3-Isoxazolidinones and Related Compounds - ACS Symposium

Chapter 2 3-Isoxazolidinones and Related Compounds A New Class of Herbicides

Synthesis and Chemistry of Agrochemicals Downloaded from pubs.acs.org by UNIV LAVAL on 05/09/16. For personal use only.

J. H. Chang, M. J. Konz, E. A. Aly, R. E. Sticker, K. R. Wilson, N. E. Krog, and P. R. Dickinson Agricultural Chemical Group, FMC Corporation, Box 8, Princeton, NJ 08543

Several 2-aryl- and 2-phenylmethyl-3,5-isoxazolidinediones were synthesized and found to be bleaching herbicides with good tolerance by soybeans. The most active member, 2-(2-chlorophenyl)methyl-4,4-dimethyl-3,5-isoxazolidinedione, failed to perform in the field due to its instability in soil. To improve the chemical stability by molecular modifications, a series of 3-isoxazolidinones were prepared and found to be highly active bleaching herbicides with excellent soybean tolerance. Synthesis and structure-activity relationships are discussed. One of the most active compounds, 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (FMC 57020), has been developed for commercial use. I n an e f f o r t t o f i n d new a g r i c u l t u r a l h e r b i c i d e s a new c l a s s o f b r o a d spectrum soybean h e r b i c i d e s , t h e 3 - i s o x a z o l i d i n o n e s , was discovered. The d i s c o v e r y , s y n t h e s i s , and 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 o f t h i s new c l a s s o f h e r b i c i d e s and t h e r e l a t e d compounds w i l l be d i s c u s s e d . 3.5 - I s o x a z o l i d i n e d i o n e s I s o x a z o l i d i n e d i o n e s have been o f i n t e r e s t i n t h e l a s t 20 y e a r s f o r t h e i r a n t i p h l o g e s t i c , a n a l g e s i c , and l o c a l a n e s t h e t i c p r o p e r t i e s ( 1 - 4 ) . As no h e r b i c i d a l a c t i v i t y h a d been r e p o r t e d and s i n c e h e t e r o c y c l i c r i n g systems have p l a y e d a l a r g e r o l e i n t h e d e v e l o p ment o f new and u s e f u l h e r b i c i d e p r o d u c t s , a s y n t h e s i s program was i n i t i a t e d t o i n v e s t i g a t e t h e p o t e n t i a l o f 2 - a r y l - and 2-phenylm e t h y l - 3 , 5 - i s o x a z o l i d i n e d i o n e s (1) as weed c o n t r o l a g e n t s . I n each c a s e , a s i m i l a r s e t o f t a r g e t s were p r e p a r e d .

0097-6156/87/0355-0010$06.00/0 © 1987 American Chemical Society


2.

CHANG ET AL.

3-Isoxazolidinones and Related Compounds

11

S y n t h e s i s . S y n t h e s i s was a c c o m p l i s h e d as shown i n Schemes 1 and 2. R e d u c t i o n o f the n i t r o b e n z e n e w i t h zinc/ammonium c h l o r i d e gave the c o r r e s p o n d i n g h y d r o x y l a m i n e 2. Due t o the d i f f i c u l t y i n p u r i f i c a t i o n , the crude r e d u c t i o n p r o d u c t was u s e d i n the r e a c t i o n w i t h d i m e t h y I m a l o n y l d i c h l o r i d e . T h i s p r o c e d u r e was s a t i s f a c t o r y i n t h a t y i e l d s o f 50 t o 80% o f the d i o n e 3 c o u l d be o b t a i n e d . Benzaldoximes ( 4 ) , o b t a i n e d from the c o r r e s p o n d i n g benzaldehyde and h y d r o x y l a m i n e , were s e l e c t i v e l y r e d u c e d t o the h y d r o x y l a m i n e 5 w i t h sodium c y a n o b o r o h y d r i d e by the p r o c e d u r e o f B o r c h , B e r n s t e i n , and D u r s t ( 5 ) . Upon s c a l i n g - u p t h i s r e d u c t i o n , we f o u n d i t c o n v e n i ent t o d i s s o l v e the oxime i n methanol c o n t a i n i n g m e t h y l orange as an i n d i c a t o r . M e t h a n o l s o l u t i o n s o f sodium c y a n o b o r o h y d r i d e and hydroc h l o r i c a c i d were t h e n added s i m u l t a n e o u s l y w i t h the r a t e o f a c i d a d d i t i o n a d j u s t e d so as t o m a i n t a i n the red-orange t r a n s i t i o n p o i n t o f the i n d i c a t o r . Y i e l d s were q u i t e s a t i s f a c t o r y , i n the range o f 60-80%. R e a c t i o n o f the h y d r o x y l a m i n e w i t h the m a l o n y l d i c h l o r i d e gave the d e s i r e d compounds ( 6 ) . H e r b i c i d a l A c t i v i t y . The 2 - p h e n y l i s o x a z o l i d i n e d i o n e s (3) were t e s t e d a t 8 kg/ha on l i m a beans, w i l d o a t s and c r a b g r a s s . Although no s i g n i f i c a n t k i l l was o b s e r v e d , the t e s t s p e c i e s were i n j u r e d as e v i d e n c e d by t h e i r c h l o r o t i c c o n d i t i o n and s t u n t e d appearance. S i m i l a r r e s u l t s were o b s e r v e d from 2 - p h e n y m e t h y l i s o x a z o l i d i n e d i o n e s (6) w i t h the e x c e p t i o n o f the compound c o n t a i n i n g a c h l o r i n e i n the two p o s i t i o n o f the a r o m a t i c r i n g , coded FMC 55626 (6, x«2Cl). I n preemergent a p p l i c a t i o n s , FMC 55626 c o m p l e t e l y c o n t r o l l e d the t e s t s p e c i e s . I n t h i s c a s e , the g e r m i n a t i n g s p e c i e s emerged b l e a c h e d , an e f f e c t t h a t p r o v e d s u f f i c i e n t t o cause the d e a t h o f the p l a n t . T h i s t e s t g e n e r a t e d a g r e a t d e a l o f i n t e r e s t because the o n l y s p e c i e s t h a t was n o t b l e a c h e d were soybeans. I n f o l i a r a p p l i c a t i o n s , b l e a c h i n g was a l s o e v i d e n t b u t no s i g n i f i c a n t c o n t r o l resulted. The h e r b i c i d a l a c t i v i t y o f FMC 55626 a t 1 kg/ha i s summarized i n T a b l e I . Crops o t h e r t h a n soybeans, e.g., c o t t o n , c o r n , and wheat, a r e n o t t o l e r a n t . V e l v e t l e a f and l a m b s q u a r t e r s were q u i t e s u s c e p t i b l e (85-98%) whereas c o c k l e b u r and jimsonweed c o n t r o l ranged from 55-80%. Among the g r a s s s p e c i e s , j o h n s o n g r a s s was the l e a s t s u s c e p t i b l e (20% c o n t r o 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 . W i t h t h i s e n c o u r a g i n g d a t a , an e x t e n s i v e s y n t h e s i s program was u n d e r t a k e n w i t h the o b j e c t i v e o f i m p r o v i n g a c t i v i t y w h i l e m a i n t a i n i n g t o l e r a n c e toward soybeans. These r e s u l t s a r e summarized i n T a b l e s I I - I V . The c h o i c e o f s u b s t i t u e n t s i n the a r o m a t i c r i n g i s l i m i t e d t o h a l o g e n w i t h c h l o r i n e b e i n g the most e f f e c t i v e . The p o s i t i o n o f t h i s s u b s t i t u e n t i s a l s o i m p o r t a n t i n t h a t i t must be on the twop o s i t i o n o f the r i n g . A s i m i l a r s i t u a t i o n e x i s t s i n m u l t i - s u b s t i t u ted analogs. The 2 , 5 - d i c h l o r o and 2 , 4 - d i c h l o r o i s o x a z o l i d i n e d i o n e were a c t i v e b u t n e i t h e r s u b s t i t u t i o n p a t t e r n was as e f f e c t i v e as a s i n g l e c h l o r i n e a t the t w o - p o s i t i o n . A number o f f u n c t i o n a l i t i e s a t the f o u r - p o s i t i o n o f the h e t e r o c y c l i c r i n g were a l s o i n v e s t i g a t e d . Geminal d i a l k y l s u b s t i t u t i o n was f o u n d t o be e s s e n t i a l f o r a c t i v i t y . Maximum e f f e c t i v e n e s s was

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS ,3,5- Isoxazolidinediones 0

1

N=0-1


Structure 1

2-Phenyl-4,4-Dimethyl-3,5-Isoxazolidinediones

N-OH

1

^ 2 H

2

3 v

>-CI

C

H

3

^V^i^ffl)

P y r i d i n e

y

+

C ^ C ,

A0

J

T 3

Yields: 5 0 - 8 0 %

X«H;2-CI

Scheme 1

4-CI;4-CH

3

2-Phenylmethyl-4,4-Dimethyl-3,5-lsoxazolidinediones

^ - C *

+ NH.0H-HCI N S O H T H i O ^

+ N 0 C N B H 3 +

HCI

H 5

X

Yield: 6 0 - 8 0 %

B

HiC

A_ , c

o

0H

- g l ^ ^ - C H e N O H ^-p

5 +

N

X

Yield: 6 0 - 8 5 %

4

"^

C H A

"0-p^S>

„/VA 0

Yield: 5 0 - 6 0 %

Scheme 2

sC

T

6 X«H;2-CI 4-CI;4-CH

3

CHANG ET AL.

S-Isoxazolidinonts and Related Compounds

Table I. Pre-emergent Herbicidal Activity of FMC 55626


H

3 v

V-N-CH

C

Crops Soybean Cotton, Corn, Wheat

2

% Control ot I Kg/ho 0 90-100

Broadleaf Weeds Velvetleaf, Lambsquater Cockle bur, Jimsonweed

85 - 9 8 55 - 80

Grass Weeds Barnyardgrass.Crabgross Johnsongrass.Greenfoxtail

100 20-50

Table II. Herbicidal Activity at 8 kg/ha HC 3

X«H;2-CI;4-CI;4-CH

8

Test Species: Lima Beans, Wild Oats, Crabgrass Results No Significant Kill (Pre-or Postemergent) Test Species Chi orotic and Stunted

Table III. Herbicidal Activity at 8 kg/ha

H C0 V° /

3

*

Test Species: Limo Bean, Wild Oots, Crobgrass

X H 4-CH 4-CI 2-CI* *FMC 55626

Preemergent % Control 7 9 14 100

Postemergent % Control 24 10 14 23

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

Table IV. Structure-Activity Relationships


Aryl Substituents

Monosubstitution 2- Position Active:CI>Br >F Inoctive: C H ; C H O ; C F N 0 s

s

si

2

3- ond 4-Position Inoctive: CI; F; CHjjCHjO.CFj Multiple Substitution Active: 2,5-DiCI >2,4-DiCI Inoctive: 2,3-DICI;3,4-DIC1i2,6-DiCI 4-Position of Heterocyclic Ring

CI

Active R, R « C H > R , » C H , , R , « C H C H j S

2

3

s

Inoctive R, « R

2

« H ; C H , C H

T

; -

( C H

F

)

8

-

R ^ J ' C H J . H J C H J J C I

2-Posltion of Heterocyclic Ring

Inoctive

R«

•CH 2

2.

CHANG ET AL.

3-Isoxazolidinonts and Related Compounds


o b s e r v e d when and R2 were m e t h y l . S u r p r i s i n g l y , s p i r o s y s t e r n s such as c y c l o p r o p y l were t o t a l l y i n a c t i v e . A s i m i l a r s i t u a t i o n o c c u r r e d when the (2-chlorophenyl)methyl was r e p l a c e d w i t h r e l a t e d s t r u c t u r e s . For example, the l - ( 2 - c h l o r o p h e n y l ) e t h y l and the 2 - ( 2 - c h l o r o p h e n y l ) e t h y l a n a l o g s n o t o n l y were i n e f f e c t i v e i n weed c o n t r o l , b u t the t y p i c a l b l e a c h i n g response was a l s o absent. The p r i n c i p a l c o n c l u s i o n was t h a t the s t r u c t u r a l r e q u i r e m e n t s f o r a c t i v i t y were q u i t e s p e c i f i c and t h a t FMC 55626 a p p a r e n t l y repr e s e n t e d the most a c t i v e compound i n t h i s c l a s s . F i e l d T e s t R e s u l t s . D u r i n g the c o u r s e o f t h i s program, FMC 55626 was f i e l d t e s t e d a t r a t e s from 0.5 t o 4 kg/ha. As under greenhouse c o n d i t i o n s , the g e r m i n a t i n g s e e d l i n g s were b l e a c h e d b u t the p l a n t s r a p i d l y outgrew t h i s i n j u r y . The r e s u l t (Table V) was minimum weed c o n t r o l o f even the most s e n s i t i v e s p e c i e s - - v e l v e t l e a f ( 6 3 % ) , p i g weed (40%) and b a r n y a r d g r a s s ( 3 3 % ) . These r e s u l t s appeared t o be i n c o n s i s t e n t w i t h the g e n e r a l e x p e r i e n c e i n t r a n s l a t i o n o f greenhouse a p p l i c a t i o n r a t e s t o f i e l d c o n d i t i o n s . One o f s e v e r a l p o s s i b l e e x p l a n a t i o n s was t h a t FMC 55626 c o u l d be s u s c e p t i b l e t o m i c r o b i a l d e g r a d a t i o n . As shown i n T a b l e V I , m i c r o b i a l d e g r a d a t i o n does appear t o be a f a c t o r . I n a u t o c l a v e d f i e l d s o i l , b a r n y a r d g r a s s and v e l v e t l e a f were r e a d i l y c o n t r o l l e d a t 0.5 kg/ha whereas, i n n o n - a u t o c l a v e d s o i l , t h e r e was e s s e n t i a l l y no control at t h i s rate. C h e m i c a l d e g r a d a t i o n c o u l d a l s o be a f a c t o r . As many s o i l s c o n t a i n n i t r o g e n o u s b a s e s , such as ammonia and e t h a n o l a m i n e , i t was o f i n t e r e s t t o determine the c h e m i c a l r e a c t i v i t y o f FMC 55626 w i t h amines. Treatment o f FMC 55626 w i t h t r i e t h y l a m i n e (Scheme 3) r e s u l t e d i n gas e v o l u t i o n , presumably c a r b o n d i o x i d e , and f o r m a t i o n o f comp l e x r e a c t i o n products. A l t h o u g h the components o f t h i s r e a c t i o n have n o t been i d e n t i f i e d , the NMR spectrum d i d show a peak t h a t c o u l d be a s s i g n e d t o the methine p r o t o n o f an i s o b u t y r i c a c i d . In the case o f two p r i m a r y amines (methylamine and a n i l i n e ) , c l e a v a g e o f the a c y l oxygen bond o c c u r r e d t o g i v e the M s - a m i d e s 7. These amides are s i m i l a r i n a c t i v i t y t o FMC 55626 and, l i k e FMC 55626, are s e v e r a l t i m e s more a c t i v e i n a u t o c l a v e d s o i l s . Conclusion. C h e m i c a l t r a n s f o r m a t i o n o f FMC 55626 c o u l d o c c u r i n the s o i l b u t w h i c h o f the two pathways i s dominant i s unknown. I n any e v e n t , the end p r o d u c t s appear t o be h e r b i c i d a l l y i n a c t i v e . I n c o n c l u s i o n , i s o x a z o l i d i n e d i o n e s were f o u n d t o be h e r b i c i d a l l y a c t i v e b u t a l s o appear t o be s u s c e p t i b l e t o m i c r o b i a l and/or c h e m i c a l degradation. 3-Isoxazolidinones I t i s c l e a r t h a t the i n s t a b i l i t y o f FMC 55626 g r e a t l y reduces i t s f i e l d performance. The s e a r c h f o r a s o l u t i o n t o t h i s p r o b l e m became our prime c o n c e r n . The o b s e r v e d gas e v o l u t i o n under m i l d l y b a s i c c o n d i t i o n s s u g g e s t s t h a t the d e c a r b o x y l a t i o n o f FMC 55626 i s a f a c i l e process. I t was, t h e r e f o r e , d e s i r a b l e t o remove the " l a c t o n e " c a r b o n y l group from the i s o x a z o l i d i n e d i o n e system 6 t o

15


Table V. Pre-emergent Herbicide Field Test CI


FMC 5 5 6 2 6 Species

% Control ot 30 Days (4 kg / ha)

Velvetleaf Pigweed Barnyardgrass

63 40 33

Table VI. Herbicidal Activity of FMC 55626 in Field Soil Samples % Control Au toe loved Species

0.5kg/ho

Bornyordgrass Velvetleaf

Non Autodoved

2kg/ho

60 100

0.5kg/ho 2kg/ho

100 100

10 10

10 96

Reaction of F M C 55626 with Amines Gas Evol. + Complex Mixture Et N / C H C I / 3

2

2

(

C

0

2

?

[

)

( C H 3

)

2

c

_ '£] c

H,C

H,C RNH /CH C^ 2

2

H CA 3

N-CH -^> 2

HcO"

NHR

s

R=CH

Scheme 3

3

2.

CHANG ET AL.



improve the s t a b i l i t y o f the h e t e r o c y c l i c r i n g by r e l e a s i n g some o f the r i n g s t r a i n and p r e v e n t i n g the d e c a r b o x y l a t i o n r e a c t i o n . The r e s u l t s o f t h i s o p e r a t i o n are the 3 - i s o x a z o l i d i n o n e s ( 8 ) , a new c l a s s o f compounds t h a t p o s s e s s a h i g h l e v e l o f h e r b i c i d a l a c t i v i t y and e x c e l l e n t soybean t o l e r a n c e . S y n t h e s i s . The s y n t h e s i s o f these new compounds are shown i n Schemes 4-8. Condensation of 3 - c h l o r o p i v a l o y l c h l o r i d e w i t h t r i m e t h y l s i l y l c h l o r i d e - t r e a t e d benzylhydroxylamine i n methylene c h l o r i d e i n the p r e s e n c e o f p y r i d i n e gave a hydroxamic a c i d d e r i v a t i v e 9 i n good y i e l d . I t i s i m p o r t a n t t o b l o c k the h y d r o x y l group o f the h y d r o x y l a m i n e t o ensure the d e s i r e d N - a c y l a t i o n ; o t h e r w i s e , a s t a b l e m i x t u r e o f 40:60 N- and O - a c y l a t e d p r o d u c t s ( 9 , 10) w i l l be obtained. T h i s i s o m e r i c m i x t u r e i s not o n l y d i f f i c u l t t o s e p a r a t e b u t a l s o reduces the e f f i c i e n c y o f the s y n t h e s i s . Upon t r e a t m e n t w i t h one e q u i v a l e n t o f b a s e , c h l o r o p i v a l o y l hydroxamic a c i d 9 w i l l smoothly c y c l i z e t o form 3 - i s o x a z o l i d i n o n e 8 i n good y i e l d . An e x c e s s o f base i n the c y c l i z a t i o n , o r t r e a t m e n t o f the r e s u l t i n g b e n z y l - 3 - i s o x a z o l i d i n o n e w i t h base w i l l r e s u l t i n a r i n g e x p a n s i o n p r o d u c t 11 -- a 1,3-oxazine-4-one. T h i s r i n g expans i o n p r o c e s s i s a p p a r e n t l y i n d u c e d by the base a b s t r a c t i o n o f the a c i d i c b e n z y l p r o t o n f o l l o w e d by N-0 bond c l e a v a g e and i n t r a m o l e c u l a r a d d i t i o n o f the r e s u l t i n g a l k o x i d e t o the newly formed a c y l i m i n e 12 t o form the 1,3-oxazine-4-one r i n g ( 6 ) . An a l t e r n a t e r o u t e t o the s u b s t i t u t e d 3 - i s o x a z o l i d i n o n e s i s shown i n Scheme 6. Condensation of $ - c h l o r o p i v a l o y l c h l o r i d e w i t h h y d r o x y l a m i n e f o l l o w e d by b a s e - i n d u c e d c y c l i z a t i o n o f the r e s u l t i n g hydroxamic a c i d gave 4 , 4 - d i m e t h y l - 3 - i s o x a z o l i d i n o n e ( 1 3 ) . Phaset r a n s f e r c a t a l y t i c a l k y l a t i o n o f the 3 - i s o x a z o l i d i n o n e gave b o t h N- and O - a l k y l a t e d p r o d u c t s (14, 15). The r a t i o o f the N- and 0i s o m e r s depends on the c a t a l y t i c c o n d i t i o n s . U s i n g K O H / t e t r a b u t y l amonium bromide (TBAB)/THF ( 7 ) , a m i x t u r e o f 77:23 N/0 isomers was obtained. I f K2C0 /18-Crown-6(18-C-6)/CH CN was used, a 95:5 mixt u r e o f N/0 isomers was o b t a i n e d . The u n d e s i r e d O - a l k y l a t e d i s o m e r s can be s e p a r a t e d by a column chromatography. When a s t r o n g e l e c t r o n - w i t h d r a w i n g group i s p r e s e n t i n the b e n z y l h a l i d e , e.g. 2 - c h l o r o - 4 - n i t r o - b e n z y l bromide (Scheme 7 ) , the normal p h a s e - t r a n s f e r a l k y l a t i o n w i l l g i v e o n l y r i n g e x p a n s i o n p r o d u c t ( 1 6 ) . However, i f the r e a c t i o n temperature i s k e p t a t 0°C, the rearrangement p r o c e s s can be s u p p r e s s e d c o m p l e t e l y . A s e r i e s o f 5 - a l k o x y - 3 - i s o x a z o l i d i n o n e s (17) was p r e p a r e d as shown i n Scheme 8. Employing the same method d i s c u s s e d p r e v i o u s l y , a 5 - c h l o r o - 3 - i s o x a z o l i d i n o n e (18) was p r e p a r e d . This r e a c t i v e c h l o r i d e can be e a s i l y r e p l a c e d by n u c l e o p h i l e s such as a l c o h o l s t o g i v e the d e s i r e d a l k o x y d e r i v a t i v e s . Some r i n g - o p e n i n g p r o d u c t s (19) d e r i v e d from d e p r o t o n a t i o n o f the a c i d i c b e n z y l p r o t o n were a l s o observed. 3

3

H e r b i c i d a l A c t i v i t y . As w i t h FMC 55626, a l l o f the a c t i v e 3i s o x a z o l i d i n o n e s cause b l e a c h i n g o f the emerging weed s e e d l i n g s . R e s u l t s o b s e r v e d t o date i n d i c a t e t h a t these compounds a f f e c t c a r o t e n e and c h l o r o p h y l l b i o s y n t h e s i s (8. 9 ) . T y p i c a l greenhouse a c t i v i t y d a t a f o r preemergence a p p l i c a t i o n o f FMC 57020 (8, X-2-C1) on some r e p r e s e n t a t i v e weed s p e c i e s are shown i n T a b l e V I I . The

17


18 SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

Scheme 5

CHANG ET AL.


CH

3

CH .CI

CH

3

CH

3

'

0

13


RX/PTC CH

3

CH

3

14

15 KOH/TBAB/THF 77:23 K C0 /l8-C-6/CH CN 95:5 2

s

Scheme 6

BrCH C

h

3

I

^

2

K2CCVI8- C-6 / C H C N

CH

3

CH ' 3

cr 16

Scheme 7

CH

CH;

3

CH

CH < 3

CI

CH

3

CH

3

OR

I

CI

ROH

18

17

ETOH/ET3 N,A CHy CH

+

e t

CH

.

9

OET

/=\

3

CH < 3

19

Scheme 8

(X«CI)

20



a c t i v i t y i s e x p r e s s e d i n terms o f BE95 w h i c h i s d e f i n e d ( i n kg/ha) r e q u i r e d t o a c h i e v e 95% c o n t r o l .

as t h e r a t e

Structure-activity Relationships. I t has been f o u n d t h a t t h e p o s i t i o n o f s u b s t i t u t i o n on t h e p h e n y l r i n g i s c r i t i c a l f o r h e r b i c i d a l activity. F o r example, a s e r i e s o f c h l o r o - s u b s t i t u t e d b e n z y l - 3 i s o x a z o l i d i n o n e s shown i n T a b l e V I I I demonstrates a c t i v i t y r a n g i n g from i n a c t i v e t o v e r y a c t i v e . I t i s c l e a r from t h i s t a b l e t h a t t h e ortho-substituent i s necessary f o r a c t i v i t y . I n a d d i t i o n t o the o r t h o - p o s i t i o n , t h e second s u b s t i t u e n t must be a t t h e C4 o r C5 p o s i t i o n t o be a c t i v e . Substituent e f f e c t s a t the o r t h o - p o s i t i o n are a l s o observed. H a l o g e n i s t h e o n l y group o f s u b s t i t u e n t s w h i c h show s i g n i f i c a n t herbicidal activity. Among t h e f o u r h a l o g e n s , c h l o r i n e g i v e s t h e most a c t i v e compound w h i c h i s f o l l o w e d by bromo, f l u o r o and i o d o d e r i v a t i v e s i n a d e s c e n d i n g o r d e r . The n o n - s u b s t i t u t e d b e n z y l d e r i v a t i v e s t i l l shows some b l e a c h i n g e f f e c t a t h i g h e r r a t e . Other s u b s t i t u e n t s , such as CH3, OCH3, CN, SCH3, , CF3 and NH2 a t t h e o r t h o - p o s i t i o n g i v e i n a c t i v e compounds. I n the case o f m u l t i p l y s u b s t i t u t e d b e n z y l analogs, halogen i s important f o r a high l e v e l o f h e r b i c i d a l 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 f o r some d i s u b s t i t u t e d a n a l o g s i s shown below. The most a c t i v e member i n t h i s s e r i e s i s 2 - c h l o r o - 4 - f l u o r o analog. V a r i o u s groups a t t h e 5 - p o s i t i o n o f t h e h e t e r o c y c l i c r i n g , were i n t r o d u c e d as d i s c u s s e d i n t h e s y n t h e s i s s e c t i o n . The h e r b i c i d a l a c t i v i t y o f t h e s e compounds ranges from t h e v e r y a c t i v e methoxy d e r i v a t i v e t o t h e t o t a l l y i n a c t i v e m e t h y l and p h e n y l d e r i v a t i v e s (Table I X ) . The c h l o r o and h y d r o x y d e r i v a t i v e s a r e f a i r l y a c t i v e w h i l e the methylthio analog i s only s l i g h t l y a c t i v e . I t appears t h a t t h e oxygen l i n k a g e i s e s s e n t i a l f o r a h i g h l e v e l o f h e r b i c i d a l activity. A g a i n , the observed h e r b i c i d a l response i s a t y p i c a l b l e a c h i n g o f emerging weed s e e d l i n g s . Among t h e 5 - a l k o x y d e r i v a t i v e s , t h e r e l a t i v e a c t i v i t y c a n be r a n k e d i n t h e o r d e r shown below. The most a c t i v e member i s 5-methoxy d e r i v a t i v e . An i n t e r e s t i n g s t r u c t u r e - a c t i v i t y o b s e r v a t i o n i s t h a t t h e 3-isoxazolidinones (8) a r e o n l y s l i g h t l y more a c t i v e t h a n t h e i r s y n t h e t i c p r e c u r s o r h y d r o x a m i c a c i d s (9) ( T a b l e X ) . F o r example, the d i f f e r e n c e i n a c t i v i t y between FMC 57020 and i t s p r e c u r s o r h y d r o x a m i c a c i d toward t h e s e 4 s p e c i e s o f weeds i s v e r y s m a l l . They b o t h show a b l e a c h i n g h e r b i c i d a l r e s p o n s e w i t h e x c e l l e n t soybean tolerance. They a l s o demonstrate a p a r a l l e l s u b s t i t u e n t e f f e c t , i . e . t h e y b o t h f o l l o w t h e same r e l a t i v e a c t i v i t y o r d e r among d i f f e r ent s u b s t i t u e n t s such as t h o s e shown i n T a b l e X. F i n a l l y , t h e s e n s i t i v i t y o f t h e C4 p o s i t i o n o f t h e h e t e r o c y c l i c r i n g w i t h r e s p e c t t o t h e a l k y l s u b s t i t u e n t was examined ( T a b l e X I ) . R e s u l t s o f t h i s i n v e s t i g a t i o n have i n d i c a t e d t h a t v e r y s m a l l changes i n t h e 4 - s u b s t i t u e n t c a n cause a s i g n i f i c a n t r e d u c t i o n o f a c t i v i t y . Summary. S y n t h e s i s o f 3 , 5 - i s o x a z o l i d i n e d i o n e s has l e d t o t h e d i s c o v e r y o f a new c l a s s o f h e r b i c i d e s , t h e 3 - i s o x a z o l i d i n o n e s . V a r i o u s s t r u c t u r a l m o d i f i c a t i o n s b a s e d on t h e p a r e n t h e t e r o c y c l i c r i n g were made. A number o f v e r y a c t i v e compounds d e r i v e d from 2b e n z y l a n a l o g s and 5 - a l k o x y d e r i v a t i v e s were found. T h i s c l a s s o f

CHANG ET AL.


Table VII. Herbicidal Activity CH

3

CH

3

Table VIII. Structure-Activity Relationships


FMC 57020

X 2-CI 2.4- CI 2.5- CI 2.4,5-Cls 4-CI 3,4-CI 2.6- CI 2,3-CI

BEgsOCg/ha) .04

Barnyard Grot* Green Foxtail

.25

Velvetleaf

.06

Wild Mustard

.50

2

2

Activity + + + + +

2

• Soybean Tolerance 2 Kg /ho

2

2

+ + :Very Active + -.Active -

CH

Inactive

:

CH
Br>F>l>H»CH

3

CH ,0CH .CN.SCH,, s

3

CeHg ,CF ,NH S

2

H A / 4-F>5-F>4-CI>5-CI >> 5-OCHs^-NOt

Inoctive

Table IX. Range of Activity CH CH

3

R OCH CI OH SCH N H

3

3

2

CeH CH

5

8

++:Very Active +: Active ±: Slightly Active Inactive

Activity + + + + ±

22


s>tV-b s . R: C H 3 ^ C 2 H , C H C H S C H J . C H J C aCH, 5

2

CH(CHs) =>C0CH


2

3

Table X. Comparison of 3-Isoxazolidinones with Hydroxamic Acids

CH-

CH3' CI

8

9

R « 2-CI BEsst Kg/ho) 8. 9. .04 .06 .25 .50 .06 .06 .50 1.00

Bornyordgross Green Foxtoil Velvetleof Wild Mustard

R: 2-Br,2-F,2,4-CI ,2,6-CI H,2-CH 2

2f

2-0CH ,3-CF ,4-CI,3 4-CI 3

3

t

3

2

Table XI. EfTect of Alkyl Substituent

Ri C«H H CHs H

5

Inactive

Rz H H CH CI CH 2

9

2. CHANG ET AL.

3-Isoxazolxdinonts and Related Compounds

herbicides generally causes severe bleaching on a broad spectrum of emerging weed seedlings with excellent safety margins toward soybeans. One of the most active compounds, FMC 57020, has been developed for commercial use by FMC Corporation under the FMC registered trademark, Command (10-13).


0

FMC 57020

Literature Cited 1.

Matter, M.; Gerber, H. U.S. Patent 3,007,936, 1961.

2. Michel, K.; Gerlach-Gerber, H.; Vogel, Ch.; Matter, M. Helv. Chim. Acta 1965, 48, 1973. 3.

Zinner, G.; Moll, R. Arch. Pharm. 1966, 299, 562.

4.

Zinner, G.; Ruthe, H.; Boese, D. Pharmazie 1974, 29, 16.

5.

Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Amer. Chem. Soc. 1971, 93, 2897.

6. A similar rearrangement was observed by Uno, H.; Kurokawa, M. Chem. Pharm. Bull. 1978, 26, 549. 7.

Takahata, H.; Hashizume, T.; Yamazaki, T. Heterocycles 1979, 12, 1449.

8. Warfield, T. R.; Carlson, D. B.; Parrish, D. S.; Zenk, G. J. NCWCC Proceedings 1983, 38, 4. 9. 10.

Sandmann, G.; Boger, P. Z. Naturforsh 1986, 41C, 729. Warfield, T. R.; Halvorson, G. C.; Dobbins, L. D.; Hopper, D. M. NCWCC Proceedings 1985, 40, 80.

11. Warfield, T. R.; Carlson, D. B.; Bellman, S. K.; Guscar, H. L. Weed Sci. Abstr. 1985, 25, 105. 12.

Konz, M. J. U.S. Patent 4,302,238, 1981.

13.

Chang, J. H. U.S. Patent 4,405,357, 1983.

RECEIVED May 12, 1987

3-Isoxazolidinones and Related Compounds - ACS Symposium

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