A new approach to benzofuran synthesis: Lewis acid mediated cycloaddition of benzoquinones with stilbene oxides

Article abstract of DOI:10.1016/j.tetlet.2009.12.047

We report a BF₃-mediated novel dehydrative cycloaddition reaction of benzoquinones with stilbene oxides to afford 2,3-diaryl-5-hydroxybenzofurans and 2,3-diaryl-5-hydroxydihydrobenzofurans in good combined yields. No change in the products or the yield is observed when using diphenylacetaldehyde and cis-stilbene oxide instead of trans-stilbene oxides. When stilbene oxide is reacted with hydroquinone instead of the corresponding benzoquinone under the same conditions, dihydrobenzofuran is isolated in high yield. On the basis of these results, we propose the following possible reaction mechanism: stilbene oxide is converted to a phenonium ion (the key intermediate), which undergoes nucleophilic attack by benzoquinone or the simultaneously generated hydroquinone and subsequent dehydrative intramolecular cyclization to afford benzofuran or dihydrobenzofuran, respectively.

Full text of DOI:10.1016/j.tetlet.2009.12.047

Tetrahedron Letters 51 (2010) 955–958
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new approach to benzofuran synthesis: Lewis acid mediated cycloaddition
of benzoquinones with stilbene oxides
*
*
Ken Kokubo , Kenji Harada, Eiko Mochizuki, Takumi Oshima
Division of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a BF3-mediated novel dehydrative cycloaddition reaction of benzoquinones with stilbene oxi-
des to afford 2,3-diaryl-5-hydroxybenzofurans and 2,3-diaryl-5-hydroxydihydrobenzofurans in good
combined yields. No change in the products or the yield is observed when using diphenylacetaldehyde
and cis-stilbene oxide instead of trans-stilbene oxides. When stilbene oxide is reacted with hydroquinone
instead of the corresponding benzoquinone under the same conditions, dihydrobenzofuran is isolated in
high yield. On the basis of these results, we propose the following possible reaction mechanism: stilbene
oxide is converted to a phenonium ion (the key intermediate), which undergoes nucleophilic attack by
benzoquinone or the simultaneously generated hydroquinone and subsequent dehydrative intramolecu-
lar cyclization to afford benzofuran or dihydrobenzofuran, respectively.
Received 4 November 2009
Revised 4 December 2009
Accepted 10 December 2009
Available online 13 December 2009
Keywords:
Benzofuran
Benzoquinone
Stilbene oxide
Dehydrative cycloaddition
Lewis acid
Ó 2009 Elsevier Ltd. All rights reserved.
Benzofurans and dihydrobenzofurans are present in a wide
variety of natural products1 and have attracted considerable atten-
tion owing to their biological2 and pharmacological activities.3
Hence, several researchers have focused on the development of
new methods for synthesizing these useful compounds.4 In gen-
eral, phenols5 and their ether derivatives6 have been frequently
employed as starting materials for benzofuran synthesis, whereas
quinones have been used sparingly because they are much less
nucleophilic than phenols. Benzoquinones that are used for the
synthesis of dihydrobenzofurans react with alkenes after being acti-
vated by a Lewis acid.7 However, the conversion of dihydrobenzo-
furans to the corresponding benzofurans requires high-temperature
heating of the precursor dihydrobenzofuran with an appropriate
leaving group;8 and hence, benzofurans have been synthesized
only via the photochemical intramolecular cyclization of vinyl-
substituted quinones.9
Oxirane, which canbe easily synthesized from alkene, isa versatile
synthon having a highly strained three-membered heterocyclic ring
with labile C–O bonds and is well known to undergo acid-induced
nucleophilic ring opening10 or Meinwald rearrangement to afford a
carbonyl compound.11 However, the cycloaddition reaction of qui-
nones with oxiranes instead of alkenes has not been explored so far.
In this Letter, we wish to report the successful and facile syn-
thesis of benzofurans and dihydrobenzofurans via the Lewis acid
mediated reaction of oxiranes with benzoquinones.
The reaction of 2,6-dimethylbenzoquinone 1a with trans-stil-
bene oxide 2a (2 equiv) in the presence of BF3ꢀEt2O (3 equiv) was
carried out in chloroform at room temperature for 1 h to give 5-
hydroxybenzofuran 3aa (77% yield based on 1a used) along with
a fair amount of 5-hydroxydihydrobenzofuran 4aa (17%) (Table 1,
entry 1). The structures of 3aa and 4aa (trans-isomer) were deter-
mined by 1H and 13C NMR analysis and further confirmed by a sin-
gle-crystal X-ray structural analysis of the representative 3aa and
3ba.12 The 1H NMR spectrum of 4aa showed two sets of doublet
protons at 5.46 and 4.45 ppm, which were assigned to the C2
and C3 methine protons, respectively. From the value of the cou-
pling constant (J = 5.9 Hz) for these doublets, it was confirmed that
4aa was present as the trans-isomer.13
The reaction of 1a with cis-stilbene oxide (cis-2a) also afforded
3aa and 4aa (with the same trans stereochemistry), and the prod-
uct yields were almost identical to those obtained when using
trans-2a (entry 2). Interestingly, when monitoring the reaction by
1H NMR, we found that 2a rapidly underwent Meinwald rearrange-
ment11 under the present reaction conditions to afford diphenyl-
acetaldehyde 20. Hence, we reacted 1a with 20 instead of 2a and
found that 20 was consumed slowly during the reaction; the prod-
ucts obtained were the same as those obtained when using 2a
(entry 3).
We then carried out the reaction of 1a with 2a under the same
conditions but in the presence of different Lewis acids. With the
use of BF3ꢀEt2O, we achieved a high conversion efficiency and high
combined yield within 1 h; however, the use of other Lewis acids
such as AlCl3, SnCl4, TiCl4, and B(C6F5)3 resulted in a decrease in
the conversion efficiency (entries 4ꢁ7). Relatively weak Lewis
* Corresponding authors. Tel.: +81 6 6879 4592; fax: +81 6 6819 4593 (K.K.).
E-mail addresses: kokubo@chem.eng.osaka-u.ac.jp (K. Kokubo), oshima@chem.
eng.osaka-u.ac.jp (T. Oshima).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.047

956
K. Kokubo et al. / Tetrahedron Letters 51 (2010) 955–958
Table 1
a
Acid-mediated cycloaddition of benzoquinone 1a with 2a, cis-2a, and 20
Ph
Ph
O
O
O
O
Ph
Ph
Acid
Ph
O
Ph
O
H
+
or
or
Ph
CHCl3, rt
Ph
Ph
Ph
O
2a
cis-2a
2'
OH
OH
1a
3aa
4aa
Entry
Compound
Acid
Time (h)
Conv (%)
Yieldb (%)
3aa
4aa
Total
1
2
3
4
5
6
7
8
9
2a
cis-2a
20
2a
2a
2a
2a
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
AlCl3
SnCl4
TiCl4
B(C6F5)3
CH3SO3H
CF3SO3H
1
1
1
100
100
100
96
79
68
7
97
100
77
75
75
45
45
11
7
17
20
22
31
21
45
0
94
95
97
76
66
56
7
5
100
24
40
6
2a
2a
60
63
27
33
87
96
0.1
a
The reaction of 1a (0.05 mmol) with 2a (0.10 mmol) was carried out with 3 equiv of acid in chloroform at room temperature.
Determined by 1H NMR using fluorene as an internal standard based on 1a used.
b
acids such as TiCl2(Et)2, Ti(iOPr)4, Sc(OTf)3, and MgBr2 were almost
ineffective for the present reaction. Further, when we used TiCl4,
the product ratio of 3aa to 4aa was reversed, and 4aa was isolated
as the major product (45%) (entry 6). Protic acids such as CH3SO3H
and CF3SO3H could also be successfully used in the present reac-
tion; notably, the reaction time was reduced to a considerable ex-
tent when using CF3SO3H, a strong acid (entries 8 and 9).
As shown in Table 2, the extended reactions of various substi-
tuted benzoquinones 1aꢁf with 2a or the bis(4-tolyl)-substituted
oxide 2b could be carried out. The conversion efficiency in the
reaction carried out using dimethoxy-substituted quinone 1b
was low, and the corresponding benzofuran 3ba was isolated in
moderate yield (47%) (entry 2). The reaction of dihalogenated qui-
nones 1c and 1d with 2b afforded benzofurans 3cb and 3db in low
yields (36 and 57%), respectively, but no dihydrobenzofuran
derivatives were detected in this case (entries 3 and 4). As ex-
pected, because of its apparent steric hindrance, the di(t-butyl)-
substituted quinone 1e remained unreacted even after 48 h (entry
5). However, the trisubstituted quinone 1f could react with 2a to
give a highly substituted benzofuran 3fa in good yield (76%) (entry
6).
In order to elucidate the reaction mechanism, we also con-
ducted the reaction of 2,6-dimethylhydroquinone 5 with 2a in
the presence of BF3ꢀEt2O under the same condition used for the
reaction with 1. Interestingly, 4aa was obtained in high yield
(80%), and no 3aa was formed (Scheme 1). This result suggested
that in the reaction of 1a with 2a, a small amount of 5 was formed,
and it was converted to 4aa immediately.
On the basis of these findings, we propose a plausible mecha-
nism for our reaction (Scheme 2). Initially, phenonium ion I is
generated as the key intermediate in the Meinwald rearrange-
ment11 of trans/cis-2a or from 20 via a cationic intermediate II, by
Table 2
BF3-mediated cycloaddition of benzoquinones 1a–f with oxiranes 2a,ba
O
Ar
R3
Ar
R1
O
O
O
Ar
Ar
BF3·Et2O
CHCl3, rt
R1
R2
Ar
R1
R2
R2
R3
+
Ar
O
R3
1 = H, R2 = R3 = Me
2a:
2b:
1a:
1b:
1c:
Ar = Ph
Ar = 4-Tol
R
R
R
OH
OH
= H, R2 = R3 = MeO
1
3
4
1 = H, R2 = R3 = Cl
1d: R1 = H, R2 = R3 = Br
1e: R1 = H, R2 = R3 = t-Bu
1f:
R
1 = R2 = MeO, R3 = Me
Entry
1
2
Time (h)
Conv (%)
Yieldb (%)
3
4
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
2a
2a
2b
2b
2a
2a
1
5
3
3
48
10
100
92
3aa
3ba
3cb
3db
77
4aa
4ba
17
13
0
0
0
47
36
100
c
—
57d
0
2
83
3fa
76
4fa
7
a
b
c
The reaction of 1 (0.05 mmol) with 2 (0.10 mmol) was carried out with 3 equiv of BF3ꢀEt2O in chloroform at room temperature.
Determined by 1H NMR based on 1 used.
Not determined.
d
Isolated yield.

K. Kokubo et al. / Tetrahedron Letters 51 (2010) 955–958
957
The reaction of 1a with an unsymmetrical oxirane 2c which has
an electron-withdrawing substituent was also carried out under
the same conditions (Scheme 3). The corresponding benzofuran
3ac and dihydrobenzofuran 4ac were obtained in the yield of 51
and 11%, respectively. In both compounds, the nitrophenyl group
was regioselectively introduced on the C2 position. The stereo-
chemistry of 4ac was determined as the trans-isomer from the va-
lue of the coupling constant (J = 6.0 Hz) and confirmed by the
Ph
OH
O
.
O
BF3 Et2O
Ph
Ph
Ph
CHCl3, rt, 1h
OH
OH
5
2a
4aa (80%)
1
measurement of differential 1Hꢁ H NOE as depicted in Scheme
Scheme 1. BF3-mediated cycloaddition of hydroquinone 5 with oxirane 2a.
3.15 The reaction was strongly retarded by the effect of the elec-
tron-withdrawing nitro group and the conversion remained lower
69% even after 50 h.
the complexation with Lewis acid in both cases. Then, quinone 1a
attacks the benzylic carbon of I from the less hindered side to form
intermediate III. Intramolecular hydride shift of III leads to the for-
mation of the IV, which then undergoes dienoneꢁphenol rear-
rangement14 to afford the intermediate V. Finally, intramolecular
cyclization of V by FriedelꢁCrafts reaction and the successive
dehydration of VI afford 3aa as the major product. Under the pres-
ent acidic conditions, V is hydrolyzed to form hydroquinone 5,
which attacks I in the manner described earlier to afford hydro-
quinol VII. Dehydrative intramolecular cyclization of VII then leads
to the formation of 4aa. The hydrolysis of V is confirmed by the
fact that a small amount of benzoin (yield: 11%) is obtained as a
byproduct in the reaction of 1a with 2a. Because of the bidentate
nature of TiCl4, Ti4+ ions form coordinate bonds with the car-
bonyl oxygen and phenol ether oxygen to form intermediate V,
which is a five-membered metallacyclic complex; hydrolysis of V
is then promoted, and 4aa is formed preferentially.
In conclusion, we have designed a novel acid-induced dehyd-
rative cycloaddition reaction of benzoquinones with stilbene oxi-
des to give 2,3-diaryl-5-hydroxybenzofurans along with 2,3-
diaryl-5-hydroxydihydrobenzofurans in moderate to high com-
bined yields. The same products were obtained (with the same
stereochemistry) when cis-stilbene oxide or diphenylacetaldehyde
was used instead of trans-stilbene oxide, and the observed yields
were essentially the same in both cases. When stilbene oxide was
reacted with hydroquinone instead of the corresponding benzo-
quinone, dihydrobenzofuran was selectively formed in high yield.
Thus, we concluded that the phenonium ion intermediate played
a crucial role in the formation of benzofuran derivatives in the
reaction involving nucleophilic attack by benzoquinone (for ben-
zofuran formation) and hydroquinone (for dihydrobenzofuran for-
mation). Further research is in progress for clarifying the details
of the reaction mechanism and for investigating the scope and
Meinwald rearrangement
O
LA
H
Ph
LA
LA
O
H
Ph shift
Ph
Ph
O
LA
Ph
Ph
O
H
Ph shift
Ph
Ph
I
II
2'
trans/cis-2a
Ph
Ph
H
O
O
LA
H
Ph
Ph
Ph
O
O
O
H
– shift
H
H
O
O
LA
LA
O
O
I
1a
III
IV
aromatization
Ph
Ph
OH
Ph
intramolecular
Friedel-Crafts
reaction
Ph
LA
O
O
dehydration
–H2O
O
3aa
–LA
OH
VI
OH
V
hydrolysis
–LA
Ph
Ph
H
Ph
Ph
O
O
OH
H
OH
H+
I
Ph
4aa
Ph
–H+
HO
–H2O
O
OH
VIII
OH
VII
OH
5
benzoin
Scheme 2. Proposed reaction mechanism for the BF3-mediated cycloaddition of benzoquinone with oxirane.

958
K. Kokubo et al. / Tetrahedron Letters 51 (2010) 955–958
NO2
NO2
3%
δ
7.46
H
H
O
NOE 5%
NO2
O
H
O
BF3·Et2O
O
+
CHCl3, rt, 50 h
H
δ
7.15
OH
OH
O
1a
2c
3ac (51%)
4ac (11%)
Scheme 3. BF3-mediated cycloaddition of benzoquinone 1a with unsymmetrical oxirane 2c.
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Acknowledgments
This work was partly supported by Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. Authors thank Professor Long Y. Chiang
and Ms. Joshna Chittigori (UMass Lowell) for their helpful discus-
sion on the reaction mechanism.
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Supplementary data
Supplementary data (compound data for new compounds 3aa,
4aa, 3ba, 4ba, 3cb, 3db, 3fa, 4fa, 3ac, and 4ac including ORTEP
drawing and CIF files of 3aa and 3ba) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2009.
12.047.
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12. General procedure for the preparation of 3aa and 4aa: To a solution of 2,6-
dimethyl-1,4-benzoquinone (136 mg, 1 mmol) and trans-stilbene oxide
(235 mg, 1.2 mmol) in dry chloroform (30 mL) was added boron trifluoride
diethyl etherate (380
lL, 3 mmol) at room temperature. The mixture was stirred
for 18 h, then quenched bythe addition of water. Theorganic layer separated was
dried over calcium chloride and concentrated in vacuo. The crude product was
purified by silica gel column chromatography using hexane–ether as the eluent.
4,6-Dimethyl-2,3-diphenylbenzofuran-5-ol (3aa): colorless prisms; mp
125.5ꢁ126.0 °C; 1H NMR (270 MHz, CDCl3) d 1.89 (s, 3H), 2.37 (s, 3H), 4.44 (s,
1H), 7.19ꢁ7.23 (m, 4H), 7.38ꢁ7.49 (m, 7H); 13C NMR (67.5 MHz, CDCl3) d 11.29,
17.15, 109.69, 115.03, 118.32, 121.74, 126.14, 127.55, 127.67, 128.14, 128.65,
129.95, 130.69, 130.92, 134.62, 147.82, 148.33, 149.98; IR (KBr) 3454 (br,
OH) cmꢁ1. Crystal structure of 3aa: C22H18O2, M = 314.4, monoclinic, space
group C12/c1 with a = 22.656(2), b = 20.763(2), c = 18.899(2) Å, b = 129.202(1),
V = 6889(1) Å3, Z = 16, Dc = 1.220 g/cm3, R = 0.0677, and Rw = 0.1780. 4,6-
Dimethyl-2,3-diphenyl-2,3-dihydrobenzofuran-5-ol (4aa): colorless crystal;
1H NMR (270 MHz, CDCl3) d 1.79 (s, 3H), 2.27 (s, 3H), 4.19 (s, 1H, OH), 4.45 (d,
1H, J = 5.9 Hz), 5.46 (d, 1H, J = 5.9 Hz), 6.65 (s, 1H), 7.13ꢁ7.44 (m, 10H); 13C NMR
(67.5 MHz, CDCl3) d 12.46, 16.77, 58.03, 92.52, 108.33, 121.09, 123.69, 125.25,
126.39, 126.89, 127.70, 127.81, 128.53, 128.79, 141.97, 142.80, 146.38, 153.39;
MS (EI) m/e = 316 (M+); HRMS calcd for C22H20O2: 316.1463. Found: 316.1472.
13. The coupling constants for trans-isomer of 4,6-substituted 2,3-diaryl-2,3-
dihydrobenzofuran-5-ols were reported as J = 5.9 to 6 Hz (Ref. 7c).
4. See some reviews: (a) Hosokawa, T.; Murahashi, S.-I. Acc. Chem. Res. 1990, 23,
49; (b) Kadieva, M. G.; Oganesyan, É. T. Chem. Heterocycl. Compd. 1997, 33,
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Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285; (e) Youn, S. W.; Eom, J. I. Org.
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5. (a) Hosokawa, T.; Maeda, K.; Koga, K.; Moritani, I. Tetrahedron Lett. 1973, 10,
739; (b) Hosokawa, T.; Ohkata, H.; Moritani, I. Bull. Chem. Soc. Jpn. 1975, 48,
1533; (c) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem. Soc.,
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14. Omura, K. J. Org. Chem. 1996, 61, 7156.
15. In Ref. 7b, the authors noted that coupling constants between the methine
protons at C2 and C3 are not sufficient for assigning stereochemistry. However,
the NOE data for dihydrobenzofurans 4 other than 4ac could not be measured
due to the overlap of the aromatic proton signals in 1H NMR.