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G. Marzaro et al. / Tetrahedron 66 (2010) 962–968
55.13, 46.93, 35.40, 29.56; HRMS (ESI-TOF) for C14H23N2O2 [MþH]þ:
calcd: 251.1754, found: 251.1888. Anal. Calcd for C14H22N2O2: C,
67.17; H, 8.86; N, 11.19. Found: C, 67.12; H, 8.88; N, 11.23.
calcd: 323.1965, found: 323.1938. Anal. Calcd for C17H26N2O4: C,
63.13; H, 8.41; N, 8.66. Found: C, 63.29; H, 8.45; N, 8.65.
4.4. General procedure for quinazolines 7 and 14a–c
4.3. General procedure for carbamates 6 and 13a–c
All the quinazolines were synthesized accordingly to previously
reported method.12 Generally, a mixture of ethyl carbamate (6, 13a–
c) (10.0 mmol) and hexamethylene-tetramine (10.0 mmol) in TFA
(30 mL) was microwave irradiated at 110 ꢀC (power set point 80 W;
ramp time 1 min; hold time 10 min). After cooling the mixture was
diluted with aqueous ethanolic (water/EtOH: 1/1) 10% KOH
(300 mL), added with K3Fe(CN)6 (80.0 mmol) and stirred to reflux for
4 h. After cooling the mixture was diluted with water (300 mL) and
extracted with CH2Cl2 (3ꢁ200 mL). The organic phase was evapo-
rated under reduced pressure to give the quinazoline 7 and 14a–c.
A mixture of aniline (5, 12a–c) (10.0 mmol), ethyl chloroformate
(20.0 mmol), and Et3N (20.0 mmol) in anhydrous THF (200 mL) was
stirred at room temperature for 30 min. The solid was filtered off
and the solvent was evaporated under reduced pressure. The
residue was dissolved in CH2Cl2 (200 mL) and the organic layer was
washed with water (2ꢁ100 mL). The organic phase was evaporated
under reduced pressure to give the title compounds in quantitative
yield (98%).
4.3.1. Ethyl (3,4-dimethoxyphenyl)carbamate (6). Brown solid; mp
4.4.1. 6,7-Dimethoxyquinazoline (7). Yield 1.6 g; 86%; yellow solid;
45 ꢀC; IR (KBr) 3323, 2974, 2938, 2840, 1693, 1605, 1520, 1452, 1417,
mp 138 ꢀC; IR (KBr) 2931, 1670, 1615, 1503, 1432, 1358, 1325, 1232,
1232, 1168, 1135, 1074, 1023, 845 cmꢂ1; 1H NMR (DMSO-d6):
d
9.39
1151, 1093, 999, 851 cmꢂ1; 1H NMR (DMSO-d6):
d
9.29 (1H, s, 4-H),
9.07 (1H, s, 2-H), 7.48 (1H, s, 5-H or 8-H), 7.35 (1H, s, 5-H or 8-H),
3.98 (3H, s, OCH3), 3.94 (3H, s, OCH3); 13C NMR (DMSO-d6):
156.71,
(1H, br s, NH), 7.16 (1H, d, J¼1.7, 2-H), 6.93 (1H, dd, J¼9.2 Hz, 1.7, 6-
H), 6.85 (1H, d, J¼9.2 Hz, 5-H), 4.09 (2H, q, J¼7.1 Hz, CO2CH2CH3),
3.70 (3H, s, OCH3), 3.69 (3H, s, OCH3), 1.23 (3H, t, J¼7.1 Hz,
d
155.88, 153.41, 150.10, 147.15, 120.58, 105.93, 104.49, 56.06, 55.79;
HRMS (ESI-TOF) for C10H11N2O2 [MþH]þ: 191.0815, found:
191.1002. Anal. Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73.
Found: C, 63.10; H, 5.32; N, 14.75.
CO2CH2CH3); 13C NMR (DMSO-d6):
d 153.51, 148.62, 144.18, 132.71,
122.32, 112.28, 59.84, 55.72, 55.25, 14.46; HRMS (ESI-TOF) for
C11H16NO4 [MþH]þ: calcd: 226.1074, found: 226.1106. Anal. Calcd
for C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C, 58.71; H, 6.72; N,
6.18.
4.4.2. 6,7-Di(20-methoxyethoxy)quinazoline (14a). Yield 2.5 g; 91%;
yellow solid; mp 114 ꢀC; IR (KBr) 2926, 1676, 1564, 1506, 1459, 1372,
4.3.2. Ethyl [3,4-di(20-methoxyethoxy)phenyl]carbamate (13a). Brown
solid; mp <40 ꢀC; IR (KBr) 3316, 2980, 2933, 2889, 1690, 1609, 1515,
1325, 1233, 1129, 1033, 859 cmꢂ1; 1H NMR (CDCl3):
d 9.10 (2H, s, 4-H
and 2-H), 7.28 (1H, s, 5-H or 8-H), 7.11 (1H, s, 5-H or 8-H), 4.33–4.24
1455, 1227, 1124, 1054, 857, 777 cmꢂ1
;
1H NMR (CDCl3):
d
7.18
(4H, m, 2ꢁOCH2CH2OCH3), 3.89–3.82 (4H, m, 2ꢁOCH2CH2OCH3), 3.47
(1H, d, J¼2.5 Hz, 2-H), 6.86 (1H, d, J¼8.4 Hz, 5-H), 6.76 (1H, dd,
J¼8.4, 2.5 Hz, 6-H), 6.49 (1H, br s, NH), 4.20 (2H, q, J¼7.1 Hz,
CO2CH2CH3), 4.17–4.09 (4H, m, 2ꢁOCH2CH2OCH3), 3.80–3.71 (4H,
m, 2ꢁOCH2CH2OCH3), 3.44 (6H, s, 2ꢁOCH3), 1.30 (3H, t, J¼7.1 Hz,
(3H, s, OCH3), 3.46 (3H, s, OCH3); 13C NMR (CDCl3):
d 156.75, 155.89,
154.05,150.17,147.98,121.04,107.42,105.50, 70.64, 70.39, 68.75, 68.61,
59.39, 59.36; HRMS (ESI-TOF) for C14H19N2O4 [MþH]þ: calcd:
279.1339, found: 279.1398. Anal. Calcd for C14H18N2O4: C, 60.42; H,
6.52; N, 10.07. Found: C, 60.39; H, 6.55; N, 10.10.
CO2CH2CH3); 13C NMR (CDCl3):
d 164.46, 159.36, 149.00, 145.11,
115.54, 112.51, 107.17, 70.83, 70.71, 69.07, 68.22, 60.79, 58.83, 58.77,
14.32; HRMS (ESI-TOF) for C15H24NO6 [MþH]þ: calcd: 314.1598,
found: 314.153. Anal. Calcd for C15H23NO6: C, 57.50; H, 7.40; N, 4.47.
Found: C, 57.42; H, 7.38; N, 4.51.
4.4.3. 7-Methoxy-6-(30-N-morpholino)propoxyquinazoline
(14b). Yield 2.5 g; 84%; yellow solid; mp 116 ꢀC; IR (KBr) 2953,1671,
1616, 1500, 1469, 1357, 1324, 1230, 1149, 1116, 1012, 860 cmꢂ1 1H
;
NMR (DMSO-d6): d 9.29 (1H, s, 4-H), 9.06 (1H, s, 2-H), 7.49 (1H, s, 5-
4.3.3. Ethyl [3-methoxy-4-(30-N-morpholino)propoxyphenyl]-carba-
mate (13b). Brown solid; mp 81 ꢀC; IR (KBr) 3307, 2957, 2933, 2810,
1697, 1628, 1604, 1521, 1462, 1409, 1264, 1236, 1139, 1117, 1071, 1035,
H or 8-H), 7.35 (1H, s, 5-H or 8-H), 4.18 (2H, t, J¼6.8 Hz,
NCH2CH2CH2O), 3.99 (3H, s, OCH3), 3.60–3.55 (4H, m, CH2OCH2),
2.46 (2H, t, J¼6.8 Hz, NCH2CH2CH2O), 2.41–2.35 (4H, m, CH2NCH2),
1.98 (2H, quint, J¼6.8 Hz, NCH2CH2CH2O); 13C NMR (DMSO-d6):
862, 798 cmꢂ1; 1H NMR (DMSO-d6):
d 9.39 (1H, br s, NH), 7.16 (1H,
d, J¼1.8 Hz, 2-H), 6.90 (1H, dd, J¼8.7, 1.8 Hz, 6-H), 6.84 (1H, d,
J¼8.7 Hz, 5-H), 4.09 (2H, q, J¼7.1 Hz, CO2CH2CH3), 3.91 (2H, t,
J¼6.8 Hz, NCH2CH2CH2O), 3.70 (3H, s, OCH3), 3.59–3.53 (4H, m,
CH2OCH2), 2.43–2.31 (6H, m, NCH2CH2CH2O and CH2NCH2), 1.82
(2H, quint, J¼6.8 Hz, NCH2CH2CH2O), 1.23 (3H, t, J¼7.1 Hz,
d 156.77,156.00,153.40, 149.41, 147.06,120.63,106.00,105.21, 66.84,
66.10, 56.11, 54.69, 53.27, 25.52; HRMS (ESI-TOF) for C16H22N3O3
[MþH]þ: 304.0656, found: 304.1012. Anal. Calcd for C16H21N3O3: C,
63.35; H, 6.98; N, 13.85. Found: C, 63.30; H, 6.98; N, 13.92.
CO2CH2CH3); 13C NMR (DMSO-d6):
d
153.47, 149.02, 143.37, 114.05,
4.4.4. 6-Methoxy-7-[(10-methylpiperidin-40-yl)methoxy]quinaz-oline
110.12, 105.58, 67.02, 66.10, 59.82, 55.33, 54.82, 53.27, 25.98, 14.45;
HRMS (ESI-TOF) for C17H27N2Oþ5 [MþH]þ: calcd: 339.1914, found:
339.2005. Anal. Calcd for C17H26N2O5: C, 60.34; H, 7.74; N, 8.28.
Found: C, 60.29; H, 7.77; N, 8.26.
(14c). Yield 2.6 g; 90%; yellow solid; mp 120 ꢀC; IR (KBr) 2933, 1616,
1578, 1500, 1456, 1357, 1326, 1232, 1153, 1099, 1001, 868 cmꢂ1 1H
;
NMR (CDCl3): d 9.14 (1H, s, 4-H), 9.13 (1H, s, 2-H), 7.27 (1H, s, 5-H or 8-
H), 7.09 (1H, s, 5-H or 8-H), 4.06 (2H, d, J¼6.2 Hz), 4.01 (3H, s, OCH3),
3.04(2 h, d,J¼11.2 Hz), 2.39(3H, s, NCH3), 2.16(2H, t, J¼11.2 Hz), 2.04–
4.3.4. Ethyl {4-methoxy-3-[(10-methylpiperidin-40-yl)methoxy]-phe-
1.91 (3H, m), 1.62 (2H, qd, J¼11.2, 3.0 Hz); 13C NMR (CDCl3):
d 156.51,
nyl}carbamate (13c). Brown solid; mp <40 ꢀC; IR (KBr) 3309, 2950,
155.81, 153.86, 150.99, 147.93, 120.89, 107.03, 103.80, 73.69, 56.15,
55.24, 46.37, 34.68, 28.99; HRMS (ESI-TOF) for C16H22N3O2 [MþH]þ:
288.1707, found: 288.1695. Anal. Calcd for C16H21N3O2: C, 66.88; H,
7.37; N, 14.62. Found: C, 66.95; H, 7.41; N, 14.55.
1697, 1604, 1515, 1466, 1413, 1231, 1134, 1070, 1026, 770 cmꢂ1 1H
;
NMR (CDCl3):
d
7.16 (1H, d, J¼2.4 Hz, 2-H), 6.78 (1H, d, J¼8.7 Hz,
5-H), 6.72 (1H, dd, J¼8.7, 2.4 Hz, 6-H), 4.19 (2H, q, J¼7.1 Hz,
CO2CH2CH3), 3.86–3.77 (5H, m), 2.91 (2H, d, J¼11.4 Hz), 2.30 (3H, s,
NCH3), 2.05–1.94 (2H, m), 1.93–1.82 (3H, m), 1.41 (2H, qd, J¼11.4, 2.6
4.5. General procedure for quinazolin-4(3H)-ones 8 and 15a–c
HZ), 1.28 (3H, t, J¼7.1 Hz, CO2CH2CH3); 13C NMR (CDCl3):
d 163.25,
157.23, 148.24, 131.90, 125.37, 112.37, 72.58, 60.89, 56.27, 53.76,
To a solution of quinazoline (7, 14a–c) (5.0 mmol) in AcOH
(2.0 mL) a solution of CAN (20.0 mmol) in water (24.0 mL) was
50.29, 45.26, 30.21,14.40; HRMS (ESI-TOF) for C17H27N2Oþ4 [MþH]þ: