Highly selective and efficient synthesis of 3-arylamino-substituted 5-aminopyrazole-4-carboxylates under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2017.01.028

An improved microwave-assisted method was developed for the preparation of ethyl 5-aminopyrazole carboxylates from ethyl 2-cyano-3-methylthioacrylates and hydrazine. It was shown that using microwave irradiation significantly reduced the reaction time and improved the process selectivity and yield. The reaction proved to be reproducible in different microwave reactors and on large scale, affording the desired products in high yields and purity. A representative library of 3-arylamino-substituted 5-aminopyrazole-4-carboxylates was successfully prepared to assess the scope of the method.

Full text of DOI:10.1016/j.tetlet.2017.01.028

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly selective and efficient synthesis of 3-arylamino-substituted
5-aminopyrazole-4-carboxylates under microwave irradiation
Felicia Phei Lin Lim a, Rowena Xin Yi Gan a, Anton V. Dolzhenko a,b,
⇑
a School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia
b School of Pharmacy, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved microwave-assisted method was developed for the preparation of ethyl 5-aminopyrazole
carboxylates from ethyl 2-cyano-3-methylthioacrylates and hydrazine. It was shown that using micro-
wave irradiation significantly reduced the reaction time and improved the process selectivity and yield.
The reaction proved to be reproducible in different microwave reactors and on large scale, affording the
desired products in high yields and purity. A representative library of 3-arylamino-substituted 5-
aminopyrazole-4-carboxylates was successfully prepared to assess the scope of the method.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 28 November 2016
Revised 27 December 2016
Accepted 10 January 2017
Available online xxxx
Keywords:
Microwave-assisted synthesis
Selectivity
Pyrazole
Hydrazine
Molecules constructed using the aminopyrazole skeleton have
attracted the significant interest of researchers due to their useful
medicinal properties. Aminopyrazoles were reported to possess
antiparasitic activity against Toxoplasma gondii1 and Plasmodium
falciparum.2 Potentially useful aminopyrazoles for the treatment
of lipid disorders, as well as highly potent and selective agonists
of the GPR109b receptor were also identified.3
The aminopyrazole scaffold was also successfully used for the
construction of various therapeutically important kinase inhibi-
tors. Thus, compounds exhibiting potential neuroprotective effects
through the inhibition of c-jun N-terminal kinase 34 and selectively
inhibiting mitogen-activated protein kinase 2,5 which plays a role
in autoimmune diseases, were developed. Recently, aminopyra-
zoles have been found to possess anticancer activity through inhi-
bition of cyclin-dependent kinase (CDK),6 p21-activated kinase7
and Rearranged during Transfection (RET) kinase.8
Compound 2 demonstrated significant cytotoxicity against the
Ehrlich ascites carcinoma cells,11 while compound 3 was found
to possess antibacterial properties.12
Aminopyrazoles have been extensively explored as useful
building blocks for more complex fused heterocyclic systems, such
as pyrazolopyridines, pyrazolopyrimidines, and pyrazolotri-
azines.13 Among 5-aminopyrazoles, their 4-cyano derivatives are
classical heterocyclic synthons, which have been well-described
in the literature and have gained a reputation as useful building
blocks for the synthesis of many pyrazole-fused heterocyclic sys-
tems.14 3-Amino-substituted 5-amino-4-cyanopyrazoles (6) have
been prepared using the straightforward reaction of 3-amino sub-
stituted 3-methylsulfanyl-2-cyanoacrylonitrile (5) with hydrazine
(Scheme 1).15 However, replacement of one of the cyano groups
of 5 with ethyl carboxylate would give 3-amino-substituted ethyl
2-cyano-3-methylthioacrylates (8), which possess both a nitrile
and an ester group competing for the nucleophile. Hence,
conducting a similar reaction of 8 with hydrazine would result in
two possible directions for pyrazole ring closure to give either
ethyl 5-aminopyrazole-4-carboxylates (9), 3-oxo-2,3-dihydro-1H-
pyrazole-4-carbonitriles (10) or a mixture of these two compounds
(Scheme 2).
3,5-Diaminopyrazoles have recently been reported as cyclin-
dependent kinase 9 (CDK9) inhibitors with the potential to treat
multiple myeloma and chronic lymphocytic leukaemia. The dia-
mine CAN508 (1)9 (Fig. 1) represents one of the first CDK inhibitors
with high selectivity towards CDK9.10 Interesting bioactive 3-ary-
lamino-substituted 5-aminopyrazoles have also been identified.
Reported synthetic procedures based on the reaction of 8 with
hydrazine under conventional heating are controversial.16,17 Initial
nucleophilic attack of hydrazine should result in the elimination of
methanethiol and subsequent intramolecular cyclization via
nucleophilic substitution occurs at the ester yielding pyrazole 10
⇑
Corresponding author at: School of Pharmacy, Monash University Malaysia,
Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia.
E-mail addresses: dolzhenkoav@gmail.com, anton.dolzhenko@monash.edu
(A.V. Dolzhenko).
http://dx.doi.org/10.1016/j.tetlet.2017.01.028
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lim F.P.L., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.01.028

2
F.P.L. Lim et al. / Tetrahedron Letters xxx (2017) xxx–xxx
N
NH
reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate (7) with ani-
line (Scheme 3).20 The structure of 8a was confirmed by NMR spec-
tra, particularly the downfield shifted signal (11.51 ppm in CDCl3)
of the NH proton involved in an intramolecular hydrogen bond
with the neighbouring ester group. The (E)-geometry of 8a was
also supported by 2D NOESY data. The cross peak observed in
the 2D NOESY spectrum of 7 between the signals of the ester group
and the methylthio groups, was absent in the spectrum of 8a.
Furthermore, single crystal X-ray data for similar compounds21
suggested the same geometry.
Initially, we attempted the reaction of 8a with hydrazine using
conventional heating at reflux in methanol. Analysis of the crude
material showed the presence of a mixture of products, with the
major product ethyl 5-amino-3-phenylaminopyrazole-4-carboxy-
late (9a) and minor product 2,3-dihydro-3-oxo-5-phenylaminopy-
razole-4-carbonitrile (10a) in a 7:3 ratio (Scheme 3). Under these
conditions, 9a was obtained in 53% yield.
H2N
NH2
N
N
1
CAN508
MeO
N
NH
O
N
N
OH
N
H
NH2
N
H
NH2
HN
HN
N
O
2
3
MeO
Me
Fig. 1. Selected bioactive 3,5-diaminopyrazoles.
(Pathway B).16 However, it was also reported that intramolecular
cyclization occurred with an alternative nucleophilic attack to
the electron deficient carbon of the cyano group affording 9
(Pathway A).17
Microwave technology has been demonstrated to speed up
reactions, often achieving good purity and product yield.18 We
decided to investigate the selectivity of the reaction between
amino-substituted ethyl 2-cyano-3-methylthioacrylates (8) and
hydrazine and explore the effect of microwave irradiation, which
in many cases has been reported to increase the selectivity of
chemical reactions.19
An attempt to carry out the reaction of 8a with hydrazine in
methanol under microwave irradiation at 160 °C for 10 min
afforded ethyl 5-amino-3-phenylaminopyrazole-4-carboxylate
(9a) as the major product in high yield (90%). The ring closure
showed almost exclusive presence of the desired 5-amino-3-
phenylaminopyrazole-4-carboxylate (9a) in the crude reaction
product; only trace amounts of side-product 10a were identified
by 1H NMR spectroscopy. The desired product 9a was easily iso-
lated in analytically pure form via recrystallization from methanol.
The ester group on the pyrazole ring remained intact as con-
firmed by the ethoxycarbonyl signals at 1.30 ppm and 4.24 ppm
in the 1H NMR spectra. In the 13C NMR spectra, the carbonyl group
signal appeared at 164.2 ppm. The deshielding effect of the
Following a previously reported method, ethyl 2-cyano-3-
methylthio-3-phenylaminoacrylate (8a) was prepared from the
NH2
N
N
N
N
N
N
N NH
R1
R2R1NH
HN
R1
MeS
MeS
MeS
R1
H2N NH2
NH2
N
R2
N
N
R2
R2
N
4
5
6
Scheme 1. Synthesis of 3-amino substituted 5-amino-4-cyanopyrazoles (6).
N NH
R1
Pathway A
Pathway B
Pathway A
R2
N
NH2
R2
N
R2
N
N
R1
MeS
N
R2R1NH
H2N NH2
O
OEt
MeS
MeS
R1
N
9
O
O
H2N NH
O
EtO
EtO
EtO
Pathway B
HN NH
R1
7
8
N
O
R2
N
10
Scheme 2. Pathways for pyrazole ring closure upon treatment of 3-amino-substituted 2-cyano-3-methylthioacrylates 8 with hydrazine.
N
N
N
NH
HN NH
MeS
MeS
MeS
i
ii
+
PhHN
NH2
PhHN
O
PhHN
OEt
O
O
EtO
O
OEt
N
8a
9a
7
10a
Scheme 3. Reagents and conditions: (i) PhNH2 (1 equiv.), MeOH, reflux, 12 h; (ii) N2H4 (1 equiv.), MeOH, reflux, 3 h (9a, 53% and 10a, 23%) or N2H4 (1 equiv.), MeOH,
microwave, 160 °C, 10 min (9a, 90% and 10a, trace).
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F.P.L. Lim et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
adjacent ester group resulted in an upfield shifted signal of the
pyrazole C-4 at 81.6 ppm. Additionally, the band at 1641 cmÀ1 in
the IR spectra corresponding to the carbonyl group, together with
no detectable nitrile band, supported the formation of 9a.
Changing the solvent in the microwave-assisted reaction of 8a
with hydrazine to acetonitrile or tetrahydrofuran had no signifi-
cant effect on the reaction outcome. The yield and selectivity of
the process were similar to those observed for the reaction con-
ducted in methanol.
To our satisfaction, increasing the scale of the microwave-
assisted reaction to 11.5 mmol under identical microwave irradia-
tion conditions led to the same high purity product and excellent
yield (97%).
Experiments were performed in triplicate and no significant dif-
ference was observed between results obtained using these three
instruments. Average yields obtained using Discover SP (CEM),
Monowave 450 (Anton Paar), and Initiator + (Biotage) were
90 0.9%, 87 0.5%, and 91 2.8%, respectively.
To test the scope of our newly developed method, a series of
3-arylamino substituted ethyl 2-cyano-3-methylthioacrylates (8)
was first prepared using the known reaction of ethyl 2-cyano-3,3-
bis(methylthio)acrylate (7) with various anilines.20 Using our
improved protocol, we obtained a library of 3-arylamino-substi-
tuted ethyl 5-aminopyrazole-4-carboxylates (9) in high yields (up
to 99%) and excellent selectivity (Table 1). Only trace amounts of
10 were detected in some of the crude reaction products. It should
be noted that the yields obtained with the microwave-assisted
method were higher compared to previously reported protocols
with a significant decrease in reaction time, requiring just 10 min
compared to the reported 3–6 h under conventional heating.16,17
The method was further validated using three different models of
microwave synthesizers: Discover SP (CEM), Monowave 450 (Anton
Paar), and Initiator+(Biotage). For all three systems, identical tem-
perature settings (160 °C) and reaction time (10 min) were used.
Table 1
Synthesis of 3-arylamino-substituted ethyl 5-aminopyrazole-4-carboxylates (9a-l).
N
N
N
NH
H2N NH2
MeS
MeS
Ar NH2
MeS
ArHN
NH2
MeOH, reflux
MeOH, MW, 160 °C, 10 min
ArHN
OEt
O
O
EtO
O
OEt
9
7
8
Product
Structure
Yield (%)a
Product
Structure
Yield (%)a
91
9a
90
9g
97b
N
NH
N NH
N
H
NH2
OEt
NH
N
H
NH2
F
O
O
OEt
9b
9c
9d
99
95
99
9h
9i
90
83
87
F
N
N
NH
N
H
NH2
Cl
N
NH2
H
O
OEt
O
OEt
Cl
N
NH
Cl
N
NH
N
H
NH2
OEt
N
NH2
OEt
H
O
O
9j
Me
N
NH
Me
N
NH
N
NH2
H
N
NH2
OEt
NH
H
O
OEt
O
9e
9f
99
96
9k
9l
70
99
N
NH
N
MeO
N
H
NH2
NH
N
H
NH2
MeO
MeO
O
OEt
O
OEt
F3CO
N
NH
N
N
NH2
N
NH2
H
H
O
OEt
O
OEt
a
Yield over two steps; Microwave-assisted step performed on a 1.5 mmol scale in MeOH (4 mL) using a Discover SP CEM microwave synthesizser.
Yield over two steps; Microwave-assisted step performed on a 11.5 mmol scale in MeOH (10 mL) using a Discover SP CEM microwave synthesizer.
b
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4
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Acknowledgements
This work is supported by the Ministry of Higher Education,
Malaysia under Fundamental Research Grant Scheme (FRGS) and
partially supported by a research grant from Gaia Science (M)
Sdn. Bhd. Technical support from Nexus Analytics Sdn. Bhd. and
Anton Paar Malaysia Sdn. Bhd. is also appreciated.
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associated with this article can be found, in the online version, at
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Please cite this article in press as: Lim F.P.L., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.01.028