Microwave-assisted controllable synthesis of 2-acylbenzothiazoles and bibenzo[b][1,4]thiazines from aryl methyl ketones and disulfanediyldianilines

Article abstract of DOI:10.1016/j.cclet.2021.05.069

A condition-controlled strategy for selectively synthesis of 2-acylbenzothiazoles and bibenzo[b][1,4]thiazines from aryl methyl ketones and disulfanediyldianilines was realized using I₂/DMSO or I₂/MeCN systems, respectively. The desired products were synthesized in only 15 min with moderate to excellent yields (50%-90%) under microwave-assisted, metal-free conditions. The strategy provides a great advantage for selective synthetic applications in the efficient synthesis of benzothiazoles and bibenzothiazines heterocycle compounds.

Full text of DOI:10.1016/j.cclet.2021.05.069

Journal Pre-proof
Microwave-assisted controllable synthesis of 2-acylbenzothiazoles
and bibenzo[b][1,4]thiazines from aryl methyl ketones and
disulfanediyldianilines
Yuquan Qi , Xiaoyu Gu , Xianqiang Huang , Guodong Shen ,
Bingchuan Yang , Qingpeng He , Zechun Xue , Mengcheng Du ,
Lilong Shi , Bing Yu
PII:
DOI:
Reference:
S1001-8417(21)00382-X
https://doi.org/10.1016/j.cclet.2021.05.069
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27 May 2021
31 May 2021
Please cite this article as: Yuquan Qi , Xiaoyu Gu , Xianqiang Huang , Guodong Shen ,
Bingchuan Yang , Qingpeng He , Zechun Xue , Mengcheng Du , Lilong Shi , Bing Yu ,
Microwave-assisted controllable synthesis of 2-acylbenzothiazoles and bibenzo[b][1,4]thiazines
from aryl methyl ketones and disulfanediyldianilines, Chinese Chemical Letters (2021), doi:
https://doi.org/10.1016/j.cclet.2021.05.069
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Chinese Chemical Letters
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Communication
Microwave-assisted controllable synthesis of 2-acylbenzothiazoles and
bibenzo[b][1,4]thiazines from aryl methyl ketones and disulfanediyldianilines
Yuquan Qia, Xiaoyu Gua, Xianqiang Huanga, Guodong Shen*a, Bingchuan Yanga, Qingpeng Hea, Zechun
Xuea, Mengcheng Duc, Lilong Shic, Bing Yu*b
a Shandong Provincial Key Laboratory of Chemical Energy Storage and Novel Cell Technology, School of Chemistry & Chemical Engineering, Liaocheng
University, Liaocheng 252059, China
b Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
c National Rubber Additive Engineering Technology Center, Liaocheng 252059, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
condition-controlled strategy for selectively synthesis of 2-acylbenzothiazoles and
bibenzo[b][1,4]thiazines from aryl methyl ketones and disulfanediyldianilines was realized using
I2/DMSO or I2/MeCN systems, respectively. The desired products were synthesized in only 15
min with moderate to excellent yields (50%-90%) under microwave-assisted, metal-free
conditions. The strategy provides a great advantage for selective synthetic applications in the
efficient synthesis of benzothiazoles and bibenzothiazines heterocycle compounds.
Available online
Keywords:
Selective synthesis
Metal-free
Microwave-assisted
Condition-controlled
Heterocycle compounds
The direct functionalization of C-H bonds for the synthesis of
heterocyclic compounds has emerged as an increasingly valuable
tool for step-economical carbon-heteroatom bond-forming
organic reactions [1-3]. Traditionally, transition metal complexes
were generally used as efficient catalysts for the functionalization
of C-H bonds, and a handful of eminent works have been
disclosed [4,5]. Although these methods are very efficient, it
often suffers from some drawbacks, such as the generation of
waste, the use of expensive hazardous transition metals and
ligands. With the development of green organic chemistry and
enhancement of environmental protection consciousness of
chemists [6,7], the application of a microwave-assisted strategy
for the functionalization of C-H bonds to synthesize heterocyclic
compounds under metal-free conditions is highly attractive.
2-Acylbenzothiazoles and bibenzo[b][1,4]thiazines are two
classes of heterocyclic compounds containing both nitrogen and
sulfur in the five- and six-membered ring, respectively, which
could be used as multifunctional building units and valuable
structural units in pharmaceutical chemistry, pesticides, industrial
dyes and functional materials [8,9]. For example, benzothiazole
is an important type of heterocyclic skeleton, which can be used
for anticancer agents and enzyme inhibitors, and so on [10]. In
recent years, some practical methodologies have been reported to
synthesize benzothiazole compounds [11]. For instance, in 2012,
Wu and co-workers reported an I2-promoted oxidative cyclization
reaction for the one-pot synthesis of 2-acylbenzothiazoles from
methyl o-aminobenzenethiols and ketones [12]. In 2016, Wan et
al. also developed a tunable procedure for the synthesis of
benzothiazole-based vicinal diketones or 2-aroylbenzothiazoles
from o-aminothiophenols [13]. For the preparation of thiazines,
several synthesis protocols have been achieved. For example, the
oxidative coupling of 3-phenyl-2H-1,4-benzothiazine with highly
explosive picric acid [14]. Later, our group and Nguyen et al.
found that bibenzo[b][1,4]thiazines can be constructed through a
one-step reaction of readily available 2,2′-dithiodianiline or 2-
aminothiophenol in the presence AIBN or TFA, respectively
[15,16]. Some other methods require halogenated reagent, harsh
reaction conditions, expensive catalysts, and additional ligands to
proceed with the reactions, which accordingly would generate
stoichiometric amounts of waste after the reactions [17].
However, in the above-mentioned advances, most of the
reactions need a long reaction time (up to 24 h) to get good
yields. Thus, there is an incentive to develop efficient and green
catalytic processes based on microwave technology to minimize
 Corresponding authors.
E-mail addresses: hxqqxh2008@163.com; shenguodong33@163.com; bingyu@zzu.edu.cn

the reaction time in terms of sustainability. We herein report an
efficient condition-controlled reaction between aryl methyl
ketones and disulfanediyldianilines under microwave-assisted
conditions, which would generate bibenzo[b][1,4]thiazines or 2-
acylbenzothiazoles as the main products in only 15 min,
respectively (Scheme 1).
methyl ketone could not proceed in the reaction (9c) probably
owing to the stereo-hindrance effect. The yields of the ketones
bearing electron-donating groups (–CH3, –OMe) (2c and 8c)
were better than those of substrates bearing electron-withdrawing
groups (–F, –Cl, –Br, –I) (3c-7c). Next, the substituted 2,2'-
disulfanediyldianilines were used to react with acetophenone
(10c-12c). No product was detected when 2,2'-disulfanediylbis(4-
chloroaniline) was used as the substrate (10c). The scope of the
reaction was further explored by substituted dithiodianilines with
substituted acetophenones bearing electron-donating groups, the
products were isolated in good yields (13c and 14c). From the
above results, we found that the reaction was significantly
influenced by both the electronic effect and stereo hindrance
effect.
Scheme 1. Condition-controlled selective synthesis of 2-
acylbenzothiazoles and bibenzo[b][1,4]thiazines.
Table 1
Optimization of the reaction conditions.a
Initially, 2,2'-disulfanediyldianiline 1a and acetophenone 1b
were selected to optimize the microwave-assisted reaction
parameters (Table 1). We conducted the reaction with the
conditions of I2 (0.12 mmol), 1a (0.25 mmol) and 1b (0.525
o
mmol) in AcOH (2 mL) at 150 W/120 C for 15 min, only 3,3'-
Yield (%)b
I2
Solvent
(mL)
AcOH
DMF
T
Entry
(mmol)
I2 (0.12)
I2 (0.12)
I2 (0.12)
I2 (0.12)
I2 (0.12)
I2 (0.12)
I2 (0.25)
I2 (0.50)
I2 (0.75)
I2 (0.50)
I2 (0.50)
I2 (0.50)
I2 (0.50)
I2 (0.16)
I2 (0.20)
I2 (0.16)
I2 (0.16)
I2 (0.16)
I2 (0.16)
(oC)
120
120
120
120
120
120
120
120
120
125
130
125
125
120
120
120
120
110
125
diphenyl-2H,2'H-2,2'-bibenzo[b][1,4]thiazine 1c was isolated in
56% yield (entry 1). Some other solvents, including DMF,
MeCN, DMSO, toluene and dioxane were tested (entries 2-6),
which disclosed that MeCN displayed the best efficiency for the
synthesis of 1c (entry 3). While the reaction performed in DMSO
gave the sole product benzo[d]thiazol-2-yl(phenyl)methanone 1d
in 72% yield (entry 4). To further optimize the reaction
conditions of product 1c, the amount of I2 was surveyed. It turns
out that 2 equiv. of I2 is the best loading for generating of 1c
(entries 7-9). Next, we checked the influence of the reaction
temperature. The reaction yield did not increase when the
reaction temperature was higher than 125 °C (entries 10 and 11).
Moreover, changing the reaction time did not increase the yield
of 1c (entries 12 and 13). On the other hand, we also evaluated
the reaction parameters including I2 loading, reaction
temperature, and reaction time for the synthesis of product 1d
(entries 14-19). From the above experimental results, it could be
found that the application of DMSO as a solvent is critical for the
formation of 1d, which is similar with that of the reported case
[18].
1c
56
69
70
0
46
65
72
74
74
78
78
70
78
0
1d
0
0
0
72
0
0
0
0
0
0
0
0
0
88
87
82
86
80
85
1
2
3
4
5
6
7
8
9
10
11
12c
13d
14e
15e
16c,e
17d,e
18e
19e
MeCN
DMSO
Toluene
Dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
0
0
0
0
a Reaction conditions: 1a (0.25 mmol) and 1b (0.525 mmol) in
solvent (2 mL) at 150 W for 15 min.
The yield was determined by 1H NMR analysis of crude
products using 1,3,5-trimethoxybenzene as the internal standard
based on 1a (for the yield of 1c) or 1b (for the yield of 1d),
respectively.
b
With the optimized reaction conditions, the scope of the
substrates for the synthesis of bibenzo[b][1,4]thiazines was firstly
investigated (Scheme 2). Initially, when aryl methyl ketones with
electron-donating groups and electron- withdrawing groups in the
meta- and para-position were used as reactants, and the
corresponding products 1c-8c could be obtained in moderate to
good yields. Unfortunately, the ortho-position substituted aryl
c The reaction time was 10 min.
d The reaction time was 20 min.
e 1b is 0.45 mmol.

Scheme 2. Scope of synthesis of bibenzo[b][1,4]thiazines. Reaction conditions: I2 (0.5 mmol), a (0.25 mmol) and b (0.525 mmol) in MeCN (2
mL) at 150 W/125 oC for 15 min. Isolated yield after flash chromatography (Al2O3) based on a.
Next, we evaluated the substrate scope for the synthesis of 2-
acylbenzothiazoles d after establishing the optimized reaction
conditions. The procedure was extended to a variety of aromatic
ketones for coupling with substituted dithiodianilines (Scheme 3,
1d-16d). The reaction of aromatic ketones with both electron-
donating and electron-withdrawing groups at ortho-, meta- and
para-position of the phenyl group were suitable for obtaining the
corresponding products in moderate to excellent yields (1d-12d).
The reaction yields of the ketones bearing electron-donating
groups at para-position (–CH3, –OMe) (2d and 3d) were slightly
better than those of substrates bearing electron-withdrawing
groups (–NO2, –CN, –F, –Cl, –Br, –I) (4d-9d). The reaction
yields were mainly influenced by the steric hindrance effect of
group R1. Relatively low yields were observed when ortho- and
meta-substituted substrates were used (10d-12d). Notably,
substituted 2,2'-disulfanediyldianilines reacted smoothly with 2a
to afford the desired corresponding products in good yields (13d-
16d). Notably, the moderate yield could also be achieved when 2-
acetylfuran was presented in the reaction (17d).
Scheme 3. Scope of the synthesis of 2-acylbenzothiazoles. Reaction conditions: a (0.25 mmol), b (0.45 mmol) and I2 (0.16 mmol) in DMSO
(2 mL) at 150 W/120 oC for 15 min. Isolated yields after flash chromatography based on b.
1
To clarify the mechanism of the two reactions, a series of
control experiments were designed and conducted. The reaction
intermediates were examined and monitored by H NMR and
GC-MS (Scheme 4). When the radical scavenger 2,2,6,6-

tetramethylpiperidin-1-oxyradical (TEMPO, 1.0 mmol) was
added to probe the radical nature of the two reactions, no
corresponding products 1c and 1d were detected. While, the
adduct 1ab was observed by GC-MS in both reactions (Scheme 4
and Fig. S29 in Supporting information), suggesting that the thiol
radical was involved in the reaction.
synthesis of bibenzo[b][1,4]thiazines c and 2-acylbenzothiazoles
d, respectively (Scheme 5). First, the thiyl radical 1aa was
generated from 1a under the irradiation of microwave. When
DMSO was applied as the solvent, 1b was transformed into α-
iodoacetophenone 1ba in presence of I2, which was further
oxidized by DMSO to form 1bb [20]. Then the condensation of
1aa and 1bb afforded the intermediate 1bc. Subsequently, 1bc
underwent an intramolecular cyclization and hydrogen atom
abstraction to afford the product 1d. On the other hand, when the
reaction was conducted in CH3CN the direct condensation of 1aa
and 1b gave the intermediate 1ab, which was converted into the
corresponding isomer 1ac. Then the intermediate 1ac suffered
from an intramolecular cyclization and hydrogen atom
abstraction to generate the intermediate 1ae, which was further
dimerized into the desired product 1c in the presence of I2
(Scheme 5). On the other hand, I2 could be regenerated from the
reaction of HI and DMSO in the pathway of the generation of
product d [12]. The reason of high I2 loading was probably due to
the low efficiency of the regeneration process.
Scheme 4. Control experiments.
On the basis of the above results and previous reports
[12,15,19], the plausible reaction pathways are proposed for the
Scheme 5. Possible mechanisms.
(2019) 1361-1368.
[2] (a) Y. Wang, J. Zhu, R. Guo, et al., Chem. Sci. 11 (2020)
12316-12322;
In summary, we have developed an efficient microwave-
assisted condition-controlled C(sp3)-H activation strategy for the
(b) X. Zhang, A. McNally, et al., ACS Catal. 9 (2019) 4862-
4866.
selective
synthesis
of
2-acylbenzothiazoles
and
bibenzo[b][1,4]thiazines from aryl methyl ketones and
disulfanediyldianilines. In these reactions, a wide array of aryl
methyl ketones were well compatible. The reaction was
switchable by simply changing the reaction conditions (I2/MeCN
or I2/DMSO) without the involvement of explosive oxidants and
additional activating reagents.
[3] (a) U.H.F. Bunz, J. Freudenberg, et al., Acc. Chem. Res. 52
(2019) 1575-1587;
(b) X.M. Xu, D.M. Chen, Z.L. Wang, et al., Chin. Chem. Lett.
31 (2020) 49-57.
[4] (a) U. Dhawa, C. Tian, W. Li, et al., ACS Catal. 10 (2020)
6457-6462;
(b) M. Liu, L. J. Li, J. Zhang, et al., Chin. Chem. Lett. 31
(2020) 1301-1304.
[5] (a) J.R. Hummel, J.A. Boerth, J.A. Ellman, et al., Chem. Rev.
117 (2017) 9163-9227;
Acknowledgments
The work was financially supported by the National Natural
Science Foundation of China (No. 21871125); the Natural
Science Foundation of Shandong Province, China (Nos.
ZR2019MB043 and ZR2019QB022) and the Construction
Project of Quality Curriculum for Postgraduate Education of
Shandong Province (No. SDYKC19057).
(b) X. Lu, S.J. He, W.M. Cheng, et al., Chin. Chem. Lett. 29
(2018) 1001-1008.
[6] (a) X.Y. Li, Y. Liu, X.L. Chen, et al., Green Chem. 22 (2020)
4445-4449;
(b) Q. Zhang, Z. Mao, K. Wang, et al., Green Chem. 22 (2020)
3239-3247.
[7] (a) W.P. Teh, D.C. Obenschain, B.M. Black, et al., J. Am.
Chem. Soc. 142 (2020) 16716-16722;
(b) J.L. Peltier, E. Tomas-Mendivil, D.R. Tolentino, et al., J.
Am. Chem. Soc. 142 (2020) 18336-18340.
[8] (a) X. Meng, X. Bi, C. Yu, et al., Green Chem. 20 (2018)
4638-4644;
References
[1] (a) J.F. Yu, J.J. Li, P. Wang, et al., Angew. Chem. Int. Ed. 58
(2019) 18141-18145;
(b) J.S. Wright, P.J.H. Scott, P.G. Steel, et al., Angew. Chem.
Int. Ed. 59 (2020) 2-28;
(c) Y. Zhang, K. Sun, Q. Lv, et al., Chin. Chem. Lett. 30
(b) K. Bahrami, M.M. Khodaei, F. Naali, et al., J. Org. Chem.
73 (2008) 6835-6837.

(c) L. Leone, O. Crescenzi, R. Amorati, et al., Org. Lett. 15
(2013) 4944-4947.
[9] D.A. Horton, G.T. Bourne, M.L. Smythe, et al., Chem. Rev.
103 (2003) 893-930.
b Green Catalysis Center, College of Chemistry, Zhengzhou University,
Zhengzhou 450001,China
c National Rubber Additive Engineering Technology Center, Liaocheng
252059, China
[10] (a) E. Meltzer-Mats, G. Babai-Shani, L. Pasternak, et al., J.
Med. Chem. 56 (2013) 5335-5350;
(b) A. Spadaro, M. Frotscher, R.W. Hartmann, et al., J. Med.
Chem. 55 (2012) 2469-2473.
[11] (a) X. Meng, X. Bi, C. Yu, et al., Green Chem. 20 (2018)
4638-4644;
(b) B. Wang, Q. Zhang, Z. Guo, et al., Synthesis 52 (2020)
3058-3064;
[12] Y.P. Zhu, M. Lian, F. C. Jia, et al., Chem. Commun. 48 (2012)
9086-9088.
[13] J.P. Wan, Y. Zhou, Y. Liu, et al., Green Chem. 18 (2016) 402-
405.
A condition-controlled strategy to selectively
synthesize nitrogen-sulfur heterocycles through
microwave-assisted high-efficiency protocol has
been proven. This method can selectively
synthesize five-membered ring and six-membered
ring benzoheterocyclic compounds through the
control of solvents and the consumption of iodine
in high yields.
[14] F. Giordano, L. Mazzarella, G. Prota, et al., J. Chem. Soc. C.
(1971) 2610-2616.
[15] X. Huang, N. Rong, P. Li, et al., Org. Lett. 20 (2018) 3332-
3336.
[16] T.B. Nguyen, P. Retailleau, et al., Adv. Synth. Catal. 23 (2020)
5380-5384.
[17] (a) O. Prakash, N. Sharma, K. Pannu, et al., Synth. Commun.
37 (2007) 1995-1999;
(b) D.C. Loukrakpam, P. Phukan, et al., Chem. Select. 4 (2019)
3180-3184;
(c) Y.P. Zhu, F.C. Jia, M.C. Liu, et al., Org. Lett. 14 (2012)
4414-4417;
(d) X. Fan, Y. He, X. Zhang, et al., Tetrahedron 67 (2011)
6369-6374;
(e) K. Yang, C. Zhang, P. Wang, et al., Chem. Eur. J. 20 (2014)
7241-7244;
(f) Q. Feng, Q. Song, Adv. Synth. Catal. 356 (2014) 2445-
2452.
Declaration of interests
[18] (a) W. Fan, Z. Yang, B. Jiang, et al., Org. Chem. Front. 4
(2017) 1091-1102;
(b) Z. Yao, X. Lin, R. Chauvin, et al., Chin. Chem. Lett. 31
(2020) 3250-3254.
[19] (a) K. Farshadfar, A. Gouranourimi, A. Ariafard, et al., Org.
Biomol. Chem. 18 (2020) 8103-8108;
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
(b) R. Fan, W. Li, D. Pu, et al., Org. Lett. 11 (2009) 1425-
1428.
[20] R. Ma, Y. Ding, R. Chen, et al., J. Org. Chem. 86 (2021) 310-
321.
Graphical Abstract
Microwave-assisted
controllable
synthesis of 2-acylbenzothiazoles and
bibenzo[b][1,4]thiazines from aryl
methyl
ketones
and
disulfanediyldianilines
Yuquan Qia, Xiaoyu Gua, Xianqiang Huang*a,
Guodong Shen*a, Bingchuan Yanga, Qingpeng Hea,
Zechun Xuea, Mengcheng Duc, Lilong Shic, Bing
Yu*b
a Shandong Provincial Key Laboratory of Chemical Energy Storage and
Novel Cell Technology, School of Chemistry & Chemical Engineering,
Liaocheng University, Liaocheng 252059, China