One-Pot Synthesis of 2-Styrylindoles from Ortho-Substituted Chloroenynes

Article abstract of DOI:10.1021/acs.joc.8b02563

A facile one-pot synthesis of 2-styrylindoles, through Suzuki arylation of ortho-substituted chloroenynes followed by N-cyclization and N-demethylation, has been developed. A variety of 2-styrylindoles were obtained in good to excellent yields and were evaluated for their anticancer properties.

Full text of DOI:10.1021/acs.joc.8b02563

Subscriber access provided by TULANE UNIVERSITY
Article
One Pot Synthesis of 2-Styrylindoles from Ortho-Substituted Chloroenynes
Guangkuan Zhao, Jérome Bignon, Helene Levaique, Joelle Dubois, Mouad Alami, and Olivier Provot
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02563 • Publication Date (Web): 06 Dec 2018
Downloaded from http://pubs.acs.org on December 7, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
One Pot Synthesis of 2-Styrylindoles from Ortho-Substituted
Chloroenynes
Guangkuan Zhao,a Jerôme Bignon,b Helène Levaique,b Joëlle Dubois,b Mouad Alamia* and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Olivier Provota*
a Univ. Paris-Sud, BioCIS, CNRS, University Paris-Saclay, Equipe Labellisée Ligue Contre Le Cancer, F-92296
Châtenay-Malabry, France
bCIBI Platform, Institut de Chimie des Substances Naturelles, UPR 2301, CNRS avenue de la terrasse, F-91198 Gif
sur Yvette, France.
olivier.provot@u-psud.fr or mouad.alami@u-psud.fr
KEYWORDS: 2-Styrylindole, palladium, Suzuki, coupling, cyclization.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
ABSTRACT: A facile one pot synthesis of 2-styrylindoles, through Suzuki-arylation of ortho-substituted chloroenynes
followed by N-cyclization and N-demethylation has been developed. A variety of 2-styrylindoles were obtained in good
to excellent yields and were evaluated for their anticancer properties.
1. INTRODUCTION
Combretastatin A-4 (CA-4, Fig. 1) is a (Z)-stilbene
isolated in 1989 by Pettit from the South African willow
tree Combretum caffrum.1
This natural compound exhibited strong antitumor
properties as for example, a nanomolar level of
cytotoxicity against a variety of cancer cell lines
including multi-drugs resistant cells.2 Moreover at very
low doses, CA-4 inhibited tubulin assembly by binding at
the colchicine binding-site,3 induced apoptosis4 and
caused in vivo spectacular vascular shutdown in
established tumors.5 In 2016, CA-4P (fosbretabulin), a
phosphate water-soluble prodrug of the natural product
has received the status of orphan drug in USA and
Europe for the treatment of ovarian cancers,
neuroendocrine tumours, certain thyroid cancers and
multiform glioma.6 Despite these excellent antitumor
properties, CA-4 has some drawbacks as a poor water-
MeO
MeO
CA-4P (fosbretabulin)6
OPO3Na2
MeO
MeO
Combretastatin A-41
Stable CA-4 analogues discovered in our group:
A
B
OH
OMe
OMe
OMe
OMe
MeO
MeO
OH
MeO
MeO
OH
MeO
MeO
N
F
OMe
OMe
OMe
OMe
isoCA-410d
GI50 (HCT-116) = 2 nM
OMe
OMe
azaFiso-erianin12
iso
GI50 (HCT-116) = 28 nM
erianin11
GI50 (HCT-116) = 20 nM
Stable CA-4 isomers having an indolic B-ring:
solubility and
a chemical instability due to the
R
N
isomerization of the Z-double bond to its less active E-
form during storage, administration7 and metabolism.8
Due to the simplicity of its chemical structure, CA-4 has
been extensively studied to find more stable analogues
and to establish structure-activity relationships (SARs).9
As a part of our research program dedicated to novel
stable vascular disrupting agents (VDAs)10 having a non-
isomerizable spacer between A- and B-rings, we found
that isoCA-4,10d isoerianin11 and azaFiso-erianin12
derivatives were as potent as CA-4 with comparable
anticancer activities (Fig. 1). Moreover, if the
replacement of the 3,4,5-trimethoxyphenyl A-ring of CA-
4 has received little attention,13 the B-ring of CA-4 has
been subject to numerous modifications and can be
replaced for example, by a variety of indole nuclei with
MeO
MeO
N
MeO
MeO
N
OMe
OMe
GI50 (HCT-116) = 7 nM12
R = H, CI50 (HT-29) = 3 nM14c
R = CN, CI50 (HT-29) = 4 nM14c
N
MeO
CHO
Cl
MeO
MeO
CI50 (HT-29) = 20 nM14e
MeO
OMe
N
N
OMe
CI50 (Lovo) = 52 nM14d
This work:
MeO
MeO
MeO
MeO
N
N
N
Ar
Ar
OMe
OMe
1
2
FIGURE 1. CA-4 and structural analogues
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 12
no loss of biological properties.14 For examples, it was
cyclization-step to furnish a small library of 2-styryl
indoles after N-demethylation. After optimization of this
“one pot” three-step process, the cytotoxicity of novel 2-
styrylindoles 1 and 2 having a trimethoxyphenyl A-ring
will be discussed.
recently showed that non-substituted N-methylindoles12
and 3-substituted indoles14 replaced with a certain
success the traditional phenolic B-ring of CA-4. To our
knowledge, introduction of styryl substituents on the C-2
position of the indole B-ring and their effects on
biological activity was not reported in the CA-4 and
isoCA-4 series.
1
2
3
4
5
6
7
8
2. RESULTS AND DISCUSSION
The required starting material, (E)-2-(4-chlorobut-3-en-1-
yn-1-yl)-N,N-dimethylaniline 3a, used as
a model
Due to the synthetic and biological interest for 2-
alkenylindoles,15 their preparations have been well
studied16 and often, involve the alkenylation of pre-
formed indoles by C-H functionalization17 or by Suzuki-
Miyaura coupling reactions.18 Otherwise, 2-styrylindoles
have also been prepared from 5-endo-dig-cyclizations of
substrate, was readily prepared by the Sonogashira
coupling of 2-ethynyl-N,N-dimethylaniline with (E)-1,2-
dichloroethylene in 78 %. Since the treatment of
chloroenyne 3 with boronic acids in the presence of
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
suitable Pd-catalysts would lead to diarylated enynes20
4
intermediates, we anticipated that the Pd species might
activated the alkyne triple bond of intermediates 4 to
2-alkynylanilines having
a free NH2 function by
electrochemistry or using various metal catalysts.19
Herein, we would like to present a novel and rapid access
to 2-alkenylindoles from an efficient “one pot” Suzuki
provide 2-styrylindoles
5 after N-cyclization and
ammonium demethylation. To identify suitable
conditions for this transformation, we evaluated the
Suzuki arylation / cyclization / N-demethylation reaction
with (E)-chloroenyne 3a in the presence of (4-acetyl)
phenylboronic acid and a variety of Pd-catalysts. The
result of this study is reported in Table 1.
arylation–heterocyclization-N-demethylation
process.
N,N-Dimethylanilines having on ortho-position
a
conjugated chloroenyne moiety were firstly arylated
using different boronic acids in the presence of a catalytic
amount of Pd(PPh3)4 which was re-used for the
TABLE 1: Optimization of the tandem Suzuki-Miyaura cyclization reaction between (E)-3 and (4-acetylphenyl) boronic
acida
O
: R1 = R2 = Me
: R1 = R2 = H
3a 4a
,
Cl
O
O
[Pd] (x mol%),
3b 4b
,
K2CO3 (2 equiv)
,
: R1 = Me, R2 = H
: R1 = H, R2 = Ts
3c 4c
+
+
R2
R2
3d 4a
,
Toluene/MeOH
90 °C, Time
(HO)2B
N
N
R1
N
R1
5a, 5c: R1 = Me
R1
: R1 = H
5b 5d
,
5
(E)-
3
(E)-
4
(E)-
Entry
[Pd]
3
x
Time
(h)
4
Yield of
5
Yield of
(E)-4 (%)b
(E)-5 (%)b
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(dba)2
PdCl2(PhCN)2
PdCl2(dppf)
XantPhos Pd G3
Pd(PPh3)4
Pd(PPh3)4
3a
5
15
15
15
15
15
15
30
48
48
48
48
4a
46
ndc
ndc
ndc
ndc
32
5a
43
ndc
ndc
ndc
ndc
55
5
5
5
5
8
8
8
8
8
8
21
67
90
Pd(PPh3)4
Pd(PPh3)4
0
3b
3c
3d
4b
4c
4d
ndc
ndc
ndc
5b
5c
5d
ndc
ndc
ndc
10 Pd(PPh3)4
11 Pd(PPh3)4
aConditions: (E)-3 (0.5 mmol), (4-acetyl)boronic acid (0.65 mmol), [Pd] (x mmol), K2CO3 (2 equiv) and toluene/MeOH (2:1) (9 mL) were
heated in a sealed tube at 90 °C for time indicated in Table 1 under an argon atmosphere. Yield of isolated product. c Complex mixture of
b
compounds.
Initially, we have tested the conditions developed in our
laboratory for the coupling of boronic acids with
chloroenynes20 using Pd(PPh3)4 (5 mol %) as the catalyst,
K2CO3 (2 equiv) as the base, and toluene/MeOH (2:1) as
the solvent combination at 90 °C in a sealed tube (entry
1). After 15 h of stirring and disappearance of
chloroenyne (E)-3a, we isolated the desired indole (E)-5a
together with diarylenyne (E)-4a in almost similar yields.
This promising first result, confirming our initial
hypothesis, led us to evaluate other Pd-catalysts to
improve the cyclization reaction of the (E)-4a
intermediate. Unfortunately, as depicted in entries 2-5,
none of the Pd(0), Pd(II) catalysts as well as the third
generation (G3) Buchwald pre-catalyst were able to
transform (E)-3a into indole (E)-5a which was not
detected in crude mixtures after 15 h of reaction. It is
likely that under these conditions, the Suzuki-arylation
reaction leading to 4a did not occur and that (E)-3a was
completely degraded. We then decided to increase the
amount of Pd(PPh3)4 quantity from 5 to 8 mol %, and we
were pleased to observe the formation of indole (E)-5a,
as the main product (90 %) after 48 h of reaction (entry
8). Further screening of solvents, solvent combinations
and bases associated to Pd(PPh3)4 were less effective for
2-styrylindole (E)-5a generation. We also examine the
efficiency of this process, under our optimized
conditions, with arylated chloroenynes 3b-d (entries 9-
11) having on ortho-position a free-NH2 (3b), a
secondary amine (NHMe, 3c) or a NH-tosylamine (3d).
In contrast to (E)-3a, none of chloroenynes 3b-d were
able to provide the desired corresponding indole
derivatives which were not detected in the crude complex
mixtures. Using 8 mol% of Pd(PPh3)4 in the presence of 2
equiv of K2CO3 in hot toluene/MeOH mixture,
2
ACS Paragon Plus Environment

Page 3 of 12
The Journal of Organic Chemistry
chloroenyne (E)-3a reacted with various boronic acids to
reacted efficiently to provide the desired 2-styryl indoles
with high to excellent yields for this three-step “one-pot”
reaction (from 71 to 92%).
1
2
3
4
5
6
7
8
generate a number of 2-styrylindoles 5a-l. As depicted in
Figure 2, the reaction exhibits excellent scope: both
electron-deficient and electron-rich arylboronic acids
Ar1
(1.3 equiv)
B(OH)2
Pd(PPh3)4 (8 mol%)
K2CO3 (2 equiv)
Ar1
Cl
toluene/MeOH (2:1), 90 °C
48 h, sealed tube
N
N
3a
(E)-5a-l
(E)-
O
F
Cl
CN
OMe
9
N
N
N
N
N
N
N
NO2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-5a (90%)
(E)-5b (88%)
(E)-5c (90%)
(E)-5d (71%)
(E)-5e (85%)
(E)-5k (84%)
(E)-5f (92%)
OMe
OMe
OMe
Me
OMe
S
N
N
N
N
Me
N
(E)-5g (86%)
(E)-5h (78%)
(E)-5i (90%)
(E)-5j (89%)
(E)-5l (86%)
FIGURE 2. Tandem Suzuki-Miyaura cyclization reaction of (E)-chloroenyne 3a using a variety of arylboronic acids.
TMS
NNHTs
TMS
Substitutions are readily tolerated at all positions of the
MeO
MeO
Br
I
Br
SiMe3
(i)
(ii)
(iii)
arylboronic acid substrates to provide the 2-styrylindoles
in similar yields (5f-h). Introduction of heterocycles on
the double bond is also permitted with this protocol since
5l was obtained in a good yield of 86 % using 2-
benzothiophene boronic acid as the nucleophile. The
following mechanism depicted in Scheme 1 can be
considered.
MeO
N
MeO
N
N
OMe
8 (86%)
OMe
7
6 (91%)
H
Cl
MeO
MeO
(iv)
MeO
MeO
Cl
N
N
Cl
OMe
OMe
9 (92%)
(E)-3e (76%)
aConditions: (i) ArI (20 mmol), alkyne (22 mmol), PdCl2(PPh3)2 (5
mol %), CuI (10 mol %), Et3N, rt. (ii) 7 (12 mmol), 6 (10 mmol),
Pd2dba3 (5 mol %), Xphos (10 mol %), LiOtBu (2.2 equiv), dioxane,
70 °C. (iii) K2CO3, MeOH, rt. (iv) (E)-1,2-dichloroethylene (10
equiv), PdCl2(PPh3)2 (5 mo%), CuI (10 mol %), piperidine (2 equiv),
Et2O, rt.
SCHEME 1. Plausible mechanism for the synthesis of
styrylindoles 5 from chloroenyne (E)-3a.
Cl
Ar
Ar B(OH)2
Pd(PPh3)4, K2CO3
toluene/MeOH, 90 °C
CH3
CH3
N
N
CH3
CH3
Then, by using a recent methodology developed by
Barluenga and co-workers,23 diarylethylene derivative 8
was synthesized in a good yield of 86% through the
palladium coupling reaction of N-tosylhydrazone 7 with 6
using Pd2dba3 as the catalyst, Xphos as the ligand and
LiOtBu as the base in hot dioxane. Under these basic
conditions, we were surprised to observe that the TMS
group of 8 remained unchanged and was finally
deprotected under classical conditions using K2CO3 in
MeOH to give 9 (92%). A further Sonogashira-
4
-3a
(E)
5-endo-dig
cyclization
Ar
Ar
N
-demethylation
- CH3OCH3
N
N
CH3
CH3
H3C
5
A plausible mechanism is depicted in Scheme 1
involving the formation of an indolinium salt according
to a 5-endo-dig cyclization of diarylenyne 4.21 Then, a N-
demethylation step of the indolinium by MeOH leads to
styrylindole 5 and dimethylether.22
Next, as part of our medicinal chemistry project, we next
have synthesized N,N-dimethylaniline (E)-3e having a
chloroenyne group on ortho-position and on para-
position a 1-(3,4,5-trimethoxyphenyl)vinyl moiety as the
future A-ring (Scheme 2).
Linstrumelle
coupling
reaction
with
(E)-1,2-
dichloroethylene furnished (E)-3e (76%) as a useful
platform to introduce a variety of styryl groups on the C-
2 position of novel substituted indole derivatives after
Pd-catalyzed arylation-cyclization reactions (Figure 3).
By applying our optimized protocol developed for the
tandem arylation-cyclization of chloroenyne (E)-3 with
boronic acids, we prepared the desired indole derivatives
(E)-1a-g in moderate yields due to difficulties
encountered during the purification step.
A Pd-catalyzed reaction of trimethylsilylacetylene with
4-bromo-2-iodo-N,N-dimethylaniline afforded trimethyl
silylated (TMS)-alkyne 6 according to a Sonogashira
coupling reaction (91%).
Next, to synthesize a series of azaisoerianin analogues
(E)-2a-d of biological interest, 3,4,5-trimethoxy-N-
methylaniline was coupled with alkyne 6 under Pd-
catalysis to give tertiary amine 10 (83%). After a
desilylation step of the alkyne function of 10, the
resulting terminal alkyne 11 (90%) was then coupled
with (E)-1,2-dichloroethylene to give (E)-3f in an
acceptable yield of 66%. This later was then transformed
into the desired indoles 2a-d using this novel Suzuki-
cyclization-N-demethylation process with good yields
(from 74% to 82%) for the three steps (Scheme 3).
SCHEME 2. Synthesis of (E)-3e.a
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
In vitro cytotoxicity of the newly synthesized indole
Page 4 of 12
Ar1 B(OH)2
(1.3 equiv)
Cl
Pd(PPh3
)4 (8 mol %)
K2CO3 (2 equiv)
1
2
3
4
5
6
7
8
Ar1
derivatives 1 and 2 was investigated against HCT116, a
human colon carcinoma cell line. A colorimetric-based
assay was used to determine the drug concentration
required to inhibit cell growth by 50% (GI50) after
incubation in the culture medium for 72 h. IsoCA-4 was
included as the reference for comparisons. The screening
revealed that all newly synthesized indole derivatives 1
and 2 evaluated against HCT cancer cell lines displayed
an average level of cytotoxicity when compared with
isoCA-4 (Table 2). The comparison of the GI50 values
obtained for compounds 1 and 2 clearly revealed that 1,1-
diarylethylenes derivatives 1a-g displayed a promising
MeO
MeO
MeO
toluene/MeOH (2:1), 90 °C
48 h, sealed tube
N
MeO
N
OMe
OMe
1a-g
N
(E)-
3e
(E)-
O
MeO
MeO
MeO
F
N
MeO
OMe
OMe
1a
1b
(E)- (55%)
(E)- (58%)
MeO
MeO
MeO
MeO
OMe
9
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
OMe
1c
1d
(E)- (61%)
(E)- (63%)
sub-micromolar level of cytotoxicity (0.18 M < GI50
<
0.74 M) whereas their N-Methyl analogues 2a-d
displayed a lower level of cytotoxicity with GI50 values
ranging from 1.32 to 4.08M. The cytotoxic of promising
derivatives 1c and 1e having respectively a p-methoxy
and a m-NO2 group on their aromatic rings displayed
encouraging GI50 values (0.26 M for 1c and 0.18 M
for1e.) will be furthermore modified in our lab in view of
possible improvements of cytotoxicity against a range
human cancer cell lines.
MeO
MeO
MeO
MeO
N
NO2
N
OMe
OMe
1e
(E)- (57%)
1f
(E)- (60%)
MeO
MeO
N
NH2
OMe
1g
(E)- (58%)
FIGURE 3. Tandem Suzuki-cyclization reaction of (E)-
chloroenyne 3e using a variety of arylboronic acids.
SCHEME 3. Synthesis of (E)-2a-d.
H
N
TMS
(ii)
H
Cl
TMS
MeO
MeO
MeO
MeO
N
MeO
MeO
N
MeO
MeO
N
Br
(iii)
Cl
(i)
(iv)
ArBH(OH)2
(E)-2a-d
N
N
N
N
OMe
OMe
OMe
Cl
OMe
(E)-3f (66%)
6
10 (83%)
11 (90%)
O
MeO
MeO
N
MeO
MeO
N
MeO
MeO
N
MeO
MeO
N
F
OMe
N
N
N
N
OMe
OMe
OMe
OMe
(E)-2a(77%)
(E)-2b (74%)
(E)-2c (82%)
(E)-2d (80%)
aConditions: (i) ArBr (1 mmol), 3,4,5-trimethoxy-N-methylaniline (1.2 mmol), Pd2dba3 (5 mol %), Xphos (10 mol %), NaOtBu (2.2 equiv),
toluene, 70 °C. (ii) K2CO3, MeOH, rt. (iii) (E)-1,2-dichloroethylene (10 equiv), PdCl2(PPh3)2 (5 mo%), CuI (10 mol %), piperidine (5 equiv),
Et2O, rt. (iv) (E)-3f (0.5 mmol), boronic acid (0.65 mmol), Pd(PPh3)4 (8 mol%), K2CO3 (2 equiv) were diluted in in toluene/MeOH (2:1) (9 mL)
and placed in a sealed tube and heated at 90 °C.
TABLE 2. Cytotoxicity against HCT116 cellsa and ITP of indoles 1a-g and 2a-d.
Compound
(E)-1a
(E)-1b
(E)-1c
(E)-1d
(E)-1e
(E)-1f
b
Cytotoxicity GI50
0.74 ± 0.17 0.43 ± 0.21 0.26 ± 0.02 0.37 ± 0.04 0.18 ± 0.06 0.52 ± 0.07
[M]
% of inhibition at
100 M
21
31
23
37
26
56
Compound
(E)-1g
(E)-2a
(E)-2b
(E)-2c
(E)-2d
isoCA-4
b
Cytotoxicity GI50
0.54 ± 0.03 1.90 ± 0.67 1.32 ± 0.32 1.84 ± 0.27 4.08 ± 0.41
40 35 36 83 19
0.002
[M]
% of inhibition at
1.0 ± 0.1c
100 M
aHCT-116 Human colon carcinoma. bGI50 is the concentration of compound needed to reduce cell growth by 50% following 72 h cell treatment
c
with the tested drug (average of three experiments). GI50 is the concentration of isoCA-4 required to inhibit 50% of the rate of microtubule
assembly (average of three experiments).
To examine if the cytotoxicity of compounds 1 and 2 was
related to an interaction with the microtubule system,
indoles 1 and 2 were next evaluated in tubulin assembly
assays in parallel with isoCA-4 (Table 2). However, 1c
and 1e which displayed the best cytotoxicity level against
HCT116 cells inhibited tubulin assembly with modest
GI50 values comparable to the GI50 of all other indole
derivatives 1 and 2. Currently, we are working to
improve the cytotoxicity of derivatives 1 through the
introduction of more suitable substituents.
4
ACS Paragon Plus Environment

Page 5 of 12
The Journal of Organic Chemistry
3. CONCLUSION
(E)-2-(4-Chlorobut-3-en-1-yn-1-yl)aniline (3b)
1
2
3
4
5
6
7
8
In summary, we have discovered a novel 3-steps Suzuki-
Miyaura arylation / cyclization / N-demethylation of (E)-
2-(4-chlorobut-3-en-1-yn-1-yl)-N,N-dimethylanilines, gi-
ving an efficient and rapid access to 2-styrylindoles with
good to excellent yields. Using this strategy, we have
rapidly achieved the synthesis of a series of 1,1-
diarylethylenes 1 and diarylmethylamines 2 bearing a
3,4,5-trimethoxyphenyl core and various functionalized
2-styrylindoles as isoCA-4 and azaisoerianin analogues.
From the preliminary biological results, indoles 1c and 1e
were the most promising compounds with nanomolar
GI50 values. Structural modifications on the indole
nucleus are currently under study in our laboratory and
will be published later.
Brown oil, yield 79%, 702 mg.
1H NMR (300 MHz, CDCl3) δ = 7.16 (d, J = 7.5 Hz, 1H),
7.01 (t, J = 8.1 Hz, 1H), 6.61 – 6.45 (m, 3H), 6.08 (d, J =
13.5 Hz, 1H), 4.01 (br, 2H). 13C NMR (75 MHz, CDCl3)
δ = 147.9 (Cq), 132.1 (CH), 130.1 (CH), 129.6 (CH),
118.0 (CH), 114.4 (CH), 113.8 (CH), 107.2 (Cq), 89.6
(Cq), 88.7 (Cq). IR (neat): 3479, 3384, 2194, 1699, 1488,
1314 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C10H9N35Cl: 178.0424; found: 178.0424.
9
(E)-2-(4-Chlorobut-3-en-1-yn-1-yl)-N,N-dimethyl-4-
(1-(3,4,5-trimethoxyphenyl)vinyl)-aniline (3e)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Brown oil, yield 76%, 1.51 g.
1H NMR (300 MHz, acetone-d6) δ = 7.36 (d, J = 2.1 Hz,
1H), 7.26 (dd, J = 8.7 Hz, J = 2.1 Hz, 1H), 6.91 (d, J =
8.7 Hz, 1H), 6.82 (d, J = 13.5 Hz, 1H), 6.62 (s, 2H), 6.33
(d, J = 13.5 Hz, 1H), 5.38 (s, 1H), 5.35 (s, 1H), 3.79 (s,
6H), 3.77 (s, 3H), 2.97 (s, 6H). 13C{1H} NMR (75 MHz,
CDCl3) δ = 159.1 (Cq), 157.9 (2 Cq), 153.1 (Cq), 142.6
(Cq), 141.7 (Cq), 138.3 (CH), 137.1 (Cq), 135.2 (CH),
134.6 (CH), 121.9 (CH), 119.4 (CH), 118.3 (CH2), 117.3
(Cq), 110.8 (2 CH), 96.7 (Cq), 94.8 (Cq), 65.2 (CH3),
61.1 (2 CH3), 47.9 (2 CH3). IR (neat): 2937, 2196, 1579,
1502, 1347, 1235 cm-1. HRMS (ESI): m/z [M+H]+ calcd
for C23H25NO335Cl: 398.1523; found: 398.1523.
4. EXPERIMENTAL SECTION
General Information and Method. All glasswares were
oven-dried at 140 °C and all reactions were conducted
under an argon atmosphere. Solvents: cyclohexane, ethyl
acetate (EtOAc), for chromatography, were technical
1
grade. The H NMR and 13C NMR and 19F spectra were
recorded in CDCl3, acetone-d6 or DMSO-d6 on Bruker
Avance 300 spectrometer. The chemical shifts of H are
reported in ppm relative to the solvent residual peak in
1
CDCl3 (δ 7.26), acetone-d6 (δ 2.05), DMSO-d6 (δ 2.50)
1
for H NMR. For the 13C NMR spectra, the solvent
(E)-2-(4-Chlorobut-3-en-1-yn-1-yl)-N1,N1,N4-trimethyl
signals of CDCl3 (δ 77.14), acetone-d6 (δ 206.26),
DMSO-d6 (δ 39.52) were used as the internal standards.
The following abreviation are used: m (multiplet), s
(singlet), d (doublet), t (triplet), dd (doublet of doublet),
td (triplet of doublet), ddd (doublet of doublet of
doublet). IR spectra were measured on a Bruker Vector
22 spectrophotometer (neat, cm-1). High-resolution mass
spectra were recorded on a Bruker Daltonics micrOTOF-
Q instrument. Analytical TLC was performed on Merck
precoated silica gel 60 F-254 plates. Merck silica gel 60
(230-400 mesh) was used for column chromatography.
The plates were visualized by either UV light (254 nm),
or by a solution of phosphomolybdic acid in ethanol.
-N4-(3,4,5-trimethoxyphenyl)-benzene-1,4-diamine (3f)
Brown oil, yield 66%, 1.32 g.
1H NMR (300 MHz, acetone-d6) δ = 7.09 – 6.90 (m, 3H),
6.83 (d, J = 13.5 Hz, 1H), 6.34 (d, J = 13.5 Hz, 1H), 6.25
(s, 2H), 3.75 (s, 6H), 3.69 (s, 3H), 3.23 (s, 3H), 2.86 (s,
6H). 13C{1H} NMR (75 MHz, acetone-d6) δ = 154.8 (2
Cq), 150.8 (Cq), 146.6 (Cq), 143.8 (Cq), 134.2 (Cq),
130.1 (CH), 127.0 (CH), 124.1 (CH), 119.1 (CH), 116.2
(Cq), 115.2 (CH), 98.9 (2 CH), 92.4 (Cq), 89.9 (Cq), 60.6
(CH3), 56.4 (2 CH3), 43.9 (2 CH3), 40.9 (CH3). IR (neat):
2937, 2197, 1585, 1496, 1235, 1128 cm-1. HRMS (ESI):
m/z [M+H]+ calcd for C22H26N2O335Cl: 401.1632; found:
401.1639.
General procedure for the synthesis of (E)-
chloroenynes 3a, 3b, 3e, 3f.
Procedure for the synthesis of (E)-chloroenynes 3c.
To a solution of alkyne (5 mmol) in Et2O (30 mL) was
added successively (E)-1,2-dichloroethylene (4 mL, 50
mmol), PdCl2(PPh3)2 (175 mg, 0.25 mmol), piperidine (1
mL, 10 mmol) and CuI (95 mg, 0.5 mmol). After
complete disappearance of starting material monitored by
TLC, the solution was filtered through a pad of celite
using EtOAc. The organic layer was washed successively
with sat. NH4Cl, sat. NaHCO3 and HCl (1 M) solutions.
After drying over MgSO4 and evaporation in vacuo, the
crude residue was purified by silica gel column
chromatography (0 to 30% AcOEt in cyclohexane) (the
crude of 3g was purified on neutral Al2O3).
To a solution of 3b (5 mmol, 888 mg) in DMF (30 mL)
was added K2CO3 (1.5 equiv) and iodomethane (1.1
equiv). The reaction was stirred at room temperature for
3 h then quenched with water (30 mL). The aqueous layer
was extracted with CH2Cl2 three times and the combined
organic extracts were dried with anhydrous MgSO4,
filtered and concentrated. The crude mixture was purified
by silica gel column chromatography (0 to 30% AcOEt in
cyclohexane).
(E)-2-(4-Chlorobut-3-en-1-yn-1-yl)-N-methylaniline
(3c)
Brown oil, yield 48%, 460 mg.
(E)-2-(4-Chlorobut-3-en-1-yn-1-yl)-N,N-dimethyl
aniline (3a)
1H NMR (300 MHz, CDCl3) δ = 7.22 – 7.10 (m, 2H),
6.63 – 6.44 (m, 3H), 6.11 (d, J = 13.8 Hz, 1H), 4.46 (br,
1H), 2.80 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ =
149.9 (Cq), 132.2 (CH), 130.5 (CH), 129.5 (CH), 116.4
(CH), 114.0 (CH), 109.2 (CH), 106.7 (Cq), 89.9 (Cq),
88.9 (Cq), 30.3 (CH3). IR (neat): 3421, 3071, 2191, 1510,
1320 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C11H11N35Cl: 192.0580; found: 192.0570.
Brown solid, mp 36.8 – 37.0 °C, yield 78%, 802 mg.
1H NMR (300 MHz, CDCl3) δ = 7.52 (dd, J = 7.5 Hz, J =
1.2 Hz, 1H), 7.28 (td, J = 7.5 Hz, J = 1.2 Hz, 1H), 6.97 –
6.86 (m, 2H), 6.63 (d, J = 13.5 Hz, 1H), 6.25 (d, J = 13.5
Hz, 1H), 2.95 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ
= 154.9 (Cq), 134.3 (CH), 129.7 (CH), 129.2 (CH), 120.7
(CH), 117.1 (CH), 114.6 (Cq), 114.4 (CH), 91.5 (Cq),
89.7 (Cq), 43.6 (2 CH3). IR (neat): 2945, 2197, 1595,
1325, 1049, 1011 cm-1. HRMS (ESI): m/z [M+H]+ calcd
for C12H13N35Cl: 206.0737; found: 206.0735.
Procedure for the synthesis of (E)-chloroenynes 3d.
A solution of 4-methylbenzene-1-sulfonyl chloride (1
equiv) in THF (20 mL) was added dropwise over 0.5 h to
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 12
a solution of 3b (5 mmol) and pyridine (1.1 equiv) in
(CH), 128.6 (2 CH), 128.2 (2 CH), 127.4 (Cq), 121.4
(CH), 119.9 (CH), 119.6 (CH), 118.2 (CH), 109.7 (CH),
98.5 (CH), 29.7 (CH3). IR (neat): 1532, 1443, 1320, 1248
cm-1. HRMS (APCI): m/z [M+H]+ calcd for C17H15N35Cl:
268.0888; found: 268.0891.
1
2
3
4
5
6
7
8
THF (30 mL) under argon. The solution was stirred at r.t.
for 12 h. The resulting mixture was evaporated under
vacuum and the residue was purified by silica gel column
chromatography (0 to 30% AcOEt in cyclohexane).
(E)-N-(2-(4-Chlorobut-3-en-1-yn-1-yl)phenyl)-4-
methylbenzenesulfonamide (3d)
(E)-1-Methyl-2-(3-nitrostyryl)-1H-indole (5d)
Yellow solid, mp 136.9 – 137.2 °C, yield 71%, 98.8 mg.
White solid, mp 125.6 – 125.9 °C, yield 63%, 1.05 g.
1H NMR (300 MHz, CDCl3) δ = 8.26 (s, 1H), 7.99 (d, J =
8.4 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.8 Hz,
1H), 7.42 (t, J = 7.8 Hz, 1H), 7.23 – 7.01 (m, 5H), 6.77
(s, 1H), 3.73 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
= 148.9 (Cq), 139.0 (Cq), 138.5 (Cq), 137.3 (Cq), 132.3
(CH), 129.7 (CH), 127.9 (Cq), 127.8 (CH), 122.5 (CH),
122.1 (CH), 120.8 (CH), 120.6 (CH), 120.3 (CH), 120.1
(CH), 109.4 (CH), 100.4 (CH), 30.1 (CH3). IR (neat):
1520, 1463, 1347, 1321 cm-1. HRMS (ESI): m/z [M+H]+
calcd for C17H15N2O2: 279.1134; found: 279.1125.
1H NMR (300 MHz, CDCl3) δ = 7.68 (d, J = 8.4 Hz, 2H),
7.59 (d, J = 8.4 Hz, 1H), 7.33 – 7.22 (m, 4H), 7.10 – 7.01
(m, 2H), 6.63 (d, J = 13.8 Hz, 1H), 6.13 (d, J = 13.8 Hz,
1H), 2.39 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ =
144.2 (Cq), 137.7 (Cq), 136.2 (Cq), 132.2 (CH), 131.8
(CH), 130.1 (CH), 129.7 (2 CH), 127.3 (2 CH), 124.7
(CH), 120.4 (CH), 114.0 (Cq), 113.0 (CH), 90.9 (Cq),
86.4 (Cq), 21.7 (CH3). IR (neat): 3074, 1489, 1396, 1159
cm-1. HRMS (ESI): m/z [M+Na]+ calcd for
C17H14NO2NaS35Cl: 354.0331; found: 354.0332.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-4-(2-(1-Methyl-1H-indol-2-yl)vinyl)benzonitrile
(5e)
General procedure for the synthesis of 2-styrylindole
5, 1, 2.
Yellow solid, mp 177.4 – 177.7 °C, yield 85%, 109.8 mg.
Under argon, chloroenyne (0.5 mmol), the desired
boronic acid (1.3 equiv), K2CO3 (2 equiv), and Pd(PPh3)4
(8 mol%) were mixed in toluene (6 mL) and MeOH (3
mL). The reaction mixture was stirred at 90°C in 30 mL
sealed tube monitored by TLC (48 h). After the mixture
were allowed to cool to room temperature and filtrated
through a pad of celite washed by CH2Cl2. Solvent was
removed under reduced pressure and the crude material
was purified by silica gel column chromatography (0 to
30% AcOEt in cyclohexane).
1H NMR (300 MHz, DMSO-d6) δ = 7.95 – 7.77 (m, 4H),
7.66 (d, J = 16.2 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.46
(d, J = 8.4 Hz, 1H), 7.38 (d, J = 16.2 Hz, 1H), 7.16 (t, J =
7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.98 (s, 1H), 3.88
(s, 3H). 13C{1H} NMR (75 MHz, DMSO-d6) δ = 141.8
(Cq), 138.0 (Cq), 137.5 (Cq), 132.5 (2 CH), 128.1 (CH),
127.3 (Cq), 127.1 (2 CH), 121.9 (CH), 121.0 (CH), 120.2
(CH), 119.7 (CH), 119.1 (Cq), 109.9 (CH), 109.3 (Cq),
99.6 (CH), 29.7 (CH3). IR (neat): 2223, 1599, 1463,
1346, 1322 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C18H15N2: 259.1235; found: 259.1246.
(E)-1-(4-(2-(1-Methyl-1H-indol-2-yl)vinyl)phenyl)
ethan-1-one (5a)
(E)-2-(4-Methoxystyryl)-1-methyl-1H-indole (5f)
Yellow solid, mp 188.5 – 188.9 °C, yield 90%, 123.9 mg.
Yellow solid, mp 141.4 – 141.8 °C, yield 92%, 121.1 mg.
1H NMR (300 MHz, CDCl3) δ = 7.99 (d, J = 8.4 Hz, 2H),
7.65 – 7.60 (m, 3H), 7.36 – 7.11 (m, 5H), 6.90 (s, 1H),
3.86 (s, 3H), 2.64 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ = 197.5 (Cq), 141.9 (Cq), 138.5 (Cq), 137.8
(Cq), 136.1 (Cq), 129.3 (CH), 129.1 (2 CH), 128.0 (Cq),
126.5 (2 CH), 122.4 (CH), 120.8 (CH), 120.2 (CH),
119.7 (CH), 109.4 (CH), 100.2 (CH), 30.1 (CH3), 26.7
(CH3). IR (neat): 3054, 1675, 1597, 1348, 1274 cm-1.
HRMS (ESI): m/z [M+H]+ calcd for C19H18NO:
276.1388; found: 276.1378.
1H NMR (300 MHz, CDCl3) δ = 7.63 (d, J = 7.5 Hz, 1H),
7.51 (d, J = 8.4 Hz, 2H), 7.34 – 7.12 (m, 4H), 7.05 (d, J =
15.9 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 3.87
(s, 3H), 3.83 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
= 159.5 (Cq), 138.8 (Cq), 138.1 (Cq), 130.6 (CH), 130.0
(Cq), 128.1 (Cq), 127.7 (2 CH), 121.5 (CH), 120.3 (CH),
119.8 (CH), 114.9 (CH), 114.2 (2 CH), 109.1 (CH), 98.4
(CH), 55.4 (CH3), 29.9 (CH3). IR (neat): 1573, 1463,
1395, 1247 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C18H18NO: 264.1388; found: 264.1387.
(E)-2-(4-Fluorostyryl)-1-methyl-1H-indole (5b)
(E)-2-(3-Methoxystyryl)-1-methyl-1H-indole (5g)
Yellow solid, mp 155.5 – 155.8 °C, yield 88%, 110.6 mg.
Yellow solid, mp 94.1 – 94.5 °C, yield 86%, 102.7 mg.
1H NMR (300 MHz, DMSO-d6) δ = 7.77 – 7.71 (m, 2H),
7.54 – 6.99 (m, 8H), 6.86 (s, 1H), 3.85 (s, 3H). 13C{1H}
NMR (75 MHz, DMSO-d6) δ = 161.7 (d, J = 243.5 Hz,
Cq), 138.2 (Cq), 137.7 (Cq), 133.6 (d, J = 2.0 Hz, Cq),
129.0 (CH), 128.4 (d, J = 8.0 Hz, 2 CH), 127.4 (Cq),
121.3 (CH), 119.8 (CH), 119.5 (CH), 117.2 (CH), 115.6
(d, J = 21.4 Hz, 2 CH), 109.7 (CH), 98.1 (CH), 29.7
(CH3). 19F NMR (188 MHz, DMSO-d6): δ = - 114.1. IR
(neat): 1531, 1470, 1349, 1247, 1157 cm-1. HRMS (ESI):
m/z [M+H]+ calcd for C17H15NF: 252.1189; found:
252.1190.
1H NMR (300 MHz, CDCl3) δ = 7.65 (d, J = 8.1 Hz, 1H),
7.43 – 7.06 (m, 8H), 6.94 – 6.82 (m, 2H), 3.91 (s, 3H),
3.84 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ = 160.0
(Cq), 138.7 (Cq), 138.4 (Cq), 138.2 (Cq), 130.8 (CH),
129.8 (CH), 128.0 (Cq), 121.9 (CH), 120.5 (CH), 120.0
(CH), 119.2 (CH), 117.5 (CH), 113.4 (CH), 111.9 (CH),
109.2 (CH), 99.2 (CH), 55.4 (CH3), 30.0 (CH3). IR
(neat): 2936, 1597, 1577, 1433, 1319, 1284, 1157, 1010,
952 cm-1. HRMS (ESI): m/z [M+H]+ calcd for C18H18NO:
264.1388; found: 264.1390.
(E)-1-Methyl-2-(3,4,5-trimethoxystyryl)-1H-indole (5h)
(E)-2-(4-Chlorostyryl)-1-methyl-1H-indole (5c)
Yellow solid, mp 180.2 – 180.3 °C, yield 78%, 126.1 mg.
Yellow solid, mp 127.6 – 127.9 °C, yield 90%, 120.5 mg.
1H NMR (300 MHz, DMSO-d6) δ = 7.63 – 7.30 (m, 3H),
7.23 (d, J = 16.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.05 -
6.95 (m, 3H), 6.83 (s, 1H), 3.87 (s, 3H), 3.86 (s, 6H),
3.69 (s, 3H). 13C{1H} NMR (75 MHz, DMSO-d6) δ =
153.0 (2 Cq), 138.4 (Cq), 137.7 (Cq), 137.4 (Cq), 132.7
(Cq), 130.6 (CH), 127.5 (Cq), 121.2 (CH), 119.8 (CH),
1H NMR (300 MHz, DMSO-d6) δ = 7.72 (d, J = 8.4 Hz,
2H), 7.55 – 7.41 (m, 5H), 7.29 (d, J = 16.2 Hz, 1H), 7.13
(t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.89 (s, 1H),
3.86 (s, 3H). 13C{1H} NMR (75 MHz, DMSO-d6) δ =
138.0 (Cq), 137.8 (Cq), 136.0 (Cq), 131.9 (Cq), 128.8
6
ACS Paragon Plus Environment

Page 7 of 12
The Journal of Organic Chemistry
119.5 (CH), 116.6 (CH), 109.6 (CH), 104.1 (2 CH), 97.9
6.55 (s, 2H), 5.38 (s, 1H), 5.31 (s, 1H), 3.82 (s, 3H), 3.79
(s, 3H), 3.73 (s, 6H), 2.55 (s, 3H). 13C{1H} NMR (75
MHz, CDCl3) δ = 197.5 (Cq), 152.9 (2 Cq), 151.0 (Cq),
141.8 (Cq), 138.4 (Cq), 138.3 (Cq), 138.2 (Cq), 137.9
(Cq), 136.2 (Cq), 133.7 (Cq), 129.5 (CH), 129.1 (2 CH),
127.8 (Cq), 126.5 (2 CH), 123.4 (CH), 120.7 (CH), 119.6
(CH), 112.7 (CH2), 109.0 (CH), 105.9 (2 CH), 100.5
(CH), 61.1 (CH3), 56.3 (2 CH3), 30.3 (CH3), 26.7 (CH3).
IR (neat): 2936, 1678, 1598, 1579, 1504, 1392 cm-1.
HRMS (ESI): m/z [M+H]+ calcd for C30H30NO4:
468.2175; found: 468.2192.
1
2
3
4
5
6
7
8
(CH), 60.1 (CH3), 55.9 (2 CH3), 29.8 (CH3). IR (neat):
2925, 1581, 1504, 1465, 1366 cm-1. HRMS (ESI): m/z
[M+H]+ calcd for C20H22NO3: 324.1600; found:
324.1600.
(E)-2-(2,5-Dimethylstyryl)-1-methyl-1H-indole (5i)
Yellow solid, mp 121.1 – 121.2 °C, yield 90%, 117.6 mg.
1H NMR (300 MHz, DMSO-d6) δ = 7.63 (s, 1H), 7.56 –
7.37 (m, 3H), 7.29 (d, J = 15.9 Hz, 1H), 7.16 – 7.08 (m,
2H), 7.05 – 6.99 (m, 2H), 6.90 (s, 1H), 3.86 (s, 3H), 2.37
(s, 3H), 2.33 (s, 3H). 13C{1H} NMR (75 MHz, DMSO-
d6) δ = 138.6 (Cq), 137.7 (Cq), 135.3 (Cq), 135.0 (Cq),
132.4 (Cq), 130.3 (CH), 128.4 (CH), 127.8 (CH), 127.4
(Cq), 125.5 (CH), 121.2 (CH), 119.8 (CH), 119.5 (CH),
117.9 (CH), 109.7 (CH), 98.3 (CH), 29.7 (CH3), 20.7
(CH3), 19.0 (CH3). IR (neat): 2921, 1463, 1319, 1236,
1104, 954 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C19H20N: 262.1596; found: 262.1597.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-2-(4-Fluorostyryl)-1-methyl-5-(1-(3,4,5-trimethoxy
phenyl)vinyl)-1H-indole (1b)
Yellow solid, mp 151.6 – 151.8 °C, yield 58%, 128.6 mg.
1H NMR (300 MHz, acetone-d6) δ = 7.74 – 7.69 (m, 2H),
7.54 (s, 1H), 7.44 – 7.26 (m, 3H), 7.26 – 7.06 (m, 3H),
6.86 (s, 1H), 6.67 (s, 2H), 5.42 (s, 1H), 5.40 (s, 1H), 3.92
(s, 3H), 3.78 (s, 3H), 3.77 (s, 6H). 13C{1H} NMR (75
MHz, acetone-d6) δ = 163.2 (d, J = 244.1 Hz, Cq), 154.0
(2 Cq), 152.2 (Cq), 140.0 (Cq), 139.1 (Cq), 139.0 (Cq),
138.9 (Cq), 134.8 (d, J = 3.2 Hz, Cq), 134.0 (Cq), 130.3
(CH), 129.2 (d, J = 7.9 Hz, 2 CH), 128.9 (Cq), 123.2
(CH), 120.8 (CH), 118.0 (CH), 116.3 (d, J = 21.7 Hz, 2
CH), 112.5 (CH2), 109.9 (CH), 106.9 (2 CH), 99.8 (CH),
60.6 (CH3), 56.4 (2 CH3), 30.2 (CH3). 19F NMR (188
MHz, acetone-d6): δ = -113.558. IR (neat): 2937, 1631,
1505, 1462, 1391, 1277, 1260, 1235 cm-1. HRMS (ESI):
m/z [M+H]+ calcd for C28H27NO3F: 444.1975; found:
444.1973.
(E)-1-Methyl-2-(4-vinylstyryl)-1H-indole (5j)
Yellow solid, mp 157.6 – 157.8 °C, yield 89%, 115.4 mg.
1H NMR (300 MHz, CDCl3) δ = 7.50 (d, J = 7.8 Hz, 1H),
7.39 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.21 –
6.99 (m, 5H), 6.72 (s, 1H), 6.63 (dd, J = 17.4 Hz, J =
10.8 Hz, 1H), 5.69 (d, J = 17.6 Hz, 1H), 5.18 (d, J = 10.8
Hz, 1H), 3.70 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
= 138.5 (Cq), 138.3 (Cq), 137.2 (Cq), 136.8 (Cq), 136.5
(CH), 130.5 (CH), 128.1 (Cq), 126.7 (4 CH), 121.9 (CH),
120.5 (CH), 120.0 (CH), 117.0 (CH), 114.0 (CH2), 109.2
(CH), 99.2 (CH), 30.0 (CH3). IR (neat): 1530, 1462,
1346, 1320, 907 cm-1. HRMS (ESI): m/z [M+H]+ calcd
for C19H18N: 260.1439; found: 260.1445.
(E)-2-(4-Methoxystyryl)-1-methyl-5-(1-(3,4,5-trimetho
xyphenyl)vinyl)-1H-indole (1c)
Yellow solid, mp 159.7 – 159.9 °C, yield 61%, 136.7 mg.
(E)-1-Methyl-2-(2-(naphthalen-2-yl)vinyl)-1H-indole
(5k)
1H NMR (300 MHz, CDCl3) δ = 7.61 (s, 1H), 7.50 (d, J =
8.4 Hz, 2H), 7.30 – 7.14 (m, 3H), 7.10 – 6.89 (m, 3H),
6.77 (s, 1H), 6.67 (s, 2H), 5.48 (s, 1H), 5.41 (s, 1H), 3.93
(s, 3H), 3.87 – 3.83 (m, 12H). 13C{1H} NMR (75 MHz,
CDCl3) δ = 159.7 (Cq), 152.9 (2 Cq), 151.2 (Cq), 139.6
(Cq), 138.4 (Cq), 138.0 (Cq), 137.8 (Cq), 133.3 (Cq),
130.9 (CH), 130.0 (Cq), 128.0 (Cq), 127.8 (2 CH), 122.5
(CH), 120.3 (CH), 114.8 (CH), 114.3 (2 CH), 112.5
(CH2), 108.7 (CH), 105.9 (2 CH), 98.7 (CH), 61.0 (CH3),
56.2 (2 CH3), 55.4 (CH3), 30.1 (CH3). IR (neat): 2935,
1766, 1604, 1578, 1508, 1464, 1348, 1252 cm-1. HRMS
(ESI): m/z [M+H]+ calcd for C29H30NO4: 456.2175;
found: 456.2189.
Yellow solid, mp 198.3 – 198.5 °C, yield 84%, 119.0 mg.
1H NMR (300 MHz, DMSO-d6) δ = 8.20 – 7.80 (m, 5H),
7.63 – 7.43 (m, 6H), 7.14 (t, J = 7.5 Hz, 1H), 7.03 (t, J =
7.5 Hz, 1H), 6.94 (s, 1H), 3.90 (s, 3H). 13C{1H} NMR
(75 MHz, DMSO-d6) δ = 138.3 (Cq), 137.8 (Cq), 134.6
(Cq), 133.3 (Cq), 132.6 (Cq), 130.2 (CH), 128.1 (CH),
127.8 (CH), 127.6 (CH), 127.5 (Cq), 126.5 (CH), 126.4
(CH), 126.0 (CH), 123.7 (CH), 121.4 (CH), 119.9 (CH),
119.6 (CH), 117.8 (CH), 109.7 (CH), 98.4 (CH), 29.7
(CH3). IR (neat): 2923, 1463, 1342, 1320 cm-1. HRMS
(ESI): m/z [M+H]+ calcd for C21H18N: 284.1439; found:
284.1438.
(E)-1-Methyl-5-(1-(3,4,5-trimethoxyphenyl)vinyl)-2-
(4-vinylstyryl)-1H-indole (1d)
(E)-2-(2-(Benzo[b]thiophen-2-yl)vinyl)-1-methyl-1H-
indole (5l)
Yellow solid, mp 139.4 – 139.8 °C, yield 63%, 142.2 mg.
Yellow solid, mp 203.7 – 203.8 °C, yield 86%, 124.4 mg.
1H NMR (300 MHz, acetone-d6) δ = 7.64 (d, J = 8.1 Hz,
2H), 7.56 – 7.26 (m, 6H), 7.19 (dd, J = 8.4 Hz, J = 1.5
Hz, 1H), 6.88 (s, 1H), 6.78 (dd, J = 17.7 Hz, J = 11.1 Hz,
1H), 6.68 (s, 2H), 5.85 (d, J = 17.7 Hz, 1H), 5.41 (d, J =
4.8 Hz, 2H), 5.26 (d, J = 11.1 Hz, 1H), 3.91 (s, 3H), 3.78
(s, 3H), 3.77 (s, 6H). 13C{1H} NMR (75 MHz, acetone-
d6) δ = 154.0 (2 Cq), 152.2 (Cq), 140.1 (Cq), 139.1 (Cq),
139.0 (Cq), 138.9 (Cq), 137.9 (2 Cq), 137.4 (CH), 134.0
(Cq), 131.1 (CH), 128.9 (Cq), 127.6 (2 CH), 127.4 (2
CH), 123.3 (CH), 120.8 (CH), 118.0 (CH), 114.1 (CH2),
112.5 (CH2), 109.9 (CH), 106.9 (2 CH), 99.9 (CH), 60.6
(CH3), 56.4 (2 CH3), 30.2 (CH3). IR (neat): 2935, 1579,
1504, 1463, 1449, 1348 cm-1. HRMS (ESI): m/z [M+H]+
calcd for C30H30NO3: 452.2226; found: 452.2223.
1H NMR (300 MHz, DMSO-d6) δ = 7.96 – 7.78 (m, 2H),
7.64 – 7.34 (m, 6H), 7.21 – 7.11 (m, 2H), 7.03 (t, J = 7.2
Hz, 1H), 6.96 (s, 1H), 3.86 (s, 3H). 13C{1H} NMR (75
MHz, DMSO-d6) δ = 142.3 (Cq), 139.9 (Cq), 138.2 (Cq),
137.9 (Cq), 137.2 (Cq), 127.4 (Cq), 125.0 (CH), 124.8
(CH), 123.8 (CH), 123.7 (CH), 123.6 (CH), 122.3 (CH),
121.7 (CH), 120.0 (CH), 119.7 (CH), 119.0 (CH), 109.8
(CH), 99.4 (CH), 29.7 (CH3). IR (neat): 2928, 1531,
1469, 1347, 1154 cm-1. HRMS (ESI): m/z [M+H]+ calcd
for C19H16NS: 290.1003; found: 290.1003.
(E)-1-(4-(2-(1-Methyl-5-(1-(3,4,5-trimethoxyphenyl)
vinyl)-1H-indol-2-yl)vinyl)phenyl)-ethan-1-one (1a)
Yellow solid, mp 170.1 – 170.5 °C, yield 55%, 128.6 mg.
1H NMR (300 MHz, CDCl3) δ = 7.90 (d, J = 8.2 Hz, 2H),
7.55 – 7.52 (m, 3H), 7.25 – 7.10 (m, 4H), 6.78 (s, 1H),
(E)-1-Methyl-2-(3-nitrostyryl)-5-(1-(3,4,5-trimethoxy
phenyl)vinyl)-1H-indole (1e)
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 12
Yellow solid, mp 191.9 – 192.1 °C, yield 57%, 134.1 mg.
(E)-2-(4-Fluorostyryl)-N,1-dimethyl-N-(3,4,5-trimetho
xyphenyl)-1H-indol-5-amine (2b)
1
2
3
4
5
6
7
8
1H NMR (300 MHz, CDCl3) δ = 8.32 (s, 1H), 8.04 (d, J =
8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.58 – 7.42 (m,
2H), 7.28 – 7.08 (m, 4H), 6.78 (s, 1H), 6.55 (s, 2H), 5.38
(s, 1H), 5.32 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.73 (s,
6H). 13C{1H} NMR (75 MHz, CDCl3) δ = 152.9 (2 Cq),
151.0 (Cq), 148.9 (Cq), 139.0 (Cq), 138.4 (Cq), 138.2
(Cq), 137.9 (2 Cq), 133.7 (Cq), 132.5 (CH), 129.8 (CH),
128.1 (CH), 127.7 (Cq), 123.5 (CH), 122.3 (CH), 120.7
(CH), 120.6 (CH), 119.9 (CH), 112.7 (CH2), 109.0 (CH),
105.9 (2 CH), 100.7 (CH), 61.1 (CH3), 56.3 (2 CH3), 30.3
(CH3). IR (neat): 2936, 1630, 1578, 1529, 1504, 1465,
1349 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C28H27N2O5: 471.1920; found: 471.1924.
Yellow solid, mp 180.1 – 180.4 °C, yield 74%, 165.2 mg.
1H NMR (300 MHz, acetone-d6) δ = 7.76 – 7.70 (m, 2H),
7.46 – 7.28 (m, 4H), 7.21 -7.14 (m, 2H), 7.00 (d, J = 8.7
Hz, 1H), 6.84 (s, 1H), 6.09 (s, 2H), 3.92 (s, 3H), 3.69 (s,
6H), 3.66 (s, 3H), 3.31 (s, 3H). 13C{1H} NMR (75 MHz,
acetone-d6) δ = 163.2 (d, J = 244.6 Hz, Cq), 154.6 (2
Cq), 148.1 (Cq), 143.2 (Cq), 139.9 (Cq), 136.6 (Cq),
134.9 (d, J = 3.2 Hz, Cq), 132.2 (Cq), 130.1 (CH), 129.7
(Cq), 129.2 (d, J = 7.8 Hz, 2 CH), 121.1 (CH), 118.1
(CH), 116.6 (d, J = 22.8 Hz, 2 CH), 116.2 (CH), 111.0
(CH), 99.4 (CH), 95.2 (2 CH), 60.6 (CH3), 56.3 (2 CH3),
41.6 (CH3), one CH3 peak was buried in the solvent
signals. 19F NMR (188 MHz, acetone-d6): δ = -115.708.
IR (neat): 2934, 1603, 1583, 1506, 1258, 1233 cm-1.
HRMS (ESI): m/z [M+H]+ calcd for C27H28N2O3F:
447.2084; found: 447.2085.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-1-Methyl-2-styryl-5-(1-(3,4,5-trimethoxy
phenyl)vinyl)-1H-indole (1f)
Yellow solid, mp 121.0 – 121.3 °C, yield 60%, 127.6 mg.
1H NMR (300 MHz, acetone-d6) δ = 7.67 (d, J = 7.2 Hz,
2H), 7.54 – 7.29 (m, 7H), 7.19 (d, J = 8.7 Hz, 1H), 6.88
(s, 1H), 6.67 (s, 2H), 5.41 (s, 1H), 5.39 (s, 1H), 3.93 (s,
3H), 3.78 (s, 9H). 13C{1H} NMR (75 MHz, acetone-d6) δ
= 153.1 (2 Cq), 151.3 (Cq), 139.2 (Cq), 138.2 (Cq), 138.1
(Cq), 138.0 (Cq), 137.4 (Cq), 133.1 (Cq), 130.6 (CH),
128.7 (2 CH), 128.0 (Cq), 127.7 (CH), 126.5 (2 CH),
122.3 (CH), 119.9 (CH), 117.1 (CH), 111.6 (CH2), 108.9
(CH), 106.0 (2 CH), 98.9 (CH), 59.7 (CH3), 55.5 (2 CH3),
29.3 (CH3). IR (neat): 1579, 1503, 1463, 1449, 1411,
1348, 1236 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C28H28NO3: 426.2069; found: 426.2065.
(E)-2-(4-Methoxystyryl)-N,1-dimethyl-N-(3,4,5-
trimethoxyphenyl)-1H-indol-5-amine (2c)
Yellow solid, mp 110.1 – 110.3 °C, yield 82%, 188.0 mg.
1H NMR (300 MHz, acetone-d6) δ = 7.61 (d, J = 8.7 Hz,
2H), 7.42 – 7.23 (m, 4H), 7.07 – 6.86 (m, 3H), 6.78 (s,
1H), 6.09 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.68 (s, 6H),
3.66 (s, 3H), 3.30 (s, 3H). 13C{1H} NMR (75 MHz,
acetone-d6) δ = 160.6 (Cq), 154.5 (2 Cq), 148.1 (Cq),
143.1 (Cq), 140.5 (Cq), 136.6 (Cq), 132.1 (Cq), 131.2
(CH), 131.0 (Cq), 129.8 (Cq), 128.7 (2 CH), 120.9 (CH),
116.8 (CH), 115.8 (CH), 115.0 (2 CH), 110.9 (CH), 98.7
(CH), 95.1 (2 CH), 60.6 (CH3), 56.2 (2 CH3), 55.6 (CH3),
41.6 (CH3). one CH3 peak was buried in the solvent
signals. IR (neat): 2958, 1604, 1582, 1507, 1483, 1465,
1247 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C28H31N2O4: 459.2284; found: 459.2291.
(E)-3-(2-(1-Methyl-5-(1-(3,4,5-
trimethoxyphenyl)vinyl)-1H-indol-2-yl)vinyl)aniline
(1g)
Yellow solid, mp 95.6 – 95.8 °C, yield 58%, 127.8 mg.
1H NMR (300 MHz, acetone-d6) δ = 7.52 (s, 1H), 7.39 –
7.05 (m, 5H), 6.96 – 6.83 (m, 3H), 6.71 – 6.58 (m, 3H),
5.41 (s, 1H), 5.39 (s, 1H), 4.68 (br, 2H), 3.90 (s, 3H),
3.78 (s, 9H). 13C{1H} NMR (75 MHz, acetone-d6) δ =
153.1 (2 Cq), 151.3 (Cq), 148.7 (Cq), 139.4 (Cq), 139.1
(Cq), 138.2 (Cq), 138.0 (Cq), 137.9 (Cq), 133.0 (Cq),
131.6 (CH), 129.2 (CH), 128.0 (Cq), 122.1 (CH), 119.8
(CH), 116.2 (CH), 115.5 (CH), 114.2 (CH), 112.2 (CH),
111.5 (CH2), 108.9 (CH), 106.0 (2 CH), 98.6 (CH), 59.7
(CH3), 55.5 (2 CH3), one CH3 peak was buried in the
solvent signals. IR (neat): 3450, 2396, 1599, 1579, 1503,
1463, 1412, 1348 cm-1. HRMS (ESI): m/z [M+H]+ calcd
for C28H29N2O3: 441.2178; found: 441.2180.
(E)-N,1-Dimethyl-N-(3,4,5-trimethoxyphenyl)-2-(4-
vinylstyryl)-1H-indol-5-amine (2d)
Yellow solid, mp 133.2 – 133.6 °C, yield 80%, 181.8 mg.
1H NMR (300 MHz, acetone-d6) δ = 7.64 (d, J = 8.4 Hz,
2H), 7.56 – 7.24 (m, 6H), 6.99 (dd, J = 8.7 Hz, J = 2.1
Hz, 1H), 6.93 – 6.62 (m, 2H), 6.10 (s, 2H), 5.85 (d, J =
18.3 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 3.91 (s, 3H),
3.69 (s, 6H), 3.67 (s, 3H), 3.31 (s, 3H). 13C{1H} NMR
(75 MHz, acetone-d6) δ = 154.6 (2 Cq), 148.1 (Cq),
143.2 (Cq), 140.1 (Cq), 138.0 (Cq), 137.9 (Cq), 137.4
(CH), 136.7 (Cq), 132.2 (Cq), 130.9 (CH), 129.8 (Cq),
127.6 (2 CH), 127.4 (2 CH), 121.2 (CH), 118.1 (CH),
116.8 (CH), 114.1 (CH2), 111.0 (CH), 99.5 (CH), 95.3 (2
CH), 60.6 (CH3), 56.3 (2 CH3), 41.6 (CH3), 30.2 (CH3).
IR (neat): 2935, 1603, 1582, 1506, 1482, 1465, 1450,
1258 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C29H31N2O3: 455.2335; found: 455.2336.
(E)-1-(4-(2-(1-Methyl-5-(methyl(3,4,5-trimethoxy
phenyl)amino)-1H-indol-2-yl)vinyl)phenyl)ethan-1-
one (2a)
Yellow solid, mp 212.8 – 213.0 °C, yield 77%, 181.2 mg.
1H NMR (300 MHz, CDCl3) δ = 7.99 (d, J = 8.4 Hz, 2H),
7.62 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 1.8 Hz, 1H), 7.33 –
7.20 (m, 3H), 7.07 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.85
(s, 1H), 6.08 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.76 (s,
6H), 3.35 (s, 3H), 2.64 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ = 197.5 (Cq), 153.6 (2 Cq), 147.2 (Cq), 143.3
(Cq), 142.5 (Cq), 141.8 (Cq), 138.5 (Cq), 136.2 (Cq),
135.9 (Cq), 129.4 (CH), 129.1 (2 CH), 128.7 (Cq), 126.5
(2 CH), 121.2 (CH), 119.6 (CH), 116.3 (CH), 110.2
(CH), 100.0 (CH), 94.2 (2 CH), 61.2 (CH3), 56.2 (2 CH3),
41.5 (CH3), 30.3 (CH3), 26.7 (CH3). IR (neat): 2958,
1678, 1598, 1507, 1307, 1263 cm-1. HRMS (ESI): m/z
[M+H]+ calcd for C29H31N2O4: 471.2284; found:
471.2286.
Procedure for the synthesis of 4-bromo-N,N-dimethyl-
2-((trimethylsilyl)ethynyl)aniline 6.
To
a
stirred mixture of 4-bromo-2-iodo-N,N-
dimethylaniline (20 mmol), PdCl2(PPh3)2 (0.05 equiv)
and CuI (0.1 equiv) in Et3N (50 mL),
trimethylsilylacetylene (1.1 equiv, 3.3 mL) was added
dropwise at 0 °C. The mixture was then stirred at room
temperature. When the starting material was disappeared
(TLC monitoring), the mixture was passed through a pad
of Celite to remove the insoluble materials. The filtrate
was concentrated in vacuo and the residue was purified
by silica gel column chromatography (0 to 10% AcOEt in
cyclohexane).
8
ACS Paragon Plus Environment

Page 9 of 12
The Journal of Organic Chemistry
4-bromo-N,N-dimethyl-2-((trimethylsilyl)ethynyl)
aniline (6)
Procedure for the Synthesis of terminal alkyne 9, 11.
1
2
3
4
5
6
7
8
To an oven dried 100 mL round-bottomed flask was
added 2-((trimethylsilyl)ethynyl)aniline (5 mmol), MeOH
(30 mL), and oven dried K2CO3 (1 equiv). The flask was
stirred under argon atmosphere at room temperature.
When TLC show the disappearance of starting material,
H2O (30 mL) was added to the flask. After extracted with
CH2Cl2 (3 × 30 mL), the organic layer was dried over
anhydrous MgSO4, and concentrated in vacuo. The crude
oil was then purified by column chromatography on silica
gel (0 to 20% AcOEt in cyclohexane).
Colorless oil, yield 91%, 5.33 g.
1H NMR (300 MHz, CDCl3) δ = 7.29 (d, J = 2.4 Hz, 1H),
7.06 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 6.48 (d, J = 9.0 Hz,
1H), 2.70 (s, 6H), 0.03 (s, 9H). 13C{1H} NMR (75 MHz,
CDCl3) δ = 154.2 (Cq), 137.0 (CH), 132.3 (CH), 118.3
(CH), 116.4 (Cq), 111.8 (Cq), 103.2 (Cq), 101.2 (Cq),
43.3 (2 CH3), 0 (3 CH3). IR (neat): 2958, 2838, 2151,
1488, 1386, 838 cm-1. HRMS (ESI): m/z [M+H]+ calcd
for C13H19N79BrSi: 296.0470; found: 296.0469.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Ethynyl-N,N-dimethyl-4-(1-(3,4,5-trimethoxy
phenyl)vinyl)aniline (9)
Procedure for the synthesis of 8.
A 50 mL flask was charged with aryl halide 6 (10 mmol),
Xphos (10 mol%), Pd2dba3 (5 mol%), LiOtBu (2.2 equiv),
the tosylhydrazone 7 (1.2 equiv) and dioxane (25 mL).
The system was stirred at 70º with monitored by TLC
analysis. When the reaction was completed, the crude
reaction mixture was allowed to cool to room
temperature and filtered through celite washed by CH2Cl2.
The solvents were evaporated under reduced pressure,
and the residue was purified by silica gel column
chromatography (0 to 20% AcOEt in cyclohexane).
Brown oil, yield 92%, 1.55 g.
1H NMR (300 MHz, CDCl3) δ = 7.41 (d, J = 2.1 Hz, 1H),
7.18 – 7.14 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.47 (s,
2H), 5.30 (s, 1H), 5.24 (s, 1H), 3.81 (s, 3H), 3.75 (s, 6H),
3.32 (s, 1H), 2.90 (s, 6H). 13C{1H} NMR (75 MHz,
CDCl3) δ = 155.2 (Cq), 153.0 (2 Cq), 149.0 (Cq), 137.3
(Cq), 134.8 (CH), 133.4 (Cq), 129.7 (CH), 116.7 (CH),
113.7 (Cq), 112.9 (CH2), 112.8 (Cq), 105.8 (2 CH), 83.1
(Cq), 82.5 (CH), 61.0 (CH3), 56.3 (2 CH3), 43.6 (2 CH3).
IR (neat): 3276, 2957, 2836, 1599, 1579, 1464, 1451,
1347, 1266 cm-1. HRMS (ESI): m/z [M+H]+ calcd for
C21H24NO3: 338.1756; found: 338.1755.
N,N-Dimethyl-4-(1-(3,4,5-trimethoxyphenyl)vinyl)-2-
((trimethylsilyl)ethynyl)aniline (8)
Brown oil, yield 86%, 3.52 g.
2-Ethynyl-N1,N1,N4-trimethyl-N4-(3,4,5-trimethoxy
phenyl)benzene-1,4-diamine (11)
1H NMR (300 MHz, CDCl3) δ = 7.47 (d, J = 1.8 Hz, 1H),
7.17 (dd, J = 8.7 Hz, J = 1.8 Hz, 1H), 6.79 (d, J = 8.4 Hz,
1H), 6.55 (s, 2H), 5.36 (s, 1H), 5.30 (s, 1H), 3.88 (s, 3H),
3.81 (s, 6H), 2.99 (s, 6H), 0.26 (s, 9H). 13C{1H} NMR
(75 MHz, CDCl3) δ = 154.8 (Cq), 153.0 (2 Cq), 149.1
(Cq), 137.9 (Cq), 137.4 (Cq), 134.6 (CH), 132.9 (Cq),
129.6 (CH), 116.3 (CH), 114.8 (Cq), 113.9 (Cq), 112.6
(CH2), 105.8 (2 CH), 104.7 (Cq), 61.0 (CH3), 56.3 (2
CH3), 43.3 (2 CH3), 0.1 (3 CH3). IR (neat): 2999, 2957,
2835, 2786, 2148, 1598, 1503, 1465, 1347 842 cm-1.
HRMS (ESI): m/z [M+H]+ calcd for C24H32NO3Si:
410.2151; found: 410.2149.
Brown oil, yield 90%, 1.53 g.
1H NMR (300 MHz, CDCl3) δ = 7.15 (d, J = 2.7 Hz, 1H),
6.96 (dd, J = 8.7 Hz, J = 2.7 Hz, 1H), 6.87 (d, J = 8.7 Hz,
1H), 6.15 (s, 2H), 3.81 (s, 3H), 3.77 (s, 6H), 3.38 (s, 1H),
3.23 (s, 3H), 2.89 (s, 6H). 13C{1H} NMR (75 MHz,
CDCl3) δ = 153.7 (2 Cq), 150.6 (Cq), 145.7 (Cq), 142.9
(Cq), 132.8 (Cq), 127.5 (CH), 123.3 (CH), 118.3 (CH),
115.8 (Cq), 97.5 (2 CH), 82.7 (Cq), 82.3 (CH), 61.1
(CH3), 56.2 (2 CH3), 44.2 (2 CH3), 40.8 (CH3). IR (neat):
2937, 2826, 1612, 1495, 1450, 1309, 1236 cm-1. HRMS
(ESI): m/z [M+H]+ calcd for C20H25N2O3: 341.1865;
found: 341.1870.
Procedure for the synthesis of 10.
Aryl bromine 6 (1 mmol) (note: the yiled will drastically
decrease when increasing the quantity of starting
material), Xphos (10 mol%), Pd2dba3 (5 mol%), NaOtBu
(2.2 equiv), 3,4,5-trimethoxy-N-methylaniline (1.2 equiv)
were mixed in 8 mL of toluene. The system was stirred at
70º in a 30 mL sealed tube with monitored by TLC
analysis. When the reaction was completed, the crude
reaction mixture was allowed to cool to room
temperature and filtered through celite washed by CH2Cl2.
The solvents were evaporated under reduced pressure,
and the residue was purified by silica gel column
chromatography (0 to 20% AcOEt in cyclohexane).
Supporting Information:
Supporting Information contains copies of 1H, 13C and 19
NMR spectra of new compounds.
F
Acknowledgment.
Authors acknowledge support of this project by CNRS,
University Paris Sud, and by La Ligue Nationale Contre
le Cancer through an Equipe Labellisée 2014 grant.
Guangkuan Zhao thanks the CSC (Chinese Scholarship
Council) for its Ph.D. funding. Our laboratory BioCIS-
UMR 8076 is a member of the Laboratory of Excellence
LERMIT supported by a grant from the Agence
Nationale de la Recherche, (ANR-10-LABX-33).
N1,N1,N4-Trimethyl-N4-(3,4,5-trimethoxyphenyl)-2-
((trimethylsilyl)ethynyl)benzene-1,4-diamine (10)
REFERENCES
Brown oil, yield 83%, 342.5 mg.
(1)
Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C.
1H NMR (300 MHz, acetone-d6) δ = 7.06 – 6.87 (m, 3H),
6.21 (s, 2H), 3.73 (s, 6H), 3.67 (s, 3H), 3.21 (s, 3H), 2.88
(s, 6H), 0.22 (s, 9H). 13C{1H} NMR (75 MHz, acetone-
d6) δ = 154.9 (2 Cq), 154.1 (Cq), 151.6 (Cq), 146.9 (Cq),
143.6 (Cq), 128.2 (CH), 124.7 (CH), 119.0 (CH), 116.7
(Cq), 105.9 (Cq), 99.6 (Cq), 98.6 (2 CH), 60.8 (CH3),
56.5 (2 CH3), 43.9 (2 CH3), 41.1 (CH3), 0.2 (3 CH3). IR
(neat): 2958, 2783, 2149, 1715, 1611, 1496, 1247, 841
cm-1. HRMS (ESI): m/z [M+H]+ calcd for C23H33N2O3Si:
413.2260; found: 413.2266.
M.; Alberts, D. S.; Garcia-Kendall, D. Isolation and
structure of the strong cell growth and tubulin inhibitor
combretastatin A-4. Experientia 1989, 45, 209-210.
(2)
Pettit, G. R.; Rhodes, M. R.; Herald, D. L.;
Hamel, E.; Schmidt, J. M.; Pettit, R. K. Antineoplastic
agents. 445. Synthesis and evaluation of structural
modifications of (Z)- and (E)-combretastatin A-4. J.
Med. Chem. 2005, 48, 4087-4099.
(3)
Lin, C. M.; Singh, S. B.; Chu, P. S.; Dempcy,
R. O.; Schmidt, J. M.; Pettit, G. R.; Hamel, E.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 12
Interactions of tubulin with potent natural and
synthetic analogs of the antimitotic agent
combretastatin: structure-activity study. Mol.
Pharmacol 1988, 34, 200-208.
(11) Messaoudi, S.; Hamze, A.; Provot, O.;
Tréguier, B.; De Losada, J. R.; Bignon, J.; Liu, J. M.;
Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.
D.; Alami, M. Discovery of isoerianin analogues as
promising anticancer agents. ChemMedChem 2011, 6,
488-497.
1
2
3
4
5
6
7
8
A
(4)
Mendez-Callejas, G. M.; Leone, S.;
Tanzarella, C.; Antoccia, A. Combretastatin A-4
induces p53 mitochondrial-relocalisation independent-
apoptosis in non-small lung cancer cells. Cell. Biol.
Int. 2014, 38, 296-308.
(12) Soussi, M. A.; Provot, O.; Bernadat, G.;
Bignon, J.; Wdzieczak-Bakala, J.; Desravines, D.;
Dubois, J.; Brion, J. D.; Messaoudi, S.; Alami, M.
Discovery of azaisoerianin derivatives as potential
antitumors agents. Eur. J. Med. Chem. 2014, 78, 178-
189.
(5)
Horsman, M. R.; Simonsen, U. The vascular-
disrupting agent, combretastatin-A4-phosphate,
Su, J.; Laursen, B. E.; Eskildsen-Helmond, Y.;
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
enhances neurogenic vasoconstriction in rat small
arteries. Eur. J. Pharmacol. 2012, 695, 104-111.
(13) (a) Soussi, M. A.; Provot, O.; Bernadat, G.;
Bignon, J.; Desravines, D.; Dubois, J.; Brion, J. D.;
Messaoudi, S.; Alami, M. Isocombretaquinazolines:
Potent cytotoxic agents with antitubulin activity.
ChemMedChem 2015, 10, 1392-1402. (b) Khelifi, I.;
Naret, T.; Renko, D.; Hamze, A.; Bernadat, G.;
Bignon, J.; Lenoir, C.; Dubois, J.; Brion, J. D.; Provot,
O.; Alami, M. Design, synthesis and anticancer
properties of isocombretaquinolines as potent tubulin
assembly inhibitors. Eur. J. Med. Chem. 2017, 127,
1025-1034.
(6)
http://investor.mateon.com/
(7)
Ohsumi, K.; Hatanaka, T.; Fujita, K.;
Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.;
Morinaga, Y.; Akiyama, Y.; Tsuji, T. Syntheses and
antitumor activity of cis-restricted combretastatins: 5-
membered heterocyclic analogues. Bioorg. Med.
Chem. Lett. 1998, 8, 3153-3158.
(8)
Aprile, S.; Del Grosso, E.; Tron, G. C.;
Grosa, G. In vitro metabolism study of combretastatin
A-4 in rat and human liver microsomes. Drug Metab.
Dispos. 2007, 35, 2252-2261.
(14) (a) Maya, A. B. S.; Pérez-Melero, C.; Mateo,
C.; Alonso, D.; Fernández, J. L.; Gajate, C.;
Mollinedo, F.; Peláez, R.; Caballero, E.; Medarde, M.
Further naphthylcombretastatins. An investigation on
the role of the naphthalene moiety. J. Med. Chem.
2005, 48, 556-568. (b) Mateo, C.; Álvarez, R.; Prez-
Melero, C.; Peláez, R.; Medarde, M. Conformationally
restricted macrocyclic analogues of combretastatins.
Bioorg. Med. Chem. Lett. 2007, 17, 6316-6320. (c)
Álvarez, R.; Puebla, P.; Fernando Díaz, J.; Bento,A. C.;
García-Navas, R.; de la Iglesia-Vicente, J.; Mollinedo,
F.; Andreu, J. M.; Medarde, M.; Peláez, R. Endowing
indole-based tubulin inhibitors with an anchor for
derivatization: Highly potent 3-substituted indole
phenstatins and isocombretastatins. J. Med. Chem.
2013, 56, 2813-2827. (d) Yan, J.; Hu, J. H.; An, B. J.;
Huang, L.; Li, X. S. Design, synthesis, and biological
evaluation of cyclic-indole derivatives as anti-tumor
agents via the inhibition of tubulin polymerization.
Eur. J. Med. Chem. 2017, 125, 663-675. (e) Mahal, K.;
Biersack, B.; Schruefer, S.; Resch, M.; Ficner, R.;
Schobert, R.; Mueller, T. Combretastatin A-4 derived
(9)
For recent reviews and refs therein, see: (a)
Seddigi, Z. S.; Malik, M. S.; Saraswati, A. P.; Ahmed,
S. A.; Babalghith, A. O.; Lamfon, H. A.; Kamal, A.
Recent advances in combretastatin based derivatives
and prodrugs as antimitotic agents. Med. Chem.
Commun. 2017, 8, 1592-1603. (b) Bukhari, S. N. A.;
Kumar, G. B.; H. M. Revankar, H. M.; Qin, H. L.
Development of combretastatins as potent tubulin
polymerization inhibitors. Bioorg. Chem. 2017, 72,
130-147. (c) Siebert, A.; Gensicka, M.; Cholewinski,
G.; Dzierzbicka, K. Synthesis of combretastatin A-4
analogs and their biological activities. Anticancer
Agents Med. Chem. 2016, 16, 942-960.
(10) (a) Renko, D.; Provot, O.; Rasolofonjatovo,
E.; Bignon, J.; Rodrigo, J.; Dubois, J.; Brion, J. D.;
Hamze, A.; Alami, M. Rapid synthesis of 4-
arylchromenes from ortho-substituted alkynols: a
versatile access to restricted isocombretastatin A-4
analogues as antitumor agents. Eur. J. Med. Chem.
2015, 79, 834-844. (b) Rasolofonjatovo, E.; Provot, O.;
Hamze, A.; Rodrigo, J.; Bignon, J.; Wdzieczak-
Bakala, J.; Lenoir, C.; Desravines, D.; Dubois, J.;
Brion, J. D.; Alami, M. Design, synthesis and
anticancer properties of 5-arylbenzoxepins as
conformationally restricted isocombretastatin A-4
analogues. Eur. J. Med. Chem. 2013, 62, 28-39. (c)
Hamze, A.; Rasolofonjatovo, E.; Provot, O.; Mousset,
C.; Veau, D.; Rodrigo, J.; Bignon, J.; Liu, J. M.;
Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.
D.; Alami, M. B-Ring-modified isocombretastatin A-4
analogues endowed with interesting anticancer
activities. ChemMedChem 2011, 6, 2179-2191. (d)
Messaoudi, S.; Tréguier, B.; Hamze, A.; Provot, O.;
Peyrat, J. F.; De Losada, J. R.; Liu, J. M.; Bignon, J.;
Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.
5-(1-methyl-4-phenyl-imidazol-5-yl)indoles
with
superior cytotoxic and anti-vascular effects on
chemoresistant cancer cells and tumors. Eur. J. Med.
Chem. 2016, 118, 9-20.
(15) see for examples: (a) Yates, P.; MacLachlan,
F. N.; Rae, I. D.; Rosenberger, M.; Szabo, A. G.;
Willis, C. R.; Cava, M. P.; Behforouz, M.;
Lakshmikantham, M. V.; Zeiger, W. Haplophytine. A
novel type of indole alkaloid. J. Am. Chem. Soc. 1973,
95, 7842-7850. (b) Fuenfschiling, P. C.; Hoehn, P.;
Muetz, J. P. An improved manufacturing process for
fluvastatin. Org. Process. Res. Dev. 2007, 11, 13−18.
(c) Fernandez, L. S.; Buchanan, M. S.; Carroll, A. R.;
Feng, Y. J.; Quinn, R. J.; Avery, V. M. Flinderoles A-
C: Antimalarial bis-indole alkaloids from flindersia
species. Org. Lett. 2009, 11, 329-332. (d) Chevolot, L.;
Chevolot, A. M.; Gajhede, M.; Larsen, C.; Anthoni, U.;
Christophersen, C. Chartelline A: A pentahalogenated
alkaloid from the marine bryozoan chartella papyracea.
J. Am. Chem. Soc. 1985, 107, 4542-4543. (e) Anthoni,
U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.;
D.; Alami, M. Isocombretastatins
A
versus
combretastatins A: The forgotten isoCA-4 isomer as a
highly promising cytotoxic and antitubulin agent. J.
Med. Chem. 2009, 52, 4538-4542.
10
ACS Paragon Plus Environment

Page 11 of 12
The Journal of Organic Chemistry
Christophersen, C. Marine alkaloids. 12. Chartellines,
Synthesis of 2-dienylindole, SB 242784, by a three-
component palladium-catalyzed coupling reaction.
Tetrahedron Lett. 1998, 39, 9347-9350. (e) Arcadi, A.;
Bianchi, G.; Marinelli, F. Gold(III)-catalyzed
annulation of 2-alkynylanilines: A mild and efficient
synthesis of indoles and 3-haloindoles. Synthesis 2004,
610-618.
1
2
3
4
5
6
7
8
halogenated β-lactam alkaloids from the marine
bryozoan chartella papyracea. J. Org. Chem. 1987, 52,
4709-4712.
(16) For selected examples, see: (a) Fayol, A.;
Fang, Y. Q.; Lautens, M. Synthesis of 2-vinylic
indoles and derivatives via a Pd-catalyzed tandem
coupling reaction. Org. Lett. 2006, 8, 4203-4206. (b)
Rossi, E.; Abbiati, G.; Canevari, V.; Celentano, G.;
Magri, E. 2-Trifluoromethanesulfonyloxyindole-1-
carboxylic acid ethyl ester: A practical intermediate
for the synthesis of 2-carbosubstituted indoles.
Synthesis 2006, 299-304. (c) Wang, Y. Z.; Liu, L. Z.;
Zhang, L. M. Combining Zn ion catalysis with
homogeneous gold catalysis: an efficient annulation
approach to N-protected indoles. Chem. Sci. 2013, 4,
739-746. (d) Das, B.; Kundu, P.; Chowdhury, C.
Facile synthesis of 2-arylmethylindoles and 2-vinylic
indoles through palladium-catalyzed heteroannulations
(20) Tikad, A.; Hamze, A.; Provot, O.; Brion J. D.;
Alami, M. Suzuki coupling reactions of (E)- and (Z)-
chloroenynes with boronic acids: Versatile access to
functionalized 1,3-enynes. Eur. J. Org. Chem. 2010,
725-731.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(21) Diarylenynes 4 were isolated after 5 h of
reaction in yields ranging from 60 to 70% (depending
of the boronic acid).
(22) Jacubert, M.; Provot, O.; Peyrat, J. F.; Hamze,
A.; Brion, J. D. Alami, M. p-Toluenesulfonic acid-
promoted selective functionalization of unsymmetrical
arylalkynes:
a regioselective access to various
of
2-(2-propynyl)aniline
and
2-(2-
arylketones and heterocycles. Tetrahedron 2010, 66,
3775-3787.
propynyl)tosylanilide. Org. Biomol. Chem. 2014, 12,
741-748. (e) Sha, F.; Tao, Y.; Tang, C. Y.; Zhang, F.;
Wu, X. Y. Construction of benzo[c]carbazoles and
their antitumor derivatives through the Diels-Alder
reaction of 2-alkenylindoles and arynes. J. Org. Chem.
2015, 80, 8122-8133. (f) Huang, L. J.; Weng, J.;
Wang, S.; Lu, G. Organocatalytic Diels–Alder reaction
of 2-vinylindoles with methyleneindolinones: An
(23) (a) Barluenga, J.; Moriel, P.; Valdés, C.;
Aznar, F. N-tosylhydrazones as reagents for cross-
coupling reactions: A route to polysubstituted olefins.
Angew. Chem. Int. Ed. 2007, 46, 5587-5590. (b)
Roche, M.; Hamze, A.; Provot, O.; Brion, J. D.;
Alami, M. Synthesis of ortho/ortho’-substituted 1,1-
diarylethylenes through cross-coupling reactions of
sterically encumbered hydrazones and aryl halides. J.
Org. Chem. 2013, 78, 445-454.
efficient
approach
to
functionalized
carbazolespirooxindoles. Adv. Synth. Catal. 2015, 357,
993-1003.
(17) (a) Sharma, S.; Han, S.; Kim, M.; Mishra, N.
K.; Park, J.; Shin, Y.; Ha, J.; Kwak, J. H.; Jung, Y. H.;
Kim, I. S. Rh-catalyzed oxidative C–C bond formation
and C–N bond cleavage: Direct access to C2-
olefinated free (NH)-indoles and pyrroles. Org.
Biomol. Chem. 2014, 12, 1703-1706. (b) Shi, L. J.;
Zhong, X.; She, H. D.; Lei, Z. Q; Li, F. W. Manganese
catalyzed C–H functionalization of indoles with
alkynes to synthesize bis/trisubstituted indolylalkenes
and carbazoles: The acid is the key to control
selectivity. Chem. Commun. 2015, 51, 7136-7139.
(18) (a) Tobisu, M.; Fujihara, H.; Koh, K.;
Chatani, N. Synthesis of 2-boryl- and silylindoles by
copper-catalyzed borylative and silylative cyclization
of 2-alkenylaryl isocyanides. J. Org. Chem. 2010, 75,
4841-4847. (b) Zhao, Z. D.; Jaworski, A.; Piel, I.;
Snieckus, V. Anionic indole N-Carbamoyl N → C
translocation. A directed remote metalation route to 2-
aryl-
and
2-heteroarylindoles.
Synthesis
of
benz[a]carbazoles and indeno[1,2-b]indoles. Org. Lett.
2008, 10, 2617-2620.
(19) (a) Arcadi, A.; Bianchi, G.; Inesi, A.;
Marinelli, F.; Rossi, L. Electrochemical-mediated
cyclization of 2-alkynylanilines: A clean and safe
synthesis of indole derivatives. Eur. J. Org. Chem.
2008, 783-787. (b) Cacchi, S.; Carnicelli, V.;
Marinelli, F. Palladium-catalysed cyclization of 2-
alkynylanilines to 2-substituted indoles under an acidic
two-phase system. J. Organomet. Chem. 1994, 475,
289-296. (c) Arcadi, A.; Cacchi, S.; Marinelli, F.
Palladium-catalysed coupling of aryl and vinyl
triflated or halides with 2-ethynylaniline: An efficient
route to functionalized 2-substituted indoles.
Tetrahedron Lett. 1989, 30, 2581-2584. (d) Yu, M. S.;
Lopez de Leon, L.; McGuire, M. A.; Botha, G.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 12
Table of contents
1
ArB(OH)2 (1.3 equiv)
Pd(PPh3)4 (8 mol %)
K2CO3 (2 equiv)
Cl
2
3
R
R
FG
4
5
6
7
N
Toluene / MeOH, (2:1)
48 h, 90 °C, sealed tube
N
R = H, NArMe, 1-Styryl
2-styrylindoles
FG = NO2, CN, F, Cl, H, Me, OMe, vinyl, naphthyl, benzothiophenyl
8
9
3 steps "one pot" rapid access to functionalized 2-styrylindoles
21 examples (55 to 92 %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Good to excellent functional group tolerance
12
ACS Paragon Plus Environment