Design, synthesis, and particular biological behaviors of chain-opening nitromethylene neonicotinoids with cis configuration

Article abstract of DOI:10.1021/jf203068a

On the basis of the structure of heterocyclic-fused cis configuration derivatives and chain-opening neonicotinoids, two series of novel chain-opening tetrahydropyridine analogues were designed and synthesized. The preliminary bioassay tests were determined on cowpea aphid (Aphis craccivora) and armyworm (Pseudaletia separata Walker). The results showed that some of the target compounds exhibited repellent effects, whereas others showed good insecticidal activities.

Full text of DOI:10.1021/jf203068a

Article
pubs.acs.org/JAFC
Design, Synthesis, and Particular Biological Behaviors of Chain-
Opening Nitromethylene Neonicotinoids with Cis Configuration
Siyuan Lu, Xusheng Shao, Zhong Li, Zhiping Xu,* Shishuai Zhao, Yinli Wu, and Xiaoyong Xu*
Shanghai Key Laboratory of Chemistry Biology, School of Pharmacy, East China University of Science and Technology, Shanghai
200237, China
ABSTRACT: On the basis of the structure of heterocyclic-fused cis configuration derivatives and chain-opening neonicotinoids,
two series of novel chain-opening tetrahydropyridine analogues were designed and synthesized. The preliminary bioassay tests
were determined on cowpea aphid (Aphis craccivora) and armyworm (Pseudaletia separata Walker). The results showed that
some of the target compounds exhibited repellent effects, whereas others showed good insecticidal activities.
KEYWORDS: chain-opening, neonicotinoids, repellent effects, cis configuration, tetrahydropyridine
neonicotinoids were designed and synthesized. Series 1 (see
Table 1) was designed and synthesized on the basis of the
structures of nitenpyram 4 (Figure 2) and acetamiprid 5
(Figure 2), wherein the substituent R3 was an alkyl group. In
the design of series 2, R3 was replaced by a hydrogen atom as
found in the structures of clothianidin 6 (Figure 2) and
dinotefuran 7 (Figure 2).
In this paper, the syntheses of two series of chain-opening
nitromethylene neonicotinoids and their particular biological
behaviors or bioactivities are reported.
INTRODUCTION
■
Neonicotinoids, as the fourth-generation insecticides after
organophosphorus, carbamates, and pyrethroids, are the fastest
growing synthetic insecticides on the market.1 Their global
sales reached U.S. $2.632 billion in 2009 and accounted for
23.7% of total market share of insecticides in 2008,2 which were
expected to take the biggest market of insecticides. With a
thorough comprehension of the action mechanism, neonicoti-
noids are a class of insecticides targeting the insect nicotinic
acetylcholine receptors (nAChRs).3,4
There are four common molecular features of neonicoti-
noids: (1) an aromatic heterocycle, (2) flexible linkage, (3)
hydroheterocycles or guanidine/amidine, and (4) an electron-
withdrawing group.5 According to the structural characteristics
of the third feature, the commercialized neonicotinoids can be
subdivided into two categories: (1) cyclic compounds,
including imidacloprid 1 (Figure 1), thiacloprid 2 (Figure 1),
and thiamethoxam 3 (Figure 1); and (2) acyclic neonicotinoids,
including nitenpyram 4 (Figure 1), acetamiprid 5 (Figure 1),
clothianidin 6 (Figure 1), dinotefuran 7 (Figure 1), and
sulfoxaflor 8 (Figure 1). Generally, compared with cyclic ones,
acyclic neonicotinoids, which are defined as ring-opening or
chain-opening neonicotinoids, exhibit a broader insecticidal
spectrum.6,7 The acyclic diamine skeleton was considered to be
an effective bioisostere of imidazolidine and other hetero-
cycles,8 which made it possible for the reconstruction of an
acyclic bioisostere to often acquire desirable bioactivities .
In previous work, we had reported the synthesis, bioactivities,
and mode of action of nitromethylene neonicotinoids with
fixed cis configuration.9 The nitro group was fixed to form the
cis configuration through the introduction of a tetrahydropyr-
idine ring, which helps to improve the photostability. The
preliminary bioassay results showed that their insecticidal
activities against resistant strain brown planthopper were higher
than that of imidacloprid.5 Accordingly, it attracted us to
investigate what chain-opening analogues of cis configuration
nitromethylene neonicotinoids would provide.
MATERIALS AND METHODS
Instrumentation and Chemicals. Unless otherwise noted,
reagents and solvents were used as received from commercial
■
suppliers. Melting points (mp) were recorded on a Buchi B540
̈
1
apparatus and are uncorrected. H NMR spectra were recorded on a
Bruker WP-500SY (500 MHz) or Bruker WP-400SY (400 MHz)
spectrometer with CDCl3 as the solvent and TMS as the internal
standard. Chemical shifts are reported in δ (parts per million) values.
High-resolution mass spectra were recorded under electron impact (70
eV) conditions using a MicroMass GCT CA 055 instrument.
Combustion analyses for elemental composition were made with an
Elementar vario EL III. GC mass spectra were recorded using a HP
6890 gas chromatograph and HP 5973 mass selective detector.
Analytical thin-layer chromatography (TLC) was carried out on
precoated plates (silica gel 60 F254), and spots were visualized with
ultraviolet (UV) light.
Synthetic Procedures. Synthesis of Series 1 (Scheme 1). N-
((6-Chloropyridin-3-yl)methyl)ethanamine (19). Compound 19 was
prepared as described in the literature10 in 70.3% yield: GC-MS, m/z
(%) 170 ([M]+, 20), 155 (80), 126 (100), 114 (10), 90 (12).
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroe-
thenamine (20). Compound 20 was prepared as described in the
literature11 in 18.5% yield: GC-MS, m/z (%) 242 ([M]+ − 46, 53),
227 (15), 213 (100), 169 (45), 155 (28), 141 (29), 126 (91), 90 (12).
N-Methyl-1-(methylthio)-2-nitroethenamine (22). To the solu-
tion of compound 21 (15.0 g, 90 mmol) in acetonitrile (50 mL) was
added dropwise 60−75% aqueous methanamine (4.7 g, 90 mmol) at 0
Received: July 29, 2011
To further explore the bioactivities of chain-opening
analogues of cis configuration nitromethylene neonicotinoids,
two series of compounds with tetrahydropyridine-fused
Revised: November 25, 2011
Accepted: November 28, 2011
Published: November 28, 2011
© 2011 American Chemical Society
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Figure 1. Commercialized neonicotinoids.
°C, and the resulting solution was stirred at room temperature for 24
h. The reaction was evaporated to dryness, and the residue was
purified by chromatography over silica gel (petroleum ether/ethyl
acetate, 1:1) to give 4.7 g (35.1% yield) of 22 as a yellow solid: GC-
2.94−3.52 (m, 4H), 2.89 (s, 3H), 2.75 (t, J = 7.7 Hz, 2H), 1.82−2.00
(m, 2H), 1.08−1.27 (m, 6H); IR (KBr, cm−1) 2891, 1559, 1469, 1380,
1281, 1246, 1249, 1096, 729; HRMS (EI+) calcd for C16H2335ClN4O3
(M+), 354.1459 (found, 354.1452).
General Synthetic Procedure for 10c−e and 11a−e. A catalytic
amount of BF3·Et2O was added to the mixture of compound 23 (0.3 g,
1.1 mmol), acrylaldehyde or crotonaldehyde (3.3 mmol), and the
corresponding alcohol (10 mL), and then the mixture was heated to
40 °C. The resulting solution was stirred at 40 °C and monitored by
TLC. The reaction was evaporated to dryness, and the residue was
purified by chromatography over silica gel (dichloromethane/acetone,
1:1) to give the corresponding product.13
MS, m/z (%) 148 ([M]+, 30), 101 (100), 84 (23), 55 (96).
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-N-methyl-2-nitroe-
thene-1,1-diamine (23). Method 1. N-((6-Chloropyridin-3-yl)-
methyl)-N-ethyl-N-methyl-2-nitroethene-1,1-diamine was prepared as
described in the literature11 in 29.5% yield: mp, 78.5−80.1 °C.
Method 2. A mixture of compound 22 (5.00 g, 34 mmol),
compound 19 (5.78 g, 34 mmol), and AgOAc (5.8 g, 17 mmol) in
anhydrous ethanol (30 mL) was stirred at 25 °C and monitored by
TLC. After filtration, the filtrate was evaporated under reduced
pressure followed by chromatography purification on silica gel
(dichloromethane/ethanol, 25:1) to give 4.0 g (38.1% yield) of 23
as a yellow solid: mp, 78.1−79.6 °C.
6-(((6-Chloropyridin-3-yl)methyl)(ethyl)amino)-1-methyl-5-nitro-
1,2,3,4-tetrahydropyridin-2-ol (10a). To a mixture of compound 23
(0.3 g, 1.1 mmol), acrylaldehyde (0.21 mL, 3.3 mol), and acetonitrile
(10 mL) were added two drops of BF3·Et2O. The resulting solution
was stirred at 40 °C for 4 h, evaporated to dryness, and purified by
chromatography over silica gel (dichloromethane/acetone, 1:1) to give
0.05 g (18.0% yield) of 10a as a pale white solid: mp, 165.1−168.2 °C;
1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.77 (d, J = 5.4 Hz,
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-6-methoxy-1-methyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine (10c): yield, 16.0%; mp,
1
151.1−155.2 °C; H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 1.9
Hz, 1H), 7.83 (d, J = 6.9 Hz, 0.5H), 7.62 (d, J = 6.9 Hz, 0.5H), 7.32
(d, J = 7.8 Hz, 1H), 4.26−4.49 (m, 2H), 4.09−4.23 (m, 1H), 2.94−
3.29 (m, 5H), 2.91 (s, 3H), 2.73 (m, 2H), 1.78−2.04 (m, 2H), 1.23
(m, 3H); IR (KBr, cm−1) 2899, 1561, 1505, 1281, 1096, 729; HRMS
(ES+) calcd for C15H21N4O335ClNa (M + Na)+, 363.1200 (found,
363.1196); calcd for C15H21N4O337ClNa (M + Na)+, 365.1170 (found,
365.1186).
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-1-methyl-3-nitro-6-pro-
poxy-1,4,5,6-tetrahydropyridin-2-amine (10d): yield, 17.8%; mp,
1
110.1−114.2 °C; H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 1.7
0.5H), 7.58 (d, J = 5.4 Hz, 0.5H), 7.31 (d, J = 8.2 Hz, 1H), 4.81 (s,
1H), 4.44−4.50 (m, 2H), 4.16 (d, J = 14.4 Hz, 0.5H), 4.14(d, J = 14.4
Hz, 0.5H), 2.96−3.26 (m, 2H), 2.96 (s, 3H), 2.70−2.88 (m, 2H),
1.92−2.05 (m, 2H), 1.16−1.26 (m, 3H); IR (KBr, cm−1) 3200, 1560,
1507, 1461, 1381, 730; MS (ES+) calcd for C14H2035ClN4O3 (M +
H)+, 327 (found, 327).
Hz, 1H), 7.79 (d, J = 7.3 Hz, 0.5H), 7.61 (d, J = 7.3 Hz, 0.5H), 7.29
(d, J = 8.2 Hz, 1H), 4.32−4.45 (m, 2H), 4.21 (d, J = 14.8 Hz, 0.5H),
4.09 (d, J = 14.8 Hz, 0.5H), 2.86−3.51 (m, 4H), 2.86 (s, 3H), 2.72 (m,
2H), 1.79−1.99 (m, 2H), 1.54 (m, 2H), 1.19 (t, J = 6.9 Hz, 3H), 0.83
(t, J = 7.2 Hz, 3H); IR (KBr, cm−1) 2900, 1561, 1507, 1458, 1381,
1281, 1248, 1096, 730; HRMS (ES+) calcd for C17H26N4O335Cl (M +
H)+, 369.1693 (found, 369.1667); calcd for C17H26N4O337Cl (M +
H)+, 371.1664 (found, 371.1671).
N-((6-Chloropyridin-3-yl)methyl)-6-ethoxy-N-ethyl-1-methyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine (10b). To a solution of
compound 10a (0.3 g, 0.9 mmol) in ethanol (10 mL) were added
two drops of BF3·Et2O. The resulting solution was refluxed for 6 h and
then evaporated to dryness. The residue was purified by chromatog-
raphy over silica gel (dichloromethane/acetone, 5:1) to give 0.06 g
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-6-isopropoxy-1-methyl-
3-nitro-1,4,5,6-tetrahydropyridin-2-amine (10e): yield, 19.8%; mp,
112.8−116.6 °C; 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.78 (d,
J = 7.6 Hz, 0.5H), 7.67 (d, J = 7.6 Hz, 0.5H), 7.32 (d, J = 7.8 Hz, 1H),
4.40−4.46 (m, 2H), 4.17 (t, J = 16.2 Hz, 1H), 2.87−3.58 (m, 6H),
2.71−2.77 (m, 2H), 1.83−1.94 (m, 2H), 1.09−1.22 (m, 9H); IR (KBr,
cm−1) 2897, 1561, 1507, 1458, 1381, 1281, 1248, 1096, 730; HRMS
(18.8% yield) of 10b as a yellow solid:12 mp, 131.1−133.7 °C; H
1
NMR (500 MHz, CDCl3) δ 8.27 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 7.5
Hz, 0.5H), 7.64 (d, J = 7.5 Hz, 0.5H), 7.3 (d, J = 8.2 Hz, 1H), 4.35−
4.48 (m, 2H), 4.18 (d, J = 14.9 Hz, 0.5H), 4.15 (d, J = 14.9 Hz, 0.5H),
323
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a
Table 1. Compounds of Series 1 and 2
Scheme 1. Preparation of Compounds 10a−11e of Series 1
compd
R1
R2
R3
R4
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
13a
13b
13c
13d
14a
14b
14c
15a
15b
15c
15d
16a
16b
16c
16d
17a
17b
17c
17d
H
H
H
H
H
H
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
ethyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
H
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
ethyl
ethyl
methyl
n-propyl
isopropyl
methyl
ethyl
methyl
methyl
methyl
methyl
methyl
H
n-propyl
isopropyl
allyl
methyl
ethyl
H
H
n-propyl
isopropyl
allyl
H
H
methyl
methyl
methyl
methyl
methyl
methyl
methyl
ethyl
methyl
ethyl
n-propyl
isopropyl
ethyl
a
Reagents and conditions: (a) ethylamine, MeCN, 0−5 °C; (b) 1,1-
bis(methylthio)-2-nitroethene, EtOH, refluxing; (c) methylamine,
EtOH, refluxing; (d) methylamine, EtOH, refluxing; (e) compound
19, AgOAc, EtOH, 25 °C; (f) acrylaldehyde or crotonaldehyde,
corresponding alcohol, BF3·Et2O, 40 °C; (g) acrylaldehyde, MeCN,
BF3·Et2O, 40 °C; (h) EtOH, BF3·Et2O, 40 °C.
n-propyl
isopropyl
methyl
ethyl
H
H
H
ethyl
H
0.98−1.18 (m, 3H); IR (KBr, cm−1) 2900, 1561, 1507, 1458, 1381,
1281, 1248, 1096, 730; HRMS (ES+) calcd for C16H23N4O3Na35Cl (M
+ Na)+, 377.1356 (found, 377.1324); calcd for C16H23N4O3Na37Cl (M
+ Na)+, 379.1327 (found, 379.1336).
N-((6-Chloropyridin-3-yl)methyl)-6-ethoxy-N-ethyl-1,4-dimethyl-
3-nitro-1,4,5,6-tetrahydropyridin-2-amine (11b): yield, 21.5%; mp,
120.1−123.7 °C; 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.95 (d,
J = 5.0 Hz, 0.5H), 7.50 (d, J = 5.0 Hz, 0.5H), 7.29 (d, J = 7.8 Hz, 1H),
4.24−4.48 (m, 3H), 3.24−3.53 (m, 4H), 2.95 (s, 3H), 2.25−2.29 (m,
1H), 1.56−1.68 (m, 2H), 1.28 (m, 3H), 1.15 (t, J = 5.8 Hz, 3H),
0.98−1.07 (m, 3H); IR (KBr, cm−1) 2900, 1561, 1507, 1458, 1381,
1281, 1248, 1096, 730; HRMS (ES+) calcd for C17H25N4O3Na35Cl (M
+ Na)+, 391.1513 (found, 391.1513); calcd for C17H25N4O3Na37Cl (M
+ Na)+, 393.1483 (found, 393.1518).
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-1,4-dimethyl-3-nitro-6-
propoxy-1,4,5,6-tetrahydropyridin-2-amine (11c): yield, 22.8%; mp,
118.1−121.2 °C; 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.98 (d,
J = 7.0 Hz, 0.5H), 7.50 (d, J = 7.0 Hz, 0.5H), 7.29 (d, J = 7.9 Hz, 1H),
4.53−4.28 (m, 3H), 3.03−3.41 (m, 4H), 2.95 (s, 3H), 2.28 (m, 1H),
1.51−1.69 (m, 2H), 1.51 (m, 2H), 1.28 (t, J = 8.7 Hz, 3H), 0.99−1.11
(m, 3H), 0.84 (t, J = 7.2 Hz, 3H); IR (KBr, cm−1) 2900, 1561, 1507,
1458, 1381, 1281, 1248, 1096, 730; HRMS (ES+) calcd for
ethyl
n-propyl
isopropyl
methyl
ethyl
H
ethyl
H
methyl
methyl
methyl
methyl
ethyl
H
H
ethyl
n-propyl
isopropyl
methyl
ethyl
H
ethyl
H
ethyl
H
ethyl
ethyl
H
ethyl
ethyl
n-propyl
isopropyl
H
ethyl
ethyl
H
ethyl
(ES+) calcd for C17H25N4O3Na35Cl (M + Na)+, 391.1513 (found,
391.1513); calcd for C17H25N4O3Na37Cl (M + Na)+, 393.1483 (found,
393.1512).
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-6-methoxy-1,4-dimeth-
yl-3-nitro-1,4,5,6-tetrahydropyridin-2-amine (11a): yield, 22.7%;
1
mp, 125.1−129.2 °C; H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H),
7.95 (d, J = 5.0 Hz, 0.5H), 7.50 (d, J = 5.0 Hz, 0.5H), 7.29 (d, J = 7.8
Hz, 1H), 4.30−4.47 (m, 2H), 4.20 (m, 1H), 3.02−3.41 (m, 5H), 2.95
(s, 3H), 2.28 (m, 1H), 1.59−1.69 (m, 2H), 1.30 (t, J = 6.7 Hz, 3H),
Figure 2. Chemical structures of cyclic and acyclic neonicotinoids, 9, and its acyclic analogues.
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C18H28N4O335Cl (M + H)+, 383.1850 (found, 383.1815); calcd for
C18H28N4O337Cl (M + H)+, 385.1820 (found, 385.1841).
N-((6-Chloropyridin-3-yl)methyl)-N,1-dimethyl-3-nitro-6-pro-
poxy-1,4,5,6-tetrahydropyridin-2-amine 12c: yield, 21.4%; mp,
1
80.1−84.2 °C; H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 2.2 Hz,
N-((6-Chloropyridin-3-yl)methyl)-N-ethyl-6-isopropoxy-1,4-di-
methyl-3-nitro-1,4,5,6-tetrahydropyridin-2-amine (11d): yield,
1H), 7.63 (m, 1H), 7.33 (d, J = 8.2 Hz, 1H), 4.39−4.50 (m, 2H), 4.18
(m, 1H), 3.33−3.39 (m, 3H), 2.89 (s, 3H), 2.75 (m, 5H), 1.88−2.07
(m, 2H), 1.51−1.58 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H); IR (KBr, cm−1)
2896, 1561, 1507, 1458, 1381, 1281, 1248, 1096, 729; HRMS (ES+)
calcd for C16H23N4O3Na35Cl (M + Na)+, 377.1356 (found, 377.1336);
calcd for C16H23N4O3Na37Cl (M + Na)+, 379.1327 (found, 379.1295).
N-((6-Chloropyridin-3-yl)methyl)-6-isopropoxy-N,1-dimethyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 12d: yield, 21.7%; mp,
1
23.2%; mp, 104.1−107.2 °C; H NMR (500 MHz, CDCl3) δ 8.28
(s, 1H), 7.99 (d, J = 7.6 Hz, 0.5H), 7.51 (d, J = 7.6 Hz, 0.5H), 7.31 (d,
J = 6.3 Hz, 1H), 4.25−4.49 (m, 3H), 3.06−3.67 (m, 3H), 2.95 (s, 3H),
2.22 (m, 1H), 1.54−1.72 (m, 2H), 1.28 (t, J = 6.69 Hz, 3H), 1.13 (d, J
= 6.0 Hz, 3H), 1.07 (d, J = 6.1 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H); IR
(KBr, cm−1) 2896, 1561, 1507, 1458, 1381, 1281, 1248, 1096, 729;
HRMS (ES+) calcd for C18H28N4O335Cl (M + H)+, 383.1850 (found,
383.1831); calcd for C18H28N4O337Cl (M + H)+, 385.1820 (found,
385.1867).
1
85.2−89.6 °C; H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 2.1 Hz,
1H), 7.66 (m, 1H), 7.34 (d, J = 8.2 Hz, 1H), 4.36−4.49 (m, 2H), 4.18
(m, 1H), 3.64 (m, 1H), 2.88 (s, 3H), 2.75−2.79 (m, 5H), 1.92 (m,
2H), 1.15 (d, J = 5.7 Hz, 3H), 1.11 (d, J = 6.2 Hz, 3H); IR (KBr,
cm−1) 2896, 1562, 1507, 1458, 1381, 1281, 1248, 1096, 729; HRMS
(ES+) calcd for C16H23N4O3Na35Cl (M + Na)+, 377.1356 (found,
377.1352); calcd for C16H23N4O3Na37Cl (M + Na)+, 379.1327 (found,
379.1326).
6-(Allyloxy)-N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1,4-dimeth-
yl-3-nitro-1,4,5,6-tetrahydropyridin-2-amine (11e): yield, 25.5%;
1
mp, 111.9−116.7 °C; H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H),
7.96 (d, J = 7.2 Hz, 0.5H), 7.50 (d, J = 7.2 Hz, 0.5H), 7.31 (d, J = 8.2
Hz, 1H), 5.75−5.83 (m, 1H), 5.15−5.24 (m, 2H), 4.28−4.49 (m, 3H),
3.77−4.02 (m, 2H), 3.01−3.36 (m, 2H), 2.92 (s, 3H), 2.28−2.32 (m,
1H), 1.56−1.78 (m, 2H), 1.28 (t, J = 6.1 Hz, 3H); IR (KBr, cm−1)
2896, 1561, 1507, 1458, 1381, 1281, 1248, 1096, 729; HRMS (ES+)
calcd for C18H25N4O3Na35Cl (M + Na)+, 403.1513 (found, 403.1520);
calcd for C18H25N4O3Na37Cl (M + Na)+, 405.1483 (found, 405.1486).
General Synthetic Procedure for 12a−e and 13a−d (Scheme 2).
Compounds 24, 25, and 26 were synthesized following the same route
as 19, 20, and 21.10,11 A catalytic amount of BF3·Et2O was added to
6-(Allyloxy)-N-((6-chloropyridin-3-yl)methyl)-N,1-dimethyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 12e: yield, 22.2%; mp,
1
76.0−80.1 °C; H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.62−
7.75 (m, 1H), 7.34 (d, J = 8.2 Hz, 1H), 5.83 (m, 1H), 5.19−5.25 (m,
2H), 3.93−4.55 (m, 5H), 2.89 (s, 3H), 2.78 (m, 2H), 2.75 (s, 3H),
1.86−2.10 (m, 2H); IR (KBr, cm−1) 2901, 1562, 1507, 1458, 1381,
1281, 1248, 1096.34, 729; HRMS (ES+) calcd for C16H21N4O3Na35Cl
(M + Na)+, 375.1200 (found, 375.1201); calcd for C16H21N4O3Na37Cl
(M + Na)+, 377.1170 (found, 377.1175).
a
Scheme 2. Preparation of Compounds 12a−13d of Series 1
N-((6-Chloropyridin-3-yl)methyl)-6-methoxy-N,1,4-trimethyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 13a: yield, 31.6%; mp,
1
126.1−130.2 °C; H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.85
(m, 0.5H), 7.52 (m, 0.5H), 7.33 (d, J = 7.9 Hz, 1H), 4.24−4.61 (m,
3H), 3.27 (m, 3H), 2.96 (s, 3H), 2.81 (s, 3H), 2.35 (m, 1H), 1.65 (m,
2H), 1.11−1.29 (m, 3H); IR (KBr, cm−1) 2896, 1562, 1507, 1459,
1381, 1281.07, 1248, 1100, 727; HRMS (ES+) calcd for
C15H21N4O3Na35Cl (M + Na)+, 363.1200 (found, 363.1202); calcd
for C15H21N4O3Na37Cl (M + Na)+, 365.1170 (found, 365.1189).
N-((6-Chloropyridin-3-yl)methyl)-6-ethoxy-N,1,4-trimethyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 13b: yield, 25.1%; mp,
126.1−129.8 °C; 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H),
7.83−7.86 (m, 0.5H), 7.52−7.53 (m, 0.5H), 7.32 (d, J = 8.2 Hz, 1H),
4.25−4.57 (m, 3H), 3.34−3.38 (m, 2H), 2.95 (s, 3H), 2.79 (s, 3H),
2.28−2.33 (m, 1H), 1.64 (m, 2H), 1.13−1.29 (m, 6H); IR (KBr,
cm−1) 2896, 1562, 1507, 1459, 1381, 1281, 1248, 1096, 727; HRMS
(ES+) calcd for C16H23N4O3Na35Cl (M + Na)+, 377.1356 (found,
377.1333); calcd for C16H23N4O3Na37Cl (M + Na)+, 379.1326 (found,
379.1327).
N-((6-Chloropyridin-3-yl)methyl)-N,1,4-trimethyl-3-nitro-6-pro-
poxy-1,4,5,6-tetrahydropyridin-2-amine 13c: yield, 32.7%; mp,
102.1−105.2 °C; 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H),
7.52−7.88 (m, 1H), 7.32 (d, J = 7.6 Hz, 1H), 4.30−4.59 (m, 3H),
3.25−3.39 (m, 2H), 2.95 (s, 3H), 2.80 (s, 3H), 2.30−2.35 (m, 1H),
1.63−2.09 (m, 2H), 1.51 (m, 2H), 1.14−1.29 (m, 3H), 0.84 (t, J = 6.9
Hz, 3H); IR (KBr, cm−1) 2899, 1562, 1507, 1459, 1381, 1281, 1248,
1096, 730; HRMS (ES+) calcd for C17H25N4O3Na35Cl (M + Na)+,
391.1513 (found, 391.1487); calcd for C17H25N4O3Na37Cl (M + Na)+,
393.1483 (found, 393.1482).
N-((6-Chloropyridin-3-yl)methyl)-6-isopropoxy-N,1,4-trimethyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 13d: yield, 30.1%; mp,
108.1−111.2 °C; 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H),
7.53−7.89 (m, 1H), 7.33 (d, J = 5.6 Hz, 1H), 4.34−4.80 (m, 3H), 3.26
(m, 1H), 2.94 (s, 3H), 2.79 (s, 3H), 2.24−2.29 (m, 1H), 1.28−2.04
(m, 2H), 1.10−1.26 (m, 6H), 1.06 (m, 3H); IR (KBr, cm−1) 2897,
1562, 1508, 1459.79, 1381, 1281, 1248, 1096, 731; HRMS (ES+) calcd
for C17H26N4O335Cl (M + H)+, 369.1649 (found, 369.1669); calcd for
C17H26N4O335Cl (M + H)+, 371.1664 (found, 371.1690).
Synthesis of Series 2 (Scheme 3). (2-Chlorothiazol-5-yl)-
methanamine (28). Compound 28 was prepared as described in the
literature14 in 32.4% yield: GC-MS, m/z(%) 148 ([M]+, 15), 132 (9),
113 (100), 96 (1).
a
Reagents and conditions: (a) methylamine, MeCN, 0−5 °C; (b) 1,1-
bis(methylthio)-2-nitroethene, EtOH, refluxing; (c) methylamine,
EtOH, refluxing; (d) acrylaldehyde or crotonaldehyde, corresponding
alcohol, BF3·Et2O, 40 °C.
the mixture of compound 26 (0.3 g, 1.1 mmol), acrylaldehyde or
crotonaldehyde (3.3 mmol), and the corresponding alcohol (10 mL).
Then the resulting solution was stirred at 40 °C, and the progress of
the reaction was monitored by TLC. The reaction mixture was
concentrated by rotary evaporator, and the residue was purified by
chromatography on silica gel (dichloromethane/acetone, 1:1) to give
the corresponding product.
N-((6-Chloropyridin-3-yl)methyl)-6-methoxy-N,1-dimethyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 12a:: yield, 26.9%; mp,
101.2−104.5 °C; H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.72
1
(m, 0.5H), 7.61 (m, 0.5H), 7.34 (d, J = 8.1 Hz, 1H), 4.31−4.50 (m,
2H), 4.15 (m, 1H), 3.29−3.34 (m, 3H), 2.91 (s, 3H), 2.76 (m, 5H),
1.84−2.09 (m, 2H); IR (KBr, cm−1) 2900, 1561, 1508, 1458, 1380,
1281, 1248, 1096, 730; HRMS (ES+) calcd for C14H19N4O3Na35Cl (M
+ Na)+, 349.1043 (found, 349.1013); calcd for C14H19N4O3Na37Cl (M
+ Na)+, 351.1014 (found, 351.1017).
N-((6-Chloropyridin-3-yl)methyl)-6-ethoxy-N,1-dimethyl-3-nitro-
1,4,5,6-tetrahydropyridin-2-amine 12b: yield, 25.8%; mp, 94.3−98.2
°C; 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.64 (d, J = 7.5 Hz,
1H), 7.33 (d, J = 8.2 Hz, 1H), 4.35−4.39 (m, 2H), 4.14−4.17 (m,
1H), 3.38−3.49 (m, 2H), 2.88 (s, 3H), 2.76 (m, 5H), 1.84−1.87 (m,
2H), 1.17 (t, J = 6.9 Hz, 3H); IR (KBr, cm−1) 2896, 1561, 1507, 1458,
1383, 1282, 1248, 1096, 730; HRMS (ES+) calcd for
C15H21N4O3Na35Cl (M + Na)+, 363.1200 (found, 363.1189); calcd
for C15H21N4O3Na37Cl (M + Na)+, 365.1170 (found, 365.1176).
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101.0−102.4 °C; 1H NMR (400 MHz, CDCl3) δ 11.04 (s, 1H),
7.49 (s, 1H), 4.59−4.62 (m, 2H), 4.39 (dd, J1 = 4.8 Hz, J2 = 8.4 Hz,
1H), 3.26 (s, 3H), 3.11 (s, 3H), 2.02−2.11 (m, 1H), 1.88−1.93 (m,
1H), 1.68−1.73 (m, 1H), 1.24−1.32 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 159.3, 152.5, 139.5, 136.8, 116.4, 89.5,
a
Scheme 3. Preparation of Series 2
53.9, 42.3, 40.5, 32.0, 29.9, 24.3, 11.5; IR (KBr, cm−1) 2962, 1595,
1409, 1335, 1212, 1134, 1049, 963, 863; HRMS (ES+) calcd for
C13H20N4O3S35Cl (M + H)+, 347.0945 (found, 347.0951); calcd for
C13H20N4O3S37Cl (M + H)+, 349.0915 (found, 349.0926).
N-((2-Chlorothiazol-5-yl)methyl)-6-ethoxy-4-ethyl-1-methyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 15b: yield, 14.3%; mp,
103.0−103.8 °C; 1H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H),
7.49 (s, 1H), 4.58−4.64 (m, 2H), 4.44 (dd, J1 = 4.8 Hz, J2 = 8.4 Hz, 1
H), 3.03−3.19 (m, 2H), 3.11 (s, 3H), 2.07−2.13 (m, 1H), 1.85−1.92
(m, 1H), 1.65−1.74 (m, 1H), 1.19−1.27 (m, 2H), 1.23 (t, J = 7.2 Hz,
3H), 0.93 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4,
152.4, 139.5, 136.8, 116.3, 88.6, 62.5, 42.3, 40.3, 32.1, 30.7, 24.2, 15.3,
11.5; IR (KBr, cm−1) 2970, 1585, 1524, 1409, 1335, 1276, 1146, 1059,
912, 748; HRMS (ES+) calcd for C14H22N4O3S35Cl (M + H)+,
361.1101 (found, 361.1107); calcd for C14H22N4O3S37Cl (M + H)+,
363.1072 (found, 363.1076).
a
Reagents and conditions: (a) NH3·H2O, EtOH, room temperature;
(b) 1,1-bis(methylthio)-2-nitroethene, EtOH, refluxing; (c) methyl-
amine or ethylamine, EtOH, refluxing; (d) CH2Cl2, crotonaldehyde or
trans-2-pentenal, corresponding alcohol, BF3·Et2O, 20 °C; (e) CH2Cl2,
crotonaldehyde or trans-2-pentenal, corresponding alcohol, BF3·Et2O,
20 °C.
N-((2-Chlorothiazol-5-yl)methyl)-4-ethyl-1-methyl-3-nitro-6-pro-
N-((2-Chlorothiazol-5-yl)methyl)-1-(methylthio)-2-nitroethen-
amine (29). Compound 29 was prepared as described in the
literature15 in 63.8% yield: MS (ES+) calcd for C7H835ClN3O2S2
(M+), 265 (found, 265).
N-((2-Chlorothiazol-5-yl)methyl)-N-methyl-2-nitroethene-1,1-di-
amine (30). Compound 30 was prepared as described in the
literature.15
poxy-1,4,5,6-tetrahydropyridin-2-amine 15c: yield, 14.2%; mp,
1
89.0−91.6 °C; H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H), 7.50
(s, 1H), 4.59−4.64 (m, 2H), 4.45 (dd, J1 = 4.8 Hz, J2 = 8.4 Hz, 1H),
3.29−3.36 (m, 2H), 3.11 (s, 3H), 2.08−2.13 (m, 1H), 1.84−1.91 (m,
1H), 1.68−1.75 (m, 1H), 1.24−1.32 (m, 2H), 0.92−0.96 (m, 8H); 13C
NMR (100 MHz, CDCl3) δ 159.4, 152.5, 139.5, 136.8, 116.4, 88.7,
68.6, 42.3, 40.3, 32.1, 30.6, 24.3, 23.0, 11.5, 10.6; IR (KBr, cm−1) 2955,
1587, 1406, 1331, 1209, 1138, 1059, 904, 748; HRMS (ES+) calcd for
C15H24N4O3S35Cl (M + H)+, 375.1179 (found, 375.1245); calcd for
C15H24N4O3S37Cl (M + H)+, 377.1228 (found, 377.1212).
General Synthetic Procedure for 14a−c, 15a−d, 16a−d and
17a−d. A mixture of compound 30 (0.375 g, 1.5 mmol),
crotonaldehyde or trans-2-pentenal (3.3 mmol), and the correspond-
ing alcohol (5 mL) in CH2Cl2 (10 mL) was stirred and cooled to 20
°C, and then a catalytic amount of BF3·Et2O was added to the mixture.
The resulting solution was stirred at 20 °C, and the progress of the
reaction was monitored by TLC. The reaction was evaporated to
dryness, and the residue was purified by chromatography over silica gel
(dichloromethane/acetone, 12:1) to give the corresponding product.
N-((2-Chlorothiazol-5-yl)methyl)-6-ethoxy-1,4-dimethyl-3-nitro-
1,4,5,6-tetrahydropyridin-2-amine 14a: yield, 14.7%; 1H NMR (400
MHz, CDCl3) δ 11.05 (s, 1H), 7.49 (s, 1H), 4.59−4.62 (m, 2H), 4.45
(dd, J1 = 4.4 Hz, J2 = 7.6 Hz, 1H), 3.38−3.48 (m, 2H), 3.11 (s, 3H),
1.91−1.98 (m, 1H), 1.13−1.33 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 1.15
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 152.5,
139.5, 136.8, 116.4, 88.4, 62.7, 42.3, 40.4, 34.2, 25.9, 17.4, 15.3.;
HRMS (ES+) calcd for C13H20N4O3S35Cl (M + H)+, 347.0945 (found,
347.0946); calcd for C13H20N4O3S37Cl (M + H)+, 349.0915 (found,
349.0932).
N-((2-Chlorothiazol-5-yl)methyl)-1,4-dimethyl-3-nitro-6-propoxy-
1,4,5,6-tetrahydropyridin-2-amine 14b: yield, 13.9%; 1H NMR (400
MHz, CDCl3) δ 11.10 (s, 1H), 7.48 (s, 1H), 4.59−4.64 (m, 2H), 4.39
(s, 1H), 3.29−3.47 (m, 2H), 3.12 (s, 3H), 1.83−1.96 (m, 1H), 1.56−
1.63 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H), 1.08−1.15 (m, 2H), 0.93 (t, J =
7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 152.4, 139.4,
137.0, 116.9, 89.0, 70.7, 42.3, 38.3, 31.5, 27.4, 22.9, 18.3, 10.7; HRMS
(ES+) calcd for C14H22N4O3S35Cl (M + H)+, 361.1101 (found,
361.1112); calcd for C14H22N4O3S37Cl (M + H)+, 363.1072 (found,
363.1082).
N-((2-Chlorothiazol-5-yl)methyl)-6-isopropoxy-1,4-dimethyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 14c: yield, 14.7%; mp,
117.7−118.5 °C; 1H NMR (400 MHz, CDCl3) δ 11.07 (s, 1H),
7.49 (s, 1H), 4.57−4.60 (m, 2H), 4.49 (dd, J1 = 5.2 Hz, J2 = 6.8 Hz,
1H), 3.18−3.23 (m, 1H), 3.10 (s, 3H), 1.91−1.94 (m, 1H), 1.15−1.22
(m, 2H), 1.22 (d, J = 4 Hz, 3H), 1.18 (d, 3H), 1.6 (d, 3H); 13C NMR
(100 MHz, CDCl3) δ 59.3, 152.5, 139.5, 136.8, 116.4, 88.4, 62.7, 42.3,
40.4, 34.2, 25.9, 17.4, 15.3; IR (KBr, cm−1) 2962, 1573, 1524, 1354,
1357, 1276, 1172, 1059, 919, 748; HRMS (ES+) calcd for
C14H22N4O3NaS35Cl (M + Na)+, 383.0921 (found, 383.0930); calcd
for C14H22N4O3NaS37Cl (M + Na)+, 385.0891 (found, 385.0880).
N-((2-Chlorothiazol-5-yl)methyl)-4-ethyl-6-methoxy-1-methyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 15a: yield, 15.2%; mp,
N-((2-Chlorothiazol-5-yl)methyl)-4-ethyl-6-isopropoxy-1-methyl-
3-nitro-1,4,5,6-tetrahydropyridin-2-amine 15d: yield, 13.4%; mp,
1
105.2−105.3 °C; H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H), 7.50
(s, 1H), 4.57−4.60 (m, 2H), 4.46 (dd, J1 = 4.8 Hz, J2 = 8.8 Hz, 1H),
3.33−3.36 (m, 1H), 3.10 (s, 3H), 2.10−2.14 (m, 1H), 1.83−1.86 (m,
1H), 1.69−1.75 (m, 1H), 1.25−1.31 (m, 2H), 1.20 (d, J = 4 Hz, 3H),
1.18 (d, J = 4 Hz, 3H), 0.95 (t, J = 14.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 159.4, 152.4, 139.6, 136.7, 116.4, 87.3, 70.4, 42.3,
40.1, 32.2, 32.1, 25.4, 24.2, 22.8, 11.6; IR (KBr, cm−1) 2962, 1613,
1509, 1409, 1357, 1224, 1149, 1045, 919, 748; HRMS (ES+) calcd for
C15H2335ClN4NaO3S (M + Na)+, 397.1077 (found, 397.1064); calcd
for C15H2337ClN4NaO3S (M + Na)+, 399.1048 (found, 399.1020).
N-((2-Chlorothiazol-5-yl)methyl)-1-ethyl-6-methoxy-4-methyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 16a: yield, 15.9%; mp,
150.4−151.3 °C; 1H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H),
7.49 (s, 1H), 4.58 (s, 2H), 4.38 (dd, J1 = 4.8 Hz, J2 = 7.2 Hz, 1H),
3.35−3.42 (m, 2H), 3.28 (s, 3H), 1.98−2.05 (m, 1H), 1.39 (t, J = 7.2
Hz, 3H), 1.27−1.31 (m, 1H), 1.09−1.17 (m, 1H), 1.00 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 158.3, 141.4, 134.1, 117.8, 85.1,
53.8, 50.9, 46.5, 42.1, 33.4, 25.5, 17.7, 15.9; IR (KBr, cm−1) 2962.96,
1584.22, 1509.98, 1432.02, 1413.46, 1205.57, 1779.58, 1038.52,
942.00, 748.96; HRMS (ES+) calcd for C13H1935ClN4NaO3S (M +
Na)+, 369.0764 (found, 369.0758); calcd for C13H1937ClN4NaO3S (M
+ Na)+, 371.0735 (found, 371.0719).
N-((2-Chlorothiazol-5-yl)methyl)-6-ethoxy-1-ethyl-4-methyl-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 16b: yield, 15.5%; mp,
1
94.1−94.4 °C; H NMR (400 MHz, CDCl3) δ 11.14 (s, 1H), 7.46
(s, 1H), 4.52−4.69 (m, 2H), 4.52−4.69 (m, 1H), 3.48−3.53 (m, 2H),
3.33−3.38 (m, 2H), 1.93−1.97 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.31
(d, J = 6.8 Hz, 3H), 1.20−1.29 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.3, 153.1, 140.4, 135.7, 87.3, 63.8, 46.6,
42.0, 31.3, 27.0, 18.5, 15.8, 15.1; IR (KBr, cm−1) 2977, 1591, 1532,
1458, 1368, 1276, 1179, 1049, 949, 774; HRMS (ES+) calcd for
C14H22N4O3S35Cl (M + H)+, 361.1101 (found, 361.1103); calcd for
C14H22N4O3S37Cl (M + H)+, 363.1072 (found, 363.1072).
N-((2-Chlorothiazol-5-yl)methyl)-1-ethyl-4-methyl-3-nitro-6-pro-
poxy-1,4,5,6-tetrahydropyridin-2-amine 16c: yield, 15.0%; 1H NMR
(400 MHz, CDCl3) δ 11.13 (s, 1H), 7.46 (s, 1H), 4.55−4.69 (m, 2H),
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4.51 (t, J = 2.8 Hz, 1H), 3.42 (t, J = 6.4 Hz, 2H), 3.33−3.38 (m, 2H),
1.93−1.97 (m, 1H), 1.59−1.67 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.31
(d, J = 6.8 Hz, 3H), 1.20−1.29 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.3, 153.0, 140.4, 135.6, 117.1, 87.5,
70.2, 46.7, 42.0, 31.3, 27.0, 18.5, 22.9, 18.6, 15.8, 10.8; HRMS (ES+)
calcd for C15H24N4O3S35Cl (M + H)+, 375.1258 (found, 375.1256);
calcd for C15H24N4O3S37Cl (M + H)+, 377.1228 (found, 377.1268).
N-((2-Chlorothiazol-5-yl)methyl)-1-ethyl-6-isopropoxy-4-methyl-
3-nitro-1,4,5,6-tetrahydropyridin-2-amine 16d: yield, 13.8%; 1H
NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 7.47 (s, 1H), 4.57 (s,
2H), 4.50 (dd, J1 = 4.0 Hz, J2 = 6.8 Hz, 1H), 3.69−3.75 (m, 1H),
3.36−3.41 (m, 2H), 1.95−2.00 (m, 1H), 1.91−1.93 (m, 2H), 1.72−
1.79 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.17 (d, J = 6.0 Hz, 3H), 1.14
(d, J = 6.0 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.5, 153.2, 141.1, 134.5, 117.9, 82.7, 69.0, 46.3, 42.0, 31.5,
27.2, 23.0, 18.6, 15.9, 14.1; HRMS (ES+) calcd for C15H24N4O3S35Cl
(M + H)+, 375.1258 (found, 375.1255); calcd for C15H24N4O3S37Cl
(M + H)+, 377.1228 (found, 377.1230).
N-((2-Chlorothiazol-5-yl)methyl)-1,4-diethyl-6-methoxy-3-nitro-
1,4,5,6-tetrahydropyridin-2-amine 17a: yield, 14.6%; mp, 117.1−
119.5 °C; 1H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 7.48 (s, 1H),
4.59 (s, 2H), 4.38 (t, J = 6.0 Hz, 1H), 3.25−3.30 (m, 2H), 3.28 (s,
3H), 1.92−1.95 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 1.20−1.32 (m, 2H),
0.96−1.08 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.5, 153.3, 141.4, 133.9, 117.2, 85.0, 53.5, 46.2, 42.1, 31.7,
29.8, 24.5, 15.9, 11.3; IR (KBr, cm−1) 2955, 1584, 1509, 1450, 1376,
1261, 1187, 967, 748; HRMS (ES+) calcd for C14H21N4O3S35ClNa (M
+ Na)+, 383.0921 (found, 383.0913); calcd for C14H21N4O3S37ClNa
(M + Na)+, 385.0891 (found, 385.0879).
N-((2-Chlorothiazol-5-yl)methyl)-6-ethoxy-1,4-diethyl-3-nitro-
1,4,5,6-tetrahydropyridin-2-amine 17b: yield, 17.0%; mp, 103.1−
103.9 °C; 1H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 7.46 (s, 1H),
4.59 (s, 2H), 4.43 (dd, J1 = 5.6 Hz, J2 = 7.2 Hz, 1H), 3.40−3.51 (m,
2H), 3.32−3.40 (m, 2H), 1.90−1.94 (m, 1H), 1.37 (t, J = 7.2 Hz, 3H),
1.21 (t, J = 7.2 Hz, 3H), 1.14−1.29 (m, 2H), 0.93−1.06 (m, 2H), 0.82
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 153.2,
141.3, 134.1, 117.1, 84.0, 61.9, 46.0, 42.2, 31.8, 30.4, 24.5, 15.9, 15.3,
11.3; IR (KBr, cm−1) 2970.37, 1584.22, 1521.11, 1446.87, 1342.92,
1187.01, 1049.65, 956.84, 745.24; HRMS (ES+) calcd for
C15H24N4O3S35Cl (M + H)+, 375.1258 (found, 375.1251); calcd for
C15H24N4O3S37Cl (M + H)+, 377.1228 (found, 377.1241).
N-((2-Chlorothiazol-5-yl)methyl)-1,4-diethyl-3-nitro-6-propoxy-
1,4,5,6-tetrahydropyridin-2-amine 17c: yield, 13.8%; mp, 90.2−
91.5 °C; 1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 7.47 (s,
1H), 4.59 (s, 2H), 4.44 (dd, J1 = 5.2 Hz, J2 = 7.2 Hz, 1H), 3.36 (t, J =
6.8 Hz, 2H), 3.27−3.33 (m, 2H), 1.91−1.96 (m, 1H), 1.58−1.62 (m,
2H), 1.38 (t, J = 7.2 Hz, 3H), 1.20−1.33 (m, 2H), 0.98−1.07 (m, 2H),
0.94 (t, J = 7.2 Hz, 3H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 158.6, 153.2, 141.3, 134.1, 117.1, 84.0, 67.9, 46.0,
42.1, 31.8, 30.4, 24.5, 23.0, 15.9, 11.3, 10.7; IR (KBr, cm−1) 2955,
1587, 1517, 1342, 1298, 1227, 1135, 1038, 956, 748; HRMS (ES+)
calcd for C16H26N4O3S35Cl (M + H)+, 389.1414 (found, 389.1401);
calcd for C16H26N4O3S37Cl (M + H)+, 391.1385 (found, 391.1373).
N-((2-Chlorothiazol-5-yl)methyl)-1,4-diethyl-6-isopropoxy-3-
nitro-1,4,5,6-tetrahydropyridin-2-amine 17d: yield, 13.5%; 1H
NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 7.46 (s, 1H), 4.58 (s,
2H), 4.48 (dd, J1 = 5.2 Hz, J2 = 8.4 Hz, 1H), 3.34−3.42 (m, 2H),
3.24−3.27 (m, 1H), 1.89−1.95 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.18
(d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.0 Hz, 3H), 1.20−1.33 (m, 2H),
0.94−1.07 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.6, 153.2, 141.1, 134.4, 117.2, 82.8, 69.0, 46.0, 42.0, 31.9,
30.0, 27.2, 24.5, 23.0, 15.9, 11.3; HRMS (ES+) calcd for
C16H26N4O3S35Cl (M + H)+, 389.1414 (found, 389.1411); calcd for
C16H26N4O3S37Cl (M + H)+, 391.1385 (found, 391.1394).
Insecticidal Test for Cowpea Aphid (Aphis craccivora). The
insecticidal activities of title compounds against cowpea aphid (A.
craccivora) were tested according to the previously reported
procedure.5,16 Horsebean seedlings with 40−60 healthy apterous
adults were dipped in diluted solutions of the chemicals containing
Triton X-100 (0.1 mg L−1) for 5 s, and then the shoots were placed in
a conditioned room (25 1 °C, 50% relative humidity (RH)). Water
containing Triton X-100 (0.1 mg L−1) was used as control. The
mortality rates were assessed after 24 h. Each treatment had three
repetitions, and the data were corrected and subjected to probit
analysis.
Bioassay on the Repellent Effects on Cowpea Aphid (A.
craccivora). To understand the responses of aphid to title
compounds, a Y-tape selective olfactometer was used for examination
in the laboratory.17 Horsebean seedlings without aphids were dipped
in diluted solution of the chemicals containing Triton X-100 (0.1 mg
L−1) for 5 s and then allowed to dry. The treated horsebean seedlings
were put in one arm of the olfactometer, and the control ones were
put in the other side arm. Apterous adult aphids were transferred into
the third arm by brush. The olfactometer was covered with black cloth
in the conditioned room (25 1 °C, 50% RH). The number of adults
in each arm was counted 1 h later. Each treatment had three
repetitions, and the data were analyzed by ANOVA.
Insecticidal Test for Armyworm (Pseudaletia separata
Walker). The insecticidal activities of title compounds against
armyworm (P. separata Walker) were tested according to a previously
reported procedure18 by foliar application. Individual corn (Zea mays)
leaves were placed on moistened pieces of filter paper in Petri dishes.
The leaves were sprayed with the solution containing compounds and
allowed to dry. The dishes were infested with 10 second-instar larvae
and then placed in a conditioned room (25 1 °C, 50% RH); 48 h
later, the mortality rates were assessed. Each treatment had three
repetitions, and the data were corrected and subjected to probit
analysis as before.
RESULTS AND DISCUSSION
■
Synthesis. Two methods were tried to synthesize the
intermediate 23. Using method 1, the reaction was carried out
at 0 °C and the yield was 29.5%. By comparison with method 1,
method 2 had a higher yield of 38.1%. However, a precipitate of
Ag2S formed in the reaction, which needed additional workup.
Thus, method 1 was chosen to synthesize 23.
When the target compounds were synthesized, the reaction
was very complicated and there were many byproducts, which
resulted in <5% yield. To optimize this reaction, several kinds
of catalysts, including protonic acid and Lewis acid, such as
AlCl3, HCl, BF3, CH3COOH, and H2SO4, were studied. In
view of increasing yield (10%) and simplicity of workup,
BF3·Et2O was used as catalyst. The solvent of this reaction was
also optimized; various solvents such as polar and nonpolar
ones were employed, including MeCN, THF, DMF, alcohols,
and dichloromethane. The result showed that dichloromethane
was suitable to carry out the reaction. Furthermore, the reaction
temperature was the vital factor for the synthesis of titled
compounds. The reaction temperature was varied from 0 to 40
°C; it was observed that temperatures over 25 °C would lead to
the formation of much more corresponding hydroxyl,
eliminating byproducts, namely, 1,4-dihydropyridine analogues.
The reaction temperature must be controlled below 25 °C.
After optimization, the factors in this reaction, such as
temperature, catalyst, and solvent, were fixed and gave relatively
higher yield. For compounds 10a−13d, the yield reached 16.0−
32.7%, whereas the yields of 14a−17d were 13.4−17.0%.
Compared to the synthesis of compounds 10a−13d, the
synthesis of compounds 14a−17d was more difficult. Although
an improvement of reaction time and temperature was tried
Biological Assay. According to statistical requirements, the
bioassay was repeated three times at 25
1 °C. All compounds
were dissolved in N,N-dimethylformamide (AP, Shanghai Chemical
Reagent Co., Ltd., Shanghai, China) and diluted with water containing
Triton X-100 (0.1 mg L−1) to obtain series concentrations of 500.0,
250.0, and 125.0 mg L−1 and others for bioassays.
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Journal of Agricultural and Food Chemistry
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Figure 3. Mechanism to synthesize series 2.
and one-pot multicomponent reaction was also used to increase
the yield and simplify the process, and even microwave
synthesis was also carried out, it is still hard to get a higher yield
during the synthesis of chain-opening nitromethylene neon-
icotinoids with cis configuration.
from the horsebean seedling after 24 h. This observation
initiated our interest in investigating the repellent effects of
these compounds. We chose compound 11b as representative
and found that its repellent percentage to apterous adults was
66.4 8.6%, which is very interesting. There is no report of the
repellent activities of known neonicotinoids such as nitenpyr-
am, which has the same structure scaffold and does not have cis
configuration present in compound 10−13. Studies on the
mechanism of repellent effects of this series of compounds are
currently under investigation. This work would be helpful for
the discovery of new leading compounds.
The insecticidal activities of compounds 14a−17d of series 2
against cowpea aphid (A. craccivora) are shown in Table 3.
Compounds 14b, 14c, and 15c showed improved insecticidal
activity against cowpea aphid with LC50 values of 0.05681,
0.08422, and 0.03855 mmol L−1, respectively, compared to
Paichongding, a commercial cis configuration cyclic compound
with an LC50 of 0.09176 mmol L−1(Table 3).19 The
bioactivities increased by 1.1−2.4-fold. Moreover, compared
to other cyclic compounds with a pyridine (PYTP)19 or
thiazole ring (TZTP), with LC50 values of 0.26218 and 0.19001
mmol L−1, respectively, the bioactivities of chain-opening series
2 also increased. Although the bioactivities of series 2 against
cowpea aphid were lower than that of imidacloprid, the series 2
compounds could display better bioactivities against resistant
strain brown planthopper similar to other known cis
configuration analogues, such as Paichongding.
On the basis of our synthesis experience of this reaction, the
main reason for very low yield was supposed. As shown in
Figure 3, it was observed that the reaction not only for
compounds 10a−13d but also for 14a−17d finished with high
conversion monitored by TLC, but many spots of the product
were observed on the TLC plate, which almost became a long
line. A relatively low yield was obtained due to the
accompanying side reactions of Michael addition, cyclization
reaction, elimination reaction, and etherification. Several
byproducts containing intermediates T and hydroxyl-eliminat-
ing products were isolated by column chromatography, and
their structures were confirmed. Especially, the hydroxyl-
eliminating compounds were the main products in the reaction.
In addition, the conversion rate of the etherification reaction
was also very low. Therefore, it was difficult to synthesize and
separate target compounds. How to decrease the hydroxyl
elimination reaction was the key problem of synthesis. Further
optimization is in progress.
Biological Activities. Compounds 10a−13d in series 1
exhibited rather poor insecticidal activity against cowpea aphid
(A. craccivora) at 500 mg L−1. The insecticidal activities are
shown in Table 2, with 11b showing the highest insecticidal
activity of 31.8%. Compared with cyclic counterparts, these
chain-opening molecules in series 1 all exhibited much reduced
Aliphatic and aromatic substituents were available for R3 and
R4. On the basis of the study of Akayama and co-workers,
aliphatic substituted compounds exhibited higher insecticidal
activities than those bearing an aromatic group.20 Therefore,
aromatic substituents were not chosen in this work.
Table 2. Insecticidal Activities of Compounds 10a−13d
against Cowpea Aphid (Aphis craccivora)
The structural difference between compounds in series 1
(10a−13d) and 2 (14a−17d) was the substituent R3. When R3
is a hydrogen atom as in series 2, compounds exhibited better
activities than those with a methyl or ethyl group as in series 1.
It suggested that this position is important for the increase of
bioactivity of chain-opening cis configuration neonicotinoids
compounds.
At the same time, we also found that its substituent effect was
different from that in the structure of commercialized
nitenpyram. The effect of substituent of nitenpyram showed
that methyl and ethyl groups have good bioactivities, with an
LC95 value of 40 ppm against green rice leafhopper
planthopper, whereas replacing those groups with a hydrogen
atom decreases bioactivities, giving an LC95 value of >200
ppm.20 When R3 changed from a hydrogen atom to methyl and
then ethyl, the larger the substituent was, the lower the
A. craccivora mortality
(%)
A. craccivora mortality
(%)
compd
at 500 mg L−1
compd
at 500 mg L−1
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
16.2
17.7
24.3
23.7
15.3
27.6
31.8
27.2
25.8
19.5
12a
12b
12c
12d
12e
13a
13b
13c
13d
21.6
23.3
15.2
17.6
15.8
23.4
17.1
28.3
25.9
insecticidal activity against cowpea aphid.9 Interestingly, we
noted that the cowpea aphids fell down and crawled far away
328
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Journal of Agricultural and Food Chemistry
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pared with substituents R4, the influence of R2 on bioactivities is
less profound.
Table 3. Insecticidal Activities of Compounds 14a−c, 15a−d,
16b−d, and 17a−d against Cowpea Aphid (Aphis craccivora)
Because some of our nitromethylene neonicotinoids with
fixed cis configuration in previous work showed good
insecticidal activities against army worm, the insecticidal activity
of compounds 14a−c against armyworm (P. separata Walker)
at 500 mg L−1 was also measured. Mortalities of these three
compounds were all 100% with LC50 values at 0.40864,
0.21781, and 0.25702 mmol L−1, respectively. Although the
bioactivities were not as high as those of other cis configuration
neonicotiniods,21,22 they are still promising candidates for
further modifications against army worm (P. separata Walker).
In conclusion, two series of chain-opening nitromethylene
neonicotinoids with cis configuration were designed and
synthesized. Compared with cyclic ones, they showed obvious
differences. The bioassays showed that some of the compounds
exhibited unique repellent effects and other compounds
showed better insecticidal activities against cowpea aphid and
armyworm than cyclic compounds. Compound 15c exhibited
the highest insecticidal activity against cowpea aphid among the
synthesized compounds; the LC50 value was 0.03855 mmol L−1.
Further studies on the particular biological behavior of
compounds 10a−13d are underway.
AUTHOR INFORMATION
■
Corresponding Author
*(X.X.) Phone: +86-21-64252945. Fax: +86-21-64252603. E-
mail: xyxu@ecust.edu.cn. (Z.X.) Phone:+86-21-64253979. Fax:
+86-21-64252603. E-mail: zhipingxu@ecust.edu.cn.
Funding
This work was financially supported by the National Basic
Research Program of China (973 Program, 2010CB126100)
and the National High Technology Research and Development
Program of China (863 Program, 2011AA10A207). This work
was also partly supported by the National Key Technology
R&D Program of China (2011BAE06B01), Shanghai Founda-
tion of Science and Technology (09391911800,
10ZR1407300), National Science Foundation of China
(21002030), Shanghai Leading Academic Discipline Project,
Project B507, and Fundamental Research Funds for the Central
Universities and Special Fund for Agro-scientific Research in
the Public Interest (201103007).
bioactivity was. Substituents on the nitrogen atom of the
tetrahydropyridine ring (R4) were important for improving
activities of compounds 14a−17d, and different substituents
resulted in distinct difference of bioactivities. Especially, the
bioactivity with the methyl group was better than that with the
ethyl group. It also suggested that the sterics of R3 and R4 are
likely playing a role in enhancing bioactivity. More analogues
will be synthesized to further evaluate the substituent effect.
As for the substituent R2, an n-propyl group led to slightly
higher activity than an iso-propyl group did, whereas both are
much better than methyl or ethyl analogues as exhibited by
compounds 14a−c. Compounds 14b and 14c displayed
comparable LC50 values of f 0.5681 and 0.8422 mmol L−1,
respectively, which are considerably higher than that of
compound 14a. To further support this observation, other
compounds with n-propyl at R2 including compounds 15−17
all exhibit higher mortality, which displayed the same rule as the
ring-closing tetrahydropyridine compounds.19 However, com-
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