Three practical approaches for the synthesis of novel 4,7- dihetarylpyrazolo[1,5-a][1,3,5]triazines

Article abstract of DOI:10.1016/j.tet.2012.09.029

Novel 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines were synthesized from three different approaches. The first one, involved a one-step reaction between 5-amino-3-hetaryl-1H-pyrazoles and O,S-diethyl hetaroylimidothiocarbonates or S,S-diethyl hetaroylimidodithiocarbonates under solvent-free conditions employing microwave irradiation as the energy source. In the second approach, conventional heating under reflux in DMF as solvent was used instead of the microwave irradiation; and the third one was achieved from a two-step sequence through the treatment of 5-amino-3-hetaryl-1H-pyrazoles with hetaroyl isothiocyanates and the subsequent S-alkylation and cyclization process in DMF as solvent. Some intermediates were isolated and characterized to support the regiochemistry of the studied reactions. The structures of the new compounds were unambiguously established by spectroscopic and analytical techniques.

Full text of DOI:10.1016/j.tet.2012.09.029

Tetrahedron 68 (2012) 9384e9390
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Three practical approaches for the synthesis of novel 4,7-dihetarylpyrazolo[1,5-a]
[1,3,5]triazines
,
a
b
b
b
Henry Insuasty a , Braulio Insuasty , Edison Castro , Jairo Quiroga , Rodrigo Abonía ,
*
Manuel Nogueras c, Justo Cobo c
a
~
Heterocyclic Compounds Research Group, Department of Chemistry, Universidad de Narino, A.A. 1175 Pasto, Colombia
b Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia
c
ꢀ
ꢀ
Department of Inorganic and Organic Chemistry, Universidad de Jaen, 23071 Jaen, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2012
Received in revised form 31 August 2012
Accepted 4 September 2012
Available online 11 September 2012
Novel 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines were synthesized from three different approaches. The
first one, involved a one-step reaction between 5-amino-3-hetaryl-1H-pyrazoles and O,S-diethyl hetar-
oylimidothiocarbonates or S,S-diethyl hetaroylimidodithiocarbonates under solvent-free conditions
employing microwave irradiation as the energy source. In the second approach, conventional heating
under reflux in DMF as solvent was used instead of the microwave irradiation; and the third one was
achieved from a two-step sequence through the treatment of 5-amino-3-hetaryl-1H-pyrazoles with
hetaroyl isothiocyanates and the subsequent S-alkylation and cyclization process in DMF as solvent.
Some intermediates were isolated and characterized to support the regiochemistry of the studied re-
actions. The structures of the new compounds were unambiguously established by spectroscopic and
analytical techniques.
Keywords:
Pyrazolo[1,5-a][1,3,5]triazines
O,S-Diethyl hetaroylimidothiocarbonates
S,S-Diethyl hetaroylimidodithiocarbonates
5-Amino-1H-pyrazoles
Ó 2012 Elsevier Ltd. All rights reserved.
Pyrazolylthioureas
1. Introduction
Me
Me
NH
The pyrazolo[1,5-a][1,3,5]triazine core may be found in the
structure of different biologically active molecules including in-
hibitors of protein kinase CK2 and cyclin-dependent kinases
(CDKs),1 which exhibit high antiproliferative activity in tumor cell
lines and high potential as cancer chemotherapy agents (compound
1, Fig. 1).2 Some pyrazolotriazines act as inhibitors of phosphodi-
esterase type 4 (PDE4),3 potential therapeutic agents for the control
of autoimmune and inflammatory diseases and more recently, it
was reported the activity of some of them against the herpes
simplex viruses HSV-1 and HSV-2.4 A variety of corticotrophin re-
leasing factor CRF1 receptor antagonists containing the pyrazolo
[1,5-a][1,3,5]triazine framework have been studied over the last
years.5 Among them is the Pexacerfont (compound 2, Fig. 1), which
has been tested as a potential agent for the control and treatment of
some diseases related to stress such as anxiety and depression.5e
It is also worth mentioning that the presence of the 2-thienyl
and 2-furyl moieties in the structure of purines 3,6 pyrazolopyr-
imidines 4,7 and triazolotriazine 58 (Fig. 1), was determinant for
their biological properties displayed.6e8 The insertion of the 2-
N
N
N
HN
Me
Me
Me
HO
Me
OH
N
N
N
N
N
H
N
N
Me
Me
2
1
OMe
Z
Y
X
N
NH2
N
N
N
N
R1
N
N
R
O
N
N
H
3, X = CH, Y = N, Z = O,S
4, X = N, Y = CH, Z = O
5 (ZM241385)
Fig. 1. Pyrazolo[1,5-a][1,3,5]triazines and analogue ring systems with pharmacological
activity.
thienyl and 2-furyl units into such interesting compounds has
been usually mediated by a common CeC coupling process based
on the Stille reaction of the corresponding hetarylstannic de-
rivatives and the appropriate starting chloro-compounds6a,7 or by
a cross-coupling reaction between a hetarylzinc halide and the
adequate chlorinated compound.6b
* Corresponding author. Tel.: þ57
2
7313062; fax: þ57
2 7313106; e-mail
addresses: hein@udenar.edu.co, henryinsuasty@gmail.com (H. Insuasty).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.029

H. Insuasty et al. / Tetrahedron 68 (2012) 9384e9390
9385
In connection with our current studies on the synthesis of fused
heterocycles containing the pyrazole moiety,9 we are describing
here the synthesis and interaction of hetaroyl (furoyl and thenoyl)
isothiocyanates 7, O,S-diethyl hetaroylimidothiocarbonates 10, and
S,S-diethyl hetaroylimidodithiocarbonates 11 with 5-amino-3-
hetaryl-1H-pyrazoles 12 as efficient and metal catalyst-free ap-
proaches to obtain novel 4,7-dihetarylpyrazolo[1,5-a][1,3,5]tri-
azines 13 and 14, bearing the well known 2-thienyl and 2-furyl
pharmacophores as part of their structures.
The reaction of thiocarbonates 10a,bwith the commerciallyavailable
5-aminopyrazoles 12a,b under solvent-free conditions using mi-
crowave irradiation (300 watts of power and 160e180 ꢀC, during
10e20 min) afforded a mixture of two new products (TLC control),
whichwere separated bycolumn chromatography (it will be referred
to as approach A). The new compounds corresponded to 2-ethylthio-
4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines 13aed and 2-ethoxy-
4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines 14aed (Scheme 2).
Het1
5
N
2. Results and discussion
6
N
4
3
N
O
SEt
XEt
Het2
7
MW,
10-20
min
2.1. Synthesis of O,S-diethyl hetaroylimidothiocarbonates and
S,S-diethyl hetaroylimidodithiocarbonates
Het1
N
8
8a
2
EtX
N
1
10a,b; X = O
11a,b; X = S
13a-d, X = S, from 10, 11 or 16
14a-d, X = O, from 10 or 17
We have developed a convenient procedure for the synthesis of
O,S-diethyl hetaroylimidothiocarbonates 10a,b and S,S-diethyl
hetaroylimidodithiocarbonates 11a,b (Scheme 1). The starting pre-
cursors 10a,b and 11a,b were prepared by the addition of
the appropriate hetaroyl chlorides 6a,b to a solution of potassium
thiocyanate in acetonitrile to provide the hetaroyl isothiocyanates
7a,b, which were immediately treated with ethanol or ethanethiol to
afford the corresponding O-ethyl hetaroylthiocarbamates 8a,b or S-
ethyl hetaroyldithiocarbamates 9a,b. Alkylation of the sulfur atom of
8a,b and 9a,b with ethyl bromide in the presence of sodium hydride
at room temperature led to the corresponding thiocarbonates 10a,b
and dithiocarbonates 11a,b (Scheme 1, Table 1). The main difference
between our protocol and the previous reported method for the
synthesis of S,S-dialkyl aroylimidodithiocarbonates10 consisted in
using a stronger base for the S-alkylation reaction, which permitted
us to obtain the precursors 10 and 11 in shorter reaction times
(1e1.5 h), and with excellent yields (89e95%), Table 1.
MW or
Het1
N
HN
Het2
N
MW,
3 min
O
N HN
Het2
H2N
EtX
N
H
12a,b
16b, X = S + 17b, X = O
from 10b and 12b
In all cases: a, Het1 = Het2 = 2-furyl; b, Het1 = Het2 = 2-thienyl;
c, Het1 = 2-furyl, Het2 = 2-thienyl; d, Het1 = 2-thienyl, Het2 = 2-furyl
Scheme 2. Synthesis of pyrazolo[1,5-a][1,3,5]triazines 13 and 14 from the reaction of
thiocarbonates 10, 11 with 5-aminopyrazoles 12.
When the mixture of thiocarbonate 10b and 5-aminopyrazole
12b was irradiated for 3 min, the intermediates 2-ethyl-1-(2-
thenoyl)-3-(3-(2-thienyl)pyrazol-5-yl)isothiourea 16b and 2-
ethyl-1-(2-thenoyl)-3-(3-(2-thienyl)pyrazol-5-yl)isourea 17b were
isolated in 10% and 24% yields, respectively. The 1H and 13C NMR
spectra of 16b and 17b taken in DMSO-d6 at room temperature
confirmed the structures of such intermediates (see 1H NMR
spectrum of 17b, Fig. 2a).
O
O
KSCN
MeCN
Het1
Cl
Het1
7a,b
N C S
6a,b
EtOH
or
EtSH
In order to confirm the intermediacy of 17b in the formation of
product 14b, once the NMR spectra was run at ambient tempera-
ture, the probe of the NMR spectrometer was heated at 100 ꢀC and
the NMR experiment was repeated for the same sample, to induce,
in situ, its cyclization. After five consecutive runs, the progressive
disappearance of the NeH signals, notorious changes of the thienyl
signals and an increasing of the water signal, corroborated that 17b
was cyclized to pyrazolotriazine 14b (see spectrum (b) in Fig. 2).
Alternatively, a sample of 17b dissolved in DMSO was cyclized to
14b by heating it in an oil bath at 180 ꢀC for 10 min. It was also
found that intermediates 16b and 17b can be cyclized to 13b and
14b, respectively, employing microwave irradiation without using
solvent, at 180 ꢀC and during 10 min of reaction.
O
S
O
SEt
XEt
NaH/DMF,
EtBr
Het1
N
H
XEt
Het1
N
10a,b; X = O
11a,b; X = S
8a,b; X = O
9a,b; X = S
In all cases: a, Het1 = 2-furyl; b, Het1 = 2-thienyl
Scheme 1. Synthesis of thio- and dithiocarbonates 10 and 11.
Table 1
Synthesis of thio-/dithiocarbamates 8, 9 and thio-/dithiocarbonates 10, 11
To avoid the mixture of both final products 13 and 14, and to
improve the yields of the target pyrazolotriazines, the microwave-
assisted reaction between dithiocarbonates 11a,b and 5-
aminopyrazoles 12a,b under solvent-free conditions to obtain ex-
clusively the pyrazolotriazines 13aed was then studied. It was
found that this reaction is highly efficient and selectively generated
compounds 13aed as unique products, in excellent yields
(90e95%) (Scheme 2, Table 2).
To evaluate the efficacy of the reaction mediated by microwave
irradiation, all reactions depicted in Scheme 2 were repeated under
conventional heating using DMF as solvent (it will be referred to as
approach B, see Experimental section). Table 2 summarizes the
comparative results and the evident improved yields and shorter
reaction times when reactions were carried out by microwave ir-
radiation rather than by conventional heating.
Product
Het1
X
Yield, %
Time, h
8a
8b
9a
9b
10a
10b
11a
11b
2-Furyl
2-Thienyl
2-Furyl
2-Thienyl
2-Furyl
2-Thienyl
2-Furyl
O
O
S
91
93
95
93
94
90
95
89
12
12
12
12
1
1
1.5
1.5
S
O
O
S
2-Thienyl
S
2.2. Synthesis of 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines
Compounds 10 and 11 were employed as starting materials to
obtain the desired pyrazolotriazines 13aed and 14aed (Scheme 2).

9386
H. Insuasty et al. / Tetrahedron 68 (2012) 9384e9390
1
Fig. 2. H NMR spectra of intermediate 17b in DMSO-d6, (a) at room temperature, (b) at 100 ꢀC into the probe of the NMR spectrometer.
Table 2
Het1
MeCN,
reflux,
Synthesis of pyrazolo[1,5-a][1,3,5]triazines 13 and 14
N
N
O
HN
H2N
12a,b
O
NHHN
Het2
Het2
S
Product
Het1
Het2
X
Yield,a,b
MW
%
Time, min
C
30 min
Het1
N
S
N
H
DMF
MW
DMF
7a,b
13a
13b
13c
13d
14a
14b
14c
14d
2-Furyl
2-Thienyl
2-furyl
2-Thienyl
2-Furyl
2-Thienyl
2-Furyl
2-Furyl
S
S
S
S
O
O
O
O
16(95)
20(90)
15(93)
11(91)
48
50
65
46
10(83)
12(71)
9(79)
5(75)
39
41
53
36
15
20
10
12
15
20
10
12
90
110
65
75
90
110
65
75
15a-d
2-Thienyl
2-Thienyl
2-Furyl
NaH, EtBr,
DMF, rt, 30 min
2-Furyl
Het1
Het1
N
6
2-Thienyl
2-Thienyl
2-Furyl
DMF,
reflux,
4
5
N
N
3
N
N
Het2
O
HN
Het2
7
2-Thienyl
45-60 min
2
8a
EtS
N
8
EtS
N
H
a
1
For products 13aed, values out of parenthesis are referred to reactions between
10 and 12. Values in parenthesis correspond to reactions between 11 and 12.
13a-d
16a-d
b
Yields after isolation by column chromatography.
In all cases: a, Het1 = Het2 = 2-furyl; b, Het1 = Het2 = 2-thienyl;
c, Het1 = 2-furyl, Het2 = 2-thienyl; d, Het1 = 2-thienyl, Het2 = 2-furyl
Formation of compounds 13 and 14 should involve an addi-
tioneelimination process. Firstly, the C]N double bond of the
starting materials 10 and 11 should suffer a nucleophilic attack
from the 5-NH2 of pyrazole 12 with subsequent elimination of
a molecule of ethanol or ethanethiol leading to adducts 16 and 17,
respectively (Scheme 2). For reaction between 10 and 12, adduct
17 should be the main intermediate because ethanethiol
(pKa¼10.6) is a better leaving group than ethanol (pKa¼15.9). Fi-
nally, adducts 16 and 17 should be intramolecularly cyclized after
the attack of 1-NH of pyrazole moiety over the C]O functionality
with elimination of a molecule of water to afford the isolated
pyrazolotriazines 13 and 14. Previous reports showing the higher
electrophilicity of the C]N double bond than the carbonyl group
in compounds type 10,1111 supports the postulated sequence of
steps depicted in Scheme 2.
Scheme 3. Synthesis of pyrazolo[1,5-a][1,3,5]triazines 13 via pyrazolylthioureas 15.
Table 3
Synthesis of pyrazolotriazines 13 via pyrazolylthioureas 15
Product
Het1
Het2
Yield,a
%
Time, min
15a
15b
15c
15d
13a
13b
13c
13d
2-Furyl
2-Thienyl
2-Furyl
2-Thienyl
2-Furyl
2-Thienyl
2-Furyl
2-Furyl
97
95
92
93
70
75
85
78
30
30
30
30
60
60
45
45
2-Thienyl
2-Thienyl
2-Furyl
2-Furyl
2-Thienyl
2-Thienyl
2-Furyl
2-Thienyl
a
The yields for products 13aed correspond to their conversion from 15.
In order to provide further evidence to support the selectivity
and mechanism of this process, an alternative two-step sequence to
prepare selectively the target compounds 13aed, (it will be re-
ferred to as approach C) was devised. In the first step, hetaroyl
isothiocyanates 7a,b and 5-aminopyrazoles 12a,b were heated
under reflux in acetonitrile for 30 min to afford the thiourea de-
rivatives 15aed (Scheme 3, Table 3). In the second step, compounds
15aed were treated with ethyl bromide in the presence of sodium
hydride in DMF and stirred at room temperature for 30 min to
generate the intermediate isothioureas 16aed, which without
isolation were heated under reflux for 45e60 min to produce the
desired compounds 13aed (Scheme 3, Table 3). Products 13aed
obtained by this approach had the same physical and spectroscopic
characteristics of those pyrazolotriazines 13aed resulting from the
direct reaction of thiocarbonates 10 or 11 and 5-aminopyrazoles 12,
as mentioned above.
To corroborate the intermediacy of 16aed in the formation of
products 13aed (Scheme 3), the isothiourea 16d, the most stable of
the series, was initially isolated and characterized. Then, it was
cyclized to its corresponding compound 13d by conventional
heating in DMF under reflux for 45 min, confirming that the con-
version of 15 to 13 passed through adducts 16.
A comparison of the overall yields among the three approaches
for the synthesis of pyrazolotriazines 13aed (calculated on the
basis of the stages of formation of precursors and products),
allowed us to establish that the synthesis of compounds 13aed
starting from dithiocarbonates 11a,b and 5-aminopyrazoles 12a,b
in the absence of solvent employing microwave irradiation gave an
overall yield in the range of 75e84%. Conventional heating in DMF
gave yield in the range of 59e71%, while reactions performed in
two steps starting from the hetaroyl isothiocyanates 7 gave an
overall yield in the range of 68e78%. These findings demonstrated

H. Insuasty et al. / Tetrahedron 68 (2012) 9384e9390
9387
that all three studied synthetic approaches are really useful for the
synthesis of the pyrazolotriazines 13aed, although the first ap-
proach should be considered the best, because it is carried out
under solvent-free conditions, employs microwaves as energy
source and proceeds in shorter reaction times.
3), 9.34 (s, 1H, NH). 13C NMR (CDCl3):
d
13.7 (CH3), 69.2 (CH2), 113.2
(C-4), 118.1 (C-3), 145.4 (C-5), 146.1 (C-2), 152.3 (C]O), 188.6 (C]S).
MS (70 eV) m/z (%): 199 (19, Mþ), 171 (29), 143 (23), 111 (18), 95
(100), 39 (33). Anal. Calcd for C8H9NO3S: C, 48.23; H, 4.55; N, 7.03.
Found: C, 48.31; H, 4.49; N, 7.11.
The structures of the obtained compounds 8e17 were un-
ambiguously established by IR, 1H and 13C NMR spectroscopic
techniques, COSY 1He1H, HSQC, and HMBC experiments, mass
spectrometry, and elemental analyses.
4.2.2. O-Ethyl 2-thenoylthiocarbamate (8b). Green solid, mp
74e75 ꢀC. IR (KBr): 3235 (NH), 1678 (C]O), 1568 (C]C) cmꢂ1. 1H
n
NMR (CDCl3):
1H, H-4), 7.64 (d, J¼4.0 Hz, 1H, H-5), 7.65 (d, J¼3.7 Hz,1H, H-3), 9.05
(s, 1H, NH). 13C NMR (CDCl3):
13.7 (CH3), 69.5 (CH2), 128.1 (C-4),
d
1.47 (t, 3H, CH3), 4.67 (q, 2H, CH2), 7.14 (t, J¼3.7 Hz,
3. Conclusions
d
130.2 (C-5), 133.4 (C-3), 137.5 (C-2), 156.4 (C]O), 189.0 (C]S). MS
(70 eV) m/z (%): 215 (12, Mþ), 187 (25), 127 (24), 111 (100), 83 (18),
39 (22). Anal. Calcd for C8H9NO2S2: C, 44.63; H, 4.21; N, 6.51. Found:
C, 44.59; H, 4.26; N, 6.47.
A practical synthesis of O,S-diethyl hetaroylimidothiocarbonates
10 and S,S-diethyl hetaroylimidodithiocarbonates 11 displaying
high yields (89e95%) and under mild reaction conditions has been
implemented. Besides, three simple and versatile approaches for
the synthesis of novel 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines
13 exhibiting good yields, from the reaction of the starting thio-
carbonates 10, 11 and isothiocyanates 7 with 5-aminopyrazoles 12
in both solution and solvent-free conditions have been developed.
Experimental evidence about reaction intermediates allowed us to
confirm the regiochemistry as well as the mechanistic approxi-
mation for this kind of reactions.
4.2.3. S-Ethyl 2-furoyldithiocarbamate (9a). Green solid, mp
56e57 ꢀC. IR (KBr): 3388 (NH), 1688 (C]O), 1563 (C]C) cmꢂ1. 1H
n
NMR (CDCl3):
4.2 Hz, 1H, H-4), 7.39 (d, J¼4.2 Hz, 1H, H-5), 7.60 (d, J¼2.6 Hz, 1H, H-
3), 10.1 (s, 1H, NH). 13C NMR (CDCl3):
12.1 (CH3), 31.5 (CH2), 113.4
d
1.41 (t, 3H, CH3), 3.29 (q, 2H, CH2), 6.62 (dd, J¼2.6,
d
(C-4), 118.8 (C-3), 146.0 (C-5), 146.2 (C-2), 152.1 (C]O), 188.5 (C]S).
MS (70 eV) m/z (%): 215 (26, Mþ), 187 (48), 177 (65), 126 (80), 95
(100), 27 (38). Anal. Calcd for C8H9NO2S2: C, 44.63; H, 4.21; N, 6.51.
Found: C, 44.71; H, 4.14; N, 6.58.
4. Experimental section
4.1. General
4.2.4. S-Ethyl 2-thenoylthiocarbamate (9b). Green solid, mp
88e89 ꢀC. IR (KBr): 3216 (NH), 1653 (C]O), 1599 (C]C) cmꢂ1. 1H
n
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 disks (or CH2Cl2 as
solvent for compounds 11a,b). 1H and 13C NMR spectra were
recorded on a Bruker Avance 400 spectrometer operating at 400
and 100 MHz, respectively, using CDCl3 or DMSO-d6 as solvent.
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 ele-
mental analyzer and the values are within ꢁ0.4% of the theoretical
values. Silica gel aluminum plates 60-F254 (Merck) were used for
analytical TLC. O,S-Diethyl hetaroylimidothiocarbonates 10 and S,S-
diethyl hetaroylimidodithiocarbonates 11 were obtained according
to a modification of published procedure.10 5-Amino-3-hetaryl-1H-
pyrazoles 12 were purchased from SigmaeAldrich Chemical Co. Ltd.
Reactions under microwave irradiation were improved using a CEM
Discover oven in open glass vessels. For describing the spectro-
scopic data of compounds 13e17, the heteroaromatic rings (Het1
and Het2) have been denoted by the letters A and B, respectively.
NMR (CDCl3):
1H, H-4), 7.71 (d, J¼5.0 Hz, 1H, H-5), 7.73 (d, J¼2.7 Hz, 1H, H-3), 9.92
(s, 1H, NH). 13C NMR (CDCl3):
13.6 (CH3), 33.0 (CH2), 129.8 (C-4),
132.1 (C-5), 135.4 (C-3), 137.7 (C-2), 159.1 (C]O), 205.2 (C]S). MS
(70 eV) m/z (%): 231 (22, Mþ), 203 (15), 177 (81), 130 (33), 111 (100),
27 (26). Anal. Calcd for C8H9NOS3: C, 41.53; H, 3.92; N, 6.05. Found:
C, 41.59; H, 3.87; N, 6.11.
d
1.43 (t, 3H, CH3), 3.31 (q, 2H, CH2), 7.19 (t, J¼3.9 Hz,
d
4.3. Procedure for the synthesis of O,S-diethyl hetaroy-
limidothiocarbonates 10 and S,S-diethyl hetaroy-
limidodithiocarbonates 11
A slight excess of sodium hydride (60% suspension in oil,
0.02 mol) was added to a solution of the corresponding carbamates
8a,b or 9a,b (0.01 mol) in DMF (6 mL). This mixture was stirred for
10 min at room temperature, then ethyl bromide (0.015 mol) was
added dropwise and the stirring was continued for a further
60e90 min to afford the compounds 10a,b and 11a,b. For isolation
of the thiocarbonates 10a,b, the reaction mixture was diluted with
ice water and the resulting solid was collected by filtration, dried at
room temperature, and recrystallized from ethanol. Isolation of the
dithiocarbonates 11a,b, was made by purification of the resulting
reaction’s oil by column chromatography on silica gel, using
a mixture of hexane/ethyl acetate (4:1) as eluent.
4.2. Procedure for the synthesis of O-ethyl hetaroylth-
iocarbamates 8 and S-ethyl hetaroyldithiocarbamates 9
A solution of potassium thiocyanate (0.043 mol) in acetonitrile
(50 mL) was heated under reflux for 10 min, then, the heating was
turned off and the appropriate hetaroyl chlorides 6a,b (0.043 mol)
were added to afford the corresponding hetaroyl isothiocyanates
7a,b, which were not isolated. Then, an excess of ethanol or etha-
nethiol (0.40 mol) was added and the reaction mixture was stirred
for 12 h to afford the carbamates 8a,b and 9a,b, respectively. After
dilution of the reaction mixture with ice water, the resulting solid
was collected by filtration, washed with hexane, and dried at room
temperature.
4.3.1. O,S-Diethyl 2-furoylimidothiocarbonate (10a). White solid,
mp 82e83 ꢀC. IR (KBr):
n
1654 (C]O), 1553, 1467 (C]C, C]N)
cmꢂ1. 1H NMR (CDCl3):
d 1.30 (t, 3H, CH3), 1.44 (t, 3H, CH3), 3.00 (q,
2H, CH2S), 4.54 (q, 2H, CH2O), 6.48 (dd, J¼1.8 Hz, J¼3.5, 1H, H-4),
7.20 (d, J¼3.7 Hz, 1H, H-5), 7.54 (d, J¼1.5 Hz, 1H, H-3). 13C NMR
(CDCl3):
d 14.0 (CH3), 14.5 (CH3), 25.3 (CH2S), 66.5 (CH2O), 111.8 (C-
4), 117.9 (C-3), 146.4 (C-5), 150.2 (C-2), 166.4 (C]O), 171.4 (C]N).
MS (70 eV) m/z (%): 227 (25, Mþ), 198 (15), 138 (22), 95 (100), 70
(23), 39 (15). Anal. Calcd for C10H13NO3S: C, 52.85; H, 5.77; N, 6.16.
Found: C, 52.83; H, 5.83; N, 6.12.
4.2.1. O-Ethyl 2-furoylthiocarbamate (8a). White solid, mp
69e70 ꢀC. IR (KBr):
n
3413 (NH), 1719 (C]O), 1583 (C]C) cmꢂ1. 1H
NMR (CDCl3):
d
1.46 (t, 3H, CH3), 4.66 (q, 2H, CH2), 6.58 (dd, J¼1.7,
4.3.2. O,S-Diethyl 2-thenoylimidothiocarbonate (10b). White solid,
3.5 Hz, 1H, H-4), 7.31 (d, J¼3.5 Hz, 1H, H-5), 7.54 (d, J¼1.7 Hz, 1H, H-
mp 39e40 ꢀC. IR (KBr): 1630 (C]O),1507,1464 (C]C, C]N) cmꢂ1
n .

9388
H. Insuasty et al. / Tetrahedron 68 (2012) 9384e9390
1H NMR (CDCl3):
d
1.32 (t, 3H, CH3), 1.43 (t, 3H, CH3), 2.96 (q, 2H,
(CH2), 91.2 (C-8), 109.7 (CB-3), 111.9 (CB-5), 113.2 (CB-4), 125.1
(CA-4), 142.9 (CA-2), 143.3 (CB-2), 143.9 (CA-5), 147.9 (C-8a),
148.2 (CA-3), 150.3 (C-7), 150.9 (C-4), 166.9 (C-2). MS (70 eV)
m/z (%): 312 (100, Mþ), 297 (19), 279 (41), 191 (51), 159 (43),
133 (28), 105 (30), 90 (55), 29 (63). Anal. Calcd for
C15H12N4O2S: C, 57.68; H, 3.87; N, 17.94. Found: C, 57.71; H,
3.85; N, 17.92.
CH2S), 4.54 (q, 2H, CH2O), 7.09 (t, J¼3.8 Hz, 1H, H-4), 7.52 (d,
J¼4.0 Hz, 1H, H-5), 7.82 (d, J¼2.5 Hz, 1H, H-3). 13C NMR (CDCl3):
d
14.0 (CH3), 14.4 (CH3), 25.2 (CH2S), 66.6 (CH2O), 127.9 (C-4), 132.5
(C-5), 132.7 (C-3), 141.5 (C-2), 170.1 (C]O), 171.9 (C]N). MS (70 eV)
m/z (%): 243 (22, Mþ), 214 (16), 154 (26), 111 (100), 83 (14), 27 (22).
Anal. Calcd for C10H13NO2S2: C, 49.36; H, 5.38; N, 5.76. Found: C,
49.28; H, 5.43; N, 5.71.
4.4.2. 2-Ethylthio-4,7-di(2-thienyl)pyrazolo[1,5-a][1,3,5]triazine
4.3.3. S,S-Diethyl 2-furoylimidodithiocarbonate (11a). Green oil, bp
(13b). Yellow solid, mp 163e164 ꢀC. IR (KBr):
n
1589, 1524, 1475
139e140 ꢀC. IR (CH2Cl2):
n
1622 (C]O), 1564, 1479 (C]C, C]N)
(C]C, C]N) cmꢂ1. 1H NMR (CDCl3):
d 1.50 (t, 3H, CH3), 3.26 (q, 2H,
cmꢂ1. 1H NMR (CDCl3):
d
1.37 (t, 6H, 2ꢃCH3), 3.15 (q, 4H, 2ꢃCH2),
CH2), 6.60 (s, 1H, H-8), 7.16 (dd, J¼1.5, 3.5 Hz, 1H, HB-4), 7.31 (dd,
J¼1.0, 4.0 Hz, 1H, HA-4), 7.45 (dd, J¼1.3, 3.3 Hz, 1H, HB-5), 7.63 (dd,
J¼1.3, 2.5 Hz, 1H, HB-3), 7.84 (dd, J¼1.3, 3.8 Hz, 1H, HA-5), 8.94 (dd,
6.52 (dd, J¼1.8, 3.5 Hz, 1H, H-4), 7.18 (d, J¼3.5 Hz, 1H, H-5), 7.61 (d,
J¼1.8 Hz, 1H, H-3). 13C NMR (CDCl3):
d
13.9 (2ꢃCH3), 27.3 (2ꢃCH2),
112.0 (C-4), 118.4 (C-3), 146.8 (C-5), 149.7 (C-2), 165.4 (C]O), 178.3
(C]N). MS (70 eV) m/z (%): 243 (100, Mþ), 297 (30), 156 (50), 95
(78), 27 (22). Anal. Calcd for C10H13NO2S2: C, 49.36; H, 5.38; N, 5.76.
Found: C, 49.35; H, 5.40; N, 5.84.
J¼1.3, 2.8 Hz, 1H, HA-3). 13C NMR (CDCl3):
d 14.4 (CH3), 25.7 (CH2),
90.9 (C-8), 127.1 (CB-3), 127.4 (CB-5), 127.9 (CB-4), 128.5 (CA-4), 132.3
(CA-2), 135.5 (CB-2), 135.9 (CA-5), 137.2 (CA-3), 147.4 (C-8a), 151.4 (C-
7), 153.4 (C-4), 166.5 (C-2). MS (70 eV) m/z (%): 344 (41, Mþ), 311
(16), 270 (16), 207 (18), 178 (35), 134 (24), 110 (48), 70 (61), 45 (54),
29 (100). Anal. Calcd for C15H12N4S3: C, 52.30; H, 3.51; N, 16.26.
Found: C, 52.31; H, 3.52; N, 16.22.
4.3.4. S,S-Diethyl 2-thenoylimidodithiocarbonate (11b). Green oil,
bp 127e128 ꢀC. IR (CH2Cl2):
n
1620 (C]O), 1560, 1478 (C]C, C]N)
cmꢂ1. 1H NMR (CDCl3):
d
1.41 (t, 6H, 2ꢃCH3), 3.10 (q, 4H, 2ꢃCH2),
7.14 (t, J¼3.8 Hz, 1H, H-4), 7.60 (d, J¼5.0 Hz, 1H, H-5), 7.86 (d,
4.4.3. 2-Ethylthio-4-(2-furyl)-7-(2-thienyl)pyrazolo[1,5-a][1,3,5]tri-
J¼3.8 Hz, 1H, H-3). 13C NMR (CDCl3):
d
13.9 (2ꢃCH3), 27.4 (2ꢃCH2),
azine (13c). Yellow solid, mp 165e166 ꢀC. IR (KBr):
n
1606, 1577,
133.0 (C-4), 133.1 (C-3), 140.8 (C-5), 168.9 (C-2), 178.3 (C]O), 179.8
(C]N). MS (70 eV) m/z (%): 259 (95, Mþ), 213 (38), 172 (100), 111
(87), 27 (22). Anal. Calcd for C10H13NOS3: C, 46.30; H, 5.05; N, 5.40.
Found: C, 46.25; H, 5.12; N, 5.35.
1455 (C]C, C]N) cmꢂ1. 1H NMR (CDCl3):
d 1.49 (t, 3H, CH3), 3.26 (q,
2H, CH2), 6.64 (s, 1H, H-8), 6.78 (dd, J¼1.6, 3.7 Hz, 1H, HA-4), 7.17
(dd, J¼3.5, 5.0 Hz, 1H, HB-4), 7.45 (d, J¼5.0 Hz, 1H, HB-5), 7.63 (d,
J¼3.6 Hz, 1H, HB-3), 7.87 (d, J¼3.3 Hz, 1H, HA-5), 8.53 (d, J¼1.6 Hz,
1H, HA-3). 13C NMR (CDCl3):
d 14.2 (CH3), 25.6 (CH2), 91.2 (C-8),
4.4. Procedure for the synthesis of pyrazolo[1,5-a][1,3,5]tri-
azines 13 and 14
113.3 (CA-4), 125.1 (CA-3), 127.1 (CB-3), 127.4 (CB-5), 127.9 (CB-4),
135.4 (CB-2), 143.1 (CA-2), 143.1 (C-4), 148.1 (CA-5), 151.1 (C-8a),
153.7 (C-7), 166.7 (C-2). MS (70 eV) m/z (%): 328 (100, Mþ), 313 (24),
295 (57), 207 (35), 175 (29), 149 (26), 134 (19), 94 (29), 70 (20). Anal.
Calcd for C15H12N4OS2: C, 54.86; H, 3.68; N, 17.06. Found: C, 54.89;
H, 3.72; N, 17.05.
Approach A: A mixture of the appropriate O,S-diethyl hetar-
oylimidothiocarbonates 10a,b or S,S-diethyl hetaroylimidodithiocar-
bonates 11a,b (0.015 mol) and the corresponding 5-amino-3-hetaryl-
1H-pyrazoles 12a,b (0.015 mol) was subjected to microwave irradia-
tion in absence of solvent (maximum power 300 W for 10e20 min at
a temperature in the range of 160e180 ꢀC), using a focused micro-
wave reactor (CEM discover). When finished (TLC control), the crude
product was dissolved in chloroform (3.0 mL) and purified bycolumn
chromatography on silica gel, using a mixture of hexanes/ethyl ace-
tate (9:1) as eluent. For reactions between 10 and 12, the first chro-
matographic fraction corresponded to compound 13 and the second
one to compound 14.
Approach B: The mixture of theappropriate thiocarbonate 10 or 11
(0.015 mol), the corresponding aminopyrazoles 12a,b (0.015 mol),
and DMF (3 mL) was heated under reflux for 65e110 min. When
finished (TLC control), the solid crudes were precipitated by adding
cold water to the reaction mixture and collected by filtration. Then
the crudes were purified as described in approach A.
Approach C: A solution of ethyl bromide (0.02 mol) was added
dropwise to a suspension of the corresponding thioureas 15aed
(0.015 mol) and sodium hydride (0.02 mol) in DMF (5 mL). The
reaction mixture was then stirred at room temperature for 30 min
and heated under reflux for 45e60 min. After dilution of the mix-
ture with cold water, precipitate was collected by filtration and
purified by column chromatography on silica gel, using a mixture of
hexanes/ethyl acetate (3:2) as eluent.
4.4.4. 2-Ethylthio-7-(2-furyl)-4-(2-thienyl)pyrazolo[1,5-a][1,3,5]tri-
azine (13d). Yellow solid, mp 108e109 ꢀC. IR (KBr):
n
1594, 1531,
1479 (C]C, C]N) cmꢂ1. 1H NMR (CDCl3):
d 1.50 (t, 3H, CH3), 3.27 (q,
2H, CH2), 6.60 (dd, J¼1.8, 3.3 Hz, 1H, HB-4), 6.64 (s, 1H, H-8), 7.07 (d,
J¼3.3 Hz, 1H, HB-5), 7.32 (t, J¼4.4 Hz, 1H, HA-4), 7.62 (d, J¼1.0 Hz,
1H, HB-3), 7.84 (d, J¼4.8 Hz, 1H, HA-5), 8.97 (d, J¼3.8 Hz, 1H, HA-3).
13C NMR (CDCl3):
d 14.4 (CH3), 25.7 (CH2), 90.9 (C-8), 109.8 (CB-3),
111.9 (CB-5), 128.5 (CB-4), 132.4 (CA-2), 135.8 (CA-4), 137.3 (CA-5),
143.9 (CA-3), 147.6 (CB-2), 147.9 (C-8a), 150.3 (C-7), 151.2 (C-4), 166.5
(C-2). MS (70 eV) m/z (%): 328 (100, Mþ), 313 (22), 268 (38), 219
(35), 191 (93), 94 (55), 27 (29). Anal. Calcd for C15H12N4OS2: C,
54.86; H, 3.68; N, 17.06. Found: C, 54.84; H, 3.65; N, 17.03.
4.4.5. 2-Ethoxy-4,7-di(2-furyl)pyrazolo[1,5-a][1,3,5]triazine
(14a). Yellow solid, mp 156e157 ꢀC. IR (KBr):
n
1613, 1572, 1497 (C]
C, C]N) cmꢂ1. 1H NMR (CDCl3):
d 1.49 (t, 3H, CH3), 4.52 (q, 2H, CH2),
6.57 (s, 1H, H-8), 6.58 (dd, J¼1.8, 3.3 Hz, 1H, HB-4), 6.76 (dd, J¼1.8,
3.5 Hz, 1H, HA-4), 7.02 (d, J¼3.3 Hz, 1H, HB-5), 7.60 (d, J¼1.7 Hz, 1H,
HB-3), 7.84 (d, J¼3.5 Hz, 1H, HA-5), 8.52 (d, J¼1.8 Hz, 1H, HA-3). 13
C
NMR (CDCl3): d 14.3 (CH3), 64.1 (CH2), 90.8 (C-8), 109.6 (CB-3), 111.8
(CB-5), 113.2 (CB-4), 124.9 (CA-4), 143.0 (CA-2), 143.8 (CA-5), 146.2
(CB-2),147.9 (C-8a),148.1 (CA-3), 150.9 (C-7), 152.1 (C-4),160.1 (C-2).
MS (70 eV) m/z (%): 296 (27, Mþ), 281 (16),175 (38),119 (19), 94 (45),
63 (34), 39 (40), 29 (100). Anal. Calcd for C15H12N4O3: C, 60.81; H,
4.08; N, 18.91. Found: C, 60.83; H, 4.06; N, 18.93.
4.4.1. 2-Ethylthio-4,7-di(2-furyl)pyrazolo[1,5-a][1,3,5]triazine
(13a). Yellow solid, mp 148e149 ꢀC. IR (KBr):
n
1611, 1571, 1498
(C]C, C]N) cmꢂ1 1H NMR (CDCl3):
. d 1.48 (t, 3H, CH3), 3.26 (q,
2H, CH2), 6.58 (dd, J¼1.8, 3.3 Hz, 1H, HB-4), 6.65 (s, 1H, H-8),
6.77 (dd, J¼1.8, 3.5 Hz, 1H, HA-4), 7.04 (d, J¼3.3 Hz, 1H, HB-5),
7.61 (d, J¼1.8 Hz, 1H, HB-3), 7.86 (d, J¼1.5 Hz, 1H, HA-5), 8.52
4.4.6. 2-Ethoxy-4,7-di(2-thienyl)pyrazolo[1,5-a][1,3,5]triazine
(14b). Yellow solid, mp 167e168 ꢀC. IR (KBr):
n
1610, 1562, 1491
1.54 (t, 3H, CH3), 4.56 (q, 2H,
CH2), 6.56 (s, 1H, H-8), 7.17 (dd, J¼1.3, 3.8 Hz, 1H, HB-4), 7.34 (dd,
(C]C, C]N) cmꢂ1. 1H NMR (CDCl3):
d
(d, J¼3.5 Hz, 1H, HA-3). 13C NMR (CDCl3):
d 14.2 (CH3), 25.6

H. Insuasty et al. / Tetrahedron 68 (2012) 9384e9390
9389
J¼1.0, 4.0 Hz, 1H, HA-4), 7.46 (d, J¼3.8 Hz, 1H, HB-5), 7.65 (d,
J¼1.3 Hz, 1H, HB-3), 7.86 (d, J¼4.0 Hz, 1H, HA-5), 9.01 (d, J¼1.1 Hz,
7.51 (d, J¼2.8 Hz, 1H, HB-5), 7.63 (d, J¼4.8 Hz, 1H, HB-3), 8.07 (d,
J¼4.8 Hz, 1H, HA-5), 8.42 (d, J¼3.5 Hz, 1H, HA-3), 11.70 (s, 1H, exo-
cyclic NH-1), 13.04 (s, 1H, endocyclic NH-1), 13.31 (s, 1H, NH-3). 13C
1H, HA-3). 13C NMR (CDCl3):
d 14.4 (CH3), 64.2 (CH2), 90.7 (C-8),
127.0 (CB-3), 127.4 (CB-5), 127.9 (CB-4), 128.4 (CA-4), 132.2 (CA-2),
135.6 (CB-2), 136.0 (CA-5), 137.3 (CA-3), 150.4 (C-8a), 152.6 (C-7),
154.0 (C-4), 160.2 (C-2). MS (70 eV) m/z (%): 328 (100, Mþ), 313 (18),
284 (18), 191 (73), 134 (27), 110 (64), 69 (19), 29 (43). Anal. Calcd for
C15H12N4OS2: C, 54.86; H, 3.68; N, 17.06. Found: C, 54.89; H, 3.70; N,
17.08.
NMR (DMSO-d6): d 79.2 (C-4), 95.8 (CB-3), 124.8 (CB-5), 126.3 (CB-4),
128.2 (CA-4), 128.8 (CA-3), 131.0 (CA-2), 132.9 (CA-5), 135.5 (CB-2),
136.3 (C-5), 147.6 (C-3), 162.5 (C]S), 176.7 (C]O). MS (70 eV) m/z
(%): 334 (100, Mþ), 301 (26), 254 (30), 226 (28), 111 (59), 74 (33).
Anal. Calcd for C13H10N4OS3: C, 46.69; H, 3.01; N, 16.75. Found: C,
46.58; H, 2.92; N, 16.71.
4.4.7. 2-Ethoxy-4-(2-furyl)-7-(2-thienyl)pyrazolo[1,5-a][1,3,5]tri-
4.5.3. 1-(2-Furoyl)-3-(3-(2-thienyl)pyrazol-5-yl)thiourea
azine (14c). Yellow solid, mp 161e162 ꢀC. IR (KBr):
n
1612, 1576,
(15c). White solid, mp 214e215 ꢀC. IR (KBr):
n
3307 (NH), 1670 (C]
1503 (C]C, C]N) cmꢂ1. 1H NMR (CDCl3):
d
1.49 (t, 3H, CH3), 4.51 (q,
O), 1577, 1528 (C]C, C]N) cmꢂ1. 1H NMR (DMSO-d6):
d
6.78 (dd,
2H, CH2), 6.54 (s, 1H, H-8), 6.77 (dd, J¼1.6, 3.6 Hz, 1H, HA-4), 7.15
(dd, J¼5.0, 3.5 Hz, 1H, HB-4), 7.43 (d, J¼5.0 Hz, 1H, HB-5), 7.60 (d,
J¼3.8 Hz, 1H, HB-3), 7.83 (d, J¼3.6 Hz, 1H, HA-5), 8.51 (d, J¼1.6 Hz,
J¼1.8, 3.5 Hz,1H, HB-4), 7.16 (dd, J¼2.3, 4.3 Hz, 1H, HA-4), 7.29 (s, 1H,
H-4), 7.50 (d, J¼3.5 Hz, 1H, HB-5), 7.61 (d, J¼1.8 Hz, 1H, HB-3), 7.89
(d, J¼4.3 Hz, 1H, HA-5), 8.09 (d, J¼2.3 Hz, 1H, HA-3), 11.40 (s, 1H,
exocyclic NH-1), 12.92 (s, 1H, endocyclic NH-1), 13.32 (s, 1H, NH-3).
1H, HA-3). 13C NMR (CDCl3):
d 14.3 (CH3), 64.1 (CH2), 90.8 (C-8),
113.3 (CA-4), 124.9 (CA-3), 127.0 (CB-3), 127.3 (CB-5), 127.9 (CB-4),
135.5 (CB-2), 143.0 (C-4), 146.0 (CA-2), 148.1 (CA-5), 152.3 (C-8a),
154.1 (C-7), 160.1 (C-2). MS (70 eV) m/z (%): 312 (100, Mþ), 297 (28),
284 (18), 268 (25), 191 (98), 94 (60). Anal. Calcd for C15H12N4O2S: C,
57.68; H, 3.87; N, 17.94. Found: C, 57.65; H, 3.89; N, 17.96.
13C NMR (DMSO-d6):
d 95.7 (C-4), 112.7 (CB-3), 118.9 (CB-5), 124.8
(CB-4), 126.3 (CA-4), 128.1 (CA-3), 134.7 (CA-5), 138.1 (CA-2), 144.5
(CB-2), 148.6 (C-5), 158.0 (C-3), 163.3 (C]S), 176.9 (C]O). MS
(70 eV) m/z (%): 318 (98, Mþ), 282 (29), 176 (100), 111 (65), 74 (33).
Anal. Calcd for C13H10N4O2S2: C, 49.04; H, 3.17; N, 17.60. Found: C,
49.12; H, 3.28; N, 17.51.
4.4.8. 2-Ethoxy-7-(2-furyl)-4-(2-thienyl)pyrazolo[1,5-a][1,3,5]tri-
azine (14d). Yellow solid; mp 134e135 ꢀC. IR (KBr):
n
1596, 1537,
4.5.4. 1-(3-(2-Furyl)pyrazol-5-yl)-3-(2-thenoyl)thiourea
1489 (C]C, C]N) cmꢂ1. 1H NMR (CDCl3):
d
1.52 (t, 3H, CH3), 4.55 (q,
(15d). White solid, mp 218e219 ꢀC. IR (KBr):
n
3287 (NH),1675 (C]
2H, CH2), 6.58 (t, J¼2.8 Hz, 1H, HB-4), 6.58 (s, 1H, H-8), 7.06 (d,
J¼3.0 Hz, 1H, HB-5), 7.33 (t, J¼4.0 Hz, 1H, HA-4), 7.62 (d, J¼3.8 Hz,
1H, HB-3), 7.85 (d, J¼3.7 Hz, 1H, HA-5), 9.01 (d, J¼2.8 Hz, 1H, HA-3).
O), 1584, 1528 (C]C, C]N) cmꢂ1. 1H NMR (DMSO-d6):
d
6.64 (dd,
J¼1.5, 3.3 Hz, 1H, HB-4), 6.90 (d, J¼2.8 Hz, 1H, HB-5), 7.26 (t,
J¼4.3 Hz, 1H, HA-4), 7.36 (s, 1H, H-4), 7.79 (br s, 1H, HB-3), 8.07 (d,
J¼4.8 Hz, 1H, HA-5), 8.42 (d, J¼3.5 Hz, 1H, HA-3), 11.72 (s, 1H, exo-
cyclic NH-1), 13.06 (s, 1H, endocyclic NH-1), 13.36 (s, 1H, NH-3). 13C
13C NMR (CDCl3):
d 14.4 (CH3), 64.2 (CH2), 90.7 (C-8), 109.8 (CB-3),
111.8 (CB-5), 128.5 (CB-4), 132.2 (CB-2), 135.9 (CA-4), 137.3 (CA-5),
143.9 (CA-3), 148.0 (CA-2), 150.6 (C-4), 150.8 (C-2a), 152.3 (C-4),
160.1 (C-2). MS (70 eV) m/z (%): 312 (100, Mþ), 297 (22), 284 (19),
175 (44), 110 (65), 27 (32). Anal. Calcd for C15H12N4O2S: C, 57.68; H,
3.87; N, 17.94. Found: C, 55.71; H, 3.86; N, 17.85.
NMR (DMSO-d6): d 94.8 (C-4),107.1 (CB-3),111.8 (CB-5),128.7 (CB-4),
132.9 (CA-4), 133.6 (CA-3), 135.5 (CA-2), 136.4 (CA-5), 143.2 (CB-2),
144.3 (C-5), 147.5 (C-3), 162.5 (C]S), 176.8 (C]O). MS (70 eV) m/z
(%): 318 (100, Mþ), 176 (38), 192 (28), 129 (28), 111 (72), 74 (45).
Anal. Calcd for C13H10N4O2S2: C, 49.04; H, 3.17; N, 17.60. Found: C,
49.13; H, 3.13; N, 17.53.
4.5. Procedure for the synthesis of 1-hetaroyl-3-(3-(2-hetaryl)
pyrazol-5-yl)thioureas 15aed
4.6. Procedure for the synthesis of 2-ethyl-1-(3-(2-furyl)
pyrazol-5-yl)-3-(2-thenoyl)isothiourea 16d
To a solution of the proper hetaroyl isothiocyanates 7a,b
(0.02 mol) in acetonitrile (15 mL) (prepared from reaction of the
respective hetaroyl chlorides 6a,b and potassium thiocyanate) were
added the corresponding 5-aminopyrazoles 12a,b (0.02 mol) and
the reaction mixture was then heated under reflux for 30 min to
obtain the thiourea derivatives 15aed. Ice water was added to the
reaction mixture and the resulting solid was collected by filtration,
washed with cold water and ethanol, and finally dried at room
temperature.
A slight excess of sodium hydride (60% suspension in oil,
0.003 mol) was added to a solution of the 1-(3-(2-furyl)pyrazol-5-
yl)-3-(2-thenoyl)thiourea 15d (0.002 mol) in DMF (5 mL). The
mixture was stirred for 10 min at room temperature and then ethyl
bromide (0.004 mol) was dropped slowly and the stirring was
continued for a further 30 min to afford compound 16d. After di-
lution of the reaction mixture with cold water, the resulting solid
was collected by filtration, washed with n-hexane, and dried at
4.5.1. 1-(2-Furoyl)-3-(3-(2-furyl)pyrazol-5-yl)thiourea (15a). White
room temperature. White solid, 75% yield. IR (KBr):
n
1633 (C]O),
d 1.32 (t, 3H,
solid, mp 204e205 ꢀC. IR (KBr):
n
3304 (NH), 1673 (C]O), 1578,
1571, 1502 (C]C, C]N) cmꢂ1 1H NMR (DMSO-d6):
.
1530 (C]C, C]N) cmꢂ1. 1H NMR (DMSO-d6):
d
6.64 (t, J¼3.3 Hz,1H,
CH3), 3.10 (q, 2H, CH2), 6.43 (s, 1H, H-4), 6.63 (d, J¼3.3 Hz, 1H, HB-4),
6.88 (d, J¼3.7 Hz, 1H, HA-4), 7.25 (d, J¼2.4 Hz, 1H, HB-5), 7.79 (br s,
2H, HA-5 and HB-3), 8.04 (d, J¼3.7 Hz, 1H, HA-3), 12.01 (s, 1H,
endocyclic NH), 13.42 (s, 1H, exocyclic NH). MS (70 eV) m/z (%): 346
(100, Mþ), 317 (32), 206 (18), 134 (25), 111 (54). Anal. Calcd for
C15H14N4O2S2: C, 52.01; H, 4.07; N, 16.17. Found: C15H14N4O2S2: C,
52.13; H, 4.15; N, 16.12.
HB-4), 6.78 (t, J¼3.7 Hz, 1H, HA-4), 6.88 (d, J¼3.5 Hz, 1H, HB-5), 7.32
(s, 1H, H-4), 7.79 (br s, 1H, HB-3), 7.90 (d, J¼3.8 Hz, 1H, HA-5), 8.09
(br s,1H, HA-3),11.42 (s.1H, exocyclic NH-1),12.95 (s.1H, endocyclic
NH-1), 13.34 (s. 1H, NH-3). 13C NMR (DMSO-d6):
d 79.2 (C-4), 94.7
(CB-3), 99.5 (CB-5), 107.1 (CB-4), 107.1 (CA-4), 111.8 (CA-3), 112.7 (CA-
5), 118.9 (CA-2), 143.2 (CB-2), 144.5 (C-5), 148.6 (C-3), 158.0 (C]S),
176.8 (C]O). MS (70 eV) m/z (%): 302 (100, Mþ), 282 (22), 191 (20),
176 (46), 111 (46), 95 (67), 74 (22). Anal. Calcd for C13H10N4O3S: C,
51.65; H, 3.33; N, 18.53. Found: C, 51.52; H, 3.38; N, 18.59.
4.7. Procedure for the synthesis of 2-ethyl-1-(2-thenoyl)-3-(3-
(2-thienyl)pyrazol-5-yl)isothiourea 16b and 2-ethyl-1-(2-
thenoyl)-3-(3-(2-thienyl)pyrazol-5-yl)isourea 17b
4.5.2. 1-(2-Thenoyl)-3-(3-(2-thienyl)pyrazol-5-yl)thiourea
(15b). White solid, mp 220e221 ꢀC. IR (KBr):
n
3300 (NH), 1658
(C]O), 1599, 1530 (C]C, C]N) cmꢂ1. 1H NMR (DMSO-d6):
7.17 (t,
J¼3.3 Hz, 1H, HB-4), 7.27 (t, J¼3.4 Hz, 1H, HA-4), 7.32 (s, 1H, H-4),
A mixture of O,S-diethyl 2-thenoylimidothiocarbonate 10b
d
(0.015 mol)
and
5-amino-3-(2-thienyl)-1H-pyrazole
12b
(0.015 mol) was submitted to microwave irradiation in absence of

9390
H. Insuasty et al. / Tetrahedron 68 (2012) 9384e9390
solvent (maximum power 300 W for 3 min at 160 ꢀC). When fin-
ished (TLC control), the crude product was dissolved in chloroform
(3 mL) and purified by column chromatography on silica gel, using
a mixture of hexanes/ethyl acetate (3:1) as eluent. The first chro-
matographic fraction corresponded to compound 16b and the
second one to compound 17b.
Raboisson, P.; Schultz, D.; Lugnier, C.; Mathieu, R.; Bourguignon, J. J. Tetrahedron
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Lugnier, C.; Bourguignon, J. J. Eur. J. Med. Chem. 2008, 44, 816e829.
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19, 5689e5692.
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He, L.; Clarke, T.; Tivitmahaisoon, P.; Lelas, S.; Li, Y. W.; Heman, K.; Fitzgerald, L.;
Miller, K.; Zhang, G.; Marshall, A.; Krause, C.; McElroy, J.; Ward, K.; Shen, H.;
Wong, H.; Grossman, S.; Nemeth, G.; Zaczek, R.; Arneric, S. P.; Hartig, P.; Rob-
ertson, D.; Trainor, G. J. Med. Chem. 2009, 52, 3073e3083; (d) Gilligan, P. J.;
Clarke, T.; He, L.; Lelas, S.; Li, Y.-W.; Heman, K.; Fitzgerald, L.; Miller, K.; Zhang,
G.; Marshall, A.; Krause, C.; McElroy, J. F.; Ward, K.; Zeller, K.; Wong, H.; Bai, S.;
Saye, J.; Grossman, S.; Zaczek, R.; Arneric, S. P.; Hartig, P.; Robertson, D.; Trainor,
G. J. Med. Chem. 2009, 52, 3084e3092; (e) Broxer, S.; Fitzgerald, M.; Sfougga-
takis, C.; Defreese, J.; Barlow, E.; Powers, G.; Peddicord, M.; Su, B.-N.; Tai-Yuen,
Y.; Pathirana, C.; Sherbine, J. Org. Process Res. Dev. 2011, 15, 343e352; (f) Zuev,
D.; Mattson, R.; Huang, H.; Mattson, G.; Zueva, L.; Nielsen, J.; Kozlowski, E.;
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Hassan, A. E. A.; Abou-Elkhair, R. A. I.; Riordan, J. M.; Allan, P. W.; Parker, W. B.;
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7. Gillespie, R. J.; Cliffe, I. A.; Dawson, C. E.; Dourish, C. T.; Gaur, S.; Jordan, A. M.;
Knight, A. R.; Lerpiniere, J.; Misra, A.; Pratt, R. M.; Roffey, J.; Stratton, G. C.;
Upton, R.; Weiss, S. M.; Williamson, D. S. Bioorg. Med. Chem. Lett. 2008, 18,
2924e2929.
4.7.1. 2-Ethyl-1-(2-thenoyl)-3-(3-(2-thienyl)pyrazol-5-yl)isothiourea
(16b). White solid. IR (KBr):
n
1623 (C]O), 1570, 1497 (C]C, C]N)
cmꢂ1. 1H NMR (DMSO-d6):
d
1.33 (t, 3H, CH3), 3.18 (q, 2H, CH2), 6.43
(s, 1H, H-4), 7.19 (t, J¼4,3 Hz, 2H, HB-4 and HA-4), 7.50 (d, J¼4.5 Hz,
1H, HB-5), 7.63 (d, J¼2.8 Hz, 1H, HB-3), 7.79 (d, J¼5.0 Hz, 1H, HA-5),
7.85 (d, J¼3.3 Hz, 1H, HA-3), 11.95 (s, 1H, endocyclic NH), 13.32 (s,
1H, exocyclic NH). MS (70 eV) m/z (%): 362 (58, Mþ), 317 (34), 235
(27), 111 (100), 45 (19). Anal. Calcd for C15H14N4OS3: C, 49.70; H,
3.89; N, 15.46. Found: C, 49.75; H, 3.81; N, 15.40.
4.7.2. 2-Ethyl-1-(2-thenoyl)-3-(3-(2-thienyl)pyrazol-5-yl)isourea
(17b). White solid. IR (KBr):
n
1622 (C]O), 1564, 1490 (C]C, C]N)
cmꢂ1. 1H NMR (DMSO-d6):
d
1.43 (t, 3H, CH3), 4.60 (q, 2H, CH2), 6.51
(s, 1H, H-4), 7.19 (t, J¼4.0 Hz, 2H, HB-4 and HA-4), 7.49 (br s, 1H, HB-
5), 7.61 (d, J¼3.7 Hz, 1H, HB-3), 7.83 (br s, 2H, HA-5 and HA-3), 11.81
(s, 1H, endocyclic NH), 13.17 (s, 1H, exocyclic NH). 13C NMR (DMSO-
d6):
d 14.7 (CH3), 65.1 (CH2), 95.5 (C-4), 125.5 (CB-3), 126.8 (CB-5),
8. (a) Ongini, E.; Dionisotti, S.; Gessi, S.; Irenius, E.; Fredholm, B. B. Arch. Phar-
macol. 1999, 359, 7e10; (b) Vu, C. B.; Shields, P.; Peng, B.; Kumaravel, G.; Jin, X.;
Phadke, D.; Wang, J.; Engber, T.; Ayyub, E.; Petter, R. C. Bioorg. Med. Chem. Lett.
2004, 14, 4835e4838; (c) Peng, B.; Kumaravel, G.; Yao, G.; Sha, L.; Van Vlijmen,
H.; Bohnert, T.; Huang, C.; Vu, C. B.; Ensinger, C. L.; Chang, H.; Engber, T. M.;
Whalley, E.; Petter, R. C. J. Med. Chem. 2004, 47, 6218e6229; (d) Vu, C. B.; Pan,
D.; Kumaravel, G.; Smits, G.; Jin, X.; Phadke, D.; Engber, T.; Huang, C.; Reilly, J.;
Tam, S.; Grant, D.; Hetu, G.; Petter, R. C. J. Med. Chem. 2005, 48, 2009e2018; (e)
Carlsson, J.; Yoo, L.; Gao, Z. G.; Irwin, J.; Shoichet, B.; Jacobson, K. J. Med. Chem.
2010, 53, 3748e3755; (f) Federico, S.; Paoletta, S.; Cheong, S. L.; Pastorin, G.;
Cacciari, B.; Stragliotto, S.; Klotz, K. N.; Siegel, J.; Gao, Z. G.; Jacobson, K.; Moro,
S.; Spalluto, G. J. Med. Chem. 2011, 54, 877e889.
128.5 (CB-4), 128.7 (CA-4), 131.3 (CA-3), 132.3 (CA-5), 133.4 (CA-2),
137.9 (CB-2), 143.2 (C-5), 145.8 (C-3), 159.4 (C-2), 172.1 (C]O). MS
(70 eV) m/z (%): 346 (100, Mþ), 328 (27), 313 (18), 191 (19), 111 (25).
Anal. Calcd for C15H14N4O2S2: C, 52.01; H, 4.07; N, 16.17. Found: C,
52.12; H, 3.93; N, 16.21.
Acknowledgements
~
Authors thank COLCIENCIAS, Universidad de Narino, Uni-
ꢀ
9. (a) Insuasty, H.; Estrada, M.; Cortes, E.; Quiroga, J.; Insuasty, B.; Abonía, R.;
ꢀ
versidad del Valle, the Spanish ‘Consejería de Innovacion, Ciencia y
Nogueras, M.; Cobo, J. Tetrahedron Lett. 2006, 47, 5441e5443; (b) Insuasty, H.;
Estrada, M.; Cobo, J.; Low, J. N.; Glidewell, C. Acta Crystallogr., Sect. C 2006, 62,
ꢀ
Empresa, Junta de Andalucía’, and ‘Centro de Instrumentacion
ꢀ
ꢀ
Científico-Tecnica de la Universidad de Jaen’ for the financial
ꢀ
o122eo124; (c) Insuasty, H.; Mier, P.; Suarez, G.; Low, J. N.; Cobo, J.; Glidewell, C.
Acta Crystallogr., Sect. C 2008, 64, o27eo30; (d) Quiroga, J.; Trilleras, J.; Insuasty,
B.; Abonía, R.; Nogueras, M.; Marchal, A.; Cobo, J. Tetrahedron Lett. 2008, 49,
3257e3259; (e) Quiroga, J.; Portilla, J.; Abonía, R.; Insuasty, B.; Nogueras, M.;
Cobo, J. Tetrahedron Lett. 2008, 49, 6254e6256; (f) Quiroga, J.; Trilleras, J.;
Pantoja, D.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J. Tetrahedron Lett.
2010, 51, 4717e4719; (g) Quiroga, J.; Portillo, S.; Perez, A.; Galvez, J.; Abonía, R.;
Insuasty, B. Tetrahedron Lett. 2011, 52, 2664e2666.
support.
References and notes
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