Solvent-free microwave-assisted synthesis of novel 4-hetarylpyrazolo[1,5-a] [1,3,5]triazines

Article abstract of DOI:10.1002/jhet.974

A series of novel 4-hetaryl substituted pyrazolo[1,5-a][1,3,5]triazines were synthesized by microwave assisted reaction between O,S-diethyl hetaroylimidothiocarbonates and 5-amino-3-aryl-1H-pyrazoles under solvent-free conditions. This procedure led to the formation of mixtures of two new pyrazolotriazine derivatives in a 1:4 ratio, which were separated by column chromatography being their corresponding structures unambiguously established by spectroscopic and analytical techniques. Comparison of the reactions mediated by microwave irradiation and by conventional heating in solution of DMF showed that both procedures afforded the same mixtures of products, but the first approach required shorter reaction times and gave higher yields than the second one.

Full text of DOI:10.1002/jhet.974

November 2012
Solvent-Free Microwave-Assisted Synthesis of Novel
1339
4-Hetarylpyrazolo[1,5-a][1,3,5]triazines
a
a
b
b
b
*
Henry Insuasty, Sandra Estrada, Jairo Quiroga, Braulio Insuasty, Rodrigo Abonia,
c
c
*
Manuel Nogueras, and Justo Cobo
aHeterocyclic Compounds Research Group, Department of Chemistry, Universidad de Nariño, A.A. 1175,
Pasto, Colombia
bHeterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360,
Cali, Colombia
cDepartment of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
*
E-mail: hein@udenar.edu.co or mmontiel@ujaen.es
Received December 3, 2010
DOI 10.1002/jhet.974
View this article online at wileyonlinelibrary.com.
A series of novel 4-hetaryl substituted pyrazolo[1,5-a][1,3,5]triazines were synthesized by microwave
assisted reaction between O,S-diethyl hetaroylimidothiocarbonates and 5-amino-3-aryl-1H-pyrazoles under
solvent-free conditions. This procedure led to the formation of mixtures of two new pyrazolotriazine
derivatives in a 1:4 ratio, which were separated by column chromatography being their corresponding
structures unambiguously established by spectroscopic and analytical techniques. Comparison of the
reactions mediated by microwave irradiation and by conventional heating in solution of DMF showed that
both procedures afforded the same mixtures of products, but the first approach required shorter reaction times
and gave higher yields than the second one.
J. Heterocyclic Chem., 49, 1339 (2012).
INTRODUCTION
pyrazolo[1,5-a] [1,3,5]triazine derivatives are currently avail-
able. The more efficient and commonly used involves the
reaction between 5-amino-1H-pyrazoles and 1,3-bis-electro-
philic compounds under conventional heating [3],[4],[7],[9],
[10]. Continuing with our current studies on the synthesis of
fused heterocycles containing the pyrazole moiety [10],[11],
we are describing here the synthesis of novel 4-hetaryl substi-
tuted pyrazolo[1,5-a][1,3,5]triazine derivatives 7-10 from the
reaction of the O,S-diethyl hetaroylimidothiocarbonates 4 and
5 with 5-amino-3-aryl-1H-pyrazoles 6 by microwave irradia-
tion under solvent-free reaction conditions.
Pyrazolo[1,5-a][1,3,5]triazine derivatives have received
considerable attention because of their pharmacological prop-
erties, and especially, by their applicability in the treatment of
various diseases. Some of them have been evaluated as corti-
cotrophin releasing factor (CRF) antagonists (compound 1,
Fig. 1) [1], for the treatment and prevention of central nervous
system disorders [2],[3], and for the treatment of eating disor-
ders, particularly bulimia and obesity associated with excess
of the neuropeptide Y (NPY) [2]. Other derivatives have been
tested as inhibitors for protein kinase CK2 [4] and cyclic-
dependent kinases (CDKs) exhibiting high antiproliferative
activity in tumor cell lines [5] and high potential for cancer
therapy (compound 2, Fig. 1) [4],[5]. Some of them were
inhibitors of phosphodiesterase type 4 (PDE4) [6], potential
therapeutic agents for the control of autoimmune and inflam-
matory diseases and more recently, the pyrazolo[1,5-a][1,3,5]
triazine 3 (Fig. 1), was reported as active against the herpes
simplex viruses HSV-1 and HSV-2 [7].
RESULTS AND DISCUSSION
In a first entry, a mixture of equimolar amounts of the O,
S-diethyl furoylimidothiocarbonate 4 and the 5-amino-3-
(4-chlorophenyl)pyrazole 6a was irradiated for 15 min. at
100ꢀC without using solvent. After reaction finished
(TLC control), the plate indicated the formation of two
new products, which were separated by column chroma-
tography on silica gel. The new products corresponded to
7-(4-chlorophenyl)-4-(2’-furyl)pyrazolo[1,5-a][1,3,5]
triazines 7a and 8a in ∼1:4 ratio, but not to their also
possible 11a and 12a isomers (Scheme 1). To evaluate
the generality of this procedure the O,S-diethyl heta-
roylimidothiocarbonates 4 and 5 were reacted with the
In the last years, solvent-free reaction conditions employ-
ing the microwave irradiation (MW) as energy source have
widely been used for the synthesis of many and diverse
organic compounds, mainly because such reactions proceed
much faster, with higher yields and sometimes more regiose-
lective than those reactions when conventional heating has
been employed [8]. Numerous methods for the synthesis of
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Vol 49
respectively. In Figure 2 it is showed the 13C NMR spectra
for the representative compounds 7a and 8a confirming the
marked differences in chemical shifts between methylenes
of the CH3CH2S- and CH3CH2O- fragments at the high-
field region.
The whole carbon atoms of the skeleton of compounds
7-10 were assigned from their 13C NMR spectra combined
with the DEPT and H, 13C shift correlation HSQC and
1
Figure 1. Some pyrazolo[1,5‐a][1,3,5]triazines of biological interest.
HMBC experiments. The 2D-NOESY experiment was
used to establish the right places of substituents at the tri-
azine ring. Thus, crossed-peaks between the methylene
protons of the ethylthio (or ethoxy) substituents and the
8-H protons of the pyrazole moiety, helped us to determine
that the ethylthio (or the ethoxy) substituents are located on
C-2 and consequently the hetaryl groups are located on C-4
of compounds 7-10 as shown in Figure 3, for the represen-
tative compound 7a, ruling out the formation of its isomer
7a0.
We consider that the formation of compounds 7-10
resulted from an addition-elimination process. First, the
C═N double bond of the starting compounds 4,5 suffered
a nucleophilic attack from the 5-NH2 of the pyrazole 6 with
subsequent elimination of a molecule of ethanol (or etha-
nethiol) affording the adducts 13/15 or 14/16, respectively
(Scheme 2). Adduct 14/16 should be the main intermediate
because the ethanethiol (pKa = 10.6) is a better leaving
group than the ethanol (pKa = 15.9). Finally, adducts
13-16 were intramolecularly cyclized after attack of the
1-NH of the pyrazole moiety over the C═O functionality
with elimination of a molecule of water affording the
isolated pyrazolotriazines 7-10. Previous reports showing
the higher electrophilicity of the C═N double bond than
the carbonyl group in compounds type 4,5 [12] support
the postulated sequence of steps depicted in Scheme 2.
5-aminopyrazoles 6a-c under similar reaction conditions
leading to the formation of their corresponding analogs (7/8)
a-c and (9/10)a-c, respectively, as shown in Scheme 1.
The structures of the obtained compounds 7, 8, 9, and 10
were unambiguously established by spectroscopic and ana-
lytical methods. The IR data are consistent with the pro-
posed structures 7-10, and the possible formation of
pyrazolo[3,4-d]pyrimidines 11 and 12 (Scheme 1), was
discarded because the expected absorption band assignable
to the N—H stretching was not present in any IR spectra.
This finding is also in agreement with the 1H NMR spectra
where the more representative signal corresponded to a sin-
glet between 6.60–6.74 ppm assigned to the 8-H protons of
the pyrazole ring, confirming that the structures assigned
for compounds 7-10 are correct.
The 1H and 13C NMR spectra for each pair of pyrazolo-
triazines 7,8 and 9,10 are too similar between them, except
for the signal of methylene groups, which, appears around
1
3.25 ppm and 25.6 ppm (for H- and 13C-NMR, respec-
tively) in compounds 7,9 and around 4.52 ppm and 64.1
1
ppm (for H- and 13C-NMR, respectively) in compounds
8,10 due to the higher electronegativity of the O atom than
the S atom, present in the ethoxy and ethylthio fragments,
Scheme 1
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Novel 4-Hetarylpyrazolo[1,5-a][1,3,5]triazines
Figure 2. 13C NMR spectra for the new pyrazolotriazines 7a (a) and 8a (b).
Figure 3. Possible isomeric structures for the pyrazolo[1,5-a][1,3,5]triazine systems 7-10.
Scheme 2
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H. Insuasty, S. Estrada, J. Quiroga, B. Insuasty, R. Abonia, M. Nogueras, and J. Cobo
Vol 49
Table 1
Analytical data for the obtained pyrazolo[1,5‐a][1,3,5]triazines 7–10.a,b
Products
Het
Ar
X
mp (°C)
Yield %b
Time (min)
7a
8a
7b
8b
7c
8c
9a
10a
9b
10b
9c
2‐furyl
4‐ClC6H4
4‐CH3C6H4
C6H5
S
O
S
O
S
O
S
O
S
212
204
158
148
144
140
146
190
110
139
112
108
12(9)
15(90)
52(41)
15(10)
63(50)
14(11)
60(53)
13(9)
54(42)
16(12)
64(55)
15(11)
62(51)
2‐furyl
16(100)
15(95)
2‐furyl
2‐thienyl
2‐thienyl
2‐thienyl
4‐ClC6H4
4‐CH3C6H4
C6H5
18(105)
20(120)
19(110)
O
S
O
10c
aValues in parenthesis are referred to reactions carried out under conventional heating using DMF as solvent.
bIsolated yields after column chromatography.
To evaluate the efficacy of the reaction mediated by
microwave irradiation, all reactions were repeated under
conventional heating using DMF as solvent (see experi-
mental). Table 1 summarizes the comparative results and
the evident improved yields and shorter reaction times
when reactions were carried out by microwave irradiation
than conventional heating.
It is worth mentioning that recently there has been
reported the synthesis of the star-shaped triazine derivative
18 of materials science interest [13], the Micobacterium
tuberculosis inhibitors purine derivatives 21 [14] and the
antagonist of the human adenosine receptors A2A pyrazolo-
pyrimidines 22 [15]. All three authors agree that the
presence of the thienyl and furyl moieties in structures
18, 21, and 22 is determinant for their physical and biolog-
ical properties displayed. In all cases, the insertion of the
2-thienyl and 2-furyl units into such interesting compounds
was mediated by a common C—C coupling process based
on the Stille reaction of the corresponding hetarylstannic
derivatives and the appropriate starting chloro-compounds
17, 19, and 20, respectively (Scheme 3). In this sense,
our protocol described here becomes an alternative proce-
dure to construct fused heterocyclic compounds bearing
the important 2-thienyl and 2-furyl units in their structures
based on an environmentally friendlier and tin-free
methodology.
In summary, we have implemented a simple, tin-free,
and practical method for the synthesis of novel 4-hetaryl
substituted pyrazolo[1,5-a][1,3,5]triazines 7-10 under sol-
vent-free conditions employing microwave irradiation as
the source of heating. Products were obtained in better
yields and in shorter times (15–20 min) than when reac-
tions were carried out in solution by conventional heating
(90–120 min). In both reaction conditions the new pyra-
zolotriazines were obtained as separable mixtures of
2-ethylthio- and 2-ethoxy-derivatives (7/9)a-c and (8/10)
a-c, respectively, depending if an ethanol or an ethanethiol
molecule being lost in the first step of the sequence of
reaction. Nevertheless structures 9 and 10 were formed as
the main components from both reaction conditions.
Scheme 3
EXPERIMENTAL
Melting points were determined on an Electrothermal melting
point apparatus and are uncorrected. The IR spectra were
recorded on a Shimadzu FTIR 8400 instrument using KBr discs.
1H and 13C NMR spectra were recorded on a Bruker Avance 400
spectrometer operating at 400 MHz and 100 MHz, respectively,
using CDCl3 as solvent and tetramethylsilane as internal standard.
Mass spectra were run on a Hewlett Packard HP Engine-5989
spectrometer (equipped with a direct inlet probe) operating at 70
eV. Microanalyses were performed on a LECO CHNS-900
elemental analyzer and the values are within ꢁ 0.4% of the theo-
retical values. Silica gel aluminum plates 60-F254 (Merck) were
used for analytical TLC. O,S-diethyl hetaroylimidothiocarbonates
4 and 5 were obtained according to a procedure previously
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Novel 4-Hetarylpyrazolo[1,5-a][1,3,5]triazines
described [16]. The starting aminopyrazoles 6 were synthesized
following a literature procedure [17]. Reactions under microwave
irradiation were performed using a CEM Discover oven, in open
glass vessels.
125.0 (C-30), 126.9 (Co), 128.8 (Cm), 129.7 (Cp), 132.2 (Ci),
143.1 (C-20), 143.3 (C-4), 148.1 (C-50), 151.2 (C-8a), 158.3 (C-7),
166.4 (C-2). MS (70 eV) m/z (%): 322 (100, M+), 307 (23), 289
(50), 201 (15), 169 (15), 143 (18), 94 (15), 77 (30), 70 (20), 69
(10), 29 (10). Anal. Calcd. for C17H14N4OS: C, 63.34; H, 4.38; N,
17.39. Found: C, 63.01; H, 4.06; N, 17.15.
General procedure for the synthesis of pyrazolo[1,5-a]
[1,3,5]triazines 7-10. Method A. A mixture of the appropriate
O,S-diethyl hetaroylimidothiocarbonate 4,5 (2.0 mmol) and the
corresponding 5-amino-3-aryl-1H-pyrazole 6a-c (2.0 mmol)
was subjected to microwave irradiation in absence of solvent
(maximum power 300W during 15–20 min. at controlled
temperature of 100ꢀC), using a focused microwave reactor (CEM
discover). After finished (TLC control), the crude product was
dissolved in THF (2.0 mL), and purified by column chromatography
on silica gel, using a mixture of hexanes/ethyl acetate (4:1) as eluent.
The first chromatographic fraction corresponded to compounds 7/9
and the second one to compounds 8/10.
7-(4-Chlorophenyl)-2-ethoxy-4-(20-furyl)pyrazolo[1,5-a]
[1,3,5] triazine (8a). From 5-amino-3-(4-chlorophenyl)-1H-
pyrazole 6a (0.387 g, 2.0 mmol), yellow solid. IR (KBr):
ν 2982, 2926, 2864 (CH3, CH2), 1624, 1574, 1534, 1501
(C═C, C═N), 1260, 1021 (C—O—C) cm-1. 1H NMR (400 MHz,
CDCl3): d 1.49 (t, 3H, CH3), 4.51 (c, 2H, CH2), 6.60 (s, 1H,
H-8), 6.76 (dd, 1H, H-40), 7.46 (d, 2H, Hm), 7.84 (d, 1H, H-50),
7.94 (d, 2H, Ho), 8.52 (d, 1H, H-30). 13C NMR (100 MHz,
CDCl3): d 14.2 (CH3), 64.1 (CH2), 91.0 (C-8), 113.1 (C-40),
124.8 (C-30), 128.0 (Co), 129.0 (Cm), 130.8 (Ci), 135.6 (Cp),
143.1 (C-20), 146.2 (C-4), 148.1 (C-50), 152.5 (C-8a), 157.7 (C-7),
160.0 (C-2). MS (70 eV) m/z (%): 342/340 (26/73, M+), 325 (22),
296 (23), 221 (15), 219 (42), 111 (20), 97 (27), 94 (57), 83 (35),
81 (46), 73 (47), 71 (44), 69 (100), 57 (61), 55 (58), 43 (74),
41 (60), 29 (27). Anal. Calcd. for C17H13ClN4O2: C, 59.90; H,
3.85; N, 16.45. Found: C, 59.67; H, 3.94; N, 16.17.
Method B. A mixture of the appropriate thiocarbonate 4,5
(2.0 mmol), the corresponding aminopyrazole 6a-c (2.0 mmol)
and DMF (3 mL) was refluxed for 1.5–2.0 h. The solid products
were precipitated by adding cold water to the reaction mixture,
collected by filtration and purified by column chromatography
as described in method A.
7-(4-Chlorophenyl)-2-ethylthio-4-(20-furyl)pyrazolo[1,5-a]
[1,3,5] triazine (7a). From 5-amino-3-(4-chlorophenyl)-1H-
pyrazole 6a (0.387 g, 2.0 mmol), light yellow solid. IR
(KBr): ν 2957, 2930, 2870 (CH3, CH2), 1604, 1564, 1498 (C═C,
2-Ethoxy-4-(20-furyl)-7-(4-methylphenyl)pyrazolo[1,5-a]
[1,3,5] triazine (8b). From 5-amino-3-(4-methylphenyl)-1H-
pyrazole 6b (0.346 g, 2.0 mmol), yellow solid. IR (KBr):
ν 2980, 2955, 2925, 2860 (CH3, CH2), 1621, 1574, 1535,
1
1
C═N) cm-1. H NMR (400 MHz, CDCl3): d 1.48 (t, 3H, CH3),
1500 (C═C, C═N), 1256, 1023 (C—O—C) cm-1. H NMR (400
3.25 (c, 2H, CH2), 6.70 (s, 1H, H-8), 6.77 (dd, 1H, H-40), 7.47
(d, 2H, Hm), 7.86 (br s, 1H, H-50), 7.96 (d, 2H, Ho), 8.53 (d, 1H,
H-30). 13C NMR (100 MHz, CDCl3): d 14.2 (CH3), 25.6 (CH2),
91.4 (C-8), 113.2 (C-40), 125.0 (C-30), 128.1 (Co), 129.1 (Cm),
130.7 (Ci), 135.7 (Cp), 143.0 (C-20), 143.3 (C-4), 148.2 (C-50),
151.3 (C-8a), 157.1 (C-7), 166.6 (C-2). MS (70 eV) m/z (%):
358/356 (7/19, M+), 341 (10), 323 (13), 235 (10), 111(12), 97
(30), 83 (42), 81 (46), 73 (54), 71 (42), 70 (29), 69 (100), 57 (74),
55 (69), 43 (84), 41 (62), 29 (20). Anal. Calcd. for
C17H13ClN4OS: C, 57.22; H, 3.67; N, 15.71. Found: C, 57.25; H,
3.88; N, 15.58.
MHz, CDCl3): d 1.49 (t, 3H, CH3), 2.43 (s, 3H, CH3-Ar), 4.51
(c, 2H, CH2), 6.62 (s, 1H, H-8), 6.76 (dd, 1H, H-40), 7.29 (d, 2H,
Hm), 7.83 (d, 1H, H-50), 7.91 (d, 2H, Ho), 8.56 (d, 1H, H-30). 13C
NMR (100 MHz, CDCl3): d 14.3 (CH3), 21.4 (CH3-Ar), 64.0
(CH2), 90.9 (C-8), 113.1 (C-40), 124.7 (C-30), 126.7 (Co), 129.4
(Ci), 129.5 (Cm), 139.8 (Cp), 143.2 (C-20), 146.2 (C-4), 148.0
(C-50), 152.3 (C-8a), 159.0 (C-7), 160.0 (C-2). MS (70 eV)
m/z (%): 320 (100, M+), 305 (34), 292 (21), 276 (27), 199 (47),
97 (21), 94 (33), 83 (26), 81 (27), 73 (28), 71 (30), 69 (61), 57
(45), 55 (42), 43 (47), 41 (39), 29 (20). Anal. Calcd. for
C18H16N4O2: C, 67.47; H, 5.04; N, 17.50. Found: C, 67.19; H,
5.11; N, 17.22.
2-Ethylthio-4-(20-furyl)-7-(4-methylphenyl)pyrazolo[1,5-a]
[1,3,5] triazine (7b). From 5-amino-3-(4-methylphenyl)-1H-
pyrazole 6b (0.346 g, 2.0 mmol), light green solid. IR (KBr):
ν 2958, 2927, 2860 (CH3, CH2), 1607, 1570, 1495 (C═C,
C═N) cm-1. 1H NMR (400 MHz, CDCl3): d 1.48 (t, 3H,
CH3), 2.44 (s, 3H, CH3-Ar), 3.24 (c, 2H, CH2), 6.71 (s, 1H,
H-8), 6.77 (dd, 1H, H-40), 7.30 (d, 2H, Hm), 7.85 (br s, 1H,
H-50), 7.93 (d, 2H, Ho), 8.57 (d, 1H, H-30). 13C NMR (100
MHz, CDCl3): d 14.2 (CH3), 21.4 (CH3-Ar), 25.6 (CH2),
91.3 (C-8), 113.1 (C-40), 124.9 (C-30), 126.8 (Co), 129.4 (Ci),
129.5 (Cm), 139.9 (Cp), 143.1 (C-20), 143.3 (C-4), 148.0
(C-50), 151.2 (C-8a), 158.5 (C-7), 166.2 (C-2). MS (70 eV) m/z
(%): 336 (100, M+), 321 (28), 303 (64), 215 (10), 97 (20), 91 (11),
83 (23), 81 (26), 71 (31), 69 (58), 57 (44), 55 (39), 43 (42), 41
(32), 29 (11). Anal. Calcd. for C18H16N4OS: C, 64.27; H, 4.80; N,
16.67. Found: C, 64.25; H, 4.83; N, 16.56.
2-Ethoxy-4-(20-furyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine
(8c). From 5-amino-3-phenyl-1H-pyrazole 6c (0.318 g, 2.0
mmol), yellow solid. IR (KBr):
ν 2982, 2926, 2861
(CH3, CH2), 1621, 1572, 1531, 1498 (C═C, C═N), 1260, 1019
1
(C—O—C) cm-1. H NMR (400 MHz, CDCl3): d 1.50 (t, 3H,
CH3), 4.53 (c, 2H, CH2), 6.66 (s, 1H, H-8), 6.77 (dd, 1H, H-40),
7.45-7.52 (m, 3H, Hm, Hp), 7.84 (dd, 1H, H-50), 8.04 (d, 2H,
Ho), 8.58 (d, 1H, H-30). 13C NMR (100 MHz, CDCl3): d 14.3
(CH3), 64.1 (CH2), 91.1 (C-8), 113.1 (C-40), 124.8 (C-30), 126.8
(Co), 128.8 (Cm), 129.6 (Cp), 132.3 (Ci), 143.2 (C-20), 146.3
(C-4), 148.0 (C-50), 152.3 (C-8a), 159.0 (C-7), 160.0 (C-2). MS
(70 eV) m/z (%): 306 (100, M+), 291 (26), 278 (20), 262 (23),
185 (60), 94 (52), 77 (40), 71 (33), 69 (36), 57 (42), 55 (26), 43
(37), 41 (19), 29 (20). Anal. Calcd. for C17H14N4O2: C, 66.64;
H, 4.61; N, 18.30. Found: C, 66.34; H, 4.72; N, 18.02.
2-Ethylthio-4-(20-furyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine
(7c). From 5-amino-3-phenyl-1H-pyrazole 6c (0.318 g, 2.0 mmol),
light green solid. IR (KBr): ν 2955, 2923, 2859 (CH3, CH2), 1609,
7-(4-Chlorophenyl)-2-ethylthio-4-(20-thienyl)pyrazolo[1,5-a]
[1,3,5] triazine (9a). From 5-amino-3-(4-chlorophenyl)-1H-
pyrazole 6a (0.387 g, 2.0 mmol), light green solid. IR (KBr): ν
2956, 2925, 2858 (CH3, CH2), 1601, 1570, 1530, 1490 (C═C,
1
1568, 1495 (C═C, C═N) cm-1. H NMR (400 MHz, CDCl3): d
1
1.48 (t, 3H, CH3), 3.25 (c, 2H, CH2), 6.74 (s, 1H, H-8), 6.77
(dd, 1H, H-40), 7.46-7.52 (m, 3H, Hm, Hp), 7.86 (br s, 1H, H-50),
8.00 (d, 2H, Ho), 8.57 (d, 1H, H-30). 13C NMR (100 MHz,
CDCl3): d 14.2 (CH3), 25.6 (CH2), 91.5 (C-8), 113.1 (C-40),
C═N) cm-1. H NMR (400 MHz, CDCl3): d 1.49 (t, 3H, CH3),
3.25 (c, 2H, CH2), 6.69 (s, 1H, H-8), 7.32 (t, 1H, H-40), 7.48 (d,
2H, Hm), 7.86 (d, 1H, H-50), 7.99 (d, 2H, Ho), 8.94 (d, 1H, H-30).
13C NMR (100 MHz, CDCl3): d 14.4 (CH3), 25.6 (CH2), 91.1
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(C-8), 128.1 (Co), 128.3 (C-40), 129.1 (Cm), 130.7 (Ci), 132.1
(C-20), 135.7 (Cp), 136.0 (C-50), 137.0 (C-30), 147.6 (C-4),
151.6 (C-8a), 157.1 (C-7), 166.5 (C-2). MS (70 eV) m/z (%):
374/372 (36/100, M+), 357 (22), 339 (33), 235 (27), 111 (39),
109 (28), 97 (59), 95 (42), 85 (44), 83 (55), 81 (42), 71 (69),
69 (63), 57 (70), 55 (62), 43 (50), 41 (28), 29 (10). Anal.
Calcd. for C17H13ClN4S2: C, 54.76; H, 3.52; N, 15.04. Found:
C, 54.41; H, 3.45; N, 14.90.
H-40, Hm), 7.84 (d, 1H, H-50), 7.93 (d, 2H, Ho), 8.97 (d, 1H,
H-30). 13C NMR (100 MHz, CDCl3): d 14.4 (CH3), 21.4
(CH3-Ar), 64.1 (CH2), 90.7 (C-8), 126.8 (Co), 128.2 (C-40),
129.4 (Ci), 129.5 (Cm), 132.1 (C-20), 135.9 (C-50), 137.0 (C-
30), 139.8 (Cp), 150.5 (C-4), 152.4 (C-8a), 158.9 (C-7), 160.0
(C-2). MS (70 eV) m/z (%): 336 (36, M+), 321 (12), 307 (13),
292 (10), 199 (100), 198 (28), 115 (24), 110 (59), 109 (11),
91 (18). Anal. Calcd. for C18H16N4OS: C, 64.27; H, 4.80; N,
16.67. Found: C, 64.09; H, 4.62; N, 16.53.
2-Ethylthio-7-(4-methylphenyl)-4-(20-thienyl)pyrazolo[1,5-a]
[1,3,5]triazine (9b). From 5-amino-3-(4-methylphenyl)-1H-
pyrazole 6b (0.346 g, 2.0 mmol), light green solid. IR (KBr): ν
2957, 2928, 2860 (CH3, CH2), 1602, 1569, 1530, 1492 (C═C,
2-Ethoxy-7-phenyl-4-(20-thienyl)pyrazolo[1,5-a][1,3,5]triazine
(10c). From 5-amino-3-phenyl-1H-pyrazole 6c (0.318 g, 2.0 mmol),
yellow solid. IR (KBr): ν 2976, 2925, 2860 (CH3, CH2), 1611, 1570,
1535, 1487 (C═C, C═N), 1245, 1049 (C—O—C) cm-1. 1H NMR
(400 MHz, CDCl3): d 1.51 (t, 3H, CH3), 4.52 (c, 2H, CH2), 6.64
(s, 1H, H-8), 7.31 (t, 1H, H-40), 7.44-7.49 (m, 3H, Hm, Hp), 7.84
(d, 1H, H-50), 8.05 (d, 2H, Ho), 8.98 (d, 1H, H-30). 13C NMR
(100 MHz, CDCl3): d 14.4 (CH3), 64.1 (CH2), 90.9 (C-8), 126.9
(Co), 128.2 (C-40), 128.8 (Cm), 129.6 (Cp), 132.1 (C-20), 132.2
(Ci), 136.0 (C-50), 137.0 (C-30), 150.6 (C-4), 152.5 (C-8a), 158.8
(C-7), 160.0 (C-2). MS (70 eV) m/z (%): 322 (92, M+), 307 (10),
293 (38), 278 (14), 185 (87), 110 (100), 109 (35), 102 (36), 77
(76). Anal. Calcd. for C17H14N4OS: C, 63.34; H, 4.38; N, 17.39.
Found: C, 63.22; H, 4.54; N, 17.18.
1
C═N) cm-1. H NMR (400 MHz, CDCl3): d 1.51 (t, 3H, CH3),
2.43 (s, 3H, CH3-Ar), 3.26 (c, 2H, CH2), 6.69 (s, 1H, H-8),
7.30-7.33 (m, 3H, H-40, Hm), 7.84 (d, 1H, H-50), 7.96 (d, 2H,
Ho), 8.96 (d, 1H, H-30). 13C NMR (100 MHz, CDCl3): d 14.4
(CH3), 21.4 (CH3-Ar), 25.6 (CH2), 91.0 (C-8), 126.8 (Co),
128.3 (C-40), 129.4 (Ci), 129.5 (Cm), 132.3 (C-20), 135.8 (C-50),
136.9 (C-30), 139.8 (Cp), 147.5 (C-4), 151.4 (C-8a), 158.4
(C-7), 166.1 (C-2). MS (70 eV) m/z (%): 352 (50, M+), 337
(12), 319 (36), 215 (53), 186 (41), 183 (43), 115 (34), 110 (40),
109 (19), 91 (27). Anal. Calcd. for C18H16N4S2: C, 61.35; H,
4.58; N, 15.91. Found: C, 61.11; H, 4.67; N, 15.68.
2-Ethylthio-7-phenyl-4-(20-thienyl)pyrazolo[1,5-a][1,3,5]
triazine (9c). From 5-amino-3-phenyl-1H-pyrazole 6c
(0.318 g, 2.0 mmol), light green solid. IR (KBr): ν 2955,
2929, 2856 (CH3, CH2), 1600, 1569, 1529, 1491 (C═C,
C═N) cm-1. 1H NMR (400 MHz, CDCl3): d 1.49 (t, 3H,
CH3), 3.26 (c, 2H, CH2), 6.72 (s, 1H, H-8), 7.32 (t, 1H,
H-40), 7.44-7.54 (m, 3H, Hm, Hp), 7.84 (d, 1H, H-50), 8.07
(d, 2H, Ho), 8.96 (d, 1H, H-30). 13C NMR (100 MHz,
CDCl3): d 14.4 (CH3), 25.6 (CH2), 91.2 (C-8), 126.9 (Co),
128.3 (C-40), 128.8 (Cm), 129.7 (Cp), 132.2 (Ci), 132.3
(C-20), 135.9 (C-50), 137.0 (C-30), 147.6 (C-4), 151.5
(C-8a), 158.3 (C-7), 166.2 (C-2). MS (70 eV) m/z (%): 338
(84, M+), 323 (15), 305 (51), 201 (62), 169 (67), 143 (85),
110 (77), 109 (51), 77 (100), 70 (68). Anal. Calcd. for
C17H14N4S2: C, 60.34; H, 4.17; N, 16.57. Found: C, 60.19;
H, 4.08; N, 16.37.
Acknowledgments. The authors thank Universidad de Nariño,
COLCIENCIAS, Universidad del Valle, the Spanish ‘Consejería de
Innovación, Ciencia y Empresa, Junta de Andalucía’, and ‘Centro
de Instrumentación Científico-Técnica de la Universidad de Jaén’
for financial support.
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