Synthesis of Fungicidal Phenylpyrroles - American Chemical Society

Chapter 37

Synthesis of Fungicidal Phenylpyrroles P. C. Knüppel, R. Lantzsch, and D. Wollweber

Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch037

Agrochemical Division, Bayer AG, D-5090 Leverkusen Bayerwerk, Germany

Dedicated to Professor Karl HeinzΒüchelon the occasion of his 60th birthday Pyrrolnitrin was used as a lead structure for new fungicides. Decomposition of members of the phenylpyrrole group was studied; the synthetic derivatives show more stability on exposure to environmental conditions than the natural compound. Fungicidal activities are presented along with some new syntheses.

Pyrrolnitrin is a natural antibiotic which has been isolated from Pseudomonas pyrrocinia.

Pyrollnitrin 3-chloro-4-(2'-nitro3'-chlorophenyl)-pyrrole

0097-6156/92/0504-0405$06.00/0 © 1992 American Chemical Society

In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

406

SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

A strong inhibition of fungicidal growth is reported (1) including fungi associated with the cotton seedling disease complex: Thielaviopsis basicola, Alternaria sp. Verticillium dahliae, Fusarium sp., and Pythium ultimum. If the cotton seeds are treated with pyrrolnitrin and planted in Rhizoctonia soiani infested soil tubes, there is also a significant increase of surviving seedlings. (2)


Decomposition Because of its photolability the natural compound only shows low fungicidal activities in field trials. Studies on different structural analogues (2) always show a photooxidation of the phenylpyrroles by atmospheric oxygen.

R ^ C l , CN R2 R3 = Cl, F, C F , NO2 3

After exposure of the phenylpyrroles to sunlight for 6 hours, the compounds on page 407 were detected and identified by mass spectroscopy. Variation of the substituents on the phenyl and pyrroleringscan significantly increase the stability. Replacement of CI and NO2 on phenyl by F and CF3, for


KNUPPEL ET

AL.

Synthesis of Fungicidal Phenylpyrroles


37.


407


408

example, and CI in the pyrrole ring by CN seems to be most favourable. The new derivatives have comparable biological activity in vitro, but the half- lives are increased more than twenty times.(J) Good fungicidal activity is now also seen in field trials.


Chemical Synthesis It was also necessary to find technically relevant syntheses for the phenylpyrroles. The original total synthesis of pyrrolnitrin involved nine steps starting with 2-nitro3-chlorobenzoic acid.(4) Several syntheses have now been developed, starting from readily accessible compounds. One of the key intermediates is the cinnamonitrile 2i

2 can be synthesized from commercially available compounds such as phenyl bromides and anilines.^, 6) The overall yield for both reactions on page 409 is in the range 85-95%. It is also possible to start from substituted benzaldehydes, which can be converted to the acrylnitrilo derivatives, (eq.4, (7)) The intermediates 2 and 2 can both be cyclised with p-toluenesulfonylmethyl isocyanide.f 9 5 * , eq. 4 )

R

3

R

2

CH =

CC^NH

2

II Ο +

NoOEt, EtOH

3h. 0°C - >

+ NoH, D M S 0 / E t 0 2

rt

15 min, r t

(eq. 6 )

(eq. 6 )

+

H j C ^ ^ - S O a -

(80 -

95

*)

10


37.

KNUPPEL ET AL.


411

Alternatively, isocyanoacetate can be used as a source of C2. Reaction with the


cyanoacrylate U (synthesized analogous to eq. 4) yields the A^-pyrroline^carboxylic acid derivative Q2). In a further reaction step the phenylpyrrole is formed by oxidative decarboxylation.^)

Biological

Activities

The new analogues of pyrrolnitrin show good fungicidal activity against a wide range of fungi including Pyricularia oryzae, Fusarium culmorum and Botrytis cinerea. This can be demonstrated by the MIC values (agar diffusion test) for the pathogens mentioned above (Table 1).



412


Table 1:MIC values*

Ί0

o-c

compound R2 R3

lfla lfib 10c

F CF F Cl CH CF 3

Pyricularia Fusarium Botrytis oryzae culmorum cinerea

3

3

32.5 5.8 1.2

2.1 3.7 4.8

4.9 5.6 1.9

MIC values in ppm, agar diffusion test

Conclusion Pyrrolnitrin was used to find a new class of fungicidally active compounds. The new fungicides inhibit a wide range of fungi. A rapid decomposition of pyrrolnitrin occurs upon exposure to environmental conditions. The stability can be increased by replacement of CI with CN on the pyrrole ring and by introducing electronwithdrawing groups, e.g. F, C F , as substituents on the phenyl ring. A technically relevant synthesis has been developed starting from readily accessible compounds. 3

Acknowledgments We would like to acknowledge the Bayer AG colleagues who have contributed to this work: D. Berg, R. Tiemann (biological data), K. Jelich (synthesis), W. Ockels (MS) and T. Hess (half- life measurements).


37.

KNUPPEL ET AL.


Literature cited


1. Arima, K.; Imanaka, H.; Kousaka, M . ; Fukuda, Α.; Tamura, G. J. Antibiotics, Ser. A 1965, 18, 201-4 2. Howell, C.R.; Stipanovic, R.D. Phytopathology 1979, 69, 480-2 3. Knüppel, P.C.; Hess, T.; unpublished results 4. Tanaka, K.; Kariyone, K.; Umio, S.; Chem. Pharm. Bull. 1969, 17, 622-628 and references therein 5. Wollweber, D.; Brandes, W., European Patent 318704, 1989 6. Knüppel, P.C.; Lantzsch R., to be published 7. Wollweber, D., German Patent 3800387, 1989 8. Wollweber, D., German Patent 3718375, 1988 RECEIVED April 27,

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Synthesis of Fungicidal Phenylpyrroles - American Chemical Society

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