title: Palladium-catalyzed enolate arylation as a key C-C bond-forming reaction for the synthesis of isoquinolines.
abstract: The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C-H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route.
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK. timothy.donohoe@chem.ox.ac.uk.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Pilgrim
authors.forename: Alice E
authors.initials: AE
authors.lastname: Gatland
authors.forename: Carlos H A
authors.initials: CH
authors.lastname: Esteves
authors.forename: Charlie T
authors.initials: CT
authors.lastname: McTernan
authors.forename: Geraint R
authors.initials: GR
authors.lastname: Jones
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Tatton
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Donohoe