Changes in the activity and selectivity of herbicides by selective fluorine substitution, taking bentranil and classic analogues as examples

Article abstract of DOI:10.2533/000942904777678226

The introduction of fluorine atoms into 2-phenyl-4H-3,1-benzoxazin-4-one (bentranil) led to sweeping changes in its herbicidal properties in some cases, and 5-fluoro-2-phenyl-4H-3,1-benzoxazin-4-one ('fluorobentranil') was found to be the most active compound. It can be prepared from 2-amino-6-fluoro-benzoic acid or by direct halogen exchange of 5-chloro-2-phenyl-4H-3,1-benzoxazin-4-one. The latter reaction was investigated on a pilot scale, including a high-temperature (350°C) potassium fluoride halogen exchange without solvent. When sulfolane was used as a solvent, a side reaction at 220°C - partial decomposition to a diphenylether - could be prevented by addition of a small amount of a radical scavenger. Other intermediates with a pseudohalogen substitution were obtained by side-chain chlorination of suitable methylsulfanyl benzoic acid precursors and halogen exchange. 'Fluorobentranil' shows good broad-leaf activity and selectivity on rice, cereals and maize. In a second case study, the fluoro-substituted anthranilic acids mentioned above were also found to be appropriate for synthesizing herbicidal sulfonylurea (SU) compounds via Meerwein reaction of their aniline function. Methyl 2-[({[(4-chloro-6-methoxy-2- pyrimidinyl)-amino]carbonyl}amino)sulfonyl]-6-fluorobenzoate is an example of a SU that is compatible with maize, whereas the unsubstituted Classic analogue is not selective.

Full text of DOI:10.2533/000942904777678226

FLUORINE IN THE LIFE SCIENCE INDUSTRY
117
CHIMIA 2004, 58, No. 3
Chimia 58 (2004) 117–122
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Changes in the Activity and Selectivity
of Herbicides by Selective Fluorine Sub-
®
stitution, Taking Bentranil and Classic
Analogues as Examples
Gerhard Hamprecht*, Bruno Würzer, and Matthias Witschel
Abstract: The introduction of fluorine atoms into 2-phenyl-4H-3,1-benzoxazin-4-one (bentranil) led to sweeping
changes in its herbicidal properties in some cases, and 5-fluoro-2-phenyl-4H-3,1-benzoxazin-4-one (‘fluoroben-
tranil’) was found to be the most active compound. It can be prepared from 2-amino-6-fluoro-benzoic acid or by
direct halogen exchange of 5-chloro-2-phenyl-4H-3,1-benzoxazin-4-one. The latter reaction was investigated on
a pilot scale, including a high-temperature (350 °C) potassium fluoride halogen exchange without solvent. When
sulfolane was used as a solvent, a side reaction at 220 °C – partial decomposition to a diphenylether – could be
prevented by addition of a small amount of a radical scavenger. Other intermediates with a pseudohalogen sub-
stitution were obtained by side-chain chlorination of suitable methylsulfanyl benzoic acid precursors and halogen
exchange. ‘Fluorobentranil’ shows good broad-leaf activity and selectivity on rice, cereals and maize. In a second
case study, the fluoro-substituted anthranilic acids mentioned above were also found to be appropriate for syn-
thesizing herbicidal sulfonylurea (SU) compounds via Meerwein reaction of their aniline function. Methyl 2-[({[(4-
chloro-6-methoxy-2-pyrimidinyl)-amino]carbonyl}amino)sulfonyl]-6-fluorobenzoate is an example of a SU that is
compatible with maize, whereas the unsubstituted Classic® analogue is not selective.
Keywords: Fluoro-2-phenyl-4H-3,1-benzoxazin-4-ones · Fluoro sulfonylureas · Pseudohalogen benzoyl halides ·
SAR
1. Introduction
2002, 15 contained one or more fluorine for the side chain and fluorine substitution
atoms, underlining the important contribu- in the heterocyclic moiety.
Fluorine substitution has, because of its tion of fluorine.
influence on activity, selectivity, toxicity
BASF research has shown great interest
and environmental behaviour, become an substituting bentranil (Table 1; 2-phenyl- 2. Material and Methods
outstanding tool in the design of modern 4H-3,1-benzoxazin-4-one) with fluorine in
agrochemicals. Of 45 new pesticide mole- both the phenyl and the benzoxazinone 2.1. Synthesis of Halide Substituted
cules presented at the annual Brighton Crop moieties to investigate the influence of flu- Benzoxazinones
Protection Conference between 1998 and orine on the relationship between structure
Halide substitution in the 8- to 6-ben-
and activity. Bentranil, an early experimen- zoxazinone positions was performed by ox-
tal BASF herbicide synthesized from an- idizing suitable o-toluidines to their an-
thranilic acid and benzoyl chloride, exhibits thranilic acids or by reacting substituted
excellent selectivity in graminaceous crops, anilines with chloral/hydroxylamine to
potatoes and to a lesser extent soybeans, has make isatoic acid intermediates (Scheme
never been commercialised, because of the 1.1). To occupy the 5-position, 2,6-
rather high dosage necessary to combat dichlorobenzonitrile was chosen as the
broadleaf weeds. While conventional σ ± starting material (Scheme 1.2). Halogen ex-
substituents like methyl or nitro reduce her- change with potassium fluoride gave 2,6-
bicidal activity, a small increase is observed difluoro-benzonitrile, which was converted
when the phenyl side chain is substituted by with ammonia under pressure at 100 °C to
halide in the m-position. On the other hand, give 2-amino-6-fluoro-benzonitrile, fol-
o- and p-derivatives are definitely inferior lowed by saponification of the nitrile to the
to the standard (Table 1). With halide as an acid, with 83% overall yield [1][2]. The
indicator for the activating positions of the next step, synthesis of the heterocycle
molecule – which are also potential posi- (Scheme 1.3) was optimized in the follow-
tions for metabolic degradation – we were ing way: Anthranilic acids were reacted
encouraged to investigate m-pseudohalides with benzoyl chloride in a two-phase sys-
*Correspondence: Dr. G. Hamprecht
BASF Aktiengesellschaft
Specialty Chemicals Research
D–67056 Ludwigshafen, Germany
Tel.: +49 621 41966
Fax: +49 621 20440
E-Mail: gerhard.hamprecht@t-online.de

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CHIMIA 2004, 58, No. 3
Table 1. SAR in the phenyl side chain (R1)
poning the expensive halogen exchange re-
action until the last step (Scheme 2) should
be advantageous. Unfortunately convention-
al halogen exchange of 1 to 5-fluoro-2-
phenyl-4H-3,1-benzoxazin-4-one (2) with
potassium fluoride at 220 °C in sulfolane
was accompanied by a strong side reaction
resulting in the formation of a heterocyclic
(ether) dimer 3 (25%), so that the yield of 2
was only 52% (reaction a1). This became
more comprehensible when pure 2, after
12 h treatment with an equimolar amount of
potassium fluoride in sulfolane at 220 °C (re-
action a2), contained only 26% of unchanged
starting material, the remainder being de-
composition products with 3 predominating.
Nucleophilic side reactions of potassium flu-
oride with acyl groups are also known from
the literature. For example, when Odinokov
and coworkers [3] reacted 3,6-di-chloroph-
thalic anhydride 4 with potassium fluoride at
190–200 °C they obtained the expected di-
fluoro compound 5, but at 240 °C partial de-
carboxylation gave rise to a dimeric lactone
6 (Scheme 3). In our search for decomposi-
tion inhibitors it was found that addition of
1.5 mol% iodine (Scheme 2, reaction b) re-
duced the side reaction from 25% to 5% and
increased the yield of 2 to 82% [4]. Our sug-
gested mechanism is only tentative. Molecu-
lar iodine acts either as a Lewis acid, reduc-
ing the basicity of soluble potassium fluo-
ride, or as a radical scavenger. In the
literature, acyl hypoiodides have also been
formulated by iodination of acetic acid in the
presence of oxidative reagents [5].
Success can sometimes be achieved by
completely omitting the solvent. Even at 300
°C, there was no reaction, but at 350 °C a
93% conversion to the 5-fluoro-benzoxazi-
none 2 with only 2% concomitant side reac-
tion was observed (Scheme 2, reaction c) [4].
The reduction of basicity and nucleophilici-
ty in our solid-liquid reaction melt compared
with the sulfolane procedure may be the rea-
son for the almost quantitative halogen ex-
change. The desired product was distilled
continuously out of the reaction melt and
therefore separated from the diphenyl ether 3
and other side products. The reaction was
further optimized under technical conditions
in a Hastelloy C4 vessel, where a reaction
time of 2 h and easy work-up conditions
were achieved.
2.3. Synthesis of Pseudohalide Sub-
stituted Benzoyl Halides
Scheme 1. Access for substituted benzoxazinones via suitable anthranilic acids and a single
To produce the side-chain-fluorinated
benzoyl halides, the precursors for the right
half of our benzoxazinone heterocycle, we
started from compounds such as 3-(methyl-
sulfanyl)benzoyl chloride (7) (Scheme 4).
Chlorination under mild conditions with
phosphorus pentachloride as a catalyst and
a temperature of 45–80 °C resulted in a high
yield of the trichloromethylsulfanyl com-
pound 8 [6]. Under similar conditions to
pot process
tem with aqueous sodium hydroxide in 2.2. Development of a Technical
dichloroethane under phase-transfer cataly- Process for 5-Fluoro-2-phenyl-4H-
sis and cyclized in a single-pot procedure in 3,1-benzoxazin-4-one
93% overall yield. The intermediate benza-
In comparison to a halogen exchange of
mide was not isolated and water was 2,6-dichlorobenzonitrile as a starting mate-
azeotropically removed before cyclization. rial for the desired anthranilic acid, post-

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CHIMIA 2004, 58, No. 3
those described for fluorinated anisoles, 8
was converted with hydrogen fluoride at low
temperature and pressure to 3{[chloro-diflu-
oro)- methyl] sulfanyl}benzoyl fluoride (9),
while reaction at 70 °C and 10 bar pressure
gave the trifluoro compound 10 [7][8]. Both
products were obtained in good yields. A
lower degree of fluorination was achieved by
adding chlorodifluoro-methane to m-cresol
11 in dioxane/water at 67–70 °C in 65%
yield, oxidizing to the acid 13 and reacting
further to give the acid chloride 14 [9]. High-
er fluorinated derivatives were obtained fol-
lowing a suggestion from Yagupolskii, the
well-known Russian pioneer in fluorine
chemistry: reaction of 3-methyl-phenyl tri-
fluoroacetate 15 with sulphur tetrafluoride in
liquid hydrogen fluoride at 25 °C and 80 bar
pressure [9][10]. The yield was 82%. We did
not optimize oxidation to the acid 17, for
which the yield was 61% [9]. This was fol-
lowed by thionylchloride reaction to the 3-
(1,1,2,2,2-penta-fluoroethoxy)benzoyl chlo-
ride 18 [9]. Mixed chloro/fluoroethoxyben-
zoyl chlorides were prepared in analogy to
D.C. England’s early work in the 1960s by
addition of 1-chloro-1,2,2-trifluoro-ethene
to methyl 3-hydroxybenzoate (19) in 68%
yield, rapid hydrolysis and further reaction
to the 3-(2-chloro-1,1,2-trifluoroethoxy)
benzoyl chloride 21 [9][11].
.
.
.
.
.
Scheme 2. Halogen exchange reactions for 5-fluoro-2-phenyl-4H-3,1-benzoxazin-4-one
–
–
Scheme 3. Potassium
fluoride induced de-
composition in the
literature
2.4. Synthesis of Fluoro Substituted
Sulfonylureas
The ready availability of a number of
new fluorine intermediates and improved
access to known ones prompted research on
other leads. In this respect our fluoroan-
thranilic esters seemed appropriate building
blocks for investigating sulfonylureas
(SUs), most of which are based on ben-
zenesulfonamides with an o-ester sub-
stituent. Classic® (chlorimuron) from
DuPont is an early example of an SU with
selectivity in soybeans and low application
rates of 35–53 g/ha for the control of
broadleaf weeds (Scheme 5) [12].
-
–
–
–
Starting material was the above-men-
tioned 2-amino-6-fluoro-benzonitrile (22).
Both its Pinner reaction to the ester 23 and
the Meerwein reaction were performed in
more than 90% yield, giving very smooth ac-
cess to substituted benzenesulfonyl chlo-
rides 24. The next steps were reaction with
aqueous ammonia and phosgenation in good
yield to the isocyanate 26, which readily al-
lowed 2-amino-4-chloro-6-methoxy-pyrim-
idine to be added to the SU 27A with 3-flu-
oro substitution in the benzene sulfonamide
moiety [13]. The yield was 75%. Similarly
the 3-chloro compound 27C was prepared.
–
2.5. Biological Tests
2.5.1. Greenhouse Experiments
All the data were taken from screening-
type trials in the greenhouse. For post-
Scheme 4. Side-chain fluorinated benzoyl halides

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CHIMIA 2004, 58, No. 3
Scheme 5. Sulfonyl ureas derived from 3-fluoro-2-methoxy-carbonyl-benzenesulfonamide
3. Results and Discussion
emergence tests, plants were cultivated in
plastic pots of 8.6 cm diameter containing
loamy sand with about 1.2% humus as the
substrate. The test plants were sown, grown
in the test pots to a height of 4–12 cm and
then treated with the test compound in a
spray chamber at a rate of 0.25–0.5 kg/ha
a.i. (active ingredient) for the benzoxazi-
nones and 62.5 g/ha a.i. for the sulfonyl-
ureas, formulated as emulsion concentrates.
The number of replicates was one and, for
comparison, four untreated control pots
were included in each test. After the
application, the test plants were kept for
18–20 days at 18–27 °C, during which pe-
riod the plants were maintained and their
reaction to the individual treatments was as-
sessed and recorded. Injury to the plants
was assessed on a scale from 0 to 100 in
comparison to the untreated controls, with
0 denoting no damage and 100 denoting
complete destruction of at least the visible
plant parts.
better parabolic relation with log P = 4.3
as the optimum.
3.1. Structure–Activity Relationship
(SAR)
3.1.1. Benzoxazinones
What can be clearly seen is the effect of
several fluorine atoms adding to the over-
all lipophilicity compared with the unsub-
stituted standard 28 with a log P = 3.3. In-
troducing only one fluorine atom into the
anthranilic acid moiety of the standard re-
sults in log P = 3.2 (compound 2). As ex-
pected, the lipophilicity difference in both
cases is small and shows once again the
similarity of hydrogen and fluorine in a
bioactive molecule as far as size and
lipophilicity are concerned. But fluorine,
being much more electronegative, appar-
ently binds better to the enzyme, resulting
in higher activity. In fact, this compound
turned out to be the most active derivative.
At 250 g/ha, 5-fluoro-2-phenyl-4H-3,1-
benzoxazin-4-one controlled numerous
weed species and possessed excellent se-
lectivity in several crops. Results were con-
firmed by field trials at rates of 0.5 kg/ha
(Table 4).
With these benzoxazinones available,
standard screening trials were conducted
in the greenhouse with post-emergence
treatment of different crops containing
broadleaf weed species at 0.5 kg/ha ai,
formulated as a suspension concentrate.
While chlorine (Table 2) induces a loss of
activity – except in the 5-position, where
it is equivalent to the standard – a contin-
uous increase in activity was observed as
the hydrogens were replaced stepwise by
fluorine on passing from the 7- to the 5-
position. The 8-fluoro derivative was
weaker than the parent compound, but
surprisingly the 5-fluoro derivative
proved to be about three times as active as
the standard. Table 3 shows the average
activity on seven plant species on a scale
of 0 to 100 and the lipophilicity (log P)
measured by standard HPLC procedure.
While dichloro 29 for both R1 and R2 or a
combination of nitro and chlorodifluo-
romethoxy 33 reaches only medium activ-
ity with less than 50%, high activity is ob-
served for chloro and pseudohalide side-
chain substituents connected to fluorine-
or chlorine-substituted anthranilic acid.
When phytotoxicity is correlated with
lipophilicity (Fig. 1), three different clus-
ters can be identified: 5-fluoro-3,1-ben-
zoxazine-4-ones and their corresponding
5-chloro derivatives, each with fluorine
side chains, as compared to the unsubsti-
tuted bentranil 28. The 5-fluoro-3,1-ben-
zoxazin-4-ones show only a very small
range of lipophilicity with 3.7 as the opti-
mum, while the chloro derivatives show a
2.5.2. Test Species
The following plant species were used:
Broadleaf weeds: velvet leaf (Abuthilon
theophrasti), redroot pigweed (Amaran-
thus retroflexus), hairy beggarticks
(Bidens pilosa), common lambs-quarters
(Chenopodium album), bengal commelina
(Commelina benghalensis), florida beggar
weed (Desmodium tortuosum), wild poin-
settia (Euphorbia heterophylla), cleavers
(Galium aparine), annual mercury (Mer-
curialis annua), chamomile (Matricaria
spp.), tall morning glory (Pharbitis pur-
purea), ladysthumb (Polygonum persi-
caria), hemp sesbania (Sesbania exaltata),
wild mustard (Sinapis arvensis), black
nightshade (Solanum nigrum), and maize
(Zea mays).
3.1.2. Sulfonylureas
The herbicidal activity of the Classic®
analogues was compared on six broadleaf
weeds in the greenhouse at an application
rate of 62.5 g/ha (Fig. 2). Derivative 27B
achieved the highest activity with a sum of
585, but was followed very closely by the
fluoro and chloro derivatives 27A and 27C
with sums of 560 and 561 respectively. The
difference in selectivity is critical.
While the unsubstituted SU has no se-
lectivity at all on maize and the chloro com-
pound still produces 50% damage on
maize, the fluoro derivative is much safer
and shows only 10% damage three weeks
after treatment – damage that later assess-
ments show to have grown out.

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Table 3. SAR in the m-phenyl side chain (R1) + anthranilic acid moiety
(R2)
Table 2. SAR in the anthranilic acid moiety (R2)
Fig. 1. SAR in the m-phenyl side-chain + an-
thranilic acid moiety – dependence of phyto-
toxicity on log P
Table 4. Weed spectrum of 5-fluoro-2-phenyl-4H-3, 1-benzoazin-4-one

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CHIMIA 2004, 58, No. 3
.
Fig. 2. Influence of halide substitution in the benzenesulfonamide moiety
4. Conclusion
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The first case study in bentranil chem-
istry gave an example of where substitution
of hydrogen by fluorine at a specific posi-
tion in the heterocycle led to an impressive
rise in activity. The second SU case study
showed what surprising selectivity can be
obtained by substituting fluorine for hydro-
gen in the right position.
[7] O. Scherer, H. Hahn (Farbwerke Hoechst
AG), DE 1 000 393, 1954.
[8] J. Varwig, G. Hamprecht (BASF AG), EP
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82, 5116
[1] H.G. Oeser, K.H. König, D. Mangold
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[2] P. Jacobs, H.G. Oeser (BASF AG), EP
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