Cyclic Imidate Derivatives of 5-Amino-2,6-bis(polyfluoroalkyl)pyridine

Chapter 6

Cyclic Imidate Derivatives of 5-Amino-2,6bis(polyfluoroalkyl)pyridine-3-carboxylates Synthesis and Herbicidal Activity

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Shridhar G. Hegde, Robert D. Bryant, Len F. Lee, Scott K. Parrish, and William B. Parker New Products Division, Agricultural Group of Monsanto, Monsanto Company, 800 North Lindbergh Boulevard, St. Louis, MO 63167

Certain 4-halobutyramide derivatives of 5-amino-2,6-bis(polyfluoro alkyl)-4-J.sobutylpyridine-3-carboxylate showed considerably higher herbicidal activity than the corresponding non-halogenated amides. Comparison of activities of several halogenated amides indicated that the unusual activity of 4-halobutyramides may be related to their ability to cyclize to afive-memberedheterocyclic system. Lewis acid catalyzed cyclization of 4-halobutyramides gave the corresponding cyclic imidates, which are highly active herbicides.

The herbicidal properties of 2,6-(polyfluoroalkyl)-pyridine-3,5-dicarboxylates were first disclosed in 1985 by Lee and coworkers (7). Since then a large number of pyridine derivatives have been synthesized and screened for herbicidal activity (28). In general, these compounds exhibit pre-emergence and early post-emergence control of annual grasses and small-seeded broadleaf weeds. The mechanism of action has been determined to be inhibition of cell division by disruption of the formation of microtubules (9). The commercial potential of pyridines has been explored thoroughly over the past several years. These efforts have led to the development of a new turf herbicide Dimension (la) which is a pyridine-3,5dithiocarboxylate derivative.

0097-6156/95/0584-0060$12.00/0 © 1995 American Chemical Society

In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

6. HEGDE ET AL.

Cyclic Imidate Derivatives of Pyridinecarboxylates 61

In the course of investigating various analogs of la, we have discovered a new family of highly active pyridine herbicides represented by the general formula lb (20, 11). These are cyclic imidate derivatives of 5-amino-2,6-bis(polyfluoroalkyl)-4isobutylpyridine-3-monocarboxylate. In this paper we present the unusual activity of certain halogenated amide derivatives of 5-armno-2,6-bis(polyfluoroalkyl)pyridine-3carboxylate and the structure-activity rationalization which led to the conception and synthesis of cyclic imidates as a new family of pyridine herbicides. Also detailed herein is a brief account of the synthesis and biological activity of some heterocyclic analogs of cyclic imidates.


Pre-emergence Herbicidal Activity. A description of the protocol of pre-emergence assay has been previously reported (10, 11). The assay included five narrowleaf weeds (Downy Brome, Proso Millet, Barnyard Grass, Large Crab Grass, and Green Foxtail) and six broadleaf weeds (Cocklebur, Wild Buckwheat, Morning Glory, Hemp Sesbania, Jimsonweed, and Velvetleaf). The application rates of test compounds ranged from 0.01 to 2.5 lb/acre in multiples of 2 (2.5, 1.25, 0.62 lb/acre, etc.). Herbicidal activity is expressed as narrowleaf weed GR80 (NL WGR80) and broadleaf weed GR80 (BL WGR80) which is the amount of herbicide in pounds per acre, averaged over all five narrowleaf species and all six broadleaf species, respectively, required to inhibit 80% of weed growth relative to that of the untreated control. Discovery of Cyclic Imidates. In the course of investigating the functional group chemistry of aminopyridinecarboxylate 2, a readily obtained intermediate from the corresponding pyridine-3,5-dicarboxylate (10, 22), several amide derivatives were prepared by acylation with aliphatic acyl halides. Upon screening for herbicidal activity, these amides proved to be generally inactive. However, an exception to the general trend was realized in the case of a 4-bromobutyramide derivative 3 which displayed unusually high narrowleaf activity (NL WGR80 = 0.04).

2 In order to determine the origin of the unusual herbicidal activity of 3, we carried out a systematic synthesis of structurally diverse halogenated amides. Compound 2 was acylated with selected acyl halides so as to obtain halogenated amide moieties which included variations in the length of the amide chain, the degree of branching, the number and position of halogen atoms, and the nature of the halogen. The biological activity of halogenated amides follows a well-defined pattern. Some of the key structure-activity correlations are as follows: 1. 4-Bromobutyryl amide 3 is substantially more active (lOOx) than the corresponding 5-bromovaleramide, 3-bromopropionamide and 2-bromoacetamide.


62

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS IV

In general, butyramide represents the optimum chain length for best activity.

C0 Me 2

F C^ ^JT Downloaded by UNIV OF GUELPH LIBRARY on June 19, 2012 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch006

3

^CHF

2

n

NL WGR80

4

4

5.2

3

3

0.04

5

2

3.6

6

1

>10

2. The linear arrangement of the amide chain is critical for high herbicidal activity. Branched amide groups containing one halogen and four carbon atoms are much less active. For example, compound 7 had a NL WGR80 of 0.7.

C02Me

F C ^ ^NT 3

^CHF

2

3. The "N-H" bond in 3 is critical for activity. Replacement of the N-H group with an N-methyl group lowers the activity by two orders of magnitude.

i-Bu

E C02Me

Br F C ^ ^N"^ ^CHF 3

3

H

0.04

8

Ivfe

3.04

2

4. Among the 4-iodo-, 4-bromo-, and 4-chlorobutyramides, the activity order with respect to the halogen substituent is I > Br > CI based on average GR80 values for all narrowleaf species. It is important to note that the activity order for the halogen substituents is also the order of their ability as leaving groups in displacement reactions.

2L

NL GR 80

9

a

1.0

3

Br

0.19

10

I

0.11

C0 Me 2


6. HEGDE ET AL.



The significant loss of activity by replacing the N-H group with N-Me, the similarity between the order of activity with respect to the halogen group and the order of reactivity in substitution reactions (I > Br > CI), and the specific requirement of a five atom amide chain for high herbicidal activity led us to postulate an intramolecular cyclization of halogenated butyramides as a mechanism of biological activity. The cyclization of 3 with the loss of HBr is effectively an intramolecular alkylation of the amide moiety to form afive-memberedring. Since the amide group is an ambident nucleophile, the alkylation can occur either at the oxygen or at the nitrogen atom. O-alkylation leads to a cyclic imidate whereas Nalkylation leads to a pyrrolidone structure (equation 1).

In order to determine the validity of the cyclization mechanism for biological activity, we needed to synthesize both the pyrrolidone and the cyclic imidate derivatives shown in equation 1 and compare their herbicidal activities. This was accomplished by cyclization of 3 under two different conditions as shown in Figure 1. Anionic cyclization of 3 with a strong base such as sodium bis(trimethyl silyl)amide gave the pyrrolidone 11 exclusively. In contrast, reaction of 3 with silver tetrafluoroborate or ferric chloride afforded the cyclic imidate 12 as the sole cyclization product. The structures of compounds 11 and 12 were assigned based on a comparison of their C NMR spectra with those of some model compounds reported in the literature (22). Further evidence for the cyclic imidate structure of 12 was derivedfromthe X-Ray structure of the a-methyl analog as described later in this paper. 1 3

3

12

Figure 1.

11

Cyclization of 4-bromobutyramide derivative 3

The two modes of cyclization depicted in Figure 1 can be broadly distinguished as SNI and SN2 type alkylations. Complexation of silver tetrafluoroborate with the halogen results in the development of a positive charge on the adjacent carbon and the cyclization then proceeds via a transition state with substantial amount of positive character (SNI type). Conversely, sodium bis(trimethylsilyl)amide



64


generates the anion of the amide moiety, which then cyclizes via an SN2 transition state. The O- versus N-alkylation is readily explained by Kornblum's hypothesis (75) concerning the reaction of ambident nucleophiles. The hypothesis states that in reactions of ambident nucleophiles with alkyl halides, as the positive nature of the transition state increases, bond formation at the ambident anion atom having the higher electron density is preferred since it can better accommodate the positive charge. In an amide nucleophile, oxygen being more electronegative than nitrogen, predominant O-alkylation can be expected under SNI conditions. In an SN2 mechanism, the preference is for bond formation at the atom less able to bear the negative charge. Consequently, amide anions are predominantly N-alkylated. Compound 12 exhibited impressive herbicidal activity against annual narrowleaf weeds (NL WGR80=0.02). The pyrrolidone 11 was at least five-fold less active (NL WGR80=0.1). Thus, the experiment added validity to the cyclization postulate and indicated that the cyclization of compound 3 to the cyclic imidate structure was most likely responsible for the high biological activity. Synthesis of Substituted Cyclic Imidates. The majority of the a-substituted cyclic imidates were prepared according to the general protocol depicted in Figure 2. The aminopyridine 2 was acylated with a variety of a-substituted 4-bromobutyryl chlorides 13a-i and the resulting amides 14a-i were cyclized with silver tetrafluoroborate to obtain the cyclic imidates 15ai.

15a-i Figure 2.

Synthesis of a-substituted cyclic imidates


6. HEGDE ET AL.


The 4-bromobutyryl chloride precursors were obtained in a two step sequence from a-substituted butyrolactones, by first cleaving the lactone ring with HBr to give the corresponding 4-bromobutyric acids followed by treatment with thionyl chloride. The general strategy described in Figure 2 can also be employed in the preparation of p-substituted cyclic imidates. Thus, the p-methyl analog 16 and the pfluoro analog 17 were synthesized starting from p-methyl and p-fluoro butyrolactones, respectively. Compound 17 proved to be extremely succeptible to dehydrofluorination and underwent decomposition upon chromatography on silica gel. Consequently, the herbicidal activity of 17 could not be determined.


16

R =Me,R =H 1

2

17 R!=F,R = H 2

18 R =H,R = Me 1

2

The synthesis of the y-methyl substituted cyclic imidate 18 is described in Figure 3. The unsaturated amide 19 was brominated and the resulting dibromo derivative was cyclized with silver tetrafluoroborate to provide the y-(bromomethyl) cyclic imidate 20. Reduction of the bromomethyl group to methyl was accomplished by treatment with tributyltin hydride.

Figure 3.

Synthesis of y-methyl substituted cyclic imidate 18

Stereochemistry of Cyclic Imidates. There are two possible geometric isomers for the cyclic imidate system, E and Z, based on the relative orientation of the imidate oxygen and the pyridine ring with respect to the carbon-nitrogen double bond. Cyclizations of haloamides 3 and 14a-i with either silver tetrafluoroborate or ferric chloride generally yielded a single isomer of the cyclic imidate product. Determination of the exact stereochemistry of


66


12 and 15a-i through NMR studies proved to be tenuous. The Z configuration of the cyclic imidate moiety was finally deduced by a single-crystal X-ray analysis of 15a. The exclusive formation of Z-cyclic imidates is ascribed to their high configurational stability. This is consistent with some earlier observations on simpler imidate systems reported by Moriarity and coworkers (14 ). The high barrier to inversion in the Z-imidates was proposed to resultfromrepulsion between the nonbonding electrons on oxygen and the electrons localized in a p-orbital on nitrogen in the transition state of inversion.


Structure-Activity Correlations of Substituted Cyclic Imidates. The narrowleaf (NL WGR80) and broadleaf (BL WGR80) herbicidal activities of cyclic imidates 12,15a-i, 16,18 and 20 are listed in Table I. Table L

Structure-Activity Correlations of Substituted Cyclic Imidates i-Bu

compd

12

15a 15b 15c 15d 15e 15f 15g 15h 15i 16 18 20

Ri

H Me F CI Br OMe SMe Me Et Me H H H

R

2

H H H H H H H Me H F H H H

R3 R4

H H H H H H H H H H Me H H

H H H H H H H H H H H Me CH Br 2

WGR80(lb/acre) NL

BL

0.02 0.02 0.04 0.06 0.20 0.05 0.12 0.14 0.10 0.06 0.20 0.16 0.48

0.14 0.24 0.80 0.21 4.60 0.75 2.91 4.46 1.73 0.30 1.86 1.38 5.77


6. HEGDE ET AL.

67 Cyclic Imidate Derivatives of Pyridinecarboxylates


Comparisons between the activities of individual compounds reveal the following structure-activity correlations: (1) Among the three possible methyl substituted cyclic imidates, a-methyl analog 15a is the most active. The p- and ymethyl derivatives 16 and 18 are approximately 8-10 fold less active toward narrowleaf weeds and 6-8 fold less active toward broadleaf weeds. (2) Among the aalkyl substituted cyclic imidates, a-methyl analog 15a is significantly more active than the corresponding ethyl and gem-dimethyl derivatives 15 h and 15g, respectively. (3) Among the halogen substituted cyclic imidates, the order of herbicidal activity is F > CI > Br for narrowleaf weeds and CI > F > Br for broadleaf weeds. (4) The highest narrowleaf weed activity was exhibited by the unsubstituted cyclic imidate 12 and the a-methyl substituted cyclic imidate 15a. Heterocyclic analogs of Cyclic Imidates. Encouraged by the high activity of 12, we proceeded to synthesize a few other fivemembered heterocyclic analogs of the cyclic imidate moiety. Herein we describe the preparation of a cyclic thioimidate 21, a cyclic amidine 22 and a cyclic iminocarbonate 26 (Figures 4 and 5). The 4-bromobutyryl amide 3 was converted to the corresponding imidoyl chloride by reaction with phosphorus pentachloride. Treatment of the imidoyl chloride with lithium sulfide resulted in cyclization to afford 21. The cyclic amidine derivative 22 was prepared in one step by condensing N-methyl pyrrolidone dimethyl acetal with the aminopyridine 2 under acid catalysis. The synthesis of cyclic iminocarbonate 26 involved three sequential steps: (i) Curtius reaction of the acid chloride 23 with sodium azide in a mixture of ethylene glycol and acetone to give the hydroxyethyl carbamate 24; (ii) Conversion of compound 24 to the corresponding chloroethyl carbamate 25 with thionyl chloride; and (iii) Cyclization with silver tetrafluoroborate.

Figure 4.

Synthesis of sulfur and nitrogen analogs of cyclic imidates




68

26

25

Figure 5.

Table II,

Synthesis of cyclic iminocarbonate 26

Structure-Activity Correlations of Heterocyclic Analogs of Cyclic Imidates i-Bu

compd

X

Y

12 21 22 26

o s

CH CH

NMe O

CH O

WGR80(lb/acre) NL BL

2

2

2

0.02 0.02 0.06 0.23

0.14 0.24 0.96 0.92


6. HEGDE ET AL.


The herbicidal activities of 12 and its five-membered heterocyclic analogs are compared in Table n. Although compounds 12 and 21 had comparable activity on narrowleaf weeds, 12 exhibited slightly higher broadleaf activity. By comparison, the cyclic amidine 22 and the cyclic iminocarbonate 26 were significantly less active on both narrowleaf and broadleaf weeds.


Conclusions In summary, the unusual herbicidal activity of a 4-halobutyramide derivative 3 was postulated to be due to its ability to cyclize to a five membered heterocyclic system based on the structure-activity correlations of related halogenated amides. Cyclization of 3 using a Lewis acid such as silver tetrafluoroborate or ferric chloride gave the cyclic imidate 12, which proved to be a highly active herbicide. The pyrrolidone derivative 13, obtained by anionic cyclization of 3 using a strong base, was significantly less active. Among the analogs of cyclic imidate 12, several otsubstituted derivatives as well as a cyclic thioimidate also showed high levels of herbicidal activity.

Literature Cited 1. 2. 3. 4. 5.

Lee, L. F. Eur. Pat. Appl. EP 133,612, 1985; Chem. Abstr. 1986, 104, 19514h. Lee, L. F. U. S. Patent 4,692,184, 1987. Lee, L. F. U. S. Patent 4,741,766, 1988. Lee, L. F. U. S. Patent 4,826,530, 1989. Lee, L. F.; Sing, Y. L. Eur. Pat. Appl. EP 278,944, 1988; Chem. Abstr. 1988, 109 230818 6. Lee, L. F.; Sing, Y. L. U. S. Patent 4,988,384, 1991. 7. Lee, L. F.; Miller, M. L. U. S. Patent 4,835,279, 1989. 8. Lee, L. F.; Stikes, G. L.; Molyneaux, J. M.; Sing, Y. L.; Chupp, J. P.; Woodard, S. S. J. Org. Chem. 1990, 55, 2872. 9. Armbruster, B. L.; Molin, W. T.; Bugg, M. W. Pestic. Biochem.Physiol.1991, 59, 110. 10. Hegde, S. G.; Lee, L. F.; Bryant, R. D. U. S. Patent 5,114,465, 1992. 11. Hegde, S. G.; Lee, L. F.; Bryant, R. D. U.S. Patent 5,129,943, 1992. 12. Deyrup, J. A.; Gingrich, H. L. J. Org. Chem. 1977, 42, 1015. 13. Kornblum, N.; Smiley, R. A.; Blackwood, R. K.; Iffland, D.C. J. Am. Chem. Soc. 1955, 77, 6269. 14. Moriarity, R. M.; Yeh, C. L.; Ramey, K.C.;Whitehurst, P. W. J. Am. Chem. Soc. 1970, 92, 6360. RECEIVED August 12, 1994


Cyclic Imidate Derivatives of 5-Amino-2,6-bis(polyfluoroalkyl)pyridine

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