Facile synthesis of 2-bromoindoles by ligand-free CuI-catalyzed intramolecular cross-coupling of gem-dibromoolefins

Article abstract of DOI:10.1016/j.tetlet.2010.09.129

A mild and efficient synthesis of 2-bromoindoles by ligand-free CuI-catalyzed intramolecular cross-coupling of gem-dibromoolefins was developed. Reactions were carried out in toluene at room temperature and the corresponding 2-bromoindoles were obtained in excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.09.129

Tetrahedron Letters 51 (2010) 6342–6344
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of 2-bromoindoles by ligand-free CuI-catalyzed
intramolecular cross-coupling of gem-dibromoolefins
Baishan Jiang a, Kemei Tao a, Wang Shen c, , Jiancun Zhang a,b,
⇑
⇑
a Guangzhou Institute of Biomedicine and Health, CAS, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China
b State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou 510120, China
c Kanion USA Inc., 3916 Trust Way, Hayward, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2010
Revised 18 September 2010
Accepted 27 September 2010
Available online 7 October 2010
A mild and efficient synthesis of 2-bromoindoles by ligand-free CuI-catalyzed intramolecular cross-cou-
pling of gem-dibromoolefins was developed. Reactions were carried out in toluene at room temperature
and the corresponding 2-bromoindoles were obtained in excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Halogenated indoles are valuable synthetic intermediates as
well as important motifs in many biologically active molecules.1,2
A number of methods have been developed for their syntheses.3
Among these transformations, the treatment of the parent indoles
with an electrophilic halogen source is the most straightforward
strategy. Halogens,3e,h N-halosuccinimides,3c,d,f phosphoryl ha-
lides/imidazole,3b,i and copper (II) halides3a,g are commonly used
agents for the halogenation of indoles. 3-Halogenated indoles can
be easily obtained as the halogenation of indoles normally takes
place preferentially at the 3-position.3e In contrast, 2-halogenated
indoles are less accessible by these methods. The preparation of
2-halogenated indoles usually requires lithiation with strong bases
such as t-butyllithium followed by treatment of halogenating elec-
trophiles.3e These harsh conditions limit its synthetic application
due to the poor regioselectivity and poor functional group compat-
ibility. Therefore, there is a need to develop a mild and practical
method for the formation of 2-halogenanted indoles.
In the preliminary experiments, treatment of N-[2-(2,2-dib-
romoethenyl)phenyl]methanesulfonamide (1a)7 with catalytic
amount of CuI was tested to screen the reaction conditions, and
the results are summarized in Table 1.
Initially, the reaction of 1a with CuI was conducted under Lau-
tens’s conditions4c (Table 1, entry 1), and 2a was obtained in 68%
Table 1
Intramolecular coupling reaction of dibromoolefinsa
Br
CuI, Base
Br
Br
NHMs
1a
N
Ms
Solvent
2a
Gem-dibromoolefins have been found to be versatile intermedi-
ates for various transformations, and great effort has been made
on their synthetic applications.4 For instance, amides,4d,5d yamide-
s,4a ketene N,N-acetals,4b 2-substitute benzofused heterocycles,
Entry
Catalyst
Base
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI/DMEDA
CuI
CuBr
CuCl
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
TEA
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
Toluene
DMF
80
80
80
80
80
80
80
80
80
25
25
25
25
68
73
48
45
41
33
49
51c
64
90
42
34
0
4c,e–n,5b,h
and other important classes of compounds4c,5a have been
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
efficiently synthesized from gem-dihaloolefins. However, to the best
of our knowledge, there is no example of constructing indoles from
gem-dihaloolefins under ligand-free copper catalysis conditions.6 In
our continuous studies of 1,1-dibromoolefins,5 we found that
2-bromoindoles can be readily prepared in an intramolecular
coupling manner. Herein, we describe a mild, efficient, and practical
method for the synthesis of 2-bromoindoles from N-protected
ortho-(gem-dibromovinyl)aniline under copper-catalyzed condi-
tions in the absence of ligands.
a
Reaction conditions: 1a (1.0 mmol), base (2.0 mmol) and CuI (0.1 mmol) in
solvent (5 mL) at N2 atmosphere for 8 h. TEA = triethylamine, DMF = N,N-dimeth-
ylformamide, DMEDA = N,N0-dimethylethylenediamine.
b
⇑
Isolated yields.
24 h.
Corresponding authors.
E-mail address: wshen@kanionusa.com (W. Shen).
c
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.129

B. Jiang et al. / Tetrahedron Letters 51 (2010) 6342–6344
6343
Table 3
yield. After various bases and solvents were tested, K3PO4 and tol-
CuI catalyzed synthesis of 2-bromo indolesa,8
uene were found to be the most efficient combination. When the
temperature was lowered to 25 °C, the yield was significantly im-
proved (Table 1, entry 10), and the addition of a ligand like DMEDA
(Table 1, entry 9) was not necessary. Other readily available Cu(I)
halides are less efficient in catalyzing the reaction (Table 1, entries
11 and 12). We then screened different protecting groups of the
aniline, and the results are summarized in Table 2. Methanesulfo-
nyl was found to be the most suitable protecting group for the
transformation possibly due to the coordinating ability of the
internal sulfonamide and relatively easy deprotonation of ‘NH’ by
a base (Table 2, entry 1).
On the basis of these findings, a wide variety of 2-bromoindoles
were prepared in excellent yields from N-methanesulfonyl pro-
tected 2-(gem-dibromovinyl)anilines under the optimized condi-
tions: CuI as the catalyst, K3PO4 as the base, and toluene as the
solvent at room temperature. The results are summarized in Table 3.
Gem-dibromoolefins with both the electron-donating (Table 3,
entries 7–9, 12) and the electron-withdrawing substitutions (Table
3, entries 10 and 11) on the aromatic ring afforded the cyclized
products in excellent yields. Substitutions next to gem-dibromo-
olefin moiety (Table 3, entry 4) or next to N-Ms group (Table 3, en-
try 12) did not impact the reaction either. Halogen substitutes on
the aromatic ring were also well tolerated, giving polyhalogenated
indoles. It thus provides an attractive route for further transforma-
tion of 2-bromoindoles into natural and unnatural products with
indole moieties (Table 3, entries 2–6).9
Br CuI (10%)
K3PO4 (2eq)
Br
R
Br
NHMs
R
N
Ms
Toluene, RT
2
1
Entry
1
Substrate
Product
Yieldb (%)
Br
Br
Br
N
Ms
90
NHMs
2a
1a
Br
Br
Br
Br
N
Ms
Cl
Cl
2
3
99
99
Cl
Cl
NHMs
2g
2h
1g
Br
Br
NHMs
N
Ms
1h
Cl
Cl
Br
Br
Br
4
97
N
Ms
NHMs
1i
2i
Since suitable ortho substitutes have been shown to promote
Ullmann-type couplings,10 a possible mechanism for the formation
of 2-bromoindoles is proposed in Scheme 1. Sulfonamide 1 reacts
with CuI in the presence of base K3PO4 to form intermediate I.
The ‘Cu’ atom in intermediate I is coordinated with the sulfon-
amide N and O atoms. Then intramolecular oxidative insertion of
the coordinated copper to the dibromoolefin group provides II,
which then undergoes reductive elimination to give the target
product 2.
In summary, we have developed a practical and efficient meth-
od for the synthesis of 2-bromoindoles. The CuI catalyzed intramo-
lecular cross-coupling reactions proceed smoothly at room
temperature without the addition of ligands. The desired 2-brom-
oindoles are obtained in excellent yields. This method provides a
facile construction of 2-bromoindoles under mild conditions from
N-[2-(2,2-dibromoethenyl)phenyl]methanesulfonamides.
Br
Br
Br
N
Ms
F
F
5
6
7
8
90
87
92
93
F
F
NHMs
2j
1j
Br
Br
Br
N
Ms
NHMs
2k
1k
1l
Br
Br
O
O
Br
N
Ms
O
O
NHMs
2l
Br
Br
Br
Br
NHMs
N
Ms
2m
2n
1m
1n
O
Br
Br
O
O
N
9
10
11
12
84
90
88
82
Ms
Table 2
O
NHMs
Screening of N-protecting groupsa
Br
Br
Br
Br
CuI, Base
N
Ms
Br
MeO2C
MeO2C
Br
N
Solvent
MeO2C
MeO2C
NHMs
NHR
2o
2p
R
2
1o
1p
1
Br
Br
Entry
Substrate/R
Product/yieldb (%)
Br
NHMs
N
Ms
1
2
3
4
5
6
1a/mesyl
1b/p-toluenesulfonyl
1c/acetyl
1d/trifluoroacetyl
1e/benzoyl
1f/ethyloxycarbonyl
2a/90
2b/88
2c/n.d.c
2d/n.d.c
2e/trace (40d)
2f/n.d.c
Br
Br
N
Ms
Br
NHMs
1q
a
Reaction conditions: 1 (1.0 mmol), K3PO4 (2.0 mmol) and CuI (0.1 mmol) in
2q
toluene (5.0 mL) at room temperature for 8 h.
a
b
Reaction conditions: 5 (1.0 mmol), K3PO4 (2.0 mmol) and CuI (0.1 mmol) in
toluene (5.0 mL) at room temperature for 8 h.
Isolated yield.
No desired products.
80 °C.
c
b
d
Isolated yield.

6344
B. Jiang et al. / Tetrahedron Letters 51 (2010) 6342–6344
Y.-Q.; Karisch, R.; Lautens, M. J. Org. Chem. 2007, 72, 1341; (k) Fayol, A.; Fang,
Br
Br
Br
Br
Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203; (l) Yuen, J.; Fang, Y.-Q.; Lautens, M.
Org. Lett. 2006, 8, 653; (m) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549; (n)
Thiegles, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907.
5. (a) Zhang, A. M.; Zheng, X. L.; Fan, J. F.; Shen, W. Tetrahedron Lett. 2010, 51, 828;
(b) Tao, K.; Zheng, J.; Liu, Z.; Shen, W.; Zhang, J. Tetrahedron Lett. 2010, 51, 3246;
(c) Shen, W.; Kohn, T.; Fu, Z.; Jiao, X.-Y.; Lai, S.; Schmitt, M. Tetrahedron Lett.
2008, 49, 7284; (d) Shen, W.; Kunzer, A. Org. Lett. 2002, 4, 1315; (e) Shen, W.;
Thomas, S. A. Org. Lett. 2000, 2, 2857; (f) Shen, W. Synlett 2000, 737; (g) Shen,
W.; Wang, L. J. Org. Chem. 1999, 64, 8873; (h) Wang, L.; Shen, W. Tetrahedron
Lett. 1998, 39, 7625.
K3PO4+CuI
K2HPO4+KI
R
R
Cu
NHMs
N
O
S
O
I
1
Br
6. While this manuscript was being prepared,
a related formation of 2-
R
R
Br
Cu Br
bromoindole was published on-line: Wang, Z.-J.; Yang, J.-G.; Yang, F.; Bao, W.
N
N
Ms
Org. Lett. 2010, 12, 3034.
A
general procedure4f–h for the preparation of gem-dibromovinylaniline
CuBr
S O
7.
substrates: To a solution of 2-nitrobenzaldehyde (5.0 g, 33 mmol) and CBr4
(21.9 g, 66 mmol) in DCM (200 mL) at 0 °C was added dropwise a solution of
PPh3 (34.6 g, 132 mmol) in DCM (100 mL) by an addition funnel. The addition
rate was controlled so that the internal temperature was at 1–5 °C. After
addition, the mixture was stirred for another 0.5 h before warmed to rt, and
stirred for an additional 1 h. The reaction mixture was filtered through a short
plug of silica gel (80 g), and was washed with a copious amount of DCM until
no product was found. Solvent was removed under vacuum to give a mixture of
the desired intermediate and triphenylphosphine oxide. To the mixture was
added EtOH (95%, 200 mL) and SnCl2ꢀH2O (37.2 g, 165 mmol). The suspension
was heated at 100 °C (reflux) for 1 h, and then cooled to rt. After most of the
ethanol was removed under vacuum, H2O (100 mL) and EtOAc (150 mL) were
added. To the resulting mixture, solid K2CO3 was added carefully until pH >10.
The EtOAc layer was separated from the heterogeneous mixture, and the
aqueous phase was extracted with EtOAc until it was free of the product
(3 ꢁ 100 mL). The combined organic solution was washed with brine and dried
over Na2SO4/K2CO3. Solvent was removed under vacuum and the residue was
redissolved in Et2O. The resulting precipitated Ph3P(O) was removed. The
residue was subjected to silica gel chromatography using using 10% EtOAc in
petroleum ether giving 2-(2,2-dibromovinyl)-phenylamine (3a, 7.3 g, 80%). 1H
NMR (400 MHz, CDCl3) d 7.35 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.18 (t, J = 7.7 Hz,
1H), 6.80 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 3.71 (br, 2H). To a solution of
3a (7.3 g, 26 mmol) and pyridine (4.2 ml, 52 mmol) in DCM (30 mL) was added
dropwise MsCl (3.0 mL, 39 mmol) 0 °C. The mixture was warmed slowly to rt,
stirred for an additional 12 h, and diluted with EtOAc (50 mL). The mixture was
washed with NaHSO4 (20%, 2 ꢁ 50 mL), NaHCO3 (50 mL), brine (50 mL), and
dried over anhydrous Na2SO4. The crude mixture was purified by column
chromatography on silica gel to afford the product 1a as a white solid (9.23 g,
100%). 1H NMR (400 MHz, DMSO) d 9.35 (s, 1H), 7.79 (s, 1H), 7.58 (d, J = 7.6 Hz,
1H), 7.45–7.35 (m, 2H), 7.31 (t, J = 7.3 Hz, 1H), 2.98 (s, 3H); 13C NMR (125 MHz,
DMSO) d 134.79, 134.75, 131.60, 129.53, 129.48, 126.07, 125.88, 92.08, 40.01;
HRMS (ESI) calcd for C9H10Br2NO2S ([M+H]+): 355.8779; found: 355.8781.
O
II
2
Scheme 1. A proposed mechanism for the copper catalyzed formation of 2-
bromoindoles.
Acknowledgments
This work was in part supported by the Grant-in-Aid for Scien-
tific Research from the Chinese Academy of Science Innovation
Grant (KSCX1-YW-10).
References and notes
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8.
A general procedure for the preparation of 2-bromo indoles: To a 25-mL
roundbottomed flask was charged with 1a (355.1 mg, 1 mmol), K3PO4
(424.5 mg, 2 mmol) and CuI (19.0 mg, 0.1 mmol). After the flask was
evacuated and backfilled with N2 (this procedure was repeated three times),
toluene (5 mL) was added. The flask was evacuated and backfilled with N2
again. Then the mixture was stirred at room temperature for 8 h. When 1a was
consumed, the mixture was diluted with EtOAc (20 mL) and filtered through
Celite. The crude material was purified by column chromatography on silica gel
to afford 2a (245.6 mg, 90%). 1H NMR (400 MHz, CDCl3) d 8.08 (d, J = 8.0 Hz,
1H), 7.53–7.47 (m, 1H), 7.34–7.23 (m, 2H), 6.84 (s, 1H), 3.19 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 137.21, 129.36, 124.94, 124.04, 120.10, 114.72, 114.59,
109.42, 41.76; HRMS (ESI) calcd for C9H9BrNO2S ([M+H]+): 273.9537; found:
273.9533.
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