Avant-garde metalating agents: Structural basis of alkali-metal-mediated metalation

Metalation, one of the most useful and widely used synthetic methodologies, transforms a relatively inert carbon-hydrogen bond to a more labile carbon-metal bond. Until recently, most organometallic reagents that facilitate this process have combined strongly electropositive metals, such as lithium, with organic reagents to form highly polar and, by implication, highly reactive carbon-metal bonds. For example, the alkyllithium reagents and bulky lithium amides that are commonly employed for this purpose can suffer from low functional group tolerance. Lithio-products of these reactions generally have low kinetic stabilities. More recently, several groups around the world have pioneered alternative metalation reagents, complex metalators, which can be interpreted as composite molecules or mixtures made up of two or more distinct compound types. Several examples include magnesiate complexes, Lochmann-Schlosser superbases, Kondo and Uchiyama's 2,2,6,6-tetramethylpiperidide (TMP)-zincate complexes, and Knochel's turbo-Grignard and related salt-supported reagents. This Account describes our rational development of novel complex metalators based on existing structural templates and designed to execute alkali-metal-mediated metalations (AMMMs). By changing the nonalkali metal in these structures, we have produced tailor-made dianionic-dicationic structures such as [(TMEDA) center dot Na(mu-TMP)(mu-Bu-n)Mg(TMP)], [(TMEDA) center dot Na(mu-TMP)(mu-Bu-t)Zn(Bu-t)], and [(TMEDA) center dot Li(mu-TMP)Mn(CH2SiMe3)(2)] (TMEDA = N,N,N',N'-tetramethylethylenediamine). These compounds can perform unprecedented magnesiations, zincations, or manganations on aromatic substrates that are generally inert toward conventional Mg, Zn, or Mn(II) reagents. Although the alkali metal is an essential component of these new complex metalators, interestingly, the less electropositive, less polar nonalkali metal [Mg, Zn, or Mn(II)] actually carries out the deprotonation. We view this unique behavior as a mixed-metal synergic effect: intramolecular communication through metal - ligand-metal bridges directs special regioselectivities or polydeprotonations. We demonstrate structurally defined alkali-metal-mediated magnesiations (AMMMg), zincations (AMMZn), and manganations [AMMMn(II)] of representative aromatic substrates (including benzene, toluene, anisole, and ferrocene). In addition, we present remarkable meta-orientated metalations of toluene and N,N-dimethylaniline. We also review 2-fold metalations of arenes, in which an arenediide guest is encapsulated within a 12-atom polymetallic cationic (NaNNaNMgN)(2) host ring to form inverse crown structures. Furthermore, using X-ray crystallography of a turbo-Grignard reagent, we establish a link between our complex metalators and turbo-Grignard reagents. Armed with this accruing knowledge of complex metalators, we think rapid progress in "low polarity metalation" should now be possible. The greatest remaining challenge is to develop methodologies that shift these processes from stoichiometric reactions into more economical catalytic ones