A simple way to join an olefin to an arene

Chemists in the US have developed a simple and effective way to carry out a key class of reaction in organic synthesis - the bolting an olefin to an aromatic ring. 

Olefination of arenes is challenging because there are a number of positions on the aromatic ring to which the olefin can attach. One widely used technique to dictate the point of attack is the palladium-catalysed Mizoroki-Heck reaction, which requires the target carbon of the ring to be halogenated. This, however, is in itself often tricky, adding to the complexity of the procedure.

Now, Jin-Quan Yu and colleagues at the Scripps Research Institute in California have shown that a particular C-H bond can be targeted by a palladium catalyst without the need for prior halogenation.

To steer the catalyst to its target the researchers adopted a twin approach. Firstly, the presence of a carboxyl group adjacent to the target C-H on the ring results in a phenomenon called the complex-induced proximity effect, which pulls the catalyst towards the relevant bond. In cases where the two ortho positions are equivalent, this approach alone can result in good yields of the desired product. 

Where the two ortho positions on the ring are different, however, as in multiply substituted arenes, the researchers found that modified amino acids can act as ligands to the Pd catalyst and can steer it towards one or other of the ortho carbons, as required. The ligands do this by differentiating between the subtle electronic or steric environments of the two ortho carbons. ’The COOH dictates the ortho position, the ligand then distinguishes between the two ortho positions when they are different in multi-substituted arenes,’ Yu says. 

Using this approach, Yu and his colleagues demonstrated the olefination of a range of complex molecules, including the drug ibuprofen and various analogous compounds. Yu points out that given the wide availability of carboxylated substrates, the reaction can be applied broadly. ’The substrates represent a major class of synthetically useful compounds abundantly available off the shelf,’ he says. 

Matthew Gaunt, an expert in synthetic organic chemistry at the University of Cambridge in the UK believes that the technique could find ’broad utility in the synthesis of complex aromatic molecules.’ ’Particularly noteworthy is the use of amino acid-derived ligands to enhance reactivity and control the selectivity of C-H olefination between sterically and electronically similar ortho positions,’ Gaunt adds. ’This selectivity has rarely been achieved before.’ 

Simon Hadlington