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M. Wang et al. / Chinese Chemical Letters 22 (2011) 1423–1426
O
O
R2
R1
(NH4)nX
or
R2NH2
SrCl2 6H2O (1 mol%)
N
O
R1CHO
+
+
EtOH/H2O, ref lux
N
H
N
H
O
1
3
4a-4q
2
Scheme 1. One-pot three-component synthesis of 2, 3-dihydroquinazolin-4(1H)-ones.
and using microwave irradiation for accelerated synthesis. Thus, there is a need for a greener and milder method that
might work under mild conditions.
In the course of our recent work on Lewis acid-catalyzed organic reactions, we found only 1 mol% strontium
chloride (SrCl2Á6H2O) could efficiently catalyze one-pot synthesis of 2, 3-dihydroquinazolin-4(1H)-ones via three-
component condensation of isatoic anhydride 1, aldehyde 2 and ammonium salts or primary amines 3 (Scheme 1). The
reaction was carried out in aqueous ethanol under reflux.
1. Experimental
Typical procedure for the synthesis of 2, 3-dihydroquinazolin-4(1H)-ones (4): a stirred mixture of isatoic anhydride
(5.5 mmol), aldehyde (5 mmol), ammonium salt or primary amine (5.5 mmol) and SrCl2Á6H2O (0.05 mmol) in 3 mL
EtOH/H2O (1/3 (v/v)) was refluxed for an appropriate time. When the reaction completed (monitored by TLC), the
reaction mixture was cooled to room temperature. The corresponding pure product was obtained by gravity filtration,
washed with 3 Â 10 mL 50% aqueous ethanol solution (v/v) for three times, and crystallized from EtOH. The products
1
were characterized by IR, H NMR, LC/MS, and elemental analysis. Spectral data for new compounds:
2, 3-Dihydro-2-(2-chlorophenyl)-3-phenyl-quinazolin-4(1H)-one (4i): White crystal. IR (KBr, cmÀ1): 3309, 3070,
2361, 1637, 1606, 1491, 1452, 757. 1H NMR (500 MHz, DMSO-d6): d 7.77 (dd, 1H, J = 1.3, 6.4 Hz), 7.60–7.58 (m,
1H), 7.46 (d, 1H, J = 2.5 Hz), 7.39–7.37 (m, 1H), 7.31–7.27 (m, 5H), 7.21–7.17 (m, 3H), 6.79–6.74 (m, 2H), 6.60 (d,
1H, J = 2.7 Hz). MS (ESI) m/z: 335 ([M+H]+, 100), 336 (23), 337 (36), 338 (8), 315 (6). Anal. Calcd. for
C20H15N2OCl: C, 71.74; H, 4.52; N, 8.37. Found: C, 71.89; H, 4.60; N, 8.43%.
2, 3-Dihydro-2-(4-nitrophenyl)-3-(4-methylphenyl)-quinazolin-4(1H)-one (4m): Pale blue crystal. IR (KBr, cmÀ1):
3650, 3030, 2361, 1660, 1594, 1515, 1457, 762. 1H NMR (500 MHz, DMSO-d6,) d: 10.41 (s, 1H), 8.82 (s, 1H), 8.37 (d,
2H, J = 8.7 Hz), 8.20 (d, 2H, J = 8.7 Hz), 7.84 (dd, 1H, J = 1.0, 6.5 Hz), 7.62–7.56 (m, 3H), 7.45 (t, 1H, J = 7.4 Hz),
7.36 (d, 1H, J = 7.8 Hz), 7.12 (d, 2H, J = 8.3 Hz), 2.25 (s, 3H). MS (ESI) m/z: 360 ([M+H]+, 100), 361 (25), 358 (7),
227 (8). Anal. Calcd. for C21H17N3O3: C, 70.18; H, 4.78; N, 11.69. Found: C, 70.01; H, 4.84; N, 11.77%.
2, 3-Dihydro-2-phenyl-3-n-propyl-quinazolin-4(1H)-one (4o): White crystal. IR (KBr, cmÀ1): 3303, 3065, 2361,
1630, 1588, 1507, 1458, 748. 1H NMR (500 MHz, DMSO-d6): d 7.65 (dd, 1H, J = 1.2, 6.5 Hz), 7.34–7.27 (m, 6H),
7.18 (dt, 1H, J = 1.5, 6.8 Hz), 6.66–6.62 (m, 2H), 5.83 (d, 1H, J = 2.5 Hz), 3.86–3.81 (m, 1H), 2.75–2.69 (m, 1H),
1.63–1.41 (m, 2H), 0.82 (t, 3H, J = 7.4 Hz). MS (ESI) m/z: 267 ([M+H]+, 100), 268 (19). Anal. Calcd. for C17H18N2O:
C, 76.66; H, 6.82; N, 10.52. Found: C, 76.82; H, 6.75; N, 10.64%.
2, 3-Dihydro-2-phenyl-3-benzyl-quinazolin-4(1H)-one (4q): White crystal. IR (KBr, cmÀ1): 3401, 3023, 2361,
1633, 1580, 1502, 1447, 749. 1H NMR (500 MHz, DMSO-d6): d 7.70 (dd, 1H, J = 1.4, 6.4 Hz), 7.36–7.20 (m, 12H),
6.69–6.63 (m, 2H), 5.74 (d, 1H, J = 2.6 Hz), 5.34 (d, 1H, J = 15.4 Hz), 3.83 (d, 1H, J = 15.4 Hz). MS (ESI) m/z: 315
([M+H]+, 100), 316 (24). Anal. Calcd. for C21H18N2O: C, 80.22; H, 5.78; N, 8.91. Found: C, 80.07; H, 5.84; N, 8.82%.
2. Results and discussion
To study the effect of solvent on the condensation, a one-pot reaction of isatoic anhydride (5.5 mmol),
benzaldehyde (5 mmol) and ammonium acetate (5.5 mmol) was chosen as a model reaction in the presence of 1 mol%
SrCl2Á6H2O (Table 1). Because of the toxicity of organic solvents, we only consider the green media such as pure
water, EtOH, and EtOH/H2O. The results show that EtOH/H2O (1/3 (v/v)) system was the best choice (entry 5).
We also investigated the optimal amount of solvent and catalyst. After several trials, the suitable amounts of solvent
and catalyst are 3 mL and 1 mol% (based on aldehyde), respectively.