[ACS Symposium Series] Synthesis and Chemistry of Agrochemicals II Volume 443 || Stereoselective Synthesis and Acaricidal Activity of Novel Thiazolidinones

Chapter 27

Stereoselective Synthesis and Acaricidal Activity of Novel Thiazolidinones

Isamu Kasahara, Nobuo Matsui, Tomio Yamada, Minora Kaeriyama, and Keiichi Ishimitsu

Odawara Research Center, Nippon Soda Company Ltd., Takada, Odawara, 250-02, Japan

Hexythiazox, trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxothiazolidine-3-carboxamide, is a new potent acaricide which has a unique thiazolidinone structure. It has broad acaricidal spectrum and excellent ovicidal, larvicidal and nymphcidal actions. Its synthesis requires stereoselective processes because the trans configuration at p o s i t i o n s 4- and 5- in the thiazolidinone structure is essential for acaricidal activity. We have studied the stereoselective synthesis of phenylpropanolamines as key- intermediates of hexythiazox derivatives and established the novel stereoselective synthetic methods for trans thiazolidinones from phenylpropanolamines.

Spider mites, which belong to Tetranychidae, are distributed widely in the world and are the most important families and species of phytophagous mites in economic terms. They have high b i o t i c potential and under favorable circumstances 1-2 weeks is long enough for a whole development cycle (1). They breed ten generations or more during one vegetation period and cause severe damage to crops. Injury to crops by spider mites has markedly increased in the last

Hexythiazox

0097-6156/91/0443-0340$06.00/0 © 1991 American Chemical Society

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In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

27. KASAHARA ET AL. Acaricidal Activity of Novel Thiazolidinones 341

few decades because of the use of nonspecific insecticides which eliminate the natural enemies of mites and the rapid development of resistance to registered acaricides. For this reason, the discovery of new acaricides which have different modes of action from existing acaricides were earnestly desired.

In the course of development research of f u n g i c i d a l h e t e r o c y c l i c compounds, we found a c a r i c i d a l a c t i v i t y among N-substituted carboxamide derivatives of some 5-membered heterocyclic compounds. In order to inquire into their activity, we synthesized and tested various skeletal compounds. We found that N-cyclohexyl-4,5-disubstituted t h i a z o l i d i n o n e carboxamides have very high ovi c i d a l and l a r v i c i d a l a c t i v i t y against spider mites both in Panonychus and Tetranychus species (2-3). A f t e r development research for optimization, hexythiazox was selected as one of the representative compounds and introduced into the market in 1985. It is now widely used for the control of spider mites in f r u i t s and vegetables in Europe and North America as well as in Japan.

In this paper, the acaricidal a c t i v i t y , structure-activity relationships and synthesis of hexythiazox are discussed.

Acaricidal Activity

In Table 1, the acaricidal activity of hexythiazox against various kinds of mites which damage f r u i t s , vegetables and tea plant i s shown. The E C 5 0 values of hexythiazox against mites are in the range of 0.2 to 1.1 ppm which are one or two orders lower than those of dicofol and cyhexatin. Not only against the mites shown in Table 1, hexythiazox is also active against Panonychus ulmi, so i t s acaricidal spectrum is very broad.

Hexythiazox is highly effective against egg, larva, protonymph and deutonymph stages but i t is not active against adult mites even at 500 ppm ( Figure 1 ). The average number of eggs laid by adult females treated by hexythiazox is almost same as the control, but the hatching of the eggs i s strongly inhibited when the adult females are treated with hexythiazox. Therefore the m i t i c i d a l feature of hexythiazox is enough to control the development of mites even though i t does not k i l l adults directly. Indeed, hexythiazox was successful in controlling citrus red mites for about 70 days in the f i e l d t r i a l when used at very low concentrations of 25-50 ppm (3).

Structure-Activity Relationships

In the course of development research, we inquired into the structure-activity relationships of the corresponding thiazolidinone derivatives. F i r s t , in order to confirm the role of the methyl group at the 4-position in trans stereoconfiguration to the phenyl group at the 5-position, the following matters were investigated.

1) Synthesis of the cis isomer. 2) Replacement of the methyl group by a hydrogen atom. 3) Introduction of another methyl group to the 4-position. 4) Introduction of a double bond between the 4- and 5-

positions. The results are shown in Table 2. The activity was completely lost by these modifications. It is aparent that the methyl group at the

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342 SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

Table 1. Acaricidal A c t i v i t y of Hexythiazox against Various Kinds of Mites. (Reproduced with permission from Ref. 3. Copyright 1987 Pesticide Science Society of Japan.)

E C so (ppm) Miticide T. T. T. P.

urt icae cinnabarinus kanzawai citrib)

Hexythiazox 0.21 0.20 0.40 1.1

Dicofol 8.0 16 13 17

Cyhexatin 6.0 13 4.0 8.0

a) Tetranychus mites : laboratory pot test. P. citri detached leaf test.

b) T. ! TelranuchuH, I*. '. I'anonychus.

L C 5 0 ( p p m )

0.1 A 1 1 1 — 1 Egg Larva Protonymph Deutonymph Adult

Mite Stage

Figure 1. Toxicity of Hexythiazox to T.urticae at Different Developmental Stages. (Reproduced with permission from Ref. 3. Copyright 1987 Pesticide Science Society of Japan.)

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4-position and the trans configuration are necessary to give acaricidal activity.

Therefore, we focussed our attention on the synthesis of the trans isomers and examined the effect of heterocyclic structures. The t h i a z o l i d i n o n e and oxazolidinone d e r i v a t i v e s (4) showed acaricidal a c t i v i t y but the compounds having the structure of imidazolidine, oxazine and aziridine were not active at a l l ( Table 3 ).

Regarding the effect of the carbamoyl moiety, the compounds having a cycloalkyl group were favorable for acaricidal activity. Among them, cyclohexyl group was the most suitable substituent for the a c t i v i t y . When another a l k y l group was introduced into the carbamoyl nitrogen, the activity was decreased remarkably (Table 4).

Then we examined the substituent effects of the benzene ring. Generally, substituents at the para position were most favorable for the a c t i v i t y as shown in the examples of the methyl and chloro substituted compounds. In the para substituted derivatives, the compound with the methyl group was almost as acti v e as the unsubstituted one, but the compounds with larger alkyl groups such as ethyl were less active than the unsubstituted one. On the contrary, the a c t i v i t y of the compounds which have halogen or trifluoromethyl group at the para position was four to six times higher than that of the unsubstituted one ( Table 5 ).

With respect to the substituent effects at the 2- and 4-positions of the t h i a z o l i d i n e r i n g , when the methyl group of hexythiazox was replaced by the ethyl group, the a c t i v i t y was decreased. The compounds having larger a l k y l groups or an ethoxycarbonyl group did not show any activity. For the effect of the position 2, the acaricidal activity varied with the structure in the order of 0 > S > N-CH3 >> NH ( Table 6 ).

Table 2. Acaricidal A c t i v i t y of 2-Thiazolidinones against T.urticae. (Reproduced with permission from Ref. 3. Copyright 1987 Pesticide Science Society of Japan.)

R, Ο R 2 |Ι··Τ-—N-C-NH—

/ Q W ^ S ^ O (di)

R, R 2 E C 50 (ppm)

C H 3 H (/) 1.3 H CH,(c) >125 H H > 125

C H 3 C H 3 >125

_ N H _0 >I25

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344 SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS H

Table 3. Acaricidal Activity of Various Heterocyclic Compounds against T.urticae. (Reproduced with permission from Ref. 3. Copyright 1987 Pesticide Science Society of Japan.)

0 —N-C-NH—

*XA0

(dl)

X EC so (ppm) 0 22 s 1.3 NH >125

H ' < V ~ N - ? - N H - 0

(dO

V > - I - N H - Q

Table 4. Acaricidal A c t i v i t y of 2-Thiazolidinones against T.urticae* (Reproduced with permission from Ref. 3. Copyright 1987 Pesticide Science Society of Japan.)

3 * | N-C -Νζ

w (dl)

R, R 2 EC so (ppm) i-C 3H 7 Η >125 n-CeH,3 Η >125 - o Η 1.3

CH 3 95 Η >125 Η 75 Η 4.9

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27. KASAHARA ET AL. Acaricidal Activity ofNovel Thiazolidinones 345


ο

X/i E C 50 (ppm) X/i E C 50 (ppm)

Η 1.3 4 -F 0.28

2 - C H 3 6.0 4-Br 0.23

3 - C H 3 8.0 4 -CF3 0.19

4-CH3 1.1 4 - C 2 H 5 12

2-CI 83 4 - O C H 3 9

3-CI 2.5 4 - N 0 2 11 4-CI (Hexythiazox) 0.21 3,4-CI 2 60

Based on the structure-activity profiles shown above, a couple of compounds were picked as the candidates from which hexythiazox was selected by considering the activity, the synthetic process and the safety etc.

Synthesis

As mentioned above, the stereochemistry of the t h i a z o l idinone structure is quite important for acaricidal activity. In order to regulate the stereochemistry, a number of synthetic pathways were considered as shown in Scheme 1. In this scheme, we focused our attention on aziridines, chloroamines and aminoalcohols as key-intermediates. We investigated the synthetic process to obtain both cis and trans or erythro and threo isomers of these intermediates (5-6). Here we intend to describe the stereoselective synthesis of the trans isomers which are important for the acaricidal activity ( Schemes 2-4 ).

The erythro aminoalcohols which were one of the most important key-intermediates were synthesized s t e r e o s e l e c t i v e l y by the cat a l y t i c reduction of the corresponding hydroxyiminoketones which were derived from the propiophenones (5) (Scheme 2). Alternatively the erythro aminoalcohols were synthesized by the sodium borohydride reduction of the aminoketones which were obtained by the Gabriel reaction or the Neber rearrangement or some other well-known methods (7-9). The sodium borohydride reduction method can be applied for

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346 SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II


ο

R Ζ E C 5 0 (ppm) CH 3 (Hexythiazox) 0 0.21 C 2 H 5 0 1.0

n - C 3 H 7 0 >125 / • C , H 7 0 >125 - C H 2 - < g > 0 >125 C 0 2 C 2 H 5 0 >125 C H 3 s 1.2 C H 3 NH >125 C H 3 N-CH 3 31

Z : 0 > S > N - C H 3 » N H

^ NR CH-CH—CH 3

SH NH 2

4 4

CH 3

\ Ν

^ N H 2 X n ^ T s J I

Xn

^O^-CH-CH-CH, Y NH 2

Y: CI.OSO3H (vruthro) ithrvo)

CH-CH-CH3 I I OH NH 2

(erythro) ithreo)

Scheme 1. Synthetic Pathway of 2-Thiazolidinones.

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KASAHARA ET AL. Acaricidal Activity of Novel Thiazolidinones

American Chemical Society Library

1155 16th St., N.W. Washington, O.C. 20036

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the compounds having halogenophenyl group whereas the c a t a l y t i c reduction method involves dehalogenation in some cases.

Using these erythro aminoalcohols we succeeded in the stereoselective synthesis of trans thiazolidinones. In Scheme 3, the convenient method to give trans thiazolidinones in an excellent y i e l d is shown (10). We found that the erythro dithiocarbamates which were obtained by the reaction with erythro aminoalcohols, carbondisulfide and benzylbromide were easily cyclized to trans t h i a z o l i d i n o n e s s t e r e o s e l e c t i v e l y by the r e a c t i o n with thionylchloride involving the elimination of the chlorosulfonyl group with inversion. The cyclized intermediates were treated with hydrochloric acid followed by sodium hydroxide to give trans thiazolidinones, retaining the stereochemistry. Furthermore, the treatment of the dithiocarbamates with concentrated hydrochloric acid in ethanol at reflux temperature provided a short-cut pass to give trans t h i a z o l i d i n o n e s . We applied t h i s method for the synthesis of the carbon-14-labeled hexythiazox at the 5-position of the thiazolidinone nucleus.

Scheme 4 shows an other convenient method to give trans thiazolidinones selectively in good yield (11). The reaction of the erythro aminosulfates with carbondisulfide under alkaline condition gave trans thiazolidin-2-thiones stereoselectively with inversion. Then the oxidation of the thiones under basic conditions leads to the trans thiazolidinones. Hexythiazox was obtained by the reaction of the corresponding thiazolidinone with cyclohexylisocyanate. The replacement of carbondisulf ide with carbonylsulf ide simplified the synthetic process but in this case, trans-oxazolin-2-thione was formed as a by-product (12).

Enantiomers

Hexythiazox i s the racemic mixture of (4fl,5i?) and (4S,5S) enantiomers. We synthesized these enantiomers using c h i r a l aminoalcohols as the starting materials and tested their acaricidal activities (13). The (4/?,5/?) enantiomer is twice as active as the racemic mixture, but the (4S,5S) enantiomer is inactive even at 500 ppm. From this result, the active form of hexythiazox is confirmed to be the (4/?,5i?) enantiomer ( Table 7 ).

Conclusion

Hexythiazox i s a new type of potent a c a r i c i d e with very high standard of safety as has been testif i e d by toxicological studies. No toxicological problems arose in chronic t o x i c i t y or in acute t o x i c i t y , e.g. the acute oral L D 5 0 value for rats i s over 5,000 mg/kg.

During the time to develop hexythiazox, we established a novel method of biological tests involving the observation of l i f e cycles of mites. Furthermore, we could overcome some problems in stereochemistry by means of the establishment of stereoselective processes in the synthesis. The success in the development of hexythiazox should depend on such efforts in b i o l o g i c a l , toxicological and synthetic studies after the finding of lead compound.

Hexythiazox, which controls mites for a long period at very low dose, should reduce the labor and expense of mite control in crop

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27. K A S A H A R A E T AI* Acaricidal Activity ofNovel Thiazolidinones 351

T a b l e 7. A c a r i c i d a l A c t i v i t y of Hexyth iazox and I t s E n a n t i o m e r s . (Reproduced wi th p e r m i s s i o n from Ref. 3. Copyright 1987 Pesticide Science Society of Japan.)

(4Λ. 5 Λ ) - ( + )

E C 5 0 (ppm)

Hexythiazox trans

trans (OH) ( 4 Λ 5Λ) (4S, 5S)

0.21 0.09 >500

a) Activity against T.urticae.

protection. We also believe that hexythiazox relieves the rotational use of acaricides so as to extend the l i f e span of other existing acaricides.

Further s tudies on the mode of ac t ion and the resistance problems of hexythiazox are under investigation.

Literature Cited

1. Lunkenheimer, W. In Chemistry of Pesticides; Büche1, Κ. Η., Ed.; John Wiley & Sons: New york, 1983; p 168

2. Iwataki, I.; Kaeriyama, M.; Matsui, N.; Yamada, T. Ger. Offen. 3,037,105, 1981, Chem. Abstr., 1981, 95, 97782d.

3. Yamada, T.; Kaeriyama, M.; Matsui, N.; Yoneda, H. J. Pesticide Sci. 1987, 12, 327.

4. Yamada, T.; Takahashi, H.; Yoneda, H.; Ishimitsu, K.; Matsui, N. Abstr. 5Th Int. Congr. Pestic. Chem., IIa-7, 1982.

5. Smith, H. E.; Burrows, E. P.; Miano, J. D. J. Med. Chem. 1974, 4, 416.

6. Brois, S. J. J. Org. Chem. 1962, 27, 3532. 7. Schmidt, Chr. Ber. 1899, 22, 3249. 8. Neber, P. W.; Gingang Huh. Ann. 1935, 515, 283. 9. Ishimitsu, K.; Hagiwara, K.; Kasahara, I.; Takakura, H.;

Kinbara, Y. Jpn. Kokai Tokkyo koho JP 58 39,648, 1983, Chem. Abstr., 1983, 99, 22085c.

10. Ishimitsu, K.; Kasahara, I.; Takakura, H.; Matsui, N. Jpn. Kokai Tokkyo Koho JP 57 175,180, 1982, Chem. Abstr., 1983, 98, 160697j

11. Ishimitsu, K.; Kasahara, I. Jpn. Kokai Tokkyo Koho JP 58 29,775, 1983, Chem. Abstr., 1983, 99, 70718h.

12. Ishimitsu, K.; Matsui, N. Jpn. Kokai Tokkyo Koho JP 58 29,777, 1983, Chem. Abstr., 1983, 99, 70717g.

13. Ishimitsu, K.; Kasahara, I.; Yamada, T.; Takahashi, H. Jpn. Kokai Tokkyo Koho JP 58 110,577, 1983, Chem. Abstr., 1983, 99, 212518u.

RECEIVED January 17, 1990

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Documents

[ACS Symposium Series] Synthesis and Chemistry of Agrochemicals II Volume 443 || Stereoselective Synthesis and Acaricidal Activity of Novel Thiazolidinones