Ytterbium(III) perfluorooctanoate catalyzed one-pot, three-component synthesis of fully substituted pyrazoles under solvent-free conditions

Article abstract of DOI:10.1055/s-2008-1072766

A convenient one-pot synthesis of fully substituted pyrazoles via three-component condensations of phenylhydrazine, aldehydes, and 1,3-dicarbonyl compounds using ytterbium perfluorooctanoate [Yb(PFO)₃] as catalyst under solvent-free conditions is described. The reusable catalyst can be easily prepared and was efficient for the reaction. A possible mechanism is suggested. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072766

LETTER
1341
Ytterbium(III) Perfluorooctanoate Catalyzed One-Pot, Three-Component
Synthesis of Fully Substituted Pyrazoles under Solvent-Free Conditions
S
ynthesis of Fu
i
lly Substitute
S
d Pyrazoles un
h
der Solvent-
e
Free Condi
n
tions , Song Cao,* Nianjin Liu, Jingjing Wu, Longjie Zhu, Xuhong Qian*
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, P. R. of China
Fax +86(21)64252603; E-mail: scao@ecust.edu.cn; E-mail: xhqian@ecust.edu.cn
Received 20 February 2008
the 1,3-dipolar cycloaddition of diazo compounds with
Abstract: A convenient one-pot synthesis of fully substituted pyra-
alkynes.8 The most general and applicable method for the
zoles via three-component condensations of phenylhydrazine, alde-
synthesis of these compounds was the cyclization of 1,3-
hydes, and 1,3-dicarbonyl compounds using ytterbium
diketones with substituted hydrazines.9 The disadvantage
perfluorooctanoate [Yb(PFO)3] as catalyst under solvent-free con-
ditions is described. The reusable catalyst can be easily prepared of this method was that when unsymmetrical 1,3-dike-
and was efficient for the reaction. A possible mechanism is suggest-
tones were used, it usually gave mixtures of structural iso-
mers with generally poor selectivity.10 Although
ed.
Key words: pyrazole, solvent-free synthesis, three-component syn-
thesis, Yb(PFO)3, catalyst
extensive research efforts were continually directed at the
discovery of versatile protocols for the formation of pyra-
zole derivatives,11 there is only very limited research on
the synthesis of fully substituted pyrazoles.12 Therefore,
Fully substituted pyrazoles and their derivatives, target the development of simple, convenient, and practical pro-
molecules of the present work, have received much atten- cedures for the synthesis of fully substituted pyrazoles
tion because they exhibit useful pharmacological proper- continues to be a challenging endeavor.
ties. Appropriately functionalized pyrazoles have
Recently, multicomponent one-pot reactions have proven
emerged as HIV-1 reverse transcriptase inhibitors,1 sodi-
to be efficient and environmentally acceptable methods
um channel blockers,2 anti-inflammatory agents,3 and an-
compared to conventional linear-step synthesis. It is a
titumor agents.4 In pesticide chemistry, the significance of
powerful tool for the construction of novel, complex, and
fully substituted pyrazoles has been well recognized.
functionally dense heterocyclic molecules.
They were disclosed as broad-spectrum insecticides, fun-
The use of rare-earth compounds has also attracted tre-
mendous interest due to their unique catalytic activities,
low toxicity, stability, and easy handling.13 They are more
widely used as powerful replacements of the conventional
Lewis acid catalysts in various organic synthetical pro-
cesses.14 Among them, rare-earth perfluorooctanoate
[RE(PFO)3] has been shown to be a mild and highly effec-
tive catalyst for the Mannich reaction.15
gicides, and herbicides.5,6 For example, a new class of in-
secticide has been discovered recently, the anthranilic
diamides containing pyrazole ring, provide exceptional
control through action on a novel target, the ryanodine re-
ceptor (Figure 1). Furthermore, pyrazoles are not only of
interest as intermediates in chemical synthesis, but also as
efficient analytical reagents in the complexation of transi-
tion-metal ions.7
Herein, we describe a one-pot construction of fully substi-
tuted pyrazoles via ytterbium perfluorooctanoate
[Yb(PFO)3]-catalyzed coupling of aldehydes, phenylhy-
drazine, and 1,3-dicarbonyl compounds under solvent-
free conditions (Scheme 1).
In view of the importance of fully substituted pyrazole de-
rivatives, many methods for the synthesis of fully substi-
tuted pyrazoles were reported including the condensation
of hydrazonyl halides with b-dicarbonyl compounds and
CF3
Cl
N
C
O
N
H
O
N
N
Cl
N
Cl
N
NH
NH
N
Cl
N
N
O
H
O
Me
Cl
Me
insecticide
HIV-1 inhibitors
fungicide
Figure 1 Bioactive fully substituted pyrazoles
SYNLETT 2008, No. 9, pp 1341–1344
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072766; Art ID: W02908ST
© Georg Thieme Verlag Stuttgart · New York

1342
L. Shen et al.
LETTER
O
Yb(PFO)3 (10 mol%)
neat, 120 °C
N
R2
R1CHO
N
+
+
NHNH2
R1
R2
Scheme 1
Table 2 Optimization of Amount of Catalysta
The catalyst plays an important role in the formation of
fully substituted pyrazole. Benzaldehyde, phenylhydra-
zine, and ethyl acetoacetate were selected as representa-
tive substrates to investigate the reaction conditions. In
the absence of the catalyst, the reaction of benzaldehyde
and phenylhydrazine with ethyl acetoacetate could be car-
ried out but the product was obtained in very low yield af-
ter prolonged time. Therefore, our efforts focused on the
search for a suitable catalyst. Initially, hydrochloric acid
was chosen as the catalyst to carry out this reaction. As a
result, long reaction times were needed and low transfor-
mation rates were observed. Attempts with Lewis acid
ZnCl2 as a catalyst were successful. The reaction was
found to furnish with 56% yield within four hours. En-
couraged by this result, we turned our attention to various
Lewis acids. They were screened in our model reaction
(Table 1). Finally, we found that Yb(PFO)3 showed high
catalytic activity in terms of reaction time as well as yields
of the products.
Catalyst amount
(mol%)
Time (h)
Yield (%)b
0
2.5
5
>24
4
trace
54
3
65
10
15
1.5
1.5
75
77
a Benzaldehyde–phenylhydrazine–ethyl acetoacetate = 1:1:1.2.
b Yields were based on GC analysis.
solvents tested such as toluene, diethyl ether, dichlo-
romethane, and N,N-dimethylformamide, only toluene
gave moderate yield (51%) of the expected product. How-
ever, toluene is on the special health hazard substance list
because of its volatile nature, considerable toxicity, and
flammability. Recently, organic synthesis involving mul-
ticomponent reactions under solvent-free conditions has
attracted much attention,16 therefore we explored the pos-
sibility of obtaining the target compounds under solvent-
free conditions. We found that the reaction proceeded
smoothly in much shorter time at elevated temperature
and resulted in the formation of products in higher yield.
The effect of amount of catalyst on the conversion and
rate of the reaction was studied by varying the amount of
Yb(PFO)3 under solvent-free conditions (Table 2). It was
found that 10 mol% of Yb(PFO)3 was sufficient to carry
out this reaction smoothly. An increase in the amount of
Yb(PFO)3 to more than 10 mol% showed no substantial
improvement in the yield, whereas the yield was reduced
by decreasing the amount of Yb(PFO)3 to 2.5 mol%.
It is desirable to minimize the amount of waste for each
organic transformation. In this context, we recycled the
catalyst for subsequent runs. As ytterbium perfluorooc-
tanoate was insoluble in dichloromethane, it could be eas-
ily recovered by simple filtration. In our experiment, the
catalyst still could be recycled after three runs without
showing obvious loss of activity (with the yields of the
product 3a being 76%, 74%, 76%, respectively).
Using the same substrates, the effect of solvents on the
yields of pyrazoles was also investigated. Among various
Table 1 One-Pot Reaction of Benzaldehyde, Phenylhydrazine, and
Ethyl Acetoacetate Using Different Catalysts
Catalysta
none
Time (h)
Yield (%)b
>24
6
trace
25
In order to explain the formation of the pyrazoles, a sug-
gested mechanism for the Yb(PFO)3-catalyzed synthesis
of 3a is shown in Scheme 2. The key step was the cycliza-
tion of the hydrazone 4 with enol tautomer 5. The interme-
diates 5-hydroxylpyrazolidine 6, pyrazoline 7, as well as
benzylic radical 8 and benzylic cation 9, are unstable and
short lived, and rapidly converted into the desired product
3a via subsequent dehydration step and oxidative aroma-
tization. In an initial step, the Lewis acid Yb(PFO)3 may
play a dual role, to activate the hydrazone and to stabilize
the enol.17 The pyrazolidine and pyrazoline could not be
detected (TLC, GC-MS analyses) and obtained (separated
by column chromatography), regardless of whether the re-
action was carried out under air or nitrogen, although one
HCl
FeCl3·6H2O
NH4Cl
4.5
6
36
39
CAN
4
40
NiCl2·6H2O
ZnCl2
4
41
4
56
InCl3·4H2O
Yb(PFO)3
3
70
1.5
76
a The amount of 10 mol% of catalyst were used
b Yields were based on GC analysis.
c CAN: cerium(IV) ammonium nitrate.
Synlett 2008, No. 9, 1341–1344 © Thieme Stuttgart · New York

LETTER
Synthesis of Fully Substituted Pyrazoles under Solvent-Free Conditions
1343
(PFO)
O
Yb
3
H
O
O
+
O
Yb(PFO)3
O
O
5
4
..
N
cyclization
N
H
Yb(PFO)3
CHO
NHNH2
N
N
N
dehydration
H
oxidation
HN
HN
N
•
– H
•
OH
COOEt
COOEt
COOEt
6
7
8
radical
further oxidation
N
H
N
aromatization
– H+
N
N
COOEt
COOEt
9
3a
carbenium ion
Scheme 2
Table 3 One-Pot Synthesis of Different Pyrazole Derivatives Cata-
could not rule out that oxidation happened during the
workup process.18
lyzed by Yb(PFO)3 under Solvent-Free Conditions22–24
It may be pointed out here that aromatization was accom-
plished most easily by dehydration and oxidation if there
were already one or two double bonds in the five- and six-
membered rings. Several oxidants including atmospheric
oxygen can be used for the dehydrogenation of pyrazo-
lines to the corresponding pyrazoles.19 According to the
relevant literature,18,20 we suggested that air was responsi-
ble for the oxidative dehydrogenation under the condi-
tions of reaction. It is well known that the benzylic C–H
bond is relatively weak (DH0 = 87 kcal/mol) and its cleav-
age is favored. Therefore, air could abstract a benzylic hy-
drogen (it is also an allylic hydrogen) from the pyrazoline
to give benzyl radical. This radical could be further oxi-
dized to a carbenium ion, followed by loss of another pro-
ton to generate the aromatic ring.21
Compd
3a
R1
R2
Yield (%)a
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2Me
COMe
75
77
79
79
54
75
81
65
81
82
76
75
3b
3c
4-BrC6H4
3-(6-Cl-pyridinyl)
4-O2NC6H4
4-MeOC6H4
n-Pr
3d
3e
3f
3g
4-F3COC6H4
4-MeC6H4
4-F3COC6H4
2-F-5-MeC6H4
3-BrC6H4
4-F3COC6H4
3h
3i
To survey the generality and scope of the method, a vari-
ety of aldehydes and 1,3-dicarbonyl compounds were ex-
amined under the optimized conditions (Table 3). In all
cases, the three-component reaction proceeded smoothly
to give the corresponding fully substituted pyrazoles. The
presences of electron-withdrawing or electron-donating
substituents on the aromatic ring make some differences
to the yields of reaction. It seems that electron-donating
substituents on the aromatic ring are unfavorable for the
reaction, only a moderate yield was obtained with 4-meth-
3j
3k
3l
a Yields were based on GC analysis.
oxybenzaldehyde as the substrate. Heterocyclic aromatic
aldehyde reacted efficiently to give the corresponding ful-
ly substituted pyrazoles in good yield (Table 3, 3c). Ali-
phatic aldehyde was a good substrate as well (Table 3, 3f).
Synlett 2008, No. 9, 1341–1344 © Thieme Stuttgart · New York

1344
L. Shen et al.
LETTER
(11) (a) Conti, P.; Pinto, A.; Tamborini, L.; Rizzo, V.;
In addition, using methyl acetoacetate and acetyl acetone
instead of ethyl acetoacetate also gave good yields of the
expected products (Table 3, 3i–k).
De Micheli, C. Tetrahedron 2007, 63, 5554. (b) Heller, S.
T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675. (c) Aggarwal,
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5381. (d) Mohamed Ahmed, M. S.; Kobayashi, K.; Mori, A.
Org. Lett. 2005, 7, 4487.
In conclusion, a one-pot process to afford diversified fully
substituted pyrazoles via a three-component reaction of
aldehydes, phenylhydrazine, and 1,3-dicarbonyl com-
pounds using ytterbium perfluorooctanoate [Yb(PFO)3]
as catalyst under solvent-free conditions has been devel-
oped. Its relatively broad scope, operational simplicity,
and the recycle of the catalyst make it more attractive for
the diversity-oriented synthesis of these heterocycle li-
braries.
(12) (a) Suen, Y. F.; Hope, H.; Nantz, M. H.; Haddadin, M. J.;
Kurth, M. J. J. Org. Chem. 2005, 70, 8468. (b) Stauffer, S.
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Acknowledgment
(14) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.
Chem. Rev. 2002, 102, 2227.
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Financially supports from National Key Project for Basic Research
(2003CB114405), the National High Technology Research and De-
velopment Program of China (863 Program, 2006AA10A201), the
Shanghai Foundation of Science of Technology (073919107),
Shanghai Leading Academic Discipline Project (B507), and the
Shanghai Education Commission are kindly acknowledged.
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References and Notes
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(22) Experimental
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Nguyen, P.; Robledo, S.; Woodward, R. M.; Hogenkamp, D.
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Benzaldehyde and phenylhydrazine were freshly distilled
before used. The catalyst Yb(PFO)3 was prepared according
to ref. 15; other chemicals were purchased commercially and
used without further purification. Melting points were
recorded in open capillary using Büchi melting point B540
apparatus and were uncorrected. The 1H NMR and 13C NMR
spectra were recorded on a Bruker AM-400 spectrometer
(400 MHz and 100 MHz, respectively) using TMS as
internal standard. High-resolution mass spectra (HRMS)
were recorded under electron-impact conditions using a
MicroMass GCT CA 055 instrument.
(3) Dawood, K. M.; Abdel-Gawad, H.; Rageb, E. A.; Ellitheyc,
M.; Mohamed, H. A. Bioorg. Med. Chem. 2006, 14, 3672.
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Akritopoulou-Zanze, I.; Bousquet, P. F.; Bouska, J. J.;
Cunha, G. A.; Davidsen, S. K.; Diaz, G. J.; Djuric, S. W.;
Gasiecki, A. F.; Gintant, G. A.; Gracias, V. J.; Harris, C. M.;
Houseman, K. A.; Hutchins, C. W.; Johnson, E. F.; Li, H.;
Marcotte, P. A.; Martin, R. L.; Michaelides, M. R.; Nyein,
M.; Sowin, T. J.; Su, Z.; Tapang, P. H.; Xia, Z.; Zhang, H.
Q. J. Med. Chem. 2007, 50, 2011.
(23) General Procedure for the One-Pot Syntheses of
Pyrazoles
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To the appropriate aldehyde 1 (1 mmol), phenylhydrazine (1
mmol) was added dropwise. The mixture was stirred for 0.5
h, 1,3-dicarbonyl compound 2 (1.2 mmol) and Yb(PFO)3
(0.1 mmol) were added, the mixture was heated at 120 °C for
another 1–1.5 h. After the reaction was complete (monitored
by TLC), the mixture was cooled to r.t., CH2Cl2 (3 mL) was
added, the catalyst recovery was accomplished simply by
filtration and drying in air or under vacuum. The filtrate was
washed with sat. aq NaCl solution and dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to
leave the crude product which was recrystallized by EtOAc
and hexane to give the pure compound. If necessary, the
product was purified by chromatography over SiO2.
(24) Typical Data for a Representative Compound: Ethyl 1-
Phenyl-3-(4-bromophenyl)-5-methylpyrazole-4-
carboxylate (3b)
White solid, mp 60.8–61.3 °C. 1H NMR (400 MHz, CDCl3):
d = 7.58 (d, J = 8.4 Hz, 2 H), 7.52–7.51 (m, 4 H), 7.48–7.46
(m, 3 H), 4.27 (q, J = 7.2 Hz, 2 H), 2.59 (s, 3 H), 1.26 (t,
J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 163.9,
152.4, 145.0, 138.6, 132.1, 131.1, 130.8, 129.3, 128.8,
125.8, 122.5, 110.5, 60.1, 14.1, 12.8. HRMS: m/z calcd for
C19H17BrN2O2 [M+]: 384.0473; found: 384.0473.
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2833. (b) Budzisz, E.; Malecka, M.; Nawrot, B. Tetrahedron
2004, 60, 1749.
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