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.