Developing the Saegusa-Ito cyclisation for the synthesis of difluorinated cyclohexenones

Percy, Jonathan M. and McCarter, Adam W. and Sewell, Alan L. and Sloan, Nikki and Kennedy, Alan R. and Hirst, David J. (2015) Developing the Saegusa-Ito cyclisation for the synthesis of difluorinated cyclohexenones. Chemistry - A European Journal, 21 (52). 19119–19127. ISSN 0947-6539

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    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 achieved the turnover of the initial palladium(II) salt, while 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.