402
M. Driowya et al. / European Journal of Medicinal Chemistry 115 (2016) 393e405
ArH), 10.59 (s, 1H, NH); 13C NMR (75 MHz, DMSO)
d
28.3, 57.4, 114.0,
7.27e7.45 (m, 8H, CH benz, ArH), 7.49e7.56 (m, 5H, CH quina, CH
benz), 7.67 (t, 1H, J ¼ 1.55 Hz, 8.55 Hz, CH quina), 8.27 (dd, 1H,
114.7, 116.0, 122.3, 123.5, 127.6, 128.6, 133.9,135.1, 139.7, 140.3, 151.0,
151.1, 152.8, 160.9. tR,LCMS ¼ 2.58 min (100%); MS (ESIþ): m/z ¼ 354
[MþH]þ.
J ¼ 1.35 Hz, 7.9 Hz, CH quina); 13C NMR (75 MHz, DMSO)
d 46.1, 56.2,
70.4, 113.8, 113.9, 116.1, 117.6, 121.2, 123.0, 127.1, 128.0, 128.4, 128.5,
128.8, 128.9, 129.7, 134.3, 135.0, 136.6, 137.1, 148.4, 148.7, 149.6,
150.0, 158.6. tR,LCMS ¼ 2.84 min (100%); MS (ESIþ): m/z ¼ 489
[MþH]þ.
4.1.5. General procedure for synthesis of triazoloquinazolinones
(9a-g, 10a-g)
A mixture of hydrazone 7a-g or 8a-g (1.5 mmol) and a 2 M
aqueous solution of FeCl3 (1.2 mL, 2.4 mmol) was refluxed for 12 h
in ethanol (80 mL). After cooling, the reaction mixture was filtered
and the resulting precipitate was washed with water, dried and
recrystallized from ethanol.
4.1.5.6. 4-Benzyl-1-(3,4-dibenzyloxyphenyl)-[1,2,4]-triazolo-[4,3-a]-
quinazolin-5-one (9f). White solid; 72% yield;
C36H28N4O3;
MW ¼ 564.6 g/mol; m.p. 225e227 ꢀC; 1H NMR (300 MHz, DMSO)
d
5.12 (s, 2H, CH2), 5.26 (s, 2H, CH2), 5.43 (s, 2H, CH2), 7.05 (dd, 1H,
J ¼ 0.95 Hz, 8.3 Hz, CH quina), 7.22 (dd, 1H, J ¼ 1.9 Hz, 8.25 Hz, ArH),
7.27e7.44 (m, 13H, CH benz, ArH), 7.48e7.55 (m, 4H, CH quina, CH
benz), 7.59 (td, 1H, J ¼ 1.7 Hz, 7.4 Hz, CH quina), 8.27 (Dd, 1H,
4.1.5.1. 4-Benzyl-1-(4-methoxyphenyl)-[1,2,4]-triazolo-[4,3-a]-qui-
nazolin-5-one (9a). White solid; 90% yield;
C23H18N4O2;
MW ¼ 382.4 g/mol; m.p. 228e230 ꢀC; 1H NMR (300 MHz, DMSO)
J ¼ 1.5 Hz, 7.6 Hz, CH quina); 13C NMR (75 MHz, DMSO)
d 46.1, 70.4,
d
3.87 (s, 3H, OCH3), 5.42 (s, 2H, CH2), 7.13 (d, 1H, J ¼ 8.3 Hz, CH
70.5, 114.7, 116.0, 117.5, 121.3, 123.6, 127.0, 127.9, 128.0, 128.1, 128.3,
128.4, 128.6, 128.8, 128.9, 129.6, 134.2, 135.0, 136.6, 137.2, 137.3,
148.3, 148.6, 148.7, 150.5, 158.6. tR,LCMS ¼ 3.17 min (97%); MS (ESIþ):
m/z ¼ 565 [MþH]þ.
quina), 7.19 (d, 2H, J ¼ 8.8 Hz, ArH), 7.28e7.37 (m, 3H, CH benz),
7.49e7.56 (m, 3H, CH benz, CH quina), 7.61e7.68 (m, 3H, CH quina,
ArH), 8.26 (dd, 1H, J ¼ 1.1 Hz, 7.65 Hz, CH quina); 13C NMR (75 MHz,
DMSO)
d 46.1, 55.8, 115.0, 115.9, 117.6, 120.9, 127.0, 128.0, 128.5,
128.8, 129.7, 131.8, 134.3, 134.9, 136.6, 148.4, 148.8, 158.6, 161.3.
tR,LCMS ¼ 2.50 min (100%); MS (ESIþ): m/z ¼ 383 [MþH]þ.
4.1.5.7. 4-Benzyl-1-(4-methoxy-3-nitrophenyl)-[1,2,4]-triazolo-[4,3-
a]-quinazolin-5-one (9g). White solid; 66% yield; C23H17N5O4;
MW ¼ 427.4 g/mol; m.p. 247e249 ꢀC; 1H NMR (300 MHz, DMSO)
4.1.5.2. 4-Benzyl-1-(3,4-dimethoxyphenyl)-[1,2,4]-triazolo-[4,3-a]-
d
4.05 (s, 3H, OCH3), 5.45 (s, 2H, CH2), 7.16 (d, 1H, J ¼ 8.3 Hz, CH
quinazolin-5-one (9b). White solid; 91% yield;
C
24H20N4O3;
quina), 7.28e7.37 (m, 3H, CH benz), 7.49 (d, 2H, J ¼ 6.65 Hz, CH
benz), 7.56 (t,1H, J ¼ 7.4 Hz, CH quina), 7.63 (d, 1H, J ¼ 8.85 Hz, ArH),
7.70 (t, 1H, J ¼ 8.65 Hz, CH quina), 8.01 (dd, 1H, J ¼ 2.1 Hz, 8.7 Hz,
ArH), 8.28 (m, 2H, CH quina, ArH). tR,LCMS ¼ 2.46 min (98%); MS
(ESIþ): m/z ¼ 428 [MþH]þ.
MW ¼ 412.4 g/mol; m.p. 240e241 ꢀC; 1H NMR (300 MHz, DMSO)
d
3.73 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.44 (s, 2H, CH2), 7.15 (d, 1H,
J ¼ 8.35 Hz, CH quina), 7.22 (t, 2H, J ¼ 8.1 Hz, CH benz), 7.25e7.36
(m, 4H, ArH, CH benz), 7.48e7.55 (m, 3H, CH quina, CH benz), 7.68 (t,
1H, J ¼ 8.65 Hz, CH quina), 8.26 (dd, 1H, J ¼ 1.35 Hz, 7.95 Hz, CH
quina); 13C NMR (75 MHz, DMSO)
d
46.1, 56.0, 56.1, 112.4, 113.5,
4.1.5.8. 1-(4-Methoxyphenyl)-4-methyl-[1,2,4]-triazolo-[4,3-a]-qui-
116.1, 117.6, 120.8, 123.1, 127.1, 128.0, 128.5, 128.8, 129.7, 134.3, 135.0,
136.6, 148.5, 148.7, 149.3, 151.0, 158.6. tR,LCMS ¼ 2.36 min (98%); MS
(ESIþ): m/z ¼ 413 [MþH]þ.
nazolin-5-one (10a). White solid; 62% yield;
C17H14N4O2;
MW ¼ 306.3 g/mol; m.p. 216e218 ꢀC; 1H NMR (300 MHz, DMSO)
d
3.63 (s, 3H, NCH3), 3.88 (s, 3H, OCH3), 7.10 (d, 1H, J ¼ 8.2 Hz, CH
quina), 7.18 (d, 2H, J ¼ 8.7 Hz, ArH), 7.50 (t, 1H, J ¼ 7.85 Hz, CH
quina), 7.58e7.66 (m, 3H, CH quina, CH benz), 8.22 (dd, 1H,
4.1.5.3. 4-Benzyl-1-(3,4,5-trimethoxyphenyl)-[1,2,4]-triazolo-[4,3-a]-
quinazolin-5-one (9c). White solid; 90% yield;
C
25H22N4O4;
J ¼ 1.3 Hz, 7.8 Hz, CH quina); 13C NMR (75 MHz, DMSO)
d 29.6, 55.9,
MW ¼ 442.5 g/mol; m.p. 270e271 ꢀC; 1H NMR (300 MHz, DMSO)
115.1, 115.8, 117.7, 120.9, 126.9, 129.5, 131.7, 134.1, 134.7, 148.2, 149.2,
158.8, 161.3. tR,LCMS ¼ 2.28 min (100%); MS (ESIþ): m/z ¼ 307
[MþH]þ. Anal. Calcd (%) for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29;
found C, 66.74; H, 4.58; N, 18.21.
d
3.76 (s, 6H, OCH3), 3.79 (s, 3H, OCH3), 5.44 (s, 2H, CH2), 7.03 (s, 2H,
ArH), 7.16 (d, 1H, J ¼ 8.25 Hz, CH quina), 7.28e7.37 (m, 3H, CH benz),
7.48e7.57 (m, 3H, CH quina, CH benz), 7.72 (td, 1H, J ¼ 1.65 Hz,
8.85 Hz, CH quina), 8.27 (dd, 1H, J ¼ 1.45 Hz, 7.95 Hz, CH quina); 13
C
NMR (75 MHz, DMSO)
d
46.2, 56.8, 60.8, 108.2, 116.3, 117.6, 123.9,
4.1.5.9. 1-(3,4-Dimethoxyphenyl)-4-methyl-[1,2,4]-triazolo-[4,3-a]-
127.1, 128.0, 128.6, 128.8, 129.7, 134.2, 135.0, 136.6, 140.1, 148.3,
148.8, 153.8, 158.6. tR,LCMS ¼ 2.43 min (100%); MS (ESIþ): m/z ¼ 443
[MþH]þ.
quinazolin-5-one (10b). White solid; 50% yield; C18H16N4O3;
MW ¼ 336.3 g/mol; m.p. 234e236 ꢀC; 1H NMR (300 MHz, DMSO)
d
3.63 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 7.13 (d,
1H, J ¼ 8.2 Hz, CH quina), 7.20 (m, 2H, ArH)), 7.24 (s, 1H, ArH), 7.50
(td, 1H, J ¼ 0.9 Hz, 8.1 Hz, CH quina), 7.66 (td, 1H, J ¼ 1.6 Hz, 8.75 Hz,
CH quina), 8.22 (dd, 1H, J ¼ 1.5 Hz, 7.85 Hz, CH quina); 13C NMR
4.1.5.4. 4-Benzyl-1-(3-benzyloxy-4-methoxyphenyl)-[1,2,4]-triazolo-
[4,3-a]-quinazolin-5-one (9d). White solid; 80% yield; C30H24N4O3;
MW ¼ 488.5 g/mol; m.p. 189e191 ꢀC; 1H NMR (300 MHz, DMSO)
(75 MHz, DMSO)
d 29.6, 56.1, 56.2, 112.4, 113.4, 116.0, 117.6, 120.9,
d
3.89 (s, 3H, OCH3), 5.06 (s, 2H, CH2), 5.44 (s, 2H, CH2), 7.11 (dd, 1H,
123.1, 127.0, 129.5, 134.1, 134.7, 148.3, 149.1, 149.4, 151.0, 158.8.
tR,LCMS ¼ 2.13 min (97%); MS (ESIþ): m/z ¼ 337 [MþH]þ. Anal. Calcd
(%) for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66; found C, 64.33; H,
4.81; N, 16.58.
J ¼ 1.1 Hz, 8.36 Hz, CH quina), 7.19e7.42 (m, 11H, CH benz, ArH),
7.48e7.55 (m, 3H, CH quina, CH benz), 7.62 (t, 1H, J ¼ 7.05 Hz, CH
quina), 8.26 (dd, 1H, J ¼ 1.25 Hz, 7.8 Hz, CH quina); 13C NMR
(75 MHz, DMSO)
d 46.1, 56.1, 70.4, 112.7, 115.1, 116.0, 117.5, 120.8,
123.5, 127.0, 128.0, 128.3, 128.4, 128.5, 128.8, 129.7, 134.3, 135.1,
136.6, 137.1, 148.3, 148.4, 148.7, 151.4, 158.6. tR,LCMS ¼ 2.81 min
(100%); MS (ESIþ): m/z ¼ 489 [MþH]þ.
4.1.5.10. 1-(3,4,5-Trimethoxyphenyl)-4-methyl-[1,2,4]-triazolo-[4,3-
a]-quinazolin-5-one (10c). White solid; 20% yield; C19H18N4O4;
MW ¼ 366.3 g/mol; m.p. 263e265 ꢀC; 1H NMR (300 MHz, DMSO)
d
3.64 (s, 3H, NCH3), 3.78 (s, 6H, OCH3), 3.79 (s, 3H, OCH3), 7.00 (s,
4.1.5.5. 4-Benzyl-1-(4-benzyloxy-3-methoxyphenyl)-[1,2,4]-triazolo-
[4,3-a]-quinazolin-5-one (9e). White solid; 80% yield; C30H24N4O3;
MW ¼ 488.5 g/mol; m.p. 210e212 ꢀC; 1H NMR (300 MHz, DMSO)
2H, ArH), 7.16 (d, 1H, J ¼ 8.3 Hz, CH quina), 7.52 (td, 1H, J ¼ 0.75 Hz,
8.05 Hz, CH quina), 7.70 (td, 1H, J ¼ 1.6 Hz, 8.75 Hz, CH quina), 8.23
(dd, 1H, J ¼ 1.4 Hz, 7.85 Hz, CH quina); 13C NMR (75 MHz, DMSO)
d
3.74 (s, 3H, OCH3), 5.21 (s, 2H, CH2), 5.44 (s, 2H, CH2), 7.15 (d, 1H,
d 29.66, 56.7, 60.8, 107.8, 116.2, 117.6, 124.0, 127.1, 129.5, 134.0, 134.9,
J ¼ 8.1 Hz, CH quina), 7.21 (dd, 1H, J ¼ 1.75 Hz, 8.3 Hz, ArH),
139.7, 148.2, 149.1, 153.8, 158.7. tR,LCMS ¼ 2.22 min (100%); MS