Synthesis and biological activity of novel 2-(3-trifluoromethylphenoxy)-4-trifluoromethylthiazole-5-carboxamide derivatives

Article abstract of DOI:10.1016/j.jfluchem.2006.02.010

Novel 2-(3-trifluoromethylphenoxy)-4-trifluoromethylthiazole-5-carboxamides were designed and synthesized utilizing ethyl 3-amino-4,4,4-trifluoro-2-butenoate as a starting material via six steps. Subsequently, their biological activities were evaluated in

Full text of DOI:10.1016/j.jfluchem.2006.02.010

Journal of Fluorine Chemistry 127 (2006) 796–799
www.elsevier.com/locate/fluor
Synthesis and biological activity of novel
2-(3-trifluoromethylphenoxy)-4-trifluoromethylthiazole-
5-carboxamide derivatives
a
a
a
Chang-Ling Liu a,b, , Miao Li , Hui-Wei Chi , Chun-Qing Hou , Zheng-Ming Li
*
b,**
a Agrochemical Discovery Department, Shenyang Research Institute of Chemical Industry, Shenyang 110021, China
b Institute of Elemento-Organic Chemistry, State Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, China
Received 9 January 2006; received in revised form 17 February 2006; accepted 22 February 2006
Available online 3 April 2006
Abstract
Novel 2-(3-trifluoromethylphenoxy)-4-trifluoromethylthiazole-5-carboxamides were designed and synthesized utilizing ethyl 3-amino-4,4,4-
trifluoro-2-butenoate as a starting material via six steps. Subsequently, their biological activities were evaluated in the greenhouse. Results
indicated that several compounds have some insecticidal or fungicidal activity at 600 g ai/ha and 300 g ai/ha, respectively.
# 2006 Elsevier B.V. All rights reserved.
Keywords: 2-Phenoxy-4-trifluoromethylthiazole-5-carboxamides; Synthesis; Fungicidal activity; Insecticidal activity
1. Introduction
methylthiazole-5-carboxamides (general structure 1) such as
compounds 1A and 1B, which were incorporated by the
active moieties of thifluzamide and diflufenican or picoli-
nofen and by using the bioisosterism method [5] in order
to find new lead compounds as potential agrochemicals.
1A–1C and comparative compounds 1D–1F were synthe-
sized, and their biological activities were evaluated in the
greenhouse.
Both thiazole-related and pyridine-related compounds have
been extensively studied from the biological point of view, in
which thiazoles such as thifluzamide [1] and metsulfovax [2]
are known as fungicides, and pyridines such as diflufenican
[3] and picolinofen [4] are known as herbicides used in
agriculture.
In the present paper we wish to report the design and
synthesis of novel 2-(3-trifluoromethylphenoxy)-4-trifluoro-
* Corresponding author. Tel.: +86 24 62353330; fax: +86 24 62353390.
** Corresponding author.
E-mail address: liuchangling@vip.163.com (C.-L. Liu).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.02.010

C.-L. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 796–799
797
Scheme 1. Reagents and conditions: (a) chloroformylsulfenyl chloride, chlorobenzene, reflux, 24 h, 67%; (b) POCl3, reflux, 30 h, 92%; (c) substituted phenols/tert-
BuOK in THF, rt, 6–10 h, 80–90%; (d) NaOH/H2O/THF, rt, 2 h, HCl(aq), 88–95%; (e) SOCl2, reflux, 2 h; (f) R2R3NH/Et3N/CH3CN, reflux, 10–30 min, 90–95%.
2. Results and discussion
with compounds 5B, 6B and 1A having the best activity with
60% control against GPA; 5A having the best activity with
100% control against PLH; and compound 5A has the best
activity with 73% control against MTA. Additionally, at 300 g
ai/ha, compounds 6B and 1D possess good fungicidal activity
with 90% control of tomato late blight (TLB) and compound
1A has the best activity with 90% control against wheat
powdery mildew (WPM). All compounds show no herbicidal
activity at 1200 g ai/ha.
2.1. Synthesis
The synthesis of 2-(3-trifluoromethylphenoxy)-4-trifluoro-
methylthiazole-5-carboxamide derivatives is illustrated in
Scheme 1.
Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (2) was used as
the starting material, which was treated with chloroformylsul-
fenyl chloride to gave ethyl 2-oxo-4-(trifluoromethyl)-2,3-
dihydrothiazole-5-carboxylate (3), followed by chlorination
with POCl3 to provide ethyl 2-chloro-4-(trifluoromethyl)thia-
zole-5-carboxylate (4) according to the literature procedure [6].
4 and phenols were treated with potassium tert-butoxide in THF
to yield ethyl 2-(substituted phenoxy)-4-(trifluoromethyl)thia-
zole-5-carboxylate (5), followed by hydrolysis with sodium
hydroxide to form 2-(substituted phenoxy)-4-(trifluoro-
methyl)thiazole-5-carboxylic acid (6) and then forming the
acid chloride (7) by reaction with thionyl chloride. Reaction of
the acid chloride 7 with the appropriate amine in the presence of
triethylamine results in the desired amide 1.
3. Conclusion
2-(3-Trifluoromethylphenoxy)-4-trifluoromethylthiazole-5-
carboxamides described in the present study were synthesized,
starting from ethyl 3-amino-4,4,4-trifluoro-2-butenoate via six
steps. Preliminary biological evaluation showed that some of
the compounds have fungicidal and insecticidal activity at
300 g ai/ha and 600 g ai/ha, respectively, suggesting that
compounds 1A, 5A, 6A and 6B may become useful leads for
further investigation.
1
The synthesized compounds were characterized by IR, H
4. Experimental
NMR, mass spectra and elemental analyses. All spectra and
data were consistent with the assigned structures. The IR
spectra of compounds showed NH and C O stretching bands at
3200–3300 and 1650–1675 cmÀ1, respectively.
Melting points were determined on a Buchi melting point
apparatus and are uncorrected. 1H NMR spectra were recorded
with Mercury 300 (Varian, 300 MHz) spectrometer with CDCl3
as the solvent and TMS as the internal standard. 19F NMR
spectra were obtained on a Mercury 300 (Varian, 300 MHz)
Spectrometer using CF3COOH (TFA) as an external standard,
positive for downfield shift. Infrared spectra were measured on
KBr disks using a PF-983G instrument (Perkin-Elmer). Mass
spectra (GC–MS) were obtained on an MD-800 (Fisons)
instrument. Combustion analyses for elemental composition
were made with an EA 1106 analyzer (Fisons). All chemicals or
reagents were purchased from standard commercial suppliers.
2.2. Biological activities
The biological activities were evaluated at Rohm and Haas
Company using previously reported procedures [7–11]. In
Table 1, zero indicates no control and 100% is complete control
of the insect or fungus. Several compounds have some
insecticidal activity against green peach aphid (GPA), potato
leafhopper (PLH) and two-spotted spider (MTA) at 600g ai/ha,

798
C.-L. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 796–799
Table 1
Biological activity of the synthesized compounds
Compound
Insecticidal activity (% control)
Fungicidal activity (% control)
GPA
PLH
MTA
TLB
WPM
5A
5B
6A
6B
1A
1B
1C
1D
0
60
0
100
40
80
60
60
20
20
20
20
0
73
0
0
0
0
0
20
20
20
0
0
0
60
60
20
20
0
90
0
75
90
50
0
0
0
0
0
90
0
0
1E
20
20
0
0
0
1F
Thifluzamide
0
0
0
40
0
20
70
4.1. Preparation of ethyl 2-(3-(trifluoromethyl)phenoxy)-4-
(trifluoromethyl)thiazole-5-carboxylate (5A)
temperature and water (100 mL) was added. The water layer
was neutralized with 10% HCl to pH 4, the carboxylic acid 6A
(20.4 g, 95%) was obtained as white crystals and was used to
prepare the acid chloride 7A without further purification, mp
138–139 8C. IR (KBr) n: 2880(m, OH), 2660, 2540, 2360,
1710(s, C O), 1550, 1470, 1360, 1324, 1257, 1160, 1083, 918,
To the mixture of potassium tert-butoxide (14.2 g,
0.127 mol) in THF (300 mL) was added 3-(trifluoromethyl)-
phenol (20.5 g, 0.127 mol), and the mixture was stirred at room
temperature for 10 min. To the reaction mixture was added
ethyl 2-chloro-4-(trifluoromethyl)thiazole-5-carboxylate 4 [6]
(30.0 g, 0.116 mol), stirred at room temperature overnight.
After evaporated in vacuum, water was added and extracted
with ethyl acetate, washed with 4 M HCl, water and brine, dried
over magnesium sulfate, evaporated in vacuum and then
purified by silica gel column chromatography to give 39.1 g
(88%) of the target compound (5A), as oil. IR (KBr) n: 2988,
1738(s, C O), 1479, 1324, 1249, 1120, 1083, 924, 887,
695 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.59(m, 4H, Ph-4H),
4.37(q, 2H, CH2), 1.37(t, J = 7.5 Hz, 3H, CH3); 19F NMR
(CDCl3, TFA): d À60.18, À62.23; GC/MS, m/z (%): 385(M+),
366, 340, 313, 288, 265, 240(100%), 216, 196, 167, 145, 125,
95, 75. Anal. Calcd. (%) for C14H9F6NO3S: C 43.64; H 2.35; N
3.64. Found: C 43.77; H 2.30; N 3.58.
883, 798, 725, 697 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
10.63(s, 1H, COOH), 7.59(m, 4H, Ph-4H); 19F NMR (CDCl3,
TFA): d À60.33, À61.75; GC/MS, m/z (%): 313 (M+-CO2, 83%).
4.4. Preparation of 2-(2-chloro-5-
(trifluoromethyl)phenoxy)-4-(trifluoromethyl)thiazole-5-
carboxylic acid (6B)
Yield 95% of white solid, mp 148–149 8C. IR (KBr) n:
3436(m, OH), 1483, 1327, 1249, 1172, 1036, 1005, 821,
726 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.75(s, 1H, Ph-6-H),
7.74–7.60(d, 1H, J = 9 Hz, Ph-3-H), 7.58–7.50(d, 1H, J = 9 Hz,
Ph-4-H), 5.40(bs, 1H, CO2H); 19F NMR (CDCl3, TFA): d
À60.33, À61.71. HRMS Calcd. for C12H4ClF6NO3S:
390.9505. Found: 390.9523.
4.2. Preparation of ethyl 2-(2-chloro-5-
(trifluoromethyl)phenoxy)-4-(trifluoromethyl)thiazole-5-
carboxylate (5B)
4.5. Preparation of 2-(3-(trifluoromethyl)phenoxy)-4-
(trifluoromethyl)thiazole-5-carbonyl chloride (7A)
Thionyl chloride (98%, 12.2 g, 0.1 mol) was added dropwise
under vigorous stirring to a solution of carboxylic acid 6A
(17.9 g, 0.05 mol) in chloroform (50 mL). The mixture was
stirred and heated to reflux for 2 h. After evaporation of the
solvent, a yellow oil, was obtained (18.2 g, 97%) and was used
directly for preparation of compounds 1A–1C.
2-(2-Chloro-5-(trifluoromethyl)phenoxy)-4-(trifluoro-
methyl)thiazole-5-carbonyl chloride (7B) was prepared by the
above method and used directly for preparation of compounds
1D–1F.
Yield 85% of white solid, mp 59–60 8C. IR (KBr) n: 2980,
2820, 1737(s, C O), 1480, 1410, 1320, 1250, 1140,
1
1080 cmÀ1; H NMR (300 MHz, CDCl3): d 7.69(m, 2H, Ph-
3,4-2H), 5.57(m, 1H, Ph-6-H), 4.38(q, 2H, CH2), 1.38(t,
J = 7.5 Hz, 3H, CH3). 19F NMR (CDCl3, TFA): d À60.67,
À61.71. Anal. Calcd. (%) for C14H8ClF6NO3S: C 40.06, H
1.92, N 3.34. Found: C 40.12, H 2.05, N 3.30.
4.3. Preparation of 2-(3-(trifluoromethyl)phenoxy)-4-
(trifluoromethyl)thiazole-5-carboxylic acid (6A)
4.6. General method for the synthesis of thiazole-5-
carboxamides (1A–1F)
The solution of the ester 5A (23.1 g, 0.06 mol), 50% NaOH
(14.0 g, 0.18 mol) and water (100 mL) in THF (200 mL) was
stirred and heated to reflux for 2 h. After evaporation of the
solvent, the reaction mixture was allowed to cool room
A solution of acid chloride 7A or 7B (2 mmol) in dry
acetonitrile (5 mL) was added dropwise under vigorous stirring

C.-L. Liu et al. / Journal of Fluorine Chemistry 127 (2006) 796–799
799
1
to a solution of the appropriate amine (2.2 mmol) and
triethylamine (2 mmol) in acetonitrile (10 mL). The mixture
was heated to reflux for 10 min and evaporated to remove the
acetonitrile, followed by addition of water (10 mL) and
extraction with ethyl acetate (3 Â 10 mL). The organic layer
was washed with 10% HCl to remove the excess of amine, then
with saturated aqueous NaHCO3 solution, water and brine,
dried over magnesium sulfate, and evaporated to give the target
compounds as a solid. Purification was performed with column
chromatography (ethyl acetate/petroleum ether 60–90; 2:3).
965, 854, 723 cmÀ1; H NMR (300 MHz, CDCl3): d 8.27(m,
1H, N-Ph-6-H), 8.04(s, 1H, NH), 7.69(m, 2H, O-Ph-3,4-2H),
7.56(m, 1H, O-Ph-6-H), 6.93(m, 2H, N-Ph-3,5-2H); 19F
NMR (CDCl3, TFA): d À61.61, À61.69, À112.79, À117.78.
HRMS Calcd. for C18H7ClF8N2O2S: 501.9789. Found:
501.9802.
4.11. Preparation of N-(4-chlorobenzyl)-2-(2-chloro-5-
(trifluoromethyl)phenoxy)-4-(trifluoromethyl)thiazole-5-
carboxamide (1E)
4.7. Preparation of N-(2,4-difluorophenyl)-4-
(trifluoromethyl)-2-(3-(trifluoromethyl)phenoxy)thiazole-5-
carboxamide (1A)
Yield 95% of white solid, mp 131–132 8C. IR (KBr) n:
3275(m, NH), 1651(s, C O), 1505, 1420, 1330, 1260, 1180,
1
1135, 1080 cmÀ1; H NMR (300 MHz, CDCl3): d 7.66(m,
2H, N-Ph-3,5-2H), 7.55(dd, J = 8.1 Hz, 1H, O-Ph-3-H),
7.34(m, 2H, N-Ph-2,6-2H), 7.26(m, 2H, O-Ph-4,6-2H),
6.48(s, 1H, NH), 4.57(d, J = 5.8 Hz, 2H, CH2); 19F NMR
(CDCl3, TFA): d À61.28, À61.69. Anal. Calcd. (%) for
C19H10Cl2F6N2O2S: C 44.29, H 1.96, N 5.44. Found: C
44.33, H 1.90, N 5.50.
Yield 93% of white solid, mp 68–69 8C. IR (KBr) n: 3238(s,
NH), 1662(s, C O), 1512, 1452, 1375, 1329, 1278, 1257, 1180,
1
1133, 1063, 970, 915, 885, 858, 805, 695 cmÀ1; H NMR
(300 MHz, CDCl3): d 8.26(m, 1H, N-Ph-6-H), 8.05(s, 1H, NH),
7.59(m, 4H, O-Ph-4H), 6.93(m, 2H, N-Ph-3,5-2H); 19F NMR
(CDCl3, TFA): d À61.53, À61.77, À112.76, À117.66; GC/MS,
m/z (%): 449 (M-19), 398, 429, 340(100%), 312, 268, 240, 218,
196, 167, 145, 101, 75, 63. Anal. Calcd. (%) for
C18H8F8N2O2S: C 46.16, H 1.72, N 5.98. Found: C 46.10, H
1.76, N 6.04.
4.12. Preparation of 2-(2-chloro-5-
(trifluoromethyl)phenoxy)-N,N-diethyl-4-
(trifluoromethyl)thiazole-5-carboxamide (1F)
Yield 92% of white solid, mp 74–75 8C. IR (KBr) n: 2980,
2830, 2880, 1640(s, C O), 1520, 1405, 1375, 1325, 1245,
4.8. Preparation of N-(4-fluorophenyl)-4-(trifluoromethyl)-
2-(3-(trifluoromethyl)phenoxy)thiazole-5-carboxamide (1B)
1
1175, 1140, 1080, 920 cmÀ1; H NMR (300 MHz, CDCl3): d
7.71(d, J = 1.8 Hz, 1H, Ph-3-H), 7.64(d, J = 8.4 Hz, 1H, Ph-4-
H), 7.55(dd, J = 1.2 Hz, 1H, Ph-6-H), 3.54(m, 2H, CH2), 3.4(m,
2H, CH2), 1.20(m, 6H, CH3); 19F NMR (CDCl3, TFA): d
À61.68, À62.74. Calcd. (%) for C16H13ClF6N2O2S: C 43.01, H
2.93, N 6.27. Found: C 43.12, H 3.02, N 6.34.
Yield 95% of white solid, mp 130–131 8C. IR (KBr) n:
3290(s, NH), 1655(s, C O), 1575, 1540, 1505, 1450, 1375,
1325, 1245, 1180, 1120 cmÀ1; 1H NMR (300 MHz, CDCl3): d
7.81(s, 1H, NH), 7.58(m, 2H, N-Ph-2,6-2H), 7.53(m, 4H, O-Ph-
4,5-2H + N-Ph-3,5-2H), 7.09(m, 2H, O-Ph-2,6-2H); 19F NMR
(CDCl3, TFA): d À61.66, À61.74, À117.88. Anal. Calcd. (%)
for C18H9F7N2O2S: C 48.01, H, 2.01, N, 6.22. Found: C 48.22,
H, 1.95, N, 6.25.
Acknowledgements
We thank Dr. R.M. Jacobson, Dr. S.H. Shaber, Dr. Y.M. Zhu
and Dr. J.M. Renga for their help in the project and paper
preparation. The authors acknowledge financial support from
the National Basic Research Program of China
(2003CB114400).
4.9. Preparation of N-(3,5-difluorophenyl)-4-
(trifluoromethyl)-2-(3-(trifluoromethyl)phenoxy)thiazole-5-
carboxamide (1C)
Yield 94% of white solid, mp 127–128 8C. IR (KBr) n:
3272(s, NH), 1675(s, C O), 1620, 1520, 1450, 1380, 1330,
1280, 1235, 1180, 1120 cmÀ1; 1H NMR (300 MHz, CDCl3): d
7.90(s, 1H, NH), 7.58(m, 4H, O-Ph-4,5-2H + N-Ph-2,6-2H),
7.17(m, 2H, O-Ph-2,6-2H), 6.66(m, 1H, N-Ph-4-H); 19F NMR
(CDCl3, TFA): d À61.70, À61.74, À109.16, À109.23. Anal.
Calcd. (%) for C18H8F8N2O2S: C 46.16, H 1.72, N 5.98. Found:
C 46.20, H 1.68, N 5.95.
References
[1] C.D.S. Tomlin, The Pesticide Manual, 12th ed., BCPC, 2000,, p. 901.
[2] C.D.S. Tomlin, The Pesticide Manual, 12th ed., BCPC, 2000,, p. 1008.
[3] C.D.S. Tomlin, The Pesticide Manual, 12th ed., BCPC, 2000,, p. 296.
[4] C.D.S. Tomlin, The Pesticide Manual, 12th ed., BCPC, 2000,, p. 742.
[5] C.L. Liu, Chin. J. Pesticides (Nong Yao) 2 (1998) 1–5.
[6] L.F. Lee, F.M. Schleppnik, R.K. Howe, J. Heterocyclic Chem. 22 (1985)
1621–1630.
[7] C.L. Liu, X.N. Liu, R.M. Jacobson, M.J. Mulvihill, China Patent CN 118
465C (2003).
4.10. Preparation of 2-(2-chloro-5-
(trifluoromethyl)phenoxy)-N-(2,4-difluorophenyl)-4-
(trifluoromethyl)thiazole-5-carboxamide (1D)
[8] C.L. Liu, Z.M. Li, B. Zhong, J. Fluorine Chem. 125 (2004) 1287–1290.
[9] R. Ross, T.T. Fujimoto, S.H. Shaber, European Patent Application EP 0
811 614A1 (1997).
[10] R.M. Jacobson, L.T. Nguyen, US Patent 6,147,062 (2000).
[11] R.M. Jacobson, L.T. Nguyen, M. Thirugnanam, US Patent 4,970,224
(1990).
Yield 94% of white solid, mp 120–121 8C. IR (KBr) n:
3229(s, NH), 1657(s, C O), 1494, 1325, 1243, 1135, 1079,