A novel method for the synthesis of 2,2-diaryl-1,1-difluoroethenes

Article abstract of DOI:10.1016/j.tetlet.2007.12.028

β,β-Difluoro-α-phenylvinylstannane 3 was prepared in 60% yield from the reaction of β,β-difluoro-α-phenylvinylsulfone 2 with tributyltin hydride in refluxing benzene for 5 h. The cross-coupling reaction of 3 with aryl iodides bearing substituents such as

Full text of DOI:10.1016/j.tetlet.2007.12.028

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Tetrahedron Letters 49 (2008) 952–955
A novel method for the synthesis of 2,2-diaryl-1,1-difluoroethenes
Ji Hoon Choi, In Howa Jeong *
Department of Chemistry, Yonsei University, Wonju 220-710, South Korea
Received 30 November 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
b,b-Difluoro-a-phenylvinylstannane 3 was prepared in 60% yield from the reaction of b,b-difluoro-a-phenylvinylsulfone 2 with tri-
butyltin hydride in refluxing benzene for 5 h. The cross-coupling reaction of 3 with aryl iodides bearing substituents such as proton,
fluoro, chloro, bromo, methoxy, methyl, trifluoromethyl, and nitro on ortho, meta, para positions of the benzene ring in the presence
of 10 mol % Pd(PPh3)4/10 mol % CuI afforded the corresponding 2,2-diaryl-1,1-difluoroethenes 4 in 22–82% yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1,1-Difluoroolefins have attracted much attention
because of their unique chemical,1 and biological proper-
ties.2 They exhibit chemical reactivities toward nucleo-
philes3,4 and thus can be utilized as useful synthetic
intermediates for the preparation of fluorinated organic
molecules.5 They are also an important class of potential
mechanism-based inhibitors6 and have been known to
behave as a bioisostere for carbonyl group.7 Although
numerous methods for the preparation of 1,1-difluoro-
olefins have been well documented in the previous litera-
tures,8,9 methods for the preparation of 2,2-diaryl-1,1-
difluoroethenes have been quite limited because the Wittig
reaction for the preparation of 2,2-diaryl-1,1-difluoro-
ethenes was not suitable due to the poor reactivity of the
diaryl ketones toward the difluoromethylene ylide and also
diaryl ketones are not easily available. The modified Wittig
reactions using (diethylphosphinyl)difluoromethyllithium10
or difluoromethyl diphenylphosphine oxide11 afforded the
only 2,2-diphenyl-1,1-difluoroethene. Nowak and Robins
have used (CF3)2Hg/NaI/R3P to generate difluoromethyl-
ene ylide in situ that was reacted with diphenyl ketone to
give 2,2-diphenyl-1,1-difluoroethene.12 Recently, Burton
et al. reported the first preparation of a-halo-b,b-difluoro-
styrene reagent that was functionalized at the halogen site
with arylboronic acids under Pd(0)-catalyzed Suzuki–Miya-
ura coupling reactions to give 2,2-diaryl-1,1-difluoro-
ethenes.13 However, the previous methods have some
drawbacks such as lack of generality10–12 because of less
ready availability of arylboronic acids.13 One promising
approach to 2,2-diaryl-1,1-difluoroethenes is to utilize b,b-
difluoro-a-arylvinylmetal reagents because of their unique
property of the carbon–carbon bond formation via
carbon–metal bond. To the best of our knowledge, the only
b,b-difluoro-a-phenylvinylzinc reagent has been reported as
precursor to provide 2,2-diaryl-1,1-difluoroethenes.13
However, this reagent is stable only in solution and less
thermostable, and thus has some limitation for the
coupling reaction with aryl iodides. Therefore, the develop-
ment of thermostable and isolable b,b-difluoro-a-arylvinyl-
metal reagent is needed to overcome this problem. The
introduction of carbon–stannane functionality into this
metal reagent will provide a stable b,b-difluoro-a-aryl-
vinylstannane which will be a promising precursor to give
2,2-diaryl-1,1-difluoroethenes. Although there have been
but a couple of reports of b,b-difluorovinylstannane which
bears carbamoyloxy14 or MEMO15 at a-position, our atten-
tion has focused on the preparation of b,b-difluoro-a-
phenylvinylstannane, which can be utilized to prepare
unsymmetrically 2,2-diaryl-1,1-difluoroethenes. Herein, we
wish to report the first preparation of novel b,b-difluoro-
a-phenylvinylstannane and its arylation reaction to give
2,2-diaryl-1,1-difluoroethenes.
*
Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 763 4323.
E-mail address: jeongih@yonsei.ac.kr (I.H. Jeong).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.028

J. H. Choi, I. H. Jeong / Tetrahedron Letters 49 (2008) 952–955
953
b,b-Difluoro-a-phenylvinylsulfone will be a potential
starting material for the preparation of b,b-difluoro-a-
phenylvinylstannane because of the successful transforma-
tion of a-fluorovinylsulfone to a-fluorovinylstannane in the
previous literature,16,17 However, this transformation
should be different from that of b-fluorovinylsulfone to
b-fluorovinylstannane because b-fluorovinyl anion formed
as a reaction intermediate18 during the reaction can easily
undergo the b-defluorination reaction. Therefore, the
transformation of b,b-difluoro-a-phenylvinylsulfone to
b,b-difluoro-a-phenylvinylstannane should be carefully
controlled not to bring about the b-defluorination reac-
tion. Precursor of b,b-difluoro-a-phenylvinylsulfone, b,b-
difluoro-a-phenylvinylsulfide 1, was prepared in 78% yield
from 1,1-bis(phenylthio)-2,2,2-trifluoroethylbenzene.19 The
oxidation of 1 with MCPBA (2.2 equiv) in refluxing
CH2Cl2 for 2 h gave the b,b-difluoro-a-phenylvinylsulfone
2 in 96% isolated yield.20
The concentration of 2 in the reaction mixture is also
very important to maximize the yield of 3, in which the best
result was obtained in 0.045 M solution (Table 2). The
lower yields were obtained in either lower concentration
or higher concentration than 0.045 M. It seems to me that
the formation of b,b-difluoro-a-phenylvinylstannane might
be maximized in this concentration by the recombination
of b,b-difluoro-a-phenylvinyl anion and tributyltin cation
as an ion pair intermediate,18 instead of b-defluorination.
We attempted the palladium-catalyzed cross-coupling
reaction of the b,b-difluoro-a-phenylvinylstannane 3 with
a variety of aryl iodides to introduce an aromatic group
at the stannane site. Initially, 3 was reacted with iodoben-
zene in the presence of 10 mol % Pd(PPh3)4/10 mol % CuI
in DMF at room temperature for 24 h, but no desired
product 4a was obtained and the starting material was
recovered from the reaction mixture. The reaction was then
performed in the presence of 10 mol % Pd(PPh3)4/10 mol %
SPh
F
Ph
F
F
Ph
TiCl4 (2 eq)/LiAlH4 (4 eq)
MCPBA (2.2 eq)
CH2Cl2, reflux, 2 h
96%
F3C
C
Ph
THF, reflux, 3 h
78%
SPh
SO2Ph
F
SPh
1
2
First, we examined the stannanylation of 2 with Bu3SnH to
give the corresponding b,b-difluoro-a-phenylvinylstannane
3. When 2 was reacted with Bu3SnH (1.0 equiv) in refluxing
benzene for 5 h, trace amount of the desired product 3 was
observed. The same reaction was performed with 3.0 equiv
of Bu3SnH in refluxing benzene for 5 h to give the desired
product 3 in 32% isolated yield. The optimized reaction con-
dition was achieved using 4.0 equiv of Bu3SnH, in which 321
was obtained in 60% isolated yield. The longer reaction time
(12 h) did not increase the yield of 3, rather decreased the
yield down to 45%. The use of 5.0 equiv of Bu3SnH under
the same reaction condition caused to decrease the yield
(41%) of 3. The use of other solvents such as ether, THF,
and toluene did not provide better results. The results of
these reactions are summarized in Table 1.
CuI in DMF at 50 °C for 9 h to give 4a in 65% isolated
yield. The treatment of 3 with iodobenzene in the presence
of 10 mol % Pd(PPh3)4/10 mol % CuI in DMF at 80 °C for
5 h resulted in the formation of 4a in 80% isolated yield.
However, the coupling reaction between 3 and iodobenzene
did not occur without 10 mol % CuI under the same reac-
tion condition. The use of other solvents such as THF,
ether, benzene, and toluene in this coupling reaction did
not provide the satisfied result. The reaction of 3 with p-
bromobenzene under the optimized reaction condition
afforded 4a in only 22% yield. Similar reactions were then
carried out with aryl iodides having substituents such as
fluoro, chloro, bromo, methyl, methoxy, nitro, and trifluoro-
methyl at ortho, meta, and para positions of the benzene
ring under the optimized reaction condition. The reactions
of 3 with aryl iodides having chloro, methyl, methoxy,
Table 1
Stannanylation of b,b-difluoro-a-phenylvinylsulfone 2
Table 2
F
Ph
F
Ph
Bu3SnH(X eq)/AIBN
solvent, T oC, t h
Stannanylation of b,b-difluoro-a-phenylvinylsulfone 2 under different
concentrations
SO2Ph
SnBu3
F
F
F
F
Ph
F
F
Ph
2
3
Bu3SnH(4.0 eq)/AIBN
benzene, reflux, 5 h
Entry
Solvent
X (equiv)
T (°C)
t (h)
Yielda,b (%)
SO2Ph
SnBu3
c
1
2
3
4
5
6
7
8
a
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
THF
1.0
3.0
4.0
4.0
5.0
6.0
4.0
4.0
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100
5
5
5
12
5
5
—
32
60
45
41
27
2
3
Entry
Concentration (M)
Yielda (%)
b
1
2
3
4
5
a
0.018
0.035
0.045
0.070
0.100
—
43
60
40
15
5
5
Trace
23
Toluene
Isolated yield.
Isolated yield.
All reactions were carried out in 0.045 M solution.
Trace amount was observed.
b
b
c
Trace amount of the product was obtained and most of the starting
material was recovered.

954
J. H. Choi, I. H. Jeong / Tetrahedron Letters 49 (2008) 952–955
nitro, trifluoromethyl on the benzene ring afforded the
corresponding difluoroalkenes 4d–j, 4l–o, 4r in 22–82%
isolated yields. Prolonged reaction time (9 h) was needed
in the reactions of 3 with aryl iodides having fluoro- and
bromo-substituents on the benzene ring and the corres-
ponding difluoroalkenes 4b,c, 4k were obtained in 50–
80% yields. o-Fluoroiodobenzene and o-bromoiodoben-
zene provided 4p and 4q in less than 5% yields from this
reaction. Especially, the reaction of 3 with p-diiodobenzene
under the same reaction condition afforded a double cou-
pling product 4s in 20% yield as well as the formation of
4f in 38% yield. The results of these reactions are summa-
rized in Table 3. 3-Iodo- and 2-iodothiophene also under-
went the cross-coupling reaction with 3 to give the
corresponding 2,2-diaryl-1,1-difluoroethene 4t and 4u in
72% and 61% yields, respectively. However, the reaction
of 3 with 2-iodopyrazine at the same reaction condition
provided a messy reaction mixture.
of Pd catalyst. One experimental result showed that the
total decomposition of 3 was observed from the reaction
of 3 with the same equivalent of CuI only, which indicates
that vinylcopper was formed. The lower yields with ortho-
substituted aryl iodides can be explained by the steric and
electronic effects of ortho-substituted aryl iodides toward
the vinylpalladium intermediate.
A typical reaction procedure for the preparation of 4h is
as follows:
A 15 mL two-neck round-bottom flask
equipped with a magnetic stirrer bar, glass stopper, and
reflux condenser connected to an argon source was charged
with
3 (0.116 g, 0.27 mmol), p-iodotoluene (0.177 g,
0.81 mmol), Pd(PPh3)4 (10 mol %), CuI (10 mol %), and
6 mL of DMF. After the reaction mixture was heated at
80 °C for 5 h, the reaction mixture was cooled to room
temperature and then quenched with water. The reaction
mixture was extracted with ether twice, washed with 5%
KF and brine, dried over anhydrous MgSO4, and chromato-
F
F
Ph
F
F
Ph
F
F
Ph
I
10 mol% Pd(PPh3)4/ 10 mol% CuI
DMF, 80 oC, 5 h
or
+
S
S
SnBu3
S
3
4u (61%)
4t (72%)
Although the role of CuI in the coupling reaction of 3 with
aryl iodides is not clear, it seems likely that CuI facilitates
the transmetalation process of vinlystannane to vinyl-
copper22 and thus speeds the cross-coupling in the presence
graphed on SiO2 column. Elution with a mixture of
n-hexane and ethyl acetate (20:1) provided 4h (0.050 g,
98% GC purity) in 80% yield. 4h: oil; 1H NMR
(400 MHz, CDCl3) d 7.35–7.29 (m, 2H), 7.28–7.25 (m,
2H), 7.14–7.11 (m, 5H), 2.35 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 153.7 (t, J = 293 Hz), 129.6, 129.5,
129.1, 128.6, 128.4, 127.5, 96.1 (t, J = 31 Hz), 21.1; 19F
NMR (376 MHz, CDCl3, internal standard CFCl3) d
À88.68 (d, J = 33.9 Hz, 1F), À88.87 (d, J = 33.9 Hz, 1F);
MS, m/z (relative intensity) 230 (M+, 60), 214 (10), 209
(16), 179 (100), 169 (67), 165 (12), 89 (12). Anal. Calcd
for C15H12F2: C, 78.25; H, 5.25. Found: C, 77.93; H, 5.18.
Table 3
Cross-coupling reactions of 3 with aryl iodides
Y
F
F
Ph
F
F
Ph
Pd(PPh3)4/CuI
DMF, T oC, t h
I (3.0 eq)
+
Y
SnBu3
3
4
Compound no.
Y
T (°C)
t (h)
Yielda (%)
Acknowledgment
4a
4a
4a
4b
4c
4d
4f
H
H
H
25
50
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
24
9
5
9
9
5
5
5
5
5
5
5
5
5
5
5
9
9
5
NRb
65
80
50
73
61
38c
79
80
82
47
80
71
76
48
37
<5
<5
22
This work was supported by the Korea Research Foun-
dation Grant funded by the Korean Government
(MOEHRD, Basic Research Promotion Fund) (KRF-
2006-312-C00241).
p-F
p-Br
p-Cl
p-I
p-OCH3
p-CH3
p-CF3
p-NO2
m-Br
m-CH3
m-CF3
m-NO2
o-CH3
o-F
4g
4h
4i
References and notes
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4j
4k
4l
4m
4n
4o
4p
4q
4r
a
o-Br
2,4-Cl
Isolated yield.
No reaction.
b
c
Double coupling product 4s was obtained in 20% yield.

J. H. Choi, I. H. Jeong / Tetrahedron Letters 49 (2008) 952–955
955
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21. The mixture of 2 (0.50 g, 1.79 mmol), tributyltin hydride (1.92 mL,
7.15 mmol), catalytic amount of AIBN, and 40 mL of benzene was
heated to reflux for 5 h and then cooled to room temperature followed
by quenching with saturated NaCl solution. The mixture was extracted
with ether twice, dried over anhydrous MgSO4, and chromatographed
on SiO2 column. Elution with n-hexane provided 3 (0.461 g, 96% GC
1
purity) in 60% yield. 3: oil; H NMR (400 MHz, CDCl3) d 7.46–7.44
(m, 1H), 7.28–7.22 (m, 2H), 7.14–7.11 (m, 1H), 7.06–7.01 (m, 2H),
1,57–1.44 (m, 6H), 1.36–1.24 (m, 6H), 1.08–0.97 (m, 6H), 0.90–0.82 (m,
9H); 13C NMR (100 MHz, CDCl3) d 153.8 (t, J = 249 Hz), 128.6,
128.3, 128.0, 127.7, 125.9, 85.7 (dd, J = 52, 13 Hz), 28.9, 27.4, 13.6,
10.6; 19F NMR (376 MHz, CDCl3, internal standard CFCl3) d À74.37
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