An Efficient and practical synthesis of benzoxazoles from acyl chlorides and 2-aminophenols catalyzed by Lewis acid in(OTf)3 under solvent-free reaction conditions

Article abstract of DOI:10.1002/cjoc.201090287

Benzoxazole derivatives have been prepared through the reaction of substituted 2-aminophenols and acyl chlorides in the presence of catalytic amount of In(OTf)₃ under solvent-free reaction conditions in good to excellent yields. The method is simple, convenient, environmental-friendly, efficient and practical.

Full text of DOI:10.1002/cjoc.201090287

FULL PAPER
An Efficient and Practical Synthesis of Benzoxazoles from Acyl
Chlorides and 2-Aminophenols Catalyzed by Lewis Acid
In(OTf)3 under Solvent-Free Reaction Conditions†
Wang, Boa(王波)
Zhang, Yichenga(张义成)
Wang, Lei*,a,b(王磊)
Li, Pinhuaa(李品华)
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Benzoxazole derivatives have been prepared through the reaction of substituted 2-aminophenols and acyl chlo-
rides in the presence of catalytic amount of In(OTf)3 under solvent-free reaction conditions in good to excellent
yields. The method is simple, convenient, environmental-friendly, efficient and practical.
Keywords benzoxazoles, 2-aminophenols, acyl chlorides, heterocycles, Lewis acid, In(OTf)3, solvent-free
Introduction
rides.15-17 However, the methods suffer from the draw-
backs for the preparation of benzoxazoles, such as the
yields sometimes quite poor18 or in some cases the
rather harsh reaction conditions involved. To develop
milder, convenient and practical approach for the con-
version of 2-aminophenols and acyl chloride into the
corresponding benzoxazoles is desirable.
Five-membered aromatic heterocyclic rings contain-
ing a C＝N bond, such as benzoxazoles, benzothiazoles,
and benzimidazoles, are important structural units in
natural products, and in synthetic pharmaceutical and
agrochemical compounds.1 These compounds have re-
ceived a considerable amount of attention for their bio-
logical and therapeutic activities.2-5 Recently, a survey
showed that only 5% of all reactions achieved in the
process research groups of three major pharmaceutical
companies involve construction of a heteroaromatic
rings.6 Therefore, the development of new methods for
the synthesis of nitrogen-containing heterocycles is still
a focus of intense and continuing interest in the organic
chemistry, as well as in pharmaceutical and agrochemi-
cal chemistry.
The benzoxazoles scaffold (Eq. 1) is found in a vari-
ety of biologically active compounds7 and pharmaceu-
tical agent,8 which have received an extensively atten-
tion in diverse areas of biology and chemistry.9-12 The
reported typical synthetic routes for the synthesis of
benzoxazoles involve the direct condensation of
2-aminophenols with carboxylic acid derivatives,13 and
the copper-catalyzed intramolecular ortho arylation of
o-haloanilides or intermolecular domino annulations of
o-aryl halides with acylamides.14 These methods gener-
ally required the presence of strong acid or additives at
high reaction temperature. To our knowledge, there are
several other reported methods for the direct synthesis
of benzoxazoles from 2-aminophenols and acyl chlo-
The utility of indium(III) salts as Lewis acids in or-
ganic synthesis has received a great deal of interest due
to their relatively low toxicity, stability in air and water,
recyclability, operational simplicity, strong tolerance to
oxygen and nitrogen-containing substrates and func-
tional groups.19 Their potential as Lewis acid catalysts
for fundamental reactions, such as the Diels-Alder,20
Friedel-Crafts,21 Mukaiyama aldol,22 and Sa-
kurai-Hosomi allylation reactions,23 has been exten-
sively investigated. As a part of our program aiming to
develop selective and environmental friendly methods
for the preparation of heterocycles, herein, we wish to
report an In(OTf)3-catalyzed efficient, simple and prac-
tical procedure for the direct synthesis of substituted
*
E-mail: leiwang@hbcnc.edu.cn; Tel.: 0086-0561-3802069; Fax: 0086-0561-3090518
Received January 15, 2010; revised March 28, 2010; accepted April 19, 2010.
Project supported by the National Natural Science Foundation of China (No. 20972057) and the Key Project of Science and Technology of De-
partment of Education, Anhui Province, China (No. ZD2007005-1).
† Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinses Academy of Sciences.
Chin. J. Chem. 2010, 28, 1697— 1703
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Wang et al.
FULL PAPER
benzoxazoles through the reaction of acyl chlorides and
2-aminophenols under solvent-free reaction conditions
(Eq. 1).
while DMF afforded the product only in 15% yield. Use
of CH3NO2, 1,2-dichloroethane, p-xylene, toluene,
CH3CN, C2H5OH and DMSO as solvents led to slower
reactions (Table 1, Entries 1—9). To our delight, 93%
of model product was isolated when the model reaction
was carried out in the absence of any solvent at 110 ℃
for 15 h (Table 1, Entry 10).
Results and discussion
In our preliminarily investigation on the model reac-
tion of 2-aminophenol and benzoyl chloride, it was
found that the reaction could be finished under very
simple reaction conditions in the presence of catalytic
amount of In(OTf)3 (5 mol%) in the absence of any
solvent and additive, which gives the desire benzoxa-
zole product in good yield. The effect of solvent, cata-
lyst, reaction temperature and time on the reaction was
systematically investigated and the results were summa-
rized in Table 1. As can be seen from Table 1, the sol-
vents play an important role in the model reaction. It
was found that dioxane is the best one among the sol-
vents tested, and the reaction proceeded smoothly in
dioxane and gave the desired product in 73% yield,
In the absence of any solvent, among a variety of
catalyst species tested, In(OTf)3 was found to be the
most effective one. InCl, InBr3, InCl3, In(OAc)3, and
InCl2 were used instead of In(OTf)3 as catalyst, but their
efficiencies were lower than that of In(OTf)3, especially
using InCl3, In(OAc)3, and InCl2 as catalysts for the
model reaction (Table 1, Entries 10—15). With respect
to the catalyst loading, when 1 mol%—3 mol% of
In(OTf)3 was used, the reaction did not go to completion,
but a higher loading (5 mol%—10 mol%) of the catalyst
gave a satisfactory results (Table 1, Entries 10, and
18—20). During the course of our further optimization
of the reaction conditions, the reactions were gen-
Table 1 Optimization of the reaction conditionsa
Entry
1
Catalyst/mol%
Solvent/(Temp./℃)
1,2-Dichloroethane/80
DMSO/110
Yieldb/%
62
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
InBr3 (5)
2
24
3
Toluene/110
59
4
CH3CN/80
46
5
DMF/110
15
6
Dioxane/100
73
7
CH3NO2/100
66
8
p-Xylene/110
60
9
C2H5OH/78
44
10
11
12
13
14
15
16
17
18
19
20
21c
22d
23e
Solvent-free/110
Solvent-free/110
Solvent-free/110
Solvent-free/110
Solvent-free/110
Solvent-free/110
Solvent-free/90
Solvent-free/70
Solvent-free/110
Solvent-free/110
Solvent-free/110
Solvent-free/110
Solvent-free/110
Solvent-free/110
93
65
InCl3 (5)
47
InCl2 (5)
21
InCl (5)
83
In(OAc)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (10)
In(OTf)3 (3)
In(OTf)3 (1)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
32
67
41
94
81
54
93
83
74
a
Reaction conditions: 2-aminophenol (0.5 mmol), benzoyl chloride (0.55 mmol), stirred in solvent (1.5 mL) or neat at the temperature
indicated in Table 1 for 15 h. b Isolated yield. c Reaction was conducted for 18 h. d Reaction was conducted for 12 h. e Reaction was con-
ducted for 9 h.
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An Efficient and Practical Synthesis of Benzoxazoles from Acyl Chlorides and 2-Aminophenols
erally complete in a matter of hours, but the time, as
expected, was inversely proportional to the temperature.
A reaction temperature of 110 ℃ for 15 h was found to
be optimal.
benzoyl chlorides containing electron-donating or elec-
tron-withdrawing groups on the benzene rings reacted
with 2-aminophenol smoothly under optimal reaction
conditions to give the desired products. Furthermore,
sterically demanding ortho substituents hampered the
reaction and the corresponding products were obtained
in 78% and 73% yields, respectively (Table 2, Entries 4
and 5). To our delight, cinnamoyl chloride was also
successfully reacted with benzoyl chloride to give the
desired product in good yield (Table 2, Entry 7).
Meanwhile, substituted 2-aminophenols with elec-
tron-donating or middle and weak electron-withdrawing
groups on the benzene rings reacted with benzoyl chlo-
rides to generate the corresponding products in high
yields (Table 2, Entries 8—15). It is important to note
that substituted 2-aminophenols with a strong elec-
tron-withdrawing group, such as nitro group on the
benzene ring, showed lower reactivity than those of ones
with electron-donating groups and middle or weak elec-
tron-withdrawing groups (Table 2, Entry 16).
At a relative low temperature (90, 70 ℃) in the ab-
sence of solvent, 67% and 41% yields were isolated,
respectively (Table 1, Entries 16 and 17). Meanwhile,
experimental data indicated that the reaction was not
completed when reaction time was less than 15 h.
However, no increase in yield was observed when the
reaction time was prolonged (Table 1, Entries 21—23).
The optimized reaction conditions for the reaction were
found to be In(OTf)3 (5 mol%) under solvent-free reac-
tion conditions at 110 ℃ for 15 h.
Having established the optimized reaction conditions,
we turned our attention to explore the scope of this pro-
tocol. The results are listed in Table 2. As shown in Ta-
ble 2, in the most cases, 2-aminophenol reacted with a
wide variety of substituted benzoyl chlorides completely
and afforded the corresponding benzoxazoles in good to
excellent yields (Table 2, Entries 1—6). Substituted
Table 2 Synthesis of benzoxazoles from 2-aminophenols and acyl chloridesa
Entry
1
2-Aminophenol
Acyl chloride
Yieldb/%
93
2
3
4
5
90
95
78
73
6
96
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Wang et al.
FULL PAPER
Continued
Entry
7
2-Aminophenol
Acyl chloride
Yieldb/%
81
83
90
93
92
87
89
82
8
9
10
11
12
13
14
15
16
91
55
a Reaction conditions: 2-aminophenol (0.5 mmol), acyl chloride (0.55 mmol), In(OTf)3 (2.8 mg, 5 mmol%) was stirred at 110 ℃ for 15 h
under solvent-free reaction conditions. b Isolated yield.
A possible mechanism of In(OTf)3-catalyzed reac-
tion of 2-aminophenol with acyl chloride for the synthe-
sis of benzoxazole is shown in Scheme 1. The catalyst
In(OTf)3 would presumably first coordinate with hy-
droxyl group in 2-aminophenol owing to stronger oxy-
philic of In(OTf)3. Meanwhile, monoacylated 2-amino-
phenol, A was formed through the reaction of amino
group with acyl chloride under the present reaction con-
ditions. Then, hydroxyl group in B attacked the carbonyl
group to accomplish intermolecular addition/cyclization
and generated intermediate product C, which followed
by dehydration to form the desired benzoxazole product
D. Further investigation on the mechanism is under way
in our laboratory.
Conclusion
In conclusion, we have developed an In(OTf)3-cata-
lyzed efficient and practical protocol for the synthesis of
benzoxazoles by using various 2-aminophenols and acyl
chlorides as the substrates without any solvent. The re-
actions were performed smoothly to generate the corre-
sponding products in high yields under safe experimen-
tal conditions, and the procedure is simple and conven-
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Chin. J. Chem. 2010, 28, 1697— 1703

An Efficient and Practical Synthesis of Benzoxazoles from Acyl Chlorides and 2-Aminophenols
ient. This method offers one of the important motifs for
synthesis of benzoxazoles, as natural products, biologi-
cally active compounds and pharmaceutical agents.
2-(4-Methylphenyl)benzoxazole10
M.p. 115 —
1
116.5 ℃; H NMR (CDCl3, 400 MHz) δ: 8.14 (d, J＝
8.10 Hz, 2 H), 7.78—7.73 (m, 2 H), 7.59—7.54 (m, 4
H), 7.36—7.31 (m, 4 H), 2.43 (s, 3 H); 13C NMR
(CDCl3, 100 MHz) δ: 163.27, 150.65, 142.13, 142.03,
129.62, 127.56, 124.84, 124.45, 124.36, 119.80, 110.46,
21.62.
Scheme 1
2-(4-Chlorophenyl)benzoxazole11 M.p. 149.5 —
1
151 ℃; H NMR (CDCl3, 400 MHz) δ: 8.20—8.17 (m,
2H), 7.79—7.75 (m, 1H), 7.60—7.55 (m, 1H), 7.51—
7.48 (m, 2H), 7.38—7.34 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ: 162.05, 150.74, 141.99, 137.75, 129.26,
128.83, 125.65, 125.33, 124.73, 120.07, 110.61.
2-(2,4-Dichlorophenyl)benzoxazole24 M.p. 118—
119 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.12 (d, J＝8.55
Hz, 1H), 7.86—7.82 (m, 1H), 7.63—7.59 (m, 2H),
7.43—7.37 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ:
160.07, 150.52, 141.59, 137.53, 134.24, 132.52, 131.29,
127.42, 125.78, 124.80, 124.75, 120.55, 110.76.
2-(2-Chlorophenyl)benzoxazole25 M.p. 70 — 72
℃; 1H NMR (CDCl3, 400 MHz) δ: 8.15 (dd, J＝1.96,
5.53 Hz, 1H), 7.88—7.83 (m, 1H), 7.64—7.60 (m, 1H),
7.59—7.54 (m, 1H), 7.47—7.36 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ: 160.93, 150.56, 141.67, 133.46,
131.87, 131.79, 131.36, 126.89, 126.24, 125.54, 124.62,
120.48, 110.71.
Experimental
2-(3-Chlorophenyl)benzoxazole24 m.p. 131.5 —
Physical measurements and materials
1
All 1H NMR and 13C NMR spectra were recorded on
400 MHz Bruker FT-NMR spectrometers. All chemical
shifts are given as δ value with reference to tetramethyl-
silane (TMS) as an internal standard. Products were pu-
rified by flash chromatography on 230—400 mesh silica
gel, SiO2.
132.5 ℃; H NMR (CDCl3, 400 MHz) δ: 8.17 (br, s,
1H), 8.07—8.04 (m, 1H), 7.72—7.68 (m, 1H), 7.53—
7.49 (m, 1H), 7.43—7.35 (m, 2H), 7.31—7.27 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ: 161.61, 150.75, 141.89,
135.05, 131.45, 130.20, 128.84, 127.59, 125.61, 125.51,
124.79, 120.20, 110.68.
(E)-2-Styrylbenzoxazole11 M.p. 82—84 ℃; 1H
NMR (CDCl3, 400 MHz) δ: 7.76 (d, J＝16.39 Hz, 1H),
7.72—7.69 (m, 1H), 7.57—7.54 (m, 2H), 7.52—7.47 (m,
1H), 7.41—7.34 (m, 3H), 7.33—7.28 (m, 2H), 7.05 (d,
J＝16.37 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ:
162.67, 150.30, 142.10, 139.34, 135.03, 129.65, 128.85,
127.45, 125.09, 124.40, 119.77, 113.83, 110.21.
The chemicals and solvents were purchased from
commercial suppliers either from Aldrich, Fluka (USA
or Shanghai Chemical Company, China), and they were
used without purification prior to use.
General procedure for the synthesis of benzoxazoles
2-Aminophenol (0.5 mmol) and acyl chloride (0.55
mmol) were placed in a sealed vessel containing
In(OTf)3 (2.8 mg, 5 mol%). The reaction mixture was
heated to 110 ℃ for 15 h with stirring under a nitrogen
atmosphere. After cooling, the reaction mixture was
2-(4-Methylphenyl)-5-chlorobenzoxazole26
M.p.
1
135—137 ℃; H NMR (CDCl3, 400 MHz) δ: 8.10 (d,
J＝8.29 Hz, 2H), 7.70 (br, s, 1H), 7.46 (d, J＝8.69 Hz,
1H), 7.33—7.27 (m, 3H), 2.43 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 164.58, 149.23, 143.31, 142.2,
129.89, 129.68, 127.69, 125.05, 123.88, 119.75, 111.13,
21.64.
－
1
treated by a diluted solution of NaOH (1.0 mol•L ).
The solution was extracted with ethyl acetate (3×5.0
mL) and the organic layer was dried over Na2SO4. Then,
the organic solution was concentrated with a rotary
evaporator, and the residue was purified by column
chromatography on silica gel using cyclohexane/ethyl
acetate (V∶V, 9∶1) as eluent to provide the desired
benzoxazole product.
2-(4-Methylphenyl)-5-methylbenzoxazole26 M.p.
1
135.5—137 ℃; H NMR (CDCl3, 400 MHz) δ: 8.14—
8.12 (m, 2H), 7.54—7.53 (m, 1H), 7.44 (d, J＝8.33 Hz,
1H), 7.34—7.31 (m, 2H), 7.16—7.13 (m, 1H), 2.48 (s,
3H), 2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ:
163.36, 148.90, 142.35, 141.86, 134.25, 129.58, 127.50,
125.94, 124.55, 119.74, 109.81, 21.60, 21.49.
1
2-Phenylbenzoxazole11 M.p. 103 — 104 ℃; H
NMR (CDCl3, 400 MHz) δ: 8.27 — 8.26 (m, 2H),
7.79—7.76 (m, 1H), 7.58—7.55 (m, 1H), 7.52—7.50 (m,
3H), 7.35—7.33 (m, 2 H); 13C NMR (CDCl3, 100 MHz)
δ: 162.99, 150.72, 142.06, 131.45, 128.85, 127.58,
127.13, 125.05, 124.53, 119.97, 110.53.
2-(4-Chlorophenyl)-5-methylbenzoxazole27 M.p.
1
145—147 ℃; H NMR (CDCl3, 400 MHz) δ: 8.14 (d,
J＝7.82 Hz, 2H), 7.52 (s, 1H), 7.46 (d, J＝7.66 Hz, 2H),
7.42 (d, J＝7.66 Hz, 1H), 7.14 (d, J＝8.32 Hz, 1H),
Chin. J. Chem. 2010, 28, 1697— 1703
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Wang et al.
FULL PAPER
2.47 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 162.07,
148.96, 142.14, 137.55, 134.55, 129.17, 128.73, 126.44,
125.77, 119.94, 109.92, 21.47.
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2-(4-Methylphenyl)-5-t-butylbenzoxazole
M.p.
1
111—112 ℃; H NMR (CDCl3, 400 MHz) δ: 8.13 (t,
J＝1.70 Hz, 1H), 8.11 (t, J＝1.70 Hz, 1H), 7.79 (br, s,
1H), 7.46—7.44 (m, 1H), 7.38—7.36 (m, 1H), 7.28 (d,
J＝7.81 Hz, 2H), 2.39 (s, 3H), 1.39 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ: 163.33, 148.63, 147.90, 142.02,
141.72, 129.51, 127.40, 124.52, 122.48, 116.30, 109.52,
34.84, 31.71, 21.52. Anal. calcd for C18H19NO: C 81.47,
H 7.22, N 5.28; found C 81.72, H 7.09, N 5.41.
2
2-Phenyl-5-chlorobenzoxazole28 M.p. 102.5—104
℃; 1H NMR (CDCl3, 400 MHz) δ: 8.21—8.19 (m, 2H),
7.71 (d, J＝1.95 Hz, 1H), 7.52—7.44 (m, 4H), 7.29 (q,
J＝1.97, 6.58 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ:
164.27, 149.26, 143.19, 131.83, 129.96, 128.90, 127.68,
126.62, 125.27, 119.91, 111.21.
3
4
5
6
7
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2-Phenyl-5-methylbenzoxazole29 M.p. 104—105
℃; 1H NMR (CDCl3, 400 MHz) δ: 8.19—8.17 (m, 2H),
7.50 (br, s, 1H), 7.45—7.44 (m, 3H), 7.37 (d, J＝8.25
Hz, 1H), 7.08 (d, J＝8.30 Hz, 1H), 2.42 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ: 162.97, 148.89, 142.21,
134.23, 131.22, 128.73, 127.43, 127.23, 126.10, 119.81,
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2-Phenyl-5-t-butylbenzoxazole M.p. 82—83 ℃;
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7.81 (q, J＝0.48, 1.46 Hz, 1H), 7.49—7.37 (m, 5H),
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6.91, N 5.72.
8
9
2-(3-Chlorophenyl)-5-chlorobenzoxazole30
M.p.
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1
152.5—154 ℃; H NMR (CDCl3, 400 MHz) δ: 8.22 (t,
J＝1.68 Hz, 1H), 8.12—8.10 (m, 1H), 7.74 (d, J＝2.18
Hz, 1H), 7.53—7.44 (m, 3 H), 7.34 (dd, J＝2.21, 1.85
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 162.92, 149.34,
143.02, 135.16, 131.87, 130.32, 130.28, 128.37, 127.72,
125.82, 125.76, 120.17, 111.40.
2-(4-Methylphenyl)-6-nitrobenzoxazole30
M.p.
160.5—162 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.38 (br,
s, 1 H), 8.27—8.23 (m, 1H), 8.09 (d, J＝8.11 Hz, 2H),
7.76—7.74 (m, 1H), 7.32 (d, J＝7.73 Hz, 2H), 2.44 (s,
3 H); 13C NMR (CDCl3, 100 MHz) δ: 167.51, 149.63,
147.41, 144.77, 143.68, 129.78, 128.06, 122.97, 120.63,
119.37, 106.93, 21.67.
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