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Whilst lithium organocuprates (Section 1.3.3) have established dominance amongst the transition metal organometallics used in synthesis, several different flavours of reagents have evolved to suit various applications. These include heteroleptic cuprates, which normally combine organyl and heteroatom‐based ligands as a means of increasing organyl transfer efficiency; organoamidocuprates are one such well‐studied member of the heterocuprate family. They have become known by virtue of their unique features and reactivities. They have many potential applications in organic transformations, especially in stereoselective synthesis because the amido ligand can act not only as a dummy (nontransferable) group but also as a chiral auxiliary [211]. The non‐transferability of amido (heteroatom) ligands on cuprates in carbon–carbon bond forming reactions has also been theoretically clarified by DFT calculations [212]. A new use for amidocuprates was investigated, wherein the amido ligand transfers (reacts) first as a base for chemoselective directed ortho‐cupration and then as a switch in successive C–C, C–O, and C–N bond formation processes [213, 214]. To develop new applications of amidocuprates, the deprotonative metalation of functionalized benzenes was investigated [215]. Initial studies used benzonitrile as a model aromatic compound with an electron‐withdrawing group to identify favourable reaction conditions. These indicated that a TMP group as the amido moiety and THF as solvent were suitable starting points for the optimization of directed metalation reaction conditions (Figure 1.21). Attempts to use the Gilman amidocuprate (TMP)₂CuLi 156 prepared from CuI proved unsuccessful in terms of reactivity and directed metalation selectivity. On the other hand, the use of CuCN was presumed to result in the incorporation of cyanide and the formation of so‐called Lipshutz amidocuprates. Two examples, putatively (TMP)₂Cu(CN)Li₂157 and MeCu(TMP)(CN)Li₂158, have been proposed to exemplify this, with reaction mixtures incorporating the appropriate amounts of the necessary components (CuCN, LTMP and, for 158, MeLi) enabling metalation without any catalyst, in good yields at 0 °C (summarized in Scheme 1.34 and explored in depth in Chapter 8). It was found that although the latter case employed a CuMe‐containing reagent, at least one TMP ligand, one of the bulkiest available amido ligands, was crucial for good yield and chemoselectivity.

Scheme 1.34 A generalized view of directed ortho‐cupration.

Figure 1.22 Molecular structure of Lipshutz cuprate dimer [(TMP)₂Cu(CN)Li₂(THF)]₂159₂.

Source: Adapted from Usui et al. [213].

Structural work has been integral to the evolution of directed cupration. The concept of organo(amido)cuprate bases can be viewed as emerging from the confluence of organocuprate chemistry and the (at the time) relatively new and evolving field of synergic base chemistry. From the perspective of cuprate chemistry, it had been recognized for some time that the replacement of an organyl group with a non‐transferable ligand [212], to give a heterocuprate could (i) reduce wastage of valuable organic groups and (ii) significantly improve reagent stability. Several classes of non‐transferable ligand have been investigated [216]. However, amido groups have offered the most compelling combination of excellent stabilizing properties and relative ease of access from commercial reagents [217]. Of course, the ability of the sterically congested amido ligand TMP to act as a potent kinetic base in directed metalation has already been discussed in this chapter in the context of highly successful synergic metalating reagents such as 1 [174]. The combination of these factors led to organo(TMP)cuprates being conceived as viable bases for directed cupration. Their successful application to the elaboration of functionalized aromatics is described in the preceding section [213] and is related in detail in Chapter 8. Most relevant to the work of an applied vein, the combination of LTMP with CuCN in THF was argued to form cyanide‐containing Lipshutz bis(amido)cuprate complex (TMP)₂Cu(CN)Li₂(THF) 159, this system demonstrating excellent reactivity in directed ortho‐cupration. As a part of the same study, 2 : 1 reaction of LTMP with CuCN in the presence of THF indeed enabled the isolation of, and X‐ray diffraction studies on, this Lipshutz cuprate. Data revealed a dimer composed of individually 7‐membered metallacycles that associate by forming a central Li₂N₂ ring (Figure 1.22). The inclusion of cyanide as a bridge between multiple Li centres without any discernable interaction with Cu was significant since it provided further important evidence (backing up prior theoretical work) [160, 161] for the absence of higher‐order structures in cyanocuprates. This motif was subsequently found to apply to structures incorporating a range of inorganic anions that led to the development of the expression ‘Lipshutz‐type’ cuprates for the recently reviewed family of complexes (TMP)₂Cu(X)Li₂ (X = inorganic anion ≠ CN, see below for specific examples) [218].

Figure 1.23 Molecular structures of organoamidocuprates (a) [MesCu(NBn₂)Li]₂160₂, (b) MeCu(TMP)Li(TMEDA) 161 and (c) PhCu(TMP)Li(THF)₃162.

Sources: Adapted from Davies et al. [219]; Haywood et al. [220].

Reports on the structures of organo(amido)cuprates emerged around the same time as the inception of directed ortho‐cupration. The combination of mesitylcopper with dibenzylamidolithium in toluene led to the isolation of Gilman heterocuprate MesCu(NBn₂)Li 160 (Bn = benzyl), which revealed a head‐to‐tail dimer in the solid state (Figure 1.23) [219]. In this case, Li salts and donor solvents were excluded during cuprate formation. On the other hand, in situ cuprate synthesis using mixtures of organolithium and amidolithium reagents in combination with CuCN offered the possibility of LiCN inclusion in the solution and/or solid‐state structures. In such cases, however, Gilman organo(amido)cuprates MeCu(TMP)Li(TMEDA) 161 and PhCu(TMP)Li(THF)₃162 (Figure 1.23) that did not include LiCN were isolated and analyzed in the solid‐state. Both species preferred to form solvated monomers [220]. However, the inactivity of these isolated cuprates in directed ortho‐metalation was in stark contrast to the behaviour of the in situ preparations, suggesting LiCN involvement to be likely in solution. This hypothesis was supported by DFT calculations, which suggested a facile equilibrium between Lipshutz and Gilman organo(amido)cuprates in solution.

Similar patterns of reactivity have been seen for bis(amido)cuprate preparations based on CuI, whereby Gilman cuprate 156 (actually a dimer – see below) proved an ineffective base, whereas Lipshutz‐type (TMP)₂Cu(I)Li₂(THF) 163 performed much better (Scheme 1.35 and Figure 1.24) [221]. Importantly, these results pointed towards a more general role for Li salts in disrupting unreactive Gilman aggregates, spawning a search for other Lipshutz‐type reagents that could offer safer alternatives to cyanide‐based preparations.

Scheme 1.35 Selective formation of Gilman and Lipshutz‐type cuprates from CuI.

Figure 1.24 Molecular structures of (a) Gilman amidocuprate dimer of (TMP)₂CuLi 156 and (b) Lipshutz‐type dimer of (TMP)₂Cu(I)Li₂(THF) 163.

Source: Adapted from Komagawa et al. [221].

Readily available copper(I) halides CuCl [222] and CuBr [223] have been investigated as sources of lithium salts for Lipshutz‐type cuprates, the structures of which have been found to be very similar to that of the dimeric iodide shown in Figure 1.24. Synthetically, in situ preparations using the putative cuprate (TMP)₂Cu(Cl)Li₂164 were found to be excellent reagents for the directed cupration of heterocycles, opening up a new route to the synthesis of pharmacologically interesting azafluorenones [222].

In an attempt to decrease the costs associated with amidocuprate preparation [224], copper(I) halides have been employed extensively in the creation of DMP‐ rather than relatively expensive TMP‐cuprates (DMP = cis‐2,6‐dimethylpiperidide) [225]. The 2 : 1 reaction of amidolithium LDMP with CuX (X = Cl, Br, I) was therefore attempted as a route to more economical Lipshutz‐type cuprates. Remarkably, the formal replacement of two methyl groups from TMP with H‐atoms led to an entirely different structure‐type that could be viewed as an adduct of Gilman and Lipshutz‐type monomers (Figure 1.25 shows X = Br 165). In the pentametallic species seen, differences in Li–X (X = Cl, Br, I) and Li–N bond lengths were rationalized in terms of competing stabilization by hard/soft donors. Experiments in which TMP‐cuprates and DMP‐cuprates were both prepared in the presence of THF or Et₂O confirmed that the difference in structure‐types was attributable to the amido ligand rather than the Lewis base. Importantly, the inclusion of LiX (X = Cl, Br, I) in adduct cuprates was consistent with their observed reactivity in directed ortho‐cupration. DFT calculations reinforced this view that adducts could affect ortho‐metalation by showing that adduct cuprates represented an energetically feasible source of reactive Gilman monomers – which prior work had already suggested to represent the active species in directed ortho‐cupration [221].

The switch in structure‐type apparently enforced by the amido ligands has led to a search for other potential replacements for HTMP that might also influence structure‐type. 2‐Methylpiperidide (MP) was quickly identified as an interesting target, in view of the low cost of its conjugate acid and its chirality. The reaction of racemic LMP with CuBr in a 2 : 1 ratio yielded {(MP)₂CuLi(THF)₂}₂LiBr 166 – evidenced by X‐ray diffraction to be an adduct cuprate in the solid‐state [226]. In spite of a precedent from organocuprate chemistry [227] stereoselective assembly was not observed in this case, with X‐ray diffraction suggesting a multi‐component crystal involving permutations of R‐ and S‐MP. Meanwhile, combining the use of either DMP or MP and TMP demonstrated the ability to produce heteroleptic Lipshutz‐type structure 167. Partnering TMP with piperidide (PIP) then suggested competition between Lipshutz‐type and Gilman structures in heterodiamide chemistry by producing Gilman cuprate paddlewheel 168 ₂ (Figure 1.26).

Figure 1.25 (a) Schematic of an adduct cuprate structure‐type and (b) molecular structure of {(DMP)₂CuLi(Et₂O)}₂LiBr 165.

Source: Adapted from Peel et al. [226].

Figure 1.26 Molecular structures of heteroleptic cuprates (a) [(TMP)(DMP)Cu(Br)Li₂(THF)₂]₂167₂ and (b) [(PIP)(TMP)CuLi]₂168₂.

Source: Adapted from Peel et al. [226].

The structural influence of inorganic anions beyond halides capable of replacing cyanide in the creation of Lipshutz‐type cuprates was investigated through the reaction of CuSCN with an amidolithium reagent. In the event, CuSCN provided straightforward access to a range of differently solvated Lipshutz‐type cuprates (TMP)₂Cu(SCN)Li₂(L) (L = THF 169, Et₂O 170 and THP 171; THP = tetrahydropyran) when introduced to LTMP in a 1 : 2 ratio in the presence of donor solvent [228]. A strong dependence of the geometry of the solid‐state dimers of these thiocyanatocuprates on the Lewis base additives was uncovered, apparently resulting from the ability of the metallacyclic (LiSCN)₂ core to adopt boat‐like, chair‐like or planar conformations (Figure 1.27). The influence of the donor solvent was not limited to the solid‐state either: Lipshutz‐type thiocyanato(amido)cuprates were found to convert to Gilman cuprate in benzene solution, with the degree of conversion being strongly influenced by the identity of the donor solvent incorporated in the cuprate (and being most pronounced for Et₂O). In a synthetic setting, thiocyanatocuprates performed competitively with CuCl‐derived bases in the directed ortho‐cupration of halopyridines.

Cyanato(amido)cuprate analogues of the thiocyanate systems described above have also been investigated. Attempts to prepare these cuprates from the direct reaction of CuOCN with LTMP were not successful, with spectroscopy suggesting multiple products and crystallography indicating Cu/Li substitution in the solid‐state in some of these [229]. Nonetheless, Lipshutz‐type (TMP)₂Cu(OCN)Li₂(THF) 172 proved accessible by inserting LiOCN into 156 in THF. The resulting solid‐state dimer offered a geometry that differed substantially from those of the known THF‐solvated thiocyanatocuprates, but otherwise retained all the features now established to be typical for Lipshutz‐type cuprates (Figure 1.28). Curiously, when reacted with CuOCN, less sterically encumbered lithium diisopropylamide (LDA) furnished a novel amidocuprate‐amidolithium adduct (DA)₄Cu(OCN)Li₄(TMEDA)₂173, which could be viewed as arising from the attachment of units of LDA(TMEDA) to a Lipshutz‐type monomer. Meanwhile, spectroscopic investigations on CuOCN/LTMP reaction mixtures suggested the production of a new amidocopper‐amidolithium aggregate (CuTMP)₂(LTMP)₂174 (Figure 1.29) – a structural isomer of previously reported Gilman dimer [(TMP)₂CuLi]₂156 ₂ (Figure 1.24a). The reactivity of the Gilman dimer was previously established to be low. However, the knowledge that monomeric Gilman amidocuprates are reactive led to an interest in the solution behaviour and reactivity of this new adduct.

Figure 1.27 Molecular structures of the dimers of thiocyananto(amido)cuprates (a) (TMP)₂Cu(SCN)Li₂(THF) 169, (b) (TMP)₂Cu(SCN)Li₂(Et₂O) 170, and (c) (TMP)₂Cu(SCN)Li₂(THP) 171.

Source: Adapted from Peel et al. [228].

Figure 1.28 Examples of cyanatocuprates (a) [(TMP)₂Cu(OCN)Li₂(THF)]₂172₂ and (b) (DA)₄Cu(OCN)Li₄(TMEDA)₂173.

Source: Adapted from Peel et al. [229].

The recent realization that 174 could be accessed in a pure form by reaction of CuCl with LTMP made possible investigations into its synthetic utility. This proved both highly unexpected and potentially useful. Notably, the adduct demonstrated an uncanny ability to smoothly deprotonate benzene. As such it suggests the use of currently underutilized chemical feedstocks in aromatic elaboration. Physical mixtures of CuTMP and LTMP replicated this reactivity towards benzene, in so doing leading to the production of a series of organoamidocuprates Ph(TMP)₃Cu _n Li_4−n (n = 1–4 175–178; Figure 1.30) [230]. This contrasted with conventional Gilman cuprate 156 ₂, which was unreactive under the same conditions. Crystallography revealed metallacyclic structures for these product organoamidocuprates in the solid‐state; the amido ligand adopted the by now usual metal‐bridging mode, whilst coordination of the Ph‐group varied substantially depending on metal content. In all cases, where Ph bridged Cu and Li, Cu–C σ‐bonding took precedence, the C···Li interactions being π‐type and suggesting an increase in hapticity with increasing Li content (a conclusion which was also supported by spectroscopy). Detailed spectroscopic discussions are reserved for Chapter 5. However, briefly, ¹H,¹H–NOESY/EXSY revealed that in solution, Ph(TMP)₃Cu₂Li₂176 was conformationally fluxional but otherwise retains its integrity. More dramatically, ⁷Li,⁷Li–EXSY established a dissociative‐associative equilibrium for the Li‐rich species Ph(TMP)₃CuLi₃175.

Figure 1.29 Isomers of (TMP)₄Cu₂Li₂; (a) dimer of conventional Gilman cuprate 156 (see Figure 1.24a) and, (b) isomeric adduct (CuTMP)₂(LTMP)₂174.

Figure 1.30 Structurally characterized organoamidocuprate aggregates (a) Ph(TMP)₃Cu₂Li₂176 and (b) Ph(TMP)₃Cu₃Li 177, illustrating changes to the hapticity of the Ph moiety in the solid‐state as a function of metal composition.

Source: Adapted from Peel et al. [230].