Microwave-assisted, water-mediated Michael addition for synthesis of kojic acid derivatives

Article abstract of DOI:10.1007/s11164-015-2419-1

A highly efficient method is described for the synthesis of substituted kojic acid derivatives in the presence of water under microwave irradiation. This transformation represents an efficient way to synthesize kojic acid derivatives from simple starting

Full text of DOI:10.1007/s11164-015-2419-1

Res Chem Intermed
DOI 10.1007/s11164-015-2419-1
Microwave-assisted, water-mediated Michael addition
for synthesis of kojic acid derivatives
Pravin R. Likhar1 G. Narshimha Reddy1
•
•
M. Ramana Reddy1
Received: 29 November 2015 / Accepted: 31 December 2015
Ó Springer Science+Business Media Dordrecht 2016
Abstract A highly efficient method is described for the synthesis of substituted
kojic acid derivatives in the presence of water under microwave irradiation. This
transformation represents an efficient way to synthesize kojic acid derivatives from
simple starting materials.
Keywords Kojic acid Á Nitro styrenes Á Amino substituted kojic acid derivatives Á
Microwave conditions
Kojic acid and its analogues have emerged as potential biologically active
molecules because of their broad spectrum of activity against various pathogens [1].
It has been known as an additive to prevent browning of food materials in the food
industry, as an antioxidant in order to preserve their freshness and to inhibit
discoloration [2]. Also, it forms stable complexes of metal kojates via reaction of
kojic acid with metal acetate salts [3–5]. Additionally, kojic acid and its derivatives
have been shown to possess various bioactivities such as antimicrobial, cosmetic
skin-whitening [6], herbicidal [7], anti-speck [8], pesticide [9], antitumor [10], anti-
diabetic [11] and antiproliferative activities [12].
In view of the importance of these heterocycles, various synthetic methods have
been developed for synthesis of kojic acid derivatives. Reddy et al. [13–15]
synthesized kojic acid derivatives from kojic acid, aldehydes and 1,3 diketones or
indoles in a neat reaction. Li et al. [16] synthesized amide-substituted kojic acid
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2419-1)
contains supplementary material, which is available to authorized users.
&
G. Narshimha Reddy
gajjalanarsireddy@gmail.com
1
Organometallic Group, Inorganic and Physical Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India
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P. R. Likhar et al.
derivatives from Meldrum’s acid, kojic acid and ammonium acetate in ionic liquids
as a green (ecologically friendly) protocol. Though the reported methods are
satisfactory, they suffer from certain drawbacks, like the use of expensive catalysts,
toxic metals, extended reaction times, and environmentally hazardous organic
solvents. Synthesis of compounds via a green, mild and simpler procedure,
eliminating the use and generation of hazardous substances is the foremost goal of
green chemistry today. In particular, microwave irradiation has become a
complementary tool in the development of green chemistry. Microwave irradiation
with water as a reaction medium is a highly reliable and sustainable chemical
approach. Water is a clean and safe solvent which is cheap, non-toxic, non-
combustible, non-explosive, and the most benign environmentally. However, water
has been rarely used as a solvent for organic reactions due to the poor solubility of
most of the organic compounds in water. But at elevated temperatures under
microwave irradiation, the physical and chemical properties of water are altered in
such a way that it behaves both as a pseudoorganic solvent and a phase transfer
catalyst too.
In this communication, we have reported the synthesis of kojic acid derivatives
by microwave-assisted, water-mediated reaction (Scheme 1). Initially, we facili-
tated reaction of kojic acid (1) with (E)-(2-nitrovinyl)benzene (2a) in the presence
of water under microwave irradiation, proceeding smoothly to give the Michael
addition product in excellent yield (4a).
To check the effectiveness of water as a solvent under similar conditions, a study
was made by changing the solvent system of the reaction. As seen in Table 1, a
Scheme 1 Synthesis of kojic acid derivative (1) and (E)-(2-nitrovinyl)benzene
Table 1 Screening of solvents
and temperature
Entry
Solvent
Temp (°C)
Yield (%)a
1
2
3
4
5
6
7
8
DMF
110
110
110
110
90
–
DMSO
PEG-400
Ionic liquid
CH3CN
Toulene
Water
–
30
55
–
Kojic acid (1 mmol) and (E)-(2-
nitrovinyl)benzene (1 mmol) in
2 ml of the solvent for 25 min
under microwave irradiation
100
80
–
60
90
Water
100
a
Isolated yield
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Microwave-assisted, water-mediated Michael addition for…
Table 2 Synthesis of different nitro-substituted kojic acid derivativesa
Isolated yields are given for each derivative in percentage
a
Reaction conditions: kojic acid 1 (1 mmol), nitro styrene 2 (1 mmol), water 3 ml, 100 °C, MWI
diversity of reaction conditions were employed to discover the optimal reaction
conditions, the results of which show that solvents such as toulene and acetonitrile
are not right for this reaction, as there is no formation of the desired product even in
a trace quantity (Table 1, entries 5–6). When dimethylformamide (DMF) and
dimethyl sulfoxide (DMSO) were employed as reaction media, the desired product
was attained in lower yields (Table 1, entries 1 and 2). However, moving on to
check some different greener media, such as polyethylene glycol 400 (PEG-400 and
an ionic liquid, the solvents formed the product in moderate yields (Table 1, entries
3 and 4). In addition, among the broad range of solvent systems examined, the
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P. R. Likhar et al.
Scheme 2 Synthesis of amino-fused kojic acid derivatives via Michael addition followed by cyclization
water-mediated reactions were the most successful in terms of yields. Furthermore,
shifting the temperature below the optimal 100 °C led to a decrease in yields
(Table 1, entry 7). The time duration of the reaction was important mainly because a
longer reaction time will result in the formation of by-products.
After optimization of experimental conditions, we next extended this process for
other (E)-(2-nitrovinyl)benzenes. The scope of the reaction is illustrated with
respect to various nitro styrenes and the results are summarized in Table 2. In all
cases, we observed good yields. Interestingly, the halogen substituents present on
the aromatic ring had shown some effect on the conversion. It was observed that
halogen substitute styrene gave the products in high yields than other aromatic
counterparts (entries c and f, Table 2). The reaction also works well with hetero
aromatic styrene. Respectively, the kojic acid react with hetero aromatic styrene in
similar conditions give the desired product in 86 % yield (entry g, Table 2).
Inspired by the results obtained with b-nitro styrenes (2), we turned our attention
to extend this process to 2-benzylidenemalononitriles. Accordingly, treatment of
kojic acid with 2-benzylidenemalononitrile in the similar conditions afforded the
respective amino-substituted, fused kojic acid derivative 5a as a sole product in
92 % yield (Scheme 2).
Inspired the above results, the scope of the reaction is illustrated with respect to
various 2-benzylidenemalononitriles and the results are summarized in Table 3. A
variety of substituted 2-benzylidenemalononitriles reacted efficiently with kojic acid
to furnish the desired products in good to high yields (85–95 %). Thus, it provides a
direct approach for the conversion of kojic acid into fused amino kojic acid
derivatives.
Based on the experimental results, we proposed a plausible mechanism of the
microwave-irradiated condensation for the formation of derivative 5, as shown in
Scheme 3 [13–15, 17, 18]. Intially, Michael addition of 3 with kojic acid 1 would
furnish intermediate 6, which underwent cyclization, aromatization, to give the
product 5.
In conclusion, an extremely efficient and green method has been developed for
the synthesis of biologically active kojic acid derivatives, by means of microwave
irradiation in aqueous medium. The operational simplicity, mild reaction conditions,
short reaction time, higher yields, (75–95 %) and environmental friendliness are
notable features of this procedure. The method is extensively applicable for the
rapid preparation of a library of biologically active kojic acid derivatives.
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Microwave-assisted, water-mediated Michael addition for…
Table 3 Synthesis of different nitro-substituted kojic acid derivativesa
Isolated yields are given for each derivative in percentage
a
Reaction conditions: kojic acid 1 (1 mmol), cyano styneres 3 (1 mmol), water, 100 °C, MWI
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P. R. Likhar et al.
Scheme 3 A plausible reaction mechanism for the formation of 5
Typical procedure for the synthesis of kojic acid derivatives
A sealed 10-mL glass tube containing kojic acid (1 mmol), 2-benzylidenemalonon-
itriles or nitro styrenes (1 mmol) and water (2 mL) was placed in the cavity of a
microwave reactor and irradiated for the appropriate time at 105 °C (temperature
monitored by a built-in infrared sensor), and power 160 W. After cooling to room
temperature by air flow, the tube was removed from the rotor. The reaction mixture
was diluted with water and extracted with ethyl acetate. The combined ethyl acetate
extracts were then dried over anhydrous Na2SO4 and after removal of the solvent,
the mixture was purified by (silica gel) column chromatography (EtoAc/Hexane,
90:10 as eluent) to give pure products.
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