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aza-Cope rearrangement

2 February 2009 - Synthetic methods

What: The aza-Cope rearrangement
Variation of: the Cope rearrangement
Discovered by: Robert M. Horowitz, T. A. Geissman in 1950 (DOI). Reaction of 1-allylbenzylamine with formic acid and formic acid did not yield the expected 1-allylbenzyldimethylamine (the result of methylation) but benzaldehyde and 1-dimethylamino-3-butene.

Mechanism: Addition of formaldehyde to the starting amine gives an iminium ion which reacts in a sigmatropic reaction to another rearranged iminium ion (but stabilized by the phenyl group). Hydrolysis splits of the benzaldehyde unit and the final step is methylation. This rearrangement reaction generally takes place at lower temperatures then the Cope reaction but still high. Catalysis is possible with Lewis acid (BF3, ZnCl2) and protic acid (HCl).

The equilibrium can also be steered in the right direction with an hydroxyl group at position 2. The resulting intermediate reacts in an intramolecular Mannich reaction to a pyrrolidine (Overman & Kakimoto DOI)

Also known as: Aza-Cope Mannich reaction, cationic aza-Cope reaction, 2-azonia-3,3-sigmatropic rearrangement
Put to use in: Total synthesis of (-)-strychnine by the Overman group in 1993 (Knight et al. DOI)
Enantioselective: an asymmetric aza-Cope was recently accomplished using a chiral phosphoric acid (Rueping et al. 2008DOI):

Examples from recent literature: An N-amino-3-aza Cope (Glória et al. 2008DOI):

A microwave assisted aza-Cope (Gonzalez et al. 2008 DOI):