Greener approach: Ionic liquid [Et3NH][HSO4]-catalyzed multicomponent synthesis of 4-arylidene-2-phenyl-5(4H)oxazolones under solvent-free condition

Article abstract of DOI:10.1080/00397911.2017.1340649

We have developed simple, greener, safer multicomponent synthesis series of 4-arylidene-2-phenyl-5(4H) oxazolones 4(a-r) catalyzed by Bronsted acid ionic liquid as triethylammonium hydrogen sulfate [Et₃NH][HSO₄] and catalytic amount of acetic anhydride and sodium acetate with excellent yields (90–99%). The protocol offers economical, environmentally benign, solvent-free conditions, and recycle–reuse of the catalyst and easily available starting as benzoyl chloride 1, amino acid 2 and a variety of aldehydes 3. The cyclization followed by condensation of benzoyl chloride, amino acid, and a variety of aldehydes catalyzed by ILs [Et₃NH][HSO₄] and catalytic amount of acetic anhydride and sodium acetate. The final products were confirmed by their characterization data such as FTIR, ¹H-NMR, ¹³C-NMR, Mass, high-resolution mass spectra and were compared with its reported method.

Full text of DOI:10.1080/00397911.2017.1340649

Synthetic Communications
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Greener Approach: Ionic Liquid [Et3NH][HSO4]
Catalyzed Multicomponent Synthesis of 4-
arylidene-2-phenyl-5(4H)oxazolones Under Solvent
Free Condition
Santosh A. Jadhav, Aniket P. Sarkate, Mazahar Farooqui & Devanand B.
Shinde
To cite this article: Santosh A. Jadhav, Aniket P. Sarkate, Mazahar Farooqui & Devanand
B. Shinde (2017): Greener Approach: Ionic Liquid [Et3NH][HSO4] Catalyzed Multicomponent
Synthesis of 4-arylidene-2-phenyl-5(4H)oxazolones Under Solvent Free Condition, Synthetic
Communications, DOI: 10.1080/00397911.2017.1340649
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Date: 14 June 2017, At: 20:27

Greener approach: Ionic liquid [Et3NH][HSO4] catalyzed multicomponent synthesis
of 4-arylidene-2-phenyl-5(4H)oxazolones under solvent free condition
Santosh A. Jadhav1, Aniket P. Sarkate2, Mazahar Farooqui3, Devanand B. Shinde4
1Department of Chemistry, Vivekanand Arts S. D. Commerce & Science College,
Aurangabad (MS), India,
2Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad (MS), India,
3Department of Chemistry, Dr. Rafiq Zakaria College for Women, Aurangabad,
Maharashtra, India,
4Shivaji University Kolhapur, Kolhapur, (MS), India
Corresponding author Address Dr. S. A. Jadhav, Department of Chemistry, Vivekanand
Arts S. D. Commerce & Science College, Aurangabad (MS), 431 001 India. E-mail:
profsantoshjadhav@gmail.com
Abstract
We have developed simple, greener, safer multicomponent synthesis series of 4-
arylidene-2-phenyl-5(4H) oxazolones 4(a-r) catalyzed by Bronsted acid ionic liquid as
triethylammonium hydrogen sulfate [Et3NH][HSO4] and catalytic amount of acetic
anhydride and sodium acetate with excellent yields (90-99%). The protocol offers
economical, environmentally benign, solvent-free conditions and recycle–reuse of the
catalyst and easily available starting as benzoyl chloride 1, amino acid 2 and variety of
aldehyde 3. The cyclisation followed by condensation of benzoyl chloride, amino acid
and variety of aldehyde catalyzed by ILs [Et3NH][HSO4] and catalytic amount of acetic
anhydride and sodium acetate. The final products were confirmed by their
characterization data such as FTIR, 1HNMR, 13CNMR, Mass, HRMS and were compared
with its reported method.
1

2

Graphical Abstract
KEYWORDS: Solvent free; Ionic liquid; Multicomponent; Oxazolone.
INTRODUCTION
Nitrogen, Oxygen containing, 2 and 4-substituted five member heterocycles specially 4-
arylidene-2-phenyl-5(4H)-oxazolones or azlactones are important class of organic
compound, which have attracted much more interest due to their extensive variety of
biological and pharmaceutical properties [1–3]. They are having proper construction and
appreciated intermediates for synthesis of diverse biologically active molecules, with
amino acids [4,5], peptides [6], heterocyclic compounds [7] as well as biosensors and
photosensitive devices for proteins [8]. Furthermore, these compounds are more active for
anticancer [9], anti-tumor [10], anti-microbial [11], anti-inflammatory [12], anti-hypertensive
and inhibitor of central nervous system(CNS) [13]. Previously reported for oxazolone or
Azlactone: First and well known synthetic route for the synthesis of azlactone by
Erlenmeyer method [14] from the condensation of benzaldehyde with N-acetylglycine or
hippuric acid in the presence of sodium acetate and acetic anhydride. After the
Erlenmeyer report, several other reagent and catalysts such as polyphosphoric acid [15]
,
3

Perchloric acid [16], Al2O3-H3BO3 [17], Zeolite catalyst [18], bismuth acetate (Bi(OAc)3 ) [19]
,
[23]
bismuth triflates (Bi(OTf)3) [20], anhydrous zinc chloride [21], Al2O3[22], Yb(OTf)3
,
POCl3 [24], [C6(MIm)2]2W10O32.2H2O [25], Nano silica supported tungsto phosphoric acid
[26], TsCl-DMF [27] and recently using SiO2-nano particle [28] has employed for
condensation and cyclization of aldehyde, hippuric acid and carbonyl compounds.
However, all of these synthetic methods have been some drawback, involvement of an
environmentally hazardous, cost effective, toxic reagent and catalyst, unsatisfactory
yields, tedious work procedure and product separation, longer reaction time, single step
of reaction etc. To overcome some of these drawbacks and the developed new
methodology, an eco-friendly route was developed to synthesize oxazolone under the
solvent free condition. Under these situations synthesized some heterocycles [29] and
effectiveness of Ionic liquid catalyzed in organic synthesis [30]. The most important
benefits of performing the multicomponent, solvent free conditions and catalyzed by ILs
are rate enhancements cleaner reaction, the higher product yields and minimum time
requirement. Thus, at the present, we wish to mention the development and
implementation of a methodology allowing for the synthesis of substituted 4-
benzylidene-2-phenyloxazol-5(4H)-ones 4(a–r) Scheme 1.
RESULTS AND DISCUSSION
In earlier our research work, environmentally benign synthetic methods have received
considerable attention and some green protocols have been developed [31]. At first we
prepared sodium 2-benzamidoacetate from benzoyl chloride (1.0 mmol) 1 and glycine
4

(1.0 mmol) 2 in 10 mol% of sodium hydroxide by simple stirring at cold condition in situ
generated sodium 2-benzamidoacetate and aromatic aldehyde (1.0 mmol) with optimizing
different mole % of catalyst (5-25 mol%)with different solvents and solvent free
condition at different temperature condition (Table 1, 2). For the model reaction we
screened different solvents like water, methanol, ethanol, tert. butyl alcohol, acetonitrile,
tetrahydrofuran (THF), polyethylene glycol (PEG) and solvent free condition under the
simple heating condition(heating at 60-90 °C to reflux) (Table 1). We observed that good
yield was obtained in polar solvents at reflux condition (Table 1, entry 1-7). If the same
reaction were performed in solvent free condition, better to excellent yield was obtained
in 20 min at 90 °C (Table 1, entry 9). The yields of the products were decreases at
decreasing temperature even also increasing the time of reaction (Table 1, entry 10-
11).At the same time for the same model reaction, we optimized different mole % of
catalyst (5, 10, 15, 20 and 25 mol%), here in we observed that excellent yield was
obtained at 20 and 25 mol% of ILs. The catalyst (ILs) were reused and observed that
better yield was obtained for the first four cycle of reaction (Table 2, entry 4,5) (Figure 1)
in 20 mol% of catalyst (Table 2, entry 4). Thus, on this practical basis we select 20 mol%
of ILs, solvent free condition, simple conventional technique at 90°C in 20-25 min for the
synthesis series of series of 4-arylidene-2-phenyl-5(4H) oxazolones 4(a-r) with better to
excellent yields = 90-99% (Table 3). The hypothetical mechanistic path for synthesis of
substituted 4-arylidene-2-phenyl-5(4H) oxazolones (4) mention at Scheme 2. Aromatic
aldehyde, Hippuric acid of glycine, cyclizes in the presence of acetic anhydride,
condensing to give 2-phenyl-oxazolone and Carbon ion is generated after abstract proton
5

by sodium acetate or ionic liquid from electrophilic carbon atom Step-I to VII at Scheme
2.
Finally, the structures of the compounds 4a were confirmed by spectral and analytical
data for example, IR, 1HNMR, 13CNMR and Mass. The spectral data was consistent with
previous literature report [21–23,27,28]
.
EXPERIMENTAL SECTION
Materials
The chemicals with high purity were purchased from Alfa Aesar. Melting points of
synthesized products were recorded on OptiMELT digital melting point apparatus and
were uncorrected. IR spectra were recorded on a FT-IR (Bruker). 1HNMR and 13CNMR
spectra were recorded on a 300, 400 MHz Bruker spectrometer in solvent CDCl3 as part
per million (ppm) downfield from a tetramethylsilane (TMS) as internal standard. The
chemical shifts were reported in ppm. High-resolution mass spectra (HRMS) were
recorded on an Agilent 6520 (QTOF) ESI-HRMS instrument and Mass spectra were
recorded QUART-MASS JEOL-Accu TOF JMS-T 100LC Mass spectrometer. The
microwave reactions were carried out in Micro SYNTH Lab station of Ethusi Milestone.
Spectral data for the entire synthesized products (4a-4r) as depicted in tabulated form and
in supplementary data as a supporting data.
SYNTHESIS
Procedure For The Synthesis Of Triethyl Ammonium Hydrogen Sulfate
[Et3NH][HSO4]Ils
6

In a small round-bottom flask (100-mL), immersed in water-bath and fitted with a reflux
condenser. Sulfuric acid, (1.96 g, 0.02 mol) was drop wise added into triethylamine (2.02
g, 0.02 mol) at 60-65 °C for one hour. After completion of addition, the reaction mixture
was stirred for an additional period of one hour at 65-70 °C. The residue was heated and
removed water molecule from reaction mixture under a high vacuum until the weight of
the residue remained constant. The obtained yield of [Et3NH] [HSO4] was 96 %. Having
characterization data: FT-IR cm-1 3020 (N–H stretch), 2816 (C–H stretch), 1232 (C–N
stretch).; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 1.13–1.25 (t, 9H, 3*9 CH3), 3.02–3.16
(q, 6H, 3*9 CH2) and 8.83 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ (ppm) 11.05
(CH3) and 52.7 (CH2).
Typical Procedure For The Synthesis Of Compound (4a-R)
In small round bottom flask benzoyl chloride (1.0 mmol), Glycine (1.0 mmol) and 10 %
sodium hydroxide were well stirred in cold conditions in situ generate sodium 2-
benzamidoacetate, aromatic aldehyde (1.0 mmol), acetic anhydride (3.0 mmol) and fused
sodium acetate (1.0 mmol) was heated on a hot plate to homogeneous, and the resulting
mixture was then heated on a water bath for appropriate time (Table 2). After completion
of the reaction (TLC) the mixture was cooled to room temperature and treated with EtOH
(4-5 ml) to this mixture was then held in a refrigerator at 4-6 °C for overnight, and the
resulting precipitate was collected by simple filtration. The solid product was then
washed with water and air-dried at room temperature then recrystallized from ethanol to
give the corresponding oxazolone 4a–r ;Yield = 90-99% (Scheme 1, Table 2). The
catalyst was recovered from the reaction mixture during synthesis of 4-benzylidene-2-
7

phenyloxazol-5(4H)-one derivative washed with aqueous alcohol (4–6 mL) followed by
water (5–6 mL) and dried well and reused for subsequent runs. The reusability of catalyst
were tested and observed to obtained excellent yields of the products for the first 3th–4th
cycles of reaction Figure 1. The yields of the products were decreased even after
increasing the reaction time (Figure 1).
Spectral Characterization Data Of Compound 4a And 4r
1. 4-Benzylidene-2-Phenyloxazol-5(4H)-One (4a)
White crystal.; Yield: 99%.; m.p. 165-167˚C; 167-168 Lit.22m.p. (°C); 1H NMR (300
MHz, CDCl3): δ(ppm) 7.89(s, 1H, H-C=C), 7.32-7.64(m, 5H, Ar-H), 7.52-7.93(m, 5H, Ar-
H).; 13C NMR (300 MHz, CDCl3): δ (ppm) 165.9, 160.6, 135.3, 131.6, 131.01, 128.8,
128.5, 128.6, 128.2, 128.4, 128.3, 128.1, 128.0, 127.3, 126.3, 112.2.; IR (KBr)νmax/cm-1:
1509 (C=C-Ar), 1792 (C=O), 1652 (C=N), 2763 (ArC-H).; Molecular Formula
C16H11NO2.; MS (ESI): m/z(%) 250.08 [M+H].; HRMS-EI: found: 249.081, calculated:
249.088.
2. 4-(3-Ethoxy-4-Hydroxybenzylidene)-2-Phenyloxazol-5(4H)-One (4r)
Yellow crystal.; Yield: 96%.;m.p. 161-163˚C;Lit.this workm.p. (°C); 1H NMR (300 MHz,
CDCl3): δ (ppm) 7.90(s, 1H, H-C=C), 7.51-7.92(m, 5H, Ar-H), 7.10(d,1H, Ar-H), 6.98(d,
1H, Ar-H) , 5.36(s, 1H, Ar-OH), 4.02(qt, 2H,-O-CH2-CH3), 1.30(t, 3H,-CH2-CH3).; 13C
NMR (300 MHz, CDCl3): δ (ppm) 165.8, 160.8, 148.3, 147.6, 131.06, 131.5, 131.1, 128.7,
128.3, 128.2, 126.3, 122.1, 116.3, 112.3, 64.7, 14.3.; IR (KBr)νmax/cm-1: 1465(Ar-OMe),
8

1508 (C=C-Ar), 1790 (C=O), 1653 (C=N), 2762 (ArC-H), 3239(Ar-OH).; Molecular
Formula C18H15NO4.; MS (ESI):m/z(%) 310.10 [M+H].; HRMS-EI: found: 309.100,
calculated: 309.106.
CONCLUSIONS
In present work, we have developed green approach multicomponent conventional
synthesis series of 4-arylidene-2-phenyl-5(4H)-oxazolones under solvent free condition
from easily available starting materials. The benefit of this research work is the starting
materials were used an easily available, simple protocol and reusable, non-hazardous
cost-effective catalyst and evaded solvents.
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13

Table 1. Screening of solvents for the synthesis of 4-arylidene-2-phenyl-5(4H)-
oxazolonea
Entry
Solvent
Temperature (°C) Time (min)
Yieldb (%)
1
EtOH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
90
25
25
25
25
25
25
25
25
20
25
25
58
62
65
40
48
43
68
93
99
80
58
2
MeOH
3
Tert-BuOH
H2O
4
5
CH3CN
THF
6
7
PEG
8
Solvent free
Solvent free
Solvent free
Solvent free
9
10
11
80
60
aReaction Conditions: Benzoyl chloride (1.0 mmol), Glycine (1.0 mmol) and
benzaldehyde (1.0 mmol), triethyl ammonium hydrogen sulfate (ILs) (20 mol%), acetic
anhydride (3.0 mmol) and fused sodium acetate (1.0 mmol) the resulting mixture was
reflux to heat at 90-60 °C.
bIsolated Yield.
14

Table 2. Optimization of catalyst [Et3NH][HSO4] with respect to its reusability under
solvent free condition
Entry
Catalyst
Quantity(mol%) No. of Cycle
Yieldb (%)
00
1
2
3
4
5
05
10
15
20
25
I
[Et3NH][HSO4]
[Et3NH][HSO4]
[Et3NH][HSO4]
[Et3NH][HSO4]
[Et3NH][HSO4]
I / II
I / II
43 / 41
68 / 66
I / II /III / IV / V 99/ 97/94 /90/83
I / II / III 99/ 97/ 94
Reaction Conditions: Benzoyl chloride (1.0 mmol), Glycine (1.0 mmol) and aromatic
aldehyde (1.0 mmol), acetic anhydride (3.0 mmol) and fused sodium acetate (1.0 mmol)
the mixture was reflux to heat at 90 °C in different mol % triethyl ammonium hydrogen
sulfate (ILs) with no. of cycles.
bIsolated Yield.
15

Table 3.Synthesis of Azlactone derivatives catalyzed by ILs [Et3NH][HSO4]
Entry Aldehyde
Producta Time
(min)
Yieldb
(%)
99
Mp. (ºC)
Found
Reported[Lit.]
1
2
C6H5CHO
20
23
165-167 167-168[22]
142-143 143-
4a
4b
4-MeC6H4CHO
97
144[22],[28]
3
4-OMeC6H4CHO
4-ClC6H4CHO
4-BrC6H4CHO
4-FC6H4CHO
20
20
23
23
20
20
20
20
23
23
98
94
95
91
95
96
90
90
90
90
163-164 164-165[2],[21]
204-205 203-204[2],[28]
197-198 196-198[28]
183-184 182-183[28]
241-242 240-241[23]
195-196 194-195[2]
163-164 164-165[2]
155-156 157-158[28]
160-162 159-160[28]
200-201 203-204[28]
4c
4d
4e
4f
4
5
6
7
4-NO2C6H4CHO
3-NO2C6H4CHO
2-NO2C6H4CHO
2-ClC6H4CHO
2,6-Cl2C6H3CHO
3,4,5-
4g
4h
4i
8
9
10
11
12
4j
4k
4l
(OMe)3C6H2CHO
4-N(Me)2C6H4CHO
13
23
91
211-212 212-
4m
214[27],[28]
14
15
16
17
Pyridine-4-CHO
Thiophene-2-CHO
Furan-2-CHO
23
25
25
23
93
90
92
96
170-171 168-169[22]
171-172 173-174[28]
168-169 170[17]
169-170 170-172[28]
4n
4o
4p
4q
Terphthalaldehyde
16

18
3-ethoxy,4-hydroxy
benzaldehyde
25
96
161-163 This work
4r
aReaction condition: Benzoyl chloride (1.0 mmol), Glycine (1.0 mmol) and 10 %
sodium hydroxide, aromatic aldehydes (1.0 mmol), acetic anhydride (3.0 mmol) and
fused sodium acetate (1.0 mmol)with 20 mol% of ILs[Et3NH][HSO4] the mixture was
reflux to heat at 90 °C to product yield (90-99%).
17

Scheme 1. Synthesis of 4-benzylidene-2-phenyloxazol-5(4H)-one
18

Scheme 2. Plausible mechanism for the synthesis of 4-benzylidene-2-phenyloxazol-
5(4H)-one
19

Figure 1. Reusability of [Et3NH][HSO4] for the synthesis of 4-arylidene-2-phenyl-5(4H)
oxazolones.
20