Efficient synthesis of 2,2-diaryl-1,1-difluoroethenes via consecutive cross-coupling reactions of 2,2-difluoro-1-tributylstannylethenyl p -toluenesulfonate

Article abstract of DOI:10.1021/ol1024037

2,2-Difluoro-1-tributylstannylethenyl p-toluenesulfonate (2) was reacted with aryl iodides in the presence of 10 mol % of Pd(PPh₃)₄ and 10 mol % of CuI in DMF at 80 °C for 10-20 h to give the cross-coupled products 3 in 35-97% yields. Further coupling reaction of 3 with arylstannanes in the presence of 5 mol % of Pd(PPh₃)₄ and 3 equiv of LiBr in DMF at 100 °C for 2-24 h afforded the desired products 5 in 25-78% yields.

Full text of DOI:10.1021/ol1024037

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5518-5521
Efficient Synthesis of
2,2-Diaryl-1,1-difluoroethenes via
Consecutive Cross-Coupling Reactions
of 2,2-Difluoro-1-tributylstannylethenyl
p-Toluenesulfonate
Seung Yeon Han and In Howa Jeong*
Department of Chemistry and Medical Chemistry, Yonsei UniVersity,
Wonju 220-710, Korea
jeongih@yonsei.ac.kr
Received October 5, 2010
ABSTRACT
2,2-Difluoro-1-tributylstannylethenyl p-toluenesulfonate (2) was reacted with aryl iodides in the presence of 10 mol % of Pd(PPh3)4 and 10 mol
% of CuI in DMF at 80 °C for 10-20 h to give the cross-coupled products 3 in 35-97% yields. Further coupling reaction of 3 with arylstannanes
in the presence of 5 mol % of Pd(PPh3)4 and 3 equiv of LiBr in DMF at 100 °C for 2-24 h afforded the desired products 5 in 25-78% yields.
The synthesis of 1,1-difluoroolefins is an important aspect
of organofluorine chemistry since they exhibit chemical
reactivities toward nucleophiles1 and can be utilized as
valuable intermediates for the synthesis of fluorinated organic
molecules via an addition-elimination reaction.2 They are
also known to act as a bioisostere for the carbonyl group,3
and they are important to many biologically active com-
pounds such as mechanism-based enzyme inhibitors.1a,4
Despite their important applications, approaches for the
synthesis of 2,2-diaryl-1,1-difluoroethenes among 1,1-dif-
luoroolefins have been quite limited in the previous literature5
since the Wittig methodology was not suitable for the
synthesis of 2,2-diaryl-1,1-difluoroethenes due to the poor
reactivity of the diaryl ketones toward the difluoromethylene
ylide, and unsymmetrical diaryl ketones are not readily
(1) (a) Bey, P.; McCarthy, J. R.; McDonald, I. A. In SelectiVe
Fluorination in Organic and Bioorganic Chemistry; Welch, J. T., Ed.;
American Chemical Society: Washington, DC, 1991. (b) Chambers, R. D.
In Synthetic Fluorine Chemistry; Olah, G. A., Chambers, R. D., Prakash,
G. K. S., Ed.; Wiley: New York, 1992. (c) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell: Oxford, 2004. (d) Uneyama, K. Organof-
luorine Chemistry; Blackwell: Oxford, 2006.
(4) (a) McDonald, I. A.; Lacoste, J. M.; Bey, P.; Palfreyman, M. G.;
Zreika, M. J. Med. Chem. 1985, 28, 186–193. (b) McCarthy, J. R.;
Matthews, D. P.; Semeric, D. M.; Huber, E. W.; Bey, P.; Lippert, B. J.;
Snyder, R. D.; Sunkara, P. S. J. Am. Chem. Soc. 1991, 113, 7439–7440.
(c) Madden, B. A.; Prestwich, D. G. Bioorg. Med. Chem. Lett. 1997, 7,
309–314. (d) Weintraub, P. M.; Holland, A. K.; Gates, C. A.; Moore, W. R.;
Resvick, R. J.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. 2003, 11, 427–
(2) (a) Hayashi, S.; Nakai, T.; Ichikawa, N. Chem. Lett. 1980, 651–
654. (b) Ichikawa, J.; Wada, Y.; Okauchi, T.; Minami, T. J. Chem. Soc.,
Chem. Commun. 1997, 1537–1538. (c) Ichikawa, J.; Wada, Y.; Fujiwara,
M.; Sakoda, K. Synthesis 2002, 1917–1936. (d) Ichikawa, J.; Miyazaki,
H.; Sakoda, K.; Wada, Y. J. Fluorine Chem. 2004, 125, 585–593. (e)
Ichikawa, J.; Sakoda, K.; Moriyama, H.; Wada, Y. Synthesis 2006, 1590–
1598.
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(5) (a) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K. Tetrahedron Lett.
1982, 23, 2323–2326. (b) Edwards, M. L.; Stemerick, D. M.; Jarvi, E. T.;
Matthews, D. P.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5571–5574.
(c) Nowak, I.; Robins, J. M. Org. Lett. 2005, 7, 721–724. (d) Raghavanpillai,
A.; Burton, D. J. J. Org. Chem. 2006, 71, 194–201. (e) Choi, J. H.; Jeong,
I. H. Tetrahedron Lett. 2008, 49, 952–955.
(3) Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc., Chem.
Commun. 1989, 1437–1438.
10.1021/ol1024037  2010 American Chemical Society
Published on Web 11/02/2010

available.6 The organometallic approaches for the synthesis
of various 1,1-difluoroalkenes also cannot be utilized to
prepare 2,2-diaryl-1,1-difluoroalkenes. Specific 1,1-difluoro-
2,2-diphenylethene was prepared from the modified Wittig
reactions of diphenyl ketone with (diethylphosphinyl)-
difluoromethyllithium5a or difluoromethyl diphenylphosphine
oxide.5b Nowak and Robins also prepared 1,1-difluoro-2,2-
diphenylethene from the reaction of diphenyl ketone with
difluoromethylene ylide generated in situ by heating
(CF3)2Hg and NaI with triphenylphosphine.5c Burton et al.
reported a general and efficient method for the synthesis of
2,2-diaryl-1,1-difluoroethenes, in which R-aryl-R-halo-ꢀ,ꢀ-
difluorostyrenes synthesized by the coupling reaction of the
corresponding R-halo-ꢀ,ꢀ-difluoroethenylzinc reagents with
aryl iodides were functionalized at the halogen site via
Suzuki-Miyaura coupling reactions.5d Recently, we prepared
ꢀ,ꢀ-difluoro-R-phenylvinylstannane that was functionalized
to give 2,2-diaryl-1,1-difluoroethenes via Pd(0)/CuI-catalyzed
coupling reaction with aryl iodides.5e However, the previous
methods have some drawbacks such as lack of generality,5a-c
tedious procedure,5a,b,e the use of expensive starting
material,5d,e and moisture-sensitive vinylmetal reagents.5a,b,d
Herein, we report a concise and efficient method for 2,2-
diaryl-1,1-difluorethenes via a consecutive cross-coupling
reaction of 2,2-difluoro-1-tributylstannylethenyl p-toluene-
sulfonate.
tributylstannyl chloride. Then, we attempted the palladium-
catalyzed cross-coupling reaction of 2 with aryl iodides to
introduce an aromatic group at the stannane site.
When 2 was reacted with iodobenzene in the presence of
10 mol % of Pd(PPh3)4 and 10 mol % of CuI in THF at
reflux temperature for 10 h, the cross-coupled product 3a
was obtained in 56% yield along with the reducing product
4 in 24% yield. The longer reaction time (24 h) promoted
the yield of 3a up to 70%. After monitoring of the reaction
under the different solvents and reaction temperature and
time (Table 1), we found that the use of DMF at 80 °C for
Table 1. Optimization Reaction of 2 with Iodobenzene
yield (%)a
entry
solvent
t (°C)
t (h)
3a
4
1b
2
3
THF
DMF
DMF
DMF
DMF
DMF
reflux
50
80
80
80
10
10
3
5
10
56
43
70
79
94
40
24
45
20
10
0
4
5
6c
80
10
50
2,2-Difluoro-1-tributylstannylethenyl p-toluenesulfonate
could be a remarkable precursor of 2,2-diaryl-1,1-difluoro-
ethenes because it has two functionally different coupling
partners at the same position such as the nucleophilic
tributylstannyl and electrophilic tosylate groups. The ret-
rosynthetic pathway for 2,2-diaryl-1,1-difluoroethenes is
outlined in Scheme 1.
a Isolated yield. b Starting material (10%) was recovered. c Only
Pd(PPh3)4 was used.
10 h provided 3a in 94% yield without any detected 4 (entry
5). It seems likely that 3a was formed not only from 2 but
also from 4. The use of only Pd(PPh3)4 as catalyst under the
same reaction condition resulted in the formation of 3a in
only 40% yield along with 50% yield of 4. A similar result
was obtained by using a mixture of Pd(PPh3)2Cl2 and CuI
as catalyst. Although the role of CuI in this coupling is not
clear, CuI may facilitate the transmetalation process to give
vinylcopper which speeds the cross-coupling reaction in the
presence of Pd catalyst.9 Coupling reaction of 2 with
bromobenzene under the same reaction condition afforded
the only reducing product 4.
Optimized reaction conditions (reaction time is 10-20 h)
were applied to prepare a variety of cross-coupled products
3b-o via reaction between 2 and aryl iodides having fluoro,
chloro, bromo, methoxy, methyl, trifluoromethyl, and nitro
on the benzene ring. Except for aryl iodides having an ortho
substituent (CH3, OCH3) or electron-withdrawing group
(NO2, CF3), the coupling reactions provided excellent yields
(81-97%) of 3. (Table 2). The longer reaction time (18-
20 h) was required for the reaction with aryl iodides having
the m-CF3, o-OCH3, or o-CH3 substituent, giving relatively
low yields (58-68%).
Scheme 1
Surprisingly, given the extensive use of 2,2-difluoroethe-
nylstannane having a carbamate7 or OMEM group8 at the
R-position, there was no report of a synthesis of 2,2-difluoro-
1-tributylstannylethenyl p-toluenesulfonate in the previous
literature.
2,2-Difluoro-1-tributylstannylethenyl p-toluenesulfonate
(2) was easily prepared in 90% yield from the reaction of
2,2,2-trifluoroethyl p-toluenesulfonate (1) with 2 equiv of
LDA in THF at -78 °C, followed by treatment with
(6) (a) Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A. Tetrahedron
Lett. 1993, 34, 7595–7598. (b) Taber, D. F.; Sethuraman, M. R. J. Org.
Chem. 2000, 65, 254–255.
Heteroaryl iodides such as 2-iodothiophene and 3-iodot-
hiophene also underwent coupling reactions with 2 under
(7) (a) Crowley, P. J.; Howarth, J. A.; Owton, W. M.; Percy, J. M.;
Stansfield, K. Tetrahedron Lett. 1996, 37, 5975–5978. (b) Crowley, P. J.;
Percy, J. M.; Stansfield, K. Tetrahedron Lett. 1996, 37, 8233–8236.
(8) (a) Patel, S. T.; Percy, J. M.; Wilkes, R. D. Tetrahedron 1995, 51,
9201. (b) DeBoos, G. A.; Fullbrook, J. J.; Percy, J. M. Org. Lett. 2001, 3,
2859.
(9) Behling, J. R.; Babiak, K. A.; Ng, J. S.; Campbell, A. L. J. Am.
Chem. Soc. 1988, 110, 2641–2643.
Org. Lett., Vol. 12, No. 23, 2010
5519

lates which are relatively unreactive compared to vinyl triflate
would be of significant interest because tosylates are more
easily handled and considerably less expensive than vinyl
triflates. Although there were several examples of the
palladium-catalyzed cross-coupling reactions of vinyl tosy-
lates derived from only R,ꢀ-unsaturated esters with aryl or
vinyl boronic acids,11 arylstannane,12 or organozinc re-
agents,13 to our knowledge there are no reports of coupling
fluorinated vinyl tosylate with organometallic reagents.
Therefore, we investigated the coupling reaction of vinyl
tosylate 3a with phenyl boronic acid or tributylphenylstan-
nane as a coupling partner. First, when Suzuki-Miyaura
cross-coupling reaction of 3a was performed with phenyl
boronic acid in the presence of 5 mol % of Pd(PPh3)2Cl2
and Na2CO3 or Cs2CO3 in THF at reflux temperature for 28 h,
conversion of 3a was incomplete, and extensive formation
of biphenyl via self-coupling reaction of the boronic acid
was observed. We then turned our attention to arylstannane
as a coupling partner of 3a (Table 3).
Table 2. Preparation of 2,2-Difluoro-1-arylethenyl
p-Tolunenesulfonate (3)
compound no.
R
t (h)
yield (%)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
H
p-F
p-Cl
p-Br
p-OCH3
p-CH3
p-NO2
m-F
m-Cl
m-Br
m-OCH3
m-CH3
m-CF3
o-OCH3
o-CH3
10
12
12
14
12
12
14
12
12
14
12
12
20
18
18
94
97
96
93
85
88
35
95
96
94
90
81
68
68
58
Table 3. Optimization Reaction of 3a with Tributylphenyl
Stannane
a Isolated yield.
similar conditions to give the cross-coupled products 3p and
3q in 65% and 79% yields, respectively (Scheme 2).
entry
MX
solvent
t (°C)
t (h)
yield (%)a
Scheme 2
1
2
3
4
5
6
7
8
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiBr
THF
reflux
reflux
reflux
25
50
80
24
24
24
24
24
18
8
60
62
61
NRb
73
73
74
78
DME
Dioxane
DMF
DMF
DMF
DMF
DMF
100
100
2
a Isolated yield. b No reaction occurred.
When 3a was reacted with tributylphenylstannane (1.2
equiv) in the presence of Pd(PPh3)4 (5 mol %) and LiCl (3
equiv) in THF at reflux temperature for 24 h, the desired
product 5a was obtained in 60% yield (entry 1). Similar
results were obtained with DME or dioxane as a solvent
(entries 2 and 3). The use of DMF as a solvent at 100 °C in
this reaction caused an increase in the yield of 5a with
relatively short reaction time (entries 5-7). The best result
for the formation of coupling product 5a was established
with the use of catalyst derived from 5 mol % of Pd(PPh3)4
and 3 equiv of LiBr in DMF (entry 8). In this case, the
reaction was complete in 2 h at 100 °C. However, arylstan-
nanes, having an electron-withdrawing group in the aromatic
However, product 3p slowly underwent the polymerization
after isolation of product. When 2 (2.5 equiv) was reacted
with m-diiodobenzene and p-diiodobenzene having two
reaction sites under the similar conditions, the cross-coupled
products 3r and 3s were obtained in 61% and 55% yields,
respectively.
We chose 2,2-difluoro-1-phenylethenyl p-toluenesulfonate
(3a) as a second coupling partner. The Stille coupling
reaction using vinyl triflate is of great practical importance
in carbon-carbon bond formation.10 However, vinyl tosy-
(10) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033–3040.
(11) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies, I. W. Org.
Lett. 2005, 7, 215–218.
(12) Schio, L.; Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41,
1543–1547.
(13) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642–3645.
5520
Org. Lett., Vol. 12, No. 23, 2010

ring, underwent the coupling reaction in much longer reaction
time to produce the corresponding cross-coupled product 5j.
The coupling reaction was also slower in the case of
arylstannanes having a substituent in the ortho position of
the benzene ring (synthesis of 5d). To check the reactivity
of 3 in the coupling reaction with arylstannane, we attempted
the reaction of 2,2-difluoro-1-arylethenyl p-toluenesulfonate
3 having an electron-donating or electron-withdrawing group.
Vinyl tosylates 3e and 3f having an electron-donating group
underwent coupling reaction in 20-24 h to give the coupling
products 5e and 5f, whereas the coupling reactions of vinyl
tosylate 3m having an electron-withdrawing group were
complete in 3 h. Vinyl tosylates 3r having two tosylate
groups as coupling partners also underwent the coupling
reaction with 2.5 equiv of tributylphenylstannane in 6 h to
give the cross-coupled product 5m in 75% yield (Scheme
3). Finally, heteroarylstannanes such as 2-(tributylstannyl)
Table 4. Preparation of 2,2-Diaryl-1,1-difluoroethenes (5)
compound no.
R
R′
t (h)
yield (%)a
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
H
2
3
6
24
20
24
3
3
3
24
78
75
60
25
58
53
55
61
75
57
p-CH3
p-Cl
o-CH3
H
H
H
p-CH3
m-CH3
m-CF3
m-CH3
p-OCH3
m-CF3
m-CF3
p-Cl
5j
p-Cl
a Isolated yield.
Scheme 3
yield the corresponding bis(organo)palladium(II) complex,
which quickly undergoes reductive elimination to give the
coupled product 5.
In summary, we have developed a new and efficient
method for the synthesis of 2,2-diaryl-1,1-difluoroethenes
from the consecutive coupling reactions of 2,2-difluoro-1-
tributylstannylethenyl p-toluenesulfonate. This method has
several advantages such as satisfaction of generality, use of
inexpensive starting material, relatively simple procedure,
and easy handling of reagents.
Acknowledgment. This work was supported by the Basic
Research Grant (2009-0073839) funded by the National
Research Foundation of Korea.
thiophene and 2-(tributylstannyl) furan are also successfully
reacted with 3a under similar reaction conditions to produce
the cross-coupled products 5k and 5l in 65% and 68% yields,
respectively (Scheme 3). The cross-coupling reactions of 3
with a variety of arylstannanes under the optimized condi-
tions were summarized in Table 4. The plausible mechanism
involves the initial oxidative addition of 3 to the palladium(0)
catalyst followed by transmetalation of the arylstannane to
Supporting Information Available: Experimental details
and characterization data of 2, 3a-3s, and 5a-5m, and 1H,
13C, and 19F NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1024037
Org. Lett., Vol. 12, No. 23, 2010
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