Site-Selective C(sp3)–H Functionalizations Mediated by Hydrogen Atom Transfer Reactions via α-Amino/α-Amido Radicals

Abstract

Amines and amides, as N-containing compounds, are ubiquitous in pharmaceutically active scaffolds, natural products, agrochemicals and peptides. Amides in nature bear key responsibility for three-dimensional structure, such as in proteins. Structural modifications to amines and amides, especially at their positions α- to N, bring about profound changes in biological activity oftentimes leading to more desirable pharmacological profiles of small molecule drugs. A number of recent developments in synthetic methodology for the functionalizations of amines and amides omit the need of directing groups or pre-functionalizations, achieving direct activation of the otherwise benign C(sp3)-H bond. Among these, hydrogen atom transfer (HAT) has proven a very powerful platform for the selective activation of amines and amides to their α-amino and α-amido radicals, which can then be employed to furnish C-C and C-X (X=heteroatom) bonds. The ability to both form these radicals and control their reactivity in a site-selective manner is of utmost importance for such chemistries to witness applications in late-stage functionalization. Therefore, this review captures contemporary HAT strategies to realize chemo- and regioselective amine and amide α-C(sp3)-H functionalization, based on bond strength, bond polarity, reversible HAT equilibria, traceless electrostatic directing auxiliaries and steric effects of in situ-generated HAT agents.

Dual Nickel/Photoredox‐Catalyzed Synthesis of N‐formyl N,N’‐Diaryl Ethylenediamines via Multiple C−N/C−C Coupling of Nitroarenes with Trimethylamine

“…Several control experiments were conducted to evaluate the effect of catalysts and reagents on the amination reaction. When PC3 was omitted, the reaction did not proceed (Table S2, Supporting Information), indicating the necessity of photocatalyst to initiate the photo‐induced single‐electron transfer events, such as the photoreduction of nitroarene [17] and the photooxidation of trimethylamine, [13c,d] to enable subsequent bond formation reactions. Likewise, in the absence of or Ni/ L1 complex, no reaction occurred as well (Table S6, Supporting Information), suggesting that the Ni catalyst likely mediates the C−C bond coupling reaction [21] to construct the ethylenediamine skeleton.…”

Recent Advances in C–H Functionalisation through Indirect Hydrogen Atom Transfer

“…The method was also showcased on 12 pharmaceuticals, such as Dextromethorphan 40.9 and Lidocaine 40.10, demonstrating potential for late-stage functionalisation. It is worth noting the contrast in selectivity compared with similar C-H functionalisation methods [244,245]. In 2021, Rovis and Schoenebeck developed a site-selective α-C-H alkylation of trialkylamines 40.1 through a Giese addition by establishing a reversible HAT step with triphenylsilanethiol 40.4 (Scheme 40) [133].…”

“…The method was also showcased on 12 pharmaceuticals, such as Dextromethorphan 40.9 and Lidocaine 40.10, demonstrating potential for late-stage functionalisation. It is worth noting the contrast in selectivity compared with similar C-H functionalisation methods [244,245]. Wendlandt used Ph3SSiH 41.4 to reversibly abstract alcohol α-C(sp 3 )-H bonds to establish an equilibrium, which leads to stereochemical editing of vicinal diols through thermodynamic control (Scheme 41) [246].…”

Photocatalytic Hydrogen Atom Transfer-Induced Arbuzov-Type α-C(sp3)–H Phosphonylation of Aliphatic Amines

“…Photocatalytic HAT-enabled activation of α-C­(sp 3 )–H bonds of amines has been utilized for diverse α-amino C–H functionalization. − Building on this, we aimed to develop a general method for the α-C­(sp 3 )–H phosphonylation of amines. To address the incompatibility issue between phosphite reagents and HAT agents, we proposed employing a radical translocating group (T) to trigger a kinetically favored intramolecular HAT event, outcompeting the premature intermolecular phosphonylation of the HAT-reactive intermediate.…”