New efficient approach to 2,2-diaryl-1,1-difluoro-1-alkenes and 1,1-difluoro-2-aryl-1,3-dienes via Suzuki coupling of α-halo-β, β-difluorostyrenes

Article abstract of DOI:10.1021/jo051842p

α-Halo-β,β-difluorostyrenes [ArCX = CF₂; X = Br, I; Ar = aryl, heteroaryl; synthesized by the Pd(0)-catalyzed coupling reaction of the corresponding α-halo-β,β-difluoroethenylzinc reagents (CF₂=CXZnCl, X = Br, I) with aryl iodides] were functionalized at the halogen site with arylboronic acids under Pd(0)-catalyzed Suzuki-Miyaura coupling reaction conditions to obtain 2,2-diaryl-1,1-difluoro-1-alkenes (ArAr'C=CF₂, Ar' = aryl, heteroaryl) in 51-91% isolated yield. The corresponding reaction with alkenylboronic acids produced 1,1-difluoro-2-aryl-1, 3-dienes in 53-80% isolated yield. Alternatively, 2,2-disubstituted-1,1- difluoro-1-alkenes were synthesized in moderate yield by a zinc-insertion reaction at the halogen site of the α-halo-β,β-difluorostyrenes, followed by Pd(0)-catalyzed cross-coupling of the zinc reagent with aryl or alkenyl iodides.

Full text of DOI:10.1021/jo051842p

New Efficient Approach to 2,2-Diaryl-1,1-difluoro-1-alkenes and
1,1-Difluoro-2-aryl-1,3-dienes via Suzuki Coupling of
r-Halo-â,â-difluorostyrenes
Anilkumar Raghavanpillai† and Donald J. Burton*
Department of Chemistry, The UniVersity of Iowa, Iowa City, Iowa 52242
donald-burton@uiowa.edu
ReceiVed August 31, 2005
R-Halo-â,â-difluorostyrenes [ArCX ) CF2; X ) Br, I; Ar ) aryl, heteroaryl; synthesized by the
Pd(0)-catalyzed coupling reaction of the corresponding R-halo-â,â-difluoroethenylzinc reagents
(CF2dCXZnCl, X ) Br, I) with aryl iodides] were functionalized at the halogen site with arylboronic
acids under Pd(0)-catalyzed Suzuki-Miyaura coupling reaction conditions to obtain 2,2-diaryl-1,1-difluoro-
1-alkenes (ArAr′CdCF2, Ar′ ) aryl, heteroaryl) in 51-91% isolated yield. The corresponding reaction
with alkenylboronic acids produced 1,1-difluoro-2-aryl-1,3-dienes in 53-80% isolated yield. Alternatively,
2,2-disubstituted-1,1-difluoro-1-alkenes were synthesized in moderate yield by a zinc-insertion reaction
at the halogen site of the R-halo-â,â-difluorostyrenes, followed by Pd(0)-catalyzed cross-coupling of the
zinc reagent with aryl or alkenyl iodides.
Introduction
carbonyl group.1,7 The synthesis of 1,1-difluoroalkenes can be
achieved by various methods that can be generalized into two
broad strategies, Wittig-type chemistry and other methods.8
In Wittig and related syntheses, a difluoromethylene unit is
introduced to aldehydes or ketones via a difluoromethylene
ylide.9 The first synthetically useful preparation of a difluo-
romethylene ylide involved the reaction of triphenylphosphine
1,1-Difluoro-1-alkenes, in general, constitute a class of fluoro-
organic compounds with interesting chemical,1 material,2 and
biological properties.3 They exhibit unique chemical reactivities
toward addition reactions,4 can be reduced to monofluoro-
alkenes, and are, therefore, considered an important intermediate
en route to other classes of fluorinated organic molecules.5 1,1-
Difluoroalkenes are also potential mechanism-based inhibitors6
and are known to behave as a bioisosteric replacement of a
(4) (a) Ichikawa, J.; Wada, W.; Okauchi, T.; Minami, T. J. Chem. Soc.,
Chem. Commun. 1997, 1537-1538. (b) Kendrick, D. A.; Kolb, M. J.
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† Current address: DuPont Central Research & Development, Experimental
Station, Wilmington, DE 19880, U.S.A.
(1) (a) Chemistry of Organic Fluorine Compounds, 2nd ed.; Hudlicky,
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fluorine Chemistry: Principles and Commercial Applications; Banks, R.
E., Tatlow, J. C., Smart, B. E., Eds.; Plenum Press: New York, 1994.
(2) (a) Reynolds, D. W.; Cassidy, P. E.; Johnson, C. G.; Cameron, M.
L. J. Org. Chem. 1990, 55, 4448-4454. (b) Emsley, J. New Sci. 1989, 122
(April 22), 46. (c) Mukai, H.; Ikukawa, S.; Nakayama, S.; Ito, A. Japanese
Patent. JP 7138204, 1995.
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Symposium Series No. 456; Welch, J. T., Ed.; American Chemical
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10.1021/jo051842p CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/01/2005
194
J. Org. Chem. 2006, 71, 194-201

Synthesis of 2,2-Disubstituted-1,1-difluoro-1-alkenes
and sodium chlorodifluoroacetate with carbonyl compounds.10
However, this route was useful only for aldehydes and poly-
fluorinated ketones to obtain the corresponding 1,1-difluoro-
alkenes and was unsuccessful for nonactivated ketones. The
reaction between nonstabilized alkylidene triphenylphosphorane
and halodifluoromethanes has been found to be a useful
alternative to the above reaction but was not practical for
nonfluorinated ketones. Reagents such as tris(dimethylamino)-
phosphine were required in the Wittig reaction with dibromodi-
fluoromethane to effect this conversion.11 Recently, 1,1-
difluoroalkenes were synthesized using the Wittig method in
moderate yield from in situ generated 1,1-difluoromethylene-
phosphorus ylides [generated from (CF3)2Hg/NaI and a suitable
phosphine] with aldehydes and ketones.12 The synthesis of 1,1-
difluoroalkenes by Wittig-Horner-Emmons chemistry is also
known, where the reaction of diethyl 2-oxo-1,1-difluoropropyl-
phosphonate with Grignard reagents produced 1,1-difluoro-
alkenes.13 A more general entry to 1,1-difluoroalkenes by Wittig-
type chemistry was by the reaction of (diethylphosphonyl)difluoro-
methyllithium14 or lithium difluoromethyldiphenylphosphine
oxide with ketones and aldehydes.6d,e,15
SCHEME 1
1,1-difluoroalkenes were synthesized in two steps from 1-tri-
fluoromethylethenylsilane, which involved an SN2′ reaction of
1-trifluoromethylethenylsilane with nucleophiles to construct
2,2-difluoroethenylsilanes and the subsequent substitution of the
ethenylic silyl group with electrophiles to produce the desired
1,1-difluoroalkene.19 The synthesis of 1,1-difluoroalkenes by
electrophilic mono- or difluorination20 of the corresponding
precursor or by the thermal decomposition of R,R-difluoro-â-
lactones has also been reported.21 A facile synthesis of 1,1-
difluoroalkenes by a base-induced elimination of alkyl-sub-
stituted difluoromethyl sulfones [prepared by the reaction of
alkyl halides with in situ generated (benzenesulfonyl)difluo-
romethide] has recently been reported.22
We have recently developed an efficient room-temperature
methodology for the synthesis of R,â,â-trifluorostyrene from
the readily available environmentally friendly precursor HFC-
134a (CF3CH2F).23 Metalation of HFC-134a with LDA in the
presence of a zinc halide, followed by the Pd(0)-catalyzed
coupling of the in situ generated trifluoroethenylzinc reagent
with aryl iodides, produced R,â,â-trifluorostyrenes in very good
isolated yields (Scheme 1). This methodology was later applied
to a convenient general synthesis of R-halo-â,â-difluorostyrenes
(Cl, Br, I) via the corresponding R-halo-â,â-difluoroethenylzinc
reagents using commercially available precursors (Scheme 1).24
The R-halo-â,â-difluorostyrenes (Cl, Br, I) thus generated could
potentially be used as important synthons in organofluorine
chemistry because they can be functionalized at the halogen
site as well as the terminal olefin site to produce other
chemically or biologically important organofluorine compounds.
To functionalize the halogen site of the R-halo-â,â-difluo-
rostyrenes, the most attractive and simple pathway was a
palladium-catalyzed cross-coupling reaction with an aryl or
alkenylboronic acid to produce the corresponding 2,2-diaryl-
1,1-difluoroalkenes or 1,1-difluoro-2-aryl-1,3-dienes.25 The
general Wittig methodology discussed for the synthesis of 1,1-
difluoroalkenes was not suitable for the synthesis of 2,2-diaryl-
1,1-difluoroalkenes as a result of the poor reactivity of the diaryl
ketones in the Wittig reaction; even with the modified chemistry,
the only product thus synthesized was 2,2-diphenyl-1,1-difluo-
The alternative methods for the synthesis of 1,1-difluoro-
alkenes are generally based on metalation or related chemistry
involving the addition of stabilized difluoroethenylanions16 to
electrophiles or to aryl and alkenyl iodides by palladium
catalysis.17 1,1-Difluoroalkenes with a wide range of substituents
were readily synthesized from commercially available 2,2,2-
trifluoroethyl p-toluenesulfonate via boron-, copper-, zinc-, or
zirconium-mediated intermediates.18 In a recent report, various
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Group Transformations II; Katritzky, A. R., Taylor, J. K., Eds.; Elsevier:
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247-259.
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1982, 23, 2323-2326. (b) Piettre, S. R.; Cabanas, L. Tetrahedron Lett.
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1986, 303, 309-315. (b) Gillet, J. P.; Sauvetre, R.; Normant, J. F. Synthesis
1986, 538-543. (c) Tellier, F.; Sauvetre, R.; Normant, J. F. J. Organomet.
Chem. 1987, 328, 1-13. (d) Tellier, F.; Sauvetre, R.; Normant, J. F. J.
Organomet. Chem. 1987, 331, 281-298. (e) Ichikawa, J.; Minami, T.;
Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1992, 33, 3779-3782. (f)
Ichikawa, J.; Ikeura, C.; Minami, T. Synlett 1992, 739-740.
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cited therein).
(19) Ichikawa, J.; Fukui, H.; Ishibashi, Y. J. Org. Chem. 2003, 68, 7800-
7805.
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J. R. Tetrahedron Lett. 1996, 37, 3223-3226.
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J. Org. Chem, Vol. 71, No. 1, 2006 195

Raghavanpillai and Burton
TABLE 1. Coupling Reactions of Various
SCHEME 2
SCHEME 3
r-Halo-â,â-difluorostyrenes with 4-Fluorophenyl- or
1-Naphthylboronic Acids
entry
X
Ar
product
time (h)
yield (%)
1
2
3
4
5
Cl
Br
Br
I
4-FC6H4-
4-FC6H4-
1-naphthyl
4-FC6H4-
1-naphthyl
24
8
12
14
32
NR
81
79
86
88
1
2
1
2
roethene.12,14,15 Unsymmetrically substituted 2,2-diaryl-1,1-
difluoroethenes are generally not readily available, and their
synthesis by the Witting method requires suitable unsymmetrical
diaryl ketones, which in turn need to be obtained either by
aroylation of suitable arylorganometallics or by Friedel-Crafts
acylation.26 The organometallic routes described for the suc-
cessful synthesis of various 1,1-difluoroalkenes were also not
useful for the synthesis of 2,2-diaryl-1,1-difluoroalkenes. Hence,
we chose to functionalize the halogen site of the R-halo-â,â-
difluorostyrenes by a palladium-catalyzed cross-coupling reac-
tion and thus provide a novel convenient synthetic route for
both symmetrical and unsymmetrical 2,2-diaryl-1,1-difluoro-
ethenes, a useful addition in the 1,1-difluoroalkenes genus. The
retrosynthetic pathway for the 2,2-diaryl-1,1-difluoroalkenes
from commercially available fluorocarbons is outlined in
Scheme 2.
I
a A total of 3-5% self-coupled product.
chose 4-fluorophenylboronic acid as our coupling partner
because the course of the reaction could be monitored via 19F
NMR with respect to both coupling partners. Thus, R-chloro-
â,â-difluorostyrene was heated with 4-fluorophenylboronic acid,
aqueous K2CO3 (1 M), and 5 mol % Pd(PPh3)4 in a benzene-
ethanol medium for 24 h, as per a typical reaction condition
described for the palladium-catalyzed cross-coupling reaction
of fluorinated vinyl bromides and arylboronic acids.25a,28 The
19F NMR spectrum of the reaction mixture at various time
intervals did not indicate any formation of 2-(4-fluorophenyl)-
2-phenyl-1,1-difluoroethene (1; Table 1), and from the reaction
mixture, R-chloro-â,â-difluorostyrene was recovered quantita-
tively. A small amount (3%) of a new product isolated from
this reaction mixture was the self-coupled product of the boronic
acid, 4,4′-difluorobiphenyl.29 The lack of reactivity of the
R-chloro-â,â-difluorostyrene in this reaction was presumably
due to the poor reactivity of the internal chlorine to undergo
oxidative addition.30 Similar experiments were then performed
with R-bromo-â,â-difluorostyrene and R-iodo-â,â-difluorosty-
rene, and the results are summarized in Table 1.
Results and Discussion
Functionalization at the Halogen Site of r-Halo-â,â-
difluorostyrenes Using Arylboronic Acids. The R-halo-â,â-
difluorostyrene, in general, was prepared by the room-
temperature metalation/coupling method described in our previous
reports.24 Metalation of 1 equiv of CF3CH2Cl (HCFC-133a),
CF3CH2Br, or CF3CH2I with 2 equiv of LDA in the presence
of ZnCl2 at 15 °C generated the corresponding R-halo-â,â-
difluoroethenylzinc reagents (CF2dCXZnCl, X ) Cl, Br, I).
The Pd(0)-catalyzed coupling reaction of these zinc reagents
with aryl iodides produced the corresponding R-halo-â,â-
difluorostyrenes in excellent isolated yields (Scheme 1). R-Bromo-
â,â-difluorostyrenes were alternatively prepared either by the
metalation of CF2dCHBr with LDA in the presence of
ZnCl2 followed by the palladium-catalyzed coupling reaction
of the zinc reagent with aryl iodides or by a zinc insertion into
CF2dCBr2 followed by the Pd(0)-catalyzed coupling reaction
of the zinc reagent with aryl iodides (Scheme 3).24c, 27
The coupling reaction between R-bromo-â,â-difluorostyrene
and 4-fluorophenylboronic acid proceeded smoothly in 8 h with
the complete disappearance of the styrene and boronic acid. 19
F
NMR analysis of the reaction mixture revealed that the cross-
coupled product 1 was formed in 93% yield along with a small
amount of the self-coupled product (4,4′-difluorobiphenyl; 4%).
The workup and purification of the reaction mixture produced
an 81% isolated yield of 1. When 1-naphthylboronic acid was
used as a coupling partner with the R-bromo-â,â-difluorostyrene,
the reaction was complete in 12 h and produced the cross-
coupled product 2 in 79% isolated yield. The coupling reaction
was then performed with R-iodo-â,â-difluorostyrene with the
anticipation of a faster reaction, but with 4-fluorophenylboronic
acid under similar reaction conditions a relatively slower reaction
resulted. The reaction was complete in 14 h to produce a clean
reaction mixture from which the cross-coupled product 1 was
isolated in 86% yield. The coupling reaction was much slower
in the case of 1-naphthylboronic acid with R-iodo-â,â-difluo-
rostyrene, where the reaction was complete only after 32 h under
similar conditions as those used for the coupling reaction of
Initially, we attempted the palladium-catalyzed cross-coupling
reaction of the R-halo-â,â-difluorostyrenes with arylboronic
acids to introduce an aromatic group at the halogen site. We
(25) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Hassan, J.; Sevington, M.; Gozzi, C.; Schultz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359-1469. (c) Suzuki, A. In Metal Catalyzed Cross-Coupling
reactions; Diederich, F., Stang, P. J., Eds.; VCH: Weinheim, Germany,
1998; pp 49-97. (d) Suzuki, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New
York, 2002; Vol. 1, pp 249-263.
(26) (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988, 110,
1557-1565. (b) Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A.
Tetrahedron Lett. 1993, 34, 7595-7598. (c) Devasagayaraj, A.; Knochel,
P. Tetrahedron Lett. 1995, 36, 8411-8414. (d) Taber, D. F.; Sethuraman,
M. R. J. Org. Chem. 2000, 65, 254-255.
(28) Chen, C.; Wilkoxen, K.; Huang, C. Q.; Strack, N.; McCarthy, J. R.
J. Fluorine Chem. 2000, 101, 285-290.
(29) Courtois, V.; Barhdadi, R.; Troupel, M.; Perichon, J. Tetrahedron
1997, 53, 11569-11576.
(30) (a) Grudhim, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(b) Fitton, P.; Rick, E. A. J. Organomet. Chem. 1971, 28, 287-291.
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196 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of 2,2-Disubstituted-1,1-difluoro-1-alkenes
TABLE 2. Coupling Reactions of
2-Bromo-2-(4-methoxyphenyl)-1,1-difluoroethene with Various
Arylboronic Acids
R-bromo-â,â-difluorostyrene and 1-naphthylboronic acid. From
this reaction mixture, the cross-coupled product was isolated
in 88% yield. This observation suggests that the bulky halogen,
the boronic acid, or both sterically influence the coupling
reaction of the R-halo-â,â-difluorostyrenes with arylboronic
acids.
The lack of reactivity of the R-chloro-â,â-difluorostyrene and
the relatively longer reaction time in the coupling reaction of
the R-iodo-â,â-difluorostyrene prompted us to consider the
R-bromo-â,â-difluorostyrene as our major coupling partner for
the further reactions. We then attempted this synthesis in a one-
pot reaction, where the R-bromo-â,â-difluoroethenylzinc reagent
(prepared by the metalation of CF3CH2Br in a THF medium)
was coupled with iodobenzene to obtain R-bromo-â,â-difluo-
rostyrene. The crude reaction mixture was then heated with
4-fluorophenylboronic acid and additional Pd(0) catalyst (5 mol
%) for 24 h. The 19F NMR analysis of the reaction mixture did
not show any cross-coupled product formation. In another
experiment, the crude mixture of R-bromo-â,â-difluorostyrene
obtained by the Pd(0)-catalyzed coupling of the R-bromo-â,â-
difluoroethenylzinc reagent and iodobenzene was heated with
additional Pd(0) catalyst (5 mol %), aqueous K2CO3, and
4-fluorophenylboronic acid for 24 h, but no cross-coupled
product was observed. We then performed a solvent exchange,
where THF/hexane from the crude solution of R-bromo-â,â-
difluorostyrene was substituted with benzene/ethanol (5:1), and
the coupling reaction was performed with 4-fluorophenylboronic
acid, aqueous K2CO3, and additional Pd(0) catalyst (5 mol %);
unfortunately, even in this reaction, we did not observe any
cross-coupled product formation. Thus, our attempts to perform
the successive coupling reactions in one pot failed to give a
fruitful result, and it was desirable to isolate the R-bromo-â,â-
difluorostyrenes before performing the second coupling reaction.
A side reaction was noted during the palladium-catalyzed cross-
coupling reaction of R-bromo-â,â-difluorostyrene with aryl-
boronic acids, namely, the formation of a small amount of the
self-coupled product of the arylboronic acids. Self-coupling of
aryl groups of the arylboronic acids is well-documented in the
literature;25b,31 the self-coupling process usually occurs when
the cross-coupling process is slow. Suzuki-Miyaura reactions
involving electron-donating aromatic halides and the presence
of oxygen are known to produce more self-coupled product.
Recent developments in this field demonstrated that the self-
coupling of arylboronic acids can be used as an effective
methodology for the quantitative preparation of biaryls by the
modification of the reaction conditions in the boronic acid
coupling reactions.32 Our cross-coupling partner, R-bromo-â,â-
difluorostyrene, being an internal halide, is expected to have a
longer reaction time in this coupling process and thus accounts
for the formation of a small amount (typically 3-5%) of the
self-coupled product. The separation of the self-coupled product
entry
Ar
product (3-8)
time (h)
yield (%)
1
2
3
4
C6H5-
3
4
5
6
7
8
5
8
12
12
12
10
79
85
85
72
78
51
1-naphthyl
4-FC6H4-
3-O2NC6H4-
3,5-dimethylphenyl
3-thienyl
5
6b
a A total of 3-6% self-coupled product. b A total of 2.2 equiv of boronic
acid was used; 8% of 3,3′-bithiopheneyl was formed.
from the cross-coupled product in some cases was difficult due
to their close Rf values and, therefore, requires careful chro-
matography. To reduce or eliminate the self-coupling reaction,
several alternative coupling conditions, such as using a stronger
base (NaOH), increasing the amount of base (5 equiv), using
different solvents (THF, acetone), and increasing the amount
of catalyst (10 mol %), were also attempted but failed to improve
the reaction or resulted in a more complex reaction mixture. In
one of those noteworthy trials, 1-bromo-2,2-difluorostyrene was
heated with 4-fluorophenylboronic acid, aqueous NaOH, and 5
mol % Pd(PPh3)4 in a THF medium for 12 h. A 19F NMR
analysis of the reaction mixture revealed that the cross-coupled
product 1 was formed in 65% yield along with the self-coupled
product (4%) and unreacted 1-bromo-2,2-difluorostyrene (20%).
To check the generality of this reaction with various aryl
or heteroarylboronic acids, we chose 2-bromo-2-(4-methoxy-
phenyl)-1,1-difluoroethene as our coupling partner. The cross-
coupled product in this case is expected to be significantly
different in Rf value than that of the self-coupled product, which
facilitates the easy isolation of the cross-coupled product. Even
though aryl halides, having electron-donating groups, are
relatively less efficient coupling partners in the Pd(0)-catalyzed
cross-coupling reaction with boronic acids,25b,33 the coupling
reaction of 2-bromo-2-(4-methoxyphenyl)-1,1-difluoroethene
with various boronic acids proceeded well under the typical
reaction conditions described earlier to give the corresponding
cross-coupled products (3-8) in good isolated yield along with
traces of the self-coupled product (3-6%) and some unidentified
byproducts (Table 2). 2-Bromo-2-(4-methoxyphenyl)-1,1-dif-
luoroethene coupled with phenylboronic acid in 5 h under the
standard reaction conditions to produce the cross-coupled
product 3 in 79% isolated yield. Under similar conditions,
1-naphthylboronic acid yielded the cross-coupled product 4 in
85% isolated yield. Boronic acids, having an electron-withdraw-
ing group in the aromatic ring, underwent the coupling reaction
in 12 h to produce the corresponding cross-coupled product in
good isolated yield. With 4-fluorophenylboronic acid as the
coupling partner, the cross-coupled product 5 was isolated in
85% yield. Even though the nitro groups in the boronic acid
and aryl halide are known to give an unwanted side reaction in
some of the reported Suzuki-Miyaura coupling reactions, the
reaction was quite successful in our case at producing the
(31) (a) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996,
61, 2346-2351. (b) Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994, 59,
33-41. (c) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C.
G. M. J. Chem. Soc., Chem. Commun. 1994, 2395. (d) Gillmann, T.; Weeber,
T.; Synlett 1994, 649-650.
(32) (a) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron
Lett. 2003, 44, 1541-1544. (b) Lei, A.; Zhang, X. Tetrahedron Lett. 2002,
43, 2525-2526. (c) Parrish, J. P.; Jung, Y. C.; Floyd, R. J.; Jung, K. W.
Tetrahedron Lett. 2002, 43, 7899-7902. (d) Falck, J. R.; Mohapatra, S.;
Bondlela, M.; Venkataraman, S. K. Tetrahedron Lett. 2002, 43, 8149-
8151. (e) Kabalka, G. W.; Wang, L. Tetrahedron Lett. 2002, 43, 3067-
3068. (f) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087-
4089. (g) Cravotto, G.; Beggiato, M.; Penoni, A.; Palmisano, G.; Tollari,
S.; Levaque, J.; Bonrath, W. Tetrahedron Lett. 2005, 43, 2267-2271.
(33) (a) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37,
2993-2996. (b) Indolese, A. Tetrahedron Lett. 1997, 38, 3513-3516.
J. Org. Chem, Vol. 71, No. 1, 2006 197

Raghavanpillai and Burton
TABLE 3. Coupling Reactions of Various r-Bromo-â,â-difluorostyrenes with Selected Arylboronic Acids
a Isolated product was contaminated with 1-3% of the self-coupled product. b A total of 2.2 equiv of boronic acid was used. c The product was contaminated
with ∼10-12% of the self-coupled product.
coupled product 6 in 72% isolated yield.33b,34a Boronic acids
with an electron-releasing group also coupled well under
standard reaction conditions to produce the corresponding cross-
coupled product 7 in 78% isolated yield. The heterocyclic
boronic acid, 3-thienylboronic acid, was also then used for this
coupling reaction. Under the prolonged reaction conditions, a
slight decomposition of the boronic acid was observed, and by
using an excess (2.2 equiv) of the boronic acid, we obtained a
51% isolated yield of the cross-coupled product 8 and 8% of
the 3,3′-bithiophenyl.35
After the successful synthesis of several 2-aryl-2-(4-meth-
oxyphenyl)-1,1-difluoroethenes, a variety of R-bromo-â,â-
difluorostyrenes with electron-releasing and electron-withdraw-
ing groups in the aromatic ring were coupled with selected
boronic acids. The Pd(0)-catalyzed Suzuki-Miyaura coupling
is known to be efficient for aryl halides with electron-
withdrawing groups,25b and there have been many examples
where Ni(0)-catalyzed coupling reactions of arylboronic acids
proceeded well for the aryl halides with electron-donating
groups, too.32,34,36 In our case, generally the reaction preceded
well for styrenes both having electron-releasing and electron-
withdrawing groups in the aromatic ring under the typical
reaction conditions to produce the corresponding 2,2-diaryl-1,1-
difluoroethenes in excellent isolated yield (Table 3). 2-Bromo-
2-(4-fluorophenyl)-1,1-difluoroethene coupled with phenyl as
well as 1-naphthylboronic acid under typical reaction conditions
to produce the corresponding 2,2-diaryl-1,1-difluoroalkenes 1
and 9 in 75 and 83% yields, respectively. 2-Bromo-2-(3-
nitrophenyl)-1,1-difluoroethene coupled with 4-fluorophenyl-
boronic acid as well as phenylboronic acid to produce the
corresponding coupled products 10 and 11 in 75 and 78%
respective isolated yields, demonstrating the tolerance of the
nitro group during this coupling process. 2-Bromo-2-(4-chlo-
rophenyl)-1,1-difluoroethene reacted with 4-fluorophenylboronic
acid and 3,5-dimethylphenylboronic acid to give the corre-
sponding cross-coupled products 12 and 13 with the chlorine
(34) (a) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024-
8030. (b) Wallow, T. I.; Novak, M. B. J. Org. Chem. 1994, 59, 5034-
5037.
(35) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Tetrahedron 1979, 35, 329-
340.
(36) Lipshutz, B. H.; Sclafani, A. J.; Blomgren, P. A. Tetrahedron 2000,
56, 2139-2144.
198 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of 2,2-Disubstituted-1,1-difluoro-1-alkenes
TABLE 4. Coupling Reactions of r-Bromo-â,â-difluorostyrenes
with trans-Hex-1-enylboronic Acid
intact in the aromatic ring in 76 and 87% isolated yields. The
coupling reaction of 2-bromo-2-(4-bromophenyl)-1,1-difluoro-
ethene with 1.1 equiv of 4-fluorophenylboronic acid produced
mainly the product resulting from the coupling of the aromatic
bromine site, leaving the vinyl bromine site intact [4-FC6H4s
C6H4sC(Br)dCF2]. When 2.2 equiv of 4-fluorophenylboronic
acid was used, the coupling reaction was feasible for both of
the bromine sites to produce the bis-coupled product 14 in 73%
isolated yield. This preference for the aromatic bromine site
over the alkenyl bromine site indicates the relatively difficult
nature of this internal alkenyl bromide to undergo a coupling
reaction with boronic acids. 2-Bromo-2-(2-methylphenyl)-1,1-
difluoroethene reacted with 4-fluoro- and 3-nitrophenylboronic
acids to produce the corresponding coupled products 15 and
16 in 91 and 90% yields, respectively. However, the coupling
reaction of the corresponding trifluoromethyl analogue, 2-bromo-
2-(2-trifluoromethylphenyl)-1,1-difluoroethene, was very slug-
gish, and only a partial reaction was noticed even after many
days when the reaction was performed with 1.1 equiv of
4-fluorophenylboronic or phenylboronic acid. With additional
boronic acid during the course of the reaction (1.1 equiv),
complete conversion of the styrene to the coupled products was
achieved. Isolation of the cross-coupled products 17 and 18 from
these reaction mixtures by chromatography was tedious, and
the isolated product was contaminated with ∼10-12% of the
self-coupled product in both cases (close Rf values). The
coupling reaction of 2-bromo-2-(2-thienyl)-1,1-difluoroethene
with three different boronic acids was attempted. Phenyl and
4-fluorophenylboronic acids reacted under normal coupling
reaction conditions to produce the cross-coupled products 19
and 20 in 78 and 79% yields, respectively. The coupling reac-
tion of 2-bromo-2-(2-thienyl)-1,1-difluoroethene with 3-thie-
nylboronic acid required an excess (2.2 equiv) of the boronic
acid for the completion of the reaction, and the cross-coupled
product 21 was formed in 74% isolated yield. 1,4-Bis-(1-bromo-
2,2-difluoroethenenyl)benzene coupled with 4-fluorophenylbo-
ronic acid to produce the corresponding bis-coupled product
22 in 76% isolated yield. Thus, in general, the palladium-
catalyzed cross-coupling reaction of the R-bromo-â,â-difluo-
rostyrenes with arylboronic acids was feasible with styrenes
having electron-donating and electron-withdrawing (including
nitro) groups at different positions in the aromatic ring (including
ortho-methyl) and with the heterocyclic 2-thienyl analogue.
Functionalization at the Bromine Site of r-Bromo-â,â-
difluorostyrenes Using Alkenylboronic Acids. The successful
completion of the coupling reaction of R-bromo-â,â-difluo-
rostyrenes with an arylboronic acid prompted us to study similar
coupling reactions with alkenylboronic acids, as the resulting
1,1-difluoro-2-aryl-1,3-dienes could be useful building blocks
in organic synthesis. Initially, the coupling reaction of R-bromo-
â,â-difluorostyrene with 1.1 equiv of trans-hex-1-enylboronic
acid was attempted. 19F NMR analysis of the reaction mixture
at various time intervals revealed that the reaction was sluggish,
and after 48 h, a mixture of products consisting mainly of the
cross-coupled product 23 (41%), the self-coupled product, and
the reduced product difluorostyrene (PhCHdCF2; 18%) were
obtained.37 At the early stage of the reaction, unreacted
bromostyrene and the coupled products were the only constitu-
ents, but the formation of the reduced product was observed
after heating the reaction mixture for a prolonged period. As
the reaction progressed, a part of the boronic acid was converted
entry
ArCFdCF2
product
time (h)
yielda (%)
1b
2b
3b
C6H5CBrdCF2
4-FC6H4CBrdCF2
4-MeOC6H4CBrdCF2
23
24
25
32
85
9
64
74
80
a Isolated dienes are unstable when neat. b A total of 2.2 equiv of boronic
acid was used
TABLE 5. Coupling Reactions of Various
r-Bromo-â,â-difluorostyrenes with
trans-2-(4-Fluorophenyl)ethenylboronic Acid
entry
ArCFdCF2
product
time (h)
yield (%)a
1b
2b
3b
C6H5CBrdCF2
4-FC6H4CBrdCF2
4-MeOC6H4CBrdCF2
26
27
28
95
168
10
53
69
79
a Isolated dienes are unstable when neat. b A total of 2.2 equiv of boronic
acid was used.
to the self-coupled product, and there was no boronic acid
available for cross-coupling. At this stage, the reduced product
began to be observed as the oxidatively added R-bromo-â,â-
difluorostyrenepalladium(II) species {PhC[Pd(PPh3)2Br]dCF2}
was converted presumably to the reduced product as a result of
the nonavailability of the boronic acid for the transmetalation
process. We then attempted this coupling reaction with an excess
(2.2 equiv) of trans-hex-1-enylboronic acid; the reaction was
complete in 32 h, and from the reaction mixture, the cross-
coupled product 23 was isolated in 64% yield. A similar reaction
with 2-bromo-2-(4-fluorophenyl)-1,1-difluoroethene was slug-
gish; with an excess of boronic acid (2.2 equiv) and refluxing
for 85 h, complete conversion occurred, and the cross-coupled
product 24 was isolated in 74% yield. R-Bromo-â,â-difluo-
rostyrene with an electron-donating group in the aromatic ring,
2-bromo-2-(4-methoxyphenyl)-1,1-difluoroethene, coupled with
trans-hex-1-enylboronic acid in 9 h to produce the cross-coupled
product 25 in 80% isolated yield. Table 4 summarizes the results
of the coupling reactions of several R-bromo-â,â-difluorosty-
renes with trans-hex-1-enylboronic acid.
Cross-coupling reactions of R-bromo-â,â-difluorostyrenes
with trans-2-(4-fluorophenyl)ethenylboronic acid were also
attempted, and a reaction trend similar to that observed in the
coupling reaction of R-bromo-â,â-difluorostyrenes with trans-
hex-1-enylboronic acid was observed (Table 5). The coupling
reaction of R-bromo-â,â-difluorostyrene with 1.1 equiv of trans-
2-(4-fluorophenyl)ethenylboronic acid was sluggish, and after
48 h, 19F NMR analysis of the reaction mixture revealed that
the cross-coupled product 26 was formed in 44% yield, along
with the self-coupled product (8%) and the reduced product
(PhCHdCF2; 18%). When the same reaction was performed
with an excess (2.2 equiv) of boronic acid, the reaction was
complete in 95 h to afford a 53% isolated yield of the cross-
coupled product 26. The reaction of 2-bromo-2-(4-fluorophenyl)-
1,1-difluoroethene with an excess (2.2 equiv) of trans-2-(4-
fluorophenyl)ethenylboronic acid was also attempted, and after
168 h at reflux, complete conversion was noted. From this
reaction mixture the cross-coupled product 27 was isolated in
(37) Nguyen, B. V.; Burton, D. J. J. Org. Chem. 1997, 62, 7758-7764.
J. Org. Chem, Vol. 71, No. 1, 2006 199

Raghavanpillai and Burton
SCHEME 4
69% yield. The coupling reaction of 2-bromo-2-(4-methoxy-
phenyl)-1,1-difluoroethene with an excess (2.2 equiv) of trans-
2-(4-fluorophenyl)ethenylboronic acid was complete in 10 h to
obtain the cross-coupled product 28 in 79% isolated yield.
A clear electronic effect on the reactivity was observed during
the coupling reactions of R-bromo-â,â-difluorostyrenes with
alkenylboronic acids (Tables 4 and 5). In general, R-bromo-
â,â-difluorostyrenes with an electron-releasing group coupled
relatively faster with alkenylboronic acids than did those having
an electron-withdrawing group or a phenyl group. However,
such a trend was not noticed during the corresponding coupling
reaction with arylboronic acids, where an electron-releasing or
electron-withdrawing group did not show any significant
difference in reactivity (Tables 2 and 3). Generally, aryl or
alkenyl halides having electron-withdrawing groups undergo
oxidative addition relatively faster than those having electron-
releasing groups, thus, are expected to couple faster.30,38 It has
also been established that the electron-withdrawing groups in
the aryl or alkenyl halide do accelerate the reductive elimination
process, whereas steric effects play a significant role in the
transmetalation process.25a,b,38d,39,40 Because aryl and alkenyl-
boronic acids expressed significant differences in reactivity
during the coupling reaction with the R-bromo-â,â-difluorosty-
renes (the oxidative addition process is the same in both
reactions), the transmetalation or the reductive elimination
process would be significant in determining the rate of this
coupling reaction. The reactivity differences of the R-bromo-
â,â-difluorostyrenes toward trans-hex-1-enylboronic acid or
trans-2-(4-fluorophenyl)ethenylboronic acid remain unclear, and
more mechanistic studies need to be performed to explain these
results.
Functionalization at the Halogen Site of the r-Halo-â,â-
difluorostyrene via the Corresponding Zinc Reagent [C6H5C-
(ZnX)dCF2]. We have also explored another possible way to
functionalize the R-bromine site of the R-halo-â,â-difluorosty-
renes, namely, via the corresponding zinc reagent followed by
a palladium-catalyzed coupling reaction with aryl or alkenyl
iodides. Thus, a solution of R-bromo-â,â-difluorostyrene was
treated with acid washed zinc powder in DMF at room
temperature or 75 °C for 12 h; 19F NMR analysis of both of
the reaction mixtures indicated that <15% of the zinc reagent
[C6H5C(ZnBr)dCF2] was formed. In another experiment, iodine
was used as an activating agent, where acid-washed zinc powder
was treated with 10 mol % iodine in DMF followed by the
addition of the R-bromo-â,â-difluorostyrene at room tempera-
ture.41 19F NMR analysis of this reaction mixture revealed the
presence of the desired zinc reagent (72% vs PhCF3 as an
internal standard) along with a small amount of the reduced
product (PhCHdCF2; 19%). To improve the yield of the zinc
reagent, the zinc-insertion reaction was also attempted under
heating conditions as well as in other solvents such as diglyme
and dimethylacetamide (DMA). The heating of the reaction
mixture containing zinc (activated with iodine) and R-bromo-
â,â-difluorostyrene in DMF at 75 °C for 12 h produced a 1:1
mixture of the zinc reagent and the reduced product. The zinc-
insertion reaction (zinc activated with iodine) of R-bromo-â,â-
difluorostyrene in diglyme produced a poor yield of the zinc
reagent (∼25%), whereas in DMA, a 68% yield of the zinc
reagent was observed. The formation of the zinc reagent was
established by hydrolysis and iodinolysis experiments; hydroly-
sis of the zinc reagent reaction mixture with acetic acid produced
the reduced product PhCHdCF2 in 84% yield,37 whereas
iodinolysis produced 67% of the R-iodo-â,â-difluorostyrene.23d
The zinc reagent was also synthesized in 65% yield from R-iodo-
â,â-difluorostyrene by treatment with activated zinc powder and
catalytic iodine (5 mol %) in DMF at room temperature, as per
the conditions described for R-bromo-â,â-difluorostyrene. After
obtaining the zinc reagent in moderate yield, we have attempted
the cross-coupling reaction of the zinc reagent with aryl or
alkenyl iodides. Thus, the zinc reagent generated in DMF was
treated with 4-fluoroiodobenzene and catalytic Pd(PPh3)4 (1.5
mol %) at 65 °C for 5 h. 19F NMR analysis of the reaction
mixture showed complete conversion of the zinc reagent to the
cross-coupled product 2-(4-fluorophenyl)-2-phenyl-1,1-difluo-
roethene (1; Scheme 4). From this reaction mixture, pure 1 was
isolated in 69% yield. The coupling reaction of the zinc reagent
with iodotrifluoroethylene was also attempted at room temper-
ature, and this reaction produced a 45% isolated yield of the
cross-coupled product 29 (Scheme 4) thus establishing that
R-halo-â,â-difluorostyrenes could be alternatively functionalized
via the corresponding zinc reagents.42 We have also attempted
to synthesize 29 by a Pd(0)-catalyzed coupling reaction of the
trifluoroethenylzinc reagent (generated by the metalation of
HFC-134a in THF) with R-iodo-â,â-difluorostyrene at 65 °C
but failed to obtain any traces of 29.23 Though the relative yields
of the coupled products are moderate in the zinc-insertion/
coupling process in comparison to the boronic acid mediated
coupling reaction, absence of the self-coupled product and the
relatively easier separation of the cross-coupled product make
this method attractive.
Conclusion
In conclusion, we have explored the possible functionalization
at the halogen site of R-halo-â,â-difluorostyrenes; R-bromo-
â,â-difluorostyrenes and R-iodo-â,â-difluorostyrenes underwent
a coupling reaction with various aryl and alkenylboronic acids
in the presence of catalytic Pd(PPh3)4 to produce the corre-
sponding 2,2-diaryl-1,1-difluoro-1-alkenes and 1,1-difluoro-2-
aryl-1,3-dienes in good isolated yield. The reactivity of various
R-halo-â,â-difluorostyrenes was compared; the R-chloro-â,â-
difluorostyrene was not reactive, whereas R-bromo-â,â-difluo-
rostyrene reacted relatively faster compared to the R-iodo-â,â-
(38) (a) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434-442.
(b) Amatore, C.; Jutanod, A. J. Organomet. Chem. 1999, 576, 254-278.
(c) Ricci, A.; Angelucci, F.; Bassetti, M.; Sterzo, C. L. J. Am. Chem. Soc.
2002, 124, 1060-1071. (d) Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4981-
4991.
(39) (a) Kim, M. Y.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696-1697.
(b) Widenhoefer, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
6504-6511.
(40) Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954-959.
(41) Huo, S. Org. Lett. 2003, 5, 423-425.
(42) Burton, D. J.; Inouye, Y.; Headley, J. A. J. Am. Chem. Soc. 1980,
102, 3980-3982.
200 J. Org. Chem., Vol. 71, No. 1, 2006

Synthesis of 2,2-Disubstituted-1,1-difluoro-1-alkenes
Synthesis of [C6H5C(ZnX)dCF2] and Subsequent Coupling
with Aryl or Alkenyl Iodides: Synthesis of 2,2-Disubstituted-
1,1-difluoro-1-alkenes. A suspension of activated (acid-washed)
zinc powder (obtained from a commercial supplier; 0.507 g, 7.8
mmol) in DMF (20 mL) was stirred with iodine (0.198 g, 0.78
mmol) at room temperature; after the iodine color disappeared, the
zinc was treated with 2-bromo-2-phenyl-1,1-difluoroethene (0.850
g, 3.9 mmol), and the mixture was heated to 80 °C for 2 min and
stirred at room temperature for 12 h. 19F NMR analysis of the
resulting brown solution showed a 72% yield of the zinc reagent
[PhC(ZnBr)dCF2] along with a 19% yield of the reduced product
(PhCHdCF2).37
difluorostyrene. The coupling reaction of R-bromo-â,â-di-
fluorostyrenes with electron-withdrawing vinylboronic acids was
sluggish. 2,2-Disubstituted-1,1-difluoro-1-alkenes were alter-
natively synthesized in moderate yield by the coupling reaction
of the zinc reagent generated from the R-halo-â,â-difluorosty-
renes with aryl or alkenyl iodides. Overall, both of these
approaches serve as a convenient first general synthetic route
for 2,2-diaryl-1,1-difluoro-1-alkenes and 1,1-difluoro-2-aryl-1,3-
dienes, virtually making it possible to introduce any aryl
(alkenyl) group at the 2 position in a symmetrical or unsym-
metrical fashion.
19F NMR of PhC(ZnBr)dCF2 (AB pattern): δ -79.4 (d, J )
57.6 Hz, 1F), -79.9 (d, J ) 58.7 Hz, 1F).
Experimental Section
General Procedure for the Coupling Reaction of r-Halo-â,â-
difluorostyrenes with Aryl- or Ethenylboronic Acids: Synthesis
of 2,2-Diaryl-1,1-difluoro-1-alkenes and 1,1-Difluoro-2-aryl-1,3-
dienes (1-28). A 50-mL three-necked round-bottom flask fitted
with a condenser attached to a nitrogen tee, a septum, and a stopper
was assembled while hot and cooled with a steady stream of
nitrogen. The flask was charged with benzene (15 mL), ethanol (3
mL), water (3 mL), and the R-halo-â, â-difluorostyrene (1.0 mmol).
With the nitrogen flow on, the boronic acid (1.1 mmol), potassium
carbonate (0.410 g, 3.0 mmol), and tetrakistriphenylphosphine
palladium (0.060 g, 5 mol %) were added through the side neck.
The mixture was heated at reflux, and the reaction progress was
monitored by 19F NMR and TLC. After the reaction period, the
crude reaction mixture was cooled to room temperature, diluted
with ethyl acetate (30.0 mL), and washed with water (2 × 25 mL).
The organic layer was dried (anhyd Na2SO4), and the solvent was
evaporated under vacuum. The residue was then subjected to careful
column chromatography over silica gel using hexanes, hexane/
CH2Cl2, or hexanes/EtOAc as the eluent, depending on the product
polarity, to afford various 2,2-diaryl-1,1-difluoroalkenes and 1,1-
difluoro-2-aryl-1,3-dienes.
The zinc reagent PhC(ZnBr)dCF2 (2.8 mmol) generated by the
above method was treated with 4-fluoroiodobenzene (0.532 g, 2.4
mmol) and Pd(PPh3)4 (0.048 g). The mixture was heated at 65 °C
for 5 h, cooled to room temperature, and triturated with hexanes
(4 × 20 mL). The organic extracts were washed with water (3 ×
20 mL) and dried over anhyd Na2SO4. The evaporation of the
solvent followed by column chromatography over silica gel
(eluent: hexane) afforded the cross-coupled product 1 as a colorless
liquid in 69% (0.386 g, 1.66 mmol) yield.
Acknowledgment. The authors greatly acknowledge NSF
for the financial support of this project.
Supporting Information Available: Experimental and char-
acterization data for 2,2-diaryl-1,1-difluoro-1-alkenes (1-22), 1,1-
difluoro-2-aryl-1,3-dienes (23-28), and 2-phenyl-1,1,3,4,4-pen-
tafluorobutadiene (29). This material is available free of charge
via the Internet at http://pubs.acs.org
JO051842P
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