Synthesis and insecticidal/acaricidal activity of novel 3-(2,4,6- trisubstituted phenyl)uracil derivatives

Article abstract of DOI:10.1002/(SICI)1526-4998(200001)56:1<65::AID-PS90>3.0.CO;2-S

A series of novel 3-(2,4,6-trisubstituted phenyl)uracil derivatives has been synthesised and assayed for insecticidal/acaricidal activity. The assay indicated certain requirements for optimal insecticidal activity, which can be summarised as follows: (a) the substituents on the phenyl ring should possess hydrophobicity and electron-withdrawing properties, and the sum of their volumes determines the level of activity; (b) the substituent at the 6- position on the uracil ring should also possess electron-withdrawing properties and hydrophobicity, together with the correct volume; (c) the 1- position on the uracil ring should be unsubstituted for activity against Nephotettix cincticeps and Epilachna vigintioctopunctata, but substituents with length C3 to C4 may be optimal for activity against Tetranychus urticae; (d) certain substituents at the 5-position of the uracil ring give activity against E vigintioctopunctata and T urticae, but not against N cincticeps; (e) a thiocarbonyl group at the 2-position of the uracil ring is less effective than a carbonyl group. Of the compounds assayed, 3-(2,6-dichloro-4- trifluoromethylphenyl)-6-trifluoromethyluracil showed high activity against all the species assayed. (C) 2000 Society of Chemical Industry.

Full text of DOI:10.1002/(SICI)1526-4998(200001)56:1<65::AID-PS90>3.0.CO;2-S

Pest Management Science
Pest Manag Sci 56:65±73 (2000)
Synthesis and insecticidal/acaricidal activity of
novel 3-(2,4,6-trisubstituted phenyl)uracil
derivatives†
Kazuo Yagi,1‡* Kazuhiko Akimoto,1§ Norihiko Mimori,2 Toshiro Miyake,2
Masaki Kudo,2‡ Kazutaka Arai1 and Shigeru Ishii1‡
1Central Research Institute, Nissan Chemical Industries Ltd, 722-1 Tsuboi-cho, Funabashi Chiba 274-8597, Japan
2Shiraoka Research Station of Biological Science, Nissan Chemical Industries Ltd, 1470 Shiraoka, Minamisaitama, Saitama 349-0294,
Japan
Abstract: A series of novel 3-(2,4,6-trisubstituted phenyl)uracil derivatives has been synthesised and
assayed for insecticidal/acaricidal activity. The assay indicated certain requirements for optimal
insecticidal activity, which can be summarised as follows: (a) the substituents on the phenyl ring
should possess hydrophobicity and electron-withdrawing properties, and the sum of their volumes
determines the level of activity; (b) the substituent at the 6-position on the uracil ring should also
possess electron-withdrawing properties and hydrophobicity, together with the correct volume; (c) the
1-position on the uracil ring should be unsubstituted for activity against Nephotettix cincticeps and
Epilachna vigintioctopunctata, but substituents with length C3 to C4 may be optimal for activity
against Tetranychus urticae; (d) certain substituents at the 5-position of the uracil ring give activity
against E vigintioctopunctata and T urticae, but not against N cincticeps; (e) a thiocarbonyl group at
the 2-position of the uracil ring is less effective than a carbonyl group.
Of the compounds assayed, 3-(2,6-dichloro-4-tri¯uoromethylphenyl)-6-tri¯uoromethyluracil
showed high activity against all the species assayed.
# 2000 Society of Chemical Industry
Keywords: heterocyclic uracil; insecticidal activity; structure±activity relationships
1
INTRODUCTION
restricted to these. Detailed information on structure±
activity relationships of the compounds has not been
reported, although such data are of great interest. If
the whole molecule ful®ls the structural requirements
for insecticidal activity shown by the reported
compounds, further optimisation with other hetero-
cycles in combination with a 2,4,6-trisubstituted
benzene ring would bring new insecticidally active
compounds.
It is known that some uracil derivatives have biological
activity, and typical examples of this can be found in
the ®eld of pharmaceuticals, such as 5-¯uorouracil as a
classic anti-tumour agent. However, in the ®eld of
agricultural chemicals, no compound of this class with
insecticidal activity has, to our knowledge, been
reported in the literature.
On the other hand, numerous heterocycles, such as
pyrazole,1,2 imidazole,3 triazole,4 triazolone5 and
pyrimidinone,6 linked with a 2,4,6-trisubstituted
benzene moiety have been reported in the literature
or patents as being insecticidal. However, molecular
design of the heterocyclic systems has tended to be
focused mainly onto 5-membered rings, and only
limited attention has been paid to 6-membered rings.
With respect to substituents, most of the compounds
reported in the literature possess electron-withdrawing
groups or atoms such as halogen, haloalkyl or cyano on
the phenyl ring, and studies appear to have been
In the course of our recent studies to ®nd novel
classes of insecticidal compounds relating to hetero-
cycles possessing a multi-substituted aryl moiety,1,7 we
focused on 6-membered heterocyclic compounds.
Amongst these compounds, a series of 3-(2,4,6-
trisubstituted phenyl)uracil derivatives, which can be
expressed by the general structure shown in Fig 1,
were selected. Through synthesis and biological assay
against Hemiptera, Coleoptera and Tetranychus spp, we
have succeeded in ®nding novel 3-phenyluracil deri-
vatives possessing insecticidal and acaricidal activity.
* Correspondence to: Kazuo Yagi, Agricultural Division, Nissan Chemical Industries Ltd, Kowahitosubashi Building, 3-7, 1-Chome, Kanda-
Nishiki-cho, Chiyoda-ku, Tokyo 101-0054, Japan
† Part III of a series of papers on nitrogen-containing heterocycles possessing a multi-substituted aryl moiety. For Parts I and II, see
References 1 and 7.
‡ Present address: Agricultural Division, Nissan Chemical Industries Ltd, Kowahitosubashi Building, 3-7, 1-Chome, Kanda-Nishiki-cho,
Chiyoda-ku, Tokyo 101-0054, Japan.
§ Present address: Toyama Works, Nissan Chemical Industries, Ltd, 635, Sakakura, Fuchu-machi, Nei-gun, Toyama 939-2792, Japan.
(Received 6 March 1999; accepted 22 September 1999)
# 2000 Society of Chemical Industry. Pest Manag Sci 1526±498X/2000/$17.50
65

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.
66
Pest Manag Sci 56:65±73 (2000)

Synthesis and activity of 3-(2,4,6-trisubstituted phenyl) uracils
Figure 2. General synthetic pathway to 6-alkyl- or
6-haloalkyl-3-(2,4,6-trisubstituted phenyl)uracil
derivatives.
2±5 are described below; the yields were not opti-
mised.
ice-water cooling and stirred for 0.5h at room tem-
perature. 1.89g (7mmol) of 2,4-dinitro-6-tri¯uoro-
methylphenyl chloride was added to the mixture and
stirred for 3h at room temperature. The resulting
solution was poured onto ice-water, acidi®ed with
hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with water, brine and
dried over sodium sulfate. After removal of the solvent,
the residue remaining was treated with hexane to
obtain 0.77g of 3-(2,4-dinitro-6-tri¯uoromethyl-
2.3.1 3-(2,4,6-Trichlorophenyl)-6-trifluoromethyluracil
(1a, General procedure for 1a±r, 2a±p, 4b±d, 4g±i, 5a,
5d and 6a±c)
To a suspension of 3.53g (80mmol) of NaH in 70ml
of DMF under ice-water cooling, a solution of 14.6g
(80mmol) of ethyl 3-amino-4,4,4-tri¯uoro-2-buteno-
ate in 30ml of DMF was added. After stirring for
30min, a solution of 14.6g (65.6mmol) of 2,4,6-
trichlorophenylisocyanate in 70ml of DMF was
added. The mixture was stirred for 2.5h at room
temperature and for 0.5h at 80°C. The resulting
mixture was poured onto ice-water, acidi®ed with
hydrochloric acid, and extracted with ethyl acetoace-
tate. The organic layer was washed with water and
brine, and dried over sodium sulfate. After removal of
the solvent, the residue was treated with isopropyl
ether to obtain 18.9g of 3-(2,4,6-trichlorophenyl)-6-
tri¯uoromethyluracil as a solid, yield 66%, mp: 224±
phenyl)-6-tri¯uoromethyluracil, yield 34%, mp:
‡
219±220.5°C;
m/z
414
(M );
[1H]NMR
(CDCl3 ‡CD3OD, dppm): 6.10 (1H, s), 8.78 (1H,
d, J=3Hz), 9.08 (1H, d, J=3Hz).
2.3.3 3-(2,6-Dichloro-4-trifluoromethylphenyl)-6-
methanesulfonyluracil (4f)
A mixture of 0.5g (1.3mmol) of 3-(2,6-dichloro-
4-tri¯uoromethylphenyl)-6-methylthiouracil, 0.57g
(3.3mmol) of MCPBA and 10ml of dichloromethane
was stirred for 2h at room temperature. The reaction
mixture was washed with water and dried over sodium
sulfate. Removal of the solvent gave 0.17g of 3-(2,6-
dichloro-4-tri¯uoromethylphenyl)-6-methanesulfo-
nyluracil as a white solid, yield 33%, mp: 219.0±
222.0°C; [1H]NMR (dppm): 3.20 (3H, s), 6.42 (1H,
s), 7.63 (2H, s).
‡
227°C; m/z 358 (M ); [1H]NMR (CDCl3‡CD3OD
dppm): 6.10 (1H, s), 7.38 (2H, s)
2.3.2 3-(2,4-Dinitro-6-trifluoromethylphenyl)-6-
trifluoromethyluracil (1q)
To a solution of 1.0g (5.5mmol) of 6-tri¯uoromethyl-
uracil in 10ml of DMF, 55% NaH was added under
Figure 3. Synthesis of 3-(2,4-dinitro-6-
trifluoromethylphenyl)-6-trifluoromethyluracil.
Pest Manag Sci 56:65±73 (2000)
67

K Yagi et al
Figure 4. Synthetic scheme to 3-(2,6-dichloro-4-trifluoromethylphenyl)-6-methansulfonyluracil.
to the mixture and stirred for 5h at 100°C. The
resulting mixture was poured onto ice-water and
extracted with ethyl acetate. The organic layer was
washed with water and dried over sodium sulfate.
Removal of the solvent gave 0.20g of 1-ethyl-3-(2,4,6-
trichlorophenyl)-6-tri¯uoromethyluracil as a solid,
yield 34%, mp: 136±137.5°C; [1H]NMR (dppm):
1.32 (3H, t, J=7.2Hz), 3.95 (2H, q, J=7.2Hz), 6.23
(1H, s), 7.33 (2H, s).
Figure 5. Halogenations at 5-position on the uracil nucleus.
2.3.4 3-(2,6-Dichloro-4-trifluoromethylphenyl)-6-
methylthiouracil (4e)
A mixture of 1.62g (4mmol) of 6-bromo-3-(2,6-
2.3.7 5-Bromo-3-(2,4,6-trichlorophenyl)-6-
trifluoromethyluracil (5c)
dichloro-4-tri¯uoromethylphenyl)uracil,
0.56g
A mixture of 3.6g (10mmol) of 3-(2,4,6-trichloro-
phenyl)-6-tri¯uoromethyluracil, 4.1g (50mmol) of
sodium acetate, 6.4g (40mmol) of bromine and
30ml of acetic acid was re¯uxed for 8h. After removal
of the solvent, the residue was dissolved in ethyl
acetate and the solution was washed with water and
brine. Removal of the solvent gave a crude product,
which was washed with isopropyl ether to obtain 0.80g
(8mmol) of methyl mercaptan sodium salt and 15ml
of DMF was stirred for 1.5h at 90°C. The reaction
mixture was poured onto ice-water and extracted with
ethyl acetate. The organic layer was washed with water
and brine, and dried over sodium sulfate. Removal of
the solvent gave a crude solid, which was treated with
hexane to give 0.68g of 3-(2,6-dichloro-4-tri¯uoro-
methylphenyl)-6-methylthiouracil as a white solid,
yield 46%, mp: 219±222°C; [1H]NMR (dppm):
2.48 (s, 3H), 5.68 (s, 1H), 7.76 (s, 2H).
of
5-bromo-3-(2,4,6-trichlorophenyl)-6-tri¯uoro-
methyluracil as a solid, yield 46%, mp: 222±225°C;
[1H]NMR (CDCl3 ‡CD3OD, dppm): 7.38 (2H, s).
2.3.5 6-Bromo-3-(2,6-dichloro-4-
trifluoromethylphenyl)uracil (4a)
2.4 Biological assays
Each compound was formulated as an emulsifable
concentrate which was then diluted with water
containing a surfactant to give AI concentrations of
500, 100 and 10mg litre 1 to assess activity levels and
to six concentrations for determinations of LC50
values.
A mixture of 3.4g (10mmol) of 3-(2,6-dichloro-4-
tri¯uoromethylphenyl)
perhydropyrimidine-2,4,6-
trione, 14.3g (50mmol) of phosphorus oxybromide,
1.57g (13mmol) of dimethylaniline and 30ml of
benzene was stirred for 1.5h at 75°C. The reaction
mixture was poured onto ice-water, washed with water
and brine, and dried over sodium sulfate. Removal of
the solvent gave a crude solid, which was treated with
isopropyl ether to give 1.4g of 6-bromo-3-(2,6-
dichloro-4-tri¯uoromethylphenyl)uracil as a solid,
yield 35%, mp: 259±260.5°C; [1H]NMR (dppm):
6.01 (1H, s), 7.77 (2H, s).
2.4.1 Brown planthopper (Nilaparvata lugens Staol),
Green rice leafhopper (Nephotettix cincticeps (Uhl), Small
brown planthopper (Laodelphax striatellus (Fall))
Rice stems were immersed in each solution for 20s.
Each treated stem was put into a glass tube (2cm
diamÂ10cm high) with a small amount of water.
After drying, seven third-instar nymphs or adults of N
cincticeps were released into each tube, which was kept
at 25°C, 70% RH under long-day (16L/8D) condi-
tions. Mortality was observed six days later. Thirty to
forty larvae were used for each treatment, and two
replications were made. A similar technique, with six
concentrations, was used to determine LC50 values of
selected compounds towards N lugens, L striatellus, and
2.3.6 1-Ethyl-3-(2,4,6-trichlorophenyl)-6-
trifluoromethyluracil (3a)
To a solution of 0.53g (1.5mmol) of 3-(2,4,6-
trichlorophenyl)-6-tri¯uoromethyluracil in 5ml of
DMF, 0.09g (2mmol) of NaH was added and stirred
for 1h under ice-water cooling. A solution of 1.17g
(7.5mmol) of ethyl iodide in 2ml of DMF was added
68
Pest Manag Sci 56:65±73 (2000)

Synthesis and activity of 3-(2,4,6-trisubstituted phenyl) uracils
Table 1. Biological activity of 3-(2,4,6-trisubstituted phenyl)-6-
susceptible and organophosphate-resistant strains of N
cincticeps.
trifluoromethyluracil derivatives
2.4.2 Twenty-eight-spotted lady beetle (Epilachna
vigintioctopunctata F)
Tomato leaf cuts were immersed in the solutions for
20s. Each treated leaf cut was placed in a Petri dish
(3cm diam) and seven third-instar larvae or adults of E
vigintioctopunctata were released into each tube.
Treated insects were kept at 25°C, 70% RH under
long-day (16L/8D) conditions. Mortality was ob-
served six days later. Thirty to forty larvae were used
for each treatment and two replications were made.
Activity
rating a
Compound Ra
Rb
Rc
mp (°C)
NC EV TU
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
a
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
F
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
F
224±227
241±243
248±250
300<
2
2
3
2
3
2
3
3
2
2
2
1
1
2
1
2
1
1
2
2
2
3
1
2
2
2
2
1
1
1
1
2
2
1
1
1
1
1
3
2
3
2
1
3
2
1
1
1
2
2
1
CF3
C2 F5
OCF3
NO2
CF3
CF3
OCF3
Br
247±220.5
221±224
206±208.5
220±223
205±208
240±241
229±231
237.5±241
264±266
213±215.5
178±181
172±174
2.4.3 Two-spotted spider mite (Tetranychus urticae
Koch)
Newly hatched larvae of T urticae on kidney bean leaf
discs (prepared by the Rothamsted method) were
sprayed with the solutions of the chemicals via a
`Rotary Spray Tower' to give a standard deposit of
2.5mlcm 2. Treated mites were kept at 25°C, 70%
RH under long-day (16L/8D) conditions. Mortality
was observed six days later. Thirty to forty larvae were
used for each treatment and two replications were
made.
F
i-Pr
c-hex
Br
F
F
F
Cl CF3
NO2 NO2
NO2
CF3 219±220.5
Lc95 (mg litre 1); >500: 1, 500±100: 2, 100±10: 3.
3
RESULTS AND DISCUSSION
Table 1 contains data on a series of 3-(2,4,6-
trisubstituted phenyl)uracil analogues in which the 2-
and 6-positions on the phenyl group were substituted
with various electron-withdrawing groups and atoms.
Emphasis was placed primarily on variations of the
substituent at the 4-position, with the 2- and 6-
positions ®xed as chlorine atoms (1a±f).
tive, 2,4,6-tribromophenyluracil (1j), gave the highest
ratings against all the three species. The introduction
of a ¯uorine atom (1k), as the smallest halogen,
reduced activity.
The introduction of alkyl groups at the 4-position on
the phenyl ring, while not leading to complete
inactivation, showed a tendency to reduce activity
(1l±m). The tri¯uoromethyl group has been recog-
nised as showing similar size effects to the isopropyl
group.9 However, the introduction of an isopropyl
group (1l) as an alternative to the tri¯uoromethyl
group at the 4-position drastically reduced overall
activity compared to those of tri¯uoromethyl ana-
logues. This suggests that the substituent at the 4-
position on the phenyl ring should possess electron-
withdrawing properties.
A chlorine atom as an electron-withdrawing sub-
stituent at the 4-position on the phenyl ring (1a) gave
activity against N cincticeps (NC), but activities against
the other two species, E vigintioctopunctata (EV) and T
urticae (TU) were rather low. As the substituent was
increased in size, the spectrum of activity tended to
expand. Replacement of chlorine at the 4-position
with bromine (1b) or tri¯uoromethyl (1c) gave activity
against EV, and that against NC increased to the
10mg litre 1 level. A penta¯uoroethyl group (1d) gave
broad-spectrum activity, including TU, and a tri¯uor-
omethoxy group (1e) gave the highest ratings against
all the three species assayed. Introduction of a nitro
group (1f), a hydrophilic electron-withdrawing group,
at the 4-position on the phenyl ring reduced the overall
activity.
The introduction of a ¯uorine atom at both the 2-
and 6-position (1n) tended to reduce activity com-
pared to 1j, which suggests that proper volume or
bulkiness is needed at these positions to provide high
insecticidal activity. Further substitution of a ¯uorine
atom at the 4-position led to a further decline in
activity (1o).
Replacement of the chlorine atom at the 6-position
of the phenyl ring, as in 1c, with a bromine atom (1g)
increased the insecticidal activity compared to the 2,6-
dichloro analogue. In the series of 2,6-dibromo
derivatives (1h±m), however, the activities of the
compounds containing tri¯uoromethyl (1h) or tri-
¯uoromethoxy (1i) groups at the 4-position, which
had high ratings in the 2,6-dichlorophenyl derivatives,
were somewhat lower. However, a 4-bromo-deriva-
The substitution of a nitro group at the ortho-
position on the phenyl ring reduced or completely
eliminated activity. (1p±q).
From all the results shown in Table 1, it is
concluded that the substituent at the 4-position should
have electron-withdrawing and hydrophobic proper-
ties, together with the correct volume. The order of
activity was OCF3 >CF3 ꢀC2F5.
Pest Manag Sci 56:65±73 (2000)
69

K Yagi et al
Although some compounds gave high activity
against TU, structure±activity relationships were not
clear.
Elongation or enlargement of the methyl group at
the 2- and/or 6-position to ethyl or isopropyl, as in
2n±p, retained activity, but no clear tendencies were
observed.
To examine the effects of substituents with electron-
donating properties at the 2- and 6-position on the
phenyl ring, some alkyl groups were introduced. The
results are shown in Table 2. Substitution of one
methyl group at the 6-position of 1a, as in 2a±b,
slightly reduced the insecticidal activity against NC
compared to that of 2,6-dichlorophenyl derivatives,
but led to some activity against EV and TU.
Introducing a cyano group at the 4-position, as an
electron-withdrawing group, led to complete loss of
activity (2c). Introduction of methyl groups at both 2-
and 6-position slightly reduced activity (2d±m). In a
series of 2,6-dimethylphenyl analogues, substitution at
the 4-position with a tri¯uoromethoxy group (2f)
produced relatively high insecticidal activity, as was
also observed in the 2,6-dihalogen derivatives (Table
1). Some insecticidal activity was retained on the
introduction of the electron-withdrawing methylsul®-
nyl group (2k), but this was reduced on replacement
by methanesulfonyl (21), and an ethoxycarbonyl
group at the 4-position led to complete inactivation
(2m). It is considered that the length and/or volume of
the substituent at the 4-position may contribute to
optimal activity in addition to the properties found in
the compounds listed in Table 1. An electron-
donating group at the 4-position, as in 2g, 2i and 2j,
led to a reduction in activity, as had been found with
the 2,6-dihalogeno derivatives (Table 1)
Considering the results shown in Tables 1 and 2,
while the 2- and 6-position on the phenyl ring do not
necessarily have to be substituted with electron-with-
drawing groups, such electronic properties at these
positions ®rmly improve the insecticidal activity. As to
size, small and compact substituents at the 2- and 6-
position are favourable to biological activity. The
substituent at the 4-position on the phenyl ring should
be hydrophobic with electron-withdrawing properties
as well as suitable size or shape.
Comparing the compounds which gave the highest
ratings for all the species, such as 1e,1g and 1j, the sum
of the volumes of the substituents on the phenyl ring is
almost identical. This result indicates that the volume
of the phenyl moiety in the whole molecule may be
responsible for optimal activity. The effects of the
electron-withdrawing substituents on the phenyl ring
suggest that the electronic properties at the 3-position
on the uracil ring may in¯uence interaction with a
receptor in the insect body system.
In order to examine the effects of substituents at the
1-position of the uracil ring, a variety of groups were
introduced. The results are shown in Table 3.
Substituents at the 1-position on the uracil ring
tended to reduce or completely eliminate activity
against NC, although some activity was retained
against EV and TU (3a±k). Introducing substituents
which were assumed to be degradable in the insect
body, such as acetyl (3b) or ethoxymethyl (3h) gave
biological activity against all species. Other groups
which were not considered to be easily degradable led
to complete inactivation against NC and EV. How-
ever, the presence of an amino group, which is also not
considered to be easily degradable, gave compounds
(eg 3k) showing activity against these two species.
Some compounds possessing slightly longer groups,
C3 to C4, as in 3e, 3f, 3g and 3i, showed activity
against TU. Against NC and EV, it was suggested that
the hydrogen atom on the nitrogen at the 1-position on
the uracil ring seemed to have a speci®c role in making
the properties of the molecule suitable for activity,
which could be postulated as hydrogen bonding
between the molecule and a receptor. The hydrogen
atoms on the amino group may play a role as hydrogen
bonding donors in place of the hydrogen atom on the
uracil ring nitrogen. Against TU, structural require-
ments seem to be different from those required for NC
and EV, and the proper length of the substituent,
which should not be easily degradable, would appear
to be important in some cases.
Table 2. Biological activity of 3-(2,4,6-trisubstituted phenyl)-6-
trifluoromethyluracil derivatives with the electron-donating substituents at 2-
and 6-positions on the phenyl ring
Activity
rating a
Compound Ra
Rb
Rc
mp (°C)
NC EV TU
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
Cl
Cl
Cl
Br
Me
Me
Me
217±219
220±224
287±289
2
1
1
2
1
3
1
1
1
1
2
1
1
2
1
1
2
2
1
2
2
2
1
1
1
1
2
1
1
2
2
2
2
1
1
1
2
2
1
1
1
1
1
1
1
1
1
1
Cl
CN
Br
Me
Me
Me
Me
Me
Me
Me
Me 242.5±243.5
Me 272±275.5
I
OCF3
Me
CN
OMe
SMe
Me
Me
Me
Me
Me
277±279
218±220
273±276
183±185
273±276
262±264
300<
Me SOMe Me
Me SO2 Me Me
Me CO2 Et Me
Table 4 contains data on a series of uracil analogues
in which the 6-position has been substituted with
various groups to examine the effects of combinations
of such substituents with those on the phenyl ring.
In the ®rst place, effects of the combination of the
substituents at the 6-position on the uracil ring and the
264±268
179.5±181
Et
Br
Br
Br
Et
Me
i-Pr
i-Pr 241±242.5
i-Pr 176±180
a See Table 1.
70
Pest Manag Sci 56:65±73 (2000)

Synthesis and activity of 3-(2,4,6-trisubstituted phenyl) uracils
Table 3. Biological activity of 1-substituted phenyl-6-trifluoromethyluracil
of the chain from tri¯uoromethyl to penta¯uoroethyl
(4c) increased the activities against EV and TU. A
methyl group (4d), as an electron-donating group, led
to complete inactivity. A methylthio (4e) or methane-
sulfonyl group (4f) instead of the tri¯uoromethyl
group also drastically reduced activity.
derivatives
Similar variations in activity were observed in 2,4,6-
trichlorophenyluracil derivatives with different sub-
stituents at the 6-position of the uracil ring (1a, 4g±i),
but these were favourable compared to those found
with the 2,6-dichloro-4-tri¯uoromethyl analogues.
Replacement of one ¯uorine atom to give a chlorodi-
¯uoromethyl group (4g) or elongation to penta¯uoro-
ethyl (4h) provided broad-spectrum activity and the
latter compound gave the highest ratings against EV
and TU. However, a hepta¯uoropropyl group (4i)
produced a slight decrease in insecticidal activity
compared with the penta¯uoroethyl group. The tert-
butyl group is one of the common constituents in
insecticidally and acaricidally active compounds,10
and is the substituent on the 1,3,4-oxadiazole-5-one
derivatives reported as giving favourable activity in our
previous paper.7 However, it was not effective in this
uracil system, as the tert-butyl analogue (4j) was
inactive in comparison with the tri¯uoromethyl
derivative (1j).
Activity
rating a
Compound
R
Rb
mp (°C)
NC EV TU
1a
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
Cl
224±227
2
1
2
1
1
1
1
1
2
1
3
1
2
1
1
2
1
1
2
2
2
2
1
2
1
2
1
1
2
1
1
2
1
2
3
2
1
1
1
Et
Cl 136±137.5
COMe
CH2 CN
CH2 Ph
n-Pr
Cl
Cl
Cl
Cl
117±120
173±175
127±129
oil
CH2 CH=CH2 Cl
104±105
131±132
H
CH2 C ꢁ CH
CH2 OEt
n-Bu
Cl
Cl
Cl
106±107
1c
3j
3k
H
CF3 248±250
CF3 145±148
CF3 198±201
Me
NH2
a See Table 1.
4-position on the phenyl ring were examined using 3-
(2,6-dichloro-4-tri¯uoromethylphenyl)uracil deriva-
tives and 3-(2,4,6-trichlorophenyl)uracil derivatives
(1c,4a±i). In the series of 2,6-dichloro-4-tri¯uoro-
methylphenyl derivatives (1a,1c, 4a±f), replacement
of the tri¯uoromethyl group (1c) at the 6-position on
the uracil ring with a bromine atom (4a), whose Van
der Waals volume is close to that of the tri¯uoromethyl
group, resulted in a decrease in activity. Replacing one
atom of the tri¯uoromethyl group with a chlorine atom
slightly increased activity against TU (4b). Elongation
Considering the results obtained here, an electron-
withdrawing group with the correct shape and hydro-
phobicity at the 6-position of the uracil ring and a
tri¯uoromethyl group or halogen atom at the 4-
position on the phenyl ring were required for the
development of optimal insecticidal activity, and
subtle changes in the properties of the substituents
affect the latter. In both cases, a penta¯uoroethyl
group at the 6-position led to relatively high potency.
Table 5 shows the effects of the substituent at the 5-
position on the uracil ring. Substituents at this position
Activity rating a
Compound
R
Ra
Rb
Rc
mp (°C)
NC
EV
TU
1c
4a
4b
4c
4d
4e
4f
1a
4g
4h
4i
CF3
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
248±250
259±260.5
236±239
207±209
246±248
219±222
219±220
224±227
268±270
236±239
203±207
240±241
286±289
3
1
2
3
1
1
1
2
3
3
3
2
1
2
1
2
2
1
1
1
1
2
3
2
2
1
1
1
2
2
1
1
1
1
2
2
1
3
1
CF2 Cl
CF3 CF2
Me
MeS
MeSO2
CF3
CF2 Cl
CF3 CF2
CF3 CF2 CF2
CF3
Cl
Cl
Cl
1j
4j
Br
t-Bu
Br
Table 4. Biological activity of 3-(2,4,6-trisubstituted
a
See Table 1.
phenyl)-6-substituted uracil derivatives
Pest Manag Sci 56:65±73 (2000)
71

K Yagi et al
Table 5. Biological activity of 3-(2,4,6-trichloro
Table 6. Biological activity of 2-thiocarbonyl-3-(2,4,6-
phenyl)-5-substituted 6-trifluoromethyluracil
derivatives
trisubstituted phenyl)uracil derivatives
Activity
rating a
Activity
rating a
Compound
R
Rb
W
mp (°C) NC EV TU
Compound
X
mp (°C) NC EV TU
6a
6b
6c
1a
1c
4g
CF3
Cl
S
S
208±210
205±207
208±214
224±227
248±250
268±270
1
1
1
2
3
3
3
1
2
1
2
2
1
1
1
1
1
2
1a
5a
5b
5c
5d
H
224±227
2
1
1
2
1
1
2
2
3
1
1
2
1
2
1
CF3 CF3
CF2Cl Cl
Me 222±225
Cl 238±239.5
Br 219±222
S
CF3
Cl
O
O
O
CF3 CF3
CF2Cl Cl
CN
Solid
a
a
See Table 1.
See Table 1.
resulted in a reduction in activity against NC, but the
compounds were effective against EV (5a±c). A
bromine atom gave a particularly high rating against
the latter (5c). The presence of a cyano group at the 5-
position (5d) resulted in a loss of activity. These results
can be construed as showing that the substituent at
this position must be hydrophobic.
is also interesting to note that activity relationships
against larvae and adults of LS are very different from
those against NC. 1c was much more active against
adult LS than against adult NC, but slightly less active
against the larvae of LS than against those of NC.
Uracil compounds were found to be effective against
organophosphate-resistant NC, which clearly shows
that there is no cross-resistance against that chemistry.
The difference in activity between the resistant and the
Table 6 shows the uracil derivatives on which the
ring carbonyl at the 2-position on the uracil ring was
replaced by a thiocarbonyl group. This resulted in a
complete loss of activity against NC (6a±c), and,
although mortalities were shown against EV and TU,
effects of structure changes were not clear.
susceptible strains of NC is negligible, with LC50
1
values for 1c against larvae of 6.5 and 6.0mg litre
,
respectively. Activities against adults were much less
than against larvae.
To assess in detail the insecticidal potential and
spectrum against Hemiptera species and EV as a
representative of Coleoptera, compounds 1c,1e and
4c were selected from the compounds showing highest
activities. Assays were conducted against N lugens
(NL), L striatellus (LS), NC and EV, and the results in
terms of LC50 values are shown in Table 7. It is
interesting to note that most of the compounds listed
in that table possessed insecticidal activity not only
against larvae but also against adults of Hempitera; in
particular, 1c was effective against all species tested. It
Compound 1c was the most active of those tested
against EV, with an LC50 value of 5mg litre 1. The
most active compound against NL was 4c with an
LC50 value of 4.3mg litre 1, only one-quarter of that
of the conventional pyrethroid insecticide, trebon.
In conclusion, a series of 3-(2,4,6-trisubstituted
phenyl)uracil derivatives has been synthesised and
assayed for insecticidal and acaricidal activity; detailed
structure±activity relationships against N cincticeps, E
vigintioctopunctata and T urticae have been elucidated.
The requirements for optimal insecticidal activity can
1
LC50 (mg litre
LS
)
NL a
R-NC
S-NC
EV
R
Rb Larvae Adult Larvae Adult Larvae Adult Larvae Adult Larvae
1c CF3 CF3
1e CF3 OCF3 24.2 145
4c C2F5 CF3
Trebon
6.0
7.7 10.9
67.0
14.1 11.8
10.1
5.5
36.3
16.4
1.7
6.5
6.8
6.8
2.1
117
>333
>333
6.0
124
5.0
19.5
26.2
±
18.8 >333
32.9 >333
4.3
18.5
±
1.0
1.0
0.9
a
NL: N lugens; LS: L striatellus; NC: N cincticeps; EV: E vigintioctopunctata; R: Resistant strain; S: Susceptible
Table 7. LC50 values of selected 3-
strain.
trisubstituted phenyluracil derivatives
72
Pest Manag Sci 56:65±73 (2000)

Synthesis and activity of 3-(2,4,6-trisubstituted phenyl) uracils
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luracil (4c) also showed good insecticidal properties.
1
Its LC50 value against larvae of N lugens, 4.3mg litre
was the highest activity recorded.
,
Pest Manag Sci 56:65±73 (2000)
73