A re-engineering approach: Synthesis of pyrazolo[1,2-a]pyrazoles and pyrano[2,3-c]pyrazoles via an isocyanide-based four-component reaction under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2016.02.051

A new protocol based on a re-engineering approach has been developed for the efficient synthesis of pyrazolo[1,2-a]pyrazoles and pyrano[2,3-c]pyrazoles via an isocyanide-based four-component reaction of dialkyl acetylenedicarboxylates, isocyanides, and et

Full text of DOI:10.1016/j.tetlet.2016.02.051

Accepted Manuscript
A Re-Engineering Approach: Synthesis of Pyrazolo[1,2-a]Pyrazoles and Pyra-
no[2,3-c]Pyrazoles via an Isocyanide-Based Four-Component Reaction under
Solvent-Free Conditions
Ahmad Shaabani, Heshmatollah Sepahvand, Mina Keramati Nejad
PII:
S0040-4039(16)30160-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.051
TETL 47326
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 December 2015
7 February 2016
12 February 2016
Please cite this article as: Shaabani, A., Sepahvand, H., Nejad, M.K., A Re-Engineering Approach: Synthesis of
Pyrazolo[1,2-a]Pyrazoles and Pyrano[2,3-c]Pyrazoles via an Isocyanide-Based Four-Component Reaction under
Solvent-Free Conditions, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.051
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Tetrahedron Letters
Tetrahedron Letters
A Re-Engineering Approach: Synthesis of Pyrazolo[1,2-a]Pyrazoles and
Pyrano[2,3-c]Pyrazoles via an Isocyanide-Based Four-Component
Reaction under Solvent-Free Conditions
Ahmad Shaabani,* Heshmatollah Sepahvand, Mina Keramati Nejad
Shahid Beheshti University, Faculty of Chemistry, P. O. Box 19396-4716, Tehran, Islamic Republic of Iran.
Abstract
A new protocol based on a re-engineering approach has been developed for the efficient synthesis of
pyrazolo[1,2-a]pyrazoles and pyrano[2,3-c]pyrazoles via an isocyanide-based four-component reaction of
dialkyl acetylenedicarboxylates, isocyanides and ethyl acetoacetate with hydrazine hydrate or
phenylhydrazine. The reactions were carried out under solvent- and catalyst-free conditions at mild
temperatures and short times in good yields.
Keywords: Re-engineering approach, Pyrazolo[1,2-a]pyrazoles, Pyrano[2,3-c]pyrazoles, Four-component
reaction, Solvent-free
Pyrazoles and their derivatives constitute an important class of natural and non-natural products,
many of which exhibit useful biological activities as pharmaceuticals and agrochemicals.1-7
Among such compounds, pyrazole fused heterocyclic derivatives are interesting due to their
pharmacological properties and clinical applications.8,9 They have been widely used as
antimicrobial, insecticidal, and anti-inflammatory compounds. In addition, pyrazolo[1,2-
a]pyrazole ring systems feature in biologically active compounds, some of which are active
bronchodilators, dopamine receptor antagonists active as gastric prokinetic agents, highly active
angiotensin-converting enzyme inhibitors and highly potent anti-hypertensives in vivo.
Moreover, some are also broad spectrum carbapenems active against aerobic and anaerobic
* Corresponding author. Tel.: +982129902800; e-mail: a-shaabani@sbu.ac.ir
2

Tetrahedron Letters
bacteria that could yield significant candidates for evaluation.10-12 Furthermore pyrano[2,3-
c]pyrazoles have shown molluscicidal activity and were identified as a screening hit for a Chk1
kinase inhibitor.13,14
Multi-component reactions (MCRs) are a useful synthetic strategy for the achievement of high
levels of diversity, as they allow three or more simple building blocks to be combined in
practical one-pot operations.15 Because of the unique reactivity of the isocyanide functional
group, isocyanide-based multi-component reactions (I-MCRs) are among the most versatile, in
terms of the number and variety of compounds that can be generated. Such considerations are of
particular importance in connection with the design and discovery of novel I-MCRs.16-19 In
recent years, the scientific community has devoted much effort to designing new isocyanide-
based multi-component cyclizations toward various heterocycles.20-23 Of particular interest to us
has been the exceptional reactivity of Huisgen 1,3-dipoles, generated in situ from the addition of
an isocyanide to electron-deficient alkynes, allowing the creation of complex and diverse drug-
like small molecules.24-26 In continuation of this project and our isocyanide-enabled
transformations, we herein describe a convenient and efficient synthesis of highly functionalized
pyrazolo[1,2-a]pyrazoles and fully substituted pyrano[2,3-c]pyrazoles via a four-component
reaction of an isocyanide, dialkyl acetylenedicarboxylate and ethyl acetoacetate with hydrazine
hydrate or phenyl hydrazine under solvent-free conditions at 70 °C (Scheme 1). From an
economic and environmental point of view, solvent-free reactions reduce waste and decrease
handling costs due to the simplification of the experimental procedure, work-up techniques, and
savings in labor compared to reactions utilizing solvents.27 These factors are especially important
during industrial production and are in agreement with the goals of green chemistry.28
Scheme 1. Synthesis of pyrazolo[1,2-a]pyrazoles and pyrano[2,3-c]pyrazoles via a four-component
reaction.
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Tetrahedron Letters
In our efforts to develop greener and more facile organic transformations, we have focused on
the four-component synthesis of pyrazolo[1,2-a]pyrazoles and pyrano[2,3-c]pyrazoles under
environmentally friendly conditions (Table 1). Initially, we chose the reaction of cyclohexyl
isocyanide 1, dimethyl acetylenedicarboxylate (DMAD) 2, and ethyl acetoacetate 3 with
hydrazine hydrate 4 as a model reaction for the synthesis of pyrazolo[1,2-a]pyrazoles. In our
efforts to optimize the reaction conditions, we ran the model reaction in water at different
temperatures. However, the reaction was unsuccessful in this case. The addition of an inorganic
or organic base gave the desired product in up to 25% yield. Additionally, this reaction was also
carried out in various organic solvents such as acetonitrile, acetone, ethyl acetate and ethanol.
The desired product was obtained in aprotic solvents, such as acetonitrile and acetone, at room
temperature in moderate yields after 12-24 h. Furthermore, the model reaction was successful
under solvent free conditions at different temperatures and the desired product was obtained in
excellent yields at 70 °C. The reaction of cyclohexyl isocyanide 1, DMAD 2, and ethyl
acetoacetate 3 with phenylhydrazine 4′ was selected as a model reaction for the synthesis of
pyrano[2,3-c]pyrazoles. Similarly, this reaction was carried out under solvent free conditions at
70 °C and provided an excellent yield of pyrano[2,3-c]pyrazole 6a (Table 1).
Table 1. Optimization of the reaction conditionsa
Entry
Solvent
Temperature (oC)
Time (h)
Catalyst (mol%)
Product
Yield (%)
Water
Water
Water
Water
Water
25
100
25
100
100
100
75
70
70
50
25
24
24
24
24
24
24
24
24
24
24
24
-
-
-
-
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
NaOH (100)
NaOH (100)
Et3N (100)
Piperidine (100)
trace
25
trace
trace
trace
48
70
76
30
Water
Ethanol
Ethyl acetate
Acetonitrile
Acetone
Solvent-free
-
-
-
-
-
10
11
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Tetrahedron Letters
Solvent-free
Solvent-free
70
70
3
2
-
-
94
97
12
13
5a
6a
aReaction conditions: cyclohexyl isocyanide (1 mmol), DMAD (1 mmol), ethyl acetoacetate (1 mmol), hydrazine
hydrate or phenylhydrazine (1 mmol).
We then applied the optimized reaction conditions to the synthesis of pyrazolo[1,2-a]pyrazole
5a-d and pyrano[2,3-c]pyrazole derivatives 6a-f using three different isocyanides: cyclohexyl,
tert-butyl and 1,1,3,3-tetramethyl-butyl isocyanides, and various dialkyl acetylenedicarboxylates
such as dimethyl and diethyl acetylenedicarboxylates. The results in Table 2 show that all
reactions proceeded smoothly to afford the desired pyrazolo[1,2-a]pyrazoles and pyrano[2,3-
c]pyrazoles in good to excellent yields. The structures of the products (5e and 5f) were deduced
by 1H NMR, 13C NMR, FTIR and elemental analysis.
Table 2. Synthesis of pyrazolo[1,2-a]pyrazole and pyrano[2,3-c]pyrazole derivativesa
Entry
R
R′
Product
Yield (%)b
Cyclohexyl
Cyclohexyl
tert-Butyl
tert-Butyl
Cyclohexyl
Methyl
Ethyl
Methyl
Ethyl
Methyl
Ethyl
Methyl
Ethyl
Methyl
Ethyl
94
92
90
89
97
94
96
92
87
84
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
Cyclohexyl
tert-Butyl
tert-Butyl
1,1,3,3-Tetramethyl-butyl
1,1,3,3-Tetramethyl-butyl
10
aReaction conditions: cyclohexyl isocyanide (1 mmol), DMAD (1 mmol), ethyl acetoacetate (1 mmol), hydrazine
hydrate or phenylhydrazine (1 mmol), solvent-free, 70 oC. bIsolated yield.
Although the mechanism of this reaction has not been established experimentally, it is reasonable
to assume that the fused heterocyclic systems (5a–f and 6e-f) result from initial formation of the
pyrazolone rings A or B. The process is continued by the addition of isocyanide to the acetylenic
5

Tetrahedron Letters
ester and subsequent protonation of the 1:1 adduct C by compound A or B, followed by attack of
the anion of the pyrazolone rings on the positively charged ions D to form ketenimines E or F.
The ketenimine intermediates can isomerize under the reaction conditions employed to produce
the fused heterocyclic systems 5a–f and 6e-f (Scheme 2).
Scheme 2. Possible mechanism for synthesis of pyrazolo[1,2-a]pyrazoles and pyrano[2,3-c]pyrazoles via
a four-component reaction.
In summary, we have developed an interesting 4-IMCR of dialkyl acetylenedicarboxylates,
isocyanides, and ethyl acetoacetate with hydrazine hydrate or phenylhydrazine providing
pyrazolo[1,2-a]pyrazoles and pyrano[2,3-c]pyrazoles under solvent-free conditions at mild
temperatures in good to excellent yields. This process is a straightforward approach for the
synthesis of the heterocyclic rings due to the change in selection of substrates which led to
simplification of the reaction procedure and solvent removal. The broad substrate scope and mild
reaction conditions of this reaction make it a useful and attractive process for the synthesis of a
library of these compounds. The potential uses of this route in synthetic and medicinal chemistry
may be significant, since the products share structural and functional group properties of
biologically active molecules.
Supplementary data
Experimental procedures, FTIR, 1H NMR, and 13C NMR spectra and also elemental analysis for
selected compounds are provided. This material is available at http://www.elsevier.com.
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Tetrahedron Letters
Supplementary data associated with this article can be found in online version, at
doi:10.1016/j.tet.2016.##.###.
Acknowledgments
We gratefully acknowledge financial support from the Iran National Science Foundation (INSF)
and Research Council of Shahid Beheshti University.
References
1
2
Lv, P.-C.; Li, H.-Q.; Sun, J.; Zhou, Y.; Zhu, H.-L. Bioorg. Med. Chem. 2010, 18, 4606.
Bonesi, M.; Loizzo, M. R.; Statti, G. A.; Michel, S.; Tillequin, F.; Menichini, F. Bioorg.
Med. Chem. Lett. 2010, 20, 1990.
3
4
5
Bondock, S.; Fadaly, W.; Metwally, M. A. Eur. J. Med. Chem. 2010, 45, 3692.
Barsoum, F. F.; Girgis, A. S. Eur. J. Med. Chem. 2009, 44, 2172.
El-Sabbagh, O. I.; Baraka, M. M.; Ibrahim, S. M.; Pannecouque, C.; Andrei, G.; Snoeck,
R.; Balzarini, J.; Rashad, A. A. Eur. J. Med. Chem. 2009, 44, 3746.
Abdel-Aziz, M.; Abuo-Rahma, G. E.-D. A.; Hassan, A. A. Eur. J. Med. Chem. 2009, 44,
3480.
6
7
8
Rosiere, C. E.; Grossman, M. I. Science 1951, 113, 651.
Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai, N.; Hiyama, Y.; Suzuki, K.;
Ito, H.; Terauchi, H.; Kawasaki, M. J. Med. Chem. 2004, 47, 3693.
Cali, P.; Nærum, L.; Mukhija, S.; Hjelmencrantz, A. Bioorg. Med. Chem. Lett. 2004, 14,
5997.
9
10
11
Zonouz, A. M.; Eskandari, I.; Khavasi, H. R. Tetrahedron Lett. 2012, 53, 5519.
Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jaeger, A.; El‐Mahrouky, S. F. Arch. Pharm.
2007, 340, 543.
12
Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson, A. G.; Surgenor, A. E.
Bioorg. Med. Chem. 2006, 14, 4792.
13
14
15
16
17
18
19
Fujimura, Y. S., Y. Nawata, Y. Matsunaga, I. J. Pharm. Soc. Jpn. 1986, 106, 1002.
Hadley, M.; King, F.; McRitchie, B.; Turner, D. Bioorg. Med. Chem. Lett. 1992, 2, 1293.
Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439.
Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
Ruijter, E.; Orru, R. V. Drug Discov. Today Technol. 2013, 10, e15.
Magedov, I.; Kornienko, A. Chem. Heterocycl. Compd. 2012, 1.
Kalinski, C.; Umkehrer, M.; Weber, L.; Kolb, J.; Burdack, C.; Ross, G. Mol. Divers.
2010, 14, 513.
20
21
22
23
Sadjadi, S.; Heravi, M. M. Tetrahedron 2011, 67, 2707.
Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Chem. Asian. J. 2010, 5, 2318.
Zhu, J. Eur. J. Org. Chem. 2003, 2003, 1133.
Nair, V.; Rajesh, C.; Vinod, A.; Bindu, S.; Sreekanth, A.; Mathen, J.; Balagopal, L. Acc.
Chem. Res.2003, 36, 899.
24
Shaabani, A.; Maleki, A.; Rezayan, A. H.; Sarvary, A. Mol. Divers. 2011, 15, 41.
7

Tetrahedron Letters
25
Adib, M.; Sayahi, M. H.; Aghaaliakbari, B.; Bijanzadeh, H. R. Tetrahedron 2005, 61,
3963.
26
27
Shaabani, A.; Sarvary, A.; Rezayan, A. H.; Keshipour, S. Tetrahedron 2009, 65, 3492.
Spaller, M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A. Curr. Opin. Chem. Biol. 1997, 1,
47.
28
Ballini, R. Eco-friendly synthesis of fine chemicals; Royal Society of Chemistry, 2009;
Vol. 3.
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Graphical Abstract
A Re-Engineering Approach: Synthesis of
Pyrazolo[1,2-a]Pyrazoles and Pyrano[2,3-c]Pyrazoles
via an Isocyanide-Based Four-Component Reaction under Solvent-Free Conditions
Ahmad Shaabani, Heshmatollah Sepahvand, Mina Keramati Nejad
Shahid Beheshti University, Faculty of Chemistry, P. O. Box 19396-4716, Tehran, Islamic Republic of Iran.
1