Cyanide as a powerful catalyst for facile synthesis of benzofused heteroaromatic compounds via aerobic oxidation

Article abstract of DOI:10.1016/j.tet.2013.05.138

Highly efficient synthesis of benzofused heteroaromatic compounds via aerobic oxidation catalyzed by cyanide anion has been developed. The Schiff bases derived from 2-aminophenol and aldehydes provided the corresponding benzoxazoles in high yields in the presence of a catalytic amount of cyanide in an open flask under ambient conditions without the use of any external metal co-oxidants and bases. Furthermore, we have developed a catalytic sequential one-step protocol for the synthesis of benzoxazoles by adding a catalytic amount of NaCN to Schiff bases generated in situ from 2-aminophenol and aldehydes without the isolation of imine intermediates. This one-pot protocol was further extended to the synthesis of benzothiazoles from 2-aminothiophenol and aldehydes. A variety of aldehydes could be applied to this sequential one-pot protocol and the desired benzofused azole products were obtained in high yields.

Full text of DOI:10.1016/j.tet.2013.05.138

Tetrahedron xxx (2013) 1e9
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Cyanide as a powerful catalyst for facile synthesis of benzofused
heteroaromatic compounds via aerobic oxidation
*
Yeon-Ho Cho, Chun-Young Lee, Cheol-Hong Cheon
Department of Chemistry, Korea University, Anam-dong, Seongbuk-gu, Seoul 136701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly efficient synthesis of benzofused heteroaromatic compounds via aerobic oxidation catalyzed by
cyanide anion has been developed. The Schiff bases derived from 2-aminophenol and aldehydes pro-
vided the corresponding benzoxazoles in high yields in the presence of a catalytic amount of cyanide in
an open flask under ambient conditions without the use of any external metal co-oxidants and bases.
Furthermore, we have developed a catalytic sequential one-step protocol for the synthesis of benzox-
azoles by adding a catalytic amount of NaCN to Schiff bases generated in situ from 2-aminophenol and
aldehydes without the isolation of imine intermediates. This one-pot protocol was further extended to
the synthesis of benzothiazoles from 2-aminothiophenol and aldehydes. A variety of aldehydes could be
applied to this sequential one-pot protocol and the desired benzofused azole products were obtained in
high yields.
Received 3 May 2013
Received in revised form 29 May 2013
Accepted 31 May 2013
Available online xxx
Keywords:
Aerobic oxidation
Benzothiazoles
Benzoxazoles
Cyanide
Ó 2013 Elsevier Ltd. All rights reserved.
One-pot reaction
1. Introduction
Benzofused heteroaromatic compounds, in particular benzo-
fused azoles, are important building blocks in biologically and
therapeutically active compounds, natural products, and functional
materials.1 Consequently, a number of methods have been de-
veloped for the synthesis of these important building blocks.2e4
One of the conventional methods for the preparation of the ben-
zofused heteroaromatic compounds involves the condensation of
the corresponding aniline derivatives bearing nucleophilic moiety
(XH in Scheme 1) at the ortho-position with carboxylic acids or
their derivatives followed by cyclization reaction in the presence of
strong acids at high temperature through dehydration (Scheme
1(a)).5 Alternatively, these important building blocks are prepared
via oxidative cyclization of Schiff bases derived from the corre-
sponding ortho-substituted aniline derivatives with aldehydes in
the presence of strong oxidants.6e8 However, this method requires
the use of stoichiometric or excess amounts of strong oxidants as
compared to the respective Schiff base substrates (Scheme 1(b)).
Recently, aerobic oxidations employing oxygen as the ultimate
oxidant have attracted much attention from the synthetic commu-
nity.9 In this regard, several examples of the synthesis of benzofused
azole compounds via aerobic oxidations have been reported.10e12
However, most aerobic oxidation protocols developed generally
Scheme 1. Conventional approaches for the synthesis of benzofused heteroazole
compounds (X¼O, S, and NH).
require toxic metal catalysts and/or excess quantities of bases under
relatively harsh reaction conditions. Thus, the development of
a more efficient method for the synthesis of benzofused hetero-
aromatic compounds via aerobic oxidation under mild conditions is
highly desired.
Recently, we have reported that a nucleophile could act as an
efficient catalyst for the synthesis of benzofused heteroaromatic
compounds through aerobic oxidation. For example, cyanide effi-
ciently converted Schiff bases derived from ortho-aminophenol and
aldehydes to the corresponding benzoxazoles in an open flask
under ambient conditions without using any other metal salts and
bases.13,14 We have also developed a one-pot protocol for the syn-
thesis of benzoxazoles from ortho-aminophenols and aldehydes in
the presence of stoichiometric amount of cyanide without the
isolation of imine intermediates. However, it was observed that the
* Corresponding author. Tel.: þ82 2 3290 3147; fax: þ82 2 3290 3121; e-mail
address: cheon@korea.ac.kr (C.-H. Cheon).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.138
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Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
Table 1
Screening of nucleophiles
yields from the one-pot protocol were somewhat lower than those
from the reactions with the corresponding imines due to benzoin
reactions of the aldehydes in the presence of NaCN.15 In addition,
although the cyanide used for this transformation could be re-
moved by a simple aqueous extraction, the need to use a stoichio-
metric amount of NaCN might lead the synthetic community to be
reluctant to use this protocol. In order to overcome the lower yields
from the one-pot protocol and stoichiometric use of NaCN, we have
developed a more efficient synthetic protocol for the synthesis of
benzoxazoles through the sequential addition of a catalytic amount
of NaCN to Schiff bases generated in situ from aldehydes and ortho-
aminophenols.
Herein we would like to report the development of highly effi-
cient cyanide-catalyzed synthesis of benzoxazoles from the corre-
sponding Schiff bases via aerobic oxidation. We also described the
improved synthetic protocol for the catalytic one-pot synthesis of
benzoxazoles through subsequent addition of a catalytic amount of
NaCN to the Schiff bases generated from 2-aminophenols with al-
dehydes without the isolation of imine intermediates. This se-
quential one-pot method was further extended to the synthesis of
benzothiazoles with 2-aminothiophenol.
Entry
Nucleophile
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
d
96
1
N.R.b
92
NaCN
NaSPh
NaOPh
NaOAc
NaOt-Bu
DMAP
NEt3
24
24
24
24
24
24
1
N.R.b
N.R.b
N.R.b
N.R.b
N.R.b
N.R.b
91
9
KCN
NaCN
10c
48
30
a
Isolated yield.
N.R. means no reaction.
Under argon atmosphere.
b
c
To our delight, the addition of a nucleophile significantly facilitated
the formation of benzoxazole; with a stoichiometric amount of
NaCN the desired product 5a was obtained in quantitative yield at
room temperature in an open flask in 1 h (entry 2), whereas no
oxidative cyclization reaction did proceed in the absence of a nu-
cleophile even after 4 days (entry 1). We further examined the
possibility of other metal salts and nitrogen-based nucleophiles as
catalysts for this transformation (entries 3e8). Rather disappoint-
ingly, no nucleophiles other than cyanide could promote this oxi-
dative cyclization reaction. The counter cation of cyanide displayed
very little difference in the reactivity and KCN was also turned out
to be effective in this transformation (entry 9). In order to confirm
that air is the terminal oxidant, the same reaction was carried out
under an argon atmosphere (entry 10). Under such conditions,
benzoxazole 5a was initially formed but no further conversion was
observed thereafter. We believed that the formation of benzoxazole
5a at the beginning of the reaction might be due to the oxidative
cyclization of Schiff base 3a with the oxygen dissolved in DMF and
the oxidation reaction proceeded until the dissolved oxygen was
completely consumed. Upon the complete consumption of the
dissolved oxygen, however, no further formation of benzoxazole
was observed. These results strongly supported that the air is the
terminal oxidant in this transformation.
2. Results and discussion
Although several methods for the synthesis of benzoxazoles via
aerobic oxidation have been developed,10 most of the aerobic oxi-
dation methods require the use of metal catalysts and super-
stoichiometric amounts of bases under relatively harsh reaction
conditions. Thus, we first attempted to develop a method to prepare
benzoxazoles from Schiff bases through the aerobic oxidative cy-
clization using air as a terminal oxidant under mild reaction con-
ditions without any assistance of metal catalysts and/or bases. It is
generally accepted that the formation of benzoxazole 5 from Schiff
base 3 proceeds in a two-step sequence (Scheme 2).6 The first step is
an equilibrium step between Schiff base 3 and benzoxazoline in-
termediate 4. Benzoxazoline 4 undergoes subsequent oxidation to
afford benzoxazole 5. We hypothesized that under aerobic oxidative
cyclization of Schiff base 3,10 the first equilibrium step might be the
rate determining step for the overall process. In this scenario, if the
rate of the first step were accelerated, the overall reaction rate for
the synthesis of benzoxazole could increase. One way to facilitate
the rate of the first step might be addition of a nucleophile. A more
reactive nucleophile could readilyadd to the imine in Schiff base 3 to
afford intermediate 6, which could more easily undergo a ring
closing reaction to generate benzoxazoline 4 due to the better
leaving ability of the nucleophile. Overall, the nucleophile was ex-
pected to decrease the activation energy for the first equilibrium
step, which eventually facilitates the formation of benzoxazole 5.
Next, other reaction parameters were optimized (Table 2). In-
terestingly, the choice of solvent had a significant effect on the
Table 2
Optimization of reaction conditions
Entry
Solvent
Time (h)
Yield (%)a
1
2
3
4
DMF
Dioxane
THF
1
24
24
24
24
1
8
48
96
92
Trace
Trace
75
EtOH
5
CH3CN
DMSO
DMSO
DMSO
DMSO
70
6b
7b,d
8b,e
9b,f
92 (99)c
93 (99)c
90 (97)c
74 (90)c
a
Scheme 2. Working hypothesis.
Isolated yield.
DMSO-d6 was used.
b
c
The yields in parentheses were determined by 1H NMR analysis of the crude
mixture.
In order to test our working hypothesis, we commenced with
our studies to find a suitable nucleophile to promote this trans-
formation via aerobic oxidation under ambient conditions (Table 1).
d
10 mol % of NaCN was used.
e
f
5 mol % of NaCN was used.
1 mol % of NaCN was used.
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Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
3
reaction rate (entries 1e6). Etherated solvents provided a trace
amount of the product (entries 2 and 3), while several polar sol-
vents gave the desired product 5a in high to excellent yield (entries
4e6). Among the solvents tested, DMF and DMSO turned out to be
the best choice of solvents and the benzoxazole 5a were obtained in
excellent yield in both solvents (entries 1 and 6). Based on our
initial hypothesis, this reaction should intrinsically proceed even
with a catalytic amount of cyanide. Thus, we explored the possi-
bility for the synthesis of benzoxazole with a catalytic amount of
cyanide (entries 6e9). Delightfully, the catalytic amount of cyanide
displayed enough reactivity to promote the reaction and the cata-
lyst loading could be lowered as low as 1 mol % without any sig-
nificant loss of its catalytic efficiency. It should be noted that this
transformation is extremely simple and convenient compared to
the methods previously developed;6,10 benzoxazole formation was
completed using air as the sole oxidant without the use of metal co-
oxidants and bases at room temperature in the presence of a cata-
lytic amount of cyanide and the catalyst loading could be lowered
to 1 mol % without any loss of its efficiency.
One of the drawbacks of the synthesis of benzoxazoles from
Schiff bases via oxidative cyclization is that the imines have to be
prepared prior to the oxidative cyclization reaction.16 We envi-
sioned that as long as cyanide did not interfere in the imine for-
mation reaction (Scheme 2), benzoxazoles could be directly
prepared from ortho-aminophenol and aldehydes without the
isolation of imines.
To test this idea, 2-aminophenol 1, benzaldehyde 2a, and
10 mol % of NaCN were dissolved in DMF and the reaction mixture
was monitored at room temperature in an open flask. However,
under such conditions only a trace amount of benzoxazole 5a was
observed even after a long reaction time (Table 4, entry 1). Since the
low yield was presumably attributed to the inefficient formation of
imine 3a,17 the same reaction was carried out at 60 ꢀC in the
presence of molecular sieves with a stoichiometric amount of
NaCN. Delightfully, the desired benzoxazole 5a was obtained in 78%
yield in 4 h (entry 2). The catalytic amount of NaCN could also af-
ford the desired benzoxazole 5a in comparable yield with the
stoichiometric reaction albeit a longer reaction time (entry 3 vs
entry 2).
Under the optimized conditions, the scope of the reaction with
respect to Schiff bases 3 derived from various aldehydes was in-
vestigated in the presence of 10 mol % of NaCN (Table 3). The
electronic properties of aldehydes (R2 moieties in Schiff bases 3)
had little effect on the formation of benzoxazoles and the desired
products were obtained in high yields regardless of the electronic
natures of the aryl groups (entries 1e6). However, the steric bulk of
aldehydes had a slightly deleterious effect on the reactivity for this
transformation. 20 mol % of NaCN should be used for Schiff bases
from sterically congested aldehydes to get high yields (entries 7, 8,
and 11). It should be noted that several functional groups, such as
ester, ether, and hydroxy groups, were well-tolerated under the
reaction conditions. The electronic properties of ortho-amino-
phenol ring (R1 in Schiff bases 3) also had minimal effect on the
formation of benzoxazoles (entries 12 and 13). Imines derived from
ortho-aminophenols bearing either electron donating or electron
withdrawing substituents provided the desired products in high
yields. In order to demonstrate practicality of this method in the
synthesis of benzoxazoles, we carried out this transformation on
a gram scale. Delightfully, the desired benzoxazole 5a was obtained
in a 10 mmol scale without any loss of its efficiency (entry 14).
Table 4
Optimization of one-pot reaction
Entry
Additive
NaCN (x mol %)
Temp (ꢀC)
Time (h)
Yield (%)a
1
2
d
10
100
10
100
10
rt
24
4
24
1
Trace
78
74
85
87
ꢀ
4 A MS
60
60
rt
ꢀ
3
4 A MS
4b
5b
4 A MS
ꢀ
ꢀ
4 A MS
rt
12
a
Isolated yield.
b
NaCN was added to the imine generated in situ from 1 and 2a at 60 ꢀC for 2 h.
However, it was observed that the yields from the one-pot
protocols with a catalytic and/or stoichiometric amount of NaCN
were lower than those with the corresponding imine 3a (Table 4
entries 2 and 3 vs Table 3, entry 1). In addition, although a 1:1 ra-
tio of 2-aminophenol and benzaldehyde was used, 2-aminophenol
remained even after the complete consumption of benzaldehyde.
We suspected that the slight lower yields from the one-pot protocol
might be due to the interference of cyanide in the imine formation
step. Indeed, cyanide promoted the benzoin reaction with aldehyde
3a and a measurable amount of the benzoin product of aldehyde
2a15 was detected in the reaction mixture (Scheme 3).
Table 3
Substrate scope
Entry
Benzoxazoles 5
Yield (%)a
5
R1
R2
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5a
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
H
Ph
93 (92)b
76
86
78
81
80
80
82
82
81
81
80
84
4-(MeO2C)C6H4
4-ClC6H4
4-(t-Bu)C6H4
4-(Me)C6H4
4-(MeO)C6H4
2-(Me)C6H4
2-(MeO)C6H4
2-(HO)C6H4
2-Naphthyl
1-Naphthyl
Ph
Scheme 3. Formation of benzoin product catalyzed NaCN.
7c
8c
9
10
11c
12
13
14d
In order to overcome the lower yield from the one-pot protocol,
we attempted to subsequently add NaCN to imine 3a generated in
situ from 2-aminophenol 1 and benzaldehyde 2a. Fortunately, this
sequential one-pot protocol provided benzoxazole 5a in higher
yield with both a stoichiometric and a catalytic amount of NaCN
(entries 4 and 5) than the simple one-pot protocol (entries 2 and 3)
and thus we decided to use this sequential one-pot method for
further investigation.
Ph
Ph
85
a
Isolated yield.
100 mol % of NaCN was used.
20 mol % of NaCN was used.
b
c
d
The reaction was carried out in 10 mmol scale.
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4
Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
Under these conditions, we examined the substrate scope for
adding benzaldehyde, 2-aminothiophenol, molecular sieves, and
10 mol % of NaCN all at once in DMF. To our delight, benzothiazole
8a was obtained in 71% yield in an open flask at room temperature
(Scheme 4).
the sequential one-pot protocol for the synthesis of benzoxazoles
from aldehydes and ortho-aminophenols with 10 mol % of NaCN
(Table 5). Imines were easily prepared from aldehydes and ortho-
aminophenols in the presence of molecular sieves at 60 ꢀC and
subsequent addition of a catalytic amount of NaCN afforded the
Table 5
Substrate scope of sequential one-pot protocol for synthesis of benzoxazoles 5
Scheme 4. One-pot synthesis of benzothiazole 8a.
However, we encountered two difficulties in the synthesis of
benzothiazole 8a. First, the yield of 8a was varied from 40 to 70%.
Second, contrary to our initial expectation, the benzoin reaction
still took place under such conditions. Thus, we decided to prepare
benzothiazole 8a by the addition of NaCN to imine 9a generated in
situ from benzaldehyde 2a and 2-aminothiophenol 7. When
benzaldehyde 2a and 2-aminothiophenol 7 were stirred at 60 ꢀC in
the presence of molecular sieves, the corresponding benzothiazo-
line 10a, rather than the imine 9a, was isolated in quantitative yield
(Scheme 5).18
Entry
Benzoxazoles 5
Yield (%)a
5
R1
R2
1
2
3
4
5
6
7
5a
5c
5e
5l
5m
5n
5o
5p
5q
5r
H
H
H
Me
Cl
H
H
H
Ph
87
88
95
82
83
90
88
81
80
76
85
4-ClC6H4
4-MeC6H4
Ph
Ph
2-Furyl
2-Thienyl
tert-Butyl
c-Hexyl
n-Hexyl
Ph
8b
9b
10b
11c
H
H
5a
H
a
Isolated yield.
b
Reaction was carried out through a simple one-pot protocol with a stoichio-
metric amount of NaCN.
c
The reaction was carried out in 10 mmol scale.
Scheme 5. Preparation of benzothiazoline 10a.
desired products in high yields at room temperature. The electronic
properties of aldehydes and/or ortho-aminophenols had little effect
on the formation of benzoxazoles (entries 1e5). Heteroaromatic
aldehydes were also employed in this method and the desired
benzoxazoles were obtained in high yields (entries 6 and 7). We
could extend the method to more challenging aliphatic substrates.
It is generally known that the aliphatic substrates are challenging in
the oxidative cyclization method not only because of instability of
imines of aliphatic aldehydes, but also unwanted side reactions,
such as intermolecular aldol reaction.10d When a catalytic amount
of NaCN was used for aliphatic substrates, the desired benzoxazoles
was obtained in low yield along with many side-products. How-
ever, when a simple one-pot protocol was used for these aliphatic
substrates with a stoichiometric amount of NaCN, aliphatic alde-
hydes afforded the desired 2-alkyl benzoxazoles in high yields
(entries 8e10). It should be noted that aliphatic aldehydes even
In our initial hypothesis (Scheme 2), we anticipated that NaCN
might catalyze this reaction by facilitating conversion of imine 3 to
benzoxazoline 4 rather than the oxidation step. Thus, we were not
sure whether NaCN could facilitate the conversion of benzothia-
zoline 10a into the corresponding benzothiazole 8a. Rather sur-
prisingly, NaCN significantly facilitated the formation of benzo
thiazole 8a from benzothiazoline 10a (Scheme 6).19 Addition of
10 mol % of NaCN to benzothiazoline 10a afforded the corre-
sponding benzothiazole 8a in 87% yield at room temperature in
12 h, whereas benzothiazoline 10a did not undergo any oxidation in
the absence of NaCN even after 24 h.
bearing acidic a-protons were also applied to this one-pot protocol
without any sacrifice of efficiency. In addition, the sequential one-
pot protocol for the synthesis of benzoxazole 5a could be per-
formed on a gram scale, and benzoxazole 5a was obtained in
a similar yield to that obtained from the reaction from the corre-
sponding imine 3a (entry 11).
After successfully developing the cyanide-catalyzed one-pot
protocol for the synthesis of benzoxazoles, we attempted to extend
this aerobic oxidative protocol to the synthesis of benzothiazole 8
with 2-aminothiophenol 7.11 Initially, we expected that the higher
nucleophilicity of the sulfur in 2-aminothiophenol 7 compared to
that of the oxygen in 2-aminophenol 1 might enable us to perform
the synthesis of benzothiazoles at a lower temperature than the
benzoxazole synthesis. We also expected that benzoin reactions of
aldehydes might be prevented or proceed at negligible rate at
a lower reaction temperature. With these expectations in mind, we
attempted to perform the synthesis of benzothiazole 8a from 2-
aminothiophenol 7 and benzaldehyde 2a at room temperature by
Scheme 6. Cyanide-catalyzed conversion of benzothiazoline 10a to benzothiazole 8a.
We have further developed a sequential one-pot synthesis of
benzothiazole 8a through the addition of a catalytic amount of
NaCN to the benzothiazoline 10a generated in situ from aldehyde
2a and 2-aminothiophenol 7 without its isolation (Scheme 7).
Subsequent addition of NaCN (10 mol %) to the above benzothia-
zoline 10a solution afforded benzothiazole 8a in 85%.
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Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
5
presumably because such a 5-endo-trig cyclization is not allowed by
Baldwin’s rule (Scheme 8(a)).20 However, once cyanide was added
to the imine, the lone pair on the oxygen atom in intermediate 6
could be properly oriented to the s* of CeCN bond, and the cycli-
zation reaction more readily take place via an allowed 5-exo-tet
cyclization to generate intermediate 4 (Scheme 8(b)).
Scheme 7. Sequential one-pot synthesis of benzothiazole 8a.
With these conditions in hand, we investigated the generality
and limitation of this protocol for the synthesis of benzothiazoles 8
(Table 6). Various aldehydes could be applied to this protocol and
the desired benzothiazoles 8 were obtained in high yields. The
electronic and steric properties of the aromatic rings in aldehydes
had little effect on the formation of benzothiazoles and the corre-
sponding benzothiazoles were obtained in high yields regardless of
the stereoelectronic properties of the aromatic systems (entries
1e8). Heteroaromatic aldehydes could be also employed in the
sequential one-pot protocol, and the desired benzothiazoles were
obtained in good to high yields (entries 9e10). This method was
further extended to aliphatic aldehydes and the corresponding
benzothiazoles were obtained in synthetically useful yields (entries
11e13). Similar to benzoxazoles from aliphatic aldehydes, a simple
one-pot protocol should be used in the presence of a stoichiometric
amount of NaCN for these aliphatic substrates to avoid unwanted
side-reactions. Notably, a gram scale synthesis of benzothiazole 8a
with this sequential one-pot protocol was possible without loss of
its efficiency (entry 14).
Scheme 8. Possible orbital interaction.
To test this idea we carried out some reactions for the synthesis
of benzoxazole under argon atmosphere (Scheme 9). On addition of
NaCN to imine 3 under argon atmosphere, the imine immediately
disappeared and a Strecker product 11-Na was obtained as the
major product along with some products and no further trans-
formation was observed even after a long reaction time under such
conditions. In addition, when Strecker product 11 prepared in-
dependently21 was treated with NaH, the similar result was ob-
tained. When both reaction mixtures were exposed to air, the
aerobic oxidation rapidly took place to afford the corresponding
benzoxazoles.
Table 6
Substrate scope of sequential one-pot protocol of synthesis of benzothiazoles 8
Entry
Benzothiazoles 8
Yield (%)a
8
R
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
Ph
85 (90)b
80
76
91
95
84
87
79
80
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-MeO2CC6H4
2-MeC6H4
2-MeOC6H4
2-Naphthyl
2-Furyl
Scheme 9. Reaction of imine 3a with NaCN under argon atmosphere.
9
10
11c
12c
13c
14d
8j
8k
8l
8m
8a
2-Thienyl
tert-Butyl
c-Hexyl
n-Hexyl
Ph
58
52
62
57
At that moment, however, we were not sure whether or not
cyanide might be involved in the aerobic oxidation step. Unlike our
initial working hypothesis, cyanide turned out to be involved in the
aerobic oxidation in the benzothiazole synthesis. Thus, we ex-
pected that cyanide would play a similar role in aerobic oxidation
step in the benzoxazole synthesis and be an active catalyst for the
aerobic oxidation in the benzoxazole synthesis.
85
a
Isolated yield.
b
c
100 mol % of NaCN was used.
Reaction was carried out through a simple one-pot protocol with a stoichio-
metric amount of NaCN.
d
The reaction was carried out in 10 mmol scale.
On the other hand, in the benzothiazole synthesis, the higher
nucleophilicity and larger size of sulfur in compound 7 compared
with oxygen in 1 readily undergoes 5-endo-trig cyclization, which
allowed us to isolate benzothiazoline rather than the correspond-
ing imines. Subsequent aerobic oxidation in the presence of cyanide
afforded the benzothiazole under mild reaction conditions. This
increase in the reaction rate for the aerobic oxidation of benzofused
azolines to benzofused azoles is presumably due to increase in the
concentration of oxygen in DMF with NaCN and/or the change in
With these results in hand, we would like to gain information to
elucidate a plausible reaction mechanism for the synthesis of
benzoxazoles 5 and benzothiazoles 8 via aerobic oxidation. In
particular, we attempted to understand the role of cyanide for these
transformations.
First, we tested our initial working hypothesis in which cyanide
might act as a catalyst for the aerobic oxidative cyclization of Schiff
base 3 through the facile conversion of imine 3 to the corre-
sponding benzoxazoline 4. In the absence of cyanide, the lone pair
on the oxygen atom in 3a could not attack the carbon on the imine
oxidation potential in DMF via activation of oxygen with NaCN11a,19
.
Considering these results, we proposed possible reaction
mechanism for the synthesis of benzoxazole 5 and benzothiazole 8
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6
Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
via aerobic oxidation (Scheme 10). Similar to our initial working
hypothesis, anilines 1 and 7 initially form imines 3 and 9 with al-
dehydes. For benzoxazole synthesis, the lower nucleophilicity and
smaller size of oxygen could not allow imine 3 to undergo cycli-
zation reaction via 5-endo-trig cyclization without any assistance of
cyanide. However, the addition of cyanide to the imine 3 furnishes
intermediate 6, which could undergo ring closure through 5-exo-tet
cyclization reaction to yield benzoxazoline 4. Subsequent aerobic
oxidation catalyzed by cyanide generates the desired benzoxazole
3. On the other hand, for the benzothiazole synthesis, the higher
nucleophilicity and larger size of sulfur in imine 9 than the coun-
terpart oxygen in imine 3 make 5-endo-trig cyclization possible to
afford benzothiazoline 10 even in the absence of cyanide. Sub-
sequent cyanide-catalyzed aerobic oxidation of 10 yields the cor-
responding benzothioazole 8.
supplied by MERCK. Yields refer to chromatographically and spec-
trographically pure compounds, unless otherwise noted. 1H NMR
spectra were recorded on Varian Gemini 300 (300 MHz) and 13C
NMR spectra were recorded on Varian Gemini 400 (100 MHz).
Tetramethylsilane and CDCl3 were used as internal standards for 1H
NMR (
were reported as follows
pling constant J, number of protons) and the carbon spectra were
reported only (position of carbon). Multiplicities are indicated by s
d
: 0.0 ppm) and 13C NMR (
(position of proton, multiplicity, cou-
d: 77.16 ppm). The proton spectra
d
d
(singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (heptet),
m (multiplet), and br (broad). Commercial grade reagents and
solvents were used without further purification. Liquid aldehydes
were freshly distilled under an atmosphere of dry argon, and solid
aldehydes were purified by flash chromatography on silica gel.
4.2. General procedures for preparation of imines 3
2-Aminophenol 1 (10. mmol; 1.0 equiv) and aldehyde 2 (10.
mmol; 1.0 equiv) were dissolved in EtOH (80 mL). Then, the re-
action mixture was stirred at 80 ꢀC for 4 h under an argon atmo-
sphere. After 4 h, the reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The crude
product was recrystallized with EtOH. The solid was collected by
filtration and washed with cooled EtOH to give a corresponding
imine 3.
4.2.1. N-Benzylidene-2-hydroxyaniline (3a).22 Yield: 1.2 g (61%).
Brown solid. 1H NMR (300 MHz, CDCl3, ppm)
d 8.71 (s, 1H),
Scheme 10. Proposed reaction mechanism for the synthesis of benzoxazoles 5 and
benzothiazole 8.
7.91e7.95 (m, 2H), 7.49e7.51 (m, 3H), 7.31 (d, J¼7.97 Hz, 1H), 7.21 (t,
J¼8.24 Hz, 1H), 7.02 (d, J¼8.24 Hz, 1H), 6.90 (t, J¼7.43 Hz, 1H).
3. Conclusion
4.2.2. Methyl 4-(((2-hydroxyphenyl)imino)methyl)benzoate (3b).23
Yield: 1.6 g (63%). Yellow solid. 1H NMR (300 MHz, CDCl3, ppm)
We have developed a highly efficient cyanide-catalyzed aerobic
oxidative cyclization protocol of Schiff bases for the synthesis of
benzoxazoles using air as the terminal oxidant at room temperature.
We have also developed the catalytic sequential one-pot protocol
for the synthesis of benzoxazoles by the addition of NaCN to imines
generated in situ from aldehydes and 2-aminophenol. A broad range
of substrates including problematic aliphatic substrates were suc-
cessfully applied to this catalytic system and the desired products
were obtained in high to excellent yields. Moreover, the sequential
one-pot reaction was successfully applied to the preparation of
benzothiazoles with 2-aminothiophenol. Although several aerobic
oxidative cyclization reactions have been developed recently, it is
noteworthy to mention that the catalytic systems developed herein
are remarkably simple, convenient, and efficient compared to the
previous methods reported. Broad substrate scope and easy scale-
up for these syntheses might be advantages for this protocol. Fur-
ther development of synthetic methods for biologically important
heteroaromatic compounds via aerobic oxidation is currently un-
derway in our laboratory.
d
8.67 (s, 1H), 7.82 (d, J¼7.97 Hz, 2H), 7.30 (d, J¼7.69 Hz, 3H), 7.19 (t,
J¼7.69 Hz, 1H), 7.01 (d, J¼7.97 Hz, 1H), 7.02 (t, J¼7.97 Hz, 1H).
4.2.3. N-4-Chlorobenzylidene-2-hydroxyaniline (3c).22 Yield: 1.6 g
(69%). Brown solid. 1H NMR (300 MHz, CDCl3, ppm)
d 8.67 (s, 1H),
7.86 (d, J¼8.52 Hz, 2H), 7.47 (d, J¼8.52 Hz, 2H), 7.30 (d, J¼7.97 Hz,
1H), 7.20 (d, J¼9.34 Hz, 1H), 7.02 (d, J¼8.24 Hz, 1H), 6.91 (d,
J¼7.97 Hz, 1H).
4.2.4. N-4-tert-Butylbenzylidene-2-hydroxyaniline (3d).24 Yield: 1.4 g
(55%). Reddish brown solid.1H NMR (300 MHz, CDCl3, ppm)
d 8.68 (s,
1H), 7.86 (d, J¼8.52 Hz, 2H), 7.47 (d, J¼8.52 Hz, 2H), 7.30 (d,
J¼7.97 Hz, 1H), 7.20 (d, J¼9.34 Hz,1H), 7.02 (d, J¼8.24 Hz,1H), 6.91 (d,
J¼7.97 Hz, 1H).
4.2.5. N-4-Methylbenzylidene-2-hydroxyaniline (3e).22 Yield: 1.4 g
(66%). Dark yellow solid. 1H NMR (300 MHz, CDCl3, ppm)
d 8.71 (s,
1H), 7.86 (d, J¼8.52 Hz, 2H), 7.51 (d, J¼8.52 Hz, 2H), 7.30 (d,
J¼7.97 Hz, 1H), 7.19 (t, J¼8.52 Hz, 1H), 7.01 (d, J¼7.97 Hz, 1H), 6.91 (t,
J¼7.69 Hz, 1H).
4. Experimental section
4.1. General methods
4.2.6. N-4-Methoxybenzylidene-2-hydroxyaniline (3f).22 Yield: 1.4 g
(62%). Brown solid. 1H NMR (300 MHz, CDCl3, ppm)
d 8.63 (s, 1H),
7.88 (d, J¼8.79 Hz, 2H), 7.28 (d, 1H), 7.18 (t, J¼7.69 Hz, 1H), 7.01 (d,
All reactions were carried out in oven- or flame-dried glassware
under air atmosphere unless otherwise noted. Except as otherwise
indicated, all reactions were magnetically stirred and monitored by
analytical thin layer chromatography (TLC) using Merck pre-coated
silica gel glass plates (0.25 mm) with F254 indicator. Visualization
was accomplished by UV light (254 nm), with combination of po-
tassium permanganate and/or phosphomolybdic acid solution as
an indicator. Flash column chromatography was performed
according to the method of Still using silica gel 60 (230e400 mesh)
J¼7.97 Hz, 3H), 6.90 (t, J¼7.69 Hz, 1H), 3.89 (s, 3H).
4.2.7. N-2-Methylbenzylidene-2-hydroxyaniline (3g).22 Yield: 1.3 g
(62%). Dark brown solid. 1H NMR (300 MHz, CDCl3, ppm)
d 9.01 (s,
1H), 8.08 (d, J¼7.42 1H), 7.18e7.41 (m, 4H), 7.02 (d, J¼7.97 Hz, 1H),
6.92 (t, J¼7.42 Hz, 1H), 2.63 (s, 3H).
4.2.8. N-2-Methoxybenzylidene-2-hydroxyaniline (3h).25 Yield: 1.5 g
(66%). Light yellow solid. 1H NMR (300 MHz, CDCl3, ppm)
d 9.19 (s,
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Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
7
1H), 8.16 (d, J¼7.69, 1H), 7.46 (t, J¼7.99 Hz, 1H), 7.33 (d, J¼7.99 Hz,
1H), 7.18 (t, J¼7.99 Hz, 1H), 7.06 (t, J¼7.69 Hz, 1H), 6.99 (t, J¼7.69 Hz,
2H), 6.90 (t, J¼7.99 Hz, 1H), 3.93 (s, 3H).
CDCl3, ppm)
(m, 1H), 7.32e7.38 (m, 4H), 2.45 (s, 3H).
d
8.15 (d, J¼7.97 Hz, 2H), 7.75e7.78 (m, 1H), 7.56e7.59
4.3.6. 2-(4-Methoxyphenyl)-benzoxazole (5f).6g Yield: 90 mg (80%).
Rf¼0.4 (EtOAc/hexanes¼1:7). Yellow solid. 1H NMR (300 MHz,
4.2.9. N-2-Hydroxybenzylidene-2-hydroxyaniline (3i).26 Yield: 1.5 g
(70%). Red solid. 1H NMR (300 MHz, DMSO-d6, ppm)
d
8.95 (s, 1H),
CDCl3, ppm)
d
8.21 (d, J¼8.79 Hz, 2H), 8.21 (d, J¼8.52 Hz, 1H)
7.59 (d, J¼7.69 Hz, 1H), 7.33e7.40 (m, 2H), 7.11 (t, J¼7.69 Hz, 1H),
7.71e7.76 (m, 1H), 7.53e7.58 (t, J¼4.12, 2H), 7.04 (d, J¼8.79 Hz, 2H),
6.93 (t, J¼7.69 Hz, 3H), 6.86 (t, J¼7.69 Hz, 1H).
3.90 (s, 3H).
4.2.10. 2-((Naphthalen-2-ylmethylene)amino)phenol (3j).22 Yield:
4.3.7. 2-(2-Methylphenyl)-benzoxazole (5g).6g Yield: 84 mg (80%).
Rf¼0.6 (EtOAc/hexanes¼1:7). White solid. 1H NMR (300 MHz,
1.7 g (69%). Brown solid. 1H NMR (300 MHz, CDCl3, ppm)
d 8.87 (s,
1H), 8.18e8.22 (m, 2H), 7.89e7.97 (m, 3H), 7.57 (t, J¼3.85 Hz, 3H),
7.34e7.39 (m, 1H), 7.21 (d, J¼7.69 Hz, 1H), 7.05 (d, J¼8.24 Hz, 1H),
6.94 (t, J¼7.69 Hz, 1H).
CDCl3, ppm)
d
8.18 (d, J¼7.14 Hz, 1H), 7.80e7.83 (m, 1H) 7.58e7.61
(m, 1H), 7.35e7.42 (m, 5H), 2.82 (s, 3H).
4.3.8. 2-(2-Methoxyphenyl)-benzoxazole (5h).3b Yield: 92 mg (82%).
Rf¼0.4 (EtOAc/hexanes¼1:7). Light yellow solid. 1H NMR (300 MHz,
4.2.11. 2-((Naphthalen-1-ylmethylene)amino)phenol (3k).22 Yield:
1.6 g (65%). Yellow solid. 1H NMR (300 MHz, CDCl3, ppm)
d
9.40 (s,
CDCl3, ppm)
d
8.14 (d, J¼7.69 Hz, 1H), 7.80e7.84 (m, 1H), 7.58e7.61
1H), 8.88 (d, J¼8.52, 1H), 8.20 (d, J¼7.14, 1H), 8.01 (d, J¼8.24 Hz, 1H),
7.95 (d, J¼7.97 Hz, 1H), 7.56e7.58 (m, 3H), 7.39 (d, J¼7.97 Hz,
1H), 7.23 (d, J¼7.69 Hz, 1H), 7.06 (d, J¼7.97 Hz, 1H), 6.97 (t,
J¼7.69 Hz, 1H).
(m, 1H), 7.51 (t, J¼7.69 Hz, 1H), 7.33e7.36 (m, 2H), 7.11 (t, J¼7.97 Hz,
2H), 4.03 (s, 3H).
4.3.9. 2-(2-Hydroxyphenyl)-benzoxazole (5i).5h Yield: 87 mg
(82%). Rf¼0.5 (EtOAc/hexanes¼1:5). White solid. 1H NMR
4.2.12. N-Benzylidene-2-hydroxy-5-methylaniline (3l).22 Yield: 1.5 g
(300 MHz, CDCl3, ppm)
d
8.04 (dd, J¼7.97, 1.37 Hz, 1H), 7.73e7.76
(71%). Yellow solid. 1H NMR (300 MHz, CDCl3, ppm)
d
8.69 (s, 1H),
(m, 1H), 7.61e7.64 (m, 1H), 7.45 (td, J¼8.52, 1.65 Hz,
1H), 7.38e7.41 (m, 2H), 7.13 (d, J¼8.24 Hz, 1H), 7.02 (t,
J¼7.42 Hz, 1H).
7.91e7.95 (m, 2H), 7.49e7.51 (m, 3H), 7.13 (s, 1H), 7.02 (d, J¼7.97 Hz,
1H), 6.91 (d, J¼8.24 Hz, 1H), 2.32 (s, 3H).
4.2.13. N-Benzylidene-2-hydroxy-5-chloroaniline
1.6 g (69%). Brown solid. 1H NMR (300 MHz, CDCl3, ppm)
(3m).26 Yield:
8.67 (s,
4.3.10. 2-(2-Naphthyl)-benzoxazole (5j).4b Yield: 99 mg (81%).
Rf¼0.6 (EtOAc/hexanes¼1:10). Yellow solid. 1H NMR (300 MHz,
d
1H), 7.91e7.95 (m, 2H), 7.49e7.54 (m, 3H), 7.30 (d, J¼2.47 Hz, 1H),
CDCl3, ppm)
d
8.80 (s, 1H), 8.33 (d, J¼8.52 Hz, 1H) 7.98e8.00 (m,
7.16 (dd, J¼8.52, 2.47 Hz, 1H), 7.95 (d, J¼8.52 Hz, 1H).
2H), 7.89e7.92 (m, 1H), 7.81e7.84 (m, 1H), 7.57e7.65 (m, 3H),
7.37e7.40 (m, 2H).
4.3. General procedures for synthesis of benzoxazoles 5 from
imines 3 (Table 3)
4.3.11. 2-(1-Naphthyl)-benzoxazole (5k).6g Yield: 1.0ꢁ102 mg
(81%). Rf¼0.6 (EtOAc/hexanes¼1:10). Yellow solid. 1H
An imine 3 (0.50 mmol: 1.0 equiv) and NaCN (2.5 mg;
0.050 mmol; 10 mol %) were dissolved in DMF (2.0 mL). The reaction
mixture was stirred at room temperature in an open flask and
monitored by TLC. On the complete consumption of the imine, the
reaction mixture was quenched with H2O, and extracted with Et2O.
The organic layer was collected, dried over MgSO4, and concentrated.
The crude product was purified by column chromatography on silica.
NMR (300 MHz, CDCl3, ppm)
d
9.48 (d, J¼8.79 Hz, 1H), 8.44
(d, J¼7.42 Hz, 1H), 8.05 (d, J¼8.24 Hz, 1H), 7.95 (d,
J¼8.24 Hz, 1H), 7.88e7.91 (m, 1H), 7.58e7.75 (m, 4H), 7.39e7.43
(m, 2H).
4.3.12. 5-Methyl-2-phenylbenzoxazole
(5l).6g Yield:
84
mg
(80%). Rf¼0.6 (EtOAc/hexanes¼1:7). Light yellow solid. 1H
NMR (300 MHz, CDCl3, ppm)
d 8.23e8.26 (m, 2H), 7.51e7.56
4.3.1. 2-Phenylbenzoxazole (5a).6g Yield: 91 mg (93%), 90 mg (92%,
100 mol % NaCN). Rf¼0.6 (EtOAc/hexanes¼1:7). White solid. 1H
(m, 4H), 7.46 (d, J¼8.24 Hz, 1H), 7.16 (d, J¼8.24 Hz, 1H), 2.49
(s, 3H).
NMR (300 MHz, CDCl3, ppm)
d 8.26e8.28 (m, 2H), 7.77e7.80 (m,
1H), 7.58e7.61 (m, 1H), 7.53e7.57 (m, 3H), 7.35e7.38 (m, 2H).
4.3.13. 5-Chloro-2-phenylbenzoxazole (5m).6g Yield: 96 mg (84%).
Rf¼0.6 (EtOAc/hexanes¼1:7). White solid. 1H NMR (300 MHz,
4.3.2. 2-(4-Acetylphenyl)-benzoxazole (5b).4b Yield: 96 mg (76%).
Rf¼0.3 (EtOAc/hexanes¼1:7). White solid.1H NMR (300 MHz, CDCl3,
CDCl3, ppm)
(m, 4H), 7.33 (dd, J¼8.52, 1.92 Hz, 1H).
d
8.23e8.26 (m, 2H), 7.75 (d, J¼1.65 Hz, 1H), 7.50e7.56
ppm)
d
8.34 (d, J¼8.24 Hz, 2H), 8.21 (d, J¼8.52 Hz, 2H) 7.80e7.83 (m,
1H), 7.60e7.63 (m, 1H), 7.38e7.42 (m, 2H), 3.97 (s, 3H).
4.4. General procedures for synthesis of benzoxazoles 5 via
catalytic sequential one-pot protocol (Table 5)
4.3.3. 2-(4-Chlorophenyl)-benzoxazole (5c).6g Yield: 87 mg (76%).
Rf¼0.6 (EtOAc/hexanes¼1:10). Light red solid. 1H NMR (300 MHz,
2-Aminophenol 1 (21.8 mg; 0.20 mmol; 1.0 equiv) and alde-
hyde 2 (0.20 mmol; 1.0 equiv), and molecular sieve (10 mg)
were dissolved in DMF (1.0 mL). The reaction mixture was stir-
red in an open flask at 60 ꢀC. On complete formation of
the corresponding imine, the mixture was cooled to room tem-
perature and NaCN (1.0 mg; 0.020 mmol; 10 mol %) was added to
the above reaction mixture and the reaction mixture was mon-
itored by TLC. After complete consumption of the corresponding
imine, the reaction mixture was concentrated under reduced
pressure. The crude product was purified by column chroma-
tography on silica to give the corresponding benzoxazole prod-
uct 5.
CDCl3, ppm)
d
8.20 (d, J¼8.24 Hz, 2H), 7.76e7.79 (m, 1H), 7.57e7.61
(m, 1H), 7.51 (d, J¼8.79 Hz, 2H) 7.36e7.39 (m, 2H).
4.3.4. 2-(4-tert-Butylphenyl)-benzoxazole (5d).2g Yield: 99 mg
(78%). Rf¼0.7 (EtOAc/hexanes¼1:10). Brown solid. 1H NMR
(300 MHz, CDCl3, ppm)
d
8.19 (d, J¼8.52 Hz, 2H), 7.75e7.78 (m, 1H),
7.58e7.60 (m, 1H), 7.55 (d, J¼8.52 Hz, 2H), 7.33e7.36 (m, 2H), 1.39
(s, 9H).
4.3.5. 2-(4-Methylphenyl)-benzoxazole (5e).6g Yield: 85 mg (81%).
Rf¼0.6 (EtOAc/hexanes¼1:7). Yellow solid. 1H NMR (300 MHz,
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8
Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
4.4.1. 2-Phenylbenzoxazole (5a).6g Yield: 33 mg (85%). White solid.
1H NMR spectrum was in good agreement with those of 5a ob-
tained via the oxidative cyclization of imine 3a.
d
8.09e8.13 (m, 3H), 7.92 (d, J¼7.97 Hz, 1H), 7.49e7.52 (m, 4H), 7.40
(t, J¼7.69 Hz, 1H).
4.5.2. 2-(4-Methoxyphenyl)-benzothiazole (8b).2h Yield: 39 mg
(80%). Rf¼0.4 (EtOAc/hexanes¼1:9). Yellow solid. 1H NMR
4.4.2. 2-(4-Chlorophenyl)-benzoxazole (5c).6g Yield: 40 mg (86%).
Light red solid. 1H NMR spectrum was in good agreement with
those of 5c obtained via the oxidative cyclization of imine 3c.
(300 MHz, CDCl3, ppm)
d
8.02e8.05 (m, 3H), 7.88 (d, J¼7.97 Hz, 1H),
7.47 (t, J¼7.14, 1H), 7.36 (t, J¼7.14, 1H), 7.00 (d, J¼8.79 Hz, 2H), 3.89
(s, 3H).
4.4.3. 2-(4-Methylphenyl)-benzoxazole (5e).6g Yield: 37 mg (89%).
Yellow solid. 1H NMR spectrum was in good agreement
with those of 5e obtained via the oxidative cyclization of
imine 3e.
4.5.3. 2-(4-Methylphenyl)-benzothiazole (8c).2h Yield: 34 mg (76%).
Rf¼0.6 (EtOAc/hexanes¼1:9). Light yellow solid. 1H NMR (300 MHz,
CDCl3, ppm)
d
d
8.06 (d, J¼7.97 Hz, 1H),
d
7.99 (d, J¼8.24 Hz, 2H),
7.90 (d, J¼7.69 Hz, 1H), 7.49 (t, J¼7.14 Hz, 1H), 7.37 (t, J¼7.14 Hz,
4.4.4. 5-Methyl-2-phenylbenzoxazole (5l).6g Yield: 38 mg (90%).
Light yellow solid. 1H NMR spectrum was in good agreement with
those of 5l obtained via the oxidative cyclization of imine 3l.
1H), 7.30 (d, J¼7.97 Hz, 2H), 2.43 (s, 3H).
4.5.4. 2-(4-Chlorophenyl)-benzothiazole (8d).2h Yield: 45 mg (91%).
Rf¼0.6 (EtOAc/hexanes¼1:9). Light yellow solid. 1H NMR (300 MHz,
4.4.5. 5-Chloro-2-phenylbenzoxazole (5m).6g Yield: 41 mg (89%).
White solid. The spectroscopic data were in good agreement
with those of 5m obtained via the oxidative cyclization of
imine 3m.
CDCl3, ppm)
d
8.02e8.09 (m, 3H), 7.92 (d, J¼7.97 Hz, 1H), 7.46e7.54
(m, 3H), 7.41 (t, J¼7.97 Hz, 2H).
4.5.5. 2-(4-Acetylphenyl)-benzothiazole (8e).2h Yield: 51 mg (95%).
Rf¼0.4 (EtOAc/hexanes¼1:7). Yellow solid. 1H NMR (300 MHz,
4.4.6. 2-(2-Furyl)-benzoxazole (5n).10d Yield: 33 mg (90%). Rf¼0.6
(EtOAc/hexanes¼1:5). Dark brown solid. 1H NMR (300 MHz, CDCl3,
CDCl3, ppm)
d
8.17 (m, 4H), 8.11 (d, J¼7.97 Hz, 1H), 7.94 (d,
J¼7.69 Hz, 1H), 7.53 (t, J¼7.42 Hz, 1H), 7.43 (t, J¼7.42 Hz, 1H), 3.97
ppm)
d
7.75e7.78 (m, 1H), 7.67 (s, 1H), 7.55e7.58 (m, 1H), 7.34e7.37
(s, 3H).
(m, 2H), 7.28 (d, J¼3.57 Hz, 1H), 6.62e6.63 (m, 1H).
4.5.6. 2-(2-Methylphenyl)-benzothiazole (8f).2h Yield: 38 mg (84%).
Rf¼0.5 (EtOAc/hexanes¼1:9). Yellow solid. 1H NMR (300 MHz,
4.4.7. 2-(2-Thienyl)-benzoxazole (5o).4b Yield: 34 mg (86%). Rf¼0.6
(EtOAc/hexanes¼1:5). Red-brown solid. 1H NMR (300 MHz, CDCl3,
CDCl3, ppm)
d
8.11 (d, J¼7.97 Hz, 1H), 7.94 (d, J¼7.97 Hz, 1H), 7.76 (d,
ppm)
d
7.92 (d, J¼3.57 Hz,1H), 7.72e7.75 (m,1H), 7.54e7.57 (m, 2H),
J¼7.69 Hz, 1H), 7.52 (t, J¼7.14 Hz, 1H), 7.42 (t, J¼7.14 Hz, 1H),
7.30e7.36 (m, 3H), 2.66 (s, 3H).
7.33e7.36 (m, 2H), 7.20 (t, J¼4.67 Hz, 1H).
4.4.8. 2-(tert-Butyl)-benzoxazole (5p).10d Yield: 28 mg (81%). Rf¼0.7
4.5.7. 2-(2-Methoxyphenyl)-benzothiazole (8g).2e Yield: 40 mg
(83%). Rf¼0.4 (EtOAc/hexanes¼1:9). White solid. 1H NMR
(EtOAc/hexanes¼1:10). Colorless oil. 1H NMR (300 MHz, CDCl3,
ppm)
d
7.68e7.71 (m, 1H), 7.47e7.50 (m, 1H), 7.28e7.31 (m, 2H),
(300 MHz, CDCl3, ppm)
d
8.53 (dd, J¼7.69, 1.65 Hz, 1H), 8.09 (d,
1.50 (s, 9H).
J¼7.97 Hz, 1H), 7.93 (d, J¼7.97 Hz, 1H), 7.44e7.52 (m, 2H), 7.37 (t,
J¼7.69 Hz, 1H), 7.14 (t, J¼7.69 Hz, 1H), 7.08 (d, J¼8.52 Hz, 1H), 4.07
(s, 3H).
4.4.9. 2-Cyclohexylbenzoxazole (5q).10e Yield: 33 mg (80%). Rf¼0.6
(EtOAc/hexanes¼1:10). Light yellow oil. 1H NMR (300 MHz, CDCl3,
ppm)
d
7.67e7.70 (m, 1H), 7.46e7.49 (m, 1H), 7.28e7.31 (m, 2H),
4.5.8. 2-(2-Naphthyl)-benzothiazole (8h).2e Yield: 41 mg (79%).
Rf¼0.6 (EtOAc/hexanes¼1:10). Yellow solid. 1H NMR (300 MHz,
2.92e3.00 (m, 1H), 2.15e2.19 (m, 2H), 1.60e1.89 (m, 5H), 1.24e1.49
(m, 3H).
CDCl3, ppm)
d
8.58 (s, 1H), 8.22 (dd, J¼8.52, 1.65 Hz, 1H), 8.12 (d,
J¼7.97 Hz, 1H), 7.94e8.00 (m, 3H), 7.88e7.91 (m, 1H), 7.55e7.58 (m,
4.4.10. 2-Hexylbenzoxazole (5r).10d Yield: 31 mg (76%). Rf¼0.7
(EtOAc/hexanes¼1:10). Colorless oil. 1H NMR (300 MHz, CDCl3,
2H), 7.51 (d, J¼7.14 Hz, 1H), 7.42 (t, J¼7.14 Hz, 1H).
ppm)
d
7.65e7.68 (m, 1H), 7.46e7.49 (m, 1H), 7.28e7.31 (m, 2H),
4.5.9. 2-(2-Furyl)-benzothiazole (8i).7b Yield: 32 mg (79%). Rf¼0.5
(EtOAc/hexanes¼1:9). Light brown solid. 1H NMR (300 MHz, CDCl3,
2.93 (t, J¼7.42 Hz, 2H), 1.89 (p, J¼7.69 Hz, 2H), 1.30e1.45 (m, 6H),
0.89 (s, 3H).
ppm)
d
8.05 (d, J¼7.97 Hz, 1H), 7.90 (d, J¼7.97 Hz, 1H), 7.61 (s, 1H),
7.50 (t, J¼7.14 Hz, 1H), 7.39 (t, J¼7.14 Hz, 1H), 7.20 (d, J¼3.30 Hz, 1H),
4.5. General procedures for synthesis of benzothiazoles 8
(Table 6)
6.61 (m, 1H).
4.5.10. 2-(2-Thionyl)-benzothiazole (8j).7b Yield: 25 mg (58%).
Rf¼0.5 (EtOAc/hexanes¼1:9). Light brown solid. 1H NMR (300 MHz,
2-Aminothiophenol 7 (25 mg; 0.20 mmol; 1.0 equiv) and al-
dehyde 2 (0.02 mmol; 1.0 equiv), and molecular sieve (10 mg)
were dissolved in DMF (1.0 mL). The reaction mixture was stirred
at 60 ꢀC. After the complete consumption of the aldehyde,
the mixture was cooled to room temperature and NaCN (1.0 mg;
0.020 mmol; 10 mol %) was added to the above reaction
mixture and the reaction progress was monitored by TLC. On
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The crude product was purified by col-
umn chromatography on silica to give the corresponding benzo-
thiazole 8.
CDCl3, ppm)
d
8.03 (d, J¼7.97 Hz,1H), 7.86 (d, J¼7.97 Hz,1H), 7.66 (d,
J¼3.57 Hz, 1H), 7.45e7.52 (m, 2H), 7.37 (t, J¼7.14 Hz, 1H), 7.14 (t,
J¼3.85 Hz, 1H).
4.5.11. 2-(tert-Butyl)-benzothiazole (8k).10d Yield: 20 mg (52%).
Rf¼0.7 (EtOAc/hexanes¼1:10). Colorless oil. 1H NMR (300 MHz,
CDCl3, ppm)
d
7.99 (d, J¼7.97 Hz, 1H), 7.85 (d, J¼7.69 Hz, 1H), 7.45 (t,
J¼7.69 Hz, 1H), 7.34 (t, J¼7.42 Hz, 1H), 1.53 (s, 9H).
4.5.12. 2-Cyclohexylbenzothiazole (8l).3g Yield: 27 mg (62%). Rf¼0.7
(EtOAc/hexanes¼1:10). Light colorless oil. 1H NMR (300 MHz,
4.5.1. 2-Phenylbenzothiazole (8a).2h Yield: 35 mg (83%). Rf¼0.6
(EtOAc/hexanes¼1:9). White solid. 1H NMR (300 MHz, CDCl3, ppm)
CDCl3, ppm)
d
7.97 (d, J¼7.97 Hz, 1H), 7.85 (d, J¼7.69 Hz, 1H), 7.45 (t,
J¼7.14 Hz, 1H), 7.34 (t, J¼7.14 Hz, 1H), 3.11 (tt, J¼11.57. 3.54 Hz, 1H),
Please cite this article in press as: Cho, Y.-H.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.138

Y.-H. Cho et al. / Tetrahedron xxx (2013) 1e9
9
by pyrolysis, see: Chou, C.-H.; Hsueh, Y.-T.; Wang, B.-C. J. Chin. Chem. Soc. 2011,
58, 301e305.
2.17e2.22 (m, 2H), 1.86e1.92 (m, 2H), 1.75e1.79 (m, 1H), 1.58e1.67
(m, 2H), 1.25e1.52 (m, 3H).
6. For selected examples of the synthesis of benzoxazoles via oxidative cyclization
with various oxidants, see: (a) DDQ: Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett.
2002, 43, 951e954; (b) PhI(OAc)2: Varma, R. S.; Saini, R. K.; Prakash, O. Tetra-
hedron Lett. 1997, 38, 2621e2622; (c) Polymer-supported hypervalent iodine:
Kumar, A.; Maurya, R. A.; Ahmad, P. J. Comb. Chem. 2009, 11, 198e201; (d) PCC:
Praveen, C.; Kumar, K. H.; Muralidharan, D.; Perumal, P. T. Tetrahedron 2008, 64,
2369e2374; (e) BaMnO4: Srivastava, R. G.; Venkataramani, P. S. Synth. Commun.
1988, 18, 1537e1544; (f) IBX: Chen, F.; Shen, C.; Yang, D. Tetrahedron Lett. 2011,
52, 2128e2131; (g) There have been a few examples of the preparation of
benzoxazoles from 2-nitrophenol as a surrogate for 2-aminophenol, see: Wu,
M.; Hu, X.; Liu, J.; Liao, Y.; Deng, G.-J. Org. Lett. 2012, 14, 2722e2725; (h) Hari, A.;
Karan, C.; Rodriguez, W. C.; Miller, B. L. J. Org. Chem. 2001, 66, 991e996; (i) Lee,
J. J.; Kim, J.; Jun, Y. M.; Lee, B. M.; Kim, B. H. Tetrahedron 2009, 65, 8821e8831;
(j) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, O.; Williams, J. M.
J. Org. Lett. 2009, 11, 2039e2042.
4.5.13. 2-Hexylbenzothiazole (8m).2j Yield: 25 mg (57%). Rf¼0.7
(EtOAc/hexanes¼1:10). Yellow oil. 1H NMR (300 MHz, CDCl3, ppm)
d
7.97 (d, J¼8.24 Hz, 1H), 7.84 (d, J¼7.97 Hz, 1H), 7.45 (t, J¼7.14 Hz,
1H), 7.34 (t, J¼7.14 Hz, 1H), 3.11 (t, J¼7.69 Hz, 2H), 1.88 (p, J¼7.56 Hz,
2H), 1.31e1.44 (m, 6H), 0.89 (t, J¼6.87 Hz, 3H).
Acknowledgements
This work was partly supported by the nuclear research and
development program through the National Research Foundation
of Korea funded by the Ministry of Education, Science and Tech-
nology. We also thank Professors D.-C. Ha and K. Choi (Korea Uni-
versity, Seoul, Korea) for their helpful discussions.
7. For selected examples of benzothiazole synthesis via oxidative cyclization, see:
(a) CAN: Jin, H.-L.; Cheng, T.-X.; Chen, J.-X. Appl. Organomet. Chem. 2011, 25,
238e240; (b) H2O2: Bahrami, K.; Khodaei, M. M.; Naali, F. Synlett 2009,
569e572; (c) See Ref. 6c,d:
8. For selected examples of the benzimidazole synthesis via oxidative cyclization,
see: (a) Weires, N. A.; Boster, J.; Magolan, J. Eur. J. Org. Chem. 2012, 6508e6512;
(b) Lin, C.; Lai, P.-T.; Liao, S. K.-S.; Hung, W.-T.; Yang, W.-B.; Fang, J.-M. J. Org.
Chem. 2008, 73, 3848e3853; (c) See Refs. 6c and 7b.
9. Modern Oxidation Methods, 2nd ed.; Backvall, J.-E., Ed.; Wiley-VCH: Weinheim,
Germany, 2004.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.138.
€
10. For the synthesis of benzoxazoles via aerobic oxidation with metal salts as
catalysts, see: (a) CuCl: Speier, G. J. Mol. Catal. 1987, 41, 253e260; (b) FeCl3: Cao,
K.; Tu, Y.; Zhang, F. Sci. China: Chem. 2010, 53, 130e134; (c) Pd(OAc)2: Chen, W.-
H.; Pang, Y. Tetrahedron Lett. 2009, 50, 6680e6683; (d) With TEMPO as a cata-
lyst, see: Chen, Y.-X.; Qian, L.-F.; Zhang, W.; Han, B. Angew. Chem., Int. Ed. 2008,
47, 9330e9333; (e) With activated carbon, see: Kawashita, Y.; Nakamichi, N.;
Kawabata, H.; Hayashi, M. Org. Lett. 2003, 5, 3713e3715; (f) For an aerobic
oxidation with nanoparticles as catalysts, see: Kidmai, M.; Bansal, V.; Saxena,
A.; Aerry, S.; Mozumdar, S. Tetrahedron Lett. 2006, 47, 8049e8053; (g) Yoo, W.-
J.; Yuan, H.; Miyamura, H.; Kobayashi, S. Adv. Synth. Catal. 2011, 353,
3085e3089.
11. For the synthesis of benzothiazoles via aerobic oxidation with surfactant as
a catalyst, see: (a) Parikh, N.; Kumar, D.; Roy, S. R.; Chakraborti, A. K. Chem.
Commun. 2011, 1797e1799; (b) See Refs. 10d,g.
12. For the synthesis of benzimidazoles via aerobic oxidation, see: (a) Lei, M.; Ma,
L.; Hu, L. Synth. Commun. 2012, 42, 2981e2993; (b) Behbahani, F. K.; Ziaei, P.
Chem. Heterocycl. Compd. 2012, 48, 1011e1017; (c) Sharghi, H.; Beyzavi, M. H.;
Doroodmand, M. M. Eur. J. Org. Chem. 2008, 4126e4138; (d) See Ref. 10d.
13. Cho, Y. H.; Lee, C.-Y.; Ha, D.-C.; Cheon, C.-H. Adv. Synth. Catal. 2012, 354,
2992e2996.
14. Prior to our report, there were a few examples of the preparation of 2-
benzofused azoles using air as an oxidant, although the reaction conditions
are much harsher than ours, see: (a) Riadi, Y.; Mamouni, R.; Azzalou, R.; Had-
dad, M. E.; Routier, S.; Guillaumet, G.; Lazar, S. Tetrahedron Lett. 2011, 52,
3492e3495; (b) Bachhav, H. M.; Bhagat, S. B.; Telvekar, V. N. Tetrahedron Lett.
2011, 52, 5697e5701.
15. Cyanide anion is known to catalyze the benzoin reaction of aldehydes, see:
March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structures,
4th ed.; Wiley-VCH: New York, USA, 1992; pp. 969e970.
16. For examples of one-pot synthesis of benzoxazoles, see Refs. 6c,f,g,i, 10def.
17. 1H NMR analysis of the crude mixture revealed that 2-aminophenol and
benzaldehyde remained intact and only a trace amount of the product was
observed (<5%).
18. For the preparation of benzothiazoline 10a, see: (a) Henseler, A.; Kato, M.; Mori,
K.; Akiyama, T. Angew. Chem., Int. Ed. 2011, 50, 8180e8183; (b) Zhu, C.; Akiyama,
T. Org. Lett. 2009, 11, 4180e4183; (c) For deuterium labelled benzothiazoline,
see: Sakamoto, T.; Mori, K.; Akiyama, T. Org. Lett. 2012, 14, 3312e3315.
19. There have been a few reports in which a base/nucleophile significantly ac-
celerated aerobic oxidation, see: (a) Kang, S.; Joo, C.; Kim, S. M.; Han, H.; Yang,
J. W. Tetrahedron Lett. 2011, 52, 502e504; (b) Kim, S. M.; Kim, Y. S.; Kim, D. W.;
Yang, J. W. Green Chem. 2012, 14, 2996e2998.
References and notes
1. (a) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A.,
Scriven, E. F. V., Taylor, R. J. K., Eds.; Pergamon: Oxford, New York, USA, 2008;
Vol. 4; (b) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry,
2nd ed.; Pergamon: Oxford, UK, 2000.
2. For selected examples of transition metal catalyzed direct arylation of benzo-
fused azoles via CeH activation, see: (a) Wu, G.; Zhou, J.; Zhang, M.; Hu, P.; Su,
W. Chem. Commun. 2012, 8964e8966; (b) Li, C.; Li, P.; Yang, J.; Wang, L. Chem.
Commun. 2012, 4214e4216; (c) Yu, P.; Zhang, G.; Chen, F.; Cheng, J. Tetrahedron
Lett. 2012, 53, 4588e4590; (d) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc.
2012, 134, 169e172; (e) Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.;
Yamaguchi, J.; Itami, K. Chem.dEur. J. 2011, 17, 10113e10122; (f) Ranjit, S.; Liu, X.
Chem.dEur. J. 2011, 17, 1105e1108; (g) Yang, F.; Xu, Z.; Wang, Z.; Yu, Z.; Wang, R.
Chem.dEur. J. 2011, 17, 6321e6325; (h) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.;
Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674e3675;
(i) Shibahara, F.; Yamaguchi, E.; Murai, T. Chem. Commun. 2010, 2471e2473; (j)
Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.dEur. J. 2010, 16, 12307e12311; (k)
Nandurkar, N. S.; Bhanushali, M. J.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett.
2008, 49, 1045e1048.
3. For selected examples of the synthesis of benzofused azoles via transition
metal catalyzed cyclization of ortho-haloanilides, see: (a) Saha, P.; Ali, M. A.;
Ghosh, P.; Punniyamurthy, T. Org. Biomol. Chem. 2010, 8, 5692e5699; (b) Naidu,
A. B.; Sekar, G. Synthesis 2010, 579e586; (c) Saha, P.; Ramana, T.; Purkait, N.; Ali,
M. A.; Paul, R.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719e8725; (d)
Kantam, M. L.; Venkanna, G. T.; Shiva Kumar, K. B.; Balasubrahmanyam, V.;
Bhargava, S. Synlett 2009, 1753e1756; (e) Ma, H. C.; Jiang, X. Z. Synlett 2008,
1335e1340; (f) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665e2667; (g) For
transition metal-free synthesis from ortho-haloanilides, see: Feng, E.; Huang,
H.; Zhou, Y.; Ye, D.; Jiang, H.; Liu, H. J. Comb. Chem. 2010, 12, 422e429; (h) Peng,
J.; Zong, C.; Ye, M.; Chen, T.; Gao, D.; Wang, Y.; Chen, C. Org. Biomol. Chem. 2011,
9, 1225e1230.
4. For selected examples of the synthesis of benzoxazoles via CeH activation of
anilides, see: (a) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272e4277; (b)
Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411e6413; (c) For the
synthesis of benzothiazoles, see: Cheng, Y.; Yang, J.; Qu, Y.; Li, P. Org. Lett. 2012,
14, 98e101; (d) For the synthesis of benzimidazoles, see: Alla, S. K.; Kumar, R.
K.; Sadhu, P.; Punniyamurthy, T. Org. Lett. 2013, 15, 1334e1337.
5. (a) With carboxylic acids, see: Soares, A. M. S.; Costa, S. P. G.; Sameiro, M.;
Goncalves, T. Tetrahedron 2010, 66, 8189e8195; (b) With esters, see: Sheng, C.;
Che, X.; Wang, W.; Wang, S.; Cao, Y.; Yao, J.; Miao, Z.; Zhang, W. Eur. J. Med.
Chem. 2011, 46, 1706e1712; (c) With acid chlorides, see: Fukuda, S.; Nakamura,
A.; Shimizu, M.; Okada, T.; Oohida, S.; Asahara, T. Patent US2004/14977 A1,
20. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734e736.
21. (a) Kobayashi, S.; Ishitani, H. Chirality 2000, 12, 540e543; (b) Ishitani, H.;
Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
762e766.
22. Zhou, L.; Ji, L. L. J.; Xie, M.; Liu, X.; Feng, X. Org. Lett. 2011, 13, 3056e3059.
23. Mandal, S.; Seth, D. K.; Gupta, P. Inorg. Chim. Acta 2013, 397, 10e20.
24. Bose, D. S.; Idrees, M. Synthesis 2010, 398e402.
ꢁ
2004; (d) With orthoesters, see: Bastug, G.; Eviolitte, C.; Marko, I. E. Org. Lett.
2012, 14, 3502e3505; (e) For microwave assisted synthesis of benzofused
azoles, see: Radi, M.; Saletti, S.; Botta, M. Tetrahedron Lett. 2008, 49,
4464e4466; (f) Seijas, J. A.; Vazquez-Tato, M. P.; Carballido-Reboredo, M. R.;
Crecente-Campo, J. Synlett 2007, 313e317; (g) Kumar, R.; Selvam, C.; Kaur, G.;
Chakraborti, A. K. Synlett 2005, 1401e1404; (h) For synthesis of benzoxazoles
ꢁ
25. Kalkhambkar, R. G.; Laali, K. K. Tetrahedron Lett. 2012, 53, 4212e4215.
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
26. Fernandez, J. J.; Fernandez, A.; Vazquez-García, D.; Lopez-Torres, M.; Suarez, A.;
ꢁ
Gomez-Blanco, N. .; Vila, J. M. Eur. J. Inorg. Chem. 2007, 5408e5418.
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