Evaluating the thermal vinylcyclopropane rearrangement (VCPR) as a practical method for the synthesis of difluorinated cyclopentenes: experimental and computational studies of rearrangement stereospecificity

Vinyl cyclopropane rearrangement (VCPR) has been utilised to synthesise a difluorinated cyclopentene stereospecifically and under mild thermal conditions. Difluorocyclopropanation chemistry afforded ethyl 3-(1'(2'2'-difluoro-3'-phenyl)cyclopropyl) propenoate as all four stereoisomers (18a, 18b, 22a, 22b) (all racemic). Trans-E isomer (18a), prepared in 70% yield over three steps, underwent near quantitative VCPR to difluorocyclopentene 23 (99%). Rearrangements were followed by 19F NMR (100-180 °C). While cis/trans cyclopropane stereoisomerisation was facile, favouring trans-isomers by a modest margin, no E/Z alkene isomerisation was observed even at higher temperatures. Neither cis nor trans Z-alkenoates underwent VCPR, even up to much higher temperatures (180 oC). Cis-cyclopropanes underwent [3,3]-rearrangement to afford benzocycloheptadiene species. The reaction stereospecificity was explored using electronic structure calculations and UB3LYP/6-31G* methodology allowed the energy barriers for cyclopropane stereoisomerisation, diastereoisomeric VCPR and [3,3]-rearrangement to be ranked in agreement with experiment.