Cerium ammonium nitrate-mediated the oxidative dimerization of p-alkenylphenols: A new synthesis of substituted (±)-trans- dihydrobenzofurans

Article abstract of DOI:10.1016/j.tet.2012.11.006

A new method for the preparation of substituted dihydrobenzofurans is described. The p-alkenylphenols, mediated by cerium ammonium nitrate (CAN), undergo the oxidative dimerization to generate substituted dihydrobenzofurans including (±)-conocarpan, (±)-licarin A, (±)-acuminatin, as well as their related substituted dihydrobenzofurans.

Full text of DOI:10.1016/j.tet.2012.11.006

Tetrahedron 69 (2013) 653e657
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cerium ammonium nitrate-mediated the oxidative dimerization
of p-alkenylphenols: a new synthesis of substituted
(ꢀ)-trans-dihydrobenzofurans
*
Po-Yuan Chen, Yi-Hua Wu, Mon-Huei Hsu, Tzu-Pin Wang, Eng-Chi Wang
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 August 2012
Received in revised form 24 October 2012
Accepted 2 November 2012
Available online 8 November 2012
A new method for the preparation of substituted dihydrobenzofurans is described. The p-alkenylphenols,
mediated by cerium ammonium nitrate (CAN), undergo the oxidative dimerization to generate
substituted dihydrobenzofurans including (ꢀ)-conocarpan, (ꢀ)-licarin A, (ꢀ)-acuminatin, as well as their
related substituted dihydrobenzofurans.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cerium ammonium nitrate
Dihydrobenzofurans
Licarin A
Acuminatin
Conocarpan
1. Introduction
oxidative dimerization of isoeugenol or relative compounds to yield
dihydrobenzofurans by means of enzyme biocatalysts including by
Due to the diverse biological activities, 2,3-dihydrobenzo-furan
derivatives have become an attractive category for researchers and
received considerable results in the passing decades.1 The major
biological activities reported include the treatment of traumatic
and ischemic central nervous system injury,2a the effectiveness in
treating of arteriosclerosis, hepatopathy, and cerebrovascular dis-
ease,2b the antitubercular activity,2c and the potent trypanocidal
and antileishmanial activities,2d as well as others. Major synthetic
methods, which were reported include the oxidative cycloaddition
of a 2-cyclohexenone or R-tetralone and an alkene with dried
horseradish peroxidase and H2O2 at citrate phosphate buffer pH 3
in methanol,14 by anionic potato peroxidase,15 by crude onion
peroxidase,16 as well as others also have been reported. However,
despite numerous methods have been disclosed, drawbacks, such
as reaction time, yield of product, reaction conditions, synthetic
steps, reagents with environmental concerning, and structures of
biocatalyst remain to be addressed. Therefore, it prompts us to
develop a new, CAN-mediated, concise, and efficient method for
the diastero-selective preparation of 2,3-substituted dihy-
drobenzofurans, i.e., (ꢀ)-conocarpan (2a),17 (ꢀ)-licarin A (2b),18
(ꢀ)-acuminatin (2c),19 as well as their relative congeners by the
oxidative dimerization of p-alkenylphenols (1) (Scheme 1).
Mn(OAc)3,3 the reactions of 2-hydroxyaryl
b-unsaturated ketones
with dimethylsulfonium carbonylmethylides,4 the reaction of o-
nitrotoluenes and aromatic aldehydes in the presence of TBAF,5 the
reaction of phenols with 2-aryl-2,2-dialkylacetaldehydes in the
presence of an acid catalyst,6 the ring-opening of arylsubstituted
epoxides, and then by cyclodehydration,7 via a diastereoselective
palladium-catalyzed oxyarylation reaction of o-aminophenols and
phenylpropenes in one pot,8 from N-thiophosphinyl imines and
sulfur ylides,9 the K2CO3-catalyzed domino reactions of salicylic
aldehyde derivatives and 2-halo-1,3-dicarbonyl compounds,10 as
well as the dimerization of p-alkenylphenol or their esters by
Ag2O,11 K3Fe(CN)6,12 and iodobenzene diacetate.13 Furthermore, the
2. Results and discussion
‘In order to conquer the common disadvantage of low yield in
radical dimerization and achieve an optimum reaction conditions,
the reaction of isoeugenol (1b) with CAN under various conditions
for yielding (ꢀ)-licarin A (2b) was carefully studied. The results
were provided in Table 1.
As shown in Table 1, the amount of CAN, reaction time, and sol-
vents have significant effects on the yield of (ꢀ)-licarin A (2b). For
example, 1.5 equiv of CAN that was used could produce 2b in the
highest yield (81%) (entry 5) but 0.5 equiv(33%) (entry 1) or 2.0 equiv
(55%) (entry 6) of CAN that was used could reduce the yield of 2b.
* Corresponding author. E-mail address: enchwa@kmu.edu.tw (E.-C. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.006

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P.-Y. Chen et al. / Tetrahedron 69 (2013) 653e657
Table 2
R1
R1
R1
The result of % of conversion of 2b to 1b by CAN from 1 h to 6 h
OR2
(i)
Entry
Time (h)
Yield (%)a (1b)
Recovery (%)a (2b)
O
OH
R
1
2
3
4
5
6
7
1
2
3
4
5
6
>24
11
19
27
43
49
52
0
82
71
62
46
40
33
0
R
R
2
1
a. R=R2=H, R1 = CH3 (conocarpin)
a. R=H, R1=CH3;
b. R=OCH3, R1=CH3
c. R=R1=H
d. R=H, R1=isoC3H9
e. R=OCH3, R1=H
f. R=H, R1=COCH3
g. R=OCH3, R1=COCH3
b. R=OCH3, R1=CH3, R2=H (licarin A)
c. R=R1=OCH3, R2=CH3 (acuminatin)
d. R=R1=H
(ii)
e. R=H, R1=isoC3H9
f. R=OCH3, R1=H
g. R=H, R1=COCH3
h. R=OCH3, R1=COCH3
a
Isolated yield from silica gel column chromatography (n-hexane/ethyl
acetate¼1:1).
Reagents and condition: i. CAN, THF, 0oC, 0.5 hr, 81-85%; ii. CH3I, K2CO3,
acetone, reflux, 5 hr, 94%
observed (entries 1e 6). But when the reaction time is over 24 h,
neither 1b nor 2b can be isolated due to yielding unidentified high
polarity products (the reaction mixture can be developed by TLC:
silica gel, ethyl acetate or MeOH). Therefore, the reaction time for
dimerization of isoeugenol by CAN should be controlled cautiously.
For increasing the diversity, a series of dihydrobenzofurans (2aeh)
are synthesized by basing on the resulting optimum condition
(CAN 1.5 equiv slowly dropped into p-alkenylphenol (1aeg) in
solvent THF, at 0 ꢁC). Furthermore, treatment of (ꢀ)-licarin A (2b)
with methyl iodide in the presence of K2CO3 to yield (ꢀ)-acumi-
natin (2c) was also reported. The yields (%) of 2aeh obtained were
provided in Table 3.
Scheme 1. CAN-mediated the oxidative coupling of p-alkenylphenols for the synthesis
of (ꢀ)-trans-2,3-substituted dihydrobenzofurans and their congeners.
Table 1
Reaction of isoeugenol (1b) with CAN to yield (ꢀ)-licarin A (2b) under various
conditions at 0 ꢁC
CH3
H3C
H3C
conditions
OH
O
OH
OCH3
OCH3
OCH3
licarin A (2b)
isoeugenol (1b)
Entry
CAN (equiv)
Time (h)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
0.5
1.0
1.5
1.5
1.5
2.0
1.5
1.5
1.5
2
2
2
0.5
0.5a
0.5
0.5
0.5
0.5
THF
THF
THF
THF
THF
THF
CH2Cl2
DMSO
1,4-Dioxane
33b
46b
60
73
81
55
0b
Table 3
The yields (%) of dihydrobenzofurans (2aeh) from p-alkenylphenols mediated by
CAN
R1
R1
OR2
O
59
51
R
R
2
a
CAN in THF was added dropwise.
Accompanied with the recovery of starting material.
a. R=R2=H, R1 = CH3 (conocarpin); b. R=OCH3, R1=CH3, R2=H (licarin A)
c. R=R1=OCH3, R2=CH3 (acuminatin); d. R=R1=R2=H
e. R=R2=H, R1=isoC3H9; f. R=OCH3, R1=R2=H
b
g. R=R2=H, R1=COCH3; h. R=OCH3, R1=COCH3, R2=H
Thus, from the above experimental results, 1.5 equiv of CAN is the
appropriate amount for producing 2b in good yield. Furthermore,
the addition of CAN to isoeugenol (1b) in THF by drops increases the
yield of (ꢀ)-licarin A (2b) to 81% (entry 5). Comparing to reaction
solvents, the yield of 2b in THF is in a range of 81e73% (entries 5 and
6), in DMSO is in 59% (entry 8), in 1,4-dioxane is 51% (entry 9), and in
CH2Cl2 is 0% (entry 7) were observed’. Furthermore, this radical di-
merization is sensitive to reaction time. While prolonged the re-
action time, the lower % yield of product 2b was observed (entries 3
and 4). Due to this given result, the oxidative dimerization reaction
of isoeugenol (1b) to yield (ꢀ)-licarin A (2b) that depends on not
only the concentration of CAN but also reaction time is understood.
To clarify and to explain this phenomenon, the same reaction con-
dition (described in Table 1, entry 4) was applied to treat pure
(ꢀ)-licarin A (2b) with CAN to see what would be happened. Sur-
prisingly, the % of conversion of 2b to 1b was discovered while ex-
amining the reaction from 1 to 6 h by 1 h interval (Scheme 2).
Compound
Yield (%)
Compound
Yield (%)
2a
2b
2c
2d
85
81
94
82
2e
2f
2g
2h
84
86
88
89
The structural elucidation of dihydrobenzofurans (2aeh) that
synthesized was determined by spectral data, such as 1H NMR, 13
C
NMR, EI-MS, and HRMS, which all matched the proposed structures.
Forexample, the1H NMR (400 MHz, CDCl3) of(ꢀ)-licarin A, 2b shown
one doublet signal with three protons at
d
1.38 (J¼6.8 Hz) indicated
the presence of methyl group (CH3CH]CH); one double doublet
signal with three protons at
1.87 (J¼6.8, 1.6 Hz) indicated the
presence of methyl group at C3eCH3, one doublet quartet signal with
one proton at
3.45 (J¼9.6, 6.8 Hz) indicated the presence of H-3, two
singlet signals each with three protons at 3.88 and 3.89 indicated
the presence of two methoxy groups, one doublet signal with one
proton at
d
d
CH3
d
H3C
H3C
CAN
THF, 0 oC, 1- 6 hr
OH
d
5.10 (d, J¼9.6 Hz) indicated the presence of H-2. Due to the
O
OH
OCH3
isougenol (1b)
coupling constant J¼9.6 Hz between H-2 and H-3, the stereochem-
OCH3
OCH3
istry of C2eC3 of 2b could be deduced as trans-form.18 Other signals,
( )-
licarin A (2b)
such as at
d
5.63 (s, 1H, ArOH), 6.11 (dq, J¼15.6, 6.8 Hz, 1H, ArCH]
Scheme 2. The % of conversion of 2b to 1b by CAN that is examined from 1 h to 6 h.
CHCH3), 6.36 (dq, J¼15.6,1.6 Hz,1H, ArCH]CHCH3), 6.77 (s,1H, ArH),
6.79 (s, 1H, ArH), 6.88 (d, J¼8.4 Hz, 1H, ArH), 6.91 (d, J¼8.4 Hz, 1H,
ArH), and 6.97 (s, 1H, ArH) are consistent with the data required for
(ꢀ)-licarin A and also matched with the pattern of previously re-
ported data.18b In addition, the spectral data of 2b including 13C NMR,
EI-MS, and HRMS all fit in the structure with (ꢀ)-licarin A.
The result of conversion of 2b to 1b by treating with CAN was
provided in Table 2.
From the results obtained in Table 2, the longer reaction time
(from 1e 6 h), the more conversion of 2b to 1b (from 11% to 52%)

P.-Y. Chen et al. / Tetrahedron 69 (2013) 653e657
655
Furthermore, the reaction mechanism of CAN-mediated the oxida-
tive dimerization of p-alkenylphenols for the synthesis of trans-2,3-
substituted or the related dihydrobenzo-furans could be rationally
proposed and illustrated as follows (Scheme 3).
4.1.1. General procedure for the preparation of p-vinylphenols (1a, 1c,
1d, and 1e). A mixture of alkyl triphenylphosphonium bromide
(15 mmol) in THF (20 mL) was treated with potassium tert-butoxide
(2.81 g, 25 mmol). After stirring for 10 min at room temperature,
a solution of p-hydroxybenzaldehydes (10 mmol) in THF (10 mL)
was added in drops to the above suspension, and the resulting
mixture was stirred at room temperature for 4 h, which was
monitored by TLC. The resulting solution was quenched with sat-
urated NH4Cl solution (50 mL), and concentrated in vacuo to
remove THF. The concentrated mixture was extracted with CH2Cl2
(5ꢂ20 mL). The organic layers were washed with brine (20 mL) and
dried over MgSO4 were filtered, evaporated, and the residue was
purified by column chromatography (ethyl acetate/n-hexane¼1:15)
to give pure 1a, 1c, 1d, and 1e.
Ce+3
Ce+4
OH
R1
R1
R1
.
+
.
.
O
.
O
.
.
H
H
+
R
R
1
R
1-I
1-II
R1
OH
R1
1
R
R1
R1
H
.
.
.
-H
R1
..O
+
4.1.1.1. ((E)-4-Propenyl)phenol (1a).20 Compound 1a (1.11 g, 83%)
was obtained as colorless liquid, Rf¼0.46 (ethyl acetate/n-
O:H
.
+
R
H
R
O
+
H
.
.
R
OH
R
hexane¼1:5); 1H NMR (CDCl3, 400 MHz)
d
1.82 (d, J¼7.2 Hz, 3H,
1-III
1-IV
ArCH]CHCH3), 5.66 (dq, J¼18.0, 7.2 Hz, 1H, ArCH]CHCH3), 6.30 (d,
J¼18.0 Hz,1H, ArCH]CHCH3), 6.79 (d, J¼8.8 Hz, 2H, ArH), 7.05 (s,1H,
R1
ArOH), 7.14 (d, J¼8.8, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d
14.4,
R1
R1
R1
-H+
115.0,123.5,125.1,127.0,129.0,130.1,130.4,153.6; EI-MS (70 eV) m/z
(rel intensity, %) 134 (Mþ, 99), 133 (100), 107 (22), 105 (58), 91 (23),
79 (29), 77 (27); HRMS calcd for C9H10O: 134.0732. Found: 134.0730.
OH
OH
O+
O
R
H
R
R
R
2
1-V
4.1.1.2. Isoeugenol (1b). Compound (1b) was purchased from
Alfa Aesar, a Johnson Matthey Co.
Scheme 3. The proposed mechanism for the formation of trans-2,3-substituted or 2-
substituted dihydrobenzofurans from p-alkenylphenols mediated by CAN.
4.1.1.3. 4-Vinylphenol (1c).21 Compound 1c (0.98 g, 82%) was
obtained as colorless liquid, Rf¼0.49 (ethyl acetate/n-hexane¼1:5);
Initially, mediated by CAN, one lone pair electron on oxygen of
p-alkenylphenol (1) is lost to give a radical cation transient 1-I,
which has stabilized by transient 1-II with resonance. Then, the
radical cation transient 1-II is coupled with p-alkenylphenol (1) to
generate the transient 1-III. Subsequently, by restoring the aro-
matic ring, a protonated 4-methylenecyclohexa-2,5-dienone-like
cation, the transient 1-IV which R1 and the neighboring group are
far apart, is generated. After undergoing the intramolecular con-
jugated addition, the protonated transient 1-V was spontaneously
generated in trans-configuration. Finally, the product trans-2,3-
substituted or 2-substituted dihydrobenzo-furan (2) is yielded af-
ter deprotonation.
1H NMR (CDCl3, 200 MHz)
d
5.10 (dd, J¼11.0, 0.8 Hz, 1H, ArCH]
CHaHb), 5.58 (dd, J¼17.6, 1.0 Hz, 1H, ArCH]CHaHb), 6.62 (s, 1H,
ArOH), 6.67 (dd, J¼17.6, 11.0 Hz, 1H, ArCH]CHaHb), 6.79 (d,
J¼8.6 Hz, 2H, ArH), 7.27 (d, J¼8.8 Hz, 2H, ArH); 13C NMR (CDCl3,
50 MHz)
d 111.4, 115.4, 127.5, 130.3, 136.1, 155.4; EI-MS (70 eV) m/z
(rel intensity, %) 120 (Mþ,100), 119 (12), 108 (4), 107 (4), 92 (9), 91
(36), 65 (4); HRMS calcd for C8H8O: 120.0575. Found: 120.0575.
4.1.1.4. 4-((E)-3-Methylbut-1-enyl)phenol (1d).22 Compound 1d
(1.29 g, 80%) was obtained as colorless liquid, Rf¼0.47 (ethyl ace-
tate/n-hexane¼1:5); 1H NMR (CDCl3, 400 MHz)
1.04 (d, J¼6.4 Hz,
d
6H, ArCH]CHCHMe2), 2.88 (m, 1H, ArCH]CHCHMe2), 5.06 (s, 1H,
ArOH), 5.38 (dd, J¼18.0, 10.4 Hz, 1H, ArCH]CHCHMe2), 6.21 (d,
J¼18.0 Hz, 1H, ArCH]CHCHMe2), 6.79 (d, J¼8.8 Hz, 2H, ArH), 7.15
3. Conclusion
In this study, a new and an efficient method for the preparation
of (ꢀ)-trans-dihydrobenzofurans and related dihydrobenzo-furans
from p-alkenylphenols mediated by CAN, is established. We also
figure out that the high concentration of CAN and long reaction
time is a disadvantage for this oxidative dimerization.
(d, J¼8.8 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 23.2, 27.1, 115.0,
125.7, 130.0, 130.6, 139.1, 154.1; EI-MS (70 eV) m/z (rel intensity, %)
162 (Mþ, 38), 147 (100), 132 (9), 119 (22), 107 (18), 89 (37), 77 (9);
HRMS calcd for C11H10O: 162.1045. Found: 162.1046.
4.1.1.5. 2-Methoxy-4-vinylphenol (1e).21 Compound 1e (1.23 g,
82%) was obtained as colorless liquid, Rf¼0.49 (ethylacetate/n-
4. Experimental
4.1. General
hexane¼1:5); 1H NMR (CDCl3, 200 MHz)
d 3.91 (s, 3H, ArOCH3), 5.10
(dd, J¼10.6, 0.8 Hz, 1H, ArCH]CHaHb), 5.60 (dd, J¼17.6, 0.8 Hz, 1H,
ArCH]CHaHb), 5.65 (s,1H, OH), 6.64 (dd, J¼17.6,10.8 Hz,1H, ArCH]
Melting points (Yanaco micro melting-point apparatus) were
uncorrected. 1H NMR and 13C NMR spectra were obtained on
a Varian Gemini-200 or Varian Unity plus 400 Spectrometer.
Chemical shifts were measured in parts per million with respect to
TMS. Elemental analyses were recorded on a Heraeus CHNeO Rapid
analyzer. Mass spectra were recorded on a Chem./hp/middle
spectrometer connected to a Hewlett Packard series II model
gaseliquid chromatography. HRMS spectra were performed on
a JEOL JMS SX/SX 102A instrument. Silica gel (230e400 mesh) for
column chromatography and precoated silica gel plates (60 F254) for
TLC was purchased from E. Merck Co. UV light (254 nm) was used to
detect spots on TLC plates after development.
CHaHb), 6.92 (m, 3H, ArH), 13C NMR (CDCl3, 50 MHz)
d 55.9, 108.0,
111.4, 114.3, 120.0, 130.3, 136.6, 145.6, 146.6; EI-MS (70 eV) m/z (rel
intensity, %) 150 (Mþ,100),137 (8),135 (54),107 (33), 80 (19), 78 (10),
77 (25); HRMS calcd for C9H10O2: 150.0681. Found: 150.0680.
4.1.2. General procedure for the preparation of compounds (1f,g). To
a stirred solution of p-hydroxybenzaldehydes (10 mmol) in anhy-
drous acetone (15 mL) was added 10% NaOH solution (25 mL), and
the mixture was stirred for 3 h at room temperature. Acidification
using 10% HCl until the color change of Congo red paper from red to
blue. The resulting mixture was extracted with dichloromethane
(30 mLꢂ3). The organic layers were washed with brine (20 mL) and

656
P.-Y. Chen et al. / Tetrahedron 69 (2013) 653e657
dried over MgSO4 were filtered, evaporated, and the residue was
purified by column chromatography (ethyl acetate/n-hexane¼1:10)
to give pure 1feg.
(Mþ, 100), 311 (25), 309 (7), 284 (11), 283 (11), 279 (6), 151 (6);
HRMS calcd for C20H22O4: 326.1518. Found: 326.1521.
4.1.3.3. Preparation of 2-(3,4-dimethoxyphenyl)-7-methoxy-3-
methyl-5-((E)-propenyl)-2,3-dihydrobenzofuran [(ꢀ)-acuminatin
(2c)].19 (ꢀ)-Licarin A (2b) (0.65 g, 2 mmol) dissolved in acetone
(30 mL) was added K2CO3 (0.41 g, 3 mmol), and respectively
added methyl iodide (0.34 mL, 2.4 mmol). The reaction mixture
was heated to reflux for 5 h (monitoring by TLC). After the end of
reaction, the mixture was filtered from Celite 545 to remove solid,
and the giving filtrate was concentrated in vacuo to remove the
solvent to give crude product. After purification by silica gel col-
umn chromatography (ethyl acetate/n-hexane¼1:10) afforded
(ꢀ)-acuminatin (2c). Compound 2c (0.64 g, 94%) was obtained as
pale yellow crystals, mp 120e121 ꢁC; Rf¼0.47 (ethyl acetate/n-
4.1.2.1. (E)-4-(4-Hydroxyphenyl)but-3-en-2-one (1f).23 Compound
1f (1.39 g, 86%) was obtained as colorless crystals, mp 109 ꢁC, Rf¼0.47
(ethyl acetate/n-hexane¼1:2); 1H NMR (CDCl3, 200 MHz)
d 2.42 (s, 3H,
COCH3), 6.63 (d, J¼16.2 Hz, 1H, ArCH]CHCOCH3), 6.95 (d, J¼8.8 Hz,
2H, ArH), 7.46 (d, J¼8.8 Hz, 2H, ArH), 7.55 (d, J¼16.2 Hz, 1H, ArCH]
CHCOCH3), 8.32 (s, 1H, ArOH); 13C NMR (CDCl3, 50 MHz)
d 27.1, 116.2,
124.0,126.1,130.5,145.2,159.3,175.7; EI-MS (70 eV) m/z (rel intensity,
%) 162 (Mþ, 33),161 (55),147 (100),146 (32),119 (70), 91 (83), 65 (25);
HRMS calcd for C10H10O2: 162.0681. Found: 162.0680.
4.1.2.2. (E)-4-(4-Hydroxy-3-methoxyphenyl)but-3-en-2-one
(1g).24 Compound 1g (1.63 g, 85%) was obtained as yellow crystals,
mp 127e128 ꢁC, Rf¼0.49 (ethyl acetate/n-hexane¼1:2); 1H NMR
hexane¼1:5); 1H NMR (CDCl3, 400 MHz)
d
1.38 (d, J¼6.8 Hz, 3H,
C3eCH3), 1.87 (dd, J¼6.4, 1.6 Hz, 3H, ArCH]CHCH3), 3.46 (dq,
J¼9.6, 6.8 Hz, 1H, H-3), 3.87 (s, 3H, ArOCH3), 3.88 (s, 3H, ArOCH3),
3.90 (s, 3H, ArOCH3), 5.12 (d, J¼9.6 Hz, 1H, H-2), 6.11 (dq, J¼15.6,
6.4 Hz, 1H, ArCH]CHCH3), 6.36 (dq, J¼15.6, 1.6 Hz, 1H, ArCH]
CHCH3), 6.78 (d, J¼8.0 Hz, 1H, ArH), 6.83 (s, 1H, ArH), 6.85 (s, 1H,
ArH), 6.96 (dd, J¼8.0, 2.0 Hz, 1H, ArH), 6.98 (d, J¼2.0 Hz, 1H, ArH);
(CDCl3, 200 MHz) d 2.37 (s, 3H, COCH3), 3.92 (s, 3H, ArOCH3), 6.24 (s,
1H, ArOH), 6.59 (d, J¼16.2 Hz, ArCH]CHCOCH3), 6.94 (d, J¼8.0 Hz,
1H, ArH), 7.08 (d, J¼8.0 Hz, 1 ArH), 7.11 (s, 1H, ArH), 7.46 (d, 1H,
J¼16.2 Hz, ArCH]CHCOCH3); 13C NMR (CDCl3, 50 MHz)
d 27.2, 55.9,
109.3, 114.8, 123.4, 124.8, 126.8, 143.8, 146.9, 148.3, 179.5; EI-MS
(70 eV) m/z (rel intensity, %) 192 (Mþ, 61), 191 (42), 177 (54), 175
(32), 145 (100), 117 (47), 89 (31); HRMS calcd for C11H12O2:
192.0786. Found: 192.0788.
13C NMR (CDCl3, 100 MHz)
d 17.6, 18.4, 45.6, 55.9, 93.7, 109.3,
109.5, 110.8, 113.3, 119.2, 123.5, 130.9, 132.2, 132.7, 132.2, 133.3,
144.2, 146.6, 149.1; EI-MS (70 eV) m/z (rel intensity, %) 340 (Mþ,
100), 325 (33), 309 (12), 297 (11), 165 (20), 164 (11), 151 (12);
HRMS calcd for C21H24O4: 340.1675. Found: 340.1677.
4.1.3. General procedure for the preparation of natural occurring
(ꢀ)-dihydrobenzofurans (2a,b). A solution of 1a,b (2 mmol) in THF
(50 mL) was added dropwise with ceric ammonium nitrate (1.64 g,
3 mmol)/THF (50 mL) under the protection of dried nitrogen at 0 ꢁC
for 1.5 h. Then, quenched with brine (20 mL), and concentrated in
vacuo to remove THF, and extracted with CH2Cl2 (40 mLꢂ3). The
organic layer was combined, dried over MgSO4, and filtered in se-
quence. The filtrate was concentrated in vacuo to remove solvent.
The resulting residue was purified by silica gel column chroma-
tography (ethyl acetate/n-hexane¼1:6) to give 2a,b, respectively.
4.1.3.4. 2-(4-Hydroxyphenyl)-5-vinyl-2,3-dihydrobenzo-furan
(2d).25 Compound 2d (0.39 g, 82%) was obtained as colorless liquid,
Rf¼0.46 (ethyl acetate/n-hexane¼1:1); 1H NMR (CDCl3, 400 MHz)
d
3.19 (dd, J¼15.8, 8.4 Hz, 1H, Ha-3), 3.57 (dd, J¼15.8, 9.2 Hz, 1H, Hb-
3), 4.98 (s, 1H, ArOH), 5.09 (dd, J¼10.6, 1.2 Hz, 1H, ArCH]CHaHb),
5.58 (dd, J¼17.6, 1.2 Hz, 1H, ArCH]CHaHb), 5.70 (dd, J¼9.2, 8.4 Hz,
1H, H-2), 6.66 (dd, J¼17.6, 10.6 Hz, 1H, ArCH]CHaHb), 6.80 (s, 1H,
ArH), 6.82 (d, J¼8.4 Hz, 2H, ArH), 7.20 (d, J¼8.4 Hz, 2H, ArH), 7.23 (d,
J¼7.6 Hz, 1H, ArH), 7.28 (d, J¼7.6 Hz, 1H, ArH); 13C NMR (CDCl3,
4.1.3.1. 2-(4-Hydroxyphenyl)-3-methyl-5-((E)-propenyl)-2,3-
dihydrobenzofuran [(ꢀ)-conocarpan, 2a]. Compound 2a (0.45 g,
85%) was obtained as colorless crystals, mp 119e120 ꢁC (lit.17 mp
120e123 ꢁC); Rf¼0.45 (ethyl acetate/n-hexane¼1:1); 1H NMR
100 MHz) d 36.8, 83.6, 107.9, 110.0, 114.6, 121.4, 125.8, 126.4, 126.8,
129.5, 131.0, 135.6, 156.5, 158.5; EI-MS (70 eV) m/z (rel intensity, %)
238 (Mþ, 100), 237 (15), 223 (8), 221 (11), 209 (7), 165 (7), 115 (6);
HRMS calcd for C16H14O2: 238.0994. Found: 238.0992.
(CDCl3, 400 MHz)
d
1.39 (d, J¼6.8 Hz, 3H, C3eCH3), 1.90 (d, J¼8.4 Hz,
3H, ArCH]CHCH3), 3.41 (dq, J¼8.8, 6.8 Hz, 1H, H-3), 5.10 (d,
J¼8.8 Hz,1H, H-2), 5.38 (s, 1H, ArOH), 5.69 (d, J¼18.4 Hz,1H, ArCH]
CHCH3), 6.37 (dq, J¼18.4, 8.4 Hz, 1H, ArCH]CHCH3), 6.78 (d,
J¼8.0 Hz, 1H, ArH), 6.83 (dd, J¼8.0, 2.0 Hz, 1H, ArH), 7.13 (d,
J¼8.4 Hz, 2H, ArH), 7.27 (d, J¼8.4 Hz, 2H, ArH), 7.29 (d, J¼2.0 Hz, 1H,
4.1.3.5. 2-(4-Hydroxyphenyl)-3-isopropyl-5(3-methylbut-1-(E)-
enyl)-2,3-dihydrobenzofuran (2e). Compound 2e (0.54 g, 84%) was
obtained as colorless liquid, Rf¼0.43 (ethyl acetate/n-hexane¼1:1);
1H NMR (CDCl3, 400 MHz)
d
0.95 (d, J¼6.8 Hz, 6H, ArCHCHCHMe2),
1.04 (dd, J¼6.8 Hz, 6H, ArCH]CHCHMe2), 2.88 (m, 1H,
CHCHCHMe2), 4.26 (dd, J¼9.2, 6.8 Hz, 1H, H-3), 4.86 (m, 1H, ArCH]
CHCHMe2), 4.92 (s, 1H, ArOH), 5.40 (d, J¼9.2 Hz, 1H, H-2), 6.78 (d,
J¼15.4 Hz,1H, ArCH]CHCHMe2), 6.80 (d, J¼15.4,1.2 Hz,1H, ArCH]
CHCHMe2), 6.84 (s, 1H, ArH), 7.12 (d, J¼8.8 Hz, 1H, ArH), 7.16 (d,
J¼8.8 Hz, 1H, ArH), 7.29 (d, J¼8.4 Hz, 2H, ArH), 7.31 (d, J¼8.4 Hz, 2H,
ArH); 13C NMR (CDCl3, 100 MHz)
d 14.7, 17.8, 45.2, 92.6, 109.0, 115.5,
120.8, 124.1, 124.8, 127.8, 126.3, 129.0, 129.6, 130.7, 155.7, 157.7; EI-
MS (70 eV) m/z (rel intensity, %) 266 (Mþ, 100), 252 (9), 251 (47),
224 (12), 223 (22), 131 (12), 121 (20); HRMS calcd for C18H18O2:
266.1310. Found: 266.1310.
ArH); 13C NMR (CDCl3, 100 MHz)
d 17.0, 17.8, 20.1, 23.2, 27.1, 29.7,
4.1.3.2. 2-(4-Hydroxy-3-methoxyphenyl)-3-methyl-5-((1E)-pro-
penyl)-2,3-dihydrobenzofuran [(ꢀ)-licarin A, 2b].13,18 Compound 2b
(0.53 g, 81%) was obtained as colorless crystals, mp 133e134 ꢁC (lit.
mp 132e133 ꢁC); Rf¼0.45 (ethyl acetate/n-hexane¼1:3); 1H NMR
74.2, 86.4, 115.1, 115.4, 115.9, 116.0, 125.8, 128.4, 128.6, 129.7, 129.8,
139.0, 155.2, 158.4; EI-MS (70 eV) m/z (rel intensity, %) 322 (Mþ, 14),
218 (68), 217 (25), 162 (98), 161 (94), 148 (23), 147 (100); HRMS
calcd for C22H26O2: 322.1933. Found: 322.1932.
(CDCl3, 400 MHz)
d
1.38 (d, J¼6.8 Hz, 3H, C3eCH3), 1.87 (dd, J¼6.8,
1.6 Hz, 3H, ArCH]CHCH3), 3.45 (dq, J¼9.6, 6.8 Hz, 1H, H-3), 3.88 (s,
3H, ArOCH3), 3.89 (s, 3H, ArOCH3), 5.10 (d, J¼9.6 Hz, 1H, H-2), 5.63
(s, 1H, ArOH), 6.11 (dq, J¼15.6, 6.8 Hz, 1H, ArCH]CHCH3), 6.36 (dd,
J¼15.6, 1.6 Hz, 1H, ArCH]CHCH3), 6.77 (s, 1H, ArH), 6.79 (s, 1H,
ArH), 6.88 (d, J¼8.4 Hz, 1H, ArH), 6.91 (d, J¼8.4 Hz, 1H, ArH), 6.97 (s,
4.1.3.6. 2-(3-Methoxy-4-hydroxyphenyl)-7-methoxy-5-vinyl-2,3-
dihydrobenzofuran (2f).26 Compound 5c (0.51 g, 86%) was obtained
as colorless liquid, Rf¼0.45 (ethyl acetate/n-hexane¼1:1); 1H NMR
(CDCl3, 400 MHz)
d
3.25 (dd, J¼15.6, 8.8 Hz, 1H, Ha-3), 3.57 (dd,
J¼15.6, 9.2 Hz, 1H, Hb-3), 3.87 (s, 3H, ArOCH3), 3.90 (s, 3H, ArOCH3),
5.14 (dd, J¼9.2, 8.8 Hz, 1H, H-2), 5.60 (dd, J¼17.6, 0.8 Hz, 1H, ArCH]
CHaHb), 5.66 (s, 1H, ArOH), 5.73 (dd, J¼10.8, 0.8 Hz, 1H, ArCH]
CHaHb), 6.65 (dd, J¼17.6, 10.8 Hz, 1H, ArCH]CHaHb), 6.85 (s, 1H,
1H, ArH); 13C NMR (CDCl3, 100 MHz)
d 17.6, 18.4, 45.6, 55.9, 56.0,
93.8, 108.9, 109.2, 113.3, 114.1, 120.0, 123.5, 130.9, 132.1, 132.2, 133.3,
144.1, 145.8, 146.6, 146.7; EI-MS (70 eV) m/z (rel intensity, %) 326

P.-Y. Chen et al. / Tetrahedron 69 (2013) 653e657
657
ArH), 6.88 (d, J¼8.0 Hz, 1H, ArH), 6.90 (d, J¼8.0 Hz, 1H, ArH), 6.91 (s,
1H, ArH), 6.95 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz)
38.5, 55.9,
56.0, 85.6, 108.7, 109.5, 111.4, 114.2, 115.1, 119.5, 128.0, 131.6, 133.1,
136.7, 144.2, 145.6, 146.6, 147.8; EI-MS (70 eV) m/z (rel intensity, %)
298 (Mþ, 100), 251 (6), 233 (9), 223 (9), 204 (8); HRMS calcd for
C18H18O4: 298.1205. Found: 298.1204.
References and notes
d
1. Bertolini, F.; Pineschi, M. Org. Prep. Proced. Int. 2009, 41, 385e418 and literatures
cited therein.
2. (a) Ohkawa, S.; Fukatsu, K.; Miki, S.; Hashimoto, T.; Sakamoto, J.; Doi, T.; Nagai,
Y.; Aono, T. J. Med. Chem. 1997, 40, 559e573; (b) Aono, T.; Ohkawa, S.; Doi, T. EP
Patent 483772, 1992, p 89. (c) Aumann, K. M.; Hungerford, N. L.; Coster, M. J.
Tetrahedron Lett. 2011, 52, 6988e6990; (d) Pereira, A. C.; Magalhaes, L. G.;
Goncalves, U. O.; Luz, P. P.; Moraes, A. C. G.; Rodrigues, V.; da Matta Guedes, P.
M.; da Silva Filho, A. A.; Cunha, W. R.; Bastos, J. K.; Nanayakkara, N. P. D.; e Silva,
M. L. A. Phytochemistry 2011, 72, 1424e1430.
3. Snider, B. B.; Han, L.; Xie, C. J. Org. Chem. 1997, 62, 6978e6984.
4. Sarika, M. S.; Nadir, U. K.; Pandey, P. S. Tetrahedron 2009, 65, 3918e3924.
5. Kuethe, J. T.; Wong, A.; Journet, M.; Davies, I. W. J. Org. Chem. 2005, 70,
3727e3729.
6. Yamashita, M.; Ono, Y.; Tawada, H. Tetrahedron 2004, 60, 2843e2849.
7. Bertolini, F.; Crotti, P.; Bussolo, V. D.; Macchia, F.; Pineschi, M. J. Org. Chem. 2007,
72, 7761e7764.
8. Ericsson, D. C. B.; Jovanovic, L.; Sefkow, M. Org. Lett. 2010, 12, 1976e1979.
9. Xie, P.; Wang, L.; Yang, L.; Li, E.; Ma, J.; Huang, Y.; Chen, R. J. Org. Chem. 2011, 76,
7699e7705.
4.1.3.7. 3-Acetyl-2-(4-hydroxyphenyl)-5-[(1E)-3-oxo-1-bute-
nyl]-2,3-dihydrobenzofuran (2g). Compound 2g (0.57 g, 88%) was
obtained as colorless liquid, Rf¼0.42 (ethyl acetate/n-hexane¼1:1);
1H NMR (CDCl3, 400 MHz)
d 2.34 (s, 3H, COCH3), 2.38 (s, 3H,
COCH3), 4.32 (d, J¼8.8 Hz, 1H, H-3), 6.03 (d, J¼8.8 Hz, 1H, H-2), 6.60
(d, J¼15.6 Hz, 1H, ArCH]CHCOCH3), 6.84 (d, J¼8.4 Hz, 2H, ArH),
6.90 (d, J¼8.8 Hz, 1H, ArH), 6.93 (s, 1H, ArH), 7.29 (s, 1H, ArOH), 7.16
(d, J¼8.8 Hz, 1H, ArH), 7.45 (d, J¼8.4 Hz, 2H, ArH), 7.51 (d, J¼15.6 Hz,
1H, ArCH]CHCOCH3); 13C NMR (CDCl3, 100 MHz)
d 27.3, 28.5, 63.3,
85.9, 110.7, 115.7, 115.8, 124.7, 127.2, 127.6, 130.3, 131.2, 132.9, 143.8,
156.7, 161.7, 199.2, 204.0; EI-MS (70 eV) m/z (rel intensity, %) 323
(Mþ, 8), 322 (34), 281 (18), 280 (100), 265 (12), 237 (10), 219 (12);
HRMS calcd for C20H19O4: 323.1283. Found: 323.1282.
10. Li, Q. B.; Zhou, F. T.; Liu, Z. G.; Li, X. F.; Zhu, W. D.; Xie, J. W. J. Org. Chem. 2011, 76,
7222e7228.
11. (a) Rakotondramanana, D. L. A.; Delomenede, M.; Baltas, M.; Duran, H.; Bedos-
Belval, F.; Rasoanaivo, P.; Negre-Salvayre, A.; Gornitzka, H. Bioorg. Med. Chem.
2007, 15, 6018e6026; (b) Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.;
Vlietinck, A.; Lemiere, G. J. Med. Chem. 1999, 42, 5475e5481.
12. Wasserman, H. H.; Brunner, R. K.; Buynak, J. D.; Carter, C. G.; Oku, T.; Robinson,
R. P. J. Am. Chem. Soc. 1985, 107, 519e521.
4.1.3.8. 3-Acetyl-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-5-
[(1E)-3-oxo-1-butenyl]-2,3-dihydrobenzofuran (2h). Compound 2h
(0.68 g, 89%) was obtained as colorless liquid, Rf¼0.40 (ethyl ace-
13. Juhasz, L.; Kuerti, L.; Antus, S. J. Nat. Prod. 2000, 63, 866e870.
ꢀ
14. Krawczyk, A. R.; Lipkowska, E.; Wrobel, J. T. Collect. Czech. Chem. Commun. 1991,
tate/n-hexane¼1:1); 1H NMR (CDCl3, 400 MHz)
d 2.32 (s, 3H,
56, 1147e1150.
15. Arrieta-Baez, D.; Stark, R. Phytochemistry 2006, 67, 743e753.
16. Moussouni, S.; Saru, M. L.; Ioannou, E.; Mansour, M.; Detsi, A.; Roussis, V.;
Kefalas, P. Tetrahedron Lett. 2011, 52, 1165e1168.
17. Derrick, L. J. C.; Elia, J. L. S. Org. Biomol. Chem. 2008, 6, 1831e1842.
18. (a) Leopold, B. Acta Chem. Scand. 1950, 4, 1523e1537; (b) Pereira, A. C.;
Magalhaes, L. G.; Januario, A. H.; Pauletti, P. M.; Cunha, W. R.; Bastos, J. K.;
COCH3), 2.37 (s, 3H, COCH3), 3.86 (s, 3H, ArOCH3), 3.93 (s, 3H,
ArOCH3), 4.40 (d, J¼8.8 Hz,1H, H-3), 6.08 (d, J¼8.8 Hz,1H, H-2), 6.61
(d, J¼16.0 Hz, 1H, ArCH]CHCOCH3), 6.86 (d, J¼8.4 Hz, 1H, ArH),
7.00 (d, J¼2.0 Hz, 1H, ArH), 7.08 (s, 1H, ArOH), 7.15 (dd, J¼8.4, 2.0 Hz,
1H, ArH), 7.17 (d, J¼2.0 Hz, 1H, ArH), 7.38 (d, J¼2.0 Hz, 1H, ArH), 7.43
(d, J¼16.0 Hz, 1H, ArCH]CHeCOCH3); 13C NMR (CDCl3, 100 MHz)
Nanayakkara, D. N. P.;
e Silva, M. L. A. J. Chromatogr., A 2011, 1218,
7051e7054.
19. Doskotch, R. W.; Flom, M. S. Tetrahedron 1972, 28, 4711e4717.
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449e451.
d
25.7, 27.3, 55.5, 56.1, 63.7, 86.8, 108.6, 111.0,112.1, 113.7, 114.6,117.8,
119.1, 122.6, 125.2, 126.0, 126.2, 127.3, 143.0, 143.2, 194.7, 198.3; EI-
MS (70 eV) m/z (rel intensity, %) 382 (Mþ, 28), 313 (21), 311 (100),
293 (22), 279 (30), 293 (22), 237 (18), 138 (22), 137 (69); HRMS
calcd for C22H22O6: 382.1416. Found: 382.1414.
21. Wuensch, C.; Glueck, S. M.; Gross, J.; Koszelewski, D.; Schober, M.; Faber, K. Org.
Lett. 2012, 14, 1974e1977.
22. Bader, A. R. J. Am. Chem. Soc. 1956, 78, 1709e1713.
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Acknowledgements
Financial support from NSC (Grant No. NSC-101-2113-M-037-
007), Taiwan is grateful.