K Yagi et al
Herein we report the synthesis of novel 3-(2,4,6-
trisubstituted phenyl)uracil derivatives, and the in-
secticidal and acaricidal activities of these compounds,
including detailed structure±activity relationships of
the substituents on the molecule and LC50 values for
representative compounds in the series.
uracils, and reactions with 2,4,6-trisubstituted phenyl
thioisocyanate derivatives gave 3-(2,4,6-trisubstituted
phenyl)-6-substituted-2-thiouracil derivatives. 5-Cya-
no-6-tri¯uoromethyluracil (5d) was prepared directly
from ethyl 3-amino-2-cyano-4,4,4-tri¯uoro-2-buteno-
ate (A, R'=CN) with phenyl isocyanate. 5-Methyl-6-
tri¯uoromethyluracil derivatives were prepared di-
rectly from ethyl 3-amino-2-methyl-4,4,4-tri¯uoro-2-
butenoate in the same manner as above.
2
EXPERIMENTAL
2.1 General
3-(2,4-Dinitro-6-tri¯uoromethylphenyl)-6-tri¯uor-
omethyluracil (1s) was alternatively synthesised via a
cross-coupling reaction between 6-tri¯uoromethyl-
uracil and 2,4-dinitro-6-tri¯uoromethylchlorobenzene
as shown in Fig 3. Thus, 6-tri¯uoromethyluracil (F),
prepared from ethyl tri¯uoroacetate (C) and S-
methylthiourea (D) via 2-methylthio-4-tri¯uoro-
methyl-6(1H)pyrimidinone (E), was reacted with
2,4-dinitro-6-tri¯uoromethylchlorobenzene (G) in
DMF in the presence of sodium hydride to give 1s.
All substitutions except for the amino group at the
1-position on the uracil ring were carried out with the
corresponding halides, such as alkyl halide or acetyl
chloride, as shown in Fig 2. 1-Amino-3-(2,6-dichloro-
4-tri¯uoromethylphenyl)-6-tri¯uoromethyluracil (3k)
was obtained from the corresponding 1-unsubstituted
uracil and 2,4-dinitrophenoxyamine in the presence of
potassium carbonate in DMF.
Melting points were measured with a Yanagimoto
micro-melting point apparatus and were uncorrected.
[1H]NMR spectra (60MHz) were recorded in deu-
terochloroform unless otherwise indicated, with tetra-
methylsilane as internal standard, using a Hitachi R-
1200 or JOEL PMX-60SI NMR spectrometer. Elec-
tron impact mass spectra were measured on a JOEL
JMS AM-50.
2.2 Chemicals
Trisubstituted phenylisocyanate or phenylisothiocya-
nate derivatives were synthesised by an established
route: reactions of trisubstituted aniline with trichloro-
methyl chloroformate, phosgene or thiophosgene.
Ethyl trisubstituted phenylcarbamate derivatives were
obtained from trisubstituted aniline and ethyl chloro-
formate.
Ethyl 3-amino-4,4,4-tri¯uoro-2-butenoate was ob-
tained commercially or prepared from ethyl tri¯uoro-
acetoacetate and liquid ammonia. Ethyl 3-amino-
5,5,5,4,4-penta¯uoro-2-pentenoate and 2-amino-4-
chloro-4,4-di¯uoro-2-butenoate were prepared from
the corresponding ethyl perhalogenated acyl acetate
and liquid ammonia in a similar manner. Ethyl 2-
tri¯uoromethylpropionate was prepared from ethyl
tri¯uoroacetate and ethyl propionate and was reacted
with liquid ammonia to give ethyl 3-amino-2-methyl-
4,4,4-tri¯uoro-2-butenoate. Ethyl 3-amino-2-cyano-
4,4,4-tri¯uoro-2-butenoate was prepared by a Refor-
matski reaction from tri¯uoroacetonitrile and ethyl
cyanoacetate.
3-(2,6-Dichloro-4-tri¯uoromethylphenyl) deriva-
tives substituted with bromine (4a), or methylthio
(4e) or methanesulfonyl (4f) groups at the 6-position
were prepared by means of a substitution reaction on
the uracil nucleus as depicted in Fig 4. Thus,
bromination of 3-(2,6-dichloro-4-tri¯uoromethylphe-
nyl)perhydropyrimidine-2,4,6-trione (H), which was
prepared from 2,6-dichloro-4-tri¯uoromethylphenyl-
urea (I) and malonyl dichloride (J), with phosphorus
oxybromide in benzene gave 6-bromo-(2,6-dichloro-
4-tri¯uoromethylphenyl)uracil (4a). The 6-bromo
derivative was allowed to react with methylmercaptan
sodium salt (MeSNa) to give 3-(2,6-dichloro-4-
tri¯uoromethylphenyl)-6-methylthiouracil (4e). Oxi-
dation of 4e to the corresponding sulfone (4f) was then
easily accomplished using two equivalents of m-
chloroperbenzoic acid (MCPBA) in methylene chlor-
ide at ambient temperature.
2.3 Synthesis
Figure 2 depicts the general synthetic pathway to the
6-alkyl or 6-haloalkyl-3-(2,4,6-trisubstituted phenyl)-
uracil derivatives extensively employed in this study,
which were synthesised using a method reported in the
literature.8
Thus, reactions of amino esters (A) with 2,4,6-
trisubstituted phenyl isocyanates (B) or 2,4,6-trisub-
stituted phenyl carbamates (B') in the presence of
sodium hydride in N,N-dimethylformamide (DMF)
afforded 3-(2,4,6-trisubstituted phenyl)-6-substituted
Halogenations of 5-unsubstituted uracil (1a) to the
corresponding 5-chloro (5b) or 5-bromo (5c) deriva-
tives were accomplished using N-chlorosuccinimide
(NCS) or N-bromosuccinimide (NBS) in re¯uxing
acetonitrile (Fig 5). Reactivity at the position was not
suf®cient to allow substitution with those agents at
room temperature.
Typical syntheses for each pathway outlined in Figs
Figure 1. General structure of 3-(2,4,6-
trisubsituted phenyl)uracil derivatives.
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Pest Manag Sci 56:65±73 (2000)