Ring lithiation

By coordinating to arenes, transition metals can facilitate ring lithiation by decreasing the electron density in the ring and acidifying the ring protons. We shall consider briefly the two most important metal-arene complexes in this regard—arenechromium tricarbonyls and ferrocenes. 

The pffa of 3-methylpyridine, whose anion cannot be delocalized onto N, is closer to that of toluene, and deprotonation gives only low yields with most bases. However, with a combination of BuLi and lithiodimethylaminoethanol (LiDMAE) deprotonation is quantitative but yields products 561 arising from apparent lithiation a to N (Scheme 224) Trying to force lateral lithiation of pyridines is generally doomed to failure, as ring lithiation or nucleophilic addition nsnally takes place first . 

The usually very powerfully orthodirecting groups such as secondary carboxamide surprisingly do not always lead to ortholithiation on pyrazine and pyridazine rings lithiation of 386 and 387, for example, takes place principally (at least kinetically) at the meta and para positions.339 340... 

It is impossible to generate these species directly by lithiation of sulfides because of competing ring-lithiation of the sulfides. 

Benzene-ring-lithiated intermediates can be prepared by metal-halogen exchange, even, in the case of indoles, without protection of the NH, i.e. it is possible to produce an N,C-dimetallated species (20.5.2). The 1,3-azoles lithiate very readily, at C-2. One may understand this in terms of a combination of the acidifying effects seen at an a-position of pyridine (both inductive and mesomeric electron withdrawal) with that at the a-positions of thiophene, furan and pyrrole (inductive only). 2-Substituted-l,3-azoles generally lithiate at C-5 °... 

The principal monotrimethylsilyltoluene is the meta isomer. This agrees with the results of earlier experiments which find mainly m-lithio-toluene in the ring-lithiated byproducts in the synthesis of benzyllithium by lithiation of toluene with n-butyllithium-TMEDA (11, 12). On the basis of the current view that metalation of aromatic compounds proceeds... 

The solution of benzyllithium (containing 10% of ring-lithiated intermediates, which give no coupling product with cyclohexyl bromide) is cooled to — 40 °C and cyclohexyl bromide (0.08 mol, I3.0g) is added over a few min. The cooling bath is then removed and the temperature allowed to rise to 0 °C. After the usual work-up the product (b.p. 117°C/12mmHg, nD(20) 1.5179) is isolated in 60% yield by careful distillation. 

Benzene ring lithiated intermediates can be prepared by metal-halogen exchange, even, in the case of indoles, without protection of the NH, i.e. it is possible to produce an A, C-dilithiated species. 

Lithiation of 2- and 4-t-butoxycarbonylaminopyridines can only take place at C-3 a neat sequence involving first, ring lithiation to allow introduction a methyl group and secondly side-chain lithiation (section 5.11) at the introduced methyl group provided a route to azaindoles (section 17.17.7), as illustrated below for the synthesis of 5-azaindole (pyrrolo[3,2-c]pyridine). ... 

Semmelhack MF (1995) Transition metal arene complexes ring lithiation. In Abel EW, Stone EGA, Wilkinson G (eds) Comprehensive organometallic chemistry II. Pergamon... 

Although they have not yet been developed to the point of synthetic application, pyrrole-rhenium complexes display the reactivity expected for a very strongly electron-attracting substituent. Complex (49) undergoes ring lithiation readily (Equation (128)). Use of the iodo rhenium complex (50) leads to addition at C2 (Equation (129)) <87JOM(333)7l, 89JOM(362)C3l>. 

Partial oxidation of 1,2-bishydroxymethylbenzene produces l-methoxy-1,3-dihydroisobenzofuran, from which methanol can be eliminated, using LDA, giving isobenzofuran. Subsequently, conditions have been defined whereby this elimination can be run in such a way as to allow immediate ring lithiation this species then can be further reacted. ... 

Tf s-pyrrolyl complexes are stable due to the polyhapto binding mode, but they are less stable than iq -cyclopentadienyl compounds. It remains controversial whether this difference in stability stems from a thermodynamic or kinetic effect.Nevertheless, the high stability of ri -pyrrolyl complexes allows several chemical modifications to be performed directly on the five-membered ring. ° Lithiation and alkylation of the resulting anion is shown in Equation 4.29. ... 

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