Avant-Garde Metalating Agents: Structural Basis of Alkali-Metal-Mediated Metalation

Abstract

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).Na(mu-TMP)(mu-(n)Bu)Mg(TMP)], [(TMEDA).Na(mu-TMP)(mu-(t)Bu)Zn((t)Bu)], and [(TMEDA).Li(mu-TMP)Mn(CH(2)SiMe(3))(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 catal...

Structural Studies of (rac)-BIPHEN Organomagnesiates and Intermediates in the Halogen–Metal Exchange of 2-Bromopyridine

“…[1][2][3][4] Alongside deprotonative metalation, 2,5 the halogen-metal exchange methodology allows for more chemoselective reactions and the direct introduction of various lowly electropositive metals onto the aromatic rings. In this context, magnesium-based ate complexes have attracted a high degree of interest.…”

“…As 1 can be easily prepared, the more straightforward cocomplexation approach (route B) was chosen for the next part of the study. After adding di-n-butylmagnesium (as a solution in heptane) to a hexane solution of 1, colorless crystals of magnesiate (THF) 3 .Li 2 Mg{(rac)-BIPHEN)} n Bu 2 2 were generated in good yield (65%) by adding THF (0.5 mL) and cooling the solution to −28°C. The molecular structure of the higher-order (i.e., the ratio of lithium to magnesium in the structure is 2:1) magnesiate 2 is shown in Figure 2.…”

“…The replacement of commercially-available n Bu 2 Mg by the -hydrogen-free (Me 3 SiCH 2 ) 2 Mg and (Me 3 CCH 2 ) 2 Mg was examined by following an identical approach to that used for 2. By slowly cooling THF solutions of the respective mixtures, the reactions produced colorless crystals of lithium magnesiates (THF) 3 .Li 2 Mg{(rac)-BIPHEN}(CH 2 SiMe 3 ) 2 3 and (THF) 4 .Li 2 Mg{(rac)-BIPHEN}(CH 2 CMe 3 ) 2 4 respectively in respective yields of 82 and 36%, the latter yield being adversely affected due to its high solubility in hydrocarbon solution. The main structural framework of 2 is preserved in 3 and 4 but in terms of THF incorporation 3 most resembles 2 as it contains three coordinated molecules of THF while 4 contains only two (c.f., 2b).…”

“…Structures 1 to 4 feature disorder in THF ligands and in butyl groups (2) and SiMe 3 groups (3). In all cases these disordered groups were refined over two sites and each required restraints to be applied on both thermal parameters and on bond lengths.…”

“…Addition of THF (0.16 mL, 2 mmol), followed by gentle heating and then slow cooling of the solution, resulted in the formation of colorless crystals of 5 (0.32 g, yield 47%; 94% based on 2-bromopyridine consumption). An alternative stoichiometric synthesis could be achieved by reacting isolated crystals of [(rac)-BIPHEN]Li 2 Mg(CH 2 SiMe 3 ) 2 (THF) 3 (3) (0.78 g, 1 mmol) with 2-bromopyridine (0.19 mL, 2 mmol) at −60°C. After slowly warming to ambient temperature, THF (0.16 mL, 2 mmol) was added, which resulted in the precipitation of a white suspension.…”