catalyst to give the corresponding ketone 72. This avoidance of the use of a noble metal catalyst was advantageous not only on cost grounds but also on account of the strict guidelines that regulate trace amounts of transition metals in pharmaceuticals. In contrast to the reaction of 2‐iodoanisole with lithium trimethylzincate 54, which gave the corresponding alcohol in a low yield of 29% upon introduction of benzaldehyde, the use of tri(tert‐butyl)zincate 65 enabled the corresponding reaction in the much higher yield of 83%.
To further investigate the synthetic potential of this halogen–zinc exchange reaction of 65, transmetalation of the putative lithium di(tert‐butyl)phenylzincate 73 with thienylcyanocuprate was surveyed (Scheme 1.19, Th = thienyl) [89]. The phenyl group was found to smoothly undergo 1,4‐addition to cyclohex‐2‐enone in the presence of lithium thienylcyanocuprate 74 to give 75, while the reaction in the absence of 74 was very sluggish.
From a structural perspective, the first fully characterized lithium alkylzincate appeared in the 1960s [83]. The structure of 60 revealed tetravalent zinc, the completion of a full outer electron shell in which has more recently characterized the reactivity of alkali metal zincates in deprotometalation, of which more later. Moving on several decades, the imperative to complete zinc’s outer shell was similarly revealed by external solvation in simple amine adducts in spite of the deployment of sterically demanding ligands in tri[di(trimethylsilyl)methyl]zincates [90]. Competition between tri‐ and tetra(organyl)zincates was further elucidated at about this time through the use of the monoanionic, potentially C,N‐chelating C6H4CH2NMe2‐2 (DMBA) ligand. This allowed the observation of 18 electron Zn centres in both (DMBA)3ZnLi 76 (following 4:1 (DMBA)2Zn:DMBALi reaction; Figure 1.9a) and spirocyclic [91] (DMBA)4ZnLi277 (2 : 1 reaction; Figure 1.9b) [92]. Interestingly though, reactions of these zincates with cyclohexanone gave a very early indication of disproportionation, a phenomenon seen more recently in alkyl, amido, and mixed alkyl–amido zincates [86]. This issue has been revisited in ate chemistry discussed elsewhere in this book that finds applications in directed aromatic deprotometalation [93, 94]. Further advances towards the isolation and full characterization of simple, trivalent, 16 electron Zn were made by the expansion of steric demands in silylmethylzincates [90, 95, 96] in combination with the introduction of Lewis bases capable of abstracting the alkali metal. Accordingly, with TMEDA present it proved possible to observe ion‐separated [Me3‐n Zn{CH(SiMe3)Ph} n ][Li(TMEDA)2] 78 (n = 1–3) [97]. Recently, remarkable insights into competing solvent‐separated ion‐pair (SIP, obtained in the presence of diglyme) and contact ion‐pair (CIP, obtained in the presence of PMDETA) formation saw the subject go full‐cycle, returning to simple lithium methylzincates but now probing 16 electron metal centres in the trimethylate (Scheme 1.20). The same work used the relatively new technique of DOSY to shed light on the solution behaviour of these species. Hence, though 1H NMR spectroscopy revealed single methyl resonances for both PMDETA 79 and diglyme 80 systems in solution, DOSY was able to establish that this was due to exchange in the former case and not SIP formation. The power of DOSY to advance our understanding of the potentially elaborate solution chemistry of polar organometallics is the subject of detailed discussion elsewhere in this book.
Scheme 1.18 Treatment of methyl 4‐iodobenzoate with 65 preceded allylation (with allyl iodide) and acylation (with catalyst‐free benzoyl chloride).
Scheme 1.19 Addition reaction involving the transmetalation of putative lithium di(tert‐butyl)phenylzincate 73 with thienylcyanocuprate.
Figure 1.9 Molecular structures of (a) solvated (DMBA)3ZnLi 76 and (b) (DMBA)4ZnLi277, which can be selectively targeted by modulating the (DMBA)2Zn:DMBALi ratio in reaction.
Sources: Adapted from Wyrwa et al. [91]; Rijnberg et al. [92].
Scheme 1.20 Competing SIP and CIP formation in Me3ZnLi chemistry.
1.3.3 Cuprates
While lithium cuprates have very recently undergone major development as versatile reagents for selective carbon–carbon bond forming reactions (see below), little attention has been paid to halogen–copper exchange using ate complexes. That said, with the aim of developing a new and facile method for the preparation of arylcuprates, the halogen–copper exchange reaction of aromatic halides using lithium cuprates was investigated in the mid‐1990s [98]. It was in this context that the suggested complex Me2Cu(CN)Li281 was found to be an excellent metalating reagent, while organocoppers were not. The application of this protocol to the high‐enantiomeric purity preparation of precursors to the CC‐1065 [99–101]/duocarmycin [102–104] pharmacophore was also conducted as outlined in Scheme 1.23.
Copper‐based organometallic complexes are the organotransition metal reagents most widely used as soft nucleophiles in organic synthesis. Hence, both organocopper and organocuprate reagents are employed for carbon–carbon bond formation owning to their characteristic reactivities in conjugate addition to α,β‐unsaturated carbonyl compounds, in substitution reactions, and in the carbometalation of carbon–carbon triple bonds. Although both organocopper and organocuprate reagents are well established as tolerating a wide range of electrophilic functional groups, the formation of functionalized organocopper reagents has not proved promising. This has largely been because transmetalation of nucleophilic organolithium or Grignard reagents has typically been required and this has been limited by functional group tolerance. In a similar vein, functionalized organocopper reagents have been prepared by the transmetalation of functionalized organozinc compounds and by direct oxidative addition of active copper, prepared from CuI(PBu3) and lithium naphthalenide, to organic halides [105]. A number of so‐called Gilman reagents – lithiocuprates of general formula R2CuLi – have been used in organic syntheses. Mixed cuprates, R2Cu(CN)Li2, have also been reported to show high reactivity towards a variety of organic substrates. Though the halogen–metal exchange reaction is one of the most useful processes for the preparation of metalated arenes,
