Staudinger [2+2] cycloaddition

What is Staudinger [2+2] cycloaddition?

The Staudinger [2+2] cycloaddition, first reported by Staudinger in 1907, is a simple and convenient method for preparing 2-azetidinones, also known as β-lactams, through the [2 + 2] cycloaddition of ketenes and imines in a stereocontrolled and convergent manner. This reaction is commonly referred to as the Staudinger ketene-imine cycloaddition, [2 + 2] Staudinger cycloaddition, Staudinger β-lactam synthesis, Staudinger reaction or Staudinger synthesis of β-lactam.

Staudinger [2+2] cycloaddition - general reaction scheme - Staudinger ketene-imine cycloaddition - [2 + 2] Staudinger cycloaddition - Staudinger β-lactam synthesis - Staudinger reaction - Staudinger synthesis of β-lactam
Staudinger [2+2] cycloaddition

Staudinger [2+2] cycloaddition is highly versatile due to the mild reaction conditions, general availability of imines and ketenes, and the ease of preparing ketenes from acyl chlorides and triethylamine. The reaction occurs rapidly at low temperatures without a catalyst or initiator, and the reaction rate is dependent on the nucleophilicity of the imines, with cis-substituted imines being more reactive than trans-imines.

The Staudinger [2 + 2] cycloaddition involves a stepwise reaction mechanism where the imine attacks the ketene to form a zwitterionic intermediate, which cyclizes conrotatorily to form the β-lactam. The reaction exhibits stereospecificity, where the formation of cis-β-lactams is favored due to a conrotatory transition structure that follows the least motion principle. The stereoselectivity is also affected by the electronic effect of substituents on the ketenes and imines, which can accelerate or retard the direct ring closure or stabilize the zwitterionic intermediate. The Staudinger [2 + 2] cycloaddition is an essential tool for synthesizing the β-lactam structural components of many commonly used antibiotics.

References

Staudinger, H. (1907), Zur Kenntniss der Ketene. Diphenylketen. [On the knowledge of ketenes. Diphenylketene] Justus Liebigs Ann. Chem., 356: 51-123. https://doi.org/10.1002/jlac.19073560106

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