Cesium carbonate mediated synthesis of 3-(α-hydroxyaryl)indoles

Article abstract of DOI:10.1016/j.tetlet.2012.10.002

A series of 3-(α-hydroxyaryl)indoles have been synthesized by the reaction of aromatic aldehydes with indoles, catalyzed by cesium carbonate in DMF medium. The reactivity of the various alkali metal carbonates is discussed. The stability of 3-(α-hydroxyaryl)indoles is also discussed.

Full text of DOI:10.1016/j.tetlet.2012.10.002

Tetrahedron Letters 53 (2012) 6901–6904
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Cesium carbonate mediated synthesis of 3-(a-hydroxyaryl)indoles
Rasokkiyam Elayaraja a, R. Joel Karunakaran b,
⇑
a Research and Development Centre, Orchid Chemicals and Pharmaceuticals Ltd, Sholinganallur, Chennai 600119, India
b Associate Professor, Department of Chemistry, Madras Christian College, Tambaram, Chennai 600059, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-(
indoles, catalyzed by cesium carbonate in DMF medium. The reactivity of the various alkali metal carbon-
ates is discussed. The stability of 3-( -hydroxyaryl)indoles is also discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
a-hydroxyaryl)indoles have been synthesized by the reaction of aromatic aldehydes with
Received 17 June 2012
Revised 30 September 2012
Accepted 1 October 2012
Available online 12 October 2012
a
Keywords:
Cs2CO3
Indole
Aldehydes
3-(a-Hydroxyaryl)indoles
3-(
a
-Hydroxyaryl)indoles are unstable toward both acids and
reaction of indoles with aldehydes in methanol or ethanol
medium.4a,6
bases, due to their tendency to undergo dehydration to form stable
vinylogous iminium intermediates. This iminium species
generated in situ triggers several chemical transformations.1 3-
On the other hand Cs2CO3 is a powerful versatile inorganic base
used in many organic reactions. Cs2CO3 has unique properties such
as compatibility with a broad range of functional groups, and
replacing sodium and potassium based compounds.12 Recently
cesium substituted heteropolyacids catalyzed synthesis of
bis(3-indolyl)phenylmethanes was reported.13 Additionally several
indolyl derivatives are prepared14 successfully with the use of
Cs2CO3. In this preliminary work, we report a novel method,15
which is free from the formation of bisindolylmethane for the
(a-Hydroxyaryl)indoles can be used in the preparation of unsym-
metrical bis(indolyl)alkanes,2,3 as a starting material for getting
prochiral compound4b and one pot synthesis of b-indolylketones.4a
Apart from these, a few selected heteroaromatic substituted
3-(a
-hydroxyaryl)indoles5 (3d) were reduced6 to their respective
3-(aryl)methylindoles that are useful in the preparation of indole
alkaloids,7 pyridiocarbazoles,8 and 4-skatylpiperidines.9,10
There are two major issues associated with the preparation of
preparation of 3-(
of our knowledge this may be the first report, which exclusively
deals with the synthesis and stability of 3-( -hydroxyaryl)indoles.
a-hydroxyaryl)indoles (Scheme 1). To the best
3-(
tion and their reactivity after formation in the reaction medium.
As per the previous reports, 3-( -hydroxyaryl)indoles are unstable
a-hydroxyaryl)indoles, namely, the stability during the isola-
a
a
In order to obtain a maximum yield, the mole ratio and catalyst
loading have been studied. Except cesium carbonate none of the
other reagents has a considerable impact on the yield. The yield
variations with respect to the cesium carbonate are tabulated (Ta-
ble 1) and the result shows that 1.0 mole of Cs2CO3 gives better
yield. The optimal reaction time for maximum yield is determined
in organic solvents, and they are degraded during isolation,4a,b and
the isolated compound needs to be stored at a lower temperature
in an inert gas atmosphere. The other major issue is the formation
of bis(indolyl)methanes during the reaction, which turned out to
be the major product. The plausible reason for its formation is
due to the formation of vinylogous iminium ion by losing a water
molecule, which can react with another molecule of indole to form
the bis(indolyl)methanes.11
R2
HO
Owing to these problems, the number of methods for the prep-
CHO
aration of 3-(
for making 3-(
a
a
-hydroxyaryl)indoles is scarce. The existing method
-hydroxyaryl)indoles is by the reaction of indole-3-
Cs2CO3, DMF
R1
R1
N
H
rt, 6-7 hrs
R2
N
H
carboxaldehyde with the corresponding aryl-magnesium halides.
An alternative synthetic procedure is the base (NaOH) catalyzed
1
2
3a-j
R1= H, NO2, Br R2 =H, F, NO2
Scheme 1. General scheme for the preparation of 3-(
(19-85%)
⇑
Corresponding author. Tel.: +91 9444350863; fax: +91 4422394352.
E-mail address: rjkmcc@yahoo.com (R. Joel Karunakaran).
a
-hydroxyaryl)indoles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.002

6902
R. Elayaraja, R. Joel Karunakaran / Tetrahedron Letters 53 (2012) 6901–6904
Table 1
as 6–7 h. If the reaction time is extended, the reaction leads to
many uncharacterized compounds in the case of nitro
benzaldehyde.
Yield variation with different mole ratios of Cs2CO3 with respect to aldehyde
Products
Yielda (%)
A number of substituted indoles and aldehydes have been
chosen for this study (Table 2). In all the reactions studied, the for-
mation of bis(indolyl)methane formation was not observed. It was
also found that the yield of the product is largely controlled by the
nature of the functional group present in the benzaldehyde, rather
than substituents in the indole moiety. Generally, aldehydes with
0.15 mole (%)
0.50 mole (%)
1.0 mole (%)
1.2 mole (%)
3b
3c
27
25
45
42
71
69
72
69
a
Isolated yield in percentage.
Table 2
Reaction of various indoles with different aldehydes in the presence of Cs2CO3
Entry
Indole
Aldehyde*
Products
Yielda (%)
O2N
O2N
CHO
HO
NO2
1
85
N
H
O2N
3a
N
H
Br
CHO
CHO
CHO
O2N
NO2
HO
N
H
2
71
Br
3b
N
H
O2N
NO2
HO
N
H
3
69
3c
N
H
O2N
O2N
O2N
HO
N
N
O2N
O2N
O2N
4
5
6
7
47
40
40
35
H
3d
N
S
N
H
S
HO
CHO
N
H
3e
N
H
CHO
F
HO
N
H
3f
N
H
F
CHO
F
HO
N
H
3g
N
H
F

R. Elayaraja, R. Joel Karunakaran / Tetrahedron Letters 53 (2012) 6901–6904
6903
Table 2 (continued)
Entry
Indole
Aldehyde*
Products
Yielda (%)
CHO
O2N
HO
8
O2N
30
N
H
3h
3i
N
H
O2N
CHO
CHO
HO
N
H
O2N
9
30
N
H
Br
HO
N
Br
10
19
H
3j
N
H
*
All reactions were carried out with minimum 1 g scale.
Isolated yield in percentage.
a
good yields which can be employed on a wide range of substrates.
Table 3
Yield variation and time duration with different alkali metal carbonates
This method not only deals with the preparation of 3-(
aryl)indoles but also explores the stability.
a-hydroxy-
Entry
Products
Bases
Time
Isolated yield (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3a
3b
3c
3a
3b
3c
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
Li2CO3/Na2CO3
Li2CO3/Na2CO3
Li2CO3/Na2CO3
6–7 h
6–7 h
6–7 h
4 days
4 days
4 days
4 days
4 days
4 days
85
71
69
80
65
60
—
Acknowledgements
We are grateful to Orchid Chemicals and Pharmaceuticals Ltd,
R&D centre, Sholinganallur and Department of Chemistry, Madras
Christian College for providing facilities to carry out this research
work. We thank the reviewers for their valuable comments and
suggestions.
—
—
electron withdrawing groups afforded good yields (Table 2, entries
1, 2, 3), while those with electron releasing substituents gave mod-
erate yield. It has also been observed that the isolation procedure
for all the substrates is tedious except in the case of compounds
with an electron withdrawing group .(Table 2, entries 1, 2, 3) From
this study it is also noted that this method is not suitable for
substituted phenolic aldehydes and benzoic acid aldehydes.
To study the reaction details, we have carried out a few of the
reactions (Table 2, entries 1, 2, 3) with different solvents and differ-
ent inorganic bases. The effect of solvent on reaction was evaluated
along with DMF, which revealed that the progress of reaction was
very slow in acetonitrile and acetone and produced lower yields. In
water medium the yield was almost similar to that of DMF med-
ium; however it took nearly 20 h for the maximum conversion.
Among the bases studied, Li2CO3 and Na2CO3 were found to be
unreactive under these conditions. The reaction with K2CO3 pro-
gressed very slow and took 4 days for completion. The product
yield and the time duration are summarized in Table 3.
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volumes of DMF for 6–7 h, and then diluted with 20 mL of water and extracted
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a-