Amino Acids: Nontoxic and Cheap Alternatives for Amines for the Synthesis of Benzoxazoles through the Oxidative Functionalization of Catechols

Article abstract of DOI:10.1002/adsc.201901096

The nano magnetic Fe₃O₄ (NM?Fe₃O₄) was applied for the synthesis of benzoxazoles via a C(aryl)?OH functionalization of catechol derivatives and amines in ethanol at room temperature. In the next step, amino acids have been applied as nontoxic and cheap alternatives for amines. The obtained products were similar with the regular amines case. This is the first report about the application of amino acids as alternatives for primary amines in organic synthesis. Furthermore, the presented method was successfully applied toward the synthesis of desired products in large scales. (Figure presented.).

Full text of DOI:10.1002/adsc.201901096

Title: Amino Acids: Nontoxic and Cheap Alternatives for Amines
for the Synthesis of Benzoxazoles through the Oxidative
Functionalization of Catechols
Authors: Hashem Sharghi, Jasem Aboonajmi, Mahdi Aberi, and
Mohsen Shekouhy
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901096
Link to VoR: http://dx.doi.org/10.1002/adsc.201901096

10.1002/adsc.201901096
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Amino Acids: Nontoxic and Cheap Alternatives for Amines for
the Synthesis of Benzoxazoles through the Oxidative
Functionalization of Catechols
Hashem Sharghia*, Jasem Aboonajmia, Mahdi Aberib, Mohsen Shekouhya
a
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
[Corresponding author: Tel: (+98)7136137136, Fax: (+98)7132280926, E-mail: shashem@chem.susc.ac.ir]
Department of Chemical and Materials Engineering, Faculty of Shahid Rajaee, Shiraz Branch, Technical and
b
Vocational University (TVU), Shiraz, Iran
Received: ((will be filled in by the editorial staff))
Supporting information for this article containing the characterization data of applied NM-Fe3O4 (FTIR, SEM, VSM, EDX
and XRD) and copy of 1H and 13C NMR of synthesized compounds is available on the WWW under
http://dx.doi.org/10.1002/adsc.201######.((Please delete if not appropriate))
Abstract The nano magnetic Fe3O4 (NM-Fe3O4) was applied
for the synthesis of benzoxazoles via a C(aryl)-OH
functionalization of catechol derivatives and amines in
ethanol at room temperature. In the next step, amino acids
have been applied as nontoxic and cheap alternatives for
amines. The obtained products were similar with the regular
amines case. This is the first report about the application of
amino acids as alternatives for primary amines in organic
synthesis. Furthermore, the presented method was
successfully applied toward the synthesis of desired products
in large scales.
Keywords: Benzaoxazole; C(aryl)-OH oxidative
functionalization; Nano magnetic Fe3O4; Amino acid
dichloroethane and ethanol as solvents
respectively. Unfortunately, these methods suffer
from some drawbacks such as application of
Introduction
Between various kinds of heterocyclic
compounds, benzoxazoles occupy an important
place because these compounds are found as the
key substructures of various natural products[1]
and functionalized materials.[2] Moreover, these
compounds show some unique biological
activities and have been widely applied as
antitumor, antiviral, and antimicrobial agents.[3]
Besides, there are recent reports about the
application of benzoxazoles as novel herbicidal
agent for the treatment of duchenne muscular
dystrophy.[4] Based on these important
applications and unique biological properties,
many efficient methods have been developed for
the synthesis of functionalized benzoxazoles.[5]
One of the newest strategies is the C(aryl)-OH
oxidative functionalization of catechols with
amines which was conducted using CuBr[6] and
non-reusable
and
expensive
catalyst[6],
application of hazardous halogenated solvents[6],
tedious preparation of catalyst[7], restriction to
micro scale synthesis[6,7] and need to the
regeneration of catalyst after each reaction
cycle.[7] As a result, there is a great demand for
introducing more practical and efficient catalytic
systems for the synthesis of benzoxazoles through
the C(aryl)-OH oxidative functionalization of
catechols in more benign reaction media.
One of the main aspects of Green Chemistry is
the design of synthetic pathways in such a way
that provide the lowest risk and hazard to the
human health. In order to gain this goal, several
strategies have been stablished such as the
elimination of hazardous organic solvents and
conducting the reactions in solvent-free
conditions [8], replacement of organic solvents
with water [9] and
mixed
oxide octahedral molecular sieve
supported Cu hydroxide[7] as catalysts in 1,2-
valent
manganese
(
OMS-2)-
1
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
Scheme 1. The NM-Fe3O4 catalyzed synthesis of benzoxazoles (4a-as) via the oxidative functionalization of 3,5-di-tert-
butylbenzene-1,2-diol (1) with primary amines (2) (Path A) or amino acids (3) (Path B).
Scheme 2. The reaction of 3,5-di-tert-butylbenzene-1,2-diol (1, 1 mmol) and 2-methylpropane-1-amine (2a, 1 mmol) in
the presence of various catalysts under different reaction conditions.
OH functionalization of catechols in the presence
of nano magnetic Fe3O4 (NM-Fe3O4) in aqueous
medium (Scheme 1).
application of less hazardous reaction media such
as ionic liquids[10] or glycerol.[11] Many attempts
have been made to replace hazardous solvents,
however, there is not any report about the
replacement of hazardous starting materials with
nontoxic alternatives. In this context, the
application of natural small compounds as
nontoxic and biodegradable alternatives for
frequently used starting materials for the
synthesis of biologically active compounds may
lead to the introducing more benign and less
hazardous synthetic pathways.
Results and Discussion
Our initial study was focused on the search for an
appropriate catalytic system and reaction conditions
for the synthesis of benzoxazoles via a C(aryl)-OH
oxidative functionalization process. For this, the
reaction of 3,5-di-tert-butylbenzene-1,2-diol (1) and
2-methylpropane-1-amine (2a) (Scheme 2) was
selected as the model reaction and the yield of
product and the reaction time were monitored in the
presence of various catalysts under different reaction
conditions. The obtained results are summarized in
Table 1. At the begining, the catalytic activity of a
variety of organic acids such as oxalic acid, succinic
acid, tartaric acid and sulfamic acid were studied and
in all cases no product was obtained (Table 1, entries
1-4 respectively). The similar result was obtained
with the application of Bu4N+Br- (Table 1, entry 5).
About 50% yield of desired product (4a) was
obtained in the presence of L-proline after 12 h
(Table 1, entry 6). In contineous, the model reaction
was studied in the presence of some Lewis acids
Amino acids are the main constituents of proteins
and are highly necessary for the health. The
simultaneous presence of two important
functional groups (amino and carboxylic groups)
in
combination
with
nontoxicity
and
biodegradability makes these compounds suitable
starting materials for the synthesis of organic
compounds under more environmentally safe
conditions. Unfortunately, there are very few
reports regarding the application of amino acids
as starting materials for the synthesis of organic
compounds.[12]
Considering these facts and in continuation of
our recent researches on the introducing more
efficient methods for the synthesis of organic
compounds[13], we herein introduce amino acids
as nontoxic and cheap alternatives for amines in
the synthesis of benzoxazoles through a C(aryl)-
including
ZrOCl2.8H2O,
Cd(NO3)2.6H2O,
NiCl2.6H2O, SnCl2 and MnCl2.4H2O and no
improvement in the reaction yield was observed
2
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
(Table 1, entries 7-11 respectively). However, with
the application of FeCl3 as the catalyst,
Table 1. The reaction of 3,5-di-tert-butylbenzene-1,2-diol (1, 1 mmol) and 2-methylpropane-1-amine (2a, 1 mmol) in the
presence of various catalysts under different reaction conditions.
Catalyst quantity
Entry
Catalyst
Solvent (2 mL) Temp. (oC) Time (h) Yield (%)a
(mol%)
20
20
20
20
20
20
20
20
20
20
20
20
2
1
2
Oxalic acid
Succinic acid
Tartaric acid
Sulfamic acid
Bu4N+Br-
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
CH3CN
DCM
DCE
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
12
12
12
12
12
12
12
12
12
12
12
12
2
N.R.
N.R.
Trace
N.R.
N.R.
50
3
4
5
6
L-proline
7
ZrOCl2.8H2O
Cd(NO3)2.6H2O
NiCl2.6H2O
SnCl2
45
8
Trace
30
9
10
11
12
13
14
15
16
17b
18
19
20
21
22
23
24
25
MnCl2.4H2O
FeCl3
40
70
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
NM-Fe3O4
-
80
2
5
72
2
3
75
2
2
85
2
PEG
12
12
12
12
2
Trace
17
2
H2O
2
CHCl3
-
30
2
61
2
EtOH
EtOH
EtOH
EtOH
98
1
5
92
-
12
12
N.R.
71
Bulked Fe3O4
2
a Isolated yields. b Polyethylene glycol 400 was applied as a solvent.
Table 2. The synthesis of benzoxazoles (4a-aa) via the reaction of 3,5-di-tert-butylbenzene-1,2-diol (1, 1 mmol) and
primary amines (2, 1 mmol) in the presence of NM-Fe3O4 (2 mol%) in ethanol (2 mL) at room temperature.
Entry
Amine
Product
Time (h)
Yield (%)a
1
2
98
2b
3c
4
4
5
89
75
90
2.5
3
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
5
6
7
3
3
88
90
75
4.5
8
2
94
9
2.5
2.5
2
90
89
93
10
11
12
13
2
2
95
95
14
2
91
15
3
94
74
16d
4.5
17d
4
79
4
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
18d
19
3.5
5
82
85
20
21
22
2
2
2
92
90
93
23
24
25
2
2
3
90
91
90
26
27
3
90
3
93
c
a Isolated yields. b A 70% aqueous solution of ethylamine was used. A 40% aqueous solution of methylamine was used. d
2 mmol of 3,5-di-tert-butylbenzene-1,2-diol has been applied.
5
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
Scheme 3. The reaction of 3,5-di-tert-butylbenzene-1,2-diol (1, 1 mmol) and glycine (3a, 1 mmol) in H2O/EtOH 3:1 (4
mL) in the presence of NM-Fe3O4 at reflux temperature.
Table 3. The synthesis of benzoxazoles via the reaction of 3,5-di-tert-butylbenzene-1,2-diol (1, 1 mmol) and amino acids
(3, 1 mmol) as nontoxic and cheap alternatives for amines in the presence of NM-Fe3O4 (2 mol%) in H2O/EtOH 3:1 (4
mL) at reflux temperature.
Yield
Entry
Amino acid
product
Time (h)
(%)a
1
5.5
83
2
3
4
3
85
92
4b
5
88
5
6
8
3
80
94
7b
6
70
8
9
5.5
4.5
85
85
6
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
10
3.5
93
11
12
5
8
8
87
85
88
13
a Isolated Yield. b 2 mmol of 3,5-di-tert-butylbenzene-1,2-diol has been applied.
Table 4. The large scale synthesis of benzoxazoles (4) via
the C(aryl)-OH functionalization of 3,5-di-tert-
butylbenzene-1,2-diol (1) with amino acids (3) in the
presence of NM-Fe3O4 (2 mol%) in H2O/EtOH 3:1 at
reflux temperature.
explored and the best result was obtained in EtOH
(Table 1, entries 13-20). The model reaction was also
studied without any catalyst and the reaction was not
proceeded even with a long reaction time (Table 1,
entry 23). This observation proves the catalytic role
and necessity of NM-Fe3O4 for this reaction.
Moreover, bulked Fe3O4 was applied as a catalyst and
lower yield of desired product (71%) was obtained
even in a long reaction time (12 h) (Table 1, entry
24). This result approves the higher efficiency of
NM-Fe3O4 in comparison with bulked Fe3O4 (comes
from the higher surface/volume ratio of NM-Fe3O4)
as it has been expected. Finally, based on the
obtained results and from summarized data in Table
1, application of 2 mol% of NM-Fe3O4 in ethanol at
room temperature was selected as the best reaction
conditions.
Amount of catechol
(mmol)
Yield
(%)a
Product
Time (h)
1
3
6
94
89
90
85
81
75
80
73
70
85
80
73
10
4a
20
6
1
4
10
10
10
8
4b
4ad
4ae
20
1
10
15
15
55
12
12
20
1
In continuous, with the optimized reaction conditions
in hand and to assess the generality and scope of our
method, various primary amines (2, 1 mmol)
containing benzylamines, aliphatic amines and
aliphatic 1,n-diamines (n= 2, 4, 6) were reacted with
3,5-di-tert-butylbenzene-1,2-diol (1, 1 mmol) and the
results are displayed in Table 2. As it is shown in
Table 2, all benzylamines bearing either electron
withdrawing or electron donating substituents on
aromatic ring reacted with 3,5-di-tert-butylbenzene-
1,2-diol (1) smoothly and offered desired
benzoxazoles in excellent yields with a short reaction
time (Table 2, entries 13 and 20-27). Therefore, the
nature of substituent on the aromatic rings of applied
benzylamines did not affected the reaction yields and
times. This can be due to the remoteness of the
reaction center from the aromatic rings of applied
benzylamines. In addition, in the case of primary
amines having acid or base sensitive groups such as
10
20
a Isolated yield.
the isolated yield of desired product (4a) was
increased to 70% (Table 1, entry 12). This
improvement in the reaction yield showed that the
Fe(III) could be a proper catalyst for the titled
reaction. However, the solubility of FeCl3 in ethanol
makes the catalyst separation and recycling process
difficult. Hence, with the consideration of
heterogeneous nature of Fe3O4 and advantages of
nanocatalysts, the catalytic activity of NM-Fe3O4 was
checked in the model reaction and
a huge
improvement in the overall yield was obtained in
shorter time with only 2 mol% of catalyst (Table 1,
entry 21). Moreover, the effect of a range of organic
solvents as well as solvent-free conditions was also
7
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
cyano and amino substituents on the aromatic rings of
benzylamines (Table 2, entries
Scheme 4. The proposed mechanism for the synthesis of benzoxazoles (4) from the reaction of 3,5-di-tert-butylbenzene-
1,2-diol (1) and amino acids (3) in the presence of NM-Fe3O4 at reflux temperature.
Table 5. The reaction of 4-(tert-butyl)benzene-1,2-diol, 4-(methoxy)benzene-1,2-diol, 3-(methyl)benzene-1,2-diol and 4-
(nitro)benzene-1,2-diol with amines or amino acids under the optimized reaction conditions.
Amine or Amino
Entry
1
R1
H
R2
R3
H
Product
Time (h)
3
Yield (%)a
91
acid
t-Bu
2
3
H
H
t-Bu
t-Bu
H
H
3
3
90
91
8
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
4
5
6
H
H
H
H
H
H
Me
Me
Me
4
4
4
88
82
85
7
8
H
H
H
H
H
H
OMe
OMe
OMe
NO2
NO2
H
H
H
3
3
84
88
9
H
3
91
10
11
12
H
12
12
7
N.R.
N.R.
80
H
Me
13
H
OMe
H
5
85
a Isolated yield.
3,4-dihydroxybenzoic
acid,
ethyl
2,3,4-
23, 24), heteroaromatic and heterocyclic groups
(Table 2, entries 8-12) and carbamates (Table 2, entry
15), the reactions were proceeded very well and
desired products were obtained in excellent yields
without any chemical changes in sensitive groups.
Also, in the case of simple linear alkyl amines,
desired products were obtained in good to excellent
yields (Table 2, entries 1-7).
trihydroxybenzoate, pyridine-2,3-diol, naphthalene-
2,3-diol, 6-(tert-butyl)naphthalene-2,3-diol and 7,8-
dihydroxy-4-methyl-2H-chromen-2-one have been
studied under the optimized reaction conditions and
unfortunately in all cases any conversion of starting
materials were not observed (Supplementary
material, Figure s6).
Encouraged by the good tolerance of the presented
method for the synthesis of benzoxazoles, glycine
(3a) as an amino acid was employed in the reaction
for the synthesis of carboxylic acid-functionalized
benzoxazoles at 2 position. As amino acids are highly
insoluble in ethanol, the reaction was not completed
even after a long time and only 30% conversion of
starting materials was obtained after 12h. To improve
the yield, the reaction conditions were optimized and
100% conversion of starting materials were obtained
in H2O/EtOH 3:1 (4 mL for each 1 mmol of
reactants)
Moreover, the presented method was successfully
applied in the case of gabapentin as a commercial
available drug for the treatment of neuropathic pains
and desired benzoxazole (4s) was obtained in good
yield (85%) after 5h (Table 2, entry 19). Besides,
some symmetrical bis(benzoxazole)s as more
complex structures were successfully synthesized
with the application of aliphatic 1,n-dimanies (Table
2, entries 16-18). In another study, the reaction of 2-
methylpropane-1-amine (2a, 1 mmol) and other
catechol derivatives (1 mmol) such as 3,4,5,6-
tetrabromobenzene-1,2-diol, 4-nitrobenzene-1,2-diol,
9
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
Scheme 5. The examination of the authenticity of suggested pathway for the synthesis of benzoxazoles via the C(aryl)-OH
functionalization of 5-di-tert-butylbenzene-1,2-diol (1) with amino acids (3).
at reflux in the presence of NM-Fe3O4 (2 mol%).
Figure S14). In fact, during the reaction of glycine
(3a) and 3,5-di-tert-butylbenzene-1,2-diol (1) under
the optimized conditions, a CO2 elimination has been
occurred and (4c) was obtained as the only product of
reaction.
1
Surprisingly, from the H and 13C NMR data, it was
detected that the isolated product was not the
carboxylic acid-functionalized benzoxazole and (4c)
was the only product of the reaction (Scheme 3). The
1H NMR spectrum of isolated product exhibited two
singlets at δ 1.38 and 1.49 ppm with the integrals of 9
that are related to the 2 tert-butyl substituents of
phenyl moiety. In addition, there are three distinct
singlet signals present in δ 7.34, 7.65 and 8.07 ppm
related to three hydrogens of phenyl and oxazole
This is noteworthy that amino acids are highly
nontoxic and cheap compounds in comparison with
amines. So we aimed to introduce amino acids as
nontoxic and cheap alternatives for amines for the
synthesis of bezoxazoles. To gain this goal, various
amino acids (3) were reacted with 3,5-di-tert-
butylbenzene-1,2-diol (1) under optimized conditions
and obtained results are summarized in Table 3.
13
rings (Supplementary data, Figure S13). In C NMR
spectrum of isolated product, eleven distinct peaks
are completely matched with the structure of (4c) and
there are not any peak of carboxylic group in the
region of 160 to 200 ppm (Supplementary data,
As it is shown in Table 3, different amino acids such
as glycine (Table 3, entry 1), L-alanine (Table 3,
10
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
entry 2), L-leucine (Table 3, entry 3), lysine (Table 3,
entry 4), glutamic acid (Table 3, entry 5), L-valine
Except the guanidine functional group, other sensitive
groups such as thiol (Table 3, entry 9), amides (Table
3, entry 8) and nonadjacent carboxylic acids to the
amino group of amino acid (Table 3, entries 5 and 12)
remained unreacted during the reaction and this will
provide
a
useful path for the synthesis of
benzoxazoles bearing sensitive functionality at 2
position.
In the next attempt, the applicability of our method
toward large scale synthesis of benzoxazoles with the
application of amino acids as nontoxic and cheap
alternatives for amines was studied. For that, some
reactions in scales of 10 and 20 mmol were
conducted and the reaction times and obtained yields
were summarized in Table 4. Based on the obtained
results, all conducted reactions were successfully
performed at large scales without significant loss of
yields.
Figure 1. The reaction of 3,5-di-tert-butylbenzene-1,2-diol
(1, 1 mmol) and 2-methylpropane-1-amine (2a, 1 mmol) in
the presence of recovered NM-Fe3O4 in EtOH (2 mL) at
room temperature.
(Table 3, entry 6), L-arginine (Table 3, entry 7), L-
asparagine (Table 3, entry 8), D-penicillamine (Table
3, entry 9), L-isoleucine (Table 3, entry 10), L-
tyrosine (Table 3, entry 11), L-aspartic acid (Table 3,
entry 12) and L-tryptophan (Table 3, entry 13) have
been successfully applied as alternatives for amines
for the synthesis of benzoxazoles via a C(aryl)-OH
functionalization approach. All reactions were
completed in a few hours and desired products were
obtained in good yields. In all cases, a CO2
elimination has been occurred and obtained products
were determined by 1H and 13C NMR and IR
spectroscopy to have the same structures with the
products of the reaction of alternant amines and 3,5-
di-tert-butylbenzene-1,2-diol.
In another study, in order to extend the substrate
scope of presented method, the reaction of some other
catechols such as 4-(tert-butyl)benzene-1,2-diol, 4-
(methoxy)benzene-1,2-diol, 3-(methyl)benzene-1,2-
diol and 4-(nitro)benzene-1,2-diol with amines and
amino acids was investigated under the optimized
reaction conditions and obtained results are
summarized in Table 5. As it is shown in Table 5,
except the 4-(nitro)benzene-1,2-diol (Table 5, entries
10 and 11), all other reactions proceeded smoothly
and desired products were obtained in good yields
(80-91%) with approximately short reaction times (3-
7 h). From these data and other data summarized in
Tables 2 and 3 it can be concluded that this reaction
is restricted to the electron donating substituted
catechols.
Based on the literature reports [6,7] and our obtained
results, we proposed a mechanistic pathway for the
synthesis of benzoxazoles via the reaction of amino
acids (3) and 3,5-di-tert-butylbenzene-1,2-diol (1) in
the presence of NM-Fe3O4 in H2O/EtOH 3:1 at reflux
temperature (Scheme 4). In the first step, oxidation of
3,5-di-tert-butylbenzene-1,2-dio (1) catalyzed by
NM-Fe3O4 gives the key intermediate ortho-quinone
(5), followed by a nucleophilic addition of amino
group of amino acids to the less hindered carbonyl
group on the meta-position of (5) to generate
intermediate (6). Subsequently, compound (6)
dehydrates to give imine (7). From this point, the
reaction can proceed in two ways, paths A and B.
During the path A, the imine (7) tautomerizes to the
Schiff base (8). Next, the Schiff base (8) converts to
the carboxyl-functionalized benzoxazoline (9) via an
addition-cyclization reaction that converts to
benzoxazoline (11) with a CO2 elimination. Finally,
aerobic oxidative dehydrogenation of decarboxylated
benzoxazoline (11) leads to the corresponding
benzoxazole (4). In the path B, the imine (7) converts
With the application of amino acids instead of
amines, readily available asymmetric amino acids
provide a facile pathway for the synthesis of
benzoxazoles bearing an asymmetric center (Table 3,
entry 10). In the case of L-arginine
a
bis(benzoxazole) product was obtained due to the
hydrolysis of guanidine moiety to the amine (Table 3,
entry 7). To check the validity of this claim, L-
aginine (1 mmol) was added to the suspension of
NM-Fe3O4 (2 mol%) in H2O/EtOH 3:1 (4 mL) and
resulted mixture was stirred at reflux temperature
without 3,5-di-tert-butylbenzene-1,2-diol (1). After 3
hours, the reaction mixture was cooled to room
temperature, the catalyst was separated with an
external magnet and the solvent was evaporated
under reduced pressure. The chemical composition of
obtained solid was analyzed with HPLC using the
fluorescamine derivatization method described by
Udenfriend et al.[14] Using this method, the obtained
solid was consisted of 43% L-arginine and 51% of L-
ornithine (the product of the hydrolysis of guanidine
part of L-arginine). This observation proves our claim
about the hydrolysis of guanidine part of L-arginine
under the optimized reaction conditions.
11
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
to the Schiff base (10) that converts to the
benzoxazoline (11) with an addition-cyclization
reaction and the rest of the steps are similar to path A
(Scheme 4).
activity (Figure 1). The chemical composition of
recovered catalyst after the 8th reuse was studied with
ICP-MS and was compared with the results of freshly
synthesized NM-Fe3O4 (Supporting information,
Figures S108 and S107 respectively) and obtained
results proved the chemical stability of the catalyst.
The authenticity of suggested pathway was studied
with the conduction of several control experiments
(Scheme 5). At first the roles of NM-Fe3O4 and O2
were investigated on the oxidation of 3,5-di-tert-
butylbenzene-1,2-diol (1) to 3,5-di-tert-butyl-o-
benzoquinone (5). As it is shown in Scheme 5, the
oxidation of 3,5-di-tert-butylbenzene-1,2-diol (1) to
3,5-di-tert-butyl-o-benzoquinone (5) was not
proceeded without NM-Fe3O4 under the optimized
reaction conditions even after 10 h (Scheme 5, b)
whereas, in the presence of NM-Fe3O4 the oxidation
reaction was proceeded rapidly and a 100%
conversion of 3,5-di-tert-butylbenzene-1,2-diol (1) to
3,5-di-tert-butyl-o-benzoquinone (5) was observed.
In continuous, 3,5-di-tert-butylbenzene-1,2-diol (1, 1
mmol) and NM-Fe3O4 (2 mol%) was added to the
H2O/EtOH 3:1 (4 mL) and resulted mixture was
refluxed under the pure O2 atmosphere. A 100%
conversion of applied catechol (1) and very low yield
of 3,5-di-tert-butyl-o-benzoquinone (5) were obtained
because of the slightly decomposition of applied
catechol (1) under the strong oxidative condition. On
the other hand, trace amount (only 19%) of
conversion of 3,5-di-tert-butylbenzene-1,2-diol (1) to
3,5-di-tert-butyl-o-benzoquinone (5) obtained under
the N2 atmosphere as an inert gas. These observations
approve the crucial role of O2 as a terminal oxidant
and the catalytic role of NM-Fe3O4 on the oxidation
steps.
Conclusion
So briefly, amino acids were successfully applied for
the first time as nontoxic and cheap alternatives for
amines for the synthesis of benzoxazoles via the
C(aryl)-OH
functionalization
of
3,5-di-tert-
butylbenzene-1,2-diol in the presence of NM-Fe3O4
in H2O/EtOH 3:1 as a benign reaction medium. This
method not only offers the high yields of desired
products in short reaction times, but also avoids the
use of hazardous and toxic substrates which leads to
the reduction of cost and economical hazards. The
promising points of presented method are generality,
high yields of desired products, short reaction times,
simplicity, application of nontoxic starting materials,
simple work-up and finally applicability for large
scale synthesis of benzoxazoles via C(aryl)-OH
functionalization process. To the best of our
knowledge this is the first report about the application
of amino acids as nontoxic and cheap alternatives for
amines and the first report about the synthesis of
benzoxazoles via a C(aryl)-OH functionalization
process in larger scales than 5 mmol.
Experimental Section
All reagents and solvents were purchased from
Finally, the reaction of 2-aminoisobutiric acid (13, 1 Merck, Fluka or Sigma-Aldrich. Melting points
mmol) as an amino acid without a H at α position and were determined in capillary tubes in a Büchi B-
3,5-di-tert-butylbenzene-1,2-diol (1, 1 mmol) was
conducted under the optimized reaction conditions
and benzoxazoline (14) was obtained in 86% yield
after 5 h (Scheme 5, e). This result clearly indicates
that after the formation of imine intermediate during
the reaction between amino acid and oxidized
catechol, there is another possible pathway besides
the tautomerization of imine (7) that is the formation
of intermediate (10) via the decarboxylation of imine
(7) (Scheme 4, path B).
545 apparatus. The progress of the reaction and
the purity of compounds were monitored by thin
layer chromatography (TLC) analytical silica gel
plates (Merck 60 F250). All known compounds
were identified by comparison of their melting
points and proton nuclear magnetic resonance (1H
NMR) data with those in the authentic samples.
1
The H NMR (250 MHz) and 13C NMR (100
MHz) were run on a Bruker Avance DPX-250
and Bruker Avance DPX-400 fourier transform
(FT)-NMR spectrometers respectively. Chemical
As the last study, the recoverability and reusability of
NM-Fe3O4 was examined. For this, the model
reaction of 3,5-di-tert-butylbenzene-1,2-diol (1) and
2-methylpropane-1-amine (2a) has been studied in
the presence of the recovered catalyst under
optimized conditions. After the completion of the
reaction, insoluble catalyst was separated using an
external magnet, washed with ethanol (2 mL, 2
times), dried under reduced pressure for 24 h and
kept for another use. The recovered catalyst was
reused eight times without any loss of catalytic
shifts are given as
δ
values against
tetramethylsilane (TMS) as the internal standard
and J values are given in Hz. The elemental
analysis was performed on a Perkin-Elmer 240-B
microanalyzer. The X-ray diffraction (XRD)
patterns were recorded on
a
Bruker D8
ADVANCE X-ray diffractometer using nickel-
filtered Cu Kα radiation (k = 1.5406 A°).
Scanning electron micrograms were obtained
using a KYKY-EM3200 instrument. The VSM
12
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
curves were recorded by Vibrating Sample
Magnetometer Model VSM 4 Daghigh Meghnatis
Kashan Co. F3O4 magnetic nanoparticles were
synthesized using a reported method.[15]
In a three neck 100 mL round bottom flask equipped
with a condenser and a gas inlet containing a
suspension of nano magnetic Fe3O4 (2 mol%, ≈ 92.6
mg) in H2O/EtOH 3:1 (80 mL), 3,5-di-tert-
butylbenzene-1,2-diol (20 mmol, 4.44 g) and amino
acid (20 mmol) were added and resulting mixture was
stirred at reflux using a mechanical stirrer bar while
the air was bubbled to the reaction mixture. The
progress of the reaction was monitored by thin layer
chromatography (TLC). After completion of the
reaction, the reaction mixture was cooled to room
temperature, insoluble catalyst was separated using
an external magnet, washed with ethanol (40 mL, 2
times), dried under reduced pressure for 24 h and
reused. The water (200 mL) was added to the
separated solution and products was extracted with
EtOAc (100 mL) dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude
products were purified by column chromatography on
silica gel to give the pure products.
General procedure for the synthesis of
benzoxazoles from amines
In a 10 mL round bottom flask containing a
suspension of nano magnetic Fe3O4 (2 mol%, ≈ 5.0
mg) in ethanol (2 mL), 3,5-di-tert-butylbenzene-1,2-
diol (1 mmol, 0.222 g) and primary amine (1 mmol)
were added and resulting mixture was stirred at room
temperature using a mechanical stir bar under the air
atmosphere. The progress of the reaction was
monitored by thin layer chromatography (TLC). After
completion of the reaction, insoluble catalyst was
separated using an external magnet, washed with
ethanol (2 mL, 2 times), dried under reduced pressure
for 24 h and reused. The water (10 mL) was added to
the separated solution and products was extracted
with EtOAc (5 mL) dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude
products were purified by column chromatography on
silica gel to give the pure products. (Note: In the case
of methylamine and ethylamine, the 40% solution in
water and 70% solution in water respectively were
prepared from Merck and used as arrived.)
Selected spectral data of synthesized compounds
5,7-di-tert-butyl-2-isopropylbenzo[d]oxazole (4a)[6]
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
Isolated yield: 98% (0.26 g). Brown liquid, H NMR
(250 MHz, CDCl3): δ (ppm) 1.27 (s, 9H), 1.35 (s,
3H), 1.37 (s, 3H), 1.38 (s, 9H), 3.06-3.23 (m, 1H),
7.15 (s, 1H), 7.49 (s, 1H); 13C{H} NMR (100 MHz,
CDCl3): δ (ppm) 20.4, 28.8, 29.9, 31.9, 34.4, 35.0,
113.9, 118.6, 133.4, 141.4, 146.9, 147.1, 170.7. Anal.
Calcd for C18H27NO: C, 79.07; H, 9.95; N, 5.12;
Found: C, 79.20; H, 10.18; N, 4.94.
General procedure for the synthesis of
benzoxazoles from amino acids
In a three neck 10 mL round bottom flask equipped
with a condenser and a gas inlet containing a
suspension of nano magnetic Fe3O4 (2 mol%, ≈ 5.0
mg) in H2O/EtOH 3:1 (4 mL), 3,5-di-tert-
butylbenzene-1,2-diol (1 mmol, 0.222 g) and amino
acid (1 mmol) were added and resulting mixture was
stirred at reflux using a mechanical stirrer bar while
the air was bubbled to the reaction mixture. The
progress of the reaction was monitored by thin layer
chromatography (TLC). After completion of the
reaction, the reaction mixture was cooled to room
temperature, insoluble catalyst was separated using
an external magnet, washed with ethanol (2 mL, 2
times), dried under reduced pressure for 24 h and
reused. The water (10 mL) was added to the
separated solution and products was extracted with
EtOAc (5 mL) dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude
products were purified by column chromatography on
silica gel to give the pure products.
5,7-di-tert-butyl-2-methylbenzo[d]oxazole (4b)[7]
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
Isolated yield: 89% (0.21 g). Brown liquid, H NMR
(250 MHz, CDCl3): δ (ppm) 1.16 (s, 9H), 1.26 (s,
9H), 2.42 (s, 3H), 7.03 (s, 1H), 7.30 (s, 1H); 13C{H}
NMR (100 MHz, CDCl3): δ (ppm) 14.7, 29.9, 31.9,
34.4, 35.0, 113.6, 118.7, 133.4, 141.7, 147.1. Calcd
for C16H23NO: C, 78.32; H, 9.45; N, 5.71; Found: C,
78.14; H, 9.62; N, 5.83.
5,7-di-tert-butylbenzo[d]oxazole (4c)[6]
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
Isolated yield: 75% (0.17 g). Colorless liquid, H
General procedure for the large scale synthesis of
benzoxazoles from amino acids
NMR (250 MHz, CDCl3): δ (ppm) 1.38 (s, 9H), 1.48
(s, 9H), 7.34 (s, 1H), 7.65 (s, 1H), 8.07 (s, 1H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 29.9, 31.8,
13
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
34.4, 35.1, 114.6, 119.9, 134.2, 140.3, 147.8, 152.0.
Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05;
Found: C, 77.70; H, 9.31; N, 6.19.
C17H23NO: C, 79.33; H, 9.01; N, 5.44; Found: C,
79.42; H, 9.24; N, 5.64.
5,7-di-tert-butyl-2-(piperazin-1-
ylmethyl)benzo[d]oxazole (4h)
5,7-di-tert-butyl-2-ethylbenzo[d]oxazole (4d)[6]
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 90% (0.23 g). Colorless liquid, H
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:20).
Isolated yield: 94% (0.30 g). Brown liquid, H NMR
1
1
NMR (250 MHz, CDCl3): δ (ppm) 1.29 (s, 9H), 1.38
(t, J= 7.5 Hz, 3H), 1.39 (s, 9H), 2.88 (q, J= 7.5 Hz,
2H), 7.16 (s, 1H), 7.47 (s, 1H); 13C{H} NMR (100
MHz, CDCl3): δ (ppm) 11.1, 22.2, 29.9, 34.4, 35.0,
113.8, 118.7, 133.4, 141.6, 147.0, 147.1, 167.5. Calcd
for C17H25NO: C, 78.72; H, 9.71; N, 5.40; Found: C,
78.60; H, 9.97; N, 5.25.
(400 MHz, CDCl3): δ (ppm) 1.30 (s, 9H), 1.40 (s,
9H), 2.58 (t, J= 4.0 Hz, 2H), 2.62 (t, J= 4.0 Hz, 2H),
3.36 (t, J= 4.0 Hz, 2H), 3.54 (t, J= 4.0 Hz, 2H), 3.87
(s, 2H), 7.22 (s, 1H), 7.50 (s, 1H), 7.93 (br, 1H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 29.9, 31.8,
34.4, 35.1, 39.9, 45.6, 51.9, 53.0, 55.0, 114.2, 119.6,
133.8, 141.2, 147.7, 160.7, 161.7. Calcd for
C20H31N3O: C, 72.91; H, 9.48; N, 12.75; Found: C,
72.77; H, 9.68; N, 12.96.
(5,7-di-tert-butylbenzo[d]oxazol-2-yl)methanol (4e)[6]
5,7-di-tert-butyl-2-(2-
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 88% (0.23 g). Colorless liquid, H
morpholinoethyl)benzo[d]oxazole (4i)[7]
1
NMR (250 MHz, CDCl3): δ (ppm) 1.29 (s, 9H), 1.38
(s, 9H), 4.77 (br, 1H), 4.88 (s, 2H), 7.21 (s, 1H), 7.48
(s, 1H); 13C{H} NMR (100 MHz, CDCl3): δ (ppm)
29.9, 31.8, 34.4, 35.1, 57.8, 113.8, 119.6, 134.0,
140.5, 147.0, 147.8, 165.7. Calcd for C16H23NO2: C,
73.53; H, 8.87; N, 5.36; Found: C, 73.29; H, 8.99; N,
5.55.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:40).
Isolated yield: 90% (0.31 g). Brown liquid, H NMR
1
(250 MHz, CDCl3): δ (ppm) 1.34 (s, 9H), 1.44 (s,
9H), 2.50-2.54 (m, 4H), 2.90 (t, J= 7.5 Hz, 2H), 3.11
(t, J= 7.5 Hz, 2H), 3.65-3.68 (m, 4H), 7.23 (s, 1H),
7.52 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm)
26.5, 29.9, 31.8, 34.4, 35.0, 53.4, 55.6, 66.9, 113.8,
118.8, 133.4, 141.5, 147.0, 147.2, 164.8. Calcd for
C21H32N2O2: C, 73.22; H, 9.36; N, 8.13; Found: C,
73.41; H, 9.19; N, 8.33.
5,7-di-tert-butyl-2-undecylbenzo[d]oxazole (4f)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
5,7-di-tert-butyl-2-(tetrahydrofuran-2-
yl)benzo[d]oxazole (4j)[7]
Isolated yield: 90% (0.34 g). Pale yellow liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 0.77 (t, J= 6.2 Hz,
3H), 1.16 (s, 16H), 1.27 (s, 9H), 1.38 (s, 9H), 1.73-
1.85 (m, 2H), 2.83 (t, J= 7.5 Hz, 2H), 7.14 (s, 1H),
7.46 (s, 1H); 13C{H} NMR (100 MHz, CDCl3): δ
(ppm) 14.1, 22.7, 26.9, 28.7, 29.2, 29.3, 29.4, 29.5,
29.6, 29.9, 31.8, 31.9, 34.4, 35.0, 113.8, 118.6, 133.4,
141.6, 147.0, 147.1, 166.7. Calcd for C26H43NO: C,
80.98; H, 11.24; N, 3.63; Found: C, 81.25; H, 10.99;
N, 3.52.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
Isolated yield: 89% (0.26 g). Pale green liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.36 (s, 9H), 1.48
(s, 9H), 2.02-2.24 (m, 2H), 2.34-3.42 (m, 2H), 3.99-
4.14 (m, 2H), 5.22 (t, J= 6.2 Hz, 1H), 7.28 (s, 1H),
7.58 (s, 1H); 13C{H} NMR (100 MHz, CDCl3): δ
(ppm) 25.77, 29.96, 30.83, 31.83, 34.42, 35.04,
69.20, 73.90, 114.32, 119.42, 133.84, 141.06, 147.11,
147.51, 165.81. Calcd for C19H27NO2: C, 75.71; H,
9.03; N, 4.65; Found: C, 75.69; H, 9.30; N, 4.83.
5,7-di-tert-butyl-2-vinylbenzo[d]oxazole (4g)[6]
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
5,7-di-tert-butyl-2-(pyridin-2-yl)benzo[d]oxazole
(4k)[6]
Isolated yield: 75% (0.19 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.37 (s, 9H), 1.50
(s, 9H), 5.82 (d, J= 12.5 Hz, 1H), 6.43 (d, J= 17.5 Hz,
1H), 6.76 (dd, J= 17.5, 10.0 Hz, 1H), 7.29 (s, 1H),
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
7.57 (s, 1H); 13C{H} NMR (100 MHz, CDCl3):
δ
1
(ppm) 30.0, 31.8, 34.4, 35.1, 114.3, 119.9, 124.2,
124.4, 133.7, 141.9, 147.7, 161.6. Calcd for
Isolated yield: 93% (0.28 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.33 (s, 9H), 1.49
14
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901096
Advanced Synthesis & Catalysis
(s, 9H), 7.29 (d, J= 2.5 Hz, 1H), 7.34 (ddd, J= 7.5,
4.7, 1.0 Hz, 1H), 7.61 (d, J= 2.5 Hz, 1H), 7.80 (td, J=
7.7, 1.7 Hz, 1H), 8.21 (d, J= 8.0 Hz, 1H), 8.76 (dd, J=
4.7, 1.5 Hz, 1H); 13C{H} NMR (100 MHz, DMSO-
d6): δ (ppm) 29.7, 31.5, 34.1, 34.8, 114.4, 119.9,
123.3, 126.0, 133.7, 137.6, 141.6, 145.5, 146.7,
147.7, 150.2, 160.9. Calcd for C20H24N2O: C, 77.89;
H, 7.84; N, 9.08; Found: C, 77.77; H, 7.69; N, 9.39.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 94% (0.33 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.28 (s, 9H), 1.38,
1.39 (2s, 18H), 4.55 (s, 2H), 5.35 (br, 1H), 7.20 (s,
1H), 7.47 (s, 1H); 13C{H} NMR (100 MHz, CDCl3):
δ (ppm) 28.3, 29.9, 31.8, 34.4, 35.0, 38.6, 80.1,
114.1, 119.4, 133.8, 141.0, 147.2, 147.6, 155.6,
162.8. Calcd for C21H32N2O3: C, 69.97; H, 8.95; N,
7.77; Found: C, 70.27; H, 8.69; N, 7.91.
1
5,7-di-tert-butyl-2-(pyridin-2-
ylmethyl)benzo[d]oxazole (4l)
5,5',7,7'-tetra-tert-butyl-2,2'-bibenzo[d]oxazole (4p)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 95% (0.30 g). Brown liquid, H NMR
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 74% (0.34 g). Pale yellow solid, mp:
214-216 C; H NMR (250 MHz, CDCl3): δ (ppm)
1.40 (s, 18H), 1.58 (s, 18H), 7.44 (s, 2H), 7.80 (s,
2H); 13C{H} NMR (100 MHz, CDCl3): δ (ppm) 30.0,
31.8, 34.6, 35.2, 115.3, 121.7, 134.7, 141.7, 141.7,
148.8. Calcd for C30H40N2O2: C, 78.22; H, 8.75; N,
6.08; Found: C, 78.00; H, 8.58; N, 6.33.
1
(400 MHz, CDCl3): δ (ppm) 1.28 (s, 9H), 1.36 (s,
9H), 4.42 (s, 3H), 7.12 (t, J= 6.0 Hz, 1H), 7.17 (d, J=
4.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.49 (s, 1H),
7.58 (ddd, J= 16.0, 8.0, 4.0 Hz, 1H), 8.50 (d, J= 4.0
Hz, 1H); 13C{H} NMR (100 MHz, CDCl3): δ (ppm)
29.9, 31.8, 34.4, 35.0, 38.0, 114.1, 119.1, 122.2,
123.3, 133.6, 136.8, 141.6, 147.3, 147.3, 149.6,
155.4, 163.4. Calcd for C21H26N2O: C, 78.22; H,
8.13; N, 8.69; Found: C, 78.40; H, 7.88; N, 8.88.
o
1
1,2-bis(5,7-di-tert-butylbenzo[d]oxazol-2-yl)ethane
(4q)
5,7-di-tert-butyl-2-phenylbenzo[d]oxazole (4m)[6]
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 79% (0.38 g). Pale yellow solid, mp:
220-221 C; H NMR (250 MHz, CDCl3): δ (ppm)
1.29 (s, 18H), 1.33 (s, 18H), 3.49 (s, 4H), 7.16 (s,
2H), 7.46 (s, 2H); 13C{H} NMR (100 MHz, CDCl3):
δ (ppm) 26.0, 29.9, 31.8, 34.3, 35.0, 113.9, 119.0,
133.6, 141.4, 147.2, 147.4, 164.2. Calcd for
C32H44N2O2: C, 78.65; H, 9.08; N, 5.73; Found: C,
78.78; H, 9.26; N, 5.94.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 95% (0.28 g). Brown liquid, H NMR
(250 MHz, CDCl3): δ (ppm) 1.41 (s, 9H), 1.56 (s,
9H), 7.32 (s, 1H), 7.53 (s, 3H), 7.68 (s, 1H), 8.27 (s,
2H); 13C{H} NMR (100 MHz, CDCl3): δ (ppm) 30.1,
31.9, 34.5, 35.1, 114.3, 119.6, 127.4, 127.6, 128.9,
131.2, 133.7, 142.4, 147.0, 147.8, 162.5. Calcd for
C21H25NO: C, 82.04; H, 8.20; N, 4.56; Found: C,
82.30; H, 8.03; N, 4.73.
1
o
1
1,4-bis(5,7-di-tert-butylbenzo[d]oxazol-2-yl)butane
(4r)
5,7-di-tert-butyl-2-(3,4-
dimethoxybenzyl)benzo[d]oxazole (4n)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 82% (0.42 g). White solid, mp: 122-
124 oC; 1H NMR (250 MHz, CDCl3): δ (ppm) 1.29 (s,
18H), 1.38 (s, 18H), 1.96-2.01 (m, 4H), 2.94 (t, J=
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:50).
Isolated yield: 91% (0.34 g). Brown liquid, H NMR
1
(400 MHz, CDCl3): δ (ppm) 1.28 (s, 9H), 1.38 (s,
9H), 3.78 (s, 3H), 3.80 (s, 3H), 4.13 (s, 2H), 6.75 (d,
J= 8.0 Hz, 1H), 6.85-6.87 (m, 2H), 7.17 (s, 1H), 7.48
(d, J= 4.0 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3):
δ (ppm) 29.9, 31.8, 34.4, 35.0, 35.0, 55.8, 55.9,
111.3, 112.1, 114.0, 118.9, 121.1, 127.6, 133.5,
141.6, 147.2, 147.3, 148.2, 149.0, 164.8. Calcd for
C24H31NO3: C, 75.56; H, 8.19; N, 3.67; Found: C,
75.69; H, 7.88; N, 3.92.
13
6.2 Hz, 4H), 7.16 (s, 2H), 7.45 (s, 2H); C{H} NMR
(100 MHz, CDCl3): δ (ppm) 26.3, 28.3, 29.9, 31.9,
34.4, 35.0, 113.8, 118.8, 133.5, 141.5, 147.0, 147.2,
165.9. Calcd for C34H48N2O2: C, 79.02; H, 9.36; N,
5.42; Found: C, 78.84; H, 9.52; N, 5.70.
2-(1-((5,7-di-tert-butylbenzo[d]oxazol-2-
yl)methyl)cyclohexyl)acetic acid (4s)
tert-butyl
yl)methyl)carbamate (4o):
((5,7-di-tert-butylbenzo[d]oxazol-2-
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:50).
15
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
1
Isolated yield: 85% (0.32 g). Colorless liquid, H
NMR (400 MHz, CDCl3): δ (ppm) 1.23 (s, 9H), 1.37
(s, 9H), 1.42-1.57 (m, 10H), 2.45 (s, 2H), 3.64 (s,
2H), 6.84 (s, 1H), 7.18 (s, 1H), 7.90 (br, 1H); 13C{H}
NMR (100 MHz, CDCl3): δ (ppm) 22.80, 25.63,
29.87, 31.55, 34.42, 35.52, 36.40, 37.89, 44.62,
62.29, 116.33, 122.36, 128.13, 140.29, 142.24,
147.20, 174.82. C24H35NO3: C, 74.77; H, 9.15; N,
3.63; Found: C, 74.89; H, 8.92; N, 3.81.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 90% (0.29 g). Colorless liquid, H
1
NMR (250 MHz, CDCl3): δ (ppm) 1.33 (s, 9H), 1.48
(s, 9H), 7.30 (s, 1H), 7.60 (s, 1H), 7.75 (d, J= 5.0 Hz,
2H), 8.28 (d, J= 7.5 Hz, 2H); 13C{H} NMR (100
MHz, CDCl3): δ (ppm) 30.0, 31.8, 34.6, 35.2, 114.4,
114.6, 118.3, 120.7, 127.7, 131.5, 132.7, 134.1,
142.1, 147.2, 148.4, 160.4. Calcd for C22H24N2O: C,
79.48; H, 7.28; N, 8.43; Found: C, 79.20; H, 7.43; N,
8.66.
5,7-di-tert-butyl-2-(4-
methoxyphenyl)benzo[d]oxazole (4t)
3-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)aniline (4x)[7]
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 92% (0.31 g). Colorless liquid, H
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 91% (0.29 g). Colorless liquid, H
1
1
NMR (250 MHz, CDCl3): δ (ppm) 1.30 (s, 9H), 1.45
(s, 9H), 3.76 (s, 3H), 6.92 (d, J= 10.0 Hz, 2H), 7.18
(s, 1H), 7.54 (s, 1H), 8.10 (d, J= 7.5 Hz, 2H); 13C{H}
NMR (100 MHz, CDCl3): δ (ppm) 30.1, 31.9, 34.5,
35.1, 55.4, 113.9, 114.3, 119.1, 120.1, 129.1, 133.5,
142.5, 146.8, 147.6, 162.1, 162.6. Calcd for
C22H27NO2: C, 78.30; H, 8.06; N, 4.15; Found: C,
78.11; H, 7.85; N, 4.38.
NMR (400 MHz, CDCl3): δ (ppm) 1.56 (s, 9H), 1.71
(s, 9H), 3.93 (s, 2H), 6.55 (s, 1H), 6.76 (d, J= 6.8 Hz,
1H), 7.26 (s, 1H), 7.31 (t, J= 7.2 Hz, 1H), 7.54 (d, J=
6.8 Hz, 1H), 7.59 (s, 1H); 13C{H} NMR (100 MHz,
CDCl3): δ (ppm) 29.4, 31.4, 35.0, 35.3, 113.3, 114.4,
117.6, 118.1, 119.9, 133.4, 141.7, 146.5, 147.6,
148.4, 162.6. Anal. Calcd for C21H26N2O: C, 78.22;
H, 8.13; N, 8.69; Found: C, 77.85; H, 7.91; N, 8.95.
5,7-di-tert-butyl-2-(4-chlorophenyl)benzo[d]oxazole
(4u)[6]
5,7-di-tert-butyl-2-(2-chlorophenyl)benzo[d]oxazole
(4y)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 90% (0.30 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.40 (s, 9H), 1.55
(s, 9H), 7.32 (s, 1H), 7.51 (d, J= 7.5 Hz, 2H), 7.65 (s,
1H), 8.18 (d, J= 10.0 Hz, 2H); 13C{H} NMR (100
MHz, CDCl3): δ (ppm) 27.9, 29.6, 32.3, 32.9, 112.1,
117.7, 123.8, 126.4, 127.1, 131.6, 135.2, 140.0,
144.8, 145.8, 159.3. Calcd for C21H24ClNO: C, 73.78;
H, 7.08; N, 4.10; Found: C, 74.04; H, 6.88; N, 4.34.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 90% (0.30 g). Colorless liquid, H
1
1
NMR (250 MHz, DMSO-d6): δ (ppm) 1.33 (s, 9H),
1.46 (s, 9H), 7.32 (s, 1H), 7.53-7.61 (m, 2H), 7.65 (d,
J= 2.5 Hz, 1H), 7.67-7.71 (m, 1H), 8.12-8.15 (m,
1H); 13C{H} NMR (100 MHz, DMSO-d6): δ (ppm)
29.6, 31.5, 34.0, 34.8, 114.2, 119.6, 125.6, 127.8,
131.2, 131.8, 131.8, 132.7, 133.5, 141.3, 146.2,
147.6, 159.8. Anal. Calcd for C21H24ClNO: C, 73.78;
H, 7.08; N, 4.10; Found: C, 73.92; H, 6.88; N, 4.22.
5,7-di-tert-butyl-2-(4-
(trifluoromethyl)phenyl)benzo[d]oxazole (4v)[6]
5,7-di-tert-butyl-2-(2-
methoxyphenyl)benzo[d]oxazole (4z)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 93% (0.34 g). Colorless liquid, H
1
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 90% (0.30 g). Colorless liquid, H
NMR (400 MHz, CDCl3): δ (ppm) 1.43 (s, 9H), 1.61
(s, 9H), 7.44 (s, 1H), 7.74 (s, 1H), 7.78 (d, J= 8.0 Hz,
2H), 8.41 (d, J=8.0 Hz, 2H); 13C{H} NMR (100
MHz, CDCl3): δ (ppm) 30.2, 31.8, 34.5, 35.1, 114.4,
119.7, 123.9 (q, JC-F= 268 Hz), 125.5, 126.7, 130.6,
131.6 (q, JC-F= 32.7 Hz), 134.4, 142.3, 147.1, 148.4,
161.0 . Calcd for C22H24F3NO: C, 70.38; H, 6.44; N,
3.73; Found: C, 69.99; H, 6.12; N, 4.44.
1
NMR (250 MHz, DMSO-d6): δ (ppm) 1.34 (s, 9H),
1.47 (s, 9H), 3.92 (s, 3H), 7.13 (t, J= 8.8 Hz, 1H),
7.23-7.27 (m, 2H), 7.54-7.60 (m, 2H), 8.01 (d, J= 7.5
Hz, 1H); 13C{H} NMR (100 MHz, DMSO-d6): δ
(ppm) 29.5, 31.5, 33.9, 34.7, 55.9, 112.8, 113.8,
115.6, 118.7, 120.7, 130.6, 133.0, 133.1, 141.5,
146.1, 147.0, 157.9, 160.8. Anal. Calcd for
C22H27NO2: C, 78.30; H, 8.06; N, 4.15; Found: C,
78.52; H, 7.89; N, 4.31.
4-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)benzonitrile
(4w)[7]
16
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901096
Advanced Synthesis & Catalysis
5,7-di-tert-butyl-2-(o-tolyl)benzo[d]oxazole (4aa)
1,3-bis(5,7-di-tert-butylbenzo[d]oxazol-2-yl)propane
(4ac) (Synthesized from lysine)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
93% (0.29 g). Colorless liquid, H NMR (250 MHz,
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 88% (0.44 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.37 (s, 18H), 1.46
(s, 18H), 2.44-2.55 (m, 2H), 3.13 (t, J= 7.5 Hz, 4H),
7.24 (s, 2H), 7.54 (s, 2H); 13C{H} NMR (100 MHz,
CDCl3): δ (ppm) 23.9, 27.9, 29.9, 31.8, 34.5, 35.2,
113.8, 118.9, 133.1, 141.6, 146.7, 147.9, 163.1. Calcd
for C33H46N2O2: C, 78.84; H, 9.22; N, 5.57; Found: C,
79.12; H, 8.93; N, 5.71.
1
1
DMSO-d6): δ (ppm) 1.33, 1.47 (2s, 18H), 2.73 (s,
3H), 7.29 (s, 1H), 7.41-7.47 (m, 3H), 7.63 (s, 1H),
8.10 (d, J= 7.5 Hz, 1H); 13C{H} NMR (100 MHz,
DMSO-d6): δ (ppm) 21.8, 29.6, 31.5, 33.9, 34.7,
114.1, 119.0, 125.7, 126.4, 129.3, 131.0, 131.8,
133.1, 137.7, 141.8, 145.8, 147.2, 162.0. Anal. Calcd
for C22H27NO: C, 82.20; H, 8.47; N, 4.36; Found: C,
81.95; H, 8.64; N, 4.19.
5,7-di-tert-butylbenzo[d]oxazole (4c)[6] (Synthesized
from glycine)
3-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)propanoic
acid (4ad) (Synthesized from glutamic acid)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 83% (0.19 g). Colorless liquid, H
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:50).
Isolated yield: 80% (0.24 g). Brown liquid, H NMR
1
1
NMR (250 MHz, CDCl3): δ (ppm) 1.38 (s, 9H), 1.49
(s, 9H), 7.34 (s, 1H), 7.65 (s, 1H), 8.07 (s, 1H);
13C{H} NMR (100 MHz, DMSO-d6): δ (ppm) 34.8,
36.7, 39.2, 39.9, 119.3, 124.5, 138.8, 145.2, 150.8,
152.5, 158.8. Calcd for C15H21NO: C, 77.88; H, 9.15;
N, 6.05; Found: C, 77.96; H, 9.33; N, 6.27.
(250 MHz, CDCl3): δ (ppm) 1.24 (s, 9H), 1.35 (s,
9H), 2.78-3.15 (m, 4H), 7.14 (s, 1H), 7.45 (s, 2H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 27.1, 29.9,
30.9, 32.5, 34.6, 36.3, 117.0, 120.5, 134.3, 142.9,
146.4, 150.4, 162.7, 173.1. Calcd for C18H25NO3: C,
71.26; H, 8.31; N, 4.62; Found: C, 71.44; H, 8.19; N,
4.81.
5,7-di-tert-butyl-2-methylbenzo[d]oxazole
(Synthesized from L-alanine)
(4b)[7]
5,7-di-tert-butyl-2-isopropylbenzo[d]oxazole (4a)[6]
(Synthesized from L-Valine)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 85% (0.20 g). Brown liquid, H NMR
(250 MHz, CDCl3): δ (ppm) 1.39 (s, 9H), 1.50 (s,
9H), 2.65 (s, 3H), 7.26 (s, 1H), 7.54 (s, 1H); 13C{H}
NMR (100 MHz, CDCl3): δ (ppm) 14.7, 29.9, 31.9,
34.4, 35.0, 113.6, 118.7, 133.4, 141.7, 147.1. Calcd
for C16H23NO: C, 78.32; H, 9.45; N, 5.71; Found: C,
78.10; H, 9.82; N, 5.49.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 94% (0.25 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.29 (s, 9H), 1.36
(s, 3H), 1.39 (s, 3H), 1.40 (s, 9H), 3.08-3.25 (m, 1H),
7.17 (s, 1H), 7.49 (s, 1H); 13C{H} NMR (100 MHz,
CDCl3): δ (ppm) 20.4, 28.8, 29.9, 31.9, 34.4, 35.0,
113.9, 118.6, 133.4, 141.4, 146.9, 147.1, 170.7. Calcd
for C18H27NO: C, 79.07; H, 9.95; N, 5.12; Found: C,
78.87; H, 10.10; N, 5.33.
1
1
5,7-di-tert-butyl-2-isobutylbenzo[d]oxazole
(Synthesized from L-leucine)
(4ab)
1,2-bis(5,7-di-tert-butylbenzo[d]oxazol-2-yl)ethane
(4q) (Synthesized from L-arginine)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 92% (0.26 g). Dark brown liquid, H
1
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
NMR (250 MHz, CDCl3): δ (ppm) 1.04, 1.07 (2s,
6H), 1.38 (s, 9H), 1.48 (s, 9H), 2.21-2.38 (m, 1H),
2.83 (d, J= 7.5 Hz, 2H), 7.25 (s, 1H), 7.55 (s, 1H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 22.4, 27.6,
29.9, 31.9, 34.4, 35.0, 37.6, 113.8, 118.6, 133.4,
141.6, 147.0, 147.1, 166.0. Calcd for C19H29NO: C,
79.39; H, 10.17; N, 4.87; Found: C, 79.47; H, 9.52;
N, 4.70.
1
Brown solid, H NMR (250 MHz, CDCl3): δ (ppm)
1.29 (s, 18H), 1.33 (s, 18H), 3.48 (s, 4H), 7.16 (s,
2H), 7.46 (s, 2H); 13C{H} NMR (100 MHz, CDCl3):
δ (ppm) 26.0, 29.9, 31.8, 34.3, 35.0, 113.9, 119.0,
133.6, 141.4, 147.2, 147.4, 164.2. Calcd for
C32H44N2O2: C, 78.65; H, 9.08; N, 5.73; Found: C,
78.84; H, 8.93; N, 5.91.
17
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901096
Advanced Synthesis & Catalysis
2-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)acetamide
(4ae) (Synthesized from L-asparagine)
C22H27NO2: C, 78.30; H, 8.06; N, 4.15; Found: C,
78.43; H, 7.93; N, 4.33.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:50).
Isolated yield: 85% (0.24 g). Pale yellow solid, mp:
199-200 C; H NMR (250 MHz, CDCl3): δ (ppm)
1.38 (s, 9H), 1.47 (s, 9H), 3.96 (s, 2H), 5.89 (br, 1H),
7.30 (s, 1H), 7.55 (s, 2H), 7.66 (br, 1H); 13C{H}
NMR (100 MHz, CDCl3): δ (ppm) 29.9, 31.8, 34.4,
35.1, 35.8, 113.9, 119.7, 134.0, 140.9, 146.8, 147.9,
160.4, 167.8. Calcd for C17H24N2O2: C, 70.80; H,
8.39; N, 9.71; Found: C, 70.71; H, 8.22; N, 9.90.
2-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)acetic
(4ai) (Synthesized from L-aspartic acid)
acid
o
1
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:50).
Isolated yield: 85% (0.24 g). Pale yellow liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.29 (s, 9H), 1.40
(s, 9H), 2.56 (s, 2H), 7.17 (s, 1H), 7.44 (s, 1H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 31.2, 32.2,
34.0, 35.8, 37.9, 118.3, 121.8, 135.8, 143.2, 147.9,
151.3, 165.3, 172.0. Calcd for C17H23NO3: C, 70.56;
H, 8.01; N, 4.84; Found: C, 70.73; H, 7.89; N, 5.11.
1
2-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)propane-2-
thiol (4af) (Synthesized from D-penicillamine)
2-((1H-indol-3-yl)methyl)-5,7-di-tert-
butylbenzo[d]oxazole (4aj) (Synthesized from L-
tryptophan)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:80).
Isolated yield: 85% (0.25 g). Brown liquid, H NMR
1
(250 MHz, CDCl3): δ (ppm) 1.32 (s, 6H), 1.34 (s,
9H), 1.39 (s, 9H), 7.16 (s, 1H), 7.38 (s, 2H), 7.68 (br,
1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 27.9,
30.6, 31.6, 35.2, 35.4, 40.5, 117.0, 121.3, 135.5,
141.9, 147.5, 151.7, 164.4. Calcd for C18H27NOS: C,
70.77; H, 8.91; N, 4.59; Found: C, 70.90; H, 8.73; N,
4.77.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:70).
Isolated yield: 88% (0.31 g). Brown liquid, H NMR
1
(250 MHz, CDCl3): δ (ppm) 1.35 (s, 9H), 1.44 (s,
9H), 4.42 (s, 2H), 7.16-7.23 (m, 5H), 7.53 (s, 1H),
13
7.76 (d, J= 7.5 Hz, 1H), 8.09 (br, 1H); C{H} NMR
(100 MHz, CDCl3): δ (ppm) 26.9, 30.3, 31.3, 34.9,
35.2, 106.1, 111.4, 117.4, 119.4, 120.1, 120.9, 121.1,
125.0, 127.6, 134.9, 136.7, 142.2, 146.9, 150.4,
163.1. Calcd for C24H28N2O: C, 79.96; H, 7.83; N,
7.77; Found: C, 80.21; H, 8.00; N, 7.50.
(R)-2-(sec-butyl)-5,7-di-tert-butylbenzo[d]oxazole
(4ag) (Synthesized from L-isoleucine)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 93% (0.26 g). Brown liquid, H NMR
5-(tert-butyl)-2-(4-chlorophenyl)benzo[d]oxazole
(4ak)[6]
1
(250 MHz, CDCl3): δ (ppm) 0.97 (t, J= 7.5 Hz, 3H),
1.36 (s, 9H), 1.42 (d, J= 7.5 Hz, 3H), 1.47 (s, 9H),
1.70-1.81 (m, 1H), 1.88-1.99 (m, 1H), 2.01-3.13 (m,
1H), 7.23 (s, 1H), 7.57 (s, 1H); 13C{H} NMR (100
MHz, CDCl3): δ (ppm) 11.6, 18.0, 28.2, 29.9, 31.9,
34.4, 35.0, 35.7, 113.8, 118.6, 133.5, 141.4, 146.9,
147.1, 170.1. Calcd for C19H29NO: C, 79.39; H,
10.17; N, 4.87; Found: C, 79.10; H, 10.20; N, 5.01.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 91% (0.0.26 g). Colorless liquid, H
1
NMR (400 MHz, CDCl3): δ (ppm) 1.44 (s, 9H), 7.46
(d, J= 12.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, 2H), 7.64 (s,
1H), 7.71 (d, J= 8.0 Hz, 1H), 8.20 (d, J= 8.0 Hz, 2H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 31.7, 35.2,
107.3, 119.1, 122.5, 125.8, 128.6, 129.2, 137.4,
139.6, 149.5, 151.0, 161.9. Calcd for C17H16ClNO: C,
71.45; H, 5.64; N, 4.90; Found: C, 71.29; H, 5.77; N,
4.88.
4-((5,7-di-tert-butylbenzo[d]oxazol-2-
yl)methyl)phenol (4ah) (Synthesized from L-
tyrosine)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:20).
Isolated yield: 87% (0.29 g). Brown liquid, H NMR
5-(tert-butyl)-2-(2-chlorophenyl)benzo[d]oxazole
(4al)
1
(250 MHz, CDCl3): δ (ppm) 1.35 (s, 9H), 1.46 (s,
9H), 4.18 (s, 2H), 6.72 (d, J= 7.5 Hz, 2H), 7.18 (d, J=
7.5 Hz, 2H), 7.39 (s, 1H), 7.53 (s, 1H), 7.57 (s, 1H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 29.9, 31.8,
34.4, 35.2, 113.7, 115.7, 119.1, 119.7, 130.1, 133.8,
141.4, 146.7, 147.9, 160.1, 163.5. Calcd for
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 91% (0.27 g). Colorless liquid, H
NMR (400 MHz, CDCl3): δ (ppm) 1.45 (s, 9H), 7.45-
7.51 (m, 3H), 7.60 (d, J= 8.0 Hz, 1H), 7.69 (s, 1H),
7.81 (d, J= 8.0 Hz, 1H), 8.17 (d, J= 8.0 Hz, 1H);
1
18
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901096
Advanced Synthesis & Catalysis
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 31.7, 35.3,
107.4, 119.6, 122.5, 126.5, 126.9, 131.4, 131.7,
133.3, 139.3, 149.8, 150.9, 160.8. Calcd for
C17H16ClNO: C, 71.45; H, 5.64; N, 4.90; Found: C,
71.15; H, 5.55; N, 5.21.
C, 73.45; H, 6.16; N, 9.52; Found: C, 73.78; H, 6.01;
N, 9.91.
5-methoxybenzo[d]oxazole (4aq)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 84% (0.12 g). Colorless liquid, H
5-(tert-butyl)-2-(p-tolyl)benzo[d]oxazole (4am)
1
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 90% (0.23 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 3.89 (s, 3H), 7.11
(d, J= 7.5 Hz, 1H), 7.46 (s, 1H), 7.57 (d, J= 10.0 Hz,
1H), 8.13 (s, 1H); C{H} NMR (62.9 MHz, CDCl3):
1
13
NMR (400 MHz, CDCl3): δ (ppm) 1.44 (s, 9H), 2.47
(s, 3H), 7.36 (d, J= 8.0 Hz, 2H), 7.45 (d, J= 8.0 Hz,
1H), 7.64 (s, 1H), 7.71 (d, J= 8.0 Hz, 1H), 8.17 (d, J=
8.0 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3): δ
(ppm) 21.6, 31.7, 35.2, 107.2, 118.9, 122.1, 124.6,
127.4, 129.6, 139.7, 141.8, 149.0, 150.9, 163.1. Calcd
for C18H19NO: C, 81.47; H, 7.22; N, 5.28; Found: C,
81.77; H, 6.90; N, 5.55.
δ (ppm) 49.2, 114.8, 115.3, 124.3, 132.6, 136.3,
137.5, 140.7. Calcd for C8H7NO2: C, 64.42; H, 4.73;
N, 9.39; Found: C, 64.90; H, 4.44; N, 9.52.
5-methoxy-2-methylbenzo[d]oxazole (4ar)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
Isolated yield: 88% (0.14 g). Colorless liquid, H
4-methyl-2-phenylbenzo[d]oxazole (4an)[7]
NMR (250 MHz, CDCl3): δ (ppm) 2.38 (s, 3H), 3.83
(s, 3H), 6.97 (d, J= 8.2, 1H), 7.25 (s, 1H), 7.36 (d, J=
13
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 88% (0.18 g). White solid, mp: 82-84
oC, 1H NMR (250 MHz, DMSO-d6): δ (ppm) 2.49 (s,
3H), 6.91 (d, J= 7.5 Hz, 1H), 7.04 (t, J= 7.5 Hz, 1H),
7.36-7.49 (m, 4H), 8.11 (d, J= 7.5 Hz, 2H); 13C{H}
NMR (62.9 MHz, DMSO-d6): δ (ppm) 16.8, 112.4,
122.4, 122.9, 125.0, 126.5, 129.0, 129.6, 130.0, 138.4,
144.7, 151.0. Calcd for C14H11NO: C, 80.36; H, 5.30;
N, 6.69; Found: C, 80.62; H, 5.11; N, 5.50.
8.0, 1H); C{H} NMR (62.9 MHz, CDCl3): δ (ppm)
21.6, 49.1, 114.0, 114.3, 123.5, 131.9, 135.3, 141.1,
151.0. Calcd for C9H9NO2: C, 66.25; H, 5.56; N,
8.58; Found: C, 66.12; H, 5.88; N, 9.01.
2-ethyl-5-methoxybenzo[d]oxazole (4as)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
Isolated yield: 91% (0.16 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.34 (t, J= 7.6 Hz,
3H), 2.91 (q, J= 7.6 Hz, 2H), 3.84 (s, 3H), 6.95 (d, J=
8.5, 1H), 7.26 (s, 1H), 7.36 (d, J= 8.2, 1H); 13C{H}
NMR (62.9 MHz, CDCl3): δ (ppm) 12.6, 22.6, 49.6,
114.1, 114.4, 123.4, 131.7, 137.1, 138.5, 156.6. Calcd
for C10H11NO2: C, 67.78; H, 6.26; N, 7.90; Found: C,
68.13; H, 5.97; N, 8.18.
4-methylbenzo[d]oxazole (4ao)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 82% (0.10 g). Colorless liquid, H
1
NMR (250 MHz, CDCl3): δ (ppm) 2.51 (s, 3H), 6.97-
7.01 (m, 1H), 7.06-7.14 (m, 1H), 7.40 (d, J= 7.5 Hz,
13
2-ethyl-5-methoxybenzo[d]oxazole (14)[7]
1H), 8.04 (s, 1H); C{H} NMR (62.9 MHz, CDCl3):
δ (ppm) 17.1, 112.4, 122.6, 123.0, 125.6, 136.9,
137.5, 140.2. Calcd for C8H7NO: C, 72.17; H, 5.30;
N, 10.52; Found: C, 71.89; H, 5.44; N, 10.83.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
Isolated yield: 86% (0.22 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 1.23 (s, 9H), 1.24
(s, 3H), 1.27 (s, 9H), 1.63 (s, 3H), 6.25 (s, 1H), 6.94
(s, 1H), 7.94 (s, 1H); 13C{H} NMR (62.9 MHz,
CDCl3): δ (ppm) 12.6, 22.6, 49.6, 114.1, 123.3, 131.7,
137.1, 138.5, 156.6. Calcd for C17H27NO: C, 78.11; H,
10.41; N, 5.36; Found: C, 78.36; H, 9.89; N, 5.82.
1
2,4-dimethylbenzo[d]oxazole (4ap)
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100).
1
Isolated yield: 85% (0.12 g). Colorless liquid, H
NMR (250 MHz, CDCl3): δ (ppm) 2.49 (s, 3H), 2.55
(s, 3H), 6.96 (d, J= 7.5 Hz, 1H), 7.06 (d, J= 8.7 Hz,
1H); 7.30 (d, J= 7.5 Hz, 1H); 13C{H} NMR (62.9
MHz, CDCl3): δ (ppm) 14.9, 17.4, 111.8, 122.3,
122.8, 125.0, 138.1, 138.6, 151.1. Calcd for C9H9NO:
Acknowledgements
19
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10.1002/adsc.201901096
Advanced Synthesis & Catalysis
We gratefully appreciate the Shiraz University Research Councils
for their financial support of this work.
1731-1736; l) H. Z. Xie, Q. Gao, Y. Liang, H.
S. Wang, Y. M. Pan, Green Chem. 2014, 16,
2132-2135, m) S. P. Marsden, A. E.
McGonagle, B. McKeever-Abbas, Org. Lett.
2008, 10, 2589-2591. n) X. Meng, Y. Wang, B.
Chen, G. Chen, Z. Jing, P. Zhao, Org. Process
Res. Dev. 2017, 21,2018-2024; o) J. He, F. Lin,
X. Yang, D. Wang, X. Tan, S. Zhang, Org.
Process Res. Dev. 2016, 20, 1093-1096.
References
[1] M. J. Don, C. C. Shen, Y. L. Lin, W. J. Syu, Y.
H. Ding, C. M. Sun, Nat. Prod. 2005, 68,
1066-1070.
[2] a) M. Taki, J. L. Wolford, T. V. OÏHalloran, J.
Am. Chem. Soc. 2004, 126, 712-713; b) Y. Q.
Xu, L. L. Xiao, S. G. Sun, Z. C. Pei, Y. X. Pei,
Y. Pang, Chem. Commun. 2014, 50, 7514-
7516; c) P. C. Xue, P. Chen, J. H. Jia, Q. X.
Xu, J. B. Sun, B. Q. Yao, Z. Q. Zhang, R. Lu,
Chem. Commun. 2014, 50, 2569-2571; d) D.
Wee, S. Yoo, Y. H. Kang, Y. H. Kim, J. W. Ka,
S. Y. Cho, C. Lee, J. Ryu, M. H. Yi, K. S. Jang,
J. Mater. Chem. C. 2014, 2, 6395-6401.
[3] a) S. Tzanopoulou, M. Sagnou, M. Paravatou-
Petsotas, E. Gourni, G. Loudos, S.
Xanthopoulos, D. Lafcas, H. Kiaris, A.
Varvarigou, I. C. Pirmettis, M. Papadopoulos,
M. Pelecanou, J. Med. Chem. 2010, 53, 4633-
4641; b) M. C. V. Zandt, M. L. Jones, D. E.
Gunn, L. S. Geraci, J. H. Jones, D. R. Sawicki,
J. Sredy, J. L. Jacot, A. T. DiCioccio, T.
Petrove, A. Mitschler, A. D. Podjarny, J. Med.
Chem. 2005, 48, 3141-3152; c) L. Katz, J. Am.
Chem. Soc. 1953, 75, 712-714; d) D. K. Dalvie,
A. S. Kalgutkar, S. C. Khojasteh-Bakht, R. S.
Obach, J. P. O. Donnell, Chem. Res. Toxicol.
2002, 15, 269-299; e) H. Z. Boeini, K. H.
Najafabadi, Eur. J. Org. Chem. 2009, 2009,
4926-4929.
[6] X. Chen, F. Ji, Y. Zhao, Y. Liu, Y. Zhou, T.
Chen, Sh.-F. Yin, Adv. Synth. Catal. 2015, 357,
2924-2930.
[7] X. Meng, Y. Wang, Y. Wang, B. Chen, Zh.
Jing, G. Chen, P. Zhao, J. Org. Chem. 2017
82, 6922-6931.
,
[8] a) P. J. Walsh, H. Li, C. A. de Parrodi, Chem.
Rev. 2007, 107, 2503-2545; b) K. Tanaka, F.
Toda, Chem. Rev. 2000, 100, 1025-1074; c) A.
L. Garay, A. Pichona, S. L. James, Chem. Soc.
Rev. 2007, 36, 846-855.
[9] a) M.-O. Simona, Ch.-J. Li, Chem. Soc. Rev.
2012, 41, 1415-1427; b) R. N. Butler, A. G.
Coyne, Chem. Rev. 2010, 110, 6302-6337; c)
A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109,
725-748.
[10] a) Sh. Zhu, Y. Wu, Q. Chen, Z. Yu, C. Wang,
Sh. Jin, Y. Dinga, G. Wu, Green Chem. 2006
,
8, 325-327; b) K. N. Marsh, A. Deev, A. C.-T.
Wu, E. Tran, A. Klamt, Korean J. Chem. Eng.
2002, 19, 357-362.
[11] a) G. M. Lari, G. Pastore, M. Haus, Y. Ding, S.
Papadokonstantakis, C. Mondelli, J. Pérez-
Ramírez, Energy Environ. Sci. 2018, 11, 1012-
1029; b) M. J. Rodríguez‐Álvarez, J. García‐
Álvarez, M. Uzelac, M. Fairley, Ch. T. O'Hara,
[4] D. R. Chancellor, K. E. Davies, O. D. Moor, C.
R. Dorgan, P. D. Johnson, A. G. Lambert, D.
Lawrence, C. Lecci, C. Maillol, P. J.
Middleton, G. Nugent, S. D. Poignant, A. C.
Potter, P. D. Price, R. J. Pye, R. Storer, J. M.
Tinsley, R. V. Well, R. Vickers, J. Vile, F. J.
Wilkes, F. X. Wilson, S. P. Wren, G. M.
Wynne, J. Med. Chem. 2011, 54, 3241-3250.
[5] a) J. W. Dankwardt, Angew. Chem. Int. Ed.
E. Hevia, Chem. Eur. J. 2018, 24, 1720-1725.
[12] a) M. T. Reetz, Angew. Chem. Int. Ed. 1991
,
30, 1531-1546; b) J.-A. Fehrentz, B. Castro,
Synthesis 1983, 8, 676-678; c) Ch. P. Holmes,
J. P. Chinn, G. C. Look, E. M. Gordon, M. A.
Gallop, J. Org. Chem. 1995, 60, 7328-7333.
[13] a) H. Sharghi, J. Aboonajmi, M. Mozaffari, M.
M. Doroodmand, M. Aberi, Appl. Organomet.
Chem. 2018, 32, e4124-e4147; b) H. Sharghi,
M. Aberi, M. M. Doroodmand, P. Shiri, J. Iran.
Chem. Soc. 2017, 14, 1557-1573; c) H. Sharghi,
I. Ghaderi, M. M. Doroodmand, Appl.
Organomet. Chem. 2017, 31, e3869-e3888; d)
H. Sharghi, M. Aberi, M. Khataminejad, P.
Shiri, Beilstein J. Org. Chem. 2017, 13, 1977-
1981; e) H. Sharghi, M. Aberi, P. Shiri, Appl.
Organomet. Chem. 2017, 31, e3761-e3781; f)
H. Sharghi, P. Shiri, M. Aberi, Catal. Lett.
2017, 147, 2844-2862; g) H. Sharghi, S.
Sepehri, M. Aberi, Mol. Divers. 2017, 21, 855-
864; h) R. Khalifeh, F. Shahriarpour, H.
2004
,
43, 2428-2432; b) S. Ueno, E.
Mizushima, N. Chatani, F. Kakiuchi, J. Am.
Chem. Soc. 2006, 128, 16516-16517; c) T. B.
Nguyen, L.Ermolenko, A. Al-Mourabit, J. Am.
Chem. Soc. 2013, 135, 118-121; d) A. Khalafi-
Nezhad, F. Panahi, ACS Catal. 2014, 4, 1686-
1692; e) L. Gu, C. Jin, J. Guo, L. Zhang, W.
Wang, Chem. Commun. 2013, 49, 10968-
10970; f) N. Thanh Binh, L. Ermolenko, W. A.
Dean, A. Al-Mourabit, Org. Lett. 2012, 14,
5948-5951; g) Y. X. Chen, L. F. Qian, W.
Zhang, B. Han, Angew. Chem. Int. Ed. 2008
,
47, 9330-9333; h) S. H. Cho, J. Y. Kim, S. Y.
Lee, S. Chang, Angew. Chem. Int. Ed. 2009, 48,
9127-9130; i) H. Hachiya, K. Hirano, T. Satoh,
M. Miura, Angew. Chem. Int. Ed. 2010, 49,
2202-2205; j) G. Altenhoff, F. Glorius, Adv.
Synth. Catal. 2004, 346, 1661-1664; k) R. D.
Carpenter, M. J. Kurth, Nat. Protoc. 2010, 5,
Sharghi, M. Aberi, J. Iran. Chem. Soc. 2018
,
15, 813-821; i) H. Sharghi, J. Aboonajmi, M.
Aberi, P. Shiri, J. Iran. Chem. Soc. 2018, 15,
1107-1118.
20
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[14] S. Udenfriend, S. Stein, P. Bohlen, W.
Dairman, W. Leimgruber, M. Weigele, Science
1972, 178, 871-872.
[15] R. Ghosh, L. Pradhan, Y. P. Devi, S. S. Meena,
R. Tewari, A. Kumar, S. Sharma, N. S.
Gajbhiye, R. K. Vatsa, B. N. Pandey, R. S.
Ningthoujam, J. Mater. Chem. 2011, 21,
13388-13398.
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FULL PAPER
Amino Acids: Nontoxic and Cheap Alternatives for
Amines for the Synthesis of Benzoxazoles through
the Oxidative Functionalization of Catechols
Adv. Synth. Catal. Year, Volume, Page – Page
Hashem Sharghi*, Jasem Aboonajmi, Mahdi Aberi,
Mohsen Shekouhy
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