A new and direct route to 3-fluoromethyl substituted pyrazol-4-acrylates via Pd-catalyzed C-H activation

Article abstract of DOI:10.1016/j.tet.2013.06.058

Direct C4-H activation of 3-fluoromethyl pyrazoles followed by an oxidative coupling with acrylates, which is perhaps the most direct method for the synthesis of 3-fluoromethyl substituted pyrazol-4-acrylates of biological interest, remains challenging. Here, the first example of the straightforward olefination via Pd-catalyzed C4-H activation of both C3-CF₃ and C3-CF₂H substituted pyrazoles is reported. The reaction of various C3-CF₃ substituted pyrazoles with acrylates proceeds smoothly in the presence of Pd(OAc)₂ and Ag₂CO₃, whereas olefination of C3-CF₂H substituted pyrazoles requires the addition of benzoquinone. A further computational study reveals that reactivity of the pyrazolyl substrates employed are strongly impacted by the substituents of different nature on their C1 or C5 position, which is in good agreement with the experimental data.

Full text of DOI:10.1016/j.tet.2013.06.058

Tetrahedron 69 (2013) 6993e7000
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A new and direct route to 3-fluoromethyl substituted pyrazol-4-
acrylates via Pd-catalyzed CeH activation
,
a
a
a
Xiaoguang Wang a, Xiang Fang a , Hongyuan Xiao , Dongming Gong , Xueyan Yang ,
*
,
Fanhong Wu b
*
a Laboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science
and Technology, 130 Meilong Road, Shanghai 200237, China
b School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 200235, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2013
Received in revised form 8 June 2013
Accepted 17 June 2013
Available online 24 June 2013
Direct C4eH activation of 3-fluoromethyl pyrazoles followed by an oxidative coupling with acrylates,
which is perhaps the most direct method for the synthesis of 3-fluoromethyl substituted pyrazol-4-
acrylates of biological interest, remains challenging. Here, the first example of the straightforward ole-
fination via Pd-catalyzed C4eH activation of both C3eCF3 and C3eCF2H substituted pyrazoles is reported.
The reaction of various C3eCF3 substituted pyrazoles with acrylates proceeds smoothly in the presence
of Pd(OAc)2 and Ag2CO3, whereas olefination of C3eCF2H substituted pyrazoles requires the addition of
benzoquinone. A further computational study reveals that reactivity of the pyrazolyl substrates em-
ployed are strongly impacted by the substituents of different nature on their C1 or C5 position, which is
in good agreement with the experimental data.
Keywords:
3-Fluoromethyl pyrazoles
Pd-catalyzed C4eH activation
Benzoquinone
Concerted metalationedeprotonation
(CMD)
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
aldehydes as intermediates,3 which have drawbacks in terms of
atomic economy. Recently, the direct arylation and alkenylation of
1,3,5-Trisubstituted pyrazoles that contain CF3 and CF2H func-
tionalities are the core structure of many agrochemical and phar-
maceutical products,1 such as the non-steroidal anti-inflammatory
drug Celecoxib,1 SC-560,1b,c which is a COX-1 inhibitor and shows
anti-tumor activity, and Deracoxib,2 a marketed agent for the
treatment of inflammation (Fig. 1).
pyrazoles have been reported independently by Doucet,4 Sames,3d
and Chappell.5 Although direct olefinations could be carried out
based on electron-rich arenes and heterocycles,6,7 reaction of
electron-deficient arenes with olefins are still challenging.8 This is
mainly due to the difficulty for electron-deficient arenes to undergo
an electrophilic attack of a Pd (II) complex to the reactant and their
poor coordination with Pd catalysts.8a,8d,8f Previous work in regard
to olefination of electron-deficient arenes mainly relies on the ac-
tivation of the meta-position8a of arenes substituted with strong
electron-withdrawing groups with only an ortho-directed9 alke-
nylation as an exception.
O
O
S
O O
Cl
S
H2N
H2N
N
N
N
N
N
N
CF3
CF3
CF2H
F
Herein, we report the first example of Pd(OAc)2 catalyzed direct
ortho-olefination of electron-deficient CF3 and CF2H substituted
pyrazoles with a range of substrates in moderate to high yields and
high regioselectivities. Moreover, a computational study was per-
formed to investigate the mechanism of action.
MeO
Me
MeO
Celecoxib
SC-560
Deracoxib
Fig. 1. Bioactive 1,3,5-trisubstituted pyrazoles.
While modification of the C4-position of 1,3,5-trisubstituted
pyrazoles may lead to a further diversification of this compound
library of biological interest, the conventional C4-functionalization
is implemented by generating pyrazol metals, halides, and
2. Results and discussion
2.1. Olefination of CF3 substituted pyrazoles
Initially, a highly electron-deficient pyrazole 1a and n-butyl
acrylate 2a were chosen as model substrates (Table 1). With
* Corrresponding authors. E-mail address: fangxiang@ecust.edu.cn (X. Fang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.058

6994
X. Wang et al. / Tetrahedron 69 (2013) 6993e7000
Table 1
Table 2
Optimization of reaction conditions for the olefination of 3-trifluoro-pyrazole 1a
Reaction of 1,3,5-trisubstituted pyrazoles (CF3) with acrylatesa
CF3
CF3
CF3
CF3
Pd(OAc)2 (10 mol%)
Ag2CO3 (2 equiv)
DMF, 120oC, 24h
n
N
N
N
N
CO2Bu
R3
Pd source
oxidants
N
N
O2N
N
N
O2N
R3
n
CO2Bu
R1
solvent
120oC
R1
R2
R2
F
F
3
2
1
1a
2a
3a
Solvent
Entry
R1
R2
R3
Product
Yield (%)b
Entry
Pd source
(10%)
Ratio
Oxidant
(2 equiv)
Yield (%)a
1
2
3
4
5
6
7
8
4-NO2eC6H4
Ph
CH3
4-OMe-C6H4
4-NO2-C6H4
Ph
CH3
4-OMe-C6H4
4-NO2-C6H4
Ph
CH3
4-OMe-C6H4
Ph
Ph
Ph
4-FeC6H4
4-FeC6H4
4-FeC6H4
4-FeC6H4
Ph
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2tBu
CO2Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
81
78
77
76
78
88
75
77
82
56
81
77
54
80
38
(1a:2a)
1
2
3
4
5
6
PdCl2
1:2
1:2
1:2
1:2
1:2
1:2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
Ag2CO3
Ag2CO3
DMF
DMF
DMF
DMF
DMF
DMFþ
22
9
40
33
52
43
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ph
Ph
Ph
DMSO (5%)
DMSO
DMA
9
4-OMeeC6H4
4-OMeeC6H4
4-OMeeC6H4
4-OMeeC6H4
4-FeC6H4
4-FeC6H4
4-FeC6H4
7
8
9
10
11
12
13
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1:2
1:2
1:4
1:1
2:1
3:1
4:1
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
20
35
50
50
69
81
83
10
11
12
13
14
15
3j
3k
3l
3m
3n
3o
DMF
DMF
DMF
DMF
CO2nBu
CO2tBu
CO2Et
CN
DMF
(E/Z¼1:0.78)c
a
d
Isolated yield.
16
Ph
4-FeC6H4
Ph
a
Unless otherwise noted, the reactions were carried out with pyrazoles
1
10 mol % Pd source as a catalyst and Cu(OAc)2 as an oxidant in N,N-
dimethylformamide (DMF), the reaction was proceeded for 24 h at
120 ꢀC. The desired product 3a was obtained in yields of 22%, 9%,
and 40% while PdCl2, PdCl2(PPh3)2, and Pd(OAc)2 were used as the
catalyst, respectively. Then we noticed that Ag2CO3 (entry 5) was
a more efficient oxidant than Cu(OAc)2 (entry 3) and AgOAc (entry
4). A screen of solvent showed that the reaction efficiency was
decreased in DMFþDMSO (5%), DMSO and DMA (entries 6e8).
Moreover, the ratio of 1a:2a was critical for the reaction efficiency,
and the good yield (81%) was obtained while 1a:2a is 3:1 (entry12).
The ratio increased to 4:1 did not improve the yield (entry 13).
Therefore, the reaction carried out with 1a (3 equiv), 2a (1 equiv)
and Ag2CO3 (2 equiv), which functions as both a base and oxidant in
the presence of Pd(OAc)2 (10 mol %) at 120 ꢀC in DMF (entry 12).
(0.42 mmol), acrylates 2 (0.14 mmol), Pd(OAc)2 (10 mol %), Ag2CO3 (2.0 equiv) in
DMF (1 mL) at 120 ꢀC for 24 h.
b
Isolated yield.
c
Determined by 1H NMR analysis of the crude product.
d
The reaction was complicated.
Table 3
Optimization of reaction conditions for the olefination of 3-difluoro-pyrazole 4b
CF2H
CF2H
n
N
N
N
N
CO2Bu
Pd(OAc)2 (10 mol%)
oxidants
n
CO2Bu
solvent
120oC
F
F
2a
4b
Entry
5b
With the optimized conditions in hand,
a variety of 3-
Oxidant (equiv)
Additive (equiv)
Yield (%)a
trifluoromethyl substituted pyrazol-4-acrylates 3 were synthe-
sized to explore the substrates scope and representative results are
listed inTable 2. The alkenylation of pyrazoles 1 proceeded well with
nearly all electron-deficient olefins bearing esters, cyanogen groups,
and moderate to excellent yields were obtained in high regiose-
lectivities (entries 1e14). However, in the cases of 3j (56%, entry 10)
and 3m (54%, entry 13), the yields are less satisfactory probably
because of the presence of their bulky tertiary butyl group.
Acrylonitrile-substituted olefin was also tolerated, but an isomeric
mixture (E/Z¼1:0.78) of 3o with a low yield of 38% was provided
(entry 15). Regrettably, the reaction of 5-(4-fluorophenyl)-1-
phenyl-3-(trifluoromethyl)-1H-pyrazole with styrene (entry 16)
was unsuccessful and no pure product was obtained.
1
2
3
4
5
6
7
8
9
10
Ag2CO3 (2)
AgOAc (2.5)
Ag2CO3 (2)
Ag2CO3 (2)
AgOAc (2.5)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
d
d
10%
36%
Trace
Trace
25%
40%
62%
78%
65%
Trace
d
K2CO3 (0.5)
COD (0.5)
BQ (0.5)
BQ (0.5)
BQ (1)
BQ (1.5)
BQ (2)
BQ (2)
Bold signifies the optimal condition.
a
Isolated yield.
improve the reactivity, we sought to adopt ligand-induced CeH ac-
tivation with Pd (II). According to Hull’s10 and Boele’s11 reports,
benzoquinone (BQ) due to its oxidability, facile coordinative ability
and small steric effect, was applied. However, addition of BQ alone
even in 2 equiv did not affect the reaction (entry 10); therefore we
attempted to mix BQ (0.5 equiv) with AgOAc or Ag2CO3 to promote
the reaction. Mixture of Ag2CO3 with BQ appeared to give more ef-
fectively the desired product 5b (entry 6), and after optimization, we
found the optimal condition to be the addition of 1.5 equiv of BQ to
a reaction system including Pd(OAc)2 (10 mol %), Ag2CO3 (2 equiv),
and 4b and 2a in a ratio of 3:1 in DMF (entry 8).
2.2. Olefination of CF2H substituted pyrazoles
Under the optimal conditions obtained for CF3 substituted pyr-
azoles, CF2H substituted pyrazole 4b was also employed for the Pd-
catalyzed oxidative olefination (Table 3). However, the correspond-
ing product 5b could not be afforded in good yield (10%, entry 1).
Considering the different inductive effect between CF3 and CF2H
group, the pka of the reaction system might influence the deproto-
nation of arenes. However, addition of K2CO3 (0.5 equiv) did not in-
crease theyield, but led tothe generation of onlya trace amount of 5b
(entry 3). Since employment of sole oxidant could not successfully
Next, we explored substrate scope of the CF2H substituted pyr-
azoles. Series of 3-difluoromethyl substituted pyrazol-4-acrylates 5

X. Wang et al. / Tetrahedron 69 (2013) 6993e7000
6995
were examined, shown in Table 4. Despite the different R1 (4-
Table 5
Reaction of 1,3,5-trisubstituted pyrazoles (CF2H) with acrylatesa (No BQ)
NO2eC6H4, Ph, CH3, and 4-OMeeC6H4) and R2 (4-FeC6H4, Ph, 4-
OMeeC6H4 and 4-NO2eC6H4) substituents on 3-CF2H substituted
pyrazoles 4 and the different acrylates 2 employed, the yields of the
majority of the reactions are moderate (40e60%). Although in some
cases the yields of the reactions could reach up to 70e80% (entries
2, 3, 8, and 14), the reactivity of CF2H-substituted pyrazoles is
weaker than that of CF3-substituted pyrazoles. Acrylonitrile could
proceed with 3-(difluoromethyl)-5-(4-fluorophenyl)-1-phenyl-1H-
pyrazole, but a ratio of isomers (E/Z¼0.87:1) was obtained in a low
yield of 35% (entry 15).
CF2H
CF2H
Pd(OAc)2 (10 mol%)
Ag2CO3 (2 equiv)
DMF, 120oC, 24h
n
N
N
CO2Bu
N
N
n
CO2Bu
R1
R1
R2
R2
2a
5
4
Entry
R1
R2
Product (5)
Yieldb (%)
1
2
3
4
5
6
7
8
4-NO2eC6H4
Ph
4-OMeeC6H4
CH3
Ph
Ph
Ph
Ph
5e
5f
39
13
Trace
Trace
Trace
30
5g
5p
5b
5h
5k
5i
Table 4
Ph
4-FeC6H4
4-OMeeC6H4
4-NO2eC6H4
4-NO2eC6H4
Reaction of 1,3,5-trisubstituted pyrazoles (CF2H) with acrylatesa
4-NO2eC6H4
4-OMeeC6H4
Ph
35
56
CF2H
CF2H
Pd(OAc)2 (10 mol%)
Ag2CO3 (2 equiv)
N
N
a
N
N
R3
Unless otherwise noted, the reaction conditions were as follows: pyrazoles 4
(0.42 mmol), n-butyl acrylate 2a (0.14 mmol), Pd(OAc)2 (10 mol %), Ag2CO3
(2.0 equiv), DMF (1 mL), 120 ꢀC 24 h.
R3
R1
BQ (1.5 equiv)
R1
DMF, 120oC, 24h
b
R2
R2
Isolated yield.
5
2
4
without BQ (Table 5, entries 1e4). Obviously, CF3-substituted pyr-
azoles are superiorly more reactive than the CF2H-substituted
counterparts regardless of the substituents on the pyrazole ring. In
addition, the presence of an electron-withdrawing group, 4-
NO2eC6H4, may enhance the reactivity to give the olefinated
product 5e in a relatively better yield (entry 1). However, products
can be hardly obtained for the reactions in entry 3 and entry 4. The
trend of reactivity is mainly oriented by the electron-withdrawing
ability of the substituent (CH3<4-OMeeC6H4<Ph<4-NO2eC6H4).
Furthermore, when R1 is remained unchanged, a better yield can be
obtained (56%, entry 8) while an electron-withdrawing group (4-
NO2eC6H4) is present (vs 13%, entry 2). In contrast, while an
electron-donating group (4-OMeeC6H4) was introduced into the
C5 position of CF2H substituted pyrazole with unchanged R2, the
yield (35%, entry 7) was decreased (vs 56%, entry 8).
Entry
R1
R2
R3
Product
(5)
Yield (%)b
1
2
3
4
5
6
7
8
4-NO2eC6H4
4-FeC6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
Ph
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2nBu
CO2But
CO2Et
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
55
78
73
52
61
29
35
80
48
51
43
43
46
73
35
Ph
CH3
4-OMeeC6H4
4-NO2eC6H4
Ph
Ph
Ph
4-OMeeC6H4
4-NO2eC6H4
4-OMeeC6H4
4-NO2eC6H4
4-NO2eC6H4
4-NO2eC6H4
4-FeC6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
9
Ph
CH3
10
11
12
13
14
15
4-OMeeC6H4
Ph
Ph
CH3
Ph
CO2Et
CN
Since generally the coordination ability (Eint(TS)) of CF3 is weaker
than that of CF2H, the different reactivity between the two differ-
ently substituted pyrazoles could mainly be ascribed to the diverse
distortion energy (Edist(TS)) of the pyrazolyl core under the partici-
pation of Pd(OAc)2.
(E/Z¼0.87:1)c
a
Unless otherwise noted, the reactions were carried out with pyrazoles
(0.42 mmol), acrylates 2 (0.14 mmol), Pd(OAc)2 (10 mol %), Ag2CO3 (2.0 equiv), BQ
4
(1.5 equiv) in DMF (1 mL) at 120 ꢀC for 24 h.
b
Isolated yield.
Determined by 1H NMR analysis of the crude product.
The mechanism of the olefination of CF3-substituted pyrazoles
1Ae1Q and CF2H-substituted pyrazoles 4Ae4Q is further evaluated
c
by density functional theory (DFT) with the B3LYP exchange-
2.3. Mechanism of pyrazole (CF3 and CF2H) palladation
16
correlation functional.
In each case, a relevant transition state
(TS-1K and TS-4K) corresponding to the CMD pathway is located
(TSs involving two acetate ligands for CF3epyrazole 1K and
CF2Hepyrazole 4K are shown in Fig. 2). This pathwaycorresponds to
the lowest energyand predicts reactivity for all pyrazoles, regardless
of their electronic properties (The blue ball stands for Pd, red balls
for O, gray balls for C, white balls for H, and light blue balls for F).
Several reaction pathways have been proposed for the Pd-
catalyzed CeH activation including oxidative CeH insertion,12
electrophilic aromatic substitution (SEAr),13 Heck-like14 anionic
cross-coupling, and concerted metalationedeprotonation (CMD).15
Two of which are most prevalent: SEAr with electron-rich,
p-nu-
cleophilic heteroarenes and CMD with simple and electron-
deficient benzenes. Fagnou15b demonstrated that the CMD path-
way predicts not only the reactivity of simple and electron-
deficient benzenes but also that of a diverse range of arenes and
that have been proposed to react via SEAr. Recently Ding15e re-
ported that the rate- and regio-determining step of CeC coupling is
a common CMD CeH activation of arenes featuring a six-membered
ring transition state to form a Pd(II)-aryl intermediate. Possible
arene/arene or alkene/alkene homocoupling pathways have been
shown to be kinetically less competitive compared to the desired
cross-coupling pathway. Therefore we performed the CMD path-
way to form the Pd (II)-aryl intermediates, exploring why the ac-
tivity is so different between the CF3 substituted and CF2H
substituted pyrazoles.
Using the same conditions, which were used in Table 2 (Table 2,
entries 5e8), we first probed the reactions compiled in Table 5
Fig. 2. Transition states TS-1K and TS-4K.

6996
X. Wang et al. / Tetrahedron 69 (2013) 6993e7000
20
To explore the factors controlling the oxidative addition, we
CF3
analyze the energies to distort isolated reactants to the transition
state geometry (the distortion energy) and the energy of in-
teraction between these distorted reactants (the interaction en-
ergy). This, which is known as an activation strain model, has been
applied by Bickelhaupt 17 to Pd (0) oxidative additions, and is also
19
18
17
16
15
CF2H
related to the deformation/interaction method developed by
E
F
G
H
18
Morokuma
for other systems. Distortion energies on which we
4-A
focuse have also been discussed by Guthrie. 19 The decomposition
of the activation energy into distortion ( Edist) and interaction
energies ( Eint) is shown (Scheme 1).
16
15
14
13
12
CF3
D
CF2H
D
E
F
G
H
4-B
35
34
33
32
31
30
CF3
CF2H
E
F
G
H
4-C
CF3
:
R2 = Ph R1 = CH3 (1E), 4-OMe-C6H4 (1F)
Ph (1G), 4-NO2-C6H4 (1H)
CF3 or CF2H
3
4
5
R2
2
Scheme 1. Activation strain analysis.
N
CF2H : R2 = Ph R1 = CH3 (4E), 4-OMe-C6H4 (4F)
Ph (4G), 4-NO2-C6H4 (4H)
R1
N
1
The analysis is carried out with compound 4G (Fig. 3), and data
of other substrates similar to 4G are summarized in Table 6 and
Fig. 4. The Edist(TS) of the heterocycle portion for all the transition
structures of oxidative addition are decomposed into their out-of-
plane (Edist(out-of-plane)) and bending components (Edist(stretch)). The
stretching contribution of the distortion is obtained by freezing the
bond length of the CeH bond upon, which the oxidative addition
occur, and the geometry is reoptimized at B3LYP/6-31G(d). The out-
of-plane component is obtained by substracting bending compo-
nents from the heterocycle portion (Fig. 3). Edist(out-of-plane) of both
CF3 and CF2H pyrazoles is 3e4 kcal/mol greater than their
Fig. 4. Relationship between the differently substituted CF3e or CF2Hepyrazoles and
their corresponding A: Eout-of-plane; B: Estrech; C: Edist
via CMD-based transition
(ArH)
state.
Edist(stretch) in the same structure (Table 6), indicating its important
contribution to Edist(TS). This is in good agreement with the exper-
imental results above (Fig. 4A and Table 5). However, the predicted
Edist(stretch) is contrary to that obtained by experimental results
(Fig. 4B and Table 5). According to the Edist(out-of-plane) values we
conclude several points as follows: (1) On a similar structural basis,
Edist(out-of-plane) of CF3 pyrazoles is 0.5e0.7 kcal/mol lesser than that
of CF2H pyrazoles with a relatively small bending angle (Table 6).
Similar to the calculation results, CF3 pyrazoles are more reactive in
experimental observations (Tables 2 and 5) as expected. (2) For
pyrazoles 4Ee4H, when electron-donating groups (4-OMeeC6H4
and CH3) are replaced by an electron-withdrawing group (4-
NO2eC6H4), values for Edist(out-of-plane) and Edist(stretch) decrease.
Thus
the
computational
activity
(CH3<4-OMeeC6H4
Fig. 3. The out-of-plane component was obtained by substraction.
<Ph<4-NO2eC6H4) is in good agreement with experimental results
in Table 5. (3) The above two points are also applicable to other
substrates (all other values of Edist(TS), Edist(out-of-plane) and Edist(-
stretch) are listed in Supplementary data).
Table 6
Decomposition of the distortion energy of the pyrazole portion with changes in CeH
bond lengths (DdCeH) and changes in HeC4eC3eN2 dihedrals (Ddihedral) in terms of
the substitution variants
3. Conclusion
Pyrazoles
Edist (TS)
Ddihedral
Edist (out-of-plane)
D
d(CeH)
Edist (stretch)
1E
1F
1G
1H
4E
4F
4G
4H
34.074
33.923
33.171
30.774
34.298
34.061
33.315
30.926
54.262
52.845
52.069
49.525
55.295
53.524
52.584
49.544
18.2737
18.3234
18.0767
16.9292
19.0107
18.8601
18.6343
17.3121
0.238
0.236
0.232
0.220
0.234
0.233
0.228
0.218
15.8003
15.5996
15.0943
13.8448
15.2873
15.2009
14.6807
13.6139
In summary, a novel protocol for the synthesis 3-fluoromethyl
substituted pyrazol-4-acrylates was developed via a Pd (II)-cata-
lyzed CeH bond activation under mild conditions. The C3eCF3
substituted pyrazoles reacted with acrylates directly under the
action of Pd(OAc)2 and Ag2CO3, while BQ was found to be addi-
tionally needed for olefination of C3eCF2H substituted pyrazoles. A
computational study suggests the reactivity of both substrate

X. Wang et al. / Tetrahedron 69 (2013) 6993e7000
6997
classes is strongly affected by substitution effects, according well
with the experimental data. Further studies to enlarge the substrate
scope and to investigate the mechanism of action using calculations
are currently underway.
367.5 MHz)
100.6 MHz)
d
ꢁ61.3 (3F, s), ꢁ109.4 (1F, s). 13C NMR (CDCl3,
166.9, 163.7 (d, J¼201.5 Hz), 144.3, 139.3 (q,
d
J¼30.9 Hz), 131.93, 131.87, 131.81, 122.4 (d, J¼209.5 Hz), 116.9, 116.7,
114.1, 64.5, 37.7, 30.7, 19.1, 13.7. MS (EI): m/z (%): 370 (Mþ, 4), 297
(23), 269 (100), 244 (36). HRMS (EI) calcd for C18H18N2O2F4:
370.1304, found: 370.1305.
4. Experimental
4.1. General
4.2.4. (E)-Butyl 3-(5-(4-fluorophenyl)-1-(4-methoxyphenyl)-3-(tri-
fluoromethyl)-1H-pyrazol-4-yl)acrylate (3d). IR (KBr): 2961, 2872,
All chemicals used in this study were obtained from commercial
sources and used without further purification. The chromato-
graphic purification of the products was conducted by flash chro-
matography using Merck silica gel 60 (200e300 mesh). IR spectra
were measured on a Nicolet Magna IR-550 spectrometer using
potassium bromide pellet. High resolution mass spectra were car-
ried out on a Finnigan GCeMS-4021 spectrometer. 1H NMR
(400 MHz) and 13C NMR (100.6 MHz) spectra were recorded on
a Brucker AM-400 spectrometer with Me4Si as the internal stan-
dard. 19F NMR spectra were obtained on a Brucker AM-400
(367.5 MHz) spectrometer in CDCl3 with CFCl3 as the external
standard, with down-field shifts being designated as negative. All
1701, 1517, 1167, 834, 703 cmꢁ1 1H NMR (CDCl3, 400 MHz):
.
d
7.48 (1H, d, J¼16.0 Hz), 7.21e7.18 (2H, m), 7.13e7.08 (4H, m),
6.82 (2H, d, J¼9.2 Hz), 6.12 (1H, d, J¼16.4 Hz), 4.14 (2H, t,
J¼6.8 Hz), 3.79 (3H, s), 1.68e1.61 (2H, m), 1.43e1.34 (2H, m),
0.94 (3H, t, J¼7.2 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.4 (3F, s),
ꢁ109.9 (1F, s). 13C NMR (CDCl3, 100.6 MHz)
d 166.9, 163.4 (d,
J¼241.4 Hz), 159.6, 144.0, 140.1 (q, J¼30.9 Hz), 132.3, 132.2, 131.8,
131.3, 126.7, 120.7 (d, J¼218.6 Hz), 116.6, 116.4, 114.6, 114.3, 64.6,
55.5, 30.7, 19.2, 13.7. MS (EI): m/z (%): 462 (Mþ, 29), 389 (22),
361 (100). HRMS (EI) calcd for C24H22N2O3F4: 462.1567, found:
462.1570.
chemical shifts (
constants (J) are given in Hertz.
d
) are expressed in parts per million and coupling
4.2.5. (E)-Butyl 3-(1-(4-nitrophenyl)-5-phenyl-3-(trifluoromethyl)-
1H-pyrazol-4-yl)acrylate (3e). IR (KBr): 3087, 2961, 2874, 1700,
1347, 1195, 856, 706 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d 8.21 (2H, d,
4.2. General procedure for olefination of CF3 substituted
pyrazoles via CeH bond activation
J¼8.8 Hz), 7.53e7.41 (6H, m), 7.25e7.23 (2H, m), 6.16 (1H, d,
J¼16.4 Hz), 4.14 (2H, t, J¼6.8 Hz), 1.67e1.60 (2H, m), 1.43e1.34 (2H,
m), 0.93 (3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.8 (3F,
To a solution of Pd(OAc)2 (10 mol %) in DMF (1 mL) were added
Ag2CO3 (2.0 equiv), the pyrazoles (3.0 equiv), and the acrylates
(1.0 equiv). The mixture was then heated to 120 ꢀC (oil bath) and
stirred for 24 h. The resulting mixture was cooled to room tem-
perature, diluted with ethyl acetate, washed with 1 N HCl and brine,
dried over Na2SO4, filtered, and then concentrated. The resulting
residue was purified with silica gel chromatography to provide the
pure product.
s). 13C NMR (CDCl3, 100.6 MHz)
d 166.6, 146.9, 145.1, 143.2, 142.0 (q,
J¼29.4 Hz), 131.1, 130.6, 130.1, 129.7, 129.0, 127.4, 125.2, 124.5, 121.8
(q, J¼219.9 Hz), 116.1, 64.6, 30.6, 19.1, 13.7. HRMS (ESI) calcd for
C23H21N3O4F3 [MþH]þ: 460.1484, found: 460.1459.
4.2.6. (E)-Butyl 3-(1,5-diphenyl-3-(trifluoromethyl)-1H-pyrazol-4-
yl)acrylate (3f). IR (KBr): 2964, 2930, 2870, 1712, 1336, 1186, 761,
702 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
7.52 (1H, d, J¼16.4 Hz),
7.44e7.38 (3H, m), 7.33e7.29 (3H, m), 7.33e7.20 (4H, m), 6.15 (1H, d,
J¼16.4 Hz), 4.14 (2H, t, J¼6.6 Hz), 1.67e1.60 (2H, m), 1.43e1.34 (2H,
4.2.1. (E)-Butyl 3-(5-(4-fluorophenyl)-1-(4-nitrophenyl)-3-(trifluoro
methyl)-1H-pyrazol-4-yl) acrylate (3a). IR (KBr): 3087, 2961, 2874,
m), 0.94 (3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.4 (3F,
1707, 1346, 1185, 857, 693 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
8.21
s). 13C NMR (CDCl3, 100.6 MHz)
d 166.9, 145.0, 140.8, 138.5 (q,
(2H, d, J¼7.2 Hz), 7.46e7.42 (3H, m), 7.25e7.18 (4H, m), 6.16 (1H, d,
J¼32.3 Hz), 132.0, 130.2, 129.9, 129.0, 128.6, 127.9, 125.2, 120.7, 120.3
(q, J¼218.8 Hz),114.8, 64.5, 30.7,19.2,13.7. MS (EI): m/z (%): 414 (Mþ,
5), 341 (11), 313 (100), 293 (12). HRMS (EI) calcd for C23H21N2O2F3:
414.1555, found: 414.1561.
J¼13.2 Hz), 4.16 (2H, t, J¼5.4 Hz), 1.68e1.62 (2H, m), 1.42e1.37 (2H,
m), 0.95 (3H, t, J¼6.0 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.7 (3F,
s), ꢁ108.1 (1F, s). 13C NMR (CDCl3, 100.6 MHz)
d 166.5, 163.8 (d,
J¼194.9 Hz), 147.0, 144.0, 143.0, 141.9 (q, J¼30.9 Hz), 132.2, 132.1,
130.8, 125.2, 124.7, 124.6, 122.1 (q, J¼209.7 Hz), 117.2, 117.0, 64.7,
30.6, 19.1, 13.7. MS (EI): m/z (%): 477 (Mþ, 7), 404 (23), 376 (100).
HRMS (EI) calcd for C23H19N3O4F4: 477.1312, found: 477.1317.
4.2.7. (E)-Butyl 3-(1-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyr-
azol-4-yl)acrylate (3g). IR (KBr): 3071, 2961, 2874, 1703, 1120, 974,
707 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d 7.56e7.55 (3H, m), 7.43 (1H,
d, J¼16.4 Hz), 7.35e7.32 (2H, m), 5.97 (1H, d, J¼16.0 Hz), 4.11 (2H, t,
4.2.2. (E)-Butyl 3-(5-(4-fluorophenyl)-1-phenyl-3-(trifluoromethyl)-
1H-pyrazol-4-yl)acrylate (3b). IR (KBr): 3071, 2962, 2874, 1713,
J¼6.8 Hz), 3.77 (3H, s), 1.65e1.58 (2H, m), 1.41e1.32 (2H, m), 0.92
(3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.2 (3F, s). 13C
1332, 1183, 844, 693 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
7.49 (1H, d,
NMR (CDCl3, 100.6 MHz)
d
167.0, 145.4, 139.3 (q, J¼30.9 Hz), 132.1,
J¼12.8 Hz), 7.35e7.34 (3H, m), 7.22e7.19 (4H, m), 7.11 (2H, t,
J¼6.8 Hz), 6.15 (1H, d, J¼12.8 Hz), 4.15 (2H, t, J¼5.4 Hz), 1.67e1.64
(2H, m), 1.42e1.37 (2H, m), 0.95 (3H, t, J¼6.0 Hz). 19F NMR (CDCl3,
130.2, 129.8, 129.4, 127.9, 120.3 (q, J¼211.3 Hz), 119.8, 113.9, 64.4,
37.7, 30.7, 19.1, 13.7. MS (EI): m/z (%): 352 (Mþ, 4), 279 (28), 251
(100), 231 (29). HRMS (EI) calcd for C18H19N2O2F3: 352.1399, found:
352.1391.
367.5 MHz)
100.6 MHz)
d
ꢁ61.6 (3F, s), ꢁ109.7 (1F, s). 13C NMR (CDCl3,
d
166.8,163.4 (d, J¼201.2 Hz),143.9, 141.1 (q, J¼33.5 Hz),
138.3, 132.3, 132.2, 131.8, 129.2, 128.7, 125.4 (q, J¼213.5 Hz), 125.3,
121.0, 116.6, 116.4, 64.6, 30.7, 19.2, 13.7. HRMS (ESI) calcd for
C23H20N2O2F4 [MþH]þ: 433.1539, found: 433.1527.
4.2.8. (E)-Butyl 3-(1-(4-methoxyphenyl)-5-phenyl-3-(trifluoromet
hyl)-1H-pyrazol-4-yl)acrylate (3h). IR (KBr): 3066, 2958, 2871,
1704, 1517, 1166, 833, 704 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d 7.51
(1H, d, J¼16.4 Hz), 7.43e7.38 (3H, m), 7.21e7.19 (2H, m), 7.13 (2H, d,
J¼9.2 Hz), 6.80 (2H, d, J¼9.2 Hz), 6.13 (1H, d, J¼16.4 Hz), 4.13 (2H, t,
J¼6.8 Hz), 3.77 (3H, s), 1.69e1.60 (2H, m), 1.43e1.33 (2H, m), 0.93
4.2.3. (E)-Butyl 3-(5-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-
1H-pyrazol-4-yl)acrylate (3c). IR (KBr): 3074, 2962, 2875, 1713,
1177, 848, 627 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
7.41 (1H, d,
(3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.3 (3F, s). 13C
J¼12.8 Hz), 7.34 (2H, dd, J¼6.6 Hz, J¼4.2 Hz), 7.27 (2H, d, J¼13.6 Hz),
5.97 (1H, d, J¼13.2 Hz), 4.12 (2H, t, J¼5.2 Hz), 3.77 (3H, s), 1.65e1.60
(2H, m), 1.40e1.35 (2H, m), 0.93 (3H, t, J¼6.0 Hz). 19F NMR (CDCl3,
NMR (CDCl3, 100.6 MHz)
d
167.0, 159.5, 145.0, 140.3 (q, J¼37.8 Hz),
132.1, 131.5, 130.3, 129.8, 129.1, 128.0, 126.6, 120.5 (q, J¼220.7 Hz),
114.5,114.1, 64.5, 55.5, 30.7,19.2,13.7. MS (EI): m/z (%): 444 (Mþ, 24),

6998
X. Wang et al. / Tetrahedron 69 (2013) 6993e7000
371,17 343 (100). HRMS (EI) calcd for C24H23N2O3F3: 444.1663,
found: 444.1661.
J¼16 Hz), 7.34e7.32 (3H, m), 7.22e7.19 (4H, m), 7.11 (2H, t, J¼8 Hz),
6.15 (1H, d, J¼16 Hz), 4.20 (2H, q, J¼7.2 Hz), 1.29 (3H, t, J¼7.2 Hz). 19
F
NMR(CDCl3, 367.5MHz)
d
ꢁ61.5 (3F, s), ꢁ109.7 (1F, s). 13C NMR(CDCl3,
4.2.9. (E)-Butyl
3-(5-(4-methoxyphenyl)-1-(4-nitrophenyl)-3-(tri-
100.6 MHz)
d
166.8, 163.4 (d, J¼241.4 Hz), 143.9, 140.6 (q, J¼32.1 Hz),
fluoromethyl)-1H-pyrazol-4-yl) acrylate (3i). IR (KBr): 3089, 2962,
138.3, 132.3, 132.2, 131.7, 129.2, 128.7, 126.3, 121.9 (q, J¼212.9 Hz),
116.6,116.4,114.9, 60.6,14.2. MS (EI): m/z (%): 404 (Mþ,10), 359,16 331
(100). HRMS (EI) calcd for C23H20N2O2F4: 404.1148, found: 404.1149.
2874, 1714, 1341, 1183, 858, 692 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
8.19 (2H, d, J¼8.0 Hz), 7.50e7.43 (3H, m), 7.15 (2H, d, J¼7.6 Hz),
6.98 (2H, d, J¼7.6 Hz), 6.18 (1H, d, J¼16.4 Hz), 4.15 (2H, t, J¼6.6 Hz),
3.87 (3H, s), 1.68e1.61 (2H, m), 1.44e1.35 (2H, m), 0.94 (3H, t,
4.2.15. 3-(5-(4-Fluorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyr-
azol-4-yl)acrylonitrile (3o) (cis:transz0.78:1). IR (KBr): 3071, 2220,
J¼7.2 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.8 (3F, s). 13C NMR
(CDCl3, 100.6 MHz)
d
166.7, 161.2, 146.8, 145.2, 143.4 (q, J¼28.9 Hz),
1630, 1489, 1236, 1059, 1022, 845, 694 cmꢁ1 1H NMR (CDCl3,
.
131.5, 125.2, 124.5, 122.2, 121.4 (q, J¼220.1 Hz), 120.0, 119.1, 115.8,
115.1, 114.5, 64.6, 55.4, 30.7, 19.1, 13.7. MS (EI): m/z (%): 489 (Mþ, 15),
459 (57), 388 (73), 358 (100), 342.12 HRMS (EI) calcd for
C24H22N3O5F3: 489.1512, found: 489.1517.
400 MHz): d cis 7.38e7.36 (1.4H, m), 7.24e7.14 (2.6H, m), 7.06
(0.44H, d, J¼8.8 Hz), 5.52 (0.42H, d, J¼9.2 Hz); trans 7.38e7.36
(1.9H, m), 7.24e7.14 (3.5H, m), 7.08 (0.62H, d, J¼8.8 Hz), 5.58 (0.54H,
d, J¼13.2 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
cis ꢁ109.9 (0.44F, s),
ꢁ61.2 (0.99F, s); trans ꢁ108.5 (0.57F, s), ꢁ61.4 (1.57F, s). 13C NMR
4.2.10. (E)-tert-Butyl
fluoromethyl)-1H-pyrazol-4-yl) acrylate (3j). IR (KBr): 3086, 2973,
2842,1712,1294,1141, 870,693cmꢁ1.1HNMR(CDCl3, 400MHz):
7.43
3-(5-(4-methoxyphenyl)-1-phenyl-3-(tri-
(CDCl3, 100.6 MHz)
d
cis 163.3 (d, J¼201.1 Hz), 142.76, 140.58 (q,
J¼30.2 Hz), 138.35, 137.81, 132.20, 132.02, 126.61, 119.97 (q,
J¼222.1 Hz), 116.78, 116.54, 115.80, 114.98, 113.46, 100.0; trans 163.6
(d, J¼201.1 Hz), 143.96, 141.02 (q, J¼31.1 Hz), 137.97, 137.92, 132.14,
131.95, 125.50, 123.33 (q, J¼232.9 Hz), 116.96, 116.37, 115.98, 115.27,
114.25, 98.9. MS (EI): m/z (%): 357 (Mþ, 100), 356 (60). HRMS (EI)
calcd for C19H11F4N3: 357.0889, found: 357.0886.
d
(1H, d, J¼16.4 Hz), 7.32e7.31 (3H, m), 7.24e7.21 (2H, m), 7.12 (2H, d,
J¼8.8 Hz), 6.91 (2H, d, J¼8.8 Hz), 6.12 (1H, d, J¼16.4 Hz), 3.83 (3H, s),
1.48 (9H, s). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.6 (3F, s). 13C NMR
(CDCl3, 100.6 MHz)
d
166.3, 160.6, 145.0, 140.3, 138.7 (q, J¼30.5 Hz),
131.6,131.1,129.0,128.4,125.2,122.5,122.1,120.4 (q, J¼217.3 Hz),120.0,
114.6, 80.5, 55.3, 28.2. MS (EI): m/z(%):444(Mþ, 9), 388 (27), 343(100),
323.14 HRMS (EI) calcd for C24H23N2O3F3: 444.1661, found: 444.1660.
4.3. General procedure for olefination of CF2H substituted
pyrazoles via CeH bond activation
4.2.11. (E)-Ethyl 3-(5-(4-methoxyphenyl)-1-methyl-3-(trifluoromet
hyl)-1H-pyrazol-4-yl)acrylate (3k). IR (KBr): 2953, 2899,1700,1332,
To a solution of Pd(OAc)2 (10 mol %) in DMF (1 mL) were added
Ag2CO3 (2.0 equiv), BQ (1.5 equiv), the pyrazoles (3.0 equiv), and the
acrylates (1.0 equiv). The mixture was then heated to 120 ꢀC (oil
bath) and stirred for 24 h. The resulting mixture was cooled to room
temperature, diluted with ethyl acetate, washed with 1 N HCl and
brine, dried over Na2SO4, filtered, and then concentrated. The
resulting residue was purified with silica gel chromatography to
provide the pure product.
1197, 835, 719 cmꢁ1 1H NMR (CDCl3, 400 MHz):
. d 7.43 (1H, d,
J¼16.4 Hz), 7.25 (2H, d, J¼8.8 Hz), 7.06 (2H, d, J¼8.8 Hz), 6.00 (1H, d,
J¼16.4 Hz), 4.17 (2H, q, J¼7.2 Hz), 3.90 (3H, s), 3.76 (3H, s), 1.27 (3H,
t, J¼7.2 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.2 (3F, s). 13C NMR
(CDCl3, 100.6 MHz)
d
167.0, 161.0, 145.4, 139.3 (q, J¼29.5 Hz), 132.3,
131.2, 121.4 (q, J¼215.5 Hz), 119.8, 119.4, 114.9, 113.8, 60.4, 55.4, 37.6,
14.2. MS (EI): m/z (%): 354 (Mþ, 19), 309,19 281 (100), 261 (29).
HRMS (EI) calcd for C17H17N2O3F3: 354.1191, found: 354.1192.
4.3.1. (E)-Butyl 3-(3-(difluoromethyl)-5-(4-fluorophenyl)-1-(4-
nitrophenyl)-1H-pyrazol-4-yl) acrylate (5a). IR (KBr): 3086, 2960,
1716, 1527, 1453, 1345, 1186, 1038, 857, 691 cmꢁ1. 1H NMR (CDCl3,
4.2.12. (E)-Butyl 3-(1,5-bis(4-methoxyphenyl)-3-(trifluoromethyl)-
1H-pyrazol-4-yl)acrylate (3l). IR (KBr): 2961, 2874, 2842, 1713, 1517,
400 MHz):
d
8.21e8.19 (2H, m), 7.44 (1H, d, J¼16.5 Hz), 7.41e7.39
1255, 837, 705 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
7.51 (1H, d,
(2H, m), 7.24e7.16 (4H, m), 6.87 (1H, t, J¼53.6 Hz), 6.38 (1H, d,
J¼16.4 Hz), 7.15e7.10 (4H, m), 6.91 (2H, d, J¼8.4 Hz), 6.81 (2H, d,
J¼9.2 Hz), 6.15 (1H, d, J¼16.4 Hz), 4.14 (2H, t, J¼6.6 Hz), 3.83 (3H, s),
3.79 (3H, s), 1.68e1.61 (2H, m), 1.42e1.36 (2H, m), 0.94 (3H, t,
J¼16.3 Hz), 4.16 (2H, t, J¼6.7 Hz), 1.69e1.62 (2H, m), 1.44e1.35 (2H,
m), 0.94 (3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ108.56 (1F,
s), ꢁ113.20 (2F, s). 13C NMR (CDCl3, 100.6 MHz)
d 166.94, 163.70 (d,
J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ61.4 (3F, s). 13C NMR
J¼252.5 Hz), 146.70, 145.82 (t, J¼29.7 Hz), 144.19, 143.26, 132.20,
131.51, 124.88, 124.65, 123.63, 121.70, 117.00 (d, J¼22.1 Hz), 116.65,
111.74 (t, J¼235.2 Hz), 64.60, 30.68, 19.17, 13.74. MS (EI): m/z (%):
459,9 386 (26), 358 (100), 338 (23). HRMS (EI) calcd for
C23H20F3N3O4: 459.1406, found: 459.1409.
(CDCl3, 100.6 MHz)
d
167.1, 160.5, 159.4, 145.1, 140.2 (q, J¼36.8 Hz),
132.4, 131.7, 131.6, 126.6, 122.8 (q, J¼219.6 Hz), 120.1, 119.9, 114.6,
114.2, 114.1, 64.5, 55.5, 55.3, 30.7, 19.2, 13.7. MS (EI): m/z (%): 474
(Mþ, 28), 401,11 373 (100). HRMS (EI) calcd for C25H25N2O4F3:
474.1766, found: 474.1770.
4.3.2. (E)-Butyl 3-(3-(difluoromethyl)-5-(4-fluorophenyl)-1-phenyl-
1H-pyrazol-4-yl)acrylate (5b). IR (KBr): 3074, 2961, 2873, 1708,
1639, 1332, 1191, 1034, 765, 523 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
4.2.13. (E)-tert-Butyl 3-(5-(4-fluorophenyl)-1-phenyl-3-(trifluoromet
hyl)-1H-pyrazol-4-yl)acrylate (3m). IR (KBr): 3072, 2976, 2936,
1709, 1313, 1123, 872, 693 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
7.41
d
7.49 (1H, d, J¼16.4 Hz), 7.34e7.33 (3H, m), 7.21e7.18 (4H, m), 7.10
(1H, d, J¼12.8 Hz), 7.35e7.33 (3H, m), 7.22e7.19 (4H, m), 7.11 (2H, t,
(2H, t, J¼8.6 Hz), 6.87 (1H, t, J¼53.8 Hz), 6.37 (1H, d, J¼16.0 Hz), 4.15
(2H, t, J¼6.6 Hz), 1.69e1.62 (2H, m), 1.44e1.35 (2H, m), 0.94 (3H, t,
J¼6.8 Hz), 6.10 (1H, d, J¼13.2 Hz), 1.49 (9H, s). 19F NMR (CDCl3,
367.5 MHz)
100.6 MHz)
d
ꢁ61.7 (3F, s), ꢁ109.8 (1F, s). 13C NMR (CDCl3,
J¼7.2 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ110.09 (1F, s), ꢁ112.62
d
166.1, 163.4 (d, J¼201.2 Hz), 143.9, 140.5 (q, J¼31.9 Hz),
(2F, s). 13C NMR (CDCl3, 100.6 MHz)
d 167.26, 163.34 (d,
138.4, 132.3, 132.2, 130.7, 129.2, 128.7, 126.3, 122.6 (q, J¼222.4 Hz),
116.6,116.4,116.0, 80.7, 28.1. MS (EI): m/z (%): 432 (Mþ, 4), 376,11 331
(100). HRMS (EI) calcd for C23H20N2O2F4: 432.1461, found:
432.1474.
J¼250.50 Hz), 144.63 (t, J¼29.6 Hz), 144.15, 138.50, 132.32, 129.17,
128.48, 125.06, 124.18, 120.60, 116.39, 115.23, 112.15 (t, J¼234.4 Hz),
64.46, 30.72,19.19,13.76. MS (EI): m/z (%): 414,12 341 (24), 313 (100),
293 (30). HRMS (EI) calcd for C23H21F3N2O2: 414.1555, found:
414.1557.
4.2.14. (E)-Ethyl
yl)-1H-pyrazol-4-yl)acrylate (3n). IR (KBr): 3070, 2983, 2904, 1696,
1329, 1127, 834, 694 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
7.49 (1H, d,
3-(5-(4-fluorophenyl)-1-phenyl-3-(trifluorometh
4.3.3. (E)-Butyl 3-(3-(difluoromethyl)-5-(4-fluorophenyl)-1-methyl-
1H-pyrazol-4-yl)acrylate (5c). IR (KBr): 3069, 2960, 1699, 1639,
d

X. Wang et al. / Tetrahedron 69 (2013) 6993e7000
6999
1471, 1323, 1201, 1032, 809, 608 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
400 MHz):
d
8.19e8.17 (2H, m), 7.48 (1H, d, J¼16.2 Hz), 7.43e7.41
d
7.40 (1H, d, J¼16.8 Hz), 7.35e7.31 (2H, m), 7.25e7.22 (2H, m), 6.77
(2H, m), 7.15 (2H, d, J¼8.6 Hz), 6.99e6.97 (2H, m), 6.86 (1H, t,
J¼53.8 Hz), 6.38 (1H, d, J¼16.3 Hz), 4.15 (2H, t, J¼6.7 Hz), 3.87 (3H,
s), 1.69e1.62 (2H, m), 1.44e1.35 (2H, m), 0.94 (3H, t, J¼7.4 Hz). 19F
(1H, t, J¼54.0 Hz), 6.18 (1H, d, J¼16.0 Hz), 4.12 (2H, t, J¼6.6 Hz), 3.74
(3H, s), 1.66e1.59 (2H, m), 1.42e1.33 (2H, m), 0.93 (3H, t, J¼7.4 Hz).
19F NMR (CDCl3, 367.5 MHz)
d
ꢁ109.88 (1F, s), ꢁ112.39 (2F, s). 13
C
NMR (CDCl3, 367.5 MHz)
100.6 MHz)
d
ꢁ113.17 (2F, s). 13C NMR (CDCl3,
NMR (CDCl3, 100.6 MHz)
d
167.31, 163.59 (d, J¼251.5 Hz), 144.66,
d
167.13, 161.03, 146.49, 146.01 (t, J¼28.2 Hz), 145.72,
143.30 (t, J¼29.0 Hz), 132.68, 131.97, 124.08, 119.49, 116.62 (d,
J¼22.0 Hz), 114.19, 111.93 (t, J¼234.2 Hz), 64.36, 37.47, 30.70, 19.16,
13.74. MS (EI): m/z (%): 352,10 279 (53), 251 (100), 231 (55). HRMS
(EI) calcd for C18H19F3N2O2: 352.1399, found: 352.1398.
145.41, 143.59, 132.11, 131.50, 124.80, 124.52, 120.99, 119.40, 116.23,
115.02, 114.49, 111.86 (t, J¼235.1 Hz), 64.49, 55.42, 30.70, 19.17,
13.75. MS (EI): m/z (%): 471 (22), 398,13 370 (100), 324.8 HRMS (EI)
calcd for C24H23F2N3O5: 471.1606, found: 471.1605.
4.3.4. (E)-Butyl 3-(3-(difluoromethyl)-5-(4-fluorophenyl)-1-(4-
methoxyphenyl)-1H-pyrazol-4-yl) acrylate (5d). IR (KBr): 3058,
2959,1712,1645,1517,1257,1193,1021, 840, 710 cmꢁ1.1H NMR (CDCl3,
4.3.9. (E)-Butyl 3-(3-(difluoromethyl)-5-(4-nitrophenyl)-1-phenyl-
1H-pyrazol-4-yl)acrylate (5i). IR (KBr): 3084, 2960, 1708, 1647,1516,
1349, 1195, 1038, 857, 763, 698 cmꢁ1 1H NMR (CDCl3, 400 MHz):
.
400 MHz):
d
7.49 (1H, d, J¼16.2 Hz), 7.20e7.17 (2H, m), 7.12e7.07 (4H,
d
8.27e8.25 (2H, m), 7.46 (1H, d, J¼16.2 Hz), 7.42e7.34 (m, 5H),
m), 6.85 (1H, t, J¼53.9 Hz), 6.83 (2H, d, J¼8.8 Hz), 6.35 (1H, d,
J¼16.2 Hz), 4.15 (2H, t, J¼6.8 Hz), 3.79 (3H, s), 1.68e1.61 (2H, m),
1.44e1.35 (2H, m), 0.94 (3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
7.20e7.18 (2H, m), 6.88 (1H, t, J¼53.7 Hz), 6.40 (1H, d, J¼16.3 Hz),
4.16 (2H, t, J¼6.7 Hz), 1.69e1.62 (2H, m), 1.44e1.35 (2H, m), 0.94
(3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ112.69 (2F, s). 13
C
d
ꢁ110.27 (1F, s), ꢁ112.50 (2F,s). 13C NMR (CDCl3,100.6 MHz)
d
167.30,
NMR (CDCl3, 100.6 MHz)
d
166.93, 148.27, 144.94 (t, J¼29.9 Hz),
163.23 (d, J¼250.5 Hz), 159.43, 144.31 (t, J¼29.6 Hz), 144.16, 132.55,
132.28, 131.54, 126.48, 124.25, 120.37, 116.32 (d, J¼21.9 Hz), 114.86,
114.26,112.19 (t, J¼234.4 Hz), 64.42, 55.50, 30.72,19.18,13.75. MS (EI):
m/z (%): 444 (31), 371,17 343 (100), 323 (21). HRMS (EI) calcd for
C24H23F3N2O3: 444.1661, found: 444.1658.
142.40, 138.09, 134.59, 131.46, 131.36, 129.46, 129.01, 125.15, 124.21,
121.92, 115.96, 111.91 (t, J¼234.8 Hz), 64.64, 30.69, 19.17, 13.75. MS
(EI): m/z (%): 441,12 368 (43), 340 (100), 320 (58), 294 (28). HRMS
(EI) calcd for C23H21F2N3O4: 441.1500, found: 444.1499.
4.3.10. (E)-Butyl 3-(3-(difluoromethyl)-1-methyl-5-(4-nitrophenyl)-
1H-pyrazol-4-yl)acrylate (5j). IR (KBr): 3087, 2960, 1704, 1526,
1384, 1270, 1180, 1026, 858, 734 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
4.3.5. (E)-Butyl 3-(3-(difluoromethyl)-1-(4-nitrophenyl)-5-phenyl-
1H-pyrazol-4-yl)acrylate (5e). IR (KBr): 3119, 2962, 1711, 1641, 1528,
1346, 1191, 1039, 857, 692 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
8.44e8.42 (2H, m), 7.58e7.56 (2H, m), 7.37 (1H, d, J¼16.2 Hz), 6.78
d
8.18e8.16 (2H, m), 7.52e7.45 (3H, m), 7.48 (1H, d, J¼16.4 Hz),
(1H, t, J¼53.9 Hz), 6.21 (1H, d, J¼16.2 Hz), 4.13 (2H, t, J¼6.7 Hz), 3.80
(3H, s), 1.66e1.59 (2H, m), 1.43e1.31 (2H, m), 0.92 (3H, t, J¼7.4 Hz).
7.42e7.38 (2H, m), 7.25e7.23 (2H, m), 6.88 (1H, t, J¼53.7 Hz), 6.38
(1H, d, J¼16.3 Hz), 4.15 (2H, t, J¼6.7 Hz),1.68e1.61 (2H, m),1.44e1.34
19F NMR (CDCl3, 367.5 MHz)
d
ꢁ112.50 (2F, s). 13C NMR (CDCl3,
(2H, m), 0.93 (3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ113.17
100.6 MHz)
d
166.99, 148.65, 143.61 (t, J¼29.3 Hz), 142.99, 134.50,
(2F, s). 13C NMR (CDCl3, 100.6 MHz)
d
167.02, 146.59, 145.78 (t,
131.77, 131.17, 124.50, 120.76, 114.83, 111.70 (t, J¼234.4 Hz), 64.55,
37.81, 30.66,19.14,13.73. MS (EI): m/z (%): 379,11 306 (100), 278 (65),
258 (88), 232 (29). HRMS (EI) calcd for C18H19F2N3O4: 379.1344,
found: 379.1350.
J¼29.8 Hz), 145.32, 143.44, 131.82, 130.41, 130.12, 129.55, 129.03,
127.63, 124.81, 124.53, 121.41, 116.49, 111.80 (t, J¼235.2 Hz), 64.51,
30.69, 19.16, 13.73. MS (EI): m/z (%): 441,5 368,17 340 (100), 320.17
HRMS (EI) calcd for C23H21F2N3O4: 441.1500, found: 441.1496.
4.3.11. (E)-Butyl 3-(3-(difluoromethyl)-1-(4-methoxyphenyl)-5-(4-
nitrophenyl)-1H-pyrazol-4-yl) acrylate (5k). IR (KBr): 3089, 2963,
1703, 1643, 1517, 1350, 1197, 1025, 835, 713 cmꢁ1. 1H NMR (CDCl3,
4.3.6. (E)-Butyl 3-(3-(difluoromethyl)-1,5-diphenyl-1H-pyrazol-4-yl)
acrylate (5f). IR (KBr): 3447, 2965, 1702, 1638, 1385, 1194, 1035, 843,
761, 694 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
7.53 (1H, d, J¼16.3 Hz),
400 MHz):
d
8.27e8.25 (2H, m), 7.46 (1H, d, J¼16.2 Hz), 7.41e7.39
7.42e7.37 (3H, m), 7.32e7.28 (3H, m), 7.22e7.19 (4H, m), 6.87 (1H, t,
J¼53.9 Hz), 6.37 (1H, d, J¼16.3 Hz), 4.14 (2H, t, J¼6.7 Hz), 1.68e1.61
(2H, m), 1.44e1.34 (2H, m), 0.93 (3H, t, J¼7.4 Hz). 19F NMR (CDCl3,
(2H, m), 7.11e7.09 (2H, m), 6.86e6.83 (2H, m), 6.86 (1H, t,
J¼54.0 Hz), 6.38 (1H, d, J¼16.3 Hz), 4.16 (2H, t, J¼6.7 Hz), 3.80 (3H,
s), 1.69e1.61 (2H, m), 1.44e1.35 (2H, m), 0.94 (3H, t, J¼7.4 Hz). 19F
367.5 MHz)
d
ꢁ112.58 (2F, s). 13C NMR (CDCl3, 100.6 MHz)
d
167.32,
NMR (CDCl3, 367.5 MHz)
100.6 MHz)
d
ꢁ112.58 (2F, s). 13C NMR (CDCl3,
145.23, 144.61 (t, J¼29.7 Hz), 138.70, 132.72, 130.28, 129.66, 129.03,
129.01, 128.29, 128.16, 125.03, 120.35, 115.14, 112.22 (t, J¼234.4 Hz),
64.36, 30.72,19.18,13.75. MS (EI): m/z (%): 396,8 323,14 295 (100), 275
(25). HRMS (EI) calcd for C23H22F2N2O2: 396.1649, found: 396.1656.
d
166.97, 159.81, 148.19, 144.61 (t, J¼29.5 Hz), 142.43,
134.69, 131.61, 131.37, 131.04, 130.69, 126.57, 124.16, 121.67, 115.55,
114.53, 111.94 (t, J¼234.8 Hz), 64.61, 55.55, 30.68, 19.17, 13.74. MS
(EI): m/z (%): 471 (89), 398 (39), 370 (100), 350 (46), 324 (29). HRMS
(EI) calcd for C24H23F2N3O5: 471.1606, found: 471.1593.
4.3.7. (E)-Butyl 3-(3-(difluoromethyl)-1-(4-methoxyphenyl)-5-
phenyl-1H-pyrazol-4-yl)acrylate (5g). IR (KBr): 3128, 2964, 1699,
1518, 1259, 1199, 1025, 841, 697 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
4.3.12. (E)-tert-Butyl 3-(3-(difluoromethyl)-5-(4-fluorophenyl)-1-
phenyl-1H-pyrazol-4-yl) acrylate (5l). IR (KBr): 3074, 2926, 1707,
d
7.52 (1H, d, J¼16.3 Hz), 7.42e7.37 (3H, m), 7.21e7.18 (2H, m),
1608, 1490, 1281, 1162, 1022, 766, 524 cmꢁ1 1H NMR (CDCl3,
.
7.13e7.10 (2H, m), 6.86(1H, t, J¼53.9Hz), 6.81e6.79 (2H, m), 6.35 (1H,
d, J¼16.2 Hz), 4.14 (2H, t, J¼6.6 Hz), 3.78 (3H, s), 1.67e1.60 (2H, m),
1.43e1.34 (2H, m), 0.93 (3H, t, J¼7.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
400 MHz):
d
7.41 (1H, d, J¼16.2 Hz), 7.34e7.31 (3H, m), 7.21e7.18
(4H, m), 7.12e7.07 (2H, m), 6.87 (1H, t, J¼53.8 Hz), 6.32 (1H, d,
J¼16.2 Hz), 1.49 (9H, s). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ110.26 (1F,
d
ꢁ112.48 (2F, s).13C NMR (CDCl3,100.6 MHz)
d
166.34,158.29,144.19,
s), ꢁ112.81 (2F, s). 13C NMR (CDCl3, 100.6 MHz)
d 166.56, 163.30 (d,
143.25 (t, J¼29.4 Hz), 131.82, 130.76, 129.27, 128.52, 127.92, 127.20,
125.39, 119.09, 113.75, 113.13, 111.22 (t, J¼234.4 Hz), 63.30, 54.45,
29.70, 18.15, 12.72. MS (EI): m/z (%): 426 (31), 353,17 325 (100), 305
(21). HRMS (EI) calcd for C24H24F2N2O3: 426.1755, found: 426.1754.
J¼251.5 Hz), 144.53 (t, J¼29.4 Hz), 144.07, 138.55, 132.28, 131.33,
129.13, 128.42, 125.06, 124.26, 122.33, 116.35 (d, J¼22.0 Hz), 115.35,
112.15 (t, J¼234.4 Hz), 80.51, 28.18. MS (EI): m/z (%): 414,9 358,16
341,17 313 (100), 293 (36). HRMS (EI) calcd for C23H21F3N2O2:
414.1555, found: 414.1557.
4.3.8. (E)-Butyl 3-(3-(difluoromethyl)-5-(4-methoxyphenyl)-1-(4-
nitrophenyl)-1H-pyrazol-4-yl) acrylate (5h). IR (KBr): 3115, 2959,
1715, 1612, 1525, 1348, 1257, 1031, 859, 692 cmꢁ1. 1H NMR (CDCl3,
4.3.13. (E)-Ethyl 3-(3-(difluoromethyl)-5-(4-fluorophenyl)-1-phenyl-
1H-pyrazol-4-yl)acrylate (5m). IR (KBr): 3078, 2954, 1703, 1639,

7000
X. Wang et al. / Tetrahedron 69 (2013) 6993e7000
1464, 1332, 1197, 1030, 767, 523 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
References and notes
d
7.50 (1H, d, J¼16.4 Hz), 7.35e7.31 (3H, m), 7.21e7.18 (4H, m), 7.10
1. (a) Clive, D. M.; Stoff, J. S. N. Engl. J. Med. 1984, 310, 563e572; (b) Elguero, J.;
Goya, P.; Jagerovic, N.; Silva, A. Syst. 2002, 6, 52e98; (c) Clapham, K. M.;
Batsanov, A. S.; Bryce, M. R.; Tarbit, B. Org. Biomol. Chem. 2009, 7, 2155e2161.
2. (a) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581e584; (b) Millis, D.
L.; Weigel, J. P.; Moyers, T.; Buonomo, F. C. Vet. Ther. 2002, 3, 453e464.
3. For functionalization of C4 on the pyrazole ring, see: (a) Jeon, S. L.; Choi, J. H.;
Kim, B. T.; Jeong, I. H. J. Fluorine Chem. 2007, 128, 1191e1197; (b) Sliskovic, D.;
Blankley, C.; Krause, B.; Newton, R.; Picard, J.; Roark, W.; Roth, B.; Sekerke, C.;
Shaw, M.; Stanfield, R. J. Med. Chem. 1992, 35, 2095e2103; (c) Sliskovic, D.; Roth,
B.; Wilson, M.; Hoefle, M.; Newton, R. J. Med. Chem. 1990, 33, 31e38; (d)
Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131, 3042e3048;
(e) Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2009, 2, 20e40; (f)
Dai, H. X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y. H.; Yu, J. Q. J. Am. Chem. Soc.
2011, 133, 7222e7223.
4. Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2, 20e40.
5. Chappell, B.; Dedman, N.; Wheeler, S. Tetrahedron Lett. 2011, 52, 3223e3225.
6. (a) Moritanl, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 8, 1119e1122; (b) Jia, C.; Piao,
D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992e1995.
7. For recent olefination of electron-rich arenes or heterocycles, see: (a) Ferreira,
E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578e9579; (b) Grimster, N. P.;
Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem. 2005, 117, 3185e3189;
(c) Miyasaka, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2010, 75,
5421e5424; (d) Cui, S.; Wojtas, L.; Antilla, J. C. Org. Lett. 2011, 13, 5040e5043;
(e) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128,
2528e2529.
(2H, t, J¼8.4 Hz), 6.87(1H, t, J¼53.6 Hz), 6.38 (1H, d, J¼16.3 Hz), 4.21
(2H, q, J¼7.1 Hz), 1.30 (3H, t, J¼7.1 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
d
ꢁ110.05 (1F, s), ꢁ112.58 (2F, s). 13C NMR (CDCl3, 100.6 MHz)
167.20,163.34 (d, J¼251.5 Hz),144.64 (t, J¼29.8 Hz),144.16,138.49,
132.42, 132.28, 129.17, 128.49, 125.07, 124.17, 120.59, 116.42 (d,
J¼22.0 Hz), 115.22, 112.17 (t, J¼234.5 Hz), 60.53, 14.31. MS (EI): m/z
(%): 386,12 341,19 313 (100), 293 (34). HRMS (EI) calcd for
C21F17H3N2O2: 386.1242, found: 352.1241.
4.3.14. (E)-Ethyl 3-(3-(difluoromethyl)-5-(4-fluorophenyl)-1-methyl-
1H-pyrazol-4-yl)acrylate (5n). IR (KBr): 3064, 2993, 1691, 1473,
1324, 1198, 1028, 866, 608 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d 7.40
(1H, d, J¼16.3 Hz), 7.36e7.31 (m, 2H), 7.28e7.23 (m, 2H), 6.77 (1H, t,
J¼53.9 Hz), 6.18 (1H, d, J¼16.3 Hz), 4.18 (2H, q, J¼7.1 Hz), 3.74 (s,
3H), 1.27 (3H, t, J¼7.1 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
ꢁ109.89
(1F, s), ꢁ112.36 (2F, s). 13C NMR (CDCl3, 100.6 MHz)
d 167.21, 163.59
(d, J¼250.5 Hz), 144.63, 143.29 (t, J¼29.1 Hz), 132.68, 131.96, 124.09,
119.45, 116.62 (d, J¼22.0 Hz), 114.15, 111.95 (t, J¼234.1 Hz), 60.41,
37.45, 14.26. MS (EI): m/z (%): 324,12 279 (46), 251 (100), 231 (74).
HRMS (EI) calcd for C16H15F3N2O2: 324.1086, found: 324.1084.
8. For direct olefination of electron-deficient arenes or heterocycles without di-
recting group, see: (a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 5072e5073; (b) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008,
130, 9254e9525; (c) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc.
2009, 131, 13888e13889; (d) Rauf, W.; Thompson, A. L.; Brown, J. M. Chem.
Commun. 2009, 3874e3876; (e) Zhang, X.; Fan, S.; He, C. Y.; Wan, X.; Min, Q. Q.;
Yang, J.; Jiang, Z. X. J. Am. Chem. Soc. 2010, 132, 4506e4507.
4.3.15. 3-(3-(Difluoromethyl)-5-(4-fluorophenyl)-1-phenyl-1H-pyr-
azol-4-yl)acrylonitrile (5o) (cis:transz1:0.87). IR (KBr): 3072, 2218,
1628, 1489, 1230, 1071, 1026, 839, 692 cmꢁ1 1H NMR (CDCl3,
.
400 MHz):
d cis 7.36e7.33 (1.6H, m), 7.23e7.11 (2.2H, m), 7.15
9. For recent directed olefination of arenes, see: (a) Zaitsev, V. G.; Daugulis, O. J.
Am. Chem. Soc. 2005, 127, 4156e4157; (b) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J.
Am. Chem. Soc. 2007, 129, 7666e7667; (c) Wang, J. R.; Yang, C. T.; Liu, L.; Guo, Q.
X. Tetrahedron Lett. 2007, 48, 5449e5453; (d) Li, J. J.; Mei, T. S.; Yu, J. Q. Angew.
(0.54H, d, J¼8.4 Hz), 7.08e7.04 (1H, m), 6.90 (0.54H, t, J¼54.4 Hz),
5.46 (0.54H, d, J¼11.7 Hz); trans 7.36e7.33 (1.4H, m), 7.23e7.11
(2.8H, m), 7.21 (0.46H, d, J¼13.6 Hz), 6.84 (0.46H, t, J¼54.0 Hz), 5.85
ꢀ
Chem. 2008, 47, 6452e6455; (e) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne,
(0.46H, d, J¼16.9 Hz). 19F NMR (CDCl3, 367.5 MHz)
cis ꢁ110.22 (1F,
d
M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130,
10066e10067; (f) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc.
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s), -112.76 (2F, s); trans ꢁ109.06 (1F, s), ꢁ112.76 (2F, s). 13C NMR
(CDCl3, 100.6 MHz)
d
cis 163.20 (d, J¼250.5 Hz), 145.01 (t,
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11. Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries,
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J¼28.5 Hz), 142.78, 138.86, 138.54, 131.96, 129.22, 125.50, 124.30,
116.51, 116.29, 115.92, 113.51, 111.62 (t, J¼234.0 Hz), 101.51; trans
163.54 (d, J¼252.5 Hz), 144.38 (t, J¼30.0 Hz), 144.22, 138.52, 138.17,
132.21, 128.72, 124.99, 123.58, 118.41, 116.80, 116.58, 114.70, 112.22
(t, J¼232.2 Hz), 98.43. MS (EI): m/z (%): 339 (100), 338 (48), 318 (22),
288 (29). HRMS (EI) calcd for C19H12F3N3: 339.0983, found:
339.0975.
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€
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This work was supported by the National Natural Science
Foundation of China (Nos. 21172148, 21202044) and Science
and Technology Commission of Shanghai Municipality (No.
10540501300).
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.06.058.
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