Synthesis of pyranopyrazole derivatives by in situ generation of trityl carbocation under mild and neutral media

Article abstract of DOI:10.1007/s11164-016-2537-4

Abstract: In this work, synthesis of pyranopyrazole derivatives by the one-pot tandem four component condensation reaction of aryl aldehydes with ethyl acetoacetate, malononitrile, and hydrazine hydrate in the presence of Ph₃CCl at 60?°C under

Full text of DOI:10.1007/s11164-016-2537-4

Res Chem Intermed
DOI 10.1007/s11164-016-2537-4
Synthesis of pyranopyrazole derivatives by in situ
generation of trityl carbocation under mild and neutral
media
Ahmad Reza Moosavi-Zare1 Mohammad Ali Zolfigol2
•
•
Ahmad Mousavi-Tashar2
Received: 13 February 2016 / Accepted: 2 April 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract In this work, synthesis of pyranopyrazole derivatives by the one-pot tandem
four component condensation reaction of aryl aldehydes with ethyl acetoacetate,
malononitrile, and hydrazine hydrate in the presence of Ph3CCl at 60 °C under neutral,
mild, and solvent-free conditions has been reported. Mechanistically, it is interesting that
trityl chloride by in situ generation of trityl carbocation (Ph3C?) promotes the reaction.
Graphical Abstract
Keywords Pyranopyrazole Á Ph3CCl Á Tandem Á Solvent-free Á Neutral media
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2537-4)
contains supplementary material, which is available to authorized users.
&
&
Ahmad Reza Moosavi-Zare
moosavizare@yahoo.com
Mohammad Ali Zolfigol
mzolfigol@yahoo.com
1
2
Sayyed Jamaleddin Asadabadi University, Asadabad 6541835583, I. R. Iran
Faculty of Chemistry, Bu-Ali Sina University, Hamadan 6517838683, I. R. Iran
123

A. R. Moosavi-Zare et al.
Introduction
Multi-component reactions (MCR), are reactions in which three or more starting
materials react together to form a target product. In other words, multicomponent
reactions are reactions where more than two compounds combine in a sequential
manner to obtain highly selective products that remain majority of the atoms of the
starting material in the products [1–6].
Pyranopyrazoles are an interesting class of heterocyclic compounds due to their
important properties. They have been used as fungicidal [7], bactericidal [8],
vasodilatory [9], anticancer [10], pharmaceutical ingredient, and biodegradable
agrochemical [11] agents. Also, pyrano[2,3-c]pyrazoles have acted as potential
insecticidal [12] and molluscicidal agents [13, 14]. Some catalysts have been used
for this transformation, including imidazole [14], per-6-amino-b-cyclodextrin [15],
phase transfer catalyst (HDBAC) [16], organocatalyst (MDOs) [17], D,L-Proline
[18], hexa decyl tri methyl ammonium bromide (HTMAB) [19], disulfonic acid
imidazolium chloroaluminate {[Dsim]AlCl4} [20], gamma-Alumina [21], magnetic
Fe3O4 nanoparticles [22], and isonicotinic acid [23]. Therefore, considerable
attention has been concentrated on the development of new methods for the
preparation of these important compounds.
Triarylmethyl chlorides are inexpensive and can be prepared commercially or
easily synthesized by the known procedure [24]. The use of these compounds in the
absence of co-catalysts is really attractive. Accordingly, we have reported
triarylmethyl chlorides (Ar3CCl) as novel, neutral, and efficient organocatalysts
for the preparation of bis(indolyl)methanes [25], N-sulfonyl imines [26], 1-ami-
doalkyl-2-naphtols [27], 1-thioamido-alkyl-2-naphthols, 1-carbamato-alkyl-2-naph-
thols [28], 12-aryl-8,9,10,12-tetrahydrobenzo[a]-xanthen-11-ones [29], 4,40-
(arylmethylene)-bis (3-methyl-1-phenyl-1H-pyrazol-5-ol)s [30], a,a0-bis(arylidene)
cycloalkanones [31], 14-Aryl-14H-dibenzo[a,j]xanthenes [32], and 1,2,4,5-tetra-
substitutedimidazoles [4].
In continuation of our previous projects involving the applications of trityl
chloride as an organocatalyst in organic transformations, we have introduced
Ar3CCl for the preparation of pyranopyrazole derivatives by the one-pot multi-
component condensation reaction of arylaldehydes with ethyl acetoacetate,
malononitrile, and hydrazine hydrate (Scheme 1).
Scheme 1 The preparation of pyranopyrazole derivatives using TrCl
123

Synthesis of pyranopyrazole derivatives by in situ…
Experimental
General
All chemicals were purchased from Merck or Fluka Chemical Companies. The
known products were identified by comparison of their melting points and spectral
data with those reported in the literature. Progress of the reactions was monitored by
TLC using silica gel SIL G/UV 254 plates. Infrared spectra of products is recorded
by Perkin Elmer PE-1600-FTIR. Melting points were recorded on a Bu¨chi B-545
apparatus in open capillary tubes.
General procedure for the synthesis of pyranopyrazole derivatives
A mixture of aromatic aldehyde (2 mmol), malononitrile (0.132 g, 2 mmol), ethyl
acetoacetate (0.26 g, 2 mmol), hydrazine hydrate (2.5 mmol), and TrCl (10 mol%)
was added to a 10 mL round-bottomed flask connected to a reflux condenser and
stirred at 60 °C. After completion of the reaction as monitored by TLC, the reaction
mixture was cooled to room temperature; the solid residue (crude product) was
triturated by a mixture of ethanol and water (9:1) to give the pure product.
Results and discussion
To optimize the reaction conditions in terms of type of catalyst, amount of catalyst,
and temperature, condensation of hydrazine hydrate (2.5 mmol), ethyl acetoacetate
(2 mmol), malononitrile (2 mmol), and benzaldehyde (2 mmol) was selected as
model reaction and studied under different conditions.
In this regard, the model reaction was tested using different amounts of TrCl at
range of 25–80 °C under solvent-free conditions (Table 1). As can be seen in
Table 1, the reaction was efficiently performed using 10 mol% of the catalyst at
Table 1 Effect of different amounts of the catalyst and temperature on the reaction of hydrazine hydrate
(2.5 mmol) with ethyl acetoacetate (2 mmol), malononitrile (2 mmol) and benzaldehyde (2 mmol) in the
absence of solvent
Entry
Mol% of catalyst
Temp. (°C)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
a
10
10
10
10
5
25
50
60
80
60
60
60
150
90
60
70
90
55
70
20
64
80
74
73
71
75
7
15
Isolated yield
123

A. R. Moosavi-Zare et al.
60 °C, and the desired product was obtained in high yield within a short reaction
time (Table 1, entry 3).
To compare the efficiency of the solution versus solvent-free conditions, a
mixture of hydrazine hydrate (2.5 mmol) with ethyl acetoacetate (2 mmol),
malononitrile (2 mmol), and benzaldehyde (2 mmol), as model reaction in the
presence of TrCl was heated in some various solvents under reflux conditions. Low
yields of the product were isolated even after elongated reaction times. Using
solvents such as water, ethanol, ethyl acetate, and acetonitrile, the product was
obtained in low yields (Table 2).
To investigate the generality of TrCl in the synthesis of 6-amino-4-(4-
methoxyphenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazolesvari-
ous aryl aldehydes (including benzaldehyde and arylaldehydes possessing electron-
releasing substituents, electron-withdrawing substituents and halogens on their
aromatic ring) were reacted with hydrazine hydrate, ethyl acetoacetate and
malononitrile under the optimal reaction conditions to obtain the desired products
in high yields. The results are depicted in Table 3.
In a proposed mechanism reported by the previous literature (Scheme 2) [4,
27–32], arylaldehyde was activated by Ph3C? , and two activated forms of aldehyde
(I and II) were generated and converted together in a reversible reaction. I and II as
1
intermediates of the activated aldehyde were confirmed by IR, H NMR, and UV
spectra of the reaction mixture [4, 27–32]. Ethyl acetoacetate was activated by
Ph3C? and hydrazine attached to the carbonyl group of the activated ethyl
acetoacetate. Then, by the intramolecular nucleophillic attachment via another NH2
of hydrazine to the next carbonyl group of ethyl acetoacetate, 5-methyl-2,4-dihydro-
pyrazol-3-one was prepared. In the next step, by the reaction of malononitrile with I
and II, a cyanoolefin compound was synthesized. Finally, by the tandem Michael
addition–cyclization reaction of 5-methyl-2,4-dihydro-pyrazol-3-one with cyanoo-
lefin compound, the desired pyranopyrazole was prepared.
To confirm that in situ generated H? in this reaction condition could not catalyze
the reaction, the model reaction was examined in the presence of TrCl and pyridine
wherein the reaction was successfully carried out, and the product was obtained at
80 % within 60 min at 60 °C. In this reaction condition, pyridine as an acid
scavenger absorbed H? and produced pyridinium chloride. In another study, the
Table 2 The reaction of hydrazine hydrate (2.5 mmol) with ethyl acetoacetate (2 mmol), malononitrile
(2 mmol), and benzaldehyde (2 mmol) using TrCl (10 mol%) in different solvents (5 mL) under reflux
conditions
Entry
Solvent
Time (min)
Yielda (%)
1
2
3
4
a
H2O
100
60
45
20
59
66
Acetonitrile
Ethanol
CH2Cl2
80
70
Isolated yield
123

Synthesis of pyranopyrazole derivatives by in situ…
Table 3 The preparation of pyranopyrazole derivatives using TrCl as catalyst at 60 °C
Entry
Product
Time (min)
Yielda (%)
Mp. °C (lit.)
1
60
80
237–239 (264–266 [33])
2
3
4
40
50
50
85
88
83
241–242 (240–242 [20])
255 (261–263 [20])
230–232 (260–263 [20])
5
75
81
217 (222–224 [21])
6
7
8
40
80
50
82
45
84
218–220 (244–246 [20])
204–205 (209–211 [10])
254 (250–251 [10])
9
60
79
227–229 (233–234 [34])
123

A. R. Moosavi-Zare et al.
Table 3 continued
Entry
10
Product
Time (min)
45
Yielda (%)
82
Mp. °C (lit.)
(225–226 [10])
11
50
71
(211–212 [10])
12
13
45
50
90
82
255–257 (158–160 [33])
231 (233–234 [10])
14
35
50
79
75
221–224 (215–217 [34])
15
182–185 (232–234 [35])
a
Isolated yield
model reaction was tested in the presence of only pyridinium chloride wherein the
product was not produced in good yield after 100 min. These experiments clearly
confirmed that in situ prepared of H? in the presented conditions could not catalyze
the reaction.
123

Synthesis of pyranopyrazole derivatives by in situ…
Scheme 2 The plausible mechanism of synthesized pyranopyrazoles
Conclusion
In summary, we have reported the efficient synthesis of pyranopyrazole derivatives
using Ph3CCl at 60 °C under neutral, mild, and solvent-free conditions. The
promising points for the presented methodology are efficiency, generality, high
yield, low cost, cleaner reaction profile, ease of product isolation, simplicity, and
finally, agreement with the green chemistry protocols.
Acknowledgments The authors gratefully acknowledge support of this work by the Research Affairs
Office of Bu-Ali Sina University, Iran National Science Foundation (INSF) (The Grant of Allameh
Tabataba’i’s Award) and Sayyed Jamaleddin Asadabadi University.
References
1. A.R. Moosavi-Zare, M.A. Zolfigol, S. Farahmand, A. Zare, A.R. Pourali, R. Ayazi-Nasrabadi, Synlett
25, 193 (2014)
2. A.R. Moosavi-Zare, M.A. Zolfigol, O. Khaledian, V. Khakyzadeh, M.H. Beyzavi, H.G. Kruger,
Chem. Eng. J. 248, 122 (2014)
3. M.A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare, V. Khakyzadeh, Appl. Catal. A: Gen. 400,
70 (2011)
4. A.R. Moosavi-Zare, Z. Asgari, A. Zare, M.A. Zolfigol, M. Shekouhy, RSC Adv. 4, 60636 (2014)
5. A.R. Moosavi-Zare, M.A. Zolfigol, M. Zarei, A. Zare, V. Khakyzadeh, J. Mol. Liq. 186, 63 (2013)
6. A.R. Moosavi-Zare, M.A. Zolfigol, V. Khakyzadeh, C. Bottcher, M.H. Beyzavi, A. Zare, A. Hasa-
ninejad, R. Luque, J. Mater. Chem. A. 2, 770 (2014)
123

A. R. Moosavi-Zare et al.
7. A. Feurer, J. Luithle, S. Wirtz, G. Koenig, J. Stasch, E. Stahl, R. Schreiber, F. Wunder, D. Lang, PCT
Int. Aool. Wo 2004009589, Baye Healtheare Ag, Germany
8. M.N. Nasr, M.M. Gineinah, Arch. Pharm. Med. Chem. 335, 289 (2002)
9. V.K. Ahluwalia, A. Dahiya, V. Garg, Indian J. Chem. 36B, 88 (1997)
10. A.B. Atar, J.T. Kim, K.T. Lim, Y.T. Jeong, Synth. Commun. 44, 2679 (2014)
11. H. Junek, H. Aigner, Chem. Ber. 106, 914 (1973)
12. E.S. El-Tamany, F.A. El-Shahed, B.H. Mohamed, J. Serb. Chem. Soc. 64, 9 (1999)
13. F.M. Abdelrazek, P. Metz, N.H. Metwally, S.F. El-Mahrouky, Arch. Pharm. 339, 456 (2006)
14. A. Siddekha, A. Nizam, M.A. Pasha, Spectrochim. Acta B 81, 431 (2011)
15. K. Kanagaraj, K. Pitchumani, Tetrahedron Lett. 51, 3312 (2010)
16. K. Ablajan, W. Liju, A. Tuoheti, Y. Kelimu, Lett. Org. Chem. 9, 639 (2012)
17. S. Muramulla, C.-G. Zhao, Tetrahedron Lett. 52, 3905 (2011)
18. T.-S. Jin, A.-Q. Wang, Z.-L. Cheng, J.-S. Zhang, T.-S. Li, Synth. Commun. 35, 137 (2005)
19. S.-B. Guo, S.-X. Wang, J.-T. Li, Synth. Commun. 37, 2111 (2007)
20. A.R. Moosavi-Zare, M.A. Zolfigol, E. Noroozizadeh, M. Tavasoli, V. Khakyzadeh, A. Zare, New J.
Chem. 37, 4089 (2013)
21. H. Mecadon, M.R. Rohman, M. Rajbangshi, B. Myrboh, Tetrahedron Lett. 52, 2523 (2011)
22. M.A.E. Aleem, A.A. El-Remaily, Tetrahedron 70, 2971 (2014)
23. M.A. Zolfigol, M. Tavasoli, A.R. Moosavi-Zare, P. Moosavi, H.G. Kruger, M. Shiri, V. Khakyzadeh,
RSC Adv. 3, 25681 (2013)
24. W.E. Bachmann, Org. Synth. Coll. 3, 841 (1955)
25. A. Khalafi-Nezhad, A. Parhami, A. Zare, A.R. Moosavi Zare, A. Hasaninejad, F. Panahi, Synthesis
2008, 617 (2008)
26. A. Khalafi-Nezhad, A. Parhami, A. Zare, A. Nasrollahi Shirazi, A.R. Moosavi Zare, A. Hasaninejad,
Can. J. Chem. 86, 456 (2008)
27. A. Khazaei, M.A. Zolfigol, A.R. Moosavi-Zare, A. Zare, A. Parhami, A. Khalafi-Nezhad, Appl.
Catal. A Gen. 386, 179 (2010)
28. A. Khazaei, M.A. Zolfigol, A.R. Moosavi-Zare, F. Abi, A. Zare, H. Kaveh, V. Khakyzadeh, M.
Kazem-Rostami, A. Parhami, H. Torabi-Monfared, Tetrahedron 69, 212 (2013)
29. A. Khazaei, M.A. Zolfigol, A.R. Moosavi-Zare, A. Zare, M. Khojasteh, Z. Asgari, V. Khakyzadeh, A.
Khalafi-Nezhad, Catal. Commun. 20, 54 (2012)
30. A. Zare, M. Merajoddin, A.R. Moosavi-Zare, M. Zarei, Chin. J. Catal. 35, 85 (2014)
31. A. Zare, M. Merajoddin, A. Hasaninejad, A.R. Moosavi-Zare, V. Khakyzadeh, Comptes Rendus
Chim 16, 380 (2013)
32. A. Zare, M. Merajoddin, F. Abi, A.R. Moosavi-Zare, M. Mokhlesi, M.A. Zolfigol, Z. Asgari, V.
Khakyzadeh, A. Hasaninejad, A. Khalafi-Nezhad, A. Parhami, J. Chin. Chem. Soc. 59, 860 (2012)
33. M. Abd-El-Aleem, A.A. El-Remaily, Tetrahedron Lett. 70, 2971 (2014)
34. G. Brahmachari, B. Banerjee, Asian. J. Org. Chem. 5, 271 (2016)
35. P.B. Pawar, S.D. Jadhav, B.M. Patil, R.V. Shejwal, Suresh Patil. Arch. Appl. Sci. Res. 6, 150 (2014)
123