One-pot multicomponent reaction of catechols, ammonium acetate, and aldehydes for the synthesis of benzoxazole derivatives using the fe(iii)-salen complex

Article abstract of DOI:10.1021/acs.joc.0c00560

The Fe(III)-salen complex has been applied successfully as a catalyst for the novel, simple, efficient, and one-pot multicomponent synthesis of benzoxazole derivatives from catechols, ammonium acetate as the nitrogen source, and aldehydes (nontoxic and cheap alternatives of amines) for the first time. Using this procedure, a wide range of benzoxazoles was successfully synthesized in the presence of a catalyst in EtOH under mild conditions, and all products were obtained in excellent yields. To the best of our knowledge, this method is the first example of the multicomponent synthesis of benzoxazole derivatives using these starting materials. The notable features such as the use of air that is considered as a benign oxidant and EtOH as a green solvent, ease of product separation, readily available and inexpensive aldehydes, and mild conditions make our procedure more efficient and practical for organic synthesis. Moreover, the current protocol is successfully applied to synthesize desirable products on a large scale.

Full text of DOI:10.1021/acs.joc.0c00560

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Article
One-Pot Multi-Component Reaction of Catechols,
Ammonium Acetate and Aldehydes for the Synthesis of
Benzoxazole Derivatives Using Fe(III)-Salen Complex
Hashem Sharghi, Jasem Aboonajmi, and Mahdi Aberi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00560 • Publication Date (Web): 24 Apr 2020
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Page 1 of 13
The Journal of Organic Chemistry
One-Pot Multi-Component Reaction of Catechols, Ammonium Acetate
and Aldehydes for the Synthesis of Benzoxazole Derivatives Using Fe(III)-
Salen Complex
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Hashem Sharghi *,a, Jasem Aboonajmi a, Mahdi Aberi b
a Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
b Department of Chemical and Materials Engineering, Faculty of Shahid Rajaee, Shiraz Branch, Technical and Vocational University
(TVU), Shiraz, Iran
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R
Toxic
Expensive
NH2
Previous Route
N
O
N
O
Fe
Cl
t-Bu
t-Bu
NH4OAC
OH
OH
O
R
EtOH, 50 oC, Air
N
t-Bu
t-Bu
t-Bu
R
CHO
The advantages of this protocol:
Short reaction time
Bioactive product
Inexpensive
ir as oxidant
Readily available aldehydes
High yields
High diversity
Green solvent
37 Examples
A
ABSTRACT: The Fe(III)-salen complex has been applied successfully as a catalyst for the novel, simple, efficient, and
one-pot multi-component synthesis of benzoxazole derivatives from catechols, ammonium acetate as the nitrogen source
and aldehydes (nontoxic and cheap alternatives of amines) for the first time. Using this procedure, a wide range of
benzoxazoles was successfully synthesized in the presence of a catalyst in EtOH under mild conditions, and all products
were obtained in excellent yields. To the best of our knowledge, this method is the first example of the multi-component
synthesis of benzoxazole derivatives using these starting materials. The notable features such as the use of air that is
considered the benign oxidant, EtOH as a green solvent, ease of product separation, readily available and inexpensive
aldehydes, and mild conditions make our procedure more efficient and practical for organic synthesis. Moreover, the current
protocol is successfully applied to synthesize desirable products in large scale.
reaction of ortho-substituted acyl anilides or ortho-
dihaloaromatic compounds were reported (Scheme 1, c-
Introduction
d).15
Multi-component reactions (MCRs) have emerged as
useful synthetic tools in drug discovery, organic synthesis,
and material science due to their advantages over
conventional multistep synthesis. Being atom economical,
efficient, time-saving and straightforward make this
approach a powerful method in the synthesis of
heterocyclic compounds in the field of industrial chemicals
and pharmaceuticals.1-4
Scheme 1. Different methods for the synthesis of benzoxazoles.
Perivious works:
X
O
R
N
H
R1
O
Y
X = H, Cl, Br, I
+
R
H2N
d
R1
OH
N
X
R
c
X: Cl, Br, I
R1
b
Y: Cl, Br, I
Between various kinds of heterocyclic compounds,5
benzoxazoles occupy a significant place since they are the
major elements of diverse natural compounds and
functionalized products.6 Benzoxazole derivatives are vital
structures in many compounds such as biologically active
compounds,7 therapeutically active molecules,8 natural
products,9 fluorescent probes,10 heat-resistant polymers,11
and functional materials.12
O
R1
R
N
R1COOH
R1CHO
R1CH2X
a
OH
e
O
C-H
R
+
NH2
activation
H
N
f
X: OH, NH2, H
R1 R1
OH
C
C
H2N
R1
R
+
OH
This work: novel method, air oxidant, readily available materials and inexpensive, mild
condition, green solvent, high yield, wide substrate scope, 37 examples
There are several pathways for the preparation of
benzoxazole derivatives. Often, 2-substituted benzoxazole
derivatives are produced through the reaction of o-
carboxylic
amines/toluene or
carbon-carbon triple bonds and subsequent oxidative
cyclization of the imine intermediate (Scheme 1, a-b).13-14
Recently, general methods for the synthesis of
benzoxazoles via intramolecular/intermolecular coupling
N
O
N
O
Fe
Cl
aminophenols
acids/aldehydes/alcohols/benzyl
with
OH
OH
O
Fe(III)-salen complex
EtOH, 50 oC, Air
NH OAc R1CHO
R1
+
+
4
N
R
R
3a-3al
1
2
Moreover, transition metal-catalyzed direct C-H bond
activation of benzoxazoles has been described (Scheme 1,
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e).16 Recently, Kerr et al., 2011; Chen et al., 2015; Meng
et al., 2017; and Sharghi et al., 2019; have presented novel
protocols for the efficient synthesis of benzoxazoles
through the oxidative functionalization of catechol
derivatives with amine derivatives in the presence of silver,
copper or iron as catalyst (Scheme 1, f).17 However,
drawbacks of these pathways include high temperatures,
using strong acids or oxidizing agents, and using expensive
and potentially toxic reactants, and reagents, which make
them to have a limited substrate scope.
Cr, V, Cu, Mn, and Mo (Table 1, entries 1-5). Then, the
1
2
3
4
5
6
7
8
effect of various solvents, such as EtOH, DMF, Toluene,
DMSO, CH3CN, DCM, EtOAc, DCE, CHCl3, MeOH as
well as solvent-free condition were explored on the model
reaction in the presence of Fe(III)-salen complex at 25 oC
(Table 1, entries 6-16). We found that EtOH is the best
solvent for the synthesis of benzoxazole 3a (Table 1, entry
6) not only it showed high reaction rate, and excellent yield
of product, but also it is an environment-friendly solvent
which makes the method more practical for different
industries. Also, no product was obtained under the
solvent-free and catalyst-free conditions, indicating that
the presence of catalyst and solvent are necessary for this
transformation (Table 1, entries 16-17). In continuous,
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As a fact, metallo-salens have shown broad applicability as
catalysts. These complexes are versatile systems and
generally applied as effective catalysts in organic
reactions.18 Due to the abundance, availability,
inexpensiveness and low toxicity of many iron compounds
and their salts they have been used by many organic
chemists as a catalyst in the synthesis of different organic
compounds.19
FeCl3
and
nano
magnetic
Fe3O4
were applied as catalyst and obtained 65% and 75% yield,
respectively (Table 1, entries 18-19). The obtained results
showed that the optimum amount of Fe(III)-salen complex
loading was 3 mol% in EtOH for the best synthesis of
product 3a (Table 1, entry 20). Increasing the amount of
catalyst (10 mol %) did not improve the yield (Table 1,
entry 21). The effect of temperature on the preparation of
benzoxazole 3a using Fe(III)-salen complex in EtOH was
investigated. This reaction was also accomplished at 50 oC,
and 95 % isolated yield of product was obtained after 3 h
(Table 1, entry 22). The role of increasing temperature to
reflux was screened and as it is shown in Table 1,
increasing the temperature did not have any effect on the
reaction progress (Table 1, entry 23).
On the other hand, the development of new and efficient
strategies by readily available starting materials under mild
reaction conditions is strongly desired for the synthesis of
benzoxazoles. In this research, for the first time we report
a novel, efficient and multi-component Fe(III)-salen
complex-catalyzed method for the synthesis of
benzoxazole derivatives via catechols, ammonium acetate
as the nitrogen source and aldehydes in EtOH as green
solvent (Scheme 1).
During our optimization studies, the optimal amount of
ammonium acetate was examined (Table 1, entries 22, 24-
25). By using 1.0 mmol ammonium acetate as the nitrogen
source, 95 % product was obtained. According to Table 1,
the best results for the one-pot multi-component synthesis
of product 3a from 3,5-di-tert-butylbenzene-1,2-diol 1,
ammonium acetate as the nitrogen source, and 4-
chlorobenzaldehyde 2a were obtained in EtOH at 50 ˚C in
the presence of Fe(III)-salen complex (3 mol%) as a
catalyst (Table 1, entry 22).
The notable features of this approach including the use of
air that is considered the benign oxidant and EtOH as a
green solvent, ease of product separation, using readily
available and inexpensive aldehydes, and performing the
reaction under mild conditions make the current protocol
practical, and eco-friendly for organic synthesis.
Results and Discussion
In continuation of our previous investigations on the
application of metallo-salens as catalysts in organic
13e, 20
Table 1. Optimization of the reaction conditions for synthesis of
4,6-di-tert-butyl-2-(4-chlorophenyl)-1H-benzo[d]imidazolea, b
synthesis,2,
and as a result of our interest in the
preparation of organic compounds,21 we introduce the
synthesis of benzoxazole derivatives in the presence of
Fe(III)-salen complex. The metal-salen complexes were
produced by previously reported procedures. 2, 13e, 20, 22 To
find out the suitable condition for the novel multi-
component synthesis of benzoxazole derivatives, a series
of experiments were performed with the model reaction of
t-Bu
CHO
t-Bu
t-Bu
OH
OH
Catalyst
NH4OAc
O
N
N
+
+
Cl
Cl
t-Bu
Solvent, Temp, Air
+
N
H
t-Bu
t-Bu
Cl
2a
1
3a
4a
exclusive
not formed
3,5-di-tert-butylbenzene-1,2-diol
1
(1.0
mmol),
Entr
y
Catalyst / mol %
Solvent
Temp.
Time
Yiel
ammonium acetate as the nitrogen source (1.0 mmol), and
4-chlorobenzaldehyde 2a (1.0 mmol) shown in Table 1.
Under these reaction conditions, we exclusively obtained
benzoxazole 3a, and no benzimidazole 4a was observed.
(h)
16
16
16
7
da %
20
1
Salen-Cr(Cl) / 5
Salen-V(Cl)2 / 5
Salen-Cu / 5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
At first, a variety of metal-salen complexes were tested to
find out the best catalyst for the synthesis of benzoxazole
3a in EtOH at 25 oC. Among various metal-salen
complexes (Cr, V, Cu, Mn, Mo, and Fe) (Table 1, entries
1-6), Fe(III)-salen complex was found to give the best
result in terms of yield and reaction time (Table 1, entry 6).
No improvement in the yield of the final product was
achieved by using other tested salen catalysts, including
2
30
3
35
4
Salen-Mn(OAc) / 5
Salen-Mo(O) / 5
Salen-Fe(Cl) / 5
70
5
16
5
40
6
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Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
Salen-Fe(Cl) / 5
-
DMF
Toluene
DMSO
CH3CN
DCM
EtOAc
DCE
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
50 oC
reflux
50 oC
50 oC
14
10
16
8
60
70
30
73
55
52
65
35
75
-
Scheme 2. Scope of the reactiona, b
1
2
3
4
5
6
7
8
OH
+
OH
O
N
3 mol% Fe(III)-salen complex
R1CHO
R1
NH4OAc+
EtOH, 50 oC, air
R
R
9
1
2
3a-3al
t-Bu
t-Bu
t-Bu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24c
25d
O
O
O
N
F
Cl
12
14
10
16
7
N
N
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Cl
3b
3a
(4h, 90%)
3c
3f
(3h, 95%)
(3h, 94%)
t-Bu
t-Bu
t-Bu
Cl
O
9
O
N
O
N
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
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47
48
49
50
51
52
53
54
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57
58
59
60
N
CHCl3
MeOH
-
Br
Cl
3e
3d
(4h, 86%)
(5h, 80%)
(3h, 97%)
t-Bu
t-Bu
t-Bu
O
N
O
N
O
24
24
8
OH
Me
N
t-Bu
t-Bu
t-Bu
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
-
3g
(4h, 89%)
3h
(3h, 96%)
3i
(3h, 92%)
FeCl3 / 5
65
75
90
75
95
83
89
80
t-Bu
t-Bu
t-Bu
O
N
O
O
NM-Fe3O4
6
N
N
t-Bu
t-Bu
t-Bu
t-Bu
Me
(3h, 92%)
t-Bu
OMe
MeO
Salen-Fe(Cl) / 3
Salen-Fe(Cl) / 10
Salen-Fe(Cl) / 3
Salen-Fe(Cl) / 3
Salen-Fe(Cl) / 3
Salen-Fe(Cl) / 3
5
3j
3k
3l
(4h, 91%)
(4h, 94%)
t-Bu
t-Bu
5
O
O
O
N
OMe
NO2
OH
OMe
N
N
3
OMe
3m
(5h, 90%)
3n
(5h, 83%)
3o
(5h, 85%)
3
t-Bu
t-Bu
t-Bu
O
N
O
N
O
N
3
CN
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
NO2
3
3q
(5h, 81%)
3p
(5h, 86%)
3r
(5h, 84%)
aGeneral conditions: 3,5-di-tert-butylbenzene-1,2-diol (1.0 mmol),
t-Bu
t-Bu
t-Bu
ammonium acetate (1.0 mmol), 4-chlorobenzaldehyde (1.0 mmol),
O
N
O
N
O
N
solvent (5.0 mL), air. Isolated yield. cAmmonium acetate (2.0 mmol).
b
N
N
dAmmonium acetate (3.0 mmol).
3s
3t
3u
(4h, 90%)
(3h,92%)
(5h, 80%)
After optimization of the reaction conditions for the
synthesis of benzoxazole 3a, we screened the scope and
generality of this method by varying the aldehydes and
catechols under the optimized conditions. The results are
shown in Scheme 2. All benzoxazole derivatives (3a-3ak)
were characterized by the melting point, FT-IR, 1H NMR,
13C NMR, and elemental analysis.
t-Bu
t-Bu
t-Bu
O
N
O
N
O
N
N
NH
S
3v
(3h, 95%)
3w
3x (4h, 92%)
(6h, 85%)
t-Bu
t-Bu
O
N
O
N
O
N
Me
S
O
t-Bu
t-Bu
t-Bu
H3C
H3C
As shown in Scheme 2, aryl aldehydes containing different
electron-donating and electron-withdrawing groups
afforded the desired benzoxazole derivatives in good to
excellent yields. Halogen groups at the ortho, meta, and
para position of benzaldehyde in reaction with 3,5-di-tert-
butylbenzene-1,2-diol worked well and gave good yields
of benzoxazoles regardless of their electronic character
(Scheme 2, 3a-e). Moreover, benzaldehyde with electron-
donating groups at the para position such as methoxy,
hydroxyl, methyl, and isopropyl participated well in the
reactions to achieve corresponding products in good to
high yields under mild reaction conditions (Scheme 2, 3f-
i). In addition, benzoxazoles 3j, 3k, and 3l with methyl and
methoxy groups in ortho and meta position of
benzaldehyde were obtained in 92%, 91%, and 94% yields,
respectively (Scheme 2, 3j-l). Moreover, benzaldehydes
3y
(5h, 87%)
O
3aa
3ad
3z
(5h, 92%)
(4h, 95%)
O
O
N
Cl
N
N
t-Bu
Cl
3ac
(5h, 88%)
(8h, 81%)
3ab
(5h, 90%)
O
N
O
N
O
N
OCH3
Cl
N
H3C
H3C
3ae (7h, 87%)
3af
(7h, 85%)
3ag
(6h, 87%)
t-Bu
t-Bu
O
N
O
O
O
N
N
N
S
t-Bu
H3C
t-Bu
CH3
3ai
3ah
3aj
3ak (12h, 30%)
(8h, 77%)
(12h, 42%)
(9h, 75%)
aGeneral conditions: 1 (1.0 mmol), NH4OAc (1.0 mmol) and 2 (1.0
mmol), Fe(III)-salen complex (3 mol%), EtOH (5.0 mL), air, 50 ˚C.
bIsolated yield.
For further investigation of the reaction scope,
benzaldehyde with electron-withdrawing groups such as
cyano and nitro reacted with 3,5-di-tert-butylbenzene-1,2-
diol to successfully form benzoxazoles in good to excellent
yields under mild reaction conditions (Scheme 2, 3o-q).
with
two
donor
substitutes
and
such
as
3,4-
dimethoxybenzaldehyde
methoxybenzaldehyde were tested (Scheme 2, 3m-n).
4-hydroxy-3-
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According to Scheme 2, benzaldehydes with electron- benzimidazole 4a was observed (Scheme 4, a). Moreover,
1
2
3
4
5
6
7
8
donating groups showed better reactivity than
benzaldehyde bearing electron-withdrawing groups.
Furthermore, sterically hindered 1-naphthaldehyde
produced naphthyl-substituted benzoxazole in 84% yield
(Scheme 2, 3r). Pleasingly, various N-heteroaryl
aldehydes, such as, pyridine-2-carbaldehyde, pyridine-3-
carbaldehyde, pyridine-4-carbaldehyde, and 1H-indole-3-
carbaldehyde were converted to the corresponding
benzoxazole derivatives in the presence of a catalytic
amount of Fe(III)-salen complex with good to excellent
yields (Scheme 2, 3t-w). S-heteroaryl aldehydes and O-
heteroaryl aldehydes such as thiophene-2-carbaldehyde,
thiophene-3-carbaldehyde, and furan-2-carbaldehyde
could also give the corresponding benzoxazoles in 92%,
87% and 95% yields, respectively (Scheme 2, 3x-z). In
continue, we turned our attention to the variation of
catechols. Notably, when 4-tert-butylbenzene-1,2-diol and
4-chlorobenzaldehyde 2a was reacted with ammonium
acetate using Fe(III)-salen complex as a catalyst in EtOH
at 50 ˚C for 2 hours. Next, 3,5-di-tert-butylbenzene-1,2-
diol 1a was added to the reaction mixture and benzoxazole
3a was just obtained with 90% yield (Scheme 4, b).
According to the obtained results, it is speculated that the
reaction pathway was going via 3,5-di-tert-butyl-o-
benzoquinone intermediate. Therefore, we used 3,5-di-
tert-butyl-o-benzoquinone 1aa as starting material to react
with ammonium acetate and 4-chlorobenzaldehyde under
the standard reaction conditions and benzimidazole
product (22%) 4a was obtained and benzoxazole 3a was
not observed (Scheme 4, c). Furthermore, different
loadings of ammonium acetate (2.0 mmol and 3.0 mmol)
were tested and product 4a was obtained in 80% and 65%
yields, respectively. Additionally, in the absence of the
catalyst, 15% product 4a was just obtained (Scheme 4, c).
According to the previous reports,23 homocoupling product
(biphenyldiol 1ab) may be produced as an intermediate in
the reaction pathway. For this purpose, the homocoupling
product (biphenyldiol 1ab) was used as the starting
material under the same conditions, however 1ab did not
react smoothly with 4-chlorobenzaldehyde 2a and
ammonium acetate to afford products 3a and 4a (Scheme
4, d). Notably, the phenylmethanimine 2aa was generated
through the reaction between 2a and ammonium acetate in
a significant amount when the reaction was quenched after
2 h (Scheme 4, e). Additionally, when the compound 2aa
reacted with 1a under the standard conditions, 96% yield
of the desired product 3a was obtained (Scheme 4, f). Also,
when the model reaction was carried out under N2, only
12% of product 3a was detected; this result indicated that
the atmosphere is necessary for this reaction (Scheme 4, g).
When, 2.0 equivalents of the TEMPO (2,2,6,6-tetramethyl-
1-piperidinyloxyl, well-known radical-capturing agent)
was added into the reaction system of 1a, 2a and
ammonium acetate under the standard conditions, the
formation of 3a was partially observed, then the reaction
was quenched by simply increasing the amount of TEMPO
to 4.0 equivalents (Scheme 4, h). This observation implies
that the reaction may happen via a radical process.
Experiment studies exhibited that the mechanism probably
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4-methyl-benzene-1,2-diol,
3-methyl-benzene-1,2-diol
were employed as the substrate in the reaction with various
functional groups (-Me, -Cl, and -OMe) on the
benzaldeyde ring as well as heteroaryl aldehydes (pyridine-
2-carbaldehyde, and thiophene-2-carbaldehyde), related
benzoxazoles were obtained in reasonable yields (Scheme
2, 3aa-ai). We also applied this synthetic procedure for the
preparation of 2-alkylbenzoxazole derivatives using
aliphatic aldehydes such as isobutyraldehyde and
acetaldehyde under the optimized reaction conditions in
the presence of Fe(III)-salen complex (Scheme 2, 3aj-ak).
However, ortho-dihydroxybenzenes such as catechol (1,2-
dihydroxybenzene), 4-nitrobenzene-1,2-diol, 3,4,5,6-
tetrabromobenzene-1,2-diol, 3,4-dihydroxybenzoic acid,
7,8-dihydroxy-4-methyl-2H-chromen-2-one,
and
naphthalene-2,3-diol did not afford the desired products in
the presented method.
Importantly, aside from screening different substrates, to
demonstrate the practicability of the current methodology,
large scale synthesis of the 5,7-di-tert-butyl-2-(4-
chlorophenyl)benzo[d]oxazole (3a) was evaluated via the
reaction between 3,5-di-tert-butylbenzene-1,2-diol (5.0
mmol), NH4OAc (5.0 mmol) and 4-chlorobenzaldehyde
(5.0 mmol). Based on the obtained result, the conducted
reaction was successfully carried out on a large-scale, and
no notable loss of yield was observed (Scheme 3).
involves
a
radical intermediate. Based on these
experimental studies, we propose the mechanism shown in
Scheme 5.
Scheme 3. Gram-Scale Synthesis of Product 3a.
CHO
t-Bu
t-Bu
First, ammonium acetate dissociates into ammonia in the
reaction, which is needed for the initial condensation with
aryl aldehyde. Ammonia reacts with aldehyde to give the
phenylmethanimine intermediate I.24
OH
OH
O
N
standard conditions
NH OAc
4
+
Cl
+
gram-scale
5.0 mmol
t-Bu
t-Bu
3a
Cl
1a
2a
(1.57 g, 92% yield)
To obtain deep insight into the reaction mechanism, several
different control experiments were performed (Scheme 4).
As it is shown in Scheme 4, at the beginning of the study,
a one-pot three-component reaction using 3,5-di-tert-
butylbenzene-1,2-diol 1a (1.0 mmol), ammonium acetate
as the nitrogen source (1.0 mmol), and 4-
chlorobenzaldehyde 2a (1.0 mmol) in the presence of 3
mol % Fe(III)-salen complex under the standard reaction
conditions, gave 95% yield of 3a in only 3 h. Also, we
applied different amounts of ammonium acetate, and
benzoxazole 3a was exclusively obtained and no
Scheme 4. Control Experiments (a-h).
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The Journal of Organic Chemistry
NH4OAc
H
NH3
HOAc
a:
t-Bu
OH
+
OH
t-Bu
O
t-Bu
N
CHO
Cl
NH
H
O
1
2
3
3 mol% Fe(III)-salen
EtOH, 50 oC, air
NH4OAc
+
Cl
Cl
+
t-Bu
EtOH
50 oC, Air
t-Bu
N
N
t-Bu
NH3
+
H
R
R
I
1a
2a
3a
4a
4
5
6
7
8
9
t-Bu
t-Bu
t-Bu
1 mmol
1 mmol
1 mmol
1 mmol
2 mmol
3 mmol
1 mmol
1 mmol
1 mmol
95%
89%
80%
0%
t-Bu
OH
OH
OH
O
OH
O
OH
N
Salen-Fe(Cl)
Air
0%
0%
t-Bu
t-Bu
H
t-Bu
t-Bu
HO
HN
1
A
B
R
Cl
b:
R
I
3 mol% Fe(III)-salen
EtOH, 50 oC, 2h, Air
t-Bu
NH4OAc
+
t-Bu
t-Bu
t-Bu
OH
OH
O
N
O
N
O
CHO
H
Cyclization
- OH
OH
t-Bu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
t-Bu
N
2a
t-Bu
- H2O
t-Bu
1a
R
t-Bu
t-Bu
D
E
C
O
N
R
R
Cl
Cl
+
N
N
H
t-Bu
t-Bu
t-Bu
O
N
Salen-Fe(Cl)
Air
3a
4a
(90% yield)
(0% yield)
c: t-Bu
t-Bu
R
CHO
Cl
t-Bu
t-Bu
O
O
F
EtOH, 50 oC, air
NH OAc
4
O
N
N
+
+
Cl
+
Cl
t-Bu
N
H
4a
t-Bu
t-Bu
CONCLUSIONS
1aa
2a
3a
1 mmol
1 mmol
2 mmol
3 mmol
2 mmol
1 mmol 3 mol% Fe(III)-salen
1 mmol 3 mol% Fe(III)-salen
1 mmol 3 mol% Fe(III)-salen
0%
22%
Fe(III)-salen complex was found as an efficient catalyst for
the novel, simple, and one-pot multicomponent synthesis
of benzoxazole derivatives from catechols, ammonium
acetate as the nitrogen source and aldehydes (nontoxic and
cheap alternatives of amines) for the first time under mild
and simple conditions. The advantages of this procedure
for the synthesis of benzoxazole derivatives, include high
product yields, using environmentally safe solvent (EtOH),
experimental simplicity, readily available and inexpensive
aldehydes, applicability for large scale and short reaction
times. The best of our knowledge, this method is the first
report for the one-pot multi-component synthesis of
benzoxazole derivatives via the reaction of catechols,
ammonium acetate as the nitrogen source and aldehydes.
1 mmol
1 mmol
1 mmol
0%
0%
0%
80%
65%
15%
1 mmol
CHO
no catalyst
t-Bu
d:
t-Bu
t-Bu
OH
3 mol% Fe(III)-salen
EtOH, 50 oC, air
N
O
N
t-Bu
Cl
+
Cl
+
t-Bu
N
H
t-Bu
t-Bu
Cl
HO
NH4OAc
t-Bu
1ab
2a
3a
4a
(0% yield)
(0% yield)
NH
CHO
e:
EtOH
50 oC, 2h, Air
NH4OAc
+
Cl
Cl
2a
2aa
(90% yield)
f:
NH
t-Bu
t-Bu
t-Bu
OH
OH
O
N
3 mol% Fe(III)-salen
EtOH, 50 oC, Air
Cl
Cl
+
+
N
N
H
t-Bu
t-Bu
t-Bu
Cl
2aa
1a
3a
4a
(0% yield)
(96% yield)
t-Bu
OH
t-Bu
CHO
g:
O
standard conditions
N2
EXPERIMENTAL SECTION
Cl
Cl
NH4OAc
+
+
+
+
N
t-Bu
OH
t-Bu
t-Bu
Cl
1a
2a
3a
(12% yield)
General Information. All reagents and solvents were
commercially obtained from Merck, Fluka, or Sigma-
Aldrich and used without further purification. Melting
points were measured in capillary tubes in a Büchi B-545
apparatus. All the reactions were conducted in an oil bath
and monitored by thin-layer chromatography on 0.25 mm
silica gel (60 F254 in aluminum foil, Merck) visualizing
with UV light. 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. IR spectra were obtained using a
CHO
t-Bu
t-Bu
OH
O
standard condition
h:
NH4OAc
N
t-Bu
OH
Cl
1a
2a
3a
3a
TEMPO (2.0 eq)
TEMPO (4.0 eq)
(18% yield)
(trace)
Next, radical intermediate A is produced from 3,5-di-tert-
butylbenzene-1,2-diol 1 via an oxidation process.25
Afterward, the nucleophilic attack of phenylmethanimine I
to radical intermediate A lead to the formation of
intermediate B.25 Subsequently, imine intermediate C is
created by eliminating the hydroxyl radical of intermediate
B. Phenoxyl radical intermediate D is generated through
single-electron transfer (SET) from imine intermediate C
and hydroxyl radical.16d Then, an intramolecular
cyclization takes place to afford intermediate E.16d Finally
the desired benzoxazole F is produced via SET and the
Shimadzu FT-IR 8300 spectrophotometer. H and 13C
NMR spectra were recorded in CDCl3 or DMSO-d6
solvents using Bruker spectrometer (1H NMR: 250, 300,
and 400 MHz; 13C NMR (62.5, 75 and 100 MHz). Proton
1
chemical shifts are given as
δ
values against
tetramethylsilane (TMS) as the internal standard and
coupling constants (J) are given in hertz (Hz). Chemical
shift multiplicities are represented as follows: (s = singlet,
d = doublet, t = triple, sep = septet, m = multiplet, dd =
double of doublet, td = triple of doublet). The elemental
analysis was performed on a Perkin-Elmer 240-B
microanalyzer.
oxidative dehydrogenation of intermediate E.13d,
16d, 20
Regarding the role of the Fe(III)-salen complex, it may be
considered to activate the aldehyde, help radical
production and promote the cyclization and the oxidative
aromatization.
Scheme 5. The proposed mechanism for the synthesis of
benzoxazole derivatives from the reaction of 3,5-di-tert-
butylbenzene-1,2-diol, ammonium acetate, and aldehyde using
Fe(III)-salen complex in EtOH (5.0 mL) at 50 ˚C.
General procedure for the synthesis of Schiff-Base
(Salen)
To a solution of ethylenediamine (0.6 g, 10.0 mmol) in
MeOH (20 mL) was added salicylaldehyde (2.44 g, 20.0
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The Journal of Organic Chemistry
Page 6 of 13
mmol). The reaction mixture was stirred at reflux for 2 h.
5,7-Di-tert-butyl-2-(4-fluorophenyl)benzo[d]oxazole
(3b).17b
1
2
3
4
5
6
7
8
After completion of the reaction, the precipitate was
filtered off and washed by additional MeOH. Then, the
residue was recrystallized from MeOH for further
purification to give pure product in high yield.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (292 mg, 90%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, CDCl3): δ (ppm) 1.32 (s, 9H),
1.47 (s, 9H), 7.13 (t, J= 7.5 Hz, 2H), 7.24 (t, J= 2.5 Hz,
1H), 7.57 (d, J= 2.5 Hz, 1H), 8.17 (dd, J= 5.0, 7.5 Hz, 2H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 30.0, 31.8, 34.5,
35.1, 114.2, 116.0, 116.2, 119.6, 123.8, 123.9, 129.5,
129.6, 133.7, 133.9, 142.2, 146.9, 147.8, 161.6, 163.3,
165.8. Anal. Calcd for C21H24FNO: C, 77.51; H, 7.43; N,
4.30; Found: C, 77.40; H, 7.36; N, 4.32.
Synthesis of iron salen complex
The salen (268 mg, 1.0 mmol) was dissolved in EtOH (15
mL) and slowly added drop wise to a suspension of FeCl3
anhydrous (162 mg, 1.0 mmol) in the same solvent (10
mL). The homogeneous solution was stirred under nitrogen
atmosphere at room temperature for 4 h. The brown Fe(III)
salen complex was filtered off, washed with water, ethanol,
and diethyl ether. Finally, the solid products dried at room
temperature. Fe(III) salen complex was obtained in 85%
(274 mg) yields.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5,7-Di-tert-butyl-2-(2-chlorophenyl)benzo[d]oxazole
(3c).17c
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (321 mg, 94%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, CDCl3): δ (ppm) 1.32 (s, 9H),
1.47 (s, 9H), 7.27 (d, J= 2.5 Hz, 1H), 7.32-7.36 (m, 2H),
7.46-7.50 (m, 1H), 7.64 (d, J= 2.5 Hz, 1H), 8.08-8.11 (m,
1H); 13C{H} NMR (75 MHz, CDCl3): δ (ppm) 29.9, 31.8,
34.4, 35.1, 114.5, 119.9, 126.6, 126.9, 131.3, 131.6, 131.7,
133.2, 134.0, 141.8, 146.9, 147.8, 160.5. Anal. Calcd for
C21H24ClNO: C, 73.78; H, 7.08; N, 4.10; Found: C, 73.72;
H, 7,06; N, 4.06.
General procedure for the Synthesis of
Benzoxazoles Derivatives
A solution of catechol (1.0 mmol), aldehyde (1.0 mmol),
NH4OAc (77 mg, 1.0 mmol) and Fe(III)-salen complex (10
mg ≈ 3.0 mol%) in EtOH (5.0 mL) were stirred in an open
tube under the air atmosphere at 50 ˚C in an oil bath for the
required time. After completion of the reaction (monitoring
by TLC), EtOH was removed under reduced pressure. The
reaction mixture was diluted with EtOAc (4 × 5 mL). The
combined organic layers were dried over anhydrous
Na2SO4 and concentrated under vacuum. The resulting
residue was purified by column chromatography on silica
using a mixture of petroleum ether / EtOAc as eluent to
achieve the pure product.
2-(3-Bromophenyl)-5,7-di-tert-butylbenzo[d]oxazole
(3d).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (308 mg, 80%). Pale green solid, mp: 103-104 C;
o
2,2’-[1,2-Ethanediylbis (nitrilomethylidyne)]-bis-phenol
1H NMR (250 MHz, DMSO-d6): δ (ppm) 1.33 (s, 9H), 1.48
(s, 9H), 7.31 (s, 1H), 7.61 (s, 2H), 7.81 (s, 1H), 8.14-8.24
(m, 2H); 13C{H} NMR (100 MHz, DMSO-d6): δ (ppm)
29.7, 31.4, 34.0, 34.7, 114.1, 119.6, 122.3, 125.9, 128.7,
129.1, 131.5, 133.4, 134.3, 141.6, 146.4, 147.6, 160.1.
Anal. Calcd for C21H24BrNO: C, 65.29; H, 6.26; N, 3.63;
Found: C, 64.66; H, 5.92; N, 3.30.
(Salen).18d
Purified by MeOH solvent. Isolated yield: (2.63 g, 98%).
Yellow solid; mp: 123-124 °C; FT-IR (KBr cm-1): 3431
1
(br, OH), 1634 (s, C=N); H NMR (CDCl3, 300 MHz): δ
(ppm) 3.90 (s, 4H), 6.88 (t, J= 7.5 Hz, 2H), 6.98 (d, J= 9.0
Hz, 2H), 7.25 (dd, J1= 9.0 Hz, J2= 3.0 Hz, 2H), 7.29-7.35
(m, 2H), 8.34 (s, 2H), 13.30 (br, 2H); 13C{H} NMR
(CDCl3, 75.0 MHz): δ (ppm) 59.7, 116.9, 118.6, 118.7,
131.5, 132.4, 161.0, 166.5.
5,7-Di-tert-butyl-2-(2,6-dichlorophenyl)benzo[d]oxazole
(3e).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
5,7-Di-tert-butyl-2-(4-chlorophenyl)benzo[d]oxazole
(3a).17a
1
yield: (323 mg, 86%). Colorless liquid; H NMR (250
MHz, DMSO-d6): δ (ppm) 1.33 (s, 9H), 1.40 (s, 9H), 7.34
(d, J= 2.5 Hz, 1H), 7.67-7.71 (m, 4H); 13C{H} NMR (100
MHz, DMSO-d6): δ (ppm) 29.5, 31.4, 34.0, 34.7, 114.5,
119.8, 126.9, 128.7, 133.6, 133.7, 134.9, 140.9, 146.4,
147.6, 156.7. Anal. Calcd for C21H23Cl2NO: C, 67.03; H,
6.16; N, 3.72; Found: C, 67.00; H, 6.12; N, 3.74.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (324 mg, 95%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, DMSO-d6): δ (ppm) 1.33 (s,
9H), 1.48 (s, 9H), 7.29 (d, J= 2.5 Hz, 1H), 7.60 (d, J= 2.5
Hz, 1H), 7.67 (d, J= 7.5 Hz, 2H), 8.16 (d, J= 7.5 Hz, 2H);
13C{H} NMR (100 MHz, DMSO-d6): δ (ppm) 29.7, 31.5,
34.0, 34.7, 114.1, 119.5, 125.4, 128.7, 129.5, 133.3, 136.4,
141.8, 146.3, 147.5, 160.8. Anal. Calcd for C21H24ClNO:
C, 73.78; H, 7.08; N, 4.10; Found: C, 73.72; H, 7.00; N,
4.14.
5,7-Di-tert-butyl-2-(4-methoxyphenyl)benzo[d]oxazole
(3f).17c
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (327 mg, 97%). Colorless liquid (lit. Colorless
liquid); 1H NMR (300 MHz, CDCl3): δ (ppm) 1.43 (s, 9H),
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The Journal of Organic Chemistry
1.58 (s, 9H), 3.90 (s, 3H), 7.05 (d, J= 9.0 Hz, 2H), 7.31 (s,
1H), 7.66 (s, 1H), 8.22 (d, J= 9.0 Hz, 2H); 13C{H} NMR
(75 MHz, CDCl3): δ (ppm) 30.0, 31.8, 34.4, 35.0, 55.4,
113.9, 114.3, 119.0, 120.0, 129.1, 133.5, 142.4, 146.8,
147.5, 162.0, 162.6. Anal. Calcd for C22H27NO2: C, 78.30;
H, 8.06; N, 4.15; Found: C, 78.24; H, 8.01; N, 4.13.
1
2
3
4
5
6
7
8
5,7-Di-tert-butyl-2-(3-methoxyphenyl)benzo[d]oxazole
(3k).17a
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (307 mg, 91%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, DMSO-d6): δ (ppm) 1.33 (s,
9H), 1.48(s, 9H), 3.85 (s, 3H), 7.16-7.21 (m, 1H), 7.29 (d,
J= 2.5 Hz, 1H), 7.52 (t, J= 7.5 Hz, 1H), 7.60 (d, J= 2.5 Hz,
1H), 7.63-7.65 (m, 1H), 7.72-7.76 (m, 1H); 13C{H} NMR
(100 MHz, CDCl3): δ (ppm) 30.0, 31.8, 34.5, 35.1, 55.5,
112.0, 114.2, 117.6, 119.6, 119.8, 128.7, 129.9, 133.7,
142.2, 146.9, 147.7, 159.9, 162.3. Anal. Calcd for
C22H27NO2: C, 78.30; H, 8.06; N, 4.15; Found: C, 78.28;
H, 8.05; N, 4.20.
4-(5,7-Di-tert-butylbenzo[d]oxazol-2-yl)phenol (3g).17a
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:10). Isolated
yield: (288 mg, 89%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, DMSO-d6): δ (ppm) 1.32 (s,
9H), 1.47 (s, 9H), 6.95 (d, J= 10.0 Hz, 2H), 7.21 (d, J= 2.5
Hz, 1H), 7.52 (d, J= 2.5 Hz, 1H), 7.99 (d, J= 10.0 Hz, 2H),
10.53 (s, OH); 13C{H} NMR (100 MHz, DMSO-d6): δ
(ppm) 29.7, 31.5, 34.0, 34.6, 113.5, 116.1, 117.1, 118.3,
128.9, 132.8, 142.1, 146.0, 147.0, 161.1, 162.3. Anal.
Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33; Found:
C, 77.95; H, 7.77; N, 4.35.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5,7-Di-tert-butyl-2-(2-methoxyphenyl)benzo[d]oxazole
(3l).17c
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (317 mg, 94%). Colorless liquid (lit. Colorless
liquid); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.45 (s, 9H),
1.52 (s, 9H), 3.91 (s, 3H), 6.99-7.05 (m, 2H), 7.06 (d, J=
4.0 Hz, 2H), 7.38-7.43 (m, 1H), 8.11 (d, J= 8.0 Hz, 1H);
13C{H} NMR (100 MHz, DMSO-d6): δ (ppm) 29.5, 31.5,
33.9, 34.7, 56.0, 112.9, 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, 78.33; H, 8.11; N, 4.21.
5,7-Di-tert-butyl-2-(p-tolyl)benzo[d]oxazole (3h).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (308 mg, 96%). Cream solid, mp: 94-95 oC; 1H NMR
(400 MHz, CDCl3): δ (ppm) 1.33 (s, 9H), 1.48 (s, 9H), 2.37
(s, 3H), 7.23 (d, J= 4.0 Hz, 1H), 7.26 (d, J= 8.0 Hz, 2H),
7.58 (d, J= 4.0 Hz, 1H), 8.07 (d, J= 8.0 Hz, 2H); 13C{H}
NMR (100 MHz, CDCl3): δ (ppm) 21.6, 30.0, 31.8, 34.5,
35.0, 114.0, 119.3, 124.8, 127.3, 129.6, 133.6, 141.6,
142.3, 146.8, 147.6, 162.7. Anal. Calcd for C22H27NO: C,
82.20; H, 8.47; N, 4.36; Found: C, 82.31; H, 8.54.18; N,
4.45.
5,7-Di-tert-butyl-2-(3,4-
dimethoxyphenyl)benzo[d]oxazole (3m).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:50). Isolated
5,7-Di-tert-butyl-2-(4-isopropylphenyl)benzo[d]oxazole
(3i).
1
yield: (330 mg, 90%). Colorless liquid; H NMR (250
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
MHz, DMSO-d6): δ (ppm) 1.32 (s, 9H), 1.47 (s, 9H), 3.83
(s, 3H), 3.86 (s, 3H), 7.15 (d, J= 10.0 Hz, 1H), 7.23 (d, J=
2.5 Hz, 1H), 7.56 (d, J= 2.5 Hz, 1H), 7.64 (d, J= 2.5 Hz,
1H), 7.73 (dd, J= 2.5, 7.5 Hz, 1H); 13C{H} NMR (100
MHz, CDCl3): δ (ppm) 30.0, 31.8, 34.4, 35.0, 56.0, 56.1,
109.9, 110.9, 113.9, 119.1, 120.2, 120.8, 133.4, 142.3,
146.8, 147.6, 149.2, 151.7, 162.5. Anal. Calcd for
C23H29NO3: C, 75.17; H, 7.95; N, 3.81; Found: C, 75.03;
H, 7.85; N, 3.68.
1
yield: (321 mg, 92%). Colorless liquid; H NMR (250
MHz, CDCl3): δ (ppm) 1.30 (s, 3H), 1.32 (s, 3H), 1.40 (s,
9H), 1.55 (s, 9H), 2.92-3.08 (m, 1H), 7.30 (d, J= 2.5 Hz,
1H), 7.39 (d, J= 10.0 Hz, 2H), 7.66 (d, J= 2.5 Hz, 1H), 8.19
(d, J= 7.5 Hz, 2H); 13C{H} NMR (100 MHz, CDCl3): δ
(ppm) 23.8, 29.0, 30.0, 31.8, 34.2, 34.4, 35.1, 114.1, 119.3,
125.1, 127.0, 127.5, 133.6, 142.3, 146.8, 147.6, 152.5,
162.7. Anal. Calcd for C24H31NO: C, 82.47; H, 8.94; N,
4.01; Found: C, 82.20; H, 8.80; N, 3.92.
4-(5,7-Di-tert-butylbenzo[d]oxazol-2-yl)-2-
methoxyphenol (3n).
5,7-Di-tert-butyl-2-(o-tolyl)benzo[d]oxazole (3j).17c
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:10). Isolated
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (295 mg, 92%). Colorless liquid (lit. Colorless
liquid); 1H NMR (300 MHz, CDCl3): δ (ppm) 1.44 (s, 9H),
1.58 (s, 9H), 2.85 (s, 3H), 7.35 (d, J= 3.0 Hz, 1H), 7.39-
7.47 (m, 3H), 7.73 (s, 1H), 8.21 (d, J= 6.0 Hz, 1H); 13C{H}
NMR (75 MHz, CDCl3): δ (ppm) 22.3, 30.0, 31.8, 34.4,
35.1, 114.3, 119.4, 126.1, 126.6, 129.9, 130.6, 131.7,
133.6, 138.3, 142.2, 146.5, 147.5, 163.0. Anal. Calcd for
C22H27NO: C, 82.20; H, 8.47; N, 4.36; Found: C, 82.02; H,
8.36; N, 4.31.
1
yield: (293 mg, 83%). Colorless liquid; H NMR (250
MHz, DMSO-d6): δ (ppm) 1.33 (s, 9H), 1.47 (s, 9H), 3.87
(s, 3H), 6.98 (d, J= 7.5 Hz, 1H), 7.22 (d, J= 2.5 Hz, 1H),
7.53 (d, J= 2.5 Hz, 1H), 7.60-7.64 (m, 2H), 9.98 (s, OH);
13C{H} NMR (100 MHz, DMSO-d6): δ (ppm) 29.7, 31.5,
34.0, 34.6, 55.6, 110.3, 113.5, 115.9, 117.5, 118.5, 120.7,
132.9, 142.0, 146.1, 147.1, 148.0, 150.3, 162.2. Anal.
Calcd for C22H27NO3: C, 74.76; H, 7.70; N, 3.96; Found:
C, 74.22; H, 7.35; N, 3.47.
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5,7-Di-tert-butyl-2-(4-nitrophenyl)benzo[d]oxazole
yield: (276 mg, 90%). Brown liquid (lit. Brown liquid); 1H
(3o).17a
NMR (300 MHz, CDCl3): δ (ppm) 1.43 (s, 9H), 1.58 (s,
9H), 7.34 (s, 1H), 7.56 (s, 3H), 7.70 (s, 1H), 8.29 (s, 2H);
13C{H} NMR (75 MHz, CDCl3): δ (ppm) 30.0, 31.8, 34.5,
35.1, 114.2, 119.6, 127.3, 127.5, 128.9, 131.2, 133.7,
142.2, 146.9, 147.7, 162.4. Anal. Calcd for C21H25NO: C,
82.04; H, 8.20; N, 4.56; Found: C, 81.90; H, 8.05; N, 4.51.
1
2
3
4
5
6
7
8
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:30). Isolated
o
yield: (299 mg, 85%). Pale yellow solid, mp: 198-200 C
o
1
(lit. White solid, mp: 194-196 C); H NMR (250 MHz,
CDCl3): δ (ppm) 1.33 (s, 9H), 1.49 (s, 9H), 7.31 (d, J= 2.5
Hz, 1H), 7.62 (d, J= 2.5 Hz, 1H), 8.32-8.35 (m, 4H);
13C{H} NMR (100 MHz, CDCl3): δ (ppm) 30.0, 31.7, 34.5,
35.1, 114.7, 120.9, 124.2, 128.0, 133.1, 134.1, 142.2,
148.5, 149.1. Anal. Calcd for C21H24N2O3: C, 71.57; H,
6.86; N, 7.95; Found: C, 71.33; H, 6.51; N, 7.65.
5,7-Di-tert-butyl-2-(pyridin-2-yl)benzo[d]oxazole (3t).17b
9
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (283 mg, 92%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, DMSO-d6): δ (ppm) 1.35 (s,
9H), 1.50 (s, 9H), 7.34 (d, J= 2.5 Hz, 1H), 7.59-7.64 (m,
1H), 7.67 (d, J= 2.5 Hz, 1H), 8.04 (td, J= 7.7, 1.7 Hz, 1H),
8.31 (d, J= 7.7 Hz, 1H), 8.81 (dd, J= 4.7, 1.7 Hz, 1H);
13C{H} NMR (100 MHz, DMSO-d6): δ (ppm) 29.6, 31.5,
34.1, 34.8, 114.4, 119.9, 123.3, 125.9, 133.7, 137.6, 141.6,
145.4, 146.6, 147.6, 150.2, 160.9. Anal. Calcd for
C20H24N2O: C, 77.89; H, 7.84; N, 9.08; Found: C, 77.87;
H, 7.80; N, 9.11.
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14
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16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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53
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60
4-(5,7-Di-tert-butylbenzo[d]oxazol-2-yl)benzonitrile
(3p).17b
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (286 mg, 86%). Colorless liquid (lit. Colorless
liquid); 1H NMR (300 MHz, CDCl3): δ (ppm) 1.42 (s, 9H),
1.57 (s, 9H), 7.39 (d, J= 3.0 Hz, 1H), 7.70 (d, J= 3.0 Hz,
1H), 7.85 (d, J= 9.0 Hz, 2H), 8.37 (d, J= 6.0 Hz, 2H);
13C{H} NMR (75 MHz, CDCl3): δ (ppm) 30.0, 31.7, 34.5,
35.1, 114.3, 114.6, 118.3, 120.7, 127.7, 131.4, 132.7,
134.0, 142.1, 147.1, 148.4, 160.3. Anal. Calcd for
C22H24N2O: C, 79.48; H, 7.28; N, 8.43; Found: C, 79.25;
H, 7.04; N, 8.27.
5,7-Di-tert-butyl-2-(pyridin-3-yl)benzo[d]oxazole (3u).17a
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
o
yield: (246 mg, 80%). White solid, mp: 99-100 C (lit.
White solid, mp: 99-101 oC); 1H NMR (250 MHz, DMSO-
d6): δ (ppm) 1.34 (s, 9H), 1.49 (s, 9H), 7.32 (d, J= 2.5 Hz,
1H), 7.62-7.67 (m, 2H), 8.47-8.52 (m, 1H), 8.78 (d, J= 5.0
Hz, 1H), 9.32 (s, 1H); 13C{H} NMR (100 MHz, DMSO-
d6): δ (ppm) 29.7, 31.4, 34.0, 34.7, 114.1, 119.6, 122.9,
124.2, 133.4, 134.4, 141.6, 146.3, 147.6, 147.7, 152.0,
159.7. Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N,
9.08; Found: C, 77.84; H, 7.76; N, 9.06.
5,7-Di-tert-butyl-2-(3-nitrophenyl)benzo[d]oxazole (3q).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:40). Isolated
o
1
yield: (285 mg, 81%). White solid, mp: 146-147 C; H
NMR (250 MHz, DMSO-d6): δ (ppm) 1.34 (s, 9H), 1.50 (s,
9H), 7.34 (d, J= 2.5 Hz, 1H), 7.65 (d, J= 2.5 Hz, 1H), 7.90
(t, J= 7.5 Hz, 1H), 8.43 (d, J= 10.0 Hz, 1H), 8.56 (d, J=
10.0 Hz, 1H), 8.80 (s, 1H); 13C{H} NMR (100 MHz,
DMSO-d6): δ (ppm) 35.0, 36.7, 39.3, 40.0, 119.6, 125.3,
126.5, 131.2, 133.2, 136.5, 138.1, 138.8, 146.8, 151.7,
153.1, 153.5, 165.0. Anal. Calcd for C21H24N2O3: C, 71.57;
H, 6.86; N, 7.95; Found: C, 71.51; H, 6.79; N, 7.92.
5,7-Di-tert-butyl-2-(pyridin-4-yl)benzo[d]oxazole (3v).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
o
1
yield: (293 mg, 95%). White solid, mp: 102-103 C; H
NMR (400 MHz, DMSO-d6): δ (ppm) 1.29 (s, 9H), 1.44 (s,
9H), 7.31 (d, J= 4.0 Hz, 1H), 7.61 (d, J= 4.0 Hz, 1H), 8.02
(d, J= 4.0 Hz, 2H), 8.79 (d, J= 8.0 Hz, 2H); 13C{H} NMR
(100 MHz, DMSO-d6): δ (ppm) 34.9, 36.7, 39.3, 40.0,
119.7, 125.6, 125.8, 138.8, 138.9, 146.8, 151.7, 153.2,
156.1, 164.9. Anal. Calcd for C20H24N2O: C, 77.89; H,
7.84; N, 9.08; Found: C, 77.83; H, 7.78; N, 9.10.
5,7-Di-tert-butyl-2-(naphthalen-1-yl)benzo[d]oxazole
(3r).17a
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (300 mg, 84%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, DMSO-d6): δ (ppm) 1.37 (s,
9H), 1.53 (s, 9H), 7.34 (d, J= 2.5 Hz, 1H), 7.62-7.77 (m,
4H), 8.08 (d, J= 10.0 Hz, 1H), 8.21 (d, J= 7.5 Hz, 1H), 8.41
(d, J= 7.5 Hz, 1H), 9.43 (d, J= 10.0 Hz, 1H); 13C{H} NMR
(100 MHz, DMSO-d6): δ (ppm) 29.7, 31.5, 34.1, 34.8,
114.3, 119.5, 122.7, 125.4, 125.6, 126.6, 127.9, 128.8,
128.9, 129.7, 132.3, 133.2, 133.5, 142.0, 145.5, 147.4,
161.4. Anal. Calcd for C25H27NO: C, 83.99; H, 7.61; N,
3.92; Found: C, 83.95; H, 7.60; N, 3.94.
5,7-Di-tert-butyl-2-(3a,7a-dihydro-1H-indol-3-
yl)benzo[d]oxazole (3w).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:60). Isolated
o
yield: (296 mg, 85%). Cream solid, mp: 206-208 C; 1H
NMR (250 MHz, DMSO-d6): δ (ppm) 1.34 (s, 9H), 1.51 (s,
9H), 7.19 (d, J= 2.5 Hz, 1H), 7.23-7.26 (m, 2H), 7.53 (d,
J= 2.5 Hz, 1H), 7.56 (d, J= 2.5 Hz, 1H), 8.27 (t, J= 5.0 Hz,
2H), 12.10 (s, NH); 13C{H} NMR (100 MHz, DMSO-d6):
δ (ppm) 29.7, 31.6, 33.9, 34.6, 103.0, 112.5, 113.0, 117.5,
120.1, 121.1, 122.6, 124.6, 128.9, 132.4, 136.6, 142.3,
5,7-Di-tert-butyl-2-phenylbenzo[d]oxazole (3s).17b
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
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The Journal of Organic Chemistry
145.2, 146.7, 160.4. Anal. Calcd for C23H28N2O: C, 79.27; yield: (256 mg, 90%). Colorless liquid (lit. Colorless
liquid); 1H NMR (300 MHz, CDCl3): δ (ppm) 1.33 (s, 9H),
7.36 (dd, J= 3.0 Hz, J= 9.0 Hz, 1H), 7.42 (d, J= 9.0 Hz,
2H), 7.53 (d, J= 3.0 Hz, 1H), 7.60 (d, J= 9.0 Hz, 1H), 8.10
(d, J= 9.0 Hz, 2H); 13C{H} NMR (75 MHz, CDCl3): δ
(ppm) 31.6, 35.2, 107.3, 119.1, 122.4, 125.8, 128.6, 129.2,
137.4, 139.5, 149.5, 151.0, 161.9. Calcd for C17H16ClNO:
C, 71.45; H, 5.64; N, 4.90; Found: C, 71.29; H, 5.47; N,
5.06.
1
2
3
4
5
6
7
8
H, 8.10; N, 8.04; Found: C, 79.17; H, 7.95; N, 8.00.
5,7-Di-tert-butyl-2-(thiophen-2-yl)benzo[d]oxazole
(3x).17a
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (288 mg, 92%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, CDCl3): δ (ppm) 1.30 (s, 9H),
1.45 (s, 9H), 7.08-7.12 (m, 1H), 7.21 (t, J= 2.5 Hz, 1H),
7.45 (dd, J= 2.5, 5.0 Hz, 1H), 7.54 (d, J= 2.5 Hz, 1H), 7.80-
7.82 (m, 1H); 13C{H} NMR (100 MHz, CDCl3): δ (ppm)
30.0, 31.8, 34.4, 35.1, 114.0, 119.5, 128.1, 129.3, 129.7,
130.1, 133.6, 142.1, 146.6, 147.8, 158.5. Anal. Calcd for
C19H23NOS: C, 72.80; H, 7.40; N, 4.47; Found: C, 72.75;
H, 7.37; N, 4.40.
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60
5-(tert-Butyl)-2-(2-chlorophenyl)benzo[d]oxazole
(3ac).17c
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (251 mg, 88%). Colorless liquid (lit. Colorless
liquid); 1H NMR (300 MHz, CDCl3): δ (ppm) 1.43 (s, 9H),
7.41-7.49 (m, 3H), 7.58 (d, J= 9.0 Hz, 1H), 7.67 (s, 1H),
7.79 (d, J= 9.0 Hz, 1H), 8.15 (d, J= 9.0 Hz, 1H); 13C{H}
NMR (75 MHz, CDCl3): δ (ppm) 31.7, 35.2, 107.4, 119.5,
122.4, 126.4, 126.9, 131.3, 131.7, 133.3, 139.2, 149.8,
150.8, 160.8. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N,
4.90; Found: C, 71.33; H, 5.51; N, 4.98.
5,7-Di-tert-butyl-2-(thiophen-3-yl)benzo[d]oxazole (3y).
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
1
yield: (272 mg, 87%). Pale yellow liquid; H NMR (250
MHz, DMSO-d6): δ (ppm) 1.33 (s, 9H), 1.48 (s, 9H), 7.27
(d, J= 2.5 Hz, 1H), 7.57 (d, J= 2.5 Hz, 1H), 7.71 (d, J= 5.0
Hz, 1H), 7.78-7.81 (m, 1H), 8.43-8.45 (m, 1H); 13C{H}
NMR (100 MHz, CDCl3): δ (ppm) 29.55, 31.36, 34.00,
34.60, 113.66, 118.97, 126.10, 126.39, 126.89, 129.19,
133.12, 141.64, 146.02, 147.23, 158.71. Anal. Calcd for
C19H23NOS: C, 72.80; H, 7.40; N, 4.47; Found: C, 72.75;
H, 7.32; N, 4.39.
5-Methyl-2-phenylbenzo[d]oxazole (3ad).14d
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (169 mg, 81%). Colorless liquid (lit. Colorless oil);
1H NMR (300 MHz, CDCl3): δ (ppm) 2.50 (s, 3H), 7.16 (d,
J= 9.0 Hz, 1H), 7.46 (d, J= 9.0 Hz, 1H), 7.51-7.55 (m, 3H),
7.59 (s, 1H), 8.26-8.29 (m, 2H); 13C{H} NMR (75 MHz,
CDCl3): δ (ppm) 21.5, 109.9, 119.9, 126.2, 127.3, 127.5,
128.8, 131.3, 134.3, 142.3, 149.0, 163.0. Calcd for
C14H11NO: C, 80.36; H, 5.30; N, 6.69; Found: C, 80.19; H,
5.14; N, 6.52.
5,7-Di-tert-butyl-2-(furan-2-yl)benzo[d]oxazole (3z).17b
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (282 mg, 95%). Colorless liquid (lit. Colorless
liquid); 1H NMR (250 MHz, CDCl3): δ (ppm) 1.39 (s, 9H),
1.53 (s, 9H), 6.60 (dd, J= 1.7, 3.5 Hz, 1H), 7.25 (dd, J= 0.8,
3.5 Hz, 1H), 7.31 (d, J= 2.0 Hz, 1H), 7.62 (d, J= 2.0 Hz,
1H), 7.65-7.66 (m, 1H); 13C{H} NMR (100 MHz, CDCl3):
δ (ppm) 29.4, 31.3, 33.9, 34.5, 111.5, 113.0, 113.8, 119.2,
133.2, 141.3, 142.5, 144.8, 145.8, 147.5, 154.3. Anal.
Calcd for C19H23NO2: C, 76.74; H, 7.80; N, 4.71; Found:
C, 76.68; H, 7.76; N, 4.68.
2-(4-Methoxyphenyl)-5-methylbenzo[d]oxazole (3ae).14b
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
o
yield: (208 mg, 87%). White solid, mp: 106-108 C (lit.
o
1
White solid, mp: 107-109 C); H NMR (300 MHz,
CDCl3): δ (ppm) 2.48 (s, 3H), 3.84 (s, 3H), 7.00 (d, J= 9.0
Hz, 2H), 7.11 (d, J= 9.0 Hz, 1H), 7.40 (d, J= 9.0 Hz, 1H),
7.53 (s, 1H), 8.18 (d, J= 9.0 Hz, 2H); 13C{H} NMR (75
MHz, CDCl3): δ (ppm) 21.5, 55.3, 109.7, 114.2, 119.5,
119.8, 125.6, 129.2, 134.1, 142.4, 148.8, 162.1, 163.2.
Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85; Found:
C, 75.18; H, 5.41; N, 7.87.
5-(tert-Butyl)-2-(p-tolyl)benzo[d]oxazole (3aa).17c
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (244 mg, 92%). Colorless liquid (lit. Colorless
liquid); 1H NMR (300 MHz, CDCl3): δ (ppm) 1.33 (s, 9H),
2.37 (s, 3H), 7.26 (d, J= 9.0 Hz, 2H), 7.34 (dd, J= 3.0 Hz,
J= 6.0 Hz, 1H), 7.52 (d, J= 3.0 Hz, 1H), 7.60 (d, J= 9.0 Hz,
1H), 8.06 (d, J= 6.0 Hz, 2H); 13C{H} NMR (75 MHz,
CDCl3): δ (ppm) 21.6, 31.7, 35.1, 107.2, 118.8, 122.2,
124.5, 127.4, 129.6, 139.6, 141.8, 149.0, 150.8, 163.1.
Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28; Found: C,
81.18; H, 7.01; N, 5.41.
2-(4-Chlorophenyl)-5-methylbenzo[d]oxazole (3af).14f
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
o
yield: (206 mg, 85%). White solid, mp: 151-153 C (lit.
o
1
White solid, mp: 149-151 C); H NMR (300 MHz,
CDCl3): δ (ppm) 2.48 (s, 3H), 7.14 (d, J= 6.0 Hz, 1H), 7.41
(d, J= 9.0 Hz, 1H), 7.45 (d, J= 6.0 Hz, 2H), 7.53 (s, 1H),
8.12 (d, J= 6.0 Hz, 2H); 13C{H} NMR (75 MHz, CDCl3):
δ (ppm) 21.5, 109.9, 119.9, 125.7, 126.4, 128.6, 129.1,
134.4, 137.4, 142.1, 148.9, 162.0. Calcd for C14H10ClNO:
5-(tert-Butyl)-2-(4-chlorophenyl)benzo[d]oxazole
(3ab).17a
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
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The Journal of Organic Chemistry
Page 10 of 13
C, 69.00; H, 4.14; N, 5.75; Found: C, 68.71; H, 4.02; N, 29.9, 31.8, 34.4, 35.0, 113.6, 118.6, 133.3, 141.7, 147.1,
1
2
3
5.68.
147.2, 163.1. Anal. Calcd for C16H23NO: C, 78.32; H, 9.45;
N, 5.71; Found: C, 78.15; H, 9.60; N, 5.84.
5-Methyl-2-(pyridin-2-yl)benzo[d]oxazole (3ag).16h
4
5
6
7
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
4,6-Di-tert-butyl-2-(4-chlorophenyl)-1H-
benzo[d]imidazole (4a).
o
yield: (183 mg, 87%). Yellow solid, mp: 87-88 C (lit.
o
1
Yellow solid, mp: 89.5-89.7 C); H NMR (300 MHz,
CDCl3): δ (ppm) 2.40 (s, 3H), 7.11 (d, J= 9.0 Hz, 1H), 7.32
(t, J= 6.0 Hz, 1H), 7.44 (d, J= 9.0 Hz, 1H), 7.52 (s, 1H),
7.76 (t, J= 7.5 Hz, 1H), 8.23 (d, J= 9.0 Hz, 1H), 8.72 (d, J=
6.0 Hz, 1H); 13C{H} NMR (75 MHz, CDCl3): δ (ppm)
21.4, 110.4, 120.3, 123.2, 125.3, 127.1, 134.6, 136.9,
141.9, 146.0, 149.2, 150.1, 161.4. Calcd for C13H10N2O: C,
74.27; H, 4.79; N, 13.33; Found: C, 74.35; H, 4.82; N,
13.47.
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (5:100). Isolated
yield: (316 mg, 93%). Colorless liquid; H NMR (250
MHz, DMSO-d6): δ (ppm) 1.33 (s, 9H), 1.55 (s, 9H), 7.09
(d, J= 2.5 Hz, 1H), 7.28 (s, 1H), 7.60 (d, J= 10.0 Hz, 2H),
8.15 (d, J= 7.5 Hz, 2H), 12.78 (s, NH); 13C{H} NMR (100
MHz, DMSO-d6): δ (ppm) 30.2, 31.6, 34.6, 35.2, 105.2,
115.2, 127.8, 128.9, 129.4, 133.9, 135.4, 139.8, 140.2,
145.0, 147.7. Anal. Calcd for C21H25ClN2: C, 73.99; H,
7.39; N, 8.22; Found: C, 73.81; H, 7.30; N, 8.18.
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9
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5-Methyl-2-(thiophen-2-yl)benzo[d]oxazole (3ah).13f
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
ASSOCIATED CONTENT
Supporting Information
Copy of 1H and 13C NMR of synthesized compounds. All
of these data are available in supporting information.
o
yield: (165 mg, 77%). Yellow solid, mp: 90-92 C (lit.
Yellow solid, mp: 89-91 oC); 1H NMR (300 MHz, CDCl3):
δ (ppm) 2.47 (s, 3H), 7.11-7.17 (m, 2H), 7.39 (d, J= 8.1 Hz,
1H), 7.51-7.53 (m, 2H), 7.88 (dd, J= 1.2, 3.9 Hz, 1H);
13C{H} NMR (75 MHz, CDCl3): δ (ppm) 21.5, 109.7,
119.7, 126.1, 128.1, 129.7, 129.8, 130.0, 134.5, 142.1,
148.6, 159.0. Calcd for C12H9NOS: C, 66.95; H, 4.21; N,
6.51; Found: C, 6.90; H, 4.09; N, 6.42.
AUTHOR INFORMATION
Corresponding Author
* Email: shashem@chem.susc.ac.ir and
hashemsharghi@gmail.com, Tel: (+98)7136137136 Fax:
(+98)7132280926.
4-methyl-2-phenylbenzo[d]oxazole (3ai).17b
Purified by column chromatography on silica gel and
eluted with ethyl acetate/petroleum ether (1:100). Isolated
yield: (156 mg, 75%). White solid, mp: 81-83 °C; 1H NMR
(250 MHz, DMSO-d6): δ (ppm) 2.52 (s, 3H), 6.95 (d, J=
5.0 Hz, 1H), 7.07 (t, J= 7.5 Hz, 1H), 7.39-7.52 (m, 4H),
8.15 (d, J= 7.5 Hz, 2H); 13C{H} NMR (75 MHz, DMSO-
d6): δ (ppm) 16.8, 112.4, 122.4, 122.8, 124.9, 126.5, 128.9,
129.6, 129.9, 138.4, 144.7, 150.9. Calcd for C14H11NO: C,
80.36; H, 5.30; N, 6.69; Found: C, 80.21; H, 5.08; N, 6.58.
ORCID ID
Hashem Sharghi: 0000-0001-6772-3332
ACKNOWLEDGMENT
We gratefully appreciate the Shiraz University Research
Councils for their financial support of this work.
5,7-Di-tert-butyl-2-isopropylbenzo[d]oxazole (3aj).17a
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