Visible-light-mediated reaction: synthesis of quinazolinones from 1,2-dihydroquinazoline 3-oxides

Abstract

1-Methyl-2-phenylquinazolin-4(1H)-ones were synthesized in good yield by exposing 1,4-dimethyl-2-phenyl-1,2-dihydroquinazoline 3-oxides or 1-methyl-2-phenyl-1,2-dihydroquinazoline 3-oxides to visible light in acetonitrile in the absence of any external photosensitizers. The key intermediate for this photochemical reaction was isolated and identified as 1-methyl-2-phenyl-1,4-dihydroquinazolin-4-ol. The mechanism of this photosensitizer-free, visible-light-mediated reaction was proposed.

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1. Introduction

Quinazolinones are crucial moieties in a wide range of relevant pharmacophores with a broad spectrum of biological activities, including antibacterial,¹ antifungal,² antiinflammatory,³ antimalarial,⁴ antimicrobial,⁵ and antitumor⁶ activities. Therefore, massive synthetic efforts have been made for their synthesis.⁷ While numerous methods for the preparation of quinazolinones have been developed, the synthesis of quinazolinones via a metal-free, visible-light-mediated methodology has yet to be described in the literature. Since visible light is an abundant and renewable energy source for green chemical reactions,⁸ the development of new light-sensitive molecular scaffolds to undergo organic reactions under visible light irradiation has recently attracted considerable attention.⁹ In this respect, we previously reported¹⁰ that 1,2-dihydroquinazoline 3-oxide 1 is light-sensitive and prone to undergo photoinduced intramolecular electron transfer from amine hydrogen to iminium oxide and subsequent dehydration to the quinazoline 2 upon visible light irradiation (Scheme 1). In an effort to extend this visible-light-mediated process to other chemical reactions rather than simple dehydration, the hydrogen atom on the NH group of 1,2-dihydroquinazoline 3-oxide is replaced with an N-methyl group to block the hydration process. Here, we report the photochemical properties of the prepared 1,4-dimethyl-2-phenyl-1,2-dihydroquinazoline 3-oxides and 1-methyl-2-phenyl-1,2-dihydroquinazoline 3-oxides. Both compounds were found to be sensitive to light and can be converted to 1-methyl-2-phenylquinazolin-4(1H)-ones upon visible light irradiation. Further, a plausible mechanism for the visible-light-mediated formation of quinazolinone was proposed on the basis of the ESR spectral data of the starting material and the molecular structure of the key intermediate isolated from the photochemical reaction.

Scheme 1 Visible-light-mediated synthesis of quinazoline 2 from 1.

2. Results and discussion

The target compounds 1,4-dimethyl-2-phenyl-1,2-dihydroquinazoline 3-oxides (3a–e) were readily prepared in three steps as described in the literature (Scheme 2).¹¹ First, the 2′-aminoacetophenone (4) was methylated by treating with methyl iodide in toluene to afford the N-methylated 5. Second, compound 5 was converted to the corresponding oxime 6 by reacting with hydroxylamine hydrochloride under basic conditions in ethanol at 60 °C. Third, the condensation of oxime 6 with benzaldehyde in the presence of a catalytic amount of p-TsOH in ethanol at room temperature furnished the target compound 3. The molecular structure of 3a was verified by ¹H and ¹³C NMR spectroscopy and further confirmed by single-crystal X-ray diffraction analysis as shown in Fig. 1.¹² Similar to 1, compound 3a were also found to be light-sensitive. When exposed to visible light irradiation (a 23 W fluorescence light bulb or blue LED) in the absence of any external sensitizers under aerobic or anaerobic conditions in acetonitrile, it was converted to the 1-methyl-2-phenylquinazolin-4(1H)-one (7a) (Scheme 2), whose molecular structure was also confirmed by single-crystal X-ray diffraction analysis as presented in Fig. 1.¹²

Scheme 2 Preparation of 3a–e and its photogenerated product 7a–e.

Fig. 1 X-ray crystal structures of 7a (left) and 3a (right).

To gain more insights into the mechanism for this visible-light-mediated reaction, the 1,4-dimethyl-2-phenyl-1,2-dihydroquinazoline 3-oxide (3a) was subjected to the EPR measurements. Fig. 2 depicts the EPR spectra of 3a recorded in degassed CH₃CN solution at different irradiation times. After irradiation with visible light at room temperature for 20 minutes, strong splitting EPR signals were clearly observed at around 3460–3520 g. Prolonged irradiation increased the intensity of the signals but did not alter the absorption shape. These results provide strong evidence to support that the photochemical reaction of 3a involves, at least in part, a radical species as a transient intermediate.

Fig. 2 EPR spectra of 3a recorded in degassed CH₃CN solution at room temperature after being exposed to visible light, 0 to 20 min, in increments of 5 min.

The molecular structure of the photogenerated product 7a suggests that one molecule of methane or its equivalent is removed from the starting material 3a. In an attempt to unambiguously confirm that this photochemical reaction indeed involves the evolution of methane gas, the powered compound 3a was irradiated under visible light in a closed argon chamber for 24 hours and then the gas sample in the reaction chamber was withdrawn and subjected to gas chromatography analysis. As shown in Fig. 3, the observation of the peak at the retention time around 2.6 minutes on the chromatogram (c) clearly indicates the generation of methane gas in this visible-light mediated reaction.

Fig. 3 Detection of methane formation by gas chromatography. (a) Methane standard (blue line); (b) before visible light irradiation of 3a (red line); (c) after visible light irradiation of 3a for 24 h (green line).

On the basis of the EPR experimental results along with the GC detection of methane gas, a plausible mechanism for the formation of the quinazolinone 7a from 3a via visible light irradiation is proposed in Scheme 3. Presumably, the photoreaction involves a visible-light-mediated single-electron transfer (SET) from the amine nitrogen atom to the nearby iminium oxide group of 3a to generate the biradical species 8 which is responsible for the observed EPR signals. The biradical 8 then undergoes electron recombination to give the charge-separated transient species 9. Since the nitrogen atom on aniline is methylated, compound 9 cannot undergo dehydration as that of compound 1. Instead, the negative charge on oxygen of 9 attacks the nearby carbon to yield the oxaziridine 10 (ref. 13) which further rearranges to the dihydroquinazolinol 11 as an intermediate upon continuing irradiation. Again, this intermediate 11 is light-sensitive and susceptible to SET to form compound 12 and the methyl radical upon visible light irradiation. The subsequent hydroxyl hydrogen abstraction by the methyl radical generates the oxidized biradical species 13 with concomitant evolution of methane gas. Final electron redistribution of 13 through contributing structures 14 and 15 affords the product quinazolinone 7a. Essentially, this mechanism proposes the formation of two key zwitterionic species 8 and 12 generated by sequential photoinduced intramolecular electron transfer between the electron-donating amine and electron-accepting iminium oxide and methyleneamino alcohol, respectively. Thus, the quinazolinone 7a is likely produced via a tandem visible-light-mediated single-electron transfer process.

Scheme 3 Proposed mechanism for the formation of quinazolinone 7a from 1,2-dihydroquinazoline 3-oxide 3a.

To explore the scope of this visible-light-mediated reaction and to provide more evidence to support our proposed mechanism, a series of alternate substrates, that is, 1-methyl-2-phenyl-1,2-dihydroquinazoline 3-oxides (16a–g) were prepared to investigate their photochemical properties. As shown in Scheme 4, the synthesis of 16a–g started with N-methylation of quinoline (17) with methyl iodide in toluene to give the 1-methylquinolin-1-ium iodide (18). The ring-opening reaction of 18 was realized by treating it with hydrogen peroxide and aqueous sodium hydroxide to afford 2-methylaminobenzaldehyde (19).¹⁴ The subsequent oxime formation and benzaldehyde coupling reactions followed the exact same procedures as those of the preparation of 3 as shown in Scheme 1.

Scheme 4 Preparation of 16a–g and its photogenerated products 7a–g.

With compound 16a in hand, its photochemical properties were then investigated. Interestingly, the photogenerated product obtained by visible light irradiation of 16a was found to be exactly the same as the photogenerated product obtained by visible light irradiation of 3a, that is, 1-methyl-2-phenylquinazolin-4(1H)-one (7a) (Scheme 5). With our delight, this time we were able to isolate and characterize the intermediate quinazolinol 21 during the irradiation process. Fig. 4 depicts the X-ray crystal structure of 21, clearly showing that the hydroxyl group is almost perpendicular to the 1,4-dihydropyrimidine ring.¹² When further exposed to visible light in acetonitrile, the quinazolinol 21 was found to be oxidized to the corresponding quinazolinone 7a, quantitatively. This observation confirms that the quinazolinol 21 indeed is the intermediate for this visible-light-induced reaction. The formation of the photogenerated product 7 upon visible light irradiation of either 3 or 16 suggests that both compounds share a similar photochemical mechanism (Scheme 3), except that the former evolves methane and the latter evolves hydrogen gas. To the best of our knowledge, this visible-light-mediated formation of quinazolinone 7a from 1,2-dihydroquinazoline 3-oxide 3a represents the first example of methane evolution that involved the cleavage of a C(sp³)–CH₃ bond using merely visible light as the energy source.¹⁵

Scheme 5 Photochemical reaction of 16a and its photogenerated products 21 and 7a.

Fig. 4 X-ray crystal structure of 21.

3. Conclusion

In summary, 1,4-dimethyl-2-phenyl-1,2-dihydroquinazoline 3-oxides (3a–e) and 1-methyl-2-phenyl-1,2-dihydroquinazoline 3-oxides (16a–g) were synthesized to investigate their photochemical properties. Our studies have demonstrated that both compounds are sensitive to visible light and prone to undergo sequential visible-light-mediated intramolecular single-electron transfers. The first electron transfer results in the rearrangement of the starting materials to the corresponding quinazolinols 11 or 21, whereas the second oxidizes the quinazolinols to the product quinazolinones 7a–g. This visible-light-mediated reaction of 1,2-dihydroquinazoline 3-oxides may provide an alternate green access to the pharmaceutical important N-substituted quinazolinone derivatives.

4. Experimental

4.1. General

Melting points were determined on a Mel-Temp melting point apparatus in open capillaries and are uncorrected. MS were performed on JEOL JMS-SX/SX 102A spectrometer. IR spectra were obtained using a 1725XFT-IR spectrophotometer. Absorption spectra were acquired using an HP8453 spectrophotometer. Single crystal structures were determined by a Bruker AXS SMART-1000 X-ray single-crystal diffractometer. The EPR spectra were recorded on a Bruker EMX 10/12 spectrometer. ¹H and ¹³C NMR spectra were recorded at 400 and 100 MHz on a BRUKER Ascend TM 400 MHz spectrometer. Chemical shifts were reported in parts per million on the δ scale relative to an internal standard (tetramethylsilane, or appropriate solvent peaks) with coupling constants given in hertz. ¹H NMR multiplicity data are denoted by s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Analytical thin-layer chromatography (TLC) was carried out on Merck silica gel 60G-254 plates (25 mm) and developed with the solvents mentioned. Flash chromatography was performed in columns of various diameters with Merck silica gel (230–400 mesh ASTM 9385 kieselgel 60H) by elution with the solvent systems. The visible light irradiation reaction was performed with a 23 W household fluorescence lamp or blue LED.

4.2. Preparation of 1-(2-(methylamino)phenyl)ethanone (5)^11a

To a solution of 1-(2-aminophenyl)ethanone (4, 5.0 g, 37.0 mmol) in dry toluene (35 mL) was added methyl iodide (10.5 g, 74.0 mmol) at room temperature. The reaction mixture was then refluxed for 48 h. After cooled down to room temperature, the precipitate was filtrated and the filtrate was evaporated to dryness. The crude product was purified by column chromatography to obtain the title compound as a colourless oil (2.43 g, yield 44%). ¹H NMR (CDCl₃, 400 MHz) δ 8.77 (bs, 1H), 7.74 (dd, J = 8.4, 1.6 Hz, 1H), 7.38 (td, J = 7.6, 1.6 Hz, 1H), 6.87 (dd, J = 8.8, 1.2 Hz, 1H), 6.59 (td, J = 7.6, 1.2 Hz, 1H), 2.91 (d, J = 4.8 Hz, 3H), 2.57 (s, 3H).

4.3. Preparation of 1-(2-(methylamino)phenyl)ethanone oxime (6)^11b

To a solution of compound 5 (2.00 g, 13.4 mmol) in a 15% (v/v) solution of H₂O/EtOH (50 mL) was added hydroxylamine hydrochloride (2.79 g, 3 equiv.) and NaOH (4.29 g, 8 equiv.). The reaction was heated at 60 °C for 3 h. After cooled down to room temperature, the ethanol was removed in vacuo and water (mL) was added to the mixture. The product was extracted with EtOAc (3 × 75 mL) and the combined organic layer was dried over Na₂SO₄, and concentrated in vacuo. The crude product was further purified by column chromatography to obtain the title compound as a white solid (1.67 g, yield 76%). Mp 73–74 °C (lit.^11b 71–72 °C); ¹H NMR (CDCl₃, 400 MHz) δ 7.39 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (td, J = 7.6, 1.6 Hz, 1H), 7.13 (bs, 1H), 6.70–6.66 (m, 2H), 2.89 (s, 3H), 2.33 (s, 3H).

4.4. General procedure for preparation of compounds 3a–e

To a solution of compound 6 (164.2 mg, 1.00 mmol) in ethanol (15 mL) was added benzaldehydes (1.00 mmol) and a catalytic amount of p-TsOH (19 mg, 0.10 mmol) at room temperature. The resulting mixture was stirred at that temperature for 1 h. After completion of the reaction, the solvent was concentrated in vacuo and the product was extracted with CH₂Cl₂/water. The combined organic layer was dried over Na₂SO₄, concentrated in vacuo, and the product was purified by column chromatography to obtain the title compound.

4.4.1. 1,4-Dimethyl-2-phenyl-1,2-dihydroquinazoline 3-oxide (3a). Yellow solid (198.3 mg, yield 79%); mp 144–145 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.33–7.24 (m, 6H), 6.88 (td, J = 8.0, 0.8 Hz, 1H), 6.73 (dd, J = 8.0, 0.8 Hz, 1H), 6.02 (s, 1H), 3.00 (s, 3H), 2.45 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 141.3, 140.1, 135.6, 130.8, 129.5, 128.8, 126.7, 124.9, 119.2, 118.1, 111.9, 118.1, 111.9, 85.9, 36.2, 12.3; IR ν (KBr) 1589, 1495, 1221, 1208, 751 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₆N₂O [M⁺] 252.1263, found 252.1264.

4.4.2. 2-(4-Methoxyphenyl)-1,4-dimethyl-1,2-dihydroquinazoline 3-oxide (3b). Yellow solid (236.6 mg, yield 84%); mp 159–160 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.28 (dd, J = 8.8, 1.2 Hz, 1H), 7.25–7.23 (m, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.87 (td, J = 7.6, 0.8 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H), 5.95 (s, 1H), 3.73 (s, 3H), 2.96 (s, 3H), 2.41 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 160.5, 141.3, 139.5, 130.7, 128.1, 127.9, 124.8, 119.0, 118.0, 114.1, 111.7, 85.6, 55.3, 36.0, 12.3; IR ν (KBr) 1505, 1253, 1203, 1173, 1019, 748 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₈N₂O₂ [M⁺] 282.1368, found 282.1365.

4.4.3. 2-(4-Bromophenyl)-1,4-dimethyl-1,2-dihydroquinazoline 3-oxide (3c). Yellow solid (313.6 mg, yield 95%); mp 161–162 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.39 (d, J = 8.8 Hz, 2H), 7.29 (td, J = 8.0, 1.2 Hz, 1H), 7.24 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 6.89 (td, J = 8.0, 1.2 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.97 (s, 1H), 3.00 (s, 3H), 2.43 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 140.9, 139.9, 134.6, 132.0, 130.9, 128.4, 124.9, 123.7, 119.6, 118.1, 112.3, 85.4, 36.5, 12.3; IR ν (KBr) 1585, 1499, 1204, 1008, 798, 748 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₅BrN₂O [M⁺] 330.0368, found 330.0371.

4.4.4. 2-(2-Methoxyphenyl)-1,4-dimethyl-1,2-dihydroquinazoline 3-oxide (3d). Yellow solid (220.9 mg, yield 78%); mp 120–121 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.31 (dd, J = 8.0, 1.2 Hz, 1H), 7.27–7.19 (m, 2H), 6.97 (dd, J = 8.0, 1.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (td, J = 8.0, 1.2 Hz, 1H), 6.75 (td, J = 8.0 Hz, 1H), 6.57 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H), 2.88 (s, 3H), 2.53 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 157.0, 141.7, 141.0, 130.7, 130.6, 126.7, 124.4, 124.1, 121.0, 118.6, 118.2, 111.9, 111.2, 79.3, 55.8, 35.3, 12.1; IR ν (KBr) 3485, 1494, 1253, 1192, 752 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₈N₂O₂ [M⁺] 282.1368, found 282.1366.

4.4.5. 2-(2-Bromophenyl)-1,4-dimethyl-1,2-dihydroquinazoline 3-oxide (3e). Yellow solid (294.8 mg, yield 89%); mp 147–148 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (dd, J = 7.6, 1.2 Hz, 1H), 7.32 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (td, J = 7.6, 1.6 Hz, 1H), 7.18–7.11 (m, 3H), 6.90 (td, J = 8.0, 1.2 Hz, 1H), 6.65 (s, 1H), 6.64 (d, J = 7.6 Hz, 1H), 2.90 (s, 3H), 2.51 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 141.2, 140.5, 135.9, 133.5, 131.0, 130.9, 128.4, 127.0, 124.6, 123.5, 119.3, 117.8, 112.4, 83.5, 35.6, 12.1; IR ν (KBr) 1735, 1718, 1504, 1308, 1214, 749 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₅BrN₂O [M⁺] 330.0368, found 330.0364.

4.5. General procedure for preparation of compounds 7a–g

To a dried 25 mL round bottom flask was charged with 3a–e and 16a–g (0.10 mmol) in CH₃CN (20 mL) at room temperature. The resulting mixture was placed at a distance of approximate 10 cm from a 23 W fluorescent lamp (Philips essential 57 lm W⁻¹, 6500 K), and was irradiated for 24 and 4 h, respectively. After the completion of the reaction, the solvent was evaporated to dryness and the residue was purified by column chromatography to obtain the photogenerated product.

4.5.1. 1-Methyl-2-phenylquinazolin-4(1H)-one (7a). Light yellow solid (yield 76% from 3a; quantitative from 16a); mp 172–173 °C; ¹H NMR (CDCl₃, 400 MHz) δ 8.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.79 (td, J = 7.6, 1.6 Hz, 1H), 7.65–7.63 (m, 2H), 7.55–7.47 (m, 5H), 3.73 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 168.8, 162.5, 141.9, 134.9, 133.9, 130.7, 128.9, 128.7, 128.6, 126.2, 120.4, 115.3, 38.0; IR ν (KBr) 1635, 1487, 1392, 1147, 764, 716, 696 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₂N₂O [M⁺] 236.0950, found 236.0952.

4.5.2. 2-(4-Methoxyphenyl)-1-methylquinazolin-4(1H)-one (7b). Light yellow solid (yield 74% from 3b; quantitative from 16b); mp 171–172 °C; ¹H NMR (CDCl₃, 400 MHz) δ 8.38 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (td, J = 8.0, 1.6 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.49 (td, J = 8.0, 1.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 169.0, 162.4, 161.8, 142.2, 133.8, 131.2, 128.7, 127.0, 126.1, 120.5, 115.4, 114.0, 55.6, 38.4; IR ν (KBr) 1645, 1485, 1433, 1385, 1257, 771 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₄N₂O₂ [M⁺] 266.1055, found 266.1050.

4.5.3. 2-(4-Bromophenyl)-1-methylquinazolin-4(1H)-one (7c). Yellow solid (yield 74% from 3c; quantitative from 16c); mp 183–184 °C; ¹H NMR (CDCl₃, 400 MHz) δ 8.38 (dd, J = 7.6, 1.2 Hz, 1H), 7.79 (td, J = 7.6, 1.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.54–7.51 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 3.72 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 168.7, 161.6, 141.9, 134.1, 133.7, 132.0, 130.7, 128.9, 126.5, 125.5, 120.5, 115.3, 38.1; IR ν (KBr) 1634, 1519, 1398, 1144, 757, 692 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₁BrN₂O [M⁺] 314.0055, found 314.0052.

4.5.4. 2-(2-Methoxyphenyl)-1-methylquinazolin-4(1H)-one (7d). Light yellow solid (yield 79% from 3d; quantitative from 16d); mp 173–174 °C; ¹H NMR (CDCl₃, 400 MHz) δ 8.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.78 (td, J = 8.0, 1.6 Hz, 1H), 7.54–7.46 (m, 4H), 7.10 (td, J = 8.0, 0.8 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 169.2, 160.9, 156.2, 141.5, 133.9, 132.0, 130.6, 128.9, 126.1, 124.6, 121.4, 120.5, 115.2, 111.0, 55.8, 36.2; IR ν (KBr) 1643, 1523, 1390, 766, 751 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₄N₂O₂ [M⁺] 266.1055, found 266.1054.

4.5.5. 2-(2-Bromophenyl)-1-methylquinazolin-4(1H)-one (7e). Yellow solid (yield 75% from 3e; quantitative from 16e); mp 228–229 °C; ¹H NMR (CDCl₃, 400 MHz) δ 8.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.80 (td, J = 8.0, 1.6 Hz, 1H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.57–7.46 (m, 4H), 7.38 (dd, J = 8.0, 1.6 Hz, 1H), 3.60 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 168.7, 160.9, 141.1, 136.5, 134.2, 132.9, 131.5, 129.9, 129.0, 128.2, 126.6, 121.1, 120.6, 115.2, 36.0; IR ν (KBr) 1645, 1522, 1394, 762, 695 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₁BrN₂O [M⁺] 314.0055, found 314.0054.

4.5.6. 2-(4-Isopropylphenyl)-1-methylquinazolin-4(1H)-one (7f). Brown solid (quantitative from 16f); mp 147–148 °C; ¹H NMR (CDCl₃, 400 MHz) δ 8.37 (dd, J = 8.0, 1.2 Hz, 1H), 7.76 (td, J = 8.0, 1.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 3.74 (s, 3H), 2.98 (sep, J = 6.8 Hz, 1H), 1.28 (d, J = 6.8 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ 168.9, 162.7, 152.1, 142.0, 133.9, 132.3, 129.2, 128.6, 126.8, 126.2, 120.5, 115.4, 38.2, 34.2, 23.9; IR ν (KBr) 1626, 1595, 1493, 761, 698 cm⁻¹; HRMS (EI) calcd for C₁₈H₁₈N₂O [M⁺] 278.1419, found 278.1426.

4.5.7. 2-(4-Cyanophenyl)-1-methylquinazolin-4(1H)-one (7g). Yellow solid (quantitative from 16g); mp 135–136 °C; ¹H NMR (CDCl₃, 400 MHz) δ 8.37 (dd, J = 8.0, 1.2 Hz, 1H), 7.83–7.80 (m, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 168.4, 160.6, 141.6, 139.0, 134.4, 132.6, 129.7, 128.9, 126.9, 120.5, 117.9, 115.3, 114.7, 37.9; IR ν (KBr) 3032, 2230, 1718, 1494, 757 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₁N₃O [M⁺] 261.0902, found 261.0905.

4.6. Preparation of N-methyl quinolinium iodide (18)

To a solution of quinoline (3.70 g, 28.7 mmol) in dry toluene (200 mL) was added iodomethane (4.50 g, 31.5 mmol) at room temperature. The resulting mixture was refluxed under argon for 1 h. After cooled down to room temperature, the precipitate was collected via vacuum filtration and washed sequentially with Et₂O (3 × 10 mL) and petroleum ether (3 × 10 mL). The product was further dried under reduced pressure to give an orange solid (7.32 g, 94%): mp 130–131 °C (lit.¹⁶ 130–132 °C); ¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (d, J = 5.6 Hz, 1H), 9.29 (dd, J = 8.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.30 (t, J = 8.4 Hz, 1H), 8.18 (dd, J = 8.4, 5.6 Hz, 1H), 8.07 (t, J = 8.0 Hz, 1H), 4.65 (s, 3H).

4.7. Preparation of N-methyl-2-aminobenzaldehyde (19)¹⁴

To a solution of potassium hydroxide (8.30 g, 0.148 mol) in water (30 mL) and 1,2-dichloroethane (30 mL) was added hydrogen peroxide (6.4 mL, 35%) and was added dropwise 1-methylquinolinium iodide (18, 4.07 g, 15 mmol in 10 mL water) over 45 min at 0 °C. The resulting mixture was then stirred at room temperature for 48 h. Thiodiethanol (0.50 g) was added to the mixture and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL × 3). The organic layer was washed with water (30 mL) and saturated sodium sulfite solution (30 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate, 20 : 1) to obtain the title compound as a yellow oil (16.6 g, yield 84%). ¹H NMR (CDCl₃, 400 MHz) δ 9.82 (s, 1H), 8.24 (bs, 1H), 7.46 (dd, J = 7.6, 1.6 Hz, 1H), 7.41 (td, J = 8.4, 1.6 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 2.93 (d, J = 4.8 Hz, 3H).

4.8. Preparation of 1-(2-(methylamino)phenyl)ethanone oxime (20)¹⁷

To a solution of compound 19 (1.81 g, 13.4 mmol) in a 15% (v/v) solution of H₂O/EtOH (50 mL) was added hydroxylamine hydrochloride (2.79 g, 3 equiv.) and NaOH (4.29 g, 8 equiv.). The reaction was heated at 60 °C for 3 h. After cooled down to room temperature, the ethanol was removed in vacuo and water (mL) was added to the mixture. The product was extracted with EtOAc (3 × 75 mL) and the combined organic layer was dried over Na₂SO₄, and concentrated in vacuo. The crude product was further purified by column chromatography to obtain the title compound as a white solid (1.65 g, yield 82%): mp 48–49 °C (lit.¹⁷ 50–51 °C); ¹H NMR (CDCl₃, 400 MHz) δ 8.25 (s, 1H), 7.27 (td, J = 7.6, 1.6 Hz, 1H), 7.12 (dd, J = 7.6, 1.6 Hz, 1H), 6.95 (bs, 1H), 6.68–6.65 (m, 2H), 2.94 (d, J = 4.0 Hz, 3H).

4.9. General procedure for preparation of compounds 16a–16g

To a solution of compound 20 (150.0 mg, 1.00 mmol) in ethanol (15 mL) was added benzaldehydes (1.00 mmol) and a catalytic amount of p-TsOH (19 mg, 0.10 mmol) at room temperature. The resulting mixture was stirred at that temperature for 1 h. After completion of the reaction, the solvent was concentrated in vacuo and the product was extracted with CH₂Cl₂/water. The combined organic layer was dried over Na₂SO₄, concentrated in vacuo, and the product was purified by column chromatography to obtain the title compound.

4.9.1. 1-Methyl-2-phenyl-1,2-dihydroquinazoline 3-oxide (16a). Light yellow solid (158.0 mg, yield 66%); mp 134–135 °C (lit.¹⁷ 132–136 °C); ¹H NMR (CDCl₃, 400 MHz) δ 8.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.79 (td, J = 7.6, 1.6 Hz, 1H), 7.65–7.63 (m, 2H), 7.55–7.47 (m, 5H), 3.73 (s, 3H).

4.9.2. 2-(4-Methoxyphenyl)-1-methyl-1,2-dihydroquinazoline 3-oxide (16b). Light yellow solid (171.2 mg, yield 74%); mp 108–109 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.66 (s, 1H), 7.30–7.25 (m, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.05 (dd, J = 8.0, 1.2 Hz, 1H), 6.85–6.80 (m, 1H), 6.80 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.0 Hz, 1H), 5.90 (s, 1H), 3.76 (s, 3H), 2.94 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 160.8, 140.8, 131.5, 131.4, 128.1, 127.6, 126.1, 119.2, 116.4, 114.3, 111.3, 86.4, 55.4, 35.7; IR ν (KBr) 2930, 1598, 1495, 1231, 1180, 737 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₆N₂O₂ [M⁺] 268.1212, found 268.1208.

4.9.3. 2-(4-Bromophenyl)-1-methyl-1,2-dihydroquinazoline 3-oxide (16c). Light yellow solid (244.5 mg, yield 77%); mp 123–124 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.67 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.29 (td, J = 8.0, 1.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.05 (dd, J = 8.0, 1.2 Hz, 1H), 6.85 (td, J = 8.0, 1.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.92 (s, 1H), 2.98 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 140.4, 134.3, 132.1, 131.60, 131.56, 128.4, 126.2, 124.1, 119.7, 116.4, 111.7, 86.2, 36.1; IR ν (KBr) 1717, 1594, 1498, 1233, 748 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₃BrN₂O [M⁺] 316.0211, found 316.0215.

4.9.4. 2-(2-Methoxyphenyl)-1-methyl-1,2-dihydroquinazoline 3-oxide (16d). Light yellow solid (161.0 mg, yield 60%); mp 185–186 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (s, 1H), 7.29 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (td, J = 8.0, 1.6 Hz, 1H), 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.81 (dd, J = 8.0, 1.6 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 3.83 (s, 3H), 2.86 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 156.9, 140.6, 133.3, 131.3, 131.0, 127.0, 125.7, 124.0, 121.2, 118.8, 116.7, 111.4, 111.3, 80.1, 55.8, 34.9; IR ν (KBr) 3027, 1717, 1496, 1237, 770, 747 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₆N₂O₂ [M⁺] 268.1212, found 268.1216.

4.9.5. 2-(2-Bromophenyl)-1-methyl-1,2-dihydroquinazoline 3-oxide (16e). Light yellow solid (230.6 mg, yield 73%); mp 213–214 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.29–7.15 (m, 4H), 7.10 (d, J = 7.6 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.64 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 2.89 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 140.0, 135.6, 133.5, 132.8, 131.6, 131.3, 128.5, 127.2, 125.9, 123.3, 119.4, 116.2, 111.7, 84.1, 35.0; IR ν (KBr) 1716, 1496, 1367, 1230, 755 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₃BrN₂O [M⁺] 316.0211, found 316.0217.

4.9.6. 2-(4-Isopropylphenyl)-1-methyl-1,2-dihydroquinazoline 3-oxide (16f). Light yellow solid (184.8 mg, yield 66%); mp 147–148 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.67 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.26–7.21 (m, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.05 (dd, J = 8.0, 1.2 Hz, 1H), 6.82 (td, J = 8.0, 1.2 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.93 (s, 1H), 2.96 (s, 3H), 2.85 (sep, J = 7.6 Hz, 1H), 1.19 (d, J = 7.6 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ 150.7, 140.9, 132.7, 131.6, 131.4, 127.0, 126.7, 126.1, 119.1, 116.4, 111.2, 86.6, 35.7, 34.0, 23.9; IR ν (KBr) 1593, 1497, 1308, 1224, 738, 655 cm⁻¹; HRMS (EI) calcd for C₁₈H₂₀N₂O [M⁺] 280.1576, found 280.1572.

4.9.7. 2-(4-Cyanophenyl)-1-methyl-1,2-dihydroquinazoline 3-oxide (16g). Light yellow solid (201.7 mg, yield 77%); mp 76–77 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.69 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.32 (td, J = 8.0, 1.2 Hz, 1H), 7.07 (dd, J = 8.0, 1.2 Hz, 1H), 6.89 (td, J = 8.0, 1.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 3.04 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 140.2, 132.7, 131.84, 131.79, 127.6, 126.35, 126.34, 120.2, 118.3, 116.5, 113.8, 112.2, 86.0, 36.7; IR ν (KBr) 2229, 1590, 1456, 1230, 1128, 748, 655 cm⁻¹; HRMS (EI) calcd for C₁₆H₁₃N₃O [M⁺] 263.1059, found 263.1060.

4.10. Preparation of 1-methyl-2-phenyl-1,4-dihydroquinazolin-4-ol (21)

A dried 250 mL round bottom flask was charged with 16a (0.5 mmol) and CH₃CN (30 mL) at room temperature. The resulting mixture was placed at a distance of approximate 10 cm from a 23 W fluorescent lamp (Philips essential 57 lm W⁻¹, 6500 K) and was irradiated for 2 h. The precipitate was carefully collected via vacuum filtration, washed with hexanes (3 × 10 mL), and dried under reduced pressure to give a white solid. Mp 76–77 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.52–7.37 (m, 7H), 7.22 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.21 (s, 1H), 3.27 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ 153.6, 138.4, 136.0, 129.3, 128.6, 128.1, 126.4, 123.5, 122.9, 112.4, 76.6, 54.9, 35.7; IR ν (KBr) 1479, 1385, 1022, 750, 721, 698 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₄N₂O [M⁺] 238.1106, found 238.1101.

4.11. Gas chromatography analysis for methane formation

Gas chromatography analysis for methane formation was carried out in a Teflon-lined stainless steel chamber (600 mL capacity) equipped with an optical entry window. The effective irradiation area of the cell is ca. 50.3 cm². In this experiment, the solid compound 3a (500 mg) was introduced into the Teflon-lined reactor and placed the Teflon-lined reactor in the stainless steel chamber. The stainless steel chamber was then irradiated using a Xe arc lamp (Newport, 300 W) equipped with an optical cutoff filter (700 nm > λ > 400 nm) for 24 h. The lamp was positioned ca. 32 cm away from the optical entry window of the chamber. After that, the evolved methane gas was analyzed by means of gas chromatography (GC, Agilent 6890N) equipped with a thermal conductivity detector and a 5 Å molecular sieve column using argon as a carrier gas.

Acknowledgements

We thank the Ministry of Science and Technology of the Republic of China, Taiwan, for financially supporting this research under Grant No. MOST 104-2113-M-029-005.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR spectra of all compounds and ¹³C NMR spectra of 19 new compounds. X-ray crystal structure data for 3a, 7a, and 21 in CIF format. CCDC 1468852–1468854. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra13972h

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