Efficient synthesis of 2-(2′-hydroxyphenyl)benzoxazole by palladium(II)-catalyzed oxidative cyclization

Article abstract of DOI:10.1016/j.tetlet.2009.09.084

An efficient method for the synthesis of 2-(2′-hydroxyphenyl)benzoxazole has been developed by using palladium-mediated oxidative cyclization.

Full text of DOI:10.1016/j.tetlet.2009.09.084

Tetrahedron Letters 50 (2009) 6680–6683
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Tetrahedron Letters
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Efficient synthesis of 2-(20-hydroxyphenyl)benzoxazole by
palladium(II)-catalyzed oxidative cyclization
*
Wei-Hua Chen, Yi Pang
Department of Chemistry and Maurice Morton Institute of Polymer Science, The University of Akron, Akron, OH 44325, United States
a r t i c l e i n f o
a b s t r a c t
An efficient method for the synthesis of 2-(20-hydroxyphenyl)benzoxazole has been developed by using
palladium-mediated oxidative cyclization.
Article history:
Received 4 August 2009
Revised 12 September 2009
Accepted 15 September 2009
Available online 19 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Schiff base
Palladium catalyst
Oxidative cyclization
Benzoxazole
2-(20-Hydroxyphenyl)benzoxazole (HBO) has emerged to be an
interesting material, due to its intrinsic property for the excited
state intramolecular proton transfer (ESIPT). A distinctive feature
of the HBO derivatives is that their fluorescence is well separated
from their absorption maxima, leading to unusually large Stokes’
shift.1 Utilization of this feature has resulted in various applica-
tions including chemical sensors for zinc(II)2,3 and anions,4 and
electronic devices.5 The benzoxazole group also occurs in many
biologically active compounds such as anticancer agents,6 antibac-
terial agents,7 and Alzheimer’s disease therapeutics.8
Two methods are commonly used for synthesizing 2-substi-
tuted benzoxazoles. One method is the condensation of carboxylic
acids with 2-aminophenols by dehydration, which is catalyzed by a
strong acid such as polyphosphoric acid (PPA).9–11 Although this
method can be used for making large quantities, the strong acidic
conditions at high temperature (>180 °C) often cause low yields
OH
oxidative
cyclization
OH
O
O
NH2
3
X
N
N
1
path a
4
X
(X= -H, -OR)
5
X
deprotection
(X= -OR)
OH
NH2
OH
N
Pd(II)
O
O
3
[O]
path b
OH
N
2
HO
H O
6
7
Scheme 1. Synthesis of HBO via protected (path a) and unprotected (path b) phenol aldehydes.
* Corresponding author.
E-mail address: yp5@uakron.edu (Y. Pang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.084

W.-H. Chen, Y. Pang / Tetrahedron Letters 50 (2009) 6680–6683
6681
and side reactions. Mechanistic study indicates that the PPA condi-
tion could generate benzoyl cation from the corresponding carbox-
ylic acid,11 which complicates the reaction and increases the by-
product formation. In addition, aromatic nitro,10 tert-butyl, and
other acid-sensitive functional groups do not survive under the
harsh acidic conditions, thereby limiting the scope of the reaction.
The second method involves the oxidative cyclization of pheno-
lic Schiff bases (e.g., from 4?5 in Scheme 1, path a), which is de-
rived from the condensation of 2-aminophenols and aldehydes 1
(X = –OR or –H). The reaction is typically carried out in the pres-
ence of various oxidants including DDQ,12,13 MnO2,14 pyridinium
chlorochromate (PCC),15 PbO2, and Pb(OAc)4.16,17 This oxidative
process, however, requires the use of at least 1 equiv mole of oxi-
dant, whose product purification often involves toxic work-up pro-
cedures to remove the transition metals. The mild conditions for
oxidative cyclization (4?5) include photon-induced cyclization18
and use of N-iodosuccinimide as an oxidant.19 In path a, the phenol
group in the aldehyde 1 (X = –OR) is protected to avoid the poten-
tial oxidation in the following steps. Some oxidants such as
DDQ20,21 can be used for the direct cyclization of the unprotected
phenolic Schiff base (transformation of 6?7), which often suffers
with lower yields. Recently, there has been a significant interest
in developing catalytic methods to synthesize benzoxazole deriva-
tives, since the transition metal oxidants will no longer be used in
the stoichiometric amount. A catalytic reaction using oxygen as a
co-oxidant is of special interest, because its green chemistry as-
pects offer the additional advantage of developing an environmen-
tally friendly process. The catalytic transformation (4?5, X = –H)
has been demonstrated by using the hydrogen-transfer catalysts,22
such as Ru(PPh3)3(CO)H2, copper(I)-catalyzed oxidation,23 and
aminoxyl radical catalyst.24 The requirement of acidic additives22
for the hydrogen-transfer catalyst, however, can limit its applica-
tion. Competitive formation of two phenoxyl radicals (Ph-
OH?Ph-OÅ) in 6 makes the aminoxyl radical route24 unsuitable
for the transformation of 6?7. Therefore, an efficient methodology
that occurs at mild conditions is still needed to overcome these
shortcomings.
Organopalladium intermediates are of primary importance in
the synthetic reactions.25 One of the fundamental properties of
the palladium(II) is that it interacts with the
p-bond electron to
Pd(II)
+
Pd(II)
N
N
Pd(II)-assisted
intramolecular
cyclization
OH
OH
OH
OH
6
8
Pd(I)
H
N
N
+
Pd(0)
O
β-elimination
O
HO
HO
7
9
Scheme 2. Reaction sequence showing the Pd(II)-catalyzed cyclization and b-
elimination.
Table 1
Effect of base, solvent, and temperature on the conversion (10?11)
HO
OH
OH
Pd(OAc)2 5%
O
N
trace 11
base, solvent, O2
N
Cs2CO3, DMF,
O2, 80oC
Br
Br
11
10
Entry
Base
Solvent
Time (h)/temp (°C)
Conversion (%)
1
2
3
4
5
6
7
8
9
Cs2CO3
NaOAc
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeCN
MeCN
MeCN
CHCl3
PhMe
THF
DMSO
DMF
DMF
24, rt
24, rt
24, rt
24, rt
24, rt
24, rt
24, rt
24, rt
4, 80 °C
5
2
0
2
0
30
50
55
97
Note: Compounds 10 and 11 had the same spectral data as reported in the literature.28
Table 2
Results of Pd(II)-catalyzed synthesis of 2-(20-hydroxyphenyl)benzoxazole29
OH
OH
HO
O
N
Pd(OAc)2 5%
R1
N
R1
Cs2CO3, DMF, O2
R2
R2
Entry
R1
R2
Substrate
Product
Time (h)
Yielda
1
2
3
4
5
–H
–C(CH3)3
–NO2
–C(CH3)3
–NO2
–Br
–CH3
–H
–H
–Br
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
3.5
3.5
3.5
3
88
88
75
85
70
3.5
a
The reported yield is based on the isolated product yield.

6682
W.-H. Chen, Y. Pang / Tetrahedron Letters 50 (2009) 6680–6683
form
p
-complexes that are subjected to nucleophilic attack. It is as-
ole groups in a single molecule. The starting material 14 was
conveniently prepared by condensation of 5-bromo-2-hydroxyis-
ophthalaldehyde with 2-aminophenol.30 Reaction of the phenolic
Schiff base 14 afforded bis(HBO) 15 in good yield,31,32 along with
partially hydrolyzed product 16. Trace amount of 2-amino-3H-
phenoxazin-3-one (17) was also found in the product mixture,
which was formed via oxidative dehydrogenation of the hydro-
lyzed by-product 2-aminophenol.33
sumed that the palladium(II) can react with C@N bond in 6 to form
-complex 8 (Scheme 2), which then undergoes nucleophilic at-
p
tack to give 9. The subsequent b-elimination should occur easily
in 9, as the process is driven by aromatization to give 7. The elim-
ination of b-hydrogen in 9 can be viewed as a reaction similar to
the palladium-catalyzed oxidation of primary and secondary alco-
hols,26,27 in which H–C–O–PdX?C@O. Reasoning that the mild
Br
Br
OH
OH
OH
EtOH
reflux
N
N
+
O
O
NH2
OH
OH
14
Br
Br
Pd(OAc)2,
O
O
O
+
+
O
N
O
NH2
O
N
OH N
Cs2CO3, O2
DMF, 80oC
N
OH
5%
16
80%
1%
15
17
reaction condition could tolerate the existence of phenol functional
group, we decided to explore the palladium(II)-catalyzed intramo-
lecular cyclization, followed by b-elimination, to give HBO. To the
best of our knowledge, the palladium(II)-assisted nucleophilic at-
tack on imines (C@N) has not been reported.
In summary, we have reported an efficient and versatile method
to prepare HBO. The proposed mechanism (Scheme 3) involves the
interaction of the imine group with Pd(II) to give
p-complexes,
which are subjected to intramolecular nucleophilic attack by phenol
to give a five-membered ring intermediate. The key step is consist-
ing of the b-elimination to generate benzoxazole ring and Pd(0)
species, which is subsequently oxidized to regenerate Pd(II) by
O2. The net reaction consumes only the phenolic Schiff base and
oxygen.
Initial experimental results showed that the transformation of
10?11 could be accomplished by using a stoichiometric amount
of Pd(OAc)2. When the reaction was monitored by TLC, the rate
of the product formation was found to occur at a relatively fast
rate, in comparison with other oxidants such as MnO2. Catalytic
amount of Pd(OAc)2 in the presence of oxygen (as a co-oxidant)
was also found to be effective in the transformation. In order to
optimize the reaction conditions, the reaction was carried out un-
der different conditions and the results are summarized in Table 1.
The employment of base was still necessary, since it could deproto-
nate the phenol in 8 to facilitate the cyclization. Cs2CO3 appeared
to be a better choice among the bases tested (entries 1–3). The po-
lar aprotic solvent would be preferred, since it facilitates the nucle-
ophilic reaction of phenoxide (entries 4–7). Although the reaction
could occur at room temperature, the rate was significantly in-
creased at 80 °C in the polar aprotic solvent. The catalytic effect
of Pd(II) was further confirmed by performing the control experi-
ment, as stirring of 10 with Cs2CO3, DMF, and O2 at 80 °C for
24 h afforded only trace amount of product (less than 5%
conversion).
R1
R2
N
PdCl2
Pd(II)
OH
OH
Pd(II)-assisted
cyclization
O2
R1
PdII
H
N
R2
Pd(0)
O
HO
Versatility of the reaction was demonstrated by using different
substrates of phenolic Schiff bases, and the results are summarized
in Table 2. The reaction proceeded smoothly even in the presence
of Ar–Br bond, which can be used for further functionalization. The
presence of an electron-withdrawing group (–NO2), which in-
creases the acidity of the phenolic proton, did not appear to influ-
ence the rate of the cyclization (entry 3). The result was consistent
with the assumption that the palladium(II) played an important
role in the cyclization step (8?9).
β
-elimination
-H+
HO
R1
N
R2
O
product
The efficiency of the reaction was further examined by synthe-
sizing compound 15, which requires construction of two benzoxaz-
Scheme 3. Proposed catalytical cycle of the palladium-catalyzed oxidative
cyclization.

W.-H. Chen, Y. Pang / Tetrahedron Letters 50 (2009) 6680–6683
6683
and washed with 5 mL of water. The solid was redissolved in 20 mL of
dichloromethane, washed with 1% EDTA aqueous solution (to remove the
palladium catalyst), and then washed with water. The organic layer was dried
over anhydrous Na2SO4. Removal of solvent afforded the desirable products.
Compound 13a (colorless crystals from ethanol solution, mp 177 ꢀ178 °C) had
the following spectral properties. 1H NMR (CDCl3, 300 MHz) d = 11.49 (s, 1H),
8.16 (s, 1H), 7.76 (m, 1H), 7.64 (m, 1H), 7.52 (dd, 1H, J = 9.0 Hz, 2.4 Hz), 7.42 (m,
2H), 7.03 (d, 1H, J = 9.0 Hz). 13C NMR (CDCl3, 75 MHz) d = 161.7, 157.8, 149.2,
140.0, 136.5, 129.5, 126.0, 125.5, 119.6, 119.6, 112.2, 111.4, 111.0. IR (KBr) mmax
(cmꢀ1): 3060 (w), 1629 (m), 1584 (m), 1541 (s), 1485 (s), 1451 (s), 1279 (s),
1250 (s), 800 (m), 762 (s).
Compound 13b (recrystallized from chloroform, mp 165–166 °C) had the
following spectral properties. 1H NMR (CDCl3, 300 MHz) d = 11.33 (s, 1H), 7.80
(s, 1H), 7.74 (s, 1H), 7.64 (m, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.43 (dd, J = 9.0 Hz,
1.8 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H) 2.36 (s, 3H), 1.40 (s,
9H). 13C NMR (CDCl3, 75 MHz) d = 163.3, 156.7, 148.7, 147.3, 140.2, 134.5,
128.9, 127.0, 123.2, 117.3, 115.9, 110.5, 109.9, 35.2, 31.9, 20.7. IR (KBr) mmax
(cmꢀ1): 3024 (w), 2951 (m), 2864 (w), 1638 (m), 1596 (m), 1547 (s), 1500 (s),
1282 (s), 1256 (s), 1055 (m), 943 (m), 805 (s).
Acknowledgments
Financial support has been provided by The University of Akron
and Coleman endowment. We also wish to thank The National Sci-
ence Foundation (CHE-9977144 and MRI-0821313) for funds used
to purchase the NMR instrument and high resolution ESI mass
spectrometer used in this work.
References and notes
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Compound 13c (needle-like crystals from methanol/chloroform, mp 190.5–
191 °C) had the following spectral properties. 1H NMR (CDCl3, 300 MHz)
d = 10.99 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.36 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 8.04
(dd, J = 7.8 Hz, 1.5 Hz, 1H), 7.73 (d, J = 9 Hz, 1H), 7.52 (dt, 1H, J = 7.8 Hz, 1.5 Hz),
7.16 (d, 1H, J = 7.8 Hz) 7.06 (t, 1H, J = 7.8 Hz). 13C NMR (CDCl3, 75 MHz)
d = 166.0, 159.4, 152.8, 145.9, 140.8, 135.1, 127.6, 121.6, 120.2, 118.0, 115.6,
111.0, 109.6. IR (KBr) mmax (cmꢀ1): 3116 (m, Ph-OH), 1628 (s), 1531 (s, –NO2),
1348 (s, –NO2), 1237 (s, Ph–O–C), 1161 (m), 1044 (m), 808 (m), 758 (m), 733
(m). HRMS (m/z): [M+H]+ calcd for C13H9N2O4, 257.0562; found, 257.0615.
Compound 13d (pale yellow crystals from chloroform, mp 158.5–159.5 °C) had
the following spectral properties. 1H NMR (CDCl3, 300 MHz) d = 11.56 (s, 1H),
8.02 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 7.76 (d, 1H, J = 1.5 Hz,) 7.53 (d, J = 9.0 Hz, 1H),
7.44 (m, 2H), 7.13 (d, 1H, J = 7.8 Hz), 7.01 (t, 1H, J = 7.8 Hz), 1.42 (s, 9H). 13C
NMR (CDCl3, 75 MHz) d = 163.1, 158.8, 148.8, 147.3, 140.1, 133.5, 127.2, 123.3,
119.7, 117.5, 115.9, 110.9, 109.9, 35.2, 31.9. IR (KBr) mmax (cmꢀ1): 2959 (m),
1630 (m), 1591 (m), 1543 (m), 1487 (s), 1257 (s), 1157 (m), 1054 (m), 751 (m).
Compound 13e had the following spectral properties. 1H NMR (CDCl3,
300 MHz) d = 11.08 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.40 (dd, 1H, J = 9.0 Hz,
2.1 Hz,), 8.19 (d, 1H, J = 2.4 Hz) 7.86 (d, J = 9.0 Hz, 1H), 7.60 (dd, 1H, J = 9.0 Hz,
2.4 Hz), 7.06 (d, 1H, J = 9.0 Hz). 13C NMR (CDCl3, 75 MHz) d = 163.3, 158.3,
152.7, 142.7, 140.7, 137.7, 129.8, 128.3, 122.0, 120.0, 115.8, 111.9, 111.2. IR
(KBr) m
max (cmꢀ1): 3108 (m), 1630 (m), 1547 (m), 1532 (s), 1482 (m), 1345 (s),
1248 (m), 1047 (m), 811 (m). HMRS (m/z): [M+H]+ calcd for C13H8BrN2O4,
334.9667; found, 334.9787.
30. Fossey, J.; Richards, C. J. Organometallics 2002, 21, 5259–5264.
31. Synthesis of 14: 4-Bromo-2,6-diformylphenol (100 mg, 0.44 mmol), prepared
from p-bromophenol by following the literature procedure (Synthesis 1998, 7,
1029–1032), and 2-aminophenol (96 mg, 0.88 mmol) were refluxed in absolute
ethanol (15 mL) for 5 h. The reaction mixture was cooled to room temperature,
and the precipitate was filtered and crystallized from absolute ethanol to give
the compound 14 as reddish needle-like crystals (mp 292–293 °C). 1H NMR
(CDCl3, 300 MHz) d = 8.78 (s, 2H), 7.79 (s, 2H), 7.04 (d, 2H, J = 7.8 Hz), 6.90 (t,
2H, J = 7.8 Hz), 6.76 (d, 2H, J = 7.8 Hz), 6.65 (t, 2H, J = 7.8 Hz).
32. Compound 15 was prepared by using the same procedure as for 13, and
27. Muzart, J. Tetrahedron 2003, 59, 5789–5816.
purified on a silica gel column with dichloromethane as an eluent. The
28. Sridharan, V.; Muthusubramanian, S.; Sivasubramanian, S. Magn. Reson. Chem.
2003, 41, 291–295.
compound 15 had the following spectral properties. 1H NMR (CDCl3, 300 MHz)
d = 12.95 (s, 1H), 8.42 (s, 2H), 7.83 (m, 2H), 7.67 (m, 2H), 7.43 (m, 4H). 13C NMR
(CDCl3, 75 MHz) d = 160.4, 156.7, 149.9, 140.8, 134.6, 126.2, 125.3, 120.3,
115.9, 111.4, 111.0. HRMS (m/z) calcd for [C20H11BrN2O3 + Na]+, 428.9851.
Found: 428.9885. IR (KBr) mmax (cmꢀ1): 3061 (w), 3027 (w), 1628 (w), 1536
(m), 1441 (s), 1248 (s), 1158 (m), 842 (m), 772 (m), 740 (m). The by-product 16
had the following spectral properties. 1H NMR (CDCl3, 300 MHz) d = 12.22 (s,
1H), 10.5 (s, 1H, CHO), 8.38 (s, 1H), 8.03 (s, 1H), 7.78 (m, 1H), 7.64 (m, 1H), 7.44
(m, 2H).
29. A typical procedure for the preparation of 13: To a 10 mL round-bottomed flask
equipped with a side arm, a magnetic stirring bar, and a connecting tube were
added the Schiff base 12 (0.2 mmol), Pd(OAc)2 (2.3 mg, 0.01 mmol), Cs2CO3
(130 mg, 0.4 mmol), and 10 mL DMF. The mixture was stirred at room
temperature for 5 min, then warmed to 80 °C, while the oxygen gas was
bubbled into the flask below the surface of the liquid. The progress of the
reaction was monitored by 1H NMR spectroscopy, which revealed the
disappearance of the imine resonance signal at around d 8.8 ppm when the
reaction was complete. Upon completion of the reaction, the mixture was
poured into 20 mL of water. The precipitate was collected by vacuum filtration
33. Simandi, L. I.; Barna, T. M.; Korecz, L.; Rockenbauer, A. Tetrahedron Lett. 1993,
34, 717–720.