One-pot synthesis of 2-substituted benzoxazoles directly from carboxylic acids

Article abstract of DOI:10.1071/CH08193

Methanesulfonic acid has been found to be a highly effective catalyst for a convenient and one-pot synthesis of 2-substituted benzoxazoles by the reaction of 2-aminophenol with acid chlorides, generated in situ from carboxylic acids. Aryl, heteroaryl, and arylalkyl carboxylic acids provided excellent yields of the corresponding benzoxazoles. The reaction conditions were compatible with various substituents such as chloro, bromo, nitro, methoxy, cyclopentyloxy, phenoxy, thiophenoxy, and conjugated double bonds. Benzoxazole formation was found to be general with respect to substituted 2-aminophenols.

Full text of DOI:10.1071/CH08193

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2008, 61, 881–887
One-Pot Synthesis of 2-Substituted Benzoxazoles
Directly from Carboxylic Acids
Dinesh Kumar,A Santosh Rudrawar,A and Asit K. ChakrabortiA,B
ADepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160 062, India.
BCorresponding author. Email: akchakraborti@niper.ac.in
Methanesulfonic acid has been found to be a highly effective catalyst for a convenient and one-pot synthesis of
2-substituted benzoxazoles by the reaction of 2-aminophenol with acid chlorides, generated in situ from carboxylic
acids. Aryl, heteroaryl, and arylalkyl carboxylic acids provided excellent yields of the corresponding benzoxazoles. The
reaction conditions were compatible with various substituents such as chloro, bromo, nitro, methoxy, cyclopentyloxy,
phenoxy, thiophenoxy, and conjugated double bonds. Benzoxazole formation was found to be general with respect to
substituted 2-aminophenols.
Manuscript received: 6 May 2008.
Final version: 14 September 2008.
O
Introduction
H/M ꢀ RBr
N
Compounds bearing the benzoxazole moiety exhibit a broad
spectrum of biological activities, for example, melatonin[1,2]
and the 5-HT3 receptor agonist,[3] the VLA-4 antagonist,[4]
inhibitors of various enzymes involved in the pathophysiology
of different diseases (e.g., fructose-1,6-bisphosphatase,[5]
kinases,[6,7] HIV-1 reverse transcriptase,[8] LPAAT-β,[9]
cyclooxygenase,[10] andelastase[11]), anticancer,[12,13] antimyco-
bacterial,[14–16] antimicrobial, and manopeptimycin glycopep-
tide antibiotics.[17–20] Thus, the benzoxazole moiety has earned
the status of a versatile pharmacophore. Benzoxazoles are also
used as fluorescent brighteners,[21] photochromatic agents,[22]
and laser dyes.[23,24] These have generated interest to develop
various methods to synthesize 2-substituted benzoxazoles by
adopting different synthetic strategies (Scheme 1).[25–34] These
methodologies suffer from the limitations of the preparation/
availability of starting materials (ortho esters, 2-hydroxy/halo/
acyloxyanilides, seleno esters/amides, acid chlorides/fluorides),
use of excess of reagents (Lawssen’s reagent, polyphospho-
ric acid (PPA), pyridinium-p-toluenesulfonate (PPTS), p-TsOH,
HF, PPh3, CBr4, diethyl azodicarboxylate (DEAD), 1,1ꢀ-
carbonyldiimidazole (CDI), N-hydroxybenzotriazole (HOBT),
O-(benzotriazol-1-yl)-N,N,Nꢀ,Nꢀ-tetramethyluronium tetraflu-
oroborate (TBTU), tri-n-butylphosphine (TBP), N,N-di-iso-
propylethylamine(DIPEA), Deoxo-Fluor, Mn(OAc)3, Pb(OAc)4
or PbO2, NiO2, BaMnO4, MnO2-SiO2, PhI(OAc)2, 2,3-
dichloro-5,6-dicyano-1,4-benzoquin−one (DDQ), thianthrene
cation radical perchlorate (Th+•ClO4 ), ionic liquids, metal cat-
alysts, etc.), tedious reaction conditions (heating in a sealed
tube under microwave), long reaction times, and are applica-
ble to the synthesis of 2-aryl substituted benzoxazoles (except
in a few cases). Many of these methodologies require stoi-
chiometric amounts of metal catalysts/oxidants that generate
harmful waste products. Some of the reagents used are corro-
sive in nature (e.g., HF). The use of metal catalysts (employed
in the radical/oxidative cyclization reactions) raises concerns
(d)
O
OH
N
OH
(a)
(b)
Y
W
R
R
ꢀ
R
Z
NH2
N
(c)
X
O
N
H
R
X ꢁ Halogen, OH, OCOR; Y ꢁ OH, Cl, F, OR, OCOR, SMe;
Z ꢁ NH2, NHꢀ2 , O, Se, (OR)2; M ꢁ H, ZnCl; W ꢁ H, CF3;
R ꢁ aryl, alkyl
Scheme 1. Various synthetic strategies for the construction of the benz-
oxazole moiety.
of contamination of the product with trace amounts of metallic
impurities that are detrimental for the determination of biologi-
cal activity of the synthesized benzoxazoles. Thus, a convenient
synthesis of benzoxazoles is still in demand, and herein we report
a one-pot synthesis of 2-substituted benzoxazoles directly from
carboxylic acids.
Results and Discussion
In a continuation of our interest in the development of new syn-
thetic methodologies for benzazoles,[34–37] we thought that a
direct condensation of carboxylic acids with 2-aminophenols
would be a better choice. However, the poor leaving group
property of the hydroxy group necessitates the requirement of
stoichiometric amounts of dehydrating agents such as PPA/PPTS
and stringent reaction conditions (heating at high temperature or
inasealedtubeundermicrowaveirradiation)fortheintermediate
formation of 2-hydroxyanilide and its subsequent cyclodehydra-
tion to construct the benzoxazole moiety (Scheme 2). Thus,
we recently employed microwave heating for the synthesis of
© CSIRO 2008
10.1071/CH08193
0004-9425/08/110881

882
D. Kumar, S. Rudrawar, and A. K. Chakraborti
Harsh condition for
cyclodehydration
OH
O
Dehydrating agent
O
Ar
N
O
Ar
OH
OH
N
H
Ar(R)
NH2
Scheme 2. Route of benzoxazole synthesis from carboxylic acids.
Table 1. Synthesis of 2-phenylbenzoxazole 3a by the reaction of
benzoyl chloride 1 with 2-aminophenol 2a in the presence of various
protic acidsA
O
O
Activating agent
(R)Ar
OH
(R)Ar
X
X ꢁ Cl, F, SH
YieldB,C
[%]
OH
Entry
Protic acid
Amount
[mL (mmol)]
Time
[h]
NH2
1
2
MeSO3H
MeSO3H
4
2
12
1
NilD
94
OH
Dehydrating agent
O
N
O
Ar(R)
3
4
5
6
MeSO3H
MeSO3H
MeSO3H
F3CSO3H
p-TsOH
1 (15.4)
0.5 (7.7)
0.25 (3.85)
0.5 (5.65)
2.5
2
2
4
2
96
95
40
91
N
H
Ar(R)
Scheme 3. Intermediates involved during benzoxazole synthesis from
7
4
35
carboxylic acids in the presence of various agents.
8
9
HClO4 (68% aq.)
HCl (conc.)
HBr (48% aq.)
H2SO4 (conc.)
HBF4 (50% aq.)
Nil
2 (13.53)
2 (65.75)
2 (11.85)
1 (18.76)
1 (5.69)
–
12
12
8
12
12
12
12
65
65
80
50
30
NilE
NilE,F
10
11
12
13
14
2-substituted benzoxazoles by a direct condensation of car-
boxylic acids with 2-aminophenol.[34] However, the evaporative
loss of the starting material/product and decarboxylative decom-
position of the carboxylic acids led to poor yields in some cases
and are limitations of the synthetic potential of this methodol-
ogy. We thought that in-situ activation of the carboxylic acid
might make the hetero-annulation feasible under milder condi-
tions. Only a few methodologies have been reported for a direct
synthesis from carboxylic acids and involve the treatment with
(i) 2 equiv. of Cl3CN and 3 equiv. of PS-PPh3 under microwave
heating;[28] (ii) stoichiometric amounts of SnCl2 in dioxan at
180◦C for 24 h;[38] (iii) 2.6 equiv. of DIPEA, excess K2CO3,
and 2.2 equiv. of Deoxo-Fluor for 2–3 h;[29] and (iv) Lawesson’s
reagent under microwave heating.[25] These procedures involve
the in-situ formation of the acid halide/amide/thiocarboxylic
acid (Scheme 3). The cyclodehydration of 2-hydroxy anilide to
the benzoxazole has recently been reported in carrying out the
reaction with 4 equiv. of PPh3 and 2 equiv. of CBr4 in MeCN
at 60◦C for 2 h.[28] Other methods involved (i) the use of TBP
and DEAD in tetrahydrofuran (THF) for 16 h;[7] (ii) heating at
230◦C under vacuum for 5 h or treatment with 2.5–3 equiv. of
p-TsOH in xylene under reflux for 32 h;[12,13] and (iii) heating
under reflux in xylene in the presence of PPTS.[1,2]
We believed that the reaction of an acid chloride, gener-
ated in situ from the carboxylic acid, with 2-aminophenol may
form the intermediate 2-hydroxyanilide, and subsequent cyclo-
dehydration in the presence of a suitable acid catalyst should
afford the benzoxazole. Thus, the procedure may constitute a
synthesis of benzoxazoles in one pot directly from carboxylic
acids.
In a model study, benzoyl chloride 1 (2.5 mmol) was
treated with 2-aminophenol 2a (2.5 mmol) at 100◦C (oil bath)
under neat conditions and also in dioxan (Table 1). However,
on each occasion no significant conversion into the desired
2-phenylbenzoxazole 3a was observed (TLC, gas chromato-
graphy mass spectrometry (GC-MS)). To follow the progress
of the reactions, aliquots (0.25 mL) of samples were withdrawn
from the reaction mixture after 0.5, 1, and 2 h and diluted
with MeOH (0.25 mL) to quench the reaction. The residues
obtained after removal of the volatile components under reduced
Nil
–
AA mixture of 1 (2.5 mmol) and 2a (2.5 mmol, 1 equiv.) in dioxan (5 mL)
was heated at 100◦C (oil bath) in the presence of various protic acids.
BYield of 3a obtained after purification by column chromatography.
CThe products were characterized by IR and NMR spectroscopies, and MS.
DThe reaction was carried out at room temperature.
EThe reaction mixture contained unreacted 2a (TLC) and amide (IR).
FThe reaction was carried out under neat conditions.
Table 2. Synthesis of 2-phenylbenzoxazoles by the reaction of benzoyl
chloride 1 with 2-aminophenol 2a in the presence of MeSO3H in various
solventsA
Entry
Solvent
Time [h]
YieldB,C [%]
1
2
3
4
5
6
7
8
Dioxan
Xylene
Toluene
THF
MeCN
DMF
2
2
4
4
4
4
4
12
95
89
78
83
55
50
45
NilD
DCE
Neat
AA mixture of 1 (2.5 mmol) and 2a (2.5 mmol, 1 equiv.) in dioxan (5 mL) was
heated at 100◦C (oil bath) in the presence of MeSO3H (0.5 mL, 7.7 mmol,
3 equiv.).
BYield of 2-phenylbenzoxazole 3a obtained after purification by column
chromatography.
CThe product was characterized by IR and NMR spectroscopies, and MS.
DThe 2-hydroxybenzanilide is formed (TLC, IR) and remained unchanged.
pressure were subjected to TLC, IR, and GC-MS analyses.
In case of the reactions carried out under neat conditions,
2a and 1 remained unchanged as determined by TLC and
IR/GC-MS (formation of methyl benzoate in the case of dilu-
tion of the sample with MeOH), and no significant amount
of formation of 3a was observed (TLC, GC-MS). Although
the reactions carried out in dioxan indicated the formation

One-Pot Synthesis of 2-Substituted Benzoxazoles
883
OH
OH
OH
OH
MeSO3H
O
PhCOCl
MeSO3H
N
Ph
(1)
N
H
I
Ph
NH2
OH
2a
II
ꢀ
N
MeSO3H
H
O
Ph
OH
VI
MeSO3H
OMs
OMs
ꢀ
Ph
N
Ph
N
H
III
IV
3a
O
O
OMs
Ph
Ph
N
H
V
N
3a
Scheme 4. The role of MeSO3H in benzoxazole formation during the reaction of PhCOCl with 2a.
of the amide (IR), no detectable (TLC, GC-MS) amounts of
3a were formed even after carrying out the reaction for 12 h.
These observations suggested the need to use a cyclodehydrating
agent to convert the intermediate 2-hydroxyanilide into the
benzoxazole. Reported methodologies require stoichiometric
quantities of costly reagents[1,2,7,12,13,25,28] and harsh reaction
conditions[12,13] that might induce polymerization.[39] Thus, we
planned to use easily available protic acids as catalysts and
we were delighted to observed that 3a was formed in 95%
yield when carrying out the reaction of 1 (2.5 mmol) with 2a
(2.5 mmol) in the presence of MeSO3H (0.5 mL, 7.7 mmol,
3 equiv.) for 2 h. Lesser yields were obtained when using smaller
amounts (0.25 mL) of MeSO3H. The use of other protic acids
afforded inferior results. However, the use of stronger protic
acids such as F3CSO3H afforded comparable results (entry
6, Table 1). The reported procedures for the formation of
2-hydroxyanilide by the reaction of 2a with acid halide required
the presence of bases such as triethylamine (TEA)[40] or
pyridine.[12] However, the use of base may be detrimental for
substrates that bear α-hydrogen atoms due to ketene forma-
tion. The methodologies reported for the cyclocondensation
of acid halides with 2a to form benzoxazoles required either
microwave-assisted dielectric heating[41] or the use of stoi-
chiometric amounts of ionic liquids.[42] However, ionic liquids
are in general costly, and the combustibility[43] and corrosion
behaviour[44] of several ionic liquids raise concerns over the
safety of their use.
To understand the pathway of the benzoxazole formation
during the MeSO3H promoted reactions of 2a with PhCOCl,
aliquots of the sample (0.25 mL) were withdrawn from the reac-
tionmixtureafter0.5, 1, and2 h, dilutedwithMeOH(0.25 mL)to
quench the reaction, and concentrated under reduced pressure.
The crude mixtures were subjected to TLC, IR, and GC-MS
analyses. The amide formation was complete after 1 h. How-
ever, GC-MS revealed that concomitant formation of 3a takes
place after 0.5 h of the addition of the catalyst. This indicates
that perhaps the 2-hydroxyanilide formation is also catalyzed by
MeSO3H.
xylene afforded comparable yields but the use of toluene orTHF
required longer times and afforded lower yields. Inferior results
were obtained in using MeCN, N,N-dimethylformamide (DMF),
and 1,2-dichloroethane (DCE) as solvents. No benzoxazole for-
mation took place under neat conditions (TLC, IR). Although
dioxan and xylene afforded similar yields, in subsequent studies
the reactions were carried out in dioxan to avoid the difficul-
ties in removing high-boiling xylene. The requirement of excess
amounts (3 equiv.) of MeSO3H for the cyclocondensation of
the 2-hydroxyanilide to form the benzoxazole led us to believe
that perhaps MeSO3H is involved in covalent bond formation
with the intermediate 2-hydroxyanilide to provide a better leav-
ing group to make the cyclocondensation facile (Scheme 4). The
in-situ generated 2-hydroxybenzanilide I undergoes an amide–
imine tautomeric change, perhaps catalyzed by MeSO3H. The
iminol II reacts with MeSO3H to form the corresponding mesy-
late III. Protonation of III with MeSO3H forms the immonium
ion IV that undergoes intramolecular nucleophilic attack by the
2-hydroxy group to form the tetrahedral intermediateV followed
by elimination of the MeSO−/MeSO3H, which results in the for-
mation of the benzoxazole 33a.An alternate pathway that involves
the intermediacy of the nitrilium ion VI arising either by a direct
MeSO3H catalyzed/assisted elimination of water from II or of
MeSO−3 from III appears unlikely as the linear configuration
of the phenylnitrilium moiety in VI does not offer appropriate
orientation/geometry for approach of the 2-hydroxy group for
nucleophilic attack at the benzylic position of the phenylnitrilum
moiety.
To determine whether the methodology is applicable to other
acid chlorides, commercially available 4-nitrobenzoyl chloride,
phenylacetyl chloride, and cinnamoyl chloride were considered
as representative electron-deficient aromatic, aryl alkyl, and
α,β-unsaturated acid chlorides, respectively, and treated with
2a in dioxan at 100◦C (oil bath) in the presence of MeSO3H
(Table 3). In each case, the corresponding benzoxazole was
obtained in excellent yields. No competitive side reactions such
as aromatic nucleophilic substitution (of the nitro group in case
of 4-nitrobenzoyl chloride), ketene formation (in case of phenyl-
acetyl chloride), or conjugate addition (in case of cinnamoyl
chloride) took place.
To evaluate the effect of solvent, the reaction was carried out
using other solvents (Table 2). The replacement of dioxan with

884
D. Kumar, S. Rudrawar, and A. K. Chakraborti
Table 3. Synthesis of benzoxazoles by the reaction of 2a with various
acid chloridesA
Table 4. One-pot synthesis of benzoxazoles directly from aryl,
heteroaryl, and arylalkyl carboxylic acidsA
YieldB,C [%]
Entry
1
Acid chloride
O2N COCl
Cl
Time [h]
2
YieldB,C [%]
92
Entry
Acid
Time [h]
R3
CO2H
R2
R1
2
3
2
3
95
95
1
2
3
4
5
6
R1 = R2 = R3 = H
2
2
2
2
2
3
95D
70
60
70
90
85
O
R1 = R2 = H; R3 = Cl
R1 = Cl; R2 = R3 = H
R1 = Br; R2 = R3 = H
R1 = R2 = H; R3 = NO2
R1 = H; R2 = OC5H9-c; R3 = OMe
O
Cl
R
AThe acid chloride (2.5 mmol) was treated with 2a (2.5 mmol, 1 equiv.) in
dioxan (5 mL) at 100◦C (oil bath) in the presence of MeSO3H (0.5 mL,
7.7 mmol, 3 equiv.).
BYield of the benzoxazole obtained after purification by column chromato-
graphy.
7
8
R = 1-CO2H
R = 2-CO2H
2
2
90
82
CThe product was characterized by IR and NMR spectroscopies, and MS.
O
9
3
2
92
85
OH
OH
OH
OH
OH
O
PhCOCl
1
N
N
H
Ph
Ph
NH2
10
2a
I
N
S
CO2H
II
SOCl2
CO2H
11
2
82
OH
Cl
O
N
OH
n
O
Ph
R
N
Ph
3a
12
13
14
R = H, n = 1
2
2
2
95
95
90
R = 3-OMe, n = 1
R = H, n = 2
IIIa
R
Scheme 5. Benzoxazole formation during the reaction of in-situ generated
and commercially available PhCOCl with 2a in the presence of SOCl2.
15
16
R = 1-CH2CO2H
R = 2-CH2CO2H
2
2
90
90
Encouraged by the above results, we further realized that
the lack of commercially available acid chlorides may limit
the generality and is a notable drawback of the reported
procedures.[41,42] Thus, we thought of a direct and one-pot con-
version of carboxylic acids into the corresponding benzoxazoles
by in-situ generation of the acid chloride. In a model study,
phenylacetic acid (2.5 mmol) was treated with SOCl2 (3.0 mmol,
1.2 equiv.) under neat conditions at 80◦C so as to generate
the phenylacetyl chloride. The reaction was monitored for the
consumption of phenylacetic acid (TLC) as well as the formation
of the acid chloride by taking out an aliquot (0.25 mL) of sample
from the reaction mixture, quenching with MeOH (0.25 mL),
followed by TLC and GC-MS and comparing with an authentic
sample of methyl phenylacetate that ensured the in-situ forma-
tion of the acid chloride. After the complete consumption of
phenyl acetic acid (1 h), the excess SOCl2 was distilled off and
the residue was treated with 2a in dioxan (5 mL) in the pres-
ence of MeSO3H (0.5 mL) for 2 h at 100◦C (oil bath). After the
usual workup, the benzoxazole was obtained in 95% yield. We
observed that the acid chloride formation takes place in a shorter
time (0.5 h) when using PhMe as solvent. However, it was pre-
ferred to adopt the in-situ acid chloride formation under neat
conditions when considering the requirement of a longer reac-
tion time for the subsequent step (Table 2, entry 3) and to avoid
the difficulty in the removal of PhMe.
O
X
OH
17
18
X = O
X = S
2.5
2
80
92
AThe carboxylic acid (2.5 mmol) was treated with SOCl2 (3.0 mmol,
1.2 equiv.) at 80◦C for 1 h, followed by distilling off the excess of SOCl2 and
treatment with 2a (2.5 mmol, 1 equiv.) in the presence of MeSO3H (0.5 mL,
7.7 mmol, 3 equiv.) in dioxane with heating at 100◦C (oil bath).
BYield of the benzoxazole obtained after purification by column chromato-
graphy.
CThe product was characterized by IR and NMR spectroscopies, and MS.
DThe product was formed in 89% yield by carrying out the reaction with
F3CSO3H (0.5 mL).
the mesylate III in Scheme 4) and enable formation of 3a by
intramolecular nucleophilic displacement of the chlorine by the
2-hydroxy group (Scheme 5). Thus, in separate experiments,
the in-situ generated (prepared by the treatment of PhCO2H
with 1.5 equiv. of SOCl2 at 80◦C for 1 h under neat condi-
tions) and commercially available PhCOCl were treated with
2a in the presence of an additional amount (3 equiv.) of SOCl2
in dioxan at 100◦C. Although in both cases 3a was formed
after 4 h (TLC), significant amounts of 2-hydroxybenzanilide
We presumed that the use of SOCl2 instead of MeSO3H
may generate the α-chloroimine IIIa (which corresponds to

One-Pot Synthesis of 2-Substituted Benzoxazoles
885
O
O
O
Table 5. One-pot synthesis of benzoxazoles from 4-methyl-
2-aminophenol 2b and 3-amino-2-naphthol 2cA
(i) SOCl2 (4 equiv.),
neat, 80°C, 1 h
OH
OH
O
(a)
(ii) 2a (2 equiv.),
MeSO3H (3 equiv.),
dioxane, 100°C, 3 h
Entry
1
Acid
Aminophenol
Time [h] YieldB,C [%]
O
[No benzoxazole was formed]
OH
3
85
85
87
O
O
CO2H
O
(i) SOCl2 (4 equiv.),
neat, 80°C, 1 h
Me
NH2
OH
OH
(b)
(c)
OH
(ii) 2a (2 equiv.),
MeSO3H (3 equiv.),
dioxane, 100°C, 3 h
2
3
2.5
2
O
O
O
[No benzoxazole was formed]
OH
O
OH
CO2H
(i) SOCl2 (4 equiv.),
neat, 80°C, 1 h
NH2
O
O
N
OH
O
(ii) 2a (2 equiv.),
MeSO3H (3 equiv.),
dioxane, 100°C, 3 h
OH
4
2
82
80%
[No bisbenzoxazole was formed]
OH
O
AThe carboxylic acid (2.5 mmol) was treated with SOCl2 (3.0 mmol,
1.2 equiv.) at 80◦C for 1 h, followed by distilling off the excess of SOCl2 and
treatment with 2b or 2c (2.5 mmol, 1 equiv.) in the presence of MeSO3H
(0.5 mL, 7.7 mmol, 3 equiv.) in dioxan under heating at 100◦C (oil bath).
BYield of the benzoxazole obtained after purification by column chromato-
graphy.
Scheme 6. Reaction of dicarboxylic acids with SOCl2 followed by the
treatment with 2a in the presence of MeSO3H.
remained unreacted. These observations further supported the
role of MeSO3H in the cyclodehydration/hetero-annulation step.
To establish generality, various aromatic, heteroaromatic,
styryl, and arylalkyl carboxylic acids were subjected to this
procedure. Since comparable results are obtained when using
MeSO3H and F3CSO3H, the reactions were carried out using
MeSO3H as it is easily available, less costly, and easier to
handle compared with F3CSO3H. In each case the correspond-
ing benzoxazoles were formed in excellent yields (Table 4).
The procedure was compatible with various substituents such
as halogen atoms, alkoxy, phenoxy, thiophenoxy, nitro, and
α,β-unsaturated carboxylic acid groups. No nucleophilic sub-
stitution of the halogen atom (entries 2–4, Table 4) or the
nitro group (entry 5, Table 4) and aza-/oxa-Michael addition
to an α,β-unsaturated carbonyl moiety (entry 9, Table 4) were
observed. Chemoselective benzoxazole formation took place
with phenoxy/thiophenoxy acetic acids (entries 17 and 18,
Table 4), with no competitive nucleophilc substitution of the
phenoxy/thophenoxy moiety.
We next extended this procedure to dicarboxylic acids such as
succinic acid, phthalic acid, and terephthalic acid so as to prepare
the corresponding bisbenzoxazoles (Scheme 6). In the case of
phthalic acid and succinic acid, no benzoxazole was obtained and
instead the corresponding anhydrides were formed. In the case
of terephthalic acid the corresponding monobenzoxazole was
the only product formed. The bisbenzoxazole was not formed
even after the use of excess of SOCl2 and 4 equiv. of 2a or
the treatment of the isolated monobenzoxazole separately with
SOCl2 and 2a.
CCharacterized by IR and NMR spectroscopies, and MS.
2-aminophenol with acid chlorides, generated in situ from car-
boxylic acids, in one pot demonstrates a direct synthesis of
2-substituted benzoxazoles from carboxylic acids. Benzoxazole
formation was found to be applicable to a large variety of sub-
strates such as aryl, heteroaryl, and arylalkyl carboxylic acids
as well as substituted 2-aminophenols. The compatibility of
the reaction conditions with various substituents (e.g., chloro,
bromo, nitro, methoxy, cyclopentyloxy, phenoxy, thiophenoxy,
and conjugated double bonds) demonstrates chemoselectivity.
Experimental
1H and 13C NMR spectra were recorded on BrukerAvance DPX
300 (300 MHz) spectrometer in CDCl3 using tetramethylsilane
as an internal standard. IR spectra were recorded on Nicolet
Impact 400 spectrometer as KBr pellets for solid samples and
neat for liquid samples. Mass spectra were recorded on a QCP
5000 (Shimadzu) GCMS. The reactions were monitored byTLC
(Merck). Evaporation of solvents was performed under reduced
pressure using a Büchi rotary evaporator. Methanesulfonic
acid, 1-naphthoic acid, 2-naphthoic acid, 1-naphthaleneacetic
acid, 2-naphthaleneacetic acid, terephthalic acid, trans-cinnamic
acid, phenoxyacetic acid, thiophenoxyacetic acid, and 4-
methyl-o-phenylendiamine were procured from Aldrich, India.
Benzoic acid, 4-chlorobenzoic acid, 2-chlorobenzoic acid,
2-bromobenzoic acid, 2-thiophenecarboxylic acid, and succinic
acid were purchased from Loba chemie pvt. Ltd., India. Benzoyl
chloride and phthalic acid were purchased from s d fine-
chem Ltd., India. 4-Nitrobenzoic acid, cinnamoyl chloride, and
pyridine-2-carboxylic acid were from Merck, India.
To claim the generality with respect to substituted
2-aminophenols, a few representative aryl and arylalkyl car-
boxylic acids were subjected to benzoxazole formation with
4-methyl-2-aminophenol 2b and 3-amino-2-naphthol 2c follow-
ing this procedure (Table 5). The corresponding benzoxazoles
were formed in 82–87% yields.
Representative Procedure for the Synthesis of Benzoxazole
from Acid Chloride. 2-Phenylbenzoxazole
(Table 1, Entry 3)
Conclusions
In conclusion, we have developed a convenient synthesis of
benzoxazoles by the reaction of acid chlorides, generated
in situ from carboxylic acids, with 2-aminophenols catalyzed
by MeSO3H. The feasibility of the cyclocondensation of
Benzoyl chloride 1 (348 mg, 2.5 mmol) was treated with
2-aminophenol 2a (272 mg, 2.5 mmol, 1 equiv.) in dioxan (5 mL)
followed by addition of CH3SO3H (0.5 mL, 7.7 mmol, 3 equiv.).

886
D. Kumar, S. Rudrawar, and A. K. Chakraborti
The resultant mixture was stirred magnetically at 100◦C (oil
bath). After complete consumption of 2a (2 h, TLC), the dioxan
was removed by rotary evaporation under reduced pressure and
the residue was diluted with EtOAc (10 mL) followed by satu-
rated aq. NaHCO3 (5 mL). The organic layer was separated and
the aqueous layer extracted with EtOAc (3 × 5 mL). The com-
bined EtOAc extracts were washed with H2O (3 × 5 mL), dried
(anhydrous Na2SO4), and concentrated under reduced pressure
to afford 2-phenylbenzoxazole 3a (463 mg, 95%), analytically
identical (mp, IR, NMR, and MS) with an authentic sample.[34]
νmax (neat)/cm−1 2920, 1620, 1545, 1245. δH (300 MHz, CDCl3)
7.33–7.37 (m, 2H), 7.51–7.54 (m, 3H), 7.56–7.59 (m, 1H), 7.77–
7.79 (m, 1H), 8.25–8.27 (m, 2H). δC (75 MHz, CDCl3) 110.6,
120.0, 124.6, 125.1, 127.2, 127.6, 128.9, 131.5, 142.1, 150.7,
163.0. m/z (APCI) 196.2 (MH+).
168.1, 150.5, 141.9, 135.0, 132.0, 131.8, 129.7, 129.5, 129.0,
128.4, 128.0, 126.0, 125.2, 117.7, 106.9, 36.0. m/z (APCI) 260.5
(MH+). (Found: C 83.37, H 5.05, N 5.40. Calc for C18H13NO:
C 83.35, H 5.08, N 5.44%.)
Reaction with Dicarboxylic Acids. 4-Benzooxazol-
2-ylbenzoic Acid (Scheme 6)
Terephthalic acid (0.41 g, 2.5 mmol) was treated with SOCl2
(357 mg, 0.22 mmol, 1.2 equiv.) at 80◦C until quenching an
aliquot with a few drops of MeOH revealed the complete con-
sumption of terephthalic acid and the appearance of a new spot
(methyl ester) by TLC (2 h). Excess SOCl2 was removed and
the reaction mixture was treated with 2a (272 mg, 2.5 mmol)
in dioxan (5 mL) and CH3SO3H (0.5 mL, 7.7 mmol, 3 equiv.)
by heating under reflux for 3 h. After completion of the reac-
tion, dioxan was removed under rotary evaporation. The residue
was diluted with EtOAc (10 mL) and treated with saturated aq.
NaHCO3 (5 mL). The organic layer was separated and washed
with H2O (3 × 5 mL), dried (anhydrous Na2SO4), and con-
centrated under reduced pressure to afford the title compound
(0.47 g, 80%). White solid, mp 303◦C. νmax (KBr)/cm−1 3802,
3451, 2999, 2542, 2363, 2068, 1683, 1603, 1576, 1449, 1242.
δH (300 MHz, CDCl3) 8.33 (d, J 8.2, 2H), 8.16 (d, J 8.2, 2H),
7.83 (m, 2H), 7.49 (m, 2H). m/z (APCI) 240.2 (MH+). (Found:
C 70.29, H 3.79, N 5.86. Calc for C14H9NO3: C 70.32, H 3.78,
N 5.85%.)
Representative Procedure for a Direct One-Pot
Synthesis of Benzoxazole from Carboxylic Acid.
2-Benzylbenzoxazole (Table 4, Entry 12)
Phenylacetic acid (340 mg, 2.5 mmol) was treated with SOCl2
(357 mg, 3.0 mmol, 0.22 mL, 1.2 equiv.) at 80◦C until quenching
of an aliquot with a few drops of MeOH revealed the com-
plete consumption of phenylacetic acid and appearance of a new
spot (methyl phenylacetate) by TLC (1 h). The excess SOCl2
was distilled off and the reaction mixture was treated with 2a
(272 mg, 2.5 mmol) in dioxan (5 mL) followed by addition of
CH3SO3H (0.5 mL). The resultant mixture was stirred magnet-
ically at 100◦C (oil bath). After complete consumption of 2a
(2 h, TLC), the dioxan was removed by rotary evaporation and
the residue was diluted with EtOAc (10 mL) followed by satu-
rated aq. NaHCO3 (5 mL). The organic layer was separated and
the aqueous layer extracted with EtOAc (3 × 5 mL). The com-
bined EtOAc extracts were washed with H2O (3 × 5 mL), dried
(anhydrous Na2SO4), and concentrated under reduced pressure
to afford 2-benzylbenzoxazole (496 mg, 95%), analytically iden-
tical (mp, IR, NMR, and MS) to an authentic sample.[34] νmax
(neat)/cm−1 3019, 1589, 1405, 1215. δH (300 MHz, CDCl3)
7.64–7.70 (m, 1H), 7.41–7.46 (m, 1H), 7.23–7.39 (m, 7H), 4.25
(s, 2H). δC (75 MHz, CDCl3) 165.1, 151.0, 141.3, 134.7, 126.8,
127.3, 124.6, 124.1, 119.8, 110.4, 35.2. m/z (APCI) 210 (MH+).
The remaining reactions were carried out following this general
procedure. The physical data (mp, IR, NMR, and MS) of the
known compounds were in complete agreement with those of
authentic samples. The following compounds are new.
Acknowledgements
The author (S.R.) thanks DST, New Delhi, India, for the award of Senior
Research Fellowship.
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White solid, mp 80–82◦C. νmax (KBr)/cm−1 2949, 2865, 2360,
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