Metal-free synthesis of 2-mercaptobenzothiazoles and 6-(4-substituted-1H-1,2,3-triazol-1-yl)-2-mercaptobenzothiazoles via microwave-assisted synthesis pathway

Article abstract of DOI:10.1080/00397911.2020.1761984

A simple, efficient, and metal-free methodology for the preparation of 2-mercaptobenzothiazole and derivatives in excellent yields via microwave-assisted pathway is reported. Our condition provides a convenient protocol for the synthesis of a diverse collection of 2-mercaptobenzothiazoles and 6-(4-substituted-1H-1,2,3-triazol-1-yl)-2-mercaptobenzothiazoles with a very simple purification process. This report provides an alternative protocol for fast access to the wide range of compounds for sequence synthesis and biological studies.

Full text of DOI:10.1080/00397911.2020.1761984

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Metal-free synthesis of 2-mercaptobenzothiazoles
and 6-(4-substituted-1H-1,2,3-triazol-1-yl)-2-
mercaptobenzothiazoles via microwave-assisted
synthesis pathway
Truong Thanh Tung & Luong Xuan Huy
To cite this article: Truong Thanh Tung & Luong Xuan Huy (2020): Metal-free synthesis of 2-
mercaptobenzothiazoles and 6-(4-substituted-1H-1,2,3-triazol-1-yl)-2-mercaptobenzothiazoles via
microwave-assisted synthesis pathway, Synthetic Communications
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https://doi.org/10.1080/00397911.2020.1761984
Metal-free synthesis of 2-mercaptobenzothiazoles and 6-(4-
substituted-1H-1,2,3-triazol-1-yl)-2-mercaptobenzothiazoles
via microwave-assisted synthesis pathway
a,b
a,b
Truong Thanh Tung
and Luong Xuan Huy
a
b
Faculty of Pharmacy, PHENIKAA University, Hanoi, Vietnam; PHENIKAA Institute for Advanced Study
PIAS), PHENIKAA University, Hanoi, Vietnam
(
ABSTRACT
ARTICLE HISTORY
A simple, efficient, and metal-free methodology for the preparation
of 2-mercaptobenzothiazole and derivatives in excellent yields via
microwave-assisted pathway is reported. Our condition provides a
convenient protocol for the synthesis of a diverse collection of 2-
mercaptobenzothiazoles and 6-(4-substituted-1H-1,2,3-triazol-1-yl)-2-
mercaptobenzothiazoles with a very simple purification process. This
report provides an alternative protocol for fast access to the wide
range of compounds for sequence synthesis and biological studies.
Received 1 March 2020
KEYWORDS
microwave-assisted synthe-
sis; metal-free; 2-
mercaptobenzothiazole
GRAPHICAL ABSTRACT
Introduction
Small molecule libraries are important sources for drug discovery and development. A
good collection of compounds could provide a higher chance of finding biologically
[
1]
active agents. Generally, the construction and designing of the library compounds
started from a privileged substructure, the structure in which they appeared or con-
[
1,2]
firmed a pivotal role in targeting many biological systems.
Due to the high demand
of constructing hundreds to thousands of compounds, a fast, convenient method for
preparation of the key skeleton is needed.
2
-Mercaptobenzothiazole is an active agent and also a privileged structure that can be
[
3–5]
found in many biologically active agents.
The compound itself was used as a derma-
tological drug for veterinary (US drug name Sulfodene) or even human use in some
countries. In addition, it showed good inhibitory activity in viruses, fungi, and many
[
6–11]
other pathogens.
Therefore, 2-mercaptobenzothiazole is an important intermediate
for the synthesis of bioactive library compounds (Figure 1).
There are several methods for the synthesis of 2-mercaptobenzothiazole derivatives.
Chaudhuri was the first to report the conversion of the 2-bromo-4-substituted-anilines
CONTACT Tung Truong Thanh
tung.truongthanh@phenikaa-uni.edu.vn
Faculty of Pharmacy, PHENIKAA
University, Hanoi 12116, Vietnam.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
T. T. TUNG AND L. X. HUY
Figure 1. 2-Mercaptobenzothiazole moiety in bioactive compounds.
to 2-mercaptobenzothiazole derivatives via reaction with potassium ethyl xanthogenate
[
12]
under reflux condition (5 examples).
The reaction afforded good yields and a
required reaction time of 4 hours. Due to very limited information and only 4-substi-
tuted-anilines tested, the selectivity of the reaction has not been reported. Intrigued by
Chaudhuri reports, Zhu et. al investigated the ortho-selectivity of this reaction which
[
13]
provides essential information to the scope of Chaudhuri’s initial report.
The
expanded version of this research was published from the same group in the same
[
14]
year.
Instead of the normal heating process, Huang et al. have used microwave-
[
15]
assisted synthesis for improvement of Chaudhuri’s reaction yields and time.
Another route to the preparation of 2-mercaptobenzothiazole derivatives is via carbon
disulfide (CS ). Mighri reacts o-haloanilines with CS under basic condition (TEA) fol-
2
2
[
16]
lowed by dehydrosulfurization to afford the products in medium to good yields.
Instead of TEA, in other research, Xi et al. have used DBU to promote the reaction.
[
17]
(Figure 2)
Overall, all of the reports focused on the simple substitution of the o-haloanilines
which may be limited in understanding the full scope of the reaction.
O-isopropylxanthic acid potassium salt (PIX) is a stable solid and easier to handle
and storage than CS . In this work, we report the first synthesis of 2-mercaptobenzo-
2
thiazole derivatives using PIX in Dimethylacetamide (DMAC) under microwave irradi-
ation .In addition, the complex system of 6-(4-substituted-1H-1,2,3-triazol-1-
yl)benzo[d]thiazole-2-thiols was constructed for the first time using our
reported condition.
Results and discussion
2
,6-dichloroaniline was chosen as a model substrate. The optimization of the reaction
condition was reported in Table 1. For comparison, normal heating condition was per-
formed along with microwave irradiation.
ꢀ
Microwave irradiation at 150 C was found to be the best condition with quantitative
yields (entries 3, 4). We were able to reduce the reaction time to only 5 min without

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Figure 2. Current methods for preparation of 2-mercaptobenzothiazole derivatives.
a
Table 1. Optimization of the reaction condition .
5
00 mg (3 mmol)
b
c
Entry
Method
Solvent
Temp.
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
MW
MW
MW
MW
MW
MW
MW
MW
MW
Heat
Heat
Heat
Heat
Heat
Heat
DMAC
DMAC
DMAC
DMAC
DMSO
90
120
100
15
5
30
200
30
30
240
300
1440
1440
1440
1440
240
70
90
99
99
60
51
63
33
87
30
62
42
18
30
89
110
150
150
150
60
100
100
150
110
110
60
ACN
Toluene
Chlorobenzene
DMF
1
1
1
1
1
1
a
0
1
2
3
4
5
DMAC
DMSO
ACN
Toluene
Chlorobenzene
DMF
110
110
110
Experiments were performed in triplicate, 500 mg (3 mmol scale).
b
required to get the highest yield(s).
Isolated yields.
c
decreasing reaction yield (entry 4). However, lowering the temperature leads to pro-
longed reaction times (to obtain the best conversion) and decreases the total yield of
the reaction (entries 1, 2). DMAC was found to be the optimal solvent since any
replacements lead to lower yields (entries 5–9).

4
T. T. TUNG AND L. X. HUY
Table 2. Scope of the reaction.
a
Entry
Cpds
R
1
R
2
R
3
X
Yield (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cl
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
F
99
89
90
81
76
85
85
94
92
91
88
97
68
63
70
F
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
CF
H
MeO
EtO
F
Cl
iPr
Me
CF O
3
3
10
11
12
13
14
15
NO
NH
2
2
F
1
1
6
7
16
17
H
H
H
H
F
F
93
90
1
1
2
8
9
0
18
19
20
H
H
H
H
H
H
F
F
87
82
90
Cl
2
1
21
H
H
Cl
81
(continued)

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Table 2. Continued.
2
2
22
H
H
Cl
88
2
2
3
4
23
24
H
H
H
H
Cl
Cl
74
92
2
2
5
6
25
26
H
H
H
H
Cl
Cl
81
65
2
2
2
3
7
8
9
0
1
27
28
29
30
31
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
70
79
61
77
82
3
a
Isolated yields.

6
T. T. TUNG AND L. X. HUY
Figure 3. Application of our reaction condition on synthesis of pma1 inhibitors.
Microwave irradiation gave higher yields within a short period of time as compared
to normal heating conditions (entries 10–15). For example, the yield of the optimized
condition (entry 4, 99%) is greatly decreased under traditional heating (entry 10, 30%).
With optimized reaction conditions in hand, we have successfully prepared 30 diverse
2-mercaptobenzothiazole derivatives as shown in Table 2.
The reaction ran smoothly with different substitutions of the o-haloanilines (500 mg,
mmol scale) to afford products in excellent yields. The presence of the halo-substi-
3
tuted groups in phenyl ring was well tolerated to our condition (entry 1–15). Under our
optimized reaction conditions, a similar reactivity of F, Cl, and Br at position 2 of anil-
ine (X group) was observed. Additionally, the reaction of 2-Iodoanilines gave very low
yields (data not shown). Overall, PIX was found to be a more powerful reagent than of
[
15]
potassium O-ethyl dithiocarbonate
in terms of reactivity.
To explore more the scope of the reaction, various 4-substituted-1,2,3-triazoles of the
o-haloanilines were tested. Interestingly, the products were formed in good to excellent
yields without forming by-products (entries 16–31). The presence of heterocycles on the
triazole ring was also well tolerated in these reactions (entries 29, 30). Overall, the reac-
tion condition is compatible with the modification of the substitutions on the phenyl
ring as well on the 1,2,3-triazole moiety.
To demonstrate the practicality of our method, the possible route to the synthesis of
[
4]
bioactive compounds in reference was depicted in Figure 3.
Conclusion
In conclusion, we have reported a fast and efficient method for the preparation of a
diverse collection of 2-mercaptobenzothiazole derivatives from the reaction between o-
haloanilines, O-isopropylxanthic acid potassium salt in DMAC under microwave irradi-
ation. The broad scope of the reaction has been demonstrated by applying to the more
complex system of triazole-containing o-haloanilines as a starting material. This report
will provide an alternative protocol for the preparation of 2-mercaptobenzothiazole

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derivatives and 6-(4-substituted-1H-1,2,3-triazol-1-yl)-2-mercaptobenzothiazoles for
organic and medicinal chemistry research.
Experimental
In a 20 mL microwave reaction vial (Biotage), a mixture of substituted 2-halogeno-anil-
ine (1 equiv, 500 mg), O-isopropylxanthic acid potassium salt (PIX) (2 equiv), and
ꢀ
DMAC (8 mL) was added. The vial was irradiated at 150 C for 5 min in a Biotage
microwave reactor. The mixture was cooled to room temperature. Then it was poured
into cold H O and adjusted to pH 3 by HCl 1 N. The precipitate was filtered and
2
washed (5 times) with H O to afford products without additional purification.
2
6
-(4-phenyl-1H-1,2,3-triazol-1-yl)benzo[d]thiazole-2-thiol (16). Yield 93%; mp 267.1-
ꢀ
68.2 C; H NMR (400 MHz, DMSO-d ) d 14.01 (s, 1H), 9.26 (s, 1H), 8.34 (d,
6
1
2
13
J ¼ 2.2 Hz, 1H), 8.00–7.90 (m, 3H), 7.55–7.46 (m, 3H), 7.39 (t, J ¼ 7.4 Hz, 1H).
C
NMR (101 MHz, DMSO-d6) d 191.0, 147.8, 141.7, 133.6, 131.2, 130.6, 129.5, 128.8,
þ
þ
11 4 2
1
3
25.8, 120.3, 120.2, 114.3, 113.6. HRMS (ESI) m/z [M þ H] calcd for C H N S
15
11.0425, found 311.0425.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Supporting Information
1
13
Full experimental detail, characterization data of new compounds, H and C NMR spectra.
This material can be found via the “Supplementary Content” section of this article’s webpage.
Funding
This research is funded by PHENIKAA University under grant number 01.2020.05.
ORCID
Truong Thanh Tung
http://orcid.org/0000-0002-5263-203X
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