Palladium-catalysed enolate arylation in the synthesis of isoquinolines

Thesis

Chapter 1. Introduction

Scientific background on the development of homogeneous palladium-catalysed cross coupling reactions, focusing on the α-arylation reaction of enolates and its application to the synthesis of heteroaromatic compounds. The classical syntheses of isoquinolines are discussed, followed by an account of modern methods for their synthesis, including the recent α-arylation-based methodology developed by the Donohoe group.

Chapter 2. Results and Discussion

2.1 Studies towards the development of a palladium-catalysed, C–H activation-based α arylation reaction of ketones, resulting in a C–H bromination/α-arylation sequence for the synthesis of isoquinolines and isoquinoline N-oxides.

2.2 The one-pot, four component coupling of a ketone, an acetal protected ortho-bromobenzaldehyde or ketone, an electrophile, and an ammonia source is described. This protocol, which ultimately provides C4 functionalised isoquinolines, is later extended to a novel α,α heterodiarylation protocol to furnish C4-aryl isoquinolines.

2.3 It is shown that the synthesis of 3 aminoisoquinolines can be achieved via the α arylation of nitriles. tert-Butyl cyanoacetate can act as a substitute for primary alkyl nitriles, with sequential α-arylation, in situ functionalisation, decarboxylation and cyclisation reactions provide C4 functionalised 3 aminoisoquinolines.

2.4 The synthetic utility of the α arylation based methodology for isoquinoline synthesis is exemplified by the total synthesis of the alkaloid berberine in 68% yield over five steps. This is followed by syntheses of pseudocoptisine, palmatine, dehydrocorydaline, and an unnatural fluorine containing analogue, in yields of 46%, 73%, 60% and 37%, respectively.

2.5 Finally, preliminary investigations demonstrate the utility of palladium-catalysed enolate arylation in the synthesis of β-carbolines.

Authors: Gatland, A; Alice Elizabeth Gatland

• Publication date: 2014
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: palladium catalysis; protoberberines; natural products; total synthesis; isoquinolines; alpha-arylation; alkaloids; synthesis
• Subjects: Heterocyclic chemistry; Catalysis; Organic chemistry; Synthetic organic chemistry; Organic synthesis