Transformations of 3-alkyl-4-(methoxyphenyl)-1H-pyrazole-5-diazonium salts

Article abstract of DOI:10.1134/S1070428009020092

The coupling of 3-alkyl-4-(methoxyphenyl)-1H-pyrazole-5-diazonium salts with acetylacetone followed by cyclization of the formed heterylhydrazones resulted in pyrazolo[5,1-c][1,2,4]triazines. The 4-(3,4-dimethoxyphenyl)-3- methyl-1H-pyrazole-5-diazonium s

Full text of DOI:10.1134/S1070428009020092

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 2, pp. 211−214. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © V.V. Didenko, V.A. Voronkova, Kh.S. Shikhaliev, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No.
2, pp. 223−226.
Transformations
of 3-Alkyl-4-(methoxyphenyl)-1H-pyrazole-5-diazonium Salts
V. V. Didenko, V.A. Voronkova, and Kh. S. Shikhaliev
Voronezh State University, Voronezh, 394006 Russia
e-mail: chocd261@chem.vsu.ru
Received January 9, 2008
Abstract—The coupling of 3-alkyl-4-(methoxyphenyl)-1H-pyrazole-5-diazonium salts with acetylacetone followed
by cyclization of the formed heterylhydrazones resulted in pyrazolo[5,1-c][1,2,4]triazines. The 4-(3,4-dimethoxy-
phenyl)-3-methyl-1H-pyrazole-5-diazonium salt was not involved into a similar reaction but suffered an
intramolecular azo coupling giving pyrazolo[3,4-c]-cinnoline.
DOI: 10.1134/S1070428009020092
an electrophilic attack (NH2, NH, SH,Ar, multiple carbon-
carbon bonds, etc.) are known to be considerably less
stable and prone to intramolecular cyclization yielding the
corresponding heterocycles [4–8]. This is also valid for
some pyrazolediazonium salts [9–13].
Diazopyrazoles are successfully used in buiding up
a series of polycyclic nitrogen heterocycles.Among these
compounds azo fused derivatives of 1,2,4-triazine,
structural analogs of natural purine bases, are well known.
The synthesis of pyrazolo[5,1-c][1,2,4]triazines consists
in the azo coupling of pyrazolediazonium salts with
compounds containing an active methylene group followed
by the cyclization of the formed hydrazones [1–3].
As shown in [14] diazopyrazoles having in the position
4 a 3,4-dimethoxyphenyl group suffer this kind cycliza-
tion. We carried out an additional investigation in order
to elucidate the direction of transformations of 3-alkyl-4-
(methoxyphenyl)-1H-pyrazole-5-diazonium salts and the
The arenediazonium salts containing in the ortho-
position to the formed diazo group a substituent active in
Scheme 1.
N NH
N NH
N NH
NH2
+
+
N NCl_
N NCl_
_
NaNO2 HCl
0oC
MeO
OMe
MeO
OMe
N
OMe
N
OMe
A
B
I
NH
NH
N
N
N
N
OMe
MeO
OMe
III
OMe
II
211

DIDENKO et al.
212
structure of the reaction products. It was established that
the diazotization of 3-methyl-4-(3,4-dimethoxyphenyl)-
1H-5-aminopyrazole (I) under standard conditions led to
the formation of brightly colored diazonium salt A that
spontaneously underwent an intramolecular azo coupling
giving 1-methyl-7,8-dimethoxy-3H-pyrazolo[3,4-c]-
cinnoline (II) (Scheme 1).
At the same time 4-(3,4-dimethoxyphenyl)-3-ethyl-
pyrazole-5-diazonium salt (IVa) and also analogous salts
containing a single methoxy group in the ortho- or para-
position IVb–IVd are more stable and easily undergo
coupling with acetylacetone (V) forming pyrazolyl-
hydrazones VIa–VId in high yields. The hydrazones
obtained are substances of bright color melting with
decomposition. We failed to perform their spectral
identification since they underwent spontaneous cycliza-
tion occurring partly already at 30–40°C (TLC data).
1
The analysis of H NMR spectrum proved that the
reaction under study resulted exclusively in compound
II. The second presumable regioisomer III did not form.
This conclusion was based on the fact that in the aromatic
region the two proton signals were observed as two
singlets at δ 7.58 and 7.98 ppm but not as doublets as
should have happened in compound III. Presumably since
in A conformation the 3-methoxy and diazo groups are
the farthest from each other the reaction is directed in
the discovered sense.
The cyclization of hydrazones VIa–VId in sulfuric acid
at cold yielded pyrazolotriazine VIIa–VIId (Scheme 2).
We believe that the different behavior of salts IVa
and A is due to the steric effect of the ethyl group. Its
large volume causes the substituted benzene ring to
deviate from the plane of the molecucle and thus prevents
the electrophilic attack of the diazo group in compound
O
Scheme 2.
N N
N NH
N NH
O
O
N
_
+
N
N NCl
N N
45% H2SO4
R
R
R
V
H
AcONa
O
X
X
X
O
R = Et, X = 3,4-(MeO)2 (a), 4-MeO (d); R = Me, X = 2-MeO (b), 4-MeO (c).
Scheme 3.
N
N
N
N
Cl
VIII
AcNMe2,
NaH, 20oC
N
NH
MeO
OMe
X
N
N
O
O
N
N
Cl
MeO
IX
OMe
II
N
N
Py, Δ
MeO
OMe
XI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

TRANSFORMATIONS OF 3-ALKYL-4-(METHOXYPHRNYL)-1H-PYRAZOLE-5-DIAZONIUM SALTS
213
IVa. In 3-methylpyrazole-5-diazonium salt A a free
rotation occurs around the σ-bond connecting the pyrazole
and benzene rings. The molecule acquires the conforma-
tion where all the substituents get into the same plane
and as a result the intramolecular azo coupling takes place.
The single methoxy group in diazonium salts IVb–IVd
insufficiently activated the benzene ring and therefore it
was possible to obtain from these compounds the target
products VIIb–VIId.
salt IVa–IVd prepared similarly from 1.0 mmol of an
appropriate aminopyrazole, 1.0 mmol of sodium nitrite,
and 3 ml of hydrochloric acid was brought by portions at
stirring into a cooled solution of 1.0 g (1.0 mmol) of
acetylacetone (V) in 15 ml of ethanol and 12 g of saturated
water solution of sodium acetate. The reaction mixture
was stirred for 1 h, the separated precipitate was filtered
off and washed with water. Yields of the hydrazones were
89–95%. Then 20–30 ml of 45% H2SO4 was added, the
reaction mixture was stirred at room temperature for 15–
30 min and poured into 300 ml of water. The separated
precipitate was filtered off, washed with water till neutral
reaction, and recrystallized from a mixture 2-propanol–
acetic acid, 2:1.
In order to carry out a secondary functionalization of
the pyrazolocinnoline we obtained it was subjected to
alkylation with benzyl chloride (VIII) and acylation with
benzoyl chloride (IX). We thus prepared in high yields
N-benzyl- and N-benzoylpyrazolo[3,4-c]cinnolines (X,
XI) respectively (Scheme 3).
1-{8-(3,4-Dimethoxyphenyl)-4-methyl-7-ethyl-
pyrazolo[5,1-c][1,2,4]triazin-3-yl}ethanone (VIIa).
Yield 2.3 g (69%), mp 152–154°C. 1H NMR spectrum,
δ, ppm: 1.37 t (3H, CH3CH2, J 7.5 Hz), 2.85 s (3H, CH3),
3.12 q (5H, CH3CH2 + CH3, J 7.8 Hz), 3.84 s (6H,
Hence the discovered direction of the transformations
of pyrazole-5-diazonium salts depending on their structure
makes it possible to forecast the synthetic routes of
pyrazolo[5,1-c][1,2,4]triazines or pyrazolo[3,4-c]-
cinnoline. These fused heterocycles are interesting as
probable biologically active substances.
2OCH3), 7.10 d (1Harom, J 8.5 Hz), 7.29 d (1Harom
,
J 8.5 Hz), 7.39 s (1Harom). Found, %: C 63.59; H 5.89;
+
N 16.40. Μ 340. C18H20N4O3. Calculated, %: C 63.52;
EXPERIMENTAL
H 5.92; N 16.46. Μ 340.38.
1-{4,7-Dimethyl-8-(2-methoxyphenyl)pyrazolo-
[5,1-c][1,2,4]triazin-3-yl}ethanone (VIIb). Yield
1.8 g (61%), mp 141–143°C. 1H NMR spectrum, δ,
ppm: 1.35 s (3H, CH3), 2.71 s (3H, CH3), 2.70 s (3H,
CH3), 3.85 s (3H, OCH3), 7.17 m (2Harom), 7.46 m
(2Harom). Found, %: C 64.94; H 5.39; N 18.87. Μ 296.
C16H16N4O2. Calculated, %: C 64.85; H 5.44; N 18.91.
Μ 296.33.
The homogeneity of the reagents and obtained
products was checked and the qualitative analysis of the
reaction mixtures was carried out by TLC on Silufol UV-
254 plates, eluents chloroform, ethyl acetate, and their
1
mixtures. H NMR spectra were registered on a spec-
+
trometer Bruker AC-300 (300 MHz) in DMSO-d6,
internal reference TMS. Mass spectra were measured
on an LKB-9000 instrument, ionizing electrons energy
70 eV. Elemental analysis was performed on an analyzer
Carlo Erba NA 1500.
1-{4,7-Dimethyl-8-(4-methoxyphenyl)pyrazolo-
[5,1-c][1,2,4]triazin-3-yl}ethanone (VIIc). Yield
2.0 g (68%), mp 120–122°C. 1H NMR spectrum, δ, ppm:
1.37 s (3H, CH3), 2.58 s (3H, CH3), 3.89 s (3H, OCH3),
7.00 d (2Harom, J 8.4 Hz), 7.27 d (2Harom, J 8.4 Hz). Found,
1-Methyl-7,8-dimethoxy-3H-pyrazolo[3,4-c]-
cinnoline (II). A solution of 2.3 g (1.0 mmol) of
aminopyrazole I [15] in 20 ml of water and 3 ml of concn.
HCl was treated with 0.7 g (1.0 mmol) of sodium nitrite
maintaining the temeperature of the reaction mixture at
0°C. The mixture was stirred additionally for 1 h at room
temperature. The separated precipitate was filtered off,
washed with water and with cold 2-propanol. Yield 1.9 g
(78%), mp >300°C (AcOH–DMF, 2:1). 1H NMR spec-
trum, δ, ppm: 2.86 s (3H, CH3), 4.02 s (3H, OCH3), 4.09 s
(3H, OCH3), 7.58 s (1Harom), 7.98 s (1Harom), 14.10 s
+
%: C 64.90; H 5.41; N 18.82. Μ 296. C16H16N4O2.
Calculated, %: C 64.85; H 5.44; N 18.91. Μ 296.33.
1-{4-Methyl-8-(4-methoxyphenyl)-7-ethylpyr-
azolo-[5,1-c][1,2,4]triazin-3-yl}ethanone (VIId).
Yield 2.3 g (70%), mp 123–125°C. 1H NMR spectrum,
δ, ppm: 1.36 t (3H, CH3CH2, J 7.5 Hz), 2.85 s (3H, CH3),
2.97 s (3H, CH3), 3.10 q (2H, CH3CH2, J 7.8 Hz), 3.85 s
(3H, OCH3), 7.02 d (2Harom, J 8.4 Hz), 7.67 d (2Harom
,
+
+
(1H, NH). Found, %: C 59.12; H 4.89; N 23.00. Μ 244.
J 8.4 Hz). Found, %: C 65.70; H 5.90; N 18.10. Μ 310.
C17H18N4O2. Calculated, %: C 65.79; H 5.85; N 18.05.
Μ 310.35.
C12H12N4O2. Calculated, %: C 59.01; H 4.95; N 22.94.
Μ 244.25.
8-Aryl-7-R-4-methylpyrazolo[5,1-c][1,2,4]-
triazin-3-ylethanones VIIa–VIId. A solution of diazo
3-Benzyl-1-methyl-7,8-dimethoxy-3H-pyrazolo-
[3,4-c]cinnoline (X). To a solution of 2.4 g (1.0 mmol)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

DIDENKO et al.
214
of compound II in 20 ml of hot anhydrous dimethy-
lacetamide was added 0.3 g (1.3 mmol) of sodium hydride,
and the reaction mixture was stirred at room temperature
till it got colored. Then 1.5 g (1.2 mmol) of benzyl chloride
(VIII) was added, the mixture was stirred for 3–3.5 h,
and poured into water. The separated precipitate was
crystallized from DMF. Yield 2.9 g (85%), mp 195–
1980, p. 579.
3. Dorn, G., Khim. Geterotsikl. Soedin., 1981, p. 3.
4. Tsollinger, G., Khimiya azokrasitelei (Chemistry of Azo
Dyes), Leningrad: Goskhimizdat, 1960, p. 92.
5. Fieser L. F., and Fieser, M., Advanced Organic Chemistry,
NewYork: Reinhold, 1962.
6. Vatsuro, K.V. and Mishchenko, G.L., Imennye reaktsii v
organicheskoi khimii (Personal Reaction in the Organic
Chemistry), Moscow: Khimiya, 1976, vol. 357, p. 507.
7. Comprehensive Organic Chemistry, Barton, D. and Ollis,
W.D., Eds., Oxford: Pergamon, 1979, vol. 8, p. 162.
8. Gilchrist, T.L., Heterocyclic Chemistry, London:
Marshfield, Mass.: Pitman, 1985.
1
197°C. H NMR spectrum, δ, ppm: 2.84 s (3H, CH3),
4.05 s (3H, OCH3), 4.10 s (3H, OCH3), 5.90 s (2H, CH2),
7.24–7.45 m (6Harom), 7.93 s (1Harom). Found, %: C 68.19;
H 5.48; N 16.72. M+ 334. C19H18N4O2. Calculated, %:
C 68.25; H 5.43; N 16.76. M 334.37.
3-Benzoyl-1-methyl-7,8-dimethoxy-3H-pyrazolo-
[3,4-c]cinnoline (XI). A mixture of 2.4 g (1.0 mmol) of
compound II, 1.7 g (1.2 mmol) of benzoyl chloride (IX),
and 15 ml of pyridine was boiled for 20 h, poured into hot
water, the separated precipitate was filtered off and
repeatedly washed with hot water. Yield 2.8 g (80%),
mp 257°C (decomp.) (from DMF). 1H NMR spectrum, δ,
ppm: 2.86 s (3H, CH3), 4.05 s (3H, OCH3), 4.11 s (3H,
OCH3), 7.57–7.74 m (4Harom), 8.02 t (3Harom, J 7.4 Hz).
Found, %: C 65.29; H 4.73; N 16.20. M+ 348. C19H16N4O3.
Calculated, %: C 65.51; H 4.63; N 16.08. M 348.36.
9. Heterocyclic Compounds, Elderfield, R.C., Ed., NewYork:
Wiley, 1957, vol. 5.
10. Stenyl, H., Staub, A., Simon, C., and Baumann, W., Helv.
Chim. Acta, 1950, vol. 33, p. 1183.
11. Schmidt, P., Eichenberger, K., and Wilhelm, M., Angew
Chem., 1961, vol. 73, p. 15.
12. Gonzalez, E. and Sarlin, R., J. Heterocycl. Chem., 1975, vol.
12, p. 279.
13. Greenhill, J.V., Comprehensive Heterocyclic Chem., Kat-
ritzky,A.R., Rees, C.W., Oxford: Pergamon, 1997, vol. 5, p.
325.
14. Pavlov, I.V., Kobrakov, K.I., and Bogza, S.L., ., Khim.
Geterotsikl. Soedin, 2004, p. 1115.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009