Synthesis and herbicidal activity of phenyl-substituted benzoylpyrazoles

Article abstract of DOI:10.1002/ps.588

A novel series of substituted 3-phenyl benzoylpyrazoles were prepared and tested as potential grass herbicides. The targeted materials were prepared by three newly developed synthetic routes, which allowed a comprehensive study of the SAR (structure-activity relationships) of this series. The best combination of grass weed activity (Avena fatua L, Setaria viridis (L) Beauv and Alopecurus myosuroides Huds) and wheat selectivity was obtained with an alkoxy group in the 4-position of the phenyl ring. Activity was further enhanced by the presence of tert-butyl on the pyrazole and a methyl group at the C-2 position of the benzoyl moiety. The alkoxy-substituted 3-phenylbenzoylpyrazoles are a novel class of herbicides with potential utility for control of important grass weeds in cereals.

Full text of DOI:10.1002/ps.588

Pest Management Science
Pest Manag Sci 58:1175–1186 (online: 2002)
DOI: 10.1002/ps.588
Synthesis and herbicidal activity of
phenyl-substituted benzoylpyrazoles
Thomas L Siddall, David G Ouse, Zoltan L Benko, Gail M Garvin,
Johnny L Jackson, Jeffrey M McQuiston, Michael J Ricks, Thomas D Thibault,
James A Turner,* John C VanHeertum and Monte R Weimer
Dow AgroSciences LLC, 9330 Zionsville Rd, Indianapolis, IN 46268-1054, USA
Abstract: A novel series of substituted 3-phenyl benzoylpyrazoles were prepared and tested as potential
grass herbicides. The targeted materials were prepared by three newly developed synthetic routes,
which allowed a comprehensive study of the SAR (structure–activity relationships) of this series. The
best combination of grass weed activity (Avena fatua L, Setaria viridis (L) Beauv and Alopecurus
myosuroides Huds) and wheat selectivity was obtained with an alkoxy group in the 4-position of the
phenyl ring. Activity was further enhanced by the presence of tert-butyl on the pyrazole and a methyl
group at the C-2 position of the benzoyl moiety. The alkoxy-substituted 3-phenylbenzoylpyrazoles are
a novel class of herbicides with potential utility for control of important grass weeds in cereals.
# 2002 Society of Chemical Industry
Keywords: herbicide; benzoylpyrazoles; hydroxyphenylpyruvate dioxygenase inhibitors
1
INTRODUCTION
diketonitrile, formed by base-catalyzed opening of the
isoxazole ring of isoxaflutole, has been shown to be the
actual herbicidal species,11,12 the isoxazole thus
functioning as a pro-form for yet another class of
diketones.7 Bioactivity of these diketone herbicides
results from an inhibition of 4-hydroxyphenylpyruvate
dioxygenase (HPPD), the enzyme which catalyzes the
formation of homogentisic acid.7,12–15 In plants
homogentisic acid is the precursor to important plant
quinones such as the plastoquinones16 which, in turn,
function as cofactors in the biosynthesis of caro-
tenoids.14 The latter are essential for protection of the
plant from light-induced radical degradation pro-
cesses. Thus, it is believed that the inability of the
treated plants to generate such quinones is responsible
for the intense bleaching symptoms typically observed
from these compounds. Ultimately plant death occurs
through some type of radical-mediated event.14
The benzoylpyrazole area of chemistry represents a
relatively new class of highly active, bleaching herbi-
cides (Fig 1; 1). The area, which was originally
discovered by Sankyo, is exemplified by two commer-
cial rice herbicides, pyrazolate1 and pyrazoxyfen.2
Each of these materials is a pro-drug for a common
active ingredient, DTP,1,3 a hydroxybenzoylpyrazole
in which a 2,4-dichloro-substituted benzoyl is attached
to a dimethyl-substituted hydroxypyrazole. The activ-
ity of these simple members of the series is rather
modest and, as a result, their utility has been some-
what limited. The benzoylpyrazole area was greatly
expanded when chemists at Nissan discovered that
activity in the series is significantly enhanced with the
presence of more complex electron-withdrawing sub-
stituents on the benzene ring (Fig 1).4,5 They, and
we,6 have shown that certain members of this family of
chemistry deliver an attractive combination of desir-
able attributes, including necrosis and plant death,
activity against both grass and broadleaf weeds,
phloem mobility, pre- and post-emergent application
flexibility, selectivity in important crops and a rela-
tively unexploited mode-of-action.
Through structural comparisons and other observa-
tions, we, and others,7 have concluded that the
pharmacophore for the diketone series of HPPD
inhibitors includes an electron-deficient enolizable
b-dicarbonyl system, a lipophilic, electron-deficient
benzene attached to one of these carbonyls, and an
ortho substituent on the benzene ring. Structure–
activity studies within the benzoylpyrazole series have
shown that highest levels of overall herbicidal activity
are attained when: (a) the nitrogen of the pyrazole (1,
R; Fig 1) is substituted with a relatively small alkyl
group; (b) the ortho substituent (X) on the benzene is a
halogen or small alkyl; (c) there is a methyl sulfone
Benzoylpyrazoles are a subset of a larger class of
‘diketone’ herbicides7 (Fig 1) which includes the
benzoylcyclohexanediones, originally discovered by
Stauffer and recently commercialized by Syngenta
(originally Zeneca) in the form of sulcotrione8 and
mesotrione,9 and the benzoylisoxazoles, typified by the
Aventis herbicide, isoxaflutole.10,11 In the latter case, a
* Correspondence to: James A Turner, Dow AgroSciences LLC, 9330 Zionsville Rd, Indianapolis, IN 46268-1054, USA
E-mail: jaturner@dowagro.com
(Received 16 January 2002; revised version received 25 April 2002; accepted 3 July 2002)
# 2002 Society of Chemical Industry. Pest Manag Sci 1526–498X/2002/$30.00
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TL Siddall et al
Figure 1. Representative examples of
the diketone class of HPPD inhibitors.
attached at the C-4 position of the benzene. The most
active compounds also contain a substituent at the
meta position (Y) on the benzene, ie the benzene is
1,2,3,4-tetrasubstituted. However, it is difficult to
draw any definitive conclusions concerning the opti-
mal nature of the C-3 substituent on the benzoyl, as
benzoylpyrazoles containing a wide variety of groups at
C-3 (including alkyl, alkoxy, amine, carboxylate and
sulfone) have exhibited very high levels of herbicidal
activity.
chemical (basicity, reactivity) properties. Thus, we
suspected that the enhanced grass activity of the
3-morpholino benzoylpyrazoles, as compared to their
acyclic analogs, was somehow related to the cyclic
nature of the morpholine group. If this hypothesis
were valid, then substitution of the morpholine with
another cyclic moiety might yield compounds with
similar high levels of cool-season grass activity.
Conceptually, one of the simplest and most direct
approaches to test this hypothesis was to replace the
morpholine with an aromatic system, such as a phenyl
(eg 4). In the event, we discovered that certain
3-phenyl-subsituted benzoylpyrazoles provided out-
standing control of important cool-season grass weeds
with excellent selectivity to wheat. In this report, we
describe the preparation of an extensive series of such
phenyl-substituted benzoylpyrazoles (Fig 2) and their
herbicidal properties.
During optimization of the 3-amino series of
benzoylpyrazoles6,17 we discovered that the addition
of certain cyclic amines at the 3-position of the
benzene, most notably morpholine, provided much
better cool-season grass activity than their close acyclic
amino analogs. For example, formation of a bond
between the two methyl groups of the (methoxyethyl)-
methylamino substituent on benzoylpyrazole 2, to give
morpholine 3a, resulted in a significant (>10-fold)
increase in activity against Avena fatua L (AVEFA,
Table 1). However, despite extensive synthetic work in
the cyclic amine series, none of the grass active analogs
synthesized had the necessary levels of safety to
relevant grass crops, such as wheat (Triticum aestivum
L, TRZAS).
2
EXPERIMENTAL
2.1 Synthesis
Three routes were devised for preparation of the
3-phenyl-substituted benzoylpyrazoles. A representa-
tive example of each is described in detail in Section 5.
The method of preparation and melting point for each
targeted product is included in the tables.
A priori, analogous cyclic or acyclic amino-sub-
stituted benzoylpyrazoles might not be expected to
have significantly different physical (eg logP) or
2.1.1 Phenyl-substituted benzoylpyrazoles—Method A
A general, one-step route (Fig 3) was used for prepara-
tion of most of the 3-phenyl-susbtituted benzoylpyra-
zole targets. This route proved to be ideal for analog
synthesis as the phenyl group, along with its sub-
stituent, was introduced onto a common, advanced
benzoylpyrazole intermediate (11) through Suzuki
condensation18 with an appropriately substituted
phenylboronic acid. Optimal reaction conditions
included a typical palladium–phosphine catalyst sys-
tem with potassium carbonate as base in refluxing
aqueous acetonitrile. In general, the reaction worked
well with boronic acids that were substituted with
electron-donating substituents; boronic acids contain-
ing only electron-withdrawing substituents tended to
give lower yields. Many of the boronic acids used in
Table 1. Comparison of the post-emergent cool-season grass activity of a C-
3-morpholine substituted benzoylpyrazole versus its acyclic analog
AVEFA a
GR80 (mg literꢀ1
ALOMY a
b
Compound No
)
2
3a
>31
2.6
>31
8.0
a AVEFA=Avena fatua; ALOMY=Alopecurus myosuroides.
b Concentration which produced 80% visual injury.
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Phenyl-substituted benzoylpyrazoles
Figure 2. Compounds discussed in the
text.
Figure 3. Method A for preparation of
3-phenylbenzoylpyrazoles.
this series were commercially available. The remaining
phenylboronic acids were prepared in standard fashion
by metallation of the corresponding bromobenzene
followed by boronation with tri-isopropyl borate.19
conditions with either iodobenzoylpyrazole 4 or iodo-
benzoic acid 5. Attempts to overcome this limitation,
using conditions reported for sterically encumbered
Suzuki reaction partners,20–22 likewise met with limited
success. Thus, a separate route for preparation of the
ortho-substituted 3-phenylbenzoylpyrazoles was de-
vised in which the biphenyl moiety was formed at an
early stage in the synthetic sequence (Fig 5)
2.1.2 Phenyl-substituted benzoylpyrazoles—Method B
The 3-iodo-substituted benzoic acid 12 was used in a
second, related method for formation of phenyl-
substituted benzoylpyrazoles. In this instance (Fig 4)
the phenyl group was added by Suzuki condensation
between the appropriate phenylboronic acid and the
iodobenzoic acid 12, and the benzoylpyrazole then
formed in a subsequent series of transformations. This
route was particularly useful for preparation of
benzoylpyrazoles with non-standard (eg methyl or
isopropyl) pyrazole substituents.
2.1.4 Intermediate 3-iodobenzoylpyrazoles 11 (for
Method A) and 3-iodobenzoic acids 12 (for Method B)
The requisite intermediate 3-iodobenzoylpyrazoles 11
and 3-iodobenzoic acid 12a were prepared as illu-
strated in Fig 6.
2.2 Biological testing
Seeds were planted in 10-cm square pots filled with a
high organic soil media, Metro mix 360. Plants were
propagated under greenhouse conditions of 18°C day
and night temperature. Natural light was supple-
mented with greenhouse metal halide lamps to a
2.1.3 Synthesis of phenyl-substituted benzoylpyrazoles—
Method C
Ortho-substituted phenylboronic acids failed to react,
presumably for steric reasons, under typical Suzuki
Figure 4. Method B for preparation of
3-phenylbenzoylpyrazoles. (a) X-
PhB(OH)2, Pd(OAc)2, P(o-Tol)3; (b)
SOCl2; (c) 1,3-dialkyl-5-
hydroxypyrazole, NEt3; (d) base, cat
CNꢀ.
Pest Manag Sci 58:1175–1186 (online: 2002)
1177

TL Siddall et al
Figure 5. Method C for preparation of
ortho-substituted 3-phenyl
benzoylpyrazoles. (a) X—PhB(OH)2,
K2CO3, Pd(OAc)2, P(o-Tol)3,
glyme–H2O–EtOH, 80°C (60–95%);
(b) H2, Pd(C), EtOH (90–95%);
(c) KSCN, Br2, MeOH–CH2Cl2, 0–5°C
(90–100%); (d) NaNO2, HCl; KI,
5–10°C, H2O–CH2Cl2 (70–100%);
(e) NaOMe, MeOH; MeI (80–95%);
(f) MCPBA, CH2Cl2 (80–100%);
(g) CO, Et3N, Pd(OAc)2, P(o-Tol)3,
CH3CN, 115°C (30–40%).
16-h day length. Plant material was overhead watered
prior to spraying. Plant material ranged from 1.5 to 2.5
leaves at the time of treatment. After treatment, plants
were returned to the greenhouse under the standard
growing condition of 18°C.
Visual assessments of weed control and crop injury
were made 3 weeks after application. In several tests,
crop injury was evaluated 1 week after treatment since
this tended to be the time when injury was at its highest
level in the greenhouse. Plant injury was visually
assessed on a scale of 0 to 100% with 0 equal to no
injury and 100 equal to complete kill. Herbicidal data
are reported as GR80, the concentration that caused
80% visual injury to the weed or, in the case of wheat,
as GR20, the concentration which caused 20% injury.
Samples of test chemicals were weighed into 25-ml
glass vials. The amount weighed depended on the high
rate in the test (eg 60mg of test material was added to
provide a rate of 512ghaꢀ1). A concentrated stock
solution was made by adding 2.2ml of acetoneþ
dimethyl sulfoxide (DMSO), (97þ3 by volume) to the
weighed sample. Most of the samples dissolved
readily, but gentle warming or sonication was occa-
sionally needed. Spray solutions were formulated at
five rates with a high rate (x) and four half-fold
dilutions (1/2x, 1/4x, 1/8x, and 1/16x). The solutions
were prepared by injecting aliquots of the stock
solution into a mixture comprised of deionized water
þacetoneþisopropyl alcoholþDMSOþcrop oil con-
centrate (COC)þTriton X-155 (38.8þ48.5þ10þ
1.5þ1þ0.02 by volume) to deliver 10ml of spray
solution. The solutions containing the highest con-
centration to be tested were prepared by diluting 1-ml
aliquots of the stock solution with 9ml of the mixture
and lower concentrations were prepared accordingly.
Solutions were applied with a mechanized track-
sprayer operated at 3.2km hꢀ1 with a spray height of
3
RESULTS AND DISCUSSION
Two probe 3-phenylbenzoylpyrazoles (4), each con-
taining a simple unsubstituted phenyl moiety, were
prepared for comparison with the corresponding
morpholine-substituted benzoylpyrazole lead com-
pounds. In each instance, the only other structural
variable was the pyrazole nitrogen substituent (ethyl or
tert-butyl). This comparison (Table 2) clearly showed
that the herbicidal activity of the two phenyl analogs
against two key grass species, AVEFA and ALOMY
(Alopecurus myosuroides Huds) was roughly equivalent
to that of the corresponding cyclic amines, and verified
our original proposal that the morpholine group could
be replaced with other cyclic systems while still
maintaining cool-season grass activity. Such a simple
modification failed to deliver the desired improvement
51cm and an application volume of 187 literhaꢀ1
.
Figure 6. Preparation of the key
intermediate iodobenzoylpyrazoles 11a
(for Method A) and iodobenzoic acid
12a (for Method B). (a) (CH3SO2)2O,
cat Tf2O, 120°C; (b) CO, NaHCO3,
10:1 t-BuOH:H2O, Pd(OAc)2, 1,4-
bis(diphenylphosphino)butane, 125°C;
(c) NH4OH, CuO, 180°C; (d) 1. NaNO2,
H2SO4, 2. KI; (e) 1. SOCl2, 2. 1-alkyl-5-
hydroxypyrazole, NEt3, 3. NEt3, cat
CNꢀ.
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Phenyl-substituted benzoylpyrazoles
Table 2. Comparison of the post-emergence activity of 3-morpholino- versus 3-phenyl-substituted benzoylpyrazole
TRZAS a
AVEFA a
ALOMY a
b
b
No
X
Y
R
GR20 (mg literꢀ1
)
GR80 (mg literꢀ1
)
3a
4a
3b
4b
5a
Cl
4-Morpholine
Phenyl
CH2CH3
CH2CH3
tert-Bu
2.0
2.6
<1
3.3
14
7.8
Cl
>250
16
Cl
4-Morpholine
Phenyl
3.9
3.9
12
Cl
tert-Bu
<1
12
CH3
Phenyl
CH2CH3
0.8
47
a
TRZAS=wheat (Triticum aestivum); AVEFA=Avena fatua; ALOMY=Alopecurus myosuroides.
b
Concentration which produced either 20% (GR20) or 80% (GR80) visual injury.
in selectivity to wheat. However, the literature is
replete with examples of wheat herbicides whose
selectivity to the crop results from differential oxida-
tion in wheat (but not in the weeds) either directly on
an aromatic ring (ring hydroxylation) or on an
attached alkyl group.23 Thus, modification of the
phenyl ring substituent(s) was seen as a potential
solution to the wheat selectivity issue.
the grass weeds, while causing unacceptable damage to
the wheat. Two other analogs in this series, 4-F (5b)
and 4-CN (5i), provided fair to good activity on all the
target weed species, but neither was selective to wheat.
We concluded that the 4-alkoxy substituents were
unique in their ability to combine attractive levels of
grass activity with crop selectivity.
While a variety of substituents were prepared at the
meta position of the phenyl group, the focus of this
series was again directed towards alkoxy groups.
However, most of these materials were, at best, weakly
active against the grass weed targets (6, Table 4). Only
two analogs, 3-fluoro (6a) and 3-isopropyl (6e),
provided reasonable levels of activity against AVEFA,
but in each case the crop selectivity was poor. Clearly,
the trend for increased activity with alkoxy substitu-
ents was not replicated in the meta-alkoxy series.
Synthetic difficulties precluded an extensive survey
of substituents on the ortho position of the phenyl
group. Furthermore, of the few ortho-substituted
materials that were prepared (Table 5), only 7d,
containing an ortho-methoxy substituent, resulted in a
significant degree of crop selectivity, but at a sub-
stantial cost in grass activity.
Initial optimization of the 3-phenylbenzoylpyrazole
series focused on varying the nature of the substituent
on the phenyl ring while keeping the other benzoyl-
pyrazole substituents constant. Thus, for consistency
of data comparison, each of these initial examples
contained an ethyl group on the nitrogen of the
pyrazole, a methyl-sulfone at the 4-position of the
benzoyl and a methyl group at the 2-position of the
benzoyl (5–8, Fig 2). The latter was chosen over
chlorine at C-2 for two reasons. First, a simple
comparison between chlorine (4a) and methyl (5a)
at C-2, using an unsubstituted phenyl at C-3, showed
that the methyl-substituted derivative provided a
higher level of herbicidal activity with little differentia-
tion in level of wheat selectivity (Table 2). Second,
compounds in the C-2 methyl series were typically
synthetically more accessible than the corresponding
chloro-substituted materials.
For synthetic reasons, only two 2,4-disubstituted
analogs were prepared, both containing the preferred
4-methoxy substituent. Neither of these materials,
however, demonstrated a significant level of activity at
the rate of 256ghaꢀ1 (8a–b, Table 6).
3.1 Structure-activity relationships of the phenyl
substituent
The bulk of the analogs in the phenyl series were
prepared with a substituent in the 4-position of the
benzene (5, Table 3). This was, in part, a result of the
ready availability of many of the key para-substituted
phenylboronic acid intermediates. More important,
however, was the discovery that certain para substi-
tuents on the benzene ring resulted in wheat-selective
compounds in which grass weed activity was not
compromised. Most notable was the excellent wheat
selectivity and very good AVEFA activity seen with
most members of the 4-alkoxy series (5m–t, Table 3).
Unfortunately, most other materials with para sub-
stituents (including chlorine, alkyls, trifluoromethyl,
or methyl-sulfone) were only weakly active, at best, on
The trend for excellent crop tolerance with a 4-
methoxy substituent was evident in the corresponding
3,4-disubstituted (8c–l, Table 6) examples as well. Of
these,the3,4-dimethoxy-substituted3-phenylbenzoyl-
pyrazole (8f) provided the best combination of activity
and selectivity, rivaling that of the corresponding C-4
mono-methoxy analog (5m). None of the remaining
disubstituted analogs (8m–p) provided the requisite
combination of grass activity and wheat selectivity.
3.2 Optimization of the pyrazole substituent
Earlier studies in the benzoylpyrazole series had shown
that the nature of the alkyl substituent on the pyrazole
nitrogen can have a significant affect on both herbi-
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TL Siddall et al
Table 3. Post-emergence activity of para-substituted 3-phenylbenzoylpyrazolesa
TRZAS b
AVEFA b
SETVI b
c
c
No
mp (°C)
X
GR20 (ghaꢀ1
)
GR80 (ghaꢀ1
)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
151–152
195–197
209–210
197–198
167–169
155–156
179–181
155–156
192–193
160–161
232–233
203–205
147–148
164
H
<8
<32
53
12
40
>128
F
<32
93
Cl
CH3
>128
>128
454
463
>256
>128
<32
>256
>256
>256
63
25
52
CH2CH3
i-Pr
127
80
217
<64
>256
24
CH=CH2
CF3
CN
>256
19
<32
>256
45
108
>256
203
>256
113
141
40
CO2CH3
SO2CH3
OH
>256
>256
>256
>256
>256
<32
>256
>256
42
OCH3
OCH2CH3
O-i-Pr
50
133
43
Foam
OCH2CH=CH2
OCF3
50
139
40
116–118
177–181
140–142
144–146
118
67
OCH2CH2F
OCH2OCH3
OCH2CH2OCH3
152
112
<32
5s
5t
<32
48
a
All materials were prepared by Method A except 5k for which Method B was used.
TRZAS=wheat (Triticum aestivum); AVEFA=Avena fatua; SETVI=Setaria viridis.
b
c Rate which produced either 20% (GR20) or 80% (GR80) visual injury in post-emergence greenhouse testing.
Table 4. Post-emergence activity of meta-substituted 3-phenylbenzoylpyrazolesa
TRZAS b
AVEFA b
SETVI b
c
c
No
mp (°C)
X
GR20 (ghaꢀ1
)
GR80 (ghaꢀ1
)
5a
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
<8
<32
8
12
<32
81
>128
185–187
160–161
138–139
164–166
176–178
157
F
40
>128
83
Cl
CH3
>128
<64
<64
227
>128
130
CH2CH3
i-Pr
80
<64
>256
>256
>256
>256
95
80
OCH3
OCH2CH3
O-i-Pr
>256
>256
>256
>256
64
151
>256
>256
>256
<32
46
165
Foam
OCH2CH=CH2
OCF3
6j
6k
6l
74–76
127–128
166–168
OCH2OCH3
OCH2OCH2OCH3
219
>256
83
<32
112
a
All materials were prepared by Method A.
b
TRZAS=wheat (Triticum aestivum); AVEFA=Avena fatua; SETVI=Setaria viridis.
c Rate which produced either 20% (GR20) or 80% (GR80) visual injury in post-emergence greenhouse testing.
1180
Pest Manag Sci 58:1175–1186 (online: 2002)

Phenyl-substituted benzoylpyrazoles
Table 5. Post-emergence activity of ortho-substituted 3-phenylbenzoylpyr-
pyrazole substituents were varied using one of the
‘best’ phenyl substituents (4-methoxy) from the survey
described above. As can be seen from the results in
Table 7, there was a clear trend for increased activity
on grass weeds as the size of the N-alkyl substituent
increased from methyl through tert-butyl. This corre-
lation fails with sec-butyl substitution, where activity
was nearly totally lost, suggesting that there is a
limitation to the size of the substituent tolerated on the
nitrogen of the pyrazole. In this limited series, there
was no observed difference in the level of crop
selectivity regardless of the nature of the N-alkyl
substituent. An additional methyl substituent on the
carbon of the pyrazole (10d–e) failed to offer any
activity advantages. Furthermore, the combination of
C-methyl and N-tert-butyl substituents on the pyrazole
(10e) resulted in a significant decrease in wheat
selectivity.
azolesa
TRZAS b
AVEFA b SETVI b
c
c
No mp (°C)
X
GR20 (ghaꢀ1
)
GR80 (ghaꢀ1
)
5a
H
F
<8
<32
<32
<16
152
12
43
>128
40
7a 176–177
7b 173–175 Cl
7c 179–180 CH3
7d 181–182 OCH3
<32
22
124
65
66
199
a All materials were prepared by Method C.
b
TRZAS=wheat (Triticum aestivum); AVEFA=Avena fatua; SETVI=Setaria
viridis.
c Rate which produced either 20% (GR20) or 80% (GR80) visual injury in post-
To explore further the effect of the N-pyrazole
substituent upon activity and selectivity, a selection of
phenyl substituents that had provided better levels of
activity in the N-ethylpyrazole series were chosen, and
the corresponding N-tert-butylpyrazole analogs pre-
pared. Most of these tert-butyl-substituted materials
provided very good levels of activity on the target weed
species (Table 8) with the sole exception being the 3,4-
dimethoxy-substituted analog (9f), which was nearly
inactive. The superiority of a methyl group, as
compared to chlorine, at C-2 on the benzoyl is clear
in the comparison of both the activity and selectivity of
9a versus the corresponding chloro analog, 9g.
emergence greenhouse testing.
cidal activity and selectivity. In particular, we have
noted that activity on certain grasses is sometimes
improved with branched alkyl substitutions (isopropyl
or tert-butyl) in comparison to the small straight-chain
alkyls, methyl or ethyl. Initial studies in the unsub-
stituted 3-phenyl series showed a similar trend with the
N-tert-butylpyrazole analog (4b, Table 2) providing
improved grass weed activity relative to the corre-
sponding N-ethylpyrazole (4a).
This observation elicited a study in which the
Table 6. Post-emergence activity of disubstituted 3-phenylbenzoylpyrazoles
TRZAS a
AVEFA a
SETVI a
b
b
No
mp (°C)
Method
X2
X3
X4
X5
GR20 (ghaꢀ1
)
GR80 (ghaꢀ1
)
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
151–152
155–157
152
C
C
A
A
A
A
A
A
A
A
A
A
A
A
A
A
F
—
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
F
—
>256
>256
>256
>256
>256
>256
<32
>256
>256
>256
>256
88
>256
>256
192
Cl
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
F
—
157
Cl
—
136
160–161
192–194
128–130
217–219
208–210
202–204
147–149
199–205
185–187
198–203
197–199
204–205
CH3
OCH3
Cl
—
>256
80
—
40
—
>256
>256
>256
>256
137
>256
127
Cl
Cl
—
67
Cl
CH3
Cl
—
>256
>256
19
>256
129
CH3
OCH3
OCH3
Cl
—
F
—
80
Cl
—
105
>256
256
>256
132
—
Cl
<16
>256
156
Cl
—
CH3
OCH3
CH3
>256
>256
>256
97
Cl
—
>256
183
CH3
—
>256
a
TRZAS=wheat (Triticum aestivum); AVEFA=Avena fatua; SETVI=Setaria viridis.
b Rate which produced either 20% (GR20) or 80% (GR80) visual injury in post-emergence greenhouse testing.
Pest Manag Sci 58:1175–1186 (online: 2002)
1181

TL Siddall et al
Table 7. Effect of pyrazole substitution on the postemergence activity of the 3-(4-methoxyphenyl)benzoylpyrazoles
TRZAS a
AVEFA a
SETVI a
ALOMY a
b
b
No
mp (°C)
Method
X
R1
R2
GR20 (g haꢀ1
)
GR80 (g haꢀ1
)
10a
5m
10b
9a
10c
10d
10e
211–213
147–148
174–175
167–168
177–179
174–176
201–204
B
A
B
A
B
B
B
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
i-Pr
—
—
>256
>256
>256
>256
>256
>256
103
137
60
>256
136
72
>256
>256
94
—
56
tert-Bu
sec-Bu
CH3
—
25
20
63
—
>256
86
<32
112
55
>256
256
CH3
CH3
tert-Bu
<16
214
a
TRZAS=wheat (Triticum aestivum); AVEFA=Avena fatua; SETVI=Setaria viridis; ALOMY=Alopecurus myosuroides.
b Rate which produced either 20% (GR20) or 80% (GR80) visual injury in post-emergence greenhouse testing.
In the optimization of any herbicide series, selecting
the candidate with the best crop safety profile is a key
factor in decision making. In the 3-phenylbenzoylpyr-
azole area, maximum crop injury on wheat was
typically observed at 7–10 days after treatment in the
greenhouse. Therefore, selection of the best candi-
dates was made by comparison of a therapeutic index
of crop safety to level of activity. This therapeutic
index was defined as follows: the wheat GR20 at 7 days
after treatment was divided by the AVEFA GR80 at 21
days after treatment. The SAR of the chemicals
described above clearly indicated that molecules in
the 4-alkoxyphenyl series coupled with an N-tert-butyl
pyrazole substituent provided the best combination of
activity and selectivity (Table 8). The top candidates
in the alkoxy series were sorted using the described
therapeutic index. Of these, the 4-methoxyphenyl
analog (9a) provided the largest therapeutic index
along with an activity level on the three target weed
species that was superior to other candidate 4-alkoxy
derivatives (Tables of 7 and 8). While the therapeutic
indices for the corresponding ethoxy (9b) and meth-
oxymethyl (9e) analogs are slightly inferior to the
methoxy, they still have very good crop safety and
provide a similar level of activity on target weed
species.
4
CONCLUSIONS
A series of 3-phenyl-substituted benzoylpyrazoles were
prepared as structural analogs of cool-season grass-
active 3-morpholino benzoylpyrazoles. The targeted
3-phenylbenzoylpyrazoles were prepared by three
newly developed synthetic routes which allowed both
a comprehensive SAR study and optimization of the
series against three important grass weeds in cereal
Table 8. Post-emergence activity of N-tert-butyl-3-phenylbenzoylpyrazoles
TRZAS a
AVEFA a SETVI a ALOMY a
c
c
No mp (°C) Method
R
X3
X4
GR20 (ghaꢀ1
)
GR80 (ghaꢀ1
)
TI b
9a 174–175
A, B
A
CH3
CH3
CH3
CH3
CH3
OCH3
OCH2CH3
O-i-Pr
>256
140
63
25
25
20
<16
19
63
55
>10.2
5.6
9b
9c
110
97
A
28
84
2.3
9d 108–109
9e 138–140
A
OCH2CH=CH2
OCH2OCH3
25
34
20
116
65
0.7
A
156
126
25
20
30
7.8
9f
205–207
A
CH3 OCH3 OCH3
Cl
>256
156
<32
<32
56
>256
256
43
<0.5
0.2
9g 225–227
9h 187–188
B
OCH3
SO2CH3
B
CH3
<32
<32
—
a
TRZAS=wheat (Triticum aestivum); AVEFA=Avena fatua; SETVI=Setaria viridis; ALOMY=Alopecurus myosuroides.
b
Therapeutic index: TRZAS GR20 divided by AVEFA GR80
.
c Rate which produced either 20% (GR20) or 80% (GR80) visual injury in post-emergence greenhouse testing.
1182
Pest Manag Sci 58:1175–1186 (online: 2002)

Phenyl-substituted benzoylpyrazoles
crops: AVEFA, SETVI (Setaria viridis (L) Beauv) and
ALOMY. Addition of certain substituents to the
phenyl ring resulted in significant activity and spec-
trum improvements against the targeted grass weeds.
In general, substitution at the para position on the
benzene ring provided compounds with the best
overall levels of activity, yet there was no clear
relationship between this activity and the usual
lipophilicity or electronic parameters associated with
these substituents. Small substituents (eg F, CN) at
any position delivered higher levels of activity. How-
ever, there were exceptions, as an isopropyl group
provided one of the most active materials in the meta
series (6e), yet the corresponding material with this
substituent in the para position (5f) was nearly
inactive. Disubstitution on the phenyl ring was
detrimental to activity, regardless of the nature or
location of the substituents.
Pd(OAc)2 (34mg; 0.15mmol), tri-o-tolylphosphine
(137mg; 0.45mmol), acetonitrile (25ml) and water
(6ml) was stirred at reflux under nitrogen for 1h. The
mixture was cooled, diluted with water, and washed
with diethyl ether. The aqueous layer was made acidic
with hydrochloric acid (3M) and the resulting mixture
extracted twice with dichloromethane. The combined
organic layers were washed with water, dried over
anhydrous sodium sulfate, and evaporated to leave an
oil. The oil was taken up in diethyl ether þhexane,
decanted from some insoluble material and allowed to
stand to give 9e (1.09g; 77%) as golden crystals; mp
139–141°C; 1H NMR (CDCl3): d 8.20 (d, 1H,
J=8Hz), 7.58 (d, 1H, J=8Hz), 7.26 (s, 1H), 7.23
(d, 2H, J=9Hz), 7.15 (d, 2H, J=9Hz), 5.25 (s, 2H),
3.54 (s, 3H), 2.67 (s, 3H), 2.08 (s, 3H), 1.66 (s, 9H);
calc for C24H28N2O6S:C, 61.00; H, 5.97; N, 5.93;
found: C, 60.65; H, 6.07; N, 5.80.
The most interesting observation from the SAR
study of the phenyl substituent was the excellent
combination of grass activity and crop selectivity seen
by most members of the para-alkoxy series. The nature
of the alkoxy substituent did not seem critical for grass
weed activity yet smaller alkoxy groups tended to
provide better levels of crop selectivity. Once again,
the superior biological properties associated with the
para-alkoxy series did not translate to alkoxy sub-
stituents at other positions on the benzene ring.
Likewise, the favorable activity/selectivity combination
of the para-alkoxy series appears to be unique to those
materials that contain a C-2 methyl group (and not a
chlorine) on the benzoyl portion of the molecule.
In contrast to the confused SAR of the phenyl series,
there was a very clear trend for increased grass weed
activity as the pyrazole substituent was varied from N-
methyl through N-tert-butyl. In addition, and much to
our delight, there were no significant differences in the
level of crop selectivity across this series of N-alkyl
substituents. This remarkable wheat selectivity of the
branched 1’-alkylpyrazoles was truly an astonishing
observation, as it coincided with a significant increase
in grass weed activity! An additional methyl substi-
tuent, on the 3’-carbon of the pyrazole, failed to offer
any activity or selectivity advantages.
5.2 Phenyl-substituted benzoylpyrazoles—
Method B
5.2.1 2-Methyl-3-(4-methoxyphenyl)-4-(methyl-
sulfonyl)benzoic acid (Fig 4, 13, X=4-OCH3, Y=CH3)
A mixture was prepared under nitrogen comprising
12a (11.9g; 35mmol), 4-methoxyphenylboronic acid
(6.91g; 45.5mmol), potassium carbonate (24.2g;
175mmol), Pd(OAc)2 (0.39g; 1.75mmol), tri-o-tolyl-
phosphine (1.07g; 3.5mmol), diglyme (150ml) and
water (15ml). The mixture was stirred at 95°C for
12h, cooled to room temperature, diluted with water,
and washed twice with diethyl ether. The aqueous
layer was made acidic with hydrochloric acid (3M) and
then extracted three times with ethyl acetate. The ethyl
acetate layers were combined and evaporated to leave
a dark oily residue. The oil was taken up in aqueous
sodium hydroxide (1M), treated with activated char-
coal, and then filtered through Celite. The filtrates
were made acidic with hydrochloric acid (3M) and
extracted three times with ethyl acetate. The com-
bined organic layers were dried over anhydrous
magnesium sulfate and evaporated to leave a solid
which was recrystallized from toluene to give 13
(X=4-OCH3, Y=CH3; 9.37g; 84%) as colorless
1
crystals; mp 178–180°C; H NMR (CDCl3): d 8.19
In summary, the para-alkoxy-substituted 3-phenyl-
2-methyl-4-(methylsulfonyl)-benzoylpyrazoles are a
novel class of HPPD-inhibiting herbicides with poten-
tial utility for control of important grass weeds in
cereals.
(d, 1H, J=8Hz), 8.08 (d, 1H, J=8Hz), 7.21 (d, 2H,
J=9Hz), 7.03 (d, 2H, J=9Hz), 3.88 (s, 3H), 2.62 (s,
3H), 2.28 (s, 3H); calc for C16H16O5S:C, 59.99; H,
5.03; S, 10.01; found: C, 59.10; H, 5.01; S, 10.08.
5.2.2 1-(1,1-Dimethylethyl)-5-hydroxy-4-(3-(4-
(methoxy)phenyl)-2-methyl-4-(methylsulfonyl)benzoyl)-
pyrazole (Fig 3, 9a)
5
SYNTHETIC METHODS
5.1 Phenyl-substituted benzoylpyrazoles—
Method A
5.1.1 1-(1,1-Dimethylethyl)-5-hydroxy-4-(3-(4-
(methoxymethoxy)phenyl)-2-methyl-4-(methylsulfonyl)-
benzoyl)pyrazole (Fig 3, 9e)
A mixture prepared from 11b (1.39g; 3mmol),
4-(methoxymethoxy)phenylboronic acid (0.66g;
3.6mm), potassium carbonate (2.07g; 15mmol),
A mixture of 13 (X=4-OCH3, Y=CH3; 12.2g;
38mmol), thionyl chloride (10ml) and 1,2-dichloro-
ethane (75ml) was stirred at reflux for 3h (gas
evolution), cooled and evaporated to dryness. Toluene
(50ml) was added and the mixture again evaporated to
dryness. The resulting yellow oil was dissolved in
dichloromethane (20ml) and added dropwise to a cold
(5°C) solution prepared from 1-tert-butyl-5-hydroxy-
Pest Manag Sci 58:1175–1186 (online: 2002)
1183

TL Siddall et al
pyrazole (6.39g; 45.6mmol), triethylamine (4.61g;
45.6mmol) and dichloromethane (150ml). The mix-
ture was allowed to warm to ambient temperature and
then washed with cold hydrochloric acid (0.5M), cold
potassium carbonate solution (50g literꢀ1), dried over
anhydrous magnesium sulfate, and evaporated to leave
an oil.
5.3.3 2’-Fluoro-2-methyl-6-thiocyanatobiphenyl-3-
ylamine (Fig 5)
A solution prepared from 14 (5.1g; 26mmol) and
potassium thiocyanate (8.3g; 86mmol) in methanol
(50ml) was cooled to 0–5°C and bromine (4.5g;
28mmol) was added dropwise with stirring. After 2h a
few ml of saturated sodium hydrogen sulfite solution
were added and the mixture then diluted with water,
extracted twice with dichloromethane, and the com-
bined organic phases washed with water and brine,
dried over anhydrous sodium sulfate and evaporated
to give 2’-fluoro-2-methyl-6-thiocyanatobiphenyl-3-
ylamine (6.4g; 95%) as an oil which was used without
further purification; 1H NMR (CDCl3): d 6.8–7.5 (m,
6H), 3.96 (s, 2H), 1.89 (s, 3H).
The oil prepared above was dissolved in acetonitrile
(75ml) and powdered, anhydrous potassium carbo-
nate (7.88g; 57mmol) was added followed by acetone
cyanohydrin (0.5ml). The resulting mixture was
stirred overnight, concentrated with a rotary evapora-
tor, and the residue partitioned between water and
ether. The aqueous phase was treated with activated
carbon, filtered through Celite, made acidic with
hydrochloric acid (3M), and then extracted three times
with dichloromethane. The combined organic layers
were dried over anhydrous magnesium sulfate and
evaporated. The resulting oil was crystallized from
ethanol to give 9a (10.9g; 65%) as off-white crystals;
5.3.4 2’-Fluoro-3-iodo-2-methyl-6-thiocyanatobiphenyl
(Fig 5, 15)
A solution of 2’-fluoro-2-methyl-6-thiocyanatobiphe-
nyl-3-ylamine (6.1g; 24mmol) in dichloromethane
(50ml) was cooled to 5°C and chilled concentrated
hydrochloric acid (150ml) was added. The mixture
was vigorously stirred and treated in portions with a
solution of sodium nitrite (2.4g; 35mmol) in water
(10ml) while keeping the temperature below 0°C.
After 25min the mixture was poured slowly in portions
into a stirred mixture of potassium iodide (5.8g;
35mmol), water (150ml) and dichloromethane
(100ml). After 30min, saturated sodium hydrogen
sulfite solution was added and the organic phase
separated, washed with water and brine, dried over
anhydrous sodium sulfate and evaporated to give
iodide 15 (8.6g; 97%) as a tan solid; 1H NMR
(CDCl3): d 7.1–8.0 (m, 6H), 2.23 (s, 3H).
1
mp 174–175°C; H NMR (CDCl3): d 8.20 (d, 1H,
J=8Hz), 7.57 (d, 1H, J=8Hz), 7.26 (s, 1H), 7.24 (d,
2H, J=9Hz), 7.02 (d, 2H, J=9Hz), 3.88 (s, 3H),
2.66 (s, 3H), 2.08 (s, 3H), 1.66 (s, 9H); calc for
C23H26N2O5S:C, 62.43; H, 5.92; N, 6.33; S, 7.24;
found: C, 62.34; H, 5.94; N, 6.25; S, 7.32.
5.3 Phenyl-substituted benzoylpyrazoles—
Method C
5.3.1 2’-Fluoro-2-methyl-3-nitrobiphenyl (Fig 5)
A mixture of palladium acetate (260mg; 1.1mmol),
tri-o-tolylphosphine (1.0g; 3.4mmol) and glyme
(70ml) was stirred for 5min under nitrogen. Then
2-iodo-6-nitrotoluene (10g; 38mmol) was added and
the mixture stirred for 10min. Finally, a solution of
2-fluorophenylboronic acid (5.3g; 38mmol) in etha-
nol (30ml) was added followed by a solution of potas-
sium carbonate (26g; 190mmol) in water (50ml) and
the mixture warmed at reflux for 20h under nitrogen.
The resulting mixture was cooled, diluted with water
and extracted three times with diethyl ether. The
organic layers were filtered, washed with brine, dried
and evaporated. The residue was chromatographed on
silica with hexaneþdichloromethane (9þ1 by
volume) to give 2’-fluoro-2-methyl-3-nitrobiphenyl
(6.9g; 97%) as a colorless solid; mp 77–79°C; 1H
NMR (CDCl3): d 7.1–7.8 (m, 7H), 2.32 (s, 3H); calc
for C13H10FNO2:C, 67.53; H, 4.36; N, 6.06; found:
C, 67.21; H, 4.46; N, 5.82.
5.3.5 2’-Fluoro-3-iodo-2-methyl-6-methylthiobiphenyl
(Fig 5)
A mixture of 15 (8.4g; 23mmol) in methanol (100ml)
was treated with sodium methoxide (2.5g; 46mmol).
After 1.5h the mixture was cooled in an ice-bath and
treated dropwise with a solution of methyl iodide
(3.6ml; 58mmol) in methanol (10ml). After 30min
further sodium methoxide (1.5g) was added and the
mixture stirred for an additional 20min. The resulting
mixture was diluted with water (200ml), extracted
with dichloromethane (2ꢁ200ml) and the combined
organic layers washed with brine, dried over anhy-
drous sodium sulfate and evaporated to give 2’-fluoro-
3-iodo-2-methyl-6-methylthiobiphenyl (6.8g; 82%)
as an oil; 1H NMR (CDCl3): d 6.8–7.8 (m, 6H),
2.33 (s, 3H), 2.17 (s, 3H).
5.3.2 2’-Fluoro-2-methylbiphenyl-3-ylamine (Fig 5,
14)
5.3.6 2’-Fluoro-3-iodo-2-methyl-6-methylsulfonylbi-
phenyl (Fig 5, 16)
Amixtureof2’-fluoro-2-methyl-3-nitrobiphenyl(6.4g;
28mmol), 5% Pd/C (1g), ethanol (100ml) and toluene
(75ml) was hydrogenated at 275–345kPa for 17h at
25°C on a Parr apparatus. The resulting mixture was
filtered and the solvents were evaporated to give 14
(5.3g; 94%) as a tan solid; 1H NMR (CDCl3): d 6.7–
7.3 (m, 7H), 3.65 (brs, 2H), 1.99 (s, 3H).
A solution of 2’-fluoro-3-iodo-2-methyl-6-methylthio-
biphenyl (6.8g; 19mmol) in dichloromethane
(200ml) was cooled in an ice-bath and treated in
portions with 60% 3-chloroperoxy benzoic acid
(MCPBA) (16.5g; 58mmol). The mixture was al-
lowed to warm to 25°C, stirred for 18h, and then
1184
Pest Manag Sci 58:1175–1186 (online: 2002)

Phenyl-substituted benzoylpyrazoles
treated with saturated sodium hydrogen sulfite to
destroy the excess oxidant. The organic phase was
separated, washed to neutrality with aqueous sodium
hydrogen carbonate and then with water (twice) and
brine, dried over anhydrous sodium sulfate, and the
solvent evaporated to give 16 (7.7g; 100%) as a
colorless solid; mp 116–117°C; 1H NMR (CDCl3): d
7.2–8.1 (m, 6H), 2.74 (s, 3H), 2.22 (s, 3H); calc for
C14H12FINO2S:C, 43.09; H, 3.10; S, 8.22; found: C,
43.41; H, 3.15; S, 8.09.
5.4.2 3-Chloro-2-methyl-4-(methylsulfonyl)benzoic
acid (Fig 6, 18)
A mixture of 17 (62g; 0.26mol), sodium hydrogen
carbonate (66g; 0.78mol), Pd(OAc)2 (1.75g;
7.8mmol), 1,4-bis(diphenylphosphino)butane (6.7g;
16mmol), and de-aerated tert-butanolþwater (10þ1
by volume; 500ml) was prepared in a 1-liter Hastelloy
C pressure reactor. The mixture was purged and
pressurized with carbon monoxide to 2000kPa, and
warmed at 125°C for 20h. After cooling, the thick
mixture was diluted with water to dissolve most of the
solids and filtered through Celite. The solids were
washed twice with sodium hydroxide solution (2M)
and the combined filtrates extracted three times with
toluene. The aqueous layer was made acidic with
concentrated hydrochloric acid, and the resulting
precipitate collected by filtration, washed well with
water, and dried to give 18 (55g; 86%) as colorless
crystals; mp 196–197°C; 1H NMR (d6-DMSO): d
7.98 (d, 1H, J=8Hz), 7.84 (d, 1H, J=8Hz), 3.40 (s,
3H), 2.55 (s, 3H); calc for C9H9ClO4S:C, 43.47; H,
3.65; S, 12.89; found: C, 43.65; H, 3.67; S, 12.68.
5.3.7 1-Ethyl-4-(-3-(2-fluorophenyl)-2-methyl-4-
(methylsulfonyl)benzoyl)-5-hydroxypyrazole (Fig 5, 7a)
A mixture was prepared from 16 (1.7g; 4.4mmol),
1-ethyl-5-hydroxypyrazole (1.5g; 13mmol), triethyl-
amine (2.1ml; 15mmol), Pd(OAc)2 (50mg;
0.22mmol) and tri-o-tolylphosphine (200mg;
0.66mmol) in acetonitrile (20ml) in a 45-ml Hastel-
loy-C pressure reactor. The reactor was purged and
pressurized with carbon monoxide to 2000kPa and
then warmed at 115°C for 19h. The mixture was
cooled, diluted with water, washed twice with diethyl
ether, made acidic with hydrochloric acid (6M) and
extracted twice with dichloromethane. The combined
organic extracts were washed with water, dried over
anhydrous sodium sulfate and evaporated. The
residue was recrystallized from ethanol to give 7a
5.4.3 3-Amino-2-methyl-4-(methylsulfonyl)benzoic
acid (Fig 6, 19)
A mixture of 18 (79g; 320mmol), copper(II) oxide
(1.0g; 12.6mmol) and concentrated aqueous ammo-
nia (500ml) was warmed in a pressure reactor at
180°C for 17h. The resulting dark mixture was
evaporated and the residue made acidic with hydro-
chloric acid (2M) and then extracted with ethyl
acetate. The organic layers were dried over anhydrous
sodium sulfate, filtered and evaporated to leave a solid.
The solid was triturated with hexane and dried to leave
1
(550mg; 31%) as a yellow solid; mp 176–177°C; H
NMR (CDCl3): d 7.2–8.2 (m, 7H), 4.09 (q, 2H,
J=7.3Hz), 2.80 (s, 3H), 2.08 (s, 3H), 1.47 (t, 3H,
J=7.3Hz); calc for C20H19FN2O4S:C, 59.69; H,
4.76; S, 6.96; found: C, 59.23; H, 4.73; S, 7.82.
1
19 (50.0g; 68%) as a tan solid; mp 199–201°C; H
NMR (d6-DMSO): d 13.25 (s, 1H), 7.50 (d, 1H,
J=8Hz), 6.92 (d, 1H, J=8Hz), 5.97 (s, 2H), 3.12 (s,
3H), 2.22 (s, 3H); calc for C9H11NO4S:C, 47.15; H,
4.84; N, 6.11; found: C, 47.08; H, 4.77; N, 5.98.
5.4 Intermediate 3-iodobenzoylpyrazoles 11 (for
Method A) and 3-iodobenzoic acids 12 (for Method B)
5.4.1 2,6-Dichloro-3-(methylsulfonyl)toluene (Fig 6,
17)24
A mixture of thionyl chloride (240g; 2.0mol) and
methanesulfonic acid (480g; 5.0mol) was warmed at
reflux for 1h. At this point the reaction temperature
had increased to 120°C and the initial gas evolution
had ceased. After cooling to 50°C, 2,6-dichloro-
toluene (161g; 1.0mol) and trifluoromethanesulfonic
acid (10g; 67mmol) were added and the mixture
warmed at 120°C for 5h. After cooling to 50°C, the
mixture was poured into ice water (2 liter) and the
resulting precipitate taken up in dichloromethane. The
aqueous layer was separated and washed twice with
dichloromethane. The combined organic layers were
washed with water, twice with sodium hydroxide
solution (2M), dried over anhydrous sodium sulfate
and evaporated. The resulting solid was recrystallized
from ethanol to give 17 (188g; 79%) as a tan solid; mp
123–124°C; 1H NMR (CDCl3): d 7.95 (d, 1H,
J=8Hz), 7.48 (d, 1H, J=8Hz), 3.28 (s, 3H), 2.58
(s, 3H); calc for C8H8Cl2O2S:C, 40.18; H, 3.37; S,
13.41; found: C, 40.40; H, 3.38; S, 13.02.
5.4.4 3-Iodo-2-methyl-4-(methylsulfonyl)benzoic acid
(Fig 6, 12a)
A solution was prepared by dissolving 19 (74g;
320mmol) in warm (50°C) sulfuric acid (18M;
500ml). The solution was cooled to 0–5°C to produce
a slurry and the mixture treated dropwise over 20min
with a solution prepared of sodium nitrite (26.7g;
387mmol) in water (70ml). The resulting yellow
solution was stirred at 5°C for 30min and then added
in portions over 15min to a stirred warm (45°C)
solution of potassium iodide (166g; 1.0mole) in water
(1 liter). When addition was complete, the mixture
was warmed at 80°C for 20–30min, cooled to 25°C
and the resulting solid collected by filtration, washed
well with water, and dried to leave 12a (99g; 90%) as a
1
colorless solid; mp 193°C; H NMR (d6-DMSO): d
13.80 (s, 1H), 7.98 (d, 1H, J=8Hz), 7.80 (d, 1H,
J=8Hz), 3.40 (s, 3H), 2.62 (s, 3H); calc for
C9H9IO4S:C, 31.78; H, 2.67; S, 9.40; found: C,
31.79; H, 2.67; S, 9.25.
Pest Manag Sci 58:1175–1186 (online: 2002)
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TL Siddall et al
and structural requirements of inhibitors of p-hydroxyphenyl-
pyruvate dioxygenase. Weed Sci 45:601–609 (1997).
8 Beraud JM, Claument J and Montury A, ICI-A 0051, a new
herbicide for the control of annual weeds in maize, in Proc
Brighton Crop Protect Conf—Weeds, BCPC, Farnham, Surrey,
UK, pp 51–56 (1991).
5.4.5 1-Ethyl-5-hydroxy 4-(3-iodo-2-methyl-4-
(methylsulfonyl)benzoyl)pyrazole (Fig 6, 11a)
A mixture of 12a (62.1g; 182mmol) and thionyl
chloride (20ml; 270mmol) in 1,2-dichloroethane
(300ml) was stirred at reflux for 3h. The solvent was
evaporated and the resulting acid chloride dissolved in
dichloromethane (100ml) and this solution added
dropwise to an ice-cold solution prepared from
1-ethyl-5-hydroxypyrazole (24.7g; 220mmol) and
triethylamine (22.3g; 220mmol) in dichloromethane
(200ml). The reaction mixture was allowed to warm
to 25°C and then washed with hydrochloric acid
(0.5M). The organic phase was separated and washed
with potassium carbonate solution (50g literꢀ1), dried
over anhydrous magnesium sulfate and evaporated to
give 84g of crude product. This material was slurried
in acetonitrile (400ml), treated with powdered, anhy-
drous sodium hydrogen carbonate (37.7g; 270mmol)
and acetone cyanohydrin (1ml), and stirred overnight.
The mixture was then concentrated under vacuum
and the residue dissolved in water, washed with diethyl
ether and acidified with hydrochloric acid (3M). The
resulting mixture was extracted three times with
dichloromethane, the combined organic layers dried
over anhydrous magnesium sulfate and evaporated to
leave a gum. This material was crystallized from
ethanol to give 11a (63.3g; 68%) as a yellow crystal-
line solid; mp 84–87°C; 1H NMR (CDCl3): d 8.21 (d,
1H, J=8Hz), 7.55 (d, 1H, J=8Hz), 7.32 (s, 1H),
4.10 (q, 2H, J=7Hz), 3.38 (s, 3H), 2.62 (s, 3H), 1.46
(t, 3H, J=7Hz); calc for C14H15IN2O4S:C, 38.70; H,
3.48; N, 6.45; S, 7.38; found: C, 39.50; H, 3.54; N,
6.44; S, 7.49.
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and grass weed control in maize and sugar cane, in Proc
Brighton Crop Protect Conf—Weeds, BCPC, Farnham, Surrey,
UK, pp 35–42 (1995).
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13 Prisbylla MP, Onisko BC, Shribbs JM, Adams DO, Liu Y, Ellis
MK, Hawkes TR and Mutter LC, The novel mechanism of
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14 Schultz A, Ort O, Beyer P and Kleinig H, SC-0051, a 2-benzoyl-
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bitor of the enzyme p-hydroxyphenylpyruvate dioxygenase.
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15 Secor J, Inhibition of barnyardgrass 4-hydroxyphenylpyruvate
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16 Fiedler E, Soll J and Schultz G, The formation of homogentisate
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