Transition-Metal-Free Synthesis of 2-Substituted Methyl Benzo[b]furan-3-carboxylates

Article abstract of DOI:10.1021/acs.joc.5b01311

A concise and highly efficient synthetic pathway was developed for 2-substituted methyl benzo[b]furan-3-carboxylates. This method provides convenient and cost-effective access for 2-substituted methyl benzo[b]furan-3-carboxylates without the use of a transition metal catalyst for synthesis. Furthermore, in most cases, this method gives excellent yields and conventional flash column chromatography is not needed for purification.

Full text of DOI:10.1021/acs.joc.5b01311

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The Journal of Organic Chemistry
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Transition Metalꢀfree Synthesis of 2ꢀSubstituted Methyl
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Benzo[b]furanꢀ3ꢀcarboxylates
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Byungsoo Kang, Min Hyung Lee, Mijung Kim, Jungwoon Hwang, Hyeong Baik Kim, and Dae Yoon
Chi*
Department of Chemistry, Sogang University, 35 Baekbeomro Mapogu, Seoul 121ꢀ742, Korea
dychi@sogang.ac.kr
ABSTRACT
A concise and highly efficient synthetic pathway was developed for 2ꢀsubstituted methyl benzo[b]furanꢀ
3ꢀcarboxylates. This method provides convenient and costꢀeffective access for 2ꢀsubstituted methyl
benzo[b]furanꢀ3ꢀcarboxylates without the use of a transition metal catalyst for synthesis. Furthermore,
in most cases, this method gives excellent yields and conventional flash column chromatography is not
needed for purification.
Introduction
The 2,3ꢀdisubstituted benzo[b]furan is a common structure found in numerous natural products. These
compounds are known for their various biological activities1 and there extensive interest for their
synthesis (Figure 1).2,3
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Figure 1. Representative examples of naturally occurring compounds containing 2,3ꢀsubstituted
benzo[b]furan structure.
Among the many strategies for the synthesis of the 2,3ꢀdisubstituted benzo[b]furan skeleton, the most
common and widely used method is by transition metal catalyzed cyclization of 2ꢀalkynylphenols.4
Other popular methods employ Pdꢀcatalyzed crossꢀcoupling of C2ꢀhalogenated or stannylated
benzo[b]furans with aryl boronic acids or aryl halides5 or direct arylation of C2ꢀ or C3ꢀsubstituted
benzo[b]furans with aryl halides6 utilizing CꢀH activation. Oxidative crossꢀcoupling reactions at the C2
position of benzo[b]furan7 and other methods8 have also been reported recently. Although these
methods give generally reasonable results, they require expensive transition metal catalysts for reactions
and/or additional purification procedures. For the synthesis of indoles which are nitrogen analogue of
benzo[b]furan, the original or modified Madelung indole synthesis9 can be used. However, these
Madelungꢀtype methods generally required harsh conditions and it could not be used to synthesize the
analogous benzo[b]furans. To overcome these shortcomings of previous synthetic strategies, we focused
to devise a more effective cyclization reaction for 2,3ꢀdisubstituted benzo[b]furans without transition
metal catalysts. The retrosynthetic strategies focused on affordable and highly effective synthetic
approach for the desired product (Scheme 1).
Scheme 1. Retrosynthetic Analysis for 2-Substituted Methyl Benzo[b]furan-3-carboxylate
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Herein is reported a simple approach toward the synthesis of 2,3ꢀdisubstituted benzo[b]furans without
the use of transition metal catalysts. We believe this may be a more useful and costꢀeffective strategy for
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the synthesis of 2,3ꢀdisubstituted benzo[b]furans (Scheme 2).
Scheme 2. Comparison Between Pd-catalyzed Cyclization and This Work
Results and Discussion
To investigate the scope of this synthetic strategy, substrates 2aꢀl having various substituents were
selected. The substituents encompass aryl groups containing the electronꢀwithdrawing or donating
groups in different positions and aliphatic groups with an acidic αꢀproton. The starting material, ethyl 2ꢀ
hydroxyphenylacetate (1), was obtained from a Fischer esterification reaction (90% yield) using
commercially available 2ꢀhydroxyphenylacetic acid, anhydrous ethanol and concentrated sulfuric acid.
The substrates 2aꢀl were prepared using modified Steglich esterification10 conditions which is initially
employed the DCCꢀmediated coupling reaction of an alcohol and a carboxylic acid catalyzed by DMAP
(Table 1).
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Table 1. Synthesis of Various Ethyl (2-Acyloxyphenyl)acetates
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3
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product
2a
R
yield (%)a
Ph
92
93
93
97
83
96
91
92
pꢀMeOC6H4
mꢀMeOC6H4
oꢀMeOC6H4
3,4ꢀ(MeO)2C6H3
pꢀFC6H4
2b
2c
2d
2e
2f
pꢀBrC6H4
2ꢀnaphthyl
2g
2h
79
2i
iꢀBu
96
96
94
2j
cyclopropyl
2k
cyclohexyl
2l
aIsolated yield.
In the early stage of study, we used acid chlorides for esterifications of the phenols. However, we
found that the crude products were always contaminated with small amount of impurities when acid
chlorides were used for esterification and it rendered the purification very laborious. Thus, we decided
to use DCC couplings of phenols and carboxylic acids for the acylation of the phenols and it gave better
results. However, to obtain pure products from the DCC coupling reaction mixtures, careful column
chromatography procedures were required for the removal of dicyclohexylurea, which is an inevitable
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byꢀproduct formed from DCC. For simple purification of products, we replaced DCC with 1ꢀethylꢀ3ꢀ(3ꢀ
1
2
3
dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl). We found that the products from these
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8
modified conditions were sufficiently pure after filtration through a small plug of silica gel such that
excellent yields were obtained and no additional purification procedures were required.
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To investigate the optimum reaction conditions for baseꢀmediated cyclization of substrate 2,
compound 2b was selected and various bases and temperature conditions were tested. The result of the
optimization for 3ꢀ(hydroxyl(4ꢀmethoxyphenyl)methylene)benzo[b]furanꢀ2(3H)ꢀone is illustrated on
Table 2. Under the condition of entry 1, side products 1, 4 and 5 were isolated, purified and confirmed
by the NMR comparison of identical compounds independently prepared from other routes. To
minimize the side products, further study focused on lowering the reaction temperature with potassium
tꢀbutoxide and substituting potassium tꢀbutoxide with other bases (sodium hydride, lithium
bis(trimethylsilyl)amide). Among these entries, entry 3 gave the best result. Under these conditions,
NMR spectra revealed that the desired product 3b was the sole product of the crude reaction mixture.
Table 2. Optimization of Synthesis of (Z)-3-(Hydroxyl(4-methoxyphenyl)methylene)benzo[b]furan
-2(3H)-one (3b)a
ratio of products (%)b
entry base
tꢀBuOKc
T (°C)
3b
70
1
4
5
1
0 to rt
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3
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tꢀBuOKc
tꢀBuOKc
NaHd
ꢀ25 to 0
ꢀ78 to 0
0 to rt
76
100
78
12
0
12
0
0
0
1
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5
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7
8
11
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0
NaHd
ꢀ78 to 0
82
0
9
LiHMDSc 0 to rt
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13
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LiHMDSc ꢀ78 to 0
73
7
aAll reactions were carried out in 1.0 mmol scale of 2b with 3 equiv of base in 3 mL of anhydrous THF.
bDetermined by integration of 1H NMR. cUsed 1.0 M solution in THF. d60% dispersion in mineral oil.
Early reaction optimization for 3ꢀ(hydroxyl(alkyl)methylene)benzo[b]furanꢀ2(3H)ꢀone was conducted
with an excess amount (3.0 equiv) of tꢀBuOK. However, additional investigations on the stoichiometry
of base revealed that a reduced amount of base has no detrimental effect. A slight excess amount (1.1
equiv) of tꢀBuOK gave comparable results with the original conditions.
Applying this standard condition to the substrates 2aꢀl, gave excellent yields of 3ꢀ
(hydroxyl(alkyl)methylene)benzo[b]furanꢀ2(3H)ꢀone products for all entries (Table 3).
Table 3. Synthesis of Various 3-(Hydroxyl(alkyl)methylene)benzo[b]furan-2(3H)-ones
product
3a
R
yield (%)a
Ph
87
89
86
77
82
66
pꢀMeOC6H4
mꢀMeOC6H4
oꢀMeOC6H4
3,4ꢀ(MeO)2C6H3
pꢀFC6H4
3b
3c
3d
3e
3f
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pꢀBrC6H4
85
3g
3h
1
2
3
4
5
6
2ꢀnaphthyl
88
76
3i
7
8
9
iꢀBu
91
88
87
3j
3k
3l
10
11
12
13
14
cyclopropyl
cyclohexyl
aIsolated yield.
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All products could be obtained as purified solids after recrystallization at low temperature (ꢀ20 °C).
According to the NMR spectra of these products, they existed as enol tautomers almost exclusively and
there was little detectable keto tautomer in each.
To elucidate the structure of 3ꢀ
(hydroxyl(alkyl)methylene)benzo[b]furanꢀ2(3H)ꢀone more clearly, we analyzed the crystal structure of
compound 3h using a single crystal Xꢀray crystallography technique. (See supporting information for
detailed XꢀRay crystallographic structure analysis for compound 3h.)
The compounds 3aꢀl were subjected to the methanolysis and dehydrative cyclization process in the
presence of concentrated sulfuric acid to give methyl 2ꢀsubstituted benzo[b]furanꢀ3ꢀcarboxylates 6aꢀl
(Table 4). In case of R = aryl, the reaction was completed within 6 h. If R = alkyl, the reaction required
longer reaction time (12 h) for completion. In the case of 3i, which has a conjugated system, it required
the longest reaction time (24 h) among these entries.
Table 4. Synthesis of Various 2-Substituted Methyl Benzo[b]furan-3-carboxylates
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product
6a
R
yield (%)a
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Ph
90
92
91
90
92
90
91
87
pꢀMeOC6H4
mꢀMeOC6H4
oꢀMeOC6H4
3,4ꢀ(MeO)2C6H3
pꢀFC6H4
6b
6c
6d
6e
6f
pꢀBrC6H4
2ꢀnaphthyl
6g
6h
89
6i
iꢀBu
85
87
88
6j
6k
6l
cyclopropyl
cyclohexyl
aIsolated yield.
This procedure proceeded very cleanly and gave excellent yields and satisfactory purities of products
without additional purification procedures. After simple recrystallization of crude products, analytical
grade products could be obtained easily. The products 6d and 6j, which are oily compounds at rt and
therefore impossible to be recrystallized, were purified by column chromatography to obtain analytical
grade samples.
Scheme 3. Plausible Mechanism for the Sythesis of 2-Substituted Methyl Benzo[b]furan-3-
carboxylates
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R
OEt
O
OEt
O
O
O
OEt
O
O
OEt
O
1
2
3
4
5
6
t-BuOK
O
O
O
R
O
O
R
O
R
O
R
O
9
2
7
8
tautomerize
7
8
9
R
R
H+
CO2Me
R
O
OH
O
CO2Me
OH
H+
H
10
11
12
13
14
15
16
17
CO2Me
OH
MeOH
-H2O
R
O
O
O
6
11
10
3
A plausible reaction mechanism for the transformation from 2 to 6 was illustrated on Scheme 3. The
proton abstraction from ester 2 gave hemiketal anion 7. The hemiketal anion 7 transformed to βꢀ
ketoester 8, whose phenolic residue attacked another ester group to give the 3ꢀacylbenzo[b]furanꢀ2(3H)ꢀ
one 9. The resulting 3ꢀacylbenzo[b]furanꢀ2(3H)ꢀone 9 is immediately tautomerized to give tautomer 3
as a sole product. The enol 3 underwent methanolysis in the presence of methanol and concentrated
sulfuric acid to give intermediate 10. The phenolic oxygen next attacked the carbonyl group of ketone to
give the hemiketal 11. The hemiketal 11 was dehydrated spontaneously in the presence of concentrated
sulfuric acid to give the desired 2ꢀsubstituted methyl benzo[b]furanꢀ3ꢀcarboxylate 6.
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Conclusion
A new method for synthesizing 2ꢀsubstituted methyl benzo[b]furanꢀ3ꢀcarboxylate derivatives has
been developed using mild conditions without using any transition metal catalysts. The method is
applicable to the preparation of various alkyl or aryl groups at the C2. Since our synthetic strategy
allows simultaneous installation of a carbonyl substituent at C3 and an alkyl or aryl substituent at C2, it
can be used to introduce other moieties. The products were obtained from 2ꢀhydroxyphenylacetic acid
in four steps in very high overall yield. Moreover, in most cases, our strategy has no complicated
purification procedure and does not need laborious column chromatography to obtain pure products.
Experimental Section
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General Information
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All reactions were conducted under inert atmosphere unless otherwise stated. For air and moisture
sensitive reactions, all glassware are dried in an convection oven and flameꢀdried. All solvents and
reagents for reaction were purchased from the chemical supplier and used as received. Analytical thin
layer chromatography (TLC) was carried out using commercial silica gel 60 TLC plates. NMR spectra
were acquired from 400 and 500 MHz spectrometer and chemical shifts were reported as parts per
million (ppm) relative to the solvent residual peak (CDCl3 = 7.26 ppm for 1H NMR, 77.16 ppm for 13C
NMR). Coupling constants were reported in Hertz (Hz). Multiplicities of NMR spectra are reported
using the following general abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. All melting point values are uncorrected. The high resolution mass spectra were obtained from an
ESI+ quadrupole timeꢀofꢀflight (QꢀTOF) mass spectrometer.
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Ethyl 2-Hydroxyphenylacetate (1). The mixture of 2ꢀhydroxyphenylacetic acid (2.0 g, 13.1 mmol)
and concentrated sulfuric acid (ca. 3 mL) in anhydrous ethanol (50 mL) was heated under reflux for 12
h. The resulting mixture was concentrated in vacuo and diluted with dichloromethane (20 mL). The
organic layer was washed with water (10 mL x 3), dried over anhydrous MgSO4 and concentrated under
reduced pressure. The resulting residue was filtered through a small plug of silica gel with a mixture of
EtOAc and nꢀhexane (1:2) to give the product as a lowꢀmelting white solid (2.13 g, 90%): 1H NMR (400
MHz, CDCl3) δ 7.67 (s, 1H), 7.21–7.14 (m, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.94–6.85 (m, 2H), 4.21 (q, J
= 7.1 Hz, 2H), 3.69 (s, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.0, 155.1,
1
13
131.0, 129.1, 120.8, 120.7, 117.3, 61.9, 37.7, 14.1. H and C NMR spectral data are consistent with
previously reported values.11
Ethyl (2-Benzoyloxy)phenylacetate (2a). The mixture of ethyl 2ꢀhydroxyphenylacetate (3.60 g, 20.0
mmol), benzoic acid (2.44 g, 20.0 mmol) and DMAP (0.489 g, 4.00 mmol) was suspended in anhydrous
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dichloromethane (100 mL). EDCI∙HCl (4.21 g, 22.0 mmol) was added to this mixture and stirred for 12
1
2
3
4
5
6
7
8
9
h at rt. The reaction mixture was diluted with dichloromethane and the organic layer was washed with
0.5 N aqueous HCl solution and water followed by a saturated aqueous sodium bicarbonate solution.
The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting
residue was filtered through a small plug of silica gel with a mixture of EtOAc and nꢀhexane (1:2) to
give the product as a colorless oil (5.16 g, 92%): 1H NMR (400 MHz, CDCl3) δ 8.24–8.17 (m, 2H), 7.64
(t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.28–7.22 (m, 2H), 4.05 (q, J = 7.1
Hz, 2H), 3.63 (s, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 164.6, 149.3,
133.7, 131.4, 130.2, 129.3, 128.7, 128.6, 126.8, 126.2, 122.7, 61.0, 36.6, 14.0. HRMS (ESI+): calcd. for
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+
C17H16NaO4 [M + Na]+: 307.0946, found 307.0942; Anal. Calcd. For C17H16O4: C, 71.82; H, 5.67,
found: C, 71.83; H, 5.68.
Ethyl 2-(4-Methoxybenzoyloxy)phenylacetate (2b). The title compound 2b (1.62 g, 93%) was
obtained from 1 (1.00 g, 5.55 mmol) and pꢀanisic acid (0.842 g, 5.55 mmol) as a colorless oil using a
procedure analogous to that described for the preparation of 2a: 1H NMR (400 MHz, CDCl3) δ 8.20 (d,
J = 8.9 Hz, 2H), 7.39 (dd, J = 13.3, 4.4 Hz, 2H), 7.30–7.24 (m, 2H), 7.03 (d, J = 8.9 Hz, 2H), 4.10 (q, J
= 7.1 Hz, 2H), 3.90 (s, 3H), 3.67 (s, 2H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7,
164.3, 163.9, 149.4, 132.3, 131.3, 128.4, 126.9, 126.0, 122.7, 121.5, 113.9, 60.9, 55.5, 36.5, 14.0.
+
HRMS (ESI+): calcd. for C18H18NaO5 [M + Na]+: 337.1052, found 337.1046; Anal. calcd. for
C18H18O5: C, 68.78; H, 5.77, found: C, 68.86; H, 5.73.
Ethyl 2-(3-Methoxybenzoyloxy)phenylacetate (2c). The title compound 2c (1.62 g, 93%) was
obtained from 1 (1.00 g, 5.55 mmol) and mꢀanisic acid (0.842 g, 5.55 mmol) as a colorless oil using a
procedure analogous to that described for the preparation of 2a: 1H NMR (400 MHz, CDCl3) δ 7.81 (d,
J = 7.7 Hz, 1H), 7.74–7.69 (m, 1H), 7.45–7.34 (m, 3H), 7.28–7.23 (m, 2H), 7.22–7.16 (m, 1H), 4.07 (q,
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J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.63 (s, 2H), 1.13 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ
1
2
3
170.7, 164.5, 159.7, 149.3, 131.3, 130.5, 129.6, 128.5, 126.8, 126.2, 122.6, 122.5, 120.2, 114.5, 61.0,
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5
6
+
55.5, 36.5, 14.0. HRMS (ESI+): m/z calcd. for C18H18NaO5 [M + Na]+: 337.1052, found 337.1046;
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Anal. calcd. for C18H18O5: C, 68.78; H, 5.77, found: C, 68.82; H, 5.74.
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Ethyl 2-(2-Methoxybenzoyloxy)phenylacetate (2d). The title compound 2d (1.93 g, 97%) was
obtained from 1 (1.14 g, 6.30 mmol) and oꢀanisic acid (1.05 g, 6.43 mmol) as a pale yellow oil using a
procedure analogous to that described for the preparation of 2a: 1H NMR (400 MHz, CDCl3) δ 8.05 (dd,
J = 7.6, 1.3 Hz, 1H), 7.56 (td, J = 8.2, 1.7 Hz, 1H), 7.40–7.33 (m, 2H), 7.30–7.22 (m, 2H), 7.06 (t, J =
7.9 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 3.70 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 170.9, 164.0, 159.8, 149.4, 134.4, 132.3, 131.2, 128.4, 126.8, 126.0, 122.9, 120.2,
+
118.9, 112.1, 60.9, 56.0, 36.3, 14.1. HRMS (ESI+): m/z calcd. for C18H18NaO5 [M + Na]+: 337.1052,
found 337.1047; Anal. calcd. for C18H18O5: C, 68.78; H, 5.77, found: C, 68.79; H, 5.76.
Ethyl 2-(3,4-Dimethoxybenzoyloxy)phenylacetate (2e). The title compound 2e (1.57 g, 83%) was
obtained from 1 (1.00 g, 5.55 mmol) and 3,4ꢀdimethoxybenzoic acid (1.01 g, 5.55 mmol) as a white
solid using a procedure analogous to that described for the preparati
n of 2a: mp 76ꢀ77 °C; 1H NMR
o
(400 MHz, CDCl3) δ 7.87 (dd, J = 8.4, 1.6 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.36 (t, J = 7.3 Hz, 2H),
7.27–7.22 (m, 2H), 6.96 (d, J = 8.5 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.98 – 3.95 (overlapped s, 6H),
3.62 (s, 2H), 1.13 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 164.4, 153.6, 149.4, 148.8,
131.4, 128.6, 126.9, 126.1, 124.5, 122.8, 121.7, 112.4, 110.4, 61.0, 56.2, 56.1, 36.6, 14.1. HRMS
+
(ESI+): m/z calcd. for C19H20NaO6 [M + Na]+: 367.1158, found 367.1152; Anal. calcd. for C19H20O6: C,
66.27; H, 5.85, found: C, 66.27; H, 5.88.
Ethyl 2-(4-Fluorobenzoyloxy)phenylacetate (2f). The title compound 2f (1.61 g, 96%) was obtained
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from 1 (1.00 g, 5.55 mmol) and 4ꢀfluorobenzoic acid (0.777 g, 5.55 mmol) as a pale yellow oil using a
1
2
3
1
procedure analogous to that described for the preparation of 2a: H NMR (400 MHz, CDCl3) δ 8.26–
4
5
6
8.17 (m, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.24 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 8.6 Hz, 2H), 4.04 (q, J = 7.1
7
8
13
1
Hz, 2H), 3.61 (s, 2H), 1.11 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ 170.7, 166.3 (d, JCꢀF
=
9
3
4
255.2 Hz), 163.7, 149.2, 132.9 (d, JCꢀF = 9.5 Hz) 131.5, 128.6, 126.8, 126.3, 125.6 (d, JCꢀF = 3.0 Hz),
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59
60
2
+
122.6, 115.9 (d, JCꢀF = 22.1 Hz), 61.0, 36.6, 14.1. HRMS (ESI+): m/z calcd. for C17H15FNaO4 [M +
Na]+: 325.0852, found 325.0847; Anal. calcd. for C17H15FO4: C, 67.54; H, 5.00, found: C, 67.54; H,
5.05.
Ethyl 2-(4-Bromobenzoyloxy)phenylacetate (2g). The title compound 2g (1.83 g, 91%) was
obtained from 1 (1.00g, 5.55 mmol) and 4ꢀbromobenzoic acid (1.11 g, 5.55 mmol) as a white solid
using a procedure analogous to that described for the preparation of 2a: mp 50ꢀ51 °C; 1H NMR (400
MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.24 (t, J =
8.5 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.6, 164.0, 149.1, 132.0, 131.7, 131.5, 129.0, 128.6, 128.3, 126.8, 126.4, 122.6, 61.1, 36.6,
14.1. HRMS (ESI+): m/z calcd. for C17H15BrNaO4 [M + Na]+: 385.0051, found 385.0048; Anal. calcd.
+
for C17H15BrO4: C, 56.22; H, 4.16, found: C, 56.23; H, 4.15.
Ethyl 2-(2-Naphthoyloxy)phenylacetate (2h). The title compound 2h (1.71 g, 92%) was obtained
from 1 (1.00 g, 5.55 mmol) and 2ꢀnaphthoic acid (0.955 g, 5.55 mmol) as a white solid using a
1
procedure analogous to that described for the preparation of 2a: mp 90ꢀ91 °C. H NMR (400 MHz,
CDCl3) δ 8.82 (s, 1H), 8.25–8.19 (m, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 12.7, 8.4 Hz, 2H),
7.68–7.57 (m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.35–7.25 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.69 (s, 2H),
1.11 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 164.8, 149.4, 135.9, 132.5, 132.0, 131.5,
129.5 128.8, 128.6, 128.5, 127.9, 126.9, 126.9, 126.5, 126.3, 125.5, 122.8, 61.0, 36.7, 14.1. HRMS
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+
(ESI+): m/z calcd. for C21H18NaO4 [M + Na]+: 357.1103, found 357.1098; Anal. calcd. for C21H18O4: C,
1
2
3
75.43; H, 5.43, found: C, 75.43; H, 5.44.
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8
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Ethyl 2-(trans-4-Methoxycinnamoyloxy)phenylacetate (2i). The title compound 2i (1.49 g, 79%)
was obtained from 1 (1.00 g, 5.55 mmol) and transꢀ4ꢀmethoxycinnamic acid (0.989 g, 5.55 mmol) as a
faint yellow solid using a procedure analogous to that described for the preparation of 2a: mp 92ꢀ93 °C;
1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 15.9 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.34 (t, J = 7.7 Hz,
2H), 7.25–7.17 (m, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 15.9 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H),
3.86 (s, 3H), 3.61 (s, 2H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.0, 165.3, 161.9,
149.4, 146.6, 131.3, 130.2, 128.5, 127.0, 126.9, 126.1, 122.7, 114.6, 114.4, 61.1, 55.6, 36.6, 14.3.
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60
+
HRMS (ESI+): m/z calcd. for C20H20NaO5 [M + Na]+: 363.1208, found 363.1204; Anal. calcd. for
C20H20O5: C, 70.58; H, 5.92, found: C, 70.60; H, 5.89.
Ethyl (2-Isovaleroyloxy)phenylacetate (2j). The title compound 2j (1.41 g, 96%) was obtained from
1 (1.00 g, 5.55 mmol) and isovaleric acid (0.612 mL, 5.55 mmol) as a colorless oil using a procedure
analogous to that described for the preparation of 2a: 1H NMR (400 MHz, CDCl3) δ 7.34–7.27 (m, 2H),
7.20 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 2.46 (d, J = 7.2
13
Hz, 2H), 2.25 (sep, J = 6.8 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.06 (d, J = 6.7 Hz, 6H); C NMR (100
MHz, CDCl3) δ 171.2, 170.8, 149.2, 131.4, 128.5, 126.7, 126.1, 122.6, 61.0, 43.2, 36.5, 25.8, 22.5, 14.2.
+
HRMS (ESI+): m/z calcd. for C15H20NaO4 [M + Na]+: 287.1259, found 287.1255; Anal. calcd. for
C15H20O4: C, 68.16; H, 7.63, found: C, 68.10; H, 7.67.
Ethyl (2-Cyclopropanecarbonyloxy)phenylacetate (2k). The title compound 2k (1.32 g, 96%) was
obtained from 1 (1.00 g, 5.55 mmol) and cyclopropanecarboxylic acid (0.501 g, 5.82 mmol) as a
1
colorless oil using a procedure analogous to that described for the preparation of 2a: H NMR (400
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MHz, CDCl3) δ 7.33–7.27 (m, 2H), 7.19 (td, J = 7.6, 1.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 4.14 (q, J =
7.1 Hz, 2H), 3.56 (s, 2H), 1.89–1.80 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.21–1.16 (m, 2H), 1.06–1.00 (m,
1
2
3
4
5
6
13
2H); C NMR (100 MHz, CDCl3) δ 173.0, 170.8, 149.2, 131.3, 128.5, 126.7, 126.1, 122.5, 61.0, 36.5,
+
14.2, 13.0, 9.2. HRMS (ESI+): m/z calcd. for C14H16NaO4 [M + Na]+: 271.0946, found 271.0943; Anal.
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calcd. for C14H16O4: C, 67.73; H, 6.50, found: C, 67.73; H, 6.54.
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Ethyl (2-Cyclohexanecarbonyloxy)phenylacetate (2l). The title compound 2l (1.52 g, 94%) was
obtained from 1 (1.00 g, 5.55 mmol) and cyclohexanecarboxylic acid (0.745 g, 5.61 mmol) as a
1
colorless oil using a procedure analogous to that described for the preparation of 2a. H NMR (400
MHz, CDCl3) δ 7.33–7.27 (m, 2H), 7.23–7.16 (m, 1H), 7.07 (d, J = 8.1 Hz, 1H), 4.13 (q, J = 7.1 Hz,
2H), 3.54 (s, 2H), 2.57 (tt, J = 11.3, 3.6 Hz, 1H), 2.09 (dd, J = 13.1, 2.6 Hz, 2H), 1.87–1.79 (m, 2H),
13
1.73–1.66 (m, 1H), 1.59 (qd, J = 12.3, 3.1 Hz, 2H), 1.42–1.26 (m, 3H), 1.23 (t, J = 7.1 Hz, 3H); C
NMR (100 MHz, CDCl3) δ 174.1, 170.8, 149.3, 131.3, 128.5, 126.7, 126.0, 122.5, 61.0, 43.3, 36.4,
29.0, 25.8, 25.5, 14.2. HRMS (ESI+): m/z calcd. for C17H22NaO4 [M + Na]+: 313.1416, found 313.1413;
+
Anal. calcd. for C17H22O4: C, 70.32; H, 7.64, found: C, 70.33; H, 7.65.
3-(Hydroxyl(phenyl)methylene)benzo[b]furan-2(3H)-one (3a). A solution of 2a (1.00 g, 3.52
mmol) in anhydrous THF was cooled to ꢀ78 °C. A 1.0 M THF solution of tꢀBuOK (3.87 mL, 3.87
mmol) was added dropwise to this mixture. The reaction mixture was allowed to warm to 0 °C and
stirred additionally for 1 h at the same temperature. The reaction mixture was quenched with 1 N
aqueous HCl solution (5 mL) and diluted with dichloromethane. The aqueous layer was extracted with
dichloromethane (10 mL x 3). The combined organic layers were dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resulting crude residue was recrystallized with dichloromethane/nꢀ
hexane at ꢀ20 °C to give the product as a greenish yellow solid (0.731 g, 87%): mp 98ꢀ99 °C; 1H NMR
(400 MHz, CDCl3) δ 12.44 (br s, 1H), 7.82 (d, J = 7.3 Hz, 2H), 7.65ꢀ7.55 (m, 3H), 7.25–7.15 (m, 3H),
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7.00 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 174.4, 172.1, 150.7, 133.0, 132.4, 128.9, 128.4,
1
2
3
+
127.2, 123.9, 122.3, 120.0, 111.0, 97.9. HRMS (ESI+): m/z calcd. for C15H10NaO3 [M + Na]+:
4
5
6
261.0528, found 261.0523; Anal. calcd. for C15H10O3: C, 75.62; H, 4.23, found: C, 75.63; H, 4.25.
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3-(Hydroxyl(4-methoxyphenyl)methylene)benzo[b]furan-2(3H)-one (3b). The title compound 3b
(0.758 g, 89%) was obtained from 2b (1.00 g, 3.18 mmol) as a greenish yellow solid using a procedure
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1
analogous to that described for the preparation of 3a: mp 134ꢀ135 °C; H NMR (400 MHz, CDCl3) δ
12.50 (br s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.24ꢀ7.16 (m, 2H), 7.08–7.00 (m,
3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 172.3, 163.0, 150.5, 130.5, 126.8, 125.2, 123.8,
+
122.7, 119.8, 114.3, 111.0, 96.9, 55.7. HRMS (ESI+): m/z calcd. for C16H12NaO4 [M + Na]+: 291.0633,
found 291.0631; Anal. calcd. for C16H12O4: C, 71.64; H, 4.51, found: C, 71.67; H, 4.46.
3-(Hydroxyl(3-methoxyphenyl)methylene)benzofuran-2(3H)-one (3c). The title compound 3c
(0.734 g, 86%) was obtained from 2c (1.00 g, 3.18 mmol) as a greenish yellow solid using a procedure
1
analogous to that described for the preparation of 3a: mp 104ꢀ105 °C; H NMR (400 MHz, CDCl3) δ
12.43 (br s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.32–7.13 (m, 5H), 7.01 (td, J = 7.8,
1.3 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.4, 171.9, 159.9, 150.7, 134.1, 130.1,
127.2, 123.9, 122.2, 120.7, 120.2, 118.5, 113.2, 111.1, 98.0, 55.7. HRMS (ESI+): m/z calcd. for
+
C16H12NaO4 [M + Na]+: 291.0633, found 291.0628; Anal. calcd. for C16H12O4: C, 71.64; H, 4.51,
found: C, 71.62; H, 4.53.
3-(Hydroxyl(2-methoxyphenyl)methylene)benzofuran-2(3H)-one (3d). The title compound 3d
(0.658 g, 77%) was obtained from 2d (1.00 g, 3.18 mmol) as a greenish yellow solid using a procedure
1
analogous to that described for the preparation of 3a: mp 145ꢀ146 °C; H NMR (400 MHz, CDCl3) δ
12.06 (br s, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.14 (m, 4H), 6.95 (t, J = 7.2 Hz, 1H),
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6.60 (d, J = 7.7 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.8, 169.6, 157.0, 150.7, 133.1,
129.9, 126.8, 123.8, 122.7, 122.0, 121.0, 120.2, 111.7, 110.7, 99.9, 55.8. HRMS (ESI+): m/z calcd. for
1
2
3
4
5
6
+
C16H12NaO4 [M + Na]+: 291.0633, found 291.0629; Anal. calcd. for C16H12O4: C, 71.64; H, 4.51,
7
8
found: C, 71.65; H, 4.51.
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3-(3,4-Dimethoxyphenyl(hydroxyl)methylene)benzofuran-2(3H)-one (3e). The title compound 3e
(0.711 g, 82%) was obtained from 2e (1.00 g, 2.90 mmol) as a greenish yellow solid using a procedure
1
analogous to that described for the preparation of 3a: mp 142ꢀ143 °C; H NMR (400 MHz, CDCl3) δ
12.51 (br s, 1H), 7.50 (dd, J = 8.3, 1.8 Hz, 1H), 7.39–7.31 (m, 2H), 7.23–7.15 (m, 2H), 7.05–6.99 (m,
2H), 4.00 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 172.1, 152.6, 150.5, 149.1, 126.9,
125.2, 123.7, 122.6, 122.4, 119.9, 111.1, 110.9, 110.8, 96.9, 56.3, 56.2. HRMS (ESI+): m/z calcd. for
+
C17H14NaO5 [M + Na]+: 321.0739, found 321.0733; Anal. calcd. for C17H14O5: C, 68.45; H, 4.73,
found: C, 68.44; H, 4.73.
3-(4-Fluorophenyl(hydroxyl)methylene)benzo[b]furan-2(3H)-one (3f). The title compound 3f
(0.798 g, 66%) was obtained from 2f (1.44 g, 4.75 mmol) as a greenish yellow solid using a procedure
1
analogous to that described for the preparation of 3a: mp 122ꢀ123 °C; H NMR (400 MHz, CDCl3) δ
12.42 (br s, 1H), 7.85 (dd, J = 8.4, 5.4 Hz, 2H), 7.30–7.16 (m, 5H), 7.02 (t, J = 7.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 174.3, 170.8, 165.0 (d, 1JCꢀF = 254.0 Hz) 150.7, 130.9 (d, 3JCꢀF = 9.0 Hz), 129.1 (d,
2
4JCꢀF = 3.4 Hz), 127.4, 124.0, 122.1, 119.8, 116.3 (d, JCꢀF = 22.1 Hz), 111.2, 97.9. HRMS (ESI+): m/z
+
calcd. for C15H9FNaO3 [M + Na]+: 279.0433, found 279.0429; Anal. calcd. for C15H9FO3: C, 70.31; H,
3.54, found: C, 70.12; H, 3.59.
3-(4-Bromophenyl(hydroxyl)methylene)benzo[b]furan-2(3H)-one (3g). The title compound 3g
(0.740 g, 85%) was obtained from 2g (1.00 g, 2.75 mmol) as a bright yellow solid using a procedure
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1
analogous to that described for the preparation of 3a: mp 149ꢀ150 °C; H NMR (400 MHz, CDCl3) δ
1
2
3
4
12.38 (br s, 1H), 7.75–7.67 (m, 4H), 7.28–7.16 (m, 3H), 7.03 (t, J = 7.5 Hz, 1H); 13C NMR (100 MHz,
5
6
CDCl3) δ 174.3, 170.5, 150.8, 132.3, 131.8, 130.0, 127.6, 127.0, 124.0, 121.9, 119.9, 111.3, 98.3.
7
8
+
HRMS (ESI+): m/z calcd. for C15H8BrNaO3 [M – H + Na]+: 337.9555, found 337.9550; Anal. calcd. for
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C15H9BrO3: C, 56.81; H, 2.86, found: C, 56.81; H, 2.86.
3-(Hydroxyl(2-naphthyl)methylene)benzo[b]furan-2(3H)-one (3h). The title compound 3h (0.759
g, 88%) was obtained from 2h (1.00 g, 2.99 mmol) as a greenish yellow solid using a procedure
1
analogous to that described for the preparation of 3a: mp 135ꢀ137 °C; H NMR (400 MHz, CDCl3) δ
12.54 (s, 1H), 8.37 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.85 (dd, J = 8.5, 1.2 Hz,
13
1H), 7.69–7.59 (m, 2H), 7.27–7.19 (m, 3H), 7.02–6.95 (m, 1H); C NMR (100 MHz, CDCl3) δ 174.5,
172.1, 150.8, 135.1, 132.6, 130.2, 129.4, 129.0, 128.9, 128.5, 128.1, 127.3, 127.2, 124.5, 123.9, 122.4,
120.0, 111.1, 98.1. HRMS (ESI+): m/z calcd. for C19H12NaO3 [M + Na]+: 311.0684, found 311.0678;
+
Anal. calcd. for C19H12O3: C, 79.16; H, 4.20, found: C, 79.17; H, 4.20.
3-(Hydroxyl((E)-4-methoxystyryl)methylene)benzo[b]furan-2(3H)-one (3i). The title compound 3i
(0.656 g, 76%) was obtained from 2i (1.00 g, 2.94 mmol) as an orange solid using a procedure
1
analogous to that described for the preparation of 3a: mp 136ꢀ137 °C; H NMR (400 MHz, CDCl3) δ
11.78 (s, 1H), 7.75 (d, J = 15.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.49–7.43 (m, 1H), 7.26ꢀ7.12 (m, 3H),
7.02 (d, J = 15.5 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.0,
167.1, 162.0, 150.7, 142.1, 130.3, 127.6, 126.4, 124.2, 123.0, 120.5, 115.2, 114.7, 111.1, 97.5, 55.6.
+
HRMS (ESI+): m/z calcd. for C18H14NaO4 [M + Na]+: 317.0790, found 317.0785; Anal. calcd. for
C18H14O4: C, 73.46; H, 4.80, found: C, 73.45; H, 4.81.
3-(Hydroxyl(isobutyl)methylene)benzo[b]furan-2(3H)-one (3j). The title compound 3j (0.749 g,
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91%) was obtained from 2j (1.00 g, 3.78 mmol) as an offꢀwhite solid using a procedure analogous to
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that described for the preparation of 3a: mp 68ꢀ70 °C; H NMR (400 MHz, CDCl3) δ 12.06 (br s, 1H),
4
5
6
7.34 (d, J = 7.2 Hz, 1H), 7.27ꢀ7.15 (m, 3H), 2.64 (d, J = 7.3 Hz, 2H), 2.26 (sep, J = 6.8 Hz, 1H), 1.11ꢀ
7
8
13
1.05 (overlapped s, 6H); C NMR (100 MHz, CDCl3) δ 178.1, 173.6, 150.5, 126.5, 124.2, 122.8, 120.1,
9
+
111.1, 98.4, 42.6, 27.1, 22.7. HRMS (ESI+): m/z calcd. for C13H14NaO3 [M + Na]+: 241.0841, found
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241.0834; Anal. calcd. for C13H14O3: C, 71.54; H, 6.47, found: C, 71.55; H, 6.48.
3-(Cyclopropyl(hydroxyl)methylene)benzo[b]furan-2(3H)-one (3k). The title compound 3l (0.716
g, 88%) was obtained from 2l (1.00 g, 4.03 mmol) as a white solid using a procedure analogous to that
described for the preparation of 3a: mp 101ꢀ102 °C; 1H NMR (400 MHz, CDCl3) δ 12.13 (s, 1H), 7.50–
13
7.43 (m, 1H), 7.25–7.12 (m, 3H), 2.27–2.19 (m, 1H), 1.48–1.40 (m, 2H), 1.26–1.20 (m, 2H); C NMR
(100 MHz, CDCl3) δ 179.2, 173.4, 150.3, 126.0, 124.0, 123.3, 119.5, 111.0, 97.2, 14.5, 10.5. HRMS
(ESI+): m/z calcd. for C12H9NaO3 [M – H + Na]+: 224.0449, found 224.0447; Anal. calcd. for
+
C12H10O3: C, 71.28; H, 4.98, found: C, 71.28; H, 4.98.
3-(Cyclohexyl(hydroxyl)methylene)benzo[b]furan-2(3H)-one (3l). The title compound 3k (0.732 g,
87%) was obtained from 2k (1.00 g, 3.44 mmol) as a white solid using a procedure analogous to that
1
described for the preparation of 3a: mp 100ꢀ101 °C; H NMR (400 MHz, CDCl3) δ 12.13 (br s, 1H),
7.28 (d, J = 7.5 Hz, 1H), 7.25–7.13 (m, 3H), 2.88 (t, J = 11.8 Hz, 1H), 1.90 (d, J = 11.0 Hz, 4H), 1.78 (d,
13
J = 12.4 Hz, 1H), 1.70–1.60 (m, 2H), 1.47–1.25 (m, 3H); C NMR (100 MHz, CDCl3) δ 182.3, 174.0,
150.4, 126.3, 124.2, 122.7, 120.1, 111.1, 96.4, 42.6, 28.6, 26.0, 25.7. HRMS (ESI+): m/z calcd. for
+
C15H16NaO3 [M + Na]+: 267.0997, found 267.0992; Anal. calcd. for C15H16O3: C, 73.75; H, 6.60,
found: C, 73.74; H, 6.62.
Methyl 2-Phenylbenzo[b]furan-3-carboxylate (6a). 3a (0.500 g, 2.10 mmol) was suspended in
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anhydrous methanol (20 mL) and concentrated sulfuric acid (ca. 2 mL) was added carefully to this
mixture. The reaction mixture was heated under reflux for 6 h. The reaction mixture was cooled and
concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (20 mL)
and washed with saturated aqueous sodium bicarbonate solution (20 mL x 3). The organic layer was
dried under anhydrous MgSO4 and concentrated in vacuo. The resulting residue was recrystallized from
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nꢀhexane to give 6a (0.478 g, 90%) as a white solid: mp 79ꢀ80 °C (lit. mp4c,4e = 77–78 °C); H NMR
(400 MHz, CDCl3) δ 8.08–7.99 (m, 3H), 7.59–7.50 (m, 4H), 7.43–7.36 (m, 2H), 3.97 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.5, 160.9, 153.8, 130.3, 129.6, 129.5, 128.2, 127.0, 125.3, 124.1, 122.7, 111.2,
+
108.8, 51.7. HRMS (ESI+): m/z calcd. for C16H12NaO3 [M + Na]+: 275.0684, found 275.0679; Anal.
calcd. for C16H12O3: C, 76.18; H, 4.79, found: C, 76.15; H, 4.82. All spectral data are consistent with
previously reported values.4c,4e
Methyl 2-(4-Methoxyphenyl)benzo[b]furan-3-carboxylate (6b). The title compound 6b (0.484 g.
92%) was obtained from 3b (0.500 g, 1.86 mmol) as a white solid using a procedure analogous to that
described for the preparation of 6a: mp 80ꢀ81 °C. (lit. mp12 = 78–79 °C); 1H NMR (400 MHz, CDCl3) δ
8.09–8.00 (m, 3H), 7.54–7.49 (m, 1H), 7.37–7.32 (m, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.95 (s, 3H), 3.89 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 164.8, 161.3, 161.3, 153.6, 131.3, 127.3, 125.0, 124.0, 122.7, 122.1,
+
113.7, 111.1, 107.6, 55.5, 51.7. HRMS (ESI+): m/z calcd. for C17H14NaO4 [M + Na]+: 305.0790, found
305.0782; Anal. calcd. for C17H14O4: C, 72.33; H, 5.00, found: C, 72.40; H, 5.03. All spectral data are
consistent with previously reported values.4c,12
Methyl 2-(3-Methoxyphenyl)benzo[b]furan-3-carboxylate (6c). The title compound 6c (0.479 g,
91%) was obtained from 3c (0.500 g, 1.86 mmol) as a white solid using a procedure analogous to that
1
described for the preparation of 6a: mp 79ꢀ80 °C; H NMR (400 MHz, CDCl3) δ 8.11–8.03 (m, 1H),
7.69–7.62 (m, 2H), 7.57–7.51 (m, 1H), 7.45–7.34 (m, 3H), 7.08–7.02 (m, 1H), 3.96 (s, 3H), 3.90 (s,
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3H); 13C NMR (100 MHz, CDCl3) δ 164.5, 160.5, 159.3, 153.7, 130.8, 129.3, 127.1, 125.4, 124.1, 122.8,
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3
+
122.0, 116.5, 114.6, 111.2, 109.0, 55.5, 51.8. HRMS (ESI+): m/z calcd. for C17H14NaO4 [M + Na]+:
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305.0790, found 305.0785; Anal. calcd. for C17H14O4: C, 72.33; H, 5.00, found: C, 72.36; H, 5.02.
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Methyl 2-(2-Methoxyphenyl)benzo[b]furan-3-carboxylate (6d). The title compound 6d (0.473 g,
90%) was obtained from 3d (0.500 g, 1.86 mmol) as a colorless film using a procedure analogous to that
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described for the preparation of 6a: H NMR (400 MHz, CDCl3) δ 8.09–8.03 (m, 1H), 7.62–7.52 (m,
2H), 7.48 (td, J = 8.4, 1.6 Hz, 1H), 7.39–7.34 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H),
13
3.85–3.82 (overlapped s, 6H); C NMR (100 MHz, CDCl3) δ 164.5, 158.2, 157.7, 154.3, 131.8, 131.4,
126.7, 125.0, 123.9, 122.1, 120.4, 119.4, 111.3, 111.2, 111.1, 55.7, 51.6. HRMS (ESI+): m/z calcd. for
+
C17H14NaO4 [M + Na]+: 305.0790, found 305.0784; Anal. calcd. For C17H14O4: C, 72.33; H, 5.00,
found: C, 72.37; H, 5.04. All spectral data are consistent with previously reported values.13
Methyl 2-(3,4-Dimethoxyphenyl)benzo[b]furan-3-carboxylate (6e). The title compound 6e (0.498
g, 92%) was obtained from 3e (0.500 g, 1.73 mmol) as a white solid using a procedure analogous to that
1
described for the preparation of 6a: mp 89ꢀ90 °C; H NMR (400 MHz, CDCl3) δ 8.07–8.01 (m, 1H),
7.77–7.72 (m, 2H), 7.54–7.49 (m, 1H), 7.36–7.31 (m, 2H), 6.99–6.95 (m, 1H), 3.99 (s, 3H), 3.95 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 164.8, 160.9, 153.5, 150.9, 148.4, 127.3, 125.1, 124.0, 123.1, 122.7,
+
122.1, 112.4, 111.0, 110.6, 107.8, 56.1, 56.1, 51.7. HRMS (ESI+): m/z calcd. for C18H16NaO5 [M +
Na]+: 335.0895, found 335.0889; Anal. calcd. For C18H16O5: C, 69.22; H, 5.16, found: C, 69.26; H, 5.16.
Methyl 2-(4-Fluorophenyl)benzo[b]furan-3-carboxylate (6f). The title compound 6f (0.475 g,
90%) was obtained from 3f (0.500 g, 1.95 mmol) as a white solid using a procedure analogous to that
1
described for the preparation of 6a: mp 92ꢀ93 °C; H NMR (400 MHz, CDCl3) δ 8.11–8.03 (m, 3H),
7.56–7.50 (m, 1H), 7.40–7.33 (m, 2H), 7.19 (t, J = 8.7 Hz, 2H), 3.96 (s, 3H); 13C NMR (100 MHz,
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CDCl3) δ 164.6, 164.0 (d, J = 251.5 Hz), 160.0, 153.8, 131.8 (d, J = 8.6 Hz), 127.0, 125.8 (d, J = 3.4
Hz), 125.5, 124.2, 122.9, 115.4 (d, J = 21.8 Hz), 111.2, 108.7, 51.8. HRMS (ESI+): m/z calcd. for
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+
C16H11FNaO3 [M + Na]+: 293.0590, found 293.0584; Anal. calcd. for C16H11FO3: C, 71.11; H, 4.10,
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found: C, 71.18; H, 4.13.
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Methyl 2-(4-Bromophenyl)benzo[b]furan-3-carboxylate (6g). The title compound 6g (0.481 g,
91%) was obtained from 3g (0.500 g, 1.58 mmol) as a white solid using a procedure analogous to that
described for the preparation of 6a: mp 101ꢀ102 °C; 1H NMR (400 MHz, CDCl3) δ 8.08–8.02 (m, 1H),
7.94 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.56–7.51 (m, 1H), 7.41–7.34 (m, 2H), 3.96 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 164.5, 159.7, 153.8, 131.5, 131.1, 128.5, 127.0, 125.7, 125.0, 124.3,
+
122.9, 111.3, 109.3, 51.9. HRMS (ESI+): m/z calcd. for C16H11BrNaO3 [M + Na]+: 352.9789, found
352.9783; Anal. calcd. for C16H11BrO3: C, 58.03; H, 3.35, found: C, 58.01; H, 3.35.
Methyl 2-(2-Naphthyl)benzo[b]furan-3-carboxylate (6h). The title compound 6h (0.456 g, 87%)
was obtained from 3h (0.500 g, mmol) as a white solid using a procedure analogous to that described for
the preparation of 6a: mp 95ꢀ96 °C (lit. mp4c = 83–84 °C); 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H),
13
8.12–8.07 (m, 2H), 8.00–7.88 (m, 3H), 7.61–7.53 (m, 3H), 7.42–7.36 (m, 2H), 3.97 (s, 3H); C NMR
(100 MHz, CDCl3) δ 164.7, 160.9, 154.0, 134.1, 132.9, 130.0, 129.1, 127.8, 127.8, 127.6, 127.3, 127.0,
+
126.6, 126.2, 125.5, 124.2, 122.8, 111.3, 109.1, 51.8. HRMS (ESI+): m/z calcd. for C20H14NaO3 [M +
Na]+: 325.0841, found 325.0835; Anal. calcd. for C20H14O3: C, 79.46; H, 4.67, found: C, 79.45; H, 4.64.
All spectral data are consistent with previously reported values.4c
Methyl (E)-2-(4-Methoxystyryl)benzo[b]furan-3-carboxylate (6i). The title compound 6i (0.465 g,
89%) was obtained from 3i (0.500 g, 1.70 mmol) as a greenish yellow solid using a procedure analogous
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to that described for the preparation of 6a and a longer reaction time (24 h): mp 90ꢀ91 °C; H NMR
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(400 MHz, CDCl3) δ 8.03ꢀ7.94 (m, 1H), 7.77 (d, J = 16.3 Hz, 1H), 7.60–7.53 (m, 3H), 7.50–7.44 (m,
1H), 7.35–7.28 (m, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.00 (s, 3H), 3.85 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.9, 160.7, 160.5, 153.9, 135.5, 129.2, 128.9, 126.8, 125.4, 124.0, 122.3, 114.4, 113.4,
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+
110.8, 108.0, 55.5, 51.7. HRMS (ESI+): m/z calcd. for C19H16NaO4 [M + Na]+: 331.0946, found
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331.0941; Anal. calcd. for C19H16O4: C, 74.01; H, 5.23, found: C, 74.04; H, 5.16.
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Methyl 2-Isobutylbenzo[b]furan-3-carboxylate (6j). The title compound 6j (0.453 g, 85%) was
obtained from 3j (0.500 g, 2.29 mmol) as a colorless oil using a procedure analogous to that described
for the preparation of 6a and a longer reaction time (12 h): 1H NMR (400 MHz, CDCl3) δ 8.02–7.93 (m,
1H), 7.47–7.40 (m, 1H), 7.32–7.23 (m, 2H), 3.94 (s, 3H), 3.08 (d, J = 7.3 Hz, 2H), 2.23 (sep, J = 6.8 Hz,
1H), 1.00 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.0, 165.0, 153.7, 126.1, 124.4, 123.8,
+
122.0, 110.9, 109.2, 51.4, 36.8, 28.4, 22.6. HRMS (ESI+): m/z calcd. for C14H16NaO3 [M + Na]+:
255.0997, found 255.0992; Anal. calcd. for C14H16O3: C, 72.39; H, 6.94, found: C, 72.35; H, 6.99.
Methyl 2-Cyclopropylbenzo[b]furan-3-carboxylate (6k). The title compound 6k (0.464 g, 87%)
was obtained from 3k (0.500 g, 2.47 mmol) as a white solid using a procedure analogous to that
described for the preparation of 6a and a longer reaction time (12 h): mp 61ꢀ62 °C; 1H NMR (400 MHz,
CDCl3) δ 7.95–7.90 (m, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.30–7.20 (m, 2H), 3.96 (s, 3H), 3.10–3.02 (m,
13
1H), 1.31–1.26 (m, 2H), 1.20–1.15 (m, 2H); C NMR (100 MHz, CDCl3) δ 168.0, 165.5, 152.8, 126.7,
+
124.1, 123.8, 121.4, 110.7, 108.3, 51.5, 9.8, 9.7. HRMS (ESI+): m/z calcd. for C13H12NaO3 [M + Na]+:
239.0684, found 239.0679; Anal. calcd. for C13H12O3: C, 72.21; H, 5.59, found: C, 72.24; H, 5.57.
Methyl 2-Cyclohexylbenzo[b]furan-3-carboxylate (6l). The title compound 6l (0.467 g, 88%) was
obtained from 3l (0.500 g, 2.05 mmol) as a white solid using a procedure analogous to that described for
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the preparation of 6a and a longer reaction time (12 h): mp 57ꢀ58 °C; H NMR (400 MHz, CDCl3) δ
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8.00–7.93 (m, 1H), 7.49–7.42 (m, 1H), 7.33–7.26 (m, 2H), 3.96 (s, 3H), 3.71 (tt, J = 12.0, 3.4 Hz, 1H),
1.97–1.84 (m, 4H), 1.82–1.67 (m, 3H), 1.51–1.26 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 165.1,
153.6, 126.2, 124.3, 123.8, 122.0, 111.1, 107.1, 51.5, 37.4, 30.8, 26.3, 26.0. HRMS (ESI+): m/z calcd.
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5
6
+
for C16H18NaO3 [M + Na]+: 281.1154, found 281.1149; Anal. calcd. for C16H18O3: C, 74.40; H, 7.02,
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found: C, 74.44; H, 7.11.
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ACKNOWLEDGMENT
This work was supported by the Converging Research Center Program through the Ministry of
Science, ICT and Future Planning, Korea (2014M3C1A8066306).
ASSOCIATED CONTENT
SUPPORTING INFORMATION.
1H and 13C NMR spectra of compounds and crystallography data (.cif) of product 3h (CCDC
1057072). This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* D.Y. Chi: dychi@sogang.ac.kr
Notes
The authors declare no competing financial interest.
REFERENCES
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S.; Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14, 455. (e) Wallez, V.; DurieuxꢀPoissonnier, S.;
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(2) For recent examples of benzofuran synthesis catalyzed by transition metal catalysts, see; (a) Lee, J.
H.; Kim, M.; Kim, I. J. Org. Chem. 2014, 79, 6153. (b) Wan J.ꢀP.; Wang, H.; Liu, Y.; H. Ding, Org.
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