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Article

A Simple, Efficient, and Eco-Friendly Method for the Preparation of 3-Substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives

1
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
2
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
3
Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 12321, Egypt
*
Author to whom correspondence should be addressed.
Submission received: 1 October 2019 / Revised: 8 November 2019 / Accepted: 8 November 2019 / Published: 9 November 2019
(This article belongs to the Collection Heterocyclic Compounds)

Abstract

:
A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The novel feature of this protocol is the use of 2-methyl tetrahydrofuran (2-MeTHF) as an eco-friendly alternative solvent to tetrahydrofuran (THF) in the first step. In the second step, methanol in the presence of potassium carbonate as a catalyst was used under conventional heating or microwave irradiation, which provided an eco-friendly method to afford the target products in excellent yields and purities. NMR (1H and 13C), elemental analysis, and LC-MS confirmed the structures of all compounds. X-ray crystallography further confirmed the structure of the intermediate 2-amino-N-(2-substituted-ethyl)benzamide 3a. The molecular structure of 3a was monoclinic crystal, with P21/c, a = 13.6879 (11) Å, b = 10.2118 (9) Å, c = 9.7884 (9) Å, β = 105.068 (7)°, V = 1321.2 (2) Å3, and Z = 4.

Graphical Abstract

1. Introduction

The dihydroquinazolinone moiety is present in numerous biologically active molecules with various potential therapeutic effects [1,2,3,4,5,6,7,8,9]. In view of the increasingly widespread applications of dihydroquinazolinone derivatives, many researchers have made great effort to develop these types of compounds using different synthetic methodologies [8,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24], such as by using TiO2 nanoparticles (TiO2 NPs) as a catalyst for the synthesis of 2,3-disubstituted dihydroquinazolin-4(1H)-one derivatives [25]; a metal reduction–condensative cyclization strategy [26]; a three-component reaction of isatoic anhydride with amine and 2-formyl benzoic acid in the presence of montmorillonite K10 as a catalyst [27]; ultrasound irradiation catalyzed by dodecylbenzenesulfonic acid [28]; microwave irradiation in the presence of Amberlyst-15 [29] or Cu-CNTs [30]; and condensation of isatoic anhydride, amine, or ammonium salts with aldehydes or ketones in the presence of p-toluenesulfonic acid [31], citric acid [32], or silica bonded with different acids [33,34,35]. Moreover, the development of a simple, efficient, easy method under environmentally benign conditions for the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives is necessary.
Herein, we report an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide from isatoic anhydride using 2-methyltetrahydrofuran (2-MeTHF), which has previously been promoted as an eco-friendly alternative solvent to tetrahydrofuran (THF) [36,37,38]. In the second step, 2-aminobenzamide intermediate was reacted with different aldehydes under conventional heating or microwave irradiation (MWI) in the presence of methanol as a solvent and K2CO3 as a catalyst to afford the new 2,3-dihydroquinazolin-4(1H)-one derivatives.

2. Results and Discussion

The target products were obtained via two simple and eco-friendly protocols. First, to select the best solvent and conditions for the reaction of isatoic anhydride 1 with two biologically active amine moieties 2a and 2b [39,40,41], 2-morpholinoethan-1-amine 2a was reacted with 1 in different solvents water–acetone [42], THF, and 2-MeTHF [36,37,38] in order to compare the yield, purity, and time required to afford the final product 3a (Scheme 1). The three methods worked satisfactorily, but using the 2-MeTHF gave higher yield and purity in somewhat less reaction time, as summarized in Table 1.
In 1951, Bost et al. [43] reported the synthesis of 3a via the reaction of ethyl-2-aminobenzoate with 2a. Later, in 1970, Bonola et al [44] reported the synthesis of 3b as a key intermediate for the synthesis of 2,3-dihydro-4(1H)-quinazolinone derivatives. Recently, Li et al. [41] reported the synthesis of 3a and 3b without isolation of the product, and they used an in situ reaction for the preparation of thioxodihydroquinazolinone derivatives. Herein we report the synthesis of 3a and 3b under eco-friendly conditions at room temperature to give the products in high yields and purities.
The structure of 3a (Figure 1) was confirmed by the 1H-NMR spectrum (Figure S1, Supporting information) which showed a broad singlet peak at δ 2.55 related to four protons (CH2NCH2, morpholine), a triplet at δ 2.63 (CH2N, H2′), a triplet at δ 3.53 (CH2N, H1′), a broad singlet peak at δ 3.74 related to four protons (CH2OCH2, morpholine), a singlet at δ 5.50 related to NH, a multiplet at δ 6.62–6.66 for the two aromatic protons (H3, H5), a broad singlet at δ 6.82 for the NH, a triplet at δ 7.17(H4), and a doublet at δ 7.34(H6). The 13C-NMR spectrum for 3a showed peaks at δ 35.5(C2′), 53.3(C–N–C, morpholine), 57.1(C1′), 66.6 (C–O–C, morpholine), 116.0(C3), 116.6(C1), 117.3(C5), 127.3(C6), 132.3(C4), 148.7(C2), and 169.3(CON) ppm.
The structure of 3a was further confirmed by the X-ray single crystal differaction technique (Figure 2). The crystallographic data and refinement information for 3a are summarized in Table 2. The selected bond lengths and bond angles are listed in Table S1 (Supporting information). The asymmetric unit contains one independent molecule, as shown in Figure 2. All the bond lengths and angles are in the normal ranges [45]. In the crystal packing (Figure 3), molecules are linked via three classical and one non-classical intermolecular hydrogen bonds (Table S2, supporting information).
Demonstrating the applicability of the method used, the 3b was obtained in high yield and purity as observed from its spectral data (Figure S2, Supporting information) using the same previous conditions.
Compounds 3a and 3b were reacted with different aldehydes using methanol in the presence of K2CO3 as a catalyst under conventional heating and microwave irradiation (Scheme 2, Table 3). Microwave irradiation (MWI) afforded the products in less reaction time with higher yields and purities without further purification, as indicated from their spectral data (Figures S3–S13, Supporting information).
1H-NMR of 4a in CDCl3 as a prototype showed a mutiplet peak at δ 2.40–2.46 related to the four protons of the morpholine residue (CH2NCH2) and the diastereotopic proton Ha, where it has two couplings with Hb and the other two protons Hc and Hd (Figure 4). The multiplet peak observed at δ 2.60 corresponds to the second diastereotopic proton Hb due to the coupling with Ha, Hc and Hd. The same observation was noticed for the other two diastereotopic protons Hc and Hd, where two multiplet peaks were observed at δ 3.04 and 3.93, respectively. The other protons for the morpholine ring showed a triplet peak at δ 3.65 (CH2OCH2). The two singlet peaks at δ 4.50 and 5.90 correspond to He and NH, respectively. The doublet peak at δ 6.52 is related to H5, the triplet at δ 6.85 corresponds to H3, the triplet at δ 7.26 corresponds to H4, the multiplet at δ 7.35–7.38 corresponds to the five protons of the phenyl group, and the doublet peak at δ 7.94 is related to H2. The 13C-NMR spectrum of 4a in CDCl3 showed peaks at δ 41.1 corresponding to –NCH2CH2N–, δ 53.2 related to CH2NCH2 (morpholine ring), δ 55.7 related to the carbon of the ethylene moiety (OC–NCH2CH2N–), δ 65.6 corresponding to CH2OCH2 (morpholine), and δ 57.0 corresponding to NCHN (quinazolinone ring). The aromatic carbon showed peaks at δ 114.7 (C5), 115.7 (C1), 119.0 (C3), 126.6 (C2′,4′,6′), 128.24 (C2), 128.9, 129.2 (C3′,5′), 133.7 (C4), 140.0 (C1′), and 148.4 (C6), while the peak at δ 163.6 corresponds to the carbonyl group (C=O).
Since the formation of the cyclic compounds, 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives 46, create a new chiral center on the final product, it is expected that this will lead to the formation of two enantiomers R and S as a racemic mixture.
Compound 7 (Scheme 2) has been reported previously by Xu et al. [46] who, using CuI/4-hydroxy-L-proline, catalyzed the reaction of N-substituted o-bromobenzamides with formamide at 80 °C in DMF for 24 h.
Herein, 3-(2-morpholinoethyl)quinazolin-4(3H)-one 7 was obtained in higher yield and purity, as observed from its spectral data (Figure S14, Supporting information) under the same conditions described above.

3. Materials and Methods

All reagents and solvents were purchased from commercial suppliers and were used without further purification. 1H-NMR and 13C-NMR spectra were recorded on a JEOL 400 MHz spectrometer (JEOL, Ltd, Tokyo, Japan), and chemical shift (δ) values are expressed in ppm. Mass spectra were recorded on a JEOL JMS-600 H (JEOL, Ltd, Tokyo, Japan). Elemental analyses were carried out on an Elmer 2400 CHNS Elemental Analyzer (PerkinElmer, Inc.940 Winter Street, Waltham, MA, USA). Melting points were measured on a Gallenkamp melting point apparatus (Sigma-Aldrich Chemie GmbH, 82024 Taufkirchen, Germany) in open glass capillaries and are uncorrected. Experiments were performed in a multimode reactor (Synthos 3000, Aton Paar GmbH, 1400 W maximum magnetron, Germany). The vessel was purged with nitrogen gas for 1 min and then placed in the corresponding rotor fixed with a screw; the rotor was then closed with a protective hood. After heating for 6–8 min (600 W at 60 °C), cooling was accomplished by a fan for 5 min.

3.1. General Method for the Synthesis of 2-amino-N-(2-substituted-ethyl)benzamide

To a solution of isatoic anhydride (1.63 gm, 10 mmol) in 2Me-THF (50 mL) was added 2-(piperidin-1-yl)ethan-1-amine or 2-morpholinoethan-1-amine (11 mmol). The reaction mixture was stirred at room temperature for 4–5 h (TLC showed complete reaction after 4 h). 2Me-THF was evaporated under reduced pressure to afford the target products in good yields and purities as observed form their spectral data. Compound 3a was obtained as single crystals by slow evaporation at room temperature from dichloromethane–hexane (4:6).
2-Amino-N-(2-morpholinoethyl)benzamide (3a). Light brown crystals in 95% yield; mp 126–128 °C (lit [43] mp 126 °C); 1H-NMR (CDCl3): δ 2.55 (4H, br.s, CH2NCH2), 2.63 (2H, t, J = 6 Hz, CH2CH2N), 3.53 (2H, t, J = 2.8, 2 Hz, NHCH2CH2N ), 3.74 (4H, br.s, CH2OCH2), 5.50 (2H, br.s, NH2), 6.62–6.66 (2H, m, Ar), 6.82 (1H, br.s, NH), 7.17 (1H, t, J = 7.2 Hz, Ar), 7.34 (1H, d, J = 8 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 35.5, 53.3, 57.1 ,66.6, 116.0, 116.6, 117.3, 127.3, 132.3, 148.8, 169.3 ppm. LC/MS (ESI): 250.12 [M + H]+; Anal. for C13H19N3O2; Calcd: C, 62.63; H, 7.68; N, 16.85; Found: C, 62.88; H, 7.87; N, 17.01.
2-Amino-N-(2-(piperidin-1-yl)ethyl)benzamide 3b. Light brown crystals in 96% yield; mp 113–114 °C; (lit [44] yield 81%, mp 130–132 °C from benzene); 1H-NMR (CDCl3): δ 1.45 (2H, m, CH2), 1.61 (4H, td, J = 4.8, 6, 5.2, 6 Hz, 2CH2), 2.46 (4H, br.s, CH2NCH2), 2.57 (2H, t, J = 5.6, 6 Hz, CH2N), 3.49 (2H, q, J = 6, 5.2, 4.8 Hz, CH2N), 5.53 (2H, br.s, NH2), 6.63–6.66 (2H, m, Ar), 6.95 (1H, br.s, NH), 7.19 (1H, t, J = 8, 6.4 , 1.6 Hz, Ar), 7.35 (1H, dd, J = 8, 6.4, 1.6 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 24.2, 25.8, 36.0, 54.2, 57.0, 116.3, 116.5, 117.1, 127.3, 132.0, 148.6, 169.2 ppm. LC/MS (ESI): 248.12 [M + H]+; Anal. for C14H21N3O; Calcd: C, 67.98; H, 8.56; N, 16.99; Found: C, 68.08; H, 8.69; N, 17.03.

3.2. General Method for the Synthesis of 3-substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives

Method A—Conventional heating: A mixture of 2-amino-N-(2-substituted-ethyl)benzamide 3a/b (1 mmol), benzaldehyde derivatives or 2-pyridine carboxaldehyde (1 mmol), and potassium carbonate (1.3 mmol) in MeOH (5 mL) was refluxed for 4–6 h. After completion of the reaction, potassium carbonate was filtered off from the hot solution and washed with hot methanol (10 mL). Pure product was obtained on the cooling and evaporation of methanol at room temperature.
Method B—Microwave irradiation: A mixture of 2-amino-N-(2-substituted-ethyl)benzamide 3a/b (1 mmol), benzaldehyde derivatives or 2-pyridine carboxaldehyde (1 mmol), and potassium carbonate (1.3 mmol) in MeOH (5 mL) was mixed at RT and then microwave irradiated (600 W and 60 °C) using a Galanz microwave oven (Guangdong Galanz Enterprise Co, ltd. China) or a multimode reactor for 6–8 min. After cooling, hot methanol was added, and potassium carbonate was filtered off from the solution and washed with hot methanol (10 mL). Pure product was obtained in excellent yield and purity after the evaporation of methanol at room temperature.
3-(2-Morpholinoethyl)-2-phenyl-2,3-dihydroquinazolin-4(1H)-one (4a). Light brown solid in 86% (Method A) or 92% (Method B) yield; mp 142–144 °C (lit [44] yield 30%, mp 144–147 °C); 1H-NMR (CDCl3): δ 2.40–2.46 (5H, m), 2.60 (1H, m), 3.04 (1H, m), 3.65 (4H, t, J = 4.4 Hz, CH2OCH2), 3.93 (1H, m), 4.50 (1H, s, HNCHN), 5.90 (1H, s, NH), 6.52 (1H, d, J = 8 .0 Hz, Ar), 6.85 (1H, d, J = 7.6 Hz, Ar), 7.26 (1H, d, J = 7.6 Hz, Ar), 7.35–7.38 (5H, m, phenyl), 7.94 (1H, dd, J = 8.0, 1.2 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 41.1, 53.2, 55.7, 65.6, 57.0, 114.7, 115.7, 119.0, 126.6, 128.2, 128.9, 129.1, 133.7, 140.0, 148.4, 163.6 ppm. LC/MS (ESI): 338.12 [M + H]+; Anal. for C20H23N3O2; Calcd: C, 71.19; H, 6.87; N, 12.45; Found: C, 71.33; H, 6.69; N, 12.23.
2-(4-Bromophenyl)-3-(2-morpholinoethyl)-2,3-dihydroquinazolin-4(1H)-one (4b). Light brown solid in 87% (Method A) or 96% (Method B) yield; mp 165–166 °C; 1H-NMR (CDCl3): δ 2.43 (4H, br.s, CH2NCH2), 2.49 (1H, m), 2.62 (1H, m), 3.01 (1H, m), 3.66 (4H, br.s, CH2OCH2), 3.99 (1H, m), 4.52 (1H, s, CH), 5.88 (1H, s, NH), 6.52 (1H, d, J = 8 Hz, Ar), 6.84 (1H, d, J = 7.6 Hz, Ar), 7.24 (3H, m, Ar), 7.45 (2H, d, J = 6.4 Hz, Ar`), 7.92 (1H, dd, J = 8, 1.6 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 40.4, 52.6, 55.1, 64.3, 71.8, 115.1, 119.5, 123.6, 127.7, 127.9, 132.1, 132.4, 134.2, 138.5, 144.9, 163.6 ppm. LC/MS (ESI): 416.12 [M + H]+; Anal. for C20H22BrN3O2; Calcd: C, 57.70; H, 5.33; N, 10.09; Found: C, 57.89; H, 5.47; N, 10.26.
2-(4-Chlorophenyl)-3-(2-morpholinoethyl)-2,3-dihydroquinazolin-4(1H)-one (4c). Light brown solid in 84% (Method A) or 96% (Method B) yield; mp 133–135 °C; 1H-NMR (CDCl3): δ 2.43 (4H, br.s, CH2NCH2), 2.49 (1H,m), 2.62 (1H, m), 3.00 (1H, m), 3.66 (4H, br.s, CH2OCH2), 3.99 (1H, m), 4.52 (1H, s, CH), 5.88 (1H, s, NH), 6.52 (1H, d, J = 8 Hz, Ar), 6.84 (1H, t, J = 7.6 Hz, Ar), 7.24 (3H, m, Ar), 7.45 (2H, d, J = 6.8 Hz, Ar), 7.92 (1H, dd, J = 8.0, 1.6 Hz, Ar) ppm. 13C-NMR (CDCl3): δ 40.6, 52.6, 54.7, 64.0, 70.5, 115.4, 118.9, 127.78, 128.1, 128.9, 134.1, 134.5, 138.9, 145.5, 164.0 ppm. LC/MS (ESI): 372.12 [M + H]+; Anal. for C20H22ClN3O2; Calcd: C, 64.60; H, 5.96; N, 11.30; Found: C, 64.78; H, 6.12; N, 11.54.
3-(2-Morpholinoethyl)-2-(p-tolyl)-2,3-dihydroquinazolin-4(1H)-one (4d). Off-white solid in 83% (Method A) or 96% (Method B) yield; mp 132–134 °C; 1H-NMR (CDCl3): δ 2.33 (3H, s, CH3), 2.52 (5H, br.s, CH2NCH2 and H ethylene), 2.70 (1H, m), 3.13 (1H, m), 3.71 (4H, t, J = 4.4 Hz, CH2OCH2), 3.94 (1H, m), 4.51 (1H, s, CH), 5.90 (1H, s, NH), 6.52 (1H, d, J = 8 Hz, Ar), 6.82 (1H, t, J = 7.2 Hz, Ar), 7.16 (2H, d, J = 6.8 Hz, Ar), 7.26–7.29 (3H, m, Ar), 7.92 (1H, dd, J = 7.6 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 21.1, 41.4, 53.6, 56.3, 66.5, 72.7, 114.3, 116.0, 119.3, 126.7, 128.4, 129.6, 133.6, 136.7, 139.4, 145.2, 163.4 ppm. LC/MS (ESI): 352.33 [M + H]+; Anal. for C21H25N3O2; C, 71.77; H, 7.17; N, 11.96; Found: C, 71.92; H, 7.32; N, 11.77.
2-(4-(Dimethylamino)phenyl)-3-(2-morpholinoethyl)-2,3-dihydroquinazolin-4(1H)-one (4e). Yellow solid in 87% (Method A) or 96% (Method B) yield; mp 183–184 °C; 1H-NMR (DMSO-d6): δ 2.31 (4H, br.s, CH2NCH2), 2.49 (2H, s, NCH2CH2N), 2.86 (6H, s, CH3NCH3), 3.50 (5H, t, J = 4.4 Hz, CH2OCH2 and H ethylene), 3.83 (1H, m), 4.51 (1H, s, CH), 5.76 (1H, s, NH), 6.59–6.66 (4H, m, Ar), 7.10–7.16 (3H, m, Ar), 7.61 (1H, dd, J = 7.6 Hz, Ar) ppm; 13C-NMR (DMSO-d6): δ 40.3, 41.0, 53.3, 55.9, 66.2, 70.7, 112.0, 114.1, 114.8, 116.8, 127.3, 127.4, 128.1, 133.1, 146.6, 150.6, 162.4 ppm. LC/MS (ESI): 381.39 [M + H]+; Anal. for C22H28N4O2; Calcd: C, 69.45; H, 7.42; N, 14.73; Found: C, 69.63; H, 7.55; N, 14.89.
3-(2-Morpholinoethyl)-2-(3,4,5-trimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (4f). Off-white solid in 86% (Method A) or 97% (Method B) yield; mp 148–150 °C; 1H-NMR (400 MHz, CDCl3): δ 2.40 (4H, t, J = 4.4, 5.2 Hz, CH2NCH2), 2.58 (1H, m), 3.13 (1H, m), 3.63 (6H, two s, 2OCH3), 3.77 (3H, s, OCH3), 3.80 (4H, br.s, CH2OCH2), 3.88–3.91 (2H, m, CONCH2CH2N), 4.46 (1H, s, CH), 5.80 (1H, s, NH), 6.53 (1H, d, J = 8 Hz, Ar), 6.59 (2H, s, Ar), 6.83 (1H, t, J = 7.4Hz, Ar), 7.23 (1H, t, J = 8 Hz, Ar), 7.92 (1H, dd, J = 8, 1.6 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 41.5, 53.8,56.1, 56.5, 60.8, 66.9, 73.2, 103.9, 114.2, 115.9, 119.3, 128.3, 133.5, 135.1, 138.8, 145.3, 153.5, 163.3 (CON) ppm. LC/MS (ESI): 428.45 [M + H]+; Anal. for C23H29N3O5; Calcd: C, 64.62; H, 6.84; N, 9.83; Found: C, 64.87; H, 6.95; N, 10.02.
2-Phenyl-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydroquinazolin-4(1H)-one (5a). Off-white solid in 80% (Method A) or 93% (Method B) yield; mp 132–134 °C (lit [44] yield 67% mp 139–143 °C); 1H-NMR (CDCl3): δ 1.43 (2H, br.s, CH2), 1.61 (4H, br.s, 2CH2), 2.50 (5H, br.s, 2CH2 and CH), 2.75 (1H, m, CH), 3.12 (1H, dd, J = 5.2 Hz, CH ), 4.02 (1H, m, CH), 4.58 (1H, s, CH), 5.96 (1H, s, NH), 6.51 (1H, d, J = 8 Hz, H8), 6.82 (1H, t, J = 7.2 Hz, H6), 7.24 (1H, t, J = 8.0 Hz, H7), 7.32–7.36 (5H, m, phenyl), 7.91 (1H, dd, J = 6.8 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 23.8, 25.2, 54.5, 41.7, 56.4, 72.7, 114.3, 116.0, 119.2, 126.6, 128.4, 128.9, 129.3, 133.5, 139.9, 145.1, 163.2 (CON) ppm. LC/MS (ESI): 336.23 [M + H]+; Anal. for C21H25N3O; Calcd: C, 75.19; H, 7.51; N, 12.53; Found: C, 75.33; H, 7.68; N, 12.87.
2-(4-Bromophenyl)-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydroquinazolin-4(1H)-one (5b). Off-white solid in 82% (Method A) or 97% (Method B) yield; mp 196–198 °C; 1H-NMR (CDCl3): δ 1.43 (2H, dd, J = 5.2, 5.6 Hz, CH2CH2CH2), 1.59 (4H, dd, J = 4.8, 5.2 Hz CH2CH2CH2), 2.46 (4H, br.s, CH2NCH2), 2.52–2.71 (2H, m, CH2), 3.01 (1H, m, CH), 4.05 (2H, m, CH), 4.75 (1H, s, CH), 5.94 (1H, s, NH), 6.53 (1H, d, J = 8 Hz, Ar ), 6.83 (1H, t, J = 8 Hz, Ar), 7.23 (2H, d, J = 8.8 Hz, Ar), 7.24 (1H, t, J = 8 Hz, Ar), 7.43 (2H, d, J = 8.8 Hz, Ar), 7.90 (1H, dd, J = 8, 1.8 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 23.7, 25.2, 54.6, 41.8, 56.4, 71.8, 114.7,116.1, 119.5, 127.9, 128.4, 129.1, 133.7, 135.1, 138.6, 144.8, 163.1 (CON) ppm. LC/MS (ESI): 415.40 [M + H]+; Anal. for C21H24BrN3O; Calcd: C, 60.87; H, 5.84; N, 10.14; Found: C, 60.99; H, 5.93; N, 10.33.
2-(4-Methoxyphenyl)-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydroquinazolin-4(1H)-one (5c). Off-white solid in 81% (Method A) or 94% (Method B) yield; mp 146–147 °C; 1H-NMR (CDCl3): δ 1.40 (2H, d, J = 5.6 Hz, CH2CH2CH2), 1.56 (4H, dd, J = 5.2, 5.6 Hz, CH2CH2CH2), 2.45 (4H, br. s, CH2NCH2), 2.48–2.65 (2H, m, CH2), 3.10 (1H, m, CH), 3.75 (3H, s, OCH3), 3.94 (1H, m, CH), 4.53 (1H, s, CH), 5.88 (1H, s, NH), 6.50 (1H, d, J = 8 Hz, Ar), 6.80 (1H, t, J = 8 Hz, Ar), 6.81 (2H, d, J = 8.8 Hz, Ar), 7.20 (1H, t, J = 7.6 Hz, Ar), 7.29 (2H, d, J = 8.8 Hz, Ar), 7.89 (1H, d, J = 7.6 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 23.9, 25.5, 54.5, 41.5, 56.4, 55.3, 72.4, 114.2,114.3, 115.93, 119.1, 128.0, 128.3, 131.9, 133.4, 145.3, 160.3, 163.25 (CON) ppm. LC/MS (ESI): 366.53 [M + H]+; Anal. for C22H27N3O2; Calcd: C, 72.30; H, 7.45; N, 11.50; Found: C, 72.56; H, 7.66; N, 11.74.
3-(2-Morpholinoethyl)-2-(pyridin-2-yl)-2,3-dihydroquinazolin-4(1H)-one (6a). Off-white solid in 83% (Method A) or 97% (Method B) yield; mp 154–155 °C; 1H-NMR (CDCl3): δ 2.48 (4H, br.s, CH2NCH2), 2.63 (2H, m, CH2), 3.15 (1H, m, CH), 3.64 (4H, td, J = 5.2, 4.4 Hz, CH2OCH2), 4.23 (1H, m, CH ), 5.20 (1H, s, CH), 5.83 (1H, s, NH), 6.51 (1H, d, J = 8 Hz, Ar), 6.77 (1H, t, J = 7.2 Hz, Ar), 7.17–7.24 (3H, m, Ar), 7.58 (1H, d, J = Hz, Ar), 7.86 (1H, dd, J = 7.2 , 1.6 Hz, Ar), 8.55 (1H, dd, J = 4.4 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 42.7, 53.7, 56.7, 66.9, 72.6, 114.8, 116.3, 119.3, 120.1, 123.3, 128.3, 133.5, 136.9, 145.2, 149.8, 159.2, 163.08 (CON) ppm. LC/MS (ESI): 340.16 [M + H]+; Anal. for C19H22N4O2; Calcd: C, 67.44; H, 6.55; N, 16.56; Found: C, 67.66; H, 6.68; N, 16.79.
3-(2-(Piperidin-1-yl)ethyl)-2-(pyridin-2-yl)-2,3-dihydroquinazolin-4(1H)-one (6b). Off-white solid in 84% (Method A) or 96% (Method B) yield; mp 135–136 1H-NMR (CDCl3): δ 1.39 (2H, m, CH2), 1.52 (4H, m, 2CH2), 2. 42 (5H, br.s, 2CH2 & CH), 2.61 (2H, m, CH2), 3.09 (1H, m, CH), 4.29 (2H, m, CH), 5.20 (1H, s, CH), 5.84 (1H, d, J = 2 Hz, NH), 6.51 (1H, d, J = 8 Hz, Ar), 6.77 (1H, t, J = 7.2 Hz, Ar), 7.17 (2H, td, J = 7.6, 1.2, 8, 4.4 Hz, Ar), 7.23 (1H, d, J = 8 Hz, Ar),7.57 (1H, td, J = 7.6, 1.6, 8, 1.6 Hz, Ar), 7.87 (1H, dd, J = 8, 1.6 Hz, Ar), 8.55 (1H, d, J = 4.4 Hz, Ar) ppm; 13C-NMR (CDCl3): δ 28.9, 30.5, 47.8, 59.4, 61.7, 77.0, 119.5, 121.2, 123.9, 124.8, 127.9, 132.9, 138.1, 141.6, 149.9, 154.5, 163.8, 167.8 (CON) ppm. LC/MS (ESI): 337.51 [M + H]+; Anal. for C20H24N4O; Calcd: C, 71.40; H, 7.19; N, 16.65; Found: C, 71.66; H, 7.41; N, 16.89.
3-(2-Morpholinoethyl)quinazolin-4(3H)-one (7). Off-white solid in 85% (Method A) or 97% (Method B) yield; mp 221–223 °C (Lit [46] 89% yield); 1H-NMR (CDCl3): δ 2.49 (4H, t, J = 4.4 Hz, CH2NCH2), 2.58 (2H, t, J = 6, 6.4 Hz, NCH2CH2N), 3.49 (2H, td, J = 6.8, 6.4, 5.2 Hz, NCH2CH2N), 3.69 (4H, td, J = 5.2, 10.4, 4.4, 4.8 Hz, CH2OCH2), 6.62–6.67 (3H, m, Ar), 7.17 (1H, td, J = 7.2, 1.6, 8, 1.2 Hz, Ar), 7.29 (1H, dd, J = 7.2, 1.6 Hz, Ar); 13C-NMR (CDCl3): δ 35.6, 53.3, 56.9, 66.9, 100.0, 116.1, 116.6, 117.3, 127.2, 132.2, 148.7, 169.29 (CON) ppm. LC/MS (ESI): 260.36 [M + H]+; Anal. for C14H17N3O2; Calcd: C, 64.85; H, 6.61; N, 16.20; Found: C, 64.99; H, 6.82; N, 16.47.

3.3. X-Ray Measurements

Compound 3a was obtained as single crystals by slow evaporation at room temperature from dichloromethane–hexane (4:6) solution. Data were collected on a Bruker APEX-II D8 Venture area diffractometer equipped with graphite monochromatic Cu Kα radiation, λ = 1.54060 Å at 23 °C. Cell refinement and data reduction were carried out using Bruker SAINT. SHELXT [47,48] was used to solve the structure. The final refinement was carried out by full-matrix least-squares techniques with anisotropic thermal data for non-hydrogen atoms on F. CCDC 1896391 contains the supplementary crystallographic data for this compound and can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

4. Conclusions

The present work described two simple protocols for the synthesis of 3-substituted-2,3-dihydro quinazolin-4(1H)-one and 3-(2-morpholinoethyl)quinazolin-4(3H)-one. The feature of this work is the use of 2-MeTHF, which offers both economical and environmentally friendly advantages over tetrahydrofuran for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide, considered a very important intermediate for the preparation of several derivatives with biological activities of interest [40,41]. In addition, microwave irradiation afforded the 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivative final products in less reaction time and with higher yield and purity than conventional heating. NMR (1H and 13C) spectra, elemental analysis, and LC-MS confirmed the structures of all compounds obtained.
Finally, this protocol could be a useful and attractive process for the synthesis of numerous 2,3-dihydroquinazolin-4(1H)-one derivatives of biological interest.

Supplementary Materials

The following are available online.

Author Contributions

Chemical synthesis of the products was carried out by Z.A., K.A.D. and R.A.A. X-ray study was carried out by H.A.G. The work was designed and supervised by A.E.-F. The results were discussed by all authors. The first drafts of the manuscript were prepared by Z.A. and the final version included contributions from all authors.

Funding

This research received no external funding.

Acknowledgments

The authors extend their appreciation to the Researchers Supporting Project at King Saud University, Riyadh, Saudi Arabia for funding this work through project No (RSP-2019/50).

Conflicts of Interest

The authors declare no conflicts of interest.

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Sample Availability: Samples of the compounds are available from the authors.
Scheme 1. Synthesis of 2-amino-N-(2-substituted-ethyl)benzamide.
Scheme 1. Synthesis of 2-amino-N-(2-substituted-ethyl)benzamide.
Molecules 24 04052 sch001
Figure 1. Structure of 3a.
Figure 1. Structure of 3a.
Molecules 24 04052 g001
Figure 2. Oak Ridge Thermal Ellipsoid Plot (ORTEP)diagram of the titled compound; displacement ellipsoids are plotted at the 40% probability level for non-H atoms.
Figure 2. Oak Ridge Thermal Ellipsoid Plot (ORTEP)diagram of the titled compound; displacement ellipsoids are plotted at the 40% probability level for non-H atoms.
Molecules 24 04052 g002
Figure 3. Molecular packing of the titled compound displaying hydrogen bonds, which are drawn as dashed lines along the c-axis.
Figure 3. Molecular packing of the titled compound displaying hydrogen bonds, which are drawn as dashed lines along the c-axis.
Molecules 24 04052 g003
Scheme 2. Synthesis of 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives.
Scheme 2. Synthesis of 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives.
Molecules 24 04052 sch002
Figure 4. Structure of 4a.
Figure 4. Structure of 4a.
Molecules 24 04052 g004
Table 1. Reaction of isatoic anhydride using different solvents to afford the product 3a.
Table 1. Reaction of isatoic anhydride using different solvents to afford the product 3a.
EntrySolventTime (h)Yield (%)Mp (°C)
1Water–acetone871104–106
2THF5–686113–114
32-MeTHF4–595113–114
Table 2. Experimental details of 3a.
Table 2. Experimental details of 3a.
Crystal Data
Chemical formulaC13H19N3O2
Mr249.31
Crystal system, space groupMonoclinic, P21/c
Temperature (K)296
a, b, c (Å)13.6879 (11), 10.2118 (9), 9.7884 (9)
β (°)105.068 (7)
V (Å3)1321.2 (2)
Z4
Radiation typeCu Kα
µ (mm−1)0.70
Crystal size (mm)0.51 × 0.45 × 0.11
Data collection
DiffractometerBruker APEX-II D8 venture diffractometer
Absorption correctionMulti-scan SADABS Bruker 2014
Tmin, Tmax0.887, 0.912
No. of measured, independent, and observed [I > 2σ(I)] reflections12783, 2298, 1393
Rint0.088
Refinement
R[F2 > 2σ( F2)], wR(F2), S0.052, 0.152, 1.02
No. of reflections2298
No. of parameters176
No. of restraintsH atoms treated by a mixture of independent and constrained refinement
H-atom treatment0.21, −0.19
Δρmax, Δρmin (e Å−3)0.052, 0.152, 1.02
Table 3. Yield (%), reaction time (h, min), and mp (°C) of 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives.
Table 3. Yield (%), reaction time (h, min), and mp (°C) of 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives.
Compound No.R1R2R3Reaction Time (h), Yield%
Conventional Heating
Reaction Time (min), Yield%
Microwave Irradiation
Mp (°C)
4aHHH4(86)6(92)142–144
4bHBrH4(87)6(96)133–135
4cHClH4(84)6(96)165–166
4dHCH3H5(83)6(96)132–134
4eHNMe2H5(87)7(96)183–184
4fOCH3OCH3OCH35(86)7(97)148–150
5aHHH4(80)6(93)120–121
5bHBrH4(82)6(97)198–198
5cHOCH3H5(81)6(94)146–147
6aHHH4(83)6(97)154–155
6bHHH4(84)6(96)135–136
7HHH6(85)8(97)221–223

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MDPI and ACS Style

Almarhoon, Z.; Dahlous, K.A.; Abd Alhameed, R.; Ghabbour, H.A.; El-Faham, A. A Simple, Efficient, and Eco-Friendly Method for the Preparation of 3-Substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives. Molecules 2019, 24, 4052. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24224052

AMA Style

Almarhoon Z, Dahlous KA, Abd Alhameed R, Ghabbour HA, El-Faham A. A Simple, Efficient, and Eco-Friendly Method for the Preparation of 3-Substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives. Molecules. 2019; 24(22):4052. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24224052

Chicago/Turabian Style

Almarhoon, Zainab, Kholood A. Dahlous, Rakia Abd Alhameed, Hazem A. Ghabbour, and Ayman El-Faham. 2019. "A Simple, Efficient, and Eco-Friendly Method for the Preparation of 3-Substituted-2,3-dihydroquinazolin-4(1H)-one Derivatives" Molecules 24, no. 22: 4052. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24224052

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