Amine α-heteroarylation via photoredox catalysis: a homolytic aromatic substitution pathway

Abstract

The direct α-heteroarylation of tertiary amines has been accomplished via photoredox catalysis to generate valuable benzylic amine pharmacophores. A variety of five-and six-membered chloroheteroarenes are shown to function as viable coupling partners for the α-arylation of a diverse range of cyclic and acyclic amines. Evidence is provided for a homolytic aromatic substitution mechanism, in which a catalyticallygenerated α-amino radical undergoes direct addition to an electrophilic chloroarene.

C–H functionalization of amines with aryl halides by nickel-photoredox catalysis

“…Notably, the high yields observed using electron-rich aryl halides demonstrate the complementarity between this approach and previously reported photoredox reactions that require electron-deficient cyanoarenes. 13 A chlorinated iodoarene ( 10 ) is also competent in the reaction, highlighting the potential for further product elaboration. The coupling of pharmaceutically relevant heterocycles is also efficient, including indole ( 11 ) and quinoline ( 12 ).…”

“…The MacMillan group has reported the photoredox-catalyzed α-C(sp 3 )–H arylation of N -aryl amines with cyanoarenes or heteroaryl halides. 13 This work highlights the ability of photoredox catalysis to generate α-amino radicals from C–H bonds under incredibly mild conditions. However, a limitation is the requirement for coupling partners derived only from electron-deficient (hetero)arenes.…”

α‐Arylation/Heteroarylation of Chiral α‐Aminomethyltrifluoroborates by Synergistic Iridium Photoredox/Nickel Cross‐Coupling Catalysis

“…The process envisioned for α-arylation/heteroarylation of N -trifluoroboratomethyl amino acids (Scheme 2) was founded on established evidence that visible-light irradiation (26 W compact fluorescent lamp, CFL) of Ir[dFCF 3 ppy] 2 (bpy)PF 6 [dFCF 3 ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine, depicted as Ir ( 5 ) in Scheme 2] generates the excited state [Ir]* species 6 , a strong oxidant (E 1/2 [Ir* III/II ] = +1.21 vs. SCE in MeCN), 22,32,34,35,38,41–43 which was anticipated to undergo single electron transfer (SET) oxidation of N -trifluoroboratomethyl amino acid 1 (e.g., Boc-N-CH 2 BF 3 K-L-Val-OMe, E 1/2 red = +1.01 V vs. SCE in MeCN), forming the desired reactive Csp 3 -centered α-amino radical 2 . Based on the developed rationale, 34 the process was expected to be an autoregulated release because the radical does not accumulate, but rather is captured by the second catalytic cycle mediated by the nickel species.…”

A new era for homolytic aromatic substitution: replacing Bu3SnH with efficient light-induced chain reactions

“…[83][84][85][86][87][88] N,N-Dimethylanilines undergo addition onto electron-deficient alkenes 9 via α-amino radical intermediates and cyclization to give quinoline derivatives 10 (Scheme 31). MacMillian utilized nucleophilic α-amino radicals generated using visible light photoredox Ir(III) catalysis in substitutions onto electron-deficient dicyanobenzenes and heterocyclic variants, where the reductive loss of cyanide occurs (Scheme 33).…”