Synthesis of some new pyridazino cinnoline derivatives

Article abstract of DOI:10.1002/jhet.5570390437

2,5-Dibromo-3,6-(dihydrazino or diphenylhydrazino)-1,4-benzoquinone 1a,b reacts with active methylene reagents to give some new functionally substituted pyridazino cinnoline derivatives.

Full text of DOI:10.1002/jhet.5570390437

Jul-Aug 2002
Synthesis of Some New Pyridazino Cinnoline Derivatives
853
A. M. Soliman
Chemistry Department, Faculty of Science, Sohag, Egypt
Received February 23, 2001
2,5-Dibromo-3,6-(dihydrazino or diphenylhydrazino)-1,4-benzoquinone 1a,b reacts with active methyl-
ene reagents to give some new functionally substituted pyridazino cinnoline derivatives.
J. Heterocyclic Chem., 39, 853 (2002).
Heterocyclic annulated pyridazines continue to attract
hydrazine groups to the cyano groups of the resultant
adducts and then tautomerization.
considerable attention which mainly arises from the large
variety of interesting pharmacological activities observed
with pyridazine derivatives [1-3]. On the other hand, many
drugs, which are used in cancer chemotherapy, contain a
quinone nucleus in their structures [4-6].
Recently, we have reported the use of tetrabromo-
quinone in the synthesis of some heterocyclic systems [7-
9]. In the present study we report the synthesis of
Cinnoline derivatives by the reaction of 3,6-dibromo-2,5-
dihydrazino-1,4-benzoquinone 1a or 3,6-dibromo-2,5-
diphenylhydrazino-1,4-benzoquinone 1b with some active
methylenes.
When compounds 1a,b reacted with diethylmalonate
they gave diethyl 3,8-dihydroxy-1,2,6,7-tetrahydro-
pyridazino[3,4-g]cinnoline-5,10-dione-4,9-dicarboxylate
4a, and diethyl 3,8-dihydroxy-2,7-diphenyl-1,2,6,7-
tetrahydropyridazino[3,4-g]cinnoline-5,10-dione-4,9-
dicarboxylate 4b, respectively, while with diethylmalonate,
they gave 4,9-diacetyl-3,8-dihydroxy-1,2,6,7-tetrahydropy-
ridazino[3,4-g]cinnoline-5,10-dione 5a and 4,9-diacetyl-
3,8-dihydroxy-2,7-diphenyl-1,2,6,7-tetrahydropyri-
dazino[3,4-g]cinnoline-5,10-dione 5b ,respectively.
In this case the reaction mechanism involves elimina-
tions of HBr from 1a,b followed by nucleophilic additions
of the hydrazine groups to the carbonyl of the ester groups
The starting materials 1a,b are prepared by a dropwise
addition of hydrazine and phenylhydrazine, respectively, to
tetrabromoquinone in the presence of Et N as catalyst and
3
dioxan as solvent. The addition was carried out over a 20
minute period with stirring and cooling, followed by stir-
ring at room temperature for further two hours (Scheme 1).
The compounds 1a,b were allowed to react with a series
of active methylene compounds in DMF as solvent and in
the presence of Et N in 2:1:2 ratio. The reaction mixture
3
was stirred for about one hour and then refluxed over dif-
ferent periods of time (1-3 hours, c.f. Table I) to give the
corresponding polyfused ring systems (Scheme 2).
The reaction of 1a,b with malononitrile gave, respec-
tively, 3,8-diamino-4,9-dicyano-1,2,6,7-tetrahydro-
pyridazino[3,4-g]cinnoline-5,10-dione 2a and 3,8-diamino-
4,9-dicyano-2,7-diphenyl-1,2,6,7-tetrahydropyridazino-
[3,4-g]cinnoline-5,10-dione 2b. With cyanoacetamide the
reaction of 1a,b gave respectively 3,8-diamino-1,2,6,7-
tetrahydropyridazino[3,4-g]cinnoline-5,10-dione-4,9-
dicarboxamide 3a and 3,8-diamino-2,7-diphenyl-1,2,6,7-
tetrahydropyridazino[3,4-g]cinnoline-5,10-dione-4,9-
dicarboxamide 3b. These reactions occured via HBr elimi-
nations from 1a,b followed by nucleophilic additions of the

854
A. M. Soliman
Vol. 39
25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of DMF was
of the resultant adducts with a subsequent loss of ethanol.
The reaction of 1a,b with 2,4-pentandione gave, respec-
tively, 4,9-diacetyl-3,8-dimethyl-1,2,6,7-tetrahydro-
pyridazino[3,4-g]cinnoline-5,10-dione 6a and 4,9-
diacetyl-3,8-dimethyl-2,7-diphenyl-1,2,6,7-tetrahydropy-
ridazino[3,4-g]cinnoline-5,10-dione 6b. The reaction
mechanism involves eliminations of HBr from 1a,b fol-
lowed by nucleophilic additions of the hydrazine groups to
the carbonyl groups of the resultant adducts with a subse-
quent loss of water and cyclization. The structures of the
obtained products were assigned by elemental analysis, IR
3
added dropwise within about 15 minutes while the reaction mix-
ture was stirred on an ice bath. Then the reaction mixture was
refluxed for 2 hours. After cooling the solid formed was isolated
by filtration and recrystallized from EtOAc to yield 2a.
3,8-Diamino-4,9-dicyano-2,7-diphenyl-1,2,6,7-tetrahydropyri-
dazino[3,4-g]cinnoline-5,10-dione (2b).
3,6-Dibromo-2,5-diphenylhydrazino-1,4-benzoquinone 1b
(4.78 g, 10 mmol) and malononitrile (1.32 g, 20 mmol) were dis-
solved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of
3
DMF was added dropwise over about 15 minutes while the reac-
tion mixture was stirred on an ice bath. Then the reaction mixture
1
and H-NMR spectra.
Table 1
Physical and Analytical Data of the Prepared Compounds
Prod.
No.
T
Hr.
Yield[a]
%
M.P.(°C)
Cryst.Solv.
M.Form.
(M.Wt.)
Analytical data
Calc./Found
C%
H%
N%
Br
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
2
72
68
63
61
76
51
62
57
56
52
55
50
255
EtOH
240
EtOH
283
EtOAc
277
EtOAc
270
THF
295
Dioxan
230
THF
300
EtOAc
215
Dioxan
310
EtOAc
307
THF
298
C H N O Br
2
325.95
22.11
22.49
45.21
45.38
48.65
48.90
64.28
64.08
43.37
43.56
59.52
59.82
48.98
49.26
61.76
61.60
50.60
50.92
64.46
64.76
58.53
58.30
69.98
70.26
1.86
2.06
2.95
3.00
2.72
2.86
3.60
3.45
3.64
3.84
4.16
4.33
4.11
4.30
4.44
4.34
3.64
3.86
4.16
4.32
4.91
4.85
5.03
5.23
17.19
16.81
11.72
11.50
37.83
37.45
24.99
24.79
33.72
33.40
23.14
22.86
14.28
14.00
10.29
10.01
16.87
16.59
11.57
11.32
17.07
16.75
11.66
11.32
49.03
49.33
33.42
33.66
6
6
4
2
2
C
H
N O Br
18 14
4
2
2
478.13
C H N O
12
2
8 8 2
296.26
2.5
2.5
3
C H N O
24 16 8
2
4
4
8
8
6
6
4
4
448.49
C
H N O
12 12 8
332.27
C
H N O
24 20 8
484.48
3
C H N O
16 16 4
392.33
3
C H N O
28 24 4
544.51
2.5
3
C H N O
14 12 4
332.28
C
H N O
26 20 4
484.46
3
C H N O
16 16 4
328.33
3
C H N O
28 24 4
EtOAc
480.51
[a] Yield of pure and crystallized products.
EXPERIMENTAL
was refluxed for 2.5 hours. After cooling the solid formed was
isolated by filtration and recrystallized from EtOAc to yield 2b.
All m.p. are uncorrected, IR spectra were obtained (KBr discs)
on a Nicolet 710 FT-IR spectrometer. H- NMR spectra were
obtained on a Varian EM 360 A at 60 MHz using TMS as an
internal standard. The elemental analyses were carried out on an
elemental analyzer model 240c.
3,8-Diamino-1,2,6,7-tetrahydropyridazino[3,4-g]cinnoline-5,10-
dione-4,9-dicarboxamide (3a).
1
3,6-Dibromo-2,5-dihydrazino-1,4-benzoquinone 1a (3.26 g,
10 mmol) and cyanoacetamide (1.68 g, 20 mmol) were dissolved
in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of DMF was
3
3,8-Diamino-4,9-dicyano-1,2,6,7-tetrahydropyridazino[3,4-
g]cinnoline-5,10-dione (2a).
added dropwise over about 15 minutes while the reaction mixture
was stirred on an ice bath. Then the reaction mixture was
refluxed for 2.5 hours. After cooling the solid formed was iso-
lated by filtration and recrystallized from THF to yield 3a.
3,6-Dibromo-2,5-dihydrazino-1,4-benzoquinone 1a (3.26 g,
10 mmol) and malononitrile (1.32 g, 20 mmol) were dissolved in

Jul-Aug 2002
Synthesis of Some New Pyridazino Cinnoline Derivatives
855
Table 2
IR and NMR Spectra of the Prepared Compounds
-1
1
Prod.
No.
IR(KBr) ν(cm
)
H- NMR (DMSO-d )
6
1a
1b
2a
2b
3a
3410, 3348, 3270(NHNH ), 1657 (CO).
3408(NH), 1656(CO).
8.20 (s, 2H, 2NH),4.00-4.40 (s,4H, 2NH ).
2
8.40 (s, 2H, 2NH),8.00 (s, 2H, 2NH), 7.70- 7.20 (m, 10H, 2C H ).
12.90 (s, 4H, 4NH),6.03 (br, 4H, 2NH )
2
2
6 5
3443(NH), 3317, 3252, 3189(NH, NH ), 2218(CN), 1659(CO).
2
3441(NH), 3325, 3230(NH ), 2006(CN), 1653(CO).
12.60 (s, 2H, 2NH),7.90-7.50 (m, 10H, 2C H ),6.00 (m, 4H, 2NH ).
2
6 5 2
3439(NH), 3325, 3218, 3190(NH, NH ), 2930(CH,aliph.),1690,
12.80 (s, 4H, 4NH), 6.30 (br, 4H, 2CONH ),5.60 (br, 4H, 2NH ).
2 2
2
1659(CO).
3b
4a
4b
3430(NH), 3325, 3220,(NH ), 1685,1655(CO).
12.60 (s, 2H, 2NH), 7.70-7.30 (m, 10H, 2C H ),6.20 (br, 4H,
6 5
2
2CONH ), 5.30 (br, 4H, 2NH ).
2
2
3440(NH), 3400(OH), 3325(NH) 2930(CH,aliph.), 1705,
1649 (CO).
3450(NH), 3420(OH), 2924(CH,aliph.), 1710, 1634(CO).
13.10 (s, 4H, 4NH), 10.50 (s, 2H, 2OH),
4.40 (q, 4H, 2OCH ), 1.30 (t, 6H, 2CH ).
2
3
12.80 (s, 2H, 2NH), 10.3 (s, 2H, 2OH),
7.60-7.20 (m, 10H, 2C H ),4.30 (q, 4H, 2OCH ) 1.20 (t, 6H, 2CH ).
6
5
3
3
5a
5b
3443(NH), 3398(OH), 3319(NH) 2925(CH,aliph.), 1700, 1651(CO). 13.10 (s, 4H, 4NH), 10.70 (s, 2H, 2OH), 3.65 (s, 6H, 2CH ).
3
3428(NH), 3418(OH), 2915(CH,aliph.), 1690, 1655(CO).
12.80 (s, 2H, 2NH), 10.40 (s, 2H, 2OH),
7.80-7.30 (m, 10H, 2C H ), 3.60 (s, 6H, 2CH ).
6
5
3
6a
6b
3448, 3320(NH), 2922(CH, aliph.), 1700, 1645(CO).
3436(NH), 2930(CH,aliph.), 1705, 1649(CO).
12.40 (s, 4H, 4NH), 3.50 (s, 6H, 2COCH ), 1.40 (s, 6H, 2CH ).
3 3
12.20 (s, 2H, 2NH), 7.50-7.10 (m, 10H, 2C H ), 3.35 (s, 6H,
6
5
2COCH ), 1.30 (s, 6H, 2CH ).
3
3
3,8-Diamino-2,7-diphenyl-1,2,6,7-tetrahydropyridazino[3,4-g]-
cinnoline-5,10-dione-4,9-dicarboxamide (3b).
was refluxed for 2.5 hours. After cooling the solid formed was
isolated by filtration and recrystallized from dioxan to yield 5a.
3,6-Dibromo-2,5-diphenylhydrazino-1,4-benzoquinone 1b
4,9-Diacetyl-3,8-dihydroxy-2,7-diphenyl-1,6-dihydropyri-
(4.78 g, 10 mmol) and cyanoacetamide (1.68 g, 20 mmol) were
dazino[3.4-g]cinnoline-5,10-dione (5b).
dissolved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of
3
3,6-Dibromo-2,5-diphenylhydrazino-1,4-benzoquinone 1b
(4.78 g, 10 mmol) and ethylacetoacetate (2.55 mL, 20 mmol)
DMF was added dropwise over about 15 minutes while the reac-
tion mixture was stirred on an ice bath. Then the reaction mixture
was refluxed for 3 hours. After cooling the solid formed was iso-
lated by filtration and recrystallized from dioxan to yield 3b.
were dissolved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10
3
mL of DMF was added dropwise over about 15 minutes while
the reaction mixture was stirred on an ice bath. Then the reac-
tion mixture was refluxed for 3 hours. After cooling the solid
formed was isolated by filtration and recrystallized from EtOAc
to yield 5b.
Diethyl 3,8-Dihydroxy-1,2,6,7-tetrahydropyridazino[3,4-g]cin-
noline-5,10-dione-4,9-dicarboxylate (4a).
3,6-Dibromo-2,5-dihydrazino-1,4-benzoquinone 1a (3.26 g,
10 mmol) and diethylmalonate (3.03 mL, 20 mmol) were dis-
4,9-Diacetyl-3,8-dimethyl-1,2,6,7-tetrahydropyridazino[3,4-g]-
cinnoline-5,10-dione (6a).
solved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of
3
DMF was added dropwise over about 15 minutes while the reac-
tion mixture was stirred on an ice bath. Then the reaction mixture
was refluxed for 3 hours. After cooling the solid formed was iso-
lated by filtration and recrystallized from THF to yield 4a.
3,6-Dibromo-2,5-dihydrazino-1,4-benzoquinone 1a (3.26 g,
10 mmol) and 2,4-pentandione (2.10 mL, 20 mmol) were dis-
solved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of
3
DMF was added dropwise over about 15 minutes while the reac-
tion mixture was stirred on an ice bath. Then the reaction mixture
was refluxed for 3 hours. After cooling the solid formed was iso-
lated by filtration and recrystallized from EtOAc to yield 6a.
Diethyl 3,8-Dihydroxy-2,7-diphenyl-1,6-dihydropyridazino[3,4-
g]cinnoline-5,10-dione-4,9- dicarboxylate (4b).
3,6-Dibromo-2,5-diphenylhydrazino-1,4-benzoquinone 1b
4,9-Diacetyl-3,8-dimethyl-2,7-diphenyl-1,2,6,7-tetrahydropyri-
(4.78 g, 10 mmol) and diethylmalonate (3.03 mL, 20 mmol) were
dazino[3,4-g]cinnoline-5,10-dione (6b).
dissolved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of
3
DMF was added dropwise over about 15 minutes while the reac-
tion mixture was stirred on an ice bath. Then the reaction mixture
was refluxed for 3 hours. After cooling the solid formed was
isoated by filtration and recrystallized from EtOAc to yield 4b.
3,6-Dibromo-2,5-diphenylhydrazino-1,4-benzoquinone 1b
(4.78 g, 10 mmol) and 2,4-pentandione (2.10 mL, 20 mmol) were
dissolved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of
3
DMF was added dropwise over about 15 minutes while the reac-
tion mixture was stirred on an ice bath. Then the reaction mixture
was refluxed for 3 hours. After cooling the solid formed was iso-
lated by filtration and recrystallized from EtOAc to yield 6b.
4,9-Diacetyl-3,8-dihydroxy-1,2,6,7-tetrahydropyridazino[3,4-g]-
cinnoline-5,10-dione (5a).
3,6-Dibromo-2,5-dihydrazino-1,4-benzoquinone 1a (3.26 g,
10 mmol) and ethylacetoacetate (2.55 mL, 20 mmol) were dis-
REFERENCES AND NOTES
solved in 25 mL of DMF. Et N (3 mL, 20 mmol) in 10 mL of
3
DMF was added dropwise over about 15 minutes while the reac-
tion mixture was stirred on an ice bath. Then the reaction mixture
*
Present address: Teachers College in Dammam, P.O. Box

856
A. M. Soliman
Vol. 39
2375, Dammam 31451, Saudi Arabia.
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