E. Marinho, M.F. Proenc¸ a / Tetrahedron xxx (2016) 1e7
5
mixture was refluxed for 1 min. The white solid that precipitated
after addition of water was filtered and washed with water. The
product (0.02 g) was identified by 1H NMR as N-(2-(4-oxo-3,4-
dihydroquinazolin-2-yl)phenyl) formamide 3a slightly contami-
129.07, 133.63, 130.99, 130.39, 126.79, 126.05, 123.70, 123.17, 122.88,
119.97, 112.70. Anal. Calcd for C18H14N4O3$0.25H2O: C, 63.80; H,
4.32; N, 16.54. Found: C, 63.85; H, 4.14; N, 16.54.
nated with 4a. 1H NMR (400 MHz, DMSO-d6):
d
12.45 (br s, 1H),
4.4. General procedure for the synthesis of carbamate 6e
10.85 (br s, 0.75H), 10.66 (br s, 0.25H), 8.36 (s, 1H), 8.32 (d, J¼8.0 Hz,
1H), 8.16 (dd, J¼1.2, 8.0 Hz, 1H), 7.84 (td, J¼1.2, 8.0 Hz, 1H), 7.79 (td,
J¼1.2, 8.0 Hz, 1H), 7.78 (d, J¼8.0 Hz, 1H), 7.74 (d, J¼8.0 Hz, 1H), 7.54
(td, J¼1.2, 8.0 Hz, 1H), 7.52 (td, J¼1.2, 8.0 Hz, 1H). 13C NMR
Ethylchloroformate (2 M equiv) was added to a suspension of
compound 2a in acetonitrile (1 mL). After 20 min, triethylamine
(1.5e3 M equiv) was added to the mixture. The reaction mixture
was stirred at room temperature for 8 h. The solid was filtered and
washed with acetonitrile, leading to the pure product.
(100 MHz, DMSO-d6):
d 162.12, 160.40, 152.51, 147.99, 136.30,
134.51, 134.38, 131.17, 129.72, 127.38, 126.83, 125.70, 122.48, 122.48,
121.55. IR (Nujol mull): 3180, 1650, 1609, 1579, 1528 cmꢁ1
.
4.4.1. Ethyl [2-(4-aminoquinazolin-2-yl)phenyl] carbamate hydro-
4.3. General procedure for the synthesis of amides 6aed
yellow suspension of compound 2a, triethylamine
chloride 6e. Beige solid, 74%. Mp>300 ꢀC. IR (Nujol mull) 3264,
3056, 1734, 1654, 1630, 1608, 1590, 1569, 1537 cmꢁ1 1H NMR
.
A
(400 MHz, DMSO-d6): d 14.18 (s, 1H), 9.83 (br s, 2H), 9.64 (br s, 1H),
(1e3 M equiv) and anhydride (2e8 M equiv), in acetonitrile or
without solvent was stirred at room temperature for 5 min (6d),
50 min (6a), 2 h (6b) or 1 day (6c). The solid was filtered and
washed with water, leading to the pure product.
8.55 (d, J¼8.4 Hz, 1H), 8.03 (td, J¼1.2, 8.4 Hz, 1H), 7.92 (d, J¼8.4 Hz,
1H), 7.85 (d, J¼8.4 Hz, 1H), 7.83 (d, J¼8.4 Hz, 1H), 7.73 (td, J¼8.4 Hz,
1H), 7.60 (td, J¼1.2, 8.4 Hz, 1H), 7.29 (td, J¼8.4 Hz, 1H), 4.01 (q,
J¼7.2 Hz, 2H), 1.12 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6):
d
163.19,158.87,153.81,140.36,137.39,136.16,132.32,130.71,127.89,
4.3.1. N-[2-(4-Aminoquinazolin-2-yl)phenyl] acetamide 6a. White
solid, 89%. Mp 229e231 ꢀC. IR (Nujol mull) 3400, 3317, 3213, 1671,
1645, 1627, 1604, 1589, 1578, 1544, 1504 cmꢁ1. 1H NMR (300 MHz,
124.96, 123.33 (2C), 121.93, 120.08, 111.45, 60.68, 14.47. Anal. Calcd
for C17H17N4O2Cl.0$2H2O: C, 58.60; H, 5.04; N, 16.08. Found: C,
58.37; H, 5.05; N, 16.34.
DMSO-d6):
d
13.63 (s, 1H), 8.61 (d, J¼1.5 Hz, 1H), 8.57 (d, J¼8.4 Hz,
1H), 8.30 (d, J¼8.1 Hz, 1H), 8.12 (br s, 2H), 7.83 (t, J¼7.2 Hz, 1H), 7.77
(d, J¼7.2 Hz, 1H), 7.53 (td, J¼1.5, 8.4 Hz, 1H), 7.42 (td, J¼1.5, 8.4 Hz,
1H), 7.15 (td, J¼1.5, 8.1 Hz, 1H), 2.24 (s, 3H). 13C NMR (75 MHz,
4.4.2. Ethyl [2-(4-aminoquinazolin-2-yl)phenyl] carbamate 6e(free
base). Pink solid, 71%. Mp 175e178 ꢀC. IR (Nujol mull) 3440, 3343,
3252, 1707, 1650, 1624, 1596, 1578, 1547, 1501 cmꢁ1 1H NMR
;
DMSO-d6):
d
168.19, 161.58, 160.61, 148.39, 139.84, 133.64, 130.82,
(300 MHz, DMSO-d6):
d
13.35 (s, 1H), 8.60 (dd, J¼1.2, 8.1 Hz, 1H),
130.36, 126.95, 125.94, 123.78, 122.89, 122.10, 119.65, 112.68, 25.26.
Anal. Calcd for C16H14N4O$0.6H2O: C, 66.46; H, 5.31; N, 19.38.
Found: C, 66.69; H, 5.36; N, 19.14.
8.32 (dd, J¼1.2, 8.1 Hz, 1H), 8.28 (dd, J¼1.2, 8.4 Hz, 1H), 8.08 (br s,
2H), 7.85 (td, J¼1.2, 8.1 Hz, 1H), 7.66 (dd, J¼1.2, 8.1 Hz, 1H), 7.53 (td,
J¼1.2, 8.1 Hz, 1H), 7.44 (td, J¼1.2, 8.1 Hz, 1H), 7.11 (td, J¼1.2, 8.1 Hz,
1H), 4.18 (q, J¼7.2 Hz, 2H), 1.29 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz,
4.3.2. N-[2-(4-Amino-7-chloroquinazolin-2-yl)-5-chlorophenyl]acet-
amide 6b. White solid, 63%. Mp>300 ꢀC. IR (Nujol mull) 3445,
3332, 3204, 1667, 1650, 1619, 1600, 1589, 1576, 1544, 1536 cmꢁ1. 1H
DMSO-d6): d 161.65, 160.66, 153.37, 148.12, 139.96, 133.70, 131.05,
130.43, 126.51, 125.97, 123.78, 122.40, 121.35, 118.22, 112.72, 60.32,
14.54. Anal. Calcd for C17H16N4O2$0.4H2O: C, 64.70; H, 5.38; N,
17.76. Found: C, 64.62; H, 5.09; N, 17.49.
NMR (300 MHz, DMSO-d6):
d
13.31 (s, 1H), 8.64 (d, J¼2.1 Hz, 1H),
8.57 (d, J¼8.7 Hz, 1H), 8.29 (d, J¼8.7 Hz, 1H), 8.10 (br s, 2H), 7.79 (t,
J¼1.8 Hz, 1H), 7.55 (dd, J¼2.1, 8.7 Hz, 1H), 7.20 (dd, J¼2.1, 8.7 Hz, 1H),
4.5. General procedure for the synthesis of ureas 6f and 6g
2.26 (s, 3H). 13C NMR (75 MHz, DMSO-d6):
d
¼168.59, 161.25, 160.72,
148.38, 140.60, 138.14, 135.31, 131.90, 126.15, 125.69, 125.57, 121.80,
121.31, 118.89, 111.25, 25.02. Anal. Calcd for C16H12N4O$0.3H2O: C,
54.49; H, 3.61; N, 15.89. Found: C, 54.51; H, 3.62; N, 15.92.
Isocyanate (1.2 M equiv) and triethylamine (1.2 M equiv) were
added to a suspension of compound 2a in acetonitrile. The reaction
mixture was stirred at room temperature for 10 min (6g) or 15 min
(6f). The solid was filtered and washed with water, leading to the
pure product.
4.3.3. 4-{[2-(4-Aminoquinazolin-2-yl)phenyl] amino}-4-oxobutanoic
acid 6c. White solid, 68%. Mp 214e216 ꢀC. IR (Nujol mull) 3411,
3337, 3245, 1770, 1719, 1665, 1648, 1611, 1579, 1536, 1505 cmꢁ1. 1H
4.5.1. 1-[2-(4-Aminoquinazolin-2-yl)phenyl]-3-phenylurea
6f. White solid, 91%. Mp 240e242 ꢀC. IR (Nujol mull) 3498, 3391,
3286, 1659, 1650, 1611, 1595, 1548 cmꢁ1. 1H NMR (400 MHz, DMSO-
NMR (400 MHz, DMSO-d6): d 13.72 (br s, 1H), 12.13 (s, 1H), 8.60 (dd,
J¼1.2, 8.4 Hz, 1H), 8.57 (d, J¼8.4 Hz, 1H), 8.29 (d, J¼8.4 Hz, 1H), 8.09
(br s, 2H), 7.85 (td, J¼1.2, 8.4 Hz, 1H), 7.78 (d, J¼8.4 Hz, 1H), 7.54 (td,
J¼1.2, 8.4 Hz, 1H), 7.42 (td, J¼1.2, 8.4 Hz, 1H), 7.15 (td, J¼1.2, 8.0 Hz,
1H), 2.78 (t, J¼6.9 Hz, 2H), 2.60 (t, J¼6.9 Hz, 2H). 13C NMR (100 MHz,
d6):
d
12.57 (s, 1H), 9.48 (s, 1H), 8.58 (dd, J¼1.2, 8.0 Hz, 1H), 8.27 (d,
J¼8.0 Hz, 1H), 8.21 (d, J¼8.0 Hz, 1H), 8.09 (br s, 2H), 7.94 (d,
J¼8.0 Hz,1H), 7.82 (td, J¼1.2, 8.0 Hz,1H), 7.55 (dd, J¼1.2, 8.8 Hz, 2H),
7.52 (t, J¼8.0 Hz, 1H), 7.40 (td, J¼2.0, 8.0 Hz, 1H), 7.28 (td, J¼1.2,
8.4 Hz, 2H), 7.08 (td, J¼1.2, 8.0 Hz, 1H), 6.98 (td, J¼1.2, 8.4 Hz, 1H).
DMSO-d6):
d 173.74, 169.99, 161.60, 160.62, 148.36, 139.80, 133.61,
130.83,130.36,126.85,125.93,123.72,122.86, 122.04,119.65,112.68,
32.31, 28.92. Anal. Calcd for C18H16N4O3$1/3H2O: C, 63.14; H, 4.92;
N, 16.37. Found: C, 63.16; H, 4.70; N, 16.25.
13C NMR (100 MHz, DMSO-d6):
d 161.44, 160.54, 152.52, 149.00,
140.54, 140.00, 133.28, 130.34, 130.29, 128.60 (2C), 127.67, 125.65,
123.50, 123.32, 121.95, 120.86, 120.82, 119.09 (2C), 112.60. Anal.
Calcd for C21H17N5O$0.1H2O: C, 70.60; H, 4.87; N, 19.61. Found: C,
70.57; H, 4.92; N, 19.43.
4.3.4. 4-{[2-(4-Aminoquinazolin-2-yl)phenyl] amino}-4-oxobut-2-
enoic acid 6d. Yellow solid, 79%. Mp 190e193 ꢀC. IR (Nujol mull)
3472, 3324, 3224, 1775, 1626, 1602, 1575, 1539 cmꢁ1 1H NMR
.
(400 MHz, DMSO-d6):
d
14.08 (br s, 1H), 13.09 (s, 1H), 8.64 (dd,
4.5.2. 1-(2-(4-Aminoquinazolin-2-yl)phenyl)-3-cyclohexylurea
6g. Yellow solid, 52%. Mp 202e204 ꢀC. IR (Nujol mull) 3490, 3299,
3179, 1630, 1569, 1545, 1503 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
J¼1.2, 8.0 Hz, 1H), 8.61 (d, J¼8.0 Hz, 1H), 8.27 (d, J¼8.0 Hz, 1H), 8.10
(br s, 2H), 7.83 (td, J¼1.2, 8.4 Hz, 1H), 7.71 (d, J¼8.0 Hz, 1H), 7.53 (td,
J¼1.2, 8.0 Hz, 1H), 7.47 (td, J¼1.2, 8.0 Hz, 1H), 7.22 (td, J¼1.2, 8.4 Hz,
1H), 6.73 (d, J¼12 Hz, 1H), 6.37 (d, J¼12 Hz, 1H). 13C NMR (100 MHz,
d
12.00 (s, 1H), 8.49 (dd, J¼1.6, 8.0 Hz, 1H), 8.23 (d, J¼8.0 Hz, 1H),
8.20 (d, J¼8.0 Hz, 1H), 8.05 (s, 2H), 7.94 (d, J¼8.0 Hz, 1H), 7.81 (td,
J¼1.6, 8.0 Hz, 1H), 7.50 (td, J¼1.6, 8.0 Hz, 1H), 7.31 (td, J¼1.6, 8.0 Hz,
DMSO-d6):
d
¼166.66, 163.36, 161.63, 160.39, 148.12, 139.35, 133.83,