title: Developing the Saegusa-Ito Cyclisation for the Synthesis of Difluorinated Cyclohexenones.
abstract: Palladium(II)-catalysed cycloalkenylation (Saegusa-Ito cyclisation) has been used for the first time to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions. The silylenol ether precursors were prepared in two high-yielding steps from trifluoroethanol, and cyclised in moderate to good yields. A combination of air and copper(I) chloride in acetonitrile gave the turnover of the initial palladium(II) salt, whereas the provision of an oxygen atmosphere ensured more rapid reaction. Annulations required a minimum level of substitution on the chain, but failed when the alkene was substituted. Annelations allowed a range of n,6-bicyclic systems to be prepared and afforded three products, in which heterocycles were fused to the new cyclohexenone. The least substituted system explored underwent cyclisation followed by terminal oxidation to a cyclic enal, which corresponded to a Wacker product of unusual regiochemistry.
authors.affiliation: WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL (UK). jonathan.percy@strath.ac.uk.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Percy
authors.affiliation: WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL (UK).
authors.forename: Adam W
authors.initials: AW
authors.lastname: McCarter
authors.affiliation: WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL (UK).
authors.forename: Alan L
authors.initials: AL
authors.lastname: Sewell
authors.affiliation: WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL (UK).
authors.forename: Nikki
authors.initials: N
authors.lastname: Sloan
authors.affiliation: WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL (UK).
authors.forename: Alan R
authors.initials: AR
authors.lastname: Kennedy
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY (UK).
authors.forename: David J
authors.initials: DJ
authors.lastname: Hirst
keywords: cyclization; difluoroketones; homogeneous catalysis; palladium; synthetic methods