Chapter 5
The Discovery of Imazamox, a New Broad-Spectrum Imidazolinone Herbicide
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ThomasM.Brady, Barrington Cross, RobertF.Doehner, John Finn, and David L. Ladner Cyanamid Agricultural Research Center, American Cyanamid Company, P.O. Box400,Princeton,NJ08543-0400
The new soybean herbicide, imazamox, 1 differs significantlyfromthe other imidazolinone herbicides because of its soil residual behavior, allowing rotational planting of imidazolinone-sensitive crops. This behavior was the key to its discovery. In order to determine if soil persistence could be related to structure, an early set of imidazolinone analogs had been field tested. A synthesis program was subsequently undertaken to optimize activity and to find active compounds with reduced hydrolytic or metabolic stability. Some of these newer analogs had much less pre- than postemergence greenhouse activity, and we hypothesized which substituents were responsible for their soil deactivation. The results pointed to advanced studies of the highly active 5-methoxymethyl compound, 1. In soil, 1 undergoes degradation to the 5-carboxy analog, 9, a compound with low herbicidal activity. With the discovery of the first imidazolinone herbicides by Dr. Marinus Los and commercial introduction of several products in the last ten years, one might wonder what would drive an effort to add yet another soybean-selective analog to the marketplace. In contrast to the initially introduced compounds in the series, second-generation compounds are guided by the luxury of experience and a firmer understanding of market needs. As a consequence, the discovery process is driven by somewhat different criteriafromthat of a totally new work area. Completely new areas of chemistry are usually discovered because of potency and commercialized if a lead can be improved through analog synthesis to a field-active material with selectivity in a useful crop. In the discovery of imazamox, field activity and soybean selectivity of imidazolinones had already been accomplished; the mission was to find an new analog which additionally had specific soil residual characteristics. The commercial reason for doing so were to expand the use of the imidazolinone chemistry into markets where existing compounds were excluded because of followcrop injury. This included the usual soybean / corn crop rotations in colder climates as well as areas where soybeans are followed by very sensitive crops such as canola or sugarbeet. Our belief was that this could be accomplished through optimization of the chemical structure, and through the use of predictive screening methods and metabolism studies for selecting field candidates. 30
©1998 American Chemical Society
In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
31
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1 imazamox
The commercialized imidazolinone herbicides are shown in Fig. 1. The differences in structure among these compounds are the key factors for determining their end utility. In other words, the substitution pattern of the benzene or pyridine ring residues is directly responsible for selectivity or lack thereof, and, as will be shown for imazamox, for soil residual characteristics. Figure 1. The Imidazolinone Herbicides
5
6
imazaquin
imazamethabenz methyl
Design Considerations Fortunately, a great deal of structure-activity information had been gathered during the development of the first imidazolinone herbicides and there had been some importantfindingsand soil metabolism studies of the commercial compounds. From this information, several points were key to the design of a shorter residual compound. First was the knowledge that in imazethapyr, 3, and in imazamethabenz methyl, 6, deactivation in plants occurs by hydroxylation of the alkyl side chain (1). This hydroxylated product is then further metabolized to non-herbicidal components within the plant. We believed that oxidation of a side chain might provide a mechanism for soil deactivation as well. ® Registered trademark, American Cyanamid Company
In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
32 Figure 2. Metabolic Pathways of Imidazolinones
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3
7
Secondly, structure-activity relationships (SAR's) had been determined and showed that functional groups which were already oxygenated, such as aldehydes 8 and carboxylic acids 9 were lower in activity than the corresponding un-oxidized analogs (2). This was most evident for preemergence herbicidal activity, lending support to the postulate that soil activity would be lower for such compounds.
8
Finally, we felt it was important to concentrate the analog work on pyridine analogs which were 5- or 5,6-substituted. Although imidazolinone modifications elsewhere provide compounds which are converted to inactive compounds in the soil (3), we concluded from our knowledge of imidazolinone SAR's that such modifications also usually decreased the initial herbicidal activity below useful levels. The strategy can be summarized as one which sought active herbicides of type I which could be converted to inactive metabolites of Type II in the soil. This parallels the profile of selective compounds, differing only in the location of the deactivation, i.e., soil instead of crops. Figure 3. General Scheme for Deactivation of Imidazolinones
Active Herbicide
Deactivated Metabolite
In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
33 Selection of Analogs and Screening
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Some early experiments had been carried out in an attempt to determine if heterocyclic ring analogs of imazaquin were more susceptible to metabolism and safer to rotational crops. In this experiment, the six greenhouse-active compounds, prepared in support of patent filings, and shown in Figure 4, were applied postemergence as soybean-selective herbicides in Minnesota and Wisconsin. The following year, corn was planted in the same plot and the level of injury due to herbicide carry-over was measured. This experiment was based on the hypothesis that the heterocycles might be more likely to chemically break down than a benzene ring. Although we had no prior evidence to support this, it was known that sulfonyl ureas containing heterocyclic ring substituents are more prone to rapid soil metabolism, for example (4). Figure 4. Heterocyclic-fused Imidazolinone Analogs
13
14
15
From this rather long-term experiment we concluded that some of these compounds were not particularly effective as herbicides in the field, and many of the more active ones caused unacceptable injury to the rotational corn crop. The only compound which looked somewhat promising was 14, the pyranopyridine compound. The similarity of this structure to that of imazamox is now evident, and this indeed provided us an important clue at the time. Field experiments, especially the kind just described, have inherent drawbacks with respect to the time required. It was important that laboratory experimental models be developed so that many more analogs could be examined for their potential as low soil residual field candidates. Indeed, many analogs had been prepared in support of patent filings, directed to some extent, by a QSAR model which suggested highly active 5-substituents (5). When short residual activity was also desired, consideration was given to two classes of compounds. Thefirstclass we believed would have a tendency to hydrolyze to less active compounds: these included masked carboxylic acids and protected aldehydes. The other class consisted of compounds whose substituents were postulated to provide some metabolic activation towards enzymatic oxidation: these included the methoxymethyl and methylthiomethyl compounds. The details of some of this
In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
34 work have already been reported (6). Table I includes the compounds which were evaluated in this investigation. The bioactivity of each shown for comparison in Table I. Both pre- and postemergence activity is shown. Some of these, such as the aldehyde, 8, and carboxylic acid, 9, were obviously inferior as herbicides. Noteworthy was the tendency of some, such as the 5-methylthiomethy 1 coompound, 25, to be substantially more active post- than preemergence. We viewed this as confirmation that the profile was being influenced by structure, since most imidazolinones are more active preemergence.
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Table I. Relative Pre- and Postemergence Herbicidal Activtiy and Soil Half-Life of Various 5-Substituted Pyridine Imidazolinones
Relative Activity* Postemergence
Relative Activity* Preemergence
Half Life, Days
MeOCH -
10
8.5
22
5,6-benzo
4
4
42
HCO
2
0
20
14 24
5,6-pyrano[4,3]HOCH -
4 4
4.5 3
44 21
25 26
MeSCH EtO-
2.5 8.5
0 7
1 23
27
MeOCH CH 0-
8.5
7
15
28
MeOCH 0-
8
6
4
29
S-CH CH -S-CH-
2.5
2
2
30
0-CH CH -0-OH-
7
5.5
18
31
MeO-N=CH-
9.5
8.5
25
32
2
2
2
2
2
2
2
2
2
2
Me-N-N(Me)-CH-
4
4
70
35
(Me>2NCO-N-CH CH O-CH-
2
2
2
r
2
0
20
2.5
2
>70
4
4
