The synthesis and biological activity of 1-alkyl-4-(3-azacyclobenzoyl)-5- hydroxypyrazole herbicides

Article abstract of DOI:10.2533/000942903777678579

The benzoylpyrazoles belong to a class of herbicides that inhibit the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). This mode of action is characterized by bleaching due to the disruption of plastoquinone and α-tocopherol biosynthesis. Early studies

Full text of DOI:10.2533/000942903777678579

CROP PROTECTION RESEARCH
720
CHIMIA 2003, 57, No.11
Chimia 57 (2003) 720–724
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
The Synthesis and Biological Activity
of 1-Alkyl-4-(3-azacyclobenzoyl)-5-
hydroxypyrazole Herbicides
Zoltan Benko*, Sharon Shinkle, John Van Heertum, Johnny Jackson, Jeffery McQuiston,
Jeffery Webster, James Turner, Monte Weimer, and Eileen Paterson
Abstract: The benzoylpyrazoles belong to a class of herbicides that inhibit the enzyme 4-hydroxy-
phenylpyruvate dioxygenase (HPPD). This mode of action is characterized by bleaching due to the disrup-
tion of plastoquinone and α-tocopherol biosynthesis. Early studies indicated that the C(3) position of
benzoylpyrazoles can accommodate a wide range of functionality. This paper describes synthetic efforts to
improve cool season grass weed activity and wheat selectivity by incorporating cyclic moieties attached
through nitrogen at this position. The aza substituents were generally installed by nucleophilic aromatic
substitution, however, an efficient four-step method was developed for constructing substituted morpholino
moieties directly on pre-formed benzoylpyrazoles. The structure–activity relationships revealed that certain
piperidino moieties provided good activity on wild oat, while exhibiting selectivity toward wheat. They also
showed that excellent levels of activity on wild oat and blackgrass can be achieved with morpholino
substituents.
Keywords: Benzoylpyrazoles · Herbicide · Hydroxyphenylpyruvate dioxygenase inhibitors ·
Morpholines · Piperidines
Introduction
Interest in these benzoylpyrazoles commodate many diverse substituents. Sul-
stems from the broad spectrum activity ob- fones and alkoxycarbonyls were particular-
1-Alkyl-4-benzoyl-5-hydroxypyrazoles are served when they are applied pre- or post ly good, as were certain alkoxy substi-
highly active novel herbicides that are emergently on broadleaves and grasses and tuents. Naturally, we wondered whether
characterized by an appropriately function- because they are mobile in both plants and nitrogen could replace the electronegative
alized benzoyl group attached to an acidic soil. Research at Dow AgroSciences and oxygen and provide bioisosteric sub-
hydroxypyrazole (Fig. 1). These materials elsewhere [4] in the late 1980s and early stituents.
are herbicidal because they inhibit the en- 1990s led to a basic understanding of the
Synthesis of the 3-NMe2 substituted
zyme hydroxyphenylpyruvate dioxygenase structure–activity relationships (SAR) of analog (Table 1, entry 1) demonstrated that
(HPPD) in the quinone biosynthesis path- the benzoylpyrazoles (Fig. 1). Small alkyl it was possible to utilize a nitrogen at this
way[1]. Inhibition of this step interrupts the substituents on the pyrazole were preferred location and retain herbicidal activity. A
synthesis of plastoquinones and α-toco- and the best compounds generally had a Cl general investigation of the area was there-
pherol, which makes the plant unable to or Me group at the C(2)-position and a fore undertaken [5]. Of primary interest to
protect itself from photo-oxidation. The un- SO2Me in the (C)4-position of the benzene us, however, was the grass activity inherent
mistakable bleaching symptomology, fol- ring. In contrast to the rest of the molecule, in these molecules. The MeOCH2CH2NH
lowed by plant death, is characteristic of however, the C(3) position was able to ac- group (entry 2) was found to be quite active
this mode of action. Other herbicidal
chemistries are known to operate at this site
as well, most notably the benzoylcyclo-
hexanediones [2] and the benzoylisoxa-
zoles [3].
Best Herbicidal Activity:
O
X
HO
A N
A = Me, Et, i-Pr, t-Bu
B = H > Me
X = Cl, Me
Z = only SO2Me
Y = CO2R, SO2Me, OR
Y
Z
N
*Correspondence: Dr. Z. Benko
Discovery Research
Dow AgroSciences
B
9330 Zionsville Road
Indianapolis, IN 46268, USA
Tel.: + 1 317 337 3068
Fax: + 1 317 337 3215
E-Mail: zlbenko@dow.com
Fig.1. Early structure-activity relationships of benzoylpyrazole herbicides established by Dow
AgroSciences and others

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
Table 1. SAR comparison of ring size and heteroatoms
OH
on broadleaves and warm season grasses,
but it was unremarkable on the cool season
grass weeds wild oat (AVEFA) and black-
grass (ALOMY). Wild oat and blackgrass
are considered to be the most important
grass weeds to control in wheat (TRZAS)
crops. It was not until this 2-methoxy-ethyl-
amino substituent was ‘tied back’ into a
ring, that there was a dramatic increase in
efficacy against these key species (entry 3).
We therefore turned our attention to explor-
ing this unique subclass of the benzoyl-
pyrazoles. This paper focuses exclusively
on the synthesis of analogs in which cyclic
amines have been incorporated at C(3) of
the benzoyl ring and the resulting biologi-
cal activity.
O
Cl
Y
Et
N
N
SO2Me
GW
AVEFA
ALOMY
GR80
TRZAS
GR20
GR80
GR80
Postb
[ppm]
Entry
Y
Posta
Postb
Postb
[ppm]
[ppm]
[ppm]
1
2
3
4
5
6
7
NMe2
50
9
295
>250
20
16
150
2
60
45
2
OMe
NH
O
N
N
2
O
Synthesis
19
16
15
19
31
16
25
31
>125
31
4
We first synthesized [5] these amine-
substituted materials by taking advantage
of the inherent regioselectivity of nucleo-
philic aromatic substitution on our 2,3,4-
trisubstituted benzoic acid starting materi-
als 1 (Scheme 1). The C(3) chlorine is the
most labile under the basic conditions of the
reaction, because the sulfone is a much
more powerful ortho director than the car-
boxylate. The functionalized benzoic acid
2 was then coupled with a 1-alkyl-5-
hydroxypyrazole to give a mixture of the
corresponding ester and amide. This mix-
ture was subsequently rearranged to the C-
acylated product 4 with a catalytic amount
of cyanide.
To improve the efficiency of analog
synthesis, we considered performing the
nucleophilic substitution later in the se-
quence, directly on a benzoylpyrazole 3
(Scheme 1). We reasoned that a deproton-
ated hydroxypyrazole moiety was not un-
like a carboxylate with respect to activation
of the aromatic ring. This approach worked
well and was general, although hindered
amines tended to give lower yields [6]. In-
creased heat or the use of the corresponding
3-fluoro version of 1 or 3 could be used to
overcome this problem. A number of com-
mercially available cyclic amines were uti-
lized directly in this sequence, although
some of the piperidines needed minor mod-
ifications [7].
16
>63
8
N
N
N
>63
63
aThe concentration of active ingredient that provides an average growth reduction of 80% compared to untreated controls when
sprayed post emergently on the following grass species: Alopecurus mysuroides (ALOMY), Avena fatua (AVEFA), Digitaria san-
guinalis (DIGSA), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA), Sorghum bicolor (SORBI). bThe concentration of ac-
tive ingredient that provides the indicated percent growth reduction compared to an untreated control when sprayed post emer-
gently on the listed species. The last column is the wheat crop Triticum aestivum (TRZAS). cMixture of cis and trans.
O
X
NR1R2 may
be cyclic or
non-cyclic
NR1R2
SO2Me
b, c
a
HO
2
O
X
Rn
O
X
HO
N
Y
A = small alkyl
X = F, Cl or Me
Y = F or Cl
O
X
R1R2
HO
N
HO
N
N
A
SO2Me
A
N
SO2Me
N
1
SO2Me
4
5
O
X
HO
N
Y
a
b, c
A
N
SO2Me
3
a) HNR1R2 neat or aqueous, 80-200 oC b) SOCl2; hydroxypyrazole,Et3N,CH2Cl2,RT or isopropylchloroformate,
Et3N, CH2Cl2; hydroxypyrazole, RT or hydroxypyrazole, DCC, CH3CN, RT c) KCN, Et3N, MeCN or
(Me)2C(OH)CN in CH3CN.
Scheme 1. General synthetic route to 3-(azacyclo)benzoylpyrazoles
zoylpyrazole intermediates, prompted us to starting from 6 then, was to install a substi-
The high level of activity obtained with consider an in situ approach to the problem tuted ethanolamine, many of which were
the morpholine ring was particularly in- (Scheme 2). Typical literature procedures commercially available or easily synthe-
triguing, but investigation was hindered by involved the use of protected ethanol- sized. Under the reaction conditions, the
the paucity of commercially available mor- amines. It occurred to us, that if we used the water soluble imine of the ketone was also
pholines. Even more troubling, however, benzoylpyrazole itself as a protecting formed, but this intermediate was readily
was the generally low yielding and experi- group, we would be working with organic hydrolyzed in a separate step before isola-
mentally difficult methods available in the soluble intermediates and no deprotection tion of the product 7. The second step was
literature for the synthesis of substituted step would be required. In fact, from earli- a cyclization to the lactone 8 achieved by
morpholines. This situation, and our recent er work, we already knew that displacement heating 7 with glyoxal [8]. A selective re-
success at manipulating advanced ben- with ethanolamine was facile. The first step duction to the lactol 9 [9] was the third step,

CROP PROTECTION RESEARCH
722
CHIMIA 2003, 57, No.11
in which the lactone was reduced with di-
isobutyl aluminum hydride in the presence
of the hydroxypyrazole. An extra equiva-
lent of this reagent was necessary for the
initial deprotonation. The propensity of
benzoylpyrazoles to chelate certain metal
ions (iron is best known, but also aluminum
and copper) made a strong acidic work-up
necessary. If this was not done, it was actu-
ally possible to isolate the tribenzoylpyra-
zolate aluminum salt by column chro-
matography! The fourth and final step was
to replace the hydroxyl of the lactol 9 with
a variety of nucleophiles or simply reduce
it with triethylsilane to obtain the final tar-
get 10. For simple alcohols, HCl was a suf-
ficient catalyst, but more complex alcohols,
as well as methylmercaptide and cyanide,
required BF3•Et2O.
R2
R2
R1
O
Cl
R1
HO
N
O
Cl
OH
Y
HO
N
O
Cl
O
HO
N
a
b
NH
N
Et
O
Et
N
SO2Me
Et
6
N
SO2Me
N
SO2Me
7
8
Y = F or Cl
R2
R2
R1
R1
O
Cl
O
O
Cl
O
HO
HO
c
d or e or f
N
R3= OMe
R3 = CN
N
g
R3
OH
Et
N
Et
N
f
N
N
SO2Me
SO2Me
9
10
by method:
R3
d
e
OMe
OEt
Oi-Pr
OCH2CF3
OtBu
OCD3
OCH2CH=CH2
OCH2CH2OMe
=
H
OCH(CH2F)2
OCH(CH3)CF3
SMe
a) H2NCHR1CHR2OH 100 oC, 18h; NaOH, EtOH/H2O, 90oC, 3 h, 40-85% b) 40% aq. glyoxal, toluene, 90-110 oC,
1-3 d, 40-70% c) DIBAL, CH2Cl2, -78oC, 30 min, 60-90% d) Et3SiH, TFA, 30 min, RT, 50-95% e) ROH/HCl, RT,
10 min, 45-95% f) ROH or MeSH with BF3 Et2O, THF, RT, 3 h, 8-80% g) TMSCN, BF3 Et2O, CH3CN, RT, 3 h, 9%
1,3 Oxazine analogs were synthesized
via the corresponding 3-amino-1-propanol
intermediate by cyclization with formal-
dehyde or phosgene. Attempts at the syn-
thesis of 5- and 7-membered oxazocycles
were unsuccessful [10].
.
.
Scheme 2. Synthesis of substituted 3-morpholinobenzoylpyrazoles
Table 2. SAR comparison of substituted piperidine substituents
OH
Cl
O
Biological Activity
Rn
N
Et
N
The outstanding activity of the morpho-
lino substituted benzoylpyrazole prompted
us to investigate a number of other cyclic
amines (Table 1). We found that morpho-
line was the best, but pyrrolidine and piperi-
dine (entry 5 and 6) still showed respectable
activity on wild oat coupled with a modest
amount of wheat selectivity. The 1,2,5,6-
terahydropyridine and 1,3-oxazine analogs
(entry 4 and 7) also showed activity on wild
oat, but with no hint of safety toward wheat.
Thiomorpholine, 4-methyl- and 4-acetyl-
piperazine, 2-oxo-1,3-oxazine (cyclic car-
bamate) and homopiperidine (7-membered
ring) were all inactive at these rates.
Because very few substituted pyrro-
lidines or morpholines were commercially
available, our research program first fo-
cused on piperidines, with the intent of im-
proving wild oat activity and wheat selec-
tivity (Table 2). A series of methyl substi-
tuted piperidines revealed that certain
3-methyl substituted compounds (entry 3
and 6) retained wild oat activity and the
N
SO2Me
GW
GR80
Posta
ALOMY
GR80
AVEFA
GR80
TRZAS
GR20
Entry
Rn
Postb
Postb
Postb
[ppm]
[ppm]
[ppm]
[ppm]
>63
125
250
>63
>250
>250
>250
250
>250
240
>250
>250
>125
>250
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
2-Me
3-Me
4-Me
3,3-diMe
3,5-diMe c
3-Cl
15
64
49
35
250
56
23
81
197
51
60
25
>125
63
55
>250
25
25
50
>250
14
31
>63
12
100
16
>250
63
4
31
>250
4
10
20
3-OH
3-(=O)
3-MeO
3-EtO
3-CO2Et
4-(=O)
4-MeO
231
125
88
>250
>125
85
125
45
aThe concentration of active ingredient that provides an average growth reduction of 80% compared to
untreated controls when sprayed post emergently on the following grass species: ALOMY, AVEFA,
DIGSA, ECHCG, SETFA, SORBI. bThe concentration of active ingredient that provides the indicated
percent growth reduction compared to an untreated control when sprayed post emergently on the listed
species. cMixture of cis and trans.
wheat selectivity. Taken together (entry 1, substituent that would allow selective me- 16) which was attributed to the ability of the
3, 4, and 6), the results are consistent with tabolism to occur in wheat. The biological fluorines to destabilize the incipient free
the hypothesis that wheat selectivity de- data (Table 3) revealed that excellent activ- radical typically formed during metabolism
pends, at least partially, on metabolism at ity on both wild oat and blackgrass could be of an alkoxy group [11]. It was also inter-
the C(4) of the piperidine ring. Unfortu- retained with small alkyl substituents (entry esting to note that the overall loss in activi-
nately, all other piperidine substituents 1–7). Reasonable activity on wild oat was ty engendered by a 2-MeO group was miti-
were not selective toward wheat, although also obtained with a 2-MeO group (entry gated by the presence of a 6-Et substituent
3-Cl, 3-MeO and 3-EtO (entry 7, 10, and 11), but this was lost very quickly with in- (entry 11, 25, and 26). Stereochemical ef-
11) were active on wild oat.
creasing size of the alkoxy substituent. (en- fects across the morpholine ring were in-
Our intent with respect to the highly ac- try 13–15). A modest recovery in this trend significant (entry 25 and 26, 27 and 28, 29
tive morpholine ring, was to incorporate a was made with the CF3CH2O group (entry and 30), though a significant effect was

CROP PROTECTION RESEARCH
723
CHIMIA 2003, 57, No.11
noted between a pair of diastereomeric
branched fluoroalkoxy substituents (entry
18 and 19). In the end, however, no selec-
tivity toward wheat was observed in any of
the analogs.
2
O
OH
O
Cl
N
Rn
Et
N
N
SO2Me
The Most Effective
3-Azacyclobenzoylpyrazoles
GW
GR80
Posta
AVEFA
GR80
ALOMY
GR80
TRZAS
GR20
Entry
Rn
Postb
Postb
Postb
[ppm]
[ppm]
[ppm]
[ppm]
To highlight the biological effect of
incorporating cyclic amines at the C(3)
position of benzoylpyrazoles in this paper,
substitution at all other positions was held
constant. Our overall research program,
however, was directed at optimizing these
novel substituents in concert with the rest of
the molecule (Table 4). The most effective
molecule with respect to overall activity on
the key cool season grass weeds wild oat
and blackgrass (entry 1), was in fact an
unsubstituted morpholino analog. The best
wild oat compound with the greatest selec-
tivity toward wheat (entry 2), however,
contained a 3-methylpiperidino moiety.
1
2
3
4
5
6
7
8
H
3-Me
3-i-Pr
2-Me
2-Et
2
7
7
6
5
2
3
10
3
7
63
4
8
20
31
31
25
14
31
12
250
>250
>62
50
2
2
<4
1
2
4
<4
5
>250
>62
12
1
>125
>125
>63
4
2-i-Pr
10
4
2,6-diMec
2-Ph
51
>250
>62
63
6
>125
>125
>63
45
70
40
4
58
199
1258
33
19
6
16
26
98
16
30
9
2=(O)
2-OH
2-MeO
2-CD3O
2-EtO
>250
>62
31
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
8
78
>125
>125
>63
50
103
54
>125
>125
>63
125
200
100
31
>250
>250
>250
125
50
8
14
100
100
63
2-i-PrO
2-t-BuO
2-CF3CH2O
2-(CH2F)2CHO
2-CF3(Me)CHO (1)d
2-CF3(Me)CHO (2)d
2-MeOCH2CH2O
2-CH2=CHCH2O
2-MeS
5
5
3
<2
31
31
10
12
4
4
4
<16
<16
3
125
>250
>250
31
20
8
12
30
30
25
2-CN
2-MeO, 5-Mec
cis-2-MeO, 6-Et
trans-2-MeO, 6-Et
cis-2-MeO, 6-i-Pr
trans-2-MeO, 6-i-Pr
cis-2-MeO, 6-Ph
trans-2-MeO, 6-Ph
14
63
10
aThe concentration of active ingredient that provides an average growth reduction of 80% compared to
untreated controls when sprayed post emergently on the following grass species: ALOMY, AVEFA,
DIGSA, ECHCG, SETFA, SORBI. bThe concentration of active ingredient that provides the indicated
percent growth reduction compared to an untreated control when sprayed post emergently on the listed
species. cMixture of cis and trans. d Separated but unassigned diastereomer.
Table 3. SAR comparison of substituted
morpholino substituents
OH
X
O
Y
A
N
N
SO2Me
GW
AVEFA
GR80
ALOMY
GR80
TRZAS
GR20
GR80
Entry
A
X
Me
Cl
Y
Posta
Postb
Postb
Postb
[ppm]
1
[ppm]
[ppm]
[ppm]
O
1
i-Pr
N
2
3
3
Me
2
Me
139
50
>250
>250
N
aThe concentration of active ingredient that provides an average growth reduction of 80% compared to
untreated controls when sprayed post emergently on the following grass species: ALOMY, AVEFA,
DIGSA, ECHCG, SETFA, SORBI. bThe concentration of active ingredient that provides the indicated
percent growth reduction compared to an untreated control when sprayed post emergently on the listed
species.
Table 4. Optimized 3-azacyclobenzoylpyra-
zoles

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
[3] a) B.M. Luscombe, K.E. Pallett, P. Lou-
biere, J.C. Millet Melgarejo, T. E. Vrabel,
‘RPA 20772: a novel herbicide for broad
leaf and grass weed control in maize and
sugar cane’, Proc. Brighton Crop Prot.
Conf.-Weeds 1995, 35; b) K.E. Pallett,
S.M. Cramp, J.P. Little, P. Veerasekaran,
A. Crudace, A.E. Slater, ‘Isoxaflutole: the
background to its discovery and the basis
of its herbicidal properties’, Pest Manag.
Sci. 2001, 57, 133.
[4] M. Baba, N. Tanaka, T. Ishi, T. Nawama-
ki, US 4744815, 1988; b) M. Baba, T
Kakuta, N Tanaka, E. Oya, T. Ikai, T.
Nawamaki, S. Watanabe, US 4885022,
1989; c) Z. Benko, T. Siddall, G. Garvin,
S. Shinkle, ‘Bis-alkylsulfonylated ben-
zoylpyrazoles: Synthetic methods for in-
corporating two alkylsulfonyl groups in a
tetrasubstituted aromatic ring’, Abstracts
of Papers – American Chemical Society
2001, 221st AGRO-075.
[5] a) Experimental details may be found in
this reference: Z.L. Benko, J.A. Turner,
M.R. Weimer, G.M. Garvin, J.L. Jackson,
S.L. Shinkle, J.D. Webster (Dow Agro-
Sciences), US 5824802 1998; b) Z. Benko,
S. Shinkle, J. McQuiston, J. Webster, J.
Jackson, G. Garvin, J. Turner, M. Ricks,
D. Ouse, E. Patterson, M. Weimer, ‘3-
Azabenzoylpyrazole herbicides’, Ab-
stracts of Papers – American Chemical
Society, 2001, 221st AGRO-002.
[6] The lower yields are largely due to the
competing formation of the corresponding
pyrazolobenzpyran, in which the hydroxy-
pyrazole cyclizes onto the C(2) of the
benzoyl when there is a leaving group
present.
Summary
A practical and general approach to
3-azacyclobenzoylpyrazoles has been de-
veloped based on aromatic substitution by
amines. The efficiency of analog synthesis
was markedly improved by performing the
substitution on advanced benzoylpyrazole
intermediates. Problems related to the pre-
paration of substituted morpholino analogs
were solved by a four-step in situ procedure
based on glyoxal cyclization. Unsubstituted
or small alkyl substituted morpholino sub-
stituents were found to provide the greatest
activity on the key cool season grass weeds
wild oat and blackgrass. On the other hand,
significant wheat selectivity with respect to
wild oat was observed with a piperidino
moiety if there was a small alkyl group
incorporated at C(3) of that ring.
Received: September 17, 2003
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[7] Hydroxypiperidines were modified by
standard methylation, oxidation and chlo-
rination procedures.
[8] D. Chassonnery, F. Chastrette, M. Chas-
trette, A. Blanc, G. Mattioda, ‘Dispropor-
tionation reactions from glyoxal and
difunctional basic molecules’, Bull. Chim.
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dielectrophiles such as methyl 2-bromo-
acetate, chloroacetaldehyde and glyco-
laldehyde dimer failed to give a reaction.
[9] The use of dichloromethane as solvent for
this reaction was important – no product
was obtained in THF. In the examples pre-
sented in this paper, the lactols existed en-
tirely in the closed form. Other researchers
have found equilibrium mixtures in relat-
ed systems: a) N.H. Cromwell, K. Tsou, J.
Am. Chem. Soc. 1949, 71, 993; b) R.E.
Lutz, R.H. Jordan, J. Am. Chem. Soc.
1949, 71, 996.
[10] The syntheses of the corresponding oxa-
zolidine, isoxazolidine and 1,4-oxazepine
analogs were attempted following litera-
ture precedents, but they failed either at
the cyclization or nucleophilic aromatic
displacement step.
[2] a) J.M. Beraud, J. Claument, A. Montury,
‘ICI-A 0051, a new herbicide for the con-
trol of annual weeds in maize’, Proc.
Brighton Crop Prot Conf.-Weeds 1991, 1,
51; b) G. Mitchell, D.W. Bartlett, T.E.M.
Fraser, T.R. Hawkes, D.C. Holt, J.K.
Townson, R.A. Wichert, ‘Mesotrione: a
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