Visible-Light-Photocatalyzed Reductions of N-Heterocyclic Nitroaryls to Anilines Utilizing Ascorbic Acid Reductant

A photoreductive protocol utilizing [Ru(bpy)3]2+ photocatalyst, blue light LEDs, and ascorbic acid (AscH2) has been developed to reduce nitro N-heteroaryls to the corresponding anilines. Based on experimental and computational results and previous studies, we propose that the reaction proceeds via proton-coupled electron transfer between AscH2, photocatalyst, and the nitro N-heteroaryl. The method offers a green catalytic procedure to reduce, e.g., 4-/8-nitroquinolines to the corresponding aminoquinolines, substructures present in important antimalarial drugs.


General information
The general experimental procedures, specific details for representative reactions and spectroscopic information for all new compounds are presented below. All commercial chemicals were used as received. Photocatalysts were purchased from TCI Europe (Ru(bpy)3Cl2*6H2O) and Ir(ppy) 3 1 H and 13 C{ 1 H} spectra were referenced to the residual solvent signals (in CDCl3 7.26 and 77.2 ppm, respectively; in DMSO-d6 2.50 and 39.5 ppm, respectively). No special notation was used for equivalent carbons. Fluorescence spectra were measured with Horiba Jobin Yvon Fluromax-4 spectrofluorometer using standard 10 mm fluorescence cuvettes. IR spectra were measured with FTIR Bruker Alpha spectrometer. GC measurements were done on Bruker Scion 436-GC with flame ionization detector with biphenyl as internal standard. High resolution mass spectra were obtained with Bruker ESI microTOFLC instrument in positive ionisation mode. Supelco silica gel TLC-cards with fluorescent indicator (254 nm) were used for TLC chromatography and Rf-value determinations. The melting points were determined in capillary tubes with Büchi 510 melting point apparatus and are reported uncorrected. All photoreductive nitro transformations were performed in 10 mL Schlenk-tubes (ca. 110 x 10 mm) under an argon atmosphere. The distance from the light source was 5 cm. The 5 x 3W blue (455 nm) LEDs were positioned in a vertical row along the Schlenk-tube.

Optimization studies
2-methoxy-6-nitroquinoline -1a (0.0408 g, 0.2 mmol), ascorbic acid (varying equiv) and respective photocatalyst (varying equiv) were weighted in a Schlenk-tube equipped with stirrer bar. The tube was evacuated and back filled with Argon three times. Solvent (10 mL) degassed by bubbling with argon for 15 minutes was added and the tube was placed under a blue light irradiation (455 nm) on a magnetic stirrer plate for 1 hour at room temperature. Next, 1 mL aliquot of the reaction mixture was quenched by Et3N (2 equiv) and the crude was filtrated trough plug of SiO2 and was washed with DCM:EtOAc (1:1). The filtrate was concentrated and 0.5 mL of biphenyl (0.02 M in EtOAc) was added as internal standart. The sample was diluted to 5 mL with EtOAc and 1 mL of it was filtrated trough 0.2 µm Phenex TM PVDF syringe filter and transfered to GC vial. The yields and convertions were determined as average of two runs by calibrated GC-FID analisys with biphenyl as internal standart. Table S1. Optimization of Photocatalyst. Conditions: 2-methoxy-6-nitroquinoline -1a (0.0408 g, 0.2 mmol), ascorbic acid (0.1409 g, 0.8 mmol) and respective photocatalyst, concentration 0.02M, 10 mL MeOH/H2O (4:1). nd -not detected

Fluorescence quenching studies
The fluorescence quenching studies were performed in degassed MeOH/H2O (4:1) solvent mixture under Argon. The concentration of the photocatalyst (Ru(bpy)3Cl2*6H2O) was set to 10 M, the excitation wavelength was set at 455 nm and the emission range was set between 500 -800 nm. The quenchers (ascorbic acid, sodium ascorbate, nitrobenzene -4, 2-methyl-8-nitroquinoline -1k and the complexes of 2-methyl-8-nitroquinoline -1k and lactic acid and ascorbic acid) with concentration of 0.2 M (1 l = 10 equiv) were added to the photocatalyst solution in steps of 10, 100, 500, 1000 and 2500 equiv. The quenching was monitored in the range from 10 equiv (2*10 -7 M) to 10000 equiv (2.8*10 -4 M) of the corresponding quencher. The Stern-Volmer plots were prepared by analyzing emission intensity at 602 nm of the titration curve ( Figure S1-S6).    The quenching ability of the ascorbic acid, sodium ascorbate, nitrobenzene -4, 2-methyl-8-nitroquinoline -1k, and 1:1 mixtures of 1k with either lactic acid (pKa 3.86) or ascorbic acid (pKa 4.12) were compared (Figure S1-S6). Sodium ascorbate was determined to be the most competent quencher compared to the others, although no amine formation was observed in the reaction with sodium ascorbate (Table S7, entry S7). The 1k:AscH2 complex was determined to be a better quencher than the respective components, and the lactic acid complex of 1k. This implies that the concentration of the 1k:AscH2 complex has a direct connectivity to the photocatalyst fluorescence quenching at the reaction related concentration. Nitrobenzene -4 appears to be a potent quencher, which is consistent with computed energetics for electron transfer (Table S9).
Distinctively, several Stern-Volmer plots show downward curvature ( Figure S7-left), which can be associated with partial inaccessibility of quencher to the fluorophore. 1 To evaluate this phenomenon further, modified Stern-Volmer plots were made to identify the linear accessible fraction (fa, Figure S7-right). The y-intercepts give reciprocal of the accessible quencher (1/fa). Possible reasons for this behavior could be e.g. limited solubility and/or ionic character of quencher. 1 Figure S7. The results from the Stern-Volmer quenching studies led us to investigate further the possibility of 1k + AscH2 to participate in PCET-type reaction. Qiu  indicative of PCET-type reaction. Following their reasoning we performed analogues Stern-Volmer titrations. The concentration of the photocatalyst and one of the quencers are kept constant, whereas the ∆c of other quencher component should cover a vast concentration range. The modified Stern-Volmer titrations were performed in degassed MeOH/H2O (4:1) solvent mixture under Argon. The concentration of the photocatalyst (Ru(bpy)3Cl2*6H2O) was set to 10 M, concentration of nitrobenzene -4 or 2-Methyl-8-nitroquinoline -1k was set to 10 mM, and the concentration of ascorbic acid was varied from 1 equiv (0.01 M) to 40 equiv (0.4 M) according to the loading of 4 or 1k ( Figure S8-S9).

Mechanistic studies NMR experiments
4-methoxy-8-nitroquinoline -1c (0.0408 g, 0.2 mmol), ascorbic acid (0.1409 g, 0.8 mmol) and Ru(bpy)3Cl2*6H2O (0.0015 g, 0.002 mmol) were weighted in a Schlenk-tube equipped with a stirrer bar. The tube was evacuated and back filled with Argon three times. A 10 mL of degassed by bubbling with argon for 15 minutes CD3OD/D2O (4:1) solvent mixture was added and the tube was placed under a blue light irradiation (455 nm) on a magnetic stirrer plate for 2 h at room temperature.   High-resolution mass spectra of the Intermediate: sample was prepared by taking an aliquot of 0.5 mL from a reaction performed as described for NMR monitoring experiments in MeOH/H2O (4:1) solvent mixture at the 45 min from the beginning of the reaction ( Figure S13).

General procedures
General procedure for photocatalytic nitro reduction to amine: The corresponding nitro compound (1 equiv), ascorbic acid (4 equiv) and Ru(bpy)3Cl2*6H2O (1 mol %) were weighted in a Schlenk-tube equipped with a stirrer bar. The tube was evacuated and back filled with Argon three times. A 10 mL of degassed (three freeze-pump-thaw cycles) MeOH/H2O (4:1) solvent mixture was added and the tube was placed under a blue light irradiation (455 nm) on a magnetic stirrer plate for a reaction period at room temperature. The reaction was monitored with TLC and after completion, the reaction mixture was quenched by Et3N (2 equiv). The crude was absorbed on SiO2 and purified with SiO2 flash chromatography. Scheme S1. Representative example for the nitro reduction according to the general procedure.
General procedure for nitration:

Method A -using hydroxyquinoline
A round-bottom flask equipped with a stirrer bar was charged with the corresponding hydroxyquinoline (1 equiv) and 5 mL conc. H2SO4 acid. The reaction mixture was cooled down to 0 o C and conc. HNO3 acid (3.5 equiv) was added dropwise. The reaction mixture was stirred for 1 hour at 0 o C on a magnetic stirrer plate and was quenched with ice/water mixture. The formed solids were filtrated off and were washed with plenty of water. The crude was dried and used without further purification. Scheme S2. Representative example for the nitration according Method A.

Method B -using chloroquinoline
A round-bottom flask equipped with a stirrer bar was charged with the corresponding chloroquinoline (1 equiv) and 5 mL conc. H2SO4 acid. The reaction mixture was cooled down to 0 o C and conc. HNO3 acid (3.5 equiv) was added dropwise. The reaction mixture was stirred for 5 minutes at 0 o C and further for 30 minutes at 40 o C on a magnetic stirrer plate. The crude was quenched with ice/water mixture. The reaction mixture was extracted with EtOAc and the organic layer was washed with sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography.

General procedure for chlorination of hydroxyquinolines:
A round-bottom flask equipped with a stirrer bar was charged with the corresponding hydroxyquinoline (1 equiv) suspended in 50 mL of dry Toluene. Phosphorous oxychloride (10 equiv) was added to the suspension and the reaction mixture was refluxed under argon for 20 hours on a magnetic stirrer plate. After completion of the reaction, the mixture was carefully quenched with water (NB! exothermic reaction) and basified with aqueous NH4OH. The reaction mixture was extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography. Scheme S4. Representative example for the chlorination of hydroxyquinolines according to the general procedure.
General procedure for the preparation of ethers:

Method A -Methyl ether
A round-bottom flask equipped with a stirrer bar was charged with the corresponding chloroquinoline (1 equiv) suspended in 20 mL of MeOH. 5 M solution of sodium methoxide (1.2 equiv) was added to the suspension and the reaction mixture was refluxed under Argon for 2 hours on a magnetic stirrer plate. After completion of the reaction, the mixture was quenched with water. The reaction mixture was extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography. Scheme S5. Representative example for the preparation of methyl ethers according to the general procedure.

Method B -Allyl and Benzyl ethers
A round-bottom flask equipped with a stirrer bar was charged with the corresponding hydroxyquinoline (1 equiv) and potassium carbonate (2 equiv) suspended in 10 mL/mmol of DMF. Corresponding allyl bromide (1.2 equiv) or benzyl bromide (1.5 equiv) was added to the suspension and the reaction mixture was kept at 80 o C under Argon for 24 hours on a magnetic stirrer plate. After completion of the reaction, the mixture was quenched with water. The reaction mixture was extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography. Scheme S6. Representative example for the preparation of allyl/benzyl ethers according to the general procedure.

General procedure for the preparation of quinoline N-oxides:
A round-bottom flask equipped with a stirrer bar was charged with the corresponding quinoline (1 equiv) dissolved in 5 mL of AcOH. Hydrogen peroxide 33% assay (1.5 equiv) was added to the solution and the reaction mixture was stirred at 70 o C for a reaction period on a magnetic stirrer plate. After completion of the reaction, the reaction mixture was extracted with EtOAc, organic layer was washed with sat. NaHCO3 and was dried over Na2SO4 followed by evaporation to dryness. The crude was purified by SiO2 flash chromatography. Scheme S7. Representative example for the preparation of quinoline N-oxides according to the general procedure.
6-methoxy-8-nitroquinoline (0.817 g, 4 mmol), ascorbic acid (2.818 g, 16 mmol) and Ru(bpy)3Cl2*6H2O (0.015 g, 0.02 mmol) were weighted in a Schlenk-tube equipped with stirrer bar. The tube was evacuated and back filled with Argon three times. A 200 mL of degassed (three freeze-pump-thaw cycles) MeOH/H2O (4:1) solvent mixture was added and the tube was placed under a blue light irradiation (455 nm) on a magnetic stirrer plate for 24 h at room temperature. The reaction was monitored with TLC and after completion, the reaction mixture was quenched by sat. NaHCO3, extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography using DCM:EtOAc (20:1) as eluent. Yield 73% (0.509 g, 2.92 mmol).

Synthesis of quinolin-6-amine -2i.
The title compound was synthesized following the general procedure for photocatalytic nitro reduction to amine.

Synthesis of quinolin-5-amine -2j.
The title compound was synthesized following the general procedure for photocatalytic nitro reduction to amine.

Synthesis of 6-bromo-8-nitroquinolin-4-ol -S7.
Step 1: Preparation of intermediate. A round-bottom flask equipped with a stirrer bar was charged with Meldrum's acid (12.972 g, 90.00 mmol) and trimethyl orthoformate (171.161 mL, 1500.00 mmol). The reaction mixture was refluxed for 4 h on a magnetic stirrer plate after which 4-bromo-2-nitroaniline (13.021 g, 60.00 mmol) was added and the refluxing was continued for 20 h. After completion of the reaction, the excess of trimethyl orthoformate was evaporated and the solids were suspended in Et2O. The solids were then filtrated off and washed with Et2O.
Step 2: Cyclization. A round-bottom flask equipped with a stirrer bar was charged with the crude intermediate (6.000 g, 16.17 mmol), which was dissolved in PhOPh (2 mL/mmol) and refluxed for 4 h in a heating mantle on magnetic stirrer plate. After completion, the reaction mixture was cooled down and diluted with Et2O. The precipitated solids were then filtrated off and washed with Et2O. Yield 55% (

Synthesis of 2-methyl-8-nitroquinolin-6-ol -S9.
A round-bottom flask equipped with a stirrer bar was charged with 4-Amino-3-nitrophenol (4.624 g, 30.00 mmol) suspended in a mixture of 35 mL of conc. HCl and 15 g o.H3PO4. The suspension was warmed up to 80 o C. Crotonaldehyde (2.734 mL, 33.00 mmol) was added to the suspension dropwise during 2 1/2 h. After the complete addition of the Crotonaldehyde the reaction mixture was kept at 95 o C for 3 h on a magnetic stirrer plate. After completion of the reaction, the mixture was quenched with water. The reaction mixture was extracted with EtOAc. The organics were discarded and the aqueous layer was neutralize with NaHCO3 and re extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography. Yield 40% (2.450 g, 12.00 mmol). Purification: Flash chromatography (SiO2) using n-hexane:EtOAc (4:1→1:1) as eluent.

Synthesis of 2-methyl-8-nitroquinolin-6-yl acetate -1n.
A round-bottom flask equipped with a stirrer bar was charged with 2-methyl-8nitroquinolin-6-ol -S9 (0.408 g, 2.0 mmol) suspended in 20 mL of DCM. Pyridine (0.322 mL, 4.0 mmol) was added to the suspension and the reaction mixture was cooled down to 0 o C. Acetic anhydride (0.284 mL, 3.0 mmol) dissolved in 5 mL of DCM was added to the cooled reaction mixture dropwise during 10 min. After the complete addition of the Acetic anhydride the reaction mixture was kept at room temperature under Argon for 24 h on a magnetic stirrer plate. After completion of the reaction, the mixture was quenched with water. The reaction mixture was extracted with DCM, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography. Yield 72% (0.354 g, 1.44 mmol). Purification: Flash chromatography (SiO2) using nhexane:EtOAc (4:1→2:1) as eluent.

Synthesis of 2-methyl-8-nitroquinolin-6-yl trifluoromethanesulfonate -1o.
A round-bottom flask equipped with a stirrer bar was charged with 2-methyl-8nitroquinolin-6-ol -S9 (1.021 g, 5.0 mmol) suspended in 50 mL of DCM. Pyridine (0.805 mL, 10.0 mmol) was added to the suspension and the reaction mixture was cooled down to 0 o C. Trifluoromethanesulfonic anhydride (1.230 mL, 7.5 mmol) dissolved in 10 mL of DCM was added to the cooled reaction mixture dropwise during 10 min. After the complete addition of the trifluoromethanesulfonic anhydride the reaction mixture was kept at room temperature under Argon for 24 h on a magnetic stirrer plate. After completion of the reaction, the mixture was quenched with water. The reaction mixture was extracted with DCM, dried over Na2SO4 and evaporated to dryness. The crude was purified by SiO2 flash chromatography. Yield 51% (0.857 g, 2.55 mmol). Purification: Flash chromatography (SiO2) using n-hexane:EtOAc (4:1) as eluent.

Synthesis of 1-(4-nitro-1H-indazol-1-yl)ethan-1-one -3d.
A round-bottom flask equipped with a stirrer bar was charged with 4-nitro-1H-indazole (0.489 g, 3.0 mmol) then acetic anhydride 10 mL was added and the reaction mixture was refluxed for 2 h on a magnetic stirrer plate. After completion of the reaction, the mixture was quenched with water. The formed solids were filtrated off and were washed with plenty of water. The solids were dissolved in EtOAc and were extracted between EtOAc and saturated solution of NaHCO3, dried over Na2SO4 and evaporated to dryness. Yield 94% (0.