Chapter 2
Anomalies and the Discovery of the Imidazolinone Herbicides
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Marinus Los Cyanamid Agricultural Research Center, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400
The imidazolinone herbicides have become important tools used by farmers around the world. The role that anomalies, both biological and chemical, played in the discovery and development of the imidazolinones is detailed. These anomalies led to new avenues for exploration, to new biologically-active structures, and sustained the project for more than fourteen years.
The imidazolinone story spans some fourteen years of research. It is of interest and instructive to reflect on the factors that both started the project and sustained it for the length of time. During this time there were milestones, better described as anomalies, which fueled the project and it is these anomalies that will be the basis for this paper. Anomalies are not an unusual happening in any research project and could, in fact, be cited as one of the characteristics of a successful one. In the imidazolinone project these anomalies occurred, for example, in the formation of a minor by-product from a seemingly trival reaction or as an unexpected outcome of what appeared to be a rational alternative synthesis for a known compound. Thomas S. Kuhn of the Massachusetts Institute of Technology stated it very clearly in his book "The Structure of Scientific Revolutions": "Discovery commences with the awareness of anomaly, i.e. with the recognition that nature has somehow violated the paradigminduced expectations that govern normal science. It then continues with a more or less extended exploration of anomaly. And it closes only when the paradigm theory has been adjusted so that the anomalous has become the expected." . This in essence describes the imidazolinone project. The project started with the screening for herbicidal activity of a phthalimide 1 which had been prepared in a pharmaceutical project as an analog of an anticonvulsant. This compound was not very active but had biological properties rarely seen in weakly active herbicides - it controlled two very important perennial weeds, Cyperus rotundus and Convolvulus arvensis. 2
8
©1998 American Chemical Society
In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
9
Χ
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1 2
Η Cl
3
(AC 94377)
This then was the impetus for a small synthesis effort. This did not result in a "better" herbicide but instead yielded a compound 2 with essentially no herbicidal activity but rather activity not unlike that of gibberellic acid. This was an anomaly and, as Professor Kuhn stated, led to the "exploration of the area of anomaly". By the usual chemical manipulations of the structure, it was possible to greatly increase the level of activity in compound 3. It is remarkable that a compound of such simplicity can indeed mimic the rather complex structure of gibberellic acid with its many chiral centers.
GA
3
AC 94377 was field tested extensively and relatively large quantities were required. This rather simple molecule can be assembled in a number of ways. The 3chlorophthalic anhydride can be reacted with the approparite α-amino nitrile, amide, or acid. All three routes were examined. The one from the α-amino amide yielded the phthalamic acid 4 as a mixture of isomers which could be cyclized with acetic anhydride to the imide 3 in high yield. As an alternative dehydrating agent, the use of trifluoroacetic anhydride was examined. Although it also afforded 3 as the major product, a small quantity of a by-product was isolated which proved to be the result of the further dehydration of 3 to give 5.
CI 5
This was another anomaly and when it found that the biological properties of 5 were very similar to those of 3, this area of chemistry demanded further exploration. A good method was required for the synthesis of compounds such as 5. In fact, the
In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
10 cyclization of the imides such a 1 with either sodium hydride or sodium hydroxide pels proved to be most efficient.
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1
6
These tricyclic derivatives such as 6 proved to be pivotal in the discovery and development of the imidazolinones. First, they were novel structures with interesting biological activities and thus deserved attention. Secondly, while they themselves did not reach the levels of activity and selectivity required for commercial development, their structures did lend themselves to further modification and manipulation. It was quickly discovered that compounds such as 6 could be reduced with sodium borohydride to the corresponding dihydro derivative which retained high herbicidal activity. The mixture of isomers could be readily separated by fractional crystallization. The field testing of 6 required that it be formulated. Ο
On standing, the experimental formulation deposited a nicely crystalline material, analysis of which indicated that this material had a molecular formula consisting of 6 plus the elements of methanol. The structure could not be assigned unambiguously based on nmr data and thus attempts were made to synthesize the compound. The reaction of 6 with methanol was examined under a variety of conditions. Under acidic conditions, methanol added to 6 to give a product identical to that isolated from the experimental formulation and this proved to have structure 7. Conditions were established under which a variety of alcohols, thiols, amines and water would add to structures such as 6.
^XOOCH
... OCH
3
^
N
3
f
HN
