Science 346, 834–837 (2014)

Credit: © 2014 AAAS

Directed ortho-metalation is a powerful and widely employed method for functionalizing aromatic molecules in which an organometallic base is used to deprotonate one position on the ring. It works through the presence of a directing group on the substrate — typically a Lewis base such as a methoxy or dimethylamino group — that enables the deprontonation of an adjacent C–H bond either through coordination to the incoming metal or by weakening the C–H bond through induction. This opens the door to site-specific addition of electrophiles. On the downside, this regiospecificity is heavily skewed towards the ortho positions, and while some reports have shown the possibility of activating non-ortho sites, these were based on clever design of the substrate rather than fundamentally changing the metalating reagent.

Charles O'Hara, Robert Mulvey and colleagues, from the University of Strathclyde, have shown that they can override this innate selectivity by using organosodium–magnesium complexes, giving access to different functionalization patterns on the aromatic substrate. The tetrasodium–dimagnesium complex acts as a template and its structure helps to guide subsequent chemistry, leading to metalation at two possible sites on the molecule, with the exact regiochemistry determined by the nature of the directing group. Ethers, amides and carbamates are metalated at both the regular ortho site and the meta′-position as shown by X-ray crystallography, and the subsequent addition of electrophiles gave the 2,5-disubstituted products.

Amino-directing groups, however, gave a different substitution configuration — a meta,meta′ (that is, 3,5) pattern was observed, showing a fundamental break from ortho-metalation protocols. X-ray crystallography gives some insight into the reasons for this, showing that the nitrogen atom within the dimethylamino group is sp2-hybridized and in the plane of the aromatic ring. Thus the lack of any ortho-metalation could be due to steric blocking by the methyl substituents. Overall, this new-found control in regioselectivity is likely to find many applications in synthesis. And although the metalating agent is not yet as easily available as butyllithium and the like, it can be made in a one-step process and stored in solution for extended periods of time.