Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes: A Mechanistic View

Abstract

Hydroamination, the addition of an N–H bond across a C–C multiple bond, is a reaction with a great synthetic potential. Important advances have been made in the last decades concerning catalysis of these reactions. However, controlling the regioselectivity in the amine addition toward the formation of anti-Markovnikov products (addition to the less substituted carbon) still remains a challenge, particularly in intermolecular hydroaminations of alkenes and alkynes. The goal of this review is to collect the systems in which intermolecular hydroamination of terminal alkynes and alkenes with anti-Markovnikov regioselectivity has been achieved. The focus will be placed on the mechanistic aspects of such reactions, to discern the step at which regioselectivity is decided and to unravel the factors that favor the anti-Markovnikov regioselectivity. In addition to the processes entailing direct addition of the amine to the C–C multiple bond, alternative pathways, involving several reactions to accomplish anti-Markovnikov regioselectivity (formal hydroamination processes), will also be discussed in this review. The catalysts gathered embrace most of the metal groups of the Periodic Table. Finally, a section discussing radical-mediated and metal-free approaches, as well as heterogeneous catalyzed processes, is also included.

Recent advances in C(sp3)–N bond formation via metallaphoto-redox catalysis

“…Transition-metal-catalyzed hydroamination and carboamination of easily available alkenes have also been established as attractive and convenient protocols to access valuable N-containing molecules. 39 In 2019, Zhang developed an effective three-component carboamination reaction of alkenes 46 , alkyl halides 47 , and amines 48 via photoinduced copper catalysis, and a variety of valuable fluoroalkyl-containing amines have been obtained (Scheme 7a). 40 In the presence of CuCl and t BuOLi and upon irradiation with blue LEDs, a number of N -nucleophiles, including carbazoles, indazoles, primary aliphatic amines, and benzenesulfonamides all worked well to give the desired products 49 in good yields.…”

“…9 Since then, substitution reactions with various nitrogen nucleophiles, Curtius rearrangement, alkene hydroamination, nitrene insertion, and reductive amination with carbonyls have been successively developed. 10…”

Generation of Aromatic N‐Heterocyclic Radicals for Functionalization of Unactivated Alkenes

“…Within this area, transition metalcatalyzed hydroamination has enabled the construction of heterocyclic amines, yet harsh conditions are typically required to activate the reaction. [33][34][35][36] Nicewicz and coworkers have made notable advances by designing a photocatalytic system for the intermolecular hydroamination of alkenes, using heterocyclic amines as nitrogen nucleophiles under mild conditions (Figure 1c). [37] Despite these advancements, electron-rich styrenes were necessary for these methods, limiting generality.…”

Generation of Aromatic N‐Heterocyclic Radicals for Functionalization of Unactivated Alkenes

“…Aromatic heterocyclic amines are conventionally challenging to react with alkenes due to their intrinsic nucleophilicity. Within this area, transition metal‐catalyzed hydroamination has enabled the construction of heterocyclic amines, yet harsh conditions are typically required to activate the reaction [33–36] . Nicewicz and co‐workers have made notable advances by designing a photocatalytic system for the intermolecular hydroamination of alkenes, using heterocyclic amines as nitrogen nucleophiles under mild conditions (Figure 1c).…”