Copper-catalyzed intramolecular tandem reaction of (2-halogenphenyl)(3- phenyloxiran-2-yl)methanones: Synthesis of (Z)-aurones

Article abstract of DOI:10.1021/jo500483u

A convenient and efficient method for the copper-catalyzed synthesis of (Z)-aurones via intramolecular tandem reaction of (2-halogenphenyl)(3- phenyloxiran-2-yl)methanones is reported. Moreover, a plausible mechanism for the formation of (Z)-aurones is proposed. This is the first report on the synthesis of (Z)-aurones through copper-catalyzed Ullmann coupling reaction employing epoxides as substrates.

Full text of DOI:10.1021/jo500483u

Note
pubs.acs.org/joc
Copper-Catalyzed Intramolecular Tandem Reaction of
(2‑Halogenphenyl)(3-phenyloxiran-2-yl)methanones: Synthesis of
(Z)‑Aurones
Yiyi Weng, Qixu Chen, and Weike Su*
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
S
* Supporting Information
ABSTRACT: A convenient and efficient method for the copper-catalyzed synthesis of (Z)-aurones via intramolecular tandem
reaction of (2-halogenphenyl)(3-phenyloxiran-2-yl)methanones is reported. Moreover, a plausible mechanism for the formation
of (Z)-aurones is proposed. This is the first report on the synthesis of (Z)-aurones through copper-catalyzed Ullmann coupling
reaction employing epoxides as substrates.
urones [2-benzylidenebenzofuran-3(2H)-ones] are iso-
mers of flavones, a subclass of the flavonoid family,1
(2-halogenphenyl)(3-phenyloxiran-2-yl)methanones could act
as active substrates for further aryl C−O coupling. Herein, we
would like to describe a copper-catalyzed intramolecular
cascade ring-opening/coupling reaction to prepare aurones
from (2-halogenphenyl)(3-phenyloxiran-2-yl)methanones
(Scheme 1).
A
widely present in fruits and the bright golden yellow color of
flowers.2 Aurones exhibit a wide range of biological activities,1
such as antioxidant,3 insect antifeedant,4 anticancer,5 inhibition
of tyrosinase,6 antiparasitic,7 antimicrobial,8 etc. Therefore, the
synthesis of aurones is still in great demand due to their wide
range of biological activities.
Scheme 1. Copper-Catalzyed Intramolecular Tandem
Process for Synthesis of Aurone
Common synthetic routes for the preparation of aurones
involve condensation of benzaldehydes with benzofuran-
3(2H)-ones catalyzed by alumina,9 acid,5 or base,6 but this
aldol-like coupling reaction always requires the multistep
synthesis of benzofuran-3(2H)-ones from available starting
materials. Other methods such as oxidative cyclization of 2′-
hydroxychalcones catalyzed by Thallium(III) nitrate (3
equiv)10 or Hg(OAc)2 (1 equiv),11 ring-closing reaction of 2-
(1-hydroxy-3-arylprop-2-ynyl)phenols catalyzed by AuCl12 or
silver nanoparticles,13 and alkynylation−cyclization of terminal
alkynes catalyzed by Cy3P−silver complex with salicylaldehydes
have also been reported.14 However, many of these methods
are limited in their use by not easily available starting materials,
harsh reaction conditions, low selectivity, expensive metal
catalysts, etc. Thus, a general and practical method to prepare
aurones is still required.
In the past two decades, Cu-mediated C-X (X = N, O, S,
etc.) bond formation reactions have come into a renaissance.15
Among them copper-catalyzed O-arylation has attracted much
attention, and many five- and six-membered oxygen hetero-
cycles have been constructed with copper-catalyzed O-
arylation.16 However, most of the reactions are hydroxyl or
carbonyl coupling arylations. There are no reports of copper-
catalyzed intramolecular arylations of epoxides. We realized that
In initial experiments, (2-bromophenyl)(3-phenyloxiran-2-
yl)methanone 1a17 was chosen to screen the optimal reaction
conditions (Table 1).18 Fortunately, the corresponding product
2a was obtained in 59% yield when the reaction was conducted
in the presence of catalyst CuI (10 mol %), ligand 2,2-bipyridyl
(20 mol %), and base Cs2CO3 (2 equiv) in DMF at 100 °C for
8 h (Table 1, entry 1). The product configuration was
confirmed with the 1H NMR spectra of 2a, in which the vinylic
proton was consistent with reported (Z)-aurones.12 Only the Z-
1
isomer was observed through H NMR spectroscopy of the
crude product.
In order to obtain more satisfactory results, a series of
experiments were carried out using different temperatures,
Received: February 27, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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Note
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
ligand
2,2′-dipyridyl
base
solvent
DMF
temp (°C)
yield (%)
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
100
105
115
105
105
105
105
105
105
105
105
105
105
105
105
105
105
105
59
2
2,2′-dipyridyl
2,2′-dipyridyl
2,2′-dipyridyl
2,2′-dipyridyl
2,2′-dipyridyl
2,2′-dipyridyl
2,2′-dipyridyl
2,2′-dipyridyl
2,2′-dipyridyl
DMF
70
3
DMF
63
4
toluene
1,4-dioxane
DMSO
DMF
trace
38
5
6
41
7
trace
54
8
DABCO
pyridine
K3PO4
DMF
9
DMF
trace
43
10
11
12
13
14
15
16
17
18
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
43
DMAP
DMF
57
8-hydroxyquinoline
L-proline
DMF
38
DMF
13
1,10-phenanthroline hydrate
1,10-phenanthroline
DMF
79
DMF
82
1,10-phenanthroline
DMF
69
1,10-phenanthroline
DMF
64
a
b
All reactions were run using 1a (1.0 mmol) as substrate under N2 protection, and the reaction time was determined by TLC. Yield based on 1a.
a
solvents, bases, ligands, and copper catalysts (Table 1). Raising
the reaction temperature to 105 °C had a good effect on the
outcome (Table 1, entry 2, 70% yield). Solvent screening
showed that using 1,4-dioxane, DMSO, and toluene made the
yields sharply decline (Table 1, entries 4−6). Among the bases
tested (Cs2CO3, K2CO3, DABCO, pyridine, K3PO4), Cs2CO3
was found to be the optimal base. Many ligands such as 2,2′-
dipyridyl, DMAP, 8-hydroxy quinolone, L-proline, 1,10-
phenanthroline, and 1,10-phenanthroline hydrate were
screened, and 1,10-phenanthroline was proved to be the most
efficient ligand (Table 1, entry 16). When the copper source
was switched to CuBr and CuCl (Table 1, entries 17 and 18),
the yields slightly decreased. Finally, the optimal reaction
conditions were identified as described in Table 1, entry 16.
With the encouraging initial results in hand, a more detailed
screening of conditions was carried out by changing the amount
of CuI, 1,10-phenanthroline, and Cs2CO3 (Table 2).
Interestingly, the yield increased slightly by decreasing the
base loading to 1.5 mmol (Table 2, entry 7, 84% yield). The
optimal reaction was established with 1.5 equiv of Cs2CO3 in
DMF catalyzed by CuI (10 mol %)/1,10-phenanthroline (20
mol %) at 105 °C.
With the optimized reaction conditions in hand, various
substituted (2-halogenphenyl)(3-phenyloxiran-2-yl)-
methanones were used to test the generality of the reaction
(Table 3). Both aryl R1 groups bearing substituents with
electron-donating (Table 3, entries 2−5) or electron-with-
drawing groups (Table 3, entries 6−8) were well tolerated.
Substituents R1 in the ortho and meta position or R1 = H usually
afforded the higher yields, while R1 in the para position gave
moderate yields. The reactions of compounds 1j, 1k, and 1l, all
with substituent R2 possessing a m-methoxy group, worked well
to give products 2j, 2k, and 2l, respectively (Table 3, entries
10−12). The successful synthesis of substituted aurones from
Table 2. Investigation of the Amount of the Reagents
b
entry catalyst (mol %) ligand (mol %)
base (mmol) yield (%)
1
2
3
4
5
6
7
8
5
10
20
10
10
10
10
10
10
20
40
10
20
20
20
20
2.0
2.0
2.0
2.0
1.0
1.2
1.5
1.7
60
82
63
66
52
75
84
77
a
All the reactions were run using 1a (1 mmol) as substrate in DMF at
105 °C, catalyst: CuI, ligand: 1,10-Phenanthroline, base: Cs2CO3
b
under N2 protect and the reaction time determined by TLC. Yield
based on 1a.
bromo precursors encouraged us to investigate the reactivity of
the corresponding iodo and chloro substituents. It is worth
mentioning that (2-chlorophenyl)(3-phenyloxiran-2-yl)-
methanones under the standard reaction conditions could
afford the corresponding products (Table 3, entries 13 and 14)
in moderate yields. We also attempted to synthesize 2-
alkylidenecoumaranone in order to test the generality of the
reaction but failed to get the desired products.19
Many articles have reported that the product aurones may
exist as E- and Z-isomers, and the Z-isomer is generally
regarded as the thermodynamically stable form.20 The relative
1
configuration of aurones can be determined by using H NMR
and 13C NMR spectroscopy.21 The regio- and stereochemistry
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Note
a
Table 3. Scope of the Copper-Catalyzed Aurones Synthesis
b
entry
R2
Ar
X
time (h)
product
yield (%)
1
Ph
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
I
4.0
4.5
4.5
4.5
4.5
5.0
5.0
5.0
5.5
5.0
5.0
6.0
6.0
6.5
4.5
4.5
2a
2b
2c
2d
2e
2f
84
79
67
81
74
80
62
57
81
66
75
43
49
59
52
59
2
3-Me-C6H4
4-Me-C6H4
2-OMe-C6H4
3-OMe-C6H4
2-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
1-naphthyl
Ph
3
4
5
6
7
2g
2h
2i
8
9
10
11
12
13
14
15
16
5-OMe
5-OMe
5-OMe
2j
3-Me-C6H4
4-Cl-C6H4
Ph
2k
2l
2a
2b
2b
2i
3-Me-C6H4
3-Me-C6H4
1-naphthyl
I
a
Reaction conditions: (2-halogenphenyl)(3-phenyloxiran-2-yl)methanones (1 mmol), CuI (10 mol %), 1,10-phenanthroline (20 mol %), Cs2CO3
b
(1.5 mmol), in DMF (6 mL), N2 protect at 105 °C. The time of the reaction monitored by TLC.
Scheme 2. Applications in the Synthesis of the Natural Product 2g
of the aurones 2a, 2d, and 2g could be determined by
2-yl)methanone (1g, 2.026g, 6 mmol) generated product (Z)-
1
comparing both H and 13C chemical shifts with the reported
2-(4-chlorobenzylidene)benzofuran-3(2H)-one (2g, 1.008g) in
65% yield through an intramolecular tandem ring-opening/
coupling cyclization process. The overall yield was 55%.
The possible mechanism of the reaction is proposed in
Scheme 3. CuIL oxidative addition of the aryl halide generated
A, followed by a coordination to the oxygen of epoxy to give B.
Subsequently, the halide ion attacks on the benzyl position of B
to give copper(III) intermediates C18d with regeneration of X-
CuIL.22,23 Then, a reductive elimination to release intermedi-
ates D occurred. At last, the intermediates D underwent an E1-
like β-elimination of HX affording the thermodynamically more
stable Z-products.
(Z)-aurones.12
The product (Z)-2-(4-chlorobenzylidene)benzofuran-3(2H)-
one 2g is a natural product that can be isolated from the marine
brown algaSpatoglossum variabile.20 It could also be systhesized
by this method (Table 3, entry 7, 62%). We took the reaction
to gram scale. The Claisen condensation reaction of 1-(2-
bromophenyl)ethanone and 4-chlorobenzaldehyde produced
(2-bromophenyl)(3-(4-chlorophenyl)oxiran-2-yl)methanone 3
(Scheme 2). Subsequently, (2-bromophenyl)(3-(4-
chlorophenyl)oxiran-2-yl)methanone 3 was oxidized to the
(2-bromophenyl)(3-(4-chlorophenyl) oxiran-2-yl)methanone
1g. To our delight, 1g could easily precipitate from the
reaction system, and the yield of the two steps was 85%. Then
the intermediate (2-bromophenyl)(3-(4-chlorophenyl)oxiran-
In summary, we have developed an original and convenient
one-pot protocol to synthesize (Z)-aurone through Cu-
catalyzed intramolecular tandem cyclization reaction. The
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Note
Scheme 3. Possible Mechanism of the Reaction
Hz, 1H), 7.41−7.30 (m, 2H), 7.27−7.20 (m, 1H), 7.15−7.12 (m, 3H),
4.10 (d, J = 1.6 Hz, 1H), 4.05 (d, J = 1.6 Hz, 1H), 2.34 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.0, 138.5, 138.3, 134.9,
133.3, 132.5, 129.6, 128.4, 127.4, 126.1, 122.9, 119.7, 62.4, 60.5, 21.4;
MS (ESI) 338.8 (98), 340.8 (100) ([M + Na]+); HRMS (ESI) m/z
[M + NH4]+ calcd for C16H17BrNO2 334.0437, found 334.0436.
(2-Bromophenyl)(3-(p-tolyl)oxiran-2-yl)methanone (1c).
reaction is applicable to a variety of (2-halogenphenyl)(3-
phenyloxiran-2-yl)methanones, and moderate to good yields
are attained. The proton NMR spectroscopic data reported for
the product match those reported for the known (Z)-aurones.
We proposed a possible mechanism to explain the results.
EXPERIMENTAL SECTION
1
■
White solid (2.38 g, 75% yield); mp 76.0−77.0 °C; H NMR (400
General Methods. All reagents were obtained from commercial
suppliers and used without further purification, unless otherwise
indicated. Reactions were performed in oven-dried round-bottom
flasks. TLC analysis was performed using precoated glass plates. NMR
MHz, CDCl3, ppm) δ 7.62 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 1.2 Hz,
2H), 7.22−7.16 (m, 5H), 4.05 (d, J = 1.6 Hz, 1H), 4.04 (d, J = 1.6 Hz,
1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.0,
138.8, 138.6, 133.4, 132.5, 132.0, 129.7, 129.2, 127.4, 125.7, 119.7,
62.5, 60.6, 21.4; MS (ESI) 338.7 (100), 340.8 (95) ([M + Na]+);
HRMS (ESI) m/z [M + NH4]+ calcd for C16H17BrNO2 334.0437,
found 334.0451.
1
spectra were recorded with 400 MHz spectrometer for H and 100
MHz for 13C, and TMS was used as internal standard. All reactions
were monitored by TLC.
Typical Procedure for Synthesis of (2-Bromophenyl)(3-
phenyloxiran-2-yl)methanone (1a).17 An aqueous solution of
NaOH (10.0 mL, 1 mol/L) was slowly added to a solution of 1-(2-
bromophenyl)ethanone (2.00 g, 10 mmol) and benzaldehyde (1.06 g,
10 mmol) in ethanol (20 mL) at 0 °C. The solution was stirred at
room temperature until disappearance of starting material (3−10 h) as
monitored by TLC. Then the reaction mixture was cooled to 0 °C,
and water was added (20 mL), resulting in a light yellow viscous liquid
that was isolated from the solution and used directly in the next step
without purification. The obtained product was dissolved in methanol
(15 mL), and 10% aqueous NaOH (0.5 mL, 0.1 mmol) was added.
Then, 3.0 mL of 30% hydrogen peroxide was added slowly to the
resulting mixture at 0 °C. The solution was stirred at room
temperature and monitored by TLC. Then the reaction mixture was
cooled to 0 °C, and water was added (20 mL), resulting in a light
yellow viscous liquid that was separated from the solution. The crude
product was purified by column chromatography on silica gel using
petroleum ether/EtOAc (20:1) to give the desired product 1a (2.27 g,
(2-Bromophenyl)(3-(2-methoxyphenyl)oxiran-2-yl)-
methanone (1d). White solid (2.36 g, 71% yield); mp 80.1−82.0 °C;
1H NMR (400 MHz, CDCl3, ppm) δ 7.61 (dd, J = 8.0, 1.2 Hz, 1H),
7.55 (dd, J = 7.6, 2.0 Hz, 1H), 7.41−7.26 (m, 3H), 7.20 (dd, J = 7.6,
1.6 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.42 (d,
J = 2.0 Hz, 1H), 4.00 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 197.2, 158.0, 138.4, 133.3, 132.2, 129.5,
129.4, 127.1, 125.0, 123.5, 120.5, 119.6, 110.2, 61.8, 56.4, 55.4; MS
(ESI) 332.7 (97), 334.8 (100) ([M + H]+); HRMS (ESI) m/z [M +
NH4]+ calcd for C16H17BrNO3 350.0386, found 350.0376.
(2-Bromophenyl)(3-(3-methoxyphenyl)oxiran-2-yl)-
1
methanone (1e). Pale yellow viscous liquid (2.43 g, 73% yield); H
NMR (400 MHz, CDCl3, ppm) δ 7.62−7.57 (dd, J = 8.0, 1.2 Hz, 1H),
7.51 (dd, J = 7.6, 2.0 Hz, 1H), 7.39−7.34 (m, 2H), 7.26 (t, J = 8.0 Hz,
1H), 6.95−6.91 (m, 1H), 6.91−6.83 (m, 2H), 4.09 (d, J = 2.0 Hz,
1H), 4.07 (d, J = 2.0 Hz, 1H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 196.8, 159.7, 138.5, 136.6, 133.4, 132.6, 129.7, 129.6,
127.4, 119.7, 118.2, 114.6, 110.8, 62.4, 60.4, 55.3; MS (ESI) 355.8
(98), 357.8 (100) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+ calcd
for C16H17BrNO3 350.0386, found 350.0392.
1
75%) as a pale yellow viscous liquid.: H NMR (400 MHz, CDCl3,
ppm) δ 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.52 (dd, J = 7.6, 1.6 Hz, 1H),
7.43−7.29 (m, 7H), 4.11 (d, J = 2.0 Hz, 1H), 4.09 (d, J = 2.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.9, 138.6, 135.0, 133.4,
132.6, 129.7, 128.9, 128.5, 127.4, 125.7, 119.7, 62.5, 60.5; MS (ESI)
324.8 (90), 326.7 (100) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+
calcd for C15H15BrNO2 320.0281, found 320.0294.
(2-Bromophenyl)(3-(m-tolyl)oxiran-2-yl)methanone (1b).
Yellow viscous liquid (2.31 g, 73% yield); 1H NMR (400 MHz,
CDCl3, ppm) δ 7.58 (dd, J = 8.0, 1.2 Hz, 1H), 7.51 (dd, J = 7.2, 2.0
(2-Bromophenyl)(3-(2-chlorophenyl)oxiran-2-yl)methanone
1
(1f). White solid (2.87 g, 85% yield); mp 55.5−57.5 °C; H NMR
(400 MHz, CDCl3, ppm) δ 7.62 (dd, J = 8.0, 1.2 Hz, 1H), 7.54 (dd, J
= 7.6, 1.6 Hz, 1H), 7.44−7.33 (m, 3H), 7.32−7.25 (m, 3H), 4.45 (d, J
= 2.0 Hz, 1H), 3.97 (d, J = 2.0 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 196.5,138.3, 133.4, 133.3, 133.1, 132.5, 129.6, 129.5,
129.2, 127.3, 127.0, 125.6, 119.7, 61.8, 57.6; MS (ESI) 358.7 (72),
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Note
360.7 (100) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+ calcd for
C15H14BrClNO2 353.9891, found 353.9892.
129.6, 128.4, 126.9, 126.1, 122.9, 62.8, 60.4, 21.4; MS (ESI) 294.8
(100), 296.9 (40) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+ calcd
for C16H17ClNO2 290.0942, found 290.0945.
(2-Bromophenyl)(3-(4-chlorophenyl)oxiran-2-yl)methanone
1
(1g). White solid (2.87 g, 85% yield); mp 80.0−80.9 °C; H NMR
(2-Iodophenyl)(3-(m-tolyl)oxiran-2-yl)methanone (1o). White
yellow viscous liquid (2.80 g, 77% yield); 1H NMR (400 MHz, CDCl3,
ppm) δ 7.88 (dd, J = 7.6, 0.8 Hz, 1H), 7.47−7.37 (m, 2H), 7.27−7.20
(m, 1H), 7.19−7.08 (m, 4H), 4.05−4.03 (m, 2H), 2.34 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.8, 141.6, 140.1, 138.3,
134.7, 132.3, 129.7, 129.0, 128.4, 127.9, 126.2, 122.9, 91.6, 61.8, 60.4,
21.4; MS (ESI) 386.7 (100), 387.8 (21) ([M + Na]+); HRMS (ESI)
m/z [M + NH4]+ calcd for C16H17INO2 382.0298, found 382.0312.
(2-Iodophenyl)(3-(naphthalen-1-yl)oxiran-2-yl)methanone
(400 MHz, CDCl3, ppm) δ 7.60 (dd, J = 7.6, 0.8 Hz, 1H), 7.54−7.47
(m, 3H), 7.44−7.33 (m, 2H), 7.22−7.20 (m, 2H), 4.06−4.08 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.5, 138.4, 134.8, 133.6,
133.4, 132.7, 129.8, 128.8, 127.5, 127.0, 119.7, 62.4, 59.9; MS (ESI)
358.7 (72), 360.7 (100) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+
calcd for C15H14BrClNO2 353.9891, found 353.9876.
(2-Bromophenyl)(3-(4-bromophenyl)oxiran-2-yl)methanone
1
(1h). White solid (3.13 g, 82% yield); mp 74.5−76.0 °C; H NMR
1
(400 MHz, CDCl3, ppm) δ 7.63 (dd, J = 8.0, 1.2 Hz, 1H), 7.57−7.54
(m, 2H), 7.45−7.27 (m, 4H), 7.24−7.18 (m, 1H), 4.39 (d, J = 2.0 Hz,
1H), 3.96 (d, J = 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 196.4,138.4, 134.1, 133.4, 132.7, 131.7, 129.8, 127.5, 127.3,
122.9, 119.7, 62.3, 59.9; MS (ESI) 404.7 (100), 406.7 (43) ([M +
Na]+); HRMS (ESI) m/z [M + NH4]+ calcd for C15H14Br2NO2
397.9386, found 397.9384.
(1p). White solid (3.16 g, 79% yield); mp 104.0−106.8 °C; H NMR
(400 MHz, CDCl3, ppm) δ 8.12−8.03 (m, 1H), 7.92 (dd, J = 8.0, 0.8
Hz, 1H), 7.89−7.79 (m, 2H), 7.59−7.39 (m, 6H), 7.19−7.15 (m, 1H),
4.72 (d, J = 2.0 Hz, 1H), 4.05 (d, J = 2.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 198.2, 141.4, 140.2, 133.1, 132.4, 131.0,131.0,
129.0, 128.9, 128.7, 127.9, 126.6, 126.0, 125.3, 122.6, 122.4, 91.8, 61.4,
58.2; MS (ESI) 422.8 (100), 423.8 (21) ([M + Na]+); HRMS (ESI)
m/z [M + H]+ calcd for C19H14IO2 401.0033, found 401.0031.
Typical Procedure for Synthesis of (Z)-2-Benzylidenebenzo-
furan-3(2H)-one (2a). A mixture of (2-bromophenyl)(3-phenyl-
oxiran-2-yl)methanone 1a (303 mg, 1 mmol), Cs2CO3 (487 mg, 1.5
mmol), CuI (10 mol %), 1,10-phenanthroline (20 mol %) and DMF
(6 mL) was heated in a Schlenk tube at 105 °C under nitrogen. The
reaction was monitored by TLC until disappearance of starting
material (4 h). Then the cooled reaction mixture was dissolved in H2O
and extracted with EtOAc. The combined organic layer was dried
(Mg2SO4). The product was further purified by column chromatog-
raphy (silica gel, petroleum ether/EtOAc (20:1)) to afford the pure
product 2a (187 mg, 84%) as a pale yellow solid: mp 102.0−104.5 °C;
1H NMR (400 MHz, CDCl3, ppm) δ 7.91−7.89 (m, 2H), 7.78 (d, J =
(2-Bromophenyl)(3-(naphthalen-1-yl)oxiran-2-yl)-
methanone (1i). Pale yellow solid (2.68 g, 76% yield); mp 105.0−
1
107.7 °C; H NMR (400 MHz, CDCl3, ppm) δ 8.11−8.04 (m, 1H),
7.91−7.81 (m, 2H), 7.65−7.33 (m, 8H), 4.75 (d, J = 1.6 Hz, 1H), 4.11
(d, J = 1.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.3,
138.4, 133.4, 133.1, 132.5, 131.0, 129.5, 128.8, 128.6, 127.3, 126.5,
125.9, 125.2, 122.5, 122.3, 119.7, 61.9, 58.3; MS (ESI) 374.8 (100),
376.8 (94) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+ calcd for
C19H17BrNO2 370.0437, found 370.0448.
(2-Bromo-5-methoxyphenyl)(3-phenyloxiran-2-yl)-
methanone (1j). White solid (2.43 g, 73% yield); mp 84.0−85.9 °C;
1H NMR (400 MHz, CDCl3, ppm) δ 7.46 (d, J = 8.8 Hz, 1H), 7.40−
7.30 (m, 5H), 7.04 (d, J = 3.2 Hz, 1H), 6.90 (dd, J = 8.8, 3.2 Hz, 1H),
4.10 (d, J = 1.6 Hz, 1H), 4.12 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.8, 158.7, 139.2,135.0,
134.2, 128.8, 128.5, 125.7, 119.1, 114.7, 109.9, 62.4, 60.6, 55.7; MS
(ESI) 354.8 (100), 356.8 (98) ([M + Na]+); HRMS (ESI) m/z [M +
NH4]+ calcd for C16H17BrNO3 350.0386, found 350.0388.
7.6 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.47−7.35 (m, 3H), 7.30 (d, J =
8.4 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.87 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 184.5, 165.9, 146.6, 136.7, 132.1, 131.4,
129.7, 128.7, 124.5, 123.3, 121.5, 113.0, 112.9; MS (ESI) 223.2 (100)
([M + H]+). The data were consistent with that reported in the
literature.12
(2-Bromo-5-methoxyphenyl)(3-(m-tolyl)oxiran-2-yl)-
methanone (1k). White solid (2.64 g, 76% yield); mp 108.9−110.0
(Z)-2-(3-Methylbenzylidene)benzofuran-3(2H)-one (2b). Yel-
1
1
°C; H NMR (400 MHz, CDCl3, ppm) δ 7.45 (d, J = 8.8 Hz, 1H),
low solid (187 mg, 79% yield); mp 72.2−74.5 °C; H NMR (400
7.24−7.22 (m, 1H), 7.15−7.12 (m, 3H), 7.03 (d, J = 3.2 Hz, 1H), 6.89
(dd, J = 8.8, 3.2 Hz, 1H), 4.11 (d, J = 1.6 Hz, 1H), 4.06 (d, J = 1.6 Hz,
1H), 3.80 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 196.9, 158.7, 139.3, 138.3, 134.9, 134.2, 129.7, 128.4, 126.2,
122.9, 119.0, 114.7, 110.0, 62.4, 60.7, 55.7, 21.4; MS (ESI) 368.7 (94),
370.8 (100) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+ calcd for
C17H19BrNO3 364.0543, found 364.0549.
MHz, CDCl3, ppm) δ 7.79 (dd, J = 7.6, 0.8 Hz, 1H), 7.74 (d, J = 7.6
Hz, 1H), 7.68 (s, 1H), 7.64−7.63 (m, 1H), 7.33 (dd, J = 7.6, 7.2 Hz,
2H), 7.22−7.20 (m, 2H), 6.85 (s, 1H), 2.41 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, ppm) δ 184.4, 165.9, 146.6, 138.3, 136.6, 132.0,
130.6, 129.7, 128.6, 128.5, 124.5, 123.3, 121.5, 113.2, 112.8, 21.5; MS
(ESI) 237.1 (100) ([M + H]+). The data were consistent with that
reported in the literature.24
(2-Bromo-5-methoxyphenyl)(3-(4-chlorophenyl)oxiran-2-
(Z)-2-(4-Methylbenzylidene)benzofuran-3(2H)-one (2c). Yel-
1
yl)methanone (1l). Pale yellow solid (2.98 g, 81% yield); mp 77.0−
low solid (161 mg, 68% yield); Mp. 91.4−94.7 °C; H NMR (400
1
78.7 °C; H NMR (400 MHz, CDCl3, ppm) δ 7.46 (d, J = 8.8 Hz,
MHz, CDCl3, ppm) δ 7.82−7.78 (m, 3H), 7.64−7.62 (m, 1H), 7.32
(d, J = 8.4 Hz, 1H), 7.26−7.24 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 6.88
(s, 1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6, ppm) δ
183.2, 165.1, 145.7, 140.1, 137.4, 131.3, 129.5, 128.9, 124.1, 123.8,
120.8, 113.1, 112.4, 21.3; MS (ESI) 495.1 (100) ([2M + Na]+). The
data were consistent with that reported in the literature.3
1H), 7.18−7.10 (m, 4H), 7.03 (d, J = 3.2 Hz, 1H), 6.90 (dd, J = 8.8,
3.2 Hz, 1H), 4.10−4.06 (m, 2H), 3.81 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 196.4, 158.8, 139.2, 134.8, 134.3, 133.7, 128.8,
127.1, 119.3, 114.9, 110.0, 62.4, 60.0, 55.8; MS (ESI) 388.6 (55), 390.7
(100) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+ calcd for
C16H16BrClNO3 383.9997, found 383.9979.
(2-Chlorophenyl)(3-phenyloxiran-2-yl)methanone (1m).
White viscous liquid (1.89 g, 73% yield); 1H NMR (400 MHz,
CDCl3, ppm) δ 7.58 (dd, J = 7.6, 1.6 Hz, 1H), 7.44−7.28 (m, 8H),
4.13 (d, J = 2.0 Hz, 1H), 4.07 (d, J = 2.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 195.8, 136.2, 135.0, 132.7, 131.8, 130.2, 129.8,
128.7, 128.4, 126.9, 125.6, 62.7, 60.2; MS (ESI) 280.8 (100), 282.8
(36) ([M + Na]+); HRMS (ESI) m/z [M + NH4]+ calcd for
C15H15ClNO2 276.0786, found 276.0795.
(2-Chlorophenyl)(3-(m-tolyl)oxiran-2-yl)methanone (1n).
White viscous liquid (2.10 g, 77% yield); 1H NMR (400 MHz,
CDCl3, ppm) δ 7.59 (m, 1H), 7.46−7.37 (m, 2H), 7.36−7.31 (m,
1H), 7.26−7.22 (m, 1H), 7.17−7.09 (m, 3H), 4.14 (d, J = 1.6 Hz,
1H), 4.05 (d, J = 1.6 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 196.0, 138.2, 136.3, 134.9, 132.7, 131.9, 130.2, 129.8,
(Z)-2-(2-Methoxybenzylidene)benzofuran-3(2H)-one (2d).
1
Yellow solid (204 mg, 81% yield); mp 170.8−172.5 °C; H NMR
(400 MHz, CDCl3, ppm) δ 8.29 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6
Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.41−7.28 (m, 2H),
7.19 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.4 Hz,
1H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 184.3,
165.7, 158.7, 146.8, 136.4, 131.9, 131.3, 124.5, 123.1, 121.8, 121.3,
120.7, 112.8, 110.7, 107.2, 55.7; MS (ESI) 253.1 (100) ([M + H]+).
The data were consistent with that reported in the literature.12
(Z)-2-(3-Methoxybenzylidene)benzofuran-3(2H)-one (2e).
1
Yellow solid (187 mg, 74% yield); mp 115.7−117.3 °C; H NMR
(400 MHz, CDCl3, ppm) δ 7.82−7.78 (m, 1H), 7.65 (ddd, J = 8.4, 7.2,
1.6 Hz, 1H), 7.50−7.48 (m, 2H), 7.39−7.30 (m, 2H), 7.21 (t, J = 7.6
Hz, 1H), 6.98−6.94 (m, 1H), 6.86 (s, 1H), 3.88 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3, ppm) δ 184.5, 165.9, 159.6, 146.8, 136.8,
4222
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The Journal of Organic Chemistry
Note
133.4, 129.7, 124.6, 124.2, 123.4, 121.5, 116.4, 115.6, 112.8, 55.4; MS
(ESI) 253.1 (100) ([M + H]+). The data were consistent with that
reported in the literature.24
AUTHOR INFORMATION
Corresponding Author
*Fax: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.
Notes
■
(Z)-2-(2-Chlorobenzylidene)benzofuran-3(2H)-one (2f). Pale
yellow solid (205 mg, 80% yield); mp 136.5−137.6 °C; 1H NMR (400
MHz, CDCl3, ppm) δ 8.32 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (d, J = 7.6
Hz, 1H), 7.70−7.60 (m, 1H), 7.43 (dd, J = 8.0, 1.2 Hz, 1H), 7.40−
7.26 (m, 4H), 7.21 (t, J = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 184.2, 165.9, 147.4, 136.9, 135.8, 132.1, 130.4, 130.2,
129.8, 126.9, 124.7, 123.5, 121.4, 112.8, 107.8; MS (ESI) 257.0 (100),
259.0 (35) ([M + H]+) ([M + H]+). The data were consistent with
that reported in the literature.25
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 21276238, 21376221) and Natural Science
Foundation of Zhejiang Province (No. LY13B020015) for
financial support.
(Z)-2-(4-Chlorobenzylidene)benzofuran-3(2H)-one (2g). Or-
1
ange solid (159 mg, 62% yield); mp 160.8−162.4 °C; H NMR (400
MHz, CDCl3, ppm) δ 7.84 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 7.6 Hz,
1H), 7.67−7.63 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz,
1H), 7.21 (d, J = 7.6 Hz, 1H), 6.82 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 184.3, 165.8, 146.7, 136.8, 135.6, 132.4, 130.6, 129.0,
124.6, 123.5, 121.3, 112.8, 111.4; MS (ESI) 257.1 (100), 259.1 (30)
([M + H]+); The data were consistent with that reported in the
literature.12
REFERENCES
■
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1
low solid (172 mg, 57% yield); mp 163.1−164.4 °C; H NMR (400
MHz, CDCl3, ppm) δ 7.84−7.74 (m, 3H), 7.66 (ddd, J = 8.4, 7.2, 1.6
Hz, 1H), 7.61−7.54 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0
Hz, 1H), 6.80 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
184.3, 165.8, 146.9, 136.9, 132.6, 132.0, 131.1, 124.6, 124.2, 123.5,
121.4, 112.8, 111.4; MS (ESI) 301.0 (98), 303.0 (100) ([M + H]+).
The data were consistent with that reported in the literature.26
(Z)-2-(Naphthalen-1-ylmethylene)benzofuran-3(2H)-one
(2i). Yellow solid (221 mg, 81% yield); mp 139.1−140.8 °C; 1H NMR
(400 MHz, DMSO-d6, ppm) δ 8.40−8.29 (m, 2H), 8.03 (dd, J = 14.8,
8.0 Hz, 2H), 7.82 (dd, J = 17.6, 8.0 Hz, 2H), 7.73−7.52 (m, 5H), 7.33
(t, J = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 184.3,
166.0, 147.5, 136.7, 133.5, 132.1, 130.4, 130.1, 128.8, 128.1, 126.9,
126.0, 125.4, 124.6, 123.4, 123.2, 121.6, 112.9, 108.4; MS (ESI) 273.0
(100) ([M + H]+); HRMS (ESI) C19H12NaO2 ([M + Na]+): calcd.:
295.0730, Found: 295.0728.
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(Z)-2-Benzylidene-5-methoxybenzofuran-3(2H)-one (2j). Yel-
1
low solid (166 mg, 66% yield); mp 122.1−124.3 °C; H NMR (400
(13) Yu, M.; Lin, M.-D.; Han, C.-Y.; Zhu, L.; Li, C.-J.; Yao, X.-Q.
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MHz, DMSO-d6, ppm) δ 7.94 (d, J = 7.2 Hz, 2H), 7.51−7.41 (m, 4H),
7.34 (dd, J = 8.8, 2.8 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 6.88 (s, 1H),
3.78 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6, ppm) δ 183.4,
160.2, 155.6, 146.8, 131.7, 131.1, 129.8, 128.8, 125.9, 120.9, 114.0,
112.00, 105.4, 55.8; MS (ESI) 253.0 (100) ([M + H]+); HRMS (ESI)
m/z [M + Na]+ calcd for C16H12NaO3 275.0679, found 275.0683.
(Z)-5-Methoxy-2-(3-methylbenzylidene) benzofuran-3(2H)-
one (2k). Yellow solid (199 mg, 75% yield); mp 125.4−127.1 °C;
1H NMR (400 MHz, CDCl3, ppm) δ 7.71 (d, J = 7.6 Hz, 1H), 7.66 (s,
(14) Yu, M.; Skouta, R.; Zhou, L.; Jiang, H.-F.; Yao, X.; Li, C.-J. J.
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(c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096−
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1H), 7.32 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 1.2 Hz, 2H), 7.19−7.17 (m,
2H), 6.82 (s, 1H), 3.81 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 184.6, 160.9, 155.8, 147.4, 138.3, 132.0, 131.9,
130.6, 128.6, 125.9, 121.6, 115.2, 113.6, 113.2, 105.1, 55.9, 21.5; MS
(ESI) 267.1 (100) ([M + H]+); HRMS (ESI) m/z [M + Na]+ calcd
for C17H14NaO3 289.0835, found 289.0834.
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(Z)-2-(4-Chlorobenzylidene)-5-methoxybenzofuran-3(2H)-
1
one (2l). Yellow solid (123 mg, 43% yield); mp 151.6−153.8 °C; H
NMR (400 MHz, CDCl3, ppm) δ 7.78 (d, J = 8.0 Hz, 2H), 7.37 (d, J =
8.4 Hz, 2H), 7.15−7.21 (m, 3H), 6.76 (s, 1H), 3.81 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3, ppm) δ 184.4, 160.9, 155.9, 147.5, 135.6,
132.4, 130.7, 129.0, 126.1, 121.4, 113.6, 111.4, 105.2, 55.9; MS (ESI)
287.1 (100), 289.1 (35) ([M + H]+); HRMS (ESI) m/z [M + Na]+
calcd for C16H11ClNaO3 309.0289, found 309.0284.
(19) The reactions was performed using (2-bromophenyl)(3-
isopropyloxiran-2-yl)methanone as substrate, CuI as catalyst, 1,10-
phenanthroline as ligand, and Cs2CO3 as base in DMF at 105 °C
under N2 protect. However, we obtained a very complex mixture and
there was no desired product observed by LC−MS analysis.
(20) Atta-ur-Rahman; Choudhary, M. I.; Hayat, S.; Khan, A. M.;
Ahmed, A. Chem. Pharm. Bull. 2001, 49, 105−107.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Investigation of the amount of the reagents, copies of H and
13C NMR spectra for 1a−p and 2a−l. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Note
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4224
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