Methyl, trifluoromethyl, and methoxycarbonyl - Introduction to the fifth position on the pyridine ring of chloronicotinyl insecticide imidacloprid

Article abstract of DOI:10.1080/00397910500516134

Imidacloprid is the first chloronicotinyl insecticide and is currently the largest-selling insecticide worldwide. As a project to find its variants of different insecticidal spectra, derivatives substituted with methyl, trifluoromethyl, and methoxy-carbonyl at the fifth position on the pyridine ring of imidacloprid were prepared. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500516134

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Methyl, Trifluoromethyl, and
Methoxycarbonyl—Introduction to the
Fifth Position on the Pyridine Ring of
Chloronicotinyl Insecticide Imidacloprid
Shinzo Kagabu a
a Department of Chemistry, Faculty of Education, Gifu University, Gifu,
Japan
Version of record first published: 24 Feb 2007
To cite this article: Shinzo Kagabu (2006): Methyl, Trifluoromethyl, and Methoxycarbonyl—Introduction to the
Fifth Position on the Pyridine Ring of Chloronicotinyl Insecticide Imidacloprid, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:9, 1235-1245
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Synthetic Communicationsw, 36: 1235–1245, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500516134
Methyl, Trifluoromethyl,
and Methoxycarbonyl—Introduction
to the Fifth Position on the Pyridine Ring
of Chloronicotinyl Insecticide Imidacloprid
Shinzo Kagabu
Department of Chemistry, Faculty of Education, Gifu University,
Gifu, Japan
Abstract: Imidacloprid is the first chloronicotinyl insecticide and is currently the
largest-selling insecticide worldwide. As a project to find its variants of different
insecticidal spectra, derivatives substituted with methyl, trifluoromethyl, and methoxy-
carbonyl at the fifth position on the pyridine ring of imidacloprid were prepared.
Keywords: Chloronicotinyl insecticide, imidacloprid, neonicotinoid, prodrug,
substituted pyridine
INTRODUCTION
Imidacloprid (1a; Scheme 1), the first chloronicotinyl insecticide (or neoni-
cotinoid), is widely used to control various plant pests.[1–3] Following imida-
cloprid, six new market products were developed by replacing its pyridine ring
with other heterocyclic rings, changing the nitroimino group to nitromethy-
lene or cyanoimine group and reconstructing the imidazolidine ring with bioi-
sosteric cyclic or acyclic moieties.[4] Among various structural modification
trials for each molecular part from the drug-design viewpoint, the substitution
variation on the pyridine ring of imidacloprid seems not have been fully
pursued, probably because of the prevailing reports that any other substituents
Received in Japan August 2, 2005
Address correspondence to Shinzo Kagabu, Department of Chemistry, Faculty of
Education, Gifu University, Gifu 501-1193, Japan. Tel.: (þ81) 58-232-1180;
Fax: (þ81) 58-293-2207; E-mail: kagabus@cc.gifu-u.ac.jp
1235

1236
S. Kagabu
Scheme 1. Imidacloprid, 5-substituted analogues, and the entry.
or other places lowered the potency of the original sixth-chloro deriva-
tive.[1,2,5] In such a background, it is no wonder that high insecticidal
activity of 5,6-dichloropyridyl derivatives of imidacloprid analogous (1b, 1c
in Scheme 1) claimed on patents[6,7] have caught little attention so far. We
noticed the documents specifying the added fifth chlorine atom on the
pyridine ring of chloronicotinyl insecticides and elaborated to introduce bioi-
sosteric methyl and trifluoromethyl groups, and similarly electron-withdraw-
ing but rather hydrophilic methoxycarbonyl groups to the position in question.
The last substituent interests us also from the viewpoint of a chloronicotinyl
prodrug,[8] because the ester group can principally be decomposed, in vivo
and/or in vitro.[9]
RESULTS AND DISCUSSION
For 6-chloro-5-methy-3-pyridylmethyl chloride (9) we started with known
2-chloro-5-methyl-3-nitropyridine (4).[10] We obtained amine (5) simply by
hydrogenation of the nitro group on palladium/C in better yield than the
described method using tin and acid.[11] The next step to iodide (6) was
carried out by a reported conversion via diazonium salt.[12]Substitution of
the iodide with CuCN in DMF gave nitrile (7) in 82% yield, keeping the
chlorine atom at the 2-position intact. The reduction of nitrile with diisobutyl
aluminum hydride (DIBAL) gave a mixture of aldehyde and alcohol, and the
subsequent treatment of the mixture with NaBH4 afforded alcohol (8) in 12%
yield from nitrile. We have not optimized the reduction conditions, but the
partial saturation of the pyridine ring and the reductive abstraction of the
chlorine atom may be responsible for the low yield. Alcohol was convention-
ally transformed to chloride (9) with thionyl chloride (i in Scheme 2).
The reported procedure for 2-hydroxy-3-trifluoromethylpyridine (11)
includes aminolysis of 2-chloro-3-trifluoromethylpyridine (10) in a high-
pressure vessel, followed by hydrolysis of the diazonium salt.[13] Instead,
we treated 10 with KOH in refluxing t-butanol and obtained pyridone (11)
in 73% yield. Introduction of iodine to the fifth position was carried out by
addition of molecular iodine in sodium carbonate solution, and the obtained

Substituted Imidacloprid
1237
Scheme 2. Preparation of the precursors.
5-iodopyridone (12) was converted to 2-chloropyridine (13) by treatment with
a mixture of POCl3 and DMF. In contrast to 3-methyl derivative (6), however,
the iodine substitution at 2-chloro-5-iodo-3-trifluoromethylpyridine (13) with
CuCN failed because of the lability of 2-chlorine atom. Then, we tried the sub-
stitution with 5-iodo-2-methoxy-3-trifluoromethylpyridine (14). However, the
iodine of this compound in turn could not be replaced by CuCN under various
conditions. Fortunately, this substitution worked well by the newly developed
method using Zn(CN)2 combined with catalytic Pd (0) complex.[14] By this
detour, we obtained cyanide (15) in 82% yield. The nitrile group was trans-
formed to hydroxylmethyl by a method described for 8, and the obtained
2-methoxy-3-trifluoromethyl-5-pyridinemethanol (16) could be directly trans-
formed to 2-chloro-3-trifluoromethyl-5-pyridinemethyl chloride (17) using
POCl3 in DMF at 1008C (ii in Scheme 2).

1238
S. Kagabu
Literature describes the preparation of methyl 2-chloro-5-methy-3-pyridi-
necarboxylate (20) by potassium permanganate oxidation of 3,5-dimethyl-2-
nitropyridine and subsequent separation of the regional methyl ester
isomers.[15] Further, the entry to the starting material required several steps
and harsh conditions. We chose an alternative precursor, 2-chloro-3-cyano-
5-methylpyridine (18), readily available by condensation of malononitrile
and propionaldehyde with POCl3,[16] to serve for our product. The cyano
group was hydrolyzed to amide with concentrated sulfuric acid, which was
next converted to methyl ester (20) with BF3 etherate in dry methanol (iii in
Scheme 2). Bromination of the fifth methyl group of ester (20) with N-bromo-
succinimide (NBS) in the presence of benzoyl peroxide and the following
chromatography afforded bromide (21) in 35% yield with a trace amount of
20, and the mixture was used in the next step without further purification.
The final products (1d, 1e, 1f) were obtained in 51–87% yield by the
coupling reaction of the halogenides (2) and 2-nitroiminoimidazolidine
(3, Y ¼ NNO2) with NaH in DMF at room temperature.
EXPERIMENTAL
All melting points (mp) are uncorrected. IR spectra were measured with a
Perkin Elmer FTIR 1600 spectrometer. NMR spectra were obtained on a
Varian Gemini 2000 C/H (400 MHz). The chemical shifts were recorded in
d (ppm) and the coupling constants J in Hz. Mass spectra (EI) were
recorded by a Jeol JMS-700.
5-Amino-2-chloro-3-methylpyridine (5). A methanol solution of 2-chloro-3-
methyl-5-nitropyridine (4) (2.50 g, 14.6 mmol) was hydrogenated on
palladium/C (10% Pd, 200 mg) under atmospheric pressure and worked up.
Yield: 1.86 g (90%). Mp: 90–948C (93–948C).[11]
2-Chloro-5-iodo-3-methylpyridine (6).The described method[12] was repro-
ducible. Mp: 57–598C (59–618C).[12]
2-Chloro-5-cyano-3-methylpyridine (7). A mixture of compound 6 (1.0 g,
4.0 mmol) and CuCN (430 mg, 4.7 mmol) in 10 ml of DMF was stirred at
1608C for 6.5 h. The cooled mixture was poured onto cold water (30 ml).
The precipitated solid was washed with water. The solid was suspended in
water (20 ml) containing 10 ml of ethylene diamine and 160 mg of NaCN,
filtered by suction, and then thoroughly washed with ethyl acetate with
weak suction. The combined filtrate was separated, and the aqueous phase
was washed with ethyl acetate (3 ꢀ 15 ml). The combined ethyl acetate
phase was washed once with brine and dried. The crude product was
purified by chromatography on SiO2 with ethyl acetate as the eluent. Yield:
500 mg (82%). Mp: 114–1168C. IR (KBr): cm21 2240 (m), 1590 (m), 1550

Substituted Imidacloprid
1239
(m), 1450 (s), 1385 (vs), 1170 (m), 1090 (s), 1080 (vs), 920 (m). NMR
(CDCl3): dH 2.46 (s, 3H, CH3), 7.83 (d, 1H, 4-Py-H, J ¼ 2.2 Hz), 8.53
(d, 1H, 6-Py-H, J ¼ 2.3); dC 19.6, 108.7, 115.8, 133.8, 141.4, 149.7, 155.8.
MS m/z (%): 154 (28), 152 (Mþ, 84), 117 (36), 116 (100), 115 (11), 90
(19), 89 (14). Anal. Found: C, 55.26; H, 3.60; N, 17.99. Calcd. for
C7H5ClN2: C, 55.10; H, 3.30; N, 18.36.
6-Chloro-5-methyl-3-pyridinemethanol (8). A solution of nitrile (7) (1.70 g,
8.5 mmol) in 20 ml of toluene was treated dropwise with a solution of DIBAL
(1.5 M toluene solution, 7 ml) with ice cooling under argon atmosphere. After
4 h of stirring, the reaction was quenched with 2 ml of water. The reaction
mixture was filtered through celite with weak suction. The celite bed was
rinsed with ethyl acetate. The filtrate was evaporated, and the residue
(400 mg) was washed with cold ether and used in the next reaction. To an
ice-cold suspension of 360 mg of this mixture in methanol (20 ml) and
water (5 ml) was added portionwise sodium borohydride (90 mg), and the
mixture was stirred overnight. The product was taken up with chloroform,
and the chloroform solution was dried. After evaporation of the solvent, the
residual liquid was purified by chromatography on SiO2 with isopropyl
ether (IPE) as the eluent. Yield: 140 mg (12%). IR (liquid): cm21 3200 (vs),
1570 (m), 1460 (m), 1400 (vs), 1070 (vs), 1035 (s), 890 (m), 720 (m).
NMR (CDCl3): dH 2.38 (s, 3H, CH3), 4.59 (s, 2H, CH2), 7.59 (d, 1H,
4-Py-H, J ¼ 1.9 Hz), 8.15 (d, 1H, 6-Py-H, J ¼ 1.9 Hz); dC 19.6, 61.6, 132.4,
135.5, 138.4, 145.3, 150.5. MS m/z (%): 159 (22), 158 (Mþ, 25), 157 (66),
156 (44), 142 (10), 130 (26), 128 (78), 127 (10), 122 (27), 120 (11), 104
(14), 94 (26), 93 (24), 92 (100), 91 (13).
6-Chloro-5-methylpyridin-3-ylmethyl chloride (9). A solution of alcohol
(8; 120 mg) in chloroform (5 ml) was treated dropwise with 1 ml of thionyl
chloride. The mixture was warmed at reflux temperature for 1 h. The
cooled mixture was poured onto ice water, and the separated organic
phase was washed successively with 5% NaHCO3 and water and dried.
Evaporation of the solvent afforded a semisolid, which was purified by
chromatography on SiO2 with IPE/hexane 5 : 1 as eluent. Yield: 120 mg
(89%). Mp: 59–618C. IR (KBr): cm21 1565 (m), 1440 (s), 1395 (vs),
1260 (m), 1180 (m), 1070 (vs), 1055 (vs), 960 (m), 720 (m), 680 (m).
NMR (CDCl3): dH 2.40 (s, 3H, CH3), 4.55 (s, 2H, CH2), 7.61 (d, 1H,
4-Py-H, J ¼ 2.2 Hz), 8.23 (d, 1H, 6-Py-H, J ¼ 2.2 Hz); dC 19.6, 42.2,
132.3, 132.8, 139.5, 146.5, 151.6. MS m/z (%): 174 (Mþ, 5), 160 (10),
140 (66), 128 (37), 126 (80), 90 (100). HRMS (EI) m/z (Mþ): calcd. for
C7H7Cl2N, 174.9956; found, 174.9933.
1-(6-Chloro-5-methyl-3-pyridylmethyl)-2-nitroiminoimidazolidine (1d).
A solution of 2-nitroimino-4-imidazoline (3; 130 mg, 1.0 mmol) in DMF
(15 ml) was treated with sodium hydride (60% oil dispersion, 52 mg,

1240
S. Kagabu
1.2 mmol) under 58C. The mixture was stirred at room temperature until
hydrogen evolution ceased and then cooled again to 08C. A solution of
chloride (9) (174 mg, 1.0 mmol) in DMF (6 ml) was added dropwise.
The cooling bath was set aside, and the mixture was stirred at room tempera-
ture for 2 h. After the reaction was quenched with one drop of acetic acid,
the DMF was evaporated in vacuum. Chromatography on SiO2 with
hexane/ethyl acetate 1:10 gave 234 mg (87% yield) of product, which was
purified by recrystallization from ethanol. Mp: 190–1918C. IR (KBr): cm21
3150 (m), 1600–1520 (s), 1420 (vs), 1250–1200 (vs), 1135 (m), 1050 (s),
940 (m), 720 (m). NMR (CDCl3): dH 2.39 (s, 3H, CH3), 3.52 (m, 2H,
NCH2CH2N), 3.81 (m, 2H, NCH2CH2N), 4.52 (s, 2H, CH2), 7.57 (d, 1H,
4-Py-H, J ¼ 1.8 Hz), 8.15 (d, 1H, 6-Py-H, J ¼ 1.8 Hz), 8.21 (bs, 1H, NH);
dC 19.6, 41.5, 45.1, 45.2, 129.8, 133.2, 139.5, 146.5, 151.8, 161.2. MS m/z
(%): 271 (16), 269 (Mþ, 46), 225 (16), 224 (76), 223 (36), 222 (100), 221
(19), 220 (17), 188 (32), 187 (40), 186 (82), 139 (18). Anal. Found: C, 44.56;
H, 4.32; N, 26.10. Calcd. for C10H12ClN5O2: C, 44.54; H, 4.48; N, 25.97.
3-Trifluoromethyl-2-pyridinol (11). 2-Chloro-3-trifluoropyridine (10; 4.50 g,
25 mmol) was treated with 2.7 g of powdered KOH in 100 ml of t-butanol.
The mixture was stirred at reflux temperature for 10 h. After neutralization
with conc. HCl, most t-butanol was distilled off. The residue was diluted
with water and acidified. The precipitated solid was filtered out and washed
with cold water (the dried amount of 2.6 g). From the aqueous filtrate
further 0.4 g were obtained by extraction with ethyl acetate. The combined
solid was used in the next step. For analysis, a small crop was dissolved in
2 N-NaOH and washed with ethyl acetate, and the alkaline solution was
acidified with conc. HCl and stood at room temperature. The precipitated
solid was separated and sublimed. Mp: 1488C. IR (KBr): cm21 2990–2800
(m), 1685–1650 (s), 1575 (vs), 1495 (vs), 1360 (m), 1315 (s), 1165 (s), 1135
(s), 1040 (s), 970 (m), 880 (s), 800 (s), 780 (vs). NMR dH (acetone-d6): 6.43
(bs, 1H, 5-Py-H), 7.77 (bs, 1H, 4-Py-H), 7.93 (bs, 1H, 6-Py-H), 12.22 (bs,
1H, OH); dC 115.8, 120.2 (q, JC-F ¼ 31.2 Hz), 123.1 (q, JC-F ¼ 271.1 Hz),
139.8, 140.7, 159.9 (q, JC-F ¼ 4.5 Hz). MS m/z (%): 164 (9), 163 (Mþ, 100),
144 (24), 135 (48), 116 (22), 115 (75), 88 (37), 85 (12), 57 (13).
5-Iodo-3-trifluoromethyl-2-pyridinol (12). In a solution of potassium
carbonate (840 g) in 10 ml of water, 12 (486 mg, 3 mmol) was dissolved,
whereupon iodine (795 mg, 3.1 mmol) was added in a small portion. The
mixture was stirred for 12 h at room temperature and then 1 h at 508C. The
cooled mixture was poured onto cold water (ca. 30 ml), and the precipitate
was filtered and thoroughly washed with water. Crude product (600 mg)
was used in the next step. For analysis a small crop was sublimed. Mp:
145–1478C. IR (KBr): cm21 1700–1650 (s), 1550 (vs), 1460 (vs), 1340 (s),
1300 (vs), 1250 (s), 1180 (vs), 1090 (s), 1045 (s), 955 (vs), 875 (vs), 785
(m), 675 (s). NMR (CDCl3): dH 7.86 (d, 1H, 4-Py-H, J ¼ 2.2 Hz), 7.98

Substituted Imidacloprid
1241
(d, 1H, 6-Py-H, J ¼ 2.2 Hz); dC 105.8, 121.5 (q, JC-F ¼ 272.4 Hz), 122.0
(q, JC-F ¼ 31.3 Hz), 144.5, 148.1 (q, JC-F ¼ 4.5 Hz), 160.0. MS m/z (%):
289 (Mþ, 100), 288 (86), 241 (52), 142 (22), 127 (27), 114 (28), 106 (22).
Anal. Found: C, 25.20; H, 0.98; N, 4.82. Calcd. for C6H3F3INO: C, 24.94;
H, 1.05; N, 4.85.
2-Chloro-5-iodo-3-trifluoromethylpyridine (13). To an ice-cold mixture of
POCl3 (770 mg) and DMF (220 mg), pyridone (12) (288 mg, 1.0 mmol) was
added. The mixture was gradually warmed to 80 8C during ca.1 h and kept
at this temperature for 2.5 h. The cooled reaction mixture was poured onto
cold water; the precipitated solid was collected by suction. Sublimation of
crude product (180 mg) afforded colorless crystals (irritant!). Mp: 438C.
NMR (CDCl3): dH 8.28 (d, 1H, 4-Py-H, J ¼ 1.4 Hz), 8.78 (d, 1H, 6-Py-H,
J ¼ 1.4 Hz); dC 89.8, 121.2 (q, JC-F ¼ 273.5 Hz), 126.9 (q, JC-F ¼ 33.6 Hz),
144.5, (q, JC-F ¼ 4.6 Hz), 148.5, 164.9. MS m/z (%): 309 (Mþ þ 2, 65), 307
(Mþ, 100), 180 (74), 160 (25), 145 (18), 127 (22). HRMS (EI) m/z (Mþ):
calcd. for C6H2ClF3I, 306.8873; found, 306.8880.
5-Iodo-2-methoxy-3-trifluoromethylpyridine (14).
A mixture of 12
(2.836 g, 9.81 mmol), iodomethane (1.630 g, 11.4 mmol), silver carbonate
(1.47 g, 13.6 mmol) in hexane (50 ml), and THF (10 ml) was stirred 25 h at
408C. After evaporating the solvent, column chromatography of the residual
solid on SiO2 with hexane afforded 920 mg (30% yield) of liquid, which
was solidified in a refrigerator overnight. A portion was sublimed for
analysis. Mp: 278C. IR (liquid): cm21 2950 (m), 1590 (s), 1565 (s), 1470
(s), 1410 (s), 1310 (vs), 1280 (vs), 1240 (m), 1140 (vs), 1045 (s), 1005 (m),
910 (m). NMR (CDCl3): dH 4.01 (s, 3H, CH3), 8.07 (s, 1H, 4-Py-H), 8.49
(s, 1H, 6-Py-H); dC 54.3, 80.3, 115.1 (q, JC-F¼ 33.5 Hz), 122.0 (q, JC-F
¼
273.5 Hz), 143.8 (q, JC-F ¼ 4.8 Hz), 144.5, 156.3, 160.3. MS m/z (%): 303
(Mþ, 53), 302 (31), 274 (49), 273 (29), 147 (28), 146 (36), 127 (43), 126
(36), 44 (100). Anal. Found: C, 27.69; H, 1.56; N, 4.81. Calcd. for
C7H5F3INO: C, 27.74; H, 1.66; N, 4.62.
5-Cyano-2-methoxy-3-trifluoromethylpyridine (15). A mixture of 14
(1.01 g, 3.3 mmol), zinc cyanide (240 mg, 2.05 mmol), and tetrakis(triphenyl-
phosphine)palladium(0) (150 mg, 0.13 mmol) in 15 ml of DMF was stirred at
808C under an argon atmosphere for 8 h. Toluene extract was washed twice
with 30 ml of 2 N ammonia, washed once with 20 ml of brine, and dried
over MgSO4. Crystallization of crude product from hexane gave 546 mg
(82%). Mp: 648C. IR (KBr): cm212235 (m), 1620 (s), 1560 (s), 1500 (vs),
1400 (vs), 1300 (s), 1245 (s), 1200 (s), 1155 (vs), 1065 (s), 1000 (vs), 945
(s), 720 (vs). NMR (CDCl3): dH 4.13 (s, 3H, CH3), 8.09 (s, 1H, 4-Py-H),
8.64 (s, 1H, 6-Py-H); dC 55.4, 102.3, 114.1 (q, JC-F ¼ 33.8 Hz), 115.9,
122.0 (q, JC-F ¼ 272.3 Hz), 139.2 (q, JC-F ¼ 4.8 Hz), 154.8, 162.8. MS m/z
(%): 201 (Mþ, 20), 199 (16), 185 (77), 184 (100), 183 (100), 170 (22),

1242
S. Kagabu
157 (33), 152 (68), 44 (100). Anal. Found: C, 47.63; H, 2.36; N, 13.74. Calcd.
for C8H5F3N2O: C, 47.53; H, 2.49; N, 13.86.
2-Methoxy-3-trifluoromethyl-5-pyridinemethanol (16). A solution of 15
(634 mg, 3.15 mmol) in 10 ml of dry toluene was treated dropwise with
DIBAL (1.5 M toluene solution; 5 ml) with ice cooling under argon atmos-
phere. The mixture was stirred at ambient temperature for 12 h. The mixture
was cooled again and treated with 30 ml of water and then 5 ml of 2 N
HCl. The toluene extracts were dried over MgSO4. The crude product
(ca. 600 mg) was dissolved in 10 ml of methanol, and cooled in ice-water
bath. Then 140 mg of NaBH4 was added in 10 min, and the stirring was
continued for 12 h at ambient temperature. The reaction mixture was neutral-
ized with 2% HCl solution and extracted with IPE (15 ml ꢀ 3). The extracts
were dried, the solvent was evaporated, and the residual liquid was
subjected to column chromatography on SiO2 with IPE. Product was
obtained as needles. Yield: 278 mg (43%). Mp: 40–438C. IR (KBr): cm21
3215 (m), 1620 (s), 1580 (s), 1490, (vs), 1445 (s), 1410 (vs), 1320 (s), 1250
(s), 1205 (s), 1140 (s), 1020 (s), 920 (s), 905 (vs), 785 (vs), 745 (m). NMR
(CDCl3): dH 4.04 (s, 3H, CH3), 4.68 (s, 2H, CH2), 7.90 (s, 1H, 4-Py-H),
8.26 (s, 1H, 6-Py-H); dC 54.3, 61.9, 113.2 (q, JC-F ¼ 33.6 Hz), 116.2, 123.0
(q, JC-F ¼ 272.3 Hz), 136.1 (q, JC-F ¼ 4.8 Hz), 149.0, 160.6. MS m/z (%):
207 (Mþ, 34), 206 (37), 190 (5), 188 (7). Anal. Found: C, 46.53; H, 3.56;
N, 7.01. Calcd. for C8H8F3NO2: C, 46.38; H, 3.89; N, 6.76.
6-Chloro-5-trifluoromethylpyridin-3-ylmethyl chloride (17). To an ice-
cold solution of 18 (207 mg, 1 mmol) in 0.5 ml DMF, 0.5 ml POCl3 was
added dropwise. After 10 min of stirring at room temperature, the temperature
was gradually raised to 1008C, where it was kept for 40 min. The cooled
reaction mixture was poured onto ice water and extracted with IPE
(15 ml ꢀ 3). The organic extract was washed with 1% aq. NaHCO3 and
water and dried. The product was separated on preparative thin-layer chrom-
atography on SiO2 with IPE/hexane 1:1. Yield: 150 mg (66%). IR (liquid):
cm211600 (m), 1570 (m), 1440 (s), 1415 (m), 1330 (vs), 1245 (m), 1170
(vs), 1150 (vs), 1050 (s). NMR (CDCl3): dH 4.63 (s, 3H, CH3), 8.07 (s, 1H,
4Py-H), 8.58 (s, 1H, 6-Py-H); dC 41.4, 121.9 (q, JC-F ¼ 270.0 Hz), 125.4
(q, JC-F ¼ 33.6 Hz), 132.5, 136.9 (q, JC-F ¼ 4.8 Hz), 148.9, 151.8. MS m/z
(%): 229 (Mþ, 10), 228 (100), 194 (42), 159 (40), 158 (24), 125 (8), 110
(12). HRMS (EI) m/z (Mþ): calcd. for C7H4Cl2F3N, 228.9673; found,
228.9691.
1-(6-Chloro-5-trifluoromethyl-3-pyridylmethyl)-2-nitroiminoimidazoli-
dine (1e). This compound was obtained in 72% yield using 17 as described
for preparation of compound 1c. Mp: 150-1518C. IR (KBr): cm21 3065
(m), 1600 ꢀ 1530 (s), 1480 (vs), 1440 (vs), 1410 (s), 1350 (vs), 1215 (vs),
1135 (vs), 980 (s), 930 (vs), 760 (s), 720 (m). NMR (CDCl3): dH˙ 3.57

Substituted Imidacloprid
1243
(m, 2H, NCH2CH2N), 3.84 (m, 2, NCH2CH2N), 4.627 (s, 2, CH2), 8.00 (s, 4-
Py-H), 8.22 (bs, 1, NH), 8.53 (s, 1H, 6-Py-H); dC 41.6, 45.3, 45.6, 121.9 (q, JC-
¼ 373.5 Hz), 125.6 (q, JC-F ¼33.6 Hz), 130.3, 136.7 (q, JC-F ¼ 4. Hz),
F
149.0, 161.4. MS m/z (%): 323 (Mþ, 3), 279 (44), 277 (100), 275 (17), 262
(11), 242 (51), 241 (80), 196 (14), 194 (42). Anal. Found: C, 37.41; H,
2.70; N, 21.41. Calcd. for C10H9ClF3N5O2: C, 37.11; H, 2.80; N, 21.64.
2-Chloro-5-methylnicotinamide (19). A mixture of 18 (460 mg, 3 mmol) and
1.2 ml of conc. H2SO4 was stirred at 60–658C for 3 h. The cooled mixture was
poured onto ice water, neutralized with sodium carbonate, and extracted with
ethyl acetate. Evaporation and recrystallization from toluene gave 310 mg
(59%) of product. Mp: 146–1478C (141–1438C).[15] IR (KBr): cm21 1700
(vs), 1565 (m), 1420 (s), 1360 (m), 1075 (m), 725 (m). NMR (CDCl3):
dH˙2.38 (s, 3H, CH3), 6.16 (bs, 1H, NH), 6.70 (bs, 1H, NH), 8.07 (d, 1H,
4-Py-H, J ¼ 1.2 Hz), 8.31 (d, 1H, 6-Py-H, J ¼ 1.2 Hz); dC 17.6, 129.1,
133.2, 141.1, 144.5, 151.86, 166.3. MS m/z (%): 172 (30), 170 (Mþ, 90),
155 (32), 153 (100), 127 (11), 125 (35), 90 (17).
Methyl 2-chloro-5-methylnicotinate (20). A mixture of 19 (620 mg,
3.62 mmol), trifluoroborane-diethyl ether (4 ml), and dry methanol (10 ml)
was heated at reflux temperature for 17 h. After concentration, the residue
was poured onto ice water. IPE extracts were washed with water and dried.
The product was purified by column chromatography on SiO2 with IPE.
Product (413 mg, 66%) was obtained as pale yellow liquid. IR (liquid):
cm21 1735 (vs), 1560 (s), 1435 (s), 1420 (vs), 1310 (s), 1235 (vs), 1135 (s),
1070 (s), 910 (m), 790 (m), 780 (m). NMR (CDCl3): dH˙ 2.37 (s, 3H, Py-
CH3), 3.95 (s, 3H, OCH3), 7.97 (d, 1H, 4-Py-H, J ¼ 1.2 Hz), 8.30 (d, 1H,
6-Py-H, J ¼ 1.2 Hz); dC 17.6, 52.9, 126.1, 132.3, 140.9, 147.2, 152.2,
165.2. MS m/z (%): 187 (18), 185 (Mþ, 57), 155 (32), 153 (100), 127 (8),
125 (35), 125 (25). HRMS (EI) m/z (Mþ): Calcd. for C8H8ClNO2,
185.0244; found, 185.0265.
Methyl 5-bromomethyl-2-chloronicotinate (21). To a suspension of 20
(160 mg, 0.86 mmol) and NBS (130 mg, 0.73 mmol) in CCl4, 10 mg of
benzoyl peroxide was added at 768C. The mixture was heated under reflux
for 1 h. After evaporating the solvent, the residue was separated by column
chromatography on SiO2 with hexane/IPE 4 : 1. Product (80 mg, 35%) was
isolated as a yellowish liquid, containing a small amount of 20. NMR
(CDCl3): dH˙ 3.97 (s, 3H, CH3), 4.48 (s, 2H, CH2), 8.21 (d, 1H, 4-Py-H,
J ¼ 2.6 Hz), 8.52 (d, 1H, 6-Py-H, J ¼ 2.6 Hz); dC 17.5, 53.0, 126.7, 132.8,
140.8, 140.9, 151.6, 164.4. MS m/z (%): 265 (17), 264 (100), 263 (Mþ,
24), 233 (20), 184 (17).
1-(6-Chloro-5-methoxycarbonyl-3-pyridylmethyl)-2-nitroiminoimidazo-
lidine (1f). This compound was obtained in 51% yield using 21 as described

1244
S. Kagabu
for preparation of compound 1d. Mp: 162–1638C. IR (KBr): cm21 3420 (m),
1720 (s), 1575 (vs), 1475 (m), 1440–1400 (m), 1290 (vs), 1240 (vs), 1135 (m),
1065 (s), 945 (m), 780 (m). NMR (CDCl3): dH˙ 3.55 (m, 2H, NCH2CH2N), 3.84
(m, 2H, NCH2CH2N), 3.97 (s, 3H, CH3), 4.59 (s, 2H, CH2), 8.12 (d, 1H, 4-Py-
H, J ¼ 2.6 Hz), 8.23 (bs, 1H, NH), 8.46 (d, 1H, 6-Py-H, J ¼ 2.6 Hz); dC 41.8,
45.4, 45.6, 53.3, 127.2, 130.3, 140.4, 150.0, 151.6, 161.5, 164.8. MS m/z (%):
315 (1), 313 (Mþ, 5), 282 (13), 269 (62), 267 (100), 265 (16), 234 (26), 231
(53), 217 (22). Anal. Found: C, 42.32; H, 3.65; N, 22.63. Calcd. for
C11H12ClN5O2: C, 42.11; H, 3.86; N, 22.33.
ACKNOWLEDGMENTS
This work was partly supported by the Grant-in AID for Scientific Research
(C) (No. 17580094) from the Japan Society for the Promotion of Science.
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