A Tailored COF for Visible-Light Photosynthesis of 2,3-Dihydrobenzofurans

Heterogeneous photocatalysis is considered as an ecofriendly and sustainable approach for addressing energy and environmental persisting issues. Recently, heterogeneous photocatalysts based on covalent organic frameworks (COFs) have gained considerable attention due to their remarkable performance and recyclability in photocatalytic organic transformations, offering a prospective alternative to homogeneous photocatalysts based on precious metal/organic dyes. Herein, we report Hex-Aza-COF-3 as a metal-free, visible-light-activated, and reusable heterogeneous photocatalyst for the synthesis of 2,3-dihydrobenzofurans, as a pharmaceutically relevant structural motif, via the selective oxidative [3+2] cycloaddition of phenols with olefins. Moreover, we demonstrate the synthesis of natural products (±)-conocarpan and (±)-pterocarpin via the [3+2] cycloaddition reaction as an important step using Hex-Aza-COF-3 as a heterogeneous photocatalyst. Interestingly, the presence of phenazine and hexaazatriphenylene as rigid heterocyclic units in Hex-Aza-COF-3 strengthens the covalent linkages, enhances the absorption in the visible region, and narrows the energy band, leading to excellent activity, charge transport, stability, and recyclability in photocatalytic reactions, as evident from theoretical calculations and real-time information on ultrafast spectroscopic measurements.


S3
Section S1: General Remarks Hex-Aza COF-3 and the organic ligands 4 and 5 used in this study were prepared according to procedures reported in the literature. Other starting materials, reagents, and solvents were purchased from commercial sources and used without further purification unless otherwise stated. 1 H and 13 C NMR spectra were recorded at ambient temperature on a Bruker Advance III instrument operating at 400 and 500 MHz ( 1 H NMR) and 100 and 125 MHz ( 13 C NMR) in the solvent indicated using the signal of the residual solvent as an internal standard (CDCl3 δ 7.26 ppm or DMSO-d6 δ 2.50 ppm for 1 H NMR and CDCl3 δ 77.16 ppm or DMSO-d6 δ 39.52 ppm for 13 C NMR). 1 H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), and integration. Solid-state 13 C NMR spectra were recorded using a Bruker 400 AVANAC III spectrometer equipped with a 4 mm double-resonance CP MAS Bruker probe. All 13 C cross-polarization magic-angle-spinning (CP-MAS) NMR spectra were recorded at a resonance frequency of 100.62 MHz under a spinning rate of 12 kHz using a 4 mm triple-resonance Bruker MAS probe. To achieve a sufficient signal-to-noise ratio in a reasonable time, the 13 C CP-MAS NMR spectra were recorded by collecting 12 k scans with a recycle delay time of 7 s. The temperature was maintained at 298 K for all the experiments and the CP contact time was set to 2 ms using ramp 100 for variable amplitude CP. Bruker Topspin 3.5pl7 software (Bruker BioSpin, Rheinstetten, Germany) was used for both data collection and spectral processing. Thin-layer chromatography (TLC) was performed using silica gel 60 F254 precoated plates and visualized with exposure to UV light (254 nm) or by iodine staining. Flash chromatography was performed on Biotage (Model: Isolera). Powder X-ray diffraction (PXRD) patterns were obtained on a D8 Advance X-ray diffractometer (Bruker, Germany) with Cu Kα radiation (λ = 1.5406 Å). Fourier transform infrared (FTIR) spectra (4000-600 cm −1 ) were recorded on a Thermo Scientific Nicolet 6700 apparatus. Low-pressure N2 adsorption studies of the Hex-Aza COF-3 were conducted on a fully automated Autosorb-IC micropore gas analyzer (Quantachrome Instruments) at relative pressures up to 1 atm. UV-vis absorption spectra of Hex-Aza-COF-3 suspensions were collected using a Shimadzu UV-1900 instrument.
Photoluminescence lifetime was measured using the time-correlated single photon counting technique (FluoTime 250, fluorescence lifetime spectrometer). Femtosecond transient absorption spectroscopic measurements were performed using a Helios spectrometer (Ultrafast Systems). The beam from an Astrella Ti:Saph (Coherent) pulsed laser (100 fs, 1 kHz, 800 nm) was split and directed to an optical parametric amplifier (Newport Spectra-Physics) to tune the excitation wavelength to 400 nm. This beam was focused on the sample after passing through a mechanical chopper (500 Hz). The other 800 nm branch of the beam went to a delay stage to obtain the time resolution and was then focused on a CaF2 crystal to generate a white-light probe. The white light was split to a reference channel S4 and overlapped in the sample with the pump beam. A cyclic voltammetry (CV) analysis was conducted using CH Instruments Electrochemical Analyzer/Workstation (Model 700E Series). The electrode ink was prepared using Hex-Aza-COF-3 (9 mg) and Nafion binder (1 mg) in water:ethanol (1:1), ultrasonicated for a few hours, coated onto a 5 mm glassy carbon electrode, and perfectly dried. Glassy carbon in anhydrous acetonitrile (CH3CN) containing 0.1 M tetrabutylammonium hexafluorophosphate was used as the working electrode, Ag/AgCl in CH3CN as the reference electrode, and Pt as the counter electrode with a scan rate of 100 mV s −1 . Light irradiation experiments were performed with a ZLED CLS 6000 lamp (ZETT OPTICS) comprising white LEDs as a cold light source. The light flux was ~650 lumen with an approximate wavelength range from 400 to 700 nm. For all experiments, the light intensity was adjusted to 100%.
Section S2: Synthesis and Characterization of Hex-Aza COF-3 1. Synthesis of 2,3,6,7-Tetraamino-phenazine Hydrochloride (4) Scheme S1: Synthesis of monomer 4 Compound 4 was prepared following a previously reported procedure (Scheme S1). 1 To a solution of 1,2,4,5tetraamino-benzene-tetrahydrochloride (3.25 g, 11.44 mmol) in distilled water (30 mL), sodium acetate (7.51 g, 37.69 mmol) was added, and the reaction mixture was refluxed while passing compressed air through the solution for 5 h. The reaction mixture was allowed to cool to room temperature, causing the precipitation of a solid. The solid was separated by filtration, washed with water, and dried under vacuum to afford 2,3,6,7-tetraaminophenazine hydrochloride (4; 2.19 g, 69% yield) as a deep-purple solid. The spectroscopic data are consistent with those previously reported in the literature.

Synthesis of Hexaazatrinaphthylene (5)
Scheme S2: Synthesis of monomer 5 Compound 5 was prepared using a reported procedure (Scheme S2). 2 To a mixture of hexaketocyclohexane octahydrate (1.52 g, 4.87 mmol) and 1,2-phenylenediamine (1.74 g, 16.09 mmol) anhydrous methanol (50 mL) was added and the mixture was refluxed for 4 h. The reaction mixture was cooled to room temperature, and a solid precipitated out. The solid was separated by filtration, washed with methanol, and dried under vacuum to give 6 (2.19 g, 89% yield, based on hexaketocyclohexane octahydrate) as yellow-green flake solids. The spectroscopic data are consistent with those previously reported in the literature.

Synthesis of Hex-Aza-COF-3
Scheme S3: Synthesis of Hex-Aza-COF-3 Hex-Aza-COF-3 was prepared as per a reported procedure (Scheme S3) 3 via solvothermal condensation reaction of hexaketocyclohexane octahydrate (93.5 mg, 0.30 mmol) and 2,3,6,7-tetraaminophenazine hydrochloride (157.1 mg, 0.45 mmol) in a 1:1 mixture of ethylene glycol (5 mL) and 6.0 M acetic acid (5 mL). Initially, reactants and solvents were transferred to 70 mL screw-capped Pyrex tubes under nitrogen atmosphere and sonicated for 15 min. After sonication, the Pyrex tubes were transferred to a preheated oven at 65 °C. The Pyrex tubes were then incubated at 65 °C for 4 h, and the temperature of the oven was then slowly raised to 120-150 °C. After four days of reaction, the Pyrex tubes were removed from the oven. Hex-Aza-COF-3 was isolated as a black powder by filtration, washed with dimethylformamide (DMF), acetone, and water and activated at room temperature under vacuum for 12 h.
This activated COF catalyst was directly employed for the photocatalytic reaction.

Characterization Data for Hex-Aza-COF-3
The data obtained for Hex-Aza-COF-3 are in full agreement with those previously published in the literature. 3
The reaction mixture was sonicated for 15 min, followed by stirring at room temperature for 9 h under white LED irradiation using ZLED CLS 600 (ZETT OPTICS) as the light source at full power. The reaction mixture was transferred to a centrifuge tube and centrifuged at 5000 rpm for 5 min, and the liquid phase was separated. To the residue was added CH3CN (5 mL), mixed thoroughly, centrifuged at 5000 rpm for 5 min, and the liquid phase was separated. The combined liquid phase was concentrated under reduced pressure, and the crude product was purified by Flash chromatography on a Biotage Snap Cartridge (KP-Sil 10 g) using a gradient solvent system (5% to 20% ethyl acetate in hexanes) to afford product 3. S8

Computational Methods and UV-Vis Spectroscopy Studies
Density functional theory (DFT) calculations were performed to optimize the ground-state geometries of substrate 1a, 4, 5 and Hex-Aza-COF-3 using the B3LYP functional and the 6-311G(d,p) basis set as implemented in Gaussian09 program (Revision D. 01). The solvent effects of CH3CN (ε = 35.688) were considered in the geometry optimizations and electronic calculations using the polarizable continuum model.
Product 3b was obtained as a white solid (1.01 g, 96% yield) after purification by flash chromatography. The same NMR data as described above were obtained. 2,3-Dihydrobenzofuran derivative 3b was then converted to (±)conocarpan.

2-(4-Methoxyphenyl)-3-methyl-2,3-dihydrobenzofuran-5-ol (6):
To a solution of compound 3b (0.4g, 1.15 mmol) in THF (25 mL), 10% Pd/C (40 mg) was added. The reaction mixture was bubbled with H2 gas using a balloon equipped with a syringe needle and stirred at room temperature in H2 atmosphere for 6 h. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure and dried at 45 ˚C in a vacuum oven. The dried crude product (0.296 g, quantitative yield) was used for the next step without further purification.

2-(4-Methoxyphenyl)-3-methyl-2,3-dihydrobenzofuran-5-yl trifluoromethanesulfonate (7):
The crude compound 6 (0.296 g, 1.15 mmol) was placed in a round bottom flask equipped with a stir bar, and CH2Cl2 (20 mL) was then added. The solution was cooled to 0 ˚C in an ice bath and then flushed with N2 gas. Subsequently, pyridine (500 µL, 6.3 mmol) was added in one portion. Triflic anhydride (391 µL, 2.32 mmol) was then added dropwise over a period of 10 min via syringe at 0 ˚C. After stirring at 0 ˚C for 10 min, the mixture was allowed to warm to room temperature S19 and stirred for an additional 3 h at this temperature. The reaction was quenched by adding 10 mL of 1 M HCl, and the resulting mixture was transferred to a separation funnel and diluted with CH2Cl2 (25 mL). The organic layer was separated from the aqueous layer, which was extracted once with CH2Cl2 (25 mL), and the combined organic extracts were washed with sat. aq. NaHCO3 (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Biotage Snap Cartridge (KP-Sil 50 g) using a gradient solvent system (5% to 20% ethyl acetate in hexanes) to afford product 7 as a white solid (0.41 g, 91% yield over two steps). The spectroscopic data are in full agreement with those previously published in the literature.

1-(3,3-Diethoxypropoxy)-3-methoxybenzene (11):
To a solution of 3-methoxyphenol (1.51 g, 12 mmol) in DMF (20 mL), NaH (0.97 g of a 60% suspension in oil, 24 mmol) was added at 0 ˚C in an ice bath. The mixture was stirred at room temperature for 30 min, and 3-bromo-1,1-diethoxypropane (2.57 g, 12 mmol) was then added.  CH3CN (15 mL). On completion of the reaction, Hex-Aza-COF-3 was recovered by centrifugation and washed with CH3CN (10 mL), water (10 mL), THF (10 mL), and acetone (10 mL), dried at room temperature under vacuum overnight, and used for the next cycle. Hex-Aza-COF-3 was used up to five consecutive cycles and after each cycle, product 3a was isolated and purified by flash chromatography on a Biotage Snap Cartridge (KP-Sil 25 g) using a gradient solvent system (5% to 20% ethyl acetate in hexanes). The results of this study are summarized in Figure S6. persulfate (55 mg, 0.24 mmol) were added. The reaction mixture was sonicated for 15 min and then stirred at room temperature for 9 h under sunlight as the light source. The reaction mixture was transferred to a centrifuge tube and centrifuged at 5000 rpm for 5 min, and the liquid phase was separated. To the residue, CH3CN (5 mL) was added, mixed thoroughly, centrifuged at 5000 rpm for 5 min, and the liquid phase was separated. The combined liquid phase was concentrated under reduced pressure and the crude product was purified by flash chromatography on a Biotage Snap Cartridge (KP-Sil 10 g) using a gradient solvent system (5%-20% ethyl acetate in hexanes) to afford product 3a.