Novel palladium-catalysed routes to aromatic heterocycles

Thesis

Chapter 1: Introduction A brief summary of the use of palladium as a catalyst, the characteristic reactivity of palladium complexes and the commonly used palladium-catalysed cross coupling reactions is given, with a special focus on the palladium-catalysed α-arylation of enolates and its application to the synthesis of aromatic heterocycles. The synthesis of aromatic heterocycles via both traditional methods and more recent metal-catalysed approaches is discussed in the context of isoquinolines.

Chapter 2: Results and Discussion The palladium-catalysed oxidation of dihydrofurans bearing an ortho-bromophenyl group at the 2-position to the corresponding 2-phenyl furans is disclosed along with some preliminary mechanistic investigations. A novel synthetic route to isoquinolines is detailed involving the palladium-catalysed α-arylation of ketone enolates with an appropriate ortho-substituted aryl halide to furnish a protected 1,5-dicarbonyl intermediate. The versatility of these intermediates is demonstrated with their conversion into isoquinolines, isoquinoline N-oxides and naphthols. The scope of the synthetic procedure is fully exemplified across more than 30 different scaffolds covering the full spectrum of electron-rich to electron-deficient moieties. The intermediates were shown to be amenable to functionalisation with electrophiles, leading to isoquinolines bearing additional substitution at the C4 position. Sequential one-pot procedures were developed allowing three and four component couplings to directly deliver highly-substituted isoquinolines from commercially available starting materials. This methodology was utilised in the total synthesis of the natural product berberine in 26% overall yield and a longest linear sequence of six steps.

Chapter 3: Experimental Full experimental procedures and characterisation data for all compounds are reported.

Authors: Pilgrim, B; Ben S. Pilgrim

• Publication date: 2013
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: heterocycle; alpha arylation; palladium; heteroaromatic; isoquinoline; berberine
• Subjects: Chemistry & allied sciences; Heterocyclic chemistry; Organic chemistry; Catalysis; Organic synthesis; Natural products; Synthetic organic chemistry