Synthesis and Fungicidal Activity of Novel 2-Heteroatomthiazole-based Carboxanilides

Article abstract of DOI:10.1002/jhet.2668

A new series of 2-heteroatomthiazole-based carboxanilides (8) are prepared by reacting 2-heteroatomthiazole-based carboxylic acid chlorides with 2,6-dibromo-4-(trifluoromethoxy)aniline. The structures of all the newly synthesized compounds were supported by spectroscopic data NMR, MS, and elemental analysis, etc. Bioassay showed that the compounds exhibited potent fungicidal activities against Rhizoctonia solani, etc. Particularly, N-(2,6-dibromo-4-(trifluoromethoxy)phenyl)-2-methoxy-4-(trifluoromethyl)thiazole-5-carboxamide (8a-2) showed fungicidal potency which was comparable to that of Thifluzamide, the only commercialized thiazole carboxanilide fungicides of succinate dehydrogenase inhibitor (SDHI).

Full text of DOI:10.1002/jhet.2668

Month 2016
Synthesis and Fungicidal Activity of Novel 2-Heteroatomthiazole-based
Carboxanilides
Aiping Liu,a,b Xiaoguang Wang,a,b Xingping Liu,a Jianming Li,a Haobin Chen,a Li Hu,a,b Wanqi Yu,a,c Lian He,a
Weidong Liu,a,b and Mingzhi Huang
a,d
*
*
aNational Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical Industry,
Changsha 410007, China
bHunan Province Key Laboratory for Agrochemicals, Changsha 410014, China
cDepartment of Chemistry, Carleton College, Northfield 55057, USA
dHunan Haili Chemical Industry Co. Ltd., Changsha 410007, China
*
E-mail: weidliu@yahoo.com; huang-mz@163.com
Received February 1, 2016
DOI 10.1002/jhet.2668
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A
new series of 2-heteroatomthiazole-based carboxanilides (8) are prepared by reacting 2-
heteroatomthiazole-based carboxylic acid chlorides with 2,6-dibromo-4-(trifluoromethoxy)aniline. The struc-
tures of all the newly synthesized compounds were supported by spectroscopic data NMR, MS, and elemental
analysis, etc. Bioassay showed that the compounds exhibited potent fungicidal activities against Rhizoctonia
solani, etc. Particularly, N-(2,6-dibromo-4-(trifluoromethoxy)phenyl)-2-methoxy-4-(trifluoromethyl)thia-
zole-5-carboxamide (8a-2) showed fungicidal potency which was comparable to that of Thifluzamide, the
only commercialized thiazole carboxanilide fungicides of succinate dehydrogenase inhibitor (SDHI).
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
sheath blight. It is thus meaningful to develop new thiazole
carboxanilide fungicides of SDHI that have fungicidal ac-
tivities comparable to that of Thifluzamide but are better
broad-spectrum control.
The fungicide market has been dominated by strobilurins
and triazoles, and consequently pathogen resistance to
these fungicides has become a serious problem. The devel-
opment of resistance to current treatments, along with
newly evolving pathogens problems, and market environ-
ment, gives rise to an emerging demand of new fungicides
that are not only active to resistance strains but also safe to
humans and the environment.
Carboxanilides are a well-known class of fungicides
whose mode of action has been determined to be inhibition
of succinate dehydrogenase [1,2]. Eighteen examples of
commercial fungicides with this mode of action include
Carboxin (Fig. 1; I) [3], Boscalid (II) [4], Fluxapyroxad
(III) [5], and Benzovindilfupyr (IV) [6], etc.
In our previous work, we found that 2-heteroatomthiazole-
based compounds showed remarkable fungicidal activity. In
order to obtain novel thiazole carboxanilides, a new series of
2-heteroatomthiazole-based carboxanilides (8) are prepared
by replacing methyl in Thifluzamide with R (R=alkoxy,
alkylamino, etc.). Bioassay results indicated that 8a-2[N-
(2,6-dibromo-4-(trifluoromethoxy)phenyl)-2-methoxy-4-
(trifluoromethyl)thiazole-5-carboxamide] not only exhib-
ited fungicidal activities against Rhizoctonia solani at the
level to that of Thifluzamide, but also showed stronger
fungicidal activities against Botrytis cinerea than that of
Thifluzamide.
Thiazole carboxanilides are also well known as members
of the carboxamide family of fungicides. Examples include
Metsulfovax (Fig. 2; V) [7], Scedlavax (VI) [8], Ethaboxam
(VII) [9], and Thifluzamide (VIII) [10], etc. However
only one member of this group, N-(2,6-dibromo-4-
(trifluoromethoxy)phenyl)-2-methyl-4-(trifluoromethyl)thia-
zole-5-carboxamide, has been developed as an agricultural
fungicide of succinate dehydrogenase inhibitor (SDHI) un-
der the trade name “Thifluzamide” by Rohm and Haas
Company, USA in 1997 (Fig. 2; VIII) [10]. Thifluzamide
(VIII) has been shown to be highly active against rice
RESULTS AND DISCUSSION
Chemistry. The synthesis scheme shown in Figure 3
provides moderate to high yields of the test compounds.
The structures of all synthesized compounds were
1
analyzed and confirmed by H NMR and MS. Because of
the structural similarity of compounds 8, only some
representative compounds, such as 8a-1, 8a-2, 8a-3, 8b-
2, and 8c-2, were analyzed and confirmed by 13C NMR
© 2016 Wiley Periodicals, Inc.

A. Liu, X. Wang, X. Liu, J. Li, H. Chen, L. Hu, W. Yu, L. He, W. Liu, and M. Huang
Vol 000
Figure 1. Carboxanilides referred to in text.
Figure 2. Thiazole carboxanilides referred to in text.
Figure 3. Synthesis pathway of thiazole carboxanilides.
and elemental analysis; 8a-2 was analyzed and confirmed
by IR analysis. Table 1 summarizes the chemical
structures, MS data, and physical characteristics of
compounds 8. NMR and elemental analysis data are
listed in Table 2.
Because of the presence of heteroatom on the 2-position
of thiazole ring, we expected to observe different δH of the
same group in 1H NMR data. When the heteroatom is oxy-
gen, the hydrogen on 2-position of thiazole ring has the
highest chemical shift value; while the heteroatom is sulfur,
the hydrogen on 2-position of thiazole ring has the lowest
chemical shift value. For example, δH =4.17 ppm for 8a-2,
δH = 3.04 ppm for 8b-2, and δH = 2.75 ppm for 8c-2.
As shown in Table 1, 8a-2 also exhibit 90% fungicidal
activity against B. cinerea at 500 mg/L.
Apparent structure–activity relationship.
The general
structure of compounds 8 (Fig. 3) was optimized through
R and R1 moieties. Different choices of R and R1 can
greatly affect fungicidal activity (Table 1).
When R was kept OCH3, the fungicidal activity against
R. solani was influenced by the nature of the R1 group.
Changing the R1 group from methyl to trifluoromethyl in-
creased the fungicidal activity. For example, the fungicidal
activities of 8a-2 were much stronger than that of 8a-1.
When R1 was kept CF3, the fungicidal activity against R.
solani was influenced by the nature of the R group. Chang-
ing the R group from 2-alkoxy to 2-alkylthio slightly re-
duced the fungicidal activity; changing the R group from
2-alkoxy or 2-alkylthio to 2-alkylamino reduced the fungi-
cidal activity. For example, the fungicidal activities were
correlated as following: 8b-2 << 8c-2 <8a-2. For 2-
substituted analogues, the results in Table 1 showed that a
C1 saturated chain alkyl was required for the development
of optimal fungicidal activity. As the chain length in-
creased, the fungicidal activities of corresponding com-
pounds decreased: 8a-2 >8a-3 >> 8a-4, 8a-5, 8a-6, 8a-7.
For R1¼CF3, R¼OCH3, the resulting compound 8a-2
showed the highest activity among compounds 8, and it
possessed comparable levels of fungicidal activity to that
of Thifluzamide.
Fungicidal activity.
All compounds prepared were
evaluated for initial activity against R. solani at 500mg/L
by typical assay above, and LC50 was calculated through
further assay in which five to six different concentrations
were used and listed in Table 1. The representative
compound 8a-2 was evaluated against B. cinerea at
500mg/L. The activities of Thifluzamide were also
shown in Table 1.
As shown in Table 1, only 8a-2, 8a-3, and 8c-2 exhibit
100% fungicidal activity against R. solani at 500 mg/L,
and 8a-2 has shown potent fungicidal activities when com-
pared with commercial fungicides. For example, 8a-2 has
LC50 (mgLꢀ1) values of 1.11 which is comparable to that
of Thifluzamide.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Fungicidal Activity of Carboxanilides
Table 1
Chemical structures, MS, physical characteristics, fungicidal activity (%) against Rhizoctonia solani, and Botrytis cinerea at 500 mg/L and LC50 (mg/L) of
compounds 8.
Botrytis
cinerea
Rhizoctonia solani
Regression
equation
No.
R1
R
Formula
MS
mp (°C)
500 mg/L 500 mg/L
r
LC50
a
8a-1 CH3 OCH3
C13H9Br2F3N2O3S
C13H6Br2F6N2O3S
488
542
158.2–162.7
184.7–185.9
—
10.0
100
—
—
>500
8a-2 CF3
8a-3 CF3
OCH3
90
Y = 4.9277 0.9629 1.11
+ 1.5918x
Y = 4.7866 0.8455 2.52
+ 0.5326x
OCH2CH3
C14H8Br2F6N2O3S
556
165.9–166.5
—
100
8a-4 CF3
8a-5 CF3
8a-6 CF3
8a-7 CF3
8b-1 CF3
8b-2 CF3
OCH2CH2CH3
OCH(CH3)2
O(CH2)3CH3
OCH2CH = CH2 C15H8Br2F6N2O3S
NH2
C15H10Br2F6N2O3S
C15H10Br2F6N2O3S
C16H12Br2F6N2O3S
570
570
584
568
527
541
504
558
131.0–132.4
133.8–136.4
Viscous solid
Viscous solid
243.0–246.3
273.0–273.2
164.0–165.6
181.0–181.3
—
—
—
—
—
—
—
—
15.7
11.1
11.1
3.43
46.8
0
—
—
—
—
—
—
—
—
—
—
—
—
—
—
>500
>500
>500
>500
≈500
>500
≈500
C12H5Br2F6N3O2S
C13H7Br2F6N3O2S
C13H9Br2F3N2O2S2
C13H6Br2F6N2O2S2
NHCH3
8c-1
8c-2
CH3 SCH3
CF3
50.0
100
SCH3
Y = 4.3562 0.9902 3.32
+ 1.2359x
Thifluzamide
aNo test.
65
100
Y = 5.5993 0.9934 0.42
+ 1.5733x
Table 2
1H NMR data of the synthesized 2-heteroatomthiazole-based carboxanilides.
No.
1H NMR (CDCl3 or DMSO, 300 MHz) and 13C NMR (CDCl3, 75 MHz), δ ppm; elemental analysis; IR (KBr)
8a-1
1H NMR (CDCl3): 2.662 (s, 3H, CH3), 4.128 (s, 3H, CH3), 7.010 (bs, 1H, NH), 7.526 (d, J = 0.9 Hz, 2H, Ph H); 13C NMR (CDCl3):
17.76, 58.82, 114.90, 116.58, 118.36, 121.81, 123.94, 124.78, 133.51, 147.80, 153.92, 159.95, 174.33; Anal. Calcd. for
C13H9Br2F3N2O3S: C31.86, H 1.85, N 5.72; found: C 31.69, H 1.82, N 5.79.
8a-2
8a-3
8a-4
1H NMR (CDCl3, 300 MHz) δ: 4.171 (s, 3H, CH3), 7.521 (s, 2H, Ph H), 7.669 (s, 1H, NH); 13C NMR (CDCl3, 75 MHz) δ: 59.31, 118.04,
118.36, 121.65, 121.81, 123.98, 124.87, 125.00, 126.16, 132.61, 148.28, 156.80, 175.04; calc for C13H6Br2F6N2O3S: C 28.70, H 1.11, N
5.15; found: C 28.62, H 1.15, N 5.12; IR (KBr) cmꢀ1: 1653 (C¼O), 3204 (NH).
1H NMR(CDCl3): 1.475 (t, J = 7.1 Hz, 1H, CH3), 4.533–4.604 (q, J = 7.1 Hz, 2H, CH2), 7.529 (d, J = 0.9 Hz, 2H, Ph H), 7.578 (s, 1H,
NH); 13C NMR (CDCl3): 14.21, 69.18, 118.02, 118.35, 121.63, 121.80, 124.00, 124.80, 125.24, 125.82, 132.65, 148.20, 156.93, 174.47;
calc for C14H8Br2F6N2O3S: C 30.13, H 1.44, N 5.02; found: C 30.09, H 1.38, N 5.11.
1H NMR(CDCl3): 1.043 (t, J = 7.5 Hz, 3H, CH3), 1.804–1.922 (m, 2H, CH2), 4.462 (t, J = 6.6 Hz, 2H, CH2), 7.527 (s, 2H, Ph H), 7.536 (s,
1H, NH).
8a-5
8a-6
1H NMR(CDCl3): 1.447 (d, J = 6.0 Hz, 6H, 2*CH3), 5.268–5.351 (m, 1H, CH), 7.516 (d, J = 1.2 Hz, 2H, Ph H), 7.581 (s, 1H, NH).
1H NMR(CDCl3): 0.986 (t, J = 7.4 Hz, 3H, CH3), 1.420–1.545 (m, 2H, CH2), 1.767–1.861 (m, 2H, CH2), 4.504 (t, J = 6.5 Hz, 2H, CH2),
7.529 (s, 2H, Ph H), 7.533 (s, 1H, NH).
8a-7
1H NMR(CDCl3): 4.987–5.014 (m, 2H, CH2), 5.368–5.521 (m, 2H, CH2), 5.996–6.127 (m, 1H, CH), 7.528 (s, 2H, Ph H), 7.559 (s, 1H,
NH).
8b-1 1H NMR(DMSO): 7.840 (s, 2H, NH2), 7.896–7.940 (m, 2H, Ph H), 10.301(s, 1H, NH); 13C NMR(DMSO): 14.21, 69.18, 118.02, 118.35,
121.63, 121.80, 124.00, 124.80, 125.24, 125.82, 132.65, 148.20, 156.93, 174.47; 118.02, 118.35, 121.44, 121.81, 124.32, 125.26, 135.05,
147.30, 156.38, 157.45, 160.98, 168.54.
8b-2 1H NMR(DMSO): 3.048 (s, 3H, CH3), 7.500 (s, 1H, NH), 7.525 (s, 2H, Ph H); 13C NMR(DMSO): 30.90, 117.80, 118.02, 118.29, 121.44,
121.90, 124.85, 125.12, 125.24, 135.04, 147.09, 157.56, 168.93; Anal. Calcd. for C13H7Br2F6N3O2S: C 28.75, H 1.30, N 7.74; found: C
28.82, H 1.22, N 7.86.
8c-1
8c-2
1H NMR(CDCl3): 2.724 (s, 3H, CH3), 2.748 (s, 3H, CH3), 7.136 (bs, 1H, NH), 7.527 (d, J = 0.9 Hz, 2H, Ph H).
1H NMR(CDCl3): 2.758 (s, 3H, CH3), 7.535 (d, J = 0.9 Hz, 2H, Ph H), 7.573 (s, 1H, NH); 13C NMR: 16.59, 118.04, 118.34, 121.66,
121.79, 124.00, 124.83, 125.27, 125.30, 132.47, 148.30, 156.50, 171.56; Anal. Calcd. for C13H6Br2F6N2O2S2: C 27.88, H 1.08, N 5.00;
found: C 27.79, H 1.02, N 4.96.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Liu, X. Wang, X. Liu, J. Li, H. Chen, L. Hu, W. Yu, L. He, W. Liu, and M. Huang
Vol 000
In general, for compounds 8:
for 2–3 h at the same temperature, then for 1 h at room
temperature followed by being poured into ice water to
Activity order of R1: CF3 >> CH3.
give
ethyl
2-bromo-4-(trifluoromethyl)thiazole-5-
Activity order of R: OCH3 > SCH3 > OCH2CH3 > >NH2,
SO2CH3 >> OCH(CH3)2, OCH2CH2CH3, O(CH2)3CH3,
OCH2CH¼CH2, NHCH3.
carboxylate (4) as a solid which was collected by
suction filtration and dried, yield 79.8%.
Ethyl 2-methoxy-4-(trifluoromethyl)thiazole-5-carboxylate (5).
The mixture of compound 4 (0.10 mol) and sodium
methanolate (30%, 0.14mol) in tetrahydrofuran (120mL)
was heated under reflux for 2.5–3.5h. The reaction mixture
was cooled to room temperature and then poured into ice
water followed by extraction with ethyl acetate. The
combined organic layer was dried and evaporated to give
ethyl 2-methoxy-4-(trifluoromethyl)thiazole-5-carboxylate
(5) which was used directly without purification.
2-Methoxy-4-(trifluoromethyl)thiazole-5-carboxylic acid (6) and
2-methoxy-4-(trifluoromethyl)thiazole-5-carboxylic acid chlorode
(7). The thiazole carboxylic acid (6) was synthesized by
base hydrolysis of the corresponding ethyl ester (5). The
thiazole acid chloride (7) was synthesized from the
corresponding carboxylic acid (6) and excess (1.2
equivalents) sulfurous dichloride in toluene under reflux.
After 4–6 h, the excess sulfurous dichloride and toluene
were removed to yield the acid chloride (7) which was used
directly without purification.
N-(2,6-dibromo-4-(trifluoromethoxy)phenyl)-4-methoxy-2-
(trifluoromethyl)thiazole-5-carboxamide (8a-2). To the mixture
of 2,6-dibromo-4-(trifluoromethoxy)aniline (0.010mol) and
xylene (20mL), the compound 7 (0.010 mol) in xylene
(5mL) was added dropwise at room temperature. The
reaction mixture was stirred for 3–5h at 90–100°C. The
reaction mixture was cooled to room temperature and poured
into ice water followed by extraction with ethyl acetate. The
combined organic layer was dried with anhydrous sodium
sulfate. After the solvent was removed, the crude product
was separated by silica-gel column chromatography using
petroleum ether and ethyl acetate (50:1 to 20:1 by volume)
as eluant to give 98.6% (HPLC) 8a-2 as a white solid
3.08g, yield 56.8%. IR (KBr) cmꢀ1: 1653 (C¼O), 3204
(NH); GC-MS (EI, 70Ev) (m/z) 465 (30% M+ ꢀ 79 + 2),
463 (30% M+ ꢀ 79), 210 (100% M+ ꢀ 332); calc for
C13H6Br2F6N2O3S: C 28.70, H 1.11, N 5.15; found: C 28.62,
H 1.15, N 5.12; 1H NMR (CDCl3, 300 MHz) δ: 4.171 (s, 3H,
CH3), 7.521 (s, 2H, Ph H), 7.669 (s, 1H, NH); 13C
NMR (CDCl3, 75MHz) δ: 59.31, 118.04, 118.36, 121.65,
121.81, 123.98, 124.87, 125.00, 126.16, 132.61, 148.28,
156.80, 175.04.
CONCLUSION
The above results demonstrate that besides methyl group
in Thifluzamide (6), a methoxy group on the 2-position of
the thiazole ring is also viable for the development of
optimal fungicidal activity. Further studies on the biologi-
cal activity and structure–activity relationships of this series
of compounds are in progress.
EXPERIMENTAL
Unless otherwise noted, reagents and solvents were used
as received from commercial suppliers. NMR spectra were
obtained with a Varian INOVA-300 spectrometer using
tetramethylsilane (TMS) as the internal standard and
deuteriochloroform (CDCl3) or deuteriodimethylsulfoxide
(DMSO) as the solvent. LC-MS were recorded with an
Agilent 1260/6120 Series and GC-MS with an Agilent
7890-5975C Series. Uncorrected melting points were taken
in a WRS-1A digital melting points apparatus. Elemental
analyses were obtained with a Vario EL III from Elementar.
Synthesis. The general synthetic methods for the target
compounds 8 are shown in Figure 3. Representative
procedures are given below. Yields were not optimized. All
reactions were carried out under a protective atmosphere of
dry nitrogen or utilizing a calcium chloride tube.
Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (2).
Sulfuryl
dichloride (1.05mol) was added dropwise to ethyl 4,4,4-
trifluoro-3-oxobutanoate (0.95 mol) at room temperature.
The reaction was stirred overnight at the same temperature.
Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (2) was
obtained after the extra sulfuryl dichloride was removed,
yield 94.7%.
Ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate (3).
The mixture of compound 2 (0.18 mol) and thiourea
(0.18mol) in ethanol (200mL) was heated under reflux for
4–6h. The reaction mixture was cooled to room temperature
and poured into ice water to give ethyl 2-amino-
4-(trifluoromethyl)thiazole-5-carboxylate (3) as a solid which
was collected by suction filtration and dried, yield 88.5%.
Ethyl 2-bromo-4-(trifluoromethyl)thiazole-5-carboxylate
The synthesis of 8a-1, 8a-3 – 8a-7, 8b-1 – 8b-2, and 8c-
1 – 8c-2 with ≥95.0% purity (HPLC) was similar to that of
8a-2, and their structures were supported by spectroscopic
data in Tables 1 and 2.
(4).
To the mixture of compound 3 (0.16 mol) and
Biological assay [11–15]
hydrobromide (40%, 120 mL) in water (100 mL),
sodium nitrite (0.18 mol) in water (30 mL) was added
dropwise at ꢀ5–0°C. The reaction mixture was stirred
Test compounds.
Stock solution of every test
compound was prepared in DMF at a concentration of
1.0 g Lꢀ1
and then diluted to the required test
,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Fungicidal Activity of Carboxanilides
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The activity against R. solani or B. cinerea. Cucumber
plants were grown under greenhouse conditions (T = 22°
C, 60 ( 5)% relative humidity and a 12-h light cycle).
Plants were maintained in plastic pots (6-cm
diameter × 10 cm). Test compound solutions were sprayed
over the plants. One day later plants were inoculated by a
spore suspension of R. solani or B. cinerea (1.0 × 105
spores mLꢀ1). One or two weeks later the symptoms were
examined. Each bioassay was conducted in triplicate, and
the biological effect was reported as the average of the
triplicates. The dose–response data were analyzed by
probit analysis as described by Bliss [16], and the
activities were evaluated as EC50 values (95% FL).
Acknowledgements. The authors are thankful to the National
Natural Science Foundation of China for the Financial support
(21272062, 21572050b).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet