G. Cirrincione et al.
MED
(s), 154.7 (s), 156.2 (d), 158.1 (s), 160.3 (s), 162.0 ppm (s); IR (CHBr3):
n˜ =3456–3409 (NH2), 1695 cmÀ1 (CO); Anal. calcd for C21H22N4O3
(378.43): C 66.65, H 5.86, N 14.81, found: C 66.47, H 6.10, N 15.03.
Ethyl 2-anilino-9-benzyl-6,9-dihydro-5H-pyrrolo[3,2-h]quinazo-
line-8-carboxylate (12 f). This product was obtained from 10 f
(2 h) as a yellow solid (0.27 g, 65%): Rf =0.54 (CH2Cl2/EtOAc, 95:5);
mp: 206–2078C; 1H NMR ([D6]DMSO): d=1.20 (t, J=7.1 Hz, 3H,
CH3), 2.69–2.75 (m, 4H, 2ꢂCH2), 4.16 (q, J=7.1 Hz, 2H, CH2), 6.45
(s, 2H, CH2Ar), 6.84–6.93 (m, 4H, Ar), 7.08–7.29 (m, 5H, H-7 and Ar),
7.48–7.52 (m, 2H, Ar), 8.30 (s, 1H, H-4), 9.38 ppm (s, 1H, NH);
13C NMR ([D6]DMSO): d=14.2 (q), 21.0 (t), 24.6 (t), 48.7 (t), 60.0 (t),
108.3 (s), 116.0 (d), 119.0 (d), 121.3 (d), 125.4 (s), 126.0 (d), 126.8 (d),
127.8 (s), 128.4 (2ꢂd), 130.5 (s), 139.5 (s), 140.4 (s), 154.5 (s), 156.2
(d), 158.3 (s), 160.0 ppm (s); IR (CHBr3): n˜ =3418 (NH), 1700 cmÀ1
(CO); Anal. calcd (%) for C26H24N4O2 (424.19): C 73.56, H 5.70, N
13.20, found: C 73.74, H 5.44, N 13.52.
General procedure for the synthesis of 2-anilino-pyrrolo[3,2-
h]quinazolines 12a-c,e-g. To a suspension of the suitable dimethyl-
amino derivative 10 (1.5 mmol) in anhydrous DMF (7 mL), phenyl-
guanidine (0.61 g, 4.5 mmol) was added. The mixture was heated
at reflux for 15–90 min, then cooled and poured onto crushed ice.
The formed precipitate was filtered and recrystallized from EtOH.
2-Anilino-9-methyl-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline
(12a). This product was obtained from 10a (15 min) as a white
solid (0.19 g, 46%): Rf =0.45 (CH2Cl2/EtOAc, 95:5); mp: 196–1978C;
1H NMR ([D6]DMSO): d=2.60–2.77 (m, 4H, 2ꢂCH2), 4.06 (s, 3H,
CH3), 6.00 (d, J=2.5 Hz, 1H, H-7), 6.87–6.95 (m, 2H, H-8 and H-4’),
7.26 (t, J=7.5 Hz, 2H, H-3’ and H-5’), 7.73 (d, J=7.4 Hz, 2H, H-2’
and H-6’), 8.14 (s, 1H, H-4), 9.20 ppm (s, 1H, NH); 13C NMR
([D6]DMSO): d=21.7 (t), 24.9 (t), 36.5 (q), 106.5 (d), 117.0 (s), 118.7
(2ꢂd), 120.7 (d), 124.8 (s), 128.3 (2ꢂd), 128.7 (d), 129.1 (s), 140.9
(s), 154.1 (d), 155.2 (s), 158.6 ppm (s); IR (CHBr3): n˜ =3419 cmÀ1
(NH); Anal. calcd (%) for C17H16N4 (276.34): C 73.89, H 5.84, N 20.27,
found: C 74.07, H 5.60, N 20.03.
Ethyl 2-anilino-9-(4-methoxybenzyl)-6,9-dihydro-5H-pyrrolo[3,2-
h]quinazoline-8-carboxylate (12g). This product was obtained
from 10g (30 min) as a yellow solid (0.48 g, 70%): Rf =0.56 (CH2Cl2/
EtOAc, 9:1); mp: 157–1588C; 1H NMR ([D6]DMSO): d=1.20 (t, J=
7.1 Hz, 3H, CH3), 2.60–2.73 (m, 4H, 2ꢂCH2), 3.65 (s, 3H, CH3), 4.18
(q, J=7.1 Hz, 2H, CH2), 6.38 (s, 2H, CH2), 6.76–6.93 (m, 6H, H-7 and
Ar), 7.16 (t, J=7.8 Hz, 2H, H-3’ and H-5’), 7.55 (d, J=7.8 Hz, 2H, H-
2’ and H-6’), 8.30 (s, 1H, H-4), 9.41 ppm (s, 1H, NH); 13C NMR
([D6]DMSO): d=14.1 (q), 21.0 (t), 24.5 (t), 47.9 (t), 54.9 (q), 59.9 (t),
99.5 (s), 113.7 (2ꢂd), 116.0 (d), 119.0 (2ꢂd), 121.2 (d), 125.3 (s),
127.4 (2ꢂd), 127.8 (s), 128.3 (2ꢂd), 130.3 (s), 131.3 (s), 140.4 (s),
154.5 (s), 156.0 (d), 158.1 (s), 158.5 (s), 160.1 ppm (s); IR (CHBr3): n˜ =
3417 (NH), 1699 cmÀ1 (CO); Anal. calcd for C27H26N4O3 (454.53): C
71.35, H 5.77, N 12.33, found: C 70.98, H 5.94, N 12.00.
2-Anilino-9-benzyl-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline
(12b). This product was obtained from 10b (15 min) as a white
solid (0.67 g, 67%): Rf =0.48 (CH2Cl2/EtOAc, 95:5); mp: 189–1918C;
1H NMR ([D6]DMSO): d=2.53–2.70 (m, 4H, 2ꢂCH2), 5.88 (s, 2H,
CH2), 6.08 (d, J=2.6 Hz, 1H, H-7), 6.87 (t, J=7.6 Hz, 1H, H-4’), 7.06–
7.31 (m, 8H, Ar and H-8), 7.60 (d, J=7.6 Hz, 2H, H-2’ and H-6’),
8.14 (s, 1H, H-4), 9.20 ppm (s, 1H, NH); 13C NMR ([D6]DMSO): d=
21.6 (t), 24.9 (t), 50.7 (t), 107.5 (d), 117.0 (s), 118.9 (2ꢂd), 120.9 (d),
124.3 (s), 126.8 (2ꢂd), 127.1 (d), 128.2 (d), 128.3 (2ꢂd), 128.4 (2ꢂ
d), 129.6 (s), 139.5 (s), 140.8 (s), 154.3 (d), 155.1 (s), 158.5 ppm (s);
IR (CHBr3): n˜ =3419 cmÀ1 (NH); Anal. calcd for C23H20N4 (352.44): C
78.38, H 5.72, N 15.90, found: C 78.02, H 5.56, N 16.12.
General procedure for the synthesis of pyrrolo[3,2-h]quinazo-
lines 13b,d. To
a suspension of the suitable ketone 7b,d
(2.14 mmol) and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in forma-
mide (10 mL) under N2, tris(formylamino)methane (0.62 g,
4.28 mmol) was added and the mixture was heated at reflux. After
24 h it was poured onto crushed ice, the formed precipitate, fil-
tered under vacuum, was purified by flash chromatography eluting
with CH2Cl2/EtOAc (9:1).
9-Benzyl-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline (13b). This
product was obtained from 7b as a yellow solid (0.25 g, 45%): Rf =
0.30 (CH2Cl2/EtOAc, 9:1); mp: 67–688C; 1H NMR ([D6]DMSO): d=
2.67–2.88 (m, 4H, 2ꢂCH2), 5.82 (s, 2H, CH2), 6.10 (d, J=2.6 Hz, 1H,
H-7), 7.14–7.33 (m, 6H, Ar and H-8), 8.39 (s, 1H, H-4), 8.78 ppm (s,
1H, H-2); 13C NMR ([D6]DMSO): d=21.0 (t), 25.3 (t), 50.9 (t), 107.6
(d), 123.7 (s), 126.3 (s), 126.8 (2ꢂd), 127.1 (d), 128.4 (2ꢂd), 128.9
(d), 129.7 (s), 139.2 (s), 153.4 (d), 154.5 (s), 156.2 ppm (d); Anal.
calcd (%) for C17H15N3 (261.33): C 78.13, H 5.79, N 16.08, found: C
78.34, H 5.62, N 16.30.
2-Anilino-9-(4-methoxybenzyl)-6,9-dihydro-5H-pyrrolo[3,2-h]qui-
nazoline (12c). This product was obtained from 10c (1 h) as a
white solid (0.26 g, 70%): Rf =0.45 (CH2Cl2/EtOAc, 95:5); mp: 178–
1
1808C; H NMR ([D6]DMSO): d=2.52–2.69 (m, 4H, 2ꢂCH2), 3.67 (s,
3H, CH3), 5.78 (s, 2H, CH2), 6.04 (d, J=2.6 Hz, 1H, H-7), 6.79–6.92
(m, 3H, H-4’ and Ar), 7.04–7.22 (m, 5H, H-8 and Ar), 7.65 (d, J=
7.7 Hz, 2H, H-2’ and H-6’), 8.13 (s, 1H, H-4), 9.23 ppm (s, 1H, NH);
13C NMR ([D6]DMSO): d=21.6 (t), 24.9 (t), 50.2 (t), 54.9 (q), 107.3 (d),
113.7 (2ꢂd), 117.0 (s), 118.9 (2ꢂd), 120.9 (d), 124.1 (s), 128.06 (d),
128.29 (2ꢂd), 128.32 (2ꢂd), 129.6 (s), 131.3 (s), 140.8 (s), 154.2 (d),
155.2 (s), 158.3 (s), 158.6 ppm (s); IR (CHBr3): n˜ =3417 cmÀ1 (NH);
Anal. calcd (%) for C24H22N4O (382.46): C 75.37, H 5.80, N 14.65,
found: C 75.63, H 5.64, N 14.88.
9-Phenyl-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline (13d). This
product was obtained from 7d as a brown solid (0.28 g, 54%): Rf =
0.35 (CH2Cl2/EtOAc, 9:1); mp: 84–868C; 1H NMR ([D6]DMSO): d=
2.79–2.98 (m, 4H, 2ꢂCH2), 6.23 (d, J=2.7 Hz, 1H, H-7), 6.97 (d, J=
2.7 Hz, 1H, H-8), 7.26–7.47 (m, 5H, Ar), 8.34 (s, 1H, H-4), 8.61 ppm
(s, 1H, H-2); 13C NMR ([D6]DMSO): d=22.0 (t), 26.1 (t), 100.0 (s),
108.6 (d), 125.4 (2ꢂd), 126.6 (s), 127.1 (d), 128.7 (2ꢂd), 129.3 (d),
132.1 (s), 140.5 (s), 153.3 (d), 154.5 (s), 156.7 ppm (d); Anal. calcd
(%) for C16H13N3 (247.30): C 77.71, H 5.30, N 16.99, found: C 77.47,
H 5.49, N 17.22.
Ethyl 2-anilino-9-methyl-6,9-dihydro-5H-pyrrolo[3,2-h]quinazo-
line-8-carboxylate (12e). This product was obtained from 10e
(1.5 h) as a white solid (0.26 g, 70%): Rf =0.59 (CH2Cl2/EtOAc, 95:5);
mp: 204–2068C; 1H NMR ([D6]DMSO): d=1.29 (t, J=7.1 Hz, 3H,
CH3), 2.64–2.70 (m, 4H, 2ꢂCH2), 4.25 (q, J=7.1 Hz, 2H, CH2), 4.40
(s, 3H, CH3), 6.80 (s, 1H, H-7), 6.93 (t, J=7.8 Hz, 1H, H-4’), 7.29 (t,
J=7.8 Hz, 2H, H-3’ and H-5’), 7.71 (d, J=7.8 Hz, 2H, H-2’ and H-6’),
8.30 (s, 1H, H-4), 9.41 ppm (1H, s, NH); 13C NMR ([D6]DMSO): d=
14.2 (q), 21.0 (t), 24.5 (t), 34.9 (q), 59.9 (t), 114.8 (d), 118.9 (2ꢂd),
119.0 (s), 121.1 (d), 125.7 (s), 127.1 (s), 128.4 (2ꢂd), 130.7 (s), 140.6
(s), 154.5 (s), 155.8 (d), 158.5 (s), 160.4 ppm (s); IR (CHBr3): n˜ =3417
(NH), 1697 cmÀ1 (CO); Anal. calcd for C20H20N4O2 (348.40): C 68.95,
H 5.79, N 16.08, found: C 69.22, H 5.58, N 15.83.
Biology
Reagents. If not otherwise indicated, all chemicals were purchased
from Sigma–Aldrich (Milan, Italy).
1246
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1238 – 1248