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. 2024 Feb 14;146(6):3591-3597.
doi: 10.1021/jacs.3c11506. Epub 2024 Jan 31.

Site-Selective Electrochemical Arene C-H Amination

Eva Maria Alvarez  1 , Griffin Stewart  1 , Mohammed Ullah  1 , Remy Lalisse  2 , Osvaldo Gutierrez  2 , Christian A Malapit  1   3
Affiliations

Site-Selective Electrochemical Arene C-H Amination

Eva Maria Alvarez et al. J Am Chem Soc. .

Abstract

Here we present the discovery and development of a highly selective aromatic C-H amination reaction. This electrochemical strategy involves a cathodic reduction process that generates highly electrophilic dicationic N-centered radicals that can efficiently engage in aromatic C-H functionalization and channel the regioselectivity of the aromatic substitution. The nitrogen-radical cation-pi interaction with arenes used throughout nature leads to a charge transfer mechanism, with subsequent aromatic C-N bond formation. This electrochemical process generates aryl DABCOnium salts in excellent yields and regioselectivities (single regioisomer in most cases). The scope of the reaction on arene is broad where various functionalities such as aryl halides (bromides, chlorides, fluorides), carbonyls (ketones, esters, imides), sulfonamides, and heteroarenes (pyridines, bipyridines, and terpyridines) are well tolerated. Moreover, we disclose the synthetic utility of the aryl DABCOnium salt adducts leading to the direct access of diverse aryl piperazines and the chemoselective cleavage of the exocyclic aryl C(sp2)-N bond over electrophilic C(sp3)-N+ bonds via photoredox catalysis to afford synthetically useful aryl radicals that can engage in aryl C-C and C-P bond formation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Selective electrochemical arene C−H amination reactions. (a) Electrochemical arene pyridination by Yoshida via anodic oxidation of electron-rich arenes, and (b, c) electrochemical arene amination (this work) via cathodic generation of N-radical cation and synthetic utility of aryl DABCOnium salts.
Figure 2.
Figure 2.
Cathodic generation of N-radical cations and their utility in selective electrochemical arene C−H amination.
Figure 3.
Figure 3.
Scope of electrochemical arene C−H amination. Reactivity and synthetic utility of aryl DABCOnium salts to access diverse set of aryl piperazines and photocatalytic conversion to aryl C−C and C−P bonds. The general reaction conditions are as follows: arene (0.30 mmol, 1.0 equiv), Selectfluor II (1.5 equiv −2.0 equiv), Et3N (50 mol %), MeCN, 25 °C, 14 h. Electrolysis parameters: constant current of 1 mA, 5 F/mol, and stirring at 1500 rpm. aSelectfluor I was used. b3.0 equiv of arene was used. cReaction conditions of C were used. Structures shown are of the observed major product and asterisks denote position for other minor regioisomers. For detailed experimental procedures on the diversification scheme, see Supporting Information.
Figure 4.
Figure 4.
Mechanistic studies using computational and experimental methods. (a) DFT studies to elucidate N-radical cation−pi interactions vs HAT. (b) Comparison between Fukui indices and experimental regioselectivity. (c) CV studies supporting charge-transfer mechanism. (d) KIE experiments (e) The role of triethylamine in the reaction. (f) Proposed mechanism.
See this image and copyright information in PMC

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