CuI-catalyzed intramolecular cyclization of 3-(2-aminophenyl)-2- bromoacrylate: Synthesis of 2-carboxyindoles

Article abstract of DOI:10.1016/j.tetlet.2013.10.048

A new approach was described for the synthesis of substituted 2-carboxyindole using 3-(2-aminophenyl)-2-bromo-acrylates through a CuI-catalyzed intramolecular coupling. The reactions were mild, rapid and with good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.10.048

Accepted Manuscript
CuI-catalyzed intramolecular cyclization of 3-(2-aminophenyl)-2-bromoacry-
late: synthesis of 2-carboxyindoles
Xiong Xiao, Tian-Qi Chen, Jiangmeng Ren, Wei-Dong Chen, Bu-Bing Zeng
PII:
S0040-4039(13)01783-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.10.048
TETL 43686
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
23 July 2013
23 September 2013
10 October 2013
Please cite this article as: Xiao, X., Chen, T-Q., Ren, J., Chen, W-D., Zeng, B-B., CuI-catalyzed intramolecular
cyclization of 3-(2-aminophenyl)-2-bromoacrylate: synthesis of 2-carboxyindoles, Tetrahedron Letters (2013), doi:
http://dx.doi.org/10.1016/j.tetlet.2013.10.048
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CuI-catalyzed intramolecular cyclization of
-(2-aminophenyl)-2-bromoacrylate:
synthesis of 2-carboxyindoles
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3
Xiong Xiao, Tian-Qi Chen, Jiangmeng Ren, Wei-Dong Chen*, Bu-Bing Zeng*

1
Tetrahedron Letters
jo u rn al ho me p ag e : w ww .e lse vie r .c om
CuI-catalyzed intramolecular cyclization of 3-(2-aminophenyl)-2-bromoacrylate:
synthesis of 2-carboxyindoles
a
Xiong Xiao , Tian-Qi Chen , Jiangmeng Ren , Wei-Dong Chen ∗ and Bu-Bing Zeng
a
a
c,
a,b,c
∗
a
Shanghai Key Laboratory of New Drug Design School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. of China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences345 Lingling Road,
Shanghai 200032, PR China
b
c
Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology,130 Meilong Road, Shanghai 200237, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
A new approach was described for the synthesis of substituted 2-carboxyindole using 3-(2-
aminophenyl)-2-bromo-acrylates through CuI-catalyzed intramolecular coupling. The
reactions were mild, rapid and with good to excelent yields.
a
Received in revised form
Accepted
2
009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Indoles
CuI-catalyzed
Intramolecular coupling
2
-Bromo-3-phenylacrylate
2
-Carboxyindole moiety was an important heterocyclic system
The literature survey showed that intramolecular coupling of
ortho-halogenvinyl anilines derivatives proved to be one of the
convenient methods for the preparation of 2-substitute indoles.
These vinyl amination protocols were mild and practical.
However, shortening the reaction time and expanding the
substrate scope in 2-carboxyindole synthesis still remains of great
in the nature products as well as a number of synthetic drugs.
This type of compounds attracted more attention because of their
various potential bioactivities such as antifungal, antibacterial,
3
1
cytotoxic, neuroregulation (Fig. 1). More than ten efficient
synthetic methods approaching indole-2-carboxylic acid ester
2
have been reported using metal-catalyzed coupling approaches
value.
It
was
assumed
that
3-(2-aminophenyl)-2-
and the azides substrates based cyclization methods with
moderate to good yield. In these literatures, harsh conditions,
rare-metal recovery and explosive substrates were the remained
difficulties to overcome.
bromoacrylic acid analogues would have the better feature in the
ring closing. This work reported may be an additional choice for
the intramolecular C-N formation leading to 2-carboxyindols.
Initially, the cyclization of 3-(2-aminophenyl)-2-bromo-
acrylate (1a) catalyzed by CuI was conducted in toluene (Table 1,
entry 1), and 2a was obtained in 85% yield. In order to optimize
the reaction condition, 1a was used as a model substrate and
different combinations of ligands, bases, and solvents were
examined and the results were summarized in Table 1. It was
found that the reaction catalyzed by CuI (10 mol %) in the
2 3
presence of DABCO (20 mol %) and K CO (5 equivalents) in
dioxane under reflux for 2 h afford 2a with 96% isolated yield.
The CuI catalyst was essential in this reaction (table 1, entry 8).
Other solvents such as toluene, pyridine and acetonitrile (entries
Fig. 1 Bioactive molecules containing 2-carboxyindole
moieties
1
-4) were found to be less effective. The reaction could proceed
—
——
∗
Corresponding author. Tel.: + 86(21)64253689; fax: +86(21)64253689; e-mail: e-mail: wdchen@ecust.edu.cn; zengbb@ecust.edu.cn.

2
Tetrahedron
well without ligand and gave 91% yield in 3 h (Table 1, entry
1). What is more, the addition of 20 mol % of DABCO was
1
recommended as the optimized condition because it could
shorten the reaction time as well as improve the final yield.
Keeping the optimized condition in hand, this methodology
was successfully applied on various substrates (1a-1t, Table 2)
which could be readily prepared from commercially available
2
1b
2b
4
85
3
4
5
1c
1d
1e
2c
2d
2e
3
2.5
3
86
90
81
2
-nitrobenzaldehydes over several steps with good yield
4
Scheme 1. Detailed in supporting information).
-5
(
Scheme 1 Preparation of Precursors for Intramolecular
Cyclization
a
Table 1 Optimization of Reaction Conditions
6
7
8
1f
1g
1h
2f
2g
2h
5
12
3
81
64
89
b
Time Yield of 2a
Entry
Ligand
Solvent
Base
(
h)
(%)
85
96
86
66
96
80
89
1
2
3
4
5
6
7
TMEDA
DABCO
DABCO
DABCO
DABCO
Toluene
Toluene
Pyridine
K
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
5
4
K
2
K
2
2
9
1i
2i
6
4
52
86
CH
3
CN
K
2
24
2
Dioxane
K
2
L-Proline Dioxane
1,10-Phen Dioxane
K
2
4
1
0
1
1j
2j
K
2
3
c
c
8
DABCO
DABCO
DABCO
-
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
K
2
12
2.5
1
0
9
K
3
PO
4
87
69
91
1
1k
1l
2k
2a
2a
3
6
2
94
ND
89
1
1
1
1
0
1
2
3
Cs
2
CO
3
K
2
CO
CO
CO
3
3
3
3
d
DABCO
DABCO
K
2
3
90
12
13
e
K
2
9
76
a
Reaction conditions: 1a (0.5 mmol), CuI (0.05 mmol), ligand (0.1 mmol),
base (2.5 mmol), solvent (4.0 mL), reflux, N atmosphere.
2
1m
b
Isolated yield.
Absence of CuI.
c
d
Br
O
O
Loading of CuI was 5 mol %.
Loading of CuI was 1 mol %.
e
N
1
1
4
5
1n
1o
H
2n
2o
2
4
95
87
Table 2 Substrate Scope by CuI-Catalyzed Intramolecular
a
Cyclization of 3-(2-Aminophenyl)-2-Halogenacrylates
b
16
1p
1q
1r
2p
2q
2r
18
6
69
83
92
Time Yield
Entry
Substrate
Product
(
h)
(%)
1
1
7
8
1
1a
2a
2
96
3

3
Acknowledgments
We are grateful for the financial support by The Fundamental
Research Funds for the Central Universities (WY1113007).
1
2
9
0
1s
2s
2t
2
2
87
89
References and notes
1t
1
.
(a) Xu, H.; Fan, L. L. Eur. J. Med. Chem. 2011, 46, 1919-1925. (b)
Tiwari, R. K.; Singh, D.; Singh, J.; Yadav, V.; Pathak, A. K.;
Dabur, R.; Chhillar, A. K.; Singh, R.; Sharma, G. L.; Chandra, R.;
Verma, A. K. Bioorg. Med. Chem. Lett. 2006, 16, 413-416. (c)
Boger, D. L.; Fink, B. E.; Hedrick, M. P. Bioorg. Med. Chem. Lett.
2000, 10, 1019-1020. (d) Piscitelli, F.; Ligresti, A.; La Regina, G.;
Coluccia, A.; Morera, L.; Allarà, M.; Novellino, E.; Di Marzo, V.;
Silvestri R. J. Med. Chem. 2012, 55, 5627-5631; (e) Boyer, S. J.;
Burke, J.; Guo, X.; Kirrane, T. M.; Snow, R. J.; Zhang, Y.; Sarko,
C.; Soleymanzadeh, L.; Swinamer, A.; Westbrook, J.; Dicapua, F.;
Padyana, A.; Cogan, D.; Gao, A.; Xiong, Z.; Madwed, J. B.;
Kashem, M.; Kugler, S.; O'Neill, M. M. Bioorg. Med. Chem. Lett.
2012, 22, 733-737.
a
Reaction conditions: aniline 1 (0.5 mmol), CuI (0.05 mmol), DABCO
0.1 mmol), K CO (2.5 mmol), dioxane (4.0 mL), reflux, N atmosphere.
Isolated yield.
(
2
3
2
b
Under the optimized condition, substrates bearing halogen,
alkyloxy, cyano and benzoic ester at aryl ring were tolerated well
and afforded corresponding indoles in moderate to excellent
yields. Substrates with electron-donating (Table 2, entries 8 and
1
0-11) or some weak electron-withdrawing (Table 2, entries 3-4
and 14-15) groups processed the rapid reaction to give excellent
yield. Halogen substitutes on the aromatic ring were also well
tolerated (Table 2, entries 3-5 and 14-16). However, the reaction
time was prolonged when strong electron-withdrawing groups
emerged on the aryl ring (Table 2, entries 2 and 6-7). Substrates
2
.
(a) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem. Int.
Ed. 2005, 44, 403-406; (b) Jensen, T.; Pedersen, H.; Bang-
Andersen, B.; Madsen, R.; Jørgensen, M. Angew. Chem. Int. Ed.
2
008, 47, 888-890; (c) Bonnamour, J.; Bolm, C. Org. Lett. 2011,
with phenol acetate group could not tolerate the K
which experienced significant hydrolysis and gave lower yield
Table 2, entry 9). Coupling was conducted well after methyl
ester was replaced by propan-1-ol, propan-2-ol or amine (Table 2,
entries 18-20). Acylation on the amino group slow down the
coupling process but the yields were kept good. Substrates
bearing α-iodoacrylate (Table 2, entry 13) give good yield.
However, α-chloroacrylate could not provide the indole product
under optimized condition (Table 2, entry 12).
2
CO
3
condition
13, 2012-2014; (d) Yamazaki, K.; Kondo, Y. Chem. Commun.
2002, 38, 210-211; (e) Shore, G.; Morin, S.; Mallik, D.; Organ, M.
G. Chem. Eur. J. 2008, 14, 1351-1356; (f) Barberis, C.; Gordon,
T. D.; Thomas, C.; Zhang, X.; Cusack, K. P. Tetrahedron Lett.
(
2
005, 46, 8877-8880; (g) Stokes, B. J.; Dong, H.; Leslie, B. E.;
Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129,
500-7501; (h) Hlasta, D. J.; Bell, M. R. Heterocycles 1989, 29,
7
849-852; (i) Tullberg, E.; Schacher, Felix H.; Peters, D.; Freijd, T.
Synthesis 2006, 1183-1187; (j) Creencia, E. C.; Kosaka, M.;
Muramatsu, T.; Kobayashi, M.; Iizuka, T.; Horaguchi, T. J.
Heterocycl. Chem., 2009, 46, 1309-1317; (k) Chen, C.-Y.;
Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J.
Org. Chem. 1997, 62, 2676-2677; (l) Yamazaki, K.; Nakamura,
Y.; Kondo, Y. J. Org. Chem. 2003, 68, 6011-6019; (m) Okano,
K.; Tokuyama, H.; Fukuyama, T.; Chem. Asian J. 2008, 3, 296-
On the basis of these findings, a possible mechanism for the
formation of 2-carboxyindoles was proposed in Scheme 2. Firstly,
coordination of 1a with CuI formed the intermediate B, which
2 3
provided C in the presence of base (K CO ). Then, “Cu” inserted
3
09; (n) Hong, D.; Chen, Z.; Lin, X.; Wang, Y. Org. Lett. 2010,
into the alkene-bromide bond by oxidative addition to provide D.
Finally, reductive elimination of intermediate D freed the copper
catalyst and afforded the product 2a. Addition of DABCO may
stabilize the copper intermediate there by further promoting the
coupling reaction.
12, 4608-4611; (o) M. C. Cruz, F.; Jiménez, F.; Delgado, F.;
Tamariz, J. Synlett. 2006, 749-755; (p) Bowman, W. R.; Fletcher,
A. J.; Pedersen, J. M.; Lovell, P. J.; Elsegood, M. R. J.; Hernández
López, E.; McKee, V.; Potts, G. B. S. Tetrahedron 2007, 63, 191-
2
03; (q) Brown, J. A. Tetrahedron Lett. 2000, 41, 1623-1626.
3
.
(a) Nugent, B. M.; Williams, A. L.; Prabhakaran, E. N.; Johnston,
J. N. Tetrahedron 2003, 59, 8877-8888; (b) Miyauchi, H.; Chiba,
S.; Fukamizu, K.; Ando, K.; Narasaka, K. Tetrahedron 2007, 63,
5
940-5953; (c) Schlosser, M.; Ginanneschi, A.; Leroux, F. Eur. J.
Org. Chem. 2006, 2956-2969; (d) Prabhakaran, E. N.; Nugent, B.
M.; Williams, A. L.; Nailor, K. E.; Johnston, J. N. Org. Lett.
2
002, 4, 4197-4200; (e) Yuen, J.; Fang, Y. Q.; Lautens, M. Org.
Lett. 2006, 8, 653-656; (f) Newman, S. G.; Lautens, M. J. Am.
Chem. Soc. 2010, 132, 11416-11417; (g) He, H. F.; Dong, S.;
Chen, Y.; Yang, Y.; Le, Y. Q.; Bao, W. L. Tetrahedron 2012, 68,
3
112-3116; (h) Chen, W.; Wang, M.; Li, P. H.; Wang, L.
Tetrahedron 2011, 67, 5913-5919; (i) Wang, Z. J.; Yang, F.; Lv,
X.; Bao, W. L. J. Org. Chem. 2011, 76, 967-970; (j) Nagamochi,
M.; Fang, Y. Q.; Lautens, M. Org. Lett. 2007, 9, 2955-2958; (k)
Wang, Z. J.; Yang, J. G.; Yang, F.; Bao, W. L. Org. Lett. 2010, 12,
3
034-3037; (l) Kunzer, A. R.; Wendt, M. D. Tetrahedron Lett.
011, 52, 1815-1818; (m) Jiang, B. S.; Tao, K. M.; Shen, W.;
2
Zhang, J. C. Tetrahedron Lett. 2010, 51, 6342-6344.
Jiang, B.; Dou, Y.; Xu, X. Y; Xu, M. Org. Lett. 2008, 10, 593-
596.
4
5
.
.
Scheme 2 Hypothesis of the catalytic cycle
Prediger, I.; Weiss, T.; Reiser, O. Synthesis. 2008, 2191-2198.
In summary, a mild and efficient CuI-catalyzed methodology
to produce 2-carboxyindoles via intromolecular C-N bond
forming reaction was developed which delivered an alternative
choice for the synthesis of the pharmacologically important
indole moieties. It allows rapid access to a variety of substituted
indoles from commercially available 2-nitrobenzaldehydes with
good yield. The substrates toleration of this catalytic system was
studied and demonstrated.

Supporting Information
CuI-catalyzed intramolecular cyclization of
-(2-aminophenyl)-2-bromoacrylate: synthesis of
3
2
-carboxyindoles
a
Xiong Xiao , Tian-Qi Chen , Jiangmeng Ren , Wei-Dong Chen *, Bu-Bing Zeng
a
a
c,
a,b,c
*
a
Shanghai Key Laboratory of New Drug Design School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, P. R. of China
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences345 Lingling Road, Shanghai 200032, PR China
c
Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology,130
Meilong Road, Shanghai 200237, P. R. of China
Fax +86(21)64253689; E-mail: wdchen@ecust.edu.cn; zengbb@ecust.edu.cn.
Table of content
Supporting Information………………………………………………………………….….….S1
General Information…………………………………………………………………….……...S2
General Procedure……………………………………………………………………….….….S2
Preparation and Characterization Data of Compounds a-m…………………………..…….…S4
Preparation and Characterization Data of Compounds 1a-1t………………………….………S6
Preparation and Characterization Data of Compounds 2a-2t…………………………………S11
Reference………………………………………………………………………………………S15
1
13
H and C Spectra……………………………………………………………………………. S16
S1

General Information
All Commercially available reagents and solvents were used without further purification. Column
1
chromatography was carried out on silica gel (200-300 mesh). H NMR spectra were recorded on
1
00 MHz and C NMR spectra were recorded on 100 MHz using TMS as internal standard.
3
4
HRMS data were determined by EI ionization. Melting points were obtained in open capillary
tubes using a micro melting point apparatus SGW X-4, which were uncorrected.
General Procedure
(
Z)-Methyl 2-bromo-3-(2-nitrophenyl)acrylates (a-m) were prepared from commercial
[1,2]
available 2-nitrobenzaldehyde via optimized procedure in terms of literature.
These nitro
[2]
compounds were reduced by Fe powder to give the corresponding anilines (1a-1m). Anilines
1n-1t and were prepared from intermediate 1a.
Scheme 1
Scheme 1 Preparation of Intramolecular Cyclization Substrate for 2-Carboxyindoles Synthesis
General Procedure for Preparation of Compounds a-g:
Scheme 2
A
mixture
triphenylphosphoranylidene) acetate (30 mmol) in CH
atmosphere for 1 h. Then, it was cooled to -78 °C. Aldehyde (20 mmol) and NEt
were added dropwise. The reaction mixture was slowly warmed to r.t. over 2 h and continued to
stir at r.t. overnight. The resulting mixture was diluted with CH Cl (50 mL), and washed with
saturated aqueous Na SO . The organic layer was separated, dried over Na SO and then
concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted
with petroleum/CH Cl to provide 2-bromoacrylates.
of
dimethylbromosulfonium
bromide
Cl (30 mL) was stirred at r.t. under N
(160 mmol)
(50
mmol)
and
methyl
(
2
2
2
3
2
2
2
3
2
4
2
2
O
(Z)-Methyl 2-bromo-3-(2-nitrophenyl)acrylate (a)
1
Yield: 91%; light yellow crystal; m.p. 82.3-83.7℃；H NMR (400 MHz, CDCl
3
) δ
O
Br
NO
2
8
.51 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.74 (t, J = 10.8, 1H), 7.65 (m, 1H), 7.62 (t,
1
3
J = 11.4, 1H), 3.96 (s, 3H); C NMR (100 MHz, CDCl ) δ 162.9, 147.0, 139.8,
3
+
1
33.9, 131.3, 130.9, 130.2, 125.0, 116.8, 54.0; HRMS (ESI): calcd for: C10
8 4
H BrNO Na [M+Na] :
S2

307.9534; found: 307.9527.
(
Z)-Methyl 3-(2-bromo-3-methoxy-3-oxoprop-1-enyl)-2-nitrobenzoate (b)
1
O
Yield: 90%; light yellow solid; m.p. 99.3-100.1℃; H NMR (400 MHz, CDCl
3
)
O
δ 8.06 (s, 1H), 8.04 - 8.02 (d, J = 7.6 Hz, 1H), 7.99 - 7.97 (d, J = 7.6 Hz, 1H),
13
Br
NO
2
7
.69 - 7.65 (t, J = 7.6 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H); C NMR (100 MHz,
COOMe
CDCl
3
) δ 163.6, 162.3, 149.0, 134.4, 133.9, 131.7, 130.4, 128.2, 124.3, 120.3, 54.0, 53.3; HRMS
+
EI): m/z [M] calcd for: C12H10BrNO ; 342.9691; found: 342.9691.
(
6
O
(Z)-Methyl 2-bromo-3-(4-chloro-2-nitrophenyl)acrylate (c)
1
Yield: 92%; light yellow solid; m.p. 112.6-113.4℃; H NMR (400 MHz,
O
Br
CDCl
.4, 2 Hz, 1H), 7.63 - 7.61 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H); C NMR
) δ 162.5, 147.3, 138.2, 135.9, 133.7, 132.3, 129.1, 125.1, 117.4, 53.8; HRMS
EI): m/z [M] calcd for: C10 BrClNO ; 318.9247; found: 318.9256.
) δ 8.43 (s, 1H), 8.22 - 8.21 (d, J = 2.4 Hz, 1H), 7.72 - 7.70 (dd, J =
3
Cl
NO
2
1
3
8
(
(
100MHz, CDCl
3
+
H
7
4
(
Z)-Methyl 2-bromo-3-(4-bromo-2-nitrophenyl)acrylate (d)
O
1
Yield: 90%; light yellow solid; m.p. 96.7-97.5℃; H NMR (400 MHz,
CDCl ) δ 8.41 (s, 1H), 8.37 - 8.36 (d, J = 1.6 Hz, 1H), 7.88 - 7.85 (dd, J =
.4, 2 Hz, 1H), 7.56 - 7.54 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H); C NMR (100
) δ 162.6, 147.3, 138.3, 136.7, 132.4, 129.6, 128.0, 123.5, 117.4, 53.9; HRMS (EI):
O
Br
NO
3
Br
2
13
8
MHz, CDCl
+
3
7 2 4
m/z [M] calcd for: C10H Br NO ; 362.8742; found: 362.8741.
(
Z)-Methyl 2-bromo-3-(4-iodo-2-nitrophenyl)acrylate (e)
O
1
Yield: 96%; light yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.54 (s, 1H),
O
8
3
.39 (s, 1H), 8.07 - 8.05 (d, J = 8.4 Hz, 1H), 7.41 - 7.38 (d, J = 8.4 Hz, 1H),
13
Br
I
NO
2
.95 (s, 3H); C NMR (100 MHz, CDCl ) δ 162.5, 147.1, 142.5, 138.3,
3
133.6, 132.3, 130.1, 117.3, 94.1, 53.8.
O
(
Z)-Methyl 4-(2-bromo-3-methoxy-3-oxoprop-1-enyl)-3-nitro-
benzoate (f)
Yield: 49%; light yellow solid; m.p. 93.8-94.5℃; H NMR (400 MHz,
O
Br
NO
2
1
MeOOC
CDCl ) δ 8.83 (s, 1H), 8.50 (s, 1H), 8.37 - 8.35 (d, J = 8.4 Hz, 1H), 7.74 - 7.72 (d, J = 8.0 Hz, 1H),
3
1
.00 (s, 3H), 3.95 (s, 3H); C NMR (100 MHz, CDCl
3
4
3
) δ 164.4, 162.5, 146.9, 138.6, 134.8, 134.1,
+
32.0, 131.6, 126.0, 117.7, 53.9, 53.0; HRMS (EI): m/z [M] calcd for: C12
1
H10BrNO; 342.9691;
found: 342.9666.
O
(
Z)-Methyl 2-bromo-3-(4-cyano-2-nitrophenyl)acrylate (g)
1
O
Yield: 42%; light yellow solid; m.p. 158.9-162.3℃; H NMR (400
MHz, DMSO-d ) δ 8.76 (s, 1H), 8.54 (s, 1H), 7.36 - 7.34 (d, J = 8.0
Hz, 1H), 7.90 - 7.88 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H); C NMR (100 MHz, DMSO-d
47.4, 139.8, 137.7, 135.3, 132.6, 129.3, 117.3, 117.1, 113.5, 54.4.
Br
NO
NC
2
6
1
3
6
) δ 162.5,
1
S3

[
2]
General Procedure for preparation of compounds h-k:
Scheme 3
Cl (30 mL) was added bromocarbethoxymethylene
triphenylphosphorane (30 mmol) at r.t. under N . The reaction mixture was stirred at r.t. for 8 h till
the aldehyde disappeared. The mixture was concentrated and purified by flash chromatography on
silica gel eluted with petroleum/CH Cl to provide 2-bromoacrylates.
To a solution of aldehyde (20 mmol) in CH
2
2
2
2
2
(
Z)-Methyl 2-bromo-3-(4,5-dimethoxy-2-nitrophenyl)acrylate (h)
O
1
O
Yield: 76% (Z/E = 7:1); light yellow solid; m.p. 210.0-211.3℃; H NMR
(400 MHz, DMSO-d ) δ 8.48 (s, 1H), 7.63 (s, 1H), 7.22 (s, 1H), 3.93 (s,
H), 3.92 (s, 3H), 3.88 (s, 3H); C NMR (100 MHz, DMSO-d
53.4, 149.4, 141.3, 140.0, 124.9, 115.4, 112.8, 108.1, 57.0, 56.7, 54.1; HRMS (EI): m/z [M]
O
Br
NO
6
O
2
1
3
3
6
) δ 163.0,
+
1
calcd for: C12
H
6
12BrNO ; 344.9848; found: 344.9852.
(
Z)-Methyl 3-(4-acetoxy-3-methoxy-2-nitrophenyl)-2-bromoacrylate (i)
1
O
Yield: 88%; white solid; m.p. 132.4-133.2℃; H NMR (400 MHz, CDCl
3
) δ
O
Br
NO
2
7.93 (s, 1H), 7.79 - 7.74 (d, J = 8.4 Hz, 1H), 7.08 -7.06 (d, J = 8.8 Hz, 1H),
AcO
1
3
O
3.93 (s, 3H), 3.88 (s, 3H), 2.38 (s, 3H); C NMR (100 MHz, CDCl
3
) δ
1
67.9, 162.4, 145.3, 144.9, 144.4, 133.9, 125.8, 125.6, 124.7, 119.1, 62.8, 53.9, 20.7; HRMS (EI):
+
6
m/z [M] calcd for: C12H12BrNO ; 344.9848; found: 344.9852.
(
Z)-Methyl 2-bromo-3-(3-methoxy-2-nitrophenyl)acrylate (j)
1
O
Yield: 68%; white solid; m.p. 102.5-103.5℃; H NMR (400 MHz, CDCl
3
) δ
O
8.06 (s, 1H), 7.53-7.49 (t, J = 8.2 Hz, 1H), 7.41 - 7.39 (d, J = 7.9 Hz, 1H),
Br
1
3
NO
2
7.13-7.11 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H); C NMR (100
MHz, CDCl ) δ 162.5, 151.2, 140.2, 134.9, 131.2, 128.5, 121.1, 119.1,
13.6, 56.6, 53.8; HRMS (EI): m/z [M] calcd for: C11
O
3
+
1
5
H10BrNO ; 314.9742; found: 314.9742.
O
(
Z)-Methyl 2-bromo-3-(3,4-dimethoxy-2-nitrophenyl)acrylate (k)
1
Yield: 78%; white solid; m.p. 135.8-136.6℃; H NMR (400 MHz, CDCl
O
3
)
Br
NO
2
δ 7.96 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 3.99 (s,
O
1
3
O
3H), 3.97 (s, 3H), 3.90 (s, 3H); C NMR (100 MHz, CDCl
54.4, 146.0, 141.1, 133.7, 125.2, 118.9, 117.0, 113.2, 62.2, 56.4, 53.8; HRMS (EI): m/z [M]
calcd for: C12 ; 344.9848; found: 344.9853.
3
) δ 162.9,
+
1
H
12BrNO
6
S4

[
1]
Preparation of (Z)-methyl 2-chloro-3-(2-nitrophenyl)acrylate (l):
Scheme 4
Oxalyl chloride (2.5 mL, 30 mmol) was added dropwise to a solution of DMSO (4.3 mL, 60 mmol)
o
(60 mL) at -78 C under N
in CH
2
Cl
2
2
. After it was stirred at the same temperature for 15 mins,
(23.0 mL, 160 mmol) and
methyl (triphenylphosphoranylidene) acetate (8.0 g, 24 mmol), NEt
3
aldehyde (3.0 g, 20 mmol) were added stepwise. The reaction mixture was slowly warmed to r.t.
over 2 h and then continued to stir at r.t. overnight. The resulting mixture was concentrated under
vacuum. The residue was purified by flash chromatography on silica gel eluted with
2 2
petroleum/CH Cl to provide a light yellow crystal (4.0 g).
(
Z)-Methyl 2-chloro-3-(2-nitrophenyl)acrylate (l)
Yield: 82%; light yellow crystal; m.p. 86.7-87.4℃; H NMR (400 MHz,
CDCl ) δ 8.25 (s, 1H), 8.20 - 8.18 (d, J = 8.1 Hz, 1H), 7.76 - 7.68 (m, 2H),
.62 – 7.57 (m, 1H), 3.94 (s, 3H); C NMR (100 MHz, CDCl
31.3, 130.0, 129.1, 125.2, 124.9, 53.6. All spectral data correspond to those given in the
COOMe
1
Cl
NO2
3
1
3
7
1
3
) δ 162.8, 147.3, 135.1, 133.6,
[3]
literature .
[1]
Preparation of (Z)-methyl 2-iodo-3-(2-nitrophenyl)acrylate (m):
Scheme 5
NIS (5.4 g, 24 mmol) was added to a solution of methyl (triphenylphosphoranylidene) acetate (6.7
g, 20 mmol) in CH Cl (60 mL) at r.t.. After it was stirred at r.t. for 2 h, aldehyde (3.0 g, 20 mmol)
and NEt (8.7 mL, 60 mmol) were added stepwise. The reaction mixture was stirred at r.t. for 8 h.
The resulting mixture was concentrated under vacuum and the residue was purified by flash
chromatography on silica gel eluted with petroleum/CH Cl to provide 2-iodoacrylate as light
yellow oil (5.0 g).
2
2
3
2
2
(
Z)-Methyl 2-iodo-3-(2-nitrophenyl)acrylate (m)
COOMe
1
Yield: 75%; light yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.49 (s, 1H),
I
NO2
8.25 - 8.22 (dd, J = 8.3, 1.0 Hz, 1H), 7.78 - 7.73 (td, J = 7.6 Hz, 0.9 Hz,
1
H), 7.64 - 7.60 (t, J = 8.0 Hz, 1H), 7.55 - 7.53 (d, J = 7.7 Hz, 1H), 3.95 (s, 3H); C NMR (100
3
1
+
MHz, CDCl
3
) δ 163.3, 147.3, 133.8, 131.0, 129.9, 124.8, 95.3, 54.0. HRMS (EI): m/z [M] calcd
for: C10 INO
H
8
4
; 332.9498; found:332.9500.
S5

[2]
General Procedure for Preparation of 3-(2-aminophenyl)-2-bromoacrylates 1a-1m:
Scheme 6
To a stirring solution of ethanol (25 mL) and AcOH (25 mL) was added nitro compound (10
mmol) followed by Fe powder (50 mmol) slowly. The resulting mixture was stirred for 5 minutes
at r.t. and then refluxed until the nitro compound was consumed (as monitored by TLC). Upon
cooling, the mixture was filtered on a diatomite pad and washed with EtOAc. The filtrate was
concentrated under vacuum to give a yellow residue which was purified by column
chromatography on silica eluted with petroleum/ethyl acetate to provide the desired aniline.
(
Z)-Methyl 3-(2-aminophenyl)-2-bromoacrylate (1a)
O
1
Yield: 75%; light yellow crystal; m.p. 69.0-70.5℃; H NMR (400 MHz,
CDCl ) δ 8.19 (s, 1H), 7.67 - 7.66 (d, J = 7.6 Hz, 1H), 7.24 - 7.21 (t, J = 7.6
Hz, 2H), 6.86 - 6.82 (t, J = 7.6 Hz, 1H), 6.76 - 6.74 (d, J = 8.0 Hz, 1H), 3.92
O
3
Br
NH
2
1
3
(
s, 3H), 3.90 - 3.60 (bs, 1H); C NMR (100 MHz, CDCl
3
) δ 163.9, 145.1, 137.9, 131.2, 129.5,
19.9, 118.4, 116.2, 115.1, 53.7; HRMS (EI): m/z [M] calcd for: C10 ; 254.9895; found:
54.9897.
+
1
2
H10BrNO
2
O
(
Z)-Methyl 2-amino-3-(2-bromo-3-methoxy-3-oxoprop-1-enyl)benzoate
(1b)
Yield: 50%; light yellow crystal; m.p. 114.7-115.4℃; H NMR (400 MHz,
CDCl ) δ 8.11 (s, 1H), 7.97 - 7.95 (d, J = 7.2 Hz, 1H), 7.72 - 7.70 (d, J = 7.2
Hz, 1H), 6.75 - 6.72 (t, J = 7.2 Hz, 1H), 5.97 - 5.96 (bs, 2H), 3.92 (s, 3H), 3.89 (s, 3H); C NMR
100 MHz, CDCl ) δ 168.3, 163.4, 148.3, 137.0, 134.6, 133.1, 120.7, 116.7, 115.6, 111.5, 53.7,
1.8; HRMS (EI): m/z [M] calcd for: C12
O
1
Br
NH
2
COOMe
3
13
(
3
+
5
4
H12BrNO ; 312.9950; found: 312.9951.
(
Z)-Methyl 3-(2-amino-4-chlorophenyl)-2-bromoacrylate (1c)
O
1
Yield: 93%; light yellow solid; m.p. 98.8-100.3℃; H NMR (400 MHz,
DMSO-d ) δ 8.05 (s, 1H), 7.60 - 7.58 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 6.64 -
.62 (d, J = 7.5 Hz, 1H), 5.82 (bs, 2H), 3.83 (s, 3H); C NMR (100 MHz,
) δ 163.7, 149.8, 137.7, 135.8, 130.9, 116.6, 115.5, 115.0, 113.1, 53.8; HRMS (EI): m/z
M] calcd for: C10 BrClNO ; 288.9505; found: 288.9508.
O
Br
NH2
6
Cl
1
3
6
DMSO-d
6
+
[
H
9
2
(
Z)-Methyl 3-(2-amino-4-bromophenyl)-2-bromoacrylate (1d)
O
1
Yield: 66%; light yellow solid; m.p. 116.5-118.8℃; H NMR (400 MHz,
DMSO-d ) δ 8.03 (s, 1H), 7.52 - 7.50 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H),
.77 - 6.75 (d, J = 8.4 Hz, 1H), 5.78 (s, 2H), 3.83 (s, 3H); C NMR (100
O
Br
NH
2
6
Br
13
6
MHz, DMSO-d
6
) δ 163.7, 149.9, 137.8, 131.0, 124.6, 118.4, 118.0, 117.0, 113.2, 53.8; HRMS
S6

+
(
9 2 2
EI): m/z [M] calcd for: C10H Br NO ; 332.9000; found: 332.9005.
(
Z)-Methyl 3-(2-amino-4-iodophenyl)-2-bromoacrylate (1e)
O
1
Yield: 40%; light yellow solid; m.p. 106.1-108.2℃; H NMR (400 MHz,
CDCl ) δ 8.07 (s, 1H), 7.37 - 7.35 (d, J = 8.4 Hz, 1H), 7.17 - 7.15 (d, J =
.4 Hz, 1H), 7.14 (s, 1H), 3.92 (s, 3H), 3.84 - 3.842 (bs, 2H); C NMR
) δ 163.5, 145.9, 136.7, 130.6, 127.2, 124.7, 119.1, 115.6, 96.9, 53.6; HRMS
EI): m/z [M] calcd for: C10 BrINO ; 380.8861; found: 380.8871.
O
3
Br
NH
I
13
2
8
(
(
100 MHz, CDCl
3
+
H
9
2
(
Z)-Methyl 3-amino-4-(2-bromo-3-methoxy-3-oxoprop-1-enyl)
benzoate (1f)
Yield: 74%; light yellow solid; m.p. 87.7-90.2℃; H NMR (400 MHz,
CDCl ) δ 8.14 (s, 1H), 7.65 - 7.63 (d, J = 7.6 Hz, 1H), 7.47 - 7.42 (m,
H), 4.02 (bs, 2H), 4.02 (s, 3H), 3.89 (s, 3H); C NMR (100 MHz, CDCl
37.0, 131.9, 129.4, 123.7, 118.8, 116.9, 116.7, 53.7, 52.2; HRMS (EI): m/z [M] calcd for:
; 312.9950; found: 312.9951.
O
O
1
Br
NH2
MeOOC
3
1
3
2
1
3
) δ 166.7, 163.3, 144.8,
+
12 4
C H12BrNO
(
Z)-Methyl 3-(2-amino-4-cyanophenyl)-2-bromoacrylate (1g)
O
1
Yield: 61%; light yellow solid; m.p. 200.5-202.3℃; H NMR (400MHz,
DMSO-d ) δ 8.04 (s, 1H), 7.61 - 7.59 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H),
.98 - 6.96 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 3.84 (s, 3H); C NMR (100
) δ 163.4, 148.3, 137.7, 130.5, 122.4, 119.4, 118.5, 118.4, 115.8, 113.0, 54.0;
O
6
Br
NH
2
NC
13
6
MHz, DMSO-d
6
+
HRMS (EI): m/z [M] calcd for: C11
9 2 2
H BrN O ; 279.9847; found: 279.9849.
(
Z)-Methyl 3-(2-amino-4,5-dimethoxyphenyl)-2-bromoacrylate (1h)
O
1
O
Yield: 61% (Z/E = 7:1); light yellow solid; m.p. 153.4-156.5℃; H
NMR (400 MHz, DMSO-d ) δ 8.14 (s, 1H), 7.51 (s, 1H), 6.42 (s, 1H),
.39 (s, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 3.65 (s, 3H); C NMR (100
) δ 164.2, 153.1, 145.9, 140.1, 137.3, 112.5, 108.7, 107.5, 100.2, 56.5, 55.6, 53.6;
O
Br
NH
6
O
2
13
5
MHz, DMSO-d
6
+
4
HRMS (EI): m/z [M] calcd for: C12H14BrNO ; 315.0106; found: 315.0107.
(
Z)-Methyl 3-(4-acetoxy-2-amino-3-methoxyphenyl)-2-bromo-
acrylate (1i)
Yield: 75%; light yellow solid; m.p. 118.3-119.7℃; H NMR (400 MHz,
CDCl ) δ 8.11 (s, 1H), 7.51 - 7.49 (d, J = 8.8 Hz, 1H), 6.55 - 6.53 (d, J =
.8 Hz, 1H), 4.13 (bs, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 2.36 (s, 3H);
) δ 168.9, 163.9, 144.8, 140.9, 139.0, 136.7, 125.0, 118.2, 114.8, 112.1,
O
O
1
Br
NH
2
AcO
3
O
1
3
8
C
NMR (100 MHz, CDCl
3
+
6
0.5, 53.7, 21.0; HRMS (EI): m/z [M] calcd for: C13H14BrNO ; 343.0055; found: 343.0052.
5
(
Z)-Methyl 3-(2-amino-3-methoxyphenyl)-2-bromoacrylate (1j)
O
1
Yield: 38%; light yellow solid; m.p. 72.0-73.2℃; H NMR (400 MHz,
DMSO-d ) δ 8.17 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 7.9 Hz,
1H), 6.62 (t, J = 8.0 Hz, 1H), 5.15 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H); C
O
6
Br
NH
2
13
O
NMR (100 MHz, DMSO-d
6
) δ 163.9, 147.2, 138.6, 138.0, 121.0, 118.0,
S7

+
15.7, 112.5, 111.9, 56.0, 53.8; HRMS (EI): m/z [M] calcd for: C11
1
H
12BrNO
3
; 285.0001; found:
285.0001.
(
Z)-Methyl 3-(2-amino-3,4-dimethoxyphenyl)-2-bromoacrylate (1k)
O
1
Yield: 55%; light yellow solid; m.p. 128.9-129.6℃; H NMR (400 MHz,
DMSO-d ) δ 8.13 (s, 1H), 7.57 - 7.55 (d, J = 8.8 Hz, 1H), 6.45 - 6.43 (d,
J = 9.2 Hz, 1H), 5.29 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.67 (s, 3H); C
NMR (100 MHz, DMSO-d ) δ 164.1, 154.3, 142.9, 137.9, 135.1, 125.2,
12.7, 110.0, 101.3, 59.8, 56.0, 53.6; HRMS (EI): m/z [M] calcd for: C12
O
6
Br
NH
O
13
2
O
6
+
1
4
H14BrNO ; 315.0106;
found: 315.0107.
(
Z)-Methyl 3-(2-aminophenyl)-2-chloroacrylate (1l)
O
1
Yield: 75%; light yellow solid; m.p. 60.5-61.1℃; H NMR (400 MHz,
CDCl ) δ 7.95 (s, 1H), 7.73 - 7.71 (d, J = 7.9 Hz, 1H), 7.25 - 7.20 (td, J
= 7.6, 1.2 Hz, 1H), 6.87 - 6.83 (t, J = 7.6 Hz, 1H), 6.77 - 6.75 (d, J = 8.1
O
3
Cl
NH
2
1
Hz, 1H), 3.93 (s, 3H), 4.00 - 3.87 (bs, 1H); C NMR (100 MHz, CDCl
3
3
) δ 163.8, 145.2, 133.3,
+
31.1, 129.7, 123.3, 118.5, 118.4, 116.2, 53.3; HRMS (EI): m/z [M] calcd for: C10H10ClNO ;
1
2
2
11.0400; found: 211.0399.
(
Z)-Methyl 3-(2-aminophenyl)-2-iodoacrylate (1m)
O
1
Yield: 72%; light yellow viscous oil; H NMR (400 MHz, CDCl
s, 1H), 7.55 - 7.53 (d, J = 7.8 Hz, 1H), 7.28 - 7.22 (td, J = 8.0, 1.3 Hz,
1H), 6.90 - 6.86 (t, J = 7.6 Hz, 1H), 6.82 - 6.80 (d, J = 8.1 Hz, 1H), 4.28
3
) δ 8.20
O
(
I
NH
2
1
3
(
3
bs, 2H), 3.90 (s, 3H); C NMR (100 MHz, CDCl ) δ 164.1, 145.3, 143.3, 130.8, 128.9, 122.8,
+
1
2
18.7, 116.5, 94.0, 53.8; HRMS (EI): m/z [M] calcd for: C10H10INO ; 302.9756; found:
302.9760.
Preparation of (Z)-methyl 3-(2-amino-5-bromophenyl)-2-bromoacrylate (1n):
Scheme 7
NBS (694 mg, 3.9 mmol) was added to a solution of 1a (1.0 g, 3.9 mmol) in CH
followed with NaHCO (656 mg, 7.8 mmol) powder. The resulting mixture was stirred for 1 h at
r.t.. The mixture was washed with 10 mL water and the organic layer was separated. It was dried
over anhydrous Na SO , filtered and concentrated under vacuum. The residue was purified on a
silica gel column eluted with petroleum/ethyl acetate to give dark yellow solid (848 mg).
2
2
Cl (30 mL) at r.t.
3
2
4
(
Z)-Methyl 3-(2-amino-5-bromophenyl)-2-bromoacrylate (1n)
Br
COOMe
1
Yield: 65%; dark yellow solid; m.p. 146.8-147.5℃; H NMR (400
MHz, CDCl ) δ 8.07 (s, 1H), 7.73 (s, 1H), 7.29 - 7.27 (d, J = 7.6 Hz,
H), 6.64 - 6.62 (d, J = 8.4 Hz, 1H), 3.91 (s, 5H); C NMR (100 MHz, CDCl
Br
NH
2
3
1
3
1
1
3
) δ 163.4, 143.8,
+
36.2, 133.5, 131.5, 121.3, 117.7, 116.2, 109.8, 53.7; HRMS (EI): m/z [M] calcd for:
S8

10 9 2 2
C H Br NO ; 332.9000; found: 332.9006.
Preparation of (Z)-methyl 3-(2-amino-5-iodophenyl)-2-bromoacrylate (1o) and (Z)-methyl
[
4]
3-(2-amino-3,5-diiodophenyl)-2-bromoacrylate (1p):
Scheme 8
a (512 mg, 2 mmol) and KI (598 mg, 3.6 mmol) were suspended in AcOH (4 mL). 30% H
0.4 mL, 3.6 mmol) was added and the vessel stirred until the starting material was consumed as
judged by TLC (16 h). The solution was diluted with EtOAc (10 mL), washed with saturated
aqueous Na and concentrated under vacuum. The product was purified by flash
1
2 2
O
(
2 2 3
S O
chromatography eluted with petroleum/ethyl acetate to provide to provide 1o (367mg, 48% yield)
and 1p (264 mg, 26% yield).
(
Z)-Methyl 3-(2-amino-5-iodophenyl)-2-bromoacrylate (1o)
I
COOMe
1
Yield: 48%; yellow solid; m.p. 139.5-140.2℃; H NMR (400 MHz,
CDCl ) δ 8.04 (s, 1H), 7.88 - 7.88 (d, J = 1.2 Hz, 1H), 7.46 - 7.44 (dd, J
8.6, 1.6 Hz, 1H), 6.53 - 6.51 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.87 (bs, 1H); C NMR (100
) δ 163.4, 144.4, 139.2, 137.3, 136.2, 121.9, 118.0, 116.1, 78.8, 53.7; HRMS (EI):
m/z [M] calcd for: C10 BrINO ; 380.8861; found: 380.8862.
Br
NH2
3
13
=
MHz, CDCl
3
+
H
9
2
(
Z)-Methyl 3-(2-amino-3,5-diiodophenyl)-2-bromoacrylate (1p)
I
COOMe
1
Yield: 26%; brown solid; m.p. 131.5-133.1℃; H NMR (400 MHz,
CDCl ) δ 8.00 (s, 1H), 7.97 - 7.96 (d, J = 1.6 Hz, 1H), 7.75 - 7.74 (d, J
1.6 Hz, 1H), 4.28 - 4.25 (bs, 2H), 3.92 (s, 3H); C NMR (100 MHz,
Br
NH2
3
I
13
=
+
CDCl
3
) δ 163.1, 146.9, 144.1, 137.5, 136.3, 121.4, 117.7, 85.9, 78.5, 53.8; HRMS (EI): m/z [M]
BrI NO ; 506.7828; found: 506.7827.
calcd for: C10
H
8
2
2
Preparation of (Z)-methyl 3-(2-acetamidophenyl)-2-bromoacrylate (1q):
Scheme 9
Acetic anhydride (1.43 mL, 15.6 mmol) and DMAP (95 mg, 0.78 mmol) were added to the
o
(50 mL) at 0 C. Then, NEt
solution of 1a (2 g, 7.8 mmol) in CH
2
Cl
2
3
(2.25 mL, 15.6 mmol) in
CH Cl
2
2
(20 mL) was added dropwise. The resulting solution was stirred until the aniline was
consumed as judged by TLC (24 h). The reaction mixture was concentrated under vacuum and
purified by flash chromatography on silica gel eluted with petroleum/ethyl acetate to provide
acetyl amide as a white solid (2.11 g).
(
Z)-Methyl 3-(2-acetamidophenyl)-2-bromoacrylate (1q)
COOMe
Br
NHAc
S9

1
Yield: 91%; white solid; m.p. 150.8-151.4℃; H NMR (400 MHz, CDCl
3
) δ 8.19 (s, 1H), 7.86 (d,
J = 7.9 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 7.1 Hz,
1
3
1
1
2
3
H), 3.91 (s, 3H), 2.20 (s, 3H); C NMR (100 MHz, CDCl ) δ 168.6, 163.3, 138.3, 135.3, 130.3,
+
3
29.0, 126.8, 124.9, 124.0, 117.1, 53.7, 24.3; HRMS (EI): m/z [M] calcd for: C12H12BrNO ;
97.0001; found: 297.0007.
Preparation of (Z)-propyl 2-bromo-3-(2-nitrophenyl)acrylate (1r):
Scheme 10
To a solution of 1a (1.28 g, 5 mmol) in propanol (50 mL) was added 1 mL of 98% H
the clear solution was refluxed for 24 h and concentrated to around 10 mL. 30 mL EtOAc was
added and then washed with saturated aqueous NaHCO . The organic layer was separated, dried
over Na SO and concentrated under vacuum. The residue was purified by flash chromatography
2
4
SO . Then,
3
2
4
on silica gel eluted with petroleum/ ethyl acetate to provide yellow solid (483 mg).
O
(
Z)-Propyl 2-bromo-3-(2-nitrophenyl)acrylate (1r)
1
Yield: 34%; yellow solid; m.p. 43.5-44.1℃; H NMR (400 MHz,
CDCl ) δ 8.19 (s, 1H), 7.67 - 7.65 (d, J = 8.0 Hz, 1H), 7.25 - 7.21
td, J = 7.8, 1.6 Hz, 1H), 6.86 - 6.83 (t, J = 7.6 Hz, 1H), 6.77-6.75 (d,
J = 8.0 Hz, 1H), 4.27 (t, J = 6.8 Hz, 2H), 3.80 (bs, 2H), 1.88 - 1.72 (m, 2H), 1.06 - 1.02 (t, J = 7.6
O
Br
NH
3
2
(
1
3
Hz, 3H); C NMR (100 MHz, CDCl ) δ 163.2, 144.8, 137.3, 130.9, 129.4, 119.8, 118.2, 116.0,
3
+
15.6, 68.2, 22.0, 10.4; HRMS (EI): m/z [M] calcd for: C12
1
2
H14BrNO ; 283.0208; found:
283.0206.
Preparation of (Z)-isopropyl 2-bromo-3-(2-nitrophenyl)acrylate (1s):
Scheme 11
To a solution of 1a (1.28 g, 5 mmol) in isopropanol (50 mL) was added 1 mL of 98% H
Then, the clear solution was refluxed for 24 h and concentrated to around 10 mL. 30 mL EtOAc
was added and then washed with saturated aqueous NaHCO . The organic layer was separated,
dried over Na SO and concentrated under vacuum. The residue was purified by flash
2
4
SO .
3
2
4
chromatography on silica gel eluted with petroleum/ethyl acetate to provide yellow solid (398
mg).
(
Z)-Isopropyl 2-bromo-3-(2-nitrophenyl)acrylate (1s)
1
O
3
Yield: 28%; yellow solid; m.p. 90.2-91.6℃; H NMR (400 MHz, CDCl )
O
δ 8.16 (s, 1H), 7.65 - 7.63 (d, J = 7.8 Hz, 1H), 7.25 - 7.21 (td, J = 7.6 Hz,
Br
NH
2
S10

0
6
1
.8 Hz, 1H), 6.86 - 6.83 (t, J = 7.5 Hz, 1H), 6.77 - 6.75 (d, J = 8.0 Hz, 1H), 5.22 - 5.16 (hept, J =
1
3
.3 Hz, 1H), 4.12 - 3.55 (bs, 2H), 1.39 - 1.37 (d, J = 6.3 Hz, 6H); C NMR (100 MHz, CDCl
62.6, 144.7, 137.1, 130.8, 129.4, 120.0, 118.2, 116.4, 116.0, 70.6, 21.8; HRMS (EI): m/z [M]
; 283.0208; found: 283.0207.
3
) δ
+
calcd for: C12H14BrNO
2
Preparation of (Z)-3-(2-aminophenyl)-2-bromoacrylamide (1t):
Scheme 12
To a solution of 1a (0.5 g, 2 mmol) in 20 mL ethanol was added 3 mL of NH
3
2
·H O. The solution
was stirred for 6 h. Then, solvent was evaporated to give a yellow residue. The crude products
were purified by flash chromatography on silica gel eluted with petroleum/ethyl acetate to provide
amide as a yellow crystalline (0.35 g).
(
Z)-3-(2-Aminophenyl)-2-bromoacrylamide (1t)
O
1
Yield: 74%; yellow solid; m.p. 164.7-167.2℃; H NMR (400 MHz,
DMSO-d6) δ 7.81 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H),
7.05 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.55 (t, J = 7.5 Hz, 1H), 5.33
NH
2
Br
NH
2
1
3
(
s, 2H); C NMR (100 MHz, DMSO-d
6
) δ 165.7, 147.9, 132.9, 130.7, 129.5, 119.0, 118.6, 116.0,
+
15.8; HRMS (EI): m/z [M] calcd for: C BrN O; 239.9898; found: 239.9899.
1
9
H
9
2
General Procedure for the CuI Catalyzed Intramolecule Coupling Reaction Using
-(2-Aminophenyl)-2-Bromo-acrylates (2a-2t):
3
Scheme 13
A dried 50 mL Schlenk tube equipped with a rubber septum and magnetic stir bar was charged
with 3-(2-aminophenyl)-2-bromoacrylate (128 mg, 0.5 mmol), K CO (345 mg, 2.5 mmol), CuI
9.5 mg, 0.05 mmol), DABCO (0.1 mmol) and dioxane (4 mL). The mixture was degassed 3 times
2
3
(
2
under N atmosphere then heated at reflux until the starting material was consumed as indicated
by TLC. The cooled mixture was partitioned between 20 mL of water and 20 mL of ethyl acetate.
The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL x
2 4
2). The combined organic layers were dried (Na SO ) and concentrated. The residue was purified
by flash chromatography on silica gel eluted with petroleum/ethyl acetate to provide
corresponding 2-carboxyindole.
Methyl 1H-indole-2-carboxylate (2a)
O
[5]
1
Yield: 96%; white solid; m.p. 151.6-152.9℃; lit . 152.5-153.0 °C. H NMR
N
O
(
(
3
400 MHz, CDCl ) δ 9.34 (s, 1H), 7.74 - 7.72 (d, J = 8.0 Hz, 1H), 7.48 - 7.46
H
d, J = 8.0 Hz, 1H), 7.38 - 7.34 (t, J = 8.0 Hz, 1H), 7.21 - 7.17 (t, J = 8.0 Hz,
S11

1
3
1
3
H), 4.00 (s, 3H); C NMR (100 MHz, CDCl ) δ 162.7, 137.0, 127.4, 127.1, 125.4, 122.6, 120.8,
[5]
1
12.0, 108.8, 52.0. All spectral data correspond to those given in the literature .
Dimethyl 1H-indole-2,7-dicarboxylate (2b)
1
Yield: 85%; white solid; m.p. 93.6-93.7℃; H NMR (400 MHz, CDCl
O
3
) δ
N
H
O
1
0.27 (s, 1H), 8.05 - 8.03 (d, J = 7.2 Hz, 1H), 7.94 - 7.92 (d, J = 8.0 Hz,
H), 7.29 (d, J = 2.0 Hz, 1H), 7.24 - 7.20 (t, J = 8.0 Hz, 1H), 4.03 (s, 3H),
COOMe
1
1
3
3
.98 (s, 3H); C NMR (100 MHz, CDCl
3
) δ 167.1, 161.8, 136.2, 128.5, 128.3, 127.7, 120.1, 113.5,
+
08.7, 52.1; HRMS (EI): m/z [M] calcd for : C12 ; 233.0688; found: 233.0682.
1
H11NO
4
Methyl 6-chloro-1H-indole-2-carboxylate (2c)
O
[6]
1
Yield: 86%; white solid; m.p. 172.8-173.5℃; lit. 176.8-178.5 °C; H
NMR (400 MHz, DMSO-d ) δ 9.11 (s, 1H), 7.63 - 7.61 (d, J = 8.4 Hz,
H), 7.44 (s, 1H), 7.21 (d, J = 1.2 Hz, 1H), 7.16 -7.13 (dd, J = 8.4, 1.6 Hz, 1H), 3.98 (s, 3H);
) δ 162.2, 137.1, 131.4, 127.8, 125.9, 123.5, 121.9, 111.7, 108.8, 52.1;
N
O
Cl
6
H
13
1
C
NMR (100 MHz, DMSO-d
6
[6]
ESI-MS: 208.0[M-1]. All spectral data correspond to those given in the literature .
Methyl 6-bromo-1H-indole-2-carboxylate (2d)
1
Yield: 90%; white solid (90%); m.p. 181.9-182.0℃; H NMR (400
O
N
O
Br
H
MHz, DMSO-d
) δ 12.04 (s, 1H), 7.64 - 7.62 (m, 2H), 7.22 - 7.20 (d, J
6
13
=
8.5 Hz, 1H), 7.18 (s, 1H), 3.89 (s, 3H); C NMR (100 MHz, DMSO-d
6
) δ 161.9, 138.5, 128.4,
126.1, 124.4, 123.7, 117.9, 115.4, 108.3, 52.3. All spectral data correspond to those given in the
[
literature .
7]
Methyl 6-iodo-1H-indole-2-carboxylate (2e)
Yield: 81%; white solid; m.p. 186.9-187.4℃; H NMR (400 MHz,
DMSO-d ) δ 12.01 (s, 1H), 7.82 (s, 1H), 7.51 - 7.49 (d, J = 8.4 Hz,
H), 7.37 - 7.35 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 3.88 (s, 3H); C NMR (100 MHz, DMSO-d
O
1
N
O
I
H
6
1
3
1
6
) δ
61.9, 139.0, 129.1, 127.9, 126.4, 124.6, 121.5, 108.3, 90.1, 52.4; HRMS (EI): m/z [M] calcd for :
INO ; 300.9600; found: 300.9605.
+
1
C
10
H
8
2
Dimethyl 1H-indole-2,6-dicarboxylate (2f)
Yield: 89%; white solid; m.p. 178.2-179.6℃; H NMR (400 MHz,
CDCl ) δ 9.41 (s, 1H), 8.24 (s, 1H), 7.85 (dd, J = 8.5, 1.2 Hz, 1H),
.74 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 1.1 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H); C NMR (100 MHz,
CDCl ) δ 167.6, 162.1, 136.1, 130.7, 129.9, 126.8, 122.3, 121.4, 114.4, 108.4, 52.3, 52.2. All
spectral data correspond to those given in the literature .
O
1
N
O
MeOOC
H
3
1
3
7
3
[5]
Methyl 6-cyano-1H-indole-2-carboxylate (2g)
O
1
Yield: 67%; white solid; m.p. 178.6-181.2℃; H NMR (400 MHz,
DMSO-d ) δ 12.49 (s, 1H), 7.89 (s, 1H), 7.87 - 7.85 (d, J = 8.4 Hz,
H), 7.42 - 7.40 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 3.91 (s, 3H); C NMR (100 MHz, DMSO-d
61.6, 136.3, 131.1, 130.1, 123.9, 122.7, 120.3, 118.1, 108.2, 106.5, 52.6; HRMS (EI): m/z [M]
; 200.0586; found: 200.0589.
N
O
NC
H
6
1
3
1
1
6
) δ
+
8 2 2
calcd for : C11H N O
S12

Methyl 5,6-dimethoxy-1H-indole-2-carboxylate (2h)
O
O
[6]
1
Yield: 89%; white solid; m.p. 163.5-166.3℃; lit. 169.3-170.0℃; H
NMR (400 MHz, DMSO-d ) δ 11.63 (s, 1H), 7.08 (s, 1H), 7.02 (s, 1H),
.87 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H); C NMR (100 MHz, DMSO-d
49.9, 146.1, 133.1, 125.5, 120.1, 108.4, 102.9, 94.7, 56.0, 55.8, 51.9. All spectral data correspond
N
O
O
H
6
1
3
6
1
6
) δ 162.0,
[
to those given in the literature .
6]
Methyl 6-acetoxy-7-methoxy-1H-indole-2-carboxylate (2i)
O
1
Yield: 52%; white solid; m.p. 137.4-138.3℃; H NMR (400 MHz,
DMSO-d ) δ 12.13 (s, 1H), 7.39 - 7.37 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H),
.85 - 8.82 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.32 (s, 3H);
C NMR (100 MHz, DMSO-d ) δ 169.6, 161.8, 139.8, 138.2, 131.8, 128.9, 127.4, 117.8, 117.1,
09.4, 61.4, 52.2, 21.0; HRMS (EI): m/z [M] calcd for : C13
N
O
AcO
H
6
O
6
1
3
6
+
1
5
H13NO ; 263.0794; found: 263.0797.
Methyl 7-methoxy-1H-indole-2-carboxylate (2j)
O
1
Yield: 86%; white solid; m.p. 140.3-141.2℃; H NMR (400 MHz,
DMSO-d ) δ 11.87 (s, 1H), 7.22 - 7.20 (d, J = 7.6 Hz, 1H), 7.13 (s, 1H),
.01 - 6.97 (t, J = 7.4 Hz, 1H), 6.78 - 6.76 (d, J = 7.2 Hz, 1H), 3.90 (s,
H), 3.83 (s, 3H); C NMR (100 MHz, DMSO-d ) δ 161.9, 147.1, 128.7, 128.6, 127.7, 121.2,
N
O
6
H
O
7
1
3
3
1
6
[6]
14.7, 108.9, 104.7, 55.7, 52.0. All spectral data correspond to those given in the literature .
Methyl 6,7-dimethoxy-1H-indole-2-carboxylate (2k)
1
Yield: 94%; white solid; m.p. 91.1-91.9℃; H NMR (400 MHz,
O
N
O
O
DMSO-d
.97 - 6.94 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H);
C NMR (100 MHz, DMSO-d ) δ 161.9, 149.3, 134.9, 133.0, 127.8, 124.0, 117.7, 110.3, 109.4,
1.0, 57.4, 51.9; HRMS (EI): m/z [M] calcd for : C12
6
) δ 11.69 (s, 1H), 7.36 - 7.34 (d, J = 8.4 Hz, 1H), 7.13 (s, 1H),
H
O
6
1
3
6
+
6
4
H13NO ; 235.0845; found: 235.0840.
Br
O
Methyl 5-bromo-1H-indole-2-carboxylate (2n)
[
8]
1
Yield: 95%; white solid; m.p. 209.1-209.3℃; lit. 211.8-213.6 ℃. H
NMR (400 MHz, DMSO-d ) δ 12.18 (s, 1H), 7.86 (s, 1H), 7.42 - 7.35
m, 2H), 7.11 (s, 1H), 3.87 (s, 3H); C NMR (100 MHz, DMSO-d ) δ 161.8, 136.4, 128.9, 128.8,
27.7, 124.6, 115.0, 113.0, 107.6, 52.4; ESI-MS: 252.9 [M-1]. All spectral data correspond to
N
O
H
6
1
3
(
6
1
[8]
those given in the literature .
Methyl 5-iodo-1H-indole-2-carboxylate (2o)
Yield: 87%; white solid; m.p. 200.3-200.4℃; H NMR (400 MHz,
DMSO-d ) δ 12.09 (s, 1H), 8.05 (s, 1H), 7.51 - 7.49 (dd, J = 8.8, 1.6 Hz,
H), 7.31 - 7.29 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 3.87 (s, 3H); C NMR
6
100 MHz, DMSO-d ) δ 161.8, 136.7, 133.0, 130.9, 129.8, 128.2, 115.4, 107.2, 84.4, 52.4; HRMS
I
O
1
N
O
6
H
1
3
1
(
(
+
8 2
EI): m/z [M] calcd for : C10H INO ; 300.9600; found: 300.9603.
Methyl 5,7-diiodo-1H-indole-2-carboxylate (2p)
I
O
N
O
H
S13
I

1
Yield: 69%; light brown solid; m.p. 203-206℃; H NMR (400 MHz, DMSO-d
6
) δ 11.74 (s, 1H),
.08 (s, 1H), 7.92 (s, 1H), 7.26 (s, 1H), 3.87 (s, 3H); C NMR (100 MHz, DMSO-d ) δ 161.3,
40.9, 139.1, 131.0, 129.8, 129.5, 109.2, 84.9, 79.8, 52.5; HRMS (EI): m/z [M] calcd for :
NO ; 426.8566; found: 426.8568.
1
3
8
1
6
+
C
10
H
7
I
2
2
Methyl 1-acetyl-1H-indole-2-carboxylate (2q)
O
1
Yield: 83%; white solid; H NMR (400 MHz, CDCl
Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.35 (s, 1H),
.31 (dd, J = 12.6, 5.2 Hz, 1H), 3.97 (s, 3H), 2.64 (s, 3H). All spectral data correspond to those
3
) δ 8.15 (d, J = 8.5
N
O
Ac
7
[9]
given in the literature .
Propyl 1H-indole-2-carboxylate (2r)
Yield: 92%; white solid; m.p. 92.0-93.4℃; H NMR (400 MHz,
CDCl ) δ 9.01 (s, 1H), 7.73 - 7.71 (d, J = 7.6 Hz, 1H), 7.46 - 7.44 (d, J
8.0 Hz, 1H), 7.37 - 7.33 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H),
.20 - 7.16 (t, J = 7.2 Hz, 1H), 4.36 - 4.33 (d, J = 6.8 Hz, 2H), 1.84 (m, 2H), 1.09 - 1.05 (d, J = 7.6
O
1
N
O
3
H
=
7
1
3
Hz, 3H); C NMR (100 MHz, CDCl ) δ 162.1, 136.8, 127.5, 125.3, 122.5, 120.8, 111.8, 108.6,
3
+
6
2
6.5, 22.1, 10.4; HRMS (EI): m/z [M] calcd for : C12H13NO ; 203.0946; found: 203.0952.
Isopropyl 1H-indole-2-carboxylate (2s)
Yield: 87%; white solid; m.p. 124.3-124.7°C; lit . 112℃; H NMR
O
[10]
1
N
O
(
-
400 MHz, CDCl
3
) δ 9.05 (s, 1H), 7.72 - 7.70 (d, J = 7.6 Hz, 1H), 7.46
H
7.44 (d, J = 8.0 Hz, 1H), 7.36 - 7.32 (td, J = 7.6, 0.8 Hz, 1H), 7.25 (d,
1
3
J = 1.2 Hz, 1H), 7.19 - 7.16 (t, J = 8.0 Hz, 1H), 5.33 (m, 1H), 1.44 - 1.42 (d, J = 6.4 Hz, 6H);
C
NMR (100 MHz, CDCl ) δ 161.9, 137.0, 127.9, 127.5, 125.2, 122.5, 120.7, 111.9, 108.5, 68.7,
3
[10]
2.0. All spectral data correspond to those given in the literature
2
.
1
H-indole-2-carboxamide (2t)
O
[
11]
Yield: 89%; white solid; m.p. 238.2-239.7 °C; lit.
1
N
NH
2
H
234-235℃; H NMR (400 MHz, DMSO-d
) δ 11.56 (s, 1H), 7.98 (s,
6
1
7
1
H), 7.60 (d, J = 7.9 Hz, 1H), 7.46 - 7.31 (m, 2H), 7.23 - 7.15 (m, 1H), 7.13 (d, J = 1.4 Hz, 1H),
1
3
.08 – 6.99 (m, 1H); C NMR (100 MHz, DMSO-d
6
) δ 163.3, 136.9, 132.2, 127.6, 123.7, 121.9,
[
11]
20.0, 112.7, 103.5. All spectral data correspond to those given in the literature
.
References
[
1] Jiang, B.; Dou, Y.; Xu, X.; Xu, M. Org. Lett. 2008, 10, 593-596.
S14

[
[
2] Prediger I.; Weiss T.; Reiser O. Synthesis 2008, 2191-2198.
3] Brenna, E.; Gatti, F. G.; Manfredi, A.; Monti, D.; Parmeggiani, F. Eur. J. Org. Chem. 2011, 4015-4022.
[
[
[
4] Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416-11417.
5] Vieira, T. O.; Meaney, L. A.; Shi Y. L.; Alper, H. Org. Lett. 2008, 10, 4899-4901.
6] Bonnamour, J.; Bolm, C. Org. Lett. 2011, 13, 2012-2014.
[
[
[
7] Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500-7501.
8] Tullberg, E.; Schacher, F.; Peters, D.; Frejd, T. Synthesis 2006, 1183-1189.
9] Kuwano, R.; Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17,
521-535.
[
[
10] Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011, 133, 4702-4705.
11] Csomós, P.; Fodor, L.; Mándity, I.; Bernáth, G. Tetrahedron 2007, 63, 4983-4989.
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S25