Pd-catalyzed decarboxylative cross coupling of potassium polyfluorobenzoates with aryl bromides, chlorides, and triflates

Article abstract of DOI:10.1021/ol100008q

Chemical Equetion Presentation Pd-catalyzed decarboxylative cross coupling of potassium polyfluorobenzoates with aryl bromides, chlorides, and triflates is achieved by using diglyme as the solvent. The reaction is useful for synthesis of polyfluorobiaryls

Full text of DOI:10.1021/ol100008q

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1000-1003
Pd-Catalyzed Decarboxylative Cross
Coupling of Potassium
Polyfluorobenzoates with Aryl Bromides,
Chlorides, and Triflates
Rui Shang,†,‡ Qing Xu,‡ Yuan-Ye Jiang,‡ Yan Wang,‡ and Lei Liu*,†,‡
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua UniVersity, Beijing 100084, and
Department of Chemistry, UniVersity of Science and Technology of China, Hefei
230026, China
lliu@mail.tsinghua.edu.cn
Received January 3, 2010
ABSTRACT
Pd-catalyzed decarboxylative cross coupling of potassium polyfluorobenzoates with aryl bromides, chlorides, and triflates is achieved by
using diglyme as the solvent. The reaction is useful for synthesis of polyfluorobiaryls from readily accessible and nonvolatile polyfluorobenzoate
salts. Unlike the Cu-catalyzed decarboxylation cross coupling where oxidative addition is the rate-limiting step, in the Pd-catalyzed version
decarboxylation is the rate-limiting step.
Transition-metal-catalyzed decarboxylative coupling reac-
tions using carboxylic acids as aryl sources have unique
advantages.1 They do not use expensive and/or sensitive
organometallic reagents and generate CO2 without producing
toxic metal halides. Goossen et al. showed that through a
Pd/Cu bimetallic catalysis they could accomplish decarboxy-
lative coupling of certain benzoic acids and R-oxo carboxy-
lates with aryl halides and triflates.2 Myers,3 Forgione,4 and
other groups5 found that Pd could catalyze the decarboxy-
lative cross coupling of some carboxylic acids with olefins
and aryl iodides or bromides. Other recent studies by Tunge,
Li, Miura, Chruma, and other groups also highlighted the
synthetic utility of related decarboxylative reactions.6
We recently found that some Cu-only catalysts could
catalyze the decarboxylative coupling of potassium poly-
fluorobenzoates with aryl iodides and bromides.7 Here we
report that certain Pd-only systems can also catalyze the same
decarboxylative cross couplings, but importantly, with aryl
bromides, chlorides, and even triflates. Like the Cu-catalyzed
versions,7 the new Pd-catalyzed reactions can replace the
(2) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(b) Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy,
L. M. J. Am. Chem. Soc. 2007, 129, 4824. (c) Goossen, L. J.; Melzer, B.
J. Org. Chem. 2007, 72, 7473. (d) Goossen, L. J.; Knauber, T. J. Org.
Chem. 2008, 73, 8631. (e) Goossen, L. J.; Zimmermann, B.; Knauber, T.
Angew. Chem., Int. Ed. 2008, 47, 7103. (f) Goossen, L. J.; Rodriguez, N.;
Linder, C. J. Am. Chem. Soc. 2008, 130, 15248. (g) Goossen, L. J.; Rudolphi,
F.; Oppel, C.; Rodriguez, N. Angew. Chem., Int. Ed. 2008, 47, 3043. (h)
Goossen, L. J.; Zimmermann, B.; Linder, C.; Rodriguez, N.; Lange, P. P.;
Hartung, J. AdV. Synth. Catal. 2009, 351, 2667. (i) Goossen, L. J.; Linder,
C.; Rodriguez, N.; Lange, P. P. Chem.sEur. J. 2009, 15, 9336.
† Tsinghua University.
‡ University of Science and Technology of China.
(1) (a) Baudoin, O. Angew. Chem., Int. Ed. 2007, 46, 1373. (b) Goossen,
L. J.; Rodriguez, N.; Goossen, K. Angew. Chem., Int. Ed. 2008, 47, 3100.
10.1021/ol100008q  2010 American Chemical Society
Published on Web 01/29/2010

use of expensive but often less reactive8 fluorobenzene
organometallics in the synthesis of polyfluorobiaryls useful
to material9 and medicinal10 sciences. The new reactions also
provide a practical method complementary to Fagnou’s11 and
Daugulis’s12 fluorobiaryl synthesis through direct C-H
arylation of polyfluoroarene. Furthermore, through compu-
tational analysis we show that the Pd-catalyzed decarboxy-
lative cross coupling has a major mechanistic difference as
compared to the Cu-catalyzed versions.
Our work started with the decarboxylative coupling of
potassium pentafluorobenzoate with aryl chlorides. Note that
there were two literature examples5d,g for Pd-catalyzed
decarboxylative coupling of pentafluorobenzoic acid with
4-iodoanisole. Through tests (Table 1) it is found that in
many solvents (entries 1-4) the desired coupling reaction
does not proceed well. Only when diglyme is used as the
solvent (entry 5), the reaction takes place readily (yield )
88%) with a simple ligand (PCy3). The use of more popular
Ar-Cl activation ligands such as tBu3P, S-Phos, and Dave-
Phos13 does not produce a higher yield (entries 6-9),
whereas the use of other Pd salts (entries 10-12) gives good
results comparable to that of Pd(OAc)2. Decrease of the Pd
loading to 1 mol % (entry 13) affords a slightly lower yield
of 86%. Moreover, the same catalyst system can also be
applied to o-tolylbromide (entry 14). It is interesting that a
less electron-rich ligand (i.e., P(o-Tol)3) is more effective
for o-tolylbromide than PCy3 (entry 15).
Table 1. Pd-Catalyzed Decarboxylative Cross Coupling of
Potassium Pentafluorobenzoate with o-Tolylhalidea
entry
X
Pd source
ligand
P(Cy)3
P(Cy)3
P(Cy)3
P(Cy)3
P(Cy)3
P(t-Bu)3
S-Phos
solvent
NMP
DMA
DMF
yield %b
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
15
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd(OAc)2
Cl Pd2 (dba)3
Cl Pd(TFA)2
trace
trace
11
Mesitylene n.r.
diglyme
diglyme
diglyme
88
79
85
28
15
84
85
73
86
87
91
(3) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250. (b) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(c) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
10323.
Dave-Phos diglyme
JohnPhos
P(Cy)3
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
(4) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey,
M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(5) (a) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.; Jung, H. M.;
Lee, S. Org. Lett. 2008, 10, 945. (b) Moon, J.; Jang, M.; Lee, S. J. Org.
Chem. 2009, 74, 1403. (c) Becht, J.-M.; Le Drian, C. Org. Lett. 2008, 10,
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Tetrahedron 2009, 65, 4635. (g) Voutchkova, A.; Coplin, A.; Leadbeater,
N. E.; Crabtree, R. H. Chem. Commun. 2008, 6312. (h) Wang, C.; Piel, I.;
Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194. (i) Shang, R.; Fu, Y.; Li,
J. B.; Zhang, S. L.; Guo, Q. X.; Liu, L. J. Am. Chem. Soc. 2009, 131,
5738.
P(Cy)3
Cl Pd(MeCN)2Cl2 P(Cy)3
Cl Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
P(Cy)3
P(Cy)3
P(o-Tol)3
a All the reactions were carried out at 0.25 mmol scale in 0.5 mL of
solvent. b GC yields using biphenyl as the internal standard. c 1 mol % of
Pd(OAc)2 and 2 mol % of ligand were used.
(6) (a) Waetzig, S. R.; Rayabarupu, D. K.; Weaver, J. D.; Tunge, J. A.
Angew. Chem., Int. Ed. 2006, 45, 4977. (b) Waetzig, S. R.; Tunge, J. A.
J. Am. Chem. Soc. 2007, 129, 14860. (c) Fields, W. H.; Khan, A. K.; Sabat,
M.; Chruma, J. J. Org. Lett. 2008, 10, 5131. (d) Pi, S.-F.; Tang, B.-X.; Li,
J.-H.; Liu, Y.-L.; Liang, Y. Org. Lett. 2009, 11, 2309. (e) Bi, H.-P.; Zhao,
L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed. 2009, 48, 792. (f) Bi,
H.-P.; Chen, W.-W.; Liang, Y.-M.; Li, C.-J. Org. Lett. 2009, 11, 3246. (g)
Duan, Z.; Ranjit, S.; Zhang, P.; Liu, X. Chem.sEur. J. 2009, 15, 3666. (h)
Yeagley, A. A.; Lowder, M. A.; Chruma, J. J. Org. Lett. 2009, 11, 4022.
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Miyasaka, M.; Fukushima, A.; Satoh, T.; Hirano, K.; Miura, M. Chem.sEur.
J. 2009, 15, 3674.
Extending the model reaction to a variety of substrates
showed that both electron-rich and electron-poor aryl bro-
mides and chlorides can be successfully converted tolerating
a range of functional groups (Table 2). In several cases
(entries 1, 4, and 15), aryl triflates (but not aryl tosylates,
see entry 13) can also be successfully converted. Ortho-
substitution can be tolerated in the transformation (entries
3, 5, 7, and 8). In addition, some heteroaryl bromides and
chlorides can be used to produce the corresponding poly-
fluorobiaryls (entries 21 and 22).
The scope of the reaction with respect to fluoroarene is
shown in Table 3, where a higher loading of Pd catalyst is
required. Under the optimized conditions, potassium monof-
luorobenzoate cannot be efficiently converted, unless an
ortho-Cl or ortho-CF3 group is added (entries 1-3). Once
two ortho-F atoms are added, decarboxylative coupling of
potassium bisfluorobenzoate can proceed smoothly with both
4-methoxyphenyl bromide and chloride (entries 4-7). Simi-
lar reactions are also observed with tri- and tetrafluoroben-
zoates carrying two ortho-F atoms (entries 9-12), but not
with a trifluorobenzoate carrying a single ortho-F (entry 8).
Note that in entries 9 and 10 some di- or triarylated byproduct
are observed. For entry 9, the yields for mono-, di-, and
triarylated products are 14%, 21%, and 49%, respectively.
(7) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.; Liu, L. Angew.
Chem., Int. Ed. 2009, 48, 9350.
(8) Sakai et al. developed a special protocol for the Suzuki coupling
reaction of pentafluorophenylboronic acid, which is an inactive substrate
under normal conditions. See: Korenaga, T.; Kosaki, T.; Fukumura, R.;
Ema, T.; Sakai, T. Org. Lett. 2005, 7, 4915.
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(b) Zacharias, P.; Gather, M. C.; Rojahn, M.; Nuyken, O.; Meerholz, K.
Angew. Chem., Int. Ed. 2007, 46, 4388.
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Z. B.; Henderson, R. A.; Keith, J. C., Jr.; Harris, H. A. J. Med. Chem.
2005, 48, 3953. (b) de Candia, M.; Liantonio, F.; Carotti, A.; De Cristofaro,
R.; Altomare, C. J. Med. Chem. 2009, 52, 1018.
(11) (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.
(12) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (c) Do,
H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185.
(13) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338.
Org. Lett., Vol. 12, No. 5, 2010
1001

For entry 10, the yields for mono- and diarylated products
are 31% and 58%. Thus, the direct arylation of acidic C-H
bonds of polyfluoroarenes11,12 is a side reaction in Pd-
catalyzed decarboxylative coupling of polyfluorobenzoates.
ligand to form IN3 and its coordination isomer IN4. Note
that the barrier between IN3 and IN4 is only +16.8 kcal/
mol meaning that they can readily isomerize to each other.
From IN4, the decarboxylation transition state (TS3) is
indentified as a four-coordinate Pd(II) species. From IN3 to
TS3, the free energy increases by +24.0 kcal/mol, and
therefore, decarboxylation is the rate-limiting step. The
immediate product of decarboxylation is a three-coordinate
Pd(II) complex (IN5), which undergoes reductive elimination
readily to form the biaryl product through TS4 with a low
barrier of +11.7 kcal/mol.
Table 2. Pd-Catalyzed Decarboxylative Cross Coupling of
C6F5COOK with Aryl Bromides, Chlorides, and Triflatesa
Table 3. Pd-Catalyzed Decarboxylative Cross Coupling of
Various Potassium Polyfluorobenzoatesa
a All the reactions were carried out at 0.25 mmol scale in 0.5 mL of
diglyme. For more details, see the Supporting Information. b Isolated yields
were calculated based on the quantity of aryl halide.
a All the reactions were carried out at 0.25 mmol scale in 0.5 mL of
diglyme. For more details, see the Supporting Information. b Isolated yields
were calculated based on the quantity of aryl halide. c Di- and triarylations
were observed.
To understand the mechanism of the Pd-catalyzed decar-
boxylative cross coupling, we carried out DFT calculations
(Figure 1).14 Through the analysis, we first concluded that
it is Pd(II), but not Pd(0), that promotes the decarboxylation
of the carboxylic acid. Accordingly, we proposed that in a
catalytic cycle a monocoordinated Pd(0) complex first
activates the aryl halide.15,16 When PMe3 is used as a model
ligand, the Pd(0) complex forms a complex with PhCl (IN1),
which undergoes oxidative addition through TS1 to produce
a Pd(II) intermediate (IN2). The energy barrier for oxidative
addition is +14.5 kcal/mol. IN2 then exchanges the anionic
The above results reveal a major difference between Cu-
and Pd-catalyzed decarboxylative couplings. In Cu-catalyzed
(15) Oxidative addition is not a rate-limiting step in the decarboxylative
cross coupling because a mechanistic related Pd-catalyzed cross coupling
reaction (e.g. Suzuki coupling) does not require a high temperature to
proceed. Therefore, we do not discuss the detailed mechanism of the
oxidative addition step, which may be complicated by many factors. For
oxidative addition of an aryl halide to monoligated Pd(0), see: (a) Ahlquist,
M.; Fristrup, P.; Tanner, D.; Norrby, P.-O. Organometallics 2006, 26, 2066.
(b) Li, Z.; Fu, Y.; Guo, Q.-X.; Liu, L. Organometallics 2008, 27, 4043.
(16) For oxidative addition to an anionic Pd(0) species, see: (a) Amatore,
C.; Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993, 115, 9531. (b) Amatore,
C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
(14) For the previous theoretical analysis on the related subject, see:
(a) Goossen, L. J.; Thiel, W. R.; Rodriguez, N.; Linder, C.; Melzer, B.
AdV. Synth. Catal. 2007, 349, 2241. (b) Zhang, S.-L.; Fu, Y.; Shang, R.;
Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2010, 132, 638.
1002
Org. Lett., Vol. 12, No. 5, 2010

Figure 1. Proposed mechanism for Pd-catalyzed decarboxylative cross-coupling.
versions, the rate-limiting step is oxidative addition of the
Cu(I) intermediate to aryl halide.8 This conclusion is
consistent with the observation that aryl chlorides cannot be
converted by the Cu catalyst. By comparison, in Pd-catalyzed
versions the rate-limiting step should be decarboxylation. To
support this mechanistic proposal, we compared the Pd-
catalyzed decarboxylative couplings of potassium 2,6-
difluorobenzoate with 4-methoxyphenyl bromide and chloride
(Scheme 1). For the bromide, the more electron-rich ligand
(PCy3) affords a worse result due to the side reaction,
whereas the less electron-rich ligand P(o-Tol)3 does not show
Note that the ligand effects can be used for selective
decarboxylative cross couplings. A good example is shown
in Scheme 2, where two different polyfluorophenyl groups
are sequentially coupled to an aryl halide.
Scheme 2. Selective Decarboxylative Cross Couplings
Scheme 1. Effects of the Ligands on the Cross Coupling
In summary, we report Pd-catalyzed decarboxylative cross
coupling of potassium polyfluorobenzoates with aryl bro-
mides, chlorides, and triflates. The reaction is practical for
synthesis of polyfluorobiaryls from readily accessible and
nonvolatile polyfluorobenzoate salts. Unlike the Cu-catalyzed
decarboxylation cross coupling where oxidative addition is
the rate-limiting step, in the Pd-catalyzed version decar-
boxylation is the rate-limiting step.
this problem. The explanation is presumably that the more
electron-rich ligand causes a faster oxidative addition and
therefore produces the aryl-Pd(II) intermediate too rapidly
to be effectively consumed by the benzoate. On the other
hand, for the aryl chloride that will undergo oxidative
addition less rapidly, the use of the PCy3 ligand does not
cause much side reaction. Thus, a good balance between the
decarboxylation and oxidative addition steps is critical to
the success of decarboxylative cross couplings. One method
to control the balance was to use a bimetallic catalyst (e.g.,
Pd for oxidative addition and Cu for decarboxylation).3 We
showed here that under some circumstances a strategic
change of ligand can also control the balance.
Acknowledgment. We thank NSFC (Nos. 20932006,
20802040).
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100008Q
Org. Lett., Vol. 12, No. 5, 2010
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