Photocatalytic C−H Azolation of Arenes Using Heterogeneous Carbon Nitride in Batch and Flow

Abstract The functionalization of aryl C(sp2)−H bonds is a useful strategy for the late‐stage modification of biologically active molecules, especially for the regioselective introduction of azole heterocycles to prepare medicinally‐relevant compounds. Herein, we describe a practical photocatalytic transformation using a mesoporous carbon nitride (mpg‐CN x ) photocatalyst, which enables the efficient azolation of various arenes through direct oxidation. The method exhibits a broad substrate scope and is amenable to the late‐stage functionalization of several pharmaceuticals. Due to the heterogeneous nature and high photocatalytic stability of mpg‐CN x , the catalyst can be easily recovered and reused leading to greener and more sustainable routes, using either batch or flow processing, to prepare these important compounds of interest in pharmaceutical and agrochemical research.


General information
All reagents and solvents were used as received without further purification, unless stated otherwise. Reagents and solvents were bought from Sigma Aldrich, TCI and Fluorochem.
Technical solvents were bought from Biosolve and were used as received. LED strips (365 nm, 5 m, 240 SMD2835 LEDs) were purchased from LuxaLight. For batch experiments, the LED strip was cut in half and 2.5 m of LED strip were coiled in a 3D-printed (PLA) reactor with an inner diameter of 12 MHz) and 13 C (100 MHz) spectra were recorded on ambient temperature using a Bruker-Avance 400. 1 H NMR spectra are reported in parts per million (ppm) downfield relative to CDCl3 (7.26 ppm) and all 13 C NMR spectra are reported in ppm relative to CDCl3 (77.16 ppm), unless stated otherwise. In the NMR spectra the following abbreviations were used to describe the multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = hextet, hept = heptet, m = multiplet, dd = double doublet, td = triple doublet. NMR data was processed using the MestReNova 12.0 software package. Known products were characterized by comparing to the corresponding 1 H NMR and 13 C NMR from literature. Melting points were recorded on a Buchi M-565 melting point apparatus. High-resolution mass spectra (HRMS) were recorded on an AccuTOF LC, JMS-T100LP Mass spectrometer (JEOL, Japan). The X-ray diffraction (XRD) patterns were obtained with a Bruker-AXS D2 Phaser powder X-ray diffractometer in Bragg-Brentano geometry using Co Kα = 1.78897 Å, operated at 30 kV. Infrared spectra of the samples were measured using a PerkinElmer Spectrum 100 spectrometer equipped with an ATR sampling accessory. UV-vis diffuse reflection spectroscopy (DRS) of powder material was carried out on an Agilent Cary machine. Scanning electron microscopy (SEM) images were collected on a high performance MIRA3 FEG-SEM system that features a high brightness 5 2. Catalyst preparation mpg-CNx was synthesized and characterized by ATR-IR, pXRD and UV-Vis DRS according to a procedure previously reported. [1] For mpg-CNx, cyanamide (3 g) was dissolved in a 40 wt.% dispersion of SiO2 (7.5 g, Ludox SM) in water, stirring at 60 °C overnight. The resulting solution was then heated at a rate of 2.3 °C·min -1 over 4 h to reach a temperature of 550 °C, and then kept at this temperature for further 4 h. The resulting brown-yellow powder was treated with 4 M NH4HF2 for 24 h in order to remove the silica template. The powders were then centrifuged at 9000 rpm and washed three times with distilled water and twice with ethanol.
Finally, the powders were dried overnight at 70 °C under vacuum.

Homemade setup for batch experiments
All the optimization experiments and scope in batch were performed with our homemade photoreactor ( Figure S1). Figure S1. Left: 3D printed reactor in use. Right: the reactor was covered with reflective tape and contains 2.5 m of near-UV LED strip (365 nm, 60W). The reactor has an inner diameter of 12.5 cm.

Vapourtec UV-150
For the experiments in flow, a Vapourtec UV-150 photochemical reactor was used, equipped with 150 W LED (365 nm). A packed-bed reactor ( Figure S2) was prepared following a reported procedure. [2] A 3 wt.% mpg-CNx mixture was prepared by gently grinding 100 mg of mpg-CNx, 540 mg of K2S2O8 and 2.
The vials were then irradiated in the batch reactor (described above) at room temperature with rapid stirring (1500 rpm) under an oxygen atmosphere. When the reaction was over (15-40 h), the crude reaction mixtures were centrifuged at 5000 rpm for 5 min and then the liquid phase was carefully separated. The catalyst was washed twice with CH3CN. The combined organic phase was dried under reduced pressure and purified by flash column chromatography on a Biotage® Isolera Four system affording the product, which was characterized by 1 H NMR, 13 C NMR, and HRMS.
Oxygen flow was set using a mass flow controller and then it was mixed with the liquid feed via a PEEK T-mixer (IDEX, P-714, inner diameter 1 mm). The gas and the liquid feed were pumped into a 10 mL pre-reactor (PFA capillary tubing, 1.59 mm I.D., equipped with two switching valves, see Figure S3) at 10 mL min -1 and 2 mL min -1 , respectively. When the loop was completely full, it was closed using the two switching valves and connected to a HPLC pump via a six-way valve (see Figure S4). Next, the inlet valve was opened, and the loop was pressurized. After pressurization, the outlet valve was opened as well, to pump the reaction mixture into the packed-bed reactor for the desired residence time (5-30 min). It was possible to add CH3CN through the six-way valve to elute the reaction mixture out. The collected volume was dried under reduced pressure and pyrazine (8 mg, 0.1 mmol, external standard) was added. Finally, 1 H-NMR analysis was performed. The scheme of the full flow set-up is shown in Figure S5.

Substrate preparation
Tert-butyl (tert-butoxycarbonyl)(9H-purin-6-yl)carbamate (S1). S1 was synthesized according to a procedure reported in the literature. [3] To a 100 mL N2-flushed round-bottomed flask equipped with a magnetic stirring bar, adenine (1.35 g, 10.0 mmol) and DMAP (0.1 equiv., 1.0 mmol, 0.122 g) were added to be then suspended in 50 mL of dry THF using a gas-tight syringe. To this suspension, 8.7 g (3.98 equiv., 39.8 mmol) of Boc2O were added under N2 atmosphere. The reaction mixture was stirred for 12 h at room temperature, after which the solvent was removed by rotary evaporation to give a yellow oil, which was diluted with ethyl acetate (400 mL). This solution was washed with 1 N HCl (30 mL) and brine (3 × 100 mL). The organic layer was dried over Na2SO4 and evaporated to give a colourless oil corresponding to tris-Boc-adenine, which was used in the next step without further purification.
The tris-Boc-adenine was first dissolved in CH3OH (100 mL), and then saturated NaHCO3 solution (45 mL) was added. The so-obtained turbid mixture was stirred at 50 o C for 1 h. The reaction progress was monitored via TLC (cyclohexane:ethyl acetate 7:3). After evaporating CH3OH, water (100 mL) was added to the mixture and the aqueous layer was extracted with CHCl3 (2 × 300 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give a white solid. The crude material was dissolved in ethyl acetate and purified through column chromatography (ethyl acetate) to give S1 (6.3 mmol, 2.1 g, 63% yield) as a white solid.