Synthesis and Chemistry of Agrochemicals II - American Chemical

Chapter 41

Synthesis and Fungicidal Properties of Cyclic Tertiary Amines Christopher J. Urch

Downloaded by UNIV OF GUELPH LIBRARY on June 22, 2012 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch041

Chemistry Department, ICI Agrochemicals, Jealott's Hill Research Station, Bracknell, Berkshire RG12 6EY, United Kingdom

The synthesis of conformationally restricted cyclic tertiary amine compounds allowed a computer graphic model of the active conformation of this class of fungicides to be developed. By using this model, together with a knowledge of the mode of action of the tertiary amine fungicides, it was possible to rationally design other cyclic tertiary amine compounds with high levels of fungicidal activity. Tertiary amine compounds such as tridemorph (1), fenpropimorph (2) and fenpropidin (3) (Figure 1) are important commercial agrochemical fungicides. In particular, they are extremely useful in controlling phytopathogenic fungi which have developed reduced sensitivity to the azole fungicides (1-substituted imidazoles and 1,2,4-triazoles). It is for this reason that tridemorph, fenpropimorph and fenpropidin are widely used on cereals in Western Europe where both wheat and barley powdery mildews have shown reduced sensitivity to the azole fungicides. Fortunately, it is against the powdery mildews that the tertiary amine fungicides are most active. Mode of Action Ergosterol (9), the principal sterol found in fungi, is a vital constituent for fungal growth and hence compounds which inhibit its biosynthesis are potent fungicides. Its biosynthesis is described in detail elsewhere (1-3) and its later stages outlined in Figure 2. In most phytopathogenic fungi lanosterol (4) is first methylenated at the C-24 position and then undergoes 14-demethylation to give 4,4-dimethylergosta-8,14,24(28)-trienol (5). It is this second step which is inhibited by the azole fungicides. The C-14(15) double bond produced as a result of 14-demethylation is then reduced to give 4,4-dimethylergosta-8,24(28)-dienol (6). 4-Demethylation then occurs to give fecosterol (7) in which the C-8(9) double bond is isomerised 0097-6156/91/0443-0515$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.


516

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

to a C-7(8) double bond in episterol (8). C-5(6) desaturation followed by side-chain modifications leads to ergosterol (9). The tertiary amine compounds tridemorph, fenpropimorph and fenpropidin are ergosterol biosynthesis inhibitors. All three compounds inhibit both 8-7-isomerase and 14-reductase. However, tridemorph inhibits 8-7 isomerase better than 14-reductase, whereas the reverse is true for fenpropidin. Fenpropimorph inhibits both enzymes well (4-5). In both enzymes the inhibition is achieved by mimicking a high energy carbonium ion intermediate by an ammonium ion (5) (at physiological pH all of the tertiary amine compounds are protonated). Thus, taking fenpropimorph inhibition of 8-7-isomerase as an example, the carbonium ion intermediate (10) in the isomerisation of fecosterol (7) to episterol (8) is mimicked by protonated fenpropimorph (11). This is shown in Figure 3 which also shows the approximate manner in which protonated fenpropimorph (11) overlays with fecosterol (7). That is, the morpholine ring overlays the sterol Β ring (with the nitrogen atom in the 8-position) and the propyl chain and t-butylphenyl group overlay the C and D rings and the side-chain. In this manner the enzyme 8-7-isomerase is blocked and hence ergosterol biosynthesis is inhibited. Computer Graphics In order to direct synthesis of potential sterol biosynthesis inhibitors a model of the active conformation of the tertiary amine compounds was necessary. Due to the flexibility of the fenpropimorph and fenpropidin molecules and their large number of torsion axes it was not possible to model these compounds directly. To build a model of the active conformation it was necessary to find a number of active compounds that were also conformâtionally restricted. This was achieved with, amongst other compounds, the tetralin (12) shown in Figure 4. It can be viewed as a "tied-back" fenpropimorph with the extra six-membered ring restricting the movement of the alkyl chain. This compound was tested in vivo and shown to be fungicidally active. Energy minimisation of this tetralin then gave an initial model of the active conformation of the fungicidal tertiary amine compounds (Figure 5). Once this initial model of the active conformation of the tertiary amine fungicides had been derived, potential targets could be energy minimised and compared with it. This allowed synthetic targets to be prioritised. In this way further fungicidally active compounds were found. These allowed the model of the active conformation to be refined by incorporating the novel active compounds into a composite structure representing those structures showing high fungicidal activity. This constant process of modelling, synthesis and refining the model guided the work to find new cyclic tertiary amine fungicides. Synthetic Chemistry Synthesis of Tetralin compound (12). The tetralin (12) has already been described. It was synthesised as shown in Figure 6. FriedelCrafts alkylation of tetralin gave the t-butyltetralin (13) which was oxidised to a mixture of the two ketones (14) and (15) which were


4L URCH

Cyclic Tertiary Amines

Π)


Figure 1.

(2)

(3)

Tridemorph (1), fenpropimorph (2) and fenpropidin (3)

Figure 2.

Figure 3.

The biosynthesis of ergosterol.

The mode of action of fenpropimorph.


518



Figure 6.

The synthesis of tetralin (12).


41. URCH


519


separated by hplc. The Mannich reaction on the ketone (14) was bond produced as a result of 14-demethylation is then reduced to give 4,4-dimethylergosta-8,24(28)-dienol (6). 4-Demethylation then occurs to give fecosterol (7) in which the C-8(9) double bond is isomerised capricious, but gave a reasonable yield of the amine (16). This was converted into the target tetralin (12) by the standard steps of reduction, dehydration and hydrogénation. A similar sequence from the ketone (15) gave the isomeric 6-t-butyltetralin which was also fungicidally active. Synthesis of Cyclopropane (19). The two isomeric cyclopropanes (19) and (20) were examined against the computer graphic model and the trans isomer (19) was predicted to be an active compound. The model also predicted that the cis isomer (20) would be considerably less active. The cyclopropanes were made as shown in Figure 7. Copper (11) catalysed addition of ethyl diazoacetate to the styrene (17) (6) gave the cyclopropane ester (18) as a 2:3 mixture of ç i s and trans isomers. Ester hydrolysis, amide formation and reduction then gave the two cyclopropane amines (19) and (20) which were separated by hplc. As predicted the trans isomer (19) showed very high fungicidal activity whereas the ç i s isomer (20) was only poorly active. Synthesis of Cyclopropane (23). This compound was made, albeit in low yield, by the route shown in Figure 8. The aldehyde (21) was treated with cis 2,6-dimethylmorpholine and magnesium sulphate in ether to give the enamine (22). Attempts to cyclopropanate this under Simmons-Smith conditions (7) failed, as did the modified reaction employing ultrasonic irradiation (8). However, Yamamoto's cyclopropanation reaction (9) gave a small yield of the target trans cyclopropane (23). This compound showed only very moderate fungicidal activity which was consistent with computer graphic studies showing this compound to be a less good fit with the model than the isomeric cyclopropane (19). Synthesis of Cvclobutane (27). The computer graphic model indicated that the trans isomer of this compound would be considerably more active than the ç i s isomer. Thus the cyclobutane ester (24) [made by Perkin ring synthesis (10-11) followed by Krapcho decarboxylation (12) ] was equilibrated to the trans isomer before hydrolysis to the acid (25). This was converted into the amide (26) and reduced to the cyclobutane amine (27) by standard methods (Figure 9). This cyclobutane (27) proved to be an active compound, though slightly less active than the closely related cyclopropane (19). Synthesis of Cvclobutanes (28) and (29). These two compounds, Figure 10, like the cyclobutane (27), were made by Perkin ring synthesis followed by the same functional group conversions, the final ç i s and trans cyclobutanes (28) and (29) being separated by hplc. Although the computer graphic model indicated that the trans isomer (29) should be considerably more active than the çis. (28), the two compounds were of almost equal, very high, activity. This is worth noting as a warning that we are trying to model highly complex biological systems with relatively simple computer graphic techniques.


520



CuS0

Figure 7.

4

t - B u ^ ^

(70%)

\-Bu^r

The synthesis of cyclopropanes (19) and (20).

Figure 8.

The synthesis of cyclopropane (23).

Figure 9.

The synthesis of cyclobutane (27).


(100%)


41. URCH


521

Synthesis of Cvclobutane (33). The initial route to this cyclobutane (Figure 11) used the addition of dichloroketene (13) to the styrene (30). The dichlorocyclobutanone (31) was dechlorinated with tributyltin hydride under radical conditions (14) to give the cyclobutanone (32). Reductive amination using an organically soluble reducing agent (15) gave the cyclobutane amines (33) and (34) in a çis:trans ratio of approximately 9:1. As predicted by the computer graphic model the ç i s isomer was more active than the trans isomer, though both were very active compounds. Following the activity of these cyclobutane amines an improved one-pot synthesis was developed (Figure 12) (16). The keteniminium ion (35) was produced by the method of Ghosez (17) and was then trapped in situ with styrene (36). The resultant cyclobutyl iminium ion (37) was then reduced in situ with tetrabutylammonium cyanoborohydride (15) to give the two cyclobutane amines (33) and (34) in a ratio of 3:2. This ratio varied depending on the precise conditions of the reaction but could be understood in terms of the reducing agent always preferentially attacking the less sterically hindered side of the cyclobutyl iminium ion (37). Synthesis of Cvclopentane (38). This compound, Figure 13, was synthesised in a similar way to cyclobutanes (27), (28) and (29) using the Perkin ring synthesis. It was tested as a mixture of ç i s and trans isomers and shown to have high fungicidal activity. Synthesis of Cvclopentanes (41) and (42). The route chosen to these compounds involved the reductive amination of the cyclopentanone (39) and hence its synthesis was of key importance. The initial route was by conjugate addition of an aryl organometallic species to cyclopentenone. Although the organocuprate did react it was not a clean reaction and gave only a very low yield of the cyclopentanone (39). Much more satisfactory was the use of organozinc chemistry following the method of Luche (1§) (Figure 14) which gave the ketone (39) in reasonable yield. This route worked well on a small scale but was not particularly convenient to scale-up. This problem was overcome by adding an organolithium to 3-ethoxycyclopentenone to give the enone (40) which was then hydrogenated to the required ketone (39). Reductive amination of the ketone gave the ç i s (41) and trans (42) cyclopentanes in a ratio of 7:3. Although computer graphics allowed a rough model of their precise conformations to be derived the flexibility of the five-membered ring made more precise modelling difficult. In the event both ci_s and trans cyclopentanes showed high fungicidal activity. Synthesis of Cvclopentane (45). This chain-extended version of the cyclopentanes (41) and (42) was made by the route shown in Figure 15. The Stetter reaction (19) was used to give the diketone (43). The differential reactivity of the two carbonyl groups allowed the selective reductive amination of the dialkyl ketone to give the aminoketone (44), albeit in moderate yield. This ketone (44) was then deoxygenated with triethylsilane in trifluoroacetic acid (20) to give the target cyclopentane (45) which showed good fungicidal activity.


522


(28)

(29)

Figure 10. Cyclobutanes (28) and (29). ci CI3CCOCI,

Zn

Cl

BU

' - - 0 - ^ο

ultrasound


(81%)

(31)

(30)

Bu SnH, 3

ΗΝ \

ΑΙΒΝ

Ο

(74%)

(33)

- -o o-v5

HCl,

i Bu

Ν

BU4NBH3CN

(78%)

mol. sieves (32)

(8%)

(34)

Figure 11. The synthesis of cyclobutanes (33) and (34) via dichloroketene cycloaddition. Tf 0 2

=C=N

lutidine

Ο

M , (35) t-Bu (36)

BU4NBH3CN

(67%) (37)

£is.(33):lian&(34) 3:2

Figure 12. The synthesis of cyclobutanes (33) and (34) via keteniminium ion cycloaddition.

t-Bu

(38)

Figure 13. Cyclopentane (38).


41. URCH

523


LBuLi 2. E t 0 ^ ^ g C 3. H 0


3

-o-

t-Bu-

(71%)

(40)

+

H2, Pd/C (96%)

1 .Li, 2.

ZnBr , 2

ultrasound Ni(acac)

2

(54%)

(39) ΗΝ

HCl,

Ο

BU4NBH3CN

mol. sieves

(85%) cJi(41):tian&(42)

7:3

Figure 14. The synthesis of cyclopentanes (41) and (42).

Figure 15. The synthesis of cyclopentane (45).


524



Synthesis of tetrahvdrofuran (51). This compound is an analogue of the cyclopentane (38) with the tetrahydrofuran ring replacing the cyclopentane ring. It was synthesised as shown in Figure 16. The diester (46) was allylated to give (47) which was in turn decarboxylated (12) to give the monoester (48). Reduction gave the alcohol (4) which was iodocyclised to give the tetrahydrofuran (50). Treatment with cis 2,6-dimethylmorpholine gave the target tetrahydrofuran (51) as a mixture of cis and trans isomers which showed moderate fungicidal activity. Synthesis of Cvclohexanes (53) and (54). Following on from the high fungicidal activity of the cyclobutane (33) and cyclopentanes (41) and (42) the cis isomer of the cyclohexane (53) was modelled. Comparison with the computer graphic model showed it to be an excellent fit. It was made as shown in Figure 17. On this occasion, the organocuprate gave the cyclohexanone (52) in good yield which was then reductively aminated under Eschweiler-Clarke conditions (21-22) to give a 3:2 mixture of ç i s (53) and trans (54) cyclohexanes. Both these compounds showed only very low levels of fungicidal activity and were very much less active than the closely related cyclopentanes (41) and (42). This was possibly due to the extra steric bulk of the cyclohexyl ring itself. Biological Results Table I shows the activity of the cyclic tertiary amine compounds described in this chapter as an eradicant treatment against barley powdery mildew (Ervsiphe graminis hordei). The results represent the concentrations of chemicals expressed in parts per million (ppm) required to give 95% disease control. Table I.

Activity of Cyclic Tertiary Amine Compounds against Barley Powdery Mildew

Compound Fenpropimorph Fenpropidin Tetralin Cyclopropane Cyclopropane Cyclopropane Cyclobutane Cyclobutane Cyclobutane

Egh (ppm) (2) (3) (12) (19) (20) (23) (27) (28) (29)

0.1 0.1-0.5 5 0.1-0.5 25-100 25 1-5 0.5-1 0.5-1

Egh (ppm)

Compound Cyclobutane Cyclobutane Cyclopentane Cyclopentane Cyclopentane Cyclopentane Tetrahydrofuran Cyclohexane Cyclohexane

(33) (34) (38) (41) (42) (45) (51) (53) (54)

0 5-1 1--5 1--5 1--5 1--5 1--5 5--25 25--100 25--100

Conclusions It has been shown that from a knowledge of the mode of action of a known inhibitor of 8-7-isomerase (and 14-reductase) and the use of a



41. URCH


525

t-Bir

(50)

^

(51)

Figure 16. The synthesis of tetrahydrofuran (51).

(52)

£l£(53):tian&(54)

3:2

Figure 17. The synthesis of cyclohexanes (53) and (54).


526


computer graphic model it has been possible to rationally design highly active novel fungicides. In particular, the cyclopropane (19) and the cyclobutanes (28), (29) and (33) are very active fungicides. The development of a computer graphic model was aided by the synthesis of comformationally restricted inhibitors which allowed energy minimisation to be carried out more easily and reliably than with more flexible structures.


Acknowledgments I would like to acknowledge the many ICI Agrochemicals personnel who have contributed to this work. For synthetic chemistry; M.P. Buck, M.V. Caffrey, I.M. Dee, A.C. Elliott, P.J. de Fraine, H.J. Highton, P. Lin, S.L. Macpherson, G. Tseriotis, G.C. Walter and P.A. Worthington. For biochemistry B.C. Baldwin and T.E. Wiggins. For biological testing V.M. Anthony, J.R. Godwin and M.C. Shephard and for computer graphic modelling K.J. Heritage. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

Mercer, E.I. Pestic. Sci. 1984, 15, 133. Mulheirn, L . J . ; Ramm, P.J. Chem. Soc. Rev. 1972, 1, 259. Fryberg, M.; Oehlschlager, A.C.; Unrav, A.M. J . Am. Chem. Soc. 1973, 95, 5747. Baloch, R.I.; Mercer, E.I.; Wiggins, T.E.; Baldwin, B.C. Phytochemistry 1984, 23, 2219. Baloch, R.I.; Mercer, E.I. Phytochemistry 1987, 26, 663. Dave, V.; Warnhoff, E.W. In Organic Reactions; John Wiley: New York, 1970; Vol. 18, p.217. Simmons, H.E.; Smith, R.D. J. Am. Chem. Soc. 1958, 80, 5323. Friedrich, E.C.; Domek, J.M.; Pong, R.Y. J . Org. Chem. 1985, 50, 4640. Marvoka, K.; Fukutani, Y.; Yamamoto, H. J. Org. Chem. 1985, 50, 4412. Perkin, W.H. J. Chem. Soc. 1887, 1. Haworth, E.; Perkin, W.H. J. Chem. Soc. 1894, 591. Krapcho, A.P.; Glynn, G.A.; Grenon, B.J. Tetrahedron Lett. 1967, 215. Mehta, G.; Rao, H.S.P. Svnth. Commun. 1985, 15, 991. Kuivila, H.G. Synthesis 1970, 499. Hutchins, R.O.; Markowitz, M. J. Org. Chem. 1981, 46, 3571. Urch, C.J.; Walter, G.C. Tetrahedron Lett. 1988, 4309. Falmagre, J.B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L. Angew. Chem. Int. Ed. Engl. 1981, 20, 879. Luche, J . L . ; Petrier, P.; Lansard, J-P.; Greene, A.E. J. Org. Chem. 1983, 48, 3887. Stetter, H.; Schreckenberg, M. Angew. Chem. Int. Ed. Engl. 1973, 81. Olah, G.A.; Arvanaghi, M.; Ohannesian, L. Synthesis 1986, 770. Eschweiler, W. Chem. Ber. 1905, 38, 880. Clarke, H.T.; Gillespie, H.B.; Weisshaus, S.Z. J. Am. Chem. Soc. 1933, 55, 4571.

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Synthesis and Chemistry of Agrochemicals II - American Chemical

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