Month 2018
Facile Synthesis of Pyrazolo[3,4-c]Pyrazoles as Anticancer Agents
1
-(2-Oxo-2H-chromene-3-carbonyl)-3-(3,4,6-triphenyl-1,6-
Alternate synthesis of 5a. Synthesis of 4-benzoyl-2-(2-oxo-
dihydropyrazolo[3,4-c]pyrazole (5a).
Brown solid (74%);
2H-chromene-3-carbonyl)-5-phenyl-2,4-dihydro-3H-pyrazol-3-
mp = 263–265°C (DMF); IR (KBr): v 1698, 1662
one (6). To a solution of compound 2 (0.664 g, 2 mmol)
ꢀ
1
1
in pyridine (15 mL) was added benzoyl chloride (0.280 g,
2 mmol) and the mixture was cooled in an ice bath while
being stirred. The reaction mixture was stirred for further
(
1
2C¼O) cm
; HNMR (DMSO-d ): δ 6.80–7.82 (m,
9H, Ar–H), 8.39 (s, 1H, Coumarine-H4); C-NMR
6
1
3
(
DMSO-d ): δ 113.5, 119.2, 119.6, 120.7, 120.9, 122.6,
6
4
h. The formed precipitate after acidification was
1
1
1
23.2, 125.6, 125.8, 127.3, 127.5, 129.2, 129.7, 130.6,
31.5, 131.8, 133.3, 133.9, 135.4, 136.3, 137.4, 139.5,
isolated by filtration, washed with water, dried and
recrystallized from ethanol to give the benzoyl
pyrazolone 6 as white solid (74%); mp = 184–186°C; IR
41.8, 144.2 (Ar–C and C¼N), 164.9, 173.0 (2C¼O);
+
MS m/z (%): 508 (M , 100), 362 (55), 211 (40), 106
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1 1
(
39), 77 (85). Anal. Calcd. for C H N O (508.53): C,
(KBr): v 1712, 1692, 1672, 1660 (4C¼O) cm ; HNMR
3
2 20 4 3
7
1
5.58; H, 3.96; N, 11.02. Found C, 75.64; H, 3.76; N,
1.01%.
(DMSO-d ): δ 7.17–7.93 (m, 14H, Ar–H), 6.30 (s, 1H,
6
pyrazole-H4), 8.37 (s, 1H, Coumarine-H4); MS m/z (%):
+
4
-Acetyl-1-(2-oxo-2H-chromene-3-carbonyl)-3,6-diphenyl-
436 (M , 100), 306 (40), 236 (38), 173 (54), 57 (84).
1
,6-dihydropyrazolo[3,4-c]pyrazole (5b).
Brown solid
Anal. Calcd. for C H N O (436.42): C, 71.56; H,
2
6 16 2 5
(
1
(
68%); mp = 271–273°C (DMF); IR (KBr): v 1703,
3.70; N, 6.42. Found C, 71.43; H, 3.76; N, 6.36%.
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1 1
688, 1660 (3C¼O) cm ; HNMR (DMSO-d ): δ 2.40
Reaction of 6 with phenyl hydrazine.
A mixture of 6
6
s, 3H, CH ), 6.83–7.77 (m, 14H, Ar–H), 8.43 (s, 1H,
(0.436 g, 1 mmol) and phenyl hydrazine (0.108 g,
1 mmol) in ethanol (10 mL) was refluxed for 8 h. The
solid that precipitated was filtered off, washed with water,
dried, and finally crystallized from DMF to give 5a
identical in all respects (mp., mixed mp., IR, MS, and H
NMR spectra) with that one obtained from 4a and POCl3.
3
+
Coumarine-H4); MS m/z (%): 474 (M , 100), 315 (39),
66 (28), 164 (60), 77 (53). Anal. Calcd. for C H N O
8 18 4 4
2
(
2
474.47): C, 70.88; H, 3.82; N, 11.81. Found C, 70.67;
1
H, 3.65; N, 11.71%.
4
-Acetyl-1-(2-oxo-2H-chromene-3-carbonyl)-3-phenyl-6-(p-
tolyl)-1,6-dihydropyrazolo[3,4-c]pyrazole (5c). Brown solid
Alternate synthesis of 4b. Synthesis of 3-(5-Oxo-1-(2-oxo-
2H-chromene-3-carbonyl)-3-phenyl-4,5-dihydro-1H-pyrazol-4-
(68%); mp = 251–253°C (DMF); IR (KBr): v 1700,
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1
1
1
(
686, 1662 (3C¼O) cm ; HNMR (DMSO-d ): δ 2.25
6
yl)pentane-2,4-dione (8).
To a mixture of equimolar
s, 3H, CH ), 2.39 (s, 3H, CH ), 6.91–7.83 (m, 13H, Ar–
3 3
quantities of 2 and 3-chloro-2,4-pentanedione (7) (2 mmol
each) in dioxane (20 mL) was added triethylamine
+
H), 8.36 (s, 1H, Coumarine-H4); MS m/z (%): 488 (M ,
51), 339 (67), 270 (100), 173 (82), 77 (83). Anal. Calcd.
for C H N O (488.49): C, 71.30; H, 4.13; N, 11.47.
8
(2 mmol). The mixture was stirred at room temperature
29 20 4 4
for 24 h, the solid that formed was collected and
crystallized from ethanol to give the respective product 8
as white solid (74%); mp = 150–152°C; IR (KBr): v 1703,
Found C, 71.16; H, 4.09; N, 11.33%.
Ethyl 6-(2-oxo-2H-chromene-3-carbonyl)-1,4-diphenyl-1,6-
dihydropyrazolo[3,4-c]pyrazole-3-carboxylate (5d).
solid (65%); mp = 250–252°C (DMF); IR (KBr): v 1724,
1
(
CH CH ), 6.93–7.69 (m, 14H, Ar–H), 8.47 (s, 1H,
Coumarine-H4); C-NMR (DMSO-d ): δ 12.8 (CH ),
6
1
1
Brown
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1 1
1
687, 1676, 1661, 1644 (5C¼O) cm ; HNMR (DMSO-
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1 1
d ): δ 2.28 (s, 3H, CH ), 2.35 (s, 3H, CH ), 4.04 (s, 1H,
6
3
3
686, 1662 (3C¼O) cm ; HNMR (DMSO-d ): δ 1.10
6
CH), 5.75 (s, 1H, pyrazole-H4), 67.17–7.92 (m, 9H, Ar–
H), 8.30 (s, 1H, Coumarine-H4); MS m/z (%): 430 (M ,
14), 340 (31), 237 (49), 143 (33), 77 (100). Anal. Calcd.
t, J = 7.8 Hz, 3H, CH CH ), 4.14 (q, J = 7.8 Hz, 2H,
2 3
+
2
3
1
3
6
3
for C H N O (430.41): C, 66.97; H, 4.22; N, 6.51.
24 18 2 6
1.3 (CH ), 109.0, 117.3, 119.0, 121.4, 122.3, 123.1,
2
Found C, 66.67; H, 4.13; N, 6.44%.
Coupling of 8 with benzenediazonium chloride.
24.5, 125.0, 126.4, 126.7, 128.5, 130.4, 132.1, 133.5,
35.4, 136.9, 137.0, 139.5, 141.6, 149.6 (Ar–C and
To a
solution of compound 8 (1 mmol) in ethanol (10 mL)
was added sodium acetate trihydrate (0.3 g) and the
mixture was cooled in an ice bath at 0–5°C while being
stirred. To the resulting cold solution was added a cold
solution of benzenediazonium chloride, prepared as usual
by diazotizing aniline (1 mmol) in hydrochloric acid
(1 mL, 6 M) with sodium nitrite (0.07 g, 1 mmol) in
water (1 mL). After all of the diazonium salt solution was
added, the reaction mixture was stirred for further 30 min
while being cooled in an ice bath. The solid that
precipitated was filtered off, washed with water, dried,
and finally crystallized from ethanol to give 4b identical
C¼N), 165.7, 170.5, 174.3 (3C¼O) MS m/z (%): 504
+
(
M , 26), 419 (73), 280 (55), 163 (37), 77 (100). Anal.
Calcd. for C H N O (504.49): C, 69.04; H, 4.00; N,
29 20 4 5
1
1.11. Found C, 69.01; H, 4.13; N, 11.01%.
Ethyl
6-(2-oxo-2H-chromene-3-carbonyl)-4-phenyl-1-(p-
tolyl)-1,6-dihydropyrazolo[3,4-c]pyrazole-3-carboxylate (5e).
Green solid (67%); mp = 236–238°C (DMF); IR (KBr): v
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1 1
1
1
4
739, 1698, 1655 (3C¼O) cm ; HNMR (DMSO-d ): δ
6
.14 (t, J = 7.8 Hz, 3H, CH CH ), 2.23 (s, 3H, CH ),
2
3
3
.16 (q, J = 7.8 Hz, 2H, CH CH ), 7.03–7.75 (m, 13H,
2
3
Ar–H), 8.44 (s, 1H, Coumarine-H4); MS m/z (%): 518
+
(
M , 100), 412 (51), 325 (28), 239 (54), 77 (60). Anal.
1
Calcd. for C H N O (518.52): C, 69.49; H, 4.28; N,
in all respects (mp., mixed mp., IR, MS, and H NMR
30 22 4 5
10.81. Found C, 69.7; H, 4.20; N, 10.76%.
spectra) with that one obtained from 2 and 3b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet