Directed magnesiation

Two examples of pyrimidines 57, 58 were included in a study of direct magnesiation of heterocycles. Both of these metallated selectively at C-4 using inverse addition i.e. substrate added to the metallating agent <06AG(I)2958>. 

Directed magnesiation. Orl/io-metallation is not limited to lithium but can be effected with magnesium diamides, which are more stable than lithium amides. Even esters can be metallated with these bases (equations I, II). 

Direct magnesiation can be achieved with TMPMgCl.LiCl 366 at 55"C, for example, 4-chloro- and 5-bromopyrimi-dines were metallated completely regioselectively (Scheme 49) <2006AGE2958>. 

Direct magnesiation of thiophenes at C-2 can be achieved with lithium tri-n-butytmagnesate (BusMgLi), at room temperature. ... 

Purine aminocuprates, formed either via direct magnesiation at C-8 with TMPMgCLLiCl, or via six-membered-ring lithio derivatives (formed from the iodides then transmetaUated to the magnesio derivatives), on oxidation undergo (reductive) elimination of copper to give amino-purines comparable... 

Scheme 4.14 Preparation of diaryl- and diheteroarylzinc reagents by direct magnesiation with TMP2Zn-2 MgC. 2 LiCI [78].

Scheme 5.4 Preparation of C(sp )-organomagnesium reagents by direct magnesiation with TMPMgCI-LiCI [29-31].

Fig. 9 Contrasting reactivity of Turbo-A and Turbo-C for direct magnesiation of isoquinoline...

The applicabihty of Turbo-Hauser A towards aromatic substrates is expertly proven by the susceptibility of the substituted aromatic ethyl 3-chlorobenzoate to undergo four consecutive direct magnesiations/electrophilic quenches to yield a hexasubstituted benzene derivative (Fig. 12) [30]. The second metallation requires careful choice of solvent in neat THF a competitive deprotonation occurs in a 90 10 ratio in favour of the desired product, which can be improved to a near quantitative level of 98.5 1.5 ratio by employing the less polar THF/Et20 (1 2) mixture. It should also be noted that the third and fourth metallations must be carried out at 50 °C, reflecting the greater sensitivity of the multi-functionalised benzenes. 

Fig. 16 Direct magnesiation of an oleflnic substrate using Turbo-A...

The excellent direct magnesiating properties of Turbo-Hauser reagent A extends beyond the confines of aromatic substrates (though these are by far the most frequently encountered substrates in such transformations). For example, the ether-functionalised ester, ethyl 2-ethoxyacrylate, can be selectively magnesiated in a reaction favoured by the stabilising effect of the adjacent carbonyl group, with work-up of the reaction mixture affording a non-aromatic cyclic lactone in an excellent yield (Fig. 16) [39]. 

This trend has been attributed to the coordination of BF3 with the pyridine nitrogen, which presents steric hindrance to magnesiation at C-2 thus favouring metalation at C-4 in the pre-complexed instance, whereas direct magnesiation with TMPMgCl-LiCl favours the C-2 position (Figure 11.2). The compatibility of the sterically hindered TMP base with a strong Lewis acid like BF3 OEta has been ascribed to the concept of frustrated Lewis pairs. ... 

---