Some Lithium metallation generalities on 5- and 6-membered heterocycles

5-membered heterocycles

Due to the inductive effect of the heteroatom (which makes alfa-H more acidic), most of five-membered heterocycles undergo alfa-lithiation. In general, H-acidity determines selectivity. The exception is the 5 member S-heterocycle: one should expect alfa position of a furan would be more prevalent when competing for the same position in a thiophene analogue. But this is not the case. This “anomaly” is often explained in part because of the higher polarisability of sulphur, which allows a more efficient charge distribution.

In pyrroles, lithiation is complicated by the presence of a much more acidic H on N. As a consequence, a protecting group is often required (tipically Boc, which allows alfa-lithiation while easily hidrolized. Boc also withdraws electron density, thus acidifying the alfa-nitrogen further, and also provides chelation assistance for the alfa-lithiation).

Llithiation at hetero-ring positions other than alfa-position is challenging. It can be achieved via halogen exchange, but at very low temperatures to prevent equilibration with the more stable 2-lithiated heterocycle.

1,3-azoles lithiate very readily at C2.

For imidazoles, the usual protecting group is SEM (trimethylsilylethoxymethyl).

1,2-azoles (pyrazoles) lithiate at C5 (the pyrrole-like alfa-position).

If the temperature is allowed to rise, hetero-ring cleavage can occur, especially in beta-lithiated five-membered systems. The heteroatom can act as a leaving group.

Other effects:

When strong bases are used, as TMEDA (N,N,N’,N’-tetramehylethylenediamine) can result in dimetallation.

The impact of directing grups can be dramatic and there’re two general categories according to the effect: (1) Those which able coordination to lithium, and (2) electronic effects. In the first case, the thiophene-2-carboxylic acid reaction with n-BuLi in THF at -78ºC doesn’t yield the normal alfa-lithiation but beta-lithiation due to the effect of the nucleophilic carboxylate moiety, but if the reaction is performed with a lithium amide, as LDA, which is more weakly coordinating, the main product is the alfa-substituted.

6-membered heterocycles

In contrast with the selective lithiation of 5-membered heterocycles, the direct metallation of pyridine is difficult and complex. In general, the main problem with 6-membered heterocycles is to overcome the nucleophilic addition/substitution by the lithium reagent. Then, they need using strong base combination, as n-butillithium/potassium t-butoxide.

In non-polar solvents kinetic 2-metallation predominates, but in more polar solvents or under equilibrated conditions 4-isomer is the major product (alfa and gamma position are more acidic than beta). Of these two options, the anion in gamma position is the most stable (since in the alfa position there is a more unfavourable repulsion between the coplanar nitrogen lone pair and the charge). Accordingly, pyridine can be selectively lithiated at C2 when the lone pair is tied up as a complex with boron trifluoride.

Pure lithio-pyridines can be prepared by halogen exchange at low temperature.

Quinolines react like pyridines, but are more susceptible to nucleophilic addition. This also happens with pyrimidines. In this later case, susbtituents at 2 and 4 positions add some stability.