Tf2O-catalyzed Friedel-Crafts alkylation to synthesize dibenzo[a,d]cycloheptene cores and application in the total synthesis of Diptoindonesin D, Pauciflorial F, and (±)-Ampelopsin B

Article abstract of DOI:10.1016/j.tet.2012.03.073

By using Tf₂O as a catalyst, we have developed a protocol for the preparation of various dibenzo[a,d]cycloheptene cores via Friedel-Crafts alkylation. Using this method as the key step, we also present concise and useful routes to synthesize the natural products Diptoindonesin D, Pauciflorial F, and (±)-Ampelopsin B. Notably, this process exhibited following very attractive features: (i) the process is metal free, with only catalytic amounts of Tf₂O being employed, and (ii) the process is simple and environmentally conscious, avoiding the use of excess amounts of base, oxidant, or other additives.

Full text of DOI:10.1016/j.tet.2012.03.073

Tetrahedron 68 (2012) 5216e5222
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tf2O-catalyzed FriedeleCrafts alkylation to synthesize dibenzo[a,d]cycloheptene
cores and application in the total synthesis of Diptoindonesin D, Pauciflorial F,
and (ꢀ)-Ampelopsin B
,
Gang-Wei Wang a, Hong-Li Wang a, David A. Capretto b, Qi Han a, Rong-Bin Hu a, Shang-Dong Yang a
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Tianshui South Road 222, Lanzhou 730000, PR China
b Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
By using Tf2O as a catalyst, we have developed a protocol for the preparation of various dibenzo[a,d]
cycloheptene cores via FriedeleCrafts alkylation. Using this method as the key step, we also present
concise and useful routes to synthesize the natural products Diptoindonesin D, Pauciflorial F, and
(ꢀ)-Ampelopsin B. Notably, this process exhibited following very attractive features: (i) the process is
metal free, with only catalytic amounts of Tf2O being employed, and (ii) the process is simple and en-
vironmentally conscious, avoiding the use of excess amounts of base, oxidant, or other additives.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 21 December 2011
Received in revised form 12 March 2012
Accepted 20 March 2012
Available online 30 March 2012
Keywords:
Tf2O
FriedeleCrafts alkylation
Dibenzo[a,d]cycloheptene
Diptoindonesin D
(ꢀ)-Ampelopsin B
1. Introduction
step, we also present concise and useful routes to synthesize the
natural products Diptoindonesin D, Pauciflorial F, and (ꢀ)-Ampe-
The dibenzo[a,d]cycloheptene framework is one type of poly-
cyclic skeleton that exists extensively in many natural products.1 As
a consequence; many strategies have been developed for the syn-
thesis of this framework. One of the most straightforward methods
is the intramolecular FriedeleCrafts acylation reaction.2 Another
popular synthetic route is the equivalent acid-catalyzed Friedele-
Crafts alkylation of olefins.3 Recently, Stoltz and co-workers de-
lopsin B. In addition, this reaction displays some very attractive
features: (i) the process is metal free, with only catalytic amounts of
Tf2O being employed, and (ii) the process is simple and environ-
mentally conscious, avoiding the use of excess amounts of base,
oxidant, or other additives.
veloped
structures by benzyne insertion into the
-ketoester.4 However, all the aforementioned methods either re-
a
novel approach to dibenzo[a,d]cycloheptene core
a,b
CeC single bond of an
a
quire stoichiometric metal salts/acids in unfavorable conditions or
require a specifically functionalized precursor, which limits scope.
Thus, the development of new and more efficient method is
attractive.
Lewis acid-catalyzed direct CeH transformation provides
a highly valuable strategy for CeC coupling reactions because of its
wide substrate scope and high atom economy.5 Herein, we describe
a versatile method to construct dibenzo[a,d]cycloheptene cores by
Tf2O-catalyzed intramolecular cyclization of alkenyl substrates via
FriedeleCrafts alkylation (Scheme 1). Using this method as the key
Scheme 1. Tf2O-catalyzed dibenzo[a,d]cycloheptene synthesis and the resulting nat-
* Corresponding author. E-mail address: yangshd@lzu.edu.cn (S.-D. Yang).
ural products.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.073

G.-W. Wang et al. / Tetrahedron 68 (2012) 5216e5222
5217
2. Results and discussion
As resveratrol-based oligomers, the polyphenol natural prod-
ucts Diptoindonesin D, (ꢀ)-Ampelopsin B, and Paucifloral F exhibit
We previously found that platinum-catalyzed the intra-
molecular cyclization of o-isopropyl or o-benzyl arylalkynes into
functionalized indenes through sp3 CeH bond activation.6 Inspired
by these results, we wished to extend this method to o-benzyl
alkenyl substrates. Disappointingly, results indicated that similar
platinum salts were completely ineffective in this reaction. After
further screening of catalysts, we found that the use of 10 mol %
FeBr2 and 20 mol % Cu(OTf)2 as co-catalyst yielded unexpected
products. Dibenzo[a,d]cycloheptene was obtained in 92% yield with
high regioselectivity. To prove our hypothesized connectivity, we
collected X-ray diffraction data of 2a and showed that our analysis
was correct (Scheme 1).7 However, we were still confused about the
role of Cu(OTf)2 in this transformation. In order to clarify, we fur-
ther tested different proton and Lewis acids. We found that TfOH
could catalyze this reaction very well, but the regioselectivity was
poor and byproduct 3a was obtained in 18% yield (Table 1, entry 1).
The screening of different acids and anhydrides (Table 1, entries
3e10) revealed that Tf2O gave the best result, yielding 95% of 2a.
Decreasing the catalyst loading to 5 mol % lowered the yield of 2a to
82% (Table 1, entry 11). Solvent screening showed that toluene and
DCE were optimal.
a wide variety of pharmacological activities including anti-
inflammatory, antioxidant, antifungal, antibacterial, anti-HIV, and
anticarcinogenic activities.8 Despite their interesting biological
activities as well as their unique carbon framework, few synthetic
approaches toward these types of compounds have been reported.9
In order to display the utility of our chemistry, we applied our
method in the synthesis of the natural products Diptoindonesin D,
Paucifloral F (Scheme 2, part A), and (ꢀ)-Ampelopsin B (Scheme 2,
part B). Our strategy to synthesize Diptoindonesin D and Pauci-
florial F began with the preparation of the biaryl alcohol 1s, which
was synthesized in 86% yield through an aldol reaction by the
lithiated form of the methyl protected resveratrol bromide 1 and
3,5-dimethoxy benzaldehyde 2 (Scheme 2, part A).10 Using this key
intermediate as the substrate, we directly synthesized the poly-
substituted indene 2s in the presence of 10 mol % Tf2O as catalyst by
FriedeleCrafts alkylation. Oxidation of 2s followed by deprotection
yielded Paucifloral F. On the other hand, 1r was first oxidized by
DesseMartin periodinane to afford ketone 1q in 90% yield.11 Then
the carbocyclic core structure of Diptoindonesin D was produced
using our FriedeleCrafts alkylation, producing 2q in 76% yield. After
oxidation and deprotection of 2q, the related natural product
Diptoindonesin D may be synthesized. In addition, our reaction can
be used in the total synthesis of the natural product (ꢀ)-Ampe-
lopsin B (Scheme 2, part B). Based on our retrosynthetic analysis,
we selected resveratrol as the starting material and treatment with
FeCl3$6H2O yielded the product (ꢀ)-Ɛ-viniferin through oxidative
coupling.12 Then the natural product (ꢀ)-Ampelopsin B was
obtained in 41% yield directly using our reaction conditions. Despite
the lower yield, our route has only two steps and omits the use of
protecting groups.
Table 1
Cyclization condition screeninga
In order to better understand the mechanism of the reaction, we
also tested other terminal substituted alkenes. If the aryl group in
1a is changed to electron-withdrawing groups, such as COOEt, CN,
and COCH3, the reaction does not work. However, when the sub-
strate is 1-benzyl-2-vinylbenzene 4a, the reaction proceeds
smoothly and the unexpected product 4ab is obtained in 38% yield,
with the minor product 9-methylanthracene 4aa (Scheme 3, Eq. 1)
formed in low yield. These results show that the formation of the
carbocation is the key step in this transformation and the regio-
selectivity is also determined by it. Based on the structure of sub-
strate 1a (Scheme 3, Eq. 2), we can see that both 1B and 2B are
benzylic carbocations, however we did not observed the six
membered-ring product at all in the case of 1B. We believe that the
ortho electronic donor effects of the benzyl group lead to a dis-
tinction of the energies of 1B and 2B, which also ensured the high
regioselectivity of reactions. In order to better understand this
difference from a thermodynamic perspective and to verify our
hypothesis, the relative activation energies of different pathways
were studied by DFT calculations with the use of Gaussian98
(B3LYP/6-31G) (Scheme 3, Eq. 2).13 The results confirmed our hy-
pothesis is logical, and the energy of the benzylic carbocation 1B is
more favorable than 2B.
In some cases protons rather than metal ions were identified as
active catalysts to promote the reaction.14 In our transformations,
Tf2O may activate trace water and produce protons as catalytic
species. The experimental data and activation energy profiles for
the considered mechanistic pathways are shown in Scheme 4. The
reaction is thought to be initiated by reaction of Tf2O with trace
water to release a proton and coordinate with the alkene to form
the cyclic intermediate 1A (R¼Ph, part A). Then, the activated 1A is
transferred to the carbocation 1B by the release of Tf2O, which is
energetically favored. The FriedeleCrafts alkylation occurs and
forms the intermediate 1C. Finally, deprotonation and aromatiza-
tion affords the desired product 2a and releases proton to reinitiate
Entry
Cat. [mol %]
Solvent
t [h]
Yield
Yield
2ab [%]
3ab [%]
1
2
3
4
5
6
7
8
TfOH 10%
TfOH 20%
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
6
6
77%
69%
18%
23%
CF3CO2H 10%
BF3$Et2O 20%
HBF4 10%
CH3SO3H10%
TiCl4 10%
(CH3SO2)2O10%
Tf2O 10%
Ac2O 10%
10
10
10
10
10
10
10
10
10
12
N.R.c
N.R.c
N.R.c
N.R.c
20%
N.R.c
N.R.c
N.R.c
N.R.c
<1%
N.R.c
<1%
N.R.c
<1%
d
N.R.c
95%
N.R.c
82%
9
10
11
12
Tf2O 5%
Tf2O 10%
69%
The data in bold font represents the optimized reaction conditions.
a
All reactions were carried out in the presence of 0.5 mmol of 1a in 5 mL solvent
at 100 ꢁC.
b
c
The isolated yield.
N.R. is no reaction.
Under the optimized conditions, we surveyed various alkenes
(Table 2). The dibenzo[a,d]cycloheptene derivatives 2aes produced
products in moderate to excellent yields and high selectivity.
Electronic effects were not evident in this reaction; high yields
were observed with both electron-withdrawing and electron-
donating groups present on the phenyl ring. However, the use of
2f and 2i only obtained moderate yields (69% and 55%, re-
spectively). When the X is an oxygen atom, the reaction also
worked smoothly and products of 2g and 2h were yielded in 88%
and 76% yield, respectively. In addition, the polymethoxyl
substituted products of 2l and 2qer were obtained in low to good
yields. If the benzylic portion was substituted with a hydroxyl
group, dehydration occurred and the poly-substituted indene
product 2s was obtained in 31% yield. Unfortunately, heterocycles,
such as pyrrole, indole, and pyridine yielded no observable product.

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G.-W. Wang et al. / Tetrahedron 68 (2012) 5216e5222
Table 2
Cyclization with different alkenesa,b
a
All reactions were carried out under the optimal conditions reported in the text for 12 h.
The isolated yield.
b
the catalytic cycle. The use of TfOH as catalyst causes some of car-
bocation 1B to react with toluene and afford the product 3a. When
the substrate is the 1-benzyl-2-vinylbenzene 4a (R¼H, part B), the
first step is same as part A and forms the cyclic intermediate 2A,
then quickly transfers into the benzylic carbocation 2B by the re-
lease of Tf2O. However, it is very interesting that the FriedeleCrafts
alkylation mainly occurs with toluene, forming the product 4ab as
the major product. The intramolecular cyclization product of 9-

G.-W. Wang et al. / Tetrahedron 68 (2012) 5216e5222
5219
methylanthracene 4aa was obtained in only 5e10% yield by aro-
matic isomerization and the structure was confirmed by X-ray
crystallography.7
3. Conclusion
By using Tf2O as a catalyst, we have developed a protocol for the
preparation of various dibenzo[a,d]cycloheptene cores via Frie-
deleCrafts alkylation. Substrate investigation showed that both
electron-donating and withdrawing groups worked smoothly to
afford the desired products in moderate to excellent yields. Notably,
this process exhibited features of green chemistry. Finally, we used
this method in key synthetic steps to synthesis the natural products
Diptoindonesin D, Pauciflorial F, and (ꢀ)-Ampelopsin B.
4. Experimental section
4.1. General procedure for the Tf2O-catalyzed FriedeleCrafts
alkylation
To a solution of the 1-benzyl-2-styryl-benzene (1a) (0.5 mmol)
dissolved in 5 mL of toluene in a tube was added 10 mol % of Tf2O.
The solution was stirred for 12 h at 100 ꢁC. Then the reaction was
cooled to room temperature and added 20 mL EtOAc. After the
organic phase was washed with water and saturated brine. The
organic layers were dried over Na2SO4, and filtrate was evaporated
under reduced pressure. The desired product 2a was obtained in
95% yields after purification by chromatography on silica gel.
4.1.1. Compound (2a). White solid; mp: 112e114 ꢁC. 1H NMR
Scheme 2. Total synthesis of natural products by FriedeleCrafts alkylation.
(400 MHz, CDCl3)
d
: 7.25e6.97 (m, 12H), 6.83 (d, J¼7.6, 1H) 4.50 (t,
J1¼7.2, J2¼14.4, 1H), 4.33 (d, J¼14.8, 1H), 4.09 (d, J¼14.8, 1H), 3.38 (d,
J¼7.2, 2H). 13C NMR (100 MHz, CDCl3)
d: 147.42, 140.81, 140.67,
138.10, 138.02, 132.49, 129.74, 129.27, 128.46, 128.26, 127.78, 126.59,
126.53, 126.50, 126.15, 126.02, 49.20, 41.26, 40.76. IR (neat): 665.22,
698.98, 753.51, 1448.74, 1490.09, 1598.68, 2928.84, 3021.30,
3058.06, 3387.63 cmꢂ1; MS (EI): m/z (%): 270 (8) [M]þ, 192 (100),
179 (41), 178 (30), 193 (19).
4.1.2. Compound (2b). Colorless oil, 1H NMR (400 MHz, CDCl3)
d:
7.25e6.96 (m, 10H), 6.82 (d, J¼7.6, 1H), 6.69 (d, J¼7.6, 1H), 4.74 (dd,
J1¼4.0, J2¼10.8, 1H), 4.40 (d, J¼14.8, 1H), 4.11 (d, J¼14.8, 1H), 3.42
(dd, J1¼11.2, J2¼14.0, 1H), 3.22 (dd, J1¼4.4, J2¼14.4, 1H), 2.41 (s, 3H).
13C NMR (100 MHz, CDCl3)
d: 145.53, 141.49, 140.41, 138.41, 138.14,
134.94, 131.58, 130.30, 129.54, 129.23, 129.11, 127.97, 126.69, 126.61,
126.51, 126.13, 126.03, 125.97, 44.79, 41.26, 39.20, 19.56. IR (neat):
757.55, 1361.46, 1454.61, 1489.17, 1706.51, 2929.89, 3019.00,
3061.07, 3363.35 cmꢂ1; MS (EI): m/z (%): 284 (6) [M]þ, 192 (100),
179 (31), 178 (27), 193 (21), 191 (17).
Scheme 3. Investigation on cyclization of 4a and DFT calculations of 1a.
4.1.3. Compound (2c). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
7.23e6.99 (m, 8H), 6.85 (d, J¼7.6, 1H), 6.72 (d, J¼8.0, 1H), 6.67 (d,
J¼7.6, 1H), 6.55 (s, 1H), 4.48 (t, J1¼7.2, J2¼14.4, 1H), 4.32 (d, J¼14.8,
1H), 4.09 (d, J¼14.8, 1H), 3.69 (s, 3H), 3.38 (d, J¼7.2, 2H). 13C NMR
(100 MHz, CDCl3) d: 159.47, 149.00, 140.67, 140.63, 138.09, 137.90,
132.42, 129.73, 129.29, 128.18, 127.77, 126.60, 126.54, 126.50, 126.17,
120.92, 114.46, 111.22, 55.08, 49.17, 41.22, 40.60. IR (neat): 701.41,
761.60, 1046.00, 1259.07, 1455.14, 1487.93, 1599.01, 1708.37,
2835.92, 2936.82, 3019.22, 3057.50, 3377.55 cmꢂ1; MS (EI): m/z (%):
300 (17) [M]þ, 192 (100), 179 (35), 178 (31), 191 (28), 193 (20).
4.1.4. Compound (2d). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
7.23e6.99 (m, 8H), 6.92e6.87 (m, 3H), 6.78 (d, J¼7.6, 1H), 4.49 (dd,
J1¼4.8, J2¼9.2, 1H), 4.19 (dd, J1¼14.8, J2¼35.2, 2H), 3.42 (dd, J1¼4.4,
J2¼14.0, 1H), 3.26 (dd, J1¼9.2, J2¼14.0, 1H). 13C NMR (100 MHz,
Scheme 4. The proposed mechanism of Tf2O-catalyzed cyclization via FriedeleCrafts
alkylation.
CDCl3) d: 145.79, 140.57, 140.24, 137.91, 137.62, 132.47, 131.74,

5220
G.-W. Wang et al. / Tetrahedron 68 (2012) 5216e5222
129.94, 129.35, 127.84, 126.67, 126.63, 126.61, 126.39, 48.55,
41.23, 40.44. IR (neat): 756.12, 828.69, 1013.96, 1091.59, 1450.71,
1489.01, 1703.50, 2881.98, 2932.62, 3021.14, 3061.56, 3384.53,
3466.46 cmꢂ1; MS (EI): m/z (%): 304 (3) [M]þ, 306 (1),192 (100),179
(35), 178 (25), 193 (17), 191 (14).
J¼14.8, 1H), 3.59 (s, 3H), 3.42e3.31 (m, 2H). 13C NMR (100 MHz,
CDCl3)
d: 158.08, 147.14, 142.03, 140.98, 138.01, 130.66, 130.59,
129.26, 127.63, 126.48, 126.43, 126.05, 117.86, 111.50, 55.05, 49.33,
40.65, 40.35. IR (neat): 701.74, 755.64, 1038.19, 1245.65, 1454.52,
1496.87, 1606.10, 1706.74, 2836.07, 2935.60, 3024.08, 3059.90,
3359.88 cmꢂ1; MS (EI): m/z (%): 300 (55) [M]þ, 192 (100), 222 (88),
178 (62), 179 (62), 209 (56), 191 (31), 165 (26), 91 (20).
4.1.5. Compound (2e). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
7.24e7.21 (m, 2H), 7.15e6.98 (m, 8H), 6.86e6.79 (m, 2H), 4.48 (dd,
J1¼5.2, J2¼9.6, 1H), 4.30 (d, J¼14.8, 1H), 4.11 (d, J¼14.8, 1H),
4.1.11. Compound (2k). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
3.42e3.29 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
: 149.38, 140.62,
7.26e7.06 (m, 8H), 6.99e6.92 (m, 2H), 6.70 (d, J¼8.0, 1H), 6.43 (d,
139.90, 137.94, 137.61, 134.01, 132.50, 129.96, 129.48, 129.26, 128.57,
127.84, 126.69, 126.62, 126.45, 126.24, 48.98, 41.18, 40.48. IR
(neat): 698.89, 752.47, 777.63, 1080.72, 1094.24, 1487.18, 1569.32,
1593.32, 1709.72, 2884.45, 2933.19, 3021.21, 3060.50, 3334.29,
3474.41 cmꢂ1; MS (EI): m/z (%): 304 (21) [M]þ, 306 (7), 179 (100),
192 (98), 178 (69), 191 (28), 193 (19).
J¼8.0, 1H), 4.56 (dd, J1¼6.0, J2¼8.8, 1H), 4.33 (dd, J1¼15.2, J2¼25.2,
2H), 3.86 (s, 3H), 3.44e3.34 (m, 2H). 13C NMR (100 MHz, CDCl3)
d:
156.28, 146.94, 142.80, 140.41, 138.50, 129.27, 128.59, 127.50, 126.46,
126.33, 126.30, 126.02, 124.13, 108.30, 55.96, 55.94, 48.79, 40.41,
29.54. IR (neat): 701.77, 757.73, 1076.90, 1253.87, 1453.65, 1491.37,
1582.44, 1707.68, 2837.75, 2931.75, 2931.86, 3023.80, 3060.65,
3398.95 cmꢂ1; MS (EI): m/z (%): 300 (33) [M]þ, 222 (100), 209 (31),
178 (25), 165 (25), 179 (22), 207 (22), 223 (21), 192 (16), 91 (18).
4.1.6. Compound (2f). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
7.30 (d, J¼0.8, 1H), 7.29e7.00 (m, 9H), 6.95 (d, J¼7.2, 1H), 6.87 (d,
J¼7.6, 1H), 6.19 (d, J¼7.6, 1H), 4.47 (dd, J1¼5.2, J2¼13.6, 1H), 4.29 (d,
J¼14.8, 1H), 4.11 (d, J¼14.8, 1H), 3.42e3.28 (m, 2H). 13C NMR
4.1.12. Compound (2l). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
7.28e7.01 (m, 9H), 6.58 (d, J¼8.4, 1H), 6.52 (d, J¼8.4, 1H), 4.50 (dd,
(100 MHz, CDCl3) d: 149.66, 140.60, 139.85, 137.91, 137.57, 132.50,
J1¼5.2, J2¼10.4,1H), 4.33 (dd, J1¼13.2, J2¼22.0, 2H), 3.87 (s, 3H), 3.77
131.44, 129.95, 129.78, 129.25, 129.16, 127.82, 127.19, 126.70, 126.68,
126.60, 126.44, 122.31, 48.96, 41.16, 40.48. IR (neat): 701.74, 754.78,
1072.05, 1222.48, 1360.29, 1423.80, 1468.52, 1488.05, 1565.87,
1591.48, 1708.51, 2928.05, 3019.67, 3317.62 cmꢂ1; MS (EI): m/z (%):
348 (10) [M]þ, 350 (10), 192 (100), 179 (90), 178 (68), 191 (29), 193
(20).
(s, 3H), 3.45e3.30 (m, 2H). 13C NMR (100 MHz, CDCl3)
d: 150.65,
147.29, 145.61, 140.07, 138.52, 134.41, 132.94, 129.36, 128.50, 127.19,
126.48, 126.46, 126.04, 110.16, 61.05, 55.60, 48.31, 40.62, 30.59. IR
(neat): 702.57, 757.91, 1048.96, 1080.35, 1222.69, 1278.91, 1451.24,
1488.77,1598.95, 1710.20, 2835.37, 2935.41, 3022.41, 3404.30 cmꢂ1
;
MS (EI): m/z (%): 330 (100) [M]þ, 208 (80), 192 (66), 299 (60), 91
(59), 239 (52), 178 (50), 237 (45).
4.1.7. Compound (2g). White solid, mp: 94e96 ꢁC. 1H NMR
(400 MHz, CDCl3)
6.99e6.90 (m, 3H), 6.84 (d, J¼8.0, 1H), 4.56 (dd, J1¼4.0, J2¼8.8, 1H),
3.46e3.35 (m, 2H). 13C NMR (100 MHz, CDCl3)
: 157.83, 156.55,
d: 7.26e7.13 (m, 7H), 7.06e7.04 (m, 2H),
4.1.13. Compound (2m). Colorless oil, 1H NMR (400 MHz, CDCl3)
d:
7.23e7.16 (m, 4H), 7.09e6.92 (m, 7H), 6.82 (d, J¼7.6, 2H), 4.51 (dd,
J1¼4.4, J2¼9.2, 1H), 4.21 (dd, J1¼15.2 J2¼31.2, 2H), 3.47 (dd, J1¼4.4,
J2¼14.4, 1H), 3.32 (dd, J1¼9.6, J2¼14.4, 1H), 1.99 (s, 3H). 13C NMR
d
145.43, 132.94, 132.31, 131.53, 130.27, 128.41, 128.29, 127.62, 127.57,
126.35, 124.28, 123.77, 121.41, 120.45, 47.17, 38.19. IR (neat): 700.30,
754.83, 1072.24, 1200.94, 1240.03, 1446.39, 1483.71, 1576.09,
2920.01, 2952.06, 3027.09, 3061.45 cmꢂ1; MS (EI): m/z (%): 272
(100) [M]þ, 178 (62), 194 (49), 195 (47), 181 (44), 165 (39), 271 (36),
255 (19).
(100 MHz, CDCl3) d: 147.45, 141.16, 142.72, 138.15, 136.48, 136.21,
132.49, 129.72, 128.45, 126.55, 126.05, 125.75, 48.46, 41.59, 35.66,
19.57. IR (neat): 702.25, 755.76, 1446.71, 1489.86, 1597.09, 1705.01,
2954.36, 3023.08, 3059.64, 3383.96, 3426.77 cmꢂ1; MS (EI): m/z
(%): 284 (25) [M]þ, 206 (100), 178 (35), 193 (33).
4.1.8. Compound (2h). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
4.1.14. Compound (2n). Yellow solid, mp: 118e120 ꢁC. 1H NMR
7.25e6.91 (m, 9H), 6.91e6.87 (m, 2H), 6.67 (d, J¼7.6, 1H), 4.82 (dd,
(400 MHz, CDCl3) d: 7.37 (s, 1H), 7.36e7.14 (m, 5H), 7.09e6.98 (m,
J1¼3.6, J2¼10.4, 1H), 3.46 (dd, J1¼10.4, J2¼14.0, 1H), 3.28 (dd, J1¼3.6,
4H), 6.84e6.08 (m, 2H), 4.48 (dd, J1¼4.8, J2¼9.2, 1H), 4.23 (d, J¼14.8,
J2¼14.4, 1H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3)
d: 157.65,
1H), 4.05 (d, J¼14.8, 1H), 3.38e3.25 (m, 2H). 13C NMR (100 MHz,
156.75, 143.26, 135.47, 133.97, 131.54, 131.14, 130.40, 130.32, 128.64,
127.58, 127.47, 136.35, 126.08, 124.25, 124.02, 121.23, 120.56, 42.56,
36.92, 19.56. IR (neat): 748.64, 763.39, 1105.39, 1201.56, 1239.34,
1445.04,1483.56,1576.19, 2921.23, 3022.80, 3063.83 cmꢂ1; MS (EI):
m/z (%): 286 (100) [M]þ, 178 (56), 181 (60), 194 (54), 195 (42), 271
(40), 192 (31), 165 (31).
CDCl3) d: 146.97, 142.72, 140.50, 137.12, 136.99, 132.55, 130.91,
130.62, 129.79, 129.39, 126.88, 126.34, 126.14, 119.91, 48.84, 40.86,
40.08. IR (neat): 701.73, 756.09, 1448.68, 1486.89, 1594.65, 1702.52,
2926.46, 3024.39, 3059.20, 3369.75 cmꢂ1; MS (EI): m/z (%): 348 (9)
[M]þ, 350 (9), 178 (100), 272 (69), 270 (67), 191 (52), 165 (49).
4.1.15. Compound (2o). Yellow solid, mp: 100e102 ꢁC. 1H NMR
4.1.9. Compound (2i). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
(400 MHz, CDCl3)
d
: 7.26e6.97 (m, 9H), 6.90 (s, 2H), 6.82 (d, J¼7.6,
7.23e6.97 (m, 8H), 6.93e6.73 (m, 3H), 6.40 (d, J¼7.6, 1H), 4.92 (dd,
1H), 4.47 (dd, J1¼4.8, J2¼9.6, 1H), 4.32 (d, J¼14.8, 1H), 4.00 (d,
J1¼4.4, J2¼9.6, 1H), 4.38 (d, J¼14.8, 1H), 4.08 (d, J¼14.4, 1H), 3.86 (s,
J¼14.8, 1H), 3.40e3.28 (m, 2H), 2.28 (s, 3H). 13C NMR (100 MHz,
3H), 3.42 (dd, J1¼10.0, J2¼14.0,1H), 3.29 (dd, J1¼4.8, J2¼14.0,1H). 13
C
CDCl3) d: 147.58, 140.89, 140.51, 138.18, 136.01, 134.97, 132.50,
NMR (100 MHz, CDCl3)
d
: 156.43, 141.23, 141.07, 138.77, 138.35,
129.65, 129.16, 128.59, 128.45, 128.27, 127.09, 126.55, 126.11,
125.98, 49.37, 41.22, 40.39, 20.99. IR (neat): 700.82, 753.63, 813.33,
1450.12, 1493.04, 1599.82, 2885.30, 2924.93, 3020.53, 3056.10,
3403.06 cmꢂ1; MS (EI): m/z (%): 284 (19) [M]þ, 206 (100), 178 (35),
193 (33).
135.95, 132.20, 130.13, 129.49, 129.17, 127.58, 127.02, 126.44, 126.41,
126.33, 125.79, 120.46, 110.61, 55.56, 42.33, 41.26, 38.31. IR (neat):
753.00, 1029.01, 1105.80, 1242.82, 1458.85, 1489.75, 1596.10,
1709.41, 2836.83, 2936.51, 3019.75, 3061.85, 3402.50 cmꢂ1; MS (EI):
m/z (%): 300 (4) [M]þ, 192 (100), 179 (27), 178 (20), 193 (18),
191 (15).
4.1.16. Compound (2p). White solid, mp: 109e111 ꢁC. 1H NMR
(400 MHz, CDCl3) d: 7.30e7.16 (m, 6H), 7.08e7.00 (m, 3H), 6.79 (s,
4.1.10. Compound (2j). Colorless oil. 1H NMR (400 MHz, CDCl3)
d:
1H), 6.48 (s, 1H), 4.62 (dd, J1¼6.0, J2¼9.6, 1H), 4.16 (dd, J1¼14.8,
7.25e7.04 (m, 9H), 6.97 (d, J¼7.2, 1H), 6.63e6.61 (m, 1H), 6.37 (d,
J2¼40.8, 2H), 3.46e3.35 (m, 2H), 2.44 (s, 3H), 2.08 (s, 3H). 13C NMR
J¼2.8, 1H), 4.45 (dd, J1¼5.6, J2¼9.2, 1H), 4.27 (d, J¼14.8, 1H), 4.02 (d,
(100 MHz, CDCl3) d: 146.47, 141.64, 139.62, 138.06, 135.27, 134.74,

G.-W. Wang et al. / Tetrahedron 68 (2012) 5216e5222
5221
134.51, 129.81, 129.46, 129.23, 128.43, 128.32, 126.35, 126.22, 126.07,
48.10, 40.21, 34.21, 21.04, 20.80. IR (neat): 700.80, 751.64, 1031.21,
1448.30, 1488.44, 1640.64, 2859.51, 2919.49, 3021.95, 3058.98,
3386.14 cmꢂ1; MS (EI): m/z (%): 298 (22) [M]þ, 220 (100), 192 (44),
207 (32), 205 (23), 221 (21), 191 (18), 91 (16).
was purified by flash chromatography (PetroleumeEtOAc 100:1) to
afford 1a as a white solid in 93% yield.
Compound (1a): 1H NMR (400 MHz, CDCl3)
d
: 7.63 (d, J¼7.6, 1H),
7.41e7.15 (m, 14H), 6.96 (d, J¼16.0, 1H), 4.13 (s, 2H). 13C NMR
(100 MHz, CDCl3) d: 140.61, 138.27, 137.54, 136.54, 130.60, 130.41,
128.68, 128.63, 128.49, 127.71, 127.57, 126.81, 126.52, 126.39, 126.05,
125.90, 39.31.
4.1.17. Compound (2q). White solid, mp: 138e140 ꢁC. 1H NMR
(400 MHz, CDCl3)
d
: 7.14 (d, J¼2.4, 1H), 6.70 (d, J¼8.8, 2H), 6.60 (d,
J¼8.8, 2H), 6.53 (d, J¼2.4, 1H), 6.27 (d, J¼2.4, 1H), 5.70 (d, J¼2.0, 1H),
4.66 (dd, J1¼2.4, J2¼6.8, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.70 (s, 3H),
3.58 (s, 3H), 3.54e3.50 (m, 4H), 2.94 (dd, J1¼6.8, J2¼17.5, 1H). 13C
4.2.2. Preparation of {2,4-dimethoxy-6-[2-(4-methoxy-phenyl)-vi-
nyl]-phenyl}-(3,5-dimethoxy-phenyl)-methanol (1s). n-BuLi (37.7
mL, 1.6 M in THF, 60.3 mmol, 1.05 equiv) was added slowly over the
course of 5 min to a solution of 2-bromo-1,5-dimethoxy-3-[2-(4-
methoxy-phenyl)-vinyl]-benzene (20.0 g, 57.4 mmol, 1.0 equiv) in
THF (400 mL) at ꢂ78 ꢁC, ultimately yielding a light yellow solution.
After 20 min of stirring at ꢂ78 ꢁC, a solution of the 3,5-dimethoxy
benzaldehyde (9.52 g, 57.4 mmol, 1.0 equiv) in THF (200 mL) was
added slowly at ꢂ78 ꢁC, and the resultant mixture was stirred for
1 h at ꢂ78 ꢁC, warmed slowly to 25 ꢁC, and stirred for an additional
4 h at 25 ꢁC. Upon completion, the reaction contents were
quenched with saturated aqueous NH4Cl (250 mL), poured into
water (100 mL), and extracted with EtOAc (3ꢃ1 L). The combined
organic layers were then washed with water (300 mL) and brine
(300 mL), dried (MgSO4), and concentrated. The resultant light
yellow oils crystallized upon standing and were then triturated
with EtOAc (3ꢃ10 mL) to give the {2,4-dimethoxy-6-[2-(4-
methoxy-phenyl)-vinyl]-phenyl}-(3,5-dimethoxy-phenyl)-metha-
nol 1s as white solid.
NMR (100 MHz, CDCl3) d: 196.87, 161.75, 158.94, 158.68, 157.74,
157.44, 141.38, 138.83, 136.04, 128.43, 125.28, 123.61, 112.99, 105.89,
104.02, 103.30, 97.31, 55.94, 55.51, 55.29, 55.10, 42.85, 40.96. IR
(neat): 527.26, 787.78, 834.87, 1057.77, 1156.00, 1206.25, 1248.20,
1323.07, 1340.07, 1461.07, 1508.46, 1601.63, 1662.25, 1712.98,
1765.81, 2840.85, 2932.81, 3001.46 cmꢂ1; HRMS: calculated for
[C26H26O6]: 435.1802; found: 435.1812.
4.1.18. Compound (2r). Brown oil. 1H NMR (400 MHz, CD3OD)
d:
7.02 (d, J¼8.8, 2H), 6.90 (d, J¼8.0, 2H), 6.69 (d, J¼4.8, 2H), 6.60 (d,
J¼4.4, 2H), 6.30e6.27 (m, 2H), 6.09 (d, J¼1.6, 1H), 6.01 (d, J¼2.0, 1H),
5.66 (d, J¼11.6, 1H), 5.13 (d, J¼3.6, 1H), 4.05 (d, J¼11.6, 1H), 3.54 (dd,
J1¼4.0, J2¼17.6, 1H), 3.17 (br d, J¼17.2, 1H). 13C NMR (100 MHz,
CD3OD)
d: 160.65, 158.94, 158.91, 157.32, 157.13, 156.13, 143.01,
138.80, 135.63, 131.26, 130.32, 129.05, 123.75, 119.77, 116.30, 115.81,
109.39, 105.41, 101.66, 95.91, 89.13, 49.69, 36.48, 34.17. IR (neat):
835.75, 1012.76, 1081.06, 1132.02, 1174.76, 1235.91, 1367.50, 1447.57,
1513.20, 1603.46, 1699.26, 2925.71, 2958.57, 3559.92 cmꢂ1; HRMS:
calculated for [C28H22O6]: 455.1489; found: 455.1491.
Compound (1s): 1H NMR (400 MHz, CDCl3)
d
: 7.34 (d, J¼8.4,
2H), 7.26 (s, 1H), 6.88e6.84 (m, 3H), 6.71 (d, J¼2.0, 1H), 6.51 (s, 2H),
6.44 (d, J¼2.0, 1H), 6.31 (s, 1H), 6.17 (d, J¼9.6, 1H), 3.86 (s, 3H), 3.81
(s, 3H), 3.73 (s, 9H). 13C NMR (100 MHz, CDCl3)
d: 160.60, 159.92,
4.1.19. Compound (2s). Colorless oil, 1H NMR (400 MHz, CDCl3)
d:
159.50, 158.77, 147.59, 138.85, 131.76, 130.01, 127.89, 124.52, 121.81,
114.10, 103.96, 103.26, 98.82, 98.49, 70.18, 55.78, 55.40, 55.31,
55.25.
7.43e7.41 (m, 2H), 7.05 (d, J¼0.8, 1H), 6.79e6.77 (m, 2H), 6.58 (d,
J¼2.0,1H), 6.36 (d, J¼2.0, 2H), 6.23e6.20 (m, 2H), 4.90 (d, J¼0.8,1H),
3.83 (s, 3H), 3.76 (s, 3H), 3.68 (s, 6H), 3.66 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d
: 161.07, 160.31, 159.00, 155.79, 151.58, 145.99,
4.2.3. Preparation of {2,4-dimethoxy-6-[2-(4-methoxy-phenyl)--
141.88, 127.90, 127.84, 127.75,125.64, 113.85, 106.62, 98.54, 98.13,
96.33, 55.55, 55.47, 55.18, 55.15, 54.14. HRMS: calculated for
[C26H26O5]: 419.1853; found: 419.1860.
vinyl]-phenyl}-(3,5-dimethoxy-phenyl)-methanone
(1q). Solid
NaHCO3 (3.30 g, 39.4 mmol, 10 equiv) and DesseMartin period-
inane (1.67 g, 3.94 mmol, 1.0 equiv) were added sequentially in
single portions to a solution of 1s (1.72 g, 3.94 mmol, 1.0 equiv) in
CH2Cl2 (30 mL) at 25 ꢁC, and the resultant slurry was stirred for 2 h
at 25 ꢁC. Upon completion, the reaction contents were quenched
with saturated aqueous Na2SO3 (10 mL) followed by stirring the
resultant biphasic system vigorously for 5 min at 25 ꢁC. The reaction
contents were then poured into saturated aqueous NaHCO3 (10 mL)
and extracted with EtOAc (3ꢃ30 mL). The combined organic layers
were washed with water (30 mL) and brine (30 mL), dried (MgSO4),
and concentrated to afford the {2,4-dimethoxy-6-[2-(4-methoxy-
phenyl)-vinyl]-phenyl}-(3,5-dimethoxy-phenyl)-methanone 1q as
a white solid.
4.1.20. Compound (4aa). Colorless oil, 1H NMR (400 MHz, CDCl3)
8.32e8.26 (m, 3H), 7.99 (d, J¼8, 2H), 7.52e7.43 (m, 4H), 3.09 (s, 3H),
13C NMR (100 MHz, CDCl3)
: 131.48, 130.13, 130.10, 129.05, 125.32,
d:
d
125.28, 125.22, 124.79, 124.67, 13.91.
4.1.21. Compound (4ab). Colorless oil, 1H NMR (400 MHz, CDCl3)
d:
7.28e7.03 (m,11H), 6.95 (d, J¼8.0, 2H), 4.27 (dd, J1¼7.2, J2¼14.4,1H),
3.97 (dd, J1¼16.0, J2¼41.2, 2H), 2.28 (s, 3H), 1.49 (d, J¼7.2, 3H). 13
C
NMR (100 MHz, CDCl3) d: 144.53, 143.22, 140.96, 138.19, 135.29,
130.73, 128.97, 128.71, 128.37, 127.43, 127.40, 126.68, 126.09, 125.91,
39.79, 38.90, 22.26, 20.95. IR (neat): 548.79, 698.31, 732.46, 764.45,
818.51, 1030.59, 1450.90, 1489.95, 1511.53, 1732.99, 2870.11,
2925.18, 2965.73, 3023.50, 3059.01 cmꢂ1; MS (EI): m/z (%): 286 (26)
[M]þ, 179 (100), 178 (46), 193 (46), 194 (44), 180 (22), 91 (19).
Compound (1q): 1H NMR (400 MHz, CDCl3)
d: 7.27e7.25 (m, 2H),
7.00e6.97 (m, 3H), 6.84e6.72 (m, 4H), 6.63e6.62 (m, 1H), 6.41 (d,
J¼2.0, 1H), 3.89 (s, 3H), 3.78 (s, 6H), 3.76 (s, 3H), 3.67 (s, 3H). 13C
NMR (100 MHz, CDCl3) d: 197.22, 161.24, 160.71, 159.48, 158.28,
140.34, 137.65, 130.91, 129.54, 127.97, 122.97, 121.26, 113.93, 107.22,
105.55, 101.06, 97.62, 55.71, 55.45, 55.40, 55.17.
4.2. Preparation and characterization of substrates
4.2.1. Preparation of 1-benzyl-2-styryl-benzene (1a). To a solution
of the 1-benzyl-2-iodo-benzene 1 (2e7 mmol) and 2 equiv of vinyl-
benzene and 2.5 equiv of potassium acetate with 1 equiv of tetra-
butyl ammonium bromide dissolved in 10 mL of DMF was added
3.0 mol % of palladium acetate under a nitrogen atmosphere. The
solution was stirred for 12 h at 100 ꢁC. When the starting 1-Benzyl-
2-iodo-benzene had disappeared (TLC), the mixture extracted with
EtOAc (3ꢃ20 mL) and water. The combined organic phase was dried
(Na2SO4) and concentrated under reduced pressure. The residue
4.2.4. Preparation of (ꢀ)-Ɛ-viniferin (1r). A solution of FeC13$6H2O
(1.24 g, 4.58 mmol) in water (8 mL) was added dropwise to a so-
lution of resveratrol (1.03 g, 4.52 mmol) in methanol (10 mL) under
stirring. The mixture was kept at room temperature for 49 h. After
removal of the methanol in vacuum, the residue was diluted with
water and extracted with EtOAc three times. Then the combined
organic layer was evaporated to dryness, which was subjected to
chromatography on silica gel column eluted with cyclo-
hexaneeacetone (3:1 to 2:1) to provide compound 1r as gray

5222
G.-W. Wang et al. / Tetrahedron 68 (2012) 5216e5222
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Compound (1r): 1H NMR (400 MHz, acetone-d6)
d: 8.29 (br, 5H),
7.22e7.17 (m, 4H), 6.91 (d, J¼16.0, 1H), 6.84 (d, J¼8.4, 2H),
6.75e6.70 (m, 4H), 6.33 (d, J¼1.6, 1H), 6.25 (s, 3H), 5.43 (d, J¼5.6,
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We are grateful for the NSFC (No. 21072079), International Co-
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Fund for the Doctoral Program of Higher Education of China (No.
20100211120014) financial support.
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Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.073.
References and notes
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