Synthesis and Chemistry of Agrochemicals II - ACS Publications

Chapter 17

Synthesis and Herbicidal Activity of 1,X-Naphthyridinyloxphenoxypropanoic Acids

Downloaded by STANFORD UNIV GREEN LIBR on June 22, 2012 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch017

James A. Turner Discovery Research, DowElanco, 2800 Mitchell Drive, Walnut Creek, CA 94598

A series of 2-(4-(1,X-naphthyridinyloxy)phenoxy)propanoic acids were prepared for evaluation as potential grass herbicides and to assess their ability to inhibit maize acetyl-CoA carboxylase (ACCase). A new regiospecific pyridine annulation procedure was employed to prepare the key 2-chloro-1,6-, 1,7-, and 1,8-naphthyridine intermediates. Of the compounds prepared, only the 6-chloro-1,5-naphthyridinyloxyphenoxy propanoic acid displayed substantial levels of herbicidal activity. The relative levels of herbicidal activity in this series of propanoic acids could be explained by the ability of these materials to inhibit ACCase. The aryloxyphenoxypropanoic acids are an important new class of extremely potent herbicides (1). Remarkable selectivity, with herbicidal activity against a single family of plants, the Gramineae, is the signature feature of this area of chemistry. These compounds, with the combination of this peculiar selectivity, meristematic inhibitory and systemic properties, are nearly ideally suited for use as postemergent graminicides in a variety of dicotyledenous crops. The mode of action of the aryloxyphenoxypropanoic acids has recently been attributed to inhibition of acetyl-CoA carboxylase (ACCase), the enzyme which catalyzes the conversion of acetyl-CoA to malonyl-CoA in the first committed step of fatty acid biosynthesis (2,3). Selectivity between the grasses and broadleaf plants is apparently due to differences in the ability of these materials to inhibit ACCase in different plant families (2,3). Although the carboxylic acids are the active species in this area of chemistry, esters are generally used to achieve increased penetration of the plant cuticle. The esters are rapidly hydrolysed to the corresponding acid within the plant. Most of the synthetic effort in the aryloxyphenoxypropanoic acid area has been directed towards the aryloxy portion of the molecule and, in particular, to variation of the substituents on 0097-6156/91/0443-0214$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.


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t h i s aromatic r i n g (see Figure 1). The e a r l i e s t work by Hoechst, who o r i g i n a l l y discovered this area of chemistry (4), was focused upon the phenoxyphenoxy series and this e f f o r t ultimately l e d to the development o f the wheat selective graminicide, diclofop (5). Later, extension of the a r y l series from benzene to monocyclic heterocycles, such as pyridine (6) and pyrimidine (7), resulted i n the discovery of haloxyfop and f l u a z i f o p , pyridinyloxyphenoxypropanoic acids which are considerably more potent graminicides than the phenoxyphenoxy compound, diclofop. While s t r u c t u r e - a c t i v i t y studies i n these monocyclic series i l l u s t r a t e d that h e r b i c i d a l a c t i v i t y was confined to an unusually narrow range of type and location of substituents on the a r y l moiety (5), Howard Johnston and co-workers at Dow demonstrated that a b i c y c l i c aromatic (quinoline) could be inserted i n place of the benzene of diclofop without s a c r i f i c i n g h e r b i c i d a l a c t i v i t y (8). This was followed by the discovery by groups at Nissan (9), DuPont (10) and ICI (11) that addition of a single nitrogen atom to t h i s quinoline r i n g system (to form a quinoxaline) resulted, s i m i l a r l y to the benzene to pyridine example, i n a substantial increase i n h e r b i c i d a l potency, as demonstrated by the commercial product q u i z a l i f o p . These i n t r i g u i n g results i l l u s t r a t e the importance of the nature of the a r y l group upon h e r b i c i d a l a c t i v i t y i n the aryloxyphenoxypropanoic acid series. With the ultimate goal of developing an understanding of the a b i l i t y of these materials to interact with ACCase, we decided to prepare a series of 1,X-naphthyridin-2-yloxyphenoxypropanoic acids. These materials would probe the e f f e c t of addition of a single nitrogen atom at various positions of a quinoline r i n g upon h e r b i c i d a l and enzymatic a c t i v i t y . Since h e r b i c i d a l a c t i v i t y i n the b i c y c l i c series i s usually maximized with a small halogen atom at the C-6 p o s i t i o n (such as the chlorine i n q u i z a l i fop) , we planned to include this substituent i n a s i m i l a r p o s i t i o n on the naphthyridines where possible. Therefore our h e r b i c i d a l targets were the series of 1,X-naphthyridines 1-4 (Figure 1). Synthesis We envisioned preparation of our targeted herbicides by a method analogous to that used for synthesis of q u i z a l i f o p (10, Scheme 1). Thus, these materials should be r e a d i l y available from the corresponding 2-chloro-l,X-naphthyridines (5-8) by nucleophilic condensat i o n with a derivative of 2-(4-hydroxyphenoxy)propanoic acid. In turn, the requisite 2-halonaphthyridine could r e s u l t from dehydrative halogenation of the corresponding 1,X-naphthyridin-2-one. Naphthyridines and naphthyridinones have been prepared from aminopyridines by one of two general approaches (12, Figure 2). The f i r s t r e l i e s on an e l e c t r o p h i l i c substitution (with attendant carbon-carbon bond formation) d i r e c t l y on a pyridine r i n g to annulate the second ring. The reluctance of pyridines to undergo such a reaction has l i m i t e d this approach to those systems i n which the s t a r t i n g aminopyridine i s either unsubstituted or functionalized with electron donating substituents. Nevertheless, two of our targeted s t a r t i n g materials, 2,6-dichloro-1,5-naphthyridine (5) and 2-chloro-1,6-naphthyridine (6) had been previously prepared i n this manner. We immediately discarded the published synthesis o f the


SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π


216



17. TURNER

1, X-Naphthyridinyloxpherwxypropanoic Acids

Β

Figure 2.

Approaches to 1,X-Naphthyridines : A - E l e c t r o p h i l i c Substitution of Aminopyridines; Β - Friedlander-type Condensation


218

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π


l a t t e r material (13), since many steps were required and the o v e r a l l y i e l d was exceptionally low (4000 2000 >4000

Broadleaves >4000 >4000 >4000 >4000 >4000

b

In V i t r o (I50, Aim)

c

e

0.041 2.42 61.2 16.5 66.7

(a) The concentration necessary to give 80% control of growth. (b) Quizalifop was tested as the ethyl ester. Naphthyridines 2-4 were tested as the methyl esters (2b-4b). (c) Maize ACCase. A l l compounds were tested as the carboxylic acids. (d) Average of 5 species. (e) Average of 9 species. the p o l a r i z a t i o n of the heterocycle as well as l o c a l i z e d hydrophobic or hydrophilic interactions between the heterocycle and the enzyme. For example, i n the h e r b i c i d a l l y inactive 1,6-naphthyridine deriva t i v e 2, the hydrophilic nitrogen atom i s located at the s i t e (6-pos i t i o n ) occupied by the large, l i p o p h i l i c chlorine atom i n q u i z a l ifop, an extremely potent enzyme i n h i b i t o r and herbicide. Neverthe l e s s , the exact reason(s) for the d i f f e r i n g a b i l i t i e s of the com pounds i n this diazanaphthalene series to i n h i b i t ACCase cannot be determined based upon the data at hand.


17. TURNER1,Χ-NaphthyridinyloxphenoxypropanoicAcids

225

In conclusion, we have employed a novel, regiospecific pyridine annulation procedure to prepare a series of l,X-naphthyridinyloxyphenoxypropanoic acids as potential herbicides. The wide variation in herbicidal activity among this seemingly very similar group of acids clearly demonstrates the importance of the nature of the heterocycle in this area of chemistry.


Acknowledgment I would like to thank Jake Secor for providing the ACCase inhibition data and Wendy Jacks for converting esters 2b-4b to the correspond ing acids. Literature Cited 1.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

For a review and leading references see: Duke, S. O.; Kenyon, W. H. In Herbicides: Chemistry, Degradation, and Mode of Action; Kearney, P. C.; Kaufman, D. D., Eds.; Marcel Dekker: New York, 1988; Vol. 3, p. 71. Secor, J.; Cseke, C. Plant Physiol. 1988, 86, 10. Burton, J . D.; Gronwald, J. W.; Somers, D. Α.; Connelly, J . Α.; Gengenbach, B. G.; Wyse, D. L. Biochem. Biophys. Res. Commun. 1987, 148, 1039. Becker, W.; Langeluddeke, P.; Leditschke, H.; Nahm, H.; Schwerdtle, F. U.S. Patent 3,954,442, 1976. Nestler, H. J.; Langeluddeke, P.; Schonowsky, H.; Schwerdtle, F. In Adv. Pestic. Science., Part 2; Geissbuhler, H.; Brooks, G. T.; Kearney, P. C., Eds.; Pergamon: New York, 1979; p. 248. Takahashi, R.; Fujikawa, K.; Yokomichi, I.; Tsujii, Y.; Sakashita, N. U.S. Patent 4,046,553, 1977. Serban, Α.; Warner, R. B.; Watson, K. G. U.S. Patent 4,248,618, 1981. Johnston, H.; Troxell, L. H.; Claus, J . S. U.S. Patent 4,236,912, 1980. Ura, Y.; Sakata, G.; Makino, K.; Kawamura, Y.; Kawamura, Y.; Ikai, T.; Oguti, T. U.S. Patent 4,629,493, 1986. Fawzi, M. M. European Patent Application 0 042 750, 1981. Serban, Α.; Watson, K. G.; Farquharson European Patent Application 0 023 785, 1981. Paudler, W. W.; Sheets, R. M. Adv.Heterocycl. Chem. 1983, 33, 147. Kobayashi, Y.; Kumadaki, I.; Sato, H. Chem. Pharm. Bull. 1969, 17, 1045. Newkome, G. R.; Garbis, S. J . J . Heterocyclic Chem. 1978, 15, 685. Hamada, Y.; Takeuchi, I. Chem. Pharm. Bull. 1971, 19, 1857. Hawes, E. M.; Gorecki, D. K. J . J . Heterocyclic Chem. 1972, 9, 703. Hawes, E. M.; Wibberley, D. G. J . Chem. Soc. (C) 1967, 1564. Turner, J . A. accepted for publication in J . Org. Chem. 1990. Turner, J . A. J . Org. Chem. 1983, 48, 3401.

Received June 14, 1990


Synthesis and Chemistry of Agrochemicals II - ACS Publications

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