Molecular design of pyrazolo[3,4-d]pyridazines

Article abstract of DOI:10.1134/S1070428008090182

Reactions of arenediazonium chlorides with ethyl 2-methyl-and 2-chloro-4-oxobutanoates gave, respectively, ethyl 2-(arylhydrazono)propanoates and chloro(arylhydrazono)acetates. Ethyl 2-(arylhydrazono)-propanoates reacted with the Vilsmeier-Haak reagent to give ethyl 1-aryl-4-formyl-1 H-pyrazole-3-carboxylates. Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3- carboxylates were obtained by reaction of chloro(arylhydrazono) acetates with acetylacetone. Reactions of the obtained pyrazole derivatives with hydrazine and methylhydrazine led to the formation of the corresponding 3,4-R ₂ ¹ -6-R²-2-aryl-2,6-dihydro-7H-pyrazolo-[3,4-d]pyridazin-7- ones (R¹, R² = H, Me) which were subjected to alkylation and sulfurization.

Full text of DOI:10.1134/S1070428008090182

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 9, pp. 1352–1361. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.S. Matiichuk, M.A. Potopnyk, N.D. Obushak, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 9,
pp. 1368–1376.
Molecular Design of Pyrazolo[3,4-d]pyridazines
V. S. Matiichuk, M. A. Potopnyk, and N. D. Obushak
Ivan Franko Lviv National University, ul. Kirilla i Mefodiya 6, Lviv, 79005 Ukraine
e-mail: obushak@in.lviv.ua
Received December 5, 2007
Abstract—Reactions of arenediazonium chlorides with ethyl 2-methyl- and 2-chloro-4-oxobutanoates gave,
respectively, ethyl 2-(arylhydrazono)propanoates and chloro(arylhydrazono)acetates. Ethyl 2-(arylhydrazono)-
propanoates reacted with the Vilsmeier–Haak reagent to give ethyl 1-aryl-4-formyl-1H-pyrazole-3-carbox-
ylates. Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates were obtained by reaction of chloro(aryl-
hydrazono)acetates with acetylacetone. Reactions of the obtained pyrazole derivatives with hydrazine and
methylhydrazine led to the formation of the corresponding 3,4-R12-6-R2-2-aryl-2,6-dihydro-7H-pyrazolo-
[3,4-d]pyridazin-7-ones (R1, R2 = H, Me) which were subjected to alkylation and sulfurization.
DOI: 10.1134/S1070428008090182
Nitrogen-containing heterocyclic compounds play
an important role in organic chemistry and attract
strong interest due to diversity of their chemical trans-
formations and broad spectrum of biological activity.
A key problem in the design of new heterocyclic sys-
tems is search for accessible multipurpose reagents.
initial hydrazines and their toxicity. On the other hand,
the corresponding hydrazones that are formed as inter-
mediate products in the above reactions can be ob-
tained from diazonium salts and compounds having
an activated CH group according to Japp–Klingemann.
As a rule, products of such reaction contain functional
groups, which makes them promising as reagents for
the synthesis of fused pyrazole derivatives.
In the present article we describe an efficient ap-
proach to the design of 2-aryl-2,6-dihydro-7H-pyra-
zolo[3,4-d]pyridazin-7-one libraries using ethyl 1-aryl-
4-formyl- and 1-aryl-4-acetyl-5-methyl-1H-pyrazole-
3-carboxylates IVa–IVc and Va–Vi as initial com-
pounds. It is known that pyrazole-3-carboxylic acid
derivatives act as CB1 cannabinoid receptor antago-
nists [1–6]; therefore, they are promising as potential
biologically active substances.
Pyrazole ring is most frequently built up via reac-
tions of hydrazines with functionalized carbonyl com-
pounds [7–11]. However, this approach is not free
from some limitations related to low accessibility of
As starting materials we used ethyl 2-(arylhydra-
zono)propionates IIIa–IIIc [12] and ethyl (arylhydra-
zono)chloroacetates IIId–IIIl [13] which were syn-
thesized from the corresponding arenediazonium chlo-
rides Ia–Ij and ethyl 2-methyl- and 2-chloro-4-oxo-
butanoates IIa and IIb (Scheme 1). The reactions were
carried out in aqueous alcohol under mild conditions,
and the products were isolated in 61–93% yield. Hy-
drazones IIIa–IIIl are colored crystalline substances
that are stable on storage. Signals from the NNHAr
1
proton in the H NMR spectra of these compounds
Scheme 1.
X
O
O
H
N2 Cl–
N
NaOAc
N
COOEt
+
R
R
Me
OEt
X
Ia–Ij
IIa, IIb
IIIa–IIIl
I, R = H (a), 4-F (b), 2-Cl (c), 3-Cl (d), 4-Cl (e), 3-Me (f), 3,4-Me2 (g), 4-MeO (h), 3-F3C (i), 2-MeOCO (j); II, X = Me (a),
Cl (b); III, X = Me, R = H (a), 3-Me (b), 4-Cl (c); X = Cl, R = H (d), 4-F (e), 2-Cl (f), 3-Cl (g), 4-Cl (h), 3,4-Me2 (i), 4-MeO (j),
3-F3C (k), 2-MeOCO (l).
1352

MOLECULAR DESIGN OF PYRAZOLO[3,4-d]PYRIDAZINES
1353
were observed in the region δ 9.65–9.76 (propionates
IIIa and IIIc) or 10.32–10.64 ppm (chloroacetates
IIId, IIIe, and IIIg–IIIk). In the spectrum of IIIl, the
NH signal was displaced downfield, presumably as
a result of intramolecular hydrogen bonding, while the
corresponding signal in the spectrum of IIIf was ob-
served in a stronger field due to shielding by the
chlorine atom in the ortho position.
exceptions [14–17], such reactions involved arylhydra-
zones derived from aromatic or heteroaromatic ketones
[17–23]; therefore, the synthetic potential of this ap-
proach was essentially limited. We examined reactions
of hydrazones IIIa–IIIc with POCl3–DMF and ob-
tained 4-formylpyrazole-3-carboxylates IVa–IVc
which may be regarded as promising building blocks
for organic synthesis (Scheme 2). 4-Acetyl derivatives
Va–Vc were synthesized by condensation of hydra-
zones IIId–IIIl with acetylacetone in the presence of
COOEt
COOEt
1
sodium ethoxide [24] (Scheme 3). In the H NMR
N
N
Cl
N
N
Cl
spectra of IVa–IVc, the aldehyde proton appeared at
δ 10.26–10.31 ppm, and proton in position 5 of the
pyrazole ring resonated at δ 9.13–9.22 ppm. Pyrazoles
H
O
H
Cl
1
Va–Vi displayed in the H NMR spectra signals from
Me
the 5-CH3 group and acetyl protons at δ 2.24–2.43 and
2.46–2.50 ppm, respectively.
IIIl
IIIf
Pyrazoles IV and V were then used to synthesize
2-aryl-1H-pyrazolo[3,4-d]pyridazin-7-ones VIa–VIk
and VIIa–VIIg (Scheme 4). Compounds like VI and
A convenient procedure for the synthesis of pyra-
zole derivatives is based on the Vilsmeier–Haak reac-
tion with methyl ketone arylhydrazones. With a few
Scheme 2.
Me
H
COOEt
R
N
N
POCl3, DMF
N
COOEt
N
R
CHO
IIIa–IIIc
IVa–IVc
R = H (a), 3-Me (b), 4-Cl (c).
Scheme 3.
COOEt
O
Cl
N
N
H
O
O
N
NaOEt
N
COOEt
Me
+
R
R
Me
Me
Me
IIId–IIIl
Va–Vi
V, R = H (a), 4-F (b), 2-Cl (c), 3-Cl (d), 4-Cl (e), 3,4-Me2 (f), 4-MeO (g), 3-F3C (h), 2-MeOCO (i).
Scheme 4.
O
O
Me
N
COOEt
NH
N
N
O
N
N
N
N
N2H4 ·H2O
MeNHNH2
N
N
R2
R2
R2
R1
R1
R1
R2
R2
R2
VIa–VIk
IVa, IVc, Va–Vi
VIIa–VIIg
VI, R1 = R2 = H (a); R1 = 4-Cl, R2 = H (b); R1 = H, R2 = Me (c); R1 = 4-F, R2 = Me (d); R1 = 2-Cl, R2 = Me (e); R1 = 3-Cl, R2 =
Me (f); R1 = 4-Cl, R2 = Me (g); R1 = 3,4-Me2, R2 = Me (h); R1 = 4-MeO, R2 = Me (i); R1 = 3-F3C, R2 = Me (j); R1 = 2-NH2NHC(O),
R2 = Me (k); VII, R1 = R2 = H (a); R1 = 4-Cl, R2 = H (b); R1 = 4-F, R2 = Me (c); R1 = 2-Cl, R2 = Me (d); R1 = 3-Cl, R2 = Me (e);
R1 = 4-Cl, R2 = Me (f); R1 = 3,4-Me2, R2 = Me (g).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MATIICHUK et al.
1354
Scheme 5.
MeS
N
N
N
Me2SO4
R1 = R2 = H
N
S
NH
XII
N
N
P2S5
O
N
R2
Ph
R1
R2
S
N
PhCOCH2Br
VIIIa–VIIIf
N
N
Xa
R1 = R2 = H
N
Me2SO4
S
Me
N
XIII
N
(1) Me2SO4
(2) P2S5
N
VIa, VId–VIh
N
R2
R1
R2
IXa–IXf
O
R3
N
R3Hlg (Xa, Xb)
N
N
R1 = R2 = H
N
XIa, XIb
VIII, IX, R1 = R2 = H (a); R1 = 4-F, R2 = Me (b); R1 = 2-Cl, R2 = Me (c); R1 = 3-Cl, R2 = Me (d); R1 = 4-Cl, R2 = Me (e); R1 =
3,4-Me2, R2 = Me (f). X, R3 = PhC(O)CH2, Hlg = Br (a); R3 = 4-MeC6H4NHC(O)CH2, Hlg = Cl (b); XI, R3 = PhC(O)CH2 (a),
4-MeC6H4NHC(O)CH2 (b).
phorus pentasulfide gave 2-aryl-2,6-dihydro-7H-pyra-
zolo[3,4-d]pyridazine-7-thiones VIIIa–VIIIf and IXa–
IXf (Scheme 5). These reactions required fairly severe
conditions, heating in boiling pyridine for 4 h. We also
examined regioselectivity in the alkylation of pyra-
zolopyridazinones VI and VII and pyrazolopyridazine-
thione VIIIa with dimethyl sulfate, chloroacetanilide
(Xa), and bromoacetophenone (Xb). The alkylation of
VI and VIII was carried out by heating the reactants in
boiling dioxane or DMF in the presence of a base. The
reactions were selective: compounds VI gave rise to
the corresponding N-substituted derivatives, while the
alkylation of VIIIa occurred exclusively at the sulfur
atom, and the products were isolated in high yields. By
treatment of compounds VIa and VId–VIh with di-
VII can be obtained by reactions of aldehydo and oxo
esters with hydrazine and its derivatives. In the pyra-
zole series, oxo esters were mostly studied. Among
pyrazole derivatives, reactions with oxo esters were
mainly reported [24–29]. Compounds IV and V fairly
readily reacted with hydrazine and methylhydrazine to
produce pyrazolopyridazines VIa–VIk and VIIa–
1
VIIg, respectively, in 57–94% yield. The H NMR
spectra of the products contained singlets from the 3-H
and 4-H protons at δ 8.25–8.26 and 9.10–9.14 ppm,
respectively.
Pyrazolopyridazines VIa–VIk and VIIa–VIIg
turned out to readily undergo further transformations
to obtain new compounds containing the pyrazolo-
[3,4-d]pyridazine system. Their reactions with phos-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MOLECULAR DESIGN OF PYRAZOLO[3,4-d]PYRIDAZINES
1355
3
1.33 t (3H, CH3CH2, J = 6.8 Hz), 2.06 s (3H, CH3),
methyl sulfate we obtained pyrazolopyridazines VIIa
and VIIc–VIIg which were identical to those synthe-
sized by cyclization of pyrazoles IV and V with meth-
ylhydrazine. Analogous reaction with pyrazolopyrida-
zinethione VIIIa gave methylsulfanyl derivative XII
rather than N-methyl isomer IXa. N-Alkylation of
structurally related compounds was described in
[30–32]. The 1H NMR spectrum of pyrazolopyridazine
XIII obtained by reaction of VIIIa with bromoaceto-
phenone lacked signal from methylene protons, but
two singlets were present at δ 6.64 and 14.71 ppm;
presumably, compound XIII in DMSO exists in the
enol form.
3
4.20 q (2H, CH2O, J = 6.8 Hz), 6.81–6.85 m (1H,
arom), 7.19–7.28 m (4H, Harom), 9.65 s (1H, NH).
Found, %: C 63.77; H 6.62; N 13.42. C11H14N2O2. Cal-
culated, %: C 64.06; H 6.84; N 13.58.
H
Ethyl 2-[(3-methylphenyl)hydrazono]propionate
(IIIb). Yield 61%, mp 77°C. Found, %: C 65.22;
H 7.24; N 12.84. C12H16N2O2. Calculated, %: C 65.43;
H 7.32; N 12.72.
Ethyl 2-[(4-chlorophenyl)hydrazono]propionate
(IIIc). Yield 64%, mp 127–128°C. 1H NMR spectrum,
δ, ppm: 1.32 t (3H, CH3CH2, 3J = 7.2 Hz), 2.05 s (3H,
CH3), 4.20 q (2H, CH2O, J = 7.2 Hz), 7.19 d (2H,
arom, J = 8.8 Hz), 7.26 d (2H, Harom, J = 8.8 Hz),
9.76 s (1H, NH). Found, %: C 54.46; H 5.32; N 11.65.
C11H13ClN2O2. Calculated, %: C 54.89; H 5.44;
N 11.64.
3
3
3
H
Ph
N
Ph
N
N
N
S
O
S
OH
Ph
Ethyl chloro(phenylhydrazono)acetate (IIId).
1
N
N
N
N
Yield 65%, mp 77°C. H NMR spectrum, δ, ppm:
3
3
Ph
1.36 t (3H, CH3, J = 7.2 Hz), 4.30 q (2H, CH2, J =
3
XIII
7.2 Hz), 6.94 t (1H, Harom, J = 7.6 Hz), 7.26 t (2H,
arom, J = 7.6 Hz), 7.37 d (2H, Harom, J = 7.6 Hz),
3
3
H
To conclude, we have developed convenient proce-
dures for the synthesis of 3,4-R12-6-R2-2-aryl-2,6-di-
hydro-7H-pyrazolo[3,4-d]pyridazin-7-ones and 7-(R3-
sulfanyl)-2-phenyl-2H-pyrazolo[3,4-d]pyridazines in
high yields from accessible starting compounds.
10.32 s (1H, NH). Found, %: C 52.72; H 4.75;
N 12.07. C10H11ClN2O2. Calculated, %: C 52.99;
H 4.89; N 12.36.
Ethyl chloro[(4-fluorophenyl)hydrazono]acetate
1
(IIIe). Yield 77%, mp 109°C. H NMR spectrum, δ,
3
ppm: 1.36 t (3H, CH3, J = 6.8 Hz), 4.30 q (2H, CH2,
EXPERIMENTAL
3
3J = 6.8 Hz), 7.02 t (2H, Harom, J = 8.8 Hz), 7.37 d.d
1
(2H, Harom, JHH = 8.8, JHF = 4.8 Hz), 10.37 s (1H, NH).
Found, %: C 48.96; H 3.95; N 11.53. C10H10ClFN2O2.
Calculated, %: C 49.09; H 4.12; N 11.45.
The H NMR spectra were recorded from solutions
in DMSO-d6 on a Varian Mercury spectrometer
(400 MHz) using TMS as internal reference.
Ethyl chloro[(2-chlorophenyl)hydrazono]acetate
Ethyl 2-(arylhydrazono)propionates IIIa–IIIc
and ethyl (arylhydrazono)chloroacetates IIId–IIIl
(general procedure). A solution of 0.02 mol of the
corresponding aromatic amine in 8 ml of dilute (1:1)
hydrochloric acid was cooled to 0°C, and a solution of
1.52 g (0.022 mol) of sodium nitrite in 10 ml of water
was added dropwise under stirring. The resulting solu-
tion of diazonium salt Ia–Ij was added dropwise to
a cold solution of 2.88 g (0.02 mol) of ethyl 2-methyl-
4-oxobutanoate (IIa) or 3.29 g (0.02 mol) of 2-chloro-
4-oxobutanoate (IIb) and 2.46 g (0.03 mol) of sodium
acetate in 60 ml of aqueous ethanol (9:1). The mixture
was stirred for 4 h and poured into 500 ml of water,
and the precipitate was filtered off, dried, and recrys-
tallized from ethanol.
1
(IIIf). Yield 89%, mp 90°C. H NMR spectrum, δ,
3
ppm: 1.38 t (3H, CH3, J = 7.2 Hz), 4.34 q (2H, CH2,
3J = 7.2 Hz), 7.03 d.t (1H, Harom, 4J = 1.2, 3J = 8.0 Hz),
7.33 d.t (1H, Har3om, 4J = 1.2, 3J = 8.0 Hz), 7.40 d.d (1H,
4
4
H
arom, J = 1.2, J = 8.0 Hz), 7.55 d.d (1H, Harom, J =
1.2, 3J = 8.0 Hz), 8.86 s (1H, NH). Found, %: C 46.23;
H 3.69; N 10.55. C10H10Cl2N2O2. Calculated, %:
C 46.00; H 3.86; N 10.73.
Ethyl chloro[(3-chlorophenyl)hydrazono]acetate
1
(IIIg). Yield 72%, mp 96°C. H NMR spectrum, δ,
3
ppm: 1.37 t (3H, CH3, J = 7.2 Hz), 4.31 q (2H, CH2,
3
3J = 7.2 Hz), 6.92 d (1H, Harom, J = 8.0 Hz), 7.24 t
3
3
(1H, Harom, J = 8.0 Hz), 7.30 d (1H, Harom, J =
8.0 Hz), 7.37 s (1H, Harom), 10.48 s (1H, NH). Found,
%: C 45.77; H 3.84; N 10.59. C10H10Cl2N2O2. Calcu-
lated, %: C 46.00; H 3.86; N 10.73.
Ethyl 2-(phenylhydrazono)propionate (IIIa).
1
Yield 88%, mp 118°C. H NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MATIICHUK et al.
The mixture was cooled, poured onto 20 g of ice, and
1356
Ethyl chloro[(4-chlorophenyl)hydrazono]acetate
(IIIh). Yield 75%, mp 143–145°C. 1H NMR spectrum,
neutralized with solid potassium carbonate. The pre-
cipitate was filtered off, dried, and recrystallized from
ethanol.
3
δ, ppm: 1.36 t (3H, CH3, J = 7.2 Hz), 4.30 q (2H,
CH2, J = 7.2 Hz), 7.25 d (2H, Harom, J = 8.4 Hz),
3
3
3
7.36 d (2H, Harom, J = 8.4 Hz), 10.44 s (1H, NH).
Found, %: C 45.89; H 3.67; N 10.57. C10H10Cl2N2O2.
Calculated, %: C 46.00; H 3.86; N 10.73.
Ethyl 4-formyl-1-phenyl-1H-pyrazole-3-carbox-
1
ylate (IVa). Yield 85%, mp 98°C. H NMR spectrum,
δ, ppm: 1.42 t (3H, CH3CH2, 3J = 7.2 Hz), 4.42 q (2H,
3
3
CH2O, J = 7.2 Hz), 7.40 t (1H, Harom, J = 7.8 Hz)
Ethyl chloro[(3,4-dimethylphenyl)hydrazono]-
3
3
1
7.51 t (2H, Harom, J = 7.8 Hz), 7.98 d (2H, Harom, J =
7.8 Hz), 9.17 s (1H, 5-H), 10.31 s (1H, CHO). Found,
%: C 63.67; H 4.84; N 11.32. C13H12N2O3. Calculated,
%: C 63.93; H 4.95; N 11.47.
acetate (IIIi). Yield 70%, mp 96°C. H NMR spec-
trum, δ, ppm: 1.28 t (3H, CH3CH2, 3J = 7.2 Hz), 2.17 s
3
(3H, CH3), 2.19 s (3H, CH3), 4.27 q (2H, CH2O, J =
7.2 Hz), 7.06 br.s (2H, Harom), 7.14 s (1H, Harom),
10.36 s (1H, NH). Found, %: C 56.42; H 5.84;
N 10.79. C12H15ClN2O2. Calculated, %: C 56.59;
H 5.94; N 11.00.
Ethyl 4-formyl-1-(3-methylphenyl)-1H-pyrazole-
3-carboxylate (IVb). Yield 73%, mp 96–97°C.
3
1H NMR spectrum, δ, ppm: 1.43 t (3H, CH3CH2, J =
3
7.2 Hz), 2.44 s (3H, CH3), 4.43 q (2H, CH2O, J =
Ethyl chloro[(4-methoxyphenyl)hydrazono]ace-
3
tate (IIIj). Yield 72%, mp 94°C. 1H NMR spectrum, δ,
7.2 Hz), 7.21 d (1H, Harom, J = 8.0 Hz), 7.38 t (1H,
3
3
3
H
arom, J = 8.0 Hz), 7.76 d (1H, Harom, J = 8.0 Hz),
ppm: 1.29 t (3H, CH3CH2, J = 7.2 Hz), 3.71 s (3H,
CH3O), 4.27 q (2H, CH2O, J = 7.2 Hz), 6.91 d (2H,
Harom, J = 7.6 Hz), 7.28 d (2H, Harom, J = 7.6 Hz),
10.40 s (1H, NH). Found, %: C 51.23; H 5.01;
N 10.74. C11H13ClN2O3. Calculated, %: C 51.47;
H 5.10; N 10.91.
7.81 s (1H, Harom), 9.13 s (1H, C5H), 10.31 s (1H,
CHO). Found, %: C 64.93; H 5.31; N 10.76.
C14H14N2O3. Calculated, %: C 65.11; H 5.46; N 10.85.
3
3
3
Ethyl 1-(4-chlorophenyl)-4-formyl-1H-pyrazole-
3-carboxylate (IVc). Yield 68%, mp 127–128°C.
3
1H NMR spectrum, δ, ppm: 1.34 t (3H, CH3CH2, J =
Ethyl chloro[(3-trifluoromethylphenyl)hydra-
3
7.2 Hz), 4.39 q (2H, CH2O, J = 7.2Hz), 7.60 d (2H,
zono]acetate (IIIk). Yield 80%, mp 131–133°C.
3
3
3
1H NMR spectrum, δ, ppm: 1.37 t (3H, CH3, J =
H
arom, J = 8.0 Hz), 7.98 d (2H, Harom, J = 8.0 Hz),
3
9.22 s (1H, 5-H), 10.26 s (1H, CHO). Found, %:
C 55.89; H 3.83; N 10.11. C13H11ClN2O3. Calculated,
%: C 56.03; H 3.98; N 10.05.
7.2 Hz), 4.31 q (2H, CH2, J = 7.2 Hz), 7.21 d (1H,
Harom, J = 8.0 Hz), 7.46 t (1H, Harom, J = 8.0 Hz),
7.62 d (1H, Harom, J = 8.0 Hz), 7.66 s (1H, Harom),
3
3
3
10.64 s (1H, NH). Found, %: C 44.51; H 3.38; N 9.37.
C11H10ClF3N2O2. Calculated, %: C 44.84; H 3.42;
N 9.51.
Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-
carboxylates Va–Vi (general procedure). Acetyl-
acetone, 5.2 ml (0.05 mol), was added to a solution of
3.4 g (0.05 mol) of sodium ethoxide in 40 ml of
anhydrous ethanol, the mixture was kept for 7 h at
room temperature, 0.05 mol of finely powdered ethyl
(arylhydrazono)chloroacetate IIId–IIIl was added, and
the mixture was stirred for 4 h, left to stand for 18 h at
room temperature, and diluted with 200 ml of water.
The precipitate was filtered off, dried, and recrystal-
lized from ethanol.
Methyl 2-[2-(1-chloro-2-ethoxy-2-oxoethylidene)-
hydrazino]benzoate (IIIl). Yield 93%, mp 105–
1
106°C. H NMR spectrum, δ, ppm: 1.38 t (3H,
CH3CH2, 3J = 7.2 Hz), 3.93 s (3H, OCH33), 4.34 q (2H,
3
CH2O, J = 7.2 Hz), 7.04 t (1H, Harom, J = 8.0 Hz),
3
7.59 t (1H, Harom, J = 8.0 Hz), 7.70 d (1H, Harom
,
3J = 8.0 Hz), 7.96 d (1H, Harom, J = 8.0 Hz), 11.71 s
(1H, NH). Found, %: C 50.75; H 4.49; N 9.64.
C12H13ClN2O4. Calculated, %: C 50.63; H 4.60; N 9.84.
3
Ethyl 4-acetyl-5-methyl-1-phenyl-1H-pyrazole-3-
carboxylate (Va). Oily substance. Yield 65%. Found,
%: C 68.35; H 6.01; N 10.20. C15H16N2O3. Calculated,
%: C 66.16; H 5.92; N 10.29.
Ethyl 1-aryl-4-formyl-1H-pyrazole-3-carbox-
ylates IVa–IVc (general procedure). Phosphoryl
chloride, 1.8 ml (0.02 mol), was added under stirring
to 1.6 ml of dimethylformamide cooled to 0°C. The
mixture was stirred for 0.5 h at that temperature, a so-
lution of 0.01 mol ethyl 2-(arylhydrazono)propionate
IIIa–IIIc in 5 ml of DMF was added, and the mixture
was stirred for 1 h at 0 to 10°C and for 4 h at 70°C.
Ethyl 4-acetyl-1-(4-fluorophenyl)-5-methyl-1H-
pyrazole-3-carboxylate (Vb). Yield 75%, mp 90–
91°C. 1H NMR spectrum, δ, ppm: 1.37 t (3H, CH3CH2,
3J = 7.2 Hz), 2.39 s (3H, CH3), 2.47 s (3H, CH3),
3
4.36 q (2H, CH2O, J = 7.2 Hz), 7.33 pseudotriplet
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MOLECULAR DESIGN OF PYRAZOLO[3,4-d]PYRIDAZINES
1357
(2H, Harom), 7.53–7.59 m (2H, Harom). Found, %:
C 61.82; H 5.23; N 9.49. C15H15FN2O3. Calculated, %:
C 62.06; H 5.21; N 9.65.
Ethyl 4-acetyl-1-(2-methoxycarbonylphenyl)-5-
methyl-1H-pyrazole-3-carboxylate (Vi). Yield 57%,
1
mp 93–95°C. H NMR spectrum, δ, ppm: 1.37 t (3H,
3
CH3CH2, J = 7.2 Hz), 2.24 s (3H, CH3), 2.50 s (3H,
Ethyl 4-acetyl-1-(2-chlorophenyl)-5-methyl-1H-
pyrazole-3-carboxylate (Vc). Yield 67%, mp 83–
84°C. 1H NMR spectrum, δ, ppm: 1.38 t (3H, CH3CH2,
3J = 7.2 Hz), 2.24 s (3H, CH3), 2.50 s (3H, CH3), 4.36 q
3
CH3), 3.68 s (3H, CH3O), 4.34 q (2H, CH2O, J =
3
7.2 Hz), 7.54 d (1H, Harom, J = 7.6 Hz), 7.71 t (1H,
3
3
Harom, J = 7.6 Hz), 7.80 t (1H, Harom, J = 7.6 Hz),
3
3
8.03 d (1H, Harom, J = 7.6 Hz). Found, %: C 61.88;
(2H, CH2O, J = 7.2 Hz), 7.55–7.69 m (4H, Harom).
H 5.22; N 8.45. C17H18N2O5. Calculated, %: C 61.81;
H 5.49; N 8.48.
Found, %: C 58.56; H 4.85; N 9.02. C15H15ClN2O3.
Calculated, %: C 58.73; H 4.93; N 9.13.
2-Aryl-2,6-dihydro-7H-pyrazolo[3,4-d]pyrida-
zin-7-ones VIa–VIk and VIIa–VIIg (general proce-
dure). A solution of 0.01 mol of pyrazole IVa–IVc or
Va–Vi in 20 ml of ethanol was mixed with 1.46 ml
(0.03 mol) of hydrazine hydrate or 0.80 ml (0.015 mol)
of methylhydrazine. The mixture was heated for 5 h
under reflux and cooled, and the precipitate was fil-
tered off, dried, and recrystallized from DMF.
Ethyl 4-acetyl-1-(3-chlorophenyl)-5-methyl-1H-
pyrazole-3-carboxylate (Vd). Yield 77%, mp 67°C.
3
1H NMR spectrum, δ, ppm: 1.38 t (3H, CH3CH2, J =
7.2 Hz), 2.43 s (3H, CH3), 2.47 s (3H, CH3), 4.36 q
3
(2H, CH2O, J = 7.2 Hz), 7.49–7.61 m (4H, Harom).
Found, %: C 58.69; H 4.86; N 9.01. C15H15ClN2O3.
Calculated, %: C 58.73; H 4.93; N 9.13.
Ethyl 4-acetyl-1-(4-chlorophenyl)-5-methyl-1H-
pyrazole-3-carboxylate (Ve). Yield 57%, mp 91°C.
2-Phenyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyrida-
zin-7-one (VIa). Yield 58%, mp 259–260°C. 1H NMR
3
1H NMR spectrum, δ, ppm: 1.37 t (3H, CH3CH2, J =
3
spectrum, δ, ppm: 7.47 t (1H, Harom, J = 7.6 Hz),
7.2 Hz), 2.41 s (3H, CH3), 2.46 s (3H, CH3), 4.36 q
(2H, CH2O, 3J = 7.2 Hz), 7.57 br.s (4H, Harom). Found,
%: C 58.51; H 4.80; N 9.05. C15H15ClN2O3. Calculat-
ed, %: C 58.73; H 4.93; N 9.13.
3
3
7.58 t (2H, Harom, J = 7.6 Hz), 8.04 d (2H, Harom, J =
7.6 Hz), 8.26 s (1H, 4-H), 9.11 s (1H, 3-H), 12.26 s
(1H, NH). Found, %: C 62.32; H 3.68; N 26.26.
C11H8N4O. Calculated, %: C 62.26; H 3.80; N 26.40.
Ethyl 4-acetyl-1-(3,4-dimethylphenyl)-5-methyl-
2-(4-Chlorophenyl)-2,6-dihydro-7H-pyrazolo-
[3,4-d]pyridazin-7-one (VIb). Yield 67%, mp 351°C.
1H-pyrazole-3-carboxylate (Vf). Yield 83%, mp 112–
1
114°C. H NMR spectrum, δ, ppm: 1.37 t (3H,
3
1H NMR spectrum, δ, ppm: 7.59 d (2H, Harom, J =
3
CH3CH2, J = 7.2 Hz), 2.33 s (6H, CH3), 2.36 s (3H,
3
3
8.4 Hz), 8.09 d (2H, Harom, J = 8.4 Hz), 8.25 s (1H,
CH3), 2.45 s (3H, CH3), 4.35 q (2H, CH2O, J =
3
4
4-H), 9.14 s (1H, 3-H), 12.27 s (1H, NH). Found, %:
C 53.30; H 2.69; N 22.86. C11H7ClN4O. Calculated, %:
C 53.57; H 2.86; N 22.71.
7.2 Hz), 7.18 d.d (1H, Harom, J = 8.0, J = 2.0 Hz),
7.25 d (1H, Harom, 4J = 2.0 Hz), 7.30 d (1H, Harom, 3J =
8.0 Hz). Found, %: C 67.85; H 6.53; N 9.13.
C17H20N2O3. Calculated, %: C 67.98; H 6.71; N 9.33.
3,4-Dimethyl-2-phenyl-2,6-dihydro-7H-pyrazolo-
[3,4-d]pyridazin-7-one (VIc). Yield 72%, mp >300°C.
1H NMR spectrum, δ, ppm: 2.49 s (3H, CH3), 2.63 s
(3H, CH3), 7.55–7.60 m (5H, Harom), 11.87 s (1H, NH).
Found, %: C 64.68; H 4.95; N 23.12. C13H12N4O. Cal-
culated, %: C 64.99; H 5.03; N 23.32.
Ethyl 4-acetyl-1-(4-methoxyphenyl)-5-methyl-
1H-pyrazole-3-carboxylate (Vg). Yield 65%,
1
mp 74°C. H NMR spectrum, δ, ppm: 1.37 t (3H,
3
CH3CH2, J = 7.2 Hz), 2.36 s (3H, CH3), 2.46 s (3H,
3
CH3), 3.86 s (3H, CH3O), 4.35 q (2H, CH2O, J =
3
7.2 Hz), 7.06 d (2H, Harom, J = 8.8 Hz), 7.40 d (2H,
2-(4-Fluorophenyl)-3,4-dimethyl-2,6-dihydro-
3
Harom, J = 8.8 Hz). Found, %: C 63.65; H 5.84;
7H-pyrazolo[3,4-d]pyridazin-7-one (VId). Yield
1
N 9.10. C16H18N2O4. Calculated, %: C 63.57; H 6.00;
N 9.27.
90%, mp 318°C. H NMR spectrum, δ, ppm: 2.49 s
(3H, CH3), 2.62 s (3H, CH3), 7.36 pseudotriplet (2H,
Harom), 7.62–7.67 m (2H, Harom), 11.85 s (1H, NH).
Found, %: C 60.51; H 4.17; N 21.78. C13H11FN4O.
Calculated, %: C 60.46; H 4.29; N 21.69.
Ethyl 4-acetyl-5-methyl-1-(3-trifluoromethyl-
phenyl)-1H-pyrazole-3-carboxylate (Vh). Yield 76%,
1
mp 70°C. H NMR spectrum, δ, ppm: 1.39 t (3H,
3
CH3CH2, J = 7.2 Hz), 2.44 s (3H, CH3), 2.47 s (3H,
2-(2-Chlorophenyl)-3,4-dimethyl-2,6-dihydro-
3
CH3), 4.37 q (2H, CH2, J = 7.2 Hz), 7.78–7.88 m
7H-pyrazolo[3,4-d]pyridazin-7-one (VIe). Yield
1
(4H, Harom). Found, %: C 56.74; H 5.38; N 8.16.
C16H15F3N2O3. Calculated, %: C 56.47; H 4.44; N 8.23.
77%, mp 336–338°C. H NMR spectrum, δ, ppm:
2.46 s (3H, CH3), 2.49 s (3H, CH3), 7.57–7.73 m (4H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MATIICHUK et al.
1358
1
Harom), 11.92 s (1H, NH). Found, %: C 56.69; H 3.97;
N 20.31. C13H11ClN4O. Calculated, %: C 56.84;
H 4.04; N 20.39.
195°C. H NMR spectrum, δ, ppm: 3.71 s (3H, CH3),
3
3
7.45 t (1H, Harom, J = 7.6 Hz), 7.56 t (2H, Harom, J =
7.6 Hz), 8.02 d (2H, Harom, J = 7.6 Hz), 8.26 s (1H,
3
4-H), 9.10 s (1H, 3-H). Found, %: C 63.86; H 4.34;
N 24.53. C12H10N4O. Calculated, %: C 63.71; H 4.46;
N 24.76.
2-(3-Chlorophenyl)-3,4-dimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazin-7-one (VIf). Yield
1
84%, mp 267–269°C. H NMR spectrum, δ, ppm:
2.49 s (3H, CH3), 2.66 s (3H, CH3), 7.56–7.65 m (3H,
2-(4-Chlorophenyl)-6-methyl-2,6-dihydro-7H-
pyrazolo[3,4-d]pyridazin-7-one (VIIb). Yield 70%,
Harom), 7.69 br.s (1H, Harom), 11.88 s (1H, NH). Found,
1
%: C 56.58; H 3.92; N 20.33. C13H11ClN4O. Calculat-
ed, %: C 56.84; H 4.04; N 20.39.
mp 293–295°C. H NMR spectrum, δ, ppm: 3.72 s
(3H, CH3), 7.58 d (2H, Harom, 3J = 8.4 Hz), 8.08 d (2H,
H
arom, 3J = 8.4 Hz), 8.25 s (1H, 4-H), 9.13 s (1H, 3-H).
2-(4-Chlorophenyl)-3,4-dimethyl-2,6-dihydro-
Found, %: C 55.19; H 3.38; N 21.32. C12H9ClN4O.
Calculated, %: C 55.29; H 3.48; N 21.49.
7H-pyrazolo[3,4-d]pyridazin-7-one (VIg). Yield
1
79%, mp 295–297°C. H NMR spectrum, δ, ppm:
2.49 s (3H, CH3), 2.64 s (3H, CH3), 7.62–7.64 m
(4H, Harom), 11.88 s (1H, NH). Found, %: C 56.96;
H 3.90; N 20.31. C13H11ClN4O. Calculated, %:
C 56.84; H 4.04; N 20.39.
2-(4-Fluorophenyl)-3,4,6-trimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazin-7-one (VIIc). Yield
1
73%, mp 225–227°C. H NMR spectrum, δ, ppm:
2.49 s (3H, CH3), 2.61 s (3H, CH3), 3.62 s (3H,
CH3N), 7.36 pseudotriplet (2H, Harom), 7.61–7.66 m
(2H, Harom). Found, %: C 61.81; H 4.69; N 20.41.
C14H13FN4O. Calculated, %: C 61.76; H 4.81; N 20.58.
2-(3,4-Dimethylphenyl)-3,4-dimethyl-2,6-dihy-
dro-7H-pyrazolo[3,4-d]pyridazin-7-one (VIh). Yield
1
90%, mp >300°C. H NMR spectrum, δ, ppm: 2.36 s
(6H, CH3), 2.50 s (3H, CH3), 2.62 s (3H, CH3), 7.24–
7.28 m (1H, Harom), 7.32–7.36 m (2H, Harom), 11.86 s
(1H, NH). Found, %: C 67.32; H 5.97; N 20.70.
C15H16N4O. Calculated, %: C 67.15; H 6.01; N 20.88.
2-(2-Chlorophenyl)-3,4,6-trimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazin-7-one (VIId). Yield
1
57%, mp 255–257°C. H NMR spectrum, δ, ppm:
2.47 s (3H, CH3), 2.52 s (3H, CH3), 3.64 s (3H,
CH3N), 7.58–7.75 m (4H, Harom). Found, %: C 58.35;
H 4.48; N 19.19. C14H13ClN4O. Calculated, %:
C 58.24; H 4.54; N 19.40.
2-(4-Methoxyphenyl)-3,4-dimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazin-7-one (VIi). Yield 89%,
1
mp 292–293°C. H NMR spectrum, δ, ppm: 2.50 s
(3H, CH3), 2.61 s (3H, CH3), 3.88 s (3H, CH3O),
7.10 d (2H, Harom, 3J = 8.4 Hz), 7.47 d (2H, Harom, 3J =
8.4 Hz), 11.83 s (1H, NH). Found, %: C 61.92; H 5.20;
N 20.61. C14H14N4O2. Calculated, %: C 62.21; H 5.22;
N 20.73.
2-(3-Chlorophenyl)-3,4,6-trimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazin-7-one (VIIe). Yield
1
64%, mp 275–277°C. H NMR spectrum, δ, ppm:
2.52 s (3H, CH3), 2.67 s (3H, CH3), 3.64 s (3H,
CH3N), 7.56–7.65 m (3H, Harom), 7.68 br.s (1H, Harom).
Found, %: C 57.98; H 4.43; N 19.45. C14H13ClN4O.
Calculated, %: C 58.24; H 4.54; N 19.40.
3,4-Dimethyl-2-(3-trifluoromethylphenyl)-2,6-di-
hydro-7H-pyrazolo[3,4-d]pyridazin-7-one (VIj).
1
Yield 67%, mp 241–242°C. H NMR spectrum, δ,
2-(4-Chlorophenyl)-3,4,6-trimethyl-2,6-dihydro-
ppm: 2.49 s (3H, CH3), 2.66 s (3H, CH3), 7.84–7.95 m
(4H, Harom), 11.92 s (1H, NH). Found, %: C 54.74;
H 3.46; N 18.11. C14H11F3N4O. Calculated, %:
C 54.55; H 3.60; N 18.17.
7H-pyrazolo[3,4-d]pyridazin-7-one (VIIf). Yield
1
94%, mp 268–270°C. H NMR spectrum, δ, ppm:
2.50 s (3H, CH3), 2.64 s (3H, CH3), 3.63 s (3H,
CH3N), 7.62 br.s (4H, Harom). Found, %: C 58.41;
H 4.43; N 19.24. C14H13ClN4O. Calculated, %:
C 58.24; H 4.54; N 19.40.
2-(3,4-Dimethyl-7-oxo-6,7-dihydro-2H-pyrazolo-
[3,4-d]pyridazin-2-yl)benzohydrazide (VIk). Yield
1
64%, mp 298–299°C. H NMR spectrum, δ, ppm:
2-(3,4-Dimethylphenyl)-3,4,6-trimethyl-2,6-
2.49 s (3H, CH3), 3.12 s (3H, CH3), 4.21 s (2H,
NHNH2), 7.46 d (1H, Harom, 3J = 7.6 Hz), 7.64–7.69 m
(3H, Harom), 9.70 s (1H, NHNH2), 11.84 s (1H, NH).
Found, %: C 56.21; H 4.62; N 28.02. C14H14N6O2. Cal-
culated, %: C 56.37; H 4.73; N 28.17.
dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (VIIg).
1
Yield 88%, mp 224–225°C. H NMR spectrum, δ,
ppm: 2.35 s (6H, CH3), 2.49 s (3H, CH3), 2.61 s (3H,
CH3), 3.63 s (3H, CH3N), 7.22–7.26 m (1H, Harom),
7.30–7.33 m (2H, Harom). Found, %: C 67.82; H 6.31;
N 19.56. C16H18N4O. Calculated, %: C 68.06; H 6.43;
N 19.84.
6-Methyl-2-phenyl-2,6-dihydro-7H-pyrazolo-
[3,4-d]pyridazin-7-one (VIIa). Yield 86%, mp 194–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MOLECULAR DESIGN OF PYRAZOLO[3,4-d]PYRIDAZINES
1359
1
Yield 84%, mp 337–338°C. H NMR spectrum, δ,
ppm: 2.36 s (6H, CH3), 2.57 s (3H, CH3), 2.65 s (3H,
CH3), 7.29–7.35 m (3H, Harom), 13.57 s (1H, NH).
Found, %: C 63.42; H 5.52; N 19.58; S 11.39.
C15H16N4S. Calculated, %: C 63.35; H 5.67; N 19.70;
S 11.28.
2-Aryl-2,6-dihydro-7H-pyrazolo[3,4-d]pyrida-
zine-7-thiones VIIIa–VIIIf and IXa–IXf (general
procedure). A mixture of 0.007 mol of compound VIa,
VId–VIh, VIIa, or VIIc–VIIg, 4.66 g (0.021 mol) of
P2S5, and 30 ml of pyridine was heated for 4 h. The
mixture was cooled and diluted with 200 ml of water,
and the precipitate was filtered off, dried, and recrys-
tallized from DMF.
6-Methyl-2-phenyl-2,6-dihydro-7H-pyrazolo-
[3,4-d]pyridazine-7-thione (IXa). Yield 76%,
1
mp 186°C. H NMR spectrum, δ, ppm: 4.15 s (3H,
2-Phenyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyrida-
zine-7-thione (VIIIa). Yield 80%, mp 255–256°C.
CH3), 7.48 t (1H, Harom, 3J = 7.2 Hz), 7.58 t (2H, Harom
,
3J = 7.2 Hz), 8.08 d (2H, Harom, J = 7.2 Hz), 8.66 s
(1H, 4-H), 9.22 s (1H, 3-H). Found, %: C 59.58;
H 4.05; N 22.84; S 13.07. C12H10N4S. Calculated, %:
C 59.48; H 4.16; N 23.12; S 13.23.
3
3
1H NMR spectrum, δ, ppm: 7.49 t (1H, Harom, J =
3
8.0 Hz), 7.58 t (2H, Harom, J = 8.0 Hz), 8.08 d (2H,
H
arom, 3J = 8.0 Hz), 8.66 s (1H, 4-H), 9.23 s (1H, 3-H),
13.89 s (1H, NH). Found, %: C 57.75; H 3.45;
N 24.31; S 14.19. C11H8N4S. Calculated, %: C 57.88;
H 3.53; N 24.54; S 14.05.
2-(4-Fluorophenyl)-3,4,6-trimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazine-7-thione (IXb). Yield
71%, mp 222–223°C. H NMR spectrum, δ, ppm:
1
2-(4-Fluorophenyl)-3,4-dimethyl-2,6-dihydro-
2.59 s (3H, CH3), 2.66 s (3H, CH3), 4.08 s (3H,
CH3N), 7.37 pseudotriplet (2H, Harom), 7.66 d.d (2H,
7H-pyrazolo[3,4-d]pyridazine-7-thione (VIIIb).
Yield 69%, mp >350°C. H NMR spectrum, δ, ppm:
1
H
arom, JHH = 8.4, JHF = 4.8 Hz). Found, %: C 58.43;
2.59 s (3H, CH3), 2.67 s (3H, CH3), 7.37–7.42 m
(2H, Harom), 7.67–7.70 m (2H, Harom), 13.61 s (1H,
NH). Found, %: C 56.75; H 3.98; N 20.20; S 11.80.
C13H11FN4S. Calculated, %: C 56.92; H 4.04; N 20.42;
S 11.69.
H 4.41; N 19.22; S 10.98. C14H13FN4S. Calculated, %:
C 58.32; H 4.54; N 19.43; S 11.12.
2-(2-Chlorophenyl)-3,4,6-trimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazine-7-thione (IXc). Yield
85%, mp 246–248°C. H NMR spectrum, δ, ppm:
1
2-(2-Chlorophenyl)-3,4-dimethyl-2,6-dihydro-
2.51 s (3H, CH3), 2.61 s (3H, CH3), 4.09 s (3H,
CH3N), 7.62–7.73 m (4H, Harom). Found, %: C 55.02;
H 4.18; N 18.16; S 10.35. C14H13ClN4S. Calculated,
%: C 55.17; H 4.30; N 18.38; S 10.52.
7H-pyrazolo[3,4-d]pyridazine-7-thione (VIIIc).
Yield 82%, mp >350°C. H NMR spectrum, δ, ppm:
2.52 s (3H, CH3), 2.60 s (3H, CH3), 7.60–7.75 m (4H,
1
Harom), 13.64 s (1H, NH). Found, %: C 53.81; H 3.68;
N 19.04; S 11.12. C13H11ClN4S. Calculated, %:
C 53.70; H 3.81; N 19.27; S 11.03.
2-(4-Chlorophenyl)-3,4,6-trimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazine-7-thione (IXd). Yield
1
72%, mp 245–247°C. H NMR spectrum, δ, ppm:
2-(3-Chlorophenyl)-3,4-dimethyl-2,6-dihydro-
2.59 s (3H, CH3), 2.69 s (3H, CH3), 4.08 s (3H,
CH3N), 7.59–7.69 m (4H, Harom). Found, %: C 55.21;
H 4.20; N 18.08; S 10.39. C14H13ClN4S. Calculated,
%: C 55.17; H 4.30; N 18.38; S 10.52.
7H-pyrazolo[3,4-d]pyridazine-7-thione (VIIId).
Yield 84%, mp 315°C. H NMR spectrum, δ, ppm:
2.77 s (3H, CH3), 2.93 s (3H, CH3), 7.59–7.65 m (2H,
1
Harom), 7.72 br.s (1H, Harom), 7.91 s (1H, Harom), 13.65 s
(1H, NH). Found, %: C 53.95; H 3.72; N 19.06;
S 11.25. C13H11ClN4S. Calculated, %: C 53.70; H 3.81;
N 19.27; S 11.03.
2-(4-Chlorophenyl)-3,4,6-trimethyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazine-7-thione (IXe). Yield
1
87%, mp 263–265°C. H NMR spectrum, δ, ppm:
2.59 s (3H, CH3), 2.68 s (3H, CH3), 4.08 s (3H,
2-(4-Chlorophenyl)-3,4-dimethyl-2,6-dihydro-
3
CH3N), 7.60 d (2H, Harom, J = 8.4 Hz), 7.64 d (2H,
7H-pyrazolo[3,4-d]pyridazine-7-thione (VIIIe).
3
1
H
arom, J = 8.4 Hz). Found, %: C 54.94; H 4.21;
Yield 89%, mp >350°C. H NMR spectrum, δ, ppm:
2.59 s (3H, CH3), 2.69 s (3H, CH3), 7.64 d (2H, Harom
,
N 18.15; S 10.40. C14H13ClN4S. Calculated, %:
C 55.17; H 4.30; N 18.38; S 10.52.
3
3J = 8.6 Hz), 7.68 d (2H, Harom, J = 8.6 Hz), 13.63 s
(1H, NH). Found, %: C 53.84; H 3.69; N 19.10;
S 11.21. C13H11ClN4S. Calculated, %: C 53.70; H 3.81;
N 19.27; S 11.03.
2-(3,4-Dimethylphenyl)-3,4,6-trimethyl-2,6-dihy-
dro-7H-pyrazolo[3,4-d]pyridazine-7-thione (IXf).
1
Yield 86%, mp 216–217°C. H NMR spectrum, δ,
2-(3,4-Dimethylphenyl)-3,4-dimethyl-2,6-dihy-
dro-7H-pyrazolo[3,4-d]pyridazine-7-thione (VIIIf).
ppm: 2.35 s (6H, CH3), 2.59 s (3H, CH3), 2.65 s (3H,
CH3), 4.08 s (3H, CH3N), 7.28–7.33 m (3H, Harom).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MATIICHUK et al.
1360
1
Found, %: C 64.23; H 5.95; N 18.62; S 10.51.
C16H18N4S. Calculated, %: C 64.40; H 6.08; N 18.77;
S 10.74.
63%, mp 206–208°C. H NMR spectrum, δ, ppm:
2.74 s (3H, CH3), 7.50 t (1H, Harom, 3J = 8.0 Hz), 7.60 t
3
3
(2H, Harom, J = 8.0 Hz), 8.10 d (2H, Harom, J =
8.0 Hz), 9.28 s (1H, 4-H), 9.34 s (1H, 3-H). Found, %:
C 59.62; H 4.04; N 23.02; S 13.32. C12H10N4S. Cal-
culated, %: C 59.48; H 4.16; N 23.12; S 13.23.
2-Aryl-2,6-dihydro-7H-pyrazolo[3,4-d]pyrida-
zin-7-ones VIIa, VIIc–VIIg, XIa, and XIb (general
procedure). a. A mixture of 3.5 mmol of pyrazolo-
pyridazine VIa or VId–VIh, 0.4 ml (4.2 mmol) of
dimethyl sulfate, 0.14 g (3.5 mmol) of NaOH dis-
solved in 1 ml of water, and 10 ml of dioxane was
stirred for 4 h at 100°C. The mixture was cooled and
poured into 50 ml of water, and the precipitate was
filtered off, dried, and recrystallized from DMF. Com-
pounds VIIa and VIIc–VIIg thus obtained were iden-
tical to samples prepared as described above in the
1H NMR data and melting points; their elemental anal-
yses were consistent with the calculated values.
1-Phenyl-2-(2-phenyl-2H-pyrazolo[3,4-d]pyrida-
zin-7-ylsulfanyl)ethanone (XIII). A solution of 1 g
(4.4 mmol) of compound VIIIa in 10 ml of DMF was
mixed with 0.25 g (4.4 mmol) of potassium hydroxide,
the mixture was stirred for 30 min at 100°C, 0.88 g
(4.4 mmol) of phenacyl bromide (Xa) was added, and
the mixture was stirred for an additional 2 h. The mix-
ture was cooled and poured into 50 ml of water, and
the precipitate was filtered off, dried, and recrystal-
lized from DMF. Yield 48%, mp 236–238°C. 1H NMR
spectrum, δ, ppm: 6.64 s (1H, CH=), 7.48 br.s (4H,
b. A mixture of 1 g (4.7 mmol) of pyrazolopyrida-
zine VIa, 4.7 mmol of halogen derivative Xa or Xb,
0.65 g (4.7 mmol) of potassium carbonate, and 40 ml
of anhydrous DMF or dioxane was stirred for 4 h at
100°C. The mixture was cooled and poured into
200 ml of water, and the precipitate was filtered off,
dried, and recrystallized from DMF.
3
H
H
arom), 7.60 t (2H, Harom, J = 7.6 Hz), 7.99 d (2H,
arom, J = 6.4 Hz), 8.09 d (2H, Harom, J = 7.6 Hz),
3
3
8.48 s (1H, 4-H), 9.18 s (1H, 3-H), 14.71 s (1H, OH).
Found, %: C 65.60; H 3.94; N 16.02; S 9.41.
C19H14N4OS. Calculated, %: C 65.88; H 4.07; N 16.17;
S 9.26.
6-(2-Oxo-2-phenylethyl)-2-phenyl-2,6-dihydro-
REFERENCES
7H-pyrazolo[3,4-d]pyridazin-7-one (XIa). Yield
1
54%, mp 222–224°C. H NMR spectrum, δ, ppm:
1. Shim, J.-Y., Welsh, W.J., Cartier, E., Edwards, J.L., and
5.65 s (2H, CH2), 7.48 t (1H, Harom, 3J = 7.2 Hz), 7.55 t
Howlett, A.C., J. Med. Chem., 2002, vol. 45, p. 1447.
3
3
(2H, Harom, J = 7.6 Hz), 7.59 t (2H, Harom, J =
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3
8.0 Hz), 7.67 t (1H, Harom, J = 7.2 Hz), 8.05 d (2H,
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3
3
H
8.36 s (1H, 4-H), 9.18 s (1H, 3-H). Found, %: C 68.93;
H 4.15; N 16.75. C19H14N4O2. Calculated, %: C 69.08;
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3. Lange, J.H.M., Coolen, H.K.A.C., van Stuivenberg, H.H.,
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1
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