Direct vinylation and difluorovinylation of arylboronic acids using vinyl- and 2,2-difluorovinyl tosylates via the Suzuki-Miyaura cross coupling

Article abstract of DOI:10.1021/jo7027097

(Chemical Equation Presented) General reaction conditions were developed for the Pd(0)-catalyzed Suzuki-Miyaura coupling reaction of aryl boronic acids with a simple electrophilic vinylation reagent, vinyl tosylate, providing access to styrene derivatives in good yields. The easily accessible vinyl tosylate represents a stable and less toxic alternative to the vinyl halides and the triflate/nonaflate derivatives. Furthermore, this methodology was expanded to provide a facile and straightforward approach for the introduction of a gem-difluorovinyl substituent onto an aromatic ring using the similar and also readily available 2,2-difluorovinyl tosylate as the electrophilic complement.

Full text of DOI:10.1021/jo7027097

Direct Vinylation and Difluorovinylation of Arylboronic Acids Using
Vinyl- and 2,2-Difluorovinyl Tosylates via the Suzuki-Miyaura
Cross Coupling
Thomas M. Gøgsig, Lina S. Søbjerg, Anders T. Lindhardt (neé Hansen), Kim L. Jensen, and
Troels Skrydstrup*
The Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the Interdisciplinary
Nanoscience Center, UniVersity of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
ReceiVed December 20, 2007
General reaction conditions were developed for the Pd(0)-catalyzed Suzuki-Miyaura coupling reaction
of aryl boronic acids with a simple electrophilic vinylation reagent, vinyl tosylate, providing access to
styrene derivatives in good yields. The easily accessible vinyl tosylate represents a stable and less toxic
alternative to the vinyl halides and the triflate/nonaflate derivatives. Furthermore, this methodology was
expanded to provide a facile and straightforward approach for the introduction of a gem-difluorovinyl
substituent onto an aromatic ring using the similar and also readily available 2,2-difluorovinyl tosylate
as the electrophilic complement.
Introduction
and others.8 Although the vinyltin reagents are the most widely
exploited in the cross-coupling approach, this strategy suffers
from drawbacks such as high cost of the tin reagent, toxicity,
and tedious chromatographic separation of the undesired tin
waste products. On the other hand, vinylboron reagents such
as boronic acids, esters, or trifluoroborate salts are less prob-
lematic and therefore represent viable alternatives to the tin-
based reagents.9
Nevertheless, the majority of published work regarding metal-
catalyzed vinylations exploits the olefinic moiety as the nu-
cleophilic species. A complementary approach for introducing
a vinyl group would be desirable, where an organometallic
reagent couples with a vinylic electrophile. However, the use
Styrene derivatives are valuable compounds both as advanced
intermediates in the synthesis of fine chemicals and as precursors
to functionalized polymers. Alkenes also act as a platform for
the introduction of numerous functionalities, as well as being
substrates for the Mizoroki-Heck1 and metathesis reactions.2
Metal-catalyzed cross-coupling strategies represent mild alterna-
tives for the introduction of vinyl substituents onto an aromatic
core, in particular due to the compatibility with a wide range of
functional groups.3 Several vinylation methods have been devel-
oped based on different organometallic reagents including vinyl-
magnesium (Kumada-Corriu),4 vinyltin (Migita-Kosugi-
Stille),5 vinylsilicon (Hiyama),6 vinylboron (Suzuki-Miyaura), 7
(5) (a) Badone, D.; Cecchi, R.; Guzzi, U. J. Org. Chem. 1992, 57, 6321. (b)
Grasa, G.; Nolan, S. P. Org. Lett. 2001, 3, 119. (c) Bumagin, N. A.; Andryukhova,
N. P.; Beletskaya, I. P. Dokl. Chem. 1989, 307, 211. (d) Chrétien, J.-M.;
Mallinger, A.; Zammattio, F.; Le Grognec, E.; Paris, M.; Montavon, G.; Quintard.,
J.-P. Tetrahedron Lett. 2007, 48, 1781.
(1) (a) Beletskaya, I. P.; Ceprakov, A. V. Chem. ReV. 2000, 100, 3009. (b)
Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
(2) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360. (b) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900. (c) Grubbs, R. H. Handbook of Metathesis; Wiley-
VCH: New York, 2003.
(3) (a) de Meijere, A.; Diederich, F. Metal-catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Tsuji, J. Palladium
Reagents and Catalysts, New PerspectiVes For the 21st Century; Wiley: West
Sussex, 2004. (c) Handbook of Organopalladium Chemistry for Organic Synthesis
Negishi E., Ed.; Wiley-Interscience: New York, 2002.
(6) (a) Tuet, J. Tetrahedron Lett. 1999, 40, 1673. (b) Denmark, S. E.; Wang,
Z. J. Organomet. Chem. 2001, 624, 372. (c) Denmark, S. E.; Butler, C. R. Org.
Lett. 2006, 8, 63. (d) Denmark, S. E.; Butler, C. R. J. Am. Chem. Soc. 2008,
130, 3690.
(7) (a) Darses, S.; Michaud, G.; Genét, J.-P. Tetrahedron Lett. 1998, 39,
5045. (b) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968. (c) Coleman,
C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054. (d) Peyroux, E.;
Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2004, 1075. (e)
Molander, G. A.; Brown, A. R. J. Org. Chem. 2006, 71, 9681.
(4) Bumagin, N. A.; Andryukhova, N. P.; Beletskaya, I. P. Bull. Acad. Sci.
USSR, DiV. Chem. Sci. 1987, 36, 1561.
3404 J. Org. Chem. 2008, 73, 3404–3410
10.1021/jo7027097 CCC: $40.75 2008 American Chemical Society
Published on Web 04/02/2008

Direct Vinylation and DifluoroVinylation of Arylboronic Acids
SCHEME 1. Synthesis of Vinyl Electrophiles
These reagents displayed good stability as they showed no sign of
degradation when stored in a freezer for several months.
Initial experiments on the suitability of these reagents for the
introduction of vinyl groups are shown in Table 1. Utilizing
the Ni(0)-catalyzed Suzuki-Miyaura conditions as previously
published afforded the desired styryl derivatives in good yields
with O-vinyl-O,O-diphenyl phosphate 1, but significant debo-
ronation of the boronic acids was detected (entries 1 and 2).12c
At this point, it should be mentioned that deboronation severely
complicates the chromatographic purification of the desired
coupling products, and that this side reaction had to be
eliminated in order to obtain an efficient protocol for the
formation of styrene derivatives. Attention was then directed
toward the more reactive vinyl tosylate 2 as the electrophile.
Unfortunately, this change did not eliminate the problematic
deboronation side reaction using the Ni(0)-catalyzed conditions
(entry 3). Changes in ligand, solvent, base, or reaction temper-
ature did not affect the yield nor the amount of deboronation in
a positive direction (results not shown), and hence, we set forth
to investigate alternative catalyst systems based on palladium(0)
complexes.
of vinyl halides is hampered by the low stability and boiling
points of these coupling partners.10 Vinyl iodide is actually the
only candidate representing a manageable liquid at atmospheric
pressure (bp 56 °C), but this particular substrate then suffers
from severe instability hampering isolation and hence the
reproducibility of its application in chemical transformations.11
In this paper, we report on general reaction conditions for
the use of a simple electrophilic vinylation reagent, represented
by vinyl tosylate, in the Pd(0)-catalyzed Suzuki-Miyaura
coupling reaction with arylboronic acids. This reagent represents
a more stable and practical alternative to the vinyl halides and
the triflate/nonaflate derivatives. Furthermore, we reveal an
adaptation of this approach for the direct introduction of a gem-
difluorovinyl substituent onto an aromatic ring starting from the
easily accessible 2,2-difluorovinyl tosylate. As there is a keen
interest in the use of difluoroalkenes as either bioisosteres of
bioactive carbonyl compounds or as precursors for the prepara-
tion of other fluorinated compounds, our novel synthetic
approach to these fluorinated styrene derivatives from a simple
fluorine containing starting material could have high impact.
Results and Discussion
Initial screenings were conducted testing commercially avail-
able bidentate ligands such as DPPF, D-t-BPF and the Josiphos
type ligands (Table 1, entries 4–6). The reactions were
performed using Pd2dba3 as the palladium source, aromatic
boronic acid (1.5 equiv), and 2 (1 equiv) in combination with
anhydrous potassium phosphate as the base in THF. Although
the Josiphos-type ligand did provide full conversion, only a 57%
yield of the desired styrene could be secured upon column
chromatography. Better results were obtained with the biphe-
nylphosphine ligand X-Phos,14 where full conversion was
obtained with a 74% isolated yield (entry 7). Unfortunately,
deboronation still remained an issue and couplings with boronic
acids carrying either electron-withdrawing or electron-donating
groups proved, that this side reaction was not influenced by
electronic factors (entries 8 and 9).15 The addition of water to
the reaction mixture provided a partial solution to this side
reaction, where lower yields of the deboronated byproduct was
observed. Addition of water to the reaction medium is believed
to increase the solubility of the preactivated organoboron-base
complex providing a faster transmetalation, and most impor-
tantly, organoboron compounds are often less prone to undergo
deboronation in the presence of water.15b
Synthesis of Vinyl Styrenes. Previously, we and others have
demonstrated the viability of nonactivated alkenyl phosphates
and tosylates, which are readily available from the corresponding
ketones, to undergo a variety of Pd- or Ni-catalyzed coupling
reactions.12 Considering the high number of commercially
available arylboronic acid derivatives, we examined the pos-
sibility of performing Suzuki-Miyaura couplings with either a
vinyl phosphate or tosylate as a viable approach for introducing
a vinyl group onto an aromatic ring.
The vinylic electrophiles were obtained in a straightforward
manner by fragmentation of tetrahydrofuran upon treatment with
butyllithium and trapping the formed enolate with either diphe-
nylphosphoryl chloride/anhydride or tosyl chloride (Scheme 1).13
(8) (a) For examples of more exotic vinyl cross-coupling reagents, see:
Mikami, S.; Yorimitsu, H.; Oshima, K. Synlett 2002, 1137. (b) Schumann, H.;
Kaufmann, J.; Schmalz, H. G.; Böttcher, A.; Gotov, B. Synlett 2003, 1783. (c)
Takami, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. Org. Lett.
2001, 3, 1997.
(9) (a) Darses, S.; Genét, J.-P. Tetrahedron Lett. 1997, 38, 4393. (b) Molander,
G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950. (c) Molander, G. A.; Fumagalli,
T. J. Org. Chem. 2006, 71, 5743. (d) Molander, G. A.; Ham, J.; Seapy, D. G.
Tetrahedron 2007, 63, 768.
(10) Boiling points at 1 atm: vinyl chloride ) –13.4 °C, vinyl bromide ) 16
°C, vinyl iodide ) 56 °C.
Changing the catalyst precursor to the commercially available
palladacycle SK-CCO1-A in combination with potassium
phosphate in a dioxane/H2O solution at 100 °C also provided a
good yield of the desired product (74%), but more importantly
deboronation was not detected (Table 1, entry 10).16 Although
the complex SK-CCO2-A afforded a slightly lower yield in
(11) Synthesis of vinylarenes was achieved from ArB(OH)2 and 1,2-
dibromoethane where vinyl bromide was generated in situ by base-promoted
elimination. Lando, V. R.; Monteiro, A. C. Org. Lett. 2003, 5, 2891.
(12) (a) For some recent examples, see: Hansen, A. L.; Ebran, J.-P.; Ahlquist,
M.; Norrby, P.-O.; Skrydstrup, T. Angew. Chem., Int. Ed. 2006, 45, 3349. (b)
Ebran, J.-P.; Hansen, A. L.; Gøgsig, T.; Skrydstrup, T. J. Am. Chem. Soc. 2007,
129, 6931. (c) Hansen, A. L.; Ebran, J.-P.; Gøgsig, T.; Skrydstrup, T. J. Org.
Chem. 2007, 72, 6464. (d) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org.
Chem. 2005, 70, 9364. (e) Larsen, U. S.; Martiny, L.; Begtrup, M. Tetrahedron
Lett. 2005, 46, 4261. (f) Klapars, A.; Campos, K. R.; Chen, C.; Volante, R. P.
Org. Lett. 2005, 7, 1185.
(14) (a) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3484. (b) Anderson, K. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 6173. (c) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman,
R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523.
(13) (a) Lyapkalo, I. M.; Webel, M.; Reissig, H.-U. Eur. J. Org. Chem. 2001,
4189 For earlier references, see: (b) Letsinger, R. L.; Pollart, D. F. J. Am. Chem.
Soc. 1956, 78, 6079. (c) Rernbaum, A.; Siao, S. P.; Indictor, N. J. Polym. Sci.
1962, 116, 517.
(15) (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am.Chem. Soc. 2003,
125, 11818. (b) Leadbeater, N. E. Chem. Commun. 2005, 2881.
J. Org. Chem. Vol. 73, No. 9, 2008 3405

Gøgsig et al.
TABLE 1. Optimization of the Suzuki-Miyaura Coupling
a Isolated yield after chromatographic purification. b Substantial deboronation observed. c Conversion rates; compound not isolated. d Reaction run with
0.3 mmol of boronic acid and 0.45 mmol of vinyl tosylate.
comparison to SK-CCO1-A (entry 11), this palladium complex
led to a much cleaner reaction as determined by H NMR
(entries 1, 4, and 9) and even improved the isolated yield of
the 2-vinyl-6-methoxynaphthalene shown in entry 6.17,18 This
coupling protocol was tested against several heteroaromatic
boronic esters and gratifyingly the styrene derivatives could be
secured in good yields ranging from 79 to 88% (entries 9–11).
A drop in reactivity was observed when the coupling was
attempted with boronic acids carrying substituents in ortho
position as exemplified in entry 12 upon comparison with entry
13. Finally, a double coupling was attempted with the diboronic
acid depicted in entry 8 providing the 4,4′-divinylbiphenyl in a
59% isolated yield.
1
analysis of the crude reaction mixture. Finally, a more reliable
system was obtained upon application of the aromatic boronic
acid as the limiting reagent with 1.5 equiv of 2 (entry 12).
These optimized coupling conditions were tested against a
variety of aromatic boronic acids, the results of which are
depicted in Table 2. Boronic acids containing either electron-
withdrawing or electron-donating groups underwent successful
coupling with vinyl tosylate 2 in good to excellent isolated yields
(entries 2–7 and 13). The neopentyl glycol ester of some of the
boronic acids was also tested and provided comparable reactivity
In order to test the utility of the vinylation methodology, the
coupling conditions were performed on a scale ten times greater
(16) The SK-CC01-A and SK-CC02-A complexes are air-stable, com-
mercially available Pd complexes from Solvias.
(17) 2-Vinyl-6-methoxynaphthalene is a key intermediate in the Albermale
synthesis of naproxen; see: de Vries, J. G. Can. J. Chem. 2001, 79, 1086.
(18) Despite the presence of water in the reaction mixture, the BF3K salt of
the naphthalen-2-yl boronic acid only afforded 55% isolated yield of the
corresponding 2-vinylnaphthalene. See ref 9.
3406 J. Org. Chem. Vol. 73, No. 9, 2008

Direct Vinylation and DifluoroVinylation of Arylboronic Acids
TABLE 2. Suzuki-Miyaura Couplings with Vinyl Tosylate 2
a Isolated yield after chromatographic purification. Conditions: boronic acid (0.3 mmol) and 2 (0.45 mmol). b The neopentyl glycol ester of the
boronic acid was used instead. c Some deboronation of the boronic acid detected.
J. Org. Chem. Vol. 73, No. 9, 2008 3407

Gøgsig et al.
SCHEME 3. Synthesis of 2,2-Difluorovinyl Tosylate
SCHEME 2. Large-Scale Coupling
The optimized conditions applied for couplings with 2 only
afforded the desired 2,2-difluorostyrenes in low yield. Instead,
conditions reported by Fu et al. using Pd2dba3 (2.5%),
HBF4PCy3 (10%) in combination with K3PO4 as the base in
a H2O/dioxane solvent mixture at 100 °C proved sufficiently
reactive providing a 79% of the desired 4-(2,2-difluorovinyl)
benzonitrile (results not shown).29 Lowering the ligand
loading to 5% increased the catalytic efficiency of the system
affording a 90% yield of the desired fluorinated styrene (Table
3, entry 1).
These slightly modified conditions were then tested against
several different boronic acids. We were pleased to find that this
catalytic system provided the fluorinated coupling products in yields
ranging from 46 to 98%. Once again the boronic esters could be
applied without loss in reactivity (entries 3, 8, and 10–12). Finally,
heteroaromatic boronic esters were subjected to the conditions at
hand and a 69% and 75% yield of the styrene derivatives could be
secured upon column chromatography (entries 11 and 12).
that those of Table 1. Coupling of the pinacol boronic ester of
2-quinoline on a 3 mmol scale (Scheme 2), furnished the desired
styrene in an 88% isolated yield, which represents a slight
increase compared to the same coupling as shown Table 2, entry
11.
Synthesis of 2,2-Difluorovinylstyrenes. We then turned our
attention to the application of a fluorinated vinylic electrophile
to obtain fluorinated styrene derivatives. Introduction of fluorine
to biologically active compounds often provides a positive effect
on their pharmacokinetic properties.19 In particular, the gem-
difluorovinyl group represents a viable bioisostere for aldehydes
and ketones,20 where the CF2 group is isopolar to an oxygen
atom.21 Furthermore, gem-difluoroalkenes have been exploit-
ed as precursors for the synthesis of other fluorinated compounds
and polymers.22 Hence effective methods for their introduction
are of high value.
There are only few methods for introducing 2,2-difluorovinyl
groups on an aromatic core. The most common approach relies
on the use of Wittig-type reactions with a difluoromethylene
phosphorus ylide.23 Thermal decomposition of gem-difluoro-
ꢀ-lactams has also been reported.24 Nenajdenko et al. recently
disclosed the conversion of hydrazones of aryl aldehydes to gem-
difluorovinyl styrenes via catalytic olefination with dibromodi-
fluoromethane in the presence of CuCl.25 However, the desired
alkenes were furnished in yields of less than 40%. A Julia
olefination was adapted by Prakash, Olah, and co-workers for
the introduction of a difluorovinyl group using bromodifluo-
romethyl phenyl sulfone, but here three steps are required for
this transformation starting from the aryl aldehyde.26 Finally, a
palladium-catalyzed cross coupling of aryl halides with 2,2-
difluorovinylzinc was reported leading to the desired fluorinated
styrenes.27 The zinc reagent was prepared from either 2,2-
difluorovinyl bromide (bp 6 °C at 1 atm) or the corresponding
iodide which is not commercially available.
Conclusion
In conclusion, two catalytic systems were developed for the
introduction of either a vinyl or 2,2-difluorovinyl moiety onto an
aromatic ring via Pd(0)-catalyzed Suzuki-Miyaura coupling with
arylboronic acids. Both catalytic systems proved insensitive to the
intrinsic nature of the boronic acid allowing the presence of both
electron-withdrawing or electron-donating functionalities and het-
eroaromatic systems. Furthermore, the protocol appears to be
scalable demonstrating the usefulness of this methodology. Further
work is now in progress to obtain systems allowing for the
introduction of both mono and fully fluorinated vinyl moieties as
well as the implementation of these new styrene derivatives in the
synthesis of biologically active compounds. This work will be
reported in due course.
In this work, we explored the possibility of using 2,2-
difluorovinyl tosylate as an electrophilic difluorovinylating agent
in a Suzuki-Miyaura cross coupling strategy for accessing these
fluorinated styrene derivatives. In a convenient manner, the
difluorinated vinyl tosylate 17 was obtained as an oil by a two-
step sequence in an overall 91% yield starting from com-
mercially available trifluoroethanol (Scheme 3).28
Experimental Section
3-Vinylquinoline30 (14): General Procedure for the Suzuki-
Miyaura Couplings of Vinyl Tosylate (2) with Boronic Acids.
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (765
mg, 3.00 mmol), and 2 (892 mg, 4.50 mmol), SK-CC02-A ((91
mg, 0.15 mmol) were dissolved in dioxane (20 mL). K3PO4 (2
M, 4.0 mL) was then added, and the reaction vessel was sealed
using a Teflon screwcap and removed from the glovebox. The
reaction mixture was heated for 19 h at 100 °C and monitored
by TLC. After the reaction was complete, the crude reaction
mixture was concentrated in vacuo and purified by flash
chromatography on silica gel using pentane/ethyl acetate (10:1)
as eluent. This afforded 408 mg of the title compound (88%
yield) as an orange oil: H NMR (400 MHz, CDCl3) δ (ppm)
(19) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 4632.
(b) Motoki, R.; Tomita, D.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006,
47, 8083. (c) Matteis, V.; Delft, F. L.; Jakobi, H.; Lindell, S.; Tiebes, J.; Rutjes,
F. P. J. T. J. Org. Chem. 2006, 71, 7572. (d) Thayer, A. M. Chem. Eng. News
2006, 84, 15.
(20) Uneyama, K. Organofluorine Chemistry; Blackwell: New Delhi, 2006.
(21) Farnham, W. B. Chem. ReV. 1996, 96, 1633. and references cited therein.
(22) Prakash, G. K. S.; Yudin, A. Chem. ReV. 1997, 97, 757.
(23) (a) Hayashi, S. I.; Nakai, T.; Ishikawa, N.; Burton, D. J.; Naae, D. G.;
Kesling, J. S. Chem. Lett. 1979, 983. (b) Burton, D. J. J. Fluorine Chem. 1999,
100, 177. (c) Nowak, I.; Robins, M. J. Org. Lett. 2005, 7, 721.
41.(24) Ocampo, R.; Dolbier, W. R.; Paredes, R. J. Fluorine Chem. 1998, 88,
(25) Nenajdenko, V. G.; Varseev, G. N.; Korotchenko, V. N.; Shastin, A. V.;
Balenkova, E. S. J. Fluorine Chem. 2003, 124, 115.
(26) Prakash, G. K. S.; Wang, Y.; Hu, J.; Olah, G. A. J. Fluorine Chem.
2005, 126, 1361.
(29) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45,
1282.
(30) Hsu, M. C.; Junia, A. J.; Haight, A. R.; Zhang, W. J. Org. Chem. 2004,
69, 3907.
(31) Koch, H. F.; Lodder, G.; Koch, G. J.; Bogdan, D. J.; Brown, G. H.;
Carlson, C. A.; Dean, A. B.; Hage, R.; Han, P.; Hopman, J. C. P.; James, L. A.;
Knape, P. M.; Roos, E. C.; Sardina, M. L.; Sawyer, R. A.; Scott, B. O.; Testa
III, C. A.; Wickham, S. D. J. Am. Chem. Soc. 1997, 119, 9965.
(27) Nguyen, B. V.; Burton, D. J. J. Org. Chem. 1997, 62, 7758.
(28) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 13,
1917.
3408 J. Org. Chem. Vol. 73, No. 9, 2008

Direct Vinylation and DifluoroVinylation of Arylboronic Acids
TABLE 3. Suzuki-Miyaura Couplings with 2,2-Difluorovinyl Tosylate 17
a Isolated yield after chromatographic purification. b Boronic acid (0.3 mmol) and 17 (0.45 mmol) was used. c THF at 70 °C for 22 h used instead.
d The neopentyl glycol ester of the boronic acid was used instead. e Some deboronation of the boronic ester detected.
9.02 (s, 1H), 8.07 (d, 1H, J ) 8.8 Hz), 8.06 (s, 1H), 7.78 (d,
1H, J ) 8.4 Hz), 7.66 (t, 1H, J ) 8.8 Hz), 7.51 (t, 1H, J ) 8.4
Hz), 6.85 (dd, 1H, J ) 17.6, 11.2 Hz), 5.97 (d, 1H, J ) 17.6
Hz), 5.45 (d, 1H, J ) 11.2 Hz); 13C NMR (100 MHz, CDCl3) δ
(ppm) 149.2, 147.8, 133.9, 132.6, 130.4, 129.38, 129.37, 128.1,
128.0, 127.0, 116.5; GCMS C11H9N [M+] calcd 155, found 155.
4-(2,2-Difluorovinyl)benzonitrile (18):31,32 Generel Procedure
for the Suzuki-Miyaura Couplings of Difluorovinyl Tosylate
J. Org. Chem. Vol. 73, No. 9, 2008 3409

Gøgsig et al.
(3) with Boronic Acids. Compound 17 (70.2 mg, 0.30 mmol),
4-cyanophenylboronic acid (66.2 mg, 0.45 mmol), HBF4PCy3 (5.5 mg,
0.015 mmol), and Pd2dba3 (6.9 mg, 0.0075 mmol) were dissolved in
dioxane (2 mL). K3PO4 (1.27 M, 0.4 mL) was then added, and the
reaction vessel was sealed using a Teflon screwcap and removed from
the glovebox. The reaction mixture was heated for 18 h at 100 °C and
monitored by TLC. After the reaction was complete, the crude reaction
mixture was concentrated in vacuo and purified by flash chromatog-
raphy on silica gel using pentane f pentane/CH2Cl2 (1:1) as eluent.
This afforded 44.7 mg of the title compound (90% yield) as a yellow
solid: mp 69 °C (lit.32 mp 69–70 °C); 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.62 (d, 2H, J ) 8.0 Hz), 7.42 (d, 2H, J ) 8.0 Hz), 5.33 (dd,
1H, J ) 25.6, 3.2 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm) 157.1
(dd, J ) 299.2, 290.1 Hz), 135.5 (t, J ) 7.0 Hz), 132.6, 128.3 (dd, J
) 6.8, 3.0 Hz), 118.8, 110.7, 81.9 (dd, J ) 29.8, 12.2 Hz); 19F NMR
(376 MHz, CDCl3) δ (ppm) –84.3 (dd, J ) 35.7, 26.3 Hz), –86.5 (dd,
J ) 35.7, 4.1 Hz); GCMS C9H4F2N [M+] calcd 165, found 165.
Acknowledgment. We thank the Danish National Research
Foundation, the Lundbeck Foundation, the Carlsberg Founda-
tion, the OChem Graduate School, and the University of
Aarhus for financial support of this work. We greatly
appreciate a generous donation of Pd complexes and ligands
from Solvias.
Supporting Information Available: Experimental details and
1
copies of H NMR, 13C NMR, and 18F NMR spectra for all
new products. This material isavailable free of charge via the
Internet at http://pubs.acs.org.
JO7027097
(32) Rae, I. D.; Smith, L. K. Aust. J. Chem. 1972, 25, 1465.
3410 J. Org. Chem. Vol. 73, No. 9, 2008