The Discovery of the Imidazolinone Herbicides from the Perspective of

Chapter 3

Downloaded by UNIV OF GUELPH LIBRARY on June 18, 2012 | http://pubs.acs.org Publication Date: May 14, 1998 | doi: 10.1021/bk-1998-0686.ch003

The Discovery of the Imidazolinone Herbicides from the Perspective of a Discovery Chemistry Manager Gerald Berkelhammer Cyanamid Agricultural Research Center, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400

Marinus Los's discovery of the imidazolinone herbicides is placed in the historical perspective of agricultural research at the American Cyanamid Company. Dr. Los's contributions to the project, as well as two milestones in the work leading to the imidazolinones, are discussed.

Marinus Los's discovery of the imidazolinone herbicides stands with Benjamin Duggar's discovery of the tetracycine antibiotics as one of the two most important scientific achievements in the history of the American Cyanamid Company. This paper will place Dr. Los's achievement in the historical perspective of agrochemical research at Cyanamid, deal with Dr. Los's contribution to the imidazolinone project, and finally, discuss two pivotal milestones in the imidazolinine story. Short History of Cyanamid Agricultural R&D American Cyanamid was created as an agricultural chemical company. It was founded in 1907 as the American licensee for the new German process to make calcium cyanamide by fixing atmospheric nitrogen. The product was sold as the first synthetic fertilizer. Although Cyanamid could be said to have entered the pesticide business in 1920 when it bought at 50% interest in the Owl Fumigating Company of Azusa, California, a company that specialized in cyanide furtigation of orange and lemon trees, thefirstreally important moves into pesticides occurred after World War II. A Cyanamid research executive was one of those who examined Gerhard Schrader's laboratory at IG Farben after the war, and he brought home news of parathion, TEPP, and the other Schrader organophosphates. This inaugurated some intensive synthesis and process work in organophosphate chemistry, which led to the discovery and commercialization of several products over the next 15 years or so, including malathion, phorate, and dimethoate.

©1998 American Chemical Society

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

17

18 S II (CH 0) P-S-CH-COOEt 3

(CH 0) P-SCH CONHCH

2

3

2

2

(C H 0)2P-SCH SEt

3

2

5

2

CH -COOEt 2

Malathion

Phorate

Dimethoate

Also emerging in the 50's were a few compounds that were not phosphates or insecticides. Ν

Ν


C H ( C H ) N H C N H · HOAc 3

2

Ν

ILΝ JLN H

II n

Η

(CH )3N CH CH C1 CI 3

2 2

2

2

2

Chlormequat

Amitrole Dodine

Of these only dodine, a fungicide, was a Cyanamid discovery. 3-Aminotriazole, a herbicide, was discovered by what was then called the American Chemical Paint Company and co-developed by Cyanamid. Chlormequat was discovered by Tolbert at Michigan State University and licensed to Cyanamid and became a rather important PGR. The above compounds were discovered in the late 1940's and 1950's. The decade of the 1960's presented a different picture. Temephos is an interesting compound in that it is so safe that it is allowed to be used in drinking water, the only insecticide that can be so used. It gained some recent renown when Cyanamid donated several million dollars worth for use in Jimmy Carter's Guinea Worm Eradication Program, but its sales have been largely limited to public health and mosquito control. Similarly, although phosfolan had some very good years on Egyptian cotton, it never was registered in the U.S. and it was not a big winner over time.

^(CH 0) PO-^^-S 3

2

S

V )=NP(OEt)2 L

Temephos

S

R = H: Phosfolan R = C H : Mephosfolan 3

A new director of agricultural research, George Sutherland, was appointed in 1970. Sutherland changed discovery approaches at the Princeton Agricultural Center in several ways. One was to make discovery chemistry more goal-oriented and leadoriented. A second was to breach the walls between discovery synthesis groups in different end-use areas, allowing a concentration of synthesis effort in promising new areas of chemistry as they emerged. Another important event occurring at about the same time was the acceptance by the corporation of the so-called Affleck prospectus. Dr James Affleck, trained as a Ph.D. organic chemist and later President and Chairman of the Board of American Cyanamid, was CEO of the Agricultural Division at the time, and he persuaded corporate management in 1969 to expand the discovery program in herbicides and PGR's by 15 people in 1970. Whether the new resources and an accompanying, almost palpable, change to a can-do atmosphere had anything to do with it or not, the fact is that by the end of 1971, Cyanamid's R&D had produced three outstanding development prospects:


19

0 N

H C

2

3

X

®,CH

3

S

Τ

CH

(C H 0)P-SCH S-f-Bu

3

2

CH Pendimethalin

5

2


3

Difenzoquat

Terbufos

These were the turnaround products for Cyanamid's agricultural business (two of them herbicides), thefirstfromCyanamid's own research after 25 years of trying. It was into this background and this atmosphere that Dr. Marinus Los was promoted to group leader of the Plant Growth Régulant Synthesis Group in early 1971. Background of Marinus Los Dr. Los was born in the Netherlands, was educated in England and Scotland, did postdoctoral work in Canada, and joined the American Cyanamid Company at the Lederle Laboratories in Pearl River, New York in 1960. From 1960 to 1969, at Pearl River and then Princeton, New Jersey, he worked on the synthesis of steroids as metabolic and estrus regulators. After a year at Edinburgh University in the pharmacology department, he rejoined Cyanamid in 1970 in the Plant Growth Régulant Synthesis Group and became group leader shortly afterwards. The Imidazolinones Compounds 1 and 2 afford an idea of the distance Los and his group traveled in the imidazolinone project. Compound 1 is the plant growth regulator lead that Los picked up in 1971 as the new PGR group leader. Compound 2 is currently Cyanamid's most important crop chemical, imazethapyr, which was synthesized 10 years later. The only characteristic the two molecules obviously have in common is a methyl and an isopropyl group joined to the same carbon. The journey from 1 to 2 involved a great number of chemists and biologists. At one point over twenty chemists, more than one-half Cyanamid's total synthesis effort in agrochemicals at the time, were engaged in the project. Many of these individuals made very important contributions to the project. However, there was no doubt that Marinus Los led the charge and set the direction. Ο

ι Beginning

2 Imazethapyr One of the "Ends"

As early as December, 1973, when his interest was still primarily in plant growth regulators, Dr. Los realized that the tricyclic compounds that he had earlier discovered as ring-closure products of compounds like 1 could likely be ring-opened to afford compounds somewhat similar to DPX 1840, a PGR reported by DuPont (1). The following is some material Los presented at an internal meeting of Cyanamid chemists and biologists engaged in PGR synthesis and testing held in December 1973. In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

20 Ο

Auxin transport inhibitor Breaks apical dominance

DuPont PGR Sugar increase, yield increase, etc.


Prepare compounds such as: Ο

As it happens, it wasn't until over a year later and for totally different reasons that this alcoholysis was actually studied, but it is clear that Los was thinking about imidazolinones long before they showed up in the laboratory. During all this time and until the successful synthesis of imazamethabenz methyl, imazapyr, imazaquin, and imazethapyr herbicides, Dr. Los called the shots and made the major decisions. Major Imidazolinone Milestones. Two of these decisions became major turning points in the imidazolinone project. The discoveries that led to both these decisions contained serendipitous elements. PGR's to Herbicides. The first occurred when synthesis of the interesting PGR AC 94377 (2) for a field trial affoarded a small amount of the tricyclic product 3.

3

This cyclized version of AC 94377 had essentially the same PGR properties of AC 94377 itself but was a bit slower acting, a fact attributed to slow hydrolysis back to AC 94377. The question was whether this was an interesting discovery worthy of followup or merely a distraction which, because of limited resources, would perhaps put off the discovery of a phthalimide more active than AC 94377. The decision was not that difficult to make. Suppose a competitor discovered these tricyclic


21


put off the discovery of a phthalimide more active than AC 94377. The decision was not that difficult to make. Suppose a competitor discovered these tricyclic compounds and found a way to make them that did not proceed through our patented phthalimides. We could not be sure that some of these isoindolediones might not compete favorably as plant regulators with the phthalimdies. There was really very little choice; we had to make a number of isoindolediones and file a patent. It was a pleasant surprise when, just a short way into this little side project, the tricyclic compounds began exhibiting interesting herbicide activity instead of, or in addition to, growth régulant properties. In particular, compound 4 soon became a field candidate for use against perennial weeds.

4

Annoying Crystals. The second important discovery occurred when some annoying white crystals separated out of a formulation of 4 that was about to be sent to the field.

CH OH 3

est CH O^HN^( 3

Spectroscopic analysis indicated that methanol, which was a minor constituent of the formulation, had added across the double bond to give the adduct shown. No doubt Los's first reaction was to tell the formulations group to get the bloody methanol out of their surfactant and come up with a new formulation quickly so we could get this compound to the field in time. Upon reflection, the methanol adduct looked interesting and deserved to be tested. Indeed, it turned out to have some herbicidal activity. The First Imidazolinone. Of much greater significant was that when an attempt was made to make some more of the adduct, this time under basic conditions, the methoxide, instead of adding to the double bond, cleaved the carbonyl-nitrogen bond, thereby forming 5. So here was our first imidazolinone. It appeared 15 months after Dr. Los first wrote down its general structure and the equation to produce it. Though it would undoubtedly have been made in due course anyway, the immediate cause of its preparation was the natural curiosity of an organnic chemist about an unexpected precipitate caused by a little methanol in a formulation. Lessons to be Learned What are the lessons to be learnedfromthe imidazolinone story? No doubt, there are many. One deserving special emphasis is that the combination of a highly creative and soundly trained individual practicing the art and science of organic chemistry was, and still is, far and away the best means of discovering new biologically active agrochemicals and pharmaceuticals. Organic chemists can discover something


22

CH CT H N - ^ t 3


COOCH3

because they are intelligent or they are lucky, they can find something because of curiosity, or based on a solid knowledge of biochemistry, or a desire to protect the economic interests of an employer through patents, or a combination of all of these. But whatever the reason for their discoveries, the things that organic chemists find are new compositions of matter, one of which just might be the one they, or somebody else, is looking for. So this story has two heroes. One is Marinus Los, the creative and talented chemist who discovered the imidazolinones, and the other is the grand and glorious science of organic chemisty itself. Literature Cited 1. Johnson, A.L.; Sweetser, P.B. (duPont), US 3,948,937 (4/6/76). 2. Los, M.; Kust, C.A.; Lamb, G., Hort. Science 1980, 15, p. 22.


The Discovery of the Imidazolinone Herbicides from the Perspective of

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