dimer (Figure 1.31). At the same time, variation of the amido component was probed, with (HMDS)2Ag(CN)Li2(THF) (180, HMDS = hexamethyldisilamide), (DA)2Ag(CN)Li2(THF) 181, and (Cy2N)2Ag(CN)Li2(THF) (182, Cy = cyclohexyl) all being formed but only 179 and 182 proving effective in proof‐of‐concept iodinations of N,N‐diisopropylbenzamide. Thereafter, 179 was deployed in a range of directed ortho‐deprotometalations using various DMG and ancillary functional group (FG) permutations (Scheme 1.36). Work demonstrated the ability to use tertiary carboxylic amide DMGs of variable lability (yielding 183–185). The success of nitrile (giving 186) and methyl ester (giving 187) DMGs was remarkable given their incompatibility with e.g. organolithiums. Likewise, in contrast to the difficulty of metalating nitroarenes using traditional strong bases [243], and the fact that this has hitherto been achievable using only specific substrates [244], 188 and 189 were now smoothly generated by 179. Notably, the yield of 188 (80%) contrasted with just 6% obtained when using 159. Elsewhere (forming 190–192), ancillary styrene‐type FGs could be employed without detectable polymerization, while halides and pseudohalides were tolerated, enabling the demonstration that OTf [(trifluoromethanesulfonyl)oxy] could survive a deprotonative metalation sequence [245].
Figure 1.31 The dimer of lithium argentate (TMP)2Ag(CN)Li2(THF) 179.
Scheme 1.36 Examples of directed deprotometalation using lithium argentate 179. a Argentation at −40 °C. b ortho : meta >29 : 1. c ortho : meta >16 : 1 (Tf = trifluoromethanesulfonyl).
The compatibility of traditionally problematic DMGs with 179 suggested the formation of ortho‐argentate intermediates. This was further hinted at by the isolation of aryl argentates such as the crystalline dimer of [2‐(i‐Pr)2NC(O)‐C6H4]2AgLi(THF) 193 (Figure 1.32), the preliminary characterization of which points to further avenues of investigation in this area.
Having established the accessibility of a range of ortho‐iodides, the replacement of I2 with various disulfides was explored. Again, the use of 179 overcame the yield variability and limited FG compatibility encountered when attempting sulfide installation by treating established aryllithium [246, 247], or ‐magnesium [248] reagents with disulfides. Moreover, this could be combined with the DMG tolerance of 179 in preparing sulfides such as 194 (Scheme 1.37, top). Lastly, the oxidative inertness of silver meant that, unlike the corresponding cuprate, 179 avoided biaryl production when preparing azo compounds from diazonium salts [forming e.g. 195 in good yield (cf. 23% using 159), Scheme 1.37, bottom]. This reactivity overcame the S N Ar or SET processes typically seen when arylmetals react with diazoniums [249] whilst achieving uniquely heterocoupled products [250].
Figure 1.32 Molecular structure of the dimer of [2‐(i‐Pr)2NC(O)‐C6H4]2AgLi(THF) 193.
Source: Adapted from Tezuka et al. [245].
Scheme 1.37 Lithium argentate 179 shows good functional group tolerance when making sulfides while the oxidative inertness of silver avoids biaryl production when making azo compounds.
1.5 Concluding Remarks
Metalation of functionalized (hetero)aromatic compounds using a new breed of polymetallic reagent that operates according to the principles of inter‐metal synergy has enabled access to otherwise challenging molecular targets that have previously resisted approach using simpler reagents with unprecedented levels of selectivity. Specifically, metal–halogen exchange and then deprotometalation reactions have been developed to provide access to versatile organometallic species. Whilst these reactions traditionally employed highly polar (often unselective) s‐block organometallics (Li and Mg), the emergence of heterobimetallic systems, based on the combination of an alkali metal with a more electronegative metal has circumvented many of the selectivity and reactivity problems that limited the usefulness of monometallic reagents. Magnesiates, zincates, and cuprates have been deployed in metal–halogen exchange with high levels of functional group tolerance and have even proved compatible with solid‐phase synthesis. Meanwhile, avoidance of unwanted nucleophilic reactivity by the use of the sterically hindered amido base 2,2,6,6‐tetramethylpiperidide (TMP) has transformed deprotometalation chemistry, offering access to magnesium, zinc, aluminium, copper, silver, and cadmium ate complexes, each of which have found their place in (hetero)aromatic derivatization. Crystallographic work has proved vital for understanding the nature of heterobimetallic species, including reaction intermediates, while recent advances in spectroscopy have shed unprecedented light on the behaviour of selected reagents in solution. However, few systems have been probed in such depth yet. This area will no doubt prove essential to providing an understanding that will enable the rational design of the next generation of synergic reagents. These will offer new reactivity and cost‐benefit ratios based upon new amide ligands with differing steric properties and potentially inclined to encourage the nonstoichiometric or even catalytic action of synergic bases reported to date in only a very few, selected examples. It will also seek to take advantage of the vast array of bimetallic combinations available to the modern chemist, seeking new and more easily handled alkali metal components – for example predicating ate complex formation on alkali metal amides rather than less stable alkali metal–carbon bonded organometallics – whilst also introducing other possibilities for the less electropositive metal.
References
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