A novel and efficient route for the synthesis of 5-nitrobenzo[d]oxazole derivatives

Article abstract of DOI:10.1016/j.jfluchem.2014.02.013

In this paper, we report a novel and efficient route for the synthesis of 5-nitrobenzoxazole derivatives starting from 2-fluoro-5-nitroaniline and various benzoyl chloride derivatives under solvent-free conditions at 130 °C in the presence potassium carbonate. Benzoyl chlorides easily underwent nucleophilic acyl substitution followed by intramolecular cyclization via concomitant removal of fluorine to obtain the title compounds in high yields.

Full text of DOI:10.1016/j.jfluchem.2014.02.013

Journal of Fluorine Chemistry 161 (2014) 83–86
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A novel and efficient route for the synthesis of 5-nitrobenzo[d]oxazole
derivatives
Mohsen Vosooghi a, Hossein Arshadi b, Mina Saeedi a, Mohammad Mahdavi a,
Farnaz Jafapour b, Abbas Shafiee a, Alireza Foroumadi a,
*
a Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences,
Tehran, Iran
b School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
In this paper, we report a novel and efficient route for the synthesis of 5-nitrobenzoxazole derivatives
starting from 2-fluoro-5-nitroaniline and various benzoyl chloride derivatives under solvent-free
conditions at 130 8C in the presence potassium carbonate. Benzoyl chlorides easily underwent
nucleophilic acyl substitution followed by intramolecular cyclization via concomitant removal of
fluorine to obtain the title compounds in high yields.
Received 8 February 2014
Received in revised form 24 February 2014
Accepted 26 February 2014
Available online 7 March 2014
ß 2014 Elsevier B.V. All rights reserved.
Keyword:
2-Fluoro-5-nitroaniline
5-Nitrobenzoxazole
Solvent-free conditions
Nucleophilic substitution of fluorine
1. Introduction
the condensation of 2-aminophenols and aldehydes using different
oxidants [9–11].
Benzoxazole derivatives have attracted considerable interest
due to their synthetic utility and significant biological activities.
For instance, this core could be found in pharmaceutical drugs such
as flunoxaprofen (Fig. 1a) which has shown remarkable anti-
inflammatory activity [1]. They have been also characterized as
melatonin receptor agonists [2], Rho kinase inhibitors [3],
amyloidogenesis inhibitors [4], and antitumor agents [5]. Further-
more, benzoxazoles are core structure of biologically active natural
products such as salvianen (Fig. 1b) possessing significant
cytotoxicity [6]. In addition to their utilization in medicinal
chemistry, benzoxazoles are well known as a significant scaffold in
fluorescent probes such as anion and metal cation sensors [7].
Therefore, systematic exploitation of benzoxales can be used as
a powerful tool for medicinal chemists and other fields of
chemistry. There are several reports concerning the preparation
of benzoxales. The most useful synthesis of benzoxales consists of
(i) coupling of carboxylic acids with 2-aminophenols followed by
dehydration which is usually catalyzed by strong acid [8] and (ii)
the oxidative cyclization of phenolic Schiff’s bases obtained from
Among various benzoxazole derivatives, 5-nitrobenzoxazoles
attracted our attention since literature review revealed that
benzoxazoles possessing nitro group exhibited important biologi-
cal activities. 5(or 6)-Nitro/amino-2-(substituted phenyl/benzyl)-
benzoxazole derivatives prepared by Ertan et al. depicted
antibacterial and antifungal activities [12]. Also 6-nitro-2-(2-
methoxyphenyl)benzoxazole was found to be an effective eukary-
otic topoisomerase II inhibitor in the study of Pinar et al. [13].
It is well recognized that nucleophilic aromatic substitution
reactions of nitro-substituted aryl halides proceed via the SNAr
mechanism and the necessity of nitro group at ortho or para
positions of the above mentioned substrates is completely
understood, otherwise prevents nucleophilic substitution [14].
The ability of fluorine as a potential substituent has been well
documented in organic synthesis [15]. Considering physical
properties of fluorine such as electronic effects and leaving-group
ability [16] encouraged us to develop an efficient synthetic route
using 2-fluoro-5-nitroaniline as a versatile substrate for the
synthesis of various 5-nitrobenzoxazole derivatives. Herein, in
continuation of our research program on the novel synthesis of
heterocycles [17,18], we prepared a series of the title compounds
through the reaction of 2-fluoro-5-nitroaniline and various
benzoyl chlorides under solvent-free conditions at 130 8C in the
presence potassium carbonate (Scheme 1).
*
Corresponding author. Tel.: +98 21 66954708; fax: +98 21 66461178.
E-mail addresses: aforoumadi@yahoo.com, aforoumadi@tums.ac.ir
(A. Foroumadi).
http://dx.doi.org/10.1016/j.jfluchem.2014.02.013
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

[
M. Vosooghi et al. / Journal of Fluorine Chemistry 161 (2014) 83–86
Table 1
Investigation of solvent and base for the reaction of 2-fluoro-5-nitroaniline 1 and
benzoyl chloride 2a
[DT$LINE]
.
Entry
Solvent
Conditions
Base
Time (h)
Yield (%)a
Fig. 1. Biologically active benzoxazole derivatives.
1
2
3
4
5
6
7
8
9
10
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
PhCH3
130 8C
130 8C
130 8C
130 8C
130 8C
Reflux
Reflux
Reflux
130 8C
130 8C
K2CO3
Et3N
12
12
12
12
12
12
12
12
12
12
90
10
25
70
60
55
45
30
60
60
Piperidine
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
[(Schme_1)TD$FIG]
EtOH
CH2Cl2
DMF
DMSO
Scheme 1. Synthesis of 5-nitrobenzoxazole derivatives 3.
a
Isolated yields.
2. Results and discussion
It is obvious that solvent plays a crucial role in the organic
reactions; hence, solvents such as toluene, ethanol (EtOH),
dichloromethane (CH2Cl2), dimethylformamide (DMF), and di-
methyl sulfoxide (DMSO) were used either at room temperature or
under reflux conditions. Some results are summarized in Table 1.
Our investigations confirmed that high temperature and utilizing
base were essential for the formation of the corresponding product
3a. Accordingly, different bases such as potassium carbonate
Initially, the reaction of 2-fluoro-5-nitroaniline 1 (1 mmol) and
benzoyl chloride 2a (1 mmol) was selected as a model reaction and
starting materials were allowed to react in various conditions.
Different solvents as well as solvent-free conditions, various bases
and temperature were examined to obtain the best reaction
conditions.
Table 2
Synthesis of 5-nitrobenzoxazole derivatives 3 through the reaction of 2-fluoro-5-nitroaniline 1 and benzoyl chloride derivatives 2.
Entry
Benzoyl chlorides 2
Product 3
Yield (%)a
mp (8C)
Observed
175–177
Reported
1
2
90
176–177 [19]
[DT$LINE]
[TD$LINE]
82
85
90
90
88
85
178–180
187–188
259–261
>250
145–146 [20]
188 [21]
261–262 [22]
–
[DT$LINE]
[TD$LINE]
3
4
5
6
7
[DT$LINE]
[TD$LINE]
[DT$LINE]
[TD$LINE]
[DT$LINE]
[TD$LINE]
217–220
162–164
218–219 [23]
[DT$LINE]
[TD$LINE]
–
[TD$LINE]
[DT$LINE]
8
80
183–185
186–188 [24]
[DT$LINE]
[TD$LINE]
a
Isolated yields.

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M. Vosooghi et al. / Journal of Fluorine Chemistry 161 (2014) 83–86
85
NO2
NO2
O
O2N
NH2
F
O2N
O2N
N
O
N
O
- F
+
Ar
Ar
Ar
Cl
N
H
N
2
F
F
O
4
1
F
3
Ar
O
Ar
Scheme 2. Sequences of the formation of 5-nitrobenzo[d]oxazole derivatives 3.
(K2CO3), triethyl amine (NEt3), piperidine, cesium carbonate
(Cs2CO3), and tripotassium phosphate (K3PO4) were investigated
(Table 1).
As can be seen in Table 1, examination of solvents revealed that
they suppressed or did not improve the reaction and the formation
of desired product. Surprisingly, when the model reaction was
conducted under solvent-free conditions, starting materials were
consumed according to the TLC and after 12 h, the expected
product, 5-nitro-2-phenylbenzo[d]oxazole 3a was obtained in 90%
yield.
Encouraged by these results, we explored the limitations of this
reaction and examined the reactivity of different benzoyl chloride
derivatives (Table 2). It was perceived that all benzoyl chlorides
participated in the reaction proficiently and the cyclized products
were obtained in high yields during 12–13 h. It is noteworthy to
mention that the presence of electron-donating or electron-
withdrawing substituents on the aromatic ring did not affect
significantly the time and yield of reactions. All products were fully
characterized and physical data of known compounds were
compared with those of authentic compounds and found to be
identical.
130 8C. After the completion of reaction (12–13 h, checked by
TLC), the crude product was purified by column chromatography
on silica gel using petroleum ether and ethyl acetate (9:1) as
eluent.
4.1.1. 5-Nitro-2-(p-tolyl)benzo[d]oxazole 3b
2-Fluoro-5-nitroaniline 1 (0.16 g, 1 mmol), 4-methylbenzoyl
chloride 2b (0.15 g, 1 mmol), and potassium carbonate (0.14 g,
1 mmol) gave a crude product that was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 9:1)
gave 5-nitro-2-(p-tolyl)benzo[d]oxazole 3b, 0.21 g (82%), pale
yellow crystals; mp 178–180 8C (145–146 8C [20]). 1H NMR
(400 MHz, DMSO-d6): 8.64 (d, J = 2.4 Hz, 1H, H4), 8.33 (dd,
0
0
J = 8.8, 2.4 Hz, 1H, H6), 8.12 (d, J = 8.0 Hz, 2H, H2 , H6 ), 8.03 (d,
0
0
J = 8.8 Hz, 1H, H7), 7.46 (d, J = 8.0 Hz, 2H, H3 , H5 ), 2.43 (s, 3H, CH3).
13C NMR (100 MHz, DMSO-d6): 165.9, 154.4, 145.5, 143.8, 142.4,
130.5, 128.2, 123.2, 121.8, 115.9, 112.1, 21.7. MS (EI): m/z (%) = 254
(M+, 100), 224 (13), 208 (45), 91 (80), 63 (92). Anal. Calcd for
C14H10N2O3: C, 66.14; H, 3.96; N, 11.02. Found: C, 65.88; H, 4.12; N,
11.17.
It is clear that 2-fluoro-5-nitroaniline 1 reacted with benzoyl
chloride derivative 2 to give the corresponding amide derivative 4
followed by the intramolecular reaction and removal of fluoride
leading to the formation of 5-nitrobenzo[d]oxazole derivatives 3
(Scheme 2).
4.1.2. 2-(4-Fluorophenyl)-5-nitrobenzo[d]oxazole 3e
2-Fluoro-5-nitroaniline
1 (0.16 g, 1 mmol), 4-flurobenzoyl
chloride 2e (0.16 g, 1 mmol), and potassium carbonate (0.14 g,
1 mmol) gave a crude product that was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 9:1)
gave 2-(4-fluorophenyl)-5-nitrobenzo[d]oxazole 3e, 0.23 g (90%),
pale yellow crystals; mp > 250 8C. 1H NMR (400 MHz, DMSO-d6):
8.66 (d, J = 2.4 Hz, 1 H, H4), 8.34 (dd, J = 8.8, 2.4 Hz, 1H, H6), 8.28 (dd,
3. Conclusion
0
0
J = 8.8, 5.2 Hz, 2H, H2 , H6 ), 8.04 (d, J = 8.8 Hz, 1H, H7), 7.50 (t,
In conclusion, we presented an efficient, clean, and user-
friendly method for preparing 5-nitrobenzoxazole derivatives. This
approach involves the reaction of 2-fluoro-5-nitroaniline and
various benzoyl chloride derivatives under solvent-free conditions
at 130 8C in the presence potassium carbonate. The procedure
possesses several advantages over previously reported methods.
No oxidizing agents, expensive catalysts, or microwave irradia-
tions have been utilized. It is worthwhile to mention that better
yields of products and reaction time were obtained under solvent-
free conditions in comparison to using different solvents. Thus,
using solvent-free conditions is vital not only due to environmen-
tally concerns but also it has other advantages.
J = 8.8 Hz, 2H, H3 , H5 ). 13C NMR (100 MHz, DMSO-d6): 164.7 (d,
1JC–F = 152.6 Hz), 163.9, 154.5, 145.5, 142.3, 131.0 (d, JC–
F = 9.2 Hz), 122.6 (d, JC–F = 2.8 Hz), 121.9, 117.2 (d, JC–
F = 22.4 Hz) 116.1, 112.2. Anal. Calcd for C13H7FN2O3: C, 60.47;
H, 2.73; N, 10.85. Found: C, 60.21; H, 2.89; N, 10.68.
0
0
3
4
2
4.1.3. 2-(2-Chlorophenyl)-5-nitrobenzo[d]oxazole 3 g
2-Fluoro-5-nitroaniline 1 (0.16 g, 1 mmol), 2-chlorobenzoyl
chloride 2 g (0.17 g, 1 mmol), and potassium carbonate (0.14 g,
1 mmol) gave a crude product that was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 9:1)
gave 2-(2-chlorophenyl)-5-nitrobenzo[d]oxazole 3 g, 0.23 g (85%),
yellow crystals; mp 162–164 8C. 1H NMR (400 MHz, DMSO-d6):
8.75 (d, J = 2.0 Hz, 1H, H4), 8.38 (dd, J = 8.8, 2.0 Hz, 1H, H6), 8.20 (dd,
4. Experimental
0
All reagents and materials were purchased from commercial
suppliers and used without further purification. Solvents for
extractions, column chromatography and thin layer chromatogra-
phy (TLC) were obtained as commercial grade. Chromatographic
purification of products was performed using Merck silica gel 60
for preparative column chromatography.
J = 8.0, 2.0 Hz, 1H, H3 ), 8.09 (d, J = 8.8 Hz, 1H, H7), 7.77 (dd, J = 8.0,
0
0
2.0 Hz, 1H, H6 ), 7.69 (dt, J = 8.0, 2.0 Hz, 1H, H5 ), 7.62 (dt, J = 8.0,
2.0 Hz, 1H, H4 ). 13C NMR (100 MHz, DMSO-d6): 163.6, 154.1, 145.6,
141.8, 134.2, 132.7, 131.9, 128.4, 127.8, 125.0, 122.4, 116.7, 112.4.
Anal. Calcd for C13H7ClN2O3: C, 56.85; H, 2.57; N, 10.20. Found: C,
56.61; H, 2.73; N, 9.96.
0
Acknowledgment
4.1. General procedure for the synthesis of 5-nitrobenzo[d]oxazole
derivatives 3
The authors gratefully acknowledge the Research Council of
Tehran University of Medical Sciences and Iran National Science
Foundation (INSF).
2-Fluoro-5-nitroaniline 1 (1 mmol), benzoyl chloride derivative
2 (1 mmol), and potassium carbonate (1 mmol) was heated at

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[12] T. Ertan, I. Yildiz, B. Tekiner-Gulbas, K. Bolelli, O. Temiz-Arpaci, S. Ozkan, F.
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