Synthesis and Herbicidal Activities of 4-Substituted 3-Aryl-5-tert-butyl-4-oxazolin-2-ones

Article abstract of DOI:10.1021/jf980281i

A series of novel 3-aryl-5-tert-butyl-4-chloro-4-oxazolin-2-ones (16) have been prepared and found to show significant herbicidal activity in the grams per are range against broadleaf and narrowleaf weeds. The key step in the introduction of the chlorine atom at the 4-position of the 4-chloro-4-oxazolin-2-one ring is dichlorination using chlorine gas and subsequent dehydrochlorination using diazabicyclo[5.4.0]undecene. 4-Alkylthio- and 4-methyl-4-oxazolin-2-one rings were synthesized from α-substituted α-bromopinacolone by cyclization reaction. Among the synthesized compounds, 5-tert-butyl-4-chloro-3-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4-oxazolin- 2-one (16h) showed the greatest activity against several weeds without damage to transplanted rice in the paddy field.

Full text of DOI:10.1021/jf980281i

J. Agric. Food Chem. 1998, 46, 5305−5312
5305
Syn th esis a n d Her bicid a l Activities of 4-Su bstitu ted
3-Ar yl-5-ter t-bu tyl-4-oxa zolin -2-on es
Noriaki Kudo,* Misa Taniguchi, Satoru Furuta, Kazuo Sato, Takeshi Endo, and
Toyokuni Honma
Agroscience Research Laboratories, Sankyo Company, Ltd., 1041 Yasu, Yasu-cho, Shiga 520-2342, J apan
A series of novel 3-aryl-5-tert-butyl-4-chloro-4-oxazolin-2-ones (16) have been prepared and found
to show significant herbicidal activity in the grams per are range against broadleaf and narrowleaf
weeds. The key step in the introduction of the chlorine atom at the 4-position of the 4-chloro-4-
oxazolin-2-one ring is dichlorination using chlorine gas and subsequent dehydrochlorination using
diazabicyclo[5.4.0]undecene. 4-Alkylthio- and 4-methyl-4-oxazolin-2-one rings were synthesized from
R-substituted R-bromopinacolone by cyclization reaction. Among the synthesized compounds, 5-tert-
butyl-4-chloro-3-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4-oxazolin-2-one (16h ) showed the great-
est activity against several weeds without damage to transplanted rice in the paddy field.
Keyw or d s: 4-Oxazolin-2-one; R-bromoketone; cyclization; herbicide; biological isostere
INTRODUCTION
a comparison of the relative herbicidal activity of com-
pounds in this series.
4-Oxazolin-2-ones have been widely studied (Filler,
1965; Filler and Rao, 1977; Rao and Filler, 1986; Boyd,
1984; Hartner, 1996) since Maselli reported the first
synthesis in 1905 (Maselli, 1905). McCombie and co-
workers reported the synthesis of 4-oxazolin-2-ones from
R-aminoketones and ethyl chloroformate (McCombie
and Parkes, 1912; Pain and Slack, 1951). Stoffel and
co-workers described the synthesis of 4-oxazolin-2-ones
from propargyl alcohol and phenyl isocyanate (Stoffel
and Dixon, 1964; Sisido et al., 1962; Cum et al., 1968).
Previously, in the course of the study of isoxazole
compounds, we discovered a novel synthetic method for
4-oxazolin-2-ones (4) from acyl Meldrum’s acids (1) and
N-hydroxyaniline derivatives (2) via N-arylhydroxamic
acids (3) as shown in Figure 1 (Sato et al., 1986).
Compounds 4 obtained in this manner did not show any
satisfactory herbicidal activities. However, 4-chloro-4-
oxazolin-2-one compounds, which were prepared by
similar cyclization from R-chloro-substituted N-arylhy-
droxamic acids, exhibited improved herbicidal activities.
The strength of herbicidal activities increased with the
bulkiness of the 5-alkyl group (Sugai et al., 1987). This
result led us to synthesize compounds having larger
substituents, such as the tert-butyl group, at the 5-posi-
tion. Unfortunately, a tert-butyl-substituted compound
(7) could not be obtained using our previous synthetic
method. To move beyond unsuccessful cyclizations, other
new cyclization methods were surveyed, and, as a result,
we discovered the novel preparation reaction of 5-tert-
butyl-4-oxazolin-2-ones (7) as shown in Figure 2 (Kudo
et al., 1996). Using this method, 5-tert-butyl-4-oxazolin-
2-ones were obtained in a single step from N-arylcar-
bamates. To extend the application of this methodology,
introduction of substituents at the 4-position was in-
vestigated. Herein, we report the first synthesis of
4-substituted 3-aryl-5-tert-butyl-4-oxazolin-2-ones and
EXPERIMENTAL PROCEDURES
Ch em ica ls a n d Rea gen ts. Chlorine was purchased from
Sumitomo Seika Chemicals Co., Ltd. 2-Nitrobenzenesulfonyl
chloride, N,N-dimethyaminopyridine (DMAP), N,N-diisopro-
pylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), ethyl mer-
captan, bromine, and N-bromosuccinimide (NBS) were pur-
chased from Wako Pure Chemical Industries, Ltd. Ethyl
chloroformate, sodium hydride, and iodomethane were pur-
chased from Nacalai Tesque, Inc. Methyl mercaptan sodium
salt 15% aqueous solution was purchased from Tokyo Chemical
Industry Co., Ltd. A 1.0 M solution of LiN(TMS)2 in tetrahy-
drofuran and diethylaminosulfur trifluoride (DAST) were
purchased from Aldrich Chemical Co. A 1.6 M solution of
n-butyllithium in hexane was purchased from Kanto Chemical
Co., Inc. All reagents were used as supplied. Carbon tetra-
chloride (CCl4), dichloromethane (CH2Cl2), ethyl acetate (AcO-
Et), dimethyl sulfoxide (DMSO), N,N-dimethyformamide (DMF),
tetrahydrofuran (THF), hexane, methanol, diethyl ether, and
benzene were purchased from Wako Pure Chemical Industries,
Ltd., and used without further purification.
Syn th esis. All melting points (mp) are uncorrected. Infra-
red (IR) spectra were measured on a Perkin-Elmer 1600
spectrometer. 1H NMR spectra were recorded at 60 MHz on a
Varian 360A spectrometer, at 200 MHz on a Varian Gemini
200 spectrometer, and at 270 MHz on
a J EOL GX-270
spectrometer with tetramethylsilane as an internal standard.
Mass spectra (MS) and high-resolution mass spectra (HRMS)
were obtained with a J EOL J MS-D300 mass spectrometer and
a VG Auto Spec M mass spectrometer.
All new compounds gave acceptable HRMS or elemental
analysis results.
5-tert-Butyl-4-chloro-3-(4-fluorophenyl)-4-oxazolin-2-one (11a )
(Table 1). Procedure B. Chlorine gas was bubbled into a
suspension of 7a (Table 1) (1.70 g, 7.23 mmol) in CCl4 (15 mL)
at room temperature, and the resulting mixture was stirred
for 0.5 h at the same temperature. The reaction mixture was
poured into saturated aqueous NaHCO3 and extracted with
CH2Cl2 (three times). The combined extracts were washed with
saturated aqueous NaHCO3, dried over MgSO4, and concen-
trated in vacuo to afford 1.29 g (62.0%) of 13a (Table 1) as an
oil, which was subjected to the next reaction without further
purification.
* Author to whom correspondence should be addressed (fax
+81 77 586 2538).
10.1021/jf980281i CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/21/1998

5306 J. Agric. Food Chem., Vol. 46, No. 12, 1998
Kudo et al.
F igu r e 1.
washed with water (three times), dried over MgSO4, and
concentrated in vacuo to give 23.5 g (61.6%) of 20 as a light
brown powder; mp 207-208 °C; 1H NMR (200 MHz, CDCl3) δ
7.45 (1H, d, J ) 7.0 Hz), 7.20 (1H, d, J ) 10.4 Hz), 7.08 (1H,
brs), 6.47 (1H, d, J ) 3.3 Hz), 1.26 (9H, s); IR νmax cm-1 (KBr)
3131, 1732, 1443; MS (m/z) 285 (M+), 270 (base), 172. Anal.
Calcd for C13H13ClFNO3: C, 54.65; H, 4.59; N, 4.90. Found:
C, 54.54; H, 4.45; N, 4.87.
5-tert-Butyl-4-chloro-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-
4-oxazolin-2-one (23) (Figure 6). Ethyl chloroformate (0.4 mL,
4.18 mmol) was added to a solution of 20 (996 mg, 3.49 mmol)
and triethylamine (0.59 mL, 4.23 mmol) in CH2Cl2 (8 mL) at
0 °C, and the resulting mixture was stirred at 0 °C for 2 h.
The reaction mixture was poured into water and extracted
with CH2Cl2 (three times). The combined extracts were washed
with diluted HCl, dried over MgSO4, and evaporated to afford
1.30 g (quantitative) of 21 as a brown powder.
Chlorine gas was bubbled into a suspension of 21 (1.27 g,
3.49 mmol) in CCl4 (15 mL) at room temperature, and the
resulting mixture was stirred for 0.5 h. The reaction mixture
was poured into saturated aqueous NaHCO3 and extracted
with CH2Cl2 (three times). The combined extracts were washed
with saturated aqueous NaHCO3, dried over MgSO4, and
concentrated in vacuo to afford 1.63 g (quantitative) of 22 as
a yellow oil.
F igu r e 2.
2-Nitrobenzenesulfonyl chloride (193 mg, 0.87 mmol) was
added to a solution of 13a (50 mg, 0.17 mmol) in CH2Cl2 (2
mL) at room temperature, followed by the addition of DMAP
(127 mg, 1.04 mmol) and N,N-diisopropylethylamine (0.18 mL,
1.04 mmol). The resulting mixture was stirred at room
temperature overnight. The reaction mixture was washed with
water, dried over MgSO4, and concentrated in vacuo. The
residue was subjected to silica gel column chromatography to
give 22.8 mg (48.6%) of 11a as a light brown powder: 1H NMR
(270 MHz, CDCl3) δ 7.34 (2H, dd, J ) 8.7, 4.8 Hz), 7.17 (2H,
t, J ) 8.7 Hz), 1.37 (9H, s); IR νmax cm-1 1760, 1650, 1605,
1515; MS (m/z) 269 (M+), 254 (base), 210, 190, 175, 159.
5-tert-Butyl-4-chloro-3-(2,4-difluorophenyl)-4-oxa zolin-2-
one (11b) (Table 1). Procedure A. Chlorine gas was bubbled
into a suspension of 7b (Table 1) (2.49 g, 9.83 mmol) in CCl4
(20 mL) for 30 s at room temperature, and the resulting
mixture was stirred for 3 min at the same temperature. The
reaction mixture was poured into saturated aqueous NaHCO3
and extracted with AcOEt (three times). The combined extracts
were dried over MgSO4 and concentrated in vacuo to afford
3.18 g (99.0%) of 12b (Table 1) as yellow crystals, which was
subjected to the next reaction without further purification.
DBU (13.2 mL, 88.3 mmol) was added to a solution of 12b
(3.18 g, 9.81 mmol) in DMSO (150 mL) at room temperature,
and the resulting mixture was stirred at room temperature
for 2 h. The reaction mixture was diluted with water and
extracted with AcOEt (three times). The combined extracts
were washed with brine, dried over MgSO4, and concentrated
in vacuo. The residue was subjected to silica gel column
chromatography to afford 1.60 g (56.6%) of 11b as a white
powder: 1H NMR (60 MHz, CDCl3) δ 7.60-6.85 (3H, s), 1.38
(9H, s); IR νmax cm-1 1780, 1745, 1645, 1605, 1515; MS (m/z)
287 (M+), 272 (base), 228, 208, 193, 174, 139, 113.
DBU (3.7 mL, 25.0 mmol) was added to a solution of 22 (1.44
g, 3.09 mmol) in DMSO (19 mL) at room temperature, and
the resulting mixture was stirred at 60 °C for 1 h. The reaction
mixture was poured into water, acidified with diluted HCl (to
pH 1), and extracted with AcOEt (five times). The combined
extracts were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was subjected to silica gel
column chromatography to afford 476 mg (51.5%) of 23 as a
1
white powder: mp 170-171.5 °C; H NMR (60 MHz, CDCl3)
δ 7.19 (1H, d, J ) 9.0 Hz), 6.91 (1H, d, J ) 7.0 Hz), 6.36 (1H,
s), 1.37 (9H, s); IR νmax cm-1 3260, 1735, 1650,1605, 1525; MS
(m/z) 319 (M+), 304 (base), 260, 240, 225, 206, 171, 117, 107,
89, 81, 57. Anal. Calcd for C13H12Cl2FNO3: C, 48.77; H, 3.78;
N, 4.78. Found: C, 48.78; H, 3.80; N, 4.41.
5-tert-Butyl-4-chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-
4-oxazolin-2-one (16a ) (Table 3). A solution of 23 (200 mg, 0.62
mmol) in DMF (2 mL) was added to a suspension of sodium
hydride (60% dispersion in mineral oil) (35 mg, 0.88 mmol) in
DMF (5 mL) at 0 °C. After 20 min, iodomethane (55 µL, 0.88
mmol) was added to the mixture, and the resulting mixture
was stirred at room temperature for 2 h. The reaction mixture
was poured into water and extracted with AcOEt (three times).
The combined extracts were washed with brine, dried over
MgSO4, and evaporated in vacuo. The residue was purified by
silica gel column chromatography to give 137 mg (65.7%) of
16a as a white powder: 1H NMR (200 MHz, CDCl3) δ 7.30
(1H, d, J ) 9.0 Hz), 6.88 (1H, d, J ) 6.5 Hz), 3.89 (3H, s), 1.35
(9H, s); IR νmax cm-1 (KBr) 2973, 1778, 1508, 1201, 1058; MS
Compounds 11c-11j were synthesized following procedure
A or B as indicated in Table 1.
5-tert-Butyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-oxazolin-
2-one (20) (Figure 6). To a solution of ethyl N-(4-chloro-2-fluoro-
5-methoxycarbonylphenyl)carbamate (19) (39.0 g, 134 mmol)
and 1-bromo-3,3-dimethyl-2-butanone (6) (33.0 g, 184 mmol)
in DMF (270 mL) was added a 1.0 M solution of LiN(TMS)2 in
THF (303 mL, 303 mmol) at room temperature, and the
resulting mixture was stirred for 1.5 h at the same tempera-
ture. The reaction mixture was diluted with water and washed
with a hexane/AcOEt (1:1) mixture. The water layer was
acidified with diluted HCl (to pH 1) and extracted with hexane/
AcOEt (1:1) mixture (five times). The combined extracts were
(m/z) 333 (M+), 318 (base), 274, 105, 57; HRMS calcd for C14H14
-
Cl2FNO3 333.0335, found 333.0336.
Compounds 16b -16m were synthesized in the same
manner.
5-tert-Butyl-4-fluoro-3-(4-fluorophenyl)-5-chloro-1,3-oxazoli-
din-2-one (24, 25) (Figure 7). DAST (0.276 mL, 2.09 mmol) was

Herbicidal Activity of 4-Substituted 3-Aryl-5-tert-butyl-4-oxazolin-2-ones
J. Agric. Food Chem., Vol. 46, No. 12, 1998 5307
Ta ble 1. Str u ctu r es a n d Ch em ica l Yield s of 3-Ar yl-4-oxa zolin -2-on e Der iva tives
entry
X
R
7
12
13
conditions
11
a
b
c
d
e
f
g
h
I
4-F
H
H
H
H
H
H
H
H
85.6
86.5
80.0
60.0
97.1
54.5
55.6
89.7
77.5
62.7
62.0
B
A
A
B
A
B
B
A
B
A
48.6
56.6
86.0
48.3
87.4
55.5
36.2
66.3
48.8
87.4
2,4-F2
4-Cl-2-F
4-Cl
2,4-Cl2
3,4-Cl2
3,5-Cl2
4-OMe
3-CF3
99.0
46.4
60.0
36.2
39.9
17.9
38.9
52.8
quant
11.0
7.7
35.4
47.1
22.9
25.8
H
Me
j
4-Cl-2-F
1770, 1740,1515, 1405; MS (m/z) 253 (M+), 238 (base), 194,
179. Anal. Calcd for C13H13NO2F2: C, 61.66; H, 5.17; N, 5.53;
F, 15.00. Found: C, 61.22; H, 5.37; N, 5.34; F, 14.18.
5-tert-Butyl-3-(4-chloro-2-fluorophenyl)-4-methy-4-oxazolin-
2-one (33a ) (Table 4). A 1.0 M solution of LiN(TMS)2 in THF
(5.7 mL, 5.7 mmol) was added to a solution of ethyl N-(4-chloro-
2-fluorophenyl)carbamate (5c) (427 mg, 1.96 mmol) and 4-bro-
mo-2,2-dimethyl-3-pentanone (32a ) (562 mg, 2.91 mmol) in
DMF (3 mL) at room temperature. After being stirred at 90
°C for 1 h, the reaction mixture was diluted with water and
extracted with AcOEt (three times). The combined extracts
were dried over MgSO4 and concentrated in vacuo. The residue
was subjected to silica gel column chromatography to give 149
mg (26.7%) of 33a : 1H NMR (CDCl3) δ 7.36-7.24 (3H, m), 1.91
(3H, s), 1.32 (9H, s); IR νmax cm-1 2973, 1755, 1505, 1385, 893;
MS (m/z) 283 (M+), 268 (base), 170, 129, 94. Anal. Calcd for
C
14H15ClFNO2: C, 59.27; H, 5.33; N, 4.94; Cl, 12.50; F, 6.70.
Found: C, 59.68; H, 5.41; N, 4.85; Cl, 12.29; F, 6.47.
Compounds 33b-33e were synthesized under the conditions
shown in Table 4.
F igu r e 3.
Alternative Synthesis of 5-tert-Butyl-3-(4-chloro-2-fluorophen-
yl)-4-(ethylthio)-4-oxazolin-2-one (33c) from 12c (Figure 10). A
solution of ethyl mercaptan (0.205 mL, 2.77 mmol) in THF (20
mL) was added to a 1.6 M solution of n-butyllithium in hexane
(1.5 mL, 2.43 mmol) at 0 °C under argon atmosphere, and the
resulting mixture was stirred at room temperature for 0.5 h.
A solution of 12c (681 mg, 2.00 mmol) in THF (5 mL) was
added to the mixture, and the resulting mixture was stirred
at room temperature for 3.5 h. The reaction mixture was
quenched with water, extracted with AcOEt (three times),
dried over MgSO4, and evaporated in vacuo to afford 34 as a
yellow oil.
DBU (1.8 mL, 12.0 mmol) was added to a solution of 34 (535
mg, 1.46 mmol) in DMSO (11 mL) at room temperature, and
the resulting mixture was stirred for 2 h. The reaction mixture
was poured into water and extracted with AcOEt (four times).
Combined extracts were washed with brine, dried over MgSO4,
and evaporated in vacuo. The residue was purified by silica
gel column chromatography to give 231 mg (48.0%) of 33c as
an oil.
carefully added to a solution of 13a (0.5 g, 1.74 mmol) in
CH2Cl2 (15 mL) at 0 °C, and the resulting mixture was stirred
at room temperature for 15 min. The reaction mixture was
poured into ice and extracted with CH2Cl2 (three times). The
combined extracts were washed with brine, dried over MgSO4,
and evaporated in vacuo. The residue was subjected to silica
gel column chromatography to afford 302 mg (60.0%) of 24 (less
polar isomer) and 81 mg (16%) of 25 (polar isomer): (24) mp
113.5-115 °C; 1H NMR (270 MHz, CDCl3) δ 7.47 (2H, dd, J )
8.8, 4.6 Hz), 7.16 (2H, t, J ) 8.8 Hz), 6.17 (1H, d, J ) 68.9
Hz), 1.33 (9H, s); IR νmax cm-1 3050, 1790, 1515, 1410; MS (m/
z) 289 (M+), 274, 254, 230, 210, 194, 170, 151, 142 (base). Anal.
Calcd for C13H14ClF2NO2: C, 53.90; H, 4.87; N, 4.83. Found:
1
C, 54.14; H, 4.89; N, 4.85. (25) H NMR (270 MHz, CDCl3) δ
7.46 (2H, dd, J ) 8.7, 4.6 Hz), 7.14 (2H, t, J ) 8.7 Hz), 5.93
(1H, d, J ) 71.3 Hz), 1.19 (9H, s); IR νmax cm-1 1785, 1605;
MS (m/z) 289 (M+), 274, 254, 233, 210, 194, 141 (base), 122,
104, 85, 69, 57 (base). Anal. Calcd for C13H14ClF2NO2: C, 53.90;
H, 4.87; N, 4.83. Found: C, 53.89; H, 4.93; N, 4.87.
5-tert-Butyl-4-fluoro-3-(4-fluorophenyl)-4-oxazolin-2-one (26)
(Figure 7). 26 was also synthesized from 24 with DBU as
11b: mp 76-79.5 °C; 1H NMR (270 MHz, CDCl3) δ 7.45-7.38
(2H, m), 7.16 (2H, t, J ) 8.7 Hz), 1.32 (9H, s); IR νmax cm-1
P r eem er gen t Her bicid e Tests. Plastic pots (surface area
) 100 cm2) were filled with a clay loam soil and kept in a
greenhouse. The test plants were five narrowleaf weeds

5308 J. Agric. Food Chem., Vol. 46, No. 12, 1998
Kudo et al.
F igu r e 4.
t-Bu). Therefore, we have developed a novel synthetic
method for 3-aryl-5-tert-butyl-4-oxazolin-2-ones (7) (Fig-
ure 2) (Kudo et al., 1996). According to this method, the
reaction of 1-chloro-substituted 1-bromo- or iodo-3,3-
dimethyl-2-butanone (9 or 10) and N-arylcarbamate (5)
was expected to afford the desired 4-chloro-4-oxazolin-
2-one (11) (Figure 3). Chlorination of 1-bromo- or 1-iodo-
3,3-dimethyl-2-butanone (6 or 8) with sulfuryl chloride
afforded the corresponding chloride (9 or 10) in good
yields. However, the reaction of the carbamate (5) and
these chlorides (9 or 10) to form 4-chloro-4-oxazolin-2-
one (11) did not proceed as expected (Figure 3). After
further attempts failed, we discovered a two-step con-
version of 4-unsubstituted 4-oxazolin-2-one (7) to the
corresponding 4-chloro-substituted derivatives (Figure
4). Thus, chlorination of 7 with chlorine gas in carbon
tetrachloride (CCl4) usually gave dichloride 12 ac-
companied by chlorohydrin 13, which may be the
hydrolysis product of an epichloronium intermediate.
Despite the completely same reaction conditions, chlo-
rination of 7 gave 12 and/or 13, depending on the
substituents on the benzene ring. There is no clear
speculation to account for the result. Dehydrochlorina-
tion of 12 using DBU in dimethyl sulfoxide (DMSO)
afforded the desired 4-chloro-4-oxazolin-2-one (11) in
good yields. Alternatively, chlorohydrin 13, which lacks
a chlorine atom at the desired position, was treated with
2-nitrobenzenesulfonyl chloride, N,N-diisopropylethyl-
amine, and DMAP to afford the desired 4-chloro-4-
oxazolin-2-one derivatives (11). This reaction may pro-
ceed through the formation of the sulfonate, followed
by subsequent chlorine substitution and dehydrochlo-
rination. The results of the present study are compiled
in Tables 1 and 2. A variety of 4-oxazolin-2-ones (7) were
dichlorinated, followed by dehydrochlorination to give
the corresponding 4-oxazolin-2-ones (11) in satisfactory
yields.
F igu r e 5.
[Echinochloa oryzicola Vasing., Scirpus juncoides Roxb var.
ohwianus T. Koyama, Eleocharis acicularis (L.) Roem. et
Schult. var. longiseta Sven., Cyperus serotinus Rottb., and
Eleocharis kuroguwai Ohwi] and one broadleaf weed [Linder-
nia pyxidaria L.], Monochoria vaginalis Presl var. plantaginea
(Roxb.) Solms-Laub, Sagittaria pygmaea Miq., and Oryza
sativa L. On the top of the soil were placed a predetermined
number of seeds of the weed. The surface of each pot was
covered with 1 cm of soil, and then Oryza sativa L. that had
reached the two-leaf stage was transplanted. For the herbicidal
test, wettable powders were prepared by mixing the com-
pounds (10%), Emulgen 810 (surfactant; 0.5%), Demol N
(surfactant; 0.5%), Kunilite 210 (diatomaceous earth; 20%),
and Dieclite CA (clay; 69%). Each compound, formulated as
the wettable powder, was applied 3 days after the seeds had
been sown. Approximately 3 weeks after treatment, the
herbicidal activity of each compound was judged by visual
observation of the symptoms of treated plants in comparison
with untreated controls. According to the extent of the injury
of plants, the herbicidal potency was scaled from 0 to 5
according to the following criteria: 5, >91% growth inhibition;
4, 71-90% growth inhibition; 3, 51-70% growth inhibition;
2, 31-50% growth inhibition; 1, 11-30% growth inhibition;
0, growth inhibition of <10%.
Among the synthesized compounds, 4-chloro-2-fluo-
rophenyl compound 11c has strong herbicidal activity,
particularly in preemergent tests on broadleaf weeds,
and the other compounds did not show any satisfactory
activities. The pattern of herbicidal activities of 11c is
very similar to that of light-dependent herbicides, such
as S-23142 (14) (Nagano et al., 1983a) or pentoxazone
(KPP-314) (15) (Hirai et al., 1987). This result let us to
synthesize new derivatives (16) having propargyloxy or
cyclopentyloxy groups in the 5-position of aryl group
(Figure 5). Compound 23 seemed to be a useful inter-
RESULTS AND DISCUSSION
Syn th esis. Previously, acyl Meldrum’s acid (1) and
N-hydroxyaniline derivatives (2) have been used to form
the 4-oxazolin-2-one ring (4) (Figure 1), but 5-tert-butyl-
substituted 4-oxazolin-2-ones were not accessible be-
cause of instability of pivaloyl Meldrum’s acid (1: R )

Herbicidal Activity of 4-Substituted 3-Aryl-5-tert-butyl-4-oxazolin-2-ones
J. Agric. Food Chem., Vol. 46, No. 12, 1998 5309
F igu r e 6.
Ta ble 2. P h ysica l P r op er ties of 3-Ar yl-4-oxa zolin -2-on e
Der iva tives
Ta ble 3. Rea ction Con d ition s a n d Meltin g P oin ts of
3-Ar yl-4-ch lor o-4-oxa zolin -2-on es (16)
analysis (%)
calcd
H
found
H
11 mp (°C)
formula
C
N
C
N
a
b
c
d
e
f
g
h
i
94.5-97
72-74
C
C
C
C
C
C
C
C
C
C
13H13ClFNO2 57.89 4.86 5.19 57.65 5.09 5.06
13H12ClF2NO2 54.54 4.42 5.00 54.27 4.20 4.87
13H12Cl2FNO2 51.34 3.98 4.61 51.55 4.17 4.61
95-97
86-87
13H13Cl2NO2
13H12Cl3NO2
13H12Cl3NO2
13H12Cl3NO2
14H16ClNO3
54.57 4.58 4.89 54.33 4.64 4.59
48.70 3.77 4.37 48.96 3.96 4.42
48.70 3.77 4.37 48.47 3.92 4.43
48.70 3.77 4.37 48.65 4.01 4.39
59.68 5.72 4.97 59.69 5.78 4.91
85-86.5
95.5-97
amorph
113-114
88-89
yield
(%)
mp
(°C)
16
RX
base
conditionsa
a
b
c
d
e
f
g
h
i
MeI
EtI
n-PrI
i-PrI
NaH
NaH
NaH
NaH
rt,, 2 h
rt, 6 h
rt, 1 h
rt, 3 h
65.7 94-96
62.4 88-90
75.4 76-76.5
57.1 78.5-80
14H13ClF3NO2 52.60 4.10 4.38 52.37 4.23 4.34
15H16Cl2FNO2 54.23 4.86 4.22 54.39 4.94 4.25
j
amorph
c-C5H9Cl
c-C6H11Cl
CH2dCHCH2Br
HCdCCH2Br
HCdCCH(Me)Br
MeOCH2Br
MeOCH2CH2Br
3-tetrahydrofuranyl NaH
tosylate
3-tetrahydropyranyl K2CO3 100 °C, 5 h
tosylate
K2CO3 110 °C, 1.5 h 94.6 94-96
mediate for the synthesis of 16. Therefore, the next
problem was how to synthesize 23 or its O-protected
compound. We chose carbonate groups as protecting
groups, and synthesis was performed as shown in
Figure 6. According to Sumitomo’s method, 2-chloro-4-
fluorophenol (17) was protected as methyl carbonate
(Nagano et al., 1983b) and nitrated (Nagano et al.,
1983c) to give 18 in 90.3% yield in two steps. Reduction
of 18 (Hirai et al., 1987) followed by carbamate forma-
tion afforded 19 (Hirai et al., 1992), which is the
precursor of cyclization. Treatment of 19 with 1-bromo-
3,3-dimethyl-2-butanone (6) and LiN(TMS)2 afforded the
deprotected compound (20) in 61.6% yield, instead of
an O-protected compound, which might result from
hydrolysis with ethoxide anion generated from carbam-
ate moiety. Compound 20 was protected as carbonate
(21) and treated with chlorine gas in CCl4, followed by
the addition of DBU in DMSO to give deprotected
compound 23 in 51.5% yield in three steps. Compound
23 was alkylated with several alkyl halides or alkyl
tosylate to give 3-(5-alkoxy)phenyl compounds as sum-
marized in Table 3. All alkyl halides or alkyl tosylates
except cyclohexyl chloride reacted in good yields.
K2CO3 110 °C, 2 h
15.4 122-125
70.4 82-86
80.9 83-84
39.0 113-114
73.0 98-99
58.1 58
NaH
NaH
NaH
NaH
NaH
rt, 1.5 h
rt, 3 h
50 °C, 1 h
rt, 3 h
130 °C, 3 h
100 °C, 3 h
j
k
l
36.9 114-115
m
61.7 111-113
a
rt, room temperature.
To improve the herbicidal activity, a fluorine atom
instead of a chlorine atom was introduced into the
4-position of 4-oxazolin-2-one ring according to a pro-
cedure illustrated in Figure 7. Chlorohydrin 13a was
treated with DAST to give syn-chloro-fluorocompound
24 in 60.0% yield and anti-chloro-fluorocompound 25 in
16.0% yield. Treatment of only one of the isomers with
DBU provided the desired 4-fluoro-4-oxazolin-2-one (26)
in 8.1% yield. This result supports that 24 was syn-
isomer.
Replacement of a chlorine atom by an alkylthio group
sometimes brings about drastic changes in biological

5310 J. Agric. Food Chem., Vol. 46, No. 12, 1998
Kudo et al.
F igu r e 7.
Ta ble 4. Rea ction Con d ition s a n d P h ysica l P r op er ties of
4-Su bstitu ted 3-(4-Ch lor o-2-flu or o)-4-oxa zolin -2-on es
et al., 1966; Roussel et al., 1971; Katz et al., 1977;
Fellmann et al., 1978). On the other hand, synthesis of
R-alkylthio compounds was performed as follows. Treat-
ment of 1-bromo-3,3-dimethyl-2-butanone (6) with an
aqueous solution of alkylmercaptide(Kano et al., 1978)
afforded a corresponding thioether (31b-31e), (Brunet
et al., 1984; Norbert et al., 1992) that was subjected to
bromination with N-bromosuccinimide (NBS) (Tamura
et al., 1980) to give R-alkylthio-R-bromopinacolones
(32b-32e). The cyclization reaction between R-substi-
tuted bromopinacolones and the carbamate was per-
formed as mentioned before. The results are summa-
rized in Table 4. The low yield of R-methyl compound
was probably due to the competitive â-elimination
reaction of R-methyl-R-bromopinacolone (32a ). In the
case of R-alkylthio compounds, the cyclization reaction
was very slow and, aided by warming, the cyclization
reaction proceeded.
R-Alkylthio compounds were also synthesized accord-
ing to an alternative method as summarized in Figure
10. Dichloro compound (12c) obtained by chlorination
of 7c was treated with ethyl mercaptan lithium salt,
generated from ethyl mercaptan and n-butyllithium to
give 34. Treatment of 34 with DBU afforded 33c, which
was identical to the compound prepared by direct
cyclization method as shown in Table 4.
R
conditions
yield (%)
mp (°C)
7c
H
Me
SMe
SEt
Sn-Pr
Si-Pr
rt, 0.5 h
80.0
26.7
42.9
28.1
50.4
46.9
95-97
129-132
oil
oil
oil
33a
33b
33c
33d
33e
90 °C, 1 h
60 °C, 2 h
rt, 2 h
90 °C, 1 h
90 °C, 1 h
oil
a
rt, room temperature.
Her bicid a l Activity. In general, 3-aryl-tert-butyl-4-
chloro-4-oxazolin-2-ones (16) exhibited moderate to
excellent herbicidal activity, particularly in preemergent
tests on broadleaf weeds. Tables 5 and 6 show the
results of herbicidal evaluations of the synthesized
compounds.
F igu r e 8.
activities (Sheets and Shaw, 1963). The chlorine atom
of s-triazine herbicide 27, named simazine (Pearlman
and Banks, 1948), was replaced with a methylthio
group, and the resulting compound 28, named simetryn
(Gysin, 1960), showed improved herbicidal activity
(Figure 8). In simetryn the methylthio group plays a
biologically isosteric role equal to a chlorine atom. This
result prompted us to synthesize 4-alkylthio-substituted
4-oxazolin-2-one derivatives. If an alkylthio group can
be introduced into the bromopinacolone moiety, 4-al-
kylthio-substituted 4-oxazolin-2-one could be synthe-
sized in a single step. We also planned to prepare
4-methyl-substituted 4-oxazolin-2-one, because the ster-
ic size of the methyl group is considered to be similar
to that of the chlorine atom. For the evaluation of the
synthetic reaction to 4-oxazolin-2-one ring, R-substituted
bromopinacolones were synthesized as illustrated in
Figure 9. R-Methyl compound (32a ) was synthesized
through condensation of methyl pivalate (29) and pro-
pionitrile (Kume et al., 1989; Abdulla, 1983) followed
by hydrolysis (Abdulla, 1983) and bromination (Dubois
Substituents in the 5-position of the 4-oxazolin-2-one
ring had the most pronounced effect on activity. As
reported previously (Sugai et al., 1987), the activity
increased with the size of the substituent at the 5-posi-
tion of the 4-oxazolin-2-one ring. In the present study
the greatest activity was observed for the tert-butyl
group (11c). However, the compound with a 1-ethyl-1-
methylpropyl group (11j), which is larger than the tert-
butyl group, was significantly less active in these tests.
4-Unsubstituted 4-oxazolin-2-one compound (7c)
showed moderate herbicidal activity, but the introduc-
tion of a chlorine atom at the 4-position of the 4-oxazo-
lin-2-one ring (11c) dramatically improved herbicidal
activity against all weeds. The introduction of a methyl
group (33a ), the steric size of which is considered to be
similar to that of a chlorine atom, did not provide the
same level of herbicidal activity. Alkylthio-substituted

Herbicidal Activity of 4-Substituted 3-Aryl-5-tert-butyl-4-oxazolin-2-ones
J. Agric. Food Chem., Vol. 46, No. 12, 1998 5311
F igu r e 9.
F igu r e 10.
Ta ble 5. Her bicid a l Activity of
3-Ar yl-4-ch lor o-4-oxa zolin -2-on es (16)
Ta ble 6. Her bicid a l Activity of 4-Su bstitu ted
3-(4-Ch lor o-2-flu or o)-4-oxa zolin -2-on es
herbicidal activitya,b
herbicidal activity
16
EO
LP
MV
SJ
EA
SP
CS
EK
OS
dose (g/a)
EO
LP
SJ
a
b
c
d
e
f
g
h
i
5
5
5
5
4
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
4
3
5
2
3
4
5
5
5
5
5
5
4
4
5
5
2
3
5
5
0
0
0
0
0
0
0
0
0
0
0
0
0
7c
10
5
10
5
10
5
10
5
10
5
10
5
10
5
10
5
5
3
5
5
5
3
0
0
2
0
0
0
2
0
1
0
5
5
5
5
5
5
0
0
2
1
0
0
0
0
1
0
5
2
5
5
5
3
0
0
1
0
0
0
0
0
1
0
ntc
2
nt
2
nt
nt
4
5
5
5
5
nt
4
nt
nt
4
5
2
3
4
nt
5
nt
nt
5
5
5
5
5
11c
33a
33b
33c
33d
33e
11j
nt
nt
1
5
3
5
5
nt
nt
j
k
l
nt
nt
nt
nt
nt
nt
m
a
b
Herbicidal activity was evaluated at a dose of 5 g/a. EO,
Echinochloa oryzicola; LP, Lindernia procumbens; MV, Mono-
choria vaginalis; SJ , Scirpus juncoides; EA, Eleocharis acicularis;
SP, Sagittaria pygmaea; CS, Cyperus serotinus; EK, Eleocharis
kuroguwai; OS, transplanted rice. c nt, not tested.
yloxy (16l) or tetrahydropyran-3-yloxy group (16m )
showed a good level of activity with rice selectivity.
In summary, novel 4-oxazolin-2-ones (16) presented
in this paper showed good to excellent levels of herbi-
cidal activity and showed rice selectivity. Although
several compounds were investigated more fully in the
greenhouse, none of the compounds was considered to
be worthy of detailed field evaluation.
compounds (33b-33e), which are considered to be bio-
logically isosteric to 4-chloro-substituted compounds
(11c), tended to reduce the overall activity. In this
series, alkylthio groups did not seem to act as a bio-
logical isostere to chlorine atom.
Aromatic phenyl ring substituents also played an
important role in activity, and a variety of substituents
maintain good herbicidal activity. Alkoxy groups such
as the MeO (16a ) or EtO (16b) group on the 5-position
of the aromatic phenyl ring showed good herbicidal
activity, but substitution of a cycloalkoxy group (16e),
which KPP-314 has in its phenyl ring, reduced the
overall activity. The introduction of the propargyloxy
group (16h ), which S-23142 has in its phenyl ring,
exhibited the greatest activity against all weeds. The
introduction of an alkoxyalkoxy group (16j and 16k )
maintained a high level of activity. The introduction of
a cyclic alkoxy group such as the tetrahydrofuran-3-
ACKNOWLEDGMENT
We are grateful to Dr. T. J ojima, the former director
of our laboratories, and Dr. S. Sugai, the director of our
laboratories, for their encouragement throughout this
work.
Su p p or tin g In for m a tion Ava ila ble: NMR, IR, MS,
HRMS, analytical data for 11c-11j, 16b-16m , and 33b-33e;
procedures and data for 30, 31a -31e, and 32a -32e (11
pages). Ordering information is given on any current masthead
page.

5312 J. Agric. Food Chem., Vol. 46, No. 12, 1998
Kudo et al.
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J F980281I