Pd/PR3-Catalyzed Cross-Coupling of Aromatic Carboxylic Acids with Electron-Deficient Polyfluoroarenes via Combination of Decarboxylation with sp2 C-H Cleavage

Article abstract of DOI:10.1021/jo102175f

By using Pd(TFA)₂/PCy₃ as a catalyst, a broad range of aromatic carboxylic acids, including heteroaromatic carboxylic acids, efficiently underwent decarboxylative coupling with an array of polyfluoroarenes in the presence of stoichiometric amount of silver salts to generate biaryls. Silver salts were adjusted to the reactivity of aromatic carboxylic acids to efficiently suppress the protodecarboxylation and therefore improve decarboxylative cross-couplings. It was established that the palladium complex containing the PCy₃ ligand was capable of catalyzing the decarboxylation of electron-rich aromatic carboxylic acids, and silver salts promoted the decarboxylation of both electron-rich and -deficient ones. To explain the two different decarboxylation processes, two possible reaction pathways are proposed, which were further supported by the facts that the stoichiometric arylpalladium complex can directly arylate pentafluorobenzene in the presence of PCy₃ and the arylpalladium complex can catalyze the decarboxylative coupling of 2,4-dimethoxybenzoic acid with pentafluorobenzene. The kinetic isotope effect of 4.0 clearly showed that theC-H bond cleavage of polyfluoroarenes is involved in the rate-determining step.

Full text of DOI:10.1021/jo102175f

pubs.acs.org/joc
Pd/PR3-Catalyzed Cross-Coupling of Aromatic Carboxylic Acids with
Electron-Deficient Polyfluoroarenes via Combination of Decarboxylation
with sp2 C-H Cleavage
Huaiqing Zhao, Ye Wei, Jing Xu, Jian Kan, Weiping Su,* and Maochun Hong
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
wpsu@fjirsm.ac.cn
Received November 1, 2010
By using Pd(TFA)2/PCy3 as a catalyst, a broad range of aromatic carboxylic acids, including
heteroaromatic carboxylic acids, efficiently underwent decarboxylative coupling with an array of
polyfluoroarenes in the presence of stoichiometric amount of silver salts to generate biaryls. Silver
salts were adjusted to the reactivity of aromatic carboxylic acids to efficiently suppress the pro-
todecarboxylation and therefore improve decarboxylative cross-couplings. It was established that
the palladium complex containing the PCy3 ligand was capable of catalyzing the decarboxylation of
electron-rich aromatic carboxylic acids, and silver salts promoted the decarboxylation of both
electron-rich and -deficient ones. To explain the two different decarboxylation processes, two
possible reaction pathways are proposed, which were further supported by the facts that the
stoichiometric arylpalladium complex can directly arylate pentafluorobenzene in the presence of
PCy3 and the arylpalladium complex can catalyze the decarboxylative coupling of 2,4-dimethox-
ybenzoic acid with pentafluorobenzene. The kinetic isotope effect of 4.0 clearly showed that the C-H
bond cleavage of polyfluoroarenes is involved in the rate-determining step.
Introduction
highly selective methods for construction of biaryl scaffolds.
Thus far, transition-metal-catalyzed cross-coupling reac-
tions (Suzuki, Stille, Kumada-Corriu, Negishi, and Hiyama)
have evolved into the most commonly used tools for syn-
theses of biaryl compounds.2 However, these traditional
cross-coupling reactions inherently suffer from their lack
of atom and step economy due to the requirement for use of
two preactivated (synthesized) coupling partners, that is, aryl
halides or triflates and expensive organometallic reagents.
Furthermore, the applications of these methodologies are
often plagued by the electron-deficient aryl organometal-
lic reagents that are difficult to prepare and of the low
reactivity.
The biaryl motif is a key structural component in a number
of natural products, medicinal compounds, and functional
materials.1 Consequently, the past decade has witnessed tre-
mendous efforts in both academic and industrial labora-
tories devoted toward achieving efficient, high-yielding, and
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As increasingly viable alternatives to traditional cross-
coupling reactions, C-H direct arylation reactions have
been a very active field of research since such transfor-
mations are capable of streamlining organic synthesis and
882 J. Org. Chem. 2011, 76, 882–893
Published on Web 01/11/2011
DOI: 10.1021/jo102175f
r
2011 American Chemical Society

Zhao et al.
JOCArticle
minimizing wasteful byproducts.3-8 Significant advances in
direct arylation reactions have been achieved by employing
a variety of catalyst systems incorporating Pd,4 Rh,5 Ru,6
Cu,7 Ni,8 and Fe.9 These established methods demonstrated
that direct arylation reactions not only offer improved ef-
ficiency to the overall processes by using simple arenes in
place of organometallics and/or aryl halides but also provide
a strategic solution to long-standing challenges associated
with the use of problematic organometallics. For example,
the elegant studies by Fagnou and Daugulis established the
direct arylation of polyfluorobenzenes with aryl halides,
eliminating the need for electron-deficient polyfluoroaryl
organoboron reagents.7b,10 The reactivity of acidic C-H
bond toward direct arylation is applicable to the syntheses
of the nitrogen-containing heterobiaryls in which readily
available and cheap electron-deficient nitrogen hetero-
cycles such as pyridine N-oxides were used as replace-
ments for unstable and/or unisolable heterocyclic organo-
metallics.11
Metal-catalyzed decarboxylative aryl-aryl cross-coupling
provides another promising access to (hetero)biaryl com-
pounds, in which aromatic carboxylic acids are used as
arylating reagents in place of expensive organometallic
reagents in traditional cross-coupling reactions.12 Owing
to ready availability of a wide range of aromatic carboxylic
acids, decarboxylative cross-coupling reactions have at-
tracted considerable interest since the pioneering studies
by Myers13 and Goossen14 were reported. As a result,
successes in decarboxylative cross-coupling of aromatic
carboxylic acids with aryl halides or olefins have been
accomplished by using Pd/Cu,14a-f Pd/Ag,13,15 Pd,16
and Cu17 catalysts, and the decarboxylative coupling reac-
tions of R-amino acids with different nucleophiles have
been established.18 Yu19 and Daugulis20 have indepen-
dently developed catalytic methods for carboxyl-directed
ortho-C-H functionalization, and Miura’s seminal work on
coupling reaction of benzoic acids with alkynes for con-
struction of fused rings has further highlighted the great
potential of benzoic acids to serve as versatile starting
materials for syntheses of complex molecules.21
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TABLE 1. Optimization of Reaction Conditionsa
entry
ligand (equiv)
additive (equiv)
MS
MS
yieldb (%)
1c
2
3
4
5
6
7
8
20
44
70
10
55
13
22
<5
60
53
25
28
66
63
60
57
60
75
44
PCy3 (0.6)
PCy3 (0.6)
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5)
Na3PO4 (1.5), MS
K2CO3 (1.5), MS
Na2CO3 (1.5), MS
K2HPO4 (1.5), MS
K3PO4 (1.5), MS
K3PO4 (1.5), MS
PCy3 (0.4)
PCy3 (0.2)
P
t-Bu3 (0.6)
Pn-Bu3 (0.6)
Pt-Bu2Me (0.6)
Pi-Pr3 (0.6)
PPh3 (0.6)
9
10
11
12
13
14
15
16
17
18e
19f
X-Phosd (0.6)
PCy3 (0.6)
PCy3 (0.6)
PCy3 (0.6)
PCy3 (0.6)
PCy3 (0.6)
PCy3 (0.45)
PCy3 (0.3)
aReaction conditions: 1a (0.2 mmol), 2a (3.0 equiv), Pd(TFA)2 (20 mol %), Ag2CO3 (3.5 equiv), 3 A MS (100 mg), 2.0 mL of solvent (7% DMSO/1,4-
dioxane), 140 °C, 22 h. bIsolated yields. c7% DMSO/DMF. d2-Dicyclohexylphosphino-20,40,60-triisopropylbiphenyl. ePd(TFA)2 (15 mol %). fPd(TFA)2
(10 mol %).
Recently, the reaction that combines decarboxylation of
benzoic acids with direct functionalization of C-H bond for
synthesis of biaryl has emerged. Such transformations take
advantage of both the high efficiency of direct C-H bond
functionalization and the wide diversity of carboxylic acids
and offer new bond-forming strategies in synthesis. In this
context, Crabtree and co-workers have reported for the first
time four examples of decarboxylative coupling of 2,
6-dimethoxybenzoic acid with arene donors in low to moderate
yields at high temperature (200 °C).22 Subsequently, Glorius
and co-workers have reported palladium catalyzed intra-
molecular direct arylation of benzoic acids by tandem
decarboxylation/C-H activation.23 Very recently, the in-
termolecular decarboxyltive C3 arylation of indoles with
electron-deficient benzoic acids was achieved by Larrosa,24
and the intermolecular decarboxylative C-H cross-
coupling between oxazoles and thiazoles was reported by
Greaney.25 We have established a versatile Pd/Ag catalyst
system for highly regioselective arylation of a wide range of
indoles with both electron-rich and -deficient benzoic acids
in which the regioselectivity is governed by the nature of
benzoic acids, and also realized decarboxylative coupling
of aromatic carboxylic acids with nitroethane via combi-
nation of decarboxylation and cleavage of sp3 C-H bond
for selective synthesis of (E)-β-nitrostyrenes.26 Despite
these advances, the reactions for the direct C-H arylation
based on decarboxylation of aromatic carboxylic acids are
still scarce. In this full article, we report direct arylation of
an array of electron-deficient fluorobenzenes with both
electron-rich and -deficient aromatic carboxylic acids as
arylating reagents using Pd catalyst supported by tricyclo-
hexylphosphine (PCy3) ligand, and present the results of a
mechanistic investigation on this reaction.27
Results and Discussion
Development of the Decarboxylative Cross-Coupling Reac-
tion of Benzoic Acid with Fluorobenzene. The reaction of 2,
4-dimethoxybenzoic acid (1a) with pentafluorobenzene (2a)
was employed as the model for optimization studies (Table 1).
Initially, the reaction of 1a with 3 equiv of 2a carried out
under the previously established conditions for the decar-
boxylative cross-coupling of benzoic acids with indoles or
nitroethane [20 mol % of Pd(TFA)2 (TFA =trifluoroace-
tate), 3.5 equiv of Ag2CO3, 3 A molecular sieves (MS 100 mg
for 0.2 mmol 1a) in a mixed solvent of DMSO (7% v/v)
in DMF at 140 °C] afforded the desired product in 20% yield
(Table 1, entry 1).26 The structure of product 3a was eluci-
dated by NMR spectra and confirmed by the X-ray crystal-
lographic analysis (Supporting Information). However,
the unreactive palladium black was formed rapidly in this
reaction, which would result in low conversion. In the
(22) Voutchkova, A.; Coplin, A.; Leadbeater, N. E.; Crabtree, R. H.
Chem. Commun. 2008, 6312.
(23) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194.
(24) Cornella, L.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11, 5506.
(25) Zhang, F.; Greaney, M. Angew. Chem., Int. Ed. 2010, 49, 2768.
(26) (a) Zhou, J.; Hu, P.; Zhang, M.; Huang, S.; Wang, M.; Su, W.
Chem.;Eur. J. 2010, 16, 5876. (b) Zhang, M.; Zhou, J.; Kan, J.; Wang, M.;
Su, W.; Hong, M. Chem. Commun. 2010, 46, 5455.
(27) When we established the optimized conditions of the reaction and
finished investigating the scope of aromatic carboxylic acids, a few examples
of decarboxylative coupling of 2,6-dimethoxybenzoic acid or four derivatives
of 2-nitrobenzoic acid with pentafluorobenzene or 2,3,5,6-tetrafluoroanisole
in moderate yields were reported; see: Xie, K.; Yang, Z.; Zhou, X.; Li, X.;
Wang, S.; Tan, Z.; An, X.; Guo, C.-C. Org. Lett. 2010, 12, 1564.
884 J. Org. Chem. Vol. 76, No. 3, 2011

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JOCArticle
TABLE 2. Reaction Scope: Aromatic Carboxylic Acidsa
Pd-catalyzed direct arylation of fluorobenzenes with aryl
halides, electron-rich trialkylphosphine ligands were re-
quired to obtain active catalyst for oxidative addition of
aryl halides and cleavage of C-H bond in fluorobenzenes
via concerted metalation-deprotonation.10a,28 In light of
this, tricyclohexylphosphine was introduced into the reac-
tion system to lead to the improved yield (Table 1, entry 2).
In this case, tricyclohexylphosphine ligand presumably not
only exerted a positive effect on Pd-mediated C-H clea-
vage but also stabilized palladium catalyst against forma-
tion of inactive palladium black. The addition of K3PO4
(1.5 equiv) led to further improvement of yield (Table 1,
entry 3), in agreement with the observation that bases
were required for direct functionalization of acidic C-H
bond.10,11 In contrast, the reaction of 1a with 2a gave a
poor yield in the absence of PCy3 under otherwise identical
conditions (Table 1, entry 4), highlighting the beneficial
effect of PCy3. Reducing the PCy3/Pd ratio from 3:1 to 2:1
and 1:1 led to a decrease in yield (Table 1, entries 5 and 6).
Screening phosphine ligands revealed that the outcomes
of this reaction are sensitive to the structure of phosphine
ligands. Compared with PCy3, both the more hindered
Pt-Bu3 and the less hindered Pn-Bu3 significantly reduced
the efficiency of reaction (Table 1, entries 7 and 8). PtBu2Me
and PiPr3 were both slightly less effective than PCy3 (Table 1,
entries 9 and 10). The aryl-substituted phosphines, for exam-
ple, PPh3, were essentially ineffective for the enhancement of
yield (Table 1, entry 11). Molecular sieves (3 A) were believed
to remove the water generated from the reaction and there-
fore avoid protodecarboxylation of aromatic carboxylic
acid, which was supported by the reaction in the absence of
molecular sieves that gave a slightly lower yield than that
obtained in the presence of molecular sieves (Table 1, entry
13 vs entry 3). The further investigation of the effect of bases
on the reaction outcome showed that K3PO4 provided the
best result (Table 1, entries 14-17). Interestingly, reducing
Pd loading from 20 to 15 mol % increased the yield of the
corresponding product, perhaps because a decrease in Pd
loading suppressed the homocoupling as well as the aggrega-
tion of Pd(0) species into palladium black (Table 1, entry 18).
However, when Pd loading was reduced to 10 mol %, only
44% yield was obtained (Table 1, entry 19). Among the pal-
ladium sources examined, Pd(TFA)2, which contains the
weakest coordination counteranion, proved to be most ef-
fective, implying that dissociation of counteranion from the
Pd center was probably involved in the reaction process.
Other solvents such as DMF, DMSO, NMP, and 1,4-dioxane
gave lower yields than the mixed solvents (7% DMSO/
1,4-dioxane), and other silver sources such as Ag2O, AgOTf,
AgOAc, and Ag3PO4 were less efficient than Ag2CO3 (see
the Supporting Information).
Scope with Regard to the Aromatic Carboxylic Acids.
Establishing the optimized reaction conditions, we explored
the scope of this reaction with respect to aromatic carboxylic
acids (Table 2). A variety of aromatic carboxylic acids can be
used for the direct arylation of polyfluorobenzenes under the
optimized conditions. However, in some cases, the optimized
reaction conditions need to be adjusted to different car-
boxylic acids to obtain the best yields. The reason behind
aReaction conditions: carboxylic acid 1 (0.2 mmol), polyfluorobenzene 2
(3.0 equiv), Pd(TFA)2 (15 mol %), PCy3 (0.45 equiv), Ag2CO3 (3.5 equiv),
K3PO4 (1.5 equiv), 3 A MS (100 mg), 2.0 mL of solvent, 140 °C, 22 h. See the
b
Supporting Information for details. The yields of 3 were isolated yields.
cAgOTf (2.5 equiv), K3PO4 (2.5 equiv). dAg3PO4 (1.5 equiv), K3PO4
(2.0 equiv). ePentafluorobenzene (5 equiv), K3PO4 (3.0 equiv).
´
(28) Garcıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 1066.
J. Org. Chem. Vol. 76, No. 3, 2011 885

Zhao et al.
JOCArticle
this is that the reactivity of aromatic carboxylic acids toward
decarboxylation, which significantly influences the efficiency
of decarboxylative coupling reactions, changes with varia-
tion of substituents on aromatic carboxylic acids. The reac-
tion of 2,4,5-trimethoxybenzoic acid with pentafluoroben-
zene conducted in 10% DMSO/1,4-dioxane with AgOTf in
place of Ag2CO3 gave a much higher yield (71%) (Table 2,
entry 3). Compared with Ag2CO3, Ag3PO4 reduced the de-
carboxylation rate of electron-deficient 2-nitrobenzoic acid,
consequently preventing protodecarboxylation and enhanc-
ing the yield of the desired product (Table 2, entry 4). For
the same reason, the use of Ag3PO4 afforded good yields in
the reactions of other nitro-containing benzoic acids and N-
methylindole-2-carboxylic acid (Table 2, entries 5, 6, 8, and
9). Under the standard conditions, heteroaromatic carbo-
xylic acids smoothly underwent this reaction to produce
heterobiaryls in good to excellent yields (Table 2, entries
10, 11, and 14). Interestingly, when 3-methylthiophene-2-
carboxylic acid was used, a bisarylated product was observed
(Table 2, entry 13). In contrast to aromatic carboxylic
acids, the reaction of phenylpropiolic acid with pentafluoro-
benzene gave the corresponding product only in 26% yield,
presumably because the decarboxylation was too fast
(Table 2, entry 15). Unfortunately, 3-nitrobenzoic acid and
other tested nonortho-substituted aromatic carboxylic acids
could not afford the coupling products under this catalytic
system, probaly due to their poor reactivity of decarboxyla-
tion compared with the ortho-substituted aromatic car-
boxylic acids.
TABLE 3. Reaction Scope: Polyfluoroarenesa
Scope with Regard to the Polyfluoroarenes. As shown in
Table 3, this reaction was applicable to a variety of fluor-
oarenes. Under the standard conditions, both 2,3,5,6-tetra-
fluoroanisole and 2,3,5,6-tetrafluorotoluene reacted with
2,4-dimethoxybenzoic acid to furnish good yields (Table 3,
entries 1 and 2). 1,2,3,5-Tetrafluorobenzene was observed to
be more reactive than 1,2,4,5-tetrafluorobenzene, probably
due to the difference in acidity between their C-H bonds to
be arylated (Table 3, entries 8 and 9). For more C-H acidic
polyfluoroarenes such as 2,3,5,6-tetrafluoropyridine, 2,3,
5,6-tetrafluorobenzonitrile, and 2,3,5,6-tetrafluorobenzotri-
fluoride, good yields were still obtained in the absence of
K3PO4 (Table 3, entries 4-6). In the reaction of less C-
H-acidic 1,3,5-trifluorobenzene, the increased amounts of
K3PO4 and fluorobenzene were required to obtain moderate
yields (Table 3, entry 10). 1,3-Difluorobenzene can also be
arylated exclusively at the most acidic C-H bond, which is
flanked by two C-F bonds, albeit in a poor yield (Table 3,
entry 12). Installing an additional electron-withdrawing
group to the aromatic ring of difluorobenzene efficiently
enhanced the reactivity of the C-H bond, as exemplified by
the reactions of (2,4-difluorophenyl)(phenyl)methanone and
methyl 3,5-difluorobenzoate (Table 3, entries 13 and 14).
Investigation of the Mechanism of Decarboxylative Cross-
Coupling Reaction. In our previous studies on decarboxyla-
tive coupling of benzoic acids with indoles, we disclosed
that the decarboxylation of electron-rich benzoic acids was
catalyzed by Pd species while the decarboxylation of elec-
tron-deficient benzoic acids resulted from the contribution
of Ag salt.26a However, for the Pd/Ag-promoted decarbox-
ylative coupling of aromatic carboxylic acids with polyfluor-
oarenes, the roles of Pd and Ag in the decarboxylation
process remain to be identified because of the presence
aReaction conditions: carboxylic acid (0.2 mmol), polyfluorobenzene
(3.0-5.0 equiv), Pd(TFA)2 (15 mol %), PCy3 (0.45 equiv), Ag2CO3
(3.5 equiv), K3PO4 (1.5 equiv), 3 A MS (100 mg), 2.0 mL of solvent,
140 °C, 22 h. See the Supporting Information for details. bThe yields of 4
were isolated yields. cIn the absence of K3PO4.
886 J. Org. Chem. Vol. 76, No. 3, 2011

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JOCArticle
SCHEME 1. Stoichiometric Palladium-Mediated Decarboxylative Arylation
of phosphine ligand in this reaction system and different
reaction conditions. Myers,13c Fu and Liu29 reported that
electron-donating ligands inhibited the Pd-mediated decar-
boxylation. Since 31P NMR studies revealed that Pd(TFA)2
combines with PCy3 with the Pd/PCy3 ratios of 1:1, 1:2, and
SCHEME 2. Silver-Promoted Protodecarboxylation
30
1:3 to initially generate Pd(TFA)2(PCy3)2 as the only Pd/
PCy3 complex, we examined the reaction of potassium 2,4,
5-trimethoxybenzoate with pentafluorobenzene with stoichio-
metric Pd(TFA)2(PCy3)2 in the absence of Ag2CO3 and
found that this reaction generated the corresponding prod-
uct in 22% yield (Scheme 1A), which indicated that the Pd
complex containing phosphine ligand was capable of med-
iating decarboxylation. Further addition of additional PCy3
(1 equiv) to this reaction system reduced the yield of product
to about 5% (Scheme 1B), which suggested that the dissocia-
tion of PCy3 from Pd complex was likely involved in the
reaction process. For the real catalyst system where the Pd/
PCy3 ratio is 3:1, it seems reasonable to assume that Ag salts
served as the scavenger of extra PCy3 ligand and therefore
allowed decarboxylative coupling to occur. However, fur-
ther investigations complicated the determination of the
roles of Pd and Ag in the decarboxylation process. Although
no decarboxylative product was detectable in the reaction of
2,4-dimethoxybenzoic acid with 3.5 equiv of Ag2CO3 in 7%
DMSO/dioxane at 140 °C in the presence of K3PO4, the
introduction of 1 equiv of PCy3 led to protodecarboxylation
of 2,4-dimethoxybenzoic acid in 55% yield (Scheme 2A),
which was presumably due to the formation of soluble Ag/
PCy3 complex. Thus, it is possible that both Pd and Ag
participated in the decarboxylation of electron-rich aromatic
carboxylic acids.
Ag salts were responsible for the decarboxylation of electron-
deficient aromatic carboxylic acids.31
By analogy to the Pd-catalyzed direct arylation of poly-
fluorobenzenes with aryl halides10a or arylboronic acids32
that was proposed to proceed through the initial formation
of arylpalladium intermediate generated from aryl halides
or arylboronic acids, subsequent palladation of polyfluor-
obenzene, and reductive elimination, we speculated that a
similar reaction pathway could operate in the Pd/Ag-mediated
decarboxylative coupling of aromatic carboxylic acids
with polyfluoroarenes. This hypothesis was supported by
the fact that the reaction of 2,4,5-trimethoxyphenylpalladium
trifluoroacetate complex 513c with pentafluorobenzene in
the presence of 3 equiv of PCy3 and 3 equiv of K3PO4 gave
rise to the arylation of pentafluorobenzene in 49% yield
(Scheme 3A). Further experiments showed that 15 mol %
of arylpalladium 5 catalyzed the direct arylation of penta-
fluorobenzene with 2,4-dimethoxybenzoic acid in 65%
yield (Scheme 3B), suggesting that the arylpalladium inter-
mediate was likely involved in the catalytic cycle.
In the cases of electron-deficient aromatic carboxylic
acids, Pd complexes were observed to be ineffective for
the decarboxylation, in agreement with Larrosa’s obser-
vation.24 The reaction of 2-nitrobenzoic acid with 3.5 equiv
of Ag2CO3 that was conducted in 7% DMSO/dioxane
at 140 °C for 22 h in the presence of K3PO4 and PCy3
generated the protodecarboxylation product in 69% yield
(Scheme 2B). These observations showed clearly that only
To explain the two different decarboxylation process-
es, two possible reaction pathways were proposed for the
Pd/Ag-mediated decarboxylative coupling of aromatic car-
boxylic acids with polyfluorobenzenes (Scheme 4). The
(31) (a) Cornella, J.; Sanchez, C.; Banawa, D.; Larrosa, I. Chem. Com-
(29) Zhang, S.-L.; Fu, Y.; Shang, R.; Guo, Q.-X.; Liu, L. J. Am. Chem.
Soc. 2010, 132, 638.
(30) Thirupathi, N.; Amoroso, D.; Bell, A.; Protasiewicz, J. D. Organo-
metallics 2007, 26, 3157.
mun. 2009, 7176. (b) Goossen, L. J.; Linder, C.; Rodrı
Fromm, A. Chem. Commun. 2009, 7173.
(32) Wei, Y.; Kan, J.; Wang, M.; Su, W.; Hong, M. Org. Lett. 2009, 11,
3346.
´
guez, N.; Lange, P. P.;
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JOCArticle
SCHEME 3. Arylpalladium-Promoted Cross-Coupling
SCHEME 4. Proposed Reaction Pathways for the Decarboxylative Arylation of Carboxylic Acids with Polyfluorobenzenes
difference between two pathways lies in the decarboxyla-
tion of aromatic carboxylic acids before the formation of
arylpalladium intermediates. Pathway A starts with the
formation of arylpalladium intermediates via Pd-mediated
decarboxylation, whereas pathway B begins by the forma-
tion of arylsilver intermediates via Ag-mediated decarbox-
ylation, followed by transmetalation from Ag to Pd to
generate arylpalladium intermediates. In their late stages,
these two pathways share common elementary steps: pal-
ladation of polyfluorobenzene, reductive elimination, and
reoxidation of Pd(0) to Pd(II).23,27,32,33
the deceleration of decarboxylation enhanced the yields
of the desired cross-coupling products and efficiently sup-
pressed the protodecarboxylation of aromatic carboxylic
acids. The competition experiment was also performed to
determine relative reactivities of polyfluorobenzenes. Com-
petition between arylation of pentafluorobenzene and 2,3,
5,6-tetrafluoroanisole with 2,4-dimethoxybenzoic acid de-
livered preferentially the product from pentafluorobenzene
(Scheme 6), indicating that the more C-H acidic polyfluor-
obenzene obtains the higher reactivity.
By running the reactions of proto- and deutero-2,3,5,
6-tetrafluoroanisoles with 2,4-dimethoxybenzoic acid side
by side in separate flasks, a kinetic isotope effect of 4.0 was
observed (Scheme 5), indicating that the C-H cleavage of
polyfluorobenzenes is involved in the rate-determining step.
This result provides an explanation for the observation that
Conclusions
In the presence of silver salts, Pd(TFA)2/PCy3 proved to
be a versatile catalyst system for the decarboxylative cou-
pling of aromatic carboxylic acids with polyfluoroarenes.
This protocol allowed using both electron-deficient and -rich
aromatic carboxylic acids as arylating reagents for the direct
arylation of a variety of polyfluoroarenes to produce biaryls
including some heterobiaryls that were synthesized for the
(33) (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126,
5074. (b) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850.
888 J. Org. Chem. Vol. 76, No. 3, 2011

Zhao et al.
JOCArticle
SCHEME 5. Kinetic Isotope Effect
SCHEME 6. Competition between Pentafluorobenzene and 2,3,5,6-Tetrafluoroanisole
first time, providing a complement to the existing methods
for the direct arylation of polyfluoroarenes with aryl halides.
The choice of silver salts depending on the reactivity of aro-
matic carboxylic acids was critical to controlling the decar-
boxylation rate and achieving high-yielding decarboxylative
cross-coupling, which can be rationalized by the fact that
the rate-determining step involves C-H cleavage step. Mech-
anistic investigations revealed that both silver salts and the
Pd-phosphine complex participated in decarboxylation of
electron-rich aromatic carboxylic acids whereas only silver
salts resulted in decarboxylation of electron-deficient ben-
zoic acids. We believe that combination of a Pd-catalyzed
process with Ag-promoted decarboxylation will continue
to lead to the establishment of new types of decarboxyla-
tive cross-coupling reactions. Our current efforts are direc-
ted toward these challenging but promising targets.
on silica gel using (5% ether/petroleum ether) as the eluent
to afford a white solid (75% yield): 1H NMR (400 MHz,
CDCl3, TMS) δ 3.80 (s, 3H), 3.87 (s, 3H), 6.59-6.62 (m, 2H),
7.15 (d, J= 8.0 Hz, 1H); 13C (100 MHz, CDCl3, TMS) δ 55.4,
55.6, 98.9, 104.8, 107.6, 112.5 - 112.9 (m), 132.2, 137.3 (dm, J=
250 Hz), 139.8 (dm, J=252 Hz), 144.6 (dm, J = 246 Hz), 158.3,
162.2; 19F NMR (377 MHz, CDCl3, TMS) δ -140.4 (dd, J=
22.6, 7.9 Hz, 2F), -156.8 (t, J=20.8 Hz, 1F), -163.5 (ddd, J=
21.6, 21.6, 7.7 Hz, 2F); mp 82-83 °C. Anal. Calcd for
C
14H9F5O2: C, 55.27; H, 2.98. Found: C, 55.38; H, 3.06.
2,3,4,5,6-Pentafluoro-20-methoxy-40-methyl-1,10-biphenyl
(3b). Reaction conditions: 2-methoxy-4-methylbenzoic acid
(0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv),
K3PO4 (0.30 mmol, 1.5 equiv), 3 A MS (100 mg), and penta-
fluorobenzene (0.60 mmol, 3.0 equiv) in 2 mL of solvent (10%
DMSO/dioxane), 150 °C, 22 h. The reaction mixture was
purified by column chromatography on silica gel using (2%
ether/petroleum ether) as the eluent to afford a white solid
(50% yield): 1H NMR (400 MHz, CDCl3, TMS) δ 2.42 (s, 3H),
3.79 (s, 3H), 6.84 (s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 7.09 (d, J =
7.7 Hz, 1H); 13C (100 MHz, CDCl3, TMS) δ 21.7, 55.6, 112.2,
112.6-113.0 (m), 131.4, 137.6 (dm, J = 251 Hz), 140.8 (dm,
J = 250 Hz), 141.6, 144.2 (dm, J = 245 Hz), 157.0; 19F NMR
(377 MHz, CDCl3, TMS) δ -140.4 (dd, J = 22.6, 8.0 Hz, 2F),
-156.6 (t, J = 21 Hz, 1F), -163.4 (ddd, J = 21.5, 21.5, 7.9 Hz,
2F); mp 72-74 °C. Anal. Calcd for C14H9F5O: C, 58.34; H,
3.15. Found: C, 58.44; H, 3.20.
2,3,4,5,6-Pentafluoro-20,40,50-trimethoxy-1,10-biphenyl (3c).
Reaction conditions: 2,4,5-trimethoxybenzoic acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol,
0.45 equiv), AgOTf (0.50 mmol, 2.5 equiv), K3PO4 (0.50 mmol,
2.5 equiv), 3 A MS (100 mg), and pentafluorobenzene
(0.60 mmol, 3.0 equiv) in 2 mL of solvent (10% DMSO/
dioxane), 140 °C, 22 h. The reaction mixture was purified by
column chromatography on silica gel using (5% ether/petro-
leum ether) as the eluent to afford a white solid (71% yield):
1H NMR (400 MHz, CDCl3, TMS) δ 3.79 (s, 3H), 3.84 (s, 3H),
3.95 (s, 3H), 6.64 (s, 1H), 6.74 (s, 1H); 13C (100 MHz, CDCl3,
TMS) δ 56.1, 56.5, 56.7, 97.6, 105.9, 112.4-112.8 (m), 114.9,
138.1 (dm, J = 250 Hz), 139.9 (dm, J = 251 Hz), 148.2, 144.6
(dm, J = 245 Hz), 151.2, 151.9; 19F NMR (377 MHz, CDCl3,
TMS) δ -140.2 (dd, J = 22.6, 8.0 Hz, 2F), -156.6 (t, J = 20.1
Hz, 1F), -163.3 (ddd, J = 21.7, 21.7, 8 Hz, 2F); mp 113-115 °C.
Experimental Section
Typical Procedure for Pd-Catalyzed Cross-Coupling of Fluor-
obenzene with Carboxylic Acid. In a glovebox, the Schlenk tube
equipped with a stir bar was charged with acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol,
0.45 equiv), silver salt, base, and 3 A MS (100 mg). The tube
was fitted with a rubber septum and removed out of the
glovebox. Solvent (2 mL) was added to the Schlenk tube
through the rubber septum using syringes. Then fluoroben-
zene was added. The rubber septum was replaced with a Teflon
screwcap under nitrogen flow. The mixture was stirred and
heated for 22 h. After cooling, the reaction mixture was diluted
with ether (10 mL) and filtered through a pad of silica gel,
followed by washing the pad of the silica gel with the same
solvent (20 mL). The filtrate was washed with water (3 ꢀ
15 mL) and then with brine (15 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was then purified by chromatography on
silica gel to provide the corresponding product.
2,3,4,5,6-Pentafluoro-20,40-methoxy-1,10-biphenyl (3a). Reac-
tion conditions: 2,4-dimethoxybenzoic acid (0.20 mmol), Pd
(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv), 3 A
MS (100 mg), and pentafluorobenzene (0.60 mmol, 3.0 equiv)
in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h. The
reaction mixture was purified by column chromatography
J. Org. Chem. Vol. 76, No. 3, 2011 889

Zhao et al.
JOCArticle
Anal. Calcd for C15H11F5O3: C, 53.90; H, 3.32. Found: C,
53.93; H, 3.38.
(t, J=3.8 Hz), 110.6 (t, J=3.8 Hz), 119.3, 125.7, 132.9, 134.1,
138.2-138.5 (m), 141.0 (dm, J=245 Hz), 141.3, 143.6 (dm, J =
245 Hz), 148.4; 19F NMR (377 MHz, CDCl3, TMS) δ -143.3
(dd, J = 21.3, 7.8 Hz, 2F), -157.8 (dd, J = 21.3, 7.8 Hz, 2F); mp
88-90 °C. Anal. Calcd for C14H9F4NO3: C, 53.34; H, 2.88; N,
4.44. Found: C, 53.29; H, 2.81; N, 4.40.
2,3,4,5,6-Pentafluoro-20-nitro-1,10-biphenyl (3d)27. Reaction
conditions: 2-nitrobenzoic acid (0.20 mmol), Pd(TFA)2 (0.03
mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv), Ag3PO4 (0.30
mmol, 1.5 equiv), K3PO4 (0.40 mmol, 2 equiv), 3 A MS (100 mg),
and pentafluorobenzene (0.60 mmol, 3.0 equiv) in 2 mL of
solvent (7% DMSO/dioxane), 140 °C, 22 h. The reaction mix-
ture was purified by column chromatography on silica gel using
(2% ether/petroleum ether) as the eluent to afford a white-
2,3,4,5,6-Pentafluoro-40,50-dimethoxy-20-nitro-1,10-biphenyl
(3h). Reaction conditions: 4,5-dimethoxy-2-nitrobenzoic
acid (0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(0.09 mmol, 0.45 equiv), Ag3PO4 (0.30 mmol, 1.5 equiv),
K3PO4 (0.40 mmol, 2 equiv), 3 A MS (100 mg), and 2,3,5,6-
tetrafluoroanisole (0.60 mmol, 3.0 equiv) in 2 mL of solvent
(10% DMSO/dioxane), 150 °C, 22 h. The reaction mixture
was purified by column chromatography on silica gel using
(2% ether/petroleum ether) as the eluent to afford a white
1
yellow solid (67% yield): H NMR (400 MHz, CDCl3, TMS)
δ 7.45 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.77 (t, J =
7.6 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H); 13C (100 MHz, CDCl3,
TMS) δ 112.5-112.9 (m), 121.5, 125.4, 130.9, 133.0, 133.7,
137.6 (dm, J = 252 Hz), 140.9 (dm, J = 253 Hz), 144.4 (dm,
J = 251 Hz), 148.4; 19F NMR (377 MHz, CDCl3, TMS)
δ -141.3 (dd, J = 21.6, 6.7 Hz, 2F), -153.5 (t, J = 20.7 Hz,
1F), -161.6 (ddd, J = 21.7, 21.7, 7 Hz, 2F); mp 83-84 °C. Anal.
Calcd for C12H4F5NO2: C, 49.84; H, 1.39; N, 4.84. Found: C,
49.85; H, 1.42; N, 4.86.
1
solid (67% yield): H NMR (400 MHz, CDCl3, TMS)δ 3.97
(s, 3H), 4.03 (s, 3H), 6.75 (s, 1H), 7.83 (s, 1H); 13C (100 MHz,
CDCl3, TMS) δ 56.5, 56.7, 108.5, 113.0-113.8 (m), 115.2,
137.7 (dm, J = 251 Hz), 141.1, 141.2 (dm, J=253 Hz), 143.5
(dm, J=245 Hz), 149.9, 153.2; 19F NMR (377 MHz, CDCl3,
TMS) δ -141.1 (dd, J = 21.6, 7.5 Hz, 2F), -154.2 (t, J =
20 Hz, 1F), -161.9 (ddd, J = 21.7, 21.7, 7.2 Hz, 2F); mp
125-127 °C. Anal. Calcd for C14H8F5NO4: C, 48.15; H, 2.31;
N, 4.01. Found: C, 48.08; H, 2.37; N, 3.97.
2,3,5,6-Tetrafluoro-4-methoxy-20-nitro-1,10-biphenyl (3e)27.
Reaction conditions: 2-nitrobenzoic acid (0.20 mmol), Pd
(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv),
3 A MS (100 mg), and 2,3,5,6-tetrafluoroanisole (0.60 mmol,
3.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h.
The reaction mixture was purified by column chromatography
on silica gel using (5% ether/petroleum ether) as the eluent to
2,3,5,6-Tetrafluoro-4-methoxy- 40-fluoro-20-nitro-1,10-biphenyl
(3i). Reaction conditions: 4-fluoro-2-nitrobenzoic acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45
equiv), Ag3PO4 (0.30 mmol, 1.5 equiv), K3PO4 (0.40 mmol, 2
equiv), 3 A MS (100 mg), and 2,3,5,6-tetrafluoroanisole
(0.60 mmol, 3.0 equiv) in 2 mL of solvent (7% DMSO/dioxane),
140 °C, 22 h. The reaction mixture was purified by column
chromatography on silica gel using (2% ether/petroleum ether)
as the eluent to afford a white-yellow solid (60% yield): 1H
NMR (400 MHz, CDCl3, TMS) δ 4.15 (s, 3H), 7.45-7.48 (m,
2H), 7.92-7.95 (m, 1H); 13C (100 MHz, CDCl3, TMS) δ 62.2 (t,
J = 3.9 Hz), 109.5 (t, J = 18.3 Hz), 113.1, 113.4, 118.3-118.4 (m),
120.7, 120.9, 134.8, 134.9, 138.8-138.9 (m), 141.0 (dm, J =
247 Hz), 144.4 (dm, J = 252 Hz), 149.3 (d, J = 9 Hz), 161.3,
163.8; 19F NMR (377 MHz, CDCl3,TMS) δ-107.0(s,1F), -143.1
(dd, J = 20.6, 7.3 Hz, 2F), -157.5 (dd, J = 20.6, 7.3 Hz, 2F);
mp 83-85 °C. Anal. Calcd for C13H6F5NO3: C, 48.92; H, 1.89,
N, 4.39. Found: C, 48.87; H, 1.92; N, 4.38.
3-Methyl-2-(pentafluorophenyl)benzo[b]thiophene (3j). Reac-
tion conditions: 3-methylbenzo[b]thiophene-2-carboxylic acid
(0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv),
K3PO4 (0.30 mmol, 1.5 equiv), 3 A MS (100 mg), and penta-
fluorobenzene (0.60 mmol, 3.0 equiv) in 2 mL of solvent (7%
DMSO/dioxane), 140 °C, 22 h. The reaction mixture was
purified by column chromatography on silica gel using petro-
leum ether as the eluent to afford a white solid (92% yield): 1H
NMR (400 MHz, CDCl3, TMS) δ 2.34 (s, 3H), 7.42-7.49 (m,
2H), 7.80 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.1 Hz, 1H); 13C
NMR(100 MHz, CDCl3, TMS) δ 12.7, 109.2-109.6 (m), 120.2,
122.3, 122.6, 124.4, 125.4, 133.9, 137.5, 137.6 (dm, J = 252 Hz),
142.5 (dm, J = 245 Hz), 144.8 (dm, J = 251 Hz); 19F NMR (377
MHz, CDCl3, TMS) δ -138.0 - 138.1 (m, 2F), -152.2 (t,
J = 20.5 Hz, 1F), -161.4 to -161.6 (m, 2F); mp 134-136 °C.
Anal. Calcd for C15H7F5S: C, 57.33; H, 2.25. Found: C, 57.30;
H, 2.31.
1
afford a white-yellow solid (67% yield): H NMR (400 MHz,
CDCl3, TMS) δ 4.14 (s, 3H), 7.45 (d, J = 7.6 Hz, 1H), 7.65
(t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 8.19 (d, J=8 Hz,
1H); 13C (100 MHz, CDCl3, TMS) δ 62.2 (t, J=3.8 Hz), 110.5
(t, J=18.5 Hz), 122.3, 125.3, 130.4, 133.2, 133.4, 138.4-138.7 (m),
140.7 (dm, J = 251 Hz), 143.9 (dm, J = 245 Hz), 148.6;
19F NMR (377 MHz, CDCl3, TMS) δ-143.3 (dd, J = 21,
7.2 Hz, 2F), -157.7 (dd, J=21, 7.2 Hz, 2F); mp 116-118 °C.
Anal. Calcd for C13H7F4NO3: C, 51.84; H, 2.34; N, 4.65. Found:
C, 51.78; H, 2.39; N, 4.62.
2,3,4,5,6-Pentafluoro-40-methyl-20-nitro-1,10-biphenyl (3f)27.
Reaction conditions: 4-methyl-2-nitrobenzoic acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol,
0.45 equiv), Ag3PO4 (0.30 mmol, 1.5 equiv), K3PO4 (0.40 mmol,
2 equiv), 3 A MS (100 mg), and pentafluorobenzene (0.60 mmol,
3.0 equiv) in 2 mL of solvent (10% DMSO/dioxane), 140 °C,
22 h. The reaction mixture was purified by column chromatog-
raphy on silica gel using (2% ether/petroleum ether) as the
eluent to afford a white-yellow solid (60% yield): 1H NMR
(400 MHz, CDCl3, TMS) δ 2.54 (s, 3H), 7.31 (d, J = 7.8 Hz,
1H), 7.56 (d, J = 7.8 Hz, 1H), 8.05 (s, 1H); 13C (100 MHz,
CDCl3, TMS) δ 21.1, 112.5-112.9 (m), 118.5, 125.8, 132.7,
134.3, 137.7 (dm, J = 251 Hz), 141.0 (dm, J=253 Hz), 141.9,
143.9 (dm, J=250 Hz),, 148.2; 19F NMR (377 MHz, CDCl3,
TMS) δ -141.3 (dd, J=22, 7 Hz, 2F), -153.9 (t, J=20.8 Hz, 1F),
-161.8 (ddd, J=22, 22, 7.8 Hz, 2F); mp 71-73 °C. Anal. Calcd
for C13H6F5NO2: C, 51.50; H, 1.99; N, 4.62. Found: C, 51.53; H,
2.03; N, 4.65.
2,3,5,6-Tetrafluoro-4-methoxy-40-methyl-20-nitro-1,10-biphe-
nyl (3g). Reaction conditions: 4-methyl-2-nitrobenzoic acid
(0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv),
K3PO4 (0.30 mmol, 1.5 equiv), 3 A MS (100 mg), and 2,3,5,
6-tetrafluoroanisole (0.60 mmol, 3.0 equiv) in 2 mL of solvent
(7% DMSO/dioxane), 140 °C, 22 h. The reaction mixture was
purified by column chromatography on silica gel using (5%
ether/petroleum ether) as the eluent to afford a white-yellow
solid (65% yield): 1H NMR (400 MHz, CDCl3, TMS) δ 2.52 (s,
3H), 4.13 (s, 3H), 7.32 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz,
1H), 8.00 (s, 1H); 13C (100 MHz, CDCl3, TMS) δ 21.1, 62.2
3-Methyl-2-(pentafluorophenyl)benzofuran (3k). Reaction con-
ditions: 3-methylbenzofuran-2-carboxylic acid (0.20 mmol), Pd-
(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv),
3 A MS (100 mg), and pentafluorobenzene (0.60 mmol, 3.0 equiv)
in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h. The
reaction mixture was purified by column chromatography on
silica gel using petroleum ether as the eluent to afford a white
890 J. Org. Chem. Vol. 76, No. 3, 2011

Zhao et al.
JOCArticle
1
solid (86% yield): H NMR (400 MHz, CDCl3, TMS) δ 2.27
(s, 3H), 7.30-7.34 (m, 1H), 7.30-7.34 (m, 1H), 7.37-7.41 (m, 1H),
7.52 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3, TMS) δ 8.6, 106.3-106.7 (m), 111.4, 118.4,
119.9, 122.8, 125.5, 129.3, 137.5, 137.6 (dm, J = 252 Hz), 142.5
(dm, J = 245 Hz), 144.8 (dm, J = 251 Hz), 155.3; 19F NMR
(377 MHz, CDCl3, TMS) δ -137.8 (dd, J = 22, 7 Hz, 2F), -152.9
(t, J = 20 Hz, 1F), -161.5 to -161.7 (m, 2F); mp 124-126 °C.
Anal. Calcd for C15H7F5O: C, 60.41; H, 2.37. Found: C, 60.31;
H, 2.45.
N-Methyl-2-(pentafluorophenyl)indole (3l). Reaction condi-
tions: 1-methylindole-2-carboxylic acid (0.20 mmol), Pd(TFA)2
(0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv), Ag3PO4
(0.30 mmol, 1.5 equiv), K3PO4 (0.40 mmol, 2 equiv), 3 A MS
(100 mg), and pentafluorobenzene (1.0 mmol, 5.0 equiv) in 2 mL
of solvent (10% DMSO/dioxane), 140 °C, 22 h. The reaction
mixture was purified by column chromatography on silica gel
using petroleum ether as the eluent to afford a white solid (88%
yield): 1H NMR (400 MHz, CDCl3, TMS) δ 3.59 (s, 3H), 6.65
(s, 1H), 7.13-7.18 (m, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.35 (d,
J = 8.2 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 30.7, 105.8, 107.8-108.1 (m), 109.8, 120.2,
121.1, 122.9, 123.7, 127.5, 138.0 (dm, J = 252 Hz), 138.2, 141.5
(dm, J = 254 Hz), 144.9 (dm, J = 252 Hz); 19F NMR (377 MHz,
CDCl3, TMS) δ -138.7 (dd, J = 22.7, 7.4 Hz, 2F), -152.8 (t,
J = 21 Hz, 1F), -161.4 to -161.5 (ddd, J = 22.1, 22.1, 8 Hz,
2F); mp 115-117 °C. Anal. Calcd for C15H8F5N: C, 60.61; H,
2.71; N, 4.71. Found: C, 60.54; H, 2.76; N, 4.70.
3-Methyl-2,5-(pentafluorophenyl)thiophene (3m). Reaction
conditions: 3-methylthiophene-2-carboxylic acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol,
0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.60 mmol,
3 equiv), 3 A MS (100 mg), and pentafluorobenzene (1.0 mmol,
5.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h.
The reaction mixture was purified by column chromatography
on silica gel using petroleum ether as the eluent to afford a white
solid (88% yield): 1H NMR (400 MHz, CDCl3, TMS) δ 2.21 (s,
3H), 7.44 (m, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 14.56,
108.0-108.4 (m), 109.2-109.5 (m), 122.7, 128.7, 132.8 (t, J =
5.5 Hz), 138.2 (dm, J = 252 Hz), 139.3, 140.8 (dm, J = 245 Hz),
144.0 (dm, J = 247 Hz); 19F NMR (377 MHz, CDCl3, TMS)
δ -138.0 (dd, J = 22.7, 7.5 Hz, 2F), -139.4 to -139.5 (m,
2F), -152.7 (t, J = 21.4 Hz, 1F), -155.0 (t, J = 21 Hz, 1F),
-161.4 to -161.5 (m, 2F), -161.7 to -161.9 (m, 2F); mp 61-
63 °C. Anal. Calcd for C17H4F10S: C, 47.46; H, 0.94. Found: C,
47.58; H, 1.01.
(0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv), Ag2CO3
(0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv), 3 A MS
(100 mg), and pentafluorobenzene (1.0 mmol, 5.0 equiv) in 2 mL
of solvent (7% DMSO/dioxane), 120 °C, 22 h. The reaction
mixture was purified by column chromatography on silica gel
using petroleum ether as the eluent to afford a white solid (26%
yield): 1H NMR (400 MHz, CDCl3, TMS) δ 7.37-7.44 (m, 3H),
7.57-7.59 (m, 2H); 13C NMR (100 MHz, CDCl3, TMS)
δ 73.0-73.1 (m), 100.2-100.3 (m), 101.5-101.6 (m), 121.6,
128.5, 129.6, 131.9, 137.7 (dm, J = 250 Hz), 141.4 (dm, J =
255 Hz), 147.1 (dm, J = 245 Hz); 19F NMR (377 MHz, CDCl3,
TMS) δ -136.3 (dd, J = 18.9, 7.3 Hz, 2 F), -153.4 (t, J = 20.7 Hz,
1 F), -162.1 to -162.2 (m, 2 F); mp 105-107 °C.
2,3,5,6-Tetrafluoro-4-methoxy-20,40-methoxyl-1,10-biphenyl
(4a). Reaction conditions: 2,4-dimethoxybenzoic acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv),
3 A MS (100 mg), and 2,3,5,6-tetrafluoroanisole (0.60 mmol,
3.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h.
The reaction mixture was purified by column chromatography
on silica gel using (5% ether/petroleum ether) as the eluent to
afford a white solid (61% yield): 1H NMR (400 MHz, CDCl3,
TMS) δ 3.80 (s, 3H), 3.86 (s, 3H), 4.10 (s, 3H), 6.58 - 6.61 (m,
2H), 7.14 (d, J = 9 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS)
δ 55.4, 55.7, 62.1 (t, J = 3.6 Hz), 98.9, 104.8, 108.5, 110.9-111.3
(m), 132.3, 137.3-137.4 (m), 141.0 (dm, J = 245 Hz), 144.7 (dm,
J = 244 Hz), 158.4, 161.9; 19F NMR (377 MHz, CDCl3, TMS)
δ -142.1 (dd, J = 22.8, 8.4 Hz, 2F), -159.1 (dd, J = 22.8, 8.4
Hz, 2F); mp 75-77 °C. Anal. Calcd for C15H12F4O3: C, 56.97;
H, 3.82. Found: C, 56.91; H, 3.85.
2,3,5,6-Tetrafluoro-4-methyl-20,40-methoxy-1,10-biphenyl
(4b). Reaction conditions: 2,4-dimethoxybenzoic acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv),
3 A MS (100 mg), and 2,3,5,6-tetrafluorotoluene (0.60 mmol,
3.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 140 °C,
22 h. The reaction mixture was purified by column chromatog-
raphy on silica gel using (5% ether/petroleum ether) as the
eluent to afford a white solid (60% yield): 1H NMR (400 MHz,
CDCl3, TMS) δ 2.31 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 6.58-6.61
(m, 2H), 7.16 (d, J = 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3,
TMS) δ 7.6, 55.2, 55.4, 55.7, 98.9, 104.7, 108.9, 114.4-114.9 (m),
132.3, 143.8 (dm, J = 247 Hz), 145.0 (dm, J = 242 Hz), 158.3,
161.9; 19F NMR (377 MHz, CDCl3, TMS) δ -142.7 (dd, J =
22.4, 12.5 Hz, 2F), -145.1 (dd, J = 22.4, 12.3 Hz, 2F); mp
74-76 °C. Anal. Calcd for C15H12F4O2: C, 60.00; H, 4.03.
Found: C, 59.82; H, 4.07.
2-(2,3,5,6-Tetrafluoro-4-methoxyphenyl)-3-methylfuran (3n).
Reaction conditions: 3-methyl-2-furoic acid (0.20 mmol), Pd-
(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv),
3 A MS (100 mg), and 2,3,5,6-tetrafluoroanisole (1.0 mmol,
5.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 120 °C, 22 h.
The reaction mixture was purified by column chromatography
on silica gel using petroleum ether as the eluent to afford a
2-(2,3,5,6-Tetrafluoro-4-methylphenyl)-3-methylbenzofuran
(4c). Reaction conditions: 3-methylbenzofuran-2-carboxylic
acid (0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv),
K3PO4 (0.30 mmol, 1.5 equiv), 3 A MS (100 mg), and 2,3,5,6-
tetrafluorotoluene (0.60 mmol, 3.0 equiv) in 2 mL of solvent
(7% DMSO/dioxane), 140 °C, 22 h. The reaction mixture was
purified by column chromatography on silica gel using petro-
leum ether as the eluent to afford a white solid (63% yield): 1H
NMR (400 MHz, CDCl3, TMS) δ 2.26 (s, 3H), 2.36 (s, 3H), 7.30
(t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.52 (d, J = 8.2 Hz,
1H), 7.60 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3,
TMS) δ 7.8, 8.7, 108.1 - 108.5 (m), 111.4, 117.2-117.7 (m),
119.8, 122.6, 125.2, 129.4, 138.9, 144.1 (dm, J = 245 Hz), 145.3
(dm, J = 242 Hz), 155.1; 19F NMR (377 MHz, CDCl3, TMS)
δ -140.5 (dd, J = 21.5, 12 Hz, 2F), -143.3 (dd, J = 21.1, 12 Hz,
2F); mp 102-104 °C. Anal. Calcd for C16H10F4O: C, 65.31; H,
3.43. Found: C, 65.27; H, 3.46.
1
colorless oil (62% yield): H NMR (400 MHz, CDCl3, TMS)
δ 2.04 (s, 3H), 4.13(s, 3H), 6.39 (d, J = 1.5 Hz, 1H), 7.51 (d, J =
1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 10.5 (t, J =
2.7 Hz), 62.1 (t, J = 3.8 Hz), 104.8 (t, J = 17.6 Hz), 113.8, 122.1,
136.4, 138.4-138.6 (m), 140.8 (dm, J = 245 Hz), 144.5 (dm, J =
247 Hz), 148.7; 19F NMR (377 MHz, CDCl3, TMS) δ -
141.1 (dd, J = 20.4, 7.8 Hz, 2F), -158.2 to -158.3 (m, 2F).
Anal. Calcd for C12H8F4O2: C, 55.39; H, 3.10. Found: C, 55.31;
H, 3.06.
1,2,3,4,5-Pentafluoro-6-(2-phenylethynyl)benzene (3o)34. Re-
action conditions: phenylpropiolic acid (0.20 mmol), Pd(TFA)2
2,3,5,6-Tetrafluoro-4-trifluoromethy-20,40-methoxyl-1,10-
biphenyl (4d). Reaction conditions: 2,4-dimethoxybenzoic
acid (0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(34) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc.
2010, 132, 2522.
J. Org. Chem. Vol. 76, No. 3, 2011 891

Zhao et al.
JOCArticle
(0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv), 3 A MS
(100 mg), and 2,3,5,6-tetrafluorobenzotrifluoride (0.60 mmol,
3.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h.
The reaction mixture was purified by column chromatography
on silica gel using (5% ether/petroleum ether) as the eluent to
afford a white solid (63% yield): 1H NMR (400 MHz, CDCl3,
TMS) δ 3.81 (s, 3H), 3.88 (s, 3H), 6.59-6.63 (m, 2H), 7.16 (d,
J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 55.4,
55.7, 98.9, 104.9, 107.3, 107.9-108.2 (m), 119.7, 121.9-122.4 (m),
131.9, 143.7 (dm, J = 255 Hz), 144.7 (dm, J = 253 Hz), 158.1,
162.6; 19F NMR (377 MHz, CDCl3, TMS) δ -56.2 (t, J =
21.5 Hz, 3F), -138.4 to -138.5 (m, 2F), -141.9 to -142.1 (m,
2F); mp 48-50 °C. Anal. Calcd for C15H9F7O2: C, 50.86; H,
2.56. Found: C, 50.78; H, 2.60.
2,3,5,6-Tetrafluoro-4-cyano-20,40-methoxy-1,10-biphenyl (4e).
Reaction conditions: 2,4-dimethoxybenzoic acid (0.20 mmol),
Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), 3 A MS (100 mg), and 2,3,5,
6-tetrafluorobenzonitrile (0.60 mmol, 3.0 equiv) in 2 mL of solvent
(7% DMSO/dioxane), 140 °C, 22 h. The reaction mixture was
purified by column chromatography on silica gel using (5%
ether/petroleum ether) as the eluent to afford a white solid (64%
yield): 1H NMR (400 MHz, CDCl3, TMS) δ 3.80 (s, 3H), 3.87 (s,
3H), 6.59-6.63 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3, TMS) δ 55.5, 55.7, 92.4, 98.9, 105.1, 107.0,
107.9, 124.7 - 124.9 (m), 131.9, 144.6 (dm, J = 248 Hz),
146.4(dm, J = 255 Hz), 158.1, 162.9; 19F NMR (377 MHz,
CDCl3, TMS) δ -133.7 to -133.9 (m, 2F), -136.9 to -137.0 (m,
2F); mp 102-104 °C. Anal. Calcd for C15H9F4NO2: C, 57.89; H,
2.91; N, 4.50. Found: C, 57.83; H, 2.97; 4.48.
4.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h.
The reaction mixture was purified by column chromatography
on silica gel using (2% ether/petroleum ether) as the eluent
to afford a white solid (50% yield): 1H NMR (400 MHz, CDCl3,
TMS) δ 3.80 (s, 3H), 3.87 (s, 3H), 6.59-6.61 (m, 2H), 7.00-7.06
(m, 1H), 7.16 (d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
TMS) δ 55.5, 55.6, 98.9, 104.2, 104.5, 104.7, 108.7, 118.2-118.6
(m), 132.1, 144.4 (dm, J=243 Hz), 145.8 (dm, J=244 Hz), 158.2,
162.1; 19F NMR (377 MHz, CDCl3, TMS) δ -140.2 (dd, J=
22.7, 12.5 Hz, 2F), -141.0 (dd, J=22.7, 12.5 Hz, 2F); mp 49-
50 °C. Anal. Calcd for C14H10F4O2: C, 58.75; H, 3.52. Found: C,
58.71; H, 3.56.
2,3,4,6-Tetrafluoro-20,40-methoxy-1,10-biphenyl (4i). Reaction
conditions: 2,4-dimethoxybenzoic acid (0.20 mmol), Pd(TFA)2
(0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv), Ag2CO3
(0.70 mmol, 3.5 equiv), K3PO4 (0.30 mmol, 1.5 equiv), 3 A MS
(100 mg), and 1,2,3,5-tetrafluorobenzene (1.0 mmol, 4.0 equiv)
in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h. The
reaction mixture was purified by column chromatography on
silica gel using (2% ether/petroleum ether) as the eluent to
afford a white solid (60% yield): 1H NMR (400 MHz, CDCl3,
TMS) δ 3.79 (s, 3H), 3.86 (s, 3H), 6.58-6.61 (m, 2H), 6.78-6.8
(m, 1H), 7.14 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3,
TMS) δ 55.4, 55.7, 98.9, 100.1 - 100.6 (m), 104.7, 108.8, 112.6,
112.8, 132.2, 137.3 (dm, J = 245 Hz), 149.1 (dm, J = 244 Hz),
150.1 (dm, J = 248 Hz), 154.8 (dm, J = 243 Hz), 153.6, 156.0,
158.3, 161.8; 19F NMR (377 MHz, CDCl3, TMS) δ -115.9 (d,
J = 10.7 Hz, 1F), -132.5 to -132.6 (m, 1F), -134.4 (dd, J =
21.6, 5.2 Hz, 1F), -165.8 to -165.9 (m, 1F); mp 42-44 °C. Anal.
Calcd for C15H9F7O2: C14H10F4O2: C, 58.75; H, 3.52. Found: C,
58.77; H, 3.55.
2,3,5,6-Tetrafluoro-4-(2,4-dimethoxyphenyl)pyridine (4f). Re-
action conditions: 2,4-dimethoxybenzoic acid (0.20 mmol), Pd-
(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), 3 A MS (100 mg), and 2,3,5,
6-tetrafluoropyridine (0.60 mmol, 3.0 equiv) in 2 mL of solvent
(7% DMSO/dioxane), 140 °C, 22 h. The reaction mixture was
purified by column chromatography on silica gel using (5%
ether/petroleum ether) as the eluent to afford a white solid (62%
2,3,6-Trifluoro-20,40-methoxy-1,10-biphenyl (4j). Reaction
conditions: 2,4-dimethoxybenzoic acid (0.20 mmol), Pd(TFA)2
(0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv), Ag2CO3
(0.70 mmol, 3.5 equiv), K3PO4 (0.40 mmol, 2.0 equiv), 3 A MS
(100 mg), and 1,3,5-trifluorobenzene (1.0 mmol, 5.0 equiv) in
2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h. The
reaction mixture was purified by column chromatography on
silica gel using petroleum ether as the eluent to afford a white
1
yield): H NMR (400 MHz, CDCl3, TMS) δ3.82 (s, 3H), 3.88
(s, 3H), 6.60-6.63 (m, 2H), 7.19 (d, J=8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3, TMS) δ 55.5, 55.7, 99.0, 105.1, 107.3,
130.9-131.1 (m), 131.7, 138.4-138.7 (m), 140.9-141.2 (m),
142.3, 144.7, 158.1, 163.0; 19F NMR (377 MHz, CDCl3, TMS)
δ -89.9 to -90.1 (m, 2F), -139.8 to -139.9 (m, 2F); mp
115-117 °C. Anal. Calcd for C13H9F4NO2: C, 54.36; H, 3.16;
N, 4.88. Found: C, 54.33; H, 3.18; N, 4.82.
1
solid (34% yield): H NMR (400 MHz, CDCl3, TMS) δ 3.78
(s, 3H), 3.86 (s, 3H), 6.57-6.59 (m, 2H), 6.70-6.73 (m, 2H), 7.14
(d, J = 9 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 55.4,
55.7, 98.9, 99.8-100.2 (m), 104.5, 109.8, 111.2-111.5 (m), 132.3,
158.3, 160.1 (dm, J = 247 Hz), 161.5, 161.9 (dm, J = 246 Hz),
163.1; 19F NMR (377 MHz, CDCl3, TMS) δ -109.1 (d, J = 5.7
Hz, 2F), -110.1 (t, J = 6.4 Hz, 1F); mp 70-72 °C. Anal. Calcd
for C14H11F3O2: C, 62.69; H, 4.13. Found: C, 62.72; H, 4.16.
2-(2,4,6-Trifluorophenyl)-3-methylbenzo[b]thiophene (4k).
Reaction conditions: 3-methylbenzo[b]thiophene-2-carboxylic
acid (0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv),
K3PO4 (0.40 mmol, 2.0 equiv), 3 A MS (100 mg), and 1,3,5-
trifluorobenzene (1.0 mmol, 5.0 equiv) in 2 mL of solvent (7%
DMSO/dioxane), 140 °C, 22 h. The reaction mixture was
purified by column chromatography on silica gel using petro-
leum ether as the eluent to afford a white solid (52% yield): 1H
NMR (400 MHz, CDCl3, TMS) δ 2.29 (s, 3H), 6.79-6.83 (m,
2H), 7.37-7.45 (m, 2H), 7.77 (d, J = 7.4 Hz, 1H), 7.86(d, J =
7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 12.6 (t, J =
1.2 Hz), 100.3 - 100.9 (m), 108.0-108.2 (m), 122.2, 122.3, 122.6,
124.1, 124.9, 132.8, 139.8, 140.2, 161.0 (dm, J = 250 Hz), 162.5
(dm, J = 250 Hz); 19F NMR (377 MHz, CDCl3, TMS) δ -106.4
(d, J = 6.7 Hz, 2F), -106.5 to -106.6 (m, 1F); mp 94-96 °C.
Anal. Calcd for C15H9F3S: C, 64.74; H, 3.26. Found: C, 64.75;
H, 3.30.
2,3,5,6-Tetrafluoro-4-(3-methylbenzofuran-2-yl)pyridine (4g).
Reaction conditions: 3-methylbenzofuran-2-carboxylic acid
(0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv), PCy3
(0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv),
3 A MS (100 mg) and 2,3,5,6-tetrafluoropyridine (0.60 mmol,
3.0 equiv) in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h.
The reaction mixture was purified by column chromatography
on silica gel using (5% ether/petroleum ether) as the eluent to
afford a white solid (75% yield): 1H NMR (400 MHz, CDCl3,
TMS) δ 2.34 (s, 3H), 7.33-7.37 (m, 1H), 7.42-7.46 (m, 1H), 7.55
(d, J = 8.3 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3, TMS) δ 9.0, 111.7, 120.3, 120.9, 123.2,
123.5-123.8 (m), 126.5, 129.0, 137.1, 138.9 (dm, J = 252 Hz),
143.9 (dm, J = 244 Hz), 155.5; 19F NMR (377 MHz, CDCl3,
TMS) δ -92.2 to -92.3 (m, 2F), -141.8 to -141.9 (m, 2F); mp
128-130 °C. Anal. Calcd for C14H7F4NO: C, 59.80; H, 2.51; N,
4.98. Found: C, 59.77; H, 2.53; N, 4.94.
2,3,5,6-Tetrafluoro-20,40-methoxy-1,10-biphenyl (4h). Reac-
tion conditions: 2,4-dimethoxybenzoic acid (0.20 mmol), Pd-
(TFA)2 (0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv),
Ag2CO3 (0.70 mmol, 3.5 equiv), K3PO4 (0.40 mmol, 2.0 equiv),
3 A MS (100 mg), and 1,2,4,5-tetrafluorobenzene (1.0 mmol,
2, 6-Difluoro-20,40-methoxy-1,10-biphenyl (4l). Reaction con-
ditions: 2,4-dimethoxybenzoic acid (0.20 mmol), Pd(TFA)2
(0.03 mmol, 0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv), Ag2CO3
892 J. Org. Chem. Vol. 76, No. 3, 2011

Zhao et al.
JOCArticle
(0.70 mmol, 3.5 equiv), K3PO4 (0.40 mmol, 2.0 equiv), 3 A MS
(100 mg), and 1,3-difluorobenzene (1.0 mmol, 5.0 equiv) in
2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h. The
reaction mixture was purified by column chromatography on
silica gel using petroleum ether as the eluent to afford a white
solid (15% yield): 1H NMR (400 MHz, CDCl3, TMS) δ 3.78 (s,
3H), 3.86 (s, 3H), 6.57-6.60 (m, 2H), 6.91-6.97 (m, 2H),
7.16-7.19 (m, 1H), 7.24-7.30 (m, 1H, overlap with the chemical
shift of CHCl3); 13C NMR (100 MHz, CDCl3, TMS) δ 55.4,
55.7, 98.9, 104.5, 110.7-111.2 (m), 115.1(t, J = 20 Hz), 128.6 (t,
Anal. Calcd for C22H14F2OS: C, 72.51; H, 3.87. Found: C,
72.47; H, 3.91.
Methyl 3,5-difluoro-4-(3-methylbenzo[b]thiophen-2-yl)benzoate
(4n). Reaction conditions: 3-methylbenzo[b]thiophene-2-car-
boxylic acid (0.20 mmol), Pd(TFA)2 (0.03 mmol, 0.15 equiv),
PCy3 (0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol, 3.5 equiv),
K3PO4 (0.40 mmol, 2.0 equiv), 3 A MS (100 mg), and methyl 3,5-
difluorobenzoate (1.0 mmol, 5.0 equiv) in 2 mL of solvent (7%
DMSO/dioxane), 140 °C, 22 h. The reaction mixture was pu-
rified by column chromatography on silica gel using (5% ether/
petroleum ether) as the eluent to afford a white solid (61%
yield): 1H NMR (400 MHz, CDCl3, TMS) δ 2.31 (s, 3H), 3.98 (s,
3H), 7.40-7.44 (m, 2H), 7.70 (d, J = 7.5 Hz, 2H), 7.78 (d, J =
7.3 Hz, 1H), 7.86 (d, J = 8 Hz, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 12.8, 52.8, 112.7-113.0 (m), 116.4 (t, J = 20 Hz),
122.3, 122.5, 122.6, 124.2, 125.1, 132.6 (t, J = 9.5 Hz), 133.2, 139.8,
140.4, 160.3 (dd, J = 252, 6.3 Hz), 164.7 (t, J = 3.2 Hz); 19F
NMR (377 MHz, CDCl3, TMS) δ -108.0 (s, 2F); mp 92-94 °C.
Anal. Calcd for C17H12F2O2S: C, 64.14; H, 3.80. Found: C,
64.10; H, 3.84.
J = 10 Hz), 132.2, 158.4, 161.9, 160.7 (dd, J = 246, 7 Hz); 19
F
NMR (377 MHz, CDCl3, TMS) δ -112.2 (s, 2F); mp 52-53 °C.
Anal. Calcd for C14H12F2O2: C, 67.20; H, 4.83. Found: C, 67.24;
H, 4.88.
(2,4-Difluoro-3-(3-methylbenzo[b]thiophen-2-yl)phenyl)-
(phenyl)methanone (4m). Reaction conditions: 3-methylbenzo-
[b]thiophene-2-carboxylic acid (0.20 mmol), Pd(TFA)2 (0.03 mmol,
0.15 equiv), PCy3 (0.09 mmol, 0.45 equiv), Ag2CO3 (0.70 mmol,
3.5 equiv), K3PO4 (0.4 mmol, 2.0 equiv), 3 A MS (100 mg), and
(2,4-difluorophenyl)(phenyl)methanone (1.0 mmol, 5.0 equiv)
in 2 mL of solvent (7% DMSO/dioxane), 140 °C, 22 h. The
reaction mixture was purified by column chromatography on
silica gel using (5% ether/petroleum ether) as the eluent to
afford a white solid (55% yield): 1H NMR (400 MHz, CDCl3,
TMS) δ 2.33 (s, 3H), 7.15-7.19 (m, 1H), 7.39-7.43 (m, 2H),
7.48-7.51 (m, 2H), 7.60-7.62 (m, 1H), 7.67-7.69 (m, 1H),
7.76-7.78 (m, 1H), 7.84-7.88 (m, 3H); 13C NMR (100 MHz,
CDCl3, TMS) δ 12.8, 112.13 (dd, J = 22.9, 3.8 Hz), 112.5, 112.7,
122.2, 122.4, 122.5, 123.7 (dd, J = 16, 3.8 Hz), 124.2, 125.0,
128.6, 129.7, 132.0 (dd, J=10.6, 4.7 Hz) (m), 133.1, 133.6, 137.3,
139.8, 140.3, 158.4 (dd, J = 257, 6.6 Hz), 162.4 (dd, J = 256,
5.9 Hz), 192.2; 19F NMR (377 MHz, CDCl3, TMS) δ -
103.1 (d, J = 8.5 Hz, 1F), -105.6 (d, J=9 Hz, 1F); mp 30-31 °C.
Acknowledgment. Financial support from the 973 Pro-
gram (2006CB932903, 2009CB939803), NSFC (20821061,
20925102), “The Distinguished Oversea Scholar Project”,
the “One Hundred Talent Project”, and the Key Project from
CAS is greatly appreciated.
Supporting Information Available: Detailed experimental
procedures about the studies of the reaction mechanism, spec-
tral data for new compounds, and X-ray crystallography data
for 3a. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 3, 2011 893