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The first reported TMP‐zincate, t‐Bu₂Zn(TMP)Li 1, was targeted on account of the nontransferability of its tert‐butyl groups [89]. It was prepared by adding t‐Bu₂Zn to a solution of LTMP in THF at −78 °C, whereupon the complex solution was allowed to warm to room temperature (Scheme 1.26). ¹³C NMR spectroscopy revealed a new set of signals that could not be attributed to either t‐Bu₂Zn or LTMP, suggesting the formation of an ate complex. No spectroscopic indications of decomposition were detected after several hours at room temperature, suggesting the reagent to be suitably robust for further application.

The ortho‐metalation of arenes with different DMGs was examined using a solution of the TMP‐zincate complex. First, the reaction of alkyl benzoates with this reagent was investigated, with metalation found to proceed smoothly at room temperature. The putative arylzincates thus prepared were treated with I₂ to give iodobenzoates in excellent yields. Substantiation of arylzincate intermediate formation came from the stepwise treatment of alkyl benzoates with LTMP followed by the addition of t‐Bu₂Zn. This was found to be an ineffective route to the formation of the arylzincates; pre‐complexation of the Li and Zn reagents was evidently essential for successful zincation. N,N‐diisopropylbenzamide was also metalated by the TMP‐zincate, and subsequent treatment with I₂ gave the iodide. The cyano group also functioned as an excellent DMG, and metalation proceeded smoothly. The arylzincate could be trapped with I₂ or benzaldehyde to give excellent yields of the iodide or alcohol, respectively. This arylzincate preparation was applied to biaryl synthesis, employing palladium‐catalyzed cross‐coupling with aryl iodides. The arylzincate derived from ethyl benzoate and TMP‐zincate was reacted with iodobenzene and 3‐iodopyridine in the presence of Pd(PPh₃)₄ at room temperature for 24 h to give biarylcarboxylates (Scheme 1.27).

The metalation of a range of heteroaromatic compounds at diverse ring positions was examined using 1. For example, just as ethyl 3‐thiophenecarboxylate has been metalated at the 2‐position using magnesium amides [38, 39], so too was this deprotonation achieved at room temperature using a zincate base, after which treatment with I₂ gave the 2‐iodo derivative in 89% yield [174]. A similar reaction using ethyl 2‐thiophenecarboxylate gave presumed 123 and thence the 5‐iododerivative in 62% yield (Figure 1.17). Ethyl 2‐furancarboxylate showed different regioselectivity (viz. 124) from that of ethyl 2‐thiophenecarboxylate, and 3‐iodo derivative was obtained in 71% yield. α‐Metalation of π‐deficient heteroaromatic compounds – considered to be a challenging target – has been investigated as part of the search for more efficient, direct methods for introducing functionalities into heteroaromatic rings. Controlling the reactivity and selectivity of the metalating species has been one of the most important and essential issues in developing this approach, and this work acted to demonstrate the versatility of the TMP‐zincate. The α‐metalation of pyridine was found to proceed smoothly at room temperature, and the putative pyridinylzincate 125 was treated with I₂ to give 2‐iodopyridine in 76% yield. Interestingly, quinoline was metalated preferentially at the 8‐position, and treatment with I₂ gave 8‐iodoquinoline in 61% yield (together with α‐metalated 2‐iodoquinoline in 26% yield). Isoquinoline was also easily metalated at the 1‐position (putatively 126), and 1‐iodoisoquinoline was obtained in 93% yield (Figure 1.17). This contrasted with the directed 1‐lithiation of isoquinoline, which is difficult to accomplish on account of the formation of isoquinoline dimers [176].

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.