A one-pot, three-component aminotriazine annulation onto 5-aminopyrazole-4-carbonitriles under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2014.12.010

A one-pot, three-component, microwave-assisted reaction of 5-aminopyrazole-4-carbonitriles, triethyl orthoformate and cyanamide afforded novel 7-arylamino-substituted 4-aminopyrazolo[1,5-a][1,3,5]triazine-8-carbonitriles. The reaction proceeded in a chemo- and regioselective manner resulting in the successful amino-1,3,5-triazine annulation onto 5-aminopyrazole-4-carbonitriles to give 4-aminopyrazolo[1,5-a][1,3,5]triazine-8-carbonitriles. The operational simplicity of the method and high purity of the products, which can be isolated via simple filtration, make this approach attractive for the preparation of a library of compounds for drug discovery processes.

Full text of DOI:10.1016/j.tetlet.2014.12.010

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot, three-component aminotriazine annulation onto
5-aminopyrazole-4-carbonitriles under microwave irradiation q
Felicia Phei Lin Lim a, Giuseppe Luna a, Anton V. Dolzhenko a,b,
⇑
a School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot, three-component, microwave-assisted reaction of 5-aminopyrazole-4-carbonitriles, triethyl
orthoformate and cyanamide afforded novel 7-arylamino-substituted 4-aminopyrazolo[1,5-a][1,3,5]
triazine-8-carbonitriles. The reaction proceeded in a chemo- and regioselective manner resulting in the
successful amino-1,3,5-triazine annulation onto 5-aminopyrazole-4-carbonitriles to give 4-aminopyrazolo
[1,5-a][1,3,5]triazine-8-carbonitriles. The operational simplicity of the method and high purity of the
products, which can be isolated via simple filtration, make this approach attractive for the preparation
of a library of compounds for drug discovery processes.
Received 30 September 2014
Revised 6 November 2014
Accepted 3 December 2014
Available online xxxx
Keywords:
Triazine
Pyrazole
Ó 2014 Published by Elsevier Ltd.
Purine isostere
Multicomponent reaction
Microwave-assisted synthesis
The development of methods for the synthesis of pyrazolo[1,5-a]
[1,3,5]triazines started more than half a century ago2,3 and has
been particularly active recently.4 The main stimulus behind these
investigations has been the identification of many biologically
active compounds constructed on the basis of this heterocyclic sys-
tem. The pyrazolo[1,5-a][1,3,5]triazine scaffold has become a very
promising, from a medicinal chemistry perspective, 1,3,5-triazine-
based purine isostere.5 Amino substituents are common motifs in
many interesting bioactive pyrazolo[1,5-a][1,3,5]triazines. Repre-
sentative examples include the casein kinase II (CK2) inhibitor 1
treatment of obesity.10 Additionally, 4a showed synergistic activity
with levodopa in Parkinson’s disease therapy.11
Recently, we developed a method for the synthesis of 4-amino-
substituted pyrazolo[1,5-a][1,3,5]triazin-2-amines, among which,
4-arylamino-substituted compounds demonstrated promising bio-
logical activity.1 Herein, we report a one-pot, three-component
synthesis of pyrazolo[1,5-a][1,3,5]triazines possessing an arylami-
no group located on C-7 of the heterocyclic system.
Previously, we successfully achieved the aminotriazine
annulation onto 3-amino-substituted 1,2,4-triazole-5-amines via
the microwave-assisted reaction with triethyl orthoformate and
cyanamide.12 Starting from 5-amino-3-arylaminopyrazole-4-
carbonitriles 5, we propose a similar approach for the synthesis
of 4-amino-7-arylaminopyrazolo[1,5-a][1,3,5]triazine-8-carbonitr-
iles 6 (Scheme 1, Pathway A). However, replacement of the N-4
atom in the triazole ring with a carbon atom bearing a cyano group
might complicate the reaction due to the potential reactivity of the
nitrile. 5-Aminopyrazole-4-carbonitriles have been known for a
long time as useful building blocks for the synthesis of various het-
erocyclic compounds.13 Their reactions with triethyl orthoformate
or its analogues, followed by treatment of the resulting intermedi-
ate with amines have been used for the construction of pyrimidine
rings in the synthesis of bioactive pyrazolo[4,3-d]pyrimidines.14
Therefore, in the case of participation of the cyano group on
the pyrazole ring in our three-component reaction, we might
expect at least one alternative transformation or side reaction,
(Fig. 1), which also demonstrated good anticancer properties.6
A
cyano group at C-8 of 1 was also important for enzyme inhibition
as changing it to a similar in size ethyl group led to an almost four-
order decrease in the inhibitory activity. The phosphodiesterase
(PDE10) inhibitor 2, active in subnanomolar concentrations, dem-
onstrated potential for the development of a new type of antipsy-
chotic.7 Pexacerfont (3) is a potent antagonist of corticotrophin
releasing factor (CRF1)8 undergoing clinical trials as a therapeutic
agent for the treatment of anxiety-related alcohol craving and
stress-induced food craving.9 Being strong cannabinoid receptor
antagonists, compounds 4a,b have been proposed for the
q
Part 27 in the series ‘Fused heterocyclic systems with an s-triazine ring’, for part
26 see Ref. 1.
⇑
Corresponding author. Tel.: +60 3 5514 5867; fax: +60 3 5514 6364.
E-mail addresses: dolzhenkoav@gmail.com, anton.dolzhenko@monash.edu
(A.V. Dolzhenko).
http://dx.doi.org/10.1016/j.tetlet.2014.12.010
0040-4039/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Lim, F. P. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.12.010

2
F. P. L. Lim et al. / Tetrahedron Letters xxx (2014) xxx–xxx
OH
Me
An attempt to carry out the reaction of 5a with triethyl ortho-
formate and cyanamide under microwave irradiation (150 °C,
25 min) led to the formation of a mixture of several products.
The main component (75%) of this mixture was the desired product
6a, which could be isolated chromatographically. We were unable
to improve the reaction outcome on manipulating the reaction
time and temperature. Adding a base [diisopropylethylamine
(DIPEA)] to the reaction mixture also did not increase the yield of
6a, but allowed isolation of this compound exclusively by simple
filtration.
NH
N
HN
N
N
Me
N
N
N
N
N
NH
N
N
N
N
HN
F
2
IC50 = 0.085 nM (PDE10)
O
Me
1
The scope of this method was explored by the preparation of a
library of 7-arylamino-substituted 4-aminopyrazolo[1,5-a][1,3,5]
triazine-8-carbonitriles 6 (Table 1).17 Compounds 6 were obtained
in pure form under similar conditions. Electron-withdrawing and
electron-donating substituents on the arylamino moiety were
equally well tolerated and the yields for all compounds within
the series were comparable.
Ki = 0.26 nM (CK2)
R
Me
Me
NH
HN CONH2
N
N
Cl
N
N
Me
N
N
N
N
Me
N
Me
The cyano group on the pyrazole ring remained intact as
confirmed by
Me
a
band at 2209–2228 cmꢀ1 in the IR spectra
N
(stretching vibrations) and resonances at 112.8–113.2 ppm in
the 13C NMR spectra, therefore supporting the cyclization
according to Pathway A (Scheme 1) and the formation of com-
pounds 6.
MeO
Cl
4
3
, pexacerfont, BMS-562086
IC50 = 6.1 nM (CRF1)
R= Et (4a, CE 178253): Ki = 0.33 nM (CB1)
R= Me (4b, PF 095453): Ki = 0.48 nM (CB1)
The low-field shifted singlet (8.14–8.19 ppm) and two broad
signals at 8.33–8.48 ppm and 8.94–8.98 ppm in the 1H NMR spec-
tra of compounds 6 were attributed to the ring proton (H-2) and
the primary amino group protons at C-4 of the newly constructed
aminotriazine ring. The lone pair of electrons of an amino group
nitrogen on a 1,3,5-triazine ring possesses a high degree of delocal-
ization resulting in the substantial p-character of the orbital and
locking the amino group and its substituents in the plane of the
heterocyclic ring.18 This phenomenon was manifested in hindered
rotation around the CAN bond of the amino group and consequent
splitting of the 1H NMR signals of this group in spectra of unsym-
metrically substituted 1,3,5-triazines. In the case of compounds 6,
intramolecular hydrogen bonding with a nitrogen atom of the pyr-
azole ring could also contribute to the magnetic inequivalence of
Figure 1. Some biologically active amino-substituted pyrazolo[1,5-a][1,3,5]
triazines 1–4.
viz. the formation of pyrazolo[4,3-d]pyrimidines 7, which might
further undergo the Dimroth rearrangement to give products 8
(Scheme 1, Pathway B).
The starting 5-amino-3-arylaminopyrazole-4-carbonitriles (5)
were prepared using a known method,15 exploiting the reaction
of 3,3-bis(methylsulfanyl)-2-cyanoacrylonitrile (9)16 with various
anilines, followed by treatment of the resulting products 10 with
hydrazine thus affording 5-amino-3-arylaminopyrazole-4-carbo-
nitriles 5 (Scheme 2).
NH2
N
Pathway A
N
N
ArHN
N
N
NH
6
N
+
HC(OEt)3
+
H2N
N
ArHN
NH2
N
NH
N
NH
N
N
ArHN
ArHN
N
N
5
HN
N
N
HN
Pathway B
N
7
8
Scheme 1. Three-component reaction of 5-amino-3-arylaminopyrazole-4-carbonitriles 5 with triethyl orthoformate and cyanamide.
N
NH
MeS
N
SMe
N
ArHN
N
SMe
N
ArNH2
N2H4
ArHN
NH2
MeOH, reflux, 24 h
MeOH, reflux, 24 h
9
10
N
5
Ar = Ph (5a),
4-ClC6H4 (5d), 3-MeC6H4 (5g), 2-MeOC6H4 (5j), 4-EtOC6H4 (5m),
5e 5h 5k 5n
5b
4-FC6H4
(
), 3-BrC6H4
(
), 4-MeC6H4
(
), 4-MeOC 6H4
(
), 3-F3CC6H4
(
)
3-ClC6H4 (5c), 4-BrC6H4 (5f), 4-EtC6H4 (5i), 2-EtOC6H4 (5l),
Scheme 2. Synthesis of 5-amino-3-arylaminopyrazole-4-carbonitriles (5).
Please cite this article in press as: Lim, F. P. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.12.010

F. P. L. Lim et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 1
Synthesis of 7-arylamino-substituted 4-aminopyrazolo[1,5-a][1,3,5]triazine-8-carbonitriles 6
NH2
N
N
NH
N
N
µW, 150 °C, 25 min
DIPEA, MeOH
H2N
N
ArHN
+
+
HC(OEt)3
ArHN
NH2
N
N
N
5
6
Product
Structure
Yield (%)
Mp (°C)
Product
Structure
Me
Yield (%)
Mp (°C)
NH2
NH2
N
N
N
N
HN
N
295–296a
6h
44
307–309c
N
6a
49
N
HN
N
N
N
F
Et
NH2
N
NH2
N
N
N
296–298b
323–325c
318–320d
325–326b
325–327a
307–308a
6i
51
43
59
57
58
43
277–279c
276–278a
254–256e
290–292a
254–256e
336–338a
N
N
6b
6c
6d
6e
6f
51
55
57
47
54
48
HN
HN
N
N
N
N
NH2
NH2
N
Cl
Cl
N
N
N
N
N
N
HN
MeO HN
6j
N
N
N
N
N
MeO
NH2
N
NH2
N
N
N
N
N
6k
HN
HN
N
N
N
NH2
N
NH2
N
Br
Br
N
N
N
HN
EtO HN
6l
N
N
N
N
EtO
NH2
N
NH2
N
N
N
N
N
6m
6n
HN
HN
N
N
N
N
NH2
NH2
Me
F3C
N
N
N
N
N
N
HN
HN
6g
N
N
N
N
Recrystallization solvents: a MeCN, b DMF and H2O, c EtOH, d methoxyethanol, e pentanol.
the two protons of the amino group at C-4 and therefore splitting
of their signals in the 1H NMR spectra.
for the preparation of libraries of molecules for biological
investigations.
In summary, we have successfully developed
a one-pot,
multicomponent, microwave-assisted synthesis of hitherto
unknown 7-arylamino-substituted 4-aminopyrazolo[1,5-a][1,3,
5]triazine-8-carbonitriles 6. The developed approach utilizes
selective annulations of the aminotriazine ring onto 5-amino-3-
arylaminopyrazole-4-carbonitriles 5. The good synthetic accessi-
bility of pyrazoles 5 makes this method a very convenient tool
Acknowledgement
This work is supported under the Microwave-Enhanced Chem-
istry Grant program by the CEM Corporation, USA and Fundamen-
tal Research Grant Scheme (FRGS) by the Ministry of Higher
Education, Malaysia.
Please cite this article in press as: Lim, F. P. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.12.010

4
F. P. L. Lim et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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Supplementary data (these data include experimental details,
copies of 1H and 13C NMR spectra of the prepared compounds
and photographs of products and the corresponding reaction mix-
tures prior to and after applying microwave irradiation) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.12.010.
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4-carbonitrile
orthoformate (0.3 mL, 1.8 mmol) and DIPEA (87
5
(1 mmol), cyanamide (50.4 mg, 1.2 mmol), triethyl
L) in MeOH (2 mL) was
l
3. For
a review on pyrazolo[1,5-a][1,3,5]triazines, see: Dolzhenko, A. V.;
irradiated in a 10 mL seamless pressure vial using a CEM Discover microwave
synthesizer operating at maximum microwave power (up to 150 W) at 150 °C
for 25 min. After cooling, the precipitated product 6 was filtered, washed with
cold MeOH and recrystallised from a suitable solvent.
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Experimental data for some representative compounds:
4-Amino-8-cyano-7-phenylaminopyrazolo[1,5-a][1,3,5]triazine (6a): mp 295–
3
296 °C; 1H NMR (400 MHz, DMSO-d6): d 6.96 (1H, t, J = 7.3 Hz, H-40), 7.29
3
3
(2H, t, J = 8.0 Hz, H-30 and H-50), 7.88 (2H, d, J = 7.7 Hz, H-20 and H-60), 8.17
(1H, s, H-2), 8.42 (1H, br s, NH), 8.94 (1H, br s, NH), 9.44 (1H, s, NH); 13C NMR
(100 MHz, DMSO-d6): d 68.4 (C-8), 113.1 (C„N), 118.1 (C-20 and C-60), 121.2
(C-40), 128.7 (C-30 and C-50), 140.6 (C-10), 149.8 (C-8a), 152.9 (C-4), 154.8 (C-7),
157.1 (C-2); IR (ATR):
m 3388 (N-H), 3284 (N-H), 3048 (C-H), 2215 (C„N),
1684, 1590, 1555, 1512, 1466 cmꢀ1. Anal. Calcd for C12H9N7: C, 57.37; H, 3.61;
N, 39.02. Found: C, 57.25; H, 3.64; N, 38.88.
4-Amino-8-cyano-7-(4-fluorophenylamino)-pyrazolo[1,5-a][1,3,5]triazine (6b):
mp 296–298 °C; 1H NMR (400 MHz, DMSO-d6): d 7.10 (2H, dd, 3J = 8.9 Hz,
3JHF = 8.9 Hz, H-30 and H-50), 7.91 (2H, dd, 3J = 9.2 Hz, 4JHF = 4.8 Hz, H-20 and H-
60), 8.16 (1H, s, H-2), 8.45 (1H, br s, NH), 8.94 (1H, br s, NH), 9.50 (1H, s, NH);
5. For
a review on 1,3,5-triazine based purine isosteres, see: Lim, F. P. L.;
13C NMR (100 MHz, DMSO-d6):
d 68.2 (C-8), 113.0 (C„N), 115.0 (d,
Dolzhenko, A. V. Eur. J. Med. Chem. 2014, 85, 371–390.
3
2JCF = 21.9 Hz C-30 and C-50), 119.7 (d, JCF = 7.5 Hz C-20 and C-60), 137.0 (d,
4JCF = 2.1 Hz C-10), 149.8 (C-8a), 152.9 (C-4), 154.8 (C-7), 157.0 (d,
6. Nie, Z.; Perretta, C.; Erickson, P.; Margosiak, S.; Lu, J.; Almassy, R.; Lu, J.; Averill,
A.; Yagera, K. M.; Chu, S. Bioorg. Med. Chem. Lett. 2007, 17, 4191–4195.
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2,013,027,794, 2013; Chem. Abstr. 2013, 158, 349780.
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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.; Hartig, P.; Robertson, D.;
Trainor, G. J. Med. Chem. 2009, 52, 3084–3092.
1JCF = 237.8 Hz C-40), 157.2 (C-2); IR (ATR):
m
3381 (N-H), 3288 (N-H), 3063
(C-H), 2219 (C„N), 1683, 1595, 1561, 1502, 1462 cmꢀ1
Anal. Calcd for
12H8FN7: C, 53.53; H, 3.00; N, 36.42. Found: C, 53.38; H, 3.09; N, 36.28.
.
C
4-Amino-7-(3-chlorophenylamino)-8-cyanopyrazolo[1,5-a][1,3,5]triazine
(6c):
mp 323–325 °C; 1H NMR (400 MHz, DMSO-d6): d 7.00 (1H, ddd, 4J = 0.8 Hz,
4J = 2.0 Hz, 3J = 7.9 Hz, H-40), 7.31 (1H, t, 3J = 8.1 Hz, H-50), 7.79 (1H, t,
3
4J = 2.1 Hz, H-20), 8.00 (1H, ddd, 4J = 0.8 Hz, 4J = 2.2 Hz, J = 8.3 Hz, H-60), 8.18
9. (a) http://clinicaltrials.gov/show/NCT01656577; (b) http://clinicaltrials.gov/
show/NCT01227980.
(1H, s, H-2), 8.56 (1H, br s, NH), 8.97 (1H, br s, NH), 9.64 (1H, s, NH); 13C NMR
(100 MHz, DMSO-d6): d 68.7 (C-8), 112.9 (C„N), 116.6 (C-60), 117.2 (C-20),
120.9 (C-40), 130.4 (C-50), 133.1 (C-30), 142.0 (C-10), 149.9 (C-8a), 153.0 (C-4),
10. (a) Wagner, J. D.; Zhang, L.; Kavanagh, K.; Ward, G. M.; Chin, J. E.; Hadcock, J. R.;
Auerbach, B. J.; Harwood, H. J., Jr. J. Pharmacol. Exp. Ther. 2010, 335, 103–113;
(b) Hadcock, J. R.; Carpino, P. A.; Iredale, P. A.; Dow, R. L.; Gautreau, D.; Thiede,
L.; Kelly-Sullivan, D.; Lizano, J. S.; Liu, X.; Van Deusen, J.; Ward, K. M.; O’Connor,
R. E.; Black, S. C.; Griffith, D. A.; Scott, D. O. BMC Pharmacol. 2010, 10, 9.
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S.; Greenamyre, J. T.; Papa, S. M. J. Pharmacol. Exp. Ther. 2007, 323, 318–326.
154.4 (C-7), 157.3 (C-2); IR (ATR):
m 3360 (N-H), 3309 (N-H) 3098 (C-H), 2215
(C„N), 1656, 1589, 1553, 1521, 1469 cmꢀ1. Anal. Calcd for C12H8ClN7: C,
50.45; H, 2.82; N, 34.32. Found: C, 50.33; H, 2.94; N, 34.19.
18. Fernandez, M. I.; Oliva, J. M.; Armesto, X. L.; Canle, L. M.; Santaballa, J. A. Chem.
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Please cite this article in press as: Lim, F. P. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.12.010