Synthesis of 1,3-dithiolane-containing nitromethene compounds and their biological activity as insecticides

Article abstract of DOI:10.1007/s11164-012-0737-0

1,3-Dithiolane-containing nitromethylene derivatives, as candidates for screening as neonicotinoid insecticides, were synthesized by reaction of compound (4) with 1,2-ethanedithiol. Compounds 7a-g were obtained via Mannich reaction of (E)-1-((1,3-dithiolan-2-yl)methyl)-2-(nitromethylene)imidazolidine (6), primary amines and formaldehyde. The synthesized compounds were identified by ¹H NMR, IR spectroscopy and elemental analysis. Preliminary bioassays indicated that most of the compounds had moderate insecticidal activity against Aphis craccivora. The relationship between molecular structure and biological activity is discussed.

Full text of DOI:10.1007/s11164-012-0737-0

Res Chem Intermed (2013) 39:2063–2070
DOI 10.1007/s11164-012-0737-0
Synthesis of 1,3-dithiolane-containing nitromethene
compounds and their biological activity as insecticides
Dongmei Li
Gaolei Wang
•
Zhongzhen Tian
•
Zhiping Xu
•
Received: 1 July 2012 / Accepted: 17 July 2012 / Published online: 1 August 2012
Ó Springer Science+Business Media B.V. 2012
Abstract 1,3-Dithiolane-containing nitromethylene derivatives, as candidates for
screening as neonicotinoid insecticides, were synthesized by reaction of compound
(
(
4) with 1,2-ethanedithiol. Compounds 7a–g were obtained via Mannich reaction of
E)-1-((1,3-dithiolan-2-yl)methyl)-2-(nitromethylene)imidazolidine (6), primary
1
amines and formaldehyde. The synthesized compounds were identified by H NMR,
IR spectroscopy and elemental analysis. Preliminary bioassays indicated that most
of the compounds had moderate insecticidal activity against Aphis craccivora. The
relationship between molecular structure and biological activity is discussed.
Keywords Neonicotinoid ꢀ Insecticides ꢀ 1,3-Dithiolane ꢀ Biological activity
Introduction
The neonicotinoids, with novel structures and mode of action on insect nicotinic
acetylcholine receptors (nAChR) [1], have become an important chemical class of
insecticides in recent decades [2]. Imidacloprid, acetamiprid, nitenpyram, clothi-
anidin, thiamethoxam, and dintefuran [3–7] had been registered as agricultural
chemicals for crop protection and veterinary pest control, and currently account for
over one-fifth of the world insecticide market [8–10]. All these insecticides have
D. Li ꢀ Z. Tian (&)
Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials,
School of Chemistry and Chemical Engineering, University of Jinan, 106 Jiwei Road,
Jinan 250022, People’s Republic of China
e-mail: Chm_tianzz@ujn.edu.cn
Z. Xu ꢀ G. Wang
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University
of Science and Technology, Shanghai 200237, People’s Republic of China
123

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D. Li et al.
high bioactivity against insects and low toxicity to non-target organisms, for
example mammals, birds, and aquatic animals [11–13].
Neonicotinoid insecticides have many molecular features in common. One
notable feature is that these compounds contain two sections—an electron-
withdrawing group and a heterocyclic group (Scheme 1). The electron-withdrawing
groups include C=NNO , C=CHNO , C=CHNO, C=NCN, and C=NCOCF . Among
2
2
3
these, the nitro group C=NNO is best [14]. The heteroatom in the heterocyclic
2
group enables hydrogen-bonding with receptor subsites and is, therefore, very
important in the bioactivity of the compounds [15]. In first-generation (subclass:
chloronicotinyl), second-generation (subclass: thianicotinyl), and third-generation
(
subclass: furanicotinyl) neonicotinoids a variety of alternative structures have been
found to be practicable, owing to the nitrogen atom in the pyridine and thiazole
rings and the oxygen atom in the tetrahydrofuran ring, all of which are very
important to bioactivity. For example, in the third-generation neonicotinids, the
nitrogen atoms in the pyridine and thiazole rings and the oxygen atom in the
tetrahydrofuran ring are very important to their bioactivity. So, introduction of a
heteroatom into the heterocycle will affect the activity of the target compounds.
Herein we report our results from the design and synthesis of a series of new
pesticide-like compounds containing the 1,3-dithiolane ring. In these compounds,
the heteratom ring in neonicotinoids was replaced by the 1,3-dithiolane structure
and the hydrophobicity was adjusted by N-substituted alkyl modification.
1
The structures of the compounds were characterized by IR and H NMR
spectroscopy and elemental analysis. Preliminary bioassays indicate that most of the
new compounds have moderate insecticidal activity against pea aphids.
Results and discussion
Synthesis
The objective of this work was to develop a synthetic strategy for compound 5 and 6
and analogues of 7. The initial route investigated was that in Scheme 2, in which the
intermediate 2-(chloromethyl)-1,3-dithiolane was synthesized by the reaction of
1
,2-ethanedithiol and compound 2 with a catalytic amount of conc. HCl. We
attempted to prepare compound 6 from 2-(chloromethyl)-1,3-dithiolane and
-(nitromethylene)imidazolidine in the presence of strong base (NaH), but the
2
experiments showed that the product was formed in low yield. In the second route,
the intermediate compound 4 was synthesized first by reaction of 1,1-
Scheme 1 Structure of neonicotinoid insecticides
1
23

The synthesis and biological activities
2065
bis(thiomethyl)-2-nitroethylene with 3, which was obtained via reaction of 2-chloro-
,1-dimethoxyethane and ethylenediamine in the presence of potassium carbonate.
1
In this reaction, use of ethylenediamine on threefold excess over 2-chloro-1,1-
dimethoxyethane avoided preparation of the disubstituted by-product. Reaction of 4
with 1,2-ethanedithiol furnished compound 6 in good yield, as shown in Scheme 3.
Products (7a–7g) in this study were obtained via Mannich reaction, by stirring
compound 6 with the corresponding primary amine and formaldehyde in THF
1
Scheme 4). The structures of the title compounds were well characterized by H
(
NMR and IR spectroscopy and elemental analysis.
Insecticidal activity
The compounds were screened for insecticidal activity against Aphis craccivora.
Most had moderate insecticidal activity at 500 mg/L. The results are listed in
Table 1. Compound 5, 6, 7a, 7b, and 7c had 50–80 % insecticidal activity at
500 mg/L and compounds 7d, 7e, and 7f had 30–50 % activity at 500 mg/L.
Compound 6 had greater insecticide activity, and the insecticidal activity of 7e was
very low, owing to substitution with longer alkyl group.
Scheme 2 Synthetic route of the compound 6
Scheme 3 Another synthetic route of the compound 5 and 6
Scheme 4 General synthetic
route for the compound 7
123

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D. Li et al.
Table 1 Insecticidal activity of
new compounds 6, 7, and 8a–g
against Aphis craccivora
Compound
no.
–R
Concentration
(mg/L)
Mortality
(%)
4
5
6
500
500
500
500
500
500
500
500
500
500
0
–
56.8
78.1
64.9
68.5
50.3
31.0
8.1
–
7
7
7
7
7
7
7
a
b
c
d
e
f
–CH
–CH
–CH
3
2
2
CH
3
2
CH
CH
3
2
–CH(CH
–CH
–C(CH
–CH
3
)
2
2
CH
2
CH
CH
3
3
)
3
38.2
30.8
g
2
COOEt
Experimental
Physical measurements
All melting points (mp) were obtained with a B u¨ chi B540 melting point apparatus
1
and are uncorrected. H NMR spectra were recorded on a Bruker AV-400
(
400 MHz) spectrometer with TMS as internal reference and CDCl as solvent.
3
Chemical shifts are reported as d (parts per million) values. Combustion analysis for
determination of elemental composition was performed with an Elementar vario EL
III. GC–MS was performed with a Micromass GCT CA055 at an electron energy of
7
0 eV. Infrared spectra were measured on a Nicolet FT-IR-20SX instrument using
potassium bromide (KBr) disks. All chemicals or reagents were purchased from
standard commercial suppliers.
0
N -(2,2-dimethoxyethyl)ethane-1,2-diamine (3)
2
-Chloro-1,1-dimethoxyethane (12.5 g 0.1 mol) was added to a solution of
ethylenediamine (18 g, 0.3 mol) and potassium carbonate (13.8 g, 0.1 mol) in
-methoxyethanol (50 mL). The mixture was heated to 100 °C for 7 h then cooled
2
to room temperature, and the resulting solution was filtered to remove insoluble
materials. The filtrate was concentrated under vacuum at a bath temperature of
8
0 °C to leave 12.7 g of a yellow liquid. Yield: 86 %; GC–MS m/z (%): 148.1
?
[M ]). The residue was used in further reactions without purification.
(
2
-(Chloromethyl)-1,3-dithiolane (8)
1,2-Ethanedithiol (22.3 g, 236 mmol) and concentrated hydrochloric acid (15 mL)
were placed in a 500-mL round-bottomed flask. After cooling of the mixture to
0
2
°C, 2-chloro-1,1-dimethoxyethane (32.5 g, 261 mmol) was added dropwise over
h. After an additional 30 min, the mixture was warmed to room temperature and
stirred for an additional 3 h. CH Cl (60 mL) and water (40 mL) were added to the
2
2
1
23

The synthesis and biological activities
2067
mixture. The aqueous layer was separated and extracted with CH Cl (40 mL). The
2
2
combined organic layers were washed with water (40 mL), saturated NaHCO3
solution (40 mL), and brine (40 mL) and then dried. Concentration under reduced
pressure and bulb-to-bulb distillation at 20–120 °C and 0.25 mm [16] yielded
?
9.1 g (54 %) of 8 as a colorless oil. GC–MS: 154 (M ).
1
(
E)-1-((1,3-Dithiolan-2-yl)methyl)-2-(nitromethylene)imidazolidine (6)
NaH (60 %, 0.18 g, 4.4 mmol) was added to a solution of 2-(nitromethylene)im-
idazolidine 12 (0.52 g, 4 mmol) in DMF (15 mL) and the resulting mixture was
stirred at room temperature for 30 min. 2-(Chloromethyl)-1,3-dithiolane (0.77 g,
5
4
mmol) in DMF (10 mL) was then added dropwise and the mixture was stirred at
5–50 °C for 5 h. Water (40 mL) was added, and the solution was extracted with
CH Cl (4 9 30 mL). The combined organic layers were washed with saturated
2
2
brine (2 9 30 mL), dried over Na SO , concentrated under reduced pressure, and
4
2
the residue was purified by column chromatography, eluting with dichloromethane–
methanol (20:1), giving the title compounds 6: 100 mg, yield, 10 %; mp
1
1
44.7–145.6 °C; H NMR (400 MHz, CDCl ): d (ppm) 3.27 (s, 4H, SCH CH S),
3
2
2
3
.36 (d, J = 6.8 Hz, 2H, NCH -dithiolane), 3.81–3.87 (m, 4H, NCH CH N), 4.64
2
2
2
(
cm ) 3287, 3110, 2932, 1581, 1554, 1384; Anal. Calcd for C H N O S : C,
t, J = 7.0 Hz, 1H, SCHS), 6.60 (s, 1H, =CHNO ), 8.70 (s, 1H, NH); IR (KBr,
2
-
1
8
13 3 2 2
3
8.85; H, 5.30; N, 16.99, Found: C, 38.87; H,5.32; N, 16.70.
(
E)-1-(2,2-Dimethoxyethyl)-2-(nitromethylene)imidazolidine (4)
A solution of compound 3 (7.41 g, 50 mmol) and 1,1-bis(thiomethyl)-2- nitroeth-
ylene (8.26 g, 50 mmol) in 50 mL ethanol was heated under reflux for 8 h then
cooled to room temperature. The solid crystalline product was isolated by filtration,
washed with ethanol, and dried to give the corresponding product as a pale yellow
1
solid: 8.82 g, yield, 81 %; m.p. 115.3–116.3 °C; H NMR (400 MHz, CDCl ): d
3
(
NCH CH N), 4.46 (t, J = 5.0 Hz, 1H, OCHO), 6.58 (s, 1H, =CHNO ), 8.86 (s, 1H,
ppm) 3.24 (d, J = 4.8 Hz, 2H, NCH ), 3.43 (s, 6H, 2CH ), 3.78 (s, 4H,
2 3
2
2
2
-
1
NH); IR (KBr, cm ) m: 3336, 3130, 2960, 2912, 2836, 1605, 1572, 1391; Anal.
Calcd for C H N O : C, 44.23; H, 6.96; N, 19.34, Found: C, 44.35; H, 6.99; N,
1
8
15 3 4
9.32.
(
E)-1-(2,2-bis(Methylthio)ethyl)-2-(nitromethylene)imidazolidine (5)
Methanethiol (2.9 g, 60 mmol) in acetonitrile (50 mL) was mixed with conc HCl
0.5 mL). A solution of (E)-1-(2,2-dimethoxyethyl)-2-(nitromethylene)imidazoli-
(
dine 4 (5.5 g, 25 mmol) in acetonitrile (25 mL) was added dropwise and the
mixture was stirred at 45–50 °C for 2 h. The mixture was added to water (50 mL),
adjusted to pH 7 with 50 % aqueous NaOH, then extracted with CH Cl
2
2
(
20 mL 9 3). The combined organic layers were washed with saturated brine
(
column chromatography, eluting with dichloromethane–methanol (40:1), to give a
20 mL), dried over Na SO , concentrated under reduced pressure, and purified by
2
4
123

2068
D. Li et al.
1
pale yellow solid 5: 4.7 g, yield, 76 %; mp 136.8–137.9 °C; H NMR (400 MHz,
CDCl ): d (ppm) 2.09 (s, 6H, CH ), 3.37 (d, J = 6.8 Hz, 2H, NCH ), 3.75–3.85 (m,
3
3
2
-
H, NCH CH N, SCHS), 6.47 (s, 1H, =CHNO ), 8.61 (s, 1H, NH). IR (KBr, cm )
1
5
3
6
2 2 2
280, 3111, 2946, 1583, 1560, 1386; Anal. Calcd for C H N O S : C, 38.53; H,
8
13 3 2 2
.06; N, 16.85, Found: C, 38.47; H,6.12; N, 16.73.
(
E)-1-((1,3-Dithiolan-2-yl)methyl)-2-(nitromethylene)imidazolidine (6)
Following the above method furnished a pale yellow solid, 6: yield, 83 %;
General synthetic procedure for (7a–g)
A solution of formaldehyde (1.6 mmol) and the corresponding amine (0.83 mmol)
was added to a solution of compound 6 (0.75 mmol) in ethanol (5 mL). The
resulting mixture was stirred overnight, concentrated under vacuum, and purified by
vacuum column chromatography on a silica gel to give the desired product.
1
Data for 7a: yield, 72 %; mp 138.2–138.9 °C; H NMR (400 MHz, CDCl ): d
3
(
dithiolane), 3.72–3.77 (m, 4H, NCH CH N), 3.90 (s, 4H, N–CH NCH –ene), 4.82
ppm) 2.42 (s, 3H, CH ), 3.16 (s, 4H, SCH CH S), 3.61–3.66 (m, 2H, NCH –
3 2 2 2
2
2
2
2
-
t, J = 7.0 Hz, 1H, SCHS); IR (KBr, cm ) 2871, 2795, 1559, 1519, 1370; Anal.
1
(
Calcd for C H N O S : C, 43.69; H, 6.00; N, 18.53, Found: C, 43.65; H,6.02; N,
1
1 18 4 2 2
1
8.57.
Data for 7b: yield, 81 %; mp 126.8–127.8 °C; H NMR (400 MHz, CDCl ): d
1
3
(ppm) 1.17 (t, J = 7.2 Hz, 3H, CH ), 2.65 (q, J = 7.1 Hz, 2H, CH N), 3.24 (s, 4H,
3 2
SCH CH S), 3.63–3.68 (m, 2H, NCH –dithiolane), 3.82–3.86 (m, 4H,
2
2
2
NCH CH N), 3.93–3.97 (m, 2H, NCH -ene), 4.01 (s, 2H, NCH N), 4.91 (t,
2
2
2
2
-
J = 7.2 Hz, 1H, SCHS); IR (KBr, cm ) 2865, 2798, 1567, 1518, 1378; Anal.
1
Calcd for C H N O S : C, 45.55; H, 6.37; N, 17.71, Found: C, 45.52; H, 6.36; N,
1
2 20 4 2 2
1
7.75.
Data for 7c: yield, 83 %; mp 109.6–110.4 °C; H NMR (400 MHz, CDCl ): d
1
3
(
ppm) 0.86 (t, J = 7.2 Hz, 3H, CH ), 1.46–1.51 (m, 2H, CH ), 2.45 (t, J = 7.4 Hz,
3 2
2
3
H, CH N), 3.16 (s, 4H, SCH CH S), 3.57–3.62 (m, 2H, NCH –dithiolane),
2 2 2 2
.75–3.77 (m, 4H, NCH CH N), 3.87–3.91 (m, 2H, NCH -ene), 3.95 (s, 2H,
2
2
2
-
1
NCH N), 4.83 (t, J = 7.2 Hz, 1H, SCHS); IR (KBr, cm ) 2913, 2811, 1559, 1534,
2
1
H, 6.72; N, 17.01.
352; Anal. Calcd for C H N O S : C, 47.25; H, 6.71; N, 16.95, Found: C, 47.19;
13 22 4 2 2
1
Data for 7d: yield, 79 %; mp 142.0–142.9 °C; H NMR (400 MHz, CDCl ): d
3
(
SCH CH S), 3.60–3.64 (m, 2H, NCH –dithiolane), 3.70 (d, J = 3.6 Hz, 2H,
ppm) 1.07 (d, J = 6.4 Hz, 2CH ), 2.82–2.91 (m, 1H, CHN), 3.16 (s, 4H,
3
2
2
2
NCH CH N), 3.77 (s, 2H, CH N–ene), 3.91 (t, J = 9.0 Hz, 2H, NCH CH N), 3.96
2
2
2
2
2
-
1
(
s, 2H, NCH N), 4.87 (t, J = 7.2 Hz, 1H, SCHS); IR (KBr, cm ) 2969, 2924,
2
2
Found: C, 47.20; H, 6.80; N, 17.89.
872, 1540, 1353; Anal. Calcd for C H N O S : C, 47.25; H, 6.71; N, 16.95,
13 22 4 2 2
1
Data for 7e: yield, 82 %; mp 93.3–94.2 °C; H NMR (400 MHz, CDCl ): d
3
(
CH ), 2.48 (t, J = 7.4 Hz, 2H, CH N), 3.16 (s, 4H, SCH CH S), 3.58–3.61 (m, 2H,
ppm) 0.86 (t, J = 7.2 Hz, 3H, CH ), 1.24–1.32 (m, 2H, CH ), 1.41–1.48 (m, 2H,
3
2
2
2
2
2
1
23

The synthesis and biological activities
2069
NCH –dithiolane), 3.75–3.76 (m, 4H, NCH CH N), 3.87–3.91 (m, 2H, N–CH –
2
2
2
2
-
ene), 3.95 (s, 2H, NCH N), 4.82 (t, J = 7.2 Hz, 1H, SCHS); IR (KBr, cm ) 2957,
1
2
2
1
925, 2857, 2818, 1549, 1364; Anal. Calcd for C H N O S : C, 48.81; H, 7.02; N,
14 24 4 2 2
6.26, Found: C, 48.76; H, 6.99; N, 16.32.
Data for 7f: yield, 76 %; mp 140.3–141.0 °C; H NMR (400 MHz, CDCl ): d
1
3
(
NCH CH N), 3.85 (s, 2H, NCH –dithiolane), 3.95–4.00 (m, 4H, NCH NCH -
ppm) 1.18 (s, 9H, 3CH ), 3.22 (s, 4H, SCH CH S), 3.66–3.82 (m, 4H,
3 2 2
2
2
2
2
2
-
ene), 5.01 (t, J = 7.0 Hz, 1H, SCHS); IR (KBr, cm ) 2977, 2925, 2883, 2824,
1
1
Found: C, 48.83; H, 7.13; N, 16.19.
569, 1527, 1341; Anal. Calcd for C H N O S : C, 48.81; H, 7.02; N, 16.26,
2
1
4
24
4
2
1
Data for 7g: yield, 81 %; mp 150.6–151.5 °C; H NMR (400 MHz, CDCl ): d
3
(
dithiolane), 3.59 (t, 2H, J = 8.8 Hz, NCH CH N), 3.75 (d, J = 7.2 Hz, 2H,
ppm) 1.22 (t, J = 7.0 Hz, 3H, CH ), 3.16 (s, 4H, SCH CH S), 3.36 (s, 2H, NCH –
3
2
2
2
2
2
NCH CH N), 3.87–3.91 (m, 4H, NCH N–CH N–ene), 4.08 (s, 2H, OCOCH N),
2
2
2
2
2
4
.15 (q, J = 7.1 Hz, 2H, CH OCO), 4.84 (t, J = 7.0 Hz, 1H, SCHS); IR (KBr,
2
-
1
cm ) 2936, 2875, 2813, 1741, 1570, 1358, 1248, 1051; Anal. Calcd for
C H N O S : C, 44.90; H, 5.92; N, 14.96, Found: C, 44.80; H, 5.89; N, 14.97.
1
4 22 4 4 2
Biological assay
All compounds were dissolved in acetone and diluted with water containing Triton
-
1
-1
X-100 (0.1 mL L ) to obtain series concentrations of 500.0 mg L and others for
bioassays.
Pea aphids (Aphis craccivora) were dipped in accordance with a slightly
modified FAO dip test. Tender shoots of soybean with 40–60 healthy apterous
adults were dipped in dilute solutions of the chemicals containing Triton X-100
-
1
(
0.1 mL L ) for 5 s, the superfluous fluid was removed, and the shoots were placed
in a conditioned room (23 ± 1 °C, RH 50 %). Water containing Triton X-100
-
1
0.1 mL L ) was used as control. Mortality was assessed after 24 h, and data were
(
corrected and subjected to probit analysis.
Acknowledgments We thank the National Science Foundation China Program (grant 20902037), the
Promotive Research Fund for Excellent Young and Middle-aged Scientists of Shandong Province (grant
BS2010NY001), and the Opening Fund of Shanghai Key Laboratory of Chemical Biology (grant
SKLCB-2008-08).
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