5
ACCEPTED MANUSCRIPT
3
.2.1. 10-Amino-12-oxo-1,3,8-triphenyl-3,12-dihydro-
3
. Experimental Part
pyrazolo[4',3':5,6]pyrimido[2,1-a]phthalazine-9-carbonitrile
Melting points were determined with a Stuart melting point
(12a)
apparatus and are uncorrected. IR spectra were recorded as KBr
Crystallized from dioxane to give 12a (0.40 g, 0.8 mmol,
0%, method A; 0.39 g, 0.8 mmol, 77%, method B; 0.38 g, 0.8
mmol, 75%, method C) as yellow crystals (m. p. > 300 ° C).]; IR
1
pellets using a FTIR Bruker – vector 22 spectrophotometer. H
8
13
and C NMR spectra were recorded in DMSO–d as solvent with
6
a Varian Gemini NMR spectrometer at 400 MHz and 100 MHz
respectively using TMS as internal standard. Chemical shifts are
reported as δ in ppm. Mass spectra were measured with a
Shimadzu GCMS–QP–1000 EX mass spectrometer in EI (70 eV)
mode. The elemental analyses were performed at the Micro
analytical center, Cairo University.
(
1
KBr) ν 3440, 3112, 3051, 2925, 2206, 1651, 1557, 1443, 1338,
302, 1151, 1053, 764, 695 cm ; H NMR (400 MHz, DMSO-
–1
1
d ) δ 7.23 (2 H, br s, NH ), 7.40–7.70 (16 H, m, Ar-H), 8.87 (1 H,
s, pyridazine CH). C NMR (100 MHz, DMSO-d ) δ 96.7, 104.9
6
2
13
6
(CCN), 106.2, 107.7, 114.6, 116.8 (CN), 126.6, 127.4, 128.6,
1
1
1
4
29.1, 129.2, 129.6, 129.7, 129.8, 130.1, 130.9, 131.1, 137.8,
39.1, 142.9, 147.8, 149.5, 150.8 (Ar C), 153.6 (pyridazine CH),
3
.1. Ethyl (E)-5-(2-(2-oxopropylidene)hydrazinyl)-1,3-
+
63.1 (CO). MS (EI, 70 eV) m/z (%) 505 (100, M ), 504 (90),
diphenyl-1H-pyrazole-4-carboxylate (9)
28 (11), 410 (12), 327 (15), 260 (28), 245 (29); HRMS (EI)
+
+
Ethyl acetoacetate (1.28 mL, 10 mmol) was diluted with
distilled water (250 mL). Then KOH (0.56 g, 10 mmol) was
added, and the solution was stirred at 25 °C for 14 h. The
resulting solution was cooled to 0 °C by addition of crushed ice
and neutralized by addition of ice-cooled 50% conc. HCl (4 mL).
calcd. for [C H N O] (M ) 505.1651; found 505.1643. . Anal.
calcd. for C H N O (505.5): C 73.65, H 3.79, N 19.39 %.
Found: C 73.54, H 3.68, N 19.25 %.
31 19 7
31
19
7
3
.2.2. 10-Amino-8-(4-chlorophenyl)-12-oxo-1,3-diphenyl-3,12-
dihydropyrazolo[4',3':5,6]pyrimido[2,1-a]phthalazine-9-car-
bonitrile (12b)
4
-Ethoxycarbonyl-1,3-diphenyl-1H-pyrazole-5-diazonium
chloride solution (prepared by a typical diazotization procedure
as follows: Ethyl 5-amino-1,3-diphenyl-1H-pyrazole-4-
Crystallized from DMF to give 12b (0.45 g, 0.8 mmol, 83%,
method A; 0.43 g, 0.8 mmol, 80%, method B; 0.44 g, 0.8 mmol,
8
ν 3441 (br), 3114, 2205, 1650, 1557, 1445, 1338, 1307, 1241,
1
δ 7.22 (2 H, br s, NH ), 7.36–7.69 (15 H, m, Ar-H), 8.86 (1 H, br
s, pyridazine CH). MS (EI, 70 eV) m/z (%) 541 (26, [M+2] ),
5
carboxylate (3.07 g, 10 mmol) was dissolved in AcOH-HCl
mixture (1:3, 4 mL). The internal temperature was cooled to 0 °C
and a 5 mL aqueous solution of sodium nitrite (0.69 g, 10 mmol)
was added dropwise keeping the temperature below 5 °C. The
diazonium chloride solution was then added dropwise to the
acetoacetic acid solution followed by a solution of sodium acetate
1%, method C) as yellow crystals (m. p. > 300 °C). ]; IR (KBr)
–1
151, 1054, 823, 755, 689 cm ; 1H NMR (400 MHz, DMSO-d )
6
2
+
+
+
40 (44, [M+1] ), 539 (57, M ), 269 (15), 180 (15), 129 (11), 77
(
2.7 g, 20 mmol) in distilled water (100 mL). A pale yellow
precipitate was separated and crystallized from ethanol to give 9
2.74 g, 7.3 mmol, 73%) as yellow crystals (m. p. 148-150 °C).];
IR (KBr) ν 3269 (br), 3276, 3061, 2983, 1678, 1549, 1513, 1429,
+ +
(100). HRMS (EI) cald. for [C H ClN O] (M ) 539.1261;
31 18 7
found 539.1256. Anal. calcd. for C H ClN O (540.0): C 68.95,
H 3.36, Cl 6.57, N 18.16 %. Found: C 68.87, H 3.29, Cl 6.53, N,
18.13 %.
31
18
7
(
–1
1
258, 1148, 1019, 697 cm ; 1H NMR (400 MHz, DMSO-d ) δ
6
(
two forms) [(1.08 (H-bonded), 1.26 (free)] (3 H, t, J 7.2 Hz,
3.2.3. 10-Amino-8-(4-methoxyphenyl)-12-oxo-1,3-diphenyl-
3,12-dihydropyrazolo[4',3':5,6]pyrimido[2,1-a]phthalazine-9-
carbonitrile (12c)
COOCH CH ), [2.36 (shielded), 2.50 (deshielded)] (3 H, s,
COCH ), [4.15 (H-bonded), 4.32 (free)] (2 H, q, J 7.2 Hz,
2
3
3
COOCH CH ), 7.25-7.72 (10 H, m, Ar-H), 10.08 (1 H, br s, NH);
2
3
Crystallized from dioxane to give 12c (0.42 g, 0.8 mmol, 78%,
method A; 0.41 g, 0.8 mmol, 76%, method B; 0.39 g, 0.7 mmol,
72%, method C) as bright yellow crystals (m. p. 292-294 °C). IR
(KBr) ν 3440 (br), 3160, 3047, 2963, 2206, 1647, 1557, 1509,
+
MS (EI, 70 eV) m/z (%) 376 (2.2, M ), 333 (42), 259 (22);
+
+
HRMS (EI), calcd. for [C H N O ] (M ) 376.1535; found
21
20
4
3
3
76.1528. . Anal. calcd. for C H N O (376.4): C 67.01, H 5.36,
21 20 4 3
–
1
1
N 14.88 %. Found: C 67.09, H 5.19, N 14.73 %.
1
446, 1335, 1299, 1244, 1152, 1046, 838, 756, 688 cm . H
NMR (400 MHz, DMSO-d ) δ 3.87 (3 H, s, OCH ), 7.14–7.66
6
3
3
.2. General Procedures for Compounds 12a-f
(15 H, m, Ar-H), 7.25 (2 H, br s, NH ), 8.91 (1 H, s, pyridazine
2
13
Method A. A mixture of azaenamine 9 (0.38 g, 1 mmol) and
CH). C NMR (100 MHz, DMSO-d ) δ 55.9 (OCH ), 96.7,
6
3
arylidine malononitrile 10a-f (1 mmol) was heated at reflux in
EtOH (20 mL) in the presence of piperidine (0.2 mL) for 3 h. The
solvent was evaporated at reduced pressure, and the crude
product was collected and crystallized from the proper solvent.
105.0 (CCN), 107.4, 114.7 (CN), 126.7, 127.5, 128.5, 128.6,
129.6, 129.7, 130.0, 130.1, 130.6, 130.7, 131.0, 131.1, 139.2,
142.9, 147.9, 148.0, 150.5, 153.8 (pyridazine CH), 160.9, 163.1
+
(Ar C), 164.4 (CO) MS (EI, 70 eV) m/z (%) 535 (37, [M+1] ),
+
5
1
5
34 (100, M ), 533 (90), 497 (23), 305 (23), 260 (63), 176 (30),
Method B. A mixture of 17 (0.38 g, 1 mmol) and arylidene
malononitrile 10a-f (1 mmol) was refluxed in DMF (10 mL) in
presence of piperidine (0.2 mL) for 3 h. The solvent was
evaporated at reduced pressure, and the crude product was
washed with 10% aq. HCl (10 mL) and then with distilled water
+
+
09 (23), 77 (60). HRMS (EI) calcd. for [C H N O ] (M )
35.1757; found 535.1765requires. Anal. calcd. for C H N O
32
21
7
2
3
2
21
7
2
(535.6): C 71.77, H 3.95, N 18.31. Found: C 71.69, H 3.86, N
1
8.25.
(
10 mL). The resulting solid was dried and crystallized from the
3.2.4. 10-Amino-8-(2-ethoxyphenyl)-12-oxo-1,3-diphenyl-
3,12-dihydropyrazolo[4',3':5,6]pyrimido[2,1-a]phthalazine-9-
carbonitrile (12d)
proper solvent.
Method C. A mixture of azaenamine 9 (0.38 g, 1 mmol),
malononitrile (14, 0.07 g, 1 mmol) and aryl aldehyde (13, 1
mmol) was heated at reflux in ethanol (20 mL) in presence of
piperidene (0.2 mL). The solvent was then evaporated at reduced
pressure, and the collected solid was crystallized from the proper
solvent.
Crystallized from dioxane-DMF (5:2) to give 12d (0.45 g, 0.8
mmol, 82%, method A; 0.46 g, 0.8 mmol, 84%, method B; 0.44
g, 0.8 mmol, 80%, method C) as brownish-yellow crystals (m. p.
2
2
88-290 °C). IR (KBr) ν 3407 (br), 3323, 3058, 2980, 2889,
208, 1646, 1552, 1346, 1273, 1238, 1155, 1047, 970, 756, 659
–1
1
cm . H NMR (400 MHz, DMSO-d ) δ 1.53 (3 H, t, J 7.2 Hz,
6
COOCH CH ), 4.22 (2 H, q, J 7.2 Hz, COOCH CH ), 7.07-8.00
2
3
2
3
5