Syntheses and herbicidal activities of novel triazolinone derivatives

Article abstract of DOI:10.1021/jf703654g

Protoporphyrinogen oxidase (Protox, EC 1.3.3.4) has been identified as one of the most important action targets of herbicides. To search for novel Protox inhibitors, a series of title compounds 1, 2, and 3 were designed and synthesized by introducing three types of pharmacophores, cyclic imide, phenylurea, and (E)-methyl 2-methoxyimino-2-o-tolylacetate, into the scaffold of triazolinone. The bioassay results indicated that the resulting cyclic imide-type triazolinones 1 displayed much better herbicidal activities than phenylurea-type triazolinones 2. Most fortunately, compound 3, methyl 2-[3-methyl-(2-fluoro-4-chloro-5-ethylsulfonamidephenyl)-4,5-dihydro-5-oxo-1H-1, 2,4-triazol-4-yl]methyl-enephenyl-2-(E)-methoxyiminoacetate, was found to be the most promising candidate due to its comparable herbicidal activity at 75-150 g of active ingredient/ha with the commercial product sulfentrazone. On the basis of test results of herbicidal spectrum and crop selectivity, compound 3 could be developed as a postemergent herbicide used for the control of broadleaf weeds in rice fields.

Full text of DOI:10.1021/jf703654g

2118 J. Agric. Food Chem. 2008, 56, 2118–2124
Syntheses and Herbicidal Activities of Novel
Triazolinone Derivatives
YAN-PING LUO, LI-LI JIANG, GUO-DONG WANG, QIONG CHEN, AND
GUANG-FU YANG*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, People’s Republic of China
Protoporphyrinogen oxidase (Protox, EC 1.3.3.4) has been identified as one of the most important
action targets of herbicides. To search for novel Protox inhibitors, a series of title compounds 1, 2,
and 3 were designed and synthesized by introducing three types of pharmacophores, cyclic imide,
phenylurea, and (E)-methyl 2-methoxyimino-2-o-tolylacetate, into the scaffold of triazolinone. The
bioassay results indicated that the resulting cyclic imide-type triazolinones 1 displayed much better
herbicidal activities than phenylurea-type triazolinones 2. Most fortunately, compound 3, methyl 2-[3-
methyl-(2-fluoro-4-chloro-5-ethylsulfonamidephenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-4-yl]methyl-
enephenyl-2-(E)-methoxyiminoacetate, was found to be the most promising candidate due to its
comparable herbicidal activity at 75-150 g of active ingredient/ha with the commercial product
sulfentrazone. On the basis of test results of herbicidal spectrum and crop selectivity, compound 3
could be developed as a postemergent herbicide used for the control of broadleaf weeds in rice
fields.
KEYWORDS: Protoporphyrinogen oxidase; triazolinone; herbicide; crop selectivity
INTRODUCTION
highly effective herbicidal activities (11, 12); if the phenylimide
or phenylurea group is introduced into the C-5 position, the
resulting compounds 1 and 2 might display interesting biological
activities (Scheme 1). Additionally, of the substituents at N-4
investigated, the CHF2 group always gave the highest herbicidal
activity. However, the success of azafenidin indicated that a
suitable group rather than only CHF2 is also acceptable at N-4.
Then, the pharmacophore of (E)-methyl 2-methoxyimino-2-o-
tolylacetate, which was found to display a variety of biological
activities (13–15), was introduced into the N-4 position to afford
the designed compound 3 as shown in Scheme 1. Herein, we
report the detailed syntheses and herbicidal activities of
compounds 1-3, and the results indicate that compound 3
displayed promising herbicidal activity with good crop safety.
Since the 1990s, phenyl triazolinone derivatives with herbi-
cidal activities, known as inhibitors of protoporphyrinogen
oxidase (Protox, EC 1.3.3.4), which is an enzyme in the
chlorophyll biosynthetic pathway (1, 2), have attracted consider-
able attention from the field of pesticide chemistry (3–6). To
date, several phenyl triazolinone derivatives have been com-
mercially available. As shown in Figure 1, for example,
sulfentrazone, the first herbicide of this class to be commercial-
ized, was put on the market for weed control in soybean by
FMC Corp. in the 1990s (7). Carfentrazone-ethyl and azafenidin
were subsequently developed as commercial products by FMC
(8) and DuPont (9), respectively. The action mode of sulfen-
trazone, carfentrazone-ethyl, and azafenidin is the inhibition of
Protox, which causes the accumulation of protoporphyrin IX
(Proto IX), which is involved in the light-dependent formation
of singlet oxygen responsible for membrane peroxidation
(Figure 2).
MATERIALS AND METHODS
All chemical reagents were commercially available and treated with
standard methods before use. Solvents were dried in a routine way and
redistilled. 1H NMR spectra was recorded on a Mercury-Plus 400
spectrometer in CDCl3 or DMSO-d6 with TMS as the internal reference.
MS spectra were determined using a Finnigan Trace MS organic mass
spectrometry, and signals were given in m/z. Elementary analyses were
performed on a Vario EL III elementary analysis instrument. Melting
points were taken on a Buchi B-545 melting point apparatus and
uncorrected. 1-Substituted phenyl-3-methyl-4H-1,2,4-triazol-5-ones 4
were prepared according to the existing methods (4).
These triazolinone-type herbicides possess a common struc-
tural feature: a 2,4,5-trisubstituted phenyl group. Of the phenyl
substitution patterns investigated, the ones that led to the most
active compounds were F or Cl at C-2 and Cl at C-4, whereas
a variety of groups were found to be acceptable at C-5 (5, 10).
The derivatives of cyclic imide and phenyl urea always showed
4a: (X ) F, Y ) Br, R ) H); yield, 88%; mp 204–206 °C [lit. (4),
201–203 °C]; 1H NMR (400 MHz, CDCl3), δ 2.28 (s, 3H, CH3),
7.22–7.44 (m, 3H, ArH), 11.72 (s, 1H, NH); EI MS, m/z (%) 272 (M+,
49), 271 (15), 188 (54), 107 (100).
* Author to whom correspondence should be addressed (telephone
+86-27-67867800; fax +86-27-67867141; e-mail gfyang@
mail.ccnu.edu.cn).
10.1021/jf703654g CCC: $40.75  2008 American Chemical Society
Published on Web 02/26/2008

Herbicidal Activities of Triazoline Derivatives
J. Agric. Food Chem., Vol. 56, No. 6, 2008 2119
Figure 1. Structures of some commercial Protox inhibitors.
Figure 2. Crystal structures of compounds 1a and 2g.
4b: (X ) Cl, Y ) Cl, R ) H); yield, 92%; mp 189–191 °C [lit. (4),
174–175 °C]; 1H NMR (400 MHz, CDCl3), δ 2.27 (s, 3H, CH3),
7.19–7.56 (m, 3H, ArH), 11.85 (s, 1H, NH).
layer was dried with sodium sulfate, filtered, and concentrated under
reduced pressure to a residue. The residue was purified by column
chromatography on silica gel using 20:1 petroleum ether/acetone as
an eluent. The appropriate fractions were combined and concentrated
under reduced pressure to yield intermediates 5.
4c: (X ) Br, Y ) F, R ) H); yield, 85%; mp 179–181 °C; 1H
NMR (400 MHz, CDCl3), δ 2.28 (s, 3H, CH3), 7.13–7.48 (m, 3H, ArH),
11.70 (s, 1H, NH); EI MS, m/z (%) 272 (M+, 32), 271 (33), 191 (100),
107 (67).
5a: (X ) F, Y ) Br, R ) H); yield, 91%; mp 176–178 °C; 1H
NMR (400 MHz, CDCl3), δ 2.48 (s, 3H, CH3), 7.05 (t, 1H, 2JH-F ) 58
Hz, CH), 7.38–7.44 (m, 3H, ArH).
1
4d: (X ) Cl, Y ) H, R ) NO2); yield, 61%; mp 232–234 °C; H
NMR (400 MHz, CDCl3), δ 2.32 (s, 3H, CH3), 7.72–8.40 (m, 3H, ArH),
11.52 (s, 1H, NH).
5b: (X ) Cl, Y ) Cl, R ) H); yield, 83%; mp 111–113 °C [lit. (4),
108–110 °C]; 1H NMR (400 MHz, CDCl3), δ 2.48 (s, 3H, CH3), 7.05
(t, 1H, 2JH-F ) 58 Hz, CH), 7.26–7.55 (m, 3H, ArH); EI MS, m/z (%)
294 (M+, 25), 257 (54), 160 (64), 158 (100), 122 (40).
4e: (X ) F, Y ) Cl, R ) C2H5SO2NH); yield, 79%; mp 216–218
°C; 1H NMR (400 MHz, DMSO-d6), δ 1.27 (t, 3H, J ) 7.2 Hz, CH3),
2.16 (s, 3H, CH3), 3.14 (q, 2H, J ) 7.2 Hz, CH2), 7.58–7.75 (m, 2H,
ArH), 9.65 (s, 1H, C2H5SO2NH), 11.82 (s, 1H, NH).
5c (X ) Br, Y ) F, R ) H); yield, 75%; mp 154–156 °C; 1H NMR
2
(400 MHz, CDCl3), δ 2.48 (s, 3H, CH3), 7.07 (t, 1H, JH-F ) 58 Hz,
Preparation of 1,4-Disubstituted 3-Methyl-4-difluoromethyl-
1,2,4-triazol-5-one (5). To a stirred solution of 0.12 mol of 1-substituted
phenyl-3-methyl-4H-1,2,4-triazol-5-ones 4 were added 13.5 g (0.24 mol)
of powdered potassium hydroxide and 3.9 g (0.012 mol) of tetrabuty-
lammonium bromide in 500 mL of THF, and CHF2Cl was bubbled
into the reaction mixture. After 12 h, an additional 6.7 g (0.12 mol) of
powdered potassium hydroxide was added to the reaction mixture, and
CHF2Cl continued to bubble into the reaction mixture. Upon completion
of addition to the reaction mixture according to thin layer chromato-
graphic (TLC) analysis, the mixture was concentrated under reduced
pressure to a residue. The residue was extracted with methylene
chloride, and the combined extracts were washed with water; the organic
CH), 7.14–7.47 (m, 3H, ArH).
1
5d (X ) Cl, Y ) H, R ) NO2); yield, 78%; mp 141–143 °C; H
NMR (400 MHz, CDCl3), δ 2.51 (s, 3H, CH3), 7.07 (t, 1H, 2JH-F ) 58
Hz, CH), 7.71–8.38 (m, 3H, ArH); EI MS, m/z (%) 305 (M+, 100),
269 (59), 172 (47), 140 (61), 123 (87).
Preparation of 1-(5-Amino-2,4-disubstituted-phenyl)-3-methyl-
4-difluoromethane-1,2,4-triazol-5-one (6). To a stirred solution of 0.04
mol of intermediate 5 in 20 mL of concentrated sulfuric acid was slowly
added 3.8 g of 68% nitric acid; the reaction mixture temperature was
maintained at 25 °C for 30 min, and then the mixture was poured into
ice–water. The resultant solid was collected by filtration and recrystal-
lized from ethanol to afford 2-(5-nitro-2,4-disubstituted-phenyl)-3-

2120 J. Agric. Food Chem., Vol. 56, No. 6, 2008
Scheme 1. Molecular Design of the Title Compounds 1-3
Luo et al.
methyl-4-substituent-1,2,4-triazol-5-one, which was not identified and
was used in next step. To a stirred solution of 0.01 mol of the above
nitro-intermediate, 0.54 g (0.01 mol) of ammonium chloride in 50 mL
of ethanol, and 5 mL of water was added portionwise 2.24 g (0.04
mol) of powered iron (16). Upon completion of addition, the
reaction mixture was refluxed for 4 h and filtered through diatomaceous
earth, and the filtrate was concentrated under reduced pressure to a
residue. The residue was recrystallized from ethanol to yield compounds
6.
22), 404 ([M - 1]+, 100), 369 (59), 278 (18), 270 (21), 235 (67), 207
(18), 179 (23), 130 (23), 104 (92). Anal. Calcd for C18H11ClF2N4O3:
C, 53.41; H, 2.74; N, 13.84. Found: C, 53.27; H, 2.53; N, 13.72.
1e: yield, 58%; mp 173–175 °C; 1H NMR (400 MHz, CDCl3), δ
1.83 (s, 4H, 2 × CH2), 2.44 (s, 4H, 2 × CH2), 2.46 (s, 3H, CH3), 7.04
(t, 1H, 2JH-F ) 58 Hz, CHF2), 7.53 (dd, 2H, 3J ) 8.8 Hz, 4J ) 6.8 Hz,
ArH). EI MS: m/z (%) 472 ([M+1]+, 15), 470 ([M-1]+, 13), 391 (100),
363 (51), 335 (19), 257 (12), 195 (15), 149 (23), 128 (12), 114 (12),
80 (22). Anal. Calcd for C18H14BrF3N4O3: C, 45.88; H, 2.99; N, 11.89.
Found: C, 46.18; H, 2.64; N, 11.95.
6a: (X ) F, Y ) Br); yield, 79%; mp 121–123 °C [lit. (4), 117–
1f: yield, 56%; mp 144–146 °C; 1H NMR (400 MHz, CDCl3), δ
1.83 (s, 4H, 2 × CH2), 2.36–2.44 (m, 4H, 2 × CH2), 2.46 (s, 3H, CH3),
119 °C].
6b: (X ) Cl, Y ) Cl); yield, 94%; mp 137–139 °C [lit. (4), 133–
135 °C].
2
7.04 (t, 1H, JH-F ) 58 Hz, CHF2), 7.39–7.70 (m, 2H, ArH); EI MS,
1
m/z (%) 444 ([M + 1]+, 18), 442 ([M - 1]+, 49), 407 (100), 379 (12),
280 (13), 236 (18), 79 (26). Anal. Calcd for C18H14Cl2F2N4O3: C, 48.78;
H, 3.18; N, 12.64. Found: C, 48.55; H, 2.88; N, 12.29.
6c: (X ) Br, Y ) F); yield, 70%; mp 113–115 °C; H NMR (400
MHz, CDCl3), δ 2.48 (s, 3H, CH3), 4.16 (s, 2H, NH2), 7.06 (t, 1H, J
) 58 Hz, CHF2), 6.82–7.40 (m, 2H, ArH).
1g: yield, 59%; mp 175–177 °C; 1H NMR (400 MHz, CDCl3), δ
1.83 (s, 4H, 2 × CH2), 2.43 (s, 4H, 2 × CH2), 2.47 (s, 3H, CH3), 7.05
(t, 1H, 2JH-F ) 58 Hz, CHF2), 7.50 (dd, 2H, 3J ) 8.8 Hz, 4J ) 6.8 Hz,
ArH); EI MS, m/z (%) 472 ([M + 1]+, 29), 470 ([M - 1]+, 27), 391
(100), 350 (25), 306 (13), 242 (12), 108 (21), 107 (28), 80 (24). Anal.
Calcd for C18H14BrF3N4O3: C, 45.88; H, 2.99; N, 11.89. Found: C,
45.81; H, 2.61; N, 11.96.
6d (X ) Cl, Y ) H); yield, 66%; mp 131–133 °C; EI MS, m/z (%)
274 (M+, 91), 238 (100), 196 (30), 138 (32).
General Procedure for the Synthesis of the Title Compounds 1.
To a stirred solution of 1 mmol of intermediate 6 was added 1.1 mmol
of cyclic anhydrate in 10 mL of acetic acid with refluxing. Upon
completion of addition, the reaction mixture was refluxed for 8 h. The
reaction mixture was diluted with water; the resultant solid was
collected by filtration and recrystallized from ethanol to yield the title
compounds 1.
1h: yield, 62%; mp 158–160 °C; 1H NMR (400 MHz, CDCl3), δ
1.82 (s, 4H, 2 × CH2), 2.42 (s, 4H, CH3), 2.48 (s, 3H, CH3), 7.06 (t,
2
1a: yield, 67%; mp 197–199 °C; 1H NMR (400 MHz, CDCl3), δ
1H, JH-F ) 58 Hz, CHF2), 7.49–7.62 (m, 3H, ArH); EI MS, m/z (%)
2.47 (s, 3H, CH3), 7.05 (t, 1H, 2JH-F ) 58 Hz, CHF2), 7.62 (dd, 2H, 3J
410 ([M + 1]+, 10), 408 ([M - 1]+, 43), 373 (100), 332 (17), 282
(17), 248 (16), 246 (54), 217 (14), 107 (18), 77 (28). Anal. Calcd for
C18H15ClF2N4O3: C, 52.89; H, 3.70; N, 13.71. Found: C, 52.88; H, 3.68;
N, 13.75.
4
) 8.8 Hz, J ) 6.8 Hz, ArH), 7.82–7.99 (m, 4H, ArH); EI MS, m/z
(%) 468 ([M + 1]+, 12), 466 ([M - 1]+, 11), 387 (100), 252 (24),
130 (15), 126 (14), 104 (28), 76 (25). Anal. Calcd for C18H10BrF3N4O3:
C, 46.27; H, 2.16; N, 11.99. Found: C, 46.57; H, 1.91; N, 12.10.
1b: yield, 70%; mp 164–166 °C; 1H NMR (400 MHz, CDCl3), δ
1i: yield, 48%; mp 167–169 °C; 1H NMR (400 MHz, CDCl3), δ
1.53–2.04 (m, 8H, 4 × CH2), 2.46 (s, 3H, CH3), 3.04–3.13 (m, 2H, 2
× CH), 7.03 (t, 1H, 2JH-F ) 58 Hz, CHF2), 7.52 (dd, 2H, 3J ) 8.8 Hz,
4J ) 6.8 Hz, ArH); EI MS, m/z (%) 474 ([M + 1]+, 10), 472 ([M -
1]+, 8), 393 (100), 365 (82), 311 (32), 285 (50), 230 (18), 149 (43),
121 (12). Anal. Calcd for C18H16BrF3N4O3: C, 45.68; H, 3.41; N, 11.84.
Found: C, 45.59; H, 3.29; N, 11.60.
2
2.47 (s, 3H, CH3), 7.05 (t, 1H, JH-F ) 58 Hz, CHF2), 7.62–7.64 (m,
2H, ArH), 7.82–7.99 (m, 4H, ArH); EI MS, m/z (%) 440 ([M + 1]+,
28), 438 ([M - 1]+, 36), 405 (37), 403 (100), 269 (27), 104 (26).
Anal. Calcd for C18H10Cl2F2N4O3: C, 49.22; H, 2.29; N, 12.76. Found:
C, 49.33; H, 2.25; N, 12.49.
1c: yield, 70%; mp 199–201 °C; 1H NMR (400 MHz, CDCl3), δ
1j: yield, 42%; mp 162–164 °C; 1H NMR (400 MHz, CDCl3), δ
1.54–1.96 (m, 8H, 4 × CH2), 2.46 (s, 3H, CH3), 3.05–3.13 (m, 2H, 2
2.48 (s, 3H, CH3), 7.06 (t, 1H, 2JH-F ) 58 Hz, CHF2), 7.59 (dd, 2H, 3J
4
2
) 8.8 Hz, J ) 6.8 Hz, ArH), 7.82–7.99 (m, 4H, ArH); EI MS, m/z
× CH), 7.04 (t, 1H, JH-F ) 58 Hz, CHF2), 7.35–7.71 (m, 2H, ArH);
(%) 468 ([M + 1]+, 33), 466 ([M - 1]+, 29), 387 (100), 346 (26),
296 (37), 253 (59), 196 (12), 130 (10), 104 (26), 76 (15). Anal. Calcd
for C18H10BrF3N4O3: C, 46.27; H, 2.16; N, 11.99. Found: C, 46.50; H,
1.91; N, 12.09.
EI MS, m/z (%) 446 ([M + 1]+, 15), 444 ([M - 1]+, 39), 409 (90),
381 (85), 299 (26), 200 (41), 165 (60), 81 (100). Anal. Calcd for
C18H16Cl2F2N4O3: C, 48.56; H, 3.62; N, 12.58. Found: C, 48.81; H,
3.38; N, 12.63.
1d: yield, 61%; mp 200–202 °C; 1H NMR (400 MHz, CDCl3), δ
1k: yield, 44%; mp 108–110 °C; 1H NMR (400 MHz, CDCl3), δ
1.51–1.92 (m, 8H, 4 × CH2), 2.47 (s, 3H, CH3), 3.07–3.09 (m, 2H, 2
× CH), 7.04 (t, 1H, 2JH-F ) 58 Hz, CHF2), 7.49 (dd, 2H, 3J ) 8.8 Hz,
2
2.49 (s, 3H, CH3), 7.07 (t, 1H, JH-F ) 58 Hz, CHF2), 7.61–7.72 (m,
3H, ArH), 7.81–7.98 (m, 4H, ArH); EI MS, m/z (%) 406 ([M + 1]+,

Herbicidal Activities of Triazoline Derivatives
J. Agric. Food Chem., Vol. 56, No. 6, 2008 2121
1
4J ) 6.8 Hz, ArH); EI MS, m/z (%) 473 (M+, 11), 393 (100), 283
(18), 282 (25), 242 (18), 191 (14), 149 (28). Anal. Calcd for
C18H16BrF3N4O3: C, 45.68; H, 3.41; N, 11.84. Found: C, 45.36; H,
3.23; N, 12.04.
1l: yield, 51%; mp 141–142 °C; 1H NMR (400 MHz, CDCl3), δ
1.51 (br, 4H, 2 × CH2), 1.88–1.93 (m, 4H, 2 × CH2), 2.48 (s, 3H,
CH3), 3.03–3.05 (m, 2H, 2 × CH), 7.05 (t, 1H, 2JH-F ) 58 Hz, CHF2),
7.20–7.64 (m, 3H, ArH); EI MS, m/z (%) 411 (M+, 12), 410 ([M -
1]+, 78), 375 (100), 325 (18), 265 (16). Anal. Calcd for
C18H17ClF2N4O3: C, 52.63; H, 4.17; N, 13.64. Found: C, 52.71; H, 4.31;
N, 13.57.
2h: white solid; yield, 95%; mp 258–259 °C; H NMR (400 MHz,
DMSO-d6), δ 2.41 (s, 3H, CH3), 7.40 (dd, 4H, J ) 8.8 Hz, ArCl), 7.50
2
(t, 1H, JH-F ) 58 Hz, CHF2), 7.91–8.44 (m, 2H, Ar), 8.59 (s, 1H,
ArNH), 9.65 (s, 1H, NHArCl); EI MS, m/z (%) 463 (M+, 23), 428
(17), 426 (25), 310 (55), 299 (22), 273 (100), 174 (24), 165 (19), 153
(45), 139 (54), 127 (99). Anal. Calcd for C17H12Cl3F2N5O2: C, 44.13;
H, 2.61; N, 15.14. Found: C, 44.41; H, 2.59; N, 14.98.
Preparation of 1,4-Disubstituted 1,2,4-Triazol-5-one (3). A mixture
of 0.33 g (1 mmol) of 1-(4- chloro-2-fluoro-5-(mercaptoethynylper-
oxyamino)phenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one 4e, 0.21 g (1.5
mmol) of anhydrous potassium carbonated, and 0.31 g (1.1 mmol) of
(E)-methyl 2-(2-bromomethyl)phenyl-2-methoxyiminoacetate in DMF
(8 mL) was stirred for 17 h at 50 °C, according to thin layer
chromatographic (TLC) analysis. Then ice–water was added to the
reaction mixture to form a precipitate, which was purified by column
chromatography on silica gel using 6:1 petroleum ether/acetone as an
eluent. The appropriate fractions were combined and concentrated
under reduced pressure to yield the title compound 3: yield, 57%; mp
178–180 °C; 1H NMR (400 MHz, CDCl3), δ 1.40 (t, 3H, J ) 7.2 Hz,
CH3), 2.00 (s, 3H, CH3), 3.19 (q, 2H, J ) 7.2 Hz, CH2), 3.88 (s, 3H,
OCH3), 4.07 (s, 3H, NOCH3), 4.77 (s, 2H, CH2), 6.74 (s, 1H,
C2H5SO2NH), 7.17–7.95 (m, 6H, ArH); EI MS, m/z (%) 540 (M+, 22),
477 (100), 451 (47), 383 (6), 116 (37). Anal. Calcd for C22H23ClFN5O6S:
C, 48.94; H, 4.29; N, 12.97. Found: C, 49.27; H, 4.33; N, 13.20.
X-ray Diffractions. Data collection was measured at 298 ( 2 K on
a Bruker SMART CCD area detector diffractometer with graphite-
monochromated Mo KR radiation (λ) 0.71073 Å: SMART (17); cell
refinement, SAINT (17); data reduction, SAINT; program(s) used to
solve structure, SHELXS97 (18); program(s) used to refine structure,
SHELXL97 (18); molecular graphics, SHELXTL (18); software used
to prepare material for publication, SHELXTL (18). Hydrogen atoms
were observed and refined with a fixed value of their isotropic
displacement parameter.
General Procedure for the Synthesis of the Title Compounds 2.
To a stirred solution of 1 mmol of intermediates 6 was added 1.1 mmol
of aryl isocyanate in 10 mL of dichloromethane with refluxing. Upon
completion of addition, the reaction mixture was concentrated under
pressure to remove solvent and then was diluted with water; the resultant
solid was collected by filtration and recrystallized from ethanol to yield
the title compounds 2.
1
2a: white solid; yield, 79%; mp 213–215 °C; H NMR (400 MHz,
2
DMSO-d6), δ 2.48 (s, 3H, CH3), 7.54 (t, 1H, JH-F ) 58 Hz, CHF2),
6.86–7.70 (m, 8H, ArH, 2 × NH); EI MS, m/z (%) 393 ([M - 1]+,
29), 274 (57), 265 (26), 239 (99), 166 (12), 140 (14), 119 (20), 93
(100). Anal. Calcd for C17H14ClF2N5O2: C, 51.85; H, 3.58; N, 17.79.
Found: C, 51.70; H, 3.70; N, 17.60.
1
2b: white solid; yield, 86%; mp 250–251 °C; H NMR (400 MHz,
DMSO-d6), δ 2.41 (s, 3H, CH3), 7.33–7.67 (m, 7H, ArH), 7.55 (t, 1H,
2JH-F ) 58 Hz, CHF2), 8.95 (s, 1H, NHAr), 9.09 (s, 1H, NHArCl); EI
MS, m/z (%) 428 (M+, 5), 429 ([M + 1]+, 20), 427 ([M - 1]+, 31),
300 (11), 274 (60), 265 (35), 239 (99), 166 (11), 153 (22), 140 (12),
129 (31), 127 (100), 113 (12), 105 (117). Anal. Calcd for
C17H13Cl2F2N5O2: C, 47.68; H, 3.06; N, 16.35. Found: C, 47.60; H,
2.90; N, 16.28.
1
2c: white solid; yield, 95%; mp 229–231 °C; H NMR (400 MHz,
Crystal data for 1a (0.30 mm × 0.20 mm × 0.20 mm): θmax ) 27.00;
DMSO-d6), δ 2.41 (s, 3H, CH3), 6.99–7.47 (m, 5H, Ar), 7.51 (t, 1H,
2JH-F ) 58 Hz, CHF2), 7.89 (d, 1H, J ) 9.6 Hz, ArH), 8.29 (s, 1H,
NH), 8.30 (d, 1H, J ) 7.6 Hz, ArH), 9.52 (s, 1H, NHAr); EI MS, m/z
(%) 455 ([M - 1]+, 17), 457 ([M + 1]+, 18), 376 (100), 338 (73),
204 (14), 202 (16), 149 (13), 123 (37), 119 (11). Anal. Calcd for
C17H13BrF3N5O2: C, 44.76; H, 2.87; N, 15.35. Found: C, 44.55; H,
2.86; N, 15.26.
10706 measured reflections; 4079 independent reflections (Rint
)
0.0270) of which 3114 had |Fo| > 2|Fo|. Data were corrected for Lorentz
and polarization effects and for absorption (Tmin ) 0.5529; Tmax
)
0.6628). Full-matrix least-squares refinement based on F2 using the
weight of 1/[σ2(Fo ) + (0.0777P)2 + 0.0996P] gave final values of R
2
) 0.0411, ωR ) 0.1125, and GOF(F) ) 1.062 for 263 variables and
4079 contributing reflections. Maximum shift/error was 0.001, and
1
maximum/minimum residual electron density ) 0.634/-0.446 e Å-3
.
2d: white solid; yield, 96%; mp 217–218 °C; H NMR (400 MHz,
DMSO-d6), δ 2.41 (s, 3H, CH3), 7.42 (dd, 4H, J ) 8.8 Hz, 4-ClArH),
7.51 (t, 1H, 2JH-F ) 58 Hz, CHF2), 7.89 (d, 1H, J ) 10 Hz, ArH), 8.28
(d, 1H, J ) 7.6 Hz, ArH), 8.31 (s, 1H, NHAr), 9.63 (s, 1H, NHArCl);
EI MS, m/z (%) 491 (M+, 20), 410 (97), 338 (78), 336 (69), 202 (19),
127 (100). Anal. Calcd for C17H12BrClF3N5O2: C, 41.61; H, 2.47; N,
14.27. Found: C, 41.56; H, 2.40; N, 14.06.
Crystal Data for 2g (0.20 mm × 0.20 mm × 0.10 mm): θmax
)
27.00; 15943 measured reflections; 4148 independent reflections (Rint
) 0.0417) of which 3174 had |Fo| > 2|Fo|. Data were corrected for
Lorentz and polarization effects and for absorption (Tmin ) 0.9270;
Tmax ) 0.9625). Full-matrix least-squares refinement based on F2 using
the weight of 1/[σ2(Fo ) + (0.0776P)2 + 0.0000P] gave final values
2
1
2e: white solid; yield, 90%; mp 199–201 °C; H NMR (400 MHz,
of R ) 0.0462, ωR ) 0.1198, and GOF(F) ) 1.008 for 260 variables
and 4148 contributing reflections. Maximum shift/error was 0.002, and
maximum/minimum residual electron density ) 0.312/-0.230 e
DMSO-d6), δ 2.33 (s, 3H, CH3), 7.01–7.68 (m, 5H, Ar), 7.30 (t, 1H,
2JH-F ) 58 Hz, CHF2), 7.84–8.42 (dd, 2H, J ) 10 Hz, 7.6 Hz, Ar),
8.88 (s, 1H, NHAr), 9.15 (s, 1H, NHPh); EI MS, m/z (%) 457 ([M +
1]+, 20), 455 ([M - 1]+, 18), 338 (31), 336 (29), 257 (100), 216 (17),
166 (15), 123 (22), 119 (15). Anal. Calcd for C17H13BrF3N5O2: C, 44.76;
H, 2.87; N, 15.35. Found: C, 44.58; H, 2.72; N, 15.39.
Å-3
.
Herbicidal ActiVities. The herbicidal activities of compounds 1-3
against Echinochloa crusgalli (EC), Digiatra sanguinalis (DS), Setaria
Viridis (SV), Brassica juncea (BJ), Amaranthus retroflexus (AR), and
Chenopodium album (CA) were evaluated according to a previously
reported procedure (19); sulfentrazone was selected as a control. All
test compounds were formulated as 100 g/L emulsified concentrates
by using DMF as solvent and TW-80 as emulsification reagent. The
concentrates were diluted with water to the required concentration and
applied to pot-grown plants in a greenhouse. The soil used was a clay
soil, pH 6.5, 1.6% organic matter, 37.3% clay particles, and CEC )
12.1 mol/kg. The rate of application [grams of active ingredient (ai)
per hectare] was calculated by the total amount of active ingredient in
the formulation divided by the surface area of the pot. Plastic pots with
a diameter of 9.5 cm were filled with soil to a depth of 8 cm.
Approximately 20 seeds of E. crusgalli, D. sanguinalis, S. Viridis, B.
juncea, A. retroflexus, and C. album were sown in the soil at the depth
of 1-3 cm and grown at 15–30 °C in a greenhouse. The diluted
formulation solutions were applied for postemergence treatment,
dicotyledon weeds were treated at the two-leaf stage, and monocoty-
1
2f: white solid; yield, 90%; mp 260–262 °C; H NMR (400 MHz,
DMSO-d6), δ 2.40 (s, 3H, CH3), 7.42 (dd, 4H, J ) 8.8 Hz, ArCl), 7.48
(t, 1H, 2JH-F ) 58 Hz, CHF2), 7.85 (d, 1H, J ) 10.8 Hz, ArH), 8.39 (d,
1H, J ) 7.6 Hz, ArH), 8.89 (s, 1H, NHAr), 9.27 (s, 1H, NHArCl); EI
MS, m/z (%) 491 ([M + 1]+, 22), 283 (23), 257 (99), 216 (32), 203
(13), 166 (32), 154 (36), 149 (31), 127 (100), 123 (72), 108 (12). Anal.
Calcd for C17H12BrClF3N5O2: C, 41.61; H, 2.47; N, 14.27. Found: C,
41.59; H, 2.34; N, 14.28.
1
2g: white solid; yield, 91%; mp 231–233 °C; H NMR (400 MHz,
DMSO-d6), δ 2.41 (s, 3H, CH3), 7.25 (m, 5H, Ar), 7.52 (t, 1H, 2JH-F
)
58 Hz, CHF2), 7.91–8.47 (m, 2H, ArH), 8.58 (s, 1H, ArNH), 9.54 (s,
1H, PhNH); EI MS, m/z (%) 428 (M+, 6), 429 ([M + 1]+, 33), 427
([M - 1]+, 48), 394 (21), 392 (64), 310 (42), 308 (69), 273 (83), 174
(34), 165 (31), 158 (10), 146 (21), 139 (76), 120 (47), 93 (100). Anal.
Calcd for C17H13Cl2F2N5O2: C, 47.68; H, 3.06; N, 16.35. Found: C,
47.51; H, 2.91; N, 16.21.

2122 J. Agric. Food Chem., Vol. 56, No. 6, 2008
Luo et al.
Table 1. Postemergence Herbicidal Activity of Compounds 1-3 (150 g of ai/ha)
no.
X
Y
R1
ECa
DS
SV
BJ
AR
CA
b
1a
1b
1c
1d
1e
1f
1g
1h
1i
F
Br
Cl
F
H
Br
Cl
F
H
Br
Cl
F
H
H
H
Br
Br
F
/
/
/
/
/
/
/
/
/
/
/
/
H
Cl
H
Cl
H
Cl
H
Cl
/
+
++
+
-
-
+
+
-
-
+
-
-
-
-
-
-
-
-
-
-
-
+
-
++
+
-
-
+
+
-
-
+
-
-
-
-
-
-
-
-
-
-
-
+
++
++
-
+++
+++
-
++
+++
-
Cl
Br
Cl
F
Cl
Br
Cl
F
Cl
Bt
Cl
Cl
Cl
F
+
-
-
+
+
-
-
+
-
-
-
-
-
-
-
-
-
-
-
+
-
-
-
-
-
-
+++
+++
+
+++
+++
-
-
+
-
-
-
+
+++
+++
-
+++
++
+
1j
1k
1l
-
+
-
-
-
2a
2b
2c
2d
2e
2f
2g
2h
3
-
-
-
-
-
-
-
-
-
F
-
-
-
Br
Br
Cl
Cl
/
-
-
-
F
-
-
-
Cl
Cl
/
-
-
-
-
-
-
++
+++
+++
+++
++
+++
sulfentrazone
/
/
/
a EC, Echinochloa crusgalli; DS, Digitaria sanguinalis; SV, Setaria viridis; BJ, Brassica juncea; AR, Amaranthus retroflexus; CA, Chenopodium album. b Rating system
for the growth inhibition percentage: +++, 100%; ++, >80%; +, 50–80%; -, <50%.
ledon weeds were treated at the 1-leaf stage, respectively. The
postemergence application rate was 150 g of ai/ha. Untreated seedlings
were used as the control group, and the solvent (DMF)-treated seedlings
were used as the solvent control group. Herbicidal activity was evaluated
visually 15 days post-treatment. The results of herbicidal activities are
shown in Table 1. Ten kinds of weeds, such as C. album, Cassia tora
(CT), B. juncea, A. retroflexus, Eclipta prostrate (EP), Cerastium
arVense (CAR), Portulaca oleracea (PO), E. crusgalli, D. sanguinalis,
and S. Viridis, were used for the test of the herbicidal spectrum of
compound 3.
Crop SelectiVity (20). The conventional rice, soybean, cotton, wheat,
rape, and maize were respectively planted in plots (diameter ) 12 cm)
containing test soil and grown in a greenhouse at 20-25 °C. After the
plants had reached the four-leaf stage, the spraying treatment was
conducted at different dosages by diluting the formulation of compound
3 with water. The visual injury and growth state of the individual plants
were observed at regular intervals. The final evaluation for crop safety
of compound 3 was conducted by visual observation in 30 days after
treatment on a 0-100 scale.
converted easily to the corresponding intermediates 5a-d by
nucleophilic substitution with CHF2Cl. Intermediates 6a-d can
be prepared in yields of 66-94% by nitration and subsequent
reduction of compounds 5a-d. Subsequently, intermediates
6a-d reacted with cyclic anhydride in the refluxing AcOH
solution to yield the title compounds 1a-l, whereas the addition
reaction of intermediates 6a-d with aryl isocyanates in the
refluxing dichloromethane solution afforded the title compounds
2a-h in yields of 79-96% (Scheme 2). Additionally, com-
pound 4e reacted with (E)-methyl 2-(2-bromomethyl)phenyl-
2-methoxyiminoacetate to give the title compound 3 in a yield
of 57%. The structures of all intermediates and title compounds
1
were confirmed by elemental analyses, H NMR, and EI-MS
spectral data. In addition, the crystal structures of 1a and 2g
were determined by X-ray diffraction analyses. As shown in
Figure 2, the indoline-1,3-dione ring of 1a adopted a planar
conformation, and the dihedral angel between the indoline-1,3-
dione and phenyl ring is 74.42°. In addition, some intramolecular
and intermolecular hydrogen bonds could be observed, such as
C(18)-H(18)· · ·O(3) (2.86 Å, 104.7°), C(4)-H(4)· · ·O(2) (3.43
Å,151.2°),C(3)-H(3)···O(1)(3.24Å,142.9°),andC(14)-H(14)···O(3)
(3.18 Å, 148.0°) in crystal 1a and C(13)-H(13)· · ·O(1) (2.86
Å,119.8°),C(1)-H(1)· · ·O(1)(2.91Å,121.6°),N(2)-H(2A)· · ·O(2)
(3.02 Å, 148.0°), and N(1)-H(1A)· · ·O(2) (2.93 Å, 168.0°) in
crystal 2g.
RESULTS AND DISCUSSION
Synthetic Chemistry of the Title Compounds. As shown
in Scheme 1, first, according to the reported method (4), the
starting material, 1-aryltriazolinone 4, was prepared by a two-
step procedure, diazotization and Curtis rearrangement of the
corresponding anilines. Then, 1-aryltriazolinones 4a-d were

Herbicidal Activities of Triazoline Derivatives
J. Agric. Food Chem., Vol. 56, No. 6, 2008 2123
Scheme 2
Table 2. Further Herbicidal Spectrum Test of Compound 3 (Postemergence)
compound
dosage (g of ai/ha)
CAa
CT
BJ
AR
EP
CAR
PO
EC
DS
SV
b
37.5
75
150
37.5
75
+
+
++
++
++
++
+++
+++
+++
+++
+++
+++
-
+
+
+
+
+
+
+
+
+
+
+
-
-
+
-
+
+
3
++
++
+++
+++
+++
++
+++
++
++
++
++
++
++
+++
+++
++
++
++
+++
+++
+++
+++
+++
+++
+++
+++
+++
+++
sulfentrazone
+++
+++
150
a CA, Chenopodium album; CT, Cassia tora; BJ, Brassica juncea; AR, Amaranthus retroflexus; EP, Eclipta prostrate; CAR, Cerastium arvense; PO, Portulaca oleracea;
EC, Echinochloa crusgalli; DS, Digitaria sanguinalis; SV, Setaria viridis. b Rating system for the growth inhibition percentage: +++, 100%; ++, >80%; +, 50–80%; -,
<50%.
Table 3. Activities of Compound 3 against Different Crops
Herbicidal Activities and Structure–Activity Relation-
ships. The postemergence herbicidal activity of compounds 1-3
dosage (g of ai/ha)
rice
cotton
soybean
maize
rape
wheat
was tested in a greenhouse at the concentration of 150 g of
ai/ha; a triazolinone-type commercial product, sulfentrazone, was
selected as a control. As shown in Table 1, some of compounds
(1a, 1b, 1e, 1f, 1i, and 3) were found to display promising and
broad-spectrum herbicidal activities; unfortunately, compounds
2a-h did not display obvious herbicidal activities against the
test weeds. For example, compound 1a displayed >80%
inhibition activities against D. sanguinalis, S. Viridis, B. juncea,
A. retroflexus, and C. album and also displayed moderate
herbicidal activity against E. crusgalli. On the contrary, sulfen-
trazone did not display obvious herbicidal activity against E.
crusgalli and D. sanguinalis. Additionally, compounds 1b, 1e,
1f, 1i, and 1j showed high herbicidal activities (>80% inhibi-
tion) against A. retroflexus and C. album.
Structure–activity relationship analysis indicated that of the
substitution patterns at the C-5 position investigated herein, an
imine group rather than a phenylurea group was found to be
acceptable. Substitution patterns at C-2 and C-4 have important
influence on the herbicidal activity of compound 1. F or Cl
substitution at C-2 always led to active compounds, whereas
Br substitution at C-2 always led to an inactive one. Meanwhile,
F, Cl, and Br substitution at C-4 did not show any different
influence on the herbicidal activity. For example, compounds
1a (X ) F, Y ) Br), 1e (X ) F, Y ) Br), and 1i (X ) F, Y
) Br) displayed broad-spectrum herbicidal activities, whereas
1c (X ) Br, Y ) F), 1g (X ) Br, Y ) F), and 1k (X ) Br, Y
) F) did not display herbicidal activities. In addition, compounds
1d and 1h displayed no herbicidal activity, which revealed that
derivatives without substitution at C-4 are not acceptable.
Herbicidal Spectrum and Crop Selectivity of Compound
3. The derivatives containing the pharmacophore of (E)-methyl
2-methoxyimino-2-o-tolylacetate have been proved to display
broad-spectrum biological activity; however, there is no report
75
150
300
450
0
0
0
10
60
60
40
80
40
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
about the synthesis and herbicidal activity of triazolinone
derivatives bearing this pharmacophore. Then, compound 3 was
selected as an interesting lead for further tests. As shown in
Table 2, overall, compound 3 displayed comparable herbicidal
activities with sulfentrazone at the dosage of 37.5-150 g of
ai/ha. Broadleaf weeds, such as C. album, B. juncea, A.
retroflexus, and E. prostrate, are generally more sensitive to
compound 3 than monocot weeds, such as E. crusgalli, D.
sanguinalis, and S. Viridis. Most interestingly, some broadleaf
weeds such as B. juncea, A. retroflexus, E. prostrate, C. arVense,
and P. oleracea are highly sensitive to compound 3 even at
dosages as low as 37.5 g of ai/ha, whereas C. album and C.
tora are slightly less sensitive.
Among tested crops, only rice exhibited high tolerance to
compound 3 by postemergence application at dosages of
75-300 g of ai/ha, whereas cotton, rape, soybean, maize, and
wheat are susceptible even at dosages as low as 75 g. of ai/ha
(Table 3). At the dosage of 450 g of ai/ha, rice still exhibited
tolerance to compound 3, which indicated that compound 3
might be developed as a potential herbicide used for weed
control in rice fields.
Conclusion. In summary, a series of 1,2,4-triazolin-5(1H)-
ones were designed and synthesized by introducing the phar-
macophore of cyclic imide, phenylurea, and (E)-methyl 2-meth-
oxyimino-2-o-tolylacetate into the scaffold of triazolinone. The
results of herbicidal activity and crop selectivity indicated that
compound 3, methyl 2-[3-methyl-(2-fluoro-4-chloro-5-ethyl-

2124 J. Agric. Food Chem., Vol. 56, No. 6, 2008
Luo et al.
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ACKNOWLEDGMENT
We thank Dr. Jie Chen for the test of biological activities.
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Received for review December 16, 2007. Revised manuscript received
January 21, 2008. Accepted January 22, 2008. We are grateful for
financial support from the National Basic Research Program of China
(No. 2007CB116302, 2003CB114400), National NSFC (No. 20572030,
20432010), and The Research Fund for the Doctoral Program of Higher
Education (No. 20060511003).
JF703654G