СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ
New pyrazolo[1,5-a][1,3,5]triazines with a heteroaromatic substituent in position 4 and dichloromethyl moiety in position 2 were obtained via a heterocyclization reaction of readily available reagents - N-(2,2-dichloro-1-cyanoethenyl)carboxamides and 3(5)-aminopyrazoles. The high efficiency of the p...
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| Дата: | 2020 |
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| Автори: | , , , , , |
| Формат: | Стаття |
| Мова: | Англійська |
| Опубліковано: |
V.I.Vernadsky Institute of General and Inorganic Chemistry
2020
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Репозитарії
Ukrainian Chemistry Journal| _version_ | 1871465461782151168 |
|---|---|
| author | Velihina, Yevgeniia Kachaeva, Maryna Pil'o, Stepan Moskvina, Viktoriia Shablykina, Olga Brovarets, Volodymyr |
| author_facet | Velihina, Yevgeniia Kachaeva, Maryna Pil'o, Stepan Moskvina, Viktoriia Shablykina, Olga Brovarets, Volodymyr |
| author_institution_txt_mv | [
{
"author": "Yevgeniia Velihina",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv,"
},
{
"author": "Maryna Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv,"
},
{
"author": "Stepan Pil'o",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv"
},
{
"author": "Viktoriia Moskvina",
"institution": "Taras Shevchenko National University of Kyiv, Faculty of Chemistry, Organic Chemistry Department"
},
{
"author": "Olga Shablykina",
"institution": "Taras Shevchenko National University of Kyiv, Faculty of Chemistry, Organic Chemistry Department"
},
{
"author": "Volodymyr Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kyiv"
}
] |
| author_sort | Velihina, Yevgeniia |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:43Z |
| description | New pyrazolo[1,5-a][1,3,5]triazines with a heteroaromatic substituent in position 4 and dichloromethyl moiety in position 2 were obtained via a heterocyclization reaction of readily available reagents - N-(2,2-dichloro-1-cyanoethenyl)carboxamides and 3(5)-aminopyrazoles. The high efficiency of the proposed method for the synthesis of 2-(dichloromethyl)-pyrazolo[1,5-a][1,3,5]triazines with furan-2-yl, thien-2-yl, and pyridine-3-yl substituents was demonstrated. |
| doi_str_mv | 10.33609/2708-129X.86.5.2020.53-62 |
| first_indexed | 2025-09-24T17:43:26Z |
| format | Article |
| fulltext |
ОРГАНІЧНА ХІМІЯ
ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5 53
УДК 547.874.8. doi: 10.33609/2708-129X.86.5.2020.53-62
Ye.S. Velihina1, M.V. Kachaeva1, S.G. Pil'o1, V.S. Moskvina1,2*, O.V. Shablykina1,2,
V.S. Brovarets1
SYNTHESIS OF 4-HETARYL-2-(DICHLOROMETHYL)PYRAZOLO[1,5-a][1,3,5]-
TRIAZINES
1 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine,
Murmanska str., 1, Kyiv, 02094, Ukraine
2 Taras Shevchenko National University of Kyiv, Volodymyrska str., 64, Kyiv, 01601, Ukraine
*е-mail: v.moskvina@gmail.com
New pyrazolo[1,5-a][1,3,5]triazines with a heteroaromatic substituent in position 4 and
dichloromethyl moiety in position 2 were obtained via a heterocyclization reaction of
readily available reagents - N-(2,2-dichloro-1-cyanoethenyl)carboxamides and 3(5)-
aminopyrazoles. The high efficiency of the proposed method for the synthesis of 2-
(dichloromethyl)-pyrazolo[1,5-a][1,3,5]triazines with furan-2-yl, thien-2-yl, and pyri-
dine-3-yl substituents was demonstrated.
K e y w o r d s: N-(2,2-Dichloro-1-cyanoethenyl)carboxamide, 1H-pyrazol-5-amine,
pyrazolo-[1,5-a][1,3,5]triazine.
INTRODUCTION. The heterocyclic
system of pyrazolo[1,5-a][1,3,5]triazine can
be considered isosteric to the purine system,
and for this reason pyrazolo[1,5-a]-
[1,3,5]triazines are also sometimes called 5-
aza-9-deazapurines [1]. Molecules with this
ring in their structure demonstrate a wide
spectrum of biological activity that is heavi-
ly dependent on the nature of substituents in
the heterocycle.
A family of pyrazolo[1,5-a]-
[1,3,5]triazines with an aminogroup in posi-
tion 4 and an aryl moiety in position 8
has demonstrated CRF (Cotricotropin-
releasing factor) inhibitory activity and
was considered as potential medicine for
curing depression and anxiety. DMP696 (1,
Fig. 1) is the best studied derivative in this
regard [2].
Introducing an arylmercapto group into
the structure of 4-amino-8-arylpyrazolo-
[1,5-a][1,3,5]triazine (2, Fig. 1) imbues these
molecules with antibacterial properties [3].
Furthermore, the research of new xan-
thin-oxidase inhibitors (to treat gout) has
established that the activity of 8-methyl-5-
aza-9-deazahypo-xanthine (3a, Fig. 1) is
roughly three orders of magnitude higher
than that of the unsubstituted 5-aza-9-
deazahypoxanthine (3b) [4]. Plenty of ex-
amples like the above exist, and when re-
viewing the literature it’s easy to notice that
© Ye.S. Velihina, M.V.Kachaeva, S.G. Pil'o, V.S.Moskvina, O.V. Shablykina, V.S. Brovarets, 2020
Ye.S. Velihina, M.V.Kachaeva, S.G. Pil'o, V.S.Moskvina, O.V. Shablykina, V.S. Brovarets
54 ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5
N
N
N
N
S
H2N
Cl
Cl
HOOC
N
N
N
N
Me
N
H
Me
MeO
MeO
Cl
Cl
1
DMP696
HN
N
N
N
R
O
IC50: 8.4
⋅
10
−
5
M
(R
=
H
(a))
,
4.7
⋅
10
−
8
M
(R
=
Me
(b))
2
3
Fig. 1. Bioactive pyrazolo[1,5-a][1,3,5]triazines
(literature data)
an important place among pyrazolo[1,5-a]-
[1,3,5]triazines that have been synthesized
and researched as bioactive compounds is
occupied by 4-aminoderivatives [1]. Partly
this is due to the peculiarities of the synthe-
sis of these compound: the usual starting
compounds for most pyrazolo[1,5-a][1,3,5]-
triazines are 3(5)-aminopyrazoles [5] that,
reacting as binucleophiles with N-cyano-
amidines and their analogues, easily form
various 4-aminopyrazolo[1,5-a][1,3,5]tria-
zines. On the other side, in reactions with
N-асуlimidates 3(5)-aminopyrazoles give
4-alkyl- and 4-arylpyrazolo[1,5-a][1,3,5]
triazines.
Therefore, varying electrophilic agents
in 3(5)-aminopyrazole heterocyclization al-
lows to obtain new functionalized pyrazolo-
[1,5-a][1,3,5]triazines, and researching their
biological activity is going to be the next
task of interest.
The bielectrophile of our choosing be-
came a derivative of ADAN – N-(2,2-
dichloro-1-cyanoethenyl)carboxamide [6].
As the results of an interesting hetero-
cyclization that was accompanied by the
elimination of the CN group and formation
of pyrazolo[1,5-a][1,3,5]triazines with a
dichloromethyl group in position 2 [7]. Al-
ternatively, previously we have synthesized
2,7-diaryl-4-(dichloro-methyl) pyrazolo-
[1,5-a][1,3,5]triazines with yields up to
46% via interaction of 3-(5)-aminopyrazoles
with 1-aryl-1,3,4,4-tetrachloro-2-azabuta-1,3-
dienes [8].
Also we have found that pyrazolo-
[1,5-a][1,3,5]triazines exhibit moderate anti-
viral activity [7]; in contrast, anticancer ac-
tivity of some compounds from the group
was quite potent [9]. Of particular interest
is the fact that 4-aryl-2-(dichloro-
methyl)pyrazolo[1,5-a][1,3,5]-triazines have
demonstrated high activity, while that of
corresponding 4-alkylderivatives was very
weak, which prompted us to synthesize de-
rivatives with heteroaromatic substituents in
position 4 for further biological studies.
EXPERIMENT AND DISCUSSION OF
THE RESULTS. Synthesis of new 4-
aminopyrazolo[1,5-a][1,3,5]triazines with a
CHCl2 group in position 2 was performed in
four stages, starting from amides 4-6 with
chloral (7). To obtain such compounds with
CHCl2 group and heterocyclic moiety, we
used the previously developed hetero-
cyclization [10, 11].
Condensation of amides of correspond-
ing heteroaromatic acids 4-6 with chloral (7)
led to N-(2,2,2-trichloro-1-hydroxyethyl)-
amides 8-10, which reacted with thionyl
chloride to give N-(1,2,2,2-tetrachloroethyl)-
amides 11-13, which can be used in the next
step without purification. The subsequent
Synthesis of 4-hetaryl-2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]-triazines
ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5 55
substitution of the chlorine atom in amides
11-13 with a cyano group gave access to N-
(2,2-dichloro-1-cyanovinyl)-amides 14-16.
The final step was heterocyclization, which
was based on the condensation of 1H-
pyrazol-5-amines 17a-d with N-(2,2-
dichloro-1-cyanovinyl) furan-2-carboxy-
amide 14, its thiophene analogue 15, and
pyridine derivative 16 (Fig. 2). Key new
compounds – 4-hetaryl-2-(dichloromethyl)-
pyrazolo[1,5-a][1,3,5]triazines 18-20a-d
were obtained in good yields (66-78%). This
cyclocondensation occurs in several stages
and involves the addition of an NH2-group to
the activated C-C double bond via form in-
termediate A with the subsequent triethyla-
mine-promoted elimination of HCN, result-
ing in B that after the final intermolecular
condensation gives products 18-20a-d. The
developed procedure for the hetero-
cyclization of the pyrazolo[1,5-a][1,3,5]
triazine system provides high yields of target
products 18-20a-d and is applicable to all
three starting heterocyclic derivatives 14-16.
The methods for the synthesis of the latter
differed: for furan and thiophene derivatives
– 14 and 15, it was possible to use the meth-
odology developed and tested for N-(2,2-
dichloro-1-cyanovinyl)carboxamides of ali-
phatic and aromatic acids [10, 11]; yet in the
case of the basic pyridine cycle, it was nec-
essary to adjust the method for processing
the reaction mixture and isolating the prod-
uct 16. We expect that this versatile protocol
may be broadly applied to the synthesis of
2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]-
triazines.
The structures of synthesized com-
pounds 18-20a-d were fully confirmed by
spectral data and elemental analysis. The
comparison of the reported 1H NMR spectral
data and spectra of compounds 18-20a-d
revealed some abnormal chemical shifts for
protons of heterocyclic moieties (furyl,
thienyl and pyridyl) associated with elec-
tron-withdrawing triazine ring.
The furyl and thienyl proton signals of
pyrazolo[1,5-a][1,3,5]triazines 18a-d and
19a-d in the NMR spectrum are deshielded
(7.5–9.0 and 7.0–.6 ppm respectively) com-
pared to unsubstituted furane and thiophene
(about 6.0-7.5 and 6.5–7.5 ppm respec-
tively). Proton chemical shifts of pyridine
moiety for heterocycles 20a-d are also de-
shielded covered a range from 7.7 to
9.9 ppm. It should be noted that unsubsti-
tuted pyridine has corresponding shifts at
about 7.0–8.5 ppm, therefore the chemical
shifts in 1H NMR of the heterocyclic moie-
ties in compounds 18-20a-d differ by 1 ppm
from those in the unsubstituted furane, thio-
phene and pyridine.
All reagents and solvents used in syn-
thetic procedures were purchased from Al-
drich and used as received. The reaction
progress was monitored by the TLC method
on Silica gel 60 F254 Merck. 1H (400 MHz)
and 13C (100 MHz) NMR spectra of ob-
tained products were recorded at Varian
Unityplus 400 spectrometer in DMSO-d6
solution with TMS as the internal standard.
IR spectra were recorded on a Vertex 70
spectrometer from KBr pellets. Melting
points were measured on a Fisher-Johns in-
strument.
Chromatomass spectra were recorded
on an Agilent 1100 Series high performance
liquid chromatograph equipped with a diode
matrix with an Agilent LC/MS mass selec-
tive detector allowing a fast switching of the
Ye.S. Velihina, M.V.Kachaeva, S.G. Pil'o, V.S.Moskvina, O.V. Shablykina, V.S. Brovarets
56 ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5
HN
Het
O
Cl
Cl
Cl Cl
HN
Het
O
OH
Cl
Cl ClNH2
Het
O
Cl
Cl
Cl
O
18: Het
=
2-furyl,
R
=
Me
(a);
Het
=
2-furyl,
R
=
Ph
(b);
Het
=
2-furyl,
4-MeC6H4
(c);
Het
=
2-furyl,
4-FC6H4
(d);
19: Het
=
2-thienyl,
R
=
Me
(a);
Het
=
2-thienyl,
R
=
Ph
(b);
Het
=
2-thienyl,
4-MeC6H4
(c);
Het
=
2-thienyl,
4-FC6H4
(d);
20: Het
=
3-Py, R
=
Me
(a);
Het
=
3-Py, R
=
Ph
(b);
Het
=
3-Py, 4-MeC6H4
(c);
Het
=
3-Py, 4-FC6H4
(d)
SOCl2 KCN
O
HN
Het CN
Cl
Cl
HN N
H2N R
N
N
N
N
CHCl2
Het
R
+
O
HN
Het
CHCl2
CN
NH
HN
N
O
N
Het NH
HN
N
CHCl2
R R
−
HCN
Et3N
A B
−
H2O17a-d:
R
=
Me
(a)
, Ph
(b)
,
4-MeC6H4
(c)
,
4-FC6H4
(d)
Het
=
(a)
,
(b)
,
(c)
N
O S
4-6
7
8-10 11-13 14-16
17a-d
18-20a-d
Fig. 2. Scheme of 4-(furan-2-yl/thien-2-yl/pyridin-3-yl)-2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]-
triazines 18-20a-d synthesis
positive/ negative ionization modes (chemi-
cal ionization).
Elemental analyses were performed
at the Analytical Laboratory of the
V.P. Kukhar Institute of Bioorganic Chemis-
try and Petrochemistry, NAS of Ukraine,
their results were found to be in good
agreement (±0.4%) with the calculated val-
ues.
General procedures of N-(2,2,2-
trichloro-1-hydroxyethyl)amides 8-10 syn-
thesis. The mixture of appropriate amide
(1 mol), chloral hydrate (1.1 mol) and con-
centrated sulfuric acid (5 ml) was refluxed
for 0.5 h. After cooling the water (300 ml)
was added and the mixture was intensively
stirred at room temperature. The precipitated
crude product was filtered off and dried.
N-(2,2,2-Trichloro-1-hydroxyethyl)-2-
furamide 8 was described in [12].
N-(2,2,2-Trichloro-1-hydroxyethyl)
thiophene-2-carboxamide 9. Yield 250 g
(91 %), white solid, mp 170‒172 °C (ben-
zene). IR, υ, cm–1: 3311, 3179, 1632, 1537,
1416, 1103, 834, 719, 662. 1H NMR, δ,
ppm: 5.95–5.98 (1H, m, CH), 7.13–7.18
(1H, m, thienyl), 7.79-7.93 (2H, m, thienyl),
8.09 (1H, s, OH), 9.14 (1H, s, NH).
13C NMR, δ, ppm: 81.8, 102.9, 128.6, 130.4,
132.7, 139.0, 161.7. MS, m/z 272 [M-H]–.
Found, %: C, 30.60; H, 2.19; Cl, 38.87; N,
5.27. C7H6Cl3NO2S. Calculated, %: C,
30.62; H, 2.20; Cl, 38.74; N, 5.10.
N-(2,2,2-Trichloro-1-hydroxyethyl)-
nicotinamide 10 was described in [13].
General procedures of N-(2,2-dichloro-
Synthesis of 4-hetaryl-2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]-triazines
ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5 57
1-cyanovinyl)amides 14 and 15 synthesis.
The mixture of N-(2,2,2-trichloro-1-
hydroxyethyl)amide 8, 9 (0.1 mol) in dry
benzene (100 ml) and thionyl chloride
(0.11 mol) was refluxed for 4 h. After cool-
ing the mixture was evaporated to dryness.
The crude product was washed by dry hex-
ane to obtain the compound 11, 12.
Solution of appropriate N-(1,2,2,2-
tetrachloroethyl)benzamide 11, 12 (0.1 mol)
in dry dioxane (70 ml) was added dropwise
to a stirred solution of KCN (0.2 mol) in wa-
ter (30 ml) at -5–(-10) ºC. The solution was
stirred for 4 h. The precipitated crude prod-
uct was filtered off, washed with cold water,
dried and recrystallized from toluene.
N-(2,2-Dichloro-1-cyanovinyl)-2-
furamide 14. Yield 19 g (82 %), brown solid,
mp 104‒106 °C (benzene). IR, υ, cm–1:
3287, 3138, 2240, 1694, 1593, 1491, 1464,
1305, 1179, 1108, 971, 948, 764, 594.
1H NMR, δ, ppm: 6.67 (1H, s, furyl), 7.35
(1H, s, furyl), 7.94 (1H, s, furyl), 10.55 (1H,
s, NH). 13C NMR, δ, ppm: 110.6, 112.9,
113.2, 117.3, 135.7, 145.8, 147.4, 156.3.
MS, m/z 233 [M+H]+. Found, %: C, 41.57;
H, 1.72; Cl, 30.83; N, 12.23. C8H4Cl2N2O2.
Calculated, %: C, 41.59; H, 1.75; Cl, 30.69;
N, 12.12.
N-(2,2-Dichloro-1-cyanovinyl)thio-
phene-2-carboxamide 15. Yield 20 g (81 %),
white solid, mp 131‒133 °C (benzene). IR,
υ, cm–1: 3217, 2963, 2233, 1639, 1602,
1529, 1488, 1299, 1102, 964, 900, 854, 636.
1H NMR, δ, ppm (J, Hz): 7.24 (1H, t, J =
4.4 Hz, thienyl), 7.96–7.98 (2H, m, thienyl),
10.69 (1H, s, NH). 13C NMR, δ, ppm: 111.1,
113.4, 129.0, 131.6, 134.2, 135.4, 136.8,
160.3. MS, m/z 249 [M+H]+. Found, %: C,
38.87; H, 1.60; Cl, 28.81; N, 11.44; S, 12.88.
C8H4Cl2N2OS. Calculated, %: C, 38.89; H,
1.63; Cl, 28.69; N, 11.34; S, 12.98.
Procedures of N-(2,2-dichloro-1-cyano-
vinyl)nicotinamide 16 synthesis.
The mixture of N-(2,2,2-trichloro-1-
hydroxyethyl)nicotinamide 10 (0.1 mol) in
dry benzene (100 ml) and thionyl chloride
(0.11 mol) was refluxed for 4 h. After cool-
ing the mixture was evaporated to dryness.
The crude product was washed by dry hex-
ane to obtain compound 13.
Solution of N-(1,2,2,2-tetrachloro-
ethyl)nicotinamide 13 (0.1 mol) in dry
dioxane (70 ml) was added dropwise to a
stirred solution of KCN (0.2 mol) in water
(30 ml) at -5– (-10) ºC. The mixture was
stirred for 4 h and evaporated until a precipi-
tate appeared. The precipitated crude prod-
uct was filtered off, washed with cold water,
dried and recrystallized.
N-(2,2-Dichloro-1-cyanovinyl)nicotin-
amide 16. Yield 19 g (78 %), brown solid,
mp 129‒131 °C (benzene). IR, υ, cm–1:
3229, 2963, 2233, 1662, 1593, 1491, 1422,
1302, 1199, 1122, 963, 890, 703, 636.
1H NMR, δ, ppm: 7.54 (1H, s, pyridyl), 8.28
(1H, s, pyridyl), 8.76 (1H, s, pyridyl), 9.06
(1H, s, pyridyl), 11.02 (1H, s, NH).
13C NMR, δ, ppm: 111.1, 113.2, 124.1,
128.0, 135.4, 136.3, 149.4, 153.6, 164.6.
MS, m/z 243 [M+H]+. Found, %: C, 44.64;
H, 2.05; Cl, 29.38; N, 17.45. C9H5Cl2N3O.
Calculated, %: C, 44.66; H, 2.08; Cl, 29.29;
N, 17.36.
General procedures of 2-(dichloro-
methyl)pyrazolo[1,5-a][1,3,5]triazines 18-
20a-d synthesis. To a solution of 2-acyl-
amino-3,3-dichloroacrylonitrile 14-16
(0.01 mol) in 10 ml of THF, 5-amino-
pyrazole 17a-d (0.01 mol) and Et3N
Ye.S. Velihina, M.V.Kachaeva, S.G. Pil'o, V.S.Moskvina, O.V. Shablykina, V.S. Brovarets
58 ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5
(1.39 ml, 0.01 mol) were added. The mixture
was stirred at room temperature for 24 h, and
then heated at 55–60 °С for 2 h. After sol-
vent evaporation the residue was triturated
with water to give a crude product which
was dried and recrystallized to obtain yellow
or brownish crystals.
2-Dichloromethyl-4-(furan-2-yl)-7-
methylpyrazolo[1,5-a][1,3,5]triazine 18a.
Yield 1.86 g (66 %), yellow solid, mp 187–
189 °C (MeCN). IR, υ, cm–1: 3118, 2996,
1606, 1577, 1502, 1459, 1361, 1262, 1143,
1031, 785, 712, 661, 533. 1H NMR, δ, ppm
(J, Hz): 2.55 (3H, s, CH3), 6.79 (1H, s,
CHCl2 or C-H pyrazole), 6.98–6.99 (1H, m,
furan), 7.38 (1H, s, CHCl2 or C-H pyrazole),
8.33 (1H, s, C-H furan), 8.44 (1H, d, J = 2.9
Hz, C-H furan). 13C NMR, δ, ppm: 15.2,
71.5, 98.1, 114.4, 125.9, 142.9, 144.8, 149.7,
150.4, 157.9, 159.2. MS, m/z 285 [M+H]+.
Found, %: C, 46.65; H, 2.82; Cl, 25.12; N,
19.70. C11H8Cl2N4O. Calculated (%): C,
46.67; H, 2.85; Cl, 25.04; N, 19.79.
2-Dichloromethyl-4-(furan-2-yl)-7-
phenylpyrazolo[1,5-a][1,3,5]triazine 18b.
Yield 2.58 g (75 %), brown solid, mp 203–
205 °C (MeCN : DMF, 4 : 1). IR, υ, cm–1:
3117, 3009, 2924, 1605, 1568, 1494, 1461,
1360, 1265, 1024, 766, 689, 654, 556. 1H
NMR, δ, ppm (J, Hz): 7.03 (1H, m, CHCl2
or C-H pyrazole), 7.41 (1H, d, J = 1.5 Hz, C-
H furan), 7.50–7.57 (4H, m, CHCl2 or C-H
pyrazole, H-3,4,5 Ph), 8.20 (2H, d, J =
7.8 Hz, H-2,6 Ph), 8.36 (1H, s, C-H furan),
8.63 (1H, d, J = 3.9 Hz, C-H furan).
13C NMR, δ, ppm: 71.5, 95.3, 114.6, 126.4,
127.4, 129.5, 130.7, 131.7, 142.9, 145.2,
150.5, 150.6, 158.1, 159.0. MS, m/z 345
[M+H]+. Found, %: C, 55.65; H, 2.88; Cl,
20.60; N, 16.30. C16H10Cl2N4O. Calculated
(%): C, 55.67; H, 2.92; Cl, 20.54; N, 16.23.
2-Dichloromethyl-4-(furan-2-yl)-7-p-
tolyl-pyrazolo[1,5-a][1,3,5]triazine 18c.
Yield 2.61 g (73 %), brown solid, mp 209–
211 °C (MeCN : DMF, 4 : 1). IR, υ, cm–1:
3129, 2923, 1605, 1564, 1496, 1448, 1358,
1261, 1228, 1150, 1024, 790, 773, 741, 659.
1H NMR, δ, ppm (J, Hz): 2.39 (3H, s, CH3,
Ar), 7.02–7.04 (1H, m, C-H furan), 7.35
(2H, d, J = 8.3 Hz, H-3,5 Ar), 7.41 (1H, s,
CHCl2 or C-H, pyrazole), 7.45 (1H, s,
CHCl2 or C-H pyrazole), 8.09 (2H, d, J =
8.3 Hz, H-2,6 Ar), 8.36 (1H, s, C-H furan),
8.63 (1H, d, J = 3.4 Hz, C-H furan).
13C NMR, δ, ppm: 21.5, 71.5, 95.0, 114.6,
126.3, 127.3, 128.9, 130.1, 140.5, 142.9,
145.1, 150.5, 150.5, 158.1, 159.1. MS, m/z
359 [M+H]+. Found, %: C, 56.80; H, 3.35;
Cl, 19.80; N, 15.55. C17H12Cl2N4O. Calcu-
lated (%): C, 56.84; H, 3.37; Cl, 19.74; N,
15.60.
2-Dichloromethyl-7-(4-fluorophenyl)-
4-(furan-2-yl)pyrazolo[1,5-a][1,3,5]tri-
azine 18d. Yield 2.40 g (66 %), brown solid,
mp 191–193 °C (MeCN : DMF, 4 : 1). IR, υ,
cm–1: 3121, 3000, 1609, 1570, 1494, 1449,
1358, 1267, 1234, 1155, 1026, 844, 783,
657, 523. 1H NMR, δ, ppm (J, Hz): 7.02–
7.03 (1H, m, furan), 7.36–7.42 (3H, m,
CHCl2 or C-H pyrazole, H-3,5 Ar), 7.50
(1H, s, CHCl2 or C-H pyrazole), 8.24–8.28
(2H, m, H-2,6 Ar), 8.36 (1H, s, C-H, furan),
8.62 (1H, d, J = 3.4 Hz, furan). 13C NMR, δ,
ppm (J, Hz): 71.5, 95.3, 114.6, 116.6 (d, J =
21.4 Hz), 126.5, 128.3 (d, J = 3.0 Hz) 129.7
(J = 8.5 Hz), 142.8, 145.2, 150.5, 150.6,
158.0, 158.2, 163.8 (d, J = 247.3 Hz). MS,
m/z 363 [M+H]+. Found, %: C, 52.96; H,
2.53; Cl, 19.58; N, 15.50. C16H9Cl2FN4O.
Calculated (%): C, 52.92; H, 2.50; Cl, 19.52;
Synthesis of 4-hetaryl-2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]-triazines
ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5 59
N, 15.43.
2-Dichloromethyl-7-methyl-4-(thien-2-
yl)pyrazolo[1,5-a][1,3,5]triazine 19a. Yield
2.03 g (68 %), light yellow solid, mp 168–
170 °C (EtOH : MeCN, 4 : 1). IR, υ, cm–1:
3107, 3029, 3107, 1595, 1527, 1475, 1247,
851, 771, 716, 652, 521. 1H NMR, δ, ppm:
2.57 (3H, s, CH3), 6.80 (1H, s, CHCl2 or C-
H pyrazole), 7.38 (1H, s, CHCl2 or C-H py-
razole), 7.45–7.47 (1H, m, C-H thiophen),
8.28–8.30 (1H, m, C-H, thiophen), 8.92–
8.93 (1H, m, C-H thiophen). 13C NMR, δ,
ppm: 15.2, 71.4, 97.9, 129.6, 131.9, 138.0,
138.5, 149.0, 150.0, 157.8, 159.3. MS, m/z
299 [M+H]+. Found, %: C, 44.20; H, 2.68;
Cl, 23.80; N, 18.77; S, 10.68. C11H8Cl2N4S.
Calculated (%): C, 44.16; H, 2.70; Cl, 23.70;
N, 18.73; S, 10.72.
2-Dichloromethyl-7-phenyl-4-(thien-2-
yl)pyrazolo[1,5-a][1,3,5]triazine 19b. Yield
2.53 g (70 %), yellow solid, mp 189–191 °C
(MeCN). IR, υ, cm–1: 3102, 2924, 1598,
1524, 1463, 1253, 853, 766, 650, 554. 1H
NMR, δ, ppm (J, Hz): 7.40 (1H, s, CHCl2 or
C-H pyrazole), 7.49–7.59 (5H, m, CHCl2 or
C-H pyrazole, C-H thiophen, H-3,4,5 Ph),
8.21 (2H, d, J = 6.8 Hz, H-2,6 Ph), 8.34 (1H,
d, J = 1.6 Hz, C-H thiophen), 8.99–9.00 (1H,
m, C-H, thiophen). 13C NMR, δ, ppm: 71.4,
95.2, 127.4, 129.6, 129.7, 130.8, 131.7,
131.8, 138.1, 139.0, 149.6, 150.8, 158.2,
159.0. MS, m/z 363 [M+H]+. Found, %: C,
53.17; H, 2.80; Cl, 19.70; N, 15.56; S, 8.82.
C16H10Cl2N4S. Calculated (%): C, 53.20; H,
2.79; Cl, 19.63; N, 15.51; S, 8.88.
2-Dichloromethyl-4-(thien-2-yl)-7-p-
tolylpyrazolo[1,5-a][1,3,5]triazine 19c. Yield
2.81 g (75 %), yellow solid, mp 195–197 °C
(MeCN). IR, υ, cm–1: 3100, 2917, 1596,
1524, 1448, 1221, 854, 794, 726, 654. 1H
NMR, δ, ppm (J, Hz): 2.39 (3H, s, CH3, Ar),
7.35–7.49 (5H, m, CHCl2, C-H pyrazole, C-
H thiophen, H-3,5 Ar), 8.08 (2H, d, J =
7.2 Hz, H-2,6 Ar), 8.32–8.33 (1H, m, C-H
thiophen), 8.97 (1H, s, C-H thiophen).
13C NMR, δ, ppm (J, Hz): 21.6, 71.5, 94.9,
127.3, 128.9, 129.7, 130.2, 131.8, 138.1,
138.9, 140.6, 149.5, 150.8, 158.2, 159.1.
MS, m/z 377 [M+H]+. Found, %: C, 54.40;
H, 3.24; Cl, 18.95; N, 15.00; S, 8.50.
C17H12Cl2N4S. Calculated (%): C, 54.41; H,
3.22; Cl, 18.89; N, 14.93; S, 8.54.
2-Dichloromethyl-7-(4-fluorophenyl)-
4-(thien-2-yl)pyrazolo[1,5-a][1,3,5]triazine
19d. Yield 2.65 g (70 %), yellow solid, mp
210–212 °C (MeCN : DMF, 3 : 1). IR, υ,
cm–1: 3100, 2924, 1606, 1584, 1525, 1478,
1451, 1228, 839, 793, 736, 667, 521.
1H NMR, δ, ppm: 7.41–7.52 (5H, m, CHCl2,
C-H pyrazole, H thiophen, H-3,5 Ar), 8.26–
8.35 (3H, m, H-2,6 Ar, C-H thiophen), 8.99–
9.00 (1H, m, C-H, thiophen). 13C NMR, δ,
ppm (J, Hz): 70.4, 94.4, 116.1, 127.8, 128.6,
129.0, 131.6, 137.3, 137.7, 150.7, 158.3,
158.6, 162.1, 164.0. MS, m/z 379 [M+H]+.
Found, %: C, 50.70; H, 2.40; Cl, 18.75; N,
14.82; S, 8.50. C16H9Cl2FN4S. Calculated
(%): C, 50.67; H, 2.39; Cl, 18.70; N, 14.77;
S, 8.45.
2-(Dichloromethyl)-7-methyl-4-(pyri-
din-3-yl)pyrazolo[1,5-a][1,3,5]triazine 20a.
Yield 2.3 g (78 %), brown solid, mp
119‒121 °C (EtOH). IR, υ, cm–1: 3085,
2995, 1600, 1505, 1469, 1371, 1219, 1126,
1018, 836, 777, 700, 530. 1H NMR, δ, ppm:
2.53 (3H, s, CH3), 6.85 (1H, s, CHCl2 or C-
H pyrazolyl), 7.43 (1H, s, CHCl2 or C-H
pyrazolyl), 7.69–7.75 (1H, m, pyridyl),
8.86–8.90 (1H, m, pyridyl), 8.95–9.00 (1H,
m, pyridyl), 9.75 (1H, s, pyridyl). 13C NMR,
Ye.S. Velihina, M.V.Kachaeva, S.G. Pil'o, V.S.Moskvina, O.V. Shablykina, V.S. Brovarets
60 ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5
δ, ppm: 71.3, 95.5, 124.0, 126.4, 127.2,
129.5, 130.7, 131.5, 139.0, 150.9, 151.8,
153.4, 153.9, 158.0, 159.0. MS, m/z 296
[M+H]+. Found, %: C, 49.02; H, 3.05; Cl,
24.21; N, 23.91. C12H9Cl2N5. Calculated, %:
C, 49.00; H, 3.08; Cl, 24.11; N, 23.81.
2-(Dichloromethyl)-7-phenyl-4-(pyri-
din-3-yl)pyrazolo[1,5-a][1,3,5]triazine 20b.
Yield 2.6 g (73 %), brown solid, mp
165‒167 °C (MeCN). IR, υ, cm–1: 3087,
3003, 1604, 1581, 1517, 1460, 1389, 1228,
1192, 1023, 796, 767, 691, 557. 1H NMR, δ,
ppm (J, Hz): 7.41 (1H, s, Ph), 7.50–7.54
(4H, m, Ph), 7.76 (1H, t, J = 8.0 Hz,
pyridyl), 8.12 (1H, s, CHCl2 or C-H
pyrazolyl), 8.13 (1H, s, CHCl2 or C-H
pyrazolyl), 8.91–8.92 (1H, m, pyridyl), 9.13
(1H, d, J = 7.2 Hz, pyridyl), 9.89 (1H, m,
pyridyl). 13C NMR, δ, ppm: 71.3, 95.5,
124.0, 126.4, 127.2, 129.5, 130.7, 131.5,
139.0, 150.9, 151.8, 153.4, 153.9, 158.0,
159.0. MS, m/z 358 [M+H]+. Found, %: C,
57.29; H, 3.10; Cl, 19.99; N, 19.78.
C17H11Cl2N5. Calculated, %: C, 57.32; H,
3.11; Cl, 19.91; N, 19.66.
2-(Dichloromethyl)-7-(4-methylphe-
nyl)-4-(pyridin-3-yl)pyrazolo[1,5-a][1,3,5]-
triazine 20c. Yield 2.9 g (78 %), brown
solid, mp 184‒186 °C (MeCN). IR, υ, cm–1:
3009, 2957, 1598, 1583, 1521, 1477, 1386,
1227, 1185, 1023, 838, 787, 692, 555.
1H NMR, δ, ppm (J, Hz): 2.39 (3H, s, CH3),
7.39–7.46 (4H, m, Ph), 7.76 (1H, t, J =
5.4 Hz, pyridyl), 8.01 (1H, s, CHCl2 or C-H
pyrazolyl), 8.02 (1H, s, CHCl2 or C-H
pyrazolyl), 8.91–8.92 (1H, m, pyridyl), 9.11-
9.13 (1H, m, pyridyl), 9.88 (1H, s, pyridyl).
13C NMR, δ, ppm: 21.5, 71.3, 95.2, 124.1,
124.3, 127.2, 129.8, 130.1, 130.7, 139.1,
150.9, 151.8, 153.3, 153.9, 159.2, 159.3.
MS, m/z 372 [M+H]+. Found, %: C, 58.35;
H, 3.55; Cl, 19.36; N, 18.99. C18H13Cl2N5.
Calculated, %: C, 58.39; H, 3.54; Cl, 19.15;
N, 18.92.
2-(Dichloromethyl)-7-(4-fluorophenyl)-
4-(pyridin-3-yl)pyrazolo[1,5-a][1,3,5]-
triazine 20d. Yield 2.9 g (78 %), brown
solid, mp 185‒187 °C (MeCN). IR, υ, cm–1:
3079, 3016, 1609, 1589, 1503, 1471, 1369,
1230, 1197, 1027, 841, 746, 562. 1H NMR,
δ, ppm (J, Hz): 2.39 (3H, s, CH3), 7.32–7.40
(3H, m, Ph), 7.47–7.48 (1H, m, Ph), 7.74
(1H, t, J = 5.6 Hz, pyridyl), 8.16 (1H, s,
CHCl2 or C-H pyrazolyl), 8.18 (1H, s,
CHCl2 or C-H pyrazolyl), 8.90–8.91 (1H, m,
pyridyl), 9.10–9.12 (1H, m, pyridyl), 9.87
(1H, s, pyridyl). 13C NMR, δ, ppm: 71.3,
95.4, 116.4, 116.6, 124.0, 126.3, 128.0,
129.5, 129.6, 139.0, 150.9, 151.8, 153.4,
153.9, 158.0. MS, m/z 374 [M+H]+. Found,
%: C, 54.59; H, 2.66, Cl, 18.88; N, 18.79.
C17H10Cl2FN5. Calculated, %: C, 54.57; H,
2.69, Cl, 18.95; N, 18.72.
CONCLUSIONS. A series of new
pyrazolo[1,5-a][1,3,5]triazines with a hetero-
aromatic substituent in position 4 and
dichloromethyl moiety in position 2 was ob-
tained via a heterocyclization accompanied
by hydrogen cyanide elimination. The reac-
tion involved readily available reagents – N-
(2,2-dichloro-1-cyanoethenyl)carboxamides
and 3(5)-aminopyrazoles. The heterocyclic
moiety has little effect on the efficiency
of the method and the yields of 2-
(dichloromethyl)pyrazolo[1,5-a][1,3,5]tri-
azines with furan-2-yl, thien-2-yl, and pyri-
dine-3-yl moieties, which makes the method
suitable for the synthesis of other 4-hetaryl-
2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]-
triazines.
Synthesis of 4-hetaryl-2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]-triazines
ISSN 2708-129X. УКР . ХІМ . ЖУРН ., 2020, т . 86, No 5 61
СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-
ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ
Є.С. Велігіна1, М.В. Качаєва1, С.Г. Пільо1,
В.С. Москвіна1,2*, O.В. Шабликіна1,2,
В.С.Броварець1
1 Інститут біоорганічної хімії та нафтохімії
ім. В.П. Кухаря НАН України, вул. Мурман-
ска, 1, Київ 02094, Україна
2 Київський національний університет імені
Тараса Шевченка, вул. Володимирська, 64/13,
Київ 01601, Україна
*е-mail: v.moskvina@gmail.com
Шляхом гетероциклізації легко-
доступних реагентів – N-(2,2-дихлор-1-ціано-
етеніл)карбоксамідів та 3(5)-амінопіразолів –
синтезовано нові піразоло[1,5-a][1,3,5]-
триазини з гетероароматичним замісником в
положенні 4 та дихлорoметильним фраг-
ментом в положенні 2. Продемонстровано
високу ефективність запропонованого спосо-
бу синтезу 2-(дихлорометил)-піразоло[1,5-а]-
[1,3,5]триазинів з фуран-2-ільним, тієн-2-
ільним і піридин-3-ільним замісниками.
К л ю ч о в і с л о в а: N-(2,2-Дихлоро-1-
ціаноетеніл)карбоксамід, 1H-піразол-5-амін,
піразоло[1,5-a][1,3,5]триазин.
СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРМЕТИЛ)-
ПИРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНОВ
Е.С. Велигина1, М.В. Качаева1, С.Г. Пильо1,
В.С. Москвина1,2*, O.В. Шаблыкина1,2,
В.С. Броварец1
1 Институт биоорганической химии и неф-
техимии им. В.П. Кухаря НАН Украины, ул.
Мурманская, 1, Киев 02094, Украина
2 Киевский национальный университет имени
Тараса Шевченко, ул. Владимирская, 64/13,
Киев 01601, Украина
*е-mail: v.moskvina@gmail.com
Путем гетероциклизации легко-
доступных реагентов – N-(2,2-дихлор-1-
цианоэтенил)карбоксамидов и 3(5)-амино-
пиразолов – получены новые пиразоло-
[1,5-a][1,3,5]триазины с гетероароматиче-
ским заместителем в положении 4 и дихлорo-
метильной группой в положении 2. Проде-
монстрирована высокая эффективность
предлагаемого способа синтеза 2-(дихлор-
метил)пиразоло[1,5-а][1,3,5]триазинов с фу-
ран-2-ильным, тиен-2-ильным и пиридин-3-
ильным заместителями.
К л ю ч е в ы е с л о в а: N-(2,2-Дихлор-1-
цианоэтенил)карбоксамид, 1H-пиразол-5-
амин, пиразоло-[1,5-a][1,3,5]триазин.
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Надійшла 08.12.2019
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| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-171 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:02:24Z |
| publishDate | 2020 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/3a/96f0cc16c58178758c753e538b49833a.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-1712026-07-22T08:23:43Z SYNTHESIS OF 4-HETARYL-2-(DICHLOROMETHYL)PYRAZOLO[1,5-a][1,3,5]-TRIAZINES СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРМЕТИЛ)-ПИРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНОВ СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ Velihina, Yevgeniia Kachaeva, Maryna Pil'o, Stepan Moskvina, Viktoriia Shablykina, Olga Brovarets, Volodymyr N-(2,2-Dichloro-1-cyanoethenyl)carboxamide, 1H-pyrazol-5-amine, pyrazolo-[1,5-a][1,3,5]triazine. New pyrazolo[1,5-a][1,3,5]triazines with a heteroaromatic substituent in position 4 and dichloromethyl moiety in position 2 were obtained via a heterocyclization reaction of readily available reagents - N-(2,2-dichloro-1-cyanoethenyl)carboxamides and 3(5)-aminopyrazoles. The high efficiency of the proposed method for the synthesis of 2-(dichloromethyl)-pyrazolo[1,5-a][1,3,5]triazines with furan-2-yl, thien-2-yl, and pyridine-3-yl substituents was demonstrated. V.I.Vernadsky Institute of General and Inorganic Chemistry 2020-07-15 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/171 10.33609/2708-129X.86.5.2020.53-62 Ukrainian Chemistry Journal; Vol. 86 No. 5 (2020): Ukrainian Chemistry Journal; 53-62 Украинский химический журнал; ##issue.vol## 86 ##issue.no## 5 (2020): Украинский химический журнал; 53-62 Український хімічний журнал; Том 86 № 5 (2020): Український хімічний журнал; 53-62 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/171/100 Copyright (c) 2020 Yevgeniia Velihina, Maryna Kachaeva, Stepan Pil'o, Viktoriia Moskvina, Olga Shablykina, Volodymyr Brovarets https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Velihina, Yevgeniia Kachaeva, Maryna Pil'o, Stepan Moskvina, Viktoriia Shablykina, Olga Brovarets, Volodymyr СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ |
| title | СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ |
| title_alt | SYNTHESIS OF 4-HETARYL-2-(DICHLOROMETHYL)PYRAZOLO[1,5-a][1,3,5]-TRIAZINES СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРМЕТИЛ)-ПИРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНОВ |
| title_full | СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ |
| title_fullStr | СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ |
| title_full_unstemmed | СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ |
| title_short | СИНТЕЗ 4-ГЕТАРИЛ-2-(ДИХЛОРОМЕТИЛ)-ПІРАЗОЛО[1,5-а][1,3,5]ТРИАЗИНІВ |
| title_sort | синтез 4-гетарил-2-(дихлорометил)-піразоло[1,5-а][1,3,5]триазинів |
| topic_facet | N-(2,2-Dichloro-1-cyanoethenyl)carboxamide 1H-pyrazol-5-amine pyrazolo-[1,5-a][1,3,5]triazine. |
| url | https://ucj.org.ua/index.php/journal/article/view/171 |
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