Polar Organometallic Reagents. Группа авторов

to promote selective reaction. This is a methodology that has come to represent one of the most effective ways of regiospecifically elaborating functionalized aromatic systems and which has, over a number of years, focused on the strategy of achieving ortho reaction of said ring. Though this technique has come to the fore in the elaboration of both aromatic and heteroaromatic systems, the low acidity of the hydrogen atoms on aromatic rings has led to a dependence on organolithium reagents as the base of choice for effecting deprotonation [4–8]. However, the high nucleophilicity of these same organolithium reagents has brought with it the associated risk of competing reaction at the DMG itself. It was the need to overcome this synthetic limitation that led to the development of the heterobimetallic complexes alluded to above, designed to promote chemoselective directed metalation reactions under mild conditions on the grounds of reduced nucleophilicity. This has now seen a range of zincates and other metal ate complexes incorporating the sterically bulky (non‐nucleophilic) 2,2,6,6‐tetramethylpiperidide ligand (TMP) successfully used to elaborate functionalized aromatics incorporating DMGs normally susceptible to competing nucleophilic degradation. The first work in this field appeared in 1999 when Kondo and coworkers reported the directed zincation of a functionalized aromatic compound. This was achieved using the, at that stage, putative base t‐Bu₂Zn(TMP)Li 1 (Figure 1.1b and Scheme 1.1) and avoided the normal (for organolithium reagents) requirement of temperatures below room temperature (r.t.) [9]. This key advance led to an explosion of interest in developing the concept of tunable ate complex reagents in directed metalation chemistry.

Figure 1.1 The general principles demonstrated by (a) a heterobimetallic ate complex designed for selective aromatic metalation, (b) as exemplified by the first reported example of such a complex, t‐Bu₂Zn(TMP)Li 1.

Scheme 1.1 A generic directed ortho‐deprotometalation strategy incorporating 1.

1.2 Deprotonation of Aromatics

       1.2.1 Monometallic Bases

Since the pioneering work of Gilman [10] and Wittig [11], directed ortho‐metalation has become widely used as a powerful and efficient method for the regioselective functionalization of aromatic compounds. A range of DMGs have been employed to facilitate the selective deprotonation of arenes, and various strong bases such as alkyllithiums (RLi) and lithium dialkylamides (R₂NLi) have been used (Scheme 1.2) [6], though often with the drawbacks outlined in Section 1.1.

Among group 1 organometallics, alkyllithium reagents are the most convenient to work with for synthetic chemists because of their solubility in ethers and/or frequently in alkanes. Moreover, or perhaps because of this, many of them are commercially available. Therefore, it has become of great practical importance to define the scope and limitations of alkyllithium‐promoted deprotonation reactions. Generally, only substrates with high C–H acidity enhanced by a DMG are amenable to deprotonative lithiation [6]. In this capacity, ester and cyano groups have long been regarded as potentially important and attractive directors of metalation. However, their use has been limited because the deprotonation requires strictly controlled reaction conditions owing to the instability of intermediary aryllithium species. For example, lithium 2,2,6,6‐tetramethylpiperidide (LTMP) has been used for directing the ortho‐lithiation of aryl carboxylic esters. However, the accompanying problems of unwanted condensation reactions between the aryllithium and electrophilic directing group have been well documented [12]. In spite of this, the in situ trapping of aryllithium species by electrophiles during the deprotonation of aryl carboxylic esters has been reported. However, the use of bulky ester groups under restricted reaction conditions is essential (Scheme 1.3) [13, 14].

Scheme 1.2 Representation of a generic directed ortho‐lithiation strategy.

Scheme 1.3 Steric effects on the directed ortho‐lithiation of aromatic esters.

The dominance of organolithiums in the deprotonation of aromatics by traditional organometallic reagents is reflected also at the structural level, and the actions of the many DMGs capable of controlling metalation have been summarized [15]. However, in spite of the long‐established importance of DMGs such as carboxylic amides in directed ortho‐metalation, it was only in 2001 that the first full structural evidence was provided for the nature of an aromatic deprotonated by an organolithium base under the influence of this directing agent [16]. Single crystal data established how it was that the simple amides i‐Pr₂NC(O)Ar (Ar = aryl) efficiently direct ortho‐lithiation [17] given the well documented, sterically induced amide‐arene twist‐angle of ~90° in the substrate [18, 19]. Crystalline i‐Pr₂NC(O)C₆H₄Li(OEt₂)‐2 4 was generated using a sterically congested DMG and t‐BuLi to avoid unwanted competition from the nucleophilic reaction. The result was a dimer where Li was stabilized by both diethyl ether and DMG groups and in which the amide‐arene twist‐angle was been modulated to 47°. More complicated behaviour was seen for 2‐alkyl‐N,N‐diisopropylbenzamides, with strongly solvent‐dependent competition observed [20]. The dimer of i‐Pr₂NC(O)‐2‐Et‐C₆H₃Li(THF) 5 (Figure 1.2a) proved to be a kinetic product, isolable from limited THF but rearranging in the presence of an excess of THF or of a stronger Lewis base [21] to give a thermodynamic benzylic metalate, presumably of the type seen in the THF‐solvate of α‐lithio‐2‐ethyl‐N,N‐diisopropyl‐1‐naphthamide [22, 23]. Meanwhile, the ortho‐lithiate of 2‐isopropyl‐N,N‐diisopropylbenzamide could be obtained from diethyl ether as a hemi‐solvate 6 (Figure 1.2b) [24].

A further area of complexity associated with the deprotonative chemistry of organolithiums is that of anionic rearrangements, such as the long known [25] and synthetically useful [26] Fries formation of ortho‐phenols from aromatic carbamates (see Section 1.4.2). According to rate studies, substituents at the meta position of the arene and the dialkylamino moiety of the carbamate DMG significantly influenced the relative rates of ortho‐lithiation and subsequent rearrangement. Solution structural studies by ⁶Li and ¹⁵N NMR spectroscopies revealed a dimer of the lithiating agent (LDA), LDA dimer‐arene complexes, an aryllithium monomer, LDA‐aryllithium mixed dimers, an LDA‐lithium