Regioselective preparation of benzo[b]furans from Phenols and α-Bromoketones

Article abstract of DOI:10.1021/jo201841y

In this paper, a fully regiocontrolled synthesis of either 2- and 3-substituted benzo[b]furans is described. Direct reaction between phenols and α-bromoacetophenones in the presence of neutral alumina yields 2-substituted benzo[b]furans with complete regiocontrol. When a basic salt such as potassium carbonate is used, the corresponding 2-oxoether is obtained. Cyclization of these latter compounds promoted by neutral alumina yields the corresponding 3-substituted benzo[b]furans. Using the former method, Moracin M and other analogues can be obtained from commercial sources in two preparative steps. DFT calculations provide reasonable reaction paths to understand the formation of 2-substituted benzo[b]furans.

Full text of DOI:10.1021/jo201841y

Article
pubs.acs.org/joc
Regioselective Preparation of Benzo[b]furans from Phenols and
α-Bromoketones
Leire Arias,† Yosu Vara,‡ and Fernando P. Cossío*,†
†Departamento de Química Organ
(UPV/EHU), Manuel de Lardizabal Etorbidea 3, 20018 San Sebastian
‡Ikerchem S. L., Paseo Mikeletegi 69, 20009 San Sebastian
− Donostia, Spain
́
ica I − Kimika Organikoa I Saila, Universidad del País Vasco − Euskal Herriko Unibertsitatea
− Donostia, Spain.
́
́
S
* Supporting Information
ABSTRACT: In this paper, a fully regiocontrolled synthesis of
either 2- and 3-substituted benzo[b]furans is described. Direct
reaction between phenols and α-bromoacetophenones in the
presence of neutral alumina yields 2-substituted benzo[b]furans
with complete regiocontrol. When a basic salt such as potassium
carbonate is used, the corresponding 2-oxoether is obtained.
Cyclization of these latter compounds promoted by neutral
alumina yields the corresponding 3-substituted benzo[b]furans.
Using the former method, Moracin M and other analogues can be
obtained from commercial sources in two preparative steps. DFT
calculations provide reasonable reaction paths to understand the
formation of 2-substituted benzo[b]furans.
bonds (Scheme 1). The corresponding synthetic equivalents
are an ortho-unsubstituted phenol 1 and a α-bromoacetophe-
INTRODUCTION
■
Benzo[b]furans have attracted considerable interest because of
the presence of these heterocycles in natural products,1 biologically
active compounds,2 and other molecules of pharmaceutical
interest.3 In particular, 2-aryl benzo[b]furans possessing methoxy
and/or hydroxy groups are attractive compounds because of
their wide spectrum of biological activity, which includes anti-
cancer,4 antioxidative,5 and anti-inflammatory6 properties.
Most of the convergent syntheses of 2-aryl benzo[b]furans
require carbonyl compounds and ortho-functionalized phenols
or phenoxy derivatives. These ortho functionalities include
bromo,7 formyl,8 and trimethylsilyl groups.9 In contrast, the
reported methods involving ortho-unsubstituted phenols are
quite scarce. These methods involve intramolecular cyclizations
of previously formed aryl ethers or sigmatropic rearrangements.10
Recently, Jing et al. have reported a convergent synthesis of
3-substituted benzo[b]furans via a one-pot reaction between
phenols and α-bromoacetophenones in the presence of Al2O3.10e
In this paper, we present a convergent and regiocontrolled
method for the synthesis of either 2-and 3-substituted
benzo[b]furans involving ortho-unsubstituted phenols or
naphthols and α-bromoacetophenones. This method provides
a general entry to these important compounds starting from
readily available reactants. In addition, we provide a rationale
of the role of alumina in this reaction on the basis of DFT
calculations.
Scheme 1. Convergent Synthesis of 2- and 3-Substituted
Benzo[b]furans via Formation of O1−C2 and C3−C3a
Bonds
none 2. In the case of reactants 1, the position(s) at which
electron-releasing group(s) is/are installed on the reacting
aromatic system may have an influence on the activation of
the corresponding ortho-centers (Scheme 1). The main issue
RESULTS AND DISCUSSION
■
The synthesis method described in this work relies on the
double nucleophilic/electrophilic character of the reactants and
on the double disconnection of the O1−C2 and C3−C3a
Received: September 12, 2011
Published: November 28, 2011
© 2011 American Chemical Society
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Article
associated with this approach is the control of the
regioselectivity of the process in order to obtain either 2- or
3-substituted benzo[b]furans using the same reactants as
starting materials.
When the reaction is carried out in refluxing xylene in the pre-
sence of neutral alumina, we have found that only the correspond-
ing 2-substituted benzo[b]furans are formed (Scheme 2, Table 1).
tolerates electron-releasing and electron-withdrawing groups
(Compounds 3g−j). In addition, a pyridyl group can also be
incorporated into the reaction product (Table 1, compound 3k).
In order to verify the regiochemistry of these compounds, the
structure of known compound 3a (see the Experimental Section)
was unambiguously determined by X-ray diffraction analysis
(see the Supporting Information).
Resorcinol 1b reacts under these conditions to yield only
products resulting from the reaction with 1 equiv of 2a,b (Table 1,
entries 4 and 5). Attempts to obtain the products associated
with the double condensation reaction met with no success.
In addition, analysis of the reaction mixtures did not permit
the detection of the regioisomers associated with the formation
of the regioisomer in which the furan ring is fused at the ortho
position in between the two oxygen atoms of resorcinol.
Deprotection of the two methoxy groups of 3d led to the
formation of natural product Moracin M11 in a two-step
synthesis from resorcinol and 2b (Scheme 3).
Scheme 2. Preparation of 2-Substituted Benzo[b]furans
3a−n from Phenols 1a−c and α-Bromoacetophenones
2a−i in the Presence of Neutral Alumina
Scheme 3. Preparation of Moracin M from 3d
Quite surprisingly, 3,4,5-trimethoxyphenol 1c in which there
is an additional activating methoxy group led to the
corresponding 2-substituted benzo[b]furans 3l−n in low yields
(Table 1, entries 12−14).
We also performed the same reaction but using potassium
carbonate as additive instead of alumina. Under these
moderately basic conditions, the corresponding ethers12 were
obtained in good to excellent yields (Scheme 4, Table 2). In
contrast with the preceding reaction, microwave irradiation
gave better yields and lower reaction times with respect to
thermal heating. Thus, the reaction in acetone in a sealed vessel
with an external bath at 130 °C required 3 h to complete,
whereas microwave irradiation under the same conditions
required only 20 min. In general, the yields of the isolated pure
products 5 were good, with the exception of compounds 5i and
5j (Table 2, entries 9 and 10, respectively). When the reaction
involved α-methyl bromoacetophenone 2k, the corresponding
ether 5h was obtained in good yield (Table 2, entry 8).
The possible 3-substituted regioisomers were not detected in
the crude reaction mixtures. The yields were, in general, mode-
rate but acceptable given the availability of the starting materials.
These yields did not improve significantly when microwave
irradiation was used instead of thermal heating. Phenol itself
and phenols incorporating electron-withdrawing groups did not
react under these conditions. On the contrary, the best results
were obtained when electron-releasing methoxy groups were
present in the starting phenol 1. The aryl group of reactant 2
Table 1. Synthesis of of 2-Substituted Benzo[b]furans 3a−n from Phenols 1a−c and α-Bromoacetophenones 2a−i
a
entry
reaction
R1
R2
R3
X
R4
R5
R6
yield (%)
1
1a + 2a → 3a
1a + 2b → 3b
1a + 2c → 3c
1b + 2b → 3d
1b + 2a → 3e
1a + 2d → 3f
1a + 2e → 3g
1a + 2f → 3h
1a + 2g → 3i
1a + 2h → 3j
1a + 2i → 3k
1c + 2b → 3l
1c + 2c → 3m
1c + 2a → 3n
OMe
OMe
OMe
OH
H
OMe
OMe
OMe
H
CH
H
OMe
H
H
50
86
75
26
32
25
44
24
49
46
53
9
2
H
COMe
COMe
COMe
CH
OMe
OMe
OMe
H
H
3
H
OMe
H
H
4
H
H
5
OH
H
H
OMe
H
H
6
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
CH
OMe
H
OMe
H
7
H
CH
NO2
CN
F
8
H
CH
H
H
9
H
CH
H
H
10
11
12
13
14
H
CF
F
H
H
H
N
H
OMe
H
OMe
H
OMe
OMe
OMe
COMe
COMe
CH
OMe
OMe
H
OMe
OMe
H
11
10
H
a
Yield of isolated pure product after column chromatography.
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microwave irradiation, lower yields were obtained. Similarly,
reaction of ethers 5 in the presence of alumina in refluxing
xylene resulted in lower yields of products 4. Using the best
conditions (Scheme 4), the observed yields of pure products 4
were, in general, moderate with the exception of the densely
substituted compound 4g (Table 3, entry 7). In the case of 2,3-
disubstituted benzo[b]furan 4h (Table 3, entry 8), the yield was
moderate but acceptable given the availability of the starting
materials. Also in this case, the structure of known compound
4a (see the Experimental Section) was secured by X-ray
diffraction analysis (see the Supporting Information).
Scheme 4. Preparation of 3-Substituted Benzo[b]furans 4a−i
from Phenols 1a−d and α-Bromoacetophenones 2a−k via
Intermediate Williamson Synthesis of Ethers 5a−k
In order to get a better understanding of the distinct behavior
of these α-bromoketones in the presence or absence of Al2O3,
we performed computational studies to assess the electrophilic
behavior of α-bromoacetophenone in both cases. DFT13,14
studies at the B3LYP/6-31+G* level15 on the reaction paths
associated with the interaction between α-bromoacetophenone
2l and phenoxide anion generated in the presence of a base
(Figure 1) showed a low activation barrier for the SN2 process,
whereas the nucleophilic addition reaction resulted to be an
uphill process with no detectable transition structure. All our
attempts to locate saddle point TS1′ were unfruitful and spon-
taneously converged to TS1. Although in this latter stationary
point the bond distance between the nucleophilic oxygen atom
and the carbon atom of the carbonyl group of 2l was quite
short, harmonic analysis revealed that TS1 corresponds to a
true SN2 transition structure. This saddle point is associated
with the reaction between the oxygen atom of the phenoxide
anion (which is the harder nucleophilic center) and the elec-
trophilic methylene moiety of 2l. This result agrees with our
experimental findings because they suggest that in the absence
of alumina, only the SN2 process is energetically available, thus
resulting in the formation of ethers 5 and finally in their
Thermal heating of a dispersion of α-alkoxy ethers 5 in Al2O3
yielded the corresponding 3-aryl benzo[b]furans 4a−i (Scheme 4,
Table 3). When this cyclization was carried out under
Table 2. Synthesis of Ethers 5a−k from Phenols 1a−d and α-Bromoacetophenones 2a−k
a
entry
reaction
R1
R2
R3
X
R4
R5
R6
R7
yield (%)
1
1a + 2a → 5a
1a + 2b → 5b
1a + 2c → 5c
1a + 2g → 5d
1a + 2j → 5e
1a + 2f → 5f
1a + 2i → 5g
1a + 2k → 5h
1a + 2h → 5i
1c + 2j → 5j
1d + 2a → 5k
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Cl
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Cl
CH
H
OMe
H
H
H
H
H
H
H
H
H
Me
H
H
H
99
93
99
97
99
99
73
84
24
20
99
2
H
COMe
COMe
CH
OMe
OMe
H
H
3
H
OMe
F
H
4
H
H
5
H
COBn
CH
OBn
H
H
H
6
H
CN
OMe
H
H
7
H
N
H
OMe
H
8
H
CH
H
9
H
CF
F
H
H
10
11
OMe
H
COBn
CH
COBn
H
H
H
OMe
H
a
Yield of isolated pure product after column chromatography.
Table 3. Synthesis of of 3-Substituted Benzo[b]furans 4a−i from Ethers 5a−i
a
entry
reaction
R1
R2
R3
X
R4
R5
R6
R7
yield (%)
1
2
3
4
5
6
7
8
9
5a → 4a
5b → 4b
5c → 4c
5d → 4d
5e → 4e
5f → 4f
5g → 4g
5h → 4h
5i → 4i
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
CH
H
OMe
H
H
H
H
H
H
H
H
H
Me
H
70
54
50
37
26
42
12
40
68
COMe
COMe
CH
OMe
OMe
H
H
OMe
F
H
H
COBn
CH
OBn
H
H
H
CN
OMe
H
H
N
H
OMe
H
CH
H
CF
F
H
H
a
Yield of isolated pure product after column chromatography.
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Figure 3. (A) Fully optimized (B3LYP/6-31+G* level) structure of
benzophenone 2l bound to Al4O6, showing the electrostatic potential
projected onto the electron density. Negative and positive potentials
are given in red and blue, respectively. Bond distances are in Å. Values
in square brackets correspond to those of isolated 2l. (B) Kohn−Sham
LUMO of the 2l-Al4O6 complex. The preferential site of a nucleophilic
attack is shown. The NBO charges of the ipso-carbonyl and the α-
methylene groups (Ci and CαH2, respectively, in a.u.) are also given.
Figure 1. (A) Model SN2 and AdN2 reactions between phenoxide
anion and acetophenone 2l. (B) Fully optimized structure of TS1,
computed at the B3LYP/6-31+G* level of theory. Bond distances and
angle are given in Å and degrees, respectively. Reaction and activation
energies are given in kcal/mol and have been computed at the B3LYP/
6-31+G*+ΔZPVE level of theory.
carbonyl group because the charge of the corresponding carbon
atom is increased with respect to isolated 2l. In addition, the
LUMO of this complex is localized mainly on the carbonyl
group, thus suggesting that this will be the preferred electrophilic
center for the interaction with the nucleophile (Figure 3B).
A similar analysis of the interaction between phenol and
Al4O6 led to two possible structures (Figure 4). The neutral
transformation into the corresponding 3-substituted benzo[b]-
furans 4 (Scheme 4). However, the presence of alumina is
needed to promote the cyclization step via carbonyl activation
of compounds 5.
Previous computational studies on the reactivity of alumina16
reveal tetrahedral and cubic reactive sites for aluminum (Figure 2A
Figure 2. Tetrahedral (A) and cubic (B) environments for aluminum
in γ-Al2O3 surface. Aluminum and oxygen atoms are represented in
light blue and red, respectively. Structural data have been taken form
ref 16a.
Figure 4. Fully optimized (B3LYP/6-31+G* level of theory)
structures for phenol on tetrahedral Al4O6. Bond distances are given
in Å. Numbers in parentheses are the corresponding relative energies,
calculated at the B3LYP/6-31+G*+ΔZPVE level.
and B, respectively). First, we considered in our calculations a
tetrahedral environment for Al4O6, denoted as A in Figure 2.
We analyzed computationally the interaction of 2l with Al4O6
according to pattern A (Figure 2) as a simplified model for the
alumina surface. This complex showed an enlargement of both
the C−O and C−Br bond distances (Figure 3A), together with
a significant CO−Al interaction. As a result, the enhancement
of the electrophilicity of the Al4O6-2l complex is localized at the
hydroxyl structure denoted as A in Figure 4 is computed to be
significantly less stable than structure B, associated with a
proton transfer from phenol to the alumina surface. Therefore,
formation of phenoxide anion in the reaction media can occur
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in a significant extent. In the following part of this study, only
phenoxide nucleophile will be considered.
DFT exploration of the reaction paths between phenoxide
anion and 2l on Al2O6 led to two possible situations. When
pattern A (Figure 2) was considered, only transition structure
TS2 could be located, associated with a SN2 process (Figure 5).
associated with an addition reaction on the carbonyl group of
benzophenone and has an activation energy 6.4 kcal/mol lower
than that associated with TS2 (Figure 5). Therefore, we
conclude that in the presence of alumina, formation of the
AdN2 product 9a is strongly favored.
Next, we studied the cyclization step leading to the
precursors of benzo[b]furans 3. We found that the SN2
transition structure TS4a leads to intermediate 10a with a
calculated activation energy of 45.6 kcal/mol (Figure 6). This
Figure 5. Possible reaction paths for the interaction between
phenoxide and α-bromoacetophenone 2l in Al4O6. Fully optimized
(B3LYP/6-31+G* level) structures of transition structures leading to
intermediates 8 and 9. Aluminum atoms are represented in light blue.
The Al4O6 clusters are represented in configurations (A) and (B),
together with the solvent accessible surfaces (probe radius: 1.4 Å).
In contrast, when the B environment (Figure 2) for alumina
was considered, another saddle point, denoted as TS3 in Figure 5,
was located and characterized. This latter transition structure is
Figure 6. Chief geometric features of transition structures TS4a,b,
associated with conversion of intermediates 9a,b into bicyclic
structures 10a,b, respectively.
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value is quite high and agrees with our experimental finding
that reaction between unsubstituted phenol and bromoaceto-
phenone in the presence of alumina does not lead to the
formation of 2-phenyl benzo[b]furan. However, adequately
located methoxy or hydroxy groups in the starting phenol can
promote the formation of the corresponding aromatic bicyclic
compounds 3. Our calculations on the SN2 process associated
with the transformation of intermediate 9b, with two methoxy
groups in ortho and para disposition with respect to the
reacting carbon atom, led to the formation of bicyclic interme-
diate 10b via TS4b, with an activation energy 6.3 kcal/mol
lower than that associated with the reaction of nonactivated
intermediate 9a (Figure 6).
Scheme 6. Reaction between Naphthols 1e,f and
α-Bromoacetophenone 2a
Therefore, on the basis of our DFT calculations, we propose
the mechanism outlined in Scheme 5 to explain the exclusive
Scheme 5. Proposed Mechanism for the Formation of
2-Substituted Benzo[b]furans 3
Scheme 7. Proposed Cyclic Intermediates for the Reaction
a
between Naphthol 1f and 2a
formation of 2-aryl benzo[b]furans 3: the reaction consists of a
stepwise process, in which the first step is a nucleophilic ad-
dition of the phenol on the carbonyl group of α-bromoacetophe-
none 2. The second step consists of an intramolecular SN2
process, where elimination of HBr and dehydration leads to the
formation of the corresponding product 3.
In the case of naphthols 1e,f (Scheme 6), no additional
activation of the aryl moiety is required. Thus, reaction between
α-naphthol 1e and 2a in the presence of alumina yields 3o,
whereas microwave irradiation in the presence of K2CO3 leads
to the formation of ether 5l. Cyclization of this latter
compound yields 4j, the 3-substituted analogue of 3o. In this
case, only one possibility exists to form the naphtho[1,2-b]-
furan scaffold, and both 2- and 3-(4-methoxyphenyl)
derivatives can be prepared from 1e and 2a. However, in
the case of β-naphthol 1f, two possible adducts can be
envisaged in its reaction with 2a in the presence of alumina.
Under these conditions, however, only compound 3p was
obtained in moderate yield, whereas the corresponding
naphtho[2,3-b]furan analogue 3p′ was not observed. This
result is compatible with the model proposed in Scheme 5
because in the cyclization step the intermediate leading to
3p preserves the aromaticity of one phenyl group in the
naphthol moiety (Scheme 7).
a
Only the resonance forms in which the aromaticity of one benzene
ring is preserved are shown.
CONCLUSIONS
■
In this paper, we describe a method for the preparation of
benzo[b]furans from α-bromoacetophenones and activated
phenols. When the reaction is carried out in the presence of
alumina, only the 2-substituted compounds are formed. The
corresponding 3-substituted derivatives can be obtained via a
two-step Williamson-cyclization sequence. Therefore, both
regioisomers can be obtained with complete control and from
the same readily available reactants. The reaction permits
the two-step preparation of natural product Moracin M. Both
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3.92 (s, 3H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.5,
157.4, 154.2, 151.6, 135.0, 132.8, 124.5, 119.1, 113.4, 110.8, 102.4,
95.0, 88.4, 56.1, 55.9. Calcd. for C17H13NO3: C, 73.1; H, 4.7; N, 5.0.
Found: C, 73.3; H, 5.0; N, 5.1.
2-(4-Fluorophenyl)-4,6-dimethoxybenzofuran, 3i. Yield = 49%.
White solid: mp 142−143 °C; IR 2914, 1614, 1496, 1220, 1145, 1116,
1043 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.74 (dd, J = 8.8, 5.4, 2H),
7.10 (t, J = 8.7, 2H), 6.96 (s, 1H), 6.68 (s, 1H), 6.33 (d, J = 1.7, 1H),
3.92 (s, 3H), 3.86 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 162.6 (d,
J = 247.7), 159.5, 156.8, 153.7, 153.0, 127.4 (d, J = 3.0), 126.2 (d, J =
8.0), 116.0 (d, J = 22.0), 113.5, 98.7, 94.6, 88.5, 56.0, 55.8. Calcd. for
C16H13FO3: C, 70.6; H, 4.8. Found: C, 70.3; H, 4.9.
α- and β-naphthols permit the preparation of naphthofurans
under these conditions and also with complete regiocontrol.
Finally, a model based on DFT calculations has been proposed
to understand the experimentally observed results.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Microwave irradiations
were conducted in a focused microwave reactor Biotage Initiator or
CEM Discover at the temperature, at the power, and for the time
indicated. All melting points are uncorrected. Column cromatog-
raphies were carried out with silica gel 60 (0.040−0.063 mm). The
aluminum oxide used was activated, neutral, Brockmann I, STD grade,
approx. 150 mesh, 58 Å. Reagents were purchased from commercial
suppliers or prepared following procedures described in the literature.
Some of the α-bromoketones 2 were prepared according to the
method reported by Chen et al.17
2-(3,5-Difluorophenyl)-4,6-dimethoxybenzofuran, 3j. Yield =
46%. Pale pink solid: mp 124−125 °C; IR 3084, 2884, 1598, 1466,
1
1338, 1224, 1145 cm−1; H NMR (500 MHz, CDCl3) δ 7.26 (d, J =
8.6, 2H), 7.06 (s, 1H), 6.71 (t, J = 8.8, 1H), 6.67 (s, 1H), 6.33 (s, 1H),
3.92 (s, 3H), 3.86 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 163.6 (dd,
J = 247.6, 13.1), 160.2, 157.0, 154.0, 151.5, 133.9 (t, J = 10.5), 113.2,
107.1 (dd, J = 20.7, 6.7), 103.0 (t, J = 25.6), 101.2, 94.9, 88.3, 56.0,
55.8. Calcd. for C16H12F2O3: C, 66.2; H, 4.2. Found: C, 66.2; H, 4.1.
3-(4,6-Dimethoxybenzofuran-2-yl)-2,6-dimethoxypyridine, 3k.
Yield = 53%. Pale pink solid: mp 155−156 °C; IR 2937, 2961, 1605,
1504, 1475, 1460, 1272, 1107, 1011 cm−1; 1H NMR (500 MHz,
CDCl3) δ 8.12 (d, J = 8.2, 1H), 7.18 (s, 1H), 6.66 (s, 1H), 6.41 (d, J =
8.2, 1H), 6.32 (s, 1H), 4.10 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.85 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 162.0, 159.1, 158.7, 156.0,
153.7, 149.5, 137.4, 113.9, 106.7, 101.7, 101.5, 94.4, 88.4, 56.0, 55.8,
53.8, 53.7. Calcd. for C17H17NO5: C, 64.8; H, 5.4; N, 4.4. Found: C,
64.9; H, 5.2; N, 4.3.
General Procedure for the Synthesis of 2-Aryl Benzo[b]-
furans 3a−n and Naphthofurans 3o−p. A mixture of the phenol
1 (3.0 mmol), the α-haloketone 2 (4.2 mmol), and neutral aluminum
oxide (21 mmol, 2.14 g) was refluxed in xylene (12 mL) for 16 h. The
resulting mixture was filtered through a Celite pad and evaporated.
The residue was purified by column chromatography on silica gel
using ethyl acetate/hexane as eluent to yield the corresponding
product 3.
4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran,18 3a. Yield =
1
50%. H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.8, 2H), 6.95
(d, J = 8.8, 2H), 6.89 (s, 1H), 6.69 (s, 1H), 6.32 (d, J = 1.6, 1H), 3.91
(s, 3H), 3.86 (s, 3H), 3.85 (s, 3H).
2-(3,5-Dimethoxyphenyl)-4,6-dimethoxybenzofuran,19 3b. Yield =
86%. 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 1H), 6.95 (s, 2H), 6.70
(s, 1H), 6.43 (s, 1H), 6.33 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.85
(s, 6H).
2-(3,5-Dimethoxyphenyl)- 4,5,6-trimethoxybenzofuran, 3l. Yield =
9%. Brown solid: mp 82−84 °C; IR 2938, 2836, 1594, 1414, 1125
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.05 (s, 1H), 6.94 (s, 2H), 6.83
(s, 1H), 6.43 (s, 1H), 4.12 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.85
(s, 6H); 13C NMR (126 MHz, CDCl3) δ 161.3, 154.2, 152.7, 152.0,
146.1, 137.5, 132.4, 115.0, 102.7, 100.8, 100.1, 90.8, 61.6, 60.8, 56.6,
55.6. Calcd. for C19H20O6: C, 66.3; H, 5.8. Found: C, 66.4; H, 5.8.
4,5,6-Trimethoxy-2-(3,4,5-trimethoxyphenyl)benzofuran, 3m.
Yield = 11%. White solid: mp 172−173 °C; IR 2940, 2836, 1415,
4,6-Dimethoxy-2-(3,4,5-trimethoxyphenyl)benzofuran, 3c. Yield =
75%. White solid: mp 131−132 °C; IR 2960, 1619, 1497, 1227, 1203,
1
1134, 1110 cm−1; H NMR (500 MHz, CDCl3) δ 7.04 (s, 2H), 7.00
(s, 1H), 6.74 (s, 1H), 6.36 (d, J = 1.8, 1H), 3.97 (s, 6H), 3.95
(s, 3H), 3.91 (s, 3H), 3.89 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
159.4, 156.7, 153.8, 153.8, 153.7, 138.4, 126.6, 113.5, 101.9, 98.7, 94.6,
88.5, 61.2, 56.4, 56.0, 55.8. Anal. Calcd. for C19H20O6: C, 66.3; H, 5.8.
Found: C, 66.0; H, 6.0.
1
1203, 1121 cm−1; H NMR (500 MHz, CDCl3) δ 7.01 (s, 2H), 6.99
(s, 1H), 6.85 (s, 1H), 4.13 (s, 3H), 3.95 (s, 6H), 3.92 (s, 3H), 3.89
(s, 3H), 3.88 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 154.3, 153.9,
152.6, 152.0, 146.1, 138.7, 137.7, 126.3, 115.3, 102.1, 99.3, 90.8, 61.6,
61.2, 60.9, 56.6, 56.5. Calcd. for C20H22O7: C, 64.1; H, 5.9. Found: C,
64.0; H, 5.8.
2-(3,5-Dimethoxyphenyl)benzofuran-6-ol,11a 3d. Yield = 26%.
1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 8.0, 1H), 7.01 (s, 1H),
6.97 (s, 2H), 6.92 (s, 1H), 6.77 (d, J = 7.9, 1H), 6.45 (s, 1H), 5.02
(s, 1H), 3.86 (s, 6H).
4,5,6-Trimethoxy-2-(4-methoxyphenyl)benzofuran, 3n. Yield =
2-(4-Methoxyphenyl)benzofuran-6-ol,19 3e. Yield = 32%. 1H
NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 7.76 (d, J = 8.7, 2H),
7.37 (d, J = 8.3, 1H), 7.09 (s, 1H), 7.03 (d, J = 8.8, 2H), 6.93 (s, 1H),
6.73 (dd, J = 8.3, 1.9, 1H), 3.81 (s, 3H).
10%. White solid: mp 120−121 °C; IR 2937, 2836, 1587, 1467,
1
1247, 1127 cm−1; H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.7,
2H), 6.96 (d, J = 8.7, 2H), 6.92 (s, 1H), 6.83 (s, 1H), 4.12 (s, 3H),
3.91 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 159.9, 154.6, 152.1, 151.9, 145.9, 137.5, 126.1, 123.7, 115.4, 114.5,
97.9, 90.9, 61.6, 60.8, 56.6, 55. 6. Calcd. for C18H18O5: C, 68.8; H, 5.8.
Found: C, 68.5; H, 5.8.
2-(2,5-Dimethoxyphenyl)-4,6-dimethoxybenzofuran, 3f. Yield =
25%. Pale pink solid: mp 82−83 °C; IR 2896, 1604, 1503, 1212, 1130
1
cm−1; H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 3.0, 1H), 7.37
(s, 1H), 6.89 (d, J = 8.9, 1H), 6.80 (dd, J = 8.9, 3.0, 1H), 6.69 (s, 1H),
6.31 (d, J = 1.6, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.84
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.5, 155.9, 153.9, 150.7,
150.0, 120.5, 114.1, 114.0, 112.5, 111.7, 104.2, 94.4, 88.3, 56.1, 56.1,
56.0, 55.8. Calcd. for C18H18O5: C, 68.8; H, 5.8. Found: C, 68.9; H,
5.7.
2-(4-Methoxyphenyl)naphtho[1,2-b]furan,20 3o. Yield = 41%.
1
Light brown solid: H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.2,
1H), 7.92 (d, J = 8.2, 1H), 7.88 (d, J = 8.8, 2H), 7.64 (s, 2H), 7.59
(t, J = 7.6, 1H), 7.47 (t, J = 7.5, 1H), 7.02 (d, J = 8.8, 2H), 7.00
(s, 1H), 3.88 (s, 3H).
2-(4-Methoxyphenyl)naphtho[2,1-b]furan,21 3p. Yield = 53%.
1
4,6-Dimethoxy-2-(4-nitrophenyl)benzofuran, 3g. Yield = 44%.
White solid: H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 8.2, 1H),
Orange solid: mp 192−193 °C; IR 2943, 2914, 1594, 1504, 1319,
7.93 (d, J = 8.1, 1H), 7.84 (d, J = 8.9, 2H), 7.67 (d, J = 2.6, 2H), 7.57
(t, J = 7.0, 1H), 7.47 (t, J = 7.0, 1H), 7.37 (s, 1H), 6.99 (d, J = 8.8,
2H), 3.86 (s, 3H).
1
1145, 1104 cm−1; H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 8.8,
2H), 7.88 (d, J = 8.8, 2H), 7.24 (s, 1H), 6.69 (s, 1H), 6.34 (s, 1H),
3.93 (s, 3H), 3.88 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 160.3,
156.7, 153.6, 150.6, 146.1, 135.9, 124.5, 124.4, 112.4, 104.0, 95.0, 88.5,
55.8, 55.7. Calcd. for C16H13NO5: C, 64.2; H, 4.4; N, 4.7. Found: C,
64.2; H, 4.3; N, 4.6.
General Procedure for the Synthesis of α-Phenoxyketones
5a−j and α-Naphthoxyketone 5l.12 A mixture of the phenol or
naphthol 1 (2 mmol), the α-haloketone 2 (2 mmol) and potassium
carbonate (4 mmol, 0.55 g) in acetone (2 mL) was irradiated with
microwaves at 130 °C and 100−400 W for 10 min (pressure 5−10
bar) in a focused Biotage Initiator microwave reactor. The resulting
mixture was filtered through a Celite pad and evaporated. The residue
was purified by precipitation in diethylether or by column chromatography
4-(4,6-Dimethoxybenzofuran-2-yl)benzonitrile, 3h. Yield = 24%.
Yellow solid: mp 220−221 °C; IR 3042, 2955, 2223, 1600, 1507, 1217,
1
1145, 1104 cm−1; H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.2,
2H), 7.67 (d, J = 8.3, 2H), 7.18 (s, 1H), 6.68 (s, 1H), 6.34 (s, 1H),
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Article
on silica gel using ethyl acetate/hexane as eluent to yield the cor-
responding product 5.
(s, 1H), 6.96 (d, J = 8.8, 2H), 6.82 (s, 2H), 5.20 (s, 2H), 3.88 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 191.8, 164.5, 159.4, 135.7, 130.6,
2-(3,5-Dimethoxyphenoxy)-1-(4-methoxyphenyl)ethanone,22
5a. Yield = 99%. 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.9, 2H),
6.96 (d, J = 8.9, 2H), 6.13 (d, J = 2.1, 2H), 6.11 (t, J = 2.0, 1H), 5.15
(s, 2H), 3.88 (s, 3H), 3.75 (s, 6H).
127.5, 122.1, 114.4, 114.2, 70.9, 55.7. Calcd. for C15H12Cl2O3: C, 57.9;
H, 3.9. Found: C, 58.1; H, 4.0.
1-(4-Methoxyphenyl)-2-(naphthalen-1-yloxy)ethanone,20 5l. Yield =
70%. White solid: 1H NMR (200 MHz, CDCl3) δ 8.44−8.27 (m, 1H),
7.85 (d, J = 7.7, 2H), 7.76−7.64 (m, 1H), 7.47−7.30 (m, 3H), 7.21 (t,
J = 7.9, 1H), 6.74 (d, J = 7.7, 2H), 6.62 (d, J = 7.5, 1H), 5.16 (s, 2H),
3.62 (s, 3H).
2-(3,5-Dimethoxyphenoxy)-1-(3,5-dimethoxyphenyl)ethanone,
5b. Yield = 93%. Yellow solid: mp 104−105 °C; IR 2931, 1709, 1209,
1160,1023 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 2.2, 2H),
6.69 (t, J = 2.2, 1H), 6.13 (d, J = 1.9, 2H), 6.12 (d, J = 1.9, 1H), 5.18
(s, 2H), 3.84 (s, 6H), 3.76 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
194.0, 161.8, 161.3, 160.1, 136.6, 106.3, 106.1, 94.1, 71.0, 55.8, 55.6.
Calcd. for C18H20O6: C, 65.0; H, 6.1. Found: C, 65.0; H, 6.1.
2-(3,5-Dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)ethanone,
5c. Yield = 99%. White solid: mp 86−87 °C; IR 2937, 1703, 1203,
1148, 1130, 1075 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.27 (s, 2H),
6.13 (d, J = 1.9, 2H), 6.12 (d, J = 1.9, 1H), 5.16 (s, 2H), 3.93 (s, 3H),
3.91 (s, 6H), 3.76 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 193.4,
161.8, 160.1, 153.5, 143.6, 129.9, 106.1, 94.1, 94.0, 71.1, 61.1, 56.6,
55.6. Calcd. for C19H22O7: C, 63.0; H, 6.1. Found: C, 62.8; H, 6.2.
2-(3,5-Dimethoxyphenoxy)-1-(4-fluorophenyl)ethanone,10c 5d.
General Procedure for the Synthesis of 3-Aryl Benzo[b]-
furans 4a−i and Naphthofuran 4j. The α-phenoxyketone or
α-naphthoxyketone 5 (2.0 mmol) was dispersed in neutral alumina
(34 mmol, 3.47 g) and heated in an oil bath at 150 °C (internal
temperature monitored by a fiber optic probe) for 3 h. The resulting
mixture was filtered through a Celite pad and evaporated. The residue
was purified by column chromatography on silica gel using ethyl
acetate/hexane as eluent to yield the corresponding product 4.
4,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran,22 4a. Yield =
1
78%. H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.7, 2H), 7.43
(s, 1H), 6.93 (d, J = 8.7, 2H), 6.67 (d, J = 1.8, 1H), 6.35 (d, J = 1.7,
1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H).
1
Yield = 97%. H NMR (500 MHz, CDCl3) δ 8.06 (dd, J = 8.1, 5.6,
3-(3,5-Dimethoxyphenyl)-4,6-dimethoxybenzofuran, 4b. Yield =
54%. White solid: mp 92−93 °C; IR 2834, 1590, 1415, 1201, 1141,
1082 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 6.82 (s, 2H),
6.68 (s, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 3.86 (s, 3H), 3.83 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 160.6, 159.4, 158.1, 154.8, 140.3, 134.4,
123.0, 109.9, 107.6, 99.9, 94.9, 88.7, 55.9, 55.6, 55.6. Calcd. for
C18H18O5: C, 68.8; H, 5.8. Found: C, 68.7; H, 5.8.
2H), 7.19 (t, J = 8.4, 2H), 6.15 (s, 3H), 5.18 (s, 2H), 3.78 (s, 6H).
1-(3,5-bis(Benzyloxy)phenyl)-2-(3,5-dimethoxyphenoxy)-
ethanone, 5e. Yield = 99%. White solid: mp 125 °C; IR 2914, 1703,
1201, 1166, 1070 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38 (ddd, J =
26.6, 13.5, 7.0, 10H), 7.20 (d, J = 2.2, 2H), 6.84 (t, J = 2.2, 1H), 6.12
(s, 3H), 5.15 (s, 2H), 5.08 (s, 4H), 3.75 (s, 6H); 13C NMR (126 MHz,
CDCl3) δ 193.8, 161.8, 160.4, 160.1, 136.6, 136.5, 128.9, 128.4, 127.8,
107.9, 107.3, 94.1, 94.0, 70.9, 70.7, 55.6. Calcd. for C30H28O6: C, 74.4;
H, 5.8. Found: C, 74.3; H, 5.8.
4,6-Dimethoxy-3-(3,4,5-trimethoxyphenyl)benzofuran, 4c. Yield
1
= 50%. Yellow oil: IR 2934, 1580, 1414, 1215, 1150, 1120 cm−1; H
NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 6.89 (s, 2H), 6.68 (d, J = 1.9,
1H), 6.38 (d, J = 1.9, 1H), 3.90 (s, 9H), 3.87 (s, 3H), 3.84 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 159.4, 158.2, 154.7, 153.0, 140.0, 128.0,
123.1, 109.8, 106.8, 94.9, 88.7, 61.2, 56.3, 56.0, 55.6.
4-(2-(3,5-Dimethoxyphenoxy)acetyl)benzonitrile, 5f. Yield =
99%. Yellow solid: mp 116−117 °C; IR 2885, 2229, 1706, 1215,
1157 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 8.3, 2H), 7.79
(d, J = 8.3, 2H), 6.12 (d, J = 1.8, 1H), 6.09 (d, J = 1.8, 2H), 5.16
(s, 2H), 3.75 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 194.0, 162.0,
159.7, 137.8, 132.8, 129.0, 117.9, 117.3, 94.2, 94.0, 71.3, 55.6. Calcd.
for C17H15NO4: C, 68.7; H, 5.1; N, 4.7. Found: C, 68.7; H, 5.0; N, 4.8.
2-(3,5-Dimethoxyphenoxy)-1-(2,6-dimethoxypyridin-3-yl)-
ethanone, 5g. Yield = 73%. White solid: mp 108−109 °C; IR 2919,
1683, 1590, 1336, 1167, 1155, 1088 cm−1; 1H NMR (500 MHz,
CDCl3) δ 8.27 (d, J = 8.4, 1H), 6.42 (d, J = 8.4, 1H), 6.12 (d, J = 1.9,
2H), 6.10 (d, J = 1.9, 1H), 5.17 (s, 2H), 4.10 (s, 3H), 4.00 (s, 3H),
3.76 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 192.0, 166.4, 162.8,
161.7, 160.5, 143.4, 111.0, 103.7, 94.1, 93.6, 73.9, 55.5, 54.3, 54.2.
Calcd. for C17H19NO6: C, 61.2; H, 5.8; N, 4.2. Found: C, 61.3; H, 5.7;
N, 4.2.
3-(4-Fluorophenyl)-4,6-dimethoxybenzofuran,10c 4d. Yield =
1
37%. H NMR (500 MHz, CDCl3) δ 7.56 (dd, J = 8.2, 5.7, 2H),
7.44 (s, 1H), 7.07 (t, J = 8.6, 2H), 6.67 (s, 1H), 6.35 (s, 1H), 3.85
(s, 3H), 3.79 (s, 3H).
3-(3,5-bis(Benzyloxy)phenyl)-4,6-dimethoxybenzofuran, 4e.
Yield = 26%. Yellow oil: IR 2935, 1585, 1453, 1213, 1144, 1050
1
cm−1; H NMR (500 MHz, CDCl3) δ 7.48 (s, 1H), 7.46−7.26 (m,
10H), 6.92 (d, J = 2.2, 2H), 6.66 (d, J = 1.9, 1H), 6.62 (t, J = 2.2, 1H),
6.35 (d, J = 1.8, 1H), 5.07 (s, 4H), 3.84 (s, 3H), 3.76 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 159.8, 159.4, 158.1, 154.8, 140.4, 137.3,
134.5, 128.8, 128.2, 127.7, 123.0, 109.9, 108.8, 101.6, 94.9, 88.7, 70.4,
56.0, 55.6.
4-(4,6-Dimethoxybenzofuran-3-yl)benzonitrile, 4f. Yield = 42%.
Yellow solid: mp 151−152 °C; IR 2938, 2220, 1598, 1503, 1215, 1044,
1085 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0, 2H), 7.66
(d, J = 8.2, 2H), 7.54 (s, 1H), 6.69 (s, 1H), 6.38 (s, 1H), 3.87 (s, 3H),
3.82 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.8, 158.3, 154.6,
140.9, 137.6, 131.9, 129.9, 121.9, 119.3, 110.7, 109.2, 95.2, 88.7, 56.0,
55.6. Calcd. for C17H13NO3: C, 73.1; H, 4.7; N, 5.0. Found: C, 73.1;
H, 4.6; N, 5.1.
2-(3,5-Dimethoxyphenoxy)-1-phenylpropan-1-one,23 5h. Yield =
84%. 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.3, 2H), 7.61−7.53
(m, 1H), 7.46 (t, J = 7.3, 2H), 6.06 (d, J = 0.6, 3H), 5.45 (q, J = 6.7,
1H), 3.71 (s, 3H), 3.70 (s, 3H), 1.68 (dd, J = 6.8, 1.0, 3H).
1-(3,5-Difluorophenyl)-2-(3,5-dimethoxyphenoxy)ethanone, 5i.
Yield = 24%. Yellow solid: mp 92−93 °C; IR 2847, 1713, 1309, 1203,
1
1150, 1056 cm−1; H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 5.6,
2H), 7.06 (t, J = 8.2, 1H), 6.13 (s, 1H), 6.11 (s, 2H), 5.12 (s, 2H), 3.76
(s, 6H); 13C NMR (126 MHz, CDCl3) δ 192.6, 163.3 (dd, J = 251.5,
11.7), 161.9, 159.7, 137.5 (t, J = 7.7), 111.5 (dd, J = 20.1, 6.6), 109.4
(t, J = 25.3), 94.3, 94.0, 71.2, 55.6. Calcd. for C16H14F2O4: C, 62.3; H,
4.6. Found: C, 62.3; H, 4.5.
3-(4,6-Dimethoxybenzofuran-3-yl)-2,6-dimethoxyppyridine, 4g.
Yield = 12%. Light yellow solid: mp 131 °C; 2943, 1586, 1481, 1315,
1
1080, 1023 cm−1; H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0,
1H), 7.58 (s, 1H), 6.67 (s, 1H), 6.36 (d, J = 8.0, 1H), 6.32 (s, 1H),
3.97 (s, 3H), 3.95 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 162.3, 160.3, 159.2, 157.5, 154.8, 143.1, 141.4, 116.0,
110.9, 106.8, 100.1, 94.8, 88.6, 56.0, 55.6, 53.8, 53.6. Calcd. for
C17H17NO5: C, 64.8; H, 5.4; N, 4.4. Found: C, 64.6; H, 5.5; 4.5.
4,6-Dimethoxy-2-methyl-3-phenylbenzofuran,10c,24 4h. Yield =
40%. 1H NMR (500 MHz, CDCl3) δ 7.47−7.27 (m, 5H), 6.63 (s, 1H),
6.30 (s, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 2.39 (s, 3H).
1-(3,5-bis(Benzyloxy)phenyl)-2-(3,4,5-trimethoxyphenoxy)-
ethanone, 5j. Yield = 20%. White solid: mp 111 °C; IR 2942, 1704,
1
1289, 1152, 1020 cm−1; H NMR (500 MHz, CDCl3) δ 7.50−7.29
(m, 10H), 7.22 (s, 2H), 6.86 (s, 1H), 6.19 (s, 2H), 5.16 (s, 2H), 5.08
(s, 4H), 3.82 (s, 6H), 3.78 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
194.1, 160.4, 154.8, 154.0, 136.5, 136.4, 133.3, 128.9, 128.5, 127.8,
107.7, 107.3, 93.1, 71.4, 70.6, 61.2, 56.4. Calcd. for C31H30O7: C, 72.4;
H, 5.9. Found: C, 72.1; H, 5.6.
3-(3,5-Difluorophenyl)-4,6-dimethoxybenzofuran, 4i. Yield =
68%. Light yellow solid: mp 102−103 °C; IR 2937, 1591, 1501,
1
1444, 1354, 1217, 1113 cm−1; H NMR (300 MHz, CDCl3) 7.49
2-(3,5-Dichlorophenoxy)-1-(4-methoxyphenyl)ethanone, 5k.
Yield = 99%. Pale pink solid: mp 95−96 °C; IR 2838, 1691, 1241,
1085 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.9, 2H), 6.96
(s, 1H), 7.20−7.11 (m, 2H), 6.75 (tt, J = 9.0, 2.3, 1H), 6.66 (d, J = 1.9,
1H), 6.36 (d, J = 1.9, 1H), 3.84 (s, 3H), 3.82 (s, 3H); 13C NMR
273
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(75 MHz, CDCl3) 162.82 (dd, J = 246.5, 13.3), 159.7, 158.2, 154.6,
140.7, 135.8 (t, J = 10.6), 121.5, 112.2 (dd, J = 8.1, 17.4), 109.2, 102.4
(t, J = 25.5), 95.1, 88.6, 55.9, 55.5. Calcd. for C16H12F2O3: C, 66.2; H,
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3-(4-Methoxyphenyl)naphtho[1,2-b]furan,20,22 4j. Yield = 16%.
1
Yellow solid: H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 8.2, 1H),
7.95 (d, J = 8.1, 1H), 7.87 (s, 1H), 7.85 (d, J = 8.7, 1H), 7.71 (d, J =
8.6, 1H), 7.61 (t, J = 9.0, 3H), 7.65−7.58 (m, 1H), 7.04 (d, J = 8.5,
2H), 3.88 (s, 3H).
Moracin M.11 Boron tribromide (1 M in dichloromethane, 1.2
mL, 1.2 mmol, 2 equiv per methoxy group to be deprotected) was
added dropwise to a solution of benzofuran 3d (0.3 mmol) in an-
hydrous dichloromethane (10 mL) at 0 °C under argon atmosphere.
The mixture was stirred for 16 h at room temperature, and then me-
thanol (1.2 mL) was added dropwise at 0 °C.25 The resulting mixture
was purified by column chromatography on silica gel using ethyl
1
acetate/hexane 1:1 as eluent to yield the product. Yield = 25%. H
NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.37 (s, 2H), 7.38 (d, J =
8.4, 1H), 7.06 (s, 1H), 6.92 (s, 1H), 6.74 (d, J = 8.3, 1H), 6.68 (s, 2H),
6.21 (s, 1H).
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of new compounds,
crystallographic data of compounds 3a and 4a, and computa-
tional data of stationary points 2l + phenoxide, TS1, 6, 7, TS2,
TS3, 9a, 9b, TS4a, and TS4b. This material is available free of
charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail: fp.cossio@ehu.es.
■
ACKNOWLEDGMENTS
■
We thank the Spanish MICINN (Grants CTQ2010-16959 and
Ingenio-Consolider CSD2007-00006) and the Basque Govern-
ment (GV-EJ, Grant IT-324-07) for financial support. L.A.
thanks the MICINN for a Ph.D. fellowship. Technical and
human support provided by SGIker (UPV/EHU, MICINN,
GV/EJ, ESF) is gratefully acknowledged.
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Kang, J. E.; Lee, W. S.; Park, K. H. J. Agric. Food Chem. 2009, 57,
1195−1203.
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