Evaluating the Thermal Vinylcyclopropane Rearrangement (VCPR) as a Practical Method for the Synthesis of Difluorinated Cyclopentenes: Experimental and Computational Studies of Rearrangement Stereospecificity

Abstract

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). The trans-E isomer (18a), prepared in 70 % yield over three steps, underwent near quantitative VCPR to difluorocyclopentene 23 (99 %). Rearrangements were monitored by (19) F 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 °C). The cis-cyclopropanes underwent [3,3]-rearrangement to afford benzocycloheptadiene species. The reaction stereospecificity was explored by 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.

A computational triage approach to the synthesis of novel difluorocyclopentenes and fluorinated cycloheptadienes using thermal rearrangements

“…The dramatic reactivity difference between the E - and Z -alkene isomers of 9j previously reported 3 was maintained when a wider range of substituents was examined. Calculated activation energies for E -substituted precursors (Table 2, entries 1–5) were lower than for the unsubstituted precursor 10e (Table 2, entry 6), whilst the barriers for the corresponding Z -diastereoisomers were higher (Table 2, entries 7–9).…”

“…The two major products were tentatively assigned as dihydrofuran 33 and benzooxepine 34 due to the strong similarities between 19 F NMR chemical shifts reported by Hammond 31 and ourselves, 3 respectively. Electronic structure calculations for the [3,3]-rearrangement via TS3 supported room temperature rearrangement with a low Δ G ‡UB3LYP value of 20.8 kcal mol –1 (Scheme 6b).…”

“…Compounds with no aromatic functionality but one ( 9s and 9t ) or two ( 9q and 9r ) alkyl substituents were also found to have higher barriers for rearrangement (ranging from +6.5 to +8.6 kcal mol –1 ). We had observed previously that temperatures of 180 °C facilitated a [3,3]-rearrangement pathway with a calculated activation energy of 32.9 kcal mol –1 (Δ G ‡B3LYP, UB3LYP/6-31G*, gas phase, 298 K, Gaussian'09), 3 suggesting that low temperature rearrangement with alkyl substituents would be unlikely. Higher reaction temperatures also have the potential to activate a competitive [1,5]-hydride shift pathway 22 so these substitution patterns were ruled out of our synthetic study.…”

“…3 This method was used to assess the impact of modification of the left-hand side of difluoro-VCP 9 , with calculated activation barriers ranked alongside phenyl-substituted precursor 9j (Table 1 and Fig. 3).…”

“…This system offers a highly atom-efficient route into a novel difluorocyclopentene at practical rearrangement temperatures (100 °C). 3 Despite recent synthetic advances for securing difluorinated 5-membered ring structures, 17 difluorinated cyclopentenes are still rare motifs in the literature. 18 To our knowledge, there are currently no reported routes for the synthesis of structures similar to fluorinated benzocycloheptadiene 3 .…”