A convenient two-step synthesis of 2-arylbenzofurans

Article abstract of DOI:10.1055/s-0029-1217129

A novel and convenient two-step synthesis of 2-arylbenzofurans is described which proceeds via a selective cross-pinacol-type coupling between a salicylaldehyde and an aromatic aldehyde, followed by an acid-promoted cyclization. One advantage of this method is that separation of the three possible pinacol products that can form during the cross-coupling is not necessary. This method is also applied to the synthesis of the 2-arylbenzofuran-containing natural product, homoegonol.

Full text of DOI:10.1055/s-0029-1217129

PAPER
515
A Convenient Two-Step Synthesis of 2-Arylbenzofurans
A
Convenient
T
w
o
i
-Ste
p
S
n
ynthesis of
-
2-Arylbe
F
nzofurans ang Duan,* Jian-Xia Feng, Zhan-Bin Zhang
Department of Chemistry, Beijing Normal University, Beijing, 100875, P. R. of China
Fax +86(10)58802075; E-mail: xinfangduan@vip.163.com
Received 15 September 2009; revised 1 October 2009
Next, the acid-promoted cyclization of the pinacol prod-
ucts to generate the corresponding benzofurans was inves-
tigated with a series of acids including sulfuric acid, p-
toluenesulfonic acid, hydrochloric acid, trifluoroacetic
Abstract: A novel and convenient two-step synthesis of 2-arylben-
zofurans is described which proceeds via a selective cross-pinacol-
type coupling between a salicylaldehyde and an aromatic aldehyde,
followed by an acid-promoted cyclization. One advantage of this
method is that separation of the three possible pinacol products that acid and ethanoic acid. The best results were obtained us-
can form during the cross-coupling is not necessary. This method is
also applied to the synthesis of the 2-arylbenzofuran-containing nat-
ural product, homoegonol.
ing p-toluenesulfonic acid in dichloromethane with heat-
ing at reflux.
Using the optimized conditions for the two reaction steps
we prepared a variety of 2-arylbenzofurans and the results
are summarized in Table 1. It was found that an electron-
donating group such as methoxy enhanced the selectivity
Key words: pinacols, pinacol-type coupling, cross-coupling, ben-
zofurans, 2-arylbenzofurans
of the cross-coupling and the acid-promoted cyclization
Benzofurans are widely distributed in nature and consti-
of the pinacol products. A slightly higher overall yield
tute a major group of natural products.1 Their useful bio-
was obtained when the pinacol product from the first step
logical activities and significant pharmacological
was isolated and purified prior to the acid-catalyzed cy-
potential have attracted extensive synthetic efforts. Many
clization (Table 1, entries 4 and 7).
of the reported approaches are based on transition metal
catalyzed Sonogashira couplings,2 and C–C3or C–O4 ary-
lation reactions. Other methods include oxidative cycliza-
tion of o-vinyl phenols,5 dehydration of a-phenoxy
ketones6 and intramolecular McMurry7 or Wittig reac-
tions.8
We have accomplished the total synthesis of the naturally
occurring benzofuran, homoegonol (7)11 using this syn-
thetic approach (Scheme 1). Thus, bromobenzofuran 4ed
was prepared in two steps from salicylaldehyde 1e and ar-
omatic aldehyde 2d in a total yield of 61%. Subsequent
Sonogashira coupling of 4ed with propargyl acetate gave
alkyne 5. Hydrogenation of 5 followed by hydrolysis of
We previously reported a two-step synthesis of benzo-
furans via a selective cross-McMurry coupling of a salicyl-
aldehyde and an aromatic aldehyde, with subsequent
oxidative cyclization of the resulting o-vinyl phenol.9 A
disadvantage of this synthetic protocol was that the three
different alkenes produced during the cross-McMurry
coupling had to be separated. Herein, we report an alter-
native two-step synthesis of benzofurans which involves
a selective cross-pinacol-type coupling of various salicyl-
aldehydes and aromatic aldehydes,10 followed by an acid-
promoted cyclization of the resulting pinacols. Gratify-
ingly, it proved unnecessary to isolate the cross-pinacol-
type product from the homo-coupled pinacols, and the
mixture of coupled products could be cyclized to afford
the desired benzofuran. This method proved to be conve-
nient and practical as the reagents are readily available
and the synthetic approach is simple.
CHO
OMe
OMe
CHO
Br
Br
i
+
OH
O
OMe
OMe
OMe
OMe
4ed
1e
2d
OMe
OMe
AcO
ii
O
OMe
5
OMe
OMe
iii
iv
AcO
O
The cross-pinacol-type coupling of the salicylaldehyde
and aromatic aldehyde was performed according to our re-
ported procedure.10 The optimum reactions conditions
employed five equivalents of titanium tetrachloride–
manganese (1:2) and equimolar amounts of the two alde-
hydes at –10 °C in tetrahydrofuran.
OMe
OMe
6
OMe
OMe
HO
O
7
Scheme 1 Reagents and conditions: (i) (1) TiCl4–Mn, THF, –10 °C;
(2) p-TsOH, CH2Cl2, reflux, 61% (over two steps); (ii) propargyl ace-
tate, CuI, Pd(PhCN)2Cl2, [HPtBu3]BF4, Et3N, DMF, 90 °C, 73%; (iii)
Pd/C, H2, MeOH, 1 atm, r.t., 95%; (iv) NaOH, EtOH, reflux, 90%.
SYNTHESIS 2010, No. 3, pp 0515–0519
Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217129; Art ID: Z19409SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

516
X.-F. Duan et al.
PAPER
the resulting saturated product 6 afforded homoegonol (7) In conclusion, a convenient two-step synthetic protocol to
in an overall yield of 38%. The reagents used in this syn- 2-arylbenzofurans based on cross-pinacol-type coupling
thesis were readily available and the synthetic procedures and acid-catalyzed cyclization has been developed. The
were straightforward.
advantages of this procedure are that the reagents are
readily available, the three possible pinacol products gen-
Table 1 Preparation of 2-Arylbenzofurans
OH
OH
Ar
CHO
two homo-
coupling
pinacols
CHO
Ar
TiCl4–Mn
TsOH
CH2Cl2
+
+
Ar
–10 °C, THF
OH
O
OH
X
X
X
1a–f
2a–g
3aa–ag
4aa–ag
Entry Salicylaldehyde
Aryl aldehyde
Product
Yielda,b
55
CHO
OH
CHO
1
2
1a
1a
2a
4aa
O
O
O
CHO
2b
4ab
4ac
60
63
OMe
O
MeO
CHO
CHO
O
3
4
1a
1a
2c
O
O
MeO
OMe
2d
4ad
57 (65)
O
MeO
OMe
Br
CHO
OH
Br
5
6
1b
1c
2b
4bb
4ca
61
52
OMe
O
MeO
CHO
MeO
2a
2a
O
OH
CHO
OH
7
8
1d
1a
4da
4ae
53 (57)
50
O
OMe
OMe
CHO
CHO
2e
O
O
S
9
1a
1e
2f
4af
52
57
S
Br
Cl
CHO
OH
Br
Cl
OMe
OMe
10
2b
2d
4eb
O
O
OMe
OMe
CHO
OH
11
12
1f
4fd
4ag
55
53
OMe
NMe2
1a
2g
OHC
NMe2
O
a Yield of isolated product after column chromatography.
b Yield in parentheses following isolation and purification of the intermediate pinacol product 3 prior to cyclization.
Synthesis 2010, No. 3, 515–519 © Thieme Stuttgart · New York

PAPER
A Convenient Two-Step Synthesis of 2-Arylbenzofurans
517
Anal. Calcd for C16H18O5: C, 66.19; H, 6.25. Found: C, 59.99; H,
6.05.
erated during the cross-coupling do not need to be separat-
ed, and the synthetic operations are simple. This method
further extends the scope of cross pinacol-type coupling
reactions.
1-(2-Hydroxy-3-methoxyphenyl)-2-phenylethane-1,2-diol (3da)
White solid; yield: 560 mg (67%); mp 111.9–113.3 °C.
IR (KBr): 3527, 3408, 1479, 1265, 1040, 860, 714 cm–1.
All glassware was oven-dried (120 °C) and cooled under a stream
of Ar gas. The reagents and solvents used for the pinacol-type cou-
plings were freshly distilled or dehydrated before use. Analytical
TLC was conducted using QDHY GF254 plates. Column chroma-
tography was performed using QDYD silica gel (200–300 mesh).
Melting points were recorded on a TECH X-4 microscopic instru-
ment and are uncorrected. IR spectra were obtained using a Vaatar
1H NMR (400 MHz, CDCl3): d = 3.88 (s, 3 H), 4.84 (d, J = 6.8 Hz,
1 H), 4.98 (d, J = 6.8 Hz, 1 H), 6.33 (s, 1 H, OH), 6.47 (dd, J1 = 7.8
Hz, J2 = 1.2 Hz, 1 H), 6.68 (t, J = 7.8 Hz, 1 H), 6.77 (dd, J1 = 8.1
Hz, J2 = 1.4 Hz, 1 H), 7.22–7.25 (m, 5 H).
MS (EI): m/z (%) = 260 (4) [M+], 243 (5), 153 (100), 125 (43), 106
(57), 93 (75), 77 (86).
1
360 FT-IR spectrophotometer. H and 13C NMR spectra were re-
Anal. Calcd for C15H16O4: C, 69.22; H, 6.20. Found: C, 68.93; H,
6.12.
corded at 400 MHz and 100 MHz, respectively, using a Bruker
Avance 400 spectrometer and TMS as the internal standard. Mass
spectra were recorded on a Traces MS spectrometer. Elemental
analyses were obtained using an Elementar Vario EL instrument.
2-(4-Methoxyphenyl)benzofuran (4ab)
White solid; mp 148.6–150.5 °C (Lit.13 145–146 °C).
IR (KBr): 2960, 1611, 1505, 1454, 1250, 1024, 836, 799, 750 cm–1.
2-Phenylbenzofuran (4aa); Typical Procedure
1H NMR (400 MHz, CDCl3): d = 3.88 (s, 3 H), 6.90 (s, 1 H), 7.00
(d, J = 8.9 Hz, 2 H), 7.20–7.28 (m, 2 H), 7.50–7.57 (m, 2 H), 7.81
(d, J = 9.2 Hz, 2 H).
A four-necked flask equipped with a magnetic stirrer was charged
with Mn powder (1.75 g, 32 mmol) and THF (50 mL) under an Ar
atm. The mixture was cooled to –10 °C and TiCl4 (1.75 mL, 16
mmol) was added slowly using a syringe. The resulting suspension
was warmed to r.t. and stirred for 0.5 h, and then heated at reflux for
2.5 h. The mixture was cooled to –10 °C, and a soln of benzaldehyde
(2a) (0.34 g, 3.2 mmol) and salicylaldehyde (1a) (0.40 g, 3.2 mmol)
in THF (20 mL) was added. The reaction mixture was kept at –10
°C until the carbonyl compounds had been consumed (monitored by
TLC). The reaction was quenched with 10% aq NaHCO3 soln and
extracted with CH2Cl2 (3 × 20 mL). The organic layers were com-
bined and dried over anhyd Na2SO4. Removal of the solvent afford-
ed a mixture of three pinacol products which was dissolved in
CH2Cl2 (100 mL). p-TsOH (0.6 g, 3.3 mmol) was added and the re-
sulting mixture was heated at reflux until the pinacols had been con-
sumed (monitored by TLC). The mixture was cooled to r.t. and
washed sequentially with H2O (2 × 50 mL), 5% aq NaHCO3 soln (2
× 50 mL) and H2O (2 × 50 mL). The organic layer was dried over
anhyd Na2SO4, the solvent was evaporated and the residue purified
by flash column chromatography over silica gel (PE–EtOAc, 3:1) to
give the title product 4aa as a white solid;12 mp 119.8–121 °C (Lit.3a
121.6–122.2 °C).
5-(1-Benzofuran-2-yl)-1,3-benzodioxole (4ac)
White solid; mp 101.3–101.8 °C (Lit.9c 102–102.7 °C).
IR (KBr): 2900, 1503, 1487, 1453, 1237, 1041, 934, 804, 749 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.95 (s, 2 H), 6.80 (s, 1 H), 6.82
(d, J = 8.1 Hz, 1 H), 7.12–7.21 (m, 2 H), 7.25 (d, J = 5.6 Hz, 1 H),
7.32 (d, J = 8.1 Hz, 1 H), 7.41–7.43 (m, 1 H), 7.47–7.49 (m, 1 H).
2-(3,4-Dimethoxyphenyl)benzofuran (4ad)
White solid; mp 119.9 °C (Lit.14 116–118 °C).
IR (KBr): 2976, 1605, 1509, 1453, 1252, 1139, 1021, 754 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3 H), 3.92 (s, 3 H), 6.83
(s, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 7.12–7.20 (m, 2 H), 7.31 (d,
J = 2.0 Hz, 1 H), 7.36 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1 H), 7.42–7.44
(m, 1 H), 7.47–7.49 (m, 1 H).
5-Bromo-2-(4-methoxyphenyl)benzofuran (4bb)
White solid; mp 175.9–176.4 °C (Lit.2a 167–169 °C).
IR (KBr): 2918, 1606, 1455, 1259, 1021, 806, 764, 747, 690 cm–1.
IR (KBr): 3445, 1611, 1504, 1444, 1253, 1177, 1038, 832, 796
cm–1.
1H NMR (400 MHz, CDCl3): d = 3.79 (s, 3 H), 6.74 (s, 1 H), 6.90
(d, J = 8.9 Hz, 2 H), 7.28–7.32 (m, 2 H), 7.59–7.60 (d, J = 1.6 Hz,
1 H), 7.70 (d, J = 8.8 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 6.95 (s, 1 H), 7.13–7.19 (m, 1 H),
7.20–7.30 (m, 2 H), 7.35–7.40 (m, 2 H), 7.51 (d, J = 7.4 Hz, 1 H),
7.57 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.6 Hz, 2 H).
MS (EI): m/z (%) = 194 (100) [M+], 165 (87), 111 (34), 97 (40), 85
(44), 71 (47), 57 (52).
5-Methoxy-2-phenylbenzofuran (4ca)
The pinacol products 3ad and 3da were isolated and characterized
as follows.
White solid; mp 128.3–129.1 °C (Lit.9c131.4–131.9 °C).
IR (KBr): 3004, 1609, 1473, 1432, 1216, 1204, 1144, 1029, 915,
813, 761, 685 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.87 (s, 3 H), 6.91 (q, J1 = 8.9 Hz,
J2 = 2.6 Hz, 1 H), 6.98 (s, 1 H), 7.05 (d, J = 2.6 Hz, 1 H), 7.36–7.47
(m, 4 H), 7.85 (d, J = 8.8 Hz, 2 H).
1-(3,4-Dimethoxyphenyl)-2-(2-hydroxyphenyl)ethane-1,2-diol
(3ad)
White solid; yield: 640 mg (69%); mp 131.4–132.6 °C.
IR (KBr): 3400, 2940, 1596, 1520, 1457, 1262, 1023, 854, 754
cm–1.
1H NMR (400 MHz, CDCl3): d = 2.83 (s, 1 H, OH), 3.67 (s, 3 H),
3.82 (s, 1 H, OH), 3.83 (s, 3 H), 4.73 (d, J = 8.2 Hz, 1 H), 4.85 (d,
J = 8.2 Hz, 1 H), 6.33 (d, J = 7.6 Hz, 1 H), 6.47 (s, 1 H), 6.58 (t,
J = 7.4 Hz, 1 H), 6.70 (m, 2 H), 6.86 (d, J = 8.2 Hz, 1 H), 7.11 (t,
J = 8.1 Hz, 1 H), 8.10 (s, 1 H, OH).
MS (EI): m/z (%) 272 = (29) [M – 18]+, 243 (37), 165 (100), 151
(46), 139 (70).
7-Methoxy-2-phenylbenzofuran (4da)
White solid; mp 82.3–83.4 °C (Lit.9c 79–80 °C).
IR (KBr): 3102, 1623, 1586, 1496, 1434, 1278, 1115, 984, 784, 735
cm–1.
1H NMR (400 MHz, CDCl3): d = 3.96 (s, 3 H), 6.78 (d, J = 7.8 Hz,
1 H), 7.15 (t, J = 7.8 Hz, 1 H), 7.29 (t, J = 7.2 Hz, 1 H), 7.34–7.41
(m, 3 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.71 (s, 1 H).
Synthesis 2010, No. 3, 515–519 © Thieme Stuttgart · New York

518
X.-F. Duan et al.
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2-(1-Naphthyl)benzofuran (4ae)
1 H), 7.22 (d, J = 1.7 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.38 (dd,
J1 = 8.3 Hz, J2 = 2.0 Hz, 1 H).
White solid; mp 158.2–159.1 °C (Lit.9c161–162 °C).
IR (KBr): 3055, 2925, 1594, 1452, 1227, 1101, 937, 799, 747 cm–1.
13C NMR (100 MHz, CDCl3): d = 55.5, 55.6, 56.2, 100.3, 108.3,
109.8, 112.0, 115.2, 115.5, 117.7, 121.9, 132.0, 142.0, 145.2, 149.0,
149.8, 156.6.
MS (EI): m/z (%) = 364 (50) [81Br, M+], 362 (50), 149 (53), 81 (69),
69 (100).
1H NMR (400 MHz, CDCl3): d = 5.95 (s, 2 H), 6.79 (s, 1 H), 6.81
(d, J = 8.2 Hz, 1 H), 7.12–7.21 (m, 4 H), 7.25 (d, J = 1.7 Hz, 1 H),
7.32 (dd, J1 = 8.2 Hz, J2 = 1.7 Hz, 1 H), 7.40–7.43 (m, 1 H), 7.46–
7.49 (m, 1 H).
Anal. Calcd for C17H15BrO4: C, 56.22; H, 4.16. Found: C, 56.32; H,
4.42.
2-(2-Thienyl)benzofuran (4af)
White solid; mp 93.6–94.4 °C (Lit.9c 95–96.5 °C).
IR (KBr): 3104, 1586, 1450, 1252, 997, 849, 802, 750, 699 cm–1.
3-[2-(3,4-Dimethoxyphenyl)-7-methoxy-1-benzofuran-5-
yl]prop-2-yn-1-yl Acetate (5)
1H NMR (400 MHz, CDCl3): d = 6.90 (s, 1 H), 7.11–7.13 (m, 1 H),
7.22–7.31 (m, 2 H), 7.35 (dd, J1 = 5.0 Hz, J2 = 1.1 Hz, 1 H), 7.50–
7.52 (m, 2 H), 7.55–7.57 (m, 1 H).
A flask equipped with a magnetic stirrer was charged with 5-bromo-
2-(3,4-dimethoxyphenyl)-7-methoxybenzofuran (4ed) (540 mg, 1.5
mmol), CuI (30 mg, 0.15 mmol), Pd(PhCN)2Cl2 (85 mg, 0.22
mmol) and [HPtBu3]BF4 (150 mg, 0.45 mmol) under an Ar atm. A
soln of propargyl acetate (500 mg, 5.1 mmol), Et3N (2 mL) and
DMF (5 mL) was added, and the reaction mixture degassed and then
heated at 90 °C for 20 h. The reaction was quenched with 10% aq
NaHCO3 soln and extracted with CH2Cl2 (3 × 20 mL). The organic
layers were combined and dried over anhyd Na2SO4. The solvent
was removed and the residue purified by flash column chromatog-
raphy on silica gel (PE–EtOAc, 3:1) to give the title product 5 as a
white solid; yield: 370 mg (65%); mp 196–197.6 °C.
5-Bromo-7-methoxy-2-(4-methoxyphenyl)benzofuran (4eb)
White solid; mp 130.1–131.5 °C.
IR (KBr): 2962, 1611, 1505, 1472, 1440, 1302, 1253, 1174, 1122,
1023, 832, 802, 768, 736 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.77 (s, 3 H), 3.94 (s, 3 H), 6.70
(s, 1 H), 6.80 (s, 1 H), 6.87 (d, J = 9.0 Hz, 2 H), 7.20 (s, 1 H), 7.71
(d, J = 9.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 55.4, 56.4, 99.3, 109.9, 114.2,
115.7, 115.8, 122.6, 126.7, 132.4, 142.8, 145.5, 157.3, 160.3.
IR (KBr): 2952, 2131, 1760, 1457, 1377 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.05 (s, 3 H), 3.82 (s, 3 H), 3.87
(s, 3 H), 3.99 (s, 3 H), 4.67 (s, 2 H), 7.06–7.09 (m, 3 H), 7.40–7.47
(m, 3 H).
13C NMR (100 MHz, CDCl3): d = 20.3, 51.5, 55.6, 55.7, 56.2, 89.7,
96.9, 100.3, 108.4, 109.8, 112.1, 115.3, 115.5, 117.8, 121.9, 132.1,
142.0, 145.3, 149.1, 149.9, 156.6, 169.6.
MS (EI): m/z (%) = 334 (91) [81Br, M+], 332 (83), 317 (42), 182
(32), 167 (32), 139 (58).
Anal. Calcd for C16H13BrO3: C, 57.68; H, 3.93. Found: C, 57.39; H,
3.99.
5-Chloro-2-(3,4-dimethoxyphenyl)benzofuran (4fd)
White solid; mp 131 °C.
MS (EI): m/z (%) = 380 (30) [M+], 365 (45), 337 (90), 139 (55).
IR (KBr): 3009, 1606, 1512, 1458, 1282, 1256, 1140, 1023, 793,
781 cm–1.
Anal. Calcd for C22H20O6: C, 69.46; H, 5.30. Found: C, 69.65; H,
5.52.
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3 H), 3.90 (s, 3 H), 6.75
(s, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 7.11 (dd, J1 = 8.9 Hz, J2 = 2.2
Hz, 1 H), 7.26 (d, J = 2.0 Hz, 1 H), 7.31–7.35 (m, 2 H), 7.42 (d,
J = 2.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 56.00, 56.03, 99.5, 108.2, 111.4,
111.9, 118.2, 120.1, 123.0, 123.9, 128.4, 130.8, 149.3, 149.9, 153.1,
157.5.
3-[2-(3,4-Dimethoxyphenyl)-7-methoxy-1-benzofuran-5-yl]pro-
pyl Acetate (6)
Alkyne 5 (500 mg, 1.3 mmol) was dissolved in MeOH (15 mL),
Pd/C (10%, 150 mg) was added, and the reaction mixture was hy-
drogenated under 1 atm of H2 at ambient temperature. After stirring
for 8 h, the reaction mixture was filtered and evaporated to provide
6 as a white solid; yield: 480 mg (95%); mp 90–91 °C (Lit.11a 90–
91 °C).
MS (EI): m/z (%) = 288 (96) [M+], 272 (28), 217 (40), 202 (38), 181
(43), 152 (100), 139 (78).
IR (KBr): 2925, 1747, 1462, 1376, 1237 cm–1.
Anal. Calcd for C16H13ClO3: C, 66.56; H, 4.54. Found: C, 66.32; H,
5.11.
1H NMR (400 MHz, CDCl3): d = 1.48–1.56 (m, 2 H), 2.16 (s, 3 H),
2.70 (t, J = 7.9 Hz, 2 H), 3.87 (s, 3 H), 3.92 (s, 3 H), 3.96 (s, 3 H),
4.26 (t, J = 6.9 Hz, 2 H), 6.27 (s, 1 H), 6.76–6.89 (m, 2 H), 7.28–
7.39 (m, 3 H).
2-[4-(Dimethylamino)phenyl]benzofuran (4ag)15
White solid; mp 184.6–186.2 °C.
IR (KBr): 2898, 1614, 1514, 1452, 1360, 1195, 820, 792, 750 cm–1.
Homoegonol (7)
Compound 6 (200 mg, 0.5 mmol) was dissolved in a soln of NaOH
(42 mg, 1.0 mmol) in 95% EtOH (15 mL). The mixture was heated
at reflux until the starting material had been consumed (monitored
by TLC). The reaction mixture was evaporated and the residue dis-
solved in EtOAc (30 mL). The organic layer was separated and
washed with H2O (2 × 30 mL) and then dried over anhyd Na2SO4.
The solvent was evaporated and the residue purified by flash col-
umn chromatography over silica gel (PE–EtOAc, 2:1) to give 7 as a
white solid; yield: 160 mg (90%); mp 118–119.6 °C (Lit.11a 120–
122 °C).
1H NMR (400 MHz, CDCl3): d = 2.94 (s, 6 H), 6.70–6.72 (m, 3 H),
7.09–7.15 (m, 2 H), 7.39–7.45 (m, 2 H), 7.65–7.68 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 40.5, 98.3, 110.8, 112.5, 120.2,
122.7, 123.2, 126.2, 129.8, 154.6, 156.9.
5-Bromo-2-(3,4-dimethoxyphenyl)-7-methoxybenzofuran (4ed)
White solid; mp 204.5–205.8 °C.
IR (KBr): 3007, 1614, 1510, 1470, 1254, 1137, 1021, 848, 772
cm–1.
IR (KBr): 3329, 2924, 1460, 1377, 1307, 1254, 1224 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.48–1.57 (m, 2 H), 2.69 (t, J = 7.9
Hz, 2 H), 3.04 (s, 1 H), 3.42 (t, J = 6.7 Hz, 2 H), 3.87 (s, 3 H), 3.92
1H NMR (400 MHz, CDCl3): d = 3.76 (s, 3 H), 3.80 (s, 3 H), 3.93
(s, 3 H), 6.89 (d, J = 1.7 Hz, 1 H), 6.95 (d, J = 8.3 Hz, 1 H), 7.02 (s,
Synthesis 2010, No. 3, 515–519 © Thieme Stuttgart · New York

PAPER
A Convenient Two-Step Synthesis of 2-Arylbenzofurans
(5) For I2-mediated cyclizations, see: (a) Pan, C.-F.; Yu, J.;
519
(s, 3 H), 3.96 (s, 3 H), 6.76 (s, 1 H), 6.82–6.87 (m, 2 H), 7.22–7.28
(m, 2 H), 7.37–7.40 (m, 1 H).
Zhou, Y.-Q.; Wang, Z.-Y.; Zhou, M.-M. Synlett 2006, 1657.
For the cyclization using DDQ, see: (b) Takeshi, K.; Koji, I.
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68, 3691.
Acknowledgment
We gratefully acknowledge the National Nature Science Founda-
tion of China (Grant 20672014) and the support of Beijing Key
Subject Program.
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as byproducts during the cross-coupling which hindered the
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it was not necessary to separate the three pinacols, the alkene
by-product was removed by chromatography.
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Synthesis 2010, No. 3, 515–519 © Thieme Stuttgart · New York