Selective synthesis of 2-aminobenzoxazoles and 2-mercaptobenzoxazoles by using o-aminophenols as starting material

Article abstract of DOI:10.1016/j.tetlet.2017.09.092

2-Aminobenzoxazoles and 2-mercaptobenzoxazoles were selectively synthesized by treating o-aminophenols with dithiocarbamates and tetramethylthiuram disulfide (TMTD), respectively. With the promotion of NaH/CuI, the reaction of o-aminophenols with dithioca

Full text of DOI:10.1016/j.tetlet.2017.09.092

Accepted Manuscript
Selective Synthesis of 2-Aminobenzoxazoles and 2-Mercaptobenzoxazoles by
Using o-Aminophenols as Starting Material
Min Liu, Meng-Tian Zeng, Wan Xu, Li Wu, Zhi-Bing Dong
PII:
S0040-4039(17)31252-2
https://doi.org/10.1016/j.tetlet.2017.09.092
TETL 49362
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 August 2017
25 September 2017
29 September 2017
Please cite this article as: Liu, M., Zeng, M-T., Xu, W., Wu, L., Dong, Z-B., Selective Synthesis of 2-
Aminobenzoxazoles and 2-Mercaptobenzoxazoles by Using o-Aminophenols as Starting Material, Tetrahedron
Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.09.092
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Selective Synthesis of 2-Aminobenzoxazoles and
2-Mercaptobenzoxazoles by Using o-
Aminophenols as Starting Material
∗ a, b
Min Liu a, Meng-Tian Zeng a, Wan Xu a, Li Wu a, Zhi-Bing Dong
a School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, P. R. China
b Key Laboratory of Green Chemical Process, Ministry of Education, Wuhan Institute of Technology, Wuhan 430205, P. R. China
R2
R2
N
N
O
CuI, NaH
DMF, 110
S
N
R2
+
R2
S
R
Me, Et, nBu
R2=
NH2
OH
10 examples
up to 92% yield
R
S
N
R= 4-tBu, 4-NO2, 4-Cl,
5-Cl, 4-Br, 3-Me, 4-Me,
5-Me, 6-Me, 4-F
K2CO3
S
N
SH
O
+
N
S
R
DMF, 120
S
9 examples
up to 80% yield

1
Tetrahedron Letters
journal homepage: www.els evier.com
Selective Synthesis of 2-Aminobenzoxazoles and 2-Mercaptobenzoxazoles by Using
o-Aminophenols as Starting Material
∗ a, b
Min Liua, Meng-Tian Zenga, Wan Xua, Li Wua, Zhi-Bing Dong
Dedicated to Prof. Herbert Mayr at Ludwig-Maximilians Universität on the occasion of his 70th birthday
a School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, P. R. China
b Key Laboratory of Green Chemical Process, Ministry of Education, Wuhan Institute of Technology, Wuhan 430205, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2-Aminobenzoxazoles and 2-mercaptobenzoxazoles were selectively synthesized by treating o-
aminophenols with dithiocarbamates and tetramethylthiuram disulfide (TMTD), respectively.
With the promotion of NaH/CuI, the reaction of o-aminophenols with dithiocarbamates gave 2-
aminobenzoxazoles with good yield (70-92%) in one pot manner, and 2-mercaptobenzoxazoles
were synthesized (yield: 55-80%) in the presence of K2CO3 by treating o-aminophenols with
tetramethylthiuram disulfide (TMTD). The feature of this method includes good to excellent
yield, easy performance and broad substrate scope, which makes the protocol practical and
attractive in the preparation of some potential pharmaceutically active compounds.
Available online
Keywords:
2-aminobenzoxazoles
2-mercaptobenzoxazoles
o-aminophenols
selective synthesis
base
2009 Elsevier Ltd. All rights reserved
———
∗ Corresponding author. Tel.: +86-13554158395; fax: +86-02787195680; e-mail: dzb04982@wit.edu.cn

2
1. Introduction
Tetrahedron Letters
and catalysts, isolation of intermediates which make them less
attractive from a sustainable point of view.
Benzoxazole derivatives have attracted medical scientists’
interest due to their potential biological activities. Benzoxazole
derivatives are used in various drugs and pesticides including
various proteases inhibitors, such as chymase inhibitors[1], HIV-1
In this work (Scheme 1), 2-aminobenzoxazoles and 2-
mercaptobenzoxazoles were selectively synthesized by 2-
aminophenols
reacting
with
dithiocarbamates
and
protease inhibitors[2-3], kinase inhibitors[4-5], receptor agonist[6-7]
,
tetramethylthiuram disulfide (TMTD), respectively. With the
mediation of CuI, o-aminophenols reacted with dithiocarbamates
to give 2-aminobenzoxazoles up to 92% yield in one pot manner.
2-Mercaptobenzoxazoles were synthesized up to 80% yield in the
presence of K2CO3 by treating o-aminophenols with
tetramethylthiuram disulfide (TMTD).
diacylglycerol
butyrylcholinesterase
acyltransferase
I
inhibitors[8],
inhibitors[9-10]
,
topoisomerase
II
inhibitors[11], and cyanine tau aggregation inhibitors[12] (Figure
1). In addition, they can be also used as potential positron
emission tomography probes for imaging of plaques in
Alzheimer’s disease[13]. Except the medical science, benzoxazole
derivatives could be also applied in the field of materials. They
could be used as dopants in the fabrication of bright-blue organic
light-emitting diodes to enhance the efficiency and stability due
R
2
R
N
N
O
2
CuI, NaH
DMF, 110
S
N
R
2
+
R
2
S
R
to their fluorescence properties[14-15]
.
n
Me, Et, Bu
R =
2
NH
2
10 examples
up to 92% yield
O
OH
R
N
N
HN
OH
S
t
N
N
N
O
R= 4- Bu, 4-NO , 4-Cl,
2
K CO
2
S
N
3
SH
O
N
+
S
F
N
O
5-Cl, 4-Br, 3-Me, 4-Me,
5-Me, 6-Me, 4-F
N
S
R
F
DMF, 120
S
O N
2
9 examples
up to 80% yield
Non-nucleoside HIV-1 reverse
ranscriptase inhibitor
butyrylcholinesterase inhibitor
F
Scheme 1. This work: selective synthesis of 2-aminobenzoxazoles
and 2-mercaptobenzoxazoles by using o-aminophenols as starting
material.
N
N
O
Cl
H
N
N
N
O
O
NH
2. Results and Discussion
NH
H N
O
2
O
O
N
HN
Initially, we used 2-aminophenol (1a) and dithiocarbamate (2a)
as starting materials to furnish 2-aminobenzoxazole, and the
reaction conditions were optimized. Among different solvents,
DMF was found to be the most suitable solvent (Table 1. Entry
5). In order to observe the effect of base on the reaction, various
organic and inorganic bases such as NaH, t-BuOK, Cs2CO3, NEt3
and t-BuONa (Table 1. Entries 5, 7-10) were tested and the
reaction could undergo better in the presence of NaH. Then
catalysts were screened to improve the yield. It’s disappointing
that the yield was not improved when CuI was added as catalyst
loading (0.1 equiv) (Table 1. Entry 15), other catalysts (Table 1.
Entries 11-14) could not help the reaction. Gratifyingly, the
reaction underwent well when the loading of CuI and the reaction
temperature increased both (Table 1. Entries 17-26), the optimal
copper loading is 1.5 equiv and the best reaction temperature is
110 °C. The optimized reaction conditions were summarized in
Entry 25.
N
O
Tyrosine kinase inhibitor
Nonpeptidic chymase inhibitor
Figure 1. Benzoxazole derivatives with biological activities.
Mercaptobenzoxazoles with essential free thiol group exhibit
the expression of potential inhibitory properties. What have been
reported are inhibition of human liver iodothyronine 5’-
deiodinase[16], tyrosinase inhibition for melanoma targeting[17]
,
.
inhibitors of alkaline nuclease[18] and antifungal activity[19]
Mercaptobenzoxazoles not only themselves but also the modified
nanoparticles and the metal complexes all show biological
activities. Haick developed a device called “SNIFFPHONE” that
use gold nanoparticles functioned with 2-mercaptobenzoxazole to
diagnose lung cancer[20-21]. Co(Ⅱ) and Ru(Ⅱ) complexes with 2-
mercaptobenzoxazoles show good antifungal and anticancer
activities[22-23]
.
Table 1. Screening reaction conditions for 2-aminophenol (1a) with
dithiocarbamate (2a)a
Various procedures for the synthesis of 2-aminobenzoxazoles
were reported, such as 2-substituted benzoxazoles reacting with
amine[24], cyclodesulfurization of 2-hydroxyarylthioureas[25] and
direct amination of benzoxazoles[26-27]. More importantly, 2-
aminobenzoxazoles can be expediently synthesized from 2-
aminophenol with chloroformamidinium salts via cyclization of
guanidine intermediate[28-30]. To the best of our knowledge, the
most widely used method to prepare 2-mercaptobenzoxazoles is
NH
2
condition
S
N
N
O
N
OH
S
1a
2a
3a
Entry Catalyst (equiv) Base (equiv)
Solvent T (°C) Yiedb (%)
60
N.D.c
N.R.d
29
1
2
3
4
5
6
7
-
-
-
-
-
-
-
NaH(1.0)
NaH(1.0)
NaH(1.0)
DMSO
MeCN
by treating 2-aminophenols with CS2 in the presence of KOH[31-
and 2-mercaptobenzoxazoles could be subsequently
transformed
aminobenzoxazoles and 2-mercaptobenzoxazoles can be
synthesized starting from 2-aminophenols with aryl
isothiocyanates under various conditions[7, 35-37]. While these
protocols have some disadvantages, such as toxicity of reactants
60
60
60
60
60
60
34]
,
DMAC
DMF
to Both 2-
2-aminobenzoxazoles[31-34]
.
NaH (1.0)
NaH (2.0)
30
DMF
DMF
DMF
43
NaH (3.0)
39
t-BuOK (2.0)
33

3
O N
2
NH
OH
2
O N
2
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
60
60
60
60
60
60
60
60
50
N
O
S
N
Cs2CO3 (2.0)
NEt3 (2.0)
t-BuONa (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
28
N
3
4
5
6
7
8
92
70
79
80
78
80
N.R.d
9
-
S
S
S
S
S
3c
3d
3e
1c
2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
17
32
Cl
NH2
OH
Cl
N
O
S
N
N
N
N
N
CuO(0.1)
FeBr3(0.1)
PdCl2(0.1)
NiCl2(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.1)
1d
1e
1f
20
2a
N.D.c
N.D.c
2
Br
Br
NH
N
O
S
N
N
OH
2a
36
10
NH2
OH
N
S
O
3f
2a
40
45
45
49
47
50
52
55
72
74
80
NH2
OH
S
100
N
N
O
3g
110
120
110
110
110
110
110
110
2a
1g
1h
NH2
OH
N
S
N
N
O
CuI(0.2)
S
3h
2a
CuI(0.3)
CuI(0.5)
N
NH
2
S
N
N
9
73
O
3i
CuI(1.0)
CuI(1.5)
CuI(2.0)
S
OH
1a
1a
2b
NH
2
N
O
N
S
N
10
85
aReaction conditions: 1a (1.0 mmol), 2a(1.2 mmol), solvent (3.0 mL) for 10 h.
OH
S
bIsolated yield. cN.D.: not determined. dN.R.: no reaction.
3j
2c
aReaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), CuI(150 mol%), NaH (2.0
mmol), DMF (3 mL) at 110 °C for 10h. bIsolated yield.
With the optimal reaction conditions in hand, we began to
scope the substrate of 2-aminophenols and dithiocarbamates.
Various 2-aminobenzoxazoles (3a-j) were synthesized in good
yields by reacting 2-aminophenols with dithiocarbamates in the
presence of CuI/NaH (Table 2). 2-Aminobenzoxazoles bearing
the substitutes at the C4 position of hydroxy group were
furnished in excellent yields (Table 2. Entries 2-6, 70-92%).
Interestingly, aminophenol substrate with electron withdrawing
group such as nitro group at the C4 position resulted in similar
high yield with aminophenol bearing electron donating group
such as tert-butyl group (Table 2. Entries 2, 3). Remarkably, 2-
aminophenols equipped with methyl group at C3 and C5 position
of hydroxyl group gave the products with satisfying yields
(Table 2. Entries 7, 8). Products bearing 2-(N,N-diethylamino)
(3i) and 2-(N,N-dibutylamino) (3j) were easily obtained in good
yields, showing broad substrate compatibility, which might offer
an alternative opportunity for the preparation of 2-
aminobenzoxazoles.
Inspired by the reaction between 2-aminophenols with
dithiocarbamates
and
the
common
block
between
tetramethylthiuram disulfide (TMTD) and dithiocarbamate, we
suspected that the same products might be obtained by 2-
aminophenols reacting with tetramethylthiuram disulfide
(TMTD). Unexpectedly, an unexpected product named 2-
mercaptobenzoxazole was formed in metal-free conditions. Then,
the reaction conditions were optimized by screening the bases
(Table 3. Entries 1-9), base loading (Table 3. Entries 2, 10-12),
solvents (Table 3. Entries 12-14) and temperature (Table 3.
Entries 12, 15-18). The addition of possible catalyst (CuI) did
not improve the reaction (Table 3. Entry 19). The optimized
reaction conditions were summarized in Entry 18.
Table 3. Screening reaction conditions for 2-aminophenol (1a) with
tetramethylthiuram disulfide (TMTD) (4a) a
S
NH
2
N
Table 2. Substrate scope for tandem reactions of 2-aminophenols
condition
S
N
N
S
+
SH
with dithiocarbamates a
OH
O
S
(TMTD)
R
N
2
5a
4a
1a
NH
S
N
O
R
2
2
CuI/NaH
R
2
N
Yieldb (%)
DMF, 110 , 10 h
Entry
Base (equiv)
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
T (°C)
110
110
110
110
110
110
110
S
R
2
OH
R
1
R
1
3
1
2
1
2
3
4
5
6
7
KOH(2.0)
K2CO3(2.0)
t-BuOK (2.0)
NaOH(2.0)
NaOCH3(2.0)
Cs2CO3(2.0)
NEt3(2.0)
24
50
17
30
34
14
14
2-
Yieldb
(%)
Entry
Dithiocarbamates
Products
Aminophenols
NH
2
N
S
N
N
1
75
89
O
3a
OH
S
S
1a
2a
NH2
S
N
N
N
2
O
OH
3b
1b
2a

4
Tetrahedron Letters
N
O
NH2
OH
SH
NaOtBu(2.0)
16
8
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
TMTD
4a
Cl
Cl
7
68
76
5g
1i
9
NaH(2.0)
32
15
NH2
OH
N
O
10
11
12
13
14
15
16
17
18
19
K2CO3(0.5)
SH
TMTD
4a
8
9
K2CO3(1.0)
K2CO3(3.0)
K2CO3(3.0)
K2CO3(3.0)
K2CO3(3.0)
K2CO3(3.0)
33
66
52
45
16
17
5h
1j
F
NH2
OH
F
N
TMTD
4a
SH
O
DMAC
DMSO
110
110
55
1k
5i
aReaction conditions: 1 (1 mmol), 4a (0.6 mmol), K2CO3 (3.0 mmol), and
DMF (3 mL) at 120 °C for 12 h. bIsolated yield.
DMF
DMF
60
80
3. Conclusions
K2CO3(3.0)
34
DMF
100
In
summary,
2-aminobenzoxazoles
and
2-
K2CO3(3.0)
DMF
120
80
mercaptobenzoxazoles were selectively synthesized. With the
promotion of NaH/CuI, the reaction of o-aminophenols with
dithiocarbamates gave 2-aminobenzoxazoles with good yield
(70-92%) in one pot manner, and 2-mercaptobenzoxazoles were
synthesized (yield: 55-80%) in the presence of K2CO3 by treating
o-aminophenols with tetramethylthiuram disulfide (TMTD). The
good to excellent yield, easy performance and broad substrate
scope make the protocol practical and attractive in the
preparation of some potential pharmaceutically active
compounds. The detailed mechanism research and the related
application of this protocol are under study in our lab.
K2CO3(3.0)
DMF
110
54c
aReaction conditions: 1a (1 mmol), 4a (0.6 mmol), solvent (3.0 mL) for 12 h.
bIsolated yield. ccatalyzed by CuI (50 mol%).
Under the optimized reaction conditions, the scope of the
substrates was investigated as shown in Table 4. A number of 2-
aminophenols bearing electron donating groups such as t-butyl
group (Table 4. Entry 2) and methyl group (Table 4. Entry 4-6,
8) all reacted smoothly to provide the desired products in good
yields (70-77%). While products bearing electron withdrawing
groups, such as halogen groups (Table 4. Entry 3, 7, 9) were
obtained in relatively lower yields (55-68%).
4. Experimental Section
General information
1HNMR (in CDCl3 or DMSO-d6) and 13CNMR (in CDCl3 or
DMSO-d6) spectra were measured using TMS as internal
standard on a Bruker 400 AC NMR spectrometer. A high-
resolution mass spectra (ESI–HRMS) were determined on an Ion
Spec (7.0 T) spectrometer. All starting materials were purchased
from commercial suppliers and used without further purification
unless otherwise stated. DMSO was dried with molecular sieves.
Yields refer to isolated compounds estimated to be 95% pure as
determined by 1HNMR and capillary GC analysis.
Table 4. Substrate scope for tandem reactions of 2-aminophenols
with tetramethylthiuram disulfide (TMTD) a
S
NH2
OH
N
O
S
N
K2CO3
SH
N
S
+
DMF, 120 , 12 h
S
R3
R3
(TMTD)
5
1
4a
2-
Yield
Entr
y
Tetramethylthiura
m Disulfide
b
Aminophenol
Products
s
(%)
Typical procedure for the preparation of 2-
aminobenzoxazoles in the presence of CuI and NaH (TP1)
N
NH
2
SH
TMTD
4a
O
5a
1
80
77
OH
2-Aminophenol (1.0 mmol), NaH (2.0 mmol) was dissolved in
DMF (3 mL) in a dried tube, equipped with a magnetic stirring
bar and a septum with a balloon. The mixture was stirred for 5
minutes, then dithiocarbamate (1.2 mmol) and CuI (150 mol %)
were added. The reaction mixture was then heated at 110 °C and
checked by TLC until the starting material was finished (around
10 hours). The reaction was cooled down to room temperature,
and quenched with sat. NH4Cl solution and extracted with ethyl
acetate, dried over anhydrous Na2SO4 and evaporated under
vacuum. The residue was purified by flash column
chromatography to afford the desired product.
1a
NH2
N
O
SH
SH
TMTD
4a
2
OH
5b
5c
1b
Cl
NH2
OH
Cl
N
TMTD
4a
O
3
4
67
1c
NH2
N
S
H
TMTD
4a
O
OH
1f
72
70
5d
NH2
OH
Typical
procedure
for
the
preparation
mercaptobenzoxazoles in the presence of K2CO3 (TP2)
of2-
N
SH
TMTD
4a
5
6
O
5e
1g
1h
2-Aminophenol (1.0 mmol), K2CO3 (3.0 mmol) was dissolved
in DMF (3 mL) in a dried tube, equipped with a magnetic stirring
bar and a septum. The mixture was stirred for 5 minutes, and then
TMTD (0.6 mmol) was added. The reaction mixture was then
heated at 120 °C and checked by TLC until the starting material
was finished (around 12 hours). The reaction was cooled down to
NH2
OH
N
SH
TMTD
4a
O
75
5f

5
21. Tisch, U.; Schlesinge, I.; Ionescu, R.; Nassar, M.; Axelrod, N.;
room temperature, and then quenched with sat. NH4Cl solution
and extracted with ethyl acetate, dried over anhydrous Na2SO4
and evaporated under vacuum. The residue was purified by flash
column chromatography to afford the desired product.
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We thank the foundation support from National Natural
Science Foundation of China (21302150) Hubei Provincial
Department of Education (D20131501), Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry [2012]1707, foundation of Chutian
distinguished fellow from Hubei Provincial Department of
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(China) for generous NMR analysis support, we also thank Prof.
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6
Tetrahedron Letters
Highlights:
●2-Aminobenzoxazoles are selectively synthesized in good yields
in the presence of CuI/NaH.
●2-Mercaptobenzoxazoles are selectively synthesized the
presence of K2CO3.
●The main difference of the two thio substrates in this work is
the S-S block.