Abstract
Antimony(III) trichloride (SbCl3) is an effective catalyst (1 mol%) for the condensation of anthranilic amide with various aldehydes or ketones to quinazolin-4(3H)-one derivatives in good to excellent yields under microwave irradiation. The process is carried out within several minutes under solvent-free conditions. This general methodology has the advantages of simplicity, mild reaction conditions and high yields of products.
Introduction
Quinoline and quinazoline derivatives have received attention due to their bioactivitives [1]. The quinazolin-4(3H)-ones have been found to exhibit antimalarial [1], [2], antiinflammatory [3], antibacterial [4], as well as antihypertensive activities [5]. Generally, quinazolin-4(3H)-ones [6], [7] can be prepared from anthranilic acids [8], anthranilamides [9], 2-halobenzamides [10], isatoic anhydrides [11] and 2-azidobenzamides [12]. Several catalytic processes have also been used [6], [7], [8], [13], [14]. However, most methods are disadvantageous with high catalyst loading, poor yields, prolonged reaction times, and the use of toxic organic reagents or solvents.
Our work has focused on using green chemistry [15], [16], [17], [18], [19], [20]. In particular, we have been interested in the application of microwave irradiation and efficient catalysts in organic synthesis [21], [22], [23], [24], [25]. In continuation of the research on the synthesis of quinazolin-4(3H)-ones using antimony trichloride (SbCl3) as a catalyst [25], [26] herein, we wish to report a general and highly efficient synthetic route to quinazolin-4(3H)-ones. The method involves condensation of anthranilic amide with aldehydes or ketones in the presence of inexpensive, commercially available SbCl3 as a Lewis acid catalyst without solvent under microwave irradiation (Schemes 1 and 2).
Synthesis of quinazolin-4(3H)-ones 3a–j.
Synthesis of quinazolin-4(3H)-ones 5a–d.
Results and discussion
In a model study, benzaldehyde (2, 2 mmol) and anthranilic amide (1, 2 mmol) were allowed to react in the presence of SbCl3 (1 mol%) under microwave irradiation (Scheme 1). The best yield of 94% of product 3a was obtained when the reaction was conducted under solvent-free conditions. Lower yields were obtained when the reaction was carried out with SbCl3 in organic solvents. For example, the reaction conducted in tetrahydrofuran (THF) furnished 3a in 85% yield. Product 3a was obtained in low yield (34%) using SbCl3 as the catalyst at room temperature without microwave irradiation, and with yield of 72% upon heating under otherwise similar conditions. As can be seen from Table 1, all products 3a–j, were obtained in yields of 80–98% after a microwave-assisted irradiation for 3–5 min. By contrast, the classical heating method requires heating for 3–5 h and provides smaller yields. The condensation of substrate 1 with ketones furnishes the corresponding 2,2-disubstituted 2,3-dihydroquinazolin-4(1H)-ones 5a–d (Scheme 2 and Table 2). Both aromatic and aliphatic carbonyl substrates can be used in the synthesis of 3 and 5. Optimization of the reaction conditions was studied with different amounts of the catalyst and under different microwave powers. The optimum amount of SbCl3 was found to be 1 mol% in respect to anthranilic amide. The microwave power of 200 W was found to give the best results. The yields of the products decrease with the increases of microwave power.
SbCl3-catalyzed synthesis of quinazolin-4(3H)-ones by condensation of anthranilamide with aldehydes.a
| R1 | Time (MW)/min | Time (thermal)/min | Product | Yield (%)a |
|---|---|---|---|---|
| C6H5 | 3 | 180 | 3a | 94, 85b, 72c |
| 2-OHC6H4 | 5 | 240 | 3b | 80, 67c |
| 3,4-(CH3O)2C6H3 | 3 | 240 | 3c | 87, 71c |
| 3-BrC6H4 | 5 | 240 | 3d | 91, 77c |
| 4-ClC6H4 | 4 | 240 | 3e | 94, 83c |
| 4-FC6H4 | 3 | 240 | 3f | 98, 86c |
| C6H5CH=CH | 3 | 240 | 3g | 87, 74c |
| 2-Furyl | 3 | 240 | 3h | 88, 69c |
| n-C2H5 | 4 | 240 | 3i | 84, 72c |
| n-C3H7 | 3 | 240 | 3j | 80, 70c |
aReaction on 2 mmol scale, MW power as specified. Catalyst loading: 1 mol% of anthranilamide. bReaction carried out using SbCl3 as catalyst at reflux in THF. cReaction carried out using SbCl3 as catalyst under thermal condition.
SbCl3-catalyzed synthesis of quinazolin-4(3H)-ones by condensation of anthranilamide with ketones.a
| R2 | R3 | Time (MW)/min | Time (thermal)/min | Product | Yield (%)a |
|---|---|---|---|---|---|
| CH3 | CH3 | 3 | 240 | 5a | 92, 85b |
| CH3 | C2H5 | 3 | 240 | 5b | 94, 89b |
| (CH2)5 | 3 | 240 | 5c | 95, 91b | |
| C6H5 | CH3 | 3 | 240 | 5d | 89, 83b |
aReaction on a 2 mmol scale, MW power and reaction time as specified. Catalyst loading: 1 mol% in respect to anthranilamide. bReaction carried out using SbCl3 as catalyst under thermal condition.
Conclusions
Quinazolin-4(3H)-ones 3a–j are efficiently prepared by the reaction of anthranilamide (1) with aldehydes in the presence of a catalytic amount of SbCl3 in the absence of solvent under microwave irradiation. 2,2-Disubstituted-2,3-dihydroquinazolin-4(1H)-ones 5a–d are the products of the reaction of 1 with ketones under otherwise similar conditions.
Experimental
Melting points are uncorrected. Infrared spectra were recorded on a Brucker Vector 22 spectrometer in KBr pellets. 1H NMR spectra were recorded on a Brucker 400 MHz spectrometer with tetramethylsilane (TMS) as internal standard and DMSO-d6 as solvent. Elemental analyses were conducted using an Elementar Vario EL instrument.
General procedure for synthesis of substituted quinazolin-4(3H)-ones 3a–j and 5a–d
Classical heating
Anthranilamide (2 mmol) and an aldehyde or ketone (2 mmol) were mixed thoroughly with SbCl3 (1 mol%) in a flask equipped with a condenser and the mixture was heated under reflux. After the reaction was completed [monitored by thin-layer chromatography (TLC)], the mixture was poured into ice-cooled water and stirred for 30 min. The resultant precipitate was filtered, washed with water and crystallized from ethanol.
Microwave irradiation
Anthranilamide (2 mmol) and an aldehyde or ketone (2 mmol) were mixed thoroughly with SbCl3 (1 mol%) and irradiated for 3–5 min in a microwave reactor equipped with a condenser. Work-up was conducted as described above.
2-Phenyl-quinazolin-4(3H)-one (3a)
This compound was obtained in yields of 72% (heat) and 94% (MW); mp 252–254°C; (lit. [27] mp 242–246°C).
2-(2-Hydroxyphenyl)quinazolin-4(3H)-one (3b)
This compound was obtained in yields of 67% (heat) and 80% (MW); mp 248–250°C (lit. [7] mp 250°C).
2-(3,4-Dimethoxyphenyl)quinazolin-4(3H)-one (3c)
This compound was obtained in yields of 71% (heat) and 87% (MW); mp 257–259°C (lit. [28] mp 231–233°C).
2-(3-Bromophenyl)quinazolin-4(3H)-one (3d)
This compound was obtained in yields of 77% (heat) and 91% (MW); mp 316–318°C (lit. [29] mp 295–296°C).
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3e)
This compound was obtained in yields of 83% (heat) and 94% (MW); mp >300°C (lit. [30] mp >300°C).
2-(4-Fluorophenyl)quinazolin-4(3H)-one (3f)
This compound was obtained in yields of 86% (heat) and 98% (MW); mp 293–295°C (lit. [31]; mp 288–289°C).
2-Styryl-quinazolin4-(3H)-one (3g)
This compound was obtained in yields of 74% (heat) and 87% (MW); mp 253–255°C (lit. [28] mp 249–250°C).
2-(2-Furyl)quinazolin-4(3H)-one (3h)
This compound was obtained in yields of 69% (heat) and 88% (MW); mp 233–235°C (lit. [28] mp 219–221°C).
2-Ethyl-quinazolin-4(3H)-one (3i)
This compound was obtained in yields of 72% (heat) and 84% (MW); mp 238–240°C (lit. [32] mp 235–236°C).
2-Propyl-4(3H)-quinazolin-4(3H)-one (3j)
This compound was obtained in yields of 70% (heat) and 80% (MW); mp 210–212°C (lit. [33] mp 208–210°C).
2,2-Dimethyl-2,3-dihydroquinazolin-4(1H)-one (5a)
This compound was obtained in yields of 92% (MW); mp 178–180°C (lit. [34] mp 183–184°C).
2-Ethyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one (5b)
This compound was obtained in yields of 94% (MW); mp 178–180°C (lit. [35] mp 184–186°C).
1′H-spiro[cyclohexane-1,2′-quinazolin]-4′(3′H)-one (5c)
This compound was obtained in yields of 95% (MW); mp 225–226°C (lit. [35] mp 224–225°C).
2-Methyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one (5d)
This compound was obtained in yields of 89% (MW); mp 226–228°C (lit. [36] mp 225–229°C).
Acknowledgments
This work was financially supported by the Natural Science Foundation of Shandong Province (Funder Id: 10.13039/501100007129, No. ZR2017PB006), the Ph.D. Programs Foundation of Ludong University (No. 32840301), the National University Student Innovation and entrepreneurship training Program (No. 201710451034, 201810451326, 201810451344) and the Innovation Foundation Plan of Ludong University (No. ld171062).
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