Synthesis of 2-acylindole-3-acetic acids: A novel base-mediated indole synthesis

Article abstract of DOI:10.1016/S0040-4039(03)01879-3

An efficient and expedient synthetic route to 2-acylindole-3-acetic acids is described. This work first demonstrates a one-pot room-temperature indole ring construction via the in situ generation of indoline intermediate.

Full text of DOI:10.1016/S0040-4039(03)01879-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7269–7271
Synthesis of 2-acylindole-3-acetic acids: a novel base-mediated
indole synthesis
Kazunari Nakao, Yoshinori Murata, Hiroki Koike, Chikara Uchida, Kiyoshi Kawamura,
Sachiko Mihara, Shigeo Hayashi and Rodney W. Stevens*
Discovery Chemistry Research, Nagoya Laboratories, Global Research & Development, Pfizer Inc., 5-2 Taketoyo,
Aichi 470-2393, Japan
Received 13 June 2003; revised 25 July 2003; accepted 4 August 2003
Abstract—An efficient and expedient synthetic route to 2-acylindole-3-acetic acids is described. This work first demonstrates a
one-pot room-temperature indole ring construction via the in situ generation of indoline intermediate.
© 2003 Elsevier Ltd. All rights reserved.
The chemistry of indoles is well-studied, and a variety
of methods for the synthesis of indoles have been
developed.1–3 One of the most important methods for
the preparation of many structurally diverse 2,3-disub-
stituted indoles is the Fisher indole synthesis.4,5
Recently, a number of novel synthetic methods to
indole-3-acetic acid derivatives have been reported on.6–8
On the other hand, several convenient synthetic meth-
ods to 2-acylondoles have been reported. Jones et al.
reported a method of the preparation of 2-acylindole
derivatives using N-alkylation followed by intramolecu-
lar aldol condensation and dehydration.9 His group
also reported the similar method to prepare indole-2-
carboxilic acids from sulfonamide derivatives.10 How-
ever, 2-acylindole-3-acetic acids have scarcely been
reported on because of the low feasibility of the chem-
istry. Fukuyama et al. have reported on a tin(IV)-medi-
ated synthesis of methyl 2-substituted-indole-3-acetate,
however our attempts to couple the intermediate 2-
stannylindole with a-halo-ketones under Stille condi-
tions proceeded in unacceptable yields.11 Herein, we
describe an efficient and expedient synthetic route to
2-acylindole-3-acetic acids. This new discovery offers
the advantage of a facile one-pot room-temperature
indole construction via the in situ generation of indo-
line intermediate.
Thus, for example, treatment of trans-2-aminocinna-
mate 1 with K2CO3 promotes an intramolecular
Michael addition that generates indoline 2 and a trace
amount of indole 3 (Scheme 1).12 Subsequent treatment
with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) or Cs2CO3, accelerates b-elimination to afford
indole 3.13 Conveniently, the reaction can be performed
in a one-pot procedure to afford the desired indole 3 in
a good to excellent yield.
Next, the scope and limitations of the reaction were
investigated and results are summarized in Table 1.
Electron-donating or -withdrawing group possessing
phenacyl (entries 2–7) or heteroarylacyl halides (entries
8–13) all reacted smoothly in situ to provide the corre-
sponding 2-acyl indole acetic esters (52–93% isolated
yield). The reaction of 2-bromo-1-cyclopropylethanone
Scheme 1. Reaction conditions: (a) RCOCH2Br, K2CO3, acetone, rt; (b) base.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01879-3

7270
K. Nakao et al. / Tetrahedron Letters 44 (2003) 7269–7271
Table 1. Methyl 2-acylindole-3-acetate derivatives produced via Scheme 1
Entry
Substrate R1
Acyl halide
Base (equiv.)
Yield (%)
1
2
3
4
5
6
7
8
H
PhCOCH2Br
4-Cl-PhCOCH2Br
4-Cl-PhCOCH2Br
4-Cl-PhCOCH2Br
4-Cl-PhCOCH2Br
4-Cl-PhCOCH2Br
4-MeO-PhCOCH2Br
5-Cl-2-(BrCH2CO)-pyridine
4-MeO-2-(BrCH2CO)-pyridine*
5-Me-2-(BrCH2CO)-thiazolea
1-Me-2-(BrCH2CO)-imidazolea
3-(BrCH2CO)-isoquinolinea
3-(BrCH2CO)-isoquinolinea
Cyclopropyl-COCH2Br
1-Bromo-2-butanone
DBU (3)
Cs2CO3 (2)
DBU (2)
DBU (3)
DBU (3)
Cs2CO3 (2)
Cs2CO3 (3)
DBU (2)
DBU (2)
DBU (3)
DBU (2)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
93
61b
52b
88
74
93
89
72b
74
44
57
53
59
94
82
6-Cl
6-Cl
5-Cl
6-MeO
5-MeO
6-Cl
5-Cl
5-Cl
5-Cl
5-Cl
6-Cl
5-Cl
6-Cl
6-Cl
9
10
11
12
13
14
15
a Hydrobromide salt.
b Yield after recrystallization.
A typical experimental procedure for preparing 3: A
mixture of 1 (1.6 mmol), a-halo-ketone (2.4 mmol) and
K2CO3 (16 mmol) in acetone (16 mL) was stirred at
ambient temperature. After stirring for 1 h, DBU (4.8
mmol) was added and the stirring was continued for an
additional 8 h. The mixture was concentrated and the
residue was diluted in ethyl acetate (100 mL). The
organic mixture was washed with water (100 mL) and
dried (MgSO4). After removal of solvent, the residual
solids were purified by silica gel column chromatogra-
phy to afford the corresponding indole 3.
and 1-bromo-2-butanone also proceeded smoothly to
afford the corresponding indole in excellent yield
(entries 14 and 15).
trans-2-Aminocinnamates 1 and the title compounds
were prepared as follows: Initially we carried out the
Wittig reaction of the benzaldehyde 4 to give trans-2-
nitrocinnamate 5 (Scheme 2) according to the proce-
dure of Carling.14 trans-2-Nitrocinnamate
5 was
reduced to trans-2-aminocinnamate 6 by treatment with
iron powder in refluxing aqueous ethanol and then
converted to the acyclic precursor 1 by sulfonylation of
6. As described above, one-pot room-temperature
based-promoted cyclization afforded indole 3 which
was hydrolyzed to the corresponding indole acetic acid
7 in excellent yield.
In summary, this work has first demonstrated a one-pot
room-temperature indole construction via the in situ
generation of indoline intermediates. This procedure
provides a simple and practical method for the synthe-
sis of 2-acylindole-3-acetic acids.
Scheme 2. Reaction conditions: (a) Ph3PꢀCHCO2Me, toluene, reflux; (b) Fe, NH4Cl, EtOH/H2O, reflux; (c) PhSO2Cl, pyridine,
CH2Cl2, rt; (d) RCOCH2Br, K2CO3, acetone, rt; (e) DBU or Cs2CO3; (f) 2N NaOH, THF/MeOH, rt.

K. Nakao et al. / Tetrahedron Letters 44 (2003) 7269–7271
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