Synthesis of new fluorinated tebufenpyrad analogs with acaricidal activity through regioselective pyrazole formation

Article abstract of DOI:10.1021/jo801729p

(Chemical Equation Presented) In previous studies, our group has shown that the use of fluorinated alcohols such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation from 1,3-diketone with methylhydrazine. We have now applied this synthetic method to the preparation of new fluorinated pyrazoles, which have then been used as synthetic intermediates in the preparation of fluorinated analogs of Tebufenpyrad, a commercial acaricide. These compounds display a strong acaricidal activity that is either comparable to or better than that of the commercial compound.

Full text of DOI:10.1021/jo801729p

Synthesis of New Fluorinated Tebufenpyrad Analogs with Acaricidal
Activity Through Regioselective Pyrazole Formation
Santos Fustero,*,†,‡ Raquel Roma´n,† Juan F. Sanz-Cervera,†,‡ Antonio Simo´n-Fuentes,†
Jorge Bueno,‡ and Salvador Villanova†
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 August 4, 2008
In previous studies, our group has shown that the use of fluorinated alcohols such as trifluoroethanol
(TFE) and hexafluoroisopropanol (HFIP) as solvents dramatically increases the regioselectivity in the
pyrazole formation from 1,3-diketone with methylhydrazine. We have now applied this synthetic method
to the preparation of new fluorinated pyrazoles, which have then been used as synthetic intermediates in
the preparation of fluorinated analogs of Tebufenpyrad, a commercial acaricide. These compounds display
a strong acaricidal activity that is either comparable to or better than that of the commercial compound.
Introduction
In the past few years, the interest in pyrazole derivatives has
increased due to their proven usefulness as intermediates in the
preparation of new biological materials. Specifically, the pyra-
zole moiety is present in many agrochemically important
compounds, such as the pesticides Cyenopyrafen,1 Tebufen-
pyrad,2 Tolfenpyrad,3 and Fenpyroximate4 (Figure 1).
Tebufenpyrad is a commercial N-methylpyrazole derivative
with important acaricidal activity against the two-spotted spider
mite Tetranychus urticae Koch, which causes significant yield
losses worldwide in many field and greenhouse crops.5 This
mite infests over 200 species of plants, including common
FIGURE 1. Some representative examples of pesticides with an
N-methylpyrazole unit.
ornamental plants such as azaleas, camellias, or roses; fruits
such as blackberries, blueberries, and strawberries; vegetables
such as tomatoes and cucumbers; and trees, including elms,
orange trees, and lemon trees. The mite affects crops through
direct feeding, which reduces the area available for photosyn-
thetic activity and, in severe infestations, can cause leaf
abscission. Unfortunately, T. urticae is difficult to control
because of its ability to quickly develop resistance to acaricides.6
This resistance has resulted in a demand for new, resistant-free
acaricides with novel modes of action.
* To whom correspondence should be addressed. Tel.: +34-963544279. Fax:
+34-963544938.
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) Murakami, H.; Masuzawa, S.; Takii, S.; Ito, T. Jpn. Patent 2003201280
A 20030718.
(2) Marcic, D. Experim. Appl. Acarology 2005, 36, 177–185.
(3) Nonata, N. Agrochem. Jpn. 2003, 83, 17–19.
(4) Kim, M.; Sim, C.; Shin, D.; Suh, E.; Cho, K. Crop Protect. 2006, 25,
542–548.
(5) Kim, M.; Shin, D.; Suh, E.; Cho, K. Appl. Entomol. Zool. 2004, 39, 401–
409.
(6) Devine, G. J.; Barber, M.; Denholm, I. Pest Manag. Sci. 2001, 57, 443–
448.
10.1021/jo801729p CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8545–8552 8545

Fustero et al.
SCHEME 1. Two Synthetic Strategies for the Preparation
of Fluorinated Analogs of Tebufenpyrad
FIGURE 2. Representative examples of N-[(trifluoromethyl)aryl]pyra-
zole derivatives with insecticidal/acaricidal activities.
By varying the functional groups and structural elements of
a model bioactive compound, the interaction of the latter with
the active site of a given target molecule can be improved, as
well as its physicochemical, pharmacokinetic, and dynamic
properties. In this context, it is widely accepted that the
introduction of fluorine atoms into organic molecules causes
significant physicochemical and biological changes.7 The so-
called “fluorine factor” described in the literature several years
ago stems from the unique combination of properties associated
with the fluorine atom itself. The introduction of fluorine into
bioactive compounds has thus become an important tool in the
quest for modern crop protection products in terms of improving
efficacy, environmental safety, user friendliness, and economic
viability. Indeed, the number of active ingredients in modern
crop protection products that contain fluorine-substituted moi-
eties has steadily increased over the past 30 years. A survey of
all halogenated commercial products available between 1940
and 2003 shows that fluorine products account for more than
28%. Moreover, about 27% of all fluoroorganic agrochemicals
on the market today are insecticides/acaricides,8 including the
N-[(trifluoromethyl)aryl]pyrazole derivatives Acetoprole, Fipronil,
and Ethiprole (Figure 2).
In a previous paper we reported on the synthesis of a series
of fluorinated analogs of the commercial acaricide Tebufen-
pyrad,9 two of which displayed acaricidal activity within the
same order of magnitude as that of the commercial product.
We have now used a different synthetic strategy for the
introduction of the desired fluorine atoms, one that again makes
use of the regioselective synthesis of key pyrazole intermediates.
In this case, however, a different pyrazole functionalization is
employed to access other pyrazoles that are partially fluorinated
on the C-3 ethyl group of Tebufenpyrad (Figure 1). This has
allowed us to prepare new Tebufenpyrad analogs with a different
fluorination pattern and improved acaricidal activity.
SCHEME 2. Reaction of Fluorinated 1,3-Diketones (1a-c)
with Methylhydrazine
ate fluorinated esters and ketones.10 In contrast, when RF )
CF3CH2, CHF2CH2, CH2FCH2, CH3CHF, or CF3CHF, the
starting fluorinated 1,3-diketone analogs were not easily avail-
able. We thus developed strategy B (Scheme 1), in which ethyl
4-(2-furyl)-2,4-dioxobutanoate 2 is used as the key 1,3-dicar-
bonylic starting material, with the fluorine atoms being incor-
porated at a later stage of the sequence. Compound 2 can be
easily prepared in 92% yield through the condensation of
2-acetylfurane and diethyl oxalate with t-BuOK as a base and
THF:DME as a solvent.10
In both strategies, the first step is the formation of the pyrazole
ring through condensation of methylhydrazine and the appropri-
ate 1,3-dicarbonyl compound (1a-c, 2). Recently, we reported
on the results of the regioselective condensation between
fluorinated 1,3-diketones 1a-c and methylhydrazine.9 The
results showed that mixtures of 5-furylpyrazoles 3a-c and
5-hydroxypyrazolines 4a-c in ca. 1:1 to 2:1 ratios were formed
when EtOH was used as a solvent at room temperature (Scheme
2), but that the regioselectivities were considerably enhanced
when the fluorinated solvents 2,2,2-trifluoroethanol (TFE) and
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) were used instead. The
targeted 5-furylpyrazoles 3a-c were thus obtained almost
exclusively when reactions were carried out in HFIP.9
However, to access pyrazoles with other partially fluorinated
groups, we needed a different, more flexible synthetic approach.
We therefore decided to introduce the ethoxycarbonyl group
as a synthetic precursor of the target groups. In this new strategy
B, the reaction of the 1,3-diketoester 2 with methylhydrazine
in ethanol at room temperature afforded an almost 1:1 mixture
of the two 5-furyl 5 and 3-furyl 6 regioisomers in high yield;
these were then easily separated with the aid of flash chroma-
tography. In contrast to the lack of regioselectivity observed in
EtOH, when the condensation reaction was carried out with the
fluorinated solvents TFE and HFPI, the ratio increased to 93:7
in favor of the desired regioisomer 5, which was obtained in
almost quantitative yield (Scheme 3).
Results and Discussion
A. Synthesis. The aim of our work was to prepare new
fluorinated pyrazoles derived from Tebufenpyrad and which
incorporate several different fluorinated substitution patterns (RF)
on the C-3 ethyl group of the heterocyclic ring. For those
pyrazoles in which RF ) CF3, CF3CF2, or CH3CF2, we have
very recently developed strategy A (Scheme 1), taking into
account that the fluorinated 1,3-diketones 1a-c were either
commercially available or easily synthesized from the appropri-
(7) (a) Baasner, B.; Hagemann, H.; Tatlow, J. C. In Houben-Weyl Organo-
Fluorine Compounds Volume E 10a-c; Thieme Stuttgart: New York, 2000. (b)
Banks, R. E.; Smart, B. E.; Tartlow, J. C. Ed. In Organofluorine Chemistry:
Principles and Commercial Applications; Plenum Press: New York, 1994. (c)
Schlosser, M. Angew. Chem., Int. Ed. 1998, 37, 1496–1513.
(8) Jeschke, P. ChemBioChem 2004, 5, 570–589.
(9) Fustero, S.; Roma´n, R.; Sanz-Cervera, J. F.; Simo´n-Fuentes, A.; Cun˜at,
A. C.; Villanova, S.; Murgu´ıa, M. J. Org. Chem. 2008, 73, 3523–3529.
(10) Jiang, X.-H.; Song, L.-D.; Long, Y.-Q. J. Org. Chem. 2003, 68, 7555–
7558.
8546 J. Org. Chem. Vol. 73, No. 21, 2008

Synthesis of New Fluorinated Tebufenpyrad Analogs
SCHEME 3. Reaction of Ethyl 4-(2-Furyl)-2,3-dioxobutanoate
(2) with Methyl-hydrazine
SCHEME 6. Preparation of Carboxylic Acids 17-21 and
Synthesis of the Fluorinated Analogs of Tebufenpyrad 23
and 24
SCHEME 4. Preparation of 3-Formyl-5-(2-furyl)-1-
methylpyrazole (8)
treatment of 8 with Ruppert-Prakash’s reagent11 (CF3SiMe3)
followed by acid hydrolysis afforded the 1-hydroxy-2,2,2-
trifluoroethyl derivative 11 in 90% yield. This was then
converted into the tetrafluorinated derivative 12 (RF ) CF3CHF)
in 85% yield through treatment with Deoxofluor. Alternatively,
11 was dehydroxylated via its thiocarbonate, which was reduced
with Bu3SnH to provide the trifluoroethyl derivative 13 (RF )
CF3CH2) in 46% yield (two steps).12 Likewise, Wittig reaction
of 8 with a basic solution of (methoxymethyl)triphenylphos-
phonium chloride followed by acid hydrolysis afforded the
homologous aldehyde 14 in 98% yield, which then gave rise to
the difluorinated derivative 15 (RF ) CHF2CH2) in 76% yield
through treatment with Deoxofluor. Finally, sodium borohydride
reduction of 14 and subsequent treatment with Deoxofluor
afforded the monofluorinated derivative 16 (RF ) CH2FCH2)
in 52% yield (two steps).
SCHEME 5. Synthesis of Fluorinated N-Methylpyrazoles
(10,12,13,15,16)
The oxidation of the furyl ring of the fluorinated N-
methylpyrazoles thus obtained with sodium periodate in the
presence of a catalytic amount of RuCl3 ·3H2O at room
temperature provided the corresponding carboxylic acids 17-21
in good to excellent yields.13 However, the next step, which
involved chlorination of C-4 at the pyrazole ring, presented
several unexpected difficulties. For example, while the reaction
was successful with the carboxylic acid 18 (RF ) CF3CHF)
(Scheme 6), providing the corresponding chlorinated derivative
22 in good yield, the carboxylic acid analog 19 (RF ) CF3CH2)
afforded a mixture of two nonseparable compounds (one of them
being the desired C-4 chlorinated derivative). Furthermore, with
the rest of the compounds (17, 20, and 21), only complex
mixtures were obtained. Nevertheless, both the chlorinated
derivative 22 and the chlorinated carboxylic acid found in the
mixture of compounds from the chlorination of 19 were
subsequently converted into the fluorinated carboxamide analogs
of Tebufenpyrad 23 and 24, respectively (Scheme 6).
3-(Ethoxycarbonyl)-5-(2-furyl)-N-methylpyrazole 5 was then
converted into the aldehyde 8, obtained in 74% combined yield
through a two-step sequence involving LiAlH4 reduction to the
corresponding alcohol 7 and subsequent oxidization with MnO2
(Scheme 4). This two-step process afforded much higher yields
than the direct reduction of the ester to the aldehyde with
DIBALH.
To avoid the aforementioned inconvenience in the chlorina-
tion reaction, we modified our strategy slightly and performed
(12) Jiang, Z.-X.; Qin, Y.-Y.; Ping, F.-L. J. Org. Chem. 2003, 68, 7544–
7547.
(13) Danishefsky, S. J.; DeNinno, M. P.; Chen, S. H. J. Am. Chem. Soc.
1988, 110, 3929–3940.
(14) Preliminary assays were carried out using the non-chlorinated carboxa-
mide analogs of Tebufenpyrad 30′ (RF) CHFCH3) and 32′ (RF) CH2CHF2),
which were obtained by amidation of the corresponding carboxylic acids 17
and 21, respectively. Under the same reaction conditions described above,
chlorination of 30′ and 32′ afforded complex mixtures of products. Likewise,
the desired results were not obtained when other chlorination agents such as
NCS, Chloramine-T, and tert-butyl hypochlorite were used in the reaction with
the carboxylic acids 17-21.
Compound 8 was then used as the key intermediate for the
preparation of the rest of the fluorinated analogs of Tebufenpyrad
in this work (Scheme 5). Reaction of 8 with MeMgBr afforded
the 1-hydroxyethyl derivative 9 in 94% yield. Subsequent
treatment of 9 with Deoxofluor provided the monofluorinated
derivative 10 (RF ) CH3CHF) in 61% yield. In a similar fashion,
(11) Singh, R. P.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999,
64, 2579–2581.
J. Org. Chem. Vol. 73, No. 21, 2008 8547

Fustero et al.
6 days
TABLE 1. Biological Activity of the Fluorinated Tebufenpyrad Analogs on Tetranychus urticae
% mortalitya
% fertility inhibitiona
4 days
entry
compound [RF]
24 h
10
4 days
6 days
60
24 h
1
2
3
4
5
6
7
8
23 [CHF-CF3]
24 [CH2-CF3]
30 [CHF-CH3]
30′ [CHF-CH3]
32 [CH2-CF2H]
32′ [CH2-CF2H]
33 [CH2-CH2F]
Tebufenpyrad
10
30
53
97
60
98
65
98
25
70
70 (48)
70 (16)
100 (80)
100 (59)
100 (96)
100 (92)
75 (44)
70 (10)
100 (71)
100 (14)
100 (100)
100 (100)
100 (66)
80 (10)
100 (75)
100 (10)
100 (100)
100 (100)
100 (95)
100 (68)
100 (100)
100 (96)
100 (100)
100 (84)
100 (95)
96 (91)
100 (100)
100 (100)
100 (100)
100 (100)
100 (96)
100 (94)
100 (100)
100 (98)
100 (100)
100 (100)
a Concentration of active principle in the assay: 5 g/L; the numbers in parentheses show the results for an active principle concentration in the assay
of 0.16 g/L.
SCHEME 7. Synthesis of Fluorinated Analogs of
Tebufenpyrad 30, 32, and 33
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. Preliminary tests were
carried out with a solution of 5 g/L for each compound. Table
1 lists the obtained results.
The results indicate that, except for 23, all the fluorinated
derivatives tested sboth chlorinated and nonchlorinated sexert
complete (100%) or nearly complete (96%) fertility inhibition
early within the 24 h period, as was also observed for
Tebufenpyrad. In contrast, whereas 32, 32′, 33, and Tebufen-
pyrad all cause 100% mortality within 24 h, 30 and 30′ display
slightly lower activity (70%), while both 23 and 24 exhibit a
very low adulticide activity within the same time period.
Solutions of 30, 30′, 32, 32′, 33, and Tebufenpyrad at 1.50,
0.67, and 0.16 g/L were then prepared to evaluate and compare
their acaricidal activity at concentrations lower than 5 g/L
(Figure 3).17
Interestingly, the results indicate that only 33 (RF
)
CH2CH2F) causes complete (100% at a concentration of 1.5
g/L) or nearly complete (96% at a concentration of 0.67 and
0.16 g/L) adult mortality within the first 24 h, with its effect
being slightly higher than that of Tebufenpyrad at the same
concentration. Within the same time period, the only other
compound to cause 100% mortality is 32 at a concentration of
1.5 g/L. Like Tebufenpyrad, the chlorinated derivatives 30, 32,
and 33 cause complete mortality at 1.5 g/L within the first 4
days. In contrast, the nonchlorinated carboxamides 32′ and
particularly 30′ display significantly lower adulticide activities
than the chlorinated analogs at both 0.67 and 0.16 g/L. These
results show the relation between the adulticide activity of
fluorinated analogs of Tebufenpyrad and the presence of the
chlorine atom in the pyrazole moiety.
the chlorination at an earlier stage.14 The furyl ring of 3-(ethox-
ycarbonyl)-5-(2-furyl)-N-methylpyrazole 5 was thus oxidized
in 90% yield and the resulting carboxylic acid 25 was success-
fully chlorinated in 60% yield (Scheme 7). Conversion of 26
into the amide 27 took place without difficulty and was followed
by chemoselective reduction of the ester group with LiBH4. The
resulting primary alcohol was easily oxidized with MnO2 to
afford aldehyde 28 in 70% combined yield. This compound, in
turn, constituted the key intermediate for the preparation of the
target molecules. The subsequent steps were similar to those
previously described (see Scheme 5) and provided the fluori-
nated Tebufenpyrad analogs 30, 32, and 33 (Scheme 7).
B. Acaricidal Activity. A standard method was used to test
the fluorinated analogs of Tebufenpyrad 23, 24, 30, 32, and 33
and the nonchlorinated carboxamides 30′ and 32′ as acaricides
against Tetranychus urticae Koch.15 The activity of the fluori-
nated compounds was then compared to that of the commercial
product Masai, the active principle of which is Tebufenpyrad.16
The fertility inhibition of Tetranychus urticae is thus clearly
increased by several of our new fluorinated analogs. While 30,
30′, 32, 32′, 33, and Tebufenpyrad all display 100% fertility
inhibition after 24 h, significant differences appear at lower
concentrations. Indeed, at the lowest concentration assayed (0.16
g/L), while the inhibitory activity for Tebufenpyrad is 84%,
compounds 32 and 33 still display 100% activity, with the
nonchlorinated analog 32′ still exerting a somewhat higher
activity (96%) than the reference compound (Figure 3).
(15) Garc´ıa-Mar´ı, F.; Roca, D.; Fonbuena, P.; Ferragut, F.; Costa-Comelles,
J. Bol. San. Veg. Plagas 1988, 14, 163–169.
(16) Masai is commercialized by BASF.
(17) The concentration of Tebufenpyrad in solution for standard field
treatment varies between 200 mg/L (pumpkin, eggplant, tomato), 130 mg/L
(cotton), and 70 mg/L (citrus fruits).
8548 J. Org. Chem. Vol. 73, No. 21, 2008

Synthesis of New Fluorinated Tebufenpyrad Analogs
FIGURE 3. Adult mortality and fertility inhibition of fluorinated analogs of Tebufenpyrad on Tetranychus urticae.
CH), 6.87 (s, 1H; CH), 7.28 (dd, J1) 2.8 Hz, J2) 0.5 Hz, 1H;
Conclusions
CH); 7.62 (dd, J1) 1.2 Hz, J2) 0.5 Hz, 1H; CH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ 13.9, 62.4, 98.8, 113.0, 118.4, 147.6, 150.7,
161.8, 165.9, 180.7 ppm. HRMS: calcd for C10H10O5 (M+):
210.0523; found 210.0528.
In summary, the use of the fluorinated alcohols TFE and HFIP
allows for the regioselective synthesis of pyrazole 5, a compound
that constitutes a versatile synthetic intermediate for the
preparation of biologically active compounds with a pyrazole
moiety. As an example, we have successfully synthesized a
small set of Tebufenpyrad analogs with several fluorination
patterns on the ethyl group that were for the most part highly
active as acaricides against Tetranychus urticae, in some cases
displaying an even higher acaricidal activity than Tebufenpyrad,
which was used as a reference. In fact, two of these compounds
(32 and 33) display a fertility inhibition superior to that of
Tebufenpyrad.
3-(Ethoxycarbonyl)-5-(2-furyl)-1-methylpyrazole (5). Meth-
ylhydrazine (36 mmol, 1.6 g) was added slowly to 1,3-diketone 2
(28 mmol, 5.9 g) dissolved in HFIP (60 mL) at 0 °C under nitrogen
atmosphere and the resulting mixture was stirred at room temper-
ature for 45 min. The solvent was evaporated and the residue was
taken up in EtOAc, washed with water and brine, dried over anh
Na2SO4, filtered, and concentrated in Vacuo to afford pyrazole 5,
which was then purified with the aid of column chromatography
on silica gel. Flash chromatography [n-hexane-EtOAc (8:1)] (Rf )
0.30) afforded 5 as a pale-yellow solid (93% yield) (mp: 50-52
°C). 1H NMR (300 MHz, CDCl3): δ 1.35 (t, J ) 7.2 Hz, 3H; CH3),
4.06 (s, 3H; CH3), 4.35 (q, J ) 7.2 Hz, 2H; CH2), 6.46 (dd, J1 )
3.5 Hz, J2) 1.4 Hz, 1H; CH), 6.51 (d, J ) 3.5 Hz, 1H; CH), 6.94
(s, 1H; CH), 7.47 (d, J ) 1.4 Hz, 1H; CH) ppm. 13C NMR (75.5
MHz, CDCl3): δ 14.8, 39.9, 61.5, 108.1, 109.8, 111.9, 135.9, 143.0,
143.6, 144.2, 162.5 ppm. HRMS: calcd for C11H12N2O3 (M+)
220.0818; found 220.0805.
3-Formyl-5-(2-furyl)-1-methylpyrazole (8). Step 1: Reduc-
tion of the Ethoxycarbonyl Group of 5 to Afford Compound
7. A solution of 3-(ethoxycarbonyl)-5-(2-furyl)-1-methylpyrazole
(5) (9 mmol, 2.0 g) in THF (30 mL) was added to a solution of
LiAlH4 (27 mmol, 1.1 g) in THF (30 mL) at 0 °C under nitrogen
atmosphere and the resulting mixture was stirred at 50-60 °C until
5 was no longer detectable through TLC (ca. 1 h). Three milliliters
of water were then added to the mixture at 0 °C, followed by 3
mL of 15% aqueous solution of NaOH and 8 mL of water. The
mixture was stirred at room temperature for 30 min and then 30
mL of Cl2CH2 were added. The organic phase was then separated
Experimental Section
Ethyl 4-(2-Furyl)-2,4-dioxobutanoate (2). A solution containing
2-acetylfurane (27 mmol, 2.9 g) and diethyl oxalate (54 mmol,
7.9 g) in dimethoxyethane (DME) (50 mL) was added slowly to a
suspension of t-BuOK (54 mmol, 6.0 g) in THF (50 mL) at room
temperature and the resulting reaction mixture was stirred for two
hours. Solvents were removed in Vacuo and the residue was
hydrolyzed with HCl 1 M (20 mL) until acid pH was reached. The
aqueous layer was extracted with EtOAc (3 × 20 mL) and the
organic phase was washed with brine, dried over anh. Na2SO4, and
filtered. The solvent was removed to give a brown solid, which
was then purified with the aid of column chromatography on silica
gel that had previously been deactivated through treatment with
2% acetic acid. Flash chromatography [n-hexane-EtOAc (2:1)] (Rf
) 0.30) afforded 2 as a brownish solid (92%, 5.2 g); mp 72-5 °C.
1H NMR (300 MHz, CDCl3): δ 1.34 (t, J ) 5.3 Hz, 3H; CH3),
4.32 (q, J ) 5.3, 2H; CH2), 6.56 (dd, J1) 2.8 Hz, J2) 1.2 Hz, 1H;
J. Org. Chem. Vol. 73, No. 21, 2008 8549

Fustero et al.
and the mixture was dried over anh Na2SO4, filtered, and concen-
trated in vacuo to give a yellow oil, which was purified by means
of column chromatography on silica gel to afford pure compound
7. Flash chromatography [n-hexane-EtOAc (3:1)] (Rf ) 0.30)
afforded 7 as a pale-yellow oil (98%, 1.6 g). 1H NMR (300 MHz,
CDCl3): δ 3.92 (s, 3H; CH3), 4.58 (s, 2H; CH2), 6.38 (s, 1H; CH),
6.42 (dd, J1) 3.4 Hz, J2) 1.7 Hz, 1H; CH), 6.46 (dd, J1) 3.4 Hz,
J2) 0.6 Hz, 1H; CH), 7.42 (dd, J1) 1.7 Hz, J2) 0.6 Hz, 1H; CH)
ppm. 13C NMR (75.5 MHz, CDCl3): δ 38.7, 58.7, 103.9, 109.0,
111.8, 135.4, 143.1, 145.0, 151.7 ppm. HRMS: calcd for C9H10N2O2
(M+) 178.0739; found 178.0742.
to 8 to Afford Compound 11. (Trifluoromethyl)trimethylsilane (7.6
mmol, 1.1 g) and tetrabutylamonium fluoride (0.09 mmol) were
added in succession to a solution of 8 (4.5 mmol, 0.8 g) in THF
(15 mL) at room temperature under nitrogen atmosphere and the
resulting mixture was stirred until 8 was no longer detectable
through TLC (ca. 3.5 h). A 6N solution of HCl (5 mL) was then
added and the reaction mixture was stirred for 1 h. Next, water (5
mL) was added and the aqueous layer was extracted with EtOAc
(3 × 10 mL), washed with brine (2 × 5 mL), dried over anh
Na2SO4, and concentrated in Vacuo to give a yellow solid, which
was purified by means of column chromatography on silica gel.
Flash chromatography [n-hexane-EtOAc (3:1)] (Rf ) 0.30) afforded
11 as a pale-yellow solid (90%, 1.0 g) (mp: 82-84 °C).1H NMR
Step 2: Oxidation of the Hydroxymethyl Group of 7. Activated
MnO2 (60 mmol, 6.1 g) was added to a solution of 7 (10 mmol,
1.8 g) in CH3CN (60 mL). The reaction mixture was refluxed until
7 was no longer detectable through TLC (ca. 4 h). The mixture
was then cooled to room temperature, filtered through celite in
Vacuo, extracted with ethyl acetate, dried over anh Na2SO4, and
concentrated in Vacuo to give a brown solid, which was purified
by means of column chromatography on silica gel to give compound
8. Flash chromatography [n-hexane-EtOAc (4:1)] (Rf ) 0.40)
afforded pure 8 as a pale-yellow solid (75%, 1.3 g) (mp: 55-57
(300 MHz, CDCl3): δ 3.98 (s, 3H; CH3), 5.01 (q, J
) 6.7 Hz,
HF
1 H; CH), 6.45 (dd, J1 ) 3.4 Hz, J2 ) 1.8 Hz, 1H; CH), 6.47 (s,
1H; CH), 6.53 (d, J ) 3.4 Hz, 1H; CH), 7.46 (dd, J1 ) 1.8 Hz, J2
) 0.8 Hz, 1H; CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ 39.1,
2
4
68.1 (q, JCF) 33.3 Hz), 103.6 (q, JCF ) 1.7 Hz), 109.6, 111.9,
1
3
124.5 (q, JCF ) 231.7 Hz), 136.3, 143.4, 144.4, 145.5 (q, JCF
)
1.2) ppm. 19F NMR (CDCl3, 282.4 MHz): δ -78.9 (d, JFH ) 6.7
Hz, 3F; CF3) ppm. HRMS: calcd for C10H9F3N2O2 (M+) 246.0606;
found 246.0586.
1
°C). H NMR (300 MHz, CDCl3): δ 4.08 (s, 3H; CH3), 6.47 (dd,
J1) 3.5 Hz, J2) 1.9 Hz, 1H; CH), 6.58 (d, J ) 3.5 Hz, 1H; CH),
6.90 (s, 1H; CH), 7.48 (dd, J1) 1.9 Hz, J2) 0.5 Hz, 1H; CH),
9.87 (s, 1H; CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ 40.0, 104.9,
110.2, 112.1, 136.6, 143.8, 143.9, 150.6, 186.6 ppm. HRMS: calcd
for C9H8N2O2 (M+) 176.0586; found 176.0585.
Step 2: Fluorination of 11 with Deoxofluor (see above,
“Fluorination of 9 with Deoxofluor” for the Procedure). Flash
chromatography [n-hexane-EtOAc (10:1)] (Rf ) 0.40) afforded 12
1
as a pale yellow oil (85%, 0.42 g). H NMR (300 MHz, CDCl3):
δ 4.00 (d, J ) 1.3 Hz, 3H; CH3), 5.61 (qd, J1HF ) 44.2 Hz, J2
)
HF
3-(1-Fluoroethyl)-5-(2-furyl)-1-methylpyrazole (10). Step 1:
Addition of Methylmagnesium Bromide to 8 to Afford Com-
pound 9. A 1 M solution of CH3MgBr (4.5 mmol) in THF was
slowly added to a solution of 8 (3 mmol, 0.5 g) in THF (11 mL)
under nitrogen atmosphere at 0 °C. The mixture was stirred
overnight at room temperature. The reaction mixture was then
hydrolyzed with a saturated solution of NH4Cl (5 mL), extracted
with EtOAc (3 × 10 mL), washed with brine, dried over anh
Na2SO4, filtered, and concentrated in Vacuo to give a yellow oil,
which was purified by means of column chromatography on silica
gel. Flash chromatography [n-hexane-EtOAc (2:1)] (Rf ) 0.30)
afforded 9 as a pale-yellow oil (94%, 0.54 g). 1H NMR (300 MHz,
CDCl3): δ 1.48 (d, J ) 4.9 Hz, 3H; CH3), 2.31 (broad, 1H; OH),
3.93 (s, 3H; CH3), 4.87 (q, J ) 4.9 Hz, 1H; CH), 6.35 (s, 1H; CH),
6.43 (dd, J1) 2.5 Hz, J2) 1.4 Hz, 1H; CH), 6.47 (dd, J1) 2.5 Hz,
J2) 0.5 Hz, 1H; CH), 7.43 (dd, J1) 1.4 Hz, J2) 0.5 Hz, 1H; CH)
ppm. 13C NMR (75.5 MHz, CDCl3): δ 1.4, 23.7, 30.1, 38.8, 65.2,
101.8, 108.9, 111.8, 143.1 ppm. HRMS: calcd for C10H12N2O2 (M+)
192.0899; found 192.0887.
6.5, 1H; CH), 6.46 (dd, J1 ) 3.4 Hz, J2 ) 1.8 Hz, 1H; CH), 6.55
(dd, J1) 3.4 Hz, J2 ) 0.5 Hz, 1H; CH), 6.63 (s, 1H; CH), 7.47
(dd, J1 ) 1.8 Hz, J2 ) 0.5 Hz, 1H; CH) ppm. 13C NMR (75.5
MHz, CDCl3): δ 39.4, 84.6 (qd, 1JCF ) 132.3 Hz, 2JCF) 36.2 Hz),
1
2
104.6, 109.7, 111.9, 122.5 (qd, JCF) 231.2 Hz, JCF ) 29.9 Hz),
2
136.3, 141.8 (d, JCF ) 24.7 Hz), 143.5, 144.2 ppm. 19F NMR
(CDCl3, 282.4 MHz): δ -78.8 (dd, J1FF ) 14.3 Hz, J2FH ) 6.5 Hz,
FH
FF
3F; CF3), -189.4 (qd, J1 ) 44.2 Hz, J2 ) 14.3 Hz, 1F; CF)
ppm. HRMS: calcd for C10H8F4N2O (M+) 248.0570; found
248.0573.
3-(2,2,2-Trifluoroethyl)-5-(2-furyl)-1-methylpyrazole (13). Mo-
lecular sieves (4 Å) (500 mg) and dimethylaminopyridine (DMAP)
(3.4 mmol, 0.42 g) were added to a solution of 11 (1.7 mmol,
0.42 g) in toluene (25 mL) at room temperature under nitrogen
atmosphere, and the resulting mixture was vigorously stirred
magnetically. Phenyl chlorothioformiate (PHOCSCl) (3.4 mmol,
0.58 g) was then slowly added and the mixture was stirred at 50-60
°C until 11 was no longer detectable through TLC. The reaction
mixture was cooled to room temperature, filtered over celite in
Vacuo, and washed with EtOAc. The filtrate was concentrated in
Vacuo to give a yellow oil, which was purified by means of column
chromatography on silica gel. Flash chromatography [n-hexane-
EtOAc (6:1)] (Rf ) 0.30) afforded 3-(1-phenoxythiocarbonyloxy-
2,2,2-trifluoro)ethyl-5-(2-furyl)-1-methyl pyrazole as a yellow oil
Step 2: Fluorination of 9 with Deoxofluor. Deoxofluor (3 mmol,
50% in toluene) was added slowly to a solution of 9 (2 mmol) in
CH2Cl2 (5 mL) at 0 °C under nitrogen atmosphere. The mixture
was stirred overnight at room temperature. The reaction mixture
was then cooled to 0 °C, hydrolyzed with saturated sodium
bicarbonate solution until neutral pH was reached, and extracted
with CH2Cl2 (3 × 5 mL). The organic layer was washed with brine,
dried over anh Na2SO4, filtered, and concentrated in Vacuo to give
a yellow oil, which was purified by means of column chromatog-
raphy on silica gel. Flash chromatography [n-hexane-EtOAc (8:
1)] (Rf ) 0.40) afforded 10 as a pale-yellow oil (61%, 0.24 g). 1H
NMR (300 MHz, CDCl3): δ 1.63 (dd, J1HF) 24.0 Hz, J2) 6.6 Hz,
3H; CH3), 3.95 (d, JHF) 1.1 Hz, 3H; CH), 5.63 (dq, J1HF) 48.3
Hz, J2) 6.6 Hz, 1H; CH), 6.43 (dd, J1) 3.4 Hz, J2) 1.8 Hz, 1H;
CH), 6.46 (s, 1H; CH), 6.49 (dd, J1) 3.4 Hz, J2) 0.6 Hz, 1H;
CH), 7.44 (dd, J1) 1.8 Hz, J2) 0.6 Hz, 1H; CH) ppm. 13C NMR
1
(61%, 0.40 g). H NMR (300 MHz, CDCl3): δ 4.00 (s, 3H; CH3),
6.45 (dd, J1 ) 3.4 Hz, J2 ) 1.7 Hz, 1H; CH), 6.54 (d, J ) 3.4 Hz,
1H; CH), 6.65 (s, 1H; CH), 6.77 (q, J HF ) 6.7 Hz, 1 H; CH), 7.03
(d, J ) 0.7 Hz, 1H; CH), 7.06 (d, J ) 1.3 Hz, 1H; CH), 7.18-7.34
(m, 3H), 7.46 (dd, J1 ) 1.7 Hz, J2 ) 0.7 Hz, 1H; CH) ppm. 13C
NMR (75.5 MHz, CDCl3): δ 39.5, 75.9 (q, 2JCF ) 34.6 Hz), 105.2,
3
1
109.6, 111.9, 122.1 (d, JCF ) 12.1 Hz), 122.9 (q, JCF ) 230.4
3
Hz), 127.3, 130.0 (d, JCF ) 2.9 Hz), 136.1, 141.5, 143.5, 144.4,
153.9, 193.8 ppm. 19F NMR (CDCl3, 282.4 MHz): δ -80.2 (d, JFH
) 6.7 Hz, 3F; CF3) ppm. HRMS: calcd for C17H13F3N2O3S (M+)
382.0640; found 382.0662.
(75.5 MHz, CDCl3): δ 21.3 (d, 2JCF) 24.7 Hz), 38.9, 86.1 (d, 1JCF
)
A solution containing Bu3SnH (5.36 mmol, 1.5 g) and R,R′-
azobis(isobutyronitrile) (AIBN) (0.8 mmol, 0.13 g) in toluene (10
mL) was added to a solution of 3-(1-phenoxythiocarbonyloxy-2,2,2-
trifluoro)ethyl-5-(2-furyl)-1-methylpyrazole (1.34 mmol; 0.51 g) in
toluene (20 mL) at 80 °C under nitrogen atmosphere. The resulting
mixture was stirred at this temperature until the starting material
was no longer detectable through TLC. The reaction mixture was
3
162.7 Hz), 102.9 (d, JCF) 2.9 Hz), 109.1, 111.8, 135.4, 143.2,
2
144.9, 151.6 (d, JCF) 24.2 Hz) ppm. 19F NMR (CDCl3, 282.4
MHz): δ -166.1 (qd, J1FH) 48.3 Hz, J2FH) 24.0, 1F; CF) ppm.
HRMS: calcd for C10H11FN2O (M+) 194.0855; found 194.0852.
3-(1,2,2,2-Tetrafluoroethyl)-5-(2-furyl)-1-methylpyrazole (12).
Step 1: Addition of (Trifluoromethyl)trimethylsilane (CF3SiMe3)
8550 J. Org. Chem. Vol. 73, No. 21, 2008

Synthesis of New Fluorinated Tebufenpyrad Analogs
2
1
then cooled to room temperature and concentrated in Vacuo. Water
(10 mL) was added to the residue, which was then extracted with
EtOAc (3 × 15 mL), washed with brine, dried over anh Na2SO4,
and concentrated in Vacuo to give a yellow oil, which was purified
by means of column chromatography on silica gel. Flash chroma-
tography [n-hexane-EtOAc (9:1)] (Rf ) 0.40) afforded 13 as a pale-
yellow oil (75%, 0.23 g). 1H NMR (300 MHz, CDCl3): δ 3.37 (q,
JHF ) 11.0 Hz, 2 H; CH2), 3.95 (s, 3H; CH3), 6.40 (s, 1H; CH),
6.43 (dd, J1 ) 3.4 Hz, J2 ) 1.9 Hz, 1H; CH), 6.49 (dd, J1 ) 3.4
Hz, J2 ) 0.7 Hz, 1H; CH), 7.43 (dd, J1 ) 1.9 Hz, J2 ) 0.7 Hz, 1H;
34.2 (t, JCF ) 23 Hz), 38.8, 105.4, 108.9, 111.8, 116.5 (t, JCF )
3
240.3 Hz), 135.6, 143.1, 143.4 (t, JCF ) 7.0 Hz), 145.0 ppm. 19F
NMR (CDCl3, 282.4 MHz): δ -125.4 (dt, J1FH ) 56.7 Hz, J2
)
FH
17.0 Hz, 2F; CF2) ppm. HRMS: calcd for C10H10F2N2O (M+)
212.0751; found 212.0739.
Preparation of 16. Step 1: Reduction of 14. NaBH4 (3.72
mmol, 0.14 g) was slowly added to a solution of 14 (1.24 mmol,
0.24 g) in MeOH (7 mL) at 0 °C under nitrogen atmosphere. The
mixture was stirred at room temperature until 14 was no longer
detectable through TLC (ca. 16 h). The reaction mixture was then
concentrated in Vacuo, hydrolyzed with a saturated NH4Cl aq.
solution (4 mL), and extracted with EtOAc (3 × 10 mL). The
organic layers were pooled together and washed with brine (2 × 3
mL), dried over anh Na2SO4, and concentrated in Vacuo to give a
yellow oil, which was purified by means of column chromatography
on silica gel. Flash chromatography [n-hexane-EtOAc (2:1)] (Rf )
0.20) afforded 5-(2-furyl)-3-(2-hydroxyethyl)-1-methylpyrazole as
2
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ 33.9 (q, JCF ) 31.1
Hz), 38.9, 105.4, 109.1, 111.8, 125.8 (q, 1JCF ) 276.5 Hz), 135.7,
3
141.3 (q, JCF ) 3.5 Hz), 143.2, 144.8 ppm. 19F NMR (CDCl3,
282.4 MHz): δ -66.2 (t, JFH ) 11.0 Hz, 3F; CF3) ppm. HRMS:
calcd for C10H9F3N2O (M+) 230.0664; found 230.0667.
3-(2,2-Difluoroethyl)-5-(2-furyl)-1-methylpyrazole (15) and
3-(2-Fluoroethyl)-5-(2-furyl)-1-methylpyrazole (16). A 1 M solu-
tion of hexamethyldisylazane sodium salt (3.13 mmol) in THF was
added dropwise to a suspension of (methoxymethyl)triphenylphos-
phonium chloride (3.13 mmol; 1.1 g) in THF (4 mL) at 0 °C under
nitrogen atmosphere. The resulting mixture was stirred at this
temperature for 45 min, after which a solution of 8 (2.61 mmol;
0.46 g) in THF (3 mL) was slowly added. The reaction mixture
was stirred at room temperature until 8 was no longer detectable
through TLC. The reaction mixture was then hydrolyzed with a
saturated solution of NH4Cl (3 mL) and extracted with EtOAc (3
× 10 mL). The organic layer was washed with brine (2 × 5 mL),
dried over anh Na2SO4, and concentrated in Vacuo to give a yellow
oil, which was purified by means of column chromatography on
deactivated silica gel. Flash chromatography [n-hexane-EtOAc (6:
1)] afforded a nonseparable mixture of the E + Z diastereomers
(Rf ) 0.40) of 5-(2-furyl)-1-methyl-3-(2-methoxy)ethenylpyrazole
1
a pale yellow oil (64%, 0.15 g). H NMR (300 MHz, CDCl3): δ
2.79 (t, J ) 5.9 Hz, 2H; CH2), 3.8 (t, J ) 5.9 Hz, 2H; CH2), 3.93
(s, 3H; CH3), 6.25 (s, 1H; CH), 6.43 (dd, J1) 3.4 Hz, J2) 1.8 Hz,
1H; CH), 6.47 (dd, J1) 3.4 Hz, J2) 0.8 Hz, 1H; CH), 7.43 (dd,
J1) 1.8 Hz, J2) 0.8 Hz, 1H; CH) ppm. 13C NMR (75.5 MHz,
CDCl3): δ 31.4, 38.8, 62.3, 104.4, 108.8, 111.8, 135.1, 143.0, 145.2,
149.9 ppm. HRMS: calcd for C10H12N2O2 (M+) 192.0899; found
192.0891.
Step 2: Fluorination of 5-(2-Furyl)-3-(2-hydroxyethyl)-1-
methylpyrazole (See Above: “Fluorination of 9 with Deoxo-
fluor” for the Experimental Procedure). Flash chromatography
[n-hexane-EtOAc (7:1)] (Rf ) 0.30) afforded 16 as a yellow oil
(81% yield). H NMR (300 MHz, CDCl3): δ 2.95 (dt, J1HF) 23.7
1
Hz, J2) 6.5, 2H; CH2), 3.91 (s, 3H; CH3), 4.61 (dt, J1 HF) 50.4
Hz, J2) 6.5, 2H; CH2), 6.29 (s, 1H; CH), 6.41 (dd, J1) 3.4 Hz,
J2) 1.8 Hz, 1H; CH), 6.45 (dd, J1) 3.4 Hz, J2) 0.6 Hz, 1H; CH),
7.41 (dd, J1) 1.8 Hz, J2) 0.6 Hz, 1H; CH) ppm. 13C NMR (75.5
MHz, CDCl3): δ 29.9 (d, 2JCF) 21.3 Hz), 38.7, 83.4 (d, 1JCF) 167.9
1
as a pale-yellow oil (82%, 0.44 g). H NMR (300 MHz, CDCl3):
δ 3.59 (s, 3H; CH3), 3.71 (s, 3H; CH3), 3.90 (s, 3H; CH3), 3.92 (s,
3H; CH3), 5.34 (d, J ) 6.8 Hz, 1H; CH), 5.69 (d, J ) 13.2 Hz,
1H; CH), 6.10 (d, J ) 6.8 Hz, 1H; CH), 6.29 (s, 1H; CH), 6.41 (d,
J ) 1.0 Hz, 1H; CH), 6.42 (d, J ) 0.8 Hz, 1H; CH), 6.45 (dd, J1
) 5.6 Hz, J2 ) 0.8 Hz, 1H; CH), 6.46 (dd, J1 ) 5.6 Hz, J2 ) 0.6
Hz, 1H; CH), 6.73 (s, 1H; CH), 7.06 (d, J ) 13.2 Hz, 1H; CH),
7.41 (dd, J1 ) 1.7 Hz, J2 ) 0.6 Hz, 1H; CH) ppm; 13C NMR (75.5
MHz, CDCl3): δ 38.7, 38.8, 56.6, 60.9, 97.3, 98.6, 100.7, 105.5,
108.6, 108.7, 111.7, 111.8, 134.8, 135.2, 142.8, 142.9, 145.3, 145.5,
147.1, 148.1, 148.7, 150.4 ppm; HRMS: calcd for (M+)
C11H12N2O2: 204.0899, found: 204.0896.
Hz), 104.7, 108.9, 111.8, 135.4, 143.0, 145.1, 147.7 (d, 3JCF) 7.0
FH
Hz) ppm. 19F NMR (CDCl3, 282.4 MHz): δ -216.7 (tt, J1
)
50.4 Hz, J2FH) 23.7 Hz, 1F; CF) ppm. HRMS: calcd for
C10H11FN2O (M+) 194.0855; found 194.0857.
General Procedure for Oxidation of the Furane Ring to the
Carboxylic Acid. RuCl3·3H2O (0.55 mol) was added to a solution
of the 5-(2-furyl)pyrazole derivative 10, 12, 13, 15, or 16 (0.011
mol) and NaIO4 (0.110 mol) in CCl4 (70 mL), CH3CN (70 mL),
and H2O (105 mL). The mixture was then stirred at room
temperature and monitored with the aid of TLC. The starting
material disappeared within 5 min, after which the reaction mixture
was filtered and the organic phase of the filtrate was separated.
The aqueous phase was acidified with HCl 1 M until pH ) 3 and
extracted with EtOAc (3 × 20 mL). The organic layers were
collected, washed with brine, dried over anh Na2SO4, and filtered.
The solvent was concentrated to give a solid, which could be
purified either by means of column chromatography over silica gel
with HOAc (2%) or through crystallization.
A 12 N solution of HCl (2.88 mmol) was slowly added to a
solution of 5-(2-furyl)-1-methyl-3-(2-methoxy)ethenylpyrazole (E
+ Z) (1.44 mmol; 0.3 g) at 0 °C and then stirred at room temperature
until the starting material was no longer detectable through TLC
(ca. 16 h). The solvent was removed in Vacuo and 2 mL of H2O
was added to the mixture. The aqueous layer was extracted with
EtOAc (3 × 5 mL) and the organic layer was washed with brine
(2 × 2 mL), dried over anh Na2SO4, and concentrated in Vacuo to
give a yellow oil (98% yield), identified as the aldehyde 14. The
compound was not purified and was used as obtained in the
subsequent reactions. 1H NMR (300 MHz, CDCl3): δ 3.64 (d, J )
2.3 Hz, 2H; CH2), 3.96 (s, 3H; CH3), 6.33 (s, 1H; CH), 6.44 (dd,
J1 ) 3.4 Hz, J2) 1.9 Hz, 1H; CH), 6.48 (dd, J1 ) 3.4 Hz, J2 ) 0.7
Hz, 1H; CH), 7.44 (dd, J1 ) 1.9 Hz, J2 ) 0.7 Hz, 1H; CH), 9.73
(t, J ) 2.3 Hz, 1H; CH) ppm; 13C NMR (75.5 MHz, CDCl3): δ
38.5, 43.1, 105.0, 108.7, 111.4, 135.4, 142.8, 144.6, 153.2, 198.7
ppm; HRMS: calcd for C10H10N2O2 (M+) 190.0739; found 190.0742.
Fluorination of 14 (See Above: “Fluorination of 9 with
Deoxofluor” for the Experimental Procedure). Flash chroma-
tography [n-hexane-EtOAc (7:1)] (Rf ) 0.40) afforded 15 as a pale-
3-(1,2,2,2-Tetrafluoroethyl)-1-methyl-1H-pyrazole-5-carboxy-
lic acid (18). Pale-yellow solid crystallized from n-hexane/ethyl
acetate (93% yield); mp 150-2 °C. 1H NMR (300 MHz, CDCl3):
δ 4.06 (s, 3H; CH3), 6.01 (qd, J1HF) 42.0 Hz, J2HF ) 6.2 Hz, 1H;
CH), 7.00 (s, 1H; CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ 40.4,
1
2
3
84.9 (qd, JCF) 179,9 Hz, JCF) 35.6 Hz), 111.5 (q, JCF) 1.8
1
2
Hz), 123.5 (dq, JCF) 150.0 Hz, JCF) 29.3 Hz), 135.6, 141.7 (d,
2JCF) 21.8 Hz), 160.5 ppm. 19F NMR (CDCl3, 282.4 MHz): δ
-190.8 (qd, J1 ) 42.0 Hz, J2FF) 13.8 Hz, 1F; CF), -79.5 (dd,
FH
J1 ) 13.8 Hz, J2FH) 6.2 Hz, 3F; CF3) ppm. HRMS: calcd for
FF
C7H6F4N2O2 (M+) 226.0365; found 226.0362.
1
yellow oil (76% yield). H NMR (300 MHz, CDCl3): δ 3.09 (td,
General Procedure for Pyrazole Ring Chlorination. The
pyrazole derivative 17-21 (18 mmol) was dissolved in HOAc (45
mL) and the resulting solution was cooled to 10-12 °C. An aq
solution of NaOCl 13% (45 mmol) was then slowly added and the
mixture was stirred at room temperature for 16 h, after which HOAc
J1HF ) 17.0 Hz, J2 ) 4.5, 2H; CH2), 3.91 (s, 3H; CH3), 5.93 (tt, J1
HF ) 56.7 Hz, J2 ) 4.5, 1H; CH), 6.32 (s, 1H; CH), 6.40 (dd, J1 )
3.4 Hz, J2 ) 1.8 Hz, 1H; CH), 6.44 (d, J ) 3.4 Hz, 1H; CH), 7.41
(d, J ) 1.8 Hz, 1H; CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ
J. Org. Chem. Vol. 73, No. 21, 2008 8551

Fustero et al.
was removed in Vacuo. The residue was hydrolyzed with HCl 1 M
(15 mL), extracted with EtOAc (3 × 20 mL), washed with brine,
and dried over anh Na2SO4. The solvent was removed to afford a
solid, which was purified either by means of column chromatog-
raphy over silica gel with HOAc (2%) or through crystallization.
4-Chloro-3-(1,2,2,2-tetrafluoroethyl)-1-methyl-1H-pyrazole-
5-carboxylic acid (22). Pale-yellow solid crystallized from n-
were collected, dried over anh Na2SO4, and filtered. The solvent
was removed in Vacuo to give the carboxamides, which were
purified by means of column chromatography over silica gel.
N-(4-tert-Butylbenzyl)-4-chloro-3-(1,2,2,2-tetrafluoroethyl)-
1-methyl-1H-pyrazole-5-carboxamide (23). Flash chromatography
[n-hexane-EtOAc (6:1)] (Rf ) 0.40) afforded 23 as a pink oil (64%
1
yield). H NMR (300 MHz, CDCl3): δ 1.26 (s, 9H; (CH3)3), 4.17
(s, 3H; CH3), 4.56 (d, J ) 5.7 Hz, 2H; CH2), 5.69 (qd, J1HF) 43.7
1
hexane/ethyl acetate (93% yield); mp 135-7 °C. H NMR (300
HF
HF
MHz, CDCl3): δ 4.21 (s, 3H; CH3), 6.21 (qd, J1HF) 43.6 Hz, J2
Hz, J2 ) 6.0 Hz, 1H; CH), 6.88 (br, 1H; NH), 7.22 (d, J ) 8.3
Hz, 2H; Ar-H), 7.34 (d, J ) 8.3 Hz, 2H; Ar-H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ 31.7, 34.9, 42.1, 43.8, 82.8 (qd, 1JCF ) 187.4
Hz, 2JCF) 37.4 Hz), 110.3, 122.1 (dq, 1JCF) 282.3 Hz, 2JCF ) 29.3
) 6.2 Hz, 1H; CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ 46.6,
87.7 (qd, 1JCF) 137.9 Hz, 2JCF) 27.5 Hz), 120.3, 128.2 (dq, 1JCF
)
151.1 Hz, 2JCF) 22.5 Hz), 136.2, 142.9 (d, 2JCF) 16.5 Hz), 163.6
Hz), 126.3, 127.8, 133.1, 134.3, 137.8 (d, 2JCF ) 23.0 Hz), 151.4,
FH
ppm. 19F NMR (CDCl3, 282.4 MHz): δ -196.5 (qd, J1 ) 43.6
FH
157.9 ppm. 19F NMR (CDCl3, 282.4 MHz): δ -197.2 (qd, J1
43.7 Hz, J2FF ) 14.3 Hz, 1F; CF), -77.5 (dd, J1FF ) 14.3 Hz, J2
)
Hz, J2FF) 13.8 Hz, 1F; CF), -77.9 (dd, J1FF ) 13.8 Hz, J2FH) 6.2
Hz, 3F; CF3) ppm. HRMS: calcd for C7H5ClF4N2O2 (M+) 259.9976;
found 259.9964.
FH
) 6.0 Hz, 3F; CF3) ppm. HRMS: calcd for C18H20ClF4N3O (M+)
405.1231; found 405.1238.
General Procedure for the Preparation of Carboxamides. A
2 M solution of oxalyl dichloride (3.96 mmol) in THF was added
dropwise to a solution of the carboxylic acid (3.6 mmol) and DMF
(0.18 mmol) in CH2Cl2 (30 mL) at 0 °C under nitrogen atmosphere.
The mixture was stirred at room temperature for 30 min, after which
Et3N (9 mmol), 4-tert-butylbencylamine (4.7 mmol), and DMAP
were added at 0 °C. The resulting mixture was stirred at room
temperature until the carboxylic acid was no longer detectable
through TLC (approximately 18 h) and then hydrolyzed with a
saturated aq. solution of NH4Cl (10 mL) and extracted with CH2Cl2
(3 × 15 mL). The aqueous phase was acidified with 3N H2SO4
and extracted again with CH2Cl2 (2 × 10 mL). The organic layers
Acknowledgment. We thank the IMPIVA and Industrias
Afrasa (IMIDTD/2007/230), the Ministerio de Educacio´n y
Ciencia of Spain (CTQ2007-61462 and CTQ2006-01317), and
the Generalitat Valenciana (GR03/193) for financial support.
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.
JO801729P
8552 J. Org. Chem. Vol. 73, No. 21, 2008