Palladium-catalyzed, one-pot, three-component approach to α-alkynyl indoles from o-bromo-(2,2-dibromovinyl)benzenes, terminal alkynes and arylamines

Article abstract of DOI:10.1055/s-0030-1259699

α-Alkynyl indoles were efficiently synthesized in one pot from o-bromo-(2,2-dibromovinyl)benzenes, terminal alkynes, and arylamines via a palladium-catalyzed three-component coupling process. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259699

LETTER
911
Palladium-Catalyzed, One-Pot, Three-Component Approach to a-Alkynyl
Indoles from o-Bromo-(2,2-dibromovinyl)benzenes, Terminal Alkynes and
Arylamines
O
ne-Pot, Three-Co
u
mponent
A
p
n
proachto
a
-
Alkyny
L
l
Indoles iang,a,b Tianhao Meng,a Hui-Jun Zhang,a Zhenfeng Xi*a,c
a
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China
Fax +86(10)62759728; E-mail: zfxi@pku.edu.cn
b
c
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Hunan Normal University,
Changsha, Hunan 410081, P. R. of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
Received 11 October 2010
Dedicated to Professor Xiyan Lu and Professor Lixin Dai
Table 1 Reaction Optimizationa
Abstract: a-Alkynyl indoles were efficiently synthesized in one
pot from o-bromo-(2,2-dibromovinyl)benzenes, terminal alkynes,
and arylamines via a palladium-catalyzed three-component cou-
pling process.
Br
+
PhNH2
+
Ph
Br
Br
2a
3a
1a
Key words: multi-component coupling, o-halo-(2,2-dihalovinyl)-
benzene, alkyne, arylamine, indole, palladium-catalyzed reaction
Pd, ligand, base
solvent, 120 °C
Ph
N
Ph
4a
We have been interested in the preparation and synthetic
applications of polyfunctional conjugated compounds,
such as polyhalo compounds, with the aim of utilizing the
cooperative effect among functional groups on conjugat-
ed systems.1,2 We envisioned that polyhalo compounds,
such as o-halo-(2,2-dihalovinyl)benzenes, might be useful
building blocks for the construction of heterocyclic com-
pounds via multi-step coupling of the different C–X
bonds.1 Herein, we would like to disclose a useful appli-
cation of o-bromo(2,2-dibromovinyl)benzenes 1 and a
novel synthetic method for the production of indoles.
Entry
Ligand
Base
Solvent
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Toluene
DMF
Dioxane
NMP
NMP
NMP
Yield (%)b
1
2
Xantphos
Ph3P
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuONa
K2CO3
80
trace
trace
trace
7
3
t-Bu3P
4
Dppf
5
DPEphos
X-phos
6
26
Indoles are very important compounds in many aspects.
Consequently, the research and development of synthetic
methods for indoles continues to be one of the most active
areas in synthetic chemistry.3–10 Recently, useful and
unique syntheses of indoles have been developed by ap-
plying Pd-catalyzed protocols.5–10 For example, o-halo-
aniline and o-alkynylaniline,6 o-dihaloarenes, alkynes,
and primary amine7 have been applied to the synthesis of
indoles. Barluenga et al. reported that o-dihaloarenes re-
acted with imines to form indoles.8 Lautens and co-work-
ers developed a series of methods to construct indole rings
starting from o-amino-gem-dihalostyrenes.9 Willis and
co-workers used o-halo-b-sulfonyl-styrenes and primary
amines to synthesize indoles.10 Although these reported
methods are useful and interesting, synthetic methods for
the synthesis of indoles, especially for indole rings substi-
tuted with functional groups such as alkynyl groups, are
7
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
trace
trace
trace
13
8
9
KOH
10
11
12
13c
14d
15e
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
5
5
45
21
a Reaction conditions: 1a (0.4 mmol), 2a (0.3 mmol), 3a (0.4 mmol),
Pd(OAc)2 (5 mol%), base (0.9 mmol), solvent (2 mL).
b Isolated yield.
c [Pd2(dba)3] was used as catalyst.
d With CuI (5 mol%).
e Reaction performed at 100 °C.
SYNLETT 2011, No. 7, pp 0911–0914
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259699; Art ID: W31910ST
© Georg Thieme Verlag Stuttgart · New York

912
Y. Liang et al.
LETTER
still in great demand. In addition, diverse starting materi- [Pd2(dba)3] and CuI benefited the construction of the C–N
als and synthetic strategies are desired to make indole de- bond and the Sonogashira reaction, the simple Pd(OAc)2
rivatives more readily accessible.
catalyst was found to be much more efficient in this three-
component coupling reaction. Thus, the optimized reac-
tion conditions were as follows: 1a (0.4 mmol), 2a (0.3
mmol), 3a (0.4 mmol), Pd(OAc)2 (5 mol%), Cs2CO3 (0.9
mmol), in NMP (2 mL) at 120 °C.
In our present work, a-alkynyl indoles were formed in
good yields from polyhalo compounds 1, arylamines, and
alkynes in one-pot, via a Pd-catalyzed, three-component
coupling reaction. One Csp2–Csp bond and two Csp2–N
bonds are constructed in the one-pot process. Table 1 As shown in Scheme 1, a variety of a-alkynyl indoles
shows the screening results obtained for optimization of could be obtained from 1, arylamines 2 and alkynes 3 un-
the reaction conditions in the one-pot, three-component der the optimal reaction conditions. In terms of terminal
coupling reaction of 1a, aniline 2a, and phenylacetylene alkynes, both aliphatic alkynes (4e) and aromatic alkynes
3a using Pd(OAc)2 as the catalyst.
could be used. Aromatic alkynes with both electron-with-
drawing groups, such as CF3 (4b and 4m), and electron-
donating groups, such as OMe (4c, 4d), on the phenyl ring
afforded the corresponding indole derivatives. Heteroat-
om aromatic alkynes (4f and 4g) could also be used in this
reaction. A wide variety of anilines were examined. The
results showed that anilines with either electron-donating
or electron-withdrawing groups were tolerated in the three
component coupling reaction. Substituted o-bromo(2,2-
dibromovinyl)benzenes were also investigated. It was
found that both F- and Me-substituted substrates also re-
acted smoothly with aniline and phenylacetylene under
First, we screened the efficiency of ligands. The results in-
dicated that Xantphos ligand was the best for this coupling
reaction. Next, it was observed that solvents significantly
affected this reaction. Toluene, dioxane, and DMF were
tested, but they were found to be much less effective than
NMP. Several bases, such as t-BuONa, K2CO3 and KOH,
were also examined. The results showed that all were less
efficient compared with Cs2CO3. Finally, in addition to
Pd(OAc)2, we also tested [Pd2(dba)3] (Table 1, entry 13)
and CuI (entry 14) as catalysts. Although the use of
Br
Pd(OAc)2, Xantphos
Cs2CO3, NMP, 120 °C
H2N R2
R3
+
R3
+
Br
N
R2
R1
Br
R1
1
2
3
4
C8H17
CF3
OMe
N
N
N
N
OMe
(4b, 75%)
(4c, 51%)
(4d, 45%)
(4e, 68%)
S
N
N
N
N
N
OMe
(4f, 52%)
(4g, 47%)
(4h, 72%)
(4i, 63%)
CF3
N
N
N
N
NO2
F
OMe
(4j, 51%)
(4k, 48%)
(4l, 57%)
(4m, 51%)
N
F
N
N
F
(4n, 59%)
(4o, 39%)
(4p, 47%)
Scheme 1 Palladium-catalyzed cross-coupling of o-bromo-(2,2-dibromovinyl)benzenes 1 with arylamine 2 and alkyne 3. Reagents and con-
ditions: 1 (0.4 mmol), 2 (0.3 mmol), 3 (0.4 mmol), Pd(OAc)2 (5 mol%), Xantphos (10 mol%), Cs2CO3 (0.9 mmol), NMP (2 mL). Isolated yields.
Synlett 2011, No. 7, 911–914 © Thieme Stuttgart · New York

LETTER
One-Pot, Three-Component Approach to a-Alkynyl Indoles
913
the conditions described above to generate the corre-
sponding indoles 4n, 4o, and 4p, respectively. To the best
of our knowledge, this three-component one-pot coupling
reaction represents the first example of such type,11 espe-
cially using the polyhalo compounds o-bromo-(2,2-dibro-
movinyl)benzenes.
Acknowledgment
This work was supported by NSFC. Y.L. is thankful for financial
support from the Postdoctorate Research Fund of China
(20090460144).
References and Notes
It should be noted that all three components are present at
the same time in the reaction system. The chemical selec-
tivity of the reaction is thus very high. Clearly, compared
with previously reported reactions involving one or two of
these components,6–10,12 the reaction mechanism of this
process is intriguing. We found that, without aniline, 1a
reacted with phenylacetene to form 5 in 17% isolated
yield (eq. 1). We also found that compound 5 could fur-
ther react with aniline smoothly to form 2-alknylindole 4a
in 68% isolated yield (eq. 2). Therefore, although the
reaction path I as proposed in Scheme 2 is more likely, the
reaction path II cannot be ruled out.
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Pd(OAc)2
Xantphos
+
1a 3a
(1)
(2)
Cs2CO3, NMP
120 °C, 4 h
(5, 17%)
Br
Pd(OAc)2
Xantphos
N
+
5
2a
Cs2CO3, NMP
120 °C, 4 h
(4a, 68%)
[Pd]
Br
[Pd]
R3
R3
Br
Br
R3
1
R3
[Pd]Br
path I
H2N R2
[Pd]
Br
A
H2N R2
Br
C
R3
path II
[Pd]
H
R3
N
[Pd]
R2
N
R2
D
B
R3
[Pd]
N
R2
[Pd]
4
Scheme 2 Proposed reaction pathways
In conclusion, we have described a novel and efficient
method for the synthesis of a-alkynyl indoles13 via a pal-
ladium-catalyzed, multi-component coupling of o-bromo-
(2,2-dibromovinyl)benzenes with arylamines and
alkynes.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 7, 911–914 © Thieme Stuttgart · New York

914
Y. Liang et al.
LETTER
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(13) Typical Procedure for the preparation of a-alkynyl-
indole 4a: Under the protection of nitrogen, Pd(OAc)2 (5
mol%) and Xantphos (10 mol%) were added to NMP (2
mL). The reaction mixture was stirred at r.t. for 15 min, then
o-bromo-2-(2,2-dibromovinyl)benzene (0.4 mmol),
phenylacetylene (0.4 mmol), and aniline (0.3 mmol) were
added and the reaction mixture was stirred at 120 °C for 5 h.
The reaction mixture was quenched with water and extracted
with Et2O. The organic extract was washed with brine and
dried over MgSO4. The solvent was then evaporated in
vacuo and the residue was purified by using a SiO2 column
(petroleum ether–ethyl acetate, 100:1) to afford 1-phenyl-2-
(phenylethynyl)-1H-indole (4a) as a colorless solid (80%, 70
mg). 1H NMR (400 MHz, CDCl3): d = 6.99 (s, 1 H), 7.12–
7.16 (m, 1 H), 7.17–7.22 (m, 4 H), 7.27–7.30 (m, 3 H), 7.38
(t, J = 8.0 Hz, 1 H), 7.46–7.54 (m, 4 H), 7.62 (d, J = 7.2 Hz,
1 H); 13C NMR (100 MHz, CDCl3): d = 81.78, 95.25,
109.35, 110.48, 120.89, 120.95, 121.88, 122.64, 123.63,
127.25, 127.49, 127.56, 128.25, 128.30, 128.95, 131.04,
137.47, 137.56; HRMS (ESI): m/z calcd for C22H16N+:
294.1277; found: 294.1274
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