Thietane 1, 1-dioxide derivatives as potential analgetics of the methadone type
Creators: name: Coates, James Everett
Publisher: name: University of British Columbia
Year: 2011

description: Thietane 1,1-dioxide derivatives were synthesized as potential narcotic analgetics of the methadone type. Thietane 1,1-dioxides are con-formationally more restricted than methadone and thus may be useful in elucidating the pharmacophoric conformation of methadone and related analgetics. The reaction of β-dimethylaminostyrene with phenylmethanesulfonyl chloride in the presence of triethylamine gave a mixture of cis- and trans-2,4-diphenyl-3-dimethylaminothietane 1,1-dioxide and the acyclic isomer, benzyl 1-phenyl-2-dimethylaminoethenyl sulfone. Of the two cyclic isomers, the trans isomer was less stable and decomposed when heated in ethanol. The nature of the decomposition products indicated that the cyclization reaction was reversible. That the trans isomer formed to a greater extent than the more stable cis isomer suggested that thietane 1,1-dioxide ring formation was subject to steric approach control. No apparent correlation was observed between solvent polarity and the amount of acyclic isomer formed. trans-2,4-Diphenyl-3-dimethylaminothietane 1,1-dioxide could be isomerized to the cis and acyclic isomers in the presence of triethylamine and triethylamine hydrochloride. In the reaction between β-dimethylaminostyrene and p-chlorophenyl-methanesulfonyl chloride in the presence of triethylamine, evidence was obtained that only two cyclic isomers were formed. This indicated that the configuration of the enamine was maintained during cyclization. Reaction of the enamine with the sulfene derived from p-nitrophenylmethane-sulfonyl bromide afforded cis-2-(4-nitropheny1)-3-dimethy 1amino-4-phenyl-thietane 1,1-dioxide and benzyl 1-(4-nitrophenyl)-2-dimethylaminoethenyl sulfone. Submitting the 3-dimethylaminothietane 1,1-dioxides to the Cope elimination reaction gave the corresponding thiete 1,1-dioxides. Examination of the isomeric thiete 1,1-dioxides obtained from cis- and trans-2-(4-chlorophenyl)-3-dimethylamino-4-phenylthietane 1,1-dioxide provided evidence supporting the configurational assignment of the cis and trans isomers. With the p-nitro-substituted thietane 1,1-dioxide, only one elimination product was isolated, which was identified as 2-(4-nitropheny1)-4-phenylthiete 1,1-dioxide. Thermolysis of 2,4-diphenylthiete 1,1-dioxide, 2-(4-chlorophenyl)-4-phenylthiete 1,1-dioxide and 2-phenyl-4-(4-chlorophenyl)-thiete 1,1-dioxide gave chalcone, benzylidene p-chloroacetophenone and p-chlorobenzyl-idene acetophenone, respectively. Refluxing 2,4-diphenylthiete 1,1-dioxide in aqueous THF afforded 1,3-diphenylpropene-3-sulfonic acid. These results supported the proposal that thiete 1,1-dioxides undergo ring opening on heating to give sulfene intermediates. From the decomposition of 2,4-diphenylthiete 1,1-dioxide in refluxing ethanol, a ketonic sulfone was isolated and characterized as bis(1,3-diphenyl-3-oxopropyl) sulfone. Michael addition of hydrogen cyanide to the thiete 1,1-dioxides followed by reduction to the primary amines and dimethylation gave the potential analgetics, 2,4-diphenyl-3-dimethylaminomethylthietane 1,1-dioxide, 2-(4-chlorophenyl)-3-dimethylaminomethyl-4-pheny1thietane 1,1-dioxide and 2-(4-nitropheny1)-3-dimethylaminomethyl-4-phenylthietane 1,1-dioxide. The fourth compound, 2,4-diphenyl-3-(1-dimethylaminoethyl)-thietane 1,1-dioxide, was prepared by addition of nitroethane to 2,4-diphenylthiete 1,1-dioxide followed by reduction and dimethylation. Configurational and conformational assignments for the four compounds were based on nmr evidence. The mouse hot plate, mouse phenylquinone writhing and electrically stimulated guinea-pig ileum methods were used to measure analgetic activity. When tested by one or more of these methods, none of the four compounds showed significant activity.