Design, synthesis, and biological activity of novel 4-(3,4-dimethoxyphenyl) -2-methylthiazole-5-carboxylic acid derivatives

Article abstract of DOI:10.1016/j.bmc.2004.03.050

Novel 4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic acid derivatives (11-23) were synthesized from 3,4-dimethoxyacetophenone (5) in six-step procedure. Their biological activities were evaluated in the greenhouse. Some of the compounds had shown f

Full text of DOI:10.1016/j.bmc.2004.03.050

Bioorganic & Medicinal Chemistry 12 (2004) 2825–2830
Design, synthesis, and biological activity of novel 4-(3,4-
dimethoxyphenyl)-2-methylthiazole-5-carboxylic acid derivatives
a
b
Chang-Ling Liu,a,b, Lin Li and Zheng-Ming Li
*
aAgrochemical Discovery Department, Shenyang Research Institute of Chemical Industry, Shenyang 110021, China
bInstitute of Elemento-Organic Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China
Received 27 February 2004; revised 21 March 2004; accepted 22 March 2004
Available online 24 April 2004
Abstract—Novel 4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic acid derivatives (11–23) were synthesized from 3,4-di-
methoxyacetophenone (5) in six-step procedure. Their biological activities were evaluated in the greenhouse. Some of the com-
pounds had shown fungicidal and insecticidal activities at 375 g ai/ha and 600 g ai/ha, respectively.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In this paper we report the design and synthesis of
4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic
acid (9) and its novel derivatives (11–23), in which a
thiazole ring is attached to the basic toxiphore moiety.
It is conceivable that new lead compounds may be
discovered for the development of potential agro-
chemicals.
The biological activity of thiazole-related molecules has
been extensively studied. Ethaboxam,1 thifluzamide,2
and metsulfovax3 are known fungicidal thiazoles used in
agriculture.
Cinnamic acid analogs4;5 have been studied as agricul-
tural fungicides. Among these, dimethomorph (devel-
oped by American Cyanamid)6 and flumorph
(developed by Shenyang Research Institute of
Chemical Industry)7 have been commercialized.
Similar compounds, such as flumetover,8 19 and 2,10
also possess fungicidal activity. All these compounds
are structurally related to the natural product 3,11
and contain a common toxiphore as illustrated in
structure 4.
2. Results and discussion
2.1. Chemistry
The synthesis of the 4-(3,4-dimethoxyphenyl)-2-methyl-
thiazole-5-carboxylic acid derivatives (compounds 11–
23) was accomplished via the routes illustrated in
Scheme 1.
H3CO
H3CO
H3CO
H3CO
H3CO
O
O
O
CH3
N
N
N
H3CO
O
O
CH3
F3C
flumetover
Cl
F
dimethomorph
flumorph
Keywords: Thiazolecarboxylic acid derivatives; Synthesis; Biological activity.
* Corresponding author. Tel.: +86-24-89351579; fax: 86-24-89351581; e-mail: liuchangling@vip.163.com
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.03.050

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C.-L. Liu et al. / Bioorg. Med. Chem. 12 (2004) 2825–2830
H3CO
H3CO
H3CO
O
O
H3CO
H3CO
O
N
N
H3CO
O
S
O
OCH3
Cl
Cl
1
2
3
H3CO
H3CO
O
H CO
O
N
3
O
R
4
N
S
N
H CO
3
R
3
R
2
R
CH3
1
4
11
5
2
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
6
Cl
ii
i
OCH3
OCH3
CH3
O
O
O
O
O
6
5
7
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
iii
2
6
2
2
v
iv
5
5
5
N
S
N
S
N
S
6
6
H3C
H3C
H3C
Cl
OH
OCH3
O
O
O
10
9
8
vi
11 NR1R2=morpholin-4-yl
12 R1=ethyl, R2=methyl
13 R1=methoxy, R2=methyl
3 14 R1=cyanomethyl, R2=H
15 R1=R2=ethyl
vii
OCH3
OCH
OCH3
OCH3
2
2
5
5
N
S
N
S
6
6
H3C
H3C
16 R1=N,N-dimethylamino, R2=H
NR1R2
OR3
17 R1=3-(1H-imidazol-1-yl)propyl, R2=H
18 R1=1,1-dimethyl-prop-2-ynyl, R2=H
19 R1=1-ethyl-1-methyl-prop-2-ynyl, R2=H
20 R1=phenyl, R2=H
O
O
22 R3=prop-2-ynyl
23 R3=2-methylpropyl
11-21
21 R1=R2=H
Scheme 1. Synthesis of the 4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic acid derivatives (11–23): (i) NaH/(CH3O)2CO in THF; (ii)
SO2Cl2/CCl4; (iii) thioacetamide/NaHCO3 in THF; (iv) NaOH/H2O, HCl(aq); (v) SOCl2; (vi) R1R2NH/Et3N in CH3CN; (vii) R3OH/Et3N in
CH3CN.
Methyl 3-(3,4-dimethoxyphenyl)-3-oxopropionate (6)
was prepared in 90% yield by using 3,4-dimethoxyace-
tophenone (5) as a starting material according to the
literature procedure.12 All new compounds, 7–23,
were synthesized at high yields based on published
methods.13 Compound 6 was converted into methyl
2-chloro-3-(3,4-dimethoxyphenyl)-3-oxopropionate (7),
which was cyclized into methyl 4-(3,4-dimethoxyphe-
nyl)-2-methylthiazole-5-carboxylate (8) by treating with
thioacetamide. Compound 8 was easily converted into
4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic
acid (9), and was subsequently transformed to 4-(3,4-
dimethoxyphenyl)-2-methylthiazole-5-carbonyl chloride
(10). The key intermediate 10 was then converted into
various derivatives, 11–21, by treating it with the
appropriate amine in the presence of triethylamine. Two
ester compounds, 22 and 23, were also synthesized and
tested for their biological activities for the comparison
with amide derivatives.
were found to be fully consistent with those expected for
assigned structures.
The IR spectra of all synthesized esters and amides
showed a readily detectable C@O band ranging between
1725–1700 cmꢀ1 and 1665–1635 cmꢀ1, with the C@O
band of the acid 9 at 1680 cmꢀ1. Compounds 14, 18, 19,
and 22 also have CBC or CBN absorption bands
between 2240 and 2120 cmꢀ1
.
Although GC–MS and TLC suggested that compound
1
12 may be a single substance, the H NMR data clearly
indicated that it has actually two isomers (1:1), possibly
reflecting trans and cis isomers around the amide bond.14
It is also possible that a sterically hindered rotation
around the C(@O)–N axis rendering that the nitrogen
atom may have a chiral characteristics.15 Saturation
transfer experiment spectrum (Fig. 1, same as in NOE a
specific peak is irradiated, and what a peak points down
means that the peak is saturated by irradiation) was
carried out by specifically saturating (or irradiating) N–
CH3 peak at d 2.61. As a result, the peak at d 3.04 was
also saturated, which indicated that these two peaks are
Physical, analytical, and spectral characterization of all
1
synthesized compounds were conducted. IR, H NMR,
and MS spectral data, as well as elemental analyses,

C.-L. Liu et al. / Bioorg. Med. Chem. 12 (2004) 2825–2830
2827
VerticalScaleFactor = 1
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Figure 1. Saturation transfer experiment spectrum of compound 12.
Table 1. Biological activity of the synthesized compounds (8, 9, 11–23)
in equilibrium to each other. This experiment unequi-
vocally confirms that they are the two peaks from the
two isomers of the same molecule.
Compound
Insecticidal activity
(% control)
Fungicidal
activity
(% control)
OCH3
OCH3
CH3
OCH3
OCH3
GPAPLH
TLB
8
0
0
40
20
20
40
20
0
0
0
N
S
CH3
N
S
9
H3C
H3C
N
11
12
13
14
15
16
17
18
19
20
21
22
23
20
40
20
0
90
0
N
CH3
O
O
CH3
50
0
Trans
Cis
1H NMR data also show that Ha and Hb in compound
19 are different. Presumably, the CH2 of compound 19
was affected by the adjacent CH3 group and the chiral
carbon center and therefore showed two sets of quartets.
0
40
60
0
0
20
0
0
75
0
60
20
20
0
40
0
90
0
40
20
20
20
OCH3
OCH3
0
20
20
0
75
N
H
H3C
CH3
N
S
*
Dimethomorpha
Flumorpha
0
0
0
100
100
H
O
Ha
CH3
Hb
0
19
a Dose for all tests: 300 g ai/ha.
2.2. Biological activity
indicates no control and 100% is complete control of the
insect or fungus. Several compounds at 600 g ai/ha have
some insecticidal activity against green peach aphid
Biological activity of the newly synthesized compounds
was evaluated at Rohm and Haas Co. In Table 1, zero

2828
C.-L. Liu et al. / Bioorg. Med. Chem. 12 (2004) 2825–2830
(GPA) and potato leafhopper (PLH), with compounds
16 and 18 having the best activities against PLH and
GPA, respectively. Additionally, some of the com-
pounds such as 11 and 19 at 375 g ai/ha possess good
fungicidal activity against tomato late blight (TLB) with
90% control. All compounds showed no herbicidal
activity at 1200 g ai/ha.
which was used directly for preparation of compound 8,
1H NMR (CDCl3): d 7.63 (d, 1H, J ¼ 8:1 Hz, phenyl-H-
6), 7.52 (s, 1H, phenyl-H-2), 6.90 (d, 1H, J ¼ 8:1 Hz,
phenyl-H-5), 5.62 (s, 1H, CH), 3.97 (s, 3H, OCH3), 3.94
(s, 3H, OCH3), 3.83 (s, 3H, OCH3).
4.1.2. Methyl 4-(3,4-dimethoxyphenyl)-2-methylthiazole-
5-carboxylate (8).13 Amixture of 7 (50 g, 0.18 mol),
thioacetamide (17 g, 0.22 mol), and NaHCO3 (17 g,
0.20 mol) in THF (400 mL) was heated to reflux for 6 h
and then filtered. After evaporation of the solvent, a
thick oil was obtained and was then purified by column
chromatography (ethyl acetate/petroleum ether 60–90;
2:3) affording the title compound (42 g, 79.6%) as a
white solid, mp 87–88 ꢁC. IR (KBr) m 2980, 1700, 1605,
1530, 1500, 1475, 1440, 1338 cmꢀ1 ; 1H NMR (CDCl3): d
7.41 (d, 1H, J ¼ 8:4 Hz, phenyl-H-6), 7.38 (s, 1H, phe-
nyl-H-2), 6.93 (d, 1H, J ¼ 8:4 Hz, phenyl-H-5), 3.94 (s,
3H, OCH3), 3.93 (s, 3H, OCH3), 3.81 (s, 3H, OCH3),
2.75 (s, 3H, CH3); GC–MS m=z 293 Mþ (100), 278 (65),
262 (23), 250 (15), 235 (50), 218 (77), 193 (26), 178 (16),
163 (8), 149 (38), 120 (26). Anal. Calcd (%) for
C14H15NO4S: C 57.32, H 5.15, N 4.77. Found: C 57.56,
H 5.08, N 4.68.
Though it is hard to tell the relationship of structure–
activity, the test results show that compounds 14 and 17
have no activities against GPAand PLH and PLB; and
compounds with higher activities against insects show
less activity against fungus; compounds with higher
fungicidal activities show less insecticidal activities by
contraries. Moreover, ester compounds (8, 9, 22) and
amide compounds (14, 15, 21) with simple substitutes
have less activities.
3. Conclusions
4-(3,4-Dimethoxyphenyl)-2-methylthiazole-5-carboxylic
acid derivatives described in the present study were
synthesized, starting from 3,4-dimethoxyacetophenone
via six steps. Preliminary biological evaluation showed
that some of the compounds have fungicidal and
insecticidal activity at 375 g ai/ha and 600 g ai/ha,
respectively, suggesting that compounds 11, 16, 18, and
19 may become useful leads for further investigation.
4.1.3. 4-(3,4-Dimethoxyphenyl)-2-methylthiazole-5-car-
boxylic acid (9).13 The solution of the ester 8 (35 g,
0.12 mol), 50% NaOH (28 g, 0.35 mol), and water
(150 mL) in THF (500 mL) was stirred and heated to
reflux for 3 h. The reaction mixture was allowed to cool
room temperature and ethyl acetate (350 mL) was added.
The water layer was separated and neutralized with 10%
HCl to pH 4, followed by addition of ethyl acetate
(300 mL). The organic layer was dried over anhydrous
magnesium sulfate. After evaporation of the solvent, the
carboxylic acid 9 (28 g, 83.6%) was obtained as white
crystals and was used to prepare the acid chloride 10
without further purification, mp 202–204 ꢁC (dec). IR
4. Experimental
4.1. Chemistry
€
Melting points were determined in a Buchi capillary
melting point apparatus and are uncorrected. H NMR
1
spectra were recorded with a Mercury or Gemini 300
(Varian, 300 MHz) spectrometer with CDCl3 as the
solvent and TMS as the internal standard. Infrared
spectra were measured on KBr pellets using a PE-983G
(Perkin–Elmer) or FTS-40 (Biorad) instrument. Mass
spectra (GC–MS) and HRMS were obtained on MD-
800 (Fisons) and Q-TOF Micro (Micromass), respec-
tively. Combustion analyses for elemental composition
were made with an EA1106 analyzer (Fisons). All
chemicals or reagents were purchased from standard
commercial suppliers.
1
(KBr) m 3500, 2500, 1680, 1600, 1500 cmꢀ1; H NMR
(CDCl3): d 7.37 (t, 2H, phenyl-H-6+H-2), 6.90 (d, 1H,
J ¼ 8:4 Hz, phenyl-H-5), 3.94 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 2.77 (s, 3H, CH3); GC–MS m=z 235 Mþ)CO2
(100), 220 (78), 192 (71), 179 (30), 164 (8), 151 (60), 136
(31). Anal. Calcd (%) for C13H13NO4S: C 55.90, H 4.69,
N 5.01. Found: C 55.79, H 4.75, N 5.15.
4.1.4. 4-(3,4-Dimethoxyphenyl)-2-methylthiazole-5-car-
bonyl chloride (10).13 Thionyl chloride (98%, 24.3 g,
0.2 mol) was added dropwise under vigorous stirring to
a solution of carboxylic acid 9 (27.9 g, 0.1 mol) in chlo-
roform (100 mL). The mixture was stirred and heated to
reflux for 2 h. After evaporation of the solvent, a yellow
solid was obtained (29.2 g, 98%), mp 120–122 ꢁC and
was used directly for preparation of compound 11–23.
IR (KBr) m 2950, 2840, 1765, 1605, 1535, 1485 cmꢀ1; 1H
NMR (CDCl3): d 7.41–7.43 (d, 1H, J ¼ 8:1 Hz, phenyl-
H-6), 7.34 (s, 1H, phenyl-H-2), 6.91–6.94 (d, 1H,
J ¼ 8:1 Hz, phenyl-H-5), 3.92 (s, 3H, OCH3), 3.90 (s,
3H, OCH3), 2.80 (s, 3H, CH3).
Methyl 3-(3,4-dimethoxyphenyl)-3-oxopropionate (6)
was prepared according to an established procedure.12
4.1.1. Methyl 2-chloro-3-(3,4-dimethoxyphenyl)-3-oxo-
propionate (7). Sulfuryl chloride (98%, 27.5 g, 0.2 mol)
was added dropwise under vigorous stirring to a solu-
tion of methyl 3-(3,4-dimethoxyphenyl)-3-oxopropio-
nate (6)12 (47.6 g, 0.2 mol) in carbon tetrachloride
(150 mL) at room temperature. The mixture was stirred
for 1 h at room temperature. After evaporation of the
solvent, a yellow oil was obtained (23.8 g, ꢁ100%),

C.-L. Liu et al. / Bioorg. Med. Chem. 12 (2004) 2825–2830
2829
4.1.5. General method for the synthesis of 4-(3,4-dimeth-
oxyphenyl)-2-methylthiazole-5-carboxylates and carbox-
amides (11–23). Asolution of acid chloride 10 (2 mmol)
in dry acetonitrile (5 mL) was added dropwise under
vigorous stirring to a solution of the appropriate amine
or alcohol (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 · 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 evapo-
rated to give the target compounds as an oil or a solid.
Purification was performed with column chromatogra-
phy (ethyl acetate/petroleum ether 60–90; 2:3).
6.15 (b s, 1H, NH), 4.17 (d, 2H, J ¼ 6 Hz, CH2CN), 3.95
(s, 3H, OCH3), 3.94 (s, 3H, OCH3), 2.75 (s, 3H, CH3).
Anal. Calcd (%) for C15 H15N3O3S: C 56.77, H 4.76, N
13.24. Found: C 56.59, H 4.83, N 13.50.
4.1.10. N,N-Diethyl-4-(3,4-dimethoxyphenyl)-2-methyl-
thiazole-5-carboxamide (15). Yield 92% of white solid,
mp 100–101 ꢁC. IR (KBr) m 2975, 2935, 2840, 1635,
1
1515 cmꢀ1; H NMR (CDCl3): d 7.34 (s, 1H, phenyl-H-
6), 7.27 (d, 1H, J ¼ 8:1 Hz, phenyl-H-2), 6.86 (d, 1H,
J ¼ 8:1 Hz, phenyl-H-5), 3.92 (s, 3H, OCH3), 3.91 (s,
3H, OCH3), 3.51 (q, 2H, NCH2), 3.07 (q, 2H, NCH2),
2.75 (s, 3H, CH3), 1.19 (t, 3H, CH3), 0.83 (s, 3H, CH3);
GC–MS m=z 334 Mþ (97), 319 (1), 305 (5), 293 (1), 277
(1), 262 (100), 247 (16), 235 (88), 220 (20), 204 (4), 193
(61), 178 (18), 167 (8), 148 (10), 131 (18), 120 (16). Anal.
Calcd (%) for C17H22N2O3S: C 61.05, H 6.63, N 8.38.
Found: C 60.89, H 6.78, N 8.54.
4.1.6.
4-[4-(3,4-Dimethoxyphenyl)-2-methylthiazole-5-
carbonyl]morpholine (11). Yield 93%, colorless oil. IR
(KBr) m 3000, 2920, 1625, 1435 cmꢀ1; 1H NMR (CDCl3):
d 7.17–7.20 (t, 2H, phenyl-H-6+H-2), 6.83 (d, 1H,
J ¼ 8:7 Hz, phenyl-H-5), 3.86 (s, 3H, OCH3), 3.84 (s,
3H, OCH3), 3.60 (m, 4H, CH2OCH2), 3.05 (m, 4H,
CH2NCH2), 2.68 (s, 3H, CH3); HRMS Calcd for
C17H20N2O4S: 348.1144. Found: 348.1168. Anal. Calcd
(%) for C17H20N2O4S: C 58.60, H 5.79, N 8.04. Found:
C 58.80, H 5.62, N 7.90.
4.1.11. N,N-Dimethylamino-4-(3,4-dimethoxyphenyl)-2-
methylthiazole-5-carboxamide (16). Yield 87% of white
solid, mp 142–143 ꢁC. IR (KBr) m 3340, 3100, 2980,
1640, 1540, 1500 cmꢀ1 ; 1H NMR (CDCl3): d 7.18 (t, 2H,
phenyl-H-6+H-2), 6.92 (d, 1H, J ¼ 8:7 Hz, phenyl-H-5),
6.42 (b s, 1H, NH), 3.94 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 2.73 (s, 3H, CH3), 2.48 (s, 6H, 2CH3). Anal.
Calcd (%) for C15H19N3O3S: C 56.06, H 5.96, N 13.07.
Found: C 56.25, H 5.81, 13.26.
4.1.7. N-Ethyl-N-methyl-4-(3,4-dimethoxyphenyl)-2-
methylthiazole-5-carboxamide (12). Yield 92%, colorless
1
oil. IR (KBr) m 2980, 2940, 2840, 1635, 1515 cmꢀ1; H
4.1.12. N-[3-(1H-Imidazol-1-yl)propyl]-4-(3,4-dimethoxy-
phenyl)-2-methylthiazole-5-carboxamide (17). Yield 85%,
colorless oil. IR (KBr) m 3440, 2920, 2850, 1645,
NMR (CDCl3): d one isomer (50%): 7.32 (m, 2H, phe-
nyl-H-6+H-2), 6.89 (d, 1H, J ¼ 8:7 Hz, phenyl-H-5),
3.92 (s, 6H, 2OCH3), 3.54 (m, 2H, NCH2), 3.04 (s, 3H,
NCH3), 2.76 (s, 3H, CH3), 1.16 (t, 3H, CH3); another
isomer (50%): 7.32 (m, 2H, phenyl-H-6+H-2), 6.89 (d,
1H, J ¼ 8:7 Hz, phenyl-H-5), 3.92 (s, 6H, 2OCH3), 3.10
(m, 2H, NCH2), 2.61 (s, 3H, NCH3), 2.76 (s, 3H, CH3),
0.86 (t, 3H, CH3); GC–MS m=z 320 Mþ (100), 305 (5),
291 (7), 278 (2), 262 (98), 247 (23), 235 (75), 220 (18), 193
(77), 178 (23), 160 (16), 148 (11), 131 (25). Anal. Calcd
(%) for C16H20N2O3S: C 59.98, H 6.29, N 8.74; Found:
C 59.81, H 6.40, N 8.58.
1
1500 cmꢀ1; H NMR (CDCl3): d 7.25 (s, 1H, N@CH–
N), 7.14 (m, 2H, phenyl-H-6+H-2), 7.01 (s, 1H, CH),
6.95 (d, 1H, J ¼ 8:1 Hz, phenyl-H-5), 6.85 (s, 1H, CH),
5.95 (b s, 1H, NH), 3.88–3.93 (m, 8H, 2OCH3+CH2),
3.25 (m, 2H, CH2), 2.72 (s, 3H, CH3), 1.95 (m, 2H,
CH2). Anal. Calcd (%) for C15H19N3O3S: C 59.05, H
5.74, N 14.50. Found: C 58.88, H 5.90, 14.37.
4.1.13. N-(1,1-Dimethyl-prop-2-ynyl)-4-(3,4-dimethoxy-
phenyl)-2-methylthiazole-5-carboxamide (18). Yield 95%
of white solid, mp 114–115 ꢁC. IR (KBr) m 3440, 3255,
1
2180, 1665, 1515 cmꢀ1 ; H NMR (CDCl3): d 7.20 (d,
4.1.8. N-Methoxy-N-methyl-4-(3,4-dimethoxyphenyl)-2-
methylthiazole-5-carboxamide (13). Yield 92%, colorless
1H, J ¼ 8:1 Hz, phenyl-H-6), 7.15 (s, 1H, phenyl-H-2),
6.99 (d, 1H, J ¼ 8:7 Hz, phenyl-H-5), 5.96 (b s, 1H,
NH), 3.95 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 2.76 (s,
3H, CH3), 2.32 (s, 1H, CBCH), 1.49 (s, 6H, 2CH3); GC–
MS m=z 344 Mþ (100), 329 (18), 313 (8), 301 (8), 288
(25), 277 (42), 262 (93), 246 (13), 231 (38), 216 (9), 203
(8), 193 (43), 178 (17), 178 (17), 163 (38), 148 (12), 120
(18). Anal. Calcd (%) for C18H20N2O3S: C 62.77, H 5.85,
N 8.13. Found: C 62.61, H 5.77, N 8.34.
1
oil. IR (KBr) m 3000, 2920, 1635, 1505 cmꢀ1; H NMR
(CDCl3): d 7.32 (d, 1H, J ¼ 8:7 Hz, phenyl-H-6), 7.24 (s,
1H, phenyl-H-2), 6.88 (d, 1H, J ¼ 8:7 Hz, phenyl-H-5),
3.93 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.57 (s, 3H,
OCH3), 3.21 (m, 4H, NCH3), 2.76 (s, 3H, CH3). Anal.
Calcd (%) for C15H18N2O4S: C 55.88, H 5.63, N 8.69.
Found: C 56.00, H 5.79, N 8.87.
4.1.9. N-Cyanomethyl-4-(3,4-dimethoxyphenyl)-2-meth-
ylthiazole-5-carboxamide (14). Yield 92% of white
solid, mp 223–224 ꢁC. IR (KBr) m 3400, 3120, 2240,
4.1.14. N-(1-Ethyl-1-methyl-prop-2-ynyl)-4-(3,4-dimeth-
oxyphenyl)-2-methylthiazole-5-carboxamide (19). Yield
96% of white solid, mp 99–100 ꢁC. IR (KBr) m 3395,
1600, 1565 cmꢀ1
;
1H NMR (CDCl3): d 7.13 (t, 2H,
phenyl-H-6+H-2), 6.98 (d, 1H, J ¼ 8:7 Hz, phenyl-H-5),
3300, 2975, 2930, 2180, 1650, 1500 cmꢀ1 1H NMR
;

2830
C.-L. Liu et al. / Bioorg. Med. Chem. 12 (2004) 2825–2830
(CDCl3) d 7.15 (d, 1H, J ¼ 8:7 Hz, phenyl-H-6), 7.10 (s,
1H, phenyl-H-2), 6.92 (d, 1H, J ¼ 8:7 Hz, phenyl-H-5),
5.91 (b s, 1H, NH), 3.94 (s, 6H, 2OCH3), 2.72 (s, 3H,
CH3), 2.30 (s, 1H, CBCH), 1.82 (m, 1H, CHaMe), 1.64
(m, 1H, CHbMe), 1.51 (s, 3H, CH3), 0.82 (t, 3H, CH2).
HRMS Calcd for C19H22N2O3S: 358.1351. Found:
358.1370. Anal. Calcd (%) for C19H22N2O3S: C 63.66, H
6.19, N 7.82 Found: C 63.75, H 6.27, N 7.69.
4.2. Biological activity assays
Evaluations of biological activities of the reported
compounds were performed as previously described.16–19
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 acknowl-
edge financial support from the National Key Project
for Basic Research (2003CB114400).
4.1.15.
N-(Phenyl)-4-(3,4-dimethoxyphenyl)-2-methyl-
thiazole-5-carboxamide (20). Yield 95% of white solid,
mp 157–158 ꢁC. IR (KBr) m 3280, 2940, 2830, 1660,
1595, 1505, 1440 cmꢀ1; H NMR (CDCl3): d 7.65 (b s,
1
1H, NH), 7.15–7.27 (m, 7H, phenyl-H-6+H-2+C6H5),
7.05 (d, 1H, J ¼ 8:1 Hz, phenyl-H-5), 3.97 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 2.76 (s, 3H, CH3). Anal.
Calcd (%) for C19H18N2O3S: C 64.39, H 5.12, N 7.90;
Found: C 64.55, H 5.03, N 7.73.
References and notes
1. Tomlin, C. D. S. The Pesticide Manual. 12th ed.; BCPC,
2000; p 355.
2. Tomlin, C. D. S. The Pesticide Manual. 12th ed.; BCPC,
2000; p 901.
3. Tomlin, C. D. S. The Pesticide Manual. 12th ed.; BCPC,
2000; p 1008.
4. Nickl, J.; Pieper, H.; Curtze, J.; Drandarevski, C.; Lust, S.
European Patent Application, EP 120,321, 1984; Chem.
Abstr. 1984, 101, 230550.
5. Liu, C. L.; Li, Z. C.; Liu, W. C. US Patent 6,020,332,
2000; Chem. Abstr. 2000, 132, 118764.
6. Tomlin, C. D. S. The Pesticide Manual. 12th ed.; BCPC,
2000; p 310.
7. Tomlin, C. D. S. The Pesticide Manual. 13th ed.; BCPC,
2003; p 462.
8. Bryant, R.; Bite, M. In AG Chem New Compound Review.
Agranova. 2000; p 29.
4.1.16. 4-(3,4-Dimethoxyphenyl)-2-methylthiazole-5-car-
boxamide (21). Yield 92% of white solid, mp 192–193 ꢁC.
IR (KBr) m 3330, 3165, 2930, 2910, 1650, 1505,
1460 cmꢀ1; 1H NMR (CDCl3): d 7.18 (d, 1H, J ¼ 8:7 Hz,
phenyl-H-6), 7.13 (s, 1H, phenyl-H-2), 6.95 (d, 1H,
J ¼ 8:7 Hz, phenyl-H-5), 5.80 (b s, 1H, NHa), 5.50 (b s,
1H, NHb), 3.94 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 2.74
(s, 3H, CH3). Anal. Calcd (%) for C13H14N2O3S:
C 56.10, H 5.07, N 10.06. Found: C 56.24, H 5.23, N
9.88.
9. Pepin, R.; Schmitz, C.; Lacroix, G. B.; Dellis, P.; Veyrat,
C. US Patent 5,342,835, 1994; Chem. Abstr. 1994, 120,
244378.
10. Riebli, P. US Patent 4,968,677, 1990; Chem. Abstr. 1990,
113, 5972.
4.1.17. Prop-2-ynyl 4-(3,4-dimethoxyphenyl)-2-methyl-
thiazole-5-carboxylate (22). Yield 91% of white solid,
mp 134–135 ꢁC. IR (KBr) m 3225, 2940, 2835, 2125,
11. Staples, M. V.; Gershon, H. C.; Renwick, J. A. A. Science
1970, 170, 539.
1725, 1500 cmꢀ1 1H NMR (CDCl3): d 7.41 (d, 1H,
;
J ¼ 8:7 Hz, phenyl-H-6), 7.39 (s, 1H, phenyl-H-2), 6.94
(d, 1H, J ¼ 8:7 Hz, phenyl-H-5), 4.81 (d, 2H,
J ¼ 2:4 Hz, CH2 CBC), 3.94 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 2.75 (s, 3H, CH3), 2.49 (s, 1H, CBCH). Anal.
Calcd (%) for C16H15NO4S: C 60.55, H 4.76, N 4.41
Found: C 60.79, H 4.63, N 4.30.
12. Morrison, G. C. European Patent Application, EP
0,126,651, 1984; Chem. Abstr. 1985, 102, 149261.
13. Lee, L. F.; Schleppnik, F. M.; Howe, R. K. J. Heterocycl.
Chem. 1985, 22, 1621.
14. Phillips, W. G.; Rejda-Heath, J. M. Pestic. Sci. 1993, 38, 1.
15. Spindler, F.; Fruh, T. In Chirality in Agrochemicals;
Kurihara, N., Miyamoto, J., Eds.; John Wiley: New York,
NY, 1998; p 141.
16. Liu, C. L.; Liu, X. N.; Jacobson, R. M.; Mulvihill, M. J.
China Patent CN 1,118,465C, 2003; Chem. Abstr. 2003,
138, 153544.
17. Ross, R.; Fujimoto, T. T.; Shaber, S. H. European Patent
Application EP 0,811,614A1, 1997; Chem. Abstr. 1998,
128, 61510.
18. Jacobson, R. M.; Nguyen, L. T. US Patent 6,147,062,
2000; Chem. Abstr. 2000, 132, 344458.
19. Jacobson, R. M.; Nguyen, L. T.; Thirugnanam, M.
US Patent 4,970,224, 1990; Chem. Abstr. 1990, 112,
198386.
4.1.18. 2-Methylpropyl 4-(3,4-dimethoxyphenyl)-2-meth-
ylthiazole-5-carboxylate (23). Yield 92%, colorless oil.
IR (KBr) m 2960, 2840, 2835, 1715, 1495 cmꢀ1; 1H NMR
(CDCl3): d 7.38 (m, 2H, phenyl-H-6+H-2), 6.94 (d, 1H,
J ¼ 8:1 Hz, phenyl-H-5), 3.99 (d, 2H, J ¼ 3:6 Hz,
OCH2), 3.92 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 2.74 (s,
3H, CH3), 1.95 (m, 1H, CH), 0.92 (d, 6H, J ¼ 6:6 Hz,
2CH3). Anal. Calcd (%) for C17H21NO4S: C 60.87, H
6.31, N 4.18. Found: C 60.68, H 6.59, N 4.01.