A facile and efficient approach for the synthesis of 3-arylthiazol-2(3H)-one

Article abstract of DOI:10.1080/00397911.2019.1615099

A facile and efficient method for synthesis of 3-arylthiazol-2(3H)-one through the reaction of acyl azide and 1,4-dithiane-2,5-diol was reported. This reaction proceeded at 80 °C at first and then in acidic condition at room temperature, to afford product

Full text of DOI:10.1080/00397911.2019.1615099

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A facile and efficient approach for the synthesis of
3-arylthiazol-2(3H)-one
Yue Zhu, Qilin Wang, Haofan Luo, Zijuan Wang, Guolin Zhang & Yongping Yu
To cite this article: Yue Zhu, Qilin Wang, Haofan Luo, Zijuan Wang, Guolin Zhang & Yongping
Yu (2019): A facile and efficient approach for the synthesis of 3-arylthiazol-2(3H)-one, Synthetic
Communications, DOI: 10.1080/00397911.2019.1615099
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https://doi.org/10.1080/00397911.2019.1615099
A facile and efficient approach for the synthesis of
3
-arylthiazol-2(3H)-one
a
b
a
a
a
ꢀ
ꢀ
Yue Zhu , Qilin Wang , Haofan Luo , Zijuan Wang , Guolin Zhang , and
a
Yongping Yu
a
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences,
b
Zhejiang University, Hangzhou, P. R. China; School of Biological and Pharmaceutical Engineering,
Wuhan Polytechnic University, Wuhan, P. R. China
ABSTRACT
ARTICLE HISTORY
A facile and efficient method for synthesis of 3-arylthiazol-2(3H)-one
through the reaction of acyl azide and 1,4-dithiane-2,5-diol was
reported. This reaction proceeded at 80 C at first and then in acidic
condition at room temperature, to afford products in good yields for
a wide range of substrates and a possible mechanism has also been
proposed.
Received 12 February 2019
ꢁ
KEYWORDS
Acyl azide; 3-arylthiazol-
2
(3H)-one; 1,4-dithiane-2,5-
diol; facile synthesis;
nucleophilic addition
GRAPHICAL ABSTRACT
o
O
S
OH
1) CH CN, 80 C, 21h
O
R
3
S
+
R
N3
N
HO
S
2) 40% a.q H SO , rt, 1h
2 4
1
2
3
Introduction
The substituted thiazol-2(3H)-one fragment is a structural motif in some biologically
active compounds (Figure 1). Kenda reported substituted thiazol-2(3H)-one derivative a
[
1]
as anticonvulsant. Substituted thiazol-2(3H)-one derivative b could be used as the
inhibitor of autotaxin (the autotaxin-lysophosphatidic acid signaling axis has been
implicated in inflammation, fibrosis, and tumor progression, rendering autotaxin an
[
2]
attractive drug target). The substituted thiazol-2(3H)-one derivative c had anti-inflam-
[
3]
matory and analgesic activity.
In view of the importance of the thiazol-2(3H)-one, a great deal of attention has been
given to its organic synthesis, such as K CO /I -mediated transformation from thiazole
2
3 2
[
4]
to thiazol-2(3H)-one (Scheme 1-A, equation (1)), the synthesis method using aryl iso-
cyanate and 1,4-dithiane-2,5-diol under microwave condition (Scheme 1-A, equation
CONTACT Guolin Zhang
guolinzhang@zju.edu.cn; Yongping Yu
yyu@zju.edu.cn
Zhejiang Province Key
Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P.
R. China.
ꢀ
Yue Zhu and Qilin Wang contributed equally to this work.
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 Taylor & Francis Group, LLC

2
Y. ZHU ET AL.
OH
OH
(
a)
(b)
O
B
O
S
H N
2
O
S
N
O
N
F
(
c)
O
S
N
F
O
S
H N
2
O
c
Figure 1. Biologically active compounds contain thiazol-2(3H)-one structural motif.
(
A) Previous work:
(
1) Ref 4
R
N
R
N
2 3 2
K CO , I
Cl
O
S
MeOH/H
O(9:1)
2
S
(
2) Ref 5
O
S
OH
S
C
Neat
N
+
O
N
Ar
3) Ref 6
o
HO
S
MW, 110 C
Ar
(
O
Cp
2
Zr(H)Cl
N
R
N R
S
S
THF, rt, 1h
O
O
(
B) Our work:
o
O
S
OH
1) CH CN, 80 C, 21h
O
R
3
S
+
R
N
3
N
HO
S
2 4
2) 40% a.q H SO , rt, 1h
1
2
3
Scheme 1. Synthesis of thiazol-2(3H)-one derivatives.

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3
O
S
OH
R
N3
HO
S
1
2
-
N2
SH
N
R
C
O
I
O
II
O
S
R
NH
S
O
OH
N
R
O
III
IV
-
H O
2
S
O
N
R
3
Scheme 2. Proposed mechanism for the synthesis of 3.
[
5]
(
2)), Schwartz reagent mediated synthesis of thiazol-2(3H)-one from thiazolidine-2,4-
[
6]
diones (Scheme 1-A, equation (3)).
Despite these procedures, establishing methods for the construction of thiazol-2(3H)-
one remains in demand. Herein, we present a facile and efficient protocol for the syn-
thesis of thiazol-2(3H)-one with good yields from acyl azide and 1,4-dithiane-2,5-diol
(Scheme 1-B). Compared to Scheme 1-A, equation (2), acyl azide is a precursor of iso-
cyanate according to the Curtius rearrangement. Acyl azide can be easily transformed
into isocyanate in our reaction avoiding the tough synthesis of isocyanate with toxic
starting material phosgene.
Results and discussion
Initially, benzoyl azide 1a and 1,4-dithiane-2,5-diol 2 were selected as model reactants
to optimize the reaction conditions (Table 1). The solvent of the reaction had a

4
Y. ZHU ET AL.
a
Table 1. Optimization of reaction conditions.
O
S
OH
O
conditions
S
+
N3
N
HO
S
1
a
2
3
a
ꢁ
b
Entry
2 (equiv.)
Solvent
T/ C
Conversion /%
1
2
3
4
5
6
7
8
9
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.525
0.75
Toluene
Dioxane
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
80
80
80
40
60
100
80
80
15
47
40
c
87(80)
0
70
82
81
87
aReaction conditions: benzoyl azide (0.5 mmol, 1.0 equiv.), 1,4-dithiane-2,5-diol, 2 mL of solvent, disappearance of acyl
ꢁ
azide could be monitored by TLC, 21 h, T/ C, then 40% H
for 1 hour.
2 4
SO (0.125 mmol, 0.25 equiv.) was added, stirred at rt
bDetermined by LC-MS, based on the disappearance of the starting benzoyl azide. The most efficient entry is high-
lighted in bold.
cIsolated yield.
significant impact on the efficiency for the formation of 3a, and MeCN was found
superior to other solvents (Table 1, entries 1–4). Subsequent screening of reaction tem-
ꢁ
peratures showed that 80 C was the best (Table 1, entries 4–7). Furthermore, optimiza-
tion of the different stoichiometric amount of 1,4-dithiane-2,5-diol 2 showed that the
conversion of 3a decreased to 81% when the amount of 1,4-dithiane-2,5-diol rose to
0.525 equiv. (Table 1, entry 8). However, there was no improvement after increasing the
amount of 1,4-dithiane-2,5-diol to 0.75 equiv. (Table 1, entry 9). On the basis of this
ꢁ
initial study, the optimal reactivity was obtained in MeCN at 80 C when the mole ratio
of benzoyl azide and 1,4-dithiane-2,5-diol was 1:0.55 (Table 1, entry 4).
With the optimized reaction conditions in hand, we next investigated the generality
and scope of the methodology for the synthesis of 3-arylthiazol-2(3H)-one using a
[
7–9]
set of acyl azides, which were readily prepared according to the literature
and
the results were summarized in Table 2. To our delight, all investigated substrates
gave good yields (70 ꢂ 87%). Aryl acyl azide 1 bearing electron-donating groups
afforded the desired products in higher yields than which bearing electron-withdraw-
ing groups (3g, 3j compared to 3c, 3d, 3e; 3h compared to 3b). In our tests, the
highest yield was obtained when 2-thienyl azide was used as the reagent (3k). The
1
13
structures of 3-arylthiazol-2(3H)-one were characterized by H NMR, C NMR, and
HRMS (ESI).
On the basis of the results above, we proposed the following possible mechanism
for this reaction, as outlined in Scheme 2. The first step presumably proceeds through
the initial formation of mercaptoacetaldehyde II from 1,4-dithiane-2,5-diol 2 which
undergoes nucleophilic addition to isocyanate I generated from acyl azide 1 leading
to the formation of intermediate III. This intermediate undergoes intramolecular
nucleophilic addition to afford product 3 with the elimination of water under
acidic condition.

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Table 2. Scope of the reaction of acyl azide and 1,4-dithiane-2,5-diol under optimal
a
conditions.
o
O
S
OH
1) CH CN, 80 C, 21h
O
R
3
S
+
R
N3
N
HO
S
2) 40% a.q H SO , rt, 1h
2 4
1
2
3
O
N
O
N
O
O
N
S
S
S
S
N
NC
F
NO2
3
a
3b
3c
3d
8
0%
70%
70%
72%
O
N
O
O
N
O
N
S
S
S
S
N
Cl
O
O
3
e
3f
3g
3
h
7
3%
82%
85%
83%
O
O
N
O
N
O
S
S
S
S
N
N
S
3
i
3j
3
k
3l
8
3%
82%
87%
78%
aReaction conditions: acyl azide (0.5 mmol, 1.0 equiv.), 1,4-dithiane-2,5-diol (0.55 equiv.), 2 mL of solvent, dis-
ꢁ
appearance of acyl azide could be monitored by TLC, 21 h, 80 C, then 40% H
was added, stirred at rt for 1 hour. Isolated yield.
2 4
SO (0.125 mmol, 0.25 equiv.)
Conclusion
In summary, we have developed a facile and efficient protocol for the synthesis of 3-arylth-
iazol-2(3H)-one with good yields from acyl azide and 1,4-dithiane-2,5-diol. This reaction
has the advantages of available starting materials and simple experimental operation. These
features made this reaction as a widely used approach in medicinal chemistry.
Experimental sections
Purifications of reaction products were carried out by chromatography using silica gel
€
(
200–300 mesh). Melting points were recorded on a BUCHI B-540 melting point

6
Y. ZHU ET AL.
1
13
apparatus. NMR spectra were recorded for H NMR at 500 MHz and C NMR at
1
1
25 MHz. For H NMR, tetramethylsilane (TMS) served as internal standard (d ¼ 0)
and data are reported as follows: chemical shift, integration, multiplicity (s ¼ singlet,
d ¼ doublet, t ¼ triplet, Q ¼ quartet, m ¼ multiplet), and coupling constant (s) in Hertz.
1
3
For C NMR, TMS (d ¼ 0) or DMSO (d ¼ 40.45) was used as internal standard and
spectra were obtained with complete proton decoupling. HRMS data were obtained
using Agilent Technologies 6224 TOF LC/MS. Unless otherwise noted, all reagents were
obtained commercially and used without further purification. The starting material acyl
[
7–9]
azide 1 was prepared according to literature methods.
General procedure for the synthesis of 3
A mixture of acyl azide 1 (0.5 mmol), 1,4-dithiane-2,5-diol 2 (0.275 mmol) was stirred
ꢁ
in MeCN 2 mL at 80 C for 21 hours. The disappearance of acyl azide 1 could be moni-
tored by TLC. Then, 40% H SO (0.125 mmol, 0.25 equiv.) was added to the solution,
2
4
stirred at room temperature for 1 hour. After the completeness of the reaction, MeCN
was removed under reduced pressure. Water was added to the crude reaction residue.
The reaction mixture was extracted with EtOAc. The combined organic extracts were
washed with brine, dried over Na SO , concentrated and purified by column chroma-
2
4
tography (PET/EA) on silica gel to afford 3a-3l.
Funding
This project was supported from Zhejiang Provincial Natural Science Foundation of China
[
8
LY16H300001] to G. Zhang; National Natural Science Foundation of China [No. 81673291 and
1473074], and Osteoporosis & Breast Cancer Research Center, U.S.A. to Y. Yu.
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