Solvent-free synthesis and safener activity of sulfonylurea benzothiazolines

Article abstract of DOI:10.3390/molecules22101601

A series of novel sulfonylurea benzothiazolines was designed by splicing active groups and bioisosterism. A solvent-free synthetic route was developed for the sulfonylurea benzothiazoline derivatives via the cyclization and carbamylation. All compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, HRMS. The biological activity tests indicated the compounds could protect maize against the injury caused by chlorsulfuron to some extent. The molecular docking result showed that the new compound competed with chlorsulfuron to bind with the herbicide target enzyme active site to attain detoxification.

Full text of DOI:10.3390/molecules22101601

molecules
Article
Solvent-Free Synthesis and Safener Activity of
Sulfonylurea Benzothiazolines
ID
Ying Fu , Jing-Yi Wang, Dong Zhang, Yu-Feng Chen, Shuang Gao, Li-Xia Zhao and Fei Ye *
Department of Applied Chemistry, College of Science, Northeast Agricultural University, Harbin 150030, China;
fuying@neau.edu.cn (Y.F.); wang-jingyi@foxmail.com (J.-Y.W.); zhangdong-qlc@163.com (D.Z.);
cyf1989919@163.com (Y.-F.C.); gaoshuang@neau.edu.cn (S.G.); zhaolixia@neau.edu.cn (L.-X.Z.)
*
Correspondence: yefei@neau.edu.cn; Tel.: +86-451-5519-1507
Received: 19 August 2017; Accepted: 21 September 2017; Published: 22 September 2017
Abstract: A series of novel sulfonylurea benzothiazolines was designed by splicing active groups
and bioisosterism. A solvent-free synthetic route was developed for the sulfonylurea benzothiazoline
1
derivatives via the cyclization and carbamylation. All compounds were characterized by IR, H-NMR,
13
C-NMR, HRMS. The biological activity tests indicated the compounds could protect maize against
the injury caused by chlorsulfuron to some extent. The molecular docking result showed that the
new compound competed with chlorsulfuron to bind with the herbicide target enzyme active site to
attain detoxification.
Keywords: active subunit combination; sulfonylurea benzothiazoline; solvent-free synthesis;
safener activity
1
. Introduction
Sulfur and nitrogen-containing heterocyclic compounds play a key role in the pharmaceutical
and chemical industries [
in the agricultural field. Several new benzothiazole compounds have been synthesized as potential
antimicrobial and antiparasitic agents [ ]. 1,2-Benzisothiazolin-3-one, used as a fungicide, shows good
1,2]. In particular, sulfur-containing heterocyclic compounds are widely used
3
sterilization and anti-corrosion performance [4]. Thiazole compounds are also reported to be herbicide
safeners [5].
Some bioactive compounds have been discovered by combining active subunits of known active
molecules. For example, new triketone derivatives with better herbicidal activity have been designed
by splicing active group alloxydim-sodium into quizalofop-ethyl (Scheme 1) [6]. Many successful
cases have been reported in recent years [7,8].
Scheme 1. The exploitation of the new herbicide.
Molecules 2017, 22, 1601; doi:10.3390/molecules22101601
www.mdpi.com/journal/molecules

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Herbicides and safeners may share common molecular characteristics, depending on the
structure-activity relationships (SAR) and the mechanisms of the safeners [ ]. A systematic review
9
of the chemical characteristics and SAR of herbicide safeners indicated that there are closely similar
structural features between herbicides and safeners [10]. For example, sulfamide compounds may be
an antidote to protect plants from the injury caused by sulfonylurea herbicides.
According to the facts mentioned above, and continuing on from our previous research, a series
of sulfonylurea substituted benzothiazoline compounds 3a–3m was designed based on active subunit
combination, bioisosteric replacement, and SAR; the sulfur- and nitrogen-containing heterocyclic was
retained and modified on the sulfonylurea functional groups (Scheme 2) [11–13].
O
Benoxacor
N
union of active group
COCHCl2
X
O
S
O
C
bioisosterism
replacement
S
O
S
O
C
N
N
N
S
N
N
N
Y
O H
N
H
O H
H
R1 R2
O
R-28725
The basic structure of
sulfonylurea compounds
N
target molecule
COCHCl2
Herbicide
Safener
Scheme 2. The design of the target compounds.
A number of synthetic routes for benzothiazoline have been reported. The most common
method is the condensation of o-aminothiophenol with carbonyl compounds in the presence of
p-toluenesulfonic acid with Ga(OTf) as catalyst [14
,15]. Other methods include the reaction of
3
2
,2’-dinitrodiphenyl disulfide with ketones in the presence of TiCl /Sm and SmI /HMPA [16 17].
,
4
2
Nevertheless, all these reported methods suffer from some drawbacks, such as the use of expensive or
toxic catalysts, long reaction times, tedious synthetic procedures, or low yields of the products. In recent
years, solvent-free organic synthesis has become a popular method, and has attracted immense interest
as an environmentally benign method. It leads to good yields, clean reactions, and shorter reaction
times [18]. In view of the facts mentioned above, a series of novel sulfonylurea benzothiazoline was
designed and synthesized with o-aminothiophenol and ketone as starting materials in the presence of
neutral alumina via a solvent-free procedure (Scheme 3) [19].
Scheme 3. Route for synthesis of the target compounds 3.
2
. Results and Discussion
2
.1. Chemistry
1,3-Benzothiazoline derivatives
2 were synthesized with o-aminothiophenol and ketone 1
smoothly in the presence of neutral alumina. All compounds were synthesized under solvent-free

Molecules 2017, 22, 1601
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conditions and further purified by column chromatography (silica gel, petroleum ether (PE):ethyl
acetate; 20:1) to give the pure product.
The yields of compounds
significantly. When the substituents were cyclopentyl or cyclohexyl, the formation of spiro compounds
made the structure more stable than others. Thus, the yields of 2l 2m were better, at 91% and 92%,
2 were 56–92% (Table 1). The substituent group affected the yields
,
respectively. The bulk substituent reduced the stability of the benzothiazoline. The yield of 2k was
only 56% which might be caused by the R and R being two n-propyl groups. The yields were similar
1
2
for 2f and 2g.
Table 1. Characterization data, reaction condition and yields for products 2 and 3.
Compound 2
Compound 3
Entry
R1
R2
◦
Yield (%) #
◦
Yield (%) #
T ( C)
Time (h)
T ( C)
Time (h)
a
b
c
d
e
f
g
h
i
j
k
l
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
r.t.
r.t.
r.t.
80
0.5
0.5
0.5
1
3
2
82
83
92
84
78
76
76
80
86
82
56
91
92
12
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
36
12
5
12
5
5
12
10
10
12
2
12
5
4
12
12
96
65
78
70
55
50
36
59
95
40
82
95
99
CH CH
2
3
CH CH CH
2
2
3
CH(CH3)2
CH COCH
50
2
3
CH CH CH CH
r.t.
r.t.
88
r.t.
r.t.
80
2
2
2
3
CH CH(CH )
0.5
1
2
3 2
C(CH3)3
PhCH CH
0.5
0.5
0.5
0.5
0.5
2
2
CH CH
CH CH
2
3
2 3
CH CH CH
CH CH CH
3
4
12
12
2
2
3
2
2
(CH2)4
(CH2)5
r.t.
r.t.
m
#
Refers to yields of crude products only; r.t.: Room temprature.
The proposed outline for the cyclization is outlined in Scheme 4. First, o-aminothiophenol reacted
with ketone to generate a Schiff base. Nucleophilic attack from nearby S atom gave the intermediate
2.
NH2
SH
N
NH
O
R1
R1
-
H O
2
C
R1
R2
R
2
S
R2
SH
1
2
Scheme 4. Mechanistic outline for cyclization reaction.
The target compounds
derivatives and tosyl isocyanate. All compounds were obtained by washing the mixture with the
solution (anhydrous benzene:Anhydrous n-hexane; 1:1) to get white powder.
The yields of compounds were 36%–99% (Table 1). When the substituents were symmetric small
3 were synthesized by direct carbamylation with 1,3-benzothiazoline
2
3
groups or cyclic structures, the yield was good. Compounds 3a, 3l, 3m were over 90% yields.
In general, there was no significant effect on the yields of the target products caused by steric
hindrance, because the substituents at the 2-position were almost perpendicular to the plane of
benzothiazoline ring. Comparing compound 3f and 3g, it was also noticeable that the presence of a
straight-chain at the 2-position of benzothiazoline increased the yield. In contrast, the yields were
decreased when there was a branch-chain with the same carbon atom number.
−
1
The peaks at 1708, 1341 and 1152 cm in the IR for compound 3a confirmed the presence of the
1
carbonyl and sulfonyl groups. The H-NMR spectrum also confirmed the proposed structure, the three
hydrogens at
δ
2.37–2.41 ppm showed the methyl of the benzene ring. The signals at
δ
6.48–7.85 ppm
related to the benzene ring. The single signal observed at
linked to a nitrogen atom.
δ 11.86 ppm was characteristic of hydrogen

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2
.2. Biological Activity
All the novel sulfonylurea benzothiazoline derivatives
3
were evaluated for their protection
of maize against the injury of chlorsulfuron (2
µg/kg) (Table 2). After a preliminary screening,
the concentration of the safener and compounds applied in the bioassay was determined. Chlorsulfuron
could provoke an obvious decrease in the growth of maize, but significant differences were observed
after the introduction of compounds. The recovery rates of the root length were attained over 25%
except for compounds 3e, 3j. Recovery rates of plant weight were over 40%, except for compound 3e.
Among all the test compounds, compound 3c showed the best safener activity against the injury of
chlorsulfuron, better than the commercialized safener AD-67. A good protection activity may be due
to the introduction of a sulfonyl group, causing the compound to bind with the herbicide target site
competitively, and reduce the injury of chlorsulfuron.
Table 2. Effect of detoxification of compounds 3a–m to growth index of maize i, ii, iii, iv
.
Root Length
Recovery Rate (%)
Plant Height
Recovery Rate (%)
Root Fresh Weight
Recovery Rate (%)
Plant Fresh Weight
Recovery Rate (%)
Compound
AD-67
32.66 efg
81.62
de
81.25 b
89.47 c
cde
f
h
ef
3a
38.05
35.02
68.57
37.50
43.75
87.50
6.25
56.25
12.50
37.50
87.50
57.89
def
54.41 g
g
21.05 h
3b
a
a
b
a
3
c
55.89
109.56
100.92
20.59
91.73b
126.31
bc
ab
m
f
3d
42.76
52.63
19.87 i
i
e
42.11 g
3
e
a
cd
l
d
3
f
56.23
73.68
84.21
gh
de
h
c
3
g
27.95
81.86
72.24
84.01
73.35
45.12 b
ef
b
105.26
110.53
b
3h
efg
cd
i
b
3
i
32.66
31.25
ij
ef
a
ef
3
j
18.18
31.31
156.25
57.89
57.89
84.21
fg
40.26 h
h
ef
3
k
37.50
18.75
12.50
efg
cd
k
c
3
l
33.00
89.34
92.65
h
bc
l
110.53 b
3m
25.93
i
Data are means of three replicates; ii Recovery Rate (
Treated with compounds − Treated with chlorsulfuron
; iii Water
%
) =
Contrast − Treated with chlorsulfuron
treated was used as contrast; iv Small letter is significant at the 0.05 level.
a
Comparing the chemical properties of compound 3c and chlorsulfuron, such as log p, pK ,
molecular weight (MW) and electronegativity, with a view to proving the hypothesis that safeners
may act as competitive antagonists for herbicides at the herbicide target site (Table 3), it was observed
a
that pK , MW and the electronegativity of compound 3c were all similar to the herbicide chlorsulfuron.
This indicated that, in terms of the investigated features, the safener/herbicide combinations were
quite similar at the molecular level. The visual evaluation of the superimposed molecular structures is
shown in Figure 1. Chlorsulfuron and 3c were perfectly aligned in a common skeleton.
Figure 1. Superimposed molecular structure modeling. The structure of chlorsulfuron is shown in red,
and compound 3c is shown in blue.

Molecules 2017, 22, 1601
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Table 3. Chemical property comparisons of chlorsulfuron with 3c.
pKa b
Electronegativity c
Compounds
log p a
MW
Chlorsulfuron
2.63
4.1 ± 0.4
357.77
3
c
4.85
4.6 ± 0.4
390.52
a
The log p was predicted by ChemBioOffice 2014; b The pK
was predicted by ACD/lab; c The Electronegativity
a
was predicted by Sybyl-X 2.0 (Tripos Inc., St. Louis, MO, USA).
Sulfonylurea herbicides are a kind of acetolactate synthase (ALS) inhibitors. The three-dimensional
structure of compound 3c and chlorsulfuron was constructed by the sketch module of SYBYL-X 2.0.
Subsequently, the molecule was optimized and Gasteiger-Huckel 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 (Accelrys Inc., San Diego, CA, USA, 2005).
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 13.0A from the center of the known ligand. The Top Hits
was set to 100, and the default values were used for the remaining parameters. 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. The molecular docking result showed that
both compound 3c and chlorsulfuron were able to bind well to the herbicide target active site of ALS
(
Figure 2). In the docking modeling, the phenyl moiety of chlorsulfuron rotated to the right side in the
active site, effectively blocking the entrance to the channel and preventing the substrate from binding
with the active site, caused herbicidal activity. In contrast, the phenyl moiety of compound 3c turned
left at the active site, partially blocking the entrance of the channel. While preventing the combination
of chlorsulfuron with the active site, the small substrate had more opportunity to thrust itself into the
channel and catalyze the active site.
When compound 3c was applied before or simultaneously with chlorsulfuron, it potentially
competed with chlorsulfuron at the target site by preventing the herbicide from reaching or acting
on the ALS active pocket, leading to counter action of the herbicide. This may be the detoxification
mechanism of the novel compound.
Figure 2. The docking modeling of chlorsulfuron (
in green ( ) and light blue ( ), the sulfur atoms are shown in yellow, the oxygen atoms are shown in
red, and the nitrogen atoms are shown in blue.
A) and 3c (B) with ALS. The carbon atoms are shown
A
B

Molecules 2017, 22, 1601
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3
. Materials and Methods
3
.1. Reagents and Analysis
All the reagents were analytical grade, and were used without further purification. The IR spectra
1
were recorded on a Bruker ALPHA-T spectrometer (BRUKER Inc., Beijing, China). The H-NMR and
13
C-NMR spectra were recorded on a Bruker AVANVE 300 MHz (BRUKER Inc., Beijing, China) using
CDCl (Energy Chemical., Shanghai, China) or DMSO-d (Energy Chemical., Shanghai, China) as
3
6
solvent and TMS (Energy Chemical., Shanghai, China) 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). The spectrogram datas of compounds could be found in the Supplementary Materials.
3
.2. General Procedure for the Preparation of 1,3-Benzothiazoline Derivatives 2
o-Aminothiophenol (0.03 mol) and ketone (0.02 mol) were mixed in a round-bottomed flask in
the presence of neutral alumina (3 g). The reaction mixture was stirred under nitrogen atmosphere at
appropriate temperature for a period of time. The reaction mixture was extracted with chloroform
and filtered. The organic layer was dried over anhydrous Na SO and chloroform was evaporated
2
4
under vacuum. The pure products were obtained by recrystallization (2a
, 2e, 2i, 2l–2m) or column
chromatography on silica gel eluting with PE and EtOAc (20:1) (2b–2d, 2f–2h, 2j–2k).
/cm 1) 3334 (N-H), 2961–2917 (C-H),
−
2
,2-Dimethylbenzothiazoline (2a): White solid, Yield 82%. IR (KBr,
ν
1
1581–1363 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.67–7.10 (m, 4H), 3.97 (s, 1H), 1.74 (s, 6H).
C-NMR (75 MHz, CDCl ): δ (ppm) 145.9, 128.5, 125.1, 122.2, 121.1, 111.5, 74.8, 31.7, 31.7.
3
13
3
/cm 1) 3353 (N-H),
−
2
3
-Ethyl-2-methyldihydro-benzothiazoline (2b): Yellow liquid, Yield 83%. IR (KBr,
ν
1
086–2875 (C-H), 1581–1375 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.60–7.05 (m, 4H), 3.89 (s, 1H),
.80–2.02 (m, 2H), 1.66 (s, 3H), 1.02–1.06 (t, J = 7.5 Hz, 3H). 13C-NMR (75 MHz, CDCl3):
δ (ppm) 146.2,
3
1
1
27.7, 125.0, 122.0, 129.5, 110.8, 78.9, 38.9, 29.6, 9.8.
−
2
-Methyl-2-propylbenzothiazoline (2c): Yellow liquid, Yield 92%. IR (KBr,
ν
/cm 1) 3353 (N-H), 3067–2871
1
(
(
(
C-H), 1583–1395 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.62–7.06 (m, 4H), 3.85 (s, 1H), 1.80–1.98
m, 2H), 1.68 (s, 3H), 1.44–1.58 (m, 2H), 0.94–0.99 (t, J = 7.5 Hz, 3H). C-NMR (75 MHz, CDCl3):
3
1
3
δ
ppm) 146.0, 127.9, 124.9, 121.9, 120.6, 110.9, 78.2, 46.4, 30.0, 18.8, 14.2.
−
2
3
(
-Isopropyl-2-methylbenzothiazoline (2d): Yellow liquid, Yield 84%. IR (KBr,
ν
/cm 1) 3348 (N-H),
1
068–2869 (C-H), 1583–1373 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.61–7.07 (m, 4H), 3.95
(ppm)
3
1
3
s, 1H), 2.13–2.22 (m, 1H), 1.66 (s, 3H), 1.05–1.11 (q, J = 6.6 Hz, 6H). C-NMR (75 MHz, CDCl3):
δ
1
46.4, 127.0, 124.9, 121.8, 120.1, 110.2, 82.6, 39.9, 27.1, 19.0, 18.2.
−
2
3
(
-(Acetonyl)-2-methylbenzothiazoline (2e): Transparent crystal, Yield 78%. IR (KBr,
ν
/cm 1) 3334 (N-H),
1
070–2969 (C-H), 1580–1338, 1706 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.52–6.95 (m, 4H), 6.42
(ppm)
3
s, 1H), 3.14–3.21 (q, J = 17.4 Hz, 2H), 2.12 (S, 3H), 1.619 (s, 3H). 13C-NMR (75 MHz, CDCl3):
δ
2
06.1, 145.9, 125.2, 124.9, 121.1, 118.2, 108.8, 74.3, 55.8, 30.8, 29.5.
−
2
-Butyl-2-methylbenzothiazoline (2f): Yellow liquid, Yield 76%. IR (KBr,
ν
/cm 1) 3349 (N-H), 3068–2859
1
(
C-H), 1583–1374 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.64–7.08 (m, 4H), 4.02 (s, 1H), 1.83–1.98
m, 2H), 1.70 (s, 3H), 1.31–1.54 (m, 4H), 0.92–0.96 (t, J = 7.2 Hz, 3H). C-NMR (75 MHz, CDCl3):
3
13
(
δ (ppm) 145.9, 127.8, 125.0, 122.0, 120.7, 110.9, 78.4, 73.8, 30.0, 27.7, 22.9, 14.1.
/cm 1) 3357 (N-H), 2967
−
2
-Isobutyl-2-methylbenzothiazoline (2g): Yellow liquid, Yield 76%. IR (KBr,
ν
1
(
C-H), 1582–1391 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.64–7.08 (m, 4H), 3.88 (s, 1H), 1.84–1.98
(ppm) 145.7, 128.1,
3
1
3
(
1
m, 3H), 1.70 (s, 3H), 1.02–1.04 (d, J = 6.3 Hz, 6H). C-NMR (75 MHz, CDCl3):
25.0, 122.0, 120.6, 111.0, 78.4, 52.1, 30.5, 25.6, 21.5, 21.0.
δ

Molecules 2017, 22, 1601
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/cm 1) 3362 (N-H),
−
2
-tert-Butyl-2-methyl benzothiazoline (2h): Yellow liquid,Yield 80%. IR (KBr,
ν
1
3
068–2871 (C-H), 1582–1385 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.59–7.06 (m, 4H), 3.96 (s, 1H),
(ppm) 146.7, 126.5, 124.8, 121.5, 119.7, 109.5,
3
1
8
.74 (s, 3H), 1.14 (s, 9H). 13C-NMR (75 MHz, CDCl3):
δ
5.7, 39.9, 27.1, 26.3, 26.3, 26.3.
−
2
3
2
-Methyl-2-phenethylbenzothiazoline (2i): Transparent crystal, Yield 86%. IR (KBr,
ν
/cm 1) 3353 (N-H),
1
060–2856 (C-H), 1602–1375 (C=C). H-NMR (300 MHz, CDCl ):
δ
3
(ppm) 6.66–7.38 (m, 9H), 3.90 (s, 1H),
.89–2.94 (t, J = 6.6 Hz, 2H), 2.22–2.30 (m, 2H), 1.82 (s, 3H). C-NMR (75 MHz, CDCl3):
3
1
δ (ppm)
1
46.1,141.7, 128.5, 128.5, 128.5, 128.5, 127.5, 126.0, 125.1, 122.0, 120.7, 110.8, 76.7, 45.9, 31.9, 30.3.
−
2
,2-Diethylbenzothiazoline (2j): Yellow liquid, Yield 82%. IR (KBr,
ν
/cm 1) 3371 (N-H), 3068–2930 (C-H),
1
1583–1398 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.59–7.05 (m, 4H), 3.89 (s, 1H), 1.88–1.95 (q,
(ppm) 146.7, 127.1, 124.8,
3
3
J = 7.5 Hz ,4H), 1.01–1.06 (t, J = 7.5 Hz, 6H). 1 C-NMR (75 MHz, CDCl3):
δ
1
21.7, 120.0, 109.9, 82.7, 34.5, 34.5, 9.2, 9.2.
−
2
,2-Dipropylbenzothiazoline (2k): Yellow liquid, Yield 56%. IR (KBr,
ν
/cm 1) 3370 (N-H), 3068–2871
1
(
C-H), 1583–1397 (C=C). H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.59–7.05 (m, 4H), 3.94 (s, 1H), 1.85–1.90
t, J = 7.8 Hz, 3H), 1.41–1.63 (m, 4H), 0.95–1.00 (t, J = 7.5 Hz, 6H). C-NMR (75 MHz, CDCl ):δ (ppm)
3
13
(
3
1
46.5, 127.3, 124.9, 121.7, 120.1, 110.0, 81.5, 44.7, 44.7, 18.2, 18.2, 14.3, 14.3.
−
3
3
4
H-spiro[1,3-benzothiazoline-2,1’-cyclopentane] (2l): Transparent crystal, Yield 91%. IR (KBr,
ν
/cm 1)
1
354 (N-H), 3066–2871 (C-H), 1581–1320 (C=C). H-NMR (300 MHz, CDCl ):
δ (ppm) 6.64–7.08 (m,
3
H), 4.00 (s, 1H), 2.16–2.25 (m, 2H), 1.99–2.08 (m, 2H), 1.77–1.82 (m, 4H). 13C-NMR (75 MHz, CDCl3):
δ
(ppm) 145.9, 128.1, 125.0, 121.8, 129.7, 110.9, 84.2, 42.5, 42.5, 22.9, 21.9.
/cm 1)
−
3
3
3
H-spiro[1,3-benzothiazoline-2,1’-cyclohexane] (2m): Transparent crystal, Yield 92%. IR (KBr,
ν
1
329 (N-H), 3063–2863 (C-H), 1579–1443 (C=C). H-NMR (300 MHz, CDCl ):
δ (ppm) 6.64–7.06 (m, 4H),
.94 (s, 1H), 2.20–2.24 (d, J = 12.6 Hz, 2H), 1.53–1.81 (m, 7H), 1.23–1.36 (m, 1H). C-NMR (75 MHz,
3
13
CDCl ): δ (ppm) 145.9, 127.1, 125.0, 121.9,120.5, 110.9, 80.0, 40.9, 40.9, 25.0, 24.0, 24.0.
3
3
.3. General Procedure for the Preparation of Sulfonylurea Benzothiazoline Derivatives 3
The intermediate
2
(5 mmol) was mixed with tosyl isocyanate (5 mmol) in a round-bottomed flask.
◦
The mixture was vigorously stirred at 10 C for 12 h. At the end of the reaction, a solid precipitated.
Then, the solid was washed with the mixed solution of anhydrous benzene and n-hexane to get
compounds 3.
2
,2-Dimethyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3(2H)-formamide (3a): White solid, Yield
◦
−1
9
6%, m.p. 129–131 C. IR (KBr,
ν
/cm ) 3242 (N-H), 3071–2928 (C-H), 1708 (C=O), 1341, 1152 (O=S=O).
(ppm) 11.86 (s, 1H), 6.48–7.85 (m, 8H), 2.37–2.41 (d, J = 10.5 Hz, 3H),
.61–1.70 (d, J = 24.9 Hz ,6H). C-NMR (75 MHz, DMSO-d6): (ppm) 147.3, 142.3, 141.9, 129.7, 127.8,
1
H-NMR (300 MHz, DMSO-d ):
δ
6
1
3
1
1
δ
26.1, 125.4, 124.3, 123.5, 121.9, 118.8, 116.4, 109.4, 75.3, 31.9, 23.0, 21.4. HR-MS (ESI): m/z calcd. for
+
C H N O S ([M + H] ) 363.0832 found 363.0827.
17
19
2
3 2
2
6
-Ethyl-2-methyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3(2H)-formamide (3b): White solid, Yield
◦
−1
5%, m.p. 91–93 C. IR (KBr,
ν
/cm ) 3234 (N-H), 3064–2934 (C-H), 1704 (C=O), 1350, 1155 (O=S=O).
1
H-NMR (300 MHz, CDCl ):
δ
(ppm) 6.97–7.98 (m, 8H), 2.43–2.45 (d, J = 6.3 Hz, 3H), 2.18–2.28 (m, 1H),
3
1
1
.86–1.98 (m, 1H), 1.77 (s, 3H), 0.78–0.83 (t, J = 7.2 Hz, 3H). 13C-NMR (75 MHz, CDCl3):
δ (ppm) 146.9,
22.9, 138.1, 136.0, 129.6, 129.6, 128.4, 128.4, 126.5, 125.6, 124.8, 123.5, 115.4, 82.8, 32.6, 26.7, 21.7, 9.3.
+
HR-MS (ESI): m/z calcd. for C H N O S ([M + H] ) 377.0988 found 377.0984.
18
21
2
3 2
2
-Propyl-2-methyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3(2H)-formamide (3c): White solid,
◦
−1
Yield 78%, m.p. 91–94 C. IR (KBr,
ν
/cm ) 3380 (N-H), 3057–2872 (C-H), 1715 (C=O), 1349, 1162
(ppm) 6.97–7.98 (m, 8H), 2.44–2.45 (d, J = 4.5 Hz, 3H), 2.13–2.23
1
(
O=S=O). H-NMR (300 MHz, CDCl ):
δ
3
(
3
m, 1H), 1.82–1.88 (m, 1H), 1.77 (s, 3H), 1.34–1.46 (m, 1H), 0.93–1.03 (m, 1H), 0.70–0.74 (t, J = 6.6 Hz,
H). C-NMR (75 MHz, CDCl3): δ (ppm) 146.9, 144.9, 138.0, 135.9, 129.5, 129.5, 128.4, 128.4, 126.5,
13

Molecules 2017, 22, 1601
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1
25.6, 124.8, 123.5, 115.4, 81.9, 41.6, 27.3, 21.7, 18.4, 13.7. HR-MS (ESI): m/z calcd. for C H N O S
19 23 2 3 2
+
([M + H] ) 391.1145 found 391.1144.
2
-Isopropyl-2-methyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3(2H)-formamide (3d): White solid,
◦
−1
Yield 70%, m.p. 105–109 C. IR (KBr,
ν
/cm ) 3347 (N-H), 3056–2973 (C-H), 1706 (C=O), 1357, 1164
(ppm) 6.96–7.97 (m, 8H), 2.60–2.69 (m, 1H), 2.45 (s, 3H), 1.79
1
(
(
O=S=O). H-NMR (300 MHz, CDCl ):
s, 3H), 0.92–0.95 (d, J = 6.9 Hz, 3H), 0.76–0.78 (d, J = 6.6 Hz, 3H). C-NMR (75 MHz, CDCl3):
δ
3
13
δ
(ppm)
1
1
47.2, 144.8, 138.9, 136.1, 129.5, 129.5, 128.4, 128.4, 126.5, 125.5, 124.7, 123.1, 115.3, 87.1, 36.4, 25.4, 21.7,
+
8.4, 17.9. HR-MS (ESI): m/z calcd. for C H N O S ([M + H] ) 391.1145 found 391.1149.
19
23
2
3 2
2
-Acetonyl-2-methyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3(2H)-formamide (3e): White solid,
◦
−1
1
Yield 55%, m.p. 128–130 C. IR (KBr,
300 MHz, CDCl3): (ppm) 6.52–7.71 (m, 8H), 6.43 (s, 1H), 3.14–3.21 (q, J = 17.4 Hz, 4H), 2.37 (s, 3H),
.12 (s, 3H), 1.61 (s, 3H). 13C-NMR (75 MHz, CDCl3):
(ppm) 206.1, 145.9, 141.8, 141.4, 129.2, 129.2,
28.3, 125.6, 125.6, 125.2, 124.9, 121.1, 118.2, 108.8, 74.3, 55.8, 30.8, 29.5, 20.8. HR-MS (ESI): m/z calcd..
ν/cm ) 3175 (N-H), 1714 (C=O), 1350, 1164 (O=S=O). H-NMR
(
2
1
δ
δ
+
)
for C H N NaO S ([M + Na] 427.0756 found 427.0754.
19
20
2
4 2
2
-Butyl-2-methyl-N-butyl-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3-(2H)-formamide (3f): White solid,
−
1
1
Yield 50%, IR (KBr,
ν
/cm ) 3245 (N-H), 3068–2871 (C-H), 1702 (C=O), 1352, 1166 (O=S=O). H-NMR
(ppm) 6.97–7.97 (m, 8H), 2.45 (s, 3H), 1.77 (s, 3H), 0.87–1.42 (m, 6H), 0.69–0.74
t, J = 7.2 Hz, 3H). 13C-NMR (75 MHz, CDCl3):
(ppm) 144.8, 129.5, 129.5, 128.3, 128.3, 126.4, 125.5,
24.7, 123.4, 121.9, 120.5, 115.4, 110.8, 82.1, 43.8, 38.9, 30.0, 27.2, 22.4, 13.8. HR-MS (ESI): m/z calcd. for
(
(
1
300 MHz, CDCl3): δ
δ
+
C H N O S ([M + H] ) 405.1301 found 405.1306.
20
25
2
3 2
2
-Isobutyl-2-methyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3-(2H)-formamide (3g): White solid,
◦
−1
Yield 36%, m.p. 96–98 C. IR (KBr,
ν
/cm ) 3248 (N-H), 2976–2864 (C-H), 1697 (C=O), 1345, 1163
(ppm) 6.98–7.98 (m, 8H), 2.45 (s, 3H), 2.07–2.13 (q, J = 5.1 Hz,
1
(
O=S=O). H-NMR (300 MHz, CDCl ):
δ
3
1
(
H), 1.83–1.89 (q, J = 5.7 Hz, 1H), 1.80 (s, 3H), 1.64–1.72 (m, 1H), 0.87–0.90 (d, J = 6.6 Hz, 3H), 0.70–0.72
d, J = 6.9 Hz, 3H). 13C-NMR (75 MHz, CDCl3):
δ
(ppm) 147.0, 144.9, 138.0, 136.1, 129.5, 129.5, 128.4,
1
28.4, 126.5, 125.6, 124.9, 123.5, 115.6, 82.0, 47.7, 27.3, 25.3, 24.3, 23.9, 21.7. HR-MS (ESI): m/z calcd. for
+
C H N O S ([M + H] ) 405.1301 found 405.1307.
20
25
2
3 2
2
-Tert-butyl-2-methyl-N-[(4-methylphenyl)sulfonyl]-1,3benzothiazoline-3(2H)-formamide (3h): White solid,
◦
−1
Yield 59%, m.p. 126–129 C. IR (KBr,
ν
/cm ) 3256 (N-H), 2972 (C-H), 1701 (C=O), 1349, 1167 (O=S=O).
1
13
H-NMR (300 MHz, CDCl3):
δ
(ppm) 7.03–7.97 (m, 8H), 2.45 (s, 3H), 1.79 (s, 3H), 0.96 (s, 9H). C-NMR
(
1
75 MHz, CDCl3):
δ
(ppm) 147.9, 144.7, 140.9, 136.2, 133.1, 129.5, 129.5, 128.3, 128.3, 126.5, 125.6, 122.1,
+
17.3, 89.4, 43.7, 25.6, 25.6, 25.6, 23.0, 21.7. HR-MS (ESI): m/z calcd. for C H N O S ([M + H] )
20
25
2
3 2
4
05.1301 found 405.1305.
2
-Phenylethyl-2-methyl-N-[(4-methylphenyl)sulfonyl]-1,3–benzothiazoline-3(2H)-formamide (3i): White solid,
◦
−1
Yield 95%, m.p. 126–129 C. IR (KBr,
ν
/cm ) 3333 (N-H), 3070–2892 (C-H), 1706 (C=O), 1364, 1118
(ppm) 12.03 (s, 1H), 6.72–7.92 (m, 13H), 2.70–2.82 (m, 1H),
1
(O=S=O). H-NMR (300 MHz, DMSO-d ):
δ
6
13
2
.48 (s, 1H), 2.42 (s, 3H), 1.99–2.14 (m, 2H), 1.68–1.72 (s, 3H). C-NMR (75 MHz, DMSO-d6): δ (ppm)
1
1
49.0, 147.6, 144.2, 142.2, 141.3, 138.9, 137.8, 129.9, 128.5, 128.1, 127.2, 126.2, 125.5, 124.2, 123.5, 121.7,
18.5, 116.3, 108.9, 80.9, 46.1, 31.7, 29.0, 21.6. HR-MS (ESI): m/z calcd. for C H N NaO S ([M +
24
24
2
3 2
+
Na] ) 475.1120 found 475.1113.
2
,2,-Diethyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3(2H)-formamide (3j): White solid, Yield 40%,
◦
−1
m.p. 103–105 C. IR (KBr,
ν
/cm ) 3280 (N-H), 2959–2934 (C-H), 1715 (C=O), 1349, 1163 (O=S=O).
(ppm) 6.98–7.98 (m, 8H), 2.46 (s, 3H), 2.13–2.24 (m, 1H), 1.83–1.88
1
H-NMR (300 MHz, CDCl3):
δ
13
(
(
m, 1H), 1.77 (s, 3H), 1.34–1.46 (m, 1H), 0.93–1.03 (m, 1H), 0.70–0.74 (t, J = 7.2 Hz, 3H). C-NMR
75 MHz, CDCl3):
δ
(ppm) 146.9, 144.9, 138.0, 135.9, 129.5, 129.5, 128.4, 128.4, 126.5, 125.6, 124.8, 123.5,
+
1
15.3, 81.9, 41.6, 27.3, 21.7, 18.4, 13.7. HR-MS (APCI): m/z calcd. for C H N O S ([M + H] ) 391.1145
19
23
2
3 2
found 391.1140.

Molecules 2017, 22, 1601
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2
8
,2,-Dipropyl-N-[(4-methylphenyl)sulfonyl]-1,3-benzothiazoline-3(2H)-formamide (3k): White solid, Yield
◦
−1
2%, m.p. 101–104 C. IR (KBr,
ν
/cm ) 3187 (N-H), 3066–2871 (C-H), 1700 (C=O), 1344, 1167 (O=S=O).
(ppm) 6.94–7.96 (m, 8H), 2.44 (s, 3H), 2.15–2.25 (m, 2H), 1.67–1.77
1
H-NMR (300 MHz, CDCl3):
δ
13
(
m, 2H), 1.35–1.47 (m, 2H), 0.81–0.98 (m, 2H), 0.66–0.71 (t, J = 7.2 Hz, 6H). C-NMR (75 MHz, CDCl3):
δ
(ppm) 147.0, 144.9, 138.5, 135.7, 129.4, 129.4, 128.6, 128.6, 126.5, 125.4, 124.6, 123.1, 114.8, 85.7, 41.4,
+
4
1.4, 21.6, 17.9, 17.9, 13.7, 13.7. HR-MS (ESI): m/z calcd. for C H N O S ([M + H] ) 419.1458
21
27
2
3 2
found 419.1461.
N-[(4-Methylphenyl)sulfonyl]-3h-screw[1,3-benzothiazoline-2,1’-cyclopentane]-3-formamide (3l): White solid,
◦
−1
Yield 95%, m.p. 120–121 C. IR (KBr,
(
1
1
ν
/cm ) 3286 (N-H), 3066–2869 (C-H), 1602 (C=O), 1343, 1153
(ppm) 6.99–7.99 (m, 8H), 2.53–2.63 (m, 2H), 2.46 (s, 3H),
(ppm) 146.8, 144.9, 138.5, 136.1, 129.6, 129.6, 128.4,
1
O=S=O). H-NMR (300 MHz, DMSO-d ):
δ
6
.65–2.02 (m, 6H). 13C-NMR (75 MHz, DMSO-d6):
δ
28.4, 126.5, 125.7, 124.9, 123.5, 115.5, 87.2, 38.1, 38.1, 23.7, 23.7, 21.7. HR-MS (ESI): m/z calcd. for
+
C H N O S ([M + H] ) 389.0988 found 389.0982.
19
21
2
3 2
N-[(4-Methyl-phenyl)sulfonyl]-3h-screw[1,3-benzothiazoline-2,1’-cyclohexane]-3-formamide (3m): White
◦
−1
solid, Yield 99%, m.p. 149–152 C. IR (KBr,
1
3
ν
/cm ) 3287 (N-H), 3071–2849 (C-H), 1692 (C=O),
(ppm) 11.95 (s, 1H), 6.96–7.89 (m, 8H), 2.44 (s,
(ppm) 149.0, 144.2, 140.0, 137.9, 129.9, 127.8,
1
346, 1160 (O=S=O). H-NMR (300 MHz, DMSO-d ):
δ
6
H), 1.09–2.38 (m, 10H). 13C-NMR (75 MHz, DMSO-d6):
δ
1
26.9, 124.1, 123.3, 121.7, 118.4, 116.4, 109.1, 84.9, 35.1, 25.0, 24.7, 24.3, 24.0, 21.6. HR-MS (ESI): m/z
+
calcd. for C H N O S ([M + H] ) 403.1145 found 403.1149.
20
23
2
3 2
4
. Conclusions
In conclusion, a series of novel sulfonylurea benzothiazoline derivatives was rationally designed
and synthesized using a solvent-free method, and identified as potential herbicide safeners for
sulfonylurea herbicides. All the synthesized compounds displayed safener activity to chlorsulfuron
to some extent, and compound 3c was even superior to the commercial safener AD-67. The results
suggest that compound 3c might be a novel candidate for a potential safener.
Supplementary Materials: Supplementary data associated with this article can be found in the online.
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 Technology Innovation of Harbin (2015RAYXJ010). The authors are grateful to Jia-Zhong Li
(Lanzhou University) for assistance with molecular docking analyses.
Author Contributions: Y.F. and F.Y. developed the concept of the work. J.-Y.W. and L.-X.Z. carried out the
synthetic work. Y.-F.C. developed the molecular docking and comparison. S.G. conducted the bioactivity assay.
D.Z. contributed to the discussed and analyzed the results. Y.F. wrote the paper.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).