Palladium-catalyzed cross-coupling of polyfluoroarenes with simple arenes

Article abstract of DOI:10.1021/ol102688e

The most efficient method to construct biaryls is the direct dehydrogenative cross-coupling of two different aromatic rings. Such an ideal cross arylation starting from distinct polyfluoroarenes and simple arenes was presented. The selectivity of the cross-coupling was controlled by both of the electronic property of fluoroarenes and steric hindrance of simple arenes. Diisopropyl sulfide was essential to promote the efficacy.

Full text of DOI:10.1021/ol102688e

ORGANIC
LETTERS
2011
Vol. 13, No. 2
276-279
Palladium-Catalyzed Cross-Coupling of
Polyfluoroarenes with Simple Arenes
Hu Li,† Jia Liu,† Chang-Liang Sun,† Bi-Jie Li,† and Zhang-Jie Shi*,†,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry and Green Chemistry Center, Peking UniVersity, Beijing 100871, and State Key
Laboratory of Applied Organic Chemistry, Lanzhou UniVersity, Lanzhou 730000, China
zshi@pku.edu.cn
Received November 5, 2010
ABSTRACT
The most efficient method to construct biaryls is the direct dehydrogenative cross-coupling of two different aromatic rings. Such an ideal cross
arylation starting from distinct polyfluoroarenes and simple arenes was presented. The selectivity of the cross-coupling was controlled by both of
the electronic property of fluoroarenes and steric hindrance of simple arenes. Diisopropyl sulfide was essential to promote the efficacy.
The importance of polyfluorobiphenyl structures has been
demonstrated by their application in medicinal chemistry1 and
numerous functional materials such as electron-transport devices
and organic light-emitting diodes (OLEDs).2 However, prepara-
tion of these important structural units is nontrivial and often
requires tedious synthetic steps through traditional cross-
coupling technology.3 Direct arylation of electron-deficient
polyfluoroarenes via C-H activation with aryl halides4 or
arylboronic acids5 has been achieved, respectively, thus provid-
ing better synthetic efficiency. However, compared with using
aryl halides or aryl organometallic reagents, dehydrogenative
cross-coupling of aromatics would be advantageous since both
arene partners do not require prefunctionalization. Recently,
oxidative cross-coupling of polyfluoroarenes with terminal
alkynes,6 alkenes,7 and electron-rich heterocycles8 has been
reported.9 Despite the significant progress achieved in the
oxidative cross-coupling of (hetero)arenes, the substrates are
mainly limited to electron-rich heteroarenes and directing-group-
containing arenes, typical structures that required achieving both
high reactivity and selectivity. In contrast, direct cross-coupling
of two simple arenes without directing group assistance,
especially electron-deficient arenes, has been achieved very
* To whom correspondence should be addressed. Phone/Fax: (+86)-
10-6276-0890. Homepage: http://www.chem.pku.edu.cn/zshi.
† Peking University.
(4) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754–8756. (b) Lafrance, M.; Shore, D.; Fagnou,
K. Org. Lett. 2006, 8, 5097–5100. (c) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2008, 130, 1128–1129. (d) Do, H.-Q.; Khan, R. M. K.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 15185–15192. (e) Do, H.-Q.; Daugulis, O.
Chem. Commun. 2009, 6433–6435. (f) Rene, O.; Fagnou, K. Org. Lett.
2010, 12, 2116–2119.
‡ Lanzhou University.
(1) Zahn, A.; Brotschi, C.; Leumann, C. J. Chem.sEur. J. 2005, 11,
2125–2129.
(2) For selected recent reviews and papers, see: (a) Amii, H.; Uneyama,
K. Chem. ReV. 2009, 109, 2119–2183. (b) Babudri, F.; Farinola, G. M.;
Naso, F.; Ragni, R. Chem. Commun. 2007, 1003–1022. (c) Tang, M. L.;
Reichardt, A. D.; Miyaki, N.; Stoltenberg, R. M.; Bao, Z. J. Am. Chem.
Soc. 2008, 130, 6064–6065. (d) Wang, Y.; Watson, M. D. J. Am. Chem.
Soc. 2006, 128, 2536–2537.
(5) Wei, Y.; Kan, J.; Wang, M.; Su, W.; Hong, M. Org. Lett. 2009, 11,
3346–3349.
(6) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc.
2010, 132, 2522–2523.
(7) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.; Jiang,
Z.-X. J. Am. Chem. Soc. 2010, 132, 4506–4507.
(3) For selected examples, see: (a) Yoon, M.-H.; Facchetti, A.; Stern,
C. E.; Marks, T. J. J. Am. Chem. Soc. 2006, 128, 5792–5801. (b) Crouch,
D. J.; Skabara, P. J.; Heeney, M.; McCulloch, I.; Coles, S. J.; Hursthouse,
M. B. Chem. Commun. 2005, 1465–1467. (c) Facchetti, A.; Yoon, M.-H.;
Stern, C. L.; Katz, H. E.; Marks, T. J. Angew. Chem., Int. Ed. 2003, 42,
3900–3903.
(8) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850–
12852.
(9) For Ni-catalyzed addition of C-H bonds of polyfluoroarenes to
alkynes and olefins, see: Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama,
T. J. Am. Chem. Soc. 2008, 130, 16170–16171.
10.1021/ol102688e  2011 American Chemical Society
Published on Web 12/20/2010

Table 1. Optimization Study of Palladium-Catalyzed Cross-Coupling of Pentafluorobenzene with Benzenea
entry
oxidant
acid
additive (equiv)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Ag2CO3
Ag2CO3
AgOAc
Ag2O
Cu(OAc)2
BQ
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
TFA
TFEol
PivOH
tert-butylacetic acid
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
<1
39
36
<1
DMSO (3.0)
DMSO (3.0)
DMSO (3.0)
DMSO (3.0)
DMSO (3.0)
DMSO (3.0)
DMSO (7.0)
DMSO (7.0)
16
ND
ND
82
53
62
88
quant
4
29
<1
17
ND
<1
quant
quant (91)
oxone
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
DMSO (7.0)
DMSO (7.0)
DMSO (7.0)
diphenyl sulfoxide (3.0)
diphenyl sulfide (3.0)
diphenyl disulfide (3.0)
tert-butyl methyl sulfoxide (3.0)
phenyl vinyl sulfoxide (3.0)
diethyl sulfide (3.0)
diisopropyl sulfide (3.0)
diisopropyl sulfide (1.0)
a The reactions were performed on a 0.20 mmol scale of pentafluorobenzene with 2.0 mL of benzene (110 equiv) as solvent. b Determined by GC with
dodecane as the internal standard. The isolated yield is given in parentheses. BQ: benzoquinone. TFA: 2,2,2-trifluoroacetic acid. TFEol: 2,2,2-trifluoroethanol.
PivOH: pivalic acid. ND: not detected. quant: quantitative yield.
recently by only one case after we submitted the manuscript.11,12
Herein we described an unprecedented palladium-catalyzed
oxidative cross-coupling of electron-deficient polyfluoroare-
nes with completely unactivated arenes.
We started to search for suitable reaction conditions for the
oxidative cross-coupling of pentafluorobenzene with benzene
as a model reaction system (Table 1). In the presence of 10
mol % of Pd(OAc)2 as a catalyst, 1.0 equiv of HOAc as an
acidic additive,13 1.5 equiv of Ag2CO3 as an oxidant, and a
large excess of benzene as the solvent, the reaction carried out
at 120 °C afforded only a trace amount of the desired product
3a (entry 1). Instead, it produced biphenyl as an undesired
byproduct from homocoupling. The addition of 3.0 equiv of
DMSO8,14 led to the formation of the desired coupling
product in 39% yield (entry 2). Among other oxidants tested,
AgOAc and Cu(OAc)2 were less effective while Ag2O,
benzoquinone (BQ), and oxone were totally ineffective
(entries 3-7). Moreover, increasing the amount of DMSO
to 7.0 equiv led to 82% yield of the arylation product (entry
8). The influence of acid additives was also examined (entries
9-12). Generally, relatively weak acids such as HOAc and
PivOH provided better results than strong acid such as 2,2,2-
trifluoroacetic acid (TFA). It is noteworthy that with the
assistance of tert-butylacetic acid, quantitative yield was
achieved, although an appreciable quantity of biphenyl
byproduct was also obtained (entry 12).15 To further improve
the reaction efficiency and selectivity, we tested various
sulfoxides and sulfides as additives since they are known to
affect the palladium-catalyzed C-H activation (entries
13-19).8,14 Fortunately, we found that when diisopropyl
sulfide was used, complete conversion was achieved and the
desired product 3a was obtained quantitatively, with only a
(10) For selected examples, see: (a) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1172–1175. (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2007, 129, 11904–11905. (c) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 12072–12073. (d) Dwight, T. A.; Rue, N. R.; Charyk,
D.; Joesselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137–3139. (e) Xia, J.-
B.; You, S.-L. Organometallics 2007, 26, 4869–4871. (f) Cho, S. H.; Hwang,
S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254–9256. (g) Li, B.-J.;
Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115–
1118. (h) Brasche, G.; Garcia-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008,
10, 2207–2210. (i) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. J. Org.
Chem. 2009, 74, 4720–4726. (j) Ackermann, L.; Jeyachandran, R.;
Potukuchi, H. K.; Novak, P.; Buttner, L. Org. Lett. 2010, 12, 2056–2059.
(11) Li, R.; Jiang, L.; Lu, W. Organometallics 2006, 25, 5973–5975.
(12) During the preparation of our manuscript, a similar report was
published online: Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377–
16379.
(13) It is believed that acidic conditions might suppress undesired
homocoupling in Pd-catalyzed oxidative cross-coupling reactions. For
details, see: Yang, S.; Sun, C.; Fang, Z.; Li, B.; Li, Y.; Shi, Z. Angew.
Chem., Int. Ed. 2008, 47, 1473–1476, and references cited therein.
(14) It is supposed that DMSO might function as a ligand to activate
the Pd catalyst and prevent the formation of palladium black. For details,
see: Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 4348–
4355, and references cited therein.
(15) The biphenyl byproduct and its quantity was detected by GC. For
details, see the Supporting Information.
Org. Lett., Vol. 13, No. 2, 2011
277

trace amount of biphenyl detected.15 Decreasing the diiso-
propyl sulfide to 1.0 equiv did not affect the result, and the
product was isolated in 91% yield (entry 20). Interestingly,
using sulfide as a ligand to accelerate C-H activation is
uncommon since it is well-known that sulfide tends to poison
palladium catalysts.
With the optimized reaction condition in hand, a variety
of polyfluoroarenes were tested as coupling partners with
benzene. Tetrafluoro-, trifluoro-, and even some difluoroben-
zene could be selectively arylated with high efficiency
(Scheme 1). For example, electron-rich or -deficient substit-
portunities to build up fluoroterphenyls (3k and 3l). Besides,
tetrafluoropyridines were also found to be suitable partners
for the coupling reactions with benzene (3m and 3n). It is
worth noting that reactions performed under an atmosphere
of air resulted in slightly lower yields (3a and 3b).
For 1,2,4,5-tetrafluorobenzene, double arylation occurred
since two reaction sites were available (3o). Similarly, double
and even triple arylation were achieved in moderate to good
yields for 1,2,3,5-tetrafluorobenzene and 1,3,5-trifluoroben-
zene (3q and 3r). Selective monoarylation of 1,2,3,4-
Table 2. Palladium-Catalyzed Oxidative Cross-Coupling of
Pentafluorobenzene with Simple Arenesa
Scheme 1
.
Palladium-Catalyzed Oxidative Cross-Coupling of
Polyfluoroarenes with Benzenea
a The reactions were performed on 0.60 mmol scales of polyfluoroarenes
with 4.0 mL of benzene (75 equiv) as solvent and isolated yields are shown
in the table. b Reactions ran under an atmosphere of air. c Reactions ran for
48 h with 15 mol % of Pd(OAc)2. d Determined by GC. e The ratios of
isomers were determined by 19F NMR.
uents such as methoxy, methyl, chloromethyl, aldehyde, nitro,
cyano, and trifluoromethyl groups all could be tolerated quite
well, wherever they located (3b-g and 3i), except 2,3,4,5-
tetrafluorobenzotrifluoride, probably because of the steric
effect (3j). Those functional groups could be further trans-
formed to other functionalities, providing the potential
application of this methodology. Nevertheless, 2,3,5,6-
tetrafluoroaniline converted incompletely under the standard
condition, while a higher catalyst loading and longer reaction
time could give a moderate yield of arylated product,
accompanying the oxidation of the substrate (3h). Moreover,
tetrafluorobenzene bearing electron-rich or -deficient phenyl
ring substituents also worked very well, offering the op-
a The reactions were performed on a 0.60 mmol scale of pentafluo-
robenzene with 4.0 mL of arene as solvent. b Isolated yields are shown in
the table and the ratios of isomers were determined by19F NMR. c Reaction
ran for 20 h. d Trace quantity of isomers were detected by GC-MS.
278
Org. Lett., Vol. 13, No. 2, 2011

tetrafluorobenzene was also achieved presumably due to
steric hindrance of the second arylation (3p). The low yield
showed that a C-H bond flanked with only one fluorine atom
was less reactive probably due to its decreased acidity. When
multiple unequal reaction sites are available, the arylation
occurred preferentially at the most acidic C-H bond, which
is ortho to a fluorine atom (3s and 3t). The decreasing
reactivity of pentafluorobenzene, 1,2,3,5-tetrafluorobenzene,
1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, 1,3-difluo-
robenzene, and 1,2,3,4-tetrafluorobenzene is reasonable since
the fluorine atoms increase the acidity of C-H bonds, which
is consistent with previous reports.4a,10g,16
exchange experiment indicated that for deprotonation of
highly acidic pentafluorobenzene and some other polyfluo-
robenzenes, inorganic bases such as Ag2CO3 were sufficient
and Pd(II) was not required (eq 3).
On the basis of the preliminary studies, the catalytic cycle
was proposed as shown in Scheme 3. Taking the coupling
Scheme 3. Plausible Mechanism To Approach Oxidative
Cross-Coupling of Pentafluorobenzene with Arenes
To further probe the scope of this novel methodology, we
tested various simple arenes as the coupling partners with
pentafluorobenzene. All the reactions ran for 48 h to achieve
complete conversion with good regioselectivity (Table 2).
It is worth mentioning that these reactions were extremely
sensitive to steric hindrance. For example, o-xylene and
m-xylene reacted at the less hindered positions to generate
single coupling products with good efficiency (entries 2 and
3). When p-xylene was presented as the coupling partner,
only moderate yield was obtained because of the steric
hindrance of the o-methyl group (entry 4). For monosubsti-
tuted arenes, C-H activation took place mainly at less
hindered meta- and para-positions (entries 5-9). In addition,
1,2,3,4-tetrahydronaphthalene was also an excellent coupling
partner with an exclusive regioselectivity (entry 10).
To investigate the mechanism, several control experiments
were further conducted (Scheme 2). The intermolecular
of pentafluorobenzene with arenes as the example, the initial
deprotonation of pentafluorobenzene afforded anion 5, fol-
lowed by palladation to generate polyfluoroarylpalladium
species 6. Then C-H activation of arene 2 via concerted
metalation-deprotonation (CMD)4a,10g,16 transition-state 7
afforded biarylpalladium species 8, which underwent reduc-
tive elimination to generate the product 4 and Pd(0) species.
Finally reoxidation of Pd(0) by Ag(I) regenerated the
catalytically active Pd(II) species to finish the catalytic cycle.
In conclusion, we have developed an unprecedented
oxidative cross-coupling of polyfluoroarenes with simple
arenes, providing an efficient method to build up polyflu-
orinated biaryls in good yields and high selectivity. The
obvious effect of dialkyl sulfide was observed to promote
direct C-H transformations for the first time. Remarkably,
we have shown that a single palladium catalyst could activate
two distinct C-H bonds through different pathways. Further
studies to uncover the mechanism and apply this methodol-
ogy to organic synthesis are currently underway in our lab.
Scheme 2. Mechanism Investigation
Acknowledgment. Support of this work by NSFC (Nos.
20672006, 20821062, 20832002, 20925207, GZ419) and the
“973” Project from the MOST of China (2009CB825300)
is gratefully acknowledged.
kinetic isotopic effect (KIE) by coupling of 2,3,5,6-tetrafluo-
roanisole with benzene/benzene-d6 revealed that C-H cleav-
age of benzene was involved in the rate-determining step
(eq 1). Although the oxidative coupling reactions did not
occur in the absence of palladium catalysts (eq 2), the H/D
Supporting Information Available: Brief experimental
details and other spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Garc´ıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 1066–1067
.
OL102688E
Org. Lett., Vol. 13, No. 2, 2011
279