Heteroatom-promoted lateral lithiation

Heteroatom-promoted lateral lithiation is the site-selective replacement of a benzylic hydrogen atom for lithium for the purpose of further functionalization.

Heteroatom-containing substituents may direct metalation to the benzylic site closest to the heteroatom or increase the acidity of the ring carbons via an inductive effect.

[1] Toluene derivatives with heteroatom-containing substituents in the ortho position undergo site-selective benzylic lithiation in the presence of organolithium compounds (either alkyllithiums or lithium dialkylamides).

Useful heteroatom-containing directing groups include dialkylamines,[3] amides (secondary or tertiary), ketone enolates,[4] carbamates, and sulfonates.

[2] The products of lateral lithiation react with a variety of electrophiles, including reactive alkyl halides (allylic, benzylic, and primary), carbonyl compounds, silyl and stannyl chlorides, disulfides and diselenides, and others.

[2] (2)As either the Lewis acidity of the base or the coordinating ability of the substituent decrease, a mechanism involving purely inductive effects becomes more important.

This result is explained by a mechanism in which the amide substituent affects the acidity of the para benzylic position solely through inductive effects and coordination of the base is not operative.

[15] (7)Sulfonamides require two equivalents of an organolithium reagent for lateral lithiation, but represent a useful class of directing groups.

The functional group compatibility of this method is greater than lateral lithiation, but more steps are required to generate the reactive organometallic species from an unfunctionalized benzylic position.

The reaction mixture was cooled to 0°, treated with cyclohexanecarboxaldehyde (4.2 mL, 35 mmol), allowed to warm to ambient temperature again, and poured into saturated aqueous ammonium chloride solution.