Extending the scope of oleic acid catalysis in diversity-oriented synthesis of chromene and pyrimidine based scaffolds

Article abstract of DOI:10.1039/c6ra02507b

Readily available, non-toxic, biodegradable oleic acid was found to catalyse 4H-chromene derivatives syntheses in good yields in a water medium. A facile domino one-pot protocol was also developed for the oleic acid catalysed pyrimidine-fused heterocycle

Full text of DOI:10.1039/c6ra02507b

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Extending the scope of oleic acid catalysis in
diversity-oriented synthesis of chromene and
Cite this: RSC Adv., 2016, 6, 20582
pyrimidine based scaffolds†
Asaithampi Ganesan,‡ Jagatheeswaran Kothandapani‡
*
and Selva Ganesan Subramaniapillai
Readily available, non-toxic, biodegradable oleic acid was found to catalyse 4H-chromene derivatives
syntheses in good yields in a water medium. A facile domino one-pot protocol was also developed for
the oleic acid catalysed pyrimidine-fused heterocycle synthesis by pseudo three-component, three-
component and four-component reactions. All the products were obtained in good to excellent yields.
Oleic acid catalysis was further extended to the synthesis of curcumin based bioactive molecules.
Received 27th January 2016
Accepted 15th February 2016
DOI: 10.1039/c6ra02507b
www.rsc.org/advances
moiety to a heterocyclic core could enhance the desirable bio-
logical properties of the parent core molecule. For example,
1. Introduction
introduction of indole moiety to 4H-chromene skeleton
improved the apoptosis potency of 4H-chromene derivatives to
nanomolar concentration.15
Diversity-oriented synthesis offers a unique way to synthesize
structurally diverse molecular scaffolds and bioactive skeletons
by varying substrate functionalities and molecular building
blocks.1 Hence, diversity-oriented synthesis carried out with
readily available environmentally benign solvents and reagents
is attractive. Water is a readily available, non-toxic, inexpensive,
and environmentally benign solvent which facilitates easy
isolation of products from the reaction medium by simple
ltration.2 Oleic acid is a naturally derived monounsaturated
liquid fatty acid distributed in plant oils.3 Until now, applica-
tions of oleic acid are largely conned to biodiesel production,
dietary and medicinal applications.4 Despite having lengthy
lipophilic alkyl chain and hydrophilic carboxylic acid head
group, oleic acid catalysis in water largely remains unexplored
due to its poor solubility in water. However, oleic acid forms
stable emulsion in water under sonication conditions.5
Recently, we have reported unmodied oleic acid catalysed
synthesis of substituted chromene derivatives in water
medium.6
Synthesis of indole tethered 4H-chromenes can be achieved
by the iodine catalysed Michael addition–intramolecular cycli-
zation reaction or by indium chloride catalysed multicompo-
nent reactions.16 The former method require reuxing the
reactants in toluene solvent and the later method use expensive
catalyst. Apart from these methods, catalysts such as nano
Bi2WO6,17 polystyrene supported sulfonic acid,18 amberlite
resin,19 Ba(OTf)2,20 triuoroethanol21 and ionic liquids22 are re-
ported for the 4H-chromene skeleton synthesis. Many of the
reported catalysts have notable disadvantages such as tedious
procedures for catalyst preparation, limited substrate scope,
excess use of organic solvents and non-biodegradability of
Chromene and their derivatives are widely sought for their
extensive use as bioactive molecules and as photochromic
materials.7 Likewise, pyrimidine-fused heterocyclic derivatives
are ubiquitous in several bioactive skeletons.8,9 Representative
example of bioactive chromene and pyrimidine-fused hetero-
cyclic derivatives are presented in Fig. 1.10–15 Insertion of indole
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
† Electronic supplementary information (ESI) available: Experimental details,
light microscopic images, NMR spectra's are presented. See DOI:
10.1039/c6ra02507b
‡ Both authors have equal contribution to this work.
Fig. 1 Bioactive 4H-chromene and pyrimidine-fused heterocycles.
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catalyst. Hence, it is of interest to investigate the catalytic At room temperature formation of product 3 was not observed.
potential of oleic acid in indole tethered 4H-chromenes Oleic acid catalysed 4H-chromene synthesis was found to be
synthesis and further extend oleic acid catalysis to pyrimidine- general for various substituted 2-hydroxychalcone derivatives
fused heterocycles synthesis.
(Fig. 2). Attempts to carry out one-pot synthesis of 4H-chromene
3a by the reaction of acetophenone, salicylaldehyde and indole
were not successful (Scheme 1B). The high nucleophilicity of
indole towards aldehyde group resulted in the facile formation
of bis(indolyl)methane by-product.23
2. Results and discussion
2.1 Oleic acid catalysed 4H-chromene synthesis
To circumvent the formation of bis(indolyl)methane by-
product, acetophenone in Scheme 1B was replaced with
highly reactive malononitrile. To our delight, oleic acid cata-
lysed three-component reaction gave the corresponding indole
tethered 4H-chromene derivatives 3h–n at room temperature
itself (Scheme 2). It was previously reported in the literature that
malononitrile readily reacts with salicylaldehyde to form imi-
nochromene type of products.24 We presume the facile forma-
tion of iminochromene in the reaction medium followed by the
nucleophilic addition of indole to iminochromene 5 paved way
for the formation of desired product 3h at room temperature
itself. Generality of oleic acid catalysis was screened with N-
methylpyrrole and various substituted indole derivatives and all
the 4H-chromene derivatives were obtained in good yields
(Fig. 2).
Addition of lipophilic oleic acid to water forms oil-in-water type
emulsion in water (ESI†). Oleic acid catalyzed reaction of 2-
hydroxychalcone derivative 1 and indole 2 on water gave the
corresponding 4H-chromene products 3a–g in good yields by
the Michael addition followed by intramolecular cyclization
reaction (Scheme 1A). Unlike previous methods,16 in the present
study intramolecular dehydration takes place in water medium.
To precisely understand the efficiency of oleic acid catalysis,
we have screened the representative 4H-chromene 3h synthesis
with various Brønsted acids and surfactants (Table 1). Since 3h
synthesis was carried out at room temperature, role of thermal
effect to drive the reaction can be nullied. Reaction of salicy-
laldehyde and malononitrile may result in the immediate
Scheme 1 Oleic acid catalysed 4H-chromene synthesis.
Fig. 2 Synthesized 4H-chromene derivatives.
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presume formation of lipophilic colloidal dispersion may act as
suitable reaction medium for hydrophobic substrates and
thereby facilitate the smooth formation of 4H-chromene
derivatives.
2.2 Oleic acid catalysed pyrimidine-fused heterocycle
synthesis
Scheme 2 Oleic acid catalysed 4H-chromene synthesis by three-
component reaction.
It is of interest to extend the oleic acid catalysis to pyrimidine-
fused heterocycle derivatives synthesis. Previously reported
pyrimidine-fused heterocycle synthesis requires sophisticated
sonication27 or microwave28 techniques or use of catalysts such
as diammonium hydrogen phosphate,29 DABCO,30 p-toluene-
sulfonic acid14 etc. Hence, it is of interest to investigate naturally
derived oleic acid catalysed pyrimidine-fused heterocycle
synthesis under conventional heating conditions in environ-
mentally benign water or ethanol medium.
Table 1 Screening of reaction condition for 3h synthesisa
Three-component reaction of salicylaldehyde, barbituric
acid, and acetophenone in water solvent at room temperature
only resulted in the formation of Knoevenagel condensation
product 6 (Scheme 3). The high acidity of barbituric acid (pKa ¼
4.01)31a compared to acetophenone (pKa ¼ 15.8)31b resulted in
the preferential nucleophilic attack of barbituric acid on sali-
cylaldehyde carbonyl group leading to the formation of spar-
ingly soluble Knoevenagel condensation product 6. Under the
reaction conditions, Michael addition of acetophenone onto 6
was not observed even at reux conditions. Similarly, three-
component reaction of salicylaldehyde, barbituric acid, and
malononitrile in water at room temperature also gave the
Entry
Catalysts (12.5 mol%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
—
Trace
28
NR
73
75
61
82
Trace
59
Acetic acid
Isonicotinic acid
Caprylic acid
Capric acid
Myristic acid
Oleic acid
SDSc
CTABd
a
All the reactions were carried out with 1 mmol of salicylaldehyde, 1
mmol of malononitrile and 1 mmol of indole in 3 mL of water.
Yields are for the isolated products. Sodium dodecyl sulfate.
b
d
c
Cetyltrimethylammonium bromide.
formation of iminochromene 5 derivatives (Table 1).25 The poor
solubility of iminochromene in water resulted in the formation
of heterogeneous reaction mixture. The protonation of imine
moiety by the Brønsted acid followed by the Michael addition of
indole could have resulted in the formation of product 3h.
Brønsted acids such as acetic acid and isonicotinic acid without
having lengthy lipophilic alkyl chain were inefficient to
accommodate the hydrophobic iminochromene 5 and indole. It
could be one of the reasons for the poor formation of product
3h with aforementioned acids (Table 1, entry 2 and 3). Lipo-
philic fatty acids such as caprylic acid (C-8), capric acid (C-10),
myristic acid (C-14) and oleic acid (C-18) gave the chromene
product 3h in good to excellent yields (Table 1, entries 4–7). The
cationic surfactant gave relatively better yield than the anionic
surfactant (Table 1, entry 9 vs. 8).
Scheme
synthesis.
3 Oleic acid catalysed pyrimidine-fused heterocycles
Kobayashi et al., reported that dodecylbenzene sulfonic acid,
a surfactant type Brønsted acid forms stable colloidal particles
in presence of organic substrates in water and asserted that
colloidal dispersion plays a seminal role in determining the rate
of Mannich-type reaction in water.26 Akin to that, oleic acid,
a naturally available, biodegradable Brønsted acid also forms
Scheme 4 Pseudo three-component synthesis of pyrimidine-fused
stable colloidal dispersion in presence of substrates (ESI†). We heterocycles.
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Akin to three-component reaction given in Scheme 3, oleic
acid catalysed pseudo three-component reaction of barbituric
acid (2 equiv.) and salicylaldehyde (1 equiv.) in water at room
temperature also stopped at the Knoevenagel condensation
stage itself due to the poor solubility of product 6 in water. The
yield of the product was boosted to 92% by slightly increasing
the reaction temperature to 50 ꢀC (Scheme 4A, condition A).
Conversely, the desired outcome of the reaction can be attained
under room temperature itself by performing the reaction in
ethanol solvent for 12 h (82% yield) or under reux condition
for 3 h (88% yield; condition B). Since condition A yielded the
pyrimidine-fused heterocyclic products in good yield in water
solvent, the rest of the derivatives 7a–c were also prepared by
following the same condition in good yields (Scheme 4A). Thus,
a facile, one-pot, domino protocol was developed for the oleic
acid catalysed pyrimidine-fused heterocycle synthesis in water
medium.
Scheme
derivatives.
5 One-pot synthesis of pyrazolopyranopyrimidine
It was surmised that replacement of salicylaldehyde with
a monosaccharide in Scheme 4A would lead to the formation of
C-glycosylated pyrimidine-fused heterocycles (Scheme 4B).
Preliminary investigation on C-glycosylation reaction of barbi-
turic acid (2 mmol) with unprotected D-glucose (1 mmol) in
water medium was not successful due to the difficulty in
isolation of hydrophilic product 8 from the aqueous medium.
Scheme 6 One-pot synthesis of pyrazolopyranopyrimidines by four-
component reaction.
Knoevenagel condensation product 6 due to the relatively lower
acidity of malononitrile (pKa ¼ 11.1)31a compared to barbituric
acid. Attempts to prepare pyrimidine tethered heterocycles by
the nucleophilic addition of barbituric acid to iminochromene
5 or 2-hydroxychalcone derivative 1 were not successful.
ꢀ
The reaction carried out in ethanol medium at 50 C gave the
corresponding product 8 in 71% yield (Scheme 4B).
Fig. 3 Oleic acid catalysed pyrimidine-fused heterocycles synthesis.
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The scope of oleic acid catalysis was further extended to
unsymmetrically substituted pyrimidine derivatives synthesis
by performing three-component reaction. The synthesis of
unsymmetrically substituted pyrimidine derivatives with two
different heterocyclic core is difficult due to the competitive
formation of homo coupled by-products (Scheme 5A).
The synthesis of 10c carried out in water at room tempera-
ture failed to yield the desired product. The relatively high
solubility of barbituric acid and pyrazolone in water could have
reduced their reactivity towards sparingly soluble aldehyde.
Interestingly, the reaction performed in ethanol solvent gave
the product 10c in 84% yield (Scheme 5B).
3. Conclusions
In conclusion, we have demonstrated the catalytic potential of
naturally derived, biodegradable, unmodied oleic acid in the
diversity oriented synthesis of chromene and pyrimidine
derivatives in environmentally benign water or ethanol
medium. Substrate scope of the oleic acid catalysis is very high
and all the chromene and pyrimidine derivatives were obtained
in good to excellent yields. Application of oleic acid catalysis was
further extended to curcumin based bioactive skeleton
synthesis.
The scope of oleic acid catalysis was further extended to
unsymmetrically substituted pyrimidine derivatives synthesis
by four-component reaction since the construction of complex
products from relatively smaller substrate scaffolds is always
attractive (Scheme 6). Four-component reaction performed at
room temperature in water or ethanol solvent did not yield the
expected product 10. Though three-component reaction was
successful at room temperature (Scheme 5B), the requirement
of elevated temperature is necessary for the in situ formation of
pyrazolone 9 in Scheme 6.
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. J. K. thanks SASTRA University for
nancial assistance. S. S. G. thanks Dr Sai Subramaniam for
light microscopic images and Dr Vairaprakash for useful
discussions.
The sequence of addition of substrates played a crucial role
in determining the yield of the product. In presence of oleic
acid, sequential addition of ethyl acetoacetate and hydrazine
hydrate followed by the addition of barbituric acid and aldehyde
aer 15 minutes resulted in the formation of corresponding
pyrazolopyranopyrimidine derivatives in good yields (Scheme
6). Conversely, combined addition of all substrates in one-pot at
room temperature or elevated temperature didn't yield the ex-
pected product. The change in the course of the reaction could
be due to the sequential in situ formation of pyrazolone 9 in the
reaction medium which on further reaction with aldehyde and
barbituric acid gave the product 10a–f in good yield. The
selectivity of the reaction is very high and the formation of
homo coupled by-products was not observed in the reaction.
The four-component reaction was found to be general for
aldehydes with electron donating and electron withdrawing
substituents gave the product in good yields (Fig. 3).
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