exchange systems is true also of copper; although the possibility of halogen–copper exchange has been suggested in the coupling reaction of aryl halides with cuprates [106, 107], the reactions of halogen‐exchange‐generated organocopper intermediates with electrophiles are still unexplored from the viewpoint of synthetic chemistry.
Moving to discuss organic transformations based on organocopper/cuprate chemistry in more detail, arylcuprates have been prepared by reaction of iodobenzene with 81 in THF at −40 °C. Subsequent reaction with benzaldehyde at −78 °C gave benzhydrol 82 in 89% yield [98]. Meanwhile, mixed cuprates Me2CuLi 83, Me2Cu(SCN)2Li284, MeCuTh(CN)Li285 were found to be less reactive. The halogen–metal exchange reaction of p‐iodoanisole with this latter cuprate proved slower than the corresponding reaction of iodobenzene. However, satisfactory results could be obtained when the metalation was conducted at −20 °C. The p‐methoxy and ester groups were tolerated in the halogen–copper exchange reaction, and the intermediary copper reagents reacted with benzaldehyde to give alcohols 86 and 87. The p‐methoxy result contrasted starkly with that obtained using an organolithium intermediate, where self‐condensation was seen. However, better yields were obtained when the metalation was conducted at −78 °C (Scheme 1.21).
Interesting conjugate addition reactions have been enabled using cuprate chemistry, obviating the traditional need for additives to promote conversion. For example, the phenylcuprate presumed to be generated from iodobenzene and 81, has been added to 2‐cyclohexenone to afford 3‐phenylcyclohexanone in 61% yield without additional reagents. Meanwhile, reaction of the same phenylcuprate with 1,2,‐epoxycyclohexane gave trans‐2‐phenylcyclohexanol in 53% yield in the absence of (normally required) additives such as Lewis acids. To obtain post mortem information about the structure of the arylcopper intermediate in these addition processes, the putative arylcuprate 88 obtained by the halogen–copper exchange reaction of methyl p‐iodobenzoate was tested against both hydrolysis and oxidation with oxygen. Hydrolysis of the cuprate in aqueous NH4Cl at −40 °C gave methyl benzoate in 85% yield with no observed formation of methyl p‐methylbenzoate, verifying the non‐transferability of the Me ligand, with MeI presumably produced during halogen exchange and giving a cuprate less prone to react with electrophiles than is MeCuAr(CN)Li2 (88). Meanwhile, oxidation of the arylcuprate by bubbling oxygen through the reaction mixture at −78 °C gave the coupling product methyl p‐methylbenzoate 89 in 76% yield (Scheme 1.22). Overall, these data pointed towards the incorporation of LiCN alongside a Me‐ligand in the arylcuprate intermediate (the structural implications of this are discussed in Section 1.4) [98].
In connection with studies into the synthesis of the CC‐1065/duocarmycin pharmacophore, the syntheses of 3‐hydroxymethyl‐2,3‐dihydroindole and 3‐hydroxy‐1,2,3,4‐tetrahydroquinoline was investigated [98]. The availability of these precursors in enantiomerically pure form is fundamental to the straightforward asymmetric synthesis of the pharmacophore. In particular, the intramolecular ring‐opening of epoxyorganometallic compounds is of interest with regard to the regioselectivity of subsequent cyclization. This led to a detailed examination of the synthesis of a precursor to CC‐1065/duocarmycin pharmacophore by intramolecular ring‐opening of epoxyarylmetal ate complexes. This precursor – a chiral epoxide – was treated with n‐BuLi at −90 °C, resulting in the formation of 5‐exo cyclization product 90 in 43% yield and without any detectable loss of enantiopurity. Meanwhile, the reaction of the epoxide with lithium trimethylzincate at −50 °C gave the 5‐exo product in 40% and the 6‐endo product in 57% yield, respectively. In contrast, the reaction of the epoxide with cuprates showed reverse regioselectivity, and the 6‐endo product was dominant when 81 was used as the metalating reagent (yield 62% 6‐endo 91 versus 6% 5‐exo). This was further improved using Me3Cu(CN)Li392, which gave a uniquely 6‐endo reaction in 73% yield. In general, enantiomeric purity was unchanged after ring opening (Scheme 1.23) [98].
Scheme 1.21 Halogen–metal exchange of p‐iodoanisole with cuprate 81 at −78 °C.
Scheme 1.22 Reaction of methyl p‐iodobenzoate and 81, with subsequent oxidation at −78 °C giving coupling product 89.
Though synthetic work outlined above is dominated by cuprate chemistry, the structures of organocopper(I) reagents continue to capture the interest of chemists in their own right. However, their thermal instability and their sensitivity towards oxygen and moisture have posed serious obstacles to the characterization of organocopper(I) species. The stability of RCu is known to depend strongly on the nature of the organic ligand, with stability increasing in the order [108] R = alkyl [109] < alkenyl [110–113] ≈ aryl [114–119] < alkynyl [120, 121]. Crystallographic studies have revealed cyclic aggregates based on (typically) two‐coordinate copper centres with, in many cases, some degree of aggregation retained in solution [116, 122, 123]. For alkylcopper compounds, crystallographic data are limited to examples featuring stabilized ligands or stabilizing additives. Hence, Me3SiCH2Cu 93 afforded a metallacyclic tetramer [109]. Meanwhile, attempts to prepare MeCu(PPh3)2 afforded unusual heterodimer MeCu(μ‐Me)Cu(PPh3)294, best viewed as contact ion pair (CIP) [Me2Cu][Cu(PPh3)] (Figure 1.10a) [124]. Indeed, a comparable ion‐separated structure (SIP) has been reported; [Me2Cu][Cu(PMe3)4] 95 was based on a linear coordinate anion and tetrahedral cation (Figure 1.10b) [125].
Scheme 1.23 The contrasting reactivity of an epoxide with n‐BuLi and different lithium cuprates.
Figure 1.10 Structures of phosphine‐stabilized (a) CIP [Me2Cu][Cu(PPh3)] or MeCu(μ‐Me)Cu(PPh3)294 and (b) SIP [Me2Cu][Cu(PMe3)4] 95.
Sources: Adapted from Molteni et al. [124]; Dempsey et al. [125].
Whilst homometallic organocopper compounds continue to evolve new interest in areas such as photoluminescence [126], the most extensively studied synthetically useful class of organocopper reagents are the heterobimetallic lithium cuprates. As first reported by Gilman [127], lithium
