Porphyric Pesticides - American Chemical Society

Chapter 2

Synthetic Organic Chemicals That Act through the Porphyrin Pathway

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 6, 2017 | http://pubs.acs.org Publication Date: April 15, 1994 | doi: 10.1021/bk-1994-0559.ch002

R. J. Anderson, A. E . Norris, and F. D . Hess Research Division, Sandoz Agro, Inc., 975 California Avenue, Palo Alto, C A 94304

A survey of the known inhibitors of protoporphyrinogen oxidase (Protox) has resulted in their classification into three main chemical classes: the diaryl ethers, the phenyl heterocycles, and the heterocyclic carboxamides. The first class, the diaryl ethers, is subdivided into the diphenyl ethers (e.g., oxyfluorfen, acifluorfen and lactofen) and the heterocyclyl phenyl ethers (e.g., AH 2.430, 6aryloxy-1H-benzotriazoles). A second major class of protox inhibitors, the phenyl heterocycles, is characterized by the 2,4,5substitution pattern of the phenyl ring and contains two major subclasses. Most prominent in the N-phenyl heterocycle subclass are the imides (e.g., S 23031, S 53482), the tetrazolones (F 5231), the triazolones (F 6285), the uracils (UBI C4243) and the pyrazoles ( M & B 39279). The smaller C-phenyl heterocycle subclass also contains several heterocyclic systems. The O-phenylcarbamates ( R H 1422) are included with the phenyl heterocycles based on their characteristic phenyl substitution pattern. A third, presently small class is the heterocyclic carboxamide class which can be subdivided into the pyridone carboxamides ( D L H 1777) and the pyridine carboxamides (LS 82 556).

Diphenyl ether herbicides have been known for many years to cause rapid membrane disruption in plants in the presence of light (7). The bipyridyliums were the only other class of herbicides that showed this rapid membrane disruption; however, these two classes of herbicides differ in their biochemical site of action (2). The bipyridyliums undergo reversible redox reactions by diverting electron flow from photosystem I and producing superoxide from triplet oxygen. Lipid peroxidation by hydroxy radicals from the superoxide results in membrane disruption (2). The diphenyl ethers act more indirectly to destroy membrane integrity. They inhibit protoporphyrinogen oxidase (Protox) (3), the

0097-6156/94/0559-0018$08.00/0 © 1994 American Chemical Society

Duke and Rebeiz; Porphyric Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1994.


2. ANDERSON ET AL.

19

Synthetic Organic Chemicals

last enzyme common to the heme and chlorophyll biosynthetic pathways, and cause protoporphyrin I X to accumulate in vivo. With light, protoporphyrin I X acts as a photosensitizer in the formation of singlet oxygen which causes lipid peroxidation and membrane disruption (4). More recently Duke, Lydon and Paul (5) showed that the herbicide oxadiazon has the same mechanism of action as the diphenyl ethers, even though its molecular structure is quite different. Currently there is significant patent and development activity on the N-phenyl imide herbicides, which are also known to act by inhibiting the Protox enzyme (6). Because several types of chemical structures have now been shown to inhibit Protox, a chemical classification system for Protox inhibitors would be useful and could help clarify the nomenclature used in literature reports. In this paper we propose the classification of the known Protox inhibitors into three major classes, with subclasses defined for each class. Specific compounds shown as examples of the various subclasses are primarily those that have been used in biological and biochemical studies reported in the literature. Patent citations for specific compounds or generic structures are listed in the text after the compound numbers or in columns within tables. Where available the patents cited are those claiming and/or disclosing the active compounds per se. U S Patent citations have been given except where unavailable. Diaryl Ethers The diaryl ether class of protox inhibitors is characterized by two substituted aromatic rings (Ai and A r ) , usually six membered, linked by an oxygen atom. The pattern of aromatic substitution required for optimal herbicidal activity and protox inhibitory activity, is indicated below: 1

2

R

Of the several subclasses of diaryl ethers, the diphenyl ethers are most prominent. A t least eleven diphenyl ethers are or have been commercial products (Table I). They are strikingly similar in structure, and typify the optimal substitution pattern for this class. Generally, phenyl ring Ar is 2,4disubstituted, R is chloro, R is trifluoromethyl or chloro, and R is hydrogen. The second phenyl ring A r is usually 3,4-disubstituted and X is nitro or chloro. The greatest variation of structure in the diphenyl ethers occurs in the substituent Y . Nitrofen, in which Y = H , was the first diphenyl ether to be commercialized. It is a relatively weak Protox inhibitor and is less herbicidally active than other commercialized diphenyl ethers (7). Other closely related analogs in which Y is also hydrogen are chloronitrofen, fluoronitrofen and fluorodifen. The latter is exceptional in structure with R = N 0 rather than chloro. Diphenyl ethers containing an alkoxy substituent ( Y = O M e , OEt) or t

x

2

3

2

t

2


20

PORPHYRIC PESTICIDES

Table I. Commercialized Diphenyl Ethers


Structure

Common Name

Patent References

X =H nitrofen (1, 7-9)

U S P 3,080,225 (Rohm & Haas)

X = CI chloronitrofen (18)

USP 3,316,080 (Mitsui)

X = F fluoronitrofen

USP 3,401,031 (Mitsui)

(I)

U0

2

fluorodifen

U S P 3,420,892 (Ciba-Geigy)

chlomethoxyfen chlomethoxynil (8)

USP 4,039,588 (Rohm & Haas)

oxyfluorfen (8-10)


(Z9)

NO.

N0

9


21


2. ANDERSON ET AL.

Table I. (continued) Commercialized Diphenyl Ethers


Structure

CI

a

Common Name

Patent References

bifenox (7>8)

USP 3,652,645 (Mobil)

O

( ^ Y ° Y Y ^ O *\S ^ N

0

2

x

acifluorfen (7, 5,12-i3)

CI


o fomesafen (7,14)

USP 4,285,723 (ICI)

lactofen (7)

E P 20 052 (Rohm & Haas)

fluoroglycofen ethyl (15)

E P 20 052 (Rohm & Haas)



22


an acyl substituent (Y = C O O H , C O O R ) predominate in the marketplace today due to their high herbicidal activity and crop selectivity. The most important of these are oxyfluorfen (Y = OEt) and acifluorfen ( Y = C O O H ) and its derivatives; fomesafen, lactofen and fluoroglycofen ethyl (Table I). Many other diphenyl ethers have been investigated for their biological and biochemical properties. Table II illustrates such compounds which display additional diversity in structure, especially in the Y substituent. Patent literature indicates that other Y ligands which have been explored include substituted alkyl, alkenyl, amino, amido, hydrazino, thio, imino; phosphoryl, phosphonyl, phosphoryloxy, and nitro. It is noteworthy that many of the diphenyl ethers contain a glycolate or a lactate moiety in the substituent Y , e.g. lactofen, fluoroglycofen ethyl. A second subclass of the diaryl ethers encompasses the heterocyclyl phenyl ethers. In this group of protox inhibitors, one of the aryl rings of the ether is an aromatic heterocycle. Some members of this subclass are listed in Table III. The pyrazolyl, pyridyl and furyl ring systems have been investigated as the heterocyclic component. As in the diphenyl ethers, the trifluoromethyl and chloro substituents are common to the Ar aromatic ring, while the nitro and a variety of Y groups are substituents on the A r aromatic ring. A special group of heterocyclyl phenyl ethers results when X and Y of aryl ring A r are linked together to form a heterocyclic ring. In these cases, highest herbicidal activity is generally observed when R of aryl ring Ar is fluoro. A few recently reported examples include the 6-aryloxy-lH-benzotriazoles (26), the 5aryloxyindolin-2(3H)-ones (27,18), the 5-aryloxybenzisoxazoles (29), and the 6aryloxyquinoxalin-2,3-diones. Specific examples of each of these systems are compounds 1 (EP 367 242; American Cyanamid), 2 (USP 4,911,754; American Cyanamid), 3 (USP 5,176,737; ICI), and 4 ( G B 2,253,846; ICI), respectively. To date, none of the members of this subclass has been commercially developed. x

2

2

3

1

x

2

H 3

4



2. ANDERSON ET AL.

23

Table II. Diphenyl Ethers


Structure

Code

CI

O

^ cvr^

>^-Na

NO.

CI

o ,0 I

^OR

I

CF,

O ^ A f T Y °

p ^^3

,

s

C G A 84446

U S P 4,221,581

( °)

(Ciba-Geigy)

P P G 1013 (7, 20)

U S P 4,344,789 (PPG)

R = Me, R H 5782 (7, 5, U, 12) R = Et, R H 8817 (21)

U S P 3,928,416 (Rohm & Haas)

AKH7088 (8, 22)

U S P 4,708,734 (Asahi)

o

CR*

C

0

2

ci

0 1

Patent Reference

R

R = M e , L S 820 340 < > 7i

U S P 3,957,852 (Ishihara)

^ ^ C l

HC-252 (23)

U S P 5,072,022 (Budapest Vegyimuvek)


24


Table III.


Heterocyclyl Phenyl Ethers Structure

Code

Patent Reference

CI

CF —fjf 3

N

°2

Y = H , A H 2.430 (24) Y = C O O H , A H 2.431 (24)

(25) NO,

»i (25) N

f

°2

U S P 4,964,895 (Monsanto)

U S P 4,493,730 (Ishihara) U S P 4,547,218 (Dow)

U S P 4,539,039 (Dow) USP 4,326,880 U S P 4,420,328 U S P 4,626,275 (Ciba-Geigy)

0

U S P 4,382,814 (RhonePoulenc)


2. ANDERSON ET AL.


25

The bridging oxygen of the diaryl ethers can be replaced by sulfur. Although diaryl thioether 5 ( R H 1460; U S P 4,124,370; Rohm & Haas) is a potent Protox inhibitor comparable to methyl acifluorfen ( R H 5782, Table II), it is nearly inactive in vivo (7).


CI

O

5

Phenyl Heterocycles The second major class of Protox inhibitors is the phenyl heterocycle class, in which either a nitrogen (N-phenyl heterocycles) or a carbon atom (C-phenyl heterocycles) of the heterocyclic ring bears a usually 2,4,5-substituted phenyl moiety, as indicated below:

Generally, R is fluoro or chloro, R is chloro, and R is variable; or R and R when linked together, form a heterocyclic ring. The N-phenyl heterocycles usually contain a carbonyl (or occasionally, thiocarbonyl) group adjacent to the nitrogen atom. The first compound of this class to be commercially developed was oxadiazon 6 (USP 3,385,862; Rhone-Poulenc) (11, 26, 27). It is an oxadiazolone, and representative of the usual phenyl substitution pattern for this class. 4

5

CI

6

o

6


5

6

26


In recent years, the N-phenyl heterocycles have received considerable attention, due in large part to the discovery that a fluorine substituent in the 2position ( R = F) of the phenyl ring markedly increased herbicidal activity. Over a dozen different heterocycles have appeared in published patent applications, and the number is steadily increasing. These heterocyclic systems are listed in Table I V along with the system name and patent references. Proforms and/or derivatives of especially the imides, hydantoins, and triazolodiones are also found in the patent literature. The last system in Table IV, the N-phenyl pyrazoles, is notable for its lack of carbonyl functionality in the heterocyclic ring. Compounds from several of these subclasses have been or are presently being investigated as developmental herbicides. Some of these are shown in Table V . The imide, triazolone, tetrazolone, uracil, pyrazole, and oxazolodione systems are all represented. The C-phenyl heterocycle subclass is an emerging one based on very recent patent activity. Although presently smaller than the N-phenyl heterocycle subclass, the C-phenyl heterocycle subclass is likely to increase in size with additional research. Presently, this subclass includes the 3-phenylpyrazoles represented by 7 (WO 92/06962; Monsanto), the 5-phenyloxadiazolones such as 8 (JP 3066656A; Mitsubishi), the 2-phenyltetrahydroimidazopyridines such as 9 ( D E 4120108; Schering) and the 3-phenylisoxazoles such as 10 (28).


4

9

10


2. ANDERSON ET AL.

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Table IV. N-Phenyl Heterocycle Systems


Heterocycle Structure

System Name

Imides (29, 50)

U S P 4,484,941 U S P 4,640,707 U S P 4,770,695 U S P 4,938,795 (Sumitomo)

Hydantoins

E P 311 135 (Schering) E P 493 323 (Sandoz)

Oxazolodiones

U S P 5,198,013 (Sagami)

Triazolodiones

U S P 4,619,687 (Sumitomo)

Oxazolones

W O 92/12139 (Sankyo)

Imidazolidinones

E P 484 776 (Bayer)

Triazolones

U S P 4,818,275 (FMC) JP 92079337 (Nihon)

O O

R

o o

V

Patent Reference

o o

R

•N

o o

R ^

R

O

Continued on next page Duke and Rebeiz; Porphyric Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

28


Table IV. (continued) N-Phenyl Heterocyle Systems Heterocycle Structure

Systems Name

Patent Reference

Oxadiazolones

U S P 3,385,862 (Rhone-Poulenc)

Tetrazolones

U S P 5,136,868 (FMC)

Uracils (10)

U S P 5,169,430 (Uniroyal) E P 540 023 (Sumitomo) W O 92/11244 (Nissan)

Oxazolinediones

E P 529 402 (Bayer)

Pyridones

E P 488 220 (Sumitomo)

Pyrazoles

U S P 4,608,080 (Sumitomo) U S P 4,804,675 U S P 4,945,165 (Bayer) U S P 4,666,507 (Nippon Kayaku) U S P 4,752,326 (Hokko)


O

O

O

O

R

R"


2. ANDERSON ET AL.

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Table V . N-Phenyl Heterocycles


Structure

0

o

F C X

-(/

Code

Patent Reference

S 23031 V 23031 (flumiclorac pentyl)

U S P 4,770,695 U S P 4,938,795 (Sumitomo)

S 23121 (flumipropyn) (6, 31)


S 23142 (6, 21, 31-33)


S 53482


o O

V - N ^ ||

(flumioxazin)

(34)

o

o

KS 307 829 (12)


Continued on next page


30


Table V. (continued) N-Phenyl Heterocycles Structure

Code

Patent Reference

F5231 (35)

USP 5,136,868 (FMC)

F6285 (36)

USP 4,818,275 (FMC)

U B I C4243 U C C C4243

U S P 4,746,352 (HoffmanLaRoche) U S P 4,943,309 U S P 5,176,735 (Uniroyal)


F O

CI

«N

o

P 9v

0=(

/

/

o

°-

Porphyric Pesticides - American Chemical Society

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