Mild and general conditions for the cross-coupling of aryl halides with pentafluorobenzene and other perfluoroaromatics

Article abstract of DOI:10.1021/ol0619967

(Chemical Equation Presented) New reaction conditions are described that enable the direct arylation of pentafluorobenzene with sterically encumbered aryl bromides and aryl chlorides. These reactions occur in high yield and under mild conditions. Notably, the reactions can be performed at 80°C in isopropyl acetate with a catalyst generated by the in situ mixing of Pd(OAc)₂ and S-Phos. The enhanced scope of these transformations should further reduce the need to use pentafluorophenylboronic acid in the construction of perfluoroarenes.

Full text of DOI:10.1021/ol0619967

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5097-5100
Mild and General Conditions for the
Cross-Coupling of Aryl Halides with
Pentafluorobenzene and Other
Perfluoroaromatics
Marc Lafrance, Daniel Shore, and Keith Fagnou*
Center for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5
keith.fagnou@uottawa.ca
Received August 11, 2006
ABSTRACT
New reaction conditions are described that enable the direct arylation of pentafluorobenzene with sterically encumbered aryl bromides and
aryl chlorides. These reactions occur in high yield and under mild conditions. Notably, the reactions can be performed at 80 C in isopropyl
°
acetate with a catalyst generated by the in situ mixing of Pd(OAc)2 and S-Phos. The enhanced scope of these transformations should further
reduce the need to use pentafluorophenylboronic acid in the construction of perfluoroarenes.
Palladium-catalyzed cross-coupling reactions of organome-
tallic reagents and aryl halides constitute one of the most
useful methods for the synthesis of biaryl molecules.1 Despite
their prevalence, there is significant waste built into these
processes because both cross-coupling components must be
activated (synthesized) prior to use. With respect to the
organometallic, this typically requires the use of other
strongly basic organometallic reagents such as butyllithium
and often necessitates more than one step. Each of these pre-
cross-coupling manipulations generates waste from reagents,
solvents, and purification.
trophile (the aryl halide) can be problematic in cases where
the substrates are challenging to activate in the necessary
fashion. Such is the case with electron-deficient arenes when
they must be preactivated as the nucleophilic component.
With these limitations in mind, our group has been inves-
tigating the use of direct arylation2-5 as a means of
establishing new reactivity parameters for the resolution of
(2) For recent reviews, see: (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res.
2002, 35, 826. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002,
102, 1731. (c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211.
(d) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (e)
Campeau, L.-C.; Fagnou, K. Chem. Commun. 2005, 1253.
(3) For recent advances with electron-rich heterocycles, see: (a) Lane,
B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (b)
Park, C. H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V.
Org. Lett. 2004, 6, 1159. (c) Lane, B. S.; Sames, D. Org. Lett. 2004, 6,
2897. (d) Li, W. J.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Javadi,
G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835. (e) Mori, A.;
Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto,
M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700. (f) Wang, X.; Lane, B.
S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996.
Other aspects of modern cross-coupling reactions that
warrant attention are the challenges and limitations imposed
by the reactivity itself. The need to activate one arene as a
nucleophile (the organometallic) and the other as an elec-
(1) For reviews on this topic, see: (a) Metal-catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(b) Hassan, J.; Se´vignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
10.1021/ol0619967 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/07/2006

long-standing challenges associated with the use of organo-
metallic reagents in cross-coupling chemistry.6
reported for this type of transformation. The successful
realization of these reaction conditions should, in most cases,
replace the use of pentafluorophenyl organometallics in the
synthesis of these biaryl molecules.
Catalyst and reaction condition screens were performed
with 2-bromotoluene (1) and bromomesitylene (2) as the
model substrates in a reaction with pentafluorobenzene.
Under the conditions we previously described,12 very poor
conversion was obtained with 1 (Table 1, entry 1) and no
As noted, electron-deficient aryl (heteroaryl) organome-
tallic reagents constitute a challenging substrate class in
cross-coupling reactions and use of pentafluorophenyl or-
ganometallics is illustrative. Recent advances include the use
of C6F5B(OMe)3Li7 or C6F5BF3K8 salts, which enable
successful cross-coupling with aryl iodides. Very recently,
the use of C6F5B(OH)2 in conjunction with a stoichiometric
silver additive was discovered to enable reactions with both
aryl iodides and bromides.9 To our knowledge, there are no
reports of high-yielding cross-couplings with aryl chlorides
or with more sterically encumbered aryl halides. Given the
importance of perfluoroarenes in medicinal10 and particularly
materials chemistry,11 a general solution to this limitation
would be valuable in the synthesis of these molecules.
We recently reported the use of perfluorobenzenes as
replacements for the corresponding organometallic reagents
in cross-coupling reactions.12 These reactions were found to
occur in high yield with several aryl bromides but suffered
from low yields with aryl chlorides or with ortho-substituted
aryl bromides. These limitations prompted a reevaluation of
the catalyst and reaction conditions, focusing on these more
challenging substrates.
Table 1. Establishment of Conditions for Sterically
Encumbered Aryl Bromidesa
Herein, we report the discovery of new conditions for
reaction with a wide range of sterically encumbered bromides
and chlorides as well as aryl iodides, triflates, and hetero-
cyclic aryl halides. Strikingly, these new reactions also occur
at 80 °C, which is milder than our initially disclosed
conditions at 120 °C, and are among the mildest conditions
a Method A: Pd(OAc)2 (5 mol %), PtBu2MeHBF4 (10 mol %), K2CO3,
DMA, 120 °C. Method B: Pd(OAc)2 (5 mol %), S-Phos (10 mol %), K2CO3,
iPrOAc, 80 °C. b Determined by GCMS analysis. c Isolated Yield.
reaction was observed with 2 (entry 3). After extensive
optimization, a catalyst generated by mixing Pd(OAc)2 with
2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos)13
in isopropyl acetate at 80 °C with K2CO3 as the base emerged
as an excellent catalyst-solvent system. Under these condi-
tions, complete conversion was achieved with both aryl
bromides 1 and 2, resulting in 99% and 98% isolated yields,
respectively. The combination of the Pd(OAc)2/S-Phos
catalyst and the iPrOAc14 solvent appears to be an excellent
combination for these reactions. Notably, use of our previ-
(4) For recent examples involving metallacyclic intermediates, see: (a)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. (b)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (c) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai,
S. J. Am. Chem. Soc. 2003, 125, 1698. (d) Bedford, R. B.; Coles, S. J.;
Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112.
(5) For recent examples of intramolecular reactions with simple arenes,
see: (a) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am.
Chem. Soc. 2004, 126, 9186. (b) Campeau, L.-C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (c) Huang, Q.; Fazio, A.;
Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460.
(d) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 1066.
i
ously reported Pd(OAc)2/PtBu2MeHBF4 catalyst in PrOAc
or use of Pd(OAc)2/S-Phos in DMA leads to significantly
diminished outcomes. We also note that the reaction tem-
perature can be lowered to 70 °C, but occasionally incom-
plete conversion is obtained; thus, we chose 80 °C as the
standard reaction temperature for subsequent studies.
The scope of the reaction with pentafluorobenzene and a
range of aryl halides were investigated and are outlined in
Table 2. In addition to ortho-substituted aryl bromides (entry
2), aryl iodides may also be employed (entry 3). With aryl
iodides, 0.5 equiv of Ag2CO3 must be employed as an
additive. An inhibitory effect of iodide salts on direct
arylation has previously been observed,5b,15 and we postulate
(6) Campeau, L. C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020.
(7) Frohn, H.-J.; Adonin, N. Y.; Bardin, V. V.; Starichenko, V. F. J.
Fluorine Chem. 2003, 122, 195.
(8) (a) Frohn, H.-J.; Adonin, N. Y.; Bardin, V. V.; Starichenko, V. F.
Tetrahedron Lett. 2002, 43, 8111. (b) Molander, G. A.; Biolatto, B. J. Org.
Chem. 2003, 68, 4302.
(9) Korenga, T.; Kosaki, T.; Fukumura, R.; Ema, T.; Sakai, T. Org. Lett.
2005, 7, 4915.
(10) (a) Zahn, A.; Brotschi, C.; Leumann, C. J. Chem. Eur. 2005, 11,
2125. (b) Russell, M. G. N.; Carling, R. W.; Atack, J. R.; Bromidge, F. A.;
Cook, S. M.; Hunt, P.; Isted, C.; Lucas, M.; McKernan, R. M.; Mitchinson,
A.; Moore, K. W.; Narquizian, R.; Macaulay, A. J.; Thomas, D.; Thompson,
S.-A.; Wafford, K. A.; Castro, J. L. J. Med. Chem. 2005, 48, 1367.
(11) (a) Sakamoto, Y.; Suzuki, T.; Miura, A.; Fujikawa, H.; Tokito, S.;
Taga, Y. J. Am. Chem. Soc. 2000, 122, 1832. (b) Hwang, D. H.; Song, S.
Y.; Ahn, T.; Chu, H. Y.; Do, L. M.; Kim, S. H.; Shim, H. K.; Zyung, T.
Synth. Met. 2000, 111, 485. (c) Montes, V. A.; Li, G.; Pohl, R.; Shinar, J.;
Anzenbacher, P. AdV. Mater. 2004, 16, 2001. (d) Tsuzuki, T.; Shirasawa,
N.; Suzuki, T.; Tokito, S. AdV. Mater. 2003, 15, 1455. (e) Kitamura, T.;
Wada, Y.; Yanagida, S. J. Fluorine Chem. 2000, 105, 305. (f) Weck, M.;
Dunn, A. R.; Matsumoto, K.; Coates, G. W.; Lobkovsky, E. B.; Grubbs,
R. H. Angew. Chem., Int. Ed. 1999, 38, 2741. (g) Nitschke, J. R.; Tilley, T.
D. J. Am. Chem. Soc. 2001, 123, 10183.
(13) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871.
(14) EtOAc can also be employed. However, the lower volatility and
i
slightly higher boiling point of PrOAc results in greater reproducibility
and greater ease in performing the reactions. Notably, it allows the reactions
to be run below the solvent boiling point (85-91 °C).
(15) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467.
(12) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 8754.
5098
Org. Lett., Vol. 8, No. 22, 2006

Table 2. Scope of Aryl Halide-Pentafluorobenzene Cross-Couplinga
a Conditions: aryl halide, pentafluorobenzene (1.5 equiv), Pd(OAc)2 (5 mol %), S-Phos (10 mol %), and K2CO3 (2 equiv) dissolved in iPrOAc and heated
at 80 °C. b Isolated yield. c Performed using Pd(OAc)2 with PtBu3HBF4 in DMA at 120 °C. d 3 equiv of pentafluorobenzene was used.
that the silver salts are serving to remove the iodide salts
from the mixture as they are generated by the catalytic cycle.
The silver carbonate may also be facilitating a bromide-
carbonate ligand exchange, which may facilitate C-H bond
cleavage.16 A variety of ortho substituents can be present
including sp3 (entries 1-5, 7, 8, and 13) and sp2 carbons
(entries 8, 9, 11, and 12), methoxy (entry 6), nitrile (entry
10), and fluoro groups (entries 14 and 15). Even more
sterically encumbered bis-ortho-substituted aryl bromides can
be arylated in high yield (entries 4 and 13).
Given the low yields associated with aryl chlorides in
Suzuki cross-coupling reactions of pentafluorophenylboronic
acid and in direct arylation of pentafluorobenzene in our
previous report,12 we were pleased to find that a wide range
of aryl chlorides can now be employed with these new
conditions. Both activated and deactivated aryl chlorides are
compatible (entries 16 and 18-23) as are sterically encum-
bered aryl chlorides (entries 1 and 24). More functionalized
aryl chlorides can also be employed as illustrated by the high-
yielding reaction of the C2 chlorinated aporphine to generate
24 in 99% yield (entry 25). An aryl triflate may also be
employed as illustrated by entry 17. We also evaluated the
compatibility of these new reaction conditions with hetero-
cyclic aryl halides. For example, 3-chloropyridine can be
cross-coupled in good yield (entry 26) as can 3-bromoquino-
line (entry 27). In contrast, the use of 2- and 4-chloropyridine
results in less than 50% of the desired product and is a focus
of continuing effort and study. Additionally, 3- and 2-bro-
mothiophene (entries 28 and 29) and 3-bromofuran (entry
30) may be arylated in 70, 63, and 55% yields, respectively.
Other perfluoroaromatic compounds can also be arylated
in high yield. To evaluate the applicability of these conditions
to other aromatic compounds, 2-chlorotoluene was employed
as a model aryl halide to maintain the challenging oxidative
addition and steric bulk (Scheme 1). Under the standard
Scheme 1. Arylation of Substituted Perfluoroaromatics
(16) For a mechanistic discussion, see: Garcia-Cuadrado, D.; Braga, A.
A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066
and ref 12.
conditions, 2,3,5,6-tetrafluoroanisole and 2,3,5,6-tetrafluo-
ropyridine both reacted to give 94 and 97% isolated yields,
Org. Lett., Vol. 8, No. 22, 2006
5099

respectively. With 2,3,5,6-tetrafluorotoluene, 3 equiv was
found to give a better yield, allowing the isolation of the
arylated product in 96% yield. 1,3,5-Trifluorobenzene can
also be employed. In this case, 5 equiv of the arene was
employed to give 82% isolated yield.
the use of stoichiometric organometallic species when the
synthesis of these molecules is called for.
Acknowledgment. We thank NSERC, the Research
Corporation (Cottrell Scholar Award, K.F.), and the Uni-
versity of Ottawa for support of this work. Merck Frosst and
Boehringer Ingelheim are thanked for unrestricted research
funding. M.L. thanks the Ontario government for an Ontario
Graduate Student Scholarship.
In conclusion, the combination of Pd(OAc)2 with S-Phos
generates a catalyst that, in the presence of K2CO3 in iPrOAc
at 80 °C, is very effective for the direct arylation of
pentafluorobenzene and other polyfluorinated aromatics with
a wide range of aryl halides including sterically hindered
aryl chlorides and bromides and heterocyclic aryl halides.
The relative mildness of the reaction conditions and the broad
scope should make this method useful in the synthesis of
perfluoroaryl molecules and reduce the current reliance on
Supporting Information Available: Complete charac-
terization data for all new metal complexes and biaryl
products as well as experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0619967
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