Pericyclic — nitrogen [3,3]-shift
2-Aza-Cope rearrangement
How the 2-Aza-Cope rearrangement works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Homoallylic amine, aldehyde (to give the iminium), acid. Conditions: Mild heat or RT (cationic variant), CH₂Cl₂ or MeCN. Bonds formed: C–C (C1–C6); new C=N⁺; bonds broken: C–C (C3–C4); old C=N⁺ π. Stereochemistry: Chair TS; stereo transferred. Rate and selectivity: Faster than all-carbon Cope (cationic N).
At a glance
Step 1: Iminium with a homoallyl group on N
An iminium ion bearing an allyl group at nitrogen (formed by ordinary condensation of an allylic amine with a carbonyl) contains the same six-atom, doubly-unsaturated array as a Cope substrate, just with one carbon replaced by a positively charged nitrogen.
Step 2: Cationic [3,3] shift
The identical three-arrow, six-membered [3,3]-sigmatropic shift proceeds — often accelerated relative to the all-carbon Cope, since the cationic nitrogen lowers the transition state energy much like the alkoxide does in the oxy-Cope.
Step 3: Hydrolysis on work-up
The product is a new, rearranged iminium ion, hydrolyzed on workup to a carbonyl — when combined with a subsequent Mannich-type trapping step, this cationic aza-Cope sets up the powerful aza-Cope/Mannich strategy used to build complex nitrogen heterocycles in a single operation.
Abbreviations and terms
- DCM
- Dichloromethane. Common non-polar-ish solvent for reactions that need no nucleophilic or protic solvent.
- MeCN
- Acetonitrile. Polar aprotic solvent.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- TS
- Transition state. The highest-energy point on the pathway between two minima; it cannot be isolated.
- Δ
- Heat. Reaction is run at elevated temperature.
How it compares with related reactions
| 2-Aza-Cope rearrangement | Eschenmoser-Claisen rearrangement | Ireland-Claisen rearrangement | |
|---|---|---|---|
| Reagents | Homoallylic amine, aldehyde (to give the iminium), acid | Allylic alcohol, Me₂NC(OMe)₂CH₃ (DMA-DMA) | LDA, then TMSCl; then H₃O⁺ workup |
| Conditions | Mild heat or RT (cationic variant), CH₂Cl₂ or MeCN | Xylene or toluene, 110–160 °C (MeOH removed) | THF, –78 °C → 25 °C or mild heat |
| Stereochemistry | Chair TS; stereo transferred | Chair TS; chirality transfer from the carbinol | Enolate geometry transferred through a chair TS to the new stereocentres |
| Rate / selectivity | Faster than all-carbon Cope (cationic N) | [3,3] step rate-limiting; no acid or base needed | [3,3] shift is rate-limiting; faster than parent Claisen |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the 2-Aza-Cope rearrangement?
Homoallylic amine, aldehyde (to give the iminium), acid. Conditions: Mild heat or RT (cationic variant), CH₂Cl₂ or MeCN.
Which bonds are formed and which are broken?
Formed: C–C (C1–C6); new C=N⁺. Broken: C–C (C3–C4); old C=N⁺ π.
What is the stereochemical outcome?
Chair TS; stereo transferred
What controls the rate or the selectivity?
Faster than all-carbon Cope (cationic N)
Study guides that help with this reaction
- Pericyclic reactions explained: cycloadditions, electrocyclisations and sigmatropic shifts
- Stereochemistry in mechanisms: inversion, retention, syn and anti