic insights will facilitate the further development of catalysts that promote selective, practical, and efficient hydroamination of alkenes.