Application of cross-coupling and metalation chemistry of 3(2H)-pyridazinones to fungicide and herbicide discovery

Full text of DOI:10.1002/jhet.5570420310

April 2005
427
Application of Cross-Coupling and Metalation Chemistry of
3(2H)-Pyridazinones to Fungicide and Herbicide Discovery
Thomas M. Stevenson*, Brett A. Crouse, Tho V. Thieu, Cristina Gebreysus,
Bruce L. Finkelstein, Maya R. Sethuraman, Christina M. Dubas-Cordery
and Donna L. Piotrowski.
DuPont Crop Protection Products, Stine Haskell Research Center, Newark, Delaware 19714
Dedicated to the memory of Michael P. Walker
J. Heterocyclic Chem., 42, 427 (2005).
Introduction.
chemistry from nucleophilic displacement to metal medi-
ated processes for C-C bond formation in hopes of discover-
ing new classes of biologically active pyridazines.
Pyridazinones have played an important role in the chem-
istry of crop protection products. The nucleophilic displace-
ment chemistry of 4,5-dihalo-3-(2H)-pyridazinones has
long been exploited for the synthesis of both commercially
important herbicides and insecticides. Two examples are
shown in Figure 1. It follows that the pyridazinone nucleus
confers biological and physical properties to molecules that
are favorable for their development as crop protection
agents. Therefore, we wished to extend halopyridazinone
Strobilurin Fungicides.
The isolation and structural determination of the fungici-
dal natural product Strobilurin A (3) from the basid-
iomycete fungus Strobilurus tenacellus was the starting
point for fruitful research programs at many companies,
which have subsequently led to commercialization of sev-
eral successful agricultural fungicides. [1] The site of
action of this compound was shown to be inhibition of
mitochodrial respiration at the cytochrome bc complex.
1
[2] The unique and simple β-methoxyacrylate containing
structure proved to be readily amenable to modification
with retention of activity. The natural product was unfortu-
nately very photolabile and therefore not very effective in
testing on whole plants in direct sunlight. A solution to the
photostability problem was soon arrived at as scientists
from both ICI (now Syngenta) and BASF simply replaced
the double bond proximal to the β-methoxyacrylate with an
aromatic ring as in 4. Further modification of the molecule
in both the pharmacophore and side chain led eventually to
Figure 1. Some Commercial Pyridazinone Containing Crop Protection
Products
Figure 2. Evolution of Strobilurin Analogs

428
Vol. 42
a number of commercial products such as Syngenta’s tri-
floxystrobin (6), which contains an oxime containing phar-
macophore and an acetophenone oxime containing side
chain. (Figure 2) The successful modification of the nat-
ural methoxyacrylate pharmacophore inspired scientists at
DuPont to investigate N-methyltriazolinones (7) as cyclic
pharmacophores, which proved to be highly active fungi-
cides. [3] In light of these last pharmacophores, replacing
the triazolinone ring with an appropriately substituted
pyridazinone became an appealing synthetic target.
Synthesis of the target pyridazinone was envisioned to
proceed via a Suzuki coupling of a 5-methoxy-4-halopyri-
dazinone (9). At the ouset of this work in 1994 no transi-
tion metal catalyzed reactions were yet known for the pyri-
dazinone ring system. [4] Our initial work began with a
simple reaction of a commercially available chloropyri-
dazinone (9) with phenyl boronic acid. The coupling car-
ried out with tetrakis-(triphenylphosphino)palladium gave
a good yield of N-methyl-5-methoxy-4-phenyl-3(2H)-
pyridazinone with standard Suzuki coupling conditions. It
turned out that inexpensive bis(triphenylphosphino) palla-
dium dichloride was almost as efficient in promoting the
cross-coupling. Coupling with a boronic acid already sub-
stituted with a typical strobilurin side chain provided the
first target molecule (10), which proved to be an active
fungicide as well as an inhibitor of mitochondrial respira-
tion. (Scheme 1) We then sought a more convergent
approach for analoging.
In order to get compounds with more diverse sidechains
we used commercially available 2-formylbenzene boronic
acid to make a common intermediate. (Scheme 2) We also
turned to the use of the 4-bromopyridazinone (12) as a more
reactive coupling partner since 2-formylphenyl boronic acid
has been reported to be prone to deboronation. [5]
Reduction of the Suzuki product (13) with either lithium
borohydride or more conveniently sodium borohydride gave
the corresponding alcohol in good yield. Bromination pro-
vided a key benzylic bromide (14) that could be used to
introduce oximes of acetophenone as side chains. While a
number of different methods could be used for halogenation
Scheme 1
of the alcohol, PBr in ether at room temperature was most
3
successful. Interestingly, an alternate synthesis via benzylic
bromination of a 4-(o-tolyl)pyridazinone was not efficient.
The reaction of the bromide with oximes of various substi-
tuted acetophenones was efficient and could be carried out
with sodium hydride or potassium carbonate as base to give
15 and related analogs. The compounds with oxime side
chains proved to be very good fungicides. Highest levels of
activity were observed for compounds with 3,5-disubstitu-
tion. Optimal activity for plant protection was seen for the
3,5-dichloroacetophenone oxime (15), which provided
Synthesis of a Pyridazinone Strobilurin Analog
Scheme 2
Analoging Scheme for Strobilurin Analogs

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429
broad-spectrum control of important plant pathogens at 40
ppm. Optimal activity at the site of action (inhibition of
intermediate alcohol gave the benzylic bromide (20),
which was coupled with acetophenone oximes to give
the desired products such as 21. The fungicidal activity
and mitochondrial respiration activity of the pyrimidi-
nones was good. However, the pyridazinone ring system
proved to be slightly more active as a strobilurin phar-
macophore replacement. However, neither of the 6-
membered pharmacophores were as effective as the tria-
zolinone pharmacophore found in 7 in fungicidal testing.
mitochondrial respiration at the cytochrome bc site) was
1
found for product from 3,5-bis(trimethylsilyl)acetophenone
oxime which exhibited low nanomolar inhibition.
We also extended the chemistry to other heterocyclic
ring systems. Most notably pyrimidinones proved to be
very good surrogates for the pyridazinone system.
(Scheme 3) The first step in the process was the synthe-
sis of the appropriately substituted pyrimidinone (17) by
an interesting N-methylation of the 4,6-dimethoxy-
pyrimidine (16). [6] The pyrimidinone (17) was bromi-
nated at the 5-position with NBS to give the Suzuki
Herbicidal Suzuki Coupling Products.
The success of the Strobilurin chemistry led us to inves-
tigate a broader range of 4-bromo, 5-methoxy substituted
Scheme 3
Pyrimdinone Strobilurin Pharmacophore Synthesis
reaction substrate (18). Suzuki reaction of 18 with
pyridazinones in Suzuki couplings. (Scheme 4) Many sub-
strates were prepared by traditional methods via reaction
of mucobromic acid with various aryl or alkyl hydrazines
followed by reaction with sodium methoxide. [7]
2-formylphenylboronic acid gave the expected
5-arylpyrimidinone (19) in good yield. Reduction with
sodium borohydride followed by bromination of the
Scheme 4
Synthetic Methods for Starting Materials

430
Vol. 42
Scheme 5
Selectivity for the methoxide displacement generally was
at least 15:1 in favor of the 5-methoxy product over the 4-
methoxy product when the reaction was carried out in
methanol as solvent. We were easily able to prepare a vari-
ety of N-alkyl pyridazinones by alkylation of commer-
cially available 4,5-dibromopyridazinone. The alkyl
groups and the methoxy group could be appended in a sin-
gle step by reaction of alkyl bromides or iodides using
sodium methoxide as both base and nucleophile. [8]
Arylation of the 4,5-dibromopyridazinone was achieved
by copper mediated reaction with triarylbismuth reagents
in the presence of triethylamine. [9] Arylation was also
possible by a related process using commercially available
boronic acids in place of the triarylbismuth reagents. [10]
We broadly investigated coupling of these pyridazinone
substrates with a variety of different commercially avail-
able phenyl boronic acids. Two active classes of herbici-
dal pyridazinones emerged from the Suzuki coupling prod-
ucts. We found interesting bleaching herbicide activity for
compounds 22-27 derived from coupling with 3-trifluo-
romethylphenyl boronic acid and 3-trifluoromethoxy-
phenyl boronic acid. (Table 1) Highest activity was found
for the N-aryl compounds (22) and (23). The most active
analogs controlled a variety of important weeds at 400-
1000 g/Ha. The site of action for these compounds was
determined to be inhibition of phytoene desaturase, which
is a key step in the biosynthesis of carotenoids in plants.
Relative pre-emergent herbicidal activity in greenhouse
testing for the compounds in Table 1 at 1000 g/Ha was 22
> 23 > 24 > 25 >> 26, 27.
Herbicidal Suzuki Coupling Products from o-Tolyl Boronic Acid
log synthesis, but poor yields were obtained in radical
bromination. Because of the resemblance of the o-tolyl
products to herbicidal acetyl coA carboxylase (ACCase)
inhibitors from Syngenta and Bayer [11], we carried out
demethylation of 28 to the hydroxypyridazinone (29) with
boron tribromide in dichloromethane. To change the phys-
ical properties of the compound, we esterified the free
hydroxy group with pivaloyl chloride to give 30. Both 29
and 30 showed good pre-emergent herbicidal activity on
grass weeds at 1000 g/Ha, as well as symptomology con-
sistent with the herbicidal effects of ACCase inhibitors.
[11] Repeating the synthetic sequence with pyridazinones
bearing larger N-substituents (phenyl, benzyl and t-butyl)
was equally successful, but only the N-methyl products
showed good levels of herbicide activity.
A second class of herbicidal compounds was derived
from o-tolyl boronic acid. (Scheme 5) We had synthesized
a sizable quantity of the N-methylpyridazinone Suzuki
adduct (28) as a potential intermediate for Strobilurin ana-
Scheme 6
Table 1
Herbicidal 4-Arylpyridazinones
R
R
Reaction
Product
Yield
(%)
1
2
3-F-Ph
3-CF
3-OCF
22
23
24
25
26
27
83
46
80
88
92
72
3
3-CF -Ph
3
3
Ph
Me
3-CF
3-CF
3-CF
3-CF
3
3
3
3
4-CF -Ph
3
t-Bu
Nonselective Coupling Reaction of 4,5-Dibromopyridazinones

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431
Selectivity of Suzuki Couplings on Dihalopyridazinones.
completely suppressed, only one monoaryl product, for
example 37, is obtained resulting from coupling at the 4-
position. Palladium catalyzed reactions or nucleophilic
displacement reactions may then be used to functional-
ize the 5-position.
As we continued to explore the chemistry we investi-
gated the reaction of 4,5-dibromopyridazinones such as
11 with boronic acids. (Scheme 6) As evidenced by the
methoxide reactions shown earlier, nucleophilic substi-
tution reactions are fairly selective for the 5-position on
these substrates. However, Suzuki couplings with vari-
ous aryl boronic acids proved quite non-selective. With
1.2 eq of a boronic acid, 2 difficult to separate monoaryl
products (31) and (32) as well as bisaryl product (33)
and starting material (11) were observed. The reactions
could readily be pushed completely to the 4,5-bisaryl
product (33) with 3 eq. of boronic acid. The lack of
selectivity limited the potential synthesis of compounds
with different carbon bound substituents at the 4- and
5-positions
The problem of how to get different carbon bound sub-
stituents on the 4- and 5-positions in a selective manner
still remained of interest. [12] We felt that we needed to
find a way to get different halogens on each of the two
positions. No direct way to accomplish this was readily
apparent, but an interesting report from Slovakian work-
ers in the 1970’s gave us one potential solution. [13]
(Scheme 7) They reported that inexpensive mucochloric
acid (34) reacted with methyl magnesium iodide in an
unusual manner to give a selective halogen exchange
reaction resulting in an iodo/chloro mixed mucohalic
acid (35). After repeating this reaction we examined the
reaction of 35 with methylhydrazine, which resulted in
ring closure to 5-chloro-4-iodopyridazinone (36).
Extension of the cyclization with other hydrazines has
not yet been investigated, but presumably would also
give analogous N-substituted pyridazinones. Suzuki
coupling reactions result in products from reaction at the
4-position with this substrate. While disubstitution is not
Pyridazinones in Other Cross Coupling Reactions.
We also investigated a number of other cross coupling
reactions. We were very interested in investigating ben-
zylic zinc reagents in Negishi type couplings. (Scheme 8)
The zinc reagents were produced from the reaction of zinc
activated by Knochel’s method with the appropriate ben-
zylic bromide. The coupling reaction was not very effi-
cient using Pd(PPh ) Cl . However good yields of 4-ben-
3 2
2
zylpyridazinones such as 39 were obtained with N-aryl-4-
bromo-5-methoxypyridazinone (38) by use of the tri-(2-
furyl)phosphine (TFP) ligand. [14] While we did not
investigate the use of iodopyridazinones like 36 in Negishi
couplings, it is probable that less active catalysts can be
successfully used with these substrates.
Scheme 8
Negishi Coupling of Benzylic Zinc Reagents
Scheme 7
Introduction of a methyl group was successful with
trimethylaluminum. (Scheme 9) Reaction of a 4-bromo-5-
methoxypyridazinone (40) with Pd(PPh) as catalyst in
4
refluxing toluene cleanly gave the desired 4-methylpyri-
dazinone (41). Under the same conditions attempted selec-
tive introduction of one methyl group into the 4,5-
dichloropyridazinone (42) using 1 equivalent of aluminum
reagent proved that trimethylaluminum was capable of
transferring at least 2 of its methyl groups to the 4,5-
dihalosubstrates to give 43. Both chloro and bromopyri-
dazinones are good coupling partners for aluminum
reagents. While we have not investigated this, based on
the work of Benneche and Undheim it seems likely that
other trialkylalanes would also transfer alkyl groups to
halopyridazinones. [15]
Synthesis and Reactivity of a Mixed Dihalopyridazinone

432
Vol. 42
Scheme 9
Scheme 11
Cross Coupling with Organoaluminum Reagents
Stille coupling reactions proved very valuable in the
strobilurin optimization program. Stille coupling of 12
with hexamethyldistannane gave a tin containing pyridazi-
none (44) suitable for further reaction with aryl iodides to
give previously elusive strobilurin analogs. (Scheme 10)
This allowed us to prepare strobilurin analogs like 45 from
substrates from which boronic acids could not be readily
synthesized due to incompatibility with organometallic
reagents. For the reactions of the stannylpyridazinone (44)
with aryl iodides we mainly used Liebeskind’s modifica-
tion of the Stille coupling, which employs CuI as a co-cat-
alyst. [16] Alternatively, TFP was also successfully
employed as a ligand for the Stille coupling. While yields
were only moderate, this sequence allowed us to easily
synthesize and test some hard to obtain strobilurin analogs
such as 45.
Sonogashira Coupling Reactions
carried out on the bromopyridazinone 12 in refluxing
acetonitrile with CuI and Pd(PPh ) Cl as catalysts to
3 2
2
give, for example, 46 from phenylacetylene. Use of an
iodosubstrate (36) allowed us to carry out similar reac-
tions at room temperature. The 4-iodo-5-chloropyri-
dazinone (36) gave a very selective coupling reaction at
the 4-position with acetylenes such as 4-fluoropheny-
lacetylene to give products such as 47. This chemistry
potentially could be used to produce heterocycles by
cyclization of 47 with nucleophiles introduced at the 5-
position in a subsequent step. [17]
Carbonylation of pyridazinones was also possible under
conditions of high pressure. (Scheme 12) The 4-bromo-5-
methoxypyridazinone (12) did not react with carbon
monoxide at atmospheric pressure (balloon) even in the
presence of a highly active carbonylation catalyst. [18]
However, when a higher pressure of carbon monoxide was
Scheme 10
Scheme 12
Stille Coupling Strategy through a Stannylpyridazinone
Introduction of acetylenes into the 4-position of the
pyridazinone can also be readily accomplished.
(Scheme 11) Sonogashira coupling reactions were
Carbonylation Chemistry of Pyridazinones

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433
used carbonylation proved much easier. For example, a
good yield of the 4,5-diester (48) could be obtained from
11 with a less active catalyst and ethanol under 100 psi of
carbon monoxide in a pressure tube. [19]
prior to quenching with the electrophile. Importantly, ben-
zaldehydes (the electrophiles needed for the HPPO targets)
were good substrates. In addition to benzaldehydes,
trimethylstannyl chloride, trimethylsilyl chloride, methyl
iodide, deuterium oxide and carbon dioxide gave the
expected products while dimethylformamide did not. The
products with benzaldehydes were generally not isolated,
but converted to ketones by stirring the crude products at
Halogen-Metal Exchange Chemistry of Pyridazinones.
Inhibition of the enzyme p-hydroxyphenylpyruvate oxy-
genase (HPPO) is the mode of action of compounds like
Sulcotrione 49 from Zeneca (Now Syngenta). Other
classes of inhibitors include hydroxypyrazoles such as 50
from Nissan. The most potent inhibitors share structural
features that include a 2,4-disubstituted or 2,3,4-trisubsti-
tuted aryl ketone and an acidic enolic hydrogen. [20]
(Figure 3) Comparing the cyclohexanedione and the pyra-
zolone rings, we envisioned a pyridazinone like 51 might
serve the same function. A pyridazinone as the dione com-
ponent could be imagined to come from demethylation of
a 5-methoxypyridazinone which might be synthesized
from one of our cross coupling intermediates.
room temperature in toluene with excess MnO prior to
2
purification. Some of our results from lithiation chemistry
are reported in Table 2.
R
E
Reaction
Product
Yield
(%)
Me
Et
t-Bu
Ph
Me
Ph
CO-(2,4-DiClPh)
CO-(2,4-DiClPh)
CO-(2,4-DiClPh)
CO-(4-FPh)
52
53
54
55
56
57
43[a]
48[a]
74[a]
49[a]
23
SnMe
3
CO H
28[b]
2
[a] Yield includes oxidation of crude alcohol with MnO . [b] Isolated
2
by esterification with methanol and thionyl chloride.
While the insolubility frustrated our attempts to repro-
ducibly use N-methyl substrates in this chemistry, using
iodopyridazinone (36) and its methoxide displacement
product (58) solved this problem. (Scheme 13) We were
able to readily carry out halogen-metal exchange on the
4-iodopyridazinones either before or after methoxide dis-
placement. The solubility of both 36 and 58 was very good
at low temperatures. In contrast to the straightforward
Figure 3. Herbicidal Inhibitors of p-Hydroxyphenylpyruvate
Dioxygenase (HPPO).
We felt it might be possible to do halogen-metal
exchange chemistry on our Suzuki substrates to make
5-benzoylpyridazinones which could serve as precursors
to the potential HPPO inhibitors. Attempts at lithiation
began with the N-methylpyridazinone (12), which was our
key intermediate for strobilurin analogs. However, the
compound was insoluble in ether and THF below –30 °C
and gave rise to capricious results upon lithiation. The
addition of TMEDA somewhat mitigated the solubility
issues, but did not fully resolve the reproducibility issues.
However, when any other pyridazinone with a larger
N-substituent (even ethyl) was used solubility was com-
plete even at – 70 °C. Under these conditions halogen-
metal exchange was smooth although the lithium reagents
were not highly reactive. [21] In a typical reaction, n-butyl
lithium and TMEDA were added to the substrate and the
resulting mixture was stirred at – 70 °C for 10-15 minutes
Scheme 13
Halogen-Metal Exchange on Iodopyridazinones

434
Vol. 42
halogen-metal exchange reaction of 36, 4,5-dibromopyri-
dazinones gave complex mixtures of products upon
attempted reaction with n-butyllithium.
Scheme 15
With the reproducible formation of the lithiated pyri-
dazinones in hand we were able to synthesize a variety of
4-benzoylpyridazinones. As outlined in Scheme 14 for the
N-ethylpyridazinone (60), lithiation of the various pyri-
dazinones followed by quenching with 2,4-dichloroben-
zaldehyde and oxidation with MnO gave the masked tri-
2
carbonyl (53). Deblocking with BBr or TMSI gave the
3
desired targets such as 62. Extension of this route to other
N-substituents and other 2,4-disubstituted benzaldehydes
allowed the synthesis of a diverse set of compounds exem-
plifying structure 51. Compounds in which the N-sub-
stituent was a small alkyl group like 62 proved to be good
herbicides. [22] Bleaching symptomology was observed
and site of action work confirmed the activity was due to
HPPO inhibition at nanomolar concentrations.
Synthesis of Bicyclic Sulfone Containing Pyridazinones
molecules such as 64. Capped compounds like 64 had
increased mobility on TLC and higher solubility in organic
solvents. Hydrolysis of these “protecting groups” in vivo
reveals the active herbicide.
Scheme 14
The 5-benzoylpyridazinones studied in this work
showed good levels of activity in post–emergence testing.
Significant safety towards corn was seen in testing of a
variety of analogs. The best compounds such as 63 con-
trolled a variety of important weeds at rates as low as 62-
125 g/Ha post-emergence in the greenhouse. Compounds
with smaller N-substituents such as methyl or ethyl had the
highest levels of activity. The structure-activity relation-
ships for substitution in the benzoyl ring followed pub-
lished trends from the cyclohexanedione literature. [20]
Synthesis Route to Benzoylpyridazinone Inhibitors of HPPO
Conclusions.
We have shown that pyridazinones are excellent sub-
strates for metal assisted chemistry. The readily available
halogenated pyridazinones are also easily substituted at the
5-position with nucleophiles. In combination, metal
assisted reactions and nucleophilic substitution chemistry
provide chemists with the opportunity to synthesize a very
diverse group of pyridazinones that could not have easily
been made earlier. The history of pyridazinones success-
fully serving as both pharmaceuticals and crop protection
agents bodes well for a new generation of pyridazinones,
which will be synthesized using emerging synthetic meth-
ods in conjunction with established pyridazinone chemistry.
An important component of a new generation of HPPO
inhibitors is the presence of a bicyclic sulfone. Our first
choice for a bicyclic sulfone was a 4,4-dimethylbenzoth-
iopyran since it would be compatible to both lithium
reagents as well as to BBr . Following the synthetic
3
method outlined in Scheme 15, we were able to make the
desired target pyridazinone (63) from the pyridazinone
(56), which showed improved activity as a herbicide.
Oxidation of the cyclic sulfide to the sulfone with Oxone
or hydrogen peroxide could be carried out either prior to or
after demethylation. No oxidation of the pyridazinone ring
was observed. In addition to the good herbicidal activity,
we also observed corn safety with 63. The physical proper-
ties of the pyridazinones could be changed readily by
using capping groups. Reaction with thionyl chloride gave
the 5-chloro derivative. Capping with sulfonyl chlorides
and acid chlorides respectively resulted in highly active
Acknowledgements.
We would like to thank the DuPont Crop Protection
plant response team for carrying out all of the herbicidal
assays for the compounds in this paper. The DuPont Crop
Protection plant disease group performed the fungicidal

April 2005
435
[5] T. Watanabe, N. Miyaura, A. Suzuki, Synlett., 207 (1992).
[6] D. J. Brown and T. Teitei, Aust. J. Chem., 17, 567 (1964).
[7] K. Dury, Angewandte Chem., 77, 282 (1965).
assays on the strobilurin analogs. John Groce, Gina
Blankenship and James Doughty generated analytical data
for all of the compounds in the paper. Rand Schwartz and
Douglas Jordan provided mitochondrial respiration inhibi-
tion data for the strobilurin analogs. Vern Wittenbach,
Wayne Hanna, Carl Maxwell and Beth Esrey provided site
of action information for the herbicidal pyridazinones dis-
closed in this paper. Dominic Chan, W. Christian Petersen
and Steve Hartzell provided triarylbismuth reagents used
for the N-arylation of pyridazinones. We would also thank
Michael P. Walker for suggesting key strobilurin analog
targets which greatly aided our optimization efforts in that
program.
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