Thiazolidinones Hexythiazox

Scheme 4. Stereoselective Synthesis of tra7is-2-Thiazolidinones ( Hexythiazox ).

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... 

Use pattern Hexythiazox is a thiazolidinone acaricide which has ovicidal, larvicidal and nymphicidal activities against many kinds of phytophagous mites infesting pome fruits, stone fruits, citrus, vegetables and other food crops. On these mites, hexythiazox works by both contact and stomach action... 

Commercial hexythiazox is a racemic mixture of the two trans enantiomers Scheme 26.2.2 shows the main synthetic pathways [11, 17, 19]. Starting from 4-chloro propiophenone the key intermediate erythro amino alcohol may be obtained by stereoselective catalytic reduction of the corresponding hydroxy imi-noketone or by sodium borohydride reduction of the aminoketones obtained via Gabriel synthesis. Different routes lead from this aminoalcohol to the trans-thiazolidinone system the basis of all routes is activation of the hydroxy group, e.g., in form of the sulfonate and a ring forming reaction with carbon disulfide or carbonyl sulfide. The final acylation of the NH group with cyclohexyl isocyanate leads to hexythiazox. 

Hexythiazox, tra/2s 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 positions 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. 

In the course of development research of fungicidal heterocyclic compounds, we found acaricidal activity 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 thiazolidinone carboxamides have very high ovicidal and larvicidal activity against spider mites both in Panonychus and Tetranychus species (2-3). After 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 fruits and vegetables in Europe and North America as well as in Japan. 

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 yield is shown (IQ). We found that the erythro dithiocarbamates which were obtained by the reaction with erythro aminoalcohols, carbondisulfide and benzylbromide were easily cyclized to trans thiazolidinones stereoselectively by the reaction 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 thiazolidinones. We applied this method for the synthesis of the carbon-14-labeled hexythiazox at the 5-position of the thiazolidinone nucleus. 

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