competition from the nucleophilic reaction. The result was a dimer where Li was stabilized by both diethyl ether and DMG groups and in which the amide‐arene twist‐angle was been modulated to 47°. More complicated behaviour was seen for 2‐alkyl‐N,N‐diisopropylbenzamides, with strongly solvent‐dependent competition observed [20]. The dimer of i‐Pr2NC(O)‐2‐Et‐C6H3Li(THF) 5 (Figure 1.2a) proved to be a kinetic product, isolable from limited THF but rearranging in the presence of an excess of THF or of a stronger Lewis base [21] to give a thermodynamic benzylic metalate, presumably of the type seen in the THF‐solvate of α‐lithio‐2‐ethyl‐N,N‐diisopropyl‐1‐naphthamide [22, 23]. Meanwhile, the ortho‐lithiate of 2‐isopropyl‐N,N‐diisopropylbenzamide could be obtained from diethyl ether as a hemi‐solvate 6 (Figure 1.2b) [24].
A further area of complexity associated with the deprotonative chemistry of organolithiums is that of anionic rearrangements, such as the long known [25] and synthetically useful [26] Fries formation of ortho‐phenols from aromatic carbamates (see Section 1.4.2). According to rate studies, substituents at the meta position of the arene and the dialkylamino moiety of the carbamate DMG significantly influenced the relative rates of ortho‐lithiation and subsequent rearrangement. Solution structural studies by 6Li and 15N NMR spectroscopies revealed a dimer of the lithiating agent (LDA), LDA dimer‐arene complexes, an aryllithium monomer, LDA‐aryllithium mixed dimers, an LDA‐lithium phenolate mixed dimer, and lithium phenolate aggregates. While monomer‐ and dimer‐based ortho‐lithiations and also monomer‐ and mixed dimer‐based Fries rearrangements were identified, only the very insoluble phenolate dimer resulting from rearrangement could be isolated [27].
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
