Room-temperature direct arylation of polyfluorinated arenes under biphasic conditions

Article abstract of DOI:10.1021/ol1006136

Figure presented New biphasic conditions for the palladium-catalyzed direct arylation of electron-poor fluorinated arenes have been developed. Taking advantage of biphasic chemistry, the use of an immiscible mixture of water and an organic solvent allows

Full text of DOI:10.1021/ol1006136

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2116-2119
Room-Temperature Direct Arylation of
Polyfluorinated Arenes under Biphasic
Conditions
Olivier Rene´* and Keith Fagnou†
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, ON, Canada K1N 6N5
orene088@uottawa.ca
Received March 15, 2010
ABSTRACT
New biphasic conditions for the palladium-catalyzed direct arylation of electron-poor fluorinated arenes have been developed. Taking advantage
of biphasic chemistry, the use of an immiscible mixture of water and an organic solvent allows complete solubilization of all components of
the system, enabling the reaction to proceed at room temperature in yields up to 99%.
Transition-metal-catalyzed transformations at C-H bonds
have undergone intensive development over the past de-
cade.1,2 Tremendous efforts have focused on C-C bond-
forming reactions to access biaryl systems using simple
arenes in place of preactivated coupling partners.3 However,
these processes require forcing conditions generally associ-
ated with the use of high temperatures, typically above 100
°C, which can represent serious limitations for both substrate
compatibility and large-scale applications. To broaden the
applicability of these transformations, there is a need to
develop milder reaction conditions that can proceed at lower
temperatures.
Scheme 1
.
Precedent in C-H Functionalization of
Polyfluoroarenes
† Prof. Keith Fagnou passed away unexpectedly on November 11, 2009.
(1) For selected reviews on C--H bond functionalization, see: (a) Lewis,
J. C.; Bergman, R. C.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (b)
Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva, A.
Synlett 2006, 3382. (c) Ferreira, E. M.; Zhang, H.; Stoltz, B. M. Tetrahedron
2008, 64, 5987. (d) Lyons, T. W.; Sanford, M. S. Chem. ReV. 2010, 110,
An alternative to using traditional organic solvents in
palladium-catalyzed direct arylation is to perform the trans-
formation in an aqueous medium.4 This strategy was
employed by Greaney and co-workers5 and proved to be
efficient for the direct arylation of heteroarenes at temper-
atures as low as 50 °C. More recently, the urea-directed C-H
1147
.
(2) For selected reviews on direct arylation, see: (a) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (b) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (c) Campeau, L.-C.;
Fagnou, K. Chem. Commun. 2006, 1253. (d) Satoh, T.; Miura, M. Chem.
Lett. 2007, 36, 200. (e) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949.
(f) Pascual, S.; de Mendoza, P.; Echavarren, A. M. Org. Biomol. Chem.
2007, 5, 2727. (g) Catellani, M.; Motti, E.; Della Ca’, N.; Ferraccioli, R.
Eur. J. Org. Chem. 2007, 4153. (h) McGlacken, G. P.; Bateman, L. M.
Chem. Soc. ReV. 2009, 38, 2447. (i) Ackermann, L.; Vicente, R.; Kapdi,
(4) For a review on organic reactions performed on water, see: Chanda,
A.; Fokin, V. Chem. ReV. 2009, 109, 725.
A. R. Angew. Chem., Int. Ed. 2009, 48, 9792
.
(3) For selected reviews on traditional cross-coupling reactions, see: (a)
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley- VCH: New York, 1998. (b) Hassan, J.; Se´vignon, M. S.; Gozzi, C.;
Shulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (c) Baudoin, O. Eur.
J. Org. Chem. 2005, 20, 4223.
(5) (a) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int.
Ed. 2007, 46, 7996. (b) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org.
Lett. 2008, 10, 2717. (c) Ohnmacht, S. A.; Patrizia, M.; Culshaw, A. J.;
Greaney, M. F. Chem Commun. 2008, 10, 1241. (d) Ohnmacht, S. A.;
Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010, 12, 224.
10.1021/ol1006136  2010 American Chemical Society
Published on Web 04/09/2010

activation of electron-rich arenes under Pd(II) catalysis was
accomplished at room temperature using water as the reaction
solvent.6 To our knowledge, no reports have appeared where
mild aqueous conditions were successfully employed for the
direct arylation of electron-deficient arenes.7 Given the broad
applicability of these types of polyarenes in material chem-
istry,8 their synthesis under mild conditions would be
valuable.
The phosphine ligand also exerted an important effect on
the reaction outcome. For example, RuPhos allowed an
improved yield of 91% over 16 h compared to S-Phos (Table
1, entry 5). Also, the reaction time could be decreased to
5 h using DavePhos (Table 1, entry 6), and ultimately the
coupling product 3 could be obtained in 90% isolated yield
in only 2 h with MePhos13 (Table 1, entry 7).
Drawing inspiration from recent advances in the develop-
ment of mild C-H functionalization conditions, we decided
to investigate new strategies for the direct arylation of
electron-deficient polyfluorinated arenes at lower tempera-
ture,9 employing water as a cosolvent in the reaction medium.
Herein, we describe the successful development of a biphasic
catalytic system10 that provides access to a variety of biaryls
at ambient temperature.
Table 1. Optimization of Reaction Conditions
Initial reaction development and optimization was per-
formed with 4-iodotoluene 1 and pentafluorobenzene 2. After
extensive screening of solvents, the best results were obtained
with the use of i-PrOAc, DMF or EtOAc. Under these
conditions, no yields higher than 68% could be obtained
without addition of water (Table 1, entries 1-3). Interest-
ingly, the yield could be significantly increased when using
a solvent mixture of water and EtOAc.10 We were pleased
to find that the use of a 2.5:1 mixture of EtOAc and water
could improve the reaction yield up to 83% (Table 1, entry
4). Taking advantage of biphasic chemistry, it was reasoned
that by performing the reaction under such conditions, a
complete solubilization of the inorganic components of the
reaction could be achieved. In particular, the base, which
has been shown to be crucial for the concerted metalation-
deprotonation transition state to occur,11 is only sparsely
soluble in organic solvents.12
time
(h)
GC
entry
solvent
i-PrOAc
DMF
EtOAc
EtOAc/H2O (2.5:1)
EtOAc/H2O (2.5:1)
EtOAc/H2O (2.5:1)
EtOAc/H2O (2.5:1)
EtOAc/H2O (2.5:1)
ligand
yield (%)a
1
2
3
4
5
S-Phos
S-Phos
S-Phos
S-Phos
RuPhos
DavePhos
MePhos
MePhos
16
16
16
16
16
5
47
59
68
83
91
92
92 (90)
0
6
7
2
16
8b
a Determined by GC analysis relative to tetradecane as an internal
standard (isolated yield in parentheses). b No Ag2CO3 added.
(6) Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Angew. Chem., Int. Ed.
2010, 49, 781.
The silver carbonate additive was required for the coupling
reaction to proceed.14 Indeed, without the addition of
Ag2CO3, no conversion to product 3 was observed (Table
1, entry 8) and only the starting materials were recovered.
The role of silver(I) is attributed to a plausible abstraction
of the iodine ligand from the Pd(II) complex, thereby
generating an electrophilic cationic palladium intermediate.15
In the course of the optimization studies, we demonstrated
that, under these biphasic conditions, the ratio of the two
solvent components is crucial to ensure optimal conversion
(Figure 1). There is a narrow window around a 2.5:1 ratio
of EtOAc and water in which the highest yields are obtained,
and any deviation from this ratio results in lower conversions.
(7) For selected examples of direct arylation of electron-poor (het-
ero)arenes, see :(a) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-
Laperle, M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.;
Lecavalier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291. (b) Do,
H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.
(c) Caron, L.; Campeau, L.-C.; Fagnou, K. Org. Lett. 2008, 10, 4533. (d)
Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 14296.
(8) (a) Weck, M.; Dunn, A. R.; Matsumoto, K.; Coates, G. W.;
Lobkovsky, E. B.; Grubbs, R. H. Angew. Chem., Int. Ed. 1999, 38, 2741.
(b) Tsuzuki, T.; Shirasawa, N.; Suzuki, T.; Tokito, S. AdV. Mater. 2003,
15, 1455. (c) Montes, V. A.; Li, G.; Pohl, R.; Shinar, J.; Anzenbacher, P.,
Jr. AdV. Mater. 2004, 16, 2001.
(9) C-H bond activation of polyfluoroarenes requires high temperatures
(80-140 °C); see: (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 8754. (b) Lafrance, M.; Shore, D.; Fagnou,
K. Org. Lett. 2006, 8, 5097. (c) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 1128. (d) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama,
T. J. Am. Chem. Soc. 2008, 130, 16170. (e) Wei, Y.; Kan, J.; Wang, M.;
Su, W.; Hong, M. Org. Lett. 2009, 11, 3346. (f) Johnson, S. A.; Huff, C. W.;
Mustafa, F.; Saliba, M. J. Am. Chem. Soc. 2008, 130, 17278. (g) Xie, K.;
Yang, Z.; Zhou, X.; Li, X.; Wang, S.; Tan, Z.; An, X.; Guo, C.-C. Org.
Lett. 2010, 12, 1564.
(13) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550.
(14) For examples of silver(I) used in direct arylation, see: (a) Lebrasseur,
N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (b) Campeau, L.-C.;
Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (c)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
(15) For examples of cationic Pd(II) complexes generated by Ag(I)
abstraction of the iodide ligand, see: (a) Grove, D. M.; van Koten, G.;
Louwen, J. N.; Noltes, J. G.; Spec, A. L. J. Am. Chem. Soc. 1982, 104,
6609. (b) Denmark, S. E.; Schnute, M. E. J. Org. Chem. 1995, 60, 1013.
(c) Hirabayashi, K.; Mori, A.; Kawashima, J.; Suguro, M.; Nishihara, Y.;
Hiyama, T. J. Org. Chem. 2000, 65, 5342. (d) Overman, L. E.; Poon, D. J.
Angew. Chem., Int. Ed. 1997, 36, 518.
(10) For selected examples of transition metal catalyzed reactions under
biphasic solvent conditions, see :(a) Kurahashi, T.; Shinokubo, H.; Osuka,
A. Angew. Chem., Int. Ed. 2006, 45, 6336. (b) Bottarelli, P.; Costa, M. J.
Mol. Catal. A: Chem. 2008, 289, 82. (c) Lautens, M.; Mancuso, J.; Grover,
H. Synthesis 2004, 2006. (d) Datta, A.; Plenio, H. Chem. Commun. 2003,
13, 1504.
(11) For an analysis of the CMD mechanism, see: Gorelsky, S. I.;
Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848.
(12) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
Org. Lett., Vol. 12, No. 9, 2010
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Table 2. Scope of Aryl Iodides with Pentafluorobenzene
Figure 1. Effect of the ratio of EtOAc to water on the yield of the
reaction using conditions from Table 1, entry 4.
Illustrative examples with respect to the aryl iodide are
shown in Table 2. In addition to 4-iodotoluene, which
possesses a minimal steric and electronic bias, (Table 2, entry
1), electron-withdrawing groups such as a ketone, an ester,
or a trifluoromethyl group are well tolerated, giving rise to
the coupling products in 85% to 96% yields (Table 2, entries
2-4). Aryl iodides bearing electron-donating groups at the
para and ortho positions also give excellent yields of 92%
and 99% (Table 2, entries 5 and 6). Sterically demanding
substrates are compatible as exemplified by products 9 and
10 obtained in 78% and 95% yields, respectively (Table 2,
entries 7 and 8). Interestingly, 5-iodoindole is also tolerated
to give biaryl 11 in 93% yield without arylation of the azole
ring (Table 2, entry 9).
With regard to the polyfluoroarene coupling partner,
tetrafluoro- and trifluoroarenes were found to be efficient for
the coupling reaction (Table 3). For example, tetrafluorinated
biaryls 12-14 (Table 3, entries 1-3) can be obtained in
excellent yields ranging from 91% to 98%. Symmetrical
arenes having more than one potential site of arylation require
a larger excess of the polyfluoroarene component in order
for the monoarylated product 15 and 16 to be obtained in
90% and 88% yields, respectively (Table 3, entries 4 and
5). Furthermore, trifluorinated arenes can also be coupled
efficiently and selectively to give only monoarylation
products in 81-99% yields (Table 3, entries 6-8).
A preliminary investigation of the applicability of our new
biphasic direct arylation conditions to classes of substrates
other than polyfluorinated arenes led to promising results.
We were pleased to observe that the method is suitable for
the direct arylation of halogenated thiophenes. We recently
demonstrated that introduction of a chlorine atom enhances
the propensity for heteroarenes to undergo C-H bond
functionalization.16
at the C5 position at only 60 °C to afford products 20 and
21 in 77% and 61% yields, respectively (Table 4, entries 1
and 2).17 3-Chlorothiophene also reacts selectively at the C2
position, providing biaryl product 22 in good yield (Table
4, entry 3).18 More interestingly, 3-bromothiophene is a
compatible coupling partner and C-H bond cleavage occurs
Whereas our previous examples with chlorinated hetero-
cycles required elevated temperatures,16 under these new
biphasic conditions, 2-chlorothiophene reacts regioselectively
(16) Lie´gault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem.
2010, 75, 1047.
(17) A yield of 31% was obtained with 2-chlorothiophene at ambient
temperature after 16 h.
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Org. Lett., Vol. 12, No. 9, 2010

Table 3. Scope of Polyfluoroarenes with 4-Iodotoluene
Table 4. Arylation of Halogenated Thiophenes
In conclusion, we have developed mild biphasic conditions
for the direct arylation of electron-deficient arenes at room
temperature. The conditions are general and effective for a
variety of aryl iodides and polyfluorinated arenes as coupling
partners, and excellent yields are generally obtained. Other
halogenated thiophenes are also compatible and led to the
heterobiaryl products in good yields. In addition to its
synthetic utility, the beneficial influence of a biphasic solvent
mixture in a direct arylation process should demonstrate the
viability of water as a cosolvent in the development of milder
reaction conditions.
Acknowledgment. We thank NSERC, the University of
Ottawa, AstraZeneca, Amgen, and Eli Lilly for financial
support. O.R. thanks OGS and FQRNT for graduate student
scholarships. Prof. Louis Barriault (University of Ottawa)
and the Fagnou Group are thanked for their critical reading
of the manuscript.
a 10 equiv of polyfluoroarene was used.
Note Added after ASAP Publication. Figure 1 was
missing the x axis of the graph in the version published asap
April 9, 2010; the correct version reposted April 16, 2010.
in the presence of a reactive C-Br bond (Table 4, entry 4).
The presence of the chlorine and bromine substituents on
these products are valuable synthetic handles that can be used
for subsequent transformations.2,3
Supporting Information Available: Detailed experimen-
tal procedures and chraracterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Traces of another regioisomer were observed by GC-MS with the
use of 3-chloro- and 3-bromothiophene.
OL1006136
Org. Lett., Vol. 12, No. 9, 2010
2119