Microwave-Assisted Erlenmeyer Synthesis of Azlactones Catalyzed by MgO/Al2O3 under Solvent-Free Conditions

Article abstract of DOI:10.1080/15533174.2014.989575

MgO/Al₂O₃ catalyzes the synthesis of azlactone derivatives from condensation reaction of aldehydes (or ketones) with hippuric acid and acetic anhydride as a dehydrating agent under microwave irradiation. The low toxicity, low cost, ease of handling, and high activity of MgO/Al₂O₃ make this procedure particularly attractive. Also, this catalyst can be easily recovered by decant and can be reused for this condensation five times in succession without considerable loss of its catalytic activity.

Full text of DOI:10.1080/15533174.2014.989575

Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry
ISSN: 1553-3174 (Print) 1553-3182 (Online) Journal homepage: http://www.tandfonline.com/loi/lsrt20
Microwave-Assisted Erlenmeyer Synthesis of
Azlactones Catalyzed by MgO/Al2O3 under Solvent-
Free Conditions
Nader Rostamizadeh, Alireza Khajeh-Amiri & Hassan Moghanian
To cite this article: Nader Rostamizadeh, Alireza Khajeh-Amiri & Hassan Moghanian (2015):
Microwave-Assisted Erlenmeyer Synthesis of Azlactones Catalyzed by MgO/Al2O3 under
Solvent-Free Conditions, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal
Chemistry, DOI: 10.1080/15533174.2014.989575
To link to this article: http://dx.doi.org/10.1080/15533174.2014.989575
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Microwave-Assisted Erlenmeyer Synthesis of Azlactones Catalyzed by MgO/Al2O3 under
Solvent-Free Conditions
Nader Rostamizadeh1, Alireza Khajeh-Amiri2 and Hassan Moghanian*1
1Department of Chemistry, Dezful Branch, Islamic Azad University, Dezful, Iran
2Young Researchers and Elites club, Shahr-e-Rey Branch, Islamic Azad University, Tehran, Iran
*Corresponding author. E-mail: moghanian@gmail.com
Abstract:
MgO/Al2O3 catalyzes the synthesis of azlactone derivatives from condensation reaction of
aldehydes (or ketones) with hippuric acid and acetic anhydride as a dehydrating agent under
microwave irradiation. The low toxicity, low cost, ease of handling and high activity of
MgO/Al2O3 make this procedure particularly attractive. Also, this catalyst can be easily
recovered by decant and can be reused for this condensation five times in succession without
considerable loss of its catalytic activity.
Keywords: Azlactone, Hippuric acid, MgO/Al2O3, Microwave irradiation, Solvent-Free
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INTRODUCTION
Azlactones or 2,4-substituted oxazolin-5-ones and their derivatives have been used in a wide
variety of reactions as precursors for the synthesis of various bioactive molecules and show a
wide range of pharmaceutical properties.[1] They are particularly useful precursors for the
synthesis of aminoacids,[2] peptides,[3] heterocycles,[4] N-substituted pyrroles,[5] biosensors[6] and
antitumor[7] or anticancer[8] compounds. Hence, synthesis of this heterocyclic nucleus is of
continuing interest.
They are usually obtained by condensation reactions of different arylaldehydes with hippuric
acid in acetic anhydride, in the presence of anhydrous sodium acetate as a basic catalyst,
according to the Erlenmeyer method.[9] A literature search revealed that different reagents have
been used to constraction of azlactones involving the perchloric acid,[10] polyphosphoric acid,[11]
carbodiimides,[12]
POCl3,[13]
Al2O3,[14]
Bi(OAc)3,[15]
Bi(OTf)3,[16]
silica-supported
heteropolyacids,[17] Yb(OTf)3,[18] Ca(OAc)2,[19] supported KF[20] and anhydrous zinc chloride.[21]
Although several methods for the synthesis of azlactones have been reported, there is still a
demand for simple and facile methodologies for the preparation of azlactones using a cheap and
readily available catalyst.
The first study of heterogeneous basic catalysts, which was pointed out by Hattori,[22] was that
pines et al.[23] studied sodium metal dispersed on alumina acted as an effective catalyst for
double bond migration of alkenes in the 1950s. In the following 50 years, until now, the studies
of solid base catalysts have been continuous and progressed steadily. From a single metal oxide,
such as MgO, to functionalized mesoporous materials, a variety of solid base catalysts have been
developed and studied.
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In recent years, the application of microwave-assisted reactions in organic synthesis have
attracted a great deal of interest due to the use of microwave irradiation (MWI) develops a facile
procedure associated with advantages of short reaction times, uniform heating, higher yields,
enhanced selectivity, and associated ease of manipulation.[24, 25]
EXPERIMENTAL
General experimental section
All chemicals including Benzoylaminoethanoic acid (known as hippuric acid) and aldehydes
were purchased from Merck or Fluka. Melting points were determined using an electro thermal
digital apparatus and are uncorrected. IR spectra were prepared on a galaxy series FT-IR 5000
1
spectrophotometer using KBr discs. H-NMR (300 MHz), 13C-NMR (75 MHz) spectra were
recorded on Bruker spectrophotometer in CDCl3 using TMS as an internal standard. Elemental
analyses (C, H and N) were conducted using the Elemental Analyser Vario EL III. Microwave
irradiation was carried out in a National Microwave Oven, Model No. NN-K571MF. (2450
MHz)
Synthesis of catalyst
A series of Metal Oxides (Metal = Mg, Ni, Pb, Bi and Ce)/Al2O3 catalysts were prepared by an
incipient wetness method.[26] The gamma Al2O3 was first crushed and sieved to 70–100 mesh,
o
o
o
then calcined at 5 C/min to 500 C, followed by holding isothermally at 500 C for 2 h.
Following the calcinations, an aqueous solution of metal nitrate hexahydrate (10 wt%) was
impregnated onto the calcined alumina then dried under vacuum at 110 oC for 8 h and calcined at
o
900 C for 2h. All calcinations mentioned above were conducted in a muffler furnace under
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atmospheric conditions. The synthesized catalysts were used in all powder catalyst activity
testings.
General procedure for preparation of azlactone derivatives
To a mixture of hippuric acid (1.1 mmol) and the appropriate aldehyde or ketone (1 mmol) were
added acetic anhydride (0.25 mL) and MgO/Al2O3 (10mol %). The reaction mixture was
irradiated using the microwave oven for the appropriate time according to Table 2. The progress
of the reaction was followed by thin layer chromatography (TLC). After completion of the
reaction, the mixture was cooled to room temperature and then added hot ethanol (2:1) to it, the
suspension stirred for 15 min and the catalyst separated by decant. Then solvent concentrated in
vacuo to leave the product, a bright yellow solid, which was recrystallized from ethanol.
Selected spectral data
(2-Bromobenzylidene)-2-phenyloxazol-5-one (3k)
1H-NMR (300 MHz, CDCl3) δ 7.35-7.65 (m, 6H), 7.77 (s, 1H), 8.21 (d, J = 7. 4 Hz, 2H), 8.95
(d, J = 7.7 Hz, 1H); IR (KBr, cm-1) 3058, 1793, 1650, 1550, 1323, 1150, 860, 761; Elemental
analysis calcd for C16H10BrNO2: C, 58.56; H, 3.07; N, 4.27 found: C, 58.06; H, 3.25; N, 4.45.
4-cyclohexylidene-2-phenyloxazol-5(4H)-one (3n)
1H-NMR (300 MHz, CDCl3) δ 1.34-2.13 (m, 10H, cyclohexyl), 7.34-7.88 (m, 5H); IR (KBr, cm-
1) 3049, 1780, 1650, 1540, 1319, 1128, 857, 738; Elemental analysis calcd for C15H15NO2: C,
74.67; H, 6.27; N, 5.81 found: C, 75.06; H, 6.19; N, 5.09.
RESULTS AND DISCUSSION
As a part of our continuous interest directed towards the development of practical safe and
environmentally friendly procedures for some important transformations,[27−31] we wish to report
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a new and efficient method for the synthesis of azlactones from condensation reaction of
aldehydes (or ketones) with hippuric acid and acetic anhydride as a dehydrating agent in the
presence of MgO/Al2O3 catalyst under microwave irradiation (Scheme1).
To achieve suitable conditions for the synthesis of azlactone 3, various reaction conditions have
been investigated in the reaction of benzaldehyde 1 and hippuric acid 2 as a model reaction
(Table 1). This reaction was carried out using benzaldehyde (1 mmol), hippuric acid (1.1 mmol)
in the presence of acetic anhydride (0.25 mL) and MgO/Al2O3 catalyst (10mol %) for 6 min
under microwave irradiation (Table 1, Entry 3).
Then, we attempted the reaction of other aldehydes or ketones with hippuric acid under
optimized conditions (Table 2). In all cases, the corresponding products were obtained in good to
high yields and in case of some aliphatic aldehydes such as propionaldehyde and
isobutyraldehyde, under optimized conditions, the corresponding products coulde not be
obtained. Also the reactivity of ketones was lower than aldehydes.
The possibility of recycling the catalyst was examined using the reaction of benzaldehyde,
hippuric acid and acetic anhydride in the presence of catalyst under optimized conditions. After
completion of the reaction as indicated by TLC, the solid product was dissolved in hot ethanol
and then the catalyst was separated from the reaction mixture by decant and were washed with
hot ethanol (2 × 5 mL), then reused for subsequent reactions for at least five times without any
activation process (Table 3).
A possible mechanism for this transformation is proposed in Scheme 2. The reaction of hippuric
acid and acetic anhydride produced intermediate (I). This intermediate upon an intermolecular
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cyclization, yielded the azlactone (II) that supported by good evidence in Erlenmeyer
synthesis.[33] Then azlactone derivatives (III) can be obtained from aldol condensation of
azlactone (II) and carbonyl compounds. In final step, Mgo/Al2O3 catalyst as Lewis acid activates
the carbonyl group of aldehyde, and then nucleophilic attack of the intermediate II to the
activated carbonyl group of aldehyde produced III.
CONCLUSION
In conclusion, we have developed preparation of a recyclable and highly efficient heterogeneous
basic catalyst for the azlactone derivatives synthesis. This procedure offers several advantages
such as: high yield of products, operational simplicity, clean reaction conditions, minimum
pollution of the environment and environmental friendly character with recyclability of the
catalyst without any noticeable loss of activity after at least 5 times.
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Table 1 Optimization of reaction conditions
Metal Oxides/Al2O (mol %)
Time
(min)
Yield/
%
Entry
1
Conditions
a
Room
Temperature
Reflux
MgO/Al2O3
10
120
26
2
3
4
5
6
7
8
9
10
MgO/Al2O3
MgO/Al2O3
MgO/Al2O3
MgO/Al2O3
MgO/Al2O3
CeO/Al2O3
Bi2O3/Al2O3
NiO/Al2O3
PbO/Al2O3
10
10
20
5
10
10
10
10
10
60
6
6
6
6
6
6
6
6
78
92
92
89
86
76
70
66
61
MW (300)
MW (300)
MW (300)
MW (450)
MW (300)
MW (300)
MW (300)
MW (300)
a Isolated yields.
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Table 2 Synthesis of azlactones
M.P (º C)
Carbonyl
Compound (1)
Time
(min)
Yeild
(%) a
Entry
Azlactone
Found
Reported
[lit.]
1
2
C6H5CHO
6
6
92
89
89
86
84
92
91
88
90
90
87
85
52
77
168-169
144-145
156-157
98-100
167-168
3a
3b
3c
3d
3e
3f
[14.]
4-CH3 C6H4CHO
143-144
[14.]
3
4-CH3O
C6H4CHO
3-CH3O
C6H4CHO
2-CH3O
C6H4CHO
4-(CH3)2N
C6H4CHO
4-F C6H4CHO
9
155-157
[18.]
4
7
99-102 [14.]
5
8
157-158
213-214
184-185
163-164
238-240
167-168
142-143
163-164
173-175
136-138
156-157
[14.]
6
7
212-214
[16.]
7
6
183-185
3g
3h
3i
[14.]
8
2,4-Cl2 C6H3CHO
4-NO2 C6H4CHO
3-NO2 C6H4CHO
2-Br C6H4CHO
2-Cl C6H4CHO
9
162-163
[18.]
9
5
237-239
[16.]
10
11
12
13
14
6
166-167
3j
[18.]
7
141-143
3k
3l
[16.]
7
162-163
[16.]
2-Thiophene
CHO
Cyclohexanone
5
174-175
3m
3n
[14.]
10
137-138
[32.]
a Isolated yields.
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Table 3 Reusability of the catalyst
Recycle Number
Yield (%)a
Fresh
92
First Second Third Fourth
87 83 78 74
Fifth
70
a Isolated yields.
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O
O
O
R'
R
AC2O, MgO/Al2O3
MW, 300W
O
N
H
COOH
+
R'
R
N
1
2
3
R, R' = Alkyl
R = Aryl, R' = H
Scheme 1. Condensation of hippuric acid and carbonyl compounds
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Scheme 2. Plausible mechanistic pathway for the synthesis of azlactone derivatives
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