Pd-catalyzed decarboxylative cross-coupling of perfluorobenzoic acids with simple arenes

Article abstract of DOI:10.1016/j.tetlet.2013.03.086

Using a Pd/Ag bimetallic system, arylations of simple arenes with perfluorobenzoic acids have been achieved by decarboxylative C-H bond functionalization, providing the desired cross-coupling products in moderate to good yields. These straightforward protocols provide new and efficient methods for the synthesis of fluorobiphenyl scaffolds under simple and mild conditions.

Full text of DOI:10.1016/j.tetlet.2013.03.086

Tetrahedron Letters 54 (2013) 2833–2836
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed decarboxylative cross-coupling of perfluorobenzoic acids
with simple arenes
Hai-Qing Luo a, , Wen Dong a, Teck-Peng Loh b
⇑
a Department of Chemistry & Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, PR China
b Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 637371 Singapore, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a Pd/Ag bimetallic system, arylations of simple arenes with perfluorobenzoic acids have been
achieved by decarboxylative C–H bond functionalization, providing the desired cross-coupling products
in moderate to good yields. These straightforward protocols provide new and efficient methods for the
synthesis of fluorobiphenyl scaffolds under simple and mild conditions.
Received 11 January 2013
Revised 10 March 2013
Accepted 19 March 2013
Available online 27 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pd-catalyzed
Crosscoupling
Fluorobiphenyl
Simple arenes
Decarboxylative
Transition-metal-catalyzed decarboxylative coupling is an
important and very attractive research point of organic synthesis
in recent years.1 This method avoids the preparation and use of
stoichiometric organometallic reagents such as boronic acids and
releases gaseous carbon dioxide as the leaving group instead of of-
ten toxic or expensive metal salts. Representative examples in-
clude the decarboxylative coupling of benzoic acids with aryl
halides or triflates with carefully optimized Pd/Cu catalytic sys-
tems,2 the decarboxylative olefination, and biaryl coupling of aro-
matic carboxylic acids with Pd/Ag catalytic systems,3 and other
recent developments of Pd-catalyzed decarboxylative coupling.4
However, the requirement of prefunctionalization of the coupling
partners to activate the aromatic C–H bonds, for example, using
aryl halides or aryl triflates as the synthetic substrates, limited
the application of these kinds of decarboxylative aryl–aryl cross-
couplings. To overcome this challenge, cross-coupling of unactivat-
ed arenes was developed via direct C–H activation. In that case, a
directing group was usually necessary for the high chemo- and reg-
ioselectivity of the transformation.5 An alternative strategy to
avoid installing a directing group for decarboxylative cross-cou-
pling was the use of electron-rich heterocycles,6 or intramolecular
direct arylation through Pd-catalyzed C–H activation.7
scaffolds,9 which have a potential value in the field of material
science.10
Studies on the preparation of polyfluorobiaryls via direct cross-
coupling are widely reported for its considerable advantages over
traditional organometallical transformation process.11,12 Among
these current progresses, it is of note that decarboxylative coupling
of electron-deficient perfluorobenzoates represented one to
polyfluorobiaryls.12
Nevertheless, to the best of our knowledge, the direct cross-
coupling of perfluorobenzoic acids with simple arenes instead of
aryl halides or triflates is unprecedented to date (Scheme 1, Eq.
1). Herein we describe the first example of direct Pd-catalyzed
decarboxylative arylation of perfluorobenzoic acids with simple
arenes via C–H bond functionalization (Scheme 1, Eq. 2). With a
low loading of Pd catalyst (5 mol %) and ligand free, this direct ary-
lation reaction provides a novel and efficient method for the syn-
thesis of perfluorobiphenyls.
We began our investigation by choosing commercially available
perfluorobenzoic acid (1a) and p-xylene (2a) as our initial model
substrates. The effect of reaction parameters on the conversion
was summarized in Table 1. It was found that the desired decarb-
oxylative crossing-coupling product 3a was provided with a
remarkable 88% isolated yield in the presence of the catalytic
amount of Pd(OAc)2 and stoichiometric Ag2CO3 at 130 °C in DMSO
solution (Table 1, entry 5), whereas, small amounts of by-products
3aa and 3ab through homo-coupling and oxidation of arene were
detected. Other commonly used palladium sources, such as
Pd(TFA)2, PdCl2, Pd(CH3CN)Cl2, and Pd(PhCN)Cl2 were less effective
As part of our ongoing research on efficient palladium-catalyzed
direct cross-coupling reaction,8 we aimed at the difficult but highly
desirable coupling for the construction of complicated fluorinated
⇑
Corresponding author. Tel.: +86 797 8393536; fax: +86 797 8393670.
E-mail address: luohaiq@sina.com (H.-Q. Luo).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.086

2834
Direct Arylation with Perfluoroarenes reported by Liu
H.-Q. Luo et al. / Tetrahedron Letters 54 (2013) 2833–2836
conversion (Table 1, entries 9 and 10). After further optimization
on the catalyst loading of Pd(OAc)2, the coupling product was ob-
tained without any alteration in yield when the amount of
Pd(OAc)2 was reduced to 5 mol % (Table 1, entries 11–13).
Based on the optimized condition of direct decarboxylative ary-
lation of pentafluorobenzoic acid with simple arenes, we pro-
ceeded to explore the scope of the decarboxylative arylation
reaction of polyfluorobenzoic acid derivatives with various simple
arenes. The results were presented in Table 2. It is intriguing to
note that chloride substituent in the substrate was tolerant to
the reaction system, despite lack of selectivity affording slightly re-
duced but acceptable yields of the desired product (Table 2, entry
3). Results of 1,2- and 1,3-disubstituted benzenes indicate that the
steric effect dominates the reaction regioselectivity at the prefera-
ble less hindered C–H position (Table 2, entries 4 and 5). Less com-
parably active polyfluorobenzoic acid substrates, even bearing
electron-donating group such as MeO – were also sustainable to
the decarboxylative arylation reaction under the same condition
(Table 2, entries 7–8).
Pd or Cu
X
Fn
Ligand
+
R
Fn
(1)
R
COOK
X = Cl, Br, I, OTf
Our work via C-H functionalization
Pd(II)
Ag2CO3
H
Fn
Fn
+
(2)
R
COOH
R
Scheme 1. Decarboxylative arylation of perfluorobenzoic acids.
or completely ineffective (Table 1, entries 1–4). The yields col-
lapsed significantly when the solvent was replaced by DMF, 1,4-
dioxane, or NMP (Table 1, entries 6–8). DMSO proved to be the best
choice, presumably because of its dual functions, not only as sol-
vent but also as a ligand to activate the Pd catalyst and prevent
the formation of palladium black.13 In addition, replacement of
the oxidant Ag2CO3 with Cu(OAc)2 or AgOAc led to lower reaction
Aromatic heterocycle was also subjected to the reaction
(Scheme 2). We are happy to find that the desired cross-coupling
Table 2
Decarboxylative arylation of polyfluorobenzoic acid 3a with various simple arenes 2a
Pd(OAc)2 (5 mol%)
Ag2CO3 (2 equiv)
Fn
Fn
+
R
0.1 mL DMSO
130 oC, 12-16 h
COOH
R
Yieldb (%)
89
H
Table 1
Direct arylation of pentafluorobenzoic acid 1a with p-xylene 2aa
3
2
1
F
Entry
1
Polyfluorobenzoic acid
Arene
Product
F
F
F
F
F
F
F
F
F
F
F
F
3a
Cat. Pd
Oxidant
COOH
3a
F
COOH
F
F
+
70c
o:m:p
=1:2:2
O
solvent, 130 °C
12 h
+
F
F
F
H
1a
2a
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
+
COOH
F
F
3ab
Cl
65
o:m:p
=1:2:2
3aa
F
F
F
Entry
1
Pd (mol %)
Oxidant
Solvent
DMSO
(0.1 mL)
DMSO
(0.1 mL)
DMSO
(0.1 mL)
DMSO
(0.1 mL)
DMSO
(0.1 mL)
DMF
(0.1 mL)
1,4-Dioxane
(0.1 mL)
NMP
(0.1 mL)
DMSO
(0.1 mL)
DMSO
(0.1 mL)
DMSO
(0.1 mL)
DMSO
(0.1 mL)
DMSO
Yield of 3ab (%)
COOH
F
F
Pd(TFA)2
(10)
PdCl2
(10)
Pd(CH3CN)Cl2
(10)
Pd(PhCN)Cl2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(7.5)
Pd(OAc)2
(5)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Cu(OAc)2
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
(2.0 equiv)
Ag2CO3
44
1
2
79
F
F
F
2:1 = 6.3:1
2
5
COOH
3
53
0
F
F
80
1
2
4
F
F
F
1:2 = 2:2:1
COOH
5
88
32
36
34
19
41
87
89
54
F
F
6
F
F
F
82
65
73
7
COOH
F
8
F
F
H3C
F
F
9
3g
3h
COOH
10
11
12
13
F
O
F
F
COOH
F
Pd(OAc)2
(2.5)
a
Reactions were performed in a sealed tube under air with polyfluorobenzoic
(2.0 equiv)
(0.1 mL)
acid 1 (0.3 mmol) and simple arenes 2 (0.9 mL).
b
a
Isolated yield based on polyfluorobenzoic acids.
Reactions were performed in a sealed tube under air with pentafluorobenzoic
c
Yield determined as a mixture of isomers, and the ratio of isomers was calcu-
acid 1a (0.3 mmol) and p-xylene 2a (0.9 mL).
lated by GC–MS or/and 19F NMR.
b
Isolated yield based on pentafluorobenzoic acid.

H.-Q. Luo et al. / Tetrahedron Letters 54 (2013) 2833–2836
2835
A mechanism similar to the one proposed by Larrosa6a could be
operative here to explain the formation of the decarboxylative cou-
pling products and by-products in two intertwined catalytic cycles
(Scheme 4). First, the palladium was inserted into the benzene ring
via a reversible electrophilic palladation (I and II) process, which
was reported by Van Helden and Sasson.15 Decarboxylation using
metal carbonates was well-established in the literature,16 so a sil-
ver species facilitated decarboxylative activation step (IV and V). In
these processes, II and V could lead to two by-products 4a and VI.
From the direct arylation of perfluoroarenes with simple arenes, 4a
could be easily recycled via oxidative arylation process with simple
arene to obtain the same product 3f (Scheme 4, catalytic cycle A).
Transmetallation of Ar–Pd species II with silver species intermedi-
ates V would then afford the palladium intermediate III, which
could produce the coupled product 3f through reductive elimina-
tion. Finally, oxidation of Pd0 to PdII (I), also performed by the silver
salt, completed the arylation cycle.
In conclusion, we have developed an efficient Pd catalyzed
method for the direct decarboxylative C–H arylation that allows
the intermolecular coupling of a variety of electron-poor benzoic
acids with simple arenes, based on a Pd/Ag bimetallic system.17
With a low loading of Pd catalyst (5 mol %) and ligand free, the
reaction provides the rapid and practical synthesis of perfluorobi-
phenyls, without any prefunctionalization chemistry being
necessary.
F
F
Pd(OAc)2 (5 mol%)
Ag2CO3 (2.0 equiv)
HOAc (1.0 equiv)
F
F
F
F
F
O
O
F
S
H
+
S
H
DMF/DMSO = 20/1
120 oC, 12 h
F
F
5
6a
4a
79% yield
F
F
Pd(OAc)2 (5 mol%)
Ag2CO3 (1.0 equiv)
HOAc (1.0 equiv)
F
F
F
F
O
O
F
S
+
H
S
COOH
DMF/DMSO = 20/1
130 oC, 12 h
F
F
1a
F
5
6a
77% yield
Scheme 2. Arylation of pentafluoroarene and pentafluorobenzoic acid with
aromatic heterocycle.
F
F
F
F
F
F
F
F
Pd(OAc)2 (7.5 mol%)
Ag2CO3 (2 equiv)
+
H
H
0.2 mL DMSO
120 oC, 12h
F
F
4a
3f
2
88%yield
Scheme 3. Arylations of pentafluorobenzene with benzene.
Acknowledgements
product was obtained both using pentafluorobenzene and penta-
fluorobenzonic acid in good yield.14
The authors thank the NSF of Jiangxi Provincial Education
Department (GJJ12570) for the financial support.
In order to confirm the possible existence of the silver species
facilitated decarboxylative activation step, the electron-deficient
pentafluorobenzene 4a was reacted with benzene under very sim-
ilar reaction conditions (Scheme 3). Interestingly, using this Pd/Ag
bimetallic system, arylations of simple arenes with perfluoroarenes
have been achieved by C–H/C–H bond functionalization in 88%
yield. On the base of these results, we think that the same silver
species existed in these two kinds of reactions.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
03.086.
F
F
F
F
F
F
F
F
F
F
COOH
F
F
F
F
F
AgX
Pd
3f
HX
III
AgI
Pd0
F
F
Cycle B
Cycle A
F
F
F
Decarboxylation
Arlation
COOAg
Ag0
F
OAc
Pd
Pd(OAc)2
F
F
F
IV
CO2
I
Ag
II
F
V
HOAc
H
H+
AgX
Sideproduct 2
Decarboxylated
Sideproduct 1
Homocoupling
F
F
F
F
H
F
4a
VI
Scheme 4. Proposed mechanism.

2836
H.-Q. Luo et al. / Tetrahedron Letters 54 (2013) 2833–2836
H.; Cheng, J. K.; Low, M. T.; Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701–
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17. Typical experimental procedure: To a septum capped 25 mL of sealed tube
with a magnetic stirring bar were added Pd(OAc)2 (5 mol %) and Ag2CO3
(164 mg, 0.6 mmol, 2.0 equiv) under air, DMSO (0.10 mL), and
perfluorobenzoic acid 1a (0.3 mmol) and p-xylene 2a (0.9 mL) were added
subsequently. The sealed tube was screwcapped and heated to 130 °C (oil
bath), and stirred for 12 h. After completion, the reaction was cooled to room
temperature, then the mixture was diluted with 10 mL water. The aqueous
layer was extracted with ethyl acetate (10 mL Â 3). The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified with silica gel chromatography to provide pure
product 3a in 89% yield (white solid). 1H NMR (400 MHz, CDCl3): d 7.19–7.26
(m, 2H), 7.02 (s, 1H), 2.37 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3): d
145.3–145.2 (m), 142.9–142.8 (m), 142.8–142.7 (m), 139.3–139.0 (m), 136.4–
136.3 (m), 135.6, 134.2, 131.1, 130.4, 130.4, 126.6, 115.8–115.4 (m); 19F NMR
(282.4 MHz, CDCl3): d À140.7 (dd, J = 23.6, 8.6 Hz, 2F), À155.7 (t, J = 21.8 Hz,
1F), À162.5–162.4 (m, 2F).