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Since the pioneering work of Gilman [10] and Wittig [11], directed ortho‐metalation has become widely used as a powerful and efficient method for the regioselective functionalization of aromatic compounds. A range of DMGs have been employed to facilitate the selective deprotonation of arenes, and various strong bases such as alkyllithiums (RLi) and lithium dialkylamides (R₂NLi) have been used (Scheme 1.2) [6], though often with the drawbacks outlined in Section 1.1.

Among group 1 organometallics, alkyllithium reagents are the most convenient to work with for synthetic chemists because of their solubility in ethers and/or frequently in alkanes. Moreover, or perhaps because of this, many of them are commercially available. Therefore, it has become of great practical importance to define the scope and limitations of alkyllithium‐promoted deprotonation reactions. Generally, only substrates with high C–H acidity enhanced by a DMG are amenable to deprotonative lithiation [6]. In this capacity, ester and cyano groups have long been regarded as potentially important and attractive directors of metalation. However, their use has been limited because the deprotonation requires strictly controlled reaction conditions owing to the instability of intermediary aryllithium species. For example, lithium 2,2,6,6‐tetramethylpiperidide (LTMP) has been used for directing the ortho‐lithiation of aryl carboxylic esters. However, the accompanying problems of unwanted condensation reactions between the aryllithium and electrophilic directing group have been well documented [12]. In spite of this, the in situ trapping of aryllithium species by electrophiles during the deprotonation of aryl carboxylic esters has been reported. However, the use of bulky ester groups under restricted reaction conditions is essential (Scheme 1.3) [13, 14].

Scheme 1.2 Representation of a generic directed ortho‐lithiation strategy.

Scheme 1.3 Steric effects on the directed ortho‐lithiation of aromatic esters.

The dominance of organolithiums in the deprotonation of aromatics by traditional organometallic reagents is reflected also at the structural level, and the actions of the many DMGs capable of controlling metalation have been summarized [15]. However, in spite of the long‐established importance of DMGs such as carboxylic amides in directed ortho‐metalation, it was only in 2001 that the first full structural evidence was provided for the nature of an aromatic deprotonated by an organolithium base under the influence of this directing agent [16]. Single crystal data established how it was that the simple amides i‐Pr₂NC(O)Ar (Ar = aryl) efficiently direct ortho‐lithiation [17] given the well documented, sterically induced amide‐arene twist‐angle of ~90° in the substrate [18, 19]. Crystalline i‐Pr₂NC(O)C₆H₄Li(OEt₂)‐2 4 was generated using a sterically congested DMG and t‐BuLi to avoid unwanted 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 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].

Scheme 1.8 The use of (^DipNacnac)MgTMP 27 in pyrazine deprotometalation.

β‐Diketiminate magnesium complexes have been developed very recently and applied to the regioselective magnesiation of aromatics. Initially, (^DipNacnac)MgTMP 27 (^DipNacnac = DipNC(Me)CHC(Me)NDip; Dip = 2,6‐(i‐Pr)₂‐C₆H₃), which combines kinetic base TMP with a sterically demanding spectator β‐diketiminate, was reacted with pyrazine at room temperature to quantitatively yield (^DipNacnac)Mg(C₄H₃N₂) 28 (Scheme 1.8) [37]. This work was then extended to using the kinetic TMP base to trap sensitive fluoroaryl anions for deployment in Negishi cross‐coupling. This trapping behavior contrasted with that of the kinetic‐amide‐lacking organyl analogue (^DipNacnac)Mg(R)(THF) 29 (R = n‐Bu, Ph, benzofuryl), which was shown to be effective in the chemically interesting [38, 39] magnesiation of perfluorinated aromatics by C–F bond alkylation/arylation [40].