Five-membered 2,3-dioxo heterocycles: LXXX. Recyclization of 1H-pyrrole-2,3-diones into pyrazolo[1,5-a]pyrimidines by the action of pyrazolamine. Crystalline and molecular structure of substituted pyrazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1134/S107042801109017X

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with 3-methyl-4-phenyl-1H-pyrazol-5-amine to give methyl 7-arylcarbamoyl-6-aroyl-2-methyl-3-phenylpyrazolo[1,5-a]-pyrimidine-5- carboxylates. The molecular and crystalline structures of methyl 6-benzoyl-7-(4-chlorophenylcarbamoyl)-2-methyl-3-phenylpyrazolo[1,5-a] pyrimidine-5-carboxylate were studied by X-ray analysis. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S107042801109017X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 9, pp. 1362–1365. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © E.S. Denislamova, N.V. Bubnov, Z.G. Aliev, A.N. Maslivets, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 9,
pp. 1341–1344.
Five-Membered 2,3-Dioxo Heterocycles: LXXX.* Recyclization
of 1H-Pyrrole-2,3-diones into Pyrazolo[1,5-a]pyrimidines
by the Action of Pyrazolamine. Crystalline and Molecular
Structure of Substituted Pyrazolo[1,5-a]pyrimidine
E. S. Denislamovaa, N. V. Bubnovb, Z. G. Alievc, and A. N. Maslivetsa, b
a Perm State University, ul. Bukireva 15, Perm, 614990 Russia
e-mail: koh2@psu.ru
b Institute of Natural Sciences, Perm State University, Perm, Russia
c Institute of Chemical Physics Problems, Russian Academy of Sciences,
Chernogolovka, Moscow oblast, Russia
Received November 30, 2010
Abstract—Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with 3-methyl-
4-phenyl-1H-pyrazol-5-amine to give methyl 7-arylcarbamoyl-6-aroyl-2-methyl-3-phenylpyrazolo[1,5-a]-
pyrimidine-5-carboxylates. The molecular and crystalline structures of methyl 6-benzoyl-7-(4-chlorophenyl-
carbamoyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate were studied by X-ray analysis.
DOI: 10.1134/S107042801109017X
Monocyclic 1H-pyrrole-2,3-diones are known to
react with difunctional nucleophiles to give various
five-, six-, and seven-membered nitrogen-containing
heterocycles, as well as fused, bridged, and spirohet-
erocyclic systems [2, 3]. Reactions of methyl 1-aryl-3-
aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carbox-
ylates I with N,N-binucleophiles are quite sensitive to
the reagent structure, and several reaction paths are
possible. For example, their reactions with o-phenyl-
enediamine [4] and arylhydrazines [5, 6] involve
successive addition of amino groups in the nucleophile
at the carbon atom in position 2 of the pyrrole ring and
aroyl carbonyl carbon atom at C3 and cleavage of the
pyrrole ring at the N1–C2 bond. In the reactions with
diphenylguanidine [7] and N-phenyl-o-phenylenedi-
amine [8] nucleophilic attack by amino groups in the
reagent is directed at the C2 carbon atom and ester
carbonyl group of the substrate; reactions of com-
pounds I with N-phenyl-o-phenylenediamine also in-
volve opening of the pyrrole ring at the N1–C2 bond.
Reactions of methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihy-
dro-1H-pyrrole-2-carboxylates I with 2-amino-1H-
azoles were not studied previously.
We found that 1-aryl-3-aroyl-4,5-dioxo-4,5-dihy-
dro-1H-pyrrole-2-carboxylates Ia–If react with
3-methyl-4-phenyl-1H-pyrazol-5-amine (II) at a ratio
of 1:1 on heating in boiling anhydrous 1,2-dichloro-
ethane (reaction time 2–3 h; TLC monitoring) to pro-
duce the corresponding methyl 7-arylcarbamoyl-6-
aroyl-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-5-
carboxylates IIIa–IIIf [9] (Scheme 1) whose structure
was confirmed by the X-diffraction data for IIIa.
Substituted pyrazolo[1,5-a]pyrimidine-5-carbox-
ylates IIIa–IIIf were isolated as bright red high-melt-
ing crystalline substances which are poorly soluble in
common organic solvents, except for dimethylform-
amide and dimethyl sulfoxide and insoluble in saturat-
ed hydrocarbons and water. Compounds IIIa–IIIf
showed a negative color test for enolic hydroxy group
upon treatment with alcoholic solution of iron(III)
chloride.
The IR spectra of IIIa–IIIf contained absorption
bands due to stretching vibrations of the amide NH
group as a narrow peak at 3320–3360 cm–1 and car-
bonyl groups in the ester (1724–1730 cm–1), carbamoyl
(1680–1690 cm–1), and aroyl fragments (1665–
1670 cm–1). Compounds IIIa–IIIf displayed in the
* For communication LXXIX, see [1].
1362

FIVE-MEMBERED 2,3-DIOXO HETEROCYCLES: LXXX.
1363
Scheme 1.
O
O
O
Ar1
HO
O
Ar1
OMe
O
O
Ph
Me
NHAr2
HN
COOMe
NH
N
O
+
Ar1
MeO
N
O
H2N
Me
N
N
N
H
Ar2
HN
H
Ph
O
Ar2
Ph
O
N
Ia–If
II
Me
H
N
O
O
O
Ar2
N
Δ
Ar1
N
Me
–H2O
MeO
N
Ph
IIIa–IIIf
Ar1 = Ph, Ar2 = 4-ClC6H4 (a); Ar1 = 4-EtOC6H4, Ar2 = 4-MeC6H4 (b); Ar1 = Ph, Ar2 = 4-MeOC6H4 (c); Ar1 = 2,4-Me2C6H3,
Ar2 = 4-MeC6H4 (d); Ar1 = 4-MeC6H4, Ar2 = Ph (e); Ar1 = 2,4-Me2C6H3, Ar2 = Ph (f).
1H NMR spectra (DMSO-d6) signals from protons in
the aromatic rings and substituents attached thereto,
a singlet from the 2-methyl group at δ 2.64–2.70 ppm,
a singlet from the ester methoxy group at δ 3.60–
3.65 ppm, and a singlet from the NH proton in the
carbamoyl group at δ 11.09–11.45 ppm. In the 13C
NMR spectrum of a solution of IIIa in DMSO-d6 we
observed the following signals, δC, ppm: 14.05 (Me),
52.96 (MeO), 163.64 (CONH), 164.42 (MeOCO),
190.60 (PhCO), which are very consistent with the
assumed structure.
Cl1
The molecular and crystalline structures of methyl
6-benzoyl-7-(4-chlorophenylcarbamoyl)-2-methyl-3-
phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (IIIa)
were studied by X-ray analysis (Fig. 1). The bicyclic
pyrazolopyrimidine fragment is planar, and bond
lengths therein indicate complete electron density de-
localization; in particular, the C1–C2 and C2–C3 bonds,
as well as N3–C3 and N3–C4 have almost equal lengths.
The observed bond distribution is very consistent with
structural data for other pyrazolo[1,5-a]pyrimidine
derivatives [10]. All bond lengths in molecule IIIa
conform to the corresponding standard values [11].
Orientation of the phenylcarbamoyl group with respect
to the bicyclic fragment is characterized by the torsion
angles C5C6C7N4 174.8°, C6C7N4C18 177°, and
C7N4C18C23 167.8°, i.e., the PhNHCO group lies
almost in the plane of the bicyclic skeleton (the
dihedral angle between their planes is 6°). This planar
structure is stabilized by the intramolecular hydrogen
bond N4–H4···N2 (2.653 Å). The phenyl ring on C2
and methoxycarbonyl group also appear in the plane of
the bicyclic fragment, whereas the phenyl ring in the
benzoyl substituent is almost orthogonal to that plane
(the corresponding dihedral angle is 86°). Thus, the
C21
C20
C19
C22
C23
C18
N4
O1
C5
C26
C27
O2
C25
C24
C7
C6
C8
C28
O3
C29
C9
N1
N2
C1
C10
C3
C4
N3
C2
C12
O4
C11
C13
C17
C16
C14
C15
Fig. 1. Structure of the molecule of methyl 6-benzoyl-7-(4-
chlorophenylcarbamoyl)-2-methyl-3-phenylpyrazolo[1,5-a]-
pyrimidine-5-carboxylate (IIIa) according to the X-ray dif-
fraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

DENISLAMOVA et al.
1364
entire molecule, except for the benzoyl fragment, is
planar. Molecules IIIa in crystal are packed as centro-
symmetric “head-to-tail” couples, as shown in Fig. 2,
so that the pyrazolopyrimidine fragment is located in
front of the benzene ring.
The distance between the molecular planes in
a couple is 3.15 Å, which is considerably shorter than
the sum of the van der Waals radii for carbon atoms;
the shortest intermolecular contact (3.27 Å) is ob-
served between the C3 and C19 atom [12]. Presumably,
additional π–π interaction exists within couples of
molecules.
Compounds IIIa–IIIf are likely to be formed via
initial nucleophilic attack by the exocyclic amino
group in pyrazole II on the C2 atom of pyrroledione
Ia–If; next follows opening of the pyrrole ring at the
N1–C2 bond and closure of pyrimidine ring as a result
of intramolecular nucleophilic attack by the endocyclic
nitrogen atom in the pyrazole fragment on the ketone
carbonyl group in the oxamoyl fragment and elimina-
tion of water molecule. The described reaction of pyr-
rolediones I with 3-methyl-4-phenyl-1H-pyrazol-5-
amine (II) as difunctional nitrogen-centered nucleo-
phile may be regarded as a new method of synthesis of
functionalized pyrazolo[1,5-a]pyrimidine derivatives.
Fig. 2. Crystalline structure of methyl 6-benzoyl-7-(4-
chlorophenylcarbamoyl)-2-methyl-3-phenylpyrazolo[1,5-a]-
pyrimidine-5-carboxylate (IIIa) according to the X-ray dif-
fraction data.
Found, %: C 66.50; H 3.91; Cl 6.94; N 10.48.
C29H21ClN4O4. Calculated, %: C 66.35; H 4.03;
Cl 6.75; N 10.67.
X-Ray diffraction data for compound (IIIa).
Compound IIIa crystallized as 2:1 solvate with 1,2-di-
chloroethane. Dark red well defined tetragonal prisms,
C29H21ClN4O4·0.5C2H4Cl2, monoclinic crystal system,
space group P21/n; unit cell parameters: a = 9.521(2),
b = 21.688(4), c = 13.257(3) Å; β = 101.82(3)°; V =
2679.4(9) Å3; M 574.42; dcalc = 1.4242 g/cm3; Z = 4.
The X-ray diffraction data were acquired on a KM-4
(KUMA Diffraction) automatic four-circle diffractom-
eter with χ-geometry (monochromatized MoKα irradia-
tion, ω/2Θ scanning, 2Θ ≤ 50.8°). Total of 4973 reflec-
tions were measured, 3746 of which were independent
(Rint = 0.0595). No correction for absorption was intro-
duced (μ = 0.287 mm–1). The structure was solved by
the direct method using SIR92 program [13], followed
by a series of calculations of electron density maps.
The H4 atom in molecule IIIa was localized objec-
tively by difference synthesis of electron density, while
positions of the other hydrogen atoms were set on the
basis of geometry considerations and refined according
to the riding model. Atoms in the solvate dichloro-
ethane molecule were characterized by large thermal
vibration parameters, and hydrogen atoms therein were
not localized. The structure was refined by the least-
squares procedure in full-matrix anisotropic approxi-
mation (for non-hydrogen atoms) using SHELXL-97
software package [14]; the final divergence factors
were R1 = 0.0677 [for 2214 reflections with I ≥ 2σ(I)]
and R1 = 0.1251 for all 3746 reflections; 364 refined
parameters, goodness of fit 1.045.
EXPERIMENTAL
The IR spectra were recorded on an FMS-1201
spectrometer from samples dispersed in mineral oil.
The 1H NMR spectra were measured on a Bruker WP-
400 spectrometer from solutions in DMSO-d6 using
tetramethylsilane as internal reference. The purity of
the products was checked by TLC on Silufol plates
using ethyl acetate as eluent; spots were visualized by
treatment with iodine vapor.
Methyl 6-benzoyl-7-(4-chlorophenylcarbamoyl)-
2-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-5-car-
boxylate (IIIa). A solution of 1 mmol of compound Ia
and 1 mmol of pyrazole II in 10 ml of anhydrous
1,2-dichloroethane was heated for 3 h under reflux.
The mixture was cooled, and the precipitate was
filtered off. Yield 69%, mp 257–258°C (from 1,2-di-
chloroethane). IR spectrum, ν, cm–1: 3350 (NH), 1730
(C=O, ester), 1690 (C=O, amide), 1665 (C=O, ketone).
1H NMR spectrum, δ, ppm: 2.65 s (3H, Me), 3.60 s
(3H, OMe), 7.24–7.97 m (14H, Harom), 11.45 s (1H,
NH). 13C NMR spectrum, δC, ppm: 14.05 (Me), 52.96
(MeO), 111.81–156.41 (Carom, C2, C3, C3a, C5, C6, C7),
163.64 (CONH), 164.42 (MeOCO), 190.60 (PhCO).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

FIVE-MEMBERED 2,3-DIOXO HETEROCYCLES: LXXX.
1365
Compounds IIIb–IIIf were synthesized in a similar
way.
(NH), 1730 (C=O, ester), 1680 (C=O, amide), 1665
(C=O, ketone). 1H NMR spectrum, δ, ppm: 2.21 s (6H,
Me), 2.65 s (3H, Me), 3.64 s (3H, OMe), 7.02–7.58 m
(13H, Harom), 11.15 s (1H, NH). Found, %: C 71.80;
H 5.05; N 10.80. C31H26N4O4. Calculated, %: C 70.85;
H 5.01; N 10.83.
Methyl 6-(4-ethoxybenzoyl)-2-methyl-7-(4-meth-
ylphenylcarbamoyl)-3-phenylpyrazolo[1,5-a]pyrim-
idine-5-carboxylate (IIIb). Yield 74%, mp 245–
246°C (from 1,2-dichloroethane). IR spectrum, ν, cm–1:
3320 (NH), 1724 (C=O, ester), 1680 (C=O, amide),
1665 (C=O, ketone). 1H NMR spectrum, δ, ppm: 1.32 t
(3H, CH3CH2, J = 7.0 Hz), 2.27 s (3H, Me), 2.64 s
(3H, Me), 3.64 s (3H, OMe), 4.09 q (2H, CH2O, J =
7.0 Hz), 6.95–7.79 m (13H, Harom), 11.12 s (1H, NH).
Found, %: C 70.06; H 5.14; N 10.21. C32H28N4O5. Cal-
culated, %: C 70.05; H 5.11; N 10.17.
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (project no. 2.19.10) and by the
Russian Foundation for Basic Research (project
no. 08-03-01032).
REFERENCES
Methyl 6-benzoyl-7-(4-methoxyphenylcarbam-
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carboxylate (IIIc). Yield 75%, mp 265–266°C (from
1,2-dichloroethane). IR spectrum, ν, cm–1: 3340 (NH),
1725 (C=O, ester), 1685 (C=O, amide), 1665 (C=O,
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ketone). H NMR spectrum, δ, ppm: 2.70 s (3H, Me),
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pyrimidine-5-carboxylate (IIId). Yield 69%,
mp 238–239°C (from 1,2-dichloroethane). IR spec-
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(C=O, amide), 1670 (C=O, ketone). H NMR spec-
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(3H, Me), 2.66 s (3H, Me), 3.65 s (3H, OMe), 7.03–
7.91 m (12H, Harom), 11.09 s (1H, NH). Found, %:
C 72.16; H 5.30; N 10.52. C32H28N4O4. Calculated, %:
C 72.15; H 5.31; N 10.57.
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7-phenylcarbamoylpyrazolo[1,5-a]pyrimidine-5-
carboxylate (IIIe). Yield 63%, mp 219–220°C (from
1,2-dichloroethane). IR spectrum, ν, cm–1: 3320 (NH),
1730 (C=O, ester), 1680 (C=O, amide), 1670 (C=O,
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ketone). H NMR spectrum, δ, ppm: 2.34 s (3H, Me),
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Harom), 11.26 s (1H, NH). Found, %: C 71.42; H 4.79;
N 11.10. C30H24N4O4. Calculated, %: C 71.45; H 4.71;
N 11.14.
Methyl 6-(2,4-dimethylbenzoyl)-2-methyl-3-
phenyl-7-phenylcarbamoylpyrazolo[1,5-a]pyrimi-
dine-5-carboxylate (IIIf). Yield 59%, mp 223–224°C
(from 1,2-dichloroethane). IR spectrum, ν, cm–1: 3360
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