The discovery of thiamethoxam: A second-generation neonicotinoid

Article abstract of DOI:10.1002/1526-4998(200102)57:2<165::AID-PS289>3.0.CO;2-G

Neonicotinoids represent a novel and distinct chemical class of insecticides with remarkable chemical and biological properties. In 1985, a research programme was started in this field, in which novel nitroimino heterocycles were designed, prepared and assayed for insecticidal activity. The methodology for the synthesis of 2-nitroimino-hexahydro-1,3,5-triazines, 4-nitroimino-1,3,5-oxadiazinanes and 4-nitroimino-1,3,5-thiadiazinanes is outlined. Bioassays demonstrated that 3-(6-chloropyridin-3-ylmethyl)-4-nitroimino-1,3,5-oxadiazinane exhibited better insecticidal activity than the corresponding 2-nitroimino-hexahydro-1,3,5-triazine and 4-nitroimino-1,3,5-thiadiazinane. In most tests, this compound was equally or only slightly less active than imidacloprid. A series of structural modifications on this lead structure revealed that replacement of the 6-chloro-3-pyridyl group by a 2-chloro-5-thiazolyl moiety resulted in a strong increase of activity against chewing insects, whereas the introduction of a methyl group as pharmacophore substituent increased activity against sucking pests. The combination of these two favourable modifications led to thiamethoxam (CGA 293 343). Thiamethoxam is the first commercially available second-generation neonicotinoid and belongs to the thianicotinyl sub-class. It is marketed under the trademarks Actara for foliar and soil treatment and Cruiser for seed treatment. The compound has broad-spectrum insecticidal activity and offers excellent control of a wide variety of commercially important pests in many crops. Low use rates, flexible application methods, excellent efficacy and the favourable safety profile make this new insecticide well-suited for modern integrated pest management programmes in many cropping systems.

Full text of DOI:10.1002/1526-4998(200102)57:2<165::AID-PS289>3.0.CO;2-G

Pest Management Science
Pest Manag Sci 57:165±176 (2001)
The discovery of thiamethoxam:
a second-generation neonicotinoid†
Peter Maienfisch,* Hanspeter Huerlimann, Alfred Rindlisbacher, Laurenz Gsell,
Hansruedi Dettwiler, Joerg Haettenschwiler, Evelyne Sieger and Markus Walti
Novartis Crop Protection AG, Research Department, WRO-1060.1.14, CH-4002 Basel, Switzerland
Abstract: Neonicotinoids represent a novel and distinct chemical class of insecticides with remarkable
chemical and biological properties. In 1985, a research programme was started in this ®eld, in which
novel nitroimino heterocycles were designed, prepared and assayed for insecticidal activity. The
methodology for the synthesis of 2-nitroimino-hexahydro-1,3,5-triazines, 4-nitroimino-1,3,5-oxadia-
zinanes and 4-nitroimino-1,3,5-thiadiazinanes is outlined. Bioassays demonstrated that 3-(6-chloro-
pyridin-3-ylmethyl)-4-nitroimino-1,3,5-oxadiazinane exhibited better insecticidal activity than the
corresponding 2-nitroimino-hexahydro-1,3,5-triazine and 4-nitroimino-1,3,5-thiadiazinane. In most
tests, this compound was equally or only slightly less active than imidacloprid. A series of structural
modi®cations on this lead structure revealed that replacement of the 6-chloro-3-pyridyl group by a 2-
chloro-5-thiazolyl moiety resulted in a strong increase of activity against chewing insects, whereas the
introduction of a methyl group as pharmacophore substituent increased activity against sucking pests.
The combination of these two favourable modi®cations led to thiamethoxam (CGA 293 343).
Thiamethoxam is the ®rst commercially available second-generation neonicotinoid and belongs to
the thianicotinyl sub-class. It is marketed under the trademarks Actara1 for foliar and soil treatment
and Cruiser1 for seed treatment. The compound has broad-spectrum insecticidal activity and offers
excellent control of a wide variety of commercially important pests in many crops. Low use rates,
¯exible application methods, excellent ef®cacy and the favourable safety pro®le make this new
insecticide well-suited for modern integrated pest management programmes in many cropping
systems.
# 2001 Society of Chemical Industry
Keywords: insecticides; neonicotinoids; thiamethoxam; discovery; synthesis; 2-nitroimino-hexahydro-1,3,5-tri-
azines; 4-nitroimino-1,3,5-oxadiazinanes; 4-nitroimino-1,3,5-thiadiazinanes; insecticidal activity; structure-
activity relationships
1
INTRODUCTION
were published in 1985,7 and this triggered extensive
research activities within several other companies.
Ciba (since 1996 Novartis), Takeda, Nippon Soda,
Agro Kanesho, Mitsui Chemicals and others immedi-
ately entered this promising research area. Shortly
after the launch of imidacloprid in 1991, nitenpyram
(4)8 (Takeda, 1995) and acetamiprid (5)9 (Nippon
Soda, 1996) were brought to the market. Each of these
three products has a 6-chloropyrid-3-ylmethyl moiety
as a heterocyclic group. This is a common structural
feature of ®rst-generation neonicotinoids.10
In 1998, Novartis launched thiamethoxam (6),10±12
a novel neonicotinoid with a unique structure and
outstanding insecticidal activity. Three other pro-
ducts, thiacloprid (7)13 (Bayer), clothianidin (8)14±16
(Takeda, Bayer) and dinotefuran (9)17 (Mitsui
Chemicals), are currently under development and
are expected to enter the marketplace in due course.
Neonicotinoids1 represent a novel and distinct chemi-
cal class of insecticides with remarkable chemical and
biological properties.2 Researchers at Shell described
in 1972 for the ®rst time the insecticidal properties of
some simple nitromethylene heterocycles (Fig 1, 1).3,4
Their work resulted in the discovery of nithiazine (2),5
a compound which has never been commercialised as
a crop-protection agent. This compound, however,
has served as a neonicotinoid lead structure. Thirteen
years later, with the synthesis of imidacloprid (3),
Nihon Tokushu Nohyaku (now Nihon Bayer)
achieved an important breakthrough in this chemistry.
By introducing a 6-chloropyridin-3-ylmethyl group as
a substituent of the nitromethylene heterocycle, the
insecticidal activity against green rice leafhoppers
could be enhanced by a factor of more than 100.6
First patent applications covering this new invention
* Correspondence to: Peter Maienfisch, Novartis Crop Protection AG, Research Department, WRO-1060.1.14, CH-4002, Basel, Switzerland
E-mail: peter.maienfisch@cp.novartis.com
† Based on a paper presented at the Symposium ‘New Chemistries for Crop Protection’ organised by Dr L Copping and the late Dr J Dingwall
on behalf of the Bioactive Sciences and Crop Protection Groups of the SCI and held at 14/15 Belgrave Square, London, UK on 19 June 2000
(Received 1 November 2000; accepted 20 November 2000)
# 2001 Society of Chemical Industry. Pest Manag Sci 1526±498X/2001/$30.00
165

P Maien®sch et al
Figure 1. Neonicotinoid lead, commercial and
development compounds.
Since the market introduction of imidacloprid, the
neonicotinoids have been the fastest growing chemical
class of insecticide. This tremendous success can be
explained by their unique chemical and biological
properties, such as broad-spectrum insecticidal activ-
ity, low application rates, excellent uptake and trans-
location in plants, new mode of action and favourable
safety pro®le.
The present communication reports the discovery of
this compound, which is marketed under the trade
names Actara1 for foliar and soil treatment, and
Cruiser1 for seed treatment.
2
MATERIALS AND METHODS
2.1 Chemical synthesis
Ciba started a research programme on neonico-
tinoids in 1985. Our efforts resulted in the synthesis of
acyclic nitroenamines, acyclic cyanoguanidines,
acyclic nitroguanidines, 3-heterocyclylmethyl-2-nitro-
methylene-pyrrolidines, isoxazoles and novel nitro-
imino heterocycles such as 4-nitroimino-1,3,5-
oxadiazinanes.10 Among these chemistries, 4-nitro-
imino-1,3,5-oxadiazinane derivatives were found to
possess the most interesting chemical and biological
properties. Thiamethoxam (6) was identi®ed as the
best representative of this novel class of compound and
selected for world-wide development. Belonging to the
sub-class of thianicotinyl compounds,10 it represents
the ®rst example of second-generation neonicotinoids.
Imidacloprid (3),7 nitenpyram (4),18 acetamiprid
(5),19S-methyl-N-nitroisothiourea (10),20 compound
24,21 6-chloropyridin-3-ylmethylamine,18 6-chloro-
pyridin-3-ylmethyl chloride,22 2-chlorothiazol-5-yl-
methyl chloride23 and 2-chlorothiazol-5-ylmethyl-
amine18 were prepared according to literature proce-
dures. The synthetic pathways used to prepare the new
nitroimino-heterocycles are discussed in detail in
Section 3.2 and the syntheses of the 4-nitroimino-
1,3,5-oxadiazinanes in Section 3.3.
Representative procedures are given below; the
yields were not optimised. All spectra were consistent
with the assigned structures, and all compounds were
>98% purity based on TLC and [1H]NMR spectra.
166
Pest Manag Sci 57:165±176 (2001)

Thiamethoxam
2.1.1 N-(6-chloropyridin-3-ylmethyl)-N'-nitroguani-
dine (11a)
®ltrate concentrated under vacuum, and the residue
puri®ed by chromatography on silica gel using di-
chloromethane‡methanol (19‡1 by volume) as
eluent to yield 13a, yield 1.1g, 24%. 3,5-Bis(6-
chloropyridin-3-ylmethyl)-4-nitroimino-1,3,5-oxadia-
zinane (19) was isolated as a by-product, yield 0.5g,
11%, mp 190±192°C. [1H]NMR (250MHz, d6-
DMSO): 8.48 (d, J =2Hz, 2H), 7.82 (dd, J1 =7Hz,
J2 =2Hz, 2H), 7.57 (d, J =7Hz, 2H), 5.12 (s, 4H),
4.60 (s, 4H).
A mixture of S-methyl-N-nitroisothiourea (10; 3.0g,
22.2mmol) and 6-chloropyridin-3-ylmethylamine
(3.17g, 22.2mmol) in ethanol (25ml) was heated at
80°C for 3h. On cooling to room temperature, N-(6-
chloropyridin-3-ylmethyl)-N'-nitroguanidine (11a)
crystallised out of the reaction mixture as a white
solid. Yield 4.26g, 84%, mp 198±200°C. [1H]NMR
(250MHz, d6-DMSO): 8.97 (bs, 1H), 8.38 (d,
J =2Hz, 1H), 8.08 (bs, 2H), 7.79 (dd, J1 =7Hz,
J2 =2Hz, 1H), 7.55 (d, J =7Hz, 1H), 4.44 (bd,
J =3Hz, 2H). Calculated for C7H8ClN5O2:C, 36.61;
H, 3.51; Cl, 15.44; N, 30.50. Found: C, 36.9; H, 3.7;
Cl, 15.4; N, 30.5.
2.1.4 3-(6-Chloropyridin-3-ylmethyl)-4-nitroimino-
1,3,5-thiadiazinane (14)
2.1.4.1 Method A. To a mixture of 11a (10.0g,
46.6mmol) and 37% aqueous formaldehyde solution
(8.7ml) in nitromethane (130ml) was added concen-
trated hydrochloric acid (43.5ml) and then, over a
10min period, sodium sul®de nonahydrate (10.4g,
43.3mmol). The mixture was heated at re¯ux tem-
perature for 5h and then concentrated under vacuum.
The residue was puri®ed by chromatography on silica
gel using dichloromethane‡methanol (19‡1 by
volume) as eluent to yield 14 as a white solid, yield
0.10g, 0.8%, mp 161±163°C. [1H]NMR (250MHz,
d6-DMSO): 10.21 (s, 1H), 8.38 (d, J =2Hz, 1H),
7.81 (dd, J1 =7Hz, J2=2Hz, 1H), 7.55 (d, J =7Hz,
1H), 4.79 (s, 2H), 4.75 (s, 2H), 4.63 (s, 2H).
Calculated for C9H10ClN5O2S:C, 37.57; H, 3.50;
Cl, 12.32; N, 24.34; S, 11.14. Found: C, 37.52; H,
3.56; Cl, 12.15; N, 24.49; S, 11.32.
2.1.2 1-(6-chloropyridin-3-ylmethyl)-5-methyl-2-nitro-
imino-hexahydro-1,3,5-triazine (12)
A mixture of 11a (2.59g, 11.3mmol), 37% aqueous
formaldehyde solution (1.75ml, 22.6mmol), 40%
aqueous methylamine solution (1.0ml, 11.3mmol)
and ethanol (10ml) was heated to 50°C for 4h. The
solution was then evaporated to dryness under
reduced pressure, and the solid residue recrystallised
from ethanol‡ethyl acetate to afford 12 as a white
solid, yield 2.78g, 86%, mp 157±159°C. [1H]NMR
(250MHz, CDCl3): 9.64 (bs, 1H), 8.32 (d, J =2Hz,
1H), 7.82 (dd, J1 =7Hz, J2=2Hz, 1H), 7.36 (d,
J =7Hz, 1H), 4.65 (s, 2H), 4.38 (bs, 2H), 4.26 (s,
2H), 2.47 (s, 3H). Calculated for C10H13ClN6O2:C,
42.19; H, 4.60; Cl, 12.45; N, 29.52. Found: C, 42.2;
H, 4.7; Cl, 12.1; N, 29.2.
2.1.4.2 Method B. A mixture of 4-nitroimino-1,3,5-
thiadiazinane (18; 27.0g, 166mmol), 6-chloropyridin-
3-ylmethyl chloride (27.0g, 166mmol) and potassium
carbonate (55.0g, 399mmol) in DMF (200ml) was
stirred at room temperature for 24h. After ®ltration,
the ®ltrate was concentrated under vacuum and the
residue was puri®ed by chromatography on silica gel
using dichloromethane‡methanol (19‡1 by volume)
as eluent to give 14, yield 11.2g, 23%. 3,5-Bis(6-
2.1.3 (6-Chloropyridin-3-ylmethyl)-4-nitroimino-
1,3,5-oxadiazinane (13a)
2.1.3.1 Method A. A mixture of 11a (3.0g, 13.1
mmol), 37% aqueous formaldehyde solution (10ml)
and formic acid (10ml) was heated to 80°C for 18h.
After cooling to 0°C, aqueous sodium hydroxide
solution (300g litre 1, approximately 30ml) was
added to adjust the solution to pH 8. The resulting
mixture was then extracted with dichloromethane.
The organic layer was separated, washed with brine,
dried with anhydrous sodium sulfate and evaporated.
The solid residue was recrystallised from ethyl
acetate‡ether to afford 13a as a white solid, yield
2.09g, 59%, mp 166±168°C. [1H]NMR (250MHz,
d6-DMSO): 9.81 (bs, 1H), 8.37 (d, J =2Hz, 1H),
7.81 (dd, J1 =7Hz, J2 =2Hz, 1H), 7.53 (d, J =7Hz,
1H), 5.02 (s, 2H), 4.95 (d, J =2Hz, 2H), 4.60 (s,
2H). Calculated for C9H10ClN5O3:C, 39.79; H, 3.71;
Cl, 13.05; N, 25.78. Found: C, 39.71; H, 3.74; Cl,
12.92; N, 25.74.
chloropyridin-3-ylmethyl)-4-nitroimino-1,3,5-thiadia
-
zinane (20) was isolated as a by-product, yield 13.0g,
19%, mp 181±182°C. [1H]NMR (250MHz, d6-
DMSO): 8.41 (d, J =2Hz, 2H), 7.85 (dd, J1 =7Hz,
J2 =2Hz, 2H), 7.58 (d, J =7Hz, 2H), 4.81 (s, 4H),
4.77 (s, 4H).
2.1.5 N-Methyl-N'-nitroguanidine (15b)
A mixture of 10 (83.0g, 0.614mol) and an 8.0M
solution of methylamine in ethanol (91.0ml,
0.737mol) in ethanol (230ml) was stirred for 1h at
room temperature and then for 3h at 80°C. On
cooling to 0°C, 15b crystallised out of the reaction
mixture as a white solid, yield 70.0g, 97%, mp 160±
162°C. [1H]NMR (250MHz, d6-DMSO): 8.60 (bs,
1H), 7.85 (bs, 2H), 2.78 (d, J =3Hz, 3H). Calculated
for C2H6N4O2:C, 20.34; H, 5.12; N, 47.44. Found:
C, 20.37; H, 5.17; N, 47.17.
2.1.3.2 Method B. A mixture of 4-nitroimino-1,3,5-
oxadiazinane (17a; 2.5g, 17mmol), 6-chloropyridin-
3-ylmethyl chloride (2.8g, 17mmol) and potassium
carbonate (5.6g, 40mmol) in N,N-dimethylforma-
mide (DMF; 20ml) was stirred at 30°C for 18h. The
reaction mixture was ®ltered through Celite, the
Pest Manag Sci 57:165±176 (2001)
167

P Maien®sch et al
2.1.6 5-Methyl-2-nitroimino-hexahydro-1,3,5-triazine
(16)
22.22; H, 3.73; N, 34.55; S, 19.77. Found: C, 22.27;
H, 3.71; N, 34.62; S, 19.37.
A mixture of nitroguanidine (15a; 26.0g, 0.25mol),
37% aqueous formaldehyde solution (38.0ml,
0.50mol), an 8.03M solution of methylamine in
ethanol (31.1ml, 0.25mol) and ethanol (100ml) was
heated to 50°C for 3h. On cooling to 0°C, 16
crystallised out as a white solid, yield 28.3g, 71%,
mp 173±175°C. [1H]NMR (250MHz, d6-DMSO):
8.72 (bs, 2H), 4.19 (s, 4H), 2.41 (s, 3H). Calculated
for C4H9N5O2:C, 30.19; H, 5.70; N, 44.00. Found:
C, 30.20; H, 5.88; N, 43.92.
2.1.10 3-(6-Chloropyridin-3-ylmethyl)-5-methyl-4-
nitroimino-1,3,5-oxadiazinane (21a)
2.1.10.1 Method A. A mixture of 3-methyl-4-nitro-
imino-1,3,5-oxadiazinane (17b; 1.44g, 9.0mmol), 6-
chloropyridin-3-ylmethyl chloride (2.20g, 13.5mmol)
and potassium carbonate (3.73g, 27.0mmol) in DMF
(20ml) was stirred at 50°C for 5h. The reaction
mixture was then ®ltered through Celite, and the
resulting solution concentrated under vacuum. The
residue was puri®ed by chromatography on silica gel
using dichloromethane‡methanol (19‡1 by volume)
as eluent to give 21a as a white solid, yield 1.93g, 75%,
mp 129±130°C. [1H]NMR (250MHz, d6-DMSO):
8.34 (d, J =2Hz, 1H), 7.77 (dd, J1 =7Hz, J2 =2Hz,
1H), 7.55 (d, J =7Hz, 1H), 5.07 (s, 2H), 5.02 (s,
2H), 4.66 (s, 2H), 2.88 (s, 3H). Calculated for
C10H12ClN5O3:C, 42.04; H, 4.23; Cl, 12.41; N,
24.51. Found: C, 42.2; H, 4.2; Cl, 12.3; N, 24.5.
2.1.7 4-Nitroimino-1,3,5-oxadiazinane (17a)
A mixture of nitroguanidine (15a; 5.0g, 38.4mmol),
37% aqueous formaldehyde solution (40ml) and
formic acid (40ml) was heated to 80°C for 16h. After
cooling to 0°C, aqueous sodium hydroxide solution
(300g litre 1, approximately 90ml) was added to
adjust the solution to pH 8. The resulting mixture
was then extracted with dichloromethane. The organic
layer was separated, washed with brine, dried with
anhydrous sodium sulfate and evaporated. The solid
residue was recrystallised from ethyl acetate to afford
17a as a white solid, yield 2.90g, 52%, mp >250°C.
[1H]NMR (250MHz, d6-DMSO): 9.17 (bs, 2H),
4.88 (s, 4H). Calculated for C3H6N4O3:C, 24.66; H,
4.14; N, 38.35. Found: C, 24.7; H, 4.1; N, 38.3.
2.1.10.2 Method B. A mixture of 3-(6-chloropyridin-
(13a;
3-ylmethyl)-4-nitroimino-1,3,5-oxadiazinane
1.50g, 5.5mmol), methyl iodide (1.18g, 8.3mmol)
and potassium carbonate (1.91g, 13.8mmol) in DMF
(20ml) was stirred at 40°C for 3h. The reaction
mixture was then ®ltered through Celite and the
resulting solution concentrated under vacuum. The
residue was puri®ed by chromatography on silica gel
using dichloromethane‡methanol (19‡1 by volume)
as eluent to give 21a as a white solid, yield 1.0g, 63%.
2.1.8 3-Methyl-4-nitroimino-1,3,5-oxadiazinane
(17b)
A mixture of N-methyl-N'-nitroguanidine (15b; 4.0g,
33.9mmol), 37% aqueous formaldehyde solution
(25ml) and formic acid (25ml) was heated to 80°C
for 15h. After cooling to 0°C, aqueous sodium hy-
droxide solution (300g litre 1, approximately 60ml)
was added to adjust the solution to pH 8. The resulting
mixture was then extracted with dichloromethane.
The organic layer was separated, washed with brine,
dried with anhydrous sodium sulfate, and evaporated.
The solid residue was recrystallised from ethyl
acetate‡diethyl ether to afford 17b as a white solid,
yield 3.84g, 71%, mp 140±142°C. [1H]NMR
(250MHz, d6-DMSO): 9.64 (bs, 1H), 4.90 (bs,
4H), 2.87 (s, 3H). Calculated for C4H8N4O3:C,
30.00; H, 5.04; N, 34.99. Found: C, 30.09; H, 4.94;
N, 34.89.
2.1.11 3-(2-Chlorothiazol-5-ylmethyl)-5-methyl-4-
nitroimino-1,3,5-oxadiazinane (thiamethoxam; 6)
2.1.11.1 Method A. A mixture of 3-methyl-4-nitro-
imino-1,3,5-oxadiazinane (17b; 8.30g, 52.0mmol), 2-
chlorothiazol-5-ylmethyl chloride (11.0g, 65mmol)
and potassium carbonate (17.3g, 125mmol) in DMF
(50ml) was stirred at 50°C for 16h. The reaction
mixture was then ®ltered through Celite and the
resulting solution concentrated under vacuum. The
residue was puri®ed by chromatography on silica gel
using dichloromethane‡methanol (19‡1 by volume)
as eluent to give 6 as a white solid, yield 10.7g, 71%,
mp 140±141°C. [1H]NMR (250MHz, d6-DMSO):
7.64 (s, 1H), 5.07 (s, 2H), 4.98 (s, 2H), 4.77 (s, 2H),
2.87 (s, 3H). Calculated for C8H10ClN5O3S:C,
32.94; H, 3.46; Cl, 12.15; N, 24.01; S, 10.99. Found:
C, 33.02; H, 3.44; Cl, 12.21; N, 24.08; S, 10.98.
2.1.9 4-Nitroimino-1,3,5-thiadiazinane (18)
To a mixture of nitroguanidine (15a; 41.6g, 0.40mol),
and 37% aqueous formaldehyde solution (80ml) in
nitromethane (120ml) was added concentrated hy-
drochloric acid (88ml) and then, over a 30-min
period, sodium sul®de nonahydrate (96g, 0.40mol).
The mixture was heated at re¯ux temperature for 5h,
then ®ltered and concentrated under vacuum to give
18 as a white solid, 53.0g, 41%, mp 222±223°C.
[1H]NMR (250MHz, d6-DMSO): 9.46 (bs, 2H),
4.51 (d, J =3Hz, 4H). Calculated for C3H6N4O2S:C,
2.1.11.2 Method B. A mixture of 3-(2-chlorothiazol-
5-ylmethyl)-4-nitroimino-1,3,5-oxadiazinane (13b;
1.50g, 5.4mmol), methyl iodide (1.15g, 8.1mmol)
and potassium carbonate (1.87g, 13.5mmol) in DMF
(20ml) was stirred at 40°C for 3h. The reaction
mixture was then ®ltered through Celite and the
resulting solution concentrated under vacuum. The
residue was puri®ed by chromatography on silica gel
168
Pest Manag Sci 57:165±176 (2001)

Thiamethoxam
using THF‡hexane (4‡1 by volume) as eluent to
give 6, yield 1.22g, 77%.
repellent effect, feeding behaviour, and growth regula-
tion 4 days later.
2.2.8 Diabrotica balteata: contact/feeding activity
Maize seedlings were placed on ®lter paper in plastic
cups, and 3ml of the test solution was pipetted onto
them. In addition, seedlings were treated in a spray
chamber and infested with 12±15 2nd-instar (L2)
larvae of Diabrotica balteata Lec (banded cucumber
beetle). The samples were checked for mortality and
growth regulation 6 days after treatment.
2.2 Biological assays
Each compound was formulated as a standard 50g
litre 1 (5% w/v) EC which was then diluted with water
containing a wetting agent to give AI concentrations of
1
200, 50, 12, 3, 0.8, 0.2 and 0.05mg litre for deter-
minations of LC80 values. Compounds were evaluated
in up to eight standard tests (primary screening assays
in Sections 2.2.1 to 2.2.8) for initial activity. Selected
compounds were tested for residual activity (second-
ary screening assays in Sections 2.2.9 to 2.2.12).
2.2.9 Diabrotica balteata: contact/feeding activity, soil
persistence
The test solutions were well mixed into a standard ®eld
soil. Thirty days after treatment, ®ve maize seedlings
and 10L2 larvae of D balteata were added into the soil.
The samples were checked for mortality and growth
regulation 10 days after infestation.
2.2.1 Aphis craccivora: contact/feeding activity
Pea seedlings, infested with an Aphis craccivora Koch
(black bean aphid) population of mixed ages, were
treated with the test solutions in a spray chamber and
checked for mortality 6 days after treatment.
2.2.10 Myzus persicae: systemic activity, soil
persistence
2.2.2 Aphis craccivora: systemic activity
Pea seedlings, infested with an A craccivora population
of mixed ages, were placed directly in the test solu-
tions. Mortality was assessed 6 days after introduction.
Potted pepper plants (in standard ®eld soil) were
treated with the test solutions by drench application.
Twenty-eight days after treatment, plants were in-
fested with a mixed M persicae population. Mortality
was assessed 2 and 7 days after infestation.
2.2.3 Myzus persicae: contact/feeding activity
Pea seedlings, infested with a Myzus persicae-Sulz
(green peach aphid) population of mixed ages, were
treated with the test solutions in a spray chamber and
assessed for mortality 6 days after treatment.
2.2.11 Nilaparvata lugens: contact/feeding activity,
foliar persistence
Rice seedlings were treated with the test solutions in a
spray chamber. After four days, they were infested
with 10±20N3 nymphs of N lugens. Samples were
checked for mortality and growth regulation 6 days
after treatment.
2.2.4 Myzus persicae: systemic activity
Pea seedlings, infested with an M persicae population
of mixed ages, were placed directly in the test solutions
and mortality was assessed 6 days after introduction.
2.2.12 Nilaparvata lugens: systemic activity,
persistence in water/soil
2.2.5 Nilaparvata lugens: contact/feeding activity
Rice seedlings were treated with the test solutions in a
spray chamber. After drying, they were infested with
10±20N3 nymphs of Nilaparvata lugens (Staol) (brown
plant hopper). Six to 12 days after treatment, samples
were checked for mortality, growth regulation, and
effects on F1 generation.
The test solutions were introduced into the water in a
paddy system in which potted rice seedlings were
grown. Twenty-eight days after treatment, the seed-
lings were infested with 10±20N3 nymphs of N lugens.
Six days after treatment, samples were checked for
mortality and growth regulation.
2.2.6 Spodoptera littoralis: contact/feeding activity
Cotton leaf discs were placed on agar in Petri dishes
and sprayed with the test solutions in a spray chamber.
After drying, the leaf discs were infested with 20±25
1st-instar (L1) larvae of Spodoptera littoralis (Boisch)
(cotton leaf worm). The samples were checked for
mortality, repellent effect, feeding behaviour, and
growth regulation 1 and 4 days after treatment.
3
RESULTS AND DISCUSSION
3.1 Design of novel neonicotinoids
The extremely high insecticidal activity of neonicoti-
noids, such as imidacloprid (3) and its six-ring
analogue 24 (Fig 2), described in a patent application
of Nihon Bayer in 19857 encouraged us to investigate
some novel structural modi®cations. From our own
work and from published data, we concluded that the
best insecticidal activity would be obtained with a
nitroamidine moiety as pharmacophore and a 6-
chloro-3-pyridyl moiety as heterocyclic group. How-
ever, little was known on the in¯uence of the
nitroimino heterocycle on the biological activity. We
therefore selected compounds 12, 13a and 14, posses-
2.2.7 Spodoptera littoralis: systemic activity
Seedlings of maize Zea mays L were placed directly in
the test solutions. Six days after introduction, the
leaves were cut and transferred into Petri dishes with
moist ®lter paper and infested with 12±15L1 larvae of
S littoralis. The samples were checked for mortality,
Pest Manag Sci 57:165±176 (2001)
169

P Maien®sch et al
Figure 2. Design of novel neonicotinoids.
sing an additional heteroatom in the nitroimino
heterocycle, as our initial target compounds. An
additional heteroatom may be capable of polar inter-
actions with nicotinic acetylcholine receptors, leading
to stronger binding and consequently to improved
insecticidal activity. Moreover, such heteroatoms may
also have a strong in¯uence on pharmaco-kinetic
behaviour (transport and metabolism), possibly re-
sulting in improved bioavailability.24
®rst concentrated our efforts towards the synthesis of
the 2-nitroimino-hexahydro-1,3,5-triazine 12. After
some experimentation, we found a two-step procedure
which proved to be widely applicable and which
produced 2-nitroimino-hexahydro-1,3,5-triazines in
excellent yields starting from S-methyl-N-nitrothio-
urea (10).25,26 Thus, treatment of 10 with 6-chloro-
pyridin-3-ylmethylamine at 80°C in ethanol for 3h
afforded the monosubstituted nitroguanidine 11a,
which could then be converted in a Mannich type
cyclisation reaction with 1 equivalent of methylamine
and 2 equivalents of formaldehyde to the nitroimino-
hexahydro-1,3,5-triazine 12 (Fig 3). Compound 12
could also be prepared from nitroguanidine via the
Any of our initial target compounds found to
possess interesting insecticidal activity were seen as
having three structural elements for further chemical
exploration: the heterocyclic group (Het), the phar-
macophore (N±C(=Y)±N) and the pharmacophore
substituent R. On the basis of this design, we planned
to prepare hexahydro-1,3,5-triazines A, oxadiazinanes
B and thiadiazinanes C, respectively, in our optimisa-
tion programme (Fig 2).
unsubstituted
nitroimino-hexahydro-1,3,5-triazine
16. However, the yield was low due to insuf®cient
selectivity in the alkylation reaction.
This ®rst representative (compound 12) of nitro-
imino-hexahydro-1,3,5-triazines was synthesised in
January 1990 and subjected to our primary greenhouse
screening. In response to the promising biological
results obtained, we started a broad optimisation
programme on the lead compound 12 which resulted
in the preparation of a series of 4-nitroimino-hexa-
hydro-1,3,5-triazines A. In October 1990 we ®led a
patent application for these compounds.25 We did not
3.2 Synthesis of the initial target compounds 12,
13a and 14
At the start of our research, no practical methods for
the preparation of the novel nitroimino heterocycles,
such as the 2-nitroimino-hexahydro-1,3,5-triazine 12,
the 4-nitroimino-1,3,5-oxadiazinane 13a and the 4-
nitroimino-1,3,5-thiadiazinane 14 were available. We
Figure 3. Methods for the preparation of novel nitroimino heterocycles.
170
Pest Manag Sci 57:165±176 (2001)

Thiamethoxam
Figure 4. First syntheses of 3-methyl-4-nitroimino-
1,3,5-oxadiazinane (17b).
know at that time, but must have feared due to the
considerable competition in this ®eld, that our
competitors had already been pursuing the same idea
and had themselves submitted patent applications for
nitroimino-hexahydro-1,3,5-triazines.27±29
(15a) via 4-nitroimino-1,3,5-oxadiazinane (17a).
Compound 17a was obtained in 52% yield from
nitroguanidine (15a) by our novel Mannich type
cyclisation method, and subsequent alkylation with
6-chloropyridin-3-ylmethyl chloride gave compound
13a in 24% yield. The dialkylated oxadiazinane 19 was
isolated in 11% yield as a by-product.
We therefore now focused our attention towards the
synthesis of 4-nitroimino-1,3,5-oxadiazinanes. How-
ever, all our initial attempts failed. A literature search
performed in 1990 revealed only one publication on 4-
nitroimino-1,3,5-oxadiazinanes.30 This paper con-
tained a two-step synthesis of 4-nitroimino-1,3,5-
oxadiazinane (17a) from nitroguanidine, but neither
the experimental procedures nor the yields were given.
Following the suggested route, we were not able to
produce pure oxadiazinane 17a. Also, a method for the
preparation of 3-methyl-4-cyanoimino-1,3,5-oxadia-
zinane from N-methyl-nitroguanidine (15b), which
was published in 1989 by Shiba et al,31 could not be
applied successfully for the synthesis of 4-nitroimino-
1,3,5-oxadiazinane.
From the good insecticidal activity shown by
compound 13a in the primary greenhouse screening
tests we were con®dent of the high biological potential
of 4-nitroimino-1,3,5-oxadiazinanes and we started an
extensive optimisation programme (see Section 3.3).
In 1992 we ®led a ®rst patent application for insecti-
cidal 4-nitroimino-1,3,5-oxadiazinanes.32 This patent
application included thiamethoxam (6) and many
other oxadiazinanes B with good insecticidal activity.
Subsequently, other companies have performed
further chemical work on neonicotinoids of the
oxadiazinane sub-class, which has resulted so far in
two patent applications.33,34
Our ®rst success towards the synthesis of 4-nitro-
imino-1,3,5-oxadiazinanes was based on serendipity.
Previously, we had converted monosubstituted nitro-
guanidines 11 or 15 to the corresponding 2-nitro-
imino-hexahydro-1,3,5-triazines A (Y = N±NO2) in
high yields with formaldehyde or paraformaldehyde
and more than 40 different amines.25 In none of these
reactions was the formation of a 4-nitroimino-1,3,5-
oxadiazinane as a side-product observed. However,
when we treated 15b with 1 equivalent of propargy-
lamine and three equivalents of paraformaldehyde in
the presence of a catalytic amount of concentrated
hydrochloric acid, the expected product 25 was not
formed; instead 3-methyl-4-nitroimino-1,3,5-oxadia-
zinane (17b) could be isolated as the only product in
41% yield (Fig 4). After some experimentation, we
discovered an improved method for the preparation of
17b. Thus, heating of 15b in a 1:1 mixture of aqueous
formaldehyde solution and formic acid for several
hours to 80°C afforded the nitroimino-1,3,5-oxadia-
zinane 17b in 71% yield.
Parallel with our optimisation programme on oxa-
diazinanes B we started to work on 4-nitroimino-
1,3,5-thiadiazinanes. The synthesis of our ®rst target
compound 14 was achieved as shown in Fig 3.
Treatment of 11a with formaldehyde and sodium
sul®de in the presence of concentrated hydrochloric
acid afforded compound 14 in only very low yield.
Alternatively, the thiadiazinane 14 could be obtained
in two steps from 15a via the cyclic intermediate 18.
Best yields for the Mannich type cyclisation reaction
15a → 18 were obtained if the reaction conditions
described by Moriie et al33 were applied. Alkylation of
18 with 6-chloropyridin-3-ylmethyl chloride gave the
target compound 14 in 23% yield and, as a by-product,
the dialkylated thiadiazinane 20 in 19% yield. The ®rst
patent application33 on the synthesis of 4-nitroimino-
1,3,5-thiadiazinanes was ®led in February 1994 by
one of our competitors in this ®eld and was, together
with the limited biological activity of compound 14,
the reason why we stopped our research on this sub-
class.
This novel method was applied to the nitroguani-
dine 11a and enabled the synthesis of our target
compound 13a in 59% yield (Fig 3). Alternatively, 13a
could be prepared in two steps from nitroguanidine
3.3 Optimisation of the oxadiazinane lead structure
13a
In the course of our optimisation program on the
Pest Manag Sci 57:165±176 (2001)
171

P Maien®sch et al
Figure 5. Syntheses of novel 4-nitroimino-1,3,5-oxadiazinanes.
oxadiazinane lead structure 13a we developed a
broadly applicable method for the preparation of
the novel 3-heterocyclylmethyl-5-alkyl-4-nitroimino-
1,3,5-oxadiazinanes 21 which allowed the introduc-
tion of the heterocyclylmethyl or arylmethyl group
either from a heterocyclylmethyl or arylmethylamine
22 or a heterocyclylmethyl or arylmethyl chloride 23
(Fig 5; Table 1).35 Thus, treatment of S-methyl-N-
nitroisothiourea (10) with amines 22 afforded N-
monosubstituted-N'-nitroguanidines 11, which could
be converted to 3-monosubtituted-4-nitroimino-
1,3,5-oxadiazinane 13 using a 1:1 mixture of formal-
Table 1. Structure and chemical data of compounds 11, 13, 15, 17, 21 and 6
Compound
Het/Aryl
R
mp [°C]
Yield (%)
Starting material
11a
11b
11c
11d
13a
13b
13c
13d
15a
15b
15c
15d
17a
17b
17c
17d
21a
21b
21c
6
Cl±Pya
Cl±Thb
Pyc
Cl±Phd
Cl±Py
Cl±Th
Py
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
H
198±200
167±169
203±205
194±195
166±168
167
84
10
10
10
10
11a/17a
11b
11c
11d
83
78
93
59/24
4
177
7 (20)
86
Cl±Ph
Ð
140±141
Ð
CH3
160±162
146±148
98±99
97
10
10
10
15a
15b
15c
15d
13a/17b
13a
Ð
CH2CH3
(CH2)2CH3
H
87
Ð
78
Ð
>250
52
Ð
CH3
140±142
96±97
71
Ð
CH2CH3
(CH2)2CH3
CH3
87
Ð
79±80
85
Cl±Py
Cl±Py
Cl±Py
Cl±Th
129±130
115±117
81±83
63/75
52
CH2CH3
(CH2)2CH3
CH3
42/70
77/71
13a/17d
13b/17b
140±141
a
6-Chloropyridin-3-yl.
2-Chlorothiazol-5-yl.
Pyridin-3-yl.
b
c
d
4-Chlorophenyl.
172
Pest Manag Sci 57:165±176 (2001)

Thiamethoxam
dehyde and formic acid. Alkylation with an alkyl halide
gave the 4-nitroimino-1,3,5-oxadiazinane 21 in good
yields. Alternatively, compounds 21 could be prepared
from N-alkyl-N'-nitroguanidines 15, which were
obtained from 10 and an alkylamine via the 3-alkyl-
4-nitroimino-1,3,5-oxadiazinanes 17. All oxadiazi-
nane ring formation reactions (11 → 13; 15 → 17)
were performed with a 1:1 mixture of formaldehyde
and formic acid at 80°C. Best yields for the alkylation
reactions (13 → 21; 17 → 21) were obtained using 2.5
equivalents of potassium carbonate as a base and
N,N-dimethylformamide as solvent. In general, the
route via the oxadiazinanes 17 gave better overall
yields than the route via compounds 13. This is mainly
due to the fact that some of the heterocyclic groups,
such as 2-chloro-5-thiazolyl (compound 11b) and
3-pyridyl (compound 11c) were found to undergo
side-reactions under the conditions used to achieve the
oxadiazinane ring formation.
evaluated in our primary screening against A cracci-
vora, M persicae, N lugens, S littoralis and D balteata in
eight different test systems and the results are shown in
Table 2. The initial target compounds 12, 13a, and 14
were found to be effective against all ®ve insect species
and to possess contact/feeding as well as systemic
activity. Among these compounds, the oxadiazinane
13a is clearly the most active compound. Compared
with our standards, imidacloprid (3) and its 6-ring
analogue 24, 13a looked very promising; in most tests
13a was equally or only slightly less active than the
standards.
In the course of our optimisation programme on the
oxadiazinane lead structure 13a we prepared the
analogues 13b±13d, 19 and 21a±21c. Removal of the
chlorine atom (compound 13c) in 13a and replace-
ment of the 6-chloro-3-pyridyl moiety by a 4-chloro-
phenyl group (compound 13d) strongly reduced the
insecticidal activity. However, the substitution of the
6-chloro-3-pyridyl moiety by a 2-chloro-5-thiazolyl
group (compound 13b) resulted in a strong increase of
the activity against chewing insects (S littoralis and D
balteata) and was found to be the most successful
modi®cation of the heterocyclic group Het. The
introduction of a pharmacophore substituent R gave
variable results. Whereas an ethyl (compound 21b), n-
propyl (compound 21c) or 6-chloropyridin-3ylmethyl
group (compound 19) undoubtedly had a negative
in¯uence on ef®cacy, especially against chewing
insects, a methyl group (compound 21a) increased
This methodology was also applied to the synthesis
of thiamethoxam (6), which was obtained in three
steps from S-methyl-N-nitroisothiourea (10) via the
oxadiazinane 17b in an overall yield of 49%. Further-
more, other methods for the preparation of thia-
methoxam have been developed. These results have
already been published by Goebel et al. 23
3.4 Insecticidal activity of novel nitroimino
heterocycles
The effects of the novel nitroimino heterocycles were
Table 2. Biological data of novel nitroimino-heterocycles (including thiamethoxam 6) in comparison with the standards imidacloprid 3 and 22
1
LC80 (mg AI litre
)
Ac a
Ac
sy g
3
Mp b
cf
Mp
sy
3
Nl c
cf
Sl d
cf
Sl
Db c
cf
f
Compound
Het/Aryl
R
X
cf
sy
12
Cl±Pyh
Cl±Py
Cl±Thi
Pyj
Cl±Phk
Cl±Py
Cl±Py
Cl±Py
Cl±Py
Cl±Py
Cl±Th
Cl±Py
Cl±Py
H
H
H
H
H
H
N±CH3
O
>200
50
12
50
50
50
12
>12
>12
3
200
3
13a
13b
13c
13d
14
0.8
0.8
0.05
O
200
>100
>100
200
>200
12
12
ntm
nt
200
nt
3
nt
>200
>100
>100
50
3
0.8
O
>100
>100
200
>200
50
nt
>100
>100
12
O
nt
>12
nt
S
12
12
>200
3
0.8
>12
>12
>12
>12
>12
19
Cl±Py±CH2
CH3
O
>12
3
>200
12
>200
50
21a
21b
21c
6
24
3
O
0.2
0.2
0.8
0.2
0.2
0.2
0.05
CH2CH3
(CH2)2CH3
CH3
O
200
>200
12
3
12
3
200
>200
>200
3
>200
200
O
12
>200
O
0.8
3
0.8
0.8
0.8
H
CH2
Ð
12
0.2
0.2
3
3
3
0.8
3
3
3
H
12
0.8
3
0.8
a
e
Test insects: Aphis craccivora, b Myzus persicae, c Nilaparvata lugens, d Spodoptera littoralis, Diabrotica balteata.
f
g
Type of activity: feeding/contact activity, systemic activity.
h 6-Chloropyridin-3-yl, i 2-Chlorothiazol-5-yl, j Pyridin-3-yl, k 4-Chloro-phenyl.
m Not tested.
Pest Manag Sci 57:165±176 (2001)
173

P Maien®sch et al
Table 3. Residual activity of thiamethoxam 6 and commercial neonicotinoids 3, 4 and 5
1
LC80 [mg AI litre
Mp b
]
Db a
cf d
Nl c
Nl
sy
sy e
cf
Compound
30 DAT f
28 DAT
4 DAT
21 DAT
3
4
5
6
3
ntg
12
0.8
3
25
12
0.05
0.2
3
>12
0.8
>100
3
0.8
0.05
Test insects: a Diabrotica balteata, b Myzus persicae, c Nilaparvata lugens.
Type of activity: d Contact/feeding activity, e Systemic activity.
f
Days after treatment.
g
Not tested.
the insecticidal activity against sucking pests, such as A
craccivora and N lugens.
of control is obtained at even low rates of application,
compared with the best products such as imidacloprid
and acetamiprid.
The combination of the two most favourable modi-
®cations, the replacement of the 6-chloro-3-pyridyl
moiety by a 2-chloro-5-thiazolyl group and the
introduction of a methyl group as pharmacophore
substituent, ®nally led to thiamethoxam (6). This
compound showed strongly improved contact/feeding
and systemic activity against all chewing and most of
the sucking insects. It was clearly the most active
compound in the 4-nitroimino-1,3,5-oxadiazinane
series and its overall performance in our primary
screening was comparable to that of the standards
imidacloprid and compound 24.
3.6 Thiamethoxam, the first second-generation
neonicotinoid
Thiamethoxam was ®rst synthesised in 1991. In many
laboratory and ®eld tests it was identi®ed as the best
compound prepared during our research programme
on neonicotinoids and was subsequently selected for
development. It is a unique molecule. Its chemical
structure differs remarkably from that of other neo-
nicotinoid commercial and development compounds
in that it possesses a novel 1,3,5-oxadiazinane ring,
which is substituted at the 5-position by a methyl
group, and is the ®rst commercially available neonico-
tinoid having a 2-chloro-5-thiazolyl heterocycle. This
unique combination of structural features is respon-
sible for its outstanding insecticidal activity eg the
methyl group at the 5-position enhances the activity
against sucking insects whereas the 2-chloro-5-thiazo-
lyl heterocycle is essential for improved ef®cacy against
chewing pests.
Thiamethoxam was further evaluated in our sec-
ondary screening for residual activity. Against D
balteata, M persicae N lugens, thiamethoxam showed
outstanding residual effects, which clearly surpassed
those of the commercial neonicotinoids imidacloprid
(3), nitenpyram (4) and acetamiprid 5) (Table 3).
3.5 Field performance of thiamethoxam
Novartis has carried out extensive ®eld trials over
several years on key target pests, and thiamethoxam
has proven to be an outstanding product. After foliar
or soil application or as a seed treatment, it provides
excellent control of a broad range of commercially
important pests, such as aphids, white¯ies, thrips, rice
hoppers, Colorado potato beetle, ¯ea beetles, wire-
worms and leaf miners, as well as some Lepidopterous
species.10
Thiamethoxam is the ®rst representative of second-
generation neonicotinoids and belongs to the thia-
nicotinyl sub-class.10 It was ®rst introduced to the
market in 1998. To date, registrations have been
granted in 52 countries, mainly in Latin America,
Eastern Europe and Asia. Registration submissions
were also made to the USA and Canadian authorities
in late 1998, and in Europe and Japan in early 1999,
and approvals are expected to be received in late 2000
or 2001.
Low use rates, ¯exible application methods and
excellent ef®cacy combined with a long-lasting resi-
dual effect are exceptional characteristics of thia-
methoxam. In general, control of most insect pests is
superior or equivalent to all currently registered
insecticides. In many situations an outstanding level
4 CONCLUSIONS
We have demonstrated that novel variations of the
174
Pest Manag Sci 57:165±176 (2001)

Thiamethoxam
JE, Roman SA, Tieman CH, Corey RA and Horne CA,
Nitromethylene insecticides, in Advances in Pesticide Science,
Part 2, ed by GeissbuÈhler H, Brooks GT and Kearney PC,
Pergamon Press, New York, USA, pp 206±227 (1979).
6 Wollweber D and Tietjen K, Chloronicotinyl insecticides: a
success of the new chemistry, in Nicotinoid Insecticides and the
Nicotinic Acetylcholine Receptor, ed by Yamamoto I and Casida
JE, Springer±Verlag, Tokyo, Japan, pp 109±125 (1999).
7 Shiokawa K, Tsuboi S, Kagabu S and Moriya K, Nitromethylene
derivatives, intermediates, and their preparation as insecti-
cides, Eur Pat Appl EP 163 855 (1985); Chem. Abstr 104:224
896 (1986).
nitroimino heterocycle of imidacloprid lead to highly
active insecticidal compounds such as the nitroimino-
hexahydro-1,3,5-triazine 12, the nitroimino-1,3,5-
thiadiazine 14 and especially the nitroimino-1,3,5-
oxadiazinane 13a. Novel methodology for the pre-
paration of these compounds and derivatives of 13a
has been developed. The synthesis and testing of a
large number of chemically modi®ed nitroimino-
1,3,5-oxadiazinanes has led to a structure-activity
pro®le for this novel type of compound. Based on
biological activity and the best overall laboratory and
®eld performance, thiamethoxam (CGA 293 343) has
been selected as the preferred compound.
8 Minamida I, Iwanaga K, Tabuchi T, Aoki I, Fusaka T, Ishizuka
H and Okauchi T, Studies on acyclic nitroethene compounds.
Part 2. Synthesis and insecticidal activity of acyclic nitroethene
compounds containing a heteroarylmethylamino group. Nihon
Noyaku Gakkaishi (J Pestic Sci) 18:41±8 (1993).
Thiamethoxam represents the ®rst commercially
available second-generation neonicotinoid and be-
longs to the thianicotinyl sub-class. It is marketed
under the trademarks Actara1 for foliar and soil treat-
ment and Cruiser1 for seed treatment. The com-
pound has broad-spectrum insecticidal activity and
offers excellent control of a wide variety of commer-
cially important pests in many crops. Control of most
insect pests with thiamethoxam is superior or equiva-
lent to that of currently registered neonicotinoid
insecticides. The compound exhibits contact, stomach
and systemic activity. Its good stability and excellent
systemic characteristics make thiamethoxam appro-
priate for foliar, granular and seed treatment applica-
tion. The long-lasting residual effect is a special bene®t
of this compound. Low use rates, ¯exible application
methods, excellent ef®cacy and the favourable safety
pro®le make this new insecticide well-suited for
modern integrated pest management programmes in
many cropping systems.
9 Takahashi H, Mitsui J, Takakusa N, Matsuda M, Yoneda H,
Suzuki J, Ishimitsu K and Kishimoto T, NI-25, a new type of
systemic and broad spectrum insecticide, in Proc Brighton Crop
Prot ConfÐPests and Diseases, BCPC, Farnham, Surrey, UK,
pp 89±96 (1992).
10 Maien®sch P, Brandl F, Kobel W, Rindlisbacher A and Senn R,
CGA 293'343: a novel, broad-spectrum neonicotinoid insecti-
cide, in Nicotinoid Insecticides and the Nicotinic Acetylcholine
Receptor, ed by Yamamoto I and Casida JE, Springer±Verlag,
Tokyo, Japan, pp 177±209 (1999).
11 Senn R, Hofer D, Hoppe T, Angst M, Wyss P, Brandl F,
Maien®sch P, Zang L and White S, CGA 293343: a novel
broad-spectrum insecticide supporting sustainable agriculture
worldwide, in Proc Brighton Crop Prot ConfÐPests and Diseases,
BCPC, Farnham, Surrey, UK, pp 27±36 (1998).
12 Maien®sch P, Gsell L and Rindlisbacher A, Synthesis and
insecticidal activity of CGA 293 343Ða novel broad-spectrum
insecticide. Pestic Sci 55:351±355 (1999).
13 Shiokawa K, Tsuboi S, Kagabu S, Sasaki S, Moriya K and
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ACKNOWLEDGEMENTS
We would like to thank the many colleagues within
Novartis Crop Protection who have contributed to the
discovery and the development of thiamethoxam, with
special acknowledgement to Dr M Angst, Mr D Hofer,
Mr R Senn, Dr P Wyss (biology); Professor H Kayser,
Mr F SchuÈrmann, Dr P Wiesner (biochemistry); Dr W
Kobel (safety assessment); Dr W Fischer, Dr A
Steinemann, Dr H Widmer (chemodynamics); Dr F
Brandl, Mr RV Cortada, Dr H Elmsheuser, Mr C
FluÈckiger, Dr T Hoppe, Mr P Camblin (product
management) and Dr R Hall for reviewing the manu-
script.
16 Kristiansen O, Maien®sch P and Gsell L, Guanidine derivatives
as insecticides, Eur Pat Appl EP 418 199 (1991); Chem Abstr
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Yasui N, MTI-446: a novel systemic insect control compound,
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amines, particularly 1,1-diamino-2-nitroethylene derivatives,
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