37<? At 8/J MO.iO^O

STUDIES OF NITROGEN-CONTAINING COMPOUNDS

HAVING PYRETHROID-LIKE

BIOACTIVITY

DISSERTATION

Presented to the Graduate Council of the

University of North Texas in Partial

Fulfillment of the Requirements

For the Degree of

DOCTOR OF PHILOSOPHY

By

Jimmy Jing-Ming Lee, B.S,

Denton, Texas

August, 1989

J,

Jimmy, Jing-ming Lee. Studies of Nitrogen-containing

Compounds Having Pyrethroid-like Bioactivity. Doctor of

Philosophy ( Chemistry ) , August, 1989, 95 pp., 6 tables,

20 illustrations, bibliography, 68 titles.

During recent years most of the successful developments

in pyrethroids have been primarily concerned with structural

or compositional variations. As a part of our continuing

interest in pyrethroid insecticides, nitrogen-containing

compounds having pyrethroid-like structures were

synthesized. Seven prolinate compounds, N-(substituted)-

phenyl-prolinates and N-carbobenzoxy-prolinates were coupled

with known pyrethroid alcohols. These structural variations

which "locked in" a specific conformation between the

nitrogen and chiral a-carbon in the acid moiety of

fluvalinate were studied to determine the influence of

certain conformations on insecticidal toxicity.

The toxicity data for the prolinate compounds showed

intermediate mortality against nonresistant cockroaches. It

was concluded that the conformation imposed by the proline

ring portion of the esters was probably close to the favored

conformation for interaction of fluvalinate-like pyrethroids

with the insect receptor site.

A second series of nitrogen-containing compounds,

twenty-five carbamate esters resulting from the condensation

of N-isopropyl-(substituted)-anilines and N-alkyl-

(substituted)-benzylamines with appropriate pyrethroid

alcohols were studied for insecticidal activity. These

studies were conducted on pyrethroid-susceptible houseflies.

Some of the carbamate esters exhibited high toxicity when

synergized by piperonyl butoxide. For example, the

toxicity ( LD 5 0 ) of O-a-cyano-3-phenoxyfaenzyl-N-a,a-di-

methyl-4-bromo-benzyl carbamate was 0.012 ug/g, which is

significantly greater than that reported for the potent

pyrethroid, fenvalerate.

Correlations of insecticidal activity with respect to

structure and conformational factors of the carbamate esters

have been made. The N-isopropyl substituent decreases

insecticidal activity in the N-benzyl-derived compounds,

while the N-isopropyl substituent enhances activity in the

N-phenyl-derived compounds. Certain substituents on the

phenyl ring of both analogs greatly affect insecticidal

potency of the carbamate esters. Also, some alkyl substi-

tuents (especially, a,cx-dimethyl and a-cyclopropyl groups)

on the benzylic carbon of the benzylamine series enhance

toxicity. The a,a-dimethyl branching of the N-benzyl

carbamate approximates the steric shape given by the gem-

dimethyl group for conventional cyclopropane ring-containing

pyrethroids. The N-benzyl compounds are significantly

synergized by piperonyl butoxide, particularly those in

which the carbamate nitrogen atom is mono-substituted.

TABLE OF CONTENTS

Page

LIST OF TABLES iv

LIST OF ILLUSTRATIONS v

CHAPTER

I. GENERAL INTRODUCTION 1

Chapter Bibliography 18

II. PROLINE-CONTAINING PYRETHROIDS 22

Introduction 22

Experimental 25

Experimental Techniques Insect Bioassays Organic Syntheses

Results and Discussion 32

Chapter Bibliography 44

III. CARBAMATE PYRETHROID ESTERS 46

Introduction 46

Experimental 49

Experimental Techniques Insect Bioassays Organic Syntheses

Results and Discussion 74

Chapter Bibliography 88

BIBLIOGRAPHY 91

ill

LIST OF TABLES

Table Page

I. The Relative Toxicity of Dihalovinyl Pyrethroids 10

II. Toxicity Data of Proline Ring-containing Esters for Cockroaches 37

III. Toxicity Data of N-Carbobenzoxy Proline Ring-containing Esters for Cockroaches 39

IV. Housefly Toxicity of Substituted N-Phenyl Carbamates 76

V. Housefly Toxicity of N-Benzyl and N-Methylbenzyl Carbamates 78

VI. Housefly Toxicity of N-(a-Substituted)-Benzyl Carbamates 79

IV

LIST OF ILLUSTRATIONS

Figure Page

1. Structure of Chrysanthemic Acid and

Pyrethric Acid 3

2. Structure of Natural Pyrethrin Esters 4

3. Four Minor Natural Pyrethrin Esters 5

4. The Structure of Allethrin 7

5. Structure of Dihalovinyl Pyrethroid Esters .... 8

6. Structure of Fenvalerate and Fluvalinate 11

7. Structure of Synthetic Alcohols 13

8. Structures of Fluvalinate and Proline Analogs 24

9. The Configuration of the Insecticidal Stereisomer of Fluvalinate-like and Proline Esters 33

10. Synthetic Scheme for N-Carbobenzoxy Proline Ring-containing Esters 35

11. Synthetic Scheme for N-(2-Nitrophenyl) Proline Ring-containing Esters 36

12. Four Possible Extreme Conformations of Fluvalinate-like Esters 41

13. The Configuration of Cypermethrin, Fenvalerate, and Fluvalinate 48

14. Synthetic Scheme for N-Isopropylaniline and N-Isopropylbenzylamine Derivatives 50

15. Synthetic Scheme for a-(Substituted)benzylamine

Derivatives 51

16. Synthetic Scheme for Various Chloroformates ... 52

17. Synthetic Scheme for the Condensation of Carbamates 53

v

18. The Apparent Steric Similarities of N-Phenyl Carbamates and Fenvalerate-like Esters 81

19. The Apparent Steric Similarities of N-Benzyl Carbamates and Fluvalinate-like Esters 85

20. The Apparent Steric Similarities of N-Benzyl Carbamates and Decamethrin 86

V I

CHAPTER ONE

GENERAL INTRODUCTION

Pyrethrins are the major insecticidal constituents of

pyrethrum, the extract from certain species of the chrysan-

themum flower, such as Chrysanthemum cinerariaefolium (1).

Pyrethrum, the oldest of the organic insecticides, was

introduced in Europe more than a century ago and in Persia

considerably earlier (2). The scientific investigation of

the chemistry of pyrethrins began in the early part of the

twentieth century (3,4_). The principle contribution in the

early studies was accomplished by Staudinger and Ruzicka in

the period 1910 to 1916; the work was published in 1924 (5̂ ).

Their work, and also the work of Yamamoto et al. (6,2) /

have shown that the prime features required for insecticidal

activity of pyrethroids are the presence of an acid moiety

and an alcohol moiety with an ester linkage.

Staudinger and Ruzicka found that the hydrolysis of the

pyrethrum extract produces two different acids. The first

was named chrysanthemum-monocarboxylic acid and the second,

chrysanthemum-dicarboxylic acid. Since that time, these

acids have been renamed-the first as chrysanthemic acid and

the second as pyrethric acid (Fig 1). The alcohol moiety was

also isolated from pyrethrum hydrolysates and partially

2

characterized. It was referred to as pyrethrolone. The

esters resulting from the coupling of chrysanthemic acid

(monocarboxylic acid) and pyrethric acid (dicarboxylic acid)

with pyrethrolone were referred to as pyrethrin I and

pyrethrin II, respectively (Fig. 2). The Roman numerals were

assigned to specify the acid moiety as either the mono- or

di-carboxylic acid. The geometric arrangement of the

cyclopropanecarboxylic acid I and II, chrysanthemic acid and

pyrethric acid, was established to be the trans-arrangement

in this early stage. It is also interesting to note that the

finding of the cyclopropane ring system was the first

indication of the occurrence of this ring system in nature

(£). In the third decade of this century two additional

alcohols of pyrethrum, cinerolone and jasmolone (9,10), were

identified from the flower extract. These alcohol

moieties,when esterified with the mono- and di-carboxylic

acids, gave four minor natural pyrethrin esters (Fig. 3),

cinerin I and cinerin II; jasmolin I and jasmolin II.

Pyrethrins have demonstrated an excellent durability of

use that no other family of insecticides can match. The

primary mode of action of the pyrethrins probably occurs at

a biophysical level and involves the disruption of ion

transport at nerve membranes, and apparently involves the

blocking of sodium activation (11). Pyrethrins (including

synthetic pyrethroids) have a high insecticidal activity (in

most cases an LDS0 of less than 0.45 mg/kg) and an extremely

Fig. 1 : Structure of chrysanthemic acid and pyrethric acid

H , C

H , C

C

/ =C /

H

\ C -

CH,

H

CH-

C H R Y S A N T H E M U M

^ " C O O H M O N O C A R B O X Y L I C ACID

( C H R Y S A N T H E M I C ACID )

HOOC

H , C

C

/ -C /

H

\ C -

CH 3

H

C H 3

H C H R Y S A N T H E M U M

COOH D I C A R B O X Y L I C ACID

( P Y R E T H R I C ACID )

Fig. 2 : Structure of natural pyrethrin esters.

H 3 C H

H 3 C ' /

\ C H , /

H C /

H

COOR P Y R E T H R I N I

CH-

HOOC V /

H

H S C ' \ C H 3 „ / H

H £ P Y R E T H R I N I I

COOR

CH-

C H S

R = \ C H 2 — C H = C H

P Y R E T H R O L O N E

CH = C H 2

II 0

Fig. 3 : Four minor natural pyrethrin esters

CH3 h CHs ClNERIN I

HOOC

\

CHs

H

ClNERIN II

h 3 c

H3C

\ / c =

H O O C

H3C

\

/ C = =

CHs H

COO

E T

J A S M O L I N I

J A S M O L I N II

E T

H

6

low toxicity for mammals (for most of them, an LD S 0 of more

than 2,000 mg/kg) (12). Another advantage of pyrethrins is

contributed by their rapid biodegradation and the fact that

they are not accumulated when passing through the food chain

- in contrast to other insecticides (13,14), e.g., DDT.

Unfortunately, adequate production of natural pyrethrins is

sometimes adversely affected by the conditions of climate

and other factors.

The first synthetic pyrethroid, allethrin (Fig. 4)

produced commercially in 1949, was ascertained to be more

effective than the native mixture of esters (15). The use

of natural pyrethrins has been augmented by synthetic

pyrethroids which are now produced commercially on a large

scale to meet the increasing world requirements for more

effective insect control. The search continues in several

countries for even better synthetic pyrethroids to continue

to meet these requirements and to overcome the developing

resistance of some insect pests to extant pesticides.

Structure-activity studies of the pyrethroids have

generally been divided into studies of the acid moiety and

of the alcohol moiety. There have been several remarkable

advances enhancing the activity of both moieties in

pyrethroids since the time of allethrin synthesis. For

example, in the acid moiety, replacing the methyl groups in

the chrysanthemic acid with halogens ( dibromo (16,17),

dichloro (18,19), and difluoro (20), (Fig. 5) ), gives a

Fig. 4 : The structure of allethrin

H H

ALLETHRIN

Fig. 5 : Structure of dihalovinyl pyrethroid esters

0

C O O — C H

H CN

X = BR ( DECAMETHRIN ) ,

CL C CYPERMETHRIN ) ,

F

9

significant increase in the insecticidal activity and

photostability (Table I) when esterified with appropriate

alcohols (21). Such dihalovinyl analogues, decamethrin

(dibromo) and cypermethrin (dichloro), provide long residual

effectiveness in the field and have become the principle

commercial pyrethroids for agricultural use.

In 1974, Ohno et al. made a significant discovery in

pyrethroid investigations (22). Certain esters of halogen-

substituted <x-isopropylaryl acetates, e.g., fenvalerate

(Fig. 6), were effective pyrethroid-like insecticides. Until

that time it was generally believed that insecticidal

activity required the presence of the cyclopropanecarboxylic

acid moiety. This was the first potent "pyrethroid"

utilizing an isopropyl group (or other alky! group) as a

substituent for the cyclopropane ring in the acid moiety.

It was demonstrated that the mode of toxicity and the

spectrum of insects affected were very similar to that of

the conventional cyclopropane ring-containing pyrethroids

(23). Another important modification of the a-isopropylaryl

acetates was made by inserting a nitrogen atom between the

phenyl ring and the a-carbon in the fenvalerate structure to

give "fluvalinate" (Fig. 6) pyrethroids (ie, 2-anilino-

-3-methylbutyrates) (2A) . These anilino "pyrethroids" show

low mammalian toxicity and stability to air and light.

With respect to the alcohol moiety of pyrethroid

esters, several important advances have been made since the

10

Table I The relative toxicity of dihalovinyl pyrethroids *

R = a-cyano-3-phenoxy-benzyl alcohol

X Houseflies Mustard Beetles

CI

Br

CH3 **

390

260

2800

100

180

430

5500

100

* Chem. Soc. Review , 1978, 473 ** Bioresmethrin ( CH3 ) for standard,

LD S 0 0.006ug/Housefly LD S 0 0.005ug/Mustard Beetle

11

Fig. 6 : Structure of fenvalerate and fluvalinate

C L Y

C H -

0

COO — C H I

CN

F E N V A L E R A T E

CF3 Y 0

N — C H — C O O — CH

C L H C N

F L U V A L I N A T E

12

use of allethrolone (the alcohol moiety of allethrin) ( Fig.

7 ) (25). In 1964, while screening a wide range of esters

of readily available alcohols, N-hydroxymethyl

3,4,5,6-tetrahydrophthalimide was discovered by Sumitomo

chemists (2_6) . The esterification of this alcohol with

appropriate pyrethroid acids, gave pyrethroid exceptional

knockdown capability. The phenyl and furfuryl ring system

were then investigated as possible substitutes for the

natural pyrethrin alcohol moiety. Thus, in two important

investigations, 5-benzyl-3-furylmethyl and 3-phenoxybenzyl

alcohols (27,28) were introduced as very effective alcohol

moieties. In another investigation of the alcohol moiety,

an <x-cyano group substitution on the 3-phenoxybenzyl

alcohol, when coupled with pyrethroid acid moieties,

tremendously increased insecticidal activity and

photostability (2£) . Additionally, a new highly active

series of insecticidal pyrethroid esters employing

2-methyl-[1,1'-bipheny]- 3-methanol as the alcohol component

were more recently prepared (3C0.

The stereochemistry of the pyrethrins has been studied

extensively since the era of Staudinger and Ruzicka. In

that time, the orientation of the vinyl substituents on the

cyclopropane ring ( relative to the carboxyl group ) of

chrysanthemic acid and pyrethric acid was established as the

trans-orientation (31). Absolute assignment of the olefinic

side chain stereochemistry was not made until the advent of

13

Fig. 7 : Structure of synthetic alcohols

0

0 CH — N

ii 0

0 — C H I I

o — C H -

0 —

0 •

•

0 CH:

14

nuclear magnetic resonance spectroscopy (NMR) (32), optical

rotatory dispersion (ORD), and X-ray crystallography (33).

The absolute configuration for both acid and alcohol

moieties of potent pyrethroids have been studied

extensively, and much effort has been expended in relating

structure, stereochemistry and bioactivity. The assignment

of configuration for new pyrethroids now allows for the

prediction of insecticidal activity.

In the acid moieties, for conventional natural

pyrethrins, trans-chrysanthemic and trans-pyrethric acids

were shown to have the 1R, 3R configurations, and these

forms exhibit considerably more bioactivity than other

stereoisomers (3j|, 35) . It has been shown that the most

sensitive site for bioactivity is the a-carbon chiral center

in the acid moiety. Likewise, the stereochemical requirement

for maximal insecticidal potency of cypermethrin and

decamethrin, is the (R)-configuration (a-carbon) of the acid

moiety (3j5, 37) . However, with fenvalerate, the

(S)-isopropyl acetates are much more active than their

(R)-enantiomers (3j3). In contrast, with fluvalinate, the

(R)-enantiomer of the <x-carbon presents good insecticidal

activity (39). Obviously, upon examination, the

stereochemical configuration in the chiral center of

fenvalerate is equivalent to that of fluvalinate and the

conventional cyclopropanecarboxylate pyrethroids, suggesting

a similar biological complementary receptor for all three

15

structural types.

Similarly, the chiral center in the alcohol moiety also

will influence insecticidal activity. The substitution of

the <x-cyano group on the 3-phenoxybenzyl alcohol created a

new chiral center; when the absolute configuration is 'S',

activity is increased up to 15-fold over the unsubstituted

compound (40).

In the structure-activity studies of pyrethroids, three

other functional variations may be considered. The first is

the ester linkage. The apparent necessity of the ester

linkage in pyrethroids must be reconsidered due to effective

pyrethroids resulting from ether, reverse esters, carbamate,

and ketonic linkages (41»42,43). However, most of these

modifications exhibit low bioactivity. Recently, new non-

ester pyrethroids (oxime and ether linkage between "acid"

and "alcohol" moieties) showing promising insecticidal

potential have been prepared. These variations were made in

order to examine further structure-activity relationships

(44,15)-

In the study of pyrethroids which do not contain the

cyclopropane ring, numerous structural variants have been

prepared. Variation of substituents on the aryl component

and of the length of the carbon chain attached to the

acetate side chain in the fenvalerate system have been

investigated (46,47,£8) (e.g., fluorinated methoxy vs chloro

substituents, ethyl and cyclopropyl vs isopropyl

16

substituents).

Another consideration in the bioactivity of pyrethroids

is conformation. Conformational studies may involve

replacement of certain atoms or groups by the introduction

of a small ring system or by the addition of other

substituents to "lock in" certain conformational variables

in the parent structure. Conversely, conformation may be

"unlocked" by replacement of a ring system in both the

alcohol and acid moieties with alkyl groups which may assume

conformations approaching the parent structure. Fenvalerate,

a potent insecticide, appears to mimic the structure of

cypermethrin, when it assumes an appropriate conformational

orientation (49).

Some conformational studies of potent pyrethroid

alcohol moieties, 3-phenoxybenzyl alcohol and its <x-cyano

derivative, have been examined. Norton et al. have studied

the effects of an imposed planar relationship between the

two aromatic rings of the pyrethroid alcohol, 3-phenoxy

benzyl alcohol (Ert)). These studies have shown that the

effective conformation for target site binding is one in

which there is non-planarity between the aryl groups.

Analogues of a 2-substituted biphenyl pyrethroid alcohol

have indicated that insecticidal activity is dependent upon

an optimum twist angle of the rings of the biphenyl group

(51).

In our recent studies of pyrethroid insecticides, we

17

began an investigation of conformational variations in the

acid moiety of fluvalinate analogs. Analogs of the amino

acid, proline, were synthesized which "lock" in a specific

conformation between the nitrogen and the chiral a-carbon in

the acid moiety of pyrethroids. The compounds were applied

in conformation-activity studies to evaluate the influence

of certain conformation imposed by the ring system.

In a second study of nitrogen-containing compounds, we

employed a carbamic linkage between the acid and alcohol

moieties to determine structure-activity effects in the

resulting pyrethroid-like molecules. Carbamate esters have

been synthesized from twenty-five carbamic acids that are

nitrogen isoteres of the acid moieties of fenvalerate- and

fluvalinate-like pyrethroids. These acid moieties were

derived, in the main, from N-isopropyl aniline and

«-(substituted)-benzylamine derivatives. The alcohol

portion of the carbamate esters were various appropriate

pyrethroid alcohols.

18

CHAPTER BIBLIOGRAPHY

1. Head, S. W. Pyrethrum, edited by J. Casida, Academic Press: New York and London, 1973, 26.

2. Gnadinger, C.B. Pyrethrum Flower, Mclaughlin Gormley King Co. : Minneapolis, Minn, 1936.

3. Fujitani, J. Arch. Exp. Pathol. Pharmakol• 1909, 61, 47 .

4. Yamamoto, R. J. Tokyo Chem. Soc. 1919, 40, 126.

5. Staudinger, H; Ruzicka, L. Helv. Chim. Acta. 1924, ]_, 177.

6. Yamamoto, R. J. Chem. Soc. Japan, 1923, 44, 311.

7. Yamamoto, R.; Sumi, M. J. J. Chem. Soc. Japan, 1923, 44, 1080.

8. Staudinger, H; Ruzicka, L. Helv. Chim. Acta. 1924, ]_, 201.

9. Laforge, F. B.; Barthel, W. F. J. Org. Chem. 1944, 9, 242.

10. Godin, P. J.;Sleeman, R. J.; Snaver, M.; Thain, E. M. J. Chem. Soc. Comm. 1966, 332.

11. Camougis, G. Pyrethrum, edited by J. Casida, Academic Press: New York and London, 1973, 211.

12. Elliott, M. Synthetic Pyrethroids, ACS Symposium series : 1977, 42, 2.

13. Gersdorff, W. A.; Barthel, W. F. Soap and San. Chem. 1946, 10, 155.

14. Elliott, M.; Janes, N. F.; Kimmel, E. C.;Casida, J. E. J. Agric. Food, Chem. 1972, 20, 300.

15. Schechter, M. S.; Green, N.; LaForge, B. J, Ameri. Chem. Soc. 1949, ~T\, 3165.

16. Brown, D G.; Bodenstein, O. F.; Norton, S. J. J. Agric. Food, Chem. 1973, 21, 767.

17. Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H.; and Pulman, D. A. Pestic. Sci. 1975, 6, 537.

19

18. Elliott, M.; Farnham, A. W. ; Janes, N. F.; Needham, P. H.; Pulman, D. AStevenson, J. H. Nature, 1973, 246, 169.

19. Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P.H.; Pulman, D. A. Pestic. Sci. 1975, 6, 537.

20. Brown, D. G.; Bodenstein, 0. F.; and Norton, S. J. J. Agric. Food, Chem. 1973, 21, 767.

21. Elliott, M.; Farnham, A. W.; Janes, N. F. Needham, P. M.; and Pulman, D. A. Nature, 1974, 248, 710.

22. Ohno, N.;Fujimoto, k.; Okuno, Y.; Mizutani, T.; Hirano, M.; Itaya, N; Honda, T.; and Yoshioka, H. Agric. Biol. Chem. 1974, 38, 881.

23. Ohno, N.; Fujimoto, K.; Okuno, Y.; Mizutani, T.; Hirano, M.; Itaya, N. Honda, T.; and Yoshioka, H. Pestic. Sci. 1976, 7, 241.

24. Henrick, C. A.; Garcia, B. G.; Cerf, D. C.; Staal, G. B.; Anderson, R. J.; Gill, K.; Chinn, H. C.; Labovitz, J. N.; Leippe, M. M.; Woo, S. L.; Carney, R. L.; Gordon, D. C.; Kohn, G. K. Pestic. Sci. 1980, 11, 224.

25. Schechter, M. S.; Green, N.; and LaForge, B. J. Amer. Chem. Soc. 1949, 71, 3165.

26. Kato, T.; Ueda, K.; Fujimoto, K. Agric. Biol. Chem. 1964, .28, 914.

27. Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H.; Pearson, B. C. Nature, 1967, 213, 493.

28. Fujimoto, K.; Itaya, N.; Okuno, Y.; Kadota, T.; Yamaguchi, T. Agric. Biol. Chem. 1973, 37, 2681.

29. Matsuo, T.; Itaya, N.; Mizutani, T.; Ohno, N.; Fujimoto, K.; Okuno, Y.; Yoshioka, H. Agric. Biol. Chem. 1976, 40, 247.

30. Plummer, E. L.; Pincus, D. S. J. Agric. Food, Chem. 1981, .29, 1118. ~

31. Staudinger, H.; Ruzicka, L. Hel. Chim. Acta, 1924, 7, 201.

32. Crombie, L.; Crossley, J.; Mitchard, D. J. Chem. Soc. London, 1963, 4957. ~

20

33. Crombie, L.; Pattenden, G.; Simmonds, D. Pestic. Sci. 1976, 7, 223.

34. Carbie, L.; Crossley, J.; Mitchard, D. J. Chem. Soc. London, 1963, 4957.

35. Matsui, M.; Yamada, Y. Agric. Biol. Chem. 1963, 27, 373.

36. Burt, P. E.; Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H. ; Pulman, D. A. Pestic. Sci. 1974, 5, 791.

37. Elliott, M.; Farnham, A. W. ; Janes, N. F.; Needham, P. H.; Pulman, D. A. Nature (London), 1974, 248, 710.

38. Mikayado, M.; Ohno, N.; Okuno, Y.; Hirano, M.; Fujimoto, K.; Yoshioka, H. Agric. Biol. Chem. 1975, 39, 267.

39. Anderson, R. J.; Adams, K. G.; Henrick, C. A. J. Agric. Food, Chem. 1985, 33, 508.

40. Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H.; Pulman. D. A. Pestic. Sci. 1976, 7, 499.

41. Berteau, P. E.; Casida, J. E. J. Agric. Food, Chem. 1969, 17, 931.

42. Sheppard, R. G.; Norton, S. J. J. Agric. Food, Chem. 1980, .28, 1300.

43. Black, M. H. Synthetic Pyrethroids, ACS Symposium Series : 1977, 42, 62.

44. Bull, M. J.; Davies, H. D.; Searle, R. J. G.; Henry, A. C. Pestic. Sci. 1980, 11, 249.

45. Chem. Abstr. 97, 5964e.

46. Ohno, N.; Fujimoto, K.; Okuno, Y.; Mizutani, T.; Hirano, M.; Itaya, N.; Honda, T.; Yoshioka, H. Agric. Biol. Chem. 1974, 3?3, 881.

47. Elliott, M.; Farnham, A. W. ; Janes, N. F.; Johnson, D. M.; Pulman, D. A. Pestic. Sci. 1980, 11, 513.

48. Henrick, C. A.; Garcia, B. G.; Staal, G. B.; Cerf, D. C.; Anderson, R. J.; Gill, K.; Chinn, H. C.; Labovitz, J. N.; Leippe, M. M.; Woo, S. L.; Carney, R.L.; Gordon, D. C.; Kohn, G. K. Pestic. Sci. 1980, 11, 224.

21

49. Ohno, N.; Fujimoto, K.; Okuno, Y.; Mizutani, T.; Hirano, M.; Itaya, N.;Honda, T.; and Yoshioka, H. Agric. Biol. Chem. 1974, 3j3, 881.

50. Tu, H; Brady, W. T.; Norton, S. J. J. Agric. Food, Chem. 1985, 33, 751.

CHAPTER TWO

PROLINE CONTAINING PYRETHROIDS

Introduction

Among the factors upon which bioactivity of pyrethroid-

like insecticides are dependent, are the conformation of the

molecule, the substituents on certain positions, and the

configuration at the asymmetric carbon atoms (1). The

relationship between conformation and bioactivity for both

the acid and alcohol moieties has become a significant

consideration in the study of pyrethroids. Insecticidal

action is presently interpreted to involve an ability of the

molecule, having appropriate structure and stereochemistry,

to adopt an optimal conformation for interaction with the

insect receptor site (2).

Conformational studies of the two aromatic centers of

some pyrethroid alcohols have been made (3̂ , A , 5).

Conformational studies concerned with the acid moiety

resulted in the fenvalerate series of compounds which show

outstanding bioactivity. The isopropyl group of this series

is able, through specific conformer formation to mimic the

steric bulk and orientation of cyclopropane ring-containing

acid groups (6, 7). More recent progress has resulted in a

new series of compounds containing substituted 2-anilino-

22

23

3-methyl-butyrates, the fluvalinate series, derived from the

structure of fenvalerate. This series exhibits high

insecticidal potency over a wide range of insect pests,

field stability and relatively low mammalian toxicity (8) .

Certain modifications of the parent fluvalinate

structure result in compounds retaining insecticidal

activity (Fig. 8A) (9). The combination of a 2-chloro or

2-fluoro atom with a 4-trifluoromethyl electron withdrawing

group in the anilino moiety gives the most highly active

compound (10). The reasons for the effects of these

substituents are presently unknown. Another important site

influencing insecticidal activity in these series is the

chiral a-carbon to the carboxylate group. In the fluvalinate

series, only the R-enantiomer exhibits high bioactivity

(11).

As a part of our continuing interest in pyrethroid

insecticides, we have begun a study of conformational and

configurational variations in the acid moiety of fluvalinate

analogues. Such variations have involved the " locking-in "

of a certain conformation by the introduction of a small

heterocyclic system from the amino acid, proline. Seven

analogs of proline (Fig. 8B) were synthesized which lock in

a specific: conformation between the nitrogen and chiral

tt-carbon and relate structurally to fluvalinate. These

compounds were employed in conformation-activity studies to

determine the importance of the specific conformation

24

Fig. 8 : (A) Structure of Fluvalinate analogs (B) Structure

of Proline analogs

(A) FLUVALINATE ANALOGS

COO-CH

RI = H , CH3

R2 = H , CH3

RA = H , CN

* = CHIRAL CENTER

(B) PROLINE ANALOGS

CH

c>C V I ^ 0

RI N ^ * COO- CH

R2

RI = XI\C)/- XI: H, BR

x 2 : NO*

CARBOBENZOXY GROUP

R2 = H , CN * = CHIRAL CENTER

25

imposed by the ring system. Thus, if the imposed

conformations were similar to the preferred one for target

site binding, bioactivity would be expected to be enhanced.

Contrarily, if the imposed conformation were not appropriate

for binding with the target site, bioactivity would be

decreased.

Experimental

Experimental Techniques

Infrared spectra were measured on a Perkin-Elmer 1330

spectrometer. The structures of products were confirmed by

NMR spectrum employing either Hitachi Perkin-Elmer R24-B or

Joel FX 900; Data are presented in & values. Melting points

are uncorrected. Elemental analyses were performed by

Midwest Microlab, Indianapolis, IN; analyses are indicated

by elemental symbols and were within ± 0.4% of the

theoretical values. (S)-Proline and (RS)-proline (Aldrich

Chemical Co., Milwaukee WI) were employed to prepare the N-

carbobenzoxy-(S)-proline esters or N-2-nitrophenyl

(S)-proline esters, and their (RS) counterparts. For column

chromatography, silica gel(60-300 mesh, Fisher Scientific

Company) was used. Radial thin-layer chromatography was

carried out with a Harrison Model Chromatotron provided with

a 2-mm silica gel rotor. For thin-layer chromatography(TLC),

silica gel plates from Eastman Kodak Company were employed.

Insect bioassays

Compounds selected for testing were submitted to the

26

Biological Evaluation Laboratory, Gilmar Center, Madison,

WI. The selected compounds were tested against two species

of insects, houseflies and cockroaches. Both insects are a

typically acceptable test insect for the preliminary

evaluation of bioactivity (12). Four-day old female

houseflies ( Musca domestica, F 58 WI II strain) and male

cockroaches (CSMA Strain,German) were anesthetized and

arranged on a screen, ventral side up. One microliter of

sample (1% in acetone) was applied to the abdomen. With

each compound studied, at least 10 insects were employed in

each test, and all tests were conducted in duplicate.

Mortalities were recorded after 24 hours for houseflies and

48 hours for cockroaches; average percent mortalities were

then determined. Controls were employed in the studies, in

which acetone alone was admitted.

Organic Syntheses

Benzyl chloroformate (I_) Benzyl chloroformate was

prepared by a modification of the procedure of Greenstein et

al. (13). Phosgene, 32 g, was condensed into 100 ml of

diethyl ether cooled to 0°C in an salt-ice bath. To this

slowly stirring solution, 8.0 g of benzyl alcohol with 9.8 g

of N,N-dimethyl aniline in 30 ml of diethyl ether were

added. The mixture was stirred for 3 hours in an ice bath,

then overnight at room temperature. The solvent was removed

in vacuo. The residue was then taken up in 100 ml of ether

and washed with 2 x 50 ml water, 3 x 50 ml 3% hydrochloric

27

acid, 3 x 20 ml 5% sodium carbonate and 1 x 50 ml of

saturated sodium chloride. The diethyl ether was removed by

rotary evaporation to give 11.4 g of product for a 90%

yield. NMR(CDCl3) : £ 7.1(5H, s, Ar), and 5.05 ppm(2H, s,

Bz); IR 1770 cm-i(OO) .

N-Carbobenzoxy-(RS)-proline(II). Benzylchloroformate

(I), 8.0 g in 10 ml of diethyl ether, and 30 ml of 2N NaOH

solution were added simultaneously during 15 min with

vigorous stirring to an ice-cooled solution of 4.6 g of

(RS)-proline in 20 ml of 2N sodium hydroxide. The mixture

was continuously stirred in an ice bath for one hour. The

mixture was extracted with 2 x 25 ml of ether. The aqueous

residue was acidified to pH 2.5-3.0 with 6N HCl in an ice

bath. The oily material separating from the aqueous solution

was taken up in 2 x 50 ml of ethyl acetate. The organic

portion was washed with 2 x 30 ml of deionized water and

dried over anhydrous magnesium sulfate. The ethyl acetate

was evaporated to give 11.0 g of white oily product for a

95% yield. NMR(CDC13): 6 3.40(2H, d, CH2-N),and 1.95 ppm(4H,

m, CH2-CH2); IR 1705 and 1675 cm-i(COOR and COOH).

N-^Carbobenzoxy-(S)-proline (III) . The carbobenzoxy-

lation and work up of the resolved proline (S-form) with

benzyl chloroformate was carried out in the same manner as

was II and gave a 90% yield. NMR (CDC13) : <5 3.40 (2H, d,

CH2-N), and 1.95 ppm (4H, m, CH2-CH2); IR 1705 and 1675 cm~i

(COOR and COOH).

28

N-Carbobenzoxy-O-3-phenoxybenzyl-(RS)-prolinate (IV).

N-Carbobenzoxy-(RS)-proline (II), 5.0 g, was added to 50 ml

of dry benzene containing 2.8 ml of thionyl chloride at room

temperature. After refluxing 3 hours, the benzene and excess

thionyl chloride were removed in vacuo. The crude acid

halide, taken up in 10ml of benzene, was added to a solution

of 0.65 g of pyridine and 1.5 g of 3-phenoxybenzyl alcohol

in 50 ml of dry benzene at 25°C. After standing, the

hydrochloride salt was removed by filtration, and the

benzene withdrawn in vacuo. The residue was then taken up

in 50 ml of ethyl ether and extracted with water, 3%

hydrochloric acid, and finally with saturated sodium

chloride solution. After drying, the ether was removed in

vacuo. The residue was purified by chromatography on silica

gel (eluted with hexane: ethyl acetate, 9:1, V/V) to give

2.4 g of colorless oil for a 75% yield. TLC (hexane: ethyl

acetate, 9:1, V/V) Rf=0.62 ; NMR (CDCl3): £ 7.49-6.70 (14H,

m, Ar), 5.05(2H, S, Bz), 4.95(2H, S, Bz), 4.40(1H, d, CH-N),

3.50(2H, d, CH2-N), and 2.00 ppm(4H, m, CH2-CH2); IR 1745

and 1705 cm~i(C=0); Elemental analysis for C 2 6H 2 5N0 s , Calcd

: C, 72.37 ; H, 5.84. Found : C, 72.05 ; H, 5.65.

N-Carbobenzoxy-0-3-phenoxybenzyl-(S)-prolinate (V).

The esterification and work up of resolved N-carbobenzoxy-

(s)-proline (III) with 3-phenoxybenzyl alcohol was carried

out in the same manner as was IV and gave a 70% yield. The

product was a single spot and had the same Rf value on TLC

29

as compound(IV). NMR(CDC13): S 7.40-6.70(14H, m, Ar),

5.05(2H, S, Bz), 4.95(2H, S, Bz), 4.40(1H, d, CH-N), 3.50

(2H, d, CH2-N), and 2.00 ppm(4H, m, CH2-CH2); IR 1745 and

1705 cm_i (C=0).

N-Carbobenzoxy-O-g-cyano-3-phenoxybenzyl-(S)-prolinate

(VI). The acid halide of N-carbobenzoxy-(S)-proline (III)

was prepared in the same manner as was IV. The crude acid

halide, approximately 2 g, with 10 ml of benzene, was added

under nitrogen to a solution of 0.65 g of pyridine and 1.6 g

of <x-cyano-3-phenoxybenzyl alcohol in 50 ml of dry benzene

at 25°C. 3-Phenoxybenzyl cyanohydrin was prepared by the

method of Ruzo et al. (14). After standing overnight,

pyridine hydrochloride was removed by filtration and the

benzene removed in vacuo. The residue was worked up and

purified by the same method as was compound IV to give 1.9 g

of light yellow oil for a 60% yield. NMR (CDC13) : £

7.40-6.70(14H, m, Ar), 6.35(1H, s, Bz), 5.05(2H, s, Bz),

4.25(1H, m, CH), 3.45(2H, d, CH2-N), 2.05(4H, m, CH2-CH2) ;

IR 2260 cm-1(CN), 1755 and 1700 cm-* ; Elemental analysis

for C 2 7H 2 4N 20 5, Calcd : C , 71.04 ; H , 5.30. Found :

C , 69.90 ; H , 5.07.

O-3-Phenoxybenzyl-(RS)-prolinate (VII). The racemic

proline, 5.0 g, was suspended in 50 ml of 3-phenoxybenzyl

alcohol and dry hydrogen chloride was passed through the

suspension for one hour at 0°C (15). The mixture was then

heated at 85°C for 1 hour, followed by removal of water and

30

hydrogen chloride under reduced pressure. The procedure was

repeated an additional time and the residue was extracted

three times with a cold mixture of 3% HCl-ether (50:150,

V/V) to remove unreacted alcohol. The aqueous phase was then

made basic with 50 ml of 10% sodium carbonate solution and

extracted by 3 x 50 ml of ether. After drying, the ether was

removed in vacuo. The residue was purified by silica gel

chromatography (eluted with hexane:ethyl acetate, 5:1, V/V)

to produce 6.5 g of oily product for a 51% yield. TLC

(hexane: ethyl acetate, 9:1, V/V) Rf= 0.45; NMR (CDCl3) : £

7.40-6.70( 9H, m, Ar), 5.00( 2H, s, Bz), 3.65( 1H, m, CH),

2.85( 2H, m, CH2), 2.70(1H, m, NH), and 1.80( 4H, m,

CH2-CH2); IR 3320 cm-i(NH) and 1710 cm-i(C=0).

O-3-Phenoxybenzyl-(S)-prolinate (VIII). The

esterification and work up of the resolved proline (S-form)

with 3-phenoxybenzyl alcohol was conducted in the same

manner as was VII and gave a 55% yield. This ester

exhibited a single spot having an Rf value on TLC identical

to that of compound (VII) . NMR (CDCl3): S 7.40-6.70( 9H,

m, Ar), 5.00(2H, s, Bz), 3.65(1H, m, CH), 2.85(2H, m, CH2),

2.70(1H, m/ NH),and 1.80 ppm ( 4H, m, CH2-CH2); IR 3320 and

1710 cm-i (NH and C=0).

N-(2-Nitro-phenyl)-O-3-phenoxybenzyl-(S)-prolinate

(IX). The procedure was similar to a previously reported

process for nucleophilic displacements by amines on nitro

group-activated aryl halides (16). O-3-Fhenoxybenzyl

31

(S)-prolinate (VIII), 1.0 g, was added with stirring to 0.7

<? of l-bromo-2-nitrobenzene in 10 ml of benzene at room

temperature. After refluxing 12 hours, the mixture was

taken up in 50 ml of diethyl ether and washed with water and

with a saturated sodium chloride solution. Purification by

silica gel chromatography was performed. Elution with

hexane:ethyl acetate (6:1) gave 0.75 g of yellow oil

product. TLC (hexane: ethyl acetate, 9:1, V/V) Rf=0.40 ;

NMR (CDCl3) : & 7.50-6.50(13H, m, Ar), 5.00(2H, s, Bz),

4.30(1H, d, CH), 3.35(2H, d, CH2-N), and 2.05 ppm(4H, m,

CH2-CH2); IR 1720 cm~ i (C=0); Elemental analysis for

C2 4H22N20s, Calcd : C , 68.88 ; H , 5.30. Found : C ,

69.07 ; H , 5.35.

N-(2-Nitro-phenvl)-O-3-phenoxybenzvl-(RS)-prolinate(X).

Nucleophilic displacement with l-bromo-2-nitro-benzene and

work up of the racemic prolinate derivative (VII) was

conducted by the same procedure as was compound IX. The

product produced a single spot and with a same Rf value on

TLC as that of compound (IX). NMR (CDC13) : <£ 7.50-6.50

(13H, m, Ar), 5.00(2H, s, Bz), 4.30(1H, d, CH), 3.35(2H, d,

CH2-N), and 2.05 ppm(4H, m, CH2-CH2); IR 1720 cm-i(C=0).

(4-Bromo-2-nitro-phenyl)-O-3-phenoxybenzyl

(^)-prolinate (XI). Compound XI was synthesized by the same

procedure as compound IX. 2,5-Dibromonitrobenezene, 0.7 g,

and 0.75 g of 0-3-phenoxybenzyl-(S)-prolinate (VIII) were

reacted, and after purification by silica gel chromatography

32

(eluted with hexane:ethyl acetate, 6:1, V/V) yielded 0.75 g

of yellow oil product. TLC (hexane: ethyl acetate, 9:1,

V/V) Rf=0.47; NMR (CDC13) : 6 7.70-6.45(12H, m, Ar),

5.00(2H, s, Bz), 4.30(1H, m, CH), 3.40(2H, d, CH2-N),

2.05(4H, m, CH2-CH2) ; IR 1725 cm" i (C=0); Elemental

analysis for C 2 4H 2 1BrN 20 5 , Calcd : C , .57.96 ; H , 4.26.

Found : C , 58.20 ; H , 4.42.

N-(4-Bromo-2-nitro-phenyl)-O-3-phenoxybenzyl

(RS)-prolinate (XII). The procedure for synthesis of

compound IX was again employed. 2.5-Dibromonitrobenzene,

0.7 g and 0.75 g of O-3-phenoxybenzyl (RS)-prolinate (VII)

were reacted. Following purification by silica gel

chromatography 0.7 g of yellow oil were produced and gave a

single spot with an Rf value on the TLC identical to that of

compound (XI). NMR (CDC13) : S 7.70-6.45 (12H, m, Ar),

5•00( 2H, s, Bz), 4.30(1H, m, CH), 3.40(2H, d, CH2-N), and

2.05 ppm(4H, m, CH2-CH2) ; IR 1725 cm-i (C=0).

Results and Discussion

Both conformational and stereochemical factors affect

the insecticidal activity of pyrethroids (17). In the

fluvalinate analogs, the introduction of a methyl group and

an ethyl group on the nitrogen atom and <x-carbon of the N-

acetate moiety respectively, still shows a significant

bioactivity and gives one of the family of the "fluvalinate-

like" compounds (Fig. 9A) (1IB) . Specific conformers of this

family could be affected by use of specific ring systems to

33

Fig. 9 : The configuration of the insecticidal stereisomer

of ( A ) F l u v a l i n a t e - l i k e esters (B) proline esters.

0 — R 3

0

RI = CF 3 R 2 = CL , F

R3 = ALCOHOLS

R

Q

r • )

0 - R 3

R:

Ri = H , BR

R3 = ALCOHOLS

R 2 = N0 2

34

lock-in certain possible conformations of substituents such

as the above mentioned methyl and ethyl groups (Fig. 9B)

In the present study, compounds which can be related to

a particular conformation of the acid moiety of

"fluvalinate-like"pyrethroids were synthesized. For these

acid analogs, the ring component of the amino acid, proline,

was employed to "lock-in" a specific conformation of the

basic structure of the parent acid moiety of a fluvalinate-

like pyrethroid. These new acids were condensed with well-

known pyrethroid alcohol moieties, 3-phenoxybenzyl alcohol

and its <x-cyano derivative, to produce the new esters.

The compounds synthesized may be divided into two major

categories : proline esters prepared with the N-carbo-

benzoxy group ( Fig. 10) and proline esters having

N-2-nitrophenyl or substituted 2-nitrophenyl groups(Fig.

11). The stereochemistry of the proline esters (chiral

center on a-carbon) was also varied to determine effects on

bioactivity. Preliminary insecticidal activity data against

houseflies indicated very low toxicities for the proline

ring-containing pyrethroids. Toxicity data against non-

resistant cockroaches are shown in Tables II and III.

Compounds(IV-VI) are those proline esters having the N-

carbobenzoxy group ( Table II), and the toxicities exhibited

indicate that the R-enantiomer is significantly more active

than the S-enantiomer. Further, it is apparent that the

<x-cyano group on the alcohol moiety enhances bioactivity.

35

Fig. 10: Synthetic scheme for N-carbobenzoxy proline ring-

containing esters.

^ N ^ r r - N — ' C 0 0 H

H

0

C H 2 0 - C - C L (CBZ) I I — » ^ N ^ C O O H

CBZ

S0CL2/R0H

N ) r C00R

CBZ

R = < C H 2 - ,

36

Fig. 11: Synthetic scheme for N-(2-nitrophenyl) proline

ring-containing esters.

a N ^ x C 0 0 H > H HCL / 0 C

N COORi H

Rl

R 2 = V . J/~ ' BR

n o 2 NO;

R 2~BR

f K x O O R !

R,

37

Table II: Toxicity data of N-carbobenzoxy proline ring-

containing esters for cockroaches.

N ^ ^ C — 0 — CH i. 11 i Ri 0 R2

0

Toxicity ( % Kill)

Compound Ri R2

Chiral*

carbon Cockroaches **

IV CBZ *** H RS 38

V CBZ H S 18

VI CBZ CN s 33

* Chiral configuration. ** 48-hour mortality for CSMA male cockroaches; 10 ug of each

test compound was applied to the abdoninal cuticle of each insect.

*** CBZ: Carbobenzoxy group.

38

This enhancement by employment of a-cyano-3-phenoxybenzyl

alcohol is typical for most pyrethroid esters studied (19).

Bioactivity of compound VI would probably be significantly

higher if the (R)-enantiomer were employed. The insecticidal

activity of compounds IV-VI is somewhat lower than that of

the parent compounds.

The second group of compounds prepared by a

nucleophilic displacement reaction on proline, followed by

esterification with 3-phenoxybenzyl alcohol, have

N-2-nitrophenyl and N-4-bromo-2-nitrophenyl substituents.

The nitro group on the phenyl ring is a substituent that has

been previously examined in other insecticide systems

(20,21). As seen in Table III, toxicity data for these

compounds show that the (S)-enantiomer of the N-2-nitro-

phenyl derivatives (compounds IX and X) is significantly

more active than the (R)-enantiomer. This finding is

surprising since the R-enantiomer of the carbobenzoxy series

is apparently the more active ( based on the higher activity

of the racemic ester, compound IX ).

In view of the analogs with the fluvalinate structure

it would be anticipated that the proline ring-containing

esters having the R-configuration would be the more active

forms (22). While the toxicities of the nitrophenyl-

substituted proline esters are not high, this stereochemical

phenomenon should be investigated further. Whether or not

the (S)-enantiomeric forms would remain the more active with

39

Table III : Toxicity data of N-(2-nitrophenyl) proline ring-

containing esters for cockroaches.

Ck t Ri

C-ii

0

0 — C H

0

Compound

Chiral*

carbon

Toxicity ( % Kill)

Cockroaches * *

IX 2-(N02)C6H4 S 70

X 2-(NOz)C6H4 RS 13

XI 4-Br-2-(N02)C6H3 S 8

XII 4-Br-2-(N02)C6H3 RS 3

* Chiral configuration. ** 48-hour mortality for CSMA male cockroaches; 10 ug of each

test compound was applied to the abdoninal cuticle of each insect.

40

other nitro-phenyl substituted proline esters remains an

intriguing question. If a suitable synthetic scheme could be

worked out for the preparation of a-cyano-3-phenoxybenzyl

esters of N-phenyl substituent proline acids, it would be

probable that further significant insecticidal potency would

result. As is also shown in Table III, the substitution of

a bromine atom in the 4-position of the N-phenyl substituent

(compounds XI and XII) results in decreased activity.

The substituents on the nitrogen atom and the <x-carbon

atom of the acid moiety of fluvalinate-like pyrethroids

might assume (among many possible conformations) four

extreme conformational forms (Fig. 12). These four possible

extreme conformers may be generated by rotation about the

C 2 " C 3 bond and C2-N5 bond. From a steric viewpoint the

probable ease of assuming these conformations is d >c >b >a.

In constructing the proline ring-containing esters it was

proposed to test whether or not a conformation resembling

conformer C (see also Fig. 9) would result in a compound

having appreciable biological activity against insects. If

its activity were high, it could be assumed that the

conformation imposed by the proline ring closely

approximated a best—fit morphology of the insect receptor

site. If the activity were negligible or very low, it could

be concluded that the imposed conformation was quite

different from the preferred one. If the activity were

intermediate it might be assumed that receptor binding is

41 Fig. 12: Four possible extreme conformations of

fluvalinate-like esters.

/ •X

CH-

C' ii 0

,0-R

/ : i f

C-ii 0

,0-R

CH-

( A ) ( B )

CHa i3 "t

\ jsL ,0-R CH3

\ j»L o

C-it 0

,0-R

( C ) ( D )

42

occurring but not optimally (e.g., conformer D might be

preferred over conformer C, Fig.12).

While the insecticidal activities of the proline esters

can at least be classified as intermediate, there is reason

to believe that the conformation imposed by the 5-membered

heterocyclic ring may approximate the preferred receptor

site morphology. For example, with compounds IX-XII, the

nature of (and the position of) the substituents on the

phenyl group are probably not optimal. The bulky nitro

group, while greatly facilitating the synthesis of the N-

phenyl proline acids, is not a group that invariably

enhances insecticidal activity (23). Furthermore, the ortho-

positioning of this bulky group could well interfere with

effective binding.

A similar argument could be given concerning the N-

carbobenzoxy group (compounds IV-VI) in that this bulky

substituent has considerably more conformational freedom

than does the N-phenyl group. Even so, it would be

anticipated, from the data of Table II, that the a-cyano-

3-phenoxybenzyl ester of the (R)-enantiomer of the acid

moiety of compound VI would be a more active insecticide.

None of the compounds in Tables II and III were tested in

the presence of a synergist ( mixed function oxididase

inhibitor ). Typical enhancements by synergists, such as

piperonyl butoxide (PB) range from 2 - 1 5 times.

In conclusion, the proline esters studied indicate, by

43

virtue of their intermediate level of insecticidal activity,

that they mimic a conformation of fluvalinate-like

pyrethroids that may be close to the preferred one. Further

modification of the N-substituents on the heterocyclic ring

might result in compounds of superior insecticidal quality.

44

CHAPTER BIBLIOGRAPHY

1. Elliott, M; Janes, N. F. Chem. Soc. Rev. 1978, 23, 443.

2. Elliott, M. Synthetic Pyrethroids, ACS Symposium. Series : 1977, 42, p 8.

3. Plummer, E. L.; Seiders, R. P.; Sealye D. E.; Steward, R* Pestic. Sci. 1984, 15, 509.

4. Plummer, E. L.; Pincus, D. S. J. Agric. Food, Chem. 1981, 29, 1118.

5. Tu, H.; Brady, W. T; Norton S. J. J. Agric. Food, Chem. 1985, 33, 751.

6. Ohno, N.; Fujimoto, K.; Okuno, Y.; Mizutani, T.; Hirano, M.; Itaya, N.;Honda, T.; and Yoshioka, H. Agric. Biol. Chem. 1974, 38, 881

7. Ohno, N.; Fujimoto, K.; Okuno, Y.; Mizutani, T.; Hirano, M.; Itaya, N.;Honda, T.; and Yoshioka, H. Agric. Biol. Chem. 1974, 38, 881.

8. Henrick, C. A.; Garcia, B. G.; Staal, G. B.; Cerf, D. C.; Anderson, R. J.; Gill, K.; Chinn, H. C.; Labovitz, J. N.; Leippe, M. M.; Woo, S. L.; Carney, R. L.; Gordon, D. C.; Kohn, G. K. Pestic. Sci. 1980, 11, 224.

9. ibid

10. ibid

11. Anderson, R. J.; Adams, K. G.; Henrick, C. A. J. Agric. Food, Chem. 1985, 33, 508.

12. Elliott, M. Pestic. Sci. 1980, 11, 119.

13. Greenstein, J. P. ; Winitz, M. Chemistry of Amino Acid, Vol 2, John Wiley and Son Inc. New York, 1961, 887.

14. Ruzo, L. 0.; Holmstead, R. L.; Casida, J. E. J. Agric. Food, Chem. 1977_, 25, 1385.

15. Greenstein, J. P. ; Winitz, M. Chemistry of Amino Acid, Vol 2, John Wiley and Son Inc. New York, 1961, 928.

16. Berliner, E.; Monack, L. C. J. Amer. Chem. Soc. 1952, 74, 1574. ~

45

17. Plummer, E. L.; Seiders, R. P.; Sealye D. E.; Steward, R. R. Pestic. Sex. 1984, 15, 509.

18. Henrick, C. A.; Garcia, B. G.; Staal, G. B.; Cerf, D. C.; Anderson, R. J.; Gill, K.; Chinn, H. C.; Labovitz, J. N.; Leippe, M. M.; Woo, S. L.; Carney, R. L.; Gordon, D. C.; Kohn, G. K. Pestic. Sci. 1980, 11, 224.

19. Elliott, M.; Janes, N. F. J. Chem. Soc. rev. 1978, 473.

20. US PATENT 4, 423, 068.

2 1 • Patent 4, 225, 553.

22. Anderson, R. J.; Adams, K. G.; Henrick, C. A. J. Agric. Food, Chem. 1985, 33, 508. ~

23. US Patent, 4, 225, 553

CHAPTER THREE

CARBAMATE PYRETHROID ESTERS

Introduction

During past years stereochemical requirements for both

acid and alcohol moieties of active pyrethroids have been

studied extensively and configurational characteristics have

been determined in an effort to relate structure and

bioactivity. (1-7). The configuration at certain chiral

centers must be properly oriented for a complementary

biological receptor. With stereoisomers of pyrethroid

esters, e.g.,cypermethrin and decamethrin, the

(R)-configurations (a-carbon) of the acid moieties are more

active than those with the S-configuration (8, 9, 10).

Similarly, with fenvalerate and related acids, the first

potent "pyrethroid" without the cyclopropane ring (11), the

(R)-isopropyl acetates are much less active than their

(S)-enantiomers (12). Again, with fluvalinate, the

(R)-enantiomer of the a-carbon of the acid moiety shows a

higher insecticidal activity than does the (S)-enantiomer

(y). However, the stereochemical structure in this chiral

carbon of fluvalinate is equivalent to that of fenvalerate

and the conventional cyclopropane-carboxylate pyrethroids,

indicating a similar biological complementary receptor for

46

47

those structures (Fig 13).

There have been some studies reporting the elimination

of certain chiral centers in the acid moieties. With a

nitrogen atom in the cyclopropane ring, forming the

aziridine group, the carbamic acid esters derived therefrom

gave pyrethroid-like compounds, but had decreased

insecticidal activity (14, 15). Later reports showed that

carbamates bearing the N tert butyl, N-benzyl, and

N-(a-substituted)benzyl groups had some insecticidal

activity when esterified to pyrethroid alcohols. (16).

It has been reported that the bioactivity of

fenvalerate-related pyrethroids is quite sensitive to

structural modifications (17, 18, 19). The substitution of

a nitrogen atom for the <x-carbon atom of the fenvalerate

acid moiety would result in the loss of a chiral center of

this acid. In the resulting fenvalerate isostere,

substituents attached to the nitrogen atom, via a rapid

inversion process (20), could assume either the (R)- or

(S)-configuration, adapting to a stereospecific receptor

site. The effects on insecticidal properties of various

substituents on the phenyl moiety of the fenvalerate

nitrogen isosteres have not been published.

In those cases where methylene or substituted methylene

has been inserted between a phenyl group and a carbamate

function (21), the esters with pyrethroid alcohols have

produced compounds with intermediate levels of insecticidal

48

Fig. 13: The configuration of cypermethrin, fenvalerate,

and fluvalinate.

H * * \ h

ACID R AL S

C Y P E R M E T H R I N

\ /

ACID S AL S FENVALERATE

V = H

N - *

H • 0 .

H C N

ACID R AL S FLUVALINATE

C H I R A L C A R B O N

49

activity. These products would closely resemble the

stereochemistry of fluvalinate if an isopropyl group were

attached to the carbamate nitrogen atom. Such compounds

would provide additional structural and stereochemical

information that could be utilized for the better

understanding of structure-activity relationships of the

pyrethroid-like insecticides.

We wish to report the synthesis and preliminary

toxicity data which relate to a structural and stereo-

chemical study of pyrethroid-like carbamates. These

carbamates were obtained from the coupling of N-isopropyl-

aniline, N-isopropyl benzylamine (synthetic scheme, Fig.14),

or a-(substituted)-benzylamine (synthetic scheme, Fig. 15)

derivatives with various chloroformates (synthetic scheme,

Fig. 16 and Fig. 17 ) prepared from appropriate pyrethroid

alcohols.

Experimental

Experimental Techniques

Infrared spectra were measured on a Perkin-Elmer 1330

spectrometer. The structures of products were confirmed by

proton nuclear magnetic resonance spectra employing either

the Hitachi Perkin-Elmer R24-B or the Varian VXR-300 FT-NMR

spectrometer. Melting points are uncorrected. Elemental

analyses were performed by Midwest Microlab, Indianapolis,

IN; analyses are indicated by elemental symbols and were

within ± 0.4% of the theoretical values. (R)-<x-Methyl-

50

Fig. 14: Synthetic scheme for N-isopropylaniline and

N-isopropylbenzylamine derivatives

R l ^ ^ N H 1) <CH3)2CO 2 2) NABH 4/ 5°C

NH

2) NABH 4/ 5 C

Ri = H , H A L O G E N , ( C H 3 0 ) N , -OCH2O-

R2 = W , CH3

51

Fig. 15: Synthetic scheme for a-(substituted)-benzylamine

and ex, ( X - ( d i m e t h y l ) b e n z y l a m i n e derivatives.

-Q-r- HSsr -Ok-

CH 3 CH d L ^ NCL3/ALCL3/T-BUBR I 3

Ri-CHh ' R>-Cb"NH2

CH3 CH3

R I = H , H A L O G E N , 4-CH30

RZ = CH3 , C2H5 , Y

52

Fig. 16: Synthetic scheme for various chloroformates.

0

C0Ct_2 / ETHER •' R ~ M / ~ \ M / / . „ x > R - O - C - C L

< ^ - N ( C H 3 ) 2

53

Fig. 17: Synthetic scheme for the condensation of

carbamates.

?4 n J , R l R4 R 5 — O C - C L , I NH

k,

R i = H , H A L O G E N , N-(CH30)N-

R2, Rs= H , CH 3 , C 2 H 5 , Y R 4 = H , ISOPROPYL D

5 = P Y R E T H R O I D A L C O H O L S

N - C O O R 5

Rl R2R4 n R 2 R K l x £ ^ \ J. L R s — O C - C L R u p ^ . ' 1 C-NH > < N ) V C - N - C 0 0 R .

3

54

benzylamine and (RS)-a-methyl-benzylamine racemic mixture

(Aldrich Chemical Co., Milwaukee WI) were individually used

to prepare the N-( (R)-<x-methyl-benzyl)-N-isopropyl carbamate

and its (RS)-counterpart. For column chromatography, silica

gel (60-300 mesh, Fisher Scientific Company )was used.

Radial thin-layer chromatography was carried out by using a

Harrison Model Chromatotron provided with a 2-mm silica gel

rotor. For thin-layer chromatography, silica gel plates

from Eastman Kodak Company were employed.

Insect Bioassays

Bioassays were conducted by the Biological Evaluation

Laboratory, Gilmar Center, Madison, WI. The experimental

protocol fellows: Four day old female houseflies (F58 WT II

strain, about 25 mg each) were anesthetized and arranged on

a screen ventral side up. One microliter of sample

(0.000025%-l.0% in acetone)was applied to the abdomen. In

synergized toxicity studies, the houseflies were dosed with

400 ppm of piperonyl butoxide (PB) applied to the abdomen,

and one hour later on one microliter of the carbamate

samples was applied. With each compound studied, 10 flies

were employed in each test, and all tests were conducted in

duplicate. Mortality was recorded after 24 hours and

average percent mortality was determined. Controls, acetone

only or synergist(PB) only, were included in each toxicity

study. The LDS0 values, the dose required for 50% mortality,

were determined by probit analyses (22). Fenvalerate and

55

fluvalinate were employed in the evaluations as referance

insecticides. In the instances where compounds exhibited

low housefly toxicities, LDS0 values were not determined.

Organic Synthesis

General procedure for the preparation of chloroformates

(synthetic scheme, page 52). Fyrethroid alcohol (20

mmoles) and N,N-dimethylaniline (26 mmoles) were dissolved

in 50 ml of dry ether. Phosgene (80 mmoles) was condensed

into 200 ml of dry ether at 0°C. To the phosgene solution,

the alcohol and N,N-dimethylaniline solution was slowly

added. The mixture was maintained at 0°C. for 3 hours and

then stirred for 3 hours (in the hood) at room temperature.

The solvent was removed in vacuo. The residue was then

taken up in 100 ml of ether and extracted with water, 3%

hydrochloric acid, and finally with saturated sodium

chloride solution. After drying, the ether was removed to

give an oil which, based upon NMR analysis, was sufficiently

pure to use in subsequent condensations with appropriate

amines.

3-Phenoxybenzyl chloroformate (I) Phosgene, 12 g, was

condensed into 100 ml of diethyl ether cooled to 0°C in a

salt-ice bath. 3-Phenoxybenzyl alcohol, 4.0 g, with 3.0 g

of N,N-dimethylaniline in 30 ml of diethyl ether was slowly

added. The mixture was stirred for 3 hours in an ice bath,

then overnight at room temperature. The diethyl ether was

removed in vacuo. The residue was then taken up in 100 ml

56

of ether and washed with 2 x 50 ml water, 3 x 50 ml 3%

hydrochloric acid, 3 x 20 ml 5% sodium carbonate and 1 x 50

ml of saturated sodium chloride solution. Upon evaporation

of the diethyl ether, 4.95 g of light yellow oil was

obtained. The yield was 95%. NMR (CDC13): £ 6.5-7.4 (9H, m,

Ar) and 5.1 (2H, s, Bz);IR 1770 cm-* (C=0).

2,3,4,5,6-Pentafluorobenzyl chloroformate (II)

2,3,4,5,6-Pentafluorobenzyl alcohol, 4.0 g, with 3.0 g of

N,N-dimethylaniline in 30 ml of diethyl ether, was slowly

added to 100 ml of diethyl ether containing 12 g of phosgene

(see the general procedure). After working-up and drying,

the ether was removed to give 4.3 g of oily product. The

yield was 81%. NMR (CDCl3): i 5.2 (2H, s, Bz); IR 1780 cm"i

(C-0).

0(-Cyano-3-phenoxybenzyl chloroformate (III)

3-Phenoxybenzyl cyanohydrin was prepared by the method of

Ruzo et al. (23). 3-Phenoxybenzyl cyanohydrin, 7 g, in 30

ml of diethyl ether, was added to 100 ml of ether containing

12 g of phosgene at 0°C. N,N-Dimethylaniline, 4.9 g, in 30

ml of ether was slowly added to the above mixture 20 minutes

later. Work up of chloroformate was by the same method as

in the general procedure and gave 7.5 g of product. The

yield was 85%. NMR (CDCl3): & 6.1(1H, s, Bz)and 6.6-7.4(9H,

m, Ar); IR 1770 cm-i (C=0)and 2240 cm-i (CN).

2-Methyl-3-phenylbenzyl chloroformate (IV) 2-Methyl-

(1,1 -biphenyl)-3-methanol, 10 g, and 22 g of phosgene with

57

6.7 g of N,N-dimethylaniline in dry diethyl ether solution

were combined dropwise as described in the general

procedure. Upon evaporation of the diethyl ether, 12.3 g of

light yellow oil was obtained. The yield was 94%. Based

upon NMR analysis, the product was sufficiently pure to use

in subsequent condensations with appropriate amines. NMR

(CDC13) : £ 7.35-7.00(8H, m, Ar), 5.25(2H, s, Bz), and 2.15

ppm (3H, s, Me); IR 1760 cm-* (C=0).

General procedure A — preparation of N-isopropyl

aniline and benzylamine derivatives (synthetic scheme, page

50). The method employed was similar to that reported

earlier (24). Glacial acetic acid, 5 ml, 2.5 g of sodium

acetate trihydrate, and 10 ml of acetone were placed in a

stirring flask at 0°C. Sodium borohydride, 4.0 g, was added

in 30 mg portions over a 20 minute period to a stirred

solution of the aniline or benzylamine derivative (20.2

mmoles) in 5 ml ethanol, keeping the temperature under 10°C.

Then the mixture was washed with 2 x 50 ml of water. The

ether solution was then evaporated to dryness. The residue

was purified by chromatography on silica gel (eluted with

hexane:ethyl acetate, 12:1, V/V).

General procedure B -- preparation of ((X-substituted)

benzylamine derivatives (synthetic scheme, page 51).

Benzylamine derivatives were prepared by a modification of

the procedure of Borch et al. (25). <x-Substituted phenyl

ketone (10 mmoles), ammonium acetate (100 mmoles), and

58

sodium , cyanoborohydride (8 mmoles) in 30 ml of absolute

methanol was stirred 48 hr at 25°C. Concentrated HCl was

added until pH 2, and the methanol was removed in vacuo.

The residue was taken up in 10 ml of water and extracted

with 3 x 20 ml portions of ether. The aqueous phase was

brought to pH 10-11 with solid KOH, saturated with NaCl, and

extracted with 5 x 15 ml portions of ether. The combined

extracts were dried with magnesium sulfate and evaporate in

vacuo to give an oil which, based on NMR analysis, was

sufficiently pure to use in subsequent condensation with

appropriate chloroformates.

N-Isopropyl-aniline (V). Sodium borohydride, 4.0 g,

and 1.8 g of aniline in 5 ml of acetone were slowly combined

using the general procedure A. After rotary evaporation 1.3

g of oily product was obtained for a 50 % yield. NMR (CDC13)

: 6 7.25-6.30(5H, m, Ar), 3.45( 1H, m, C-H), 2.1(1H, d, N-

H), and 1.08 ppm(6H, d, Me).

N-Isopropyl-4-chloroaniline (VI). 4-Chloroaniline, 2.6

g in 5 ml of acetone, and 4.0 g of sodium borohydride were

combined according to the general procedure A. The

evaporation of diethyl ether left 2.1 g of oily product for

a 61% yield. NMR (CDCl3) : £ 7.15-6.35 (4H, m, Ar), 3.40(

1H, m, C-H), 2.2(1H, d, N-H), 1.14(6H, d, Me).

N-Isopropyl-4-methoxyaniline (VII). Sodium

borohydride, 4.0 g, and 2.45 g of 4-methoxyaniline in 5 ml

of acetone were slowly reacted in the same manner as in

59

general procedure A and gave 1.82 g of oily product for a

55% yield. NMR (CDC13) : S 7.35-6.80 (4H, m, Ar), 3.80(3H,

s, MeO), 3.45 (1H, m, C-H), 2.15 (1H, d, N-H), 1.07(6H, d.

Me) .

N-Isopropyl-3-methoxyaniline (VIII). Sodium

borohydride, 3-methoxyaniline, and acetone were slowly mixed

in the same manner and proportions as for compound VII and

gave 1.95 g of oily product for a 60% yield. NMR (CDC13) :

& 7.40-6.85 (4H, m, Ar), 3.75 (3H, s, MeO), 3.40 (1H, m, C-

H), 2.10 (1H, d, N-H), and 1.10 ppm(6H, d, Me).

N-Isopropyl-3,4-methylenedioxyaniline(IX). Sodium

borohydride, 4 g, was portionally added to the solution

containing the 2.75 g of 3,4-methylenedioxyaniline in 5 ml

of acetone following as the general procedure A. The

purification 2.1 g of product was received and given a 58%

yield. NMR(CDC13) : 6 7.35-6.60 (3H, m, Ar), 5.90 (2H, s,

OCHzO), 3.45 (1H, m, CH) , 2.05 (1H, d, NH), and 1.16 ppm

(6H, d, Me).

N-Isopropyl-3,5-dimethoxyaniline (X). Sodium

borohydride, 4.0 g, was portionally added to 3.1 g of

3,5-dimethoxyaniline in 5 ml of acetone in the same manner

as were general procedure A and given 1.9 g of product after

the purification. NMR (CDC13) : 6 7.30-6.65 (3H, m, Ar),

3.75 (6H, s, MeO), 3.45( 1H, m, CH), 2.15( 1H, d, NH), and

1.11 ppm( 6H, d, Me).

60

N-Isopropyl-3,4,5-trimethoxyaniline (XI). Sodium

borohydride, 4.0 g, was added to 3.6 g of 3,4,5-trimethoxy

aniline in 5 ml of acetone following the general procedure

A. The purification of crude product gave 2.2 g of product

for a 48% yield. NMR (CDC13) : £ 7.15(2H, s, Ar), 3.85(9H,

d, MeO), 3.50(1H, m, CH), 2.25(1H, d, NH), and 1.13 ppm (6H,

d, Me).

N-Isopropyl-4-chlorobenzylamine (XII). Compound XII

was synthesized by the general procedure A. Sodium

borohydride, 4.0 g, was portionally added to 2.83 g of

4-chlorobenzylamine in 5 ml of acetone. Purification by

silica gel chromatography gave 2.6 g of product for a 70%

yield. NMR (CDC13): 6 7.00-7.25 (4H, d, Ar), 3.20 (2H, d,

Bz), 2.75 (1H, m, CH-N), 1.50 (1H, m, NH), and 1.13 ppm (6H,

d, Me).

N-Isopropyl-(RS)-methylbenzylamine(XIII). Sodium

borohydride, 4 g, was added to the solution containing 2.40

g of (RS)-methylbenzylamine in 5 ml of acetone in the same

method as the general procedure A. After purification 2.1 g

of oily product was obtained for a 65% yield. NMR (CDCl3):£

7.15 (5H, s, Ar), 3.80 (1H, m, Bz). 2.65 (1H, m, CH-N),

1.40 (4H, d, NH and Me-Bz) and 1.15 ppm (6H, d, Me).

N-Isopropyl-(R)-methylbenzylamine (XIV). The procedure

for synthesis of compound XIII was employed. Following

purification by silica gel chromatography 1.95 g of product

was obtained. NMR (CDC13):<S 7.15 (5H, s, Ar), 3.80 (1H, m,

61

Bz) 2.65 (1H, m, CH-N), 1.40 (4H, d, NH and Me-Bz) and 1.15

ppm (6H, d, Me) .

ot-Methyl-4-chlorobenzylamine (XV). A solution of 4-

chloroacetophenone, 5.0 g, and ammonium acetate, 24.9 g, and

sodium cyanoborohydride, 1.6 g, was prepared according to

the general procedure B. After dryness 3 g of oily product

was obtained and gave a 74% yield. NMR(CDCl3) : £ 7.10 (4H,

s, Ar), 3.95(1H, m, Bz), and 1.45 ppm (5H, m, NH2 and Me).

<x-Ethyl-4-chlorobenzylamine (XVI) . 4-Chloropropio-

phenone, 5.0 g, ammonium acetate, 22.8 g, and sodium

cyanoborohydride, 1.48g, were reacted in the same method as

the general procedure B. The light yellow oily product (

2.8 g ) was obtained for a 70% yield. NMR(CDC13) : £

7.17(4H, s, Ar), 3.80(1H, m, Bz), 1.65(4H, m, NH2 and CH2),

and 0.90 ppm(3H, t, Me).

(X-Cyclopropyl-4-chlorobenzylamine (XVII) .

4-Chlorophenyl cyclopropyl ketone, 3.0 g, ammonium acetate,

12.8 g, and sodium cyanoborohydride, 0.84 g, were combined

and stirred at 65°C for 1 day. The work up and purification

by general procedure B gave 1.8 g of light yellow oil for a

61% yield. NMR(CDCl3) : £ 7.15 (4H, s, Ar), 3.85(1H, H,

Bz), 2.05(1H, m, CH), 1.60 (2H, m, NHZ), and 0.30 ppm(4H, d,

CH2) .

tt-Ethyl-4-fluorobenzylamine (XVIII). Sodium cyanoboro-

hydride, 1.50 g, was added to the mixture of 4.5 g of

4-fluoropropiophenone and 22.8 g of ammonium acetate. After

62

work up and purification 3.0 g of white oil was obtained for

a 66% yield. NMR(CDCl3) : £ 7.15(4H, s, Ar), 3.85(1H, m,

Bz), 1.55(4H, m, NH2 and CH2), and 0.88 ppm (3H, t, Me).

<x-Ethyl-4-bromobenzylamine (XIX) . 4-Bromopropio-

phenone, 5.0 g, ammonium acetate, 18.0 g, with 1.25 g of

sodium cyanoborohydride were combined according to the

general procedure B and gave 2.8 g of white oily product for

a 63 % yield. NMR(CDC13) : £ 7.05(4H, s, Ar), 3.82(1H, m,

Bz), 1.50(4H, m, NH2 and CH2), and 0.85 ppm(3H, t, Me).

<x-Ethyl-4-methoxybenzylamine (XX) . Sodium

cyanoborohydride, 1.53 g, was added to 5.0 g of 4-methoxy-

propiophenone with 23.4 g of ammonium acetate according to

the general procedure B to give a 3.2 g of white oily

product for a 65% yield. NMR(CDCl3) : £ 7.10(4H, s, Ar),

3.80(1H, m, Bz), 3.78(3H, s, MeO) 1.65(4H, m, NH2 and CH2),

and 0.84 ppm (3H, t, Me).

tt-Ethyl-2,4-dichlorobenzylamine (XXI). 2.4-Dichloro-

propiophenone, 5.0 g, 18.9 g of ammonium acetate, and 1.24 g

of sodium cyanoborohydride were reacted as in the general

procedure B to give 3.0 g oily product for a 60% yield.

NMR(CDC13) : £ 7.13(3H, s, Ar), 3.91(1H, m, Bz), 1.60(4H, m,

NH2 and CH2), and 0.86 ppm(3H, t, Me).

ot, «-Dimethyl-4-bromobenzylamine (XXII). The method

employed for the preparation of <x, <x-dimethyl-4-bromo-

benzylamine was similar to that reported earlier (26).

4-Bromocumene, 20 g, in 50 ml of 1.2-dichloroethane was

63

cooled to 0°C, and 2.7 g of aluminum chloride was added in

one portion followed immediately by 3.4 ml of t butyl

bromide. At this point, the reaction mixture became

homogeneous except for a very small amount of solid,

presumably undissolved aluminum chloride. Trichloramine was

prepared by the method of Kovacic et al. (27).

Trichloroamine, 20 ml, was added dropwise to the above

mixture under nitrogen during 10 min at 0°C. After an

additional 5 min, the reaction mixture was poured over ice-

hydrochloric acid and extracted with 3 x 30 ml portions of

ether. The acidic aqueous phase was neutralized by 2N KOH

solution and extracted with diethyl ether. After rotary

evaporation of the acidic extract, 0.75 g of oily product

was obtained for a 35% yield. NMR(CDCl3) : £ 7.20(4H, s,

Ar), 1.70(2H, s, NH), and 1.45 ppm (6H, s, Me).

General procedure C -- preparation of carbamate esters

of N-isopropyl-N-phenyl derivatives (synthetic scheme, page

53). A solution of the appropriate chloroformate (5 mmoles)

in 10 ml of anhydrous benzene was added dropwise to a

stirred solution of the N-isopropylaniline (5 mmoles) with

0.5 g of triethylamine in 5 ml of anhydrous benzene. The

solution was maintained at 0°C for 3 hours under nitrogen.

Stirring was continued overnight at room temperature. The

precipitated triethylamine hydrochloride salt was filtered;

the benzene was washed with 2 x 25 ml 3% hydrochloric acid

and 1 x 25 ml saturated sodium chloride solution and removed

64

in vacuo. The residue was purified by radial chromatography

on silica gel (developed with hexane: ether, 12:1,V/V). If

the pure product was a solid, it was recrystallized from

petroleum ether.

General procedure D -- preparation of carbamate esters

of N-isopropyl-N-benzyl and N-benzyl derivatives (synthetic

scheme, page 53). An appropriate chloroformate (5 mmoles)

and an N-isopropylbenzylamine derivative (10 mmoles) were

combined dropwise as in procedure C. The mixture was

stirred for three hours in an ice bath, then washed with 2 x

25 ml 3% hydrochloric acid and 1 x 25 ml saturated sodium

chloride solution. The mixture was purified by radial

chromatography on silica gel (developed with hexane: ethyl

acetate, 10:1, V/V).

0-3-Phenoxvbenzyl-N-3,4-methylenedioxyphenyl carbamate

(XXIII). Chloroformate (I), 1.3 g, 0.7 g of 3,4-methylene-

dioxyaniline, and 0.55 g of triethylamine were combined

according to procedure C. The rotary evaporation of ether

left 1.54 g of a white solid with a melting point of 85 to

86 °C after the recrystallization. NMR (CDC13): S 7.45-6.75

(12H, m, Ar), 5.93 (2H, S, 0CH20), and 5.15 ppm (2H, s, Bz);

IR 1710 cm-1 (C=0); Elemental analysis for C 2 1 H17N05, Calcd

: C , 69.40 ; H , 4.71. Found : C , 69.04 ; H , 4.50.

O-3-Phenoxybenzyl-N-isopropyl-N-phenyl carbamate

(XXIV). Triethylamine, 1.5 g, and 0.68g of aniline

derivative (V) were combined with 1.3 g of chloroformate (I)

65

according to general procedure C. The diethyl ether was

rotary evaporated and purified to give 1.45 g of oily

product for a 80% yield. NMR (CDCl3): £ 7.45-6.80 (14H, m,

Ar), 5.12 (2H, s, Bz), 4.62 (1H, m, CH), and 1.13 ppm (6H,

d, Me); IR 1690 cm-i (C=0) ; Elemental analysis for

C2 3H2 3N03' Calcd : C , 76.43 ; H , 6.41. Found : C ,

76.05 ; H , 6.10.

0-3-Phenoxybenzyl-N-isopropyl-N-4-chloro-phenyl

carbamate (XXV). N-Isopropyl-4-chloroaniline (VI), 0.84 g,

and 1.5 g of triethylamine were reacted with 1.3 g of

chloroformate (I) according to general procedure C. After

purification by silica gel chromatography and

recrystallization from petroleum ether, 1.48 g of a white

solid was obtained (m.p. 54-55°C ). NMR (CDC13): S

7.47-7.47 (13H, m, Ar), 5.17 (2H, s, Bz), 4.66 (1H, m, CH),

and 1.18 ppm (6H, d, Me); IR 1695 cm-1 (c=0); Elemental

analysis for CZ3H2ZC1N03, Calcd : C ,69.77 ; H , 5.60.

Found : C , 6 9 . 8 6 ; H , 5.49.

0-3-Phenoxybenzyl-N-isopropyl-N-4-methoxyphenyl

carbamate (XXVI). Compound XXVI was synthesized by the same

method as general procedure C. Chloroformate (I), 1.5 g, 0.9

g of aniline derivative (VII), and 0.6 g of triethylamine

were combined; after purification by silica gel

chromatography and recrystallization 1.5 g of white solid

was obtained for a 70% yield. The melting point of the

product was 59° to 61°C. NMR (CDCl3): S 7.38-6.85 (13H, m,

66

Ar), 5.09 (2H, s, Bz), 4.60 (1H, m, CH), 3.81 (3H, s, MeO),

and 1.09 ppm (6H, d, Me); IR 1675 cm-i (C=0); Elemental

analysis for C 2 4H 2 5N0 4, Calcd : C , 73.64 ; H , 6.44.

Found : C , 73.85 ; H , 6.42.

0-3-Fhenoxybenzyl-N-isopropyl-N-3-methoxyphenyl

carbamate (XXVII). The procedure for synthesis of compound

XXVI was employed. Following purification by silica gel

chromatography 1.3 g of oil was produced for a 66% yield.

NMR (CDC13): £ 7.40-6.64 (13H, m, Ar), 5.09 (2H, s, Bz),

4.58 (1H, m, CH), 3.77 (3H, s, MeO), and 1.12 ppm (6H, d,

Me); IR 1695 cm"* (C=0). Elemental analysis for C 2 4H 2 5No 4,

Calcd : C , 73.63 ; H , 6.44. Found : C , 73.42 ; H , 6.49.

0-3-Phenoxybenzyl-N-isopropyl-N-3,4-methylenedioxy-

phenyl carbamate (XXVIII). Compound (XXVIII) was

synthesized employing general procedure C. Chloroformate

(I), 1.3 g, 0.9 g of aniline derivative (IX), and 0.55 g of

triethylamine were combined and gave 1.3 g of oily product

after silica gel chromatography. NMR (CDC13): £ 7.45-6.56

(12H, m, Ar), 5.94 (2H, s, 0-CH20), 5.16 (2H, S, Bz), 4.62

(1H, m, CH), and 1.17 ppm (6H, d, Me); IR 1695 cm-1 (C=0);

Elemental analysis for C 2 4H 2 3N0 4, Calcd : C , 71.09 ; H ,

5.71. Found : C , 70.85 ; H , 5.54.

0-3-Phenoxybenzyl-N-isopropyl-N-3,5-dimethoxyphenyl

Carbamate(XXIX). 3-Phenoxybenzyl chloroformate (I), 1.4 g,

1.05 g of the 3,5-dimethoxyaniline derivative (X), and 0.6 g

of triethylamine were combined as in general procedure C.

67

Following purification by silica gel chromatography 1.2 g of

oily product was obtained for a 60% yield. NMR (CDCl3):

7.40-6.85 (12H, m, Ar), 5.10(2H, s, Bz), 4.54(1H, m, CH),

3.75(3H, s, MeO), and 1.13 ppm (6H, d. Me); IR 1695 cm"i;

Elemental analysis for C25H2<t:N05 , Calcd : C , 71.23 ; H ,

6.46 . Found : C , 71.26 ; H , 6.65.

0-3-Phenoxybenzyl-N-isopropyl-N-3,4,5-trimethoxyphenyl

carbamate (XXX). Aniline derivative (XI), 1.15 g, and 1.5 g

of triethylamine were reacted with 1.35 g chloroformate (I)

according to the general procedure C in the absence of

light. After purification by silica gel chromatography 1.35

g oily product was obtained. NMR (CDC13) : £ 7.40-6.88(11H,

m, Ar), 5.12 (2H, s, Bz), 4.57(1H, m, .CH), 3.83(9H, d, MeO),

and 1.14 ppm(6H, d, Me); IR 1675 cm-i (C=0); Elemental

analysis for C26H29N06 , Calcd : C , 69.16 ; H, 6.47.

Found ; C , 69.39 ; H , 6.62.

0-2,3,4,5,6-Pentafluorobenzyl-N-isopropyl-N-

-3,4-methylene dioxyphenyl carbamate (XXXI). Compound

(XXXI) was synthesized by general procedure C.

Pentafluorobenzyl chloroformate (II), 1.3 g, 0.9 g of

aniline derivative (IX), and 0.55 g of triethylamine were

combined and gave 1.2 g of white solid after

recrystallization. (m.p. 88-89°C.) NMR (CDC13) : 6

6.85-6.50 (9H, m, Ar), 5.99(2H, s, 0CH20), 5.17(2H, s, Bz),

4.53(1H, m, CH), and 1.09 ppm (6H, d, Me); IR 1695 cm-1

(C=0); Elemental analysis for C 1 8H 1 4F 5N0 4, Calcd : C ,

68

53.56 ; H , 3.23. Found : C , 53.83 ; H , 3.34.

0- C(-Cy a n o-3-phenoxybenzyl-N-isopropyl-N-3,4-methylene-

dioxyphenyl carbamate (XXXII) . <x-Cyano-3-phenoxybenzyl

chloroformate (III), 1.44 g, and 1.8 g of aniline derivative

(IX) were combined as in general procedure C. Following

purification by silica gel chromatography 1.1 g of oily

product (50% yield) was obtained. NMR (CDCl3) : S

7 .50-6.70(12H, m, Ar), 6.35(1H, s, Bz), 6.00(2H, s, OCHzO),

4.51(1H, m, CH), and 1.15 ppm(6H, d, Me); IR 1705 cm 1

(C=0); Elemental analysis for C 2 5H 2 2N 20 5 , Calcd : C ,

69.80 ; H , 5.15. Found : C , 70.44 ; H , 5.30.

0-«-Cyano-3-phenoxybenzyl-N-isopropyl-N-4-chlorophenyl

carbamate (XXXIII). Compound (XXXIII)was synthesized by

general procedure C. Chloroformate (III), 1.4 g, was

combined with the 1.7 g of aniline derivative (VI). After

purification by silica gel chromatography 1.05 g of oily

product was obtained. NMR (CDC13) : <S 7.50-6.80(13H, m,

Ar), 6.37(1H, m, Bz), 4.53(1H, m, CH), 1.14 ppm(6H, d, Me);

IR 1705 cm-1 (C=0); Elemental analysis C2 4H 2 ̂ lN^jC^, Calcd :

C , 68.48 ; H , 5.03. Found : C , 68.46 ; H , 5.02.

Q-(X-cyano-3-phenoxybenzyl-N-4-chloro-benzyl Carbamate

(XXXIV). Chloroformate (III), 1.43 g, slowly added to 1.45

g of 4-chlorobenzylamine according to general procedure D.

After work up and purification by chromatography 1.3 g of

white solid was obtained for a 66% yield. (m.p. 77-75°C.)

NMR (CDCl3) : £ 7.35-6.85(13H, m, Ar), 6.30(1H, s, Bz-CN),

69

5.30 (1H, d, NH), and 4.25 ppm(2H, d, Bz); IR 1720 cm-i

(C=0); Elemental analysis for C 2 2H X 7ClN 20 3, Calcd : C ,

67.26 ; H , 4.36. Found : C , 67.01 ; H , 4.15.

0-«-Cyano-3-phenoxybenzyl-N-isopropyl-N-4-chloro-benzyl

carbamate (XXXV). Compound XXXV was synthesized by the same

manner as compound XXXIV. Chloroformate (III), 1.4 g, was

slowly added to 1.85 g of N-isopropylbenzylamine derivative

(XII). After purification by chromatography 1.1 g of oily

product was produced for a 51% yield. NMR (CDC13) : £

7.45-6.90(13H, m, Ar), 6.38(1H, s, Bz-CN), 4.39 (1H, m, CH),

3.46(2H, s, Bz), and 1.14 ppm(6H, d, Me); IR 1700 cm-*

(C=0); Elemental analysis for C 2 SH 2 3C1N Z0 3, Calcd : C ,

69.04 ; H , 5.33. Found : C , 69.41 ; H , 5.60.

0-ot-Cyano-3-phenoxybenzyl-N-isopropyl-N-<x-(RS) -methyl-

benzyl carbamate (XXXVI). Chloroformate(III), 1.43 g was

slowly added to 1.65 g of N-isopropyl-(RS)-methyl

benzylamine in the same manner as in general procedure D.

Following purification by silica gel chromatography 1.05 g

of product was obtained for a 52% yield. Rf=0.28 (TLC, ethyl

acetate: hexane, 1:9, V/V); NMR (CDC13) : S 7.50-6.90(14H,

m, Ar), 6.39(1H, s, Bz-CN), 4.26(1H, m, CH), 3.46(1H, m,

Bz), 1.56(3H, d, Me), and 1.22 ppm (6H, d, Me); IR 1700cm-i

(C=0); Elemental analysis for C2!AH26N203, Calcd : C ,

75.33 ; H , 6.32. Found : c: , 75.01 ; H , 6.15.

0-«-Cyano-3-phenoxybenzvl-N-isopropyl-N-«-(R)-methyl-

benzyl carbamate (XXXVII). The procedure for synthesis of

70

compound XXXVI was again employed. Following purification

by silica gel chromatography there resulted 1.0 g of oily

product for a 49% yield. The product had a single spot and

the same Rf value on TLC as compound (XXXVI). NMR (CDCl3) :

& 7.50-6.90(13H, m, Ar), 6.39(1H, s, Bz-CN), 4.26 (1H, m,

CH) , 3.45(1H, m, Bz), 1.56(3H, d, Me), and 1.20 ppm (6H, d,

Me); IR 1700 cm"i (C=0).

0-(X-Cyano-3-phenoxybenzyl N-(x-methyl-4-chlorobenzvl

carbamate (XXXVIII). Chloroformate (III), 1.35 g, and 1.50

9 of benzylamine derivative (XV) were combined according to

procedure D. The residue was purified by chromatography and

gave 1.4 g of oily product for a 70% yield. Rf=0.44 (TLC ,

ethyl acetate: hexane, 1:9, V/V); NMR(CDC13) : £

7.45-6.55(13H, m, Ar), 6.10(1H, s, CHCN), 5.22(1H, d, NH),

4.58(1H, m, CH), and 1,28 ppm (3H, d, Me); IR 1715

cm-i(C=0).

0-tt-Cyano-3-phenoxybenzyl N-«-ethyl-4-chlorobenzyl

carbamate (XXXIX) . <x-Ethyl-4-chlorobenzylamine (XVI), 1.7

g, and 1.35 g chloroformate (III) were combined by the same

method as general procedure D. Following purification by

chromatography 1.36 g of oil was produced for a 65% yield.

Rf=0.51 (TLC, ethyl acetate: hexane, 1:9, V/V); NMR(CDC13) :

S 7.40-6.60(13H, m, Ar), 6.15 (1.H, s, CHCN), 5.30(1H, d,

NH), 4.38(1H, m, CH), 1.70(2H, m, CHZ), and 0.88 ppm(3H, t,

Me); IR 1715 cm-1 (C=0); Elemental analysis for

Calcd : C , 68.48 ; H , 5.03. Found : C ,

71

68.54 ; H , 5.17.

O-Qt-Cyario-3-phenoxvbenzvl N-<x-ethyl-2,4-dichlorobenzvl

carbamate (XXXX). Compound (XXXX) was synthesized by the

same method as general procedure D. Benzylamine derivative

(XXI), 2.04 g, and 1.35 g of chloroformate (III) were

combined and gave 1.25 g of oily product after silica gel

chromatography. Rf=0.53 (TLC, ethyl acetate: hexane, 1:9,

V/V); NMR(CDC13) : & 7.40-6.58 (12H, m, Ar), 6.10(1H, s,

CHCN), 5.22(1H, d, NH), 4.35(1H, m, CH), 1.65(2H, m, CH2),

and 0.84 ppm(3H, t, Me); IR 1710 cm-i (C=0).

0-(X-Cyano-3-phenoxybenzyl N-«-ethyl-4-fluorobenzyl

carbamate (XXXXI). Compound (XXXXI) was synthesized by

general procedure D. Benzylamine derivative (XVIII), 1.53

g,and 1.35 g of chloroformate (III) were combined and gave

1.25 g of oily product for a 62 % yield after

chromatography. Rf=0.48 (TLC, ethyl acetate: hexane, 1:9,

V/V); NMR(CDC13) : £ 7.35- 6,60 (13H, m, Ar), 6.10(1H, s,

CHCN), 5.25(1H, d, NH), 4.36(1H, m, CH), 1.67(2H, m, CH2),

and 0.82 ppm(3H, t, Me); IR 1710 cm~i (C=0),

O-ot-Cyano-3-phenoxybenzyl N-ot-ethyl-4-bromobenzvl

carbamate (XXXXII). Chloroformate (III), 1.35 g, was added

dropwise to 2,.14 g of a-ethyl-4-bromobenzyl-amine (XIX) as

in general procedure D. Following purification by

chromatography 1.25 g of oily product was obtained for a 55%

yield. Rf=0.46 (TLC, ethyl acetate: hexane, 1:9, V/V);

NMR(CDC13) : £ 7.35-6.60(13H, m, Ar), 6.10(1H, s, CHCN),

72

5.20(1H, d, NH), 4.37(1H, m, CH) , 1.65(2H, m, CH2), and 0.85

ppm(3H, t, Me); IR 1715 cm~i (C=0); Elemental analysis

*-2 4^2 iBrN203, Calcd : C , 61..94 ; H , 4.55. Found : C

, 62.13 ; H , 4.62.

O-g-Cyano-3-phenoxybenzyl N-<x-ethyl-4-methoxybenzyl

carbamate (XXXXIII) . <x-Ethyl-4-methoxybenzylamine(XX), 1.65

g, and 1.35 g of chloroformate (III) were combined according

to general procedure D. After purification by

chromatography 1.30 g of oily product was obtained. Rf=0.44

(TLC, ethyl acetate: hexane, 1:9, V/V); NMR(CDC13) : &

7.32-6.58(13H, m, Ar), 6.10(1H, s, CHCN), 5.18(1H, d, NH),

4.35(1H, m, CH), 3.80(3H, s, MeO), 1.68(2H, m, CHZ), and

0.87 ppm (3H, t, Me); IR 1710 cm~i (C=0); Elemental analysis

C2sH2 4N204' Calcd : C , 72.10 ; H , 5.81. Found : C ,

72.25 ; H , 6.04. C and H.

0-(x-Cyano-3-Phenoxybenzvl N-«-cyclopropyl-4-chloro-

benzyl carbamate (XXXXIV). Chloroformate (I), 1.35 g, was

added to 1.80 g of <x-cyclopropyl-4- chlorobenzylamine

employing general procedure D. After purification 1.0 g of

oily product was obtained for a 48% yield. Rf=0.35 (TLC,

ethyl acetate: hexane, 1:9, V/V); NMR(CDC13) : S

7.45-6.60(13H, m, Ar), 6.12(1H, s, CHCN), 5.20(1H, d, NH),

4.30(1H, m, Bz), 2.15(1H, m, CH), and 0.28 ppm (4H, d, CH2);

IR 1715cm~ 1 (C==0) .

0-«-Cyano-3-phenoxybenzyl N-«,g-dimethyl-4-bromobenzvl

carbamate (XXXXV). a-Cyano-chloroformate (III), 0.45 g, was

73

added slowly to 0.7 g of a, a- dimethyl-4-bromobenzylamine

(XXII) according to general procedure D. After purification

by chromatography 0.37 g of oil was obtained for a 50%

yield. Rf=0.2 (TLC, ethyl acetate: hexane, 1:9, V/V);

NMR(CDCl3) : £ 7.40-6.65(14H, m, Ar), 6.10(1H, s, Bz),

5.15(1H, s, NH), and 1.52 ppm(6H, s, Me); IR 1720 cm"i

(C=0); Elemental analysis C 2 4H 2 1BrN 20 3, Calcd : C , 61.94

; H , 4.55. Found : C , 62.03 ; H , 4.49.

0-2-methyl-3-phenylbenzyl N-<x-ethvl-4-chlorobenzyl

Carbamate (XXXXVI). Chloroformate (IV), 1.30 g, was added

1-7 g of ot—ethyl-4-chlorobenzylamine by the same method

as general procedure D. Following purification by

chromatography 1.60 g of product was obtained for a 81%

yield. Rf—0.52 (TLC, ethyl acetate: hexane, 1:9, V/V);

NMR(CDCl3) : S 7.45-6.90 (12H, m, Ar), 5.02(2H, s, Bz),

4.42(1H, m, CH), 2.10(3H, s, Me-Ar), 1.65(2H, m, CH2), and

0.87 ppm(3H, t, Me); IR 1695 cm™1 (C=0); Elemental analysis

C 2 5H2 4 C 1 N 0 2 , Calcd : C , 73.18 ; H , 6.14. Found : C ,

73.16 ; H , 6.30.

0-2-methyl-3-phenylbenzyl N-<x-ethyl-4-bromobenzyl

Carbamate (XXXXVII) . Benzylamine derivative (XIX), 2.14 g,

and 1.30 g of chloroformate (IV) were combined according to

the general procedure D. After purification by

chromatography 1.70 g of product was obtained for a 78%

yield. Rf=0.57 (TLC, ethyl acetate: hexane, 1:9, V/V);

NMR(CDC13) : £ 7.40-6.90(12H, m, Ar), 5.00(2H, s, Bz),

74

4.40(1H, m, CH), 2.10(3H, s, Me-Ar), 1.68(2H, m, CH2), and

0.88 ppm(3H, t, Me); IR 1695 cm-i(C=0).

Results and Discussion

The insecticidal activity of pyrethroids has been shown

to be very sensitive to structural and stereochemical

variations at certain key regions of the molecule

(28'29/30)- This is particularly true in pyrethroids

structurally related to fenvalerate and fluvalinate (31,32).

In the present study, structural and stereochemical

sensitives relating to the latter two insecticides have been

examined further. Thus, carbon atom chiral centers bearing

the isopropyl group have been replaced with a nitrogen atom.

Such substitutions in the acid moiety were made in an effort

to determine if these compounds (carbamates), which may

undergo nitrogen inversion (33), and thus assume either (R)-

or (S)-configurations, act as effective pyrethroid-like

insecticides.

The compounds prepared fall into two major categories:

carbamate esters derived from 1) N-isopropyl N-phenyl

derivatives and 2) N-isopropyl-N-benzyl and N-benzyl

derivatives. The alcohols employed were among the most

effective of those utilized in other pyrethroid esters.

Preliminary insecticidal activities for these compounds

against pyrethroid-susceptible female houseflies are shown

in Tables IV , V and VI.

The first category is that in which the compounds of

75

interest are carbamates (Table IV) derived mainly from N-

isopropy1-N-phenyl derivatives. Among the compounds XXIII-

XXX, in which the alcohol group is 3-phenoxybenzyl alcohol,

only the one having an N-isopropyl and also a

3,4-methylenedioxy group (compound XXVIII) has any

appreciable housefly toxicity. It should be noted that

compound XXIII, which has a 3,4-methylenedioxy substituent,

but no N-isopropyl substituent, shows very low toxicity

(LE)50 > 400 ppm) . Further, compound XXIV, which has the N-

isopropyl group but does not have an Rx substitution on the

phenyl ring, is of equally low toxicity.

Compound XXXI, which has a carbamic acid moiety

identical to that of compound XXVIII, but is esterified to

pentafluorobenzyl alcohol, has the highest toxicity of the

compounds tested in this series. When synergized with

piperonyl butoxide, its housefly toxicity is enhanced 28

fold. With certain other pyrethroid acids, the use of the

pentafluorobenzyl alcohol substituent has been reported to

give significant insecticidal activities (34). Compounds

XXXII and XXXIII, having the same carbamic acid moiety as in

compounds XXVIII and XXV respectively, but esterified to

a-cyano-3- phenoxybenzyl alcohol, did not exhibit

anticipated enhancement of housefly toxicity.

The second category of compounds studied are the

a-cyano-3-phenoxybenzyl and 2-methyl-3-phenylbenzyl esters

of N-benzyl derivatives (compounds XXX-XXXXVII). Housefly

76

Table IV. Housefly toxicity of substituted N-phenylcarbamates

R i >.

R2 0

I 11

N — C — 0 R 3

Number

LDso ( ug/g )*, **

R 2 Unsynergized Synergized***

R 3 = 3-phenoxybenzyl

XXIII 3,4-•(0CH20) H > 400

XXIV H isopropyl > 400

XXV 4-•CI isopropyl > 400

XXVI 4-•CH3O isopropyl > 4Q * * * *

XXVII 3-•CH3O isopropyl > 400

XXVIII 3,4- (OCH2O) isopropyl 27

XXIX 3,5- (CH30)2 isopropyl > 400

XXX 3 ,4,5- (CH30)3 isopropyl > 400

R3 = 2, 3,4,5,6--pentafluorobenzyl

XXXI 3,4- (0CH20) isopropyl 7

R3 = a-Cyano-3--phenoxybenzyl

XXXII 3,4- (0CH20) isopropyl > 40 * * * *

XXXIII 4-CI isopropyl > 4Q * * * *

Fenvalerate 1.1

0.25

Footnotes see page 80

77

toxicity data for these compounds, are shown in Tables V and

VI. Compound XXXIV, XXXIX, XXXXIII, XXXXIV and XXXXV show

reasonably good potencies against houseflies; compound XXXXV

has a toxicity that is considerably greater than any of the

other compounds studied in this series.

The insecticidal activities of the compounds

synthesized in the present study give some insight into the

requisite structural and steric effects required for

bioactivity. While the relatively high toxicities of some

of the compounds tested do not prove a pyrethroid-like mode

of bioactivity, it is tempting to propose that a mimicry of

such activity is involved. It is apparent, when one

constructs appropriate Dreiding molecular models, that the

steric similarities of these carbamate esters of N-phenyl

derivatives and fenvalerate-like pyrethroids is quite great

( Fig. 18).

Further, because of possible inversions about the

nitrogen atom of the carbamate ester, which negate the

chirality of the <x-position, one may envision a ready steric

fit to the appropriate insect binding site. That such a

ready fit does not apparently occur (based on lower

activities as compared with fenvalerate), suggests that the

conformation envisioned is not cictually produced. One

explanation is that there is coplanarity of the groups about * i

the -N-C=0 functionality of the carbamate esters. Studies

involving carbamates in the solid state (35) and in solution

78

Table v : Housefly toxicity of N-benzyl and N-(a-methyl)-

benzyl carbamates

R

R2 R3 0

H CN

L D s o ( u g / g )*, **

Number Rx R 2 * * * R 3 Unsynergized Synergized****

XXXIVa H

XXXIV 4-C1

XXXV 4-CI

H

H

H

H

H

isopropyl

XXXVI

XXXVII

H

H

CH3(RS) isopropyl

CH3(R) isopropyl

XXXVIII 4-Cl CH- H

> 600*****

24

> 160

> 160

> 1 6 0

> 40

> 600

3.0

40

Fluvalinate 4.0

Footnotes see page 80

79

Table VI Housefly toxicity of N-(a-substituted)-benzyl

and N-((x, (X-dimethyl)-benzyl carbamates

R 2 0

— c -

R 3

— N — r H

• c 0 — R 4

" > s o ( ug/g )*,**

Number RI R 2 *3 Unsynergized Synergized**

R 4 = a-Cyano-3-phenoxybenzyl

XXXIX 4-Cl C2H5 H 26

xxxx 2,4-CI C2H5 H 45

XXXXI F C2H5 H > 160

XXXXII Br C2H5 H > 4Q * * * *

XXXXIII 4 - C H 3 O C2H5 H 35

XXXXIV 4-Cl C3H5 H 18 0.15

xxxxv 4-Br CH3 CH3 3.5 0.012

R 4 = 2-Methyl-3-phenylben zy1

XXXXVI C1 C2H5 H > 160

XXXXVII Br C2H5 H > 400

Fluvalinate

Fnnf nnfcic ^

4.0

80

Table IV notes: ( from page 76 )

*

* *

24-hour mortality for pyrethrin-susceptible female houseflj.es. LD^Q values were obtained by probit analysis of the % kill ; see the biological evaluation section for further details.

^ 5 o values were determined only on those compounds exhibiting 100% kill at 80 ppm or lower.

Synergist, piperonyl butoxide, 400 ppm. See biological evaluation section for further details.

**** Compounds XXVI, XXXII, and XXXIII gave 10%, 10%, 25% kills respectively at the 400 ppm level.

Table V notes: ( from page 78 )

* 24-Hour mortality for pyrethrin-susceptible female houseflies. LD S 0 values were obtained by probit analysis of the % kill; see the Biological Evaluation section for further details.

kDS(j values were determined only on those compounds exhibiting 100% kill at 80 ppm or lower.

*** 2R2; r configuration ; 2RS2: RS racemic mixtures.

**** Synergist, piperonyl butoxide, 400 ppm, see biological evaluation section for further details.

***** Kirino and casida, 1985 (Chapter referance 16)

Table IV notes: ( from page 79 )

* 24-Hour mortality for pyrethrin-susceptible female houseflies. LD50 values were obtained by probit analysis of the % kill; see the Biological Evaluation section for further details.

\

^ s o values were determined only on those compounds exhibiting 100% kill at 801 ppiti or lower.

*** Synergist, piperonyl butoxide, 400 ppm, see biological evaluation section for further details.

**** Compound XXXXII gave 25% kill at 40 ppm level

81

Fig. 18: The apparent steric similarities of N-phenyl

carbamates and fenvalerate-like esters.

: - © R RI

H;

II

N-ANILINE CARBAMATES

iS R l

0

FENVALERATE-LIKE ESTERS

X = SUBSTITUENTS

RI = ALCOHOLS

82

(36) by X-ray crystallography and proton NMR respectively,

indicate that there is indeed some double bond character in

the N-C linkage, similar to that found in amides. The

consequence of this is restricted rotation and coplanarity

of N-substituted groups. An isopropyl group attached to an

sp2 hybridized nitrogen, as in the N—phenyl-derived

carbamates of this study, is thus held in a steric position

that is significantly different from that in which the

attachment is to an sp3 hybridized atom. While the N-

isopropyl substituent appears to be important in these

carbamates in conferring bioactivity (compound XXIII

compared to compound XXVIII), an inability of the N-

isopropyl group to assume a "best fit" alignment for

interacting with the insect binding site may be the

explanation for the generally lower insecticidal activity of

these carbamates as compared with the activities of

fenvalerate derivatives (37).

Several compounds were synthesized that are carbamate

esters of N-benzyl derivatives (compounds XXXIV-XXXXVII).

Compound XXXIVa is placed in Table V for comparative

purposes; biological data for this compound are literature

values (38). The insecticidal data of Table V and VI show

that 1) the isopropyl group on the carbamate nitrogen is

not necessary for bioactivity (compound XXXIV vs. XXXV), 2)

t h e para-chloro group significantly enhances the

insecticidal potency (compound XXXIV vs. XXXIVa; XXXIX vs.

83

XXXX), and 3) a single methyl or ethyl group substitution

on the a-position of the carbamic acid moiety does not

further enhance bioactivity of compounds containing a para-

halo group (compound XXXVIII and XXXIX vs. XXXXV). 4) The

(X cyano-3-phenoxybenzyl alcohol moiety for benzylcarbamates

apparently shows better insecticidal activity than

2-methy-3-phe:nylbenzyl alcohol (compound XXXIX vs. XXXXVI).

Studies by others (39) have also shown that alkyl

substituents (particularly the <x, (X-dimethy substitution) on

the benzylic carbon atom may significantly enhance

insecticidal activity of carbamates derived from non-halo-

substituted N-benzyl group. The halogen-compounds XXXXIV

and XXXXV, having the benzylic substituents cyclopropyl and

dimethyl respectively, do show enhanced activity. Compound

XXXXV, when unsynergized, has a housefly toxicity comparable

to that of fluvalinate (40). This compound is significantly

synergized by piperonyl butoxide (about 300X), and its

housefly toxicity exceeds that reported for synergized

fenvalerate (41)* Comparable pronounced enhancements of

toxicities by the presence of synergist have been reported

for other carbamates, particularly for those in which the

carbamate nitrogen atom is monosubstituted (42, 43, 44).

This could explain the enhanced activity of compound XXXXV.

It would appear that the suggested explanation for the

housefly toxicity patterns of the N—phenyl—derived

carbamates (planarity about the carbamate grouping) is also

84

a valid explanation for the N-benzyl-derived carbamates.

The steric properties of the N-benzyl carbamates appear

ikingly similar to those of the fluvalinate pyrethroids,

if one assumes an sp3 hybridized carbamate nitrogen atom

( Fig. 19). On the other hand, planarity about the

carbamate function, induced by an sp^ hybridized nitrogen

atom, introduces a different geometry. Stereo models show

that the bulky isopropyl group, when attached to the

carbamate nitrogen, is thrust into a very different spacial

region when there is double bond character associated with

the carbamate N-C grouping. Such a steric orientation could

explain why compound XXXIV, which has an unsubstituted

carbamate nitrogen atom, exhibits much greater insect

toxicity than the isopropyl group-substituted compound

XXXV.

An additional interesting product of these observations

results when planarity about the carbamate group is imposed

on the N-benzyl carbamate molecular models. For example,

the Drieding molecular model of the carbamic acid portion of

compound XXXXV, which has gem-dimethyl substituents on the

benzylic carbon atom, can conform to a steric shape similar

to that of the molecular model for cyclopropane ring-

containing pyrethroid acids (e.g. decamethrin, Fig. 20).

This finding suggests that various alkyl substitutions on

the benzylic carbon, coupled with appropriate substituents

on the phenyl group of the N-benzyl moiety, could result in

85

Fig. 19". The apparent steric similarities of N-benzyl

carbamates and fluvalinate-like esters

C -/ \

R R

.N. •c-II 0

0-• R ,

X H

N-i R

c-II 0

N-BENZYL CARBAMATES

-R,

FLUVALINATE-LIKE ESTERS

X = SUBSTITUENTS R : = ALCOHOLS

R = H , ALKYL GROUPS

86

Fig. 20; The apparent steric similarities of N-benzyl

carbamates and cyclopropane ring containing

pyrethroids (e. g. Decamethrin).

BR

CH3 CH3 \ /

?c. H

£

BR

II

0

0 RAL

D E C A M E T H R I N

BR • C

II

0

0 R A L

HALO P Y R E T H R O I D - L I K E

N - B E N Z Y L CARBAMATES

87

compounds having enhanced pyrefchroid-like properties.

Syntheses following these guidelines should be undertaken.

88

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