Polar Organometallic Reagents. Группа авторов
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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 cuprates differ from typical organocopper compounds in forming homogenous solutions in ethereal solvent, a property which is not only essential for their usability and reactivity but which also underpins their amenity towards structural characterization by enabling crystallization (Scheme 1.24).
It has been recognized for some time that the Cu : Li stoichiometry employed in cuprate formation offers a profound structural impact upon the resulting complex. Two fundamentally different types of cuprate have been recognized in consequence; so‐called ‘lower‐order’ and ‘higher‐order’ forms. The former are characterized by two‐coordinate Cu, the latter by Cu bearing a higher coordination number. Early structural data was gathered largely in the solution‐state, where evidence from vapour pressure depression, 1H NMR spectroscopy and solution X‐ray scattering all lent weight to the dominance of cyclic dimers [128]. It was not until the 1980s that the first reports on the X‐ray structures of lithium cuprates appeared. However, these revealed atypical copper‐rich anions. The synthetic utility of phenylcuprates has been alluded to above, and the first clusters of these species to be characterized, [Ph6Cu5][Li(THF)4] 96 [129], [Ph6CuLi4][Li(Et2O)4] 97 [130] and [Ph6Cu3Li2]2[Li4Cl2(Et2O)10] 98 [131], were obtained by reacting PhLi with CuBr and CuCN, respectively. The cuprate moieties in these SIPs revealed the same fundamental architecture, based upon a compressed trigonal bipyramidal arrangement of metal atoms in which the apical sites could be considered to bridge three [Ph2Cu]− units (Figure 1.11a) [132]. The subsequent isolation of the neutral phenylcuprate dimer of Ph2CuLi(Et2O) 99 (whose structure could be derived from [Ph6Cu3Li2]− by the formal replacement of one [Ph2Cu]− unit by Et2O (Figure 1.11b)) [133] lent support to this interpretation. Similar aggregates have also been reported where dimethyl sulfide replaces Et2O [134].