Iodine-catalyzed amination of benzothiazoles with KSeCN in water to access primary 2-aminobenzothiazoles

Article abstract of DOI:10.1016/j.cclet.2021.08.070

A facile and sustainable approach for the amination of benzothiazoles with KSeCN using iodine as the catalyst in water has been disclosed under transition-metal free conditions. The reaction proceeded smoothly to afford various primary 2-amino benzothiazoles in up to 96% yield. A series of control experiments were performed, suggesting a ring-opening mechanism was involved via a radical process. This protocol provides efficient synthesis of primary 2-aminobenzothiazoles

Full text of DOI:10.1016/j.cclet.2021.08.070

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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Iodine-catalyzed amination of benzothiazoles with KSeCN in water to
access primary 2-aminobenzothiazoles
Yu-Shen Zhu1, Linlin Shi1, Lianrong Fu, Xiran Chen, Xinju Zhu, Xin-Qi Hao∗,
Mao-Ping Song∗
College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and sustainable approach for the amination of benzothiazoles with KSeCN using iodine as the cat-
alyst in water has been disclosed under transition-metal free conditions. The reaction proceeded smoothly
to afford various primary 2-amino benzothiazoles in up to 96% yield. A series of control experiments were
performed, suggesting a ring-opening mechanism was involved via a radical process. This protocol pro-
vides efficient synthesis of primary 2-aminobenzothiazoles
Received 14 April 2021
Revised 11 August 2021
Accepted 13 August 2021
Available online xxx
© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia
Medica, Chinese Academy of Medical Sciences.
Keywords:
Iodine-catalyzed
Benzothiazoles
KSeCN
Water
Primary 2-benzothiazolamines
2-Aminobenzothiazoles are important building blocks in or-
ganic synthesis [1] with wide applications in pharmaceuti-
cals, agrichemicals, and medicinal science [2–5]. Meanwhile, 2-
aminobenzothiazole derivatives also serve as fluorescent sensor in
the detection of metal ions [6]. Accordingly, great effort has been
made for the synthesis of 2-aminobenzothiazoles [7]. The success-
ful approaches include transition-metal-catalyzed tandem conden-
sation and cyclization between o-haloaniline and isothiocyanates
or other reagents (Scheme 1a) [8–10], intramolecular cyclization
of N-arylthioureas or 2-haloarylthioureas (Scheme 1b) [11–13], and
amination of benzothiazoles with amines or formaides (Scheme 1c)
[14–19]. Recently, cascade reaction between aryl isothiocyanates
with amines or formamides has also proved to be an effective
strategy (Scheme 1d) [20–24]. Despite the above elegant work,
the aforementioned protocols mainly focused on synthesis of sec-
ondary and tertiary amino-substituted benzothiazoles. Meanwhile,
transition-metal catalysts and toxic organic solvents are generally
required, which is not environmentally benign. Therefore, it is
highly imperative to explore a novel and facile synthetic method
to access primary 2-amino-substituted benzothiazoles while meet-
ing green and sustainable chemistry.
Facing the challenge of environmental issues and depletion of
nonrenewable resources, the concept of green chemistry and prin-
ciples has been proposed to reduce chemical waste. Specially, the
utilization of green solvents is a key principle in the synthetic
community [25,26]. As a non-toxic, commercially available, and re-
newable resource, water has become an excellent reaction medium
for organic transformation with improved selectivity, efficiency,
and work-up procedures [27–29]. On the other hand, selenocyanate
potassium (KSeCN) is a cheap readily, and versatile reagent with
wide applications in organic chemistry. In general, KSeCN could be
utilized as selenocyano source via nucleophilic reactions or radical
pathways [30–33]. Meanwhile, KSeCN has been applied as a sele-
nium transfer reagent [34–37]. In our recent work, we have also
reported temperature-controlled selenation and selenocyanation of
imidazopyridines with KSeCN in water [38]. Nevertheless, the em-
ployment of KSeCN as the cyano synthon has not been achieved.
In accordance with principles of green chemistry, we have
achieved C-H sufonylmethylation of imidazopyridines and indoles
in nontoxic media [39,40]. We also have reported iodine-mediated
C-H sulfonylation and sulfenylation of imidazopyridines under
metal-free conditions [41]. Recently, Li and co-workers have re-
ported iron-catalyzed arylation of benzothiazoles with aryl alde-
hydes (Scheme 1e) [42]. In view of the increased attention to de-
sign green and transition-metal-free methods for the formation of
heterocyclic compounds, we herein develop a one-pot synthesis
of primary 2-aminobenzothiazoles from benzothiazoles and KSCN
through the in-situ formation of an aminobenzenethiol intermedi-
∗
Corresponding authors.
E-mail addresses: xqhao@zzu.edu.cn (X.-Q. Hao), mpsong@zzu.edu.cn (M.-P.
Song).
1
These authors equally contributed to this work.
https://doi.org/10.1016/j.cclet.2021.08.070
1001-8417/© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Please cite this article as: Y.-S. Zhu, L. Shi, L. Fu et al., Iodine-catalyzed amination of benzothiazoles with KSeCN in water to access
primary 2-aminobenzothiazoles, Chinese Chemical Letters, https://doi.org/10.1016/j.cclet.2021.08.070

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Scheme 1. Synthetic strategies for 2-substituted benzothiazoles.
Table 1
Optimization of the reaction conditions.a
Entry
Oxidant (equiv.)
Additive (equiv.)
Solvent
2a (%)
Scheme 2. Substrate scope of benzothiazolesa. Reaction conditions: 1 (0.2 mmol),
KSeCN (0.3 mmol), I2 (20 mol%), PIDA (1.5 equiv.), Tf2O (0.8 equiv.), H2O (3 mL), 110
°C, 6 h, under air. Isolated yield.
1
-
-
H2O
DMF
DMSO
CH3OH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
18
2
-
-
NR
3
-
-
NR
4
-
-
10
5
PIDA (1.0)
TBHP (1.0)
K2S2O8 (1.0)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
-
36/40b
36/27b
trace
59
6
-
CH3OH, were investigated, which all gave inferior results (Table 1,
entries 2–4). Next, a series of oxidants were screened (Table 1, en-
tries 5–7), indicating addition of PIDA (1.5 equiv.) was beneficial to
provide 2a in 40% yield (Table 1, entry 5). To further improve re-
action efficiency, different additives were examined, such as TFA,
TsOH.H2O, Tf2O, and K2CO3, which gave 2a in up to 70% yield
when the reaction was heated for 6 h (Table 1, entry 10). Finally,
the molar ratio of reactants and amount of solvent were examined,
which gave 2a in up to 94% yield (Table 1, entry 14). The structure
of 2a (CCDC No. 2034721) was further confirmed by X-ray crystal-
lography analysis (see Supporting information for details).
7
-
8
TFA (1.0)
TsOH•H2O (1.0)
Tf2O (0.5)
K2CO3 (1.0)
Tf2O (0.5)
Tf2O (0.8)
Tf2O (0.8)
9
50
63/70c
10
11
12
13
14
11
73d
91e
94f
PIDA = (diacet oxyiodo)benzene.
a
Reaction Conditions: 1a (0.2 mmol), KSeCN (0.2 mmol), I2 (20
mol%), oxidant (equiv.), additives (equiv.), solvent (1 mL), under air, 110
°C, 3 h. Isolated yields.
b
Oxidant (1.5 equiv.).
With the optimized reaction conditions in hand (entry 14,
Table 1), the substrate scope of benzothiazoles was investigated
(Scheme 2). Initially, 4-halogen-substituted benzothiazoles were
examined to give products 2b and 2c in 72% and 74% yields, re-
spectively. Subsequently, a series of 5- and 6-substituted benzoth-
iazoles were employed, which reacted with KSeCN to afford the
desired products 2d-2q in 17%–96% yields.
c
6 h.
d
H2O (2 mL), 6 h.
e
KSeCN (0.3 mmol), H2O (2 mL), 6 h.
f
KSeCN (0.3 mmol), H2O (3 mL), 6 h.
ate, intermolecular condensation, and cyclization process catalyzed
by iodine (Scheme 1f). The advantages of this methodology include
nonmetallic catalyst, novel CN source, green reaction media, and
operational convenience.
Especially, benzothiazoles bearing strong electron-withdrawing
groups, including NO2 and CN, were also well tolerated to give
products 2i, 2o and 2p in 77%–91% yields. Unfortunately, for 6-
hydroxy-substituted benzo-thiazole, the aminated product 2q was
isolated in 17% yield. Next, 7-bromo and 7-ester substituted ben-
zothiazoles proceedes smoothly to provide aminated products 2r
and 2s in 83% and 62% yields. Moreover, for disubstituted benzoth-
iazole, the corresponding products 2t was obtained in 54% yields.
We initiated our studies using benzothiazole 1a (0.2 mmol) and
KSeCN (0.2 mmol) as the model substrates in the presence of I2
(20 mol%) in water (1 mL). To our delight, the aminated product
2a was obtained in 18% yield at 110°C for 3 h under air (Table 1,
entry 1). Subsequently, various solvents, such as DMF, DMSO, and
2

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Scheme 3. Investigation of “CN” reagents and other substrates.
Scheme 5. Control experiments.
uct 6 in 56% and 61%, respectively. In this case, KSeCN was utilized
as SeCN and Se source selectivity.
To explore reaction mechanism, a set of control experiments
were conducted (Scheme 5). Initially, 1a could be converted to
aminothiophenol in 18% yield without KSeCN under standard con-
ditions (Scheme 5a). Aminothiophenol is not stable (decomposed)
under the current conditions, which might explain the low isolated
yield (Scheme 5b). Meanwhile, both I2 and PIDA are required for
this transformation. Without I2 and PIDA, aminothiophenol could
not be generated (Scheme 5a). Next, reaction between aminothio-
phenol and KSeCN under standard conditions would afford 2a in
29% yield, suggesting aminothiophenol could be an intermediate
in the reaction system (Scheme 5c). When the reaction was per-
formed in the absence of I2 and PIDA, the aminated product 2a
could be obtained in 42% yield. Finally, the radical scavenger reac-
tions were performed (Scheme 5d). In the presence of TEMPO and
BQ, the formation of corresponding amino-benzothiazole 2a was
substantially depressed, indicating a radical mechanism might be
involved.
Scheme 4. Gram-scale reaction and further derivatizations.
On the basis of above discussion and relevant literatures, two
plausible reaction mechanisms were proposed (Scheme 6) [49–53].
In the mechanism A, benzothiazole 1a underwent oxidative ring-
opening process in the presence of I2 and PIDA to give aminoth-
iophenol A in situ [54], which reacted with KSeCN and Tf2O to
afford imine intermediate B. The subsequent intramolecular addi-
tion generated intermediate C, followed by aromatization to deliver
the aminated product 2a. Alternatively, the iminium species D was
initially formed from benzothiazole in the presence of KSeCN and
Tf2O [51]. Subsequently, nucleophilic attack of iminium D by H2O
gave hemiacetal intermediate E [52]. Next, the intermediate E un-
derwent ring-opening process to give intermediate F, which pro-
duced sulfur radical G through the reaction of PIDA with I2 [53].
Finally, thioyl radical G underwent tautemerization and annulation
process to afford intermediate H, followed by release of TfSe· to
give the desired product 2a.
Finally, heterocyclic thiazoles were also compatible with the opti-
mized conditions to deliver 2u-2w in 54%–70% yields.
Encouraged by the above results, other thiocyanate salts were
also evaluated as the cyano source (Scheme 3) [43–45]. Pleasingly,
when KSCN, NaSCN, CuSCN, and NH4SCN was employed, the am-
inated product 2a was isolated in 39%–46% yields. Nevertheless,
compared with thiocyanate salts, KSeCN demonstrates superior re-
activity, which could be utilized as a novel CN source. Next, 2-
methylbenzothiazole could also react with KSeCN to afford the
desired product 2a in 36% yield. Finally, when aminophenol and
aminothiophenol were examined, the desired products 2a and 3
[46] could be obtained in 91% and 45% yields, respectively, without
I2 and PIDA. These promising results enable the current protocol
as a reliable and practical procedure to access 2-aminobenzoxazole
derivatives.
In conclusion, we have demonstrated the direct amination
of benzoxazoles with KSeCN under transition-metal-free condi-
tions. This methodologly provided efficient access to primary 2-
benzothiazolamines using cheap and non-toxic iodine as cata-
lyst and water as reaction media, which is more environmentally
friendly. Various functional groups, including OMe, OCF3, F, Cl, Br,
COOMe, CN and NO2, and heterocyclic thiazoles were all well tol-
erated under the optimized conditions. Mechanism studies indi-
To demonstrate the synthetic utility of this methodology, a
gram-scale reaction was performed to give 2-aminobenzothiazole
2a in 82% yield (Scheme 4). Meanwhile, the obtained 2a could be
converted to imidazoheterocycles 4 in 85% yield [47,48], which is
difficult to realize from benzothiozole. Moreover, imidazoheterocy-
cles 4 could undergo further functionalizations to afford the corre-
sponding chalcogenated product 5 and chalcogenocyanated prod-
3

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Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.cclet.2021.08.070.
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Scheme 6. Proposed mechanism.
cated this transformation proceeded via a ring-opening process.
Notably, 2-methyl benzothiazole was also compatible to give the
corresponding aminated product, which is less reported. This pro-
tocol featured with unique characterizations, including transition-
metal free, novel CN reagent, green reaction media, operational
convenience, high efficiency, and gram-scale production.
Declaration of competing interest
The authors declare no competing financial interest.
Acknowledgment
Financial support from the National Natural Science Foundation
of China (Nos. 21672192, 21803059, and U1904212) is gratefully ap-
preciated.
4