Synthesis of derivatives of pyrazolo[1,5-a]pyrimidines and imidazo[1,5-a]pyrimidines proceeding from alkyl 2-benzylidene-3-oxo-3- fluoroalkylpropionates

Article abstract of DOI:10.1134/S1070428009020158

Methods were developed of the synthesis of alkyl 2-hydroxy-2-fluoroalkyl-4- phenyl-1,2,3,4-tetrahydroimidazo-[1,5-a]pyrimidine-3-carboxylates and alkyl-5-hydroxy-2,7-diphenyl-5-fluoroalkyl-4,5,6,7-tetrahydropyrazolo[1,5-a] pyrimidine-6-carboxylates by reg

Full text of DOI:10.1134/S1070428009020158

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 2, pp. 242−247. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © M.V. Pryadeina, Ya.V. Burgart, V.I. Saloutin, P.A. Slepukhin, E.V. Sadchikova, E.N. Ulomskii, 2009, published in Zhurnal
Organicheskoi Khimii, 2009, Vol. 45, No. 2, pp. 254−259.
Synthesis of Derivatives of Pyrazolo[1,5-a]pyrimidines
and Imidazo[1,5-a]pyrimidines proceeding
from Alkyl 2-Benzylidene-3-oxo-3-fluoroalkylpropionates
M. V. Pryadeinaa, Ya. V. Burgarta, V. I. Saloutina, P.A. Slepukhina,
E. V. Sadchikovab, and E. N. Ulomskiib
aPostovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
Yekaterinburg, 620041 Russia
e-mail: saloutin@ios.uran.ru
bUral State Technical University, Yekaterinburg
Received April 3, 2008
Abstract—Methods were developed of the synthesis of alkyl 2-hydroxy-2-fluoroalkyl-4-phenyl-1,2,3,4—
tetrahydroimidazo-[1,5-a]pyrimidine-3-carboxylates and alkyl-5-hydroxy-2,7-diphenyl-5-fluoroalkyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxylates by regioselective [3+3]-cycloaddition of 5-aminoimidazole or
5-aminopyrazole to alkyl 2-benzylidene-3-oxo-3-fluoroalkylpropionates at the fluoroacylvinyl fragment.
DOI: 10.1134/S1070428009020158
Azoloazines constitute an important class of biological-
ly active compounds for they include a group of purine
bases playing a significant role in the vital activity of
organisms [1].Aspecial interest attract azolopyrimidines,
structural analogs (isosters) of purine bases, some families
of which are endowed with antiviral action [2]. We
showed recently that 2-arylmethylene-3-oxo-3-fluoro-
alkylpropionates are convenient blocks for preparation
of 7-aryl-6-alkoxycarbonyl-5-fluoroalkyl-1,2,4-triazolo-
[1,5-a]-pyrimidines and 7-aryl-6-alkoxycarbonyl-5-
fluoroalkyltetrazolo[1,5-a]pyrimidines by reactions with
3-amino-1,2,4-triazole and 5-aminotetrazole [3].
combinations. In this connections the reactions of esters
Ia–Ic with diamines IIa, IIb, and III can provide isomers
of various structures.
It was found that esters Ia–Ic reacted both with
5-aminoimidazoles IIa and IIb and with 5-amino-3-
phenylpyrazole (III) regioselectively at the polyfluoro-
acylvinyl fragment giving the corresponding alkoxy-
carbonyl-substituted tetrahydroimidazopyrimidines IVa–
IVc and tetrahydropyrazolopyrimidines Va and Vb
(Scheme 1). The reactions were carried out by heating
in DMF. The use of other organic solvents (ethanol,
benzene) was inefficient for either tarring occurred or
the conversion of initial substrates Ia–Ic was incomplete.
In this study we investigated the ways of building up
derivatives of pyrazolo[1,5-a]pyrimidine and imidazo-
[1,5-a]pyrimidine by reactions of alkyl 2-benzylidene-3-
oxo-3-fluoroalkylpropionates Ia–Ic with 5-aminoimid-
azoles IIa and IIb and 5-amino-pyrazole (III).
The cyclic nature of compounds IVa–IVc, Va, Vb
and not the isomeric structure with an open chain [isomers
A, B (Scheme 2)] was confirmed by their spectral
characteristics. For instance, in the IR spectra of mono-
alkoxycarbonyl-containing compounds IVc, Va, and Vb
recorded in mineral oil appeared a single high-frequency
band (ν 1743–1706 cm–1), and in each spectrum of
dialkoxycarbonyl-substituted products IVa and IVb two
bands were observed (ν 1752–1654 cm–1) corresponding
to the stretching vibrations of the ester carbonyl group
as was characteristic of cyclic forms C and D. The
Initial esters Ia–Ic contain three nonequivalent electro-
philic reaction sites that might be attacked by a nucleo-
phile: the alkoxycarbonyl carbon atom, the carbonyl atom
of the polyfluoroacyl group, and the carbon atom of the
methylidene fragment. The dinucleophilic reagents used
in the study IIa, IIb, and III also contain two unequal
reaction sites and can react with the substrates in various
242

SYNTHESIS OF DERIVATIVES OF PYRAZOLO[1,5-A]PYRIMIDINES
243
Scheme 1.
R
N
.
HCl
Ph
Ph
H2N
N
H
AlkO2C
RF
HO2C
HO
IIà, IIb
N
N
TsOH, Δ
toluene
N
N
NaHCÎ3
Ph
Ph
O
N
H
N
H
HO
HCF2
R
CO2Et
RF
OAlk
IVà_IVc
VI
DMF
N
N
H
III
O
H2N
Ph
Ià_Ic
AlkO2C
RF
N
N
Ph
N
H
HO
Và, Vb
I, RF = HCF2,Alk = Me (a); RF = CF3,Alk = Et (b); RF = H(CF2)2,Alk = Me (c); II, R = CO2Et (a), NO2 (b); IV, RF = HCF2,
Alk = Me, R = CO2Et (a); RF = CF3,Alk = Et, R = CO2Et (b), NO2 (c); V, RF = CF3,Alk = Et (a); RF = H(CF2)2,Alk = Me (b).
Scheme 2.
CO2Alk
Ph
Ph
CO2Alk
Ph
Ph
RF
AlkO2C
RF
RF
NH
Y
AlkO2C
RF
W
R
N
O
N
Y
NH2
R
O
HN
W
N
HO
N
H
Y
HO
Y
W
R
HN
W
R
C
B
D
A
W = CH, Y = N (IV), W = N, Y = CHPh (V).
of the spectrum 2D 1H–13C HSQC made it possible more
precise assignment of the protonated carbon atoms.
signals of fluorine atoms of the groups α-CF3- and α-
CF2 in the 19F NMR spectra of compounds IVa–IVc,
Va, Vb taken in (CD3)2SO were observed in a strong
field [δ(CF3) ~81–82, δ(CF2) ~31–35 ppm) indicating that
these groups were contiguous to the quaternary carbon
atom of the cyclic isomers C and D (Scheme 2) [3].
The comparison of 1H, 13C NMR spectral character-
istics of compounds IVa–IVc, Va, Vb, VI with the data
of previously obtained alkyl 5-hydroxy-7-phenyl-5-fluoro-
alkyl-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine-6-
carboxylates [3] having a structure analogous to that of
isomer C, and of alkyl 2-oxo(thioxo)-6-phenyl-4-fluoro-
alkylhexahydropyrimidine-5-carboxylates [4, 5] containing
a structural fragment Ph–CH–NH present in isomer D
permits the assignment to tetrahydroazolopyrimidines
IVa–IVc, Va, Vb, VI the structure of isomer C.
1
The data of H, 19F NMR and IR spectra cannot be
decisive for the choice between the possible structures
C and D of heterocycles IVa–IVc, Va, Vb. For
compound IVb additional measurements were performed
1
1
of spectra 2D H–13C HSQC and 2D H–13C HMBC
1
(see the table). It turned out that the spectrum 2D H–
13C HMBC contained cross-peaks of groups HO and
NH with atom C3 which was possible for both isomers
C and D. However in this spectrum was absent a cross-
peak between the proton of NH group and atom C4 that
should be present in the case of isomer D. The registering
We failed to obtain heterocycles IVa–IVc, Va, Vb by
three-component condensation of esters I with aldehydes
and aminoazoles IIa, IIb and III unlike analogous
reactions with 3-amino-1,2,4-triazole and 5-aminotetrazole
[3]. Besides in reactions of esters I with the latter
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

PRYADEINA et al.
244
~4.81_4.79 ppm
~5.63_5.58 ppm [3]
~5.38_5.54 ppm
δH
δC ~60 ppm [4, 5]
AlkO2C
δH
δH
δC ~55 ppm
Ph
H
Ph
H
Ph H
AlkO2C
XO2C
N
N
W
R
NH
N
N
N
Y
RF
HO
RF
HO
RF
HO
N
H
Z
N
H
N
H
IV_VI
aminoazoles the main products were dihydrotri(tetr)azolo-
[1,5-a]pyrimidines, and only in reactions with 5-amino-
tetrazole were isolated tetrahydrotetrazolo[1,5-a]-
pyrimidines containing the hydroxy group at the cyclic
carbon atom bearing the fluoroalkyl substituent. Therewith
the tetrahydrotetrazolo[1,5-a]-pyrimidines at boiling in
toluene in the presence of p-toluenesulfonic acid readily
underwent dehydration into the corresponding dihydro-
tetrazolo[1,5-a]pyrimidines [3].
The attempts to carry out the dehydration of hetero-
cycles IVa–IVc, Va, Vb under similar conditions or by
heating in acetic acid always resulted in formation of
intractable mixtures. Only from compound IVa we
succeeded to obtain a small amount of tetrahydroimidazo-
pyrimidinecarboxylic acid VI formed by hydrolysis of one
of the ester groups (Scheme 1).
The XRD analysis of a single crystal of acid VI
showed that this compound has a structure of 2-hydroxy-
2-difluoromethyl-4-phenyl-8-ethoxycarbonyl-1,2,3,4-
tetrahydroimidazo[1,5-a]-pyrimidine-3-carboxylic acid
(see the figure). This information confirmes our isomer
assignment of heterocycles IVa–IVc, Va, Vb , VI.
13C NMR spectrum of compound IVb in (CD3)2SO
ï
ì
î
1
O
è
Besides the H NMR and XRD data show, that the
4
15
14
hydrolysis in compound IVa occurred at the methoxy-
carbonyl group of the tetrahydropyrimidine part of the
molecule whereas the ester substituent in the imidazole
fragment remained intact. The higher resistance to the
hydrolysis of this substituent may be due to its conjugation
with the imidazole ring or by involvement into an
intramolecular hydrogen bond with the NH group of the
tetrahydropyrimidine ring. The presence of an
intramolecular hydrogen bond is suggested by the data
of IR spectra of compounds IVa and IVb having an
ethoxycarbonyl substituent at the imidazole ring which
contains low-frequency absorption bands (ν 1660–
1654 cm–1) of the stretching vibrations of the ester
carbonyl group.
CH3CH2O
N5
3
13
6
HO
1
N 7
O
8à
2
N
8
CF3
12
H
9
11
10
CH3CH2O
Atom
C2
δ, ppm (JC–F, Hz)
80.05 br.q (J 30.9)
C3
49.65
55.19
C4
C6
129.82
140.40
110.37
163.37
59.09
C8
C8a
C9
Analogous intramolecular hydrogen bond is also
C10
C11
C12
C13
C14
C15
Cθ
present in acid VI as confirmed by the XRD data:
...
intramolecular distance O1 H1 is 2.39(6) , angles N1–
13.40
...
...
H1 O1 and C9–O1 H1 equal 121.89 and 99.63°.
123.11 q (J 286.1)
165.94
60.84
In the molecule of acid VI a formation is possible of
one more intramolecular hydrogen bond between the OH
group and the carboxy moiety of the tetrahydropyrimidine
ring, but the XRD data exclude this possibility.
14.37
134.53
128.91
129.00
129.55
CO
Cm
Cï
Tetrahydroimidazo- and -pyrazolo[1,5-a]pyrimidines
IVa–IVc, Va, Vb , VI contain three asymmetric carbon
atoms and therefore four diastereomeric forms are
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

SYNTHESIS OF DERIVATIVES OF PYRAZOLO[1,5-A]PYRIMIDINES
245
presumable for them. However their NMR spectra
indicate the presence in each case of a single form. The
coupling constant [J(H3–H4) 10.9–12.0 Hz] for protons
at the phenyl and alkoxycarbonyl substituents in the
1H NMR spectra of compounds IVa–IVc, Va, Vb , VI
corresponds to their axial-axial coupling [6]. The values
of conformational energies for the groups CF3 [ΔG(CF3)
8.8 kJ mol−1] and OH [ΔG(OH) 2.28 kJ mol−1] reported
in [7] for substituted cyclohexanones make it possible to
suggest the preferable equatorial position of the poly-
fluoroalkyl substituent. In keeping with the above
reasoning in compounds IVa–IVc, Va, Vb , VI apparently
exists the conformation with the equatorial orientation
of the phenyl, alkoxycarbonyl, and fluoroalkyl groups. This
is confirmed by the XRD data on acid VI that show the
equatorial position of the bulky substituents (phenyl,
difluormethyl, and carboxy groups) and axial orientation
of atoms H3, H4 , and OH group (see the figure).
In case of compounds IVa and IVb containing an
ethoxycarbonyl substituent in the imidazole ring the signal
of proton H3 appeared as a doublet of doublets due to the
coupling through three bonds with the proton H4 (J 11.7–
12.0 Hz) and through four bonds with the proton of HO
group (J 0.9–1.1 Hz) indicating the W-like position of H3
and HO [8].
Crystal structure of 2-hydroxy-2-difluoromethyl-4-phenyl-
8-ethoxycarbonyl-1,2,3,4-tetrahydroimidazo[1,5-a]-
pyrimidine-3-carboxylic acid (VI).
1
In the H NMR spectrum of acid VI the signal of
proton H3 also possesses a doublet character (J 3.3 Hz),
but from a coupling through four bonds with the proton
of COOH group, also indicating their W-like position. Just
this position of these atoms in the molecule of acid VI
was shown by XRD data (see the figure). Evidently this
orientation prevents the formation of an intramolecular
bond between the OH group and the carboxy residue of
the tetrahydropyrimidine ring.
of a water molecule leading to the formation of azolo-
[1,5-a]pyrimidines [10]. The formation of stable hetero-
cycles including a gem-aminoalcohol fragment at the
fluoroalkyl substituent is the distinguishing feature of
3-oxo-3-fluoroalkylpropionates compared with the analogs
from the hydrocarbon series. This feature originates from
the electron-acceptor effect of the fluoroalkyl substituent
preventing the easy elimination of the water molecule.
Thus we demonstrated that esters I enter into reac-
tions of regioselective [3+3]-cycloaddition with 5-amino-
imidazoles IIand 5-aminopyrazole (III) furnishing [1,5-a]-
azolofused tetrahydropyrimidines resulting from the addi-
tion of the free amino group of azoles to the fluoroacyl
fragment of esters I, and of α-NH group of the azole to
the C=C bond. However the cyclization of esters I with
hetarylamines is not always regioselective. For instance,
from the reaction with 2-aminopyridine we isolated
condensation product at the ester fragment, 4-aryl-2-
hydroxy-3-polyfluoroacyl-4H-pyrido[1,2-a]pyrimidines
[9]. The reactions of alkyl 2-arylmethylene-3-oxobutano-
ates with aminoazoles have the same regiodirection, but
the addition of the NH2 group of dinucleophile to the acetyl
fragments accompanied with an immediate elimination
EXPERIMENTAL
Melting points of compounds IVa–IVc, Va, Vb , VI
were measured on a device Stuart SMP3. IR spectra
were recorded on an IR Fourier spectrophotometer Perkin
Elmer Spectrum One from mulls in mineral oil. NMR
spectra were registered on a spectrometer Bruker DRX-
400 (1H: 400 MHz, relative to TMS; 19F: 376 MHz, relative
to C6F6; 13C: 100 MHz, relative toTMS) in (CD3)2SO.
Elemental analysis was carried out on an analyzer Perkin
Elmer 2400 series 2 CHNS-O EA 1108.4. The reaction
progress was monitored by TLC on Sorbfil PTSKh-AF-
V-UV plates.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

PRYADEINA et al.
246
(O–H, N–Hstretch), 1752, 1661 (C=O), 1614, 1525, 1496
X-ray diffraction study of compound VI. The single
1
(C=C, C=N, N–Hbend), 1204–1093 (C–F). H NMR
crystals were grown by slow evaporation of ethanol
solution. Crystals monoclinic, M 381.34, C17H17F2N3O5,
space group P21/c, a 13.0061(19), b 11.0239(17),
c 14.046(3) , α 90, β 113.989(15), γ 90 deg, V 1840.0(5)
3, Z 4, dcalc 1.377 g cm–3, μ(MoKα) 0.115 cm–1, (2θ)max
63.32°, λ 0.71073 , F(000) 792, –19 ≤ h ≤ 19, –15 ≤ k ≤
15, –20 ≤ l ≤ 20. The overall number of reflections (29584)
was measured on a diffractometer XCalibur 3 at 295(2)
K (ù/2θ-scanning, MoKα radiation, graphite mono-
chromator, CCD-detector), number of independent
reflections 5787 (Rint 0.0671), number of reflections with
Fo > 4σ(Fo) 1823. The structure was solved by the direct
method and refined by the least-squares method using
software SHELXL-97 [11] till R 0.0550, wR2 0.1026, GOF
1.000. The complete set of crystallographic data is
deposited into the Cambridge Structural Database
(registered number 662765) and is available at the address
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
spectrum, δ, ppm: 0.88 t (3H, OCH2CH3, 3JH–H 7.0 Hz),
1.27 t (3H, OCH2CH3, 3JH–H 7.1 Hz), 3.58 d.d [1H, H3,
4
3J(H3–H4) 11.7, J(H3–OH) 1.1 Hz], 3.88 m (2H,
OCH2CH3, AΒ system, ΔAB 0.01, 2JH(A)–H(B) 10.9, 3JH–H
3
7.1 Hz), 4.22 q (2H, OCH2CH3, JH-H 7.0 Hz), 5.49 d
3
[1H, H4, J(H4–H3) 11.7 Hz], 6.58 s (1H, H6), 6.68 C
(1H, H1), 7.43–7.53 m (5H, Ph), 8.00 d [1H, OH, 4J(OH–
H3) 1.1 Hz]. 19F NMR spectrum, δ, ppm: 81.4 s (CF3).
Found, %: C 52.92; H 4.58; F 13.33; N 9.93.
C19H20F3N3O5. Calculated, %: C 53.40; H 4.72; F 13.33;
N 9.83.
Ethyl 2-hydroxy-8-nitro-2-trifluoromethyl-4-
phenyl-1,2,3,4-tetrahydroimidazo[1,5-a]pyrimi-
dine-3-carboxylate (IVc) was obtained similarly from
2.72 g (0.01 mol) of ester Ib and 1.37 g (0.01 mol) of
aminoimidazole hydrochloride IIb. Yield 2.48 g (62%),
colorless powder, mp 178–180°C. IR spectrum, ν, cm–1:
3363, 2963 (N–Hstretch, O–H), 1743 (C=O), 1632, 1610,
1535 (C=C, C=N, N–Hbend), 1488 (NO2), 1212–1078 (C–
F). 1H NMR spectrum, δ, ppm: 0.86 t (3H, OCH2CH3,
Initial esters I were prepared by procedure [12].
3
3JH–H 7.2 Hz), 3.74 d [1H, H3, J(H3–H4) 11.8 Hz],
8-methyl, 3-ethyl 2-hydroxy-2-difluoromethyl-4-
phenyl-1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine-
3,8-dicarboxylate (IVa). Amixture of 2.40 g (0.01 mol)
of ester Ia, 1.92 g (0.01 mol) of 5-aminoimidazole
hydrochloride (IIa), and 1.00 g (0.012 mol) of NaHCO3
in 10 ml of dry DMF was stirred for 8–12 h at 70°C, then
cooled and poured into water with ice (~100 ml), the
separated precipitate was filtered off, washed with warm
water and Et2O. Yield 2.77 g (70%), colorless powder,
mp 187–188°C. IR spectrum, ν, cm–1: 3359, 3110 (O–H,
N–Hstretch), 1709, 1654 (C=O), 1605, 1524, 1498 (C=C,
C=N, N–Hbend), 1056–1182 (C–F). 1H NMR spectrum,
δ, ppm: 1.26 t (3H, OCH2CH3, 3JH–H 7.1 Hz), 1.99 s (3H,
3.88 m (2H, OCH2CH3, AΒ system, ΔAB 0.02, 2JH(A)–H(B)
10.9, 3JH–H 7.1 Hz), 5.55 d [1H, H4, 3J(H4–H3) 11.8 Hz],
6.74 s (1H, H6), 7.44–7.46 m (3H, Ph), 7.58–7.60 m (2H,
Ph), 7.63 br.s (1H, OH), 8.28 s (1H, H1). 19F, δ, ppm:
81.88 s (CF3). Found, %: C 47.92; H 3.72; F 13.87; N 14.17.
C16H15F3N4O5. Calculated, %: C 48.01; H 3.78; F 14.00;
N 14.24.
Ethyl 5-hydroxy-5-trifluoromethyl-2,7-diphenyl-
4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidine-6-
carboxylate (Va). A mixture of 2.72 g (0.01 mol) of
3-oxoester Ib and 1.91 g (0.01 mol) of 5-amino-3-
phenylpyrazole (III) in 10 ml of anhydrous DMF was
stirred for 5–6 h at 70°C, then cooled and poured into
water with ice (~100 ml), the separated precipitate was
filtered off and recrystallized from EtOH. Yield 3.02 g
(70%), colorless powder, mp 204–206°C. IR spectrum,
ν, cm–1: 3399, 3304, 2928 (N–Hstretch, O–H), 1715 (C=O),
1593, 1580, 1525, 1513 (C=C, C=N, N–Hbend), 1200–1092
(C–F). 1H NMR spectrum, δ, ppm: 0.88 t (3H, OCH2CH3,
3
4
OCH3), 3.56 d.d [1H, H3, J(H3–H4) 12.0, J(H3–OH)
3
0.9 Hz], 4.20 q (2H, OCH2CH3, JH–H 7.1 Hz), 5.53 d
3
2
[1H, H4, J(H4–H3) 12.0 Hz], 6.33 t (1H, HCF2, JH–F
54.6 Hz), 6.49 s (1H, H6), 6.92 s (1H, H1), 7.25 d [1H,
OH, J(OH–H3) 0.9 Hz], 7.42–7.47 m (5H, Ph). 19F NMR
spectrum, δ, ppm: 31.12 m (2F, HCF2, AΒ system, ΔAB
0.35, JF(A)–F(B) 279.0, JF–H 54.6 Hz). Found, %: C 55.00;
H 4.85; F 9.38; N 10.69. C18H19F2N3O5. Calculated, %:
C 54.69; H 4.84; F 9.60; N 10.63.
3
3JH–H 7.1 Hz), 3.33 d [1H, H6, J(H6–H7) 11.6 Hz],
3.88 m (2H, OCH2CH3, AB system, ΔAΒ 0.03, JH(A)–H(Β)
10.7, 3JH–H 7.1 Hz), 5.46 d [1H, H7, 3J(H7–H6) 11.6 Hz],
5.88 s (1H, H3), 7.22–7.54 m (10H, 2Ph), 7.56 s (1H,
OH), 7.86 s (1H, H4). 19F NMR spectrum, δ, ppm: 82.12 s
(CF3). Found, %: C 60.96; H 4.53; F 13.18; N 9.69.
C22H20F3N3O3. Calculated, %: C 61.25; H 4.67; F 13.21;
N 9.74.
Diethyl 2-hydroxy-2-trifluoromethyl-4-phenyl-
1,2,3,4-tetrahydroimidazo[1,5-a]-pyrimidine-3,8-
dicarboxylate (IVb) was obtained similarly from 2.72 g
(0.01 mol) of ester Ib. Yield 2.78 g (65%), colorless
powder, mp 115–116°C. IR spectrum, ν, cm–1: 3353, 3119
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

SYNTHESIS OF DERIVATIVES OF PYRAZOLO[1,5-A]PYRIMIDINES
247
Methyl 5-hydroxy-5-(1,1,2,2-tetrafluoroethyl)-
2,7-diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrimidine-6-carboxylate (Vb) was similarly obtained
from 2.90 g (0.01 mol) of 3-oxoester Ic.Yield 2.61 g (58%),
colorless crystals, mp 197–199°C. IR spectrum, ν, cm–1:
3368, 3292 (N–Hstretch, O–H), 1706 (C=O), 1591, 1579,
1525, 1513 (C=C, C=N, N–Hbend), 1114–1082 (C–F). 1H
NMR spectrum, δ, ppm: 3.38 s (3H, OCH3), 3.41 d [1H,
The study was carried out under the financial support
of the Ministry of Education and Science of the Russian
Federation and American Civil Research and
Development Foundation (CRDF) (grant Y3-C-05-15),
of Ural Division of the Russian Academy of Sciences
(grant for young scientists and post-graduate students
for 2008) and of the Council for grants of the President
of the Russian Federation (program supporting the
Leading scientific schools, grant 3758.2008.3).
3
3
H6, J(H6–H7) 11.5 Hz], 5.47 d [1H, H7, J(H7–H6)
2
11.5 Hz], 5.91 s (1H, H3), 6.71 t.t [1H, H(CF2)2, JH–F
51.2, 3JH–F 6.3 Hz], 7.21–7.40 m (8H, 2 Ph), 7.36 s (1H,
OH), 7.52–7.54 m (2H, Ph), 7.53 C (1H, H4). 19F NMR
spectrum, δ, ppm: 27.89 m (2F, HCF2, AB system,
REFERENCES
1. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1985, vol. 8.
2. Ulomskii, E.N., Shestakova, T.S., Deev, S.L., Rusinov, V.L.,
and Chupakhin, O.N., Izv. Akad. Nauk, Ser. Khim., 2005,
p. 713.
3. Pryadeina, M.V., Burgart,Ya.V., Saloutin, V.I., Kodess, M.I.,
Ulomskii, E.N., and Rusinov, V.L., Zh. Org. Khim., 2004,
vol. 40, p. 938.
2
3
ΔAΒ 0.95, JF(A)–F(Β) 295.0, JF–H 51.2, JF–H 6.3,
3JF–F 9.6 Hz), 35.14 m (2F, CF2, AB system, ΔAΒ 3.20,
JF(A)–F(Β) 268.0 Hz). Found, %: C 58.64; H 4.08; F 16.66;
N 9.21. C22H19F4N3O3. Calculated, %: C 58.80; H 4.26;
F 16.91; N 9.35.
2-Hydroxy-2-difluoromethyl-4-phenyl-8-ethoxy-
carbonyl-1,2,3,4-tetrahydroimidazo[1,5-a]pyrimi-
dine-3-carboxylic acid (VI). A solution of 1.19 g
(0.003 mol) of compound IVa in 100 ml of toluene in the
presence of p-toluenesulfonic acid was boiled for 5 days
with azeotropic removal of water. Then the hot reaction
mixture was filtered, concentrated in a vacuum, and the
formed precipitate was recrystallized from EtOH. Yield
0.11 g (10%), colorless crystals, mp 180–182°C. 1H NMR
spectrum, δ, ppm: 1.09 t (3H, OCH2CH3, 3JH–H 7.0 Hz),
3.89 d.d [H, H3, 3J(H3–H4) 10.9, J(H3–CO2H) 3.3 Hz],
4. Kappe, C.O., Falsone, S.F., Fabian, W.M.F., and Belaj, F.,
Heterocycles, 1994, vol. 51, p. 77.
5. Burgart,Ya.V., Kuzueva, O.G., Pryadeina, M.V., Kappe, S.O.,
Saloutin, V.I. ., Zh. Org. Khim., 2001, vol. 37, p. 915.
6. Ionin, B.I., Ershov, B.A., and Kol’tsov, A.I., YaMR-
spektroskopiya v organicheskoi khimii (NMR Spectro-
scopy in Organic Chemistry), Leningrad: Khimiya, 1983,
p. 154.
7. Potapov, V.M., Stereokhimiya (Stereochemistry),
Moscow: Khimiya, 1988, p. 211.
..
8. Pretsch, E., Buhlmann, P., and, Affolter, C., Structure
Determination of Organic Compounds: Tables of Spectral
Data, Springer, 2004.
9. Pryadeina, M.V., Burgart, Ya.V., Kodess, M.I., and Salou-
tin, V.I., Izv. Akad. Nauk, Ser. Khim., 2005, p. 2745.
10. Atwal, K.S. and Moreland, S., Bioorg. Med. Chem. Lett.,
1991, vol. 1, p. 291.
11. Sheldrick, G.M., SHELXS 97, University of Göttin-
gen, Germany, 1997.
12. Pryadeina, M.V., Kuzueva, O.G., Burgart, Ya.V., Salou-
tin, V.I., Lyssenko, K.A., and Antipin, M.Yu., J. Fluor.
Chem., 2002, vol. 117, p. 1.
3
4.21 q (2H, OCH2CH3, JH–H 7.0 Hz), 5.38 d [1H, H4,
3J(H4–H3) 10.9 Hz], 6.09 d.d (1H, HCF2, 2JH–F(A) 55.1,
2JH–F(B) 54.6 Hz), 6.53 d [1H, H1, J(H1–OH) 0.5 Hz],
6.74 s (1H, H6), 7.51 br.d [1H, CO2H, J(CO2H–H3)
3.3 Hz], 7.56 d [1H, OH, J(OH–H1) 0.5 Hz], 7.65–
7.74 m (5H, C6H5). 19F NMR spectrum, δ, ppm: 29.03 d.d
(1F, CF2, JF(A)–F(B) 282.8, JF(A)–H 54.6 Hz), 34.16 d.d (1F,
CF2, JF(B)–F(A) 282.8, JF(B)–H 55.1 Hz). Found, %: C 53.28;
H 4.37; F 9.36; N 10.73. C17H17F2N3O5. Calculated, %:
C 53.54; H 4.49; F 9.96; N 11.02.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009