Synthesis of 2-bromo-1H-indenes via copper-catalyzed intramolecular cross-coupling of gem-dibromoolefins

Article abstract of DOI:10.1016/j.tetlet.2011.11.102

A novel copper-catalyzed intramolecular C-C coupling reaction of activated methylene aromatic compounds with gem-dibromoolefins is described. The reaction can tolerate various functional groups and lead to efficient formation of 2-bromo-1H-indenes.

Full text of DOI:10.1016/j.tetlet.2011.11.102

Tetrahedron Letters 53 (2012) 560–563
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-bromo-1H-indenes via copper-catalyzed intramolecular
cross-coupling of gem-dibromoolefins
Peijun Liu a, Kemei Tao a, Liwen Zhao a, Wang Shen c, , Jincun 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 94545, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel copper-catalyzed intramolecular C–C coupling reaction of activated methylene aromatic com-
pounds with gem-dibromoolefins is described. The reaction can tolerate various functional groups and
lead to efficient formation of 2-bromo-1H-indenes.
Received 21 October 2011
Revised 12 November 2011
Accepted 18 November 2011
Available online 25 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyzed reaction
Cross-coupling reaction
Gem-dibromoolefins
Indenes
Indene scaffolds are valuable synthetic targets as they exist in
many molecules with diverse bioactivities1 and are also present
in various metallocene complexes used for the catalysis of olefin
polymerizations.2 In addition, indene derivatives are also of inter-
est in the field of material science.3 As a result, a number of syn-
thetic methods for the construction of indene ring systems have
been developed.4 However, less attention has been paid to the syn-
thesis of haloindenes which can be easily transformed into func-
tionalized indene derivatives through subsequent coupling
reactions. The preparation of haloindenes usually involves the
bromination of indanes or indenes5 and HI-mediated cyclization
of o-(alkynyl)styrenes.6 These traditional approaches to haloind-
enes often suffer from either long reaction sequences or strong
acidic conditions under which many functional groups cannot be
tolerated. Recently, several protocols for the synthesis of the halo-
indenes have been developed. These methods include Lewis-acid
catalyzed cyclization of iodinated allylic alcohols,7 iodonium-pro-
moted carbocyclization of 2-substituted ethynylmalonates,8 Pd-
catalyzed carbocyclization of 2-alkenylphenylacetylenes in the
presence of copper halide9 and halocyclization of o-(alkynyl)sty-
renes.10 Very recently, an efficient strategy for the synthesis of
substituted N-(2-haloinden-1-yl)arenesulfobnamides from propar-
gylic alcohols and sulfonamides has been reported.11
The chemistry of gem-dihaloolefins,12 once limited mainly to
the synthesis of terminal alkynes, has made remarkable progress
in organic synthesis especially in transition metal-catalyzed reac-
tions. A number of novel and elegant reactions using gem-dihalo-
olefins as building blocks have been developed and compounds
such as dienes,13 enynes,14 heterocycles15, and carbocycles16 are
prepared efficiently from various gem-dihaloolefins. In conjunction
with our study of gem-dibromoolefins for the synthesis of hetero-
cycles,17 we have developed a straightforward and efficient meth-
od for the synthesis of 2-bromo-1H-indenes via copper-catalyzed
intramolecular C–C cross-coupling reaction of activated methylene
aromatic compounds bearing gem-dibromoolefins, and herein we
report these results.
ethylene glycol
PTSA, toluene
CuI, NaH, DMF
diethyl malonate
1)
2)
CHO
CO2Et
CO2Et
CHO
I
3)
PTSA, CH3CN, H2O
Br
CBr4, PPh3, DCM
Br
CO2Et
CO2Et
⇑
Corresponding authors.
E-mail addresses: wshen@kanionusa.com (W. Shen), zhang_jiancun@gibh.ac.cn
1a
(J. Zhang).
Scheme 1. Preparation of diethyl 2-(2-(2,2-dibromovinyl)phenylmalonate 1a.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.102

P. Liu et al. / Tetrahedron Letters 53 (2012) 560–563
561
Table 1
Diethyl 2-(2-(2,2-dibromovinyl)phenylmalonate 1a, readily
prepared from 2-iodobenzaldehyde through -arylation of malon-
Reaction condition screening for the synthesis of 2a from 1aa
a
ate18 and subsequent gem-dibromoolefination of the aldehyde
(Scheme 1),19 was chosen as the model substrate to optimize the
reaction conditions. The results are shown in Table 1. The substrate
1a was first subjected to the following reaction conditions: CuI
(20 mol %), Cs2CO3 (3 equiv) in THF at 75 °C under an argon atmo-
sphere without any ligand. The desired cyclized product 2a was
obtained in a 68% yield (entry 1), while other reaction conditions
gave lower yields (entries 2–7). Treating substrate 1a with Cs2CO3
in the absence of the catalyst led to a lower yield of the desired
product 2a (entry 8). In addition, treating substrate 1a with DBU
gave the elimination product diethyl 2-(2-(bromoethynyl)phenyl)
malonate exclusively, while the desired product 2a was not ob-
served even after a prolonged reaction time (entry 9). To further
optimize the reaction conditions, we then investigated the reaction
Br
Cu cat., ligand, base
THF, Ar, 75 oC
Br
CO2Et
Br
CO2Et
EtO2C
2a
CO2Et
1a
Entry
Cat.
Ligandb
Base
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
None
None
None
None
None
None
None
None
None
L1
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
17
17
17
17
17
17
17
24
12
24
24
12
12
12
12
68
37d
41e
Trace
Trace
43
CuI
CuCl
CuBr
None
None
CuI
CuI
CuI
CuI
CuI
42
38
9
0
in the presence of various ligands including L-proline (L1), N,N-
10
11
12
13
14
15
48f
52
dimethylglucine (L2), 2-picolinic acid (L3), 1,10-phenanthroline
(L4), and 2-acetylcyclohexanone (L5) (entries 10–15). Ligand
1,10-phenanthroline (L4) was found to be the most suitable addi-
tive for this coupling reaction (entries 13 and 14). Reduction of
L4 and CuI loading gave very similar results (entry 14). Thus, the
optimized conditions included the use 10 mol % CuI as the catalyst,
20 mol % of 1,10-phenanthroline (L4) as the ligand, and 3 equiv of
Cs2CO3 as the base in THF at 75 °C under an argon atmosphere.
With the optimal reaction conditions in hand, we set to investi-
gate the generality of this coupling reaction. As shown in Table 2,20
a broad range of substrates underwent this coupling reaction
smoothly to afford the corresponding desired products in moder-
ate to good yields. For example, substrates bearing different acti-
L2
L3
L4
L4
63
79
79f
54f
CuI
L5
a
Reaction condition: 1a (0.5 mmol), catalyst (20 mol %), ligand (40 mol %), base
(3 equiv), THF (5 mL), 75 °C under an argon atmosphere.
L1 = L-proline, L2 = N,N-dimethylglycine, L3 = 2-picolinic acid, L4 = 1,10-phe-
nanthroline, L5 = 2-acetylcyclohexanone.
b
c
Isolated yield.
d
DMSO as the solvent.
10 mol % of CuI was used.
10 mol % of CuI and 20 mol % of ligand were used.
e
f
Table 2
Copper-catalyzed synthesis of 2-bromo-1H-indenesa,b
Br
Br
CuI, Phen, Cs2CO3
R
Br
THF, 75 oC
R
E
E
E
E
1
2
Entry
1
Substrate
Product
Time (h)
16
Yield (%)
80
Br
Br
CO2Et
Br
PhO2S
CO2Et
2b
SO2Ph
1b
1c
Br
Br
Br
CO2Et
2
3
4
16
16
15
72
62
CO2Et
(EtO)2OP
2c
PO(OEt)2
Br
Br
Br
CO2i-Pr
CO2i-Pr
i-PrO2C
2d
CO2i-Pr
1d
Br
Br
CO2Et
Br
MeO2C
73
CO2Et
EtO2C
2e
MeO2C
1e
CO2Et
(continued on next page)

562
P. Liu et al. / Tetrahedron Letters 53 (2012) 560–563
Table 2 (continued)
Entry
Substrate
Product
MeO2C
Br
Time (h)
11
Yield (%)
72
Br
MeO2C
Br
5
6
7
CO2Et
CO2Et
EtO2C
1f
CO2Et
2f
Br
Br
Cl
Cl
CO2Et
Br
14
16
75
64
EtO2C
2g
CO2Et
Cl
1g
CO2Et
Br
Cl
Br
Br
CO2Et
CO2Et
EtO2C
2h
1h
CO2Et
Br
Br
Br
F
F
CO2Et
8
16
16
15
74
60
77
EtO2C
CO2Et
F
F
2i
1i CO2Et
Br
Br
CO2Et
Br
9
CO2Et
EtO2C
2j
CO2Et
1j
Br
Br
MeO
Br
10
EtO2C
2k
CO2Et
CO2Et
MeO
CO2Et
1k
Br
Me2N
Me2N
Br
Br
11
12
13
15
15
24
24
67
56
44
59
CO2Et
EtO2C
CO2Et
2l
CO2Et
1l
Br
MeO
MeO
MeO
MeO
Br
CO2Et
Br
CO2Et
EtO2C
2m
CO2Et
1m
1n
O2N
Br
O2N
Br
Br
CO2Et
EtO2C
2n
CO2Et
CO2Et
Br
I
I
Br
Br
CO2Et
14
CO2Et
EtO2C
2o
CO2Et
1o
a
Reactions were carried out using 0.5 mmol of substrate 1, 10 mol % of CuI, 20 mol % of 1,10-phenanthroline, and 3 equiv of Cs2CO3 in THF (5 mL) at 75 °C under an argon
atmosphere.
b
Isolated yield.
vated methylenes at 2-position of the aromatic ring smoothly pro-
ceeded to furnish the corresponding indenes (entries 1–3). Among
these results, the substrate 1b gave the highest yield (entry 1). The
presence of a more sterically hindered isopropyl malonate led to a
lower yield for the cyclized product (entry 3). Meanwhile, sub-
strate bearing a nitro substituent on the aromatic ring gave a poor
result (entry 13). Interestingly, while chloro and fluoro substitu-
ents on the aromatic ring were well tolerated (entries 6–9), a reac-
tive iodo derivative (2o) also afforded the desired product with
high chemoselectivity (entry 14).21 No iodo reduction was detected
from the reaction mixture.
A possible mechanism of the reaction is depicted in Scheme 2. It
is likely that the malonate is deprotonated transiently under the
reaction conditions. The anion is then coordinated with copper,

P. Liu et al. / Tetrahedron Letters 53 (2012) 560–563
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Cu
L
EtO2C
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1
Br
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7015.
19. Typical procedure for the synthesis of diethyl 2-(2-(2,2-dibromovinyl)
phenylmalonate (1a): To a well-stirred mixture of ethyl 2-(2-formylphenyl)
malonate (2.60 g, 9.85 mmol), CBr4 (6.60 g, 19.90 mmol) in DCM (100 mL) was
added dropwise a solution of PPh3 (10.40 g, 39.65 mmol) in DCM (50 mL) over
0.5 h at 0 °C. At the end of addition, the reaction mixture was further stirred at
0 °C for 0.5 h, and then allowed to warm to room temperature. After 2 h
stirring, hexane was added to precipitate as much Ph3PO as possible, and the
suspension was filtered through silica (washed with EtOAc). The solution was
concentrated under reduced pressure, and the residue was purified by column
chromatography on silica gel (petroleum ether–EtOAc = 15:1) to give 1a as a
clear, colorless oil (2.96 g, 72%). 1H NMR (400 MHz, CDCl3) d 7.58 (s, 1H), 7.50
(d, J = 6.8 Hz, 1H), 7.35–7.40 (m, 3H), 4.76 (s, 1H), 4.17–4.29 (m, 4H), 1.28 (t,
J = 7.1 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 167.7, 136.2, 136.0, 130.9, 129.5,
129.3, 128.7, 128.2, 94.2, 61.9, 55.0, 14.0; HRMS (ESI) exact mass calculated for
[M+H]+ (C15H17Br2O4) requires m/z 420.9473, found m/z 420.9469.
20. Typical procedure for the synthesis of diethyl 2-bromo-1H-indene-1,1-
EtO2C
EtO2C
CO2Et
2
Scheme 2. Possible mechanism for the formation of 2 from compound 1.
directing Cu insertion into the ‘cis’-Br, and leading to the desired
product. This mechanism explains the high selectivity over the dis-
tal iodo substitution (Table 2, entry 14).
In conclusion, we have developed an efficient method for the
synthesis of 2-bromo-1H-indenes via copper-catalyzed intramo-
lecular C–C cross-coupling reaction. A variety of 2-bromo-1H-ind-
enes were obtained in moderate to good yields. This method may
provide a new way for the synthesis of highly functionalized
indenes.
Acknowledgment
We are grateful to the Grant-in-Aid for Scientific Research from
the Chinese Academy of Science Innovation Grant (KSCX1-YW-10)
for financial support of this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.102.
References and notes
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dicarboxylate (2a):
A mixture of 1a (210 mg, 0.5 mmol), CuI (9 mg,
0.05 mmol, 10 mol %), 1,10-phenanthroline(18 mg, 0.10 mmol, 20 mol %), and
Cs2CO3 (489 mg, 1.50 mmol) in THF (5 mL) was stirred for 12 h under an argon
atmosphere at 75 °C. The resultant mixture was cooled to room temperature
and filtered through celite. The filtrate was concentrated under reduced
pressure, and the residue was purified by column chromatography on silica gel
(petroleum ether–EtOAc = 15:1) to afford 2a as a clear, yellow oil (134 mg,
79%).1H NMR (400 MHz, CDCl3) d 7.61 (d, J = 7.4 Hz, 1H), 7.30–7.34 (m, 1H),
7.23–7.27 (m, 2H), 7.08 (s, 1H), 4.19–4.32 (m, 4H), 1.27 (t, J = 7.2 Hz, 6H); 13C
NMR (125 MHz, CDCl3) d 166.2, 142.6, 140.5, 137.3, 128.9, 126.4, 124.8, 123.8,
120.8, 72.3, 62.4, 13.9; HRMS (ESI) exact mass calculated for [M+H]+
(C15H16BrO4) requires m/z 339.0232, found m/z 339.0232.
21. Similarly, iodo is tolerated in the analogous indole preparation: Newman, S. G.;
Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416–11417.