Design, Synthesis, Safener Activity, and Molecular Docking of Novel N-Substituted Thiazide/Thiazole Derivatives

Article abstract of DOI:10.1002/jhet.3393

A series of novel substituted thiazide/thiazole compounds were designed by splicing active groups and bioisosterism. The title compounds were synthesized via the cyclization, acylation, and carbamylation. All the compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, and HRMS. The single crystal of compound 3f was determined by X-ray crystallography. The biological activity tests indicated that all the compounds showed potential safener activity to the herbicide chlorsulfuron, in which compound 3e showed almost the same level as the commercialized safener AD-67. The molecular docking results were in good agreement with the bioassay results, which demonstrated that compound 3e might compete with chlorsulfuron in the acetolactate synthase active site, causing the herbicide ineffective in maize.

Full text of DOI:10.1002/jhet.3393

Month 2018
Design, Synthesis, Safener Activity, and Molecular Docking of Novel N-
Substituted Thiazide/Thiazole Derivatives
*
Ying Fu, Ke-Han Yi, Ming-Qiang Li, Jing-Yi Wang, Yu-Feng Chen, and Fei Ye
Department of Applied Chemistry, Northeast Agricultural University, Harbin 150030, China
*E-mail: yefei@neau.edu.cn
Received May 31, 2018
DOI 10.1002/jhet.3393
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel substituted thiazide/thiazole compounds were designed by splicing active groups and
bioisosterism. The title compounds were synthesized via the cyclization, acylation, and carbamylation. All
the compounds were characterized by IR, 1H-NMR, 13C-NMR, and HRMS. The single crystal of compound
3f was determined by X-ray crystallography. The biological activity tests indicated that all the compounds
showed potential safener activity to the herbicide chlorsulfuron, in which compound 3e showed almost
the same level as the commercialized safener AD-67. The molecular docking results were in good agreement
with the bioassay results, which demonstrated that compound 3e might compete with chlorsulfuron in the
acetolactate synthase active site, causing the herbicide ineffective in maize.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
pyrrol-2(5H)-one derivatives with antibacterial activity
bearing 1,3,4-oxadiazole moiety were also designed via
placing the natural substructure 1-aryl-4-hydroxy-1H-
pyrrol-2(5H)-one at the two positions of 1,3,4-oxadiazole
through a sulfide bridging group [11]. Many successful
cases have been reported in recent years [12,13].
In continuation of our previous investigations on the
synthesis of nitrogen-containing heterocyclic compounds
[14–16], a series of substituted thiazide/thiazole compounds
were designed based on active subunit combination and
bioisosteric replacement; the sulfur and nitrogen-containing
heterocycle were retained with modification on the
sulfonylurea functional groups (Scheme 2). The synthesis
of novel substituted thiazide/thiazole compounds 3 was via
cyclization acylation and carbamylation without any
expensive reagent or catalyst (Scheme 3). The bioactivity
determination was carried out on maize from the injury
of chlorsulfuron.
The sulfur and nitrogen-containing heterocycle is one of
the most important moieties in heterocycles and has been
widely used as building block for pharmaceutical agents
as well as biologically active compounds [1,2]. Besides,
thiazole and thiazine skeletons constitute the core
structure of many natural and synthesized products,
which exhibit diverse pharmacological properties as
exemplified by antimicrobial, insecticidal, and anti-
inflammatory activities [3–5]. In particular, thiazole and
thiazine are widely used in agricultural field. Several new
benzothiazole compounds have been synthesized as
potential antimicrobial and antiparasitic agents [6]. 1,2-
Benzisothiazolin-3-one was used as fungicide with good
sterilization and anticorrosion performance [7].
Benzothiazinone derivatives showed good control effect
on bacterial blight of tomato seedlings [8]. Thiazole
compounds are also reported as herbicide safener for
alachlor on grain sorghum [9].
Many bioactive compounds have been discovered by
combining active subunits of known active molecules.
For example, the new fungicide fluopyram was designed
by splicing active groups of fluopicolide and flutolanil
(Scheme 1) [10]. A variety of 1-aryl-4-hydroxy-1H-
RESULTS AND DISCUSSION
The substituted five-membered ring thiazoles 2a–d were
synthesized with mercaptoethylamine hydrochloride and
ketone 1 in methanol at room temperature for 24 h. The
© 2018 Wiley Periodicals, Inc.

Y. Fu, K.-H. Yi, M.-Q. Li, J.-Y. Wang, Y.-F. Chen, and F. Ye
Vol 000
Scheme 1. The design of the new fungicide. [Color figure can be viewed
at wileyonlinelibrary.com]
yields of compounds 2a–d were 54–85% (Table 1). The
substitutes affected the yields significantly. When the
substitutes were cyclopentyl, the formation of spiro
compounds made the structure more stable, which made
the yield of 2d was better than others. The bulk
substituents decreased the stability of the thiazole and led
to the lower yields with only 54% yield of 2c. The
benzothiazine 2e was synthesized according to the
literature with o-aminothiophenol and 1,2-dibromoethane
as the raw materials [17]. The conjunctive effect of
hydroxyl and amino with the benzene ring made the
cyclization hard to occur. The yield of 2e was only 30%.
The title compounds 3a–e were synthesized by direct
carbamylation with intermediate 2a–e and tosyl
isocyanate in anhydrous benzene in 59–85% yields
Scheme 2. The design of the title compounds. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 3. Route for synthesis of the title compounds 3. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, Safener Activity of Novel N-Substituted Thiazide/Thiazole
Derivatives
Table 1
Reaction condition and yields of product 2a–e and 3a–e.
Compound 2
T (°C)
Compound 3
T (°C)
Entry
R1
R2
Time (h)
Yield (%)#
Time (h)
Yield (%)#
a
b
c
d
e
-CH3
-CH3
-CH3
-(CH2)5
-
-CH3
-CH2CH3
-CH2CH2Ph
26
26
26
26
80
24
24
24
24
10
64
66
54
85
30
8
8
8
8
25
0.5
0.5
0.5
0.5
2
76
74
56
85
62
-
#Refers to yields of crude products only.
(Table 1). In general, the substitutes have little effect on the
yields of title products because the R1 and R2 at two
positions were not at the same plane with thiazole ring.
But they were related with the thiazole stability. When
the substituents were symmetric small groups or cyclic
structures (3a, 3b, and 3d), the thiazole was very stable,
and the yields were relatively good with 74–85%. Chiral
compounds would be obtained when R1 and R2 being
different alkyl.
Compounds 3f–h were obtained via acylation with 3,4-
dihydro-2H-benzo [1,4] thiazine 2e and acyl chloride as
the starting materials, benzene as solvent, and anhydrous
Na2CO3 as acid-binding agent. The yields were influenced
greatly by the electronegativity of R3 (Table 2). It can be
seen that the yield of 3h was 72%, far higher
than others. This might be the acetoxy electron-
withdrawing inductive effect made the chloride more
likely to lose.
The structures of all the title compounds 3 were
supported by IR, 1H-NMR, 13C-NMR, and HRMS
spectral data. The original spectral data was provided in
the Supporting Information. IR analysis confirmed the
presence of a carbonyl group at 1701 cmꢀ1 and a
sulfonyl group at 1357 and 1160 cmꢀ1 for compounds
3a–e. The 1H-NMR spectrum also confirmed the
proposed structure; the three hydrogens at δ 2.38 ppm
indicated the methyl of benzene ring. The signals at δ
7.39–7.79 ppm related to benzene ring. The single signal
observed at δ 7.26 ppm was a characteristic of hydrogen
linked to nitrogen atom. The IR spectra of compounds
3f–h showed bands at 3019 cmꢀ1 due to C-H and a
characteristic carbonyl band at 1685 cmꢀ1. In the 13C-
NMR spectra, the signals observed in the region of δ
167.32–163.66 ppm accounted for the carbon of C=O.
The compound 3f was further characterized by X-ray
crystallography. The single crystal of 3f was obtained by
dissolving it in EtOAc, followed by slow evaporation at
room temperature. The diffraction data of 3f was
collected with a Rigaku RAXIS-RAPID area detector
using a graphite monochromated Mo Kα radiation
(λ = 0.71073 Å) at 293(2) K. The structure was solved
by direct methods using SHELXS-97 and refined by full
matrix least squares on F2, SHELXL-97 [18]. The
molecular structure of 3f was shown in Figure 1.
The bond distances of C(9)-N(1) and C(6)-N(1)
[1.358(3) and 1.429(3) Å, respectively] are shorter than
the standard C-N distance [C-N = 1.472 Å], which
indicates the existence of p-π conjunctive effect between
O(1), C(9), N(1), and benzene. The bond lengths of C(1)-
Table 2
Reaction condition and yields of product 3f–h.
Compound 3
Entry
R3
T (°C)
Time (h)
Yield (%)#
3f
3g
3h
-CHCl2
-CH2OPh
-CH2OCOCH3
25
25
25
2
2
2
33
37
72
Figure 1. Molecular structure for compound 3f. [Color figure can be
viewed at wileyonlinelibrary.com]
#Refers to yields of crude products only.
Journal of Heterocyclic Chemistry
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Y. Fu, K.-H. Yi, M.-Q. Li, J.-Y. Wang, Y.-F. Chen, and F. Ye
Vol 000
S(1) [1.764(3) Å] are also shorter than typical C-S bond
length [C-S 1.864 Å]. The presence of the
=
intermolecular hydrogen bond C(10)-H … S(1) leads to
the stability of the compound (Fig. 2). No significant π-π
and C-H … π interactions are found in the crystal structure.
Compound 3 were evaluated for their protection of
maize in vivo against the injury of chlorsulfuron at the
concentration of 2 μg/kg (Table 3). Compounds 3a–h
Figure 2. Packing view of the compound 3f. [Color figure can be viewed
at wileyonlinelibrary.com]
Table 3
, ,
Effect of detoxification of compounds 3a–h to growth index of maize a b c
.
Plant
Root
length
Plant
height
Root fresh
weight
fresh
weight
recovery
rate (%)
recovery
rate (%)
recovery
rate (%)
recovery
rate (%)
Compound
AD-67
3a
3b
3c
3d
3e
3f
3g
3h
32.66
8.41
3.70
17.17
13.80
39.73
35.02
1.68
81.62
38.97
24.63
37.87
43.01
84.93
18.93
83.82
59.01
81.25
6.25
12.50
68.75
50.00
6.25
25.00
18.75
18.75
89.47
5.26
15.79
131.58
5.26
63.16
52.63
21.05
10.53
2.69
aData are means of three replicates.
Treated with compounds-Treated with chlorsulfuron
Contrast-Treated with chlorsulfuron
bRecoveryRateð%Þ ¼
cWater treated was used as contrast.
Journal of Heterocyclic Chemistry
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Month 2018
Design, Synthesis, Safener Activity of Novel N-Substituted Thiazide/Thiazole
Derivatives
systematic review of the chemical characteristics
indicated that there is a close similar structural feature
between the herbicides and safeners [22]. For example,
dichlormid exhibited a remarkable degree of chemical
and botanical specificity in protection of maize against
thiocarbamates such as S-ethyl dipropylcarbamothioate
(EPTC). Many sulfamide compounds were also used as
antidote to sulfonylurea herbicides. According to these,
the physicochemical properties such as molecular weight;
partition coefficient value (log p), which indicates the
lipophilicity of the ligand; number of hydrogen bond
donor and hydrogen bond acceptor, total polar surface
area, number of rotatable bonds, and pKa were obtained
as shown in Table 4. It was observed that compound 3e
has the closest physicochemical properties to the
herbicide chlorsulfuron in all parts, which also verifies
the theory that the safener/herbicide combination is very
similar at the molecular level. In contrast, the undesirable
pKa makes it hard for compounds 3f–g to be absorbed by
plant tissues and difficult to exhibit biological activity.
The results are consistent with bioassay. As shown in
Figure 3, chlorsulfuron and 3e were perfectly aligned in a
common skeleton. Although the triazine and benzene ring
did not coincide completely, both of the aromatic rings
provided the similar substitution.
Figure 3. Superimposed molecular structures modeling. The structure of
chlorsulfuron was shown in red, and compound 3e was shown in blue.
[Color figure can be viewed at wileyonlinelibrary.com]
showed some recovery rate for plant height, plant fresh
weight, root length, and root fresh weight. Among all the
tested compounds, the compounds with sulfonyl group
(3a–e) led to better activity than benzothiazine
compounds (3f–h). Compound 3e showed the best
activity against the injury of chlorsulfuron, almost the
same level as the commercialized safener AD-67.
Herbicide and its safener may share common molecular
characteristics according to the structure–activity
relationships and mechanism of safeners [19–21]. A
Figure 4. The docking modeling of chlorsulfuron (A) and 3e (B) with ALS. Interactions: Green is convential hygrogen bond; White is C-H bond; Orange
is π-cation; Yellow is π-S interaction; Dark pink is π-π stacked; Pink is π-alkyl interaction. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Y. Fu, K.-H. Yi, M.-Q. Li, J.-Y. Wang, Y.-F. Chen, and F. Ye
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The compound 3e may bind with the herbicide target site
competitively and reduce the injury of chlorsulfuron. In
order to learn the possible interaction between compound
3e and the herbicide target, docking analysis was
performed at the active site of ALS using DS2.5. The
molecular docking result showed that both compound 3e
and chlorosulfuron could bind well to the herbicide target
active site of ALS (Fig. 4). In the docking modeling, the
phenyl moiety of chlorsulfuron rotated to the right side in
the active site, effectively blocking the entrance of channel
and preventing the substrate binding with active site,
played herbicidal activity. In contrast, the phenyl moiety of
compound 3e turned left in the active site, partially blocked
the entrance of the channel. While preventing the
combination of chlorosulfuron with active site, the small
substrate could have more opportunity to thrust itself into
this channel and catalyze active site. Meanwhile, the
energies of interaction between chlorsulfuron and 3e with
1YHY are 24.04 and 21.04 kcal/mol. This different
interaction between chlorosulfuron and 3e also contributed
to the explanation that compound 3e didn’t affect the
physiological process of maize while eliminate the injury
caused by chlorsulfuron.
coupling device area detector diffractometer. The spectro-
gram data of compounds could be found in Supporting
Information.
General procedure for docking. The three-dimensional
structure of compound 3e and chlorsulfuron was
constructed by the Sketch module of SYBYL-X 2.0.
Subsequently, the molecule was optimized, and
GasteigerꢀHuckel charges were calculated. The crystal
structure of ALS was taken from the Protein Data Bank
(PDB ID 1YHY). Docking modeling used the
“CDOCKER” method in Accelrys Discovery Studio 2.5.
Before docking, the protein structure was given the
CHARMm force field and removed the water and some
other co-crystallized small molecules. After the protein
preparation, the docking studies active site was defined,
with a subset region of 13.0 Å from the center of the
known ligand. The Top Hits set to 100, the remaining
parameters were used “CDOCKER” the default value.
The binding energy of the small molecule-receptor protein
complex was used as an evaluation index, with the largest
negative representation of the most stable conformation.
General procedure for the preparation of substituted
thiazole
derivatives
2a–d.
Mercaptoethylamine
hydrochloride (0.03 mol) was dissolved in anhydrous
MeOH (20 mL) in a round-bottomed flask, and ketone
(0.02 mol) was dropwise added into the solution. The
reaction mixture was stirred at room temperature for
24 h. The reaction mixture was quenched with cold
K2CO3 aq. and extracted with CH2Cl2 and filtered. The
organic layer was dried over anhydrous Na2SO4, and
CH2Cl2 was evaporated under vacuum. The crude
products were obtained without further purified.
CONCLUSIONS
A series of novel substituted thiazide/thiazole were
synthesized via cyclization acylation and carbamylation.
All the synthesized compounds displayed good safener
activity to chlorsulfuron, especially compound 3e was
almost the same level as the commercial safener AD-67.
Molecular structure comparison and molecular docking
gave the possible detoxification mechanism of these
compounds. The results suggested that compound 3e
might be a lead compound for design novel safener.
General procedure for the preparation of benzothiazine
derivatives 2e. o-Aminothiophenol (0.04 mol) and 1,2-
dibromoethane (0.06 mol) were mixed in a round-
bottomed flask and 20-mL dimethylformamide as solvent.
The reaction mixture was stirred under nitrogen
atmosphere at 60°C. Then, 10-mL Et3N was dropwise
added into the solution. The resulting solution was
refluxed for 10–12 h. Then, the reaction mixture was
extracted with EtOAc and filtered. The organic layer was
dried over anhydrous Na2SO4, and EtOAc was
EXPERIMENTAL
All the reagents were analytical grade and were used
without further purification. The IR spectra were recorded
on a Bruker ALPHA-T spectrometer (KBr, BRUKER
Inc., Beijing, China). The 1H-NMR and 13C-NMR spectra
were recorded on a Bruker AVANVE 300 MHz
(BRUKER Inc., Beijing, China) and a Bruker AVANVE
600 MHz (BRUKER Inc., Beijing, China) using CDCl3
or DMSO-d6 as solvent and tetramethylsilane as internal
standard. The melting point was measured on a Beijing
Taike melting point apparatus (X-4) (Beijing, China) and
was uncorrected. The high-resolution mass spectrometry
was recorded on a FT-ICR MS spectrometer (BRUKER
Inc., Beijing, China). Crystallographic data of the com-
pound were mounted on a Rigaku RAXIS-RAPID charged
evaporated
under
vacuum.
The
intermediate
benzothiazine was distilled under reduced pressure.
General procedure for the preparation of sulfonylurea
thiazole/benzothiazine derivatives 3a–e. The intermediate
2a–e (5 mmol) was mixed with tosyl isocyanate
(5 mmol) in round bottomed flask with anhydrous
benzene. The mixture was vigorously stirred at 10°C for
12 h. At the end of the reaction, solid was precipitated.
Then, the solid was washed with the mixed solution of
anhydrous benzene and n-hexane [V (anhydrous
benzene):
V (anhydrous n-hexane) = 1:1] to get
compounds 3a–e.
Journal of Heterocyclic Chemistry
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Month 2018
Design, Synthesis, Safener Activity of Novel N-Substituted Thiazide/Thiazole
Derivatives
2,2-Dimethyl-N-[(p-methylphenyl)sulfonyl]-thiazolidine-3-
formamide (3a).
2.45 (s, 3H). 13C-NMR (75 MHz, CDCl3, ppm): δ: 149.38,
144.93, 135.93, 135.09, 130.18, 129.62, 128.53, 128.53,
128.39, 128.39, 127.48, 124.99, 41.55, 28.33, 21.77. HRMS
(ESI): m/z calcd for C24H24N2NaO3S2 ([M + Na]+) 371.0602
found 371.0494.
White solid. Yield 76%. m.p. 147–
149°C. IR (KBr, cmꢀ1) ν: 3310 (N-H), 2970 (C-H), 1701
(C=O), 1347, 1164 (O=S=O). 1H-NMR (600 MHz,
DMSO-d6, ppm): δ: 7.79–7.38 (m, 4H), 7.26 (s, 1H), 3.82
(t, J = 6.0 Hz, 1H), 3.23 (t, J = 6.0 Hz, 1H), 3.00 (t,
J = 6.0 Hz, 1H), 2.95 (t, J = 6.0 Hz, 1H), 2.38 (d,
J = 8.4 Hz, 1H), 1.59 (s, 3H), 1.49(s, 3H). 13C-NMR
(150 MHz, DMSO-d6, ppm): δ: 141.82, 141.42, 129.27,
129.27, 127.32, 125.59, 125.59, 52.60, 31.09, 28.30,
28.27, 27.04, 20.89. HRMS (ESI): m/z calcd for
General procedure for the preparation of acylation
benzothiazine derivatives 3f–h.
The intermediate 2e
(4 mmol), anhydrous Na2CO3 (3 mmol), and 10-mL
benzene were mixed. Acyl chloride (4.8 mmol) was added
dropwise at room temperature. The mixture was stirred for
1–2 h, washed with saturated NaCl, and then dried over
anhydrous MgSO4. Benzene was evaporated under vacuum.
C13H18N2O3S2 ([M + H]+) 315.0759 found 315.0836.
2-Ethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-thiazolidine-
The pure products were obtained by recrystallization.
N-Dichloroacetyl-3,4-dihydro-2H-1,4-benzothiazine (3f).
3-formamide (3b).
White solid. Yield 74%. m.p. 167–
169°C. IR (KBr, cmꢀ1) ν: 3321 (N-H), 2934 (C-H), 1696
(C=O), 1368, 1163(O=S=O). 1H-NMR (600 MHz,
CDCl3, ppm): δ: 7.94–7.33 (m, J = 8.4 Hz, 4H), 3.84–
3.80 (m, 1H), 3.75–3.71 (m, 1H), 2.96–2.86 (m, 2H),
2.45 (s, 3H), 2.19–2.05 (m, 1H), 1.85–1.91 (m, 1H), 1.68
(s, 3H), 0.79 (s, 3H). 13C-NMR (150 MHz, CDCl3,
ppm): δ: 148.04, 144.48, 136.43, 129.54, 129.54, 128.08,
128.08, 77.18, 52.87, 32.19, 27.66, 27.48, 21.66, 9.56.
HRMS (ESI): m/z calcd for C14H20N2O3S2 ([M + H]+)
Yellow solid. Yield 33%. m.p. 139–141°C. IR (KBr,
cmꢀ1) ν: 3019 (C-H), 1685 (C=O), 1475–1315 (C=C). 1H-
NMR (300 MHz, CDCl3, ppm): δ: 7.33–7.15 (m, 4H),
6.40(s, 1H), 4.14–3.27 (m, 4H). 13C-NMR (75 MHz,
CDCl3, ppm): δ: 163.66, 136.12, 130.83, 128.29, 128.06,
125.41, 124.84, 63.59, 42.95, 28.01. MS (ESI): m/z calcd
for C10H9Cl2NOS ([M + H]+) 261.9855 found 261.9852.
Crystal data for compound 3f. C10H9Cl2NOS, monoclinic,
space group P21/c, a = 8.9954(18) Å, b = 12.302(3) Å,
c = 10.472(2) Å, V = 1101.7(4) Å3, β = 108.07(3), Z = 4,
Dc = 1.580 g/cm3, μ = 0.748 mmꢀ1, F(000) = 536.
Independent reflections were obtained in the range of
3.10 < θ < 24.97°, 7979. The final least-square cycle gave
R1 = 0.0384, ωR2 = 0.0919 for 1900 reflections with
I > 2σ(I). The maximum and minimum differences of peak
and hole are 0.930 and ꢀ0.606 e/Åꢀ3, respectively.
Crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC1856303. These data can be obtained free of
charge from The Cambridge Crystallographic Data via
329.0915 found 329.0990.
2-Phenylethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-1,3–
benzothiazoline-3-formamide (3c).
White solid. Yield
56%. m.p. 143–145°C. IR (KBr, cmꢀ1) ν: 3346 (N-H),
2928 (C-H), 1694 (C=O), 1363, 1164 (O=S=O). 1H-
NMR (600 MHz, CDCl3, ppm): δ: 8.17 (s, 1H), 7.97–
6.90 (m, 9H), 3.88–3.84 (m, 1H) 3.74 (q, J = 7.8 Hz,
1H), 3.04–2.99 (m, 1H), 2.96–2.92 (m, 1H), 2.67–2.63
(m, 1H), 2.49–2.44 (m, 1H), 2.40 (s, 3H), 2.12–2.17
(m, 1H), 2.02–1.97 (m, 1H), 1.73 (s, 3H). 13C-NMR
(150 MHz, DMSO-d6, ppm): δ: 148.06, 144.63, 141.40,
136.33, 129.59, 129.59, 128.46, 128.46, 128.20,
128.20, 126.46, 125.75, 125.75, 76.10, 52.80, 41.01,
31.62, 28.46, 27.63, 21.65. HRMS (ESI): m/z calcd for
www.ccdc.cam.ac.uk/data_request/cif.
N-Phenoxyacetyl-3,4-dihydro-2H-1,4-benzothiazine (3g).
Yellow solid. Yield 37%. m.p. 125–127°C. IR (KBr,
cmꢀ1) ν: 3050 (C-H), 1665 (C=O), 1599–1397 (C=C).
1H-NMR (300 MHz, CDCl3, ppm): δ: 7.31–6.80 (m,
9H), 4.75 (s, 2H), 4.03 (s, 2H), 3.23 (t, J = 6.0 Hz, 2H).
13C-NMR (75 MHz, CDCl3, ppm): δ: 167.32, 157.81,
136.66, 129.92, 129.51, 129.51, 127.82, 127.31, 125.47,
124.91, 121.61, 114.63, 114.63, 66.30, 41.84, 28.41.
HRMS (ESI): m/z calcd for C16H15NO2S ([M + H]+)
286.0823 found 286.0898.
C20H24N2O3S2 ([M + H]+) 405.1228 found 405.1302.
N-tosyl-1-thia-4-azaspiro[4.5]decane-4-formamide (3d).
White solid. Yield 85%. m.p. 162–164°C. IR (KBr, cmꢀ1
)
ν: 3265 (N-H), 2937 (C-H), 1694 (C=O), 1363, 1164
1
(O=S=O). H-NMR (600 MHz, DMSO-d6, ppm): δ: 7.71–
7.36 (m, 4H), 7.26 (s, 1H), 3.16 (t, J = 6.0 Hz, 2H), 2.79
(t, J = 6.0 Hz, 2H), 2.37(s, 3H), 1.76–1.74 (m, 2H), 1.68–
1.64 (m, 2H), 1.51–1.45 (m, 2H), 1.41–1.37 (m, 2H),
1.27–1.24 (m, 2H). 13C-NMR (150 MHz, DMSO-d6,
ppm): δ: 141.81, 141.43, 129.27, 129.27, 125.59, 125.59,
124.18, 82.44, 50.21, 34.68, 25.03, 25.03, 24.42, 24.42,
20.89, 20.89. HRMS (ESI): m/z calcd for C16H22N2O3S2
N-Acetoxyacetyl-3,4-dihydro-2H-1,4-benzothiazine (3h).
Yellow solid. Yield 72%. m.p. 107–108°C. IR (KBr,
cmꢀ1) ν: 3020–2932 (C-H), 1739 (C=O), 1586–1368
1
(C=C). H-NMR (300 MHz, CDCl3, ppm): δ: 7.29–7.08
([M + H]+) 355.1144 found 355.1144.
(m, 4H), 4.73 (s, 2H), 3.99 (s, 2H), 3.24 (t, J = 6.0 Hz,
2H), 2.14 (s, 2H). 13C-NMR (75 MHz, CDCl3, ppm): δ:
170.62, 166.42, 136.17, 129.95, 127.81, 127.33, 125.54,
124.84, 61.88, 47.72, 28.17, 20.56. HRMS (ESI): m/z
calcd for C12H13NO3S ([M + H]+) 274.0616 found
274.0513.
N-[(p-Methylphenyl)sulfonyl]-2,3-dihydro-4H-1,4-benzothiazine-
4-formamide (3e). White solid. Yield 62%. m.p. 162–164°C.
IR (KBr, cmꢀ1) ν: 3236 (N-H), 3066 (C-H), 1693 (C=O),
1334, 1159 (O=S=O). 1H-NMR (300 MHz, CDCl3, ppm): δ:
7.96–7.18 (m, 8H), 3.86 (s, 2H), 3.11 (t, J = 6.4 Hz, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Fu, K.-H. Yi, M.-Q. Li, J.-Y. Wang, Y.-F. Chen, and F. Ye
Vol 000
[11] Wang, P. Y.; Chen, L.; Zhou, J.; Fang, H. S.; Wu, Z. B.; Song,
B. A.; Yang, S. J. Chem Soc 2017, 21, 315.
[12] Chen, J. L.; Tang, W.; Che, J. Y.; Chen, K.; Yan, G.; Gu, Y.
C.; Shi, D. Q. J Agric Food Chem 2015, 63, 7219.
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[15] Fu, Y.; Kang, J. X.; Wang, Y. K.; Liu, J.; Zhao, L. X.; Gao, S.;
Ye, F. Heterocycles 2016, 92, 740.
Acknowledgments. This work was supported by the National
Nature Science Foundation of China (31572042), the National
Nature Science Foundation of Heilongjiang Province
(ZD2017002), and the Research Science Foundation in Technol-
ogy Innovation of Harbin (2015RAXXJ032). The authors are
grateful to Prof. Jia-Zhong Li (Lanzhou University) for assistance
with molecular docking analyses.
[16] Ye, F.; Wu, S. L.; Zhao, L. X.; Qu, H. T.; Gao, S.; Fu, Y. Het-
erocycles 2015, 91, 1256.
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