1,3-Dibromo-5,5-dimethylhydantoin as an efficient homogeneous catalyst for synthesis of benzoxazoles, benzimidazoles, and oxazolo[4,5-b]pyridines

Article abstract of DOI:10.1007/s00706-010-0412-3

A simple and highly efficient method for synthesis of benzoxazoles, benzimidazoles, and oxazolo[4,5-b]pyridines is described. Condensation of orthoesters with o-substituted anilines or 2-amino-3-hydroxypyridine was performed in the presence of catalytic amounts of commercially available, inexpensive, and moisture-stable 1,3-dibromo-5,5-dimethylhydantoin under solvent-free conditions. The corresponding heterocycles were obtained in good to excellent yields. The main advantages of the present procedure are mild reaction conditions, short reaction times, high yields of products, easy work-up, and absence of solvent. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-010-0412-3

Monatsh Chem (2011) 142:87–91
DOI 10.1007/s00706-010-0412-3
ORIGINAL PAPER
1,3-Dibromo-5,5-dimethylhydantoin as an efficient homogeneous
catalyst for synthesis of benzoxazoles, benzimidazoles,
and oxazolo[4,5-b]pyridines
•
Seyedeh Fatemeh Hojati Behrooz Maleki
•
Zahra Beykzadeh
Received: 24 August 2010 / Accepted: 23 October 2010 / Published online: 13 November 2010
Ó Springer-Verlag 2010
Abstract A simple and highly efficient method for
synthesis of benzoxazoles, benzimidazoles, and oxazolo-
[4,5-b]pyridines is described. Condensation of orthoesters
with o-substituted anilines or 2-amino-3-hydroxypyridine
was performed in the presence of catalytic amounts of
commercially available, inexpensive, and moisture-stable
1,3-dibromo-5,5-dimethylhydantoin under solvent-free con-
ditions. The corresponding heterocycles were obtained in
good to excellent yields. The main advantages of the present
procedure are mild reaction conditions, short reaction times,
high yields of products, easy work-up, and absence of
solvent.
[25] with o-substituted anilines, Beckmann rearrangement
of o-acylphenol oximes [26], and photocyclization of phe-
nolic Schiff bases [27]. However, some of these methods
suffer from one or more drawbacks such as strong acidic
conditions, long reaction times, low yields of the products,
tedious work-up, need for excess amounts of reagent, and
use of toxic reagents, catalysts, and/or solvents.
Hence, development of new catalytic methods for syn-
thesis of benzoxazoles, benzimidazoles, and oxazolo[4,5-
b]pyridines in terms of operational simplicity, nontoxicity,
and economical acceptability of the catalyst is of interest.
1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) is a five-
membered heterocycle which has been extensively used as
a brominating and oxidating agent in organic synthesis.
During the last decade, DBDMH has attracted special
attention as an efficient homogeneous catalyst in organic
transformation, because this compound is relatively non-
toxic, commercially available, inexpensive, and insensitive
to air and moisture. Therefore, in continuation of our
studies on preparation of benzoxazoles, benzimidazoles,
and oxazolo[4,5-b]pyridines [28, 29], we were interested in
examining the catalytic ability of DBDMH in the synthesis
of these biologically active heterocycles.
Keywords 1,3-Dibromo-5,5-dimethylhydantoin ꢀ
Benzoxazole ꢀ Benzimidazole ꢀ Oxazolo[4,5-b]pyridine ꢀ
Orthoester
Introduction
Benzoxazoles, benzimidazoles, and oxazolopyridines are
of great interest in diverse areas of chemistry [1–6] because
of their different pharmacological activities such as anti-
viral [7], antibacterial [8], antifungal [9], antiparkinson
[10], anticancer [11], and antibiotic [12] properties. They
have been also used as ligands in asymmetric transforma-
tions [13]. Numerous methods have been reported for
synthesis of these heterocycles, including condensations of
carboxylic acids [14], orthoesters [15–20], acid chlorides
[21], nitriles [22], amides [23], aldehydes [24], and esters
Results and discussion
For optimization of reaction conditions, first, triethyl ortho-
acetate (2b) was reacted with o-aminophenol (1a) in the
presence of DBDMH (Scheme 1). Different molar ratios of
substrate and catalyst, different solvents, absence of sol-
vent, and various temperatures were examined in the model
reaction. The best result was obtained in the reaction of
1 mmol o-aminophenol with 1.1 mmol triethyl ortho-
acetate in the presence 2 mol% of DBDMH at room
S. F. Hojati (&) ꢀ B. Maleki ꢀ Z. Beykzadeh
Department of Chemistry,
Sabzevar Tarbiat Moallem University, Sabzevar, Iran
e-mail: hojatee@yahoo.com
123

88
S. F. Hojati et al.
Scheme 1
NH2
OH
N
DBDMH (2 mol%)
r.t.
CH3
+
3 EtOH
+
CH3C(OEt)3
O
1a
2b
3d (95%)
Table 1 Synthesis of benzoxazoles, benzimidazoles, and oxazolo[4,5-b]pyridines
Entry
1
2
3a
X
Y
R
R0
DBDMH (mol%)
Time (min)
Yield (%)b
M.P. (°C) [Ref]
1
1a
1b
1c
1a
1b
1c
1a
1b
1c
1a
1b
1c
1d
1e
1f
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
O
H
Et
Et
Et
Me
Me
Me
H
2
2
98
90
98
95
85
98
95
85
95
90
92
95
95
95
88
97
93
88
92
90
80
90
88
98
97
98
80
Oil [17]
2
O
Cl
1
2
58–60 [26]
29–31 [26]
Oil [17]
3
O
Me
H
1.5
2
6
4
O
2
5
O
Cl
1
2
52–54 [26]
Oil [26]
6
7c
8c
9c
O
Me
H
2
8
3g
3h
3i
O
2
8
Oil [17]
O
Cl
H
1.5
1
5
34–36 [30]
43–45 [31, 32]
Oil [17]
O
Me
H
H
12
10
10
20
5
10c
11c
12c
13c
14c
15c
16c
17c
18c
19c
20c
21c
22c
23c
24c
25c
26c
27c
a
3g
3h
3i
O
H
2
O
Cl
H
1.5
3
34–36 [30]
43–45 [31, 32]
163–165 [33]
159–161 [34]
150–152 [35]
172–174 [36]
197–199 [34]
188–190 [35]
170–172 [15]
113–115 [37]
184–186 [35]
170–172 [15]
113–115 [37]
50–52 [16]
71–73 [38]
70–72 [16]
70–72 [16]
O
Me
H
H
3j
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
Et
Et
Et
Me
Me
Me
H
1
3k
3l
Me
NO2
H
2
5
3
8
1d
1e
1f
3m
3n
3o
3p
3q
3r
3p
3q
3s
2
5
Me
NO2
H
2
6
3
8
1d
1e
1f
2
7
Me
NO2
H
H
2
8
H
4
12
7
1d
1e
1g
1g
1g
1g
H
2
Me
H
H
2
9
Et
Me
H
1
10
7
3t
O
H
1
3u
3u
O
H
3
20
20
O
H
H
5
Products were identified by comparison of their physical and spectral data with those of authentic samples
b
c
Yields refer to pure products after isolation
Reaction performed at 85 °C
temperature under solvent-free conditions, 2-methylbenz-
o-aminophenols 1a–1c, o-phenylenediamines 1d–1f, or
2-amino-3-hydroxypyridine (1g) under optimized reaction
conditions (Scheme 2). Results showed that all corre-
sponding heterocycles 3a–3u were successfully generated
in high to excellent yields in very short time (Table 1).
As shown in Table 1, 2-ethyl- and 2-methylbenzoxazoles
were produced at room temperature by reaction of
2-aminophenols with trialkyl orthoacetate or trialkyl ortho-
propionate (Table 1, entries 1–6). Trialkyl orthoformates
did not react with o-aminophenols at room temperature, but
the corresponding benzoxazoles were obtained at 85 °C
in high yields (Table 1, entries 7–12). Reactions of
oxazole being obtained in 95% yield after 2 min (Table 1,
entry 4).
To show the catalytic effect of DBDMH, triethyl ortho-
acetate (1.2 mmol) was reacted with o-aminophenol
(1 mmol) in the absence of catalyst at the same reaction
conditions. Analysis of the reaction mixture after 20 min
illustrated that only 5% 2-methylbenzoxazole had been
formed. This result confirms the high catalytic activity of
DBDMH in the current synthesis.
The applicability of this method was investigated
by the reaction of a series of orthoesters 2a–2d with
123

1,3-Dibromo-5,5-dimethylhydantoin as an efficient homogeneous catalyst
89
Scheme 2
NH2
YH
R
X
X
R
N
Y
DBDMH
+
R'C(OR")3
+
R'
3 R"OH
1a-1g
2a-2d
3a-3u
X
Y
R
1
2
R'
Et
Me Et
H
H
R"
Et
a
b
c
d
e
f
a
b
c
d
C
C
C
C
C
C
O
O
O
H
Cl
Me
H
Et
Me
NH
NH Me
NH NO2
g
N
O
H
X
NH2
YH
R
+
OR'
_
R'OBr
R'O
A
Br
_
+ OR'
A
I2
R'OH
C
R
OR'
: OR'
I1
RC(OR')3
_
Br
A
+
DBDMH
OR'
R
X
NH
OR'
:
YH
I3
X
N
Y
R
_
H
Br
R'OH
+
..
N
A
_
+
OR'
+OR
R
X
A
H
X
N
R'OBr
Y
R
..
YH
I5
I4
R'OH
_
O
N
_
O
A
R = H, Me, Et
R' = Me, Et
=
X = C, N
H3C
N
CH3
Y = NH, O
Br
Scheme 3
123

90
S. F. Hojati et al.
Yield (%) [Ref]
Table 2 Comparison of some
other procedures with the
present method for synthesis of
2-methylbenzoxazole (3d) from
triethyl orthoacetate
Entry
Catalyst
Solvent
Reaction conditions
Time
1
2
3
4
5
DBDMH (2 mol%)
ZrOCl2ꢀ8H2O (1 mol%)
KSF (180% w/w)
KSF (180% w/w)
H2SO4 (4 mol%)
–
r.t.
2 min
5 min
12 h
95
–
r.t.
93 [28]
75 [15]
76 [15]
75 [17]
Toluene
Reflux under N2
MW under N2
175–185 °C
–
–
5 min
2 h
o-phenylenediamines or 2-amino-3-hydroxypyridine with
orthoesters were performed at 85 °C under optimized condi-
tions to afford benzimidazoles and oxazolo[4,5-b]pyridines,
respectively (Table 1, entries 13–27).
was added a catalytic amount of DBDMH (1–5 mol%)
according to Table 1. The mixture was stirred at room
temperature or at 85 °C for the appropriate time according to
Table 1. Progress of the reaction was monitored by tin-layer
chromatography (TLC, eluent: n-hexane/ethyl acetate 2:1).
After completion of the reaction, the reaction mixture
was concentrated to afford crude product. Then 10–15 cm3
n-hexane was added, and the mixture was stirred at room
temperature for 5–10 min and then filtered. The solvent
of the filtrate was evaporated to give the corresponding
heterocycle in high to excellent yield (Table 1). All products
were identified by comparing their physical and spectral data
with those reported in the literature.
Although the actual mechanism of reaction is unclear, a
reasonable explanation with respect to the high catalytic
activity of DBDMH and mechanistic operation of DBDMH
in similar reactions is shown in Scheme 3. First, DBDMH
releases a bromium ion, which activates the orthoester
to give I1 and then I2. Nucleophilic attack of aniline or
2-amino-3-hydroxypyridine to the electrophilic center of I2
yields I3. Compound I3 is activated by a bromium ion and
gives I4. Next, an intramolecular nucleophilic attack gen-
erates I5. Finally, elimination of methanol or ethanol from
compound I5 produces the corresponding heterocycle, and
in this step, the bromium ion is released for the next cat-
alytic cycle (Scheme 3).
Acknowledgments The author is grateful to the Research Council
of Sabzevar Tarbiat Moallem University for partial support of this
work.
To show the superiority of the present method over
previous ones, we compared our results with some other
results reported in the literature (Table 2).
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