Pericyclic — amide acetal [3,3]-shift
Eschenmoser-Claisen rearrangement
How the Eschenmoser-Claisen 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: Allylic alcohol, Me₂NC(OMe)₂CH₃ (DMA-DMA). Conditions: Xylene or toluene, 110–160 °C (MeOH removed). Bonds formed: C–C (new σ); C=O (amide); bonds broken: C–O (allylic); π C=C. Stereochemistry: Chair TS; chirality transfer from the carbinol. Rate and selectivity: [3,3] step rate-limiting; no acid or base needed.
At a glance
Step 1: N,O-ketene acetal forms
An allylic alcohol condenses with N,N-dimethylacetamide dimethyl acetal, losing methanol to form an N,O-ketene acetal — the nitrogen analog of the vinyl ether intermediate in the Johnson-Claisen rearrangement.
Step 2: The six-atom array is ready
This ketene acetal already contains the fully conjugated six-atom array needed for rearrangement, so no further activation step is required before heating.
Step 3: [3,3]-Sigmatropic shift
The same [3,3]-sigmatropic shift delivers a γ,δ-unsaturated amide rather than an ester — swapping the orthoester of the Johnson variant for an amide acetal reagent changes only the final functional group installed, while the pericyclic step itself is identical.
Abbreviations and terms
- OMe
- Methoxy. –OCH₃.
- DMA
- N,N-Dimethylacetamide. High-boiling polar aprotic solvent.
- MeOH
- Methanol. Polar protic solvent (also a nucleophile in solvolysis).
- 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
| Eschenmoser-Claisen rearrangement | Ireland-Claisen rearrangement | 2-Aza-Cope rearrangement | |
|---|---|---|---|
| Reagents | Allylic alcohol, Me₂NC(OMe)₂CH₃ (DMA-DMA) | LDA, then TMSCl; then H₃O⁺ workup | Homoallylic amine, aldehyde (to give the iminium), acid |
| Conditions | Xylene or toluene, 110–160 °C (MeOH removed) | THF, –78 °C → 25 °C or mild heat | Mild heat or RT (cationic variant), CH₂Cl₂ or MeCN |
| Stereochemistry | Chair TS; chirality transfer from the carbinol | Enolate geometry transferred through a chair TS to the new stereocentres | Chair TS; stereo transferred |
| Rate / selectivity | [3,3] step rate-limiting; no acid or base needed | [3,3] shift is rate-limiting; faster than parent Claisen | Faster than all-carbon Cope (cationic N) |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Eschenmoser-Claisen rearrangement?
Allylic alcohol, Me₂NC(OMe)₂CH₃ (DMA-DMA). Conditions: Xylene or toluene, 110–160 °C (MeOH removed).
Which bonds are formed and which are broken?
Formed: C–C (new σ); C=O (amide). Broken: C–O (allylic); π C=C.
What is the stereochemical outcome?
Chair TS; chirality transfer from the carbinol
What controls the rate or the selectivity?
[3,3] step rate-limiting; no acid or base needed
Study guides that help with this reaction
- Carbonyl chemistry: addition, acyl substitution and enolates
- Pericyclic reactions explained: cycloadditions, electrocyclisations and sigmatropic shifts
- Stereochemistry in mechanisms: inversion, retention, syn and anti