Polar Organometallic Reagents. Группа авторов
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and more strongly directed towards Li+ compared to peripheral K+, again likely reflecting a competing preference for hard/soft stabilization (Figure 1.6) [60].
Whilst providing encouraging evidence for the reactivity of mixed Li–K species, the high potassium content of 35 leaves some doubt surrounding its validity as a model superbase since pure PhK can achieve the same reactivity towards toluene [61]. However, further evidence for Li–K cooperativity has been gathered by the judicious choice of neopentyllithium (NpLi, Np = CH2C(CH3)3) as a stable and hydrocarbon‐soluble alkyl equivalent. When partnered with t‐BuOK, to form a LICKOR mixture, its use has allowed for the isolation of mixed‐metal aggregate Li4K4Np2.75(t‐BuO)5.2536 [62]. Though detailed analysis of the structure was complicated by the positional disorder of the ligands and metal, the fundamental motif – a central, square planar arrangement of K centres, bicapped by [RLi(Ot‐Bu)2LiR]2⁻ (R = Np/t‐BuO) – was clear (Figure 1.7a). Meanwhile, the NMR spectroscopic monitoring of experiments in which the NpLi : LiOt‐Bu : KOt‐Bu ratio was varied revealed evidence for equilibria involving Li‐rich mixed Np/Ot‐Bu species (represented by the series Li4K3Np x (Ot‐Bu)7‐ x ) in solution. In this work, the excess of Li could be rationalized by the tendency of poorly soluble NpK to precipitate. Consistent with this, cooling solutions rich in Np⁻ led to crystallization of the Li‐rich mixed metal species, Li4K3Np3.16(Ot‐Bu)3.8437. X‐ray diffraction exposed in this the coordination of alkyl moieties to both K and Li centres (Figure 1.7b). This suggested hybrid Li/K–C bond polarity, which was in turn postulated to be responsible for superbasic activity.
Recently, this work has been extended to examine other Li–K compounds of the type described above, whose compositions are dominated by either metal. Thus, the structure of Li4KNp2(Ot‐Bu)338 has been elucidated in the solid‐state, revealing a square pyramidal metal architecture wherein interaction of apical K with the CH3 component of an Np unit in an adjacent monomer results in a solid‐state dimer (Figure 1.8) [63]. Meanwhile, exploring K‐rich end members has lately provided the first crystallographic evidence for the existence of a mixed organo/alkoxypotassium species, K4Np(Ot‐Am)339 (t‐Am = CH2C(CH3)2CH2CH3). Based on its favourable solubility profile and donor solvent‐free constitution, reactivity comparable with or superior to organopotassium reagents was anticipated. In the event, this was realized in the polymetalation of ferrocene. Though isolation of metalated intermediates was not possible, the regioselectivity of metalation could be competently assessed through the study of carboxylated intermediates and the crystallization of selected ferrocene methyl ester derivatives (Scheme 1.10).
Figure 1.6 Molecular structure of the core of (PhK)4(PhLi)(t‐BuOLi)(THF)6(C6H6)235 (K = dark purple, Li = pink, O = red).
Source: Adapted from Unkelbach et al. [60].
Figure 1.7 Molecular structures of (a) Li4K4Np2.75(t‐BuO)5.2536 and (b) Li4K3Np3.16(Ot‐Bu)3.8437. Minor ligand disorder omitted (K = dark purple, Li = pink, O = red).
Source: Adapted from Benrath et al. [62].
Figure 1.8 Molecular structure of [Li4KNp2(Ot‐Bu)3]2382 (K = dark purple, Li = pink, O = red).
Source: Adapted from Jennewein et al. [63].
Scheme 1.10 The elaboration of ferrocene employing 39. Fc = ferrocenyl, n = 2–4.
The issues of reactivity that plagued the use of organolithium reagents have then, in many cases, been overcome by the advent of LICKOR superbases. However, the introduction of higher alkali metal reagents has led to new issues that have limited the applicability of heterometallic reagents except in the hands of specialists in air‐sensitive and nonstandard techniques. So though they offer significant, and often unique advantages, the limitations expressed here of the bases conventionally used for metalation have led to the search for new organometallic combinations capable of similar functionality, ideally under mild conditions. This has led researchers to utilize alkali metals in tandem with metals from elsewhere in the periodic table. This search has ultimately revealed new chemistry for the metalation of aromatic compounds and the advent of ate complexes as synthetic tools [64]. However, first it is worth briefly exploring the use of group 2 elements in conjunction with alkali metals–covered at more length in Chapter 3.
1.2.2.2 Group 1/2 Reagents
In 2006 Knochel et al. augmented the synthetic toolbox available to chemists by improving on Hauser bases through the introduction of a lithium salt. The resultant family of R2NMgCl(LiCl) reagents has become known as turbo‐Hauser reagents. They were prepared by combining i‐PrMgCl(LiCl) 40 with i‐Pr2NH or HTMP and displayed a range of benefits. It was quickly perceived that, unlike many straightforward magnesium amide compounds, they show excellent THF solubility at e.g. room temperature, avoid the need of traditional bases like organolithiums for the use of depressed temperatures (of −78 °C or so), which complicates scale‐up, and exhibit kinetic basicity so enabling the regioselective magnesiation of heterocyclic substrates [65]. For example, the selective deprotonation of pyrimidines has typically proved challenging on account of competing addition reactions exhibited by many organometallics. However, pyrimidine derivatives reacted smoothly with TMPMgCl(LiCl) 41 in THF at 55 °C to afford putative selectively magnesiated intermediates 42 (Scheme 1.11, top) that could be worked‐up with a range of electrophiles – a strategy that subsequently underpinned the successive regio‐ and chemoselective elaboration of halogenated pyrimidines [66]. Similar reactivity was reported for pyridines, quinolones, and isoquinolines, as well as for heterocycles like thiazole, thiophene, furan, benzothiophene, and benzothiazole heterocycles that bear relatively acidic hydrogens. This work led, later the same year, to the deployment of turbo‐Hauser reagents in directed ortho‐magnesiation [67]. Impressively, the