A simple protocol for the synthesis of 2-arylbenzoxazoles by oxidation with o-iodoxybenzoic acid (IBX) and its application in the synthesis of arylbenzoxazole-containing amino acids

Article abstract of DOI:10.1016/j.tetlet.2010.11.057

A simple protocol for the preparation of 2-arylbenzoxazoles has been developed based on the oxidation of phenolic Schiff bases with o-iodoxybenzoic acid (IBX), wherein the oxidant can be recycled. The robustness of this new protocol has been demonstrated in the synthesis of arylbenzoxazole-containing amino acids.

Full text of DOI:10.1016/j.tetlet.2010.11.057

Tetrahedron Letters 52 (2011) 2128–2131
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Tetrahedron Letters
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A simple protocol for the synthesis of 2-arylbenzoxazoles by oxidation
with o-iodoxybenzoic acid (IBX) and its application in the synthesis
of arylbenzoxazole-containing amino acids
⇑
Fei Chen, Chengjie Shen, Dan Yang
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 16 November 2010
A simple protocol for the preparation of 2-arylbenzoxazoles has been developed based on the oxidation of
phenolic Schiff bases with o-iodoxybenzoic acid (IBX), wherein the oxidant can be recycled. The robust-
ness of this new protocol has been demonstrated in the synthesis of arylbenzoxazole-containing amino
acids.
This paper is dedicated with gratitude to our
friend Professor Harry H. Wasserman on the
occasion of his 90th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Arylbenzoxazole
IBX
Arylbenzoxazole-containing amino acids
2-Arylbenzoxazoles are an important group of target molecules
by virtue of their special photophysical properties1–3 and biological
activities, including antitumor, antimicrobial, and antiviral proper-
ties.4–6 It has also been reported that arylbenzoxazole-containing
amino acids have high fluorescence quantum yields and can be
engineered into convenient fluorescent probes.7–13 Recently, it has
been reported that 2-arylbenzoxazoles are novel cholesteryl ester
transfer protein inhibitors,14 and some 2-arylbenzoxazoles are
highly selective amyloidogenesis inhibitors.15 Generally, the syn-
thesis of 2-arylbenzoxazoles can proceed by two strategies. One is
the coupling of 2-aminophenol with carboxylic acid derivatives by
dehydration, which can be catalyzed by a strong acid,16 assisted
by microwave condition,17–21 or mediated by hexachloroethane
and triphenylphosphine.22 The other is the oxidative cyclization of
phenolic Schiff bases, which are derived from the condensation of
2-aminophenols and aldehydes. In the latter case, various oxidants
have been used, such as DDQ,23 O2 (promoted by activated carbon or
catalyzed by Cu-nanoparticle),24,25 Mn(OAc)3,26 PhI(OAC)2,27,28
ThþꢀClO4ꢁ,29,30 BaMnO4,31 NiO2,32 Pb(OAc)4,33 Deoxo-Fluor re-
we report a simple protocol for the synthesis of 2-arylbenzoxazoles
with o-iodobenzoic acid (IBX)39 as the oxidant (Scheme 1), wherein
the oxidant can be recycled.
IBX is an old hypervalent iodine reagent, but previously it has
rarely been used in reactions due to its insolubility in most organic
solvents.39 In recent years, IBX has been rediscovered as a versatile
oxidant in dimethyl sulfoxide (DMSO) and dimethyl formaldehyde
(DMF) to oxidize alcohols to carbonyl compounds,40,41 secondary
amines to imines,42 saturated carbonyl compounds to
a,b-unsatu-
rated carbonyl compounds,43,44 phenols to o-quinones,45 and so
on.46–48 Other than DMSO and DMF, it has also been reported that
IBX can oxidize alcohols to aldehydes in ethyl acetate (EtOAc) at
80 °C.49 This is an important improvement for the oxidative reac-
tions with IBX, since the new protocol is very clean and the oxidant
can be easily recycled. Therefore, we proposed the use of IBX for
oxidizing phenolic Schiff bases to arylbenzoxazole in EtOAc.
The preparation of arylbenzoxazoles through the oxidative
cyclization of phenolic Schiff bases involves three steps (Scheme 2).
The first step is the condensation between aromatic aldehyde 1
and o-aminophenol 2 to form Schiff base 3. The second step is
the five-membered-ring formation from 3 to 4. The third step is
the oxidation of 4 to arylbenzoxazole 5. In steps 1 and 3, water is
produced, and in the presence of water, the equilibrium of the
reaction moves backwards. Thus, part of the Schiff base 3 is hydro-
lyzed to form o-aminophenol 2, which is in turn oxidized by IBX to
form side products and results in a decrease in reaction yield.
Therefore, removing water and increasing the stability of 2 under
oxidative condition would be beneficial to the reaction yield. In
35
agent,34 [Cp IrI2]2,
Dess-Martin Periodinane,36 and tert-butyl
*
hypochlorite.37 Preparation of 2-arylbenzozaxoles from phenolic
Schiff bases in the presence of base and phototrigger have also been
reported.38 In the research on the preparation of arylbenzoxazole-
containing amino acids, Pb(OAc)4 was reported as the best oxi-
dant,11 though it is toxic and deleterious to the environment. Herein
⇑
Corresponding author. Tel.: +852 28592159; fax: +852 28571586.
E-mail address: yangdan@hku.hk (D. Yang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.057

F. Chen et al. / Tetrahedron Letters 52 (2011) 2128–2131
2129
CHO
R
OH
OH
O
N
IBX, MS
80oC for 6h
EtOAc, MS
R
+
N
°
80 C for 1h
NH2
45°C for 12h
R
Scheme 1. Synthesis of 2-arylbenzoxazoles by IBX oxidation.
CHO
OH
O
N
O
[O]
−H2O
OH
+
N
N
H
H2O
NH2
5
3
4
2
1
[O]
Side Product
Scheme 2. Pathway for the synthesis of 2-arylbenzoxazole.
the reaction system, a Schiff base was generated from the conden-
sation between o-aminophenol and aromatic aldehyde (1:1) in
EtOAc. 4 Å molecular sieves (MS) were added to absorb water
and 2 equiv of IBX was used as the oxidant.50 A comparison
between the yields of the reactions with or without the addition
of MS is made in Table 1 (Scheme 1). With the addition of MS, in
the case of benzaldehyde, the yield was improved from 69% to
73%. In the case of p-fluorobenzaldehyde, the yield was improved
from 63% to 73%. Therefore, the addition of MS leads to improve-
ment of the reaction yield. We also tried to mix o-aminophenol,
benzaldehyde, IBX, and MS together in a one-pot reaction, but
the yield was found to be low according to TLC analysis, which
probably resulted from the fact that o-aminophenol is not stable
under oxidative condition.
Then, we screened various o-aminophenols and aromatic alde-
hydes to explore the scope of the reaction. The reaction yields
CHO
Table 1
OH
O
N
EtOAc
80ºC, 2h
45ºC, 2h
IBX
Yields of the synthesis of 2-arylbenzoxazoles with or without MS
+
EtOAc, 80 ºC, 12h
NH2
40mmol
Entry
R
Yield (without MS)
Yield (with MS)
12
, 87%
1
2
H
F
69%
63%
73%
73%
Scheme 3. Large-scale synthesis of 12.
Table 2
Synthesis of 2-arylbenzoxazoles by oxidative cyclization of phenolic Schiff bases derived from the condensation of 2-aminophenols and aldehydes
O
N
OH
IBX, MS
MS,EtOAc
Ar
+
Ar-CHO
EtOAc,80ºC for 6h
80ºC for 1h
R
R
NH2
45ºC for 12h
Entry
1
R
Ar
Ph
Product
Yield (%)
O
H
73
73
74
70
70
78
88
98
N
O
6
F
2
3
4
5
6
7
8
H
p-F–C6H4
N
O
7
8
H
p-Me–C6H4
p-OMe–C6H4
2-Pyridine
p-Me–C6H4
Ph
N
O
OMe
H
N
9
O
H
N
N
10
O
Me
Me
Me
N
O
11
N
O
12
13
2-Pyridine
N
N

2130
F. Chen et al. / Tetrahedron Letters 52 (2011) 2128–2131
OH
OH
OH
H2, Pd/C, 12h
MeOH
HNO3
HOAc
96%
NH2
NO2
BOC
OMe
BOC
O
BOC
O
N
H
N
H
N
H
O
16
O
15
O
14
O
N
Ar
Ar CHO
MS, EtOAc
IBX, MS
BOC
OMe
80oC, 1h
45oC, 6h
N
EtOAc, 80oC, 12h
H
O
Entry
Ar
Product
Yield/%
1
2
3
2-pyridine
Ph
17
18
19
79
81
71
p-Me-C6H4
Scheme 4. Synthesis of derivatives of arylbenzoxazole-containing amino acids.
are listed in Table 2. When o-aminophenol was used (entries 1–5),
70–74% yields of the desired products were obtained, regardless of
the electronic properties of aromatic aldehydes. The substituents
on aromatic aldehydes seem to have no major impact on the yield.
When 4-methyl-2-aminophenol was used (entries 6–8), the yields
were higher than those of the cases where o-aminophenol was
used, probably because 4-methyl-2-aminophenol is more stable
than o-aminophenol under oxidative condition. In addition, the
reaction yield increased markedly with the electron deficiency of
the aromatic rings of the aldehydes, among which 2-pyridinecar-
boxaldehyde gave the highest yield (98%). One possible reason is
that the electron-withdrawing group on the aldehyde can deter
the reversible hydrolysis of imine formed in the first step, thus sup-
pressing byproduct formation from the oxidation of o-aminophe-
nol (Scheme 2).
We then raised the scale of the reaction to 40 mmol (Scheme 3).
In this large-scale reaction, Dean-Stark trap was used instead of MS
to remove water and the amount of IBX was reduced to 1.5 equiv.
The yield of the reaction reached 87% and the byproduct IBA from
IBX could be easily recovered by filtration after the reaction.44 The
collected IBA was reoxidized to IBX by the standard procedure51 in
80% yield.
This new protocol for 2-arylbenzoxazole synthesis was subse-
quently applied to the synthesis of arylbenzoxazole-containing
amino acids. Three different arylbenzoxazole groups, that is, 2-
pyridinyl (17), phenyl (18), and p-methylphenyl (19) benzoxazoles,
were introduced in good yields (71–81% from 15; Scheme 4). Com-
pound 15 was synthesized from 14 by nitration with nitric acid in
acetic acid.52 Then, it was reduced to 16 by hydrogenation cata-
lyzed by palladium (Pd) on activated carbon in methanol. After fil-
tration and solvent removal, 16 was used directly in the next step.
The arylbenzoxazole-containing amino acids 17–19 with sensitive
BOC and CO2Me protecting groups were successfully synthesized
with our new protocol.
In summary, a simple protocol is developed for the synthesis of
2-arylbenzoxazoles from o-aminophenols and aromatic aldehydes
with IBX as a recyclable oxidant. This protocol has been success-
fully employed in the synthesis of arylbenzoxazole-containing
amino acids with interesting fluorescent properties.
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Acknowledgments
We thank The University of Hong Kong for financial support.
We thank Dr. On-Yi Lee for the preparation of this manuscript.

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