Sulfur in Pesticide Action and Metabolism - ACS Publications

3 Sulfur in Propesticide Action 1

T. R. F U K U T O and M. A. H. FAHMY

Downloaded by UCSF LIB CKM RSCS MGMT on November 27, 2014 | http://pubs.acs.org Publication Date: June 11, 1981 | doi: 10.1021/bk-1981-0158.ch003

Division of Toxicology and Physiology, Department of Entomology, University of California, Riverside, CA 92521

It is well known that phosphorothionate insecticides such as parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate) and malathion [O,O-dimethyl S-(1,2-dicarbethoxy)ethyl phosphorodithioate] are intrinsically poor inhibitors of acetylcholinesterase and in vivo activation to the respective anticholinesterases paraoxon and malaoxon is required before animals exposed to the phosphorothionates are intoxicated. Since metabolic activation is essential to the biological activity of these thiono sulfur-containing organophosphorus insecticides, compounds of this type may be considered as propesticides or, more specifically, proinsecticides. The introduction of a thiono sulfur in an organophosphorus insecticide has advantages and disadvantages. From a favorable viewpoint, compared to phosphate esters, the phosphorothionates are generally more stable to hydrolysis and, therefore, may have greater insecticidal activity. Perhaps the most important contribution which a thiono sulfur atom may make is the "delay factor" provided by P=S to P=0 activation. This factor gives mammals the opportunity to detoxify the toxicant, and in many cases the phosphorothionate is substantially less toxic to warmblooded animals than the corresponding phosphate ester. A c l a s s i c a l example of the "delay f a c t o r " i s found i n the safe organophosphorus i n s e c t i c i d e malathion f o r which i t was demons t r a t e d over two decades ago that slow i n v i v o o x i d a t i o n to the a n t i c h o l i n e s t e r a s e malaoxon provided the opportunity f o r det o x i f y i n g enzymes i n mammals, most l i k e l y a carboxylesterase, to degrade malathion to nontoxic metabolic products (_1). The mouse LD50 of p u r i f i e d malathion i s 3 , 2 0 0 mg/kg C2), compared to 75 mg/kg f o r malaoxon (_1) . Among the d i f f e r e n t c l a s s e s of organic i n s e c t i c i d e s i n use today, the methylcarbamate e s t e r s rank at or near the top i n acute mammalian t o x i c i t y and i n many cases the methylcarbamates are as t o x i c to mammals as they are to i n s e c t s (_3) . For 1

Current address: FMC Corporation, Agricultural Chemical Division, P.O. Box 8, Princeton, N J 08540. 0097-6156/81/015 8-0035$05.00/0

© 1981 American Chemical Society In Sulfur in Pesticide Action and Metabolism; Rosen, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

SULFUR IN PESTICIDE ACTION AND METABOLISM

36

example, a l d i c a r b and carbofuran, with r a t o r a l LD50 values of 0.3-0.5 mg/kg and 11 mg/kg, r e s p e c t i v e l y , are among the most a c u t e l y t o x i c p e s t i c i d e s c u r r e n t l y being used. The p r i n c i p a l reason f o r the high t o x i c i t y of methylcarbamate i n s e c t i c i d e s to mammals as w e l l as i n s e c t s probably i s a t t r i b u t a b l e to the absence of a "delay f a c t o r " (such as that provided by the thiono s u l f u r i n phosphorothionate i n s e c t i c i d e s ) , i . e . , most methylcarbamate i n s e c t i c i d e s are d i r e c t i n h i b i t o r s of e i t h e r i n s e c t or mammalian a c e t y l c h o l i n e s t e r a s e .


Derivatized

Carbamates

During the past decade, a wide v a r i e t y of new d e r i v a t i v e s of t o x i c methylcarbamate i n s e c t i c i d e s w i t h improved p r o p e r t i e s of s e l e c t i v i t y have been discovered and s e v e r a l are c u r r e n t l y undergoing development as u s e f u l i n s e c t i c i d e s . The f i r s t group of compounds of t h i s type were the N-acylated methylcarbamate d e r i v a t i v e s (4,5) which were reported to be good i n s e c t i c i d e s but l e s s t o x i c to mammals. The N-acyl-N-methylcarbamate der i v a t i v e s also were appreciably l e s s e f f e c t i v e as a n t i c h o l i n esterases, leading to the conclusion that the o r i g i n a l methylcarbamate was r e s p o n s i b l e f o r i n t o x i c a t i o n i n the i n s e c t a f t e r i n v i v o formation from the N-acyl d e r i v a t i v e (6). In mice, however, d e t o x i f i c a t i o n to nontoxic p h e n o l i c products occurred and t h i s accounted f o r t h e i r low t o x i c i t y to mammals. One of the N-acyl d e r i v a t i v e s , 3-isopropyl-5-methylphenyl N-butyryl-Nmethy1carbamate (promacyl) i s reported to be h i g h l y e f f e c t i v e against s u s c e p t i b l e and r e s i s t a n t s t r a i n s of c a t t l e t i c k s , Boophilus microplus ( 7 ) . The b a s i s f o r the s e l e c t i v e t o x i c i t y of malathion provided the r a t i o n a l e f o r the design of the N-dimethoxyphosphinothioyl d e r i v a t i v e s of methylcarbamates e s t e r s as s e l e c t i v e l y t o x i c i n s e c t i c i d e s (general s t r u c t u r e below). CH

3

By analogy with malathion, d e r i v a t i v e s of t h i s type were expected to be m e t a b o l i c a l l y degraded to nontoxic products i n mammals by carboxylesterase a c t i o n but to the parent methylcarbamate i n i n s e c t s by phosphatase a c t i o n (8). Thus, these d e r i v a t i v e s were expected and found to be t o x i c to i n s e c t s and safe to mammals. Subsequent i n v e s t i g a t i o n s on the comparative metabolism of the N-dimethoxyphosphinothioyl d e r i v a t i v e of carbofuran i n i n s e c t s and rodents provided d i r e c t support f o r the r a t i o n a l e used i n the design of these d e r i v a t i v e s ( 9 ) .

In Sulfur in Pesticide Action and Metabolism; Rosen, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

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FUKUTO AND FAHMY

37

Sulfur in Propesticide Action


A r y l - and A l k y l s u l f e n y l Methylcarbamates The favorable order of s e l e c t i v i t y achieved by the dimethoxyphosphinothioyl d e r i v a t i v e s prompted the examination of other f u n c t i o n a l groups f o r i n t r o d u c t i o n of the "delay f a c t o r " i n methylcarbamate i n s e c t i c i d e s . Of the various groups examined, those leading to d e r i v a t i v e s which contain an N-S linkage have generated the l a r g e s t number of new compounds with improved p r o p e r t i e s of s e l e c t i v i t y . These s u l f u r - c o n t a i n i n g d e r i v a t i v e s may be considered to be carbamate p r o i n s e c t i c i d e s . The f i r s t p r o i n s e c t i c i d e s of t h i s type were the N - a r y l s u l f e n y l and N - a l k y l s u l f e n y l d e r i v a t i v e s of t o x i c methylcarbamate i n s e c t i c i d e s (10,11). These compounds proved to be h i g h l y t o x i c to house f l i e s and mosquito l a r v a e and were much l e s s t o x i c to mice than the parent methylcarbamate e s t e r . Typical toxicological data f o r these compounds are presented i n Table I (11). TABLE I T o x i c o l o g i c a l P r o p e r t i e s of N - A r y l s u l f e n y l and N - A l k y l s u l f e n y l D e r i v a t i v e s of I n s e c t i c i d a l Methylcarbamates

No.

Housefly LDso, yg/g

R

Culex fatigans L C S Q , ppm 0

Mouse (oral) mg/kg

II

2,2-Dimethyl-2,3-dihydrobenzofuranyl-7-OCN(CH^)-R 1 2 3 4 5 6 7 8 9

H (carbofuran) Phenyl-S 4-Tolyl-S 3-Tolyl-S 2-Tolyl-S 2,4-Xylyl-S 4-_t-Butylphenyl-S 2-Me-4-t-Butylphenyl-S MeS

6.7 9.3 9.0 6.5 3.7 9*0 2.7 7.5 4.9

0.052 0.0045 0.0045 0.004 0.004 0.003 0.0025 0.002 0.024

2 25-50 100-125 25-50 100-125 50-100 75 75-125 20

0.33 0.039 0.028 0.020 0.024 0.014 0.013 0.014 0.105

24 300 350-400 300-400 400 400 750-1000 >850 300-400

0 I!

2-Isopropoxypheny1-0CN(CHJ-R 10 11 12 13 14 15 16 17 18

H (propoxur) Phenyl-S 4-Tolyl-S 3-Tolyl-S 2-Tolyl-S 2,4-Xylyl-S 4-t-Butylphenyl-S 2-Me-4-t-Butylphenyl-S MeS

24.0 36.0 36.0 23.5 24.0 27.5 9.0 24.5 65.0


38

SULFUR IN PESTICIDE ACTION AND METABOLISM TABLE I (0011't)

ÎÎ2J

*

Housefly LDsn yg/g 0 il CH SC(CH ) CH=NOCN(CH )-R


3

19 20 21

H (aldicarb) 2-Tolyl-S 4-t-Butylphenyl-S

3

2

Culex fatigans LCsn, ppm

Mouse (oral) mg/kg

3

5.5 12.5 7.5

0.16 0.084 0.014

0.3-0.5 3-5 10

According to the data, the s u l f e n y l a t e d d e r i v a t i v e s were q u i t e e f f e c t i v e i n s e c t i c i d e s and i n many cases were more t o x i c to house f l i e s and mosquito l a r v a e than the parent methylcarbamates. In c o n t r a s t , the d e r i v a t i v e s were without exception l e s s t o x i c to mice. The a r y l s u l f e n y l a t e d methylcarbamates g e n e r a l l y were h i g h l y e f f e c t i v e against mosquito l a r v a e . This i s probably a t t r i b u t a b l e to t h e i r greater l i p o p h i l i c p r o p e r t i e s , i . e . , compared to the parent methylcarbamate the d e r i v a t i v e s are able to p a r t i t i o n more r a p i d l y out of the aqueous h a b i t a t of the mosquito l a r v a e i n t o the hydrophobic e p i c u t i c u l a r wax l a y e r of the l a r v a e . In t h i s regard, i n f i e l d and l a b o r a t o r y t e s t s , the N - p h e n y l s u l f e n y l d e r i v a t i v e of 3-sec-butylphenyl methylcarbamate was reported to be outstanding i n c o n t r o l l i n g l a r v a e and adults of s u s c e p t i b l e and organophosp h a t e - r e s i s t a n t s t r a i n s of mosquitoes (10). The r e s u l t s of a comparative metabolism study of an a r y l s u l f e n y l d e r i v a t i v e of carbofuran [2,2-dimethyl-2,3-dihydrobenzofuranyl-7 N-methyl-N-(2-toluenesulfenyl)carbamate] i n the house f l y and white mouse i n d i c a t e d the s e l e c t i v e a c t i o n of t h i s compound to be a consequence of d i f f e r e n t metabolic pathways i n i n s e c t s and mammals (12). The a r y l s u l f e n y l group on the carbamate moiety allows the mammal to carry out metabolic r e a c t i o n s l e a d i n g to l e s s t o x i c products which are r a p i d l y conjugated, while the t o x i c parent methylcarbamate i s formed i n the i n s e c t . A r y l s u l f e n y l a t e d methylcarbamates a l s o may have other i n t e r e s t i n g types of s e l e c t i v i t y . An example i s given i n the honey bee and house f l y t o x i c i t y data i n Table I I f o r s e v e r a l d e r i v a t i v e s of propoxur (13). Propoxur and most of the d e r i v a t i v e s were h i g h l y t o x i c to the honey bee; i n f a c t , compounds 10-15 were s u b s t a n t i a l l y more t o x i c to the honey bee than to the house f l y (also see Table I ) . The order of t o x i c i t y , however, was reversed with the 4-jt-butylphenyl analog (16) and the 2-methyl-4-t-butylphenyl analog (17) was v i r t u a l l y nontoxic to the honey bee, although i t was s t i l l e f f e c t i v e against the house f l y .


FUKUTO AND FAHMY

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39


TABLE II T o x i c i t y of N - A r y l s u l f e n y l D e r i v a t i v e s of Propoxur to the Honey Bee and House F l y


0 Κ 2-Isopropoxyphenyl-OCN-SR

No. 10 11 14 15 16 17

R (Propoxur) Phenyl 2-Tolyl 2,4-Xylyl 4-t-Butylphenyl 2-Me-4-t-Butylphenyl

Honey Bee LD (yg/g) 5 0

4.48 6.4 10.0 16.8 36.0 >800.0

House F l y LD (yg/g) 5 0

24.0 36.0 24.0 27.5 9.0 24.5

Examination of the p e n e t r a t i o n and metabolism of 17 i n the house f l y and honey bee showed that i t penetrated i n t o the honey bee at a much slower r a t e than i n t o the house f l y (14). Further, owing to the combined a c t i o n of slow conversion r a t e of 17 to propoxur and r a p i d r a t e of degradation of propoxur to nontoxic products, the amount of propoxur i n the honey bee r e mained at a low, n o n - i n t o x i c a t i n g , steady-state l e v e l . A number of reports d e s c r i b i n g a wide v a r i e t y of Na r y l s u l f e n y l and N - a l k y l s u l f e n y l d e r i v a t i v e s of d i f f e r e n t types of methylcarbamate i n s e c t i c i d e s have been d i s c l o s e d i n the patent l i t e r a t u r e (15,16,17,18,19). Two of these reports (18,19) describe t r i c h l o r o m e t h y l - or t r i f l u o r o m e t h y l s u l f e n y l d e r i v a t i v e s of the h i g h l y t o x i c methylcarbamates carbofuran and aldicarb. f

Ν,Ν -Thiodicarbamates The discovery of the improved t o x i c o l o g i c a l p r o p e r t i e s of the a r y l - and a l k y l s u l f e n y l d e r i v a t i v e s of methylcarbamate i n s e c t i c i d e s stimulated examination of other types of d e r i v a t i v e s containing an N-S l i n k a g e . In most of the cases where highest i n s e c t i c i d a l a c t i v i t y i s found, the methylcarbamate n i t r o g e n i s attached to a s u l f u r atom which i s attached to another n i t r o g e n atom, as shown i n the general s t r u c t u r e below.



40

Rl i s g e n e r a l l y an a l k y l group and R2 may be a l k y l , alkoxycarbonyl, a r y l o x y c a r b o n y l , d i a l k o x y p h o s p h i n o t h i o y l , a l k y l s u l f o n y l , a r y l s u l f o n y l , d i a l k y l a m i n o s u l f o n y l or ( a l k y l ) ( a r y l ) aminos ulfony1. The f i r s t methylcarbamate d e r i v a t i v e c o n t a i n i n g an N-S-N l i n k a g e was reported by Brown (20) who described compounds of the type below, where Ar i s 2-isopropoxyphenyl, 3-isopropylphenyl, 3-s-butylphenyl, 1-naphthyl, e t c . These were reported to be


0 Il

0 H

C

S

C

ArO^ ^N^ ^N-^ ^OAr I I CH CH 3

3

e f f e c t i v e i n t e s t s against a v a r i e t y of i n s e c t s . They were pre pared by r e a c t i o n between two moles of the methylcarbamate and one mole of s u l f u r d i c h l o r i d e i n the presence of a base. N,N -Thiobiscarbamates a l s o may be prepared by the r e a c t i o n between a methylcarbamate e s t e r and s u l f u r monochloride (21). For example, r e a c t i o n between two moles of carbofuran and one mole of s u l f u r monochloride i n the presence of p y r i d i n e gave Ν,Ν -thiobiscarbofuran i n s t e a d of the corresponding d i s u l f i d e . f

1

0 II

0 II

?

N,N -thiobiscarbofuran This compound was much l e s s t o x i c to the white mouse but compar able to carbofuran i n i n s e c t i c i d a l a c t i v i t y . Toxicological p r o p e r t i e s f o r some of these compounds are presented i n Table III. I t i s apparent from the data that the thiobiscarbamates TABLE I I I T o x i c o l o g i c a l P r o p e r t i e s of I n s e c t i c i d a l Methylcarbamates and the Corresponding Ν,Ν'-Thiobiscarbamates House f l y Compound

No.

LD50 (yg/g)

Culex fatigans LD.sn (ppm)

Mouse o r a l

11 50-100

LD50

(mg/kg)

1 22

Carbofuran N,N -Thiobiscarbofuran

6.7 19

0.052 0.007

10 23

Propoxur Ν,N -Thiobispropoxur

22 35

0.33 0.041

24 700

19 24

Aldicarb N,N -Thiobisaldicarb

5.5 8.5

0.16 0.17

0.3-0.5 1.6-2.5

f

1

f


FUKUTO AND FAHMY

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41


r e t a i n e d much of the i n s e c t i c i d a l a c t i v i t y e x h i b i t e d by the parent methylcarbamates but were 5- to 2 9 - f o l d l e s s t o x i c to the white mouse. The improved systemic i n s e c t i c i d a l a c t i v i t y of N , N - t h i o b i s a l d i c a r b (24) was of i n t e r e s t s i n c e t h i s compound gave more than a month longer c o n t r o l of c o t t o n aphids and p e r f o r a t o r than a l d i c a r b i n a l a b o r a t o r y systemic t e s t with cotton p l a n t s . One of the symmetrical N,N -thiobiscarbamates, N,N thiobismethorny1 or LARVIN, i s c u r r e n t l y under development as a new, broad spectrum i n s e c t i c i d e (22,23). This compound was f


f

CH 3

C=N

C

CH S

3

CH

S

0

3

f

3

C 0

N=C S C H

3

LARVIN p a r t i c u l a r l y e f f e c t i v e i n l a b o r a t o r y and f i e l d t e s t s f o r c o n t r o l of lepidopterous l a r v a e which i n f e s t a wide v a r i e t y of crops. Further, with a reported r a t o r a l LD50 of 160 mg/kg, LARVIN i s s i g n i f i c a n t l y l e s s a c u t e l y t o x i c to mammals than methorny1 ( r a t oral L D 17-24 mg/kg). High i n s e c t i c i d a l a c t i v i t y i s not r e s t r i c t e d to symmetri c a l l y s u b s t i t u t e d N,N -thiodicarbamates and subsequent work revealed a number of unsymmetrical thiodicarbamates with e x c e l l e n t i n s e c t i c i d a l a c t i v i t i e s (24,25,26). In these cases, only one of the two carbamate m o i e t i e s i s represented by an i n s e c t i c i d a l methylcarbamate. Table IV provides t y p i c a l t o x i c o l o g i c a l data f o r some of these d e r i v a t i v e s (24). 5 0

f

TABLE IV T o x i c o l o g i c a l P r o p e r t i e s of Ν,Ν'-Thiodicarbamates

N o

>

R

Rj

House f l y LD.sn» yg/g

Culex p i p i e n s L C , ppm

Mouse o r a l LPs η » mg/kg

S 0

0

0

il

II

2,2-Dimethyl-2,3-dihydrobenzofuranyl-7-OC-N-S-N-C-OR CH 1 25 26 27 28

(carbofuran) CH C H CH C H -n CH C H i-n C H C H 3

2

2

3

5

3

1 0

5

2

5

n

2

5

6.7 9.0 10.5 14.0 9.25

0.052 0.016 0.0022 0.0012 0.010

3

1

R 11 72 140 250 85


42

SULFUR IN PESTICIDE ACTION AND METABOLISM TABLE IV (con't)

N o

-

House f l y Culex p i p i e n s LDso> yg/g LCso, ppm 0 0 M II 2-Isopropoxyphenyl-0C-N-S-N-C-0R

R

Rj

Mouse o r a l L D Q , mg/kg 5

1


CH 10 29 30 31

(propoxur) CH 0 Η -η CH C H -n C H C H 3

5

3

1 0

2

5

2

24 35 44 37.5

η

2 1

5

3

R 0.33 0.008 0.009 0.046

62 >1000 >1000 >1000

CH 0 0 ι 3 M H CH S-C-CH=N-OC-N-S-N-C-OR 3 ι I ι 1 CH CH R Q

Q

1

3

19 32

(aldicarb) CH C H -n 3

1 0

3

5.5 13

2 1

CH

Q

0.16 0.0064

0

0.4 12.5

0

CH S-C=N-0C-N-S-N-C-0R3 I I 1 CH R o

3

33 34 35

(me thorny 1) CH C H C H C H -n 3

2

5

2

5

6

1 3

3.7 7.3 7.5

0.64 0.70 0.08

CH.S 0 0 31 I! M (CHJ NC-C=N0C-N-S-N-C-0R l i I » CH R o

3

2

10 310 600

1 1

3

36 37 38 -Rat

(oxamyl) CH C H C H C H -n 3

2

L D

5

5

0

2

5

6

1 3

3.6 3.7 6.0

0.33 0.41 0.19

5^ 10 12

.

As i n the case of the examples given i n Tables I and I I I , the N-thiocarbamate d e r i v a t i v e s were g e n e r a l l y equal to the parent methylcarbamate i n t o x i c i t y to house f l i e s , p a r t i c u l a r l y a f t e r taking i n t o c o n s i d e r a t i o n increase i n molecular weights. Except f o r the methomyl and oxamyl d e r i v a t i v e s , s u b s t a n t i a l improvement i n mosquito l a r v i c i d a l a c t i v i t y again appeared to be a f u n c t i o n of the l i p o p h i l i c p r o p e r t i e s of the d e r i v a t i v e . With the exception of the oxamyl d e r i v a t i v e s , the data c l e a r l y i n d i cate that the N-thiocarbamate d e r i v a t i v e s are markedly l e s s t o x i c to the white mouse than the parent methylcarbamate. Since


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43

Sulfur in Propeslicide Action

methorny1 and oxamyl are somewhat s i m i l a r i n s t r u c t u r e and i n p h y s i c a l p r o p e r t i e s , the reason f o r the high mammalian t o x i c i t y of the oxamyl d e r i v a t i v e s i s not c l e a r . On an o v e r a l l b a s i s , mouse t o x i c i t y was d i r e c t l y r e l a t e d to the hydrophobic p r o p e r t i e s of the d e r i v a t i v e , i . e . , d e r i v a t i v e s with l a r g e r l o g 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 ) were l e s s t o x i c to the white mouse.


Sulfonamidothio- and

Phosphinoaminothiomethylcarbamates

A number of other d e r i v a t i v e s a l s o containing the N-S-N linkage have r e c e n t l y been reported i n the patent l i t e r a t u r e . These are compounds where R i n the general s t r u c t u r e (I) i s dialkoxyphosphinothioyl (26), a l k y l s u l f o n y l , a r y l s u l f o n y l , d i a l k y l a m i n o s u l f o n y l or ( a l k y l ) ( a r y l ) a m i n o s u l f o n y l (27). In the case of the s u l f o n y l compounds, d e r i v a t i v e s were prepared of v i r t u a l l y a l l of the commercially important methylcarbamate insec t i c i d e s and many of these d e r i v a t i v e s were reported to be h i g h l y e f f e c t i v e against a v a r i e t y of i n s e c t s which a f f e c t a g r i c u l t u r a l crops and p u b l i c h e a l t h . T y p i c a l s t r u c t u r e s f o r these compounds are exemplified below by d e r i v a t i v e s of carbofuran. 0 0 2

S

0^-N- -N-

ο

CH

3

S 0

0-^N- -N- V S

2-@

i H -n 3

CH

7

S

N ( C H

}

3 2

3

Of the dialkoxyphosphinothioyl d e r i v a t i v e s (26), Upjohn experimental i n s e c t i c i d e U-47,319, a d e r i v a t i v e of methomyl, has shown promise against l a r v a e and ova of lepidopterous i n s e c t s . I t s acute r a t o r a l LD50 of 278 mg/kg i s a s i g n i f i c a n t improvement CH

3

C H -i 3

y

CH 3

^C=N-°-C-^S-^-pI ϋ CH 3 0 S

(

O

C

H

)

2 5 2

U-47,319 over the LD50 of 17-24

mg/kg f o r methomyl.

Dialkylaminosulfenylmethylcarbamates Compounds with improved p r o p e r t i e s of s e l e c t i v i t y may a l s o be obtained with d e r i v a t i v e s where R i n the general s t r u c t u r e (I) i s a l k y l (28,29), exemplified below with carbofuran where R and Ri are a l k y l , c y c l o a l k y l or p a r t of a r i n g system. 0 2



44

R and Rj may be the same or d i f f e r e n t and the compound where R = Ri = η-butyl (trade name: MARSHAL) i s c u r r e n t l y undergoing development as a new i n s e c t i c i d e . I t s acute r a t o r a l LD50 ^ 209 mg/kg and i t may be used by e i t h e r s o i l or f o l i a r a p p l i c a t i o n . In c o n t r a s t , carbofuran with a r a t LD50 °f H mg/kg, i s r e l a t i v e l y t o x i c to mammals and i t has been used mainly as a s o i l insecticide. A number of aminosulfenyl d e r i v a t i v e s of methomyl have been examined f o r i n s e c t i c i d a l a c t i v i t y (30). In general, the d e r i v a t i v e s were s i m i l a r to methomyl i n t h e i r a c t i v i t i e s against a number of a g r i c u l t u r a l l y important i n s e c t s . One of these compounds, U-46,855 showed greater f o l i a r r e s i d u a l l i f e , l e s s


s

0

U-46,885 p h y t o t o x i c i t y and lower mammalian t o x i c i t y (acute r a t o r a l LD50 105 mg/kg) than methomyl. In f i e l d t r i a l s f o r the c o n t r o l of the cotton bollworm, use of U-46,855 r e s u l t e d i n s i g n i f i c a n t l y higher cotton y i e l d s compared to methomyl. A r y l t h i o - and

Alkylthiosulfenylmethylcarbamates

A number of methylcarbamate d e r i v a t i v e s containing the N-S-S linkage a l s o have been d i s c l o s e d r e c e n t l y i n the patent l i t e r a t u r e as s e l e c t i v e l y t o x i c i n s e c t i c i d e s (31,32). T y p i c a l examples of these compounds are given as f o l l o w s :

C=N

X

C

S — S-C(CHJ II 0

3

In v i r t u a l l y a l l examples given, the d e r i v a t i v e s were described as being lower i n mammalian t o x i c i t y compared to the parent methylcarbamate but g e n e r a l l y of equal i n s e c t i c i d a l activity. N-Sulfinylmethylcarbamates The s u l f u r d e r i v a t i v e s of methylcarbamate i n s e c t i c i d e s which have been described are those containing a s u l f e n y l (or thio) s u l f u r attached to the methylcarbamate n i t r o g e n atom. N - A l k y l s u l f i n y l or N - a r y l s u l f i n y l d e r i v a t i v e s (general s t r u c t u r e


3.

FUKUTO AND FAHMY

45


below) of i n s e c t i c i d a l methylcarbamates a l s o have been as u s e f u l i n s e c t i c i d e s (33). 0 II ^ C


0

N

N

0 II ^ S ^

reported

R = a l k y l , a r y l , or a r a l k y l

R

These d e r i v a t i v e s were described as having strong i n s e c t i c i d a l , a c a r i c i d a l , and nematocidal a c t i v i t y , along with low mammalian toxicity. More r e c e n t l y , an i n t e r e s t i n g r e a c t i o n was discovered which provides the means f o r the synthesis of a wide v a r i e t y of methylcarbamate d e r i v a t i v e s containing the N - s u l f i n y l [ N - S ( O ) ] moiety (34). In attempting to prepare isopropoxy-N-methyliminoyl c h l o r i d e by the r e a c t i o n between i s o p r o p y l methylcarbamate and t h i o n y l c h l o r i d e , an unexpected product, i s o p r o p y l N - c h l o r o s u l f i n y l - N - m e t h y l c a r b a m a t e was obtained according to the equa t i o n below. The same product a l s o was obtained when the

i-PrO

X

NHCH

+

+

0

soci

b U L 1

r e f l u x

2

>

i-PrO

Ν

Cl CH

3

r e a c t i o n was c a r r i e d out i n the presence of a proton acceptor such as p y r i d i n e . Further, the r e a c t i o n occurred with i n s e c t i c i d a l methylcarbamate esters of s u b s t i t u t e d phenols and oximes. The N-chlorosulfinyl-N-methylcarbamate intermediates reacted with d i f f e r e n t n u c l e o p h i l e s (Y) i n the presence of a proton acceptor to give a v a r i e t y of N - s u l f i n y l d e r i v a t i v e s as shown below where HY may be an a l c o h o l , phenol, a l k a n e t h i o l , 0 II

0 II

C

S

R0^ ^N^ ^C1

I

CH

3

0 II +

H-Y

>

0 II

C

S

R0^ ^N^ ^Y

I

CH

+

BH

+

3

a r e n e t h i o l , N-alkylcarbamate, a l k y l - o r arylsulfonamide, and sulfondiamide. T o x i c o l o g i c a l p r o p e r t i e s are given i n Table V f o r examples of each of the d i f f e r e n t types of d e r i v a t i v e s using carbofuran as the parent methylcarbamate.



46

TABLE V


T o x i c o l o g i c a l P r o p e r t i e s of the N - S u l f i n y l D e r i v a t i v e s of Carbofuran

House f l y LD50 (yg/g)

No. 1 39 40 41 42 43 11

45 46 ll

(carbofuran) -0C H -n -0-phenyl -S-Ci+Hg-t -S-phenyl . -carbofuran— -N(CH )C(0)OC H -n -N(C H )S(0) CH -N(CH )S(0) -phenyl -N(CH ) S(0)N-(Bu-n) 6

13

3

2

7

5

2

3

3

15

3

2

2

2

6.7 13 6.4 9 7 20 13.5 12.5 9.5 12

Culex pipiens LC50 (ppm)

Mouse o r a l (mg/kg)

0.052 0.0025 0.0055 0.01 0.05

0.015

—

11 280 42 70 40 165 150 75 35 25

— Attached at the carbamate n i t r o g e n atom of carbofuran. Most of the N - s u l f i n y l d e r i v a t i v e s i n the t a b l e show good i n s e c t i c i d a l a c t i v i t y along with a s i g n i f i c a n t r e d u c t i o n i n mouse t o x i c i t y (2- to 25-fold r e d u c t i o n ) . The number of new d e r i v a t i v e s with improved t o x i c o l o g i c a l p r o p e r t i e s which can be synthesized through the N - c h l o r o s u l f i n y l intermediates i s exceedingly l a r g e . (Alkoxycarbonyl)(alkylamino)sulfenylphosphoramidothioates The phosphoramidothioate i n s e c t i c i d e methamidophos (0,jSdimethyl phosphoroamidothioate) i s s i m i l a r to the methylcarbamates i n that i t a l s o contains a r e p l a c e a b l e hydrogen on a n i t r o g e n atom and, t h e r e f o r e , may be d e r i v a t i z e d i n an analogous manner. In f a c t , the N-acetylated product of methamidophos i s acephate (0,S-dimethyl N-acetylphosphoramidothioate), a compound which r e t a i n s the outstanding i n s e c t i c i d a l a c t i v i t y of methamidophos but i s approximately 45-fold l e s s t o x i c to the r a t (acute r a t o r a l L D Q of 900 mg/kg compared to 20 mg/kg f o r methamidophos) (35). With t h i s i n mind, a number of ( a l k o x y c a r b o n y l ) ( a l k y l a m i n o ) - s u l f e n y l d e r i v a t i v e s of methamidophos were prepared and examined f o r t o x i c o l o g i c a l p r o p e r t i e s (36). These compounds 5


FUKUTO AND FAHMY

3.

47


were r e a d i l y prepared by the r e a c t i o n between the N-chloro s u l f enyl-N-alkylcarbamate (24,37) and methamidophos i n the presence of p y r i d i n e as shown below. 0 II

CH,S. .0

C.

_

CH.S

...

N

M

,0

X Ν , xΝ / \ OR CH 0 S

VV

CH3O' NH Downloaded by UCSF LIB CKM RSCS MGMT on November 27, 2014 | http://pubs.acs.org Publication Date: June 11, 1981 | doi: 10.1021/bk-1981-0158.ch003

3

CISN' I

+

2

OR'

P

?

R

I

D

I

N

E

>

1

o

3

ι H

! R

Housefly and mouse t o x i c i t i e s of some of these compounds are presented i n Table VI. A l l of the d e r i v a t i v e s were h i g h l y t o x i c

TABLE VI T o x i c i t y of 0,^-Dimethyl Ν-(N -Alkoxycarbony1-N -Alkylaminosulfenyl)phosphoramidothioates to House F l i e s and Mice 1

1

0

CH S.

1;

Q

s

P.

CH 0

Ν ; H

3

No.

R

R

48 (methamidophos) 11 C H 50 C H 51 C H -n 52 C H -i 53 C H -i 2

2

54

5

5

3

7

3

7

3

7

(\H9-t

Ν' ι R

3

0

2

T

House f l y L D , yg/g

Mouse o r a l L D , rog/ 8

1.3 2.8 3.8 1.9 1.9 2.5 1.6

14 30 34 36 50 50 50

5 0

T

CH C H C H C H C H C H 3

0R

-n -n

13

7

5

3

7

3

7

-n -n

k

5 0

to house f l i e s with r e l a t i v e l y l i t t l e d i f f e r e n c e i n t o x i c i t i e s . Although the improvement i n mouse t o x i c i t y was not as l a r g e as with most of the methylcarbamate d e r i v a t i v e s , i n a l l cases the d e r i v a t i v e was l e s s t o x i c than methamidophos. The p o s s i b i l i t y remains f o r greater improvement i n s e l e c t i v i t y with other de r i v a t i v e s of t h i s type.

American Chemical Society Library 1155 16th St. N. W. In Sulfur in Pesticide Action and Rosen, J., et al.; Washington, D.Metabolism; C. 20036 ACS Symposium Series; American Chemical Society: Washington, DC, 1981.


48


Summary The foregoing d i s c u s s i o n has provided examples of the s u c c e s s f u l d e r i v a t i z a t i o n of methylcarbamate and phosphoramidothioate i n s e c t i c i d e s with d i f f e r e n t f u n c t i o n a l groups to give a v a r i e t y of s u l f u r p r o p e s t i c i d e s . In most cases, notable improvement i n mammalian t o x i c i t y was achieved along with the r e t e n t i o n of i n s e c t i c i d a l a c t i v i t y . The favorable t o x i c o l o g i c a l p r o p e r t i e s of the d e r i v a t i v e s may be a t t r i b u t e d to a combination o f : (1) the "delay f a c t o r " provided by the f u n c t i o n a l group, (2) d i f f e r e n c e s i n metabolic pathways between d i f f e r e n t animals and (3) d i f f e r e n c e s i n the p h y s i c a l p r o p e r t i e s of the d e r i v a t i v e s . The examples given i n t h i s review represent but a s m a l l f r a c t i o n of the m o d i f i c a t i o n s which may be made with t o x i c methylcarbamate i n s e c t i c i d e s . Further work along these l i n e s i s warranted, p a r t i c u l a r l y with those methylcarbamate i n s e c t i c i d e s having the highest order of i n s e c t i c i d a l a c t i v i t y , r e g a r d l e s s of t h e i r mammalian t o x i c i t y . Needless to say, t h i s type of approach i s not r e s t r i c t e d only to i n s e c t i c i d e s but may be a p p l i e d to other p e s t i c i d e s , e.g. h e r b i c i d e s and f u n g i c i d e s which c o n t a i n the appropriate groups f o r d e r i v a t i z a t i o n .

Literature Cited

1. Kreuger, H.R.; O'Brien, R.D. J. Εcon. Entomol. 1959, 52, 1063. 2. Umetsu, N.; Grose, H.F.; Allahyari, R.; Abu-El-Haj, S.; Fukuto, T.R. J. Agr. Food Chem., 1977, 25, 946. 3. Brooks, G.T., in "The Future for Insecticides," ed. by Metcalf, R.L., McKelvey, J.J., Jr., Wiley-Interscience, New York, 1976, pp. 97-143. 4. Fraser, J . ; Clinch, P.J.; Ray, R.C. J. Sci. Food Agr., 1965, 14, 615. 5. Fahmy, M.A.H.; Metcalf, R.L.; Fukuto, T.R.; Hennessy, D.J., J. Agr. Food Chem., 1966, 14, 79. 6. Miskus, R.P.; Andrews, T.L.; Look, M.L. J. Agr. Food Chem., 1969, 17, 842. 7. Gunew, D.S., in "Analytical Methods for Pesticide and Plant Growth Regulators, ed. by Zweig, G; Sharma, J . , Academic Press, New York, 1976, p. 207. 8. Fahmy, M.A.H.; Fukuto, T.R.; Myers, R.O.; March, R.B. J. Agr. Food Chem., 1970, 18, 793. 9. Krieger, R.I.; Lee, P.W.; Fahmy, M.A.H.; Chen, M.; Fukuto, T.R. Pestic. Biochem. Physiol., 1976, 6, 1. 10. Schaeffer, C.H.; Wilder, W.H. J. Εcon. Entomol., 1970, 63, 480. 11. Black, A.L., Chiu, Y.C.; Fahmy, M.A.H.; Fukuto, T.R. J. Agr. Food Chem., 1973, 21, 747.



3.

FUKUTO AND FAHMY


49

12. Black, A.L.; Chiu, Y.C.; Fukuto, T.R.; Miller, T.A. Pestic. Biochem. Physiol., 1973, 3, 435. 13. Mallipudi, N.M.; Fukuto, T.R. J. Agr. Food Chem., 1979, 27, 261. 14. Mallipudi, N.M.; Fukuto, T.R. Pestic. Biochem. Physiol., 1979, 12, 55. 15. Serban, Α.; Gregory, J.M., So. Afr. Pat. 710,959, Feb., 1971. 16. Brown, M.S.; Kohn, G.K., U.S. Pat. 3,663,594, May 16, 1972. 17. Kohn, G.K.; Brown, M.S., U.S. Pat. 3,847,951, Nov. 21, 1974. 18. Farbenfab. Bayer AG, Belg. Pat. 772,634, March 1972. 19. Farbenfab. Bayer AG, Ger. Pat. 2,106,300, Feb. 1971. 20. Brown, M.S., U.S. Pat. 3,679,733, July 25, 1972. 21. Fahmy, M.A.H.; Chiu, Y.C.; Fukuto, T.R. J. Agr. Food Chem. 1974, 22, 59. 22. Sousa, Α.Α.; Frazer, J.R.; Weiden, M.H.J.; D'Silva, T.D.J. J. Εcon. Entomol., 1977, 70, 803. 23. Drabek, J . , U.S. Pat. 4,004,031, Jan. 18, 1977. 24. Fahmy, M.A.H.; Mallipudi, N.M.; Fukuto, T.R. J. Agr. Food Chem., 1978, 26, 550. 25. Liang, W.C., Ger. Offen. 2,654,314, June 23, 1977. C.A., 1977, 101, 101,988. 26. Nelson, S.J., U.S. Pat. 4,081,536, March 28, 1978. 27. Hartmann, Α.; Kühle, Ε.; Hammann, I.; Behrenz, W.; Homeyer, B., U.S. Pat. 4,148,910, April 10, 1979. 28. Fukuto, T.R.; Black, A.L.; Chiu, Y.C.; Fahmy, M.A.H. Environ. Quality Safety, 1975, Suppl. Vol. III, 394. 29. Black, A.L.; Fukuto, T.R., U.S. Pat. 4,006,231, Feb. 1, 1977. 30. Gemrich, E.G.; Lee, B.L.; Nelson, S.J.; Rizzo, V.L. J. Agr. Food Chem., 1978, 26, 391. 31. D'Silva, T.D.J., U.S. Pat. 4,122,204, Oct. 24, 1978. 32. D'Silva, T.D.J., U.S. Pat. 4,138,423, Feb. 6, 1979. 33. Ueda, M.; Ooba, S.; Hirano, M.; Takeda, Η., U.S. Pat. 3,950,374. 34. Fahmy, M.A.H.; Fukuto, T.R. J. Agr. Food Chem. (submitted). 35. Magee, P.S. Residue Rev., 1974, 53, 3. 36. Fahmy, M.A.H.; Fukuto, T.R. (unpublished work). 37. Brown, M.S.; Kohn, G.K., U.S. Pat. 3,843,689, Oct. 22, 1974. RECEIVED January 26, 1981.


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