Evaluating the Thermal Vinylcyclopropane Rearrangement (VCPR) as a Practical Method for the Synthesis of Difluorinated Cyclopentenes: Experimental and Computational Studies of Rearrangement Stereospecificity |
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Authors: | David Orr Prof. Dr. Jonathan M. Percy Dr. Tell Tuttle Dr. Alan R. Kennedy Dr. Zoë A. Harrison |
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Affiliation: | 1. WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL (UK), Fax: (+44)?141‐548‐4822;2. Refractory Respiratory Inflammation DPU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY (UK) |
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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 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 °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. |
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Keywords: | activation parameters density functional calculations difluorocyclopentene rearrangements stereoselectivity |
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