Of enamines by ketones

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 chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

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]... 

Table I gives many examples of the preparation of enamines by the reaction of secondary amines with aldehydes and ketones.

The synthesis of enamines by the reaction of some ketones or aldehydes with a secondary amine can lead to saturated by-products when the enamine is heated in a nitrogen atmosphere with a catalytic amount of p-toluenesulfonic acid [48-50] (Eq. 10). 

Preparation of Enamines by the Reaction of Secondary Amines with Aldehydes and Ketones... 

A procedure for the formation of enamines by condensation of the parent ketone and secondary amines in the presence of molecular sieves was studied. The role of the molecular sieve is to trap the water formed. The enamine-forming reaction is acid catalyzed and both Bronsted acids and Lewis acids can be used. 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

The synthesis of enamines by the modified titanium tetrachloride method was discussed in Chapter 12. The final yield and the rate of enamine formation depend on the molar ratios of TiCl4/substrate and amine/substrate. The optimum conditions with regard to these variables were determined by response surface technique and/or simplex technique for a series of carbonyl compounds. The results obtained for the morpholine enamines are summarized in Fig. 14.2. It is seen that the more crowded substrates require an excess of the reagents. The use of standardized conditions would have led to the wrong conclusions as to the utility of the method. For instance, when the optimum conditions for synthesis of the morpholine enamine from methyl isobutyl ketone were applied to diisopropyl ketone a yield of 12 % was obtained after 4 h. Under optimized conditions yields > 70 % could be obtained. 

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. 

Attempts to induce cyclopropanation of enamines by carbene transfer from the tungsten complex (332) were unsuccessful. Under a high pressure of carbon monoxide, a combined addition of the carbene and CO led to formation of ketones (333) and (334). ... 

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. 

Synthesis at 4-chromanones by condensation of saiicylaldehydes or o-hydroxyaryi ketones with enamines or ketones. 

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

These steric factors are also indicated by the relative basicity of enamines derived from five-, six-, and seven-membered ketones. The five- and seven-membered enamines are considerably stronger bases, indicating better conjugation between the amine lone pair and the double bond. The reduced basicity of the cyclohexanone enamines is related to the preference for exo and endo double bonds in six-membered rings (see Section 3.10). 

Androst-4-ene-3,l 1,17-trionehas been converted into several 3,17-dienamine derivatives which, on reduction with LiAlH4 followed by removal of the protecting groups, give 11 jS-hydroxyandrost-4-ene-3,17-dione. An unsaturated 3-ketone has also been protected as an enamine in the LiAlH4 reduction of a 21-ester group a further example is the conversion of 7-methylene-5a-an-drostane-3,17-dione into the 3-pyrrolidine enamine followed by reduction of the 17-ketone by Li[OC(CH3)3]3 AlH. ... 

Enamines of A" -3-ketones (45) are stable to lithium aluminum hydride, but lithium borohydride reduces the 3,4-double bond of the enamine system." In the presence of acetic acid the enamine (45) is reduced by sodium borohydride to the A -3-amine (47) via the iminium cation (46). ... 

With strong acids, enamines give iminium salts, from which the parent enamine is regenerated by treatment with piperidine or triethylamine. Enamines are usually cleaved by warming in acetic acid-sodium acetate solution. The more labile enamines of saturated 3-ketones are hydrolyzed simply by heating in 95% ethanol. ... 

At reflux, tetrahydrafuran slowly adds to terminal perfluoroalkylethylenes, perfluoroalkylacetylenes, and ethyl perfluoroalkylpropynoates [25] (equation 18) By contrast, the ionic addition of enamines to hexaJluoro-2-butyne is exothermic and gives dieneamines that, on acidic hydrolysis, yield fluoroalkenyl ketones [26] (equation 19)... 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

Mimk and Kim (60) have reported the preparation of the enamines of several acyclic ketones by refluxing the ketone with the amine for 66 hr to 76 days. For example the morpholine enamine of 2-pentanone was found to consist only of 121. 

Similar results were encountered by Bianchetti et al. (i52), who found that e ketal derivatives of //-alkyl methyl ketones with morpholine led to the enamines of the condensation products of these ketones. The authors have Suggested the following probable mechanism for the dienamine formation. 

Morpholine enamine of methyl isopropyl ketone prepared by this method was found to be a 3 7 mixture of di- and tetrasubstituted isomers (126 and 127). 

This innovation was exploited by Stork and his co-workers (6-8) for a study of enamine formation from a variety of ketones and secondary amines. 

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