Supramolecular catalysis by β-cyclodextrin for the synthesis of kojic acid derivatives in water

Article abstract of DOI:10.1039/c5nj01902h

An efficient and green method has been developed for the synthesis of kojic acid derivatives by employing 20 mol% β-cyclodextrin in aqueous media. The high functional group tolerance and shorter reaction times make this method suitable for the synthesis o

Full text of DOI:10.1039/c5nj01902h

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Supramolecular catalysis by b-cyclodextrin for the
synthesis of kojic acid derivatives in water†
Cite this:DOI: 10.1039/c5nj01902h
Evgeny A. Kataev,*a Mittapalli Ramana Reddy,a Gangarpu Niranjan Reddy,b
Vemulapati Hanuman Reddy,b Cirandur Suresh Reddy*c and Basi V. Subba Reddy*b
Received (in Montpellier, France)
21st July 2015,
Accepted 8th December 2015
An efficient and green method has been developed for the synthesis of kojic acid derivatives by
employing 20 mol% b-cyclodextrin in aqueous media. The high functional group tolerance and shorter
reaction times make this method suitable for the synthesis of kojic acid derivatives with a wide
substitution pattern.
DOI: 10.1039/c5nj01902h
www.rsc.org/njc
Introduction
In recent years, environmental protection laws and global warming
effects have impelled the researchers to utilize renewable sources
for chemical processes with minimum of waste or zero discharge.
Therefore, the development of eco-friendly processes is one of the
great challenges for organic chemists. On the other hand, kojic
acid and its analogues have emerged as promising scaffolds1
because of their broad spectrum of biological activities such as
herbicidal,2 antimicrobial,3 pesticidal and insecticidal behaviour.4
In particular, kojic acid is used as a skin lightening/depigmentation
Fig. 1 Bis and tris-kojic acid metal complexes.
agent in personnel care products.5 It is known to inhibit tyrosinase, Meldrum’s acid, kojic acid, and ammonium acetate using ionic
which is responsible for the formation of melanin in skin.6 Further- liquid.14 Imafuku et al. reported the formation of amino-
more, it is used as an antioxidant in food stuff.7 In addition, it acts substituted kojic acid derivatives from arylidene malononitrile
as a bidentate ligand to form a stable metal complex with different and kojic acid.15 Although different approaches have been
metal ions (Fig. 1).8 These metal complexes are used as drugs for the reported for the derivatization of kojic acid,16 there are some
treatment of various diseases.9,10
limitations such as the use of strong basic conditions, elevated
In view of the importance of these heterocycles, various temperature, long reaction time, hazardous organic solvents
synthetic methods have been developed for the synthesis of and low conversions. However, the development of green, mild
kojic acid derivatives.11 Recently our group has reported the and simpler procedures to eliminate the use and generation of
synthesis of kojic acid derivatives through a three-component hazardous substances is the foremost goal of green chemistry.
reaction of kojic acid, aldehyde and 1,3-diketone or indole In a quest for easy and eco-friendly synthesis of amino kojic
under solvent-free conditions.12 Mukherjee et al. synthesized acid derivatives, we were interested to explore cyclodextrins as
the derivatives of kojic acid by means of the aldol reaction catalysts in aqueous medium.17
using an alumina supported base catalyst.13 Li et al. reported
The most prominent feature of cyclodextrins is their capability
the synthesis of amide derivatives from aromatic aldehyde to form inclusion complexes (host–guest complexes) with differ-
ent classes of compounds.18 Cyclodextrins contain hydrophobic
a
cavities inside and hydrophilic hydroxyl groups outside. These
macrocycles act as host molecules and form stable complexes
with hydrophobic compounds.19 Thus, by complexation they can
boost solubility in water and reduce toxicity. Cyclodextrins are
cyclic oligomers of D-glucose and are named a, b and g-cyclo-
dextrin for the hexamer, heptamer and octamer, respectively.
The cavity size of cyclodextrins determines the selectivity for a
¨
Institute of Chemistry, Faculty of Natural Sciences, Technische Universitat Chemnitz,
09107 Chemnitz, Germany. E-mail: evgeny.kataev@chemie.tu-chemnitz.de;
Web: http://www.tu-chemnitz.de/chemie/supchem/
b Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India. E-mail: basireddy@iict.res.in
c Department of Chemistry, Sri Venkateswara University, Tirupathi 517502, AP, India
† Electronic supplementary information (ESI) available: Characterization data,
copies of 1H and 13C NMR spectrum of products. See DOI: 10.1039/c5nj01902h
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Table 1 Screening cyclodextrins in the formation of 2a
particular guest. For instance, a-cyclodextrin can typically
complex low molecular weight molecules or compounds with
aliphatic side chains, b-cyclodextrin will complex aromatics
and heterocycles and g-cyclodextrin can accommodate larger
molecules such as macrocycles and steroids.20,21 Cyclodextrins
are promising supramolecular catalysts in aqueous medium22
because they are non-toxic, biodegradable and, in many
instances, they are recyclable.
Entry
Catalyst
Solvent
Temp. (1C)
Time (h)
Yielda (%)
1
2
3
4
—
Water
Water
Water
Water
70
70
70
70
—
3
3
—
40
90
35
a-CD
b-CD
g-CD
3
a
Isolated yield.
Results & discussion
In this communication, we report the use of b-cyclodextrin as
a catalyst in the synthesis of amino-substituted kojic acid
derivatives in aqueous medium (Scheme 1). Initially, we per-
formed the three-component condensation using 20 mol%
b-cyclodextrin in water at room temperature. The reaction
was found to be sluggish at room temperature; however, by
increasing the temperature to 70 1C, the corresponding product
(2a) was obtained in 90% yield (Scheme 1).
To optimize the catalyst, the above reaction was carried out
by using different cyclodextrins. Based on screening results in
Table 1, b-CD is the best catalyst among others. Low conver-
sions were observed with either a- or g-cyclodextrin. It is clear
that a-CD was not a good catalyst because the cavity of a-CD
might be too small to hold three reagents. In addition, the
cavity of g-CD was too big compared to b-CD. This observation
is in a good agreement with the known fact that b-CD has
usually one order of magnitude higher affinity for the benzene
of naphthalene derivatives as compared to a- and g-CD.23 No
product formation was detected in the absence of cyclodextrin,
which clearly demonstrates the catalytic role of cyclodextrin.
Therefore, b-CD was preferred as a catalyst for this reaction.
Furthermore, the reaction was also performed in different
solvents such as DMF, DMSO, CH3OH, EtOH, DCM, THF and
water. However, b-CD is insoluble in MeOH or EtOH.24 After
several experiments, water was found to be the best solvent due
to high solubility of b-CD in water.
Fig. 2 Recyclability of the catalyst.
summarized in Table 2. Both electron-rich and electron-deficient
aromatic aldehydes such as 4-cyano, 4-methoxy-, 3-methoxy,
4-hydroxy-, 3-methyl-, and 3-nitrobenzaldehydes reacted efficiently
with kojic acid and malononitrile to furnish the corresponding
amino-substituted kojic acid derivatives in good yields (entries 2k,
2j, 2g, 2h and 2d, Table 2). The substituents present on the
aromatic ring had shown some effect on the conversion. It was
observed that both activated aromatic aldehydes (entries 2b, 2g, 2j
and 2h, Table 2) and deactivated aromatic aldehydes (entries 2d
and 2k, Table 2) gave the products slightly in lower yields than
halogenated aromatic counterparts (entries c, e and f, Table 2).
Similarly, hetero aromatic aldehydes like furan-2-carboxaldehyde
reacted well to furnish the corresponding amino kojic acid in good
yield (entry i, Table 2).
After the reaction, the reaction mass was cooled to RT and
b-CD was filtered and washed with ice-cold water and then
dried under reduced pressure. The recovered b-CD was further
used in subsequent reactions with the same substrate. The
catalytic activity of the recovered catalyst is shown in Fig. 2.
The catalyst quantity and yields after two recycles were almost
the same.
Inspired by above results, we extended this method to
the condensation of kojic acid, aldehyde and 1,3-diketone.
Accordingly, treatment of kojic acid (1) with benzaldehyde
and dimedone under similar conditions afforded the cyclized
product 3a as a sole product in 83% yield (Scheme 2).
The scope of the reaction is illustrated with respect to various
aldehydes and diketones and the results are summarized in
Scheme 2. In all cases, kojic acid reacted efficiently with diketones
to furnish the desired products in good to high yields (73–85%).
Encouraged by the results obtained with aldehydes and
malononitrile and diketones, we turned our attention to b-nitro
styrenes. Accordingly, the treatment of kojic acid with 2-(E)-(2-
nitrovinyl)benzene under similar conditions afforded the
corresponding nitro-substituted acyclic kojic acid derivative
4a as a sole product in 90% yield. We next extended this
process to other (E)-(2-nitrovinyl)benzenes. The scope of the
reaction is illustrated with respect to various nitro styrenes,
After optimizing the reaction conditions, we extended this
process to other substrates. The scope of the reactions is illu-
strated with respect to various aldehydes and the results are
Scheme 1 Synthesis of 2-amino-6-(hydroxymethyl)-8-oxo-4-phenyl-
4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile 2a.
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Table 2 Synthesis of amino-substituted kojic acid derivativesa,b
Table 3 Synthesis of different nitro-substituted kojic acid derivativesa,b
a
Reaction condition: kojic acid 1 (1 mmol), nitro styrene (1 mmol),
b
b-CD (20 mol%) water, 100 1C. Isolated yields.
a
20 mol% b-cyclodextrin, kojic acid (1 mmol), aromatic aldehyde (1 mmol)
b
malononitrile (1 mmol), water, 70 1C. Isolated yields.
Scheme 2 Synthesis of (3) by three-component condensation reaction.
and the results are summarized in Table 3. In all cases, we
observed good yields. Interestingly, the substituent present on
the aromatic ring had shown some effect on the conversion. It
was observed that the halogen-substituted nitro styrene gave
Scheme 3 Synthesis of 2a and 4a in the presence of different
cyclodextrins.
the products in higher yields than other aromatic counterparts b-cyclodextrin in the presence and absence of starting materials
(entries c and f, Table 3). The reaction also works well with and products. Unfortunately, the products were not sufficiently
hetero aromatic nitro olefin (entry g, Table 3).
soluble in water in order to understand if they are encapsulated by
Next, we studied the catalytic activity of cyclodextrins in the cyclodextrin or not. The spectra (500 MHz, D2O) of the b-CD–kojic
reaction of kojic acid with benzylidene malononitrile or nitro acid complex, b-CD–benzaldehyde mixtures and free b-CD are
styrene in the presence of a, b and g-cyclodextrins (Scheme 3). depicted in Fig. 3 and 4. Upfield shifts of H3 (0.02 ppm,
High yields were observed when the reaction was performed 0.09 ppm) and H5 (0.04, 0.16 ppm) protons of cyclodextrin in
using b-CD as a catalyst and lower yields were observed with the b-CD kojic acid and b-CD–benzaldehyde mixtures were
a- and g-cyclodextrins.
observed compared to the spectrum of free b-CD. These shifts
Next, we investigated the role of b-cyclodextrin in the reaction indicate that the aldehyde and kojic acid are ideally located for the
with the help of 1H NMR. Because it is known that b-cyclodextrin Knoevenagel condensation/Michael addition in the hydrophobic
can encapsulate aromatic compounds, we recorded the spectra of environment of the b-CD cavity. Thus, it is suggested that the
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Based on experimental studies, we proposed a plausible
mechanism (Scheme 4). The Knoevenagel condensation of an
aldehyde with malononitrile generates intermediate A. Subse-
quently the Michael addition of the kojic acid encapsulated in
b-CD on activated olefin A affords product B, which further
cyclizes to give the desired products 2 or 3 (Scheme 4).
Conclusions
In conclusion, an efficient method has been developed for the
synthesis of biologically relevant kojic acid derivatives using
b-cyclodextrin as a catalyst in aqueous medium. The operational
simplicity, mild reaction conditions, short reaction time, high
yields (75–95%) and environmental friendliness are the notable
features of this procedure. The reusability of the catalyst for
more than two cycles without any significant loss of activity adds
to the salient features of this reaction, making this process very
useful and attractive.
Fig. 3 1H NMR spectra (500 MHz) of (a) b-CD–kojic acid complex and
(b) b-CD obtained in D2O.
Experimental
General
All the solvents were dried according to standard procedures.
Reactions were performed in oven-dried round bottom flasks.
The flasks were fitted with rubber septa and the reactions were
conducted under nitrogen atmosphere. Glass syringes were used
to transfer the solvent. Crude products were purified by column
chromatography on silica gels of 60–120 or 100–200 mesh. TLC
plates were visualized by exposure to ultraviolet light and/or
by exposure to iodine vapors and/or by exposure to acidic
methanolic solution of p-anisaldehyde followed by heating
(o1 min) on a hot plate (B250 1C). The organic solutions were
concentrated on a rotary evaporator at 35–40 1C. The IR spectra
Fig. 4 1H NMR spectra (500 MHz) of (a) b-CD–benzaldehyde complex
and (b) b-CD obtained in D2O.
reaction is accelerated by encapsulation and eventually the activa-
tion of starting materials during the reaction.
1
The catalytic activity of cyclodextrins for these reactions is
documented by the fact that in the absence of cyclodextrin, the
reactions were observed to proceed in very low yields even at
high temperatures. Initially, the complexation of aldehyde with
b-CD can increase the reactivity of the carbonyl group through
the hydrogen bonding with b-CD hydroxyl groups. This activation
facilitates the Knoevenagel condensation with malononitrile or
diketones to form benzylidene malononitrile or dimedone deri-
vatives. Similar activation of the kojic acid in the cavity of b-CD
enhances its reactivity in the Michael addition.
were recorded using an FT-IR spectrometer. The H NMR and
13C NMR (proton-decoupled) spectra were recorded on 300, 500
or 600 MHz NMR spectrometers in CDCl3 and DMSO solvents.
Chemical shifts (d) were reported in parts per million (ppm) with
respect to TMS as an internal standard. Coupling constants ( J) are
quoted in Hertz (Hz). The mass spectra were recorded on a mass
spectrometer by using the ESI technique. Commercially available
starting materials were used without further purification.
Typical procedure for the synthesis of kojic acid derivatives
Kojic acid (1 mmol), aldehyde (1 mmol) and malononitrile
(1 mmol) were mixed in 5 mL distilled water in a 50 mL round
bottom flask. To this mixture was added b-cyclodextrin
(20 mol%). Then the reaction mixture was heated to 70–100 1C
(70 1C for 2 and 100 1C for 3 & 4) until the completion of the
reaction as indicated by TLC. The reaction mixture was cooled to
room temperature and b-CD was filtered, and washed with ethyl
acetate. The aqueous phase was extracted with ethyl acetate
(3 Â 10 mL). The aqueous layer was cooled to 0 1C and the
remaining b-CD was filtered again. The combined b-CD was
reused for the next reaction. The organic layers were washed
with water, saturated using a brine solution and dried over
Scheme 4 Proposed reaction mechanism.
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