in 44% yield. The metalation gave the expected products in slightly higher yields when the reaction was instead conducted with a combination of lithium trimethylzincate and TMEDA. Importantly, although 3‐lithio‐1‐phenylsulfonylindole has long been known to isomerize easily to the thermodynamically stable 2‐lithioindole 57, the alternative use of lithium zincates avoided the formation of 2‐substituted isomers (Scheme 1.14). The heterobimetallic method, therefore, became considered to be advantageous for the selective metalation of the indole 3‐position, giving 58.
Scheme 1.13 Halogen–zinc exchange in a para‐substituted aromatic iodide.
The outer shell of the zinc centre in a lithium trialkylzincate is occupied by 16 electrons and, as will be explored more fully in Chapter 2, this leaves room for additional ligand coordination to form an 18 electron state [82]. With this in mind, reports on tetraalkylzincates have presented X‐ray studies that have disclosed a tetrahedral arrangement about the zinc [83–86]. However, the reactivities of tetraalkylzincates have not been well studied. Intramolecular carbometalation has been examined using the iodine–zinc exchange of allyl 2‐iodophenyl ether. When the iodo ether was treated with 54, halogen–metal exchange proceeded smoothly, but no intramolecular carbometalation was observed, yielding 59. In contrast, the reaction of the iodo ether with Me4ZnLi260 was followed by hydrolysis to give 3‐methyldihydrobenzo[b]furan 61 in 42% yield, which behaviour was explained by invoking an intramolecular carbozincation (Scheme 1.15) [87, 88].
As they emerged as a practically applicable new subset of organozinc reagent, organozincates rapidly became regarded as attractive candidates for carbon–carbon bond formation. To evaluate the non‐transferability of alkyl groups, the migratory aptitude of various alkyls from a range of lithium aryldialkylzincates was investigated [89]. Tert‐butyl turned out to be the best non‐transferable group and lithium tri(tert‐butyl)zincate was therefore found to represent a highly effective reagent for the chemoselective halogen–zinc exchange of functionalized organic halides. As an exemplar, the migratory aptitude of lithium dialkylphenylzincates was investigated as illustrated in Scheme 1.16. Phenyllithium was reacted with a range of dialkylzinc substrates to form the corresponding ate complexes 62, and these were then treated with 0.5 equivalent benzaldehyde. Spectroscopic analysis of the resulting crude mixture of products then elucidated the ratio of the two alcoholic products.
The status of tert‐butyl as the most effective non‐transfer group led to the performance of lithium tri(tert‐butyl)zincate 65 also being examined in the halogen–zinc exchange of functionalized aryl halides. It was observed that the exchange reaction generally proceeded smoothly and that electrophilic quenching of the arylzincate intermediates also completed, giving 66–69, without transferring the tert‐butyl group (Scheme 1.17).
Scheme 1.14 Use of a lithium zincate to avoid intermediate rearrangement of the type undergone by the 3‐lithio‐1‐phenylsulfonylindole.
Scheme 1.15 The contrasting reactivity of an allyl 2‐iodophenyl ether with Me3ZnLi 54 and Me4ZnLi260.
Scheme 1.16 Investigation of the migratory aptitude of lithium dialkylphenylzincates using phenyllithium, a dialkylzinc and benzaldehyde.
Scheme 1.17 Tert‐butyl as a nontransfer group; 65 incurs the halogen–zinc exchange of functionalized aryl halides.
To demonstrate the compatibility of this reaction with diverse electrophilic substituents, methyl 4‐iodobenzoate was treated with 65 and the resulting assumed arylzincate 70 was then treated with a range of electrophiles. Attempts at 1,2‐addition with benzaldehyde, alkylation with methyl iodide and allylation with allyl iodide all gave the expected products (e.g. 71, Scheme 1.18), and acylation with benzoyl chloride proceeded smoothly without a palladium 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;