Synthesis and biological activity of novel 2-methyl-4-trifluoromethyl-thiazole-5-carboxamide derivatives

Article abstract of DOI:10.1016/j.jfluchem.2004.03.006

Nine novel 2-methyl-4-trifluoromethylthiazole-5-carboxamide derivatives were designed and synthesized utilizing ethyl 4,4,4-trifluoroacetoacetate as a starting material. Subsequently, the biological activity of the compounds was evaluated in the greenhouse. Results indicated that all of the compounds have some fungicidal and insecticidal activity but no herbicidal activity. Compound 1 has fungicidal activity with 90% control of tomato late blight at 375 g ai/ha, while two compounds 2F and 2H show insecticidal activity with 80 and 100% control, respectively, against potato leafhopper at 600 g ai/ha.

Full text of DOI:10.1016/j.jfluchem.2004.03.006

Journal of Fluorine Chemistry 125 (2004) 1287–1290
Synthesis and biological activity of novel
-methyl-4-trifluoromethyl-thiazole-5-carboxamide derivatives
2
a,b
Chang-Ling Liu , Zheng-Ming Li , Bin Zhong
a,*
a
a
Institute of Elemento-Organic Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, PR China
b
Shenyang Research Institute of Chemical Industry, Shenyang 110021, PR China
Received 26 December 2003; received in revised form 9 March 2004; accepted 12 March 2004
Available online 25 June 2004
Abstract
Nine novel 2-methyl-4-trifluoromethylthiazole-5-carboxamide derivatives were designed and synthesized utilizing ethyl 4,4,4-trifluor-
oacetoacetate as a starting material. Subsequently, the biological activity of the compounds was evaluated in the greenhouse. Results indicated
that all of the compounds have some fungicidal and insecticidal activity but no herbicidal activity. Compound 1 has fungicidal activity with
9
0% control of tomato late blight at 375 g ai/ha, while two compounds 2F and 2H show insecticidal activity with 80 and 100% control,
respectively, against potato leafhopper at 600 g ai/ha.
2004 Elsevier B.V. All rights reserved.
#
Keywords: Synthesis; Biological activity; 2-Methyl-5-trifluoromethyl-thiazolecarboxamides
1
. Introduction
of discovering new fungicides we incorporated the two active
moieties of thifuzamide and propamocarb into a single
compound, 1. The hydrochloride salt (2A), and additional
analogs (2B–2D) and comparative compounds (2E–2H) were
synthesized, and their biological activities were evaluated in
the greenhouse.
The thiazole nucleus plays a vital role in many biological
activities making it one of the extensively studied hetero-
cycles [1–9]. For example 2,4-dimethylthiazole-5-carboxa-
mide and 2-methyl-4-trifluoromethylthiazole-5-carboxamide
derivatives such as metsulfovax [10] and thifluzamide [11] are
known as agricultural fungicides where the 4-trifluoro-
methylthiazole-5-carboxamide derivatives are usually better
than the 4-methylthiazole-5-carboxamides [3]. Propamocarb
2. Results and discussion
2.1. Synthesis
[
12] is also a known agricultural fungicide and with the goal
Scheme 1 illustrates the synthetic route used to prepare
the derivatives.
*
Compound 6 was synthesized from ethyl 4,4,4-trifluor-
oacetoacetate [13] and reacted easily with amines in acet-
onitrile to afford 1 and 2 in high purity and yield. Compound
Corresponding author.
E-mail addresses: liuchangling@vip.163.com (C.-L. Liu),
nkzml@nk.sina.net (Z.-M. Li).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.03.006

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C.-L. Liu et al. / Journal of Fluorine Chemistry 125 (2004) 1287–1290
O
O
O
O
CF3
OCH3
N
S
a
b
H3C
F3C
OC2H5
CF3
F3C
OC H5
2
Cl
3
4
O
c
CF3
CF3
OH
N
S
N
S
N
S
e
d
H3C
H3C
H3C
NHR
Cl
O
2
6
5
O
O
Scheme 1. Synthesis of 2-methyl-4-trifluoromethyl-thiazole-5-carboxamide derivatives. (a) SO
d) SOCl ; (e) amine/Et N/CH CN. R: 2A, 3-(dimethylamino)propyl HCL salt; 2B, 3-(diethylamino)propyl; 2C, 3-(1H-imidazol-1-yl)propyl; 2D, 3-(2-oxo-
pyrrolidin-1-yl)propyl; 2E, 1,1-dimethyl-prop-2-ynyl; 2F, 1-ethyl-1-methyl-prop-2-ynyl; 2G, tert-butyl; 2H, (N-tert-butyl)amino.
2 2 4 2
Cl CCl ; (b) thioacetamide/DMF; (c) NaOH/H O, HCl (aq);
(
2
3
3
2
nol.
A was prepared from 1 with hydrochloride acid in metha-
ment. Combustion analyses for elemental composition
were made with an EA 1106 analyzer (Fisons). All che-
micals or reagents were purchased from standard commer-
cial suppliers.
The synthesized compounds 1 and 2 were characterized
1
by IR, H NMR, mass spectra and elemental analyses were
consistent with the assigned structures. The IR spectra of
compounds showed NH and C¼O stretching bands at 3240–
3.1. Preparation of N-(3-(dimethylamino)propyl)-2-
methyl-4-trifluoromethylthiazole-5-carboxamide (1)
À1
1
3
440 and 1640–1675 cm , respectively. The H NMR of
spectra of compounds 1 and 2 showed signals at d 5.98–
.45 ppm attributed to NH, while the CH of compound 2F
was affected by CH and chiral carbon simultaneously, and
8
To the solution of 3-(dimethylaniino)propylamine (1.1 g,
0.01 mol) and triethylamine (1.0 g, 0.01 mol) in 10 mL
acetonitrile was added 2-methyl-4-trifluoromethylthiazole-
5-carbonyl chloride (6) [13] (2.3 g, 0.01 mol), the mixture
was heated to reflux for 10 min, rotovaped to remove the
acetonitrile. Water was added and extracted with ethyl
2
3
showed two groups of quadruple peak 2.11–2.15 (m, 1H,
J ¼ 7:5 Hz, CH Me), and 1.85–1.92 (m, 1H, J ¼ 7:5 Hz,
a
CH Me).
b
acetate, washed with saturated aqueous NaHCO , water
3
and brine, dried over magnesium sulfate and rotovaped to
give 2.36 g of the target compound (1) as an oil, yield 80%.
IR (KBr) n: 3300 (N–H), 2960, 2840, 1660, 1565, 1495,
À1
1
(
465, 1360, 1295, 1175, 1140, 910, 730 cm ; GC–MS, m/z
þ
%): 295 (M , 15%), 273 (25%), 254, 245 (10%), 232 (8%),
2
.2. Biological activities
222 (88%), 206 (10%), 194 (75%), 181 (18%), 166 (70%),
47, 125 (40%), 106 (10%), 97 (100%), 84 (20%), 71 (25%),
1
1
The biological activities were evaluated at Rohm and
58 (25%), 42 (80%); H NMR (300 MHz, CDCl ) d: 8.45
3
Haas Co. using a previously reported procedure [14–17]. All
of the compounds have some flingicidal and insecticidal
activity with no herbicidal activity, where 100% is complete
control of the flingus. Compound 1 showed good activity of
tomato late blight providing 90% at 375 g ai/ha. Addition-
ally, two compounds, 2F and 2H, have insecticidal activity
with 80 and 100% control, respectively, against potato
leafhopper at 600 g ai/ha.
(bs, 1H, NH), 3.53 (d, 2H, J ¼ 5:4 Hz, CH ), 2.73 (s, 3H,
2
CH ), 2.60 (t, 2H, J ¼ 6 Hz, CH ), 2.34 (s, 6H, NMe ), 1.82
3
2
2
(t, 2H, J ¼ 6 Hz, CH ); Anal. Calc. (%) for C H F N OS:
2
11 16 3 3
C, 44.73; H, 5.46; N, 14.24. Found: C, 44.49; H, 5.56; N,
14.28.
3.2. Preparation of N-(3-(dimethylamino)propyl)-2-
methyl-4-trifluoromethylthiazole-5-carboxamide
hydrochloride salt (2A)
3
. Experimental
Yield 90%, 143–144 8C. IR (KBr) n: 3440 (N–H), 2980,
960, 1640, 1520, 1505, 1475, 1440, 1320, 1250, 1160,
2
1135, 1080, 905, 850, 710 cm ; GC–MS, m/z (%): 331
À1
Melting points were determined on a B u¨ chi melting
1
þ
point apparatus and are uncorrected. H NMR spectra were
recorded with Mercury 300 (Varian, 300 MHz) spectro-
meter with CDCl3 as the solvent and TMS as the internal
standard. Infrared spectra were measured on KBr disks
using a PF-983G instrument (Perkin-Elmer). Mass spectra
(M ), 295 (13%), 280, 275, 251, 194 (15%), 166 (22%), 151,
1
125 (22%), 106 (5%), 84 (10%), 72 (20%), 58 (100%); H
NMR (300 MHz, CDCl ) d: 11.76 (bs, 1H, HCl), 8.22 (bs,
3
1H, NH), 3.60 (bs, 2H, CH ), 3.15 (bs, 2H, CH ), 2.84 (d,
2
2
6H, J ¼ 3:6 Hz, NMe ), 2.73 (s, 3H, CH ), 2.18 (bs, 2H,
2
3
(
GC–MS) were obtained on an MD-800 (Fisons) instru-
CH ).
2

C.-L. Liu et al. / Journal of Fluorine Chemistry 125 (2004) 1287–1290
1289
1
3
4
.3. Preparation of N-(3-(diethylamino)propyl)-2-methyl-
-trifluoromethylthiazole-5-carboxamide (2B)
(48%), 52 (39%), 41 (65%); H NMR (300 MHz, CDCl )
3
d: 6.21 (bs, 1H, NH), 2.73 (s, 3H, CH ), 2.42 (s, 1H, BCH),
3
1
.73 (s, 6H, 2CH ); Anal. Calc. (%) for C H F N OS: C,
3 11 11 3 2
Oil, yield 86%. IR(KBr) n: 3280 (N–H), 2980, 2820,
660, 1565, 1490, 1360, 1295, 1200, 1175, 1135, 910,
30 cm ; GC–MS, m/z (%): 323 (M , 15%), 308 (68%),
94 (45%), 231 (5%), 223 (8%), 183 (3%), 166 (65%), 125
47.82; H, 4.02; N, 10.15. Found: C, 47.68; H, 3.90; N,
10.28.
1
7
2
(
(
À1
þ
3.7. Preparation of N-(1-ethyl-1-methyl-prop-2-ynyl)-2-
methyl-4-trifluoromethylthiazole-5-carboxamide (2F)
50%), 112 (20%), 100 (22%), 86 (100%), 72 (75%), 58
1
65%), 42 (38%); H NMR (300 MHz, CDCl ) d: 8.44 (bs,
3
1
H, NH), 3.56 (d, 2H, J ¼ 6 Hz, CH ), 2.70–2.81 (m, 9H,
Yield 95%, 79–80 8C. IR (KBr) n: 3310 (CBCH), 3280
(N–H), 2980, 2940, 2880, 2180 (CBC), 1665, 1575, 1540,
1485, 1485, 1465, 1360, 1320, 1295, 1205, 1185, 1135,
2
CH , 3CH ), 1.92 (t, 2H, J ¼ 6 Hz, CH ), 1.13–1.18 (m, 6H,
3
2
2
2
6
CH ); Anal. Calc. (%) for C H F N OS: C, 48.29; H,
3 13 20 3 3
À1
.23; N 12.99. Found: C, 48.40; H, 6.18; N 12.78.
1000, 910, 840, 730, 675, 635 cm ; GC–MS, m/z (%): 291
(
M þ 1, 2%), 275 (10%), 261 (100%), 255 (15%), 242
3.4. Preparation of N-(3-(1H-imidazol-1-yl)propyl)-2-
methyl-4-trifluoromethylthiazole-5-carboxamide (2C)
(70%), 235, 221, 194 (90%), 173 (10%), 166 (80%), 146
(15%), 125 (65%), 106 (32%), 96 (15%), 79 (52%), 65
1
(12%), 53 (25%), 42 (20%); H NMR (300 MHz, CDCl ) d:
3
Oil, yield 78%. IR (KBr) n: 3240 (N–H), 2950, 2880,
660, 1570, 1505, 1495, 1440, 1360, 1295, 1230, 1205,
6.20 (bs, 1H, NH), 2.73 (s, 3H, CH ), 2.11–2.15 (m, J ¼ 7:5,
3
1
1
(
1H, CH Me), 1.85–1.92 (m, J ¼ 7:5, 1H, CH Me), 2.43 (s,
a
b
À1
175, 1140, 1090, 910, 820, 730, 670 cm ; GC–MS, m/z
þ
1H, CBCH), 1.71 (s, 3H, CH ), 1.58 (t, 3H, J ¼ 7:2 Hz,
3
%): 318 (M , 5%), 300, 275, 341, 259 (6%), 251, 203 (3%),
CH ); Anal. Calc. (%) for C H F N OS: C, 49.64; H, 4.52;
3
12 13 3 2
1
1
94 (80%), 183 (15%), 175 (18%), 166 (90%), 146 (8%),
25 (65%), 107 (42%), 95 (100%), 82 (85%), 69 (28%), 55
N, 9.65. Found: C, 49.45; H, 4.42; N, 9.78.
1
(
45%), 41 (35%); H NMR (300 MHz, CDCl ) d: 7.62 (bs,
3.8. Preparation of N-tert-butyl-2-methyl-4-
trifluoromethylthiazole-5-carboxamide (2G)
3
1
2
H, NH), 7.45 (s, 1H, CH), 6.95 (s, 2H, CH¼CH), 4.04 (t,
H, J ¼ 6:6 Hz, CH ), 3.38 (d, 2H, J ¼ 6:3 Hz, CH ), 2.73
2
2
(s, 3H, CH ), 2.10 (t, 2H, J ¼ 6:6 Hz, CH ); Anal. Calc. (%)
for C H F N OS: C, 45.27; H, 4.12; N 17.61. Found: C,
4
Yield 95%, 110–112 8C. IR (KBr) n: 3300 (N–H), 2980,
2940, 1650, 1575, 1540, 1495, 1375, 1305, 1200, 1175,
3
2
1
2 13 3 4
À1
þ
5.08; H, 4.25; N 17.45.
1140, 910, 850, 730, 695 cm ; GC–MS, m/z (%): 266 (M ,
5%), 251 (88%), 231, 223, 211 (60%), 194 (100%), 171
(44%), 166 (88%), 151 (25%), 146 (10%), 125 (75%), 118
3
3.5. Preparation of N-(3-(2-oxo-pyrrolidin-1-yl)propyl)-2-
methyl-4-trifluoromethylthiazole-5-carboxamide (2D)
(20%), 106 (30%), 96 (8%), 87 (5%), 70 (8%), 56 (48%), 42
1
(
41%); H NMR (300 MHz, CDCl ) d: 5.98 (bs, 1H, NH),
3
Oil, yield 85%. IR (KBr) n: 3265 (N–H), 2940, 2880,
675, 1655, 1560, 1500, 1475, 1440, 1365, 1295, 1205,
2.72 (s, 3H, CH ), 1.44 (s, 9H, 3CH ); Anal. Calc. (%) for
C H F N OS: C, 45.10; H, 4.92; N, 10.53. Found: C,
10 13 3 2
3
3
1
1
(
(
À1
175, 1140, 905, 820, 730 cm ; GC–MS, m/z (%): 335
þ
45.29; H, 4.78; N, 10.37.
M , 30%), 315, 302, 287 (5%), 266 (10%), 251 (5%), 237
15%), 224 (23%), 211, 194 (62%), 183 (15%), 175 (12%),
3.9. Preparation of N-((N-tert-butyl)amino)-2-methyl-4-
trifluoromethylthiazole-5-carboxamide (2H)
1
66 (62%), 146 (3%), 141 (12%), 125 (64%), 112 (78%), 98
1
(
(
100%), 84 (38%), 70 (64%), 56 (52%), 41 (49%); H NMR
300 MHz, CDCl ) d: 7.66 (bs, 1H, NH), 3.33–3.46 (m, 6H,
Yield 85%, 123–124 8C. IR (KBr) n: 3260 (N–H), 3205
(N–NH), 2980, 1675, 1530, 1460, 1375, 1340, 1210, 1155,
3
3
CH ), 2.73 (s, 3H, CH ), 2.43 (t, 2H, J ¼ 8:1 Hz, CH ),
2
3
2
À1
þ
2
C H F N O S: C, 46.55; H, 4.81; N, 12.54. Found: C,
.11 (m, 2H, CH ), 1.80 (m, 2H, CH ); Anal. Calc. (%) for
910, 865, 780, 715 cm ; GC–MS, m/z (%): 281 (M , 20%),
266 (52%), 246 (15%), 225 (75%), 205 (25%), 194 (100%),
2 2
1
3 16 3 3 2
4
6.72; H, 4.67; N, 12.62.
186 (10%), 166 (45%), 148 (2%), 146 (3%), 125 (30%), 106
1
(
10%), 87 (15%), 75 (4%), 576 (95%), 41 (55%); H NMR
3.6. Preparation of N-(1,1-dimethyl-prop-2-ynyl)-2-
methyl-4-trifluoromethylthiazole-5-carboxamide (2E)
(300 MHz, CDCl ) d: 7.64 (bs, 1H, NH), 3.56 (bs, 1H, NH),
3
2.75 (s, 3H, CH ), 1.14 (s, 9H, 3CH ); Anal. Calc. (%) for
C H F N OS: C, 42.69; H, 5.02; N, 14.95. Found: C,
3
3
1
0 14 3 3
Yield 95%, 99–100 8C. IR (KBr) n: 3320 (CBCH), 3290
N–H), 2980, 2920, 2180 (CBC), 1660, 1560, 1530, 1485,
42.88; H, 5.21; N, 14.78.
(
1
6
2
1
360, 1295, 1205, 1175, 1135, 1000, 905, 850, 730, 665,
À1
þ
40 cm ; GC–MS, m/z (%): 276 (M , 50%), 261 (60%),
56 (78%), 241 (15%), 228 (12%), 220 (8%), 207 (15%),
94 (100%), 187 (60%), 171 (15%), 166 (88%), 146
Acknowledgements
Thanks to Dr. R.M. Jacobson, Dr. S.H. Shaber, Dr. Y.M.
Zhu, and Dr. J.M. Renga for their help in the project and
(
15%), 125 (78%), 106 (50%), 96 (15%), 84 (55%), 67

1290
C.-L. Liu et al. / Journal of Fluorine Chemistry 125 (2004) 1287–1290
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[
10] C.D.S. Tomlin, The Pesticide Manual, 12th ed., BCPC, 2000, p.
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