Synthesis and biological activities of novel trifluoromethylpyridine amide derivatives containing sulfur moieties

Article abstract of DOI:10.1039/d0ra07301f

A series of trifluoromethylpyridine amide derivatives containing sulfur moieties (thioether, sulfone and sulfoxide) was designed and synthesized. Their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo), Ralstonia solanacearum (R. solana

Full text of DOI:10.1039/d0ra07301f

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Synthesis and biological activities of novel
trifluoromethylpyridine amide derivatives
containing sulfur moieties†
Cite this: RSC Adv., 2020, 10, 35658
*
S. X. Guo,‡ F. He,‡ A. L. Dai, R. F. Zhang, S. H. Chen and J. Wu
A series of trifluoromethylpyridine amide derivatives containing sulfur moieties (thioether, sulfone and
sulfoxide) was designed and synthesized. Their antibacterial activities against Xanthomonas oryzae pv.
oryzae (Xoo), Ralstonia solanacearum (R. solanacearum) and insecticidal activities against P. xylostella
were evaluated. Notably, the half-maximal effective concentration (EC50) value of sulfone-containing
compound F10 is 83 mg Lꢀ1 against Xoo, which is better than that of commercial thiodiazole copper
(97 mg Lꢀ1) and bismerthiazol (112 mg Lꢀ1). Thioether-containing compounds E1, E3, E5, E6, E10, E11
and E13 showed much higher activities against R. solanacearum with the EC50 value from 40 to
78 mg Lꢀ1, which are much lower than that of thiodiazole copper (87 mg Lꢀ1) and bismerthiazol
(124 mg
L
ꢀ1). Generally, most of the sulfone-containing compounds and sulfoxide-containing
Received 25th August 2020
Accepted 17th September 2020
compounds showed higher activities against Xoo than that of the corresponding thioether-containing
compound, but most of the thioether-containing compounds contributed higher antibacterial activities
against R. solanacearum. Furthermore, title compounds E3, E11, E24 and G2 showed good insecticidal
activities of 75%, 70%, 70% and 75%, respectively.
DOI: 10.1039/d0ra07301f
rsc.li/rsc-advances
Consequently, the development of eco-friendly pesticides with
novel action modes is urgently needed.
1 Introduction
Sulfur element is a crucial part of proteins and amino acids.
It can be found in many secondary metabolites in living
organisms, and exits also in many bio-active compounds (Fig. 1)
with broaden biological activities,7–14 especially using for anti-
cancer,15–18 anti-HIV,19,20 and treating acid-related disorder,21
and also using for the inhibitors of topoisomerase 1,22 anhy-
drase II,23 mutated B-Raf,24,25 cyclooxygenase-2.26,27 Particularly,
compounds containing thioether, sulfone or sulfoxide moieties
could exhibit signicantly anti-bacterial,28–32 anti-fungal,33,34
herbicidal35 and insecticidal36,37 activities for crop protection.
Thus, sulfur-containing molecules show promising properties
for drug design and medicinal chemistry.38–40
Crop diseases caused by bacteria, fungi, viruses, nematodes and
oomycetes have posed a huge challenge for crop production, so
that it is hard to provide sufficient food for the growing pop-
ulation.1,2 Particularly, rice bacterial leaf blight caused by Xan-
thomonas oryzae pv. oryzae (Xoo) can reduce rice yields by 80%.3,4
Tobacco bacterial wilt caused by Ralstonia solanacearum (R.
solanacearum), is another devastating disease.5 Pesticides play
a crucial role in controlling crop diseases for agricultural
cultivating systems, rapidly increasing the crop yields and food
production.1,6 However, along with the resistance and cross
resistance, the efficiencies of many pesticides have gradually
reduced. Currently, because of the potential environmental,
ecological and health risks, some pesticides have been gradu-
ally banned and withdrawn from the market. For example,
bismerthiazol, used as a bactericide against rice bacterial
blight, was banned by the Ministration of Agriculture, P. R.
China due to its harmful effects towards some creatures.
State Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Research and Development Center for Fine Chemicals,
Guizhou University, Huaxi District, Guiyang 550025, P. R. China. E-mail:
wujian2691@126.com; jwu6@gzu.edu.cn
† Electronic supplementary information (ESI) available: The copies of 1H NMR,
19F NMR, 13C NMR and HR-MS spectrograms for all the synthesized
compounds. See DOI: 10.1039/d0ra07301f
Fig. 1 Some bio-active molecules containing thioether, sulfoxide or
sulfone.
‡ Co-rst author for the manuscript.
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Over decades, triuoromethylpyridine ring, a special uori-
RSC Advances
nated nitrogen heterocycle, has been a hot spot for the creation
of novel pesticides.41–43 For the period 2000–2017, among a total
166 ISO common name proposals, 10 (6%) contain a tri-
uoromethylpyridine, including 3 fungicides, 2 herbicides and
5 insecticides.43 Our previous works44–46 also revealed that some
compounds containing triuoromethyl pyridine showed excel-
lent anti-virus, anti-bacterial and insecticidal activities.
Consequently, considering the concepts mentioned above,
this work focused on the synthesis of triuoromethylpyridine
amide derivatives containing the thioether, sulfoxide or sulfone
substructure, and their biological evaluation. Their primary
structure–activity
relationship
for
these
novel
tri-
uoromethylpyridine amide derivatives was also discussed.
2 Results and discussion
2.1 Design
The commercial fungicides such as uopicolide and uopyram
(Fig. 2) are typical triuoromethylpyridine derivatives.43 Our
previous work has revealed that triuoromethyl pyridinamide
derivatives containing a structure of “–S]N–CN” showed
signicantly bactericidal activities.46 Wang and co-workers29 has
reported that some novel sulfur contained compounds can be
used as potential antibacterial agents.29 Thus as shown in Fig. 2,
this work sought to modify the previous structure through
changing the “–S]N–CN” to “–S–”, “–SO2–” or “–SO–” to obtain
a series of novel thioether-containing compounds E1–E26.
Then, the chemoselectivities of sulfone-containing compounds
F1–F10 and sulfoxide-containing compounds G1–G16, were
obtained by the oxidation of compounds E1–E26 in different
conditions (Scheme 1). Their antibacterial activities against Xoo
and R. solanacearum, and insecticidal activities against P.
xylostella were evaluated. Desirably, some synthesized
compounds could show higher antibacterial activities than that
of commercialized thiodiazole copper and bismerthiazol. It's
the rst time that triuoromethylpyridine amide derivatives
containing the sulfur moiety were designed and synthesized for
anti-bacterial and insecticidal applications.
Scheme 1 The synthetic route of the title compounds E1–E26, F1–
F10, and G1–G16.
rstly synthesized via two steps. Firstly, haloalkane (A) was
treated with aminoethyl mercaptan (B) using LiOH as base and
the mixture of ethanol and H2O in a ratio of 3 : 1 as solvent
under room temperature (rt) to obtain differently substituted 2-
(ethylthio)amines (C).29,47,48 Aer being activated by POCl3, 3-
chloro-5-(triuoromethyl)picolinic acid (D) condensed with
intermediate C to obtain thioether-containing compounds E1–
E26.29,47,48 Thioether-containing compounds E1–E10 were then
converted to corresponding sulfone-containing compounds F1–
F10 in the presence of ammonium molybdate, 30% H2O2 as
oxidant and ethanol as solvent at 100 ꢁC.47,48 Different with the
synthesis of sulfone compounds F1–F10, sulfoxide-containing
compounds G1–G16 were obtained through the oxidation of
E11–E26 in the presence of sodium tungstate dehydrate, 30%
H2O2 as oxidant and the mixture of acetonitrile and water in
a ratio of 3 : 1 as solvent at rt.47,48
The title thioether-containing compounds E1–E26, sulfone-
containing compounds F1–F10 and sulfoxide-containing
compounds G1–G16 were characterized by the 1H NMR, 19F
NMR, 13C NMR and HR-MS. Taking sulfone-containing
compound F1 as an example, in the 1H NMR spectrum, the
proton near “N” atom of triuoromethylpyridine ring appeared
as a doublet at d 8.72 ppm. The proton of –CONH– was split into
2.2 Chemistry
According to the reported methods,29,47,48 the title compounds
E1–E26, F1–F10 and G1–G16 could be easily obtained as shown
in Scheme 1. The thioether-containing compounds E1–E26 were
a
triplet at
d
8.40 ppm. Another proton of tri-
uoromethylpyridine ring appeared also as a doublet at d 8.07.
The four protons of benzene ring were characterized as two
multiples at d 7.33–7.23 and d 7.15–7.00. The protons of meth-
ylene near the benzene ring appeared as a quartet at d 4.03. The
protons of methylene near the carbonyl appeared as multiple at
d 3.11–2.77, and the protons of methylene appeared at d 3.96 as
double doublets. In 13C NMR spectrum, the carbons near
“–CF3” or “F” were all split into quartets due to the coupling
coefficients of “F”. For instance, the carbon of “–CF3” group was
split into a quartet at dC 122.1 ppm with the coupling constant
Fig. 2 The design of the title compounds.
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of (1JF–C) 273.3 Hz. Carbon at the position 5 in the pyridine, was against Xoo of 35%, 35%, 33%, 33%, 32% and 31% respectively,
split into another quartet with coupling constant of 34.1 Hz at which are close to that of BT (31%). Desirably, when two electron
dC 129.4. Two carbons at the position 4 and 6 of tri- withdraw groups, 3,4-dimethoxypyridine, substituted in the
uoromethylpyridine, were also split into two quartets with phenyl, sulfone-containing compound F10 exhibited the highest
smaller coupling constants. Other carbons near the atom “F” activities of 53% (100 mg Lꢀ1) and 42% (50 mg Lꢀ1) against Xoo,
could also be split with different coupling constants. In the 19
F
which are slightly higher than that of TC (53%, 39%) and BT (51%,
NMR spectra, the uorine of “–CF3” appeared at the shi of 31%). Sulfone-containing compounds F1–F10 showed the
ꢀ62.57 ppm, and the uorine on the benzene ring appeared at different activities against Xoo as follows: 3,4-dimethoxypyridin
the shi of ꢀ112.80 ppm.
(F10) > benzyl (F9) > 4-bromo-2-uorobenzyl (F3) > 4-uorobenzyl
(F1) > 3-uorobenzyl (F5) > 2,3-dichlorobenzyl (F6) > 2-uoro-5-
triuoromethylbenzyl (F2) > 2-bromo-5-uorobenzyl (F4) > 3-
chloro-2-uorobenzyl (F7) > 3,4-diuorobenzyl (F8). Among
sulfone-containing compounds, compounds F3 (31%), F5 (31%)
and F9 (32%) showed activities of 31%, 31% and 32% respectively
against Xoo at 50 mg Lꢀ1, which are close to than that of BT (31%).
Among sulfoxide-containing compounds, compounds G5 where R
is 3-bromobenzyl and G16 where R is 2,5-diuorobenzyl showed
2.3 Preliminary in vitro antibacterial activity test
According to the reported method,49 the method of turbidity was
adopted to evaluate the antibacterial activities of title compounds
against Xanthomonas oryzae pv. oryzae (Xoo), Ralstonia sol-
anacearum (R. solanacearum). The commercial thiodiazole copper
(TC) and bismerthiazol (BT) were used as the positive controls.
The results shown in Table 1 revealed that some of the synthe-
sized compounds showed higher activities against Xoo and R.
solanacearum than that of commercial bactericides at the
concentration of 100 and 50 mg Lꢀ1. For example, at the
concentration of 50 mg Lꢀ1, compounds E20 (R is 4-tert-butyl-
benzyl), E15 (R is 3-bromobenzyl), E9 (R is benzyl), E16 (R is 2,6-
diuorobenzyl), E13 (R is 4-isopropylbenzyl) and E24 (R is 3-
methyl-4-(2,2,2-triuoroethoxy)pyridine) showed good activities
activities of 32% and 35%, respectively against Xoo at 50 mg Lꢀ1
,
which are closed to that of BT (31%). The majority of oxidized
compounds (sulfone or sulfoxide-containing compounds) could
show higher activities against Xoo, compared with the thioether-
containing compounds. For example, oxidizing thioether-
containing compounds E3 (9%), E4 (13%), E7 (7%) and E17
(4%) to corresponding F3 (47%), F4 (32%), F7 (31%) and G7 (36%)
Table 1 Antibacterial activities of title compounds E1–E26, F1–F10 and G1–G16 against Xoo and R. solanacearum
Activitya (%)
Activitya (%)
Xoo
R. solanacearum
Xoo
R. solanacearum
Compounds
100 mg Lꢀ1 50 mg Lꢀ1 100 mg Lꢀ1 50 mg Lꢀ1 Compounds
100 mg Lꢀ1 50 mg Lꢀ1 100 mg Lꢀ1 50 mg Lꢀ1
E1
E2
E3
E4
E5
E6
E7
E8
40 ꢂ 1.2
26 ꢂ 0.3
9 ꢂ 2.7
18 ꢂ 2.4
16 ꢂ 3.0
—
2 ꢂ 1.2
21 ꢂ 2.3
10 ꢂ 4.2
—
57 ꢂ 0.3
44 ꢂ 3.0
53 ꢂ 2.5
30 ꢂ 1.9
64 ꢂ 4.4
67 ꢂ 2.2
48 ꢂ 1.6
8 ꢂ 5.0
54 ꢂ 0.8
30 ꢂ 1.3
44 ꢂ 3.3
10 ꢂ 2.3
50 ꢂ 3.5
52 ꢂ 4.7
45 ꢂ 2.9
—
11 ꢂ 3.4
45 ꢂ 3.6
27 ꢂ 4.5
40 ꢂ 1.2
56 ꢂ 2.0
14 ꢂ 4.0
—
14 ꢂ 3.0
24 ꢂ 0.7
33 ꢂ 4.4
27 ꢂ 5.0
—
9 ꢂ 0.8
18 ꢂ 0.5
32 ꢂ 2.3
28 ꢂ 0.6
—
F1
F2
F3
F4
F5
F6
F7
F8
41 ꢂ 1.9
33 ꢂ 1.6
47 ꢂ 3.5
32 ꢂ 2.8
45 ꢂ 3.8
38 ꢂ 2.2
31 ꢂ 0.3
19 ꢂ 0.1
47 ꢂ 3.5
53 ꢂ 4.2
28 ꢂ 1.5
29 ꢂ 1.6
35 ꢂ 1.2
35 ꢂ 3.0
48 ꢂ 2.0
46 ꢂ 2.2
36 ꢂ 2.3
44 ꢂ 4.9
37 ꢂ 4.4
33 ꢂ 2.2
36 ꢂ 1.4
18 ꢂ 1.1
39 ꢂ 4.1
35 ꢂ 3.9
36 ꢂ 2.2
40 ꢂ 2.9
29 ꢂ 1.4
28 ꢂ 2.3
31 ꢂ 0.4
22 ꢂ 0.8
31 ꢂ 1.7
24 ꢂ 2.3
21 ꢂ 0.3
21 ꢂ 1.4
32 ꢂ 3.1
42 ꢂ 4.8
29 ꢂ 2.0
20 ꢂ 2.8
17 ꢂ 2.4
24 ꢂ 2.6
32 ꢂ 1.0
30 ꢂ 0.9
26 ꢂ 0.2
24 ꢂ 5.0
20 ꢂ 3.5
23 ꢂ 3.8
22 ꢂ 4.8
10 ꢂ 1.4
29 ꢂ 3.9
17 ꢂ 0.3
26 ꢂ 0.8
35 ꢂ 3.8
31 ꢂ 1.8
30 ꢂ 1.0
10 ꢂ 1.1
9 ꢂ 1.8
25 ꢂ 4.1
—
—
13 ꢂ 0.5
27 ꢂ 1.5
14 ꢂ 0.8
7 ꢂ 2.2
43 ꢂ 1.8
48 ꢂ 4.8
1 ꢂ 0.1
18 ꢂ 2.8
45 ꢂ 3.5
—
14 ꢂ 5.0
12 ꢂ 0.3
21 ꢂ 1.1
34 ꢂ 3.3
—
2 ꢂ 0.3
8 ꢂ 0.3
21 ꢂ 1.5
14 ꢂ 3.5
11 ꢂ 3.5
18 ꢂ 3.2
23 ꢂ 1.5
29 ꢂ 1.2
20 ꢂ 1.1
—
28 ꢂ 2.6
21 ꢂ 3.4
32 ꢂ 1.8
36 ꢂ 1.9
2 ꢂ 1.3
32 ꢂ 0.5
45 ꢂ 4.4
29 ꢂ 0.3
16 ꢂ 4.9
14 ꢂ 4.3
39 ꢂ 2.6
35 ꢂ 4.7
41 ꢂ 2.3
43 ꢂ 2.7
4 ꢂ 1.5
16 ꢂ 2.4
33 ꢂ 1.7
10 ꢂ 1.6
7 ꢂ 2.3
4 ꢂ 2.4
32 ꢂ 4.8
30 ꢂ 1.0
35 ꢂ 4.5
33 ꢂ 0.4
—
3 ꢂ 0.9
26 ꢂ 0.5
35 ꢂ 3.6
21 ꢂ 2.1
25 ꢂ 4.1
21 ꢂ 2.8
31 ꢂ 4.2
23 ꢂ 3.9
15 ꢂ 2.0
39 ꢂ 4.6
E9
50 ꢂ 4.0
62 ꢂ 2.3
54 ꢂ 2.0
50 ꢂ 3.5
63 ꢂ 3.3
40 ꢂ 2.2
7 ꢂ 3.1
F9
E10
E11
E12
E13
E14
E15
E16
E17
E18
E19
E20
E21
E22
E23
E24
E25
E26
F10
G1
G2
G3
G4
G5
G6
G7
G8
G9
G10
G11
G12
G13
G14
G15
G16
15 ꢂ 2.3
14 ꢂ 1.7
28 ꢂ 2.0
19 ꢂ 2.0
36 ꢂ 4.3
25 ꢂ 3.1
26 ꢂ 0.4
34 ꢂ 0.3
37 ꢂ 5.0
2 ꢂ 0.2
30 ꢂ 2.1
40 ꢂ 1.1
49 ꢂ 3.4
34 ꢂ 3.8
5 ꢂ 1.0
23 ꢂ 1.6
44 ꢂ 1.7
43 ꢂ 1.7
35 ꢂ 2.7
42 ꢂ 4.2
42 ꢂ 1.6
38 ꢂ 4.0
33 ꢂ 2.6
28 ꢂ 3.9
23 ꢂ 3.9
34 ꢂ 3.9
40 ꢂ 3.2
50 ꢂ 0.3
3 ꢂ 0.9
3 ꢂ 1.8
—
11 ꢂ 0.7
43 ꢂ 5.0
42 ꢂ 3.4
25 ꢂ 2.3
38 ꢂ 2.5
7 ꢂ 0.5
19 ꢂ 2.3
38 ꢂ 2.4
23 ꢂ 0.1
17 ꢂ 1.5
10 ꢂ 4.2
51 ꢂ 3.0
—
40 ꢂ 4.3
Thiodiazole copper (TC) 53 ꢂ 0.8
Bismerthiazol (BT) 51 ꢂ 3.7
a
The antibacterial activities are mean of three independent experiments.
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could provide 38%, 26%, 24% and 32% higher activities against exhibited much lower activities than that of corresponding
Xoo at 100 mg Lꢀ1, respectively. However, compounds E8 (32%), thioether-containing compounds, which is totally different with
E22 (42%) and E24 (38%) showed higher activities against Xoo the activities against Xoo. Particularly, when R is 2,3-dichlor-
than that of corresponding oxidized compounds F8 (19%), G9 obenzyl, thioether-containing compound E6 could show the
(18%) and G24 (28%). Thioether-containing compounds E13 highest activity (67%), which is much higher than that of TC and
(39%), E19 (44%), E20 (43%) and E23 (42%) showed slightly BT, but the corresponding oxidized sulfone-containing
higher activities against Xoo at 100 mg Lꢀ1 than that of corre- compound F6 owned no activity (1%) against R. solanacearum.
sponding oxidized compounds G3 (35%), G9 (37%), G10 (33%) In addition, thioether-containing compound E13 also exhibited
and G13 (39%). The rest of oxidized compounds owned higher much higher activity (63%) against R. solanacearum than that of
activities against Xoo than that of corresponding thioether- both TC and BT, however, sulfoxide-containing compound G3, the
containing compounds. Regarding R. solanacearum, thioether- oxidized product of E13, are almost no activity against R.
containing compounds E1 (57%, 54%), E3 (53%, 44%), E5 solanacearum.
(64%, 50%), E6 (67%, 52%), E10 (62%, 45%), E11 (54%) and E13
(63%, 56%) exhibited higher activities than that of TC (51%, 40%)
2.4 The EC50 values of active title compounds against Xoo or
and much higher activities than that of BT (38%, 17%) at 100 or
R. solanacearum
50 mg Lꢀ1. According to their activities, the R groups of them can
The half-maximal effective concentration (EC50) values of
sulfone-containing compound F10 against Xoo, and thioether-
containing compounds E1, E3, E5, E6, E10, E11, and E13
against R. solanacearum were further evaluated. The results
listed in Table 2 indicated the EC50 value against Xoo of sulfone-
containing compound F10 is 83 mg Lꢀ1, which is much lower
than that of TC (97 mg Lꢀ1) and BT (112 mg Lꢀ1). Furthermore,
the EC50 values against R. solanacearum of thioether-containing
compounds E6 and E13 are 41 mg Lꢀ1 and 40 mg Lꢀ1 respec-
tively, which are twice lower than that of TC (87 mg Lꢀ1) and
third lower than that of BT (124 mg Lꢀ1). Thioether-containing
compounds E1, E3, E5, E10 and E11 had the EC50 values of 53,
75, 53, 78 and 73 mg Lꢀ1 respectively, which are also much
lower than that of TC and BT.
be sorted as follows: 2,3-dichlorobenzyl (E6) > 3-uorobenzyl (E5)
> 4-isopropylbenzyl (E13) > 3,4-dimethoxypyridin (E10) > 4-uo-
robenzyl (E1) > 4-triuoromethylbenzyl (E11) > 4-bromo-2-
uorobenzyl (E3). At 100 or 50 mg Lꢀ1, there are other
thioether-containing compounds showing higher activities
against R. solanacearum than that of BT (38%, 17%), including R
groups are 3-methyl-4-(2,2,2-triuoroethoxy)pyridine (E24, 50%,
28%), 2-triuoromethylbenzyl (E18, 49%, 33%), 3-chloro-2-
uorobenzyl (E7, 48%, 45%), 2-uoro-5-triuoromethylbenzyl
(E2, 44%, 30%), 3,5-diuorobenzyl (E23, 40%, 32%), 2-bromo-4-
uorobenzyl (E14, 40%) and 2-methylbenzyl (E17, 40%, 24%).
Sulfone-containing compounds F4 (43%) and F5 (48%) could also
show higher activities than that of BT against R. solanacearum.
Among the sulfoxide-containing compounds, compounds G14
(43%) and G15 (42%) showed higher activities against R. sol-
anacearum than that of BT. Their R groups are 3-methyl-4-(2,2,2-
triuoroethoxy)pyridine and 3,4,4-triuorobut-3-en-1-yl, respec-
tively. Sulfone-containing compound F4 (43%) and sulfoxide-
containing compounds G6 (36%), G10 (37%), G15 (42%), G16
(25%) showed higher activities against R. solanacearum than that
of corresponding thioether-containing compounds E4 (30%), E16
(30%), E20 (5%), E25 (3%) and E26 (10%). But the rest of sulfone-
containing compounds or sulfoxide-containing compounds
2.5 Insecticidal activity test
The insecticidal activities of synthesized compounds against P.
xylostella are shown in Table 3. The chlorpyrifos and avermectin
were used as positive controls. The results (Table 3) revealed
that some compounds could show moderate insecticidal activ-
ities. Thioether-containing compound E3 where R is 4-bromo-2-
uorobenzyl showed the highest activity of 75% against P.
xylostella, but the activity could sharply decrease aer being
Table 2 The EC50 values of title compounds against Xoo or R. solanacearum
Xoo
R. solanacearum
Regression
equation
Compounds
Regression equation R2
y ¼ 0.8557x + 3.3573 1.00
EC50a (mg Lꢀ1
)
Compounds
R2
EC50a (mg Lꢀ1
)
F10
83 ꢂ 0.1
97 ꢂ 1.2
E1
E3
E5
E6
E10
E11
E13
y ¼ 0.7768x + 3.661
0.98
53 ꢂ 0.3
75 ꢂ 0.5
53 ꢂ 0.9
41 ꢂ 0.2
78 ꢂ 0.2
73 ꢂ 1.2
40 ꢂ 2.1
87 ꢂ 1.1
Thiodiazole copper (TC) y ¼ 0.996x + 3.065
0.99
y ¼ 2.4159x + 0.4676 0.94
Bismerthiazol (BT)
y ¼ 2.5861x ꢀ 0.0104 0.97 112 ꢂ 1.2
y ¼ 1.4452x + 2.5102 1.00
y ¼ 2.3726x + 1.167
y ¼ 1.34x + 2.4627
1.00
0.97
y ¼ 1.3523x + 2.4812 0.99
y ¼ 0.9336x + 3.507
0.99
Thiodiazole copper (TC) y ¼ 1.6934x + 1.7154 0.94
Bismerthiazol (BT)
y ¼ 2.0182x + 0.7772 0.97 124 ꢂ 1.3
a
Each experiment of EC50 value is performed in triplicates.
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oxidized into corresponding sulfone-containing compound F3 thioether-containing compounds E13, E16 and E17. The activ-
(10%). When R was changed to 4-triuoromethylbenzyl (E11) or ities of the rest of sulfoxide-containing compounds are all less
3-methyl-4-(2,2,2-triuoroethoxy)pyridine (E24), the activity than 50%.
could slightly decrease to 70%. Thioether-containing
compounds E5 and E12 both showed the activities of 55%
against P. xylostella, and their R groups are 3-uorobenzyl and
3 Conclusion
2-chloro-4-uorobenzyl, respectively. Thioether-containing
compounds E1 (2-bromo-5-uorobenzyl), E4 (4-uorobenzyl),
E7 (3-chloro-2-uorobenzyl), E15 (3-bromobenzyl) all showed
activities of 50%. The rest of thioether-containing compounds
showed lower activities less than 50%. In addition, the insecti-
cidal activities of sulfone-containing compounds could be sor-
A series of sulfur-containing triuoromethylpyridine amide
derivatives has been designed and synthesized. Their antibac-
terial activities against Xanthomonas oryzae pv. oryzae (Xoo),
Ralstonia solanacearum (R. solanacearum) and insecticidal
activities against P. xylostella were evaluated. Notably, sulfone-
containing compound F10 (53%, 42%) showing the highest
activity against Xoo had the EC50 of 83 mg Lꢀ1, which is much
lower than that of TC (97 mg Lꢀ1) and BT (112 mg Lꢀ1).
Thioether-containing compounds E1 (57%, 54%), E3 (53%,
44%), E5 (64%, 50%), E6 (67%, 52%), E9 (50%, 11%), E10 (62%,
45%), E11 (54%, 27%), and E13 (53%, 44%) showed higher
activities than that of TC (51%, 40%) showed excellent anti-
bacterial activities against R. solanacearum with EC50 values
ranging from 40–73 mg Lꢀ1, which are all much lower than that
of TC (87 mg Lꢀ1) and BT (124 mg Lꢀ1). Generally, most of
oxidized compounds could show higher activities against Xoo
than that of corresponding thioether-containing compounds,
but most of thioether-containing compounds contributed
higher activities against R. solanacearum. Furthermore,
compounds E3, E11, E24 and G2 showed also moderate insec-
ticidal activities of 75%, 70%, 70% and 75%, respectively.
ted as follows: 3-chloro-2-uorobenzyl (F7)
> 2-uoro-5-
triuoromethylbenzyl (F2) > 2-bromo-5-uorobenzyl (F4) > 4-
uorobenzyl (F1) > 2,3-dichlorobenzyl (F6) ¼ 3,4-diuorobenzyl
(F8) ¼ benzyl (F9) ¼ 3,4-dimethoxypyridin (F10) > 4-bromo-2-
uorobenzyl (F3) > 3-uorobenzyl (F5). Specially, sulfone-
containing compounds F2, F7, F9 and F10 all showed higher
activities than that of corresponding thioether-containing
compounds E2, E7, E9 and E10, but the rest of sulfone-
containing compounds all showed activities less than that of
corresponding thioether-containing compounds. When R is 2-
chloro-4-uorobenzyl, sulfoxide-containing compound G2
showed activity of 75%. Sulfoxide-containing compounds G3,
G6 and G7 showed the activities of 60%, 60% and 50%
respectively, which are all higher than that of corresponding
Table 3 Insecticidal activities of title compounds against P. xylostella
4 Experimental section
4.1 Materials and methods
Activitya (%)
Activitya (%)
Compounds
at 500 mg Lꢀ1
Compounds
at 500 mg Lꢀ1
All reagents and solvents were purchased from Accela Chem-Bio
Co., Ltd (Shanghai, China) and Innochem Co., Ltd (Beijing,
China). Melting points of the synthesized compounds were
measured using a XT-4 binocular microscope (Beijing Tech
Instrument Co., China). Using CDCl3 as solvent, the spectra of
1H, 19F and 13C NMR of title compounds were recorded on
AVANCE III HD 400M NMR (Bruker Corporation, Switzerland)
spectrometer operating at room temperature. HR-MS was
recorded on an Orbitrap LC-MS instrument (Q-Exative, Thermo
Scientic™, and American). The course of the reactions was
monitored by TLC.
E1
E2
E3
E4
E5
E6
E7
E8
50 ꢂ 0
45 ꢂ 2.9
75 ꢂ 0
50 ꢂ 0
55 ꢂ 0
40 ꢂ 2.9
50 ꢂ 3.3
30 ꢂ 0
10 ꢂ 5
10 ꢂ 0
70 ꢂ 0
55 ꢂ 3.3
30 ꢂ 2.9
10 ꢂ 2.9
50 ꢂ 0
20 ꢂ 0
40 ꢂ 0
30 ꢂ 0
20 ꢂ 0
30 ꢂ 5
20 ꢂ 3.3
30 ꢂ 0
35 ꢂ 0
70 ꢂ 0
10 ꢂ 0
10 ꢂ 0
100 ꢂ 0
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
G1
G2
G3
G4
G5
G6
G7
35 ꢂ 0
50 ꢂ 0
10 ꢂ 3.3
40 ꢂ 3.3
10 ꢂ 0
30 ꢂ 3.3
60 ꢂ 0
30 ꢂ 0
30 ꢂ 0
30 ꢂ 0
30 ꢂ 0
75 ꢂ 0
60 ꢂ 0
40 ꢂ 0
30 ꢂ 0
60 ꢂ 0
50 ꢂ 2.9
20 ꢂ 0
20 ꢂ 0
10 ꢂ 0
30 ꢂ 0
10 ꢂ 0
20 ꢂ 0
10 ꢂ 3.3
40 ꢂ 0
30 ꢂ 3.3
100 ꢂ 0
E9
E10
E11
E12
E13
E14
E15
E16
E17
E18
E19
E20
E21
E22
E23
E24
E25
E26
Chlorpyrifos
4.2 Synthetic procedures
4.2.1 Synthesis of substituted aminoethyl sulde (C).
According to the reported literatures,47,48 substituted interme-
diate C could be easily obtained as shown in Scheme 1. Taking
2-((4-uorobenzyl)thio)ethanamine as an example, to a mixture
of LiOH (72.63 mmol) resolving in 15 mL water and EtOH
(45 mL) stirred at room temperature was added 2-aminoethyl
mercaptan (B, 34.58 mmol). Subsequently, 1-(chloromethyl)-4-
uorobenzene (A, 34.58 mmol) was added dropwise and stir-
red at room temperature for about 7 h. The reaction was
monitored by TLC. Aer the completion of the reaction, the
reaction mixture was concentrated under reduced pressure, and
the residue was extracted with dichloromethane and water. The
G8
G9
G10
G11
G12
G13
G14
G15
G16
Avermectin
a
The each insecticidal test were performed in triplicates.
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organic phase was washed with NaOH solution to provide Hz), 38.4, 31.2, 28.4 (d, J ¼ 2.6 Hz). 19F NMR (376 MHz, CDCl3)
a crude production, which was puried using silica gel (200–300 d ꢀ62.52, ꢀ115.12. HRMS: [M + H]+ calcd for C16H13BrClF4N2-
mesh) column chromatography with dichloromethane/ OS: 470.95511; found: 470.95456.
methanol (20 : 1).
N-(2-((2-Bromo-5-uorobenzyl)thio)ethyl)-3-chloro-5-
4.2.2 The synthesis of thioether-containing compounds (triuoromethyl)picolinamide (E4). Yield 87%; gray solid; mp
E1–E26.29,47,48 Taking E1 as an example, 2-(((2-aminoethyl)thio) 111–112 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.77–8.68 (m, 1H,
methyl)-5-uorobenzene-1-ylium (C, 2.64 mmol), 3-chloro-5- pyridine-H), 8.14–8.01 (m, 2H, pyridine-H, –CO–NH), 7.50 (dd, J
(triuoromethyl)picolinic acid (D, 2.64 mmol) and Et3N ¼ 8.8, 5.3 Hz, 1H, Ar–H), 7.20 (dd, J ¼ 9.1, 3.0 Hz, 1H, Ar–H),
(2.64 mmol) were added in one portion using 1,2-dichloro- 6.85 (td, J ¼ 8.3, 3.0 Hz, 1H, Ar–H), 3.87 (s, 2H, –CH2), 3.69 (q, J ¼
ethane (DCE, 6 mL) as solvent, which was stirred at room 6.4 Hz, 2H, –CH2), 2.78 (t, J ¼ 6.5 Hz, 2H, –CH2). 13C NMR (100
temperature. Subsequently, POCl3 diluted by DCE was added MHz, CDCl3) d 162.3, 161.9 (d, J ¼ 247.6 Hz), 149.0, 142.9 (q, J ¼
dropwise and reuxed for 8 h. The resulted mixture was 3.8 Hz), 139.6 (d, J ¼ 7.3 Hz), 137.7 (q, J ¼ 3.6 Hz), 134.2 (d, J ¼
concentrated under reduced pressure, and washed with 8.0 Hz), 132.2, 129.3 (q, J ¼ 34.0 Hz), 122.2 (d, J ¼ 273.4 Hz),
Na2CO3. The resulting solid was ltrated and washed with water 118.5 (d, J ¼ 3.3 Hz), 117.8 (d, J ¼ 23.3 Hz), 116.1 (d, J ¼ 22.4 Hz),
to provide crude product, which was puried by silica gel (200– 38.5, 36.1, 31.4. 19F NMR (376 MHz, CDCl3) d ꢀ62.52, ꢀ114.19.
300 mesh) column chromatography with ethyl acetate/ HRMS: [M + H]+ calcd for C16H13BrClF4N2OS: 470.95511; found:
petroleum ether (1 : 3). Along with similar method, thioether- 470.95468.
containing compounds E2–E26 could be also obtained. The
spectral data of E1–E26 are listed below, and the spectra are picolinamide (E5). Yield 66%; yellow solid; mp 103–104 C. H
3-Chloro-N-(2-((3-uorobenzyl)thio)ethyl)-5-(triuoromethyl)
1
ꢁ
shown in the ESI data.†
3-Chloro-N-(2-((4-uorobenzyl)thio)ethyl)-5-(triuoromethyl)
NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H, pyridine-H),
8.08 (d, J ¼ 1.3 Hz, 1H, pyridine-H), 8.02 (s, 1H, –CO–NH),
picolinamide (E1). Yield 83%; yellow solid; mp 96–97 ꢁC. 1H 7.33–7.19 (m, 1H, Ar–H), 7.13–7.06 (m, 2H, Ar–H), 6.92 (td, J ¼
NMR (400 MHz, CDCl3) d 8.72 (s, 1H, pyridine-H), 8.08 (s, 1H, 8.3, 2.0 Hz, 1H, Ar–H), 3.76 (s, 2H, –CH2), 3.63 (q, J ¼ 6.3 Hz, 2H,
pyridine-H), 7.99 (s, 1H, CO–NH), 7.30 (dd, J ¼ 8.4, 5.4 Hz, 2H, –CH2), 2.71 (t, J ¼ 6.5 Hz, 2H, –CH2). 13C NMR (100 MHz, CDCl3)
Ar–H), 6.98 (t, J ¼ 8.6 Hz, 2H, Ar–H), 3.75 (s, 2H, –CH2), 3.62 (q, J d 162.9 (d, J ¼ 246.4 Hz), 162.3, 149.0, 142.9 (q, J ¼ 3.8 Hz), 140.6
¼ 6.4 Hz, 2H, –CH2), 2.69 (t, J ¼ 6.5 Hz, 2H, –CH2). 13C NMR (100 (d, J ¼ 7.2 Hz), 137.7 (q, J ¼ 3.5 Hz), 132.2, 130.1 (d, J ¼ 8.3 Hz),
MHz, CDCl3) d 162.3, 161.9 (d, J ¼ 245.8 Hz), 149.1, 142.8 (q, J ¼ 129.3 (q, J ¼ 33.9 Hz), 124.6 (d, J ¼ 2.8 Hz), 122.2 (d, J ¼ 273.4
3.8 Hz), 137.7 (q, J ¼ 3.6 Hz), 133.7 (d, J ¼ 3.2 Hz), 132.2, 130.4 Hz), 115.8 (d, J ¼ 21.7 Hz), 114.2 (d, J ¼ 21.1 Hz), 38.3, 35.5 (d, J
(d, J ¼ 8.1 Hz), 129.3 (q, J ¼ 34.0 Hz), 122.2 (q, J ¼ 273.4 Hz), ¼ 1.8 Hz), 31.0. 19F NMR (376 MHz, CDCl3) d ꢀ62.52, ꢀ112.81.
115.5 (d, J ¼ 21.5 Hz), 38.4, 35.2, 30.9. 19F NMR (376 MHz, HRMS: [M ꢀ H]ꢀ calcd for C16H12ClF4N2OS: 391.02895; found:
CDCl3) d ꢀ62.52, ꢀ115.22. HRMS: [M + H]+ calcd for C16H14
ClF4N2OS: 393.04460; found: 393.04370.
-
391.03027.
3-Chloro-N-(2-((2,3-dichlorobenzyl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E6). Yield 80%; white solid; mp
3-Chloro-N-(2-((2-uoro-5-(triuoromethyl)benzyl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E2). Yield 83%; yellow solid; mp 130–132 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (dd, J ¼ 1.8,
1
ꢁ
101–103 C. H NMR (400 MHz, CDCl3) d 8.73 (s, 1H, pyridine- 0.7 Hz, 1H, pyridine-H), 8.12–8.01 (m, 2H, pyridine-H, –CO–
H), 8.08 (d, J ¼ 1.3 Hz, 2H, pyridine-H, CO–NH), 7.69 (dd, J ¼ NH), 7.35 (dd, J ¼ 8.0, 1.6 Hz, 1H, Ar–H), 7.31 (dd, J ¼ 7.7, 1.6 Hz,
6.7, 2.0 Hz, 1H, Ar–H), 7.54–7.49 (m, 1H, Ar–H), 7.16 (t, J ¼ 1H, Ar–H), 7.16 (t, J ¼ 7.8 Hz, 1H, Ar–H), 3.92 (s, 2H, –CH2), 3.68
8.9 Hz, 1H, Ar–H), 3.85 (s, 2H, –CH2), 3.69 (q, J ¼ 6.4 Hz, 2H, (q, J ¼ 6.4 Hz, 2H, –CH2), 2.77 (t, J ¼ 6.5 Hz, 2H, –CH2). 13C NMR
–CH2), 2.77 (t, J ¼ 6.5 Hz, 2H, –CH2). 13C NMR (100 MHz, CDCl3) (100 MHz, CDCl3) d 162.3, 149.0, 142.9 (q, J ¼ 3.8 Hz), 138.2,
d 162.5 (dd, J ¼ 252.5, 1.3 Hz), 162.3, 148.9 (d, J ¼ 1.0 Hz), 142.9 137.7 (q, J ¼ 3.6 Hz), 133.6, 132.4, 132.2, 129.4, 129.3 (q, J ¼ 34.0
(q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.6 Hz), 132.2, 129.3 (dd, J ¼ Hz), 128.9, 127.2, 122.2 (d, J ¼ 273.5 Hz), 38.6, 34.5, 31.4. 19F
102.0 Hz, J ¼ 34.0 Hz), 128.6–128.0 (m), 127.0 (dd, J ¼ 33.1, 3.6 NMR (376 MHz, CDCl3) d ꢀ62.51. HRMS: [M + H]+ calcd for
Hz), 126.7 (d, J ¼ 16.0 Hz), 126.4 (dt, J ¼ 13.0, 3.7 Hz), 123.6 (q, J
¼ 272.0 Hz), 122.2 (q, J ¼ 273.4 Hz), 116.2 (d, J ¼ 23.4 Hz), 38.3,
C
16H13Cl3F3N2OS: 442.97608; found: 442.97546.
3-Chloro-N-(2-((3-chloro-2-uorobenzyl)thio)ethyl)-5-
31.5, 28.5 (d, J ¼ 2.7 Hz). 19F NMR (376 MHz, CDCl3) d ꢀ61.97, (triuoromethyl)picolinamide (E7). Yield 81%; gray solid; mp 97–
ꢀ62.57, d ꢀ112.57 (dd, J ¼ 14.2, 7.8 Hz). HRMS: [M + H]+ calcd 98 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H,
for C17H13ClF7N2OS: 461.03199; found: 461.03098.
pyridine-H), 8.07 (t, J ¼ 3.1 Hz, 2H, pyridine-H, –CO–NH), 7.35–
7.16 (m, 2H, Ar–H), 7.04 (td, J ¼ 7.9, 1.1 Hz, 1H, Ar–H), 3.81 (d, J
N-(2-((4-Bromo-2-uorobenzyl)thio)ethyl)-3-chloro-5-
(triuoromethyl)picolinamide (E3). Yield 77%; brown solid; mp ¼ 0.8 Hz, 2H, –CH2), 3.68 (q, J ¼ 6.4 Hz, 2H, –CH2), 2.76 (t, J ¼
1
95–96 C. H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.0 Hz, 1H, 6.5 Hz, 2H, –CH2). 13C NMR (100 MHz, CDCl3) d 162.3, 157.5,
ꢁ
pyridine-H), 8.08 (d, J ¼ 1.3 Hz, 1H, –CO–NH), 8.05 (s, 1H, 149.0, 142.9 (q, J ¼ 3.9 Hz), 137.7 (q, J ¼ 3.6 Hz), 132.2, 129.6,
pyridine-H), 7.30–7.12 (m, 3H, Ar–H), 3.75 (s, 2H, –CH2), 3.67 (q, 129.3 (q, J ¼ 34.0 Hz), 129.2 (d, J ¼ 3.3 Hz), 127.3 (d, J ¼ 14.8 Hz),
J ¼ 6.4 Hz, 2H, –CH2), 2.73 (t, J ¼ 6.5 Hz, 2H, –CH2). 13C NMR 124.6 (d, J ¼ 4.8 Hz), 122.2 (q, J ¼ 273.3 Hz), 121.3 (d, J ¼ 18.0
(100 MHz, CDCl3) d 162.3, 160.6 (d, J ¼ 251.4 Hz), 149.0, 142.9 Hz), 38.4, 31.3, 29.0 (d, J ¼ 2.8 Hz). 19F NMR (376 MHz, CDCl3)
(q, J ¼ 3.7 Hz), 137.7 (q, J ¼ 3.6 Hz), 132.2, 132.0 (d, J ¼ 4.5 Hz), d ꢀ62.52, ꢀ119.81. HRMS: [M ꢀ H]ꢀ calcd for C16H11Cl2F4N2OS:
129.3 (q, J ¼ 34.0 Hz), 127.7 (d, J ¼ 3.7 Hz), 124.7 (d, J ¼ 14.9 Hz), 424.98998; found: 424.99158.
122.2 (d, J ¼ 273.4 Hz), 121.2 (d, J ¼ 9.5 Hz), 119.2 (d, J ¼ 25.1
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3.5 Hz), 134.6 (d, J ¼ 10.3 Hz), 132.2, 131.8, 131.7, 129.3 (q, J ¼
34.0 Hz), 122.2 (q, J ¼ 273.4 Hz), 117.2 (d, J ¼ 24.7 Hz), 114.2 (d, J
¼ 21.1 Hz), 38.6, 32.8, 31.2. 19F NMR (376 MHz, CDCl3)
d ꢀ62.52, ꢀ112.69. HRMS: [M + H]+ calcd for C16H13Cl2F4N2OS:
427.00563; found: 427.00470.
3-Chloro-N-(2-((3,4-diuorobenzyl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E8). Yield 68%; white solid; mp
97–98 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (s, 1H, pyridine-H),
8.09 (s, 1H, pyridine-H), 8.02 (s, 1H, –CO–NH), 7.29–7.17 (m, 1H,
Ar–H), 7.14–7.01 (m, 2H, Ar–H), 3.73 (s, 2H, –CH2), 3.67–3.58 (m,
2H, –CH2), 2.70 (td, J ¼ 6.5, 1.6 Hz, 2H, –CH2). 13C NMR (100
MHz, CDCl3) d 162.3, 150.3 (dd, J ¼ 248.8, 12.9 Hz), 149.5 (dd, J
¼ 247.9, 12.7 Hz), 148.9, 142.9 (q, J ¼ 3.7 Hz), 137.8 (q, J ¼ 3.6
Hz), 135.1 (dd, J ¼ 5.2, 4.1 Hz), 132.2, 129.3 (q, J ¼ 33.9 Hz),
124.8 (dd, J ¼ 6.2, 3.6 Hz), 122.2 (q, J ¼ 273.5 Hz), 117.7 (d, J ¼
17.4 Hz), 117.2 (d, J ¼ 17.2 Hz), 38.3, 35.1, 30.9. 19F NMR (376
MHz, CDCl3) d ꢀ62.54, d ꢀ137.19 (d, J ¼ 21.2 Hz), ꢀ139.64 (d, J
¼ 21.2 Hz). HRMS: [M ꢀ H]ꢀ calcd for C16H11ClF5N2OS:
409.01953; found: 409.02078.
N-(2-(Benzylthio)ethyl)-3-chloro-5-(triuoromethyl)picolinamide
(E9). Yield 75%; brown solid; mp 109–110 ꢁC. 1H NMR (400
MHz, CDCl3) d 8.73 (d, J ¼ 1.0 Hz, 1H, pyridine-H), 8.07 (d, J ¼
1.3 Hz, 1H, pyridine-H), 8.01 (s, 1H, –CO–NH), 7.36–7.27 (m, 4H,
Ar–H), 7.26–7.20 (m, 1H, Ar–H), 3.78 (s, 2H, –CH2), 3.62 (q, J ¼
6.3 Hz, 2H, –CH2), 2.70 (t, J ¼ 6.5 Hz, 2H, –CH2). 13C NMR (100
MHz, CDCl3) d 162.3, 149.2, 142.9 (q, J ¼ 3.8 Hz), 138.0, 137.7 (q,
J ¼ 3.6 Hz), 132.2, 129.2 (q, J ¼ 34.1 Hz), 128.9, 128.6, 127.2,
122.2 (q, J ¼ 273.5 Hz), 38.3, 35.9, 30.9. 19F NMR (376 MHz,
CDCl3) d ꢀ62.51. HRMS: [M ꢀ H]ꢀ calcd for C16H13ClF3N2OS:
373.03955; found: 373.03837.
3-Chloro-N-(2-((4-isopropylbenzyl)thio)ethyl)-5-(triuoromethyl)
1
ꢁ
picolinamide (E13). Yield 79%; yellow solid; mp 98–100 C. H
NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H), 8.11–8.06 (m,
1H), 8.03 (s, 1H), 7.28–7.23 (m, 2H), 7.17 (d, J ¼ 8.1 Hz, 2H), 3.75
(s, 2H), 3.64 (dd, J ¼ 12.7, 6.3 Hz, 2H), 2.88 (dt, J ¼ 13.9, 6.9 Hz,
1H), 2.70 (t, J ¼ 6.5 Hz, 2H), 1.23 (d, J ¼ 6.9 Hz, 6H). 13C NMR
(100 MHz, CDCl3) d 162.2, 149.2, 147.9, 142.8 (q, J ¼ 3.8 Hz),
137.6 (q, J ¼ 3.5 Hz), 135.1, 132.1, 129.2 (d, J ¼ 34.0 Hz), 128.8,
126.7, 122.2 (q, J ¼ 273.5 Hz), 38.3, 35.5, 33.8, 30.8, 24.0. 19F
NMR (376 MHz, CDCl3) d ꢀ62.52. HRMS: [M ꢀ H]ꢀ calcd for
C
19H19ClF3N2OS: 415.08532; found: 415.08630.
N-(2-((2-Bromo-4-uorobenzyl)thio)ethyl)-3-chloro-5-
(triuoromethyl)picolinamide (E14). Yield 64%; yellow solid; mp
92–94 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H),
8.08 (d, J ¼ 1.3 Hz, 1H), 8.05 (s, 1H), 7.39 (dd, J ¼ 8.5, 5.9 Hz,
1H), 7.29 (dd, J ¼ 8.2, 2.6 Hz, 1H), 6.99 (td, J ¼ 8.3, 2.6 Hz, 1H),
3.87 (s, 2H), 3.68 (q, J ¼ 6.4 Hz, 2H), 2.76 (t, J ¼ 6.5 Hz, 2H). 13
C
NMR (100 MHz, CDCl3) d 162.3, 161.4 (d, J ¼ 250.8 Hz), 149.1,
142.8 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.6 Hz), 133.5 (d, J ¼ 3.6 Hz),
132.2, 131.7 (d, J ¼ 8.4 Hz), 129.3 (q, J ¼ 34.0 Hz), 124.4 (d, J ¼
9.6 Hz), 122.2 (q, J ¼ 273.4 Hz), 120.3 (d, J ¼ 24.5 Hz), 114.8 (d, J
¼ 21.1 Hz), 38.6, 35.5, 31.3. 19F NMR (376 MHz, CDCl3)
d ꢀ62.55, ꢀ112.79. HRMS: [M + H]+ calcd for C16H13BrClF4N2-
OS: 470.95511; found: 470.95468.
3-Chloro-N-(2-(((3,4-dimethoxypyridin-2-yl)methyl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E10). Yield 60%; gray solid; mp
1
ꢁ
76–77 C. H NMR (400 MHz, CDCl3) d 8.72 (d, J ¼ 1.0 Hz, 1H,
pyridine-H), 8.45 (s, 1H, pyridine-H), 8.14 (d, J ¼ 5.5 Hz, 1H,
pyridine-H), 8.06 (d, J ¼ 1.3 Hz, 1H, –CO–NH), 6.76 (d, J ¼
5.6 Hz, 1H, pyridine-H), 3.97–3.86 (m, 8H, –(OCH3)2, –CH2), 3.73
(dd, J ¼ 12.3, 6.0 Hz, 2H, –CH2), 2.86 (t, J ¼ 6.2 Hz, 2H, –CH2).
13C NMR (100 MHz, CDCl3) d 162.5, 158.8, 152.7, 150.0, 145.4,
143.4, 142.9 (q, J ¼ 3.8 Hz), 137.3 (q, J ¼ 3.6 Hz), 131.9, 129.0 (q, J
¼ 33.9 Hz), 122.2 (q, J ¼ 273.4 Hz), 106.9, 61.1, 55.7, 39.1, 31.69,
31.4. 19F NMR (376 MHz, CDCl3) d ꢀ62.50. HRMS: [M + H]+
calcd for C17H18ClF3N3O3S: 436.07040; found: 436.06998.
3-Chloro-5-(triuoromethyl)-N-(2-((4-(triuoromethyl)benzyl)
thio)ethyl)picolinamide (E11). Yield 88%; yellow solid; mp 114–
115 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.75–8.70 (m, 1H, pyridine-
H), 8.12–8.06 (m, 1H, pyridine-H), 8.03 (s, 1H, –CO–NH), 7.57 (d,
J ¼ 8.1 Hz, 2H, Ar–H), 7.47 (d, J ¼ 8.1 Hz, 2H), 3.82 (s, 2H), 3.65
(q, J ¼ 6.5 Hz, 2H), 2.69 (t, J ¼ 6.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3) d 162.3, 148.9, 142.9 (q, J ¼ 3.9 Hz), 142.2, 137.8 (q, J ¼
3.6 Hz), 132.2, 129.4 (q, J ¼ 32.6 Hz), 129.3 (q, J ¼ 34.0 Hz),
129.2, 125.6 (q, J ¼ 3.8 Hz), 124.1 (q, J ¼ 272.0 Hz), 122.1 (q, J ¼
273.4 Hz), 38.3, 35.4, 30.9. 19F NMR (376 MHz, CDCl3) d ꢀ62.48,
ꢀ62.54. HRMS: [M + H]+ calcd for C17H14ClF6N2OS: 443.04041;
found: 443.04141.
N-(2-((3-Bromobenzyl)thio)ethyl)-3-chloro-5-(triuoromethyl)
picolinamide (E15). Yield 82%; gray solid; mp 89–91 ꢁC. 1H NMR
(400 MHz, CDCl3) d 8.74 (d, J ¼ 1.0 Hz, 1H), 8.07 (d, J ¼ 1.4 Hz,
1H), 8.01 (s, 1H), 7.51 (t, J ¼ 1.6 Hz, 1H), 7.36 (d, J ¼ 7.9 Hz, 1H),
7.26 (t, J ¼ 3.8 Hz, 1H), 7.17 (t, J ¼ 7.8 Hz, 1H), 3.73 (s, 2H), 3.63
(q, J ¼ 6.3 Hz, 2H), 2.71 (t, J ¼ 6.5 Hz, 2H). 13C NMR (100 MHz,
CDCl3) d 162.3, 149.1, 142.9 (q, J ¼ 3.8 Hz), 140.4, 137.7 (q, J ¼
3.5 Hz), 132.2, 131.9, 130.3, 130.1, 129.3 (q, J ¼ 33.9 Hz), 127.5,
122.7, 122.2 (q, J ¼ 273.4 Hz), 38.4, 35.5, 31.1. 19F NMR (376
MHz, CDCl3) d ꢀ62.54. HRMS: [M + H]+ calcd for C16H14-
BrClF3N2OS: 452.96454; found: 452.96402.
3-Chloro-N-(2-((2,6-diuorobenzyl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E16). Yield 72%; white solid; mp
112–113 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.76–8.70 (m, 1H), 8.07
(dd, J ¼ 1.2, 0.6 Hz, 2H), 7.25–7.16 (m, 1H), 6.93–6.85 (m, 2H),
3.82 (s, 2H), 3.71 (q, J ¼ 6.2 Hz, 2H), 2.80 (t, J ¼ 6.4 Hz, 2H). 13
C
NMR (100 MHz, CDCl3) d 161.1 (dd, J ¼ 248.7, 7.9 Hz), 162.2,
149.1, 142.9 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.4 Hz), 132.2, 129.2 (q, J
¼ 34.0 Hz), 128.8 (t, J ¼ 10.3 Hz), 122.2 (q, J ¼ 273.4 Hz), 115.0 (t,
J ¼ 19.2 Hz), 111.4 (q, J ¼ 12.6 Hz), 38.3, 31.6, 22.3. 19F NMR (376
MHz, CDCl3) d ꢀ62.52, ꢀ115.00. HRMS: [M + H]+ calcd for
3-Chloro-N-(2-((2-chloro-4-uorobenzyl)thio)ethyl)-5-
C
16H13ClF5N2OS: 411.03518; found: 411.03448.
(triuoromethyl)picolinamide (E12). Yield 68%; gray solid; mp
90–91 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (s, 1H), 8.08 (d, J ¼
0.4 Hz, 2H), 7.38 (dd, J ¼ 8.5, 6.1 Hz, 1H), 7.18–7.06 (m, 1H), 6.95
(ddd, J ¼ 8.2, 2.5, 1.2 Hz, 1H), 3.86 (s, 2H), 3.68 (q, J ¼ 6.4 Hz,
2H), 2.75 (t, J ¼ 6.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 162.3,
161.6 (d, J ¼ 249.7 Hz), 149.0, 142.9 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼
3-Chloro-N-(2-((2-methylbenzyl)thio)ethyl)-5-(triuoromethyl)
picolinamide (E17). Yield 82%; gray solid; mp 84–85 ꢁC. 1H NMR
(400 MHz, CDCl3) d 8.72 (d, J ¼ 1.0 Hz, 1H), 8.07 (d, J ¼ 1.3 Hz,
1H), 8.02 (s, 1H), 7.25–7.19 (m, 1H), 7.16–7.11 (m, 3H), 3.78 (s,
2H), 3.65 (q, J ¼ 6.3 Hz, 2H), 2.74 (t, J ¼ 6.5 Hz, 2H), 2.41 (s, 3H).
13C NMR (100 MHz, CDCl3) d 162.2, 149.1, 142.9 (q, J ¼ 3.9 Hz),
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137.7 (q, J ¼ 3.6 Hz), 136.7, 135.6, 132.2, 130.9, 129.7, 129.2 (d, J (376 MHz, CDCl3) d ꢀ62.51. HRMS: [M ꢀ H]ꢀ calcd for C17
-
¼ 33.9 Hz), 127.5, 126.0, 122.2 (d, J ¼ 273.3 Hz), 38.6, 34.2, 31.3, H12ClF3N3OS: 398.03362; found: 398.03470.
19.2. 19F NMR (376 MHz, CDCl3) d ꢀ62.50. HRMS: [M + H]+
calcd for C17H17ClF3N2OS: 389.06967; found: 389.06924.
3-Chloro-5-(triuoromethyl)-N-(2-((2-(triuoromethyl)benzyl)
3-Chloro-N-(2-((3,5-diuorobenzyl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E23). Yield 83%; white solid; mp
94–95 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.74 (d, J ¼ 1.1 Hz, 1H),
thio)ethyl)picolinamide (E18). Yield 60%; yellow solid; mp 77– 8.13–8.07 (m, 1H), 8.03 (s, 1H), 6.99–6.82 (m, 2H), 6.68 (tt, J ¼
78 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 0.8 Hz, 1H), 8.08 8.9, 2.3 Hz, 1H), 3.74 (s, 2H), 3.64 (q, J ¼ 6.4 Hz, 2H), 2.72 (t, J ¼
(dd, J ¼ 1.3, 0.5 Hz, 2H), 7.64 (t, J ¼ 8.4 Hz, 2H), 7.52 (t, J ¼ 6.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 163.0 (dd, J ¼ 249.0,
7.5 Hz, 1H), 7.35 (t, J ¼ 7.6 Hz, 1H), 3.96 (s, 2H), 3.66 (q, J ¼ 12.8 Hz), 162.3, 148.9, 142.9 (q, J ¼ 3.8 Hz), 142.1 (t, J ¼ 9.0 Hz),
6.4 Hz, 2H), 2.79 (t, J ¼ 6.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) 137.8 (q, J ¼ 3.6 Hz), 132.3, 129.3 (q, J ¼ 33.9 Hz), 122.2 (q, J ¼
d 162.3, 149.0, 142.9 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.6 Hz), 136.8 273.5 Hz), 111.8 (q, J ¼ 11.7 Hz), 102.8 (t, J ¼ 25.3 Hz), 38.3, 35.5,
(d, J ¼ 1.4 Hz), 132.2, 132.1, 131.5, 129.3 (q, J ¼ 33.9 Hz), 128.5 31.1. 19F NMR (376 MHz, CDCl3) d ꢀ62.53, ꢀ109.51. HRMS: [M
(q, J ¼ 29.9 Hz), 127.3, 126.2 (q, J ¼ 5.6 Hz), 124.3 (d, J ¼ 274.0 ꢀ H]ꢀ calcd for C16H11ClF5N2OS: 409.01953; found: 409.02075.
Hz), 122.2 (d, J ¼ 273.5 Hz), 38.5, 32.5 (d, J ¼ 2.0 Hz), 31.9. 19F
3-Chloro-N-(2-(((3-methyl-4-(triuoromethoxy)pyridin-2-yl)
NMR (376 MHz, CDCl3) d ꢀ59.05, ꢀ62.53. HRMS: [M ꢀ H]ꢀ methyl)thio)ethyl)-5-(triuoromethyl)picolinamide (E24). Yield
calcd for C17H12ClF6N2OS: 441.02704; found: 441.02576.
3-Chloro-N-(2-((2-chlorobenzyl)thio)ethyl)-5-(triuoromethyl)
77%; gray solid; mp 124–125 ꢁC. 1H NMR (400 MHz, CDCl3)
d 8.72 (s, 1H), 8.40 (s, 1H), 8.27 (d, J ¼ 5.7 Hz, 1H), 8.06 (d, J ¼
picolinamide (E19). Yield 43%; brown solid; mp 77–78 ꢁC. 1H 1.1 Hz, 1H), 6.63 (d, J ¼ 5.7 Hz, 1H), 4.39 (q, J ¼ 7.9 Hz, 2H), 3.93
NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H), 8.07 (d, J ¼ (s, 2H), 3.70 (dd, J ¼ 12.4, 6.0 Hz, 2H), 2.82 (t, J ¼ 6.3 Hz, 2H),
1.3 Hz, 2H), 7.39 (dd, J ¼ 7.3, 1.9 Hz, 1H), 7.36 (dd, J ¼ 7.6, 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3) d 162.5, 161.8, 158.1,
1.6 Hz, 1H), 7.25–7.16 (m, 2H), 3.90 (s, 2H), 3.68 (q, J ¼ 6.3 Hz, 149.8, 147.5, 142.9 (q, J ¼ 3.8 Hz), 137.4 (q, J ¼ 3.7 Hz), 131.9,
2H), 2.76 (t, J ¼ 6.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 162.3, 129.0 (q, J ¼ 33.8 Hz), 123.0 (q, J ¼ 277.8 Hz), 122.2 (q, J ¼ 273.3
149.1, 142.9 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.6 Hz), 135.8, 134.0, Hz), 121.1, 105.4, 65.4 (q, J ¼ 36.3 Hz), 39.2, 35.4, 31.1, 10.6. 19
F
132.2, 130.9, 129.9, 129.2 (q, J ¼ 34.1 Hz), 128.7, 127.0, 122.2 (q, J NMR (376 MHz, CDCl3) d ꢀ62.53, ꢀ73.85. HRMS: [M + H]+ calcd
¼ 273.5 Hz), 38.6, 33.5, 31.3. 19F NMR (376 MHz, CDCl3) for C18H17ClF6N3O2S: 488.06287; found: 488.06143.
d ꢀ62.51. HRMS: [M + H]+ calcd for C16H14Cl2F3N2OS:
409.01505; found: 409.01443.
3-Chloro-N-(2-((3,4,4-triuorobut-3-en-1-yl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E25). Yield 84%; brown solid; mp
69–70 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.74 (d, J ¼ 1.0 Hz, 1H),
N-(2-((4-(tert-Butyl)benzyl)thio)ethyl)-3-chloro-5-
(triuoromethyl)picolinamide (E20). Yield 84%; gray solid; mp 8.11 (s, 1H), 8.08 (d, J ¼ 1.4 Hz, 1H), 3.68 (q, J ¼ 6.5 Hz, 2H), 2.83
111–113 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.74 (d, J ¼ 1.1 Hz, 1H), (t, J ¼ 5.4 Hz, 2H), 2.79 (t, J ¼ 6.0 Hz, 2H), 2.60 (dddd, J ¼ 11.1,
8.08 (d, J ¼ 1.3 Hz, 1H), 8.04 (s, 1H), 7.37–7.31 (m, 2H), 7.30–7.18 7.1, 5.3, 3.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 162.3, 153.6
(m, 2H), 3.75 (s, 2H), 3.64 (q, J ¼ 6.3 Hz, 2H), 2.70 (t, J ¼ 6.5 Hz, (ddd, J ¼ 287.1, 273.3, 46.3 Hz), 148.9, 142.9 (q, J ¼ 3.8 Hz),
2H), 1.30 (s, 9H). 13C NMR (100 MHz, CDCl3) d 162.3, 150.2, 137.7 (q, J ¼ 3.6 Hz), 132.2, 129.3 (q, J ¼ 34.0 Hz), 127.2 (ddd, J ¼
149.2, 142.9 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.5 Hz), 134.7, 132.2, 69.7, 56.0, 16.2 Hz), 122.2 (q, J ¼ 273.4 Hz), 38.7, 31.6, 27.6, 26.4
129.2 (q, J ¼ 33.9 Hz), 128.6, 125.6, 122.2 (d, J ¼ 273.4 Hz), 38.3, (dd, J ¼ 21.9, 2.6 Hz). 19F NMR (376 MHz, CDCl3) d ꢀ62.55,
35.4, 34.5, 31.3, 30.9. 19F NMR (376 MHz, CDCl3) d ꢀ62.51. ꢀ103.74 (dd, J ¼ 85.2, 32.5 Hz), ꢀ123.06 (dd, J ¼ 114.4, 85.2 Hz),
HRMS: [M + H]+ calcd for C20H23ClF3N2OS: 431.11662; found: ꢀ175.59 (dd, J ¼ 114.2, 32.4 Hz). HRMS: [M + H]+ calcd for
431.11563.
C
12H8ClF4N2OS: 393.04372; found: 393.04463.
3-Chloro-N-(2-(((6-chloropyridin-3-yl)methyl)thio)ethyl)-5-
3-Chloro-N-(2-((2,5-diuorobenzyl)thio)ethyl)-5-
(triuoromethyl)picolinamide (E21). Yield 48%; brown solid; mp (triuoromethyl)picolinamide (E26). Yield 62%; white solid; mp
88–89 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (s, 1H), 8.34 (d, J ¼ 111–112 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.74 (d, J ¼ 1.1 Hz, 1H),
2.2 Hz, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.70 (dd, J ¼ 8.2, 2.4 Hz, 8.08 (d, J ¼ 1.3 Hz, 1H), 7.12 (ddd, J ¼ 8.8, 5.8, 3.1 Hz, 1H), 7.00
1H), 7.29 (d, J ¼ 8.2 Hz, 1H), 3.76 (s, 2H), 3.66 (q, J ¼ 6.5 Hz, 2H), (td, J ¼ 9.0, 4.5 Hz, 1H), 6.94–6.86 (m, 1H), 3.77 (s, 2H), 3.67 (q, J
2.70 (t, J ¼ 6.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 162.4, ¼ 6.3 Hz, 2H), 2.76 (t, J ¼ 6.5 Hz, 2H). 13C NMR (100 MHz,
150.3, 149.7, 148.8, 142.9 (q, J ¼ 3.8 Hz), 139.3, 137.8 (q, J ¼ 3.6 CDCl3) d 162.3, 158.6 (dd, J ¼ 242.8, 2.4 Hz), 156.8 (dd, J ¼ 242.2,
Hz), 132.9, 132.3, 129.4 (q, J ¼ 34.0 Hz), 124.3, 122.1 (q, J ¼ 273.4 2.5 Hz), 149.0, 142.9 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.6 Hz), 132.2,
Hz), 38.4, 32.3, 31.0. 19F NMR (376 MHz, CDCl3) d ꢀ62.52. 129.3 (q, J ¼ 34.0 Hz), 127.1 (dd, J ¼ 17.4, 7.6 Hz), 122.2 (q, J ¼
HRMS: [M ꢀ H]ꢀ calcd for C15H11Cl2F3N3OS: 407.99465; found: 273.3 Hz), 117.2 (dd, J ¼ 24.4, 4.1 Hz), 116.6 (dd, J ¼ 24.9, 8.7
407.99591.
Hz), 115.4 (dd, J ¼ 22.8, 7.3 Hz), 38.3, 31.3, 28.6. 19F NMR (376
MHz, CDCl3) d ꢀ62.53, d ꢀ118.44 (d, J ¼ 17.8 Hz), ꢀ124.24 (d, J
3-Chloro-N-(2-((4-cyanobenzyl)thio)ethyl)-5-(triuoromethyl)
picolinamide (E22). Yield 83%; gray solid; mp 87–89 ꢁC. 1H NMR ¼ 17.8 Hz). HRMS: [M ꢀ H]ꢀ calcd for C16H11ClF5N2OS:
(400 MHz, CDCl3) d 8.73 (d, J ¼ 1.0 Hz, 1H), 8.12–8.07 (m, 1H), 409.01953; found: 409.02078.
8.03 (s, 1H), 7.61 (d, J ¼ 8.1 Hz, 2H), 7.47 (d, J ¼ 8.2 Hz, 2H), 3.81
4.2.3 The synthesis of sulfone-containing compounds F1–
(s, 2H), 3.64 (q, J ¼ 6.5 Hz, 2H), 2.68 (t, J ¼ 6.7 Hz, 2H). 13C NMR F10. Taking F1 as an example, to a mixture of 3-chloro-N-(2-((4-
(100 MHz, CDCl3) d 162.3, 148.9, 143.7, 142.9 (q, J ¼ 3.8 Hz), uorobenzyl)thio)ethyl)-5-(triuoromethyl)picolinamide
(E1,
137.8 (q, J ¼ 3.6 Hz), 132.4, 132.3, 129.7, 129.4 (q, J ¼ 33.3 Hz), 1.27 mmol) and 20 mL EtOH stirred at room temperature, H2O2
122.1 (d, J ¼ 273.4 Hz), 118.7, 111.1, 38.4, 35.6, 31.0. 19F NMR (53.46 mmol) and ammonium molybdate (0.089 mmol) were
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added. The resulting solution was stirred at 100 C and moni- –CH2–), 3.25–2.90 (m, 2H, –CH2–). 13C NMR (100 MHz, CDCl3)
tored by TLC. Aer about 7–8 h, the reaction could be d 162.8, 161.7 (d, J ¼ 249.1 Hz), 148.8, 143.1 (q, J ¼ 3.8 Hz), 137.6
completed. The solvent was removed under reduced pressure to (q, J ¼ 3.6 Hz) 134.5 (d, J ¼ 8.1 Hz), 132.1, 131.8 (d, J ¼ 8.0 Hz),
provide crude product, which was puried by silica gel (200–300 129.4 (q, J ¼ 34.0 Hz), 122.1 (q, J ¼ 273.4 Hz), 119.5 (d, J ¼ 23.5
mesh) column chromatography with ethyl acetate/petroleum Hz), 119.2 (d, J ¼ 3.5 Hz), 117.6 (d, J ¼ 22.4 Hz), 58.3, 50.1, 34.5.
ether (1 : 3) to obtain pure sulfone-containing compound F1. 19F NMR (376 MHz, CDCl3) d ꢀ62.57, ꢀ113.05. HRMS: calcu-
The sulfone-containing compounds F2–F10 could be also lated for C16H13O3N2BrClF4S [M + H]+: 502.94494; found:
synthesized with similar method. The data of F1–F10 are listed 502.94223.
ꢁ
below, and the spectra are shown in ESI data.†
3-Chloro-N-(2-((4-uorobenzyl)sulfonyl)ethyl)-5-
3-Chloro-N-(2-((3-uorobenzyl)sulfonyl)ethyl)-5-
(triuoromethyl)picolinamide (F5). Yield 50%; yellow solid; mp
1
ꢁ
(triuoromethyl)picolinamide (F1). Yield 41%; white solid; mp 97–98 C. H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H,
132–133 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.72 (d, J ¼ 1.1 Hz, 1H, pyridine-H), 8.41 (t, J ¼ 5.3 Hz, 1H, –CO–NH–), 8.07 (d, J ¼
pyridine-H), 8.40 (t, J ¼ 5.3 Hz, 1H, –CO–NH–), 8.07 (d, J ¼ 1.3 Hz, 1H, pyridine-H), 7.41–7.30 (m, 1H, Ar–H), 7.16–6.94 (m,
1.4 Hz, 1H, pyridine-H), 7.33–7.23 (m, 2H, Ar–H), 7.15–7.00 (m, 3H, Ar–H), 4.10–4.00 (m, 2H, –CH2–), 4.00–3.93 (m, 2H, –CH2–),
2H, Ar–H), 4.03 (q, J ¼ 13.2 Hz, 2H, –CH2–), 3.96 (dd, J ¼ 12.1, 3.13–2.79 (m, 2H, –CH2–). 13C NMR (100 MHz, CDCl3) d 162.9 (d,
6.1 Hz, 2H, –CH2–), 3.11–2.77 (m, 2H, –CH2–). 13C NMR (100 J ¼ 247.8 Hz), 162.8, 148.8, 143.1 (q, J ¼ 3.8 Hz), 137.6 (q, J ¼ 3.6
MHz, CDCl3) d 162.9 (d, J ¼ 248.2 Hz), 162.8, 148.7, 143.0 (q, J ¼ Hz), 132.1, 131.7 (d, J ¼ 7.7 Hz), 130.6 (d, J ¼ 8.3 Hz), 129.4 (q, J
3.8 Hz), 137.6 (q, J ¼ 3.6 Hz), 132.1, 131.9 (d, J ¼ 8.3 Hz), 129.4 ¼ 34.0 Hz), 125.9 (d, J ¼ 3.0 Hz), 122.1 (q, J ¼ 273.4 Hz), 117.1 (d,
(q, J ¼ 34.1 Hz), 125.2 (d, J ¼ 3.3 Hz), 122.1 (q, J ¼ 273.3 Hz), J ¼ 22.0 Hz), 115.7 (d, J ¼ 21.0 Hz), 57.8, 49.7, 34.4. 19F NMR (376
116.1 (d, J ¼ 21.7 Hz), 57.4, 49.5, 34.4. 19F NMR (376 MHz, MHz, CDCl3) d ꢀ62.57, ꢀ111.70. HRMS: calculated for C16H14-
CDCl3) d ꢀ62.57, ꢀ112.80. HRMS: calculated for C16H14O3N2- O3N2ClF4S [M + H]+: 425.03443; found: 425.03293.
ClF4S [M + H]+: 435.03443; found: 425.03378.
3-Chloro-N-(2-((2,3-dichlorobenzyl)sulfonyl)ethyl)-5-
3-Chloro-N-(2-((2-uoro-5-(triuoromethyl)benzyl)sulfonyl)
(triuoromethyl)picolinamide (F6). Yield 44%; faint yellow solid;
ethyl)-5-(triuoromethyl)picolinamide (F2). Yield 50%; white mp 161–162 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz,
solid; mp 150–151 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1H, pyridine-H), 8.41 (t, J ¼ 5.5 Hz, 1H, –CO–NH–), 8.07 (d, J ¼
0.9 Hz, 1H, pyridine-H), 8.37 (s, 1H, –CO–NH–), 8.07 (d, J ¼ 1.3 Hz, 1H, pyridine-H), 7.48 (dd, J ¼ 8.0, 1.6 Hz, 1H, Ar–H), 7.32
1.4 Hz, 1H, pyridine-H), 7.71–7.60 (m, 2H, Ar–H), 7.26 (dd, J ¼ (dd, J ¼ 7.7, 1.6 Hz, 1H, Ar–H), 7.23 (t, J ¼ 7.8 Hz, 1H, Ar–H), 4.27
11.5, 6.1 Hz, 1H, Ar–H), 4.14 (dd, J ¼ 38.7, 13.2 Hz, 2H, –CH2–), (dd, J ¼ 39.0, 12.9 Hz, 2H, –CH2–), 4.01 (dd, J ¼ 12.1, 6.1 Hz, 2H,
3.99 (q, J ¼ 6.1 Hz, 2H, –CH2–), 3.33–2.55 (m, 2H, –CH2–). 13C –CH2–), 3.23–2.89 (m, 2H, –CH2–). 13C NMR (100 MHz, CDCl3)
NMR (100 MHz, CDCl3) d 162.8, 162.8 (d, J ¼ 253.8 Hz), 148.6, d 162.8, 148.7, 143.1 (q, J ¼ 3.8 Hz), 137.6 (q, J ¼ 3.6 Hz), 134.0,
143.0 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.6 Hz), 132.2, 129.9 (q, J ¼ 8.0 133.0, 132.1, 130.9, 130.6, 130.3, 129.4 (q, J ¼ 34.0 Hz), 127.7,
Hz), 129.4 (q, J ¼ 34.1 Hz), 128.0 (d, J ¼ 9.4 Hz), 127.4 (q, J ¼ 33.4 122.1 (q, J ¼ 273.5 Hz), 57.0, 50.2, 34.4. 19F NMR (376 MHz,
Hz), 123.4 (q, J ¼ 272.2 Hz), 122.1 (d, J ¼ 273.5 Hz), 118.3 (d, J ¼ CDCl3) d ꢀ62.56. HRMS: calculated for C16H13O3N2Cl3F4S [M +
16.4 Hz), 116.5 (d, J ¼ 23.2 Hz), 50.8, 50.3, 34.3. 19F NMR (376 H]+: 474.96591; found: 474.96579.
MHz, CDCl3) d ꢀ62.03, ꢀ62.60, ꢀ110.62. HRMS: calculated for
3-Chloro-N-(2-((3-chloro-2-uorobenzyl)sulfonyl)ethyl)-5-
(triuoromethyl)picolinamide (F7). Yield 40%; pale yellow solid;
mp 145–146 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz,
C
16H14O3N2ClF4S [M + H]+: 477.02690; found: 477.02563.
N-(2-((4-Bromo-2-uorobenzyl)sulfonyl)ethyl)-3-chloro-5-
(triuoromethyl)picolinamide (F3). Yield 47%; yellow solid; mp 1H), 8.39 (t, J ¼ 5.5 Hz, 1H), 8.07 (d, J ¼ 1.3 Hz, 1H), 7.45–7.36
124–125 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.72 (d, J ¼ 1.0 Hz, 1H, (m, 1H), 7.30–7.24 (m, 1H), 7.12 (td, J ¼ 7.9, 1.0 Hz, 1H), 4.13
pyridine-H), 8.38 (t, J ¼ 5.2 Hz, 1H, –CO–NH–), 8.07 (d, J ¼ (ddd, J ¼ 30.9, 13.2, 1.1 Hz, 2H), 4.02–3.94 (m, 2H), 3.19–2.83
1.2 Hz, 1H, pyridine-H), 7.32 (d, J ¼ 8.8 Hz, 2H, Ar–H), 7.25 (dd, J (m, 2H). 19F NMR (376 MHz, CDCl3) d ꢀ62.56, ꢀ117.99. 13C
¼ 14.0, 6.0 Hz, 1H, Ar–H), 4.06 (dd, J ¼ 36.8, 13.4 Hz, 2H, –CH2– NMR (100 MHz, CDCl3) d 162.8, 156.5 (d, J ¼ 249.8 Hz), 148.7,
), 3.96 (dt, J ¼ 7.1, 3.4 Hz, 2H, –CH2–), 3.15–2.79 (m, 2H, –CH2–). 143.0 (q, J ¼ 3.9 Hz), 137.6 (q, J ¼ 3.5 Hz), 132.1, 131.2, 130.6 (d, J
13C NMR (100 MHz, CDCl3) d 162.8, 160.7 (d, J ¼ 252.3 Hz), ¼ 2.7 Hz), 129.4 (q, J ¼ 34.0 Hz), 125.1 (d, J ¼ 4.8 Hz), 122.1 (q, J
148.7, 143.0 (q, J ¼ 3.8 Hz), 137.6 (q, J ¼ 3.5 Hz), 133.4 (d, J ¼ 3.9 ¼ 273.4 Hz), 121.7 (d, J ¼ 17.9 Hz), 118.7 (d, J ¼ 15.2 Hz), 51.2,
Hz), 132.1, 129.4 (q, J ¼ 34.1 Hz), 128.1 (d, J ¼ 3.7 Hz), 123.2, 50.1, 34.4. HRMS: calculated for C16H13O3N2Cl2F4S [M + H]+:
122.1 (q, J ¼ 273.5 Hz), 119.5 (d, J ¼ 24.9 Hz), 116.0 (d, J ¼ 15.3 458.99546; found: 458.99557.
Hz), 50.6, 50.0, 34.4. 19F NMR (376 MHz, CDCl3) d ꢀ62.57,
3-Chloro-N-(2-((3,4-diuorobenzyl)sulfonyl)ethyl)-5-
ꢀ113.50. HRMS: calculated for C16H13O3N2BrClF4S [M + H]+: (triuoromethyl)picolinamide (F8). Yield 84%; white solid; mp
502.94494; found: 502.94443.
N-(2-((2-Bromo-5-uorobenzyl)sulfonyl)ethyl)-3-chloro-5-
163–164 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.74 (d, J ¼ 1.1 Hz, 1H,
pyridine-H), 8.32 (t, J ¼ 5.5 Hz, 1H, –CO–NH–), 8.09 (d, J ¼
(triuoromethyl)picolinamide (F4). Yield 44%; white solid; mp 1.3 Hz, 1H, pyridine-H), 7.35–7.27 (m, 1H, Ar–H), 7.25–7.11 (m,
146–147 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H, 2H, Ar–H), 4.26 (s, 2H, –CH2–), 3.96 (dd, J ¼ 12.2, 6.2 Hz, 2H,
pyridine-H), 8.41 (t, J ¼ 5.3 Hz, 1H, –CO–NH–), 8.07 (d, J ¼ –CH2–), 3.44–3.07 (m, 2H, –CH2–). 13C NMR (100 MHz, CDCl3)
1.3 Hz, 1H, pyridine-H), 7.58 (dd, J ¼ 8.8, 5.2 Hz, 1H, Ar–H), 7.17 d 162.6, 151.1 (dd, J ¼ 248.7, 9.4 Hz), 150.5 (dd, J ¼ 257.0, 19.3
(dd, J ¼ 8.7, 3.0 Hz, 1H, Ar–H), 6.97 (ddd, J ¼ 8.8, 7.9, 3.0 Hz, 1H, Hz), 148.2, 143.1 (q, J ¼ 3.8 Hz), 137.8 (q, J ¼ 3.5 Hz), 132.3,
Ar–H), 4.22 (dd, J ¼ 48.0, 13.0 Hz, 2H, –CH2–), 4.05–3.95 (m, 2H, 129.6 (q, J ¼ 34.1 Hz), 127.1 (dd, J ¼ 6.6, 3.8 Hz), 124.0 (dd, J ¼
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6.1, 4.1 Hz), 122.1 (d, J ¼ 273.5 Hz), 120.0 (d, J ¼ 18.0 Hz), 118.1 ꢀ62.76. HRMS: calculated for C17H14O2N2ClF6S [M + H]+:
(d, J ¼ 17.5 Hz), 59.4, 50.8, 33.1. 19F NMR (376 MHz, CDCl3) 459.03632; found: 459.03659.
d ꢀ62.59, ꢀ135.47 (d, 3JF–F ¼ 21.2 Hz), ꢀ135.85 (d, 3J F–F ¼ 21.2
3-Chloro-N-(2-((2-chloro-4-uorobenzyl)sulnyl)ethyl)-5-
Hz). HRMS: calculated for
443.02501; found: 443.02417.
C
16H13O3N3ClF5S [M
+
H]+: (triuoromethyl)picolinamide (G2). Yield 60%; soil white solid;
mp 165–166 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz,
N-(2-(Benzylsulfonyl)ethyl)-3-chloro-5-(triuoromethyl)
1H, pyridine-H), 8.38 (t, J ¼ 5.2 Hz, 1H, –CO–NH–), 8.12–8.02
ꢁ
picolinamide (F9). Yield 39%; soil white solid; mp 137–138 C. (m, 1H, pyridine-H), 7.46–7.37 (m, 1H, Ar–H), 7.32–7.23 (m, 1H,
1H NMR (400 MHz, CDCl3) d 8.72 (d, J ¼ 1.1 Hz, 1H, pyridine-H), Ar–H), 7.12 (td, J ¼ 8.0, 0.8 Hz, 1H, Ar–H), 4.14 (dt, J ¼ 29.9,
8.41 (t, J ¼ 4.8 Hz, 1H, –CO–NH–), 8.06 (d, J ¼ 1.3 Hz, 1H, 7.1 Hz, 2H, –CH2–), 3.99 (q, J ¼ 6.1 Hz, 2H, –CH2–), 2.98 (ddt, J ¼
pyridine-H), 7.41–7.33 (m, 3H, Ar–H), 7.30 (dt, J ¼ 5.3, 4.3 Hz, 13.2, 11.1, 6.1 Hz, 2H, –CH2–). 13C NMR (100 MHz, CDCl3)
2H, Ar–H), 4.13–4.03 (m, 2H, –CH2–), 3.96 (hd, J ¼ 9.2, 6.1 Hz, d 162.8, 156.5 (d, J ¼ 249.8 Hz), 148.7, 143.0 (q, J ¼ 3.8 Hz), 137.6
2H, –CH2–), 3.08–2.76 (m, 2H, –CH2–). 13C NMR (100 MHz, (q, J ¼ 3.5 Hz), 132.1, 131.2, 130.6 (d, J ¼ 2.8 Hz), 129.4 (q, J ¼
CDCl3) d 162.7, 148.9, 143.1 (q, J ¼ 3.8 Hz), 137.6 (q, J ¼ 3.6 Hz), 34.1 Hz), 125.0 (d, J ¼ 4.8 Hz), 122.1 (q, J ¼ 273.5 Hz), 121.8 (d, J
132.1, 130.1, 129.4 (q, J ¼ 23.9 Hz), 129.3, 129.1, 128.6, 122.1 (q, J ¼ 18.0 Hz), 118.7 (d, J ¼ 15.2 Hz), 51.3, 50.2, 34.4. 19F NMR (376
¼ 273.4 Hz), 58.5, 49.3, 34.4. 19F NMR (376 MHz, CDCl3) MHz, CDCl3) d ꢀ62.58, ꢀ117.98. HRMS: calculated for C16H13-
d ꢀ62.56. HRMS: calculated for C16H15O3N2ClF3S [M + H]+: O2N2Cl2F4S [M + H]+: 443.00054; found: 442.99860.
407.04385; found: 407.04343.
3-Chloro-N-(2-((4-isopropylbenzyl)sulnyl)ethyl)-5-
3-Chloro-N-(2-(((3,4-dimethoxypyridin-2-yl)methyl)sulfonyl)
(triuoromethyl)picolinamide (G3). Yield 45%; faint yellow solid;
ethyl)-5-(triuoromethyl)picolinamide (F10). Yield 35%; pale mp 180–181 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz,
yellow solid; mp 113–114 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.72 1H, pyridine-H), 8.44 (t, J ¼ 5.4 Hz, 1H, –CO–NH–), 8.06 (d, J ¼
(d, J ¼ 1.0 Hz, 1H, pyridine-H), 8.63 (t, J ¼ 5.2 Hz, 1H, –CO–NH– 1.4 Hz, 1H, pyridine-H), 7.26–7.19 (m, 4H, Ar–H), 4.05 (q, J ¼
), 8.21 (d, J ¼ 5.5 Hz, 1H, pyridine-H), 8.05 (d, J ¼ 1.3 Hz, 1H, 13.0 Hz, 2H, –CH2–), 4.00–3.92 (m, 2H, –CH2–), 3.02 (ddd, J ¼
pyridine-H), 6.82 (d, J ¼ 5.5 Hz, 1H, pyridine-H), 4.37 (dd, J ¼ 13.1, 7.4, 5.5 Hz, 1H, –CH–), 2.93–2.78 (m, 2H, –CH2–), 1.24 (d, J
63.7, 12.4 Hz, 2H, –CH2–), 4.03 (dt, J ¼ 8.4, 3.9 Hz, 2H, –CH2–), ¼ 6.9 Hz, 6H, –CH3). 13C NMR (100 MHz, CDCl3) d 162.7, 149.5,
3.92 (d, J ¼ 3.4 Hz, 6H, –CH3), 3.28–3.04 (m, 2H, –CH2–). 13C 149.0, 143.1 (q, J ¼ 3.8 Hz), 137.6 (q, J ¼ 3.6 Hz), 132.0, 130.1,
NMR (100 MHz, CDCl3) d 162.69, 158.83, 149.33, 146.07, 145.09, 129.3 (q, J ¼ 34.0 Hz), 127.2, 126.4, 122.1 (q, J ¼ 273.5 Hz), 58.2,
144.29, 143.01 (q, J ¼ 3.8 Hz), 137.40 (q, J ¼ 3.5 Hz), 131.90, 49.2, 34.5, 33.9, 23.9. 19F NMR (376 MHz, CDCl3) d ꢀ62.56.
129.13 (q, J ¼ 34.0 Hz), 122.16 (q, J ¼ 273.4 Hz), 107.74, 61.50, HRMS: calculated for C19H21O2N2ClF3S [M + H]+: 433.09589;
55.79, 54.66, 49.85, 34.33. 19F NMR (376 MHz, CDCl3) d ꢀ62.56. found: 433. 09573.
HRMS: calculated for C17H18O5N3ClF3S [M + H]+: 468.06023;
found: 468.06030.
N-(2-((2-Bromo-4-uorobenzyl)sulnyl)ethyl)-3-chloro-5-
(triuoromethyl)picolinamide (G4). Yield 38%; faint yellow solid;
4.2.4 The synthesis of sulfoxide-containing compounds mp 184–185 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz,
G1–G16. According to the reported method,14 sulfoxide- 1H, pyridine-H), 8.38 (t, J ¼ 5.1 Hz, 1H, –CO–NH–), 8.07 (d, J ¼
containing compounds G1–G16 were also synthesized via the 1.4 Hz, 1H, pyridine-H), 7.39 (ddd, J ¼ 8.1, 7.5, 4.2 Hz, 2H, Ar–
oxidation of thioether-containing compounds E11–E26. For G1 H), 7.11–6.99 (m, 1H, Ar–H), 4.22 (dd, J ¼ 46.5, 13.1 Hz, 2H,
as an example, compound E11 (1.27 mmol) were treated with –CH2–), 4.01 (ddd, J ¼ 8.0, 5.5, 1.4 Hz, 2H, –CH2–), 3.25–2.84 (m,
a mixture of H2O2 (26.73 mmol) and Na2WO4$2H2O (0.089 2H, –CH2–). 13C NMR (100 MHz, CDCl3) d 162.8, 162.4 (d, J ¼
mmol). The resulting mixture was stirred at room temperature 253.3 Hz), 148.8, 143.1 (q, J ¼ 3.9 Hz), 137.62 (q, J ¼ 3.6 Hz),
for about 24 h. Aer the completion of the reaction, solvent was 133.5 (d, J ¼ 8.6 Hz), 132.1, 129.4 (q, J ¼ 34.1 Hz), 125.8 (d, J ¼
removed under reduced pressure to provide crude product, 3.7 Hz), 125.2 (d, J ¼ 9.7 Hz), 122.1 (q, J ¼ 273.4 Hz), 120.7 (d, J ¼
which was puried by silica gel (200–300 mesh) column chro- 24.7 Hz), 115.3 (d, J ¼ 21.2 Hz), 57.7, 49.9, 34.5. 19F NMR (376
matography with ethyl acetate/petroleum ether (1 : 3). Other MHz, CDCl3) d ꢀ62.58, ꢀ110.16. HRMS: calculated for C16H13-
sulfoxide-containing compounds G2–G16 could be also O2N2BrClF4S [M + H]+: 489.95003; found: 489.95001.
synthesized with the similar method. The conrming data are
listed below, and the spectra are listed in ESI data.†
3-Chloro-5-(triuoromethyl)-N-(2-((4-(triuoromethyl)benzyl)
N-(2-((3-Bromobenzyl)sulnyl)ethyl)-3-chloro-5-(triuoromethyl)
1
ꢁ
picolinamide (G5). Yield 50%; white solid; mp 158–159 C. H
NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.0 Hz, 1H, pyridine-H),
sulnyl)ethyl)picolinamide (G1). Yield 54%; white solid; mp 184– 8.41 (t, J ¼ 5.4 Hz, 1H, –CO–NH–), 8.07 (d, J ¼ 1.3 Hz, 1H,
1
ꢁ
185 C. H NMR (400 MHz, CDCl3) d 8.72 (s, 1H, pyridine-H), pyridine-H), 7.52–7.45 (m, 2H, Ar–H), 7.33–7.19 (m, 2H, Ar–H),
8.37 (br, 1H, –CO–NH–), 8.07 (s, 1H, pyridine-H), 7.65 (d, J ¼ 4.06–3.99 (m, 2H, –CH2–), 3.99–3.93 (m, 2H, –CH2–), 3.21–2.69
8.0 Hz, 2H, Ar–H), 7.45 (d, J ¼ 7.9 Hz, 2H, Ar–H), 4.10 (dd, J ¼ (m, 2H, –CH2–). 13C NMR (100 MHz, CDCl3) d 162.8, 148.7, 143.1
37.2, 13.0 Hz, 2H, –CH2–), 3.96 (dt, J ¼ 10.8, 5.6 Hz, 2H, –CH2–), (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.5 Hz), 133.0, 132.1, 131.8, 131.7,
3.0 (dtd, J ¼ 18.8, 12.8, 5.9 Hz, 2H, –CH2–). 13C NMR (100 MHz, 130.6, 129.4 (q, J ¼ 34.1 Hz), 128.8, 123.0, 122.1 (q, J ¼ 273.4 Hz),
CDCl3) d 162.83, 148.61, 143.03 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.6 57.7, 49.8, 34.4. 19F NMR (376 MHz, CDCl3) d ꢀ62.56. HRMS:
Hz), 133.5, 132.2, 130.8 (q, J ¼ 32.7 Hz), 130.6, 129.5 (q, J ¼ 34.0 calculated for C16H14O2N2BrClF3S [M + H]+: 468.95945; found:
Hz), 126.0 (q, J ¼ 3.7 Hz), 123.9 (q, J ¼ 272.3 Hz), 122.1 (q, J ¼ 468.95941.
273.5 Hz), 57.6, 50.0, 34.4. 19F NMR (376 MHz, CDCl3) d ꢀ62.59,
3-Chloro-N-(2-((2,6-diuorobenzyl)sulnyl)ethyl)-5-
(triuoromethyl)picolinamide (G6). Yield 40%; white solid; mp
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144–145 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 1H, ¼ 34.0 Hz), 126.1, 126.1, 122.1 (q, J ¼ 273.4 Hz), 58.1, 49.2, 34.7,
pyridine-H), 8.43 (t, J ¼ 5.3 Hz, 1H, –CO–NH–), 8.06 (d, J ¼ 34.5, 31.3. 19F NMR (376 MHz, CDCl3) d ꢀ62.56. HRMS: calcu-
1.3 Hz, 1H, pyridine-H), 7.33 (tt, J ¼ 8.4, 6.5 Hz, 1H, Ar–H), 7.04– lated for C20H23O2N2ClF3S [M
6.91 (m, 2H, Ar–H), 4.30–4.15 (m, 2H, –CH2–), 4.01 (ddd, J ¼ 8.4, 477.11038.
+
H]+: 447.1154; found:
5.3, 1.6 Hz, 2H, –CH2–), 3.20–2.86 (m, 2H, –CH2–). 13C NMR (100
3-Chloro-N-(2-(((6-chloropyridin-3-yl)methyl)sulnyl)ethyl)-5-
MHz, CDCl3) d 161.5 (d, J ¼ 250.7 Hz), 161.5 (d, J ¼ 250.7 Hz), (triuoromethyl)picolinamide (G11). Yield 72%; soil yellow solid;
148.9, 143.1 (q, J ¼ 3.9 Hz), 137.5 (q, J ¼ 3.6 Hz), 132.0, 130.8 (t, J mp 136–137 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz,
¼ 10.2 Hz), 129.3 (q, J ¼ 34.0 Hz), 122.1 (q, J ¼ 273.5 Hz), 111.8 1H, pyridine-H), 8.38 (t, J ¼ 5.2 Hz, 1H, –CO–NH–), 8.35 (d, J ¼
(q, J ¼ 25.3 Hz), 106.3 (t, J ¼ 19.4 Hz), 50.2, 45.8, 34.4. 19F NMR 2.3 Hz, 1H, pyridine-H), 8.08 (d, J ¼ 1.3 Hz, 1H, pyridine-H), 7.68
(376 MHz, CDCl3) d ꢀ62.57, ꢀ112.09. HRMS: calculated for (dd, J ¼ 8.2, 2.4 Hz, 1H, pyridine-H), 7.37 (d, J ¼ 8.2 Hz, 1H,
C
16H13O2N2ClF5S [M + H]+: 427.03009; found: 427.03006.
3-Chloro-N-(2-((2-methylbenzyl)sulnyl)ethyl)-5-
pyridine-H), 4.16–3.86 (m, 4H, –CH2–), 3.25–2.76 (m, 2H, –CH2–
). 13C NMR (100 MHz, CDCl3) d 162.9, 151.9, 150.7, 148.4, 143.0
(triuoromethyl)picolinamide (G7). Yield 52%; white solid; mp (q, J ¼ 3.8 Hz), 140.4, 137.8 (q, J ¼ 3.6 Hz), 132.2, 129.5 (q, J ¼
136–137 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.72 (d, J ¼ 0.9 Hz, 1H, 34.0 Hz), 124.7, 124.5, 122.1 (q, J ¼ 273.5 Hz), 53.9, 50.3, 34.3.
pyridine-H), 8.45 (t, J ¼ 5.1 Hz, 1H, –CO–NH–), 8.06 (d, J ¼ 19F NMR (376 MHz, CDCl3) d ꢀ62.56. HRMS: calculated for
1.3 Hz, 1H, pyridine-H), 7.26–7.17 (m, 4H, Ar–H), 4.15 (dd, J ¼
52.1, 12.9 Hz, 2H, –CH2–), 4.05–3.91 (m, 2H, –CH2–), 3.13–2.87
C
15H13O2N3Cl2F3S [M + H]+: 426.00521; found: 426.00473.
3-Chloro-N-(2-((4-cyanobenzyl)sulnyl)ethyl)-5-(triuoromethyl)
(m, 2H, –CH2–), 2.41 (s, 3H, –CH3). 13C NMR (100 MHz, CDCl3) picolinamide (G12). Yield 39%; pale yellow solid; mp 172–173 ꢁC.
d 162.7, 149.0, 143.1 (q, J ¼ 3.8 Hz), 137.5 (q, J ¼ 7.2 Hz), 137.4, 1H NMR (400 MHz, CDCl3) d 8.72 (s, 1H, pyridine-H), 8.36 (t, J ¼
132.0, 131.1, 131.0, 129.3 (q, J ¼ 34.0 Hz), 128.9, 128.0, 126.7, 5.3 Hz, 1H, –CO–NH–), 8.08 (s, 1H, pyridine-H), 7.69 (d, J ¼
122.1 (q, J ¼ 273.5 Hz), 57.2, 49.6, 34.5, 19.9. 19F NMR (376 MHz, 7.7 Hz, 2H, Ar–H), 7.45 (d, J ¼ 7.9 Hz, 2H, Ar–H), 4.09 (dd, J ¼
CDCl3) d ꢀ62.56. HRMS: calculated for C17H17O2N2ClF3S [M + 53.4, 13.0 Hz, 2H, –CH2–), 4.00–3.83 (m, 2H, –CH2–), 3.31–2.77
H]+: 405.06459; found: 495.06454.
3-Chloro-5-(triuoromethyl)-N-(2-((2-(triuoromethyl)benzyl)
(m, 2H, –CH2–). 13C NMR (100 MHz, CDCl3) d 162.9, 148.5, 143.0
(q, J ¼ 3.8 Hz), 137.8 (q, J ¼ 3.6 Hz), 135.0, 132.7, 132.2, 131.0,
sulnyl)ethyl)picolinamide (G8). Yield 35%; white solid; mp 131– 129.5 (q, J ¼ 34.1 Hz), 122.1 (q, J ¼ 273.5 Hz), 118.3, 112.6, 57.6,
1
132 ꢁC. H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.0 Hz, 1H, 50.3, 34.3. 19F NMR (376 MHz, CDCl3) d ꢀ62.56. HRMS: calcu-
pyridine-H), 8.43 (t, J ¼ 5.2 Hz, 1H, –CO–NH–), 8.07 (d, J ¼ lated for C17H11O2N3Cl2F3S [M + H]+: 432.03910; found:
1.3 Hz, 1H, pyridine-H), 7.72 (d, J ¼ 7.8 Hz, 1H, Ar–H), 7.61–7.54 432.03787.
(m, 2H, Ar–H), 7.49 (td, J ¼ 8.2, 4.7 Hz, 1H, Ar–H), 4.29–4.12 (m,
3-Chloro-N-(2-((3,5-diuorobenzyl)sulnyl)ethyl)-5-
2H, –CH2–), 4.10–3.94 (m, 2H, –CH2–), 3.21–2.93 (m, 2H, –CH2– (triuoromethyl)picolinamide (G13). Yield 34%; soil white solid;
). 13C NMR (100 MHz, CDCl3) d 162.7, 148.8, 143.1 (q, J ¼ 3.8 mp 154–155 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz,
Hz), 137.6 (q, J ¼ 3.6 Hz), 132.9, 132.3, 132.1, 129.3 (q, J ¼ 34.1 1H, pyridine-H), 8.40 (t, J ¼ 5.5 Hz, 1H, –CO–NH–), 8.08 (d, J ¼
Hz), 129.1 (q, J ¼ 30.1 Hz), 128.8, 128.8, 126.7 (q, J ¼ 5.5 Hz), 1.4 Hz, 1H, pyridine-H), 6.93–6.85 (m, 2H, Ar–H), 6.82 (ddt, J ¼
124.1 (q, J ¼ 273.9 Hz), 122.1 (q, J ¼ 273.5 Hz), 56.2, 50.7, 34.5. 11.2, 8.9, 2.5 Hz, 1H, Ar–H), 4.11–3.87 (m, 4H, –CH2–), 3.23–2.80
19F NMR (376 MHz, CDCl3) d ꢀ58.50, ꢀ62.58. HRMS: calculated (m, 2H, –CH2–). 13C NMR (100 MHz, CDCl3) d 163.2 (d, J ¼ 250.3
for C17H14O2N2ClF6S [M + H]+: 459.03632; found: 459.03586.
3-Chloro-N-(2-((2-chlorobenzyl)sulnyl)ethyl)-5-
(triuoromethyl)picolinamide (G9). Yield 45%; faint yellow solid; Hz), 122.1 (q, J ¼ 273.4 Hz), 113.2 (dd, J ¼ 11.4 Hz, 25.9 Hz),
mp 127–128 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 1.1 Hz, 104.3 (t, J ¼ 25.1 Hz), 57.5, 50.2, 34.3. 19F NMR (376 MHz, CDCl3)
1H, pyridine-H), 8.42 (t, J ¼ 5.2 Hz, 1H, –CO–NH–), 8.06 (d, J ¼ d ꢀ62.58, ꢀ108.29. HRMS: calculated for C16H13O2N2ClF5S [M +
1.3 Hz, 1H, pyridine-H), 7.46–7.38 (m, 2H, Ar–H), 7.34–7.28 (m, H]+: 427.03009; found: 427.02844.
Hz), 163.0 (d, J ¼ 250.3 Hz), 162.9, 148.6, 143.1 (q, J ¼ 3.9 Hz),
137.7 (q, J ¼ 3.5 Hz), 133.2 (t, J ¼ 9.6 Hz), 132.2, 129.5 (q, J ¼ 34.1
2H, Ar–H), 4.26 (dd, J ¼ 29.2, 13.0 Hz, 2H, –CH2–), 4.08–3.92 (m,
3-Chloro-N-(2-(((3-methyl-4-(2,2,2-triuoroethoxy)pyridin-2-yl)
2H, –CH2–), 3.20–2.85 (m, 2H, –CH2–). 13C NMR (100 MHz, methyl)sulnyl)ethyl)-5-(triuoromethyl)picolinamide (G14). Yield
1
ꢁ
CDCl3) d 162.7, 148.9, 143.1 (q, J ¼ 3.9 Hz), 137.6 (q, J ¼ 3.6 Hz), 41%; white solid; mp 126–127 C. H NMR (400 MHz, CDCl3)
134.6, 132.5, 132.1, 130.1, 130.0, 129.3 (q, J ¼ 34.0 Hz), 127.8, d 8.72 (d, J ¼ 1.0 Hz, 1H, pyridine-H), 8.62 (t, J ¼ 5.1 Hz, 1H,
127.4, 122.1 (q, J ¼ 273.5 Hz), 56.1, 49.8, 34.5. 19F NMR (376 –CO–NH–), 8.35 (d, J ¼ 5.6 Hz, 1H, pyridine-H), 8.06 (d, J ¼
MHz, CDCl3) d ꢀ62.55. HRMS: calculated for C15H14O3N2Cl2F3S 1.4 Hz, 1H, pyridine-H), 6.70 (d, J ¼ 5.6 Hz, 1H, pyridine-H),
[M + H]+: 441.00488; found: 441.00427.
4.51–4.25 (m, 4H, –CH2–), 4.02 (dd, J ¼ 11.8, 5.9 Hz, 2H,
N-(2-((4-(tert-Butyl)benzyl)sulnyl)ethyl)-3-chloro-5-
–CH2–), 3.50–2.79 (m, 2H, –CH2–), 2.32 (s, 3H, –CH3). 13C NMR
(triuoromethyl)picolinamide (G10). Yield 55%; faint creamy (100 MHz, CDCl3) d 162.7, 161.9, 150.9, 149.2, 148.4, 143.0 (q, J
yellow solid; mp 131–133 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 ¼ 3.8 Hz), 137.5 (q, J ¼ 3.5 Hz), 132.0, 129.2 (q, J ¼ 34.0 Hz),
(d, J ¼ 0.9 Hz, 1H, pyridine-H), 8.45 (t, J ¼ 5.4 Hz, 1H, –CO–NH– 122.8 (q, J ¼ 277.7 Hz), 122.141 (q, J ¼ 273.5 Hz), 123.4, 105.9,
), 8.06 (d, J ¼ 1.2 Hz, 1H, pyridine-H), 7.40 (d, J ¼ 8.2 Hz, 2H, Ar– 65.4 (q, J ¼ 36.5 Hz), 57.5, 50.2, 34.3, 11.2. 19F NMR (376 MHz,
H), 7.23 (d, J ¼ 8.2 Hz, 2H, Ar–H), 4.05 (q, J ¼ 13.0 Hz, 2H, –CH2– CDCl3) d ꢀ62.57, ꢀ73.78. HRMS: calculated for C18H17O3N3-
), 4.00–3.93 (m, 2H, –CH2–), 3.09–2.78 (m, 2H, –CH2–), 1.31 (s, ClF6S [M + H]+: 504.05779; found: 504.05603.
9H, –C(CH3)3). 13C NMR (100 MHz, CDCl3) d 162.8, 151.7, 149.0,
143.1 (q, J ¼ 3.8 Hz), 137.6 (q, J ¼ 3.6 Hz), 132.0, 129.8, 129.3 (d, J (triuoromethyl)picolinamide (G15). Yield 30%; pale yellow solid;
3-Chloro-N-(2-((3,4,4-triuorobut-3-en-1-yl)sulnyl)ethyl)-5-
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mp 100–101 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.74 (s, 1H, avermectin were used as positive control and water without any
pyridine-H), 8.45 (s, 1H, –CO–NH–), 8.08 (d, J ¼ 1.2 Hz, 1H, compounds was used as negative control at the same condition.
pyridine-H), 4.01 (dd, J ¼ 11.8, 5.9 Hz, 2H, –CH2–), 3.31–2.94 (m, Fieen larvae of second instar P. xylostella were carefully
2H, –CH2–), 2.86 (ddd, J ¼ 12.6, 10.7, 8.4 Hz, 2H, –CH2–). 13C transferred to the Petri dish and cultivated for 72 h. Three
NMR (100 MHz, CDCl3) d 162.8, 153.1 (ddd, J ¼ 288.2, 275.3, replicates were measured for each treatment.
45.7 Hz), 148.6, 143.1 (q, J ¼ 3.8 Hz), 137.7 (q, J ¼ 3.5 Hz), 132.2,
129.5 (q, J ¼ 34.4 Hz), 126.3 (ddd, J ¼ 234.8, 53.5, 17.5 Hz), 122.1
(q, J ¼ 273.5 Hz), 51.2, 48.1, 34.5, 19.8 (dd, J ¼ 22.2, 2.3 Hz). 19
Conflicts of interest
F
NMR (376 MHz, CDCl3) d ꢀ62.59, ꢀ102.12 (dd, J ¼ 82.1, 33.0
Hz), ꢀ121.38 (ddd, J ¼ 115.7, 82.5, 4.4 Hz), ꢀ175.45 (dd, J ¼
114.8, 33.0 Hz). HRMS: calculated for C13H11O2N3Cl2F3S2 [M +
H]+: 431.96163; found: 431.96161.
There are no conicts to declare.
Acknowledgements
3-Chloro-N-(2-((2,5-diuorobenzyl)sulnyl)ethyl)-5-
This work was supported by the National Natural Science
Foundation of China (No. 21762012), and Program of Intro-
ducing Talents to Chinese Universities (111 Program, D20023),
and the S&T Planning Project of Guizhou Province (No. [2017]
1402, [2017]5788).
(triuoromethyl)picolinamide (G16). Yield 30%; white solid; mp
123–125 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.73 (d, J ¼ 0.9 Hz, 1H),
8.40 (t, J ¼ 4.8 Hz, 1H), 8.07 (d, J ¼ 1.4 Hz, 1H), 7.18–6.93 (m,
2H), 4.08 (dd, J ¼ 36.3, 13.2 Hz, 2H), 3.98 (dd, J ¼ 12.0, 6.1 Hz,
2H), 3.17–2.82 (m, 2H). 13C NMR (100 MHz, CDCl3) d 162.8,
158.5 (dd, J ¼ 244.3, 2.3 Hz), 157.0 (dd, J ¼ 243.6, 2.6 Hz), 148.7,
143.0 (q, J ¼ 3.8 Hz), 137.6 (q, J ¼ 3.5 Hz), 132.1, 129.4 (q, J ¼
34.1 Hz), 122.1 (q, J ¼ 273.4 Hz), 118.9 (d, J ¼ 3.6 Hz), 118.6 (d, J
¼ 3.6 Hz), 118.4 (dd, J ¼ 17.9, 8.3 Hz), 117.0 (td, J ¼ 24.4, 8.6 Hz),
50.8, 50.0, 34.4. 19F NMR (376 MHz, CDCl3) d ꢀ62.57, ꢀ117.43
(d, J ¼ 17.9 Hz), ꢀ122.28 (d, J ¼ 17.8 Hz). HRMS: calculated for
Notes and references
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16H13O2N2ClF5S [M + H]+: 427.03009; found: 427.02939.
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ꢁ
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