Polar Organometallic Reagents. Группа авторов

[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 [Me_3‐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, as noted above, examples have tended to be limited to the use of lithium and magnesium compounds. The rather limited coverage of other halogen–metal 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