Synthesis and Biological Activity of Heteroalkyl Analogues of the

Chapter 13

Synthesis and Biological Activity of Heteroalkyl Analogues of the Broadleaf Herbicide Isoxaben R. S. Brinkmeyer, Ν. H. Terando, and T. William Waldrep

Downloaded by OHIO STATE UNIV LIBRARIES on June 22, 2012 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch013

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 i e s of various heteroalkyl substituted 2,6-dimethoxybenzamides are discussed. B i o l o g i c a l a c t i v i t y varied s i g n i f i c a n t l y depending on the heteroatom and i t s p o s i t i o n on the side chain compared to the a l k y l model.

A new herbicide which has recently reached the marketplace i s EL-107, N-[3-(l-ethyl-l-methylpropyl)-5-isoxazolyl]-2,6-dimethoxybenzamide (Figure 1), also known by the tradename of isoxaben. This compound represents the f i r s t of a new class of herbicides (1), the 2,6-dimethoxybenzamides. Currently, EL-107 i s used for preemergence control of a v a r i e t y of broadleaf weeds (Figure 2) i n cereal crops. This paper discusses the syntheses and h e r b i c i d a l a c t i v i t y of heteroalkyl analogs of EL-107. During the study of structure a c t i v i t y relationship with EL-107, analogs were also found to be predominantly broadleaf herbicides, very active against common weeds such as redroot p i g weed, jimsonweed, and nightshade and s l i g h t l y less active against morning glory, v e l v e t l e a f , and f o x t a i l m i l l e t . As a result of the SAR work, the following conclusions were reached: 1) the 2,6-dimethoxybenzoyl moiety gives the greatest a c t i v i t y ; 2) the amide linkage i s important f o r a c t i v i t y ; 3) two of the most active hetero cycles are isoxazole and thiadiazole; and, 4) the substituted a l k y l group i s necessary f o r a c t i v i t y , and some f l e x i b i l i t y i s allowed i n t h i s region of the molecule (1). Our goal was to explore what e f f e c t changes i n the a l k y l substituent had on b i o l o g i c a l a c t i v i t y . S p e c i f i c a l l y , we intended to substitute these a l k y l groups with heteroalkyl groups, i n that the presence of a hetero atom may have affected not only a c t i v i t y but also metabolism, persistence, s t a b i l i t y , s o l u b i l i t y , and receptor binding.

0097-6156/91/0443-0158$06.00A) © 1991 American Chemical Society

In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


13. BRINKMEYER ET AL

Heteroalkyl Analogues ofa BroadleafHerbicide159

0-N

Λ O Me Figure 1.

EL-107 Structure of Isoxaben.

Brassica napus

Ranunculus sp

Centaurea cyanus

Sperguia arvensis

Lamium purpureum

Stellaria media

Matricaria recutia

Thlaspi arvense

Papaver sp

Tripleurospermum maritimum

Veronica sp Figure 2. Major weeds in Europe controlled by Isoxaben.


160

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

SYNTHESIS


Our goal was to substitute oxygen and sulfur into the two most active a l k y l substituents, the 1-methyl-1-ethylpropyl group (found i n EL-107), and the 1-methyleyelohexyl group (Figure 3). The choice of heterocycle was isoxazole, found on EL-107, and thiadiazole. The synthetic aspects of this problem presented the greatest challenge since each compound required a separate t o t a l synthesis route. Holding the 2,6-dimethoxybenzamide constant, the heteroalkyl groups considered were divided into four subgroups: dithianes, dioxanes, dihydroxy compounds and t h e i r analogs, and diheteroalkyls. DITHIANES (SCHEME I ) . The dithiane benzamides were synthesized from the commercially available (Aldrich Chemical Co.) ethyl 1,3dithiane-2-carboxylate. Treatment (2-4) with a base (e.g. lithium diisopropylamide) followed by methyl iodide or ethyl iodide gave the substituted dithiane esters 1. For the synthesis of isoxazoles, the esters were treated with a c e t o n i t r i l e and base to give the keto n i t r i l e 2. Treatment with hydroxylamine gave the desired aminoisoxazolyldithiane 3. Condensation with 2,6-dimethoxybenzoyl chloride yielded dithianes 4a-c. Overall y i e l d s f o r these compounds were good. The dithianethiadiazolylbenzamides were synthesized from the dithiane esters, 1, by hydrolysis of the esters followed by t r e a t ment of the acids with phosphorous oxychloride and then thiosemicarbazide, y i e l d i n g the aminothiadiazolyldiathianes 5. Condensation of the amino group of 5 with 2,6-dimethoxybenzoyl chloride gave the benzamides 6a-c i n high y i e l d . DIOXANES (SCHEME I I ) . The dioxanes were made from the commercially available (Aldrich) 2,2-bis(hydroxymethyl)propionic acid. This material, condensed with an aldehyde or ketone, gave the desired dioxanecarboxylic acid 7. The carbonyl containing compounds employed were formaldehyde (7a,R ,R"=H), acetone (7b, R ,R"=Me), and benzaldehyde ( 7c, R*=H, R"=Ph). These condensations proceeded smoothly under acid c a t a l y s i s i n good y i e l d s (80-95%). In addition to condensation with carbonyls, the d i o l was also condensed with triethylorthoformate to give a c y c l i c orthoester (7d, R H, R"=0Et). Condensation with dimethylcarbonate gave the c y c l i c carbonate (7e, R',R"=0). The carboxylic acids 7a-e were converted to the i s o x a z o l y l benzamides as depicted i n Scheme I: e s t e r i f i c a t i o n ( B F 3 , MeOH) followed by conversion to the k e t o n i t r i l e (CH CN,NaH) and then c y c l i z a t i o n with hydroxylamine gave the aminoisoxazole 8. Condensa t i o n with 2,6-dimethoxybenzoyl chloride yielded the dioxanylisoxazolylbenzamides 9a-e. Likewise, acids 7a-e were transformed to the thiadiazole analogs as i n Scheme I by treatment with phosphorous oxychloride then thiosemicarbazide to y i e l d the aminothiadiazole 10. Condensation with 2,6-dimethoxybenzoyl chloride gave the dioxanylthiadiazolylbenzamides l l a - e . Good y i e l d s were obtained throughout. !

f

,=

3



13. BRINKMEYER ET AL

Heteroalkyl Analogues ofa BroadleafHerbicide

(Χ,Υ = O or S)

9 Figure 3.

Synthetic goals of the heteroalkyl program.


161

162

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

y—SC0 Et 2

\

A S

H

S cO Et

"

©

6b

9c OMe

OMe N-N NHCO

Τ=

NHCO

OMe

Figure 4. Rank of activity of the most active heteroalkyl analogs.

100η

Ρ J

75-

o 50H Ο 25-

Compound:

EL-107

P= Pigweed, J = Jimsonweed, Ν = Nightshade, M = Morning glory

Figure 5:

Comparison of EL-107 to heteroalkyl analogs surface applied at 0.5 lb/A on four weed species.


OMe

13.

BRINKMEYER ET AL.


TABLE:

Heteroalkyl Analogues ofa Broadleaf Herbicide

169

Comparison of EL-107 to Heteroalkyl Analogs Preplant Incorporated at 0.25 lb/Acre on Four Weed Species and Surface Applied at 0.5 lb/Acre on Four Weed Species

% Control Jimsonweed

Nightshade

Morning Glory

Compound

Application

Pigweed

EL-107

PPI SA

100 100

100 100

100 80

85 35

4b

PPI SA

100 100

100 80

100 80

90 10

18

PPI SA

90 60

80 60

80 60

25 10

9c

PPI SA

100 100

100 100

90 5

85 5

LITERATURE CITED 1. 2. 3. 4. 5.

Burow, K. W. (Eli L i l l y ) , EP49071 (1982); Chem. Abstr. 1982, 97, 72372. Corey, E. J.; Seebach, D. Angew. Chem. Int. Ed. 1965, 4, 1075. Greene, A. E.; LeDrian, C . ; Crabbé, P. J . Org. Chem. 1980, 45, 2713. Cregge, R. J.; Herrmann, J . L . ; Richman, J . E.; Romanet, R. F . ; Schlessinger, R. H. Tetrahedron Lett. 1972, 2595. Brook, Μ. Α.; Chan, T. H. Synthesis, 1983, 203.

RECEIVED January 17, 1990


Synthesis and Biological Activity of Heteroalkyl Analogues of the

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