Synthesis and Chemistry of Agrochemicals II - American Chemical

Chapter 15

Hydroxyoxazolidinones and Hydroxypyrrolidinones New Classes of Herbicides R. S. Brinkmeyer, T. W. Balko, Ν. H. Terando, T. William Waldrep, D. E. Dudley, and R. K. Mann

Downloaded by CORNELL UNIV on June 22, 2012 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch015

Lilly Research Laboratories, Eli Lilly and Company, P.O. Box 708, Greenfield, IN 46140

The synthesis and h e r b i c i d a l a c t i v i t y of two new classes of compounds, the hydroxyoxazolidinones and the hydroxypyrrolidinones, i s described. The key reaction to both of these molecules i s ozonolysis of the precursor o l e f i n s . S i g n i f i c a n t changes i n a c t i v i t y are seen when ring substitutions on the o x a z o l i d i nones and pyrrolidinones are made.

The design and synthesis of new herbicides has been h i s t o r i c a l l y a process based on the a b i l i t y of chemists and b i o l o g i s t s to predict structures which have b i o l o g i c a l a c t i v i t y . Although new techniques i n modeling, QSAR, and biochemistry have added much i n the way of explaining the results a f t e r the f a c t , the use of these tools to predict a c t i v i t y a p r i o r i i s s t i l l i n the future. Our discovery of the new h e r b i c i d a l classes of compounds referred to here as hydroxyoxazolidinones and hydroxypyrrolidinones i s based on the former approach; however, we f e e l that as we learn more about t h e i r mode of action and receptor binding s i t e , we w i l l greatly enhance our chances for future herbicide discoveries. The systems to be discussed, the hydroxyoxazolidinones, 1, and the hydroxypyrrolidinones, 2, are shown below. These structures were derived by considering the known (1) classes of carbamate and amide herbicides such as barban, 3, chlorpropham, 4, and propanil, 5. We envisioned that c y c l i z a t i o n of these classes of herbicides, combined with location of a hydroxy on the r i n g , would lead to herbicidal activity. We were e s p e c i a l l y interested i n such com pounds as they provide at l e a s t two p o t e n t i a l binding s i t e s at the receptor, the hydroxy and the amide. Furthermore, as a r e s u l t of c y c l i z a t i o n , the change i n s i z e and shape of molecules 1 and 2 r e l a t i v e to the simpler carbamates and amides, could provide addi t i o n a l information on the binding s i t e s of a l l of these molecules 1-5.

0097-6156/91/0443-0182$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.


15.

BRINKMEYER ET AL

Hydroxyoxazolidinones and Hydroxypyrrolidinones

5 The above mentioned molecules were pursued as targets p r i m a r i l y because: 1) they represent new targets for herbicide design; and 2) they incorporate aspects of the model compounds 3 - 5 , which may result i n new insights into SAR requirements for the h e r b i c i d a l a c t i v i t y of amides and carbamates. Since the models for t h i s work are photosystem II i n h i b i t o r s , insight into the binding and receptor s i t e at or near photosystem II was expected. Synthesis of the Hydroxypyrrolidinones and Hydroxyoxazolidinones. The process by which these compounds were synthesized was novel and heretofore not reported. The key step i n the synthesis of the hydroxypyrrolidinone 2 was the ozonolysis of a substituted pentenamide. The N-heterocyclic pentenamides were synthesized in a straightforward manner s t a r t i n g with 2-methyl-4-pentenoic acid (Scheme I ) . The 2-methyl-4-pentenoic acid, 6, was prepared v i a an orthoester Claisen rearrangement (2) between a l l y l alcohol and triethylorthopropionate using propionic acid as a c a t a l y s t i n the reaction. The ester from t h i s reaction was saponified to y i e l d the corresponding acid, 6. Conversion to the acid chloride was accomplished using oxalyl chloride. This material was condensed with a v a r i e t y of heterocyclic amines y i e l d i n g the desired N-heterocyclic pentenamides, 7.


183

184

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π a) CH CH C(OEt) 3

2

CH

3

3

OH CH CH C0 H (cat) 3

2

2

H0 C^^% 2

b) NaOH a)

(COCI)

2

b) R-NH

2

Ο

o


CH,

3

MeS-SMe OH

Ο

8, R" = COCH 10, R" = CH

3

3

SCHEME I The pentenamides were then treated with ozone. Changes i n solvent and temperature (-78° to room temperature) did not a l t e r s i g n i f i c a n t l y the course or y i e l d of t h i s reaction. The ozonolysis of the o l e f i n gave an intermediate aldehyde which could not be isolated but cyclized immediately to the desired hydroxypyrrolidinone, 2. This general procedure was applicable to a large number of heterocyclic amines (Table I I ) . In a l l cases, good o v e r a l l y i e l d s were obtained. Several routes to the hydroxyoxazolidinones, 1, were designed. The route which proved most successful was based on the approach used for the hydroxypyrrolidinones 2. The key step i n t h i s approach was the ozonolysis of the double bond to y i e l d the 5-hydroxyoxazolidinone ring, 1 (3). With this as the anchoring reaction i n the process, two routes to the double bond carbamate 9 were envi sioned.


15.

BRINKMEYER ET AL ROUTE 1

Hydroxyoxazolidinones and HydroxypyrroUdinones R 0

'

CICO

R-NH,

O R-NÔ ROUTE 2


R-N=C=0-

•γχ

HQ

O R—N -N O

' OR"

Λ 9

OH

R'

11, R" = COCH 12, R" = CH,

3

SCHEME II Route 1 (Scheme II) began with an amine which was reacted with allylchloroformate to y i e l d the o l e f i n i c carbamate 9. This same intermediate was obtained, as shown i n Route 2, by reacting an isocyanate and an a l l y l i c alcohol. These routes were complementary i n that where the isocyanate was not available or not r e a d i l y synthesized, the appropriate amine precursor to the isocyanate could be reacted with allylchloroformate. The key step, ozonolysis of the o l e f i n i c carbamate 9 to the bydroxyoxazolidinone 1, proceeded smoothly under a variety of d i f f e r e n t solvent and temperature conditions. In a l l cases the o v e r a l l syntheses were quite f a c i l e with good to excellent y i e l d s . Hydroxy groups on either the oxazolidinone or pyrrolidinone rings could be functionalized e a s i l y (4, 5). We concentrated on conversion of the hydroxy to the acetoxy and the methoxy analogs. These conversions were straightforward and proceeded i n high y i e l d


185

186

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

(Schemes I and I I ) . Thus the hydroxyl group of either the p y r r o l i dinone or oxazolidinone was treated with acetic anhydride i n p y r i dine to provide the acetoxy compounds 8 and 11, respectively. The methoxy compounds were formed by the treatment of the hydroxyl group with methanol i n aqueous hydrochloric acid. Again, t h i s conversion was e f f i c i e n t and proceeded i n high y i e l d to provide 10 and 12, respectively.


BIOLOGICAL METHODS Compounds were evaluated at 8 lb/acre as preemergence and postemergence herbicides. The test plants were large crabgrass ( D i g i t a r i s sanguinalis), f o x t a i l m i l l e t (Setaria i t a l i c a ) , redroot pigweed (Amaranthus r e t r o f l e x u s ) , morning glory (Ipomoea spp.), and wild mustard (Brassica kaber). In the preemergence and postmeergence t e s t s , each compound was dissolved i n a spray solution containing acetone-ethanol (1:1 r a t i o ) with Toximul R and S surfactants added, and then was diluted with deionized water. For the preemergence t e s t s , the spray solution was sprayed on s o i l immediately after the test species were planted. Approximately three weeks a f t e r spraying, the h e r b i c i d a l a c t i v i t y of the compound was determined by v i s u a l observation of the treated area i n comparison with untreated controls. These observations are reported on a control rating scale of 1-5, where 1 = no e f f e c t , 2 = s l i g h t e f f e c t , 3 = moderate e f f e c t , 4 = severe e f f e c t , and 5 = death of plants. For the postemergence t e s t s , developing plants were sprayed about two weeks a f t e r the seeds were sown. Approximately two weeks after spraying, the h e r b i c i d a l a c t i v i t y of the compound was determined by v i s u a l observation of the treated plants i n comparison with the untreated controls. The rating scale was the same as that f o r the postemergence t e s t s . The h e r b i c i d a l a c t i v i t i e s presented i n Tables I (hydroxyoxazolidinones 1) and II (hydroxy pyrrolidinones 2) are averaged control ratings f o r a l l 5 species tested at 8 lb/acre f o r both the preemergence and postemergence tests. In addition to the 8 lb/acre t e s t s , several compounds with prominent postemergence a c t i v i t y were retested at either 0.12 and 0.25 lb/acre or 0.25 and 0.5 lb/acre on four annual grasses and 5 annual broadleaf weeds. As well as the f i v e species l i s t e d above, other weed species evaluated included barnyard grass (Echinochloa c r u s g a l l i ) , v e l v e t l e a f (Abutilon theophrasti), wild oat (Avena fatua), and zinnia (Zinnia elegans). The postemergence h e r b i c i d a l a c t i v i t i e s of these compounds on weeds are summarized i n the text below. Also, several compounds with prominent preemergence a c t i v i t y were retested at 0.25, 0.5 and 1 lb/acre on a broad spectrum of grass and broadleaf species and the results are shown i n Table I I I . In addition to the f i v e species l i s t e d above, other plant species evaluated included corn (Zea mays), cotton (Gossypium hirsutum), soybean (Glyane max,) wheat (Triticum alstivum), a l f a l f a (Medicago s a t i v a ) , sugarbeet (Beta v u l g a r i s ) , r i c e (Oryza s a t i v a ) , cucumber (Cucumis sativus), tomato (Lycopersicon esculentum), common lambsquarters (Chenopodium album), and jimsonweed (Datura stramonium).


15. BRINKMEYER ET AL.

Hydroxyoxazolidinones and Hyaôxypyrrolidinones


STRUCTURE ACTIVITY RELATIONSHIP The hydroxyoxazolidinones 1 and the hydroxypyrrolidinones 2 were active as postemergence, preemergence and preplant incorporated materials. The structure a c t i v i t y relationships are discussed below. Three aspects of these molecules were altered i n order to maximize h e r b i c i d a l a c t i v i t y . These are: 1) the substituent on the ring nitrogen; 2) the substituents on either the oxazolidinone or pyrrolidinone rings; and 3) the hydroxyl substituent. 1) E f f e c t of Substitution on the Ring Nitrogen. The goal of changing the nitrogen substituent was to increase both b i o l o g i c a l a c t i v i t y and crop safety. Tables I and II show the results of varying this substituent f o r a v a r i e t y of heterocyclic groups. The heterocycles which imparted the best a c t i v i t y common to both systems were 5-t-butylisoxazol-3-yl ( l a and 2a), 5-t-butyl-l,3,4-thiadiazol2-yl ( I f and 2b), and 5-t-butylpyrazol-3-yl ( l p and 2 f ) . As seen i n the tables, other heterocycles contributed s i g n i f i c a n t l y to the h e r b i c i d a l a c t i v i t y of either the oxazolidinone or pyrrolidinone systems, but not always to both. In the cases where the substituents on nitrogen were substituted phenyl, a l k y l , and a c y l , these analogs had l i t t l e or no a c t i v i t y i n the pyrrolidinone and oxazolidinone systems. This i s unlike the model herbicides 3-5. 2) The E f f e c t of the Substituents on Either the Oxazolidinone or Pyrrolidinone Rings. A series of a l k y l substitutions were made on both the pyrrolidinone and oxazolidinone rings to determine t h e i r e f f e c t on a c t i v i t y . These analogs were synthesized by simple modif i c a t i o n s of the syntheses presented i n Schemes I and I I . Figure 1 shows the order of a c t i v i t y f o r d i f f e r e n t l y substituted rings wherein the nitrogen substituent i s held constant. In both systems, the monomethyl compounds are the most active. In the pyrrolidinone series where the methyl can be at either of the two positions, the analog with the methyl alpha to the carbonyl i s much more active than that with the methyl beta to the carbonyl. As to why the location of these p a r t i c u l a r methyl substituents so dramatically affects b i o l o g i c a l a c t i v i t y cannot yet be explained. For example, i n Figure 2, a comparison of the 4-methyloxazolidinone and 4-methylpyrrolidinone (same R group) shows that chemically and s p a t i a l l y these are s i m i l a r systems, i n that the methyl group occupies the same r e l a t i v e s p a t i a l orientation. However, the difference i n a c t i v i t y of the two groups i s quite substantial - the hydroxyoxazolidinone i s active at less than 1 lb/acre, while the hydroxypyrrolidinone i s active at 8 lb/acre (postemergence). 3) E f f e c t Due to Changes of the Hydroxy Group. The third aspect of the molecules examined i n t h i s SAR study was the hydroxy group, which was changed to either an acetoxy or a methoxy group. Comparison of the hydroxy compound with either of these indicated that while the hydroxy and acetoxy analogs had s i m i l a r a c t i v i t y , (cf. compounds I f and 2b, Table I I I ) , the methoxy compound 14 (Table III) provided s l i g h t l y less weed control.


187

188

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

Table I. N-Heterocyclic-4-Substituted-5-hydroxyoxazolidinones, 1_.

ο

A Μ

R —Ν

R'

AVG CONTROL RATING AT 8 lb/A PRE POST

Η

4.6

4.8

Me

5.0

5.0

Η

1.0

1.0

Η

1.0

1.0

Η

2.2

2.8

Me

4.8

5.0

Η

1.0

1.0

Me

4.8

5.0

Me

1.0

1.0

Me

1.0

1.0

Me

1.0

1.0

HO

ENTRY

R O-N


la

If

lb

Ο

R»

O-N

lc

O-^N

Id

N-N

le

If

N-N ig

y-«.>-

lh

tt

N-N

li

ij

lk

F C-J« )J3

s

N —S

Continued on next page


15. BRINKMEYER ET AL Table I.

N-Heterocyclic-4-Substituted-5-hydroxyoxazolidinones, 1. (continued)

R

R'

AVG CONTROL RATING AT 8 lb/A PRE POST


ENTRY

Hydroxyoxazolidinones and Hydroxypyrrolidinones


189

190

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π Table I I . N-Heterocyclic-3-methyl-5-hydroxypyrrolidinones, 2.

NO 2a

AVG RATING AT 8 lb/A PRE POST

HET 0

, "*

4.6

5.0

N-N


2b

I (|

y_

4.4

5.0

3.2

4.4

N-°

2 c

2d 2e

I β

Ν χ

>—

^^ls

3

4

'

2

0

1

β

2

8

4

N-N"

2f

"i-^îL-

2h

4-ô

5.0

3

8

5.0

3

6

O-N

2i

J - t U—

4.6

4.8

4.0

3.4

N^N

2k

ci—

Synthesis and Chemistry of Agrochemicals II - American Chemical

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