One-pot synthesis of trifluoromethyl-containing pyrazoles via sequential Yb(PFO)3-catalyzed three-component reaction and IBX-mediated oxidation

Article abstract of DOI:10.1055/s-0028-1087348

Fourteen trifluoromethyl-containing fully substituted pyrazoles were synthesized via Yb(PFO)₃-catalyzed three-component condensations of aromatic hydrazines, aldehydes, and ethyl trifluoroacetoacetate, followed by IBX-mediated oxidation of pyrazolones. A possible mechanism is suggested. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087348

3058
LETTER
One-Pot Synthesis of Trifluoromethyl-Containing Pyrazoles via Sequential
Yb(PFO)3-Catalyzed Three-Component Reaction and IBX-Mediated
Oxidation
S
ynthesis of
Tri
i
fluoromethyl
S
-
Containing P
h
yrazoles en,a Jian Zhang,a Song Cao,*a,b Jinlong Yu,a Nianjin Liu,a Jingjing Wu,a Xuhong Qian*a
a
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
Key Laboratory of Organofluorine Chemistry, Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Shanghai
200032, P. R. of China
b
Fax +86(21)64252603; E-mail: scao@ecust.edu.cn; E-mail: xhqian@ecust.edu.cn
Received 15 July 2008
blocks, the second is becoming an important and popular
tool to construct the fluoro-containing compounds.
Abstract: Fourteen trifluoromethyl-containing fully substituted
pyrazoles were synthesized via Yb(PFO)3-catalyzed three-compo-
nent condensations of aromatic hydrazines, aldehydes, and ethyl tri-
fluoroacetoacetate, followed by IBX-mediated oxidation of
pyrazolines. A possible mechanism is suggested.
Nowadays, multicomponent reactions have attracted great
interest due to the fact that the products are formed in a
single step and the diversity can be simply achieved by
varying the reacting components.7 When searching in the
literature, we found that there were only a few reports on
the use of fluoro-containing building block as one of the
components in the multicomponent reactions.8 Therefore,
we believe that the strategy, multicomponent reactions in-
cluding fluoro-containing building blocks (MCR-FBB),
will prove to be a powerful tool for the construction of flu-
oro-containing compounds. The fascinating scope of this
strategy lies in the straightforward assembly of complex
fluorinated compounds from simple and available fluoro-
containing building blocks as well as the high level of di-
versity that can be obtained by varying the fluoro-contain-
ing components taking part in the MCR.
Key words: trifluoromethyl-containing pyrazole, IBX, Yb(PFO)3,
three-component synthesis
Pyrazoles and, in particular, trifluoromethyl-containing
pyrazoles have been shown to be an increasingly impor-
tant class of biologically active compounds for the access
to agricultural chemicals and pharmaceutical products.1
For example, fluazolate is a new trifluoromethyl-contain-
ing phenylpyrazole herbicide, intended for pre-emergence
use to control a range of annual grasses and broad-leaved
weeds in winter wheat.2 Others can act as potential anti-
inflammatory drugs I3 or antihyperglycemic agents II4
(Figure 1).
Recently, much attention has been paid to the synthesis of
trifluoromethyl-containing pyrazoles starting from differ-
ent fluoro-containing building blocks.9 However, there
are few reports on the synthesis of trifluoromethyl-con-
taining fully substituted pyrazoles. Herein we describe the
application of this MCR-FBB strategy for the straightfor-
ward synthesis of fourteen trifluoromethyl-containing
fully substituted pyrazoles via sequential Yb(PFO)3-cata-
lyzed three-component condensations of aromatic hydra-
There are two main methods for the synthesis of fluorine-
containing organic compounds: the direct introduction of
fluorine replacing hydrogen5 and the usage of simple re-
active fluoro-containing building blocks.6 However, the
first is associated with several shortcomings such as harsh
reaction conditions, high toxicity, tedious work-up proce-
dures, and co-occurrence of several side reactions. With
the increasing number of new fluoro-containing building
F
CF3
N
N
O
MeS
OMe
F3C
N
O
N
N
F3C
Br
MeO2S
N
F
Cl
fluazolate
I
II
Figure 1 Bioactive trifluoromethyl-containing pyrazoles
SYNLETT 2008, No. 19, pp 3058–3062
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1087348; Art ID: W11408ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Trifluoromethyl-Containing Pyrazoles
3059
R2
N
N
Me
R1
O
CO2Et
COOEt
R3
3
Yb(PFO)3
+
neat, 120 °C
R1CHO
R2NHNH2
R2
R2
1
2
N
N
IBX
N
N
CF3
CO2Et
CF3
R1
R1
CO2Et
5a–n
4
5a
5d
5g
5j
R
1 = Ph, R2 = Ph
5b R1 = 4-CF3OC6H4, R2 = Ph
5c R1 = 4-MeC6H4 , R2 = Ph
R
R
1 = 4-CNC6H4, R2 = Ph
1 = Me2CHCH2, R2 = Ph
5e
5h
5k
R
R
R
1 = 3-(6-Clpyridinyl), R2 = Ph
1 = Me2CH, R2 = Ph
1 = 4-BrC6H4, R2 = 4-FC6H4
5f
5i
5l
R
1 = MeCH2CH2, R2 = Ph
R
R
1 = MeCH2, R2 = Ph
1 = 4-CF3OC6H4, R2 = 4-MeC6H4
R
1 = Ph, R2 = 4-FC6H4
5m R1 = Ph, R2 = 4-MeC6H4
5n R1 = MeCH2CH2, R2 = 4-MeC6H4
Scheme 1
zines, aldehydes, and ethyl trifluoroacetoacetate followed pling constant of 3.6 Hz due to coupling with Ha, whereas
by IBX-mediated oxidation (Scheme 1, R3 = CF3).
Ha appeared as quadruplet of doublets (qd, d = 5.05 ppm),
indicating ortho coupling between the proton Ha and Hb
(3JHaHb = 3.6 Hz) and ortho coupling between the proton
Ha and the fluoro atom (3JHaF = 6.8 Hz). In the 13C NMR
spectrum of 4a, C-5 (d = 65.6 ppm) was split into a qua-
druplet because of coupling with CF3. The coupling con-
stant (2JC–F) was 31 Hz. The CF3 group resonated at d =
124.4 ppm and was split into a quartet with 1JC–F = 281 Hz
due to one-bond C–F coupling. The signal from C-4 atom
was a doublet at d = 53.1 ppm, indicating that it is a satu-
rated carbon in the pyrazoline ring.
In our preceding paper, we briefly reported a novel ap-
proach to fully substituted pyrazoles via three-component
condensations of phenylhydrazine, aldehydes, and ethyl
acetoacetate using ytterbium perfluorooctanoate
[Yb(PFO)3] as catalyst under solvent-free conditions
(Scheme 1, R3 = Me).10 To extend our previous work, we
try to prepare trifluoromethyl-containing pyrazole by the
replacement of ethyl acetoacetate with a simple and avail-
able trifluoromethyl-containing building block, ethyl tri-
fluoroacetoacetate. But this reaction only afforded an
unexpected product – pyrazoline 4 in moderate to good Moreover, heteronuclear (1H–13C) correlation further con-
yield, whereas the anticipated trifluoromethyl-containing firmed the conclusions drawn from the 1H and 13C NMR,
pyrazole 5 was not obtained. Therefore, our initial efforts and clearly showed coupling between the Ha (d = 5.05
were directed toward isolating two representative inter- ppm) and C-5 (d = 65.6 ppm) and the Hb (d = 4.50 ppm)
mediates 4a (Figure 2) and 4f and determination of their and C-4 (d = 53.1 ppm). The determination of the position
structures by 1H NMR, 13C NMR, 19F NMR spectroscopy of hydrogen atom in the pyrazoline ring should be helpful
and HRMS studies.
to understand the mechanism of the reaction.
The position of hydrogen atom in the pyrazoline ring of 4a After the confirmation of the structure of the product, we
was also identified on the basis of the 1H NMR, 13C NMR, then envisaged the transformation of the pyrazoline to the
and HMQC (two-dimensional heteronuclear multiple corresponding pyrazoles by simply adding a supplemen-
quantum coherence) spectrum of 4a (see Supporting In- tary oxidant in one-pot process without any purification of
formation).
the crude pyrazoline intermediates 4. Although a variety
of oxidants, such as DDQ (2,3-dichloro-5,6-dicyano-1,4-
benzoquinone),11 Pd/C,12 Zr(NO3)4,13 cobalt soap of fatty
acids,14 MnO2,15 trichloroisocyanuric acid16 and 4-(p-
chloro)phenyl-1,2,4-triazole-3,5-dione,17 can be used to
oxide pyrazoline, as far as current one-pot reaction system
is concerned, a suitable oxidant should be properly
screened. Our next efforts focused on the search of a prac-
tical oxidant. To achieve this projected transformation,
the oxidant has to be stable enough at present reaction
temperature (120 °C) and be compatible with the solvent-
free conditions. Thus, benzaldehyde, phenylhydrazine,
and ethyl trifluoroacetoacetate were chosen as model
compounds to accomplish the one-pot, three component
In the 1H NMR spectrum of 4a, the proton of pyrazoline
ring Hb appeared at d = 4.50 ppm, as a doublet with a cou-
1N
Ha
2
N
CF3
5
4
3
CO2Et
Hb
4a
Figure 2 Structure of 4a
Synlett 2008, No. 19, 3058–3062 © Thieme Stuttgart · New York

3060
L. Shen et al.
LETTER
O
O
F3C
O
H
+
H
Yb(PFO)3
cyclization
Yb(PFO)3
N
N
[1,3-shift ]
N
CF3
N
HN
N
+
CF3
OH
CO2Et
CF3
+
H
H
CO2Et
CO2Et
CHO
NHNH2
2a
7
6
1a
8
N
– H+
N
IBX
N
N
CF3
H
CF3
aromatization
H
CO2Et
CO2Et
4a
5a
Scheme 2
and aromatic hydrazines 2. In the case of aliphatic alde-
hydes, the reaction proceeded efficiently giving the corre-
sponding pyrazoles in good yield. Aromatic aldehydes
produced only moderate yield of pyrazoles irrespective of
electronic effects. However, heterocyclic aromatic alde-
hyde (such as 5e) yielded only 40% of the desired product.
When furan aldehyde and thiophene aldehyde were used,
few products were observed. The substituted phenylhy-
drazine having electron-donating group on the aromatic
moiety is favorable for the reaction and afforded pyra-
zoles in good yield.
Table 1 One-Pot Reaction of Benzaldehyde, Phenylhydrazine, and
Ethyl Trifluoroacetoacetate Using Different Oxidants
Entry
Oxidant
H2O2
CANb
MnO2
PCC
Oxidant (equiv)
Yield (%)a
–
1
2
3
4
5
10
2
15.3
10
2.5
1.5
30.1
50.5
IBX
54.5
A mechanism for the formation of 523,24 is outlined in
Scheme 2. Unlike previously proposed mechanisms in-
volving the reaction of the phenylhydrazines, aldehydes,
and ethyl acetoacetate10 and known mechanisms of the
condensation of substituted hydrazine with ethyl acetoac-
etate (or ethyl trifluoroacetoacetate),19 a novel intermedi-
ate, pyrazoline 4,20–22 can be isolated in moderate to good
yield. The successful isolation of 4 can provide a lot of in-
sight into the mechanism of the reaction. The 5-hydroxyl
pyrazolidine 6, which is formed from the cyclization of
hydrazone with enol tautomer of ethyl trifluoroacetoace-
tate, is converted by the Lewis acid to the carbenium ion
7. Because of the strong electronic-withdrawing effect of
the trifluoromethyl group, this intermediate is unstable
and rapidly undergoes a 1,3-proton migration to form rel-
atively stable benzyl carbenium ion 8, followed by loss of
another proton to generate pyrazoline 4. This key interme-
diate can be further oxidized and subsequent aromatized
to afford the desired product in the presence of IBX.
a Yields were based on GC analysis.
b CAN: ceric (IV) ammonium nitrate.
process that involves first cyclization, followed by oxida-
tive aromatization. Several oxidants were used to aroma-
tize the pyrazoline. The results are summarized in
Table 1.
Among various oxidants tested, both PCC and IBX gave
moderate yield (ca. 50%) of the expected product in the
one-pot procedure. Pyridinium chlorochromate (PCC), a
chromium-based oxidant, is useful in the research labora-
tory, but its large-scale use generates toxic heavy-metal
waste product. It is not all eco-friendly and often entail se-
vere environment pollution during the process of waste
disposal. Even worse, compared with IBX, nearly twice
the amount of PCC was required. On the other hand, as a
safe, economical, and environmentally friendly oxidizing
agent, IBX has attracted increasing interest in organic
synthesis in recent years.18 It is proved that IBX is a ver-
satile oxidizing agent for synthetic organic chemistry.
Therefore, we used it as oxidant to perform the aromatiza-
tion of the pyrazoline.
In summary, a novel one-pot, three-component synthesis
of trifluoromethyl-containing pyrazoles via sequential
Yb(PFO)3-catalyzed cyclization followed by IBX-medi-
ated oxidation is described. The combination of multi-
component reactions and fluoro-containing building-
To investigate the generality of this novel one-pot reac-
tion, we applied this protocol to a variety of aldehydes 1,
Synlett 2008, No. 19, 3058–3062 © Thieme Stuttgart · New York

LETTER
Synthesis of Trifluoromethyl-Containing Pyrazoles
3061
(14) Shah, J. N.; Shah, C. K. J. Org. Chem. 1978, 43, 1266.
(15) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem.
Res. 2005, 38, 851.
block strategy provide an efficient and practical method to
the access of fully substituted trifluoromethyl-containing
pyrazoles as well as a useful trifluoromethyl-containing
pyrazoline synthon.
(16) Zolfigol, M. A.; Azarifar, D.; Maleki, B. Tetrahedron Lett.
2004, 45, 2181.
(17) Zolfigol, M. A.; Azarifar, D.; Mallakpour, S.;
Mohammadpoor-Baltork, I.; Forghaniha, A.; Maleki, B.;
Abdollahi-Alibeik, M. Tetrahedron Lett. 2006, 47, 833.
(18) (a) Wirth, T. Angew. Chem. Int. Ed. 2001, 40, 2812.
(b) Zhdankin, V. V. Curr. Org. Synth. 2005, 2, 121.
(c) Mazitschek, R.; Mülbaier, M.; Giannis, A. Angew. Chem.
Int. Ed. 2002, 41, 4059. (d) Ngouansavanh, T.; Zhu, J.
Angew. Chem. Int. Ed. 2007, 46, 5775.
(19) (a) Dinoiu, V.; Lü, J. J. Serb. Chem. Soc. 2006, 71, 323.
(b) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008,
49, 397. (c) Gilbert, A. M.; Bursavich, M. G.; Lombardi, S.;
Georgiadis, K. E.; Reifenberg, E.; Flannery, C. R.; Morris,
E. A. Bioorg. Med. Chem. Lett. 2007, 17, 1189.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financially supports from the National High Technology Research
and Development Program of China (863 Program,
2006AA10A201), the Shanghai Foundation of Science of Techno-
logy (073919107), Shanghai Leading Academic Discipline Project
(B507), National Key Project for Basic Research (2003CB114405),
and the Shanghai Education Commission are kindly acknowledged.
(20) Experimental
All chemicals were purchased commercially and used
without further purification. Melting points were measured
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.
The 19F NMR and HMQC spectra were obtained using a
References and Notes
(1) (a) Zhang, X.; Li, X.; Allan, G. F.; Sbriscia, T.; Linton, O.;
Lundeen, S. G.; Sui, Z. J. Med. Chem. 2007, 50, 3857.
(b) Lahm, G. P.; Selby, T. P.; Freudenberger, J. H.;
Stevenson, T. M.; Myers, B. J.; Seburyamo, G.; Smith,
B. K.; Flexner, L.; Clark, C. E.; Cordova, D. Bioorg. Med.
Chem. Lett. 2005, 15, 4898. (c) Mozziconacci, J.; Arnoult,
E.; Bernard, P.; Do, Q. T.; Marot, C.; Morin-Allory, L.
J. Med. Chem. 2005, 48, 3857. (d) Harald, W.; Camilla, C.;
Josef, E.; Clemens, L.; Hans, T. WO 2006037632, 2006;
Chem. Abstr. 2006, 144, 364543.
Bruker Avance-500 spectrometer (470 MHz), and the 19
F
NMR spectra were measured with external CF3CO2H as the
standard. High-resolution mass spectra (HRMS) were
recorded under electron-impact conditions using a
MicroMass GCT CA 055 instrument.
(21) General Procedure for the One-Pot Synthesis of
Trifluoromethyl-Substituted Pyrazolines
(2) Blair, A. M.; Jones, P. A.; Ingle, R. H.; Tillett, N. D.; Hague,
T. J. Agric. Sci. 2002, 139, 385.
(3) Lee, L. F. US 5401765, 1995; Chem. Abstr. 1995, 123:
83360.
(4) Kees, K. L.; Fitzgerald, J. J.; Steiner, K. E.; Mattes, J. F.;
Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med.
Chem. 1996, 39, 3920.
Aldehydes 1 (1 mmol) and aromatic hydrazines 2 (1 mmol)
were stirred for 20 min before ethyl trifluoroacetoacetate
(2.5 mmol) and Yb(PFO)3 (0.05 mmol) were added. The
mixture was heated at 120 °C for 0.5 h. After completion of
the reaction (monitored by TLC), the reaction mixture was
cooled to r.t. Dichloromethane (3 mL) was added and then
filtered. The filtrate was washed with sat. aq NaCl solution
and dried over anhyd Na2SO4, filtered, and concentrated
under reduced pressure to leave the crude product which was
recrystallized by EtOH to give the pure compound. If
necessary, the product was purified by chromatography over
SiO2.
(5) Wilkinson, J. A. Chem. Rev. 1992, 92, 505.
(6) (a) Schlosser, M. Angew. Chem. Int. Ed. 2006, 45, 5432.
(b) Zapata, A. J.; Gu, Y.; Hammond, G. B. J. Org. Chem.
2000, 65, 227. (c) Asakura, N.; Usuki, Y.; Iio, H.; Tanaka,
T. J. Fluorine Chem. 2006, 127, 800. (d) Li, D.; Song, L.;
Song, S.; Zhu, S. J. Fluorine Chem. 2007, 128, 952.
(7) (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org.
Chem. 2004, 4957. (b) Bremner, W. S.; Organ, M. G.
J. Comb. Chem. 2007, 9, 14. (c) Dömling, A. Chem. Rev.
2006, 106, 17.
(8) (a) Gouge, V.; Jubault, P.; Quirion, J. Tetrahedron Lett.
2004, 45, 773. (b) Prakash, G. K. S.; Mandal, M.;
Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org. Chem.
2002, 67, 3718. (c) Shibata, N.; Das, B. K.; Takeuchi, Y.
J. Chem. Soc., Perkin Trans. 1 2000, 4234. (d) Song, S.;
Song, L.; Dai, B.; Yi, H.; Jin, G.; Zhu, S.; Shao, M.
Tetrahedron 2008, 64, 5728.
(22) Typical Data for Representative Compound:
Ethyl 1,3-Diphenyl-5-trifluoromethyl-D2-pyrazolin-4-
carboxylate (4a)
Yield 70.4%; white solid; mp 82.2–82.8 °C. 1H NMR (400
MHz, CDCl3): d = 7.89–7.86 (2 H, m, Ph), 7.45–7.40 (3 H,
m, Ph), 7.38–7.29 (4 H, m, Ph), 7.03–6.98 (1 H, m, Ph), 5.05
(1 H, qd, 3JHF = 6.8 Hz, JHH = 3.6 Hz, CHCF3), 4.50 (1 H, d,
J = 3.6 Hz, 4-H), 4.20–4.09 (2 H, m, CO2CH2CH3,
nonequivalent geminal hydrogens), 1.12 (3 H, t, J = 7.2 Hz,
CO2CH2CH3). 13C NMR (100 MHz, CDCl3): d = 167.9,
145.9, 144.7, 130.4, 129.6, 129.1, 128.5, 126.9, 124.4 (q,
1JCF = 281 Hz), 121.5, 114.9, 65.6 (q, 2JCF = 31 Hz), 62.5,
53.1 (d, 3JCF = 1.5 Hz), 13.8. 19F NMR (470 MHz, CDCl3):
d = –76.33 (d, 3JHF = 6.6 Hz). HRMS: m/z calcd for
C19H17N2O2F3 [M+]: 362.1242; found: 362.1242.
(23) General Procedure for the One-Pot Synthesis of
Trifluoromethyl-Substituted Pyrazoles
(9) (a) Montoya, V.; Pons, J.; García-Antón, J.; Solans, X.;
Font-Bardia, M.; Ros, J. J. Fluorine Chem. 2007, 128, 1007.
(b) Hanamoto, T.; Egashira, M.; Ishizuka, K.; Furuno, H.;
Inanaga, J. Tetrahedron 2006, 62, 6332.
(10) Shen, L.; Cao, S.; Liu, N.; Wu, J.; Zhu, L.; Qian, X. Synlett
2008, 1341.
(11) Jung, M. E.; Min, S.; Houk, K. N.; Ess, D. J. Org. Chem.
2004, 69, 9085.
(12) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002,
4, 3955.
(13) Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Fatima, N.;
Yadav, J. S. Synthesis 2003, 1267.
Aldehydes 1 (1 mmol) and aromatic hydrazines 2 (1 mmol)
were stirred for 20 min before ethyl trifluoroacetoacetate
(2.5 mmol) and Yb(PFO)3 (0.05 mmol) were added. The
mixture was heated at 120 °C for 0.5 h and stirred for another
10 min after IBX (1.5 mmol) was added. After completion of
Synlett 2008, No. 19, 3058–3062 © Thieme Stuttgart · New York

3062
L. Shen et al.
LETTER
the reaction (monitored by TLC), the reaction mixture was
cooled to r.t. Dichloromethane (3 mL) was added, and the
mixture was passed through a Celite pad, which was
successively washed with PE and EtOAc. The filtrate was
washed with sat. aq NaCl solution and dried over anhyd
Na2SO4, filtered, and concentrated under reduced pressure to
leave the crude product which was recrystallized by EtOH to
give the pure compound. If necessary, the product was
purified by chromatography over SiO2.
Yield 54.5%; white solid; mp 83.1–83.6 °C; 1H NMR (400
MHz, CDCl3): d = 7.73–7.71 (2 H, m, Ph), 7.53 (5 H, s, Ph),
7.44–7.42 (3 H, m, Ph), 4.36 (2 H, q, J = 7.2 Hz,
CO2CH2CH3), 1.31 (3 H, t, J = 7.2 Hz, CO2CH2CH3). 13
C
NMR (100 MHz, CDCl3): d = 162.8, 151.5, 139.0, 132.5 (q,
2JCF = 39 Hz), 131.9, 130.9, 129.8, 129.2, 129.0, 128.4,
125.9, 119.1 (q, 1JCF = 270 Hz), 115.1, 61.9, 13.8. 19F NMR
(470 MHz, CDCl3): d = –56.87. HRMS: m/z calcd for
C19H15N2O2F3 [M+]: 360.1086; found: 360.1086.
(24) Typical Data for Representative Compound: Ethyl 1,3-
Diphenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylate (5a)
Synlett 2008, No. 19, 3058–3062 © Thieme Stuttgart · New York