href="#ulink_575190f6-a9c6-51bd-82a9-67e49d4eaddc">Scheme 1.26 Synthesis oft‐Bu2Zn(TMP)Li 1.
Scheme 1.27 Application of 1 in biaryl synthesis.
Figure 1.17 Proposed intermediates in the metalation of selected heteroaromatics.
Since the advent of directed aromatic deprotometalation using 1 [174], efforts have been ongoing to establish in detail the nature of potential intermediates in this process. This has led to extensive structural studies that will be visited throughout this book. To summarize, however, the earliest work focused on the nature of so‐called synergic bases themselves and rapidly established the predominance of a metallacyclic core based on the ability of the amido ligand and one of the two alkyl groups (in the case of Zn) to chelate the alkali metal irrespective of the presence of coordinating solvents or reagents [177]. The alkali metal can be a higher group 1 element such as sodium [178] or even potassium [179, 180], though the use of lithium has dominated synthetically applied work [82]. Representative examples that have been fully elucidated crystallographically include Et2Zn(TMP)Li 127 and t‐Bu2Zn(TMP)Li(TMEDA) 128. They are based on 4‐membered NZnCLi metallacyclic cores deriving from the intermetal bridging ability of TMP and one of the two alkyl groups (e.g. Figure 1.18). Theirs and closely related single‐crystal structures are explored in detail in Chapter 2, Figures 2.13 and 2.14.
More instructive in terms of understanding deprotometalation, have been investigations into model intermediates that have incorporated simple aromatics. An early example of this involved the reaction of anisole, with the corresponding ortho‐zincates prepared under a variety of solvent conditions by transmetalation. Isolation revealed solvated aryl(dialkyl)zincates of the type R2Zn(C6H4OMe‐2)Li(THF) n (R = Me, n = 2 129; R = t‐Bu, n = 3 130), in which the zincated alkyl groups stabilized the alkali metal or not depending on the level of solvent inclusion in the structure (Scheme 1.28) [181].
Figure 1.18 A generalized alkali metal zincate.
Scheme 1.28 Transmetalation of lithioanisole to variously solvated ortho‐zincates 129 and 130.
Moving away from transmetalation reactions, the isolation and characterization of intermediates in deprotonative zincation reactions at the aromatic ortho position have been the subject of study. Spectroscopy quickly suggested a structural basis for the creation alongside dominant ortho‐metalates of meta and even a small amount of para‐metalates [182]. Directed meta reactivity [183,184] will be dealt with alongside more recent developments in the polydeprotonation of model aromatics at length in Chapter 2. However, immediately synthetically useful ortho reaction formed the basis of a range of synthetic studies. One practical advantage of ortho‐zincation that quickly emerged surrounded the observation of apparent ambibasicity. That is to say, it rapidly became apparent that nonstoichiometric zincate activity was evidenced. This was exemplified by the observation that reaction of N,N‐diisopropylbenzamide led to the isolation of t‐BuZn(TMP) m {C6H4C(O)Ni‐Pr2‐2} n M(TMEDA) (m = 0, n = 2, M = Li 131; m = 1, n = 1, M = Na 132) [185]. Similar work afforded both EtZn{C10H6C(O)Ni‐Pr2‐2}2Li(THF)2133 and Zn{C6H4C(O)Ni‐Pr2‐2}3Li(THF) 134 (the solid‐state structures of which are explored in Chapter 2, Scheme 2.20), with spectroscopic [186] and theoretical [187] analysis ultimately elucidating the basis for all of these observations; TMP was acting as a kinetic base whose conjugate acid could then be quenched by intermediate ortho‐zincates up to three times before HTMP was finally being liberated once a tri(aryl)zincate had been obtained [187]. Other advantages of this realm of chemistry manifested themselves, most particularly through the recognition that traditionally underused DMGs were compatible with relatively (wrt organolithium bases) nonnucleophilic zincates. In possibly the most dramatic example of the newfound ability to sidestep unwanted nucleophilicity, 128 was reacted with aromatic nitriles to give ortho‐zincated products instead of addition products [188]. A further manifestation of this new selectivity for ortho reaction saw the quantitative avoidance [189] of anionic Fries rearrangement by phenyl N,N‐dialkylcarbamates of ortho‐lithiates e.g. 135 to ortho‐phenoxides e.g. 136, enabling the isolation of 137 (Scheme 1.29) [27] whilst elsewhere the ortho reaction of benzyl methyl ester was recorded in place of the expected abstraction of a thermodynamic α‐hydrogen [190]. The isolation and full characterization of the intermediate mono(aryl)zincate was investigated theoretically [189], with results suggesting that factors such as external solvation [191] and aggregation [189] interfered with the ability of zincate intermediates to undergo polybasic reactions. Applications in the deprotonation of a range of N‐heteroaromatics (pyrazine, pyrazidine, pyrimidine, quinoxaline) to give both mono‐ and disubstituted products have also been demonstrated using a variant on R2Zn(TMP)Li; namely Zn(TMP)3Li 138, created in situ from ZnCl2 and LTMP [192]. This work was then rapidly extended to the preparation of functionalized pyrroles [193] and finally O‐ and S‐containing five‐membered aromatic heterocycles [194].
Scheme 1.29 The anionic Fries rearrangement and its avoidance using lithium zincate 127.
1.4.3 Cadmates
Limited synthesis using ate complexes has been achieved with the higher elements of group 12. However, in recent years limited reports of the deprotometalation of functionalized aromatics and heterocycles have appeared. These have sought to extend the role of organocadmiums as soft nucleophilic reagents in organic synthesis [195, 196]. Whereas Ph3CdLi 139 was first reported almost 70 years ago [197], the combination of CdCl2(TMEDA) and LTMP was reported just a decade ago. This work evolved from studies suggesting the cooperative action of LTMP and (TMP)2Zn [194]. In the current case, neither CdCl2(TMEDA) nor LTMP satisfactorily deprotonated anisole,
