Regiocontroled palladium-catalysed direct arylation at carbon C2 of benzofurans using benzenesulfonyl chlorides as the coupling partners

Article abstract of DOI:10.1002/cctc.201301077

The regioselective palladium-catalysed direct arylation of benzofurans with aryl halides is a challenging reaction because carbons C2 and C3 display similar reactivity. Such couplings generally lead to mixtures of C2 and C3 arylation products together wit

Full text of DOI:10.1002/cctc.201301077

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DOI: 10.1002/cctc.201301077
Regiocontroled Palladium-Catalysed Direct Arylation at
Carbon C2 of Benzofurans using Benzenesulfonyl
Chlorides as the Coupling Partners
Lenka Loukotova,[a, b] Kedong Yuan,[a] and Henri Doucet*[a]
The regioselective palladium-catalysed direct arylation of ben-
zofurans with aryl halides is a challenging reaction because
carbons C2 and C3 display similar reactivity. Such couplings
generally lead to mixtures of C2 and C3 arylation products to-
gether with C2,C3 diarylation products. We found that the use
of benzenesulfonyl chlorides instead of aryl halides as the cou-
pling partner allows for controlling the regioselectivity of the
palladium-catalysed arylation of benzofurans in favour of
carbon C2. This method tolerates a variety of substituents on
the benzenesulfonyl derivative.
Introduction
The arylation of heteroaromatics such as benzofurans is an im-
portant field of research in organic chemistry owing to the bio-
logical properties of some benzofuran derivatives (Figure 1).
For example, saprisartan is an AT1 receptor antagonist and fur-
aprofen is a non-steroidal anti-inflammatory drug.
heteroaryl derivatives has proved to be a very powerful
method for the synthesis of a wide variety of arylated hetero-
cycles.[2,3] However, relatively little effort has been expended
towards developing such metal-catalysed direct arylation reac-
tions for the synthesis of arylated benzofurans, and they are
still often prepared by using more classical coupling
procedures.[4,5]
The first example of a palladium-catalysed direct arylation at
carbon C2 of benzofuran was reported by Ohta who obtained
a low yield of 23% for its coupling with bromobenzene using
Pd(PPh3)4 as the catalyst.[1] Similarly, Fagnou and co-workers re-
ported the coupling of benzofuran with 2-bromotoluene using
2 mol% Pd(OAc)2 and 4 mol% PCy3 (Cy=cyclohexyl) as the
catalyst, and again, the 2-arylated benzofuran was formed in
a low yield of 29%.[6a] Higher yields of 41–53% were obtained
by Mori and co-workers using PdCl2(PPh3)2 as the catalyst asso-
ciated to AgF as the base.[6c] It should be noted that an exam-
ple of 2,3-diarylation of benzofuran in the presence of 5 mol%
Pd(OAc)2 and 10 mol% PnBu(Ad)2 (Ad=adamantyl) as the cata-
lyst system has also been described by Chiong and Daugulis.[7]
The Pd-catalysed synthesis of 2-arylbenzofurans using aryldia-
zonium trifluoroacetates or arylboronic acids as coupling part-
ners,[8] or under oxidative coupling conditions[9] has also been
reported. Recently, Glorius and co-workers prepared 2-arylben-
zofurans through rhodium-catalysed oxidative arylation.[10]
The low yields often obtained for the Pd-catalysed coupling
of aryl halides with benzofuran are attributable to the lack of
reactivity and/or regioselectivity observed in the course of
these couplings (Scheme 1). For example, we observed that
the reaction of 4-bromobenzene with benzofuran in the pres-
ence of 2 mol% Pd(OAc)2 using KOAc as the base in N,N-dime-
thylacetamide (DMA) led to a mixture of the mono-arylated
benzofurans 1a and b and also to the 2,3-diarylation product
1c in a 50:17:33 ratio making this process unattractive. The
use of other bases such as CsOAc, NaOAc, K2CO3 or K3PO4 led
to lower conversions of benzofuran and also to mixtures of
products.
Figure 1. Examples of bioactive arylbenzofurans.
In 1990, Ohta and co-workers reported that the 2- or 5-aryla-
tion of several heteroaromatics including furans with aryl hal-
ides, through a CÀH bond activation, proceeds in moderate to
good yields using Pd(PPh3)4 as the catalyst.[1] Since these excit-
ing results, the palladium-catalysed so-called direct arylation of
[a] L. Loukotova, K. Yuan, Dr. H. Doucet
Institut des Sciences Chimiques de Rennes, UMR 6226
CNRS-Universitꢀ de Rennes 1
“Organomꢀtalliques, matꢀriaux et Catalyse”
Campus de Beaulieu, 35042 Rennes (France)
Fax: (+33)0223236939
E-mail: henri.doucet@univ-rennes1.fr
[b] L. Loukotova
Charles University in Prague, Faculty of Science
Department of Physical and Macromolecular Chemistry
Hlavova 2030, CZ-128 40 Prague (Czech Republic)
This manuscript is part of a Special Issue on the 2nd International Symposi-
um on Chemistry of Energy Conversion and Storage. The Table of Contents
will appear here. This text will be updated once the Special issue has been
assembled.
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Scheme 2. Pd-catalysed direct arylation of benzofuran with benzenesulfonyl
chloride.
Scheme 1. Regioselectivity of the Pd-catalysed direct arylation of benzofuran
with bromobenzene.
According to Gorelsky calcula-
tions, in the concerted metallation
Herein, we describe a regioselective access to C2-arylated
benzofurans using desulfitative palladium-catalysed CÀH bond
functionalisation of benzofurans with benzenesulfonyl chlor-
ides as the coupling partners (Scheme 2). The influence of the
benzenesulfonyl chloride substituents is reported.
deprotonation
carbon 2 of benzofuran should be
slightly more reactive than
carbon 3 (energies: 26.3 and
27.5 kcalmolÀ1
respectively,
(CMD)
process
Based on our previous results on palladium-catalysed desul-
fitative coupling with thiophene derivatives,[18] we first exam-
ined the influence of several reaction conditions on the prod-
ucts formation (Table 1). The reaction of 1.3 equivalents of ben-
zenesulfonyl chloride with one equivalent of benzofuran in the
presence of 5 mol% Pd(OAc)2 catalyst and Li2CO3 as the base
at 1408C gave a mixture of products 1a and b in a 26:1 ratio
with a conversion of benzofuran of 87%; whereas no forma-
tion of diarylation product 1c was detected by GC–MS analysis
of the crude mixture (Table 1, entry 1). Then, we examined the
influence of the palladium catalyst. The use of 5 mol% PdCl2
led to similar results to the use of Pd(OAc)2; whereas PdCl-
(C3H5)(dppb) (dppb=1,4-bis(diphenylphosphino)butane was
completely ineffective (entries 2 and 3). On the other hand,
PdCl2(MeCN)2 catalyst gave the regioselective product 1a (ratio
1a:b 35:1) in 81% yield with full conversion of benzofuran
(entry 4). The influence of the nature of the base was also ex-
amined. The use of Na2CO3, K2CO3, KOAc or K3PO4 led to low to
Figure 2. Benzofuran Gibbs
free energies of activation
(DG298K) of the cleavage of CÀ
H bonds in the CMD process
using the [Pd(C6H5)(PMe3)-
(OAc)] catalyst.
,
Figure 2).[11] This minor difference
of energy of activation explains
the poor regioselectivity observed
for Pd-catalysed arylations that
proceed through a CMD process.
Therefore, the discovery of
a new process for the regioselective intermolecular direct cou-
pling of benzofuran derivatives with arenes, especially using
easily available catalyst, base and substrates, would be a con-
siderable advantage.
Results and Discussion
In 2009, Dong and co-workers reported the Pd-catalysed cou-
pling of 2-phenylpyridine with benzenesulfonyl chlorides to
prepare sulfones.[12] In the course of this study, they also ob-
served in one case a desulfitative[13] direct arylation
of a quinoline derivative if using elevated tempera-
Table 1. Influence of the reaction conditions on the Pd-catalysed direct arylation of
tures in the presence of Ag2CO3 and CuBr. Then, the
use of benzenesulfonyl chlorides[14–16] as the coupling
partners for the palladium-catalysed desulfitative
direct arylation has been extended to benzoxazoles
derivatives by Cheng et al. using 10 mol% Pd(OAc)2
catalyst, K2CO3 as a base and one equivalent of CuI as
an additive to produce 2-arylbenzoxazoles in high
yields.[17] We also recently reported the first palladi-
um-catalysed desulfitative b-arylation of thiophene
derivatives.[18] On the other hand, to our knowledge,
the desulfitative direct arylation of benzofurans with
benzenesulfonyl chlorides has not been reported. As
the use of benzenesulfonyl chlorides instead of aryl
halides drastically modifies the regioselectivity of pal-
ladium-catalysed direct arylations,[18] their behaviour
in the presence of benzofurans needed to be investi-
gated.
benzofuran with benzenesulfonyl chloride.[a]
Catalyst (mol%)
Solvent
Base
Ratio
Conv. Yield
1a:b:c
[%]
[%]
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (5)
PdCl2 (5)
PdCl(C3H5)(dppb) (5) dioxane
PdCl2(CH3CN)2 (5)
PdCl2(CH3CN)2 (5)
PdCl2(CH3CN)2 (5)
PdCl2(CH3CN)2 (5)
PdCl2(CH3CN)2 (5)
PdCl2(CH3CN)2 (5)
dioxane
dioxane
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Na2CO3
K2CO3
KOAc
26:1:0
35:1:0
–
34:1:0 100
60:1:0
7:1:0
87
70
0
68
60
dioxane
dioxane
dioxane
dioxane
dioxane
pentan-1-ol
Ethyl-benzene Li2CO3
DMA
dioxane
dioxane
81
50
19
10
37
18
38
0
24:1:0
15:1:5
K3PO4
Li2CO3
sideproducts
6:1:0
10 PdCl2(CH3CN)2 (5)
11 PdCl2(CH3CN)2 (5)
12 PdCl2(CH3CN)2 (2.5)
13 PdCl2(CH3CN)2 (5)
Li2CO3
Li2CO3
Li2CO3
–
27:1:0
90:1:0
90
58[b]
73
[a] Benzofuran (1 equiv), benzenesulfonyl chloride (1.3 equiv), base (3 equiv), 1408C,
18 h, isolated yields, conversion of benzofuran. [b] 1208C.
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moderate conversions of benzofuran and/or to lower regiose-
lectivities than the use of Li2CO3 (entries 5–8). The influence of
a few other solvents was then examined. Pentan-1-ol only
gave unidentified side-products, and ethylbenzene afforded 1a
in low yield attributable to a lower regioselectivity of the aryla-
tion and a poor conversion of benzofuran (entries 9 and 10).
The polar solvent DMA was completely ineffective for this cou-
pling (entry 11). Then, we examined the influence of the cata-
lyst loading and reaction temperature. With Li2CO3 as the base
and dioxane as the solvent, a catalyst loading of 2.5 mol% of
PdCl2(MeCN)2 gave 1a in 73% yield with 90% conversion of
benzofuran, but a reaction temperature of 1208C instead of
1408C was relatively ineffective (entries 12 and 13). Finally, we
also studied the reactivity of benzenesulfinic acid sodium salt
as the coupling partner instead of benzenesulfonyl chloride,
because the Pd-catalysed synthesis of biaryls with such reac-
tants was recently reported.[19a] However, no formation of de-
sired products 1a–c was detected by GC–MS analysis of the
crude mixtures.[19b]
Table 2. Influence of the benzenesulfonyl chloride substituents on the
Pd-catalysed direct C2-arylation of benzofuran.
Benzenesulfonyl chloride Product
Yield [%]
69
1
2
3
4
5
6
7
2
3
4
5
6
7
8
80
71
77
90
89
39
Then, the influence of the substituents on benzenesulfonyl
chloride for the reaction with benzofuran was examined by
using 5 mol% Pd(MeCN)2Cl2 catalyst in the presence of Li2CO3
in dioxane at 1408C (Table 2). We initially employed electron-
deficient benzenesulfonyl chlorides. Nitro-, cyano- and trifluor-
omethyl substituents at C4 of benzenesulfonyl chlorides gave
very regioselectively the C2-arylated benzofurans 2–4 in 69–
80% yields (Table 2 entries 1–3). High yield in 5 was also ob-
tained from 4-chlorobenzenesulfonyl chloride (entry 4). It
should be noted that no cleavage of the CÀCl bond was ob-
served in the course of this reaction, allowing further transfor-
mations. From the slightly electron-deficient 4-fluorobenzene-
sulfonyl chloride, a good yield of 90% in 6 was also obtained
(entry 5). Even the electron-rich 4-methylbenzenesulfonyl chlo-
ride gave the desired coupling product 7 in high yield and
very high regioselectivity (entry 6). On the other hand, the use
of the more electron-rich 4-methoxybenzenesulfonyl chloride
gave 8 in only 39% yield attributable to a poor conversion of
this reactant (entry 7).
8
9
9
64
77
10
10
11
85
11
12
12
13
50
91
13
14
14
73
Then, we studied the influence of some meta and ortho sub-
stituents on the benzenesulfonyl derivative on the regioselec-
tivity and yield for this coupling. Meta substituents have
a minor influence on the reactivity of the benzenesulfonyl
chlorides. 3-(Trifluoromethyl)benzenesulfonyl chloride gave 9
in 64% yield (Table 2, entry 8). High yields of 10 and 11 were
also obtained from two di-meta-subtituted benzenesulfonyl
chlorides (entries 9 and 10). Satisfactory result was also ob-
tained from 2-cyanobenzenesulfonyl chloride to give 12 in
50% yield (entry 11). From 2-fluorobenzenesulfonyl chloride
and naphthalene-1-sulfonyl chloride, the expected products 13
and 14 were obtained in 91% and 73% yields, respectively
(entries 12 and 13). On the other hand, an ortho-methyl sub-
stituent on benzenesulfonyl chloride had a detrimental effect,
as the desired product 15 was only observed as trace amount
by GC–MS analysis (entry 14).
15 trace
[a] PdCl2(CH3CN)2 (0.05 equiv), benzofuran (1 equiv), benzenesulfonyl chlo-
ride (1.3 equiv), Li2CO3 (3 equiv), dioxane, 1408C, 40 h, isolated yields.
fonyl chloride was coupled at C2 position of benzofuran with-
out cleavage of the CÀBr bond to give 16 in 88% yield. Then,
using PdCl(C3H5)(dppb) catalyst[20a] with KOAc as the base in
DMA and 2-ethyl-4-methylthiazole as the coupling partner,
target product 17 was obtained in 88% yield.
The influence of a bromo substituent on benzofuran was
also examined, because such substituent would allow the easy
access to a variety of benzofuran derivatives (Scheme 4). Using
1.3 equivalents of differently substituted benzenesulfonyl chlo-
ride and 5 mol% Pd(MeCN)2Cl2 catalyst in the presence of
Consecutive arylations using 4-bromobenzenesulfonyl chlo-
ride were also studied (Scheme 3). Using the Pd(MeCN)2Cl2 cat-
alyst in the presence of Li2CO3 in dioxane, 4-bromobenzenesul-
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Scheme 3. Consecutive Pd-catalysed direct arylations using 4-bromobenze-
nesulfonyl chloride as the coupling partner.
Scheme 6. Proposed catalytic cycle.
mobenzonitrile, 3-bromoquinoline or 4-bromofluorobenzene
as the coupling partners to afford products 21–24 in 76–83%
yields.
Scheme 4. Pd-catalysed direct arylation of 5-bromobenzofuran with benze-
nesulfonyl chlorides bearing different substituents R.
Although the mechanism cannot yet be elucidated, the cata-
lytic cycle shown on Scheme 6 can be proposed. The first step
of the catalytic cycle is probably the oxidative addition of the
benzenesulfonyl chloride to PdII to afford the PdIV intermediate
A. Such oxidative addition on PdII have been found to proceed
even at room temperature.[12b] Then, after elimination of SO2,
coordination of benzofuran gives B. The migration of the aryl
group to the a-carbon atom of benzofuran gives C. Finally,
a proton abstraction assisted by the base gives the a-arylated
benzofuran and regenerates the PdII species.
Li2CO3 in dioxane, the desired coupling products 18–20 were
obtained in 52–82% yields without cleavage of the CÀBr bond.
Finally, as the C3 position of benzofurans is known to be re-
active for direct arylations with aryl halides using palladium
catalysts with acetate bases in polar solvents,[20b] the reactivity
of some of the prepared 2-arylbenzofurans for such couplings
was examined (Scheme 5). 1a, 3, 4 and 9 were reacted with
a set of aryl bromides in the presence of 2 mol% PdCl(C3H5)-
(dppb) catalyst, KOAc as the base in DMA. Selective 3-aryla-
tions of these 2-arylbenzofurans were observed by using 4-bro-
Conclusions
In summary, we report here the first palladium-catalysed desul-
fitative arylation of benzofuran derivatives. The reaction was
found to provide very selectively the C2-arylated benzofurans,
and proceeds with easily accessible ligand-free Pd(MeCN)2Cl2
catalyst and Li2CO3 as the base. Moreover, this procedure toler-
ates a variety of substituents on the benzenesulfonyl chloride.
Owing to the wide availability of diversely functionalised ben-
zenesulfonyl chlorides at an affordable cost, such simple reac-
tion conditions (no expensive base and ligand) should be very
attractive to synthetic chemists for gaining access to 2-arylben-
zofurans. Moreover, from these 2-arylbenzofurans, a second
palladium-catalysed CÀH bond functionalization at carbon C3
of the benzofuran ring allows the synthesis of 2,3-diarylbenzo-
furans with two different aryl groups.
Experimental Section
General
All reactions were performed under an inert atmosphere with stan-
dard Schlenk techniques. HPLC grade 1,4-dioxane was used and
stored under argon without further purification. 1H NMR spectra
Scheme 5. Pd-catalysed direct C3-arylation of 2-arylbenzofurans with aryl
bromides.
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were recorded on a Bruker GPX (400 MHz) spectrometer. Chemical
89% (0.185 g) yield. 1H NMR (400 MHz, CDCl3): d=7.79 (d, J=
7.8 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.8 Hz, 2H), 7.52 (d,
J=8.0 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 6.99
(s, 1H), 2.43 ppm (s, 3H).
shifts (d) were reported in parts per million relative to residual
1
chloroform (7.26 ppm for H; 77.0 ppm for 13C), constants were re-
1
ported in Hertz. H NMR assignment abbreviations were the follow-
ing: singlet (s), doublet (d), triplet (t), quartet (q), doublet of dou-
blets (dd), doublet of triplets (dt), and multiplet (m). 13C NMR spec-
tra were recorded at 100 MHz on the same spectrometer and re-
ported in ppm. All reagents were weighed and handled in air.
2-(4-Methoxyphenyl)benzofuran (8)[22]: 4-Methoxybenzenesulfonyl
chloride (0.269 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) af-
1
fords 9 in 39% (0.087 g) yield. H NMR (400 MHz, CDCl3): d=7.82
(d, J=7.8 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H),
7.30 (t, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 6.99 (d, J=7.8 Hz,
2H), 6.90 (s, 1H), 3.87 ppm (s, 3H).
General procedure for the synthesis of C2-arylated benzo-
furans
2-(3-Trifluoromethylphenyl)benzofuran (9)[25]
benzenesulfonyl chloride (0.318 g, 1.3 mmol) and benzofuran
(0.118 g, 1 mmol) affords
in 64% (0.168 g) yield. 1H NMR
: 3-(Trifluoromethyl)-
9
To
a 25 mL oven-dried Schlenk tube, arylsulfonyl chloride
(400 MHz, CDCl3): d=8.12 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.65–7.52
(m, 4H), 7.34 (t, J=7.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.10 ppm (s,
1H).
(1.3 mmol), benzofuran derivative (1 mmol), Li2CO3 (0.222 g,
3 mmol), 1,4-dioxane (2 mL) and bis(acetonitrile)dichloropalladiu-
m(II) (12.9 mg, 0.05 mmol) were successively added. The reaction
mixture was evacuated by vacuum–argon cycles (5 times) and
stirred at 1408C (oil bath temperature) for 18 or 40 h (see tables
and schemes). After cooling the reaction at RT and concentration,
the crude mixture was purified by silica column chromatography
to afford the C2-arylated benzofurans.
2-(3,5-Bis-trifluoromethylphenyl)benzofuran (10)[24]: 3,5-Bis(trifluoro-
methyl)benzenesulfonyl chloride (0.406 g, 1.3 mmol) and benzofur-
an (0.118 g, 1 mmol), affords 10 in 77% (0.254 g) yield. 1H NMR
(400 MHz, CDCl3): d=8.25 (s, 2H), 7.83 (s, 1H), 7.63 (d, J=7.8 Hz,
1H), 7.56 (d, J=7.8 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.28 (t, J=
8.0 Hz, 1H), 7.18 ppm (s, 1H).
2-Phenylbenzofuran (1a)[21]
: Benzenesulfonyl chloride (0.230 g,
2-(3,5-Dichlorophenyl)benzofuran (11)[26]
: 3,5-Dichlorobenzenesul-
1.3 mmol) and benzofuran (0.118 g, 1 mmol), affords 1a in 81%
(0.157 g) yield. 1H NMR (400 MHz, CDCl3): d=7.89 (d, J=7.8 Hz,
2H), 7.60 (d, J=7.8 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.47 (t, J=
7.8 Hz, 2H), 7.37 (t, J=7.8 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.25 (t,
J=7.8 Hz, 1H), 7.04 ppm (s, 1H).
fonyl chloride (0.318 g, 1.3 mmol) and benzofuran (0.118 g,
1 mmol) affords 11 in 85% (0.223 g) yield. 1H NMR (400 MHz,
CDCl3): d=7.70 (s, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz,
1H), 7.40–7.22 (m, 3H), 7.02 ppm (s, 1H).
2-(4-Nitrophenyl)-benzofuran (2)[22]: 4-Nitrobenzenesulfonyl chloride
(0.287 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) affords 2 in
69% (0.165 g) yield. 1H NMR (400 MHz, CDCl3): d=8.32 (d, J=
7.8 Hz, 2H), 8.10 (d, J=7.8 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.56 (d,
J=8.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H),
7.26 ppm (s, 1H).
2-Benzofuran-2-ylbenzonitrile (12)[27]: 2-Cyanobenzenesulfonyl chlo-
ride (0.263 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) affords
1
12 in 50% (0.109 g) yield. H NMR (400 MHz, CDCl3): d=8.10 (d, J=
8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.71–7.65 (m, 2H),
7.55 (d, J=8.2 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz,
1H), 7.28 ppm (t, J=8.0 Hz, 1H).
4-Benzofuran-2-ylbenzonitrile (3)[22]: 4-Cyanobenzenesulfonyl chlo-
ride (0.263 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) affords 3
in 80% (0.175 g) yield. 1H NMR (400 MHz, CDCl3): d=7.95 (d, J=
7.8 Hz, 2H), 7.72 (d, J=7.8 Hz, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.54 (d,
J=8.0 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H),
7.18 ppm (s, 1H).
2-(2-Fluorophenyl)benzofuran (13)[28]
:
2-Fluorobenzenesulfonyl
chloride (0.252 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) af-
1
fords 13 in 91% (0.193 g) yield. H NMR (400 MHz, CDCl3): d=8.07
(t, J=7.7 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H),
7.68–7.24 (m, 5H), 7.19 ppm (dd, J=8.6, 8.0 Hz, 1H).
2-Naphthalen-1-ylbenzofuran (14)[29]: Naphthalene-1-sulfonyl chlo-
2-(4-Trifluoromethylphenyl)-benzofuran (4)[22]
benzenesulfonyl chloride (0.318 g, 1.3 mmol) and benzofuran
(0.118 g, 1 mmol) affords
in 71% (0.186 g) yield. 1H NMR
: 4-(Trifluoromethyl)-
ride (0.294 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) affords
1
14 in 73% (0.178 g) yield. H NMR (400 MHz, CDCl3): d=8.48 (d, J=
4
7.8 Hz, 1H), 7.95–7.87 (m, 3H), 7.68 (d, J=7.8 Hz, 1H), 7.62–7.53
(m, 4H), 7.35 (t, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.09 ppm (s,
1H).
(400 MHz, CDCl3): d=7.96 (d, J=7.8 Hz, 2H), 7.70 (d, J=7.8 Hz,
2H), 7.62 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.35 (t, J=
7.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.13 ppm (s, 1H).
2-(4-Bromophenyl)benzofuran (16)[30]
:
4-Bromobenzenesulfonyl
2-(4-Chlorophenyl)-benzofuran (5)[23]
:
4-Chlorobenzenesulfonyl
chloride (0.333 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) af-
1
chloride (0.274 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) af-
fords 16 in 88% (0.240 g) yield. H NMR (400 MHz, CDCl3): d=7.73
1
fords 5 in 77% (0.176 g) yield. H NMR (400 MHz, CDCl3): d=7.79
(d, J=7.8 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.56 (d, J=7.8 Hz, 2H),
7.52 (d, J=8.0 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz,
1H), 7.02 ppm (s, 1H).
(d, J=7.8 Hz, 2H), 7.59 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H),
7.42 (d, J=7.8 Hz, 2H), 7.31 (t, J=7.8 Hz, 1H), 7.26 (t, J=7.8 Hz,
1H), 7.00 ppm (s, 1H).
5-(4-Benzofuran-2-ylphenyl)-2-ethyl-4-methylthiazole (17): 2-(4-Bro-
mophenyl)benzofuran 16 (0.273 g, 1 mmol), 2-ethyl-4-methylthia-
zole (0.381 g, 3 mmol), KOAc (0.294 g, 3 mmol), DMA (2 mL) and
PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) were successively added in
a Schlenk tube. The reaction mixture was evacuated by vacuum-
argon cycles (5 times) and stirred at 1308C (oil bath temperature)
for 20 h. After cooling the reaction to RT and concentration, the
crude mixture was purified by silica column chromatography to
2-(4-Fluorophenyl)-benzofuran (6)[24]: 4-Fluorobenzenesulfonyl chlo-
ride (0.252 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) affords 6
1
in 90% (0.191 g) yield. H NMR (400 MHz, CDCl3): d=7.85 (dd, J=
5.8, 5.5 Hz, 2H), 7.59 (d, J=7.5 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.31
(t, J=7.3 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.15 (t, J=7.5 Hz, 2H),
6.95 ppm (s, 1H).
2-p-Tolylbenzofuran (7)[23]
:
4-Methylbenzenesulfonyl chloride
1
afford product 17 in 88% (0.281 g) yield. H NMR (400 MHz, CDCl3):
(0.248 g, 1.3 mmol) and benzofuran (0.118 g, 1 mmol) affords 8 in
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d=7.90 (d, J=8.3 Hz, 2H), 7.60 (d, J=7.6 Hz, 1H), 7.53 (d, J=
7.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.22 (t,
J=7.6 Hz, 1H), 7.07 (s, 1H), 3.05 (q, J=7.6 Hz, 2H), 2.52 (s, 3H),
1.42 ppm (t, J=7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): d=155.3,
154.9, 130.5, 129.6, 129.4 (m), 129.1, 125.1, 124.5, 123.0, 121.0,
111.2, 101.8, 26.9, 16.2, 14.3 ppm. Elemental analysis: calcd (%) for
C20H17NOS (319.42): C 75.20, H 5.36; found: C 75.34, H 5.19.
4-[2-(3-Trifluoromethylphenyl)-benzofuran-3-yl]-benzonitrile (22): 2-
(3-Trifluoromethylphenyl)benzofuran 9 (0.262 g, 1 mmol) and 4-
bromobenzonitrile (0.273 g, 1.5 mmol) affords 22 in 76% (0.276 g)
1
yield. H NMR (400 MHz, CDCl3): d=7.95 (s, 1H), 7.78 (d, J=8.3 Hz,
2H), 7.70 (d, J=7.9 Hz, 1H), 7.65–7.56 (m, 4H), 7.50 (d, J=7.8 Hz,
1H), 7.45 (t, J=7.2 Hz, 1H), 7.43 (t, J=7.2 Hz, 1H), 7.31 ppm (t, J=
7.2 Hz, 1H). 13C NMR (400 MHz, CDCl3): d=154.2, 149.7, 137.4,
132.9, 131.4 (q, J=32.6 Hz), 130.7, 130.3, 130.1, 129.1, 128.9, 125.8,
125.5 (q, J=4.0 Hz), 123.9 (q, J=4.0 Hz), 123.7, 123.6 (q, J=
272.6 Hz), 119.7, 118.6, 117.1, 111.8, 111.6 ppm. Elemental analysis:
calcd (%) for C22H12F3NO (363.33): C 72.73, H 3.33; found: C 72.80,
H 3.18.
5-Bromo-2-phenylbenzofuran (18)[31]
:
Benzenesulfonyl chloride
(0.230 g, 1.3 mmol) and 5-bromobenzofuran (0.197 g, 1 mmol) af-
1
fords 18 in 82% (0.224 g) yield. H NMR (400 MHz, CDCl3): d=7.84
(d, J=7.8 Hz, 2H), 7.70 (s, 1H), 7.46 (t, J=7.8 Hz, 2H), 7.42–7.35 (m,
3H), 6.95 ppm (s, 1H).
3-[2-(4-Trifluoromethylphenyl)benzofuran-3-yl]quinoline (23): 2-(4-
Trifluoromethylphenyl)-benzofuran 4 (0.262 g, 1 mmol) and 3-bro-
moquinoline (0.312 g, 1.5 mmol), affords 23 in 83% (0.323 g) yield.
1H NMR (400 MHz, CDCl3): d=8.99 (s, 1H), 8.38 (s, 1H), 8.24 (d, J=
8.3 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.83 (t, J=8.0 Hz, 1H), 7.76 (d,
J=7.8 Hz, 2H), 7.70–7.50 (m, 5H), 7.44 (t, J=8.0 Hz, 1H), 7.33 ppm
(t, J=8.0 Hz, 1H). 13C NMR (400 MHz, CDCl3): d=154.7, 150.7, 150.4,
137.4, 133.7, 131.0 (q, J=32.0 Hz), 130.9, 129.8, 129.1, 128.5, 128.2,
128.1, 127.4, 126.3, 126.1 (q, J=4.0 Hz), 124.2 (q, J=272.6 Hz),
124.1, 120.1, 115.7, 112.9, 111.9 ppm. Elemental analysis: calcd (%)
for C24H14F3NO (389.37): C 74.03, H 3.62; found: C 74.18, H 3.74.
5-Bromo-2-(4-trifluoromethylphenyl)-benzofuran (19): 4-(Trifluoro-
methyl)benzenesulfonyl chloride (0.318 g, 1.3 mmol) and 5-bromo-
benzofuran (0.197 g, 1 mmol) affords 19 in 68% (0.232 g) yield.
1H NMR (400 MHz, CDCl3): d=7.88 (d, J=7.8 Hz, 2H), 7.71 (s, 1H),
7.70 (d, J=7.8 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz,
1H), 7.03 ppm (s, 1H). 13C NMR (100 MHz, CDCl3): d=155.4, 153.8,
133.1, 130.7, 130.6 (q, J=31.0 Hz), 127.9, 125.8 (q, J=4.6 Hz), 125.1,
123.9 (q, J=272.0 Hz), 123.8, 116.3, 112.7, 102.5 ppm. Elemental
analysis: calcd (%) for C15H8BrF3O (341.12): C 52.81, H 2.36; found:
C 53.00, H 2.17.
5-Bromo-2-(4-bromophenyl)benzofuran (20): 4-Bromobenzenesul-
fonyl chloride (0.333 g, 1.3 mmol) and 5-bromobenzofuran
(0.197 g, 1 mmol) affords 20 in 52% (0.183 g) yield. 1H NMR
(400 MHz, CDCl3): d=7.72–7.66 (m, 3H), 7.58 (d, J=8.5 Hz, 2H),
7.38 (s, 2H), 6.95 ppm (s, 1H). 13C NMR (100 MHz, CDCl3): d=156.1,
153.6, 132.1, 128.8, 127.4, 126.5, 123.6, 123.1, 116.2, 112.6,
101.1 ppm. Elemental analysis: calcd (%) for C14H8Br2O (352.02): C
47.77, H 2.29; found: C 47.58, H 2.34.
4-[3-(4-Fluorophenyl)benzofuran-2-yl]benzonitrile (24): 4-Benzofur-
an-2-ylbenzonitrile 3 (0.219 g, 1 mmol) and 4-bromofluorobenzene
(0.263 g, 1.5 mmol) affords 24 in 79% (0.247 g) yield. 1H NMR
(400 MHz, CDCl3): d=7.75 (d, J=8.5 Hz, 2H), 7.62–7.55 (m, 3H),
7.50–7.35 (m, 4H), 7.28 (t, J=7.0 Hz, 1H), 7.21 ppm (t, J=7.0 Hz,
2H). 13C NMR (100 MHz, CDCl3): d=162.7 (d, J=248.7 Hz), 154.2,
148.2, 134.7, 132.3, 131.3 (d, J=8.1 Hz), 129.9, 127.9 (d, J=3.6 Hz),
126.9, 126.0, 123.5, 120.3, 119.5, 118.6, 116.5 (d, J=21.3 Hz), 111.5,
111.4 ppm. Elemental analysis: calcd (%) for C21H12FNO (313.32): C
80.50, H 3.86; found: C 80.34, H 3.74.
Preparation of the PdCl(C3H5)(dppb) catalyst[20]
An oven-dried 40 mL Schlenk tube equipped with a magnetic stir-
ring bar under argon atmosphere, was charged with [Pd(C3H5)Cl]2
(182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol). Anhydrous di-
chloromethane (10 mL) were added, then the solution was stirred
at RT for 20 min. The solvent was removed in vacuum. The yellow
powder was used without purification. 31P NMR (81 MHz, CDCl3)
d=19.3 (s).
Acknowledgements
We thank the ministꢁre de la recherche for a fellowship to K. Y.
and the Centre National de la Recherche Scientifique and
“Rennes Metropole” for providing financial support. The authors
are grateful to the European ERASMUS Programme for a grant to
L. L. from Charles University in Prague (CZ).
General procedure for the synthesis of C3-arylated benzo-
furans
Keywords: arenes · CÀC coupling · halides · palladium ·
To a 25 mL oven dried Schlenk tube, aryl bromide (1.5 mmol), 2-ar-
ylbenzofuran derivative (1 mmol), KOAc (0.294 g, 3 mmol), DMA
(2 mL) and PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) were successive-
ly added. The reaction mixture was evacuated by vacuum–argon
cycles (5 times) and stirred at 1508C (oil bath temperature) for
20 h. After cooling the reaction at RT and concentration, the crude
mixture was purified by silica column chromatography to afford
the C3-arylated products.
regioselectivity
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4-(2-Phenylbenzofuran-3-yl)benzonitrile (21). 2-Phenylbenzofuran
1a (0.194 g, 1 mmol) and 4-bromobenzonitrile (0.273 g, 1.5 mmol),
affords 21 in 76% (0.224 g) yield. 1H NMR (400 MHz, CDCl3): d=
7.75 (d, J=7.8 Hz, 2H), 7.63 (d, J=7.8 Hz, 2H), 7.60–7.55 (m, 3H),
7.49 (d, J=7.8 Hz, 1H), 7.40–7.33 (m, 4H), 7.29 ppm (d, J=7.8 Hz,
1H). 13C NMR (100 MHz, CDCl3): d=154.1, 151.6, 138.1, 132.7, 130.4,
129.9, 129.0, 128.7, 127.3, 125.2, 123.4, 119.4, 118.8, 115.7, 111.4,
111.2 ppm. Elemental analysis: calcd (%) for C21H13NO (295.33): C
85.40, H 4.44; found: C 85.24, H 4.57.
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Received: December 16, 2013
Published online on && &&, 0000
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L. Loukotova, K. Yuan, H. Doucet*
&& – &&
Regiocontroled Palladium-Catalysed
Direct Arylation at Carbon C2 of
Benzofurans using Benzenesulfonyl
Chlorides as the Coupling Partners
Low cost, high regioselectivity: The
use of benzenesulfonyl chlorides as the
coupling partner in the palladium-cata-
lysed direct arylation of benzofurans
allows for controlling the regioselectivi-
ty in favor of carbon C2. This method
tolerates a variety of substituents on
the benzenesulfonyl derivative.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 8
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