Of enamines

Another similar example concerns the alkylation of enamines. This reaction works well with reactive a-halocarbonyl compounds (frames 175ff) but simple alkyl hahdes often react on nitrogen ... 

Later it turned out that activation of enamine components could not only be achieved by deprotonation of the nitrogen atom but also by connecting it with certain metals, e.g. Ni(II), Pd(II), or Co(II), and subsequent treatment with base. 

Dyke, S. F. 1973, 77ie Chemistry of Enamines, Cambridge Univ. Press Cambridge... 

Aminothiazole derivatives (243) can be prepared by treatment of enamines of type 240 with sulfur and cyanamide at room temperature in ethanol (701) yields range from 30 to 70%, and no catalyst is required. Initial formation of the thiolated intermediate (241) is probably followed by addition of cyanamide, yielding 242 (Scheme 124). 

The addition of 1,3-dicarbonyl compounds to /3-chloroazoalkenes is the basis of a pyrrole synthesis (Scheme 70a) 81TL1059). Pyrroles are also obtained by the reaction of enamines with azoalkenes (Scheme 70b) (79TL2969,81TL1475), and the copper(II) chloride catalyzed addition of 1,3-dicarbonyl compounds to arylazoalkenes (Scheme 70c) (82JOC684). 

The higher frequencies of the /3-lactam carbonyl absorption in fused systems has been attributed to increased inhibition of amide resonance as the /3-lactam ring becomes less planar (b-72mI50900 p. 303). For the 3-cephems (61) there is also the possibility of enamine resonance which could further reduce the ability of the /3-lactam nitrogen to contribute to amide resonance. 

A very efficient one-pot procedure for the production of 3-hydroxy-3-cephems (45) has been developed which gives the desired product in almost 80% overall yield from (43a) which is readily available from penicillin. TTie sequence of reactions is (1) mesylation to give (43b), (2) formation of enamine (43c), (3) bromination to afford (44) and (4) hydroly-sis/cyclization with hydrochloric acid in methanol to afford (45) which, in some cases, crystallizes directly from the reaction mixture (B-82MI51000). 

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%. 

Alkylations of enamines of a,)9-unsaturated ketones with alkyl halides often give very poor yields of C-alkylated products because of competing. -alkylation.In the type of transformation illustrated here, direct alkylations of enamines are completely unsuccessful, even in cases where hindered enamines are used. On the other hand, the metaUoenamine method can be applied generally with good success in the problem of monoalkylation of ,)3-unsaturated ketones. ... 

An interesting and useful property of enamines of 2-alkylcyclohexanones is the fact that there is a substantial preference for the less substituted isomer to be formed. This tendency is especially pronounced for enamines derived from cyclic secondaiy amines such as pyrrolidine. This preference can be traced to a strain effect called A or allylic strain (see Section 3.3). In order to accommodate conjugation between the nitrogen lone pair and the carbon-carbon double bond, the nitrogen substituent must be coplanar with the double bond. This creates a steric repulsion when the enamine bears a p substituent and leads to a... 

A. G. Cook, Enamines, 2nd ed., Marcell Dekker, New York, 1988, Chapter 1 Z. Rappoport, ed.. Chemistry of Enamines, John Wiley Sons, Chichester, UK., 1994. 

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). 

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. 

C. Reaction of Enamines of 3-Ketones with Cyanogen Azide... 

Annelation of enamines or enolates with fluorinated methyl vinyl ketones gives the corresponding cyclohexenones [116, 117] (equation 101)... 

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 tetrasubstituted isomer of the morpholine enamine of 2-methyl-cyclohexanone (20) because cf the diminished electronic overlap should be expected to exhibit lower degree of enamine-type reactivity toward electrophilic agents than the trisubstituted isomer. This was demonstrated to be the case when the treatment of the enamine with dilute acetic acid at room temperature resulted in the completely selective hydrolysis of the trisubstituted isomer within 5 min. The tetrasubstituted isomer was rather slow to react and was 96% hydrolyzed after 22 hr (77). The slowness might also be due to the intermediacy of quaternary iminium ion 23, which suffers from a severe. 4< strain 7,7a) between the equatorial C-2 methyl group and the methylene group adjacent to the nitrogen atom, 23 being formed by the stereoelectronically controlled axial protonation of 20. 

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. 

In their original communication on the alkylation and acylation of enamines, Stork et al. (3) had reported that the pyrrolidine enamine of cyclohexanone underwent monoacylation with acid chlorides. For example, the acylation with benzoyl chloride led to monobenzoylcyclohexanone. However, Hunig and Lendle (33) found that treatment of the morpholine enamine of cyclopentanone with 2 moles of propionyl chloride followed by acid hydrolysis gave the enol ester (56), which was proposed to have arisen from the intermediate (55). 

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