From palladium to iron: towards more sustainable catalysis
Jones, Alison Sarah
The construction of bonds in a controlled and selective manner and the development of operationally simple, general and reliable methods to achieve these aims remains a key goal of chemical synthesis and the countless industries it impacts upon. With this in mind, the chemo-, regio- and stereoselective introduction of a number of functionalities into small molecules was investigated. Traditionally the majority of functionalisations have used precious metals; the scope of transformations that can be achieved using these catalysts is remarkable. Palladium in particular has found widespread application in new bond-forming processes and, in addition to cross-coupling reactions, palladium catalysis has been used to effect a wide variety of asymmetric reactions. This work describes investigations into the palladium-catalysed enantioselective electrophilic fluorination of azaarylacetates and amides A2 and the oxidative annulation of ferrocene derivatives A4 (Scheme A1). Both products have structural significance; heterocycles and stereogenic fluorinated centres, present in A3, are important motifs in the pharmaceutical industry, and ferrocenes are important rigid scaffolds in chiral ligands such as those in the Josiphos family e.g. A7. Scheme A1. Palladium catalysis for a) enantioselective fluorination and b) oxidative annulation Whilst a general catalyst remained elusive for the asymmetric fluorination of azaarylacetates and amides, benzoxazole-containing substrates were consistently fluorinated with excellent enantioselectivity (up to 96% ee) using palladium catalyst A1 (Scheme 1a). The oxidative annulation of ferrocene derivatives proved challenging and although the reaction was successful, the product could only be isolated in up to 24% yield (Scheme 1b). In order to determine the yield-limiting step of the reaction, mechanistic studies were conducted and palladacycle A6 was synthesised as a possible reaction intermediate. Recently there has been a shift towards the development of more sustainable, environmentally benign and economic catalyst systems and iron is quickly becoming recognised as a viable alternative owing to its high natural abundance and low toxicity. A general iron-catalysed hydrofunctionalisation procedure is described that was used to form a wide variety of carbon-carbon and carbon-heteroatom bonds (Scheme A2). Scheme A2. Iron catalysis for carbon-carbon and carbon-heteroatom bond formation With just 0.5 mol% iron catalyst, the broad scope formal hydrofunctionalisation of styrene derivatives was achieved using commercially available and bench-stable catalysts and reagents. An iron-catalysed highly regioselective hydromagnesiation gave a common benzylic Grignard reagent, which was reacted with an array of electrophiles in a highly chemo- and regioselective manner. Significantly, the products of formal hydroboration, hydrosilylation and cross-coupling reactions were obtained.