Enamines ketones with secondary

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

Enamines from the Condensation of Aldehydes and Ketones with Secondary Amines. ... 

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. 

Condensation of aldehydes and ketones with secondary amines in the presence of dehydrating agents (often potassium carbonate69-71) represents a general method of enamine preparation. By this procedure ketones afford the enamines directly, whereas aldehydes are converted in the first step into diamino derivatives which decompose on distillation to give the enamine and a molecule of the secondary amine. In the case of ketones and disubstituted acetaldehydes, the water formed by the reaction can be removed by azeotropic distillation with benzene, toluene, or xylene.27,31,72-75 In the case of derivatives of aromatic aldehydes, the formation of intermediary carbinolamines 76 is sometimes observed. 

Enamines are formed from aldehydes or ketones with secondary amines... 

Note. Aza-enolates are formed from imines, which can be made only from primary am ines. Enamines are made from aldehydes or ketones with secondary am ines. 

Enamines of steroids formed in situ by condensation of the corresponding ketones with secondary amines, followed by treatment with formic acid, gave the 3/ -saturated amine derivatives as the main products206. 

The formation of enamines by the reaction of aldehydes and ketones with secondary amines was described in Section 17.11. As the following equation illustrates, the reaction is reversible. 

It will be recalled (Scheme 9.66) that reaction of ketones with secondary amines (such as azacylopentane [pyrrolidine]) produces enamines. Now, as shown in Scheme 9.88, when the unsymmetrically substituted ketone (2-methylcyclohexanone) forms an enamine, that specific enamine which is less sterically encumbered is favored and alkylation occurs on the previously unsubstituted side producing 2,6-dime thylcyclohexanone. 

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. 

Secondary amines react smoothly with 3-ketones to give enamines and good selectivity is achieved in the presence of 7-, 12-, 17- and 20-ketones. With pyrrolidine the reaction takes place under very mild conditions and no catalyst is usually required. Hydrolysis occurs by simply heating in ethanol. 

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... 

Spectroscopic investigation of enamines conjugated with ketone, ester and nitrile groups established the prevalence of enamine rather than imine-enol tautomers in examples of secondary amines (206-212). Similar studies have been made with enamines of acylpyridines and acetophenones (213,214). 

The long known catalyses of some ketone condensation reactions by secondary amines, can be postulated to have their basis in the reactions of enamine intermediates with ketones. The unsuitability of methyl ketones for azeotropic enamine formation is based on this phenomenon. Recent studies in cyclization reactions have added further support to this concept (354). 

Certain ketones react reversibly with secondary amines to give enamines. By removal of water, the equilibrium can be driven to the right, and the enamine can be isolated. 

Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the a carbon), yielding an enamine (Figure 19.10). 

Mechanism of enamine formation by reaction of an aldehyde or ketone with a secondary amine, R2NH. The iminium ion intermediate has no hydrogen attached to N and so must lose H+ from the carbon two atoms away. 

An aldehyde or ketone reacts with a primary amine, RNH.2, to yield an imine, in which the carbonyl oxygen atom has been replaced by the =N-R group of the amine. Reaction of the same aldehyde or ketone with a secondary amine, R2NH, yields an enamine, in which the oxygen atom has been replaced by the -NR2 group of the amine and the double bond has moved to a position between the former carbonyl carbon and the neighboring carbon. 

Stork Enamine Reaction Aldehydes and ketones react with secondary amines to form compounds called enamines. The general reaction for enamine formation can be written as... 

The enol content of simple ketones is much lower than that of /1-ketoesters or /3-diketones. For a number of electrophiles it is often too low. Hence, functionalizations with the respective electrophile via the enol form do not succeed in these cases. This problem can be managed, though, by converting the ketone (Formula A in Figure 12.16) into an enamine D with the aid of a condensation with a secondary amine that is in line with Figure 9.29 and the mechanism given there. Enamines are common synthetic equivalents for ketonic and aldehyde enols. 

The reaction of an aldehyde or a ketone with a secondary amine follows exactly the same mechanism as the reaction with a primary amine (see Figure 18.3) until the final step. Unlike the case with a primary amine, the nitrogen of the iminium ion does not have a proton that can be removed to produce a stable imine. Therefore, a proton is removed from an adjacent carbon, resulting in the formation of an enamine. Enamine formation is illustrated in the following equations. In each case the equilibrium is driven toward the products by removal of water. 

Ketones and aldehydes react with primary amines to give imines. They react with secondary amines to give enamines (vinyl amines). 

Enamines are formed when aldehydes or ketones react with secondary amines. The mechanism is given in Chapter 14. The mechanism below shows how they react with alkylating agents to form new... 

Rearrangement of an enamine to an equilibrium mixture of isomeric enamines will occur under acid catalysis, but will not take place under neutral or basic conditions304. The reaction of non-symmetric ketones 193 with secondary enamines leads to a mixture of both possible enamines 194 and 195 (equation 20) as was shown by -NMR spectroscopy305. 

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