Application of novel multi-cationic ionic liquids in microwave assisted 2-amino-4H-chromene synthesis

Article abstract of DOI:10.1039/c6ra01062h

Novel multi-cationic ionic liquids containing a mesitylene backbone with acetate and methane sulphonate anions have been synthesized. These ionic liquids were used for the synthesis of 2-amino-4H-chromenes under microwave heating. The effects of nature and amount of ionic liquids on the yield and reaction time were thoroughly investigated. The ionic liquids showed a considerable level of reusability without a significant decrease in catalytic activity. We have successfully combined the advantages of microwave technology with ionic liquids to facilitate the rapid construction of chromene skeletons from readily obtainable and inexpensive materials via a multicomponent strategy.

Full text of DOI:10.1039/c6ra01062h

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DOI: 10.1039/C6RA01062H
Application of novel multi-cationic ionic liquids in microwave assisted 2-
amino-4H-chromene synthesis
Arjun Kumbhara*, Sanjay Jadhavb, Rajendra Shejwalc, Gajanan Rashinkarb, Rajshri
Salunkheb*
aDepartment of Chemistry, Padmabhushan Dr. Vasantraodada Patil College, Tasgaon,
(Sangli), Maharashtra India
bDepartment of Chemistry, Shivaji University, Kolhapur, Maharashtra India
cDepartment of Chemistry, L.B.S. College, Satara, Maharashtra India
E-mail: arjun2win@yahoo.co.in
Abstract: A novel multi-cationic ionic liquids containing mesitylene backbone with
acetate and methane sulphonate anions has been synthesized. These ionic liquids
were used for the synthesis of 2-amino-4Hchromenes under microwave heating.
The effects of nature and amount of ionic liquids on the yield and reaction time were
thoroughly investigated. The ionic liquids showed considerable level of reusability
without significant decrease in catalytic activity. We have successfully combined the
advantages of microwave technology with ionic liquids to facilitate the rapid
construction of chromene skeletons from readily obtainable and inexpensive
materials via multicomponent strategy.
Keywords: Mesitylene, Task Specific Ionic Liquids, 2-amino-4H-chromenes,
Microwave, Multicomponent synthesis.
Introduction
Multi-component reactions (MCRs) play an important role in modern
synthetic chemistry. Since MCRs generally occur in a single pot, exhibit a high atom
economy and good selectivity, it provide a powerful tool towards the synthesis of
1

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diverse and complex compounds as well as small heterocycles.1 Molecules with the
chromene structure constitute one of the most interesting classes of compounds in
organic chemistry due to their biological and pharmacological importance such as
antimicrobial,2 antiviral,3 antiproliferation4 antitumor5 and central nervous system
activities.6 These compounds are also employed in cosmetics, pigments and used as
potential biodegradable agrochemicals.7 Generally, 2-amino-4H-chromenes are
synthesized by heating aldehydes, malononitrile and phenols in presence of organic
bases like piperidine in organic solvents8 and also by several modified procedures
using Triton B,9 Phase Transfer Catalysts (PTCs),10. γ-alumina,11 Preyssler type
heteropolyacid (H14[NaP5W30O110),12 K2CO3,13 TiCl4,14 p-toluenesulfonic acid,15
nanostructured diphosphate Na2CaP2O7,16 and nanosize MgO17 Due to the
environmentally benign nature of electro-organic synthesis,18 Elinson et al.19
reported the electrocatalytic chain procedure for the preparation of 4H-chromenes
by the combined electrolysis of salicylaldehydes and alkyl cyanoacetates in ethanol
in an undivided cell. In order to avoid some of the drawbacks of reported methods,
the discovery of a new and efficient catalyst with high potential, short reaction time,
recyclability and simple workup procedure is highly desirable.
The research in the field of ionic liquids (ILs) has grown exponentially over
the last few decades due to their environmentally friendly nature, non-volatility,
recyclability, thermal stability and easy workup.20 One of the most attractive
features offered by IL is both the cationic and anionic components can be varied and
modified so that liquid properties can be tailored for specific applications. This
modification of ILs can result in unique solvent properties that can dramatically
influence the outcome of various reactions. The multi-cationic ILs are superior to
mono-cationic ILs as they provide more opportunities to tune their physical and
chemical properties. Conventional synthesis of IL is complicated and often suffers
from halogen impurities. Hydroxide based ILs now offers the simplest synthetic tool
for synthesize large number of halogen free ILs. An exchange reaction of the acid
2

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with an aqueous hydroxide solution of ILs affords the desired Task Specific Ionic
Liquids (TSILs).
The efficiency of microwave to reduce reaction times dramatically with other
advantages, it becomes one of the widely used alternative heating technologies to
carry out organic transformations efficiently21. Due to the ionic character, IL absorbs
microwave radiations extremely well and transfer of energy is quick by ionic
conduction. The transfer of energy is more efficient with increase in temperature.
Hence, when ILs are coupled with MW they exhibit dramatic effect on rate
enhancement due to synergistic couple22. In view of the emerging importance of the
ILs as reaction media and our general interest in microwave as an energy source for
chemical processes23, we decided to build up a new class of mono, bis and
trisimidazolium based ILs containing 1,3,5 alkylidene 2,4,6 trimethyl benzene
linkers, where the alkyl arm could be a methylene fragments (Fig. 1). In this study
prepared multi-cationic ILs, which can be used for syntheses of a 2-amino-4H-
chromenes using microwave irradiation.
N
N
+
N
+
N
N
N
N
N
N
N
+
+
+
2X-
3X-
X-
N
N
+
ILs IIId, X - = CH3COO-
ILs IId, X - = CH3COO-
ILs Id, X - = CH3COO-
-
IIIe, X - = CH3SO3
-
IIe, X - = CH3SO3
-
Ie, X - = CH3SO3
Fig. 1 Mesitylene tagged multi-cationic ILs containing acetate and methane
sulphonate anions
Results and Discussion
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A development of a novel synthetic route to the imidazolium IL scaffold that
has one, two and three imidazolium cations with mesitylene backbone and each
-
cation entity was paired with two different anions (CH3COO and CH3SO3 ) is
described in Scheme 1.
The known compounds mono, bis and tris (bromomethyl) mesitylenes (Ia, IIa,
and IIIa) were synthesized from the mesitylene according to the procedure
described by Made et al.24 The imidazolium bromide salts (Ib, IIb and IIIb) were
obtained in high yields by treatment of compounds Ia, IIa and IIIa with 1-methyl
imidazole in acetonitrile at 80 °C. Ion- exchange approach was used for synthesis of
hydroxide salts Ic, IIc and IIIc as reported by Fukumoto et al.25 The method uses the
hydroxide loaded resin (Amberlyst IR 120 OH) to displace the bromide anion from
thebromide salts Ib, IIb and IIIb to produce the corresponding hydroxide salts Ic, IIc
and IIIc. The absence of any bromide ions in aqueous ILs solution was confirmed by AgNO3
test. The concentration of hydroxide ions in aqueous solution of salts Ic, IIc and IIIc
was determined by titration with standard HCl (0.1N) solution conductometrically
.
Aqueous salt solutions of Ic, IIc and IIIc were then treated with equimolar amount of
acetic acid and methane sulphonic acid at room temperature. The desired acetate
ILs (Id, IId and IIId) and methane sulphonate ILs (Ie, IIe and IIIe) were isolated in
excellent yields by simple evaporative removal of the water. The resin material was
recycled using aqueous sodium hydroxide solution (1.0 M). ILs IId, IIe, IIId and IIIe
are transparent and yellowish colored liquids at room temperature, while ILs, Id
and Ie are solids at room temperature and melt at 90-92°C and 87-89°C
respectively. The structures of newly synthesized ILs have been confirmed on the
basis of IR, 1H and 13C NMR data.
4

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Bromomethylation
Bromomethylation
(HCHO)n
HBr-CH3COOH
40-45 0C
(HCHO)n
HBr-CH3COOH
95 0C
(HCHO)n
HBr-CH3COOH
80 0C
Br
Br
Br
Br
Br
IIa
1.
Ia
1.
IIIa
Br
N
N
N
1.
3
2
N
N
N
MeCN, 80 0C
MeCN, 80 0C
2. Anion-exchange
Amberlyst IR 120 OH-
MeCN, 80 0C
2. Anion-exchange
Amberlyst IR 120 OH-
2. Anion-exchange
Amberlyst IR 120 OH-
N
N
+
+
N
N
N
N
N
N
+
N
+
N
+
2OH-
3OH-
OH-
N
N
+
Ic
IIc
IIIc
3CH3COOH
or
2CH3COOH
or
2CH3SO3H
CH3COOH
or
CH3SO3H
3CH3SO3H
N
N
+
+
N
N
N
N
N
N
+
N
+
N
+
2X-
3X-
X-
N
N
+
ILs IIId, X - = CH3COO-
ILs IId, X - = CH3COO-
ILs Id, X - = CH3COO-
-
IIIe, X - = CH3SO3
-
IIe, X - = CH3SO3
-
Ie, X - = CH3SO3
Scheme 1 Synthesis of mesitylene tagged multi-cationic ILs.
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Next, these ILs were employed as a catalyst and reaction media for the
synthesis of 2-amino-4H-chromene under microwave heating (100 W). An initial
screening was done using benzaldehyde, malononitrile and α-naphthol as starting
materials to obtain maximum yield of the product in shortest reaction time under
microwave heating in IL IIId (Scheme 2). The progress of the reaction was
monitored by TLC.
R
R
CHO
X
N
N
N
Y
IL, MW
OR
+
+
O
NH2
O
NH2
R
N
X, Y = H, OH -alpha-naphthol
X, Y = H, OH -beta-naphthol
R = H
Scheme 2 Synthesis of 2-amino 4H-chromenes using IL (IIId) under microwave
irradiationα
To optimize the quantity of IL required for the catalytic effect, the above
model reaction was carried out in presence of 1, 5, 10, 15, 20 and 25 mol % of IL IIId
(Fig. 2). Optimization of IL concentration showed that 20 or 25 mol% IL was found
to be the most effective with a high yield (89%) of the desired product in 7 min. The
lower IL concentrations gave less yields of the desired product.
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Fig. 2 Effect of the amount of IL (IIId) on the synthesis of 2-amino 4H-
chromene
Next, the influence of the number of imidazolium ions as well as the nature
and number of counter ions on the catalytic efficiency of the ILs (20 mol%) on
model reaction was investigated. The results revealed in Table 1 shows that not only
the number of imidazolium ions, but also the nature and number of counter anions
makes a significant influence on the catalytic efficiency of the ILs. ILs Id, IId, and IIId
showed high activity while ILs Ie, IIe and IIIe showed moderate catalytic activity
under the identical conditions. It is worth of note that although the similar
conversions were obtained for the IL Id, IId, and IIId (Table 1, entries 1, 3 and 5),
ionic liquid IIId required less reaction time. It may be due to the presence of three
acetate anions in the IL framework. To demonstrate effect of microwave heating, the
model reaction was investigated in presence of IIId under conventional heating at
100 °C (Table 1, entry 7). The reaction was sluggish indicating that microwaves
remarkably increases the rate of the reaction due to the synergistic couple with
ILs.24
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Table 1 Screening of various ILs for the synthesis of 2-amino 4H-chromenesa
Entry
IL
Id
Time (min)
Yieldb
83
1
2
12
17
9
Ie
56
3
IId
IIe
IIId
IIIe
IIId
83
4
16
7
62
5
89
6
14
180
66
7c
85
aReaction conditions: bezaldehyde (1 mmol), malononitrile (1
mmol) and α-naphthol (1 mmol), IIId (20 mol%), under
microwave irradiation.
bIsolated yields after purification. cReaction at conventional
heating at 100°C.
To establish the generality of the catalytic activity of IIId in synthesis of chromene,
various aromatic aldehydes were reacted with α and β-naphathols under microwave
heating. The results are depicted in Table 2. With electron poor and electron rich
benzaldehydes, sterically hindered 2-substituted benzaldehydes as well as heteroaromatic
aldehydes, the corresponding 2-amino-4H-chromenes were obtained in good to excellent
yields. The electronic property of the substituent on the aromatic ring of aldehyde had a
noticeable effect on the yield of the product. The aryl aldehydes bearing electron
withdrawing groups gave slightly better yields than those with electron donating groups.
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Table 2 Synthesis of 2-amino 4H-chromenes using IL (IIId) under microwave irradiationa
Mp (°C)c
Observed Reported
Time
(min)
Yield
( %)b
Entry
Aryl aldehyde
Chromene
CHO
N
210-211
236-237
1
7
89
79
209-210
O
NH2
Cl
CHO
Cl
N
2
10
235
O
NH2
Cl
CHO
N
3
7
83
231-232
232
Cl
O
NH2
OMe
CHO
OMe
N
4
9
80
190-191
191
O
NH2
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OH
CHO
OH
N
5
10
79
244-245
245-247
O
NH2
NO2
CHO
N
6
7
8
7
84
87
212-214
279-281
212-214
278-280
NO2
O
NH2
CHO
N
O
NH2
OMe
CHO
8
9
N
182
188
9
8
80
86
183
OMe
CHO
O
NH2
NO2
N
188-189
NO2
O
NH2
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Cl
CHO
10
11
N
7
7
82
86
207-209
208-210
211-213
Cl
O
NH2
NO2
CHO
N
210-212
NO2
O
NH2
aReation conditions: aldehydes (1 mmol), α/β-naphthol (1 mmol), malononitrile (1 mmol) (1
mmol), IIId (20 mol%), under microwave heating.
bIsolated yields after purification.
cIdentified by comparison with authentic samples.10,12,13,15,26
For any chemical process, recovery and recycling of the catalyst as well as reaction
media is a very important aspect for sustainability. Compared to the traditional catalysts
and solvents, easy recycling is an attractive property of many ILs. Consequently we
investigated catalytic activity of recycled IL (IIId) under microwave heating using a model
reaction (Fig. 3). After completion of the reaction, water (5 mL) was added in reaction
mixture and the solid product was filtered off and washed with water. The recovered
aqueous layer containing IL was washed with ethyl acetate (2 x 5 mL) to remove organic
compounds. The aqueous layer was concentrated under vacuum and the recovered IL was
reused for next reaction cycle. The recycling results showed that IL (IIId) can be recycled
five times with moderate decrease in product yield.
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Fig. 3 Reuse of the ionic liquid (IIId)
Conclusion
In summary, a new mesitylene backbone containing acetate and methane
sulphonate ILs were prepared using efficient multi-step synthetic route. In addition
importantly these ILs are inherently halide-free, which offer number of benefits for the
development of new IL based technologies. We have successfully combined the advantages
of microwave technology with ILs to facilitate the rapid construction of chromene
skeletons from readily obtainable and inexpensive materials via multi-component strategy.
The operational simplicity of the procedure, shorter reaction time, simple workup,
environmental friendliness, and reusability of the catalyst for a number of times without
appreciable loss of activity are noteworthy features of the protocol.
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Supporting Information.
IR, 1H NMR and 13C NMR data of the compounds.
Corresponding authors
Department of Chemistry, Padmabhushan Dr. Vasantraodada Patil College, Tasgaon,
416312, Maharashtra India.
E-mail: arjun2win@yahoo.co.in.
Acknowledgement
We gratefully acknowledge financial support from the Science and Engineering Research
Board, Department of Science and Technology (SERB-DST), Government of India, New
Delhi, under the scheme of Start-Up research grants for Young Scientists (SB/FT/CS-
153/2013).
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Application of novel multi-cationic ionic liquids in microwave assisted 2-
amino-4H-chromene synthesis
Arjun Kumbhara*, Sanjay Jadhavb, Rajendra Shejwalc, Gajanan Rashinkarb, Rajshri
Salunkheb*
aDepartment of Chemistry, Padmabhushan Dr. Vasantraodada Patil College, Tasgaon,
(Sangli), Maharashtra India
bDepartment of Chemistry, Shivaji University, Kolhapur, Maharashtra India
cDepartment of Chemistry, L.B.S. College, Satara, Maharashtra India
E-mail: arjun2win@yahoo.co.in
Graphical Abstract