Synthesis and insecticidal activity of N-substituted (1,3-thiazole)alkyl sulfoximine derivatives

Article abstract of DOI:10.1021/jf802802g

The N-substituted alkyl sulfoximine derivatives are a new chemical family of neonicotinoid insecticides. We have designed and synthesized 10 (1,3-thiazole)alkyl sulfoximine derivatives. All compounds were identified by ¹H and ¹³C nuc

Full text of DOI:10.1021/jf802802g

11356 J. Agric. Food Chem. 2008, 56, 11356–11360
Synthesis and Insecticidal Activity of N-Substituted
(1,3-Thiazole)alkyl Sulfoximine Derivatives
HAIBO YU, ZHENFANG QIN, HONG DAI, XIN ZHANG, XUE QIN, TINGTING WANG,
AND JIANXIN FANG*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry and Tianjin Key Laboratory of Pesticide Science, Nankai University,
Tianjin 300071, People’s Republic of China
The N-substituted alkyl sulfoximine derivatives are a new chemical family of neonicotinoid insecticides.
We have designed and synthesized 10 (1,3-thiazole)alkyl sulfoximine derivatives. All compounds
were identified by 1H and 13C nuclear magnetic resonance (NMR), IR, and elemental analyses.
Preliminary bioassays indicated that some title compounds exhibited good insecticidal activities at
10 mg/L against Myzus persicae. The relationship between structure and biological activity was also
discussed.
KEYWORDS: Sulfoximine derivatives; bioisosterism; synthesis; insecticidal activity; pharmacophore;
peach aphid
INTRODUCTION
insecticides that lack cross-resistance to currently available insec-
ticides are imminent.
Since the introduction of midacloprid (1a) in the 1980s as
an insecticide for crop protection (1), neonicotinoid insecticides
have been rapidly developed worldwide for controlling insects
because of their high potency, low mammalian toxicity, broad
insecticidal spectra, and good systemic properties. Neonicoti-
noids, which interact with nicotinic acetylcholine receptors
(nAChR), have a higher affinity for the insect receptor than for
the mammalian receptor (2-5) and are relatively safe toward
mammals and aquatic life. Imidacloprid was the first major
active ingredient of the neonicotinoid class to reach market.
Research on molecules with a similar structure containing the
6-chloro-3-pyridylmethyl moiety led to acetamiprid (1b), ni-
tenpyram (1c), and thiacloprid (1d). The substitution of the
chloropyridyl moiety by a chlorothiazolyl group resulted in
second-generation neonicotinoid insecticides, including clothiani-
din (1e) and thiamethoxam (1f) (Figure 1) (6).
The development of resistance to insecticide in insect populations
is a well-recognized phenomenon, and there are well-documented
cases of resistance for the major classes of insecticides. Although
the neonicotinoids have proven relatively resilient to the develop-
ment of resistance, stronger resistance has been confirmed in some
populations of the whitefly, Bemisa tabaci, and the Colorado potato
beetle, Leptinotarsa decemlineata. During the late 1990s, resistant
species increased in potency, with more recently collected strains
of this whitefly exhibiting more than 100-fold resistance to
imidacloprid and comparable levels of resistance to thiamethoxam
and acetamiprid (7-9). Historically, the problem of insect resistance
to insecticides was tackled by continuously introducing new active
ingredients to replace ones lost through resistance. Therefore, new
N-Substituted (pyridyl)alkyl sulfoximine derivatives (2a-d)
(Figure 2) were described by Dow AgroSciences (10-13). It has
been reported that these compounds lack cross-resistance on insect
pests that have developed resistance to one ore more classes of
insecticides, including imidacloprid and other neonicotinoids (14).
The thiazole group can be taken as a bioisostere of the pyridine.
Hence, when the thiazolyl group was used to replace pyridyl, a
series of novel N-substituted (1,3-thiazolyl-5-yl)alkyl sulfoximine
derivatives were designed and synthesized. This paper describes
the syntheses and bioactivities. The relationship between structure
and biological activity was also discussed.
MATERIALS AND METHODS
Synthetic Procedures. Melting points were measured using a RY-1
melting-point apparatus (TaiKe Co.) and are uncorrected. 1H and 13C
nuclear magnetic resonance (NMR) spectra were recorded on a Bruker-
300 (Bruker Co.) spectrometer using tetramethylsilane (TMS) as an internal
reference. Chemical-shift values (δ) were given in parts per million (ppm).
Infrared spectra were obtained on a Bio-Rad spectrophotometer (Bio-Rad
Co.) using potassium bromide pellets or neat oils and are reported as
wavenumbers (cm-1). Mass spectra [gas chromatography-mass spec-
trometry (GC-MS)] were obtained on an Agilent 6890-5973 instrument
(Agilent Co.). Elemental analysis was performed on a Yanaco Corder MT-3
(Yanaco Co. Ltd.) elemental analyzer. Analytical thin-layer chromatography
(TLC) was carried out on precoated plates (silica gel 60 F254), and spots
were visualized with ultraviolet (UV) light. The reference compound 2a
(98%) was provided by Mrs. Aiying Guan. Cyanamide (98%), iodobenzene
diacetate (98%), and 3-chloroperoxy-benzoid acid (85%) were obtained
from Sigma (St. Louis, MO). The solvents [dichloromethane (99%), ethanol
(99%), and methanol (99%)] were used directly without further
purification.
General Procedure for the Preparation of Methyl (1,3-Thiazole-
5-yl)methyl Sulfide. To a solution of 5-halomethyl-1,3-thiazole (10
* To whom correspondence should be addressed. E-mail: fjx@
nankai.edu.cn.
10.1021/jf802802g CCC: $40.75  2008 American Chemical Society
Published on Web 11/14/2008

N-Substituted (1,3-Thiazole)alkyl Sulfoximine Derivatives
J. Agric. Food Chem., Vol. 56, No. 23, 2008 11357
Figure 1. Commercial neonicotinoids.
Figure 2. Chemical structure of N-substituted (pyridyl)alkyl sulfoximine derivatives.
Scheme 1a
a Reagents and conditions: (a) MeSNa/EtOH, room temperature (80-85%); (b) PhI(OAc)2, NH2CN/CH2Cl2, 0 °C (62-70%); (c) m-CPBA, K2CO3/EtOH (60-65%).
Scheme 2a
a Reagents and conditions: (a) MeSNa/EtOH, room temperature (90%); (b) PhI(OAc)2, NH2CN/CH2Cl2, 0 °C (90%); (c) m-CPBA, K2CO3/EtOH (85%).
Scheme 3a
under reduce pressure, and the residue was purified by silica gel (65 g)
column chromatography (1:10 ethyl acetate/petroleum ether) to afford
the title compounds as a yellow oil.
2-Chloro-5-(methylthiomethyl)-4-(trifluoromethyl)thiazole (5a).
Yield: 85% (2.10 g). 1H NMR (CDCl3, δ): 2.15 (s, 3H, CH3), 3.92 (s,
2H, CH2).
2-Bromo-5-(methylthiomethyl)-4-(trifluoromethyl)thiazole (5b).
Yield: 83% (2.42 g). 1H NMR (CDCl3, δ): 2.15 (s, 3H, CH3), 3.93 (s,
2H, CH2).
2-Ethoxy-5-(methylthiomethyl)-4-(trifluoromethyl)thiazole (5c).
Yield: 80% (2.12 g). 1H NMR (CDCl3, δ): 1.44 (t, 3H, J ) 7.2 Hz, CH3),
2.16 (s, 3H, CH3), 3.94 (s, 2H, CH2), 4.49 (q, 2H, J ) 7.2 Hz, CH2).
2-Chloro-4-methyl-5-(methylthiomethyl)thiazole (8). Yield: 90%
(1.85 g). H NMR (CDCl3, δ): 2.09 (s, 3H, CH3), 2.31 (s, 3H, CH3),
3.73 (s, 2H, CH2).
2-Chloro-5-(methylthiomethyl)thiazole (13a). Yield: 90% (1.62 g).
1H NMR (CDCl3, δ): 2.08 (s, 3H, CH3), 3.79 (s, 2H, CH2), 7.64 (s,
1H).
2-Bromo-5-(methylthiomethyl)thiazole (13b). Yield: 92% (1.93 g).
1H NMR (CDCl3, δ): 2.08 (s, 3H, CH3), 3.81 (s, 2H, CH2), 7.38 (s,
1H).
a Reagents and conditions: (a) HCl or HBr, NaNO2 (60-65%); (b) NCS or
NBS, CCl4 (65-68%); (c) MeSNa/EtOH, room temperature (90-92%) (d)
PhI(OAc)2, NH2CN/CH2Cl2, 0 °C (80-85%); (e) m-CPBA, K2CO3/EtOH, 0 °C
(65-70%).
1
mmol) in ethanol (10 mL) was added in one portion sodium thi-
omethoxide (1.05 mmol) at room temperature. The reaction was stirred
for 2 h, and then the solvent was removed under reduced pressure.
The residue was partitioned between dichloromethane (30 mL) and
dilute hydrochloric acid (10 mL, 5%), washed with saturated brine (20
mL), and dried over anhydrous Na2SO4. The solvent was again removed
General Procedure for the Preparation of N-(Cyano) Sulfilimine.
To a solution of sulfide (5 mmol) and cyanamide (10 mmol) in

11358 J. Agric. Food Chem., Vol. 56, No. 23, 2008
Yu et al.
Scheme 4a
a Reagents and conditions: (a) TFAA/CH2Cl2 (92%); (b) K2CO3, MeOH (85%).
Scheme 5a
a Reagents and conditions: (a) m-CPBA/CHCl3, 0 °C (80%); (b) NaN3, H2SO4/CHCl3 (72%); (c) RSO2Cl or RCOCl, DMAP/CH2Cl2 (80-92%).
Figure 3. Structure relationships for sulfoximine derivatives.
dichloromethane (10 mL) cooled to 0 °C was added iodobenzene
diacetate (7.5 mmol). The mixture was allowed to warm to room
temperature over 1 h; the solvent was removed under reduced pressure;
and the residue was purified by silica gel (45 g) column chromatography
(5:1 ethyl acetate/ethanol) to afford the title compounds.
peracid. The resulting mixture was extracted with dichloromethane (30
mL) and dried over anhydrous Na2SO4. The solvent was removed under
reduce pressure, and the residue was purified by silica gel (25 g) column
chromatography (10:1 ethyl acetate/ethanol) to afford the title
compounds.
N-(Cyano) Methyl (2-Chloro-1,3-thiazole-4-(trifluoromethyl)-5-
yl)methyl Sulfilimine (6a). Yield: 65% (0.93 g). White crystalline solid.
mp: 119-120 °C. 1H NMR (CDCl3, δ): 2.87 (s, 3H, CH3), 4.57 (s,
2H, CH2). IR (KBr, cm-1) ν: 2100 (CN).
N-(Cyano) Methyl (2-Bromo-1,3-thiazole-4-(trifluoromethyl)-5-
yl))methyl Sulfilimine (6b). Yield: 62% (1.01 g). White crystalline
solid. mp: 106-107 °C. 1H NMR (CDCl3, δ): 2.87 (s, 3H, CH3), 4.53
(s, 2H, CH2). IR (KBr, cm-1) ν: 2130 (CN).
N-(Cyano) Methyl (2-Chloro-1,3-thiazole-4-(trifluoromethyl)-5-
yl)methyl Sulfoximine (3a). Yield: 60% (0.36 g). White crystalline
1
solid. mp: 128-131 °C. H NMR (DMSO-d6, δ): 3.65 (s, 3H, CH3),
5.54 (q, 2H, CH2). 13C NMR (100 M Hz, DMSO-d6, δ): 39.95, 51.43,
111.23 (CN), 125.84, 154.49, 161.81, 161.85. IR (KBr, cm-1) ν: 2190
(CN).
Anal. Calcd for C7H5ClF3N3OS2: C, 27.68; H, 1.66; N, 13.84. Found:
C, 27.59; H, 1.69; N, 13.96.
N-(Cyano) Methyl (2-Ethoxy-1,3-thiazole-4-(trifluoromethyl)-5-
yl)methyl Sulfilimine (6c). Yield: 70% (1.04 g). White crystalline solid.
mp: 110-111 °C. 1H NMR (CDCl3, δ): 1.45 (t, J ) 7.2 Hz, 3H, CH3),
2.84 (s, 3H, CH3), 4.45 (q, 2H, J ) 6.9 Hz, CH2), 4.54 (q, 2H, J ) 7.2
Hz, CH2). IR (KBr, cm-1) ν: 2100 (CN).
N-(Cyano) Methyl (2-Bromo-1,3-thiazole-4-(trifluoromethyl)-5-
yl)methyl Sulfoximine (3b). Yield: 62% (0.45 g). White crystalline
1
solid. mp: 105-106 °C. H NMR (DMSO-d6, δ): 3.64 (s, 3H, CH3),
5.54 (q, 2H, CH2). 13C NMR (100 M Hz, DMSO-d6, δ): 39.99, 51.32,
111.22 (CN), 127.86, 140.52, 161.83, 166.01. IR (KBr, cm-1) ν: 2200
(CN).
N-(Cyano) Methyl (2-Chloro-1,3-thiazole-4-(methyl)-5-yl)methyl
Sulfilimine (9). Yield: 90% (1.05 g). White crystalline solid. mp: 88-90
Anal. Calcd for C7H5BrF3N3OS2: C, 24.15; H, 1.45; N, 12.07. Found:
C, 24.20; H, 1.49; N, 12.11.
1
°C. H NMR (CDCl3, δ): 2.46 (s, 3H, CH3), 2.84 (s, 3H, CH3), 4.39
(q, 2H, CH2). IR (KBr, cm-1) ν: 2120 (CN).
N-(Cyano) Methyl (2-Ethoxy-1,3-thiazole-4-(trifluoromethyl)-5-
yl)methyl Sulfoximine (3c). Yield: 65% (0.41 g). White crystalline
solid. mp: 112-113 °C. 1H NMR (DMSO-d6, δ): 1.38 (t, 3H, J ) 7.2
Hz, CH3), 3.59 (s, 3H, CH3), 4.49 (q, 2H, J ) 6.9 Hz, CH2), 5.36 (q,
2H, J ) 7.2 Hz, CH2). 13C NMR (100 M Hz, DMSO-d6, δ): 14.01,
39.99, 51.67, 69.03, 111.43 (CN), 127.84, 161.83, 166.02, 174.58. IR
(KBr, cm-1) ν: 2190 (CN).
N-(Cyano) Methyl (2-Chloro-1,3-thiazole-5-yl)methyl Sulfilimine
(14a). Yield: 80% (0.93 g). White crystalline solid. mp: 105-106 °C.
1H NMR (CDCl3, δ): 2.83 (s, 3H, CH3), 4.48 (s, 2H, CH2), 7.64 (s,
1H). IR (KBr, cm-1) ν: 2130 (CN).
N-(Cyano) Methyl (2-Bromo-1,3-thiazole-5-yl)methyl Sulfilimine
(14b). Yield: 85% (1.12 g). White crystalline solid. mp: 109-110 °C.
1H NMR (CDCl3, δ): 2.81 (s, 3H, CH3), 4.72 (q, 2H, CH2), 7.73 (s,
1H). IR (KBr, cm-1) ν: 2120 (CN).
Anal. Calcd for C9H10F3N3O2S2: C, 34.50; H, 3.22; N, 13.41. Found:
C, 34.58; H, 3.18; N, 13.49.
General Procedure for the Preparation of N-(Cyano) Sulfox-
imines. To a stirred solution 3-chloroperoxy-benzoid acid (0.81 mg, 4
mmol) in ethanol (5 mL) cooled to 0 °C was added a solution of
potassium carbonate (0.82 mg, 6 mmol) in water (4 mL). The resulting
mixture was stirred at 0 °C for 20 min. Then, the solution of the
sulfilimine starting material (2 mmol) in ethanol (4 mL) was added all
at once. The resulting mixture was stirred for 40 min at 0 °C, and
saturated sodium bisulfite (5 mL) was added to quench the excess
N-(Cyano) Methyl (2-Chloro-1,3-thiazole-4-(methyl)-5-yl)methyl
Sulfoximine (3d). Yield: 85% (0.42 g). White crystalline solid. mp: 97-99
°C. 1H NMR (DMSO-d6, δ): 2.40 (s, 3H, CH3), 3.50 (s, 3H, CH3), 5.34
(q, 2H, CH2). 13C NMR (100 M Hz, DMSO-d6, δ): 15.21, 38.68, 51.94,
111.79 (CN), 117.89, 150.85, 153.88. IR (KBr, cm-1) ν: 2198 (CN). MS
(EI) m/z (%): 250.3 ([M + 1]+, 40), 248.2 ([M - 1]+, 100).
Anal. Calcd for C7H8ClN3OS2: C, 33.66; H, 3.23; N, 16.83. Found:
C, 33.68; H, 3.21; N, 16.77.

N-Substituted (1,3-Thiazole)alkyl Sulfoximine Derivatives
J. Agric. Food Chem., Vol. 56, No. 23, 2008 11359
N-(Cyano) Methyl (2-Chloro-1,3-thiazole-5-yl)methyl Sulfoximine
(3e). Yield 65% (0.31 g). White crystalline solid. mp: 109-110 °C.
1H NMR (DMSO-d6, δ): 3.48 (s, 3H, CH3), 5.43 (q, 2H, CH2), 7.80 (s,
1H). 13C NMR (100 M Hz, DMSO-d6, δ): 38.89, 52.25, 111.71 (CN),
125.29, 114.79, 152.94. IR (KBr, cm-1) ν: 2200 (CN).
CH2), 7.69 (s, 1H). 13C NMR (100 M Hz, DMSO-d6, δ): 39.78, 45.01,
53.99, 125.04, 144.33, 162.35.
Anal. Calcd for C6H9ClN2O3S3: C, 24.95; H, 3.14; N, 9.70. Found:
C, 24.87; H, 3.15; N, 9.80.
N-(Tosyl) Methyl (2-Chloro-1,3-thiazole-5-yl)methyl Sulfoximine
(3i). Following the preparation precudure of 3h, the reaction of 3g with
4-methylbenzenesulfonyl chloride gave 3i. Yield: 80% (0.39 g). White
crystalline solid. mp: 137-138 °C. 1H NMR (CDCl3, δ): 2.42 (s, 3H,
CH3), 3.20 (s, 3H, CH3), 4.997 (q, 2H, CH2), 7.29 (d, 2H, J ) 8.4 Hz,
Ph), 7.67 (s, 1H), 7.83 (d, 2H, J ) 8.4 Hz, Ph). 13C NMR (100 M Hz,
DMSO-d6, δ): 21.53, 39.96, 54.37, 125.20, 126.57, 129.45, 140.08,
143.39, 144.36, 155.37.
Anal. Calcd for C6H6ClN3OS2: C, 30.57; H, 2.57; N, 17.83. Found:
C, 30.41; H, 2.61; N, 17.88.
N-(Cyano) Methyl (2-Bromo-1,3-thiazole-5-yl)methyl Sulfoximine
(3f). Yield: 70% (0.39 g). White crystalline solid. mp: 99-100 °C. 1H
NMR (DMSO-d6, δ): 4.03 (s, 3H, CH3), 5.32 (q, 2H, CH2), 7.77 (s,
1H). 13C NMR (100 M Hz, DMSO-d6, δ): 38.98, 52.08, 111.72 (CN),
126.74, 138.60, 146.15. IR (KBr, cm-1) ν: 2198 (CN).
Anal. Calcd for C12H13ClN2O3S3: C, 39.50; H, 3.59; N, 7.68. Found:
C, 39.40; H, 3.55; N, 7.66.
Anal. Calcd for C6H6BrN3OS2: C, 25.72; H, 2.16; N, 15.00. Found:
C, 25.82; H, 2.17; N, 15.08.
N-(4-Methylbenzoyl) Methyl (2-Chloro-1,3-thiazole-5-yl)methyl
Sulfoximine (3j). Following the preparation precudure of 3h, the
reaction of 3g with 4-methylbenzoyl chloride gave 3j. Yield: 82% (0.53
g). White crystalline solid. mp: 160-161 °C. 1H NMR (CDCl3, δ):
2.42 (s, 3H, CH3), 3.27 (s, 3H, CH3), 4.93 (d, 1H, J ) 10.8 Hz, CH),
5.06 (d, 1H, J ) 10.8 Hz, CH), 7.24 (d, 2H, J ) 6 Hz, Ar-H), 7.62
(s, 1H), 8.01 (d, 2H, J ) 6 Hz, Ar-H).
N-(Trifluoroacetyl) Methyl (2-Chloro-1,3-thiazole-5-yl)methyl
Sulfoximine (15). To a stirring solution of sulfoximine 3e (0.24 g, 1.0
mmol) in CH2Cl2 (18 mL) at 0 °C, TFAA (417.0 µL, 3.0 mmol) was
added. The mixture was allowed to react at room temperature until the
starting material was consumed (monitored by TLC). The mixture was
poured into water. The aqueous layer was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered, and evaporated. The residue was purified by flash silica
gel (20 g) column chromatography (1:2 ethyl acetate/petroleum ether)
to afford the title compound 3g (0.28 g, 92% yeild) as a colorless oil.
1H NMR (CDCl3, δ): 3.33 (s, 3H, CH3), 4.96 (s, CH2, CH2), 7.68 (s,
1H). 13C NMR (100 M Hz, DMSO-d6, δ): 37.93, 52.47, 123.52, 144.47,
155.85, 162.31, 162.35.
Anal. Calcd for C13H13ClN2O2S2: C, 47.48; H, 3.98; N, 8.52; Found:
C,47.58; H, 3.89; N, 8.58.
Biology Assay. The bioassay was performed on a representative test
organism reared in the laboratory. The bioassay was repeated at 25 (
1 °C according to statistical requirements. Assessments were made on
a dead/alive basis, and mortality rates were corrected using Abbott’s
formula (15). Evaluations are based on a percentage scale of 0-100,
in which 0 ) no activity and 100 ) total kill.
Anal. Calcd for C7H6ClF3N2O2S2: C, 27.41; H, 1.97; N, 9.13. Found:
C, 27.51; H, 1.98; N, 9.19.
2-Chloro-5-(S-methylsulfonimidoylmethyl)thiazole (3g). Method
A. To a stirring solution of 15 (0.31 g, 1.0 mmol) in MeOH (7 mL)
was added K2CO3 (0.38 g, 3.0 mmol). The mixture was allowed to
react at room temperature for 30 min until the starting material was
consumed (monitored by TLC). The solvent was removed under reduced
pressure, and the residue was purified by flash silica gel (18 g) column
chromatography (10:1 ethyl acetate/ethanol) to afford the title compound
The insecticidal activities of the title compounds were tested against
peach aphid (Myzus persicae) by foliar application. About 60 aphids
were transferred to the shoot with 3-5 fresh leaves of horsebean. The
shoot with aphids was cut and dipped into the solution of 10 mg/L of
test compound for 2 s, after removing extra solutions on the leaf; the
aphids were raised in the shoot at 25 ( 1 °C and 85% relative humidity
for 16 h. Each experiment for one compound was triplicated. The
revised death rate was calculated by Abbott’s formula. The reference
compound was compound 2a.
1
3g (0.18 g, 82% yield) as a yellow oil. H NMR (CDCl3, δ): 2.99 (s,
3H, CH3), 4.46 (q, 2H, CH2), 7.57 (s, 1H).
Anal. Calcd for C5H7ClN2OS2: C, 28.50; H, 3.35; N, 13.30. Found:
C, 28.52; H, 3.30; N, 13.29.
RESULTS AND DISCUSSION
Method B. To a solution of 2-chloro-5-(methylthiomethyl)thiazole
13a (0.90 g, 5 mmol) in CHCl3 (15 mL) at -5 °C was added a solution
of m-MCPBA (1.00 g, 85%, 5 mmol) in CHCl3 over the course of 3 h.
The solution was stirred an additional 1 h, and then it was concentrated
and purified by flash silica gel (45 g) chromatography (10:1 ethyl
acetate/ethanol) to afford 2-chloro-5-(methylsulfinylmethyl)thiazole 16
(0.78 g, 80% yield) as a white solid. mp: 53-55 °C. 1H NMR (CDCl3,
δ): 2.51 (s, 3H, CH3), 4.00 (d, 1H, J ) 14.1 Hz, CH), 4.22 (d, 1H, J
) 14.1 Hz, CH), 7.50 (s, 1H).
To a solution of 2-chloro-5-(methylsulfinylmethyl)thiazole 16 (0.98
g, 5 mmol) in CHCl3 (10 mL) at -5 °C was added sodium azide (0.52
g, 8 mmol) and H2SO4 (2 mL). The reaction was heated to 60 °C and
kept the temperature for 4 h. Then, the liquid was decanted into a
separated flask, and residual syrup was dissolved in water (10 mL),
basified with K2CO3, and extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over anhydrous MgSO4, concen-
trated, and purified by flash silica gel (40 g) column chromatography
(10:1 ethyl acetate/ethanol) to afford the title compound 3g (0.18 g,
72% yield) as a yellow oil.
Synthesis. The N-cyano sulfoximine derivatives 3a-f were
prepared according to Schemes 1-3. Methyl (1,3-thiazolyl-5-
yl)methyl sulfide derivatives of 5, 8, and 13 were prepared starting
from 5-halomethyl-1,3-thiazole. 5-Halomethyl-1,3-thiazole were
prepared according to the procedures in the literature (16, 17). The
syntheses of 12a and 12b are described in Scheme 3. 2-Amine-
5-methyl-thiazole was subjected to the Sandmeyer reaction to give
2-halo analogues, which convereted into 5-halomethyl derivatives
12a and 12b by side-chain halogeration (18). Sulfide is oxidized
with iodobenzene diacetate in the presence of cyanamide at 0 °C
to give sulfilimine derivatives 6, 9, and 14. The reaction was carried
out in a polar aprotic solvent, such as dichloromethane. The
sulfilimine was oxidized with 3-chloroperoxy-benzoid acid (m-
CPBA), and potassium carbonate as a base was employed to
neutralize the acidity of m-CPBA (Schemes 1-3) and afforded
the N-cyano sulfoximines 3a-f in good (60-85%) yields (12).
Protic polar solvent ethanol and water were used to increase the
solubility of sulfilimines starting material.
To synthesize NH-free sulfoximine 3g, two methods were
explored (Schemes 4 and 5). The N-cyano group proved to be
easily cleaved upon treatment with TFAA, affording N-
trifluoroacetyl sulfoximine 15 in 92% yield. Sulfoximine 15 was
converted into NH-free sulfoximine 3g by methanolysis of the
trifluoroacetyl moiety in 85% yield (Scheme 4). In another
method, first, oxidation of 13a with m-CPBA afforded the
sulfoxide 16 in good (90%) yield. Finally, sulfoxide was
imintated with sodium azide in the presence of concentrated
N-(Methylsulfonyl) Methyl (2-Chloro-1,3-thiazole-5-yl)methyl
Sulfoximine (3h). A mixture of 3g (0.42 g, 2 mmol), DMAP (0.25 g,
2 mmol), and methyl sulfonyl chloride (0.23 g, 2 mmol) in CH2Cl2 (5
mL) was stirred at room temperature for 1 h. The reaction mixture
were treated with water (10 mL) and extracted with CH2Cl2 (2 × 5
mL), and the combined extracts were dried over anhydrous MgSO4.
The organic phase were evaporated under reduced pressure, and the
crude product were purified by flash silica gel column (30 g) column
chromatography (1:2 ethyl acetate/petroleum ether) to afford the tiltle
compound (0.52 g, 92% yield) as a white solid. mp: 132-134 °C. 1H
NMR (CDCl3, δ): 3.15 (s, 3H, CH3), 3.21 (s, 1H, CH3), 4.97 (q, 2H,

11360 J. Agric. Food Chem., Vol. 56, No. 23, 2008
Yu et al.
Table 1. Insecticidal Activities against M. persicae of Compounds 3a-j
and 2a
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compound
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3a
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Cl
Cl
Cl
CH3SO2
4-CH3-Ph-SO2
4-CH3-Ph-CO
3j
2a
H
sulfuric acid under heating to provide NH-free sulfoximine
(Scheme 5) (19). The title compounds 3h-j were prepared by
the reaction of sulfonyl or benzoyl chloride with NH-free
sulfoximine in dichloromethane, using DMAP as the acid
acceptor (Scheme 5).
Structure-Activity Relationship. Some title compounds
exhibited good insecticidal activities at 10 mg/L against M.
persicae.
The results of insecticidal activities are listed in Table 1.
The insecticidal activity of compound 3a is similar to the
reference compound 2a and better than other compounds. The
structure-activity relationships for the pharmacophore S(O)d
N-X and the heterocyclic group thiazole were elucidated. A
summary of results is outlined in Figure 3.
We first focused our attention on the influence of the
pharmacophore S(O)dN-X. Among the compounds tested, the
best activity was observed for the N-cyano sulfoximine phar-
macophore (S(O)dN-CN). Replacement of the cyano group
by a tosyl, 4-methylbenzoyl, or a methylsulfonyl group clearly
diminished the activity, while the compounds with X ) H were
not effective at 10 mg/L.
The structure-activity relationships for the thiazole group
were also investigated. 2-Chloro-4-trifluomethyl-5-thiazolyl
derivatives gave the best activity, and the 2-bromo-5-thiazolyl
compound was somewhat less active. Replacement of the chloro
group by ethoxy caused a loss of activity. Adding a methyl
group at the 4 position of the thiazole heterocycle led to a
significant decrease in activity. These data show that efficacy
is strongly influenced by the nature of the substitutes and their
position on the thiazolyl ring.
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the N-cyano sulfoximine (S(O)dN-CN) is the best. 2-Chloro-
4-trifluomethyl-5-thiazolyl is the most promising thiazole
heterocyclic system.
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Received for review September 11, 2008. Revised manuscript received
October 24, 2008. Accepted October 27, 2008. We gratefully acknowl-
edge the National Natural Science Foundation of China (NNSFC)
(20772068) and the National Key Project of Scientific and Technical
Supporting Programs funded by the Ministry of Science and Technology
of China (2006BAE01A01-5) for financial support.
ACKNOWLEDGMENT
The authors thank Dr. Bin Li for providing us invaluable
suggestions. We thank Mr. Hong Zhang and Mrs. Yanmei Luo
for the test of biological activities. We thank Mrs. Aiying Guan
for providing us compound 2a.
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