Polar Organometallic Reagents. Группа авторов

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, whereas a 1 : 3 mixture of the two did so in 74% yield according to trapping with I₂ [198]. At the same time, ¹³C NMR spectroscopy suggested the absence of LTMP in solution, pointing to lithiocadmate formation. Subsequently, a range of aromatic amides, esters, nitriles, and even ketones were shown to undergo selective ortho reaction. Aromatic halides revealed chemoselective iodination remote to the halogen (Scheme 1.30). Efforts next turned to the deprotometalation of aromatic heterocycles (both π‐deficient and π‐excessive), where impressive results were obtained, beating those reported for Zn (see above) [192, 194]. The reactions of a wide range of N‐, O‐, and S‐heterocycles were subsequently probed [199]. Particularly interesting, very sensitive reagents such as diazines proved amenable to reaction (Scheme 1.30).

Scheme 1.30 Comparing the performance of Cd and Zn reagents in aromatic halogenation.

       1.4.4 Aluminates

Aromatic aluminium compounds are potentially attractive as functional materials and synthetic building blocks [200–202]. However, aromatic aluminium chemistry has not been well developed, mainly due to the lack of efficient preparative methods compatible with the presence of ancillary functional groups. A common synthetic route to aliphatic aluminium compounds is transmetalation of organolithiums or Grignard reagents to the corresponding aluminium compounds [203]. Unfortunately, these metalating reagents or the intermediary aromatic lithium or Grignard species they form are often too reactive to coexist with electrophilic functional groups like halogens, amides, nitriles, and π‐deficient heterocycles [12]. Neither insertion of aluminium into carbon–halogen bonds nor halogen–metal exchange reactions of aluminium on aromatic rings have been realized to date and this led to an interest in the development of new Al‐based ate reagents for effecting direct deprotometalation. Hence, a regio‐ and chemoselective direct alumination of functionalized aromatics using a newly designed aluminium ate base was investigated [204]. To develop this area, halogen–metal

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