Electrooxidation enables highly regioselective dearomative annulation of indole and benzofuran derivatives

The dearomatization of arenes represents a powerful synthetic methodology to provide three-dimensional chemicals of high added value. Here we report a general and practical protocol for regioselective dearomative annulation of indole and benzofuran derivatives in an electrochemical way. Under undivided electrolytic conditions, a series of highly functionalized five to eight-membered heterocycle-2,3-fused indolines and dihydrobenzofurans, which are typically unattainable under thermal conditions, can be successfully accessed in high yield with excellent regio- and stereo-selectivity. This transformation can also tolerate a wide range of functional groups and achieve good efficiency in large-scale synthesis under oxidant-free conditions. In addition, cyclic voltammetry, electron paramagnetic resonance (EPR) and kinetic studies indicate that the dehydrogenative dearomatization annulations arise from the anodic oxidation of indole into indole radical cation, and this process is the rate-determining step.


Procedure for gram scale synthesis of 1-(10b-methyl-3-phenyl-3,4-dihydro-[1,4]dioxepino
General procedure for kinetic study between 1a and 2a monitored by GC: In an oven-dried undivided three-necked bottle (25 mL) equipped with a stir bar, 1a (0.50 mmol) and n Bu4NBF4 (98.8 mg, 0.3 mmol) was added. Diphenyl (20.0 mg) was added as an internal standard. The bottle was equipped with carbon cloth (20 mm×20 mm) as the anode and cathode and charged with nitrogen. Subsequently, 2a (1.2 mL) and CH3CN (9.0 mL) were added. Then the electrolysis system was stirred at a constant current of 10 mA. 0.1 mL solution were taken out from the cell via syringe at designated time interval (30, 60 min).

Order in Current:
The order in current was determined by studying the initial rate of reaction under different current (4, 7, 10, 13, 16, 20 mA). Using the above mentioned general procedure, product yield from the corresponding reaction was monitored by GC using diphenyl as an internal standard. Finally, the profiles of relative concentrations vs time for product 3aa could be obtained to analyse the initial rate of reaction. As shown below, the reaction rate changed under different current, which demonstrated to be a first-order dependence.
Order in substrate 1a: The order in 1a was determined by studying the initial rate of reaction with different concentration of 1a (0.00952, 0.01429, 0.02381, 0.03333, 0.04, 0.04762, 0.05714， 0.06667, 0.07619 M). Using the above mentioned general procedure, product yield from the corresponding reaction was monitored by GC using diphenyl as an internal standard. Finally, the profiles of relative concentrations vs time for product 3aa could be obtained to analyse the initial rate of reaction. As shown below, the reaction rate changed with different concentration of 1a, which demonstrated to be a saturation kinetics.
Order in substrate 2a: The order in 2a was determined by studying the initial rate of reaction with different volume of 2a (0.8, 1.0, 1.2, 1.5, 1.8, 2.1 mL), and the total volume maintain 10.2 mL.
Using the above mentioned general procedure, product yield from the corresponding reaction was monitored by GC using diphenyl as an internal standard. Finally, the profiles of relative concentrations vs time for product 3aa could be obtained to analyse the initial rate of reaction. As shown below, the reaction rate did not change with different concentration of 2a. General procedure for kinetic study between 1a and 2o monitored by GC: In an oven-dried undivided three-necked bottle (25 mL) equipped with a stir bar, 1a (0.50 mmol) and n Bu4NBF4 (98.8 mg, 0.3 mmol) was added. Diphenyl (10.0 mg) was added as an internal standard. The bottle was equipped with carbon cloth (20 mm×20 mm) as the anode and cathode and charged with nitrogen. Subsequently, 2o (8 equiv) and CH3CN/DCM (5.0/4.0 mL) were added. Then the electrolysis system was stirred at a constant current of 15 mA. 0.1 mL solution were taken out from the cell via syringe at designated time interval (4h, 8h).
Order in substrate 1a: The order in 1a was determined by studying the initial rate of reaction with different concentration of 1a (0.01064, 0.01596, 0.0266, 0.03723, 0.05319, 0.06383 M). Using the above mentioned general procedure, product yield from the corresponding reaction was monitored by GC using diphenyl as an internal standard. Finally, the profiles of relative concentrations vs time for product 3ao could be obtained to analyse the initial rate of reaction. As shown below, the reaction rate changed with different concentration of 1a, which demonstrated to be a first-order kinetic.
Order in substrate 2o: The order in 2o was determined by studying the initial rate of reaction with