An efficient two-step synthesis of novel 2-amino-substituted pyrazolo[1,5-a][1,3,5]triazines

Article abstract of DOI:10.1016/j.tetlet.2013.01.073

A series of novel 2-amino-substituted pyrazolo[1,5-a][1,3,5]triazines were selectively synthesized by a two-step reaction between 5-amino-3-hetaryl-1H- pyrazoles and hetaroyl isothiocyanates with subsequent amination and cyclization promoted by the couple HgCl₂/TEA and DMF as solvent. This approach provided the title compounds in good to excellent yields and under mild reaction conditions. The structures of the new compounds were unambiguously established by spectroscopic and analytical techniques.

Full text of DOI:10.1016/j.tetlet.2013.01.073

Tetrahedron Letters 54 (2013) 1722–1725
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient two-step synthesis of novel 2-amino-substituted
pyrazolo[1,5-a][1,3,5]triazines
Henry Insuasty a, , Braulio Insuasty b, Edison Castro a,b, Jairo Quiroga b, Rodrigo Abonia b
⇑
a Heterocyclic Compounds Research Group, Department of Chemistry, Universidad de Nariño, A.A. 1175 Pasto, Colombia
b Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 2-amino-substituted pyrazolo[1,5-a][1,3,5]triazines were selectively synthesized by a
two-step reaction between 5-amino-3-hetaryl-1H-pyrazoles and hetaroyl isothiocyanates with
subsequent amination and cyclization promoted by the couple HgCl2/TEA and DMF as solvent. This
approach provided the title compounds in good to excellent yields and under mild reaction conditions.
The structures of the new compounds were unambiguously established by spectroscopic and analytical
techniques.
Received 20 December 2012
Revised 14 January 2013
Accepted 16 January 2013
Available online 24 January 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
5-Amino-1H-pyrazoles
Pyrazolo[1,5-a][1,3,5]triazines
Pyrazolylthioureas
Guanylation
Nucleophilic amination
Mercury(II) chloride
Introduction
one of the most used reactions to produce guanidines6 including
some examples of cyclic products such as monocyclic triazines,7
The pyrazolo[1,5-a][1,3,5]triazine core can be found in the
structure of different biologically active molecules such as antitu-
moral,1 antidepressant,2 anti-inflammatory,3 and antiviral agents.4
In particular, 2-amino-derivatives of this system are inhibitors of
protein kinase CK2 and cyclin-dependent kinases (CDKs), which
exhibit high antiproliferative activity in tumor cell lines and high
potential as cancer chemotherapy agents.1 Recently, it was re-
ported the activity of some 2-aminopyrazolotriazines as corticotro-
pin releasing factor CRF1 receptor antagonists, hence their
potential usefulness for the control and treatment of stress-related
diseases such as anxiety and depression.2e
pyridotriazines,8 and triazino-b-carbolines.9 However, to the best
of our knowledge its use for the synthesis of 2-amino-functional-
ized pyrazolo[1,5-a][1,3,5]triazines has not been reported. There-
fore, in connection with our current studies on the synthesis of
fused heterocycles containing the pyrazole moiety,10 we are
describing here a two-step reaction between 5-amino-3-hetaryl-
1H-pyrazoles and hetaroyl isothiocyanates with subsequent ami-
nation and cyclization process in the presence of HgCl2/TEA, as
an alternative approach to obtain the potentially bioactive 2-ami-
no-substituted pyrazolo[1,5-a][1,3,5]triazines in good to excellent
yields and under mild reaction conditions.
The insertion of an amino group into such interesting com-
pounds has usually been accomplished by a reaction of aromatic
nucleophilic substitution (SNAr) between the corresponding 2-
chloro-, 2-thiomethyl-, or 2-alkylsulfonylpyrazolotriazine deriva-
tives and the appropriate amine.1,2e,5 Several steps to prepare the
starting pyrazolotriazines are often required, causing an important
decrease in the overall yield of the target pyrazolotriazines. There-
fore, the development of alternative approaches for efficiently
introducing the amino group into the pyrazolotriazine skeleton
continues being a significant challenge.
Results and discussion
An efficient two-step sequence to selectively obtain novel 2-
aminopyrazolotriazines 5 via the appropriately substituted thio-
urea derivatives 3 was devised. In the first step, thioureas 3a–d
were prepared according to a procedure recently reported by our
group,10g by heating a solution of the corresponding hetaroyl iso-
thiocyanates 1a,b and the commercially available 5-aminopyraz-
oles 2a,b in acetonitrile under reflux for 30 min (Scheme 1). In
the second step, pyrazolylthioureas 3a–d were dissolved in DMF
and stirred at room temperature with dimethylamine 4a or mor-
pholine 4b for 30 min in the presence of HgCl2/TEA (1:2) equiv to
afford the desired 2-aminopyrazolotriazines 5a–h in excellent
yields (Scheme 1, Table 1).11
On the other hand, amination of thioureas promoted by the cou-
ple mercury(II) chloride and triethylamine (HgCl2/TEA) has been
⇑
Corresponding author. Tel.: +57 2 7313062; fax: +57 2 7313106.
E-mail address: hein@udenar.edu.co (H. Insuasty).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.073

H. Insuasty et al. / Tetrahedron Letters 54 (2013) 1722–1725
1723
when secondary amines 7a,b were used, the isolated products cor-
responded to pyrazolotriazines 8, 9. However, when primary
amines 7c–f were employed in the process, guanidines 10a,b and
11a,b12 were formed and they required further heating under re-
flux to produce the respective pyrazolotriazines 12a,b and 13a,b
(Scheme 2, Table 1). Indeed, products 12a,b and 13a,b were di-
rectly obtained by heating their starting reaction mixtures under
reflux for 60–120 min.11
Besides, it was found that the less nucleophilic p-nitroaniline 7d
did not react at room temperature with thiourea 3a, but after heat-
ing in DMF under reflux for 120 min, the reaction proceeded and
the isolated product corresponded to pyrazolotriazine 12b in 60%
yield (Scheme 2). This fact demonstrated that the reaction is also
feasible with amines of low nucleophilicity and that there is a clear
influence on both yield and reaction time, depending on the nucle-
ophilic character of the aromatic amine. Accordingly, the reaction
with the p-nitroaniline 7d produced a lower yield and required a
longer reaction time than their higher nucleophilic analogues p-
toluidine 4c (90%, 45 min) and aniline 7c (71%, 90 min), as shown
in Table 1.
Scheme 1. Synthesis of 2-amino-substituted pyrazolo[1,5-a][1,3,5]triazines 5 via
pyrazolylthioureas 3.
The structures of the obtained compounds 5–13 were unambig-
uously established by IR, 1H and 13C NMR spectroscopic
techniques, COSY 1H–1H, HSQC, and HMBC experiments, mass
spectrometry, and elemental analyses. Spectroscopic data are con-
sistent with the proposed structures 5–13, and the possible forma-
tion of the isomeric pyrazolo[3,4-d]pyrimidines 14 (Scheme 3),
was discarded because the expected absorption bands assignable
to the 1-NH stretching were not present in the IR spectra of the iso-
lated cyclic products. This characteristic was easily observed in
compounds 5a–h, 8, and 9, which contain a secondary amino group
as substituent. This finding is also in agreement with their 1H NMR
The reaction of thioureas 3a–d with p-toluidine 4c under the
same conditions used for amines 4a,b led to pyrazolylguanidines
6a–d12 instead of the expected pyrazolotriazines 5i–l. The thermal
cyclization of guanidines 6a–d in DMF under reflux afforded the
respective pyrazolotriazines 5i–l. It was also found that com-
pounds 5i–l may be directly obtained without the isolation of
intermediate guanidines 6a–d by heating the reaction mixture un-
der reflux for 45 min (Scheme 1, Table 1).11
In order to expand the scope of the approach described in
Scheme 1, pyrazolylthiourea 3a was reacted with several primary
and secondary amines 7a–f (Scheme 2) under the same conditions
employed for amines 4a–c in Scheme 1. It was newly found that
S
S
N
N
S
N
S
N
N
N
Table 1
N
N
N
N
Synthesis of 2-amino-substituted pyrazolotriazines 5, 8, 9, 12, and 13 via pyra-
zolylthioureas 3
8
9
Product Het1
Het2
NRR1
Mp (°C) Yielda,b (%)
S
3a
5a
2-Thienyl 2-Thienyl Dimethylamino
182
165
163
161
164
211
166
186
172
200
188
173
212
208
216
222
102
124
79
81
76
82
78
81
85
77
90
94
92
91
92
95
93
94
71
70
7c or 7d, i
7e or 7f, i
5b
5c
5d
5e
2-Furyl
2-Thienyl 2-Furyl
2-Furyl
2-Thienyl 2-Thienyl Morpholino
2-Furyl
Dimethylamino
Dimethylamino
N
NHHN
S
O
2-Thienyl Dimethylamino
S
N
H
S
S
11a,b
10a,b
5f
5g
5h
5i
2-Furyl
2-Thienyl 2-Furyl
2-Furyl
2-Thienyl 2-Thienyl p-Toluidino
2-Furyl
Morpholino
Morpholino
1
N
N HN
S
N
S
O
R
O
N HN
3
2-Thienyl Morpholino
5
N
H
HN
N
N
H
H
5j
5k
5l
2-Furyl
2-Thienyl 2-Furyl
2-Furyl
2-Thienyl 2-Thienyl p-Toluidino
2-Furyl
p-Toluidino
p-Toluidino
ii
2-Thienyl p-Toluidino
ii
R
R
6a
6b
6c
6d
8
2-Furyl
2-Thienyl 2-Furyl
2-Furyl
2-Thienyl 2-Thienyl Diethylamino
2-Thienyl 2-Thienyl Piperidino
2-Thienyl 2-Thienyl Anilino
2-Thienyl 2-Thienyl p-Nitroanilino
2-Thienyl 2-Thienyl Benzylamino
2-Thienyl 2-Thienyl Cyclohexylamino 186
2-Furyl
p-Toluidino
p-Toluidino
S
S
2-Thienyl p-Toluidino
N
N
S
N
N
S
N
N
R
9
N
H
N
N
N
10a
10b
11a
11b
12a
12b
13a
13b
198
89
H
c
c
13a, R = Benzyl
13b, R = Cyclohexyl
12a, R = H
12b, R = NO2
122
88
92
71
60
80
83
Reaction conditions: i) HgCl2/TEA, DMF, rt, 30 min; ii) DMF, reflux, 60-120 min;
iii) HgCl2/TEA, DMF, reflux, 60-120 min.
2-Thienyl 2-Thienyl Anilino
2-Thienyl 2-Thienyl p-Nitroanilino
2-Thienyl 2-Thienyl Benzylamino
213
215
160
NH
R
NH2
RNH2
HN(Et)2
2-Thienyl 2-Thienyl Cyclohexylamino 110
7a
7c, R = H
7d, R = NO2
7e, R = Benzyl
7f, R = Cyclohexyl
7b
a
The yields for products 5i–l, 12a,b and 13a,b correspond to their direct con-
version from 3.
b
Yields after isolation by column chromatography.
Not isolated.
Scheme 2. Synthesis of 2-amino-substituted pyrazolo[1,5-a][1,3,5]triazines 8, 9,
12, and 13.
c

1724
H. Insuasty et al. / Tetrahedron Letters 54 (2013) 1722–1725
Het1
NH
Het1
(Scheme 4), are efficiently promoted by the couple HgCl2/TEA,
Het2
Het2
3
4
3
which are indispensable for removing the sulfur atom and to trap
the two chloride ions, in the form of HgS and Et3NH+ClÀ,
respectively.
HgCl2/TEA,
DMF, rt or
5
O
4
5
N
HNRR1
2
N
1
2
1 N
N
R
N
6
N
N
R1
S
N
4 or 7
H
H
H
7
14
3
Conclusions
Scheme 3. Discarded isomeric pyrazolo[3,4-d]pyrimidines 14.
A practical two-step HgCl2-promoted synthesis of novel 2-ami-
no-substituted pyrazolo[1,5-a][1,3,5]triazines displaying good to
excellent yields (60–94%) and under mild reaction conditions has
been developed. The reaction is applicable to several N-het-
aroylpyrazolylthioureas and aromatic and aliphatic primary and
secondary amines. Various assays demonstrated that pyra-
zolylthioureas reacted with secondary amines under milder
reaction conditions and in shorter reaction times than primary
amines. Nevertheless, both primary and secondary amines gave
good results for the preparation of the title compounds. The biolog-
ical interest of the obtained pyrazolotriazines is under investiga-
tion and will be reported later.
spectra, where one of the most representative signals of the prod-
ucts 5, 8, 9, 12, and 13 corresponded to a singlet between 6.28 and
6.51 ppm assigned to the 8-H proton of their pyrazole moiety, con-
firming that the structures assigned to the isolated pyrazolotria-
zines are correct.
A possible mechanistic approach for the selective synthesis of
products 5, 8, 9, 12, and 13 is outlined in Scheme 4. Initially, the
N@C@S functionality of the starting materials 1 should suffer a
nucleophilic attack from 5-NH2 of pyrazole 2 leading to the forma-
tion of thioureas 3. Afterward, the HgCl2-promoted guanylation of
thioureas 3 with primary and secondary amines 4 or 7 should af-
ford pyrazolylguanidines 6, 10, or 11, presumably, passing through
intermediates 15 and 16. Finally, adducts 6, 10, or 11 should be
intramolecularly cyclized after the attack of 1-NH of pyrazole moi-
ety over the C@O functionality releasing a molecule of water and
generating the isolated pyrazolotriazines 5, 8, 9, 12, and 13. Previ-
ous reports showing a higher nucleophilicity of 1-NH than the C-4
in intermediates containing a similar pyrazole moiety,2e,10 support
the selective formation of pyrazolotriazines shown in Scheme 4
over their isomeric analogues 14 of Scheme 3.
In order to provide further evidence to support the mechanism
depicted in Scheme 4, the following attempts to produce the
guanylation and cyclization of the thiourea 3a with dimethylamine
4a, were performed. When the experiment was carried out in the
absence of the thiophile (HgCl2) and the base (TEA), no reaction
was detected after 24 h of stirring at room temperature. However,
after HgCl2/TEA (1:2) equiv were added the reaction took place in
just 30 min leading to the formation of the expected pyrazolotri-
azine 5a in 79% yield. In the other experiment, when the reaction
was performed only in the presence of HgCl2, product 5a was iso-
lated in just 18% yield along with unreacted starting materials.
These findings, enabled us to establish that the guanylation/cycli-
Acknowledgments
Authors wish to thank COLCIENCIAS, Universidad de Nariño,
and Universidad del Valle for financial support.
References and notes
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Het1
NEt3
H
N
N HN
1
N
O
HN
O
Het2
Het2
S
3
C
Het1
N
5
N
Cl
Cl
S
H2N
H
Hg
2
1
3
- Et3N.HCl
Het1
N
Het1
6
N
4
N
O
HN
Het2
N
N
Het2
R
2
N
S
Hg
N
R1
N
8
H
15
Cl
5 (or 8, 9, 12, 13)
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Nogueras, M.; Cobo, J. Tetrahedron Lett. 2006, 47, 5441–5443; (b) Insuasty, H.;
Estrada, M.; Cobo, J.; Low, J. N.; Glidewell, C. Acta Crystallogr., Sect. C 2006, 62,
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HNRR1
4 or 7
- H2O
NEt3
Het1
Het1
N
H
1
N
N
- HgS
- Et3N.HCl
O
N
HN
O
R
HN
Het2
Het2
3
R1RN
5
N
N
N
H
H
S
R1
16
Cl Hg
6 (or 10, 11)
Scheme 4. A possible mechanism for the formation of 2-amino-substituted
pyrazolotriazines 5, 8, 9, 12, and 13.

H. Insuasty et al. / Tetrahedron Letters 54 (2013) 1722–1725
1725
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Nogueras, M.; Cobo, J. Tetrahedron 2012, 68, 988–994; (g) Insuasty, H.;
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(CA-4), 129.5 (Cm), 132.8 (CA-2), 132.9 (CB-2), 134.9 (CA-5), 136.0 (Ci), 136.2
(Cp), 136.8 (CA-3), 149.0 (C-4), 152.5 (C-8a), 153.6 (C-7), 154.0 (C-2). MS
(70 eV) m/z (%): 389 (100, M+), 280 (41), 240 (15), 207 (13), 121 (16), 108 (24),
91 (36), 77 (10), 65 (22), 39 (17). Anal. Calcd for C20H15N5S2: C, 61.67; H, 3.88;
N, 17.98. Found: C, 61.73; H, 3.81; N, 17.82.
11. Procedure for the synthesis of 2-N-alkyl, 2-N-aryl, and 2-N,N-dialkylamino-
susbstitued pyrazolo[1,5-a][1,3,5]triazines 5, 8, 9, 12, and 13. Step 1:
Pyrazolylthioureas 3 were obtained according to the reported procedure.10g
12. Procedure for the synthesis of 2-N-alkyl, 2-N-aryl, and 2-N,N-dialkylamino-
substituted 1-hetaroyl-3-(2-hetaryl-1H-pyrazol-5-yl)guanidines 6, 10, and 11.
The same conditions used to synthesize compounds 5a–h, 8, and 9 were
employed to prepare guanidines 6, 10, and 11. These products were purified by
column chromatography on silica gel, using a mixture of hexanes/ethyl acetate
(3:2) as eluent. Data for 1-(2-thenoyl)-3-(2-thienyl-1H-pyrazol-5-yl)-2-(N-p-
tolyl)guanidine (6a). For describing the NMR data of compound 6a, the
heteroaromatic rings (Het1 and Het2) were denoted with the letters A and B,
Step 2: HgCl2 (0.02 mol) was added to
pyrazolylthioureas 3a–d (0.02 mol), the corresponding amine
a
solution of the respective
or
4
7
(0.02 mol), and triethylamine (0.04 mol) in DMF (5 mL). The reaction mixture
was then stirred at room temperature for 30 min to afford the target
pyrazolotriazines 5a–h, 8, and 9. Conventional heating of the reaction
mixture for 45–120 min was required for the synthesis of pyrazolotriazines
5i–l, 12a,b, and 13a,b. When the reaction finished (TCL control), the crude was
diluted with ethyl acetate and filtered through a Celite pad to remove the black
precipitate of HgS. Then, the filtrate was concentrated under vacuum and
purified by column chromatography on silica gel, using a mixture of hexanes/
respectively. White solid; mp 210–212 °C. IR (KBr):
m 3428, 3250 (NH), 1653
(C@O), 1572, 1474 (C@C, C@N) cmÀ1 1H NMR (400 MHz, DMSO-d6): d 2.34 (s,
.
3H, CH3), 6.55 (s, 1H, H-4), 7.16 (dd, J = 1.8, 3.2 Hz, 1H, HB-4), 7.19 (t, J = 4.3, 1H,
HA-4), 7.27 (d, J = 8.3 Hz, 2H, Ho), 7.54 (d, J = 3.3 Hz, 1H, HB-5), 7.60 (d,
J = 8.3 Hz, 2H, Hm), 7.63 (d, J = 3.3 Hz, 1H, HB-3), 7.69 (d, J = 4.8 Hz, 1H, HA-5),
7.75 (d, J = 3.8 Hz, 1H, HA-3), 10.75 (s, 1H, N-H p-tolyl), 12.46 (s, 1H, exocyclic
N–H), 13.37 (s, 1H, endocyclic N–H),. 13C NMR (100 MHz, DMSO-d6): d 20.5
(CH3), 93.2 (C-4), 122.4 (Cm), 125.6 (CB-5), 127.0 (CA-5), 127.9 (CB-4), 128.2
(CA-4), 129.2 (Co), 130.5 (Ci), 131.8 (Cp), 133.6 (CA-3), 134.8 (CB-3), 137.8 (CA-
2), 144.1 (CB-2), 147.8 (C-5), 154.0 (C-3), 163.1 (C-2), 171.4 (C@O). MS (70 eV)
m/z (%): 407 (12, M+), 389 (97), 280 (44), 240 (11), 207 (100), 193 (17), 147
(18), 133 (15), 121 (12), 108 (16), 91 (39), 73 (54), 65 (11), 44 (57), 39 (17).
Anal. Calcd for C20H17N5OS2: C, 58.95; H, 4.20; N, 17.19. Found: C, 58.67; H,
4.01; N, 17.35.
ethyl
acetate
(7:3)
as
eluent.
Data
for
4,7-di(2-thienyl)-2-p-
toluidinopyrazolo[1,5-a][1,3,5]triazine (5i). For describing the NMR data of
compound 5i, the heteroaromatic rings (Het1 and Het2) were denoted with the
letters A and B, respectively. Yellow solid; mp 170–172 °C. IR (KBr):
m 3425
(NH), 1604, 1516 (C@C, C@N) cmÀ1 1H NMR (400 MHz, CDCl3): d 2.36 (s, 3H,
.
CH3), 6.51 (s, 1H, H-8), 7.08 (d, J = 5.0 Hz, 1H, HB-5), 7.18 (t, J = 2.7 Hz, 1H, HB-
4), 7.23 (d, J = 8.7 Hz, 2H, Ho), 7.24 (s, 1H, exocyclic N–H), 7.32 (t, J = 3.8, 1H,
HA-4), 7.60 (d, J = 2.7 Hz, 1H, HB-3), 7.63 (d, J = 8.3 Hz, 2H, Hm), 7.75 (d,
J = 4.0 Hz, 1H, HA-5), 8.94 (d, J = 3.3 Hz, 1H, HA-3). 13C NMR (100 MHz, CDCl3): d
20.9 (CH3), 89.7 (C-8), 119.9 (Co), 126.7 (CB-5), 127.0 (CB-3), 127.8 (CB-4), 128.5