Syntheses of 2-(trifluoromethyl)-1,3-dicarbonyl compounds through direct trifluoromethylation with CF3I and their application to fluorinated pyrazoles syntheses

Article abstract of DOI:10.1016/j.tet.2012.01.075

Direct trifluoromethylation of 1,3-dicarbonyl compounds with CF ₃I in the presence of a Fenton reagent in dimethylsulfoxide was investigated. 1,3-Diketones, 3-oxocarboxylates and 3-oxocarboxamides were readily trifluoromethylated at the methyle

Full text of DOI:10.1016/j.tet.2012.01.075

Tetrahedron 68 (2012) 2636e2649
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Syntheses of 2-(trifluoromethyl)-1,3-dicarbonyl compounds through direct
trifluoromethylation with CF3I and their application to fluorinated pyrazoles
syntheses
,
,
Yuhki Ohtsuka a, Daisuke Uraguchi a y, Kyoko Yamamoto a, Kenji Tokuhisa b, Tetsu Yamakawa a
*
a Sagami Chemical Research Institute, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
b Tosoh F-Tech Inc., Kaisei-cho 4988, Shunan, Yamaguchi 746-0006, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct trifluoromethylation of 1,3-dicarbonyl compounds with CF3I in the presence of a Fenton reagent in
dimethylsulfoxide was investigated. 1,3-Diketones, 3-oxocarboxylates and 3-oxocarboxamides were
readily trifluoromethylated at the methylene carbon between two oxo groups. Cycloaddition of hydra-
zine derivatives to the obtained 2-(trifluoromethyl)-1,3-dicarbonyl compounds provided fluorinated
pyrazoles. 4-(Trifluoromethyl)pyrazole derivatives were formed from 2-(trifluoromethyl)-1,3-diketones,
while 3-oxo-2-(trifluoromethyl)carboxylates or carboxamides gave 5-fluoropyrazole-4-carboxylates or
carboxamides, respectively, via 3-hydrazono-2-(trifluoromethyl)carboxylates or carboxamides as an
intermediate.
Received 22 December 2011
Received in revised form 24 January 2012
Accepted 24 January 2012
Available online 30 January 2012
Keywords:
Trifluoromethylation
Fenton reagent
2-(Trifluoromethyl)-1,3-dicarbonyl
compounds
Ó 2012 Elsevier Ltd. All rights reserved.
Cycloaddition
Fluorinated pyrazole
1. Introduction
material, direct trifluoromethylation of 1,3-dicarbonyl compounds
has been reported for the synthesis of 2-(trifluoromethyl)-1,3-
Pyrazole derivatives are important compounds in the area of
medicines1 and agrichemicals.2 Fluorinated pyrazoles, in particular,
frequently exhibit significant biological activity.3 Therefore, effi-
cient synthetic methods for these compounds have been in high
demand. Among fluorinated pyrazoles, the derivatives having tri-
fluoromethyl group at the 3- and/or 5-position are synthesized
through the classical cycloaddition of hydrazine derivatives to 1,3-
dicarboyl compounds that possess one or two (trifluoromethyl)
carbonyl group at the 1- and/or 3-position.4 In contrast, 2-(tri-
dicarbonyl compounds. So far, trifluoromethylation of the 2-
position of 1,3-diphenylpropane-1,3-dione using (4-
fluorophenyl)(3-nitorophenyl)trifluoromethylsulfonium salt6 and
electrochemical trifluoromethylation of various 1,3-dicarbonyl
compounds with trifluoroacetic acid7 have been reported. Never-
theless, these methods are unsuitable for general purposes owing
to the need for expensive trifluoromethylating reagent or special
apparatus.
Recently, we found that an electrophilic trifluoromethyl radical
is generated from CF3I by a Fenton reagent in dimethylsulfoxide
(DMSO) and catalytic trifluoromethylation of various nucleobases8
and five- or six-membered (hetero)aromatic compounds9 can be
achieved with this radical. The orientation of this tri-
fluoromethylation was virtually explained by the general trend of
electrophilic substitution, for example, the electron-rich 5-position
of uracil is selectively trifluoromethylated.8
fluoromethyl)-1,3-dicarbonyl compounds, in which
a
tri-
fluoromethyl group is positioned between two oxo groups, have
not thus far been used in the synthesis of pyrazole derivatives. This
is presumably owing to unavailability of 2-(trifluoromethyl)-1,3-
dicarbonyl compounds, since previously reported methods for the
synthesis of 2-(trifluoromethyl)-1,3-dicarbonyl compounds require
uncommon compounds as a starting material.5 With regard to
the methods using the more available and relatively simple starting
On the basis of the fact that the 2-position of 1,3-dicarbonyl
compounds
is
electron-rich,
we
investigated
direct
trifluoromethylation of the 2-position of 1,3-diketones, 3-
oxocaroboxylates, and 3-oxocarboxamides with CF3I in the
presence of the Fenton reagent in DMSO. Furthermore, we dem-
onstrated 4-trifluoromethylpyrazole derivatives syntheses through
cycloaddition of hydrazine derivatives to 2-(trifluoromethyl)-1,3-
* Corresponding author. Tel.: þ81 467769268; fax: þ81 467774113; e-mail
address: t_yamakawa@sagami.or.jp (T. Yamakawa).
y
Present address: Nagoya University, Graduate School of Engineering,
Department of Chemical and Biological Engineering, Furo-cho, Chikusa-ku, Nagoya,
Aichi 464-8603, Japan.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.075

Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
2637
diketones. This study also revealed that 5-fluoropyrazole de-
rivatives were obtained from 3-oxo-2-(trifluoromethyl)carobox-
the bulkiness of R1 and R2 for 1,3-diketones as a substrate. In entry
3, a small amount of the product that was trifluoromethylated at
the para-position of the phenyl ring in R1 was detected (<5%).
Table 2 lists the results of trifluoromethylation of various ethyl
3-oxocarboxylates under the same conditions as Table 1. The cor-
responding 3-oxo-2-(trifluoromethyl)carboxylates were obtained
though the yields were not satisfactory. Successive repetition of the
trifluoromethylation increased the yield up to a satisfactory value
as shown in entry 1 (43%/73%). In entry 3 (R1¼Ph), a small
amount of the product in which the trifluoromethylation occurred
at the para-position of R1 was also detected (<5%).
ylates
and
3-oxo-2-(trifluoromethyl)oxocaboxamides
by
cycloaddition of hydrazine derivatives via 3-hydrazono-2-(tri-
fluoromethyl)carboxylates or carboxamides as an intermediate.
2. Results and discussion
2.1. Direct trifluoromethylation of various 1,3-dicarbonyl
compounds
When a 30% H2O2 aqueous solution was added to a DMSO so-
lution of pentane-2,4-dione, CF3I, and an FeSO4 aqueous solution
followed by stirring for 1 h at room temperature, the formation of
3-(trifluoromethyl)pentane-2,4-dione (1a) was confirmed by 19F
NMR in 71% yield (Scheme 1).
Table 2
Trifluoromethylation of ethyl 3-oxocarboxylates with CF3I in the presence of the
Fenton reagenta
O
O
O
O
+ CF3I
R
OEt
R
OEt
CF3
3.0 eq CF3I
0.3 eq FeSO4
2.0 eq H2O2
Entry
1
R
Product
O
Yield/%b
43
O
O
O
O
O
DMSO, rt, 1 h
Me
OEt
CF3
2a
CF3
1a
71% (19F-NMR yield)
O
O
2
3
4
iPr
Ph
73 (63)c
40 (32)
Scheme 1.
OEt
2b
CF3
The screening of Fe(II) compounds and peroxides revealed that
FeSO4 and H2O2 aqueous solution exhibited the highest activity.
Table 1 shows the results of trifluoromethylation of 1,3-diketones
under the condition delineated in Scheme 1. All the substrates
were trifluoromethylated at the position between two oxo groups.
The highest yield was obtained with 3-(trifluoromethyl)pentane-
2,4-dione (entry 1), suggesting that the yield is partly dependent on
O
O
OEt
CF3
O
2c
O
p-Tolyl
47 (33)
60 (49)
OEt
OEt
CF3
O
2d
Me
Cl
Table 1
Trifluoromethylation of 1,3-diketones with CF3I in the presence of the Fenton
O
reagenta
5
4-ClPh
O
O
O
O
CF3
2e
R1
R2
+ CF3I
R1
R2
a
The reaction conditions are same as those in Table 1.
19F NMR yield. The values in the parentheses are isolated yields.
The trifluoromethylation was successively carried out three times (see Experi-
CF3
b
c
Entry
1
R1
R2
Product
Yield/%b
71 (42)
mental Section 4.2.2).
O
O
Me
Me
Me
Furthermore, we examined trifluoromethylation of 3-
oxocarboxiamides as shown in Table 3. The desired 3-oxo-2-(tri-
fluoromethyl)carboxiamides were obtained in moderate yields
under the same condition as Table 1.
1a
CF3
O
O
The mechanism of trifluoromethylation is presumably the same
as that of nucleobases and aromatic compounds.8,9 Fig.1 depicts the
postulated mechanism where trifluoromethylation of pentane-2,4-
dione is typified. The hypothetical steps involved in the tri-
fluoromethylation are as follows; (i) Fe(II) reduces H2O2 to a hydroxyl
radical, (ii) the hydroxyl radical is rapidly trapped by the DMSO
solvent to form a radical adduct A, (iii) a methyl radical is generated
from A, (iv) the reaction of CF3I and the methyl radical releases
a trifluoromethyl radical, (v) the trifluoromethyl radical adds to the
3-position of pentane-2,4-dione or 4-hydroxypent-3-ene-2-one,
that is, the enol-form of pentane-2,4-dione to form a radical species
B, and (vi) Fe(III) oxidizes B to 1a and is reduced to Fe(II).
2
3
Pentyl
51 (38)
CF3
O
1b
O
Ph
Me
tBu
38 (32)
27 (25)
1c
CF3
O
O
4
tBu
1d
CF3
a
Solvent DMSO, [1,3-diketones]¼0.2 M. The used amount of FeSO4, CF3I, and
H2O2 were 0.3 equiv, 3.0 equiv, and 2.0 equiv to a 1,3-diketone, respectively. All the
reactions were carried out for 1 h at room temperature.
The substrates evaluated in Tables 1e3 ought to exist in tauto-
meric equilibrium between keto- and enol-forms. 1H NMR in the
DMSO-d6 solution at room temperature revealed that keto/enol
19F NMR yield. The values in the parentheses are isolated yields.
b

2638
Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
Table 3
ratio was ca. 1:1 for pentane-2,4-dione, while ethyl 3-
oxocarboxylate and 3-oxobutyramide were mainly in the keto-
form. On the other hand, the trifluoromethylation of dimethyl or
diethyl malonate, which exists only in the keto-form, did not afford
trifluoromethylated products at all. This suggests that the tri-
fluoromethylation proceeds chiefly with the enol-form of 1,3-
dicarbonyl compounds in the step (v). However, the order of the
yield of trifluoromethylated products is 3-oxobutyramide (entry 1 in
Table 3) >pentane-2,4-dione (entry 1 in Table 1) >ethyl 3-
oxocarboxylate (entry 1 in Table 2); this order does not agree with
the amount of each enol-form estimated by 1H NMR. Recently,
Belova and co-workers reported the quantum chemical in-
vestigation of various 1,3-dicarbonyl compounds.10 According to
their report, the orders of the net charge of the carbon atom between
two oxo groups are 3-oxobutyramide (ꢀ0.585) >pentane-2,4-dione
(ꢀ0.579) >methyl 3-oxobutanoate (ꢀ0.575) in the keto-form and 3-
oxobutyramide (ꢀ0.472) >pentane-2,4-dione (ꢀ0.471) >methyl 3-
oxobutanoate (ꢀ0.468) in the enol-form. Taking into account the
electrophilicity of the trifluoromethyl radical, it is reasonable that
this trend in the electron density is exactly the same as the yields of
the trifluoromethylated compounds. Therefore, whether reacting
species be keto- or enol-form, the difference in the reactivity can be
explained in the term of the electron density.
Trifluoromethylation of 3-oxobutyramide derivatives with CF3I in the presence of
the Fenton reagenta
O
O
O
O
R1
NHR2
+ CF3I
R1
NHR2
CF3
Entry
1
R1
R2
H
Product
Yield/%b
92 (75)
O
O
Me
Me
NH2
3a
CF3
O
O
O
2
4-iPrPh
58 (52)
51 (44)
N
H
CF3
O
3b
3c
3c
Me
Me
Biphenyl-2-yl
N
H
CF3
O
A trace amount of a trifluoromethylated enol-form as a product
O
O
was detected only with 1a, 1b, and 2c by 19F NMR (
d
¼ꢀ51.3, ꢀ50.7,
4
5
4-BrPh
50 (42)
N
H
and ꢀ57.1 ppm, respectively), indicating that the keto-form is the
3d
Br
Cl
CF3
O
main species in the tautomeric equilibrium of the products.
2.2. Cycloaddition of hydrazine derivatives to 2-
(trifluoromethyl)-1,3-diketone
Me
Ph
4-ClPh
Ph
46 (39)
55 (45)
N
H
3e
CF3
O
It is well-known that cycloaddition of hydrazine derivatives to
1,3-diketones readily proceeds to form 3,5-disubstituted pyr-
azoles.11 The 2-(trifluoromethyl)-1,3-diketones obtained in Table 1
were thus expected to provide potentially biological active 3,5-
disubstituted 4-(trifluoromethyl)pyrazoles12 via this cycloaddi-
tion. As expected, 3,5-dimethyl-4-(trifluoromethyl)pyrazole de-
rivatives were obtained in satisfactory yields by the cycloaddition
of hydrazine derivatives to 1a under a mild condition (Table 4).
Because 1a is a symmetric 2-(trifluoromethyl)-1,3-diketone, the
reactions in Table 4 necessarily generate a sole product. In contrast,
O
6
N
H
3f
CF3
a
The reaction conditions are same as those of Table 1.
b
c
19F NMR yield. The values in the parentheses are isolated yields.
The trifluoromethylation was successively carried out twice.
H
H2O2
O
O
Fe(II)
CF3
OH-
O
S
H+
Fe(III)
H
Me
Me
O
O
OH
O
O
CF3
B
CF3
1a
O
OH
S
Me
Me
A
Me
CF3
O
S
O
O
OH
O
CF3I
MeI
or
Me
OH
Fig. 1. Postulated mechanism of trifluoromethylation of pentane-2,4-dione.

Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
2639
Table 4
The nitrogen lone pair in hydrazine derivatives should selec-
tively attack to the methylcarbonyl carbon in 1c, which is less
sterically hindered than the phenylcarbonyl.13 In the cycloaddition
of methylhydrazine to 1c (Scheme 2), the nucleophilic attack of
both sterically favored NH2 and electronically favored NHMe will
occur, resulting in the formation of the mixture of 4d and 4e. In
contrast, 4f was exclusively formed presumably owing to the fact
that the sterically small NH2 is more nucleophilic than NHPh. A
similar selectivity as seen in Scheme 3 was observed in the cyclo-
addition of arylhydrazines to 4,4,4-trifluoro-1-arylbutane-1,3-
diones to form 1,5-diaryl-3-(trifluoromethyl)pyrazoles.4g
Many synthetic methods for obtaining biologically active 4-
(trifluoromethyl)pyrazole derivatives have been reported.4h,12,14
We believe that the present method is more preferable than
those methods because it offers the advantages of improved
availability, cost, and handling of the reagents.
Cycloaddition of hydrazine derivatives to 1aa
CF3
O
O
+ RNHNH2
N
N
R
CF3
1a
Entry
1b
R
Product
Isolated yield (%)
94
CF3
H
N
N
4a
N
H
CF3
CF3
2c
Me
76
92
4b
N
Me
2.3. Cycloaddition of hydrazine derivatives to 3-oxo-2-
(trifluoromethyl)carboxylates
Cycloaddition of hydrazine derivatives to 3-oxo-2-(tri-
fluoromethyl)carboxylates was also examined. In the cycloaddition
of methylhydrazine to ethyl 3-oxo-2-(trifluoromethyl)butanoate
(2a), it was anticipated that 5-hydroxy-1,3-dimethyl-4-(tri-
fluoromethyl)pyrazole would be formed on the basis of the pre-
cedence that 4-fluoro-5-hydroxy-1,3-dimethylpyrazole is formed
from methylhydrazine and methyl 2-fluoro-3-oxobutanoate.15
However, 1H, 13C, and 19F NMR spectra indicated that the product
actually obtained was ethyl 5-fluoro-1,3-dimethylpyrazole-4-
carboxylate (5a). In order to determine the structure of 5a, X-ray
crystallography was attempted. However, the poor crystallinity of
5a necessitated chemical conversion. Consecutive performing hy-
drolysis of 5a with HCl/CH3COOH, chlorination with oxalyl
dichloride and amidation in an aqueous NH3 solution successfully
provided colorless and transparent plate-like crystal, which pos-
sessed crystallinity good enough for X-ray crystallography. The
ORTEP diagram shown in Fig. 2 clearly revealed that this crystal was
5-fluoro-1,3-dimethylpyrazole-4-carboxamide (7a).
3d
Ph
N
4c
N
Ph
a
[1a]¼0.50e0.63 M, [hydrazine]/[1a]¼1.0, EtOH 3e10 mL. All the reactions were
carried out for 5 h.
b
Reaction temperature was 60 ꢁC.
c
Reaction temperature was 70 ꢁC.
d
Reaction temperature was 80 ꢁC.
two product isomers may be formed from asymmetric 2-(tri-
fluoromethyl)-1,3-diketones. Indeed, the cycloaddition of methyl-
hydrazine to 1-phenyl-2-(trifluoromethyl)butane-1,3-dione (1c)
afforded a mixture of 1,3-dimethyl-5-phenyl-4-(trifluoromethyl)
pyrazole (4d), and 1,5-dimethyl-3-phenyl-4-(trifluoromethyl)pyr-
azole (4e) in a 1:1 ratio (Scheme 2). The 1H, 13C, and 19F NMR
spectra of 4d and 4e were in agreement with those of the com-
pounds that were synthesized by the trifluoromethylation of 1,3-
dimethyl-5-phenylpyrazole and 1,5-dimethyl-3-phenylpyrazole,
respectively, with CF3I in the presence of the Femton reagent.9
CF3
Ph
Ph
CF3
O
O
1.0 eq MeHNNH2
EtOH, 70 ° , 5 h
+
N
N
N
N
C
CF3
Me
4d
Me
4e
1c
35%
35%
(isolated yield)
Scheme 2.
In contrast to the formation of two isomers from 1c and meth-
ylhydrazine, it is interesting that the cycloaddition of phenyl-
hydrazine
to
1c
produced
3-methyl-1,5-diphenyl-4-
(trifluoromethyl)pyrazole (4f, Scheme 3) as a sole products; 4f was
identified in the same manner as 4d and 4e.
CF3
Ph
O
O
1.0 eq PhHNNH2
EtOH, 80 ° , 5 h
N
N
C
CF3
Ph
4f
1c
63% (isolated yield)
Scheme 3.
Fig. 2. The ORTEP diagram of 7a.

2640
Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
Because the fluorine atom at the 5-position should have
On the basis of the results obtained from Schemes 5, 7 and those
presented in Table 6, it can be concluded that 3-(arylhydrazono)-2-
(trifluoromethyl)butanoates are the intermediates of the cycload-
dition of arylhydrazines to 2a. On the other hand, the cycloaddition
remained intact throughout the chemical conversion of 5a to 7a as
illustrated in Scheme 4, we concluded that 5a is the product of the
cycloaddition of methylhydrazine to 2a.
O
O
OEt
F
OH
F
O
O
1.5 eq MeHNNH2
N
N
OEt
N
N
EtOH, 80 °C, 2 h
CF3
2a
Me
Me
5a
5a'
O
O
Cl
F
NH2
F
N
N
N
N
Me
Me
7a
Scheme 4.
Table
5
lists the yields of various 1,3-disubstituted 5-
of alkylhydrazine derivatives to 2aee (Table 5) afforded no 3-
(alkylhydrazono)-2-(trifluoromethyl)butanoate, which is expected
to be the intermediate for entries 1, 2, 6, 7, and 8 in Table 5.
In general, the nucleophilicity of the lone pair of nitrogen in
alkylhydrazono group is higher than that in arylhydrazono group.
fluoropyrazole-4-carboxylates obtained through cycloaddition of
various hydrazine derivatives to 2aee.
The poor crystallinity of 5beh precluded X-ray structural eval-
uation. Nonetheless, the 19F NMR data supported the formation of
1,3-disubstituted 5-fluoropyrazole-4-carboxylates. The 19F NMR
chemical shifts of the products fell within the range of ꢀ118.6 to
ꢀ123.4 ppm, which is consistent with those of methyl 1-aryl-5-
fluoropyrazole-4-carboxylates, from ꢀ118.8 to ꢀ123.3 ppm.16
Interestingly, the cycloaddition of phenylhydrazine to 2a affor-
ded not ethyl 5-fluoro-3-methyl-1-phenylpyrazole-4-carboxylate
(5i) but ethyl 3-(phenylhydrazono)-2-(trifluoromethyl)butanoate
(6) as shown in Scheme 5. Given that the addition of NEt3 to the
EtOH solution of isolated 6 smoothly provided ethyl 5-fluoro-3-
methyl-1-phenylpyrazole-4-carboxylate (5i), 6 is considered to be
an intermediate of this cycloaddition.
Scheme 6 illustrates the postulated mechanism for conversion
of 6 to 5i. NEt3 abstracts the hydrogen atom at the 2-position of 6 to
generate an anionic species C. In succession, C releases a fluoride
anion from trifluoromethyl group to form ethyl 3-(phenyl-
hydrazono)-2-(difluoromethylene)butanoate (D). Because the
difluoromethylene carbon having two fluorine atoms in D should
be more electropositive than the carbonyl carbon, the lone pair of
the terminal nitrogen atom attacks the former olefinic carbon se-
lectively, resulting in the formation of 5i. A similar mechanism is
proposed in the cycloaddition of methyl 3-methoxy-2-
trifluoromethylacrylate and arylhydrazines to form methyl 1-aryl-
5-fluoropyrazole-4-carboxylates.16
Ethyl 3-(arylhydrazono)-2-(trifluoromethyl)butanoates were
also isolated from the reaction mixture of 2a and the other aryl-
hydrazines and were converted to the corresponding 1-aryl-5-
fluoro-3-methylpyrazole-4-carboxylates by the addition of NEt3
(Scheme 7).
Unfortunately, these 3-(arylhydrazono)-2-(trifluoromethyl)
butanoates were not sufficiently stable for full characterization.
With regard to 5jel, the 19F and 13C NMR data confirmed 1-aryl-5-
fluoro-3-methylpyrazole-4-carboxylates structure.
Based on the results presented in Schemes 5 and 7, we attempted
the one-pot synthesis of 1-aryl-5-fluoro-3-methylpyrazole-4-
carboxylates starting from 2a and arylhydrazines. This method in-
volved the reaction of 2a and an arylhydrazine performed in EtOH at
80 ꢁC for 2 h (process A) followed by the addition of NEt3 to the
reaction mixture (process B). Table 6 shows that this one-pot syn-
thesis gave the desired products in moderate yields.
Consequently,
3-(alkylhydrazono)-2-(trifluoromethyl)butanoate
should convert quickly to 5-fluoropyrazole-4-carboxylates, resulting
in non-detection of an intermediate. Indeed, even when the re-
actions in entries 1 and 6 in Table 5 were carried out with lower ratio
of [hydrazine]/[butanoate] (¼1.0), no 3-(alkylhydrazono)-2-(tri-
fluoromethyl)butanoate intermediate was formed and only the de-
cline of the yields of 5-fluoropyrazole-4-carboxylates was observed
(5a 57% and 5f 70%). This suggests that the nucleophilic attack of the
lone pairof the terminal nitrogen in the alkylhydrazono group is very
fast. In addition to nucleophilicity, the basicity of the hydrazine de-
rivatives and intermediates should also be taken into account. The
stronger basicity of alkylhydrazines and 3-(alkylhydrazono)-2-(tri-
fluoromethyl)butanoates than the corresponding each aryl de-
rivatives should facilitate the abstraction of the hydrogen atom at the
2-position of a 3-oxo-2-(trifluoromethyl)carboxylate.
In order to detect a 3-(alkylhydrazono)-2-(trifluoromethyl)
butanoate intermediate, the cycloaddition of isopropylhydrazine to
2a (entry 2 in Table 5) was carried out under milder conditions than
those employed in Table 5, as shown in Scheme 8. Under the out-
lined conditions, both of ethyl 3-(isopropylhydrazono)-2-(tri-
fluoromethyl)butanoate and 5b were observed using 19F NMR. At
longer reaction times, 3-(isopropylhydrazono)-2-(trifluoromethyl)
butanoate disappeared and only 5b was detected. In this way, the
intermediate of this cycloaddition was successfully detected.
The yield of 5b after the consumption of the intermediate was
smaller than the total amount of the intermediate and 5b after 1 h
reaction, 69%. Because this intermediate decomposed within a few
days at 5 ꢁC after the isolation probably due to the basicity itself, the
disappearance of this intermediate is derived from the de-
composition during the reaction.
Nevertheless, the non-detection of 3-phenyl and 3-isopropyl-3-
(arylhydrazono)-2-(trifluoromethyl)butanoates that are the antic-
ipated intermediates in entries 3e5 in Table 5 has not been clarified
yet. In a similar manner to entries 1 and 6 in Table 5, only the de-
cline of the yield (5d 38%) were observed with the lower ratio of
[hydrazine]/[butanoate] (¼1.0) in entry 4 in Table 5. Instability
derived from the repulsion between the phenyl or isopropyl group
and an aryl group may facilitate the nucleophilic attack and/or the
abstraction of the hydrogen atom at the 2-position.

Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
2641
Table 5
to the nucleophilic attack of the lone pair of nitrogen in the hy-
drazine derivatives. This difference in the reactivity between 3-oxo-
Cycloaddition of hydrazine derivatives to 3-oxo-2-(trifluoromethyl)carboxylatesa
O
2-(trifluoromethyl)carboxylates
and
2-(trifluoromethyl)-1,3-
R1
OEt
diketones is reasonable from the general trend of their reactivity.
In addition, the electron-withdrawing nature of the trifluoromethyl
group may also contribute to the high reactivity of the 2-(tri-
fluoromethyl)-1,3-diketones.
O
O
R2HNNH2
N
R1
+
OEt
F
N
R2
CF3
It is known that the cycloaddition of arylhydrazines to methyl 3-
methoxy-2-trifluoromethylacrylate forms methyl 1-aryl-5-
fluoropyrazole-4-carboxylate.16 Since the 2-position of 3-
oxopropionates or malonates was not trifluoromethylated by the
Fenton reagent, 1-aryl-5-fluoropyrazole-4-carboxylates could not
be synthesized using the current method. Nevertheless, our
method can be utilized as a supplement to the reported method for
5-fluoropyrazole-4-carboxylates synthesis.
Entry
1
R1
R2
Product
Isolated yield/%
78
O
OEt
Me (2a)
Me
N
F
5a
N
Me
O
2.4. Cycloaddition of hydrazine derivatives to 3-oxo-2-
OEt
iPr
Ph
41
57
(trifluoromethyl)propinonamides
2
3
Me (2a)
iPr (2b)
N
F
5b
N
In the same manner as described in Section 2.3, cycloaddition of
hydrazine derivatives to 3-oxopropinonamides provided 1,3-
disubstituted 5-fluoro-4-carboxamides. Table 7 lists the results of
the cycloaddition of methyl or phenylhydrazine to 3aed and f.
As a matter of course, the ORTEP diagram of 7a obtained in entry
1 in Table 7 agreed with 7a synthesized from 5a in Scheme 4. With
regard to the other products, the 19F NMR chemical shifts were
O
OEt
N
F
5c
N
Ph
consistent
methylpyrazole-4-carboxamides.
with
the
formation
of
1-aryl-5-fluoro-3-
O
Ph
OEt
The addition of NEt3 was necessary for the cycloaddition of
phenylhydrazine to 3-oxo-2-(trifluoromethyl)butyramide de-
rivatives as well as the cycloaddition of arylhydrazines to 3-oxo-2-
(trifluoromethyl)butanoates. Table 8 summarizes the results of the
one-pot synthesis of 5-fluoro-3-methyl-1-phenylpyrazole-4-
carboxiamides from 3aec, e performed in a similar manner as
that in Table 6.
The desired products were obtained in satisfactory yields. The
19F NMR chemical shifts of the products also indicate that the 5-
position of each compound was fluorinated.
4
Ph (2c)
Ph (2c)
Ph
70
58
N
F
5d
N
Ph
O
Ph
OEt
N
5b
4-ClPh
F
5e
N
Cl
3-(Phenylhydrazono)-2-(trifluoromethyl)butyramide (8) was
isolated from the reaction mixture of 3a and phenylhydrazine in
75% isolated yield after process A. Furthermore, we confirmed that
8 was converted into 7g by the addition of NEt3 or K2CO3 in EtOH
(Scheme 9).
In the reactions of phenylhydrazine and 3b, 3c, 3e, we also
isolated the corresponding 3-(arylhydrazono)-2-(trifluoromethyl)
butyramides in 40e71% yields, respectively, though various spectra
data were not obtained due to their instability. Since 1-aryl-5-
fluoro-3-methylpyrazole-4-carboxamides were formed from iso-
lated these compounds in the presence of NEt3 (Scheme 10),
a similar reaction as proposed in Scheme 5 can be applied here.
Because carbonyl carbons of amides are generally unreactive in the
nucleophilic attack, that mechanism is within reason.
O
Ph
OEt
6
7
Ph (2c)
Me
Me
88
60
N
F
5f
N
Me
O
OEt
p-Tolyl (2d)
N
F
5g
N
Me
Cl
O
N-[2-(1,3-Dimethyl)butylphenyl]-5-fluoro-1,3-
OEt
dimethylpyrazole-4-carboxamide is a commercially available fun-
gicide17 and derivatives of this compound having isopropyl17 or
aryl18 group in the ortho-position of N-phenyl group are also known
to be biologically active. The compounds 7aej are potential ana-
logues of these fungicides. A previously reported synthesis of N-
aryl-5-fluoro-1,3-dimethylpyrazole-4-carboxamide19 involves the
following processes; (i) cycloaddition of methylhydrazine to 3-
oxobutyrates to give 5-hydroxy-1,3-dimethylpyrazole derivatives,
(ii) chlorination at the 5-position with POCl3, and (iii) the sub-
stitution of this chlorine by fluorine with KF. The present method is
undisputedly simpler than the reported method. Moreover, this
method is highly versatile, furnishing a variety of derivatives, be-
cause N-aryl-3-oxobutyramides, which are used as the starting
8
4-ClPh (2e)
Me
74
N
F
5h
N
Me
a
[3-Oxo-2-(trifluoromethyl)carboxylate]¼0.17e0.20 mM, [hydrazine]/[3-oxo-2-
(trifluoromethyl)carboxylate]¼1.5e2.0, EtOH 3e5 mL. All the reactions were carried
out at 80 ꢁC for 2 h.
b
Since 4-chlorophenylhydrazine was supplied as a HCl salt, its EtOH solution
including the same equivalent of NEt3 was used.
The cycloaddition of hydrazine derivatives to 2-(tri-
fluoromethyl)-1,3-diketones afforded no 5-fluoropyrazole de-
rivatives as described in Section 2.2. This indicates that the carbonyl
carbon in a 2-trifluoromethyl-1,3-diketone is remarkably reactive

2642
Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
O
OEt
NHPh
O
O
N
O
2.0 eq PhNHNH2
1.5 eq NEt3
N
F
OEt
OEt
N
Ph
EtOH, 80 °C, 2 h
EtOH, 80 °C, 1 h
CF3
CF3
5i
2a
6
69% (isolated yield)
62% (isolated yield)
Scheme 5.
Scheme 6.
O
OEt
NHAr
O
O
N
O
ArNHNH2
NEt3
N
F
OEt
OEt
N
CF3
2a
CF3
Ar
isolated yield:
Ar = m-tolyl 60%
isolated yield:
Ar = m-tolyl (5j) 72%
= 2-ClPh 75%
= 2-ClPh (5k) 69%
= 4-MeOPh 38%
= 4-MeOPh (5l) 22%
Scheme 7.
materials are readily obtainable from diketene and the corre-
sponding aniline compounds.20
quint (quintet), sept (septet), and m (multiplet). 19F NMR yields
were calculated with 2,2,2-trifluoroethanol as an internal standard.
IR, high-resolution mass spectroscopy (HRMS), X-ray crystallogra-
phy, and melting point (mp) measurements were carried out using
HORIBA FT-720, Waters LCT Premier XE, Rigaku R-AXIS PAPID II and
Stanford Research Systems MPA100, respectively. IR spectra were
obtained in the reflective mode. All the commercially available
reagents were used without further purification.
3. Conclusion
We achieved direct trifluoromethylation at the 2-position of 1,3-
dicarbonyl compounds with CF3I in the presence of the Fenton re-
agent in DMSO. Furthermore, we were able to demonstrate that the
obtained 2-trifluoromethyl-1,3-dicarbonyl compounds are very
useful C3 unit for the synthesis of biologically active fluorinated
pyrazole derivatives. 4-(Trifluoromethyl)pyrazole, 5-fluoropyrazole-
4-carboxylates orcarboxamides derivatives were readilyobtained by
cycloaddition of hydrazine derivatives to these 2-(trifluoromethyl)-
1,3-dicarbonyl compounds. The simplicity of this method makes it
applicable to the synthesis of novel fluorinated heteroaromatic
compounds. Other applications of 2-(trifluoromethyl)-1,3-
dicarbonyl compounds are now under investigation.
4.2. General procedure
4.2.1. Trifluoromethylation of 1,3-dicarbonyl compounds. The pro-
cedure for synthesis of 3-(trifluoromethyl)pentane-2,4-dione (1a)
is used as a representative example. A 30% H2O2 aqueous solution
(2.0 mL) was added dropwise to the mixture of pentane-2,4-dione
(10 mmol), DMSO (40 mL), 3.0 M DMSO solution of CF3I (10 mL),
and 1.0 M aqueous solution of FeSO4 (3.0 mL) in an Ar atmosphere.
The resulting mixture was stirred for 1 h at room temperature. After
the reaction, an aliquot of the mixture was analyzed using 19F NMR,
confirming the formation of 3-(trifluoromethyl)pentane-2,4-dione
(1a) in 71% yield. The reaction mixture was poured into H2O and
the product was extracted to diethyl ether. The diethyl ether layer
was washed with a saturated aqueous solution of NaCl, dried with
Na2SO4, and then concentrated by distillation. The product was
isolated using silica gel chromatography.
4. Experimental
4.1. General techniques
1H, 13C, and 19F NMR spectra were recorded in CDCl3 or DMSO-d6
using Bruker DRX-500 (1H 500 MHz, 13C 125 MHz) and DRX-250
(
19F 235 MHz) spectrometers. Tetramethylsilane was used as an
internal reference for 1H and 13C NMR. The chemical shift of 19F
NMR was referenced to the resonance frequency, 19F 376.27 MHz,
with a negative sign indicating an upfield shift. Chemical shifts
4.2.2. Successive trifluoromethylation of ethyl 3-oxobutanoate. A
30% H2O2 aqueous solution (1.0 mL) was added dropwise to the
mixture of ethyl 3-oxobutanoate (5.0 mmol), DMSO (20 mL), 3.0 M
DMSO solution of CF3I (5.0 mL), and 1.0 M aqueous solution of
were expressed in parts per million (d). Multiplicties were indicated
by s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet),

Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
2643
19F NMR 61% yield. Furthermore, the same reagent was added to
this reaction mixture and 2a formation was confirmed by 19F NMR
in 73%. Finally, the resulting mixture was poured into H2O and the
product was extracted to diethyl ether. The diethyl ether layer was
washed with a saturated aqueous solution of NaCl, dried with
Na2SO4, and then concentrated by distillation. The product was
isolated using silica gel chromatography.
Table 6
Cycloaddition of various arylhydrazines to 2aa
O
OEt
O
O
ArHNNH2
process A
NEt3
N
OEt
F
N
R
process B
CF3
2a
4.2.3. Cycloaddition of hydrazine derivatives to 3-(trifluoromethyl)
pentane-2,4-dione (1a). The procedure for synthesis of 3,5-
dimethyl-4-(trifluoromethyl)-1H-pyrazole (4a) is used as a repre-
sentative example. Hydrazine monohydrate (2.5 mmol) was added
to a mixture of 3-(trifluoromethyl)pentane-2,4-dione (2.5 mmol),
and EtOH (4.0 mL) in an Ar atmosphere. The resulting mixture was
stirred for 5 h at 60 ꢁC. After cooling to room temperature, the
product was extracted to ethyl acetate. The ethyl acetate layer was
washed with a saturated aqueous solution of NaCl, dried with
Na2SO4 and, then concentrated under vacuo. The product was
isolated using silica gel chromatography.
Entry
Ar
Product
Isolated yield/%
O
OEt
F
43 (46c)
(38d)
1
Ph
N
N
N
5i
N
Ph
O
OEt
4.2.4. Cycloaddition of hydrazine derivatives to 3-oxo-2-(tri-
fluoromethyl)butanoates. The procedure for synthesis of ethyl 5-
fluoro-1,3-dimethylpyrazole-4-carboxylate (5a) is used as a repre-
sentative example. A mixture of methylhydrazine (0.75 mmol), ethyl
3-oxo-2-(trifluoromethyl)butanoate (0.50 mmol), and EtOH (3.0 mL)
in an Aratmosphere was stirred for 2 h at 80 ꢁC. Aftercooling to room
temperature, the product was extracted to ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution of NaCl,
dried with Na2SO4, and then concentrated under vacuo. The product
was isolated using silica gel chromatography.
2b
m-Tolyl
44
F
5j
N
N
O
O
OEt
3b
2-ClPh
58
F
Cl
5k
4.2.5. Synthesis of ethyl 3-(phenylhydrazono)-2-(trifluoromethyl)
butanoate (6) from ethyl 3-oxo-2-(trifluoromethyl)butanoate (2a). A
mixture of phenylhydrazine (2.0 mmol), ethyl 3-oxo-2-(tri-
fluoromethyl)butanoate (1.0 mmol), and EtOH (5.0 mL) in an Ar
atmosphere was stirred for 2 h at 80 ꢁC. After cooling to room
temperature, the product was extracted to ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution of
NaCl, dried with Na2SO4, and then concentrated under vacuo. The
product was isolated using silica gel chromatography.
OEt
N
4b
4-MeOPh
33
F
5l
N
OMe
a
The reaction conditions of process A: 2a 0.5 mmol, hydrazine 0.5e0.75 mmol,
EtOH 3 mL. All the reactions were carried out at room temperature or 80 ꢁC for 2 h.
The reaction conditions of process B: NEt3 0.5e0.75 mmol. All the reactions were
carried out at 80 ꢁC for 1 h.
4.2.6. Synthesis of ethyl 5-fluoro-3-methyl-1-phenyllpyrazole-4-
carboxylate (5i) from ethyl 3-phenylhydrazono-2-(trifluoromethyl)
butanoate (6). A mixture of ethyl 3-(phenylhydrazono)-2-(tri-
fluoromethyl)butanoate (0.50 mmol), NEt3 (0.75 mmol), and EtOH
(3.0 mL) in an Ar atmosphere was stirred for 1 h at 80 ꢁC. After
cooling to room temperature, the product was extracted to ethyl
acetate. The ethyl acetate layer was washed with a saturated aqueous
solution of NaCl, dried with Na2SO4, and then concentrated under
vacuo. The product was isolated using silica gel chromatography.
b
Since m-tolylhydrazine, (o-chlorophenyl)hydrazine, and (p-methoxyphenyl)
hydrazine were supplied as a HCl salt, their EtOH solutions including the same
equivalent of NEt3 were used in process A.
c
19F NMR yield.
d
19F NMR yield in the reaction with K2CO3 (1.0 mmol) instead of NEt3.
FeSO4 (1.5 mL) in an Ar atmosphere. The resulting mixture was
stirred for 1 h at room temperature. After the reaction, an aliquot of
the mixture was analyzed using 19F NMR, confirming the formation
of ethyl 3-oxo-2-(trifluoromethyl)butanoate (2a) in 43% yield. To
this reaction mixture were added 3.0 M DMSO solution of CF3I
(5.0 mL), 1.0 M aqueous solution of FeSO4 (1.5 mL), and 30% H2O2
aqueous solution (1.0 mL). After stirring for 1 h, 2a was formed in
4.2.7. Cycloaddition of arylhydrazines to ethyl 3-oxo-2-(tri-
fluoromethyl)butanoates (2a). The procedure for synthesis of ethyl
5-fluoro-3-methyl-1-phenylpyrazole-4-carboxylate (5i) is used as
a
representative example.
A
mixture of phenylhydrazine
(0.50
mmol),
ethyl
3-oxo-2-(trifluoromethyl)butanoate
O
O
OEt
OEt
NH
O
O
O
1.5 eq iPrHNNH2
rt, 1 h
N
N
N
F
+
OEt
F
N
N
rt, 11 h
OEt
CF3
2a
5b
5b
CF3
22%
47%
58%
Scheme 8.

2644
Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
Table 7
Table 8
Cycloaddition of methyl or phenylhydrazine to 3-oxopropinonamidesa
Cycloaddition of phenylhydrazine to 3-oxo-2-(trifluoromethyl)butyramide
derivativesa
O
NHR2
R1
O
O
O
NHR
O
O
R3NHNH2
R1
NHR2
+
N
PhNHNH2
process A
NEt3
F
N
N
CF3
NHR
F
N
process B
R3
CF3
Ph
Entry R1 R2
R3
Product
Isolated yield/%
Entry
R
Product
Isolated yield/%
O
O
NH2
7a
NH2
1
2
Me H (3a)
Me
75
N
N
1
H (3a)
57
F
N
F
7g
N
Me
Ph
O
H
N
O
H
N
Me 2-iPrPh (3b) Me
52
44
85
N
N
F
F
F
7b
7c
7d
2-iPrPh (3b)
76
68
N
2
3
N
F
7h
N
Me
Ph
O
H
N
O
H
N
Biphenyl-2-yl
(3c)
3b
Me
Me
Me
Biphenyl-2-yl (3c)
N
N
F
7i
N
Me
Ph
O
H
N
O
H
N
Br
4
Me 2-BrPh (3d)
N
Cl
4
2-ClPh (3e)
80
N
N
F
7j
N
Me
Ph
O
H
N
Ph
a
The reaction conditions of process A: substrate 0.5 mmol, phenylhydrazine
0.5e0.75 mmol, EtOH 3e6 mL. All the reactions were carried out at room temper-
ature for 2 h. The reaction conditions of process B: NEt3 1.5e2.25 mmol. All the
reactions were carried out at 80 ꢁC for 2 h.
5c
Ph Ph (3e)
Me
Ph
74
58
N
F
7e
N
Me
O
a
representative example.
A
mixture of methylhydrazine
H
N
Ph
(0.75 mmol), 3-oxo-2-(trifluoromethyl)butanamide (0.50 mmol),
and EtOH (3.0 mL) in an Ar atmosphere was stirred for 2 h at 80 ꢁC.
After cooling to room temperature, the product was extracted to
ethyl acetate. The ethyl acetate layer was washed with a saturated
aqueous solution of NaCl, dried with Na2SO4, and then concen-
trated under vacuo. The product was isolated using silica gel
chromatography.
6d
Ph Ph (3f)
N
F
7f
N
Ph
a
The used amounts of a 3-oxo-2-(trifluoromethyl)carboxiamide derivative and
methylhydrazine were 0.5 mmol and 0.75 mmol, respectively. All the reactions were
carried out in 3.0 mL of EtOH for 2 h at 80 ꢁC.
b
4.2.9. Synthesis of 3-(phenylhydrazono)-2-(trifluoromethyl)butana-
mide (8) from 3-oxo-2-(trifluoromethyl)butanamide (3a). A mixture
of phenylhydrazine (0.50 mmol), 3-oxo-2-(trifluoromethyl)buta-
namide (0.50 mmol), and EtOH (3.0 mL) in an Ar atmosphere was
stirred for 2 h at room temperature. After the reaction, the product
was extracted to ethyl acetate. The ethyl acetate layer was washed
with a saturated aqueous solution of NaCl, dried with Na2SO4, and
then concentrated under vacuo. The product was isolated using
silica gel chromatography.
EtOH (6.0 mL) was used.
c
Methylhydrazine (1.0 mmol) was used in 2.0 mL of EtOH and 1.0 mL of DMSO.
Phenylhydrazine (1.5 mmol) was used in 2.0 mL of EtOH and 1.0 mL of DMSO.
d
(0.50 mmol), and EtOH (3.0 mL) in an Ar atmosphere was stirred for
2 h at 80 ꢁC (process A). NEt3 (0.75 mmol) was subsequentlyadded to
the mixture and was further stirred for 1 h at 80 ꢁC (process B). After
cooling to room temperature, the product was extracted to ethyl
acetate. The ethyl acetate layerwaswashedwitha saturatedaqueous
solution of NaCl, dried with Na2SO4, and then concentrated under
vacuo. The product was isolated using silica gel chromatography.
4.2.10. Synthesis of 5-fluoro-3-methyl-1-phenylpyrazole-4-carbo-
xamide (7h) from 3-(phenylhydrazono)-2-(trifluoromethyl)butana-
mide (8). A mixture of 3-(phenylhydrazono)-2-(trifluoromethyl)
butanamide (0.25 mmol), NEt3 (1.13 mmol), and EtOH (2.0 mL) in
an Ar atmosphere was stirred for 2 h at 80 ꢁC. After cooling to room
4.2.8. Cycloaddition of hydrazine derivatives to 3-oxo-2-(tri-
fluoromethyl)butanamide derivatives. The procedure for synthesis
of 5-fluoro-1,3-dimethylpyrazole-4-carboxamide (7a) is used as

Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
2645
O
NH2
NHPh
O
O
N
O
base
PhNNH
2
N
F
NH2
NH2
N
EtOH, 1 h
CF3
CF3
Ph
7g
3a
8
80 ºC, 4.5 eq. NEt3 71% (isolated yield)
rt, 2.0 eq. K2CO3 51% (19F-NMR yield)
75% (isolated yield)
Scheme 9.
O
NHAr
NHPh
O
O
N
O
NEt
PhNNH
3
2
N
F
NHAr
NHAr
N
CF3
CF3
Ph
isolated yield:
isolated yield:
Ar = 2-iPrPh (3b)
Ar = 2-iPrPh 40%
Ar = 2-iPrPh (7h) 22%
= biphenyl-2-yl (3c)
= 2-ClPh (3e)
= biphenyl-2-yl 71%
= 2-ClPh 64%
= biphenyl-2-yl (7i) 61%
= 2-ClPh (7j) 64%
Scheme 10.
temperature, the product was extracted to ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution of
NaCl, dried with Na2SO4, and then concentrated under vacuo. The
product was isolated using silica gel chromatography.
1261, 1247, 1146, 1099, 1016, 739 cmꢀ1. HRMS: calcd for C10H14F3O2
(MꢀHꢀ): 223.0951; found: m/z 223.0938.
4.3.3. 1-Phenyl-2-(trifluoromethyl)butane-1,3-dione (1c). Pale yel-
low solid. Mp 40.5e42.9 ꢁC. 1H NMR (DMSO-d6)
d
2.29 (3H, s), 6.44
4.2.11. Cycloaddition of phenylhydrazine to 3-oxo-2-(trifluoromethyl)
butanamide derivatives. The procedure for synthesis of 5-fluoro-3-
methyl-1-phenylpyrazole-4-carboxamide (7h) is used as a repre-
sentative example. A mixture of phenylhydrazine (0.50 mmol), 3-
oxo-2-(trifluoromethyl)butanamide (0.50 mmol), and EtOH
(3.0 mL) in an Ar atmosphere was stirred for 2 h at room temper-
ature (process A). NEt3 (1.50 mmol) was subsequently added to the
mixture and was further stirred for 2 h at 80 ꢁC (process B). After
cooling to room temperature, the product was extracted to ethyl
acetate. The ethyl acetate layer was washed with a saturated
aqueous solution of NaCl, dried with Na2SO4, and then concen-
trated under vacuo. The product was isolated using silica gel
chromatography.
(1H, q, JHF¼8.8 Hz), 7.56e7.66 (2H, m), 7.71e7.80 (1H, m), 8.04e8.12
(2H, m). 13C NMR (DMSO-d6)
d
30.3, 62.3 (q, JCF¼23.8 Hz), 123.1 (q,
JCF¼280.6 Hz), 129.2, 129.3, 134.9, 135.6, 189.5, 196.5. 19F NMR
(DMSO-d6)
d
ꢀ62.2 (d, JFH¼8.8 Hz). IR 1724, 1687, 1597, 1450, 1360,
1261, 1232, 1147, 1119, 827, 766, 687, 642 cmꢀ1. HRMS: calcd for
C11H8F3O2 (MꢀHꢀ): 229.0482; found: m/z 229.0477.
4.3.4. 2,2,6,6-Tetramethyl-4-(trifluoromethyl)heptane-3,5-dione
(1d). Pale yellow solid. Mp 79.8e82.2 ꢁC. 1H NMR (DMSO-d6)
d
1.14
(18H, s), 5.91 (1H, q, JHF¼8.3 Hz). 13C NMR (DMSO-d6)
d 26.5, 45.2,
56.7 (q, JCF¼23.8 Hz), 122.6 (q, JCF¼281.3 Hz), 202.8. 19F NMR
(DMSO-d6)
d
ꢀ60.4 (d, JFH¼8.3 Hz). IR 1734, 1481, 1342, 1282, 1250,
1153, 1130, 1043, 999, 874, 852, 785, 631 cmꢀ1. HRMS: calcd for
C12H19F3O2 (MþHþ): 253.1415; found: m/z 253.1411.
4.3.5. Ethyl 3-oxo-2-(trifluoromethyl)butanoate (2a). Colorless oil.
4.3. Characterization of products
1H NMR (DMSO-d6)
d
1.21 (3H, t, J¼7.1 Hz), 2.31 (3H, s), 4.23 (2H, q,
J¼7.1 Hz), 5.34 (1H, q, JHF¼9.0 Hz). 13C NMR (DMSO-d6)
d 13.8, 30.3,
4.3.1. 3-(Trifluoromethyl)pentane-2,4-dione (1a). Colorless oil. 1H
60.9 (q, JCF¼25.7 Hz), 62.5, 122.6 (q, JCF¼279.6 Hz), 162.6 (q,
NMR (DMSO-d6)
(DMSO-d6)
d
2.30 (6H, s), 5.47 (1H, q, JHF¼9.4 Hz). 13C NMR
JCF¼3.1 Hz), 195.5. 19F NMR (DMSO-d6)
d
ꢀ63.8 (d, JFH¼9.0 Hz). IR
d
31.0, 66.9 (q, JCF¼23.7 Hz), 122.7 (q, JCF¼280.4 Hz),
1751, 1732, 1371, 1348, 1223, 1167, 1144, 1109, 1034, 916, 702,
671 cmꢀ1. HRMS: calcd for C7H8F3O3 (MꢀHꢀ): 197.0431; found: m/z
197.0435.
196.9. 19F NMR (DMSO-d6)
d
ꢀ62.7 (d, JFH¼9.4 Hz). IR 1718, 1560,
1419, 1346, 1248, 1151, 1097, 1016, 922, 741 cmꢀ1. HRMS: calcd for
C6H6F3O2 (MꢀHꢀ): 167.0325; found: m/z 167.0331.
4.3.6. Ethyl
4-methyl-3-oxo-2-(trifluoromethyl)pentanoate
1.06 (6H, d, J¼6.8 Hz),
4.3.2. 3-(Trifluoromethyl)nonane-2,4-dione (1b). Pale yellow oil. 1H
(2b). Colorless oil. 1H NMR (DMSO-d6)
d
NMR (DMSO-d6)
d
0.85 (3H, t, J¼7.1 Hz), 1.17e1.31 (4H, m), 1.49 (2H,
1.19 (3H, t, J¼7.1 Hz), 2.86 (1H, sept, J¼6.8 Hz), 4.20 (2H, q,
quint, J¼7.2 Hz), 2.28 (3H, s), 2.65 (2H, t, J¼7.2 Hz), 5.45 (1H, q,
J¼7.1 Hz), 5.59 (1H, q, JHF¼8.8 Hz). 13C NMR (DMSO-d6)
d 13.8,
JHF¼9.3 Hz). 13C NMR (DMSO-d6)
d
13.9, 22.0, 22.3, 30.4, 30.8, 43.4,
17.4, 17.5, 41.4, 58.0 (q, JCF¼25.7 Hz), 62.4, 122.7 (q, JCF¼279.6 Hz),
66.3 (q, JCF¼23.5 Hz), 122.7 (q, JCF¼280.4 Hz), 196.7, 199.0. 19F NMR
162.7 (q, JCF¼3.2 Hz), 201.8. 19F NMR (DMSO-d6)
d
ꢀ63.7 (d,
(DMSO-d6)
d
ꢀ62.6 (d, JFH¼9.3 Hz). IR 1743, 1718, 1560, 1415, 1340,
JFH¼8.8 Hz). IR 2981, 1757, 1728, 1346, 1261, 1227, 1159, 1113, 1020,

2646
Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
920, 837 cmꢀ1. HRMS: calcd for C9H14F3O3 (MþHþ): 227.0895;
found: m/z 227.0912.
m), 7.54e7.58 (1H, m), 7.69e7.73 (1H, m), 10.37 (1H, br s). 13C NMR
(DMSO-d6)
d
29.4, 62.0 (q, JCF¼24.6 Hz), 118.6, 123.0 (q,
JCF¼280.1 Hz), 127.7, 128.4, 128.5, 133.1, 135.1, 160.3, 195.5. 19F NMR
4.3.7. Ethyl 3-oxo-3-phenyl-2-(trifluoromethyl)propionate
(DMSO-d6)
d
ꢀ63.5 (d, JFH¼8.7 Hz). IR 3240, 1739, 1658, 1541, 1369,
(2c). Colorless oil. 1H NMR (DMSO-d6)
d
1.09 (3H, t, J¼7.1 Hz), 4.17
(2H, q, J¼7.1 Hz), 6.31 (1H, q, JHF¼8.5 Hz), 7.58e7.63 (2H, m),
7.72e7.77 (1H, m), 8.05e8.09 (2H, m). 13C NMR (DMSO-d6)
13.7,
1259,1151,1111, 752 cmꢀ1. HRMS: calcd for C11H10BrF3NO2 (MþHþ):
323.9847; found: m/z 323.9849.
d
56.0 (q, JCF¼25.8 Hz), 62.5, 122.9 (q, JCF¼279.9 Hz), 129.1, 129.3,
4.3.14. N-(2-Chlorophenyl)-3-oxo-2-(trifluoromethyl)butanamide
134.9, 135.2, 162.9 (q, JCF¼2.9 Hz), 188.3. 19F NMR (DMSO-d6)
(3e). Colorless solid. Mp 127.6e128.7 ꢁC. 1H NMR (DMSO-d6)
d 2.32
d
ꢀ63.4 (d, JFH¼8.5 Hz). IR 1747, 1693, 1599, 1450, 1234, 1155, 1111,
(3H, s), 5.09 (1H, q, JHF¼8.7 Hz), 7.26e7.31 (1H, m), 7.35e7.40 (1H,
1026, 687 cmꢀ1. HRMS: calcd for C12H10F3O3 (MꢀHꢀ): 259.0588;
m), 7.53e7.57 (1H, m), 7.63e7.67 (1H, m), 10.40 (1H, br s). 13C NMR
found: m/z 259.0580.
(DMSO-d6)
d
29.3, 62.0 (q, JCF¼24.8 Hz), 123.0 (q, JCF¼279.6 Hz),
126.9, 127.4, 127.9, 129.9, 133.7, 160.4 (q, JCF¼2.4 Hz), 195.6. 19F NMR
4.3.8. Ethyl 3-oxo-3-(p-tolyl)-2-(trifluoromethyl)propionate
(DMSO-d6)
d
ꢀ63.6 (d, JFH¼8.7 Hz). IR 3249, 1734, 1660, 1541, 1377,
(2d). Colorless oil. 1H NMR (DMSO-d6)
d
1.09 (3H, t, J¼7.1 Hz), 2.40
1261, 1144, 1111, 746 cmꢀ1. HRMS: calcd for C11H10ClF3NO2 (MþHꢀ):
280.0352; found: m/z 280.0348.
(3H, s), 4.16 (2H, q, J¼7.1 Hz), 6.27 (1H, q, JHF¼8.5 Hz), 7.41 (2H, d,
J¼8.2 Hz), 7.97 (2H, d, J¼8.2 Hz). 13C NMR (DMSO-d6)
d 13.8, 21.4,
55.8 (q, JCF¼25.7 Hz), 62.4, 123.0 (q, JCF¼279.9 Hz), 129.3, 129.8,
4.3.15. 3-Oxo-N,3-diphenyl-2-(trifluoromethyl)propanamide
132.8, 145.9, 163.1 (q, JCF¼2.9 Hz), 187.7. 19F NMR (DMSO-d6)
d
ꢀ63.4
(3f). Colorless solid. Mp 183.0e184.4 ꢁC. 1H NMR (DMSO-d6)
d 5.79
(d, JFH¼8.5 Hz). IR 1749, 1685, 1606, 1346, 1234, 1155, 1109, 1026,
827, 622 cmꢀ1. HRMS: calcd for C13H14F3O3 (MþHþ): 275.0895;
found: m/z 275.0889.
(1H, q, JHF¼8.3 Hz), 7.07e7.16 (1H, m), 7.27e7.37 (2H, m), 7.45e7.61
(4H, m), 7.63e7.73 (1H, m), 7.96e8.04 (2H, m), 10.85 (1H, br s). 13C
NMR (DMSO-d6)
JCF¼280.1 Hz), 124.8, 128.3, 129.19, 129.24, 134.5, 135.2, 138.0, 159.6,
187.9. 19F NMR (DMSO-d6)
ꢀ63.2 (d, JFH¼8.3 Hz). IR 3275, 1693,
d
58.5 (q, JCF¼24.4 Hz), 119.7, 123.5 (q,
4.3.9. Ethyl 3-(4-chlorophenyl)-3-oxo-2-(trifluoromethyl)propionate
d
(2e). Colorless oil. 1H NMR (DMSO-d6)
d
1.09 (3H, t, J¼7.1 Hz), 4.17
1664, 1533, 1446, 1333, 1250, 1149, 1115, 901, 868, 737, 685 cmꢀ1
.
(2H, q, J¼7.1 Hz), 6.34 (1H, q, JHF¼8.4 Hz), 7.70 (2H, d, J¼8.5 Hz), 8.08
HRMS: calcd for C16H13F3NO2 (MþHþ): 308.0898; found: m/z
(2H, d, J¼8.5 Hz). 13C NMR (DMSO-d6)
d
13.7, 56.0 (q, JCF¼25.8 Hz),
308.0896.
62.6, 122.8 (q, JCF¼279.9 Hz), 129.5, 131.0, 133.9, 140.2, 162.7 (q,
JCF¼2.9 Hz), 187.4. 19F NMR (DMSO-d6)
d
ꢀ63.3 (d, JFH¼8.4 Hz). IR
4.3.16. 3,5-Dimethyl-4-(trifluoromethyl)-1H-pyrazole
yellow solid. Mp 80.5e82.3 ꢁC. 1H NMR (CDCl3)
(4a). Pale
2.35 (6H, q,
1751, 1697, 1589, 1346, 1236, 1153, 1111, 1092, 1024, 835, 631 cmꢀ1
.
d
HRMS: calcd for C12H9ClF3O3 (MꢀHꢀ): 293.0192; found: m/z
JHF¼1.2 Hz), 11.47 (1H, br s). 13C NMR (CDCl3)
d 11.4, 108.2 (q,
293.0198.
JCF¼36.0 Hz), 124.0 (q, JCF¼266.4 Hz), 143.9. 19F NMR (CDCl3)
d
ꢀ56.1. IR 2945, 2889, 1601, 1527, 1329, 1308, 1147, 1093, 1045, 777,
4.3.10. 3-Oxo-2-(trifluoromethyl)butanamide (3a). Colorless solid.
742 cmꢀ1. HRMS: calcd for C6H8F3N2 (MþHþ): 165.0640; found: m/
Mp 116.7e117.6 ꢁC. 1H NMR (DMSO-d6)
d 2.20 (3H, s), 4.62 (1H, q,
z 165.0658.
JHF¼8.9 Hz), 7.75 (1H, br s), 8.00 (1H, br s). 13C NMR (DMSO-d6)
d
29.0, 61.8 (q, JCF¼24.3 Hz), 123.2 (q, JCF¼279.7 Hz), 162.9 (q,
4.3.17. 1,3,5-Trimethyl-4-(trifluoromethyl)pyrazole (4b). Colorless
JCF¼2.4 Hz), 196.1. 19F NMR (DMSO-d6)
d
ꢀ63.9 (d, JFH¼8.9 Hz). IR
oil. 1H NMR (CDCl3)
d
2.28 (3H, q, JHF¼0.9 Hz), 2.32 (3H, q,
3386, 3197, 1730, 1674, 1352, 1252, 1159, 1109, 984, 804, 741,
665 cmꢀ1. HRMS: calcd for C5H7F3NO2 (MþHþ): 170.0429; found:
m/z 170.0425.
JHF¼0.7 Hz), 3.72 (3H, s). 13C NMR (CDCl3)
d 10.1, 12.5, 35.8, 108.5 (q,
JCF¼35.8 Hz), 123.9 (q, JCF¼266.4 Hz), 139.1 (q, JCF¼2.8 Hz), 145.7 (q,
JCF¼2.1 Hz). 19F NMR (CDCl3)
d
ꢀ55.8. IR 1572, 1493, 1439, 1392,
1333, 1271, 1149, 1095, 1051, 742 cmꢀ1. HRMS: calcd for C7H10F3N2
4.3.11. N-(2-Isopropylphenyl)-3-oxo-2-(trifluoromethyl)butanamide
(MþHþ): 179.0796; found: m/z 179.0787.
(3b). Colorless solid. Mp 132.6e134.1 ꢁC. 1H NMR (DMSO-d6)
d 1.13
(3H, d, J¼6.9 Hz), 1.16 (3H, d, J¼6.9 Hz), 2.30 (3H, s), 3.13 (1H, sept,
J¼6.9 Hz), 4.94 (1H, q, JHF¼8.7 Hz), 7.18e7.23 (1H, m), 7.24e7.29
(2H, m), 7.34e7.38 (1H, m), 10.14 (1H, br s). 13C NMR (DMSO-d6)
4.3.18. 3,5-Dimethyl-1-phenyl-4-(trifluoromethyl)pyrazole
(4c). Pale yellow oil. 1H NMR (CDCl3)
d
2.36 (3H, q, JHF¼1.3 Hz), 2.38
(3H, q, JHF¼1.2 Hz), 7.36e7.40 (2H, m), 7.41e7.45 (1H, m), 7.46e7.51
(2H, m). 13C NMR (CDCl3)
11.1, 12.5, 109.7 (q, JCF¼35.7 Hz), 123.9 (q,
JCF¼266.8 Hz), 125.6, 128.4, 129.1, 138.5, 139.6 (q, JCF¼2.8 Hz), 147.1.
d
23.19, 23.22, 27.4, 29.1, 62.1 (q, JCF¼24.5 Hz), 123.2 (q,
d
JCF¼279.9 Hz), 125.9, 126.2, 126.9, 127.4, 133.6, 143.6, 160.7 (q,
JCF¼2.3 Hz), 195.8. 19F NMR (DMSO-d6)
d
ꢀ63.7 (d, JFH¼8.7 Hz). IR
19F NMR (CDCl3)
d
ꢀ56.0. IR 1570, 1506, 1429, 1335, 1259, 1153, 1101,
3240, 1732, 1657, 1529, 1244, 1155, 1115, 760 cmꢀ1. HRMS: calcd for
1053, 764, 696 cmꢀ1. HRMS: calcd for C12H12F3N2 (MþHþ):
241.0953; found: m/z 241.0941.
C14H17F3NO2 (MþHþ): 288.1211; found: m/z 288.1210.
4.3.12. N-(Biphenyl-2-yl)-3-oxo-2-(trifluoromethyl)butanamide
4.3.19. 1,3-Dimethyl-5-phenyl-4-(trifluoromethyl)pyrazole
(3c). Colorless solid. Mp 146.5e147.8 ꢁC. 1H NMR (DMSO-d6)
d
2.08
(3H, s), 4.77 (1H, q, JHF¼8.7 Hz), 7.33e7.48 (9H, m), 10.11 (1H, br s).
13C NMR (DMSO-d6)
29.0, 61.9 (q, JCF¼24.5 Hz), 123.1 (q,
JCF¼279.9 Hz), 127.1, 127.2, 127.6, 128.2, 128.6, 129.0, 130.7. 133.6,
137.4, 138.6, 160.5, 195.6. 19F NMR (DMSO-d6)
(4d). Colorless oil. 1H NMR (CDCl3)
d
2.39 (3H, q, JHF¼1.0 Hz), 3.63
(3H, s), 7.31e7.35 (2H, m), 7.45e7.49 (3H, m). 13C NMR (CDCl3)
d
d
12.7, 36.7, 109.3 (q, JCF¼35.7 Hz), 123.3 (q, JCF¼267.0 Hz), 128.5,
128.6, 129.5, 129.6, 143.4 (q, JCF¼2.9 Hz), 146.2. 19F NMR (CDCl3)
d
ꢀ63.6 (d,
d
ꢀ54.6. IR 1495, 1338, 1273, 1207, 1149, 1101, 1051, 764, 737,
JFH¼8.7 Hz). IR 3248, 1736, 1657, 1529, 1255, 1232, 1151, 1107, 744,
702 cmꢀ1. HRMS: calcd for C17H15F3NO2 (MþHþ): 322.1055; found:
m/z 322.1058.
700 cmꢀ1. HRMS: calcd for C12H12F3N2 (MþHþ): 241.0953; found:
m/z 241.0936.
4.3.20. 1,5-Dimethyl-3-phenyl-4-(trifluoromethyl)pyrazole
4.3.13. N-(2-Bromophenyl)-3-oxo-2-(trifluoromethyl)butanamide
(4e). Colorless oil. 1H NMR (CDCl3)
d
2.43 (3H, q, JHF¼1.2 Hz), 3.85
(3H, s), 7.35e7.42 (3H, m), 7.54e7.59 (2H, m). 13C NMR (CDCl3)
10.4, 36.3, 107.9 (q, JCF¼35.9 Hz), 123.6 (q, JCF¼267.0 Hz), 128.1,
(3d). Colorless solid. Mp 132.5e134.3 ꢁC. 1H NMR (DMSO-d6)
d
2.33
(3H, s), 5.06 (1H, q, JHF¼8.7 Hz), 7.20e7.25 (1H, m), 7.39e7.44 (1H,
d

Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
2647
128.3, 128.6, 132.4, 139.8 (q, JCF¼2.9 Hz), 149.1 (q, JCF¼2.1 Hz). 19F
JCF¼7.7 Hz), 124.1 (d, JCF¼3.6 Hz), 128.0, 129.1, 129.2, 129.8, 131.8,
133.1, 134.6 (d, JCF¼2.5 Hz), 151.4 (d, JCF¼6.8 Hz), 153.2 (d,
NMR (CDCl3)
d
ꢀ53.6. IR 1556,1456,1333,1167,1097,1034, 972, 775,
698 cmꢀ1. HRMS: calcd for C12H12F3N2 (MþHþ): 241.0953; found:
m/z 241.0935.
JCF¼293.6 Hz), 160.4 (d, JCF¼5.8 Hz). 19F NMR (DMSO-d6)
ꢀ117.8. IR
d
1730, 1572, 1508, 1485, 1323, 1302, 1149, 1086, 825, 758, 687,
654 cmꢀ1. HRMS: calcd for C18H15ClFN2O2 (MþHþ): 345.0806;
found: m/z 345.0806.
4.3.21. 3-Methyl-1,5-diphenyl-4-(trifluoromethyl)pyrazole (4f). Pale
yellow solid. Mp 50.7e52.0 ꢁC. 1H NMR (CDCl3)
d
2.49 (3H, q,
JHF¼1.3 Hz), 7.13e7.18 (2H, m), 7.21e7.29 (5H, m), 7.30e7.40 (3H,
m). 13C NMR (CDCl3)
12.9, 110.9 (q, JCF¼35.8 Hz), 123.3 (q,
4.3.28. Ethyl 5-fluoro-1-methyl-3-phenylpyrazole-4-carboxylate
d
(5f). Colorless solid. Mp 48.0e50.0 ꢁC. 1H NMR (DMSO-d6)
d
1.18
(3H, t, J¼7.1 Hz), 3.77 (3H, d, JHF¼1.4 Hz), 4.17 (2H, q, J¼7.1 Hz),
7.36e7.44 (3H, m), 7.58e7.66 (2H, m). 13C NMR (DMSO-d6)
14.1,
JCF¼267.5 Hz), 125.2, 127.8, 128.3, 128.6, 128.8, 129.3, 130.1, 138.9,
143.1 (q, JCF¼3.0 Hz), 147.6. 19F NMR (CDCl3)
d
ꢀ54.3. IR 1508, 1487,
d
1427, 1313, 1248, 1142, 1109, 1047, 762, 692 cmꢀ1. HRMS: calcd for
34.4, 60.0, 92.9 (d, JCF¼7.8 Hz), 127.9, 128.7, 128.9, 132.4, 150.0 (d,
C17H14F3N2 (MþHþ): 303.1109; found: m/z 303.1095.
JCF¼6.8 Hz), 153.9 (d, JCF¼288.1 Hz), 160.7 (d, JCF¼5.7 Hz). 19F NMR
(DMSO-d6)
d
ꢀ121.5. IR 1711,1545,1450,1389,1306,1142,1053, 766,
4.3.22. Ethyl 5-fluoro-1,3-dimethylpyrazole-4-carboxylate
696, 654 cmꢀ1. HRMS: calcd for C13H14FN2O2 (MþHþ): 249.1039;
found: m/z 249.1031.
(5a). Colorless solid. Mp 42.8e43.9 ꢁC. 1H NMR (DMSO-d6)
d 1.24
(3H, t, J¼7.1 Hz), 2.25 (3H, s), 3.63 (3H, d, JHF¼1.5 Hz), 4.19 (2H, q,
J¼7.1 Hz). 13C NMR (CDCl3)
d
14.3, 14.6, 33.7, 59.9, 98.3 (d,
4.3.29. Ethyl 5-fluoro-1-methyl-3-(p-tolyl)pyrazole-4-carboxylate
JCF¼7.6 Hz), 149.8 (d, JCF¼6.4 Hz), 153.8 (d, JCF¼289.0 Hz), 161.8 (d,
(5g). Colorless solid. Mp 83.2e85.1 ꢁC. 1H NMR (DMSO-d6)
d 1.19
JCF¼5.5 Hz). 19F NMR (DMSO-d6)
d
ꢀ123.1. IR 1699, 1576, 1560, 1421,
(3H, t, J¼7.1 Hz), 2.33 (3H, s), 3.75 (3H, d, JHF¼1.5 Hz), 4.17 (2H, q,
1311, 1261, 1182, 1093, 775, 687 cmꢀ1. HRMS: calcd for C8H12FN2O2
J¼7.1 Hz), 7.20 (2H, d, J¼8.1 Hz), 7.53 (2H, d, J¼8.1 Hz). 13C NMR
(MþHþ): 187.0883; found: m/z 187.0878.
(DMSO-d6)
d
14.2, 21.0, 34.4, 60.0, 92.8 (d, JCF¼7.8 Hz), 128.5, 128.7,
129.6, 138.1, 149.9 (d, JCF¼7.0 Hz), 153.9 (d, JCF¼288.2 Hz), 160.7 (d,
4.3.23. 5-Fluoro-1,3-dimethylpyrazole-4-carboxylic
acid
2.24 (3H, s),
(5a0).
JCF¼5.7 Hz). 19F NMR (DMSO-d6)
ꢀ121.5. IR 1703, 1579, 1541, 1442,
d
Colorless solid. Mp 208 ꢁC (dec). 1H NMR (DMSO-d6)
d
1321, 1182, 1051, 829, 777, 681 cmꢀ1. HRMS: calcd for C14H16FN2O2
3.62 (3H, d, JHF¼1.2 Hz), 12.51 (1H, br s). 13C NMR (DMSO-d6)
d
14.4,
(MþHþ): 263.1196; found: m/z 263.1187.
33.9, 93.6 (d, JCF¼7.8 Hz), 148.5 (d, JCF¼6.7 Hz), 153.3 (d,
JCF¼286.8 Hz), 162.6 (d, JCF¼5.1 Hz). 19F NMR (DMSO-d6)
d
ꢀ123.8.
4.3.30. Ethyl 5-fluoro-3-(4-chlorophenyl)-1-methylpyrazole-4-
carboxylate (5h). Pale yellow solid. Mp 83.8e85.8 ꢁC. 1H NMR
IR 1701, 1579, 1556,1421,1306,1269, 1184, 1099, 899, 762, 681 cmꢀ1
.
HRMS: calcd for C6H8FN2O2 (MþHþ): 159.0570; found: m/z
(DMSO-d6)
d
1.19 (3H, t, J¼7.1 Hz), 3.77 (3H, d, JHF¼1.4 Hz), 4.18 (2H,
159.0568.
q, J¼7.1 Hz), 7.47 (2H, d, J¼8.6 Hz), 7.67 (2H, d, J¼8.6 Hz). 13C NMR
(DMSO-d6)
d
14.1, 34.5, 60.1, 93.0 (d, JCF¼8.0 Hz), 128.0, 130.6, 131.2,
4.3.24. Ethyl 5-fluoro-1-isopropyl-3-methylpyrazole-4-carboxylate
133.6, 148.7 (d, JCF¼7.1 Hz), 154.0 (d, JCF¼288.6 Hz), 160.6 (d,
(5b). Pale yellow solid. Mp 49.6e51.3 ꢁC. 1H NMR (CDCl3)
d
1.34
JCF¼5.7 Hz). 19F NMR (DMSO-d6)
ꢀ121.0. IR 1705, 1545, 1439, 1298,
d
(3H, t, J¼7.1 Hz), 1.47 (6H, d, J¼6.7 Hz), 2.40 (3H, s), 4.29 (2H, q,
1140, 1092, 1038, 849, 783, 642 cmꢀ1
. HRMS: calcd for
J¼7.1 Hz), 4.47 (1H, sept, J¼6.7 Hz). 13C NMR (DMSO-d6)
d
14.3, 14.7,
C13H13ClFN2O2 (MþHþ): 283.0650; found: m/z 283.0643.
21.5, 49.4, 59.7, 93.1 (d, JCF¼8.2 Hz), 148.3 (d, JCF¼6.8 Hz), 152.1 (d,
JCF¼287.0 Hz), 161.2 (d, JCF¼5.6 Hz). 19F NMR (CDCl3)
d
ꢀ123.4. IR
4.3.31. Ethyl 5-fluoro-3-methyl-1-phenylpyrazole-4-carboxylate
2989, 1707, 1574, 1529, 1487, 1454, 1306, 1228, 1136, 1088, 1066, 822,
773, 625 cmꢀ1. HRMS: calcd for C10H16FN2O2 (MþHþ): 215.1196;
found: m/z 215.1197.
(5i). Colorless solid. Mp 51.5e52.2 ꢁC. 1H NMR (DMSO-d6)
d 1.28
(3H, t, J¼7.1 Hz), 2.38 (3H, s), 4.25 (2H, q, J¼7.1 Hz), 7.41e7.49 (1H,
m), 7.50e7.59 (2H, m), 7.60e7.68 (2H, m). 13C NMR (DMSO-d6)
d
14.3, 14.7, 60.1, 94.9 (d, JCF¼8.0 Hz), 122.2 (d, JCF¼3.5 Hz), 128.4,
4.3.25. Ethyl 5-fluoro-3-isopropyl-1-phenylpyrazole-4-carboxylate
129.7, 135.8 (d, JCF¼2.8 Hz), 149.9 (d, JCF¼6.9 Hz), 152.5 (d,
(5c). Yellow solid. Mp 45.5e47.2 ꢁC. 1H NMR (DMSO-d6)
d
1.25
JCF¼292.2 Hz), 160.9 (d, JCF¼5.7 Hz). 19F NMR (DMSO-d6)
d
ꢀ119.8.
(6H, d, J¼6.9 Hz), 1.28 (3H, t, J¼7.1 Hz), 3.43 (1H, sept, J¼6.9 Hz),
IR 1709,1577,1518,1489,1309,1240,1134,1099, 762, 687, 648 cmꢀ1
.
4.26 (2H, q, J¼7.1 Hz), 7.41e7.69 (5H, m). 13C NMR (DMSO-d6)
d
14.3,
HRMS: calcd for C13H14FN2O2 (MþHþ): 249.1039; found: m/z
21.2, 27.5, 60.1, 93.8 (d, JCF¼7.7 Hz), 122.3 (d, JCF¼3.5 Hz), 128.4,
249.1031.
129.7, 135.9, 152.7 (d, JCF¼293.0 Hz), 158.4 (d, JCF¼5.4 Hz), 160.8 (d,
JCF¼5.9 Hz). 19F NMR (DMSO-d6)
d
ꢀ119.6. IR 2962, 2931, 1716, 1577,
4.3.32. Ethyl 5-fluoro-3-methyl-1-(m-tolyl)pyrazole-4-carboxylate
(5j). Pale yellow solid. Mp 44.8e45.2 ꢁC. 1H NMR (DMSO-d6)
1520, 1456, 1342, 1232, 1134, 1090, 1041, 752, 687 cmꢀ1. HRMS:
calcd for C15H18FN2O2 (MþHþ): 277.1352; found: m/z 277.1343.
d
1.28 (3H, t, J¼7.1 Hz), 2.37 (6H, s), 4.25 (2H, q, J¼7.1 Hz), 7.22e7.31
(1H, m), 7.38e7.49 (3H, m). 13C NMR (DMSO-d6)
d
14.3, 14.6, 21.0,
4.3.26. Ethyl 5-fluoro-1,3-diphenylpyrazole-4-carboxylate
60.1, 94.9 (d, JCF¼8.0 Hz), 119.1 (d, JCF¼4.0 Hz), 122.5 (d, JCF¼3.1 Hz),
129.0, 129.5, 135.7 (d, JCF¼2.6 Hz), 139.5, 149.8 (d, JCF¼6.7 Hz), 152.4
(d, JCF¼292.2 Hz), 160.9 (d, JCF¼5.6 Hz). 19F NMR (DMSO-d6)
(5d). Colorless solid. Mp 73.8e75.1 ꢁC. 1H NMR (DMSO-d6)
d 1.21
(3H, t, J¼7.1 Hz), 4.22 (2H, q, J¼7.1 Hz), 7.40e7.79 (10H, m). 13C NMR
(DMSO-d6)
d
14.1, 60.4, 94.8 (d, JCF¼7.8 Hz), 122.6 (d, JCF¼3.1 Hz),
d
ꢀ119.7. IR 1714, 1585, 1516, 1483, 1462, 1333, 1254, 1101, 1082, 771,
128.0, 128.8, 129.11, 129.14, 129.8, 132.0, 135.7 (d, JCF¼2.7 Hz), 151.3
681, 650 cmꢀ1. HRMS: calcd for C14H16FN2O2 (MþHþ): 263.1196;
(d, JCF¼6.7 Hz), 153.1 (d, JCF¼292.8 Hz), 160.5 (d, JCF¼5.8 Hz). 19F
found: m/z 263.1191.
NMR (DMSO-d6)
d
ꢀ118.6. IR 1728, 1570, 1510, 1456, 1313, 1149,
1090, 1022, 785, 754, 687, 654 cmꢀ1. HRMS: calcd for C18H16FN2O2
4.3.33. Ethyl 5-fluoro-1-(2-chlorophenyl)-3-methylpyrazole-4-
carboxylate (5k). Pale yellow solid. Mp 70.1e71.6 ꢁC. 1H NMR
(MþHþ): 311.1196; found: m/z 311.1198.
(DMSO-d6)
d
1.27 (3H, t, J¼7.1 Hz), 2.38 (3H, s), 4.26 (2H, q,
4.3.27. Ethyl 5-fluoro-1-(4-chlorophenyl)-3-phenylpyrazole-4-
carboxylate (5e). Orange solid. Mp 92.9e93.7 ꢁC. 1H NMR (DMSO-
J¼7.1 Hz), 7.52e7.77 (4H, m). 13C NMR (DMSO-d6)
d 14.3, 14.7, 60.2,
94.0 (d, JCF¼7.4 Hz), 128.7, 129.9, 130.4, 130.5, 132.3, 132.6 (d,
d6)
d
1.21 (3H, t, J¼7.1 Hz), 4.22 (2H, q, J¼7.1 Hz), 7.41e7.49 (3H, m),
JCF¼2.3 Hz), 150.5 (d, JCF¼6.5 Hz), 153.3 (d, JCF¼290.1 Hz), 160.9 (d,
7.62e7.82 (6H, m). 13C NMR (DMSO-d6)
d
14.1, 60.4, 95.0 (d,
JCF¼5.7 Hz). 19F NMR (DMSO-d6)
ꢀ119.2. IR 1711, 1585, 1529, 1485,
d

2648
Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
1321, 1242, 1126, 1084, 1041, 758, 717 cmꢀ1. HRMS: calcd for
(DMSO-d6)
7.35e7.43 (1H, m), 7.65e7.71 (1H, m), 7.84e7.90 (1H, m), 8.89 (1H, br
s). 13C NMR (DMSO-d6)
14.5, 33.9, 96.2 (d, JCF¼9.5 Hz), 117.2, 125.6,
d
2.33 (3H, s), 3.68 (3H, d, JHF¼1.2 Hz), 7.10e7.18 (1H, m),
C13H13ClFN2O2 (MþHþ): 283.0650; found: m/z 283.0643.
d
4.3.34. Ethyl 5-fluoro-1-(4-methoxyphenyl)-3-methylpyrazole-4-
carboxylate (5l). Pale yellow solid. Mp 68.5e69.2 ꢁC. 1H NMR
126.7,128.3,132.7,136.2,147.5 (d, JCF¼7.6 Hz),151.4 (d, JCF¼282.2 Hz),
159.2 (d, JCF¼4.7 Hz). 19F NMR (DMSO-d6)
d
ꢀ125.5. IR 3404, 1674,
(DMSO-d6)
d
1.27 (3H, t, J¼7.1 Hz), 2.36 (3H, s), 3.80 (3H, s), 4.24 (2H,
1577, 1529, 1417, 1319, 1167, 1086, 1018, 748 cmꢀ1. HRMS: calcd for
q, J¼7.1 Hz), 7.08 (2H, d, J¼9.0 Hz), 7.54 (2H, d, J¼9.0 Hz). 13C NMR
C12H12BrFN3O (MþHþ): 312.0148; found: m/z 312.0151.
(DMSO-d6)
d
14.3, 14.6, 55.6, 60.0, 94.5 (d, JCF¼8.1 Hz), 114.8, 124.1
(d, JCF¼2.7 Hz), 128.7 (d, JCF¼2.3 Hz), 149.5 (d, JCF¼6.7 Hz), 152.2 (d,
4.3.40. 5-Fluoro-1-methyl-N,3-diphenylpyrazole-4-carboxamide
JCF¼290.8 Hz), 159.2, 161.0 (d, JCF¼5.5 Hz). 19F NMR (DMSO-d6)
(7e). Colorless solid. Mp 147.9e150.1 ꢁC. 1H NMR (DMSO-d6)
d
3.81
(3H, d, JHF¼1.0 Hz), 7.04e7.12 (1H, m), 7.28e7.45 (5H, m), 7.58e7.74
(4H, m), 10.29 (1H, br s). 13C NMR (DMSO-d6)
34.4, 98.1 (d,
d
ꢀ120.7. IR 1701, 1579, 1525, 1500, 1446, 1306, 1238, 1136, 1093,
1020, 825, 777 cmꢀ1. HRMS: calcd for C14H16FN2O3 (MþHþ):
d
279.1145; found: m/z 279.1138.
JCF¼11.9 Hz), 119.8, 123.9, 127.3, 128.5, 128.6, 128.9, 132.5, 139.1,
147.3 (d, JCF¼7.7 Hz), 151.4 (d, JCF¼280.8 Hz), 159.5 (d, JCF¼4.2 Hz).
4.3.35. Ethyl
3-(phenylhydrazono)-2-(trifluoromethyl)butanoate
19F NMR (DMSO-d6)
d
ꢀ128.2. IR 1670, 1591, 1537, 1439, 1383, 1331,
(6). Yellow oil. 1H NMR (DMSO-d6)
d
1.20 (3H, t, J¼7.1 Hz), 1.98 (3H,
1246, 1167, 754, 690 cmꢀ1. HRMS: calcd for C17H15FN3O (MþHþ):
296.1199; found: m/z 296.1198.
s), 4.20 (2H, q, J¼7.1 Hz), 4.66 (1H, q, JHF¼9.0 Hz), 6.71e6.79 (1H, m),
7.03e7.09 (2H, m), 7.14e7.21 (2H, m), 9.25 (1H, br s). 13C NMR
(CDCl3)
d
12.6 (d, JCF¼1.4 Hz), 14.0, 58.3 (d, JCF¼28.1 Hz), 62.1, 113.2,
4.3.41. 5-Fluoro-N,1,3-triphenylpyrazole-4-carboxamide (7f). Pale
120.8, 123.6 (d, JCF¼280.8 Hz), 129.2, 133.6 (d, JCF¼2.1 Hz), 144.3,
yellow solid. Mp 160.9e162.5 ꢁC. 1H NMR (DMSO-d6)
d
7.06e7.16
(1H, m), 7.30e7.55 (6H, m), 7.57e7.68 (4H, m), 7.72e7.84 (4H, m),
10.50 (1H, br s). 13C NMR (DMSO-d6)
165.2 (d, JCF¼2.6 Hz). 19F NMR (DMSO-d6)
ꢀ65.0 (d, JCF¼9.0 Hz). IR
d
1739, 1601, 1236, 1161, 1134, 1107, 1026, 750, 692 cmꢀ1. HRMS: calcd
d
100.1 (d, JCF¼12.4 Hz), 119.7,
for C13H16F3N2O2 (MþHþ): 289.1164; found: m/z 289.1159.
122.1 (d, JCF¼3.2 Hz), 124.1, 127.5, 128.5, 128.7, 129.0, 129.1, 130.0,
132.0, 136.1, 138.9, 148.8 (d, JCF¼7.9 Hz), 150.5 (d, JCF¼285.2 Hz),
4.3. 36. 5-Fluoro-1,3-dimethylpyrazole-4-carboxamide
159.0. 19F NMR (DMSO-d6)
d
ꢀ124.8. IR 1653, 1597, 1549, 1485, 1448,
(7a). Colorless solid. Mp 139.4e141.4 ꢁC. 1H NMR (DMSO-d6)
d
2.23
1321, 1259, 1074, 989, 883, 831, 750, 687. HRMS: calcd for
(3H, s), 3.61 (3H, d, JHF¼1.2 Hz), 6.89 (1H, br s), 7.12 (1H, br s). 13
C
C22H17FN3O (MþHþ): 358.1356; found: m/z 358.1351.
NMR (DMSO-d6)
d
14.3, 33.8, 96.3 (d, JCF¼9.9 Hz), 147.1 (d,
JCF¼7.9 Hz), 151.3 (d, JCF¼281.8 Hz), 162.4 (d, JCF¼4.6 Hz). 19F NMR
4.3.42. 5-Fluoro-3-methyl-1-phenylpyrazole-4-carboxamide
(DMSO-d6)
d
ꢀ127.4. IR 3437, 3167, 1662, 1618, 1585, 1541, 1477,
(7g). Colorless solid. Mp 164.9e167.0 ꢁC. 1H NMR (DMSO-d6)
d
2.35
(3H, s), 7.16 (1H, br s), 7.36 (1H, br s), 7.37e7.46 (1H, m), 7.48e7.64 (4H,
m). 13C NMR (DMSO-d6)
14.5, 98.5 (d, JCF¼10.2 Hz), 121.8 (d,
1404, 1119, 793, 733 cmꢀ1. HRMS: calcd for C6H9FN3O (MþHþ):
158.0730; found: m/z 158.0727.
d
X-ray crystal data: C6H8FN3O, M¼157.15, monoclinic, space
group, P21/ꢁc, Z¼4, a¼6.5182(1), b¼12.9452(2), c¼8.4421(2),
JCF¼3.6 Hz), 128.0, 129.8, 136.1, 149.0 (d, JCF¼7.8 Hz), 150.5 (d,
JCF¼287.1 Hz), 162.1 (d, JCF¼4.5 Hz). 19F NMR (DMSO-d6)
ꢀ123.9. IR
d
3
ꢀ
b
¼95.813(1) , V¼708.69(2) A , d¼1.473 g cmꢀ3, 1086 independence
3388, 3192, 1635, 1614, 1514, 1495, 1444, 1267, 1109, 1051, 750, 685.
reflections were collected with Cu K
a
radiation on a Rigaku R-AXIS
HRMS: calcd for C11H11FN3O(MþHþ):220.0886;found:m/z220.0885.
RAPID II. Data analysis was carried out with the Rigaku Crystal
Structure, the structure was solved by direct methods using SHELXS
and refined on F2 using SHELXL to R1¼0.0524, wR2¼0.1522. Atomic
coordinates, bond lengths and angles, and thermal parameters have
been deposited with the Cambridge Crystallographic Database
Service. Please quote reference number CCDC 859473.
4.3.43. 5-Fluoro-N-(2-isopropylphenyl)-3-methyl-1-phenylpyrazole-
4-carboxamide (7h). Pale yellow solid. Mp 112.6e114.0 ꢁC. 1H NMR
(DMSO-d6)
d
1.17 (6H, d, J¼6.8 Hz), 2.40 (3H, s), 3.21 (1H, sept,
J¼6.8 Hz), 7.18e7.69 (9H, m), 9.32 (1H, br s). 13C NMR (DMSO-d6)
d
14.3, 23.2, 27.5, 99.1 (d, JCF¼10.5 Hz), 121.9 (d, JCF¼3.4 Hz), 125.7,
126.0, 126.7, 127.1, 128.1, 129.8, 134.6, 136.1 (d, JCF¼2.5 Hz), 143.7,
148.8 (d, JCF¼7.9 Hz), 150.5 (d, JCF¼286.1 Hz), 159.8 (d, JCF¼4.5 Hz).
4.3.37. 5-Fluoro-N-(2-isopropylphenyl)-1,3-dimethylpyrazole-4-
carboxamide (7b). Colorless solid. Mp 110.8e112.7 ꢁC. 1H NMR
19F NMR (DMSO-d6)
d
ꢀ123.7. IR 1651, 1577, 1533, 1514, 1452, 1248,
(DMSO-d6)
J¼6.9 Hz), 3.66 (3H, d, JHF¼1.1 Hz), 7.13e7.26 (2H, m), 7.30e7.36 (2H,
m), 9.02 (1H, br s). 13C NMR (DMSO-d6)
14.1, 23.1, 27.5, 33.8, 96.9
d
1.15 (6H, d, J¼6.9 Hz), 2.28 (3H, s), 3.16 (1H, sept,
1051, 823, 752, 687. HRMS: calcd for C20H21FN3O (MþHþ):
338.1669; found: m/z 338.1670.
d
(d, JCF¼10.2 Hz), 125.6, 125.9, 126.5, 127.2, 134.8, 143.7, 147.0 (d,
4.3.44. N-(Biphenyl-2-yl)-5-fluoro-3-methyl-1-phenylpyrazole-4-
carboxamide (7i). Pale yellow solid. Mp 104.6e106.1 ꢁC. 1H NMR
JCF¼7.9 Hz), 151.2 (d, JCF¼281.6 Hz), 160.1 (d, JCF¼4.8 Hz). 19F NMR
(DMSO-d6)
d
ꢀ127.0. IR 1672,1576,1523,1446, 1417, 1317, 1171, 1097,
(DMSO-d6)
d 2.23 (3H, s), 7.27e7.60 (13H, m), 7.69e7.77 (1H, m),
1066, 931, 752 cmꢀ1. HRMS: calcd for C15H19FN3O (MþHþ):
276.1512; found: m/z 276.1504.
9.04 (1H, br s). 13C NMR (DMSO-d6)
d
14.2, 98.7 (d, JCF¼10.2 Hz),
121.8 (d, JCF¼3.4 Hz), 126.0, 126.1, 127.6, 128.1, 128.2, 128.6, 129.0,
129.8, 130.4, 134.7, 136.0 (d, JCF¼2.4 Hz), 136.6, 138.8, 148.8 (d,
JCF¼7.7 Hz), 150.3 (d, JCF¼289.0 Hz), 159.3 (d, JCF¼4.4 Hz). 19F NMR
4.3.38. N-(Biphenyl-2-yl)-5-fluoro-1,3-dimethylpyrazole-4-
carboxamide (7c). Colorless solid. Mp 145.2e146.5 ꢁC. 1H NMR
(DMSO-d6)
d
ꢀ123.9. NMR (DMSO-d6) ꢀ123.7. IR 1676, 1579, 1514,
d
(DMSO-d6)
d
2.12 (3H, s), 3.58 (3H, d, JHF¼1.2 Hz), 7.24e7.48 (8H, m),
1435, 1313, 1273, 1232, 1134, 893, 837, 750, 702. HRMS: calcd for
7.75e7.81 (1H, m), 8.63 (1H, br s). 13C NMR (DMSO-d6)
d
14.1, 33.8,
C23H19FN3O (MþHþ): 372.1512; found: m/z 382.1512.
96.4 (d, JCF¼9.8 Hz), 125.4, 125.7, 127.6, 128.0, 128.7, 129.0, 130.3,
134.9, 136.0, 138.7, 147.0 (d, JCF¼7.6 Hz), 151.0 (d, JCF¼282.3 Hz),
4.3.45. N-(2-Chlorophenyl)-5-fluoro-3-methyl-1-phenylpyrazole-4-
carboxamide (7j). Pale yellow solid. Mp 128.6e129.0 ꢁC. 1H NMR
159.4 (d, JCF¼4.6 Hz). 19F NMR (DMSO-d6)
d
ꢀ127.1. IR 3392, 1672,
1577, 1522, 1435, 1319, 1273, 1078, 930, 750, 706 cmꢀ1. HRMS: calcd
(DMSO-d6)
d
2.43 (3H, s), 7.18e7.27 (1H, m), 7.33e7.70 (7H, m),
14.5, 98.5 (d,
for C18H17FN3O (MþHþ): 310.1356; found: m/z 310.1356.
7.90e7.96 (1H, m), 9.27 (1H, br s). 13C NMR (DMSO-d6)
d
JCF¼10.2 Hz), 122.0 (d, JCF¼3.4 Hz), 125.5, 126.47, 126.50, 127.8, 128.3,
4.3.39. N-(2-Bromophenyl)-5-fluoro-1,3-dimethylpyrazole-4-
carboxamide (7d). Colorless solid. Mp 149.3e151.4 ꢁC. 1H NMR
129.6,129.8,134.8,136.0 (d, JCF¼2.5 Hz),149.2 (d, JCF¼7.5 Hz),150.7 (d,
JCF¼287.0 Hz), 159.1 (d, JCF¼4.9 Hz). 19F NMR (DMSO-d6)
ꢀ122.3. IR
d

Y. Ohtsuka et al. / Tetrahedron 68 (2012) 2636e2649
2649
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N.; Sato, M.; Kaneko, C. J. Chem. Soc., Perkin Trans. 1 1992, 1393; (d) Blazejewski,
J.-C.; Dorme, R.; Wakselman, C. Synthesis 1985, 1120.
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8. Uraguchi, D.; Yamamoto, K.; Otsuka, Y.; Tokuhisa, T.; Yamakawa, T. Appl. Catal., A
2008, 342, 137.
9. Kino, T.; Nagase, Y.; Uraguchi, D.; Yamamoto, K.; Otsuka, Y.; Tokuhisa, T.; Ya-
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1963; Collect. Vol. No. IV; 351.
3133, 1649, 1577, 1535, 1516, 1439, 1244, 1047, 829, 750, 683. HRMS:
calcd for C17H14ClFN3O (MþHþ): 330.0809; found: m/z 330.0810.
4.3.46. 3-(Phenylhydrazono)-2-(trifluoromethyl)butanamide
(8). Colorless solid. Mp 118 ꢁC (dec). 1H NMR (DMSO-d6)
d 1.99 (3H,
s), 4.18 (1H, q, JHF¼9.5 Hz), 6.70e6.78 (1H, m), 7.06e7.13 (2H, m),
7.14e7.23 (2H, m), 7.42 (1H, br s), 7.76 (1H, br s), 9.13 (1H, br s). 13C
NMR (DMSO-d6)
d
14.0, 57.2 (d, JCF¼25.5 Hz), 113.0, 119.4, 124.8 (d,
JCF¼280.6 Hz), 129.0, 135.6, 145.9, 165.8. 19F NMR (DMSO-d6)
d
ꢀ64.6 (d, JFH¼9.5 Hz). IR 3431, 3290, 1660, 1603, 1329, 1246, 1155,
1128, 1099, 850, 744, 692, 654 cmꢀ1. HRMS: calcd for C11H13F3N3O
(MþHþ): 260.1011; found: m/z 260.1010.
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B.; Behrenz, W.; Stendel, W. EP 0243636. (g) Guillaune, M.; Janousek, Z.; Viehe,
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Bolton, R.; Moore, C.; Candall, P. B. J. Chem. Soc., Perkin Trans. 2 1982, 1593; (i)
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Kawasaki, H. JP 2000-219679.
Acknowledgements
We thank Prof. Tohru Yamada and Dr. Satoshi Kikuchi at Keio
University for HRMS characterization and Dr. Ryoji Tanaka at
Sagami Chemical Research Institute for X-ray analysis.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2012.01.075.
References and notes
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