Synthesis of 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl containing 1,2,3-thiadiazole derivatives via ugi reaction and their biological activities

Article abstract of DOI:10.1002/cjoc.201190080

A series of novel 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl containing 4-methyl-1,2,3-thiadiazole derivatives were designed and synthesized via Ugi reaction. Their structures were confirmed by IR, ¹H NMR, ¹³C NMR and high-resolution mass spectroscopy. The preliminary bioassay results indicated that some title compounds had good fungicide activity at 50 μg/mL; most of the compounds presented a certain degree of direct inhibition activity, good inactivation and curative activity against tobacco mosaic virus at 500 μg/mL and 100 μg/mL; some compounds showed good larvicidal activity against Plutella xylostella L. at 200 μg/mL and excellent larvicidal activities against Culex pipiens pallens at 2 μg/mL. Copyright

Full text of DOI:10.1002/cjoc.201190080

FULL PAPER
Synthesis of 3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl
Containing 1,2,3-Thiadiazole Derivatives via Ugi
Reaction and Their Biological Activities†
Wang, Shouxina,b(王守信)
Fu, Yifengb(付一峰)
Wang, Huanb(王唤)
Fan, Zhijin*,b(范志金)
Mi, Nab(米娜)
Zhang, Jufangb(张聚方)
Zhang, Zhengcaib(张正财)
Belskaya, Nataliya P.c
Bakulev, Vasiliy A.c
a School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
b State Key Laboratory of Elemento Organic Chemistry, Nankai University, Tianjin 300071, China
c The Ural Federal University Named After the First President of Russia B. N. Yeltsin,
Yeltsin UrFU, 620002, Ekaterinburg, Russia
A series of novel 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl containing 4-methyl-1,2,3-thiadiazole de-
1
rivatives were designed and synthesized via Ugi reaction. Their structures were confirmed by IR, H NMR, 13C
NMR and high-resolution mass spectroscopy. The preliminary bioassay results indicated that some title compounds
had good fungicide activity at 50 µg/mL; most of the compounds presented a certain degree of direct inhibition ac-
tivity, good inactivation and curative activity against tobacco mosaic virus at 500 µg/mL and 100 µg/mL; some
compounds showed good larvicidal activity against Plutella xylostella L. at 200 µg/mL and excellent larvicidal ac-
tivities against Culex pipiens pallens at 2 µg/mL.
Keywords 1,2,3-thiadiazole, Ugi reaction, synthesis design, biological activity, multicomponent reactions
Introduction
it is convenient to implement structural modification via
alternation of diverse starting materials and is applied in
combinatorial chemistry.12,13
1,2,3-Thiadiazoles are a versatile class of compounds
which present a wide range of biological activities such
as antivirus activity,1 systemic acquired resistance,2,3 fun-
gicide activity,2,4 insecticide activity,5 antitumor activity,6
and herbicide activity.7,8 Moreover, the properties of easy
breakdown of the 1,2,3-thiadiazole ring into low molecu-
lar weight compounds through releasing of N2 favor the
use of its derivatives as environmental friendly pesticide
candidates with low toxicity.9
Combinatorial chemistry has attracted much atten-
tion as an efficient tool for drug discovery. The use of
combinatorial chemistry or parallel synthesis for the
optimization of highly promising lead compounds aris-
ing from the drug-discovery processes around privileged
structures and their combinations has been successful in
many science and development fields.10 The Ugi reac-
tion is one of the most prominent multiple component
coupling reactions (MCRs) due to its wide applications
in organic syntheses and medicinal chemistry.11 Ugi
reaction is an efficient and convenient green method to
combine several active moieties into one molecule, and
Fluorine and chlorine containing compounds have sig-
nificant applications in drug and pesticide research and
development. Introducing F and Cl into target molecules
can be a feasible method to improve its biological activi-
ties. Xu et al.14a has reported that some fluoroalkoxyl
containing S-methyl benzo-1,2,3-thiadiazole-7-carboxyl-
ate derivatives exhibited good systemic acquire resistance.
The excellent example for novel pesticide development is
the successful discovery of fungicide flumorph, which
was designed and synthesized by substituting the Cl of the
dimethomorph by the F.14b Our group4c,15 has designed
and synthesized series of 1,2,3-thiadiazole derivatives
containing 3-chloro-4-methyl-phenyl and 3-fluoro-4-
methylphenyl via Ugi four-components condensation re-
action (U-4CR). The results indicated that some com-
pounds showed broad-spectrum of activities against sev-
eral fungi tested and excellent potential antivirus activities.
Encouraged by these observations, here we introduced
3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl, the ac-
tive substructure of a commercial insecticide hexaflu-
*
E-mail: fanzj@nankai.edu.cn; Tel.: 0086-022-23499464
Received October 7, 2010; revised November 23, 2010; accepted December 21, 2010.
Project supported by the National Natural Science Foundation of China (Nos. 20872071, 20911120069), the Tianjin Natural Science Foundation (No.
10JCZDJC17500), the National Key Project for Basic Research (No. 2010CB126105), the National Key Technology Research and Development
Program (Nos. 2011BAE06B02, 2011BAE06B05) and the Foundation of Achievements Transformation and Spreading of Tianjin Agricultural Sci-
ence and Technology (No. 201002250), the Russian Foundation for Basic Research (Nos. RFBR 08-03-00376 a and RFBR/NNSF 08-03-92208 a).
† Dedicated to Professor Chuanfan Qian for her 80th birthday.
288
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 288— 296

Synthesis of 3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl Containing 1,2,3-Thiadiazole
muron, into the 1,2,3-thiadiazoles via Ugi U-4CR. Like
our previous work,4c 4-methyl-1,2,3-thiadiazole-5-car-
boxylic acid was chosen as the acid component; substi-
tuted benzaldehydes were chosen as the carbonyl compo-
nents; cyclohexyl isocyanide was chosen as the isocyanide
component. This will provide useful information for the
study of the structure-activity relationship of these new
structures for their insecticide activity. The synthetic route
was shown in Scheme 1. The structures of title com-
carboxylic acid (0.43 g, 3.0 mmol), and cyclohexyl iso-
cyanide (0.33 g, 3.0 mmol) were added to a solution of
benzaldehyde (0.35 g, 3.0 mmol) in 10 mL of methanol
in sequence. The color of the mixture grew darker dur-
ing this procedure. The solution was then stirred for
another 1 h at room temperature; afterward, removal of
solvent under reduced pressure and purification by flash
column chromatography on silica gel using ethyl acetate
and petroleum ether (60—90 ℃; 1∶3, V∶V) as an
eluent obtain the products 5a—5r.
1
pounds were confirmed by IR, H NMR, 13C NMR and
high-resolution mass spectroscopy.
N-[2-(Cyclohexylamino)-2-oxo-1-phenylethyl]-N-
[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-
methyl-1,2,3-thiadiazole-5-carboxamide (5a) White
Scheme 1 General synthetic route of the title compounds 5a— 5r
1
solid, yield 40%, m.p. 178—181 ℃; H NMR (CDCl3,
400 MHz) δ: 7.38—7.05 (m, 7H, ph-H), 6.18 (s, 1H,
COCH), 6.12—5.85 (m, 1H, OCF2CF2H), 5.37 (d, J＝7.6
Hz, 1H, CONH), 3.90—3.82 (m, 1H, cyclohexyl-H), 2.88
(s, 3H, thiadiazolyl-CH3), 2.02—1.04 (m, 10H, cyclo-
hexyl-H); 13C NMR (CDCl3, 400 MHz) δ: 167.3, 161.1,
142.4, 140.7, 137.7, 132.8, 132.2, 130.8, 130.3, 129.7,
129.1, 65.7, 49.3, 32.8, 25.4, 24.8, 24.7, 14.0; IR (KBr) ν:
3280, 3080, 2933, 2855, 1647, 1557, 1459, 1353, 1285,
－1
1233, 1142 cm ; HRMS calcd for C26H24Cl2F4N4O3S
(M＋H)＋ 619.0955, found 619.0959.
N-[1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5b)
R ＝ phenyl (5a); p-chlorophenyl (5b); o-chlorophenyl (5c);
m-chlorophenyl (5d); o-nitrophenyl (5e); m-nitrophenyl (5f);
p-nitrophenyl (5g); m-methylbenzyl (5h); p-methylbenzyl (5i);
o-fluorophenyl (5j); m-fluorophenyl (5k); m-trifluoromethylphenyl (5l);
p-trifluoromethylphenyl (5m); m-hydroxyphenyl (5n); p-hydroxyphenyl
(5o); o-methoxyphenyl (5p); m-methoxyphenyl (5q); p-methoxy-
phenyl (5r).
1
White solid, yield 30%, m.p. 187—189 ℃; H NMR
(CDCl3, 400 MHz) δ: 7.38—7.05 (m, 6H, ph-H), 6.18 (s,
1H, COCH), 6.14—5.87 (m, 1H, OCF2CF2H), 5.37 (d,
J ＝ 7.6 Hz, 1H, CONH), 3.90 — 3.83 (m, 1H,
cyclohexyl-H), 2.87 (s, 3H, thiadiazolyl-CH3), 2.01—
13
1.08 (m, 10H, cyclohexyl-H); C NMR (CDCl3, 400
MHz) δ: 167.3, 161.1, 160.8, 149.7, 142.5, 140.8, 137.4,
133.2, 132.1, 131.0, 130.8, 127.4, 125.0, 60.7, 49.6,
32.4, 25.3, 24.8, 24.6, 13.7; IR (KBr) ν: 3293, 3077,
2937, 2856, 1649, 1552, 1460, 1347, 1287, 1234, 115＋2
Experimental
Materials and instruments
－1
cm ; HRMS calcd for C26H23Cl3F4N4O3S (M＋H)
Melting points of all compounds were determined on
an X-4 binocular microscope (Gongyi Technical In-
strument Co., Henan, China), and the thermometer was
not corrected. Proton NMR spectra were obtained using
a Bruker AVANCE-400 MHz spectrometer, and
chemical shift values (δ) were reported with deuteron
chloroform (CDCl3) as the solvent and tetramethylsilane
(TMS) as the internal standard. High resolution mass
spectrometry (HRMS) data were obtained on an
FTICR-MS Varian 7.0T FTICR-MS instrument. All
solvents and liquid reagents were of analytical reagent
grade and were dried in advance and distilled before use.
Column chromatography purification was carried out by
using silica gel. 4-Methyl-1,2,3-thiadiazole-5-carboxylic
acid (1) and cyclohexyl isocyanide (4) were synthesized
according to Ref. 2 and 4c, respectively.
653.0565, found 653.0573.
N-[1-(2-Chlorophenyl)-2-(cyclohexylamino)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5c)
1
White solid, yield 62%, m.p. 163—166 ℃; H NMR
(CDCl3, 400 MHz) δ: 7.43—7.02 (m, 6H, ph-H), 6.56 (s,
1H, COCH), 6.10—5.84 (m, 1H, OCF2CF2H), 5.52 (d,
J ＝ 6.4 Hz, 1H, CONH), 3.91 — 3.87 (m, 1H,
cyclohexyl-H), 2.87 (s, 3H, thiadiazolyl-CH3), 2.06—
1.09 (m, 10H, cyclohexyl-H); 13C NMR (CDCl3, 400
MHz) δ: 167.4, 161.3, 160.9, 149.7, 142.4, 140.7, 137.3,
135.2, 131.3, 131.0, 130.7, 129.8, 127.3, 62.3, 49.5,
32.6, 25.4, 24.8, 24.7, 13.8; IR (KBr) ν: 3286, 3079,
2934, 2857, 1651, 1561, 1460, 1383, 1341, 1286, 1226,
－1
1159, 1136 cm ; HRMS calcd for C26H23Cl3F4N4O3S
(M＋H)＋ 653.0565, found 653.0570.
General procedure for preparation of the title com-
N-[1-(3-Chlorophenyl)-2-(cyclohexylamino)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5d)
pounds 5a—5r
3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)benzenam-
ine (0.83 g, 3.0 mmol), 4-methyl-1,2,3-thiadiazole-5-
1
White solid, yield 40%, m.p. 119—123 ℃; H NMR
Chin. J. Chem. 2011, 29, 288— 296
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
289

Wang et al.
FULL PAPER
(CDCl3, 400 MHz) δ: 7.72—7.00 (m, 6H, ph-H), 6.09 (s,
1H, COCH), 6.13—5.87 (m, 1H, OCF2CF2H), 5.43 (d,
J ＝ 6.4 Hz, 1H, CONH), 3.89 — 3.83 (m, 1H,
cyclohexyl-H), 2.88 (s, 3H, thiadiazolyl-CH3), 2.02—
1.12 (m, 10H, cyclohexyl-H); 13C NMR (CDCl3, 400
MHz) δ: 166.9, 161.9, 161.1, 142.6, 140.4, 137.4, 135.1,
134.7, 132.1, 131.0, 130.5, 130.2, 129.8, 128.3, 65.1,
49.5, 32.7, 25.3, 24.8, 24.7, 14.1; IR (KBr) ν: 3282,
3075, 2919, 2857, 1654, 1568, 1458, 1380, 1285, 1220,
N-[2-(Cyclohexylamino)-2-oxo-1-m-tolylethyl]-N-
(3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl)-4-
methyl-1,2,3-thiadiazole-5-carboxamide (5h) White
1
solid, yield 24%, m.p. 138—140 ℃; H NMR (CDCl3,
400 MHz) δ: 7.52—6.88 (m, 6H, ph-H), 6.14 (s, 1H,
COCH), 6.12—5.86 (m, 1H, OCF2CF2H), 5.37 (d, J＝8.0
Hz, 1H, CONH), 3.88—3.82 (m, 1H, cyclohexyl-H), 2.89
(s, 3H, thiadiazolyl-CH3), 2.25 (s, 3H, ph-CH3), 2.01—
1.10 (m, 10H, cyclohexyl-H); 13C NMR (CDCl3, 400
MHz) δ: 167.5, 161.5, 161.0, 142.3, 140.8, 139.1, 137.7,
132.6, 132.2, 131.0, 130.6, 130.3, 128.9, 127.4, 65.6,
49.3, 32.8, 25.4, 24.8, 24.7, 14.0; IR (KBr) ν: 3274,
3078, 2931, 2856, 1651, 1559, 1458, 1385, 1345, 1288,
－1
1151, 1135, 1114 cm ; HRMS calcd for C26H23Cl3-
F4N4O3S (M＋H)＋ 653.0565, found 653.0570.
N-[2-(Cyclohexylamino)-1-(2-nitrophenyl)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5e)
－1
1225, 1120 cm ; HRMS calcd for C27H26Cl2F4N4O3S
White solid, yield 25%, m.p. 189—191 ℃; H NMR
(M＋H)＋ 633.1112, found 633.1118.
1
(CDCl3, 400 MHz) δ: 7.97—7.28 (m, 6H, ph-H), 6.57 (s,
1H, COCH), 6.10—5.84 (m, 1H, OCF2CF2H), 5.61 (d,
J ＝ 6.4 Hz, 1H, CONH), 3.87 — 3.84 (m, 1H,
cyclohexyl-H), 2.88 (s, 3H, thiadiazolyl-CH3), 2.05—
N-[2-(Cyclohexylamino)-2-oxo-1-p-tolylethyl]-N-
(3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl)-4-
methyl-1,2,3-thiadiazole-5-carboxamide (5i) White
1
solid, yield 38%, m.p. 125—127 ℃; H NMR (CDCl3,
13
1.09 (m, 10H, cyclohexyl-H); C NMR (CDCl3, 400
400 MHz) δ: 7.35 (s, 1H, ph-H), 7.12 (s, 1H, ph-H), 7.08
(d, J＝8.0 Hz, 2H, ph-H), 6.98 (d, J＝8.0 Hz, 2H, ph-H),
6.13 (s, 1H, COCH), 6.13—5.86 (m, 1H, OCF2CF2H),
5.36 (d, J＝8.0 Hz, 1H, CONH), 3.87—3.83 (m, 1H,
cyclohexyl-H), 2.88 (s, 3H, thiadiazolyl-CH3), 2.30 (s,
3H, ph-CH3), 2.01 — 1.01 (m, 10H, cyclohexyl-H);
13C NMR (CDCl3, 400 MHz) δ: 167.6, 161.5, 161.0,
142.3, 140.9, 139.8, 137.8, 132.2, 130.6, 131.0, 130.2,
129.7, 65.5, 49.3, 32.8, 25.4, 24.8, 24.7, 14.0; IR (KBr)
ν: 3321, 3379, 2938, 2956, 1653, 1562, 1525, 1460,
MHz) δ: 167.3, 161.1, 160.9, 149.8, 142.5, 140.8, 137.4,
133.2, 132.1, 131.0, 130.8, 127.4, 125.0, 60.6, 49.6, 32.4,
25.3, 24.8, 24.6, 13.7; IR (KBr) ν: 3302, 3076, 2936,
2857, 1650, 1561, 1527, 1460, 1349, 1286, 1227,113＋2
－1
cm ; HRMS calcd for C26H23Cl2F4N5O5S (M＋H)
664.0806, found 664.0815.
N-[2-(Cyclohexylamino)-1-(3-nitrophenyl)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5f)
1
－1
White solid, yield 40%, m.p. 214—216 ℃; H NMR
1392, 1338, 1289, 1235, 1158, 1126 cm ; HRMS calcd
(CDCl3, 400 MHz) δ: 8.19 (d, J＝7.2 Hz, 1H, ph-H), 8.14
(s, 1H, ph-H), 7.67—7.31 (m, 4H, ph-H), 6.19 (s, 1H,
COCH), 5.86—6.18 (m, 1H, OCF2CF2H), 5.53 (d, J＝8.4
Hz, 1H, CONH), 3.91—3.86 (m, 1H, cyclohexyl-H),
2.90 (s, 3H, thiadiazolyl-CH3), 2.04—1.05 (m, 10H,
cyclohexyl-H); 13C NMR (CDCl3, 400 MHz) δ: 166.7,
162.0, 161.1, 148.1, 142.7, 140.3, 137.2, 136.0, 135.1,
132.2, 131.3, 130.0.4, 125.3, 124.2, 64.7, 49.5, 32.6, 25.3,
24.7, 24.6, 14.0; IR (KBr) ν: 3264, 3079, 2933, 2855,
1649, 1561, 1536, 1457, 1349, 1286, 1253, 1224, 112＋5
for C27H26Cl2F4N4O3S (M ＋ H) ＋ 633.1112, found
633.1118.
N-[2-(Cyclohexylamino)-1-(2-fluorophenyl)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5j)
1
Light yellow oil, yield 36%; H NMR (CDCl3, 400
MHz) δ: 7.32—6.98 (m, 4H, ph-H), 6.64 (s, 2H, ph-H),
6.42 (s, 1H, COCH), 6.15—5.85 (m, 1H, OCF2CF2H),
5.54 (d, J＝5.2 Hz, 1H, CONH), 3.89—3.84 (m, 1H,
cyclohexyl-H), 2.88 (s, 3H, thiadiazolyl-CH3), 2.25 (s,
3H, ph-CH3), 2.04 — 1.06 (m, 10H, cyclohexyl-H);
13C NMR (CDCl3, 400 MHz) δ: 167.1, 161.9, 159.5,
146.2, 142.5, 140.7, 137.4, 132.8, 131.9, 131.8, 131.0,
130.8, 130.5, 124.7, 58.9, 49.5, 32.6, 25.3, 24.8, 24.6,
13.8; IR (KBr) ν: 3292, 3078, 2935, 2858, 1653, 1563,
－1
cm ; HRMS calcd for C26H23Cl2F4N5O5S (M＋H)
664.0806, found 664.0812.
N-[2-(Cyclohexylamino)-1-(4-nitrophenyl)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5g)
1
－1
White solid, yield 34%, m.p. 179—181 ℃; H NMR
1460, 1286, 1215, 1166, 1131 cm ; HRMS calcd for
(CDCl3, 400 MHz) δ: 8.16 (d, J＝7.6 Hz, 2H, ph-H),
7.43 (d, J＝8.0 Hz, 2H, ph-H), 7.35 (s, 1H, ph-H), 7.12
(s, 1H, ph-H), 6.15 (s, 1H, COCH), 6.12—5.86 (m, 1H,
OCF2CF2H), 5.48 (d, J＝7.6 Hz, 1H, CONH), 3.88—
3.83 (m, 1H, cyclohexyl-H), 2.89 (s, 3H, thiadiazolyl-
CH3), 2.03—1.05 (m, 10H, cyclohexyl-H); 13C NMR
(CDCl3, 400 MHz) δ: 166.5, 162.1, 161.1, 148.2, 142.8,
140.1, 140.0, 137.4, 132.0, 131.3, 123.9, 65.0, 49.6, 32.7,
25.3, 24.8, 24.7, 14.1; IR (KBr) ν: 3325, 3077, 2932,
2857, 1650, 1548, 1459, 1347, 1280, 1214, 1161, 113＋3
C26H23Cl2F5N4O3S (M＋H)＋ 637.0861, found 637.0866.
N-[2-(Cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-
ethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (5k)
1
White solid, yield 36%, m.p. 162—164 ℃; H NMR
(CDCl3, 400 MHz) δ: 7.30—7.25 (m, 3H, ph-H), 7.06—
7.20 (t, J＝8.0 Hz, 1H, ph-H), 6.94—6.92 (m, 2H, ph-H),
6.10 (s, 1H, COCH), 6.13—5.87 (m, 1H, OCF2CF2H),
5.42 (d, J＝8.0 Hz, 1H, CONH), 3.90—3.81 (m, 1H,
cyclohexyl-H), 2.89 (s, 3H, thiadiazolyl-CH3), 2.02—
1.03 (m, 10H, cyclohexyl-H); 13C NMR (CDCl3, 400
MHz) δ: 167.0, 163.9, 161.8, 161.5, 161.0, 142.5, 140.5,
－1
cm ; HRMS calcd for C26H23Cl2F4N5O5S (M＋H)
664.0806, found 664.0818.
290
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 288— 296

Synthesis of 3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl Containing 1,2,3-Thiadiazole
137.5, 135.2, 135.1, 132.1, 130.9, 130.7, 130.6, 126.0,
117.4, 117.2, 116.7, 116.5, 65.1, 49.4, 32.7, 25.3, 24.8,
24.6, 14.0; IR (KBr) ν: 3303, 3090, 2936, 2854, 1645,
OCF2CF2H), 5.63 (s, 1H, OH), 5.44 (d, J＝8.0 Hz, 1H,
CONH), 3.88—3.81 (m, 1H, cyclohexyl-H), 2.87 (s, 3H,
thiadiazolyl-CH3), 2.00—1.02 (m, 10H, cyclohexyl-H);
13C NMR (CDCl3, 400 MHz) δ: 166.6, 162.0, 161.1,
148.1, 142.7, 140.3, 137.3, 136.0, 135.1, 132.2, 131.3,
130.0, 125.3, 124.3, 64.8, 49.5, 32.6, 25.3, 24.7, 24.6,
14.0; IR (KBr) ν: 3271, 3086, 2933, 2856, 1648, 1560,
－1
1560, 1460, 1390, 1352, 1288, 1167, ＋1124 cm ; HRMS
calcd for C26H23Cl2F5N4O3S (M＋H) 637.0861, found
637.0862.
N-{2-(Cyclohexylamino)-2-oxo-1-[3-(trifluorometh-
yl)phenyl]ethyl}-N-[3,5-dichloro-4-(1,1,2,2-tetrafluo-
roethoxy)phenyl]-4-methyl-1,2,3-thiadiazole-5-carb-
oxamide (5l) White solid, yield 36%, m.p. 164—166
－1
1518, 1459, 1384, 1351, 1287, 1216, 1127 cm ; HRMS
calcd for C26H24Cl2F4N4O4S (M＋H)＋ 635.0904, found
635.0914.
1
℃; H NMR (CDCl3, 400 MHz) δ: 7.60—7.26 (m, 6H,
N-[2-(Cyclohexylamino)-1-(2-methoxyphenyl)-2-
oxoethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenyl]-4-methyl-1,2,3-thiadiazole-5-carbox-
amide (5p) White solid, yield 33%, m.p. 144—145
ph-H), 6.20 (s, 1H, COCH), 6.12 — 5.87 (m, 1H,
OCF2CF2H), 5.46 (d, J＝8.0 Hz, 1H, CONH), 3.92—
3.83 (m, 1H, cyclohexyl-H), 2.90 (s, 3H, thiadiazolyl-
CH3), 2.05—1.03 (m, 10H, cyclohexyl-H); 13C NMR
(CDCl3, 400 MHz) δ: 166.9, 162.0, 161.0, 142.6, 140.3,
137.2, 134.0, 133.5, 132.2, 131.7, 131.4, 131.1, 129.6,
127.3, 127.2, 126.2, 124.7, 121.9, 65.0, 49.5, 32.7, 32.6,
1
℃; H NMR (CDCl3, 400 MHz) δ: 7.30—6.79 (m, 6H,
ph-H), 6.43 (s, 1H, COCH), 6.10 — 5.84 (m, 1H,
OCF2CF2H), 5.38 (d, J＝8.0 Hz, 1H, CONH), 3.93—
3.88 (m, 1H, cyclohexyl-H), 3.80 (s, 3H, OCH3), 2.88 (s,
25.3, 24.7, 24.6, 14.0; IR (KBr) ν: 3292, 3081, 2936,
3H, thiadiazolyl-CH3), 2.01—1.02 (m, 10H, cyclohexyl-
H); 13C NMR (CDCl3, 400 MHz) δ: 167.8, 157.2, 142.0,
141.2, 137.8, 131.7, 131.3, 131.1, 120.9, 120.8, 110.5,
107.4, 60.3, 55.3, 49.2, 32.8, 25.4, 24.8, 24.7, 13.9; IR
(KBr) ν: 3282, 3074, 2930, 2857, 16－54, 1557, 1494, 1461,
2857, 1651, 1559, 1459, 1332, 1288, 1222, 1171, 113＋1
－1
cm ; HRMS calcd for C27H23Cl2F7N4O3S (M＋H)
687.0829, found 687.0832.
N-{2-(Cyclohexylamino)-2-oxo-1-[4-(trifluorometh-
yl)phenyl]ethyl}-N-[3,5-dichloro-4-(1,1,2,2-tetrafluo-
roethoxy)phenyl]-4-methyl-1,2,3-thiadiazole-5-carb-
oxamide (5m) White solid, yield 60%, m.p. 176—178
1
1386, 1289, 1253, 1224, 1112 cm ; HRMS calcd for
C27H26Cl2F4N4O4S (M＋H)＋ 649.1061, found 649.1065.
N-[2-(Cyclohexylamino)-1-(3-methoxyphenyl)-2-
oxoethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenyl]-4-methyl-1,2,3-thiadiazole-5-carbox-
amide (5q) White solid, yield 27%, m.p. 116—118
1
℃; H NMR (CDCl3, 400 MHz) δ: 7.57—6.96 (m, 6H,
ph-H), 6.15 (s, 1H, COCH), 6.12 — 5.86 (m, 1H,
OCF2CF2H), 5.42 (d, J＝8.0 Hz, 1H, CONH), 3.91—
3.82 (m, 1H, cyclohexyl-H), 2.89 (s, 3H, thiadiazolyl-
CH3), 2.03—1.03 (m, 10H, cyclohexyl-H); 13C NMR
(CDCl3, 400 MHz) δ: 166.8, 161.9, 161.1, 142.6, 140.3,
137.4, 136.9, 132.1, 132.0, 131.7, 131.1, 130.7, 125.9,
125.8, 124.7, 122.0, 65.2, 49.5, 32.7, 25.3, 24.8, 24.7,
14.0; IR (KBr) ν: 3293, 3082, 2939, 2858, 1649, 1553,
1
℃; H NMR (CDCl3, 400 MHz) δ: 7.52—6.61 (m, 6H,
ph-H), 6.13 (s, 1H, COCH), 6.19 — 5.92 (m, 1H,
OCF2CF2H), 5.44 (d, J＝8.0 Hz, 1H, CONH), 3.89—
3.82 (m, 1H, cyclohexyl-H), 3.69 (s, 3H, OCH3), 2.88 (s,
3H, thiadiazolyl-CH3), 2.01—1.03 (m, 10H, cyclohexyl-
H); 13C NMR (CDCl3, 400 MHz) δ: 167.2, 160.0, 142.4,
140.7, 137.7, 134.0, 132.1, 130.8, 130.1, 122.6, 115.8,
115.3, 65.7, 55.3, 49.4, 32.8, 25.4, 24.8, 24.7, 14.0; IR
(KBr) ν: 3281, 3076, 2931, 2855, 1650, 1585, 1561, 1459,
－1
1461, 1328, 1232, 1127,1＋113 cm ; HRMS calcd for
C27H23Cl2F7N4O3S (M＋H) 687.0829, found 687.0828.
N-[2-(Cyclohexylamino)-1-(3-hydroxyphenyl)-2-
oxoethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenyl]-4-methyl-1,2,3-thiadiazole-5-carbox-
amide (5n) White solid, yield 39%, m.p. 191—194
－1
1381, 1355, 1281, 1228, 1156, 1114 cm ; HRMS calcd
for C27H26Cl2F4N4O4S (M ＋ H) ＋ 649.1061, found
649.1063.
1
℃; H NMR (CDCl3, 400 MHz) δ: 7.52—6.65 (m, 6H,
N-[2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-
oxoethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenyl]-4-methyl-1,2,3-thiadiazole-5-carbox-
amide (5r) White solid, yield 74%, m.p. 152—155 ℃;
1H NMR (CDCl3, 400 MHz) δ: 7.52—6.77 (m, 6H,
ph-H), 6.13 (s, 1H, COCH), 6.13 — 5.87 (m, 1H,
OCF2CF2H), 5.38 (d, J＝8.0 Hz, 1H, CONH), 3.88—
3.3 (m, 1H, cyclohexyl-H), 3.77 (s, 3H, OCH3), 2.88 (s,
3H, thiadiazolyl-CH3), 2.01—1.05 (m, 10H, cyclohexyl-
H); 13C NMR (CDCl3, 400 MHz) δ: 167.7, 161.4, 160.9,
160.4, 142.3, 140.9, 137.8, 134.0, 132.2, 131.7, 130.7,
124.5, 114.3, 107.4, 65.2, 55.3, 49.2, 32.8, 25.4, 24.8,
24.7, 14.0; IR (KBr) ν: 3290, 3076, 29－35, 2856, 1647,
ph-H), 6.07 (s, 1H, COCH), 6.13 — 5.86 (m, 1H,
OCF2CF2H), 5.47 (d, J＝8.0 Hz, 1H, CONH), 5.31 (s,
1H, OH), 3.88—3.81 (m, 1H, cyclohexyl-H), 2.87 (s,
3H, thiadiazolyl-CH3), 2.05—1.03 (m, 10H, cyclohexyl-
H); 13C NMR (CDCl3, 400 MHz) δ: 166.7, 160.8, 159.8,
142.5, 140.6, 140.2, 138.9, 137.7, 134.3, 132.3, 132.0,
130.9, 130.4, 122.5, 65.8, 49.4, 32.8, 25.4, 24.8, 24.7,
14.0; IR (KBr) ν: 3278, 3150, 293－5, 2857, 1645, 1553,
1
1459, 1355, 1285, 1231, 136 cm ; HRMS calcd for
C26H24Cl2F4N4O4S (M＋H)＋ 635.0904, found 635.0906.
N-[2-(Cyclohexylamino)-1-(4-hydroxyphenyl)-2-
oxoethyl]-N-[3,5-dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenyl]-4-methyl-1,2,3-thiadiazole-5-carbox-
amide (5o) White solid, yield 24%, m.p. 123—125
1
1555, 1512, 1460, 1350, 1257, 1128 cm ; HRMS calcd
for C27H26Cl2F4N4O4S (M ＋ H) ＋ 649.1061, found
1
℃; H NMR (CDCl3, 400 MHz) δ: 7.52—6.65 (m, 6H,
649.1060.
ph-H), 6.13 (s, 1H, COCH), 6.13 — 5.87 (m, 1H,
Chin. J. Chem. 2011, 29, 288— 296
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
291

Wang et al.
FULL PAPER
Biological screening
the upper three leaves using the conventional
juice-robbing method, and the solvent was smeared on
the lower three leaves as a control. The local lesion
numbers were then recorded 2—3 d after inoculation.
For each compound, three repetitions were conducted.
All compounds tested were conducted at 500 and 100
µg/mL, respectively.
Fungicide screening Preliminary screening was
conducted by fungi growth inhibition method according
to the reference using potato dextrose agar (PDA) as
cultivation medium.2 A stoc－k solution of each compound
was prepared at 500 µg•mL 1 using sterilized water con-
taining 2 drops of N,N-dimethylformamide (DMF) as a
solvent, then 1 mL of the stock solution was transferred
into a 10 cm diameter of Petri dish, 9 mL of PDA was
Curative effect of target compounds on TMV in
vivo Healthy fresh tobacco leaves growing at six-leaf
age were sel－ected for the tests. TMV at a concentration
－1
then added to prepare the plate containing 50 µg•mL
2
－1
of 5.88×10 µg•mL was inoculated on the whole
leaves using the conventional juice-robbing method.
After the leaves were dried in the greenhouse, the com-
pound solution was smeared on the upper three leaves,
and the solvent was smeared on the lower three leaves
as control. The local lesion numbers were then recorded
2—3 d after inoculation. For each compound, three
repetitions were conducted. All compounds tested were
of the test compound. Before the plate solidification, the
PDA was thoroughly mixed by turning around the Petri
dish in the sterilized operation desk 5 times to scatter
the compound in PDA evenly. Then, 4 mm of diameter
of fungi cake was inoculated on the plate and cultured in
the culture tank at 24—26 ℃. The diameter of fungi
spread was measured 2 d later. Growth inhibition was
then calculated using corresponding control. Azox-
ystrobin and tricyclazole were used as positive controls.
Fungi used in this study included Alternaria solani (AS),
Botrytis cinerea (BC), Cercospora arachidicola (CA),
Gibberella zeae (GZ), Phytophthora infestans (Mont)
de Bary (PI), Physalospora piricola (PP), Pellicularia
sasakii (PS), Sclerotinia sclerotiorum (SS), and
Rhizoctonia cerealis (RC).
－1
conducted at 500 and 100 µg•mL , respectively.
The activities of protection, inactivation, and cura-
tive effects against TMV were calculated by the average
number of viral inflammations on the inoculated leaves
with the corresponding control according to the follow-
ing equation:
CK－A
Systemic acquired resistance screening Systemic
acquired resistance of the target compounds was detected
using tobacco against the tobacco mosaic virus (TMV)
system as described in Ref. 2. The induction activity was
evaluated using the antivirus inhibition ratio, which was
calculated by the average number of viral inflammations
on the inoculated leaves with corresponding control ac-
cordingly. Tiadinil (TDL) and ribavirin were chosen as
positive control and negative control, respectively, and all
compounds tested were conducted at 100 and 50 µg•
Y
100%
×
＝
CK
where Y is the antivirus inhibition ratio (protection, in-
activation, and curative effects in vivo) (%), CK is the
average number of viral inflammations on the control
leaves in vivo, and A is the average number of viral in-
flammations on the target compound treated leaves in
vivo.
Larvicidal activity against Culex pipiens pallens.
The larvicidal activity of target compounds 5a—5r was
evaluated against mosquito Culex pipiens pallens ac-
cording to the reported procedure.16 The test solutions
were prepared by dissolving 2 mg of the compounds in
10 mL of acetone and add－ing distilled water respec-
tively t－o prepare 200 µg•mL 1 of mother solution; the 2
－1
mL , respectively. Before the test of induction activity
of systemic acquired resistance, the antivirus activity
against TMV was conducted by half leaf juice robbing
methods according to reference.2
Protective effects of the target compounds against
TMV in vivo Healthy fresh tobacco leaves growing at
six-leaf age were selected for the tests. The compound
solution was smeared on the whole leaves, and then the
leaves were dried in greenhouse. A－fter 12 h, TMV at a
1
µg•mL working solution was prepared by diluting 1
mL of mother solution with 89 mL of water and 10 mL
of feeding solution into a 100 mL breaker, and 10
forth-instar of Culex pipiens pallens larvae were trans-
fered into the beaker. Thereafter, the mosquito larvae in
the beakers were cultured in the standard conditioned
rooms at 25 ℃ with humidity of 80% for 8 d. The re-
sults are expressed as percentage mortality by compari-
sion with the corresponding CK. For comparative pur-
poses, tebufenozide was tested under the same condi-
tion.
－2
concentration of 5.88×10 µg•mL 1 was inoculated on
the upper three leaves using the conventional
juice-robbing method, and the solvent was smeared on
the lower three leaves as a control. The local lesion
numbers were then recorded 2—3 d after inoculation.
For each compound, three repetitions were conducted.
Most c－ompounds tested were conducted at 500 and 100
1
µg•mL , respectively.
Stomach toxicity against Plutella xylostella L.
The stomach toxicities of the target compounds 5a—5r
against Plutella xylostella were tested by the leaf dip
method using the reported procedure.17 A stock solution
of each test sample was prepared in dimethylformamide
Inactivate effect of the target compounds against
TMV in vivo Healthy fresh tobacco leaves growing at
six-leaf age were selected －for the tests. TMV virus at a
2
－1
concentration of 5.88×10 µg•mL was inhibited by
mixing with the target compound solution at the same
volume for 30 min. Then the mixture was inoculated on
－1
at a concentration of 200 mg•L and then diluted to the
292
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 288— 296

Synthesis of 3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl Containing 1,2,3-Thiadiazole
Table 1 The antifungal activities of title compounds in vitro at
required concentration with water containing TW-20.
Leaf disks (6 cm×2 cm) were cut from fresh cabbage
leaves and then were dipped into the test solution for 3 s.
After air-drying, the treated leaf disks were placed indi-
vidually into glass tubes. Each dried treated leaf disk
was infested with seven third-instar diamondback moth
larvae. Percentage mortalities were evaluated 3 d after
treatment. Leaves treated with water and dimethylfor-
mamide were provided as controls. Each treatment was
repeated for three times.
50 µg•mL－
1
Compound GZ SS PI PP BC RC PS AS CA
5a
5b
5c
5d
5e
5f
0
0
0
0
0
0
0
0
45.5
0
64.1 18.2 41.9 14.1 33.3 14.3
72.7 23.8 46.2 18.2 41.9 14.1 4.8 21.4
54.6
0
33.3
0
32.3 14.1 9.5
0
0
0
0
36.4 14.3 71.8 27.3 48.4 14.1 33.3
72.7
54.6
45.5
0
0
0
20.5 4.6
0
42.3 4.8
20.5 36.4 22.6 42.3 33.3
5g
5h
5i
38.5 27.3 32.3 4.2 33.3 14.3
Results and discussion
36.4 19.1 38.5
0
0
22.6 42.3
0
14.3
23.8 45.5 23.8 61.5
9.7 14.1 47.6 21.4
Synthesis
5j
0
0
0
0
0
0
0
0
0
0
23.8 71.8 27.3 64.5 21.1 61.9 42.9
This study used U-4CR as the parallel synthesis
method, and the target compounds were proved to be
easily synthesized and purified. Following the method
developed in our previous study,4c,15 an amine compo-
nent and an aldehyde component were first mixed to get
an intermediate imine, and then a carbonyl component
was added into the mixture for certain time of intervals
before the mixing with an isocyanide component. The
amount of methanol as solvent added to the reaction
mixture was as small as possible, just enough to make
the agitation effective. After all components were mixed,
products usually precipitated into solvent within 1 h. To
obtain high yields, solvent was removed under reduced
pressure and then the products were purified by column
chromatography on silica gel using ethyl acetate and
petroleum ether (60—90 ℃) at 1∶3 (V∶V) as an elu-
ent.
5k
5l
45.5 9.5 28.2 27.3 41.9
0
47.6
0
0
0
0
0
36.4
63.6
27.3
18.2
54.6
0
0
0
0
0
53.9 4.6 29.0 14.1 14.3
33.3 4.6 32.3 42.3 33.3
5m
5n
5o
5p
5q
5r
7.7 4.6 16.1 14.1
33.3 48.4 7.0 14.3
59.0 4.6
0
0
0
42.3 42.9 21.4
27.3 23.8 28.2 13.6 16.1
27.3 33.3 22.6
0
0
23.8
33.3
0
0
0
0
Azoxystrobin 40.0 100 88.9 85.0 21.2 100 69.74 63.1 80.0
Tricyclazole 24.0 100 29.6 25.0 36.8 65.9 29.0 5.3 13.3
Antivirus activity
Tiadinil, ribavirin and ninamycin were used as posi-
tive controls. The results of activity screening by
half-leaf juice-robbing method against TMV indicated
that (Table 2) most compounds showed certain degree
of direct inhibition activities against TMV in vitro with
results no more than 50% except 5j. However, com-
pounds 5d, 5k, 5m and 5o, 5j had direct inhibition
activiti－es of 45%, 46%, 43% and 45%, 53% at 100
Biological activities
Fungicidal activity
The newly synthesized compounds 5a—5r were
tested for their fungicidal activity against following
fungi, which represented the pathogen of typical dis-
eases occurring in the Chinese agricultural ecosystem.
AS (Alternaria solani), BC (Botrytis cinerea), CA
(Cercospora arachidicola), GZ (Gibberella zeae), PI
(Phytophthora infestans (Mont.) de Bary), PP (Physa-
lospora piricola), PS (Pellicularia sasakii), SS (Scle-
rotinia sclerotiorum) and RC (Rhizoctonia cerealis).
The results of Table 1 indicated that, most compounds
showed lower fungicide activity at 50 µg/mL compared
to the two positive controls azoxystrobin and tricycla-
zole. Some compounds had good fungicide activity, for
example, compounds 5b, 5e and 5m exhibited 72.7%,
72.7% and 63.6% of fungicidal activity against SS, re-
spectively; the activity of compounds 5a, 5d, 5i and 5j
against PP were of 64.1%, 71.8%, 61.5% and 71.8%,
respectively, which were higher than that of tricyclazole;
the inhibition percentages of 5j to RC and AS were
64.5% and 61.9%, respectively.
1
µg•mL , respectively. These were as twice as－that of
1
ribavirin. However, the activities at 500 µg•mL were
lower. Only compound 5j had high activity at both 500
and 100 µg•mL with inhibition above 50%, and they
are significantly higher than those of the positive control
agents ribavirin and tiadinil.
－1
The antivirus activity of all title compounds includ-
ing protective, inactivate and curative effect, and the
inductive activities were also evaluated. The results
listed in Table 2 indicated that, most of the compounds
had good inactivation and curative activity against to-
bacco mosaic virus. Among these, compounds 5a—5d
and 5o had inactivation activities of 66%, 87%, 73%,
－1
70% and 71% at 500 µg•mL , respectively, and 49%,
－1
59%, 51%, 48% and 52% at 100 µg•mL , respectively.
These were better than that of the positive control agent
ribavirin; compounds 5g, 5h, 5j, 5m and 5o had good
curative act－ivities of 65%, 59%, 59%, 72% and 72% at
1
500 µg•mL , respectively, and 43%, 52%, 47%, 56%
Chin. J. Chem. 2011, 29, 288— 296
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
293

Wang et al.
FULL PAPER
Table 2 Antivirus activity of the title compounds 5a—5r against TMV
Concentration/
(Half leaf
activity±SD)/%
36±4
36±5
31±6
26±5
24±5
27±6
45±2
45±3
28±5
22±2
38±3
37±3
34±5
35±3
37±3
33±3
35±5
33±3
51±9
53±6
37±5
46±1
27±1
34±3
20±3
43±3
37±3
33±3
37±6
45±3
43±1
34±8
16±1
29±10
26±8
25±2
32±1
20±2
49±4
39±6
32±3
36±4
(Protective
activity±SD)/%
45±7
22±7
48±3
16±7
22±3
13±6
55±8
42±8
34±4
16±7
36±5
29±7
56±7
27±0
49±2
9±9
(Inactivate
activity±SD)/%
66±5
49±8
87±3
59±4
73±8
51±3
70±8
48±4
58±5
48±4
49±7
23±6
55±8
36±7
43±4
11±8
24±6
13±2
9±7
(Curative
activity±SD)/%
55±7
39±3
50±8
50±3
59±1
41±9
47±6
14±5
48±8
41±9
11±4
7±3
(Inductive
Compound
(µg•mL－
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
)
activity±SD)/%
65±1a
57±7b
38±6a
7±8b
1
5a
5b
5c
30±5a
64±3b
61±4a
22±3b
36±6a
25±6b
38±5a
5±4b
5d
5e
5f
5g
65±9
43±7
59±7
52±6
38±4
21±7
59±3
47±9
30±5
10.37±3
61±5
37±9
72±1
56±3
47±7
13±5
72±3
43±8
37±9
30±3
34±6
16±3
49±2
33±8
52±7
30±4
55±8
41±8
50±9
36±6
12±8a
6±3b
5h
64±3a
49±8b
57±1a
56±4b
54±10a
60±3b
28±4a
72±4b
41±3a
45±2b
75±5a
75±3b
59±1a
67±4b
30±4a
15±7b
65±5a
14±6b
15±2a
45±8b
83±4a
67±3b
20±5a
65±8b
46±5a
63±5b
57±2a
65±4b
5i
58±5
45±5
60±4
33±8
51±2
35±7
76±2
59±6
58±5
51±3
41±1
337±2
57±3
46±10
34±6
22±7
72±4
48±5
69±5
59±3
65±3
50±8
73±5
56±3
66±3
55±4
5j
14±5
43±9
12±1
15±8
14±5
47±7
11±7
50±6
10±8
71±3
52±3
34±6
11±3
62±7
12±7
13±6
8±5
5k
5l
5m
5n
5o
5p
5q
5r
Ribavirin
Ninamycin
Tiadinil
48±4
26±4
63±9
43±9
56±7
47±9
a 50 µg•mL－ 1 of concentration; b 100 µg•mL－ 1 of concentration.
294
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 288— 296

Synthesis of 3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl Containing 1,2,3-Thiadiazole
and 43% at 100 µg/mL, respectively. These were also
better than the positive control agent ribavirin. As for
the protection effect and induction activities, most of
them had lower activities as compared with the positive
control. However, some compounds stood out, com-
pounds 5l, 5q and 5r had good protection activities of
substituted compounds. For example, compounds 5b, 5d,
5f, 5g, 5n, 5o and 5r displayed higher larvicidal activi-
ties against Plutella xylostella L. than compounds 5a, 5c,
－1
5e, 5j and 5p at 200 µg•mL . Compounds 5b, 5f, 5g,
5n, 5o and 5r had good larvicidal activity against
Plutella xylostella L., which were approximately equal
to that of the commercialized product tebufenozide at
－1
76%, 72% and 69% at 500 µg•mL , respectively, and
－ 1
－1
58%, 47% and 59% at 100 µg•mL , respectively.
200 µg•mL . Compounds 5o and 5q also exhibited
Compounds 5m, 5n and 5r had good induction activities
excellent larvicidal activities against Culex pipiens
pallen among the test compounds, which had 100%
mortality at 2 µg•mL .
－1
of 75%, 59% and 83% at 500 µg•mL－ , respectively,
1
－1
and 75%, 67% and 67% at 100 µg•mL , respectively.
These were approximately equal to or higher than that of
the positive controls. We observed no phytotoxicity to
tobacco during the course of experiments. No significant
structure-activity relationship was observed from these
studies. This indicated that the whole molecular struc-
ture played an important role in these activities rather
than one moiety in the molecule.
Conclusion
In summary, a series of new 4-methyl-1,2,3-thiadi-
azole derivatives containing active substructure of
3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl were
conveniently synthesized and easily purified via 4 com-
ponent Ugi reaction. Bioassay results indicated that all
of these title compounds showed a certain degree of
Larvicidal activity
－1
fungicidal activity at 50 µg•mL . The larvicidal activi-
Table 3 showed the larvicidal activities of com-
pounds 5a — 5r and positive control tebufenozide
against Plutella xylostella L. and Culex pipiens pallens.
The results indicate that most of the compounds exhib-
ited different larvicidal activities against Plutella xylos-
tella L. and Culex pipiens pallens. On the whole, the
larvicidal activities of the meta-substituted and
para-substituted benzoyl against Plutella xylostella L.
were better than those of ortho-substituted and non-
ties of the benzoyl meta-substituted or para-substituted
compounds against Plutella xylostella L. were better than
those of benzoyl ortho-substituted or non-substituted
compounds. Compounds 5o and 5q exhibited excellent
larvicidal activities against Culex pipiens pallens with
100% mortality at 2 µg•mL . Most of the compounds
presented different extent of anti-TMV activity with
different mode of action.
－1
Table 3 Insecticidal activities of of the title compounds 5a—5r
Plutella xylostella L.
Culex pipiens pallens
Compound
Concentration/(µg•mL－
)
Larvicidal activity/%
Concentration/(µg•mL－
)
Larvicidal activity/%
1
1
5a
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
7.89
22.86
7.69
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
20
20
40
20
0
5b
5c
5d
17.50
5.41
5e
5f
21.05
23.68
5.26
10
0
5g
5h
10
0
5i
7.89
5j
15.00
nda
20
30
20
20
40
100
nd
100
20
100
5k
5l
2.63
5m
15.79
22.92
21.62
10.81
7.90
5n
5o
5p
5q
5r
20.00
26.30
Tebufenozide
a nd: not detected.
Chin. J. Chem. 2011, 29, 288— 296
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
295

Wang et al.
FULL PAPER
References
8
9
Wang, T. T.; Bing, G. F.; Zhang, X.; Qin, Z. F.; Yu, H. B.;
Qin, X.; Dai, H.; Fang, J. X. ARKIVOC 2010, (ii), 330.
Bakulev, V.; Mokrushin, V. Chem. Heterocycl. Compd.
1986, 22, 811.
1
(a) Zhan, P.; Liu, X. Y.; Fang, Z. J.; Li, Z. Y.; Pannecouque,
C.; Clercq, E. D. Eur. J. Med. Chem. 2009, 44, 4648.
(b) Zhan, P.; Liu, X. Y.; Li, Z. Y.; Fang, Z. J.; Li, Z.; Wang,
D. F.; Pannecouque, C.; Clercq, E. D. Bioorg. Med. Chem.
2009, 17, 5920.
10 (a) Ojima, I.; Griffen, E.; Clark, J.; Breeden, S.; Summerton,
L.; Barker, R.; Iddon, B.; Hall, A.; Hardy, B.; Peltason, L.
Future Med. Chem. 2009, 1, 401.
(c) Pannecouque, C.; Szafarowicz, B.; Volkova, N.; Bakulev,
V.; Dehaen, W.; Mély, Y.; Daelemans, D. Antimicrob.
Agents Chemother. 2010, 54, 1461.
(b) Zhou, Z. Z.; Huang, W.; Ji, F. Q.; Ding, M. W.; Yang, G.
F. Heteroat. Chem. 2007, 18, 381.
(c) Zhou, Z. Z.; Yang, G. F. Bioorg. Med. Chem. 2006, 14,
8666.
2
3
4
Fan, Z. J.; Shi, Z. G.; Zhang, H. K.; Liu, X. F.; Bao, L. L.;
Ma, L.; Zuo, X.; Zheng, Q. X.; Mi, N. J. Agric. Food Chem.
2009, 57, 4279.
Fan, Z. J.; Ai, Y. W.; Chen, J. Y.; Wang, H. Y.; Liu, F. L.;
Bao, L. L.; Shi, Z. G. J. Sichuan Normal Univ. (Nat. Sci.)
2005, 28, 608 (in Chinese).
(a) Fan, Z. J.; Yang, Z. K.; Zhang, H. K.; Mi, N.; Wang, H.;
Cai, F.; Zuo, X.; Zheng, Q. X.; Song, H. B. J. Agric. Food
Chem. 2010, 58, 2630.
(b) Yang, Z. K.; Zhang, H. K., Fan, Z. J.; Mi, N.; Song, H.
B; You, J. M.; Sun, X. J.; Belskaia, N. P.; Bakulev, V. A.
Chin. J. Pestic. Sci. 2009, 11(1), 19 (in Chinese).
(c) Zuo, X.; Mi, N.; Fan, Z. J.; Zheng, Q. X.; Zhang, H. K.;
Wang, H.; Yang, Z. K. J. Agric. Food. Chem. 2010, 58,
2755.
11 (a) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007,
73, 125.
(b) Hulme, C.; Dietrich, J. Mol. Diversity 2009, 13, 195.
(c) Liu, N.; Liu, N. J.; Cao, S.; Shen, L.; Wu, J. J.; Yu, J. L.;
Zhang, J.; Li, H.; Qian, X. H. Tetrahedron Lett. 2009, 50,
1982.
12 Zohreh, N.; Alizadeh, A.; Bijanzadeh, H. R.; Zhu, L. G. J.
Comb. Chem. 2010, 12, 497.
13 Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23.
14 (a) Xu, Y. F.; Zhao, Z. J.; Qian, X. H.; Qian, Z. G.; Tian, W.
H.; Zhong, J. J. J. Agric. Food Chem. 2006, 54, 8793.
(b) Zhu, S.; Liu, P.; Liu, X.; Li, J.; Yuan, S.; Si, N. Pest
Manag. Sci. 2008, 64, 255.
(d) Wang, Z. H.; Guo, Y. Z.; Zhang, J.; Ma, L.; Song, H. B.;
Fan, Z. J. J. Agric. Food Chem. 2010, 58, 2715.
Nombela, G.; Pascual, S.; Aviles, M.; Guillard, E.; Muniz,
M. J. Econ. Entomol. 2005, 98, 2266.
Wu, M. J.; Sun, Q. M.; Yang, C. H.; Chen, D. D.; Ding, J.;
Chen, Y.; Lin, L. P.; Xie, Y. Y. Bioorg. Med. Chem. Lett.
2007, 17, 869.
15 Zheng, Q. X.; Mi, N.; Fan, Z. J.; Zuo, X.; Zhang, H. K.;
Wang, H.; Yang, Z. K. J. Agric. Food Chem. 2010, 58,
7846.
5
6
16 Chen, L.; Huang, Z. Q.; Wang, Q. M.; Shang, J.; Huang, R.
Q.; Bi, F. C. J. Agric. Food Chem. 2007, 55, 2659.
17 Sun, R. F.; Zhang, Y. L.; Chen, L.; Li, Y. Q.; Li, Q. S.;
Song, H. B.; Huang, R. Q.; Bi, F. C.; Wang, Q. M. J. Agric.
Food Chem. 2009, 57, 3661.
7
Chen, Y. F.; Zhang, C. R.; Huang, X. Plant Physiol. Com-
mun. 2006, 42, 127 (in Chinese).
(E1010071 Ding, W.; Zheng, G.)
296
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 288— 296