Pesticide Synthesis Through Rational Approaches - American

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T. ROY FUKUTO Division of Toxicology and Physiology, Department of Entomology and Department of Chemistry, University of California, Riverside, CA 92521 During the past decade a number of new derivatives of toxic methylcarbamate insecticides with improved toxicological properties have been discovered and several are now close to reaching commercial prominence. These proinsecticides have in common a sulfur atom which bridges the nitrogen atom of the carbamyl moiety to the derivatizing group. The toxicological properties of the original methylcarbamate insecticide may be markedly affected by derivatization, resulting generally in substantial improvement in mammalian toxicity and retention or improvement in insecticidal activity. Derivatization may greatly alter the physical properties of a pesticide, e.g. from polar to non-polar, and this change often affects the spectrum of activity of the compound. The development of chlorosulfenyl- and chlorosulfinylmethylcarbamates as intermediates in derivatization opens up many possibilities for the design and synthesis of new proinsecticides with unusual properties. The intermediates may be used in derivatizing a wide variety of other pesticidal compounds. A p r o p e s t i c i d e i s a p e s t i c i d a l l y a c t i v e m a t e r i a l or compound which i n i t s o r i g i n a l form i s i n a c t i v e and i s transformed i n t o an a c t i v e s t a t e by a p l a n t , animal, or microorganism. In most cases, the target organism which i s being a f f e c t e d u n w i t t i n g l y c a r r i e s out a s e l f - i n f l i c t i n g l e t h a l synthesis by chemically or b i o c h e m i c a l l y converting an i n a c t i v e compound i n t o an a c t i v e p r o duct. The concept behind the development o f p r o p e s t i c i d e s has been known for h a l f a century and has been e x p l o i t e d f o r many years i n the design o f drugs by the pharmaceutical i n d u s t r y . An e a r l y example o f a s y n t h e t i c prodrug i s p r o n t o s i l , a drug used

0097-6156/ 84/0255-0087506.00/0 © 1984 American Chemical Society

Magee et al.; Pesticide Synthesis Through Rational Approaches ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

PESTICIDE SYNTHESIS T H R O U G H RATIONAL APPROACHES

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88

for the treatment of s t r e p t o c o c c a l and pneumococcal i n f e c t i o n s . Recognition f o r the d i s c o v e r y of the chemotherapeutic value of p r o n t o s i l was given to Domagk (I) who was awarded the Nobel P r i z e i n Medicine for 1938. Following the discovery of p r o n t o s i l , s c i e n t i s t s at the Pasteur I n s t i t u t e showed that p r o n t o s i l was m e t a b o l i c a l l y converted i n t o s u l f a n i l a m i d e (p-aminobenzenesulfonamide) and that i t was s u l f a n i l a m i d e which was r e s p o n s i b l e f o r the therapeutic value of p r o n t o s i l (2^,_3). P r o n t o s i l i t s e l f was f i r s t synthesized as a p o s s i b l e azo dye. Since the discovery of p-aminobenzenesulfonamide as an a n t i b a c t e r i a l agent, vast numbers of s u l f a n i l a m i d e d e r i v a t i v e s have been synthesized and

NH

mtes bacter 2

S0 NH 2

prontosil

2

sulfanilamide

evaluated and s e v e r a l have a t t a i n e d c l i n i c a l importance ( 4 ) . The d i s c o v e r y of p r o n t o s i l was f o r t u i t o u s and was not based on r a t i o n a l e design. There are a large number of p e s t i c i d e s which f a l l i n the same category as p r o n t o s i l , i . e . , they are a c t i v e by v i r t u e of t h e i r s u s c e p t i b i l i t y to metabolic or chemical m o d i f i c a t i o n to a c t i v e intermediates. The c l a s s i c a l example of an i n s e c t i c i d e of t h i s type i s p a r a t h i o n , a phosphorothionate e s t e r which i n animals or p l a n t s i s o x i d a t i v e l y d e s u l f u r a t e d to the potent a n t i c h o l i n e s t e r a s e paraoxon (_5). The i n s e c t i c i d a l a c t i v i t y of parathion was known f o r s e v e r a l years before the p u r i f i e d m a t e r i a l was shown to be a poor a n t i c h o l i n e s t e r a s e and that metabolic a c t i v a t i o n to paraoxon was necessary for i n t o x i c a tion. In c o n t r a s t to "pro" compounds of the type described above, a large number of p r o p e s t i c i d e s have a l s o been developed i n recent years which were designed on the basis of t h e i r a n t i c i pated a c t i v a t i o n i n b i o l o g i c a l systems. In these cases, a c t i v e compounds were modified by d e r i v a t i z a t i o n i n t o products which r e v e r t e d back to the o r i g i n a l compound w i t h i n the target organism. This kind of approach to the design of new p e s t i c i d e s has many v i r t u e s and the most important of these are described b r i e f l y as follows. The a c t i v i t y spectrum of a p e s t i c i d a l compound i s o f t e n determined by the p h y s i c a l p r o p e r t i e s of the compound. For example, systemic i n s e c t i c i d e s u s u a l l y r e q u i r e both water and l i p i d s o l u b i l i t y since i t i s necessary f o r them to pass through



6.

FUKUTO

Propesticides

89

aqueous and l i p i d phases while moving through a p l a n t or animal ( 6 ) . Therefore, by a t t a c h i n g an appropriate f u n c t i o n a l group to an i n s e c t i c i d e , i t i s p o s s i b l e to convert a non-systemic compound i n t o one which i s systemic. Moreover, by proper s e l e c t i o n o f the d e r i v a t i z i n g moiety, the p h y s i c a l p r o p e r t i e s o f an i n s e c t i c i d a l compound may be manipulated to o b t a i n products with other s e l e c t e d types o f a c t i v i t y . However, i t should be added that d e r i v a t i z a t i o n may a l s o lead to a p a r t i a l or complete loss o f insecticidal activity. Another important v i r t u e to d e r i v a t i z a t i o n o f i n s e c t i c i d e s to p r o i n s e c t i c i d e s i s the s i g n i f i c a n t improvement i n the t o x i c o l o g i c a l p r o p e r t i e s o f t e n observed i n the d e r i v a t i z e d product. This has been p a r t i c u l a r l y evident with the methylcarbamate and phosphoramidothioate i n s e c t i c i d e s where i n almost a l l cases d e r i v a t i z a t i o n has r e s u l t e d i n improved mammalian t o x i c i t y . F u r t h e r , i n many cases, equal or greater i n s e c t i c i d a l a c t i v i t y has a l s o been observed although i n some cases i n s e c t i c i d a l a c t i v i t y may be s u b s t a n t i a l l y reduced. Improvement i n mammalian t o x i c i t y has been a t t r i b u t e d to the delayed f a c t o r provided by the d e r i v a t i z i n g group, g i v i n g the animal the o p p o r t u n i t y to metabolize the compound to non-toxic products. D e r i v a t i z a t i o n , t h e r e f o r e , has been widely a p p l i e d t o improve the t o x i c o l o g i c a l p r o p e r t i e s o f known i n s e c t i c i d e s and t h i s paper w i l l attempt to review accomplishments and d i s c u s s p o s s i b i l i t i e s f o r future s t r a t e g y f o r the design o f new compounds with t h i s group o f p e s t i c i d e s . Methylcarbamates The methylcarbamate i n s e c t i c i d e s are p a r t i c u l a r l y s u i t a b l e to d e r i v a t i z a t i o n owing to the a v a i l a b i l i t y o f the r e p l a c e a b l e p r o ton on the methylcarbamyl n i t r o g e n atom. The proton may be replaced by a wide v a r i e t y o f groups to give reasonably s t a b l e products, as i n d i c a t e d by the general scheme below (7,8).

The number of groups represented by Y which give a c t i v e products i s very large and include the f o l l o w i n g (R, R*, e t c . = a l k y l or aryl).


PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

90 O S II Y = -CR ,

II -P(0R)

,

2

-SR ,

-SOR,

0 II S-NCOR

-SSR,

,

-SNR

Rl

-SNS0 R 2


R

-SNS0 NR 2

R

0 0 il I! -SNCOR R

,

1

,

2

R

S

0

0

il

H

H

-SNP(0R) R

0 Μ -SNS0 R

1

,

2

1

,

,

2

-SOR ,

2

2

,

OS M I! -SNP(OR)

1

R

-SSR

1

0 (Ι -SNS0 NR

1

Rl

R

2

1

Group Y must be of such a s t r u c t u r e to give a product with a moderately l a b i l e N-Y bond so that a c t i v a t i o n to the t o x i c methylcarbamate may occur r e a d i l y w i t h i n the t a r g e t organism. A number of p r o i n s e c t i c i d e s o f methylcarbamate e s t e r s have a t t a i n e d commercial importance or are c u r r e n t l y being developed f o r commercial use. The s t r u c t u r e s of some o f these are given below. 0 Il

0 II

carbosulfan

0 H ^C

0 if

CGA-73,102

k

-S ^ „ CH CH COOEt ι ι CH Pr-i N

2

2

3

ONCOL

CH

CH

3

3

C -N

N ^

Bu-t »

υ —\

• v * 0

CH S 3

U-56,299


91

Propesticides

6. FUKUTO

CH3 C

H

3

> = N -

0

CH3

- C - ^ S ^ - C - ° - N = C

CH3S

»

JJ

V

/

C

H

3

SCH

3


thiodicarb

Carbosulfan, CGA-73,102, and ONCOL are d e r i v a t i v e s of carbofuran (2,3-dihydro-2,2-dimethylbenzofuran-7-yl methylcarbamate) which have broad spectrum a c t i v i t y s i m i l a r to that o f carbofuran but are s u b s t a n t i a l l y less t o x i c to mammals, CGA-73,102 i s par t i c u l a r l y e f f e c t i v e as a s o i l i n s e c t i c i d e by both contact and systemic a c t i o n ( 9 ) . T h i o d i c a r b (10) and U-56,299 (11) are h i g h l y e f f e c t i v e lepidopterous l a r v i c i d e s but are less t o x i c to p l a n t s and mammals than methomyl. U-56,299, with a r a t acute o r a l L D 5 0 of 8000 mg/kg, i s very safe to mammals. An example of the profound e f f e c t which change i n p h y s i c a l property may have on the t o x i c o l o g i c a l p r o p e r t i e s o f a methylcar bamate i n s e c t i c i d e i s made apparent from t o x i c o l o g i c a l data f o r a s e r i e s of thiocarbamate d e r i v a t i v e s of carbofuran (Table 1) (12).

Table I.

T o x i c i t y of Thiocarbamate D e r i v a t i v e s o f Carbofuran to House F l i e s , Mosquito Larvae and Mice

0 ^

1 2 3 4 5 6 7 8 9 10 11 12

Rl

R

(carbofuran) Me Me Et Me Et Me i-Pr Me Pr Me Et Et Et i-Pr Bu Me Me C5HII C H Me Me C8H17 Me C H l 7

1 0

1 5

2

0

li

II

C

Ι

XI No.

0 S

"N^ ^N^ CH

R

3

C

_ 2.28 2.78 2.78 3.08 3.28 3.28 3.58 3.78 4.28 5.28 5.78 6.78

LD50,

ymol/g

0.030 0.027 0.025 0.025 0.024 0.025 0.025 0.031 0.026 0.027 0.026 0.027 0.030

"

R

1

Housefly log P

^ 0

Mosq. l a r v . L C , μΜ 5 0

Mice LD50,

0.235 0.068 0.045 0.045 0.024 0.045 0.027 0.015 0.011 0.0056 0.0024 0.0019 0.0026


ymoly

9 132 203 175 141 238 231 327 340 353 412 433 5.36



92

The compounds are arranged i n order of i n c r e a s i n g log Ρ values (P = octanol/water p a r t i t i o n c o e f f i c i e n t ) . Increase i n log Ρ values had l i t t l e e f f e c t on house f l y t o x i c i t y with a l l of the compounds showing equal t o x i c i t y although there was a broad range i n octanol/water p a r t i t i o n i n g p r o p e r t i e s . In c o n t r a s t , t o x i c i t y to mosquito larvae and the white mouse changed markedly with change i n log Ρ with mosquito larvae t o x i c i t y i n c r e a s i n g and mouse t o x i c i t y decreasing with increase i n log P. In the case of mosquito l a r v a e , t o x i c i t y of the carbofuran d e r i v a t i v e s increased to a maximum l e v e l when log Ρ was i n the range of 5-6 and then decreased. The r e l a t i o n s h i p between log Ρ and mosquito larvae t o x i c i t y f o r d e r i v a t i v e s of carbofuran, propoxur and m-isopropylphenyl methylcarbamate i s shown i n Figure 1.

Or

ο m

S

3 MIP

J2

3

4

5

Log Ρ

Figure 1. R e l a t i o n s h i p between the mosquito l a r v i c i d a l t o x i c i t y (log LC50) of the thiocarbamate d e r i v a t i v e s of carbofuran, pro poxur and m-isopropylphenyl methylcarbamate (MIP) and logarithm of the octanol/water p a r t i t i o n c o e f f i c i e n t ( l o g P ) .



6.

FUKUTO

93

Propesticides

The N - c h l o r o s u l f e n y l and N - c h l o r o s u l f i n y l d e r i v a t i v e s o f methylcarbamate e s t e r s are u s e f u l intermediates f o r the synthesis of a large v a r i e t y o f new d e r i v a t i v e s having favorable t o x i c o l o g i c a l p r o p e r t i e s (12,13,14). Examples of the types o f compounds which may be synthesized are i n d i c a t e d i n Figure 2. The N - c h l o r o s u l f e n y l and N - c h l o r o s u l f i n y l intermediates r e a c t with an array of n u c l e o p h i l e s i n the presence o f a proton acceptor, e.g. a l c o h o l s , t h i o l s , carbamates, sulfonamides and phosphoramidates, to give the r e s p e c t i v e d e r i v a t i v e s . The Iï-chlorosulfenyl i n t e r mediates a l s o r e a c t with amines to give s t a b l e products analogous to c a r b o s u l f a n and ONCOL. These intermediates provide the means to modify carbamate i n s e c t i c i d e s i n many d i f f e r e n t ways and the p o t e n t i a l f o r the design o f tailored-made compounds by a p p l i c a t i o n o f the r e a c t i o n s depicted i n Figure 2 i s enormous.

0 0 li !! , ROCN - S - NCOR CH

R

3

0 S Il H ROCN-S-NPÎOR )* ι S CH R

0

Λ

1

1

ROCN- S - OR

2

CH

1

2

3

3

\

1

1

R OH

0

R^CNHR

(R 0) PNHR

2

2

2

0 0 II II Same f o r ROCN — S - C I

0 I! ROCN - S - C I

I

CH

1

R S0 NHR

1

\

X

R SH

0

2

R R NS0 NHR

2

2

3

3

2

0

I!

ROCN - S-NSOoR ι I CH R 2

3

1

ROCN — S - SR ι CH 3

1

ROCN—S - NS0 NR*R

2

2

CH

3

13

Figure 2. Equations showing the r e a c t i o n between an N-chlorosul f e n y l -N-methylcarbamate intermediate (or corresponding N-chloro s u l f inyl-N-methylcarbamate) and d i f f e r e n t n u c l e o p h i l i c agents.

H y p o t h e t i c a l examples of the p o s s i b l e e x p l o i t a t i o n of t h i s kind of chemistry are given as f o l l o w s .



94


The usefulness of a downward-moving systemic i n s e c t i c i d e or nematicide i s obvious. It would be h i g h l y advantageous to c o n t r o l root-damaging i n s e c t s and nematodes by systemic a c t i o n , i . e . , by f o l i a r a p p l i c a t i o n of a p e s t i c i d e which w i l l move downward i n t o the r o o t s . While there have been reports of the downward movement of methylcarbamate p e s t i c i d e s i n p l a n t s f o l l o w i n g f o l i a r a p p l i c a t i o n (15,16), the extent of t h e i r downward movement has not been large enough f o r them to e f f e c t i v e l y c o n t r o l root p a r a s i t e s by systemic a c t i o n . It i s p o s s i b l e that these methylcarbamates, e.g. carbofuran, methomyl and oxamyl, a l l of which are potent i n s e c t i c i d e s and nematicides, r e q u i r e a s s i s t a n c e i n g e t t i n g i n t o the root zone i n e f f e c t i v e concentrations. There are a number of substances which are phloem mobile, i . e . , are downward moving. These include carbohydrates, amino a c i d s , organic acids and, i n general, compounds of high p o l a r i t y (17). These substances may act as a c a r r i e r group i n a s s i s t i n g an a c t i v e compound i n t o the root zone. We have r e c e n t l y demonstrated the f e a s i b i l i t y of using r e a c t i o n s described i n Figure 2 to attach a c a r r i e r group to a methylcarbamate e s t e r f o r t h i s purpose (18). A protected sugar, e.g., a d i i s o p r o p y l i d e n e f r u c t o s e or glucose, was reacted with the c h l o r o s u l f i n y l i n t e r mediate obtained from s e v e r a l methylcarbamate i n s e c t i c i d e s to give the r e s p e c t i v e s u l f i n y l - s u g a r d e r i v a t i v e s . A t y p i c a l example using the c h l o r o s u l f i n y l intermediate of oxamyl and 1,2,4,5-di-O-isopropylidene-a-D-fructose i s shown below.

The r a t i o n a l e for the synthesis of t h i s compound and l i k e i t i s made apparent from the equation below.


others

6.

FUKUTO

Propesticides

95

0

penetration

removal of

i n t o plant

isopropylidene

oxamyl — S — d i i s o p r o p y l i d e n e f r u c t o s e 0 I!

0 l!

(CH ) NC 3

2

c CH S Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on May 2, 2016 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch006

3

Ν CH

OH 3

HO OH

(phloem mobile)

P r o t e c t i o n o f fructose by the l a b i l e isopropylidene groups was considered necessary f o r two reasons, (1) i t f a c i l i t a t e s the s u l f i n y l a t i o n r e a c t i o n because o f the much higher s o l u b i l i t y of the protected sugar i n the organic r e a c t i o n medium and (2) d e r i v a t i z a t i o n with a l e s s polar protected sugar would give a d e r i v a t i v e which could penetrate the waxy c u t i c l e o f the plant l e a f . The r a t i o n a l e i s that the protected sugar d e r i v a t i v e s must f i r s t penetrate i n t o the p l a n t , and f o l l o w i n g p e n e t r a t i o n hydrol y t i c removal of the isopropylidene groups would generate the methylcarbamate c o n t a i n i n g the h i g h l y p o l a r deprotected sugar which would a s s i s t i n phloem m o b i l i t y . Because of the l a b i l i t y of the N-S bond the t o x i c methylcarbamate should e v e n t u a l l y be regenerated i n the roots or w i t h i n organisms feeding on the r o o t s . Owing to the u n a v a i l a b i l i t y o f an adequate bioassay, unfortunately these d e r i v a t i v e s were not tested f o r downward moving systemic a c t i v i t y . However, some o f them proved to be e f f e c t i v e against d i f f e r e n t i n s e c t s by contact a c t i o n . Further work along these l i n e s i s i n progress. The downward systemic movement o f ONCOL ( s t r u c t u r e given e a r l i e r ) , a new i n s e c t i c i d e derived from carbofuran, has been observed (19). A s i g n i f i c a n t amount o f r a d i o a c t i v i t y was observed i n the roots of cotton and bean plants t r e a t e d t o p i c a l l y at the base of b i f o l i a t e or t r i f o l i a t e d leaves with [carbamate carbonyl-^C]ONCOL. Downward movement o f the r a d i o l a b e l e d m a t e r i a l may be explained by h y d r o l y t i c degradation o f the ethoxycarbonyl moiety i n ONCOL to the c a r b o x y l i c a c i d d e r i v a t i v e , the a c i d f u n c t i o n serving as a downward moving c a r r i e r . The N - c h l o r o s u l f i n y l intermediates of i n s e c t i c i d a l methylcarbamate e s t e r s a l s o reacted with p o l y a l c o h o l s to form the polysulfinylmethylcarbamate d e r i v a t i v e s (18). For example, three moles o f the N - c h l o r o s u l f i n y l intermediate o f propoxur (2-isopropoxyphenyl methylcarbamate) and one mole g l y c e r o l r e s u l t e d i n a good y i e l d o f the t r i s ( o x y s u l f i n y l ) p r o p o x u r d e r i v a tive.



96

0 C H 2 O S - propoxur

propoxur - SOCH ι

Λ

?,


C H 2 O S - propoxur

This compound was e s s e n t i a l l y non-toxic to house f l i e s by t o p i c a l a p p l i c a t i o n but showed moderate a c t i v i t y against the green r i c e leafhopper and brown planthopper as a r e s i d u a l spray. These r e s u l t s r a i s e the p o s s i b i l i t y o f applying d e r i v a t i z a t i o n r e a c t i o n s f o r the synthesis o f polymeric i n s e c t i c i d a l m a t e r i a l s which may act as slow r e l e a s e agents. Formamidines 1

There i s evidence to i n d i c a t e that chlordimeform [N. - ( 4 - c h l o r o - o tolyl)-N,N-dimethylformamidine] r e q u i r e s metabolic a c t i v a t i o n to demethylchlordimeform (DCDM) and that i t i s DCDM which i s respon s i b l e f o r the b e h a v i o r a l and t o x i c o l o g i c a l p r o p e r t i e s o f c h l o r dimeform (20).

chlordimeform

demethylchlordimeform (DCDM)

Support for t h i s i s found i n the s u b s t a n t i a l l y greater octopaminomimetic a c t i v i t y o f DCDM compared t o chlordimeform (20) and the observation that mixed f u n c t i o n oxidase i n h i b i t o r s , e.g. p i p e r o n y l butoxide and sesamex, s t r o n g l y antagonized the t o x i c i t y of chlordimeform t o the southern c a t t l e t i c k larvae and synergized the t o x i c i t y o f DCDM (21). Therefore, chlordimeform may be considered to be a p r o p e s t i c i d e of DCDM. I n s e c t i c i d a l and a c a r i c i d a l formamidines such as DCDM possess a r e p l a c e a b l e hydrogen and therefore are s u i t a b l e f o r d e r i v a t i z a t i o n . DCDM and a number o f r e l a t e d formamidines have been converted to the corresponding j i - a r y l t h i o d e r i v a t i v e s and these have been examined f o r a c t i v i t y against eggs, larvae and adults of i n s e c t s and spider mites (22). In g e n e r a l , the N a r y l t h i o d e r i v a t i v e s r e t a i n e d the a c t i v i t y e x h i b i t e d by the parent formamidine and i n some cases were superior i n a c t i v i t y . For example, the two spotted spider mite L C 5 0 (ppm) of the phen y l t h i o d e r i v a t i v e of DCDM i s 6 compared to 12 f o r DCDM and 19


6.

FUKUTO

97

Propesticides


phenylthio d e r i v a t i v e

for chlordimeform (23). The phenylthio d e r i v a t i v e was a l s o superior to chlordimeform against c e r t a i n i n s e c t s , e.g. cabbage looper eggs and green peach aphid (22). Needless to say, i t would be i n t e r e s t i n g to apply the same type of chemistry described i n Figure 2 f o r the methylcarbamate e s t e r s to the synthesis o f d e r i v a t i v e s o f the formamidine i n s e c ticides. However, a d d i t i o n a l work with the formamidines, part i c u l a r l y those r e l a t e d to chlordimeform, has been discouraged because o f the mutagenic and c a r c i n o g e n i c p o t e n t i a l of the a r y l a mine metabolic products. Phosphoramidothioates As i n the case of the methylcarbamate e s t e r s , the organophosphorus i n s e c t i c i d e methamidophos (Ç),j5-dimethyl phosphoramidothioate) may be d e r i v a t i z e d by s u b s t i t u t i o n o f a hydrogen atom on the phosphoramido n i t r o g e n atom. An outstanding example o f the b e n e f i t from t h i s type of s u b s t i t u t i o n i s found i n acephate, the

CH S 3

CH 0 3

V

^0 NH

CH S 3

2

V

^0

CH 0

NHCCH

3

3

0 methamidophos

acephate

a c e t y l a t e d product o f methamidophos, which i s 4 5 - f o l d less t o x i c to the r a t than methamidophos while s t i l l r e t a i n i n g approximately the same i n s e c t i c i d a l a c t i v i t y (24). In i n s e c t s , acephate i s converted i n t o methamidophos which i s b e l i e v e d to be r e s p o n s i b l e for poisoning (25). The r e a c t i o n between a phosphoramidothioate and NchlorosuIfenylcarbamate d e s c r i b e d i n Figure 2 has been a p p l i e d to methamidophos. In Figure 2, the r e a c t i o n was used t o d e r i v a t i z e a t o x i c methylcarbamate e s t e r by a non-toxic phosphoramidothioate; however, i n the case of methamidophos the r e a c t i o n was used to d e r i v a t i z e a t o x i c phosphoramidothioate with a nont o x i c carbamate moiety. The N-alkoxycarbonyl-N -alkylaminos u l f e n y l d e r i v a t i v e s of methamidophos thus prepared, where R 1


98


0

CH S 3

χ

CH 0 3

.0

V

Ρ

+

χ

NH

2

» CISN'^OR ^1

Base

CH S 3

χ

0 „

^0

v

Ρ

χ

X

CH 0

S

X

Ν

3

Ν

H

R

OR 1


1

ranged from methyl to n-hexyl and R ranged from e t h y l to t b u t y l , a l l show good a c t i v i t y against house f l i e s along with a 2to 3 - f o l d r e d u c t i o n i n mouse t o x i c i t y (26). Attempts to react methamidophos with the corresponding chlorosulfinylcarbamate intermediate, however, r e s u l t e d i n pro ducts which were unstable and of no value as p r o i n s e c t i c i d e s . In general, phosphoramidothioates such as methamidophos are more d i f f i c u l t to d e r i v a t i z e than the methylcarbamate e s t e r s and therefore are l e s s u s e f u l as precursors to p r o i n s e c t i c i d e s . Nereistoxin N e r e i s t o x i n or 4-(N,N-dimethylamino)-l,2-dithiolane i s a n a t u r a l l y o c c u r r i n g substance found i n the marine annelid Lumbriconereis heteropoda Marenz (27). N e r e i s t o x i n causes para l y s i s of i n s e c t s by a g a n g l i o n i c b l o c k i n g a c t i o n on the c e n t r a l nervous system. Neurophysiological studies have shown that n e r e i s t o x i n suppresses the s e n s i t i v i t y of the n i c o t i n i c p o s t synaptic membrane to a c e t y l c h o l i n e . It i s categorized as a non d e p o l a r i z i n g neuromuscular b l o c k i n g agent (28). Cartap or JS,S/-[2-(dimethylamino)-l,3-propanediyl]dicarbamot h i o a t e i s a p r o i n s e c t i c i d e of n e r e i s t o x i n which was discovered by analog synthesis f o l l o w i n g e l u c i d a t i o n of the s t r u c t u r e of n e r e i s t o x i n (27). In i n s e c t s , cartap i s r a p i d l y converted i n t o n e r e i s t o x i n by breakdown, probably h y d r o l y t i c , of the t h i o c a r bamate moiety to e v e n t u a l l y give n e r e i s t o x i n (29). Nereistoxin e v i d e n t l y binds to the a c e t y l c h o l i n e receptor s i t e ( n i c o t i n i c r e c e p t o r ) and blocks the d e p o l a r i z i n g a c t i o n of a c e t y l c h o l i n e , probably i n a manner s i m i l a r to that proposed f o r n i c o t i n e . 0 II

CH2-S I

(CH ) N-CH 3

2

CH 2

S

/

CH SCNH 2

2

(CH ) N-CH 3

2

CH SCNH 2

2

0 nereistoxin

cartap

A v a r i e t y of d e r i v a t i v e s of 2-dimethylamino-l,2-propanedit h i o l have been synthesized and evaluated as p r o i n s e c t i c i d e s of n e r e i s t o x i n (29). The most prominent of these at present i s J>JJL'-f2-(dimethylamino)-l,3-propanediy1] b i s ( b e n z e n e t h i o s u l f o -


6. FUKUTO

Propesticides

99

nate) (TI-78 or bensultap) (30).

CH

Bensultap has shown e x c e l l e n t

/Η 880

Pesticide Synthesis Through Rational Approaches - American

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