Biologically Active Organosilicon Compounds - ACS Symposium

Chapter 26 Biologically Active Organosilicon Compounds Fungicidal Silylmethyltriazoles

Downloaded by NORTH CAROLINA STATE UNIV on May 7, 2015 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch026

William K. Moberg, Gregory S. Basarab, John Cuomo, and Paul H . Liang Agricultural Products Department, Ε. I. du Pont de Nemours & Co., Experimental Station, Building 402, Wilmington, D E 19898

Silylmethyltriazoles represent a new, highly active class of triazole fungicides, whose success in a wide variety of crops and climatic conditions confirms the utility of organosilicon compounds as agrichemicals. This paper describes their discovery, synthesis, and structure -activity relationships. Based on the results of worldwide field evaluations, some of which are presented, a member of this class, DPX-H6573, is being developed as a broad spectrum foliar fungicide. R e s e a r c h a t Du P o n t o n s i l i c o n - c o n t a i n i n g a g r i c h e m i c a l s h a s p r o v i d e d a new c l a s s o f t r i a z o l e f u n g i c i d e s , t h e s i l y l m e t h y l t r i a z o l e s (1, 2). We d e s c r i b e h e r e i n t h e discovery andoptimization of this class, concluding with some f i e l d r e s u l t s f o r D P X - H 6 5 7 3 ( p r o p o s e d common name: f l u s i l a z o l e ) , a n a c t i v e i n g r e d i e n t i n t h e new f u n g i c i d e s Nustar®, Punch®, Triumph™, a n d Olymp®.

0097-6156/87/0355-0288$06.00/0 © 1987 American Chemical Society

In Synthesis and Chemistry of Agrochemicals; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

26.

MOBERG ET AL.

Biologically Active Organosilicon Compounds

Discovery


S i l y l m e t h y l t r i a z o l e s combine a l i t t l e - e x p l o r e d a r e a , t h a t o f s i l i c o n - c o n t a i n i n g a g r i c h e m i c a l s , w i t h a w e l l known a r e a , t h a t o f t r i a z o l e f u n g i c i d e s . We b e g i n b y c o n s i d e r i n g e a c h f a c e t s e p a r a t e l y , t h e n s h o w how they came t o g e t h e r t o p r o v i d e t h e i n i t i a l d i s c o v e r y t h a t e v e n t u a l l y p r o d u c e d DPX-H6573. Incorporating S i l i c o n Into Agrichemicals. This concept a t t r a c t e d us f o r s e v e r a l r e a s o n s . F i r s t , i t was r e l a t i v e l y unexplored. Industrial interest in silicon has c o n c e n t r a t e d a l m o s t e n t i r e l y on p o l y m e r s , a n d t o o u r k n o w l e d g e t h e o n l y s i l i c o n compounds e v e r commercialized as a g r i c h e m i c a l s a r e c h l o r o e t h y l s i l a n e s such as etacelasil [2-chloroethyl-tris(2-methoxyethoxy)silane; Ciba-Geigy] Q ) , w h i c h a r e u s e d as p l a n t g r o w t h modifiers. However, t h e s e compounds a c t by d e c o m p o s i n g i n p l a n t s t o r e l e a s e t h e hormone e t h y l e n e . Thus, although they represent a very c l e v e r a p p l i c a t i o n of s i l i c o n chemistry, they are not a c t i v e per se and t h e a c t i v e p r i n c i p l e t h e y r e l e a s e no l o n g e r c o n t a i n s s i l i c o n . S e c o n d , t h e r e was a v a s t l i t e r a t u r e o n o r g a n o s i l i c o n c h e m i s t r y g o i n g b a c k a l m o s t 100 y e a r s , a n d a c a d e m i c w o r k i n t h e a r e a has been e x t e n s i v e i n r e c e n t y e a r s . F o r t u n a t e l y f o r us, however, i n v i r t u a l l y a l l contemporary studies s i l i c o n i s used to f a c i l i t a t e c h e m i c a l t r a n s f o r m a t i o n s , and i t d i s a p p e a r s g r a c e f u l l y as the d e s i r e d product i s formed. T h u s t h e r e was an e x c e l l e n t background of s y n t h e t i c l i t e r a t u r e , but still r e l a t i v e l y l i t t l e i n t e r e s t i n the b i o l o g i c a l a c t i v i t y of organosilanes. T h i r d , thanks to the polymer research m e n t i o n e d e a r l i e r , t h e r e were s e v e r a l s i m p l e but h i g h l y f u n c t i o n a l i z e d b u i l d i n g b l o c k s a v a i l a b l e i n b u l k and a t r e a s o n a b l e c o s t : t h e monomers f o r s i l i c o n e polymers. F i n a l l y , t h e r e was t h e s c i e n t i f i c i n t e r e s t o f w o r k i n g w i t h an e l e m e n t whose c h e m i c a l p r o p e r t i e s a r e p r a c t i c a l l y unique i n the p e r i o d i c t a b l e . r

Triazole Fungicides. A t t h e same t i m e , we h a d a n independent i n t e r e s t i n the area of t r i a z o l e f u n g i c i d e s . These compounds, w h i c h a c t by i n t e r f e r i n g w i t h s t e r o i d biosynthesis in sensitive fungi ϋ) , s h o w h i g h a c t i v i t y against a broad spectrum of economically important plant diseases. The a r e a was p i o n e e r e d b y B a y e r and J a n s s e n i n t h e e a r l y 1970's, and two o f t h e most s u c c e s s f u l compounds t o emerge f r o m t h i s work a r e t r i a d i m e f o n , i n v e n t e d and d e v e l o p e d by B a y e r , and p r o p i c o n a z o l e , i n v e n t e d by J a n s s e n and l i c e n s e d t o C i b a Geigy f o r development. Discovery Strategy. Our d i s c o v e r y b e g a n w i t h t h e o b s e r v a t i o n t h a t t h e s e and r e l a t e d compounds f r o m


other

289

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS


290

c o m p a n i e s s h a r e d common s t r u c t u r a l f e a t u r e s ( F i g u r e 1 ) . Each h a s a t r i a z o l e r i n g ; a two-atom spacer, w i t h o r without heteroatoms and v a r i o u s l y s u b s t i t u t e d a t e i t h e r p o s i t i o n ; and a benzene r i n g , u s u a l l y s u b s t i t u t e d . The common e l e m e n t s a r e r e p r e s e n t e d s c h e m a t i c a l l y , w i t h X a n d Y as t h e b r i d g i n g atoms. In c o n s i d e r i n g t h i s s t r u c t u r a l template, i t occurred t o u s t h a t we m i g h t u s e i t t o t e s t t h e o r g a n o s i l i c o n s t r a t e g y , by making X o r Y s i l i c o n . We i n i t i a l l y r u l e d o u t Y, s i n c e N - s i l y l a z o l e s a r e k n o w n t o h y d r o l y z e readily. T h i s l e f t X a s s i l i c o n , a n d we s e t o u t t o prepare the simplest structure f i t t i n g t h i s template, compound X .

Figure

1.

Discovery

Strategy

Triadimefon

n-C H 3

7

Propiconazole

C I

Common

Structure

Compound

this

I

O f c o u r s e , we w e r e a w a r e o f p o t e n t i a l p i t f a l l s i n sort of reasoning. One o f t e n s t a r t s w i t h a n



26.

MOBERG ET AL.

Biologically Active Organosilicon Compounds

a p p a r e n t i n s i g h t t h a t t u r n s out t o be f a u l t y , and e v e n with a b i o c h e m i c a l l y accurate i n s i g h t such a d r a s t i c m o d i f i c a t i o n s e l d o m l e a d s t o a c t i v e compounds. F u r t h e r m o r e , i n t h i s c a s e t h e r e was t h e a d d e d u n c e r t a i n t y t h a t l i t t l e i s known a b o u t t h e s t a b i l i t y o f organosilanes i n b i o l o g i c a l systems. And t h e r e were q u i t e s p e c i f i c n e g a t i v e p r e c e d e n t s , s u c h as t h e w o r k o f F u k u t o on DDT a n a l o g s (£), w h e r e r e p l a c e m e n t o f a t r i c h l o r o m e t h y l g r o u p with t r i m e t h y l s i l y l completely destroyed a c t i v i t y . F i n a l l y , t h e r e was e v e n some q u e s t i o n a s t o w h e t h e r i c o u l d be p r e p a r e d , s i n c e t h e l i t e r a t u r e on chloromethylsilane d i s p l a c e m e n t c h e m i s t r y h a s many examples of u n d e s i r e d c a r b o n - s i l i c o n bond c l e a v a g e intervening. H o w e v e r , t h e i d e a h a d one v e r y a t t r a c t i v e f e a t u r e : i t was e a s y t o t e s t . I n t h e e v e n t , we w e r e p l e a s a n t l y s u r p r i s e d t o f i n d t h a t i c o u l d b e made, a n d e v e n m o r e s u r p r i s e d (and p l e a s e d ) t o f i n d t h a t i t was a c l a s s i c c h e m i c a l l e a d . I t s a c t i v i t y was r e l a t i v e l y m o d e s t a n d i t s s p e c t r u m r e l a t i v e l y narrow, but i t had t h e k i n d o f a c t i v i t y we were h o p i n g f o r , and i t showed o t h e r d e s i r a b l e p r o p e r t i e s s u c h a s t h e a b i l i t y t o move s y s t e m i c a l l y i n p l a n t t i s s u e s a n d some a b i l i t y t o c u r e e s t a b l i s h e d f u n g a l i n f e c t i o n s . Equally important, i t was a v e r y s i m p l e s t r u c t u r e t h a t c o u l d be m o d i f i e d a t s e v e r a l s i t e s . We therefore undertook a s y n t h e s i s program aimed at o p t i m i z i n g t h i s a c t i v i t y , and e v e r y p o r t i o n o f t h e m o l e c u l e e x c e p t t h e s i l i c o n a t o m was v a r i e d s y s t e m a t i c a l l y . Chemistry We a l l u d e d e a r l i e r t o t h e f a c t t h a t s e v e r a l p o l y m e r intermediates a r e r e a d i l y a v a i l a b l e as s t a r t i n g m a t e r i a l s , and t h e s e formed t h e b a s i s f o r our work. The e n t i r e s e r i e s of s i l a n e s i n which s i l i c o n bears varying numbers o f c h l o r i n e s and m e t h y l g r o u p s i s p r o d u c e d i n t h e i n d u s t r i a l process f o r making d i c h l o r o d i m e t h y l s i l a n e , the p r o t o t y p i c a l s t a r t i n g material for s i l i c o n e polymers. These compounds a r i s e f r o m d i r e c t r e a c t i o n o f m e t a l l i c s i l i c o n and c h l o r o m e t h a n e , c a t a l y z e d by c o p p e r (Equation 1) .

MeCl S

i°

•

ClSiMe

3

+ Cl SiMe 2

2

+ Cl SiMe 3

(1)

Cu F o r e v e n t u a l i n t r o d u c t i o n o f a t r i a z o l e r i n g , one m e t h y l g r o u p m u s t be f u n c t i o n a l i z e d s e l e c t i v e l y , a n d this i s r e a d i l y a c c o m p l i s h e d by l i g h t - c a t a l y z e d p h o t o c h l o r i n a t i o n , as i l l u s t r a t e d i n E q u a t i o n 2 f o r dichlorodimethyl silane. The o t h e r m e t h y l c h l o r o s i l a n e s c a n be monoc h l o r i n a t e d i n t h e same way.


291

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

292

CH

CI, Cl SiMe 2

3

(2)

Cl SiCH Cl 2

2

2


light

I n t r o d u c i n g S u b s t i t u e n t s About S i l i c o n . With d i s p l a c e a b l e c h l o r i n e atoms a t a l l t h e r e q u i r e d positions, we t o o k a d v a n t a g e o f t h e u n i q u e c h e m i s t r y o f s i l i c o n t o introduce a wide v a r i e t y o f s u b s t i t u e n t s about t h e s i l i c o n atom, s i n c e t h e S i - C l b o n d s a r e much more r e a c t i v e than t h e C - C l bond. Typically, organometallic reagents a r e used, and s i n c e t h e c h l o r i n e s on s i l i c o n can be r e p l a c e d s t e p w i s e , t h e s y n t h e s i s o f f e r s considerable f l e x i b i l i t y (Equation 3 ) . R R

Cl SiCH Cl 3

2

l

L

i

R

»

2

L

i

R

»

3

L

i

-

1

2

R -Si"CH Cl 2

(3)

T h i s c h e m i s t r y was g e n e r a l l y u n e v e n t f u l , b u t t w o f i n d i n g s u s e f u l from t h e p r e p a r a t i v e point o f view deserve mention. First, b e l o w -60°C l i t h i u m - h a l o g e n exchange between a r y l bromides and a l k y l l i t h i u m s i s so much f a s t e r t h a n r e a c t i o n o f a l k y l l i t h i u m s w i t h chlorosilanes that I n situ metalation i s possible. The a r y l bromide and c h l o r o s i l a n e a r e simply mixed t o g e t h e r , then coupled by dropwise a d d i t i o n o f a l k y l l i t h i u m . This h a s a d v a n t a g e s when t h e d e s i r e d a r y l l i t h i u m t e n d s t o p r e c i p i t a t e from t h e r e a c t i o n mixture, and i t a l s o allows us t o work w i t h u n s t a b l e a l p h a - h a l o a r y l l i t h i u m s t h a t could form benzyne, s i n c e t h e a r y l l i t h i u m r e a c t s w i t h t h e c h l o r o s i l a n e as f a s t as i t i s generated. This reaction can even be u s e d t o i n t r o d u c e two d i f f e r e n t s u b s t i t u e n t s i n one p o t . F o r e x a m p l e ( E q u a t i o n 4 ) , when a n e q u i m o l a r m i x t u r e o f a d i c h l o r o s i l a n e and an a r y l bromide i s t r e a t e d w i t h two e q u i v a l e n t s o f n - b u t y l l i t h i u m , t h e f i r s t e q u i v a l e n t forms t h e a r y l - s i l i c o n bond and t h e second r e a c t s w i t h t h e remaining s i l i c o n - c h l o r i n e bond, producing the f u l l y s u b s t i t u t e d s i l a n e i n useable yield after distillation.

Biologically Active Organosilicon Compounds - ACS Symposium

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