Mechanistic Investigations into Amination of Unactivated Arenes via Cation Radical Accelerated Nucleophilic Aromatic Substitution

Abstract

A mechanistic investigation into the amination of electron-neutral and electron-rich arenes using organic photoredox catalysis is presented. Kinetic and computational data support rate-limiting nucleophilic addition into an arene cation radical using both azole and primary amine nucleophiles. This finding is consistent with both fluoride and alkoxide nucleofuges, supporting a unified mechanistic picture using cation radical accelerated nucleophilic aromatic substitution (CRA-SNAr). Electrochemistry and time-resolved fluorescence spectroscopy confirm the key role solvents play in enabling selective arene oxidation in the presence of amines. The synthetic limitations of xanthylium salts are elucidated via photophysical studies. An alternative catalyst scaffold with improved turnover numbers is presented.

I(III)-Mediated Arene C–H Amination Using (Hetero)Aryl Nucleophiles

“…Finally, we examined brominated arene 8 , and under standard conditions, we were surprised to find that we obtained a 1.0:1.15 ratio of expected C–H pyridinium product 6g to C4-pyridinium 6b , the latter resulting from an S N Ar reaction on the aryl bromide. While similar S N Ar reactivity was previously observed by both Sanford and Nicewicz , under photoredox catalysis, with our conditions it is unclear what is serving as the reductant in this net redox netural process; ongoing studies seek to fully understand this reactivity. Nonetheless, running the reaction under a balloon of O 2 , improved the ratio to 2.7:1.0 in favor of C–H amination, giving 6g in 72% yield.…”

I(III)-Mediated Arene C-H Amination using (Hetero)Aryl Nucleophiles

“…Finally, we examined brominated arene 8, and under standard conditions we were surprised to find that we obtained a 1.0:1.15 ratio of expected C-H pyridinium product 6g to C4-pyridinium 6b, the latter resulting from SNAr on the aryl bromide. While similar SNAr reactivity was previously observed by both Sanford 25 and Nicewicz 31,32 under photoredox catalysis, with our conditions it is unclear what is serving as the reductant in this net redox netural process; further studies are ongoing to fully understand this reactivity. Nonetheless, running the reaction under a balloon of O2, 6,25 improved the ratio to 2.7:1.0 in favor of C-H amination, giving 6g in 72% yield.…”

Visible-light acridinium-based organophotoredox catalysis in late-stage synthetic applications

“…Further, Nicewicz and co-workers 69 also reported mechanistic investigations into site-selective arene amination of unactivated arenes via cation radical accelerated nucleophilic aromatic substitution ( Scheme 41 ).…”