Directed ortho-meta′- and meta-meta′-dimetalations: A template base approach to deprotonation

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Science  14 Nov 2014:
Vol. 346, Issue 6211, pp. 834-837
DOI: 10.1126/science.1259662

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The regioselectivity of deprotonation reactions between arene substrates and basic metalating agents is usually governed by the electronic and/or coordinative characteristics of a directing group attached to the benzene ring. Generally, the reaction takes place in the ortho position, adjacent to the substituent. Here, we introduce a protocol by which the metalating agent, a disodium-monomagnesium alkyl-amide, forms a template that extends regioselectivity to more distant arene sites. Depending on the nature of the directing group, ortho-meta′ or meta-meta′ dimetalation is observed, in the latter case breaking the dogma of ortho metalation. This concept is elaborated through the characterization of both organometallic intermediates and electrophilically quenched products.

Bring your own template for deprotonation

When manufacturing pharmaceuticals and agrochemicals, chemists need to add substituents to specific carbon sites in hexagonal benzene rings. If there's already a substituent on the ring, it can often direct a base to deprotonate the site next to it. But what if you want the base to attack the site two carbons away? Martínez-Martínez et al. devised a method to do this by taking advantage of the sodium and magnesium counterions associated with their base. These ions form a template that orients the base to attack the more distant site.

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