Syntheses and herbicidal activity of pyrazolyl benzoxazole derivatives

Article abstract of DOI:10.1002/jhet.134

(Chemical Equation Presented) In recent years, protoporphyrinogen oxidase (Protox) inhibitor herbicides are developed rapidly, because of this type of herbicides shows high herbicidal activity and low toxicity. In this paper, we prepared a series of new substituted pyrazolyl benzoxazole derivative, which were synthesized from 4-fluorophenol, via a serial of reactions included chlorination, acylation, condensation, ring closure, methylation, nitration, and so on. All the structures are confirmed by ¹H NMR, MS and element analysis. Preliminary bioassay shows that most substituted pyrazolyl benzoxazole derivatives exhibit high herbicidal activity to the tested gramineous weeds and latifoliate weeds.

Full text of DOI:10.1002/jhet.134

January 2010
Syntheses and Herbicidal Activity of
Pyrazolyl Benzoxazole Derivatives
15
Na Xue, Yuhan Zhou,* Guowei Wang, Weirong Miao, and Jingping Qu*
State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian 116012, People’s Republic of China
*E-mail: zhouyh@dl.cn or qujp@chem.dlut.edu.in
Received October 3, 2009
DOI 10.1002/jhet.134
Published online 21 December 2009 in Wiley InterScience (www.interscience.wiley.com).
In recent years, protoporphyrinogen oxidase (Protox) inhibitor herbicides are developed rapidly,
because of this type of herbicides shows high herbicidal activity and low toxicity. In this paper, we pre-
pared a series of new substituted pyrazolyl benzoxazole derivative, which were synthesized from 4-fluo-
rophenol, via a serial of reactions included chlorination, acylation, condensation, ring closure,
1
methylation, nitration, and so on. All the structures are confirmed by H NMR, MS and element analy-
sis. Preliminary bioassay shows that most substituted pyrazolyl benzoxazole derivatives exhibit high
herbicidal activity to the tested gramineous weeds and latifoliate weeds.
J. Heterocyclic Chem., 47, 15 (2010).
INTRODUCTION
ities [15–19]. Earlier work at our laboratory involved
some pyrazole [20] and isoxazole [21] derivatives with
high herbicidal activity. In this article, we described the
syntheses and herbicidal activity of pyrazolyl benzoxa-
zole derivatives. Preliminary bioassay showed that most
of them had good herbicidal activity.
Herbicides play an important role in agricultural prac-
tices. In recent 30 years, herbicides targeting the enzyme
protoporphyrinogen IX oxidase (Protox), which have
been used commercially to control annual grasses and
weeds in soybean, peanut, cotton, rice, and other crops,
are developed rapidly [1–3], because this type of herbi-
cides shows high bioactivity and low toxicity. Diphenyl
ether (DPE) herbicides are the first widely used family
of Protox inhibitor herbicides. Nitrofen was the leading
compound of this kind [4].
RESULTS AND DISCUSSION
The syntheses of the compounds are described in the
Schemes 1 and 2, and the yields were not optimized.
The intermediates 10a–10c and 11a–11c were synthe-
sized from 4-fluorophenol, via a serial of reactions
included chlorination, acylation, condensation, ring clo-
sure, methylation, nitration, and so on (Scheme 1). The
title compounds can be obtained through the different
ring-close and alkyl reactions from compounds 10a–10c
or 11a–11c (Scheme 2).
The synthesis of 11 is the key step, which involves
reducing nitro group to amino group in the phenyl ring.
At the beginning, we used sodium sulfide to reduce nitro
group, the yield was only 10%. We also used the
method of catalytic hydrogenation with Pt/C, but the
selectivity was not good. Finally, we found reduction of
10 with iron and saturated ammonium chloride has the
higher yield (86%) and selectivity. For the product 11 is
sensitive to air, reaction should be carried out under
The bicyclic nature of diphenyl ethers is similar to
the structure of half of protoporphyrinogen IX, which
allows competitive inhibition of Protox located in the
plastid by occupying the binding site for protoporphyri-
nogen IX [5–7]. Besides, many other chemical structures
belong to this family are reported, such as phenyl het-
erocycle (Heterocycle including triazolinone, oxazoli-
done, pyrazole, phthalamide, etc.) and benzoheterocycle.
Many of them are commercial and of high bioactivity
[8–11]. Some samples of commercial Protox inhibitors
are shown in Figure 1.
As the development of Protox inhibitor, many benzo-
heterocyclic compounds have shown good herbicidal
activity, which are effective at controlling grass and
broadleaf weeds at low dose [12–14]. In recent years,
benzoxazole derivatives were found to be high bioactiv-
C
V
2009 HeteroCorporation

16
N. Xue, Y. Zhou, G. Wang, W. Miao, and J. Qu
Vol 47
as anhydrous potassium carbonate as the catalyst, and
acetone as solvent, alkyl was attached to atom N. But
when silver (I) oxide and methylene chloride were
employed, alkyl was attached to atom O. The distin-
guishing of 15 and 16 can be determined by the shift of
1H NMR. For example, 15a: d: 3.18 (s, 3H, NCH3);
16a: d: 4.31 (s, 3H, OCH3).
The herbicidal activity of the compounds were tested
against Setaria viridis, Ditaria sanguinalis (monocot
crops) and Abutilon theophrasti (dicot crops) using
Fomesafen and Fluazolate for comparison. The results
shown in Table 1 were the effect visual measurement
treat after 10 days.
From Table 1 we can conclude that most of them had
good herbicidal activity. When no substituent on pyraz-
ole position 4, there is no herbicidal activity or low ac-
tivity (13a, 14a, 15a, 16a, 17a), but when halogen (such
as chlorine or bromine) is on pyrazole, most of them
show good herbicidal efficacy. Similar results have been
reported by Meazza et al. [22]. Their study on pyrroles
showed that the halopyrrole nucleus is important for
biological activity; if there is only hydrogen on pyrrole
the compounds are virtually inactive.
Figure 1. Samples of commercial protox inhibitors.
nitrogen, and the crude product is used directly in the
next reaction without further purification.
13 can be synthesized by stirring the mixture of com-
pounds 11 and acetyl chloride or acetic anhydride at
room temperature, but the selectivity was not satisfied.
So we changed to another pathway. At first, 10 was
acetylation to form 12, then 12 was reduced with iron
and subjected to ring-closed in acetic acid. By that way
13 was made in good yield.
The herbicidal activity of compound 14 is not high,
mainly because of its poor lipophilicity. When its lipo-
philicity is increased by introducing methyl or allyl to N
or O atom, which form 15 or 16, the activity is much
increased.
15 and 16 are isomers. The different reacting condi-
tions lead to different products. When using base such
Compared with corresponding compounds 15 (b, c, e,
f) and 16 (b, c, e, f) , we can find that the herbicidal
Scheme 1. Syntheses of the intermediates.
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Syntheses and Herbicidal Activity of Pyrazolyl Benzoxazole Derivatives
17
Scheme 2. Syntheses of the aimed compounds.
activities of the compounds alkyl attached to atom O is
higher than that of alkyl attached to atom N. And the
activity of 16b is all 100% even at the usage dose of
37.5 g/hm2, so it is a valuable compound that fit for
dicot crops and monocot crops. 15b and 15e are good
for dicot crops, reached more than 80% at the usage
Table 1
Herbicidal activity of the title compounds.a
Setaria viridis
Ditaria sanguinalis
Abutilon theophrasti
Comp.
37.5b
150b
600b
37.5b
150b
600b
37.5b
150b
600b
13a
13b
13c
14a
14b
14c
15a
15b
15c
15e
15f
16a
16b
16c
16e
16f
17a
0
4
0
7
1
8
0
5
1
0
1
0
0
1
3
2
5
3
10
9
3
8
0
5
7
4
9
0
7
1
8
0
6
0
6
1
7
2
0
4
0
5
0
3
0
5
0
2
0
4
0
6
0
1
0
5
1
6
2
3
1
4
2
2
1
6
3
7
4
0
0
0
0
0
0
0
1
1
3
3
6
8
8
4
4
8
7
9
5
10
9
10
10
10
10
9
10
10
9
10
1
10
10
10
10
2
2
4
3
5
7
5
5
6
7
8
7
10
8
1
2
4
3
5
3
6
10
10
5
10
10
5
10
0
10
10
6
10
0
10
10
5
10
0
10
10
6
10
0
10
10
5
10
0
10
10
8
10
1
10
10
9
8
0
3
17b
17c
7
9
6
9
7
8
4
10
9
10
10
10
9
9
10
10
10
10
10
6
Fomesafen
Fluazolate
9
10
9
10
a 0 ¼ no activity and 10 ¼ total kill.
b The usage dose of compounds (g a.i./ hm2).
Journal of Heterocyclic Chemistry
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N. Xue, Y. Zhou, G. Wang, W. Miao, and J. Qu
Vol 47
dose of 37.5 g/hm2, but for monocot crops, the activity
not very high. The activity of 17c is higher than 17b for
monocot crops, but for dicot crops, they are the same.
The activity of compounds 16b, 16c, 16f, and 17c is
obviously higher than Fomesafen, 16b and 16c is even a
little higher than Fluazolate.
purification. A sample suiting for analysis was obtained by
recrystallization with a mixture of petroleum ether and ethyl
acetate (3:1); m.p. 94.0–97.0ꢀC; MS (API-ES, negative), m/z:
338 ([M-H]ꢂ); 1H NMR, d: 7.53 (d, 1H, J ¼ 9.6 Hz, Ph-H),
6.95 (d, 1H, J ¼ 3.2 Hz, Pyr-H), 4.01 (s, 3H, Pyr-CH3). Anal.
Calcd. for C11H6ClF4N3O3 (339.6): C, 38.90; H, 1.78; N,
12.37. Found: C, 38.84; H, 1.71; N, 12.42.
6-Chloro-3-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-
3-yl)-4-fluoro-2-nitrophenol (10b). The compound was a light
yellow powder and was used directly in the next reaction with-
out purification. The yield of two steps was 82%. A sample
suiting for analysis was obtained by recrystallization with a
mixture of petroleum ether and ethyl acetate (3:1); m.p. 85.2–
EXPERIMENTAL
Melting points were taken on a Micro melting point appara-
tus (X-6, Beijing Tech Instrument Co. Ltd.) and were uncor-
rected. 1H NMR spectra were measured in deuterochloroform
on a Varian VA400 MHz spectrometer with TMS as an inter-
nal standard. Elemental analyses were performed on a Vario
EL III (Elementar, German) elemental analysis instrumenta-
tion. MS were obtained with a HP1100 high Performance
Liquid Chromatography/Mass Selective Detector.
1
87.1ꢀC; MS (API-ES, negative), m/z: 372 ([M-H]ꢂ); H NMR,
d: 7.58 (d, 1H, J ¼ 8.4 Hz, Ph-H), 4.03 (s, 3H, Pyr-CH3).
Anal. Calcd. for C11H5Cl2F4N3O3 (374.1): C, 35.32; H, 1.35;
N, 11.23. Found: C, 35.64; H, 1.43; N, 11.42.
3-(4-Bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-6-
chloro-4-fluoro-2-nitrophenol (10c). The compound was a
yellow powder and was used directly in the next reaction with-
out purification. The yield of two steps was 83%. A sample
suiting for analysis was obtained by recrystallization with a
mixture of petroleum ether and ethyl acetate (3:1); m.p. 86.3–
8 were synthesized from 4-Fluorophenol according to the
existing methods [23,24].
General procedure for 9a–9c.
3-(4-Chloro-6-fluoro-3-
methoxy-2-nitrophenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole
(9a) A mixed acid (27 mL, V(acetic anhydride): V(fuming ni-
tric acid)¼ 2:1) was added dropwise to a solution of 8a ( 8 g,
0.026 mol) in acetic acid (25 mL) while maintaining the reac-
tion solution at 0ꢀC, and the resulting mixture was stirred at
0ꢀC for 2 h. The reaction solution was poured into water, fil-
trated, and washed with water. The crude product was recrys-
tallized with ethanol. 9a was obtained in 83% yield as a faint
yellow solid; m.p. 94.0–96.0ꢀC; MS (API-ES, positive), m/z:
1
88.6ꢀC; MS (API-ES, negative), m/z: 416 ([M-H]ꢂ); H NMR,
d: 7.58 (d, 1H, J ¼ 8.4 Hz, Ph-H), 4.04 (s, 3H, Pyr-CH3).
Anal. Calcd. for C11H5BrClF4N3O3 (418.5): C, 31.57; H, 1.20;
N, 10.04. Found: C, 31.69; H, 1.23; N, 10.25.
General procedure for 11a–11c.
2-Amino-6-chloro-4-
fluoro-3-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)phenol
(11a). Under nitrogen a mixture of 10a (3.7 g, 10.9 mmol),
iron (3.8 g, 0.068 mol), a solution of saturated ammonium
chloride (120 mL) and methanol (80 mL) were stirred at 55ꢀC
for 6 h. Then methanol was removed under vacuum. The reac-
tion solution was filtrated and the filtrate was extracted with
ethyl acetate (40 mL ꢁ 3). The combined organic layer was
washed with water, dried over anhydrous magnesium sulfate
and concentrated under vacuum. 11a was obtained in 86%
yield as a brown solid and was used directly in the next reac-
tion without purification.
2-Amino-6-chloro-3-(4-chloro-1-methyl-5-trifluoromethyl-
1H-pyrazol-3-yl)-4-fluorophenol (11b). The crude product
was obtained as brown paste and was used directly in the next
reaction without purification. The yield of crude product was
95%.
354 ([MþH]þ); H NMR, d: 7.37 (d, 1H, J ¼ 9.6 Hz, Ph-H),
1
6.94 (d, 1H, J ¼ 3.2 Hz, Pyr-H), 4.02 (s, 3H, Pyr-CH3), 3.98
(s, 3H, OCH3). Anal. Calcd. for C12H8ClF4N3O3 (353.7): C,
40.75; H, 2.28; N, 11.88. Found: C, 40.87; H, 2. 35; N, 11.67.
4-Chloro-3-(4-chloro-6-fluoro-3-methoxy-2-nitrophenyl)-1-
methyl-5-trifluoromethyl-1H-pyrazole (9b). The compound was
orange pasty matter and was used directly in the next reaction
without purification; MS (API-ES, positive), m/z: 388
([MþH]þ); H NMR, d: 7.42 (d, 1H, J ¼ 7.6 Hz, Ph-H), 4.02
1
(s, 3H, Pyr-CH3), 4.01 (s, 3H, OCH3). Anal. Calcd. for
C12H7Cl2F4N3O3 (388.1): C, 37.14; H, 1.82; N, 10.83. Found:
C, 36.87; H, 1.63; N, 10.67.
4-Bromo-3-(4-chloro-6-fluoro-3-methoxy-2-nitrophenyl)-1-
methyl-5-trifluoromethyl-1H-pyrazole (9c). The compound
was orange pasty matter and was used directly in the next
reaction without purification; MS (API-ES, positive), m/z: 432
2-Amino-3-(4-bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-
3-yl)-6-chloro-4-fluorophenol (11c). The crude product was
obtained as brown paste and was used directly in the next
reaction without purification. The yield of crude product was
90%.
([MþH]þ); H NMR, d: 7.42 (d, 1H, J ¼ 7.6 Hz, Ph-H), 4.03
1
(s, 3H, Pyr-CH3), 4.01 (s, 3H, OCH3). Anal. Calcd. for
C12H7BrClF4N3O3 (432.6): C, 33.32; H, 1.63; N, 9.71. Found:
C, 32.99; H, 1.60; N, 9.62.
General procedure for 12a–12c. 6-Chloro-4-fluoro-3-(1-
methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-2-nitrophenyl acetate
(12a). A mixture of 10a (650 mg, 1.91 mmol), acetyl chloride
(0.2 mL, 2.96 mmol), triethylamine (0.3 mL, 2.16 mmol) and
methylene chloride (25 mL) was stirred at 40ꢀC for 1 h. The
reaction solution was poured into water. The organic layer was
washed with a solution of 5% sodium bicarbonate and water,
dried over anhydrous magnesium sulfate and concentrated
under vacuum. The crude product was recrystallized with etha-
nol. 12a was obtained in 85% yield as a white powder; mþ.p.
137.5–139.2ꢀC; MS (API-ES, positive), m/z: 382 ([MþH] ),
General procedure for 10a-10c. 6-Chloro-4-fluoro-3-(1-
methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-2-nitrophenol (10a). A
mixture of 9a (3.9 g, 11 mmol), anhydrous aluminium chloride
(3.7 g, 27.7 mmol) and dichloromethane (70 mL) were stirred
at room temperature for 2 h. The reaction solution was poured
into icy hydrochloric acid and extracted with dichloromethane
(20 mL ꢁ 3). The combined organic layer was washed with
water, dried over anhydrous magnesium sulfate and concen-
trated under vacuum. 10a was obtained in 100% yield as a yel-
low powder and was used directly in the next reaction without
1
404 ([MþNa]þ); H NMR d: 7.45 (d, J ¼ 9.6 Hz, 1H, Ph-H),
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Syntheses and Herbicidal Activity of Pyrazolyl Benzoxazole Derivatives
19
6.95 (d, J ¼ 3.2 Hz, 1H, Pyr-H), 4.00 (s, 3H, Pyr-CH3), 2.36
(s, 3H, COCH3). Anal. Calcd. for C13H8ClF4N3O4 (381.7): C,
40.91; H, 2.11; N, 11.01. Found: C, 40.62; H, 2.20; N, 11.25.
6-Chloro-3-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-
3-yl)-4-fluoro-2-nitrophenyl acetate (12b). The compound was
obtained in 75% yield as a light brown powder; m.p.þ103.8–
105.3ꢀC; MS (API-ES, positive), m/z: 416 ([MþH] ), 438
d: 9.48 (s, 1H, N-H), 7.16 (d, J ¼ 3.6 Hz, 1H, Pyr-H), 6.97 (d,
J ¼ 11.6 Hz, 1H, Ph-H), 4.11 (s, 3H, Pyr-CH3). Anal. Calcd.
for C12H6ClF4N3O2 (335.6): C, 42.94; H, 1.80; N, 12.52.
Found: C, 43.12; H, 1.95; N, 12.58.
7-Chloro-4-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-
3-yl)-5-fluoro-3H-benzoxazol-2-one (14b). The compound was
obtained in 59% yield as a white powder; m.p. 217.2–218.5ꢀC;
MS (API-ES, positive), m/z: 392 ([MþNa]þ); 1H NMR d:
8.86 (s, 1H, N-H), 7.01 (d, J ¼ 10.4 Hz, 1H, Ph-H), 4.13 (s,
3H, Pyr-CH3). Anal. Calcd. for C12H5Cl2F4N3O2 (370.1): C,
38.94; H, 1.36; N, 11.35. Found: C, 38.78; H, 1.42; N, 11.36.
4-(4-Bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-7-
chloro-5-fluoro-3H-benzoxazol-2-one (14c). The compound
was obtained in 84% yield as a brown powder; m.p.ꢂ217.1–
219.8ꢀC; MS (API-ES, negative), m/z: 412 ([M-H] ), 450
1
([MþNa]þ); H NMR d: 7.51 (d, J ¼ 8.4 Hz, 1H, Ph-H), 4.02
(s, 3H, Pyr-CH3), 2.37 (s, 3H, COCH3). Anal. Calcd. for
C13H7Cl2F4N3O4 (416.1): C, 37.52; H, 1.70; N, 10.10. Found:
C, 37.69; H, 1.73; N, 10.27.
3-(4-Bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-6-
chloro-4-fluoro-2-nitrophenyl acetate (12c). The compound
was obtained in 72% yield as a brown powder; m.p. þ107.9–
109.0ꢀC; MS (API-ES, positive), m/z: 460 ([MþH] ); 1H
NMR d: 7.51 (d, J ¼ 8.0 Hz, 1H, Ph-H), 4.04 (s, 3H, Pyr-
CH3), 2.37 (s, 3H, COCH3). Anal. Calcd. for
C13H7BrClF4N3O4 (460.6): C, 33.90; H, 1.53; N, 9.12. Found:
C, 34.02; H, 1.68; N, 8.91.
1
([MþCl]ꢂ); H NMR d: 8.67 (s, 1H, N-H), 7.01 (d, J ¼ 10.4
Hz, 1H, Ph-H), 4.15 (s, 3H, Pyr-CH3). Anal. Calcd. for
C12H5BrClF4N3O2 (414.5): C, 34.77; H, 1.22; N, 10.14.
Found: C, 35.03; H, 1.31; N, 10.32.
General procedure for 13a–13c.
7-chloro-5-fluoro-2-
General procedure for 15a–15f. A mixture of Compound
14a (600 mg, 1.62 mmol), a small amount of anhydrous potas-
sium carbonate, dimethyl sulfate (0.5 mL, 5 mmol) or bro-
moallylene (0.3 mL, 3.1 mmol)and acetone (15 mL) was
stirred at ambient temperature for 3 h. The reaction solution
was poured into water and extracted with ethyl acetate (10 mL
ꢁ 3). The combined organic layer was washed with water,
dried over anhydrous magnesium sulfate and concentrated
under vacuum. The crude product was purified by silica gel
chromatography with eluent (petroleum ether:ethyl acetate ¼
6:1).
7-Chloro-5-fluoro-3-methyl-4-(1-methyl-5-trifluoromethyl-
1H-pyrazol-3-yl)-3H-benzoxazol-2-one (15a). The Compound
was obtained in 34% yield as a light yellow powdeþr; m.p.
194–198ꢀC; MS (API-ES, positive), m/z: 350 ([MþH] ), 372
([MþNa]þ); 1H NMR d: 6.97 (d, J ¼ 10.0 Hz, 1H, Ph-H),
6.85 (s, 1H, Pyr-H), 4.09 (s, 3H, Pyr-CH3), 3.18 (s, 3H,
NCH3). Anal. Calcd. for C13H8ClF4N3O2 (349.7): C, 44.65; H,
2.31; N, 12.02. Found: C, 44.58; H, 2.45; N, 12.01.
7-Chloro-4-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-
3-yl)-5-fluoro-3-methy-3H-benzoxazol-2-one (15b). The com-
pound was obtained in 29% yield as a light brown powder;
m.p. 103.1–104.8ꢀC; MS (API-ES, positive), m/z: 384
([MþH]þ), 406 ([MþNa]þ); 1H NMR d: 7.00 (d, J ¼ 10.0
Hz, 1H, Ph-H), 4.11 (s, 3H, Pyr-CH3), 3.08 (s, 3H, NCH3).
Anal. Calcd. for C13H7Cl2F4N3O2 (384.1): C, 40.65; H, 1.84;
N, 10.94. Found: C, 40.97; H, 2.00; N, 10.28.
methyl-4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-benzox-
azole (13a). Under nitrogen a mixture of 12a (680 mg, 1.78
mmol), iron (1.0 g, 0.017 mol), and acetic acid (35 mL) were
stirred at 80ꢀC for 3 h. The reaction solution was filtrated and
the filtrate was poured into water, filtrated, and washed with
water, recrystallized with ethanol. 13a was obtained in 74%
yield as a white solid; m.p. 124.9–126.9ꢀC; MS (API-ES, posi-
tive), m/z: 334 ([MþH]þ), 356 ([MþNa]þ); H NMR d: 7.27
1
(s, 1H, Pyr-H), 7.21 (d, J ¼ 10.8 Hz, 1H, Ph-H), 4.14 (s, 3H,
Pyr-CH3), 2.73 (s, 3H, Oxa-CH3). Anal. Calcd. for
C13H8ClF4N3O (333.7): C, 46.79; H, 2.42; N, 12.59. Found:
C, 46.84; H, 2.41; N, 12.72.
7-Chloro-4-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyra-
zol-3-yl)-5-fluoro-2-methyl-benzoxazole (13b). The compound
was obtained in 70% yield as a light yellow paste; MS (API-
ES, positive), m/z: 368 ([MþH]þ), 390 ([MþNa]þ); H NMR
1
d: 7.23 (d, J ¼ 9.6 Hz, 1H, Ph-H), 4.11 (s, 3H, Pyr-CH3), 2.70
(s, 3H, Oxa-CH3). Anal. Calcd. for C13H7Cl2F4N3O (368.1):
C, 42.42; H, 1.92; N, 11.41. Found: C, 42.53; H, 1.94; N,
11.40.
4-(4-Bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-7-
chloro-5-fluoro-2-methyl-benzoxazole (13c). The compound
was obtained in 74% yield as a white powder; m.p. þ139.4–
140.9ꢀC; MS (API-ES, positive), m/z: 412 ([MþH] ); 1H
NMR d: 7.23 (d, J ¼ 9.6 Hz, 1H, Ph-H), 4.13 (s, 3H, Pyr-
CH3), 2.70 (s, 3H, Oxa-CH3). Anal. Calcd. for
C13H7BrClF4N3O (412.6): C, 37.85; H, 1.71; N, 10.19. Found:
C, 38.08; H, 1.71; N, 10.32.
4-(4-Bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-7-
chloro-5-fluoro-3-methy-3H-benzoxazol-2-one (15c). The com-
pound was obtained in 28% yield as a light yellow powder;
m.p. 126.8–128.9ꢀC; MS (API-ES, positive), m/z: 428
General procedure for 14a–14c. 7-Chloro-5-fluoro-4-(1-
methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-3H-benzoxazol-2-one
(14a). A solution of 11a (600 mg, 1.94 mmol) in toluene
(6 mL) was added dropwise to a solution of triphosgene
(210 mg, 0.71 mmol) in toluene (2 mL). After the reaction
solution was stirred at room temperature for 1 h, triethylamine
(0.2 mL) was added. Stirred for 0.5 h, the reaction solution
was poured into water. The organic layer was washed with a
solution of 5% sodium bicarbonate and water, dried over anhy-
drous magnesium sulfate and concentrated under vacuum.
After recrystallization with ethanol, 14a was obtained in 69%
yield as a light brown powder; m.p. 213.6–215.2ꢀC; MS (API-
1
([MþH]þ), 450 ([MþNa]þ); H NMR d: 6.99 (d, J ¼ 9.6 Hz,
1H, Ph-H), 4.13 (s, 3H, Pyr-CH3), 3.05 (s, 3H, NCH3). Anal.
Calcd. for C13H7BrClF4N3O2 (428.6): C, 36.43; H, 1.65; N,
9.80. Found: C, 36.46; H, 1.68; N, 9.55.
3-Allyl-7-chloro-5-fluoro-4-(1-methyl-5-trifluoromethyl-1H-
pyrazol-3-yl)-3H-benzoxazol-2-one (15d). The compound was
obtained in 33% yield as a white powder; m.p. 93.3–95.2ꢀC;
MS (API-ES, positive), m/z: 376 ([MþH]þ), 398 ([MþNa]þ);
1H NMR d: 6.98 (d, J ¼ 10.0 Hz, 1H, Ph-H), 6.80 (s, 1H,
Pyr-H), 5.44 (m, 1H, CH¼CH2), 4.96 (d, J ¼ 10.4 Hz, 1H, 1/
2 CH2¼), 4.68 (d, J ¼ 17.2 Hz, 1H, 1/2 CH2¼), 4.47 (d, J ¼
ES, positive), m/z: 336 ([MþH]þ), 358 ([MþNa]þ); H NMR
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

20
N. Xue, Y. Zhou, G. Wang, W. Miao, and J. Qu
Vol 47
5.2 Hz, 2H, N-CH2), 4.09 (s, 3H, Pyr-CH3). Anal. Calcd. for
C15H10ClF4N3O2 (375.7): C, 47.95; H, 2.68; N, 11.18. Found:
C, 48.11; H, 2.69; N, 11.09.
O-CH2), 4.11 (s, 3H, Pyr-CH3). Anal. Calcd. for
C15H10ClF4N3O2 (375.7): C, 47.95; H, 2.68; N, 11.18. Found:
C, 48.24; H, 2.86; N, 10.79.
3-Allyl-7-chloro-4-(4-chloro-1-methyl-5-trifluoromethyl-1H-
pyrazol-3-yl)-5-fluoro-3H-benzoxazol-2-one (15e). The com-
pound was obtained in 36% yield as a light brown powder;
m.p. 89.4–91.3ꢀC; MS (API-ES, positive), m/z: 410
([MþH]þ), 432 ([MþNa]þ); 1H NMR d: 7.02 (d, J ¼ 10.0
Hz, 1H, Ph-H), 5.44 (m, 1H, CH¼CH2), 4.99 (d, J ¼ 10.4 Hz,
1H, 1/2 CH2¼¼), 4.67 (d, J ¼ 16.8 Hz, 1H, 1/2 CH2¼), 4.31
(d, J ¼ 17.2 Hz, 2H, N-CH2), 4.10 (s, 3H, Pyr-CH3). Anal.
Calcd. for C15H9Cl2F4N3O2 (410.2): C, 43.93; H, 2.21; N,
10.25. Found: C, 44.33; H, 2.49; N, 9.86.
2-(Allyloxy)-7-chloro-4-(4-chloro-1-methyl-5-trifluoromethyl-
1H-pyrazol-3-yl)-5-fluoro-benzoxazole (16e). The compound
was obtained in 13% yield as transparent pasty matter. MS
1
(API-ES, positive), m/z: 410 ([MþH]þ); H NMR d: 7.08 (d,
J ¼ 10.0 Hz, 1H, Ph-H), 6.05 (m, 1H, CH¼CH2), 5.50 (d, J ¼
14.8 Hz, 1H, 1/2 CH2¼), 5.39 (d, J ¼ 9.6 Hz, 1H, 1/2 CH2¼),
5.05 (d, J ¼ 6.0 Hz, 2H, O-CH2), 4.10 (s, 3H, Pyr-CH3). Anal.
Calcd. for C15H9Cl2F4N3O2 (410.2): C, 43.93; H, 2.21; N,
10.25. Found: C, 44.00; H, 2.07; N, 9.84.
2-(Allyloxy)-4-(4-bromo-1-methyl-5-trifluoromethyl-1H-pyr-
azol-3-yl)-7-chloro-5-fluoro-benzoxazole (16f). The compound
was obtained in 16% yield as transparent pasty matter. MS
(API-ES, positive), m/z: 454 ([MþH]þ), 476 ([MþNa]þ); 1H
NMR d: 7.08 (d, J ¼ 10.0 Hz, 1H, Ph-H), 6.06 (m, 1H,
CH¼CH2), 5.50 (d, J ¼ 17.2 Hz, 1H, 1/2 CH2¼), 5.38 (d, J ¼
10.4 Hz, 1H, 1/2 CH2¼), 5.05 (d, J ¼ 6.0 Hz, 2H, O-CH2),
4.12 (s, 3H, Pyr-CH3). Anal. Calcd. for C15H9BrClF4N3O2
(454.6): C, 39.63; H, 2.00; N, 9.24. Found: C, 39.72; H, 1.93;
N, 9.09.
General procedure for 17a–17c. 7-Chloro-5-fluoro-4-(1-
methyl-5-trifluoromethyl-1H-pyrazol-3-yl)benzoxazole (17a). A
mixture of 11a (500 mg, 1.62 mmol), ethylorthoformate
(0.4 mL, 2.42 mmol), Celite (160 mg) and toluene (15 mL)
was stirred under nitrogen at 110ꢀC for 18 h. Celite was fil-
tered and filtrate was concentrated under vacuum. The crude
product was purified by silica gel chromatography with eluent
(petroleum ether:ethyl acetate ¼ 6:1). 17a was obtained in
42% yield as a light yellow powder; m.p. 158.3–160.5ꢀC; MS
(API-ES, positive), m/z: 320 ([MþH]þ), 342 ([MþNa]þ); 1H
NMR d: 8.25 (s, 1H, Oxa-H), 7.35 (s, 1H, Pyr-H), 7.33 (d,
J ¼ 10.0 Hz, 1H, Ph-H), 4.15 (s, 3H, Pyr-CH3). Anal. Calcd.
for C12H6ClF4N3O (319.6): C, 45.09; H, 1.89; N, 13.15.
Found: C, 45.42; H, 2.04; N, 12.75.
3-Allyl-4-(4-bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-
yl)-7-chloro-5-fluoro-3H-benzoxazol-2-one (15f). The compound
was obtained in 42% yield as a white powder; m.p.þ130.2–
132.0ꢀC; MS (API-ES, positive), m/z: 454 ([MþH] ), 476
1
([MþNa]þ); H NMR d: 7.01 (d, J ¼ 9.6 Hz, 1H, Ph-H), 5.42
(m, 1H, CH¼CH2), 5.00 (d, J ¼ 10.4 Hz, 1H, 1/2 CH2¼), 4.69
(d, J ¼ 16.8 Hz, 1H, 1/2 CH2¼), 4.37 (m, 1H,1/2 N-CH2),
4.19 (m, 1H,1/2 N-CH2), 4.12 (s, 3H, Pyr-CH3). Anal. Calcd.
for C15H9BrClF4N3O2 (454.6): C, 39.63; H, 2.00; N, 9.24.
Found: C, 39.41; H, 1.98; N, 9.19.
General procedure for 16a–16f. A mixture of 14a (600
mg, 1.62 mmol), methyl iodide (0.51 g, 3 mmol), and sliver(I)
oxide (417 mg, 1.80 mmol) in methylene chloride (50 mL)
was stirred at ambient temperature for 24 h. Sliver(I) oxide
was filtered and filtrate was concentrated under vacuum. The
crude product was purified by silica gel chromatography with
eluent (petroleum ether:ethyl acetate ¼ 6:1).
7-Chloro-5-fluoro-2-methoxy-4-(1-methyl-5-trifluoromethyl-
1H-pyrazol-3-yl)-benzoxazole (16a). The compound was
obtained in 42% yield as a light yellow powder; m.p.þ129.7–
132.1ꢀC; MS (API-ES, positive), m/z: 350 ([MþH] ), 372
([MþNa]þ); 1H NMR d: 7.31 (s, 1H, Pyr-H), 7.08 (d, J ¼
11.6 Hz, 1H, Ph-H), 4.31 (s, 3H, OCH3), 4.12 (s, 3H, Pyr-
CH3). Anal. Calcd. for C13H8ClF4N3O2 (349.7): C, 44.65; H,
2.31; N, 12.02. Found: C, 44.58; H, 2.45; N, 12.01.
7-Chloro-4-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-
3-yl)-5-fluoro-benzoxazole (17b). The compound was obtained
in 30% yield as a light brown powder; m.p. 110.7–112.1ꢀC;
7-Chloro-4-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-
3-yl)-5-fluoro-2-methoxy-benzoxazole (16b). The compound
was obtained in 19% yield as a light yellow pasty matter. MS
(API-ES, positive), m/z: 384 ([MþH]þ), 406 ([MþNa]þ); 1H
NMR d: 7.08 (d, J ¼ 10.0 Hz, 1H, Ph-H), 4.24 (s, 3H,
OCH3), 4.10 (s, 3H, Pyr-CH3). Anal. Calcd. for
C13H7Cl2F4N3O2 (384.1): C, 40.65; H, 1.84; N, 10.94. Found:
C, 40.41; H, 1.89; N, 10.51.
4-(4-Bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-7-
chloro-5-fluoro-2-methoxy-benzoxazole (16c). The compound
was obtained in 45% yield as a light yellow pasty matter. MS
(API-ES, positive), m/z: 428 ([MþH]þ), 450 ([MþNa]þ); 1H
NMR d: 7.08 (d, J ¼ 10.0 Hz, 1H, Ph-H), 4.24 (s, 3H,
OCH3), 4.13 (s, 3H, Pyr-CH3). Anal. Calcd. for
C13H7BrClF4N3O2 (428.6): C, 36.43; H, 1.65; N, 9.80. Found:
C, 36.73; H, 1.79; N, 9.58.
2-(Allyloxy)-7-chloro-5-fluoro-4-(1-methyl-5-trifluoromethyl-
1H-pyrazol-3-yl)benzoxazole (16d). The compound was obtained
in 19% yield as a white powder; m.p. 122.4–123.4ꢀC; MS
(API-ES, positive), m/z: 376 ([MþH]þ), 398 ([MþNa]þ); 1H
NMR d: 7.32 (s, 1H, Pyr-H), 7.08 (d, J ¼ 11.2 Hz, 1H, Ph-H),
6.09 (m, 1H, CH¼CH2), 5.55 (d, J ¼ 16.8 Hz, 1H, 1/2 CH2¼),
5.42 (d, J ¼ 10.4 Hz, 1H, 1/2 CH2¼), 5.13 (d, J ¼ 6.0 Hz, 2H,
1
MS (API-ES, positive), m/z: 354 ([MþH]þ); H NMR d: 8.22
(s, 1H, Oxa-H), 7.35 (d, J ¼ 9.6 Hz, 1H, Ph-H), 4.13 (s, 3H,
Pyr-CH3). Anal. Calcd. for C12H5Cl2F4N3O (354.1): C, 40.70;
H, 1.42; N, 11.87. Found: C, 40.34; H, 1.67; N, 11.54.
4-(4-Bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-7-
chloro-5-fluoro-benzoxazole (17c). The compound was obtained
in 23% yield as a light yellow powder; m.p. 92.1–93.3ꢀC; MS
(API-ES, positive), m/z: 398 ([MþH]þ); 1H NMR d: 8.21 (s,
1H, Oxa-H), 7.35 (d, J ¼ 9.6 Hz, 1H, Ph-H), 4.14 (s, 3H, Pyr-
CH3). Anal. Calcd. for C12H5BrClF4N3O (398.5): C, 36.16; H,
1.26; N, 10.54. Found: C, 36.43; H, 1.56; N, 10.45.
Herbicidal activity test. The target plants for the test were
Setaria viridis (Linn.), Digitaria sanguinalis (Linn.) Scop. and
Abutilon theophrasti Medic.A solution of new compounds or
check sample (Fomesafen or Fluazolate) in a small amount of
acetone was diluted with stewing tap water which containing
0.1% Tween 80. The solution of the compound to be tested
was prepared. Weeds (Setaria viridis (Linn.), Digitaria sangui-
nalis (Linn.) Scop. and Abutilon theophrasti Medic., two or
three leaf stage) which growth well and the same leaf stage
were selected, and were spray treated with atomizing machine.
The amount of spray was 600 L/hm2. After that the weeds
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Syntheses and Herbicidal Activity of Pyrazolyl Benzoxazole Derivatives
21
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6,121,458 (2000); (b) Hamper, B. C.; Mao, M. K.; Phillips, W. G.
Chem Abstr 2000, 130, 168364.
were aeration-drying and then were cultured at room tempera-
ture. Weeds treated with water were the blank test. The herbi-
cidal activity of the compounds was determined after 10 days
of treatment. Evaluations were based on a score of 0–10 in
which 0 ¼ no activity and 10 ¼ total kill.
[12] Huang, M. Z.; Huang, K. L.; Ren, Y. G.; Lei, M. X.;
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´
[14] Macfas, F. A.; Marın, D.; Oliveros-Bastidas, A.; Castellano,
Acknowledgments. This work was supported financially by the
National Natural Science Foundation of China (No. 20606005),
the Doctor Foundation of Liaoning Province, China (No.
20031068) and the Program for Changjiang Scholars and Innova-
tive Research Team in University (No. IRT0711).
D.; Simonet, A. M.; Molinillo, J. M. G. J Agric Food Chem 2006, 54,
1040.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet