Synthesis of 2-(1-phenylvinyl)benzofurans and 2-(1-phenylvinyl)indoles as antimitotic agents by a tandem palladium-assisted coupling-cyclization reaction between 1-phenylvinyl iodides and ortho-substituted arylalkynes

Article abstract of DOI:10.1002/ejoc.201100540

A series of functionalized 2-(1-phenylvinyl)benzofurans 2 and 2-(1-phenylvinyl)indoles 3 were prepared from 1-phenylvinyl iodides and silylated alkynes in a one-pot reaction. After a desilylation step, the Sonogashira coupling reaction between the resulti

Full text of DOI:10.1002/ejoc.201100540

FULL PAPER
DOI: 10.1002/ejoc.201100540
Synthesis of 2-(1-Phenylvinyl)benzofurans and 2-(1-Phenylvinyl)indoles as
Antimitotic Agents by a Tandem Palladium-Assisted Coupling-Cyclization
Reaction between 1-Phenylvinyl Iodides and ortho-Substituted Arylalkynes
Bret Tréguier,[a] Evelia Rasolofonjatovo,[a] Abdallah Hamze,*[a] Olivier Provot,[a]
Joanna Wdzieczak-Bakala,[b] Joëlle Dubois,[b] Jean-Daniel Brion,[a] and Mouad Alami*[a]
Keywords: Styrenes / Benzofurans / Indoles / Cyclization / Tandem reaction / Antimitotic agents / Multicomponent
reactions / Synthesis design
A series of functionalized 2-(1-phenylvinyl)benzofurans 2
and 2-(1-phenylvinyl)indoles 3 were prepared from 1-phen-
ylvinyl iodides and silylated alkynes in a one-pot reaction.
After a desilylation step, the Sonogashira coupling reaction
between the resulting terminal alkynes and 1-phenylvinyl
iodide derivatives 6 gave enyne intermediates, which under-
went a 5-endo-dig cyclization to afford 2-(1-phenylvinyl) het-
erocycles 2 and 3 in good yields. This method provides a ra-
pid and efficient approach to build up benzoheterocycle-
based isocombretastatin A-4 analogues of biological interest.
From this series of compounds, the indoles 3o and 3r in-
hibited tubulin assembly at a micromolar level comparable
to that of isoCA-4.
Introduction
The development of anticancer agents that target the col-
chicine binding site has been an area of major interest over
recent decades. Among a large number of antimitotic com-
pounds, combretastatin A-4 (CA-4), a stilbene isolated by
Pettit from an African tree, Combretum caffrum, is arguably
the most studied molecule due to its structural simplicity
(Scheme 1).[1] CA-4 is highly cytotoxic against a variety of
human cancer cells including those that express multidrug
resistant phenotypes.[2] Moreover, it has been demonstrated
that the water-soluble phosphate prodrug CA-4P and AVE-
8062, a serinamido derivative, are currently in clinical trials
(phase III) for the treatment of anaplastic thyroid and ad-
vanced cancers.[3] In addition, these compounds exert selec-
tive effects in proliferating endothelial cells, and as a conse-
quence, demonstrate strong suppressive activity on tumor
blood flow, leading to tumor necrosis.[4]
Our interest in 1,1-diarylethylene unit synthesis[5] com-
bined with our efforts to discover new tubulin assembly in-
hibitors,[6] led us to identify isocombretastatin A-4 (isoCA-
4),[7] a synthetic CA-4 isomer, which could be regarded as
a phenstatin[8] analogue (Scheme 1); isoCA-4 was found to
be more potent than phenstatin,[7] displaying cytotoxic and
Scheme 1. Structure of CA-4 and its water-soluble prodrugs CA-
4P, AVE-8062, and isoCA-4, some bioactive derivatives isoFCA-4,
isoNH2CA-4, and 2-aroylindoles 1, and target structures 2 and 3.
antitubulin activities comparable to that of CA-4. We dem-
onstrated that the bioisosteric replacement of the 1,2-ethyl-
ene bridge by 1,1-ethylene resulted in highly bioactive and
nonisomerizable compounds.[7] By varying the isoCA-4 B-
ring, we have also identified isoNH2CA-4 and isoFCA-4,
two potent antimitotic agents with strong antiproliferative
activities.[9] In this article, we further investigate 1,1-diaryl-
[a] Laboratoire de Chimie Thérapeutique, Université Paris-Sud 11,
CNRS, BioCIS-UMR 8076, Faculté de Pharmacie,
5 Rue J.-B. Clément, 92296 Châtenay-Malabry, France
Fax: +33-1-46835828
E-mail: abdallah.hamze@u-psud.fr
mouad.alami@u-psud.fr
[b] Institut de Chimie des Substances Naturelles, UPR 2301,
CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
4868
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4868–4876

Synthesis of 2-(1-Phenylvinyl)benzofurans and -indoles
ethylenes by extending our earlier studies to benzohetero- planned to define optimal conditions for C–Si bond cleav-
cycle-based isoCA-4. We describe the effects of replacing age of 4 to generate the corresponding terminal alkyne,
the isoCA-4 B-ring with benzofuran and indole. The target which could undergo a further C–C coupling with 2-iodo-
molecules, represented by general structures 2 and 3 phenol 5a and then cyclization. All of our attempts to desi-
(Scheme 1), could be seen as 2-aroylindole 1[10] analogues, lylate 4 under classical conditions [tetra-n-butylammonium
in which the carbonyl group of 1 is replaced by an ethylene fluoride (TBAF)/THF or K2CO3/MeOH at 0 °C] gave very
moiety.
low yields of the pure terminal enyne (Ͻ10%) due to its
Herein, we report rapid access to 2-(1-phenylvinyl)benzo- instability at room temperature. Therefore, to obviate ma-
furans 2 and 2-(1-phenylvinyl)indoles 3 using a convergent nipulation of the sensitive terminal enyne we decided to
synthetic strategy. These compounds were evaluated in vitro achieve the desilylation step, the Sonogashira coupling, and
to assess their tubulin assembly and growth inhibitory ac- the 5-endo-dig cyclization in a one-pot process. To this end,
tivity.
after extensive screening of various reaction parameters
(base, palladium catalyst, solvent, temperature, etc.), opti-
mal conditions for the reaction of silylated enyne 4 with
5a required the use of K2CO3 (8 equiv.), MeOH (8 equiv.),
Pd(PPh3)4 (10 mol-%), and CuI (20 mol-%) in DMF. With
this protocol, the desired benzofuran 2a was obtained, how-
ever, in a low overall yield of 13%. Difficulties in obtaining
2a in good yield led us to explore an alternative route
(Path b, Scheme 2). Thus, the coupling of 1-phenylvinyl
iodide 6a with silylated alkyne 7a was first examined in the
presence of Pd(PPh3)4 as the catalyst and K2CO3 as the
base,[14] useful for the two sequential steps (desilylation and
Sonogashira coupling); some results of this study are re-
ported in Table 1. After testing a variety of solvents (En-
tries 1–4), the use of DMF gave the desired 2a in a satisfac-
tory 40% overall yield (Entry 4). Next, the effect of base
and additives for the C–Si bond cleavage was examined.
Unfortunately, the reaction did not proceed when K2CO3/
MeOH was replaced by TBAF or AgOTf[15] (Entries 5 and
6). On the contrary, employing DBU/H2O[16] proved to be
an efficient choice. We were pleased to find that the system
containing 6a/7a in a 1:1.6 ratio in the presence of 5 mol-%
Pd(PPh3)4, 10 mol-% CuI, DBU (12 equiv.), and H2O
Results and Discussion
Although syntheses of 2-substituted benzofurans[11] and
indoles[12] are well documented, only a few reports deal
with the preparation of 2-(1-phenylvinyl)benzofurans 2[11a]
and indoles 3.[12b–12d] To access our target molecules 2 and
3, we envisioned a strategy based on a sequential C–Si bond
cleavage of silylated alkynes[13] followed by a Pd-catalyzed
Sonogashira coupling and subsequent 5-endo-dig cycliza-
tion of the intermediate enyne I. These can be obtained
according to two synthetic routes (Paths a and b,
Scheme 2).
We anticipated that the palladium and copper catalysts
used in the Sonogashira coupling could assist the subse-
quent cyclization of I affording 2 and 3 in a one-pot
process. To the best of our knowledge, there is no report
describing the formation of such 2-(1-phenylvinyl) hetero-
cycles using this strategy.
At the outset of this work, we studied the synthesis of 2-
(1-phenylvinyl)benzofuran 2a according to Path a. First, we
Scheme 2. Synthetic strategies to 2-(1-phenylvinyl)benzofurans 2 and 2-(1-phenylvinyl)indoles 3 by Pd-assisted cyclization of enyne inter-
mediates I.
Eur. J. Org. Chem. 2011, 4868–4876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4869

A. Hamze, M. Alami, et al.
FULL PAPER
(0.8 equiv.) in DMF at room temperature was the optimum Table 2. Synthesis of 2-(1-phenylvinyl)benzofurans 2.[a]
to obtain 2a in an excellent 78% overall yield for the three
steps (Entry 8). Finally, examination of other catalytic sys-
tems [e.g. Pd2(dba)3/PPh3, PdCl2(MeCN)2/XPhos, etc.] was
not effective (data not shown).
Table 1. Optimization of reaction parameters for the synthesis of
2-(1-phenylvinyl)benzofuran 2a.
Entry
6a/7a
[equiv.]
Pd/CuI[a]
Base/additive
([equiv.])
Solvent Yield
[%][b]
1
2
3
4
5
6
7
8
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.6
Pd(PPh3)4 K2CO3/MeOH
(8:8)
Pd(PPh3)4 K2CO3/MeOH toluene
(8:8)
THF
0
0
Pd(PPh3)4 K2CO3/MeOH
DMA
DMF
DMF
DMF
DMF
DMF
0
(8:8)
Pd(PPh3)4 K2CO3/MeOH
(8:8)
40[c]
0
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
AgOTf
(1)
TBAF
5
(2)
DBU/H2O
(12:0.8)
DBU/H2O
(12:0.8)
46
78[d]
[a] 5 mol-% Pd(PPh3)4 and 10 mol-% CuI are used in the various
experiments. [b] Isolated yield of 2a. [c] Performing the reaction at
40 °C gave a 30% yield. [d] Using DBU (Ͻ 12 equiv.) led to incom-
plete cyclization of intermediate I.
Once key reaction parameters had been established, we
decided to expand the scope of this process. As summarized
in Table 2, the present three-step sequence in a single pot
proceeded well with a variety of 1-phenylvinyl iodides 6 and
silylated alkynes 7 affording a variety of 2-(1-phenyl-
vinyl)benzofurans 2 in good yields (60–91%). Both elec-
tron-donating and electron-withdrawing groups such as
OMe, CO2Me, and CHO on the silylated arylalkynes 7 were
well tolerated (Entries 2–6). Variations with respect to the
1-phenylvinyl iodide partner 6 were examined next. To our
satisfaction, the reaction proceeded well with both 1-phen-
ylvinyl iodides, bearing electron-donating or electron-with-
drawing groups on the aromatic ring, affording benzofurans
2g–i in good yields (60–80%, Table 2, Entries 7–9).
[a] Compound 6 (1 equiv.) in DMF was mixed with 5 mol-%
Pd(PPh3)4, 10 mol-% CuI, DBU (12 equiv.), H2O (0.8 equiv.). After
stirring at room temperature for 5 min, alkyne 7 (1.6 equiv.) in
DMF was added. [b] Isolated yield of 3.
Encouraged by the results obtained with the benzofurans
2, we applied this protocol to the synthesis of various 2-
(1-phenylvinyl)indoles 3. Thus, when coupling 6a with o-
alkynylaniline derivatives 8, under our optimized reaction yield of the desired product 3e (43%, Entry 5), together
conditions, we found that the distribution of the products with indole 10e (35%). Finally, we were delighted to find
3, 9, and 10 was greatly affected by the substituent on the that with N-mesylanilide[18] 8f, the domino desilylation/cou-
aniline nitrogen atom. As summarized in Table 3, aniline 8a pling/cyclization process was effective providing 2-(1-phen-
gave no trace amount of the desired indole 3 even after a ylvinyl)indole 3f in a good yield of 73% (Entry 6). This re-
prolonged reaction time (16 h, Entry 1). N-Tosylanilide 8b sult clearly suggests that the methylsulfonyl group facilitates
and trifluoromethyl acetanilide[17] 8c gave enynes 9b and 9c, the cyclization step and would be useful in the cleavage step
respectively, along with unsubstituted indoles 10b and 10c to form free (NH)-indole derivatives.
(Entries 2 and 3). Acetamide 8d reacted with 6a to furnish
The scope of this one-pot reaction was then studied. As
the desired indole 3d, but only with an isolated yield of 8% seen from Table 4, a variety of o-(trimethylsilylethynyl)-N-
(Entry 4). The use of N-Boc carbamate 8e gave a promising mesylanilides 8f–k were treated with 1-phenylvinyl iodides
4870
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4868–4876

Synthesis of 2-(1-Phenylvinyl)benzofurans and -indoles
Table 3. Product distribution from the reaction of 6a with N-substituted anilines 8.[a]
Entry
Alkyne 8
Yield of 3
Yield of 9
Yield of 10
[%][b]
[%][b]
[%][b]
1
2
3
4
5
6
8a: R = H
8b: R = Ts
8c: R = COCF3
8d: R = Ac
8e: R = Boc
8f: R = Ms
0
n.d.
n.d.
8
43
73
n.d.[c]
40
32
n.d.
n.d.
0
n.d.
9
28
n.d.
35
10
[a] 6a (1 equiv.) in DMF was mixed with 5 mol-% Pd(PPh3)4, 10 mol-% CuI, DBU (12 equiv.), and H2O (0.8 equiv.). After stirring at
room temperature for 5 min, N-substituted aniline 8 (1.6 equiv.) in DMF was added. [b] Yield of isolated product. [c] Not determined.
Scheme 3. Cleavage of N-mesyl-2-(1-phenylvinyl)indoles 3f–i to give free (NH)-2-(1-phenylvinyl)indoles 3o–r.
6 in a single synthetic operation affording N-mesyl-2-(1- Biological Evaluation of the Inhibition of Tubulin
phenylvinyl)indoles 3 in good to excellent overall yields (55– Polymerization (ITP) and in vitro Cellular Growth
95%). Various substituents (e.g. OMe, F, Cl, Br, CF3) pres- Inhibitory Activity
ent on the aromatic group in both coupling partners were
tolerated well during the course of the reaction. Moreover,
Selected benzofurans 2a–f, N-mesylindole 3f, and free
this protocol proceeds equally efficiently with 1-phenyl- (NH)-indoles 3o–r were evaluated for their ITP capacity.
vinyl iodides 6d–g containing a carbon–fluorine, carbon– The newly synthesized compounds were compared in con-
chlorine, or carbon–bromine bond on the aromatic group temporaneous experiments to the potent tubulin polymeri-
(Entries 6–9). It is worth noting that a total selectivity was zation inhibtors isoCA-4 and CA-4.[24] As shown in Table 5,
observed with substrates 6d as well as 6g, and the remaining of the evaluated compounds, indoles 3o and 3r exhibit sim-
C–Br and C–Cl bonds in indoles 3n and 3m, respectively, ilar inhibition of tubulin assembly as isoCA-4 (IC50 = 3.3
could enjoy further metal-catalyzed functionalization pro- and 3.5 μm, respectively). In terms of structure–activity re-
cesses.[5c,19]
lationship (SAR) information, a lower inhibition of tubulin
Next, N-mesyl-2-(1-phenylvinyl)indoles 3f–i having a assembly was found for the derivative 3f containing an N-
3,4,5-trimethoxyphenyl unit in their structure were sub- mesyl group instead of the NH moiety (compound 3o).
jected to deprotection before being biologically evaluated. Substituting the indole structure with a methoxy group in
Among several methods tried to achieve this goal (K2CO3/ the C-5 or C-6 position yielded (NH)-indoles 3p and 3q,
MeOH/THF,[20] TBAF/THF,[21] NaOH/dioxane/MeOH,[22] respectively, which were found to be less potent as tubulin
KOH/MeOH[23]), the use of KOH in methanol in a sealed inhibitors than 3o with no substituent on the indole group.
tube at 80 °C, gave the best results. As summarized in Interestingly, the replacement of the 5-OMe substituent (3p)
Scheme 3, free (NH)-2-(1-phenylvinyl)indoles 3o–r were by a 5-CF3 group (3r) restores the activity. Next, the cyto-
cleanly prepared in good to excellent yields.
toxic activity was evaluated against the human colon carci-
Eur. J. Org. Chem. 2011, 4868–4876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4871

A. Hamze, M. Alami, et al.
FULL PAPER
Table 4. One-pot synthesis of N-mesyl-2-(1-phenylvinyl)indoles 3f– difference between the dose required to affect cell prolifera-
n.[a]
tion and/or viability and that required to disrupt other
cellular cytoskeletal functions.[25]
Conclusions
We have successfully developed the synthesis of function-
alized 2-(1-phenylvinyl)benzofurans 2 and 2-(1-phenyl-
vinyl)indoles 3 in good overall yields in a single synthetic
operation under palladium/copper catalysis. Notably, this
process involving tandem C–Si bond cleavage, Sonogashira
coupling, and a subsequent cyclization reaction proved ef-
fective for various o-substituted silylated arylalkynes and
1-phenylvinyl iodides. This method features mild reaction
conditions, simple operation, good substrate scope, and
good yields. Using this methodology, we have synthesized
compounds 3o and 3r that inhibit tubulin polymerization
at micromolar concentrations but do not exhibit a strong
cytotoxic effect against HCT-116 cells. Such agents interfer-
ing with microtubules may prove useful as selective vascular
disrupting agents. Investigations of structure/activity rela-
tionships in the indole series are in progress.
Experimental Section
General: Commercial reagents were used without further purifica-
tion unless otherwise stated. All glassware was oven-dried at
140 °C, and reactions were conducted under argon. Solvents: cyclo-
hexane and ethyl acetate (EtOAc) for chromatography were dis-
tilled before use; DMF was stirred with CaH2 (5% w/v) overnight,
filtered, then distilled at 20 Torr; The distilled DMF was stored
over 4 Å molecular sieves. The compounds prepared were identified
1
by usual physical methods, i.e. H NMR, 13C NMR, and IR spec-
troscopy and elemental analysis. 1H and 13C NMR spectra were
measured in CDCl3 with a Bruker ARX 400 or a Bruker Avance
300, and chemical shifts are reported in ppm. The following ab-
breviations are used: m (multiplet), s (singlet), br. s (broad singlet),
d (doublet), t (triplet) dd (doublet of doublet), td (triplet of doub-
let), q (quadruplet), ddd (doublet of doublet of doublet). IR spectra
[cm–1] were measured neat with a Bruker Vector 22 spectrophotom-
eter. Elemental analyses were performed with a Perkin–Elmer 240
analyser. Analytical TLC was performed with Merck precoated sil-
ica gel 60F plates with detection by exposure to UV light (254 nm)
and by immersion in a staining solution of 20% phosphomolybdic
[a] Compound 6 (1 equiv.) in DMF was mixed with 5 mol-%
Pd(PPh3)4, 10 mol-% CuI, DBU (12 equiv.), and H2O (0.8 equiv.).
After stirring at room temperature for 5 min, N-mesylanilide 8
(1.6 equiv.) in DMF was added, and the mixture was stirred at
room temperature for 12 h. [b] Isolated yield of 3. [c] Stirring was
continued at 50 °C for 4 h.
acid in EtOH or vanillin stain (vanillin, concentrated H2SO4,
EtOH). Merck silica gel 60 (230–400 mesh) was used for column
chromatography. Melting points were recorded with a Büchi B-450
apparatus and are uncorrected.
General Procedure for the Synthesis of 2-(1-Phenylvinyl)benzofurans
2 and N-Mesyl-2-(1-phenylvinyl)indoles 3: To a solution of 1-phen-
ylvinyl iodide 6 (1 equiv.) in DMF (4 mL per mmol) was success-
ively added tetrakis(triphenylphosphane)palladium (5 mol-%), cop-
per iodide (10 mol-%), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(12 equiv.), and water (0.8 equiv.). The reaction mixture was stirred
at room temperature for 2 min, and a solution of ortho-alkynyl-
phenol 7 or N-mesylanilide 8 (1.6 equiv.) in DMF (8 mL per mmol)
was added dropwise. The reaction mixture was stirred at room tem-
perature for 12 h. For indoles 3i, 3j, 3k, and 3n additional stirring
at 50 °C for 4 h was needed. The crude mixture was quenched with
noma cell line (HCT-116). All tested benzofurans 2a–f were
found to be much less active than their indole congeners 3.
The best cytotoxicities were observed for indoles 3o, 3p, and
3r, which displayed moderate antiproliferative effects on the
growth of HCT-116 cells (IC50 Ͻ 1 μm). Compounds such
as 3o and 3r, which inhibit tubulin polymerization at micro-
molar concentrations, but do not exhibit a significant cyto-
toxic effect, may prove useful as selective vascular dis-
rupting agents. In principle, it is desirable to maximize the ammonium chloride and extracted into EtOAc. The combined or-
4872 Eur. J. Org. Chem. 2011, 4868–4876
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of 2-(1-Phenylvinyl)benzofurans and -indoles
Table 5. Cytotoxicity and ITP of selected benzofuran and indole derivatives against colon carcinoma cells (HCT-116).
Compound
GI50 [μm][a]
ITP IC50 [μM][b]
Compound
GI50 [μm][a]
ITP IC50 [μm][b]
2a
2b
2c
2d
2e
2f
6
10
16
10
3o
3p
0.74
0.9
3.7
0.71
0.002
0.002
3.3
NC[c]
15
3.5
2.2
NC[c]
8
NC[c]
30
3q
3r
3.5
1
10
66
isoCA-4[d]
CA-4[d]
16
1.0
3f
NC[c]
[a] GI50 is the concentration of compound needed to reduce cell growth by 50% following 72 h cell treatment with the tested drug (average
of three experiments). [b] ITP IC50 is the concentration of compound required to inhibit 50% of the rate of microtubule assembly (average
of three experiments). [c] IC50 value not calculated owing to the low activity of the compound. [d] The GI50 and IC50 values for isoCA-
4 and CA-4 were determined in this study.
ganic layers were washed with water and brine, dried with MgSO4,
filtered, and the solvent was removed in vacuo. The crude product
was purified by chromatography on silica gel.
H), 7.64 (s, 1 H), 9.97 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 56.2 (3 C), 60.9, 105.1, 105.8 (2 C), 106.3, 116.1, 119.5, 130.4,
133.4, 134.3, 138.3, 138.7, 146.0, 147.8, 153.1 (2 C), 157.6,
191.6 ppm. APCI-MS: m/z = 369 [M + H]+. IR (neat): ν = 1124,
˜
2-[1-(3,4,5-Trimethoxyphenyl)vinyl]benzofuran (2a): The crude ma-
terial was purified by using cyclohexane/ethyl acetate (9:1) as the
eluent to give benzofuran 2a (61 mg, 0.20 mmol, 78%) as a light
brown solid. M.p. 74–76 °C 1H NMR (300 MHz, CDCl3): δ = 3.88
(s, 6 H), 3.92 (s, 3 H), 5.44 (s, 1 H), 6.02 (s, 1 H), 6.61 (s, 1 H),
6.73 (s, 2 H), 7.21 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 8.3 Hz, 1 H),
1136, 1235, 1301, 1338, 1412, 1463, 1505, 1580, 1689, 2035, 2255,
2935 cm–1. C21H20O6 (368.13): calcd. C 68.47, H 5.47; found C
68.35, H 5.33.
6-Methoxy-2-[1-(3,4,5-trimethoxyphenyl)vinyl]benzofuran (2e): The
crude material was purified by using cyclohexane/ethyl acetate (8:2)
7.48–7.54 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.3 (2 as the eluent to give benzofuran 2e (51 mg, 0.15 mmol, 60%) as a
1
C), 61.1, 105.9 (2 C), 106.1, 111.2, 114.9, 121.3, 123.0, 125.0, 128.9,
135.0, 138.3, 139.5, 153.2 (2 C), 155.1, 155.9 ppm. Atomic pressure
brownish oil. H NMR (300 MHz, CDCl3): δ = 3.84 (s, 3 H), 3.88
(s, 6 H), 3.91 (s, 3 H), 5.41 (d, J = 1.0 Hz, 1 H), 5.98 (d, J = 1.0 Hz,
1 H), 6.54 (s, 1 H), 6.71 (s, 2 H), 6.91 (dd, J = 8.9, 2.6 Hz, 1 H),
chemical ionization (APCI)-MS: m/z = 311 [M + H]+. IR (neat): ν
˜
= 1002, 1125, 1235, 1326, 1413, 1452, 1505, 1583, 2935 cm–1. 6.97 (d, J = 2.6 Hz, 1 H), 7.39 (d, J = 8.9 Hz, 1 H) ppm. 13C NMR
C19H18O4 (310.12): calcd. C 73.53, H 5.85; found C 73.41, H 5.72.
(75 MHz, CDCl3): δ = 55.8, 56.3 (2 C), 61.1, 95.8, 105.8 (2 C),
105.9, 112.1, 113.6, 121.4, 122.3, 135.1, 138.1, 139.5, 153.2 (2 C),
155.2, 156.2, 158.6 ppm. APCI-MS: m/z = 341 [M + H]+. IR (neat):
Methyl-2-[1-(3,4,5-trimethoxyphenyl)vinyl]benzofuran-5-carboxylate
(2b): The crude material was purified by using cyclohexane/ethyl
acetate (9:1) as the eluent to give benzofuran 2b (55 mg, 0.15 mmol,
60%) as a white solid. M.p. 99–101 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.87 (s, 6 H), 3.90 (s, 3 H), 3.92 (s, 3 H), 5.47 (s, 1 H),
6.04 (s, 1 H), 6.65 (s, 1 H), 6.70 (s, 2 H), 7.51 (d, J = 8.7 Hz, 1 H),
8.02 (dd, J = 8.7, 1.6 Hz, 1 H), 8.24 (d, J = 1.6 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 52.1, 56.2 (2C), 60.9, 105.6 (2 C),
106.0, 110.9, 115.7, 123.6, 125.3, 126.6, 128.8, 134.4, 138.2, 139.0,
153.1 (2 C), 157.2, 157.5, 167.2 ppm. APCI-MS: m/z = 369 [M +
ν = 1005, 1028, 1108, 1125, 1150, 1196, 1223, 1238, 1272, 1303,
˜
1412, 1465, 1491, 1506, 1579, 1624, 2029, 2834 cm–1. C20H20O5
(340.13): calcd. C 70.57, H 5.92; found C 70.51, H 5.87.
5-Methoxy-2-[1-(3,4,5-trimethoxyphenyl)vinyl]benzofuran (2f): The
crude material was purified by using cyclohexane/ethyl acetate (8:2)
as the eluent to give benzofuran 2f (71 mg, 0.21 mmol, 85%) as an
orange oil. 1H NMR (300 MHz, CDCl3): δ = 3.84 (s, 3 H), 3.88 (s,
6 H), 3.91 (s, 3 H), 5.41 (d, J = 1.0 Hz, 1 H), 5.98 (d, J = 1.0 Hz,
1 H), 6.54 (s, 1 H), 6.71 (s, 2 H), 6.91 (dd, J = 8.9, 2.6 Hz, 1 H),
6.97 (d, J = 2.6 Hz, 1 H), 7.39 (d, J = 8.9 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.9, 56.2 (2 C), 60.9, 103.5, 105.7 (2 C),
106.1, 111.5, 113.6, 114.6, 129.3, 134.9, 138.1, 139.5, 150.0, 153.0
(2 C), 156.0, 156.5 ppm. APCI-MS: m/z = 341 [M + H]+. IR (neat):
H]+. IR (neat): ν = 1006, 1088, 1124, 1157, 1238, 1296, 1412, 1444,
˜
1505, 1580, 1715, 2947 cm–1. C21H20O6 (368.13): calcd. C 68.47, H
5.47; found C 68.29, H 5.32.
2-[1-(3,4,5-Trimethoxyphenyl)vinyl]benzofuran-6-carbaldehyde (2c):
The crude material was purified by using cyclohexane/ethyl acetate
(8:2) as the eluent to give benzofuran 2c (55 mg, 0.16 mmol, 65%)
as a yellow oil. 1H NMR (300 MHz, CDCl3): δ = 3.86 (s, 6 H),
3.89 (s, 3 H), 5.53 (s, 1 H), 6.11 (s, 1 H), 6.65 (s, 1 H), 6.67 (s, 2
H), 7.61 (d, J = 7.9 Hz, 1 H), 7.74 (d, J = 7.9 Hz, 1 H), 7.97 (s, 1
H), 10.04 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.3 (2
C), 60.9, 105.8 (2 C), 105.9, 112.4, 117.0, 121.5, 124.7, 133.6, 134.1,
ν = 1007, 1030, 1127, 1149, 1180, 1205, 1238, 1308, 1337, 1362,
˜
1412, 1450, 1473, 1504, 1580, 1621, 2830 cm–1. C20H20O5 (340.13):
calcd. C 70.57, H 5.92; found C 70.44, H 5.79.
2-(1-Phenylvinyl)benzofuran (2g): The crude material was purified
by using cyclohexane/Et2O (98:2) as the eluent to give benzofuran
2g (42 mg, 0.19 mmol, 76%) as a colorless oil. 1H NMR (300 MHz,
134.7, 138.4, 139.0, 153.2 (2 C), 154.7, 159.6, 191.6 ppm. APCI- CDCl3): δ = 5.34 (d, J = 1.1 Hz, 1 H), 5.96 (d, J = 1.1 Hz, 1 H),
MS: m/z = 339 [M + H]+. IR (neat): ν = 1004, 1125, 1169, 1239,
1275, 1292, 1356, 1412, 1463, 1505, 1580, 1611, 1689, 2089,
2937 cm–1. C20H18O5 (338.12): calcd. C 70.99, H 5.36; found C
70.71, H 5.12.
6.44 (s, 1 H), 7.06–7.71 (m, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 105.9, 111.1, 115.1, 121.2, 123.4, 124.8, 128.2, 128.4 (2 C), 128.5
(2 C), 130.3, 139.3, 139.5, 155.0, 155.9 ppm. APCI-MS: m/z = 221
˜
[M + H]+. IR (neat): ν = 1009, 1071, 1174, 1229, 1264, 1397, 1452,
˜
1487, 1547, 1587, 1729, 2225, 2932 cm–1. C16H12O (220.09): calcd.
C 87.25, H 5.49; found C 87.08, H 5.36.
7-Methoxy-2-[1-(3,4,5-trimethoxyphenyl)vinyl]benzofuran-4-carb-
aldehyde (2d): The crude material was purified by using cyclohex-
ane/ethyl acetate (8:2) as the eluent to give benzofuran 2d (84 mg,
0.23 mmol, 91%) as an orange solid. M.p. 98–100 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.88 (s, 6 H), 3.90 (s, 3 H), 4.08 (s, 3 H),
5.50 (s, 1 H), 6.11 (s, 1 H), 6.68 (s, 1 H), 6.70 (s, 2 H), 7.38 (s, 1
2-(1-p-Tolylvinyl)benzofuran (2h): The crude material was purified
by using cyclohexane as the eluent to give benzofuran 2h (46 mg,
0.20 mmol, 80%) as a white solid. M.p. 145–147 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.28 (s, 3 H), 5.28 (d, J = 1.2 Hz, 1 H),
Eur. J. Org. Chem. 2011, 4868–4876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4873

A. Hamze, M. Alami, et al.
FULL PAPER
5.88 (d, J = 1.2 Hz, 1 H), 6.42 (s, 1 H), 7.11 (m, 4 H), 7.27 (d, J = (71 mg, 0.16 mmol, 62%) as a colorless oil. 1H NMR (300 MHz,
8.5 Hz, 2 H), 7.36 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.2, 105.7, 111.0, 114.6, 121.1, 122.8, 124.7, 128.3 (2
C), 129.0 (2 C), 138.0, 139.3, 156.1 ppm; signals of 3 C missing.
CDCl3): δ = 2.77 (s, 3 H), 3.78 (s, 6 H), 3.85 (s, 3 H), 5.55 (s, 1 H),
5.75 (s, 1 H), 6.52 (s, 2 H), 6.84 (s, 1 H), 7.60 (d, J = 8.8 Hz, 1 H),
7.92 (s, 1 H), 8.08 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 40.8, 56.1 (2 C), 60.8, 104.4 (2 C), 111.5, 114.6, 118.4,
118.5, 121.5, 123.0 (q, J = 272 Hz), 126.3 (q, J = 32 Hz), 128.8,
135.1, 138.2, 138.4, 140.8, 141.8, 153.0 (2 C) ppm. 19F NMR
(188 MHz, CDCl3): δ = –61.7 ppm. APCI-MS: m/z = 456
APCI-MS: m/z = 235 [M + H]+. IR (neat): ν = 1066, 1174, 1257,
˜
1302, 1451, 1511, 2925 cm–1. C17H14O (234.10): calcd. C 87.15, H
6.02; found C 87.04, H 5.97.
2-[1-(3,4-Dichlorophenyl)vinyl]benzofuran (2i): The crude material
[M + H]+. IR (neat): ν = 1005, 1038, 1062, 1118, 1167, 1237, 1276,
˜
was purified by using cyclohexane as the eluent to give benzofuran
1331, 1372, 1413, 1450, 1505, 1550, 2936 cm–1. C21H20F3NO5S
(455.10): calcd. C 55.38, H 4.43, N 3.08; found C 55.06, H 4.26, N
2.99.
1
2i (43 mg, 0.15 mmol, 60%) as a yellow oil. H NMR (300 MHz,
CDCl3): δ = 5.44 (s, 1 H), 6.06 (s, 1 H), 6.53 (s, 1 H), 7.22–7.35
(m, 3 H), 7.51 (t, J = 8.5 Hz, 3 H), 7.60 (d, J = 1.9 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 106.0, 111.1, 116.1, 121.3, 123.0,
125.1, 127.8, 130.4 (2 C), 132.3, 132.5, 137.4, 139.1, 143.7, 144.8,
5-Fluoro-1-(N-methylsulfonyl)-2-[1-(3,4,5-trimethoxyphenyl)vinyl]-
1H-indole (3j): The crude material was purified by using cyclohex-
ane/ethyl acetate (7:3) as the eluent to give indole 3j (65 mg,
0.16 mmol, 64 %) as a light brown solid. M.p. 147–149 °C. 1H
NMR (300 MHz, CDCl3): δ = 2.74 (s, 3 H), 3.78 (s, 6 H), 3.84 (s,
3 H), 5.52 (s, 1 H), 5.72 (s, 1 H), 6.52 (s, 2 H), 6.74 (s, 1 H), 7.08
(m, 1 H), 7.27 (m, 1 H), 7.92 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 40.3, 56.2, 60.9 (2 C), 104.4 (2 C), 106.7 (d, J =
24.0 Hz), 112.1 (d, J = 3.5 Hz), 112.9 (d, J = 25.3 Hz), 115.7 (d, J
= 9.2 Hz), 118.1, 130.4 (d, J = 10.1 Hz, 1 C), 133.3, 135.4, 138.4,
141.3, 142.0, 153.1 (2 C), 159.9 (d, J = 241 Hz) ppm. 19F NMR
(188 MHz, CDCl3): δ = –119.2 ppm. APCI-MS: m/z = 406 [M +
146.0 ppm. APCI-MS: m/z = 289, 291 [M + H]+. IR (neat): ν =
˜
1011, 1094, 1224, 1250, 1377, 1 1011, 1094, 1224, 1250, 1377, 1404,
1454, 1569, 1619, 1652, 2953, 3253 cm–1. C16H10Cl2O (288.01):
calcd. C 66.46, H 3.49; found C 66.39, H 3.37.
1-(N-Methylsulfonyl)-2-[1-(3,4,5-trimethoxyphenyl)vinyl]-1H-indole
(3f): The crude material was purified by using cyclohexane/ethyl
acetate (8:2) as the eluent to give indole 3f (71 mg, 0.18 mmol,
1
73%) as a light brown oil. H NMR (300 MHz, CDCl3): δ = 2.75
(s, 3 H), 3.78 (s, 6 H), 3.85 (s, 3 H), 5.53 (d, J = 0.9 Hz, 1 H), 5.72
(d, J = 0.9 Hz, 1 H), 6.55 (s, 2 H), 6.79 (s, 1 H), 7.30–7.40 (m, 2
H), 7.64 (d, J = 6.9 Hz, 1 H), 7.99 (d, J = 7.7 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 40.2, 56.2 (2 C), 60.9, 104.4 (2 C),
112.4, 114.5, 117.8, 121.2, 123.8, 125.0, 129.4, 135.6, 137.0, 138.2,
140.2, 141.5, 152.9 (2 C) ppm. APCI-MS: m/z = 388 [M + H]+. IR
H]+. IR (neat): ν = 1037, 1074, 1126, 1171, 1240, 1294, 1340, 1370,
˜
1415, 1448, 1516, 1578 cm–1. C20H20FNO5S (405.10): calcd. C
59.25, H 4.97, N 3.45; found C 59.07, H 4.79, N 3.39.
2-[1-(3-Fluoro-4-methoxyphenyl)vinyl]-1-(N-methylsulfonyl)-1H-
indole (3k): The crude material was purified by using cyclohexane/
ethyl acetate (8:2) as the eluent to give indole 3k (64 mg,
(neat): ν = 1005, 1125, 1150, 1170, 1234, 1338, 1367, 1413, 1441,
˜
1504, 1580, 2937 cm–1. C20H21NO5S (387.11): calcd. C 62.00, H
5.46, N 3.62; found C 61.68, H 5.35, N 3.49.
1
0.19 mmol, 76%) as a yellow oil. H NMR (300 MHz, CDCl3): δ
= 2.76 (s, 3 H), 3.88 (s, 3 H), 5.49 (s, 1 H), 5.69 (s, 1 H), 6.77 (s, 1
H), 6.88 (t, J = 8.6 Hz, 1 H), 7.00 (m, 1 H), 7.08 (dd, J = 12.4,
2.1 Hz, 1 H), 7.33 (m, 1 H), 7.38 (m, 1 H), 7.62 (dd, J = 6.4, 1.9 Hz,
1 H), 7.98 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 40.1, 56.2, 112.8 (d, J = 10 Hz), 114.4 (d, J = 19 Hz), 117.1,
121.2, 122.6 (d, J = 3.1 Hz), 124.0, 125.2, 129.5, 133.3 (d, J =
5.8 Hz), 135.0, 137.2, 140.2 (d, J = 19.6 Hz), 153.8 ppm; signals of
3 C missing. 19F NMR (188 MHz, CDCl3): δ = –133.3 ppm. APCI-
5-Methoxy-1-(N-methylsulfonyl)-2-[1-(3,4,5-trimethoxyphenyl)-
vinyl]-1H-indole (3g): The crude material was purified by using cy-
clohexane/ethyl acetate (7:3) as the eluent to give indole 3g (195 mg,
1
0.47 mmol, 95%) as a yellow oil. H NMR (300 MHz, CDCl3): δ
= 2.72 (s, 3 H), 3.78 (s, 6 H), 3.84 (s, 3 H), 3.87 (s, 3 H), 5.50 (d, J
= 1.2 Hz, 1 H), 5.70 (d, J = 1.2 Hz, 1 H), 6.53 (s, 2 H), 6.72 (s, 1
H), 6.97 (dd, J = 9.1, 2.6 Hz, 1 H), 7.08 (d, J = 2.6 Hz, 1 H), 7.86
(d, J = 9.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 39.9,
55.7, 56.2 (2 C), 60.9, 103.6, 104.3 (2 C), 112.8, 113.9, 115.6, 117.6,
130.5, 131.8, 135.7, 138.2, 141.1, 141.7, 153.0 (2 C), 156.8 ppm.
MS: m/z = 346 [M + H]+. IR (neat): ν = 1021, 1081, 1110, 1126,
˜
1170, 1231, 1276, 1326, 1367, 1448, 1515, 1580, 1610, 2932 cm–1.
C18H16FNO3S (345.08): calcd. C 62.59, H 4.67, N 4.06; found C
62.55, H 4.69, N 4.09.
APCI-MS: m/z = 418 [M + H]+. IR (neat): ν = 100, 1032, 1044,
˜
1098, 1125, 1149, 1174, 1215, 1236, 1340, 1367, 1413, 1451, 1474,
1504, 1580, 1613, 2832 cm–1. C21H23NO6S (417.12): calcd. C 60.42,
H 5.55, N 3.36; found C 60.30, H 5.49, N 3.29.
2-[1-(4-Fluorophenyl)vinyl]-1-(N-methylsulfonyl)-1H-indole (3l): The
crude material was purified by using cyclohexane/ethyl acetate (8:2)
as the eluent to give indole 3l (46 mg, 0.15 mmol, 58%) as a light
6-Methoxy-1-(N-methylsulfonyl)-2-[1-(3,4,5-trimethoxyphenyl)-
vinyl]-1H-indole (3h): The crude material was purified by using cy-
clohexane/ethyl acetate (8:2) as the eluent to give indole 3h (74 mg,
1
yellow oil. H NMR (300 MHz, CDCl3): δ = 2.64 (s, 3 H), 5.45 (s,
1 H), 5.62 (s, 1 H), 6.71 (s, 1 H), 6.91 (td, J = 8.7, 2.6 Hz, 2 H),
7.19–7.27 (m, 4 H), 7.54 (dd, J = 6.2, 1.9 Hz, 1 H), 7.88 (d, J =
7.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.1, 112.7,
114.7, 115.2 (d, J = 22 Hz, 2 C), 117.6, 121.2, 124.0, 125.2, 128.5
(d, J = 8 Hz, 2 C), 129.5, 136.2, 137.2, 140.3, 140.8, 162.8 (d, J =
248 Hz) ppm. 19F NMR (188 MHz, CDCl3): δ = –113.8 ppm.
1
0.18 mmol, 71%) as an orange solid. M.p. 102–104 °C. H NMR
(300 MHz, MeOD): δ = 2.82 (s, 3 H), 3.74 (s, 6 H), 3.76 (s, 3 H),
3.86 (s, 3 H), 5.51 (d, J = 1.2 Hz, 1 H), 5.71 (d, J = 1.2 Hz, 1 H),
6.57 (s, 2 H), 6.76 (s, 1 H), 6.96 (dd, J = 8.7, 2.2 Hz, 1 H), 7.51–
7.52 (m, 2 H) ppm. 13C NMR (75 MHz, MeOD): δ = 40.0, 56.2,
56.6 (2 C), 61.2, 103.3, 105.7 (2 C), 113.8, 113.9, 117.8, 122.9, 124.7,
137.8, 139.3, 139.8, 140.6, 143.4, 154.3 (2 C), 159.7 ppm. APCI-
APCI-MS: m/z = 316 [M + H]+. IR (neat): ν = 1018, 1056, 1151,
˜
1171, 1206, 1228, 1270, 1343, 1367, 1410, 1450, 1506, 1533, 1599,
1656, 2929 cm–1. C17H14FNO2S (315.07): calcd. C 64.75, H 4.47,
N 4.44; found C 64.56, H 4.18, N 4.11.
MS: m/z = 418 [M + H]+. IR (neat): ν = 1002, 1121, 1154, 1172,
˜
1193, 1236, 1246, 1271, 1336, 1365, 1413, 1489, 1578, 1614,
2939 cm–1. C21H23NO6S (417.12): calcd. C 60.42, H 5.55, N 3.36;
found C 60.32, H 5.45, N 3.24.
2-[1-(3,4-Dichlorophenyl)vinyl]-1-(N-methylsulfonyl)-1H-indole
(3m): The crude material was purified by using cyclohexane/ethyl
acetate (9:1) as the eluent to give indole 3m (59 mg, 0.16 mmol,
1-(N-Methylsulfonyl)-5-(trifluoromethyl)-2-[1-(3,4,5-trimethoxy-
phenyl)vinyl]-1H-indole (3i): The crude material was purified by
using cyclohexane/ethyl acetate (8:2) as the eluent to give indole 3i
1
64%) as a yellow oil. H NMR (300 MHz, CDCl3): δ = 2.79 (s, 3
H), 5.61 (d, J = 0.7 Hz, 1 H), 5.78 (d, J = 0.7 Hz, 1 H), 6.82 (d, J
4874
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4868–4876

Synthesis of 2-(1-Phenylvinyl)benzofurans and -indoles
= 0.7 Hz, 1 H), 7.14 (dd, J = 8.4, 2.0 Hz, 1 H), 7.21–7.40 (m, 3 H),
13C NMR (75 MHz, MeOD): δ = 55.9, 56.6 (2 C), 61.2, 95.0, 104.1,
7.65 (d, J = 4.6 Hz, 2 H), 8.00 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR 107.2 (2 C), 110.7, 111.1, 122.1, 124.2, 138.2, 138.4, 139.6, 143.6,
(75 MHz, CDCl3): δ = 40.0, 113.5, 114.8, 119.1, 121.4, 124.3, 125.5,
154.2 (2 C), 158.2 ppm; signal of 1 C missing. APCI-MS: m/z =
126.0, 128.3, 129.6, 130.3, 132.0, 132.5, 135.2, 139.3, 139.9, 340 [M + H]+. IR (neat): ν = 1003, 1031, 1126, 1169, 1220, 1310,
˜
140.1 ppm. APCI-MS: m/z = 366, 368 [M + H]+. IR (neat): ν = 1331, 1355, 1412, 1451, 1465, 1492, 1504, 1579, 1624, 2832 cm–1.
˜
1030, 1131, 1171, 1202, 1226, 1368, 1450, 1479, 2962 cm–1
.
C20H21NO4 (339.15): calcd. C 70.78, H 6.24, N 4.13; found C
70.59, H 6.17, N 4.08.
C17H13Cl2NO2S (365.00): calcd. C 55.75, H 3.58, N 3.82; found C
55, H 3.55, N 3.79.
5-(Trifluoromethyl)-2-[1-(3,4,5-trimethoxyphenyl)vinyl]-1H-indole
(3r): The crude material was purified by using cyclohexane/ethyl
acetate (6:4) as the eluent to give indole 3r (32 mg, 0.085 mmol,
80 %) as a red solid. M.p. 147–149 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.85 (s, 6 H), 3.91 (s, 3 H), 5.43 (s, 1 H), 5.65 (s, 1 H),
6.67 (m, 3 H), 7.42 (s, 2 H), 7.88 (br. s, 1 H), 8.44 (br. s, 1 H, NH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 55.7 (2 C), 60.9, 103.6,
105.7 (2 C), 111.0, 113.7, 118.4 (d, J = 3.9 Hz, 1 C), 119.3 (d, J =
3.1 Hz, 1 C), 123.4, 127.9, 135.2, 137.7, 139.5, 142.2, 153.1 (2 C)
ppm; signals of 2 C missing. 19F NMR (188 MHz, CDCl3): δ =
2-[1-(4-Bromophenyl)vinyl]-1-(N-methylsulfonyl)-1H-indole (3n):
The crude material was purified by using cyclohexane/ethyl acetate
(9:1) as the eluent to give indole 3n (52 mg, 0.14 mmol, 55%) as a
1
yellow oil. H NMR (300 MHz, CDCl3): δ = 2.75 (s, 3 H), 5.58 (d,
J = 0.9 Hz, 1 H), 5.76 (d, J = 0.9 Hz, 1 H), 6.80 (s, 1 H), 7.18 (d,
J = 8.5 Hz, 2 H), 7.35–7.37 (m, 2 H), 7.44 (d, J = 8.5 Hz, 2 H),
7.63 (dd, J = 6.1, 1.7 Hz, 1 H), 7.97 (d, J = 7.9 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 40.1, 112.9, 114.7, 118.2, 121.3, 122.2,
124.1, 125.3, 128.3 (2 C), 129.5, 131.5 (2 C), 137.2, 139.0, 139.9,
140.8 ppm. APCI-MS: m/z = 376, 378 [M + H]+. IR (neat): ν =
˜
–62.1 ppm. APCI-MS: m/z = 378.6 [M + H]+. IR (neat): ν = 1003,
˜
1009, 1070, 1135, 1151, 1170, 1206, 1228, 1267, 1323, 1367, 1450,
1487, 1530, 2930 cm–1. C17H14BrNO2S (374.99): calcd. C 54.27, H
3.75, N 3.72; found C 54.07, H 3.59, N 3.62.
1126, 1238, 1327, 1412, 1452, 1504, 1580, 2504, 2941 cm–1
.
C20H18F3NO3 (377.12): calcd. C 63.66, H 4.81, N 3.71; found C
63.55, H 4.71, N 3.59.
General Procedure for the Deprotection of N-Mesyl-2-(1-phenyl-
vinyl)indoles 3f–i: 3f–i (1 mmol) was dissolved in 5% KOH solution
in MeOH (8 mL) and heated in a sealed tube at 80 °C for 1.5 h.
The cooled crude mixture was quenched with water and extracted
into EtOAc. The combined organic layers were washed with brine,
dried with MgSO4, filtered, and the solvent was removed in vacuo.
The crude product was purified by chromatography on silica
gel.
Cell Culture and Proliferation Assay: Cancer cell lines were ob-
tained from the American Type Culture Collection (Rockville,
USA) and were cultured according to the supplier’s instructions.
HCT116 colorectal carcinoma cells were grown in RPMI 1640 con-
taining 10% FCS and 1% glutamine. All cell lines were maintained
at 37 °C in a humidified atmosphere containing 5% CO2. Cell via-
bility was assessed by using Promega CellTiter-Blue reagent ac-
cording to the manufacturer’s instructions. Cells were seeded in 96-
well plates (5ϫ103 cells per well) containing growth medium
(50 mL). After 24 h of culture, the cells were supplemented with
the test compound (50 mL) dissolved in DMSO (less than 0.1% in
each preparation). After 72 h of incubation, resazurin (20 mL) was
2-[1-(3,4,5-Trimethoxyphenyl)vinyl]-1H-indole (3o): The crude ma-
terial was purified by using cyclohexane/ethyl acetate (7:3) as the
eluent to give indole 3o (72 mg, 0.23 mmol, 90%) as a yellow oil.
1H NMR (300 MHz, MeOD): δ = 3.79 (s, 6 H), 3.80 (s, 3 H), 5.32
(s, 1 H), 5.66 (s, 1 H), 6.30 (s, 1 H), 6.76 (s, 2 H), 6.95 (ddd, J =
8.0, 7.1, 1.0 Hz, 1 H), 7.08 (ddd, J = 8.2, 7.1, 1.2 Hz, 1 H), 7.34
(dd, J = 8.1, 0.8 Hz, 1 H), 7.44 (dd, J = 7.9, 0.8 Hz, 1 H) ppm;
signal of NH not detected. 13C NMR (75 MHz, MeOD): δ = 56.7
(2 C), 61.2, 104.0, 107.2 (2 C), 111.9, 112.4, 120.3, 121.4, 123.2,
129.8, 138.2, 138.7, 139.2 (2 C), 143.5, 154.2 (2 C) ppm. APCI-MS:
added for 2 h before recording fluorescence (λex = 560 nm, λem
=
590 nm) by using a Victor microtiter plate fluorimeter (Perkin–El-
mer, USA). The IC50 value corresponds to the concentration of test
compound that caused a decrease of 50% in fluorescence of drug-
treated cells compared with untreated cells. Experiments were per-
formed in triplicate.
m/z = 310 [M + H]+. IR (neat): ν = 1003, 1126, 1238, 1327, 1412,
˜
1452, 1504, 1580, 2504, 2941 cm–1. C19H19NO3 (309.14): calcd. C
73.77, H 6.19, N 4.53; found C 73.69, H 6.14, N 4.55.
Tubulin Binding Assay: Sheep brain tubulin was purified according
to Shelanski’s method[26] by two cycles of assembly/disassembly and
then dissolved in the assembly buffer containing 0.1 m MES (2-
morpholinoethanesulfonic acid), 0.5 mm MgCl2, 1 mm EGTA [eth-
ylene glycol bis(2-aminoethyl ether) N,N,NЈ,NЈ-tetraacetic acid],
and 1 mm GTP (guanosine triphosphate) (pH = 6.6) to give a tubu-
lin concentration of ca. 2–3 mg/mL. Tubulin assembly was moni-
tored and recorded continuously by turbidimetry at 350 nm with a
UV spectrophotometer equipped with a thermostatted cell at
37 °C. The GI50 value of each compound was determined as the
5-Methoxy-2-[1-(3,4,5-trimethoxyphenyl)vinyl]-1H-indole (3p): The
crude material was purified by using cyclohexane/ethyl acetate (8:2)
as the eluent to give indole 3p (27 mg, 0.08 mmol, 76%) as a light
1
yellow oil. H NMR (300 MHz, MeOD): δ = 3.79 (s, 3 H), 3.81 (s,
3 H), 3.83 (s, 6 H), 5.30 (s, 1 H), 5.63 (s, 1 H), 6.25 (s, 1 H), 6.76
(dd, J = 8.8, 2.5 Hz, 1 H), 6.77 (s, 2 H), 6.98 (d, J = 2.5 Hz, 1 H),
7.23 (d, J = 8.8 Hz, 1 H) ppm; signal of NH not detected. 13C
NMR (75 MHz, MeOD): δ = 57.1, 57.4 (2 C), 62.1, 103.6, 104.5,
107.5, 113.0 (2 C), 113.3, 114.2, 130.3, 134.2, 138.5, 140.2, 143.6, concentration at which the maximum assembly rate of tubulin was
154.3 (2 C), 155.5 ppm; signal of 1 C missing. APCI-MS: m/z =
decreased by 50% compared to the rate in the absence of com-
pound. The GI50 values for all compounds were compared to the
GI50 of CA-4, isoCA-4, and measured the same day under the same
conditions.
340 [M + H]+. IR (neat): ν = 1127, 1221, 1334, 1412, 1450, 1504,
˜
1579, 2997 cm–1. C20H21NO4 (339.15): calcd. C 70.78, H 6.24, N
4.13; found C 70.51, H 6.14, N 4.00.
6-Methoxy-2-[1-(3,4,5-trimethoxyphenyl)vinyl]-1H-indole (3q): The
crude material was purified by using cyclohexane/ethyl acetate (6:4)
as the eluent to give indole 3q (22 mg, 0.065 mmol, 72 %) as a
Acknowledgments
1
brownish oil. H NMR (300 MHz, MeOD): δ = 3.81 (s, 3 H), 3.81
(s, 3 H), 3.82 (s, 6 H), 5.24 (s, 1 H), 5.58 (s, 1 H), 6.21 (s, 1 H),
6.64 (dd, J = 8.6, 2.3 Hz, 1 H), 6.77 (s, 2 H), 6.88 (d, J = 2.3 Hz,
1 H), 7.31 (d, J = 8.6 Hz, 1 H) ppm; signal of NH not detected.
The authors thank the Centre National de la Recherche Sci-
entifique (CNRS) and the University Paris 11 for financial support,
including a CNRS fellowship to B. T. and E. R.
Eur. J. Org. Chem. 2011, 4868–4876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4875

A. Hamze, M. Alami, et al.
FULL PAPER
Lan, J. You, Angew. Chem. 2009, 121, 8885–8888; Angew.
Chem. Int. Ed. 2009, 48, 8729–8732; d) M. Jacubert, A. Hamze,
O. Provot, J. F. Peyrat, J. D. Brion, M. Alami, Tetrahedron Lett.
2009, 50, 3588–3592; e) M. Jacubert, O. Provot, J. F. Peyrat, A.
Hamze, J. D. Brion, M. Alami, Tetrahedron 2010, 66, 3775–
3787; f) M. Jacubert, A. Tikad, O. Provot, A. Hamze, J. D.
Brion, M. Alami, Eur. J. Org. Chem. 2010, 4492–4500; g) G.
Le Bras, O. Provot, J. F. Peyrat, M. Alami, J. D. Brion, Tetrahe-
dron Lett. 2006, 47, 5497–5501.
[1]
[2]
G. R. Pettit, S. B. Singh, E. Hamel, C. M. Lin, D. S. Alberts,
D. Garcia-Kendall, Experientia 1989, 45, 209–211.
a) Q. Li, H. L. Sham, S. H. Rosenberg, in Annu. Rep. Med.
Chem. Vol. 34 (Ed.: M. D. Annette), Academic Press, 1999, pp.
139–148; b) Q. Li, K. W. Woods, A. Claiborne, I. I. S. L.
Gwaltney II, K. J. Barr, G. Liu, L. Gehrke, R. B. Credo, Y. H.
Hui, J. Lee, R. B. Warner, P. Kovar, M. A. Nukkala, N. A. Ziel-
inski, S. K. Tahir, M. Fitzgerald, K. H. Kim, K. Marsh, D.
Frost, S.-C. Ng, S. Rosenberg, H. L. Sham, Bioorg. Med. Chem.
Lett. 2002, 12, 465–469.
a) J. Lee, S. Bae, S.-h. Lee, H. Choi, Y. H. Kim, S. J. Kim, G. T.
Park, S. K. Moon, D.-H. Kim, S. Lee, S. K. Ahn, N. S. Choi,
K. J. Lee, Bioorg. Med. Chem. Lett. 2010, 20, 6327–6330; b)
J. W. Lippert Iii, Bioorg. Med. Chem. 2007, 15, 605–615; c)
D. M. Patterson, G. J. Rustin, Clin. Oncol. (R. Coll. Radiol.)
2007, 19, 443–456.
a) D. W. Siemann, D. J. Chaplin, P. A. Walicke, Expert Opin.
Invest. Drugs 2009, 18, 189–197; b) S. L. Young, D. J. Chaplin,
Expert Opin. Invest. Drugs 2004, 13, 1171–1182.
a) A. Hamze, D. Veau, O. Provot, J. D. Brion, M. Alami, J.
Org. Chem. 2009, 74, 1337–1340; b) B. Treguier, A. Hamze, O.
Provot, J. D. Brion, M. Alami, Tetrahedron Lett. 2009, 50,
6549–6552; c) E. Brachet, A. Hamze, J. F. Peyrat, J. D. Brion,
M. Alami, Org. Lett. 2010, 12, 4042–4045.
[12] a) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–2920; b)
K. S. Feldman, D. K. Hester II, M. R. Iyer, P. J. Munson, C. S.
Lopez, O. N. Faza, J. Org. Chem. 2009, 74, 4958–4974; c) C.
Ferrer, C. H. M. Amijs, A. M. Echavarren, Chem. Eur. J. 2007,
13, 1358–1373; d) R. Gao, C. S. Yi, J. Org. Chem. 2010, 75,
3144–3146.
[13] Silylated enynes and arylalkynes are readily available by Sono-
gashira coupling of trimethylsilylacetylene with vinyl or aryl
halides, respectively; see: a) K. Sonogashira, Y. Tohda, N.
Hagihara, Tetrahedron Lett. 1975, 16, 4467–4470; b) M. Alami,
G. Linstrumelle, Tetrahedron Lett. 1991, 32, 6109–6112; c) M.
Alami, B. Crousse, G. Linstrumelle, Tetrahedron Lett. 1995, 36,
3687–3690; d) M. Alami, B. Crousse, F. Ferri, J. Organomet.
Chem. 2001, 624, 114–123.
[14] a) A. Arcadi, S. Cacchi, R. C. Larock, F. Marinelli, Tetrahe-
dron Lett. 1993, 34, 2813–2816; b) M. Rosillo, G. Domínguez,
L. Casarrubios, U. Amador, J. Pérez-Castells, J. Org. Chem.
2004, 69, 2084–2093.
[15] A. Orsini, A. Vitérisi, A. Bodlenner, J. M. Weibel, P. Pale, Tet-
rahedron Lett. 2005, 46, 2259–2262.
[16] a) M. J. Mio, L. C. Kopel, J. B. Braun, T. L. Gadzikwa, K. L.
Hull, R. G. Brisbois, C. J. Markworth, P. A. Grieco, Org. Lett.
2002, 4, 3199–3202; b) C.-E. Yeom, M. J. Kim, W. Choi, B. M.
Kim, Synlett 2008, 4, 565–568.
[17] For the synthesis of 2-vinylindoles by cyclization of ethyl 3-(o-
trifluoroacetamidophenyl)-1-propargylic esters, see: I. Ambro-
gio, S. Cacchi, G. Fabrizi, A. Prastaro, Tetrahedron 2009, 65,
8916–8929.
[18] T. Sakamoto, Y. Kondo, S. Iwashita, T. Nagano, H. Yamanaka,
Chem. Pharm. Bull. 1988, 36, 1305–1308.
[19] A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 4176–
4211.
[20] K. Hiroya, S. Matsumoto, M. Ashikawa, H. Kida, T. Sakam-
oto, Tetrahedron 2005, 61, 12330–12338.
[21] K.-J. Chang, B.-N. Kang, M.-H. Lee, K.-S. Jeong, J. Am.
Chem. Soc. 2005, 127, 12214–12215.
[22] R. L. Mackman, B. A. Katz, J. G. Breitenbucher, H. C. Hui, E.
Verner, C. Luong, L. Liu, P. A. Sprengeler, J. Med. Chem. 2001,
44, 3856–3871.
[23] S. Tumkevicius, V. Masevicius, Synlett 2004, 13, 2327–2330.
[24] A. Giraud, O. Provot, A. Hamze, J. D. Brion, M. Alami, Tetra-
hedron Lett. 2008, 49, 1107–1110.
[25] D. J. Kerr, E. Hamel, M. K. Jung, B. L. Flynn, Bioorg. Med.
Chem. 2007, 15, 3290–3298.
[26] M. L. Shelanski, F. Gaskin, C. R. Cantor, Proc. Natl. Acad.
Sci. USA 1973, 70, 765–768.
[3]
[4]
[5]
[6] a) C. Mousset, A. Giraud, O. Provot, A. Hamze, J. Bignon,
J. M. Liu, S. Thoret, J. Dubois, J. D. Brion, M. Alami, Bioorg.
Med. Chem. Lett. 2008, 18, 3266–3271; b) E. Rasolofonjatovo,
O. Provot, A. Hamze, J. Bignon, S. Thoret, J. D. Brion, M.
Alami, Eur. J. Med. Chem. 2010, 45, 3617–3626; c) S. Messa-
oudi, A. Hamze, O. Provot, B. Tréguier, J. Rodrigo De Losada,
J. Bignon, J.-M. Liu, J. Wdzieczak-Bakala, S. Thoret, J. Dubois,
J.-D. Brion, M. Alami, ChemMedChem 2011, 6, 488–497.
[7] S. Messaoudi, B. Treguier, A. Hamze, O. Provot, J. F. Peyrat,
J. R. De Losada, J. M. Liu, J. Bignon, J. Wdzieczak-Bakala, S.
Thoret, J. Dubois, J. D. Brion, M. Alami, J. Med. Chem. 2009,
52, 4538–4542.
[8] G. R. Pettit, B. Toki, D. L. Herald, P. Verdier-Pinard, M. R.
Boyd, E. Hamel, R. K. Pettit, J. Med. Chem. 1998, 41, 1688–
1695.
[9] A. Hamze, A. Giraud, S. Messaoudi, O. Provot, J. F. Peyrat, J.
Bignon, J. M. Liu, J. Wdzieczak-Bakala, S. Thoret, J. Dubois,
J. D. Brion, M. Alami, ChemMedChem 2009, 4, 1912–1924.
[10] a) T. Beckers, T. Reissmann, M. Schmidt, A. M. Burger, H. H.
Fiebig, U. Vanhoefer, H. Pongratz, H. Hufsky, J. Hockemeyer,
M. Frieser, S. Mahboobi, Cancer Res. 2002, 62, 3113–3119; b)
S. Mahboobi, H. Pongratz, H. Hufsky, J. Hockemeyer, M.
Frieser, A. Lyssenko, D. H. Paper, J. Bürgermeister, F.-D.
Böhmer, H.-H. Fiebig, A. M. Burger, S. Baasner, T. Beckers, J.
Med. Chem. 2001, 44, 4535–4553.
[11] For the synthesis of 2-substituted benzofurans, see: a) S. Cac-
chi, G. Fabrizi, A. Goggiomani, Heterocycles 2002, 56, 613–
632; b) C. Adelwöhrer, T. Rosenau, W. H. Binder, P. Kosma,
Tetrahedron 2003, 59, 3231–3235; For the one-pot synthesis of
benzofurans see: c) D. Zhao, N. Wu, S. Zhang, P. Xi, X. Su, J.
Received: April 18, 2011
Published Online: July 18, 2011
4876
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4868–4876