Benzylic metalation

BuLi, THF, -78° O2 or MoOPH, [oxodiperoxymolybdenum-(hexa-methylphosphorictriamide)(pyridine)], 30-68% yield. This method uses the amide carbonyl to direct benzylic metalation. 

For a review of directive effects in allylic and benzylic metalation, see Klein, J. Tetrahedron, 1983, 39, 2733-2759. For a review of propargylic metalation, see Klein, J. in Patai The Chemistry of the Carbon-Carbon Triple Bond, pt. 1 Wiley NY, 1978, p. 343. 

While metallation of 625 with a LiCKOR reagent such as BuLi—KOBu-f again leads to orthometallation and 626, reversible metallation of 625 by LDA-KOBu-f generates the more stable benzylically metallated species 627. Carboxylation and alkylation (2 equiv. LDA-KOBu-f then Mel) of 627 gives flurbiprofen 622. 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

THE EFFECT OF /7-SUBSTITUENTS ON THE ELECTROPHILIC CLEAVAGE OF BENZYL-METAL AND (X-CARBETHOXYBENZYL-METAL BONDS... 

RELATIVE RATES OF ELECTROPHILIC CLEAVAGE OF THE CARBON-METAL BOND IN SOME /7-SUBSTITUTED BENZYL-METAL AND... 

The allyl-metal, cyclopropyl-metal, and phenyl-metal bonds are all generally cleaved by electrophilic reagents much more readily than are bonds between the simple alkyl groups and metals. Aralkyl-metal bonds, such as benzyl-metal bonds, on the other hand do not seem to be especially reactive in SE2 substitutions compared with alkyl-metal bonds29. 

As shown by the last reaction in Scheme 5.23, the metalation of benzamides is complicated by several potential side reactions (Scheme 5.24). Thus, benzamides can also undergo ortho-metalation [181, 217-222] or metalation at benzylic positions [223-225], Ortho-metalation seems to be promoted by additives such as TMEDA, and benzylic metalation can be performed selectively with lithium amide bases [217,224], which are often not sufficiently basic to mediate ortho- or a-amino metalation. If deprotonation of the CH-N group succeeds, the resulting product might also undergo cydization by intramolecular attack at the arene [214, 216] (see also Ref. [226] and Scheme 5.27) instead of reacting intermolecularly with an electrophile. That this cydization occurs, despite the loss of aromatidty, shows how reactive these intermediates are. 

According to the principle of least nuclear motion [45] aromatic deprotonation should be faster than benzylic metalation, because the benzylic carbanion is expected to rehybridize slightly toward sp2 to achieve stabilization by conjugation with the aromatic n system. This is, in fact, often observed [217, 401, 423-425], but with some substrates benzylic metalation can effectively compete with aromatic metalation[181, 425, 426] (Scheme 5.47). Thus, treatment of toluene with BuLi/TMEDA or BuLi/DABCO at 80 °C for 0.5 h or with BuLi/KOtBu in Et20 at -20 °C for 4 h leads to clean formation of benzyllithium [85, 427, 428], The kinetic preference for aromatic deprotonation, because of the principle of least nuclear motion, thus seems to be too weak to control the regioselectivity of deprotonations in all instances. 

Ach, D. Reboul, V. Metzner, P. Atroposelec-tivity of reactions of benzylic metalated thio-benzamides and thionaphthamides. Ear. J. 

Methyl and methylene groups attached to an imidazole nitrogen can be metallated. In 1-benzylimidazole the extent of benzylic metallation increases with temperature and with the amount of butyllithium used. Although 1-phenylthio-methylbenzimidazole is initially lithiated at C(2) at low temperatures, when the temperature is raised, rearrangement to the rather unstable methylene-lithiated species occurs, but this anion can be trapped by electrophiles. 

The benzyl- metal bond, M-CH,Ph, appears particularly weak (c /. the naturally selected adenosyl group of vitamin Bp)... 

Trunethylsilylmethylpotassium, KCH2Si(CH3)3. This base is prepared by reduction of bis(trimethylsilylmethyl)mercury with potassium sand. It is comparable in reactivity to n-BuLi/KOC(CH,)3 for allylic and benzylic metallation. ... 

Transition metal-carbonyl-diimine complexes [Ru(E)(E ) (CO)2(a-diimine)] (E, E = halide, alkyl, benzyl, metal fragment a-diimine = 1, 4-diazabutadiene or 2,2 -bipyridine) are widely studied for their unconventional photochemical, photophysical, and electrochemical properties. These molecules have a great potential as luminophores, photosensitizers, and photoinitiators of radical reactions and represent a challenge to the understanding of excited-state dynamics. The near-UV/visible electronic spectroscopy of [Rn(X)(Me)(CO)2(/Pr-DAB)] (X = Cl or I iPr-DAB = A,A -di-isopropyl-l,4-diaza-l,3-butadiene) has been investigated throngh CASSCF/C ASPT2 and TD-DFT calculations on the model complexes [Ru(X)(Me)(CO)2(Me-DAB)] (X = Cl or I) (Table 2). 

Beak and Du [1007] performed the asymmetric alkylation of racemic dipole-stabilized dilithium reagents generated by benzylic metalation of 5.2 (X = H or n-BujSn) with s-BuLi (Figure 5.2). Sparteine 2.5 must be added to anionic species prior to the electrophile. These reactions are run in THF/fert-butyl methyl ether at -78°C. No asymmetric induction is observed when this experimental procedure is used for the alkylation of 4.2. 

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