Ligand-free copper-catalyzed one-pot synthesis of indole-2-carboxylic esters

Article abstract of DOI:10.1002/ejoc.201301607

A simple, efficient, and facile synthetic route for the preparation of indole-2-carboxylic esters was described. The cascade reactions of 2-bromobenzaldehyde and glycine ester hydrochloride were promoted by Cu ₂O and a base to provide the corresponding products in good yields. Commercially available, inexpensive substrates and reagents were employed under mild reaction conditions in this one-pot operation, which is complementary to existing methods for access to 2-substituted indoles. A simple, efficient, and facile synthetic route to indole-2-carboxylic esters through copper-catalyzed one-pot cascade reactions of commercially available, inexpensive 2-bromobenzaldehyde and glycine ester hydrochloride without the use of any external ligand under mild conditions is reported. Copyright

Full text of DOI:10.1002/ejoc.201301607

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301607
Ligand-Free Copper-Catalyzed One-Pot Synthesis of Indole-2-carboxylic
Esters
Zhiqiang Zhu,[a] Jiangjun Yuan,[b] Yirong Zhou,[b] Yang Qin,[b] Jingshi Xu,[a] and
Yiyuan Peng*[a,b]
Keywords: Synthetic methods / Domino reactions / Nitrogen heterocycles / Copper
A simple, efficient, and facile synthetic route for the prepara-
tion of indole-2-carboxylic esters was described. The cascade
reactions of 2-bromobenzaldehyde and glycine ester hydro-
chloride were promoted by Cu2O and a base to provide the
corresponding products in good yields. Commercially avail-
able, inexpensive substrates and reagents were employed
under mild reaction conditions in this one-pot operation,
which is complementary to existing methods for access to 2-
substituted indoles.
which is associated with dangerous azidoacetates[7,20a] and
the Horner–Wadsworth–Emmons olefination/cyclization
approach, which has poor atom economy,[11c,20e] are the two
most commonly used routes. Cusack et al. described the
CuI-catalyzed intramolecular cyclization of ene-carbamates
to synthesize indole-2-carboxylates.[20e] Nevertheless, ene-
carbamates must be first synthesized by Horner–Wads-
worth–Emmons condensation of the corresponding aro-
matic aldehydes and expensive N-benzyloxycarbonyl-α-
phosphonoglycine trimethyl ester was necessary. Cai et al.
demonstrated a ligand-free reaction of ethyl isocyanoacet-
ate and 2-haloaryl aldehydes or ketones to form indole-2-
carboxylate esters.[20c] However, the need to handle foul-
smelling and costly isocyano compounds is highly undesir-
able.[21] Another method was reported by Koenig et al.
starting from 2-halobenzaldehydes and ethyl benz-
amidoacetate through a cascade sequence reaction in
DMSO.[20b] However, the starting benzamidoacetates are
not easy to obtain. Therefore, the development of novel
methods to further improve the synthetic efficiency of di-
versified indole-2-carboxylate esters from inexpensive start-
ing substrates and reagents is still highly desirable. Herein,
we present a simple and efficient one-pot synthesis of in-
dole-2-carboxylate esters from 2-bromoarenecarbaldehydes
with glycine ester hydrochloride catalyzed by Cu2O without
the addition of any ligand or additive. The reaction pro-
Introduction
The indole scaffold as a “biologically privileged struc-
ture”[1] represents one of the most significant heterocycles
in biologically active and naturally occurring molecules.[2]
A great number of methods for the synthesis of indoles have
been developed, and this continues to be a very active re-
search area.[3–5] The classic routes for the preparation of
indoles include Fischer[6] and Sundberg/Hemetsberger in-
dole synthesis,[4e,7] olefination/cyclization,[8] and some other
examples. In this context, transition-metal-catalyzed reac-
tions are the most attractive methods for the facile con-
struction of complicated heterocyclic molecules from read-
ily accessible starting materials under mild conditions.[9–11]
Among them, copper catalysis has proven to be increasingly
powerful for the synthesis of indoles[12,13] and other nitro-
gen-containing heterocycles.[14,15] Although much progress
has been achieved in the synthesis of indole derivatives, the
preparation of some specific substituted patterns remains a
challenge.[16] Especially, indole-2-carboxylate esters have
been reported to display a wide range of biological func-
tions such as cPLA2 inhibition,[17] histamine H4 receptor
antagonism,[18] and HIV-1 inhibition.[19] However, straight-
forward strategies are relatively rare for the ready and flexi-
ble preparation of indole-2-carboxylate esters.[20] While pur-
suing our research in the area of indole-2-carboxylate syn-
thesis, we found that the Hemetsberger–Knittel reaction,
[a] Key Laboratory of Green Chemistry, Jiangxi Province and
College of Chemistry, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China
E-mail: yypeng@jxnu.edu.cn
http://www.jxnu.edu.cn/s/2/t/690/q/51/c/3427/list.jspy
[b] Key Laboratory of Small Fuctional Organic Molecule, Ministry
of Education and College of Life Science, Jiangxi Normal
University,
Nanchang, Jiangxi 330022, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301607.
Scheme 1. Possible reaction pathway.
Eur. J. Org. Chem. 2014, 511–514
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
511

Z. Zhu, J. Yuan, Y. Zhou, Y. Qin, J. Xu, Y. Peng
SHORT COMMUNICATION
ceeds though a cascade sequence involving an aldol conden- occurred through a base-promoted aldol condensation and
sation and the Cu-catalyzed intramolecular amidation of was followed by Cu-catalyzed intramolecular amidation
aryl bromides (Goldberg reaction, Scheme 1).
(Scheme 1). Several bases including K2CO3, Na2CO3,
K3PO4, and tBuOK were then screened, and Cs2CO3 was
found to be the most effective (Table 1, entries 9–12). The
solvent effects were also investigated, and N-methylpyrrol-
idone (NMP) proved to be the best solvent, as it delivered
the product in the highest yield (72%; Table 1, entries 13–
18). Evaluation of the reaction temperature suggested that
100 °C was the best choice (Table 1, entries 18–20). The
yield of desired product 3aa further improved to 85% if
2 equivalents of Cs2CO3 was used (Table 1, entry 22).
The reaction scope was probed under the optimized con-
ditions [Cu2O (10 mol-%), Cs2CO3 (2 equiv.) in NMP under
a nitrogen atmosphere at 100 °C], and the results are sum-
marized in Table 2. In general, most of the substrates exam-
Results and Discussion
In our initial studies, the reaction of 2-bromobenzalde-
hyde (1a) with glycine methyl ester hydrochloride (2a) was
chosen as a model reaction to optimize the reaction condi-
tions. Several parameters including copper catalysts, sol-
vents, and bases were examined at 100 °C under a nitrogen
atmosphere (Table 1). First, both monovalent and divalent
copper salts, such as CuI, CuBr, CuCl, CuCl2, Cu(OAc)2,
Cu(OTf)2, and Cu2O, were tested in DMF in the presence
of Cs2CO3 (3 equiv. relative to 1a) as the base (Table 1, en-
tries 1–7; Tf = trifluoromethanesulfonyl). Cu2O exhibited
the highest activity, for which the target product ethyl in-
dole-2-carboxylate (3aa) was obtained in 52% yield
(Table 1, entry 5). A control experiment showed that no
product was detected by TLC during the reaction process
without the addition of a copper catalyst (Table 1, entry 8).
Moreover, a new product was observed, which was isolated
and identified to be ethyl 2-amino-3-(2Ј-bromophenyl)acryl-
ate (4). This result indicted that the transformation first
Table 2. Exploration of the substrate scope.[a]
Table 1. Optimization of the reaction conditions for the copper-
catalyzed cascade synthesis of 1H-indole-2-carboxylic methyl es-
ter.[a]
Entry
Catalyst
Base
Solvent
T [°C]
Yield [%][b]
1
2
3
4
5
6
CuI
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
30
27
37
35
52
29
36
–
26
15
33
–
CuBr
CuCl
CuCl2
Cu2O
Cu(OAc)2 Cs2CO3 DMF
Cu(OTf)2 Cs2CO3 DMF
–
7
8[c]
9
Cs2CO3 DMF
K2CO3 DMF
Na2CO3 DMF
K3PO4 DMF
tBuOK DMF
Cs2CO3 toluene
Cs2CO3 DCE
Cs2CO3 dioxane
Cs2CO3 DMSO
Cs2CO3 DMA
Cs2CO3 NMP
Cs2CO3 NMP
Cs2CO3 NMP
Cs2CO3 NMP
Cs2CO3 NMP
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
10
11
12
13
14
15
16
17
18
19
20
21
22[d]
–
–
–
32
50
72
trace
28
67
85
80
120
100
[a] Reaction conditions: 2-bromobenzaldehyde (0.5 mmol), glycine
methyl ester hydrochloride (0.75 mmol), catalyst (0.1 mmol), base
(1.5 mmol), and solvent (3 mL) under a nitrogen atmosphere. DCE
= 1,2-dichloroethane, DMA = dimethylacetamide. [b] Yield of iso-
lated product. [c] In the absence of a copper catalyst. [d] 2 equiv.
Cs2CO3 was used.
[a] Reaction conditions: substituted 2-bromobenzaldehyde
1
(0.5 mmol), glycine ester hydrochloride (0.75 mmol), Cu2O
(10 mol-%), Cs2CO3 (2 equiv.) in NMP (3 mL) under a nitrogen
atmosphere at 100 °C. [b] Yield of isolated product.
512
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 511–514

One-Pot Synthesis of Indole-2-carboxylic Esters
ined provided the corresponding indole-2-carboxylate esters
products in good to excellent yields. An array of functional
groups including alkyl, ether, and halide groups were well
tolerated. For various substituted 2-bromobenzaldehydes,
the results indicated that electron-poor substrates reacted
better than electron-rich ones. The reactions of 5-fluoro-,
5-chloro-, and 4-fluoro-substituted 2-bromobenzaldehydes
Experimental Section
General Procedure: To a mixture of Cu2O (7.2 mg, 0.01 mmol) and
glycine methyl ester hydrochloride (94.2 mg, 0.75 mmol) was added
cesium carbonate (325.6 mg, 1 mmol) and NMP (3 mL). Then, 2-
bromobenzaldehyde (0.06 mL, 0.5 mmol) was dropped into the
mixture under a nitrogen atmosphere at room temperature. The
reaction tube was sealed, and the resulting mixture was heated to
(i.e., 1b, 1c, and 1d) proceeded smoothly to deliver good 100 °C under a nitrogen atmosphere with good agitation. After
16 h, the mixture was cooled to room temperature, diluted with
ethyl acetate (10 mL), and quenched with water (10 mL). After
transferring to a separatory funnel with EtOAc and water (30 mL/
30 mL), the organic layer was removed. The aqueous layer was ex-
tracted with ethyl acetate (2ϫ 5 mL), and the combined organic
fraction was washed with water (5 mL) and brine (5 mL). The com-
bined organic layer was dried with anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel; EtOAc/petroleum ether, 1:50) to afford
desired product 3.
results, whereas 4-methyl- and 4,5-dimethoxy-substituted 2-
bromobenzaldehydes (i.e., 1e and 1f) as well as 6-bromo-
benzo[1,3]dioxole-5-carbaldehyde (1g) only gave moderate
yields of the desired products. Notably, the yields decreased
slightly as the steric hindrance of the ester was increased.
To verify our proposed reaction mechanism outlined in
Scheme 1, 4 was used directly and anticipated product 3aa
was obtained in quantitative yield under the optimized con-
ditions [Scheme 2, Eq. (1)]. Upon replacing 2-bromobenz-
aldehyde (1a) with 2-chlorobenzaldehyde (5) under identical
reaction conditions, only intermediate ethyl 2-amino-3-(2Ј-
chlorophenyl)acrylate (6) was isolated in 96% yield [Scheme
2, Eq. (2)]. This result indicated that the Cu-catalyzed intra-
molecular amidation did not take place as a result of the
lower reactivity of the aryl chloride. At last, in the case of
2-bromoacetophenone (7), the reaction did not proceed at
all and no new product was noticed [Scheme 2, Eq. (3)].
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data as well as NMR spectra of the products.
Acknowledgments
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (grant numbers 20962010 and 21162012),
Jiangxi Provincial Department of Science and Technoloy (for
Jiangxi’s Key Laboratory of Green Chemistry), and the Science
Foundation of Education Department of Jiangxi provice (grant
number GJJ10386) for their financial support.
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Conclusions
In summary, we have demonstrated a simple, efficient,
and facile route for the preparation of indole-2-carboxylic
esters through copper-catalyzed cascade reactions of 2-
bromobenzaldehyde and glycine ester hydrochloride with-
out the use of any external ligand. Commercially available,
inexpensive substrates and reagents were employed under
mild reaction conditions in a one-pot operation; this
method provides an alternative that can be used to access
2-substituted indoles.
Eur. J. Org. Chem. 2014, 511–514
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
513

Z. Zhu, J. Yuan, Y. Zhou, Y. Qin, J. Xu, Y. Peng
SHORT COMMUNICATION
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Received: October 27, 2013
Published Online: December 11, 2013
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