Enamines, imines and hydrazones

Enamines, metalated imines and hydrazones are nitrogen equivalents of enolates. They are prepared from the carbonyl compound, alkylated at the α carbon and, on hydrolysis, give back the alkylated ketone: a milder, more selective or even enantioselective alternative to direct alkylation.

Enamines: the Stork alkylation

A ketone with α hydrogens reacts with a secondary amine such as pyrrolidine or morpholine, in the presence of an acid and removing the water formed, to give an enamine:

Cyclohexanone and pyrrolidine, with p-toluenesulfonic acid in refluxing benzene and removal of water, give 1-(cyclohex-1-enyl)pyrrolidine

The nitrogen lone pair is conjugated with the double bond and makes the β carbon of the enamine, which is the former α carbon of the ketone, nucleophilic. Gilbert Stork showed (1954) that enamines are alkylated at that carbon and that the resulting iminium salt is easily hydrolysed:

The nitrogen lone pair pushes electrons into the double bond, which attacks the carbon of the alkyl halide; an iminium salt forms, which aqueous acid hydrolyses to the 2-alkylcyclohexanone

Enamines are neutral and much less basic than enolates, so no strong bases are needed and there is no polyalkylation: the iminium salt formed is no longer nucleophilic.
They are moderate nucleophiles: they work well with reactive electrophiles (allylic and benzylic halides, α-halo ketones and esters, acyl halides) and with Michael acceptors. With simple alkyl halides N-alkylation competes.
With unsymmetrical ketones the less substituted enamine forms preferably, because in the more substituted one the substituent clashes with the amine ring (A^1,3 allylic strain). That is why enamines alkylate the less substituted side.

Metalated imines (aza-enolates)

Imines derived from primary amines still have an acidic α hydrogen. With LDA or a Grignard reagent they give an aza-enolate, more nucleophilic than the enamine and less basic than the ketone enolate: it alkylates well even with secondary alkyl halides and does not cause self-condensation. The final hydrolysis releases the alkylated ketone:

Cyclohexanone and cyclohexylamine form an imine; LDA gives the metalated imine, which is alkylated and hydrolysed to the 2-alkylcyclohexanone

Hydrazones: the Enders SAMP/RAMP method

N,N-Dimethylhydrazones are deprotonated by LDA and alkylated just like imines. Dieter Enders exploited this chemistry for asymmetric synthesis by using as chiral auxiliary (S)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP), derived from proline, or its enantiomer (RAMP). In the aza-enolate, lithium is chelated by the methoxymethyl oxygen, which blocks one of the faces; after alkylation, the auxiliary is removed by ozonolysis (or with methyl iodide and acid) to give the ketone in very high enantiomeric excess:

3-Pentanone forms the hydrazone with SAMP; with LDA and propyl iodide it is alkylated with a single facial preference, and ozonolysis releases (S)-4-methyl-3-heptanone

(S)-4-Methyl-3-heptanone is the alarm pheromone of several ant species. Its synthesis was one of the first examples of the Enders method.

A synthesis example

Robinson annulation through the Stork enamine