Synthesis of new imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one derivatives by iodocyclization of 6-alkenyl(alkynyl)-aminopyrazolo[3,4-d] pyrimidin-4(5H)-ones

Article abstract of DOI:10.1134/S1070428011070165

6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)- ones reacted with iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R- imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-[4,3-e] pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydroimidazo[ 1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(5H)- ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo- [1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4- one on heating in sulfuric acid.

Full text of DOI:10.1134/S1070428011070165

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 7, pp. 1066–1073. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.V. Bentya, R.I. Vas’kevich, A.V. Turov, E.B. Rusanov, M.V. Vovk, V.I. Staninets, 2011, published in Zhurnal Organicheskoi
Khimii, 2011, Vol. 47, No. 7, pp. 1049–1056.
Synthesis of New Imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-
4(6H)-one Derivatives by Iodocyclization of 6-Alkenyl(alkynyl)-
aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones
A. V. Bentyaa, R. I. Vas’kevicha, A. V. Turovb, E. B. Rusanova,
M. V. Vovka, and V. I. Staninetsa
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: bentya@gmail.com
b Taras Shevchenko Kiev National University, Kiev, Ukraine
Received May 4, 2010
Abstract—6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones reacted with
iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-
ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-
[4,3-e]pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydro-
imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-
[4,3-e]pyrimidin-4(5H)-ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo-
[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-
dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one on heating in sulfuric acid.
DOI: 10.1134/S1070428011070165
We previously showed [1, 2] that cyclization of
6-allyl(prop-2-yn-1-yl)sulfanylpyrazolo[3,4-d]pyrimi-
din-4(5H)-ones by the action of iodine or sulfuric acid
provides a convenient method for the synthesis of
4H-pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4-one
derivatives. Taking into account pronounced pharma-
cological effect of their bioisosters (in particular,
imidazo[1,2-a]pyrazolo[4,3-e]pyrimidines are efficient
phosphodiesterase inhibitors [3–6]), it seemed impor-
tant to develop new preparatively simple procedures
for the synthesis of such compounds. Known proce-
dures [3, 7] generally include a number of steps and
utilize difficultly accessible reagents. Furthermore,
compounds having functional substituents in the imid-
azole ring cannot be obtained by the known methods,
whereas the presence of such substituents is necessary
for subsequent modifications with pharmacophoric
fragments.
din-4(5H)-ones Ia and Ib as initial compounds to
develop a convenient procedure for the synthesis of
6-allylamino-, 6-diallylamino-, and 6-(prop-2-yn-1-yl-
amino)-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones II–
ІV and studied in detail their cyclization by the action
of iodine, as well as some interesting transformations
of the cyclization products (Scheme 1).
The presence in molecules ІI–ІV of two nucleo-
philic centers (N5 and N7) could give rise to formation
of both angularly and linearly fused cyclization prod-
ucts. However, reactions of ІI–ІV with 3 equiv of
iodine in acetic acid at room temperature and subse-
quent treatment with sodium sulfite resulted in the
formation of only angular 8-iodomethyl-substituted
1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-
ones Va, Vb, VIa, VIb, and VII. Pyrazolopyrimidines
IIIa and IIIb having two allyl groups on the exocyclic
nitrogen atom reacted only at one allyl fragment.
6-Allyl derivatives VIa and VIb thus obtained were
used as reference compounds for the determination of
the position of hydrogen atom in compounds Va, Vb,
and VII containing a guanidine fragment. The struc-
ture of compounds Va, Vb, VIa, VIb, and VII was
A promising synthetic approach to the desired com-
pounds may be that based on electrophilic cyclization
of pyrazolo[3,4-d]pyrimidines having allylamino or
prop-2-yn-1-ylamino group in the 6-position. In the
present work we used 6-chloropyrazolo[3,4-d]pyrimi-
1066

SYNTHESIS OF NEW IMIDAZO[1,2-a]PYRAZOLO[4,3-e]PYRIMIDIN-4(6H)-ONE
1067
Scheme 1.
O
N
O
O
N
NH
NH
NH
HN(CH2CH=CH2)2
CH2=CHCH2NH2
N
N
N
CH2
CH2
CH2
N
N
N
N
N
Cl
N
H
R
R
R
IIIa, IIIb
Ia, Ib
IIa, IIb
(1) 3I2
(1) 3I2
(2) Na2SO3
HC
≡
CCH2NH2
(2) Na2SO3
O
N
O
N
O
N
NH
N
N
N
N
N
N
N
N
N
N
NH
CH2
H
CH
R
Ph
R
I
I
VIa, VIb
AcONa
IV
Va, Vb
AcONa
(1) 3I2
(2) Na2SO3
H2SO4
O
N
O
O
O
N
N
Me
N
N
N
H2SO4
R = Ph
N
N
N
N
N
N
N
N
N
N
N
NH
NH
CH2
R
Ph
Ph
R
I
H2C
H2C
IXa, IXb
VII
XII
VIIIa, VIIIb
Δ
Δ
H2SO4 (R = H)
O
N
O
N
NH
N
N
N
Ph
N
N
N
N
CH2
R
Me
Me
Xa, Xb
XI
R = H (a), Ph (b).
1
confirmed by their IR and H and 13C NMR spectra.
The IR spectra of these compounds displayed absorp-
tion bands due to carbonyl stretching vibrations in the
region 1660–1600 cm–1, which is consistent with their
angular structure implying the presence of conjugated
O=C–N= bond sequence in the pyrimidine ring. The
carbonyl carbon atom resonated in the 13C NMR spec-
tra at δC 164–166 ppm [8].
at 60°C led to the formation of 8-methylidene deriva-
tives VIIIa, VIIIb, IXa, and IXb as a result of elim-
ination of hydrogen iodide. Compound VIIIb charac-
1
teristically showed in the H NMR spectrum a large
difference in the positions of signals from olefinic
protons, one of which was displaced strongly upfield
(δ 3.50 ppm) due to deshielding effect of the benzene
ring on N1 oriented orthogonally to the exocyclic
double bond plane. Analogous shifts of olefinic proton
signals were observed by us previously [1], and angu-
Treatment of compounds Va, Vb, VIa, and VIb
with an equimolar amount of sodium acetate in DMSO
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

BENTYA et al.
Compound IXb at 275°C was converted into
1068
8.08H
O
imidazopyrazolopyrimidine XI via migration of the
exocyclic double bond into the imidazole ring. The
position of the carbonyl absorption band in the IR
spectrum of XI did not differ considerably from that
observed in the spectrum of IXb; it was located at
1615 cm–1. The carbonyl carbon signal appeared in the
13C NMR spectrum of XI at δC 163 ppm. Comparison
N
158.0
105.0
N
140.7
7.5–H7.6
N
9.0
N
NH
126.0
138.7
138.1
48.0
7.5–7.6 H129.6
94.8
1
of the IR and H and 13C NMR spectra of compound
H
H
4.19
H
3.46
XІ with those of Xa and Xb ensures fairly reliable
interpretation of their structures.
H
129.7
4.40
H 7.5–7.6
Unlike unsubstituted analog VIIIa, compound
VIIIb having a phenyl group on the nitrogen atom in
the pyrazole ring underwent isomerization to linearly
fused tricyclic structure XII in sulfuric acid at room
temperature. The same product was also obtained by
electrophilic cyclization of 6-(prop-2-yn-1-ylamino)-
substituted pyrazolopyrimidine IVb by the action of
concentrated sulfuric acid at 55°C. Compound XII
displayed in the IR spectrum absorption band at
1710 cm–1 due to stretching vibrations of the carbonyl
group. The chemical shift of the carbonyl carbon atom
was equal to δC 155 ppm.
Fig. 1. Correlations in the HMBC spectrum of 8-methyli-
dene-1-phenyl-7,8-dihydro-1H-imidazo[1,2-a]pyrazolo-
[4,3-e]pyrimidin-4(6H)-one compound VIIIb.
lar structure of the corresponding cyclization product
was proved by X-ray analysis. The positions of the
carbonyl absorption band in the IR spectrum and of the
C4 signal in the 13C NMR spectrum were almost simi-
lar. Reliable assignment of carbon signals in the
13C NMR spectrum of VIIIb was made on the basis of
1
heteronuclear H–13C correlations (HMQS and
HMBC; see table and Fig. 1).
The structure of XII was unambiguously deter-
mined by X-ray analysis (Fig. 2). We have found no
crystallographic data for representatives of this tri-
cyclic system. Compounds containing particular frag-
ments of such system were studied, e.g., in [9, 10]. The
bond lengths and bond angles in the tricyclic fragment
clearly indicate delocalization of electron density
therein. The tricyclic skeleton is almost planar, the
average deviation of atoms from the mean-square
plane is as small as 0.023 Å, and the phenyl ring
(C9–C14) is turned through a dihedral angle of 29° with
respect to that plane. Molecules XII in crystal (Fig. 3)
are linked to infinite chains along the z crystallo-
graphic axis by hydrogen bonds N5–H5n···O1′ with the
following parameters: N5–H5 0.957(18), N5 ···O1
2.7375(16) Å, ∠N5H5O1′ 162.7(15)° (the primed
number corresponds to the oxygen atom in the
neighboring molecule, which is related to the initial
atoms through the symmetry transformation x, –y +
1.5, z – 0.5).
Heating of compounds VIIIa and VIIIb above their
melting points (360 and 285°C, respectively) promoted
1,3-prototropic shifts in the allyl fragment in the imid-
azole ring and in the guanidine fragment of the imid-
azopyrimidine system, which resulted in the formation
of isomeric 8-methyl-1R-imidazo[1,2-a]pyrazolo-
[4,3-e]pyrimidin-4(5H)-ones Xa and Xb. The isomer-
ization of compound VIIIa also occurred at room tem-
perature in concentrated sulfuric acid. In the IR spectra
of Xa and Xb, the carbonyl absorption band was
observed at higher frequencies (1690–1685 cm–1), and
the carbonyl carbon signal in the 13C NMR spectrum
was displaced upfield by 8–10 ppm.
Cross peaks in the HMQC and HMBC spectra of 8-meth-
ylidene-1-phenyl-7,8-dihydro-1H-imidazo[1,2-a]pyrazolo-
[4,3-e]pyrimidin-4(6H)-one (VIIIb)
δC, ppm
δ, ppm
HMQC
HMBC
8.08
7.55
138.75
140.67, 105.05
EXPERIMENTAL
129.73, 129.62, 126.03 138.75, 129.73, 129.61,
126.03
The IR spectra were recorded in KBr on a UR-20
1
instrument. The H NMR spectra were measured on
4.40
4.17
3.46
94.84
46.35
94.89
–
a Varian VXR-300 spectrometer (300 MHz) using
tetramethylsilane as internal reference. The 13C NMR
spectra were obtained on a Bruker Avance DRX-500
158.02, 138.14, 94.84
–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

SYNTHESIS OF NEW IMIDAZO[1,2-a]PYRAZOLO[4,3-e]PYRIMIDIN-4(6H)-ONE
1069
O1
spectrometer (125.75 MHz), and the HMQC and
HMBC spectra of compound VIIIb were recorded on
a Varian Mercury-400 instrument (400 MHz for H)
from solutions in DMSO-d6 using tetramethylsilane as
internal reference. The mass spectra of VIIIa, IXa,
IXb, and Xa were obtained on an Agilent 1100/DAD/
HSD/VLG119562 instrument.
C8
C1
C4
1
C2
N3
C6
N2
C7
C3
N1
C5
N5
The X-ray diffraction data for compound XII were
acquired from a 0.08×0.20×0.41-mm single crystal at
room temperature on a Bruker Smart Apex II diffrac-
tometer (λMoKα irradiation, graphite monochromator,
θmax = 28.27°, spherical segment –17 ≤ h ≤ 17, –9 ≤
k ≤ 9, –18 ≤ l ≤ 17). Monoclinic crystal system, space
group P21/c; unit cell parameters: a = 13.2138(6), b =
7.0193(3), c = 13.9798(6) Å; β = 112.473(2)°; V =
1198.18(9)Å3; Z = 4; dcalc = 1.245 g/cm3; µ =
0.082 mm–1; F(000) = 884; C14H11N5O; M 265.28.
Total of 12369 reflections were measured, 2971 of
which were independent (merging factor R = 0.0454).
A correction for absorption was introduced using
SADABS program (ratio of the minimal and maximal
corrections Tmin/Tmax = 0.722666). The structure was
solved by the direct method and was refined by the
least-squares procedure in full-matrix anisotropic ap-
proximation using SHELXS97 and SHELXL97 soft-
ware packages [11, 12]. Hydrogen atoms were visual-
ized objectively, and their positions were refined in
isotropic approximation. The refinement procedure
involved 1996 reflections with I > 2σ(I) (225 refined
parameters, 8.87 reflections per parameter), and the
weight scheme ω = 1/[σ2(Fo2) + (0.0551R)2 + 0.0471P]
was used, where R = (Fo2 + 2Fc2)/3 [ratio of the
maximal (average) shift to the error in the last iteration
0.019 (0.001)]. The final divergence factors were
R1(F) = 0.0436, wR2(F2) = 0.0963 for reflections with
I > 2σ(I) and R1(F) = 0.0751, wR2(F2) = 0.1101 for all
reflections; goodness of fit 1.007. The residual electron
density from the Fourier difference series after the last
iteration was 0.15 and –0.25 e/Å3. The X-ray diffrac-
tion data for compound XII were deposited to the
Cambridge Crystallographic Data Centre (entry
no. CCDC 771233).
N4
C9
C10
C14
C13
C11
C12
Fig. 2. Structure of the molecule of 6-methyl-1-phenyl-1,8-
dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one
(XII) according to the X-ray diffraction data. Principal bond
lengths (Å) and bond angles (deg): C1–N2 1.307(2), C1–C2
1.410(2), C2–C3 1.398(2), C3–N1 1.3685(18), N1–N2
1.3877(17), C2–C4 1.410(2), C4–O1 1.2306(16), C4–N3
1.4130(18), C5–N3 1.3906(17), C5–N4 1.3236(17), C3–N4
1.3468(17), C6–N3 1.4176(18), C6–C7 1.332(2), C7–N5
1.3802(19), C5–N5 1.3398(17); C2C4N3 111.03(12), C5N3C4
122.48(12), N4C5N3 127.10(12), C5N4C3 110.68(12), N4C3C2
127.55(13), C3C2C4 121.09(13).
x
0
z
y
Fig. 3. A fragment of crystal packing of compound XII. Hy-
drogen-bonded chains of molecules along the z crystallo-
graphic axis are shown; hydrogen atoms (except for N5–H)
are not shown.
6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyra-
zolo[3,4-d]pyrimidin-4(5H)-ones IIa, IIb, IIIa, IIIb,
and IV (general procedure). A mixture of 10 mmol of
6-chloropyrazolo[3,4-d]pyrimidin-4(5H)-one Ia or Ib
and 40 mmol of prop-2-en-1-amine, N-(prop-2-en-1-
yl)prop-2-en-1-amine, or prop-2-yn-1-amine in 15 ml
of ethanol was heated for 4 h at 90–100°C in a sealed
ampule. The mixture was cooled, and the precipitate
was filtered off, washed with ethanol, and dried in air.
Compounds IIb, IIIb, and IV were additionally puri-
fied by recrystallization from ethanol.
6-(Prop-2-en-1-ylamino)-1H-pyrazolo[3,4-d]py-
rimidin-4(5H)-one (IIa). Yield 1.61 g (84%),
mp 295–297°C. IR spectrum, ν, cm–1: 3090 (NH),
1680 (C=O), 1600, 1520, 1370, 1300, 1130, 1080,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

BENTYA et al.
1070
1
1010, 940, 830, 780, 720. H NMR spectrum, δ, ppm:
3.93 t (2H, CH2, J = 4.8 Hz), 5.12 d (1H, =CH, J =
10.2 Hz), 5.21 d (1H, =CH, J = 17.1 Hz), 5.86–5.99 m
(1H, =CH), 6.54–6.63 m (1H, NH), 7.74 s (3-H),
10.42 s (1H, NH), 12.90 s (1H, NH). 13C NMR spec-
trum, δC, ppm: 42.42 (CH2), 99.39 (C3a), 115.38
(=CH2), 134.56 (C3, =CH), 153.37 (C7a) 155.88 (C6),
157.89 (C4). Found, %: C 50.44; H 4.86; N 36.39.
C8H9N5O. Calculated, %: C 50.26; H 4.74; N 36.63.
3460, 3280 (NH), 1690 (C=O), 1610, 1590, 1550,
1500, 1400, 1300, 1110, 1070, 980, 860, 780, 760,
720. H NMR spectrum, δ, ppm: 3.20–3.25 m (1H,
≡CH), 4.11–4.20 m (2H, CH2), 7.05–7.13 m (1H, NH),
7.33 t (1H, Harom, J = 7.5 Hz), 7.52 t (2H, Harom, J =
7.8 Hz), 8.08 s (3-H), 8.19 d (2H, Harom, J = 7.8 Hz),
10.98 s (1H, NH). Found, %: C 63.22; H 4.06;
N 26.39. C14H11N5O. Calculated, %: C 63.39; H 4.18;
N 26.40.
1
1-Phenyl-6-(prop-2-en-1-ylamino)-1H-pyrazolo-
[3,4-d]pyrimidin-4(5H)-one (IIb). Yield 2.38 g
(89%), mp 211–213°C (from ethanol). IR spectrum, ν,
cm–1: 3480, 3400, 3250, 3150 (NH), 1690 (C=O),
1620, 1590, 1550, 1500, 1400, 1290, 1110, 1060, 990,
8-Iodomethyl-1-R-7,8-dihydroimidazo[1,2-a]-
pyrazolo[4,3-e]pyrimidin-4(6H)-ones Va and Vb
and 6-allyl-8-iodomethyl-1-R-7,8-dihydroimidazo-
[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones VIa and
VIb (general procedure). A solution of 1.52 g
(6 mmol) of iodine in 150 ml of acetic acid was added
at room temperature to a suspension of 2 mmol of
6-allyl(diallyl)aminopyrazolo[3,4-d]pyrimidin-4(5H)-
one ІІa, IIb, IIIa, or IIIb in 10 ml of acetic acid, and
the mixture was stirred for 24 h. The solution was
evaporated to dryness, 30 ml of acetonitrile was added
to the residue (in the reactions with ІІa, IIIa) or the
salt-like precipitate was filtered off, washed with
diethyl ether, and dissolved in 30 ml of acetonitrile (in
the reactions with ІІb and IIIb). The solution was
treated under stirring with a 5% solution of sodium
sulfite until brown color disappeared, the mixture was
evaporated to 2/3 of the initial volume, and the precip-
itate was filtered off, washed with distilled water, and
dried in air.
1
960, 920, 830, 780, 750, 710. H NMR spectrum, δ,
ppm: 4.00 t (2H, CH2, J = 5.4 Hz), 5.15 d (1H, =CH,
J = 10.5 Hz), 5.27 d (1H, =CH, J = 17.1 Hz), 5.88–
6.01 m (1H, =CH), 6.82–6.94 m (1H, NH), 7.30 t (1H,
Harom, J = 7.5 Hz), 7.51 t (2H, Harom, J = 7.8 Hz), 8.04 s
(3-H), 8.13 d (2H, Harom, J = 7.8 Hz), 10.77 s (1H,
NH). 13C NMR spectrum, δC, ppm: 42.87 (CH2),
101.17 (C3a), 115.81 (=CH2), 120.19 (2C, Carom),
126.08 (Carom), 128.73 (2C, Carom), 134.42 (=CH),
135.83 (C3), 139.00 (Carom), 153.73 (C7a), 154.24 (C6),
157.58 (C4). Found, %: C 62.84; H 4.87; N 26.18.
C14H13N5O. Calculated, %: C 62.91; H 4.90; N 26.20.
6-Bis(prop-2-en-1-yl)amino-1H-pyrazolo[3,4-d]-
pyrimidin-4(5H)-one (IIIa). Yield 1.80 g (78%),
mp 242–244°C. IR spectrum, ν, cm–1: 3190, 3120
(NH), 1690 (C=O), 1600, 1410, 1320, 1290, 1260,
1070, 1010, 930, 770, 720. 1H NMR spectrum, δ, ppm:
4.09–4.23 m (4H, CH2), 5.11–5.24 m (4H, CH2), 5.76–
5.93 m (2H, CH), 7.80 s (3-H), 10.54 br.s (1H, NH),
12.94 br.s (1H, NH). Found, %: C 57.02; H 5.61;
N 30.17. C11H13N5O. Calculated, %: C 57.13; H 5.67;
N 30.28.
8-Iodomethyl-7,8-dihydro-1H-imidazo[1,2-a]-
pyrazolo[4,3-e]pyrimidin-4(6H)-one (Va). Yield
0.52 g (82%), mp 327–329°C. IR spectrum, ν, cm–1:
3290 (NH), 1600 (C=O), 1500, 1460, 1340, 1270,
1180, 1120, 1020, 980, 850, 780. 1H NMR spectrum, δ,
ppm: 3.32–3.38 m (1H, CH), 3.71–3.74 m (1H, CH),
3.85–3.91 m (1H, CH), 3.95–4.00 m (1H, CH), 4.60–
4.70 m (1H, CH), 8.19 s (3-H), 9.46–11.94 br.s (1H,
NH). 13C NMR spectrum, δC, ppm: 10.04 (CH2I),
47.23 (C7), 55.40 (C8), 102.34 (C3a), 128.21 (C3),
148.29 (C9a), 158.03 (C5a), 165.85 (C4). Found, %:
C 30.21; H 2.46; I 39.96; N 22.03. C8H8IN5O. Cal-
culated, %: C 30.30; H 2.54; I 40.02; N 22.09.
6-Bis(prop-2-en-1-yl)amino-1-phenyl-1H-pyra-
zolo[3,4-d]pyrimidin-4(5H)-one (IIIb). Yield 2.70 g
(88%), mp 190–192°C (from ethanol). IR spectrum, ν,
cm–1: 1710 (C=O), 1580, 1500, 1390, 1310, 1260,
1
1120, 960, 910. H NMR spectrum, δ, ppm: 4.18–
4.26 m (4H, CH2), 5.18–5.26 m (4H, CH2), 5.82–
5.97 m (2H, CH), 7.31 t (1H, Harom, J = 7.2 Hz), 7.52 t
8-Iodomethyl-1-phenyl-7,8-dihydro-1H-imidazo-
[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one (Vb).
Yield 0.61 g (78%), mp 220–222°C. IR spectrum, ν,
cm–1: 1640 (C=O), 1580, 1420, 1330, 1280, 1230,
(2H, Harom, J = 7.5 Hz), 8.07 s (3-H), 8.13 d (2H, Harom
,
J = 8.1 Hz), 10.90 s (1H, NH). Found, %: C 66.33;
H 5.46; N 22.64. C17H17N5O. Calculated, %: C 66.43;
H 5.58; N 22.79.
1
1170, 1050, 1030, 990, 960, 930, 780, 760. H NMR
1-Phenyl-6-(prop-2-yn-1ylamino)-1H-pyrazolo-
[3,4-d]pyrimidin-4(5H)-one (IV). Yield 2.23 g (84%),
mp 242–244°C (from ethanol). IR spectrum, ν, cm–1:
spectrum, δ, ppm: 2.58–2.64 m (1H, CH), 2.77–2.81 m
(1H, CH), 3.25–3.29 m (1H, CH), 3.79–3.86 m (1H,
CH), 4.45–4.54 m (1H, CH), 7.59–7.77 m (5H, Harom),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

SYNTHESIS OF NEW IMIDAZO[1,2-a]PYRAZOLO[4,3-e]PYRIMIDIN-4(6H)-ONE
1071
7.99 s (3-H), 8.26–9.15 br.s (1H, NH). 13C NMR spec-
trum, δC, ppm: 7.50 (CH2I), 46.35 (C7), 56.59 (C8),
103.06 (C3a), 126.36 (2C, Carom), 129.46 (2C, Carom),
129.70 (Carom), 137.26 (C3, Carom), 141.32 (C9a), 157.25
(C5a), 165.42 (C4). Found, %: C 42.67; H 3.05; I 32.11;
N 17.73. C14H12IN5O. Calculated, %: C 42.77; H 3.08;
I 32.28; N 17.81.
and the solution was treated with a 5% solution of
sodium sulfite until brown color disappeared. The mix-
ture was evaporated to 2/3 of the initial volume, and
the precipitate was filtered off, washed with water,
dried in air, and transferred into 20 ml of acetic acid.
The undissolved material was filtered off, the filtrate
was evaporated, 20 ml of hexane was added to the
residue, and the precipitate was filtered off and dried in
air. Yield 0.65 g (83%), mp 199–201°C. IR spectrum,
ν, cm–1: 3430, 3020, 2810 (NH), 1670 (C=O), 1600,
1410, 1380, 1330, 1240, 1180. 1080, 970, 820, 780,
8-Iodomethyl-6-(prop-2-en-1-yl)-7,8-dihydro-
1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-
one (VIa). Yield 0.51 g (71%), mp 158–160°C. IR
spectrum, ν, cm–1: 3340, 2930 (NH), 1640 (C=O),
1590, 1530, 1510, 1440, 1410, 1370, 1330, 1270,
1
760, 740. H NMR spectrum, δ, ppm: 4.12–4.17 m
(2H, CH2), 4.56–4.59 m (1H, =CHІ), 7.51–7.61 m (5H,
1
1180, 1080, 940, 780. H NMR spectrum, δ, ppm:
H
arom,), 8.10 s (3-H), 8.82–9.94 br.s (1H, NH).
3.33–3.38 m (1H, CH), 3.73–3.77 m (1H, CH), 3.84–
3.90 m (1H, CH), 3.93–4.12 m (3H, CH), 4.59–4.66 m
(1H, CH), 5.24 d (1H, =CH, J = 10.2 Hz), 5.34 d (1H,
=CH, J = 17.1 Hz), 5.77–5.90 m (1H, CH), 8.18 s
(3-H), 13.20 br.s (1H, NH). 13C NMR spectrum, δC,
ppm: 10.17 (CH2I), 45.99 (CH2), 51.04 (C7), 52.98
(C8), 102.76 (C3a), 117.93 (=CH2), 132.28 (C3, =CH),
141.36 (C9a), 156.55 (C5a), 166.87 (C4). Found, %:
C 36.78; H 3.28; I 35.43; N 19.54. C11H12IN5O. Cal-
culated, %: C 36.99; H 3.39; I 35.53; N 19.61.
13C NMR spectrum (CF3COOD), δC, ppm: 52.56 (C7),
64.61 (=CHІ), 102.86 (C3a), 125.73 (2C, Carom), 130.32
(2C, Carom), 131.72 (C9a), 132.35 (Carom), 136.16 (C8),
139.38 (C3, Carom), 154.97 (C5a), 156.17 (C4). Found,
%: C 43.25; H 2.72; І 32.75; N 18.08. C14H10IN5O.
Calculated, %: C 42.99; H 2.58; I 32.44; N 17.90.
8-Methylidene-1-R-7,8-dihydroimidazo[1,2-a]-
pyrazolo[4,3-e]pyrimidin-4(6H)-ones VIIIa and
VIIIb and 6-allyl-8-methylidene-1-R-7,8-dihydro-
imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones
IXa and IXb (general procedure). A mixture of
2 mmol of compound Va, Vb, VIa, or VIb and 0.25 g
(3 mmol) of sodium acetate in 15 ml of dimethyl
sulfoxide was stirred for 1h at 60°C. The mixture was
evaporated under reduced pressure (2 mm, oil pump;
in the reactions with Va and VІa) or cooled (in the
reactions with Vb and VІb), 20 ml of water was added,
and the precipitate was filtered off, washed in succes-
sion with ethanol and diethyl ether, and dried.
8-Iodomethyl-1-phenyl-6-(prop-2-en-1-yl)-7,8-di-
hydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-
4(6H)-one (VIb). Yield 0.81 g (93%), mp 235–237°C.
IR spectrum, ν, cm–1: 1660 (C=O), 1620, 1580, 1540,
1450, 1400, 1320, 1280, 1080, 980, 940, 780, 760,
1
740, 720. H NMR spectrum, δ, ppm: 2.57–2.61 m
(1H, CH), 2.80–2.84 m (1H, CH), 3.24–3.27 m (1H,
CH), 3.81–3.87 m (1H, CH), 4.04 d (2H, CH2, J =
5.4 Hz), 4.44–4.49 m (1H, CH), 5.25 d (1H, =CH, J =
10.2 Hz), 5.33 d (1H, =CH, J = 17.1 Hz), 5.77–5.91 m
(1H, CH), 7.59–7.75 m (5H, Harom), 8.00 s (3-H).
13C NMR spectrum, δC, ppm: 7.49 (CH2I), 46.39
(CH2), 50.49 (C7), 54.53 (C8), 103.05 (C3a), 118.38
(=CH2), 126.25 (2C, Carom), 129.46 (2C, Carom), 129.79
(Carom), 131.55 (=CH), 137.14 (Carom), 137.27 (C3),
141.36 (C9a), 154.96 (C5a), 164.87 (C4). Found, %:
C 47.01; H 3.66; I 29.16; N 16.12. C17H16IN5O. Cal-
culated, %: C 47.13; H 3.72; I 29.29; N 16.16.
8-Methylidene-7,8-dihydro-1H-imidazo[1,2-a]-
pyrazolo[4,3-e]pyrimidin-4(6H)-one (VIIIa). Yield
0.28 g (74%), mp >360°C. IR spectrum, ν, cm–1: 3270,
3130, 3080, 2910 (NH), 1640 (C=O), 1600, 1500,
1400, 1380, 1360, 1310, 1260, 1240, 1180, 850, 780.
1H NMR spectrum, δ, ppm: 4.41 m (2H, CH2), 4.73 m
(1H, =CH), 5.60 m (1H, =CH), 8.31 s (3-H), 8.51–
9.53 br.s (1H, NH), 12.97–13.92 br.s (1H, NH). Mass
spectrum: m/z 190 [M + 1]+. Found, %: C 50.63;
H 3.58; N 36.99. C8H7N5O. Calculated, %: C 50.79;
H 3.73; N 37.02. M 189.18.
8-Iodomethylidene-1-phenyl-7,8-dihydro-1H-
imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one
(VII). A solution of 1.52 g (6 mmol) of iodine in
150 ml of acetic acid was added at room temperature
to a suspension of 0.53 g (2 mmol) of 6-(prop-2-yn-1-
ylamino)pyrazolo[3,4-d]pyrimidin-4(5H)-one (IV) in
10 ml of acetic acid, and the mixture was stirred for
24 h. The salt-like precipitate was filtered off, washed
with hexane, and dissolved in 30 ml of acetonitrile,
8-Methylidene-1-phenyl-7,8-dihydro-1H-imid-
azo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one
(VIIIb). Yield 0.41 g (77%), mp 325–328°C. IR spec-
trum, ν, cm–1: 3100, 3040, 2800 (NH), 1660 (C=O),
1620, 1590, 1540, 1490, 1410, 1360, 1320, 1230,
1
1140, 960, 870, 780, 760. H NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

BENTYA et al.
1072
3.50 m (1H, =CH), 4.21 m (2H, CH2), 4.42 m (1H,
=CH), 7.47–7.65 m (5H, Harom), 8.09 s (3-H), 9.02 br.s
(1H, NH). 13C NMR spectrum, δC, ppm: 45.72 (C7),
93.81 (=CH2), 104.25 (C3a), 125.11 (2C, Carom), 128.67
(Carom), 128.77 (2C, Carom), 137.44 (Carom), 137.80 (C3),
138.81 (C9a), 139.88 (C8), 157.06 (C5a), 164.64 (C4).
Found, %: C 63.14; H 4.08; N 26.35. C14H11N5O. Cal-
culated, %: C 63.39; H 4.18; N 26.40.
3100, 1685, 1590, 1420, 1390, 1260, 1210, 1140, 930,
850, 800, 760, 710. H NMR spectrum, δ, ppm: 2.56 s
1
(3H, CH3), 6.72 s (7-H), 8.60 s (3-H), 11.50–12.38 br.s
(1H, NH), 13.22–14.15 br.s (1H, NH). Mass spectrum:
m/z 190 [M + 1]+. Found, %: C 50.68; H 3.67; N 36.95.
C8H7N5O. Calculated, %: C 50.79; H 3.73; N 37.02.
M 189.18.
8-Methyl-1-phenyl-1H-imidazo[1,2-a]pyrazolo-
[4,3-e]pyrimidin-4(5H)-one (Xb). Yield 0.21 g (79%)
(a), mp 336–338°C (from EtOH–DMSO). IR spec-
trum, ν, cm–1: 2750 (NH), 1690 (C=O), 1630, 1590,
1550, 1500, 1450, 1410, 1380, 1140, 960, 770, 760,
8-Methylidene-6-(prop-2-en-1-yl)-7,8-dihydro-
1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-
one (IXa). Yield 0.26 g (57%), mp 244–246°C. IR
spectrum, ν, cm–1: 3110, 2900, 2820, 1660 (C=O),
1600, 1510, 1430, 1360, 1330, 1270, 1160, 1090, 990,
940, 830, 790. 1H NMR spectrum, δ, ppm: 4.09 d (2H,
CH2, J = 5.7 Hz), 4.40 m (2H, CH2), 4.80 m (1H,
=CH), 5.23–5.32 m (2H, =CH2), 5.64 m (1H, =CH),
5.81–5.94 m (1H, CH), 8.32 s (3-H), 13.48 s (1H, NH).
Mass spectrum: m/z 230 [M + 1]+. Found, %: C 57.55;
H 4.71; N 30.38. C11H11N5O. Calculated, %: C 57.63;
H 4.84; N 30.55. M 229.24.
1
700. H NMR spectrum, δ, ppm: 1.36 s (3H, CH3),
6.66 s (7-H), (1H, Harom), 7.58–7.70 m (5H, Harom),
8.28 s (3-H), 12.24 br.s (1H, NH). 13C NMR spectrum,
δC, ppm: 10.99 (CH3), 104.21 (C3a), 119.93 (C9a),
126.85 (C7), 127.88 (2C, Carom), 129.56 (2C, Carom),
130.40 (Carom), 137.87 (C3), 139.92 (C8), 140.83
(Carom), 144.10 (C5a), 156.39 (C4). Found, %: C 63.23;
H 4.11; N 26.32. C14H11N5O. Calculated, %: C 63.39;
H 4.18; N 26.40.
8-Methylidene-1-phenyl-6-(prop-2-en-1-yl)-7,8-
dihydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimi-
din-4(6H)-one (IXb). Yield 0.47 g (77%), mp 246–
248°C. IR spectrum, ν, cm–1: 1660 (C=O), 1610, 1560,
1520, 1410, 1350, 1310, 1280, 1240, 1170, 1130,
8-Methyl-1-phenyl-6-(prop-2-en-1-yl)-1H-imid-
azo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one (XI).
Compound IXb, 0.31 g (1 mmol), was heated for
5 min on a sand bath at 275°C, cooled to room tem-
perature, and treated with 5 ml of diethyl ether, and the
precipitate was filtered off and recrystallized from
ethanol. Yield 0.28 g (91%), mp 307–309°C (from
EtOH). IR spectrum, ν, cm–1: 1615 (C=O), 1560, 1490,
1420, 1250, 1120, 1050, 1010, 980, 940, 770, 740,
1
1070, 1000, 980, 940, 880, 780, 770. H NMR spec-
trum, δ, ppm: 3.51–3.56 m (1H, =CH), 4.12 d (2H,
CH2, J = 5.4 Hz), 4.23 m (2H, CH2), 4.49–4.53 m (1H,
=CH), 5.24–5.34 m (2H, =CH2), 5.78–5.94 m (1H,
=CH), 7.47–7.64 m (5H, Harom), 8.11 s (3-H). Mass
spectrum: m/z 306 [M + 1]+. Found, %: C 66.56;
H 4.88; N 22.87. C17H15N5O. Calculated, %: C 66.87;
H 4.95; N 22.94. M 305.34.
1
700. H NMR spectrum, δ, ppm: 1.39 s (3H, CH3),
4.56 d (2H, CH2, J = 5.4 Hz), 5.14–5.26 m (2H,
=CH2), 5.90–6.05 m (1H, =CH), 7.02 s (7-H), 7.60–
7.68 m (5H, Harom), 8.15 s (3-H). 13C NMR spectrum,
δC, ppm: 11.42 (CH3), 46.26 (CH2), 106.73 (C3a),
115.76 (C7), 117.61 (=CH2), 117.94 (C8), 127.75 (2C,
8-Methyl-1R-imidazo[1,2-a]pyrazolo[4,3-e]py-
rimidin-4(5H)-ones Xa and Xb (general procedure).
a. Compound VIIIa or VIIIb, 1 mmol, was heated for
5 min on a sand bath at 360°C (VIIIa) or 285°C
(VIIIb). The resulting material was cooled and treated
with 5 ml of diethyl ether, and the precipitate was
filtered off. Compound Xb was purified by recrystal-
lization from EtOH–DMSO.
C
arom), 129.39 (2C, Carom), 130.08 (Carom), 132.07 (C3),
137.11 (=CH), 140.11 (Carom), 140.27 (C9a), 148.05
(C5a), 163.07 (C4). Found, %: C 66.78; H 4.83;
N 22.85. C17H15N5O. Calculated, %: C 66.87; H 4.95;
N 22.94.
6-Methyl-1-phenyl-1,8-dihydro-4H-imidazo-
[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one (XII).
a. A solution of 0.27 g (1 mmol) of compound VIIIa in
10 ml of concentrated sulfuric acid was kept for 6 h at
room temperature. It was then poured onto ice and
neutralized to pH 7 with 25% aqueous ammonia, and
the precipitate was filtered off, washed with water, and
dried.
b. A solution of 0.27 g (1 mmol) of compound
VIIIa in 10 ml of sulfuric acid was left to stand for 8 h
at room temperature. It was then poured onto ice and
neutralized to pH 7 with 25% aqueous ammonia, and
the precipitate was filtered off, washed with water, and
dried.
8-Methyl-1H-imidazo[1,2-a]pyrazolo[4,3-e]py-
rimidin-4(5H)-one (Xa). Yield 0.16 g (85%) (a),
0.14 g (74%) (b); mp >360°C. IR spectrum, ν, cm–1:
b. A solution of 0.27 g (1 mmol) of compound IV in
10 ml of concentrated sulfuric acid was heated for 6 h
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

SYNTHESIS OF NEW IMIDAZO[1,2-a]PYRAZOLO[4,3-e]PYRIMIDIN-4(6H)-ONE
1073
3. Xia, Y., Chackalamannil, S., Czarniecki, M., Tsai, H.,
Vaccaro, H., Cleven, R., Cook, J., Fawzi, A.,
Watkins, R., and Zhang, H., J. Med. Chem., 1997,
vol. 40, p. 4372.
4. Beavo, J.A., Physiol. Rev., 1995, vol. 75, p. 725.
5. Syberts, E.J., Czarniecki, M., and Ahn, H.-S., Curr.
Pharm. Des., 1995, vol. 1, p. 373.
at 55°C. The mixture was then treated as described
above in a. Yield 0.21 g (78%) (a), 0.23 g (87%) (b);
mp 349–351°C (from DMSO). IR spectrum, ν, cm–1:
3100, 2980, 2810 (NH), 1710 (C=O), 1610, 1540,
1460, 1400, 1250, 1210, 1150, 1100, 1060, 980, 910,
1
820, 790, 760, 700. H NMR spectrum, δ, ppm: 2.63 s
(3H, CH3), 7.10 s (7-H), 7.33 t (1H, Harom, J = 7.8 Hz),
7.54 t (2H, Harom, J = 7.8 Hz), 8.17 d (2H, Harom, J =
8.4 Hz), 8.23 s (3-H), 12.00–12.69 br.s (1H, NH).
13C NMR spectrum, δC, ppm: 13.28 (CH3), 101.29
(C3a), 114.00 (C7), 120.90 (C6), 121.03 (2C, Carom),
126.37 (Carom), 129.67 (2C, Carom), 137.07 (C3), 139.84
(Carom), 149.28 (C8a), 153.97 (C9a), 155.67 (C4). Found,
%: C 63.29; H 4.17; N 26.37. C14H11N5O. Calculated,
%: C 63.39; H 4.18; N 26.40.
6. Syberts, E.J. and Ahn, H.-S., Annu. Rep. Med. Chem.,
1996, vol. 31, p. 61.
7. Jiang, M.X-W., Warshakoon, N.C., and Miller, M.J.,
J. Org. Chem., 2005, vol. 70, p. 2824.
8. Shawali, A.S. and Gomha, S.M., Tetrahedron, 2002,
vol. 58, p. 8559.
9. Suwinska, K., Golankiewicz, B., and Zielenkiewicz, W.,
Acta Crystallogr., Sect. C, 2001, vol. 57, p. 767.
10. Hong-Qing Wang, Zhao-Jie Liu, and Ming-Wu Ding,
Phosphorus, Sulfur Silicon Relat. Elem., 2004, vol. 179,
p. 2039.
REFERENCES
11. Sheldrick, G.M., SHELXS97. Program for the Solution
of Crystal Structure, Göttingen, Germany: Univ. of
Göttingen, 1997.
12. Sheldrick, G.M., SHELXL97. Program for the Refine-
ment of Crystal Structures, Göttingen, Germany: Univ.
of Göttingen, 1997.
1. Bentya, A.V., Vas’kevich, R.I., Bol’but, A.V., Vovk, M.V.,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011