K2CO3-promoted domino reactions: Construction of functionalized 2,3-dihydrobenzofurans and clofibrate analogues

Article abstract of DOI:10.1021/jo2008675

The K₂CO₃-catalyzed domino reactions (Michael alkylation, Mannich alkylation, and aldol alkylation) of salicylic aldehyde derivatives (2-hydroxyaryl-α,β-unsaturated ketones, 2-hydroxyarylnitroalkenes, 2-hydroxyarylimines, and salicyl

Full text of DOI:10.1021/jo2008675

NOTE
pubs.acs.org/joc
K2CO3-Promoted Domino Reactions: Construction of Functionalized
2,3-Dihydrobenzofurans and Clofibrate Analogues
Qu-Bo Li,† Fei-Ting Zhou,† Zheng-Geng Liu,† Xue-Feng Li,‡ Wei-Dong Zhu,† and Jian-Wu Xie*,†
†Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life Science,
Zhejiang Normal University, 321004 Jinhua, People’s Republic of China
‡College of Chemistry and Environment Protection Engineering, Southwest University for Nationalities, Chengdu,
People’s Republic of China
S Supporting Information
b
ABSTRACT:
The K2CO3-catalyzed domino reactions (Michael alkylation, Mannich alkylation, and aldol alkylation) of salicylic aldehyde
derivatives (2-hydroxyaryl-R,β-unsaturated ketones, 2-hydroxyarylnitroalkenes, 2-hydroxyarylimines, and salicylic aldehydes) and
2-halo-1,3-dicarbonyl compounds (diethyl R-bromomalonate, diethyl R-chloromalonate, ethyl 2-chloroacetoacetate, and 3-chloro-
pentane-2,4-dione) were carried out under mild conditions to provide a series of functionalized 2,3-dihydrobenzofurans in moderate
to excellent yields. The novel transformations simultaneously gave a series of clofibrate analogues, which possess various substitution
patterns.
uran heterocycles occupy a central position in modern
heterocyclic chemistry, principally because this hetero-
couplings of quinones and phenylpropenyl moieties,11
radical,12 transition-metal-mediated cyclizations,13 benzyne,14
electrocyclic,15 anionic,16 organocatalytic, and dehydrative
techniques.17 As part of our medicinal chemistry research
program, we required a robust facile synthesis of 2,3-dihydro-
benzofuran derivatives wherein we could vary the different
substitutions. Herein we report an efficient, mild, and convenient
method for the preparation of these derivatives by domino
reactions (Michael alkylation, Mannich alkylation, and aldol
alkylation).
Recently, we have established that 2-hydroxyaryl-R,β-unsatu-
rated ketones could behave as acceptors and donors in domino
reactions (eq 1) under easily mild conditions.18 Encouraged
by the successful results mentioned above, we conceived that
2,3-dihydrobenzofuran derivatives A could be synthesized as
well from the reaction of C with nucleophile 5 (Scheme 1).
The proposed synthetic route is described in Scheme 1. We
envisioned that the target compound A could be traced back to B,
which might be generated from the domino reaction of diethyl
F
cyclic ring is an important recognition element in many natural
products and biologically active compounds.1 Among this class of
compounds, 2,3-dihydrobenzofurans are recognized to be very
important due to their biological activities2 and their applications
in a wide range of chemical transformations and other important
targets. Natural products and pharmaceuticals possessing the
dihydrobenzofuran skeleton exhibit a wide range of biological
activities (Figure 1).3 For example, (+)-Conocarpan, which was
first isolated from the wood of Conocarpus erectus,4 exhibits a
diverse array of biological activities, including insecticidal,5
antifungal,6 and antitrypanosomal properties.7 Megapodiol is
an antileukemic agent,8 and Furaquinocines are antibiotics.9
More and more, 2,3-dihydrobenzofurans have been developed
for the treatment of traumatic and ischemic central nervous
system (CNS) injury3a,10 and have been reported to be useful in
the treatment of arteriosclerosis, hepatopathy, and cerebrovas-
cular disease.3b Consequently, new and efficient methods for the
preparation of this important heterocyclic ring system are of
contemporary interest because of the many reported applications
in the fields of medicinal and agrochemistry. Classical routes
for the formation of dihydrobenzofurans include biomimetic
Received: April 28, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2008675 J. Org. Chem. 2011, 76, 7222–7228
|

The Journal of Organic Chemistry
NOTE
Figure 1. Natural products and pharmaceuticals that contain dihydrobenzofuran rings.
Scheme 1. General Strategy for the Synthesis of Dihydro-
benzofuran Derivatives
Table 1. Reaction of 2-Hydroxyaryl-r,β-unsaturated Ketone
2a and Diethyl R-Bromomalonate 5 under Different
Conditionsa
entry
base
solvent
yieldb (%)
1
2
3
4
5
6
7
8
KOH
THF
46
78
31
60
54
86
66
47
K2CO3
KOAc
THF
R-bromomalonate (DBM) 5 with C (2ꢀ4). The compounds
2ꢀ4 were readily obtained from salicylic aldehydes 1.
THF
DABCO
K2CO3
K2CO3
K2CO3
K2CO3
THF
toluene
acetone
ethanol
H2O
a Otherwise noted, reactions performed with 0.20 mmol of 2a, 0.40
mmol of 5, 120 mol % of base in 1 mL of solvent at room temperature.
b Isolated yield.
In an initial study, we studied the domino reaction of 5 with
2-hydroxyphenyl-R,β-unsaturated ketone 2a, which can easily be
prepared in good yields according to the reported procedure.19 A
series of organic solvents and bases were screened for the domino
reaction. A few representative results are shown in Table 1. To
our delight, the domino reaction proceeded smoothly to provide
desired product 6a when the reaction was carried out in the
presence of bases (120 mol %) in THF at room temperature for
5 h (Table 1, entries 1ꢀ4). A good yield was obtained when the
domino reaction was catalyzed by K2CO3 (78% yield, entry 2).
However, when the stronger base KOH was used as the catalyst,
the reaction became complicated and low yield was isolated
(entry 1). Similarly, when the reaction was catalyzed with the
weaker base KOAc, the reaction rate was very slow and a low
yield was obtained after 5 h (entry 3). However, the organic base
DABCO (1,4-diazabicyclo[2.2.2]octane) was used as the cata-
lyst, and the yield of the desired product was higher than those
using KOH and KOAc as the catalysts but still lower than that
using K2CO3 as the catalyst (entry 4). Subsequently, we inves-
tigated the effects of solvent on the reactivity when K2CO3 was
used as the catalyst. A rather low yield was obtained when toluene
was used as the solvent (entry 5). Among the solvents examined,
the use of acetone gave the best result (entry 6). However, the
yield was dramatically decreased when ethanol was used (entry 7).
We were pleased to find that the domino reaction proceeded
smoothly to provide desired product 2,3-dihydrobenzofuran 6a
using water as solvent, but the yield was low due to the low
solubility of 2a in water (entry 8).
reaction of 5 with 2-hydroxyaryl-R,β-unsaturated ketones 2 was
explored. The results are summarized in Table 2. To assess the
impact of the structural and functional motifs on the reaction, we
tested a range of 2-hydroxyaryl-R,β-unsaturated ketones 2. For
all cases, diethyl R-bromomalonate 5 reacted with 2-hydroxyaryl-
R,β-unsaturated ketones 2, leading to the corresponding poly-
substituted 2,3-dihydrobenzofuran derivatives 6 in moderate to
excellent yields. For instance, reaction of 2-hydroxyaryl-R,
β-unsaturated ketone 2b and 5 gave rise to the desired product
6b in 90% yield (Table 2, entry 2). When 2-hydroxyaryl-R,
β-unsaturated ketone 2d was employed in the above reaction, the
desired product 6d was isolated in 83% yield (Table 2, entry 4).
A lower yield was obtained when 2-hydroxyaryl-R,β-unsaturated
ketone 2c was used as a replacement (70% yield, Table 2, entry 3).
The reaction with aromatic enones 2gꢀ2i also gave desired
products 6gꢀ6i in good yields (Table 2, entries 5ꢀ9).
Clofibrate is a lipid lowering agent used for controlling the high
cholesterol and triacylglyceride level in the blood.20,21 In order to
study the activity of clofibrate and related analogues, there is an eager
desire for a new synthetic method that allows the easy preparation of
clofibrate analogues with high efficiency and, more importantly,
good feasibility to assemble various substitution patterns.22 Gratify-
ingly, this novel transformation could be applied in the synthesis of
clofibrate analogues containing 2,3-dihydrobenzofurans (Table 2).
Under the same conditions, clofibrate analogues were obtained with
good to excellent yields (74ꢀ95% yield). Aromatic enones with
electron-donating substituents on the ortho, meta, or para positions
afford clofibrate analogues with slightly inferior yields (Table 2,
With the optimal reaction conditions [K2CO3 (120 mol %),
acetone, room temperature] in hand, the scope of the domino
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The Journal of Organic Chemistry
NOTE
Table 2. Reaction Scopes of 2-Hydroxyaryl-r,β-unsaturated
Table 3. Synthesis of Differently Substituted 2,
Ketones in the Domino Reactiona
3-Dihydrobenzofuransa
entry
R1
XR2
7
yieldb (%)
entry
R1
R2 (2)
CH3 (2a)
6
yieldb (%)
1c
2c
3c
4c
5c
6c
7c
8c
9d
H
CHNO2 (3a)
CHNO2 (3b)
CHNO2 (3c)
CHNO2 (3d)
NC6H5 (4a)
NC6H5 (4b)
NC6H5 (4c)
NC6H5 (4d)
O (1a)
7a
7b
7c
7d
7e
7f
55
47
68
50
82
87
82
87
92
97
94
83
1
2
H
6a
6b
6c
6d
6e
6f
86
90
70
83
78
71
80
77
72
95
80
75
70
74
81
79
5-F
5-Br
5-NO2
4-CH3O
H
CH3 (2b)
5-Cl
5-Br
H
3
CH3 (2c)
4
CH3 (2d)
5
p-BrC6H4 (2e)
m-BrC6H4 (2e)
p-MeC6H4 (2f)
p-MeC6H4 (2g)
p-ClC6H4 (2h)
CH3 (2i)
5-Cl
5-Br
4-MeO
H
6
H
7g
7h
7i
7
H
6g
6h
6i
8
5-Br
5-Br
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
9
10d
11d
12d
5-Cl
5-Br
4-MeO
O (1b)
7j
10
11
12
13
14
15
16
6j
O (1c)
7k
7l
Ph (2j)
6k
6l
O (1d)
p-MeOC6H4 (2k)
m-MeOC6H4 (2l)
o-MeOC6H4 (2m)
p-MeC6H4 (2n)
p-BrC6H4 (2o)
a Otherwise noted, reactions performed with 0.20 mmol of 1 or 3 or 4,
0.40 mmol of 5, and 120 mol % of K2CO3 in 1 mL of acetone at room
temperature. b Isolated yield. c For 3 h. d For 5 h.
6m
6n
6o
6p
a Otherwise noted, reactions performed with 0.20 mmol of 2, 0.40 mmol
of 5, 120 mol % of K2CO3 in 1 mL of acetone at room temperature.
b Isolated yield.
Table 4. Domino Reaction of 2-Hydroxyaryl-r,β-unsatu-
rated Ketones 2, 2-Hydroxyarylimines 4, 2-Hydroxyarylni-
troalkenes 3, and Salicylic Aldehydes 1 to 1,3-Dicarbonyl
Compounds (8a and 8b)a
entries 12ꢀ14). The structure of clofibrate analogues was first
characterized by spectroscopic analysis, then the structure was estab-
lished unambiguously by X-ray analysis.23
Having succeeded in synthesizing 2,3-dihydrobenzofuran
derivatives 6 possessing three carbonyl groups from 2-hydro-
xyaryl-R,β-unsaturated ketones 2 and 5 under base-mediated
conditions, we turned our attention to the possible synthesis of
2,3-dihydrobenzofuran derivatives which possess other useful
groups, such as nitro, amino, and hydroxyl groups. A series of
potential substrates (1, 3, and 4) were investigated. The results
are summarized in Table 3. Only moderate yields were isolated
when 2-hydroxyarylnitroalkenes (3aꢀ3d) were treated with 5
(Table 3, entries 1ꢀ4). This could be explained by the relatively
slower nitroalkene polymerization under the base conditions.
The electronic effect was very marginal when 2-hydroxyaryli-
mines 4 were treated with 5, and 2,3-dihydrobenzofuran deriva-
tives 7eꢀ7h possessing a phenylamino group were obtained in
good yields (Table 3, entries 5ꢀ8). During our ongoing studies
of the domino reaction, salicylic aldehydes 1aꢀ1e exhibited high
reactivity.24 The domino reaction of salicylic aldehydes to 5
proceeded with clean products 7iꢀ7l in good to excellent yields
(Table 3, entries 9ꢀ12). It is worthy of note that clofibrate
analogues with different useful functionalities were also obtained
in good to excellent yields (Table 3, entries 3, 6, and 10).
To extend the scope of the domino reaction further, other
2-halo-1,3-dicarbonyl compounds 8aꢀ8c, which also contain
another leaving group, were utilized as nucleophiles in the domino
reaction under the same conditions as aforementioned (Table 4).
The domino process took place with diethyl R-chloromalonate,
which possesses a different leaving group (Cl), to provide the
entry
substrates (1ꢀ4)
substrate (8)
product
yieldb (%) (dr)d
1
2
1a
2a
3a
4a
2j
8a
8a
8a
8a
8b
8b
8b
8b
8c
8c
8c
8c
7i
81
6a
7a
7e
9a
9b
9c
9d
9e
9f
75
3
57
4
5c
77
37
6
3a
4
48
7
69
8
1b
2j
63
9c
10
11
12
41 (>99:1)
54 (79:21)
61 (>99:1)
57 (57:43)
3a
4a
1b
9g
9h
a Otherwise noted, reactions performed with 0.20 mmol of 1 or 2 or 3 or
4, 0.40 mmol of 5, 120 mol % of K2CO3 in 1 mL of acetone at room
temperature. b Isolated yield. c At 40 °C. d Determined by 1H NMR.
desired products, and it appeared that the yields were somewhat low
(Table 4, entries 1ꢀ4). Moreover, the domino reactions of other
2-halo-1,3-dicarbonyl compounds 8b,8c with 2-hydroxyarylimine,
7224
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The Journal of Organic Chemistry
NOTE
2-hydroxyarylnitroalkene, and salicylic aldehyde proceeded to provide
desired products 9aꢀ9f. Moderate yields were obtained when 1b and
4a, respectively, were treated with 2-chloro-1,3-dicarbonyl com-
pounds 8b and 8c (entries 7,8 and 11,12). 2-Hydroxyarylnitroalkene
2j furnished 2,3-dihydrobenzofuran derivatives in low yields
(37 and 41%, in Table 4, entries 6 and 10). The reactions were
very slow for bulkier aromatic enone 2j under the same condi-
tions. Fortunately, desired products 9a and 9e were obtained
when the reaction temperature was increased (Table 4, entries
5 and 9). Moreover, 2,3-dihydrobenzofuran derivatives 9f and 9h
were isolated as a mixture of diastereomers, while 9e and 9g were
obtained with high diastereoselectivities (Table 4, entries 9ꢀ12).
The relative stereochemistry of products 9eꢀ9h was established
by single-crystal X-ray diffraction study of compound 9g.23
In conclusion, we have developed an efficient, mild, and
convenient domino reaction to synthesize differently substituted
2,3-dihydrobenzofurans in moderate to excellent yields from
readily available starting materials. In this transformation, a broad
substrate scope has been demonstrated. This methodology
provides facile access to various multifunctional clofibrate analo-
gues that, to date, have not been reported in the literature. The
2,3-dihydrobenzofuran products may serve as a platform for
further manipulation leading to structurally unique benzofurans
and other pharmaceutically intriguing compounds. Our future
efforts will focus on an asymmetric version of this reaction and
biological activities of clofibrate analogues.
CDCl3) δ 6.97 (d, J = 8.3 Hz, 1H), 6.51ꢀ6.42 (m, 2H), 4.68ꢀ4.65
(m, 1H), 4.34ꢀ4.23 (m, 4H), 3.74 (s, 3H), 2.88ꢀ2.68 (m, 2H), 2.17
(s, 3H), 1.33ꢀ1.28 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 205.3,
167.2, 166.5, 160.8, 158.4, 124.8, 119.9, 107.7, 96.5, 91.8, 62.6, 62.4, 55.4,
45.4, 42.3, 30.3, 14.0, 13.8; IR (KBr) cmꢀ1 3447, 2974, 1767, 1735, 1671,
1602, 1574; ESI-HRMS calcd for C18H22O7 + Na 373.1270, found 373.1266.
Diethyl 3-(2-(4-Bromophenyl)-2-oxoethyl)benzofuran-2,
2(3H)-dicarboxylate (6e): white solid; mp 95ꢀ97 °C; 1H NMR (400
MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H),
7.16ꢀ7.08 (m, 2H), 6.94ꢀ6.83 (m, 2H), 4.98ꢀ4.94 (m, 1H), 4.31ꢀ4.24
(m, 4H), 3.46ꢀ3.20 (m, 2H), 1.30ꢀ1.21 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 196.0, 167.6, 157.6, 135.5, 132.3, 132.3, 132.3, 129.9, 129.8,
129.3, 128.9, 128.3, 125.0, 122.5, 110.4, 110.3, 91.6, 63.0, 43.4, 40.87, 14.3,
14.2; IR (KBr) cmꢀ1 3444, 2977, 1755, 1732, 1668, 1600, 1571;
ESI-HRMS calcd for C22H21BrO6 + Na 483.0419, found 483.0414.
Diethyl 3-(2-(3-Bromophenyl)-2-oxoethyl)benzofuran-2,
1
2(3H)-dicarboxylate (6f): white solid; mp 101ꢀ103 °C; H NMR
(400 MHz, CDCl3) δ 7.82ꢀ7.74 (m, 2H), 7.61ꢀ7.59 (m, 2H), 7.18ꢀ7.12
(m, 2H), 6.98ꢀ6.89 (m, 2H), 5.02ꢀ5.98 (m, 1H), 4.35ꢀ4.18 (m, 4H),
3.44ꢀ3.29 (m, 2H), 1.34ꢀ1.25 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 195.7, 167.3, 166.7, 157.3, 135.1, 132.0, 129.6, 129.0, 128.6, 128.0, 124.7,
122.2, 110.1, 91.3, 62.8, 62.5, 43.1, 40.5, 14.0, 14.0; IR (KBr) cmꢀ1 3461,
2980, 1759, 1742, 1670, 1590, 1568; ESI-HRMS calcd for C22H21BrO6 +
Na 483.0419, found 483.0416.
Diethyl 3-(2-Oxo-2-(p-tolyl)ethyl)benzofuran-2,2(3H)-di-
carboxylate (6g): yellow oil; H NMR (400 MHz, CDCl3) δ 7.85
1
(d, J = 8.2 Hz, 2H), 7.32ꢀ7.10 (m, 4H), 6.99ꢀ6.85 (m, 2H), 5.05ꢀ5.01
(m, 1H), 4.34ꢀ4.28 (m, 4H), 3.48ꢀ3.27 (m, 2H), 2.41 (s, 3H),
1.34ꢀ1.23 (m, 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 196.6,
167.6, 167.0, 157.6, 144.6, 134.3, 129.7, 129.2, 128.6, 128.4, 125.1, 122.4,
110.3, 110.2, 91.7, 63.0, 62.7, 43.4, 40.8, 21.9, 14.3, 14.2; IR (KBr) cmꢀ1
3440, 2973, 1752, 1729, 1665, 1599, 1562; ESI-HRMS calcd for
C23H24O6 + Na 419.1478, found 419.1474.
’ EXPERIMENTAL SECTION
General Procedure for the Domino Reaction of 2-Hydroxyar-
yl-r,β-unsaturated Ketones 2 with Diethyl R-Bromomalonate
(DBM) 5. First, 64.8 mg (0.4 mmol) of 2-hydroxyphenyl-R,β-unsaturated
ketone (2a), 189 mg (0.8 mmol) of diethyl R-bromomalonate (5), and
65.8 mg (0.48 mmol) of K2CO3 were stirred in acetone (1.5 mL) at room
temperature for 5 h. The solvent was removed and flash chromatography
on silica gel (15% ethyl acetate/petroleum ether) gave 6a as pale yellow oil
(110 mg, 86% yield).
Diethyl 3-(2-Oxopropyl)benzofuran-2,2(3H)-dicarboxy-
late (6a): pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.15ꢀ7.09
(m, 2H), 6.93ꢀ6.88 (m, 2H), 4.76ꢀ4.73 (m, 1H), 4.31ꢀ4.24 (m, 4H),
2.91ꢀ2.72 (m, 2H), 2.17 (s, 3H), 1.31ꢀ1.26 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 205.2, 166.6, 157.2, 128.9, 128.0, 124.6, 122.1,
110.1, 110.0, 109.9, 62.7, 62.4, 45.3, 42.8, 30.3, 14.0, 13.9; IR (KBr) cmꢀ1
3446, 2979, 1757, 1734, 1670, 1602, 1573; ESI-HRMS calcd for C17H20O6
+ Na 343.1169, found 343.1152.
Diethyl 5-Bromo-3-(2-oxopropyl)benzofuran-2,2(3H)-dicar-
boxylate (6b): yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.34ꢀ7.22
(m, 2H), 6.81 (d, J = 8.5 Hz, 1H), 4.74ꢀ4.71 (m, 1H), 4.33ꢀ4.26 (m, 4H),
2.95ꢀ2.73 (m, 2H), 2.20 (s, 3H), 1.32ꢀ1.20 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 205.1, 167.1, 166.4, 156.7, 132.0, 130.9, 128.0, 114.2,
111.8, 91.7, 63.1, 62.8, 45.1, 42.9, 30.4, 14.2, 14.1; IR (KBr) cmꢀ1 3398,
2881, 1741, 1726, 1668, 1551, 1568; ESI-HRMS calcd for C17H19BrO6 +
Na 421.0270, found 421.0265;
Diethyl 5-Nitro-3-(2-oxopropyl)benzofuran-2,2(3H)-dicar-
boxylate (6c): yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.16ꢀ8.00
(m, 2H), 7.01 (d, J = 8.9 Hz, 1H), 4.80ꢀ4.76 (m, 1H), 4.40ꢀ4.27
(m, 4H), 3.06ꢀ2.89 (m, 2H), 2.25 (s, 3H), 1.35ꢀ1.23 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 204.9, 166.5, 166.0, 162.8, 143.4, 130.2, 126.5,
121.5, 110.3, 92.7, 63.5, 63.2, 44.8, 42.6, 30.3, 14.3, 14.2; IR (KBr) cmꢀ1
3448, 2978, 1756, 1737, 1668, 1606, 1576; ESI-HRMS calcd for
C17H19NO8 + Na 388.1012, found 388.1005.
Diethyl 5-Bromo-3-(2-oxo-2-(p-tolyl)ethyl)benzofuran-2,
1
2(3H)-dicarboxylate (6h): white solid; mp 79ꢀ81 °C; H NMR
(400 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H), 7.27 (t, J = 6.5 Hz, 4H),
6.83 (d, J = 9.1 Hz, 1H), 4.99ꢀ4.95 (m, 1H), 4.35ꢀ4.20 (m, 4H),
3.48ꢀ3.43 (m, 1H), 3.30ꢀ3.24 (m, 1H), 2.40 (s, 3H), 1.32ꢀ1.24 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 196.2, 167.2, 166.7, 156.9, 144.8,
134.1, 132.1, 131.2, 129.7, 128.5, 128.3, 114.4, 111.9, 92.1, 63.2, 62.9,
43.3, 40.5, 22.0, 14.3; IR (KBr) cmꢀ1 3451, 2985, 1762, 1739, 1661,
1616, 1569; ESI-HRMS calcd for C23H23BrO6 + Na 497.0585, found
497.0581.
Diethyl 5-Bromo-3-(2-(4-chlorophenyl)-2-oxoethyl)benzo-
1
furan-2,2(3H)-dicarboxylate (6i): white solid; mp 95ꢀ97 °C; H
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz,
2H), 7.29ꢀ7.25 (m, 2H), 6.84 (d, J = 8.5 Hz, 1H), 4.94 (d, J = 3.6 Hz,
1H), 4.34ꢀ4.28 (m, 4H), 3.47ꢀ3.22 (m, 2H), 1.33ꢀ1.25 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 195.1, 166.9, 166.3, 156.5, 140.1, 134.5,
131.9, 130.5, 129.5, 129.1, 127.9, 114.1, 111.7, 91.7, 62.9, 62.7, 43.0, 40.3,
14.0, 13.9; IR (KBr) cmꢀ1 3439, 2957, 1768, 1740, 1663, 1581, 1550;
ESI-HRMS calcd for C22H20BrClO6 + Na 517.0007, found 517.0024.
Diethyl 5-Chloro-3-(2-oxopropyl)benzofuran-2,2(3H)-di-
carboxylate (6j): yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.08ꢀ6.98
(m, 2H), 6.78 (d, J = 8.5 Hz, 1H), 4.67ꢀ4.63 (m, 1H), 4.29ꢀ4.16 (m, 4H),
2.89ꢀ2.83 (m, 1H), 2.73ꢀ2.66 (m, 1H), 2.13 (s, 3H), 1.26ꢀ1.22 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 205.2, 167.2, 166.5, 156.3, 130.4, 129.1,
127.1, 125.2, 111.3, 91.9, 63.1, 62.9, 45.2, 43.0, 30.5, 14.3, 14.2; IR
(KBr) cmꢀ1 3445, 2968, 1748, 1728, 1666, 1608, 1556; ESI-HRMS calcd
for C17H19ClO6 + Na 377.0754, found 377.0750.
Diethyl 5-Chloro-3-(2-oxo-2-phenylethyl)benzofuran-2,
2(3H)-dicarboxylate (6k): yellow solid; mp 91ꢀ93 °C; H NMR
1
Diethyl 6-Methoxy-3-(2-oxopropyl)benzofuran-2,2(3H)-
(400 MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 2H), 7.59ꢀ7.53 (m, 1H), 7.47
(t, J = 7.0 Hz, 2H), 7.18ꢀ7.06 (m, 2H), 6.87 (d, J = 9.0 Hz, 1H),
dicarboxylate (6d): gray solid; mp 52ꢀ54 °C; 1H NMR (400 MHz,
7225
dx.doi.org/10.1021/jo2008675 |J. Org. Chem. 2011, 76, 7222–7228

The Journal of Organic Chemistry
NOTE
4.98ꢀ4.94 (m 1H), 4.35ꢀ4.19 (m, 4H), 3.50ꢀ3.45 (m, 1H), 3.33ꢀ3.26
(m, 1H), 1.33ꢀ1.24 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 196.7,
167.4, 166.8, 156.5, 136.7, 134.0, 130.7, 129.3, 129.2, 128.5, 127.4, 125.6,
111.5, 92.3, 63.3, 63.1, 43.5, 40.8, 14.5, 14.4; IR (KBr) cmꢀ1 3441, 2975,
1767, 1721, 1664, 1618, 1563; ESI-HRMS calcd for C22H21ClO6 + Na
439.0935, found 439.0931.
4.85ꢀ4.80 (m, 1H), 4.66ꢀ4.63 (m, 1H), 4.36ꢀ4.28 (m, 4H), 1.34ꢀ1.26
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.4, 165.4, 116.9, 116.7,
111.7, 111.5, 111.3, 111.3, 90.3, 74.5, 63.4, 63.3, 45.4, 13.9; IR (KBr) cmꢀ1
2987, 1763, 1744, 1560, 1485; ESI-HRMS calcd for C15H16FNO7 + Na
364.0806, found 364.0796.
Diethyl 5-Chloro-3-(nitromethyl)benzofuran-2,2(3H)-di-
carboxylate (7c): yellow solid; mp 101ꢀ103 °C; 1H NMR (400 MHz,
CDCl3) δ 7.24ꢀ7.21 (m, 1H), 7.12 (d, J = 1.2 Hz, 1H), 6.93 (d, J =
8.6 Hz, 1H), 5.00 (s, 1H), 4.80 (d, J = 6.5 Hz, 1H), 4.66 (d, J = 7.0 Hz,
1H), 4.36ꢀ4.28 (m, 4H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 166.2, 156.1, 130.3, 127.6, 125.4, 124.4, 124.4, 111.8, 90.2, 74.5,
63.4, 63.4, 45.3, 13.8; IR (KBr) cmꢀ1 2989, 1770, 1746, 1555, 1478; ESI-
HRMS calcd for C15H17NO7 + Na 346.0898, found 346.0891.
Diethyl 5-Bromo-3-(nitromethyl)benzofuran-2,2(3H)-di-
carboxylate (7d): yellow solid; mp 214ꢀ216 °C; 1H NMR (400 MHz,
CDCl3) δ 7.37 (d, J = 8.6 Hz, 1H), 7.26 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H),
5.01 (s, 1H), 4.80 (d, J = 6.4 Hz, 1H), 4.66 (d, J = 7.0 Hz, 1H), 4.36ꢀ4.28
(m, 4H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 166.2,
165.3, 156.6, 133.2, 127.3, 125.9, 114.6, 112.3, 90.1, 74.5, 63.4, 63.3, 45.2,
13.9, 13.8; IR (KBr) cmꢀ1 2966, 1757, 1746, 1549, 1478; ESI-HRMS
calcd for C15H16BrNO7 + Na 424.0001, found 424.0005.
Diethyl 3-(Phenylamino)benzofuran-2,2(3H)-dicarboxy-
late (7e): gray solid; mp 137ꢀ139 °C; 1H NMR (400 MHz, CDCl3)
δ 7.28ꢀ7.23 (m, 2H), 7.20 (t, J = 7.8 Hz, 2H), 7.07ꢀ6.91 (m, 2H), 6.83
(d, J = 7.9 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.17 (d, J = 9.0 Hz, 1H),
4.40ꢀ4.29 (m, 1H), 4.28ꢀ4.09 (m, 1H), 4.07ꢀ3.92 (m, 1H), 3.91
(d, J = 9.0 Hz, 1H), 3.76ꢀ3.74(m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 0.93
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 165.5, 157.8,
146.2, 130.6, 129.2, 125.6, 125.4, 122.5, 118.5, 113.4, 110.8, 92.6, 62.7,
62.3, 61.6, 13.9, 13.5; IR (KBr) cmꢀ1 3398, 2987, 1752, 1736, 1621, 1476;
ESI-HRMS calcd for C20H21NO5 + Na 378.1310, found 378.1312.
Diethyl 5-Chloro-3-(phenylamino)benzofuran-2,2(3H)-di-
carboxylate (7f): white solid; mp 143ꢀ145 °C; 1H NMR (400 MHz,
CDCl3) δ 7.26ꢀ7.18 (m, 4H), 6.93 (d, J = 8.5 Hz, 1H), 6.84ꢀ6.78 (m,
3H), 6.15 (d, J = 9.5 Hz, 1H), 4.40ꢀ4.29 (m, 2H), 4.05ꢀ3.97 (m, 2H),
3.76ꢀ3.73 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.3, 165.6, 156.8, 146.3, 130.9, 129.6,
127.8, 127.6, 125.9, 119.2, 113.9, 112.3, 93.6, 63.3, 62.8, 61.7, 14.3, 13.9;
IR (KBr) cmꢀ1 3394, 2983, 1750, 1734, 1602, 1473; ESI-HRMS calcd
for C20H20ClNO5 + Na 412.0932, found 412.0922.
Diethyl 5-Chloro-3-(2-(4-methoxyphenyl)-2-oxoethyl)
benzofuran-2,2(3H)-dicarboxylate (6l):yellow solid; mp 89ꢀ92 °C;
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.9 Hz, 2H), 7.13ꢀ7.11
(m, J2H), 7.00ꢀ6.81 (m, 3H), 4.98ꢀ4.95 (m, 1H), 4.36ꢀ4.29 (m, 4H),
3.87 (s, 3H), 3.42ꢀ3.26 (m, 2H), 1.32ꢀ1.25 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 195.0, 167.3, 166.7, 164.1, 156.4, 130.7, 130.7,
129.7, 129.1, 127.2, 125.5, 114.2, 111.3, 92.2, 63.2, 62.9, 55.8, 43.5, 40.2,
14.3, 14.3; IR (KBr) cmꢀ1 3450, 2972, 1751, 1727, 1663, 1603, 1563;
ESI-HRMS calcd for C23H23ClO7 + Na 469.1026, found 469.1024.
Diethyl 5-Chloro-3-(2-(3-methoxyphenyl)-2-oxoethyl)
benzofuran-2,2(3H)-dicarboxylate(6m):yellow solid; mp 87ꢀ89 °C;
1H NMR (400 MHz, CDCl3) δ 7.49 (s, 2H), 7.37 (s, 1H), 7.12 (d, J =
5.9 Hz, 3H), 6.88 (d, J = 9.1 Hz, 1H), 4.98ꢀ4.95 (m, 1H), 4.36ꢀ4.20
(m, 4H), 3.85 (s, 3H), 3.47ꢀ3.30 (m, 2H), 1.33ꢀ1.21 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 196.5, 167.3, 166.7, 160.2, 156.4, 137.9, 130.5, 130.1,
129.2, 127.2, 125.4, 120.9, 120.4, 112.6, 111.3, 92.2, 63.2, 63.0, 55.7, 43.4, 40.7,
14.3, 14.3; IR (KBr) cmꢀ1 3439, 2973, 1756, 1738, 1666, 1605, 1560;
ESI-HRMS calcd for C23H23ClO7 + Na 469.1026, found 469.1022.
Diethyl 5-Chloro-3-(2-(2-methoxyphenyl)-2-oxoethyl)
benzofuran-2,2(3H)-dicarboxylate (6n):yellow solid; mp 85ꢀ87 °C;
1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.7 Hz, 1H), 7.54ꢀ7.43
(m, 1H), 7.18ꢀ7.07 (m, 2H), 7.06ꢀ7.01 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H),
6.85 (d, J = 8.5 Hz, 1H), 4.90ꢀ4.88 (m, 1H), 4.47ꢀ4.18 (m, 4H), 3.85
(d, J = 2.2 Hz, 3H), 3.49--3.29 (m, 2H), 1.32ꢀ1.26 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 198.3, 167.4, 166.9, 159.2, 156.5, 134.6, 131.1, 131.0,
129.0, 127.5, 127.2, 125.7, 121.2, 112.0, 111.3, 92.5, 63.2, 62.8, 55.8, 55.8, 55.8,
46.1, 43.7, 14.4, 14.3; IR (KBr) cmꢀ1 3440, 2982, 1755, 1736, 1667, 1612,
1579; ESI-HRMS calcd for C23H23ClO7 + Na 469.1026, found 469.1024.
Diethyl 5-Chloro-3-(2-oxo-2-(p-tolyl)ethyl)benzofuran-2,
2(3H)-dicarboxylate (6o): white solid; mp 119ꢀ121 °C; 1H NMR
(400 MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.26 (t, J = 9.4 Hz, 2H),
7.17ꢀ7.12 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H),
5.03ꢀ5.00 (m, 1H), 4.34ꢀ4.13 (m, 4H), 3.46ꢀ3.41 (m, 1H),
3.30ꢀ3.24 (m, 1H), 2.39 (s, 3H), 1.32ꢀ1.22 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 196.6, 167.6, 167.0, 157.6, 144.6, 134.3, 129.7,
129.2, 128.6, 128.4, 125.1, 122.4, 110.3, 110.2, 91.7, 63.0, 62.7, 43.4, 40.8,
21.9, 14.3, 14.2; IR (KBr) cmꢀ1 3443, 2977, 1760, 1734, 1670, 1607,
1571; ESI-HRMS calcd for C23H23ClO6 + Na 453.1085, found 453.1075.
Diethyl 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-chlorobenzo-
furan-2,2(3H)-dicarboxylate (6p): white solid; mp 106ꢀ108 °C; 1H
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 7.9 Hz,
2H), 7.19ꢀ7.04 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.95ꢀ4.91 (m, 1H),
4.38ꢀ 4.18 (m, 4H), 3.43ꢀ3.22 (m, 2H), 1.33ꢀ1.25 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 195.8, 167.4, 166.8, 156.5, 135.4, 132.5, 130.5,
130.0, 129.4, 129.3, 127.4, 125.5, 111.5, 92.2, 63.3, 63.1, 43.4, 40.7, 14.4,
14.4; IR (KBr) cmꢀ1 3451, 2984, 1762, 1733, 1675, 1604, 1577; ESI-
HRMS calcd for C22H20BrClO6 + Na 517.0022, found 517.0018.
Diethyl 3-(Nitromethyl)benzofuran-2,2(3H)-dicarboxylate
(7a): yellow solid; mp 52ꢀ54 °C; 1H NMR (400 MHz, CDCl3) δ 7.27ꢀ
7.14 (m, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.03ꢀ6.94 (m, 2H), 5.05 (t, J =
6.8 Hz, 1H), 4.85ꢀ4.64 (m, 2H), 4.38ꢀ4.27 (m, 4H), 1.34ꢀ1.30
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.6, 165.7, 157.3, 130.3,
124.2, 123.4, 122.7, 110.7, 89.8, 74.9, 63.3, 63.2, 45.4, 13.9, 13.8; IR (KBr) cmꢀ1
2985, 1765, 1718, 1561, 1483; ESI-HRMS calcd for C15H17NO7 + Na
346.0910, found 346.0897.
Diethyl 5-Bromo-3-(phenylamino)benzofuran-2,2(3H)-di-
carboxylate (7g): white solid; mp 151ꢀ153 °C; 1H NMR (400 MHz,
CDCl3) δ 7.39 (d, J = 7.2 Hz, 1H), 7.38ꢀ7.36 (m, 1H), 7.22ꢀ7.18 (m,
2H), 6.90ꢀ6.76 (m, 4H), 6.15 (d, J = 7.7 Hz, 1H), 4.45ꢀ3.94 (m, 4H),
3.76ꢀ3.70 (m, 1H), 1.35ꢀ0.9 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 167.2, 165.5, 157.3, 146.3, 133.8, 129.7, 129.7, 129.6, 128.8, 128.3, 119.3,
114.6, 113.9, 112.8, 93.5, 63.3, 62.8, 61.7, 14.3, 13.9; IR (KBr) cmꢀ1 3401,
2991, 1761, 1742, 1618, 1477; ESI-HRMS calcd for C20H20BrNO5 + Na
456.0412, found 456.0409.
Diethyl 6-Methoxy-3-(phenylamino)benzofuran-2,2(3H)-
1
dicarboxylate (7h): pale yellow solid; mp 126ꢀ128 °C; H NMR
(400 MHz, CDCl3) δ 7.26ꢀ7.18 (m, 4H), 6.81 (d, J = 8.5 Hz, 1H),
6.57ꢀ6.53 (m, 3H), 6.09 (d, J = 9.5 Hz, 1H), 4.43ꢀ4.24 (m, 2H),
4.10ꢀ4.02 (m, 2H), 3.90ꢀ3.70 (m, 3H), 1.33 (t, J = 7.1 Hz, 3H), 0.92
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 165.9, 162.5,
159.6, 146.6, 129.6, 126.0, 118.8, 117.8, 113.8, 109.5, 96.8, 63.1, 62.7, 61.7,
56.0, 14.4, 13.9; IR (KBr) cmꢀ1 3396, 2987, 1755, 1735, 1608, 1476; ESI-
HRMS calcd for C21H23NO6 + Na 408.1411, found 408.1418.
Diethyl 3-Hydroxybenzofuran-2,2(3H)-dicarboxylate (7i):
gray green solid; mp 79ꢀ81 °C; 1H NMR (400 MHz, CDCl3) δ 7.39
(d, J = 7.2 Hz, 1H), 7.31ꢀ7.27 (m, 1H), 7.02ꢀ6.98 (m, 2H), 5.90 (d, J =
7.7 Hz, 1H), 4.35ꢀ4.18 (m, 4H), 3.24 (d, J = 7.8 Hz, 1H), 1.32ꢀ1.24
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.8, 165.7, 158.7, 131.4,
131.4, 126.2, 126.1, 122.8, 111.2, 93.2, 76.6, 63.1, 63.0, 14.4, 14.2; IR
Diethyl 5-Fluoro-3-(nitromethyl)benzofuran-2,2(3H)-di-
carboxylate (7b): yellow solid; mp 110ꢀ112 °C; 1H NMR (400 MHz,
CDCl3) δ 6.95 (t, J = 5.8 Hz, 2H), 6.87 (d, J = 7.7 Hz, 1H), 5.01 (s, 1H),
7226
dx.doi.org/10.1021/jo2008675 |J. Org. Chem. 2011, 76, 7222–7228

The Journal of Organic Chemistry
NOTE
(KBr) cmꢀ1 3446, 2979, 1762, 1738, 1466; ESI-HRMS calcd for
C14H16O6 + Na 303.0866, found 303.0839.
196.6, 166.8, 155.8, 136.9, 133.1, 130.5, 128.1, 128.8, 128.6, 127.8, 125.5,
110.3, 96.7, 62.7, 41.9, 40.5, 25.6, 14.7; IR (KBr) cmꢀ1 3446, 2978, 1764,
1712, 1664, 1618, 1563; ESI-HRMS calcd for C21H19ClO5 + Na 409.0813,
found 409.0817.
Diethyl 5-Chloro-3-hydroxybenzofuran-2,2(3H)-dicarbox-
ylate (7j): white solid; mp 89ꢀ92 °C; 1H NMR (400 MHz, CDCl3)
δ 7.30 (d, J = 7.2 Hz, 1H), 7.20ꢀ7.17 (m, 1H), 6.88ꢀ6.86 (m, 2H), 5.85
(d, J = 7.7 Hz, 1H), 4.28ꢀ4.15 (m, 4H), 3.80 (d, J = 7.8 Hz, 1H),
1.26ꢀ1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.5, 165.4,
157.2, 131.2, 128.0, 127.4, 126.1, 112.2, 93.7, 76.1, 63.2, 63.1, 14.2, 14.1;
IR (KBr) cmꢀ1 3442, 2977, 1755, 1735, 1470; ESI-HRMS calcd for
C14H15ClO6 + Na 337.0476, found 337.0449.
Ethyl 2-Acetyl-3-(nitromethyl)-2,3-dihydrobenzofuran-
2-carboxylate (9f): yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 7.25 (t, J = 8.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.99ꢀ6.96 (m, 2H),
4.96 (s, 1H), 4.73 (d, J = 6.6 Hz, 1H), 4.62 (d, J = 6.9 Hz, 1H), 4.33ꢀ4.27
(m, 2H), 2.48 (s, 1H), 2.33 (s, 2H), 1.33ꢀ1.27 (m, 3H); 13C NMR
(101 MHz, CDCl3) δ 199.7, 165.7, 156.7, 130.3, 130.7, 124.71, 124.7,
123.6, 122.7, 122.6, 110.9, 110.5, 94.2, 75.1, 73.6, 63.4, 63.3, 45.2, 43.6,
27.9, 25.4, 13.9, 13.8; IR (KBr) cmꢀ1 2981, 1772, 1716, 1549, 1490; ESI-
HRMS calcd for C14H15NO6 + Na 316.0792, found 316.0797.
Ethyl 2-Acetyl-3-(phenylamino)-2,3-dihydrobenzofuran-
2-carboxylate (9g): gray solid; mp 122.1ꢀ124.3 °C; 1H NMR (400
MHz, CDCl3) δ 7.27 (d, J = 7.4 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H),
7.01ꢀ6.98 (m, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 6.12 (s, 1H),
4.06ꢀ4.02 (m, 1H), 3.87 (s, 1H), 3.79ꢀ3.74 (m, 1H), 2.36 (s, 3H), 0.92
(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 199.9, 165.7, 157.9,
146.7, 130.6, 129.5, 129.3, 129.1, 125.2, 125.0, 122.2, 118.7, 113.1, 110.4,
96.9, 62.7, 59.6, 26.3, 13.3; IR (KBr) cmꢀ1 3447, 2969, 1751, 1727, 1537;
ESI-HRMS calcd for C19H19NO4 + Na 348.1206, found 348.1212.
Ethyl 2-Acetyl-5-chloro-3-hydroxy-2,3-dihydrobenzofur-
Diethyl 5-Bromo-3-hydroxybenzofuran-2,2(3H)-dicarboxy-
1
late (7k): gray green solid; mp 101ꢀ103 °C; H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 7.2 Hz, 1H), 7.47ꢀ7.37 (m, 1H), 6.89ꢀ6.87
(m, 2H), 5.88 (d, J = 7.7 Hz, 1H), 4.35ꢀ4.20 (m, 4H), 3.28 (d, J = 7.8 Hz,
1H), 1.32ꢀ1.26 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.5, 165.5,
157.9, 134.3, 129.2, 128.5, 114.7, 113.0, 93.6, 76.3, 63.4, 63.3, 14.4, 14.3;
IR (KBr) cmꢀ1 3440, 2974, 1753, 1731, 1471; ESI-HRMS calcd for
C14H15BrO6 + Na 380.9943, found 380.9938.
Diethyl 3-Hydroxy-6-methoxybenzofuran-2,2(3H)-dicar-
boxylate (7l): colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J =
9.0 Hz, 1H), 6.55ꢀ6.53 (m, 2H), 5.82 (d, J = 7.8 Hz, 1H), 4.34ꢀ4.19
(m, 4H), 3.76 (s, 3H), 1.32ꢀ1.26 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 166.7, 165.7, 162.8, 160.3, 126.4, 118.3, 109.4, 109.4, 96.8, 94.2,
76.2, 63.1, 63.0, 55.9, 14.4, 14.2; IR (KBr) cmꢀ1 3451, 2982, 1760, 1742,
1474; ESI-HRMS calcd for C15H18O7 + Na 333.0943, found 333.0937.
1,10-(5-Chloro-3-(2-oxo-2-phenylethyl)-2,3-dihydroben-
zofuran-2,2-diyl)diethanone (9a): gray solid; mp 124.1ꢀ126.3 °C;
1H NMR(400 MHz, CDCl3) δ 7.90 (d, J = 7.3 Hz, 2H), 7.57 (s, 1H), 7.45
(t, J = 7.6 Hz, 2H), 7.16ꢀ6.90 (m, 1H), 7.09 (s, 1H), 6.91 (d, J = 8.5 Hz,
1H), 4.68ꢀ4.66 (m, 1H), 3.49ꢀ3.44 (m, 1H), 3.32ꢀ3.28 (m, 1H), 2.41
(s, 3H), 2.31(s, 3H); 13CNMR (101 MHz, CDCl3) δ 204.3, 201.2, 196.8,
155.8, 136.2, 133.6, 130.5, 128.9, 128.7, 128.7, 127.1, 125.3, 110.8, 101.3,
42.4, 39.3, 29.7, 28.2, 26.1; IR (KBr) cmꢀ1 3447, 2982, 1771, 1768, 1667,
1609, 1547; ESI-HRMS calcd for C20H17ClO4 + Na 379.0708, found
379.0698.
1
an-2-carboxylate (9h): white solid; mp 72.1ꢀ75.3 °C; H NMR
(400 MHz, CDCl3) δ1H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.33
(m, 1H), 7.27ꢀ7.24 (m, 1H), 6.95ꢀ6.90 (m, 1H), 5.86 (s, 1H),
4.31ꢀ4.20 (m, 2H), 3.76 (s, 1H), 2.32 (s, 2H), 2.30 (s, 1H), 1.31ꢀ1.24
(m, 3H); 13C NMR (101 MHz, CDCl3) δ 202.0, 199.6, 166.7, 165.2, 157.9,
156.3, 130.5, 130.1, 128.5, 127.9, 127.4, 127.20, 126.7, 111.9, 111.8, 98.2, 97.5,
76.2, 74.5, 62.4, 27.7, 25.8, 13.9, 13.8; IR (KBr) cmꢀ1 3451, 2976, 1748, 1741,
1455; ESI-HRMS calcd for C13H13ClO5 + Na 307.0344, found 307.0343.
Crystal Data for 6k: C22H21ClO6 (416.84120), triclinic, P1, a =
9.0198(4) Å, b = 11.6551(6) Å, c = 11.6797(5) Å, U = 1060.22(9) Å3,
Z = 2, specimen 0.586 ꢁ 0.378 ꢁ 0.259 mm3, T = 296(2) K, SIEMENS
P4 diffractometer, absorption coefficient 2.090 mmꢀ1, reflections col-
lected 17 106, independent 5709 [R(int) = 0.0394], refinement by full-
matrix least-squares on F2, data/restraints/parameters 5709/0/262,
goodness-of-fit on F2 = 1.056, final R indices [I > 2σ(I)] R1 = 0.0735,
wR2 = 0.2184, R indices (all data) R1 = 0.1263, wR2 = 0.2603, largest diff.
1,10-(3-(Nitromethyl)-2,3-dihydrobenzofuran-2,2-diyl)dietha-
none (9b): yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.25ꢀ7.23
(m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.02ꢀ6.93 (m, 2H), 4.77 (d, J = 5.3
Hz, 2H), 4.63 (s, 1H), 2.48 (s, 3H), 2.30 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 203.9, 157.1, 130.2, 124.5, 123.3, 122.7, 110.5, 99.8, 87.5, 74.1,
44.7, 28.2, 25.9; IR (KBr) cmꢀ1 2991, 1779, 1774, 1568, 1508; ESI-
HRMS calcd for C13H13NO5 + Na 286.0686, found 286.0698.
1,10-(3-(Phenylamino)-2,3-dihydrobenzofuran-2,2-diyl)di-
peak and hole 0.664 and ꢀ0.550 Åꢀ3
.
Crystal Data for 6p: C22H20BrClO6 (495.74), monoclinic, space
group P2(1)/c, a = 15.7744(6) Å, b = 10.0072(4) Å, c = 14.5277(5) Å,
U = 2131.50(14) Å3, Z = 4, specimen 0.499 ꢁ 0.453 ꢁ 0.364 mm3, T =
296(2) K, SIEMENS P4 diffractometer, absorption coefficient 2.090 mmꢀ1
,
1
ethanone (9c): white solid; mp 141.1ꢀ143.3 °C ; H NMR (400
reflections collected 17 622, independent 4844 [R(int) = 0.0497], refinement
by full-matrix least-squares on F2, data/restraints/parameters 4844/0/271,
goodness-of-fit on F2 = 1.036, final R indices [I > 2σ(I)] R1 = 0.0483, wR2 =
0.1232, R indices (all data) R1 = 0.0902, wR2 = 0.1413, largest diff. peak and
MHz, CDCl3) δ 7.33 (s, 1H), 7.28ꢀ7.21 (m, 3H), 7.07ꢀ7.02 (m, 2H),
6.83 (t, J = 7.9 Hz, 3H), 5.94 (d, J = 8.0 Hz, 1H), 3.62 (s, 1H), 2.28 (t, J =
6.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 202.7, 201.8, 157.3, 146.8,
130.6, 129.9, 125.8, 122.8, 119.30, 113.8, 110.7, 61.6, 27.6, 26.5; IR
(KBr) cmꢀ1 3403, 2985, 1763, 1759, 1618, 1480; ESI-HRMS calcd for
C18H17NO3 + Na 318.1101, found 318.1100.
hole 0.697 and ꢀ0.598 Åꢀ3
.
Crystal Data for 9g: C19H19NO4 (325.35), triclinic, space group
P1, a = 7.9833(5) Å, b = 11.2090(7) Å, c = 11.4737(12) Å, U =
848.75(12) Å3, Z = 2, specimen 0.257 ꢁ 0.0157 ꢁ 0118 mm3, T =
296(2) K, SIEMENS P4 diffractometer, absorption coefficient 0.090
mmꢀ1, reflections collected 17 622, independent 13 331 [R(int) =
0.0277], refinement by full-matrix least-squares on F2, data/restraints/
parameters 3846/0/271, goodness-of-fit on F2 = 1.036, final R indices
[I > 2σ(I)] R1 = 0.0533, wR2 = 01429, R indices (all data) R1 = 0.0979,
1,10-(3-Hydroxy-2,3-dihydrobenzofuran-2,2-diyl)dietha-
1
none (9d): white solid; mp 103.1ꢀ105.3 °C; H NMR (400 MHz,
CDCl3) δ 7.34 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 6.94 (d, J =
8.6 Hz, 1H), 5.78 (d, J = 6.2 Hz, 1H), 4.00 (d, J = 6.4 Hz, 1H), 2.32
(s, 3H), 2.20 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 202.7, 201.7,
156.5, 131.1, 128.5, 127.5, 126.3, 111.5, 103.8, 75.4, 27.8, 26.8; IR
(KBr) cmꢀ1 3445, 2982, 1757, 1742, 1465; ESI-HRMS calcd for
C12H11ClO4 + Na 277.0238, found 277.0244.
wR2 = 0.1429, largest diff. peak and hole 0.260 and ꢀ0.210 Åꢀ3
.
Ethyl 2-Acetyl-5-chloro-3-(2-oxo-2-phenylethyl)-2,3-dihydro-
benzofuran-2-carboxylate (9e): colorless liquid; 1H NMR (400 MHz,
CDCl3) δ 7.93ꢀ7.91 (m, 2H), 7.56 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz,
2H), 7.13ꢀ7.10 (m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 4.88ꢀ4.86 (m, 1H),
4.28ꢀ4.21 (m, 2H), 3.43ꢀ3.28 (m, 1H), 3.28ꢀ3.26 (m, 1H), 2.34 (d, J=2.2
Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 199.9,
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra and
b
X-ray structural data for 6k, 6p, 9g (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
7227
dx.doi.org/10.1021/jo2008675 |J. Org. Chem. 2011, 76, 7222–7228

The Journal of Organic Chemistry
NOTE
’ AUTHOR INFORMATION
(15) Ponpipom, M. M.; Yue, B. Z.; Bugianesi, R. L.; Brooker, D. R.;
Chang, M. N.; Shen, T. Y. Tetrahedron Lett. 1986, 27, 309.
(16) Solladiꢀe, G.; Boeffel, D.; Maignan, J. Tetrahedron 1995, 51, 9559.
(17) (a) Bertolini, F.; Crotti, P.; Di Bussolo, V.; Macchia, F.;
Pineschi, M. J. Org. Chem. 2007, 72, 7761. (b) Stafford, J. A.; Valvano,
N. L. J. Org. Chem. 1994, 59, 4346. (c) Procopiou, P. A.; Brodie, A. C.;
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(18) Xie, J.-W.; Huang, X.; Fan, L.-P.; Xu, D.-C.; Li, X.-S.; Su, H.;
Wen, Y.-H. Adv. Synth. Catal. 2009, 351, 3077.
Corresponding Author
*E-mail: xiejw@zjnu.cn.
’ ACKNOWLEDGMENT
We are grateful for the financial support from the National
Natural Science Foundation of China (20902083), the Natural
Science Foundation of Zhejiang Province, China (Y4090082,
R4080084), and the Program for Changjiang Scholars and
Innovative Research Team in Chinese Universities (IRT0980).
(19) Cui, P.; Liu, X.-H.; Zhi, L.-P.; Wang, X.-H.; Song, B.-A.; Zuo,
R.-B. Yingyong Huaxue 2008, 25, 820.
(20)
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