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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
