Palladium-catalyzed direct arylation of polysubstituted benzofurans

Article abstract of DOI:10.1021/jo202060k

An efficient access to 2-substituted 3-arylbenzofurans through a palladium-catalyzed C3 direct arylation of 2-substituted benzofurans with aryl bromides is described. The scope and limitation of this reaction was studied. The method tolerates a variety of functional groups on the aryl halide and has been successfully extended to polysubstituted benzofurans to obtain the corresponding 3-arylbenzofurans with good to excellent yields.

Full text of DOI:10.1021/jo202060k

Article
pubs.acs.org/joc
Palladium-Catalyzed Direct Arylation of Polysubstituted Benzofurans
Amandine Carrer,†,‡ Dimitri Brinet,†,‡ Jean-Claude Florent,†,‡ Patricia Rousselle,§
̈
and Emmanuel Bertounesque*,†,‡
†CNRS UMR 176, 26 rue d’Ulm, 75248 Paris, France
‡Institut Curie, Centre de Recherche, 26 rue d’Ulm, 75248 Paris, France
§Institut de Biologie et de Chimie des Protei
́
nes, CNRS UMR 5086, 7, passage du Vercors, 69367 Lyon, France
S
* Supporting Information
ABSTRACT: An efficient access to 2-substituted 3-arylben-
zofurans through a palladium-catalyzed C3 direct arylation of
2-substituted benzofurans with aryl bromides is described. The
scope and limitation of this reaction was studied. The method
tolerates a variety of functional groups on the aryl halide and
has been successfully extended to polysubstituted benzofurans
to obtain the corresponding 3-arylbenzofurans with good to
excellent yields.
Scheme 1. Strategy for the Synthesis of 3-Aryl-2-
aroylbenzofurans
INTRODUCTION
■
Benzo[b]furan derivatives are an important class of heterocyclic
compounds that exhibit biological activity on a wide range of
targets.1 Recently, benzofurans have been identified as selective
adenosine A2A receptor antagonists2 for a novel nondopaminer-
gic approach to PD therapy, nonacidic benzofuran EP1 receptor
antagonists for the treatment of inflammatory pain,3 kinase CK2
inhibitors as antitumor agents,4 antagonists of the CXCR2
receptor as potential use for the treatment of inflammatory and
related diseases,5 uric acid transporter 1 (hURAT1) inhibitors
with uricosuric activity,6 and agonists of the retinoic acid
receptor (RAR) subtypes for cancer therapy and prevention.7
They are found as a key structural unit in many natural products,
and pharmaceuticals, such as, for example, amiodarone,
befunolol, or bergapten. As part of an ongoing medicinal
chemistry project,8 our interest was focused on the synthesis
of 3-aryl-2-aroylbenzofurans. Two possible approaches to the
construction of this class of compounds have already been
described, by acylation of 3-arylbenzofurans9a,b or by con-
densation of 2-hydroxybenzophenone derivatives with α-bromo-
arylketones.9c−e However, these approaches required either
drastic conditions or multistep synthesis of precursors and gave
access to a limited variety of compounds. For these reasons,
the developement of a more efficient method to obtain a wider
range of polysubstituted benzofurans was needed. 2-Aroylben-
zofurans are easily synthesized by Rap−Stoermer condensation
from salicylaldehydes and α-bromoketones.10 Recently, this
reaction has been extensively studied, and novel applications
under microwaves11 or solvent-free12 conditions gave excellent
yields with a good tolerance toward functional groups. As an
alternative, our investigations were focused on the direct aryla-
tion of 2-benzoylbenzofurans at the 3-position as a method for
generating 3-aryl-2-benzoylbenzofurans (Scheme 1).
to prepare biaryl molecules. It has also been successfully applied
to many heteroaromatic compounds.15 With this new synthetic
pathway, there is no more need to preactivate the coupling
partner as its halide or organometallic derivative (boron for
Suzuki coupling or tin for Stille coupling). Therefore, direct
arylation is more atom-economical and environmentally
friendly. Up to now, very few examples of C3-arylation of
benzofurans have been reported in the literature and only two
of them deal with intermolecular arylation.16,17 Indeed, in
2010, Fagnou et al. described the Pd(OAc)2-catalyzed direct
arylation of chlorine-containing heteroaromatics, among which
only two examples were reported from 2-chlorobenzofuran.
The same year, the palladium-catalyzed direct C3-arylation of
2-substituted benzofuran derivatives was published by Doucet
et al., a study using Pd(C3H5)Cl(dppb) or Pd(OAc)2 in which
few examples with benzofurans bearing electron-withdrawing
groups (i.e., acetyl, formyl) at the 2-position are given. On the
other hand, it should be noted that arylation of the C−H bonds
of benzofuran is regioselective on position 2,18 and in some
cases, a C2/C3-diarylation was observed.19 In the quest to
expand the knowledge on the reactivity of 2-substituted
benzofurans with aryl bromides using Pd(OAc)2, we have
studied herein the scope and limitation of the direct arylation
with various electron-withdrawing groups (benzoyl, nitro,
Over the past decade, direct arylation has become a powerful
Received: October 4, 2011
Published: December 5, 2011
alternative to traditional cross-coupling reactions13,14 in order
© 2011 American Chemical Society
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Table 1. Optimization of Direct Arylation of 2-Benzoylbenzofuran
c
d
entry
phosphine
additive
solvent
conversion (%)
a
1
P(t-Bu)2Me (10)
PCy3 (10)
PivOH (30)
PivOH (30)
PivOH (60)
PivOH (120)
PivOH (60)
PivOH (30)
PivOH (60)
PivOH (30)
PivOH (30)
PivOH (30)
DMA
DMA
DMA
DMA
Mes
55
11
75
80
95
>95
95
30
85
a
2
a
3
P(t-Bu)2Me (10)
P(t-Bu)2Me (10)
P(t-Bu)2Me (10)
P(t-Bu)2Me (10)
PCy3 (10)
a
4
a
5
b
6
Mes
a
7
Mes
b
8
PPh3 (10)
Mes
b
9
P(t-Bu)2Me (4)
P(t-Bu)2Me (8)
P(t-Bu)2Me (8)
Mes
b
e
10
Mes
>95 (90 )
b
11
Mes
22
a
Conditions: 2-benzoylbenzofuran (1 equiv), bromobenzene (2 equiv), Pd(OAc)2 (2 mol %), phosphine (4−10 mol %), Cs2CO3 (2 equiv), and
b
c
PivOH (30−120 mol %); 150 °C overnight; solvent. K2CO3 was used as base instead of Cs2CO3. Alkyl phosphines were used as HBF4 salts.
d
e
1
Determined by H NMR. Isolated yield (%).
cyano, acetyl, tert-butyl-carbonyl, methyl ester) and electron-
donating groups (ethyl, phenyl) in the position 2.
2-benzoylbenzofuran were investigated under optimal con-
ditions (Table 2).
As general indications, a reaction time from 16 to 63 h was
required depending on the aryl bromide used. In several cases
(entries 1, 5, 6, 13, 15, and 16), complete conversion of 1 was
not observed despite prolonged reaction times. Both electron-
donating (entries 1, 4, 5, and 15) and electron-withdrawing
(entries 6−14) aryl bromides were found to be reactive,
providing the corresponding arylated benzofurans with moderate
to excellent yields (37−96%). The method turned out to be
tolerant toward a broad range of functional groups, such as
nitrile, amide, ester, ether, or amine. The effect of sterical
hindrance of the aryl group was then briefly evaluated. Aryla-
tion occurred with 1-bromo-2-methylbenzene in 61% yield
(entry 15), but no conversion was observed with 2-bromo-1,3-
dimethylbenzene. Surprisingly, an aryl iodide, such as 1-iodo-4-
methoxybenzene, did not react with 1 (entry 2), whereas the
literature reported many examples of direct arylations using aryl
iodides, providing good yields.22 Importantly, Fagnou and co-
workers have already observed this phenomenon with aryl
iodides and have demonstrated that this behavior is due to
catalyst poisoning by the iodide anion.23 Indeed, when Ag2CO3
was added to the reaction involving 1-iodo-4-methoxybenzene
in order to sequester iodide anion, the highest yield in 3b
(98%) was reached (entry 3 vs entry 1). Direct arylation of
benzofuran 1 has also been successfully performed with
heteroaryl bromides, such as 2-bromopyridine and 3-
bromopyridine, to provide the desired coupling products in
23 and 83% yields, respectively (entries 16 and 17).
RESULTS AND DISCUSSION
■
Accordingly, our study began with the optimization of the
reaction between 2-benzoylbenzofuran 1 and bromobenzene
under various reaction conditions (Table 1).
The first attempt was performed under Fagnou direct arylation
conditions.16b The catalytic system was composed of Pd(OAc)2,
an alkyl-phosphine as its phosphonium tetrafluoroborate salt
(P(t-Bu)2Me·HBF4) and pivalic acid as a cocatalyst,20 and
cesium carbonate was used as a base (Table 1, entry 1). The
reaction was heated at 150 °C in DMA overnight, and 55% of
conversion to 3a was then obtained without any degradation or
presence of side products. Several bases were screened (K2CO3,
KOAc, CsOAc), resulting in little improvement of the
conversion rate, but rather in the formation of inseparable
byproduct.21 The conversion dropped when the phosphine was
changed from P(t-Bu)2Me·HBF4 to PPh3, PEt3·HBF4, or
PCy3·HBF4 (entry 2).21 Increasing the proportion of pivalic
acid to 60 and 120 mol % allowed an improvement of the
conversion from 55% to 75% and 80%, respectively (entries 3
and 4). Conducting the reaction in mesitylene (Mes) gave the
best results with a conversion reaching 90% in 8 h, and even
95% after 16 h (entry 5). Prolonged heating had no further
effect. Moreover, the optimal conversion was also obtained
using 30 mol % pivalic acid in the presence of K2CO3 as a base
(entry 6). Without pivalic acid, a significant drop in conversion
was observed, which confirms its essential role as a cocatalyst
(entry 11). The use of another alkyl phosphine, such as
PCy3·HBF4, gave a similar result in mesitylene, in contrast to that
in DMA (entry 7 vs entry 2). However, with an aryl phosphine,
the conversion decreased to only 30% (entry 8). Decreasing the
amount of phosphine to 4 mol % lowered the conversion slightly
(85%), and Pd black was observed (entry 9). Finally, reduc-
tion of the phosphine amount to 8 mol % led to the optimized
reaction conditions (entry 10).
The application of the method to other 2-substituted
benzofurans was also examined under the optimized conditions
(Table 3, Method A). Benzofurans substituted by electron-
withdrawing groups were arylated in good yields (entries 1−3,
5−7). By contrast, no arylation was observed using the same
method with benzofurans featuring electron-donating groups
(entries 8 and 10), and the starting material was entirely
recovered. Thus, to overcome the lack of reactivity in the latter
case, another method was developed using the catalytic system
Pd(OAc)2/P(t-Bu)2Me·HBF4 with KOAc as a base in DMA
To explore the scope and limitation of this method, the
coupling reactions between a variety of aryl halides and
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Table 2. Scope of Direct Arylation of 2-Benzoylbenzofuran
with Various Aryl and Heteroaryl Bromides
Table 3. Scope of Direct Arylation of 2-Substituted
ab
ab c
, ,
,
Benzofurans with Aryl Bromides
a
Method A: benzofuran (1 equiv), arylbromide (2 equiv), Pd(OAc)2
(2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3 (2 equiv), and
PivOH (30 mol %); 150 °C; mesitylene. Method B: benzofuran
(1 equiv), arylbromide (2 equiv), Pd(OAc)2 (2 mol %), P(t-Bu)2Me·
b
HBF4 (8 mol %), and KOAc (2 equiv); 150 °C; DMA. Starting
material yield.
should be noted that a benzofuran substituted with a non-
protected alcohol could be arylated even though in low yield
(entry 12).
It is noteworthy to point out the specific reactivity of the
latter benzofuran when arylation was performed using Method
A. Indeed, a one-pot oxidation/arylation sequence occurred to
provide 3-phenylbenzofuran-2-carbaldehyde 22j in 79% yield
(Table 4, entry 1). It was possible to extend this reaction to the
preparation of 3-aryl-2-ketobenzofurans from the correspond-
ing secondary alcohols in very good yields (entries 2 and 3).
Importantly, it has been reported that aryl halides could be
used as cooxidants in Pd-catalyzed oxidation of primary and
secondary alcohols.25 Accordingly, to understand the mecha-
nism of this one-pot transformation, the influence of the aryl
bromide on the reactivity was evaluated from benzofuran-2-
yl(phenyl)methanol 21 (Table 5).
a
Conditions: 2-benzoylbenzofuran (1 equiv), aryl bromide (2 equiv),
Pd(OAc)2 (2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3 (2 equiv),
and PivOH (30 mol %); 150 °C; mesitylene. 1-Iodo-4-methoxy-
benzene was used instead of 4-bromo-4-methoxybenzene. Ag2CO3
b
c
(1 equiv) was added.
(Method B).24 The arylation reaction could be thus
accomplished with 2-ethyl- or 2-phenyl benzofurans in good
yields (Table 3, entries 9 and 11). This is a striking result with
probable mechanistic consequences (vide infra) since Method B
differs from Method A only in that it does not employ pivalate,
replaces K2CO3 by KOAc, and uses a polar solvent (DMA).
However, these reaction conditions were not well adapted for
a benzofuran substituted with an electron-withdrawing group at
C2, such as acetyl, as only traces of product were formed, and
the reaction led mainly to degradation (entry 4). In addition, it
First, in the absence of methyl 4-bromobenzoate, 95% of
the starting material 21 was recovered, and the ketone 1 was
isolated in 5% yield (entry 1). The low yield formation of the
latter could result from oxidation of the benzylic alcohol by a
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arylation (Scheme 2). Several mechanisms have been proposed
for direct arylation. In the case of Method A, the difference of
reactivity between 2-substituted benzofurans featuring electron-
donating groups versus electron-withdrawing groups provided
evidence against an SEAr mechanism27 and led us to propose a
concerted metalation−deprotonation (CMD) pathway.28 In-
deed, it has been shown that the arylation process following this
latter route was faster with electron-deficient arenes. Moreover,
the influence of pivalic acid has been demonstrated for this
method (Table 1, entry 11), and with the CMD mechanism, it
has been proposed that the pivalate anion could replace the
bromine in the complex Ar−Pd−X, inducing a lower energy of
C−H bond cleavage, explaining the key role of pivalic acid as a
cocatalyst. As regards to Method B, wherein the palladium
source, ligand, reactants, and temperatures are the same as in
Method A, it is not obvious why the changes (i.e., no pivalic
acid, KOAc, and DMA) would make such a large difference in
reactivity, or how Method B fits into the overall mechanistic
model. The results suggest another mechanism for electron-rich
substrates, possibly the SEAr pathway. This needs to be proven.
Finally, given the favorable reactivity of benzofurans sub-
stituted by electron-withdrawing groups on position 2 when
method A was applied, it was interesting to evaluate its feasibility
for the direct arylation of polysubstituted benzofurans. The
question arose how the presence of electron-donating groups on
the benzenic ring can affect the arylation process of benzofurans.
For this purpose, a series of 2-benzoylbenzofurans 23−28
bearing electron-donating groups on positions 4, 5, 6, and/or 7
were synthesized by Rap−Stoermer condensation (Table 6).
The required polysubstituted benzofurans were obtained in
good to high yields (86−94%) no matter the position and
number of substituents (entries 1−5 and 7−9). Subsequent
arylation of 23−28 by Method A led to 31−36, respectively
(Table 6). The position of the substitution on the benzenic
ring turned out to be critical for the yields of the reaction.
Indeed, methoxy substituents at positions 5 and 6 (entry 10) or
at positions 5, 6, and 7 (entry 11) gave good yields. However,
incomplete conversions were achieved with a methoxy
substituent at position 4 whatever the presence or not of
other methoxy substituents (entries 12−15) and even after a
prolonged heating time (16−64 h, entries 12−15). Similar yields
were found when this reaction was carried out with hydroxyl or
methyl substituents at position 4 (entries 16 and 17). The
effects of electron-donating groups at position 4 appear steric
in nature, rather than electronic. Indeed, direct arylation on a
2-benzoylbenzofuran substituted by an electron-withdrawing
substituent, such as the carbomethoxy group, on position 4
failed, and the starting material was almost entirely recovered
(entry 18). By contrast, 2-benzoylbenzofuran substituted by this
group on position 7 was arylated in 89% yield (entry 19). These
results show that sterical hindrance was an important factor to
take into account in C-3 direct arylation of benzofurans.
Table 4. Direct Arylation of Benzofurans Substituted by an
Alcohol
a
a
Method A: 2-substituted benzofuran (1 equiv), aryl bromide 2a or 2j
(2 equiv), Pd(OAc)2 (2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3
(2 equiv), and PivOH (30 mol %); 150 °C; mesitylene.
Table 5. Influence of the Aryl Bromide on the One-Pot
Oxidation/Direct Arylation
yield (%)
entry
equiv of 2j
21
1
3j
1
2
3
0
1
2
95
5
89
6
84
catalytic Pd(II) species, typically Pd(OAc)2, according to
literature data, with no cooxidant, such as molecular oxygen.
With 1 equiv of aryl bromide 2j, the reaction proceeded first
by oxidation of the alcohol functionality in 21 to generate
benzofuran-2-yl(phenyl)methanone 1 in 89% yield, and subse-
quent arylation produced phenyl(3-phenylbenzofuran-2-yl)-
methanone 3j in 6% yield (entry 2). With 2 equiv of the
aryl bromide, the arylated ketone 3j was obtained in 84% yield
and no C3-arylated alcohol was observed (entry 3). We could
thus conclude that alcohol 21 was first oxidized into the
corresponding ketone 1, which was then arylated to afford 3j.
This result is in full agreement with the fact that the arylation
conditions of Method A are only applicable to benzofurans
substituted by electron-withdrawing groups at C2.
This one-pot reaction oxidation/arylation of benzofurans can
be assimilated to an autotandem catalysis according to Fogg et al.
classification.26 It involves two distinct catalytic mechanisms
promoted by a single catalyst. The first catalytic cycle concerns
the oxidation of the alcohol with an aryl halide as a cooxidant,
whereas the second catalytic cycle corresponds to the C-3
In summary, we have developed a straightforward and efficient
access to 2-substituted 3-arylbenzofurans through a palladium-
catalyzed C3 direct arylation of 2-substituted benzofurans with
aryl bromides. Electron-donating and electron-withdrawing aryl
bromides underwent arylation successfully along with pyridinyl
bromides, and the method was compatible with many functional
groups. This direct arylation was successfully extended to poly-
substituted benzofurans, highlighting its sensitivity to the steric
and electronic environment of the benzofuran core.
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Scheme 2. Proposed Mechanism for the One-Pot Oxidation/Arylation of Benzofurans
acetate 95:5) to afford the desired product 1 (5.45 g, 24.5 mmol,
100%) as a white powder: mp 87 °C (recrystallized from hexane to
give white crystals); 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz,
2H), 7.74 (d, J = 8.1 Hz, 1H), 7.67−7.62 (m, 2H), 7.56−7.48 (m, 4H),
7.37−7.31 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 184.4, 156.0, 152.2,
137.2, 132.9, 129.4 (2C), 128.5 (2C), 128.4, 127.0, 124.0, 123.3, 116.5,
112.6; IR (CDCl3) νmax 3068, 1647, 1547, 1330, 1300, 1280, 1187,
1117 cm−1; HRMS (ES+) m/z calculated for C15H11O2 [M + H]+,
223.0759; found, 223.0765.
EXPERIMENTAL SECTION
■
General Procedure for Direct Arylation of Benzofurans
(Method A). Benzofuran (1 equiv), K2CO3 (2 equiv), P(t-Bu)2
Me·HBF4 (8 mol %), and Pd(OAc)2 (2 mol %) were weighed in air
and placed in a screw cap vial equipped with a magnetic stir bar under
argon. PivOH (30 mol %) was weighed in air, dissolved in mesitylene,
and added to the vial. Aryl halide (2 equiv) was finally added (if liquid,
otherwise it was introduced at the beginning with
the other solids). The reaction mixture was then vigorously stirred
at 150 °C (oil bath temperature) during the indicated time. After
cooling to room temperature, the reaction was diluted with EtOAc and
washed with water. The aqueous layer was extracted twice with EtOAc.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated under reduced pressure. The crude
product was purified by flash chromatography over silica gel to afford
the desired product.
General Procedure for Direct Arylation of Benzofurans
(Method B). Benzofuran (1 equiv), KOAc (2 equiv.), P(t-Bu)2Me·
HBF4 (8 mol %), and Pd(OAc)2 (2 mol %) were weighed in air and
placed in a screw cap vial equipped with a magnetic stir bar under
argon. DMA and the aryl halide (2 equiv) were then added. The
reaction was then vigorously stirred at 150 °C (oil bath temperature)
during the indicated time. The solution was cooled, diluted with
EtOAc, and washed with water. The aqueous layer was extracted twice
with EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and evaporated under reduced pressure.
The residue was purified by flash chromatography over silica gel to
afford the desired product.
General Procedure for the Rap−Soermer Condensation. To
a solution of 2-bromo-1-phenylethanone (1.2 equiv) in acetone was
added potassium carbonate (4.0 equiv) and the appropriate 2-hydro-
xybenzaldehyde (1.0 equiv) under argon. The resulting mixture was
stirred at reflux overnight. After removal of the solvent, water and ethyl
acetate were added. The aqueous layer was extracted two times with
ethyl acetate. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography over silica gel to
afford the desired product.
Benzofuran-2-yl(phenyl)methanone 1. Following the general
procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-
phenylethanone (5.14 g, 25.8 mmol) and 2-hydroxybenzaldehyde
(3.00 g, 24.6 mmol) was stirred at reflux for 20 h. The residue was
purified by flash chromatography over silica gel (cyclohexane/ethyl
Phenyl(3-phenylbenzofuran-2-yl)methanone 3a. Following
the general procedure for direct arylation (Method A), a mixture of
benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and
bromobenzene (0.12 mL, 2.00 mmol) was stirred for 16 h. The residue
was purified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 199:1) twice to afford the desired product 3a (272 mg,
0.91 mmol, 91%) as a pale yellow solid: mp 93 °C (recrystallized from
1
hexane to give pale yellow crystals); H NMR (300 MHz, CDCl3) δ
7.88 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.4 Hz,
1H), 7.57−7.47 (m, 4H), 7.41−7.32 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 185.8, 154.6, 147.1, 137.2, 132.6, 130.9, 130.0 (2C), 129.8
(2C), 129.4, 128.33 (2C), 128.28, 128.2, 128.0 (2C), 123.9, 122.4,
112.4; IR (CDCl3) νmax 3066, 1648, 1601, 1559, 1492, 1447, 1371,
1292, 1261, 1013 cm−1; HRMS (ES+) m/z calculated for C21H15O2
[M + H]+, 299.1072; found, 299.1079.
(3-(4-Methoxyphenyl)benzofuran-2-yl)(phenyl)methanone
3b. Following the general procedure for direct arylation (Method A),
a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol)
and 1-bromo-4-methoxybenzene (0.63 mL, 5.00 mmol) was stirred
during 26 h. The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 98:2) to afford the desired product
3b (666 mg, 2.03 mmol, 81%) as a yellow solid: mp 84 °C (recrystallized
from hexane); 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 6.9 Hz, 2H),
7.72 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55−7.44 (m, 4H),
7.39−7.32 (m, 3H), 6.91 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 185.8, 159.7, 154.6, 146.9, 137.3, 132.6, 131.3
(2C), 129.8 (2C), 129.3, 128.2, 128.15, 128.05 (2C), 123.8, 123.0,
122.4, 113.9 (2C), 112.4, 55.3; IR (CDCl3) νmax 3066, 2960, 2839,
1647, 1612, 1560, 1508, 1447, 1375, 1290, 1251, 1175, 1035, 1014
cm−1; HRMS (ES+) m/z calculated for C22H16O3Na [M + Na]+,
351.0997; found, 351.1008.
Phenyl(3-(3,4,5-trimethoxyphenyl)benzofuran-2-yl)-
methanone 3c. Following the general procedure for direct aryla-
tion (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1
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a b c d
, , ,
Table 6. Direct Arylation of Polysubstituted 2-Benzoylbenzofurans with Bromobenzene
a
b
Rap−Stoermer condensation: salicylaldehyde (1 equiv), bromoacetophenone (1.2 equiv), K2CO3 (4 equiv), acetone at reflux overnight. Obtained
c
by deprotection of 25 with BBr3 (2 equiv), dichloromethane at r.t., 4 h. Method A: benzofuran (1 equiv), bromobenzene (2 equiv), Pd(OAc)2
(2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3 (2 equiv), and PivOH (30 mol %); 150 °C; mesitylene. NMR yields of the arylated product and
starting material (in brackets), calculated from the isolated mixture.
d
1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.2 Hz, 2H), 7.79
(222 mg, 1.00 mmol) and 5-bromo-1,2,3-trimethoxybenzene (494 mg,
2.00 mmol) was stirred for 40 h. The residue was purified by flash
chromatography over silica gel (cyclohexane/ethyl acetate 90:10) to
afford the desired product 3c (342 mg, 0.88 mmol, 88%) as a yellow
solid: mp 104−105 °C (recrystallized from hexane/dichloromethane
(d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.53−7.31 (m, 7H), 6.71 (d,
J = 9.0 Hz, 2H), 2.99 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 185.8,
154.7, 150.4, 146.5, 137.6, 132.3, 131.0 (2C), 130.1, 129.8 (2C), 128.4,
128.0 (3C), 123.5, 122.7, 118.1, 112.3, 111.9 (2C), 40.3 (2C); IR (CDCl3)
νmax 2926, 2853, 2807, 1645, 1611, 1562, 1514, 1360, 1292, 1164 cm−1;
HRMS (ES+) m/z calculated for C23H20NO2 [M + H]+, 342.1494; found,
342.1507.
4-(2-Benzoylbenzofuran-3-yl)benzonitrile 3e. Following the
general procedure for direct arylation (Method A), a mixture of
benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and
4-bromobenzonitrile (364 mg, 2.00 mmol) was stirred for 18 h. The
residue was purified by flash chromatography over silica gel (cyclo-
hexane/ethyl acetate 98:2 to 96:4) to afford the desired product 3e
(226 mg, 0.70 mmol, 70%) as a white solid: mp 145 °C (recrystallized
from hexane/dichloromethane to give white crystals); 1H NMR
(300 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 2H), 7.73−7.55 (m, 8H),
7.46−7.37 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 185.1, 154.5, 147.6,
136.8, 136.0, 133.2, 132.1 (2C), 130.7 (2C), 129.9 (2C), 128.6, 128.3
(2C), 127.4, 127.3, 124.5, 121.7, 118.6, 112.6, 112.0; IR (CDCl3) νmax
3067, 2231, 1651, 1612, 1567, 1501, 1371, 1291, 1262, 1014 cm−1;
1
to give yellow needles); H NMR (300 MHz, CDCl3) δ 7.82 (d, J =
6.9 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57−
7.45 (m, 2H), 7.40−7.31 (m, 3H), 6.68 (s, 2H), 3.86 (s, 3H), 3.79
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 185.9, 154.6, 153.2 (2C), 147.1,
138.4, 137.5, 132.7, 129.6 (2C), 129.3, 128.3, 128.04 (2C), 127.99,
126.2, 124.0, 122.4, 112.5, 107.7 (2C), 60.8, 56.2 (2C); IR (CDCl3)
νmax 3007, 2940, 2834, 1645, 1582, 1560, 1503, 1463, 1416, 1384,
1306, 1282, 1239, 1158, 1130 cm−1; HRMS (ES+) m/z calculated for
C24H20O5Na [M + Na]+, 411.1208; found, 411.1227.
(3-(4-(Dimethylamino)phenyl)benzofuran-2-yl)(phenyl)-
methanone 3d. Following the general procedure for direct aryla-
tion (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1
(555 mg, 2.50 mmol) and 4-bromo-N,N-dimethylaniline (1.0 g,
5.00 mmol) was stirred for 40 h. The residue was purified by flash
chromatography over silica gel (cyclohexane/ethyl acetate 98:2 to 95:5) to
afford the desired product 3d (318 mg, 0.93 mmol, 37%) as an orange oil:
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HRMS (ES+) m/z calculated for C22H14NO2 [M + H]+, 324.1025;
found, 324.1034.
acetate 96:4) to afford the desired product 3j (837 mg, 2.35 mmol,
94%) as a yellow solid: mp 122 °C (recrystallized from hexane/dichloro-
methane to give yellow needles); H NMR (300 MHz, CDCl3) δ 8.07
1
(3-(4-Nitrophenyl)benzofuran-2-yl)(phenyl)methanone 3f.
Following the general procedure for direct arylation (Method A), a
mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol)
and 1-bromo-4-nitrobenzene (1.01 g, 5.00 mmol) was stirred for 16 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 99:1 to 98:2) to afford the desired product
3f (536 mg, 1.56 mmol, 63%) as an orange solid: mp 162 °C (recry-
stallized from hexane/dichloromethane to give a pale yellow powder);
1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 8.7 Hz, 2H), 7.98 (d, J =
7.2 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.70−7.64 (m, 2H), 7.61−7.56
(m, 2H), 7.48−7.38 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 185.1,
154.5, 147.7, 147.5, 138.0, 136.8, 133.3, 130.9 (2C), 129.9 (2C), 128.7,
128.4 (2C), 127.3, 127.0, 124.6, 123.6 (2C), 121.6, 112.7; IR (CDCl3)
νmax 3070, 1651, 1602, 1560, 1521, 1350, 1292, 1262, 1014 cm−1;
HRMS (ES+) m/z calculated for C21H13NO4Na [M + Na]+, 366.0742;
found, 366.0755.
(d, J = 8.4 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 7.69−7.65 (m, 2H), 7.61−
7.49 (m, 4H), 7.41−7.35 (m, 3H), 9.94 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 185.4, 166.7, 154.6, 147.4, 137.0, 135.8, 133.0,
130.0 (2C), 129.9 (2C), 129.8, 129.6 (2C), 128.4, 128.2 (3C), 127.7,
124.2, 122.0, 112.5, 52.2; IR (CDCl3) νmax 3067, 2954, 1719, 1650,
1612, 1571, 1438, 1289, 1114, 1014 cm−1; HRMS (ES+) m/z calculated
for C23H16O4Na [M + Na]+, 379.0946; found, 379.0959.
(4-(2-Benzoylbenzofuran-3-yl)phenyl)(morpholino)-
methanone 3k. Following the general procedure for direct aryla-
tion (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1
(222 mg, 1.00 mmol) and (4-bromophenyl)(morpholino)methanone
(540 mg, 2.00 mmol) was stirred for 24 h. The residue was purified by
flash chromatography over silica gel (dichloromethane/methanol 99:1)
to afford the desired product 3k (397 mg, 0.96 mmol, 96%) as a white
solid: mp 254 °C (recrystallized from hexane/dichloromethane); 1H
NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.69−7.64 (m,
2H), 7.60−7.35 (m, 9H), 3.73−7.48 (m, 8H); 13C NMR (75 MHz,
CDCl3) δ 185.6, 169.9, 154.6, 147.3, 137.2, 135.1, 132.7 (2C), 130.2
(2C), 129.9 (2C), 128.4, 128.2 (3C), 127.8, 127.1 (2C), 124.2, 122.1,
112.5, 66.9 (4C); IR (CDCl3) νmax 3067, 2924, 2861, 1630, 1568, 1433,
1280, 1261, 1114, 1013 cm−1; HRMS (ES+) m/z calculated for
C26H22NO4 [M + H]+, 412.1549; found, 412.1566.
(3-(4-Chlorophenyl)benzofuran-2-yl)(phenyl)methanone
3g. Following the general procedure for direct arylation (Method A),
a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol)
and 1-bromo-4-chlorobenzene (383 mg, 2.00 mmol) was stirred for
18 h. The residue was purified by flash chromatography over silica
gel (cyclohexane/ethyl acetate 199:1) to afford the desired product 3g
(315 mg, 0.95 mmol, 95%) as a pale yellow solid: mp 108 °C (recry-
1
stallized from hexane to give yellow crystals); H NMR (300 MHz,
(3-(3-Fluorophenyl)benzofuran-2-yl)(phenyl)methanone
3l. Following the general procedure for direct arylation (Method A), a
mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol)
and 1-bromo-4-chlorobenzene (0.64 mL, 5.00 mmol) was stirred for 48 h.
The residue was purified twice by flash chromatography over silica gel
(cyclohexane/ethyl acetate 199:1) to afford the desired product 3l
(468 mg, 1.48 mmol, 59%) as a pale yellow solid: mp 58 °C (recry-
stallized from hexane to give a pale yellow powder); 1H NMR (300 MHz,
CDCl3) δ 7.90 (d, J = 7.5 Hz, 2H), 7.71−7.64 (m, 2H), 7.57−7.50 (m,
2H), 7.42−7.22 (m, 6H), 7.09−7.02 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 185.5, 162.6 (d, J = 245 Hz), 154.5, 147.3,
137.1, 133.0 (d, J = 8.4 Hz), 132.9, 129.9 (d, J = 8.3 Hz), 129.8 (2C),
128.4, 128.2 (2C), 128.0 (d, J = 2.4 Hz), 127.7, 125.8 (d, J = 2.9 Hz),
124.1, 122.1, 116.9 (d, J = 22.3 Hz), 115.3 (d, J = 20.9 Hz), 112.5; IR
(CDCl3) νmax 3068, 1650, 1614, 1563, 1448, 1292, 1262, 1233, 1168,
1021 cm−1; HRMS (ES+) m/z calculated for C21H14O2F [M + H]+,
317.0978; found, 317.0991.
CDCl3) δ 7.92 (d, J = 6.9 Hz, 2H), 7.68−7.63 (m, 2H), 7.57−7.34 (m,
9H); 13C NMR (75 MHz, CDCl3) δ 185.4, 154.5, 147.2, 137.1, 134.4,
132.9, 131.2 (2C), 129.8 (2C), 129.4, 128.6 (2C), 128.4, 128.19 (2C),
128.16, 127.8, 124.1, 122.0, 112.5; IR (CDCl3) νmax 3067, 2955, 1701,
1649, 1601, 1555, 1492, 1370, 1291, 1250, 1092, 1014 cm−1; HRMS
(ES+) m/z calculated for C21H14O2Cl [M + H]+, 333.0682; found,
333.0697.
Phenyl(3-(4-(trifluoromethyl)phenyl)benzofuran-2-yl)-
methanone 3h. Following the general procedure for direct aryla-
tion (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1
(222 mg, 1.00 mmol) and 1-bromo-4-(trifluoromethyl)benzene
(0.28 mL, 2.00 mmol) was stirred for 40 h. The residue was purified
by flash chromatography over silica gel (cyclohexane/ethyl acetate
199:1 to 196:4) to afford the desired product 3h (343 mg, 0.94 mmol,
94%) as a pale yellow solid: mp 135 °C (recrystallized from hexane to
give pale yellow crystals); 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J =
7.2 Hz, 2H), 7.68−7.65 (m, 6H), 7.59−7.52 (m, 2H), 7.44−7.36 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 185.3, 154.5, 147.5, 137.0, 134.8,
133.0, 130.31 (q, J = 32 Hz), 130.31 (2C), 129.9 (2C), 128.5, 128.3
(2C), 127.9, 127.7, 125.3 (q, J = 3.8 Hz, 2C), 124.3, 124.0 (q, J = 270 Hz),
121.9, 112.5; IR (CDCl3) νmax 3067, 1650, 1564, 1322, 1292, 1262, 1171,
1132, 1068, 1014 cm−1; HRMS (ES+) m/z calculated for C22H13O2F3Na
[M + Na]+, 389.0765; found, 389.0782.
1-(4-(2-Benzoylbenzofuran-3-yl)phenyl)ethanone 3i. Fol-
lowing the general procedure for direct arylation (Method A), a
mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol)
and 1-(4-bromophenyl)ethanone (995 mg, 5.00 mmol) was stirred for
23 h. The residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 99:1 to 97:3) to afford the desired product
3i (450.5 mg, 1.33 mmol, 53%) as a pale yellow solid: mp 90 °C
(recrystallized from hexane/dichloromethane to give yellow crystals);
1H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 8.7 Hz, 2H), 7.94 (d, J =
7.2 Hz, 2H), 7.69−7.63 (m, 4H), 7.59−7.71 (m, 2H), 7.43−7.36 (m,
3H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 197.6, 185.3, 154.5,
147.5, 137.0, 136.6, 136.0, 133.0, 130.2 (2C), 129.9 (2C), 128.4, 128.3
(2C), 128.24 (2C), 128.18, 127.6, 124.2, 122.0, 112.5, 26.7; IR
(CDCl3) νmax 3067, 1683, 1650, 1610, 1567, 1363, 1290, 1266, 1012
cm−1; HRMS (ES+) m/z calculated for C23H17O3 [M + H]+, 341.1178;
found, 341.1189.
(3-(4-Fluorophenyl)benzofuran-2-yl)(phenyl)methanone
3m. Following the general procedure for direct arylation (Method A),
a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol)
and 1-bromo-4-fluorobenzene (0.22 mL, 2.00 mmol) was stirred during
21 h. The residue was purified twice by flash chromatography over silica
gel (cyclohexane/ethyl acetate 199:1) to afford the desired product 3m
(267 mg, 0.84 mmol, 84%) as a pale yellow solid: mp 80 °C (recry-
stallized from hexane to give a pale yellow powder); 1H NMR (300 MHz,
CDCl3) δ 7.90 (d, J = 7.2 Hz, 2H), 7.69−7.64 (m, 2H), 7.57−7.48 (m,
4H), 7.41−7.34 (m, 3H), 7.08 (t, J = 9.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 185.6, 162.7 (d, J = 247 Hz), 154.5, 147.2, 137.2,
132.8, 131.75 (d, J = 8.2 Hz, 2C), 129.8 (2C), 128.4, 128.3, 128.1
(2C), 128.0, 126.8 (d, J = 3.4 Hz), 124.0, 122.1, 115.4 (d, J = 21.5 Hz,
2C), 112.4; IR (CDCl3) νmax 3066, 2959, 1649, 1601, 1563, 1506,
1374, 1292, 1261, 1227, 1161, 1014 cm−1; HRMS (ES+) m/z
calculated for C21H14O2F [M + H]+, 317.0978; found, 317.0982.
Phenyl(3-o-tolylbenzofuran-2-yl)methanone 3n. Following
the general procedure for direct arylation (Method A), a mixture of
benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and 1-
bromo-2-methylbenzene (0.24 mL, 2.00 mmol) was stirred for 24 h.
The residue was purified twice by flash chromatography over silica gel
(cyclohexane/ethyl acetate 199:1) to afford the desired product 3n
1
(190 mg, 0.61 mmol, 61%) as a pale yellow oil: H NMR (300 MHz,
Methyl 4-(2-benzoylbenzofuran-3-yl)benzoate 3j. Following
the general procedure for direct arylation (Method A), a mixture of
benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and methyl
4-bromobenzoate (1.08 g, 5.00 mmol) was stirred for 23 h. The residue
was purified by flash chromatography over silica gel (cyclohexane/ethyl
CDCl3) δ 7.91 (d, J = 6.9 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.56−7.19
(m, 10H), 2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.3, 154.5,
147.8, 137.1, 136.8, 132.6, 130.7, 130.2 (2C), 129.6 (2C), 129.1, 128.6,
128.3, 128.2, 128.0 (2C), 125.6, 123.8, 122.6, 112.4, 20.0; IR (CDCl3)
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νmax 2926, 1647, 1601, 1560, 1368, 1334, 1294, 1011 cm−1; HRMS (ES+)
m/z calculated for C22H17O2 [M + H]+, 313.1229; found, 313.1231.
Phenyl(3-(pyridin-2-yl)benzofuran-2-yl)methanone 3o. Fol-
lowing the general procedure for direct arylation (Method A), a
mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol)
and 2-bromopyridine (0.48 mL, 5.00 mmol) was stirred for 63 h. The
residue was purified by flash chromatography over silica gel (cyclo-
hexane/ethyl acetate 90:10) to afford the desired product 3o (170 mg,
0.57 mmol, 23%) as a pale yellow solid: mp 87 °C (recrystallized from
hexane/dichloromethane to give pale yellow crystals); 1H NMR (300 MHz,
CDCl3) δ 8.70 (dt, J = 4.8, 1.5 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.90 (d, J
= 7.2 Hz, 2H), 7.67−7.60 (m, 3H), 7.56−7.48 (m, 2H), 7.41−7.34 (m,
3H), 7.26−7.21 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 185.9, 154.7,
150.9, 149.6, 148.1, 137.2, 136.0, 132.9, 129.9 (2C), 128.16 (2C),
128.14, 127.9, 127.4, 125.9, 124.2, 123.2, 122.7, 112.2; IR (CDCl3)
νmax 3064, 1651, 1595, 1563, 1464, 1369, 1293, 1260, 1168, 1018
cm−1; HRMS (ES+) m/z calculated for C20H14NO2 [M + H]+,
300.1025; found, 300.1028.
Phenyl(3-(pyridin-3-yl)benzofuran-2-yl)methanone 3p. Fol-
lowing the general procedure for direct arylation (Method A), a
mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol)
and 3-bromopyridine (0.48 mL, 5.00 mmol) was stirred for 63 h. The
residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 70:30) to afford the desired product 3p
(622 mg, 2.08 mmol, 83%) as a white solid: mp 125 °C (recrystallized
from hexane/dichloromethane to give white crystals); 1H NMR
(300 MHz, CDCl3) δ 8.79 (d, J = 1.8 Hz, 1H), 8.62 (dd, J = 4.8,
1.5 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.90 (dt, J = 7.8, 2.1 Hz, 1H),
7.70−7.66 (m, 2H), 7.60−7.53 (m, 2H), 7.45−7.33 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 185.2, 154.5, 150.3, 149.3, 147.7, 137.4,
136.9, 133.0, 129.9 (2C), 128.6, 128.3 (2C), 127.6, 127.3, 125.9, 124.3,
123.1, 121.8, 112.6; IR (CDCl3) νmax 3064, 1650, 1600, 1555, 1371,
1292, 1262, 1229, 1013 cm−1; HRMS (ES+) m/z calculated for
C20H13NO2Na [M + Na]+, 322.0844; found, 322.0856.
hexane/dichloromethane to give a pale yellow powder); 1H NMR (300 MHz,
CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H), 7.68−7.51 (m, 5H), 7.36−
7.31 (m, 1H), 3.97 (s, 3H), 2.56 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 189.7, 166.7, 154.1, 147.2, 135.6, 130.2, 130.0 (2C), 129.6
(2C), 128.6, 128.2, 126.5, 124.1, 122.2, 112.4, 52.2, 28.2; IR (CDCl3)
νmax 3004, 2954, 1719, 1683, 1572, 1438, 1287, 1116, 1106 cm−1
;
HRMS (ES+) m/z calculated for C18H14O4Na [M + Na]+, 317.0790;
found, 317.0795.
Methyl 4-(2-pivaloylbenzofuran-3-yl)benzoate 15j. Follow-
ing the general procedure for direct arylation (Method A), a mixture of
1-(benzofuran-2-yl)-2,2-dimethylpropan-1-one 732 (202 mg, 1.00 mmol)
and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was stirred for 24 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 99:1 to 97:3) to afford the desired product
15j (229 mg, 0.68 mmol, 68%) as a white solid: mp 82 °C (recrystallized
from hexane to give white crystals); 1H NMR (300 MHz, CDCl3) δ 8.15
(d, J = 8.4 Hz, 2H), 7.63−7.59 (m, 3H), 7.55−7.50 (m, 2H), 7.35−7.30
(m, 1H), 3.95 (s, 3H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
197.5, 166.8, 153.6, 147.1, 136.3, 129.9 (2C), 129.7, 129.5 (2C), 128.1,
127.8, 123.9, 121.9, 112.1, 52.2, 44.2, 26.4 (3C); IR (CDCl3) νmax 2956,
2909, 2875, 1719, 1673, 1613, 1559, 1438, 1281, 1183, 1114, 1053 cm−1;
HRMS (ES+): m/z calculated for C21H21O4 [M + H]+, 337.1440; found,
337.1449.
Methyl 3-phenylbenzofuran-2-carboxylate 16a. Following
the general procedure for direct arylation (Method A), a mixture
of methyl benzofuran-2-carboxylate 833 (440 mg, 2.50 mmol) and
bromobenzene (0.53 mL, 5.00 mmol) was stirred for 15 h. The residue
was purified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 95:5) to afford the desired product 16a (582.5 mg,
2.31 mmol, 92%) as a white solid: mp 92 °C (recrystallized from
hexane to give a white powder); 1H NMR (300 MHz, CDCl3) δ 7.65−
7.58 (m, 4H), 7.54−7.45 (m, 4H), 7.35−7.29 (m, 1H), 3.89 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 160.2, 154.5, 139.8, 130.5, 129.9 (2C),
129.5, 128.5, 128.3, 128.2 (2C), 128.1, 123.8, 122.1, 112.3, 52.1; IR
(CDCl3) νmax 3036, 2954, 1723, 1579, 1496, 1439, 1376, 1295, 1267,
1226, 1157, 1141 cm−1; HRMS (ES+) m/z calculated for C16H12O3Na
[M + Na]+, 275.0684; found, 275.0686.
Methyl 4-(2-nitrobenzofuran-3-yl)benzoate 12j. Following
the general procedure for direct arylation (Method A), a mixture of
2-nitrobenzofuran 429 (147 mg, 0.90 mmol) and methyl 4-bromoben-
zoate (387 mg, 2.00 mmol) was stirred during 20 h. The residue was
purified by flash chromatography over silica gel (cyclohexane/ethyl
acetate 95:5) to afford the desired product 12j (207 mg, 0.70 mmol,
77%) as an orange solid: mp 154 °C (recrystallized from hexane/
Methyl 3-(4-(methoxycarbonyl)phenyl)benzofuran-2-car-
boxylate 16j. Following the general procedure for direct arylation
(Method A), a mixture of methyl benzofuran-2-carboxylate 8 (176 mg,
1.00 mmol) and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was
stirred during 23 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 95:5) to afford the desired
product 16j (241.6 mg, 0.78 mmol, 78%) as a white solid: mp 127 °C
1
dichloromethane to give an orange powder); H NMR (300 MHz,
CDCl3) δ 8.22 (d, J = 8.4 Hz, 2H), 7.71−7.61 (m, 5H), 7.44 (ddd, J =
8.1, 6.0, 2.1 Hz, 1H), 3.98 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
166.4, 151.7 (2C), 132.8, 131.1, 130.5, 130.0 (2C), 129.8 (2C), 127.2,
125.5, 123.1, 121.3, 112.7, 52.4; IR (CDCl3) νmax 3002, 2954, 2848,
1722, 1525, 1373, 1325, 1282, 1113 cm−1; HRMS (ES+) m/z calculated
for C16H11NO5Na [M + Na]+, 320.0535; found, 320.0538.
Methyl 4-(2-cyano-6-methoxybenzofuran-3-yl)benzoate
13j. Following the general procedure for direct arylation (Method
A), a mixture of 6-methoxybenzofuran-2-carbonitrile 530 (173 mg,
1.00 mmol) and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was
stirred for 23 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/dichloromethane 50:50) to afford the
desired product 13j (250 mg, 0.81 mmol, 81%) as a white solid: mp
197 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 8.1 Hz, 2H), 7.81
(d, J = 8.1 Hz, 2H), 7.66 (d, J = 9.3 Hz, 1H), 7.06−7.04 (m, 2H),
3.97 (s, 3H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4,
161.5, 157.3, 133.2, 132.4, 130.9, 130.5 (2C), 128.3 (2C), 123.0, 121.9,
117.9, 115.2, 112.5, 95.7, 55.9, 52.4; IR (CDCl3) νmax 2954, 2842,
2225, 1722, 1619, 1496, 1436, 1286, 1196, 1154, 1115 cm−1; HRMS
(ES+) m/z calculated for C18H13NO4Na [M + Na]+, 330.0742; found,
330.0755.
1
(recrystallized from hexane/dichloromethane); H NMR (300 MHz,
CDCl3) δ 8.17 (d, J = 8.4 Hz, 2H), 7.68−7.63 (m, 3H), 7.58−7.49 (m,
2H), 7.33 (t, J = 8.1 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.8, 160.0, 154.5, 140.1, 135.3, 130.1, 130.0
(2C), 129.5 (2C), 128.4, 128.3, 127.8, 124.1, 121.8, 112.4, 52.5 (2C);
IR (CDCl3) νmax 3003, 2954, 2360, 1722, 1614, 1590, 1438, 1376,
1291, 1142, 1110 cm−1; HRMS (ES+) m/z calculated for C18H15O5
[M + H]+, 311.0919; found, 311.0928.
2-Ethyl-3-phenylbenzofuran 17a.34 Following the general
procedure for direct arylation (Method B), a mixture of 2-ethylbenzo-
furan 9 (146 mg, 1.0 mmol) and bromobenzene (0.210 mL, 2.0 mmol)
was stirred for 16 h. The residue was purified by flash chromatography
over silica gel (pentane) to afford the desired product 17a (153 mg,
0.69 mmol, 69%) as a transparent liquid: 1H NMR (300 MHz, CDCl3)
δ 7.62−7.59 (m, 1H), 7.54−7.47 (m, 5H), 7.41−7.36 (m, 1H), 7.32−
7.21 (m, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.39 (q, J = 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 156.1, 154.0, 132.8, 129.0 (2C), 128.8,
128.7 (2C), 126.9, 123.5, 122.5, 119.4, 116.1, 110.8, 20.2, 12.9; IR
(CDCl3) νmax 3062, 2979, 2939, 1612, 1456, 1241, 1196, 1176 cm−1;
MS (ES+) m/z 245 [M + Na]+.
Methyl 4-(2-acetylbenzofuran-3-yl)benzoate 14j. Following
the general procedure for direct arylation (Method A), a mixture of
1-(benzofuran-2-yl)ethanone 631 (160 mg, 1.00 mmol) and methyl
4-bromobenzoate (430 mg, 2.00 mmol) was stirred for 23 h. The
residue was purified by flash chromatography over silica gel (cyclo-
hexane/ethyl acetate 95:5) to afford the desired product 14j (164 mg,
0.56 mmol, 56%) as a pale yellow solid: mp 195 °C (recrystallized from
2,3-Diphenylbenzofuran 18a.35 Following the general proce-
dure for direct arylation (Method B), a mixture of 2-phenylbenzofuran
1036 (97 mg, 0.50 mmol) and bromobenzene (0.105 mL, 1.00 mmol)
was stirred for 16 h. The residue was purified by flash chromatography
over silica gel (pentane) to afford the desired product 18a (93 mg,
0.345 mmol, 69%) as a white solid: mp 123 °C (recrystallized from
1323
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1
hexane to give white crystals) (lit. mp 123 °C); H NMR (300 MHz,
CDCl3) δ 7.68−7.65 (m, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.53−7.30 (m,
10H), 7.27−7.22 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 153.9,
150.5, 132.8, 130.6, 130.2, 129.7 (2C), 128.9 (2C), 128.4 (2C), 128.3,
127.6, 127.0 (2C), 124.6, 122.9, 120.0, 117.4, 111.1; IR (CDCl3) νmax
3064, 3037, 1604, 1503, 1455, 1443, 1258, 1207, 1064, 1028 cm−1; MS
(ES+) m/z 293 [M + Na]+.
solid: mp 92 °C (recrystallized from hexane to give a white product);
1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 6.9 Hz, 2H), 7.66−
7.60 (m, 1H), 7.53 (t, J = 6.9 Hz, 2H),7.48 (s, 1H), 6.82 (s, 1H), 4.27
(s, 3H), 3.96 (s, 3H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
183.5, 152.8, 151.8, 143.2, 142.0, 139.3, 137.3, 132.7, 129.4 (2C),
128.4 (2C), 123.1, 116.7, 97.2, 61.6, 61.0, 56.3; IR (CDCl3) νmax 3006,
2940, 2835, 1645, 1553, 1486, 1357, 1302, 1256, 1226, 1124 cm−1;
HRMS (ES+) m/z calculated for C18H17O5 [M + H]+, 313.1076;
found, 313.1077.
(3-Phenylbenzofuran-2-yl)methanol 19a.37 Following the
general procedure for direct arylation (Method B), a mixture of
benzofuran-2-ylmethanol 1138 (148 mg, 1.00 mmol) and bromoben-
zene (0.21 mL, 2.00 mmol) was stirred for 16 h. The residue was
purified by flash chromatography over silica gel (dichloromethane) to
afford the desired product 19a (40 mg, 0.18 mmol, 18%) as a yellow
solid: mp 79 °C (recrystallized from hexane to give white crystals);
1H NMR (300 MHz, CDCl3) δ 7.67−7.64 (m, 1H), 7.58−7.48 (m,
5H), 7.44−7.33 (m, 2H), 7.30−7.25 (m, 1H), 4.84 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 154.3, 151.6, 131.6, 129.1 (2C), 128.9 (2C),
127.9, 127.6, 124.9, 123.0, 120.4, 119.8, 111.4, 56.4; IR (CDCl3) νmax
3608, 3063, 2930, 2874, 1613, 1454, 1262, 1222, 1177, 1016 cm−1; MS
(ES+) m/z 247 [M + Na]+.
Phenyl(4,5,6-trimethoxybenzofuran-2-yl)methanone 25.
Following the general procedure for Rap−Stoermer condensation, a
mixture of 2-bromo-1-phenylethanone (0.98 g, 4.94 mmol) and
2-hydroxy-4,5,6-trimethoxybenzaldehyde (1.00 g, 4.72 mmol) was
stirred at reflux for 17.5 h. The residue was purified by flash chromato-
graphy over silica gel (cyclohexane/ethyl acetate 90:10 to 80:20) to
afford the desired product 25 (1.34 g, 4.30 mmol, 91%) as a yellow
powder: mp 90 °C (recrystallized from hexane to give a white
1
product); H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 7.2 Hz, 2H),
7.65−7.59 (m, 2H), 7.53 (t, J = 7.2 Hz, 2H), 6.87 (s, 1H), 4.13 (s,
3H), 3.95 (s, 3H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 183.5,
156.0, 153.5, 151.0, 147.2, 137.5, 137.4, 132.6, 129.2 (2C), 128.5 (2C),
115.7, 113.4, 90.2, 61.4, 61.3, 56.4; IR (CDCl3) νmax 2967, 2940, 1641,
1649, 1541, 1485, 1469, 1301, 1274, 1200, 1152, 1129 cm−1; HRMS
(ES+) m/z calculated for C18H17O5 [M + H]+, 313.1076; found,
313.1082.
(4-Methoxybenzofuran-2-yl)(phenyl)methanone 26. Follow-
ing the general procedure for Rap−Stoermer condensation, a mixture
of 2-bromo-1-phenylethanone (1.36 g, 6.83 mmol) and 2-hydroxy-4-
methoxy-benzaldehyde (1.00 g, 6.50 mmol) was stirred at reflux for
16.5 h. The residue was purified by flash chromatography over silica
gel (cyclohexane/ethyl acetate 95:5 to 90:10) to afford the desired
product 26 (1.54 g, 6.10 mmol, 94%) as a white powder: mp 100 °C
(recrystallized from heptane to give white crystals); 1H NMR (300 MHz,
CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H), 7.66−7.61 (m, 2H), 7.53 (t, J = 7.2
Hz, 2H), 7.43 (t, J = 8.1 Hz, 1H), 7.26−7.23 (m, 1H), 6.71 (d, J = 7.8
Hz, 1H), 3.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.1, 157.1,
155.1, 150.9, 137.3, 132.7, 129.5, 129.3 (2C), 128.5 (2C), 118.0, 114.7,
105.2, 103.5, 55.6; IR (CDCl3) νmax 2965, 2946, 2842, 1646, 1542, 1498,
1339, 1266, 1134, 1089 cm−1; HRMS (ES+) m/z calculated for
C16H13O3 [M + H]+, 253.0865; found, 253.0874.
Methyl 4-(2-formylbenzofuran-3-yl)benzoate 22j. Following
the general procedure for direct arylation (Method A), a mixture of
benzofuran-2-ylmethanol 11 (148 mg, 1.00 mmol) and methyl
4-bromobenzoate (430 mg, 2.00 mmol) was stirred for 23 h. The
residue was purified by flash chromatography over silica gel (cyclo-
hexane/ethyl acetate 95:5) to afford the desired product 22j (220 mg,
0.79 mmol, 79%) as a white solid: mp 136 °C (recrystallized from
hexane/dichloromethane to give a white powder); 1H NMR (300 MHz,
CDCl3) δ 9.90 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.77−7.67 (m, 4H),
7.63−7.57 (m, 1H), 7.43−7.38 (m, 1H), 3.99 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 179.5, 166.4, 155.4, 147.8, 133.8, 132.5, 131.0, 130.3
(2C), 130.0 (2C), 129.8, 126.8, 124.5, 122.4, 112.9, 52.4; IR (CDCl3)
νmax 2954, 2853, 1722, 1673, 1287, 1115 cm−1; HRMS (ES+) m/z
calculated for C17H13O4 [M + H]+, 281.0814; found, 281.0822.
1-(3-Phenylbenzofuran-2-yl)ethanone 14a.39 Following the
general procedure for direct arylation (method A), a mixture of
1-(benzofuran-2-yl)ethanol 2040 (405 mg, 2.50 mmol) and bromo-
benzene (0.53 mL, 5.00 mmol) was stirred for 17 h. The residue was
purified by flash chromatography over silica gel (cyclohexane/ethyl
acetate 99:1 to 95:5) to afford a mixture of the desired product 14a
(566 mg, 2.40 mmol, 96%) as a yellow solid: mp 95 °C (recrystallized
(4-Hydroxybenzofurane-2-yl)(phenyl)methanone 27. To a
solution of (4-methoxybenzofuran-2-yl)(phenyl)methanone 26 (100 mg,
0.40 mmol, 1.0 equiv) in dichloromethane was added a solution of
boron tribromide in dichloromethane (0.80 mL, 0.80 mmol, 2.0 equiv)
under argon at 0 °C. The resulting mixture was stirred at room tem-
perature for 4 h. After quenching with water, saturated Na2CO3
solution was added until pH = 7. The aqueous layer was extracted two
times with dichloromethane. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and evaporated under
reduced pressure. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 90:10) to afford the desired
product 27 (46 mg, 0.19 mmol, 48%) as a brown powder: mp 180 °C
1
from hexane to give white crystals); H NMR (300 MHz, CDCl3) δ
7.63−7.46 (m, 8H), 7.34−7.28 (m, 1H), 2.49 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 189.6, 154.1, 147.1, 130.8, 129.9 (2C), 128.7,
128.44 (2C), 128.42, 127.9, 123.8, 122.5, 112.2, 28.3; IR (CDCl3) νmax
3066, 3035, 1680, 1562, 1494, 1375, 1290, 1214, 1103 cm−1; MS
(ES+) m/z 259 [M + Na]+.
(5,6-Dimethoxybenzofuran-2-yl)(phenyl)methanone 23.
Following the general procedure for Rap−Stoermer condensation,
a mixture of 2-bromo-1-phenylethanone (1.15 g, 5.80 mmol) and
2-hydroxy-4,5-dimethoxybenzaldehyde (1.00 g, 5.49 mmol) was stirred
at reflux for 16 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 80:20 to 70:30) to afford
the desired product 23 (1.39 g, 4.93 mmol, 90%) as a yellow solid: mp
130 °C (recrystallized from heptane/ethyl acetate to give a yellow
1
(recrystallized from hexane/ethyl acetate to give brown crystals); H
NMR (300 MHz, CDCl3) δ 8.03 (d, J = 6.9 Hz, 2H), 7.68 (s, 1H),
7.63 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 8.4 Hz,
1H), 7.20 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.04 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 184.9, 158.0, 151.7, 151.5, 137.6, 133.4,
130.0, 129.9 (2C), 129.0 (2C), 117.6, 115.0, 108.8, 105.5; IR (CDCl3)
νmax 3359, 3066, 1648, 1622, 1603, 1544, 1342, 1274, 1180 cm−1;
HRMS (ES+) m/z calculated for C15H11O3 [M + H]+, 239.0708;
found, 239.0700.
1
powder); H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H),
7.65−7.59 (m, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.46 (d, J = 0.9 Hz, 1H),
7.13 (s, 1H), 7.07 (s,1H), 3.98 (s, 3H), 3.94 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 183.5, 151.9, 151.8, 151.77, 147.7, 137.5, 132.5, 129.3
(2C) 128.4 (2C), 119.1, 117.4, 102.6, 95.1, 56.3 (2C); IR (CDCl3)
νmax 2964, 2941, 2837, 1638, 1541, 1490, 1296, 1252, 1234, 1214,
1197, 1120 cm−1; HRMS (ES+) m/z calculated for C17H15O4 [M +
H]+, 283.0977; found, 283.0970.
Phenyl(5,6,7-trimethoxybenzofuran-2-yl)methanone 24.
Following the general procedure for Rap−Stoermer condensation,
a mixture of 2-bromo-1-phenylethanone (0.98 g, 4.94 mmol) and
2-hydroxy-4,5,6-trimethoxybenzaldehyde (1.00 g, 4.72 mmol) was
stirred at reflux for 16 h. The residue was purified by flash chromato-
graphy over silica gel (cyclohexane/ethyl acetate 85:15 to 80:20) to
afford the desired product 24 (1.27 g, 4.07 mmol, 86%) as a brown
(4,6-Dimethylbenzofuran-2-yl)(phenyl)methanone 28. Fol-
lowing the general procedure for Rap−Stoermer condensation,
a mixture of 2-bromo-1-phenylethanone (0.70 g, 3.50 mmol) and
2-hydroxy-4,6-dimethylbenzaldehyde (0.50 g, 3.33 mmol) was stirred
at reflux for 16 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 95:5 to 90:10) to afford the
desired product 28 (0.83 g, 3.32 mmol, 100%) as a yellow solid: mp
1
77 °C (recrystallized from hexane to give yellow crystals); H NMR
(300 MHz, CDCl3) δ 8.03 (d, J = 6.9 Hz, 2H), 7.67−7.61 (m, 1H),
1324
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7.57−7.50 (m, 3H), 7.26 (s, 1H), 6.96 (s, 1H), 2.52 (s, 3H), 2.48
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.3, 156.6, 151.4, 139.5,
137.5, 133.0, 132.6, 129.3 (2C), 128.5 (2C), 125.9, 124.7, 115.7, 109.8,
22.0, 18.5; IR (CDCl3) νmax 3028, 2921, 1642, 1539, 1343, 1270 cm−1;
HRMS (ES+) m/z calculated for C17H15O2 [M + H]+, 251.1072;
found, 251.1063.
stirred for 64 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 97:3 to 95:5) to afford
a mixture of the starting material 25 and the desired product 33
(326 mg, 25/33 = 1.30 determined by 1H NMR, calculated yield: 41%
of 33 and 53% of 25) as a brown solid: mp 94 °C (recrystallized from
1
hexane to give yellow crystals); H NMR (300 MHz, CDCl3) δ 7.77
Methyl 2-benzoylbenzofuran-4-carboxylate 29. Following
the general procedure for Rap−Stoermer condensation, a mixture
of 2-bromo-1-phenylethanone (829 mg, 4.16 mmol) and methyl
2-formyl-3-hydroxybenzoate (500 mg, 2.78 mmol) was stirred at reflux
for 20 h. The residue was purified by flash chromatography over silica
gel (cyclohexane/ethyl acetate 95:5) to afford the desired product 29
(d, J = 7.2 Hz, 2H), 7.44−7.39 (m, 3H), 7.31−7.26 (m, 5H), 6.92 (s,
1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.49 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 185.0, 155.8, 151.9, 148.4, 146.8, 139.5, 137.4, 132.1, 131.4,
130.3 (2C), 130.1, 129.6 (2C), 127.9 (3C), 127.4 (2C), 114.9, 91.1,
61.5, 61.3, 56.4; IR (CDCl3) νmax 2967, 2940, 2835, 1615, 1552, 1494,
1305, 1273, 1229, 1200, 1137, 1052 cm−1; HRMS (ES+) m/z calculated
for C24H20O5Na [M + Na]+, 411.1208; found, 411.1199.
1
(643 mg, 2.30 mmol, 83%) as a white solid: H NMR (300 MHz,
(4-Methoxy-3-phenylbenzofuran-2-yl)(phenyl)methanone
34.41 Following the general procedure for direct arylation, a mixture
of (4-methoxybenzofuran-2-yl)(phenyl)methanone 26 (252 mg,
1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for
64 h. The residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 99:1 to 90:10) to afford a mixture of the
starting material 26 and the desired product 34 (254 mg, 26/34 = 1.15
determined by 1H NMR, calculated yield: 41% of 34 and 47% of 26) as a
brown solid: mp 86 °C (recrystallized from hexane to give yellow
crystals); 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 7.2 Hz, 2H), 7.47−
7.39 (m, 4H), 7.31−7.24 (m, 6H), 6.70 (d, J = 7.8 Hz, 1H), 3.74 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 185.7, 156.2, 155.8, 146.6, 137.2, 132.3,
CDCl3) δ 8.09−8.05 (m, 4H), 7.86 (d, J = 8.4 Hz, 1H), 7.69−7.64 (m,
1H), 7.60−7.54 (m, 3H), 4.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
184.2, 166.0, 155.9, 152.9, 136.8, 133.0, 129.4 (2C), 128.5 (2C), 127.4,
127.0, 126.5, 124.6, 117.0, 116.8, 52.1; IR (CDCl3) νmax 3067, 3002,
2954, 1718, 1650, 1600, 1544, 1438, 1331, 1289, 1274, 1208, 1169,
1120 cm−1; HRMS (ES+) m/z calculated for C17H13O4 [M + H]+,
281.0814; found, 281.0805.
Methyl 2-benzoylbenzofuran-7-carboxylate 30. Following
the general procedure for Rap−Stoermer condensation, a mixture of
2-bromo-1-phenylethanone (1.20 g, 5.84 mmol) and methyl 3-formyl-
2-hydroxybenzoate (1.00 g, 5.56 mmol) was stirred at reflux for 16 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 98:2) to afford the desired product 30
(0.944 g, 3.40 mmol, 61%) as a yellow solid: mp 75 °C (recrystallized
from hexane to give a white product); 1H NMR (300 MHz, CDCl3) δ
8.28 (d, J = 7.2 Hz, 2H), 8.19 (dd, J = 7.5, 1.2 Hz, 1H), 7.95 (dd, J =
8.1, 1.2 Hz, 1H), 7.69−7.64 (m, 2H), 7.59−7.54 (m, 2H), 7.43 (t, J =
7.8 Hz, 1H), 4.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 183.3,
164.9, 153.8, 153.6, 136.5, 133.2, 130.6, 129.9 (2C), 128.51, 128.48
(2C), 128.2, 123.7, 116.1, 114.9, 52.5; IR (CDCl3) νmax 3072, 2954,
1721, 1650, 1600, 1556, 1296, 1217, 1143 cm−1; HRMS (ES+) m/z
calculated for C17H13O4 [M + H]+, 281.0814; found, 281.0800.
(5,6-Dimethoxy-3-phenylbenzofuran-2-yl)(phenyl)-
methanone 31. Following the general procedure for direct arylation,
a mixture of (5,6-dimethoxybenzofuran-2-yl)(phenyl)methanone 23
(282 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was
stirred for 16 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 80:20 to 75:25) to afford the
desired product 31 (279 mg, 0.78 mmol, 78%) as a brown solid: mp
109 °C (recrystallized from hexane to give a yellow powder); 1H NMR
(300 MHz, CDCl3) δ 7.84 (d, J = 6.9 Hz, 2H), 7.49−7.41 (m, 3H),
7.40−7.30 (m, 5H), 7.13 (s, 1H), 6.99 (s, 1H), 3.99 (s, 3H), 3.90 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 184.8, 151.8, 150.2, 147.9, 146.9,
137.6, 132.2, 131.3, 130.5, 129.8 (2C), 129.7 (2C), 128.3 (2C), 128.2,
127.9 (2C), 120.1, 101.7, 95.0, 56.4 (2C); IR (CDCl3) νmax 2963, 2940,
2836, 1637, 1552, 1492, 1302, 1256, 1223, 1135 cm−1; HRMS (ES+)
m/z calculated for C23H19O4 [M + H]+, 359.1283; found, 359.1288.
Phenyl(5,6,7-trimethoxy-3-phenylbenzofuran-2-yl)-
methanone 32. Following the general procedure for direct arylation,
a mixture of phenyl(5,6,7-trimethoxybenzofuran-2-yl)methanone 24
(312 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was
stirred for 16 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 95:5 to 85:15) to afford the
desired product 32 (332 mg, 0.86 mmol, 86%) as a brown solid: mp
131.5, 130.7 (2C), 129.64 (2C), 129.57, 129.1, 127.9 (2C), 127.7, 127.1
(2C), 117.4, 105.1, 103.9, 55.5; IR (CDCl3) νmax 3063, 2965, 2944, 1643,
1602, 1501, 1370, 1267, 1254, 1098 cm−1; HRMS (ES+) m/z calculated
for C22H17O3 [M + H]+, 329.1178; found, 329.1168.
(4-Hydroxy-3-phenylbenzofuran-2-yl)(phenyl)methanone
35.41 Following the general procedure for direct arylation, a mixture
of (4-hydroxybenzofurane-2-yl)(phenyl)methanone 27 (186 mg,
0.78 mmol) and bromobenzene (0.165 mL, 1.56 mmol) was stirred
for 16 h. The residue was purified by flash chromatography over silica
gel (cyclohexane/ethyl acetate 98:2 to 95:5) to afford the desired
product 35 (102 mg, 0.33 mmol, 42%) as a brown solid: mp 181 °C
(recrystallized from hexane to give a yellow powder); 1H NMR (300 MHz,
CDCl3) δ 7.88 (d, J = 7.2 Hz, 2H), 7.53−7.34 (m, 9H), 7.22 (d, J = 7.8
Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.26 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 185.0, 155.5, 152.1, 146.4, 137.0, 132.7, 131.3, 129.7 (2C),
129.6, 129.5 (2C), 129.0 (2C), 128.98, 128.1 (2C), 127.9, 116.1,
109.3, 104.7; IR (CDCl3) νmax 3066, 3032, 1648, 1598, 1558, 1499,
1273, 1171, 1043 cm−1; HRMS (ES+) m/z calculated for C21H15O3
[M + H]+, 315.1017; found, 315.1017.
(4,6-Dimethyl-3-phenylbenzofuran-2-yl)(phenyl)methanone
36. Following the general procedure for direct arylation, a mixture of
(4,6-dimethylbenzofuran-2-yl)(phenyl)methanone 28 (250 mg, 1.00
mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for 16 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 97:3) to afford a mixture of the starting
material 28 and the desired product 36 (254 mg, 28/36 = 1.99
1
determined by H NMR, calculated yield: 33% of 36 and 65% of 28)
as a yellow liquid: 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 6.9 Hz,
2H), 7.50−7.44 (m, 1H), 7.38−7.33 (m, 7H), 7.29 (s, 1H), 6.89 (s,
1H), 2.48 (s, 3H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.2,
155.1, 147.4, 138.9, 137.4, 134.0, 132.8, 132.3, 130.6, 130.0 (2C),
129.6 (2C), 127.9 (2C), 127.85, 127,80 (2C), 127.1, 124.4, 109.9,
21.8, 19.4; IR (CDCl3) νmax 3064, 3029, 2924, 1643, 1556, 1364, 1269,
1234 cm−1; HRMS (ES+) m/z calculated for C23H19O2 [M + H]+,
327.1385; found, 327.1392.
1
113 °C (recrystallized from hexane to give yellow crystals); H NMR
(300 MHz, CDCl3) δ 7.90 (d, J = 6.9 Hz, 2H), 7.51−7.47 (m, 3H),
7.44−7.35 (m, 5H), 6.73 (s, 1H), 4.25 (s, 3H), 3.97 (s, 3H), 3.86 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 184.8, 151.9, 147.5, 141.8, 141.6,
139.1, 137.3, 132.5, 130.9, 129.9, 129.8 (2C), 129.7 (2C), 128.4 (2C),
128.3, 128.0 (2C), 124.2, 96.2, 61.6, 60.9, 56.4; IR (CDCl3) νmax
3053, 3011, 2986, 2940, 1645, 1462, 1423, 1376, 1264, 1238,1137,
1048 cm−1; HRMS (ES+) m/z calculated for C24H21O5 [M + H]+,
389.1389; found, 389.1370.
Phenyl(4,5,6-trimethoxy-3-phenylbenzofuran-2-yl)-
methanone 33. Following the general procedure for direct arylation,
a mixture of phenyl(4,5,6-trimethoxybenzofuran-2-yl)methanone 25
(312 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was
Methyl 2-benzoyl-3-phenylbenzofuran-7-carboxylate 38.
Following the general procedure for direct arylation, a mixture of
methyl 2-benzoylbenzofuran-7-carboxylate 30 (280 mg, 1.00 mmol) and
bromobenzene (0.21 mL, 2.00 mmol) was stirred for 16 h. The residue
was purified by flash chromatography over silica gel (cyclohexane/ethyl
acetate 95:5) to afford the desired product 38 (315 mg, 0.89 mmol,
89%) as a brown solid: mp 124 °C (recrystallized from hexane to give a
1
yellow powder); H NMR (300 MHz, CDCl3) δ 8.21 (dd, J = 7.5,
1.2 Hz, 1H), 8.17 (d, J = 7.2 Hz, 2H), 7.90 (dd, J = 7.8, 1.2 Hz, 1H), 7.58−
7.54 (m, 3H), 7.48−7.41 (m, 6H), 4.04 (s, 3H); 13C NMR (75 MHz,
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Article
CDCl3) δ 184.3, 165.0, 152.5, 147.8, 136.9, 133.0, 130.7, 130.7, 130.4, 130.3
(2C), 129.9 (2C), 129.8, 128.9, 128.6, 128.4 (2C), 128.1 (2C), 123.7,
116.0, 52.4; IR (CDCl3) νmax 3069, 3032, 2954, 1720, 1651, 1298, 1215,
1141 cm−1; HRMS (ES+) m/z calculated for C23H16O4Na [M + Na]+,
379.0946; found, 379.0941.
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́
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
C
spectra for new compounds are included. This material is
available free of charge via the Internet at http://pubs.acs.org.
Gorelsky, S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047−1060.
(17) For intramolecular arylation: (a) Huang, Q.; Fazio, A.; Dai, G.;
Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460−7461.
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Angew. Chem., Int. Ed. 2009, 48, 572−577. (e) Romagnoli, R.; Baraldi,
P. G.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez, O.; Tolomeo, M.;
Grimaudo, S.; Cristina, A. D.; Pipitone, M. R.; Balzarini, J.; Zonta, N.;
Brancale, A.; Hamel, E. Bioorg. Med. Chem. 2009, 17, 6862−6871.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: emmanuel.bertounesque@curie.fr.
■
ACKNOWLEDGMENTS
■
This work was financially supported by the Centre National de
la Recherche Scientifique, the Institut Curie, and the Agence
Nationale de la Recherche (Grant ANR-08-PCVI-0031-
CHEMISPIKE).
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