Design, synthesis and biological activity of novel sulfonylurea oxazolidines

Article abstract of DOI:10.3987/COM-16-13412

A series of N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide 4 was synthesized by cycloaddition and acylation reaction with alkamine, ketones, and p-methylbenzenesulfonyl isocyanate as the starting materials. The structures of all the compounds

Full text of DOI:10.3987/COM-16-13412

740
HETEROCYCLES, Vol. 92, No. 4, 2016
HETEROCYCLES, Vol. 92, No. 4, 2016, pp. 740 - 750. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 22nd January, 2016, Accepted, 23rd February, 2016, Published online, 2nd May, 2016
DOI: 10.3987/COM-16-13412
DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL
SULFONYLUREA OXAZOLIDINES
Ying Fu, Jing-Xin Kang, Yun-Kai Wang, Jing Liu, Li-Xia Zhao, Shuang Gao,
and Fei Ye*
Department of Applied Chemistry, College of Science, Northeast Agricultural
University, Harbin, 150030, P.R. China; email: yefei@neau.edu.cn
Abstract
–
A
series of N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-
3
-carboxamide 4 was synthesized by cycloaddition and acylation reaction with
alkamine, ketones, and p-methylbenzenesulfonyl isocyanate as the starting
1
materials. The structures of all the compounds were characterized by IR, H NMR,
13C NMR, MS, and elemental analysis. The configuration of 4d was determined
by X-ray crystallography. The preliminary biological test showed that all
compounds could protect maize against injury caused by chlorsulfuron to certain
extent. The sulfonylurea oxazolidines were possible acted as antagonists of
sulfonylureas herbicides at target enzyme pocket site by docking analysis.
Sulfonylureas (SUs) compounds have a wide range of practical applications such as insecticides,1
2
3
4
antimicrobial agents, anticancer agents, as well as herbicides. SUs are the very popular herbicides used
for controlling a range of weeds and some grasses in a variety of crops and vegetables because of their
good herbicidal activity, low mammalian toxicity, high selectivity, and benign environmental activity.
However their phytotoxicities and the residues to succeeding crops have caused some concerns. Some
sulfonylurea herbicides (such as Chlorsulfuron, Metsulfuron, Chlorimuron-ethyl) are long residual
5
herbicides, and persistent in soil which is poisonous to susceptive crops. More and more novel safeners
for SUs herbicides have been commercialized, such as Dimepiperate, Dymron, and Cyprosulfamide
(
Scheme 1).6
Structure-activity relationship theory (SAR) are very important in the search for bioactive materials
because it provides useful molecular structure information that are necessary for the target bioactivity.7
Base on the SAR, active substructure combination, and bioisosteric replacement, the novel aniline
derivatives of Chlorothalonil was designed and synthesized by substitution of Cl atom on Chlorothalonil
8
with aryl amine moiety of Fluazinam, another commercially available agent (Scheme 2). Recently many

HETEROCYCLES, Vol. 92, No. 4, 2016
741
9
such successful cases have been reported. In the same way, the safeners could be used as herbicide
antidotes if the herbicides and their respective safeners are similar at the molecular level. Based on the
1
0
above and continuous our previous work on N-containing heterocycles herbicide safeners, herein we
designed a series of novel N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide utilizing active
substructure combination and similarity theory (Scheme 3).
O
O
O
O
O
O
S
N
H
S
N
N
N
H
H
H
N
Dimepiperate
Dymron
Cyprosulfamide
O
Scheme 1. Safeners for sulfonylurea herbicides
CN
Cl
Cl
Cl
NC
Cl
CN
Cl
CN
Cl
Cl
Cl
NH
Cl
NH
HC
Cl
bioisosteric
replacement
Chlorothalonil
active substructure
combination
N
NC
Cl
NO2
NC
Cl
NO2
NO2
Cl
H
N
2
,4,5-trichloro-6-(6-chloro-4-
2
,4,5-trichloro-6-(6-chloro-4-
N
NO2
nitropyridinamino)isophthalonitrile
nitrophenylamino)isophthalonitrile
F3C
CF3
Cl
Fluazinam
Scheme 2. Design of novel aniline derivatives of Chlorothalonil
Cl
R1
R2
O
S
O
H
H
O
S
O
N
N
N
C
N
N
O
N
N
H
O
O
O
R4
R3
Chlorsulfuron
active substructure
combination
O
structure of the target compounds
N
O
Cl
Cl
R-28725
Scheme 3. Design of the target compound

742
HETEROCYCLES, Vol. 92, No. 4, 2016
1
1
12
Several approaches had been developed to sulfonylurea derivatives with isocyanate or carbamic ester
as the starting materials. Riehen reported the N-(2-methoxyethoxyphenylsulfony)-N`-(p-methoxy-6-
methylpyrimidin-2-yl)urea being synthesized by acylation and aminolysis reaction with sulfonamide,
dimethylformamide and 2-amino-4-methoxy-6-methylpyrimidine as the starting materials at low
1
3
temperature with about 60% yield. Hagana reported the synthesis of Nicosulfuron by amidation reaction
with aminopyrimidine, phosgene (which is highly toxic and the procedure is difficult to control) and
1
4
phenyl carbamate as the starting materials at room temperature with the yield of 80%. Most of these
reported methods required harsh reaction conditions, expensive materials, or phosgene. In view of the
facts mentioned above, substituted N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide 4 were
synthesized with alkamine, ketone and p-methylbenzenesulfonyl isocyanate as the starting materials via
cyclization and acylation reactions (Scheme 4).
R1
R1
R1
O
SO2NCO
a)30 °C,1 h
SO NHCO
N
O
+ R2
HN
O
2
R3
H N
2
OH
b)100 °C, reflux£¬4 h
anhydrous benzene
R2
R3
10 °C , 3-12 h
R2
R3
4a-k
1
2
3a-k
1
2
3
1
2
3
1
2
3
a) R =H, R =R =Me; b) R =H, R =Me, R =Et; c) R =H, R =Me, R =n-propyl;
1
2
3
1
2
3
1
2
3
d) R =H, R =Me, R =phenethyl; e) R =H, R ~R =(CH ) ; f) R =H, R ~R =(CH ) ;
2
4
2 5
1
2
3
1
2
3
1
2
3
g) R =Et, R =R =Me; h) R =Et, R =Me, R =Et; i) R =Et, R =Me, R =phenethyl;
1
2
3
1
2
3
J) R =Et, R ~R =(CH ) ; k) R =Et, R ~R =(CH ) .
2
4
2 5
Scheme 4. Route for synthesis of the target compound 4
Oxazolidine derivatives were synthesized according to the literature.11 Acylation reaction proceeded
smoothly in anhydrous benzene with compound 3 and p-methylbenzenesulfonyl isocyanate to give the
target compound 4. The yields of compounds 4f, 4k were more than 90%. However, the yield of 4i was
the lowest. The yields were significantly influenced by steric hindrance of alkyls connecting to at C-4
1
position of oxazolidine. The yields were lower as the structure of R being ethyl. It was hard for
p-methylbenzenesulfonyl isocyanate to react with N atom. It was failed in getting the target molecule
2
3
when there were two methyl at C-4 position of oxazolidine. The effects of R and R were negligible
because they were not at the same plane with oxazolidine. But they were related with the oxazolidine
1
0
2
3
stability. When R and R forming a spiro compound, the oxazolidine was very stabile. Six-membered
ring yields (4f and 4k) were significantly better than the five-membered ring (4e and 4j). Chiral
2
3
compounds would be obtained when R and R being different alkyl moieties.
It was worth note that the solvent must be water-free otherwise compound 5 would be obtained. In
addition, compound 6 was obtained when the crude product was washed with water. Different solvents
were employed to synthesize the target compound, but the isocyanate condensation carried out when
alcohol was used as solvent (Scheme 5).

HETEROCYCLES, Vol. 92, No. 4, 2016
743
hydrolysis of
sulfonylurea bridge
O
S
NH2
HN
R2
O
CO2
O
R3
5
O
S
O
O
S
O
C
oxazolidine ring
opening
N
H
N
OH
N
N
O
O
H
H
O
R3
R2
6
4
O
O
O
isocyanate
condensation
S
C
S
N
N
O H
H O
7
Scheme 5. The schematic diagram of the cleavage products
1
13
The structures of all the target compounds 4 were supported by MS, IR, H NMR, C NMR spectral data
-1
and elemental analysis. The IR spectra of compounds 4a-k showed bands at 3268-3350 cm due to N-H;
-1
-1
1
665-1699 cm due to C=O, 1134-1167 and 1354-1370 cm due to S=O, which confirmed the formation
1
of urea bridge. The H NMR spectra of compounds 4a-k exhibited a single signal in the range δ
1
0.41-10.79 for the proton of N-H; multiplet in the range δ 3.99-3.50 for the proton of oxazolidine. The
elemental analysis of 4a-k agreed with the molecular formula of all these compounds.
Finally, the single crystal of 4d was obtained by dissolving it in CH Cl and light petroleum, followed by
2
2
slow evaporation at room temperature. The diffraction data of 4d was collected with a Bruker AXSⅡ
CCD area detector using a graphite monochromated Mo Kα radiation (λ=0.71073 Å) at 293(2) K. The
1
5
structure was solved by direct methods using SHELXS-97, and refined by full matrix least squares on
F2, SHELXL-97.16
The molecular structure of compound 4d is shown in Figure 1. In the structure the oxazolidine, phenethyl
and p-methylphenylsulfonylamine groups are not in a coplane. The dihedral angle of oxazolidine and
phenethyl is 63.3°, and the dihedral angle of phenethyl group and p-methylphenylsulfonylamine group is
4
2.0°.
As depicted in the crystal packing of compound 4d, two molecules are connected by one intermolecular
hydrogen bond (C5-H5…O3) in Figure 2. Intermolecular and adjacent molecules are assembled through
strong C-H…π stacking interaction in Figure 3. No significant π-π interactions were found in the crystal
structure.

744
HETEROCYCLES, Vol. 92, No. 4, 2016
Figure 1. Molecular structure of product 4d
Figure 2. Packing diagram of finacompound 4d
in a unit cell
Figure 3. C-H… π interactions of the compound 4d
The bioactivity determination of all the novel compounds 4a-k was carried out on maize from the injury
of Chlorsulfuron. The results were summarized in Table 1. The recovery rates of the growth index could
be attained almost 50% with 10 mg/kg of the 4a-k when the concentration of Chlorsulfuron in the soil
was 2 μg/kg. Among the compounds tested, 4j and 4k showed the best activity against the injury of
Chlorsulfuron, similar as the commercial safener R-28725. Further bioassay was carrying out to probe the
structure-activity relationship.
For the structural similarity of safener and herbicide, the competition of the target enzyme was probed.
The acetolactate synthetase (ALS) crystal structure data was taken from the PDB data bank (PDB ID:
1
N0H). Docking calculations were performed by using Docking Suite. Molecular structure of 4k was
constructed and optimized using SKETCH and MINIMIZE option, and Gasteiger−Hückel charges were
calculated for them. Geometry optimization was carried out using Triops force field supplied within
SYBYL, with convergence criterion set at 0.005 kcal/(Å mol), and iterations criterion set at 1000.

HETEROCYCLES, Vol. 92, No. 4, 2016
745
Docking calculations were performed on the two molecules using Docking Suite option. The protein was
prepared with BIOPOLYMER option. Docked structure was scored by the built-in scoring function and
clustered by 0.8 Å of root-mean-square deviation (RMSD) criterions. The best binding modes were
determined by docking scores and also the comparison to available complex crystal structure of ALS.
Standard Amber FF99 force field parameters were assigned to protein, and general AMBER force field
(gaff) was assigned to ligand. The safener 4k was binding by hydrogen bonds with two active site
residues (Ser163 and Ala117). The cofactor FAD 701 and AYD 700 were surrounding the active site
pocket (Figure 4). The urea linkage moiety was binding by two active site residues at the entrance of the
pocket. The oxazolidine moiety was deeply buried in the active site pocket (Figure 5). Based on the SAR,
active substructure combination, docking analysis and the bioactivity data, the sulfonylurea oxazolidine
safeners were possible acted as antagonists of SUs herbicides at target enzyme pocket site.
Table 1. Effect of detoxification of compounds 4a-k to growth index of maizea,b,c
Recovery of root Recovery of plant Recovery of root Recovery of plant
Compound
length (%)
52.57
36.21
58.88
60.75
64.72
42.29
53.27
37.62
35.05
57.01
89.95
84.81
height (%)
73.39
33.19
65.58
38.83
45.05
53.73
70.21
26.98
74.12
90.02
65.58
92.34
weight (%)
108.43
6.51
weight (%)
105.13
38.46
R-28725
4
a
4
b
81.54
36.6
52.56
4
c
18.59
4
d
45.83
23.36
49.44
55.46
56.26
95.59
61.48
101.60
74.36
4
e
89.10
4
f
122.44
27.56
4
g
4
h
103.21
130.77
89.74
4
i
4
j
4
k
142.31
adata are means of three replicates
Treat with compounds - Treat with Chlorsulfuron
Contrast - Treat with Chlorsulfuron
bRecovery Rate(%) =
cwater treated was used as contrast

746
HETEROCYCLES, Vol. 92, No. 4, 2016
Figure 4. Safener 4k in the ALS active site
Figure 5. Active pocket of ALS occupied
by Safener 4k
In conclusion, we have developed an efficient, fast and convenient method for the preparation of
N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide derivatives. The advantages of this method
were readily available starting materials, mild reaction conditions, and good yields. The preliminary
bioactivity results showed that compound 4j and 4k attained the best herbicide safener activity to
Chlorsulfuron. The sulfonylurea oxazolidine were possible acted as antagonists of sulfonylureas
herbicides at target enzyme pocket site by docking analysis.
EXPERIMENTAL
1
The IR spectra were taken on a KJ-IN-27G infrared spectrophotometer in KBr pellets. The H NMR and
13C NMR spectra were recorded on Bruker AVANVE 300 MHz or 400 MHz, respectively, with CDCl
or
3
DMSO-d as the solvent and TMS as the internal standard. The elemental analysis was performed on
6
FLASH EA1112 elemental analyzer. The mass spectrum was recorded on a Waters Xevo TQ
spectrometer. X-Ray diffraction data were collected on a Brukcr AXSⅡ CCD area-detector
diffractometer, Mo K
apparatus(X-4) and are uncorrected. All the reagents were of analytical reagents grade.
General procedure for the preparation
N-[(p-Methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide(4a-k)
α
. The melting points were determined on a Beijing Taike melting point
of
Solution of p-methylbenzenesulfonyl isocyanate (1.98g, 0.01 mol, in 10 mL anhydrous benzene) was
added dropwise to a stirred mixture of oxazolidine 3 (0.01 mol) and anhydrous benzene (50 mL) at
1
0-12 °C for 3 h. After the reaction completed, the product was recovered by filtration, extraction and
drying, the crude product 4 was received. The pure product was obtained by soaking and filtration with a
mixture of benzene and a little of CH Cl
,2-Dimethyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4a). Yield 84%. White
2
2
.
2
-1
1
solid, mp 95-96 °C. IR (KBr, cm ): ν 3268 (N-H), 1696 (C=O), 1166, 1364 (S=O); H NMR (DMSO-d
6
,
3
00MHz): δ 7.34-7.77 (m, 4H, Ph-H), 3.88 (t, 2H, J=6.1Hz, N-CH ), 3.51 (t, 2H, J=6.3Hz, O-CH ), 2.37
2
2

HETEROCYCLES, Vol. 92, No. 4, 2016
747
(
s, 3H, Ph-CH
3
), 1.34 (s, 6H, C-(CH
3
)
2
); 13C NMR (DMSO-d
6
, 75MHz): δ 151.93, 144.06, 137.96,
+
1
6
2
29.92, 127.72, 60.15, 42.27, 21.53; ESI-MS: 299 [M+H ]. Anal. Calcd for C13
H
18
N
2
4
O S: C 52.33, H
.08, N 9.39, S 10.75. Found: C 52.48, H 6.02, N 9.31, S 10.65.
-Ethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4b). Yield 72%.
-1
1
White solid, mp 98-99 °C. IR (KBr, cm ): ν 3274 (N-H), 1699 (C=O), 1165, 1363 (S=O); H NMR
DMSO-d , 300MHz): δ 10.60 (s, 1H, N-H), 7.35-7.76 (m, 4H, Ph-H), 3.79-3.98 (m, 2H, N-CH ),
.45-3.64 (m, 2H, O-CH ), 2.37 (s, 3H, Ph-CH ), 0.59-1.86 (m, 8H, C-CH and C-CH
); 13C NMR
(
6
2
3
2
3
2
3
(DMSO-d
6
, 75MHz): δ 149.49, 143.27, 138.98, 129.59, 127.74, 96.05, 63.37, 46.49, 29.89, 23.27, 21.52,
+
7
5
2
.82; ESI-MS: 313 [M+H ]. Anal. Calcd for C14
H
20
N
2
O S: C 53.83, H 6.45, N 8.97, S 10.26. Found: C
4
3.75, H 6.52, N 8.88, S 10.32.
-Methyl-N-[(p-methylphenyl)sulfonyl]-2-propyl-1,3-oxazolidine-3-carboxamide (4c). Yield 52%.
-1
1
White solid, mp 90-91 °C. IR (KBr, cm ): ν 3342 (N-H), 1700, 1673 (C=O), 1157, 1364 (S=O); H NMR
DMSO-d , 300MHz): δ 10.65 (s, 1H, N-H), 7.36-7.76 (m, 4H, Ph-H), 3.80-3.96 (m, 2H, N-CH ),
.41-3.61 (m, 2H, O-CH ); C NMR
(
6
2
13
3
2
), 2.37 (s, 3H, Ph-CH
3
), 0.69-1.82 (m, 10H, C-CH
2
and C-CH
3
(DMSO-d
6
, 75MHz): δ 149.00, 143.61, 138.42, 129.65, 127.85, 95.91, 63.39, 46.26, 23.38, 21.52, 16.51,
+
1
5
2
8
4.33; ESI-MS: 327 [M+H ]. Anal. Calcd for C15
H
22
N
2
O S: C 55.19, H 6.79, N 8.58, S 9.82. Found: C
4
5.26, H 6.66, N 8.48, S 9.96.
-Methyl-N-[(p-methylphenyl)sulfonyl]-2-(2-phenylethyl)-1,3-oxazolidine-3-carboxamide (4d). Yield
-1
1
5%. White solid, mp 115-116 °C. IR (KBr, cm ): ν 3344 (N-H), 1698 (C=O), 1161, 1361 (S=O); H
, 300MHz): δ 10.74 (s, 1H, N-H), 6.81-7.82 (m, 9H, Ph-H), 3.86-4.05 (m, 2H, N-CH ),
.51-3.66 (m, 2H, O-CH ), 1.78-2.43 (m, 4H, (CH ), 1.34 (s, 3H, C-CH
); 13C NMR (DMSO-d
NMR (DMSO-d
6
2
3
7
4
2
2
)
2
3
6
,
5MHz): δ 148.99, 143.73, 142.10, 138.27, 129.70, 128.81, 128.66, 128.59, 128.01, 126.09, 95.66, 63.55,
+
6.31, 29.61, 23.47, 21.56; ESI-MS: 389 [M+H ]. Anal. Calcd for C20
H
24
N
2
4
O S: C 61.83, H 6.23, N 7.21,
S 8.25. Found: C 61.78, H 6.26, N 7.39, S 8.14.
Crystal data for compound 4d: C20
H
24
N
2
O
4
S, monoclinic, space group P2 /c, a=9.3912(19) Å,
1
3
-3
-1
b=19.483(4) Å, c=10.837(2) Å, V=1933.7(7) Å , β= 102.78(3), Z=4, D
c
=1.334 cm , μ=0.196 mm ,
F(000)= 824. Independent reflections were obtained in the range of 3.05° < θ < 27.48, 4369. The final
least-square cycle gave R
1
= 0.0385, ωR
2
= 0.0960 for 3412 reflections with I > 2σ(I). The maximum and
3
minimum differences of peak and hole are 0.509 and -0.289 e/Å , respectively.
N-[(p-Methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.4]nonane-4-carboxamide (4e). Yield 68%. White
-1
1
solid, mp 102-103 °C. IR (KBr, cm ): ν 3276 (N-H), 1695 (C=O), 1165, 1364 (S=O); H NMR
DMSO-d , 300MHz): δ 10.72 (s, 1H, N-H), 7.37-7.76 (m, 4H, Ph-H), 3.84-3.86 (m, 2H, N-CH ),
.94-3.48 (t, 2H, O-CH , 75MHz):
δ 163.81, 157.62, 140.34, 129.64, 128.69, 127.77, 127.35, 103.43, 63.39, 60.86, 45.92, 34.75, 24.24,
(
6
2
13
2
2
), 2.38 (s, 3H, Ph-CH
3
), 1.48-2.32 (m, 8H, C
4
H
8
); C NMR (DMSO-d
6

748
HETEROCYCLES, Vol. 92, No. 4, 2016
+
2
1.53, 21.38; ESI-MS: 325 [M+H ]. Anal. Calcd for C15
Found: C 55.44, H 6.30, N 8.68, S 9.75.
N-[(p-Methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.5]decane-4-carboxamide (4f). Yield 92%. White
H
20
N
2
O
4
S: C 55.54, H 6.21, N 8.64, S 9.88.
-1
1
solid, mp 105-106 °C. IR (KBr, cm ): ν 3275 (N-H), 1693 (C=O), 1165, 1361 (S=O); H NMR
(DMSO-d
6
, 400MHz): δ 7.34-7.75 (m, 4H, Ph-H), 3.85 (t, 2H, J=3.0Hz, N-CH
2
), 3.50 (t, 2H, J=6.0Hz,
13
O-CH
2
), 2.36 (s, 3H, Ph-CH
3
), 1.35-2.13 (m, 10H, C
5
H
10); C NMR (DMSO-d , 100MHz): δ 151.94,
6
1
2
5
4
51.87, 149.98, 144.07, 143.25, 139.05, 137.93, 137.88, 129.60, 127.86, 95.04, 62.98, 45.93, 32.27, 23.29,
+
1.52; ESI-MS: 339 [M+H ]. Anal. Calcd for C16
H
22
N
2
4
O S: C 56.78, H 6.55, N 8.28, S 9.47. Found: C
6.72, H 6.64, N 8.35, S 9.41.
-Ethyl-2,2-dimethyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4g). Yield 80%.
-1
1
White solid, mp 120-121 °C. IR (KBr, cm ): ν 3283(N-H), 1686 (C=O), 1167, 1363 (S=O); H NMR
DMSO-d , 300MHz): δ 10.70 (s, 1H, N-H), 7.36-7.75 (m, 4H, Ph-H), 4.01 (s, 1H, N-CH), 3.74-3.84 (m,
H, O-CH), 2.37 (s, 3H, Ph-CH ), 0.86-1.60 (m, 11H, C-CH and C-CH
); 13C NMR (DMSO-d
(
6
2
7
1
5
2
3
2
3
6
,
5MHz): δ 148.77, 143.59, 138.62, 129.71, 127.83, 94.45, 66.45, 57.26, 27.20, 25.86, 23.68, 21.53,
+
0.42; ESI-MS: 327 [M+H ]. Anal. Calcd for C15
H
22
N
2
O S: C 55.19, H 6.79, N 8.58, S 9.82. Found: C
4
5.32, H 6.71, N 8.49, S 9.84.
,4-Diethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-1,3-oxazolidine-3-carboxamide (4h). Yield 53%.
-1
1
White solid, mp 121-122 °C. IR (KBr, cm ): ν 3301 (N-H), 1695 (C=O), 1153, 1367 (S=O); H NMR
DMSO-d , 300MHz): δ 10.68 (s, 1H, N-H), 7.36-7.78 (m, 4H, Ph-H), 3.96 (m, 1H, N-CH), 3.76-3.86 (m,
H, O-CH ), 2.37 (s, 3H, Ph-CH ), 0.88-1.88 (m, 13H, C-CH and C-CH
); 13C NMR (DMSO-d
(
6
2
7
8
5
4
2
3
2
3
6
,
5MHz): δ 148.61, 143.58, 138.57, 139.70, 127.80, 96.89, 66.24, 57.09, 31.00, 26.07, 21.74, 21.53, 10.66,
+
.55; ESI-MS: 341 [M+H ]. Anal. Calcd for C16
H
24
N
2
O S: C 56.45, H 7.11, N 8.23, S 9.42. Found: C
4
6.54, H 7.22, N 8.15, S 9.35.
-Ethyl-2-methyl-N-[(p-methylphenyl)sulfonyl]-2-(2-phenylethyl)-1,3-oxazolidine-3-carboxamide
-1
(
4i). Yield 23%. White solid, mp 117-118 °C. IR (KBr, cm ): ν 3281 (N-H), 1686 (C=O), 1156, 1354
1
(
S=O); H NMR (DMSO-d
6
, 300MHz): δ 10.79 (s, 1H, N-H), 6.81-7.78 (m, 9H, Ph-H), 3.72-4.00 (m, 3H,
), 2.34 (s, 3H, Ph-CH ), 1.40-2.23 (m ,4H, C(CH -Ph), 0.89-1.25 (m, 5H, CH CH );
13C NMR (DMSO-d
, 75MHz): δ 148.99, 143.60, 142.33, 138.58, 129.68, 128.63, 127.91, 126.12, 96.33,
O-CH and N-CH
2
3
2
)
2
2
3
6
+
6
8.04, 66.33, 57.17, 30.32, 26.19, 21.52, 10.71; ESI-MS: 417 [M+H ]. Anal. Calcd for C22
3.44, H 6.78, N 6.73, S 7.70. Found: C 63.52, H 6.65, N 6.77, S 7.62.
-Ethyl-N-[(p-methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.4]nonane-4-carboxamide (4j). Yield 45%.
H
28
N
2
O S: C
4
6
3
-1
1
White solid, mp 108-109 °C. IR (KBr, cm ): ν 3259 (N-H), 1688 (C=O), 1160, 1370 (S=O); H NMR
(DMSO-d
6
, 300MHz): δ 10.78 (s, 1H, N-H), 7.36-7.77 (m, 4H, Ph-H), 4.03 (s, 1H, N-CH), 3.74 (m, 2H,
13
O-CH
2
), 2.37 (s, 3H, Ph-CH
3
), 0.85-2.23 (m, 13H, 5×CH
2
and C-CH
3
); C NMR (DMSO-d , 75MHz): δ
6

HETEROCYCLES, Vol. 92, No. 4, 2016
749
1
1
5
3
49.21, 142.33, 138.85, 129.63, 127.68, 103.78, 66.78, 56.79, 36.22, 34.09, 25.53, 24.41, 24.11, 21.52,
+
0.16; ESI-MS: 353 [M+H ]. Anal. Calcd for C17
H
24
N
2
4
O S: C 57.93, H 6.86, N 7.95, S 9.10. Found: C
7.85, H 6.96, N 7.91, S 9.13.
-Ethyl-N-[(p-methylphenyl)sulfonyl]-1-oxa-4-aza-spiro[4.5]decane-4-carboxamide (4k). Yield 90%.
-1
1
White solid, mp 164-165 °C. IR (KBr, cm ): ν 3284 (N-H), 1687 (C=O), 1165, 1366 (S=O); H NMR
DMSO-d , 300MHz): δ 10.41 (s, 1H, N-H), 7.35-7.75 (m, 4H, Ph-H), 3.99 (s, 1H, N-CH), 3.49-3.76 (s,
H, O-CH ), 2.37 (s, 3H, Ph-CH ), 0.85-1.90 (m, 15H, 6×CH and C-CH
); 13C NMR (DMSO-d
(
6
2
7
2
2
3
2
3
6
,
5MHz): δ 149.21, 143.37, 138.93, 129.65, 127.80, 95.64, 66.20, 57.28, 35.20, 30.17, 26.07, 24.73, 23.45,
+
1.52, 10.50; ESI-MS: 367 [M+H ]. Anal. Calcd for C18
H
26
N
2
O S: C 58.99, H 7.15, N 7.64, S 8.75.
4
Found: C 59.06, H 7.21, N 7.52, S 8.71.
-(2’-Hydroxyethyl)-3-p-methylphenyl)sulfonylurea (6). White solid, mp 136-137 °C. IR (KBr,
1
-
1
1
cm ): ν 3338 (N-H), 1673 (C=O), 1157, 1335 (S=O). H NMR (DMSO-d
SO N-H), 7.36-7.74 (m, J=8.4Hz, 8H, Ph-H), 6.43 (t, J=5.2Hz, 1H, O-H), 4.68 (s, 1H, N-H),3.29 (s, 2H,
OH), 2.98 (t, J=5.6Hz, 2H, N-CH
6
, 400MHz): δ 10.42 (s,1H,
2
13
2
), 2.36 (s, 3H, Ph-CH
44.03, 137.94, 129.89, 129.89, 127.68, 127.68, 60.12, 42.24, 21.49. Anal. Calcd for C10
6.50, H 5.46, N 10.85, S 12.41. Found: C 46.44, H 5.52, N 10.78, S 12.55.
3
); C NMR (DMSO-d
6
, 100MHz): δ 151.89,
1
4
1
1
H
14
N
2
O
4
S: C
-1
,3-Bis(p-methylphenyl)sulfonylurea (7). White solid, mp 69-70 °C. IR (KBr, cm ): ν 3299-3181 (N-H),
1
701, 1748 (C=O), 1348 (S=O). H NMR (CDCl
3
, 400MHz): δ 8.86 (s, 2H, N-H), 7.25-7.79 (m, 8H,
, 100MHz): δ 172.06, 147.02, 147.02, 145.58,
45.58, 135.24, 135.24, 129.93, 129.93, 129.93, 129.93, 127.95, 127.95, 127.95,127.95, 60.81, 21.68,
Ph-H), 2.38 (s, 6H, 2×Ph-CH
3
); 13C NMR (DMSO-d
6
1
2
7
1.68, 14.14. Anal. Calcd for C15
H
16
N
2
O
5
S : C 48.90, H 4.38, N 7.60, S 17.41. Found: C 48.88, H 4.42, N
2
.68, S 17.56.
Biological activity: Maize (Dongnong 253) seeds were moistened with warm water about 30 min. The
untreated or safener-treated maize were soaked by title compounds (10 mg/kg) for 12 h, and then
germinated for 24 h at 26.5 °C. The seeds were planted 1.5 cm deep in plastic trays, in which soil was
treated with 2 μg/kg Chlorsulfuron. Trays were incubated at 28 °C for 7 days. The effects of the title
compound on the detoxification of Chlorsulfuron in soil were determined by testing the growth level.
SUPPLEMENTARY MATERIAL
Crystallographic data for the structural analysis of 4d has been deposited with the Cambridge
Crystallographic Data Centre (CCDC 1044046). These data can be obtained free of charge from The
Cambridge Crystallographic Data via www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGEMENTS
This work was supported by the National Nature Science Foundation of China (No. 31401787), Natural
Science Foundation of Heilongjiang Province (No. B201303), the Research Science Foundation in

750
HETEROCYCLES, Vol. 92, No. 4, 2016
Technology Innovation of Harbin (No. 2015RAYXJ010), and Young Talents Project of Northeast
Agricultural University (No. 14QC38).
REFERENCES
1.
2.
3.
4.
R. F. Sun, Y. L. Zhang, L. Chen, Y. Q. Li, Q. S. Li, H. B. Song, R. Q. Huang, F. C. Bi, and Q. M.
Wang, J. Agric. Food Chem., 2009, 57, 3661.
K. R. Prosen, R. K. Carroll, W. N. Burda, C. N. Krute, B. Bhattacharya, M. L. Dao, E. Turos, and L.
N. Shaw, Bioorg. Med. Chem. Lett., 2011, 21, 5293.
S. H. Jung, J. S. Song, H. S. Lee, S. U. Choi, and C. O. Lee, Bioorg. Med. Chem. Lett., 1996, 6,
2
553.
J. Y. Ma, L. G. Xu, S. F. Wang, R. G. Zheng, S. H. Jin, S. Q. Huang, and Y. J. Huang, Ecotoxicol.
Environ. Saf., 2002, 51, 128.
5
6
.
.
F. Saczewski, A. Kornicka, and Z. Brzozowski, Green Chem., 2006, 7, 647.
A. J. Price and J. A. Kelton, 'Herbicides-Current Research and Case Studies in Use', InTech Press,
2
013.
7
.
.
D. D. Buono, L. Scarponi, and L. Espen, Phytochemistry, 2007, 68, 2614.
8
A. Y. Guan, C. L. Liu, G. Huang, H. C. Li, S. L Hao, Y. Xu, and Z. N. Li, J. Agric. Food Chem.,
2
013, 61, 11929.
(a) J. L. Chen, W. Tang, J. Y. Che, K. Chen, G. Yan, Y. C. Gu, and D. Q. Shi, J. Agric. Food Chem.,
015, 63, 7219; (b) Y. Xie, H. W. Chi, A. Y. Guan, C. L. Liu, H. J. Ma, and D. L. Cui, J. Agric.
Food Chem., 2014, 62, 12491.
9
.
2
1
0. (a) F. Ye, C. G. Liu, X. M. Wang, Y. Fu, and S. Gao, Heterocycl. Commun., 2013, 19, 201; (b) Y.
Fu, L. Yang, F. Ye, and S. Gao, J. Heterocycl. Chem., 2012, 49, 1235.
1. (a) R. Mengel and W. Sttansky, DE3151450, 1983; (b) F. Kurzer, J. Chem. Soc., 1951, 5, 1258.
2. (a) H. Irie, M. Nishimura, M. Yoshida, and T. Ibuka, J. Chem Soc., Perkin Trans. 1, 1989, 1209; (b)
W. Meyer and W. Fory, US4419121, 1983.
1
1
1
1
1
3. F. Maurer, S. Dutzmann, and W. Paulus, DE4005116, 1991.
4. M. A. Hangan and D. Newark, US4786734, 1987.
5. G. M. Sheldrick, SHELXS-97, Program for X-Ray Crystal Structure Solution, University of
Göttingen, Göttingen, Germany (1997).
1
6. G. M. Sheldrick, SHELXL-97, Program for X-Ray Crystal Structure Refinement, University of
Göttingen, Göttingen, Germany (1997).