Studies of the new herbicide KIH-6127. Part III. Synthesis and structure-activity studies of analogues of KIH-6127 against barnyard grass (Echinochloa oryzicola)

Article abstract of DOI:10.1002/(SICI)1096-9063(199701)49:1<76::AID-PS491>3.0.CO;2-E

The previously evaluated prototype, methyl 6-acetyl-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate, was modified by the introduction of an oximino group. Further extensive synthetic modifications were then made to the 6-alkyl moiety (R¹), the est

Full text of DOI:10.1002/(SICI)1096-9063(199701)49:1<76::AID-PS491>3.0.CO;2-E

Pestic. Sci. 1997, 49, 76È84
Studies of the New Herbicide KIH-6127. Part III.
Synthesis and Structure–Activity Studies of
Analogues of KIH-6127 against Barnyard Grass
*
(Echinochloa oryzicola)
Masatoshi Tamaru,” Naoshi Masuyama, Masahiro Sato, Fumiaki Takabe,
Jun Inoue
K-I Chemical Research Institute Co. Ltd, Fukude-cho, Iwata-gun, Shizuoka 437-12, Japan
& Ryo Hanai
Kumiai Chemical Industry Co. Ltd, Life Science Research Institute, Kikugawa, Ogasa-gun, Shizuoka 439,
Japan
(Received 16 May 1995; revised version received 21 April 1996; accepted 21 August 1996)
Abstract: The previously evaluated prototype, methyl 6-acetyl-2-[(4,6-
dimethoxypyrimidin-2-yl)oxy]benzoate, was modiÐed by the introduction of an
oximino group. Further extensive synthetic modiÐcations were then made to the
6-alkyl moiety (R1), the ester moiety (R2), the alkoxyimino moiety (R3), the
bridge-atom (X) and the 4,6-disubstituted-pyrimidine moiety (A, B, Z). StructureÈ
activity relationships of the synthesized compounds were studied by examining
their herbicidal activity against Barnyard grass (Echinochloa oryzicola) in paddy
rice at various growth stages, including pre-emergence. The novel herbicide
methyl
2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[1-(methoxyimino)ethyl]ben-
zoate, (KIH-6127) was found to be the most e†ective compound. The commercial
development of this compound is currently in progress.
Key words: herbicide, barnyard grass, PS compound, KIH-6127, rice, acetolac-
tate synthase (ALS)
1
INTRODUCTION
pyrimidin-2-yl-salicylates are converted into the active
carboxylic acid in vivo.3
Our previous work reported that methyl 6-acetyl-2-[(4,
6-dimethoxypyrimidin-2-yl)oxy]benzoate (Fig. 1, I)
exhibited a good proÐle as a lead compound for the
control of barnyard grass (Echinochloa oryzicola Frit.).
Most 6-substituted pyrimidin-2-yl salicylate com-
pounds bearing an ester group showed reduced herbi-
cidal and ALS inhibitory activities as compared with
their 6-substituted carboxylic acid analogues.2 This sug-
gested that ortho-disubstitution is capable of preventing
the metabolic hydrolysis of the ester moiety, by which
As brieÑy discussed in Part II,4 the 6-acyl pyrimidin-
2-yl salicylates possess herbicidal activity, especially
against barnyard grass, for a variety of ester moieties.
For a series of 6-acyl compounds, only the 6-acetyl
derivative I was sufficiently selective in rice whilst
showing good control of barnyard grass.
Our optimization focused on the modiÐcation of the
6-acyl group. The introduction of an oximino group
into the 6-acyl moieties was attempted to give a hypo-
thetical bio-isosteric analogue of I. The methoxyimino
group has a similar [p ] value (CH OwNxCHw:
p
3
0É30, OxCHw: 0É42)5 value and a steric similarity to
* Part II Pestic. Sci. 47 (1996) 327È35.
” To whom correspondence should be addressed.
carbonyl, and the hydrophilicity of the oximino (R3)
76
Pestic. Sci. 0031-613X/97/$09.00 ( 1997 SCI. Printed in Great Britain

Studies of the new herbicide KIH-6127. Part III
77
All test compounds were obtained by the reactions
(Methods A, B, C and D) summarized as shown in Fig.
2. Compounds 10, 12, 13, 15 and 16 were synthesized by
Methods E and F as shown in Figs 3 and 4, respec-
tively. The synthetic intermediates for the test com-
pounds were obtained by our reported method.1,4,6h9
Other starting compounds, such as the corresponding
alkoxy amines, were prepared by standard
procedures10,11 or were commercially available. Typical
examples of synthetic procedures are as follows:
2.1.1 Method A
2.1.1.1 Synthesis of methyl 2-[(4,6-dimethoxypyrimidin-
2-yl)oxy]-6-[1-(methoxyimino)propyl]benzoate
Methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-
(3).
propionylbenzoate1,4 (0É62 g, 1É79 mmol), methoxy-
lamine hydrochloride (0É45 g, 5É40 mmol) and potassium
acetate (0É53 g, 5É40 mmol) were added to methanol
(80 ml), and the mixture was heated at reÑux for 6 h.
The precipitate was Ðltered o†, and the Ðltrate was
evaporated. The residue was added to water and
extracted with ethyl acetate. The organic layer was
washed with water, separated and dried. The solvent
was evaporated and the mixture puriÐed using a silica-
gel column with hexane ] ethyl acetate (7 ] 3 by
volume) as eluent and crystallized from isopropyl ether/
ethyl acetate to give 3 (0É6 g; 85É9%); m.p. 75È77¡C,
[1H]NMR d: 1É06 (t, J \ 7 Hz, 3H), 2É73 (q, J \ 7 Hz,
2H), 3É73 (s, 3H), 3É83 (s, 6H), 3É92 (s, 3H), 5É86 (s, 1H),
7É00È7É63 (m, 3H) ppm:
Fig. 1. Structures of compounds discussed. I Prototype com-
pound. II General structure of test compounds. 1 KIH-6127.
moiety can be varied by alkylation or acylation. (Fig. 1,
II).
This paper describes the modiÐcation of the alkyl
(R1), the ester (R2), the oximino (R3), the bridge (X) and
the pyrimidine (A,B,Z) moieties II and the structureÈ
activity proÐles for barnyard grass control and rice
safety.
2
MATERIALS AND METHODS
2.1.1.2 Synthesis of methyl 6-[1-(allyloxyimino)ethyl]-2-
[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate (34). Com-
pound I (1É0 g, 0É30 mmol), allyloxyamine hydro-
chloride (1É0 g, 0É92 mmol) and potassium acetate
(0É9 g, 0É92 mmol) were added to methanol (30 ml), and
the mixture was heated at reÑux with stirring for 5 h.
The reaction mixture was then poured into cold water
and extracted with ethyl acetate. The organic layer was
washed in turn with dilute hydrochloric acid, then with
aqueous sodium hydrogen carbonate and water. The
organic layer was dried, concentrated, and the oily
2.1 Synthesis of test compounds
[1H] and [13C]NMR spectra were recorded in deutero-
chloroform on a JEOL JMN-PMX-60Si and a JEOL
JMN-GSX-400 with trimethylsilane as an internal stan-
dard, while IR spectra and mass spectra were measured
on a Shimadzu IR-240 and a JEOL JMS-SX-102A
spectrometer, respectively. All melting points are uncor-
rected. The structures of compounds were conÐrmed by
NMR, IR and mass spectroscopies.
Fig. 2. General synthetic schemes (Methods A, B, C & D) for compounds II.

78
Masatoshi T amaru et al.
Fig. 3. Introduction of the R2 moiety in the presence of CDI (N,N@-carbonyl diimidazole).
residue puriÐed by silica-gel column chromatography
using hexane ] isopropyl ether (10 ] 1 by volume) as
eluent to give 34 as colourless crystals (0É54 g; 46%);
m.p. 76È78¡C, [1H]NMR d: 2É20 (s, 3H), 3É66 (s, 3H),
3É79 (s, 6H), 4É60 (d, J \ 6 Hz, 2H), 5É0È5É60 (m, 2H),
5É69 (s, 1H), 5É75È6É15 (m, 1H), 7É0È7É50 (m, 3H) ppm.
106¡C, [1H]NMR d: 2É17 (s, 3H), 3É76 (s, 3H), 3É82 (s,
6H), 3É96 (s, 3H), 5É73 (s, 1H), 7É16È7É50 (m, 3H) ppm.
2.1.2.2 Synthesis of methyl 2-[(4,6-dimethoxypyrimidin-
2-yl)-N-formylamino-6-[1-methoxyimino)ethyl]benzoate
(26). Methyl 2-formylamino-6-[1-(methoxyimino)ethyl]
benzoate (10 g, 0É04 mol) was added to a suspension of
sodium hydride (1É0 g, 0É04 mol) in benzene (100 ml),
and the resultant mixture was stirred at room tem-
perature for 10 min. DMSP (8É7 g, 0É04 mol) was then
added and the mixture heated at reÑux for 6 h. After
cooling, the reaction mixture was poured into ice/water,
and extracted with ethyl acetate. The organic layer was
washed with water, dried and concentrated. The residue
was puriÐed by silica-gel column chromatography as in
Section 2.1.1.2 to give 26 (8É3 g; 54%); m.p. 147È149¡C.
[1H]NMR d: 2É15 (s, 3H), 3É59 (s, 3H), 3É73 (s, 6H), 3É85
(s, 3H), 5É69 (s, 1H), 7É15È7É59 (m, 3H), 10É15È10É30 (brs,
1H) ppm.
2.1.2 Method B
2.1.2.1 Synthesis of methyl 2-[(4,6-dimethoxypyrimidin-
2-yl)oxy-6-[1-(methoxyimino)ethyl]benzoate (1). Methyl
6-[1-(methoxyimino)ethyl]salicylate (1É15 g, 5É0 mmol),
4,6-dimethoxy-2-methanesulfonylpyrimidine
(DMSP)
(1É12 g, 5É1 mmol) and potassium carbonate (0É71 g,
5É65 mmol) were added to N,N-dimethylformamide
(DMF; 50 ml), and the mixture was heated at 100¡C for
2 h. After cooling, the reaction mixture was poured into
water, and extracted with ethyl acetate. The organic
layer was washed with water, dried and concentrated to
give 1 as a crude solid, which was then washed with
isopropyl ether to give pure 1 (1É35 g; 73%); m.p. 105È
2.1.2.3 Synthesis of methyl 2-[(4,6-dimethoxypyrimidin-
2-yl)amino]-6-[1-(methoxyimino)ethyl]benzoate
Concentrated hydrochloric acid (1 ml) was added to a
(27).
Fig. 4. Synthesis of N,N-dimethyl-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[1-(methoxyimino)ethyl]benzamide (16).

Studies of the new herbicide KIH-6127. Part III
79
solution of 26 (1É34 g, 3É45 mmol) in methanol (50 ml).
The mixture was allowed to stand overnight at room
temperature, poured onto ice/water, and then extracted
with ethyl acetate. The organic layer was washed with
aqueous sodium hydrogen carbonate and then with
water, dried and concentrated. The residue was puriÐed
by silica-gel column chromatography as in Section
2.1.1.2 to give 27 (0É87 g; 70%) m.p. 82È84¡C,
[1H]NMR d: 2É15 (s, 3H), 3É85 (s, 3H), 3É90 (s, 9H), 5É56
(s, 1H), 6É92 (d, J \ 7 Hz, 1H), 7É39 (t, J \ 7 Hz, 1H),
8É56 (d, J \ 7 Hz, 1H), 8É90È9É20 (brs, 1H) ppm.
ethyl acetate. The organic layer was washed with water,
dried and concentrated to give crude V in 80% yield.
According to Method B, a mixture of crude V (2É9 g,
9É9 mmol), DMSP (2É2 g, 1É0 mmol) and potassium car-
bonate (1É38 g, 10 mmol) in DMF (20 ml) was stirred at
90¡C for 1 h to give 13 (51%); m.p. 103È105¡C,
[1H]NMR d: 1É00 (t, J \ 7 Hz, 3H), 1É13 (t, J \ 7 Hz,
3H), 1É20È2É50 (m, 4H), 2É26 (s, 3H), 3É79 (s, 6H), 4É10 (s,
1H), 5É79 (s, 1H), 7É15È7É85 (m, 3H) ppm.
2.1.6 Method F
2.1.3 Method C
2.1.6.1 Synthesis of N,N-dimethyl-2-[(4,6-dimethoxy-
pyrimidin-2-yl)oxy]-6-[1-(methoxyimino)ethyl]benzamide
(16). n-Butyllithium (9 g, 20É4 mmol: 14% hexane
solution) was added dropwise to a solution of 3-
benzyloxyacetophenone ethylene ketal1,4 VII; (5 g,
18É5 mmol) in toluene (25 ml) with stirring at 6È7¡C for
10 min. The mixture was stirred at room temperature
for a further 30 min, and N,N-dimethylcarbamoyl chlo-
ride (1É98 g, 18É5 mmol) added dropwise at room tem-
perature. This mixture was gradually heated to 60¡C,
and maintained for 2 h, then poured into water and
extracted with ethyl acetate. The organic layer was
washed with water, dried and concentrated. The residue
was puriÐed by silica-gel column chromatography as in
Section 2.1.1.2 to give VIII (43%); m.p. 85È87¡C,
[1H]NMR d: 1É76 (s, 3H), 2É83 (s, 3H), 3É09 (s, 3H),
3É66È4É10 (m, 4H), 5É13 (s, 2H), 6É85È7É62 (m, 3H), 7É43
(s, 5H) ppm.
2.1.3.1 Synthesis of ethyl 2-[(4,6-dimethoxypyrimidin-2-
yl)oxy]-6-[1-(methoxyimino)ethyl]benzoate (6). Sodium
hydride (0É14 g, 6É0 mmol) was added to a solution of 5
(2 g, 6É0 mmol) in DMF (50 ml) with stirring at room
temperature. After the generation of hydrogen had Ðn-
ished, ethyl bromide (0É76 g, 7É0 mmol) was added. The
resultant mixture was stirred for 1 h at 60¡C, and then
poured into cold water, and the oily product thus
formed extracted with ethyl acetate. The organic layer
was washed with water, dried and concentrated, and the
residue puriÐed by silica-gel column chromatography as
in Section 2.1.1.2 to obtain 6 (1É5 g; 69%) m.p. 65È68¡C,
[1H]NMR d: 1É26 (t, J \ 7 Hz, 3H), 2É23 (s, 3H), 3É73 (s,
6H), 3É81 (s, 3H), 4É07 (q, J \ 7 Hz, 2H), 5É76 (s, 1H),
7É15È7É60 (m, 3H) ppm.
2.1.4 Method D
A solution of VIII (1É5 g, 4É46 mmol) and methoxy-
ammonium chloride (1É2 g, 14 mmol) in methanol
(15 ml) was heated at reÑux for 1 h to give IX (0É9 g,
2É76 mmol), which was then catalytically hydrogenated
in the presence of Pd/C under standard conditions to
give X quantitatively (0É68 g, 2É87 mmol). According to
the procedure of Method B, X was converted into 16
2.1.4.1 Synthesis of methyl 6-[1-(acetyloxyimino)ethyl]-
2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate (39). Tri-
ethylamine (0É434 g, 4É3 mmol) was added to a solution
of 28 (1É5 g, 4É3 mmol) in acetone (20 ml) below 0¡C.
Acetyl chloride (0É34 g, 4É3 mmol) was added dropwise
to the resultant mixture below 5¡C, and the mixture
stirred at 5È10¡C for 2 h. The reaction mixture was then
poured onto ice/water, extracted with ethyl acetate, and
the organic layer washed with water, dried and concen-
trated below 30¡C. The residue was puriÐed by silica-gel
column chromatography as in Section 2.1.1.2 to give 39
(72%); n20: 1É5491, [1H]NMR d: 2É20 (s, 3H), 2É83 (s,
D
3H), 3É00 (s, 3H), 3É79 (s, 6H), 3É86 (s, 3H), 5É73 (s, 1H),
7É15È7É43 (m, 3H) ppm.
as
a
colourless oil (0É86 g; 52%); n20: 1É5510,
2.1.7 Syntheses of other compounds
D
[1H]NMR d: 2É16 (s, 3H), 2É26 (s, 3H), 3É66 (s, 3H), 3É76
2.1.7.1 Synthesis of methyl 6-[1-(methoxyimino)ethyl]
salicylate. According to Method A, methyl 6-
acetylsalicylate8 was converted to methyl 6-[1-(methy-
(s, 6H), 5É73 (s, 1H), 7É08È7É73 (m, 3H) ppm.
2.1.5 Method E
oxyimino)ethyl]salicylate
[1H]NMR d: 2É07 (s, 3H), 3É83 (s, 3H), 3É86 (s, 3H),
6É53È7É53 (m, 3H), 10É66È11É00 (brs, 1H) ppm.
(83%);
n20:
1É5423,
D
2.1.5.1 Synthesis of O-[2-[(4,6-dimethoxypyrimidin-
2-yl)oxy]-6-[1-(methoxyimino)ethyl]benzoyl]-N-(3-penty-
lidene)hydroxyamine (13). A solution of III (2É6 g,
12É4 mmol) and 1,1@-carbonyldiimidazole (CDI; 2É0 g,
12É4 mmol) in tetrahydrofuran (20 ml) was stirred at
room temperature for 1 h. Pentane-3-one oxime (1É25 g,
12É4 mmol) and potassium carbonate (0É85 g,
12É4 mmol) were added to the resultant mixture (IV),
and the mixture was heated at reÑux for 1 h. The reac-
tion mixture was poured into water, and extracted with
2.1.7.2 Synthesis of 6-[1-(methoxyimino)ethyl]salicylic
acid (III). A solution of methyl 6-[1-(methoxyimino)
ethyl]salicylate (25É4 g) in aqueous potassium hydrox-
ide (200 g litre~1; 100 ml) was stirred at 80¡C for 1 h to
give 6-[1-(methoxyimino)ethyl]salicylic acid (III). The
reaction mixture was acidiÐed with citric acid, then
extracted with ethyl acetate. The organic layer was

80
Masatoshi T amaru et al.
washed with water, dried and concentrated, and the
residue triturated with isopropyl ether ] hexane (1 ] 1
by volume) and recrystallized from isopropyl ether to
give III as yellow crystals (31É4% yield); m.p. 110É5È
112¡C, [1H]NMR d: 1É85 (s, 3H), 3É53 (s, 3H), 6É17È7É17
(m, 3H), 8É50È9É56 (brs, 1H) ppm.
3.1 Stereochemistry
The condensation of crude methyl 6-[1-(methoxyimino)
ethyl]salicylate with DMSP gave a mixture of 1E (E-
isomer) and 1Z (Z-isomer) in a [9 : 1 (E/Z) ratio. The
isomers were separated by silica-gel column chromatog-
raphy and [1H] and [13C]NMR spectra recorded to
conÐrm their stereochemistry. The chemical shifts are
summarized as shown in Table 3.
2.2 Stereochemistry
According to the resonances of [1H] and [13C]NMR
spectra, both proton and carbon chemical shifts for the
3-position of 1E were observed to be more downÐeld
than those of 1Z. Conversely, those for the 1-position of
1E were more upÐeld than those of 1Z in accordance
with the literature.12,13 A weak NOE spectrum was
observed between the 1-position and the 3-position of
1E, but no NOE spectrum was observed for 1Z. Conse-
quently, the major isomer was tentatively assigned as
being the E-isomer.
All reaction product oxime derivatives obtained by the
present synthetic methods were E/Z mixtures. Usually
one isomer was major, forming [90% of the mixture.
The isomers were easily separated by silica-gel
(Wakogel C-300) column chromatography using
hexane ] ethyl acetate (10 ] 1 to 6 ] 1 by volume) as
eluent and with subsequent recrystallization. Each com-
pound was found to have greater than 98% purity by
HPLC. The stereochemistry of E/Z isomers in typical
compounds was conÐrmed by high resolution NMR
spectroscopy, with the major isomer being E, as dis-
cussed in Section 3.1.
3.2 Synthesis of test compounds
2.3 Biological tests
Four synthetic schemes for PS compounds (Methods A,
B, C and D) were developed and employed for the prep-
aration of a variety of compounds of general structure
II (Fig. 1). The target ethylthio (10), alkylidene iminooxy
(12 and 13) ester and amide (16) derivatives required
alternative approaches (Figs 3 and 4).
When a mixture of 5 and ethylmercaptan was treated
at room temperature in the presence of 1,1@-carbonyl
diimidazole (CDI) only starting material was recovered.
A second attempt under reÑux conditions and with the
addition of potassium carbonate gave undesired VI. The
latter compound was also obtained quantitatively by
heating 15 at reÑux in tetrahydrofuran.
It would appear that the bulky ortho pyrimidine ring
of 15 tends to enhance undesirable cyclization to give
VI.
We then performed a similar reaction on the analo-
gous compound lacking the bulky pyrimidine moiety.
Thus, a mixture of IV and ethylmercaptan or ketone
oximes was reacted under reÑux in the presence of pot-
assium carbonate to give the desired intermediates (V),
which were subsequently transformed into 10, 12 and
13.
Each test compound was formulated as a 100 g kg~1
wettable powder, containing “EmalgenÏ 810 (5É0 g kg~1;
Kao Ltd), “DemolnÏ (5É0 g kg~1, Kao Ltd), Kunilite 250
(diatomaceous earth; 180 g kg~1), Carplex No/80 (white
carbon; 60 g kg~1) and Zeeklite (clay). The wettable
powder was diluted with water to the desired concentra-
tion. Plastic pots (square, 100 cm2 in surface area) were
packed with clay loam soil (organic matter 1É44%,
pH 5É6) and water was added up to 3 cm in depth. E.
oryzicola (Ec) was seeded at a depth of 0É5 cm 1 day
after puddling and fertilization. Rice seedlings (Oryza
sativa, two-leaf growth stage) (Or) were transplanted in
depths of 3 cm in the same pot. One day after seeding,
or when E. oryzicola reached the desired leaf-growth
stage, a diluted suspension (10 ml) of wettable powder
was poured into the pots, individually. The test pots
were maintained at 20È35¡C and the water temperature
at 15È30¡C during the test period. No artiÐcial light
was used. A water depth of 3 cm was maintained during
the test period. Three weeks later (DAT 21), the herbi-
cidal activity and rice injury ratings were visually evalu-
ated on a percentage scale, where 0% \ no control or
Figure 4 shows the preparation of the amide (16)
derivative. In the Ðrst step, we performed an ortho-
lithiation reaction in toluene with the addition of N,N-
dimethylcarbamoyl chloride. Reaction occurred only
above 60¡C, and when the mixture was maintained at
this temperature for 2 h, VIII was obtained in 43%
yield. Subsequent treatment of VIII,8 a†orded X and 16
without problem.
crop injury and 100% \ complete mortality. ED and
90
ED values were calculated as the amounts of active
10
ingredient (g ha~1) required for 90% control of barn-
yard grass, and 10% injury of rice, respectively.
3
RESULTS AND DISCUSSION
The herbicidal activities and physical properties of the
test compounds are shown in Tables 1 and 2 respec-
tively.
The intermediate lithium salt of VII was sufficiently
stable to require carbamoylation at the unusually high
temperature of 60¡C.14

Studies of the new herbicide KIH-6127. Part III
81

82
Masatoshi T amaru et al.

Studies of the new herbicide KIH-6127. Part III
83
TABLE 2
Physical Properties of Test Compounds and Synthetic Procedure Employed
Compound
number
m.p. [¡C]
Compound
number
m.p. [¡C]
n 20
Methoda
n 20
Methoda
D
D
1
2
105È106
78È79
75È77
1É5343
125È127
65È68
1É5449
1É5301
1É5545
73È88
1É5687
1É5355
103È105
95È98
194È199
1É5491
1É5221
1É5587
126È129
1É5342
79É80
B
A
A
A
C
C
C
C
A
E
C
E
E
C
E
F
A
A
A
A
A
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
110È113
1É5378
131È135
1É5709
147È149
82È84
131È132
93È95
73È76
A
A
B
A
B
B
A
A
A
A
A
A
A
A
A
A
A
D
D
D
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
74È75
1É5374
1É5681
76È78
77È80É5
1É5588
1É5540
1É5539
1É5510
121È125
110È111
a See Section 2 and Figs 2, 3, 4.
3.3 Structure–activity of test compounds
In the 6-acetyl series, the e†ects of the ester moiety
(R2) can be observed. Only the methyl ester derivative
(1) exhibited both potent barnyard grass control activity
and selectivity. The carboxylic acid (5) and oxime ester
(12) also showed potent activity against barnyard grass
but were less selective.
The esters 10È13 had been prepared with the objec-
tive of improving selectivity by reducing metabolic acti-
vation in vivo.
Comparing the e†ects of acyl moieties (R1) (Table 1),
these compounds exhibited herbicidal activity in the
order: CH (1), H (2) [ C H (3) ? C H (4). The hydro-
3
2 5
3 7
gen derivative (2) showed poor selectivity in rice.
Clearly, increasing chain length in R1 led to a reduction
in herbicidal activity.
In contrast to the esters, the amides (15) and (16) were
very weakly active. It seems probable that the ester
linkage of this series is converted to an activated sub-
stance by an esterase in the metabolic pathway to the
target site (ALS)15 in barnyard grass.
TABLE 3
[1H] and [13C]NMR Chemical Shifts of 1E & 1Z KIH-6127
The introduction of other pyrimidine substitution
patterns (17È22), or triazine analogues (23, 24) and thio
(25) or nitrogen bridged compound (26, 27) led to less
herbicidally active compounds than 1.
Table 1 also shows the e†ects of changing the imino
(R3) moiety. The pre-emergence activity of the test com-
pounds (1, 28È41) was not very sensitive to changing R3
and all of compounds retained activity.
Chemical shiftsa
[1H]NMR
[13C]NMR
The introduction of bulky substituents (31È33)
decreased the three-leaf growth-stage activity. The
hydroxy (28) and acyloxy (39È41) derivatives were much
less selective than the alkoxyimino esters.
In conclusion, the structureÈactivity study has shown
that the methyl ester group was critical for selective pre-
emergence control of barnyard grass in rice. The novel
Compound
1
3
1
2
3
1E
1Z
2É185
2É252
3É929
3É724
14É80
21É84
154É27
154É33
62É00
61É45
a d [ppm] from trimethylsilane as an internal standard in deu-
terochloroform.

84
Masatoshi T amaru et al.
4. Tamaru, M., Takehi, T., Masuyama, N. & Hanai, R.,
Studies of the new herbicide KIH-6127, Part II. Synthesis
and herbicidal activity of 6-acyl pyrimidin-2-yl salicylates
and analogues against barnyard grass. Pestic. Sci., 47
(1996) 327È35.
5. Hansch, C., Rockwell, S., D., Jow, P. Y. C., Leo, A.,
Steller, E. E., J. Med. Chem., 20 (1977) 304È6.
6. Tamaru, M., Kawamura, N., Sato, F., Tachikawa, S.,
Yoshida, R. & Takabe, F., Kumiai Chemical Ind. Co. Ltd
& Ihara Chemical Ind. Co. Ltd, Eur. Pat. Appl., EP-
435170, (1991).
7. Tamaru, M., Kawamura, N., Sato, M., Takabe, F., Tachi-
kawa, S. & Yoshida, R., Kumiai Chemical Ind. Co. Ltd &
Ihara Chemical Ind. Co. Ltd, Jpn. Kokai Tokkyo Koho,
JP 4-134080 (1993).
8. Umezu, K., Isozumi, K., Miyazaki, T., Tamaru, M.,
Takabe, F., Masuyama, N. & Kimura, Y., Synlett. (1)
(1994) 61È2.
herbicide KIH-61276,16 (1) was found to be the most
e†ective compound.
The herbicidal activity of KIH-6127* has also been
evaluated in paddy Ðelds in Japan since 1990 and
shown a remarkable herbicidal activity at low dose
(30 g AI ha~1) applications.16
ACKNOWLEDGEMENTS
We wish to express our thanks to Prof. Toshiro Fujita
of Kyoto University for his invaluable suggestions. We
also thank Dr Yoshikazu Kimura of Ihara Chemical
Industry Co., Ltd for fruitful discussions.
9. Tamaru, M., Umezu, K., Isozumi, K., Maejima, C.,
Kageyama, H. & Kimura, Y., Synth. Commun., 24(19)
(1994) 2749È56.
10. Major, R. T. & Feck, E. E., J. Am. Chem. Soc., 50 (1928)
1479È81.
11. Lutz, W. B., J. Org. Chem., 36 (1971) 3835È7.
12. Padwa, A. & Albrecht, F., J. Am. Chem. Soc., 96 (1974)
4849È56.
13. Hawkes, G. E., Harwing, K. & Roberts, J. D., J. Org.
Chem., 39 (1974) 1017È29.
14. Snieckus, V., Chem. Rev., 90 (1990) 879È933.
15. Shimizu, T., Nakayama, I., Nakao, T., Nezu, Y. & Abe,
H., Nihon Noyaku Gakkaishi (J. Pestic. Sci.), 19 (1984) 59È
67.
16. Hanai, R., Kawano, K., Shigematsu, S. & Tamaru, M.,
Proc. Brighton Crop Prot. Conf.ÈW eeds., 1 (1993) 47È52.
REFERENCES
1. Tamaru, M. & Saito, Y., Study of new herbicide KIH-
6127 Part 1. Novel synthesis of methyl 6-acetylsalicylate
as
a key intermediate for the preparation of 6-
acetylpyrimidin-2-yl salicylates and analogues. Pestic. Sci.,
47 (1996) 125È30.
2. Wada, S., Saito, Y., Kaku, K., Nezu, M. & Shigematsu, S.,
Annu. Meeting of Pesticide Society of Japan (1992) 15 (in
Japanese).
3. Shimizu, T., Nakayama, I., Nakao, T., Takahashi, S.,
Tamaru, M., Wada, N. & Abe, H., Eighth Internat. Congr.
Pestic. Chem., Washington, DC, 1994, 9BÈ669.
* The name pyriminobac-methyl for this compound, has been
approved by ISO.