Synthesis of N- and C-azolyl-substituted pyrazolo[1,5-a]pyrimidines by recyclization of pyrimidinium salts

Article abstract of DOI:10.1007/s10593-015-1724-3

We studied the reaction of 2-(ethoxycarbonyl)methyl-1,4,6-trimethylpyrimidinium iodide with hydrazides of N-azolyl- and C-pyrazolyl-substituted carboxylic acids, which were synthesized by reacting the respective esters with hydrazine hydrate. This reaction was shown to result in recyclization and formation of ethyl 2-(pyrazolylalkyl)- and 2-(azolylalkyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine- 3-carboxylates. Besides pyrazolopyrimidines, the separation of reaction mixture provided in some cases also another recyclization product, 2-hydroxy-5,7-dimethylpyrazolo[1,5-a]pyrimidine.

Full text of DOI:10.1007/s10593-015-1724-3

DOI 10.1007/s10593-015-1724-3
Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
Synthesis of N- and C-azolyl-substituted pyrazolo[1,5-a]pyrimidines
by recyclization of pyrimidinium salts
Gevorg G. Danagulyan1,2*, Araksya K. Tumanyan1,2, Oganes S. Attaryan2,
Rafael A. Tamazyan3, Anna G. Danagulyan1,2, Armen G. Ayvazyan3
1 Russian-Armenian (Slavonic) University,
123 Hovsep Emin St., Yerevan 0051, Armenia; e-mail: gdanag@email.com
2 Institute of Organic Chemistry,
Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia,
26 Azatutyan Ave., Yerevan 0014, Armenia
3 Molecular Structure Research Center,
Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia,
26 Azatutyan Ave., Yerevan 0014, Armenia; e-mail: rafael@msrc.am
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(5), 483–490
Submitted March 19, 2015
Accepted April 21, 2015
O
R
Me
OEt
R2 R1
X
R, R1, R2 = H, Me;
X = CH, CHal, N;
n = 0, 1
Me
N
I–
EtOH
N
O
N
R1
+
O
N
+
N
Me
X
N
, 20–40 h
N
N
( )n
EtO
Me
NH2
R2
( )n
N
H
N
R
Me
We studied the reaction of 2-(ethoxycarbonyl)methyl-1,4,6-trimethylpyrimidinium iodide with hydrazides of N-azolyl- and С-pyrazolyl-
substituted carboxylic acids, which were synthesized by reacting the respective esters with hydrazine hydrate. This reaction was shown to
result in recyclization and formation of ethyl 2-(pyrazolylalkyl)- and 2-(azolylalkyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-
3-carboxylates. Besides pyrazolopyrimidines, the separation of reaction mixture provided in some cases also another recyclization
product, 2-hydroxy-5,7-dimethylpyrazolo[1,5-a]pyrimidine.
Keywords: hydrazide, pyrazole, pyrazolo[1,5-a]pyrimidine, pyrimidinium iodide, rearrangement.
Two synthetic strategies are currently known for the
preparation of pyrazolo[1,5-a]pyrimidines, as well as other
azolopyrimidines: starting either from the pyrimidine ring
or from the five-membered ring, and constructing the other
heterocycle.1,2 Thus, syntheses of similar annulated systems
from 5-aminopyrazoles and other α-aminoazoles have been
described, where reactions with β-dicarbonyl compounds
and their derivatives were used.1,2 For example, synthesis
of azolopyrimidines from a pyrimidine derivative was
achieved by reacting 2-hydrazinopyrimidines with
orthoformate and some other carboxylic acid derivatives.3,4
During an earlier study of recyclization reactions
between pyrimidine derivatives and nitrogen-containing
nucleophilic agents, we identified an unusual transfor-
mation of 2-(ethoxycarbonyl)methyl-1,4,6-trimethylpyrimi-
dinium iodide (1) in the presence of certain acyl hydrazides,
which unexpectedly provided pyrazolo[1,5-a]pyrimidine
derivatives.5 Recently we described such rearrangement in
another short report.6 This previously unknown
transformation was performed in a single step by
substituting the N(1)–CH3 fragment in the starting salt with
the terminal nitrogen atom of hydrazide group, with
subsequent intramolecular cyclization, leading to the
formation of pyrazole ring condensed with a pyrimidine
ring.
In order to investigate the possibility of using this
transformation for the synthesis of otherwise unavailable
azolyl-substituted pyrazolopyrimidines, we performed the
reaction of iodide 1 with hydrazides of azolyl-substituted
carboxylic acids 11–19 (Scheme 1), which were prepared
by reacting esters of pyrazole-3-carboxylic, (pyrazol-1-yl)-
acetic, (1,2,4-triazol-1-yl)acetic, and (pyrazol-1-yl)propionic
acids 2–10 with hydrazine hydrate. The subsequent heating
of hydrazides 11–19 with iodide 1 in a sealed glass ampoule
(at 2:1 stoichiometry) gave the 2-azolyl- and 2-(azolylalkyl)-
substituted pyrazolo[1,5-a]pyrimidines 20–28. We should
0009-3122/15/5105-0483©2015 Springer Science+Business Media New York
483

Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
Scheme 1
O
O
X
X
H
N
NH2
OMe
N
N
N2H4
N2H4·H2O
N
N
H
N
EtOH, H2O
, 5–6 h
90–100°C
10 min (for 12)
, 5 h (for 18)
OEt
N
N
NH2
N
H
N
H
3, 12 X = CH,
4, 18 X = N
O
O
2
11
3, 4
12, 18
N2H4·H2O (for 13, 15–17, 19)
60% N2H4 in H2O (for 14)
5 Alk = Et, 6–10 Alk = Me
R
R
N
N
5, 13 R = H, 6, 14 R = 3,5-Me2
7, 15 R = 4-Br-3-Me, 8, 16 R = 4-Br-3,5-Me2
9, 17 R = 4-Cl-3-Me, 10, 19 R = 3-Me
5–9, 13–17 R1 = H, 10, 19 R1 = Me
O
O
N
N
NH2
90–100°C, 10 min (for 13, 15–17)
35–38°C, 10 min (for 14)
, 8 h (for 19)
OAlk
N
H
R1
R1
5–10
13–17, 19
O
O
Me
Me
OEt
N
Me
N
Me
EtOH
I–
Me
11
OEt
N
O
+
OH
+
+
N
Me
N
NH
Me
N
, 20–40 h
N
N
N
Me
N
NH
Me
EtO
Me
Me
1
20
29
30
Me
N
O
O
O
OEt
OEt
R1
Me
+
N
OEt
Me
N
N
12, 18
13–17, 19
31
R
+
29
+
30
+
31
+
29
N
N
X
N
N
N
N
N
N
N
X
Me
Me
N
22–26, 28
22 R = H, 23 R = 3,5-Me2, 24 R = 4-Br-3-Me, 25 R = 4-Br-3,5-Me2,
26 R = 4-Cl-3-Me, 28 R = 3-Me; 22–26 R1 = H, 28 R1 = Me; 33 X = CH, 34 X = N
OH
21 (X = CH)
27 (X = N)
O
33, 34
note that, along with pyrazolopyrimidines 20–28, another
recyclization product, 2-hydroxy-5,7-dimethylpyrazolo-
[1,5-a]pyrimidine (29), was isolated from the reaction
mixtures in all cases. In some experiments, the starting salt
1 gave small amounts of enamine rearrangement product,
ethyl 4,6-dimethyl-2-methylaminopyridine-3-carboxylate
(30), and demethylation product, ethyl 4,6-dimethyl-
pyrimidinyl-2-acetate (31), which were typically formed
also in other nucleophilic recyclization reactions of
pyrimidines by interaction of salt 1 with primary amines
(Kost–Sagitullin enamine rearrangement and recyclization
to 1,2,4-triazole derivatives).7–10 In two cases, the
formation of azolylcarboxylic acids 33, 34 corresponding
to the starting hydrazides was also noted. The reaction of
salt 1 with hydrazide 14 also resulted in isolation of
hydroiodide of the starting hydrazide.
pyrazole ring at 6.91 ppm (br. d, J = 1.9 Hz, H-5') and
7.52 ppm (d, J = 1.9 Hz, H-4'), a quartet due to pyrimidine
proton at 6.97 ppm (J = 0.8 Hz, H-6), as well as the signals
of two methyl groups at 2.64 ppm (s, 5-CH3) and 2.80 ppm
(d, J = 0.8 Hz, 7-CH3). The coupling constants between
pyrimidine ring protons and one of the methyl groups
allowed to unequivocally assign each methyl group signal.
Similar coupling constants (J = 0.8–0.9 Hz) between the
protons of pyrimidine ring and the 7-СН3 methyl group
1
were also observed in the Н NMR spectra of the other
synthesized pyrazolo[1,5-a]pyrimidines 21–29.
The rearrangements leading to pyrazolo[1,5-a]pyri-
midine derivatives 20–29 can be apparently interpreted as
involving an intermediate adduct, compound 32, with a
mechanism consisting of attack by terminal nitrogen atom
of hydrazide at position 2 of the salt 1, opening of
pyrimidine ring at the the N(1)–C(2) bond, followed by a
cyclization that includes hydrazine nitrogen atom into the
pyrimidine ring. The last stage of recyclization, namely, the
reaction of intermediate 32 leading to closure of five-
membered ring, can occur in two different directions (I and
II), leading to either compounds 20–28 or 29 (Scheme 2).
The products of this recyclization were characterized by
NMR spectroscopy (and X-ray structural analysis in the
case of compound 26), while the purity and individuality of
the compounds were proved by TLC and elemental
analysis.
The 1Н NMR spectra of all synthesized pyrazolo[1,5-a]-
pyrimidines 20–29 contained signals of ester and methyl
group protons, as well as aromatic protons belonging to
pyrimidine and pyrazole rings.
1
The Н NMR signal of methylene bridge between the
two heterocycles in pyrazolo[1,5-a]pyrimidines 21 and 27
was observed at an unusually downfield location (5.72 and
5.79 ppm, respectively), apparently due to the high СН
acidity of this fragment. The ethylene bridge protons
between the rings in compounds 22–26 were observed as a
The 1Н NMR spectrum of pyrazolo[1,5-a]pyrimidine
2-pyrazolyl derivative 20 contained signals of ester group
protons, doublets of two protons at the ortho positions of
484

Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
Scheme 2
Me
Me
Me
N
RCONHNH2
N
N
CO2Et
H
1
+
N
HN
CO2Et
NHCOR
–MeNH2
NHCOR
Me
Me
Me
N
N
H
Me
N
NH
Me
CO2Et
Me
R
O
–H+
+H+
Me
CO2Et
N
Me
N
Me
Path I
–H2O
Path II
–RCOOEt
N
N
OH
R
+
N
HN
–
N
N
N
N
Me
Me
N
CO2Et
O
HN
Me
Me
R
20–28
OEt
29
R
O
O
32
pair of multiplets at stronger field, and the methylеne group
linked to pyrazole ring nitrogen atom gave a downfield
signal (4.32–4.55 ppm) compared to the adjacent
methylеne group (3.43–3.60 ppm).
Thus, we have used a large number of examples to
demonstrate the general applicability of pyrimidine salt
recyclization to polysubstituted 2-(azolylalkyl)pyrazolo-
[1,5-a]pyrimidines that would be otherwise difficult to
obtain. Such compounds may be of interest as novel
bisheteroarylalkyl ligands for the synthesis of metal
complexes.
The reactions of iodide 1 with hydrazides 12 and 18
allowed us to isolate also N-azolylacetic acids 33 and 34,
corresponding to the starting hydrazides. The formation of
these acids apparently could be explained by the
elimination of azolylalkyl fragment during hetero-
cyclization by route II and its reaction with water,
eliminated by heterocyclization according to route I.
The molecular structure of compound 26 is presented in
Figure 1 and features two planar cyclic fragments: pyrazole
ring and bicyclic pyrazolo[1,5-a]pyrimidine. The maxi-
mum deviation of atoms from the respective least squares
planes did not exceed 0.0042(2) Å in the pyrazole ring and
0.0284(3) Å in the pyrazolo[1,5-a]pyrimidine fragment.
The three-dimensional molecular packing in the crystal
featured an unusual C(8)–H(8)···O(13) hydrogen bond (the
interatomic distances were the following: C–H 1.01(3) Å,
H···O 2.46(3) Å, C···O 3.409(3) Å, while the С–H–О
angle was 157(2)°). This hydrogen bond between
pyrimidine Н-5 proton of one molecule and carbonyl group
oxygen of another molecule linked the molecules of this
compound in an infinite chain in the [1 0 0] direction
(Fig. 2).
Experimental
IR spectra were recorded in Nujol on a Specord UR-75
1
spectrometer. Н and 13С NMR spectra were acquired on a
Varian Mercury 300 spectrometer (300 and 75 MHz,
respectively), the solvents were CDCl3 (compound 23) and
1:3 DMSO-d6–ССl4, (the rest of the compounds), internal
standard was TMS. Mass spectra were recorded on an
MK-1321 instrument with direct introduction of sample
into the ion source, EI ionization (70 eV). Silufol UV-254
plates were used for TLC analysis of reaction mixtures and
the obtained products, visualization with iodine vapor and
Ehrlich's reagent. Column chromatography was performed
with L 40/100 silica gel. The starting esters 2,11 3,12 5,12 6,12
and 1013 were synthesized according to published
procedures.
Ethyl (1H-1,2,4-triazol-1-yl)acetate (4). A mixture of 1,2,4-
triazole (6.9 g, 0.1 mol), ethyl chloroacetate (24.5 g, 0.3 mol),
Figure 1. Molecular structure of compound 26
according to X-ray structural analysis with atoms
represented by thermal vibration ellipsoids of 50%
probability.
Figure 2. Infinite molecular chain in the structure of compound 26 along the
[1 0 0] direction.
485

Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
Et3BnN+Cl– (1.0 g, 5.2 mmol), K2CO3 (27.6 g, 0.2 mol), and
NCH2); 7.55 (1H, s, H-5). Found, %: C 47.61; H 5.65;
N 13.57. C8H11ClN2O2. Calculated, %: C 47.42; H 5.47;
N 13.82.
Me2CO (150 ml) was stirred for 4 h at 50–55°С. The
reaction mixture was then cooled and filtered. Acetone was
removed by evaporation, and the residue was distilled under
vacuum. Yield 11.5 g (76%), colorless liquid, bp 123–130°С
Hydrazide of 1Н-pyrazole-3-carboxylic acid (11). A
solution of methyl 1H-pyrazole-3-carboxylate (2) (1.0 g,
8 mmol) in EtOH (10 ml) was treated with 60% aqueous
hydrazine (1.5 g, 18 mmol), the mixture was heated for 5–
6 h on a water bath. Ethanol and excess hydrazine were
removed by evaporation, the residue was washed with hot
hexane and Et2O. Yield 1.0 g (99%), white crystals, mp
172–174°C (EtOH), Rf 0.1 (2:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 4.22 (2H, br. s, NH2);
6.66 (1H, d, J = 2.2, H-4); 7.52 (1H, d, J = 2.2, H-5); 9.03
(1H, br. s, NHNH2); 12.95 (1H, br. s, 1-NH). Found, %:
C 37.89; H 4.83; N 44.51. C4H6N4O. Calculated, %:
C 38.09; H 4.80; N 44.42.
20
(3 mmHg) (oil,14,15 bp 145–146°С16), nD 1.4647. IR
spectrum, ν, cm–1: 1500 (ring), 1730 (C=O). 1H NMR
spectrum, δ, ppm (J, Hz): 1.30 (3Н, t, J = 7.1, ОCH2CH3);
4.81 (2Н, q, J = 7.1, ОCH2CH3); 4.94 (2Н, s, NCH2); 7.62
(1Н, s, Н-3); 8.25 (1Н, s, Н-5). Found, %: C 46.28; H 5.99;
N 27.25. C6H9N3O2. Calculated, %: C 46.45; H 5.85;
N 27.08.
Methyl 3-(4-bromo-3-methylpyrazol-1-yl)propionate (7).
mixture of methyl 3-(3-methyl-1H-pyrazol-1-yl)-
A
propionate (26.8 g, 0.16 mol), AcONa (32.0 g, 0.40 mol),
and H2O (112 ml) was charged into a four-necked flask,
stirred at room temperature, and treated by dropwise addition
of a mixture of AcOH (19 ml) and Br2 (10 ml, 31.2 g,
0.20 mol) at such rate that the reaction mixture temperature
did not exceed 20–25°С. The reaction mixture was
neutralized with aqueous Na2CO3, extracted with CHCl3,
and dried over MgSO4. Chloroform was removed by
evaporation and the residue was distilled under vacuum.
Yield 24.1 g (61%), bp 127–128°С (3 mmHg), nD210 1.5082.
IR spectrum, ν, cm–1: 1520 (ring), 1710 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 2.18 (3Н, s, 3-CH3); 2.82 (2Н,
t, J = 6.7, CHCO); 3.65 (3Н, s, OCH3); 4.26 (2Н, t,
J = 6.7, NCH2); 7.56 (1Н, s, H-5). Found, %: C 39.07;
H 4.57; N 11.11. C8H11BrN2O2. Calculated, %: C 38.89;
H 4.49; N 11.34.
Synthesis of hydrazides 12, 13, 15–17 (General
method). A mixture of N2H4·H2O (3.0 g, 0.06 mol) and
ester 3, 5, 7–9 (0.02 mol) was stirred for 10 min at 90–100°С
until complete dissolution. The obtained precipitate was
filtered off after several minutes, washed on filter with a
small amount of Et2O, dried, and recrystallized from EtOH.
Hydrazide of (1Н-pyrazol-1-yl)acetic acid (12). Yield
2.3 g (82%), white crystals, mp 110–112°С, Rf 0.2 (1:1
benzene–Me2CO). 1H NMR spectrum, δ, ppm (J, Hz): 4.23
(2H, br. s, NH2); 4.70 (2H, s, NCH2); 6.18 (1H, dd, J = 2.3,
J = 1.8, H-4); 7.35 (1H, dd, J = 1.8, J = 0.7, H-3); 7.61
(1H, dd, J = 2.3, J = 0.7, H-5); 9.16 (1H, br. s, NH). Found,
%: C 42.65; H 5.49; N 39.79. C5H8N4O. Calculated, %:
C 42.85; H 5.75; N 39.98.
Methyl 3-(4-bromo-3,5-dimethylpyrazol-1-yl)propio-
nate (8). A mixture of methyl 3-(3,5-dimethyl-1H-pyrazol-
1-yl)propionate (12.70 g, 70 mmol), AcONa (14.35 g,
175 mmol), and Н2О (49 ml) was charged into a four-
necked flask, stirred at room temperature, and treated by
dropwise addition of a mixture of AcOH (7 ml) and Br2
(4.3 ml, 13.40 g, 84 mmol). Stirring was continued until
complete fading of bromine color, then the reaction
mixture was treated analogously to the procedure described
for compound 7. Yield 13.20 g (72%), colorless liquid, bp
Hydrazide of 3-(1Н-pyrazol-1-yl)propionic acid (13).
Yield 2.8 g (91%), white shiny crystals, mp 63–65°С,
1
Rf 0.2 (1:1 benzene–Me2CO). H NMR spectrum, δ, ppm
(J, Hz): 2.59 (2H, t, J = 6.9, CH2CO); 3.97 (2H, br. s,
NH2); 4.34 (2H, t, J = 6.9, NCH2); 6.11 (1H, dd, J = 2.3,
J = 1.8, H-4); 7.31 (1H, dd, J = 1.8, J = 0.6, H-3); 7.49 (1H,
dd, J = 2.3, J = 0.6, H-5); 8.95 (1H, br. s, NH). Found, %:
С 46.89; Н 6.64; N 36.55. C6H10N4О. Calculated, %:
С 46.74; Н 6.54; N 36.34.
Hydrazide of 3-(4-bromo-3-methyl-1Н-pyrazol-1-yl)-
propionic acid (15). Yield 4.0 g (81%), white crystals, mp
120–122°С, Rf 0.4 (2:1 benzene–Me2CO). 1H NMR
spectrum, δ, ppm (J, Hz): 2.13 (3H, s, CH3); 2.56 (2H, t,
J = 6.8, CH2CO); 3.90 (2H, br. s, NH2); 4.24 (2H, t, J = 6.8,
NCH2); 7.55 (1H, s, H-5); 8.97 (1H, br. s, NH). Found, %:
С 34.28; Н 4.21; N 22.45. C7H11BrN4О. Calculated, %:
С 34.03; Н 4.49; N 22.67.
20
117–119°С (1 mmHg), nD 1.5098. IR spectrum, ν, cm–1:
1
1540 (ring), 1720 (C=O). H NMR spectrum, δ, ppm (J,
Hz): 2.27 (3Н, s, 5-CH3); 2.73 (2Н, t, J = 6.8, CH2CO);
2.75 (3Н, s, 3-CH3); 3.60 (3Н, s, OCH3); 4.12 (2Н, t,
J = 6.8, NCH2). Found, %: C 41.48; H 5.19; N 10.58.
C9H13BrN2O2. Calculated, %: C 41.40; H 5.02; N 10.73.
Methyl 3-(4-chloro-3-methylpyrazol-1-yl)propionate (9).
A mixture of methyl 3-(3-methylpyrazol-1-yl)propionate
(33.6 g, 0.2 mol), AcOH (65 ml), and conc. HCl (27 ml)
was charged into a two-necked flask with a reflux condenser
and thermometer, then treated with 30% H2O2 (73 ml) in one
portion. The reaction mixture was left overnight, diluted
with Н2О, extracted with Et2O, washed with aqueous
Na2CO3, and dried over Na2SO4. Ether was removed at
reduced pressure, the residue was distilled under vacuum,
collecting the fraction with bp 105–120°С (3 mmHg).
Yield 19.7 g (64%), yellowish liquid, nD20 1.4908. 1H NMR
spectrum, δ, ppm (J, Hz): 2.13 (3H, s, 3-CH3); 2.81 (2H, t,
J = 6.7, CH2CO); 3.65 (3H, s, OCH3); 4.24 (2H, t, J = 6.7,
Hydrazide of 3-(4-bromo-3,5-dimethyl-1Н-pyrazol-1-yl)-
propionic acid (16). Yield 4.5 g (86%), white shiny
crystals, mp 153–155°С, Rf 0.2 (1:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 2.11 (3H, s, CH3); 2.25
(3H, s, CH3); 2.55 (2H, t, J = 6.9, CH2CO); 3.92 (2H, br. s,
NH2); 4.17 (2H, t, J = 6.9, NCH2); 8.95 (1H, br. s, NH).
Found, %: С 36.58; Н 5.15; N 21.57. C8H13BrN4О.
Calculated, %: С 36.80; Н 5.02; N 21.46.
Hydrazide of 3-(4-chloro-3-methyl-1H-pyrazol-1-yl)-
propionic acid (17). Yield 4.0 g (91%), yellow crystals,
1
mp 105–107°С, Rf 0.3 (1:1 benzene–Me2CO). H NMR
spectrum, δ, ppm (J, Hz): 2.13 (3H, s, CH3); 2.55 (2H, t,
486

Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
J = 6.8, CH2CO); 4.22 (2H, t, J = 6.8, NCH2); 5.19 (2H, br. s,
1H NMR spectrum (1:3 DMSO-d6–CCl4), δ, ppm (J, Hz):
1.43 (3H, t, J = 7.1, OCH2CH3); 2.64 (3H, s, 5-CH3); 2.80
(3H, d, J = 0.8, 7-CH3); 4.41 (2H, q, J = 7.1, OCH2CH3);
6.91 (1H, br. d, J = 1.9, H-5'); 6.97 (1H, q, J = 0.8, H-6);
7.52 (1H, d, J = 1.9, H-4'); 13.25 (1H, br. s, NH). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.52 (3H, t, J = 7.1,
OCH2CH3); 2.69 (3H, s, 5-CH3); 2.82 (3H, d, J = 0.9,
7-CH3); 4.54 (2H, q, J = 7.1, OCH2CH3); 6.78 (1H, q,
J = 0.9, H-6); 7.08 (1H, br. s, H-5'); 7.68 (1H, d, J = 1.5,
H-4'). 13C NMR spectrum (CDCl3), δ, ppm: 14.5; 17.2;
25.4; 61.5; 98.6; 105.6; 111.0; 136.0; 140.0; 146.1; 147.8;
149.2; 162.4; 165.4. Found, %: C 59.21; H 5.16; N 24.42.
C14H15N5O2. Calculated, %: C 58.94; H 5.30; N 24.55.
Compound 29. Yield 0.28 g (23%), white crystals, mp
237–240°С (mp 239–240°С),5 Rf 0.6 (1:1 benzene–Me2CO).
Compound 30. Yield 0.3 g (19%), colorless crystals, mp
39–40°С (mp 39–40°С),7,9,17 Rf 0.8 (2:1 benzene–Me2CO,
2:1). Compounds 29 and 30 had the same 1H and 13C NMR
spectra, as well as chromatographic retention times as the
previously obtained samples.
Reaction of iodide 1 with hydrazide of (1Н-pyrazol-1-yl)-
acetic acid (12). A solution of iodide 1 (1.35 g, 4 mmol) in
abs. EtOH (10 ml) was mixed with a solution of hydrazide
12 (1.12 g, 8 mmol) in abs. EtOH (15 ml). The reaction
mixture was refluxed for 36 h, then ethanol was
evaporated, and the oily residue was treated with hot
hexane. Hexane was evaporated, the residue was separated
by silica gel column chromatography (3:1 benzene–
Me2CO), giving ethyl 5,7-dimethyl-2-(1H-pyrazol-1-yl-
methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (21),
compound 29 (0.10 g, 15%), the product from demethylation
of iodide 1, ethyl (5,7-dimethylpyrimidin-2-yl)acetate (31),
as well as (1Н-pyrazol-1-yl)acetic acid (33).
Compound 21. Yield 0.50 g (44%), white crystals, mp
180–182°С (hexane), Rf 0.5 (2:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 1.40 (3H, t, J = 7.2,
OCH2CH3); 2.62 (3H, s, CH3); 2.73 (3H, d, J = 0.9, CH3);
4.35 (2H, q, J = 7.2, OCH2CH3); 5.72 (2H, s, CH2N); 6.14
(1H, dd, J = 2.4, J = 1.8, H-4'); 6.94 (1H, q, J = 0.9, H-6);
7.30 (1H, dd, J = 1.8, J = 0.7, H-5'); 7.61 (1H, dd, J = 2.4,
J = 0.7, H-3'). 13C NMR spectrum, δ, ppm: 14.0; 16.3; 24.2;
48.3; 58.9; 98.8; 104.5; 110.3; 129.2; 137.8; 145.5; 147.6;
153.8; 161.3; 161.8. Found, %: С 59.95; Н 5.39; N 23.64.
C15H17N5O2. Calculated, %: С 60.19; Н 5.72; N 23.40.
Compound 31. Yield 80 mg (10%), white crystals, mp
65–66°С (mp 65–66°С)9, Rf 0.67 (1:1 benzene–Me2CO).
Compound 33. Yield 80 mg (16%), white crystals, mp
175–176°С (mp 175–178°С)18, Rf 0.35 (2:1 benzene–
Me2CO). The physicochemical and spectral characteristics
of compounds 319 and 3318 matched the literature.
Reaction of iodide 1 with 3-(1H-pyrazol-1-yl)propionic
acid hydrazide (13). A solution of iodide 1 (1.68 g, 5 mmol)
in abs. EtOH (10 ml) was mixed with a solution of
hydrazide 13 (1.54 g, 10 mmol) in abs. EtOH (10 ml). The
reaction mixture was refluxed for 36 h, then ethanol was
evaporated, the oily residue was treated with hot hexane.
Hexane was evaporated, the residue was separated by silica
gel column chromatography (3:1 benzene–Me2CO), giving
ethyl 5,7-dimethyl-2-[2-(1H-pyrazol-1-yl)ethyl]pyrazolo-
NH2); 7.53 (1H, s, H-5); 8.95 (1H, br. s, NH). Found, %:
С 41.77; Н 5.59; N 27.41. C7H11ClN4О. Calculated, %:
С 41.49; Н 5.47; N 27.65.
Hydrazide of 3-(3,5-dimethyl-1Н-pyrazol-1-yl)propio-
nic acid (14). Methyl 3-(3,5-dimethyl-1Н-pyrazol-1-yl)pro-
pionate (6) (10.0 g, 0.055 mol) was mixed at room temperature
with 60% aqueous hydrazine (4 ml). The solution
spontaneously heated up to 35–38°С, and the reaction
product precipitated after 10 min. The mixture was cooled
and the precipitate was filtered off, washed with hot
hexane, and dried. Yield 9.7 g (97%), white shiny crystals,
1
mp 125–127°С (EtOH), Rf 0.1 (1:1 benzene–Me2CO). H
NMR spectrum, δ, ppm (J, Hz): 2.09 (3H, s, CH3); 2.23
(3H, s, CH3); 2.53 (2H, t, J = 7.1, CH2CO); 3.79 (2H, br. s,
NH2); 4.10 (2H, t, J = 7.1, NCH2); 5.62 (1H, s, H-4); 8.93
(1H, br. s, NH). Found, %: C 52.85; H 7.69; N 30.61.
C8H14N4O. Calculated, %: C 52.73; H 7.74; N 30.75.
Hydrazide of (1Н-1,2,4-triazol-1-yl)acetic acid (18). A
mixture of ethyl (1Н-1,2,4-triazol-1-yl)acetate (4) (5 g,
0.03 mol) and N2H4·H2O (6 g, 0.12 mol) was refluxed for
5 h. The obtained precipitate was filtered off, washed on
filter with a small amount of Et2O and dried. Yield 3.96 g
(94%), white crystals, mp 108–110°С (EtOH), Rf 0.1 (1:1
benzene–Me2CO). 1H NMR spectrum, δ, ppm (J, Hz): 4.27
(2H, br. s, NH2); 4.80 (2H, s, NCH2); 7.75 (1H, s, H-3);
8.34 (1H, s, H-5); 9.37 (1H, br. s, NH). Found, %: C 34.27;
H 5.19; N 49.35. C4H7N5O. Calculated, %: C 34.04;
H 5.00; N 49.62.
Hydrazide of 2-methyl-3-(3-methyl-1Н-pyrazol-1-yl)-
propionic acid (19). A mixture of methyl 2-methyl-3-(3-
methyl-1Н-pyrazol-1-yl)propionate (10) (5.5 g, 0.03 mol)
and N2H4·H2O (5.5 g, 0.11 mol) was refluxed for 8 h. The
obtained precipitate was filtered off, washed on filter with a
small amount of Et2O, and dried. Yield 3.5 g (64%), white
crystals, mp 78–80°С (EtOH), Rf 0.3 (1:1 benzene–
1
Me2CO). H NMR spectrum, δ, ppm (J, Hz): 1.01 (3H, d,
J= 6.9, CHCH3); 2.17 (3H, s, 3-CH3); 2.74–2.87 (1H, m,
CHCH3); 3.89 (1H, dd, J = 13.3, J = 7.0) and 4.18 (1H, dd,
J = 13.3, J = 7.6, NCH2); 3.90 (2H, br. s, NH2); 5.85 (1H,
d, J = 2.1, H-4); 7.28 (1H, d, J = 2.1, H-5); 8.93 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm: 13.1; 15.0; 38.9; 53.6; 103.7;
130.0; 146.7; 172.5. Found, %: C 52.95; H 7.89; N 30.55.
C8H14N4O. Calculated, %: C 52.73; H 7.74; N 30.75.
Reaction of 2-(ethoxycarbonyl)methyl-1,4,6-trimethyl-
pyrimidinium iodide (1) with hydrazide of 1Н-pyrazole-
3-carboxylic acid (11). A solution of iodide 1 (2.52 g,
7.5 mmol) in abs. EtOH (10 ml) was mixed with a solution
of hydrazide 11 (1.89 g, 15.0 mmol) in abs. EtOH (8 ml).
The reaction mixture was refluxed for 40 h, ethanol was
evaporated, and the oily residue was treated with hot
hexane. Hexane was evaporated, the residue was separated
by silica gel column chromatography (2:1 benzene–
Me2CO), giving ethyl 5,7-dimethyl-2-(1H-pyrazol-3-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxylate (20), 2-hydroxy-
pyrazolo[1,5-a]pyrimidine (29), and ethyl 5,7-dimethyl-
2-(dimethylamino)pyridine-3-carboxylate (30).
Compound 20. Yield 0.51 g (24%), white crystals, mp
171–173°С (hexane), Rf 0.5 (2:1 benzene–Me2CO).
487

Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
[1,5-a]pyrimidine-3-carboxylate (22), compound 29
dine-3-carboxylate (24), hydroxy derivative 29 (0.05 g,
6%), pyridine derivative 30 (0.10 g, 10%), and demethylation
product 31 (0.05 g, 5%).
(150 mg, 18%), and compound 31 (70 mg, 7%).
Compound 22. Yield 0.6 g (38%), white crystals, mp
118–120°С (hexane), Rf 0.6 (2:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 1.42 (3H, t, J = 7.1,
OCH2CH3); 2.62 (3H, s, CH3); 2.72 (3H, d, J = 0.8, CH3);
3.53–3.59 (2H, m, CH2CH2N); 4.35 (2H, q, J = 7.1,
OCH2CH3); 4.49–4.55 (2H, m, CH2CH2N); 6.11 (1H, dd,
J = 2.3, J = 1.8, Н-4'); 6.89 (1H, q, J = 0.8, Н-6); 7.32 (1H,
dd, J = 1.8, J = 0.6, Н-5'); 7.48 (1H, dd, J = 2.3, J = 0.6,
Н-3'). 13C NMR spectrum, δ, ppm: 14.1; 16.3; 24.2; 29.8;
49.7; 58.7; 98.8; 104.3; 109.7; 128.4; 138.0; 145.1;
147.8; 156.4; 160.8; 162.1. Found, %: С 61.59; Н 6.30;
N 22.61. C16H19N5O2. Calculated, %: С 61.33; Н 6.11;
N 22.35.
Reaction of iodide 1 with 3-(3,5-dimethyl-1Н-pyrazol-
1-yl)propionic acid hydrazide (14). A solution of iodide 1
(1.68 g, 5 mmol) and hydrazide 14 (1.82 g, 10 mmol) in
abs. EtOH (20 ml) was refluxed for 20 h. After the reaction
was complete, ethanol was evaporated, the oily residue was
treated with hexane, resulting in crystallization. The
crystals were filtered off and treated with Ме2СО (3 ml),
the insoluble residue was filtered off and washed on filter
with acetone, yielding hydroiodide of the unreacted 3-(3,5-
dimethyl-1Н-pyrazol-1-yl)propionic acid hydrazide (0.60 g,
67%), mp 170–171°С (neutralization of aqueous solution of
the isolated salt with dilute KОН solution gave a
precipitate of hydrazide 14, mp 125–126°С; the 1:1 ratio of
hydrazide : HI was established by titration). The filtrate
was evaporated, the residue was separated by silica gel
column chromatography (2:1 benzene–Me2CO), giving
ethyl 5,7-dimethyl-2-[2-(3,5-dimethyl-1Н-pyrazol-1-yl)-
ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (23),
compound 29 (0.29 g, 25%), compound 30 (0.07 g, 7%),
and compound 31 (0.10 g, 10%).
Compound 23. Yield 0.44 g (26%), white crystals, mp
155–156°С (hexane), Rf 0.51 (1:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 1.45 (3Н, t, J = 7.1,
ОСН2СН3); 2.19 (3H, s, 5'-CH3); 2.25 (3H, s, 3'-CH3); 2.65
(3H, s, 7-CH3); 2.74 (3H, s, 5-CH3); 3.58–3.64 (2H, m,
СН2СН2N); 4.40–4.47 (2H, m, СН2СН2N); 4.44 (2H, q,
J = 7.1, ОСН2СН3); 5.73 (1H, s, Н-4'); 6.67 (1H, s, Н-6).
13C NMR spectrum, δ, ppm: 10.9; 12.2; 14.7; 17.3; 25.3;
29.6; 49.4; 60.3; 96.3; 105.1; 106.0; 110.2; 142.0; 145.9;
148.8; 156.4; 162.2; 163.3. Mass spectrum m/z (Irel, %):
342 (20), 341 [M]+ (100), 313 (39), 270 (9), 269 (45), 248
(11), 245 (10), 217 (10), 173 (28), 132 (21). Found, %:
C 63.59; H 6.71; N 20.70. C18H23N5O2. Calculated, %:
C 63.32; H 6.79; N 20.51.
Reaction of iodide 1 with 3-(4-bromo-3-methyl-1Н-
pyrazol-1-yl)propionic acid hydrazide (15). A solution of
iodide 1 (1.68 g, 5 mmol) in abs. EtOH (10 ml) was mixed
with a solution of hydrazide 15 (2.47 g, 10 mmol) in abs.
EtOH (15 ml). The reaction mixture was refluxed for 40 h,
then ethanol was evaporated, the oily residue was treated
with hot hexane. Hexane was evaporated, the residue was
separated by silica gel column chromatography (3:1
benzene–Me2CO), giving ethyl 2-[2-(4-bromo-3-methyl-
1Н-pyrazol-1-yl)ethyl]-5,7-dimethylpyrazolo[1,5-a]pyrimi-
Compound 24. Yield 1.10 g (54%), white crystals, mp
128–130°С (hexane), Rf 0.5 (2:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 1.42 (3H, t, J = 7.1,
ОСН2CH3); 2.16 (3H, s, 3'-CH3); 2.62 (3H, s, 5-CH3); 2.72
(3H, d, J = 0.9, 7-CH3); 3.50–3.56 (2H, m, CH2CH2N);
4.35 (2H, q, J = 7.1, ОCH2CH3); 4.39–4.45 (2H, m,
CH2CH2N); 6.90 (1H, q, J = 0.9, H-6); 7.53 (1H, s, H-5').
13C NMR spectrum, δ, ppm: 11.2; 14.1; 16.3; 24.2; 29.5;
50.1; 58.7; 91.8; 98.8; 109.7; 129.2; 144.9; 145.4; 147.7;
156.2; 160.8; 162.1. Found, %: С 50.51; Н 4.75; N 17.45.
C17H20BrN5O2. Calculated, %: С 50.26; Н 4.96; N 17.24.
Reaction of iodide 1 with 3-(4-bromo-3,5-dimethyl-
1Н-pyrazol-1-yl)propionic acid hydrazide (16).
A
solution of iodide 1 (1.68 g, 5 mmol) in abs. EtOH (10 ml)
was mixed with a solution of hydrazide 16 (2.61 g,
10 mmol) in abs. EtOH (10 ml). The reaction mixture was
heated for 40 h in a sealed ampoule at 90–100°С, then
ethanol was evaporated, and the oily residue was treated
with hot hexane. Hexane was evaporated, the residue was
separated by silica gel column chromatography (3:1
benzene–Me2CO), giving ethyl 2-[2-(4-bromo-3,5-dimethyl-
1Н-pyrazol-1-yl)ethyl]-5,7-dimethylpyrazolo[1,5-a]pyrimi-
dine-3-carboxylate (25), as well as compound 29 (0.10 g,
12%), pyridine derivative 30 (0.09 g, 9%), and demethylation
product 31 (0.05 g, 4%).
Compound 25. Yield 1.05 g (50%), white crystals, mp
151–153°С (hexane), Rf 0.6 (2:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 1.42 (3H, t, J = 7.1,
ОCH2CH3); 2.12 (3H, s, 3'(5')-CH3); 2.24 (3H, s, 5'(3')-CH3);
2.62 (3H, s, 5-CH3); 2.72 (3H, d, J = 0.9, 7-CH3); 3.43–3.50
(2H, m, CH2CH2N); 4.32–4.38 (2H, m, CH2CH2N); 4.36
(2H, q, J = 7.1, ОCH2CH3); 6.90 (1H, q, J = 0.9, H-6).
13C NMR spectrum, δ, ppm: 9.4; 11.7; 14.1; 16.3; 24.2; 29.3;
47.7; 58.8; 92.5; 98.9; 109.8; 135.9; 144.3; 145.0; 147.7; 156.3;
160.9; 162.2. Found, %: С 51.59; Н 5.11; N 16.45.
C18H22BrN5O2. Calculated, %: С 51.44; Н 5.28; N 16.66.
Reaction of iodide 1 with 2-(4-chloro-3-methyl-1H-pyr-
azol-1-yl)propionic acid hydrazide (17). A solution of
iodide 1 (1.68 g, 5 mmol) in abs. EtOH (10 ml) was mixed
with a solution of hydrazide 17 (2.03 g, 10 mmol) in abs.
EtOH (10 ml). The reaction mixture was refluxed for 36 h,
then ethanol was evaporated, the oily residue was treated
with hot hexane. Hexane was evaporated, the residue was
separated by silica gel column chromatography (3:1
benzene–Me2CO), giving ethyl 2-[2-(4-chloro-3-methyl-
1H-pyrazol-1-yl)ethyl]-5,7-dimethylpyrazolo[1,5-a]pyri-
midine-3-carboxylate (26), compound 29 (0.10 g, 12%),
and demethylation product 31 (0.09 g, 9%).
Compound 26. Yield 0.75 g (42%), white crystals, mp
135–137°С (hexane), Rf 0.7 (2:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 1.42 (3H, t, J = 7.1,
OCH2CH3); 2.15 (3H, s, 3'-CH3); 2.62 (3H, s, 5-CH3); 2.72
(3H, d, J = 0.8, 7-CH3); 3.49–3.55 (2H, m, CH2CH2N);
4.35 (2H, q, J = 7.1, OCH2CH3); 4.38–4.43 (2H, m,
CH2CH2N); 6.90 (1H, q, J = 0.8, H-6); 7.51 (1H, s, H-5').
13C NMR spectrum, δ, ppm: 10.4; 14.1; 16.3; 24.2; 29.5;
488

Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
50.1; 58.7; 98.8; 107.0; 109.7; 126.9; 143.7; 145.0; 147.7;
X-ray structural analysis of compound 26 was
performed at room temperature on an Enraf-Nonius CAD-4
automated diffractometer (graphite monochromator, МоKα
radiation, ω-scanning). The parameters of monoclinic unit
cell were determined and refined by 24 reflections with
θ 13.1...14.2°. The correction for absorption was intro-
duced by experimental azimuthal scan curves (Tmin
0.56262, Tmax 0.60134).19 The structure was solved directly,
hydrogen atom coordinates were partially determined by
differential Fourier synthesis. The methyl group hydrogen
atoms were calculated geometrically and refined by the
"rider" model with the following constraints: C–H bond
length 0.96 Å, Uiso(H) = 1.5Ueq(C). The structure was
refined by full matrix method of least squares in
anisotropic approximation for non-hydrogen atoms and
isotropically for hydrogen atoms. All structural calculations
were performed with the SHELXTL software suite.20
The crystallographic data were deposited at the
Cambridge Crystallographic Data Center (deposit CCDC
1005179).
156.2; 160.8; 162.1. Found, %: С 56.19; Н 5.41;
N 19.55. C17H20ClN5O2. Calculated, %:
Н 5.57; N 19.36.
С 56.43;
Reaction of iodide 1 with (1Н-1,2,4-triazol-1-yl)acetic
acid hydrazide (18). A solution of iodide 1 (0.84 g,
2.5 mmol) in abs. EtOH (10 ml) was mixed with a solution
of hydrazide 18 (0.71 g, 5 mmol) in abs. EtOH (8 ml). The
reaction mixture was refluxed for 40 h, then ethanol was
evaporated, and the oily residue was treated with hot
hexane. Hexane was evaporated, the residue was separated
by silica gel column chromatography (2:1 benzene–
Me2CO), giving ethyl 5,7-dimethyl-2-(1,2,4-triazol-1-yl-
methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (27),
hydroxypyrazolo[1,5-a]pyrimidine 29 (0.03 g, 8%), demethylation
product 31 (0.05 g, 10%), and (1Н-1,2,4-triazol-1-yl)-acetic
acid (34).
Compound 27. Yield 0.23 g (31%), white crystals, mp
193–195°С (hexane), Rf 0.4 (1:1 benzene–Me2CO).
1H NMR spectrum, δ, ppm (J, Hz): 1.40 (3H, t, J = 7.1,
CH2CH3); 2.63 (3H, s, 5-CH3); 2.73 (3H, d, J = 0.9,
7-CH3); 4.36 (2H, q, J = 7.1, OCH2); 5.79 (2H, s, CH2);
6.97 (1H, q, J = 0.9, H-6); 7.72 (1H, s, H-3'); 8.34 (1H, s,
H-5'). 13C NMR spectrum, δ, ppm: 14.0; 16.2; 24.2; 46.2;
59.0; 98.8; 110.4; 143.7; 145.6; 147.6; 150.4; 152.8; 161.6;
161.9. Found, %: C 56.15; H 5.59; N 28.25. C14H16N6O2.
Calculated, %: C 55.99; H 5.37; N 27.98.
This work was performed within the framework of Russian-
Armenian grant 13RF-087 by the State Committee for
Science at the Ministry of Education and Science, Republic
of Armenia and the Russian Foundation for Basic
Research, as well as with financial support from the State
Committee for Science at the Ministry of Education and
Science, Republic of Armenia (grant 13-1D334).
NMR spectra were acquired at the Molecular Structure
Research Center, National Academy of Sciences of the
Republic of Armenia (program US CRDF RESC 17-5).
Compound 34. Yield 40 mg (13%), white crystals, mp
196–199°С (mp 199–202°С)15, Rf 0.2 (1:1 benzene–Me2CO).
The physicochemical and spectral characteristics of
carboxylic acid 34 matched those of a sample obtained by
the opposite route of synthesis (ethyl ester hydrolysis)
according to a published procedure.15
References
Reaction of iodide 1 with 2-methyl-3-(3-methyl-
1. Danagulyan, G. G.; Boyakhchyan, A. P.; Danagulyan, A. G.;
Panosyan, H. A. Chem. Heterocycl. Compd. 2011, 47, 321.
[Khim. Geterotsikl. Soedin. 2011, 393.]
2. Danagulyan, G. G.; Boyakhchyan, A. P.; Tumanyan A. K.;
Danagulyan, A. G.; Kirakosyan V. G. Chem. Heterocycl. Compd.
2011, 47, 386. [Khim. Geterotsikl. Soedin. 2011, 465.]
3. Shirakawa, K. Yakugaku Zasshi 1958, 78, 1395; Chem. Abstr.
1959, 53, 8150e.
4. Allen, C. F. H.; Beilfuss, H. R.; Burness, D. M.; Reynolds, G. A.;
Tinker, J. F.; Van Allan, J. A. J. Org. Chem. 1959, 24, 787.
5. Danagulyan, G. G.; Tadevosyan, D. A.; Tamazyan, R. A.;
Panosyan, G. A. Chem. Heterocycl. Compd. 2006, 42, 233.
[Khim. Geterotsikl. Soedin. 2006, 262.]
6. Danagulyan, G. G.; Tumanyan, A. K.; Attaryan, O. S.;
Danagulyan, A. G.; Chupakhin, O. N. Khim. Zh. Armenii
2014, 67(1), 85.
7. Danagulyan, G. G.; Sahakyan, L. G.; Katritzky, A. R.;
Denisenko, S. N. Heterocycles 2000, 53, 419.
8. Danagulyan, G. G. Chem. Heterocycl. Compd. 2005, 41,
1205. [Khim. Geterotsikl. Soedin. 2005, 1445.]
9. Danagulyan, G. G.; Saakyan, L. G., Panosyan G. A. Chem.
Heterocycl. Compd. 2001, 37, 323. [Khim. Geterotsikl.
Soedin. 2001, 351.]
10. Danagulyan, G. G.; Panosyan, G. A.; Sahakyan, L. G. Chem.
Heterocycl. Compd. 2007, 43, 996. [Khim. Geterotsikl.
Soedin. 2007, 1175.]
11. Attaryan, O. S.; Grigoryan, A. J.; Panosyan, G. A.; Matsoyan, S. G.
Khim. Zh. Armenii 2001, 54(1–2), 102.
1Н-pyrazol-1-yl)propionic acid hydrazide (19).
A
solution of iodide 1 (1.00 g, 3 mmol) in abs. EtOH (10 ml)
was mixed with a solution of hydrazide 19 (1.09 g,
6 mmol) in abs. EtOH (10 ml). The reaction mixture was
refluxed for 40 h, then ethanol was evaporated, the oily
residue was treated with hot hexane. Hexane was
evaporated, the residue was separated by silica gel column
chromatography (1:1 benzene–Me2CO), giving ethyl
5,7-dimethyl-2-[1-methyl-2-(3-methyl-1Н-pyrazol-1-yl)-
ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (28), hydroxy-
pyrazolo[1,5-a]pyrimidine 29 (0.07 g, 14%), and
demethylation product 31 (0.09 g, 16%).
Compound 28. Yield 0.35 g (34%), white crystals, mp
1
78–80°С (hexane), Rf 0.6 (2:1 benzene–Me2CO). H NMR
spectrum, δ, ppm (J, Hz): 1.26 (3H, d, J = 6.2, CHCH3);
1.41 (3H, t, J = 7.1, OCH2CH3); 2.18 (3H, s, 3'-CH3); 2.61
(3H, s, 5-CH3); 2.74 (3H, d, J = 0.9, 7-CH3); 4.09–4.25 (2H,
m, CH2N); 4.34 (2H, q, J = 7.1, ОCH2CH3); 4.43–4.53 (1H,
m, CHCH3); 5.84 (1H, d, J = 2.1, H-4'); 6.88 (1H, q,
J = 0.9, H-6); 7.30 (1H, d, J = 2.1, H-5'). 13C NMR
spectrum, δ, ppm: 13.1; 14.1; 16.3; 17.0; 24.2; 33.9; 55.2;
58.7; 98.4; 103.8; 109.6; 129.6; 145.0; 146.5; 147.9;
160.7; 161.0; 162.1. Found, %: C 63.57; H 6.91;
N 20.61. C18H23N5O2. Calculated, %: C 63.32; H 6.79;
N 20.51.
489

Chemistry of Heterocyclic Compounds 2015, 51(5), 483–490
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2002, 41, 1937.
12. Rstakyan, V. I.; Hakobyan, A. E.; Zakaryan, G. B.;
Hayotsyan, S. S.; Attaryan, H. S.; Asratyan, G. V. Russ. J.
Gen. Chem. 2014, 84, 1641. [Zh. Obsch. Khim. 2014, 84, 1397.]
13. Attaryan, O. S.; Baltayan, A. O.; Matsoyan, S. G. Russ. J.
Gen. Chem. 2007, 77, 297. [Zh. Obsch. Khim. 2007, 77, 325.]
14. Katritzky, A. R.; Kuzmierkiewicz, W.; Greenhill, J. V. Rec.
Trav. Chim. Pays-Bas 1991, 110(9), 369.
17. Sagitullin, R. S.; Kost, A. N.; Danagulyan, G. G. Tetrahedron
Lett. 1978, 19, 4135.
18. Badalyan, K. S.; Asratyan, A. G.; Attaryan, O. S. Russ. J.
Gen. Chem. 2012, 82, 946. [Zh. Obsch. Khim. 2012, 82, 876.]
19. North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta
Crystallogr., Sect. A: Cryst. Phys., Diffr., Theor. Gen.
Crystallogr. 1968, A24, 351.
20. Sheldrick, G. M. SHELXTL-97, Program for X-ray Crystal
Structure Solution; Göttingen University: Göttingen, 1997.
15. Nagao, Y.; Sano, S.; Ochiai, M.; Fujita, E. Tetrahedron 1990,
46, 3211.
16. Srivastava, S. K.; Srivastava, S.; Srivastava, S. D. Indian J.
490