A ligand-free, copper-catalyzed cascade sequence to indole-2-carboxylic esters

Article abstract of DOI:10.1016/j.tetlet.2010.10.035

A variety of indole-2-carboxylic esters are accessible in yields up to 61% through a ligand-free, coppercatalyzed reaction of a series of commercially available 2-halo aryl aldehydes with benign glycine amidoesters, including the common reagent ethyl acetamidoacetate. This one-pot, three-reaction format allows ready entry to the desired heterocycles from starting substrates in the reactivity order of iodo > bromo ≥ chloro substituents. An assortment of functional groups is tolerated, adding to the generality of this methodology.

Full text of DOI:10.1016/j.tetlet.2010.10.035

Tetrahedron Letters 51 (2010) 6549–6551
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Tetrahedron Letters
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A ligand-free, copper-catalyzed cascade sequence to indole-2-carboxylic esters
⇑
Stefan G. Koenig , John W. Dankwardt, Yanbing Liu, Hang Zhao, Surendra P. Singh
Chemical Process Research and Development, Sepracor Inc., 84 Waterford Drive, Marlborough, MA 01752, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of indole-2-carboxylic esters are accessible in yields up to 61% through a ligand-free, copper-
catalyzed reaction of a series of commercially available 2-halo aryl aldehydes with benign glycine amido-
esters, including the common reagent ethyl acetamidoacetate. This one-pot, three-reaction format allows
ready entry to the desired heterocycles from starting substrates in the reactivity order of iodo > bro-
mo P chloro substituents. An assortment of functional groups is tolerated, adding to the generality of this
methodology.
Received 9 September 2010
Revised 29 September 2010
Accepted 6 October 2010
Available online 14 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The indole nucleus, highlightedas a ‘biologically privileged struc-
ture,’1 has been targeted with metal-mediated catalysis under a
variety of synthetic strategies.2 A subset of this approach to indoles,
copper-catalyzed reactions have proven to be powerful tools to
assemble several types of aromatic amines.3 Though this type of
copper chemistry regularly includes a co-ordinating species to
accelerate the reaction, some examplesof C–N bond formation with-
out the use of such ligands have been reported.4 In fact, while we
were pursuing our research in the area of indole formation, a report
was published detailing the ligand-free reaction of ethyl isocyanoac-
etate and 2-halo aryl aldehydes or ketones.5 This method, reported
by Cai et al., worked under reasonably mild conditions to give the de-
sired heterocyclic systems from an elegant cascade process. How-
ever, the transformation benefited from the use of reactive
isocyano functionality and the need to handle these foul-smelling
and costly compounds is highly undesirable.6 An alternate coupling
partner would be most welcome from a chemical development
perspective.
that included aldol condensation, Cu-catalyzed aryl amidation
(Goldberg reaction),9 and deacylation,10 with the cascade sequence
likely occurring in that order (1 and 2 ? 3 ? 4 ? 5, Scheme 1).
Curious to see whether the external ligand was necessary for this
three-step sequence, we attempted the slurry-based transforma-
tion with the more reactive 2-iodobenzaldehyde and ethyl acet-
amidoacetate 2 (R = Me, R0 = Et) in the absence of the diamine
additive. Gratifyingly, this ligand-free reaction proceeded at ambi-
ent temperature to give the indole ester 5 in 61% isolated yield, all
with a lower catalyst loading (Table 1, entry 4).
In order to explore the scope and limitations of this ligandless
reaction, we examined other substrates and conditions. 2-Bromo-
benzaldehyde provided a slower, but still productive reaction at
ambient temperature (47%, Table 1, entry 5) while reacting more
efficientlyat a moderatelyelevated temperature (80 °C) to give ethyl
indole-2-carboxylate in 53% isolated yield (entry 6). The results with
this substrate were particularly encouraging for the generality of
such a methodology due to the wide commercial availability of
substituted bromobenzaldehydes compared to the iodo-substrates.
Meanwhile, 2-chlorobenzaldehyde, which did not react in the
presence of the ligand at 60 °C (entry 3), did react in its absence at
During the course of our work, we became interested in a route to
indole-2-carboxylic esters 5 (Scheme 1). In order to avoid using the
more direct Hemetsberger-Knittel reaction strategy and the danger
associated with azidoacetates7 or the lower atom economy Horner-
Wadsworth-Emmons olefination/cyclization approach,8 we tar-
geted the indole structures with a Cu(I)-mediated cascade sequence
occurring in one-pot under basic conditions. Starting from 2-halo-
benzaldehydes 1 and ethyl benzamidoacetate 2 (R = Ph, R0 = Et),
we were delighted to discover that heterocycle formation proceeded
well in this fashion using 2-iodo- or 2-bromobenzaldehyde 1 (X = I
or Br) in DMSO at 60 °C (Table 1, entries 1 and 2).
Using CuI with N,N0-dimethylethylenediamine,3a a frequently
used chelating ligand, with 1 (X = I or Br) and 2 (R = Ph, R0 = Et)
enabled the reaction to deliver ethyl indole-2-carboxylate 5 in
74% and 55% yields, respectively, as part of a presumed process
⇑
Corresponding author. Tel.: +1 508 357 7461; fax: +1 508 357 7808.
E-mail address: stefan.koenig@sepracor.com (S.G. Koenig).
Scheme 1. One-pot, three-reaction indole-2-carboxylic ester formation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.035

6550
S. G. Koenig et al. / Tetrahedron Letters 51 (2010) 6549–6551
Table 1
Table 2
Indole-2-carboxylic ester formation
Screening of conditions with 2-bromobenzaldehyde
Entry
Catalyst
Mol %
Solvent
Mol % base
% yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
20
20
20
20
20
10
5
20
20
20
20
20
20
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CH3CN
NMP
EtOH
Toluene
Dioxane
200
200
200
150
100
200
200
200
200
200
200
200
200
31
33
50
46
42
50
49
45
36
12
5
Entry
X=
R=
Cu (mol %)
T (°C)
% yieldb
1a
2a
3a
4
5
6
I
Ph
Ph
Ph
Me
Me
Me
Me
20
20
20
10
20
20
20
60
60
60
25
25
74
55
ND
61
47
53
16
Br
Cl
I
Br
Br
Cl
21
19
80
140
7
a
All unoptimized, isolated yields from 4.0 mmol reactions with 120 mol % ethyl
a
N,N0-dimethylethylenediamine (25 mol %) was included as the ligand.
All values are unoptimized, isolated yields from 4.0 mmol reactions with
acetamidoacetate, Cs2CO3 as base, 80 °C, 16 h.
b
120 mol % ethyl amidoacetate, 16 h.
substrates with varying substituent groups (Table 3, entries 1–8).
With our conditions refined, a series of starting aldehydes were
subjected to the reaction in DMSO. All substrates reacted to give
the expected indole product in the range of 41–56% yield, encour-
aging for a three-step cascade process using mild reagents. An
array of functionality was tolerated under these conditions, includ-
ing alkyl, ether, nitrile, and halide groups.
Curiously, aromatic ketones did not react well with this system
(Table 3, entries 9 and 10). In the earlier paper using ethyl iso-
cyanoacetate to form indole-2-carboxylic esters, Cai et al. reported
that ketones reacted very well, on par with the corresponding alde-
hydes. It appears that in our case with ethyl acetamidoacetate, the
initial aldol condensation does not proceed with the less reactive ke-
tone functionality and thus the crucial intramolecular amidation
step cannot occur. This selectivity is indicative of the more benign
nature of the glycine amidoesters. Overall, this chemistry presents
mild conditions to indole-2-carboxylic esters where the unoccupied
3-position remains available for further derivatization, if necessary.
In conclusion, we have demonstrated that a copper-catalyzed
cascade sequence provides ready access to indole-2-carboxylic es-
ters without the use of an external ligand. To our knowledge, this is
the first report showing the one-pot formation of indole products
a higher temperature (140 °C), albeit giving the desired product in
only 16% yield from a complex reaction mixture (entry 7). Due to
the poor result with the chloro analog and the plentiful supply of
bromo-substituted aryl aldehydes, we focused on optimizing the
reaction conditions for these latter substrates.
A brief screen of copper complexes showed that CuI was a pre-
ferred mediator of the reaction (Table 2, entries 1–3). A screening
of bases demonstrated that Cs2CO3 was the superior species for
this reaction. Other inorganic/insoluble bases, such as K2CO3,
KHCO3, K3PO4, and NaOAc—even when finely ground—as well as
organic/soluble species, such as DBU, TMG, EtN(i-Pr)2, and pyri-
dine, all failed to provide more than a trace amount of the desired
product. Further focus on Cs2CO3 showed that levels below
200 mol % were inadequate for the best conversion (entry 3 vs en-
tries 4 and 5). Meanwhile, catalyst loadings of 10 and 5 mol % gave
similarly successful results (entries 6 and 7). Not surprisingly, a
series of experiments in different media demonstrated that the
highly polar aprotic solvents DMSO and DMF were preferred for
this transformation (entries 3 and 8 vs entries 9–13).
To further demonstrate the broader generality of this method,
we examined
a series of 2-bromo-substituted aryl aldehyde
Table 3
CuI-catalyzed formation of various indole-2-carboxylic esters
Entry
1
Starting material
Desired product
% yielda
50
Entry
6
Starting material
Desired product
% yielda
53
2
3
53
47
7
8
41
55
4
5
56
44
9
NDb,c
10
NDb
a
b
c
All isolated yields from unoptimized, 4.0 mmol reactions with 120 mol % ethyl acetamidoacetate, 20 mol % CuI, 200 mol % Cs2CO3, 80 °C, 16 h.
No desired product was detected from reactions under standard conditions (see previous note) and a majority of the starting material was recovered.
When the reaction was run at 140 °C, the hydrodehalogenated derivative of the starting material, acetophenone, was the major product detected.

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inexpensive coupling partner.
Supplementary data
Supplementary data (general experimental and accompanying
spectroscopic data for the compounds) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2010.
10.035.
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