A Practical Route to Cyclobutylcarbinols and Fluorocyclobutanes

1-[(Ethoxycarbonothioyl)sulfanyl]cyclobutyl acetate (xanthate 7) was found to add to electronically unbiased alkenes and to certain heteroarenes. In the latter case, this corresponds to a variant of the Minisci reaction and allows the late-stage modification of biologically active substances. Saponification of the acetate furnishes the corresponding carbinols, which, in the case of the nicotine adduct, can be converted into fluorocyclobutanes by the action of DAST. Fluorocyclobutyl substituted aromatics and heteroaromatics are increasingly present in drug candidates. Heating of the acetoxycyclobutyl derivative of caffeine with TFA gives rise to the cyclobutene analogue. Finally, O-ethyl S-[1-(2,2,2-trifluoroethoxy)cyclobutyl] carbonodithioate, obtained unexpectedly while optimizing the synthesis of xanthate 7, is a very promising reagent for the introduction of the very rare 2,2,2-trifluoroethoxycyclobutyl motif.

Automated summary

A new reaction was discovered for modifying alkenes and heteroarenes, particularly in biologically active substances. The saponification of acetate produces fluorocyclobutanes, which could lead to new drug candidates with potential therapeutic effects.