Cascade cyclization of 3(5)-aminopyrazoles with aromatic aldehydes and cyclohexanediones

Article abstract of DOI:10.1134/S1070428010090216

Three-component condensation of 5(3)-amino-3(5)-methylpyrazole with aromatic aldehydes and 1,3-cyclohexanedione afforded mixtures of 3-methyl-4-aryl-2,4,6,7,8,9-hexa hydro-5H-pyrazolo[3,4-b]quinolin-5-ones and 2-methyl-9-aryl-5,6,7,9-tetrahydro pyrazolo[5

Full text of DOI:10.1134/S1070428010090216

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 9, pp. 1388−1398. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.V. Lipson, N.V. Svetlichnaya, V.V. Borodina, M.G. Shirobokova, S.V. Shishkina, O.V. Shishkin, V.I. Musatov, 2010, published in Zhurnal
Organicheskoi Khimii, 2010, Vol. 46, No. 9, pp. 1385−1394.
Cascade Cyclization of 3(5)-Aminopyrazoles
with Aromatic Aldehydes and Cyclohexanediones
V. V. Lipsona, N. V. Svetlichnayaa, V. V. Borodinaa, M. G. Shirobokovaa,
S. V. Shishkinab, O. V. Shishkinb, and V. I. Musatovb
aDanilevskii Institute of Endocrine Pathology Problems, Academy of Medical Sciences of Ukraine, Kharkov, 61002 Ukraine
e-mail: lipson@ukr.net
bInstitute of Single Crystals, National Academy of Sciences of Ukraine, Kharkov, Ukraine
Received January 4, 2010
Abstract—Three-component condensation of 5(3)-amino-3(5)-methylpyrazole with aromatic aldehydes and
1,3-cyclohexanedione afforded mixtures of 3-methyl-4-aryl-2,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-
5-ones and 2-methyl-9-aryl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-ones. The reaction of 3-amino-
pyrazolo-4-carbonitrile and ethyl 3-aminopyrazolo-4-carboxylate with aldehydes and cyclohexanedione or
dimedome is regioselective and leads to the formation of partially hydrogenated pyrazolo[5,1-b]quinazolin-8-one
systems. In all compounds the dihydroazine ring exists in the enamine tautomeric form.
DOI: 10.1134/S1070428010090216
Multicomponenet condensations and cascade trans-
formations of amidine (guanidine) derivatives having
synthetic precursors or equivalents of carbonyl bielec-
trophiles underlie the combinatorial synthesis of libraries
of versatile nitrogen heterocyclic systems for pharmaco-
logic testing by the procedure of the “high-throughput
screening”. The set of transformations providing the
one-pot assembling of such substances is wide [1], yet
the search for new reactions and building blocks for the
creation of original basic structures continues. Among
the objects of high attentions pyrazolo-azine systems
should be mentioned containing the partially hydroge-
nated pyridine or pyrimidine ring due to the wide range
of pharmacologically important kinds of activity inherent
to these compounds. In particular, in the pyrazolo[3,4-b]
pyridines a vasodilatatory effect was observed [2]. In the
same substance group inhibitors of glycogen synthase
kinase-3 (GSK-3) were found, promising means for treat-
ing the insulinoresistance [3].Antagonists of the cortico-
tropin releasing factor (CRF) were also found, efficient
against the stress-induced disturbancies [4]. Among the
pyrazolo[1,5-a]-pyrimidine derivatives quite a number of
substances were found exhibiting anti-inflammatory and
analgesic [5], antihypertensive [2, 6], hypocholesterol-
emic [7], and hypnotic [8] qualities.
It was formerly established that the condensation of
5(3)-amino-3(5)-methylpyrazole with aromatic aldehydes
and dimedone, and also with the products of their intermo-
lecular condensation, arylmethylene derivatives of dime-
done and Michael adducts, involved the nucleophilic atom
C4 of the pyrazole ring and the amino group and led to
the formation of 3,7,7-trimethyl-4-aryl-2,4,6,7,8,9-hexa-
hydropyrazolo[3,4-b]quinolin-5-ones [9, 10].At the same
time in the reactions of this amine with α,β-unsaturated
ketones [11, 12], diethyl benzylidenemalonate [13], and
methyl cinnamate [14] the endo- and exocyclic nitrogen
atoms act as nucleophilic sites and the processes afford
partially hydrogenated pyrazolo[1,5-a]pyrimidines. All
the mentioned two- and tree-component condensations
are characterized by a high regioselectivity of the forma-
tion of the partially hydrogenated azine ring. Alongside
the high yields the regioselectivity is the main criterion
in the evaluation of the suitability of these processes for
the combinatorial synthesis. The goal of this study is the
establishment of the reaction direction of 5(3)-amino-
3(5)-methylpyrazole (I), 3-aminopyrazolo-4-carbonitrile
(X), and ethyl 3-aminopyrazolo-4-carboxylate (XI) with
aromatic aldehydes IIa–IIh, 1,3-cyclohexanedione (III),
and dimedone (XII) under various conditions.
At boiling equimolar amounts of amine I, aldehydes
1388

CASCADE CYCLIZATION OF 3(5)-AMINOPYRAZOLES
1389
Scheme 1.
R
O
O
HN
N
O
N
N
N
NH
NH
Me
R
+
+
H
Me
N
H
Me
N
R
IIà_ç
H
DMF
N
NH
NH2
Va_Vc, Ve_Vh
O
+
VI
IVa_IVf
Me
O
O
I
HN
Me
N
N
N
O
NH
+
III
Me
N
H
R
R
O
VII
VIII
R = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c), 4-Me2NC6H4 (d), 4-ClC6H4 (e), 4-FC6H4 (f), 4-HOOCC6H4 (g), 4-NO2C6H4 (h).
IIa–IIh, and 1,3-cyclohexanedione (III) in DMF over 2
h we obtained a mixture of quinolinones IVa–IVf and
quinazolinones Va–Vc, Ve–Vh with enaminoketone VI
(Scheme 1). Tricyclic systems of the angular structure VII
and VIII were not detected in any experiment.
Schiff bases IXa, IXd, and IXh and cyclohexanedione
(III) we obtained again mixtures of tricyclic derivatives
IVa, Va and individual compounds IVd and Vh respec-
tively (Scheme 2). Hence even if the azomethines form
in the condensations they play the role of benzaldehydes
depositary and do not accumulate in the reaction mixtures.
The ratio of isomers IV and V depends on the electron-
ic properties of the substituent in the aryl fragment. In the
reactions involving the para-substituted benzaldehydes
IIb–IIe having donor substituent IVb–IVe prevailingly
were obtained. In the case of 4-dimethylaminobenzalde-
hyde (IId) tricyclic compound IVd was a single product.
With the growing electron-withdrawing properties of
the substituent in the aromatic ring (aldehydes IIf–IIh)
quinazolines Vf–Vh became the prevailing or single
cyclocondensation products.
Compounds IVa–IVf, Va–Vc, Ve–Vh, VI, IXa were
identified by spectral methods, their composition was
established by elemental analysis. The physicochemical
characteristics of azomethines IXd and IXh coincide with
published data [15]. The structure of quinazolinone Ve
was proved by XRD analysis.
In the IR spectra of pyrazolo[3,4-b]quinolinones IVa–
IVf the most characteristic absorption bands are those
of the carbonyl group at 1584–1588 and a wide band in
the region 2850–3268 cm–1 from the overlapping of the
vibrations of the NH group and of the methylene groups.
The stretching vibrations of the C=C bond in the dihydro-
pyridine ring conjugated with the carbonyl group and with
The attempts were unsuccessful of the conversion
of enaminone VI into the fused systems IVa, IVd, and
Va by prolonged heating with aldehydes IIa, IId in
DMF. In all events the initial reagents IIa, IId and VI
were recovered with an admixture of tar. Consequently
compound VI is not an intermediate in the formation of
pyrazolo[3,4-b]quinolin-5-ones IV or pyrazolo[5,1-b]-
quinazolin-8-ones V, but forms in a process competing
with the cyclocondensation and therefore is present in
all reaction mixtures.
Scheme 2.
N
NH
IIa, IId, IIh
I
+
Me
N
R
EtOH
IXa, IXd, IXh
The formation of azomethines IX in the reactions
under study is not excluded, but in contrast to enaminone
VI they were never detected in the reaction products. In
the independent synthesis applying the specially prepared
III
IVa, IVd +
Va, Vh
DMF
R = Ph (a), 4-Me2NC6H4 (d), 4-NO2C6H4 (h).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

LIPSON et al.
1390
the pyrazole ring through the electron pair of the nitrogen
atom give rise to a weak band at 1626–1615 cm–1. In the
spectra of pyrazolo[5,1-b]quinazolinones Va–Vc, Ve–Vh
the absorption band of the carbonyl group appears virtu-
ally in the same range 1580–1576, and the vibrations
band of the C=C bond, at somewhat larger wavenumbers,
1628–1640 cm–1, than in the spectra of quinolinones IV
due to its location in the dihydropyrimidine and not in the
dihydropyridine ring. The absorption of the NH and CH2
groups in the spectra of quinazolinones Va–Vc, Ve, Vf,
Vh were observed at 2732–3216 cm–1. In the spectrum
of compound Vg a strong absorption was observed in the
region 2500–3600 cm–1 originating from the overlapping
of bands corresponding to the methylene fragments and
also of the associated groups COOH and NH. The IR
spectra are insufficient for the assignments of the com-
pounds obtained to quinoline IV, VII or quinazoline V,
VIII systems.
The signal of the methine proton C9H of the azine ring is
shifted downfield by 0.5 ppm compared to the proton H4
of quinolinones indicating the presence in the tricyclic
system of the dihydropyrimidine and not the pyridine
ring. The structure of compounds V was finally proved
by XRD analysis of compound Ve (Fig. 1).
Therefore owing to the presence in the molecule of
5(3)-amino-3(5)-methylpyrazole of two nonequivalent
endocyclic reaction centers, atoms C4 and N2, in its reac-
tion with aromatic aldehydes and 1,3-cyclohexanedione
the formation of the dihydroazine ring occurs in two op-
posite directions. The soft nucleophile, atom C4, reacts
with the soft electrophilic center, β-carbon atom of the in-
termediate unsaturated carbonyl compound formed by the
condensation of the aldehyde with the cyclohexanedione,
prevailingly in the cases when this carbon atom bears the
lowest positive charge due to the direct conjugation with
the electron-donor substituent in the aryl ring.As a result
quinolinones IV become the dominant reaction products.
The choice between isomers IV and VII, V and VIII
1
was done by the analysis of H NMR spectra. In the
In the molecules of 3-aminopyrazolo-4-carbonitrile
(X) and ethyl 3-aminopyrazolo-3-carboxylate (XI) the
C4 atom cannot be the center of the electrophilic attack,
consequently, at the use of these amines in the three-
component condensation with 1,3-cyclohexanedione (III)
or dimedone (XII) and aromatic aldehydes IIa, IIb, IIe,
IIh two isomers only may form, partially hydrogenated
pyrazolo[5,1-b]- or -[1,5-a]quinazolinones.
spectra of compounds IVa–IVf signals were observed
from aromatic protons, three methylene, and methyl
groups. The presence in the spectra of a singlet from the
proton H4, signals of two NH groups and the absence of
the resonance of the CH proton of the pyrazole ring is
consistent with structures IV and VII. The choice be-
tween them was based on NOE experiment on compound
IVb. The irradiation of the protons of the methyl group
linked to atom C3 (δ 1.87 ppm) had a response from
the NH proton of the NH pyrazole ring (δ 11.68 ppm),
ortho-protons of the aryl fragment, and a methine proton
of the dihydropyridine ring (δ 4.88 ppm), located in the
direct spatial nearness to the irradiated CH3 group. It
allows the assignment to compound IVb the structure
of pyrazolo[3,4-b]quinolin-5-one existing in DMSO en-
vironment in the tautomeric form N2H. As a whole, the
1H NMR spectra of compounds IVa–IVf are analogous
to the spectra of 3,7,7-trimethyl-4-aryl-2,4,6,7,8,9-hexa-
hydropyrazolo[3,4-b]quinolin-5-ones synthesized previ-
ously by the cyclocondensation of methylaminopyrazole
with dimedone and substituted benzaldehydes whose
structure was proved by XRD [9, 10].
At boiling equimolar amounts of amines X or XI, alde-
hydes IIa–IIc, IId, IIh, and 1,3-cyclo-hexanedione (III)
or dimedone (XII) in DMF for 20–30 min pyrazolo[5,1-
b]-quinazolinones XIIIa, XIIIb, XIIIe, XIIIh, XIVa,
1
In the H NMR spectra of quinazolinones Va–Vc,
Ve–Vh unlike the spectra of the above discussed quino-
linones a proton signal is present of a single NH group
located in the dihydropyrimidine ring (br.s in the region
10.20–10.52 ppm) which disappears as a result of deu-
terium exchange with D2O. The singlet of the methine
proton of the pyrazole ring appears at δ 6.05–5.99 ppm.
Fig. 1. Molecular structure of 2-methyl-9-(4-chlorophenyl)-
5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one (Ve).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

CASCADE CYCLIZATION OF 3(5)-AMINOPYRAZOLES
1391
XIVb, XIVe, XIVh, XVa, XVb, XVe, XVIa, XVIc, XVIe
were obtained respectively (Scheme 3). Compounds of
the alternative structure XVII were not detected.
The structure of compounds XIII–XVI was proved
by spectral methods. In the IR spectra of pyrazolo-
quinazolinones XIII, XV the most characteristic absorp-
tion bands are those of CN and C=O groups in the regions
2268–2228 and 1648–1590 cm–1 respectively, and in
the spectra of ethoxycarbonyl analogs XIV and XVI the
strongest bands are those of vibrations of two C=O groups.
In the 1H NMR spectra all signals of the proton-containing
fragments of molecules XIII–XVI are observed; the
spectra confirm their structures as partially hydrogenated
9-aryl-substituted pyrazolo[5,1-b]-quinazolin-8-ones.
The spectra of compounds XIII, XIV obtained from
1,3-cyclohexanedione are distinguished from those of
the condensation products of dimedone XV, XVI only
in the resonance region of the methylene and methyl
protons. The formation in the three-component reaction
of linear structures XIII–XVI and not angular structure
XVII and the existence of the dihydropyrimidine ring
in the enamine tautomeric form is proved by the singlet
resonance of the protons NH and C9H. The structure
of pyrazolo[5,1-b]-quinazolinones was unambiguously
proved by XRD analysis on single crystals of esters XIVa
and XVIc (Figs. 2, 3).
Fig. 2. Molecular structure of ethyl 8-oxo-9-phenyl-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carboxylate (XIVa).
substituents in all the three compounds it is presumable
that the variation of its conformation is due to the effect
of the packing in the crystal. It was shown before [12]
that the dihydropyrimidine ring in the azolopyrimidines
possesses a high conformational flexibility therefore
even the relatively small changes in the character of the
intermolecular interactions in the crystal can result in
notable deformation of the dihydroazine ring.
The conformation of the cyclohexenone ring also
changes in relatively considerable limits (Table 1) from
the practically ideal sofa in compound Ve to the con-
formation intermediate between sofa and semichair in
pyrazoloquinazolinones XIVa and XVIc. The maximum
change in the conformation of the tetrahydroring in the
direction of semichair occurs in compound XVIc presum-
ably due to the influence of the methyl substituents at the
atom C8. The conformational difference in compounds
Ve and XIVa is caused presumably by the intermolecular
The structural investigations revealed also certain
conformational features of the partially hydrogenated
pyrazoloquinazolinones. According to XRD data the
conformation of the dihydropyrimidine ring in the mol-
ecules of compounds Ve, XIVa, and XVIc varies from
confortmation boat (XIVa) to twist-boat (Ve) (Table 1).
Therewith the folding degree of the heterocycle consid-
erably changes. Considering that the dihydropyrimidine
fragment is fused with identical rings and has similar
Scheme 3.
R3
R3
R2
O
O
R3
N
NH
NH2
R1
X, XI
R2
O
N
N
N
N
R3
R3
+
+
DMF
R3
III, XII
O
N
H
R2
N
H
O
R1
R1
IIa_IIc, IIe, IIh
XVII
XVa, XVb, XVe
XVIa, XVIc, XVIe
XIIIa, XIIIb, XIIIe, XIIIh
XIVa, XIVb, XIVe, XIVh
R1 = CN (X), COOEt (XI); R3 = H (III), Me (XII); R3 = H, R1 = CN (XIII), COOEt (XIV);R3 = Me, R1 = CN (XV),
COOEt (XVI); XIII–XVI: R2 = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c), 4-ClC6H4 (e), 4– NO2C6H4 (h).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

LIPSON et al.
Table 1. Conformations (folding parameters) of partially hydrogenated rings in compounds Ve, XIVa, and XVIc
1392
Pyrimidine ring
Cyclohexenone ring
Compound no.
S
Θ, deg
Ψ, deg
S
Θ, deg
Ψ, deg
Ve
0.27
0.24
0.31
60.6
61.2
60.3
22.4
0.6
0.69
0.68
0.68
41.6
42.4
36.7
1.6
XIVa
XVIc
11.9
14.1
14.4
interactions in the crystal and may be ascribed to the flex-
ibility of the cyclohexenone fragment [10].
1.372(2) Å and O1–C6 1.250(2) Å are longer (mean val-
ues 1.326 and 1.210 Å) than in the structures Ve [C5–C10
1.355(2) and O1–C6 1.225(2) Å] and XIVa [1.356(3)
and 1.230(3) Å]. These differences in the geometric pa-
rameters cannot originate from the substituents effects.
It is therefore presumable that the variations in the bond
lengths in the molecule XVIc is caused by the different
polarizing influence of its surrounding in the crystal due to
the formation of various intermolecular hydrogen bonds
involving the NH group of the dihydropyrimidine ring.
The molecules XVIc form in the crystal endless chains
owing to intermolecular hydrogen bonds N1–H1N···O1'
(–0.5 + x, y, 0.5 – z ) d(H···O) 2.17 Å, angle NH···O
156 deg, whereas the molecules Ve and XIVa form
endless chains owing to intermolecular hydrogen bonds
N1–H1N···N2' (x, 2.5–y, –0.5+z) d(H···N) 2.02 Å, angle
N–H···N 174 deg and N1–H1N···N2’ (0.5 + x, 0.5 – y, z)
d(H···N) 2.28 Å, angle N–H···N 162 deg.
The substituent at the atom C4 in all compounds has
the axial orientation [torsion angle C1N3C4C11 102.2(2)
deg in molecule Ve, –106.9(3) deg in compound XIVa,
and –101.4(1) deg in molecule XVIc] and is considerably
turned with respect to the plane of the dihydropyrimidine
ring [torsion angle N3C4C11C12 –47.8(2) deg in compound
Ve, 70.7(4) deg in molecule XIVa, and –96.5(1) deg
in quinazoline XVIc]. The carboxy group of the ester
substituent in structures XIVa and XVIc is practically
coplanar with the plane of the pyrazole ring [torsion angle
C1C2C17O2 5.4(5) deg in molecule XIVa and –6.2(2) deg
in compound XVIc].
It should be also mentioned that in the dihydropyrazo-
lopyrimidine fragment of the molecule XVIc the bond
distances N1–C10 and N1–C1 are equal [1.387(2) Å] un-
like the analogous bonds in the structures Ve [1.360(2)
and 1.374(2) Å] and XIVa [1.365(3) and 1.375(3) Å] and
also in the previously studied dihydroazolopyrimidines
[16–20]. Besides in the molecule XVIc the bonds C5–C10
Thus the structure of pyrazoloquinazolines XIII–XVI
corresponds to the reaction of the endocyclic nitrogen
atom in the molecules of aminopyrazoles X or XI with
the β-carbon atom, and of the exocyclic amino group,
with the carbonyl group of the enone formed as a result of
the condensation of the aromatic aldehyde with diketone.
Consequently in the three-component condensation in
question is realized the same direction of the pyrimidine
ring formation as in the reactions of 2-aminobenzimid-
azole and 3-amino-1,2,4-triazole with C arylmethylene-
cycloalkanones [20–22].
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer Spe-
cord M-82 from pellets with KBr. 1H NMR spectra were
registered on a spectrometer Varian Mercury VX-200
from solutions in DMSO-d6, internal reference TMS. The
melting points were measured on a Koeffler heating block.
Fig. 3. Molecular structure of ethyl 6,6-dimethyl-8-oxo-9-
(4-methoxyphenyl)-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]
quinazoline-3-carboxylate (XVIc).
XRD analysis. The X-ray diffraction experiments
were carried out on a diffractometer Xcalibur-3 (MoKa
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

CASCADE CYCLIZATION OF 3(5)-AMINOPYRAZOLES
1393
Table 2. Crystallographic data and parameters of experiment for compounds Ve, XIVa, and XVIc
Parameter
Empirical formula
Compound Ve
C17H16ClN3O
13.5421(5)
9.7133(3)
11.7702(3)
90
Compound XIVa
C17H16N3O
12.5848(8)
15.450(1)
8.6991(6)
90
Compound XVIc
C22H25N3O4
13.026(2)
18.061(5)
18.093(4)
90
Unit cell parameters a, Å
b, Å
c, Å
α, deg
β, deg
γ, deg
V, Å3
102.849(3)
90
90
90
90
90
1509.47(8)
1691.4(2)
4257(2)
Mr
313.78
293
337.37
293
395.45
293
T, K
F(000)
Crystal system
Space group
Z
656
712
1680
Rhombic
Pbca
8
Monoclinic
P21/C
4
Rhombic
Pna21
4
Μ, mm–1
0.258
1.381
50
0.091
1.325
50
0.086
1.234
60
d
calc, g/cm3
2Θmax, deg
Measured reflections
Independent reflections
7394
2634
9433
2199
20787
6150
Rint
0.020
0.041
0.044
Reflections with F > 4σ(F)
1876
0.033
0.089
1465
0.036
0.086
2313
0.039
0.090
R1
wR2
S
0.940
0.923
0.707
radiation, CCD-detector, graphite monochromator,
ω-scanning). The structures were solved by the
direct method using software SHELXTL [23]. The
crystallographic data and the experimental parameters
are presented in Table 2.
e-mail: deposit@ccdc.cam.ac.uk), CCDC: Ve, 772360;
XIVa, 772359; XVIc, 772361.
Reaction of 5(3)-amino-3(5)-methylpyrazole (I)
with benzaldehydes IIa–IIh and 1,3-cyclohexane-
dione (III). A mixture of 5 mmol of amine I, 5 mmol of
aldehyde IIa–IIh, and 5 mmol of 1,3-cyclohexanedione
(III) in 2 ml of DMF was boiled for 2 h. The reaction
mixture was cooled, 10 ml of 2-propanol was added,
and the amorphous precipitate consisting of a mixture of
compounds IV and V was filtered off. The products were
separated by fractional crystallization from 2-propanol.
From the oily residue formed after removal of solvents
from the primary filtrate enaminoketone VI was crystal-
lized by ethanol.
The positions of the hydrogen atoms in all structures
were revealed from the difference synthesis of the electron
density and in structures XIVa and Ve they were refined
along the rider model with Uiso = nUeq of the nonhydrogen
atom linked to this hydrogen (n is 1.5 for the methyl group
and n is 1.2 for the other hydrogen atoms). Hydrogen
atoms in compound Ve involved into hydrogen bonds
and all hydrogen atoms of compound XVIc were refined
in the isotropic approximation. Atomic coordinates and
complete tables of bond distances and bond angles are
deposited into the Cambridge Crystallographic Data
Center (The Cambridge Crystallographic Data Centre,
12 Union Road, CB2 1EZ, UK, fax: +44–1223–336033;
3-Methyl-4-phenyl-2,4,6,7,8,9-hexahydro-5H-
pyrazolo[3,4-b]quinolin-5-one (IVa). Yield 1.9 mmol
(37%), mp >300°C. IR spectrum, cm–1
: 3260–2850
1
(NH, CH2), 1626 (C=C), 1584 (CO). H NMR spec-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

LIPSON et al.
1394
trum, δ, ppm: 11.71 br.s (1H, N2H), 9.70 br.s (1H, N9H),
7.05–7.15 m (5H, C6H5), 4.93 s (1H, C4H), 2.11 m (2H,
CH2), 1.88 s (3H, CH3), 1.76 m (4H, CH2). Found, %:
C 73.14; H 6.10; N 15.10. C17H17N3O. Calculated, %:
C 73.12; H 6.09; N 15.05.
(1H, N9H), 7.09 m (4H, C6H4), 4.91 s (1H, C4H), 2.12 m
(2H, CH2), 1.86 s (3H, CH3), 1.79 m (4H, CH2). Found,
%: C 68.69; H 5.39; N 14.14. C17H16FN3O. Calculated,
%: C 68.66; H 5.40; N 14.11.
2-Methyl-9-phenyl-5,6,7,9-tetrahydropyrazolo-
[5,1-b]quinazolin-8(4H)-one (Va). Yield 1.7 mmol
(34%), mp >300°C. IR spectrum, cm–1: 3220–2800 (NH,
3-Methyl-4-(4-methylphenyl)-2,4,6,7,8,9-hexahy-
dro-5H-pyrazolo[3,4-b]quinolin-5-one (IVb). Yield
2.6 mmol (52%), mp 203–206°C. IR spectrum, cm–1:
3244–2850 (NH, CH2), 1616 (C=C), 1584 (CO). 1H NMR
spectrum, δ, ppm: 11.68 br.s (1H, N2H), 9.65 br.s (1H,
N9H), 6.91–7.01 m (4H, C6H4), 4.88 s (1H, C4H), 2.17 s
(3H, CH3), 2.10 m (2H, CH2), 1.87 s (3H, CH3), 1.79 m
(4H, CH2). Found, %: C 73.70; H 6.45; N 14.36.
C18H19N3O. Calculated, %: C 73.72; H 6.48; N 14.33.
1
CH2), 1640 (C=C), 1580 (CO). H NMR spectrum, δ,
ppm: 10.35 br.s (1H, N4H), 7.11–7.21 m (5H, C6H5),
6.06 s (1H, C3H), 5.51 s (1H, C9H), 2.58 m (2H, CH2),
2.19 m (2H, CH2), 1.99 s (3H, CH3), 1.87 m (2H, CH2).
Found, %: C 73.11; H 6.07; N 15.10. C17H17N3O. Cal-
culated, %: C 73.12; H 6.09; N 15.05.
2-Methyl-9-(4-methylphenyl)-5,6,7,9-tetra-
hydropyrazolo[5,1-b]quinazolin-8(4H)-one (Vb).
Yield 0.9 mmol (17%), mp 303–305°C. IR spectrum,
cm–1: 3216–2732 (NH, CH2), 1628 (C=C), 1576 (CO).
1H NMR spectrum, δ, ppm: 10.30 br.s (1H, N4H), 6.98 m
(4H, C6H4), 6.00 s (1H, C3H), 5.48 s (1H, C9H), 2.56 m
(2H, CH2), 2.18 s (3H, CH3), 2.16 m (2H, CH2), 1.98
s (3H, CH3), 1.86 m (2H, CH2). Found, %: C 73.72;
H 6.47; N 14.34. C18H19N3O. Calculated, %: C 73.72;
H 6.48; N 14.33.
3-Methyl-4-(4-methoxyphenyl)-2,4,6,7,8,9-hexa-
hydro-5H-pyrazolo[3,4-b]quinolin-5-one (IVc). Yield
2.9 mmol (57%), mp 228–230°C. IR spectrum, cm–1:
3248–2850 (NH, CH2), 1620 (C=C), 1582 (CO). 1H NMR
spectrum, δ, ppm: 11.69 br.s (1H, N2H), 9.64 br.s (1H,
N9H), 6.68–7.03 d.d (4H, C6H4, J 8.2 Hz), 4.88 s (1H,
C4H), 3.64 s (3H, OCH3), 2.17 m (2H, CH2), 1.87 s (3H,
CH3), 1.78 m (4H, CH2). Found, %: C 69.91; H 6.15;
N 13.60. C18H19N3O2. Calculated, %: C 69.90; H 6.15;
N 13.59.
2-Methyl-9-(4-methoxyphenyl)-5,6,7,9-
tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one (Vc).
Yield 1.1 mmol (21%), mp >300°C. IR spectrum, cm–1:
3212–2750 (NH, CH2), 1636 (C=C), 1576 (CO). 1H NMR
spectrum, δ, ppm: 10.20 br.s (1H, N4H), 6.73–7.02 m
(4H, C6H4, J 7.8 Hz), 6.00 s (1H, C3H), 5.48 s (1H, C9H),
3.65 s (3H, OCH3), 2.56 m (2H, CH2), 2.17 m (2H, CH2),
1.98 s (3H, CH3), 1.86 m (2H, CH2). Found, %: C 69.88;
H 6.16; N 13.57. C18H19N3O2. Calculated, %: C 69.90;
H 6.15; N 13.59.
4-(4-Dimethylaminophenyl)-3-methyl-2,4,6,7,8,9-
hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one (IVd).
Yield 3.6 mmol (72%), mp 238–240°C. IR spectrum,
cm–1: 3260–2850 (NH, CH2), 1615 (C=C), 1588 (CO).
1H NMR spectrum, δ, ppm: 11.64 br.s (1H, N2H), 9.60
br.s (1H, N9H), 6.51–6.93 d.d (4H, C6H4, J 8.4 Hz), 4.83
s (1H, C4H), 2.76 s [6H, N(CH3)2], 2.10 m (2H, CH2),
1.89 s (3H, CH3), 1.79 m (4H, CH2). Found, %: C 70.60;
H 6.85; N 17.41. C19H22N4O. Calculated, %: C 70.59;
H 6.83; N 17.39.
2-Methyl-9-(4-chlorophenyl)-5,6,7,9-tetra-
hydropyrazolo[5,1-b]quinazolin-8(4H)-one (Ve). Yield
0.7 mmol (14%), mp 295–298°C. IR spectrum, cm–1:
3212–2750 (NH, CH2), 1636 (C=C), 1576 (CO). 1H NMR
spectrum, δ, ppm: 10.37 br.s (1H, N4H), 7.07–7.29 d.d
(4H, C6H4,J 8.4 Hz), 6.05 s (1H, C3H), 5.52 s (1H, C9H),
2.60 m (2H, CH2), 2.19 m (2H, CH2), 1.96 s (3H, CH3),
1.87 m (2H, CH2). Found, %: C 65.10; H 5.12; N 13.37.
C17H16ClN3O. Calculated, %: C 65.07; H 5.10; N 13.40.
3-Methyl-4-(4-chlorophenyl)-2,4,6,7,8,9-hexahy-
dro-5H-pyrazolo[3,4-b]quinolin-5-one (IVe). Yield
1.6 mmol (32%), mp 236–238°C. IR spectrum, cm–1:
3268–2850 (NH, CH2), 1620 (C=C), 1584 (CO). 1H NMR
spectrum, δ, ppm: 11.74 br.s (1H, N2H), 9.73 br.s (1H,
N9H), 7.09–7.23 d.d (4H, C6H4, J 8.6 Hz ), 4.94 s (1H,
C4H), 2.11 m (2H, CH2), 1.87 s (3H, CH3), 1.79 m (4H,
CH2). Found, %: C 65.10; H 5.11; N 13.43. C17H16ClN3O.
Calculated, %: C 65.07; H 5.10; N 13.40.
2-Methyl-9-(4-fluorophenyl)-5,6,7,9-tetra-
hydropyrazolo[5,1-b]quinazolin-8(4H)-one (Vf). Yield
1.9 mmol (37%), mp 282–284°C. IR spectrum, cm–1:
3196–2800 (NH, CH2), 1636 (C=C), 1576 (CO). 1H NMR
spectrum, δ, ppm: 10.39 br.s (1H, N4H), 7.11 m (4H,
C6H4), 6.05 s (1H, C3H), 5.49 s (1H, C9H), 2.58 m (2H,
3-Methyl-4-(4-fluorophenyl)-2,4,6,7,8,9-hexahy-
dro-5H-pyrazolo[3,4-b]quinolin-5-one (IVf). Yield
0.6 mmol (12%), mp 262–264°C. IR spectrum, cm–1:
1
3242–2850 (NH, CH2), 1624 (C=C), 1586 (CO). H
NMR spectrum, δ, ppm: 11.73 br.s (1H, N2H), 9.69 br.s
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CASCADE CYCLIZATION OF 3(5)-AMINOPYRAZOLES
1395
CH2), 2.17 m (2H, CH2), 1.98 s (3H, CH3), 1.87 m (2H,
CH2). Found, %: C 68.70; H 5.41; N 14.15. C17H16FN3O.
Calculated, %: C 68.69; H 5.39; N 14.14.
C 71.74; H 5.43; N 22.83. Compounds IXd and IXh were
obtained similarly [15].
8-Oxo-9-phenyl-4,5,6,7,8,9-hexahydropyrazolo-
[5,1-b]quinazolin-3-carbonitrile (XIIIa). A mixture
of 0.22 g (2 mmol) 5-aminopyrazol-4-carbonitrile (X),
0.21 g (2 mmol) of benzaldehyde (IIa), and 0.22 g
(2 mmol) of 1,3-cyclohexanedione (III) in 1 ml of DMF
was boiled for 20 min, cooled, 5 ml of 2-propanol was
added, the precipitate was filtered off. Yield 0.32 g
(1.1 mmol, 56%), mp 350–353°C. IR spectrum, cm–1:
3228 (NH, H-bound), 2940, 2904, 2856 (CH2), 2228
(CN), 1644 (C=O). 1H NMR spectrum, δ, ppm: 11.22 br.s
(1H, NH), 7.84 s (1H, C2H), 7.26–7.14 m (5H, C6H5),
6.17 s (1H, C9H), 2.68 m (2H, CH2), 2.25 m (2H, CH2),
1.93 m (2H, CH2). Found, %: C 70.37; H 4.80; N 19.36.
C17H14N4O. Calculated %: C 70.34; H 4.83; N 19.31.
Compounds XIIIb, XIIId, XIIIh were obtained similarly.
9-(4-Carboxyphenyl)-2-methyl-5,6,7,9-
tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one (Vg).
Yield 3.7 mmol (61%), mp >300°C. IR spectrum, cm–1:
3600–2500 (OH, NH, CH2), 1716 (CO), 1628 (C=C),
1578 (CO). 1H NMR spectrum, δ, ppm: 10.45 br.s (1H,
N4H), 7.16–7.80 d.d (4H, C6H4, J 8.4 Hz), 6.01 s (1H,
C3H), 5.53 s (1H, C9H), 2.59 m (2H, CH2), 2.18 m (2H,
CH2), 1.99 s (3H, CH3), 1.86 m (2H, CH2). Found, %:
C 66.83; H 5.25; N 13.10. C18H17N3O3. Calculated, %:
C 66.87; H 5.26; N 13.00.
2-Methyl-9-(4-nitrophenyl)-5,6,7,9-tetra-
hydropyrazolo[5,1-b]quinazolin-8(4H)-one (Vh).
Yield 3.5 mmol (69%), mp 263–265°C. IR spectrum,
cm–1: 3216–2750 (NH, CH2), 1640 (C=C), 1576 (CO),
1348 (NO2). 1H NMR spectrum, δ, ppm: 10.61 br.s (1H,
N4H), 7.31–8.11 d.d (4H, C6H4, J 8.4 Hz), 6.17 s (1H,
C3H), 5.57 s (1H, C9H), 2.59 m (2H, CH2), 2.19 m (2H,
CH2), 1.99 s (3H, CH3), 1.86 m (2H, CH2). Found, %:
C 62.96; H 4.95; N 17.30. C17H16N4O3. Calculated, %:
C 62.96; H 4.94; N 17.28.
9-(4-Methylphenyl)-8-oxo-4,5,6,7,8,9-hexahydro-
pyrazolo[5,1-b]quinazoline-3-carbonitrile (XIIIb).
Yield 1.2 mmol (59%), mp 310–313°C. IR spectrum,
cm–1 : 3232 (NH, H-bound), 2972, 2940, 2856 (CH2),
1
2228 (CN), 1648 (C=O). H NMR spectrum, δ, ppm:
11.18 br.s (1H, NH), 7.82 s (1H, C2H), 7.04 m (4H, C6H4),
6.13 s (1H, C9H), 2.64 m (2H, CH2), 2.27 m (2H, CH2),
1.93 (2H, CH2), 2.20 s (3H, CH3). Found, %: C 71.10;
H 5.22; N 18.45. C18H16N4O. Calculated, %: C 71.05;
H 5.26; N 18.42.
3-[5-Methyl-1(2)H-pyrazol-3-ylamino]cyclohex-2-
en-1-one (VI). A solution of 0.3 g (3 mmol) of amine I
and 0.34 g (3 mmol) of cyclohexanedione (III) in 1 ml
of DMF was boiled for 15 min till crystalline precipitate
formed. The reaction mixture was cooled, 5 ml of 2-pro-
panol was added, 2.2 mmol (75%) of compound VI was
filtered off, mp 274–276°C. Yield of compound VI in
the three-component condensation involving aldehydes
IIa–IIh was 12–17%. IR spectrum, cm–1: 3272–2800
(NH, CH2), 1624 (C=C), 1560 (CO). 1H NMR spectrum,
δ, ppm: 12.07 br.s (1H, NH), 8.94 br.s (1H, NH), 5.94 s
(1H, CH), 5.69 s (1H, C4H), 2.16 s (3H, CH3), 2.41 m
(2H, CH2), 2.07 m (2H, CH2), 1.83 m (2H, CH2). Found,
%: C 62.79; H 6.84; N 22.04. C10H13N3O. Calculated, %:
C 62.83; H 6.81; N 21.99.
8-Oxo-9-(4-chlorophenyl)-4,5,6,7,8,9-hexahydro-
pyrazolo[5,1-b]quinazoline-3-carbonitrile (XIIIe).
Yield 0.9 mmol (44%), mp 313–315°C. IR spectrum,
cm–1: 3232 (NH, H-bound), 2968, 2940, 2856 (CH2),
1
2232 (CN), 1644 (C=O). H NMR spectrum, δ, ppm:
11.29 br.s (1H, NH), 7.85 s (1H, C2H), 7.34–7.17 d.d (4H,
C6H4, J 8.6 Hz), 6.18 s (1H, C9H), 2.67 m (2H, CH2),
2.27 m (2H, CH2), 1.92 m (2H, CH2). Found, %: C 62.90;
H 3.98; Cl 10.93; N 17.23. C17H13ClN4O. Calculated, %:
C 62.87; H 4.01; Cl 10.94; N 17.26.
8-Oxo-9-(4-nitrophenyl)-4,5,6,7,8,9-hexahydro-
pyrazolo[5,1-b]quinazoline-3-carbonitrile (XIIIh).
Yield 1.1 mmol (54%), mp 307–309°C. IR spectrum,
cm–1: 3116 (NH, H-bound), 2936, 2900, 2842 (CH2),
N-Benzylidene-1(2)H-pyrazol-3-amine (IXa).Aso-
lution of 0.3 g (3 mmol) of amine I and 0.32 g (3 mmol)
of benzaldehyde (IIa) in 5 ml of ethanol containing
0.03 ml (0.3 mmol) of piperidine was boiled for 3 h.
The reaction mixture was cooled, the precipitate was
filtered off. Yield 2.2 mmol (72%), mp 242–244°C. IR
spectrum, cm–1: 3416–2920 (NH, CH3), 1684 (N=C).
1H NMR spectrum, δ, ppm: 12.50 br.s (1H, NH), 8.80 s
(1H, C4H), 6.31 s (1H, CH), 1.98 s (3H, CH3). Found,
%: C 72.03; H 5.47; N 22.89. C11H10N3. Calculated, %:
1
2232 (CN), 1648 (C=O), 1520, 1348 (NO2). H NMR
spectrum, δ, ppm: 11.43 br.s (1H, NH), 7.88 s (1H, C2H),
8.11–7.45 d.d (5H, C6H4, J 8.6 Hz), 6.32 s (1H, C9H),
2.68 m (2H, CH2), 2.24 m (2H, CH2), 1.93 m (2H, CH2).
Found, %: C 60.86; H 3.85; N 20.87. C17H13N5O3. Cal-
culated, %: C 60.90; H 3.88; N 20.90.
Ethyl 8-oxo-9-phenyl-4,5,6,7,8,9-hexahydro-
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LIPSON et al.
1396
6,6-Dimethyl-8-oxo-9-phenyl-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carbonitrile
(XVa). A mixture of 0.22 g (2 mmol) of amine X, 0.22
g (2 mmol) of benzaldehyde (IIa), and 0.28 g (2 mmol)
of dimedone (XII) in 1 ml of DMF was boiled for 1 h,
cooled, 7 ml of 2-propanol was added, the precipitate was
filtered off. Yield 1.3 mmol (63%), mp 303–305°C. IR
spectrum, cm–1: 3412 (NH, H-bound), 2980 (CH2, CH3),
pyrazolo[5,1-b]quinazoline-3-carboxylate (XIVa).
Amixture of 0.31 g (2 mmol) of ester XI, 0.21 g (2 mmol)
of aldehyde IIa, and 0.22 g (2 mmol) of ketone III in 1 ml
of DMF was boiled for 30 min, cooled, 5 ml of 2-propanol
was added, the precipitate was filtered off. Yield 0.8 mmol
(40%), mp 202–204°C. IR spectrum, cm–1: 3220 (NH,
H-bound), 2988, 2956 (CH2, CH3), 1700, 1648 (C=O).
1H NMR spectrum, δ, ppm: 9.77 br.s (1H, NH), 7.66 s
(1H, C2H), 7.30–7.12 m (5H, C6H5), 6.17 s (1H, C9H),
4.25 q (2H, CH2, J 6.8 Hz), 2.98–2.84 m (2H, CH2),
2.25 m (2H, CH2), 1.99–1.87 m (2H, CH2), 1.26 t (3H,
CH3). Found, %: C 67.70; H 5.62; N 12.48. C19H19N3O3.
Calculated, %: C 67.66; H 5.64; N 12.46.
1
2268 (CH2, CH3), 1596 (C=O). H NMR spectrum, δ,
ppm: 11.22 br.s (1H, NH), 7.84 s (1H, C2H), 7.21 m (5H,
C6H5), 6.15 s (1H, C9H), 2.56 s (2H, CH2), 2.26–2.01 d.d
(2H, CH2, J –16 Hz), 1.03, 0.92 s (3H, CH3). Found, %:
C 71.71; H 5.65; N 17.59. C19H18N4O. Calculated, %:
C 71.70; H 5.66; N 17.61.
Compounds XIVb, XIVe, XIVh were obtained simi-
Compounds XVb and XVe were similarly obtained.
larly.
6,6-Dimethyl-9-(4-methylphenyl)-8-oxo-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carbonitrile
(XVb). Yield 1.5 mmol (71%), mp 271–274°C. IR
spectrum, cm–1: 3398 (NH, H-bound), 2980 (CH2, CH3),
Ethyl 9-(4-methylphenyl)-8-oxo-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carboxylate
(XIVb). Yield 1.3 mmol (66%), mp 229–232°C. IR spec-
trum, cm–1: 3196 (NH, H-bound), 2944, 2900 (CH2, CH3),
1676, 1624 (C=O). 1H NMR spectrum, δ, ppm: 9.79 br.s
(1H, NH), 7.65 s (1H, C2H), 6.98 m (4H, C6H4), 6.13 s
(1H, C9H), 4.24 q (2H, CH2, J 6.8 Hz), 2.97–2.66 m (2H,
CH2), 2.26 m (2H, CH2), 2.19 s (3H, CH3), 1.98–1.73 m
(2H, CH2), 1.25 t (3H, CH3). Found, %: C 68.41; H 5.95;
N 11.95. C20H21N3O3. Calculated, %: C 68.38; H 5.98;
N 11.97.
1
2262 (CN), 1592 (C=O). H NMR spectrum, δ, ppm:
11.18 br.s (1H, NH), 7.83 s (1H, C2H), 7.04 m (4H, C6H4),
6.11 s (1H, C9H), 2.57 s (2H,CH2), 2.25–2.03 d.d (2H,
CH2, J –16 Hz), 2.20, 1.03, 0.92 C (3H, CH3). Found,
%: C 72.27; H 6.0; N 16.84. C20H20N4O. Calculated, %:
C 72.29; H 6.02; N 16.87.
6,6-Dimethyl-8-oxo-9-(4-chlorophenyl)-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carbonitrile
(XVe). Yield 0.15 mmol (75%), mp >310 °C. IR spec-
trum, cm–1: 3398 (NH, H-bound), 2980 (CH2, CH3),
Ethyl 8-oxo-9-(4-chlorophenyl)-4,5,6,7,8,9-hexa-
hydropyrazolo[5,1-b]quinazoline-3-carboxylate
(XIVe). Yield 0.9 mmol (45%), mp 206–208°C. IR spec-
trum, cm–1: 3248 (NH, H-bound), 2952, 2924 (CH2, CH3),
1676, 1624 (C=O). 1H NMR spectrum, δ, ppm: 9.90 br.s
(1H, NH), 7.67 s (1H, C2H), 7.33–7.14 d.d (4H, C6H4,
J 8.4 Hz), 6.18 s (1H, C9H), 4.25 q (2H, CH2, J 6.8 Hz)
2.96–2.58 m (2H, CH2), 2.27 m (2H, CH2), 1.94–1.89 m
(2H, CH2), 1.25 t (3H, CH3). Found, %: C 61.35; H 4.83;
Cl 9.53; N 11.34. C19H18ClN3O3. Calculated, %: C 61.37;
H 4.85; Cl 9.56; N 11.37.
1
2262 (CN), 1592 (C=O). H NMR spectrum, δ, ppm:
11.27 br.s (1H, NH), 7.86 s (1H, C2H), 7.35–7.16 d.d
(4H, C6H4, J 8.2 Hz), 6.17 s (1H, C9H), 2.55 s (2H, CH2),
2.26–2.02 d.d (2H, CH2 , J –16 Hz), 1.03, 0.92 s (3H,
CH3). Found, %: C 64.66; H 4.80; N 15.90. C19H17ClN4O.
Calculated, %: C 64.68; H 4.82; N 15.89.
Ethyl 6,6-dimethyl-8-oxo-9-phenyl-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carboxylate
(XVIa).Amixture of 0.31 g (2 mmol) of amine XI, 0.22 g
(2 mmol) of benzaldehyde (IIa), and 0.28 g (2 mmol)
of dimedone (XII) in 1 ml of DMF was boiled for 1 h,
cooled, 5–7 ml of 2-propanol was added, the precipitate
was filtered off. Yield 1.1 mmol (58%), mp 139–141°C.
IR spectrum, cm–1: 3408 (NH, H-bound), 2976 (CH2,
Ethyl 9-(4-nitrophenyl)-8-oxo-4,5,6,7,8,9-hexa-
hydropyrazolo[5,1-b]quinazoline-3-carboxylate
(XIVh). Yield 0.9 mmol (45%), mp 185–188°C. IR
spectrum, cm–1: 3368 (NH, H-bound), 2952 (CH2, CH3),
1688, 1640 (C=O), 1520, 1344 (NO2). 1H NMR spectrum,
δ, ppm: 10.01 br.s (1H, NH), 8.13–7.39 d.d (4H, C6H4,
J 8.8 Hz), 7.69 s (1H, C2H), 6.31 s (1H, C9H), 4.25 q
(2H, CH2, J 6.8 Hz), 2.96–2.62 m (2H, CH2), 2.24 m
(2H, CH2), 1.91 m (2H, CH2), 1.26 t (3H, CH3). Found,
%: 59.70; H 4.69; N 14.63. C19H18N4O5. Calculated, %:
59.69; H 4.71; N 14.66.
1
CH3), 1684, 1592 (C=O). H NMR spectrum, δ, ppm:
9.76 br.s (1H, NH), 7.66 s (1H, C2H), 7.20 m (5H, C6H5),
6.15 s (1H, C9H), 4.23 q (2H, CH2), 2.81–2.57 d.d (2H,
J –17.4 Hz), 2.27–2.02 d.d (2H, J –16.2 Hz), 1.26 t (3H,
CH3), 1.03, 0.91 s (3H, CH3). Found, %: 69.00; H 6.31;
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CASCADE CYCLIZATION OF 3(5)-AMINOPYRAZOLES
1397
Fathala, O.A., Zaki, M.E., Swelam, S.A., Nofal, S.M., and
el-Eraky, W.I., Acta Pol. Pharm., 2003, vol. 60, p. 51.
N 11.48. C21H23N3O3. Calculated, %: 69.04; H 6.30;
N 11.51.
6. Shiota, T., Yamamori, T., Sakai, K., Kiykawa, M.,
Honma, T., Ogawa, M., Hayashi, K., Ishizuka, N.,
Matsumura, K.-I., Hara, M., Fujimoto, M., Kawabata,
T., and Nakajima, S., Chem. Pharm. Bull., 1999, vol. 47,
p. 928; Bru-Magniez, N., Guengor, T., and Teulon, J.-M.,
French Patent 2690442, 1993; Chem. Abstr., 1994, p.
120, 323592; Roehter,G.., Schotten, T., Stenzel, W., and
Paol, M., German Patent 628559, 1993; Chem. Abstr.,
1995, vol. 123, 169666.
Esters XVIc and XVIe were similarly obtained.
Ethyl 6,6-dimethyl-9-(4-methoxyphenyl)-8-oxo-
4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazoline-3-
carboxylate (XVIc). Yield 1.2 mmol (62%), mp 225–
227°C. IR spectrum, cm–1: 3410 (NH, H-bound), 2960
1
(CH2, CH3), 1682, 1594 (C=O). H NMR spectrum, δ,
ppm: 9.75 br.s (1H, NH), 7.68 s (1H, C2H), 7.11–6.80 d.d
(4H, C6H4, J 8.8 Hz), 6.13 s (1H, C9H), 4.25 q (2H,
CH2), 2.83–2.67 d.d (2H, J –17.8 Hz), 2.29–2.02 d.d (2H,
J–16.2 Hz), 3.69 s (3H, OCH3), 1.28 t (3H, CH3), 1.05,
0.96 s (3H, CH3). Found, %: C 66.86; H 6.30; N 10.64.
C22H25N3O4. Calculated, %: C 66.84; H 6.33; N 10.63.
7. Suzuki, T., Yuasa, M., Takakuwa, T., Kishi, K.,
Matsunaga, H., Shimizu, H., Kaneda, S., Kumagai, T.,
and Nagase, H., Japan Patent 07242670, 1995; Chem.
Abstr., 1996, vol. 124, 146184; Tsujitani,N., Yuasa, M., and
Motoki, Y., Japan Patent 05255337, 1993; Chem. Abstr.,
1994, vol. 120, 245137.
Ethyl 6,6-dimethyl-8-oxo-9-(4-chlorophenyl)-
4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazoline-3-
carboxylate (XVIe). Yield 1.2 mmol (60%), mp 184–
186°C. IR spectrum, cm–1: 3400 (NH, H-bound), 2968
8. Graul, A.I., Drug News and Perspectives, 2000, vol. 13,
p. 37; Selleri, S., Bruni, F., Costagli, C., Costanzo, A.,
Guerrini, G., Ciciani, G., Gratteri, P., Bonaccini, C.,
Malmberg, Aiello, P., Besnard, F., Renard, S., Costa, B.,
and Martini, C., J. Med. Chem., 2003, vol. 46, p. 310;
Sullivan, S.K., Petroski, R.E., Verge, G., Gross, R.S.,
Foster, A.C., and Grigoriadis, D.E., J. Pharmacol. Exp.
Ther., 2004, vol. 311, 537; Radl, S., Czech Patent 293015,
2004; Chem. Abstr., 2005, vol. 143, 43894.
1
(CH2, CH3), 1680, 1590 (C=O). H NMR spectrum, δ,
ppm: 9.81 br.s (1H, NH), 7.68 s (1H, C2H), 7.34–7.13 d.d
(4H, C6H4, J 8.8 Hz), 6.17 s (1H, C9H), 4.22 q (2H, CH2),
2.87–2.66 d.d (2H, J –12.8 Hz), 2.26– 2.02 d.d (2H,
J–16.4 Hz), 1.26 t (3H, CH3), 1.02, 0.91 s (3H, CH3).
Found, %: C 63.20; H 5.50; N 10.50. C21H22ClN3O3.
Calculated, %: C 63.24; H 5.52; N 10.54.
9. Quiroga, J., Mejia, D., Insuasti, B., Abonia, R.,
Nogueras, M., Sanchez, A., Cobo, J., and Low, J.N.,
Tetrahedron, 2001, vol. 57, p. 6947.
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