Metal-Free [3+2] Oxidative Coupling of Phenols with Alkenes: Synthesis of Dihydrobenzofurans

Article abstract of DOI:10.1055/s-0034-1380419

Herein, we demonstrated a benign and metal-free [3+2]-cycloaddition reaction using simple and readily available phenols and styrenes as substrates and sodium persulfate as an inexpensive and environmentally friendly oxidant for the direct synthesis of dih

Full text of DOI:10.1055/s-0034-1380419

SYNTHESIS
0
0
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9
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7
8
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1
1
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3
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-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2731–2737
2731
special topic
Y. Zhao et al.
Special Topic
Synthesis
Metal-Free [3+2] Oxidative Coupling of Phenols with Alkenes:
Synthesis of Dihydrobenzofurans
Yating Zhao
R4
R3
O
R3
Binbin Huang
Chao Yang
Bing Li
O
R2
R4
50 °C, Na2S2O8
R1
+
O
R1
R2
Wujiong Xia*
8–72%
TMS+
metal-free
[3+2]
OTMS
State Key Lab of Urban Water Resource and Environment,
The Academy of Fundamental and Interdisciplinary Sciences,
Harbin Institute of Technology, Harbin 150080, P. R. of China
xiawj@hit.edu.cn
O
R1 = H, Cl
R2, R4 = alkyl
R3 = F, Br, alkyl, alkenyl, alkoxy
O
O
corsifuran A
Received: 11.03.2015
Accepted after revision: 14.04.2015
Published online: 27.05.2015
and the biosynthesis of natural products.10 Recently, Lei and
co-workers11 reported an iron(III) chloride catalyzed radical
cross-coupling of alkenes with phenols for the construction
of the dihydrobenzofuran moiety [Scheme 1 (a)]. Based
upon our continued work on radical chemistry,12 we found
that phenols could undergo single-electron transfer and
generate a putative phenoxyl cation by oxidative quenching
of the photoredox catalytic conditions, and this is then
trapped by styrene to form dihydrobenzofurans with little
to no side products. Coincidentally, similar work was re-
cently reported by the group of T. P. Yoon13 while our manu-
script was in preparation. However, our investigations
showed that such an oxidative [3+2]-cycloaddition reaction
could also be achieved in the absence of photoredox cataly-
sis using trimethylsilyl-protected phenols by heating
[Scheme 1 (b)].
DOI: 10.1055/s-0034-1380419; Art ID: ss-2015-c0155-st
Abstract Herein, we demonstrated a benign and metal-free [3+2]-cy-
cloaddition reaction using simple and readily available phenols and sty-
renes as substrates and sodium persulfate as an inexpensive and envi-
ronmentally friendly oxidant for the direct synthesis of
dihydrobenzofurans. This methodology was applied to the synthesis of
corsifuran A in a single step.
Key words metal-free, phenols, alkenes, sodium persulfate, dihydro-
benzofuran
Hydrobenzofurans have attracted the attention of many
chemists by virtue of their potential biological and pharma-
cological activity and structural diversity; the 2,3-dihydro-
benzofuran skeleton represents the core of many interest-
ing bioactive compounds,1 such as 3′,4-di-O-methylced-
rusin,2 (+)-conocarpan,3 and corsifuran A.4 There are
numerous reports of their synthesis in the literature and
new synthetic methods have also been extensively investi-
gated,5 of which inter- and intramolecular cyclization reac-
tions play a vital role. Previous examples of the synthesis of
dihydrobenzofurans have generally focused on the applica-
tion of transition-metal catalysis,6 organic acids,7 and elec-
trochemical methods8 to enable cycloaddition of phe-
nols/quinones to olefins/alkynes or other complex synthet-
ic substrates; their limitations are that the conditions are
not economic or the product is accompanied by a number
of byproducts. Therefore, the development of a benign and
practical avenue to access dihydrobenzofurans remains of
interest.9
It is well precedented that persulfate (S2O82–) decompos-
es on heating or by light irradiation to form the sulfate radi-
cal14 which is a strong oxidant. Thus our initial investigation
was carried out on 4-methoxyphenol and styrene (2a) (4
equiv) in the presence of sodium persulfate (3 equiv) in ace-
tonitrile at 50 °C. To our delight, the desired cycloaddition
product 3aa was obtained in 28% yield after 48 hours.
When trimethylsilyl-protected 4-methoxyphenol 1a was
used, the yield improved to 34% under similar reaction con-
ditions (Table 1, entry 3). Other protective groups, such as
acetyl led to low yields or no reaction. Therefore, (4-meth-
oxyphenoxy)trimethylsilane (1a) and styrene (2a) were
used as model substrates to optimize the reaction condi-
tions (Table 1). A brief screening of other oxidants, such as
ammonium persulfate and potassium persulfate, indicated
that sodium persulfate was the ideal oxidant (entries 1 and
2). An examination of the reaction temperature showed
that 50 °C was the optimal choice when compared with
room temperature or higher temperatures (70 °C) (entries
4–6). It is noteworthy that a higher temperature could pro-
Phenols are largely commercially available chemicals
and they are readily oxidized in the presence of a variety of
oxidants. Over the past few decades, oxidative phenol cou-
pling has been applied to the formation of dimeric products
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2731–2737

2732
Y. Zhao et al.
Special Topic
Synthesis
a) Lei's work
OH
Ph
Ph
FeCl3
O
O
O
O
radical
addition
•
Ph
FeCl3 (10 mol%)
•
H
+
DDQ, r.t.
toluene
– H•
O
O
O
radical coupling
b) this work
Ph
Ph
H
O
OTMS
O
O
heat
Ph
+
+
•
+
– TMS+
Na2S2O8, MeCN
OTMS
O
O
O
metal-free oxidative coupling
Scheme 1 Reported synthesis of dihydrobenzofuran and our strategy
mote the consumption of starting material, yet more com-
plicated byproducts were formed. Further optimization of
the reaction conditions examined the solvent, which has a
significant effect on the reaction efficiency. No reaction of
the starting material was observed by TLC when the reac-
tion was performed in N,N-dimethylformamide, methanol,
tetrahydrofuran, and dichloromethane (entries 7–10). Fur-
ther examination of the amount of oxidant led to the de-
sired product 3aa in lower yields (entries 11 and 12). Final-
ly, the optimal reaction conditions, (4-methoxyphen-
oxy)trimethylsilane (1a) (1 equiv) and styrene (2a) (4
equiv) in acetonitrile with heating to 50 °C in the presence
of sodium persulfate (3 equiv), gave the desired product 3aa
in 72% isolated yield (entry 5).
With the optimized conditions in hand, we next exam-
ined the scope of the reaction using various alkenes bearing
either electron-donating or electron-withdrawing groups
on aromatic rings. As shown in Scheme 2, terminal alkenes
substituted with para- or ortho-electron-donating groups,
such as methyl and tert-butyl, reacted smoothly with 1a to
afford the corresponding products 3ab, 3ac, and 3ad in
good yields. However, 4- and 3-methoxystyrene produced
the expected products 3af and 3ag in moderate yields to-
gether with byproducts from the oxidation of styrene con-
taining a methoxy group by sodium persulfate. Halogen
groups (Br and F) were also tolerated well in this protocol to
afford the 2,3-dihydrobenzofurans 3ah and 3ai, respective-
ly. Moreover, we tested steric effects of α- and β-substituted
styrenes. To our delight, 3ak and 3al containing a quaterna-
ry center were readily prepared from α-methyl- and α-cy-
clopropylstyrenes in 61% and 70% yield, respectively. In ad-
dition, styrenes with β-substitution were also competent
substrates and produced the corresponding cycloadducts
3am, 3an, and 3ao in moderate yields. Indene also reacted
with 1a successfully to give the desired product 3aj. Nota-
Table 1 Optimization of the Reaction Conditions
O
O
oxidant, heat
+
solvent
O
2a
3aa
OTMS
1a
Entrya
Oxidant
Temp (°C) Solvent
Yieldb (%)
1c
2c
3c
4
(NH4)2S2O8
K2S2O8
50
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
14
50
9
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
50
34
r.t. (~30)
50
9
5
82 (72d)
6
70
50
0
7
50
8
50
MeOH
THF
0
9
50
0
10
50
CH2Cl2
MeCN
MeCN
0
11
12
Na2S2O8 (2 equiv)
Na2S2O8 (4 equiv)
50
27
49
50
a Reaction conditions: 1a (0.15 mmol), 2a (0.6 mmol), oxidant (3 equiv),
solvent (0.1 M), 70 h, unless otherwise stated.
b Yield determined by GC-MS.
c Reacted for 48 h.
d Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2731–2737

2733
Y. Zhao et al.
Special Topic
Synthesis
bly, the monocycloadduct 3ae was obtained in moderate
yield when 1.5 equivalents of 1,4-divinylbenzene reacted
under the optimal reaction conditions. We, therefore, envi-
sioned that modifying the reaction conditions by decreas-
ing of the amount of 1,4-divinylbenzene (2e) to one equiva-
lent and increasing the amount of 1a to three equivalents
could potentially give benzodifuran 3ae′ in one step (Equa-
tion 1). However, the reaction provided a mixture of 3ae
and 3ae′′ with a reduced C=C double bond. In addition, 4-
methoxyphenols containing halogen groups, such as the
chloride 1b (R1 = Cl), were prepared and found to be suit-
able substrates giving the corresponding cycloadducts 3bd
and 3bk, which may have potential applications by further
functionalization, albeit the starting materials 1 and 2 were
recovered after reacting for 72 hours.
O
O
50 °C
3ae
+
+
O
Na2S2O8
(3 equiv)
MeCN
3ae''
OTMS
1a
2e
O
(3 equiv) (1 equiv)
O
O
O
3ae'
not observed
Equation 1 Reaction of 1a with 2e
To test the application of this protocol in organic syn-
thesis, we carried out a scaled up experiment to prepare
the natural product corsifuran A (3af). When 1a (500 mg)
R4
R3
O
R3
O
R2
R4
50 °C
R1
+
Na2S2O8, MeCN
R2
R1
O
3
2
OTMS
1
R1 = H
O
O
O
t-Bu
O
O
O
3ab, 69%
3ac, 65%
3ad, 52%
O
O
O
O
O
O
O
O
O
3ag, 42%
3ae, 50%
3af, 38%
O
O
Br
F
O
O
O
3ah, 35%
3ai, 41%
3aj, 38%
O
O
O
O
3ak, 61%
3al, 70%
O
O
O
O
O
O
O
3am, 50%
3an, 43%
3ao, 45%
R1 = Cl
O
O
t-Bu
O
O
Cl
Cl
3bd, 42%a
3bk, 8%b
Scheme 2 Substrate scope of the metal-free [3+2] cycloaddition. Reagents and conditions: 1 (0.15 mmol), 2 (0.6 mmol), Na2S2O8 (0.45 mmol), MeCN
(0.1 M), except in the case of 3ae: alkene 2e (0.3 mmol). Yields were based on the isolated products (after reaction, substrates 1 remain in most cases).
a 2-Chloro-4-methoxyphenol (25%) was recovered. b 2-Chloro-4-methoxyphenol (49%) was recovered.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2731–2737

2734
Y. Zhao et al.
Special Topic
Synthesis
reacted under the standard conditions, corsifuran A (3af)
was obtained in 21% yield after 72 hours (Equation 2).
dition (more examples, see the Supporting Information).
This observation is consistent with the report by Lei11 and
Yoon.13
O
According to previous reports, oxidation utilizing per-
sulfate (S2O82–) is known to involve radical processes.9,14 To
gain preliminary mechanistic information about this trans-
formation, a radical trapping experiment was performed by
addition of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO,
1.5 equiv) to the system of 1a and 2a (Equation 3); after 72
hours, three products including a small amount of 3aa were
separated by flash chromatography on silica gel. No feature
signals of the TEMPO fragment were observed when ana-
lyzing the 4-methoxyphenol or styrene fragments by NMR
of the other two products. The failure to trap radical inter-
mediate with TEMPO was not sufficient to prove a non-rad-
ical addition process, because of the possibility that the oxi-
dative cyclization took place immediately after the phenox-
yl radical had been generated.15
O
O
50 °C
O
+
Na2S2O8
MeCN
O
3af, corsifuran A, 21%
OTMS
1a
2f
(500 mg)
Equation 2 One-step synthesis of corsifuran A
Additionally, a number of styrenes with electron-with-
drawing groups in the β-position were also examined un-
der the optimal reaction conditions, but the reactions failed
to give the desired cycloaddition products (see the Support-
ing Information). We also examined the oxidative [3+2] cy-
clization of styrene with other phenol derivatives, such as
4-chlorophenol and 3-methoxyphenol, but they failed to
give the corresponding products (Scheme 3). The experi-
mental results presented show that electron-rich phenols
bearing 4-methoxy were necessary for successful cycload-
O
Na2S2O8
(3 equiv)
50 °C
O
+
OTMS
TEMPO
(1.5 equiv)
MeCN
O
3aa, <10%
2a (4 equiv)
1a
Na2S2O8, MeCN
R1
+
Equation 3 Control experiment by addition of TEMPO
50 °C
O
R1
Therefore, a possible mechanism for this reaction is pre-
OTMS
2–
sented in Scheme 4. When heated, S2O8 obtains an elec-
1
2
1 = 4-Cl
1 = 3-OMe
3ca, 0%
3ea, 0%
tron from 1a and is reduced to SO4•–. The generated radical
cation 4 undergoes TMS+ elimination and leads to a neutral
phenoxyl radical 5. Then the radical is transferred from an
O-radical 5 to C-radical 6, which could subsequently under-
go [3+2] radical addition with styrene 2a to afford the cyclic
R
R
Scheme 3 Study on the limitation of the reaction. Reagents and condi-
tions: 1 (0.15 mmol), 2 (0.6 mmol), Na2S2O8 (0.45 mmol), MeCN (0.1
M).
O
radical
O
O
O
addition
path A
3aa
– TMS+
+
•
– H•
•
•
OTMS
•
O
O
O
Ph
4
Ph
5
6
2a
7
–
SO4
Δ
path B [O]
2–
S2O8
O
O
O
cationic
addition
3aa
– H+
+
+
OTMS
O
Ph
2a
O
Ph
1a
7'
6'
Scheme 4 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2731–2737

2735
Y. Zhao et al.
Special Topic
Synthesis
radical intermediate 7, as shown in path A; a hydrogen
atom is then displaced to generate the final product 3aa.
Such a hydrogen atom displacement might lead to C=C bond
reduction product 3ae′′ (Equation 1). Alternatively, as path
B shows, intermediate 6 would be further oxidized to give
cation 6′, which is then intercepted by styrene (2a) to form
a carbon-centered cation intermediate 7′. Finally, dihydro-
benzofuran 3aa is delivered by H+ elimination.
In summary, we have demonstrated a benign and
metal-free oxidative [3+2] cross-coupling reaction of phe-
nols with alkenes for the preparation of dihydrobenzofu-
rans. A variety of alkenes that tolerate electronic and steric
effects served as suitable nucleophiles to give the corre-
sponding cycloadducts. The features of this approach are its
simple operation and mild reaction conditions. Notably, so-
dium persulfate is an inexpensive, efficient, and environ-
mentally friendly oxidant. The naturally occurring product
corsifuran A was synthesized in a single step using this pro-
tocol.
13C NMR (100 MHz, CDCl3): δ = 154.27, 153.84, 138.97, 137.77,
129.29, 127.66, 125.82, 113.01, 111.22, 109.19, 84.27, 56.06, 38.83,
21.16.
HRMS (ESI): m/z [M + H]+ calcd for C16H17O2: 241.1229; found:
241.1221.
5-Methoxy-2-(o-tolyl)-2,3-dihydrobenzofuran (3ac)
Colorless oil; yield: 23 mg (65%).
1H NMR (400 MHz, CDCl3): δ = 7.48–7.42 (m, 1 H), 7.19 (d, J = 3.6 Hz, 3
H), 6.80 (d, J = 8.6 Hz, 1 H), 6.76 (s, 1 H), 6.71 (dd, J = 8.5, 2.6 Hz, 1 H),
5.92 (t, J = 8.8 Hz, 1 H), 3.76 (s, 3 H), 3.63 (dd, J = 15.6, 9.5 Hz, 1 H),
3.07 (dd, J = 15.5, 8.2 Hz, 1 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.31, 153.87, 140.29, 134.19,
130.50, 127.60, 127.35, 126.26, 124.99, 113.06, 111.29, 109.21, 81.74,
56.06, 37.90, 19.22.
GC-MS (EI): m/z = 240.1, 239.1, 211.1, 165.1, 91.1, 28.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H17O2: 241.1229; found:
241.1186.
2-(4-tert-Butylphenyl)-5-methoxy-2,3-dihydrobenzofuran (3ad)7a
Pale yellow solid; yield: 22 mg (52%); mp 46–47 °C.
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.3
Hz, 2 H), 6.80–6.73 (m, 2 H), 6.72–6.67 (m, 1 H), 5.71 (t, J = 8.7 Hz, 1
H), 3.76 (d, J = 6.2 Hz, 3 H), 3.57 (dd, J = 15.7, 9.3 Hz, 1 H), 3.22 (dd, J =
15.7, 8.2 Hz, 1 H), 1.31 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 154.25, 153.83, 151.07, 138.84,
127.70, 125.68, 125.55, 113.00, 111.22, 109.19, 84.21, 56.06, 38.61,
34.58, 31.33.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on
a Bruker AV-400 spectrometer in CDCl3. For 1H NMR (400 MHz), TMS
served as internal standard (δ = 0 ppm). For 13C NMR (100 MHz),
CDCl3 was used as internal standard (δ = 77.23 ppm) and spectra were
obtained with complete proton decoupling. HRMS spectra were re-
corded on a Bruker Esquire LC mass spectrometer using electrospray
ionization.
HRMS (ESI): m/z [M + H]+ calcd for C19H23O2: 283.1698; found:
283.1695.
2-Aryl-5-methoxy-2,3-dihydrobenzofurans 3; General Procedure
To a 10-mL round-bottomed flask equipped with magnetic stir bar
was charged with TMS-protected phenol 1 (0.15 mmol), alkene 2 (0.6
mmol), Na2S2O8 (0.45 mmol), and dried MeCN (1.5 mL); the flask put
under vacuum and purged with N2 (3 ×). The mixture was heated at
50 °C until consumption of starting material ceased (monitored by
TLC). The mixture was filtered, and the filtrate was concentrated in
vacuo. The residue was purified by flash column chromatography to
give the final product.
5-Methoxy-2-(4-vinylphenyl)-2,3-dihydrobenzofuran (3ae)
Pale yellow oil; yield: 18 mg (50%).
1H NMR (400 MHz, CDCl3): δ = 7.36 (ddd, J = 28.3, 13.8, 6.1 Hz, 4 H),
6.77 (dt, J = 10.1, 5.0 Hz, 2 H), 6.74–6.64 (m, 2 H), 5.74 (ddd, J = 12.6,
9.3, 3.7 Hz, 2 H), 5.25 (dd, J = 10.9, 3.9 Hz, 1 H), 3.77 (s, 3 H), 3.64–3.55
(m, 1 H), 3.19 (dt, J = 15.6, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 154.28, 153.72, 136.38, 127.47,
126.45, 125.98, 114.08, 113.00, 111.18, 109.22, 84.02, 56.03, 38.83.
GC-MS (EI): m/z = 252.2, 237.2, 220.2, 165.1, 152.1, 77.1.
5-Methoxy-2-phenyl-2,3-dihydrobenzofuran (3aa)7a
HRMS (ESI): m/z [M + Na]+ calcd for C17H16O2Na: 275.1043; found:
Colorless oil; yield: 24 mg (72%).
275.1037.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.30 (m, 5 H), 6.83–6.73 (m, 2 H),
6.70 (dd, J = 8.6, 2.6 Hz, 1 H), 5.74 (t, J = 8.8 Hz, 1 H), 3.77 (s, 3 H), 3.60
(dd, J = 15.7, 9.3 Hz, 1 H), 3.20 (dd, J = 15.7, 8.2 Hz, 1 H).
5-Methoxy-2-(4-methoxyphenyl)-2,3-dihydrobenzofuran (3af)1a
13C NMR (100 MHz, CDCl3): δ = 154.33, 153.81, 142.04, 128.63,
Pale yellow oil; yield: 15 mg (38%).
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 8.6 Hz, 2 H), 6.90 (d, J = 8.6
Hz, 2 H), 6.83–6.63 (m, 3 H), 5.68 (t, J = 8.8 Hz, 1 H), 3.81 (s, 3 H), 3.77
(s, 3 H), 3.55 (dd, J = 15.8, 9.2 Hz, 1 H), 3.19 (dd, J = 15.7, 8.3 Hz, 1 H).
127.99, 127.51, 125.77, 113.04, 111.23, 109.21, 84.24, 56.06, 38.89.
HRMS (ESI): m/z [M + H]+ calcd for C15H15O2: 227.1066; found:
227.1027.
13C NMR (100 MHz, CDCl3): δ = 159.48, 154.25, 153.75, 133.95,
127.72, 127.30, 114.02, 113.00, 111.20, 109.18, 84.19, 56.06, 55.33,
38.73.
HRMS (ESI): m/z [M + H]+ calcd for C16H17O3: 257.1178; found:
257.1182.
5-Methoxy-2-(p-tolyl)-2,3-dihydrobenzofuran (3ab)7a
Colorless solid; yield: 24 mg (69%); mp 62–63 °C.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.28 (m, 2 H), 7.18 (d, J = 7.8 Hz, 2
H), 6.77 (d, J = 10.7 Hz, 2 H), 6.70 (d, J = 11.1 Hz, 1 H), 5.70 (t, J = 8.8
Hz, 1 H), 3.77 (s, 3 H), 3.57 (dd, J = 15.7, 9.3 Hz, 1 H), 3.19 (dd, J = 15.7,
8.2 Hz, 1 H), 2.35 (s, 3 H).
5-Methoxy-2-(3-methoxyphenyl)-2,3-dihydrobenzofuran (3ag)
Colorless oil; yield: 16 mg (42%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2731–2737

2736
Y. Zhao et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 7.9 Hz, 1 H), 6.97 (d, J = 8.5
Hz, 2 H), 6.87–6.83 (m, 1 H), 6.78 (d, J = 8.2 Hz, 2 H), 6.70 (d, J = 8.6 Hz,
1 H), 5.71 (t, J = 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.59 (dd, J =
14.9, 10.2 Hz, 1 H), 3.19 (dd, J = 15.7, 8.2 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H17O2: 241.1223; found:
241.1217.
2-Cyclopropyl-5-methoxy-2-phenyl-2,3-dihydrobenzofuran (3al)
13C NMR (100 MHz, CDCl3): δ = 159.86, 154.34, 153.78, 143.68,
129.72, 127.47, 118.01, 113.45, 113.05, 111.22, 111.26, 109.23, 84.09,
56.06, 55.27, 38.88.
Colorless oil; yield: 27 mg (70%).
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.6
Hz, 2 H), 7.26–7.22 (m, 1 H), 6.80–6.55 (m, 3 H), 3.73 (s, 3 H), 3.45 (d,
J = 15.7 Hz, 1 H), 3.39 (d, J = 16.0 Hz, 1 H), 1.51–1.40 (m, 1 H), 0.57–
0.48 (m, 2 H), 0.48–0.40 (m, 2 H).
GC-MS (EI): m/z = 256.1, 239.2, 225.2, 181.1, 152.1, 115.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H17O3: 257.1178; found:
13C NMR (100 MHz, CDCl3): δ = 154.07, 153.41, 146.15, 128.12,
127.59, 127.05, 125.23, 112.89, 111.15, 109.00, 90.33, 55.99, 43.24,
21.63, 1.79, 1.35.
257.0991.
2-(4-Bromophenyl)-5-methoxy-2,3-dihydrobenzofuran (3ah)
Pale yellow oil; yield: 16 mg (35%).
HRMS (ESI): m/z [M + H]+ calcd for C18H19O2: 267.1385; found:
267.1384.
1H NMR (400 MHz, CDCl3): δ = 7.75 (dd, J = 24.5, 8.4 Hz, 2 H), 7.52 (d,
J = 8.4 Hz, 2 H), 7.31 (s, 1 H), 6.79 (s, 1 H), 6.76–6.70 (m, 1 H), 5.72 (t,
J = 8.7 Hz, 1 H), 3.79 (s, 3 H), 3.63 (dd, J = 15.4, 9.2 Hz, 1 H), 3.15 (dd,
J = 15.5, 8.1 Hz, 1 H).
5-Methoxy-3-methyl-2-(p-tolyl)-2,3-dihydrobenzofuran (3am)
Colorless oil; yield: 19 mg (50%).
13C NMR (100 MHz, CDCl3): δ = 154.47, 153.58, 141.17, 132.47,
131.74, 130.98, 127.44, 113.16, 111.24, 109.28, 83.43, 56.05, 38.87.
HRMS (ESI): m/z [M + H]+ calcd for C15H14BrO2: 305.0177; found:
305.0164.
1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 7.9
Hz, 2 H), 6.78–6.73 (m, 1 H), 6.70 (d, J = 7.5 Hz, 2 H), 5.10 (d, J = 8.9 Hz,
1 H), 3.78 (s, 3 H), 3.45–3.35 (m, 1 H), 2.36 (s, 3 H), 1.39 (d, J = 6.8 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 154.44, 153.36, 137.99, 137.80,
133.09, 129.28, 126.15, 112.92, 110.13, 109.35, 92.69, 56.07, 45.85,
21.19, 17.76.
2-(4-Fluorophenyl)-5-methoxy-2,3-dihydrobenzofuran (3ai)
Colorless oil; yield: 15 mg (41%).
GC-MS (EI): m/z = 254.2, 239.1, 211.1, 165.1, 115.1, 91.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H19O2: 255.1385; found:
255.1387.
1H NMR (400 MHz, CDCl3): δ = 7.37 (dd, J = 8.6, 5.4 Hz, 2 H), 7.03 (s, 2
H), 6.77 (d, J = 8.6 Hz, 2 H), 6.70 (dd, J = 8.5, 2.2 Hz, 1 H), 5.71 (t, J = 8.8
Hz, 1 H), 3.77 (s, 3 H), 3.59 (dd, J = 15.7, 9.3 Hz, 1 H), 3.16 (dd, J = 15.7,
8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.70, 154.40, 153.59, 127.60,
127.52, 115.62, 115.40, 113.09, 111.21, 109.25, 83.61, 56.05, 38.93.
5-Methoxy-2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzofu-
ran (3an)7a
Colorless oil; yield: 17 mg (43%).
GC-MS (EI): m/z = 244.1, 229.1, 211.1, 183.1, 109.1, 55.1.
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 8.6 Hz, 2 H), 6.93–6.90 (m, 2
H), 6.77–6.69 (m, 3 H), 5.08 (d, J = 9.1 Hz, 1 H), 3.82 (s, 3 H), 3.79 (s, 3
H), 3.47–3.36 (m, 1 H), 1.39 (d, J = 6.8 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H14FO2: 245.0978; found:
245.0979.
13C NMR (100 MHz, CDCl3): δ = 159.66, 154.43, 153.29, 133.13,
132.73, 127.65, 114.02, 112.89, 110.11, 109.35, 92.61, 56.07, 55.32,
45.69, 17.60.
HRMS (ESI): m/z [M + K]+ calcd for C17H18O3K: 309.0893; found:
309.0777.
8-Methoxy-9b,10-dihydro-4bH-benzo[b]indeno[2,1-d]furan (3aj)
Pale yellow oil; yield: 14 mg (38%).
1H NMR (400 MHz, CDCl3): δ = 7.55 (t, J = 8.60 Hz, 1 H), 7.28–7.21 (m,
3 H), 6.81 (s, 1 H), 6.65–6.64 (m, 2 H), 6.18 (d, J = 8.23 Hz, 1 H), 4.28 (t,
J = 17.23 Hz, 1 H), 3.75 (s, 3 H), 3.51 (dd, J = 8.58, 8.56 Hz, 1 H), 3.20
(dd, J = 1.34, 1.38 Hz, 1 H).
5-Methoxy-2-phenyl-3-propyl-2,3-dihydrobenzofuran (3ao)
13C NMR (100 MHz, CDCl3): δ = 154.38, 152.99, 142.17, 140.91,
131.83, 129.23, 127.26, 125.90, 125.09, 113.51, 110.88, 109.81, 90.73,
56.06, 45.27, 38.97.
Pale yellow oil; yield: 18 mg (45%).
1H NMR (400 MHz, CDCl3): δ = 7.33 (dd, J = 13.1, 3.7 Hz, 5 H), 6.74 (dt,
J = 8.5, 7.3 Hz, 3 H), 5.31 (d, J = 6.3 Hz, 1 H), 3.77 (s, 3 H), 3.38 (dd, J =
13.1, 6.6 Hz, 1 H), 1.77 (ddd, J = 22.7, 11.6, 6.3 Hz, 2 H), 1.47 (dd, J =
14.3, 7.2 Hz, 2 H), 0.94 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.30, 153.57, 142.12, 131.62,
128.61, 127.99, 125.93, 112.98, 110.92, 109.18, 90.18, 56.06, 50.93,
37.23, 20.12, 14.17.
GC-MS (EI): m/z = 238.2, 223.1, 207.2, 165.2, 152.1, 115.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H15O2: 239.1072; found:
239.0994.
5-Methoxy-2-methyl-2-phenyl-2,3-dihydrobenzofuran (3ak)7a
Pale yellow solid; yield: 22 mg (61%); mp 53–54 °C.
HRMS (ESI): m/z [M + H]+ calcd for C18H21O2: 269.1542; found:
269.1493.
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 7.4 Hz, 2 H), 7.34 (t, J = 7.6
Hz, 2 H), 7.25 (d, J = 4.8 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 6.69 (dd, J =
12.4, 3.9 Hz, 2 H), 3.74 (s, 3 H), 3.41 (d, J = 15.6 Hz, 1 H), 3.34 (d, J =
15.5 Hz, 1 H), 1.76 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.16, 153.07, 146.90, 128.35,
127.47, 127.01, 124.54, 113.03, 111.38, 109.40, 89.19, 56.03, 45.17,
29.23.
2-(4-tert-Butylphenyl)-7-chloro-5-methoxy-2,3-dihydrobenzofu-
ran (3bd)
Pale yellow oil; yield: 20 mg (42%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2731–2737

2737
Y. Zhao et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.3
Hz, 2 H), 6.71 (d, J = 2.3 Hz, 1 H), 6.68 (s, 1 H), 5.79 (t, J = 8.6 Hz, 1 H),
3.75 (s, 3 H), 3.63 (dd, J = 16.1, 9.0 Hz, 1 H), 3.28 (dd, J = 15.9, 8.0 Hz, 1
H), 1.31 (s, 9 H).
(3) (a) Chauret, C. D.; Bernard, C. B.; Arnason, J. T.; Durst, T. J. Nat.
Prod. 1996, 59, 152. (b) De Campos, M. P.; Filho, V. C.; Da Silva, R.
Z.; Yunes, R. A.; Zaccino, S.; Juarez, S.; Bella Cruz, R. C.;
Bella Cruz, A. Biol. Pharm. Bull. 2005, 28, 1527.
(4) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Sweton, J. S.
J. Org. Chem. 1992, 57, 2135.
13C NMR (100 MHz, CDCl3): δ = 154.49, 151.29, 149.92, 138.10,
128.98, 125.71, 125.58, 113.18, 110.21, 84.70, 56.17, 39.26, 31.32.
(5) (a) Chen, M. W.; Gao, L. L.; Ye, Z. S.; Jiang, G. F.; Zhou, Y. G. Chem.
Commun. 2013, 49, 1660. (b) Li, Q. B.; Zhou, F. T.; Liu, Z. G.; Li, X.
F.; Zhu, W. D.; Xie, J. W. J. Org. Chem. 2011, 76, 7222.
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Journet, M.; Davies, I. W. J. Org. Chem. 2005, 70, 3727. (e) Li, W.
S.; Guo, Z. R.; Thornton, J.; Katipally, K.; Polniaszek, R.;
Thottathil, J.; Vu, T.; Wong, M. Tetrahedron Lett. 2002, 43, 1923.
(f) Stafford, J. A.; Valvano, N. L. J. Org. Chem. 1994, 59, 4346.
(g) Meijs, G. F.; Beckwith, A. L. J. J. Am. Chem. Soc. 1986, 108,
5890.
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Cacchi, S.; Fabrizi, G. Tetrahedron 1998, 54, 7343. (b) Wang, X. S.;
Lu, Y.; Dai, H. X.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 12203.
(c) Kshirsagar, U. A.; Regev, C.; Parnes, R.; Pappo, D. Org. Lett.
2013, 15, 3174. (d) Gaster, E.; Vainer, Y.; Regev, A.; Narute, S.;
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Chem. Int. Ed. 2015, 54, 4198.
HRMS (ESI): m/z [M + H]+ calcd for C19H22ClO2: 317.1308; found:
317.1312.
7-Chloro-5-methoxy-2-methyl-2-phenyl-2,3-dihydrobenzofuran
(3bk)
Colorless oil; yield: 4 mg (8%).
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.7
Hz, 3 H), 6.71 (d, J = 2.2 Hz, 1 H), 6.61 (s, 1 H), 3.72 (s, 3 H), 3.48–3.43
(m, 2 H), 1.81 (s, 3 H).
Data are consistent with literature values.10
2-(4-Ethylphenyl)-5-methoxy-2,3-dihydrobenzofuran (3ae′′)
Pale yellow oil; yield: 7 mg (18%).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.27 (m, 1 H), 7.25–7.13 (m, 3 H),
6.80–6.74 (m, 2 H), 6.72–6.67 (m, 1 H), 5.71 (t, J = 8.9 Hz, 1 H), 3.77 (s,
3 H), 3.58 (dd, J = 15.9, 9.3 Hz, 1 H), 3.21 (dd, J = 15.7, 8.5 Hz, 1 H), 2.65
(q, J = 7.6 Hz, 2 H), 1.25–1.21 (t, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.83, 143.69, 140.88, 127.59,
126.53, 124.35, 122.13, 112.00, 110.20, 108.19, 83.44, 55.05, 37.84,
28.68, 14.52.
(7) (a) Dohi, T.; Hu, Y. J.; Kamitanaka, T.; Washimi, N.; Kita, Y. Org.
Lett. 2011, 13, 4814. (b) Li, Q. B.; Hu, X. C. Chem. Lett. 2012, 41,
1633.
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Chiba, K. Tetrahedron Lett. 2011, 52, 4690.
GC-MS (EI): m/z = 254.2, 239.2, 224.1, 211.2, 105.2, 91.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H19O2: 255.1385; found:
255.1401.
(9) Dai, C. H.; Meschini, F.; Narayanam, J. M. R.; Stephenson, C. R. J.
J. Org. Chem. 2012, 77, 4425.
(10) (a) Tomakinian, T.; Guillot, R.; Kouklovsky, C.; Vincent, G.
Angew. Chem. Int. Ed. 2014, 53, 11881. (b) Beaud, R.; Guillot, R.;
Kouklovsky, C.; Vincent, G. Angew. Chem. Int. Ed. 2012, 51,
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Fischer, A.; Waldvogel, S. R. Chem. Eur. J. 2009, 15, 2273.
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Puetter, H.; Waldvogel, S. R. Chem. Eur. J. 2006, 12, 7482.
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A. Angew. Chem. Int. Ed. 2004, 43, 6709.
Acknowledgment
We are grateful for financial support from China NSFC (Nos.
21272047, 21372055, and 21472030), SKLUWRE (No. 2015DX01),
and the Fundamental Research Funds for the Central Universities
(Grant No. HIT.BRETIV.201310).
(11) Huang, Z. L.; Jin, L. Q.; Feng, Y.; Peng, P.; Yi, H.; Lei, A. W. Angew.
Chem. Int. Ed. 2013, 52, 7151.
Supporting Information
Supporting information for this article is available online at
(12) (a) Zhao, G. L.; Yang, C.; Guo, L.; Sun, H. N.; Chen, C.; Xia, W.
Chem. Commun. 2012, 48, 2337. (b) Zhao, G. L.; Yang, C.; Guo, L.;
Sun, H. N.; Lin, R.; Xia, W. J. Org. Chem. 2012, 77, 6302. (c) Sun,
H. N.; Yang, C.; Gao, F.; Li, Z.; Xia, W. Org. Lett. 2013, 15, 624.
(d) Guo, L.; Yang, C.; Zheng, L. W.; Xia, W. Org. Biomol. Chem.
2013, 11, 5787. (e) Zhao, Y. T.; Li, Z.; Yang, C.; Lin, R.; Xia, W. Bel-
stein J. Org. Chem. 2014, 10, 622. (f) Sun, H. N.; Yang, C.; Lin, R.;
Xia, W. Adv. Synth. Catal. 2014, 356, 2775.
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Ed. 2014, 53, 11056.
(14) Minisci, F.; Citterio, A.; Giordano, C. Acc. Chem. Res. 1983, 16, 27.
(15) Meng, L. K.; Zhang, G. H.; Liu, C.; Wu, K.; Lei, A. W. Angew. Chem.
Int. Ed. 2013, 52, 10195.
http://dx.doi.org/10.1055/s-0034-1380419.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2731–2737