Silica sulfuric acid-mediated synthesis of β-enaminones and β-enaminoesters under microwave irradiation

Article abstract of DOI:10.1080/10426507.2010.492365

Silica sulfuric acid, a heterogeneous reagent, has been found to be an efficient catalyst for the synthesis of β-enaminones and β-enaminoesters under microwave irradiation in a microwave reactor within 2 min. The experimental procedure is simple and environment-friendly, and results in excellent yields of the products. Further, the catalyst is recyclable, and the reaction is 60 times faster than the reaction at room temperature. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon and the
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Silica Sulfuric Acid–Mediated Synthesis
of β-Enaminones and β-Enaminoesters
Under Microwave Irradiation
Bandita Datta a & M. A. Pasha a
a Department of Studies in Chemistry, Central College Campus ,
Bangalore University , Bengaluru, India
Published online: 13 Jan 2011.
To cite this article: Bandita Datta & M. A. Pasha (2010) Silica Sulfuric Acid–Mediated Synthesis of β-
Enaminones and β-Enaminoesters Under Microwave Irradiation, Phosphorus, Sulfur, and Silicon and the
Related Elements, 186:1, 171-177, DOI: 10.1080/10426507.2010.492365
To link to this article: http://dx.doi.org/10.1080/10426507.2010.492365
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Phosphorus, Sulfur, and Silicon, 186:171–177, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.492365
SILICA SULFURIC ACID–MEDIATED SYNTHESIS OF
β-ENAMINONES AND β-ENAMINOESTERS UNDER
MICROWAVE IRRADIATION
Bandita Datta and M. A. Pasha
Department of Studies in Chemistry, Central College Campus, Bangalore
University, Bengaluru, India
GRAPHICAL ABSTRACT
O
O
O
R
O
O
Si
O
SO3H
N
H
NH2
O
3a-m
1a
+
R
R
MW,
1-2 mins.
O
O
O
HN
2
EtO
EtO
4a-c
1b
Abstract Silica sulfuric acid, a heterogeneous reagent, has been found to be an efficient
catalyst for the synthesis of β-enaminones and β-enaminoesters under microwave irradiation
in a microwave reactor within 2 min. The experimental procedure is simple and environment-
friendly, and results in excellent yields of the products. Further, the catalyst is recyclable, and
the reaction is 60 times faster than the reaction at room temperature.
Keywords β-Enaminoesters; β-enaminones; microwave irradiation; recyclable catalyst; silica
sulfuric acid
INTRODUCTION
Solid phase synthesis1 has become one of the most important applications in organic
synthesis. The solid phase chemistry concept includes substrates becoming chemically
bound to the surface of the solid support, then being converted into the product, and,
after the completion of the reaction, released from the solid support.2 The solid-phase
Received 8 April 2010; accepted 7 May 2010.
We thank Dr. Y. S. Bhat, Professor and Head, Department of Chemistry, Bangalore Institute of Technology,
Bengaluru, India, for providing the MILESTONE Microwave Reactor facility, and Mr. Yedunandan, Assistant
Professor, V. V. Pura Science College, Bengaluru, India, for the timely help.
Address correspondence to M. A. Pasha, Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bengaluru – 560 001, India. E-mail: m af pasha@ymail.com
171

172
B. DATTA AND M. A. PASHA
reagents can be either functionalized organic polymers3 or silica gel grafted catalysts.4
The wide application of solid-supported catalysts is enhanced rate, higher yields, easy
work-up procedures, safety, and economy. There are cases in which solid-phase catalysts
can be recycled with very minor changes in activity and selectivity.5 In this view, several
types of solids have been synthesized and applied as very efficient catalysts in chemical
transformations,6a and one such catalyst is silica sulfuric acid (Scheme 1),6b,c which can be
synthesized by treating silica with chlorosulfonic acid.7 The use of silica sulfuric acid is
more advantageous over conventional homogenous acid catalysts because the catalyst can
be handled safely and it is nonhygroscopic.
O
O
O
O
O
O
rt.
neat
+ HCl
Si O SO3H
+
Si OH
ClSO3H
Scheme 1 Synthesis of silica sulfuric acid from chlorosulfonic acid and silica gel.
In the recent past, in our laboratory, we have been actively engaged in the synthesis
of various heterocyclic compounds under different reaction conditions.8 As part of our
ongoing search program on the synthesis of some important pharmaceutical chemicals9a
and bioactive heterocycles,9b we have aimed to synthesize some useful synthons such as β-
enaminones and β-enaminoesters. β-Enaminones are useful in the synthesis of unsymmet-
rical 4-arylacridinediones.10 β-Enaminones containing the structural unit N C C C O
find application in the synthesis of many therapeutic agents such as antibacterial,11a,b anti-
convulsant,11b anti-inflammatory,11b and antitumor agents.11b,c β-Enaminones are also im-
portant as intermediates for the synthesis of several amino acids,12a aminols,12b peptides,12c
and alkaloids.12d
The method for the synthesis of β-enaminones involves the direct condensation of
β-dicarbonyls with amines under reflux in an aromatic solvent with azeotropic removal of
water.13 The other reported methods involve use of a number of catalysts.14–25 Although
these catalysts improve the yields and the reaction rates, they still require drastic conditions
such as high temperatures or use of solvents. Non-availability or use of very expensive
reagents is another disadvantage. Moreover, some of the catalysts cannot be recycled,
which limits their use.
Recently, microwave irradiation was used for this conversion in water,26 and without
any catalyst and solvent27 in the reactor. However, in these methods, the condensation of
aromatic amines takes a longer amount of time, and the reactions are possible at high
temperatures. Subsequently, a solid-state synthesis using KHSO4.SiO2 28 has been reported
that also requires longer time (10–120 mins) for the complete conversion. Hence, there is
still a need to develop a simpler and “greener” method for the condensation of amines and
β-dicarbonyl compounds to obtain β-enaminones and β-enaminoesters.
Since the introduction of microwave-induced organic reaction enhancement (MORE)
chemistry,29a,b microwave-assisted organic reactions have emerged as an important tool in
organic synthesis owing to its uniform heating effect.29c Microwave-induced reactions
require open vessels with no or very little solvents; the method is free of risk of explosion
and can be scaled up. Despite the attractiveness of silica sulfuric acid, to the best of our
knowledge there are no reports in the literature on the applicability of silica sulfuric acid
for the enamination of β-dicarbonyls.

SSA SYNTHESIS OF β-ENAMINONES AND β-ENAMINOESTERS
173
In continuation of our work on the development of efficient and environmentally
friendly methods for the synthesis of various organic molecules under different reaction
conditions, synthesis of a series of β-enaminones and β-enaminoesters from dimedone and
ethyl acetoacetate, respectively, in the presence of a minimum amount of acetonitrile is
being reported in Scheme 2.
O
O
O
R
O
O
Si O SO3H
N
H
NH2
O
3a-m
1a
+
R
R
MW,
1-2 mins.
O
O
O
HN
2
EtO
EtO
4a-c
1b
Scheme 2 Silica sulfuric acid–catalyzed synthesis of β-enaminones and β-enaminoesters.
RESULTS AND DISCUSSION
Initially we carried out the reaction between aniline (5 mmol) and dimedone (5 mmol)
with a catalytic amount of silica sulfuric acid (0.1 g equal to 0.26 mmol of H+) at room
temperature in acetonitrile, as this condensation works well in polar solvents, and the
yield of the product was found to be around 60% after 30 min. After acknowledging the
advantages of MORE, we executed the same reaction under MW irradiation in a microwave
reactor in the presence of a minimum amount of acetonitrile to get β-enaminone in 98%
yield within 30 sec (which is 60 times faster than reaction conditions at room temperature).
A minimum amount of solvent was required for reflux in the microwave reactor. Reactions
in solvents such as THF, CH2Cl2, DMF, and EtOAc were also carried out, but they gave
lower yields of the desired product after prolonged reaction time.
To examine the catalytic activity of the reagent, a mixture of aniline and dimedone
was irradiated with varying amount of silica sulfuric acid in a microwave reactor for 30 sec.
It was found that the best results were obtained when 0.1 g of the catalyst was loaded with
the substrates. The excellent yield obtained led us to expand this protocol for the synthesis
of β-enaminones and β-enaminoesters by MW irradiation of a variety of substituted amines
with dimedone or ethylacetoacetate along with a small amount of acetonitrile (2 mL) in
the presence of a catalytic amount of silica sulfuric acid. Quantitative conversions were
obtained within 2 min of irradiation, and the results are presented in Table 1.
Anilines containing electron-donating groups such as CH3 and OCH3 (entries
3b–3d, 3j, 3k) and electron-withdrawing substituents such as NO2 and Cl (entries
3f–3i, 4c) afforded the corresponding β-enaminone in excellent yield. It is noteworthy
that substituents such as &bond;COOH (entry 3m) were tolerated, and benzyl amine
(entries 3e and 4b) was also shown to be a good substrate for the reaction. After applying
this protocol for the synthesis of β–enaminone from cyclic β-dicarbonyl, dimedone, we

174
B. DATTA AND M. A. PASHA
Table 1 β-Amination of dimedone (1a) or ethylacetoacetate (1b) with amines (2) using silica sulfuric acid under
solvent-free MWI
Producta (3)
(1)
(2)
C6H5NH2
Time (Sec)
Yieldb (%)
Melting point∗ (◦C)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
4a
4b
4c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
30
70
50
60
40
95
50
60
80
60
80
70
120
50
60
65
98
96
95
97
97
89
95
93
90
95
93
90
93
96
97
91
181[181–183]22
201[203–204]22
Oil17c
185[186–188]22
130[130–131]22
241[242–245]22
209[208–210]22
Oil17c
142[142–144]17c
130[130–132]18
126[126–128]17b
185[185]22
4-CH3C6H4NH2
3-CH3C6H4NH2
4-CH3OC6H4NH2
C6H5CH2NH2
4-NO2C6H4NH2
4-ClC6H4NH2
3-ClC6H4NH2
2-ClC6H4NH2
2-CH3C6H4NH2
2-CH3OC6H4NH2
α-C10H7NH2
2-HOOCC6H4NH2
C6H5NH2
C6H5CH2NH2
4-ClC6H4NH2
187[188–189]26
Oil[Oil]22
Oil[Viscous liquid]22
57[57–58]18
aAll reactions were performed using amine (5 mmol), dimedone/ethylacetoacetate (5 mmol), and silica sulfuric
acid (0.26 mmol of H+ = 100 mg).
bIsolated yield; all the compounds are known, and physical properties agree with the reported values. Mass
spectral data of all the products match with the reported data.
∗Observed melting point [lit. melting point]ref
.
wanted to prepare β-enaminoesters from aliphatic dicarbonyl compounds. Hence, we took
ethylacetoacetate (5 mmol) and treated it with an amine (5 mmol) in the presence of 0.1 g of
silica sulfuric acid and irradiated it at 400 W in a microwave oven for the appropriate time
as indicated by the TLC. Since the yield of the products was extremely high, we continued
the reaction with a variety of amines. The structures of all the products were confirmed by
mass spectral analysis and their melting points, which were found to be comparable with
the authentic samples.
Comparison of the present method with the reported methods was done in order to
determine the efficacy of our work, and the results are represented in Table 2. It is evident
from this table that the present method is superior to the existing methods.
Table 2 A comparative study of the present system with the reported methods
Entry
Reagent
Conditions
Time
Yielda (Ref.)
1
2
3
4
5
6
CAN
ZrCl4
HClO4-SiO2
I2
Silica gel
Silica sulfuric acidb
Acetonitrile/RT
Solvent-free/RT
Solvent-free/RT
Solvent-free/RT
Solvent-free/RT
Acetonitrile/MW
9 min
40 min
8 min
2.5 min
24 h
7522
9525
9518
8120
8621
96∗
50 sec
aIsolated yield.
bPresent method.
∗Reaction conditions: Dimedone (5 mmol), amine (5 mmol), silica sulfuric acid (100 mg), and acetonitrile
(2 mL) in a MW reactor at 400 W.

SSA SYNTHESIS OF β-ENAMINONES AND β-ENAMINOESTERS
175
Reusability of the Silica sulfuric acid
120
100
80
60
40
20
0
1
2
3
4
5
Number of cycles
Figure 1 Reusability of silica sulfuric acid (0.1 g) in the condensation of aniline (5 mmol) with dimedone
(5 mmol) for 30 sec.
Finally, the possibility of recycling the catalyst was examined. For this, the reaction
of aniline and dimedone under the optimized conditions was studied in the presence of
0.1 g of silica sulfuric acid. When the reaction was complete, the mixture was filtered;
the residue was washed with warm ethanol and recycled 4 times. The results of five runs
showed that more than 90% of the catalyst was recovered, and it retained its activity in
terms of product yields: 98%, 95%, 90%, 93%, and 91% respectively (Figure 1).
EXPERIMENTAL
Materials and Methods
All amines and β-dicarbonyl compounds were commercial products and were used
without further purification. Yields refer to isolated products. Melting points were measured
on a Raaga (Chennai, India) melting point apparatus; GC-Mass spectra were recorded
on a Shimadzu GC-MS QP 5050A instrument. Infrared spectra were recorded using a
Shimadzu FT-IR-8400s spectrophotometer as KBr pellets for solids, and liquids/oils as thin
films between NaCl pellets. All microwave reactions were conducted in a MILESTONE
microwave reactor at 400 W.
Typical Experimental Procedure
A mixture of amine (5 mmol), dimedone or ethylacetoacetate (5 mmol), and silica
sulfuric acid (0.1g, equal to 0.26 mmol of H+) was taken in a Pyrex glass tube. A minimum
amount of acetonitrile (2 mL) was added, homogenized, and placed in a microwave reactor,
and the mixture was irradiated (400 W) for a period of 1−2 min with 20 sec intervals
(Table 1). After completion of the reaction, as indicated by the TLC, EtOAc (3 mL) was
added to the reaction mixture. The solid catalyst was removed by filtration and washed
with warm ethanol for reuse. The reaction mixture was then washed with hot water (5
mL) followed by dil. HCl (5 mL) to remove any unreacted amine and dried over MgSO4.
The solvent was removed under vacuum to get the product. Analytical grade samples were
then obtained by recrystallization from aq. alcohol. Yields and physical constants of all the
products prepared by this procedure are presented in Table 1.

176
B. DATTA AND M. A. PASHA
CONCLUSIONS
In conclusion, silica sulfuric acid has been proven to be an active and excellent
catalyst for the effective amination of β-dicarbonyls by a variety of amines under microwave
irradiation. The ready availability and cost of the reagents, reusability of the catalyst, and
easy procedure and work-up make this method attractive for large-scale operations.
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