Introduction

Five- and six-membered heterocyclic compounds are important constituents that often exist in biologically active natural products and synthetic compounds of medicinal interest [1, 2]. Among them quinazolinones and 1,2,4-triazoloquinazolinone derivatives are known for diverse pharmacological activities as anti-HIV [3], muscle relaxant [4], neuroleptic [5], hypnotic [6], antihistaminic [7–9], analgesic [10], anti-inflammatory [11], anticonvulsant [12], antifertility [13], latent leishmanicidal [14], anticancer [15], and antihypertensive [10, 16–18]. An alternative strategy for the synthesis of quinazolinones is using multicomponent reactions (MCRs). Recently, MCRs have emerged as a powerful synthetic tool in organic synthesis due to their advantages over the conventional multi-step synthesis [19–24]. In addition, MCRs are eco-friendly, highly atom economic, and they avoid costly purification processes and protection–deprotection steps with minimum synthetic effort and time [25, 26]. Therefore, MCRs satisfy some of the tenets of ‘Green Chemistry’. Literature reveals only a few methods to synthesis [1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one and hexahydro[4,5]benzimidazolo[2,1-b]quinazolinone derivatives via MCRs using catalysts, such as H6P2W18O62·18H2O [27], refluxing in DMF [28, 29], molecular iodine (I2) [30], microwave [31]. The aforesaid methods have some disadvantages such as use of expensive and excess amount of catalysts and failure in some of the cases to obtain the desired product. However, although the generality of the existing reports for the construction of quinazolinone derivatives are relatively good, there is a need for simple and greener methods, which are applicable to a broad range of substrates to access these compounds. In conclusion, in continuation of our study on the effective and green methodology [32], herein we wish to report the synthesis of [1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one and hexahydro[4,5]benzimidazolo[2,1-b]quinazolinone derivatives by a one-pot three-component condensation reaction of dimedone, aromatic aldehydes, and 3-amino-1,2,4-triazole or 2-aminobenzimidazole using dual role of acetic acid as solvent and catalyst at 60 °C (Scheme 1).

Scheme 1
scheme 1

Synthesis of quinazolinones in the presence of acetic acid as reaction medium

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Experimental

General

Melting point and IR spectra of all compounds were obtained on an Electrothermal 9100 apparatus and a JASCO FT/IR-460 plus spectrometer, respectively. 1H and 13C NMR spectra of compounds were recorded on a Bruker DRX-400 Avance instrument in DMSO or CDCl3 as the solvent with TMS as internal standard at 400 MHz. Elemental analyses for C, H, and N for the new compounds were performed using a Heraeus CHN-O-Rapid analyzer. The mass spectra for the new compounds were recorded on an Agilent Technology (HP) mass spectrometer, operating at an ionization potential of 70 eV. All reagents were purchased from Merck (Darmastadt, Germany), Acros (Geel, Belgium) and Fluka (Buchs, Switzerland), and used without further purification.

General procedure for the preparation of [1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one and hexahydro[4,5]benzimidazolo[2,1-b]quinazolinone derivatives

A mixture of aromaticaldehyde (1.0 mmol) and dimedone (1.0 mmol) with 2-aminobenzimidazole or 3-amino-1,2,4-triazole (1.0 mmol) was stirred in acetic acid (5 mL) at 60 °C for the appropriate time (Tables 3, 4). The progress of the reaction was monitored by TLC. After completion of the reaction, a thick precipitate was obtained. The solid product was filtered off and washed with acetic acid (3 × 2 mL) to give the pure products 4 and 6, and subsequently dried in air. The pure products were characterized by conventional spectroscopic methods. Physical and spectral data for the compounds, 4b, 4c, 4h, 4j, 6a, 6c, and 6h are represented below:

6,7-dihydro-6,6-dimethyl-9-p-tolyl-[1,2,4]triazolo[5,1-b]quinazolin-8(4H,5H,9H)-one (4b)

White solid (95 % yield), m.p. = 262–264 °C; IR (KBr, cm−1) 3421, 3036, 2964, 1649, 1578, 1364, 1259, 757; 1H NMR (400 MHz, DMSO) δ = 0.96 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.07 (d, 1H, J = 16.0 Hz, H-5), 2.20 (d, 1H, J = 12.0 Hz, H’-5), 2.28 (s, 3H, CH3), 2.48–2.59 (m, 2H, H-7), 6.16 (S, 1H, H-9), 7.07 (s, 4H, Ar–H), 7.67 (s, 1H, H-2), 11.09 (s, 1H, NH).

6,7-dihydro-9-(2,4-dimethoxyphenyl)-6,6-dimethyl-[1,2,4]triazolo[5,1-b]quinazolin-8(4H,5H,9H)-one (4c)

White solid (88 % yield); m.p. 211–212 °C; IR (KBr, cm−1): 3150, 3093, 3030, 2959, 2933, 1694, 1652, 1579, 1508, 1416, 1338, 1294, 1183, 1038, 826; 1H NMR (400 MHz, CDCl3): δ 1.07 (s, 3H, CH3), 1.15 (s, 3H, CH3), 2.22 (d, J = 16.0 Hz, 1H, H-5), 2.29 (d, J = 16.0 Hz, 1H, H’-5), 2.48 (d, J = 16.0 Hz, 1H, H-7), 2.59 (d, J = 16.0 Hz, 1H, H’-7), 3.71 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 6.40 (d, J = 2.4 Hz, 1H, Ar–H), 6.47 (dd, J = 8.0, 4.0 Hz, 1H, Ar–H), 6.56 (s, 1H, H-9), 7.38 (d, J = 8.0 Hz, 1H, Ar–H), 7.64 (s, 1H, H-2), 11.76 (s, 1H, NH).

6,7-dihydro-6,6-dimethyl-9-(naphthalen-2-yl)-[1,2,4]triazolo[5,1-b]quinazolin-8(4H,5H,9H)-one (4h)

White solid (98 % yield); m.p. 266–268 °C; IR (KBr, cm−1): 3416, 3246, 3091, 2963, 2927, 1652, 1574, 1469, 1410, 1364, 1335, 1251, 779; 1H NMR (400 MHz, DMSO): δ 0.97 (s, 3H, CH3), 1.05 (s, 3H, CH3), 2.06 (d, J = 16.0 Hz, 1H, H-5), 2.23 (d, J = 16.0 Hz, 1H, H’-5), 2.58 (dd, J = 16.0, 24.0 Hz, 2H, H-7), 6.38 (S, 1H, H-9), 7.26 (dd, J = 4.0, 8.0 Hz, 1H, Ar–H), 7.48–7.50 (m, 2H, Ar–H), 7.69 (s, 1H, H-2), 7.80 (d, J = 4.0 Hz, 1H, Ar–H), 7.84 (d, J = 8.0 Hz, 2H, Ar–H), 7.90 (t, J = 4.0 Hz, 1H, Ar–H), 11.20 (s, 1H, NH).

6,7-dihydro-9-(2,3-dimethoxyphenyl)-6,6-dimethyl-[1,2,4]triazolo[5,1-b]quinazolin-8(4H,5H,9H)-one (4j)

White solid (98 % yield); m.p. 227–229 °C; IR (KBr, cm−1): 3415, 3143, 3093, 2959, 2931, 1642, 1579, 1455, 1369, 1264, 736; 1H NMR (400 MHz, CDCl3): δ 1.13 (s, 3H, CH3), 1.15 (s, 3H, CH3), 2.24 (d, J = 16.0 Hz, 1H, H-5), 2.29 (d, J = 16.0 Hz, 1H, H’-5), 2.53 (d, J = 16.0 Hz, 1H, H-7), 2.60 (d, J = 16.0 Hz, 1H, H’-7), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.68 (s, 1H, H-9), 6.85 (dd, J = 8.0, 2.0 Hz, 1H, Ar–H), 6.97 (dd, J = 8.0, 2.0 Hz, 1H, Ar–H), 7.01 (t, J = 8.0 Hz, 1H, Ar–H), 7.64 (s, 1H, H-2), 11.71 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): δ 28.0, 28.6, 32.8, 40.7, 50.5, 55.1, 55.7, 60.4, 107.0, 112.8, 121.2, 123.7, 133.4, 147.2, 147.4, 148.1, 149.3, 152.8, 193.8; MS (EI, 70 eV) m/z (%): 354 (M+, 27), 323 (100), 296 (49), 270 (5), 239 (2), 217 (10), 185 (2), 161 (13), 138 (1), 115 (4), 84 (11), 55 (5); Anal. Calcd for C19H22N4O3: C, 64.39; H, 6.26; N, 15.81. Found: C, 64.50; H, 6.45; N, 15.94 %.

3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1-one (6a)

White solid (94 % yield), m.p. = >300 °C; IR (KBr, cm−1) 3430, 3093, 2956, 1643, 1615, 1569, 1376, 1257, 750; 1H NMR (400 MHz, DMSO) δ 0.92 (s, 3H, CH3), 1.05 (s, 3H, CH3), 2.05 (d, 1H, J = 16.0 Hz, H-4), 2.26 (d, 1H, J = 16.0 Hz, H’-4), 2.45 (d, 1H, J = 16.0 Hz, H-2), 2.58 (d, 1H, J = 16.0 Hz, H’-2), 6.41 (S, 1H, H-12), 6.95 (t, 1H, J = 8.0 Hz, Ar–H), 7.04 (t, 1H, J = 8.0 Hz, Ar–H), 7.15 (t, 1H, J = 8.0 Hz, Ar–H), 7.24 (t, 1H, J = 8.0 Hz, Ar–H), 7.33 (d, 3H, J = 8.0 Hz, Ar–H), 7.37 (q, 3H, J = 8.0 Hz, Ar–H), 10.18 (s, 1H, NH).

3,3-dimethyl-12-[2,4] dichlorophenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1-one (6c)

White solid (94 % yield); m.p. >300 °C; IR (KBr, cm−1): 3238, 3061, 2963, 2931, 1650, 1615, 1595, 1573, 1563, 1459, 1374, 1270, 737; 1H NMR (400 MHz, DMSO): δ 0.95 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.04 (d, J = 16.0 Hz, 1H, H-4), 2.24 (d, J = 16.0 Hz, 1H, H’-4), 2.29 (d, J = 12.0 Hz, 1H, H-2), 2.33 (d, J = 16.0 Hz, 1H, H’-2), 6.65 (S, 1H, H-12), 6.96 (t, J = 8.0 Hz, 1H, Ar–H), 7.03 (s, 1H, Ar–H), 7.08–7.12 (m, 1H, Ar–H), 7.38 (s, 1H, Ar–H), 7.40 (s, 1H, Ar–H), 7.48 (d, J = 8.0 Hz, 1H, Ar–H), 11.25 (s, 1H, NH).

3,3-dimethyl-12-(2-bromophenyl)-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1-one (6h)

White solid (99 % yield); m.p. >300 °C; IR (KBr, cm−1): 3421, 3227, 3066, 2962, 2923, 1654, 1643, 1615, 1594, 1573, 1459, 1373, 1364, 1263, 742; 1H NMR (400 MHz, DMSO): δ 0.97 (s, 3H, CH3), 1.06 (s, 3H, CH3), 2.03 (d, J = 16.0 Hz, 1H, H-4), 2.23 (d, J = 16.0 Hz, 1H, H’-4), 2.51 (d, J = 12.0 Hz, 1H, H-2), 2.63 (d, J = 16.0 Hz, 1H, H’-2), 6.64 (S, 1H, H-12), 6.95 (t, J = 8.0 Hz, 1H, Ar–H), 7.05 (t, J = 8.0 Hz, 1H, Ar–H), 7.12 (t, J = 8.0 Hz, 1H, Ar–H), 7.29 (s br s, 1H, Ar–H), 7.38 (d, J = 8.0 Hz, 1H, Ar–H), 7.52 (d, J = 8.0 Hz, 1H, Ar–H), 10.72 (s, 1H, NH); 13C NMR (100 MHz, DMSO): δ 27.1, 29.1, 32.8, 40.2, 50.3, 110.0, 117.5, 121.0, 122.4, 128.4, 130.1, 132.5, 132.8, 133.3, 142.2, 145.5, 151.2,193.0; MS (EI, 70 eV) m/z (%): 423 (M+1, 21), 422 (M+, 8), 387 (1), 364 (1), 342 (100), 310 (1), 266 (57), 236 (1), 210 (1), 182 (9), 155 (6), 129 (4), 90 (5), 55(2); Anal. Calcd for C22H20BrN3O: C, 62.57; H, 4.77; N, 9.95. Found: C, 62.70; H, 4.84; N, 9.98 %.

Results and discussion

In a preliminary experiment, treatment of 4-methyl benzaldehyde (1) with dimedone (2) and 3-amino-1,2,4-triazole (3) in 5 mL acetic acid as both solvent and catalyst at room temperature for 40 min afforded the 6,6-dimethyl-9(4-Methyl-phenyl)-5,6,7,9-tetrahydro-4H-1,2,4-triazolo[5,1-b] quinazolin-8-one 4b in 80 % yield. Product 4b was characterized by spectroscopic analysis. Encouraged by this result, we proceeded to study the effect of volume of solvent and reaction conditions for the synthesis of 6,6-dimethyl-9(4-Methyl-phenyl)-5,6,7,9-tetrahydro-4H-1,2,4-triazolo[5,1-b] quinazolin-8-one (4b) (Table 1). As shown in Table 1, the best conversion was observed when the reaction was performed in the presence of 5 mL of acetic acid for 40 min at room temperature for 1 mmol of starting materials (entry 4, Table 1). According to the Table 1, when the reaction was carried out under solvent-free conditions and in the presence of any catalyst, no product was produced that may be due to lack of effective interaction of reactants in the absence of solvent (also in the absence of catalyst) (entry 1, Table 1).

Table 1 Condensation reaction of 3-amino-1,2,4-triazole, 4-methyl benzaldehyde and dimedone in the presence of acetic acid at ambient conditions
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Subsequently, the effect of temperature was studied by carrying out the model reaction at different temperatures (room temperature, 40, 50, 60, 70 and 80 °C) in 5 mL acetic acid as the most appropriate medium, and the best results were obtained at 60 °C, efficiency of 98 % was generated (entry 4, Table 2) at the higher temperature did not increase the reaction yield (entries 5 and 6, Table 2).

Table 2 Reaction of 3-amino-1,2,4-triazole, 4-methyl benzaldehyde and dimedone in acetic acid at different temperature
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Therefore, in this work 5 mL of acetic acid and 60 °C were selected as standard reaction conditions. The optimized conditions were used to construct a variety of [1,2,4]triazolo[5,1-b]quinazolin-8(4H)-ones (4a–j). Various substituted aldehydes were reacted with dimedone and 3-amino-1,2,4-triazole and gave excellent yields of the desired quinazolinone products. As shown in Table 3, the electron withdrawing or donating group on the phenyl rings did not affect the reaction. The procedure is very simple: 1 equiv of aldehyde was mixed with 1 equiv of dimedone and 1 equiv of 3-amino-1,2,4-triazole in 5 mL acetic acid in a vial equipped and stirred at 60 °C for 10–35 min. After completion of the reaction, solid products were washed with acetic acid to remove organic impurities. The results are summarized in Table 3.

Table 3 Synthesis of 1,2,4-triazolo[5,1-b]quinolin-8(4H)-ones 4 in acetic acid as reaction medium
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Under the optimized reaction conditions, we continued to demonstrate the generality and high potency of this friendly methodology, the same reaction was applied for the synthesis of hexahydro[4,5]benzimidazolo[2,1-b]quinazolinone derivatives including the compounds numbering 6a–h by replacing 3-amino-1,2,4-triazole (3) with 2-aminobenzimidazole (5). For this, we enlarged our study using 2-aminobenzimidazole 5 as amine source, reacting with dimedone 2 and different substituted aromatic aldehydes in the presence of acetic acid as reaction medium for the synthesis of a series of benzimidazolo quinazolinones (Scheme 1; Table 4). Electron donating and electron withdrawing groups on the aldehydes show equal ease toward the product formation in good to high yields. The results are shown in Table 4. The results show that the substituent groups did not play any significant role in the reactivity of the substrate.

Table 4 Synthesis of hexahydro[4,5]benzimidazolo[2,1-b]quinazolinones 6 in acetic acid as reaction medium
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The notable advantages of this method are easy isolation of products by simple filtration, no need to column chromatogaphy, and no need to further purification. All known products were characterized by comparison of the melting points and the analytical data (IR, 1H NMR) with those reported for authentic samples. The structure of new compounds 4j and 6h were deduced on the basis of IR, 1H, 13C NMR spectroscopies, mass spectrometry, and elemental analysis. For example, the mass spectrum of 4j displayed the molecular ion peak (M+) at m/z = 354, which is consistent with the proposed structure. The 1H NMR spectrum of 4j exhibited two singlet at δ = 1.13 and 1.15 ppm for the geminal methyl protons. Four doublets were observed at δ = 2.24 (J = 16.0 Hz), 2.29 (J = 16.0 Hz), 2.53 (J = 16.0 Hz) and 2.60 (J = 16.0 Hz) for the diastereotopic methylene protons of H-5, H’-5, H-7 and H’-7, respectively. Two singlets were monitored at δ = 3.81 and 3.83 ppm for the methyl protons on aromatic ring. The methine proton of the central ring (H-9) was observed as a singlet at δ = 6.68 ppm. The aromatic proton resonance was observed as mixture of doublet of doublet and triplet at δ = 6.84–7.03 ppm. The proton of CH (H-2) appeared as a singlet at δ = 7.64 ppm and a singlet was observed at δ = 11.71 ppm for the NH group. Therefore, all of the spectral data are in agreement with the proposed structure.

Based on the observations, obtained results and according to the previous reports on the catalytic synthesis of quinazolinone derivatives we propose a tentative mechanism as depicted below (Scheme 2). This reaction may proceed via Knoevenagel condensation for the formation of α,β-unsaturated carbonyl compounds 11 upon the loss of a water molecule. In the next step, the intermediate 12 achieved via an intermolecular reaction undergoing nucleophilic attack by amine. Further intermediate 12 undergoes intra-molecular cyclization by the loss of a water molecule to yield the observed quinazolinones 4.

Scheme 2
scheme 2

Tentative mechanism for the synthesis of quinazolinone derivatives

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In conclusion, in continuation of our study on the effective methodology [33, 34] for the synthesis of [1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one and hexahydro[4,5]benzimidazolo[2,1-b]quinazolinone derivatives an efficient, simple, and acetic acid-promoted protocol is developed by one-pot multicomponent reaction using readily available starting materials under metal-free conditions. The advantageous features of this procedure are mild reaction conditions, high atom economy, good yields, operational simplicity, no tedious separation procedures, inexpensive starting materials, metal-free synthesis, environmentally benign reaction, and short reaction times when compared to the reaction catalyzed by the catalyst. In this procedure, the products were collected easily by simple filtration with no need for further purification. The advantageous features of this procedure make it a useful and attractive process for the synthesis of a wide variety of biologically active compounds.