Synthesis of 1,3,5-trisubstituted [4-tert-butyl 2-(5,5-difluoro-2,2- dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate]pyrazoles via a Pd-catalyzed C-H activation

Article abstract of DOI:10.1002/cjoc.201201100

The gem-difluoromethylenated acetonide 2 was efficiently synthesized as new precursor of HMG-CoA reductase inhibitor. Straightforward olefination via Pd-catalyzed C⁴-H activation of 1,3,5-trisubstituted pyrazoles 1 was proceeded smoothly in the presence of Pd(OAc)₂ and AgCO₃. This protocol has merits in terms of the improved atomic economy and prevention from the generation of by-products. Copyright

Full text of DOI:10.1002/cjoc.201201100

FULL PAPER
DOI: 10.1002/cjoc.201201100
Synthesis of 1,3,5-Trisubstituted [4-tert-Butyl 2-(5,5-difluoro-
2,2-dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate]pyrazoles via
a Pd-Catalyzed C—H Activation†
Wang, Xiaoguanga(王晓光)
Fang, Xiang*,a(方向)
Yang, Xueyana(杨雪艳)
Ni, Menga(倪萌)
Wu, Fanhong*,a,b(吴范宏)
a Key Laboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry and Molecular En-
gineering, East China University of Science and Technology, Shanghai 200237, China
b School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 200235, China
The gem-difluoromethylenated acetonide 2 was efficiently synthesized as new precursor of HMG-CoA reduc-
tase inhibitor. Straightforward olefination via Pd-catalyzed C4-H activation of 1,3,5-trisubstituted pyrazoles 1 was
proceeded smoothly in the presence of Pd(OAc)2 and AgCO3. This protocol has merits in terms of the improved
atomic economy and prevention from the generation of by-products.
Keywords C—H activation, Pd-catalyzed, pyrazole, HMG-CoA reductase inhibitor
Introduction
by-products. Recently, the direct arylation and alkenyla-
tion of pyrazoles have been reported independently by
Doucet,[11] Sames[10d] and Chappell.[12] Although direct
olefinations could be carried out based on electron-rich
arenes and heterocycles,[13,14] reactions of electron-de-
ficient arenes with pyrazoles are still challenging.[15]
Herein, we report Pd(OAc)2 catalyzed direct ortho-
olefination of electron-deficient CF3 substituted pyra-
Statins are well-known inhibitors of 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase,
which have become the most frequently prescribed
agents for the treatment of hypercholesterolemia due to
their compelling action on significantly reducing the
rates of cardiovascular events.[1] A large number of
statin analogs including Lovastatin, Simvastatin,
Pravastatin, Fluvastatin, Atorvastatin, Rosuvastatin and
Pitavastatin have been synthesized, in which modifica-
tions were mainly focused on the variation of their hy-
drophobic fragment to improve the biological activity
and reduce the side effects.[2] The hydrophobic groups
used are mainly six-membered quinoline[3] and
pyrimidine[4] and five-membered pyrrole[5] and imida-
zole[6] rings. While hepatoselectivity is as a demand for
statins, pyrazole has been again introduced into the
statins because of its special electron nature.[7] Sliskovic
et al.[8] has reported the synthesis and biological activity
of 1,3,5-trisubstituted pyrazole mevalonolactones (Fig-
ure 1, A and B). Recently, Pfefferkorn et al.[9] has per-
formed the study of 1,3,4-trisubstituted pyrazole meva-
lonolactones, some of which (Figure 1, C and D) exhibit
preferable biological activity.
zoles with gem-difluoromethylenated acetonide
2
(Scheme 1).
Results and Discussion
Recently, special attention has been paid to the gem-
difluoromethylene group because many compounds
with this functional group exhibit extraordinary bio-
logical activities with potential pharmaceutical applica-
tions.[16] We have reported in a previous study the in-
troduction of the gem-difluoromethylene group into hy-
droxyl-valerolactones,[17] because it has been revealed
by structure-activity relationship (SAR) studies that the
hydroxyl-valerolactone fragment is essentially respon-
sible for the biological activity of statins.[18] We envi-
sion that this strategy would also work if the gem-di-
fluoromethylene moiety is introduced into the hydro-
philic portion of pyrazole. The starting material, gem-di-
fluoromethylenated acetonide 2 was obtained in a syn
form in 20% overall yield (Scheme 2) according to our
previous method.[17] Zinc-mediated Reformatsky reac-
The conventional C4-functionalization of pyrazole is
implemented by generating pyrazol metals, halides and
aldehydes as intermediates,[10] which has drawbacks in
terms of atomic economy and inappropriately generated
*
E-mail: fangxiang@ecust.edu.cn, wfh@sit.edu.cn
Received November 8, 2012; accepted December 6, 2012; published online December 13, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201100 or from the author.
Dedicated to the 60th Anniversary of East China University of Science and Technology.
†
Chin. J. Chem. 2012, 30, 2767—2773
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wang et al.
FULL PAPER
R2
OH OH
O
OH OH
O
N
N
N
N
ONa
ONa
R1
F
F
A
a R1 = 2-Pyridinyl, R2 = i-Pr
b R1 = 2-Pyrazinyl, R2 = i-Pr
c R1 = 2-Pyridinyl, R2 = CF3
B
OH OH
O
R3
O
OH OH
R1
R2
CO2Na
CO2Na
N
R1
R2
N
H
N
N
N
N
F
F
a: R1 = H, R2 = H
b: R1 = H, R2 = CH3
a: R1 = H, R2 = H, R3 = H
b: R1 = F, R2 = H, R3 = F
c: R1 = F, R2 = F, R3 = H
C
D
Figure 1 The reported pyrazole HMG-CoA reductase inhibitors.
Scheme 1 Sketch of previous reports and essence of this work
Previous report
(PPh3)2PdCl2, Et3N
reflux, 24 h
O
O
N
N
N
N
N
N
N
N
CO2Et
Br
CO2Et
H
+
O
O
Ph
Ph
Ph
Ph
O
O
CO2Et
F
F
by-product
F
F
Sliskovic D. R.
This work
CF3
Pd(OAc)2 (20 mol%)
Ag2CO3 (2 equiv.)
CF3
O
O
F
O
O
O
O
N
N
+
H
O
N
O
R1
N
DMF, 120 oC, 24 h
R1
F
R2
F
F
R2
Scheme 2
tion of acrylic aldehyde with ethyl bromodifluoroacetate
gave the corresponding ester. Subsequent Claisen con-
densation of ester with tert-butyl acetate produced
δ-hydroxy-β-keto ester, which was then reduced to
β,δ-diol in the presence of NaBH4. Considering the dif-
ficulty in separating syn and anti diols, crude diols were
transformed to the desired acetonide without further
purification in the presence of iso-propylidene acetal
useful for removing the trace amount of hydroxy epimer
produced in the stereoselective reduction of the
δ-hydroxy-β-keto ester. Finally, the intermediate 2 was
isolated in a single syn form by column chromatography
on silica gel.
OH
F
O
O
a
b
BrCF COOEt
+
2
O
H
F
OH
O
O
O
OH OH
O
c
O
F
F
F
F
O
O
O
d
O
F
F
2
Reagents and conditions: (a) Zn, THF, 60 ℃; (b) tert-butyl ace-
tate, LDA, － 78 ℃ ; (c) NaBH4, THF/MeOH; (d) acetone,
(CH3O)2C(CH3)2, TsOH
With acetonide 2 in hand, we carried out the
Pd-catalyzed direct ortho-olefination of CF3 substituted
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Chin. J. Chem. 2012, 30, 2767—2773

Synthesis of [4-tert-Butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate]pyrazoles
pyrazoles by using a highly electron-deficient 1a as
model substrate (Table 1). With 10 mol% Pd source as
catalyst and Cu(OAc)2 as oxidant in N,N-dimethyl-
formamide (DMF), the reaction was proceeded for 24 h
at 120 ℃. The desired product 3a was obtained in
yields of 25%, 10% and trace while Pd(OAc)2,
PdCl2(PPh3)2 and PdCl2 were used as the catalyst, re-
spectively (Entries 1—3). Then we noticed that Ag2CO3
(Entry 4) was a more efficient oxidant than Cu(OAc)2
and AgOAc (Entry 5). Yu et al.[19] has pointed out that
Ag2CO3 releases Ag＋ and CO32－ slowly during the
reaction, which appears to be important for the catalysis.
A screen of solvent showed that the reaction efficiency
was decreased in DMSO, DMF-DMSO (5%) and DMA
(Entries 6—8). Moreover, the quantity of Pd(OAc)2 was
critical for the reaction efficiency, and the best yield
(57%) was obtained while 20 mol% Pd(OAc)2 was used
as catalyst (Entry 9). However, increase of the catalyst
to 50 mol% did not improve the yield (Entry 10).
Therefore, the optimal reaction condition was found to
be the mixture of 3 equiv. of 1a with 1 equiv. of 2 in the
presence of Ag2CO3 (2 equiv.) as both base and oxidant
and Pd(OAc)2 (20 mol%) as catalyst in DMF (Entry 9).
With the optimized reaction conditions in hand, a
variety of 3-trifluoromethyl substituted pyrazol-4-ace-
tonides 3 (Table 2) were employed to test the substrate
scope. Despite the different R1 (4-NO2C6H4, C6H5, CH3
and 4-OMeC6H4) and R2 (4-FC6H4, C6H5 and
4-OMeC6H4) substituents on the pyrazole derivatives
employed, the alkenylation of pyrazole 1 proceeded
well in moderate yields (40%—65%). The results were
comparable with those of Sliskovic’s.[8] Moreover, our
protocol is deemed to have merits such as increased
atomic economy and generation of less by-products.
Next, we investigated whether this reaction is also
suited for a variety of olefines. Series of acrylates 4
were used, as shown in Table 3. The alkenylation of
pyrazoles 1 proceeded well with nearly all electron-
deficient acrylates in the presence of 10 mol% Pd(OAc)2
as the catalyst, and high yields were obtained (Entries 1
—4 and 6). However, in the case of 5e (54%, Entry 5),
the yield was less satisfactory probably because of the
presence of a bulky tertiary butyl group.
Conclusions
In summary, a novel protocol for the synthesis of
1,3,5-trisubstituted
[4-tert-butyl-2-(5,5-difluoro-2,2-
dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate]pyrazoles has
been developed via a Pd(II)-catalyzed C—H bond acti-
vation under mild conditions. The straightforward ole-
finations of pyrazoles 1 were proceeded well with acry-
lates 4 in high yields in the presence of 10 mol%
Pd(OAc)2 as the catalyst. Further biological studies of
the 1,3,5-trisubstituted pyrazoles obtained in this paper
are currently underway in our laboratory.
Table 1 Optimization of reaction conditionsa
CF3
CF3
O
O
O
N
N
N
N
O
O
O
O
Pd source, oxidants
solvent, 120 oC
+
F
F
O
O2N
F
F
O2N
F
3a
F
1a
2
Entry
Pd source
Oxidant (2 equiv.)
Solvent
DMF
DMF
DMF
DMF
DMF
Yieldb/%
25
1
2
Pd(OAc)2 (10%)
PdCl2(PPh3)2 (10%)
PdCl2 (10%)
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
AgOAc
10
3
trace
35
4
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (20%)
Pd(OAc)2 (50%)
5
13
6
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
DMF＋DMSO (5%)
26
7
DMSO
DMA
DMF
DMF
15
8
20
9
57
10
60
a Unless otherwise noted, the reaction conditions were as follows: pyrazole 1a (0.42 mmol), acetonide 2 (0.14 mmol), Pd source, oxidant
(2.0 equiv.), solvent, 120 ℃, 24 h. b Isolated yield.
Chin. J. Chem. 2012, 30, 2767—2773
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Wang et al.
FULL PAPER
Table 2 Reaction of 1,3,5-trisubstituted pyrazoles 1 with gem-difluoromethylenated acetonide 2a
CF3
CF3
Pd(OAc)2 (20 mol%)
Ag2CO3 (2 equiv.)
O
O
O
O
O
O
N
N
N
N
O
O
R1
R1
DMF, 120 oC, 24 h
F
F
F
F
R2
R2
2
3
1
Entry
1
R1
R2
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
Ph
Product
3a
3b
3c
3d
3e
3f
3g
3h
3i
Yieldb/%
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-NO2C6H4
Ph
57
65
46
52
40
49
54
56
52
43
CH3
4-MeOC6H4
4-NO2C6H4
Ph
4-MeOC6H4
4-NO2C6H4
Ph
Ph
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
10
1j
4-MeOC6H4
3j
a Unless otherwise noted, the reaction conditions were as follows: pyrazole 1 (0.42 mmol), acetonide 2 (0.14 mmol), Pd(OAc)2 (20 mol%),
Ag2CO3 (2.0 equiv.), DMF, 120 ℃, 24 h. b Isolated yield.
Table 3 Reaction of 1,3,5-trisubstituted pyrazoles 1 with acry-
lates 4a
δ: 5.94—5.86 (m, 1H), 5.47 (dd, J＝28.0, 14.0 Hz, 2H),
4.48—4.30 (m, 2H), 2.71—2.48 (m, 2H), 1.59 (s, 3H),
1.47 (s, 3H), 1.46 (s, 9H); 19F NMR (CDCl3, 367.5 MHz)
δ: －122.2 (d, J＝244.0 Hz, 1F), －135.4 (d, J＝241.8
Hz, 1F); 13C NMR (CDCl3, 125 MHz) δ: 169.0, 128.8,
120.5, 120.2, 102.2, 81.1, 73.2 (t, J＝30.0 Hz), 69.1 (t,
J＝36.3 Hz), 33.7, 28.0, 23.7; IR (KBr) ν: 3101, 2924,
2851, 1736, 1255, 1159 cm ; MS (EI) m/z (%): 292
(M＋, 25), 277 (30), 219 (100), 73 (28); HRMS (EI)
calcd for C14H22O4F2 292.1486, found 292.1481.
CF3
CF3
Pd(OAc)2 (10 mol%)
Ag2CO3 (2 equiv.)
N
N
R3
N
N
R3
R1
R1
DMF, 120 oC, 24 h
4
R2
R2
1
5
－
1
Entry 1
R1
R2
R3
Product Yieldb/%
1
2
3
4
5
6
1a 4-NO2C6H4 4-FC6H4 CO2Bu-n 5a
81
78
88
77
54
80
1b
1f
Ph
Ph
4-FC6H4 CO2Bu-n 5b
Ph CO2Bu-n 5c
General procedure for oxidative olefination of
1,3,5-trisubstituted pyrazoles via C—H bond activa-
tion
1j 4-OMeC6H4 4-OMeC6H4 CO2Bu-n 5d
1b
Ph
4-FC6H4 CO2Bu-t
5e
To a solution of Pd(OAc)2 (20 mol% or 10 mol%) in
DMF (1 mL) were added Ag2CO3 (2.0 equiv.), pyrazole
(3.0 equiv.) and alkene (1.0 equiv.). The mixture was
then heated to 120 ℃ (oil bath) and stirred for 24 h.
The resulting mixture was cooled to room temperature,
1b
Ph
4-FC6H4 CO2Et
5f
a Unless otherwise noted, the reaction conditions were as follows:
pyrazole 1 (0.42 mmol), acrylate 4 (0.14 mmol), Pd(OAc)2 (10
b
mol%), Ag2CO3 (2.0 equiv.), DMF, 120 ℃, 24 h. Isolated
diluted with ethyl acetate and washed with 1 mol•L－
1
yield.
HCl and brine. The resulting residue was dried over
Na2SO4, filtered, and then concentrated, which was then
purified by silica gel chromatography to provide the
pure product.
Experimental
General
(E)-tert-Butyl 2-(5,5-difluoro-6-(2-(5-(4-fluoro-
phenyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyra-
zol-4-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate
(3a): 1H NMR (CDCl3, 400 MHz) δ: 8.19 (d, J＝9.2 Hz,
2H), 7.41 (d, J＝9.2 Hz, 2H), 7.25—7.22 (m, 2H), 7.15
(t, J＝8.6 Hz, 2H), 6.55 (d, J＝16.4 Hz, 1H), 5.80 (dd,
J＝16.4, 6.0 Hz, 1H), 4.46—4.38 (m, 2H), 2.68—2.46
(m, 2H), 1.57 (s, 3H), 1.46 (s, 9H), 1.44 (s, 3H); 19F
NMR (CDCl3, 367.5 MHz) δ: －61.4 (s, 3F), －109.2
(s, 1F), －121.8 (d, J＝241.8 Hz, 1F), －134.5 (d, J＝
241.8 Hz, 1F); 13C NMR (CDCl3, 100.6 MHz) δ: 169.2,
163.5 (d, J＝201.2 Hz), 146.8, 143.4, 141.9, 132.3,
132.2, 125.5, 125.3, 125.2, 124.7, 124.6, 121.7 (t, J＝
IR spectra were measured on a Nicolet Magna
IR-550 spectrometer. High-resolution mass spectra were
carried out on a Finnigan GC-MS-4021 spectrometer.
1H (400 MHz) and 13C (100.6 MHz) NMR spectra were
recorded on a Bruker AC-500 spectrometer with Me4Si
as an internal standard. 19F NMR spectra were obtained
on a Bruker AC-500 (367.5 MHz) spectrometer in
CDCl3 with CFCl3 as an external standard, in which
downfield shifts were designated as negative.
The procedure for preparation acetonide 2, see ref 17.
tert-Butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-1,3-
dioxan-4-yl)acetate (2): [17] 1H NMR (CDCl3, 400 MHz)
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Chin. J. Chem. 2012, 30, 2767—2773

Synthesis of [4-tert-Butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate]pyrazoles
218.6 Hz), 117.5, 116.9, 116.7, 100.0, 81.2, 72.9 (t, J＝
21.3 Hz), 68.8 (t, J＝21.5 Hz), 33.8, 28.7, 28.0; IR (KBr)
ν: 3077, 2983, 2875, 1730, 1521, 1347, 1161, 856, 691
cm ; HRMS (ESI) calcd for C30H29N3O6F6Na [M＋
Na]: 664.1858, found 664.1853.
found 626.2211.
(E)-tert-Butyl 2-(5,5-difluoro-2,2-dimethyl-6-(2-(1-
(4-nitrophenyl)-5-phenyl-3-(trifluoromethyl)-1H-
pyrazol-4-yl)vinyl)-1,3-dioxan-4-yl)acetate (3e): 1H
NMR (CDCl3, 400 MHz) δ: 8.16 (d, J＝9.2 Hz, 2H),
7.48—7.40 (m, 5H), 7.25—7.23 (m, 2H), 6.56 (d, J＝
16.4 Hz, 1H), 5.82 (dd, J＝16.4, 6.4 Hz, 1H), 4.44—
4.36 (m, 2H), 2.68—2.45 (m, 2H), 1.56 (s, 3H), 1.45 (s,
9H), 1.43 (s, 3H); 19F NMR (CDCl3, 367.5 MHz) δ:
－61.4 (s, 3F), －121.8 (d, J＝242.2 Hz, 1F), －134.6
(d, J＝242.2 Hz, 1F); 13C NMR (CDCl3, 100.6 MHz) δ:
169.2, 157.5, 146.7, 143.6, 142.9, 141.8, 141.5, 130.2,
130.1, 129.4, 128.0, 125.1, 124.4 (t, J＝213.4 Hz),
120.2, 117.4, 100.0, 81.2, 73.1 (t, J＝21.4 Hz), 68.8 (t,
J＝21.5 Hz), 33.8, 28.7, 28.0; IR (KBr) ν: 3084, 2992,
2937, 1737, 1539, 1349, 1167, 861, 701 cm ; MS (EI)
m/z (%): 623 (M＋, 15), 492 (37), 388 (42), 358 (100),
84 (20); HRMS (EI) calcd for C30H30N3O6F5 623.2055,
found 623.2056.
(E)-tert-Butyl 2-(6-(2-(1,5-diphenyl-3-(trifluoro-
methyl)-1H-pyrazol-4-yl)vinyl)-5,5-difluoro-2,2-dime-
－
1
(E)-tert-Butyl 2-(5,5-difluoro-6-(2-(5-(4-fluoro-
phenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (3b): 1H
NMR (CDCl3, 400 MHz) δ: 7.32—7.31 (m, 3H), 7.21—
7.18 (m, 4H), 7.06 (t, J＝8.6 Hz, 2H), 6.57 (d, J＝16.4
Hz, 1H), 5.78 (dd, J＝16.4, 6.4 Hz, 1H), 4.38—4.45 (m,
2H), 2.69—2.46 (m, 2H), 1.57 (s, 3H), 1.46 (s, 9H),
1.43 (s, 3H); 19F NMR (CDCl3, 367.5 MHz) δ: －61.0
(s, 3F), －110.7 (s, 1F), －121.7 (d, J＝241.8 Hz, 1F),
－134.6 (d, J＝241.8 Hz, 1F); 13C NMR (CDCl3, 100.6
MHz) δ: 169.3, 163.1 (d, J＝201.2 Hz), 141.7, 140.5,
140.2, 138.7, 129.0, 128.4, 125.4, 125.2, 124.6, 124.3,
122.6 (t, J＝216.7 Hz), 120.5, 116.1, 100.0, 81.2, 73.2 (t,
J＝22.0 Hz), 68.8 (t, J＝21.3 Hz), 33.8, 29.7, 28.1; IR
(KBr) ν: 2981, 2927, 2875, 1729, 1506, 1380, 1128, 759,
689 cm－1; MS (EI) m/z (%): 596 (M＋, 3), 465 (27), 361
(37), 331 (100), 191 (29), 57 (33); HRMS (EI) calcd for
C30H30N2O4F6 596.2110, found 596.2114.
(E)-tert-Butyl 2-(5,5-difluoro-6-(2-(5-(4-fluoro-
phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (3c): 1H
NMR (CDCl3, 400 MHz) δ: 7.35—7.31 (m, 2H), 7.22 (t,
J＝8.6 Hz, 2H), 6.50 (d, J＝16.0 Hz, 1H), 5.61 (dd, J＝
16.4, 6.8 Hz, 1H), 4.41—4.33 (m, 2H), 3.74 (s, 3H),
2.67—2.43 (m, 2H), 1.55 (s, 3H), 1.45 (s, 9H), 1.41 (s,
3H); 19F NMR (CDCl3, 367.5 MHz) δ: －60.8 (s, 3F),
－110.4 (s, 1F), －121.7 (d, J ＝242.2 Hz, 1F),
－134.9 (d, J＝241.8 Hz, 1F); 13C NMR (CDCl3, 100.6
MHz) δ: 169.3, 163.4 (d, J＝201.2 Hz), 142.1, 138.9,
138.6, 132.0, 124.6, 123.1, 123.0, 120.5 (t, J＝221.0
Hz), 116.6, 116.4, 115.3, 99.9, 81.2, 73.3 (t, J＝21.4
Hz), 68.8 (t, J＝21.3 Hz), 37.6, 33.8, 28.7, 28.0; IR
(KBr) ν: 2983, 2931, 2857, 1733, 1507, 1371, 1127, 849,
667 cm－1; HRMS (ESI) calcd for C25H28N2O4F6Na
[M＋Na] 557.1851, found 557.1832.
－
1
1
thyl-1,3-dioxan-4-yl)acetate (3f): H NMR (CDCl3, 400
MHz) δ: 7.39—7.33 (m, 3H), 7.30—7.28 (m, 3H),
7.22—7.20 (m, 4H), 6.58 (d, J＝16.4 Hz, 1H), 5.81 (dd,
J＝16.4, 6.8 Hz, 1H), 4.45—4.36 (m, 2H), 2.68—2.46
(m, 2H), 1.56 (s, 3H), 1.45 (s, 9H), 1.43 (s, 3H); 19F
NMR (CDCl3, 367.5 MHz) δ: －61.0 (s, 3F), －121.7
(d, J＝242.2 Hz, 1F), －134.8 (d, J＝242.2 Hz, 1F);
13C NMR (CDCl3, 100.6 MHz) δ: 169.3, 142.8, 140.4,
140.1, 138.9, 130.3, 129.3, 128.9, 128.6, 128.2, 125.3,
123.9, 122.9 (t, J＝222.4 Hz), 120.5, 116.0, 99.9, 81.1,
73.3 (t, J＝21.3 Hz), 68.9 (t, J＝21.4 Hz), 33.8, 28.8,
28.0; IR (KBr) ν: 3064, 2983, 2930, 1732, 1489, 1318,
－
＋
1
1128, 763, 699 cm ; MS (EI) m/z (%): 578 (M , 12),
444 (25), 343 (62), 313 (100); HRMS (EI) calcd for
C30H31N2O4F5 578.2204, found 578.2203.
(E)-tert-Butyl 2-(5,5-difluoro-6-(2-(1-(4-methoxy-
phenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (3g): 1H
NMR (CDCl3, 400 MHz) δ: 7.37—7.34 (m, 3H), 7.21—
7.19 (m, 2H), 7.12 (d, J＝9.2 Hz, 2H), 6.79 (d, J＝9.2
Hz, 2H), 6.58 (d, J＝16.4 Hz, 1H), 5.79 (dd, J＝16.4,
6.8 Hz, 1H), 4.43—4.35 (m, 2H), 3.78 (s, 3H), 2.68—
2.45 (m, 2H), 1.56 (s, 3H), 1.45 (s, 9H), 1.42 (s, 3H);
19F NMR (CDCl3, 367.5 MHz) δ: －60.9 (s, 3F),
－121.7 (d, J＝242.2 Hz, 1F), －134.8 (d, J＝242.2 Hz,
1F); 13C NMR (CDCl3, 100.6 MHz) δ: 169.3, 159.3,
149.1, 142.8, 131.9, 130.3, 129.2, 128.8, 128.7, 128.6,
126.7, 123.6, 123.1, 117.8 (t, J＝232.5 Hz), 115.7,
114.1, 99.9, 81.2, 73.6 (t, J＝22.7 Hz), 68.8 (t, J＝25.6
Hz), 55.5, 33.8, 28.8, 28.0; IR (KBr) ν: 3438, 2988,
2851, 1730, 1517, 1251, 1127, 839, 700 cm ; MS (EI)
m/z (%): 608 (M＋, 32), 552 (24), 494 (40), 372 (100),
331 (13); HRMS (EI) calcd for C31H33N2O5F5 608.2310,
found 608.2308.
(E)-tert-Butyl 2-(5,5-difluoro-6-(2-(5-(4-methoxy-
phenyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyra-
zol-4-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate
(E)-tert-Butyl 2-(5,5-difluoro-6-(2-(5-(4-fluoro-
phenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-
pyrazol-4-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)ace-
tate (3d): 1H NMR (CDCl3, 400 MHz) δ: 7.13—7.09 (m,
2H), 7.05—6.96 (m, 4H), 6.74 (d, J＝8.8 Hz, 2H), 6.49
(d, J＝16.4 Hz, 1H), 5.69 (dd, J＝16.4, 7.2 Hz, 1H),
4.37—4.30 (m, 2H), 3.72 (s, 3H), 2.60—2.39 (m, 2H),
1.50 (s, 3H), 1.38 (s, 9H), 1.36 (s, 3H); 19F NMR
(CDCl3, 367.5 MHz) δ: －60.9 (s, 3F), －110.9 (s, 1F),
－121.7 (d, J＝241.8 Hz, 1F), －134.7 (d, J＝242.2 Hz,
1F); 13C NMR (CDCl3, 100.6 MHz) δ: 169.3, 162.5 (d,
J＝251.5 Hz), 159.4, 141.7, 139.8, 132.3, 131.7, 126.8,
124.6, 124.0, 122.8, 116.3, 116.0 (t, J＝232.5 Hz),
115.8, 114.2, 100.0, 81.2, 73.2 (t, J＝26.7 Hz), 68.6 (t,
J＝26.4 Hz), 55.5, 33.8, 28.8, 28.0; IR (KBr) ν: 2982,
－
1
－
1
2931, 1730, 1518, 1379, 1161, 841, 519 cm ; MS (EI)
m/z (%): 626 (M＋, 38), 570 (28), 512 (37), 390 (100),
361 (30); HRMS (EI) calcd for C31H32N2O5F6 626.2215,
Chin. J. Chem. 2012, 30, 2767—2773
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2771

Wang et al.
FULL PAPER
(3h): 1H NMR (CDCl3, 400 MHz) δ: 8.17 (d, J＝9.2 Hz,
2H), 7.42 (d, J＝8.8 Hz, 2H), 7.14 (d, J＝8.4 Hz, 2H),
6.94 (d, J＝8.8 Hz, 2H), 6.55 (d, J＝16.4 Hz, 1H), 5.81
(dd, J＝16.4, 6.8 Hz, 1H), 4.45—4.38 (m, 2H), 3.86 (s,
3H), 2.68—2.46 (m, 2H), 1.57 (s, 3H), 1.46 (s, 9H),
1.44 (s, 3H); 19F NMR (CDCl3, 367.5 MHz) δ: －61.4
(s, 3F), －121.7 (d, J＝242.2 Hz, 1F), －134.6 (d, J＝
241.8 Hz, 1F); 13C NMR (CDCl3, 100.6 MHz) δ: 169.3,
160.8, 146.6, 143.7, 142.9, 131.5, 131.1, 128.6, 127.7,
127.0, 125.1, 124.6, 124.4, 122.2 (t, J＝212.5 Hz),
119.9, 114.9, 100.0, 81.2, 73.4 (t, J＝20.0 Hz), 68.9 (t,
J＝22.7 Hz), 55.4, 33.8, 28.8, 28.0; IR (KBr) ν: 3446,
13.2 Hz, 1H), 4.16 (t, J＝5.4 Hz, 2H), 1.68—1.62 (m,
2H), 1.42—1.37 (m, 2H), 0.95 (t, J＝6.0 Hz, 3H); 19F
NMR (CDCl3, 367.5 MHz) δ: －61.7 (s, 3F), －108.1
(s, 1F); 13C NMR (CDCl3, 100.6 MHz) δ: 166.5, 163.8
(d, J＝194.9 Hz), 147.0, 144.0, 143.0, 141.9 (q, J＝30.9
Hz), 132.2, 132.1, 130.8, 125.2, 124.7, 124.6, 122.1 (q,
J＝209.7 Hz), 117.2, 117.0, 64.7, 30.6, 19.1, 13.7; IR
(KBr) ν: 3087, 2961, 2874, 1707, 1346, 1185, 857, 693
－
＋
1
cm ; MS (EI) m/z (%): 477 (M , 7), 404 (23), 376
(100); HRMS (EI) calcd for C23H19N3O4F4 477.1312,
found 477.1317.
(E)-Butyl 3-(5-(4-fluorophenyl)-1-phenyl-3-(trifluo-
romethyl)-1H-pyrazol-4-yl)acrylate (5b): 1H NMR
(CDCl3, 400 MHz) δ: 7.49 (d, J＝12.8 Hz, 1H), 7.35—
7.34 (m, 3H), 7.22—7.19 (m, 4H), 7.11 (t, J＝6.8 Hz,
2H), 6.15 (d, J＝12.8 Hz, 1H), 4.15 (t, J＝5.4 Hz, 2H),
1.67—1.64 (m, 2H), 1.42—1.37 (m, 2H), 0.95 (t, J＝6.0
Hz, 3H); 19F NMR (CDCl3, 367.5 MHz) δ: －61.6 (s,
3F), －109.7 (s, 1F); 13C NMR (CDCl3, 100.6 MHz) δ:
166.8, 163.4 (d, J＝201.2 Hz), 143.9, 141.1 (q, J＝33.5
Hz), 138.3, 132.3, 132.2, 131.8, 129.2, 128.7, 125.4 (q,
J＝213.5 Hz), 125.3, 121.0, 116.6, 116.4, 64.6, 30.7,
19.2, 13.7; IR (KBr) ν: 3071, 2962, 2874, 1713, 1332,
－
1
2925, 2853, 1736, 1527, 1348, 1165, 859, 693 cm ;
MS (EI) m/z (%): 653 (M＋, 31), 539 (37), 522 (55), 418
(79), 388 (100), 358 (35); HRMS (EI) calcd for
C31H32N3O7F5 653.2160, found 653.2162.
(E)-tert-Butyl 2-(5,5-difluoro-6-(2-(5-(4-methoxy-
phenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (3i): 1H
NMR (CDCl3, 400 MHz) δ: 7.31—7.30 (m, 3H), 7.23—
7.21 (m, 2H), 7.12 (d, J＝8.0 Hz, 2H), 6.87 (d, J＝8.0
Hz, 2H), 6.57 (d, J＝16.4 Hz, 1H), 5.85 (dd, J＝16.2,
6.2 Hz, 1H), 4.37—4.44 (m, 2H), 3.82 (s, 3H), 2.69—
2.46 (m, 2H), 1.57 (s, 3H), 1.46 (s, 9H), 1.44 (s, 3H);
19F NMR (CDCl3, 367.5 MHz) δ: －61.0 (s, 3F),
－121.6 (d, J＝241.8 Hz, 1F), －134.7 (d, J＝242.2 Hz,
1F); 13C NMR (CDCl3, 100.6 MHz) δ: 169.3, 160.2,
142.7, 139.0, 138.9, 131.6, 128.9, 128.8, 128.1, 125.3,
123.5, 123.4, 123.2, 120.6 (t, J＝232.5 Hz), 115.7,
114.4, 99.9, 81.1, 73.3 (t, J＝21.7 Hz), 68.8 (t, J＝25.6
Hz), 55.3, 33.8, 28.8, 28.0; IR (KBr) ν: 3425, 2924,
－
1
1183, 844, 693 cm ; HRMS (EI) calcd for C23H20N2-
O2F4 [M＋H] 433.1539, found 433.1527[M＋H].
(E)-Butyl 3-(1,5-diphenyl-3-(trifluoromethyl)-1H-
1
pyrazol-4-yl)acrylate (5c): H NMR (CDCl3, 400 MHz)
δ: 7.52 (d, J＝16.4 Hz, 1H), 7.44—7.38 (m, 3H), 7.33—
7.29 (m, 3H), 7.33—7.20 (m, 4H), 6.15 (d, J＝16.4 Hz,
1H), 4.14 (t, J＝6.6 Hz, 2H), 1.67—1.60 (m, 2H),
1.43—1.34 (m, 2H), 0.94 (t, J＝7.4 Hz, 3H); 19F NMR
(CDCl3, 367.5 MHz) δ: －61.4 (3F, s); 13C NMR
(CDCl3, 100.6 MHz) δ: 166.9, 145.0, 140.8, 138.5 (q,
J＝32.3 Hz), 132.0, 130.2, 129.9, 129.0, 128.6, 127.9,
125.2, 120.7, 120.3 (q, J＝218.8 Hz), 114.8, 64.5, 30.7,
19.2, 13.7; IR (KBr) ν: 2964, 2930, 2870, 1712, 1336,
－
1
2850, 1737, 1506, 1255, 1159, 762, 692 cm ; MS (EI)
m/z (%): 608 (M＋, 48), 537 (28), 477 (38), 373 (76),
343 (100), 57 (18); HRMS (EI) calcd for C31H33N2O5F5
608.2310, found 608.2312.
(E)-tert-Butyl 2-(6-(2-(1,5-bis(4-methoxyphenyl)-3-
(trifluoromethyl)-1H-pyrazol-4-yl)vinyl)-5,5-difluoro-
2,2-dimethyl-1,3-dioxan-4-yl)acetate (3j): 1H NMR
(CDCl3, 400 MHz) δ: 7.14—7.10 (m, 4H), 6.87 (d, J＝
8.4 Hz, 2H), 6.80 (d, J＝8.8 Hz, 2H), 6.57 (d, J＝16.4
Hz, 1H), 5.83 (dd, J＝16.4, 6.8 Hz, 1H), 4.45—4.37 (m,
2H), 3.82 (s, 3H), 3.78 (s, 3H), 2.69—2.46 (m, 2H),
1.57 (s, 3H), 1.46 (s, 9H), 1.43 (s, 3H); 19F NMR
(CDCl3, 367.5 MHz) δ: －60.9 (s, 3F), －121.6 (d, J＝
241.8 Hz, 1F), －134.8 (d, J＝241.8 Hz, 1F); 13C NMR
(CDCl3, 100.6 MHz) δ: 169.3, 160.1, 159.2, 142.8,
139.9, 139.6, 132.0, 131.6, 126.7, 123.4, 123.2, 120.6,
120.4, 115.4 (t, J＝232.5 Hz), 114.3, 114.1, 99.9, 81.2,
73.5 (t, J＝26.8 Hz), 68.9 (t, J＝26.8 Hz), 55.5, 55.3,
33.8, 28.8, 28.0; IR (KBr) ν: 2981, 2939, 2841, 1733,
－
＋
1
1186, 761, 702 cm ; MS (EI) m/z (%): 414 (M , 5),
341 (11), 313 (100), 293 (12); HRMS (EI) calcd for
C23H21N2O2F3 414.1555, found 414.1561.
(E)-Butyl 3-(1,5-bis(4-methoxyphenyl)-3-(trifluoro-
methyl)-1H-pyrazol-4-yl)acrylate (5d): 1H NMR
(CDCl3, 400 MHz) δ: 7.51 (d, J＝16.4 Hz, 1H), 7.15—
7.10 (m, 4H), 6.91 (d, J＝8.4 Hz, 2H), 6.81 (d, J＝9.2
Hz, 2H), 6.15 (d, J＝16.4 Hz, 1H), 4.14 (t, J＝6.6 Hz,
2H), 3.83 (s, 3H), 3.79 (s, 3H), 1.68—1.61 (m, 2H),
1.42—1.36 (m, 2H), 0.94 (t, J＝7.4 Hz, 3H); 19F NMR
(CDCl3, 367.5 MHz) δ: －61.4 (s, 3F); 13C NMR
(CDCl3, 100.6 MHz) δ: 167.1, 160.5, 159.4, 145.1,
140.2 (q, J＝36.8 Hz), 132.4, 131.7, 131.6, 126.6, 122.8
(q, J＝219.6 Hz), 120.1, 119.9, 114.6, 114.2, 114.1,
64.5, 55.5, 55.3, 30.7, 19.2, 13.7; IR (KBr) ν: 2961,
－
1
1518, 1253, 1161, 837, 736 cm ; MS (EI) m/z (%): 638
(M＋, 20), 567 (12), 402 (32), 373 (100), 348 (34);
HRMS (EI) calcd for C32H35N2O6F5 638.2415, found
638.2416.
－
1
2874, 2842, 1713, 1517, 1255, 837, 705 cm ; MS (EI)
m/z (%): 474 (M＋, 28), 401 (11), 373 (100); HRMS (EI)
calcd for C25H25N2O4F3 474.1766, found 474.1770.
(E)-tert-Butyl 3-(5-(4-fluorophenyl)-1-phenyl-3-(tri-
(E)-Butyl 3-(5-(4-fluorophenyl)-1-(4-nitrophenyl)-3-
(trifluoromethyl)-1H-pyrazol-4-yl)acrylate (5a): 1H
NMR (CDCl3, 400 MHz) δ: 8.21 (d, J＝7.2 Hz, 2H),
7.46—7.42 (m, 3H), 7.25—7.18 (m, 4H), 6.16 (d, J＝
1
fluoromethyl)-1H-pyrazol-4-yl)acrylate (5e): H NMR
(CDCl3, 400 MHz) δ: 7.41 (d, J＝12.8 Hz, 1H), 7.35—
7.33 (m, 3H), 7.22—7.19 (m, 4H), 7.11 (t, J＝6.8 Hz,
2772
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2767—2773

Synthesis of [4-tert-Butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate]pyrazoles
2H), 6.10 (d, J＝13.2 Hz, 1H), 1.49 (s, 9H); 19F NMR
1851.
[6] Sarver, R. W.; Bills, E.; Bolton, G.; Bratton, L. D.; Caspers, N. L.;
(CDCl3, 367.5 MHz) δ: －61.7 (s, 3F), －109.8 (s, 1F);
13C NMR (CDCl3, 100.6 MHz) δ: 166.1, 163.4 (d, J＝
201.2 Hz), 143.9, 140.5 (q, J＝31.9 Hz), 138.4, 132.3,
132.2, 130.7, 129.2, 128.7, 126.3, 122.6 (q, J＝222.4
Hz), 116.6, 116.4, 116.0, 80.7, 28.1; IR (KBr) ν: 3072,
Dunbar, J. B.; Harris, M. S.; Hutchings, R. H.; Kennedy, R. M.;
Larsen, S. D.; Pavlovsky, A.; Pfefferkorn, J. A.; Bainbridge, G. J.
Med. Chem. 2008, 51, 3804.
[7] (a) Tang, J. Y.; Cai, Z. Y.; Zhou, W. C. J. Int. Pharm. Res. 2011, 38,
189; (b) Pfefferkorn, J. A.; Song, Y.; Sun, K. L.; Miller, S. R.;
Trivedi, B. K.; Choi, C.; Sorenson, R. J.; Bratton, L. D.; Unangst, P.
C.; Larsen, S. D. Bioorg. Med. Chem. Lett. 2007, 17, 4538;
(c) Bratton, L. D.; Auerbach, B.; Choi, C.; Dillon, L.; Hanselman, J.
C.; Larsen, S. D.; Lu, G.; Olsen, K.; Pfefferkorn, J. A.; Robertson, A.
Bioorg. Med. Chem. 2007, 15, 5576.
[8] (a) Sliskovic, D. R.; Blankley, C. J.; Krause, B. R.; Newton, R. S.;
Picard, J. A.; Roark, W. H.; Roth, B. D.; Sekerke, C.; Shaw, M. K.;
Stanfield, R. L. J. Med. Chem. 1992, 35, 2095; (b) Sliskovic, D. R.;
Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. J. Med.
Chem. 1990, 33, 31.
[9] (a) Pfefferkorn, J. Curr. Opin. Invest. Dr. 2009, 10, 245;
(b) Pfefferkorn, J. A.; Choi, C.; Larsen, S. D.; Auerbach, B.;
Hutchings, R.; Park, W.; Askew, V.; Dillon, L.; Hanselman, J. C.;
Lin, Z.; Lu, G. H.; Robertson, A.; Sekerke, C.; Harris, M. S.;
Pavlovsky, A.; Bainbridge, G.; Caspers, N.; Kowala, M.; Tait, B. D.
J. Med. Chem. 2008, 51, 31.
[10] For fuctionalization 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,
1191; (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, 2095; (c) Sliskovic, D.; Roth, B.; Wilson,
M.; Hoefle, M.; Newton, R. J. Med. Chem. 1990, 33, 31;
(d) Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009,
131, 3042; (e) Roger, J.; Gottumukkala, A. L.; Doucet, H.
ChemCatChem 2009, 2, 20; (f) Dai, H. X.; Stepan, A. F.; Plummer,
M. S.; Zhang, Y. H.; Yu, J. Q. J. Am. Chem. Soc. 2011, 133, 7222.
[11] Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2,
20.
－
1
2976, 2936, 1709, 1313, 1123, 872, 693 cm ; MS (EI)
m/z (%): 432 (M＋, 4), 376 (11), 331 (100); HRMS (EI)
calcd for C23H20N2O2F4 432.1461, found 432.1474.
(E)-Ethyl 3-(5-(4-fluorophenyl)-1-phenyl-3-(tri-
1
fluoromethyl)-1H-pyrazol-4-yl)acrylate (5f): H NMR
(CDCl3, 400 MHz) δ: 7.49 (d, J＝16 Hz, 1H), 7.34—
7.32 (m, 3H), 7.22—7.19 (m, 4H), 7.11 (t, J＝8 Hz, 2H),
6.15 (d, J＝16 Hz, 1H), 4.20 (q, J＝7.2 Hz, 2H), 1.29 (t,
J＝7.2 Hz, 3H); 19F NMR (CDCl3, 367.5 MHz) δ:
－61.5 (s, 3F), －109.7 (s, 1F); 13C NMR (CDCl3,
100.6 MHz) δ: 166.8, 163.4 (d, J＝241.4 Hz), 143.9,
140.6 (q, J＝32.1 Hz), 138.3, 132.3, 132.2, 131.7, 129.2,
128.7, 126.3, 121.9 (q, J＝212.9 Hz), 116.6, 116.4,
114.9, 60.6, 14.2; IR (KBr) ν: 3070, 2983, 2904, 1696,
－
＋
1
1329, 1127, 834, 694 cm ; MS (EI) m/z (%): 404 (M ,
10), 359 (16), 331 (100); HRMS (EI) calcd for
C23H20N2O2F4 404.1148, found 404.1149.
Acknowledgement
This work is supported by the National Natural Sci-
ence Foundation of China (Nos. 20972050, 21172148
and 21202044) and the Science and Technology Com-
mission of Shanghai Municipality (No. 10540501300).
[12] Chappell, B.; Dedman, N.; Wheeler, S. Tetrahedron Lett. 2011, 52,
3223.
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(Zhao, C.)
Chin. J. Chem. 2012, 30, 2767—2773
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