Synthesis of (Z) isomers of benzoheterocyclic derivatives of combretastatin A-4: A comparative study of several methods

Article abstract of DOI:10.1016/j.tet.2013.01.005

Several methods for the preparation of (Z) trimethoxystyrene derivatives 1 were investigated. After finding that the Wittig reaction led to unsatisfactory results, three different strategies were considered: a Suzuki coupling with a stereodefined monobromoalkene, a combination of hydrosilylation/vinylsilane hydrolysis and a palladium-catalyzed semi-hydrogenation step, using DMF/KOH as the hydrogen source. Our studies led us to prepare a series of diarylacetylene derivatives via a Sonogashira coupling reaction, and also to find out a copper-free basic cyclization leading to benzo[b]thiophenes. The final choice for the synthesis method of 1 strongly depends on the target compound but the semi-hydrogenation, which avoids the use of a toxic tin reducing agent, should be generally preferred.

Full text of DOI:10.1016/j.tet.2013.01.005

Tetrahedron 69 (2013) 2336e2347
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (Z) isomers of benzoheterocyclic derivatives of
combretastatin A-4: a comparative study of several methods
*
Thi Thanh Binh Nguyen, Thierry Lomberget , Ngoc Chau Tran, Roland Barret
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Universite de Lyon, Universite Lyon 1, Faculte de Pharmacie e ISPB, EA 4446 Biomolecules, Cancer et Chimioresistances,
ꢀ
SFR Sante Lyon-Est CNRS UMS3453 e INSERM US7, 8 avenue Rockefeller, F-69373 Lyon cedex 08, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Several methods for the preparation of (Z) trimethoxystyrene derivatives 1 were investigated. After
finding that the Wittig reaction led to unsatisfactory results, three different strategies were considered:
a Suzuki coupling with a stereodefined monobromoalkene, a combination of hydrosilylation/vinylsilane
hydrolysis and a palladium-catalyzed semi-hydrogenation step, using DMF/KOH as the hydrogen source.
Our studies led us to prepare a series of diarylacetylene derivatives via a Sonogashira coupling reaction,
and also to find out a copper-free basic cyclization leading to benzo[b]thiophenes. The final choice for the
synthesis method of 1 strongly depends on the target compound but the semi-hydrogenation, which
avoids the use of a toxic tin reducing agent, should be generally preferred.
Received 21 October 2012
Received in revised form 31 December 2012
Accepted 3 January 2013
Available online 9 January 2013
Keywords:
Suzuki coupling
Sonogashira coupling
Diarylacetylene
Semi-hydrogenation
Alkene
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Behind the numerous analogues of this natural product,2 first
isolated by Pettit and co-workers from the bark of the south-african
The design of new active molecules has always been the driving
force for the development of efficient synthetic methodologies.
Indeed, the preparation of original structures and their analogues
to study the StructureeActivity Relationships of a future drug has
prompted organic chemists to imagine new and elegant strategies.
For a research project directed towards the elaboration of new
Microtubule Binding Agents,1 we were interested in the prepara-
tion of original combretastatin A-4 (CA-4) derivatives 1, by re-
placement of the B ring with various heterocycles, attached to the
2-position (Fig. 1).
bush willow tree Combretum caffrum,3,4 3,4,5-trimethoxystyrene
derivatives appears to be of interest.5 However, to maintain an ef-
ficient activity against the inhibition of the dynamic assembly/
disassembly of the microtubules,6 it is essential to have a cis con-
figuration of the alkene.7
As a contributor to the design of new 3,4,5-trimethoxystyrene
derivatives active against tubulin,8 our objective was to have in
hand an efficient method for the selective preparation of our cis
derivatives 1.
Several strategies were possible (Fig. 2), based on literature
precedents for the preparation of (Z) alkenes and especially for the
synthesis of combretastatin A-4 itself.
The simplest way could be a Wittig reaction9 between hetero-
aromatic carboxaldehydes 2 and the appropriate phosphonium salt
3. The cis double bond could also be obtained after a Suzuki cou-
pling10 between heterocyclic 2-boronic acids 4 and the stereo-
defined monobromoalkene 5 (Fig. 2). Another possibility lies in the
stereocontrolled reduction of the triple bond in 6 into the cis al-
kene, either by using hydrolysis of a vinyl derivative precursor or
a semi-hydrogenation step. The most direct access to these struc-
tures 6 could be a Sonogashira coupling reaction11 of halogenated
heterocycles 7 with the known acetylenic derivative 8 (Fig. 2).
To prepare the (Z) stereoisomers of compounds 1 for subsequent
biological evaluations, we have investigated these strategies and
we wish now to report in this paper our different approaches.
2
X
MeO
MeO
B
OH
OMe
MeO
MeO
A
OMe
CA-4
OMe
1
Fig. 1. Combretastatin A-4 and benzoheterocycles derivatives 1.
* Corresponding author. Tel./fax: þ33 478 777 082; e-mail address: thierry.
lomberget@univ-lyon1.fr (T. Lomberget).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.005

T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
2337
compound was used for subsequent Suzuki couplings with oxygen,
sulfur and nitrogen-containing boronic reagents. After the coupling
reaction, under classical conditions (Scheme 2),16 the crude product
was analyzed by 1H NMR and we were surprised to see that the Z/E
ratio significantly decreased in most of the cases, except when
benzo[b]thiophene-2-boronic acid was used (Table 1, entry 2). With
benzofuran- and thiophene boronic acids, this ratio dropped to
77/23 and 67/33, respectively, and the (Z) isomer of 1a and 1e were
isolated with 57 and 38% yields (Table 1, entries 1 and 4).18
Br
PPh3
OMe
OMe
+
CHO
X
2
OMe
3
MeO
1
MeO
MeO
X
6
Br
X
b
MeO
MeO
Z/E 90/10 to 67/33
MeO
OMe
Hal
B(OH)2
MeO
X
OMe
5
X
OMe
7
4
1
Br
+
MeO
MeO
MeO
Z/E 91/9
OMe
OMe
+
Scheme 2. Reagents and conditions: (b) HetArB(OH)2 or HetArBF3K 1.15 equiv,
Pd(PPh3)4 5 mol %, Na2CO3 1.0 equiv, DME/water, 90 ꢁC, 20 h.
5
8
Table 1
Suzuki coupling reaction to derivatives 1
Fig. 2. Strategies for the preparation of cis compounds 1.
Entry (Benzo)
heterocycle
Product
Z/E ratio Yieldd
(Z)
%
2. Results and discussion
2.1. Wittig reaction
OMe
OMe
O
1
2
Benzofurana
77/23c
57
57
Our first attempts used a Wittig reaction between benzofuran-
and benzo[b]thiophene-2-carboxaldehydes
thoxybenzylphosphonium salt 3. But this led to unsatisfactory re-
sults, both in term of stereoselectivity (Z/E ratio 49/51 for 1a and
45/55 for 1b, determined by 1H NMR on the crude product) and
isolated yields for the (Z) stereoisomers (Scheme 1).12
MeO
2 and 3,4,5-trime-
1a
Benzo[b]
S
90/10c
OMe
OMe
thiophenea
MeO
Br
1b
PPh3
OMe
OMe
CHO
a
+
X
X
OMe
OMe
NBoc
MeO
3
N-Boc indoleb
nd
47
OMe
MeO
MeO
2
3
1c
X = O or S
OMe
(Z)-1
26%
8%
X = O
X = S
OMe
OMe
S
4
Thiophenea
67/33c
38e
Scheme 1. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 ꢁC, 1 h then rt, 18 h; global
yields 65% for 1a (X¼O) and 77% for 1b (X¼S). Yields indicated above are for isolated
stereopure (Z)-1.
MeO
1e
nd: not determined.
a
2-Boronic acid was used.
b
2.2. Suzuki coupling
2-Potassium trifluoroborate was used.
c
Determined by 1H NMR on the crude product.
d
e
Yield of stereopure (Z) isomer of compound 1.
Beside isolation of pure (Z), a Z/E mixture (36%) was also obtained after chro-
Several coupling reactions are described for the preparation of
CA-4, such as KumadaeCorriu,13 Negishi14 or Suzuki.15,16 During the
preparation of N-methylindole analogues of the B ring of CA-4
using a Negishi coupling, Mass and co-workers first made the se-
lective reduction of a dibromovinyl substrate, using tributyltin
matographic purification.
When the reaction was carried out using N-Boc indole-2-
boronic acid, no traces of the desired N-Boc protected (Z)-1c was
detected in the reaction mixture: after purification, only indole, 1,4-
bis(3,4,5-trimethoxyphenyl)buta-1,3-diene and deprotected (E)
indole-3,4,5-trimethoxy styrene 1d were obtained.19 The use of the
hydride as the reducing agent and
a catalytic amount of
Pd(PPh3)4.17 In our hands, this palladium-catalyzed mono-
dehalogenation afforded the monobromo derivative 5 with a fairly
good 91/9 stereopurity, in the favour of the (Z) isomer. This

2338
T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
potassium salt of trifluoroborate20 drastically improved the re-
action outcome as stereopure (Z)-1c was obtained with a 47% yield
(Table 1, entry 3).
Br
Br
O
SAc
SAc
R
R
d
e
Br
2.3. Reduction of diarylacetylene derivatives
S
R
10a,b
7f,g
Regarding the moderate yields and selectivity obtained using
the Suzuki coupling strategy, we believed at this stage that a sig-
nificant improvement could be achieved using another approach:
the reduction of diarylacetylenes 6.
11a,b
Br
Br
R
2.3.1. Synthesis of the diarylacetylene derivatives 6. One of the most
efficient ways for the preparation of diacetylenes derivatives is the
Sonogashira coupling. This reaction, though discovered almost 40
years ago, remains a very efficient tool for the creation of CeC bonds
between vinyl/aryl halides or triflates and acetylenic substrates.21
To synthesize the diarylacetylene derivatives 6,22,23 different
2-halogeno (benzo)heterocycles 7 were prepared and coupled with
3,4,5-trimethoxyphenylacetylene 8, obtained in two steps starting
from 3,4,5-trimethoxybenzaldehyde.24 The 2-iodo derivatives 7
(except commercially available 2-iodo-thiophene) were prepared
using a deprotonation/iodination strategy, either by using the Zn/Li
mixed aggregates developed by Mongin25 and co-workers (for
benzofuran and benzo[b]thiophene), or taking advantage of the
ortho-directing properties of the sulfonyl group during the depro-
tonation of the indole core.26 2-Iodo-N-phenylsulfonyl-indole was
also the precursor of 2-iodo-indole after its fluoride-mediated
deprotection.27
Concerning the 5-substituted 2-bromo-benzothiophenes, an
alternative strategy based on a copper-catalyzed ring closure of
ortho-dibromoalkene thiophenols was envisaged.28 After bromi-
nation of m-methoxybenzaldehyde using N-bromosuccinimide
(NBS) in refluxing acetonitrile,29 the resulting para-methoxy bromo
derivative 9a underwent an aromatic nucleophilic substitution
with a sulfur atom, using sodium sulfide. The resulting thiophenol
was protected as a thioester by in situ action of acetic anhydride
(Scheme 3).
S
Scheme 4. Reagents and conditions: (d) CBr4 1.5 equiv, PPh3 3 equiv, CH2Cl2, 0 ꢁC, 2 h
then rt, 3 h, 58% for 11a (R¼OMe) and 23% over the last two steps for 11b (R¼NO2). (e)
K2CO3 1.5 equiv, MeOH, rt, 6 h, 89% for 7f (R¼OMe) and rt, 2 h, 12% for 7g (R¼NO2).
These two partners, the acetylenic derivative
8 and 2-
halogenoheteroaromatics 7, were then engaged under classical
Sonogashira coupling conditions31 to prepare a series of seven
diarylacetylenes 6 (Scheme 5 and Table 2).
OMe
OMe
OMe
f
R
Hal
I
R
X
X
6
7
OMe
OMe
OMe
or
S
or
S
6e
Scheme 5. Reagents and conditions: (f) 3,4,5-trimethoxyphenylacetylene 8 1.15 equiv,
PdCl2(PPh3)2 2 mol %, CuI 4 mol %, Et3N 1.3 equiv, THF, rt, 5e23 h.
The cross-coupling reaction was very efficient with 2-iodo-
benzofuran and 2-iodobenzo[b]thiophene and, to a lesser extent,
with 2-iodo-thiophene, as these compounds were isolated in al-
most quantitative yields for 6a and 6b (Table 2, entries 1 and 2) and
79% for 6e32 (Table 2, entry 5).
When carried out with N-phenylsulfonyl-2-iodo-indole, the
product 6c was obtained with a fairlygood 67% yield (Table 2, entry 3)
but led to a more disappointing result when the NH of indole was not
protected (Table 2, entry 4). Lastly, with 5-substituted 2-bromo-benzo
[b]thiophene 7f,g, the reaction allowed us to obtain the 5-methoxy
derivative 6f with a moderate yield (Table 2, entry 6) whereas the
reaction appears to be more efficient when realized on a substrate
bearing a strong electron-withdrawing nitro group (Table 2, entry 7).
Several protocols are known in the literature for the selective
transformation of acetylenic substrates into cis alkenes, such as
Lindlar hydrogenation,33 alkyne hydroboration,21 or hydrolysis of
a preformed titanium complex.34
R
R
c
O
O
X
SAc
(X = Br)
R = OMe 9a
10a
10b
R = NO2 9b (X = Cl)
Scheme 3. Reagents and conditions: (c) (1) Na2S$9H2O 1.2 equiv, DMAc, 90 ꢁC, 6.5 h
for 10a and 4.5 h for 10b. (2) Ac2O, 0 ꢁC, 50% for 10a.
The nitro derivative 10b was synthesized following a similar
procedure from commercially available 2-chloro-5-nitro-benzal-
dehyde 9b (Scheme 3).
Rather than a lead-poisoned Lindlar palladium catalyst (to avoid
leadtraces inthefinalproduct 1, whichcould haveaninfluenceduring
subsequent biological evaluations), we were looking for alternative
strategies: in the following, we will describe our results using two
of these alternatives: a hydrosilylation/deprotection sequence and
a semi-hydrogenation using the PdOAc2/KOH/DMF system.
These two protected aromatic aldehydes 10 were then engaged
in CoreyeFuchs reactions30 with carbon tetrabromide to give the
dibromoalkenes 11 (Scheme 4). Following Lautens’ protocol, the
acetyl group should have been removed under basic conditions to
get the free thiophenols, which could be cyclized using a copper
catalyst and a soft phosphate base (intramolecular Ullmann cou-
pling). But when the basic deprotection using potassium carbonate
in methanol was realized on 5-methoxy compound 11a, the cyclized
product 7f was isolated with an excellent 89% yield, after the
intramolecular attack of the thiolate anion onto the vinyl bromide.
Applied to the 5-nitro substrate 11b, these copper-free conditions
led to the formation of the corresponding benzothiophene 7g with
a very disappointing 12% yield (Scheme 4). Changing the base to
NaOH significantly improved the yield of 7g to 44%, albeit lower
compared to the methoxy analogue synthesis (Scheme 4).
2.3.2. Reduction via a hydrosilylation/deprotection sequence. First
described by Alami and co-workers for the preparation of CA-4 and
analogues,35 this method implies two steps that could also be re-
alized ina one-pot fashion: first a platinum-catalyzed hydrosilylation
of the triple bond with a silicon hydride reagent followed by a fluo-
ride-mediated deprotection of the vinylsilane compound.
Applied to our unsymmetrical diarylacetylene derivatives
6a,b,d, the hydrosilylation step using triethylsilane (Scheme 6) led

T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
2339
Table 2
Synthesis of diarylacetylenes 6
Entry
Substrate
Product
Yield %
OMe
OMe
1
2-Iodo-benzofuran
94
94
67
O
S
6a
OMe
OMe
2
3
2-Iodo-benzothiophene
OMe
6b
OMe
OMe
OMe
N-Phenylsulfonyl-2-iodo-indole
N
6c
OMe
OMe
SO2Ph
4
5
6
2-Iodo-indole
39
79
OMe
OMe
OMe
OMe
OMe
N
H
6d
2-Iodo-thiophene
S
6e
OMe
OMe
MeO
O2N
2-Bromo-5-methoxy-benzothiophene
30a
S
6f
OMe
OMe
7
2-Bromo-5-nitro-benzothiophene
66
OMe
OMe
S
6g
a
Homo-coupling product of starting material 8 was isolated with a 19% yield.
to the expected vinylsilanes 12 with very good (Table 3, entry 4) to
excellent yields (Table 3, entries 1 and 3). Compounds 12a,b were
obtained as a mixture a two regioisomers (not separable by flash
chromatography), depending on the position of the triethylsilyl
group on the double bond, i.e.,
a
or b 36
.
However, we were sur-
prised to see that, with the free indole substrate 6d, the reaction
gave only one regioisomer. In addition, this single regioisomer of
12d gave, after treatment with a TBAF solution, stereopure (Z)
isomer of the trimethoxystyrene derivative 1d (Table 3, entry 4).37
With the other vinylsilane compounds 12a (X¼O) and 12b (X¼S),
Z/E mixtures were obtained after the deprotection step (Table 3,
entries 1 and 3).38
SiEt3
α
β
g
HetAr1
Ar2
OMe
OMe
X
Table 3
6a,b,d
Preparation of trimethoxystyrenes 1 using a hydrosilylation/deprotection sequence
MeO
12
Entry
X
Hydrosilylation stepa
Deprotection stepc
1
2
3
4
O (6a)
95%,
72%,
92%,
78%,
a
a
a
a
/b
/b
/b
/b
ratio 79/21
ratio 54/46
ratio 18/82
ratio 100/0
84%, Z/E 62/38d
68%, Z/E 57/43d
94%, Z/E 24/76e
80%, Z/E 100/0
h
O (6a)b
S (6b)
NH (6d)
a
a/b
Ratio was determined by 1H NMR on the purified product, without attri-
OMe
OMe
bution of the major regioisomer.
X
b
Et3SiH was replaced by Me2EtOSiH.
Isolated yields of trimethoxystyrenes 1, obtained as a mixture of (Z) and (E)
c
MeO
stereoisomers, except for entry 4.
1
d
Z/E Ratio was determined by 1H NMR on the crude product.
Z/E Ratio was determined after purification of the crude product by flash
e
Scheme 6. Reagents and conditions: (g) Et3SiH 3 equiv, PtO2 5 mol %, 60 ꢁC, 4e23 h.
(h) TBAF 1.1 equiv, THF, 60 ꢁC, 1e2.5 h.
chromatography.

2340
T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
By using another hydrosilylating agent, Me2EtOSiH, that gave
100
80
60
40
20
0
better a/b
regioselectivities during the synthesis of CA-4,35 no im-
provement of this regioselectivity was observed on benzofuran
substrate as 1a was obtained with a lower global yield and a less
favourable Z/E ratio (Table 3, entry 2).
(Z)-1b
Starting material 6b
(E)-1b
2.3.3. Palladium acetate/DMF/KOH hydrogenation. When looking
for other semi-hydrogenation protocols, our attention was attrac-
ted by a method recently developed by Li and co-workers: the
partial reduction of acetylenic derivatives using the in situ hydro-
gen generation, after hydrolysis of DMF under basic conditions, and
catalyzed by palladium acetate.39 This method appeared us to be
practical and proved to have excellent stereoselectivities: so, we
decided to apply it on substrates 6 (Scheme 7).
0
50
100 150 200 250 300 350
Reaction time (min)
400
Pd(OAc)2
2 mol%
HetAr1
Ar2
OMe
OMe
X
Fig. 3. Kinetic profile of the semi-hydrogenation of 6b.
KOH 1.5 eq
DMF 145°C, 6h
6
MeO
2.4. Biological evaluations
R
1
Scheme 7.
Compounds (Z) and (E)-1 were thereafter evaluated for their
abilities to inhibit tubulin polymerization and the results were quite
encouraging, as described in our preliminary communication.8
Compound (Z)-1b appeared to be the most active derivative hav-
When the reaction was performed on the oxygen-containing
substrate 6a, we observed in 6 h the complete conversion of the
starting material and the major formation of the (Z)-alkene, to-
gether with a small amount of its (E) stereoisomer (Table 4, entry 1).
After a careful purification by flash chromatography, the desired
isomer (Z)-1a was obtained with a 66% yield.
ing an IC50¼2.6
mM, comparable to that of colchicine (IC50¼1.7
mM).
It showed also an interesting anti-proliferative activity against
keratinocyte cell lines (on HaCaT cells, IC50¼16 nM whereas IC50 of
colchicine¼12 nM), although lower than CA-4 itself. Flow cyto-
metry experiments also demonstrated that (Z)-1b caused the cell
mitosis arrest at G2/M transition, a common feature with CA-4.
Table 4
Semi-hydrogenation of acetylenes 6
Z/E Ratio,a global yield
(Z) Isomer, yield %
3. Conclusion
Entry
X
R
1
2
3
4
O
S
S
S
H (6a)
H (6b)
OMe (6f)
NO2 (6g)
93/7, 92%
91/9, 74%
100/0, 40%
db
1a, 66
1b, 63
1f, 40
db
The objective of this study was to have in hand new CA-4 de-
rivatives (Z)-1 for biological evaluations. As a consequence, it allows
us to establish a comparison between methods used for the prep-
aration of (Z) stereoisomer of these tubulin-targeting agents. The
final choice was in fact strongly dependent on the structure of the
target compound. Concerning the Suzuki coupling, the desired
stereochemistry was fixed by a palladium-catalyzed reduction step
with tributyltin hydride but could be altered by subsequent cou-
pling conditions, except in the case of benzothiophene compound
1b. Although efficient for the preparation of CA-4,35 the triple bond
hydrosilylation/hydrolysis sequence was quite disappointing when
applied to our benzoheterocyclic substrates 6a,b as Z/E mixtures
were observed for 1a,b. Nevertheless, this strategy would be the
method of choice for the preparation of the indole analogue 1d, for
which a perfect stereoselectivity and very good yield were ob-
served. The semi-hydrogenation method, using the in situ hydrogen
formation after basic hydrolysis of DMF, proved to be practical and
very efficient in term of stereoselectivity. This latter method is
preferable as it would avoid traces of toxic tin (coming from
HSnBu3) in the final product.
Determined by 1H NMR on the crude product.
No traces of the desired product was observed.
a
b
With its sulfur analogue 6b, the selectivity was slightly higher
(Table 4, entry 2) and the reaction afforded (Z)-1b with a good
63% yield. The electron-donating 5-methoxy substituent on the
benzothiophene ring seems to be of interest since the cis selec-
tivity of this hydrogenation increased: only (Z)-1f was detected,
with a low 40% yield as the major drawback (Table 4, entry 3).
However, the presence at the same position of a strong electron-
withdrawing nitro group completely inhibited the reaction
(Table 4, entry 4).
To complete our study, we wished to determine the kinetic
profile of the semi-hydrogenation reaction on the substrate 6b,40
to see if the Z/E ratio was modified during the reaction. The re-
action was carried out in a Schlenk tube, under an argon atmo-
sphere and aliquots of the reaction mixture were periodically
collected after the beginning of the heating at 145 ꢁC and analyzed
by uHPLC/MS.
We observed fast consumption of the starting material, which
was not further detected by MS after a 5 h reaction time (Fig. 3).
In parallel, the quantity of the desired (Z)-1b rapidly increased.
The Z/E ratio did not evolve during all the heating time and remains
around 92/8, which matches with an NMR estimation on the crude
product. This observation means that the (Z) to (E) isomerization
did not occur under the reaction conditions: once the stereoisomer
was formed during the hydrogen approach onto the triple bond, no
further change took place.
4. Experimental
4.1. General
All reactions were carried out under a positive pressure of argon
and with oven-dried glassware. Melting points were measured on
€
a Buchi B-540 melting point apparatus and are uncorrected. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded on
Bruker ALS300, DRX300 and DRX 400 Fourier transform spec-
trometers, using an internal deuterium lock, operating at 300 or

T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
2341
400 MHz. Chemical shifts are reported in parts per million (ppm)
relative to internal standard (tetramethylsilane, dH¼0.00; CDCl3,
dH¼7.26 and DMSO-d6, dH¼2.50).41 Data are presented as follows:
49/51, determined by 1H NMR) was purified by silica gel flash col-
umn chromatography (PE/AcOEt, 75:25 to 60:40) to afford the (Z)
isomer of 1a as a pale yellow viscous oil (0.282 g, 26%), a mixture of
(Z) and (E) isomers (0.040 g, 4%) and the (E) isomer as a white solid
(0.384 g, 35%).
chemical shift
(d
,
ppm), multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quadruplet, m¼multiplet, br¼broad), coupling con-
stant, integration. Atom numbering refers to and benzoheterocycle
nomenclature. Carbon magnetic resonance (13C NMR) spectra were
recorded on Bruker ALS300 or DRX 400 Fourier transform spec-
trometers, using an internal deuterium lock, operating at 75 and
100 MHz, respectively. Chemical shifts are reported in parts per
million (ppm) relative to internal standard (tetramethylsilane,
dC¼0.00; CDCl3, dC¼77.16 and DMSO-d6, dC¼39.52).41 Carbon mul-
tiplicities (indicated in parentheses) were determined by DEPT
experiments. High-resolution mass spectra were recorded on
a Bruker MicroTOF Q or Thermoquest Finnigan MAT 95 XL spec-
trometer (for chemical ionizations, isobutane was used).
Agilent uHPLC/MS consists of a 1290 Infinity system with a bi-
nary pump, degasser, autosampler, thermostated column com-
partment, 1260 Infinity Diode Array Detector and 6120 single
quadrupole mass spectrometer. The entire system was controlled
by ChemStation (Agilent Technologies, Rev B.04.02 SP1). The col-
Stereoisomer (Z). IR: nmax (film, cmꢀ1) 2997, 2937, 2835, 1581,
1505, 1463, 1452, 1418, 1328, 1240, 1183, 1167, 1129, 1007, 970, 940,
890, 854, 811, 751. 1H NMR (400 MHz, CDCl3):
d
¼3.83 (s, 6H), 3.91
(s, 3H), 6.44 (d, J¼12.7 Hz, 1H), 6.59 (d, J¼12.7 Hz, 1H), 6.70 (s, 1H),
6.84 (s, 2H), 7.18e7.27 (m, 2H), 7.36e7.38 (m, 2H), 7.37 (d, J¼8.0 Hz,
1H), 7.50 (d, J¼7.2 Hz,1H). 13C NMR (100 MHz, CDCl3):
¼56.1 (CH3),
d
61.0 (CH3), 106.2 (CH), 106.9 (CH), 110.8 (CH), 117.3 (CH), 120.9 (CH),
123.0 (CH), 124.7 (CH), 128.6 (C), 131.2 (CH), 132.1 (C), 137.9 (C),
152.9 (C), 153.8 (C), 154.3 (C). HRMS (ESIþ): m/z calcd for
C19H18O4Na [MNaþ]: 333.1097; found: 333.1084.
Stereoisomer (E). Mp 121e124 ꢁC. IR: nmax (film, cmꢀ1) 2959,
2934, 1581, 1503, 1449, 1416, 1335, 1326, 1254, 1242, 1197, 1152,
1123, 1044, 1006, 992, 983, 967, 948, 840, 816, 784, 748, 670, 636,
616, 499. 1H NMR (400 MHz, CDCl3):
d
¼3.87 (s, 3H), 3.90 (s, 6H),
6.66 (s, 1H), 6.75 (s, 2H), 6.90 (d, J¼16.0 Hz, 1H), 7.14e7.28 (m, 3H),
7.45 (d, J¼8.1 Hz, 1H), 7.52 (d, J¼8.2 Hz, 1H). 13C NMR (100 MHz,
umn was a Zorbax Eclipse Plus C18 RRHD, 2.1ꢂ50 mm, 1.8
m
m. The
CDCl3):
d¼56.1 (CH3), 60.9 (CH3), 103.8 (CH), 105.0 (CH), 110.8 (CH),
samples were analyzed in the positive ion mode of the Electron
Spray Ionization (ESI) source, whose conditions were as follow: gas
temperature, 350 ꢁC, drying gas at 12.0 L/min, nebulizer gas at
35 psig, Vcap at 3000 V, fragmentor at 110 or 115 V.
115.9 (CH), 120.8 (CH), 122.9 (CH), 124.6 (CH), 129.1 (C), 130.2 (CH),
132.2 (C), 138.4 (C), 153.4 (C), 154.8 (C), 154.9 (C). HRMS (ESIþ): m/z
calcd for C19H19O4 [MHþ]: 311.1278; found: 311.1276.
Reactions were monitored with analytical Thin Layer Chroma-
tography (TLC), which was carried out using Merck commercial
aluminium sheets coated (0.2 mm layer thickness) with Kieselgel
60 F254, with visualization by ultraviolet and anisaldehyde stain
solution.
4.2.2. Preparation of (Z)-2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-benzo
[b]thiophene 1b. To a stirred suspension of 3,4,5-trimethoxybenzyl-
triphenylphosphonium bromide (0.806 g, 1.54 mmol) in THF (16 mL)
at ꢀ78 ꢁC was added dropwise (10 min) n-BuLi 2.5 M in hexane
(1.23 mL, 3.08 mmol). The stirring was continued at ꢀ78 ꢁC for
30 min and at room temperature for 1 h. The dark red reaction
mixture was cooled to ꢀ78 ꢁC and a solution of benzo[b]thiophene-
2-carboxaldehyde (0.250 g, 1.54 mmol) in THF (6 mL) then was
added dropwise (15 min). The stirring was continued at ꢀ78 ꢁC for
1 h and at room temperature for 18 h. Subsequently, the mixture was
quenched with ice-cold water (20 mL) and ethyl acetate (20 mL) was
then added. After decantation, the aqueous layer was extracted with
ethyl acetate (2ꢂ20 mL) and dichloromethane (3ꢂ20 mL). The
combined organic layers were dried over Na2SO4, filtered and con-
centrated under reduced pressure to give a yellow residue. The crude
product (Z/E ratio 45/55, determined by 1H NMR) was purified by
silica gel flash column chromatography (PE/AcOEt, 80:20) to afford
the (Z) isomer of 1b as a yellow oil (0.040 g, 8%), a mixture of (Z) and
(E) isomers (0.198 g, 39%) and the (E) isomer as a yellow solid
(0.149 g, 30%).
Product purification by flash column chromatography was per-
ꢁ
formed using Merck Kieselgel 60 A (40e63
mm). N,N-Dime-
thylformamide (DMF), N,N-dimethylacetamide (DMAc), 1,2-
dimethoxyethane (DME) and methanol were of analytical grade
and were used as received without purification. THF (AcrosealÒ,
over molecular sieves) are purchased by Acros Organics. Dichloro-
methane was distilled over LiAlH4 prior to use. For extraction/pu-
rification, diethyl ether, cyclohexane and ethyl acetate (AcOEt) were
of reagent grade. Petroleum ether (PE) refers to the 40e60 ꢁC
boiling point fraction. Resveratrol trimethyl ether (ꢃ98% purity)
was used as the internal standard for kinetic studies and was pur-
chased from SigmaeAldrich.
All otherchemical reagents were used as received. Commercial n-
BuLi solutions in hexanes were titrated using N-Benzylbenzamide.42
3,4,5-Trimethoxybenzyl-triphenylphosphonium bromide,43 3,4,5-
trimethoxy-phenylacetylene24 and tetrakis(triphenylphosphine)
palladium(0)44 were prepared according to known procedures.
Stereoisomer (Z). IR: nmax (film, cmꢀ1) 3056, 2999, 2936, 2833,
1579, 1502, 1463, 1430, 1413, 1395, 1328, 1238, 1182, 1149, 1127,
1040, 1007, 966, 855, 834, 746, 726. 1H NMR (300 MHz, CDCl3):
4.2. Wittig reactions
d
¼3.79 (s, 6H), 3.91 (s, 3H), 6.65 (d, J¼11.7 Hz, 1H), 6.65 (s, 2H), 6.76
(d, J¼12 Hz, 1H), 7.22e7.31 (m, 3H), 7.65e7.68 (m, 2H). (300 MHz,
DMSO-d6):
4.2.1. Preparation of 2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-benzofu-
ran 1a. To a stirred suspension of 3,4,5-trimethoxybenzyltriphenyl-
phosphonium bromide (1.83 g, 3.5 mmol) in THF (35 mL) at ꢀ78 ꢁC
was added dropwise (10 min) n-BuLi 2.5 M in hexane (2.8 mL,
7.0 mmol). The stirring was continued at ꢀ78 ꢁC for 30 min and at
room temperature for 1 h. The dark red reaction mixture was cooled
to ꢀ78 ꢁC and a solution of benzofuran-2-carboxaldehyde (0.512 g,
3.5 mmol) in THF (13 mL) then was added dropwise (15 min). The
stirring was continued at ꢀ78 ꢁC for 1 h and at room temperature for
18 h. Subsequently, the mixture was quenched with ice-cold water
(35 mL) and ethyl acetate (35 mL) was then added. After de-
cantation, the aqueous layer was extracted with ethyl acetate
(2ꢂ35 mL) and dichloromethane (3ꢂ35 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated under re-
duced pressure to give a yellow residue. The crude product (Z/E ratio
d
¼3.70 (s, 3H), 3.7 (s, 6H), 6.70 (d, J¼11.7 Hz, 1H), 6.71 (s,
2H), 6.88 (d, J¼12.3 Hz, 1H), 7.25e7.34 (m, 2H), 7.48 (s, 1H),
7.75e7.78 (m, 1H), 7.81e7.84 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
¼56.0 (CH3), 61.0 (CH3), 106.0 (CH), 122.0 (CH), 123.2 (CH), 123.6
(CH), 124.2 (CH), 124.6 (CH), 125.4 (CH), 130.9 (CH), 131.9 (C), 137.8
(C), 138.9 (C), 139.8 (C), 140.0 (C), 153.1 (C). HRMS (ESIþ): m/z calcd
for C19H18O3SNa [MNaþ]: 349.0869; found: 349.0864.
Stereoisomer (E). Mp 158e160 ꢁC. IR: nmax (film, cmꢀ1) 3001,
2926, 2831, 1723, 1579, 1505, 1450, 1415, 1350, 1326, 1245, 1234,
1184, 1155, 1123, 1002, 963, 858, 835, 811, 754, 727, 707, 683, 635,
566, 521, 496. 1H NMR (400 MHz, CDCl3):
d¼3.88 (s, 3H), 3.92 (s,
6H), 6.73 (s, 2H), 6.92 (d, J¼16.0 Hz, 1H), 7.22 (d, J¼16.0 Hz, 1H), 7.24
(s, 1H), 7.28e7.34 (m, 2H), 7.68e7.70 (m, 1H), 7.76e7.78 (m, 1H). 13C
NMR (100 MHz, CDCl3):
(CH),122.2 (CH),123.1 (CH),123.3 (CH),124.5 (CH),124.7 (CH),130.8
d
¼56.1 (CH3), 60.9 (CH3), 103.6 (CH), 121.8

2342
T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
(CH), 132.3 (C), 138.3 (C), 138.8 (C), 140.2 (C), 142.7 (C), 153.4 (C).
HRMS (ESIþ): m/z calcd for C19H19O3S [MHþ]: 327.1049; found:
327.1040.
8.05 (d, J¼8.1 Hz, 1H). 13C NMR (100 MHz, CDCl3):
¼28.2 (CH3),
d
55.8 (CH3), 60.8 (CH3), 84.2 (C), 105.8 (CH), 109.5 (CH), 115.3 (CH),
120.4 (CH), 121.7 (CH), 122.8 (CH), 124.1 (CH), 129.3 (C), 130.7 (CH),
132.2 (C), 136.0 (C), 136.2 (C), 137.4 (C), 150.3 (C), 152.9 (C). HRMS
(ESIþ): m/z calcd for C24H27NO5Na [MNaþ]: 432.1781; found:
432.1785.
4.3. Suzuki couplings
4.3.1. Substrates synthesis. Benzofuran-, benzo[b]thiophene- and
thiophene-2-boronic acids were purchased from Acros Organics. N-
Boc indole-2-boronic acid and N-Boc indole-2-potassium tri-
fluoroborate were synthesized according to known protocols.20 1-
(2-Bromovinyl)-3,4,5-trimethoxybenzene (Z/E 91/9) was prepared
according to a literature reference by palladium-catalyzed selective
halogenolysis of the dibromovinyl precursor.17a
4.3.5. Preparation of (Z)-2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-thio-
phene 1e. According to general procedure 1, scale: 1-(2-bromovinyl)-
3,4,5-trimethoxybenzene (Z/E¼91:9) (0.132 g, 0.48 mmol), tetra-
kis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol), 1,2-
dimethoxyethane (7 mL), thiophen-2-ylboronic acid (0.070 g,
0.55 mmol), sodium carbonate (0.051 g, 0.48 mmol), water (4.2 mL).
The residue containing 67% of (Z)- and 33% of (E)-2-(2-(3,4,5-
trimethoxyphenyl)vinyl)thiophene was purified by column chro-
matography (cyclohexane/ethyl acetate, 90:10) to give (Z)-1e as
a yellow oil (0.050 g, 38%) and a mixture of (Z) and (E) isomer
(0.048 g, 36%).
4.3.2. General procedure 1. Suzuki coupling reactions: preparation of 2-
[2-(3,4,5-trimethoxy-phenyl)-vinyl]-benzofuran 1a. 1-(2-Bromovinyl)-
3,4,5-trimethoxybenzene (Z/E ratio 91/9, determined by 1H NMR)
(0.126 g, 0.46 mmol) and tetrakis(triphenylphosphine)palladium(0)
(0.027 g, 0.023 mmol) were stirred in 1,2-dimethoxyethane (7 mL)
under argon for 20 min. Benzofuran-2-ylboronic acid (0.086 g,
0.53 mmol) and sodium carbonate (0.049 g, 0.46 mmol) in water
(4.2 mL) were added, the mixture was heated under reflux during
20 h. After cooling and decantation, the aqueous layer was separated
and extracted with ethyl acetate (2ꢂ7 mL). The combined organic
phases were washed with brine (7 mL), dried over Na2SO4, filtered
and concentrated under reduced pressure. The residue was analyzed
by 1H NMR and has shown a mixture of (Z) (77%) and (E) isomers
(33%). This crude product was purified by column chromatography
(cyclohexane/ethyl acetate 80:20) to give the (Z) isomer of 1a as
a yellow oil (0.081 g, 57%) and a mixture of (Z) and (E) isomer (0.047 g,
33%). This fraction was purified a second time by column chroma-
tography (cyclohexane/ethyl acetate 80:20) followed by washing
with diethyl ether to obtain (E)-1a (0.032 g, 22%) as a white solid.
Stereoisomer (Z). IR: nmax (film, cmꢀ1) 2935, 2833, 1737, 1577,
1501, 1462, 1451, 1429, 1411, 1326, 1234, 1184, 1122, 1036, 1004, 966,
849, 700, 573, 527, 478. 1H NMR (300 MHz, CDCl3):
d
¼3.80 (s, 6H),
3.88 (s, 3H), 6.50 (d, J¼12.0 Hz, 1H), 6.61 (s, 2H), 6.67 (d, J¼12.3 Hz,
1H), 6.91 (dd, J¼5.2e3.6 Hz, 1H), 7.01 (d, J¼3.6 Hz, 1H), 7.13 (dd,
J¼4.8e1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3):
¼56.0 (CH3), 61.0
d
(CH3), 105.8 (CH), 123.1 (CH), 125.6 (CH), 126.4 (CH), 128.4 (CH),
128.8 (CH),132.5 (C),137.5 (C),139.6 (C),153.2 (C). HRMS (ESIþ): m/z
calcd for C15H16O3SNa [MNaþ]: 299.0712; found: 299.0714.
4.4. 2-Halogenated heterocycles
2-Iodothiophene was purchased by Alfa Aesar. 2-Iodobenzofuran,
2-iodobenzothiophene were synthesized via a zinc/lithium mixed
aggregate 2-deprotonation and subsequent iodination, according to
Mongin’s method.25 5-Nitro and 5-methoxy-2-bromobenzo[b]thio-
phene 7f,g were prepared according to the following protocols.
4.3.3. Preparation of (Z)-2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-benzo
[b]thiophene 1b. According to general procedure 1, scale: 1-(2-
bromovinyl)-3,4,5-trimethoxybenzene (Z/E 91/9) (0.137 g,
0.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.029 g,
0.025 mmol), 1,2-dimethoxyethane (7.6 mL), benzo[b]thiophen-2-
yl-boronic acid (0.101 g, 0.57 mmol), sodium carbonate (0.053 g,
0.5 mmol), water (4.6 mL). The residue containing 90% of (Z)- and
10% of (E)-1b was purified by column chromatography on silica gel
deactivated by Et3N (cyclohexane/ethyl acetate, 80:20) to give (Z)-
1b as a yellow oil (0.093 g, 57%) and a mixture of (Z) and (E) isomer
(0.062 g, 38%).
4.4.1. Preparation of 2-bromo-5-methoxybenzaldehyde. A solution
of m-anisaldehyde (3.66 mL, 30 mmol) and N-bromosuccinimide
(5.874 g, 33 mmol) in acetonitrile (90 mL) was heated at 90 ꢁC for
11 h then at 70 ꢁC for 18 h. After cooling, the reaction mixture was
quenched with water (50 mL), extracted with ethyl acetate
(3ꢂ100 mL). The combined organic layers were dried over Na2SO4
and evaporated under reduced pressure. The crude product was
purified by column chromatography (cyclohexane/ethyl acetate,
90:10) to afford a first fraction (2.80 g, white solid). The second
fraction (1.60 g) was further purified by flash chromatography
(cyclohexane/ethyl acetate, 97.5:2.5) to give another fraction
(0.82 g, white solid). These two fractions were collected to give the
title compound (2.80þ0.82¼3.62 g, 56%) as a white solid; mp
4.3.4. Preparation of (Z)-2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-in-
dole-1-carboxylic acid tert-butyl ester 1c. According to general
procedure 1, scale: 1-(2-bromovinyl)-3,4,5-trimethoxybenzene (Z/
E¼91:9) (0.297 g, 1.09 mmol), tetrakis(triphenylphosphine)palla-
dium(0) (0.063 g, 0.054 mmol), 1,2-dimethoxyethane (16.5 mL), 1-
(tert-butoxycarbonyl)-1H-indol-2-yl potassium trifluoroborate
(0.402 g, 1.24 mmol), sodium carbonate (0.116 g, 1.09 mmol), water
(10 mL). The residue was purified by column chromatography
(cyclohexane/ethyl acetate, 90:10) to give (Z)-1c as a yellow oil
(0.210 g, 47%) and a mixture of two isomers (0.040 g, 9%, Z/
E¼78:22).
78e79 ꢁC (lit.45 78e80 ꢁC). 1H NMR (300 MHz, CDCl3):
3H), 7.04 (dd, J¼8.7e3.0 Hz, 1H), 7.42 (d, J¼3.6 Hz, 1H), 7.53 (d,
J¼9.3 Hz, 1H), 10.32 (s, 1H). Spectral data were in agreement to
those reported in the literature.45
d¼3.84 (s,
4.4.2. Preparation of thioacetic acid S-(2-formyl-4-methoxy-phenyl)
ester 10a. To a two-neck round-bottomed flask (fitted with a con-
denser and an addition funnel) containing Na2S$9H2O (3.757 g,
15.6 mmol) was added DMAc (39 mL) and the resulting suspension
was heated at 90 ꢁC. After stirring for 90 min, 2-bromo-5-
methoxybenzaldehyde (2.796 g, 13 mmol) was added, the sus-
pension turned from blue/green to reddish brown and the reaction
was stirred at 90 ꢁC until TLC indicated consumption of starting
material (5 h). The reaction was then cooled to 0 ꢁC and freshly
distilled Ac2O (15 mL, 158.7 mmol) was added dropwise. The re-
action was stirred at 0 ꢁC for 1 h, then warmed to room temperature
and stirred overnight (16 h). The reaction was then diluted with
Stereoisomer (Z). IR: nmax (KBr, cmꢀ1) 2978, 2936, 2835, 1732,
1580, 1556, 1505, 1452, 1418, 1395, 1370, 1330, 1240, 1210, 1160,
1128, 1085, 1039, 1008, 980, 942, 847, 798, 770, 748, 662. 1H NMR
(300 MHz, CDCl3):
d
¼1.68 (s, 9H), 3.62 (s, 6H), 3.84 (s, 3H), 6.56 (d,
J¼12.3 Hz,1H), 6.57 (2s, 3H), 6.80 (dd, J¼12.3e1.2 Hz, 1H), 7.17e7.22
(m, 1H), 7.26e7.31 (m, 1H), 7.41e7.45 (m, 1H), 8.11e9.14 (m, 1H).
(300 MHz, DMSO-d6):
(s, 2H), 6.60 (d, J¼12.1 Hz, 1H), 6,60 (s, 1H), 6.73 (dd, J¼12.4e1.1 Hz,
1H), 7.16e7.22 (m, 1H), 7.26e7.31 (m, 1H), 7.52 (d, J¼6.9 Hz, 1H),
d
¼1.56 (s, 9H), 3.48 (s, 6H), 3.60 (s, 3H), 6.54

T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
2343
Et2O (60 mL) and 10% aqueous HCl (40 mL): after decantation, the
aqueous phase was extracted with Et2O (2ꢂ40 mL). The combined
organic phases were washed by water (40 mL) and brine (40 mL).
The organic phase was dried over Na2SO4, filtered and the volatiles
were removed under vacuum. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 90:10) to give
11b (1.751 g, 23% for two steps) of as a light yellow solid; mp
125e126 ꢁC. IR: nmax (film/cmꢀ1) 2923, 1714, 1592, 1568, 1517, 1455,
1345, 1300, 1264, 1115, 1102, 1051, 947, 912, 850, 831, 815, 800, 740,
720, 606, 577, 539, 519, 453. 1H NMR (300 MHz, CDCl3):
d
¼2.51 (s,
3H), 7.47 (s, 1H), 7.68 (d, J¼8.7 Hz, 1H), 8.22 (dd, J¼8.7e2.1 Hz, 1H),
8.51 (d, J¼2.1 Hz, 1H). 13C NMR (100 MHz, CDCl3):
¼30.7 (CH3),
d
compound 10a (1.388 g, 50%) as a yellow oil; IR: nmax (KBr, cmꢀ1
)
95.8 (C), 123.2 (CH), 124.6 (CH), 133.5 (CH), 134.9 (CH), 136.7 (C),
140.6 (C), 148.3 (C), 190.5 (C). HRMS (CI): m/z calcd for
C10H8Br2NO3S [MHþ]: 379.8586; found: 379.8584.
3006, 2938, 2848, 2747, 1705, 1593, 1566, 1478, 1422, 1388, 1354,
1311, 1278, 1231, 1192, 1165, 1111, 1060, 1025, 951, 870, 828, 757, 617.
1H NMR (300 MHz, CDCl3):
d
¼2.48 (s, 3H), 3.89 (s, 3H), 7.17 (dd,
J¼8.4e3 Hz, 1H), 7.38 (d, J¼8.4 Hz, 1H), 7.54 (d, J¼3 Hz, 1H), 10.20 (s,
1H). 13C NMR (100 MHz, CDCl3):
4.4.6. Preparation of 2-bromo-5-methoxy-benzo[b]thiophene 7f. A
suspension of compound 11a (0.207 g, 0.56 mmol) in methanol
(2.8 mL) and K2CO3 (0.117 g, 0.85 mmol) was stirred at room tem-
perature for 6 h. The reaction mixture was diluted with ethyl ace-
tate and washed with 10 mL of brine. Aqueous phases were
extracted with ethyl acetate (3ꢂ10 mL). Organic layers were com-
bined, dried over Na2SO4, filtered and evaporated to obtained crude
product, which was purified by silica gel flash column chroma-
tography (cyclohexane/ethyl acetate, 95:5) to afford 2-bromo-5-
methoxy-benzo[b]thiophene 7f as a yellow solid (0.163 g, 89%);
IR: nmax (KBr, cmꢀ1) 3007, 2958, 2934, 2833, 1591, 1560, 1462, 1438,
1417, 1304, 1283, 1233, 1165, 1067, 1026, 958, 942, 872, 817, 703. 1H
d
¼30.1 (CH3), 55. 7 (CH3), 112.3
(CH),121.6 (CH),122.2 (C),137.8 (CH),138.0 (C),161.2 (C),190.7 (CH),
193.5 (C). HRMS (CI): m/z calcd for C10H11O3S [MHþ]: 211.0423;
found: 211.0421.
4.4.3. Preparation of thioacetic acid S-(2-formyl-4-nitro-phenyl) es-
ter 10b. Following the same experimental procedure as for com-
pound 10a, scale: Na2S$9H2O (5.76 g, 24 mmol), DMAc (60 mL), 2-
chloro-5-nitrobenzaldehyde (3.711 g, 20 mmol), Ac2O (28 mL,
296 mmol), reaction time at 90 ꢁC: 3 h. As this compound seems not
to be stable on the silica gel, the crude product was used without
further purification (see x 4.4.5.).
NMR (400 MHz, CDCl3):
d
¼3.83 (s, 3H), 6.83 (dd, J¼6.6e2.1 Hz, 1H),
During one reaction, an analytic sample of 10b was obtained
after a flash chromatography purification (cyclohexane/ethyl ace-
tate, 80:20); mp 72e75 ꢁC. IR: nmax (film/cmꢀ1) 2920, 2850, 1693,
1599, 1573, 1517, 1456, 1342, 1299, 1247, 1186, 1112, 1053, 968, 935,
922, 845, 816, 741, 732, 609, 546, 502. 1H NMR (300 MHz, CDCl3):
7.15 (d, J¼2.1 Hz, 1H), 7.40 (d, J¼6.3 Hz, 1H), 7.47 (s, 1H). 13C NMR
(100 MHz, CDCl3):
135.7 (CH), 136.2 (CH), 139.8 (C), 160.2 (C). HRMS (EI): m/z calcd for
d
¼55.5 (CH3), 92.2 (C), 115.1 (2CH), 126.5 (C),
C9H8BrOS [MHþ]: 241.9396; found: 241.9395.
d
¼2.57 (s, 3H), 7.74 (d, J¼8.4 Hz, 1H), 8.43 (dd, J¼8.4e2.7 Hz, 1H),
4.4.7. Preparationof2-bromo-5-nitro-benzo[b]thiophene7g. According
to the procedure used for the preparation of 7f, scale: compound 11b
(0.482 g, 1.26 mmol), methanol (6.3 mL), K2CO3 (0.261 g, 1.89 mmol),
reaction time at room temperature: 2 h. The crude product (0.084 g)
was purified by flash column chromatography (cyclohexane) to afford
2-bromo-5-nitrobenzo[b]thiophene 7g (0.039 g, 12%) as a light yellow
solid.
Optimized procedure. A suspension of compound 11b (0.100 g,
0.26 mmol), in methanol (1.3 mL) and NaOH (0.150 g, 3.64 mmol)
was stirred at room temperature for 8 h. The reaction mixture was
quenched with water (5 mL), extracted with ethyl acetate
(3ꢂ15 mL). Organic phases were washed with saturated NaCl, dried
over Na2SO4, filtered and evaporated. The crude product was pu-
rified by flash column chromatography (cyclohexane/ethyl acetate,
95:5) to afford 2-bromo-5-nitrobenzo[b]thiophene 7g (0.030 g,
8.84 (d, J¼2.4 Hz, 1H), 10.20 (s, 1H). 13C NMR (100 MHz, CDCl3):
d
¼30.7 (CH3), 123.9 (CH), 127.6 (CH), 137.4 (CH), 137.5 (C), 137.9 (C),
148.8 (C), 188.2 (CH), 190.5 (C). HRMS (CI): m/z calcd for C9H8NO4S
[MHþ]: 226.0169; found: 226.0168.
4.4.4. Preparation of thioacetic acid S-[2-(2,2-dibromo-vinyl)-4-
methoxy-phenyl] ester 11a. In a round-bottom flask fitted with an
addition funnel, a solution of aldehyde 10a (1.143 g, 5.44 mmol) and
CBr4 (2.706 g, 8.16 mmol) in freshly distilled dichloromethane
(32.5 mL) was cooled at 0 ꢁC. PPh3 (4.281 g, 16.32 mmol) in freshly
distilled dichloromethane (22 mL) was added dropwise during 1 h.
The reaction was stirred at 0 ꢁC for 2 h, then at room temperature
for 3 h. Petroleum ether was added until no more precipitation of
triphenylphosphine oxide was observed. Insoluble solids were
eliminated by filtration on a sintered-glass funnel, washing with
Et2O. After evaporation of the solvents under reduced pressure, the
crude product was purified by flash chromatography (cyclohexane/
ethyl acetate, 90:10) to give compound 11a (1.155 g, 58%) as a yel-
low solid; mp 60e62 ꢁC. IR: nmax (film/cmꢀ1) 3011, 2937, 1737, 1694,
1590, 1477, 1457, 1434, 1349, 1313, 1233, 1171, 1098, 1062, 1023, 951,
873, 827, 816, 732, 712, 691, 654, 638, 626, 610, 577, 554, 518, 508,
44%) as a light yellow solid. 1H NMR (300 MHz, CDCl3):
d
¼7.50 (s,
1H), 7.86 (d, J¼9.3 Hz, 1H), 8.19 (dd, J¼8.7e2.4 Hz, 1H), 8.59 (d,
J¼2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3):
¼118.1 (CH), 118.8 (CH),
d
119.2 (C), 122.2 (CH), 127.1 (CH), 139.2 (C), 145.8 (C), 146.6
(C). Spectral data were in agreement to those reported in the
literature.28a
468. 1H NMR (300 MHz, CDCl3):
(dd, J¼8.7, 3 Hz, 1H), 7.19 (d, J¼2.7 Hz, 1H), 7.35 (d, J¼8.7 Hz, 1H),
7.45 (s, 1H). 13C NMR (100 MHz, CDCl3):
92.8 (C),115.0 (CH),115.4 (CH),117.9 (C), 135.7 (CH), 137.3 (CH),141.0
(C), 160.7 (C), 193.8 (C). HRMS (CI): m/z calcd for C11H11Br2OS
[MHþ]: 364.8841; found: 364.8841.
d¼2.42 (s, 3H), 3.84 (s, 3H), 6.92
4.5. Diacetylene derivatives 6
d¼30.0 (CH3), 55.5 (CH3),
4.5.1. General procedure 2. Sonogashira coupling reactions: prepa-
ration of 2-(3,4,5-trimethoxy-phenylethynyl)-benzofuran 6a. To
a
solution of 2-iodo-benzofuran (1.030 g, 4.60 mmol) and
PdCl2(PPh3)2 (0.065 g, 0.09 mmol) in THF (28 mL) under an argon
atmosphere was added CuI (0.034 g, 0.18 mmol), triethylamine
(0.83 mL, 5.98 mmol) and then 3,4,5-trimethoxyphenylacetylene 8
(1.061 g, 5.22 mmol). After stirring for 5 h at room temperature, the
4.4.5. Preparation of thioacetic acid S-[2-(2,2-dibromo-vinyl)-4-
nitro-phenyl] ester 11b. The crude product obtained after nucleo-
philic substitution reaction with sodium sulfide/thioester forma-
tion (x 4.4.3.) was used in this step, according to procedure used for
the preparation of 11a, scale: crude thioacetic acid S-(2-formyl-4-
nitro-phenyl) ester 10b (4.193 g), CBr4 (8.95 g, 27 mmol) in
dichloromethane (90 mL), PPh3 (14.16 g, 54 mmol) in dichloro-
methane (60 mL). The crude product was purified by flash chro-
matography (cyclohexane/ethyl acetate, 90:10) to give compound
reaction mixture was filtered over a 0.45 mm porosity glass fibre
filter and washed with diethyl ether (2ꢂ20 mL). The combined
organic layers were concentrated under vacuum. The crude brown
oil was purified by column chromatography (cyclohexane/ethyl
acetate 80:20) to afford compound 6a (1.333 g, 94%) as an orange
yellow solid; mp 89e91 ꢁC. IR: nmax (film, cmꢀ1) 2934, 1574, 1501,
1448, 1425, 1411, 1345, 1267, 1237, 1185, 1165, 1126, 1105, 1003, 986,

2344
T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
927, 823, 811, 771, 745, 656, 646, 628, 555, 525, 510. 1H NMR
(400 MHz, CDCl3):
¼3.88 (s, 6H), 3.89 (s, 3H), 6.82 (s, 2H), 7.00 (d,
J¼0.8 Hz, 1H), 7.24e7.28 (m, 1H), 7.32e7.36 (m, 1H), 7.47e7.49 (m,
1H), 7.57e7.59 (m, 1H). 13C NMR (100 MHz, CDCl3):
61.0 (CH3), 78.7 (C), 95.2 (C), 108.8 (CH), 111.2 (CH), 111.4 (CH), 116.7
(C), 121.1 (CH), 123.3 (CH), 125.6 (CH), 127.7 (C), 138.6 (C), 139.5 (C),
153.1 (C), 154.8 (C). HRMS (ESIþ): m/z calcd for C19H17O4 [MHþ]:
309.1121; found: 309.1111.
(CH3), 60.1 (CH3), 81.7 (C), 91.9 (C), 107.4 (CH), 108.5 (CH),111.2 (CH),
116.9 (C),118.1 (C),119.7 (CH),120.3 (CH),122.8 (CH),127.2 (C),136.4
(C), 138.55 (C), 153.0 (C). HRMS (ESIþ): m/z calcd for C19H18NO3
[MHþ]: 308.1281; found: 308.1267.
d
d¼56.2 (CH3),
4.5.5. Preparation of 2-(3,4,5-trimethoxy-phenylethynyl)-thiophene
6e. According to general procedure 2, scale: 2-iodothiophene
(0.23 mL, 2.2 mmol), PdCl2(PPh3)2 (0.031 g, 0.044 mmol), THF
(12 mL), CuI (0.017 g, 0.09 mmol), triethylamine (0.40 mL,
2.8 mmol), trimethoxyphenylacetylene 8 (0.508 g, 2.64 mmol),
reaction time at room temperature: 5 h. The crude product was
then purified by silica gel column chromatography (cyclohexane/
ethyl acetate, 80:20) to afford 6e (0.477 g, 79%) as a brown solid; mp
79e81 ꢁC (lit.32 80e81 ꢁC). IR: nmax (film, cmꢀ1) 3100, 2933, 2832,
1572, 1522, 1498, 1461, 1407, 1364, 1329, 1231, 1204, 1180, 1128, 995,
951, 851, 834, 816, 778, 737, 720, 685, 623, 590, 523, 506. 1H NMR
4.5.2. Preparation of 2-(3,4,5-trimethoxy-phenylethynyl)benzo[b]thio-
phene 6b. According to general procedure 2, scale: 2-iodobenzo[b]
thiophene (0.520 g, 2.00 mmol), PdCl2(PPh3)2 (0.028 g, 0.04 mmol),
THF (12 mL), CuI (0.015 g, 0.08 mmol), triethylamine (0.36 mL,
2.6 mmol), trimethoxyphenylacetylene 8 (0.461 g, 2.40 mmol), re-
action time at room temperature: 19 h. The crude product was then
purified by column chromatography (cyclohexane/ethyl acetate,
90:10) to afford compound 6b (0.610 g, 94%) as a pale orange solid;
mp 95e98 ꢁC. IR: nmax (film, cmꢀ1) 2928,1738,1573,1497,1452,1433,
1424, 1351, 1326, 1236, 1183, 1171, 1124, 1099, 1069, 1039, 1002, 944,
970, 849, 838, 823, 752, 726, 691, 630, 564, 524, 505. 1H NMR
(400 MHz, CDCl3):
d
¼3.80 (s, 9H), 6.75 (s, 2H), 7.01 (dd,
J¼4.8e3.6 Hz), 7.27e7.29 (m, 2H). 13C NMR (100 MHz, CDCl3):
d¼56.1 (CH3), 60.9 (CH3), 81.7 (C), 93.0 (C), 108.5 (CH), 117.8 (C),
123.1 (C), 127.1 (CH), 127.2 (CH), 131.8 (CH), 138.9 (C), 153.1 (C).
HRMS (ESIþ): m/z calcd for C15H15O3S [MHþ]: 275.0736; found:
275.0736.
(400 MHz, CDCl3):
d
¼3.89 (s, 9H), 6.80 (s, 2H), 7.35e7.39 (m, 2H),
7.50 (s, 1H), 7.74e7.84 (m, 2H). 13C NMR (100 MHz, CDCl3):
d¼56.1
(CH3), 61.0 (CH3), 82.0 (C), 94.9 (C), 108.7 (CH), 117.4 (C), 122.0 (CH),
123.1 (C), 123.7 (CH), 124.7 (CH), 125.4 (CH), 128.6 (CH), 139.1 (C),
139.2 (C), 140.2 (C), 159.1 (C). HRMS (ESIþ): m/z calcd for C19H17O3S
[MHþ]: 325.0893; found: 325.0893.
4.5.6. Preparation of 5-methoxy-2-(3,4,5-trimethoxy-phenylethynyl)-
benzo[b]thiophene 6f. According to general procedure 2, scale:
5-methoxy-2-bromobenzo[b]thiophene (0.163 g, 0.67 mmol),
PdCl2(PPh3)2 (0.009 g, 0.013 mmol), THF (5 mL), CuI (0.005 g,
0.03 mmol), triethylamine (0.12 mL, 0.87 mmol), trimethox-
yphenylacetylene 8 (0.154 g, 0.80 mmol), reaction time at room
temperature: 18 h. The crude product was purified by silica gel flash
column chromatography (cyclohexane/ethyl acetate, 85:15) to af-
ford compound 6f (0.072 g, 30%) as a yellow solid and homo-
coupling diacetylenic product 1,4-bis(3,4,5-trimethoxyphenyl)
buta-1,3-diyne (0.023 g, 19%) as a yellow solid.
4.5.3. Preparation of 1-benzenesulfonyl-2-(3,4,5-trimethoxy-phenyl-
ethynyl)-1H-indole 6c. According to general procedure 2, scale: 2-
iodo-1-benzenesulfonyl-1H-indole (0.766 g, 2.00 mmol),
PdCl2(PPh3)2 (0.028 g, 0.04 mmol), THF (12 mL), CuI (0.015 g,
0.08 mmol), triethylamine (0.36 mL, 2.6 mmol), trimethox-
yphenylacetylene 8 (0.461 g, 2.40 mmol), reaction time at room
temperature: 23 h. The crude product was then purified by silica gel
column chromatography (cyclohexane/ethyl acetate, 80:20) to af-
ford compound 6c (0.604 g, 67%) as an off-white solid; mp
121e123 ꢁC. IR: nmax (film, cmꢀ1) 2939, 1738, 1576, 1499, 1448, 1411,
1367, 1354, 1289, 1229, 1181, 1150, 1123, 1091, 1050, 995, 836, 819,
Less polar fraction: compound 6f; mp 105e106 ꢁC. IR: nmax (film,
cmꢀ1) 2993, 2928, 2843, 1728, 1599, 1573, 1499, 1448, 1407,
1344, 1299, 1233, 1223, 1154, 1131, 1098, 1069, 1026, 995, 943,
855, 824, 794, 777, 698, 624, 537. 1H NMR (400 MHz, CDCl3):
757, 731, 686, 631, 583, 566, 550. 1H NMR (300 MHz, CDCl3):
d¼3.73
d
¼3.86 (s, 3H), 3.88 (s, 9H), 6.79 (s, 2H), 7.02 (dd, J¼6.6e1.8 Hz, 1H),
(s, 3H), 3.85 (s, 6H), 6.89 (s, 2H), 7.24 (d, J¼0.6 Hz, 1H), 7.31e7.36 (m,
1H), 7.44e7.50 (m, 1H), 7.59e7.65 (m, 3H), 7.69e7.75 (m, 1H), 7.93
(d, J¼1.5 Hz, 1H), 7.95 (d, J¼1.5 Hz, 1H), 8.14e8.17 (m, 1H). 13C NMR
7.20 (d, J¼1.8 Hz, 1H), 7.41 (s, 1H), 7.63 (d, J¼6.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3):
d¼55.5 (CH3), 56.1 (CH3), 61.0 (CH3), 82.2 (C),
94.8 (C), 105.5 (CH), 108.7 (CH), 115.9 (CH), 117.5 (C), 122.6 (CH),
124.2 (C), 128.3 (CH), 132.6 (C), 139.2 (C), 140.1 (C), 153.1 (C), 157.8
(C). HRMS (ESIþ): m/z calcd for C20H19O4S [MHþ]: 355.0999; found:
355.0981.
(100 MHz, CDCl3):
d
¼56.1 (CH3), 56.2 (CH3), 61.0 (CH3), 79.7 (C),
96.9 (C), 108.6 (CH), 109.6 (CH), 114.6 (CH), 116.8 (CH), 117.4 (C),
120.9 (C), 121.0 (CH), 124.0 (CH), 126.0 (CH), 126.9 (CH), 129.0 (C),
129.1 (CH), 133.9 (CH), 136.5 (C), 138.6 (C), 139.4 (C), 153.1 (C), 153.2
(C). HRMS (ESIþ): m/z calcd for C25H21NO5SNa [MNaþ]: 470.1033;
found: 470.1012.
More polar fraction: 1,4-bis(3,4,5-trimethoxyphenyl)buta-1,3-
diyne; mp 199e201 ꢁC (lit.46 199e201 ꢁC). 1H NMR (300 MHz,
CDCl3):
d
¼3.86 (s, 12H), 3.87 (s, 6H), 6.76 (s, 4H). Spectral data were
in agreement to those reported in the literature.46
4.5.4. Preparation of 2-(3,4,5-trimethoxy-phenylethynyl)-1H-indole
6d. According to general procedure 2, scale: 2-iodo-1H-indole
(0.437 g, 1.80 mmol), PdCl2(PPh3)2 (0.028 g, 0.04 mmol), THF
(12 mL), CuI (0.015 g, 0.08 mmol), triethylamine (0.36 mL,
2.6 mmol), trimethoxyphenylacetylene 8 (0.461 g, 2.40 mmol),
reaction time at room temperature: 5 h. The reaction mixture was
filtered; the solid was washed with diethyl ether (2ꢂ10 mL). The
combined organic layers were concentrated in vacuo. The crude
brown oil was purified by silica gel flash column chromatography
(cyclohexane/ethyl acetate, 70:30) to afford 6d (0.216 g, 39%) as
a pale orange solid; mp 175e177 ꢁC. IR: nmax (film, cmꢀ1) 3328,
2933, 1736, 1575, 1498, 1458, 1430, 1409, 1362, 1344, 1327, 1234,
1184, 1169, 1128, 1004, 992, 938, 841, 828, 801, 790, 769, 749, 739,
732, 655, 626, 610, 574, 555, 526. 1H NMR (400 MHz, DMSO):
4.5.7. 5-Nitro-2-(3,4,5-trimethoxy-phenylethynyl)-benzo[b]thio-
phene 6g. According to general procedure 2, scale: 5-nitro-2-
bromobenzo[b]thiophene (0.152 g, 0.41 mmol), PdCl2(PPh3)2
(0.006 g, 0.008 mmol), THF (2.5 mL), CuI (0.003 g, 0.016 mmol),
triethylamine (0.074 mL, 0.53 mmol), trimethoxyphenylacetylene 8
(0.095 g, 0.49 mmol), reaction time at room temperature: 23 h. The
crude product was purified by silica gel flash column chromatog-
raphy (cyclohexane/ethyl acetate, 85:15) to afford compound 6g
(0.099 g, 66%) as a pale orange solid; mp 164e166 ꢁC. IR: nmax (film,
cmꢀ1) 2928, 2200, 1731, 1576, 1510, 1468, 1435, 1412, 1343, 1246,
1177, 1124, 1098, 1062, 1038, 995, 946, 889, 839, 825, 806, 775, 736,
691, 626, 578, 527, 499. 1H NMR (300 MHz, CDCl3):
d
¼3.89 (s, 3H),
3.90 (s, 6H), 6.80 (s, 2H), 7.60 (s, 1H), 7.89 (d, J¼9 Hz, 1H), 8.22 (dd,
d
¼3.71 (s, 3H), 3.82 (s, 6H), 6.80 (d, J¼2 Hz, 1H), 6.88 (s, 2H), 7.04
J¼9e2.4 Hz, 1H), 8.64 (d, J¼2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
(1H, t, J¼7.6, Hz), 7.17 (t, J¼7.6 Hz, 1H), 7.34 (d, J¼8.4 Hz, 1H), 7.54 (d,
d
¼56.2 (CH3), 60.1 (CH3), 80.8 (C), 97.4 (C), 108.9 (CH), 116.7 (C),
J¼8 Hz, 1H), 11.68 (br s, 1H). 13C NMR (100 MHz, DMSO):
d¼56.0
119.1 (CH), 119.5 (CH), 122.5 (CH), 127.1 (C), 128.5 (CH), 138.9 (C),

T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
2345
139.7 (C), 145.7 (C), 145.8 (C), 153.2 (C). HRMS (ESIþ): m/z calcd for
then purified by column chromatography (cyclohexane/ethyl ace-
tate, 90:10) to afford compound 12b (0.404 g, 92%, ratio 18:82)
C19H16NO5S [MHþ]: 370.0744; found: 370.0737.
a/b
as a light yellow solid. Only the major product will be described. IR:
nmax (film, cmꢀ1) 2919, 2908, 2871, 1572, 1501, 1454, 1431, 1327,
1234, 1184, 1151, 1119, 1066, 1038, 1001, 977, 958, 915, 886, 826, 783,
743, 734, 725, 717, 698, 635, 594, 515. 1H NMR (300 MHz, CDCl3):
4.6. Preparation of compounds 1 by using hydrosilylation/
deprotection sequence
4.6.1. General procedure 3 for the synthesis of vinylsilane derivatives:
preparation of [2-benzofuran-2-yl-1-(3,4,5-trimethoxy-phenyl)-vi-
nyl]-triethylsilane 12a. In a 3 mL tube, PtO2 (0.011 g, 0.05 mmol)
and 2-((3,4,5-trimethoxyphenyl)ethynyl)benzofuran 6a (0.299 g,
0.97 mmol) were placed under argon atmosphere. Triethylsilane
(0.47 mL, 2.92 mmol) was slowly introduced, the tube was sealed
and the mixture was stirred at 60 ꢁC in an oil bath for 23 h. After
removal of the volatiles under reduced pressure, the crude product
was purified by column chromatography (cyclohexane/ethyl ace-
tate, 90:10) to afford compound 12a (0.392 g, 95%), which is an
d
¼0.74 (q, J¼8.4 Hz, 6H), 1.01 (t, J¼7.8 Hz, 9H), 3.42 (s, 6H), 3.76 (s,
3H), 6.42 (s, 2H), 6.80 (s, 1H), 6.90 (s, 1H), 7.18e7.24 (m, 1H),
7.27e7.32 (m, 1H), 7.67 (d, J¼7.5 Hz, 1H), 7.75 (d, J¼7.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3):
d¼2.6 (CH2), 7.4 (CH3), 55.4 (CH3), 60.8
(CH3), 106.7 (CH), 119.7 (CH), 122.0 (CH), 122.7 (CH), 123.4 (CH),
124.1 (CH), 135.5 (C), 137.6 (C), 140.0 (C), 140.7 (C), 142.5 (CH), 145.2
(C), 152.5 (C), 153.7 (C). HRMS (ESIþ): m/z calcd for C25H33O3SSi
[MHþ]: 441.1914; found: 441.1923.
4.6.4. Preparation of 2-[2-triethylsilanyl-2-(3,4,5-trimethoxy-phe-
nyl)-vinyl]-1H-indole 12d. According to general procedure 3,
scale: 2-((3,4,5-trimethoxyphenyl)ethynyl)-1H-indole 6d (0.079 g,
0.26 mmol), PtO2 (0.003 g, 0.013 mmol), Et3SiH (0.125 mL,
0.78 mmol), reaction time at 60 ꢁC¼4 h. The residue was purified by
column chromatography (cyclohexane/ethyl acetate, 85:15) to af-
inseparable mixture of
yellow solid.
a and b isomers (a/b ratio 79:21), as a light
Only the major product will be described. IR: nmax (film, cmꢀ1
)
2951, 2932, 2873, 1738, 1580, 1503, 1450, 1414, 1329, 1234, 1163,
1125, 1104, 1002, 958, 950, 911, 898, 826, 792, 750, 736, 719, 708,
678, 662, 649, 591, 528. 1H NMR (400 MHz, CDCl3):
d¼0.77 (q,
ford a- or b-(Z)-2-(triethylsilanyl-2-(3,4,5-trimethoxyphenyl)vi-
J¼8 Hz, 6H), 1.00 (t, J¼7.8 Hz, 9H), 3.47 (s, 6H), 3.79 (s, 3H), 6.33 (s,
nyl)-1H-indole 12d as a light yellow solid (0.086 g, 78%); IR: nmax
(film, cmꢀ1) 3360, 2922, 2871, 2851, 1737, 1581, 1505, 1454, 1412,
1331, 1321, 1279, 1247, 1233, 1187, 1128, 1006, 974, 960, 926, 908,
896, 823, 780, 725, 696, 680, 647, 610, 574. 1H NMR (300 MHz,
2H), 6.43 (s, 1H), 6.89 (s, 1H), 7.18e7.21 (m, 2H), 7.40e7.43 (m, 1H),
7.48e7.50 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
¼3.0 (CH2), 7.3
(CH3), 55.5 (CH3), 60.8 (CH3), 103.0 (CH), 106.1 (CH), 110.9 (CH),
120.3 (CH), 122.6 (CH), 123.4 (CH), 129.2 (C), 130.5 (C), 132.4 (C),
137.9 (C),144.2 (CH),152.7 (C),154.3 (C),156.7 (C). HRMS (ESIþ): m/z
calcd for C25H33O4Si [MHþ]: 425.2143; found: 425.2141.
CDCl3):
d
¼0.75 (q, J¼6.2 Hz, 6H), 1.00 (t, J¼7.8 Hz, 9H), 3.37 (s, 6H),
3.77 (s, 3H), 6.19 (s, 2H), 6.32e6.33 (m, 1H), 6.80 (s, 1H), 7.02e7.12
(m, 2H), 7.21e7.24 (m, 1H), 7.53e7.56 (m, 1H), 7.68 (br s, 1H). 13C
NMR (100 MHz, CDCl3):
d
¼5.8 (CH2), 6.6 (CH3), 55.5 (CH3), 60.8
4.6.2. Preparation of [2-benzofuran-2-yl-1-(3,4,5-trimethoxy-phe-
nyl)-vinyl]-ethoxydimethylsilane 12a0. According to general pro-
cedure 3, scale: 2-((3,4,5-trimethoxyphenyl)ethynyl)benzofuran 6a
(0.299 g, 0.97 mmol), PtO2 (0.011 g, 0.05 mmol), Me2EtOSiH
(0.40 mL, 2.92 mmol), reaction time at 60 ꢁC: 23 h. The crude
product was then purified by column chromatography (cyclohex-
(CH3), 100.1 (CH),106.2 (CH),110.5 (CH), 119.7 (CH),119.8 (CH),121.3
(CH), 129.3 (C), 132.3 (C), 133.5 (C), 135.8 (C), 137.6 (C), 141.9 (CH),
152.7 (2C). HRMS (ESIþ): m/z calcd for C25H34NO3Si [MHþ]:
424.2302; found: 424.2287.
4.6.5. General procedure 4 for the hydrolysis of vinylsilane de-
rivatives: preparation of 2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-ben-
zofuran 1a. To a TBAF 1 M solution in THF (0.55 mL, 0.55 mmol) was
added compound 12a (0.213 g, 0.5 mmol). The resulting mixture
was stirred at 60 ꢁC for 1 h. After concentration in vacuo, the crude
product containing 62% (Z) and 38% (E) isomer was purified by
column chromatography (cyclohexane/ethyl acetate, 80:20) to ob-
tain the Z/E mixture of 1a (0.132 g, 84%) (both stereoisomers were
collected in a single fraction) as a yellow viscous oil.
ane/ethyl acetate, 85:15) to afford compound 12a0 (0.288 g, 72%,
a/b
ratio 54:46) as a yellow oil. In NMR analysis, determination of peaks
corresponding to each regioisomer relied on peak intensity (major
product: Ar-1 and minor product: Ar-2).
IR: nmax (film, cmꢀ1) 2969, 2937, 1581, 1505, 1464, 1452, 1417,
1330, 1254, 1184, 1169, 1127, 1105, 1078, 1009, 950, 903, 873, 821,
786, 751, 742, 646, 612. 1H NMR (400 MHz, CDCl3):
d
¼0.146 (s, 6H,
Ar-2), 0.28 (s, 6H, Ar-1), 1.06 (t, J¼6.8 Hz, 3H, Ar-2), 1.16 (t, J¼7.2 Hz,
1H, Ar-1), 3.44 (s, 6H, Ar-1), 3.53e3.58 (m, 2H, Ar-2), 3.68e3.74 (m,
5H, Ar-1), 3.80 (s, 3H, Ar-2), 3.81 (s, 6H, Ar-2), 6.25 (s, 1H, Ar-2), 6.33
(s, 2H, Ar-1), 6.49 (s, 1H, Ar-1), 6.63 (s, 2H, Ar-2), 6.75 (s, 1H, Ar-2),
6.96 (s, 1H, Ar-1), 7.08e7.19 (m, 4H, Ar-1 and Ar-2), 7.30e7.31 (m,
1H, Ar-1), 7.36 (d, J¼6 Hz, 1H, Ar-2), 7.40e7.42 (m, 1H, Ar-1),
7.45e7.47 (m, 1H, Ar-2).
4.6.6. Preparation of 2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-benzo[b]
thiophene 1b. According to general procedure 4, scale: TBAF 1 M
solution in THF (0.84 mL, 0.84 mmol), compound 12b (0.334 g,
0.76 mmol), reaction time at 60 ꢁC¼2.5 h. The crude product was
then purified by flash chromatography (cyclohexane/ethyl acetate,
80:20) to give (Z)-2-(3,4,5-trimethoxystyryl)benzo[b]thiophene
1b (0.058 g, 23%) as a light yellow oil and (E)-2-(3,4,5-
trimethoxystyryl)benzo[b]thiophene 1b (0.175 g, 71%) as a light
yellow solid.
Major product: 13C NMR (100 MHz, CDCl3):
d
¼ꢀ1.9 (CH3), 18.4
(CH3), 55.6 (CH3), 58.8 (CH2), 60.8 (CH3), 104.2 (CH), 106.3 (CH),
110.9 (CH), 120.4 (CH), 122.7 (CH), 123.7 (CH), 129.1 (C), 130.6 (C),
132.3 (C), 138.1 (C), 143.7 (CH), 152.7 (C), 153.7 (C), 154.3 (C).
Minor product: 13C NMR (100 MHz, CDCl3):
d¼0.3 (CH3), 18.2
(CH3), 56.1 (CH3), 58.5 (CH2), 61.0 (CH3), 103.9 (CH), 106.3 (CH),
110.7 (CH), 120.6 (CH), 122.6 (CH), 124.0 (CH), 129.3 (C), 130.6 (C),
134.1 (C), 138.0 (C), 145.8 (CH), 152.7 (C), 154.2 (C), 155.6 (C).
HRMS (ESIþ): C21H24O5Si: m/z calcd for C21H25O5Si [(MꢀEt)Hþ]:
385.1466; found: 385.1445.
4.6.7. Preparation of (Z)-2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-1H-
indole 1d. According to general procedure 4, scale: TBAF 1 M solu-
tion in THF (0.19 mL, 0.19 mmol), (Z)-2-(triethylsilyl-2-(3,4,5-
trimethoxyphenyl)vinyl)-1H-indole 12d (0.074 g, 0.18 mmol),
reaction time at 60 ꢁC¼2.5 h. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 80:20) to af-
ford (Z)-2-(2-(3,4,5-trimethoxyphenyl)vinyl)-1H-indole 1d (0.043 g,
80%) as a light yellow solid.
4.6.3. Preparation of [2-benzo[b]thiophen-2-yl-1-(3,4,5-trimethoxy-
phenyl)-vinyl]-triethylsilane 12b. According to general procedure 3,
scale: 2-((3,4,5-trimethoxyphenyl)ethynyl)benzo[b]thiophene 6b
(0.324 g, 1.00 mmol), PtO2 (0.011 g, 0.05 mmol), Et3SiH (0.48 mL,
3.00 mmol), reaction time at 60 ꢁC¼5.5 h. The crude product was
Stereoisomer (Z). Mp 97e99 ꢁC. IR: nmax (film, cmꢀ1) 3333, 2933,
1738, 1583, 1501, 1443, 1428, 1396, 1330, 1294, 1231, 1177, 1126, 992,
958, 854, 801, 782, 764, 748, 692, 618, 601, 576, 528, 596. 1H NMR

2346
T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
(400 MHz, DMSO):
d
¼3.65 (s, 6H), 3.69 (s, 3H), 6.48 (d, J¼1.2 Hz,
NMR (300 MHz, CDCl3):
d
¼3.79 (s, 6H), 3.84 (s, 3H), 3.90 (s, 3H),
1H), 6.52 (d, J¼12.8 Hz, 1H), 6.55 (d, J¼12.4 Hz, 1H) (coalescence of
these last two peaks), 6.79 (s, 2H), 6.93 (t, J¼7.4 Hz, 1H), 7.04 (t,
J¼7.4 Hz, 1H), 7.31 (d, J¼8 Hz, 1H), 7.44 (d, J¼8 Hz, 1H), 10.97 (s, br,
6.63 (d, J¼12.0 Hz,1H), 6.64 (s, 2H), 6.73 (d, J¼12.0 Hz,1H), 6.91 (dd,
J¼8.7e2.4 Hz, 1H), 7.11 (d, J¼2.4 Hz, 1H), 7.17 (s, 1H), 7.53 (d,
J¼8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3):
¼55.5 (CH3), 56.0 (CH3),
d
1H). 13C NMR (100 MHz, DMSO):
d¼55.6 (CH3), 60.0 (CH3), 101.6
61.0 (CH3), 150.2 (CH), 105.9 (CH), 114.9 (CH), 122.7 (CH), 123.7 (CH),
125.1 (CH), 130.8 (CH), 132.0 (C), 132.5 (C), 137.7 (C), 139.9 (C), 141.0
(C), 153.2 (C), 157.4 (C). HRMS (ESIþ): m/z calcd for C20H21O4S
[MHþ]: 357; 1155; found: 357.1143.
(CH), 105.7 (CH), 111.0 (CH), 119.1 (CH), 119.8 (CH), 119.9 (CH), 121.5
(CH), 127.9 (C), 129.6 (CH), 132.2 (C), 134.2 (C), 135.9 (C), 137.0 (C),
152.6 (C). HRMS (ESIþ): m/z calcd for C19H20NO3 [MHþ]: 310.1438;
found: 310.1427.
4.7.4. Palladium acetate/DMF/KOH semi-hydrogenation of diary-
lacetylene derivatives 6b: kinetic studies. In a Schlenk tube were in-
troduced 2-((3,4,5-trimethoxyphenyl)ethynyl)benzo[b]thiophene 6b
(0.324 g, 1.0 mmol), KOH (0.84 g, 1.5 mmol) and Pd(OAc)2 (0.0045 g,
0.02 mmol). The Schlenk tube was put under high vacuum for 2 min
and then filled with argon. After four cycles of vacuum/argon, the
tube was put under argon and DMF (2.5 mL) was added. The
4.6.7.1. Alternative method by basic deprotection of the Boc-
protected derivative 1c. A solution of (Z)-1-(tert-butoxycarbonyl)-
2-(3,4,5-trimethoxystyryl)-1H-indole (0.065 g, 0.16 mmol) and
K2CO3 (0.066 g, 0.48 mmol) in MeOH (1.5 mL) and water (0.5 mL)
was stirred at room temperature for 22 h then at 60 ꢁC for 24 h. The
solvent was evaporated. The residue was quenched with water and
extracted with ethyl acetate. The organic phases were combined
and washed with brine, dried over Na2SO4, filtered and concen-
trated under reduced pressure. The crude product was purified by
column chromatography over silica gel (cyclohexane/ethyl acetate,
resulting mixture was heated at 145 ꢁC and 50
mL aliquots of the
reaction mixture were taken at different heating time: 5 min, 15 min,
30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h and 6 h.
In a test tube, to 25
saturated solution (25
Na2SO4. The resulting mixture was then submitted to a vortex
stirrer for 30 s. After filtration through a 0.2 M PTFE syringe filter,
200 L of water was added to 300 L of the filtrate. To 50 L of this
solution was then added 50 L of resveratrol trimethyl ether so-
lution (1 mg/mL) in water/acetonitrile, 40/60 v/v. 0.1 L of this final
mL of the aliquot were added NH4Cl aqueous
ꢀ
80:20) to afford (Z)-2-(2-(3,4,5-trimethoxyphenyl)vinyl)-1H-indole
m
L), acetonitrile (750 L) and 0.30 g of
m
(0.014 g, 28%) as a light yellow solid. 1H NMR spectrum was iden-
tical to the one described above.
m
m
m
m
4.7. Preparation of compounds 1 after semi-hydrogenation
reaction
m
m
sample was then injected in an uHPLC/MS system, with isocratic
elution (solvent mixture: water/acetonitrile 40/60 v/v, HCOOH 0.1%
v/v) at 40 ꢁC, flow rate 0.5 mL/min, Single Ion Monitoring detection
at m/z¼271.1, 327.1 and 325.1 (MHþ ions of the internal standard,
(Z/E) products 1b and starting material 6b, respectively). Retention
times: resveratrol trimethyl ether 1.74 min, (Z)-1b 2.10 min, (E)-1b
2.49 min and 6b 3.06 min.
4.7.1. General procedure 5 for the semi-hydrogenation of diary-
lacetylene derivatives 6 using palladium acetate/DMF/KOH system:
preparation of compound 1a. In a reactor flushed with argon was
introduced 2-((3,4,5-trimethoxyphenyl)ethynyl)benzofuran 6a
(0.308 g, 1 mmol), KOH (0.084 mg, 1.5 mmol), Pd(OAc)2 (0.0045 mg,
0.02 mmol) and then DMF (2.5 mL). The tube was sealed and heated
at 145 ꢁC under stirring for 6 h, then cooled to room temperature
and quenched with 10 mL of water. The mixture was extracted with
EtOAc (3ꢂ30 mL). The combined organic layer was dried over
Na2SO4 and evaporated under reduced pressure. The crude product
containing 93% of (Z)- and 7% of (E)-2-(2-(3,4,5-trimethoxyphenyl)
vinyl)benzofuran 1a was purified by column chromatography (cy-
clohexane/ethyl acetate, 80:20) to give (Z) isomer as a yellow oil
(0.180 g, 58%) and a mixture of (Z) and (E) isomer (0.106 g, 34%). This
second fraction was further purified by flash chromatography to
give stereopure (Z)-1a (0.025 g, 8%) and a mixture (0.074 g, 24%) of
Z/E isomers.
Acknowledgements
ꢂ
T.T.B.N. would like to thank the Ministere de l’Enseignement
ꢀ
Superieur et de la Recherche for a PhD fellowship. N.C.T. thanks the
ˇ
ꢀ
Region Rhone Alpes for a MIRA fellowship. The authors thank Miss
ꢀ
Chloe Midena for the preparation of a ‘significant amount’ of
compound 6b. The Institut des Sciences Pharmaceutiques et Bio-
logiques (ISPB) of Lyon is also gratefully acknowledged (special
thanks to Pr Franc¸ ois Locher) for the funding of an uHPLC/DAD/MS
system.
4.7.2. Preparation of compound 1b. According to general procedure
5, scale: 2-((3,4,5-trimethoxyphenyl)ethynyl)benzo[b]thiophene
6b (0.162 g, 0.5 mmol), KOH (0.042 g, 0.75 mmol), Pd(OAc)2
(0.002 g, 0.01 mmol), DMF (1.25 mL), reaction time at 145 ꢁC¼6 h.
The crude product (Z/E¼91/9) was purified by column chroma-
tography on silica gel deactivated by Et3N (cyclohexane/ethyl ace-
tate, 90:10) to give (Z)-2-(2-(3,4,5-trimethoxyphenyl)vinyl)benzo
[b]thiophene 1b (0.103 g, 63%) as a yellow oil and a mixture of Z and
E isomer (0.018 g, 11%).
References and notes
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thiophene 6f (0.044 g, 0.124 mmol), KOH (0.011 g, 0.187 mmol),
Pd(OAc)2 (0.0006 g, 0.0025 mmol), DMF (0.2 mL), reaction time at
145 ꢁC¼6 h. The crude product (Z/E¼100/0) was purified by column
chromatography on silica gel deactivated by Et3N (cyclohexane/
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phenyl)-vinyl]-benzo[b]thiophene 1f (0.018 g, 40%) as a very vis-
cous yellow oil. IR: nmax (film, cmꢀ1) 2997, 2934, 2832, 1726, 1597,
1577, 1501, 1452, 1411, 1384, 1327, 1300, 1235, 1214, 1182, 1160, 1123,
1070,1025, 1005, 965, 946, 854, 805, 772, 718, 690, 621, 548, 460. 1H
5. Two water-soluble cis trimethoxystyrenes derived from CA-4 currently
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9. For an example concerning the application of Wittig reaction for the prepa-
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eoselectivity of the Wittig reaction using cooperative ortho-effects has also
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2006, 2977e2980.

T.T.B. Nguyen et al. / Tetrahedron 69 (2013) 2336e2347
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~
~
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€
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8 and 2-iodo-thiophene:
Hadfield, J. A.; McGown, A. T. Synth. Commun. 1998, 28, 1421e1431.
€
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d
¼3.
49, 1107e1110.
88 (s, 3H), 3.92 (s, 6H), 6.62 (s, 1H), 6.73 (s, 2H), 6.84 (d, J¼16.8 Hz, 1H), 7.03 (d,
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starting material 1c), according to this protocol: Chakrabarty, M.; Kundu, T.;
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2 h.
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€