Chapter 2
Discovery of the Sulfonylurea Herbicides 1
G. Levitt
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Agricultural Products Department, E. I. du Pont de Nemours and Company, Stine-Haskell Research Center, Newark, DE 19714
Sulfonylurea herbicides are characterized by unprecedented use rates, as low as 2 ga.i./ha, effectiveness by both pre- and postemergence applications, a high degree of selectivity, and excellent environmental safety. Since the first of these, chlorsulfuron, was commercialized in 1981 for cereal crops, additional sulfonylureas have been introduced for most major crops. Their discovery began with the modest growth retardant activity shown by N-(p-cyanophenylaminocarbonyl)-benzenesulfonamide in a primary plant response screen at 2kg a.i./ha. This activity was upgraded by a synthesis strategy in which the benzeneringwas retained and the p-cyanophenyl group was replaced with 4,6-disubstituted pyrimidines and similarly substituted 1,3,5-triazines. When sulfonylureas were prepared with these heterocyclic systems and o-substituents on the benzene portion a 1000-fold increase in activity over the lead compound was realized. This chapter reviews the genesis, inventive process, optimization strategy, development of empirical structure activity relationships, and general synthetic methods for these compounds. When I was a boy in Newburgh, New York, I looked forward to mornings when I would awaken to see the ground covered with a new snowfall. I would rush out to be the first person to leave footprints in the yard outside my window. As a synthesis chemist making new compounds, I could continue to be the first to leave footprints in the snow. That is, I could be the first person to make new molecules, and even more exciting, that these could effect living systems. Best of all, that these compounds could serve a useful purpose for mankind. The discovery of the sulfonylurea herbicides, was certainly a dream fulfilled. As you will see, they provided ample opportunity to continue leaving footprints in the newly fallen snow.
ACS Award for Creative Invention, award address Current address:110Downs Drive, Wilmington, DE 19807
NOTE: 1
0097-6156/91/0443-0016$06.00/0
© 1991 American Chemical Society
In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
2. LEVITT
Discovery ofthe Sulfonylurea Herbicides
17
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Genesis Shortly after I joined Du Pont, my supervisor, the late Henry J. Gerjovich, suggested I synthesize derivatives of arylsulfonylisocyanates. He had used these intermediates to prepare sulfonylureas (II), analogous to Du Pont's urea herbicides such as Monuron (I), with a S O 2 group between theringand urea group. He also discovered that sulfonylisocyanates and Ν,Ν-dialkylamides reacted to form sulfonylamidines (ΠΙ) (See Figure 1). This reaction was also discovered independently by C. King (1) of Du Pont's Textile Fibers Department in a lab across the street from Gerjovich's. Although no biological activity was observed for these amidines he thought this chemistry merited additional investigation. Since arylsulfonyl isocyanates reacted with the carbonyl of a Ν,Ν-dialkylamide and vigorously with the NH of amines, I was curious to investigate which of these reactions would be favored by a N-arylsubstituted amide in which the basicity of the NH was reduced. The product obtainedfromthe reaction of benzenesulfonylisocyanate and β-chloroformanilide was the N-formylsulfonylurea (IV) resultingfromthe addition of the NH to the isocyanate. This compound, which was prepared in 1957, did not show any interesting activity. It then rested in our files for sixteen years when serendipity intervened. Around the end of 1973, one of our entomologists, S. S. Sharp created a new screen for mite chemosterilant activity. He found that IV was sufficiently active to suggest the synthesis of analogs. The compound lacking the formyl group (V) was prepared and found to be slightly more active. Other variations in substituents and their locations on bothringsresulted in compounds which were less active as mite chemosterilants. The rj-Cyano analog (VI), was a weak plant growth retardant at 2 kg/ha in our primary plant response screen (See Figure 2.) This activity was not enough to mention at my research review to management, but interesting enough to discuss with my supervisor, Raymond W. Luckenbaugh. He encouraged me to continue synthesizing sulfonylureas and he gave me a computer print-out of our in-house sulfonylureas already studied. These compounds (Figure 3) were mostly the alkyl and phenyl substituted types I had been making. None of these compounds were better growth régulants than (VI). The only heterocyclic substituted compounds were the two in Figure 3 which I had prepared in 1963. I then decided to synthesize heterocyclic substituted sulfonylureas because of the dearth of these compounds in our file and the prominence of heterocyclic derivatives as herbicides, fungicides, and pharmacological agents. This appeared to be a potentially fruitful area for synthesis since I reasoned that each heterocyclic system could produce a different type of biological response. This guess was critical to success as it led to the key pyrimidine (VII), which was synthesized in June 1975.
CH
3
Inventive Process Kev Compounds. David J. Fitzgerald, the biologist who did our primary plant response screening, really got excited when he discovered that this compound was so potent that minor residues in the spray system injured plants treated subsequently with other compounds. The code number of VII, R4321, led to it being called "Countdown," and the sulfonylureas were dubbed the "Countdown compounds." This activity led to the assignment of an additional chemist to our synthesis effort.
In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
S Y N T H E S I S A N D C H E M I S T R Y O F A G R O C H E M I C A L S II
CD
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Ο —SO NCO + 2
R NH—^^^^—SO NH!:NR 2
2
, 2
(Π)
-SO NCO 2
R + R I "
„R
3
O=C-NC
R4
(ΠΙ)
Figure 1 Sulfonylisocyanate Reactions with Amines and Amides
SC^NOO
M ^ y
-
S
0
2
N
=
C
H
N
H
— ( ( .
) ) —
α
(IV) H
'
W
-S0 NH1L 2
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