One-pot green synthesis of benzoxazole derivatives through molecular sieve-catalyzed oxidative cyclization reaction

Article abstract of DOI:10.1002/hc.21360

An one-pot approach to benzoxazole ring from 2-aminophenol and aldehydes utilizing molecular sieve as the catalyst have been developed. The new oxidative cyclization reaction excluded the usage of hazardous chemical reagents, transition-metal catalysts, chemical oxidants, or strong acids, and, therefore, reduced the production of toxic chemical waste. This offers an environmentally friendly pathway for the synthesis of various benzoxazole derivatives.

Full text of DOI:10.1002/hc.21360

Received: 5 October 2016
DOI: 10.1002/hc.21360
Revised: 24 November 2016
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R E S E A R C H A R T I C L E
One-pot green synthesis of benzoxazole derivatives through
molecular sieve-catalyzed oxidative cyclization reaction
Weichieh Chang1
Yukai Sun2
Yungtzung Huang1
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1Department of Applied
Chemistry, National University of
Kaohsiung, Kaohsiung, Taiwan
Abstract
An one-pot approach to benzoxazole ring from 2-aminophenol and aldehydes utiliz-
ing molecular sieve as the catalyst have been developed. The new oxidative cycliza-
tion reaction excluded the usage of hazardous chemical reagents, transition-metal
catalysts, chemical oxidants, or strong acids, and, therefore, reduced the production
of toxic chemical waste. This offers an environmentally friendly pathway for the
synthesis of various benzoxazole derivatives.
2Department of Chemistry, National Tsing
Hua University, Hsinchu, Taiwan
Correspondence
Yungtzung Huang, Department of
Applied Chemistry, National University of
Kaohsiung, Kaohsiung, Taiwan.
Email: ythuang@nuk.edu.tw
Molecular sieve
NH2
Funding information
Ministry of Science and Technology, Grant/
Award Number: MOST 105-2113-M-390-
004 and MOST 104-2633-M-390-001;
National Science Council, Grant/Award
Number: NSC-102-2113-M-390-002
N
O
OH
R
+
O
2
H
R
1
INTRODUCTION
cleavage,[11] and dehydrogenative coupling[12] were devel-
oped to synthesize benzoxazole derivatives.
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The five-member N,O-heteroatom ring of benzoxazole is an
important building block in natural products/pharmaceutical
targets,[1] polymers,[2] materials,[3] etc. Consequently, devel-
oping new methodologies for construction of benzoxazole
derivatives have been continuously investigated and reported
(Figure 1). In addition to traditional ways using condensation
of 2-aminophenol and carboxylic acids/acid halides under
strong acids,[4] various organometallic catalyzed reactions
were applied in the synthesis of benzoxazole derivatives. For
example, oxidative coupling of acetals/imines[5] and cross cou-
pling of amides[6] were reported. Moreover, arylation,[7] one-
pot reactions of domino cross coupling,[8] multi-component
process,[9] tandem oxidation process,[10] C,C-triple bond
However, unlike electrochemical way using anodic coupling
reaction of the imine to synthesize benzoxazole ring,[13] those
methods usually require to use and/or consume reactive chem-
ical reagents, transition-metal catalysts, chemical oxidants, or
strong acids. The resulting toxic chemical wastes cause pollu-
tions to the environment. Organic chemical wastes may be de-
stroyed by burning, and the resulting gas like CO2 and water will
be recycled by plants and other forms of life. However, combus-
tion does not destroy transition metals, and the cost of recycling
these transition metals from the chemical wastes is high. Also,
when these reactions are applied in the synthesis of pharmaceu-
tical drugs or food additives, accumulation of the remaining haz-
ardous chemical impurities in the bodies may cause unexpected
Contract grant sponsor: Ministry of Science and Technology.
Contract grant number: MOST 105-2113-M-390-004.
Contract grant number: MOST 104-2633-M-390-001.
Contract grant sponsor: National Science Council.
Contract grant number: NSC-102-2113-M-390-002.
|
Heteroatom Chemistry 2017; 00: e21360;
DOI: 10.1002/hc.21360
wileyonlinelibrary.com/journal/hc
© 2017 Wiley Periodicals, Inc.
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CHANG et Al.
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O
H
N
N
R
dehydration
H
R
or
R
imine
H
N
O
O
OH
R
X
acetal
condensation
NH2
OH
X
X
R
R
oxidative coupling
or anodic coupling
O
Y
dehydrogenative
coupling
amide
cross
coupling
Y R
arylation
O
R
R
N
O
C,C-triple bond celavage
N
O
O
R
tandem oxidation
H
R
X
X
H2N
domino
cross-coupling
R
benzoxazole
derivatives
-C N+ R
+
R-X
FIGURE 1 Reported methods to
synthesize benzoxazole ring
multi-component process
additional chemical oxidants were added to oxidize the al-
dehyde to carboxylic acid, and no other catalysts were used
to promote this oxidative cyclization reaction. Comparing
to those reported methods in Figure 1 using and/or consum-
ing various reactive chemical reagents and transition-metal
catalysts, this synthesis only utilized harmless commercial
molecular sieve in the reaction, which offers a simple, low
pollution, efficient, low cost, low toxicity pathway to syn-
thesize benzoxazole ring. This matches the goal of Green
Chemistry. Therefore, we turned to investigate how this one-
pot reaction of benzoxazole synthesis proceeded.
EWG
EWG
N
NH2
OH
R
MgSO4 or Na2SO4
R
THF or CH2Cl2
O
+
2
H
OH
3
anodic coupling
EWG
O
Dean Stark trap
&
N
H
R
R
molecular sieve
O
1
FIGURE 2 Synthesis of imine 2 and benzoxazole 1
In the beginning, toluene was chosen as the solvent and
1.1 equivalent of benzaldehyde were added to react with
2-aminophenol in the reaction. After heating to 150°C and
using Dear-Stark trap under argon for 12 hours, only 40% of
imine 2a was obtained (Table 1, entry 1). The yield of imine 2a
was increased to 62% when reaction time was raised to 36 hour
(entry 2). Similar yield was obtained while 2.2 equivalent of
benzaldehyde was added in the reaction (entry 3). When 3.1 g/
mmol of oven-dried 5A molecular sieve was added, 30% of
benzoxazole 1a and 20% imine 2a were obtained (entry 4).
Increasing the amount of molecular sieve to 4.2 or 6.3 g/mmol
obtained little progress in yields (entries 5 and 6). Using pure
O2 to facilitate the oxidation of benzaldehyde or imine 2a ob-
served little more benzoxazole 1a (entry 7, 38%), but no imine
2a was obtained. While changing to 3A or 4A molecular sieve
(entries 8 and 9), less benzoxazole 1a was obtained than using
5A molecular sieve. When heating time was raised to 48 hour,
similar yield of benzoxazole 1a was obtained (entry 10).
At this moment, we were not sure whether the low yield
of benzoxazole 1a was caused by evaporation of benzalde-
hyde with toluene in Dean & Stark trap. The condition was
changed to heat the reaction under refluxing at 150°C with-
out Dean & Stark trap, but less amount of benzoxazole 1a
and imine 2a was obtained (entry 11). While using methanol
as the solvent and heating the reaction at 130°C, the yield
dramatically dropped and only 5% of imine 2a was obtained
(entry 12). However, when the solvent was changed to xylene
side effects and increase the risk of health problems, especially
for the patients taking long-term dosage of medicines.
2
RESULTS AND DISCUSSIONS
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For environmental pollutions and health concerns, developing
green pathways of syntheses have attracted more attentions.
More efforts in the design of low-pollution pathways have
continuously reported. Based on the principle of green chemis-
try—“design of chemical products and process that reduces or
eliminate the use and generation of hazardous substances”,[14]
we reported a green synthesis of benzoxazole ring 1 through
MgSO4 dehydration and an anodic coupling.[13] While this
electrochemical pathway was applied in the total synthesis of
natural products containing benzoxazole ring, it is hard to ob-
tain imine 2 by MgSO4 dehydration when there is an electron-
withdrawing group (EWG) on 2-aminophenol 3 (Figure 2).
Even if using methanol or toluene as the solvent and
heating the reaction under refluxing or Dean & Stark trap at
130~150°C, the yield of imine 2 was not high. Surprisingly,
when adding molecular sieve to promote the dehydration
reaction to form the imine 2, benzoxazole 1 was obtained
directly from 2-aminophenol 3 and aldehydes after heating
the reaction to reflux under Dean-Stark trap at 150°C. No

CHANG et Al.
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TABLE 1 One-pot synthesis of benzoxazole ring
NH2
O
N
Ph
2a
N
O
+
Ph
1a
H
Ph
OH
OH
Molecular sieve (g/
mmol)
Entry
Benzaldehyde (eq.)
Solvent and temperature (°C)
Reaction time (h)
Yield
1
2
3
4
1.1
1.1
2.2
1.1
0
0
0
Toluene, 150
Toluene, 150
Toluene, 150
Toluene, 150
12
36
36
36
40% (2a)
62% (2a)
61% (2a)
3.1 (5A)
20% (2a)
31% (1a)
5
6
1.1
1.1
4.2 (5A)
6.3 (5A)
Toluene, 150
Toluene, 150
36
36
21% (2a)
31% (1a)
22% (2a)
32% (1a)
7a
8
1.1
1.1
6.3 (5A)
6.3 (3A)
Toluene, 150
Toluene, 150
36
36
38% (1a)
33% (2a)
14% (1a)
9
1.1
1.1
1.1
6.3 (4A)
6.3 (5A)
6.3 (5A)
Toluene, 150
Toluene, 150
Toluene, 150
36
48
48
34% (2a)
13% (1a)
10
11b
22% (2a)
36% (1a)
18% (2a)
29% (1a)
12b
13b
14
15
16
1.1
1.1
1.1
2.2
2.2
2.2
2.2
6.3 (5A)
6.3 (5A)
6.3 (5A)
6.3 (5A)
5.3 (5A)
4.2 (5A)
3.1 (5A)
Methanol, 130
48
48
48
48
48
48
48
5% (2a)
41% (1a)
45% (1a)
86% (1a)
80% (1a)
74% (1a)
70% (1a)
Xylene, 180~190
Xylene, 180~190
Xylene, 180~190
Xylene, 180~190
Xylene, 180~190
Xylene, 180~190
17
18
aReaction was under O2.
bOnly refluxing, 150°C.
and the reaction was heating to reflux at 180-190°C, the yield
of benzoxazole 1a increased to 41% (entry 13). When using
Dean-Stark trap of refluxing at 180-190°C, 45% of benzoxaz-
ole 1a was obtained (entry 14).
15). To search for suitable amount of molecular sieve, 5.3, 4.2
and 3.1 g/mmol of molecular sieve were tested (entries 16, 17
and 18) and 6.3 g/mmol is the best ratio (entry 15).
To further probe whether aldehyde does play dual roles
as a reactant/oxidant and molecular sieve serves as a cat-
alyst, we performed the benzoxazole synthesis from the
imine 2a (Table 2). When imine 2a with 5A molecular
sieve in xylene was heated to reflux at 180-190°C and no
additional aldehyde was added, only 41% of benzoxazole
1a was obtained (entry 1). With additional 1.1 equivalent
of aldehyde, the yield of benzoxazole 1a dramatically dou-
bled to 87% (entry 2). These two conditions prove that mo-
lecular sieve is not the oxidant to oxidize the imine 2a to
form benzoxazole 1a. Instead, the results indicate that it
may be the additional equivalent of aldehyde to serve as
The content of commercial 5A molecular sieve is [0.7
CaO:0.3 Na2O:1.0 Al2O3:2.0 SiO2:x H2O].[15] It is stable and
normally does not serve as oxidant or reductant. Comparing the
oxidation states of reagents and products, it is an oxidation re-
action when the carbonyl carbon of aldehyde becomes the car-
bon of benzoxazole. If the aldehyde serves as a reactant and an
oxidant, it is reasonable to obtain 45% of benzoxazole product
(entry 14) when 1.1 equivalent of benzaldehyde was used and
no additional oxidation reagent was used. To prove this specula-
tion, 2.2 equivalent of benzaldehyde was added and, inspiringly,
86% of benzoxazole 1a was obtained directly in one step (entry

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CHANG et Al.
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TABLE 2 Synthesis of benzoxazole
1a from imine 2a
molecular sieve (5A)
N
Ph
2a
N
O
Ph
1a
xylene, 180~190oC
Dean & Stark trap
OH
Molecular
Benzaldehyde
(eq.)
sieve (g/
mmol)
Reaction time
(h)
Entry
Yield
1
0
6.3
48
41% (1a)
1.1
6.3
48
87% (1a)
2
3
4
5
6
7
8a
1.1
0
0
6.3
6.3
6.3
0
48
48
48
24
12
48
99% (2a)
99% (2a)
66% (1a)
72% (1a)
60% (1a)
N/A
0.55
0.55
1.1
1.1
1.1
a1.0 equivalent of LiOCH3 was added.
the oxidant. When no molecular sieve was added, 99% of
imine 2a was recovered, even if benzaldehydes were added
(entries 3 and 4). This further implies that molecular sieve
plays an important role of the catalyst for oxidative cy-
clization reaction to form benzoxazole 1a from imine 2a
and a benzaldehyde. Adding molecular sieve but reducing
the amount of aldehyde to 0.55 equivalent (entry 5) or re-
action time (entries 6 and 7) lowered the yields of ben-
zoxazole 1a. When 1.0 equivalent of LiOMe was added,
only the spot of imine 2a and a spot with a very low Rf
value were shown on TLC plate, the latter of which sug-
gests the formation of N,O-acetal in the reaction, and no
benzoxazole 1a was obtained (entry 8). This proves that
it did not go through the pathway of Cannizzaro reaction
or Tischchenko reaction, in which the resulting carbox-
ylic acid derivatives from the aldehyde condensed with
2-aminophenol to form benzoxazole 1a.
Although benzyl alcohol signal is hard to be detected
by mass spectrometer, its existence could not be excluded.
Based on previous results, reaction mechanism of molec-
ular sieve-catalyzed oxidative cyclization was proposed
(Figure 3). In the beginning, the first equivalent of benzal-
dehyde condenses with amino group of 2-aminophenol to
form the imine 2 during refluxing. Then the weak base of
5A molecular sieve deprotonates the phenol group to form
phenolate 4-1, which favors to form 5-membered ring of
N,O-acetal anion 4-2.[13] Comparing to Na+ or Ca2+ ions,
it is more possible that Al3+ in molecular sieve plays the
role of Lewis acid, which facilitates the reduction of the
second equivalent benzaldehyde to benzyl alcohol and the
oxidation of N,O-acetal anion to obtain the benzoxazole
product under Dean & Stark trap condition.[16]
With the success of benzoxazole synthesis using benz-
aldehyde, experiments were extended to other aldehydes
to synthesize various benzoxazole derivatives (Table 3).
Methyl-, methoxy-, and chloro-substituents achieved 66%-
85% yield (entries 1-9). The yields for acidic aldehydes
of hydroxyl-substituents were 41%-61% (entry 10-11) and
benzyloxy-substituent was 66% (entry 12). For the basic al-
dehydes, the yields were 34%-42% (entry 13-14). As to the
alkyl-substituent like cyclohexane, 67% of product 1p was
obtained (entry 15). Heteroatom aldehydes got 22%-89% of
benzoxazole 1q-t (entry 16-19). The low yield for the furan-
2-carbaldehyde 1q might be because the low boiling point
(160°C). For aldehydes with nitrogen atom on the ring (1n,
1o, and 1t), the nitrogen is a better Lewis base to chelate
with molecular sieve than the oxygen of carbonyl group of
the aldehyde, which may interfere the process of reduction
reaction.
From these results, it can almost confirm that the first
equivalent of aldehyde is the reactant to form imine 2a. The
molecular sieve works as the catalyst and utilizes the second
equivalent of aldehyde as the oxidant to proceed oxidative
cyclization of imine 2a to form benzoxazole 1a.
To verify whether the second equivalent of benzaldehyde
serves as the oxidant, benzyl alcohol product is the evident.
Therefore, after refluxing by Dean-Stark trap, the reaction
mixture was filtered and washed by xylene. The crude solu-
tion and pure benzyl alcohol were tested, respectively, by ESI
and CI mass spectrometer. However, no signal of m/z=108
was obtained, even for the pure benzyl alcohol. This might
be because low boiling point and tendency to dehydration of
benzyl alcohol make it difficult to obtain the molecular ion
peak of benzyl alcohol in ESI and CI mass spectrum.

CHANG et Al.
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O
Cannizzaro reaction
pathway
2
H
Ph
+
LiOH
CH3OH
O
2
O
H
Ph
CH3OLi
Ph
HO
LiO
Ph Tishchenko reaction
O
molecular sieve 5A
+
pathway
Ph
+
O
H
2O
O
Al
O
O O
Si
O O
Si
Ph
NH2
N
Ph
+Na-O
O
O
O
H
Ph
2
condesation
OH
OH
H
..
N
Ph
N
Ph
O
Al
O O
Si
O O
Si
O
H
Ph
HO
-
O Na+
OH
not observed
4-1
4-2
O
O
O
O
+
H
Na+
..
N-
N
..
Ph
O
Ph
H
O
O
-
H
2O
1
H
Ph
FIGURE 3 Propose reaction
mechanism
To date, our newly developed pathway is the first method
which do not using and consuming additional chemical re-
agents in the synthesis of benzoxazole derivatives. Only
2-aminophenol, two equivalents of aldehyde reactant, and
non-toxic commercial 5A molecular sieve were added in the
reaction. Since hazardous chemical reagents and transition-
metal catalysts are not required, their corresponding harm-
ful chemical wastes are excluded then. Also, it simplifies
the reaction conditions in the synthesis of benzoxazole
derivatives and is no need to use complicated chemical
reagents, comparing to other reported methods (Figure 1).
This matches the goal of Green Chemistry. Moreover, it re-
duces the risks of remaining transition-metals or other toxic
chemicals in the products. This prevents the accumulation
of toxic contents for people who take daily food additives
or long-term dosage of drugs from artificial synthesis.
In summary, we have developed a clean and one-pot
reaction to synthesize benzoxazole derivatives through
molecular sieve-catalyzed oxidative cyclization reaction.
The new pathway offers an environmentally friendly reac-
tion conditions and excludes the usage of toxic chemical
reagents and catalysts. This not only reduces the pollutions
of various chemicals in the environment, but also keeps
away the toxic chemical contents, like transition metals, in
the artificially synthesized products from our diet. Also,
the simplified reaction pathway is suitable for industrial
large-scale synthesis because the cost of purchasing chem-
ical reagents is saved and the expenses to deal with the
resulting chemical wastes are reduced. Further reactions
applied in the green synthesis of pharmaceutical drugs are
in progress.[17]
3
EXPERIMENTAL SECTION
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All the chemical reagents were purchased from commer-
cial suppliers (Sigma-Aldrich, Acros, Alfa Aesar, etc.)
and used as received, unless otherwise indicated. The
molecular sieves (3A, 4A, and 5A) were made by J. T.
Baker, and used in the reaction after 96°C oven-dried.
Column chromatography separations were performed
using silica gel (70-230 mesh). Thin-layer chromatogra-
phy was carried out on glass plates (pre-coated TLC plates
DURASIL-25 UV254). 1H-NMR (300 MHz) and 13C-NMR
(75 MHz) spectra were recorded with 300 MHz spec-
trometers (VARIAN Mercury 300 Plus) in chloroform-d
or DMSO-d6. Chemical shifts (δ) are given in parts per
million and coupling constants are given as absolute val-
ues expressed in Hertz. LRMS and HRMS analyses were
performed on Fourier-transfer mass spectrometry (Bruker
APEX II) at High Valued Instrument Center of Ministry of
Science and Technology in Taiwan.
3.1
General experiment procedure
|
Under argon, oven-dried molecular sieve (3A, 4A or 5A)
and a stir bar were added to a 100-mL round bottle. After
cooled to room temperature, 45 mL anhydrous CH3OH or
distilled solvent (toluene or xylene) was added to dissolve
2-amino-phenol (0.2076 g, 1.8833 mmol) and aldehyde (1.1
or 2.2 equivalent) in the bottle. Then, a 10-mL Dean-Stark
receiver, containing oven-dried 5A molecular sieve with a
Graham condenser was inserted to the bottle. The resulting

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CHANG et Al.
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TABLE 3 Synthesis of benzoxazole derivatives
6.3 g/mmol
molecular sieve (5A)
NH2
OH
N
O
O
R
+
R
H
xylene
1b-t
Dean Stark trap
&
o
180~190 C, 48 h
Enrty
Aldehyde, R
Yield
1
74% (1b)
H
3C
2
75% (1c)
CH3
3
4
85% (1d)
78% (1e)
CH3
H
3CO
5
77% (1f)
OCH3
6
7
76% (1g)
72% (1h)
OCH3
Cl
8
66% (1i)
Cl
9
85% (1j)
41% (1k)
Cl
10
HO
(Continues)

CHANG et Al.
7 of 12
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TABLE 3 (Continued)
6.3 g/mmol
molecular sieve (5A)
NH2
+
OH
N
O
O
R
R
H
xylene
1b-t
Dean Stark trap
&
o
180~190 C, 48 h
Enrty
Aldehyde, R
Yield
11
61% (1l)
OH
12
13
66%
(1m)
OBn
CH3
34% (1n)
N
CH3
14
15
16
42% (1o)
67% (1p)
22% (1q)
N
O
17
58% (1r)
S
18
19
89% (1s)
31% (1t)
S
H
N
mixture was stirred very slowly in order not to grind the mo-
lecular sieve into powder by stir bar. After heating to reflux-
ing with or without Dean-Stark trap for 12~48 hours [130°C
for methanol; 150°C for toluene; 180~190°C for xylene],
the solution was filtered and the molecular sieve was thor-
oughly washed by EtOAc. The filtrate was concentrated and
the residue was purified via column chromatography (SiO2).
The elute solutions for column packing was 100% hexane
with 10% NEt3 (no NEt3 for 1k and 1l), and for purification
of benzoxazole derivatives (1a-t) was mixture of hexane
and EtOAc with 5% NEt3 (no NEt3 for 1k and 1l).
3.2
2-phenyl-benzoxazole (1a)[5a]
|
Elute solution (hexane:EtOAc=10:1 with 5% NEt3);
yield 86%; white solid; mp=95~97°C. H-NMR (CDCl3,
1
300 MHz): δ=8.29-8.23 (m, 2H), 7.82-7.76 (m, 1H),
7.58-7.53 (m, 1H), 7.53-7.47 (m, 3H), 7.36-7.31 (m,

8 of 12
CHANG et Al.
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2H) ppm. 13C-NMR (CDCl3, 75 MHz): δ=163.1, 150.8,
142.2, 131.5, 128.9, 127.7, 127.2, 125.1, 124.6, 120.1,
110.6 ppm. IR (KBr): 3059, 1617, 1552, 1471, 1454,
3.6
2-(2-methoxy-phenyl)-benzoxazole
|
(1e)[5a]
1446, 1343, 1290, 1242, 1052, 923, 744, 702, 688 cm−1
.
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield 78%;
yellow solid; mp=55~57°C. H-NMR (CDCl3, 300 MHz):
1
LRMS (ESI): C13H9NO, m/z=196 for [M+H]+; HRMS
(ESI): C13H9NO, m/z calcd. for [M+H]+: 196.0757;
found: 196.0758.
δ=8.10 (dd, J=7.8, 1.5 Hz, 1H), 7.84-7.77 (m, 1H), 7.57-
7.50 (m, 1H), 7.45-7.37 (td, J=7.8, 1.5 Hz, 1H), 7.32-7.25
(m, 2H), 7.06-6.97 (m, 2H), 3.93 (s, 3H) ppm. 13C-NMR
(CDCl3, 75 MHz): δ=161.5, 158.4, 150.2, 142.1, 132.7,
131.2, 124.9, 124.2, 120.6, 120.1, 116.0, 112.0, 110.4, 56.1
ppm. IR (KBr): 3048, 2958, 2924, 2835, 1614, 1597, 1583,
1550, 1536, 1494, 1483, 1452, 1432, 1309, 1264, 1245, 1122,
1035, 1021, 783, 750, 702 cm−1. LRMS (ESI): C14H11NO2,
m/z=226 for [M+H]+. HRMS (ESI): C14H11NO2, m/z calcd.
for [M+H]+: 226.0863; found: 226.0861.
3.3
2-(2-methyl-phenyl)-benzoxazole
|
(1b)[5a]
Elute solution (hexane:EtOAc=20:1 with 5% NEt3); yield
74%; yellow solid; mp=58~60°C. 1H-NMR (CDCl3,
300 MHz): δ=8.19 (d, J=8.4 Hz, 1H), 7.86-7.78 (m, 1H),
7.65-7.56 (m, 1H), 7.47-7.42 (m, 1H), 7.41-7.35 (m, 4H),
2.83 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ=163.6, 150.5,
142.3, 139.0, 132.0, 131.1, 130.1, 126.4, 126.2, 125.2,
124.5, 120.3, 110.6, 22.4. IR (KBr): 3059, 2958, 2924,
2846, 1613, 1550, 1485, 1452, 1239, 1029, 741, 724 cm−1.
LRMS (ESI): C14H11NO, m/z=210 for [M+H]+; HRMS
(ESI): C14H11NO, m/z calcd for [M+H]+: 210.0913; found:
210.0915.
3.7
2-(3-methoxy-phenyl)-benzoxazole
|
(1f)[5a]
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield
77%; yellow solid; mp=63~66°C. 1H-NMR (CDCl3,
300 MHz): δ=7.85 (dt, J=7.5, 1.3 Hz, 1H), 7.81-7.76 (m,
2H), 7.60-7.55 (m, 1H), 7.45-7.38 (t, J=8.0 Hz, 1H), 7.38-
7.32 (m, 2H), 7.08 (ddd, J=9, 2.3, 1.0 Hz, 1H), 3.89 (s, 3H)
ppm. 13C-NMR (CDCl3, 75 MHz): δ=163.1, 160.0, 150.9,
142.2, 130.1, 128.4, 125.3, 124.7, 120.2, 120.1, 118.4, 112.0,
110.7, 55.6 ppm. IR (KBr): 3059, 2997, 2952, 2936, 2829,
1603, 1583, 1552, 1491, 1479, 1452, 1297, 1242, 1041, 867,
761, 744, 683 cm−1. LRMS (ESI): C14H11NO2, m/z=226 for
[M+H]+. HRMS (ESI): C14H11NO2, m/z calcd. for [M+H]+:
226.0863; found: 226.0862.
3.4
2-(3-methyl-phenyl)-benzoxazole
|
(1c)[5a]
Elute solution (hexane:EtOAc=20:1 with 5% NEt3); yield
75%; yellow solid; mp=73~76°C. 1H-NMR (CDCl3,
300 MHz): δ=8.10 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.83-
7.76 (m, 1H), 7.60-7.54 (m, 1H), 7.45-7.37 (t, J=7.5 Hz,
2H), 7.37-7.32 (m, 2H), 2.45 (s, 3H) ppm. 13C-NMR
(CDCl3, 75 MHz): δ=163.4, 150.8, 142.2, 138.8, 132.5,
128.9, 128.3, 127.1, 125.2, 124.9, 124.7, 120.1, 110.7, 21.5
ppm. IR (KBr): 3048, 2913, 2952, 2852, 1611, 1550, 1474,
1452, 1242, 1175, 1055, 862, 744, 716, 685, 439 cm−1.
LRMS (ESI): C14H11NO, m/z=210 for [M+H]+. HRMS
(ESI): C14H11NO, m/z calcd. for [M+H]+: 210.0913; found:
210.0915.
3.8
2-(4-methoxy-phenyl)-benzoxazole
|
(1g)[5a]
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield 76%;
white solid; mp=97~98°C. 1H-NMR (CDCl3, 300 MHz):
δ=8.19 (d, J=9 Hz, 2H), 7.77-7.71 (m, 1H), 7.57-7.51 (m,
1H), 7.35-7.28 (m, 2H), 7.01 (d, J=8.7 Hz, 2H), 3.85 (s, 3H)
ppm. 13C-NMR (CDCl3, 75 MHz): δ=163.3, 162.4, 150.8,
142.4, 129.5, 124.7, 124.5, 119.8, 119.7, 114.5, 110.5, 55.5
ppm. IR (KBr): 3048, 2975, 2952, 2919, 2840, 1620, 1614,
1606, 1580, 1502, 1455, 1421, 1253, 1242, 1169, 1018, 831,
758, 741, 727, 632, 517 cm−1. LRMS (ESI): C14H11NO2,
m/z=226 for [M+H]+. HRMS (ESI): C14H11NO2, m/z calcd.
for [M+H]+: 226.0863; found: 226.0861.
3.5
2-(4-methyl-phenyl)-benzoxazole
|
(1d)[5a]
Elute solution (hexane:EtOAc=20:1 with 5% NEt3); yield
85%; yellow solid; mp=112~113°C. 1H-NMR (CDCl3,
300 MHz): δ=8.16 (d, J=8.1 Hz, 2H), 7.81-7.74 (m, 1H),
7.61-7.55 (m, 1H), 7.38-7.31 (m, 4H), 2.45 (s, 3H) ppm.
13C-NMR (CDCl3, 75 MHz): δ=163.5, 150.9, 142.4, 142.3,
129.9, 127.8, 125.1, 124.7, 124.6, 120.1, 110.7, 21.9 ppm.
IR (KBr): 3053, 2958, 2913, 2852, 1620, 1552, 1499,
1449, 1242, 1178, 1055, 820, 744, 736, 724, 498 cm−1.
LRMS (ESI): C14H11NO, m/z=210 for [M+H]+. HRMS
(ESI): C14H11NO, m/z calcd for [M+H]+: 210.0913; found:
210.0915.
3.9
2-(2-chloro-phenyl)-benzoxazole (1h)[5a]
|
Elute solution (hexane:EtOAc=20:1 with 5% NEt3); yield
72%; yellow solid; mp=64~66°C. 1H-NMR (CDCl3,
300 MHz): δ=8.11-8.06 (m, 1H), 7.85-7.79 (m, 1H), 7.56-
7.52 (m, 1H), 7.50-7.45 (m, 1H), 7.34-7.29 (m, 4H) ppm.

CHANG et Al.
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|
13C-NMR (CDCl3, 75 MHz): δ=160.8, 150.4, 141.6, 133.3,
131.8, 131.7, 131.3, 126.8, 126.1, 125.5, 124.6, 120.4, 110.7
ppm. IR (KBr): 3064, 1611, 1592, 1569, 1552, 1536, 1471,
1452, 1432, 1239, 1083, 1027, 811, 758, 741, 727, 652,
459 cm−1. LRMS (ESI): C13H8ClNO, m/z=230 for [M+H]+.
HRMS (ESI): C13H8ClNO, m/z calcd. for [M+H]+: 230.0367;
found: 230.0366.
3.13
3-(benzoxazol-2-yl)phenol (1l)[12a]
|
Elute solution (hexane:EtOAc=2:1); yield 61%; white solid;
mp=218~222°C.1H-NMR (DMSO-d6, 300 MHz): δ=9.97
(s, 1H), 7.83-7.74 (m, 2H), 7.67-7.57 (m, 2H), 7.46-7.35
(m, 3H), 7.02 (d, J=8.1 Hz, 1H) ppm. 13C-NMR (DMSO-d6,
75 MHz): δ=162.3, 157.9, 150.2, 141.5, 130.5, 127.5, 125.5,
124.8, 119.8, 119.1, 118.0, 113.6, 110.9 ppm. IR (KBr): 3412,
1650, 1631, 1614, 1597, 1547, 1449, 1298, 1236, 758, 747,
666 cm−1. LRMS (ESI): C13H9NO2, m/z=212 for [M+H]+.
HRMS (ESI): C13H9NO2, m/z calcd. for [M+H]+: 212.0706;
found: 212.0708.
3.10
2-(3-chloro-phenyl)-benzoxazole
|
(1i)[5a]
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield
66%; yellow solid; mp=131~132°C. 1H-NMR (CDCl3,
300 MHz): δ=8.18 (s, 1H), 8.06 (d, J=7.5 Hz, 1H),
7.78-7.71 (m, 1H), 7.55-7.49 (m, 1H), 7.46-7.29 (m,
4H) ppm. 13C-NMR (CDCl3, 75 MHz): δ=161.6, 150.8,
141.9, 135.1, 131.5, 130.2, 128.8, 127.6, 125.6, 125.6,
124.8, 120.3, 110.7 ppm. IR (KBr): 3053, 1614, 1572,
1547, 1469, 1452, 1432, 1340, 1295, 1281, 1239, 1192,
1049, 929, 822, 758, 738, 713, 671, 436 cm−1. LRMS
(ESI): C13H8ClNO, m/z=230 for [M+H]+. HRMS (ESI):
C13H8ClNO, m/z calcd. for [M+H]+: 230.0367; found:
230.0366.
3.14
2-(4-(benzyl-oxy)phenyl)benzoxazole
|
(1m)[5e]
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield 66%;
white solid; mp=149~150°C. H-NMR (CDCl3, 300 MHz):
1
δ=8.22 (d, J=8.4 Hz, 2H), 7.79-7.73 (m, 1H), 7.60-7.54 (m,
1H), 7.50-7.31 (m, 7H), 7.12 (d, J=8.7 Hz, 2H), 5.16 (s, 2H)
ppm. 13C-NMR (CDCl3, 75 MHz): δ=163.3, 161.6, 150.8,
142.4, 136.5, 129.6, 128.9, 128.4, 127.7, 124.8, 124.6, 120.1,
119.8, 115.4, 110.6, 70.3 ppm. IR (KBr): 3047, 2930, 2913,
2857, 1617, 1600, 1577, 1497, 1451, 1248, 1172, 1057,
1010, 831, 744, 697, 523 cm−1. LRMS (ESI): C20H15NO2,
m/z=302 for [M+H]+. HRMS (ESI): C20H15NO2, m/z calcd.
for [M+H]+: 302.1176; found: 302.1175.
3.11
2-(4-chloro-phenyl)-benzoxazole
|
(1j)[5a]
Elute solution (hexane:EtOAc=10:1 with 5% NEt3); yield
85%; white solid; mp=147~148°C. 1H-NMR (CDCl3,
300 MHz): δ=8.18 (d, J=8.4 Hz, 2H), 7.80-7.74 (m, 1H),
7.60-7.54 (m, 1H), 7.53-7.46 (d, J=8.7 Hz, 2H), 7.40-7.33
(m, 2H) ppm. 13C-NMR (CDCl3, 75 MHz): δ=162.2, 150.9,
142.2, 137.9, 129.4, 129.0, 125.8, 125.5, 124.9, 120.3, 110.8
ppm. IR (KBr): 3059, 1614, 1555, 1536, 1483, 1452, 1404,
1343, 1273, 1245, 1091, 1055, 1010, 923, 890, 831, 758, 738,
495 cm−1. LRMS (ESI): C13H8ClNO, m/z=230 for [M+H]+.
HRMS (ESI): C13H8ClNO, m/z calcd. for [M+H]+: 230.0367;
found: 230.0367.
3.15
4-(benzoxazol-2-yl)-N,N-di-methyl-
|
aniline (1n)[7e]
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield
34%; brown solid; mp=177~179°C. 1H-NMR (CDCl3,
300 MHz): δ=8.11 (d, J=8.7 Hz, 2H), 7.72-7.67 (m, 1H),
7.54-7.49 (m, 1H), 7.32-7.24 (m, 2H), 6.77 (dt, J=9.5,
2.3 Hz, 2H), 3.06 (s, 6H) ppm. 13C-NMR (CDCl3, 75 MHz):
δ=164.4, 152.6, 150.8, 142.8, 129.3, 124.3, 124.1, 119.3,
114.4, 111.8, 110.3, 40.3 ppm. IR (KBr): 3048, 2896, 1614,
1566, 1513, 1454, 1373, 1242, 1180, 1055, 917, 811, 747,
509 cm−1. LRMS (ESI): C15H14N2O, m/z=239 for [M+H]+.
HRMS (ESI): C15H14N2O, m/z calcd. for [M+H]+: 239.1179;
found: 239.1178.
3.12
2-(benzoxazol-2-yl)phenol (1k)[5d]
|
Elute solution (hexane:EtOAc=5:1); yield 41%; yellow solid;
mp=121~122°C. 1H-NMR (CDCl3, 300 MHz): δ=11.48 (bs,
1H), 8.03 (dd, J=8.0, 1.8 Hz, 1H), 7.76-7.71 (m, 1H), 7.64-
7.59 (m, 1H), 7.44 (td, J=7.8, 1.8 Hz, 1H), 7.41-7.36 (m,
2H), 7.13 (dd, J=8.4, 1.1 Hz, 1H), 7.01 (td, J=7.2, 1.1 Hz,
1H) ppm. 13C-NMR (CDCl3, 75 MHz): δ=163.1, 158.9,
149.3, 140.2, 133.8, 127.3, 125.6, 125.2, 119.8, 119.5, 117.6,
110.9, 110.8 ppm. IR (KBr): 3059, 1631, 1586, 1544, 1485,
1451, 1259, 1248, 1236, 1049, 738, 704, 683, 669, 464 cm−1.
LRMS (ESI): C13H9NO2, m/z=212 for [M+H]+. HRMS
(ESI): C13H9NO2, m/z calcd. for [M+H]+: 212.0706; found:
212.0708.
3.16
2-(pyridin-4-yl)benzoxazole (1o)[7i]
|
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield
42%; white solid; mp=128~129°C. 1H-NMR (CDCl3,
300 MHz): δ=7.78 (dd, J=4.5, 1.5 Hz, 2H), 8.03 (dd, J=4.8,
1.5 Hz, 2H), 7.81-7.75 (m, 1H), 7.61-7.55 (m, 1H), 7.43-
7.32 (m, 2H) ppm. 13C-NMR (CDCl3, 75 MHz): δ=160.6,
150.9, 150.8, 141.8, 134.4, 126.4, 125.2, 121.0, 120.7, 111.0
ppm. IR (KBr): 3042, 1614, 1594, 1538, 1469, 1449, 1410,
1345, 1292, 1225, 1110, 1055, 926, 831, 750, 703, 515 cm−1.

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CHANG et Al.
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LRMS (ESI): C12H8N2O, m/z=197 for [M+H]+. HRMS
(ESI): C12H8N2O, m/z calcd. for [M+H]+: 197.0709; found:
197.0710.
1001, 940, 864, 800, 758, 744, 719, 601 cm−1. LRMS (ESI):
C11H7NOS, m/z=202 for [M+H]+. HRMS (ESI): C11H7NOS,
m/z calcd. for [M+H]+: 202.0321; found: 202.0323.
3.17
2-cyclohexyl-benzoxazole (1p)[4d]
3.21
2-(1H-pyrrol-2-yl)benzoxazole (1t)
|
|
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield 67%;
yellow solid; mp=36~37°C. H-NMR (CDCl3, 300 MHz):
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield
31%; white solid; mp=144~145°C. 1H-NMR (CDCl3,
300 MHz): δ=11.64 (bs, 1H), 7.73-7.65 (m, 1H), 7.61-7.53
(m, 1H), 7.39-7.29 (m, 2H), 7.19-7.13 (m, 1H), 7.10-7.04 (m,
1H), 6.45-6.37 (m, 1H) ppm. 13C-NMR (CDCl3, 75 MHz):
δ=158.8, 150.3, 141.7, 124.8, 124.5, 123.6, 119.8, 118.7,
113.7, 110.9, 110.6 ppm. IR (KBr): 3171, 3137, 3020, 1630,
1614, 1586, 1572, 1555, 1536, 1519, 1504, 1455, 1401,
1241, 1127, 1032, 948, 730, 666, 430 cm−1. LRMS (ESI):
C11H8N2O, m/z=185 for [M+H]+. HRMS (ESI): C11H8N2O,
m/z calcd. for [M+H]+: 185.0709; found: 185.0709.
1
δ=7.65-7.57 (m, 1H), 7.40-7.33 (m, 1H), 7.20-7.15 (m, 2H),
2.93-2.77 (m, 1H), 2.15-2.02 (m, 2H), 1.82-1.56 (m, 5H), 1.42-
1.22 (m, 3H) ppm. 13C-NMR (CDCl3, 75 MHz): δ=170.6,
150.8, 141.5, 124.5, 123.1, 119.8, 110.4, 38.0, 30.6, 25.9,
25.8 ppm. IR (KBr): 3053, 2930, 2852, 1611, 1566, 1455,
1241, 1155, 1010, 940, 834, 764, 741 cm−1. LRMS (ESI):
C13H15NO, m/z=202 for [M+H]+. HRMS (ESI): C13H15NO,
m/z calcd. for [M+H]+: 202.1226; found: 202.1228.
3.18
2-(furan-2-yl)benzoxazole (1q)[7e]
|
3.22
2-(benzylideneamino)phenol (2a)[13]
|
Elute solution (hexane:EtOAc=10:1 with 5% NEt3); yield
22%; red brown solid; mp=83~85°C. 1H-NMR (CDCl3,
300 MHz): δ=7.77-7.72 (m, 1H), 7.65 (m, 1H), 7.57-7.52
(m, 1H), 7.36-7.31 (m, 2H), 7.26 (d, J=3.8 Hz, 1H), 6.60
(m, 1H) ppm. 13C-NMR (CDCl3, 75 MHz): δ=155.5, 150.3,
145.9, 142.8, 141.8, 125.5, 125.0, 120.3, 114.5, 112.4, 110.7
ppm. IR (KBr): 3126, 3109, 3064, 1645, 1634, 1620, 1589,
1536, 1474, 1449, 1396, 1343, 1301, 1245, 1158, 1080, 1013,
940, 901, 884, 794, 758, 744, 590, 431 cm−1. LRMS (ESI):
C11H7NO2, m/z=186 for [M+H]+. HRMS (ESI): C11H7NO2,
m/z calcd. for [M+H]+: 186.0550; found: 186.0550.
Under argon, 2-aminophenol (2.0005 g, 0.0181 mol) and
MgSO4 (7.2955 g, 0.0605mol) were dissolved in anhydrous
THF or CH2Cl2 (20 mL) before benzaldehyde (2.4 mL,
0.0234 mol) was added to the solution. Aft stirred at room
temperature for overnight, the reaction was filtered, washed
by EtOAc and concentrated. The crude product was purified
through a pad of silica gel twice using hexane:EtOAc=10:1 with
10% NEt3 as elute solution to afford 2a as an red-brown solid
(3.4735 g, 0.0176 mol, 97%); mp=88~89°C. 1H-NMR (CDCl3,
300 MHz): δ=8.71 (s, 1H), 7.97-7.91 (m, 2H), 7.55-7.47 (m,
3H), 7.32 (dd, J=8.1, 1.5 Hz, 1H), 7.22 (td, J=7.7, 1.5 Hz,
1H), 7.05 (dd, J=8.1, 1.5 Hz, 1H), 6.93 (td, J=7.7, 1.5 Hz, 1H)
ppm. 13C-NMR (CDCl3, 75 MHz): δ=157.3, 152.4, 135.9,
135.6, 131.7, 129.0, 128.9, 120.2, 116.1, 116.1, 115.2 ppm. IR
(KBr): 3333, 3036, 3014, 1623, 1583, 1572, 1480, 1449, 1379,
1248, 1147, 1027, 850, 763, 688, 632, 501 cm−1. LRMS (ESI):
C13H11NO, m/z=198 for [M+H]+. HRMS (ESI): C13H11NO,
m/z calcd. for [M+H]+: 198.0913; found: 198.0915.
3.19
2-(thiophen-2-yl)benzoxazole (1r)[7e]
|
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield 58%;
yellow solid; mp=94~96°C. H-NMR (CDCl3, 300 MHz):
1
δ=7.89 (dd, J=3.9, 1.2 Hz, 1H), 7.76-7.71 (m, 1H), 7.55-
7.49 (m, 2H), 7.35-7.29 (m, 2H), 7.15 (t, J=4.4 Hz, 1H)
ppm. 13C-NMR (CDCl3, 75 MHz): δ=159.1, 150.5, 142.1,
130.3, 130.0, 129.7, 128.3, 125.2, 124.8, 119.9, 110.5 ppm.
IR (KBr): 3081, 1614, 1569, 1494, 1452, 1421, 1245, 1225,
1049, 1004, 850, 792, 758, 741, 716 cm−1. LRMS (ESI):
C11H7NOS, m/z=202 for [M+H]+. HRMS (ESI): C11H7NOS,
m/z calcd. for [M+H]+: 202.0321; found: 202.0323.
ACKNOWLEDGMENTS
We thank Ministry of Science and Technology (MOST
105-2113-M-390-004)/(MOST 104-2633-M-390-001) and
National Science Council (NSC-102-2113-M-390-002) for
the financial support, Prof. Tsengchang Tsai for assistance of
research work and Ms. Hsiaoching Yu for the assistance of
LRMS and HRMS.
3.20
2-(thiophen-3-yl)benzoxazole (1s)[7e]
|
Elute solution (hexane:EtOAc=5:1 with 5% NEt3); yield 89%;
white solid; mp=132~134°C. H-NMR (CDCl3, 300 MHz):
1
δ=8.18 (s, 1H), 7.79 (d, J=5.1 Hz, 1H), 7.77-7.73 (m, 1H),
7.56-7.51 (m, 1H), 7.45-7.40 (m, 1H), 7.35-7.31 (m, 2H)
ppm. 13C-NMR (CDCl3, 75 MHz): δ=159.8, 150.5, 142.1,
129.4, 128.2, 127.1, 126.7, 125.1, 124.7, 120.0, 110.6 ppm. IR
(KBr): 3092, 1620, 1580, 1494, 1452, 1407, 1278, 1242, 1055,
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How to cite this article: Chang W, Sun Y, and Huang
Y. One-pot green synthesis of benzoxazole derivatives
through molecular sieve-catalyzed oxidative cyclization
reaction. Heteroatom Chem. 2017;00:e21360.
doi:10.1002/hc.21360
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