b Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK
1.1 Introduction
Multifunctionalized organometallic species have played a vital role as versatile intermediates in modern synthetic organic chemistry for many years [1, 2]. Identifying a suitable metal and controlling reaction conditions have been crucial to underpinning the handling of functionalized organometallics because the reactivity and stability of these species and the effectiveness, selectivity, and safety of the process(es) by which they display metalation are strongly dependent upon the identity of the metal. This chapter describes the advent of controlled and selective metalation using traditional monometallic reagents but also outlines its limitations and the recognition that reactivity can be tuned by introducing a second metal centre. It was this view that eventually gave rise to a major theme of the current book; the concept of ate complexation of organometallics containing a very electropositive (highly reactive but perhaps unselective) metal using a more electronegative (less reactive, more selective) metal (Figure 1.1a). This idea led, in the late 1990s, to the use of not only organozinc halides or di‐organozincs but also of the development of organozincates and their extensive use in a range of organic transformations including nucleophilic addition, halogen–metal exchange, metal carbenoid synthesis, de‐protonative metalation, ring‐opening, and cross‐coupling [3]. The prolific ability of organozinc compounds and complexes to effect efficient yet highly selective transformations in tandem with inherent functional group compatibility resulted in great interest from synthetic chemists. In particular, because the latter characteristic feeds into applications in directed aromatic metalation, whereby a pre‐existing substituent on an aromatic ring acts as a directing group (DMG) 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
