Q2(c). Directed aldol reaction through an aza-enolate

Introduction. A crossed aldol reaction between acetaldehyde (as the enol component) and acetophenone fails under ordinary base: acetaldehyde condenses with itself much faster. Converting the aldehyde first into an imine and then into its lithium aza-enolate makes a single, specific nucleophile. This is the directed aldol reaction (Wittig's aza-enolate method).

Step 1: imine A

Scheme: A = N-ethylidene-tert-butylamine (an aldimine), formed by addition–elimination.

The amine nitrogen adds to C=O to give a carbinolamine; proton transfer and loss of water (acid-catalysed, or with a drying agent) give the C=N bond. The primary amine is only a weak base, so the imine forms faster than the aldehyde can self-condense. The bulky tert-butyl group stops the imine reacting with itself.

Step 2: aza-enolate B

Scheme: LDA removes the α-H of the imine quantitatively; Li binds the nitrogen.

LDA is a strong, hindered, non-nucleophilic base. It removes a proton from the CH₃ next to C=N (the conjugate base is delocalised over C and N), and does not add to C=N. B is the lithium aza-enolate CH₂=CH-N(Li)ᵗBu, the nitrogen analogue of an enolate. All the imine is converted before the ketone is added, so no uncombined aldehyde remains.

Step 3: aldol addition to acetophenone, C

Scheme: C–C bond formation: the nucleophilic CH₂ of B attacks the ketone C=O while Li moves from N to O.

The ketone oxygen coordinates Li and the terminal carbon of the aza-enolate attacks the carbonyl carbon through a cyclic, six-membered (Zimmerman–Traxler type) transition state. The new C–C bond links the acetaldehyde α-carbon to the ketone carbon. C is ᵗBuN=CH-CH₂-C(OLi)(CH₃)Ph: the imine is regenerated and the lithium is now on the alkoxide oxygen. The imine of C is a weak electrophile, so it does not react further.

Step 4: hydrolysis, D

Scheme: Water protonates the alkoxide and hydrolyses the imine; acid and heat dehydrate the aldol to the conjugated enal.

Water protonates the alkoxide to the tertiary alcohol. Water then adds to the protonated imine (iminium) to give a carbinolamine that expels tert-butylamine (the reverse of step 1). D = 3-hydroxy-3-phenylbutanal, the crossed aldol. If the work-up is acidic and warm, the tertiary benzylic alcohol dehydrates (E1: the cation is tertiary and benzylic) to the conjugated (E)-3-phenylbut-2-enal.

Conclusion. A = CH₃CH=NᵗBu (imine); B = CH₂=CH-N(Li)ᵗBu (lithium aza-enolate); C = ᵗBuN=CHCH₂C(OLi)(CH₃)Ph; D = 3-hydroxy-3-phenylbutanal, which dehydrates to 3-phenylbut-2-enal in acid. The name reaction is the directed aldol reaction (Wittig's imine/aza-enolate method).

Application. Aza-enolates (and the related SAMP/RAMP hydrazone anions) let chemists use aldehydes as the enol partner in crossed aldol and alkylation reactions, which ordinary base-catalysed aldol conditions cannot do cleanly.