Synthesis and properties of thiamethoxam and related compounds

Article abstract of DOI:10.1515/znb-2006-0401

The neonicotinoids are the most successful chemical class of insecticides reaching sales of more than $1 billion in 2003, mainly due to the excellent market performance of imidacloprid and thiamethoxam. This paper describes the discovery, the synthesis and the insecticidal activity of thiamethoxam and related compounds and reports the hydrolytic stability and the degradation pathways of thiamethoxam together with the synthesis of the degradation products.

Full text of DOI:10.1515/znb-2006-0401

Synthesis and Properties of Thiamethoxam and Related Compounds*
Peter Maienfisch
Syngenta Crop Protection AG, Research & Technology, Schwarzwaldallee 215, CH-4002 Basel,
Switzerland
Reprint requests to Dr. P. Maienfisch. E-mail: peter.maienfisch@syngenta.com
Z. Naturforsch. 61b, 353 – 359 (2006); received July 20, 2005
The neonicotinoids are the most successful chemical class of insecticides reaching sales of more
than $1 billion in 2003, mainly due to the excellent market performance of imidacloprid and thiameth-
oxam. This paper describes the discovery, the synthesis and the insecticidal activity of thiamethoxam
and related compounds and reports the hydrolytic stability and the degradation pathways of thiameth-
oxam together with the synthesis of the degradation products.
Key words: Neonicotinoids, Thiamethoxam, Clothianidin, 4-Nitroimino-1,3,5-oxadiazinanes,
Insecticidal Activity
Introduction
Table 1. Neonicotinoid sales products [2].
Common Name
Company
Year of Market Sales 2003
Introduction
1991
An important milestone in the history of modern
insect control is marked by the discovery of the neo-
nicotinoid insecticides [1]. As the first representative
of this chemical class, imidacloprid 1 was introduced
to the market in 1991, and since then, a series of
analogues (compounds 2 – 7) have been launched (Ta-
ble 1). The neonicotinoids are the fastest growing
chemical class of insecticides, now exceeding 15%
of the total insecticide market. This tremendous suc-
cess is based on their unique chemical and biological
properties, such as broad-spectrum insecticidal activ-
ity, low application rates, excellent systemic character-
istics, favourable safety profile, and a new mode of ac-
tion.
Neonicotinoids bind selectively to insect nicotinic
acetylcholine receptors (nAChRs) with nanomolar
affinity to act as potent insecticides. However, they do
not act as a homogenous class of insecticides. Recent
findings suggest that thiamethoxam binds, compared
to the other neonicotinoid sales products, in a differ-
ent way, possibly to a different site of the receptor in
aphids [3].
Mio $a
665
Imidacloprid (1)
Nitenpyram (2)
Acetamiprid (3)
Thiamethoxam (4) Syngenta
Thiacloprid (5)
Clothianidin (6)
Bayer
Takeda
Nippon Soda
1995
45
1996
1998
2000
2002
60
215/298b
< 30
< 30
< 30
Bayer
Takeda, Bayer
Mitsui Chemicals
Dinotefuran (7)
2002
a
Data from Phillips McDougall; b sales 2004, data from Syngenta
Annual Report 2004.
1
4
2
3
6
5
7
Our own research in this area resulted in the dis-
covery of thiamethoxam (4) [4]. This compound is
a second-generation neonicotinoid and belongs to the
thianicotinyl subclass. It was first synthesized in 1991
and is now developed worldwide for use in more than
100 crops. Thiamethoxam is marketed since 1998 un-
R
der the trademarks Actaraꢀ for foliar and soil treat-
R
ment and Cruiserꢀ for seed treatment. In all these
* Presented in part at the 7th Conference on Iminium Salts
(ImSaT-7), Bartholoma¨/Ostalbkreis, September 6 – 8, 2005.
usages, thiamethoxam provides excellent control of
a broad range of commercially important pests, such
c
0932–0776 / 06 / 0400–0353 $ 06.00 ꢀ 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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354
P. Maienfisch · Synthesis and Properties of Thiamethoxam and Related Compounds
Scheme 1. Optimization of the lead structure 9.
Table 2. Insecticidal activity of compounds 8 – 10 in compar-
ison to imidacloprid 1 and its six-ring analogue 11.
as aphids, whiteflies, thrips, rice hoppers, Colorado
potato beetle, flea beetles, wireworms, leaf miners as
well as some lepidopterous species [5]. Low use rates,
flexible application methods, excellent efficacy, and
the favourable safety profile make this new insecti-
cide well suited for modern integrated pest manage-
ment programs in many cropping systems.
Compound
Structure
Type
LC80 [mg AI liter−1
]
Aphis
Myzus
Diabrotica
craccivora persicae
balteata
m. p.
Pea,
m. p.
Pea,
L2
Filter paper,
foliar spray into water
spray
200
3
12
3
8
9
10
11
Triazinane
Oxadiazinane
Thiadiazinane
Hexahydro-
pyrimidine
> 200
50
3
0.05
0.8
0.2
Discovery of Thiamethoxam
200
12
As part of our program on neonicotinoid chem-
istry we have investigated novel variations of the
nitroimino-heterocycleof imidacloprid, which resulted
in the synthesis of compounds 8, 9, and 10 [4a].
1
4
12
12
0.05
0.05 – 0.2
0.8
0.8
Oxadiazinane
hydro-1,3,5-triazine 8 and the 4-nitroimino-1,3,5-thia-
diazinane 10 and that its potency is close to imidaclopr-
id and its six-ring analogue 11, respectively (Table 2).
Chemical and biological exploration of the lead
structure 9 showed that replacement of the 6-chloro-
3-pyridyl group by a 2-chloro-5-thiazolyl moiety
(→ compound 12) resulted in a strong increase of the
activity against chewing insects, whereas the introduc-
tion of a methyl group as pharmacophore substituent
(→ compound 13) increased the activity against suck-
ing pests (Scheme 1). The combination of these two
favourable modifications led to thiamethoxam (4). This
compound was clearly the most active 4-nitroimino-
Bioassays revealed that among these compounds, 1,3,5-oxadiazinane, and its performance in our green-
the 4-nitroimino-1,3,5-oxadiazinane 9 exhibits clearly house screening was comparable or better than that of
better insecticidal activity than the 2-nitroimino-hexa- the standard imidacloprid 1 [4a].
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P. Maienfisch · Synthesis and Properties of Thiamethoxam and Related Compounds
355
Table 3. Mannich type cycliza-
tion of N-methyl nitroguani-
dine to 4-nitroimino-1,3,5-oxa-
diazinane 17b.
Method
Reaction conditions
Yield
traces
21%
21%
0% (dec.)
47%
61%
28%
71 – 90%
A
B
C
D
E
F
G
H
5 eq. HCHO, pH = 9, 90 ◦C
4 eq. (CH2O)n, 1 eq. Et3N, toluene/1,4-dioxane 1:1, 110 ◦C
3 eq. (CH2O)n, cat. HCl , toluene / 1,4-dioxane 1:1, 110◦C
2 eq. (CH2O)n, CF3COOH, ClCH2CH2Cl, r. t.
HCHO, 1.1 eq. p-TsOH, 90 ◦C
HCHO, 1.1 eq. CF3COOH, 90 ◦C
HCHO / CH3COOH 1:1, 90 ◦C
HCHO / HCOOH 1:1, 90 ◦C
Scheme 2. Synthesis of monosubstituted-4-nitroimino-1,3,5-oxadiazinanes 17.
Scheme 3. Synthesis of thiamethoxam (4) and
other disubstituted 4-nitroimino-1,3,5-oxadiazin-
anes 19.
Synthesis of Thiamethoxam
anol at 50 ◦C or 80 ◦C afforded N-monosubstituted-N’-
nitroguanidines 16. Heating of compounds 16 in a 1:1
mixture of formaldehyde and formic acid for several
At the start of our research, no practical syn-
thetic route for the preparation of 4-nitroimino-1,3,5-
oxadiazinanes was known. After much experimenta-
tion, we discovered a broadly applicable method for
the synthesis of monosubstituted 4-nitroimino-1,3,5-
oxadiazinanes 17 (Scheme 2). Thus, treatment of S-
methyl-N-nitro-isothiourea(14) with amines 15 in eth-
◦
hours at 80 – 90 C provided the 4-nitroimino-1,3,5-
oxadiazinanes 17 in good to excellent yields. Key step
in this synthesis is the Mannich type cyclisation reac-
tion. Many different reaction conditions were investi-
gated; some examples are shown in Table 3. Among
the many acids tested only formic acid gave good re-
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356
P. Maienfisch · Synthesis and Properties of Thiamethoxam and Related Compounds
Scheme 4. Pharmacophore modifications – synthesis of compounds 23 – 25.
sults. Other acids such as acetic acid, trifluoroacetic sium hydroxide in tert-butanol provided the urea 24,
acid and HCl strongly decreased the yields.
which was reacted with Lawesson’s reagent to yield
the thiourea 25 in only 13% yield. Replacement of
Lawesson’s reagent by phosphorus pentasulfide re-
sulted in much better yields (57%) in the sulfuration
reaction.
Compounds 17 could be coupled with heterocyclyl-
methyl halides 18 to afford the disubstituted 4-nitro-
imino-1,3,5-oxadiazinanes 19 (Scheme 3). Optimal
yields for these alkylation reactions were obtained
using 2.5 equivalents of potassium carbonate as a
The biological evaluation of these compounds re-
base and dimethylformamide as solvent. Following the vealed that the potency is highly dependent on the
methodologies described above, thiamethoxam (4) has pharmacophore. Replacement of the nitroimino group
been synthesised in three steps from S-methyl-N-nitro- by a cyanoimino moiety (compound 23) clearly di-
isothiourea (14) in an overall-yield of 62%.
minished the activity, while compounds like the urea
24 (X = O) and the thiourea 25 (X = S) were not
active at the highest concentration tested (100 ppm).
These differences in the biological activities seem to be
clearly related to the electronic properties of the phar-
macophore moiety. Activity is only found if the func-
tional group at C-4 is strongly electron-withdrawing
and has a hydrogen accepting head like in N-NO2 and
in N-CN.
Variation of the Pharmacophore
Several variations of the pharmacophore (N-
C(N)=N-NO2) have been carried out. The cyanoimino
derivative 23 was prepared starting from N-methyl-N’-
cyanoguanidine 21, which was obtained in 56% from
sodium dicyanamide and methylamine (Scheme 4).
The conversion of 21 to 3-methyl-4-cyanoimino-1,3,5-
oxadiazinane (22) was not achieved under the re-
action conditions applied for the preparation of the
4-nitroimino-1,3,5-oxadiazinanes 17. However, treat-
ment of 21 with a large excess of aqueous formalde-
hyde at pH 8 gave compound 22 in moderate yield.
Alkylation of 22 with the chloride 20 afforded the
cyanoimino-analogue 23.
Variation of the Pharmacophore Substituent
A wide range of modifications of the pharma-
cophore substituent has been carried out as shown in
Scheme 5. The key intermediate 12 was prepared by
Mannich type cyclisation of nitroguanidine (26) fol-
lowed by selective monoalkylation with the chloride
The urea 24 and the thiourea 25 were prepared start- 20. Under optimized reaction conditions (1.◦2 eq. 20,
ing from thiamethoxam 4. Treatment of 4 with potas- 1.0 eq. KOC(CH3)3, DMF-pyridine 4:1, −5 C to r. t.)
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P. Maienfisch · Synthesis and Properties of Thiamethoxam and Related Compounds
357
Scheme 5. Variation of the pharmacophore substituent: synthesis of compounds 27 – 32.
Table 4. Kinetic data of the hydrolytic degradation of thi-
amethoxam (4).
and a special work-up procedure (crude dissolved in
CH2Cl2, extracted with 2N NaOH, after acidification
of the aqueous phase with HCl to pH = 4, the prod-
uct separates as pale brown solid), compound 12 was
obtained in 60% yield from 17a.
Compounds of type 27–30 and 32 showed moder-
ate to good insecticidal activity, whereas the oxalic
acid derivative 31 was found to be inactive. How-
ever, none of these new compounds exhibited the po-
tency and the broad-spectrum insecticidal activity of
thiamethoxam 4. Best activity was observed for com-
pounds with the pharmacophore substituent being H,
Et, allyl, propargyloxymethyland ethylcarbonyl.Steric
as well as electronic factors seem to have an important
influence on the biological activity. When the phar-
macophore substituent is an alkyl group, the activity
pH
T
[◦C]
70
70
25
Rate constant Half-life Estimated half-life at 25◦C
[h−1
]
[h]
2718
59
[days]
6990
152
5
7
9
2.55×10−4
1.18×10−2
4.72×10−3
147
6.1
drops significantly when a methyl group is introduced
as pharmocophore substituent.
Hydrolytic Degradation of Thiamethoxam
The hydrolytic degradation of thiamethoxam 4 was
investigated in the pH range from 5 to 9 and was found
to follow pseudo-first order kinetics (Table 4) [6].
Two major degradation pathways were observed in
decreases with the chain length and the steric bulk the pH range from 5 to 9. The first pathway led to the
(Me >Et>n-Pr ꢀ i-Pr, n-Bu). Somewhat surprisingly, corresponding 1,3,5-oxadiazinan-4-one24 and the sec-
the methyl-substituted compound 4 is clearly more ac- ond pathway to the ring opened N-nitro-urea 33 and
tive than the unsubstituted compound 12. This is in to the 2-chloro-5-aminomethyl-thiazole (34), respec-
contrast to the imidacloprid series where the activity tively (Scheme 6).
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358
P. Maienfisch · Synthesis and Properties of Thiamethoxam and Related Compounds
Scheme 6. Hydrolytic degradation pathways of thiamethoxam (4).
Scheme 7. Cleavage of thiamethoxam (4) under acidic and basic conditions.
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P. Maienfisch · Synthesis and Properties of Thiamethoxam and Related Compounds
359
The product distribution was also pH-dependent. ing acyclic nitroguanidine 6 (clothianidin) was not ob-
The formation of the N-nitro-urea 33 at higher concen- served (for synthesis of clothianidin see lit. [7]). Under
trations was only observed at pH 9. This intermediate more drastic conditions very similar results were ob-
was not observed (or only at very low concentrations) tained as shown in Scheme 6. Our studies have shown
at pH 5 and pH 7 due to the further rapid hydrolytic that thiamathoxam (4) is only converted to clothiani-
degradation to the corresponding amine 34. The cleav- din (6) under very drastic conditions such as heating to
age of the 1,3,5-oxadiazinane ring to the correspond- 80 ◦C for several hours in conc. HCl.
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