Ziegler-Hafner azulene synthesis

What is Ziegler-Hafner azulene synthesis?

The Ziegler-Hafner azulene synthesis was first reported in 1955 by Ziegler and Hafner. This method is widely used for synthesizing azulene derivatives by condensing a cyclopentadienyl anion with the intermediate formed by nucleophilic addition of dimethylamine onto an activated pyrinium salt. The reaction is commonly known as the Ziegler-Hafner azulene synthesis or Ziegler-Hafner method. While other synthetic methods for azulenes exist, the Ziegler-Hafner azulene synthesis is the most versatile, particularly for azulene derivatives with substituents at the seven-membered ring.

Ziegler-Hafner azulene synthesis - general reaction scheme - Ziegler-Hafner method
Ziegler-Hafner azulene synthesis

DNCB = 2,4-dinitrochlorobenzene
C5H5–NaβŠ• = sodium cyclopentadiene (see list of acronyms)

Typically, 2,4-dinitrochlorobenzene is used to activate the pyridine moiety in this reaction. However, in cases where the pyridine ring connects to other structures that reduce the basicity of the pyridine moiety, 2,4-dinitrochlorobenzene is not suitable for activation. Trifluoromethanesulfonic anhydride (Tf2O) is a suitable alternative for activating the pyridine moiety in such cases.

Additionally, isoquinoline can be activated by methyl iodide, but the yield is typically low. Interestingly, when the residue after addition of cyclopentadienyl anion is diluted with diethylene glycol and heated by superheated steam, a higher yield of benz[f]azulene can be obtained.

References

Ziegler, K. and Hafner, K., Angew. Chem., 1955, 67, 301

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