Site-selective electrooxidation of methylarenes to aromatic acetals

Aldehyde is one of most synthetically versatile functional groups and can participate in numerous chemical transformations. While a variety of simple aromatic aldehydes are commercially available, those with a more complex substitution pattern are often difficult to obtain. Benzylic oxygenation of methylarenes is a highly attractive method for aldehyde synthesis as the starting materials are easy to obtain and handle. However, regioselective oxidation of functionalized methylarenes, especially those that contain heterocyclic moieties, to aromatic aldehydes remains a significant challenge. Here we show an efficient electrochemical method that achieves site-selective electrooxidation of methyl benzoheterocycles to aromatic acetals without using chemical oxidants or transition-metal catalysts. The acetals can be converted to the corresponding aldehydes through hydrolysis in one-pot or in a separate step. The synthetic utility of our method is highlighted by its application to the efficient preparation of the antihypertensive drug telmisartan.

The reaction was stirred at 110 °C for 8 h and then cooled to RT. The reaction mixture was diluted with H2O (50 mL) and ethyl acetate (50 mL). The layers were separated and organic phase was washed twice with H2O. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford S25, which was used in the next step without purification.
The reaction mixture was heated to reflux for 4 h. AcOH was then removed under reduced pressure. The residue was basified with ammonium hydroxide to pH 9. The resulting mixture was extracted with ethyl acetate (3 × 80 mL) and washed with brine. The combined organic solution was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography to afford the product S32 as a white solid (2.3 g, 81% yield). 1
The resulting mixture was stirred at RT for 30 min. Then MeI (0.23 mL, 3.6 mmol, 1.2 equiv) was added dropwise at -20 °C. The reaction mixture was stirred at RT for another 2 h and then water (15 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic solution was dried over anhydrous Na2SO4, filtrated and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford the product S33 as white solid in 98% yield (0.65 g). The structure was confirmed by nuclear Overhauser effect (NOE) experiment. 1
The crude product S48 was used directly in the next step without further purification.  mmol, 1.2 equiv) by following the the procedure described for the synthesis of S5. 1  NaHCO3. The layers were separated and the aqueous layer was extracted twice with CH2Cl2.

tert-Butyl
The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford S56 as a white solid in 89% yield (0.33 g), which was used directly in the next step without further purification.

N-(3-Ethyl-4-methylphenyl)benzamide (S76).
To a solution of 3-ethyl-4-methylaniline (0.17 g, 1.2 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added PhCOCl (0.21 g, 1.5 mmol, 1.2 equiv), followed by Et3N (0.26 mL, 1.9 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 0.5 h, diluted with EtOAc and washed with saturated NaHCO3. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to afford S76 as a white solid in 98% (0.29 g), which was used directly in the next step without further purification.
The filtrate was washed with brine and then dried over MgSO4. The solvent was removed under reduced pressure to afford crude S84, which was used in the next step without further purification.
After being stirred for 30 min at this temperature, the crude S99 obtained above (50 mmol, 1.0 equiv) was added. The reaction mixture was stirred at -78 °C for 1 h and then warmed to RT for 1 h. Water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic solution was dried over Na2SO4, filtrated and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford S100 as a white solid in 73% yield (13 g

Procedures for the Electrochemical Oxidation
The electrolysis was carried out at 80 °C (oil bath temperature). The reaction mixture was refluxed for 12.5 h (electricity = 8.3 F mol −1 ) and isolated 8.