Figure 1.2 Dimer structures of (a) i‐Pr₂NC(O)‐2‐Et‐C₆H₃Li(THF) 5 and (b) hemi‐solvate [i‐Pr₂NC(O)‐2‐(i‐Pr)‐C₆H₃Li]₂(OEt₂) 6.

      Sources: Adapted from Armstrong et al. [20]; Campbell Smith et al. [24].

Though anionic Fries rearrangements compromise the regioselectivity of directed deprotonation, they are well documented. In contrast, an unusual post ortho‐lithiation rearrangement was noted more recently for 1‐lithio‐naphthyllithium compounds with an ortho‐directing 2‐(dimethylamino)‐methyl group [28]. The lithiation of 2‐[(dimethylamino)methyl]naphthalene (dman) allowed elucidation of the 3‐lithio regioisomer as a tetramer of 2‐(Me₂NCH₂)C₁₀H₆Li‐3 7 in both the solid and solution states. In contrast, the 1‐lithio regioisomer proved insoluble except in the presence of additional coordinating solvents, which gave [2‐(Me₂NCH₂)C₁₀H₆Li‐1]₂L (L = Et₂O 8, dman 9) in apolar solution. In the case of 9, heating to 90 °C in toluene induced quantitative 1‐lithio to 3‐lithio rearrangement (10). Isotope labelling experiments suggested a rearrangement mechanism catalytic in dman and proceeding via heteroleptic intermediate [{2‐(Me₂NCH₂)C₁₀H₆‐1}{2‐(Me₂NCH₂)C₁₀H₆‐3}Li₂](dman) 11; the dman is lithiated at its 3‐position, while the formerly 1‐lithio‐naphthalene fragment is converted into new N‐donor amine (Scheme 1.4).

Prior to the advent of ate chemistry, attempts to overcome the problem of organometallic nucleophilicity focused on the deployment of other metals. For example, in 1989, Eaton et al. reported the selective magnesiation of alkyl benzoates using sterically demanding magnesium amide 12 (Scheme 1.5) [29], suggesting the possibility of highly chemoselective conversion to e.g. 13 in the presence of ester and amide moieties. This protocol was used to ortho‐carboxylate methyl benzoate, giving 14 in 81% yield.

Using a similar thesis, 1‐substituted indole derivatives have been deprotonated using a magnesium diamide to give magnesioindoles, which were then successfully reacted with electrophiles. The compatibility of the magnesiated intermediates with a range of electrophilic functional groups was examined. For example, methyl 1‐phenylsulfonylindole‐3‐carboxylate was treated with (i‐Pr₂N)₂Mg 15 followed by iodine or benzaldehyde to give 2‐iodo derivative 16 and alcohol 17 in the respective yields 85 and 93% (Scheme 1.6) [30]. 1‐Phenylsulfonylindole‐3‐carbonitrile was also tested in this iodination using i‐Pr₂NMgBr 18 at the outset. In a similar vein, ethyl n‐thiophenecarboxylate (n = 2, 3) has been selectively deprotonated with retention of the ester group, using i‐Pr₂NMgCl 19 to give 2,5‐ and 2,3‐disubstituted thiophenes, respectively [31]. Meanwhile, the selective deprotonation of pyridine carboxamides and carbamates in conjunction with the more sterically congested magnesium amide TMPMgCl 20 has been reported [32]. Deprotonative magnesiation has been further investigated by Knochel and its scope and limitations have been the subject of review [33].

Scheme 1.4 The rearrangement of [2‐(Me₂NCH₂)C₁₀H₆Li‐1]₂(dman) 9 in hot toluene.

Scheme 1.5 Selective magnesiation of an alkyl benzoate using magnesium amide 12.

Scheme 1.6 Treatment of methyl 1‐phenylsulfonylindole‐3‐carboxylate with (i‐Pr₂N)₂Mg 15 en route to 2‐iodinated 16 and alcohol 17.

Detailed elucidation of the products of directed aromatic magnesiation has been enabled using air‐sensitive crystallographic techniques. The same is true of precursors to deprotonation, with for example, the constitution of the deprotonating agents Grignard and Hauser bases probed. In these contexts, upon exposure to THF, MeMgCl 21 was found to form MeMg₂(μ‐Cl)₃(THF)_4‐622, but to dimerize to give Me₂Mg₄Cl₆(THF)₆23 in the solid‐state [34]. In contrast, externally solvated alkyl‐and halo(amido)magnesiums formed straightforward monomers and dimers [35]. Moving to ortho‐magnesiation, the bisamide 12 has been used to smoothly react boron‐substituted benzenes. This work evolved from the advent of TMP‐bases as ortho‐metalating agents and enabled the ortho‐magnesiation of borylbenzenes via internal reaction of an N‐magnesiated intermediate 24. The resulting C,N‐magnesiate 25 was then electrophilically quenched using Me₂SO₄ to provide methylated product 26 that could be converted to a pinacolate (Scheme 1.7). The structure of a representative ortho C,N‐magnesiated intermediate proved to be a TMP‐intercepted spirocycle (in effect, a dimer of 25(12); Figure 1.3) [36].

Scheme 1.7 Ortho‐magnesiation of a borylbenzene via internal reaction of N‐magnesiated intermediate 24 to give C,N‐magnesiate 25.

Figure 1.3 Structure of the orthoC,N‐magnesiated dimer of 25(12).

      Source: Adapted from Kawachi et al. [36].

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