INTRODUCTION

The dihydroquinazolinone core is incorporated in various biologically important natural and synthetic compounds like Quinethazone, Benzouracil, Evodiamine, Fenquizone, NC1 substance 1D19143, and Proquazone (Fig. 1). Such compounds proved to be excellent pharmacores and exhibited numerous therapeutic properties, including anticancer [1, 2], antihypertension [3], anticonvulsant [4], antibacterial [5, 6], anti-inflammatory [7, 8], antianxietic [9], and antidiabetic [10]. In addition, the dihydroquinazolinone moiety is found in antidepressants, antihistamines, and vasodilating agents. Because of their biological activity, the synthesis of dihydroquinazolinones has always been of great interest to researchers, and many methods for synthesizing different derivatives of dihydroquinazolinone have been reported (Scheme 1) [11–24]. However, each method has its own limitations, such as harsh reaction conditions, use of expensive metal catalysts, or low yields. As a continuation of our earlier efforts [25–29] toward the synthesis of various heterocyclic compounds, in the present work we developed a simple and efficient Amberlite 15-catalyzed one-pot synthesis of α,β-unsaturated esters of dihydroquinazolinone.

Fig. 1.
figure 1

Some biologically important dihydroquinazolinone compounds.

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Scheme
scheme 1

1.

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RESULTS AND DISCUSSION

The retrosynthetic analysis of the proposed molecule of dihyroquinazolinone is depicted in Scheme 2. Accordingly, we developed our method for the synthesizing these compounds, using the synthesis of dihyroquinazolinone 1a by the reaction of 6-bromoisatoic anhydride (2a), cyclopropylamine (3a), and (E)-methyl-4-(2-formylphenoxy)but-2-enoate (4) as model substrates. During optimization we carried out the reaction in various solvents and catalysts and after fine tuning we found a good conversion rate with Amberlite 15 in 1,4-dioxane under reflux conditions (Table 1). However the yield of compound 1a was low, when the reaction was conducted at room temperature. In addition few more experiments were conducted by varying the amount of Amberlite 15 (0.05–0.5 wt %) and good yields were obtained with Amberlite 15 (0.1 wt %) under similar conditions. The reaction was further tried to undergo aza-Michael reaction with tetrabutylammoniumfluoride (TBAF), but this attempt may have failed due to the lack of electrophilicity at the allylic carbon atom [24]. However the obtained α,β-unsaturated ester 1a was characterized by 1H and 13C NMR. Furthermore, the substrate scope of this reaction has been studied by varying different types of amines and to our delight all the substrates have been well tolerated under the given optimized reaction conditions in order to get novel functionalized dihyroquinazolinones with reasonably good yields (Table 2). In addition the single crystal X-ray diffraction analysis of dihyroquinazolinone 1b was used to confirm the structure (for details of the XRD experiment, see Supporting Information). The ORTEP diagram of the molecule (Fig. 2) provides clear evidence for the presence of the bromine atom, three phenyl rings, and methyl groups attached to aromatic ring.

Scheme
scheme 2

2.

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Table 1. Solvent and catalyst screening for the synthesis of dihyroquinazolinone 1aView full size image
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Table 2. Substrate scope for the synthesis of dihydroquinazolinonesView full size image
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Fig. 2.
figure 2

ORTEP diagram of compound 1b (the thermal ellipsoids of non-hydrogen atoms are drawn at a 50% probability level).

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To gain insight to the mechanism of the reaction, we performed few control experiments (Scheme 3). First we treated isatoic anhydride (2b) with cyclopropylamine (3a), the reaction involved ring opening to form an amide [Scheme 3, reaction (1)]. Cyclopropylamine (3a) was further treated with aldehyde 4 to form imine 5 [Scheme 3, reaction (2)]. However, no product formation was observed, when isatoic anhydride (2b) was reacted with aldehyde 4 [Scheme 3, reaction (3)]. The results of the control experiments clear evidence to suggest initial amide formation followed by imine formation and, finally, aza-Michael addition and allowed us to propose the reaction mechanism which is depicted in Scheme 4.

Scheme
scheme 3

3.

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Scheme
scheme 4

4.

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EXPERIMENTAL

All reactions were carried out in oven or flame-dried glassware under an argon atmosphere, employing standard techniques for handling air-sensitive materials. All solvents were reagent grade. All other reagents were used as received. Unless otherwise noted, reactions were magnetically stirred and monitored by TLC on Merck-Kiesegel 60 F plates. Flash chromatography was performed on silica gel (230–400 mesh) using distilled hexane and ethyl acetate. The yields refer to chromatographically and spectroscopically pure compounds. The 1H and 13C NMR spectra were recorded using a Bruker instrument at 400 and 100 MHz, respectively, from solutions in DMSO-d6 with tetramethylsilane as internal standard.

Synthesis of dihydroquinazolin-4(1H)-ones 1a–1e (general procedure). To a solution of isatoic anhydride 2a or 2b (1 mmol) in 1,4-dioxane (5 mL), amine 3a–3e (1 mmol) was added and stirred for 1 h at 70°C. (E)-Methyl-4-(2-formylphenoxy)but-2-enoate 4 (1 mmol) and Amberlite 15 (0.1 wt %) were added to the reaction mixture at room temperature and the was stirred for 4 h at 70°C. After completion of the reaction, the solvent in the reaction mass was evaporated under vacuum and the crude residue was purified by column chromatography (ethylacetate–hexane, 3 : 7) to get pure product 1a–1e.

Methyl-(Z)-4-[2-(6-bromo-3-cyclopropyl-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)phenoxy]but-2-enoate (1a). White solid, yield 65%, mp 221–223°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 0.59–0.66 m (2H), 0.85–0.90 m (1H), 1.10–1.23 m (1H), 2.33–2.39 m (1H), 3.69 s (3H), 4.89 s (2H), 6.08 s (1H), 6.16 d (1H, J 16.0 Hz), 6.66 d (1H, J 8.4 Hz), 6.89–6.93 m (1H), 7.04–7.12 m (3H), 7.29–7.31 m (3H), 7.73 s (1H). 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 5.3, 9.1, 27.9, 51.5, 66.5 (2C), 107.5, 112.6, 115.8, 116.7, 120.7, 120.9, 125.9, 128.2, 129.1, 129.8, 135.6, 143.8, 144.8, 154.5, 163.2, 165.7. Mass spectrum, m/z: 457.10 [M + 1].

Methyl-(Z)-4-{2-[3-(3,4-dimethylbenzyl)-6-bromo-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl]phenoxy}but-2-enoate (1b). Yellow solid, yield 72%, mp 199–201°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 2.15 s (3H), 2.17 s (3H), 3.52 d (1H, J 14.8 Hz), 3.67 s (3H), 4.73–4.86 m (2H), 5.31 d (1H, J 17.6 Hz), 5.97 d (J 13.6 Hz, 1H), 6.01 d (1H, J 2.8 Hz), 6.63 d (1H, J 8.8 Hz), 6.91–6.95 m (2H), 6.99–7.01 m (2H), 7.02–7.06 m (2H), 7.11–7.14 d.d (1H, J1 7.6, J2 4.0 Hz), 7.22 d (1H, J 2.0 Hz), 7.29–7.35 m (2H), 7.79 d (1H, J 2.4 Hz). 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 19.0 (2C), 26.8, 46.1, 51.5, 63.8, 66.5, 107.7, 112.6, 115.6, 116.7, 120.6, 127.6, 128.9, 129.6, 130.0, 133.9, 135.3, 135.7, 136.3, 143.5, 145.3, 154.7, 161.2, 165.7. Mass spectrum, m/z: 537.20 [M + 1].

Methyl-(Z)-4-(2-{4-oxo-3-[(tetrahydrofuran-2-yl)methyl]-1,2,3,4-tetrahydroquinazolin-2-yl}phenoxy)but-2-enoate (1c). Yellow solid, yield 59%, mp 215–217°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 0.82–0.85 m (0.5H), 1.10–1.14 m (1H), 1.39–1.47 m (0.5H), 1.59–1.61 m (0.5H), 1.76–1.93 m (4H), 2.75 d.d (0.5H, J1 10.4, J2 3.2 Hz), 3.60–3.83 m (5H), 4.01–4.10 m (2H), 4.88 s (2H), 6.17 d.d (1H, J1 9.2, J2 2.6 Hz), 6.42 d (1H, J 19.6 Hz), 6.67 t (1H, J 9.2 Hz), 6.91 t (1H, J 7.2 Hz), 7.00–7.13 m (3H), 7.23–7.33 m (3H), 7.72 s (1H). 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 15.1 (2C), 25.4, 28.8, 47.9, 59.0, 65.6, 67.2 (2C), 67.3, 77.8, 107.6, 112.6, 115.9, 116.8, 120.7, 125.9, 129.4, 129.8, 135.6, 145.2, 154.6, 162.0, 165.7. Mass spectrum, m/z: 423.10 [M + 1].

Methyl-(Z)-4-{2-[3-(4-methoxybenzyl)-6-bromo-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl]cyclohexyloxy}but-2-enoate (1d). White solid, yield 59%, mp 215–217°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 3.56–3.66 m (2H), 3.69 s (3H), 3.72 s (3H), 4.76–4.88 m (2H), 5.28 d (1H, J 14.8 Hz), 5.97–6.03 m (2H), 6.64 d (1H, J 8.8 Hz), 6.85–6.87 m (2H), 6.89–6.94 m (1H), 6.94–7.00 m (2H), 7.04–7.13 m (2H), 7.22 m (1H), 7.28–7.35 m (2H), 7.79 d (J 2.4 Hz, 1H). 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 29.6, 45.9, 51.5, 54.9, 64.0, 66.5, 107.8, 112.6, 113.9 (2C), 115.6, 116.7, 120.9, 126.2, 127.6, 128.6 (2C), 129.6, 130.3, 135.3, 135.7, 143.5, 145.3, 154.7, 158.6, 161.2, 165.7. Mass spectrum, m/z: 537.20 [M + 1].

Methyl-(Z)-4-{2-[6-bromo-3-(3-methoxypropyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl]phenoxy}but-2-enoate (1e). White solid, yield 74%, mp 232–234°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.61–1.71 m (1H), 3.34–3.37 m (1H), 3.70 s (3H), 3.77–3.85 m (1H), 4.82–4.91 m (2H), 6.14–6.17 m (2H), 6.67 d (1H, J 8.8 Hz, 1H), 6.91 d (1H, J 6.8 Hz), 7.03–7.08 m (2H), 7.11 t (1H, J 4.4 Hz), 7.20 d (1H, J 2.4 Hz), 7.30–7.33 m (2H), 7.71 d (1H, J 2.0 Hz). 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 27.5, 41.9, 51.5, 57.8, 65.7, 66.6, 69.3, 107.7, 112.6, 116.0, 116.7, 120.8, 120.9, 126.2, 128.1, 129.2, 129.9, 135.5, 143.7, 145.3, 154.8, 161.3, 165.8. Mass spectrum, m/z: 489.20 [M + 1].

CONCLUSIONS

In conclusion, we have developed a simple procedure for the preparation of different dihyroquinazolinones by employing Amberlite 15 as a catalyst. The scope of the reaction has been demonstrated with various amines, and the plausible mechanism of the reaction has been proposed based on control experiments.