Fungicidal -Methoxyacrylates - American Chemical Society

Chapter 29

Fungicidal

ß-Methoxyacrylates

N-Linked Pyrroles Kevin Beautement, John M . Clough, Paul J. de Fraine, and Christopher R. A. Godfrey

Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch029

Zeneca Agrochemicals, Jealott's Hill Research Station, Bracknell, Berkshire RG12 6EY, United Kingdom

Methyl ß-methoxy-α-pyrrol-l-ylacrylates 7 (Figure 2), which we have termed N-linked pyrroles, have a broad spectrum of fungicidal activity when suitably substituted at the 2-position of the pyrrole ring. This paper describes the synthesis of a variety of acrylates of this type, and outlines structure-activity relationships for this class of compound. We have reported previously on the origins of our interest in the P-methoxyacrylates, and the evolution of ideas which led from a family of natural products, such as strobilurin A, to ICIA5504 (Figure l)(7-5). The main driving forces behind this work were the need to improve the stability and levels of activity of the natural products, and the desire to discover compounds which move systemically in plants without producing phytotoxic effects. During the course of this project, we discovered that although most structural changes to the (2s)-methyl P-methoxyacrylate unit found in the natural products cause a sharp fall in fungicidal activity, many modifications are permitted to the group to which this unit is attached. For example, the P-methoxyacrylate toxophore can be linked to an orf/io-substituted benzene ring, and this is a feature of many of our most active synthetic compounds, such as ICIA5504 itself. In view of the high activity of these analogues of the natural products, it occurred to us that related compounds in which the toxophore is linked to a heterocycle might also be active. Of course, many possible heterocyclic systems could be envisaged, and it could not be predicted at the outset which of these would lead to active compounds. Indeed, the synthesis and testing of numerous different classes of such compound has confirmed that some have good activity, while others have little or none. Amongst those which were found to be active were pyridines 1 (6-8), furans 2 and 3 (9), thiophenes 4, 5 and 6 (9), pyrroles 7 (10-12) and 8 (9), imidazoles 9 (10), pyrazoles 10 (10) and indoles 11 (13), where X represents a variety of substituents in each case (Figure 2). The subject of this paper is our work in one of these areas, the synthesis and fungicidal activity of compounds in which the P-methoxyacrylate toxophore is linked 0097-6156/95/0584-0326$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.

29. BEAUTEMENT ET AL.

327

Fungicidal /3-Methoxyacrylates

Strobilurin A

ICIA5504


Figure 1. Strobilurin A and ICIA5504.

9

2

3

5

6

10

11

Figure 2. Heterocyclic p-methoxyacrylates.


328

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS IV

to the nitrogen atom of a pyrroleringto give compounds 7, which we have termed Nlinked pyrroles. These compounds, when the substituent X has a suitable value, have good fungicidal activity; as with strobilurin A and ICIA5504, this is a result of their ability to inhibit mitochondrial respiration in fungi. They have the added attraction of being easy to prepare.


2-Styrylpyrroles The 2-styrylpyrrole 12, an analogue of both the stilbene 13 (14) and the amide 14 (15), both of which had earlier been shown to be good fungicides (1), was selected as the first target for synthesis. It was readily prepared from 2-formylpyrrole by the four steps shown in Figure 3. Thus 2-formylpyrrole reacted successively with benzylidene triphenylphosphorane and methyl bromoacetate to give, after chromatography and crystallisation, the (E)-styrylpyrrolylacetate 15. Claisen condensation with methyl formate then gave a P-hydroxyacrylate which, on 0-methylation with dimethyl sulphate, led stereospecifically to the required styrylpyrrole 12 (10). Although the styrylpyrrole 12 was a potent inhibitor of mitochondrial respiration [IC = 40 nM, equivalent to the stilbene 13, mitochondria isolated from lamb's heart tissue (1)], it was only weakly active in the glasshouse. This difference could be explained by the very short photochemical persistence of the styrylpyrrole: as a thin film, it was rapidly degraded on irradiation with a xenon lamp which simulated sunlight. These results were similar to those recorded earlier for the stilbene 13 (1,2), although the styrylpyrrole 12 was even less stable than the stilbene under the xenon lamp, with the time taken for loss of the first 50% of the two compounds being one and three minutes, respectively. The degradation products from the styrylpyrrole were not identified. Nevertheless, it is known that electron-rich pyrroles are readily photo-oxidised (16) and photochemically-induced electrocyclisation reactions of 2styrylpyrroles have also been described (17). 50

2-BenzoyIpyrroles In general, pyrroles become less susceptible to photo-oxidation when substituted with electron-withdrawing groups (16). Consequently, 2-benzoylpyrroles 16 were chosen as our next targets for synthesis, and these were prepared by the steps shown in Figure 4. The required intermediates 17 were generally made from pyrrole itself and the Vilsmeier-Haack reagents derived from benzamides and phosphorus oxychloride (18). These reactions led in good yields to the required 2-benzoylpyrroles, except in cases where the substituents on the benzamide were too electron-withdrawing or stericallydemanding and the Vilsmeier-Haack reagents formed too slowly to be practicable. In such cases, an alternative route to the intermediates 17, involving the reaction between pyrrol-1-ylmagnesium bromide and benzoyl chlorides, was used. A disadvantage of this second approach was that 3-benzoylpyrroles were usually formed in addition to the required 2-benzoylpyrroles. However, chromatographic separation of these regioisomeric products was straightforward. The intermediates 17 were then converted into the target compounds 16 using the two steps described previously for the styrylpyrrole 12. Analogues of the benzoylpyrroles 16 in which the benzene ring was replaced with pyridine, thiophene or furan were prepared in the same way (10). More than seventy benzoyl- or heteroaroylpyrroles were prepared. Many of these were tested in the mitochondrial assay and, without exception, were found to be In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.


29. BEAUTEMENT ETAL.

Fungicidal f3-Methoxyacrylates

329

Reagents: i,PhCH:PPh ; ii, NaH, BrCH C0 Me; 3

2

2

iii, NaH, HC0 Me; iv, K C 0 , M e S 0 2

2

3

2

4

Figure 3. Synthesis of the styrylpyrrole 12.




330

Reagents: i,POCl ; ii, BrCH C0 Me, NaH; iii, BrCH C0 Me, B ^ O K , 18-crown-6 3

2

2

2

2

Figure 4. Synthesis of benzoylpyrroles 14.



Fungicidal /3-Methoxyacrylates

331

intrinsically weaker than the styrylpyrrole 12, with the most active compounds having IC -values of about 700 nM. However, many of these benzoylpyrroles had high fungicidal activity in the glasshouse, and the best compounds were taken to field trials where they were particularly active against Pyricularia oryzae on rice, with useful systemic properties. Interestingly, analogues of the benzoylpyrroles with benzene in place of the pyrrole ring, i.e. benzophenones, are only weakly active, both in the mitochondrial assay and in the glasshouse. One of the most active benzoylpyrroles was the 3,5-dimethyl-derivative 18, and a single crystal X-ray structure was determined for this compound. Two crystallographically independent molecules were observed in the asymmetric unit, but these had similar conformations. It was interesting to note that the almost planar methoxyacryiate toxophore is strongly twisted in comparison to the pyrrole ring (torsion angle = 60° and 62° in the two independent molecules). This is a feature which we had previously observed with compounds in which the acrylate is linked to a benzene ring. In the stilbene 13, for example, the corresponding torsion angle is 86° (i). Also noteworthy is the fact that the ketone carbonyl group is closer to coplanarity with the pyrrole ring (torsion angle =16° and 21° in the two independent molecules) than with the dimethylbenzene ring (torsion angle = 51° and 35° respectively). Figure 5 depicts the molecule in which the torsion angles reported above are 60°, 16° and 51°. The torsion angles reported above are those between least squares mean planes calculated for the almost planar P-methoxyacrylate, carbonyl, pyrrole and dimethylbenzene units of the benzoylpyrrole 18 using Sybyl Version 6.03 (Tripos Associates, St. Louis, Missouri).


50

Pyrroles with other 2-Substituents: Esters, Amides and Ketones In view of the high activity of the benzoylpyrroles, other compounds, such as the ketones 19, the esters 20 and the amides 21, were identified as worthwhile targets (Figure 6: R and R represent aliphatic, aromatic or heteroaromatic groups). However, when we began to apply the methods with which we had prepared the benzoylpyrroles to the synthesis of these new compounds, problems were very soon encountered. For example, we found that although the intermediate 22, required for the synthesis of the ketone 19 in which R is ^-propyl, could readily be made using Vilsmeier-Haack chemistry, it was converted into the indolizine 23 rather than the expected P-hydroxyacrylate 24 on treatment with sodium hydride and methyl formate (Figure 7). Furthermore, although the pyrrole 25 with a methoxycarbonyl side-chain could easily be made by the usual Claisen condensation, attempts to prepare higher homologues under the same conditions led to mixtures of products (see, for example, Figure 8). We reasoned that one solution to these problems was to prepare the pyrrole-2carboxylic acid 26 which, it was anticipated, could be converted into a variety of esters, ketones and amides. However, base-catalysed hydrolysis of the methyl ester 25 led, after acidification, to the P-hydroxyacrylate 27 rather than the required acid 26 (Figure 9). The structure of 27, difficult to determine directly, was confirmed by conversion into the P-w-propyloxyacrylate 28. As well as using spectroscopy to determine the structure of 28, it was clear from its inactivity in the mitochondrial assay that the propyl substituent was part of the toxophore rather than in the side-chain as we would have liked (1). The regiochemistry of this hydrolysis was surprising in view of the fact that, when linked at the a-position to a benzene ring, base-catalysed 1

2

1


332


Me0 C Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch029

2

18 Figure 5. Single crystal X-ray structure of the pyrrolylacrylate 18.

l

V

Q

MV-^ *

MV^° '

MV^ "'

19

20

21

0

M

0

Figure 6. Targets for synthesis: ketones, esters and amides.

1,U

5>J Me0 C 2

22 i 35%

N H

24

Cl NMe, CHO

Reagents: i, NaH, HC0 Me; i i , H 0 2

+

3

Figure 7. Attempted synthesis of a pyrrolylacrylate with an aliphatic ketone sidechain. In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.


Fungicidal 0-Methoxyacrylates

Me0 C^\/

^

2

333

Me0 C-^ / 2

Me0 C^

N

M e 0

2

C ^ °

2

M

e


25

Pr"0,C^\ /

(Pr"/Me)0 C^ /

N

2

N

OMe

n

Me0 CT

(Pr /Me)0 C

2

2

Reagents: i, NaH, H C 0 M e ; ii, K C 0 , M e S 0 2

2

3

2

4

Figure 8. Synthesis of pyrrolylacrylates with ester side-chains. Esters H0 C

r->>

2

MeO.C Me0 C

- -

2

N

Me0 C

^

^

Amides

.OMe

Ketones

2 6

J H

Me0 C-^V 2

M e 0

27

2

C ^

28

Reagents: i, 1 equiv. KOH, aq. 1,4-dioxan; ii, Pr !, K 2 C O 3 11

Figure 9. Base-catalysed hydrolysis of the pyrrolylacrylate 25.


a


334


hydrolysis of the methyl p-methoxyacrylate toxophore takes place at the methoxycarbonyl group, leading to the corresponding a-phenyl-P-methoxyacrylic acid. A more successful approach to the required esters 20 involved the use of a modified Claisen condensation described by Mukaiyama and his co-workers (19). An example is shown in Figure 10. The pyrrolylacetate 29, on successive treatment with lithium di-isopropylamide (LDA) and trimethylsilyl chloride, reacted to form the methyl silyl ketene acetal 30 as a single unidentified stereoisomer. On exposure to a mixture of trimethyl orthoformate and titanium tetrachloride, this ketene acetal was converted into the required ester 31, elimination of methanol from the intermediate acetal 32 occurring in situ, presumably triggered by the Lewis acid. One interesting feature of this sequence was the stability of the ketene acetal 30. The related species derived from phenylacetates or 3-phenylpropanoates react with the trimethyl orthoformate-titanium tetrachloride adduct at temperatures of well below 0°C (19-21), while the pyrrole derivative 30 reacted at a useful rate only in refluxing dichloromethane. In fact, in a first run the reaction was interrupted before completion and a sample of the ketene acetal 30 was isolated, unscathed after an aqueous work up. While this approach to the target esters was successful, it was laborious and did not lend itself to the rapid preparation of a series of compounds for testing. A better procedure was to use (Z)-methyl a-pyrrol-l-yl-P-methoxyacrylate 33 (Figure 11) which, we discovered, was a convenient intermediate from which to make not only the esters 20, but also a variety of ketones such as 19, the amides 21 and other derivatives. The pyrrolylacrylate 33 was prepared in two steps from methyl pyrrol-1ylacetate (Figure 11) which, in turn, was derived from 2,5-dimethoxytetrahydrofuran and the methyl ester of glycine (10). Claisen condensation of methyl pyrrol-1ylacetate with methyl formate and sodium hydride in JV,iV-dimethylformamide (DMF), the solvent we had used with success in many previous cases, gave an intractable mixture of products. However, when toluene containing a few drops of methanol was used instead, the reaction mixture precipitated the sodium salt 34 which could be filtered off, dissolved in DMF and then treated with methyl iodide to give the required product 33 as a crystalline solid, melting at 88-9 °C, in an overall yield of 66%. Its (Z)-stereochemistry was established by the chemical shift of the olefmic proton at 87.51 ppm (deuterochloroform). Multi-gram samples of this acrylate were readily prepared and, as described below, were derivatized to produce a multitude of pyrroles of the type 7. One idea was to lithiate the pyrrolylacrylate 33, which we anticipated would occur on the pyrrole ring (22), and to treat the resulting organometallic species with various electrophiles. However, in a model reaction, a mixture of the pyrrolylacrylate 33 and trimethylsilyl chloride was added to LDA in tetrahydrofuran at -65 °C, and the reaction mixture was allowed to warm to -50 °C over two hours (23). To our surprise, clean silylation at the olefmic position occurred, giving a 90% yield of the Psilylacrylate 35, a solid melting at 49-50 °C (Figure 12). P-Lithiated P-alkoxyacrylates are, in fact, well documented, and Schmidt, in particular, has shown that such compounds are valuable synthetic intermediates (24). Much more useful were Friedel-Crafts acylations of the pyrrolylacrylate 33 which occurred exclusively on the pyrrole ring, and mainly at the required 2-position (25). For example, acylation with valeryl chloride in the presence of aluminium chloride gave a 95 : 5 mixture of the regioisomeric products 36 and 37 respectively In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.



Fungicidal P-Methoxyacrylates

335

j .

Reagents: i, LDA; ii, Me SiCI; iii, (MeO) CH, TiCl 3

3

4

Figure 10. Synthesis of a pyrrolylacrylate with an ester side-chain using the Mukaiyama modification of the Claisen condensation.

34 Reagents: i, NaH, HC0 Me, PhMe, catalytic MeOH; ii, Mel, DMF 2

Figure 11. Synthesis of the pyrrolylacrylate 33.



336

LDA/Me SiCl/-50°C Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch029

3

Me0 C

OMe

Me0 C

90%

2

2

SiMe, 33

35 Figure 12. Silylation of the pyrrolylacrylate 33.

N

• OMe

Me0 C 2

Me0 C

OMe

.,^^^Ut^

MeO,C

2

36

33

37 95

:

5

Reagents: i, Bu COCl, AICI3,0 °C n

Figure 13. Acylation of the pyrrolylacrylate 33.


0 M e



Fungicidal ^Methoxyacrylates

337

(Figure 13). This chemistry worked for a variety of aliphatic and aromatic acid chlorides (12). Related chemistry provided access to pyrroles with ester side-chains (Figure 14). Acylation of the pyrrolylacrylate 33 with trichloroacetyl chloride, which was reactive enough to not require a Lewis acid catalyst (25), led to the trichloroacetylpyrrole 38 which, in turn, gave esters 20 on treatment with primary alcohols (12). Treatment of 38 with phenol gave a low yield of the expected ester, but secondary alcohols failed to react. Amides were not accessible via the trichloroacetylpyrrole 38 because amines did not displace the trichloromethyl group but, instead, the P-methoxy group from the acrylate. Thus morpholine gave the Paminoacrylate 39, and aniline gave the interesting 7-azaindolizine 40. w-Propylamine led to an intractable mixture of products. Acylation of the pyrrolylacrylate 33 with phosgene gave the pyrroloyl chloride 41 which was more reactive than the trichloroacetylpyrrole and led to the expected esters and amides on treatment with secondary alcohols and primary amines respectively (Figure 15). Alternatively, esters and amides could be prepared directly by acylation of the pyrrolylacrylate with chloroformates or carbamoyl chlorides (Figure 16) (12). The pyrrolylacrylate 33 also reacted with a variety of other electrophiles (7). For instance, treatment with the simple Vilsmeier-Haack reagent derived from phosphorus oxychloride and DMF gave the 2-formyl-derivative (together with some of the readily-separable 3-formyl-isomer), a useful intermediate which, in turn, led to pyrroles with other novel side-chains. Furthermore, 33 gave Mannich products, and could be chlorinated and brominated. Finally, it should be emphasised that the unoptimised yields of many of the reactions between electrophiles and the pyrrolylacrylate 33 described above were not high. Nevertheless, this disadvantage was outweighed by the benefits of being able to quickly prepare a variety of compounds for testing, allowing structure-activity patterns for this family of compounds to be established within a short period of time. Structure-Activity Relationships The purpose of this final section is to briefly review the structure-activity relationships which were found for the AMinked pyrroles, established from the synthesis and testing of more than 150 examples. The results were determined in 24-hour protectant tests in the glasshouse, i.e., tests in which the plants were treated first with the acrylate, either as a foliar spray or as a root drench, and then, 24 hours later, with a spore suspension of a fungal pathogen as a foliar spray. Activity in the root drench test indicated that the acrylate was likely to have systemic movement in plants when applied as a foliar spray (3-5). The pathogens used were representative of those which are of global commercial importance in agriculture. 2-Benzoylpyrroles 16 were the earliest N-linked pyrroles to show good activity in the glasshouse (the regioisomeric 3-benzoylpyrroles 42 were uniformly weak fungicides)(Figure 17). The parent compound (16 in which X = Y = H) had high activity, and the introduction of simple substituents at the 3-position, or the 3- and 5positions, of the benzoyl group was often beneficial. Examples with octanol/water log P values below about 3.5 (e.g. 16 in which X = H and Y = H, 3-F, 3-Me or 3-MeO) were active not only when applied to the foliage, but also in the root drench test. Introduction of a 3-phenoxy group to give 43 did not result in a marked improvement In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.


338


40 Reagents: i, CI3C.COCI, 2,6-dimethylpyridine; ii, R ^ H , K C 0 ; 2

Hi, morpholine, K2CO3; iv, aniline, K2CO3 Figure 14. Reactions of the trichloroacetylpyrrole 38.


3




s

339

1

Reagents: i, C0C1 ; ii, Bu OH, pyridine; iii, R N H (R = alkyl, phenyl); 2

1

2

2

iv, R R C:NOH, pyridine Figure 15. Reactions of the pyrroloyl chloride 41.

33 1

Reagents: i, Et NCOCl, A1C1 ; ii, R ^ C O C l , A1C1 (R = alkyl, phenyl) 2

3

3

Figure 16. Reactions of the pyrrolylacrylate 33 with diethyl carbamoyl chloride and chloroformates.




340

45

46

Figure 17. Key classes of ]V-linked pyrroles.




341

in activity in the way which had been observed in other series (3-5): 43 was similar in activity to the parent compound when applied as a foliar spray, and was much weaker as a root drench. The 4-position of the benzoyl group of 16 could accommodate a fluorine atom, but other substituents were detrimental to activity. The best of the 2-heteroaroylpyrroles which we prepared was the thienoylpyrrole 44, while the simple unsubstituted pyridinoylpyrroles 45 were poorly active. Pyrroles with simple ester side-chains 20 were highly active, rather volatile, and, as a consequence of their low partition coefficients, very systemic compounds [log P (octanol/water) = 1.8 for 20 in which R = allyl, for example]. Pyrroles with simple aliphatic keto groups as side-chains 19 presented a similar picture [log P (octanol/water) = 2.1 for 19 in which R = w-propyl]. By contrast, pyrroles with ketoester 46 or amide side-chains 21 were poorly fungicidal. Finally, we prepared a series of benzoylpyrroles incorporating an additional small substituent, such as a methyl group or a chlorine or bromine atom, on the pyrrole ring, but none had better activity than the corresponding compound without this substituent. 1


1

Conclusions The JV-linked pyrroles described in this paper are fungicides with a broad spectrum of activity and a novel mode of action. Examples with suitably low partition coefficients often exhibit systemic movement in plants. The most promising compounds in the glasshouse were taken forward for field trials, where they showed good activity, especially against Pyricularia oryzae on rice. Our work on the JV-linked pyrroles was discontinued when other classes of (3-methoxyacrylates, especially ICIA5504 and related tricyclic compounds, were found to have superior levels of fungicidal activity. Acknowledgments We wish to thank our colleagues at ZENECA Agrochemicals and ZENECA Specialties who have participated in this project, especially K. Anderton, V.M. Anthony, T.E.M. Fraser, I.R. Matthews, G.J. Sexton, B.K. Snell, R. Taylor, T.E. Wiggins and D. Youle. We thank D.J. Williams, Imperial College of Science, Technology and Medicine, London, for the X-ray crystallography. Literature Cited 1. 2.

3.

Beautement, K.; Clough, J.M.; deFraine,P.J.; Godfrey, C.R.A. Pestic. Sci., 1991, 31, 499-519. Clough, J.M.; de Fraine, P.J.; Fraser, T.E.M.; Godfrey, C.R.A. In Synthesis and Chemistry of Agrochemicals III, Baker, D.R.; Fenyes, J.G.; Steffens, J.J., Eds., ACS Symposium Series No. 504, American Chemical Society, Washington, D.C, 1992, 372-383. Godwin, J.R.; Anthony, V.M.; Clough, J.M.; Godfrey, C.R.A. Brighton Crop Prot. Conf: Pests and Diseases - 1992, Vol. 1, British Crop Protection Council, Farnham, U.K., 1992, 435-442.


342



4.

Clough, J.M.; Evans, D.A.; de Fraine, P.J.; Fraser, T.E.M.; Godfrey, C.R.A.; Youle, D. In Natural and Engineered Pest Management Agents, Hedin, P. A.; Menn, J.J.; Hollingworth, R.M., Eds., ACS Symposium Series No. 551, American Chemical Society, Washington, D.C., 1994, 37-53. 5. Clough, J.M. Nat. Prod. Reports, 1993, 10, 565-574. 6. Anthony, V.M.; Clough, J.M.; de Fraine, P.J.; Godfrey, C.R.A.; Crowley, P.J.; Anderton, K. EP 243 012, priority 17 April 1986. 7. Clough, J.M.; Godfrey, C.R.A.; Heaney, S.P.; Anderton, K. EP 312 243, priority 15 Oct. 1987. 8. Anderton, K.; Clough, J.M.; Godfrey, C.R.A. EP 312 221, priority 15 Oct 1987. 9. Anthony, V.M.; Clough, J.M.; de Fraine, P.J.; Beautement, K.; Godfrey, C.R.A. EP 243 014, priority 17 April 1986. 10. de Fraine, P.J.; Snell, B.K.; Clough, J.M.; Anthony, V.M.; Beautement, K. EP 206 523, priority 18 June 1985. 11. Clough, J.M.; Godfrey, C.R.A.; de Fraine, P.J.; Snell, B.K. EP 273 572, priority 16 Dec. 1986. 12. Beautement, K.; Clough, J.M.; de Fraine, P.J.; Godfrey, C.R.A.; Snell, B.K. GB 2 198 726, priority 16 Dec. 1986. 13. Anthony, V.M.; Clough, J.M.; Godfrey, C.R.A.; de Fraine, P.J. EP 274 825, priority 5 Dec. 1986. 14. Bushell, M.J.; Beautement, K.; Clough, J.M.; de Fraine, P.J.; Anthony, V.M.; Godfrey, C.R.A. EP 178 826, priority 19 Oct. 1984. 15. Clough, J.M.; Kay, IT. EP 178 808, priority 19 Oct. 1984. 16. Jones, R.A.; Bean, G.P. The Chemistry of Pyrroles; Vol. 34 of Organic Chemistry, A Series of Monographs, Blomquist, A.T.; Wasserman, H.H., Eds., Academic Press: London, New York, San Francisco, 1977. See Chapter 5. 17. Rawal, V.H.; Jones, R.J.; Cava, M.P. Tet. Letts., 1985, 26, 2423-2426. 18. White, J.; McGillivray, G. J. Org. Chem., 1977, 42, 4248-4251. 19. Saigo, K.; Osaki, M.; Mukaiyama, T. Chem. Letts., 1976, 769-770. 20. Anthony, V.M.; Clough, J.M.: de Fraine, P.J.; Godfrey, C.R.A. EP 242 070, priority 17 April 1986. 21. Clough, J.M.; Godfrey, C.R.A. EP 212 859, priority 22 Aug. 1985. 22. Rewcastle, G.W.; Katritzky, A.R. Adv. Het. Chem., 1993, 56, 155-302. See pp. 164-170. 23. Krizan, T.D.; Martin, J.C. J. Amer. Chem. Soc, 1983, 105, 6155-6157. 24. Miyata, O.; Schmidt, R.R. Tet. Letts., 1982, 23, 1793-1796 and references therein. 25. Patterson, J.M. Synthesis, 1976, 281-304. RECEIVED September 16, 1994


Fungicidal -Methoxyacrylates - American Chemical Society

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