Christopher M. Rayner

USE OF FLUORINATED PALLADIUM SOURCES FOR EFFICIENT PD-CATALYSED COUPLING REACTIONS IN SUPERCRITICAL CARBON DIOXIDE

Abstract Commercially available palladium sources [Pd(OCOCF 3 ) 2 and Pd(F 6 -acac) 2 ] containing fluorinated ligands are superior to non-fluorinated sources [Pd(OCOCH 3 ) 2 and Pd 2 (dba) 3 ] for carrying out a variety of palladium catalysed coupling reactions in supercritical carbon dioxide. Significantly reduced temperatures and catalyst loadings are possible, and also the range of phosphine ligands which can be used is increased, including those that are often considered to be poor ligands for coupling reactions under conventional conditions (PCy 3 , PBu 3 ).

Suppression of double bond isomerisation in intramolecular Heck reactions using supercritical carbon dioxide

The modified reagent system [Pd(OCOCF3)2/P(2-furyl)3/EtNiPr2] gives enhanced conversions compared with standard conditions [Pd(OAc)2/PPh3/NEt3] for intramolecular Heck cyclisations, and when used in scCO2 results in the suppression of double bond isomerisation to minimal levels, which is otherwise a serious competing side reaction in conventional solvents.

Enantioselective enzymatic synthesis of the anti-viral agent lamivudine (3TC™)†

A novel enzymatic resolution of α-acetoxysulfides has been used as the key step in the synthesis of the important antiviral nucleoside analogue lamivudine. The synthesis proceeds via a configurationally stable hemithioacetal which cyclises in situ to form the required oxathiolane nucleus, which can then be converted into the target nucleoside in 4 steps.

Reactions in Unusual Media

This review provides an introduction to three of the most well-developed solvent replacement strategies currently under investigation for synthetic chemistry: Ionic liquids, fluorous phase techniques, and supercritical carbon dioxide. They are all fascinating reaction media, and have considerable potential for use in pharmaceutical synthesis. However, this has to be balanced with problems and limitations of the new methods. This review aims to provide an overall account of recent advances in the use of unusual media for synthetic chemistry, with an emphasis on highlighting potential benefits, but also limitations, of each of the methods described.

The first examples of dynamic kinetic resolution by enantioselective acetylation of hemithioacetals: An efficient synthesis of homochiral α-Acetoxysulfides

The Pseudomonas fluorescens lipase catalysed irreversible acetylation of a hemithioacetal using vinyl acetate proceeds via a novel dynamic kinetic resolution. Thus a thiol and an aldehyde are mixed together to form a racemic hemithioacetal, essentially a single enantiomer of which is acylated under the reaction conditions. Racemisation of the unrecognised hemithioacetal by a dissociation-recombination process catalysed by silica gel, allows greater than 50% conversion in the reaction. High yields and enantioselectivities can be obtained with suitable substrates.

Pd-catalysed coupling reactions in supercritical carbon dioxide and under solventless conditions

The homocoupling of iodoarenes catalysed by Pd(OCOCF3)2/P(2-furyl)3 occurs best in scCO2 and under solventless reaction conditions, and provides an attractive alternative to previously reported procedures. A comparison of the results in these cases suggests interesting preferential solvation effects are occurring in scCO2. Each of the methods investigated has advantages and disadvantages which need to be carefully considered before the method of choice is determined.

Lewis acid induced rearrangement of 2,3-epoxy sulfides; regiospecific trapping of thiiranium ion intermediates with nitrogen heterocycles and amides. Use of imines as nucleophilic equivalents for the selective monoalkylation of primary amines

Abstract The Lewis acid induced conversion of 2,3-epoxy sulfides into the corresponding 3-trimethylsilyloxy-1,2-thiiranium ions is described. Such intermediates react with silylated nitrogen heterocycles and amides regiospecifically to form 1-substituted-3-hydroxy-2-thioethers in good to moderate yields with full stereochemical control. Exclusive N-alkylation is observed. When simple primary amines are used as nucleophiles, only products of polyalkylation are isolated. However, imines can be effectively used as the nucleophilic equivalent of a primary amine, the initially formed iminium ions being readily hydrolysed by aqueous base to liberate a secondary amine, the product of overall selective monoalkylation of a primary amine.

Formation and catalytic activity of Pd nanoparticles on silica in supercritical CO2

Metal complexes of polydimethylsiloxane-derived ligands can be adsorbed onto silica and subsequently reduced in-situ in supercritical CO2 (scCO2) to generate metal nanoparticles. Pd nanoparticles on silica, generated during C–C coupling reactions in scCO2, can be recycled several times without any loss in activity. Focusing on Heck and Suzuki coupling reactions, the products showed no contamination of the organic products with Pd using quantitative ICP emission spectroscopy. The use of scCO2 prevents the desorption of the Pd nanoparticles from their support. Build-up of ammonium salts as by-products in these coupling reactions leads to reduced activity for these heterogeneous catalysts after four runs.

Potential tuning and reaction control in the Diels–Alder reaction between cyclopentadiene and methyl acrylate in supercritical carbon dioxide

The ratio of endo- to exo-products in the Diels–Alder reaction between cyclopentadiene and methyl acrylate in supercritical carbon dioxide, plotted vs. the density of the medium, was found to go through a maximum at a density higher than the critical density. The effect can be explained in terms of the adjustment of the position of the nearest-neighbour solvent molecules with respect to the transition state. A theoretical discussion is given, which justifies this process being described as ‘potential tuning’.

Discovery, characterisation, and utilisation of selenoxide-sulfonic acid salts: A new class of selenoxide-based oxidant and stable selenoxide equivalent.

Abstract The preparation and characterisation of a novel class of salts of selenoxides with sulfonic acids are described. They are readily prepared by simple addition of the sulfonic acid to a solution of selenoxide, and removal of solvent. In most cases they are colourless crystalline solids and are considerably more stable than the parent selenoxides, allowing full characterisation and X-ray crystallographic analysis. They also efficiently oxidise sulfides to sulfoxides, with no overoxidation, and clean regeneration of selenide. Their structure has been confirmed by 1H NMR spectroscopy and X-ray crystallography.