Preparation of enamines

Enamines such as 510 are bidentate nucleophiles, with both nitrogen and carbon functioning as nucleophiles.267 Alkylation at nitrogen is a problem with reactive halides such as methyl iodide or allyl bromide and when the groups on nitrogen are small. Nucleophilicity usually parallels that of the unsubstituted amine. 

In general, the kinetic nitrogen enolate (the less substituted enamine) is formed due to reduced steric hindrance.268 The enamine exists primarily as a planar species (513 or 514) in which the lone pair electrons on 

Enamines react with a.p-unsaturated compounds almost exclusively by conjugate addition to give the corresponding substituted ester, ketone, or nitrile. Reaction of 507 with acrylonitrile, for example, gave a new enamine (521). Subsequent hydrolysis liberated the substitute ketone (522) in 80% overall yield from enamine 507.268a,272 

Enamines have been used extensively in synthesis. 26.277 example is the synthesis of lupinine (529) 

The pyrolysis of choline to A -Af-dimethylvinylamine 68 was probably the first reported preparation of an enamine, but it is of historical interest only. A variety of methods for the preparation of enamines have been developed, and these compounds are now readily accessible. 

Preparation op Enamines by Condensation of Aldehydes and Ketones with Amines 

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. 

Kostianovskij and V. F. Bystrov, Izv. Akad. NaukSSSR, Otd. Khim. Nauk 171 (1963) R. G. Kostianovskij and O. A. Panshin, Izv. Akad. Nauk SSSB, Otd. Khim. Nauk 182 (1963). 

In the preparation of enamines from a-substituted ketones, e.g. 2-alkylcyclohexanones, the less-substituted enamine is always formed because of steric interactions77. This makes possible the introduction of a 

Meerwein and his collaborators968 showed that the acetals derived from amides or lactams, e.g., the diethyl acetals of dimethylformamide, dimethyl-acetamide, l-methyl-2-pyrrplidone, and l-methyl-2(l )-quinolone, react with compounds containing a reactive methylene group to give enamines in good yield without the need for addition of a catalyst. The compounds shown in the attached Table have been prepared by using dimethylformamide diethyl acetal. 

Condensation with R in the product Reaction temp. Yield (%) 

Bredereck and Bredereck,969 however, found that it was unnecessary to start with acetals, and that enamines are formed in about 80% yield when compounds containing reactive methylene groups are treated with dimethylformamide or other amides in the presence of phosphoryl chloride. Eiden970 used acetic anhydride instead of phosphoryl chloride, but the yields then sank to 25-40%. 

4-(2-Alkylidene-2-alkenyl)morpholines971 are formed when equivalent amounts of morpholine and a w-alkyl methyl ketal are heated together for 36-48 hours, yields being 55-80%  

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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%. 

The preparation of enamines will be discussed in Chapter 8, and their application as carbon nucleophiles in synthesis is discussed in Chapter 1 of Part B. 

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 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. 

The preceding section described the preparation of enamines by mercuric acetate oxidation of tertiary amines. The initial product in these oxidations is the ternary iminium salt, which is converted to the enamine or mixture of enamines by reaetion with base. Thus iminium salts synthesized by methods other than the oxidation of tertiary amines or the protonation of enamines are potential enamine sources. 

The preparation of enamines by reduction of aromatic heterocyclic bases and their quaternary salts or of lactams is not the most useful approach (97). The lithium aluminum hydride reduction of N-acyl enamines has been used with both fruitful and unsuccessful results. A series of 3-N-acetyl -d -cholestenes (104) has been prepared by desulfurization of the appropriate thiazolidine (105) (98,99). Lithium aluminum hydride reduction of the... 

B. The preparation of enamines by heating seeondary amines and ketals was originated by Hoch (118) and has been extended by Bianchetti and eo-workers (119-121). 

The preparation of enamine ketones by addition of a,jS-unsaturated ketones to enamines is described in Chapter 4. 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

The preparation of enamines of unsubstituted cyclic ketones is convenient and unambiguous in that only a single product results. Moreover, such enamines have found wide application as means of chain extension or ring formation. 

It is occasionally necessary to carry out special operations in connection with a synthetic procedure. An example frequently encountered is the removal of water from a reaction mixture in order to alter equilibrium concentrations (for example, in the preparations of enamines). For this purpose, a Dean-Stark trap is employed as shown (Fig. A3.6). The reaction is carried out in a solvent that forms an azeotrope with water... 

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). 

For the preparation of enamines or imines from ketones, see Section 356 (Amine-Alkene). 0 1. CFsSOsSiMes, MeCN S... 

B. By Hydrolysis Reactions.—Details have appeared of the synthesis of dibenzophosphorin oxides (15) from 5-alkyldibenzophospholes, by reaction with methyl propiolate in the presence of water, and of confirmatory syntheses from phosphinic acid chlorides, as shown below. Evidence for the suggested mechanism of the ring-expansion reaction is presented. The hydrolysis of enamine phosphine oxides is an efficient, although somewhat indirect, method for the preparation of j8-ketoalkylphosphine oxides (16) [see Section 3(iii), for the preparation of enamine oxides]. Reasonable yields (48—66%) of trialkylphosphine oxides (17) have been obtained by the alkaline hydrolysis of the products from the pyrolysis at 220 °C of red phosphorus with alkyl halides, in the presence of iodine. 

The intermolecular ruthenium enyne Alder-ene reaction has been extended to the stereoselective preparation of enamines (Equation (26)).39 The yields obtained for this reaction were high with allylacetamides, -benzamides,... 

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... 

Preparation of enamine 2,4,6,8-nonanetetraones by the reaction of pyrrolidine with acylpyrones [198]. 

The procedure is that of Hiinig, Benzing and Liicke. It is based on earlier work on the preparation of enamines.4 6... 

Preparation of enamines, 409 Preparation of enol acetates, 411 Preparation of enol ethers, 409 Preparation of a-halo ketones, 267 Preparation of 3/3-hydroxyandrosta-5,15-dien-17-one, 302... 

Another convenient method for the preparation of enamines involves the dehydrogenation of saturated bases with mercuric acetate. A trans- 1,2-elimination probably occurs. The electron pair on the nitrogen atom and the hydrogen atom to be eliminated must both be axial. Thus, for example, yohimbine (24) can be dehydrogenated by mercuric acetate, whereas reserpine (25) or pseudoyohimbine (26) do... 

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