Pesticide Synthesis Through Rational Approaches - American

2 Sulfonylureas: New High Potency Herbicides RICHARD F. SAUERS and GEORGE LEVITT Ε. I. du Pont de Nemours and Company, Experimental Station, Wilmington, DE 19898

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The sulfonylureas are new herbicides which exhibit both preemergence and postemergence activity at extra ordinarily low rates of application. Two of these compounds have been commercialized by Du Pont. Glean weed killer controls most broadleaf weeds and some grasses in wheat at 5-35 g a.i./ha. The active ingredient in this product is chlorsulfuron. Oust weed killer is especially useful for control of seed ling and rhizome johnsongrass with safety to Bermudagrass. The active component of this product is sulfometuron methyl.

The discovery, mode of action, and empirical structure -activity relationships of these new herbicides will be reviewed. The s u l f o n y l u r e a s described here are new h e r b i c i d e s with unpre cedented a c t i v i t y . A c t i v i t y at e x t r a o r d i n a r i l y low rates o f a p p l i c a t i o n has been demonstrated by both preemergence and postemergence a p p l i c a t i o n s (Réf. 1 ) . These rates are best describee i n grams per hectare compared to kilograms per hectare f o r most h e r b i c i d e s c u r r e n t l y marketed. Furthermore, the combination of low a p p l i c a t i o n r a t e s , h a l f l i v e s o f g e n e r a l l y l e s s than two months i n the s o i l (Ref. 2) and e x c e l l e n t s a f e t y to mammals [LD5Q s o f g e n e r a l l y >5000 mg/kg f o r t e c h n i c a l m a t e r i a l i n male r a t s ] (Réf. 1C) makes these compounds a t t r a c t i v e products from an environmental viewpoint. ,

0097-6156/ 84/ 0255-0021 $06.00/ 0 © 1984 American Chemical Society

In Pesticide Synthesis Through Rational Approaches; Magee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES


22

The DuPont Company has commercialized two of these compounds. The f i r s t of these i s c h l o r s u l f u r o n ( F i g . 1), formerly DPX-W4189, the a c t i v e i n g r e d i e n t i n Glean weed k i l l e r . I t i s being marketed by DuPont f o r use i n small grains such as wheat and b a r l e y . This compound i s e s p e c i a l l y e f f e c t i v e f o r the c o n t r o l of most broadleaf weeds and some grasses found i n these crops. Recom mended use r a t e s vary from 5 to 35 g a.i./ha depending on the nature of weeds present, the type of s o i l i n v o l v e d , and intended r o t a t i o n a l crops. The second candidate i s sulfometuron methyl ( F i g . 1), formerly DPX-T5648, the a c t i v e i n g r e d i e n t i n Oust® weed k i l l e r . I t i s a potent h e r b i c i d e e s p e c i a l l y u s e f u l f o r long term c o n t r o l of johnsongrass (Sorghum halepense) with s a f e t y to Bermudagrass (Cynodon d a c t y l o n ) . Oust i s not s e l e c t i v e on most agronomic crops.

4

OCH

C0 CH 2

3

3

S0 NHCNH-^^^^ 2

ζ

Ν

CH

3

DPX-T5648 Sulfometuron methyl

DPX-W4189 Chlorsulfuron Figure 1.

Commercialized s u l f o n y l u r e a s

Synthesis Both c h l o r s u l f u r o n and sulfometuron methyl can be prepared by the r e a c t i o n of the appropriate a r y l s u l f o n y l isocyanate and the s u b s t i t u t e d h e t e r o c y c l i c amine as shown i n F i g . 2. R

R S0 NCO 2

+

H N-/ί 2

^

J Ζ Y

Figure 2.

Synthesis of s u l f o n y l u r e a s

This r e a c t i o n i s t y p i c a l f o r the s y n t h e s i s of s u l f o n y l u r e a s ; i t i s m i l d l y exothermic and proceeds smoothly i n a v a r i e t y of i n e r t a p r o t i c s o l v e n t s . The product i s u s u a l l y obtained i n very high y i e l d , as a f i n e c r y s t a l l i n e p r e c i p i t a t e . The s u l f o n y l isocyanates are r e a d i l y prepared from the s u b s t i t u t e d benzene sulfonamides by r e a c t i o n with phosgene, F i g . 3, i n the presence of an a l k y l isocyanate, f o r example, b u t y l isocyanate i n an i n e r t solvent at 120 to 140°C according to the general procedure of H. U l r i c h and A. A. R. Sayigh (Ref. 3).


2.

SAUERS AND LEVITT

23

Sulfonylureas

n-BUNCO

+

cocio

C H C1 reflux 6

S0 NH 2

2


Figure 3.

5

^

S u l f o n y l isocyanate

S0 NCO 2

formation

o-Chlorobenzenesulfonamide can be prepared from o ^ c h l o r o a n i l i n e by d i a z o t i z a t i o n and treatment o f the r e s u l t i n g diazonium s a l t with s u l f u r d i o x i d e and h y d r o c h l o r i c a c i d i n the presence o f cuprous or c u p r i c c h l o r i d e to y i e l d the s u l f o n y l c h l o r i d e (Ref. 4) which i s converted to the sulfonamide with ammonia.

Figure 4.

C h l o r s u l f u r o n intermediate

sulfonamide synthesis

This procedure i s s a t i s f a c t o r y f o r the synthesis o f a v a r i e t y of a r y l sulfonamides. The h e t e r o c y c l i c intermediate used i n the synthesis o f c h l o r s u l f u r o n i s prepared according to K. R. Hoffmann and F. C. Schaeffer (Ref. 5) as shown i n F i g u r e 5.

CH3CN

HOCH3 - —

^NH >

X

Toluene

0CH

N

H NCN -HCl — >

-HCl

> V

Na0CH

NH

2

>

N

-HCl

X

3

NH

CH3OC

C

^ CH3-C 0CH

2

CH3C

3

2

jut

HC

N

3

OCH3

3

Figure 5.

Chlorsulfuron heterocycle

synthesis



24

Condensation of guanidine carbonate and acetylacetone y i e l d s the required 2-amino-4,6-dimethylpyrimidine (Ref. 6) f o r s u l f o meturon methyl (Figure 6).

CH


Figure 6.

3

Sulfometuron methyl h e t e r o c y c l e

CH

3

synthesis

Mode of A c t i o n Extensive mode of a c t i o n studies have been c a r r i e d out (Ref. 7) with c h l o r s u l f u r o n . C h l o r s u l f u r o n enters plants e i t h e r through the f o l i a g e or roots and moves r a p i d l y through the e n t i r e p l a n t . C h l o r s u l f u r o n i s a potent i n h i b i t o r of plant c e l l d i v i s i o n and q u i c k l y causes the plant to stop growing. Even nanomolar concent r a t i o n s have been found to i n h i b i t plant c e l l d i v i s i o n w i t h i n s i x hours. Seeds germinate, however, s e e d l i n g growth i s i n h i b i t e d . Other l i f e processes i n the plant such as photosynthesis, r e s p i r a t i o n , c e l l elongation and p r o t e i n and RNA synthesis do not appear to be i n i t i a l l y a f f e c t e d . S u s c e p t i b l e plants d i e slowly showing c h l o r o s i s , v e i n d i s c o l o r a t i o n , terminal bud death and f i n a l l y n e c r o s i s . This type of a c t i o n appears t y p i c a l f o r these s u l f o n y l u r e a h e r b i c i d e s . Resistant plants such as wheat, b a r l e y or oats have been shown to r a p i d l y metabolize c h l o r s u l furon. P. B. Sweetser and J . M. Hutchison (Ref. 8), using phenyl l a b e l e d c h l o r s u l f u r o n c h a r a c t e r i z e d the major metabolite as a nonphytotoxic compound i n which the phenyl r i n g had undergone h y d r o x y l a t i o n i n the 5 - p o s i t i o n followed by conjugation with glucose.

Figure 7.

Glucose conjugate of the major of c h l o r s u l f u r o n

metabolite

They found a good inverse c o r r e l a t i o n between s e n s i t i v i t y of a plant to c h l o r s u l f u r o n and the r a t e of metabolism to t h i s metabolite. For purposes of t h e i r study, p l a n t s such as wheat, b a r l e y and oats which showed only s l i g h t to moderate temporary growth i n h i b i t i o n by a f o l i a r spray of 50-400 ppm s o l u t i o n of


2.

SAUERS AND LEVITT

25

Sulfonylureas

the compound were considered t o l e r a n t . S e n s i t i v e p l a n t s such as sugarbeet, mustard, rape and galium showed severe growth r e t a r d a t i o n from a 0.1 to 0.5 ppm spray. Twenty-four hours a f t e r treatment o f sugarbeet leaves with ^-^C-labeled c h l o r s u l furon, n e a r l y 97% of the r a d i o a c t i v i t y could be recovered as c h l o r s u l f u r o n , whereas with wheat 95% of the r a d i o a c t i v i t y had been converted to the nonphytotoxic metabolite.


Discovery

and E m p i r i c a l S t r u c t u r e - A c t i v i t y R e l a t i o n s h i p s

The o r i g i n a l lead was N-(j>-cyanophenylaminocarbonyl) benzenesulfonamide. This compound showed weak plant growth régulant activity. The synthesis of compounds with v a r i a t i o n s i n s u b s t i t u t i o n s on the phenyl r i n g s and the bridge f a i l e d to s u b s t a n t i a l l y increase t h i s a c t i v i t y . A review of the s u l f o n y l u r e a s p r e v i o u s l y i n v e s t i g a t e d by us revealed only a l i m i t e d amount of work with s u l f o n y l u r e a s i n which h e t e r o c y c l e s replaced the j>-cyanophenyl of the lead compound. This appeared to be a p o t e n t i a l l y f r u i t f u l area f o r synthesis since i t was reasoned that each d i f f e r e n t h e t e r o c y c l i c type might produce a very d i f f e r e n t b i o l o g i c a l response.

Weak Growth Retardant a t 2 kg/ha Figure 8. Lead Compound Benzenesulfonylureas were prepared from 2-aminopyrimidines subs t i t u t e d i n the 4- and 6 - p o s i t i o n s . Growth retardant a c t i v i t y was found i n the 4-methyl-6-chloro compound (Figure 9). This a c t i v i t y was l o s t when both s u b s t i t u e n t s were c h l o r i n e . However, a s u b s t a n t i a l improvement i n growth retardant a c t i v i t y was observed with the 4,6-dimethyl analog. X

Y Y

X CH CI CH

Activity

3

3

CI CI CH

3

Growth Retardant Inactive Improved Growth Retardant

Figure 9. Analogs o f the lead compound


26

PESTICIDE SYNTHESIS T H R O U G H RATIONAL APPROACHES


When the dramatic improvement i n a c t i v i t y was found with the 4,6-dimethylpyrimidine h e t e r o c y c l e , s u l f o n y l u r e a s of t h i s system were prepared from the three isomeric t o l y l s u l f o n y l isocyanates. The para compound, which was a l i t e r a t u r e compound (Ref. 9 ) , was devoid o f a c t i v i t y ; whereas, the meta compound was found to have s u b s t a n t i a l a c t i v i t y . When the ortho t o l y l compound was prepared, another major boost i n a c t i v i t y was observed

R

Activity

4-CH3 3-CH3 2-CH3

Inactive Active Herbicide Highly A c t i v e H e r b i c i d e

Figure 10.

The e f f e c t o f a r y l

substitution

Further m o d i f i c a t i o n s o f the h e t e r o c y c l e showed that 4,6-disubs t i t u t e d sym-triazines were a l s o a c t i v e , and that replacement of a methyl group with a methoxy group gave another s l i g h t boost i n a c t i v i t y (Figure 11). More importantly, the t r i a z i n e compounds were found to have s a f e t y on wheat. The a d d i t i o n o f an ortho c h l o r o s u b s t i t u e n t to the aromatic r i n g gave a compound-chlorsulfuron-possessing both high h e r b i c i d a l a c t i v i t y and good s a f e t y on wheat and b a r l e y .

CH3

R

Ζ

Η

Ν

A c t i v e Broadleaf Wheat Safety

CI

CH

Highly A c t i v e H e r b i c i d e Phytotoxic to Wheat

Cl

Ν

C h l o r s u l f u r o n - Highly A c t i v e and Safe on Wheat, Barley

Figure 11.

Discovery o f c h l o r s u l f u r o n

Herbicide-


2.

SAUERS AND LEVITT

27

Sulfonylureas


Turning to d i s u b s t i t u t e d benzenesulfonylureas we found they retained a c t i v i t y . In f a c t , the 2,6-dichloro d e r i v a t i v e was almost equivalent to the 2-chloro analog. The a c t i v i t y lowering e f f e c t o f 4 s u b s t i t u t i o n i s seen again by comparing the 2,4 with the 2,3 or 2,5 s u b s t i t u t e d compounds. This i s f u r t h e r confirmed by comparing the 3,4 with the more a c t i v e 3,5 compound (Figure 12). The comparison o f 2,4 with 3,5 i s not c l e a r cut. The 2,4 has the p o t e n t i a t i n g e f f e c t o f a 2-substituent countered by the a c t i v i t y reducing e f f e c t o f the 4-substituent whereas the 3,5 has the minor improvement due to the meta s u b s t i t u e n t s . The 3,4 d e r i v a t i v e , not being helped by ortho s u b s t i t u t i o n and hindered by para, i s the weakest o f these compounds.

Isomer:

2,6

2,3 2,5 2,4 3,5 3,4

ACTIVITY: Increasing A c t i v i t y Figure 12.

R e l a t i v e o v e r a l l p l a n t response o f isomeric dichlorophenylsulfonylureas

Many f u n c t i o n a l groups have been found which p o t e n t i a t e a c t i v i t y when present i n the ortho p o s i t i o n (Figure 13). A v a r i e t y o f electron-withdrawing and e l e c t r o n - d o n a t i n g groups have a potent i a t i n g e f f e c t . The free c a r b o x y l i c a c i d group i s one group that does not have a p o t e n t i a t i n g e f f e c t . OCH

CH

R R = A c t i v a t i n g Groups:

Figure 13.

3

C0 CH , N0 , F, Br, C l , S0 CH , SCH , S 0 N ( C H ) , C F CH C1, OCH , OCF , C H C0 H 2

3

2

3

2

Nonactivating:

3

2

3

3

2

3

3

3

2

3

2

Examples o f p o t e n t i a t i n g ortho s u b s t i t u e n t s on benzene ( r e l a t i v e to hydrogen)



28

In a d d i t i o n to benzene compounds, p y r i d i n e , thiophene, furan and naphthalene s u l f o n y l u r e a s are a l s o a c t i v e . Compounds with the unmodified s u l f o n y l u r e a bridge are g e n e r a l l y more a c t i v e than compounds with s u b s t i t u t e d b r i d g i n g groups. Compounds with the bridges shown i n Figure 14 have shown some a c t i v i t y . The r e l a t i v e a c t i v i t y o f compounds f o r each bridge type i s deter mined by the s u b s t i t u e n t s on the a r y l and the h e t e r o c y c l i c r i n g . ARYL

1 BRIDGE |

HETEROCYCLE

-S0 NHCNH-


2

ΠΠ -S0 NHÎNH-

I S-Alk I -S0 N=0-NH-

2

2

ο

I O-Alk 1 -S0 N=ONH2

9

-S0 ljICNH-

-S0 NHCN-

2

Figure

2

14.

9 -S0 N 2

CN-

Bridge systems showing a c t i v i t y

Summary In summary, the s u l f o n y l u r e a s are new h e r b i c i d e s which e x h i b i t a c t i v i t y at extremely low r a t e s o f a p p l i c a t i o n and show very low mammalian t o x i c i t y . E x c e p t i o n a l l y high a c t i v i t y i s shown by compounds c o n t a i n i n g a benzene r i n g s u b s t i t u t e d i n the ortho p o s i t i o n , an unsubstituted s u l f o n y l u r e a bridge, and a pyrimidine or t r i a z i n e h e t e r o c y c l e s u b s t i t u t e d with methyl or methoxy groups.

Literature Cited 1a. b. c.

G. Levitt, U.S. Patent 4 127 405, 1978. G. Levitt, U.S. Patent 4 169 719, 1979. G. Levitt, et a l . , J . Agric. and Food Chem. 1981, 29, 416. 2. H. L. Palm, et a l . , W.S.S.A. Conf., 1982, Boston. 3. H. Ulrich, A. A. R. Sayigh, Angew Chem. (Int. Ed.) 1966, 78, 761. 4. H. Meerwein, et a l . , Chem. Ber. 1957, 90, 841. 5. K. R. Hoffmann, F. C. Schaeffer, J . Org. Chem. 1963, 28, 1916. 6. T. F. Scholz, G. M. Smith, U.S. Patent 2 660 579, 1953. 7a. T. Ray, Proc. British Crop Protection Conference-Weeds 1980, I, 7. b. T. Ray, Pesticide Biochem. and Physiol. 1982, 17, 10. 8. P. B. Sweetser, G. S. Schow, J . M. Hutchison, Pesticide Biochem. and Physiol. 1982, 17, 18. 9. W. Logemann, L. Caprio, D. Artini, Farmaco (Pavia) Ed. Sci. 1957, 12, 586. RECEIVED

December 23, 1983


Pesticide Synthesis Through Rational Approaches - American

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