Synthesis of imidacloprid analogues from novel chloronicotinaldehydes

Article abstract of DOI:10.1002/jhet.208

(Chemical Equation Presented) A serious of imidacloprid analogues have been synthesized from novel chloronicotinaldehydes. The chloronicotinaldehydes are the important synthons obtained from Vilsmeier reaction of various enamides. Thus synthesized imidacloprid analogues are new heterocyclic compounds obtained in very good yields.

Full text of DOI:10.1002/jhet.208

November 2009
Synthesis of Imidacloprid Analogues from Novel
Chloronicotinaldehydes
1213
B. Gangadasu,a B. China Raju,b* and V. Jayathirtha Raoa,c
aOrganic Chemistry Division-II, Indian Institute of Chemical Technology,
Uppal Road, Tarnaka, Hyderabad 500 607, India
bOrganic Chemistry Division-I, Indian Institute of Chemical Technology,
Uppal Road, Tarnaka, Hyderabad 500 607, India
cNational Institute of Pharmaceutical Education and Research, Balanagar,
Hyderabad 500 037, India
*E-mail: chinarajuiict@yahoo.co.in
Received November 11, 2008
DOI 10.1002/jhet.208
Published online 5 November 2009 in Wiley InterScience (www.interscience.wiley.com).
A serious of imidacloprid analogues have been synthesized from novel chloronicotinaldehydes. The
chloronicotinaldehydes are the important synthons obtained from Vilsmeier reaction of various enam-
ides. Thus synthesized imidacloprid analogues are new heterocyclic compounds obtained in very good
yields.
J. Heterocyclic Chem., 46, 1213 (2009).
INTRODUCTION
RESULTS AND DISCUSSION
Neonicotinoids [1] are used worldwide for controlling
insects because of their low mammalian toxicity, po-
tency, and broad insecticidal and systemic properties.
Imidacloprid (Fig. 1) is a new systemic insecticide for
crop protection [2], and it is the first chloronicotinyl
nonnatural insecticide, which consists of 2-(N-nitroimi-
no)imidazolidine coupled with (6-chloropyridin-3-
yl)methyl (CPM) residue [3]. It belongs to chloronico-
tinyl subclass of nicotinoids, which are a novel and
distinct chemical class of insecticides with remarkable
chemical and biological properties. It has a novel mode
of action—binding to the nicotinergic acetylcholine re-
ceptor in the postsynaptic region of the insect nerve.
Because of the importance of neonicotinoids, several
imidacloprid analogues has been synthesized and
reported in the literature [4].
The imidacloprid analogues reported in this article are
synthesized from substituted chloronicotinaldehydes by
Vilsmeier reaction of various enamide substrates accord-
ing to our earlier reported method [5a]. Thus, prepared
chloronicotinaldehydes were an important synthons used
for various organic transformations such as synthesis of
2-chloro-5-methylpyridine-3-carbaldehydeimines (Schiff
bases) [5b], Baylis-Hillman adducts [5e], reactions with
cyclic enones [5c], and conversion of Baylis-Hillman
adducts to synthesis of biologically important quinolines
[5d]. As mentioned in the Scheme 1, the carboxalde-
hydes (1a–k) were subjected for reduction using sodium
borohydride in methanol to give corresponding alcohols
(2a–k). Under these reaction conditions, all the alde-
hydes (1a–k) were smoothly converted to alcohols (2a–
k) without disturbing other functional groups present in
the compounds. These alcohols (2a–k) were then con-
verted to corresponding chlorides (3a–k) by using thi-
onyl chloride, with catalytic amounts of dimethylforma-
mide (DMF) as chlorinating agent in heptane solvent.
The DMF used in catalytic amounts enhances the rate of
reaction, subsequently, the reaction proceeds efficiently
because of the formation of a complex between thionyl
chloride and DMF, which actually acts as chlorinating
agent.
Synthesis of large number of new heterocyclic mole-
cules and their bioevaluation in agrochemical and phar-
maceutical areas is the worldwide current interest. Dis-
covery of new insecticides is an ongoing process and
challenging area for organic chemists. Because of our
continuous interest on synthesis of bioactive heterocyclic
molecules [5a–g], we report the synthesis of novel imi-
dacloprid derivatives from the substituted chloronicoti-
naldehydes in very good yields.
C
V
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B. Gangadasu, B. C. Raju, and V. J. Rao
Vol 46
phy (TLC) on precoated silica gel 60 F254 (mesh); spots were
visualized under UV light. Merck silica gel (60–120; 100–200
mesh) was used for chromatography.
General procedure for the synthesis of 2-chloro-5/6-sub-
stituted pyridyl methanol (2a–k). Methyl 6-chloro-5-formyl-
2-pyridinecarboxylate (1j; 200 mg, 0.0012 mol) was dissolved
in methanol solvent, and sodium borohydride (15 mg, 0.00039
moles) was added slowly at 0ꢀC over a period of 15 min. The
reaction was monitored by TLC, and after completion of the
reaction, the reaction mixture was quenched with saturated am-
monium chloride solution, solvent was removed under reduced
pressure, and the residue was extracted with dichloromethane
and obtained methyl-6-chloro-5-(hydroxymethyl)-2-pyridine-
carboxylate (2j) on column chromatography. All the alcohols
were synthesized by using the similar procedure.
(2-Chloro-5-methyl-3-pyridyl)methanol (2a). Yield: 92%,
solid; mp: 59–61ꢀC. 1H NMR (CDCl3): d 2.35 (s, 3H, CH3),
4.73 (s, 2H, -CH2OH), 7.66 (s, 1H, heteroaromatic), 8.07 (s,
1H, heteroaromatic). EI-MS (m/z): 157 (90) (Mþ), 142 (23),
130 (9), 122 (100), 106 (20), 99 (4), 92 (57), 78 (10), 65 (25),
51 (8), 39 (14), 31 (3). UV: kmax ¼ 268 nm in acetonitrile. IR
(KBr): m ¼ 3325, 2969, 2932, 2874, 1568, 1432, 1399, 1355,
1164, 1083, 1044, 904, 731 cmꢁ1. Anal. Calcd for C7H8ClNO:
C, 53.35; H, 5.12; N, 8.89. Found: C, 53.39; H, 5.19; N, 8.72.
(2-Chloro-5-ethyl-3-pyridyl)methanol (2b). Yield: 91%,
solid; mp: 62–64ꢀC. 1H NMR (CDCl3): d 1.31 (t, 3H, CH3),
2.65 (q, 2H, CH2), 4.75 (s, 2H, CH2OH), 7.73 (s, 1H, heteroar-
omatic), 8.09 (s, 1H, heteroaromatic). EI-MS (m/z): 171 (50)
(Mþ), 174 (40), 154 (100), 140 (5), 91 (20), 77 (15). UV: kmax
¼ 272 nm in acetonitrile. IR (KBr): m ¼ 3330, 2960, 2935,
2870, 1575, 1340, 1160, 1090, 1040, 906, 735 cmꢁ1. Anal.
Calcd for C8H10ClNO: C, 55.99; H, 5.87; N, 8.18. Found: C,
56.02; H, 5.84; N, 8.21.
Figure 1. Imidacloprid.
The formed chlorides (3a–k) were allowed to react
with nitroimino imidazole moiety (4) in acetonitrile
using potassium carbonate and CsCl (5 mol%) under
reflux conditions to give corresponding imidacloprid
analogues (5a–k, Scheme 2) in very good yields. Thus
prepared imidacloprid analogues (5a–k) are new com-
pounds and are characterized by spectral data.
The 2-nitroiminoimidazole (4) is synthesized from
ethylenediamine and nitroguanidine in the presence of
hydrochloric acid as per our reported procedure [6]. In
conclusion, the imidacloprid analogues have been syn-
thesized from chloronicotinaldehydes in very good
yields. Thus prepared new heterocyclic compounds are
well characterized by spectral data. To achieve these tar-
get molecules, the important synthons such as chloroni-
cotinaldehydes and nitraminoimidazolidine were used to
complete the imidacloprid analogues.
(2-Chloro-5-propyl-3-pyridyl)methanol (2c). Yield: 90%,
solid; mp: 64–65ꢀC. 1H NMR (CDCl3): d 0.9 (t, 3H, CH3),
1.7 (m, 2H, CH2), 2.64 (t, 2H, CH2), 4.75 (s, 2H, CH2OH),
7.73 (s, 1H, heteroaromatic), 8.09 (s, 1H, heteroaromatic).
EI-MS (m/z): 185.
(2-Chloro-5-isopropyl-3-pyridyl)methanol (2d). Yield: 90%,
solid; mp: 70–72ꢀC. 1H NMR (CDCl3): d 1.2–1.4 (m, 6H,
2CH3), 3.20 (m, 1H, CH), 4.75 (s, 2H, CH2OH), 7.73 (s, 1H,
heteroaromatic), 8.09 (s, 1H, heteroaromatic). EI-MS (m/z):
185.
EXPERIMENTAL
1H-NMR and 13C-NMR spectra were recorded on a Varian,
Gemini 200 and Avance 300 MHz spectrometer in CDCl3 with
TMS as internal standard. Infrared (IR) spectra were recorded
on Nicollet 740 FT spectrometer. EI-MS obtained on 7070H
spectrometer operating at 70 eV using a direct inlet system.
Melting points were determined in open glass capillary tubes
on a Metler FP 51 melting point apparatus and are uncor-
rected. The CHN analyses were recorded on Vario EL ana-
lyzer. All reactions were monitored by thin layer chromatogra-
(2-Chloro-5-pentyl-3-pyridyl)methanol (2e). Yield: 87%,
solid; mp: 58–60ꢀC. 1H NMR (CDCl3): d 0.9 (t, 3H, CH3),
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
Synthesis of Imidacloprid Analogues from Novel Chloronicotinaldehydes
1215
Scheme 2
1.38 (m, 4H, 2CH2), 1.70 (q, 2H, CH2), 2.7 (t, 2H, CH2), 4.75
(s, 2H, CH2OH), 7.73 (s, 1H, heteroaromatic), 8.09 (s, 1H, het-
eroaromatic). EI-MS (m/z): 213.
Calcd for C8H8ClNO3: C, 47.76; H, 4.00; N, 6.95. Found: C,
47.69; H, 4.11; N, 6.99.
Methyl-6-chloro-5-(hydroxymethyl)-3-methyl-2-pyridinecar-
boxylate (2k). Yield: 91%, Solid; mp: 86–88ꢀC. 1H NMR
(CDCl3): d 2.57 (s, 3H, CH3), 3.93 (s, 3H, OCH3), 4.78 (s,
2H, CH2OH), 7.78 (s, 2H, heteroaromatic). EI-MS (m/z): 215
(Mþ) (55), 200 (5), 183 (100), 157 (70), 137 (11), 126 (20),
92 (17), 65 (11), 51 (3), 39 (6). UV: kmax ¼ 282 nm. IR
(KBr): m ¼ 3468, 1705, 1440, 1406, 1327, 1243, 1120, 1063,
722 cmꢁ1. Anal. Calcd for C9H10ClNO3: C, 50.23; H, 4.67; N,
6.50. Found: C, 50.14; H, 4.68; N, 6.46.
General procedure for the synthesis of 2-chloro-3-chloro-
methyl-5/6-substituted pyridines (3a–k). Methyl-6-chloro-5-
(hydroxymethyl)-2-pyridinecarboxylate (2j) (200 mg, 0.0009
moles) was dissolved in heptane (50 mL) and added one drop
of DMF. The reaction mixture was heated to 60–65ꢀC. Thionyl
chloride (150 mg; 0.00135 mol) was added dropwise to the
hot reaction mixture. After completion of the addition, the
temperature was raised to 80ꢀC and maintained for 2 h. Pro-
gress of the reaction was monitored by TLC. The organic sol-
vent was removed under reduced pressure, and obtained crude
(2-Chloro-5-phenyl-3-pyridyl)methanol (2f). Yield: 90%,
solid; mp: 89–91ꢀC. 1H NMR (CDCl3): d 4.85 (s, 2H,
-CH2OH), 7.46 (m, 3H, aromatic), 7.59 (m, 2H, aromatic),
8.08 (m, 1H, heteroaromatic), 8.55 (m, 1H, heteroaromatic).
EI-MS (m/z): 219 (100) (Mþ), 184 (45), 166 (5), 154 (38), 140
(5), 127 (24), 115 (9), 102 (8), 77 (10). UV: kmax ¼ 254 nm
in acetonitrile. IR (KBr): m ¼ 3420, 2240, 1665, 1520, 1370,
1037, 1030, 760 cmꢁ1. Anal. Calcd for C12H10ClNO: C,
65.75; H, 4.56; N, 6.39. Found: C, 65.66; H, 4.62; N, 6.36.
[2-Chloro-5-(4-methoxyphenyl)-3-pyridyl]methanol (2g). Yield:
94%, solid; mp: 63–64ꢀC. 1H NMR (CDCl3): d 3.76 (s, 3H,
OCH3), 4.62 (s, 2H, CH2OH), 6.93 (d, 2H, aromatic), 7.49 (d, 2H,
aromatic), 8.07 (s, 1H, heteroaromatic), 8.34 (s, 1H, heteroaro-
matic). EI-MS (m/z): 249 (Mþ) (100), 206 (13), 179 (25), 162
(60), 137 (70), 105(55), 66 (100), 43 (80). UV: kmax ¼ 272 nm in
acetonitrile. IR (KBr): m ¼ 3423, 2253, 2127, 1653, 1516, 1433,
1378, 1027, 764 cmꢁ1. Anal. Calcd for C13H12ClNO2: C, 62.65;
H, 4.82; N, 5.62. Found: C, 62.61; H, 4.84; N, 5.71.
(2-Chloro-5-methyl-6-phenyl-3-pyridyl)methanol (2h). Yield:
96%, solid; mp: 78–80ꢀC, 1H NMR (CDCl3): d 2.34 (s, 3H,
CH3), 4.71 (s, 2H, CH2OH), 7.35–7.45 (m, 5H), 7.69 (s, 1H,
heteroaromatic). EI-MS (m/z): 233 (42) (Mþ), 232 (100), 196
(5), 167 (10), 115 (6), 77 (4). UV: kmax ¼ 284 nm acetonitrile.
IR (KBr): m ¼ 3384, 3059, 2924, 2856, 1591, 1550, 1415,
1054, 701 cmꢁ1. Anal. Calcd for C13H12ClNO: C, 66.95; H,
5.18; N, 5.99. Found: C, 66.91; H, 5.22; N, 6.01.
Ethyl-6-chloro-5-(hydroxymethyl)-2-phenylnicotinate (2i). Yield:
90%, light yellow liquid. 1H NMR (CDCl3): d 1.12 (t, 3H,
CH3), 4.20 (q, 2H, CH2), 4.80 (s, 2H, CH2OH), 7.42 (m, 3H),
7.60 (m, 2H), 8.76 (s, 1H, heteroaromatic). EI-MS (m/z): 291
(15) (Mþ), 262 (100), 246 (37), 218 (6), 190 (6), 127 (7). UV:
kmax ¼ 252 nm acetonitrile. IR (KBr): m ¼ 3443, 3269, 2985,
2922, 2853, 1732, 1540, 1431, 1305, 1221, 1134, 1016, 701
cmꢁ1. Anal. Calcd for C15H14ClNO3: C, 61.85; H, 4.84; N,
4.80. Found: C, 61.80; H, 4.89; N, 4.82.
methyl-6-chloro-5-(chloromethyl)-2-pyridinecarboxylate
was recrystallized in hexane.
(3j)
2-Chloro-3-(chloromethyl)-5-methylpyridine
(3a). Yield:
88%, solid; mp: 55–58ꢀC. 1H NMR (CDCl3): d 2.37 (s, 3H,
CH3), 4.62 (s, 2H, -CH2Cl), 7.65 (s, 1H, heteroaromatic), 8.17
(s, 1H, heteroaromatic). EI-MS (m/z): 175 (40) (Mþ), 140
(100), 104 (12), 77 (23), 51 (9), 39 (5). UV: kmax ¼ 258 nm
in acetonitrile. IR (KBr): m ¼ 2971, 2934, 2874, 1563, 1429,
1407, 1076, 908, 758 cmꢁ1. Anal. Calcd for C7H7 Cl2N: C,
48.02; H, 4.01; N, 8.00. Found: C, 48.09; H, 4.08; N, 7.99.
2-Chloro-3-(chloromethyl)-5-ethylpyridine
(3b). Yield:
94%, solid; mp: 63–64ꢀC. 1H NMR (CDCl3): d 1.32 (t, 3H,
CH3), 2.70 (q, 2H, CH2), 4.75 (s, 2H, CH2Cl), 7.65 (s, 1H, heter-
oaromatic), 8.18 (s, 1H, heteroaromatic). EI-MS (m/z): 189 (23)
(Mþ), 174 (13), 154 (100), 91 (5), 77 (4), 51 (3). UV: kmax
¼
266 nm in acetonitrile. IR (KBr): m ¼ 2990, 2960, 1560, 1420,
1417, 1070, 900, 750 cmꢁ1. Anal. Calcd for C8H9 Cl2 N: C,
50.79; H, 4.77; N, 7.40. Found: C, 50.71; H, 4.82; N, 7.38.
Methyl-6-chloro-5-(hydroxymethyl)-2-pyridinecarboxylate
(2j). Yield: 92%, solid; mp: 68–70ꢀC. 1H NMR (CDCl3): d
3.99 (s, 3H, OCH3), 4.84 (s, 2H, CH2OH), 8.07 (s, 2H, hetero-
aromatic). EI-MS (m/z): 201 (3) (Mþ), 171 (20), 143 (100),
112 (19), 78 (11), 51 (4). UV: kmax ¼ 276 nm. IR (KBr): m ¼
3416, 2923, 2853, 1730, 1310, 1258, 1046, 778 cmꢁ1. Anal.
2-Chloro-3-(chloromethyl)-5-propylpyridine
(3c). Yield:
88%, solid; mp: 65–66ꢀC. 1H NMR (CDCl3): d 0.9 (t, 3H,
CH3), 1.7 (m, 2H, CH2), 2.64 (t, 2H, CH2), 4.75 (s, 2H, CH2-
Cl), 7.65 (s, 1H, heteroaromatic), 8.18 (s, 1H, heteroaromatic).
EI-MS (m/z): 217.
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B. Gangadasu, B. C. Raju, and V. J. Rao
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for C9H9Cl2NO2: C, 46.18; H, 3.84; N, 5.98. Found: C, 46.18;
H, 3.92; N, 5.92.
2-Chloro-3-(chloromethyl)-5-isopropylpyridine (3d). Yield:
89%, solid; mp: 66–68ꢀC. 1H NMR (CDCl3): d 1.2–1.4 (m,
6H, 2CH3), 3.20 (m, 1H, CH), 4.75 (s, 2H, CH2-Cl), 7.65 (s,
1H, heteroaromatic), 8.18 (s, 1H, heteroaromatic). EI-MS
(m/z): 217.
General procedure for the synthesis of (substituted pyri-
dyl)-methyl]tetrahydro-1H-2-imidazolyliden}-1-oxo-1-hydra-
ziniumolate (5a–k). A mixture of pyridine substituted methyl
chloride (3; 0.5 g, 0.002 moles), 2-nitraimino imidazole (0.67
g, 0.005 mol), K2CO3 (0.33 g, 0.002 mol), and CsCl (5 mol
%) in CH3CN (10 mL) was refluxed for 2.5 h. After comple-
tion of the reaction, acetonitrile was removed. The solid crude
was washed with water. The solid when recrystallized by
methanol gave the title compounds in good yield.
2-Chloro-3-(chloromethyl)-5-pentylpyridine
(3e). Yield:
88%, solid; mp: 70–72ꢀC. 1H NMR (CDCl3): d 0.9 (t, 3H,
CH3), 1.38 (m, 4H, 2CH2), 1.70 (q, 2H, CH2), 2.7 (t, 2H,
CH2), 4.75 (s, 2H, CH2-Cl), 7.65 (s, 1H, heteroaromatic), 8.18
(s, 1H, heteroaromatic). EI-MS (m/z): 231.
2-Chloro-3-(chloromethyl)-5-phenylpyridine
(3f). Yield:
91%, solid; mp: 78–80ꢀC. 1H NMR (CDCl3): d 4.77 (s, 2H,
CH2), 7.44–7.58 (m, 5H), 8.06 (s, 1H, heteroaromatic), 8.58 (s,
1H, heteroaromatic). EI-MS (m/z): 237 (82) (Mþ), 202 (100),
166 (18), 139 (17), 115 (11), 101 (6), 69 (5). UV: kmax ¼ 256
nm in acetonitrile. IR (KBr): m ¼ 2970, 2910, 2880, 1420,
1240, 1170, 1060, 1020 cmꢁ1. Anal. Calcd for C12H9 Cl2 N:
C, 60.75; H, 3.79; N, 5.90. Found: C, 60.77; H, 3.72; N, 5.88.
2-Chloro-3-(chloromethyl)-5-(4-methoxyphenyl)pyridine
(3g). Yield: 91%, solid; mp: 79–80ꢀC. 1H NMR (CDCl3): d
3.84 (s, 3H, OCH3), 4.77 (s, 2H, -CH2Cl), 6.97 (d, 2H, aro-
matic), 7.49 (d, 2H, aromatic), 7.98 (s, 1H, heteroaromatic),
8.50 (s, 1H, heteroaromatic). EI-MS (m/z): 267 (100) (Mþ),
2-{1-[(2-Chloro-5-methyl-3-pyridyl)methyl]-tetrahydro-1H-
2-imidazolyliden}-1-oxo-1-hydraziniumolate
(5a). Yield:
1
82%, solid; mp: 193–195ꢀC. H NMR (DMSO-d6): d 2.36 (s,
3H, CH3), 3.5–3.8 (m, 4H, -CH2-CH2-), 4.62 (s, 2H, -CH2N-),
7.62 (s, 1H, heteroaromatic), 8.20 (s, 1H, heteroaromatic), 9.05
(s, NH, 1H). UV: kmax ¼ 272 nm in acetonitrile. EI-MS (m/z):
269; IR (KBr): m ¼ 3792, 3307, 2922, 2861, 1584, 1546,
1439, 1286, 1240, 1148, 1053, 724, 679, 642 cmꢁ1. Anal.
Calcd for C10H12Cl N5O2: C, 44.61; H, 4.48; N, 26.06. Found:
C, 44.64; H, 4.51; N, 26.12.
2-{1-[(2-Chloro-5-ethyl-3-pyridyl)methyl]-tetrahydro-1H-2-
imidazolyliden}-1-oxo-1-hydraziniumolate (5b). Yield: 81%,
solid; mp: 197–199ꢀC. 1H NMR (DMSO-d6): d 1.32 (t, 3H,
CH3), 2.70 (q, 2H, CH2), 3.5–3.8 (m, 4H, -CH2-CH2-), 4.60 (s,
2H, -CH2N-), 7.62 (s, 1H, heteroaromatic), 8.20 (s, 1H, hetero-
aromatic), 9.05 (s, NH, 1H). EI-MS (m/z): 283; IR (KBr): m ¼
252 (15), 232 (45), 189 (6), 154 (6), 127 (12), UV: kmax
¼
276 nm in acetonitrile. IR (KBr): m ¼ 2957, 2925, 2854, 1735,
1606, 1426, 1249, 1182, 1082, 1027, 832, 753 cmꢁ1. Anal.
Calcd for C13H11 Cl2 NO: C, 58.43; H, 4.13; N, 5.24. Found:
C, 58.33; H, 4.22; N, 5.21.
3790, 3300, 2855, 1580, 1540, 1280, 1240, 1050, 724, cmꢁ1
.
Anal. Calcd for C11H14ClN5O2: C, 46.56; H, 4.97; N, 24.68.
Found: C, 46.59; H, 4.99; N, 24.70.
2-{1-[(2-Chloro-5-propyl-3-pyridyl)methyl]-tetrahydro-1H-
2-Chloro-3-(chloromethyl)-5-methyl-6-phenylpyridine (3h). Yield:
88%, solid; mp: 78–82ꢀC. 1H NMR (CDCl3): d 2.43 (s, 3H,
CH3), 4.70 (s, 2H, -CH2Cl), 7.28–7.38 (m, 5H), 7.73 (s, 1H,
heteroaromatic). EI-MS (m/z): 251 (44) (Mþ), 250 (100), 216
(39), 180 (11), 153 (13), 140 (4), 128 (5), 115 (5), 89 (5), 76
(10), 63 (4), 51 (5). UV: kmax ¼ 288 nm in acetonitrile. IR
(KBr): m ¼ 2967, 2927, 1588, 1543, 1443, 1412, 1383, 1185,
1067, 984, 735, 702 cmꢁ1. Anal. Calcd for C13H11 Cl2N: C,
62.16; H, 4.40; N, 5.57. Found: C, 60.81; H, 4.42; N, 5.61.
Ethyl-6-chloro-5-(chloromethyl)-2-phenylnicotinate (3i). Yield:
91%, light yellow liquid. 1H NMR (CDCl3): d 1.13 (t, 3H,
CH3), 4.24 (q, 2H, CH2), 4.74 (s, 2H, -CH2Cl), 7.46 (m, 3H,
aromatic), 8.76 (s, 1H, heteroaromatic). EI-MS (m/z): 309 (18)
(Mþ), 280 (100), 264(34), 245 (11), 229 (7), 202 (6), 166 (14),
139 (17), 105 (7). UV: kmax ¼ 256 nm in acetonitrile. IR
(KBr): m ¼ 2925, 2853, 1724, 1573, 1531, 1440, 1237, 1129,
757 cmꢁ1. Anal. Calcd for C15H13Cl2NO2: C, 58.28; H, 4.22;
N, 4.52. Found: C, 58.21; H, 4.28; N, 4.61.
Methyl-6-chloro-5-(chloromethyl)-2-pyridinecarboxylate
(3j). Yield: 93% solid; mp: 78–80ꢀC. 1H NMR (CDCl3): d
4.04 (s, 3H, OCH3), 4.76 (s, 2H, -CH2Cl), 8.08 (q, 2H). EI-
MS (m/z): 219 (4) (Mþ), 189 (20), 161 (100), 124 (15), 90
(11), 63 (10). UV: kmax ¼ 258 nm in acetonitrile. IR (KBr): m
¼ 2925, 2854, 1728, 1562, 1450, 1369, 1137, 744 cmꢁ1. Anal.
Calcd for C8H7 Cl2NO2: C, 43.84; H, 3.20; N, 6.39. Found: C,
37.21; H, 2.69; N, 7.21.
2-imidazolyliden}-1-oxo-1-hydraziniumolate
(5c). Yield:
82%, solid; mp: 196–198ꢀC. 1H NMR (DMSO-d6): d 0.9 (t,
3H, CH3), 1.7 (m, 2H, CH2), 2.64 (t, 2H, CH2), 3.5–3.8 (m,
4H, -CH2-CH2-), 4.60 (s, 2H, -CH2N-), 7.64 (s, 1H, heteroaro-
matic), 8.22 (s, 1H, heteroaromatic), 9.05 (s, 1H, NH). EI-MS
(m/z): 297.
2-{1-[(2-Chloro-5-isopropyl-3-pyridyl)methyl]-tetrahydro-1H-
2-imidazolyliden}-1-oxo-1-hydraziniumolate (5d). Yield: 84%,
solid; mp: 190–192ꢀC. 1H NMR (DMSO-d6): d 1.2–1.4 (m,
6H, 2CH3), 3.20 (m, 1H, CH), 3.5–3.8 (m, 4H, -CH2-CH2-),
4.64 (s, 2H, -CH2N-), 7.60 (s, 1H, heteroaromatic), 8.21 (s,
1H, heteroaromatic), 9.05 (s, 1H, NH). EI-MS (m/z): 297.
2-{1-[(2-Chloro-5-pentyl-3-pyridyl)methyl]-tetrahydro-1H-2-
imidazolyliden}-1-oxo-1-hydraziniumolate (5e). Yield: 86%,
solid; mp: 198–201ꢀC. 1H NMR (DMSO-d6): d 0.9 (t, 3H,
CH3), 1.38 (m, 4H, 2CH2), 1.70 (q, 2H, CH2), 2.7 (t, 2H,
CH2), 3.5–3.8 (m, 4H, -CH2-CH2-), 4.60 (s, 2H, -CH2N-), 7.62
(s, 1H, heteroaromatic), 8.20 (s, 1H, heteroaromatic), 9.05 (s,
1H, NH). EI-MS (m/z): 325.
2-{1-[(2-Chloro-5-phenyl-3-pyridyl)methyl]-tetrahydro-1H-
2-imidazolyliden}-1-oxo-1-hydraziniumolate
(5f). Yield:
80%, solid; mp: 248–250ꢀC. 1H NMR (DMSO-d6): d 3.60–
3.80 (m, 4H, -CH2-CH2-), 4.62 (s, 2H, -CH2N-), 7.50 (m,
3H, aromatic), 7.75 (d, 2H, aromatic), 8.05 (s, 1H, heteroaro-
matic), 8.68 (s, 1H, heteroaromatic), 9.05 (s, 1H, NH). EI-
MS (m/z): 331; UV: kmax ¼ 262 nm in acetonitrile. IR
(KBr): m ¼ 3253, 3065, 2879, 1580, 1542, 1438, 1284, 1240,
Methyl-6-chloro-5-(chloromethyl)-3-methyl-2-pyridinecar-boxy-
1
late (3k). Yield: 90%, solid; mp: 75–77ꢀC. H NMR (CDCl3):
d 2.60 (s, 3H, CH3), 3.99 (s, 3H, OCH3), 4.69 (s, 2H, CH2Cl),
7.80 (s, 1H, heteroaromatic). EI-MS (m/z): 234 (43) (Mþ), 218
(5), 201(100), 175 (64), 138 (46), 102 (20), 77 (15), 51 (9).
UV: kmax ¼ 286 nm in acetonitrile. IR (KBr): m ¼ 2915,
2850, 1729, 1560, 1455, 1360, 1130, 740 cmꢁ1. Anal. Calcd
1
1145, 1050, 953, 759, 687 cmꢁ . Anal. Calcd for
C15H14ClN5O2: C, 54.30; H, 4.25; N, 21.11. Found: C,
55.41; H, 4.32; N, 21.21.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
Synthesis of Imidacloprid Analogues from Novel Chloronicotinaldehydes
1217
(q, 2H, CH2), 3.98 (s, 3H, OCH3), 4.72 (s, 2H, -CH2N), 7.72
(s, 1H, heteroaromatic), 8.24 (s, 1H, NH). EI-MS (m/z): (Mþþ
23) 350. UV: kmax ¼ 272 nm in acetonitrile. IR (KBr): m ¼
3412, 2921, 2852, 1712, 1579, 1441, 1320, 1293, 1240, 1120,
1045 cmꢁ1. Anal. Calcd for C12H14ClN5O4: C, 43.97; H, 4.30;
N, 21.36. Found: C, 43.99; H, 4.32; N, 21.41.
2-(1-{[2-Chloro-5-(4-methoxyphenyl)-3-pyridyl]methyl}-tetrahy-
dro-1H-2-imidazolyliden)-1-oxo-1-hydraziniumolate (5g). Yield:
81%, solid; mp: 159–160ꢀC. 1H NMR (DMSO-d6): d 3.60–
3.80 (m, 4H, -CH2-CH2-), 3.84 (s, 3H, OCH3), 4.62 (s, 2H,
-CH2N-), 6.97 (d, 2H, aromatic), 7.49 (d, 2H, aromatic), 8.05
(s, 1H, heteroaromatic), 8.68 (s, 1H, heteroaromatic), 9.05 (s,
1H, NH). IR (KBr): m ¼ 3416, 2923, 2853, 1572, 1540, 1436,
1282, 1237 cmꢁ1
. EI-MS (m/z): 361; Anal. Calcd for
Acknowledgments. The authors thank the Head, Organic Chem-
istry Division-II, and Director-IICT for their constant encourage-
ment. BG thanks UGC, New Delhi, for the award of fellowship.
C16H16Cl N5O3: C, 53.11; H, 4.45; N, 19.39. Found: C, 53.21;
H, 4.29; N, 19.35.
2-{1-[(2-Chloro-5-methyl-6-phenyl-3-pyridyl)methyl]-tetrahydro-
1H-2-imidazolyliden)-1-oxo-1-hydraziniumolate (5h). Yield:
1
89%, solid; mp: 168–170ꢀC. H NMR (DMSO-d6): d 2.38 (s,
REFERENCES AND NOTES
3H, CH3), 3.60–3.78 (m, 4H, -CH2-CH2-), 4.58 (s, 2H,
-CH2N-), 7.40–7.60 (m, 5H, aromatic), 7.78 (s, 1H, heteroaro-
matic), 9.05 (s, 1H, NH). UV: kmax ¼ 272 nm in acetonitrile.
IR (KBr): m ¼ 3331, 2925, 2854, 1554, 1433, 1292, 1261,
1228, 1126, 1044, 982, 701 cmꢁ1. EI-MS (m/z): 345; Anal.
Calcd for C16H16Cl N5O2: C, 55.57; H, 4.66; N, 20.25. Found:
C, 55.61; H, 4.77; N, 20.21.
[1] (a) Samaritoni, J. G.; Demeter, D. A.; Gifford, J. M.; Wat-
son, G. B.; Kempe, M. S.; Bruce, T. J. J. Agri Food Chem 2003, 51,
3035; (b) Tian, Z.; Jiang, Z.; Li, Z.; Song, G.; Huang, Q. J Agri Food
Chem 2007, 55, 143.
[2] Moriya, K.; Shibuya, K.; Hattori, Y.; Tsuboi, S.; Shiokawa,
K.; Kagabu, S. Biosci Biotechnol Biochem 1992, 56, 364.
[3] Jeschke, P.; Moriya, K.; Lantzsch, R.; Seifert, H.; Linder,
W.; Jelish, K.; Gohrt, A.; Beck, M. E.; Etzel, W. Pflanzenschutz-Nach-
richten Bayer. 2001, 54, 147.
2-(1-{[2-Chloro-5-(ethoxycarbonyl)-6-phenyl-3-pyridyl]-meth-
yl}tetrahydro-1H-2-imidazolyliden)-1-oxo-1-hydraziniumolate
1
(5i). Yield: 88%, solid; mp: 133–135ꢀC. H NMR (CDCl3): d
[4] (a) Novak, L.; Hornyanszky, G.; Kiraly, I.; Rohaly, J.;
Kolonits, P.; Szantay, C. Heterocycles 2001, 55, 45; (b) Brackmann,
F.; Yufit, D. S.; Howard, J. A. K.; Es-Sayed, M.; De Meijere, A. Eur
J Org Chem 2005, 3, 600; (c) Latli, B.; D’Amour, K.; Casida, J. E.
J Med Chem 1999, 42, 2227; (d) Zhang, N.; Tomizawa, M.; Casida, J.
E. J Med Chem 2002, 45, 2832; (e) Kagabu, S.; Maienfisch, P.; Zhang,
A.; Granda-Minones, J.; Haettenschwiler, J.; Kayser, H.; Maetzke, T.;
Casida, J. E. J Med Chem 2000, 43, 5003; (f) Zhang, N.; Tomizawa,
M.; Casida, J. E. J Org Chem 2004, 69, 876; (g) Kagabu, S. Synth
Commun 2006, 36, 1235.
1.13 (t, 3H, CH3), 3.62 (m, 2H,CH2), 3.80 (m, 2H, CH2), 4.22
(q, 2H, CH2), 4.78 (s, 2H, -CH2N-), 7.42 (m, 3H, aromatic),
7.60 (m, 2H, aromatic), 8.28 (s, 1H, NH), 8.72 (s, 1H, hetero-
aromatic). UV: kmax ¼ 270 nm in acetonitrile. EI-MS (m/z):
403; IR (KBr): m ¼ 3255, 2899, 1734, 1570, 1525, 1441,
1402, 1259, 1230, 1114, 1049, 1008, 951, 777, 695, 622 cmꢁ1
.
Anal. Calcd for C18H18ClN5O4: C, 53.53; H, 4.49; N, 17.34.
Found: C, 53.61; H, 4.52; N, 17.41.
2-(1-{[2-Chloro-6-(methoxycarbonyl)-3-pyridyl]methyl}-tetrahy-
dro-1H-2-imidazolyliden)-1-oxo-1-hydraziniumolate (5j). Yield:
86%, solid; mp: 169–170ꢀC. 1H NMR (CDCl3 þ DMSO-d6):
d 3.69 (q, 2H, CH2), 3.82 (q, 2H, CH2), 3.94 (s, 3H, OCH3),
4.66 (s, 2H, -CH2N-), 7.88 (d, 1H, heteroaromatic), 8.03 (d,
1H, heteroaromatic), 8.16 (s, 1H, NH). 13C NMR (DMSO-d6):
d 41.63, 44.62, 45.32, 52.10, 115.53, 124.80, 136.27, 149.57,
151.48, 161.55, 168.28. EI-MS (m/z): (Mþ þ 23) 336. UV:
kmax ¼ 272 nm. IR (KBr): m ¼ 3341, 2924, 1713, 1574, 1445,
1322, 1264, 1055, 786 cmꢁ1. Anal. Calcd for C11H12ClN5O4:
C, 42.11; H, 3.85; N, 22.32. Found: C, 42.18; H, 3.98; N,
22.33.
[5] (a) Gangadasu, B.; Narender, P.; Kumar, S. B.; Ravinder,
M.; Anada Rao, B.; Ramesh, Ch.; China Raju, B.; Jayathirtha Rao, V.
Tetrahedron 2006, 62, 8398; (b) Gangadasu, B., China Raju, B.; Jaya-
thirtha Rao, J. Heterocyclic Commun 2002, 8, 243; (c) Narender, P.;
Gangadasu, B.; Ravinder, M.; Jayathirtha Rao, V. Tetrahedron 2006,
62, 954; (d) Narender, P.; Srinivas, U.; Ravinder, M.; Ramesh, Ch.;
Anand Rao, B.; Harakishore, K.; Gangadasu, B.; Murthy, U. S. N.;
Jayathirtha Rao, J. Bioorg Med Chem 2006, 14, 4600; (e) Narender,
P.; Srinivas, U.; Gangadasu, B.; Jayathirtha Rao, V. Bioorg Med
Chem Lett 2005, 15, 5378; (f) Narender, P.; Gangadasu, B.; Ramesh,
Ch.; China Raju, B.; Jayathirtha Rao, V. Synth Commun 2004, 34,
1097; (g) Srinivas, K.; Srinivas, U.; Kishore, K. H.; Jayathirtha Rao,
V.; Bhanuprakash, K.; Murthy, U. S. N. Bioorg Med Chem Lett 2005,
15, 1121.
2-(1-{[2-Chloro-6-(methoxycarbonyl)-5-methyl-3-pyridyl]-
methyl}-tetrahydro-1H-2-imidazolyliden)-1-oxo-1-hydraziniu-
molate (5k). Yield: 80%, solid; mp: 175–177ꢀC. 1H NMR
(CDCl3): d 2.58 (s, 3H, CH3), 3.6–3.7 (q, 2H, CH2), 3.8–3.9
[6] China Raju, B.; Jayathirtha Rao, V. Indian J Chem 2002,
41B, 2180.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet