The History of Azole Chemistry - ACS Symposium Series (ACS

1 The History of Azole Chemistry Karl H . Büchel

Downloaded by UNIV OF SASKATCHEWAN on July 19, 2012 | http://pubs.acs.org Publication Date: April 22, 1986 | doi: 10.1021/bk-1986-0304.ch001

Bayer A G , Forschung und Entwicklung, D5090 Leverkusen, Federal Republic of Germany

Since the earliest days of agriculture, insect pests, weeds and plant diseases have been some of the major problems of agriculture. Insect pests are visible and could, at least in some cases be countered by hand removal. A certain level of weed elimination was achieved by hoeing and hand weeding, an never ending task. However, rust, powdery mildew and smut being invisible enemies, spread throughout the fields like an unpredictable fate. Thus they occupied the imagination of rural folk, and magical concepts of disease control predominated in the early days of agriculture. Until the discovery of Bordeaux mixture in 1880, farmers had no real possibility of defending their crops against the ravages of fungal diseases. Fungi had only been identified a few years previ ously as the cause of plant diseases. Apart from a few empirical measures to prevent disease, active control was not possible. Massive disease epidemics often had catastrophic social consequences. The legacy of the Irish potato famine of the 1840's can be seen even today. It is difficult to imagine the significance of the pioneer fungicides, ones based on copper, sulphur and mercury, had in their time. The organic fungicides of the dithiocarbamate and phthalimide type (e.g. Captan) were a breakthrough in this field in the nineteen thirties and forties. Although they only have protective activity and thus must be used prophylactically, they found broad applications due to their high plant compatibility and broad disease control spectrum. A further milestone in the development of fungicides was the discovery of the so-called systemic fungicides, chemicals that are taken up by the plant and transported within it. The fungicide classes found in the sixties, including the oxathiines, pyrimidines and organophosphates, are characterized by being absorbed by the leaves, often also by the seeds and roots, and being transported acropetally within the plant. These products have only a very narrow disease control spectrum. The oxathiines are active against Basidiomycetes, mainly against rusts and smuts; the pyrimidine derivatives are active against powdery mildews. The organophosphates are used for Pyricularia control in rice. 0097-6156/86/0304-0001$07.00/0 © 1986 American Chemical Society

In Fungicide Chemistry; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

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The much w i d e r d i s e a s e c o n t r o l spectrum of the b e n z i m i d a z o l e f u n g i c i d e s (eg. benomyl, BCM, thiabendazole) - permitted f a r wider usage. I n the b e g i n n i n g , these were s u i t a b l e f o r c o n t r o l o f numerous p l a n t d i s e a s e s , but a new phenomenon soon emerged - r e s i s t a n c e ! Due t o the s p e c i f i c mode of a c t i o n of these f u n g i c i d e s , r e s i s t a n c e c o u l d appear q u i t e r a p i d l y . The c o n v e n t i o n a l f u n g i c i d e s p r e v i o u s l y used had a broad b i o c i d a l a c t i v i t y and r e s i s t a n c e had n e v e r been e x p e r i enced.


H i s t o r y of Azole

Chemistry

W i t h the c l a s s of 1 - s u b s t i t u t e d i m i d a z o l e s and 1 , 2 , 4 - t r i a z o l e s , we found a new group o f h i g h l y a c t i v e f u n g i c i d e s and a n t i m y c o t i c s (1 »3) . S i n c e t h e i r d i s c o v e r y i n the l a t e s i x t i e s , s e v e r a l compounds from t h i s c h e m i c a l c l a s s have been c o m m e r c i a l l y developed and s u c c e s s f u l l y used f o r the c o n t r o l of p l a n t d i s e a s e s and f o r the treatment o f human f u n g a l i n f e c t i o n s . These s o - c a l l e d " a z o l e f u n g i c i d e s and a n t i m y c o t i c s " have s e t new s t a n d a r d s i n m e d i c i n e and a g r i c u l t u r e w i t h r e s p e c t to e f f i c a c y and range o f d i s e a s e c o n t r o l spectrum. Among t h i s group, we f i n d the most a c t i v e compounds known today f o r c o n t r o l of p l a n t d i s e a s e s and human mycoses. "Carbocation Hypothesis". Our work on N - s u b s t i t u t e d i m i d a z o l e s and t r i a z o l e s began i n the m i d - s i x t i e s w i t h a v e r y s i m p l e h y p o t h e s i s . It was known t h a t t r o p y l i u m compounds, c y c l o h e p t a t r i e n e d e r i v a t i v e s and some N - t r i t y l a m i n e s had b i o l o g i c a l a c t i v i t y . For example N - t r i t y 1 m o r p h o l i n e ( F r e s c o n ; S h e l l ) had been developed as a m o l l u s c i c i d e and used f o r c o n t r o l of w a t e r s n a i l s ( F i g u r e 1 ) . The a c t i v i t y o f some triphenylmethane d y e s t u f f s against c e r t a i n endoparasites and the b i o l o g i c a l a c t i v i t y of n a t u r a l l y o c c u r r i n g t r o p o l o n e d e r i v a t i v e s had a l s o been r e p o r t e d (_3). From the v i e w p o i n t of a c h e m i s t , these systems a l l have one f e a t u r e i n common: they are a l l a b l e to form r e l a t i v e l y s t a b l e carbonium i o n s . To e x p l a i n the b i o l o g i c a l a c t i v i t y of these com pounds, we s p e c u l a t e d a t t h a t time t h a t t h e i r c o r r e s p o n d i n g carbonium i o n s c o u l d p o s s i b l y i n t e r f e r e i n the m e t a b o l i c p r o c e s s e s o f b i o l o g i c a l systems, f o r example i n p r o t e i n m e t a b o l i s m . The N - t r i t y l i m i d a z o l e s and t r i a z o l e s seemed s u i t a b l e to us s i n c e they have a tendency t o form s t a b l e c a r b o c a t i o n s ( F i g u r e 2 ) . Analogous t o the N - a c y l i m i d a z o l e s , i n w h i c h the enhanced r e a c t i v i t y of the a c y l group towards n u c l e o p h i l e s i s f a v o u r e d by i n c l u s i o n o f the a m i d e - n i t r o g e n l o n e e l e c t r o n p a i r i n the Δ - s y s t e m o f the h e t e r o c y c l e , n u c l e o p h i l i c a t t a c k on the t r i t y l p a r t of the N - t r i t y l a z o l e s a l s o s h o u l d be a f a c i l e p r o c e s s ( 1 1 ) . N - T r i t y l a z o l e s , D i p h e n y l m e t h y l a z o l e s and R e l a t e d Compounds. On the b a s i s of t h i s h y p o t h e s i s , we began the s y n t h e s i s of N - t r i t y l i m i d a z o l e s and sent them f o r b i o l o g i c a l t e s t i n g . Very s h o r t l y , the e x c e l l e n t a c t i v i t y of t h i s type of compound a g a i n s t human and p l a n t p a t h o g e n i c f u n g i and y e a s t s was e v i d e n t i n our b i o l o g i c a l s c r e e n s . The a c t i v i t y a g a i n s t powdery mildew f u n g i was p a r t i c u l a r l y remark able. F o l l o w i n g these i n i t i a l , h i g h l y e n c o u r a g i n g r e s u l t s , we c o o p e r a t e d w i t h the b i o l o g i s t s and m y c o l o g i s t s , to t r y t o o p t i m i z e the



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The History of Azole Chemistry

Experimental Molluscicide

Molluscicide

(ICI)

(Frescon; Shell)

( > o

R

Q- > 9 ) . C h e m i c a l V a r i a b i l i t y o f the A z o l e

Class

The c h e m i c a l v a r i a b i l i t y of the 1 - s u b s t i t u t e d a z o l e s can a l r e a d y be recognized from the subgroups p r e s e n t e d thus f a r , i n c l u d i n g the N - t r i t y l a z o l e s and t h e i r a n a l o g u e s , the N - d i p h e n y l m e t h y l a z o l e s , the phenethylazoles and the a z o l y l - 0 , N - a c e t a l s . The only e s s e n t i a l f e a t u r e i s the i m i d a z o l e o r 1 , 2 , 4 - t r i a z o l e r i n g . The q u a l i t y o f the f u n g i c i d a l a c t i o n and of the p r o p e r t i e s n e c e s s a r y f o r p r a c t i c a l use are determined o n l y by the s e l e c t i o n of a s u i t a b l e s u b s t i t u e n t R. A s i m p l e c a l c u l a t i o n can s e r v e to demonstrate t h i s c h e m i c a l v a r i a b i l i t y ( F i g u r e 14). I f one d e s i g n a t e s the s u b s t i t u e n t s o f the N - s u b s t i t u t e d a z o l e s as Χ, Υ, Ζ and the number of v a r i a t i o n s as n, then the t o t a l number Ν o f a z o l e d e r i v a t i v e s p o s s i b l e can e a s i l y be calculated. If η 200, w h i c h i s c e r t a i n l y a v e r y modest number of d i f f e r e n t Χ, Υ, Ζ s u b s t i t u e n t s , then t h i s means t h a t w i t h i m i d a z o l e and t r i a z o l e as components, i t i s p o s s i b l e t o make 5.4 million d i f f e r e n t compounds! One o f the s p e c i a l f e a t u r e s o f a z o l e compounds i s the abundance of s y n t h e t i c p o s s i b i l i t i e s and t h e r e f o r e the abundant s e l e c t i o n o p p o r t u n i t i e s f o r b i o l o g y and m e d i c i n e . By e x a m i n a t i o n o f the p r o p e r t i e s o f a z o l e d e r i v a t i v e s , one can r e c o g n i z e o t h e r a p p l i c a t i o n s f o r them a p a r t from the c o n t r o l of f u n g i p a t h o g e n i c t o p l a n t s and man. Some of the a z o l e d e r i v a t i v e s , such as l o m b a z o l e , e x h i b i t a



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F i g u r e 12. Pathways f o r t h e s y n t h e s i s o f t r i a d i m e f o n and t r i a d i menol. (Reproduced w i t h p e r m i s s i o n from R e f . 9. C o p y r i g h t 1983 Pergamon P r e s s . )

Triadimefon Bayleton® Systemic Fungicide

Triad imenol Baytan® Systemic Seed Protectant

Climbazole Baypival®

Bitertanol Baycor® Nonsystemic Fungicide

F i g u r e 13. A z o l y l - 0 , N - a c e t a l s . (Reproduced w i t h p e r m i s s i o n R e f . 9. C o p y r i g h t 1983 Pergamon P r e s s . )


from

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a c t i v i t y against gram-positive b a c t e r i a . C e r t a i n a z o l e compounds i n t e r f e r e w i t h the b i o s y n t h e s i s of g i b b e r e l l i n s and i n f l u e n c e the morphogenesis o f green p l a n t s , i n d i c a t i n g t h e i r p o s s i b l e use as p l a n t growth r e g u l a t o r s . I t comes as no s u r p r i s e t h a t i n the y e a r s f o l l o w i n g the r e c o g n i t i o n o f the e x t r a o r d i n a r y b i o l o g i c a l p r o p e r t i e s o f the a z o l e s , i n t e n s i v e r e s e a r c h work was i n i t i a t e d w o r l d w i d e i n many l a b o r a t o r i e s on i m i d a z o l e and t r i a z o l e d e r i v a t i v e s .


A z o l e Compounds from o t h e r

Classes

To d a t e , t h i s w o r l d w i d e a c t i v i t y has l e d t o a whole s e r i e s o f h i g h l y a c t i v e a z o l e d e r i v a t i v e s developed f o r p r a c t i c a l use i n m e d i c i n e and a g r i c u l t u r e ( F i g u r e 15). T r i a z o l e d e r i v a t i v e s of the d i c h l o b u t r a z o l e and p a c l o b u t r a z o l e types are c l o s e l y r e l a t e d c h e m i c a l l y t o the t r i a z o l y l - 0 , N - a c e t a l s p r e v i o u s l y mentioned. The oxygen atom of the a c e t a l f u n c t i o n was m e r e l y r e p l a c e d by a methylene group. D i c h l o b u t r a z o l e ( I C I ) was d e v e l o p e d f o r the c o n t r o l of powdery mildew, r u s t and scab i n c e r e a l s . P a c l o b u t r a z o l e i s under development as a growth r e g u l a t o r . P r o p i c o n a z o l e and e t a c o n a z o l e , two t r i a z o l e d e r i v a t i v e s d i s c o v ered by J a n s s e n and developed under l i c e n s e by C i b a - G e i g y f o r c o n t r o l of f u n g a l d i s e a s e s i n c e r e a l s and f r u i t , b e l o n g to a n o t h e r a z o l e subgroup, the a z o l y l m e t h y l - d i o x o l a n e s . T h e i r c h e m i c a l g e n e s i s from the p h e n e t h y l a z o l e s of the i m a z a l i l and m i c o n a z o l e type i s e a s i l y r e c o g n i z a b l e . K e t o c o n a z o l e ( J a n s s e n ) , an o r a l a n t i m y c o t i c i n t r o d u c e d i n t o human t h e r a p y , a l s o b e l o n g s t o t h i s group. The i m i d a z o l e d e r i v a t i v e , p r o c h l o r a z , has a p e c u l i a r f e a t u r e compared t o the a z o l e d e r i v a t i v e s . The n i t r o g e n atom i n the 1 - p o s i t i o n o f the i m i d a z o l e i s bonded t o a carbamoyl group and not t o alkyl. T h i s compound, w h i c h i s r e g a r d e d as a t e t r a s u b s t i t u t e d u r e a , has a v e r y broad spectrum and can be used i n c e r e a l s b o t h as a seed d r e s s i n g and a f o l i a r f u n g i c i d e ( 9 ) . B i o l o g i c a l A c t i v i t y and

Stereochemistry

The N - v i n y l - a z o l e c l a s s , i n w h i c h the 1-N atom of the a z o l e i s d i r e c t l y bonded t o an s p - h y b r i d i z e d carbon o f a s u b s t i t u t e d o l e f i n , b e l o n g s t o the r e l a t i v e l y r e c e n t l y s y n t h e s i z e d subgroup of b i o a c t i v e azoles. Compounds o f t h i s n a t u r e can be o b t a i n e d by c o n d e n s a t i o n of a l d e h y d e s w i t h t r i a z o l y l - p i n a c o l o n e r e s u l t i n g i n a m i x t u r e of the Ε and Ζ isomers o f the c o r r e s p o n d i n g α, β-unsaturated ketones. Borohyd r i d e r e d u c t i o n e a s i l y c o n v e r t s these k e t o n e s i n t o the c o r r e s p o n d i n g a l c o h o l s ( 9 ) ( F i g u r e 16). I n these compounds, t h e r e i s a marked r e l a t i o n s h i p between m o l e c u l a r geometry and b i o l o g i c a l a c t i v i t y . From v a l u e s r e p o r t e d i n the l i t e r a t u r e and a c c o r d i n g t o our own s t u d i e s , the Ε i s o m e r s , i n w h i c h the r e s i d u e o r i g i n a t i n g from the aldehyde i s i n the t r a n s p o s i t i o n t o the t r i a z o l e , are markedly s u p e r i o r t o the Ζ isomers i n t h e i r biological activity. By s u i t a b l e c o n t r o l o f the r e a c t i o n c o n d i t i o n s , i t i s p o s s i b l e t o a c h i e v e an almost complete i s o m e r i z a t i o n t o the u n s a t u r a t e d E - t r i a z o l y l k e t o n e s . Subsequent r e d u c t i o n l e a d s t o the more a c t i v e Ε-alcohols. T h i s group of N - v i n y l a z o l e s i n c l u d e s the t r i a z o l e d e r i v a t i v e S 3308 (Sumitomo), c u r r e n t l y under development as 2


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(ÇH )o.i

(CH )o.i

2

2

X-C-Z

N

X-C-Z

_ ^

+ £

4


3

+

2

4 6

N—Number of possible active compounds in the azole group [for imidazoles and 1,2,4-triazoles] η=Number of different substituents X, Y, and Ζ η

10

50

100

Ν

880

88,400

688,800

200_ 5,413,600

F i g u r e 14. The c h e m i c a l v a r i a b i l i t y o f t h e a z o l e c l a s s .

Diclobutrazole ( X - C I ) (Fungicide; ICI)

Etaconazole (R-C H ) Propiconazole (R (Fungicides; Ciba-Geigy/Janssen) 2

5

C3H7)

Paclobutrazole ( X - H ) (Plant growth regulator; ICI)

Prochloraz (Fungicide; Boots)

Figure 15. subgroups.

Azole

fungicides

and a n t i m y c o t i c s

from


other


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FUNGICIDE CHEMISTRY

a f u n g i c i d e , as w e l l as the growth r e g u l a t o r s S 3307 and t r i a p e n t h e n o l (RSW 0411, B a y e r ) . As i n the use o f d i c h l o b u t r a z o l e and p a c l o b u t r a z o l e , the b i o l o g i c a l spectrum o f the two e x p e r i m e n t a l compounds S 3307 and S 3308, whether f u n g i c i d e o r growth r e g u l a t o r , i s d i c t a t e d o n l y by the s u b s t i t u t i o n p a t t e r n i n one p a r t o f the m o l e c u l e . Triapenthenol, w h i c h i s of p a r t i c u l a r i n t e r e s t as a growth r e g u l a t o r i n r i c e and r a p e , a l s o p o s s e s s e s a marked f u n g i c i d a l a c t i v i t y . Two enantiomers of t r i a p e n t h e n o l were o b t a i n e d from the racemate v i a d i a s t e r e o m e r i c e s t e r d e r i v a t i v e s ( F i g u r e 17). I n the b i o l o g i c a l t e s t i n g of the e n a n t i o m e r s , a c l e a r s e p a r a t i o n of the b i o l o g i c a l p r o p e r t i e s was observed. The (-)-S-enantiomer i s almost solely r e s p o n s i b l e f o r the growth r e g u l a t o r p r o p e r t i e s ; the (+)-R-enantiomer has a markedly h i g h e r f u n g i c i d a l a c t i v i t y ( F i g u r e s 18-19). Many of the a z o l e f u n g i c i d e s mentioned p r e v i o u s l y e x i s t as two g e o m e t r i c a l i s o m e r s , t h a t i s two c o r r e s p o n d i n g enantiomer p a i r s w i t h 1R, 2R / I S , 2S and 1R, 2S / I S , 2R c o n f i g u r a t i o n s , due t o the presence o f two c h i r a l c e n t r e s i n the m o l e c u l e . Examples o f t h i s a r e the t r i a z o l e compounds e t a c o n a z o l e , p r o p i c o n a z o l e , d i c h l o b u t r a z o l e , b i t e r t a n o l and t r i a d i m e n o l . I n the s y n t h e s i s of t r i a d i m e n o l , the second asymmetric c e n t e r i s i n t r o d u c e d by the r e d u c t i o n o f the k e t o function i n triadimefon. T h i s r e s u l t s i n the f o r m a t i o n o f two d i a s t e r e o m e r i c forms w h i c h have been found t o have d i f f e r e n t f u n g i c i d a l a c t i v i t i e s (Figure 20). The c h e m i s t i s then f a c e d w i t h the task of developing s t e r e o s e l e c t i v e syntheses, i n order to o b t a i n a p r o d u c t w i t h the h i g h e s t p o s s i b l e p r o p o r t i o n of the more a c t i v e diastereomer. I n the c o n v e r s i o n of t r i a d i m e f o n t o t r i a d i m e n o l , i t was p o s s i b l e t o s t e e r the r e a c t i o n i n the d e s i r e d d i r e c t i o n by c a r e f u l s e l e c t i o n o f the r e d u c t i o n system (9)· From s t u d i e s of the b i o l o g i c a l a c t i v i t y o f the individual e n a n t i o m e r s , we o b t a i n e d a d e t a i l e d i n s i g h t i n t o the r e l a t i o n s h i p between a b s o l u t e c o n f i g u r a t i o n o f the t r i a z o l y l - 0 , N - a c e t a l s and t h e i r fungicidal properties. R- and S - t r i a d i m e f o n were o b t a i n e d i n h i g h o p t i c a l p u r i t y (99% e.e.) from racemic p r o d u c t by s e p a r a t i o n of i t s diastereomeric -bromocamphorsulphonate s a l t s ; the a b s o l u t e c o n f i g u r a t i o n s b e i n g d e t e r m i n e d by X-ray c r y s t a l l o g r a p h y . E a s i l y s e p a r a b l e diastereomeric mixtures of enantiomeric t r i a d i m e n o l s are t h e n ob t a i n e d by r e d u c t i o n o f the two t r i a d i m e f o n e n a n t i o m e r s , the c o n f i g u r a t i o n at p o s i t i o n 1 being preserved (Figure 21). A l t h o u g h R- and S - t r i a d i m e f o n e x h i b i t p r a c t i c a l l y no d i f f e r e n c e s i n a c t i v i t y w i t h i n the a c c u r a c y l i m i t s of b i o l o g i c a l t e s t i n g , the f o u r enantiomeric t r i a d i m e n o l s show marked g r a d a t i o n s i n t h e i r a c t i v i t y s p e c t r a . The h i g h e s t f u n g i c i d a l a c t i v i t y of a l l 4 enantiomers r e s i d u e s was w i t h the ( - ) - l S , 2R enantiomer. A similar r e l a t i o n s h i p between a b s o l u t e configuration and f u n g i c i d a l a c t i v i t y was a l s o observed w i t h the enantiomers o f b i t e r tanol. As w i t h t r i a d i m e n o l , the f u n g i c i d a l a c t i v i t y of the ( - ) - l S , 2R enantiomer i s markedly g r e a t e r than t h a t of the o t h e r 3 e n a n t i o mers ( F i g u r e 22). D i f f e r e n c e s i n the b i o l o g i c a l p r o p e r t i e s o f the enantiomers have a l s o been r e p o r t e d f o r o t h e r a z o l e p r o d u c t s t h a t p o s s e s s one o r more c h i r a l c e n t e r s i n the m o l e c u l e . These few r e s u l t s c l e a r l y show t h a t , as i n many o t h e r b i o l o g i c a l l y a c t i v e c l a s s e s o f compounds, the



1.

BUCHEL

17


F i g u r e 16.

N-Vinyl-azoles.

OH

R, S-Triapenthenol

The History of Azole Chemistry - ACS Symposium Series (ACS

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