An efficient and green synthesis of novel benzoxazole under ultrasound irradiation

abstract
Ultrasound as green process and an alternative energy source was investigated for the environmentally benign synthesis of novel benzoxazoles from different
azo-linked salicylic acid derivatives and 2-amino-4-chlorophenol in short reaction time and high yield. These benzoxazole compounds have been charac-terized
1

by elemental analysis, FT-IR, H NMR and

13

C NMR spectroscopy.

1. Introduction

Oxazole containing ring systems occur in many natural prod-ucts and it is well known that benzoxazole derivatives act as diverse medicinal
mediators, such as antimicrobial [1], Alzheimers disease [2], Rho kinase [3], antitumor [4], anti-inflammatory, fungicides, adrenergic
antagonists, anti-hypertensive, anti-ulcer, leukotriene A4 hydrolase [5] and fatty acid amide hydrolase [6]. In recent times it has been
observed that oxazole containing com-pounds are investigated thoroughly for cancer and anti-HIV-1 agents [7,8], leukemia, and potent
selective 5-HT1A serotonin receptor ligands [9] and some other noticeable activities [1013].

2-Substituted benzoxazoles are generally prepared by condensa-tion of o-aminophenol and carboxylic acids [14] or derivatives of acyl
halides and bromoanilines [15]. N-benzoylo-chloroaniline is trans-formed to 2-phenylbenzoxazole by potassium amide in liquid nitro-gen
[16]. Benzoxazoles can be prepared from o-chlorocarboxylic acid esters and o-aminophenol in good yields [17].

On the other hand, in comparison with conventional thermal heating, ultrasound irradiation have some important advantages: improved
yields, substantial decreases of reaction time, increased selectivity, lower costs and simplicity in handling and processing and high purity of
the compounds. At the same time, in many cases, reactions under ultrasound irradiation could be considered environmentally friendly
processes, using small amounts of sol-vents and being less energy consumer [18]. So ultrasonic irradia-tion provides minimal side reactions
[19].

2. Material and methods

2.1. Apparatus and analysis

For the ultrasound reactions, ultrasound apparatus astra 3D (9.5 dm , 45 kHz frequency, input power with heating, 305 W, number of
transducers, 2) from TECNO-GAZ and EUROSONIC 4D ultrasound cleaner with a frequency of 50 kHz and an output power of 200 W
were used. Chemicals were purchased from Merck and Fluka and used as purchased. Melting points were measured on an Electro-thermal
1

9100 apparatus and are uncorrected. H NMR spectra were obtained on a Bruker DRX 500Avance spectrom-eter in DMSO-d 6 as solvent
and with TMS as internal standard. FT-IR spectra were recorded on a Shimadzu FT-IR-8400S spectrome-ter. Elemental analyses were
recorded on a Carlo-Erba EA1110CNNO-S analyzer.

2.2. General procedure for the synthesis of benzoxazole

A mixture of azo-linked salicylic acids (1 mmol: 0.29 g of acid 1a, 0.24 g of acid 1b, 0.32 g of acid 1c, 0.32 g of acid 1d, 0.33 g of

acid 1e, 0.34 g

of acid 1f, 0.27 g
of acid 1g, 0.30 g of acid 1h,
0.28 g of acid
1i, 0.28 g of acid
1j), 2-amino-4-chlorophenol

(1 mmol: 1.14 g) and 10 mL EtOH were placed into Pyrex-glass open vessel and irradiated in a water bath under silent condition by
ultrasound (45 kHz) at room temperature for the required reac-tion times (1030 min). The progress of the reaction was moni-tored by Thin
Layer Chromatography (TLC) (EtOAc: petroleum ether 1:2). Then the reaction mixture was filtered to separate the

8.03 (m, 3H), 8.6 (s, 1H), 8.99 (s, 1H) ppm.
product and recrystallized from EtOH. The pure
products were col-lected in 9096% yields.

2.2.1. (E)-4-(2-(4-nitrophenyl)diazenyl)-2-(5chlorobenzo[d]oxazol-2-yl)phenol 3a

brown solid, mp 273275 LC, IR (KBr, cm ) mmax

1 1

3486, 1703, 1616, 1527, 1343 cm . H NMR (400

13

NMR (100 MHz, DMSO-d6): dC; 106.8, 110.6,

119.3, 121.1, 120.4, 122.3, 124.6, 128.8, 129.2,
130.2, 131.9, 138.8, 146.2, 147.3, 154.5, 158.8,
173.9 ppm. Anal. Calcd. for C19H12ClN3O2: C,
65.24; H, 3.46; N, 12.01. Found: C, 65.31; H, 3.52;
N, 11.92.

2.2.3. (E)-4-(2-(2-chloro-4-nitrophenyl)diazenyl)-2(5-chlorobenzo [d]oxazol-2-yl)phenol 3c

MHz, DMSO-d6): dH; 6.69

(dd, J = 8.4 Hz,
1

light Brown solid, mp 243245 LC, IR (KBr, cm )

J = 2 Hz,

mmax 3369, 1684, 1611, 1519 cm 1. 1H NMR (400

MHz, DMSO-d6): dH; 7.16 (d, J = 8. 4 Hz, 1H), 7.36
(d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H),

1H), 7.06
(d, J = 8.8 Hz,
1H),

7.62 (s. 1H), 7.96 (d, J = 5.6 Hz, 1H), 8.04 (s,
1H),

7.32
(d,

8.11 (d,

J = 8.4 Hz, 1H),

J = 7.2 Hz, 1H), 8.24 (dd, J = 6.8 Hz, J = 2.4 Hz,

1H), 8.56

7.41 (d,

(s, 1H),

J = 8.4 Hz,

8.91 (s, 1H) ppm.

1H), 7.69 (s,

d6): dC; 117.2,

1H),
8.1
122.3,

(d,
J = 8.4 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.66 (s,
13

106.9,

1H) ppm. C NMR (100 MHz, DMSO-d6): dC;

106.4, 110.7, 119.8, 120.4, 120.4, 122.9, 124.0,
125.3, 129.0, 131.9, 138.8, 145.9, 147.4, 150.5,
158.7, 159.9, 172.7 ppm. Anal. Calcd. for

110.7,

C19H11ClN4O4: C, 57.81; H, 2.81; N, 14.19. Found:

C, 57.73; H, 2.89; N, 14.08.

120.1,

119.2,

120.4,
124.4,

2.2.2. (E)-4-(2-phenyldiazenyl)-2-(5chlorobenzo[d]oxazol-2-yl) phenol 3b

127.6,
129.9,
130.7,
1

cream solid, mp 253 LC, IR (KBr, cm ) mmax 3362,

1 1

1696, 1621 cm . H NMR (400 MHz, DMSO-d6):

dH; 7.16 (dd, J = 8 Hz, J = 1.6 Hz, 1H), 7.31 (d, J =
8.4 Hz, 1H), 7.497.52 (m, 4H), 7.62 (s, 1H), 8.0

131.7,
138.8,

13

C NMR (100 MHz, DMSO-

146.2,

Brown solid, mp 278280 LC, IR (KBr, cm ) mmax

1 1

1411, 1690, 1610, 1572 cm . H NMR (400 MHz,

147.4,

DMSO-d6): dH; 7.16 (d, J = 8.8 Hz, 1H), 7.36 (d, J =

8.4 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.62 (d, J = 8.4
Hz, 2H), 7.597.97 (m, 2H), 8.56 (s, 1H), 8.93 (s,

152.6,
158.8,

13

160.2,
173.97 ppm. Anal. Calcd. for C19H10Cl2N4O4: C,
53.17; H, 2.35; N, 13.05. Found: C, 53.10; H, 2.42;
N, 12.94.

1H) ppm. C NMR (100 MHz, DMSO-d6): dC;

106.9, 110.7, 119.2, 120.1, 120.4, 124.5, 125.7,
128.8, 131.3, 131.7, 132.3, 135.7, 136.0, 138.8,
146.2, 146.7, 156.2, 158.8, 173.97 ppm. Anal. Calcd.
for C19H9Cl4N3O2: C, 50.36; H, 2.00; N, 9.27.
Found: C, 50.28; H, 1.92; N, 9.19.

2.2.4. (E)-4-(2-(4-chloro-2-nitrophenyl)diazenyl)-2(5-chlorobenzo [d]oxazol-2-yl)phenol 3d

light brown solid, mp 236238 LC, IR (KBr, cm )

2.2.7. (E)-4-(2-(2,4-dimethylphenyl)diazenyl)-2-(5chlorobenzo[d] oxazol-2-yl)phenol 3g

mmax 3476, 1664, 1606, 1572, 1523, 1347 cm 1. 1H

NMR (400 MHz, DMSO-d6): dH; 7.16 (d, J = 8.4
Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8 Hz,
1H), 7.62 (s, 1H), 7.89 (dd, J = 8.4 Hz, J = 2 Hz,
1H), 7.98 (s, 1H), 8.02 (d, J = 5.6 Hz, 1H), 8.11 (d, J
= 8.4 Hz, 1H), 8.88 (s, 1H) ppm.

13

C NMR (100

MHz, DMSO-d6): dC; 106.9, 110.7, 119.2, 120.1,

120.4, 121.8, 122.1, 128.8, 129.3, 130.7, 135.1,
135.5, 138.8, 142.7, 145.6, 146.2, 149.6, 158.8,
173.97 ppm. Anal. Calcd. for C19H10Cl2N4O4: C,
53.17; H, 2.35; N, 13.05. Found: C, 53.09; H, 2.29;
N, 12.95.

light Brown solid, mp 210212 LC, IR (KBr, cm )

1 1

mmax 3269, 1635, 1611, 1458, 1370 cm . H NMR

(400 MHz, DMSO-d6): dH; 2.29 (s, 3H), 2.65 (s,
3H), 7.15 (t, J = 8.8 Hz, 2H), 7.15 (s, 1H), 7.36 (d, J
= 8.4 Hz, 1H) 7.54 (t, J = 8.4 Hz, 2H), 7.62 (s, 1H),
7.98 (dd, J = 8.0 Hz, J = 2.4 Hz, 1H), 8.54 (s, 1H),
8.96 (s, 1H) ppm.

13

C NMR (100 MHz, DMSO-d6):

dC; 18.7, 20.7, 106.4, 110.7, 119.2, 120.1, 120.4,

125.6, 128.1, 128.3, 128.8, 130.8, 132.1, 137.1,
137.9, 138.8, 146.0, 146.3, 152.4, 158.9, 173.97
ppm. Anal. Calcd. for C12-H16ClN3O2: C, 66.76; H,
4.27; N, 11.12. Found: C, 66.69; H, 4.33; N, 11.05.

2.2.5. (E)-4-(2-(2,4-dinitrophenyl)diazenyl)-2-(5chlorobenzo[d] oxazol-2-yl)phenol 3e

Brown solid, mp 189191 LC, IR (KBr, cm ) mmax

3298, 1632, 1605, 1585, 1525, 1348 cm . H NMR

(E)-4-(2-(2-nitrophenyl)diazenyl)-2-(5chlorobenzo[d]oxazol-

(400 MHz, DMSO-d6): dH; 7.16 (d, J = 8.8 Hz, 1H),

7.36 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.62
(s, 1H), 8.02 (d, J = 7.2 Hz, 1H), 8.638.70 (m, 2H),
8.82 (s,1H), 8.848.85 (m, 1H), 8.98 (s, 1H) ppm.

2-yl)phenol 3h

1 1

13

C NMR (100 MHz, DMSO-d6): dC; 106.8, 110.7,

119.2, 120.1, 120.4, 123.9, 128.7, 128.8, 129.3,
130.6, 130.9, 138.8, 142.4, 146.2, 148.8, 149.1,
152.6, 158.8, 173.97 ppm. Anal. Calcd. for
C19H10ClN5O6: C, 51.89; H, 2.29;N, 15.93. Found:
C, 51.72; H, 2.32; N, 15.85.

2.2.6. (E)-4-(2-(2,4,5-trichlorophenyl)diazenyl)-2-(5chlorobenzo[d] oxazol-2-yl)phenol 3f

Brown solid, mp 285287 LC, IR (KBr, cm ) mmax

1 1

3407, 1705, 1668, 1614, 1543, 1528, 1351 cm . H

NMR (400 MHz, DMSO-d6): dH; 7.6 (dd, J = 8.4
Hz, J = 1.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H),

(t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.57 (d,
J = 7.6 Hz, 1H), 7.62 (s, 1H), 8.02 (d, J = 6.8 Hz,
1H), 8.13 (d, J = 7.6 Hz, 1H),

(s, 1H), 8.63 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H) ppm.

131.1, 132.3, 140.1, 140.0, 147.1, 151.3, 152.1,

13

154.1, 169.07 ppm. Anal. Calcd. for C22H18ClN3O2:

C, 67.43; H, 4.63; N, 10.72. Found: C, 67.50; H,
4.69; N, 10.65.

C NMR (100 MHz, DMSO-d6): dC; 112.3, 118.8,

120.1, 125.3, 128.3, 128.5, 128.7, 129.3, 129.8,
130.8, 131.0, 132.6, 136.3, 141.7, 147.0, 147.2,
154.4, 155.2, 170.07 ppm. Anal. Calcd. for
C19H11ClN4O4: C, 57.81; H, 2.81; N, 14.19. Found:
C, 57.76; H, 2.76; N, 14.22.

2.2.10. (E)-4-(2-(2-chlorophenyl)diazenyl)-2-(5chlorobenzo[d] oxazol-2-yl)phenol 3j

1

brown solid, mp 239241 LC, IR (KBr, cm ) mmax

3417, 1688,

(E)-4-(2-mesityldiazenyl)-2-(5chlorobenzo[d]oxazol-2-yl)

1 1

1611, 1575 cm . H NMR (400 MHz,

phenol 3i

DMSO-d6): dH; 7.16 (t,

J = 8.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H),
1

Brown solid, mp 206208 LC, IR (KBr, cm ) mmax

7.36 (d, J = 8.4 Hz, 1H),

1 1

3264, 1662, 1616, 1545, 1373 cm . H NMR (400

MHz, DMSO-d6): dH; 2.31
7.497.54 (m, 3H), 7.62 (s, 1H), 7.88 (d, J = 7.6 Hz,
1H), 7.96 (d, J = 6.4 Hz, 1H), 8.56 (s, 1H), 8.87 (d, J
= 2.0 Hz, 1H) ppm.
(s, 3H), 2.41 (s, 6H), 7.07 (s, 2H), 7.16 (d, J = 8.4
Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0
Hz, 1H), 7.62 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 8.56
(d, J = 2.0 Hz, 1H), 8.86 (s, 1H) ppm.

13

C NMR

(100 MHz, DMSO-d6): dC; 19.27, 19.48, 110.4,

118.9, 120.1, 128.6, 129.6, 129.9, 130.55, 130.8,

13

C NMR (100 MHz, DMSO-

d6): dC; 110.4, 118.9, 120.1, 125.4, 126.8, 127.5,

128.7, 129.3, 129.6, 129.9, 130.7, 130.8, 130.9,
132.3, 147.4, 153.1, 153.6, 154.5, 169.77 ppm. Anal.
Calcd. for C19H11Cl2N3O2: C, 59.39; H, 2.89; N,
10.94. Found: C, 59.43; H, 2.94; N, 11.00.

nano-Fe3O4 or ionic liquids [BMIM]Br. The results

are summarized in Table 3.
3. Results and discussion

In continuation of our ongoing studies to synthesize

of hetero-cyclic and pharmaceutical compounds at
mild and practical proto-cols [2023]. Here in we
wish to report mild and efficient procedures for
synthesis of some novel benzoxazoles via the reaction of different salicylic acid derivatives and 2amino-4-chlorophenol under ultrasound irradiation
at room temperature ( Scheme 1).

In order to optimize the reaction conditions, a small

solvent screen were studied ( Table 1). In these
experiments, we have observed that the reaction
between 1a with 2-amino-4-chlorophenol under
ultrasonic irradiation was solvent dependent ( Table
1). We found that the EtOH was the appropriated
solvent for these reactions.

For expansion of generality and efficiency of

ultrasound irradi-ation, we checked some aldehydes
with electron donating and electron withdrawing
substituent in this reaction condition. The results are
summarized in Table 4. According to Table 4, the
rate of nucleophile attack of 2-amino-4-chlorophenol
to azo-linked sal-icylic acid and the reaction time
were improved by electron with-drawing groups of
salicylic acid rather than salicylic acids bearing
electron donating groups. Although a considerable
improvement of yields was not observed.

All of compounds summarized in Table 2 were

1

characterized by spectroscopic methods (IR, H

NMR and

Table 2 compares efficiency of ultrasound condition

(time, yield, reaction conditions) in various
ultrasonic power and temperature for the synthesis of
3a. It is clear from Table 2, increasing of power of
ultrasonics has no effect in reaction time and yield.
On the other hand, the best temperature for the
synthesis of benzoxazoles was under ultrasound
irradiation at room temperature.

Table 3 compares efficiency of ultrasound condition

(time, yield, reaction conditions) with efficiency of
some other conditions in synthesis of benzoxazole. It
is clear from Table 3, our method is simpler, more
efficient, and less time consuming for the synthesis
of benzoxazole derivatives.

In an initial endeavor, 1a and 2-amino-4chlorophenol were refluxed in 10 mL EtOH. After 7

h only, 60% of expected product after purification of
crude product was obtained. To improve the product
yields and to optimize the reaction condition, the
same reaction was carried out in the presence of
ultrasound irradiation and using some catalysis
without ultrasound irradiation. As indi-cated in
Table 3, ultrasound irradiation accelerates the
reaction time from 7 h to 10 min. Also, under
ultrasonic irradiation the yield of product is higher.
On the other hand, ultrasound irradiation is more
efficient than classical Lewis acids such as K10 and

13

C NMR) and elemental analysis.

All of synthesized compounds are new. They were

prepared from azo-linked salicylic acids that most of
them are not commer-cially available material. Azo
dyes are wellknown class of organic photoactive
materials due to their excellent optical switching
properties, good chemical stabilities and high
solution process

Table 1

Optimization for the synthesis of benzoxazole 3a in 10 mL of

solvent.

Entry
Solvent
Time (min)
Yield (%)

Time (min)

EtOAc

Yield (%)

20
80
2
EtOH
10
96
3
1
H2 O
45
25
0 LC
82
60
4
78
Hexane
2
30
45
78
r.t.
5
10
CHCl3
45
78
6
DMF
30
80

96
3
45
60 LC
10
96
4
50
0 LC
50
80
5
50

Table 2

r.t.
10
95

The efficiency of various ultrasonic power and temperature in

synthesis of 3a.

6
50
60 LC

Entry
10
Ultrasonic power (kHz)
96
Temperature

70
4
Nano-Fe3O4
Reflux
240
75
5

Table 3

Ultrasound irradiation, rt
10

The efficiency of ultrasound rather than some other methods in

4-nitro benzaldehyde.

96

Entry
Catalyst
Condition
Time (min)
Yield (%)

Table 4

Ultrasound assisted synthesis of benzoxazoles.

Entry
1

Ar

Reflux
Ultrasound condition
420
60
2
[BMIM]Br
Heat, 80 LC
120
82

Time (min)

Yield (%)

K10

Reflux

3a

240

4-NO2-C6H4

10

3g

96

2,4-(CH3)2-C6H3
10

90

3b
C6H5

25

3h

90

2-NO2-C6H4
25

92

3c
2-Cl-4-NO2-C6H3

10

3i

95

2,4,6-(CH3)3-C6H2
30

85

3d
4-Cl-2-NO2-C6H3

10

15

3j

92

2-Cl-C6H4
15

90

3e
2,4-(NO2)2-C6H3
10
95

All products were characterized by their physical constant, IR,

NMR and ele-mental analyses.
Yields based upon starting aldehyde.

6
3f
2,4,5-Cl3-C6H2
15

abilities [24,25], These materials are widely used in

heat transfer printing and textile industries [26],
optical data storage [27] and photo-refractive
polymer industries [28]. Because of their proper-ties
and activities, we were interested in using azo
compounds as starting materials.

88

Following these results, we further investigated the

potential of this procedure for the selective synthesis
of benzoxazoles of differ-

Cl

COOH
OH

OH
NH2

Ar
N

N
+
)))

Room Tempereture
N

Ar
N

OH

1a-j
2 Cl

3a-j

Scheme 1. Synthesis of benzoxazole under ultrasound irradiation.

Cl

COOH

O2N

NO2
OH

N
OH

NO2
OH

O2N

NH2

(1mmol)

)))

96%
Cl

10 min

COOH

H3C

CH3
OH
Cl

H3C
(1mmol)

CH3

OH

0%

Scheme 2. selective synthesis of benzoxazoles of different types of azo-linked acids.

HO

COOH

O
N
Cl

HO

OH

)))

OH

H2N
Cl

ArN

Ar

HO

Cl

HO

Cl

Ar
N
O

OH

- H2O

Ar
N

OH

Scheme 3. Possible mechanism for synthesis of 2-phenyl benzoxazoles.

ent types of azo-linked acids with 2-amino-4-chlorophenol. The

results showed that ultrasound irradiation is able to discriminate
between aromatic compounds containing electron donating and
electron withdrawing groups, a transformation that is difficult to
accomplish via conventional methods ( Scheme 2).
The important points of this reaction process include the easier
work-up, shorter reaction time, and higher yields than the
conven-tional method.

Mechanistically, the use of ultrasound in chemical reactions in

solution provides specific activation based on a physical phenomenon: acoustic cavitation. Cavitation is a process in which
mechanical activation destroys the attractive forces of
molecules in the liquid phase. One advantage of using
cavitation as an energy source to promote organic reactions
includes shorter reaction times [29]. Applying ultrasound,
compression of the liquid is fol-lowed by rarefaction
(expansion), in which a sudden pressure drop forms small,
oscillating bubbles of gaseous substances. These bub-bles
expand with each cycle of the applied ultrasonic energy until
they reach an unstable size; they can then collide or violently
col-lapse. As these bubbles rapidly collapse, they can be seen as
micro reactors that offer the opportunity of speeding up certain
reactions [2931].

We propose a possible mechanism for synthesis of 2-phenyl

benzoxazoles ( Scheme 3). Initially, the bubbles can be speeded
up the nucleophile attack of 2-amino-4-chlorophenol to salicylic
acid, and finally, tautomerization and dehydration, compound 3
was produced ( Scheme 3).

Finally, we develop an efficient, green, fast and convenient procedure for the synthesis of azo-linked benzoxazoles under ultra-

sound irradiation. This procedures offer advantages such as

reduced reaction time, mild reaction condition, productivity and
higher yield, ease of execution and economic viability. To the
best of knowledge, this is the first report on the synthesis of azo
linked benzoxazole derivatives using different salicylic acid
derivatives and 2-amino-4-chlorophenol.

Acknowledgement

Financial support by Rasht Branch, Islamic Azad University

Grant No. 4.5830 is gratefully acknowledged.