Improved regioselectivity in pyrazole formation through the use of fluorinated alcohols as solvents: Synthesis and biological activity of fluorinated tebufenpyrad analogs

Article abstract of DOI:10.1021/jo800251g

(Chemical Equation Presented) The preparation of N-methylpyrazoles is usually accomplished through reaction of a suitable 1,3-diketone with methylhydrazine in ethanol as the solvent. This strategy, however, leads to the formation of regioisomeric mixtures of N-methylpyrazoles, which sometimes are difficult to separate. We have determined that the use of fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation, and we have used this modification in a straightforward synthesis of fluorinated analogs of Tebufenpyrad with acaricide activity.

Full text of DOI:10.1021/jo800251g

Improved Regioselectivity in Pyrazole Formation through the Use of
Fluorinated Alcohols as Solvents: Synthesis and Biological Activity
of Fluorinated Tebufenpyrad Analogs
Santos Fustero,*,†,‡ Raquel Roma´n,† Juan F. Sanz-Cervera,†,‡ Antonio Simo´n-Fuentes,†
Ana C. Cun˜at,† Salvador Villanova,† and Marcelo Murgu´ıa†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot, Spain, and Laboratorio
de Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe Felipe, E-46013 Valencia, Spain
santos.fustero@uV.es
ReceiVed January 30, 2008
The preparation of N-methylpyrazoles is usually accomplished through reaction of a suitable 1,3-diketone
with methylhydrazine in ethanol as the solvent. This strategy, however, leads to the formation of
regioisomeric mixtures of N-methylpyrazoles, which sometimes are difficult to separate. We have
determined that the use of fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole
formation, and we have used this modification in a straightforward synthesis of fluorinated analogs of
Tebufenpyrad with acaricide activity.
Introduction
tumor cells,4 whereas others constitute important agrochemicals
used, for instance, as insecticides.5 Of particular importance as
a pharmacophore, the N-methylpyrazole unit forms part of
several drugs such as the antidepressant Zometapine,6 the
inhibitor of type 5 cGMP phosphodiesterase Sildenafil,7 and the
antibacterial agent FR21818.8 Good examples of the usefulness
Pyrazole derivatives have become increasingly important in
the past few years because they have proven to be extremely
useful intermediates for the preparation of new biological
materials. The pyrazole ring is present in numerous pharma-
cologically and agrochemically important compounds, including
those used as inhibitors of HIV-1 reverse transcriptase,1 sodium
hydrogen ion exchanger NHE-1,2 and dipeptidyl peptidase IV
(DPP-IV).3 Several compounds of this type act as antagonists
of the Rvꢀ3 receptor, which is present on the surface of many
(4) Penning, T. D.; Khilevich, A.; Chen, B. B.; Russell, M. A.; Boys, M.;
Wang, Y.; Duffin, T.; Engleman, V. W.; Finn, M. B.; Freeman, S. K.; Hanneke,
M. L.; Keene, J. L.; Klover, J. A.; Nickols, G. A.; Nickols, M. A.; Rader, R. K.;
Settle, S. L.; Shannon, K. E.; Steininger, C. N.; Westlin, M. M.; Westlin, W. F.
Bioorg. Med. Chem. Lett. 2006, 16, 3156–3161.
* To whom correspondence should be addressed. Tel.: +34-963544279; fax:
+34-963544939.
(5) Gandhale, D. N.; Patil, A. S.; Awate, B. G.; Naik, L. M. Pesticides 1982,
16, 27–28.
† Universidad de Valencia.
(6) De Wald, H. A.; Lobbestael, S.; Poschel, B. P. H. J. Med. Chem. 1981,
24, 982–987.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.; Swaney, S. M.;
Tarpley, W. G.; Yagi, Y.; Romero, D. L. J. Med. Chem. 2000, 43, 1034–1040.
(2) Guzma´n-Pe´rez, A.; Webster, R. T.; Allen, M. C.; Brown, J. A.; Buchholz,
A. R.; Cook, E. R.; Day, W. W.; Hamanaka, E. S.; Kennedy, S. P.; Knight,
D. R.; Kowalcyk, P. J.; Marala, R. B.; Mularski, C. J.; Novomisle, W. A.;
Ruggeri, R. B.; Tracy, W. R.; Hill, R. J. Bioorg. Med. Chem. Lett. 2001, 11,
803–807.
(7) Terret, N. K.; Bell, A. S.; Brown, D.; Ellis, P Bioorg. Med. Chem. Lett.
1996, 6, 1819–1824.
(8) Azami, H.; Barrett, D.; Tanaka, A.; Sasaki, H.; Matsuda, K.; Sakurai,
M.; Terasawa, T.; Shirai, F.; Chiba, T.; Matsumoto, Y.; Tawara, S. Bioorg. Med.
Chem. 2001, 9, 961–982.
(9) Marcic, D. Exp. Appl. Acarol. 2005, 36, 177–185, and references cited
therein.
(3) Ashton, W. T.; Sisco, R. M.; Dong, H.; Lyons, K. A.; He, H.; Doss,
G. A.; Leiting, B.; Patel, R. A.; Wu, J. K.; Marsilio, F.; Thornberry, N. A.;
Weber, A. E. Bioorg. Med. Chem. Lett. 2005, 15, 2253–2258.
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(11) Murakami, H.; Masuzawa, S.; Takii, S.; Ito, T. Jpn. Patent
2,012,802,003, 2003.
10.1021/jo800251g CCC: $40.75
Published on Web 04/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3523–3529 3523

Fustero et al.
FIGURE 1. Some representative examples of commercial pyrazoles.
of this same unit in the preparation of insecticides and acaricides
include the pesticides Tebufenpyrad,9 Tolfenpyrad,10 Cyanopy-
rafen,11 and Fenpyroximate12(Figure 1).
solvent. For the preparation of 1c, ethyl pyruvate was treated
with Deoxofluor in CH2Cl2 to afford ethyl 2,2-difluoropro-
panoate, which in turn was condensed with 2-acetylfuran with
NaOEt as the base and ethanol as the solvent to give the desired
starting material in 70% overall yield. In addition, we also
decided to synthesize the corresponding pyrazoles with an
ethoxycarbonyl group (CO2Et) as an example of a nonfluorinated
electron-withdrawing group. Thus, the condensation of 2-acetyl-
furan with diethyl oxalate in the presence of tert-BuOK in a
mixture of THF and DME as solvents afforded compound 1d
in 64% yield.15,16
The introduction of fluorine atoms or fluorine-containing
groups into heterocyclic rings has made possible the discovery
of new bioactive products.13 In particular, pyrazoles containing
fluoroalkyl groups are of considerable interest due to their
agrochemical and pharmaceutical properties.14 Because Tebufen-
pyrad is a commercially available N-methylpyrazole derivative
that displays important acaricidal activity, we decided to pursue
the preparation of fluorinated N-methylpyrazoles derived from
Tebufenpyrad with several different fluorinated substitution
patterns (RF) to replace the ethyl group on the C-3 of the
heterocyclic ring (Scheme 1).
One widely used method for the synthesis of fluorinated
N-methylpyrazoles consists of the condensation of methylhy-
drazine with an appropriate 1,3-diketone.17 In these reactions,
ethanol is generally used as the solvent. In principle, the reaction
between a monosubstituted hydrazine and a nonsymmetrical 1,3-
diketone can lead to the formation of a mixture of two pyrazole
regioisomers (Table 1).
SCHEME 1. Retrosynthetic Analysis for the Preparation of
Tebufenpyrad Analogs
Although several papers have been published on the synthesis
of N-arylpyrazoles from monosubstituted arylhydrazines and 1,3-
diketones bearing an electron-withdrawing group, mainly CF3,18
studies on the preparation of N-methylpyrazoles with methyl-
hydrazine as a reagent are scarce. In the few examples published
to date, the observed regioselectivities are generally low.19 In
our experiments, when a mixture of 1-(2-furyl)-4,4,4-trifluoro-
1,3-butanedione (1a) and methylhydrazine in absolute ethanol
was allowed to react at room temperature, the reaction was
complete in less than an hour and two products were formed,
Results and Discussion
In our work, the corresponding fluorinated 1,3-diketone
starting materials 1a-c were either commercially available or
synthesized from the appropriate fluorinated ester and ketone.
Thus, commercially available compound 1a was used as
received, whereas compound 1b was prepared in 70% yield
through the condensation of 2-acetylfuran and ethyl 2,2,3,3,3-
pentafluoroacetate with NaOEt as the base and ethanol as the
(16) See Supporting Information for details on the preparation of compounds
1b-d.
(17) Elguero, J. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds. Pergamon Press: New York, 1996;
Vol. 3, pp 58-61.
(18) (a) Lyga, J. W.; Patera, R. M. J. Heterocyclic Chem. 1990, 27, 919–
921. (b) Singh, S. P.; Kapoor, J. K.; Kumar, D.; Threadgill, M. D. J. Fluorine
Chem. 1997, 83, 73–79. (c) Singh, S. P.; Kumar, D.; Jones, B. G.; Threadgill,
M. D. J. Fluorine Chem. 1999, 94, 199–203. (d) Singh, S. P.; Kumar, D.; Batra,
H.; Naithani, R.; Rozas, I.; Elguero, J. Can. J. Chem. 2000, 78, 1109–1120. (e)
Song, L.-P.; Zhu, S.-Z. J. Fluorine Chem. 2001, 111, 201–205. (f) Singh, S. K.;
Reddy, M. S.; Shivaramakrishna, S.; Kavita, D.; Vasudev, R.; Babu, J. M.;
Sivalaksmidevi, A.; Rao, Y. K. Tetrahedron Lett. 2004, 45, 7679–7682. (g)
Norris, T.; Colon-Cruz, R.; Ripio; D.H.B, Org. Biomol. Chem. 2005, 3, 1844–
1849. (h) Humphries, P. S.; Finefield, J. M. Tetrahedron Lett. 2006, 47, 2443–
2446.
(12) Kim, M.; Sim, C.; Shin, D.; Suh, E.; Cho, K. Crop Protect 2006, 25,
542–548, and references cited therein.
(13) (a) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303–319.
(b) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029. (c) Jeschke, P.
ChemBioChem 2004, 5, 570–589. (d) Bo¨hm, H.-J.; Banner, D.; Bendels, S.;
Kansy, M.; Kuhn, B.; Mu¨ller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem
2004, 5, 637–643.
(14) (a) Hamper, B. C.; Mao, M. K.; Phillips, W. G. U.S. Patent 5,698,708,
1997. (b) Dryden, M. W.; Denenberg, T. M.; Bunch, S. Vet. Parasitol. 2000,
93, 69–75. (c) Phillips, J.; Pilato, M.; Wu, T-t. PCT Int. Appl. WO 9,828,277,
1998. (d) Arthur, F. H. J. Econ. Entomol. 2002, 95, 1314–1318. (e) Penning,
T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.;
Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory,
S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang,
Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347–1365. (f) Kees, K. L.;
Fitzgerald, J. J.; Steiner, K. E.; Mattes, J.; Mihan, B.; Tosi, T.; Mondoro, D.;
McCaleb, L. J. Med. Chem. 1996, 39, 3920–3928.
(19) For example, ethyl 2,4-dioxopentanoate or ethyl 2,4-dioxo-4-phenylbu-
tanoate reacted with methylhydrazine in boiling EtOH to yield a 2:1 mixture of
the two regioisomeric pyrazoles. See: Schmidt, A.; Habeck, T.; Kindermann,
M. K.; Nieger, M. J. Org. Chem. 2003, 68, 5977–5982. In contrast, reaction
between 4-(2-thienyl)-1,1,1-trifluoromethyl-1,3-butanedione and methylhydrazine
in EtOH-AcOH (10:1) at reflux afforded 1-methyl-3-trifluoromethyl-5-(2-
thienyl)pyrazole in 60% yield (no presence of the other regioisomer was
indicated). See: (a) Yonetoku, Y.; Kubota, H.; Okamoto, Y.; Toyoshima, A.;
Funatsu, M.; Ishikawa, J.; Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg. Med.
Chem. 2006, 14, 4750–4760. See also: (b) Yonetoku, Y.; Kubota, H.; Okamoto,
Y.; Ishikawa, J.; Ishikawa, J.; Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg.
Med. Chem. 2006, 14, 5370–5383.
(15) (a) Kipnis, F.; Levy, I.; Ornfelt, J. J. Am. Chem. Soc. 1948, 70, 4265.
(b) Gardner, T. S.; Wenis, E.; Lee, J. J. Org. Chem. 1961, 26, 1514–1518.
3524 J. Org. Chem. Vol. 73, No. 9, 2008

Synthesis of Fluorinated Tebufenpyrad Analogs
TABLE 1. Results for the Reaction of N-Methyl and N-Phenylhydrazine with 1,3-Dicarbonyl Derivatives in EtOH, TFE, and HFIP
2: 3 or 4 (%)a
entry
1
R1
R2
CF3
CF2CF3
CF2CH3
CO2Et
CF3
CF3
CF3
CF3
CF3
CF2CF3
CF2CH3
CO2Et
CF3
CF3
CF3
CF3
CF3
CF3
R3
products
EtOH
TFE
HFIP
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1a
1e
1f
1b
1c
1d
1g
1g
1h
1h
1i
2-Furyl
2-Furyl
2-Furyl
2-Furyl
Ph
PMP
2-Furyl
Ph
CH3
CH3
CH3
CH3
CH3
CH3
Ph
Ph
Ph
Ph
Ph
Ph
CH3
Ph
CH3
Ph
CH3
Ph
2a, 3a
2b, 3b
2c, 3c
2d, 4d
2e, 3e
2f, 4f
2g, 4g
2h, 3h
2i, 3i
36:64 (99)
64:36 (93)
45:55 (99)
44:56 (86)
36:64 (99)
30:70 (99)
48:52 (75)
24:76 (60)
55:45 (60)
18:72 (52)
33:67 (62)
49:51 (69)
65:35 (98)
5:95 (60)
85:15 (99)
98:2 (99)
98:2 (99)
89:11 (99)
79:21 (98)
80:20 (99)
87:13 (93)
81:19 (98)
90:10 (80)
91:9 (92)
99:1 (65)
89:11 (65)
88:12 (99)
30:70 (50)
80:20 (85)
86:14 (89)
75:25 (97)
99:1 (40)
97:3 (98)
>99:<1 (99)
98:2 (98)
93:7 (98)
92:8 (98)
88:12 (99)
97:3 (92)
99:1 (96)
99:1 (85)
99:1 (93)
99:1 (65)
94:4 (67)
96:4 (98)
99:1 (73)
88:12 (94)
99:1 (94)
80:20 (90)
99:1 (61)
9
PMP
10
11
12
13
14
15
16
17
18
2-Furyl
2-Furyl
2-Furyl
CH3
2j, 3j
2k, 3k
2l,b 4lb
2m, 3m
2n, 3n
2o, 3o
2p, 3p
2q, 3q
2r, 3r
CH3
p-ClC6H4
p-ClC6H4
2,4-Cl2C6H3
2,4-Cl2C6H3
12:88 (90)
33:67 (90)
70:30 (93)
87:13 (63)
1i
a The results show the proportion of compounds 2 and 3 formed or, in the case of entries 4 and 12, compounds 2 and 4. The reaction yield is shown
in parentheses. b Compounds 2l and 4l had been previously described in the literature, but NOESY experiments on the alcohols that resulted from
DIBALH reduction of the CO2Et group showed that the original structural assignment was incorrect. See: Flores, A. F.; Brondani, S.; Pizzuti, L.;
Martins, M. A.; Zanatta, N.; Bonacorso, H. G.; Flores, D. C. Synthesis, 2005, 2744-2750.
SCHEME 2. Formation of Fluorinated Pyrazoles 2 and 5-Hydroxypyrazolines 3
namely the 3-trifluoromethylpyrazole (2a) and the 5-hydroxy-
5-trifluoromethylpyrazoline (3a), in almost quantitative overall
yield and in a ratio of 1:1.8. Compound 3a is the hydrated
precursor of 4a, the regioisomeric pyrazole of 2a (Scheme 2).20
(20) 5-Hydroxy-5-trifluoromethylpyrazoline derivatives have been previously
isolated and identified as intermediates in reactions between non-alkylated
hydrazines and trifluoromethyl 1,3-diketones. See: (a) Elguero, J.; Yranzo, G. I.
J. Chem. Res., Synopses 1990, 120–121, and references 18a-g. These intermedi-
ates have also been observed in reactions with methylhydrazine when RF ) CF3.
See: (b) Khudina, O. G.; Shchegol’kov, E. V.; Burgart, Y. V.; Kodess, M. I.;
Kazheva, O. N.; Chekhlov, A. N.; Shilov, G. V.; Dyachenko, O. A.; Saloutin,
V. I.; Chupakhin, O. N. J. Fluorine Chem. 2005, 126, 1230–1238.
(21) A possible alternative to the general method for the synthesis of
N-methylpyrazoles entails the preparation of the N-unsubstituted pyrazole,
followed by methylation with methyl iodide or dimethyl sulphate under basic
conditions. See: Hamper, B. C.; Leschinsky, K. L.; Mischke, D. A.; Prosch,
S. D. In Asymmetric Fluoroorganic Chemistry. Synthesis, Applications and Future
Directions; ACS Symposium Series 746; Ramachandran, P. V., Ed.; American
Chemical Society: Washington, D.C., 2000; pp 274-275.
J. Org. Chem. Vol. 73, No. 9, 2008 3525

Fustero et al.
SCHEME 3. Addition of CD3OH to Compounds 1a and 1d
Compounds 2a and 3a were readily separated by means of
column chromatography and spectroscopically identified. Under
the same reaction conditions, 1-(2-furyl)-4,4,5,5,5-pentafluoro-
1,3-pentanedione 1b afforded pyrazole 2b and the 5-hydroxy-
pyrazoline 3b, whereas 1-(2-furyl)-4,4-difluoro-1,3-pentanedione
1c afforded the pyrazole 2c and the 5-hydroxypyrazoline 3c.
In both cases, compounds 2 and 3 were obtained with very low
regioselectivity, with a ratio of ca. 1:1 (Scheme 2). We were
able to assign the structures for the reaction products 2 and 3
through 13C and NOESY NMR experiments (see Supporting
Information).
In all cases, it was possible to transform the 5-hydroxy-5-
trifluoromethylpyrazolines 3a-c into their respective 5-trifluo-
romethylpyrazoles 4a-c in almost quantitative yields through
treatment with 3 M HCl in THF solution under reflux conditions
(Scheme 2).
In contrast, the condensation of the nonfluorinated ethyl 4-(2-
furyl)-2,4-dioxobutanoate 1d with methylhydrazine led directly
to the formation of a ca. 1:1.3 mixture of the two isomeric
pyrazoles 2d and 4d. In this case, the corresponding 5-hydroxy-
5-trifluoromethylpyrazoline was not detected (Table 1).
The results obtained up to this point showed that under these
reaction conditions there was either no regioselectivity or, if
there was, the major product was the undesired 5-fluoroalkyl
pyrazole regioisomer.21 In an effort to find simple regioselectiVe
routes to compounds 2, we thus decided to investigate the effect
of using fluorinated alcohols instead of ethanol in the pyrazole
formation.
Fluorinated alcohols have been shown to display unique
properties as solvents, cosolvents, and additives in synthetic
chemistry. The presence of fluoroalkyl groups lends specific
properties to fluorinated alcohols, differentiating them from their
nonfluorinated counterparts and other protic solvents in that they
are neither nucleophilic nor are they hydrogen bond acceptors.22
For this reason, we decided to investigate the effect of
substituting trifluoroethanol (TFE) or hexafluoroisopropanol
(HFIP) for ethanol in the key pyrazole-forming step of our
synthesis.
In our first assay with TFE as the solvent at room temperature,
1a reacted with methylhydrazine to afford a mixture of
3-trifluoromethylpyrazole 2a and 5-hydroxy-5-trifluorometh-
ylpyrazoline 3a in less than 1 h. In contrast with the previous
results for this reaction when performed in EtOH, the regiose-
lectivity was much higher, with a ratio for the two compounds
of 85:15 in favor of the desired 3-trifluoromethyl derivative.
The selectivity was further improved to 97:3 when the conden-
sation reaction was carried out with HFIP as the solvent (entry
1, Table 1).
Subsequent assays with the 1,3-diketones 1b-f and methyl-
hydrazine (entries 2-6, Table 1) confirmed the influence of the
fluorinated alcohols in the regioselectivity of this reaction,
especially with HFIP as the solvent.23 In this case, the 5-(2-
furyl)pyrazole derivatives 2 were obtained almost exclusively
(Table 1, entries 1-4, 7, and 10-12).
and CF3 groups have been carried out with monosubstituted
hydrazines derived from aromatic structures. In all cases, the
3-CF3 pyrazole derivatives were obtained as the major isomers
when either phenylhydrazine or 4-methoxyphenylhydrazine was
used under neutral (EtOH, i-PrOH), basic (NaOAc, TEA), or
acidic (HCl, H2SO4, p-TsOH) reaction conditions at reflux.18a,d,f–h
Only when a strong electron-withdrawing substituent was
attached to the hydrazine group were 5-hydroxy-5-trifluorom-
ethylpyrazolines 3 isolated as the major or exclusive products.24
With this in mind, we further extended our study to examine
the influence of the fluorinated solvents TFE and HFIP on the
regioselectivity of the synthesis of 5-arylpyrazoles bearing an
electron-withdrawing group at C-3. We thus examined the
reactions between 1,3-diketones 1 and phenylhydrazine in
absolute EtOH, TFE, and HFIP at room temperature. The results
are summarized in Table 1 (entries 7-12). In absolute EtOH,
the observed regioselectivities for the reactions with phenyl-
hydrazine were very similar to those obtained with methylhy-
drazine, with isomer ratios in the reaction mixtures from about
1:1 to 3:1, the latter in favor of the 5-hydroxypyrazoline. As
was the case in the analogous reaction with methylhydrazine,
the 5-ethoxycarbonyl-5-hydroxypyrazoline 3l was not detected
as a product in the reaction of 1d with phenylhydrazine (entry
12, Table 1). In sharp contrast, when the reactions were carried
out in TFE or HFIP, the regioselectivities improved up to 99:1
in favor of the 5-arylpyrazole isomers (entries 7-12, Table 1).
This increase in regioselectivity was also observed when R1 )
methyl (Table 1, entries 13-14). However, when R1 is an aryl
group with electron-withdrawing groups, as in diketones 1 h
and 1i, the reactivity of the two carbonyl groups is expected to
be more similar than when the substituents are neutral or
electron-donating. Although lower regioselectivity might be
anticipated in these cases, in fact this only occurs with
methylhydrazine in HFIP (Table 1, entries 15 and 17 versus
entry 5). In the other cases, the observed regioselectivity does
not change significantly (Table 1, entries 16 and 18). The
increased regioselectivity thus seems to be general, although it
is more noticeable with phenylhydrazine in HFIP.
To explain the enhanced regioselectivity induced by the use
of fluorinated alcohols in the pyrazole ring formation, we
performed an NMR experiment. Addition reactions of nucleo-
philes such as water,25 alcohols,26 ethanethiol, and pyrrolidine18a
to the COCF3 carbonyl group have been previously reported.
In our case, when an excess of CD3OH was added to an NMR
1
sample tube containing the 1,3-diketone 1a, the H spectrum
showed the presence of a mixture of the adduct at the COCF3
carbonyl (hemiketal A, Scheme 3) and the diketone starting
material in a ratio of 8:1 in favor of the former. Under the same
conditions, CD3OH also reacted with the COCO2Et ketone
As mentioned above, most of the previously published
pyrazole syntheses that start with 1,3-diketones with both aryl
(22) Review: (a) Be´gue´, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004,
18–29. For a recent paper, see: (b) Dubrovina, N. V.; Shuklov, I. A.; Birkholz,
M.-N.; Michalik, D.; Paciello, R.; Bo¨rner, A. AdV. Synth. Catal. 2007, 349, 2183–
2187.
(24) (a) Singh, S. P.; Kumar, V.; Aggarwal, R.; Elguero, J. J. Heterocyclic
Chem. 2006, 43, 1003–1014. (b) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E.
J. Med. Chem. 2001, 44, 3039–3042. See also refs18b-e, g. .
(25) Camps, F.; Coll, J.; Messeguer, A.; Roca, A. Tetrahedron 1977, 33,
1637–1640, and references cited therein.
(23) Diketone 1e (R1 ) Ph, R2 ) CF3) is commercially available whereas
1f (R1 ) p-MeOC6H4, R2 ) CF3) can be easily prepared. See Supporting
Information.
(26) Moriyasu, M.; Kato, A.; Hashimoto, V. J. Chem. Soc., Perkin Trans.
1986, 2, 515–520.
3526 J. Org. Chem. Vol. 73, No. 9, 2008

Synthesis of Fluorinated Tebufenpyrad Analogs
SCHEME 4. Possible Mechanism for the Formation of Fluorinated Pyrazoles 2 When Fluorinated Alcohols Are Used As
Solvents
SCHEME 5. Addition of Methyl- Or Phenylhydrazine to
Compounds 1
carbonyl of 1d to afford a mixture containing one-third of the
corresponding adduct in equilibrium with the starting material
(Scheme 3). These results confirm the stronger electrophilic
character of carbonyl groups attached to electron-withdrawing
groups such as CF3 or CO2Et as compared with those attached
to an aryl group. In sharp contrast, when deuterated TFE or
HFIP were added to 1a, the corresponding adduct was not
detected, which is not surprising because both fluorinated
alcohols are non-nucleophilic. The low regioselectivities ob-
served when methyl- and phenylhydrazine react with these 1,3-
diketones in EtOH may thus be due to the competition between
the two nucleophiles, hydrazine and alcohol, toward the more
reactive carbonyl group. Because both TFE and HFIP are non-
nucleophilic, they do not compete with hydrazine in the attack
to the more reactive carbonyl group, thus increasing the
formation can be easily predicted by taking into account that
regioselectivity of the attack.
the more nucleophilic NH2 group of phenylhydrazine would be
To explain the excellent levels of regioselectivity observed
expected to react preferentially with the more reactive carbonyl
in the synthesis of pyrazoles in fluorinated solvents, especially
group. In contrast, in the case of methylhydrazine, the observed
in HFIP, we agree with Norris et al.27 that the process must
results can be explained by considering that the attack of the
proceed via a step-by-step pathway. The highly electrophilic
NH group of methylhydrazine on the more reactive carbonyl
character of the carbonyl group attached to CF3, CF2CH3,
group leads to a hemiaminal which does not dehydrate easily
CF2CF3, or CO2Et is probably enhanced by the high hydrogen
to yield a hydrazone and can therefore revert to the starting
bond donating ability of the fluorinated solvents, which causes
materials if equilibrium is achieved. The dehydration of the
the rate of the attack of the hydrazine NH2 group to be faster
hemiaminal to the enamine is disfavored due to the presence
than that of the other carbonyl group, COAr. Subsequent loss
of the RF group, as the persistent formation of 5-hydroxy-5-
trifluoromethylpyrazolines 3 in similar cases shows (see Table
of a water molecule from the adduct would afford the hydrazone
intermediate, a process that is facilitated by both the strong
1). In contrast, the NH2 group of methylhydrazine can attack
ionizing power of the fluorinated alcohols as solvents and their
the more electrophilic carbonyl leading to irreversible hydrazone
ability to solvate water. Finally, the attack of the substituted
formation (since hydrazone hydrolysis is probably slow under
nitrogen of the hydrazone to the activated COAr carbonyl and
these reaction conditions), thus preventing a return to the starting
the subsequent loss of water would give rise to the major isomer
compounds (Scheme 5).
Having obtained the required fluorinated pyrazoles, we
continued our synthesis by unmasking the carboxyl group
through oxidation of the furan ring with sodium periodate in
of the pyrazole derivative (Scheme 4).28
Interestingly, analogous 5-aryl regioisomers 2 were obtained
as major pyrazole formation products with either methyl- or
phenylhydrazine in spite of the fact that the NH2 is the more
the presence of catalytic amounts of RuCl3 ·3H2O at room tem-
perature.29 The reactions were fast and proceeded with good to
nucleophilic nitrogen in phenylhydrazine and the less nucleo-
philic one in methylhydrazine. The major product in pyrazole
excellent yields (Scheme 6). The pyrazole carboxylic acids were
then chlorinated in excellent yields upon the addition of an
aqueous solution of sodium hypochlorite to the substrate
dissolved in acetic acid. For the final amide formation step, we
(27) These authors proposed a mechanism with a sequential loss of two water
molecules that could explain the observed high regioselectivity. The first loss of
water would be fast, corresponding to the formation of the CdN bond conjugated
with the aryl ring, whereas the second loss of water would be much slower,
even requiring acid catalysis for the elimination to proceed. See ref 18g.
(28) An alternative mechanism would involve addition to the carbonyl
attached to the RF group followed by a second addition to the other carbonyl to
form a 3,5-dihydroxypyrazoline, which would then evolve to the corresponding
pyrazole through sequential double dehydration. See ref 20a.
chose to transform the carboxylic acids into their corresponding
acyl chlorides, followed by in situ addition of the amine. Thus,
(29) Danishefsky, S. J.; DeNinno, M. P.; Chen, S.-h. J. Am. Chem. Soc. 1988,
110, 3929–3940.
J. Org. Chem. Vol. 73, No. 9, 2008 3527

Fustero et al.
SCHEME 6. Synthesis of Fluorinated Analogs of Tebufenpyrad 7 and 10
TABLE 2. Biological Activity of the Fluorinated Tebufenpyrad
pyrazole ring formation step, an essential point for improving
the regioselectivity toward the desired isomer. Two of the
prepared fluorinated analogs display acaricidal activity within
the same order of magnitude as that of Tebufenpyrad. We are
currently working on the development of other fluorinated
analogs of Tebufenpyrad with the purpose of improving its
biological activity as acaricide.
Analogs on Tetranychus urticaea
mortality (%)
fertility inhibition (%)
entry compound [RF] 24 h 4 days 6 days 24 h 4 days 6 days
1
2
3
4
5
6
7
7a [CF3]
3
0
4
0
0
23
0
31
0
0
0
50
0
90
0
0
0
41
0
69
0
0
0
49
0
83
0
0
0
52
0
84
0
7b [CF2-CF3]
7c [CF2-CH3]
10a [CF3]
10b [CF2-CF3]
10c [CF2-CH3]
Tebufenpyrad
0
0
Experimental Section
0
100
100
100
100
100
100
4,4-Difluoro-1-(2-furyl)-1,3-pentanedione (1c). Deoxofluor (0.046
mol, 50% in toluene) was added slowly to a solution of ethyl
pyruvate (27 mmol, 3.13 g) in CH2Cl2 (45 mL) at 0 °C under
nitrogen atmosphere. The mixture was stirred overnight at room
temperature. The reaction mixture was cooled to 0 °C, hydrolyzed
with 5% aq sodium bicarbonate solution (25 mL), and extracted
with CH2Cl2 (2 × 20 mL). The organic layer was dried over
Na2SO4. The solvent was removed cautiously under reduced
pressure in order not to lose the resulting crude ethyl 2,2-
difluoropropanoate, which has a low boiling point. This solution
was then added at 0 °C to a previously prepared solution of
acetylfuran enolate, which was obtained by adding acetylfuran (23
mmol, 3.11 g) to a solution of Na (35 mmol, 790 mg) in EtOH (35
mL). The reaction mixture was stirred at room temperature for 3 h.
The solvent was concentrated in Vacuo, hydrolyzed with H2O (15
mL), and acidified with 3 M aq H2SO4 until neutral pH was reached.
The aqueous layer was extracted with EtOAc (3 × 20 mL), washed
with brine, dried over anhyd Na2SO4, and filtered. The solvent was
concentrated to give a yellow oil, which was purified through
column chromatography on silica gel (6:1 hexane:EtOAc) to afford
pure compound 1c (70%, 3.25 g). Pale-yellow oil; Rf 0.3 (3:1
hexane:EtOAc). 1H NMR (300 MHz, CDCl3): δ 1.75 (t, JHF ) 18.6
Hz, 3H; CH3), 6.39 (s, 1H; CH), 6.52 (dd, J1 ) 3.6 Hz, J2 ) 1.7
Hz, 1H; CH), 7.19 (dd, J1) 3.6 Hz, J2) 0.6 Hz, 1H; CH), 7.56
(dd, J1 ) 1.7 Hz, J2 ) 0.6 Hz, 1H; CH) ppm; 13C NMR (75.5
a Concentration of active principle in the assay: 5 g/L.
oxalyl chloride was added to a solution of the carboxylic acid
in dichloromethane, followed by the addition of the amine plus
Et3N and DMAP at room temperature. The desired amides 7
were obtained with yields that ranged from good to excellent.
In a similar manner, regioisomeric fluorinated derivatives of
Tebufenpyrad 10 were prepared when pyrazoles 4 were used
as starting materials (Scheme 6).
Finally, a standard method was used to test the fluorinated
analogs of Tebufenpyrad as acaricides against Tetranychus
urticae.30 The activity of the fluorinated compounds was thus
compared to that of the commercial product Masai, the active
principle of which is Tebufenpyrad.31 The effects of applying
the assayed compounds as adulticides and fertility inhibitors
was evaluated for each compound 24 h, 4 days, and 6 days
after application. Table 2 lists the obtained results.
The results indicate that the regioisomeric pyrazole analogs
10a-c are completely devoid of acaricidal activity. Among the
Tebufenpyrad fluorinated analogs 7a-c, whereas compound 7b
is inactive, analogs 7a, and particularly 7c display significant
acaricidal activity. Although they are slower to take effect than
Tebufenpyrad, the final activity after 6 days is only slightly
inferior in the case of 7c.
In summary, we have prepared a series of biologically active
fluorinated analogs of the commercial acaricide Tebufenpyrad.
The preparation of these compounds involves the use of the
fluorinated alcohols TFE and HFIP as solvents in the key
1
3
MHz, CDCl3): δ 20.2 (t, JCF ) 26.0), 90.8 (t, JCF ) 3.6), 111.9,
1
2
116.3 (t, JCF ) 244.0), 116.5, 146.2, 148.6, 175.9, 180.9 (t, JCF
) 31.0) ppm; 19F-NMR (CDCl3, 282.4 MHz): δ -100.3 (q, JFH
)
18.6 Hz, 2F; CF2) ppm. HRMS: calcd for C9H8F2O3 (M+):
202.0441; found 202.0393.
General Procedure for Preparation of Pyrazoles 2 and
5-Hydroxypyrazolines 3. The substituted hydrazine (MeNHNH2
or PhNHNH2) (0.45 mmol) was slowly added to the corresponding
1,3-diketone 1 (0.3 mmol) in the chosen solvent (0.5 mL), and the
mixture was stirred at room temperature for 45 min. The solvent
was evaporated and the residue was taken up in EtOAc, washed
(30) Garc´ıa-Mar´ı, F.; Roca, D.; Fonbuena, P.; Ferragut, F.; Costa-Comelles,
J. Bol. San. Veg. Plagas 1988, 14, 163–169.
(31) Masai is commercialized by BASF.
3528 J. Org. Chem. Vol. 73, No. 9, 2008

Synthesis of Fluorinated Tebufenpyrad Analogs
with water and brine, dried over anhyd Na2SO4, filtered, and
concentrated in Vacuo to give the corresponding pyrazoles, which
were purified by means of column chromatography on silica gel to
afford pure compounds 2 and 3/4.
and HCl 3N (0.042 mol) in THF (60 mL) was heated to reflux for
30 min. The reaction mixture was cooled to room temperature,
extracted with EtOAc (3 × 20 mL), and then washed sequentially
with H2O (15 mL) and brine. The organic layer was dried over
anhyd Na2SO4 and filtered. The solvent was removed under reduced
pressure to give pyrazoles 4, which were purified by means of
column chromatography on silica gel.
3-(1,1-Difluoroethyl)-5-(2-furyl)-1-methylpyrazole (2c). Flash
chromatography [n-hexane-EtOAc (10:1)] (Rf ) 0.40) afforded 2c
as a pale-yellow oil (45% yield in EtOH, 97% in TFE, 96% in
HFIP). 1H NMR (300 MHz, CDCl3): δ 1.95 (t, JHF ) 18.5 Hz, 3H;
CH3), 3.98 (s, 3H; CH3), 6.45 (dd, J1 ) 3.4 Hz, J2 ) 1.7 Hz, 1H;
CH), 6.52 (dd, J1 ) 3.4 Hz, J2 ) 0.8 Hz, 1H; CH), 6.57 (s, 1H;
CH), 7.46 (dd, J1 ) 1.7 Hz, J2 ) 0.8 Hz, 1H; CH) ppm; 13C NMR
5-(1,1-Difluoroethyl)-3-(2-furyl)-1-methylpyrazole (4c). Flash
chromatography [n-hexane-EtOAc (8:1)] (Rf ) 0.30) afforded 4c
1
as a pale-yellow solid; (yield 95%); mp 103-105 °C. H NMR
(300 MHz, CDCl3): δ 1.91 (t, JHF ) 18.3 Hz, 3H; CH3), 3.88 (d,
JHF ) 0.1 Hz, 3H; CH3), 6.31 (dd, J1 ) 1.9 Hz, J2 ) 1.5 Hz, 1H;
CH), 6.45 (d, J ) 0.9 Hz, 1H; CH), 6.50 (d, J ) 3.21 Hz, 1H;
CH), 7.29 (t, J ) 0.8 Hz, 1H; CH) ppm; 13C NMR (75.5 MHz,
CDCl3): δ 24.4 (t, 2JCF ) 26.9), 38.9 (t, 3JCF ) 2.9), 103.7 (t, 3JCF
2
(75.5 MHz, CDCl3): δ 22.0 (t, JCF ) 27.6), 37.0, 100.3, 107.2,
1
2
109.6, 117.0 (t, JCF ) 232.8), 133.2, 141.1, 142.2, 146.4 (t, JCF
) 33.3) ppm. 19F-NMR (CDCl3, 282.4 MHz): δ -85.2 (q, JFH
)
18.5 Hz, 2F; CF2) ppm. HRMS: calcd for C10H10F2N2O (M+)
212.0761; found 212.0797.
1
2
) 4.9), 106.2 (d), 111.7, 117.5 (t, JCF ) 234.0), 139’3 (t, JCF
)
5-(1,1-Difluoroethyl)-3-(2-furyl)-1-methyl-4,5-dihydro-1H-
pyrazol-5-ol (3c). Flash chromatography [n-hexane-EtOAc (10:
1)] (Rf ) 0.25) afforded 3c as a white solid; mp 92-94 °C (54%
28.7), 142.3, 142.7, 148.4 ppm; 19F-NMR (CDCl3, 282.4 MHz): δ
-86.3 (c, JFH ) 18.3 Hz, 2F; CF2) ppm. HRMS: calcd for
C10H10F2N2O (M+) 212.0761; found 212.0749.
1
yield in EtOH, 2% in TFE, 2% in HFIP). H NMR (300 MHz,
CDCl3): δ 1.67 (t, J ) 19.0 Hz, 3H; CF2CH3), 2.90 (s, 3H; CH3),
Acknowledgment. We thank the IMPIVA and Industrias
Afrasa (IMIDTD/2007/230), the Ministerio de Educacio´n y
Ciencia (CTQ2007-61462 and CTQ2006-01317), and the Gen-
eralitat Valenciana (GR03/193) for financial support.
2
3.03 (dt, J1 ) 17.7 Hz, JHF ) 1.3 Hz, 1H; CHH), 3.25 (d, J )
17.7 Hz, 1H; CHH), 6.39 (dd, J1 ) 3.5 Hz, J2 ) 1.7 Hz, 1H; CH),
6.45 (dd, J1 ) 3.5 Hz, J2 ) 0.6 Hz, 1H; CH), 7.39 (dd, J1 ) 1.7
Hz, J2 ) 0.6 Hz, 1H; CH); 13C NMR (75.5 MHz, CDCl3): δ 21.2
(t, 2JCF) 26.9), 35.2, 44.5, 95.8 (t, 2JCF ) 26.9), 110.1, 112.3, 139.9,
1
144.1, 148.4; 19F-NMR (CDCl3, 282.4 MHz): δ -112.4 (qd, JFH
Supporting Information Available: Experimental proce-
dures and NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
) 19.0 Hz, J2 ) 6.0 Hz, 2F; CF2); HRMS: calcd for (M+)
C10H12F2N2O2 230.0867; found 230.0862.
General Procedure for Dehydration of Hydroxypyrazolines
3 to Pyrazoles 4. A solution of hydroxypyrazoline 3 (0.014 mol)
JO800251G
J. Org. Chem. Vol. 73, No. 9, 2008 3529