through the sequential reaction of a 4‐halo reagent with sulfuryl chloride, N‐bromosuccinimide and/or iodine (Scheme 1.33) [210]. Of course, the impressive compatibility of the base with halogenated reagents underpins this reactivity. This contrasts strongly with that of many traditional organometallics and it extended to the ability to isolate and fully elucidate ortho‐aluminated intermediates in both the first (154) and second (155) halogenation processes (Figure 1.20).
Scheme 1.33 i‐Bu2Al(TMP)2Li 150 has enabled the conversion of 4‐halo‐anisoles to triheterohalogenated anisoles 151–153.
Figure 1.20 Molecular structures of aluminated precursors 154 and 155 to (a) di‐, and (b) triheterohalogenated anisole derivatives, respectively.
Source: Adapted from Conway et al. [210].
Figure 1.21 Representation of the Gilman amidocuprate (TMP)2CuLi.
1.4.5 Cuprates
Whilst lithium organocuprates (Section 1.3.3) have established dominance amongst the transition metal organometallics used in synthesis, several different flavours of reagents have evolved to suit various applications. These include heteroleptic cuprates, which normally combine organyl and heteroatom‐based ligands as a means of increasing organyl transfer efficiency; organoamidocuprates are one such well‐studied member of the heterocuprate family. They have become known by virtue of their unique features and reactivities. They have many potential applications in organic transformations, especially in stereoselective synthesis because the amido ligand can act not only as a dummy (nontransferable) group but also as a chiral auxiliary [211]. The non‐transferability of amido (heteroatom) ligands on cuprates in carbon–carbon bond forming reactions has also been theoretically clarified by DFT calculations [212]. A new use for amidocuprates was investigated, wherein the amido ligand transfers (reacts) first as a base for chemoselective directed ortho‐cupration and then as a switch in successive C–C, C–O, and C–N bond formation processes [213, 214]. To develop new applications of amidocuprates, the deprotonative metalation of functionalized benzenes was investigated [215]. Initial studies used benzonitrile as a model aromatic compound with an electron‐withdrawing group to identify favourable reaction conditions. These indicated that a TMP group as the amido moiety and THF as solvent were suitable starting points for the optimization of directed metalation reaction conditions (Figure 1.21). Attempts to use the Gilman amidocuprate (TMP)2CuLi 156 prepared from CuI proved unsuccessful in terms of reactivity and directed metalation selectivity. On the other hand, the use of CuCN was presumed to result in the incorporation of cyanide and the formation of so‐called Lipshutz amidocuprates. Two examples, putatively (TMP)2Cu(CN)Li2157 and MeCu(TMP)(CN)Li2158, have been proposed to exemplify this, with reaction mixtures incorporating the appropriate amounts of the necessary components (CuCN, LTMP and, for 158, MeLi) enabling metalation without any catalyst, in good yields at 0 °C (summarized in Scheme 1.34 and explored in depth in Chapter 8). It was found that although the latter case employed a CuMe‐containing reagent, at least one TMP ligand, one of the bulkiest available amido ligands, was crucial for good yield and chemoselectivity.
Scheme 1.34 A generalized view of directed ortho‐cupration.
Figure 1.22 Molecular structure of Lipshutz cuprate dimer [(TMP)2Cu(CN)Li2(THF)]21592.
Source: Adapted from Usui et al. [213].
Structural work has been integral to the evolution of directed cupration. The concept of organo(amido)cuprate bases can be viewed as emerging from the confluence of organocuprate chemistry and the (at the time) relatively new and evolving field of synergic base chemistry. From the perspective of cuprate chemistry, it had been recognized for some time that the replacement of an organyl group with a non‐transferable ligand [212], to give a heterocuprate could (i) reduce wastage of valuable organic groups and (ii) significantly improve reagent stability. Several classes of non‐transferable ligand have been investigated [216]. However, amido groups have offered the most compelling combination of excellent stabilizing properties and relative ease of access from commercial reagents [217]. Of course, the ability of the sterically congested amido ligand TMP to act as a potent kinetic base in directed metalation has already been discussed in this chapter in the context of highly successful synergic metalating reagents such as 1 [174]. The combination of these factors led to organo(TMP)cuprates being conceived as viable bases for directed cupration. Their successful application to the elaboration of functionalized aromatics is described in the preceding section [213] and is related in detail in Chapter 8. Most relevant to the work of an applied vein, the combination of LTMP with CuCN in THF was argued to form cyanide‐containing Lipshutz bis(amido)cuprate complex (TMP)2Cu(CN)Li2(THF) 159, this system demonstrating excellent reactivity in directed ortho‐cupration. As a part of the same study, 2 : 1 reaction of LTMP with CuCN in the presence of THF indeed enabled the isolation of, and X‐ray diffraction studies on, this Lipshutz cuprate. Data revealed a dimer composed of individually 7‐membered metallacycles that associate by forming a central Li2N2 ring (Figure 1.22). The inclusion of cyanide as a bridge between multiple Li centres without any discernable interaction with Cu was significant since it provided further important evidence (backing up prior theoretical work) [160, 161] for the absence of higher‐order structures in cyanocuprates. This motif was subsequently found to apply to structures incorporating a range of inorganic anions that led to the development of the expression ‘Lipshutz‐type’ cuprates for the recently reviewed family of complexes (TMP)2Cu(X)Li2 (X = inorganic anion ≠ CN, see below for specific examples) [218].
