Continuous flow photolysis of aryl azides: Preparation of 3H-azepinones

Photolysis of aryl azides to give nitrenes, and their subsequent rearrangement in the presence of water to give 3H-azepinones, is performed in continuous flow in a photoreactor constructed of fluorinated ethylene polymer (FEP) tubing. Fine tuning of the reaction conditions using the flow reactor allowed minimization of secondary photochemical reactions.

The inlet valve of the R2+ pump system (Vapourtec) was used for rapid switching from pure solvent to the solution containing the dissolved starting material at the intake pump.
FEP tubing was selected for its high transmittance and stability in the UV-vis light range, [4] its flexibility and its high chemical resistance. The 2 mm thick Pyrex filter was essential to absorb wavelengths below 300 nm, to prevent degradation of the tubing, and to avoid any undesired side reactions caused by short wavelength radiation. The temperature in the tube during the reaction is estimated to range from 25 to 30 °C, based on temperature measurements taken between the cooling jacket and the tube. For safety reasons, the lamp was placed inside an aluminium box to block UV irradiation. Two fans were installed for additional cooling.

2-Azidobenzoic acid (8c)
To a solution of anthranilic acid (3.25 g, 23.7 mmol) in aqueous hydrochloric acid (3 M, 125 mL) at 0 °C was added a solution of sodium nitrite (3.11 g, 45.0 mmol, 1.9 equiv) in water (25 mL) dropwise, while maintaining a temperature below 5 C. After stirring for 1 h at 0 °C, a solution of sodium azide (3.08 g, 47.4 mmol, 2.0 equiv) in water (50 mL) was added dropwise while maintaining the same low temperature.
The mixture was stirred for an additional 2 h at 0 °C, then allowed to warm up to rt overnight. The
After stirring for 2 h at rt, the solution was acidified with aqueous hydrochloric acid (1 M). EtOAc was added and the two phases were separated. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated under reduce pressure to afford 2-

4-Azidobiphenyl (8g)
To a solution of 4-aminobiphenyl (2.50 g, 14.8 mmol) in aqueous hydrochloric acid (3 M, 60 mL) at 0 ºC was added a solution of sodium nitrite (1.94 g, 28.1 mmol, 1.9 equiv) in water (24 mL) dropwise, while maintaining a temperature below 5 C. Additional DMF (5 mL) was added. After stirring for 1 h at 0 °C, a solution of sodium azide (1.92 g, 29.5 mmol, 2.0 equiv) in water (20 mL) was added dropwise while maintaining the same low temperature, and the mixture was stirred for an additional 1.5 h at 0 °C. The resulting suspension was filtered, and the residual solid was washed thoroughly with water and dried in air.
The solid was taken up in EtOAc, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to

3-Azidoquinoline (8i)
To a solution of 3-aminoquinoline (2.00 g, 13.9 mmol) in aqueous hydrochloric acid (3 M, 20 8, 143.8, 133.9, 129.5, 128.7, 128.1, 127.7, 126.8, 122.5; in agreement with published data. [12] General Procedure for Preparation of 3H-azepinones The UV lamp was turned on 30 min prior to use. A Vapourtec R2 series flow reactor system connected to a FEP photoreactor was set up as described above. THF and H 2 O were injected simultaneously into the reactor at the specified rates, and mixed by a PTFE T-mixer. After stabilization of the system, the intake of one of the pumps was switched to a solution containing the arylazide 8 in THF. The entire reaction mixture was collected and extracted with EtOAc (3X). The combined organic phases were washed with brine (2X), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The conversion of each run was determined by 1 H NMR of the crude product, and the desired 3H-azepin-2-one products were purified by flash chromatography.