Ketones, from enamines

The most versatile method for preparing enamines involves the condensation of aldehydes and ketones with secondary amines [Eq. (1)]. Mannich and Davidsen (/) discovered that the reaction of secondary amines with aldehydes in the presence of potassium carbonate and at temperatures near 0° gave enamines, while calcium oxide and elevated temperatures were required to cause a reaction between ketones and secondary amines, although usually in poor yield. The introduction by Herr and Heyl 2-4) of the removal of the water produced in the condensation by azeotropic distillation with benzene made possible the facile preparation of enamines from ketones and disubstituted aldehydes. 

The intermediacy of an aminal in the formation of enamines from ketones and secondary amines is not usually proposed. The only direct evidence for this is the infrared spectra of the reaction mixtures produced when dimethyl-or diethylamine was allowed to react with cyclohexanone or cyclopentanone... 

Mannich and Davidsen [31] also reported that most of the aldehydes were first converted to a diamino intermediate which on distillation afforded the enamine. Less successful was the attempt to extend the reaction to ketones. Only with the use of calcium oxide at elevated temperatures were the enamines directly obtained, but in poor yields. Herr and Heyl [32, 33] found that better yields of enamines from ketones can be obtained by the azeotropic removal of water in the presence or absence [32, 33] of acid catalysts [12a, b, 34, 35]... 

Both tetrahydro-l,4-oxazine (morpholine) and its thia analogue (thiomorpholine) find application as solvents and bases, morpholine having particular value in synthesis as it is often used to prepare enamines from ketones with a free a-hydrogen atom. TV-Acylation and -alkylation are readily accomplished and a great diversity of TV-substituted morpholines and thiomorpholines are encountered in the patent literature, some having biological activity. 

Enamines from ketones can react with double Michael multicoupling reagents to give, after aqueous workup, mono- and bicyclic ketones, products of a,a -annulation55-59. 

The reductive coupling of carbonyl compounds with formation of C-C double bonds was developed in the early seventies and is now known as McMurry reaction [38, 39]. The active metal in these reactions is titanium in a low-valent oxidation state. The reactive Ti species is usually generated from Ti(IV) or Ti(III) substrates by reduction with Zn, a Zn-Cu couple, or lithium aluminum hydride. A broad variety of dicarbonyl compounds can be cyclized by means of this reaction, unfunctionalized cycloalkenes can be synthesized from diketones, enolethers from ketone-ester substrates, enamines from ketone-amide substrates [40-42], Cycloalkanones can be synthesized from external keto esters (X = OR ) by subsequent hydrolysis of the primary formed enol ethers (Scheme 9). 

There are other methods for preparing enamines from ketones that utilize strong dehydrating reagents to drive the reaction to completion. For example, mixing carbonyl compounds and secondary amines followed by addition of titanium tetrachloride rapidly gives enamines. This method is applicable to hindered as well as to ordinary amines. Another procedure involves converting the secondary amine to... 

Without additional reagents Reactions with tris(dialkylamino)boranes Carboxylic acid amides from carboxylic acids Enamines from ketones... 

A method that uses BSA and a catalytic amount of methyl iodide for the preparation of enamines from ketones has been reported. A variety ofenaminescanbe prepared by this method,... 

A further advance in the synthesis of enamines from ketones has been made by the use of dimethyl azoethylphosphonate (32), The elaboration of ketones to aldehydic enamines occurs with secondary amines having nitrogen atoms in a variety of steric environments, and the flexibility of having a single phosphonate reagent is obvious from a practical synthetic viewpoint. Unfortunately, however, the reaction fails when an aldehyde or aryl ketone is used as the carbonyl component. 

Enamines from ketones Azeotropic water entrainment... 

For the preparation of enamines from ketones see section 356 (Amine -Olefin)... 

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