A new, efficient and chemoselective one-pot protocol for synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones from aryl aldehyde bisulfite adducts promoted by POCl3

Article abstract of DOI:10.1002/jhet.5570450308

(Chemical Equation Presented) A one-pot procedure for the synthesis of 4-arylidene-2-phenyl-5(4H)oxazolones directly from aryl aldehyde bisulfite adducts in the absence of Ac₂O in good to excellent yields using phosphoryl chloride is reported. In addition, the observed chemoselectivity can be considered as a noteworthy advantage of this method.

Full text of DOI:10.1002/jhet.5570450308

May-Jun 2008
683
A New, Efficient and Chemoselective One-Pot Protocol for
Synthesis of 4-Arylidene-2-phenyl-5(4H)-oxazolones from Aryl
Aldehyde Bisulfite Adducts Promoted by POCl3
Ahmad R. Khosropour,*a Mohammad M. Khodaei,b and Seyed J. Hoseini Jomorb
aCatalysis Division, Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
bDepartment of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Received March 5, 2007
O
Ph
O
PhCONHCH2CO2H
ArCH(OH)SO3Na
N
POCl3, CH3CN
ArCH
A one-pot procedure for the synthesis of 4-arylidene-2-phenyl-5(4H)oxazolones directly from aryl
aldehyde bisulfite adducts in the absence of Ac2O in good to excellent yields using phosphoryl chloride is
reported. In addition, the observed chemoselectivity can be considered as a noteworthy advantage of this
method.
J. Heterocyclic Chem., 45, 683 (2008).
INTRODUCTION
4-Arylidene-2-phenyl-5(4H)oxazolones
RESULTS AND DISCUSSION
Recently, one-pot multicomponent reactions have
attracted a great deal of interest due to the possibility of
generating molecular diversity in a minimum number of
steps [19]. As a part of our continuous interest directed
towards the development of new methodologies for the
synthesis of heterocyclic compounds [20], we report in
preliminary form the results of our recent efforts devoted
to the synthesis of functionalized azalactones. In this
manuscript, we wish to report a new and efficient method
for the one-pot synthesis of azalactones using aryl
aldehyde bisulfite adducts in the presence of POCl3 in the
absence of acetic anhydride (Scheme I).
(azlactones)
and their derivatives, occupy an important place in the
realm of biological and pharmaceutical sciences. They
have served as versatile substrates to a variety of synthetic
targets such as synthesis of peptides [1] and amino acids
[2] or antitumor [3], antimicrobial [4], biosensor [5] or
new heterocyclic compounds [6]. Hence, synthesis of this
heterocyclic nucleus is of continuing interest.
The simple and direct method for the synthesis of the
azlactones involves the one-pot condensation of an
aldehyde and hippuric acid using anhydrous sodium
acetate as a basic catalyst in acetic anhydride [7].
Alternative
catalysts,
including
inorganic
or
organometallic compounds such as SO3 in DMF [8],
Pb(OAc)4 [9], PPA [10], Al2O3-H3BO3 [11], supported KF
[12], ZnCl2 [13], Bi(CH3CO2)3 [14] and Ca(OAc)2 [15]
were applied to improve the yield of the process. Also, we
recently reported a practical procedure for the synthesis of
azlactones catalyzed by BiCl3, Bi(TFA)3, and Bi(NO3)3
[16]. Although each of these methods has its own merit,
the presence of acetic anhydride may cause side reactions
such as esterification or acylation. Therefore replacement
of acetic anhydride by other reagents is required.
Aldehydes hold a central position in synthesis and
sometimes they are difficult to isolate due to their
volatility or sensitivity (hydrolyzation or polymerization)
[17]. The exchange of this functional group for a more
stable one is therefore desirable. Aldehyde bisulfite
adducts are frequently used as protecting groups for
aldehydes under basic conditions and due to their highly
crystalline forms are extensively utilized [18]. Thus using
these masked aldehyde forms directly could allow for
more substituent variation.
Scheme I
O
O
PhCONHCH2CO2H
ArCH(OH)SO3Na
POCl3, CH3CN
N
ArCH
1
2
In order to determine the optimum reaction conditions,
benzaldehyde bisulfite and hippuric acid were treated with
phosphoryl chloride under various conditions (Table 1).
Thus, treatment of 1 equiv. of benzaldehyde bisulfite with
1.1 equiv. of hippuric acid and 2 equiv. of POCl3 in
acetoniltrile (2 mL) for 20 min under reflux, resulted in
the formation of the corresponding azlactone in 86%
yield, with high purity.
Under similar conditions various substituted aromatic
aldehyde bisulfite adducts carrying either electron-
donating or –withdrawing substituents were converted to

684
A. R. Khosropour, M. M. Khodaei, and S. J. Hoseini Jomor
Vol 45
of products was much lower than those obtained with aryl
aldehyde bisulfite adducts (Table 2, entries 1 and 9). On
the other hand, aliphatic aldehyde bisulfites are inert
toward POCl3 during this transformation. For example,
bisulfite of 2-phenylethanal did not provide the desired
azalactone under similar reaction conditions. It seems
necessary that the aldehyde bisulfite group should be
activated by its α-substituents such as the phenyl ring for
reaction to take place. The proposed mechanism of this
process is shown in Scheme II.
This method was found to be highly chemoselective. In
a binary mixture of aryl bisulfite adduct and aryl
aldehydes or other protecting forms of aldehydes like
acetals or acylals the aryl bisulfites were quantitatively
converted to their azalactones while the aryl aldehydes,
acetals or acylals remained intact (Table 3).
Table 1
Reaction of Benzaldehyde Bisulfite Adduct and Hippuric Acid with
Phosphoryl Chloride Under Various Conditions.
Entry
Solvent/Conditions
Equivalent Time(min)
of POCl3
Yield
(%)
Nil
4
1
2
3
4
5
6
7
8
Solvent-free/Δ
CHCl3/reflux
CH3CN/r.t.
2
2
2
120
120
120
5
9
CH3CN/reflux
CH3CN/reflux
CH3CN/reflux
CH3CN/reflux
CH3CN/reflux
2
53
74
86
69
87
2
10
20
60
20
2
1.5
2.5
the azalactones in good to excellent yields and the results
are summarized in Table 2.
In all cases, the reactions proceeded rapidly (7-30 min)
with high efficiency (Table 2). The products were
characterized from their H-NMR, IR and mass spectra
Table 3
1
Competitive azlactone synthesis with aryl aldehyde bisulfite
adducts in the presence of POCl3
and also by comparison with authentic samples [7-15].
This method is clean and free from the side products
which are normally observed under Bi(III) catalysts [16].
To the best of our knowledge, this is the first report of the
preparation of azalactones in the absence of acetic
anhydride. It is noteworthy that the existence of activated
substitutents on the aromatic ring that in the traditional
methods (using of catalyst/acetic anhydride system) may
give a mixture of side products that were not detected
under these reaction conditions while at the same time the
purification of product were simplified.
Entry
Substrates
Products
Yields
(%) [a]
O2N
O
NO2
OH
96
O
N
1 [b]
SO3Na
Ph
100
O
O
O
O
O2N
O2N
O
OH
Interestingly, we found that under the same reaction
conditions, aryl aldehydes reacted sluggishly and the yield
86
O
N
SO3Na
Ph
2 [c]
OAc
OAc
OAc
OAc
100
O2N
Table 2
O2N
Synthesis of 4-arylidene-2-phenyl-5(4H)oxazolones from aryl
aldehyde bisulfite adducts in the presence of POCl3
O
O
Ar
[a]
Time
min
Yield
[b]
Mp
Mp
OH
SO3Na
(°C) (°C) [16]
H3C
N
CH3
3 [d]
86
0
Ph
2a
2b
2c
2d
2e
2f
C6H5
20 (120) [c] 86 (5) [c] 165
168
143
152
156
167
172
213
171
185
147
189
152
165
241
O
p-CH3C6H4
10
10
10
25
10
7
89
88
73
85
82
96
68
141
149
155
170
174
210
173
CHO
O
2,4-(CH3)2C6H3
p-CH3OC6H4
2,5-(CH3O)2C6H3
2,4-(CH3O)2C6H3
p-(CH3)2NC6H4
o-HOC6H4
N
Ph
[a] Isolated yield. [b] After 20 min. [c] After 25 min. [d] After 15
min.
2g
2h
2i
2j
2k
2l
30
p-ClC6H4
15(120) [c] 95 (8) [c] 186
m-ClC6H4
15
20
15
15
15
90
89
91
96
90
148
188
152
164
238
In conclusion, we have demonstrated a new, clean,
simple and chemoselective one-pot conversion of aryl
aldehyde bisulfite adducts to their azlactones in good to
excellent yields. Moreover, this procedure uses
advantageously a more stable substrate than an aldehyde
and replaces acetic anhydride by phosphorus oxychloride
in traditional methods for azalactone synthesis.
2,4-Cl2C6H3
o-O2NC6H4
2m
2n
m-O2NC6H4
p-O2NC6H4
[a] All products were characterized by 1H-NMR, 13C-NMR, IR and
comparison of their physical and spectral data with those of literature
samples [16]. [b] Isolated yield. [c] Achievement from aldehyde form.

May-Jun 2008
Synthesis of 4-Arylidene-2-phenyl-5(4H)-oxazolones
685
Scheme II
Ph
N
Ph
N
Ph
N
Ph
H
Ph
O
O
+
Cl
-
OH
+
O
-H
O
POCl3
- Cl
O
N
N
H
O
O
OH
O
H
O
Ph
Ph
Ph
N
O
O
O
N
N
H
H
O
O
O
CHAr
CHAr
H
_
Cl2OPO
SO3Na
ArCHSO3Na
OPOCl2
_
EXPERIMENTAL
REFERENCES
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presence of POCl3. A mixture of aryl bisulfite 1 (1 mmol),
phosphorus oxychloride (0.306 g, 2 mmol) and hippuric acid
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reflux for the specified time (see Table II). After completion of
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4-Benzylidene-2-phenyloxazole-5(4H)-one (2a). solid, mp
1
165 º; ir (KBr): 3075, 1790, 1650, 1160, 760, 690 cm-1; H nmr
(200 MHz, CDCl3): δ 7.28 (s, 1H), 7.62 (m, 6H), 8.25 ppm (m,
4H). Anal. Calcd. for C16H11NO2: C, 77.09; H, 4.44; N, 5.61.
Found: C, 76.60; H, 4.80 ; N, 5.49.
4-(4'-Methylbenzylidene)-2-phenyloxazole-5(4H)-one (2b).
solid, mp 141 º; ir (KBr): 3060, 2925, 1795, 1650, 1600, 1160,
1
860, 820, 765, 695 cm-1; H nmr (200 MHz, CDCl3): δ 2.42 (s,
3H), 7.29 (m, 3H), 7.54 (m, 3H), 8.19 (m, 4H). Anal. Calcd. for
C17H13NO2: C, 77.25; H, 5.34; N, 5.30. Found: C, 77.05; H,
5.77; N, 5.30.
4-(2',4'-Dimethoxybenzylidene)-2-phenyloxazole-5(4H)-
o
one (2f). solid, mp 174 ; ir (KBr): 3020, 2920, 1775, 1640,
1600, 1270, 1160, 850, 765, 695 cm-1; 1H nmr (200 MHz,
CDCl3): δ 3.9 (s, 6H), 6.53 (s, 1H), 6.69 (m, 1H), 7.61 (m, 3H),
7.88 (s, 1H), 8.25 (m, 2H), 8.95 (m, 1H). Anal. Calcd. for
C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.65; H,
5.28; N, 4.51.
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1
650, 1600, 1530, 1370, 1160, 810,690 cm-1; H nmr (200 MHz,
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Acknowledgement.
We are thankful to the Isfahan
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support of this work.

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