Triphenylphosphine (PPh3) Catalyzed Erlenmeyer Reaction for Azlactones under Solvent-free Conditions

Article abstract of DOI:10.1002/jhet.2600

This study presents triphenylphosphine catalyzed process for the synthesis of azlactones and their derivatives using hippuric and substituted aromatic aldehydes. The methodology also found to be effective for the synthesis of azlactones from 5-(2,6-dichlorophenyl)-3-methyl-1,2-oxazol-4-yl carbonyl amino acetic acid and offers several advantages such as solvent-free conditions, excellent yields, simple procedure, mild conditions, and reduced environmental consequences.

Full text of DOI:10.1002/jhet.2600

Month 2016 Triphenylphosphine (PPh3) Catalyzed Erlenmeyer Reaction for Azlactones
under Solvent-free Conditions
a,b
Alapati Mohan Lakshmi Punna Rao,a,b Abburi Sridhar Rao, Mukkamala Saratchandra Babu,a and M. Krishnaji Raob
*
aDepartment of Chemistry, GITAM Institute of Science, GITAM University, Visakhapatnam 530045, India
bQuality Control Department, Unit-II, DIVIS Laboratories Ltd., Visakhapatnam 531163, India
*
E-mail: mohan.alapati9@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received September 4, 2015
DOI 10.1002/jhet.2600
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
This study presents triphenylphosphine catalyzed process for the synthesis of azlactones and their deriv-
atives using hippuric and substituted aromatic aldehydes. The methodology also found to be effective for the
synthesis of azlactones from 5-(2,6-dichlorophenyl)-3-methyl-1,2-oxazol-4-yl carbonyl amino acetic acid
and offers several advantages such as solvent-free conditions, excellent yields, simple procedure, mild con-
ditions, and reduced environmental consequences.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
o-vinyloximes [26], [3+ 2] cycloaddition reactions [27],
Michael Addition [28], and Reductive Cyclization [29].
In this report, we have adopted the eco-friendly PPh3 as cata-
lyst for the synthesis 4-arylidene-2-phenyl-5(4H)-oxazolones
and 4-(substitutedarylidene)-2-[5-(2,6-dichlorophenyl)-3-
methyl isoxazol-4-yl]oxazol-5(4H)-one.
Oxazolones are an important class of heterocyclic com-
pounds because of their wide range of biological proper-
ties, such as their peptides [1], analgesic [2], antibacterial
and antifungal [3], biosensors [4], anti-obesity [5], antican-
cer [6], antimicrobial [7], antitumor [8], and antidiabetic
activities [9]. Moreover, they are used in the asymmetric
synthesis of amino acids [10] and in active site titration
of enzymes [11]. Because of their biological importance,
many synthetic routes are proposed for oxazolones.
The most well-known route for the synthesis of
azlactones, involves the direct condensation of aromatic al-
dehydes and hippuric acid with a stoichiometric amount of
fused sodium acetate as a base in the presence of acetic an-
hydride as the dehydrating agent, which is known as
Erlenmeyer–Plochl reaction [12,13]. Further number of
methods have been used for the synthesis of oxazolones
such as Nano-MgO [14], Bi(OTf)3 [15], Pb(OAc)2 [16],
I2 [17], K3PO4 [18], Al2O3–H3BO3 [19], Bi(OAc)3 [20],
[C6(MIm)2]2W10O32, 2H2O [21], Montmorillonite K-10
[22], and alumina [23], instead of sodium acetate.
Microwave-assisted reactions have also been employed
successfully in the synthesis of the oxazolones [24]. Most
of the reported methods are suitable for the synthesis of
oxazolones and their derivatives, but these methods require
high temperature, longer reaction times results in unsatis-
factory yields. In this regard, a simple, efficient, and envi-
ronmentally friendly method is highly desirable for the
synthesis of azlactones.
RESULT AND DISCUSSION
First, to investigate the reaction conditions for the
synthesis of substituted oxazolones, we have chosen the
reaction of hippuric acid, aromatic aldehydes under
solvent-free condition as a model reaction (Scheme 1), and
the results are summarized in Table 1.
Thus, hippuric acid (1a) (14 mmol) was treated with
benzaldehyde (2a) (11.6mmol) under solvent free at 130°C
without any catalyst. The product was not obtained (Table 1,
entry 1). Therefore, our efforts were focused on the search
for a suitable base catalyst. Initially, NH4OAc (5mol%)
was chosen as a catalyst to carry out this reaction. As a result,
long reaction times with poor yields were observed (Table 1,
entry 2). In addition, the catalytic activity of other catalysts
such as K2CO3, Ca(OAc)2, CaCO3, Yb(OTf)3, and Cu
(OTf)2 were tested (Table 1, entries 3–7). Under the same
conditions, triphenylphosphine was found to be the excellent
catalyst for azlactone synthesis. On the other hand, Yb(OTf)3
shows moderate catalytic activity , and K2CO3 and Cu(OTf)2
give the unsatisfactory yields. Encouraged by these results,
we turned our attention to find out the effect of amount of
catalyst; reaction temperature and time were investigated
(Table 1, entries 8–14). Amounts of 5, 10, and 15mol% of
PPh3 were used, and it was found that 10mol% of PPh3
was enough to accomplish the reaction (Table 1, entry 9).
Triphenylphosphine (PPh3) has been reported as envi-
ronmentally friendly, mild, and commercially available
catalyst in several organic transformations such as the tra-
ditional Morita Baylis–Hillman reaction [25], synthesis of
© 2016 Wiley Periodicals, Inc.

A. M. L. Punna Rao, A. Sridhar Rao, M. Saratchandra Babu, and M. Krishnaji Rao
Vol 000
Scheme 1. Model reaction.
When catalyst loading was dropped to 5mol%, only 73% of
the desired product was afforded (Table 1, entry 8). Further,
reaction temperature was also studied; the reaction at room
temperature did not result in desired product (Table 1, entry
11). The yield 63% was low at 120°C (Table 1, entry 12),
and increasing the temperature did not help to obviously im-
prove the yield (Table 1, entries 13–14). Moreover, the reac-
tion could be performed on a large scale and gave
satisfactory yield (Table 1, entry 9). Finally, we achieved
an optimized condition using 10mol% of PPh3 as the cata-
lyst at 130°C.
With the optimized conditions in hand, we focused our
study on different benzaldehydes for the synthesis of wide
range of azlactone derivatives. In this reaction (Scheme 2),
we have used hippuric acid and aromatic aldehydes deriv-
atives. As shown in Table 2, both the electron-donating
(Table 2, entries 2–5) and the electron-withdrawing
(Table 2, entries 6–10) substitutions on aromatic aldehydes
were effective for the reaction, providing the products good
to excellent yields under the optimized conditions.
variety of aromatic aldehydes was effective for this reac-
tion and afforded the corresponding products in good
yields (Scheme 3).
To excellent a suitable mechanism was for the synthesis
of 4-arylidene-2-phenyl-5(4H)-oxazolone 3a as shown in
Scheme 4.
On the basis of the above results and previous reports
[30], a plausible mechanism was proposed and shown in
Scheme 4. This mechanism involves the initial activation
of carboxylic group of hippuric acid 1a using acetic anhy-
dride, followed by cyclization to form A, which was con-
firmed by proton nuclear magnetic resonance (1H NMR),
carbon-13 nuclear magnetic resonance (13C NMR), and
electrospray ionization mass spectrometry (ESI-MS).
Deprotonation of A in presence of triphenylphosphine affords
anion B. Compound C was formed by the nucleophilic at-
tack of B on the carbonyl carbon of 2a followed by the pro-
tonation. Finally, dehydration of compound C furnished
the corresponding product 3a.
In conclusion, we have demonstrated a practical applica-
tion of PPh3 catalyzed Erlenmeyer reaction under solvent-
free condition, with a wide range of substrate scope even
hydroxy substituted aldehydes can undergo the desired
condensation affording quantitative yields. In addition, the
notable advantages of this procedure are (a) no need of
neutralization and (b) no need of further purification. The
reactions are conducted under mild conditions to afford
4-arylidene-2-phenyl-5(4)-oxazolones and 4-(substituted
arylidene)-2-[5-(2,6-dichlorophenyl)-3-methylisoxazol-4-yl]
oxazol-5(4H)-ones in good to excellent yields. These results
suggests that PPh3 is eco-friendly and cheap catalyst and can
be employed for industrial applications for the synthesis of
wide range of heterocyclic compounds.
Encourage by their results, we further switch hippuric
acid to 5-(2,6-dichlorophenyl)-3-methylisoxazole-4-car-
boxylic acid with aromatic aldehyde derivatives that were
investigated under the same reaction conditions. The re-
sults are summarized in Table 3. It was observed that a
Table 1
Synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones (3a) under different
optimization conditions.
Catalyst
(mol %)
Temperature
(°C)
Time
(min)
Entry
Yield (%)a
1
2
3
4
5
6
7
8
—
130
130
130
130
130
130
130
130
130
130
25
50
60
55
50
50
50
50
18
18
18
60
35
18
18
NDb
25
32
50
45
NH4OAc (5)
K2CO3 (5)
Ca(OAc)2 (5)
CaCO3 (5)
Yb(OTf)3 (5)
Cu(OTf)2 (5)
PPh3 (5)
PPh3 (10)
PPh3 (15)
PPh3 (10)
PPh3 (10)
EXPERIMENTAL
All chemicals were purchased from Merck (Kenilworth,
NJ) or Sigma-Aldrich (St. Louis, MO). All compounds
were identified by comparison of their melting points
and spectral data with those reported in the literature.
Melting point (m.p.): Buchi-530 capillary apparatus; open
capillary method and are uncorrected. IR spectra: Shimadzu
75
NDb
73
9
95
10
11
12
13
14
94
NDb
63
120
135
140
1
IR-Affinity spectrometer, KBr disks; ν in cmÀ1. H NMR
PPh3 (10)
PPh3 (10)
92
89
and 13C NMR spectra: Bruker Advance DPX 400MHz; at
400(1H) and 100 (13C) spectrometer in CDCl3; DMSO-d6;
δ in parts per million, TMS as internal standard, j in Hz. Data
aIsolated yield after column chromatography.
bNo product was detected.
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DOI 10.1002/jhet

Month 2016
One-Pot Synthesis of Azlactone
Scheme 2. Preparation of product 3a–3j.
reported as follows: chemical shift [multiplicity (s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet), coupling
constant(s) in Hertz, integration assignment]. ESI-MS: JEOL
SX 102/DA-6000 mass spectrometer; in m/z.
Table 2
Erlenmeyer–Plochl reaction of substituted aromatic aldehydes with
hippuric acid promoted by PPh3 (3a–3j).
S. No
Product
R1
Yield (%)a
General Procedure for Synthesis of 4-arylidene-2-phenyl-5
(4H)-oxazolones (3a). To the aromatic aldehyde (1.63g,
11.6 mmol), hippuric acid (2.5 g, 14 mmol), anhydrous
acetic anhydride (3.14 g, 31 mmol), and 10 mol%
triphenylphosphine. The reaction mixture was stirred at
130oC for 18 min under solvent-free condition. After
completion of the reaction (thin-layer chromatography
monitoring), reaction mixture was cooled to room
temperature, 5 mL of 95% ethyl alcohol was added, and
a yellow solid was obtained. The yellow solid was
filtered off and washed with water and recrystallized
from acetone to afford 4-arylidene-2-phenyl-5(4)-
oxazolones (3a) in 94% yield.
3a
Ph
94
3b
3c
3d
4-MePh
86
92
96
General Procedure for Synthesis of 4-benzylidene-2-(5-
(2,6-dichlorophenyl)-3-methylisoxazol-4-yl)oxazol-5(4H)-
one (5a). To the aromatic aldehyde (1.63 g, 11.6 mol),
4-benzylidene-2-(5-(2,6-dichlorophenyl)-3-
4-N(Me)2Ph
methylisoxazol-4-yl)oxazol-5(4H)-one (5.6 g, 14 mmol),
anhydrous acetic anhydride (3.14 g, 31 mol), and 10 mol
% triphenylphosphine. The reaction mixture was stirred
at 130oC for 18 min under solvent-free condition. After
completion of the reaction (thin-layer chromatography
monitoring), reaction mixture was cooled to room
temperature, 5 mL of 95% ethyl alcohol was added, and
a pale-yellow solid was obtained. The pale-yellow solid
was filtered off and washed with water and recrystallized
from acetone to afford 4-benzylidene-2-(5-(2,6-
dichlorophenyl)-3-methylisoxazol-4-yl)oxazol-5(4H)-
one (5a) in 91% yield.
4-N(Et)2Ph
3e
4-OMePh
90
83
2-phenyloxazol-5(4H)-one (A).
Yield 84%. m.p:
84–86oC. 1H NMR (400MHz, CDCl3, δ, ppm): 4.42 (s, 2H,
methylene CH2), 7.48–7.51 (m, 2H, Ar-H), 7.58 (t,
J = 7.2 Hz, 2H, ArH), 7.99–8.00 (m, 1H, ArH), 13C
NMR (100MHz, CDCl3, δ, ppm): 55.0, 125.8, 127.8,
128.8, 132.8, 163.5, 175.9; ESI-MS: m/z 162.20 [M+1]+.
4-benzylidene-2-phenyloxazol-5(4H)-one (3a). Yield 94%.
3f
4-ClPh
4-FPh
1
m.p: 168–170oC. H NMR (400MHz, DMSO, δ, ppm):
6.84–6.85 (m, 1H, ArH), 7.23 (s, 1H, benzylidene CH),
7.61–7.65 (m, 3H, ArH), 7.69–7.73 (t, 1H, ArH), 8.10 (s,
1H, ArH), 8.11 (d, J=7.6Hz, 2H, ArH); 13C NMR
(100MHz, DMSO, δ, ppm): 114.2, 117.5, 120.6, 125.1,
127.3, 127.9, 129.3, 133.5, 148.0, 149.9, 162.2, 166.5;
ESI-MS: m/z 249 [M+1]+ Anal. Calcd for C16H11NO2: C,
77.10; H, 4.45; N, 5.62. Found: C, 77.15; H, 4.43; N, 5.61.
3g
86
(Continued)
Journal of Heterocyclic Chemistry
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A. M. L. Punna Rao, A. Sridhar Rao, M. Saratchandra Babu, and M. Krishnaji Rao
Vol 000
Table 2
Table 3
(Continued)
Erlenmeyer–Plochl reaction of substituted aromatic aldehydes with 5-(2,6
dichloro phenyl)-3-methylisoxazole-4-carboxylic acid promoted by PPh3
(5a–5k)
S. No
Product
R1
Yield (%)a
S. No
Product
R1
Yield (%)a
3h
4-NO2Ph
91
5a
Ph
91
3i
3j
2-furyl
80
86
5b
4-MePh
88
2-thionyl
aIsolated yield after column chromatography.
5c
4-MeOPh
90
4-(4-methylbenzylidene)-2-phenyloxazol-5(4H)-one (3b).
Yield 86%. m.p: 146–148oC. 1H NMR (400 MHz,
DMSO, δ, ppm): 2.39 (s, 3H, CH3), 7.25 (s,1H,
benzylidene CH), 7.29 (d, J = 8.0 Hz 2H, ArH), 7.52–
7.65 (m, 3H, ArH), 8.12 (d, J = 8.1 Hz 2H, ArH), 8.12–
8.17(m, 2H, ArH) ; 13C NMR (100 MHz, DMSO, δ,
ppm): 22.8, 125.4, 128.2, 128.6, 130.0, 131.4, 133.1,
133.5, 133.6, 134.9, 142.0, 163.5, 167.2; ESI-MS: m/z
264 [M + 1]+ Anal. Calcd for C17H13NO2: C, 77.55; H,
4.98; N, 5.32. Found: C, 77.58; H, 4.95; N, 5.34.
4-(4-(dimethylamino)benzylidene)-2-phenyloxazol-5(4H)-one
(3c). Yield 92%. m.p: 213–216oC. 1H NMR (400 MHz,
DMSO, δ, ppm): 3.16 (s, 6H, 2xCH3), 6.85 (d, J = 8.4 Hz,
2H, ArH), 7.16(s, 1H, benzylidene CH), 7.50–7.57 (m,
3H, ArH), 8.21–8.26(m, 4H, ArH); 13C NMR
(100 MHz, DMSO, δ, ppm): 38.6, 110.3, 122.8, 126.4,
127.3, 128.1, 128.8, 132.2, 134.6, 154.6, 161.5,
168.4; ESI-MS: m/z 293 [M + 1]+ Anal. Calcd for
C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
73.91; H, 5.54; N, 9.60.
5d
4-N(Me)2Ph 89
5e
4-N(Et)2Ph 87
4-(4-(diethylamino)benzylidene)-2-phenyloxazol-5(4H)-one
1
(3d). Yield 96%. m.p: 193–195oC. H NMR (400MHz,
DMSO, δ, ppm): 1.01 (t, 6H, 2×CH3), 3.01 (s, 4H,
2xCH2), 6.81 (d, J = 8.8 Hz, 2H, ArH), 7.14(s, 1H,
benzylidene CH), 7.52–7.59 (m, 3H, ArH), 8.16–8.21(m,
4H, ArH); 13C NMR (100 MHz, DMSO, δ, ppm): 20.1,
34.6, 114.6, 123.6, 125.3, 127.3, 128.6, 128.8, 131.4,
134.1, 156.3, 163.4, 169.4; ESI-MS: m/z 321 [M + 1]+
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74.
Found: C, 74.93; H, 6.32; N, 8.76.
5f
4-ClPh
89
(Continued)
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Month 2016
One-Pot Synthesis of Azlactone
Table 3
C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 73.16;
(Continued)
H, 4.65; N, 5.01.
4-(4-chlorobenzylidene)-2-phenyloxazol-5(4H)-one (3f).
Yield 83%. m.p: 205–207oC. 1H NMR (400 MHz,
DMSO, δ, ppm): 7.14 (s, 1H, benzylidene CH), 7.39 (d,
J=8.0Hz, 2H, ArH), 7.51–7.60 (m, 3H, ArH), 8.14–8.17
(m, 3H, ArH); 13C NMR (100MHz, DMSO, δ, ppm):
124.6, 128.4, 129.4, 129.6, 130.4, 132.1, 133.52, 133.55,
133.7, 137.4, 162.7, 168.5; ESI-MS: m/z 284 [M+1]+
Anal. Calcd for C16H10Cl NO2: C, 67.74; H, 3.55; Cl,
12.50; N, 4.94. Found: C, 67.70; H, 3.54; Cl, 12.52; N, 4.97.
4-(4-fluorobenzylidene)-2-phenyloxazol-5(4H)-one (3g).
Yield 86%. m.p: 162–164oC. 1H NMR (400 MHz,
DMSO, δ, ppm): 7.14–7.17 (m, 2H, ), 7.21 (s, 1H,
benzylidene CH), 7.48–7.55(m, 3H, ArH), 8.11 (d,
J = 7.6 Hz, 2H, ArH), 8.26–8.31(m, 2H, ArH); 13C
NMR (100 MHz, DMSO, δ, ppm): 118.3, 118.9, 125.3,
128.1, 128.6, 129.8, 130.6, 132.4, 133.9, 135.1, 135.6,
161.4, 163.6, 167.9; ESI-MS: m/z 268 [M + 1]+ Anal.
Calcd for C16H10FNO2: C, 71.91; H, 3.77; Cl, 7.11; N,
5.24. Found: C, 71.88; H, 3.78; Cl, 7.12; N, 5.25.
S. No
Product
R1
Yield (%)a
5g
2-BrPh
80
5h
4-NO2Ph
85
4-(4-nitrobenzylidene)-2-phenyloxazol-5(4H)-one
(3h).
Yield 91%. m.p: 238–240oC. 1H NMR (400MHz, DMSO,
δ, ppm): 7.12 (s, 1H, benzylidene CH), 7.51–7.62 (m, 3H,
ArH), 8.21 (d, J=7.6Hz, 2H, ArH), 8.31–8.45 (m, 4H,
ArH); 13C NMR (100MHz, DMSO, δ, ppm): 121.9, 125.0,
127.6, 128.8, 129.5, 132.5, 134.2, 136.6, 139.1, 148.6,
165.7, 166.8; ESI-MS: m/z 295 [M+1]+ Anal. Calcd for
C16H10N2O4: C, 65.31; H, 3.43; N, 9.52. Found: C, 65.28;
H, 3.45; N, 9.53.
5i
2-NO2Ph
75
4-((furan-2-yl)methylene)-2-phenyloxazol-5(4H)-one (3i).
Yield 80%. m.p: 172–174oC. 1H NMR (400 MHz,
DMSO, δ, ppm): 6.84–6.85 (m, 1H, ArH), 7.23 (s, 1H,
benzylidene CH), 7.61–7.65 (m, 3H, ArH), 7.69–7.73 (t,
1H, ArH), 8.10 (s, 1H, ArH), 8.11 (d, J = 7.6 Hz, 2H,
ArH); 13C NMR (100 MHz, DMSO, δ, ppm): 114.2,
117.5, 120.6, 125.1, 127.3, 127.9, 129.3, 133.5, 148.0,
149.9, 162.2, 166.5; ESI-MS: m/z 240 [M + 1]+ Anal.
Calcd for C14H9NO3: C, 70.29; H, 3.79; N, 5.86. Found:
C, 70.23; H, 3.82; N, 5.89.
5j
2-furyl
90
5k
2-thionyl
92
2-phenyl-4-((thiophen-2-yl)methylene)oxazol-5(4H)-one
1
(3j). Yield 86%. m.p: 156–159oC. H NMR (400 MHz,
DMSO, δ, ppm): 7.26 (t, 1H), 7.62–7.74 (m, 4H, ArH),
7.86 (d, J = 3.2 Hz, 1H), 8.01–8.10 (m, 4H, ArH); 13C
NMR (100 MHz, DMSO, δ, ppm): 124.9, 125.1, 127.7,
128.2, 129.3, 130.1, 133.4, 136.3, 136.7, 137.1, 161.6,
166.2; ESI-MS: m/z 256 [M + 1]+ Anal. Calcd for
C14H9NO2S: C, 65.87; H, 3.55; N, 5.49. Found: C,
65.92; H, 3.53; N, 5.46.
4-benzylidene-2-(5-(2,6-dichlorophenyl)-3-methylisoxazol-4-
yl)oxazol-5(4H)-one (5a). Yield 91%. m.p: 166–168oC.
1H NMR (400 MHz, DMSO, δ, ppm): 2.86(s, 3H, CH3),
7.21(s, 1H, benzylidene CH), 7.31(t, 2H, ArH), 7.66(d,
J = 7.2 Hz, 1H, ArH), 7.72–7.77(m, 3H, ArH); 13C
aIsolated yield after column chromatography.
4-(4-methoxybenzylidene)-2-phenyloxazol-5(4H)-one (3e).
1
Yield 90%. m.p: 160–163oC. H NMR (400MHz, DMSO,
δ, ppm): 3.78(s, 3H, OCH3), 6.83(d, J=8.6Hz, 2H, ArH),
7.24(s, 1H, benzylidene CH), 7.46–7.53(m, 3H, ArH),
8.09–8.14 (m, 2H, ArH), 8.12 (d, J= 8.7 Hz, 2H, ArH); 13C
NMR (100MHz, DMSO, δ, ppm): 56.2, 114.6, 125.2,
126.6, 127.9, 128.6, 131.2, 131.8, 132.9, 135.1, 158.3,
162.6, 167.6; ESI-MS: m/z 280 [M+1]+ Anal. Calcd for
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A. M. L. Punna Rao, A. Sridhar Rao, M. Saratchandra Babu, and M. Krishnaji Rao
Vol 000
Scheme 3. Preparation of product 5a–5k.
Scheme 4. Plausible mechanism.
NMR (100 MHz, DMSO, δ, ppm): 13.8, 105.2, 127.3,
128.7, 129.2, 131.42, 131.45, 131.6, 132.4, 132.9,
133.4, 134.9, 156.4, 158.3, 166.2, 172.5; ESI-MS: m/z
399 [M]+ Anal. Calcd for C20H12Cl2N2O3: C, 60.17; H,
3.03; N, 7.02. Found: C, 60.11; H, 3.07; N, 7.04.
7.22 (s, 1H, benzylidene CH), 7.58 (d, J = 8.4 Hz, 2H,
ArH), 7.75–7.83 (m, 3H, ArH); 13C NMR (75 MHz,
DMSO) δ : 13.8, 22.4, 40.1, 74.2, 105.9, 111.4, 121.6,
126.6, 127.9, 128.3, 130.8, 133.6, 134.8, 136.1, 152.2,
153.5, 158.2, 167.2, 173.2, 203.1. ESI-MS: m/z 443 [M
+ 1]+ Anal. Calcd for C22H17 Cl2N3O3: C, 59.74; H, 3.87;
N, 9.50. Found: C, 59.66; H, 3.93; N, 9.52.
4-(4-methylbenzylidene)-2-[5-(2,6-dichlorophenyl)-3-methy-
lisoxazol-4-yl)]oxazol-5(4H)-one (5b).
Yield 88%. m.p:
156–159oC. H NMR (300 MHz, DMSO, δ, ppm): 2.38
(s, 3H, CH3), 2.86 (s, 3H, CH3), 7.15 (d, J = 6.3 Hz, 2H,
ArH), 7.19 (s, 1H, benzylidene CH), 7.55 (d, J = 6.6 Hz,
2H, ArH), 7.75–7.84 (m, 3H, ArH); 13C NMR (75 MHz,
DMSO, δ, ppm): 13.7, 21.6, 105.2, 127.3, 128.6, 129.6,
130.5, 130.7, 132.6, 133.0, 134.8, 142.3, 155.8, 158.1,
166.2, 174.8; ESI-MS: m/z 414 [M + 1]+ Anal. Calcd for
C21H14 Cl2N2O3: C, 61.03; H, 3.41; N, 6.78. Found: C,
61.09; H, 3.38; N, 6.75.
4-(4-(diethylamino)benzylidene)-2-(5-(2,6-dichlorophenyl)-3-
methylisoxazol-4-yl)oxazol-5(4H)-one (5e). Yield 87%. m.p:
1
1
244–246oC. H NMR (300 MHz, DMSO) δ: 1.18 (t, 6H,
2xCH3), 2.81 (s, 3H, CH3), 3.46 (q, 4H, 2xCH2), 6.52 (d,
J = 9.0 Hz, 2H, ArH), 7.08 (s, 1H, benzylidene CH), 7.55
(d, J =9.0 Hz, 2H, ArH), 7.72–7.79 (m, 3H, ArH); 13C
NMR (75 MHz, DMSO) δ : 12.6, 13.6, 44.1, 105.3,
111.5, 120.5, 124.7, 127.8, 128.8, 132.6, 133.6, 134.8,
135.3, 150.4, 152.5, 157.9, 166.7, 173.1; ESI-MS: m/z
471 [M + 1]+ Anal. Calcd for C24H21Cl2N3O3: C, 61.29;
H, 4.50; N, 8.93. Found: C, 61.23; H, 4.54; N, 5.91.
4-(4-chlorobenzylidene)-2-(5-(2,6-dichlorophenyl)-3-methyl-
isoxazol-4-yl)oxazol-5(4H)-one (5f). Yield 89%. m.p: 161–
163oC. 1H NMR (300MHz, DMSO) δ : 2.86 (s, 3H, CH3),
7.24 (s, 1H, benzylidene CH), 7.36 (d, J=8.7Hz, 2H,
ArH), 7.61 (d, J=8.4Hz, 2H, ArH), 7.73–7.84 (m, 3H,
ArH); 13C NMR (75MHz, DMSO) δ: 13.7, 105.0, 127.1,
128.8, 129.1, 129.7, 131.9, 132.3, 133.1, 133.8, 134.9,
136.4, 156.8, 158.1, 165.8, 175.4; ESI-MS: m/z 433 [M
+1]+ Anal. Calcd for C20H11Cl3N2O3: C, 55.39; H, 2.56;
N, 5.86. Found: C, 70.23; H, 3.82; N, 5.89.
4-(4-methoxybenzylidene)-2-(5-(2,6-dichlorophenyl)-3-methyl-
isoxazol-4-yl)oxazol-5(4H)-one (5c). Yield 90%. m.p: 156–
1
159oC. H NMR (300MHz, DMSO, δ, ppm): 2.87(s, 3H,
CH3), 3.84 (s, 3H, OCH3), 6.87 (d, J=9.0Hz, 2H, ArH),
7.21 (s, 1H, benzylidene CH), 7.67 (d, J=9.0Hz, 2H,
ArH), 7.75–7.81 (m, 3H, ArH); 13C NMR (75MHz,
DMSO, δ, ppm): 13.5, 21.6, 105.4, 127.3, 128.6, 129.8,
130.4, 130.6, 131.4, 132.8, 133.1, 134.7, 142.5, 155.7,
158.3, 166.3, 174.6; ESI-MS: m/z 430 [M+1]+ Anal.
Calcd for C21H14 Cl2N2O4: C, 58.76; H, 3.29; N, 6.53.
Found: C, 58.79; H, 3.28; N, 6.52.
4-(4-(dimethylamino)benzylidene)-2-(5-(2,6-dichlorophenyl)-
3-methylisoxazol-4-yl)oxazol-5(4H)-one(5d). Yield 89%. m.p:
4-(4-bromobenzylidene)-2-(5-(2,6-dichlorophenyl)-3-methyl-
1
232–234oC. H NMR (300 MHz, DMSO) δ: 2.34 (s, 3H,
isoxazol-4-yl)oxazol-5(4H)-one (5g).
Yield 80%. m.p:
1
CH3), 2.98 (s, 6H, 2xCH3), 7.18 (d, J = 8.1 Hz, 2H, ArH),
168–170oC. H NMR (300MHz, DMSO) δ: 2.86 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
One-Pot Synthesis of Azlactone
CH3), 7.21 (s, 1H, benzylidene CH) 7.52–7.56 (m, 4H,
ArH), 7.76–7.78 (m, 3H, ArH); 13C NMR (75MHz,
DMSO) δ: 13.4, 105.1, 125.4, 127.0, 128.9, 129.8, 131.9,
132.1, 132.5, 133.6, 133.9, 134.6, 156.8, 158.2, 165.6,
175.6; ESI-MS: m/z 479 [M+ 1]+ Anal. Calcd for
C20H11BrCl2N2O3: C, 50.24; H, 2.32; N, 5.86. Found: C,
50.29; H, 2.28; N, 5.85.
4-(4-nitrobenzylidene)-2-(5-(2,6-dichlorophenyl)-3-methyl-
isoxazol-4-yl)oxazol-5(4H)-one (5h). Yield 85%. m.p: 170–
173oC. 1H NMR (300 MHz, DMSO) δ: 2.89 (s, 3H, CH3),
7.31 (s, 1H, benzylidene CH), 7.76–7.86 (m, 3H, ArH),
7.87 (d, J = 9.0Hz, 2H, ArH), 8.11–8.15 (m, 2H, ArH);
13C NMR (75 MHz, DMSO) δ: 13.6, 103.8, 123.8, 127.2,
127.5, 128.8, 132.8, 133.0, 134.3, 134.9, 139.5, 148.0,
155.5, 158.4, 165.8 176.3; ESI-MS: m/z 445 [M + 1]+
Anal. Calcd for C20H11Cl2N3O5: C, 54.07; H, 2.50; N,
9.46. Found: C, 54.13; H, 2.46; N, 9.44.
Acknowledgments. We thank the DIVIS LABORATORIES for
financial support for this work. We are grateful to the Academic
Paper Editing Saratchandra Babu at GITAM University.
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4-(2-nitrobenzylidene)-2-(5-(2,6-dichlorophenyl)-3-methyl-
isoxazol-4-yl)oxazol-5(4H)-one (5i).
Yield 75%. m.p:
179–181oC. H NMR (400 MHz, DMSO, δ, ppm): 2.88
(2, 3H, CH3), 7.18 (s, 1H, benzylidene CH), 7.64–7.74
(m, 5H, ArH), 7.95 (d, J = 5.2 Hz, 1H, ArH); 13C NMR
(100 MHz, DMSO, δ, ppm): 13.3, 104.8, 125.4, 126.7,
128.1, 128.2, 128.6, 132.6, 134.5, 136.3, 136.6, 137.0,
154.7, 157.4, 165.0, 174.8; ESI-MS: m/z 445 [M + 1]+
Anal. Calcd for C20H11Cl2N3O5: C, 54.07; H, 2.50; N,
9.46. Found: C, 54.11; H, 2.48; N, 9.44.
1
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2-yl)methylene)oxazol-5(4H)-one (5j).
Yield 90%. m.p:
216–218oC. H NMR (400 MHz, DMSO, δ, ppm): 2.91
(s, 3H, CH3), 6.67–6.71 (m, 2H, ArH), 7.14 (s, 1H,
benzylidene CH), 7.72–7.75 (m, 3H, ArH), 7.98 (d,
J = 1.6 Hz, 1H, ArH); 13C NMR (100 MHz, DMSO, δ,
ppm): 13.3, 104.8, 114.0, 116.1, 118.0, 120.1, 126.9,
128.1, 128.4, 132.7, 134.5, 134.6, 147.9, 155.4, 157.6,
165.1, 174.9; ESI-MS: m/z 390 [M + 1]+ Anal. Calcd for
C18H10Cl2N2O4: C, 55.55; H, 2.59; N, 7.20. Found: C,
55.50; H, 2.63; N, 7.21.
1
2-(5-(2,6-dichlorophenyl)-3-methylisoxazol-4-yl)-4-((thiophen-
2-yl)methylene)oxazol-5(4H)-one (5k). Yield 92%. m.p: 196–
198oC. 1H NMR (400MHz, DMSO, δ, ppm): 2.88 (2, 3H,
CH3), 7.18 (s, 1H, benzylidene CH), 7.64–7.74 (m, 5H,
Ar-H), 7.95 (d, J=5.2Hz, 1H, ArH); 13C NMR (100MHz,
DMSO, δ, ppm): 13.3, 104.8, 125.4, 126.7, 128.1, 128.2,
128.6, 132.6, 134.5, 136.3, 136.6, 137.0, 154.7, 157.4,
165.0, 174.8; ESI-MS: m/z 406 [M+1]+ Anal. Calcd for
C18H10Cl2N2O3S: C, 53.35; H, 2.49; N, 6.91. Found: C,
53.33; H, 2.46; N, 6.96.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet