Palladium catalyzed direct 3-arylation of benzofurans using low catalyst loadings

Article abstract of DOI:10.1002/cssc.200900258

The palladium-catalyzed direct 3-arylation of benzofurans provides a cost-effective and environmentally attractive route for the preparation of 3-arylbenzofuran derivatives. The reactions were carried out using a wide variety of electronically and sterica

Full text of DOI:10.1002/cssc.200900258

DOI: 10.1002/cssc.200900258
Palladium Catalyzed Direct 3-Arylation of Benzofurans
using Low Catalyst Loadings
Marina Ionita, Julien Roger, and Henri Doucet*[a]
The palladium-catalyzed direct 3-arylation of benzofurans pro-
vides a cost-effective and environmentally attractive route for
the preparation of 3-arylbenzofuran derivatives. The reactions
were carried out using a wide variety of electronically and ster-
ically diverse aryl or heteroaryl bromides with low catalyst
loadings. In the presence of only 0.1–0.5 mol% catalyst, prod-
ucts in moderate to good yields were obtained. The aryl bro-
mide reactants were able to tolerate a wide range of function-
alities, such as acetyl, propionyl, formyl, ester, nitrile, trifluoro-
methyl, or fluoro groups. Higher yields were obtained using
electron-deficient aryl bromides as reactants compared to
using electron-rich aryl bromides. Functionalized benzofuran
derivatives, bearing formyl or hydroxymethyl on C2, were also
successfully employed.
Introduction
The direct arylation of heteroaromatics, such as benzofurans is
an important field for research in green chemistry due to the
biological properties of some benzofuran derivatives
(Figure 1).[1]
example of 2,3-diarylation of benzofuran in the presence of
5 mol% Pd(OAc)2 and 10 mol% PnBu(Ad)2 as the catalyst has
been described by Chiong and Daugulis.[11] The direct arylation
on C3 of a 2-substituted benzofuran, via an intramolecular cyc-
lization, has also been reported.[12]
The palladium-catalyzed direct 3-arylation of benzofurans
should provide a cost-effective and environmentally attractive
route for the preparation of 3-arylbenzofurans. The major by-
product of the reaction is a base associated to HX, instead of
metallic salts produced under classical cross-coupling proce-
dures,[13–16] such as Suzuki,[14] Negishi,[15] or Stille[16] reactions.
Moreover, the method avoids the preliminary preparation of a
requisite organometallic, which reduces the number of steps
to prepare these compounds.
Therefore, the discovery of more effective conditions, for the
direct coupling of benzofuran derivatives with aryl bromides,
especially using low catalyst loading conditions (less than
1 mol%), would be a considerable advantage for industrial ap-
plications and also for sustainable development. Herein, we
report the use of 2-substituted benzofurans for the palladium-
catalyzed synthesis of 3-arylated benzofuran derivatives, using
a wide variety of electronically and sterically diverse aryl or
heteroaryl bromides at low catalyst loadings.
Figure 1. Examples of bioactive benzofurans.
In 1990, Ohta and co-workers reported that the direct 2- or
5-arylation of several heteroaromatics, including furans, with
aryl halides proceed in moderate to good yields using Results and Discussion
Pd(PPh3)4 as the catalyst.[2a] Since these exciting results, the pal-
In order to determine the reactivity of the 2-substituted benzo-
ladium-catalyzed direct arylation of heteroaryl derivatives with
aryl halides or triflates has proved to be a very powerful
method for the synthesis of a wide variety of arylated hetero-
cycles.[2–9] The direct arylation of furans, thiophenes, or thia-
zoles has been largely described; however, benzofurans have
rarely been employed.[10–12] Recently, Fagnou and co-workers
reported the coupling of benzofuran with 2-bromotoluene
using 2 mol% Pd(OAc)2 and 4 mol% PCy3 as the catalyst. 2-Ary-
lated benzofuran was obtained in a low yield of 29%.[10b] An
furan derivatives for palladium-catalyzed direct arylations, a set
of direct arylation reactions of 2-ethylbenzofuran with 4-bro-
[a] Dr. M. Ionita, J. Roger, Dr. H. Doucet
Institut Sciences Chimiques de Rennes
UMR 6226 CNRS-Universitꢀ de Rennes 1
“Catalyse et Organometalliques”, Campus de Beaulieu
35042 Rennes (France)
Fax: (+33)0223236939
E-mail: henri.doucet@univ-rennes1.fr
ChemSusChem 2010, 3, 367 – 376
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
367

H. Doucet et al.
moacetophenone using several reaction conditions was carried
out (Scheme 1, table 1). Firstly, the influence of several bases
was explored using 0.1 mol% Pd(OAc)2 as the catalyst and
to be ineffective to promote this coupling reaction (Table 1,
entry 13). The influence of a few catalyst precursors was also
studied (Table 1, entries 14–22). The direct arylation of 2-ethyl-
benzofuran proceeded nicely using only 0.1 mol% of Pd(OAc)2/
dppb, Pd(OAc)2/dppe, Pd(OAc)2/PPh3, [Pd(C3H5)Cl]2, PdCl(C3H5)-
(dppb), or PdCl2 as the catalyst precursors to provide 1 in high
yields. However, the use of only 0.01 mol% of these catalysts
gave very low yields of 1. In the presence of the electron-defi-
cient aryl bromide, 4-bromoacetophenone, the presence of a
phosphine ligand in the reaction mixture appeared to be quite
useless (Table 1, entry 8, 15, and 20). These results demonstrat-
ed that the 3-arylation rate of a 2-alkylbenzofuran is faster
than the 3-arylation of 2,5-dialkylfuran derivatives,[5c] which
might be due to the higher acidity at the C3 position of ben-
zofuran.
Scheme 1. Coupling of 2-ethylbenzofuran with 4-bromoacetophenone.
We studied the scope and limitations of this reaction, using
a wide variety of aryl bromides (Scheme 2, Tables 2–4). In all
cases, we initially employed the phosphine-free procedure
(Pd(OAc)2 0.1 mol%, DMAc, KOAc, 1508C). When low conver-
sions of the aryl bromides were observed, then we employed
0.5 mol% of Pd(C3H5)Cl(dppb) as the catalyst. 4-Bromobenzal-
dehyde, 4-bromopropiophenone, 4-bromobenzophenone, 4-
bromobenzonitrile, or 4-trifluoromethylbromobenzene reacted
with 2-ethylbenzofuran in the presence of 0.1 mol% Pd(OAc)2
as the catalyst to give the expected products 2–6 in 72–82%
yields (Table 2, entries 2–6). However, in the presence of 4-bro-
monitrobenzene, a mixture of several unidentified products
was obtained (Table 2, entry 7). 4-Bromofluorobenzene and the
electron-rich aryl bromides, 4-tert-butylbromobenzene or 4-
bromoanisole, were found to give low to moderate yield of 8,
10, and 11 due to partial conversions of these aryl bromides,
when we employed 0.1 or 0.2 mol% Pd(OAc)2 as the catalyst.
This was probably due to a slow oxidative addition of these
aryl bromides to palladium. With these substrates, the oxida-
tive addition to palladium appeared to be the rate-limiting
step of the catalytic cycle. With these three reactants, 0.5–
1 mol% Pd(C3H5)Cl(dppb) had to be employed as the catalyst
in order to obtain high yields of the coupling products
(Table 2, entries 9, 12, and 13).
DMAc as the solvent (Table 1, entries 1–9). Carbonates or K3PO4
were found to be ineffective bases for this reaction (Table 1,
entries 2–5). The use of KF, NaOAc, or CsOAc led to 15–48%
conversion of 4-bromoacetophenone; whereas, in the presence
of KOAc as the base, a complete conversion of the aryl bro-
mide was observed (Table 1, entries 1, 6–9). We then examined
the influence of the solvent. Good conversions were obtained
with DMAc or DMF; however, less side-products resulted in the
presence of DMAc (Table 1, entries 7 and 11). A slower reaction
was observed with NMP (Table 1, entry 12). Xylene was found
Table 1. Influence of the reaction conditions on the palladium-catalyzed
direct coupling of 2-ethylbenzofuran with 4-bromoacetophenone
(Scheme 1).
Entry Solvent Base
Catalyst
Substrate/ Temp Conversion
catalyst
ratio
[8C]
[%][a]
1
2
3
4
5
6
7
8
DMAc KF
Pd(OAc)2
1000
1000
1000
1000
1000
1000
1000
10000
1000
1000
1000
1000
1000
150
150
150
150
150
150
150
150
150
130
150
150
150
150
150
150
150
150
150
150
150
150
150
150
40
0
8
0
0
DMAc Cs2CO3 Pd(OAc)2
DMAc Na2CO3 Pd(OAc)2
DMAc K2CO3 Pd(OAc)2
DMAc K3PO4 Pd(OAc)2
DMAc NaOAc Pd(OAc)2
DMAc KOAc Pd(OAc)2
DMAc KOAc Pd(OAc)2
DMAc CsOAc Pd(OAc)2
DMAc KOAc Pd(OAc)2
48
100 (82)
13
15
85
91
47
0
100
13
100
11
100
18
85
100
28
100
7
The reactivity of the four meta-substituted aryl bromides
were examined (Table 3). As expected, similar results as in the
presence of para-substituted aryl bromides were obtained. 3-
Bromobenzaldehyde, 3-bromoacetophenone, 3-bromobenzoni-
trile, or 3,5-bis(trifluoromethyl)bromobenzene gave 12–15 in
74–78% yields (Table 3, entries 1–6). 2-Bromonaphthalene was
also found to be a suitable coupling partner for this reaction,
but 0.5 mol% Pd(C3H5)Cl(dppb) had to be employed as the cat-
alyst in order to obtain a high yield of 16 (Table 3, entries 7
and 8).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DMF
NMP
KOAc Pd(OAc)2
KOAc Pd(OAc)2
xylene KOAc Pd(OAc)2
DMAc KOAc Pd(OAc)2/dppb 1000
DMAc KOAc Pd(OAc)2/dppb 10000
DMAc KOAc Pd(OAc)2/dppe 1000
DMAc KOAc Pd(OAc)2/dppe 10000
DMAc KOAc Pd(OAc)2/PPh3
DMAc KOAc Pd(OAc)2/PPh3
DMAc KOAc 1= [Pd(C3H5)Cl]2 1000
DMAc KOAc Pd(C3H5)Cl(dppb) 1000
DMAc KOAc Pd(C3H5)Cl(dppb) 10000
DMAc KOAc PdCl2
DMAc KOAc PdCl2
1000
10000
Ortho-substituents on the aryl bromides generally have a
more important influence on the yields of palladium-catalyzed
reactions, due to their steric and/or coordination properties.[18]
Ortho-substituted 2-bromobenzaldehyde, 2-bromobenzonitrile,
2-fluorobromobenzene, or 1-bromonaphthalene reacted with
2-ethylbenzofuran using 0.1 mol% Pd(OAc)2 to give 17, 18, 21,
and 22 in 62–78% yields (Table 3, entries 9, 10, 14, and 15). 2-
Bromobenzotrifluoride of 2,4-difluorobromobenzene gave only
2
1000
10000
[a] Conditions: 2-ethylbenzofuran (2 equiv.), 4-bromoacetophenone
(1 equiv.), base (2 equiv.), 16 h, conversion of 4-bromoacetophenone,
value in parentheses is the isolated yield.
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Direct Arylation of Benzofurans
Table 2. Palladium-catalyzed coupling of 2-ethylbenzofuran with para-
substituted aryl bromides (Scheme 2).
Table 3. Palladium-catalyzed coupling of 2-ethylbenzofuran with meta- or
ortho-substituted aryl bromides (Scheme 2).
Entry
1
Aryl bromide
Product
Yield [%][a]
Entry
Aryl bromide
Product
Yield [%][a]
1
2
3
4
82
1
12
13
75
2
3
4
79
72
74
2
78
3,4,5
14
15
16
51, 50[b], 74[c]
6
78
5
5
6
7
8
9
81
7,8
31, 73[c]
6
82
9
17
71
7
0
8,9
10
11, 12
13
52,[b] 80[c]
10
18
19
20
21
78
61
11, 12
13
58,[b] 80[c]
10 11, 65[d]
69[c]
11
78[c]
14
62
[a] Conditions: Pd(OAc)2 (0.001 equiv.), 2-ethylbenzofuran (2 equiv.), aryl
bromide (1 equiv.), KOAc (2 equiv.), DMAc, 1508C, 16 h, isolated yields.
[b] Pd(OAc)2 (0.002 equiv.) was employed as the catalyst. [c] Pd(C3H5)Cl-
(dppb) (0.005 equiv.) was employed as the catalyst. [d] Pd(C3H5)Cl(dppb)
(0.01 equiv.) was employed as the catalyst.
15
22
78
[a] Conditions: Pd(OAc)2 (0.001 equiv.), 2-ethylbenzofuran (2 equiv.), aryl
bromide (1 equiv), KOAc (2 equiv.), DMAc, 1508C, 16 h, isolated yields.
[b] Pd(OAc)2 (0.002 equiv.) was employed as the catalyst. [c] Pd(C3H5)Cl-
(dppb) (0.005 equiv.) was employed as the catalyst.
moderate yields of 19 and 20 in the presence of Pd(OAc)2. For
these two substrates, Pd(C3H5)Cl(dppb) should be employed as
the catalyst (Table 3, entries 11–13).
Next, we explored the reactivity of 2-ethylbenzofuran with
heteroaryl bromides. The results depicted in Table 4 reveals the
good performance of the ligandless procedure in direct cou-
pling with some bromopyridines or bromoquinolines. Selective
reactions were observed using 3-bromopyridine, 3-bromoqui-
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369

H. Doucet et al.
Table 4. Palladium-catalyzed coupling of 2-ethylbenzofuran with hetero-
aryl bromides (Scheme 2).
Entry
1,2
Heteroaryl bromide
Product
Yield [%][a]
0, 0[b]
23
24
25
Scheme 3. Coupling of 2-n-butylbenzofuran with aryl bromides.
3
84
Table 5. Palladium-catalyzed coupling of 2-n-butylbenzofuran with (het-
ero)aryl bromides (Scheme 3).
43, 66[b]
Entry
1
Aryl bromide
Product
Yield [%][a]
4,5
29
30
78
6
26
67
2
3
72
74
7
8
27
28
61[c]
31
32
70
[a] Conditions: Pd(OAc)2 (0.001 equiv.), 2-ethylbenzofuran (2 equiv.), aryl
bromide (1 equiv.), KOAc (2 equiv.), DMAc, 1508C, 16 h, isolated yields.
[b] Pd(C3H5)Cl(dppb) (0.005 equiv.) was employed as the catalyst.
[c] Pd(OAc)2 (0.002 equiv.) was employed as the catalyst.
4
70
[a] Conditions: Pd(OAc)2 (0.001 equiv.), 2-n-butylbenzofuran (2 equiv.), aryl
bromide (1 equiv.), KOAc (2 equiv.), DMAc, 1508C, 16 h, isolated yields.
bromoacetophenone, 1-bromonaphthalene, or 3-bromoquino-
line gave the expected compounds 29–32 in 70–78% yield
using as little as 0.1 mol% Pd(OAc)2 as the catalyst.
Scheme 2. Coupling of 2-ethylbenzofuran with aryl bromides.
Next, we examined the reactivity of 2-acetylbenzofuran
(Scheme 4). In the presence of this reactant, when we em-
ployed Pd(OAc)2 as the catalyst, DMAc as the solvent and
KOAc as the base at 1508C, an inseparable mixture of several
products, which did not contain 33, was obtained. When we
employed lower reaction temperatures (100 or 1308C), low
conversions of 3-bromopyridine were observed, and the de-
sired product 33 was not detected. The use of PdCl(C3H5)-
(dppb) as the catalyst gave a similar mixture of unidentified
products. These results might be explained by a partial depro-
tonation of the acetyl function of this benzofuran derivative by
KOAc to form an enolate. In order to avoid such deprotona-
tion, the reaction was performed using KF as the base
(Scheme 4, bottom). Under these reaction conditions, the cou-
pling product 33 was obtained in 29% yield.
noline, or 5-bromopyrimidine. With these substrates, the target
products 24, 26, and 28 were obtained in 67–84% yields
(Table 4, entries 3, 6, and 8). The reaction in the presence of 4-
bromoisoquinoline, which is more congested than 3-bromo-
quinoline, was found to be quite slow. However, a high yield
of 61% was obtained in the presence of 0.2 mol% Pd(OAc)2 as
the catalyst (Table 4, entry 7). On the other hand, 2-bromopyri-
dine was found to be unreactive in this reaction (Table 4, en-
tries 1 and 2). We had previously found that 2-bromopyridine
is less reactive than 3- or 4-bromopyridine for the Heck reac-
tion.[19]
As expected, the reactivity of 2-nbutylbenzofuran was found
to be very similar to 2-ethylbenzofuran (Scheme 3; Table 5).
The coupling of this reactant with 4-bromobenzaldehyde, 3-
We also studied the reactivity of 2-formylbenzofuran
(Scheme 5; Table 6). With this reactant, a selective 3-arylation
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Direct Arylation of Benzofurans
Table 6. Palladium-catalyzed coupling of 2-formylbenzofuran with (heter-
o)aryl bromides (Scheme 5).
Entry
1
Aryl bromide
Product
Yield [%][a]
34
35
51
2
60
Scheme 4. Reaction of 2-acetylbenzofuran with 3-bromopyridine.
3
4
36
37
53
32[b]
Scheme 5. Coupling of 2-formylbenzofuran with aryl bromides.
[a] Conditions: Pd(OAc)2 (0.001 equiv.), 2-formylbenzofuran (1.5 equiv.),
aryl bromide (1 equiv.), KOAc (2 equiv.), DMAc, 1508C, 16 h, isolated
yields. [b] Pd(C3H5)Cl(dppb) (0.005 equiv.) was employed as the catalyst.
reaction took place in the presence of 4-bromobenzonitrile
(Table 6, entry 1). In the course of this reaction, some side-
products formed; however, 34 was easily obtained in pure
form in 51% yield by chromatography on silica gel. The reac-
tion of 2-formylbenzofuran with 4-bromobenzophenone, 2-
bromobenzaldehyde, or 3-bromopyridine also gave the desired
3-arylated benzofurans 35–37 in moderate yields (Table 6, en-
tries 2–4).
The use of benzofurans bearing an unprotected hydroxy-
methyl function could be very useful in organic synthesis, be-
cause the hydroxyl protection/deprotection sequence could be
avoided, thus providing a more environmentally and economi-
cally attractive route to such arylated benzofurans. The direct
arylation of 2-hydroxymethylbenzofuran with aryl bromides
gave the desired 3-arylation products 38–40 (Scheme 6;
Table 7). However, only moderate yields were obtained due to
the formation of some side-products.
Scheme 6. Coupling of 2-hydroxymethylbenzofuran with aryl bromides.
Table 7. Palladium-catalyzed coupling of 2-hydroxymethylbenzofuran
with (hetero)aryl bromides (Scheme 6).
Entry
1
Aryl bromide
Product
Yield [%][a]
In conclusion, these results demonstrate that 2-substituted
benzofurans can be employed for palladium-catalyzed direct
arylation. In the presence of electron-deficient aryl bromides, a
low loading of a phosphine-free catalyst generally gave the 3-
arylated benzofurans in moderate to high yields. When low
yields were obtained with this phosphine-free catalyst, the use
of 0.5 mol% Pd(C3H5)Cl(dppb) as the catalyst improved the
yields. It should be noted that a wide range of functional
groups such as acetyl, propionyl, formyl, ester, nitrile, trifluoro-
methyl, or fluoro on the aryl bromide is tolerated. Higher
yields were obtained in the presence of electron-deficient aryl
bromides than with electron-rich aryl bromides. Valuable func-
tionalized benzofuran derivatives bearing formyl or hydroxy-
methyl groups on C2, have also been successfully employed.
38
39
40
68
2
3
54[b]
55[b]
[a] Conditions: Pd(OAc)2 (0.001 equiv.), 2-hydroxymethylbenzofuran
(1.5 equiv.), aryl bromide (1 equiv.), KOAc (2 equiv.), DMAc, 1508C, 16 h,
isolated yields. [b] Pd(C3H5)Cl(dppb) (0.005 equiv.) was employed as the
catalyst.
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371

H. Doucet et al.
4-(2-Ethylbenzofuran-3-yl)-benzophenone 4: The reaction of 4-bro-
mobenzophenone (0.261 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
0.001 mmol) affords 4 (0.241 g, 74% ). 1H NMR (200 MHz, CDCl3):
d=7.96 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.3 Hz, 2H), 7.70–7.48 (m,
7H), 7.40–7.25 (m, 2H), 2.95 (q, J=7.5 Hz, 2H), 1.42 ppm (t, J=
7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=196.2, 157.0, 154.0,
137.6, 137.4, 135.9, 132.4, 130.6, 130.0, 128.7, 128.3, 128.2, 123.8,
122.8, 119.2, 115.4, 110.9, 20.4, 12.9 ppm. Elemental analysis:
calcd (%) for C23H18O2 (326.39): C 84.64, H 5.56; found: C 84.81, H
5.64.
The major byproducts of these coupling reactions were AcOH
associated to KBr instead of metallic salts which result from
more classical coupling procedures. Therefore, this reaction
should give an economically viable and environmentally attrac-
tive route to 3-arylated benzofurans. Moreover, most of the
products prepared by this method are new, indicating a fastidi-
ous access using more traditional coupling reactions, such as
Suzuki, Negishi, or Stille couplings.
4-(2-Ethylbenzofuran-3-yl)-benzotrifluoride 5: The reaction of 4-tri-
fluoromethylbromobenzene (0.225 g, 1 mmol), 2-ethylbenzofuran
(0.292 g, 2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
Experimental Section
2-Ethylbenzofuran and 2-acetylbenzofuran were provided by PCAS.
2-Formylbenzofuran, ethyl 7-methoxybenzofuran-2-carboxylate, 2-
hydroxymethylbenzofuran, and DMAc (99%) were purchased from
Acros. 2-Butylbenzofuran, Pd(OAc)2, and KOAc (99%) were pur-
chased from Alfa Aesar. These compounds were not purified
before use.
1
(0.23 mg, 0.001 mmol) affords 5 (0.235 g, 81%). H NMR (200 MHz,
CDCl3): d=7.77 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.64–7.45
(m, 2H), 7.40–7.25 (m, 2H), 2.91 (q, J=7.5 Hz, 2H), 1.42 ppm (t, J=
7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=156.9, 154.0, 136.7,
129.2, 129.1 (q, J=32.5 Hz), 128.2, 125.6 (m), 123.9, 122.3, 119.1,
115.2, 111.0, 20.3, 12.8 ppm. Elemental analysis: calcd (%) for
C17H13F3O (290.28): C 70.34, H 4.51; found: C 70.50, H 4.52.
Preparation of the PdCl(C3H5)(dppb) catalyst:[17] An oven-dried
40 mL Schlenk tube equipped with a magnetic stirring bar under
an argon atmosphere, was charged with [Pd(C3H5)Cl]2 (182 mg,
0.5 mmol) and dppb (426 mg, 1 mmol). Anhydrous dichlorome-
thane (10 mL) was added, then the solution was stirred at room
temperature 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).
4-(2-Ethylbenzofuran-3-yl)-benzonitrile 6: The reaction of 4-bromo-
benzonitrile (0.182 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
0.001 mmol) affords 6 (0.203 g, 82% ). 1H NMR (200 MHz, CDCl3):
d=7.80 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.60–7.50 (m,
2H), 7.40–7.25 (m, 2H), 2.91 (q, J=7.5 Hz, 2H), 1.44 ppm (t, J=
7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=157.2, 154.0, 138.0,
132.5, 129.4, 127.8, 124.1, 123.0, 122.0, 119.0, 118.9, 111.1, 110.5,
20.4, 12.8 ppm. Elemental analysis: calcd (%) for C17H13NO (247.29):
C 82.57, H 5.30; found: C 82.59, H 5.41.
As a typical experiment, the reaction of 4-bromoacetophenone
(0.199 g, 1 mmol), 2-ethylbenzofuran (0.292 g, 2 mmol), and KOAc
(0.196 g, 2 mmol) at 1508C during 16 h in DMAc (5 mL) in the pres-
ence of Pd(OAc)2 (0.23 mg, 0.001 mmol) under argon affords the
corresponding product 4-(2-ethylbenzofuran-3-yl)-acetophenone 1
after evaporation and filtration on silica gel (pentane/ether) in 82%
(0.217 g) yield. 1H NMR (200 MHz, CDCl3): d=8.10 (d, J=8.3 Hz,
2H), 7.62 (d, J=8.3 Hz, 2H), 7.64–7.48 (m, 2H), 7.40–7.25 (m, 2H),
2.93 (q, J=7.5 Hz, 2H), 2.69 (s, 3H), 1.42 ppm (t, J=7.5 Hz, 3H).
13C NMR (50 MHz, CDCl3): d=197.6, 157.0, 154.0, 138.1, 135.5,
129.0, 128.8, 128.2, 123.9, 122.8, 119.2, 115.4, 111.0, 26.6, 20.4,
12.8 ppm. Elemental analysis: calcd (%) for C18H16O2 (264.32): C
81.79, H 6.10; found: C 81.61, H 6.02.
2-Ethyl-3-(4-fluorophenyl)-benzofuran 8: The reaction of 4-fluoro-
bromobenzene (0.175 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)(dppb) (3 mg,
0.005 mmol) affords 8 (0.192 g, 80%). 1H NMR (200 MHz, CDCl3):
d=7.55–7.45 (m, 2H), 7.44 (dd, J=8.0 and 6.0 Hz, 2H), 7.30–7.20
(m, 2H), 7.19 (t, J=8.0 Hz, 2H), 2.88 (q, J=7.5 Hz, 2H), 1.37 ppm (t,
J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=161.9 (d, J=
246.1 Hz), 156.2, 153.9, 130.6 (d, J=8.0 Hz), 128.7, 128.6, 123.6,
122.6, 119.2, 115.6 ppm(d, J=21.4 Hz), 115.2, 110.8, 20.2, 12.9. Ele-
mental analysis: calcd (%) for C16H13FO (240.27): C 79.98, H 5.45;
found: C 79.82, H 5.57.
4-(2-Ethylbenzofuran-3-yl)-benzaldehyde 2: The reaction of 4-bro-
mobenzaldehyde (0.185 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
0.001 mmol) affords 2 (0.198 g, 79%). 1H NMR (200 MHz, CDCl3):
d=10.10 (s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H),
7.64–7.48 (m, 2H), 7.40–7.25 (m, 2H), 2.94 (q, J=7.5 Hz, 2H),
1.42 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=191.7,
157.2, 154.0, 139.5, 134.9, 130.2, 129.3, 128.0, 124.0, 122.9, 119.2,
115.4, 111.0, 20.4, 12.8 ppm. Elemental analysis: calcd (%) for
C17H14O2 (250.29): C 81.58, H 5.64; found: C 81.67, H 5.92.
[4-(2-Ethylbenzofuran-3-yl)-phenyl]-acetonitrile 9: The reaction of
(4-bromophenyl)-acetonitrile (0.195 g, 1 mmol), 2-ethylbenzofuran
(0.292 g, 2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
1
(0.23 mg, 0.001 mmol) affords 9 (0.160 g, 61%). H NMR (200 MHz,
CDCl3): d=7.60–7.35 (m, 6H), 7.35–7.10 (m, 2H), 3.84 (s, 2H), 2.88
(q, J=7.5 Hz, 2H), 1.37 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz,
CDCl3): d=156.4, 153.9, 132.8, 132.2, 129.6, 128.5, 128.3, 123.7,
122.6, 119.2, 117.8, 115.3, 110.9, 23.4, 20.2, 12.9 ppm. Elemental
analysis: calcd (%) for C18H15NO (261.32): C 82.73, H 5.79; found: C
82.70, H 5.97.
4-(2-Ethylbenzofuran-3-yl)-propiophenone 3: The reaction of 4-bro-
mopropiophenone (0.213 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
0.001 mmol) affords 3 (0.200 g, 72%). 1H NMR (200 MHz, CDCl3):
d=8.13 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.64–7.48 (m,
2H), 7.40–7.25 (m, 2H), 3.09 (q, J=7.5 Hz, 2H), 2.93 (q, J=7.5 Hz,
2H), 1.42 (t, J=7.5 Hz, 3H), 1.30 ppm (t, J=7.5 Hz, 3H). 13C NMR
(50 MHz, CDCl3): d=200.2, 156.9, 154.0, 137.7, 135.3, 128.9, 128.4,
128.2, 123.8, 122.8, 119.2, 115.4, 110.9, 31.7, 20.4, 12.8, 8.3 ppm. Ele-
mental analysis: calcd (%) for C19H18O2 (278.35): C 81.99, H 6.52;
found: C 81.80, H 6.37.
3-(4-tert-Butylphenyl)-2-ethylbenzofuran 10: The reaction of 4-tert-
butylbromobenzene (0.213 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)(dppb) (6 mg,
0.01 mmol) affords 10 (0.180 g, 65%). 1H NMR (200 MHz, CDCl3):
d=7.65–7.30 (m, 6H), 7.30–7.10 (m, 2H), 2.88 (q, J=7.5 Hz, 2H),
1.40 (s, 9H), 1.37 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d=156.1, 154.0, 149.8, 129.8, 128.9, 128.6, 125.6, 123.4, 122.4,
119.6, 115.9, 110.7, 34.6, 31.4, 20.3, 13.0 ppm. Elemental analysis:
372
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2010, 3, 367 – 376

Direct Arylation of Benzofurans
calcd (%) for C20H22O (278.39): C 86.29, H 7.97; found: C 86.40, H
8.07.
(q, J=7.5 Hz, 2H), 1.42 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz,
CDCl3): d=156.5, 154.0, 133.6, 132.4, 132.1, 130.3, 128.3, 127.8,
127.7, 127.6, 127.2, 126.3, 125.9, 123.6, 123.2, 122.6, 119.4, 110.9,
20.3, 13.0 ppm. Elemental analysis: calcd (%) for C20H16O (272.34): C
88.20, H 5.92; found: C 88.40, H 5.91.
2-Ethyl-3-(4-methoxyphenyl)-benzofuran 11: The reaction of 4-bro-
moanisole (0.187 g, 1 mmol), 2-ethylbenzofuran (0.292 g, 2 mmol),
and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)(dppb) (3 mg,
1
0.005 mmol) affords 11 (0.197 g, 78%). H NMR (200 MHz, CDCl3):
2-(2-Ethylbenzofuran-3-yl)-benzaldehyde 17: The reaction of 2-bro-
mobenzaldehyde (0.185 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
d=7.60–7.50 (m, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.40–7.25 (m, 2H),
7.05 (d, J=8.3 Hz, 2H), 2.91 (q, J=7.5 Hz, 2H), 1.40 ppm(t,
J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=158.6, 155.8, 153.9,
130.1, 129.0, 125.0, 123.4, 122.4, 119.4, 115.7, 114.2, 110.7, 20.2,
13.0 ppm. Elemental analysis: calcd (%) for C17H16O2 (252.31): C
80.93, H 6.39; found: C 80.90, H 6.27.
1
0.001 mmol) affords 17 (0.178 g, 71% ). H NMR (200 MHz, CDCl3):
d=9.98 (s, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H),
7.64–7.45 (m, 3H), 7.40–7.25 (m, 3H), 2.75 (q, J=7.5 Hz, 2H),
1.32 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=192.2,
157.8, 153.8, 136.1, 134.9, 134.2, 131.9, 129.9, 128.2, 127.7, 124.2,
123.2, 119.1, 112.4, 111.0, 20.2, 12.5 ppm. Elemental analysis:
calcd (%) for C17H14O2 (250.29): C 81.58, H 5.64; found: C 81.51, H
5.54.
3-(2-Ethylbenzofuran-3-yl)-benzaldehyde 12: The reaction of 3-bro-
mobenzaldehyde (0.185 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
1
0.001 mmol) affords 12 (0.188 g, 75%). H NMR (200 MHz, CDCl3):
d=10.12 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.77 (d, J=
8.3 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.64–7.45 (m, 2H), 7.40–7.25 (m,
2H), 2.92 (q, J=7.5 Hz, 2H), 1.42 ppm (t, J=7.5 Hz, 3H). 13C NMR
(50 MHz, CDCl3): d=192.2, 156.8, 154.0, 136.9, 134.9, 134.0, 130.0,
129.5, 128.4, 128.3, 123.9, 122.8, 119.1, 115.1, 111.0, 20.3, 12.8 ppm.
Elemental analysis: calcd (%) for C17H14O2 (250.29): C 81.58, H 5.64;
found: C 81.60, H 5.82.
2-(2-Ethylbenzofuran-3-yl)-benzonitrile 18: The reaction of 2-bro-
mobenzonitrile (0.182 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
1
0.001 mmol) affords 18 (0.193 g, 78%). H NMR (200 MHz, CDCl3):
d=7.85 (d, J=8.3 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.62–7.45 (m,
3H), 7.42–7.25 (m, 3H), 2.85 (q, J=7.5 Hz, 2H), 1.38 ppm (t, J=
7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=157.6, 153.9, 136.6,
133.5, 132.7, 131.2, 128.4, 127.8, 123.9, 122.8, 119.0, 118.2, 113.2,
113.1, 111.0, 20.8, 11.9 ppm. Elemental analysis: calcd (%) for
C17H13NO (247.29): C 82.57, H 5.30; found: C 82.54, H 5.50.
1-[3-(2-Ethylbenzofuran-3-yl)-phenyl]-ethanone 13: The reaction of
3-bromoacetophenone (0.199 g, 1 mmol), 2-ethylbenzofuran
(0.292 g, 2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(0.23 mg, 0.001 mmol) affords 13 (0.206 g, 78%). 1H NMR
(200 MHz, CDCl3): d=8.16 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.73–
7.40 (m, 4H), 7.38–7.25 (m, 2H), 2.95 (q, J=7.5 Hz, 2H), 2.70 (s,
3H), 1.40 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=
197.9, 156.6, 153.9, 137.6, 133.5, 133.4, 129.0, 128.7, 128.4, 126.9,
123.8, 122.7, 119.1, 115.4, 110.9, 26.7, 20.3, 12.9 ppm. Elemental
analysis: calcd (%) for C18H16O2 (264.32): C 81.79, H 6.10; found: C
81.80, H 6.19.
2-(2-Ethylbenzofuran-3-yl)-benzotrifluoride 19: The reaction of 2-tri-
fluoromethylbromobenzene (0.225 g, 1 mmol), 2-ethylbenzofuran
(0.292 g, 2 mmol), and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)-
(dppb) (3 mg, 0.005 mmol) affords 19 (0.232 g, 80%). 1H NMR
(200 MHz, CDCl3): d=7.82 (d, J=8.3 Hz, 1H), 7.70–7.10 (m, 7H),
2.63 (q, J=7.5 Hz, 2H), 1.25 ppm (t, J=7.5 Hz, 3H). 13C NMR
(50 MHz, CDCl3): d=156.8, 153.5, 133.3, 131.6, 130.7 (q, J=
32.6 Hz), 130.4, 128.0, 126.2, 123.4, 123.3 (q, J=273.6 Hz), 122.5,
119.5, 113.7, 110.6, 20.3, 12.2 ppm. Elemental analysis: calcd (%) for
C17H13F3O (290.28): C 70.34, H 4.51; found: C 70.31, H 4.43.
3-(2-Ethylbenzofuran-3-yl)-benzonitrile 14: The reaction of 3-bro-
mobenzonitrile (0.182 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)(dppb) (3 mg,
3-(2,4-Difluorophenyl)-2-ethyl-benzofuran 20: The reaction of 2,4-
difluorobromobenzene (0.193 g, 1 mmol), 2-ethylbenzofuran
(0.292 g, 2 mmol), and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)-
(dppb) (3 mg, 0.005 mmol) affords 20 (0.178 g, 69%). 1H NMR
(200 MHz, CDCl3): d=7.55–7.20 (m, 5H), 7.10–6.90 (m, 2H), 2.81 (q,
J=7.5 Hz, 2H), 1.35 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz,
CDCl3): d=162.9 (dd, J=167.4, 11.7 Hz), 159.5 (dd, J=168.8,
11.9 Hz), 157.4, 154.0, 132.3 (m), 128.7, 123.6, 122.6, 119.3, 111.5 (d,
J=3.7 Hz), 110.9, 109.3, 104.4 (m), 20.3, 12.9 ppm. Elemental analy-
sis: calcd (%) for C16H12F2O (258.26): C 74.41, H 4.68; found: C
74.60, H 4.55.
1
0.005 mmol) affords 14 (0.183 g, 74%). H NMR (200 MHz, CDCl3):
d=7.85–7.45 (m, 6H), 7.40–7.25 (m, 2H), 2.91 (q, J=7.5 Hz, 2H),
1.44 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=156.9,
154.0, 136.1, 134.4, 133.3, 132.3, 130.5, 129.6, 127.9, 124.1, 123.0,
118.8, 118.7, 113.0, 111.1, 20.2, 12.8 ppm. Elemental analysis:
calcd (%) for C17H13NO (247.29): C 82.57, H 5.30; found: C 82.41, H
5.24.
3-[3,5-bis(trifluoromethyl)phenyl]-2-ethylbenzofuran 15: The reac-
tion of 3,5-bis(trifluoromethyl)bromobenzene (0.293 g, 1 mmol), 2-
ethylbenzofuran (0.292 g, 2 mmol), and KOAc (0.196 g, 2 mmol)
with Pd(OAc)2 (0.23 mg, 0.001 mmol) affords 15 (0.279 g, 78%).
1H NMR (200 MHz, CDCl3): d=7.95 (s, 2H), 7.91 (s, 1H), 7.60–7.45
(m, 2H), 7.40–7.25 (m, 2H), 2.91 (q, J=7.5 Hz, 2H), 1.44 ppm (t, J=
7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=157.4, 154.0, 135.3, 132.4
(q, J=33.3 hz), 128.9 (m), 127.6, 124.3, 123.2, 123.1 (q, J=
272.3 Hz), 120.6 ppm(m), 118.6, 114.0, 111.2, 20.3, 12.7. Elemental
analysis: calcd (%) for C18H12F6O (358.28): C 60.34, H 3.38; found: C
60.43, H 3.20.
2-Ethyl-3-(2-fluorophenyl)-benzofuran 21: The reaction of 2-fluoro-
bromobenzene (0.175 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
1
0.001 mmol) affords 21 (0.149 g, 62%). H NMR (200 MHz, CDCl3):
d=7.55–7.20 (m, 8H), 2.82 (q, J=7.5 Hz, 2H), 1.35 ppm (t, J=
7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=160.0 (d, J=247.3 Hz),
157.4, 154.1, 131.6 (d, J=3.5 Hz), 129.1 (d, J=8.0 Hz), 128.8, 124.2,
123.5, 122.6, 120.2 (d, J=14.1 Hz), 119.6, 116.1 ppm(d, J=22.3 Hz),
110.8, 110.1, 20.6, 12.4. Elemental analysis: calcd (%) for C16H13FO
(240.27): C 79.98, H 5.45; found: C 79.87, H 5.37.
2-Ethyl-3-naphthalen-2-ylbenzofuran 16: The reaction of 2-bromo-
naphthalene (0.207 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)(dppb) (3 mg,
2-Ethyl-3-(1-naphtyl)-benzofuran 22: The reaction of 1-bromonaph-
thalene (0.207 g, 1 mmol), 2-ethylbenzofuran (0.292 g, 2 mmol),
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg, 0.001 mmol)
1
0.005 mmol) affords 16 (0.199 g, 73%). H NMR (200 MHz, CDCl3):
d=8.05–7.85 (m, 4H), 7.70–7.45 (m, 5H), 7.40–7.25 (m, 2H), 2.98
ChemSusChem 2010, 3, 367 – 376
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373

H. Doucet et al.
1
affords 22 (0.212 g, 78%). 1H NMR (200 MHz, CDCl3): d=7.97 (d,
J=8.2 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H),
7.62–7.05 (m, 8H), 2.74 (q, J=7.5 Hz, 2H), 1.30 ppm (t, J=7.5 Hz,
3H). 13C NMR (50 MHz, CDCl3): d=156.9, 154.3, 135.3, 134.2, 132.9,
130.6, 128.7, 128.6, 128.5, 126.5, 126.4, 126.3, 126.0, 123.9, 122.9,
120.5, 115.0, 111.2, 20.9, 13.2 ppm. Elemental analysis: calcd (%) for
C20H16O (272.34): C 88.20, H 5.92; found: C 88.14, H 5.99.
0.001 mmol) affords 29 (0.217 g, 78%). H NMR (200 MHz, CDCl3):
d=10.10 (s, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H),
7.64–7.48 (m, 2H), 7.40–7.25 (m, 2H), 2.91 (t, J=7.5 Hz, 2H), 1.80
(quint., J=7.5 Hz, 2H), 1.44 (sext., J=7.5 Hz, 2H), 0.94 ppm (t, J=
7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=191.7, 156.3, 154.0,
139.5, 134.8, 130.1, 129.3, 128.0, 123.9, 122.8, 119.1, 115.9, 111.0,
30.3, 26.6, 22.4, 13.7 ppm. Elemental analysis: calcd (%) for C19H18O2
(278.35): C 81.99, H 6.52; found: C 81.87, H 6.70.
3-(2-Ethylbenzofuran-3-yl)-pyridine 24: The reaction of 3-bromopyr-
idine (0.158 g, 1 mmol), 2-ethylbenzofuran (0.292 g, 2 mmol), and
KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg, 0.001 mmol) af-
1-[3-(2-Butyl-benzofuran-3-yl)-phenyl]-ethanone 30: The reaction of
3-bromoacetophenone (0.199 g, 1 mmol), 2-n-butylbenzofuran
(0.348 g, 2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(0.23 mg, 0.001 mmol) affords 30 (0.210 g, 72%). 1H NMR
(200 MHz, CDCl3): d=8.16 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.73–
7.40 (m, 4H), 7.38–7.25 (m, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.69 (s, 3H),
1.80 (quint., J=7.5 Hz, 2H), 1.45 (sext., J=7.5 Hz, 2H), 0.92 ppm (t,
J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3): d=197.8, 155.7, 153.9,
137.6, 133.6, 133.5, 129.0, 128.8, 128.4, 126.9, 123.7, 122.7, 119.1,
116.0, 110.9, 30.4, 26.7, 26.5, 22.4, 13.7 ppm. Elemental analysis:
calcd (%) for C20H20O2 (292.37): C 82.16, H 6.89; found: C 82.24, H
6.74.
1
fords 24 (0.187 g, 84%). H NMR (200 MHz, CDCl3): d=8.78 (s, 1H),
8.65 (d, J=4.0 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H), 7.62–7.40 (m, 3H),
7.36–7.25 (m, 2H), 2.90 (q, J=7.5 Hz, 2H), 1.41 ppm (t, J=7.5 Hz,
3H). 13C NMR (50 MHz, CDCl3): d=157.0, 154.1, 149.8, 148.2, 136.2,
128.3, 123.9, 123.6, 122.8, 118.9, 112.9, 111.0, 20.2, 12.9 ppm. Ele-
mental analysis: calcd (%) for C15H13NO (223.27): C 80.69, H 5.87;
found: C 80.68, H 5.69.
4-(2-Ethylbenzofuran-3-yl)-pyridine 25: The reaction of 4-bromopyr-
idine hydrochloride (0.195 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with PdCl(C3H5)(dppb) (3 mg,
1
2-Butyl-3-(1-naphtyl)-benzofuran 31: The reaction of 1-bromonaph-
thalene (0.207 g, 1 mmol), 2-n-butylbenzofuran (0.348 g, 2 mmol),
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg, 0.001 mmol)
affords 31 (0.222 g, 74%). 1H NMR (200 MHz, CDCl3): d=7.97 (d,
J=8.2 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H),
7.62–7.05 (m, 8H), 2.76 (t, J=7.5 Hz, 2H), 1.75 (quint., J=7.5 Hz,
2H), 1.45 (sext., J=7.5 Hz, 2H), 0.92 ppm (t, J=7.5 Hz, 3H).
13C NMR (50 MHz, CDCl3): d=156.4, 153.9, 144.2, 133.8, 132.5,
130.2, 128.3, 128.2, 128.1, 126.1, 125.9, 125.8, 125.5, 123.4, 122.4,
120.0, 115.2, 110.7, 30.2, 26.6, 22.3, 13.7 ppm. Elemental analysis:
calcd (%) for C22H20O (300.39): C 87.96, H 6.71; found: C 87.10, H
6.81.
0.005 mmol) affords 25 (0.147 g, 66%). H NMR (200 MHz, CDCl3):
d=8.72 (m, 2H), 7.66–7.40 (m, 4H), 7.36–7.25 (m, 2H), 2.93 (q, J=
7.5 Hz, 2H), 1.41 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d=157.7, 154.1, 149.9, 141.4, 127.5, 124.2, 123.6, 123.1, 119.1,
113.9, 111.2, 20.4, 12.8 ppm. Elemental analysis: calcd (%) for
C15H13NO (223.27): C 80.69, H 5.87; found: C 80.54, H 5.98.
3-(2-Ethylbenzofuran-3-yl)-quinoline 26: The reaction of 3-bromo-
quinoline (0.208 g, 1 mmol), 2-ethylbenzofuran (0.292 g, 2 mmol),
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg, 0.001 mmol)
affords 26 (0.183 g, 67%). 1H NMR (200 MHz, CDCl3): d=9.10 (d,
J=1.8 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.91
(d, J=8.0 Hz, 1H), 7.79 (t, J=7.7 Hz, 1H), 7.70–7.50 (m, 3H), 7.40–
7.25 (m, 2H), 2.97 (q, J=7.5 Hz, 2H), 1.44 ppm (t, J=7.5 Hz, 3H).
13C NMR (50 MHz, CDCl3): d=157.4, 154.1, 150.9, 146.8, 135.3,
129.6, 129.1, 128.4, 128.1, 127.7, 127.1, 126.2, 124.1, 122.9, 119.0,
113.5, 111.1, 20.4, 13.0 ppm. Elemental analysis: calcd (%) for
C19H15NO (273.33): C 83.49, H 5.53; found: C 83.38, H 5.41.
3-(2-Butylbenzofuran-3-yl)-quinoline 32: The reaction of 3-bromo-
quinoline (0.208 g, 1 mmol), 2-n-butylbenzofuran (0.348 g, 2 mmol),
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg, 0.001 mmol)
affords 32 (0.211 g, 70%). 1H NMR (200 MHz, CDCl3): d=9.10 (d,
J=1.8 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 7.91
(d, J=8.0 Hz, 1H), 7.79 (t, J=7.7 Hz, 1H), 7.70–7.50 (m, 3H), 7.40–
7.25 (m, 2H), 2.94 (t, J=7.5 Hz, 2H), 1.84 (quint., J=7.5 Hz, 2H),
1.45 (sext., J=7.5 Hz, 2H), 0.94 ppm (t, J=7.5 Hz, 3H). 13C NMR
(50 MHz, CDCl3): d=156.4, 154.1, 151.1, 147.0, 135.1, 129.4, 129.3,
128.4, 128.0, 127.7, 127.0, 126.2, 123.9, 122.9, 118.9, 113.5, 111.1,
30.4, 26.6, 22.4, 13.7 ppm. Elemental analysis: calcd (%) for
C21H19NO (301.28): C 83.69, H 6.35; found: C 83.50, H 6.40.
4-(2-Ethylbenzofuran-3-yl)-isoquinoline 27: The reaction of 4-bro-
moisoquinoline (0.208 g, 1 mmol), 2-ethylbenzofuran (0.292 g,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.45 mg,
1
0.002 mmol) affords 27 (0.167 g, 61%). H NMR (200 MHz, CDCl3):
d=9.35 (s, 1H), 8.56 (s, 1H), 8.12 (m, 1H), 7.70–7.42 (m, 3H), 7.57
(d, J=8.0 Hz, 1H), 7.40–7.25 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 2.77
(q, J=7.5 Hz, 2H), 1.32 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz,
CDCl3): d=158.1, 154.1, 152.3, 143.9, 135.2, 130.6, 129.8, 128.0,
127.4, 125.1, 123.8, 122.7, 119.7, 111.2, 111.0, 20.4, 12.9 ppm. Ele-
mental analysis: calcd (%) for C19H15NO (273.33): C 83.49, H 5.53;
found: C 83.56, H 5.60.
1-(3-Pyridin-3-ylbenzofuran-2-yl)-ethanone 33: The reaction of 3-
bromopyridine (0.158 g, 1 mmol), 2-acetylbenzofuran (0.320 g,
2 mmol), and KF (0.116 g, 2 mmol) with PdCl(C3H5)(dppb) (3 mg,
1
0.005 mmol) affords 33 (0.069 g, 29%). H NMR (200 MHz, CDCl3):
d=8.65–8.48 (m, 2H), 7.75–7.20 (m, 6H), 4.27 ppm (s, 3H). 13C NMR
(50 MHz, CDCl3): d=187.3, 155.6, 151.8, 150.5, 148.4, 137.0, 129.3,
128.5, 126.8, 124.0, 123.4, 123.3, 113.6, 112.3, 42.5 ppm. Elemental
analysis: calcd (%) for C15H11NO2 (237.25): C 75.94, H 4.67; found: C
75.90, H 4.49.
5-(2-Ethylbenzofuran-3-yl)-pyrimidine 28: The reaction of 5-bromo-
pyrimidine (0.159 g, 1 mmol), 2-ethylbenzofuran (0.292 g, 2 mmol),
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg, 0.001 mmol)
affords 28 (0.157 g, 70%). 1H NMR (200 MHz, CDCl3): d=9.26 (s,
1H), 8.92 (s, 2H), 7.60–7.50 (m, 2H), 7.40–7.25 (m, 2H), 2.93 (q, J=
7.5 Hz, 2H), 1.41 ppm (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d=157.8, 157.2, 156.4, 154.2, 127.5, 124.4, 123.2, 118.6, 115.7, 111.3,
109.6, 20.3, 12.9 ppm. Elemental analysis: calcd (%) for C14H12N2O
(224.26): C 74.98, H 5.39; found: C 74.92, H 5.47.
4-(2-Formylbenzofuran-3-yl)-benzonitrile 34: The reaction of 4-bro-
mobenzonitrile (0.182 g, 1 mmol), 2-formylbenzofuran (0.219 g,
1.5 mmol), and KOAc (0.192 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
1
0.001 mmol) affords 34 (0.126 g, 51%). H NMR (200 MHz, CDCl3):
d=9.93 (s, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.81 (d, J=8.3 Hz, 2H),
7.75–7.60 (m, 3H), 7.47 ppm (t, J=7.8 Hz, 1H). 13C NMR (50 MHz,
CDCl3): d=179.4, 155.4, 147.6, 134.1, 132.8, 130.9, 130.6, 130.0,
126.4, 124.8, 122.1, 118.2, 113.2, 113.1 ppm. Elemental analysis:
4-(2-Butylbenzofuran-3-yl)-benzaldehyde 29: The reaction of 4-bro-
mobenzaldehyde (0.185 g, 1 mmol), 2-n-butylbenzofuran (0.348,
2 mmol), and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.23 mg,
374
www.chemsuschem.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2010, 3, 367 – 376

Direct Arylation of Benzofurans
calcd (%) for C16H9NO2 (247.25): C 77.72, H 3.67; found: C 77.31, H
3.60.
mental analysis: calcd (%) for C14H11NO2 (225.24): C 74.65, H 4.92;
found: C 74.70, H 4.87.
3-(4-Benzoyl-phenyl)-benzofuran-2-carbaldehyde 35: The reaction
of 4-bromobenzophenone (0.261 g, 1 mmol), 2-formylbenzofuran
(0.219 g, 1.5 mmol), and KOAc (0.192 g, 2 mmol) with Pd(OAc)2
(0.23 mg, 0.001 mmol) affords 35 (0.196 g, 60%). 1H NMR
(200 MHz, CDCl3): d=9.97 (s, 1H), 8.04 (d, J=8.3 Hz, 2H), 7.91 (d,
J=8.3 Hz, 2H), 7.85–7.35 ppm (m, 9H). 13C NMR (50 MHz, CDCl3):
d=195.8, 179.5, 155.4, 147.7, 138.2, 137.1, 133.2, 132.8, 130.7,
130.1, 130.0; 129.9, 129.8, 128.4, 126.7, 124.5, 122.4, 112.9 ppm. Ele-
mental analysis: calcd (%) for C22H14O3 (326.34): C 80.97, H 4.32;
found: C 80.84, H 4.20.
Acknowledgements
M. I. is grateful to CNRS for a grant. J. R. is grateful to “Ministꢁre
de la Recherche” for his grant. We thank CNRS and “Rennes Met-
ropole” for providing financial support, and PCAS for providing
some benzofuran derivatives.
Keywords: benzofurans · catalysis · CÀH activation · halides ·
palladium
3-(2-Formylphenyl)-benzofuran-2-carbaldehyde 36: The reaction of
2-bromobenzaldehyde (0.185 g, 1 mmol), 2-formylbenzofuran
(0.219 g, 1.5 mmol), and KOAc (0.192 g, 2 mmol) with Pd(OAc)2
(0.23 mg, 0.001 mmol) affords 36 (0.132 g, 53% ). 1H NMR
(200 MHz, CDCl3): d=10.00 (s, 1H), 9.79 (s, 1H), 8.19 (d, J=8.3 Hz,
1H), 7.85–7.25 ppm (m, 7H). 13C NMR (50 MHz, CDCl3): d=190.4,
179.3, 154.9, 148.4, 134.9, 134.1, 131.5, 132.1, 129.9, 129.8, 129.2,
129.1, 128.4, 124.8, 122.1, 112.9 ppm. Elemental analysis: calcd (%)
for C16H10O3 (250.25): C 76.79, H 4.03; found: C 76.89, H 3.90.
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3-Pyridin-3-ylbenzofuran-2-carbaldehyde 37: The reaction of 3-bro-
mopyridine (0.158 g, 1 mmol), 2-formylbenzofuran (0.219 g,
1.5 mmol), and KOAc (0.192 g, 2 mmol) with PdCl(C3H5)(dppb)
(3 mg, 0.005 mmol) affords 37 (0.072 g, 32%). 1H NMR (200 MHz,
CDCl3): d=9.92 (s, 1H), 8.93 (s, 1H), 8.81 (d, J=6.0 Hz, 1H), 8.01 (d,
J=7.2 Hz, 1H), 7.82–7.35 ppm (m, 5H). 13C NMR (50 MHz, CDCl3):
d=179.3, 155.4, 147.7, 150.4, 150.1, 137.7, 130.0, 126.7, 125.6,
124.7, 123.8, 122.1, 113.0 ppm. Elemental analysis: calcd (%) for
C14H9NO2 (223.23): C 75.33, H 4.06; found: C 75.47, H 4.00.
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4-(2-Hydroxymethylbenzofuran-3-yl)-benzonitrile 38: The reaction
of 4-bromobenzonitrile (0.182 g, 1 mmol), 2-hydroxymethylbenzo-
furan (0.222 g, 1.5 mmol), and KOAc (0.192 g, 2 mmol) with
1
Pd(OAc)2 (0.23 mg, 0.001 mmol) affords 38 (0.170 g, 68%). H NMR
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(200 MHz, CDCl3): d=7.84 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.3 Hz,
2H), 7.73–7.60 (m, 2H), 7.48–7.25 (m, 2H), 4.83 (s, 2H), 3.40 ppm (s,
1H). 13C NMR (50 MHz, CDCl3): d=154.3, 152.6, 136.7, 132.6, 130.1,
129.6, 125.5, 123.5, 122.0, 119.9, 118.2, 111.7, 111.0, 56.3 ppm. Ele-
mental analysis: calcd (%) for C16H11NO2 (249.26): C 77.10, H 4.45;
found: C 77.20, H 4.52.
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3-(2-Hydroxymethylbenzofuran-3-yl)-benzaldehyde 39: The reac-
tion of 3-bromobenzaldehyde (0.185 g, 1 mmol), 2-hydroxymethyl-
benzofuran (0.222 g, 1.5 mmol), and KOAc (0.192 g, 2 mmol) with
PdCl(C3H5)(dppb) (3 mg, 0.005 mmol) affords 39 (0.136 g, 54%).
1H NMR (200 MHz, CDCl3): d=10.12 (s, 1H), 8.10 (s, 1H), 7.95 (d,
J=8.3 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.75–7.53 (m, 3H), 7.48–7.23
(m, 2H), 4.84 (s, 2H), 3.40 ppm (s, 1H). 13C NMR (50 MHz, CDCl3):
d=192.1, 154.3, 152.2, 136.9, 135.0, 133.2, 132.9, 130.1, 129.6,
128.9, 127.5, 125.3, 123.3, 120.1, 111.6, 56.3 ppm. Elemental analy-
sis: calcd (%) for C16H12O3 (252.26): C 76.18, H 4.79; found: C 76.28,
H 4.97.
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mopyridine
(0.158 g,
1 mmol),
2-hydroxymethylbenzofuran
(0.222 g, 1.5 mmol), and KOAc (0.192 g, 2 mmol) with PdCl(C3H5)-
(dppb) (3 mg, 0.005 mmol) affords 40 (0.124 g, 55%) yield. H NMR
(200 MHz, CDCl3): d=8.78 (s, 1H), 8.58 (d, J=4.0 Hz, 1H), 7.90 (d,
J=6.5 Hz, 1H), 7.60–7.25 (m, 5H), 4.83 (s, 2H), 3.96 ppm (s, 1H).
13C NMR (50 MHz, CDCl3): d=154.3, 153.2, 149.3, 148.2, 136.7,
128.3, 127.4, 125.1, 123.8, 123.2, 119.7, 115.8, 111.5, 55.7 ppm. Ele-
1
ChemSusChem 2010, 3, 367 – 376
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
375

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Received: November 6, 2009
Published online on December 28, 2009
376
www.chemsuschem.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2010, 3, 367 – 376