Scope and Limitations of the Birch Reduction

The birch reduction is used in sterically controlled transformation of aromatic compounds, especially the benzene derivatives. The stereochemical specificity is shown in the figure below.

S. Rao, Pure Appl. Chem. 2003, 75, 1443-1451.

The Birch reduction was also implemented to synthesize cyclohexanes from benzenoids as an intermediate of other reactions. Specifically, cyclohexane-based gamma-lactams have shown their ability to either bind to opioid receptors (thus having the potential to act as pain relievers) or inhibit enzyme acitivties in medical research.

Krueger, T.; Kelling, A.; Schilde, U.; Linker, T. Eur. J. Org. Chem. 2017, 6, 1074-1077.

The Birch reduction does have certain limitations. When reacting with an aryl ether, the Birch reduction causes a partial or complete loss of an alkoxy group. In addition, when the Birch reduction occurs in the presence of Sodium in combination with aromatic esters, a competitive carbonyl reduction occurs. However, using Li/KNH3 and tBuOH will mitigate this effect.

Recent improvements on the Birch reduction include a safer reaction that does not involve ammonia, which can be achieved by using carbon-based materials such as graphene and carbon nanotubes. Additionally, it was found that 15-crown-5 can contain the sodium cation after radical transfer.

Lei, P.; Ding, Y.; Zhang, X.; Adijiang, A.; Li, H.; Ling, Y.; An, J. Org.Lett. 2018, 20, 3439-3442.