Enamines secondary amines, preparation

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 next seven references are cited not because of the experimental procedures described but because they indicate diversification in the types of enamines prepared and studied. Both Paquette (25) and Kasper 26) have condensed 2,5-methylene-l,2,5,6-tetrahydrobenzaldehyde (5-nor-bornene-2-carboxyaldehyde) (2) with several cyclic and open-chain aliphatic secondary amines. Kasper studied the ratio of endo to exo aldehyde formed upon hydrolysis of these enamines and the dihydro enamines. Paquette investigated the addition of sulfene to the enamines. -Fluoro-... 

The secondary amines used in the preparation of enamines have been primarily simple dialkylamines or cyclic amines of five- or higher-membered rings. Azetidine (4) yields a stable enamine with cyclopentanone (28). No simple enamines formed by condensation of ethylenimine (5) or a substituted ethylenimine with an aldehyde or ketone have been reported. 

An interesting preparation of substituted o-aminophenols has been developed by Birkofer and Daum (30). 2-Acylfurans (8) plus an aliphatic secondary amine presumably condense to give the eorresponding enamine (9) (not isolated), which undergoes thermal isomerization to the o-amino-phenol (10). 

The overall reaction pathway usually presented (/,9,/9,36)for the preparation of an enamine from an aldehyde bearing an a-hydrogen and a secondary amine is given in Eqs. (2) and (3). Intermediate 16, which can be isolated in... 

Displacement of Vinyl fluorine or chloride by secondary amines has given some unusual enamines as illustrated for the preparation of 1,1-difluoro-2-piperidino-3-phenyl-2-cyclobutene (151) (US), l,l-difluoro-2,4-dipiperidino-3-phenyl-2-cyclobutene (152) (114), and 2-phenyl-3-(l -aziridinyl)-2-cyclohexenone (153) (115). 

A recent adaptation of the procedure employing perchlorate and fluoro-borate salts has been reported by Leonard and Paukstelis (J5). This report includes proof of structure by direct comparison to iminium salts prepared by protonation of enamines. The general reaction reported was that of a ketone or aldehyde with a secondary amine perchlorate to give iminium salts. A large structural variety of carbonyl compounds and several amine... 

An enamine is easily prepared by reaction of the corresponding aldehyde or ketone 4 and a secondary amine 5. A cyclic secondary amine like pyrrolidine, piperidine or morpholine is most often used. A general procedure has been reported by Mannich and Davidseti in 1936 ... 

This is the most common method for the preparation of enamines and usually takes place when an aldehyde or ketone containing an a hydrogen is treated with a secondary amine. The water is usually removed azeotropically or with a drying agent, but molecular sieves can also be used. Stable primary enamines have also been prepared.Enamino-ketones have been prepared from diketones and secondary amines using microwave irradiation on silica gel. ° Secondary amine perchlorates react with aldehydes and ketones to give iminium salts (2, p. 1178). Tertiary amines can only give salts (12). 

MW-expedited dehydration reactions using montmorillonite K 10 clay [70] (Schs. 6.20 and 6.21) or Envirocat reagent, EPZG [71] (Schs. 6.20 and 6.21) have been demonstrated in a facile preparation of imines and enamines via the reactions of primary and secondary amines with aldehydes and ketones, respectively. The generation of polar transition state intermediates in such reactions and their enhanced... 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

The alkylation of caclohexanone has been studied as a model reaction in detail. Generally, enamino compounds (126) are allowed to react with alkyl halides or a, 3-unsaturated carbonyl compounds. The enamine (126a) is prepared directly from the ketone and a chiral secondary amine (route A). A metalloenamine (126b) can be synthesized from chiral azomethine, derived from the model ketone and a primary chiral amine (route B). The primary amine used for the formation of (126b) must possess an oxygen function. This oxygen function plays a key role in the coordination of the lithium ion in the complex (126b). 

Addition of secondary amine to carbonyl compounds preparation of enamines... 

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

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

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

A much more generally useful process was developed by Robinson to prepare cyclohexenones from ketones and methyl vinyl ketone or its derivatives. Again, because good compilations of the Robinson annulation exist,8 only a few examples are given here. The first step of this process, the Michael addition, is carried out by normal base catalysis, while the second step, the aldol condensation, is best accomplished by the use of a secondary amine to form the enamine of the acyclic ketone, which then cyclizes... 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

Enamines are highly valued intermediates in organic synthesis. Almost invariably they are prepared by reaction of a carbonyl compound with a secondary amine. In principle, another attractive route to enamines could be based on construction of the double bond by a Wittig- or Horner-Wittig reaction. The enamines J thus obtained could be easily converted into the corresponding homologous aldehydes, if desired fitted with an extra electrophilic substituent at the original carbonyl carbon atom. 

Enamines.1 Enamines are generally prepared by condensation of the carbonyl compound with a secondary amine with removal of the water formed. In a new... 

Aminoquinolines 62 have been prepared in a two-step, one-pot, three-component reaction of 2-azidobenzophenones, secondary amines and arylac-etaldehydes [110]. The microwave-assisted reaction proceeded via the initial formation of enamines 59. Subsequent addition of 2-azidobenzophenones 60 afforded the triazoline intermediates 61, which underwent thermal rearrangement and cyclocondensation to furnish 2-aminoquinolines 62 (Scheme 41). Direct comparison with conventional thermal conditions demonstrated the superiority of microwave dielectric heating in terms of yields (73% vs. 31% of heterocycle 63 after 10 min at 180 °C). Furthermore, the formation of by-products due to decomposition of azide 60 was diminished in the microwave-assisted synthesis. Purification of the products was achieved using solid-phase extraction techniques. 

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. 

Secondary amines react with ketones that contain an H atom in the a-position through an addition and subsequent El elimination to form enamines (Figure 9.29). In order for enamines to be formed at all in the way indicated, one must add an acid catalyst. In order for them to be formed completely, the released water must be removed (e.g. azeotropically). The method of choice for preparing enamines is therefore to heat a solution of the carbonyl compound, the amine, and a catalytic amount of toluenesulfonic acid in cyclohexane to reflux in an apparatus connected to a Dean-Stark trap. Did someone say Le Chateher ... 

As discussed in Section 18.8, enamines are prepared by the reaction of a secondary amine with a ketone in the presence of an acid catalyst. The equilibrium is usually driven toward product formation by removal of water. 

After the enamine has been used as a nucleophile, it can easily be hydrolyzed back to the ketone and the secondary amine by treatment with aqueous acid. This is simply the reverse of the process used to prepare it. Overall, enamines serve as the synthetic equivalent of ketone enolate anions. Examples are provided in the following equations ... 

The Swiss chemist Oppolzer used just such a reaction. He first prepared an acid chloride from cyclopentadiene, and the enamine from cyclopentanone and the secondary amine morpholine. 

The acid-catalysed cyclization of the dienamines (150) prepared from citral (152) and a range of secondary amines has been studied acid treatment of citral-pyrrolidine enamines (151) gave exclusively a-cyclocitral in 41% yield. When enamines derived from optically active (—)-pyrro idines were used, optically active... 

The general procedures for the preparation of enamines, such as condensation of an open-chain aldehyde with a secondary amine in the presence of potassium carbonate or azeotropic removal of water from a solution of a ketone and secondary amine in benzene (frequently in the presence of an acid catalyst), fail to incorporate the desirable feature of stereospecificity. The spectra of a series of enamines prepared from both aldehydes and ketones indicated that the Zs-isomer predominated, but not to the total exclusion of the Z-isomer. 

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