Practical synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones

Article abstract of DOI:10.1080/00397911.2012.696301

A simple and alternative method has been developed for the synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones via reactions of hippuric acid with various aldehydes in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine/N- methylmorpholine at 75 °C. Co

Full text of DOI:10.1080/00397911.2012.696301

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Practical Synthesis of 4-Benzylidene-2-
phenyl-5(4H)-oxazolones
V. Siddaiah a , G. Mahaboob Basha a , D. Sudhakar a , R. Srinuvasarao
a & Y. Santosh Kumar a
a Department of Organic Chemistry and Foods, Drugs and Water
Analysis , Andhra University , Visakhapatnam , India
Accepted author version posted online: 05 Mar 2013.Published
online: 03 Jun 2013.
To cite this article: V. Siddaiah , G. Mahaboob Basha , D. Sudhakar , R. Srinuvasarao & Y.
Santosh Kumar (2013): Practical Synthesis of 4-Benzylidene-2-phenyl-5(4H)-oxazolones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:16, 2191-2197
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Synthetic Communications1, 43: 2191–2197, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.696301
PRACTICAL SYNTHESIS OF 4-BENZYLIDENE-2-
PHENYL-5(4H)-OXAZOLONES
V. Siddaiah, G. Mahaboob Basha, D. Sudhakar,
R. Srinuvasarao, and Y. Santosh Kumar
Department of Organic Chemistry and Foods, Drugs and Water Analysis,
Andhra University, Visakhapatnam, India
GRAPHICAL ABSTRACT
Abstract A simple and alternative method has been developed for the synthesis of
4-benzylidene-2-phenyl-5(4H)-oxazolones via reactions of hippuric acid with various
aldehydes in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine/N-methylmorpholine
at 75 ꢀC.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords 4-Benzylidene-2-phenyl-5(4H)-oxazolone; CDMT; cynuric chloride; hippuric
acid; NMM
INTRODUCTION
4-Benzylidene-2-phenyl-5(4H)-oxazolones are important intermediates in the
synthesis of several bioactive compounds that have analgesic,[1] anti-inflammatory,[2]
antidepressant,[3] anticancer,[4] antimicrobial,[5] antidiabetic,[6] antiobesity,[7]
antitumor,[8] and immunomodulatory[9] activities. They also act as precursors for
the synthesis of important heterocyclic drugs, amino acids, and peptides.[10]
4-Benzylidene-2-phenyl-5(4H)-oxazolones have potential applications in photonics,
Received March 1, 2012.
Address correspondence to V. Siddaiah, Department of Organic Chemistry and FDW, Andhra
University, Visakhapatnam 530 003, India. E-mail: siddaiah_v@yahoo.com
2191

2192
V. SIDDAIAH ET AL.
Scheme 1. Synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones.
electronics, and nonlinear optics.[11] Because of pharmacological and other diverse
applications, synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones has interested
organic chemists for a long time. Generally their preparation can be accomplished
by the reaction of N-benzoylglycine (hippuric acid) with different araldehydes in
the presence of acetic anhydride and various acetate salts in ethanol. In recent years,
a number catalysts, such as Pb(OAc)2,[12] Al2O3-H3BO3,[13] Bi(OAc)3,[14] ZnCl2,[15]
ZnO,[16] and Montmorillonite K-10[17] have been reported in place of anhydrous
sodium acetate in the Erlenmeyer azlactone synthesis. Microwave synthesis also
has become an important tool, and there have been several reports describing synth-
eses of 4-arylidene-2-phenyl-5(4H)-oxazolones.[18] However, most of the methods
reported use excess acetic anhydride and expensive acetate salts. Removal of the
excess acetic anhydride from the reaction mixture is difficult and additional purifi-
cation of the reaction product is often required. Therefore, a simple, efficient, and
alternative method for the synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones is
highly desirable.
Over the past few years, there has been considerable application of cyanuric
chloride or its derivatives in organic synthesis.[19] 2-Chloro-4,6-dimethoxy-1,3,5-
triazine (CDMT) is commercially available, easily prepared from inexpensive cyan-
uric chloride, and has applications as a condensing reagent in peptide chemistry.[20]
CDMT was used for the in situ activation of the carboxylic group in many organic
transformations, such as the synthesis of carboxamides,[21] Weinreb amides,[22] mono-
acylated piperazines,[23] formyl amides,[24] aldehydes,[25] a-amino ketones,[26] and
2-oxazolines.[27] Thus in continuation of our work[28] on the development of efficient
new synthetic methodologies for heterocyclic compounds and the use of cyanuric
chloride derivatives in organic synthesis, herein we describe an efficient alternative
approach using CDMT and N-methylmorpholine (NMM) at 75 ꢀC, which avoids
the usage of acetic anhydride and acetate salts in the synthesis of 4-benzylidene-2-
phenyl-5(4H)-oxazolones (Scheme 1).
RESULTS AND DISCUSSION
To optimize the reaction conditions, we investigated the reaction of hippuric
acid (1.1 mmol) (1) with benzaldehyde (2a) (1.0 mmol) as a model reaction in the pres-
ence of CDMT (1.1 mmol) and NMM (1.5 mmol) in tetrahydrofuran (THF) at room
temperature. It was found that the reaction led to the desired 4-(4-benzylidene)-
2-phenyl-5(4H)-oxazolone with a yield of 65% after 3 h (Table 1, entry 1). Subse-
quently, we attempted to shorten the reaction time and increase the reaction yield.
Thus, we investigated the effect of various aprotic solvents on the model reaction.

4-BENZYLIDENE-2-PHENYL-5(4H)-OXAZOLONES
2193
Table 1. Optimization of reaction conditions
(CDMT=NMM)a
(Cy ꢁ Cl=NMM)b
Entry
Solvent
Temperature (ꢀC)
Time (min)
Yield (%)c
Time (min)
Yield (%)c
1
2
3
4
5
6
7
THF
rt
rt
180
180
180
180
180
15
65
60
55
—
10
90
90
600
600
600
600
600
190
190
32
30
CH3CN
CH2Cl2
DMSO
DMF
THF
rt
10
—
rt
rt
Trace
70
70
75
80
THF
15
a1.1=1.5 mmol.
b0.5=1.5 mmol.
cIsolated yield.
The progress of the reaction was monitored by thin-layer chromatography (TLC),
and the results are summarized in Table 1. Among the studied solvents THF gave
the best result. Acetonitrile and dichloromethane also afforded good yields of 3a,
but other solvents were not as efficient for this purpose (Table 1, entries 2–5). We then
evaluated the effect of temperature on the reaction model. The reaction temperature
had great influence on the reaction; thus, when the reaction temperature was
increased from room temperature to 75 ꢀC, the reaction was completed within
15 min and compound 3a afforded in 90% yield (Table 1, entry 6).
With the optimized conditions in hand, the reactions of hippuric acid with a var-
iety of aldehydes such as aromatic, heterocyclic, and aliphatic were investigated. As
shown in Table 2, all the aromatic and heteroaromatic aldehydes gave the corresponding
Table 2. Synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones
Entry
R
Product
3a
Method
Time (min)
Yielda (%)
1
2
C6H5
A
B
A
B
A
A
A
A
A
A
A
B
A
A
A
A
B
A
15
190
14
90
70
91
72
92
90
88
85
84
92
86
66
84
89
82
22
—
25
4-MeC6H4
3b
195
14
3
4
5
6
7
8
9
4-OMe C6H4
3,4-(OMe)2C6H3
5-Cl- 2,3-(OMe)2C6H2
4-ClC6H4
3c
3d
3e
3f
14
16
16
17
4-FC6H4
4-N(Me)2C6H4
4-NO2C6H4
3g
3h
3i
15
17
210
18
10
11
12
13
3- NO2C6H4
2-C10H7
3j
3k
3l
15
16
2-C4H3O
3-C6H9
3m
20
220
20
14
C2H5
3n
aIsolated yields.

2194
V. SIDDAIAH ET AL.
Scheme 2. Plausible mechanism for the formation of 4-benzylidene-2-phenyl-5(4H)-oxazolones.
products in good yields (Table 2, entries 1–13), whereas aliphatic aldehydes afforded the
corresponding products in lower yields (Table 2, entries 14 and 15).
We have also synthesized 4-benzylidene-2-phenyl-5(4H)-oxazolones by using
inexpensive commercially available cyanuric chloride (method B). In this method,
reactions proceeded very slowly, probably owing to various salts present in the
reaction mixture.
To explain the formation of 4-benzylidene-2-phenyl-5(4H)-oxazolones,
a suggested mechanism of method A using CDMT and NMM is shown in
Scheme 2. This mechanism involves the initial activation of carboxylic group of
hippuric acid (1) using CDMT and NMM, followed by cyclization to form I.
This is then apparently deprotonated to form anion II, which adds to the aldehyde
(2) to furnish the intermediate alcohol, which is dehydrated to form the final
product (3).
EXPERIMENTAL
General Experimental Procedure for 4-Benzylidene-2-phenyl-
5(4H)-oxazolone (3a): Method A
Hippuric acid (196 mg, 1.1 mmol) was added to a solution of CDMT (189 mg,
1.1 mmol) and NMM (151 mg, 1.5 mmol) in THF (10 mL) at room temperature under
continuous stirring. A white precipitate was formed after 30 min, and then benzal-
dehyde (106 mg, 1.0 mmol) in the THF solution (5 mL) was added dropwise. The
reaction mixture was stirred at 75 ꢀC for 15 min. Solvent was then removed under
reduced pressure. To the resulting residue, aqueous Na2CO3 solution (15 ml) was
added and extracted with ethyl acetate (2 ꢂ 10 mL). The organic layer was separated,
washed with water (2 ꢂ 50 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. The resulting crude product was recrystallized in hot ethanol to give pure
compound 3a.
Yellow solid, yield 90%, mp: 169–171 ꢀC (lit. mp 170 ꢀC)[2]; 1H NMR (400 MHz,
CDCl3): d ¼ 7.27 (1H, s), 7.44–7.63 (m, 6H), 8.15–8.23 (m, 4H); 13C NMR (100 MHz,
CDCl3): d ¼ 125.6, 128.4, 128.9, 131.1, 131.7, 132.4, 133.3, 133.5, 163.6, 167.5; MS
(ESI): m=z ¼ 250 [M þ 1]þ.

4-BENZYLIDENE-2-PHENYL-5(4H)-OXAZOLONES
2195
Method B
Cyanuric chloride (91 mg, 0.5 mmol) and NMM (151 mg, 1.5 mmol) were
added to a solution of hippuric acid (179 mg, 1.0 mmol) in THF (25 mL) at room
temperature. A white precipitate was immediately formed. After stirring for 1 h,
the solid formed was filtered off on celite and the solution containing the activated
ester was transferred into a flask containing benzaldehyde (106 mg, 1.0 mmol) in
THF solution (5 mL). The reaction mixture was stirred for additional 190 min at
75 ꢀC and then worked up as before to give 3a (70%).
CONCLUSION
In conclusion, we have successfully developed a convenient and straightforward
method for the synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones. The method
can be used as a valid alternative to reported methods, thereby avoiding the usage
of acetic anhydride. Furthermore, this process is amenable to scaling up. The uses
of inexpensive and easily available reagents are noteworthy advantages of this
method.
ACKNOWLEDGMENT
The authors thank the Department of Science and Technology (DST), New
Delhi, for financial support (through A Project SR=FT=CS-052=2008).
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