N-Hydroxyphthalimide-Mediated Electrochemical Iodination of Methylarenes and Comparison to Electron-Transfer-Initiated C-H Functionalization

Abstract

An electrochemical method has been developed for selective benzylic iodination of methylarenes. The reactions feature the first use of N-hydroxyphthalimide as an electrochemical mediator for C-H oxidation to nonoxygenated products. The method provides the basis for direct (in situ) or sequential benzylation of diverse nucleophiles using methylarenes as the alkylating agent. The hydrogen-atom transfer mechanism for C-H iodination allows C-H oxidation to proceed with minimal dependence on the substrate electronic properties and at electrode potentials 0.5-1.2 V lower than that of direct electrochemical C-H oxidation.

Figure 1

CVs of NHPI (1 mM) in acetonitrile (a); in the presence of pyridine/pyridinium perchlorate (0.1 M each) (b); pyridine (0.01 M) and solid KHCO₃ (100 equiv) (c); and in the presence of pyridine/pyridinium perchlorate (0.1 M each), and 4-^tBu-toluene (20 mM) (d). Other conditions: glassy carbon working electrode, scan rate = 10 mV/s, and 0.1 M KPF₆ electrolyte for (a) and (c).

Figure 2

Comparison of PINO-mediated-HAT- and direct-ET-initiated C–H oxidation of methylarenes, including the influence of electronic effects (1 and 2) and product yields from representative methods (3). Data for the Figure 2B-3 adapted from Ref. .

Scheme 1

Electrochemical NHPI/PINO-mediated strategy for oxygenation of benzylic and allylic C–H bonds.

Scheme 2

Electrochemical NHPI/PINO-mediated iodination/functionalization of methyl arenes.

Scheme 3

Sequential methylarene iodination/alkylation to access pharmaceutical intermediates and compounds. a) 2f (0.12 mmol), acetylpyrrole (2.0 equiv.), NaH (2.0 equiv.), DMF (1 mL), RT; b) 2h (0.2 mmol), permethric acid (1.1 equiv.), Na₂CO₃ (4.0 equiv.), DMF (2.0 mL), 50 °C; c) 2g (0.1 mmol), anisole (4.0 equiv.), AgOTf (1.5 equiv.), lutidine (2.0 equiv.), CDCl₃ (1.0 mL), RT.