2-Phenoxynicotinamides - ACS Symposium Series (ACS Publications)

Chapter 5 2-Phenoxynicotinamides A New Class of Bleaching Herbicides W.J. Michaely and A. D. Gutman

Downloaded by UNIV LAVAL on May 9, 2016 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch005

Organic Synthesis Department, ICI Americas Inc., 1200 South 47th Street, Box 4023, Richmond, CA 94804-0023

The 2-phenoxynicotinamides were shown to be excellent bleaching herbicides. The optimum substitution on the 2-phenoxy ring was the meta-CF group. There are significant differences in the optimum substitution patterns for the N-phenyl and N-benzyl nicotinamide series. The aryl analogs (replacing the pyridine ring) were only slightly active. 3

There are several ways to discover biologically active molecules. Three possible ways seem logical to us. (a) Knowing a three dimensional structure of an enzyme and/or the mechanism of action of the enzyme, appropriate inhibitors can be designed, (b) If one knows several different inhibitors of an enzyme and they inhibit at (or near) the same site, then molecular modeling and QSAR techniques can be used to design new and/or better inhibitors. Sometimes this approach deteriorates to an analogue (me-too) synthesis program. (c) "Randomly" prepare (or buy) compounds about which nothing is known or presumed and apply them to your test systems (insects, plants, fungi, enzymes, etc.). Our colleagues in the pharmaceutical industry have had success in all three approaches, with some excellent success in category (a). Unfortunately, when herbicide chemists attempt to emulate this success, we immolate ourselves because there are very few plant enzymes that are well characterized. Therefore, the two most common approaches are (b) and (c). The nicotinamide class of herbicides was discovered via the "random," (c) synthesis approach. The initial synthesis was prompted by some interesting chemistry described by Villani Q ) . which showed that the chloro group in 2-chloro-nicotinic acid could be displaced by a phenol (in the presence of a base) to produce the 2-phenoxynicotinic acid. Because the chemistry was interesting and a number of herbicides contain a phenoxy moiety and a benzoic acid group, a few compounds were prepared to determine i f there was significant pesticidal activity. 0097-6156/87/0355-0054506.00/0 © 1987 American Chemical Society

Baker et al.; Synthesis and Chemistry of Agrochemicals ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

5. MICHAELYANDGUTMAN

2-Phenoxy nicotinamides

55

The initial compounds prepared were the 2-(substituted)phenoxynicotinic acids (I, Figure 1). These (substituted)2-phenoxynicotinic acids were devoid of herbicidal activity at our 4 lb/acre screening rate. In order to change the polarity of the products, these nicotinic acids were converted to N-alkyl amides by merely heating them with alkyl isocyanates in the absence of a solvent (II, Figure 1).


OH

Figure 1.

Preparation of N-alkylnicotinamides.

These nicotinic acid intermediates were also converted to their corresponding ethyl esters by reaction with ethyl alcohol in the presence of sulfuric acid. Surprisingly, the alkyl amides had some pre- and postemergent herbicidal activity with bleaching symptomology. The activity was quite weak, less than 50% weed control was observed at 2 lb/acre. The esters, on the other hand, were almost devoid of herbicidal activity. A research program was initiated to explore the scope of the activity of the 2-phenoxynicotinamides. Holding the amide portion constant, as N-methyl, compounds were prepared from a number of substituted phenols, and after preparing a relatively small number of compounds, it became evident that only the 3-substitution pattern possessed high activity (Figure 2). The results of the study indicated that the 3-trifluoromethyl substitution provided the highest level of activity followed in descending order by: 3-chloro, 3-ethyl and 3-methyl (III, Figure 2). It is interesting to speculate that the herbicidal activity is the result, in part, of a f i t on an enzyme site, since CF3, CI and CH3 all have about the same molecular size.


56

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

0 ii

C-NHCH3

N

0

R

III Downloaded by UNIV LAVAL on May 9, 2016 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch005

3-CF3 > 3-C1 > 3-C2H5 > 3-CH3

Fi- gure 2. Relative Herbicidal Activity vs.

the Phenyl Ether Substituent. Work was next conducted to determine the optimum substitution of the amide group. The substituted phenoxynicotinic acids were reacted with thionyl chloride to produce the acid chlorides, which, in turn, were reacted with a wide variety of primary and secondary amines and anilines to produce the corresponding amides. The most active compounds were the N-phenyl amides and the N-benzyl amides. The N-phenyl Nicotinamides (Table I) In the N-phenyl case all of the secondary aryl amides were very weak or inactive. The biodata on the primary amides is shown in Table I. When considering a combination of pre- and postemergent herbicidal activity, the 4-chlorophenyl derivative (compound 4, Table I) had clearly superior activity (89% pre- and 74% postemergent). Considering only the preemergent application method, several compounds showed good levels of activity. The most active compounds contained the 3-chlorophenoxy group and were either unsubstituted or had a 4-chloro or 3-chloro substituent on the N-phenyl group (compounds 15, 7 and 6 in Table I). The comparable 3-trifluoromethylphenoxy compounds were less active (compounds 14, 4 and 3 in Table I), the major difference can be correlated with decreased wild oat control. Despite these clear activity differences, we were unable to obtain a clear Structure Activity Relationship (SAR) for the N-(substituted)nicotinamides. For example, comparing compounds 10, 11, and 13 (all have the N-[4methylphenyl] group), the order of increasing activity for the phenoxy substituent is 3-CF3 < 3-CH2H5 < 3-C1. But, comparing compounds 14, 15 and 16 (all have the unsubstituted N-phenyl group) and compounds 5 and 8 (both have the N-[3,4-dichlorophenyl] group) the orders of activity for the phenoxy substituents are


57

5. MICHAELYANDGUTMAN 2-Phenoxynicotinamides

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58


3-C2H5 < 3-CF3 < 3-C1 and 3-C1 « 3-CF3, respectively. Hence, we found no consistent structural correlations in the N-phenyl series. After our initial patent applications in this area (2 _3> were filed, a research group at May and Baker Limited filed patents in the same area (J5, 6). The information in these patents is covered in a recent publication {]_). They came to several conclusions about the SAR of the N-phenyl-2-phenoxynicotinamides. They concluded that the optimum substitution pattern on the 2-phenoxy group was the 3-trifluoromethyl moiety. Their optimum pyridine substituents were the unsubstituted and the 5-methyl nicotinamides. Their optimum N-phenyl substituents were the 4-fluoro and 2,4-difluorophenyl compounds. Combining the greenhouse optimization with field trial results led the May and Baker group to select N-( 2,4-difluorophenyl )-2- (3-trifluoromethyl phenoxy ^ - p y r i dine carboxamide (diflufenican) for development as a herbicide for winter wheat and barley. Sandman et. aK (8) have found the N-phenyl-2-phenoxynicotinamides to be powerful inhibitors of phytoene desaturase. Several bleaching herbicides that inhibit the phytoene to phytofluene transformation have the same 3-trifluoromethylphenyl group (8, 9). This group includes norflurazon, metflurazon, fluridone, fluometuron and fluorochloridone. In the nicotinamide series the same 3-trifluoromethylphenyl group gives optimum herbicide activity.


9

The N-Benzylnicotinamides The N-benzylnicotinamides have an interesting herbicidal SAR. There are several important effects of substitution patterns on bioactivity. The variation of herbicidal activity with the nitrogen substituent can be seen in Table II. From Table II it is clear that the secondary amide (R=H) is the most active. Surprisingly, the highly polar hydroxamic acid (R=0H) is slightly active. This might be explained by in vivo reduction to the active parent or possibly polarity in this position is not detrimental to activity. The alkyl amides in Table II appear (with the exception of N-ethyl) to rapidly lose herbicidal activity as the length of the alkyl group increases. For example, when the N-alkyl group contains four or more carbons, all herbicidal activity is lost. The herbicidal activity differences, as a function of application method, are noteworthy. For preemergent application, grass control is usually superior to broadleaf control, but the opposite is true in postemergent application. We do not know the reason for this phenomenon. This result could be due to simple physical differences between grasses and broadleaves. Broadleaves have more exposed horizontal leaf surfaces than grasses, hence, postemergent applications usually produce better leaf coverage on broadleaves. The substitution pattern for the benzylic carbon is quite simple. Replacing the benzylic hydrogens decreases activity. Polar groups eliminate activity. This can be seen in Table III.


5. MICHAELYANDGUTMAN 2'Phtnoxynicotinamidts Table II Herbicide A c t i v i t y o f N-Substituted, N-Benzylnicotinamides 0 R


n

i

Weed Control (% Grass/% Broadleaf) R

Preemergent

Postemergent

Rate lb/acre

H

100/90 100/71 61/52 39/17

87/89 59/84 32/62 12/50

4 2 1 1/2

OH

37/20

27/60

4

40/16

15/48

4

65/49 42/23 25/8

27/85 13/67 6/54

4 2 1

27/12

12/39

4

IC3H7

7/3

5/11

4

J2C4H9

0/0

0/0

4

3/0

5/10

4

CH

3

CH 2

5

nC H 3

7

CH CH CN 2

2



60

Table III Herbicide A c t i v i t y o f Benzylic Substituted Nicotinamides


R R' 0 H I /

Weed Control (% Grass/% Broadleaf) R

R'

H

H

100/90 100/71

87/89 59/84

4 2

H

87/75 40/14

68/76 40/38

4 2

0/0

0/0

4

0/3

10/3

4

CH z CN

3

C=0 H

Preemergent Surface (PES)

Postemergent

Rate lb/acre



5. MICHAELY AND GUTMAN 2-Phenoxynicotinamides

61

We have also replaced the benzyl ic CH2 by an NH. These (substituted) phenyl hydrazides were inactive. The optimum substitution pattern on the phenyl group of the ether moiety in the N-benzyl series of compounds is consistent with the pattern seen in N-alkyl and N-phenyl series. In the N-benzyl series, consistently high levels of herbicidal activity are obtained with the 3-trifluoromethylphenyl ethers. Replacing the phenyl ether by a 3-trifluoromethylphenyl amine or N-methyl-3trifluoromethylphenyl amine group resulted in total loss of herbicide activity. The substituted benzyl ethers and aliphatic ethers had very low levels of herbicide activity. The SAR for the N-benzyl phenyl substitution pattern is very different than that for the N-phenyl substitution pattern. In the N-benzyl derivatives, only small groups are tolerated in the para position, even para fluoro is less than half as active as the unsubstituted parent. This phenomenon appears to be a simple size requirement since groups of varying 1ipophilicities and electronic characteristics such as CI, Br, CN, CF3, OCH3 and CH3 are all essentially inactive at the 4 lb/acre screening rate. For substituents in the meta position, size is not as critical as it is for the para position. However, only the meta fluoro compound has herbicidal activity comparable to the unsubstituted parent. All of the other derivatives are substantially less active than these two compounds. The effect of substituents in the ortho position, on preemerqent herbicidal activity, is unclear. The ranking of ortho substituents is NO2 > CF > CH3 > CI > F > H > Br > OCH3 > OC2H5. The more active compounds also have a flatter dose response curve. Hence, ortho CF3 is 93/98 (Gr/Bl) at 4 lb/acre but s t i l l 74/92 (Gr/Bl) at 1/2 lb/acre. Surprisingly, most of the ortho substituted compounds are less active, than their corresponding parent, when comparing their postemergent activity. 3

The Phenyl Analogs of the Pyridine Ring It has been suggested by Thornber and others (10) that the nitrobenzene ring is equivalent to the pyrdine ring ("Figure 3). This makes some sense based upon electron density and reactivity considerations, but, the nitro group occupies a much larger space than the pyridine nitrogen lone pair of electrons. In order to test this equivalence, we prepared some 3-nitro-2-phenoxybenzamides for comparison to their pyridine analogs. Two of these are shown in Table IV. As can be seen from Table IV, the nitrophenyl analogs of the nicotinamides are inactive. Interestingly, the 2-(3-trifluoromethylphenyl) benzamides (compound IV minus the nitro group) were moderate herbicides (less than 50% weed control at 1 lb). These compounds are also bleaching herbicides as are the well known 3-phenoxybenzamides. The 3-phenoxybenzamides are also known to be inhibitors of phytoene desaturase (11).



62


Figure 3.

Nitrobenzene and Pyridine Structural

Equivalence.


63

5. MICHAELY AND GUTMAN 2-Phenoxynicotinamides Table IV Comparison o f B i o l o g i c a l A c t i v i t i e s , Some Nicotinamides Versus Their Nitrophenyl Analogs


0

0

II

IV

Rate (lb/acre)

Structure

R2

PES* Weed Control

II

2-CIC6H4CH2-

95%

4

84%

2

74%

1

60%

1/2

40%

1/4

IV

2-ClC H CH -

II

C H CH -

6

6

IV

5

4

2

2

C H CH 6

5

2

0%

4

88%

4

89%

2

57%

1

29%

1/2

0%

4

*PES = preemergent surface


64


Conclusion The phenoxynicotinamides represent a novel class of promising preemergence and postemergence herbicides. The results obtained to date indicate that relatively minor variations in structure can have a significant effect on the level of herbicidal activity and spectrum of weeds controlled.


L i t e r a t u r e Cited 1.

V i l l a n i , F. J., et.

al.,

J . Med. Chem. 18, 1-8 (1975).

2.

Gutman, A. D. U.S. Patent 4,251,263 (Filed, Sept. 4, 1979; issued, Feb. 17, 1981).

3.

Gutman, A. D. U.S. Patent 4,270,946 (Filed, Oct. 1, 1979; issued, June 2, 1981).

4.

Gutman, A. D. U.S. Patent 4,327,218 (Filed, Nov. 28, 1980; issued, April 27, 1982).

5.

Cramp, M. C . ; Gilmour, J.; Parnell, E. W. U.K. Patent App. 2,087,887A (Filed, Nov. 19, 1981).

6.

Cramp, M. C . ; Gilmour, J.; Parnell, E. W. U.S. Patent 4,618,366 (Filed, June 15, 1984; issued, Oct. 21, 1986).

7.

Cramp, M. C . ; Gilmour, J.; Hatton, L. R.; Hewett, R. H; Nolan, C. J.; Parnell, E. W. Pestic. Sci. 18, 15-28 (1987).

8.

Sandman, G . ; Clarke, I. E . ; Bramley, P. M.; Boger, P. Naturforsch., C.; Biosci, 39C, 443-9 (1984).

9.

Dodge, A. D. Progress in Pesticide Biochemistry and Toxicology; Hutson, D. H. and Roberts, T. R., Ed.; John Wiley and Sons Ltd.: New York, 1983; pp 163-197.

Z.

10. Thornber, C. W. Chem. Soc. Rev. 8, 563-580 (1979) and references cited therein. 11. Clarke, I. E . ; Sandman, G . ; Bramley, P. M.; Boger, P. Biochem. and Phys., 23, 335-340 (1985). RECEIVED May 12,

Pest.

1987


2-Phenoxynicotinamides - ACS Symposium Series (ACS Publications)

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