Rh-catalyzed cyclization of carbamates-synthesis of a new heterocyclic system: tetrahydro-3H-4-oxa-2-thia-2b-azacyclopropa[cd] pentalen-3-one 2,2-dioxide

A simple method for the synthesis of five- and six-membered ring sulfone carbamates was elaborated. The method includes reaction of the corresponding starting alcohols with trichloroacetyl isocyanate following the hydrolysis of trichloroacetyl protecting group with potassium carbonate in methanol. Rh-2(OAc)(4) catalyzed cyclization of carbamates was investigated. It was shown that carbamates with saturated sulfone moiety tend to give products of elimination of carbamic acid ( corresponding unsaturated sulfones) due to high acidity of C-H bond in alpha-position of sulfone ring. Unsaturated sulfone carbamate (1,1-dioxido-2,3-dihydrothiophen-3-yl carbamate) in similar reaction conditions afforded new heterocyclic system confirmed by 2D NMR: tetrahydro-3H-4-oxa-2-thia-2b-azacyclopropa[cd] pentalen-3-one 2,2-dioxide. This result can be explained by more favorable aziridination of the double C=C bond by the nitrenoid intermediate compared to the elimination pathway. In silico pharmacological profile of new heterocyclic compound was evaluated. The compound showed good ADME and acute toxicity properties and high probability level of anticancer activity for prostate carcinoma cell line PC-3.

Automated summary

A simple method for synthesizing five- and six-membered ring sulfone carbamates was developed. The method involves the reaction of starting alcohols with trichloroacetyl isocyanate and subsequent hydrolysis of the protecting group using potassium carbonate in methanol. The cyclization of carbamates was catalyzed by Rh-2(OAc)(4). The study found that carbamates with saturated sulfone moiety tend to undergo elimination of carbamic acid, while unsaturated sulfone carbamates form a new heterocyclic system through aziridination pathway. In vitro pharmacological evaluation revealed that the new heterocyclic compound had good ADME properties, low acute toxicity, and a high probability of anticancer activity against prostate carcinoma cell line PC-3.