Efficient one-step synthesis of benzazoles in aqueous media

Article abstract of DOI:10.1002/ejoc.200900740

Benzazoles (benzoxazoles, benzothiazoles, and benzimidazoles) were efficiently prepared by the aquatic reaction of the corresponding thioamidinium salts and 2-aminophenol, 2-aminothiophenol, and 1,2-diaminobenzene, respectively. The thioamidinium salt was successfully applied as an alternative to a carboxylic acid derivative to react smoothly with an amino precursor and in the presence of catalytic amounts of hexadecyltrimethylammonium bromide salt to produce benzazoles in good to excellent yields. Wiley-VCH Verlag GmbH & Co. KGaA 2009.

Full text of DOI:10.1002/ejoc.200900740

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900740
Efficient One-Step Synthesis of Benzazoles in Aqueous Media
Hassan Zali Boeini*[a] and Khadijeh Hajibabaei Najafabadi[b]
Keywords: Heterocycles / Organic salts / Acid derivatives / Onium compounds
Benzazoles (benzoxazoles, benzothiazoles, and benzimid-
azoles) were efficiently prepared by the aquatic reaction of
the corresponding thioamidinium salts and 2-aminophenol,
2-aminothiophenol, and 1,2-diaminobenzene, respectively.
The thioamidinium salt was successfully applied as an alter-
native to a carboxylic acid derivative to react smoothly with
an amino precursor and in the presence of catalytic amounts
of hexadecyltrimethylammonium bromide salt to produce
benzazoles in good to excellent yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
The standard approach to the synthesis of benzazole de-
rivatives is cyclocondensation reaction of the corresponding
2-aminophenol, 2-aminothiophenol, or 1,2-diaminoben-
zene with carboxylic acids or derivatives and under some-
what severe reaction conditions.[8] Benzothiazoles can be
also synthesized directly by the reaction of 2-aminothio-
phenol with an aromatic aldehyde under various reaction
conditions.[9] They are also prepared by means of oxidative
cyclization of thiobenzanilides with a large number of oxi-
dizing agents.[10] Recently, a one-step preparation of benz-
oxazole[11] and benzimidazole[12] derivatives by direct oxi-
dation of the respective benzanilides and amidines with air
and/or oxygen and in the presence of catalytic amounts of
copper salts or complexes has been reported. More recently,
transition-metal-catalyzed hydrogen transfer reaction of
alcohols has been utilized for the synthesis of benzazoles in
moderate to very good yields.[13] However, use of expensive
catalysts and rather harsh reaction conditions (refluxing in
toluene) accompanied with long reaction times (8–24 h) are
some disadvantages of this method.
Introduction
Benzazoles are very important compounds due to their
presence in natural products,[1] and their use in medicinal
chemistry[2–5] (Figure 1) and industry.[6–7]
Undoubtedly, thioamides are very important building
blocks in the synthesis of heterocyclic compounds and espe-
cially sulfur heterocycles.[14] To increase the reactivity of
thioamides toward nuleophilic reactions and to block the
sulfur atom in the heterocyclization process, S-alkylation is
often employed. The resulting S-alkylthioamidinium salts
have gained wide applications in the synthesis of five-mem-
bered heterocycles.[15] On the other hand, both the nitrogen
and sulfur atoms of the thioamide moiety in a thioamidin-
ium salt undergo substitution in the reaction with dinucleo-
philic compounds (such as 1,2-diaminobenzene, 2-ami-
nophenol, and 2-aminothiophenol) leading to the corre-
sponding benzo-fused azoles (benzazoles). The only re-
ported procedure for the synthesis of benzazoles from
thioamidinium salts is restricted to 2-arylbenzoxazole and
benzothiazoles.[16] However, the use of reflux conditions in
an environmentally unfriendly and noxious solvent (pyr-
Figure 1. Representative examples of benzazoles in medicinal
chemistry.
[a] Department of Chemistry, University of Isfahan,
81746-73441 Isfahan, Iran
Fax: +98-311-6689732
E-mail: h.zali@chem.ui.ac.ir
[b] Department of Chemistry, University of Isfahan,
81746-73441 Isfahan, Iran
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900740.
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Eur. J. Org. Chem. 2009, 4926–4929

Efficient One-Step Synthesis of Benzazoles in Aqueous Media
idine), the preparation of the thioamidinium salts under reaction course in less polar solvents takes place sluggishly
drastic multi-step reaction conditions, and the rather nar- and produces some tarry materials.
row aryl group scope (only examples with indol-3-yl and
Table 1. Solvent screening in the synthesis of the benzazoles.
pyrrol-2-yl substituents were reported) are other major
drawbacks.
Results and Discussion
Recently, we reported that benzothiazoles could be
formed by oxidative cyclization of thiobenzanilide deriva-
tives.[17] We were eager to synthesize all three kinds of
benzazoles by a unique and environmentally benign method
due to their considerable applications in medicinal and in-
dustrial chemistry. Herein we disclose a novel one-step and
eco-friendly procedure for the synthesis of the three dif-
ferent types of benzazoles (benzoxazole, benzothiazole, and
benzimidazole derivatives) by reaction of the corresponding
2-amino precursors with a suitable S-methylthioamidinium
salt in water and in the presence of a catalytic amount of
hexadecyltrimethylammonium bromide (HTAB) (Scheme 1).
Entry
1
Solvent
Y
Compound
Yield (%)
DMF
EtOH
THF
CHCl3
DMF
EtOH
THF
CHCl3
DMF
EtOH
THF
O
O
O
O
S
S
S
S
NH
NH
NH
NH
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
78
70
51
25
81
73
54
31
72
63
37
17
2
3
CHCl3
According to these results, we were intrigued to investi-
gate the reaction in aqueous media. Surprisingly, it was
found that the reaction course could also be successfully
performed in water and in the presence of hexadecyltrime-
thylammonium bromide (HTAB) to afford benzazoles in
good to excellent yields and in shorter time (40 min). This
approach would remove the requirement for the use of or-
ganic solvents as reaction media and consequently, the reac-
tion course is quite eco-friendly. After optimizing the condi-
Table 2. Efficient synthesis of benzazoles in water.
Scheme 1. Convenient synthesis of benzazoles in water.
Starting thioamides in this study were readily obtained
by the Willgerodt–Kindler reaction of the corresponding
benzaldehydes and quantitatively transformed to the de-
sired S-methylthioamidinium salts by the action of methyl
iodide in THF and at ordinary temperatures. We started
our study with examining the reaction of the S-methyl-
thioamidinium salt 2a as a test substrate with 2-aminophe-
nol, 2-aminothiophenol, and o-phenylenediamine, to pro-
duce 2-phenyl-substituted benzoxazole (3a), benzothiazole
(3b), and benzimidazole (3c), respectively. At the outset of
our study, DMF was used as reaction medium. Therefore,
the starting phenyl S-methylthioamidinium salt and equi-
molar amounts of one of the 2-amino precursors were dis-
solved in small quantities of DMF, and the reaction mixture
was heated at 80 °C to produce the corresponding benz-
azoles in rather good yields. Besides DMF, other solvents
were also examined, and the results indicate a significant
increase of the yields in polar solvents (Table 1). These out-
comes are in accordance with the ionic nature of the
thioamidinium salts and the low solubility of such sub-
Entry
1
Y
2
Ar
Product[a] Ref. Yield (%)[b]
[18]
[18]
[18]
[13]
[18]
[18]
[18]
[18]
[18]
[18]
[18]
[18]
[18]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
a
b
c
a
b
c
a
b
c
a
b
c
a
b
c
a
b
O
S
NH
O
S
NH
O
S
NH
O
S
NH
O
a
a
a
b
b
b
c
c
c
d
d
d
e
e
e
f
Ph
Ph
Ph
4-tolyl
4-tolyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
85
89
75
86
88
70
62
69
59
88
91
76
77
81
71
69
73
4-tolyl
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-Me2NC6H4
4-Me2NC6H4
4-Me2NC6H4
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
4-biphenylyl
4-biphenylyl
S
NH
O
–
[18]
[18]
[18]
S
f
1
[a] All products were characterized by melting points, IR and H
NMR spectroscopy, and their spectroscopic data were similar to
those reported in the literature. [b] All yields refer to pure isolated
strates in less polar solvents. It is also noteworthy that the products.
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H. Zali Boeini, K. Hajibabaei Najafabadi
SHORT COMMUNICATION
Scheme 2. Synthesis of a functionalized benzimidazole.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental procedures, 1H NMR spectroscopic
data (including their copies), and elemental microanalysis for some
compounds.
tions, we next examined the generality of these conditions
to other substrates by using several thioamidinium salts and
2-amino precursors. The results are summarized in Table 2.
A variety of substituted phenyl groups were tolerated on
the thioamidinium salts, and reactions occurred with dif-
ferent 2-amino precursors to lead to 2-aryl-substituted
benzazoles.
Acknowledgments
We are grateful to the University of Isfahan research council for
partial support of this work.
It is also worthwhile to note that the 2-amino precursor
should be dissolved in water prior to addition of the
thioamidinium salt to the reaction mixture. Otherwise, sig-
nificant decrease in the yield of the product is observed.
Our investigations revealed that partial hydrolysis occurred
in this case. In addition, thioamidinium salts bearing elec-
tron-withdrawing groups (Entries 7, 8, 9) had more tenden-
cies to hydrolysis when the reaction was run in water. Inter-
estingly, the presence of a carboxylic acid moiety on the 2-
amino precursor does not affect the efficiency of the reac-
tion. Hence, the reaction of 3,4-diaminobenzoic acid with
the S-methylthioamidinium iodide 2d led to the formation
of corresponding benzimidazole (3r, Scheme 2) in rather
good yield (62%).
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Received: July 4, 2009
Published Online: September 2, 2009
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