A brief note on the use of enolates in syntheses.
Enolate alkylation
Condition overview
By electrophile
| Electrophile type | Conditions | Note |
|---|---|---|
| Activated R-X | Best with enamines 1. \(\ce{R2NH},\ \rm{cat\ }\ce{H+}\) 2. \(\ce{R-X}\) 3. \(\ce{H+}\) |
|
| Tertiary R-X | Lewis acid to form cation \(\ce{TiCl4}\), TMS enol ether one pot |
Also \(2^\circ\) if preferred |
By enol(ate)
| Enol(ate) type | Conditions | Note |
|---|---|---|
| Ketone, ester, carboxylic acid | LDA, \(-78^\circ\rm{C}\), THF | |
| Nitro, nitrile | \(\ce{OH-}\), one pot with
phase separating conditions e.g. \(\ce{BnEt3N+Cl-}\) |
|
| Aldehydes | Aza-enolate 1. \(\ce{t-BuNH2}\), cat \(\ce{H+}\) 2. LDA, \(-78^\circ\rm{C}\), THF 3. \(\ce{H+}\) |
Can’t use LDA directly |
| \(\beta\)-dicarbonyl | One-pot with \(\ce{NaOH}\). | To remove, decarboxylate. \(\ce{NaOH}\) then \(\ce{H+ / H2O}\) to yield acid; \(\ce{NaCl}\) heat for ester. |
Regioselectivity
For more substituted side,
| Substrate | Condition | Note |
|---|---|---|
| Single carbonyls | 1. \(\ce{TSMCl}\), \(\ce{Et3N}\) 2. \(\ce{MeLi}\) 3. R-X |
No need MeLi for Sn1 electrophiles. |
| Enones | Dissolved metal - only alkylate at the conjugated side 1. \(\ce{Li}\), \(\ce{NH3}\) 2. R-X |
|
| \(\beta\)-dicarbonyl | Alkylate in the middle twice, then decarboxylate. |
For less substituted side,
| Substrate | Condition | Note |
|---|---|---|
| Single carbonyls | LDA | Aza-enolate for aldehyde; Change to TMS enol-ether if needed. |
| \(\beta\)-dicarbonyl | 1. Alkylate di-anion 2. Alkylate in the middle twice. |
|
| Activated R-X | Enamine |
Aldol reactions
Notes
- In acidic conditions, condensation product is usually given (via E1).
- For cross condensation, make sure
- Only 1 species enolisable,
- Electrophile is more electrophilic than enolisable carbonyl.
Choices
By electrophile
Non-enolisable groups next to the carbonyl:
- H
- tert-alkyl
- tri-substituted
- Ar
- heteroatoms
For formaldehyde, Mannich reagent must be used.
By enolate
- Nitro-compounds - not electrophilic, easily enolised.
- Use SSE -
- LDA
- TMS enol ether: need \(\ce{TiCl4}\) catalyst, and \(\ce{H2O}\) work-up.
- Conjugated Wittig reagent: (aka stabilised ylid) gives trans-alkene.
- \(\beta\)-dicarbonyl: one-pot mixture of weak base in weak acid buffer, e.g. \(\ce{R2NH}\), \(\ce{AcOH}\).
- Special choices
| Enolate | Equivalent |
|---|---|
| Ester | Zn enolate: no reactions with esters. |
| Aldehyde | Aza-enolate instead of LDA. |
Claisen reactions
Choices
Non-enolisable electrophile
Decreasing reactivity:
EtOCOCOOEt > HCOOEt > EtOCOOEt
SSE
- Li, Mg and Zn enolates as above all OK, except
- Need aza-enolate for aldehydes
- No BuLi with carboxylic acids - LDA OK
- Enamine only reacts well with RCOCl
- \(\ce{BF3}\) can be used for enolisation