INTRODUCTION

Green chemistry concerns environmentally friendly construction of novel products and chemical processes [1] while minimizing the usage and generation of hazardous chemicals. Organic solvents are the key factor in environmental pollution, and many of them are carcinogenic and toxic, which makes reactions not requiring the use of organic solvents desirable. Water is an alternative solvent for many chemical reactions; it possesses many valuable properties such as ready avail­ability, chemical stability, nontoxicity, recycl­ability, and easy handling. Moreover, in many reac­tions, water has been shown to significantly enhance the reaction rate in comparison to organic solvents due to hydrogen bonding, hydrophobic effect, high heat capacity, and high cohesive energy density [2].

Quinazolin-4-ones and their derivatives are core structural subunits that exist in a number of bioactive natural products [3]. Quinazolin-4-one derivatives exhibit a broad spectrum of biological and pharma­ceutical activities, including antihypertensive [4], anti­diabetic [5], anti-inflammatory [6], antibacterial [7], anticonvulsant, antitumor [8], central nervous system (CNS), depressant, and diuretic [9] activities. Quinazo­linone moiety is a building block for approximately 150 naturally occurring alkaloids [10] such as glycos­minine, luotonin, and deoxyvasicinone and drugs like methaqualone and piriqualone.

The construction of complex molecules through multicomponent reactions (MCRs) constitutes a very attractive strategy in organic synthesis [11]. In a multi-component reaction [12], three or more reactants are involved in a cascade of bond-forming individual steps to provide a complex molecule without isolation of intermediates or modification of the reaction conditions [13]. Attractive features of MCRs are simplicity of operation, reduction of isolation and purification steps, and minimization of costs, time, energy, solvents, and waste production [14]. Moreover, by employing an array of diverse reagents, molecular diversity is efficiently generated. In fact, MCRs have been exten­sively employed in combinatorial and diversity-oriented synthesis [15].

RESULTS AND DISCUSSION

Isatoic anhydride, 1H-indole-3-carbaldehyde, and aniline were chosen as model substrates to optimize the reaction conditions including the solvent and catalyst. As illustrated in Scheme 1, one pot three-component reaction of equimolar amounts of isatoic anhydride (1), aniline (2a), and 1H-indole-3-carbaldehyde (4a) (1 mmol each) was carried out by stirring the reactants in water as a green solvent in the presence of L-proline at room temperature for 10 min. The product, previ­ously unknown 2-(1H-indol-3-yl)-3-phenyl-2,3-dihy­dro­quinazolin-4(1H)-one (5a) was isolated in excellent yield after simple workup. The structure of 5a was confirmed by IR, NMR, and mass spectra.

Scheme
scheme 1

1.

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The reaction of 1, 2a, and 4a was then optimized by performing a series of experiments using different solvents at different temperatures (Table 1). However, the one-pot reaction in water at room temperature for 10 min (entry no. 1) gave reasonably high yield (93%) of 5a compared to other solvents such as ethanol, ethylene glycol, PEG-600, glycerol, acetic acid, DMF, DMSO, or PPA. The reaction conditions were further optimized to find the best catalyst. For this purpose, various Lewis acid catalysts like L-proline, InCl3, SnCl2, ZnCl2, and FeCl3 and solvents such as ethanol, acetic acid, and aqueous HCl were tried. Nevertheless, the reaction in water in the presence of L-proline at room temperature for 10 min provided the best yield of 5a (Table 2, entry no. 1).

Table 1. One-pot reaction of isatoic anhydride (1), aniline (2a), and 1H-indole-3-carbaldehyde (4a) in the presence of L-proline in different solvents (room temperature, 10 min)
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Table 2. One-pot reaction of isatoic anhydride (1), aniline (2a), and 1H-indole-3-carbaldehyde (4a) in the presence of different catalysts (water, room temperature, 10 min)
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The synthesis of 5 was also achieved through a step­wise method (Scheme 2). Initially, isatoic anhy­dride (1) was reacted with aniline (2) in presence of L-proline in water for 5 min to yield intermediate 3, and the latter reacted with 1H-indole-3-carbaldehyde (4a) in the presence of L-proline in water for 5–10 min to afford target compound 5a. To better understand the scope and generality of this simple procedure, the reaction of 1 with various substituted anilines 2a–2g containing electron-donating or electron-withdrawing groups and 1H-indole-3-carbaldehydes 4a and 4b was performed in one-pot under the optimized conditions to form compounds 5a–5n, and the results are sum­marized in Table 3.

Scheme
scheme 2

2.

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Table 3. One-pot synthesis of compounds 5a–5n from isatoic anhydride (1), substituted anilines 2a–2g, and 1H-indole-3-carbaldehydes 4a and 4b or (1H-indole-3-yl)methanols 6a and 6b
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In view of these results, we proposed the reaction mechanism shown in Scheme 3. The reaction starts with the condensation of 1 and aniline 2 in the presence of L-proline, followed by decarboxylation, to yield the corresponding 2-amino-N-phenylbenzamide (3). The condensation between the amino group of 3 and alde­hyde group of 4 gives the corresponding Schiff base intermediate which undergoes nucleophilic cyclization to form final product 5.

Scheme
scheme 3

3.

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Compound 5a could also be prepared via an alter­native method using (1H-indol-3-yl)methanol (6a) instead of aldehyde 4a (Scheme 4). The condensation of 1, 2a, and 4a in the presence of L-proline/K2CO3 in water at room temperature for 30 min afforded 91% of 5a with a good purity. Likewise, other compounds 5 were synthesized in this way with high yields (Table 3). A plausible mechanism of this reaction is shown in Scheme 5.

Scheme
scheme 4

4.

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Scheme
scheme 5

5.

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EXPERIMENTAL

The melting points were determined in open capil­lary tubes using a sulfuric acid bath and are uncor­rected. TLC was run on silica gel G, and visualization was done using iodine vapor or UV light. The IR spectra were recorded in KBr pellets on a Perkin Elmer 1000 spectrometer. The 1H NMR spectra were recorded in DMSO-d6 on a Varian 400 MHz spectrometer using TMS as internal standard. The mass spectra were re­corded on an Agilent 1200 Series LC/MS instrument.

3-Aryl-2-(1H-indol-3-yl)-2,3-dihydroquinazolin-4(1H)-ones 5a–5n (general procedures). a. One-pot synthesis. A mixture of isatoic anhydride (1, 10 mmol), substituted aniline 2a–2g (10 mmol), 1H-indole-3-carb­aldehyde 4a or 4b (10 mmol), L-proline (0.1 mmol), and water (20 mL) was stirred at room temperature for 15 min. The off-white solid separated from the mixture was collected by filtration, washed with hexane (10 mL), dried, and recrystallized from ethanol.

b. Stepwise synthesis. A mixture of 1 (10 mmol), 2 (10 mmol), L-proline (0.1 mmol), and water (20 mL) was stirred at room temperature for 5 min. The off-white solid separated from the mixture was collected by filtration, washed with hexane (10 mL), dried, and recrystallized from ethanol to obtain pure 2-amino-N-arylbenzamide 3. A mixture of 3 (10 mmol), 4 (10 mmol), L-proline (0.1 mmol), and water (20 mL) was stirred at room temperature for 5–10 min. The off-white solid separated from the mixture was collected by filtration, washed with hexane (10 mL), dried, and recrystallized from ethanol.

c. One-pot synthesis using alcohol 6 instead of aldehyde 4. A mixture of 1 (10 mmol), 2 (10 mmol), 6 (10 mmol), L-proline (0.1 mmol), K2CO3 (0.15 mmol), and water (20 mL) was stirred at room temperature for 30 min. The off-white solid separated from the mixture was collected by filtration, washed with water (5 mL) and hexane (10 mL), dried, and recrystallized from ethanol.

2-(1H-Indol-3-yl)-3-phenyl-2,3-dihydroquinazo­lin-4(1H)-one (5a). Yield 93%, white solid, mp 221–223°C. IR spectrum, ν, cm–1: 3351 br (N–H), 1657 s (C=O). 1H NMR spectrum, δ, ppm: 5.90 s (1H, CH), 7.26–8.59 m (14H, Harom), 9.79 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 110.00, 111.60, 113.55, 114.13, 114.21, 114.33, 117.79, 118.11, 122.55, 122.63, 124.78, 124.88, 127.55, 129.65, 131.17, 131.21, 138.39, 138.55, 164.92. Mass spec­trum: m/z 340.15 [M + 1]+. Calculated for C22H17N3O: M 339.14.

3-(2-Chlorophenyl)-2-(1H-indol-3-yl)-2,3-dihy­dro­quinazolin-4(1H)-one (5b). Yield 90%, white solid, mp 218–220°C. IR spectrum, ν, cm–1: 3420 br (N–H), 1660 s (C=O). 1H NMR spectrum, δ, ppm: 5.98 s (1H, CH), 7.31–8.67 m (13H, Harom), 10.20 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 110.15, 111.74, 113.39, 114.20, 114.64, 114.90, 117.35, 118.24, 122.40, 122.78, 124.36, 124.67, 127.13, 129.47, 131.34, 131.59, 138.50, 138.81, 164.71. Mass spectrum: m/z 374.23 [M + 1]+. Calcu­lated for C22H16ClN3O: M 373.10.

3-(3-Chlorophenyl)-2-(1H-indol-3-yl)-2,3-dihy­droquinazolin-4(1H)-one (5c). Yield 90%, white solid, mp 216–218°C. IR spectrum, ν, cm–1: 3411 br (N–H), 1624 s (C=O). 1H NMR spectrum, δ, ppm: 5.71 s (1H, CH), 7.03–8.55 m (13H, Harom), 10.01 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.28, 103.57, 105.08, 106.31, 108.01, 110.37, 112.17, 113.82, 113.93, 114.22, 116.40, 119.36, 120.58, 124.15, 125.17, 127.66, 129.39, 160.57. Mass spec­trum: m/z 374.48 [M + 1]+. Calculated for C22H16ClN3O: M 373.10.

3-(4-Chlorophenyl)-2-(1H-indol-3-yl)-2,3-dihy­droquinazolin-4(1H)-one (5d). Yield 89%, white solid, mp 220–222°C. IR spectrum, ν, cm–1: 3428 br (NH), 1639 s (C=O). 1H NMR spectrum, δ, ppm: 5.25 s (1H, CH), 7.13–8.40 m (13H, Harom), 9.69 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.10, 103.28, 105.00, 106.27, 108.13, 110.45, 112.05, 113.77, 113.80, 114.25, 116.39, 119.19, 120.67, 124.03, 125.44, 127.57, 129.20, 160.46. Mass spec­trum: m/z 374.37 [M + 1]+. Calculated for C22H16ClN3O: M 373.10.

2-(1H-Indol-3-yl)-3-(2-nitrophenyl)-2,3-dihydro­quinazolin-4(1H)-one (5e). Yield: 84%, white solid, mp 212–214°C. IR spectrum, ν, cm–1: 3480 br (N–H), 1652 s (C=O). 1H NMR spectrum, δ, ppm: 5.42 s (1H, CH), 7.29–8.68 m (13H, Harom), 9.51 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.38, 103.42, 105.14, 106.56, 108.71, 110.39, 112.62, 113.52, 113.79, 114.25, 116.51, 119.30, 120.58, 124.14, 125.36, 127.71, 129.12, 160.51. Mass spec­trum: m/z 385.13 [M + 1]+. Calculated for C22H16N4O3: M 384.12.

2-(1H-Indol-3-yl)-3-(3-nitrophenyl)-2,3-dihydro­quinazolin-4(1H)-one (5f). Yield 85%, white solid, mp 215–217°C. IR spectrum, ν, cm–1: 3428 br (N–H), 1637 s (C=O). 1H NMR spectrum, δ, ppm: 5.17 s (1H, CH), 7.05–8.18 m (13H, Harom), 9.85 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.27, 103.33, 105.04, 106.47, 108.31, 110.22, 112.54, 113.31, 113.80, 114.19, 116.50, 119.17, 120.43, 124.27, 125.19, 127.49, 129.37, 160.28. Mass spec­trum: m/z 385.26 [M + 1]+. Calculated for C22H16N4O3: M 384.12.

2-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-2,3-dihy­droquinazolin-4(1H)-one (5g). Yield 92%, white solid, mp 224–226°C. IR spectrum, ν, cm–1: 3410 br (N–H), 1667 s (C=O). 1H NMR spectrum, δ, ppm: 3.89 s (3H, OCH3), 5.26 s (1H, CH), 7.25–8.72 m (13H, Harom), 9.68 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.38, 103.45, 105.38, 106.67, 108.44, 110.35, 112.29, 113.57, 113.72, 114.25, 116.37, 119.40, 120.59, 124.88, 125.35, 127.12, 129.46, 160.49. Mass spectrum: m/z 370.13 [M + 1]+. Calculated for C23H19N3O2: M 369.15.

2-(5-Chloro-1H-indol-3-yl)-3-phenyl-2,3-dihy­dro­quinazolin-4(1H)-one (5h). Yield 90%, white solid, mp 217–219°C. IR spectrum, ν, cm–1: 3461 br (N–H), 1649 s (C=O). 1H NMR spectrum, δ, ppm: 5.68 s (1H, CH), 7.35–8.81 m (13H, Harom), 9.90 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.31, 103.49, 105.63, 106.09, 108.15, 110.44, 112.37, 113.27, 113.84, 114.51, 116.14, 119.50, 120.46, 124.80, 125.77, 127.63, 129.09, 160.59. Mass spec­trum: m/z 374.34 [M + 1]+. Calculated for C22H16ClN3O: M 373.10.

2-(5-Chloro-1H-indol-3-yl)-3-(2-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5i). Yield 88%, white solid, mp 213–215°C. IR spectrum, ν, cm–1: 3490 br (N–H), 1677 s (C=O). 1H NMR spectrum, δ, ppm: 5.75 s (1H, CH), 7.43–8.96 m (12H, Harom), 9.87 s (1H, NH, D2O exchangeable). 13C NMR spec­trum, δC, ppm: 101.43, 103.56, 105.71, 106.16, 108.22, 110.59, 112.43, 113.37, 113.92, 114.60, 116.37, 119.74, 120.55, 124.31, 125.83, 127.79, 129.25, 160.63. Mass spectrum: m/z 408.41 [M + 1]+. Calculated for C22H15Cl2N3O: M 407.06.

2-(5-Chloro-1H-indol-3-yl)-3-(3-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5j). Yield 88%, white solid, mp 215–217°C. IR spectrum, ν, cm–1: 3484 br (N–H), 1660 s (C=O). 1H NMR spectrum, δ, ppm: 5.69 s (1H, CH), 7.26–8.82 m (12H, Harom), 9.83 s (1H, NH, D2O exchangeable). 13C NMR spec­trum, δC, ppm: 101.23, 103.47, 105.62, 106.12, 108.17, 110.40, 112.39, 113.24, 113.71, 114.10, 116.21, 119.05, 120.43, 124.58, 125.77, 127.80, 129.38, 160.80. Mass spectrum: m/z 408.31 [M + H]+. Calculated for C22H15Cl2N3O: M 407.06.

2-(5-Chloro-1H-indol-3-yl)-3-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (5k). Yield 82%, white solid, mp 218–220°C. IR spectrum, ν, cm–1: 3470 br (N–H), 1656 s (C=O). 1H NMR spectrum, δ, ppm: 5.55 s (1H, CH), 7.18–8.70 m (12H, Harom), 10.06 s (1H, NH, D2O exchangeable). 13C NMR spec­trum, δC, ppm: 101.14, 103.34, 105.41, 106.05, 108.11, 110.35, 112.49, 113.39, 113.60, 114.14, 116.30, 119.00, 120.32, 124.44, 125.52, 127.71, 129.23, 160.65. Mass spectrum: m/z 408.20 [M + H]+. Calculated for C22H15Cl2N3O: M 407. 06.

2-(5-Chloro-1H-indol-3-yl)-3-(2-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (5l). Yield 84%, white solid, mp 211–213°C. IR spectrum, ν, cm–1: 3486 br (N–H), 1686 s (C=O). 1H NMR spectrum, δ, ppm: 5.90 s (1H, CH), 7.30–8.90 m (12H, Harom), 10.00 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.29, 103.48, 105.57, 106.15, 108.37, 110.58, 112.67, 113.45, 113.75, 114.22, 116.38, 119.05, 120.47, 124.63, 125.82, 127.41, 129.67, 160.79. Mass spec­trum: m/z 419.30 [M + H]+. Calculated for C22H15ClN4O3: M 418.08.

2-(5-Chloro-1H-indol-3-yl)-3-(3-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (5m). Yield 84%, white solid, mp 213–215°C. IR spectrum, ν, cm–1: 3480 br (N–H), 1679 s (C=O). 1H NMR spectrum, δ, ppm: 5.86 s (1H, CH), 7.25–8.87 m (12H, Harom), 10.12 s (1H, NH, D2O exchangeable). 13C NMR spec­trum, δC, ppm: 101.14, 103.37, 105.46, 106.08, 108.27, 110.24, 112.52, 113.31, 113.64, 114.15, 116.47, 119.12, 120.43, 124.55, 125.70, 127.38, 129.50, 160.66. Mass spectrum: m/z 419.15 [M + H]+. Calculated for C22H15ClN4O3: M 418.08.

2-(5-Chloro-1H-indol-3-yl)-3-(4-methoxy­phe­nyl)-2,3-dihydroquinazolin-4(1H)-one (5n). Yield 91%, white solid, mp 220–222°C. IR spectrum, ν, cm–1: 3471 br (N–H), 1653 s (C=O). 1H NMR spec­trum, δ, ppm: 3.89 s (3H, OCH3), 5.69 s (1H, CH), 7.25–8.78 m (12H, Harom), 10.05 s (1H, NH, D2O exchangeable). 13C NMR spectrum, δC, ppm: 101.23, 103.45, 105.57, 106.18, 108.35, 110.36, 112.60, 113.20, 113.74, 114.26, 116.50, 119.16, 120.57, 124.62, 125.81, 127.40, 129.63, 160.71. Mass spec­trum: m/z 404.10 [M + H]+. Calculated for C23H18ClN3O2: M 403.11.

CONCLUSIONS

The syntheses of novel 2,3-dihydroquinazolin-4(1H)-one derivatives of potential synthetic and pharmacological interest via one-pot three-component and alternative methods using L-proline and L-propline/K2CO3 as catalyst in water have been described. The desired products have been obtained in high yields without any unwanted by-products. The new protocol features operational simplicity, high atom economy, and broad substrate scope. Further applica­tion of this protocol to total synthesis of biologically important natural products and more detailed mecha­nistic studies for this transformation are currently underway in our laboratory.