Oleic acid: A benign Br?nsted acidic catalyst for densely substituted indole derivative synthesis

Article abstract of DOI:10.1039/c5ra02906f

Oleic acid was identified to catalyse bis(indolyl)methane and densely functionalized 4H-chromene, spirooxindole and spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivative synthesis in good to excellent yields. The synergy between Br?nsted acidity and surfa

Full text of DOI:10.1039/c5ra02906f

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Oleic acid: a benign Brønsted acidic catalyst for
densely substituted indole derivative synthesis†
Cite this: RSC Adv., 2015, 5, 28597
a
a
b
Asaithampi Ganesan, Jagatheeswaran Kothandapani, Jagadeesh Babu Nanubolu
and Subramaniapillai Selva Ganesan*a
Received 14th February 2015
Accepted 4th March 2015
DOI: 10.1039/c5ra02906f
www.rsc.org/advances
Oleic acid was identified to catalyse bis(indolyl)methane and densely Reports on Brønsted acid catalysed synthesis of 4H-chromenes
0
functionalized 4H-chromene, spirooxindole and spiro[indoline-3,4 - and spirooxindole derivatives are limited to dodecyl benzene-
17
pyrano[2,3-c]pyrazole] derivative synthesis in good to excellent yields. sulfonic acid, gluconic acid and proline. To the best of our
The synergy between Brønsted acidity and surfactant ability of natu- knowledge, unmodied oleic acid catalysed substituted indole
rally available oleic acid was exploited to carry out the aforementioned derivative synthesis hasn't been reported.
transformations.
During the investigation on “oleic acid functionalized iron
oxide” catalyzed bis(indolyl)methane synthesis, we have iden-
tied the excellent catalytic potential unmodied oleic acid
itself. Oleic acid and other C-18 fatty acid counterparts are
Indole and its derivatives are widely abundant in natural
products and bioactive skeletons. Indole derivatives were used
as novel efflux pump inhibitors, neuroprotective agents,
1
18a
diversely distributed in plant oils. Oleic acid being scarcely
2
3
ꢁ1 18b
soluble in water (ꢀ0.1 mmol l
)
has a commendable cata-
4
5

uoride ion sensors, cox-2 inhibitors and promising anti-
lytic ability to promote the reaction (Table 1, entry 3). Further-
more, isolation of the products from the reaction mixture was
done by simple ltration. Reactions carried out in oleic acid
soluble solvents such as ethanol and acetonitrile did not yield
the corresponding bis(indolyl)methane 3a (Table 1, entry 6, 7).
For the reactions carried out in water, Breslow hydrophobic
effect, hydrogen-bonding and polarity effects greatly assist the
1
cancer agents. Similarly, spirooxindole and chromene deriva-
tives are present in a vast array of biologically signicant
6–11
molecules.
Mitraphylline is a representative example of a
spirooxindole molecule with excellent anticancer activity
against neuroblastoma cell lines. Though several catalysts are
available for the synthesis of such molecules,
12
13–15
many of them
have notable disadvantages such as limited substrate scope,
high cost, toxicity, difficulty in catalyst preparation etc. Hence,
identication of a robust, readily available, non-toxic catalyst
that yields a library of 3-substituted indole skeletons in an
environmentally benign solvent is always attractive. Unlike
surfactants, fatty acids are lesser explored as catalyst primarily
due to their mild Brønsted acidity and poor solubility in water.
Kobayashi and co-workers reported decanoic acid catalysed
19
easy formation of products. Oleic acid mediated bis(indolyl)-
methane synthesis was found to be general for various
substituted aldehydes (Scheme 1).
Reaction carried out at room temperature increased the
reaction completion time to 10 h (Table 1, entry 2). Catalyst
loading of 12.5 mol% was necessary to achieve optimum yield
16a
Table 1 Reaction condition optimization for 3a synthesis
3-substituted indole synthesis. Mase et al., showed that the
presence of fatty acid reduce the catalyst loading and improved
the product yield in organocatalytic direct aldol reaction.
a
Catalyst
(mol%)
Time (h)/
(temp C)
Yield
(%)
16b
ꢂ
Entry
Solvent
b
1
2
3
4
5
6
7
OA(12.5)
OA(12.5)
OA(12.5)
OA(5.0)
H
H
H
H
H
2
2
2
2
2
O
O
O
O
O
2(RT)
Trace
84
98
65
96
a
10(RT)
2(100)
2(100)
1(100)
2(100)
2(100)
Department of Chemistry, School of Chemical and Biotechnology, SASTRA University,
Thanjavur-613401, India. E-mail: selva@biotech.sastra.edu; Fax: +91 4362 264120;
Tel: +91 8973104963
c
d
b
OA(12.5)
OA(12.5)
OA(12.5)
Room No 150, Centre for X-ray Crystallography, Indian Institute of Chemical
C
2
H
5
OH
Trace
Trace
Technology, Hyderabad- 500607, India. E-mail: jagadeesh81@gmail.com; Tel: +91
CH
3
CN
0
40 27193118
a
b
c
†
Electronic supplementary information (ESI) available. CCDC 1034527. For ESI
Yields are for the isolated products. OA is oleic acid. In the absence
d
and crystallographic data in CIF or other electronic format see DOI:
0.1039/c5ra02906f
of oleic acid, product was formed in 56% yield. Reaction performed
with 20 mol% catalyst also gave 98% yield in 2 h.
1
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Scheme 1 Oleic acid catalysed bis(indolyl)methane synthesis.
Fig. 2 Crystal structure of product 5e. Ellipsoids are drawn at the 20%
probability level and H atoms are shown as small spheres of arbitrary
radius.
acid catalysed reaction in water relative to organic solvents
(Table 1, entry 3 vs. 6, 7) could be attributed to the high
concentration of substrates inside the micelle-like spherical
droplet formed by oleic acid on water. Each droplet may act as a
hydrophobic reaction site that enables the smooth trans-
21
formation of substrate to the product.
Representative 4H-chromene synthesis was chosen as model
Fig. 1 Light microscopic image of oleic acid, indole and benzaldehyde reaction to evaluate the scope of oleic acid catalysis (Table 2).
in water.
The synthesis of 4H-chromene is challenging due to the
competitive formation of bis(indolyl)methane by-product 3. It
should be noted that bis(indolyl)methane formed even in the
(Table 1, entry 3 vs. 4). Further increase in catalyst load to
absence of catalysts (Table 1, footnote c). Reaction with rela-
tively stronger acids such as acetic acid resulted in the forma-
tion of bis(indolyl)methane by-product (Table 2, entry 2). Since
saturated solid fatty acids (palmitic acid, stearic acid) failed to
accommodate all lipophilic substrates readily, competitive
uncatalyzed reaction yielded bis(indolyl)methane by-product
along with product 5d (Table 2, entry 4, 5).
2
0 mol% did not improve the reaction outcome (Table 1, foot-
note d). Addition of oleic acid and organic substrates in water
resulted in the initial formation of two distinctly separate layers.
The formation of white emulsion (oil-in-water type) during the
course of reaction could be due to the formation of micelle or
micelle-like colloidal aggregate.
microscopic observation of colloidal dispersion of oleic acid
and organic substrates in water. The high reaction rate of oleic
20a,b
Fig. 1 shows the light
Micelle-like environment provided by the liquid fatty acids
(caprylic acid, oleic acid) readily incorporated hydrophobic
substrates and resulted in facile formation of product (Table 2,
entry 3, 6). Reaction carried out with cationic surfactant (CTAB)
proved micellar environment favours product formation (Table
Table 2 Screening of catalytic efficiency of 4H-chromene synthesis
2, entry 7). It should be noted that CTAB is toxic to human skin
a
b
Entry
Additive
5d Yield (%)
1
2
3
4
5
Benzoic acid
Acetic acid
Caprylic acid
Palmitic acid
Stearic acid
Oleic acid
Tracec
Trace
79
c
57
43
c
d
e
6
84
7
8
CTAB
Triton-X-100
87
Trace
a
b
1
2.5 mol% of additives were used. Yields are for the isolated
c d
products. Formation of bis(indolyl)methane observed.
In the
absence of catalyst only 29% of product is formed. Oleic acid was Scheme 2 Oleic Acid catalysed 4H-chromenes and spirooxindole
recyclable up to 4 cycles.
synthesis.
e
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Fig. 3 Synthesized 4H-chromene and spirooxindole derivatives.
cells (HaCaT keratinocyte) even in 10 mM concentration.
22
malononitrile in the reaction medium. Apart from barbituric
Interestingly, non-ionic surfactant didn't yield product 5d. acid, dimedone, 1,3-cyclohexandione, N-methylbarbituric
These studies revealed that the both Brønsted acidity and acid, thiobarbituric acids also gave spirooxindole in good yield
surfactant nature of oleic acid was utilized in the synthesis of (Scheme 2, Fig. 3).
5d. Studies on recyclability of oleic acid revealed that the cata-
At this juncture, the precise mechanism by which oleic acid
lyst retain its activity till four cycles (Table included in ESI†). catalyse the reaction is unclear. The success of the oleic acid
Wider substrate scope, ready availability, non-toxic nature, catalysis in bis(indolyl)methane and substituted indole
recyclability put oleic acid distinctly ahead of the rest of the synthesis could be attributed to the inherent Brønsted acid-
screened catalysts. Oleic acid catalysed 4H-chromene synthesis surfactant-combined catalytic effect. Out of interest we have
was found to be general for various nucleophiles such as further extended the scope of oleic acid catalysis to the spiro-
0
b-naphthol, N-methylindole and 5-methoxyindole (Fig. 3). The [indoline-3,4 -pyrano[2,3-c]pyrazole] 7 synthesis by the four-
structure of a representative 4H-chromene product 5e was component reaction of isatin, hydrazine hydrate, ethyl acetoa-
further conrmed unequivocally by single crystal XRD studies cetate and malononitrile in water. To our delight the expected
23
(Fig. 2).
product 7 was formed in 94% yield (Scheme 3).
Unlike 4H-chromenes and bis(indolyl)methanes, spiroox-
indoles 6 synthesis carried out in water solvent failed to yield
the product in good yield. This could be due to the high
solubility of malononitrile in water which restrict the free
passage of malononitrile to the micelle-like hydrophobic
pocket formed by the oleic acid. Reaction performed in
amicable polar protic solvent such as ethanol provided spi-
rooxindole 6a in 91% yield within 30 minutes (images of
sequence of addition was given in ESI†). The high reaction rate
could be attributed to the presence of highly reactive
Conclusions
In conclusions, biodegradable, non-toxic, naturally available
oleic acid was identied to catalyze substituted indole deriva-
tives synthesis. The reaction was found to be general and hence
the scope of the reaction is very high.
Acknowledgements
S.S.G. thanks DST for DST-Fast Track Grant (no: SR/FT/CS-09/
2011). The authors thank the SASTRA University for providing
lab space and NMR facility. S.S.G. thanks Director, IICT for
CCDC facility and Prof. M. Periasamy, University of Hyderabad
for his encouragement and support. Authors thank Dr Sai
Subramaniam for light microscopic images. S.S.G. thanks Dr
Anbazhagan for useful discussion on micellar catalysis.
Scheme 3 Oleic Acid catalysed pyrazole synthesis.
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