Ketone via enamines

From a preparative point of view, the acylation of ketones via enamines is of particular interest. In comparison with pyrrolidine and piperidine enamines, the less reactive morpholine enamines give better yields, as found by Hiinig et al.2iZ j8-Diketones are the products of acylation with an acyl halide followed by acid hydrolysis, whereas with ethyl chloroformate, /J-ketoesters are obtained.212 Hiinig and his collaborators242-247 have used the acylation of 1-morpholino-l-cyclopentene and 1-morpholino-l-cyclohexene to lengthen the chains of acids by five and six carbon atoms, respectively. The reaction may... 

Allevi, P, Anastasia, M, Ciuffreda, P, Eicchim, A, Scala, A, Efficacious C-glucosidation of (3-keto esters and ketones via enamines, J. Chem. Soc., Chem. Commun., 57-58, 1988. 

ASYMMETRIC HALOGENATION OF KETONES VIA ENAMINES OF L-PROLENE ESTERS... 

Ketocarboxylic acid esters from ketones via enamines... 

SCHEME 11.4. a-Atnination of aromatic ketones via enamine catalysis by primary amines. 

Catalytic reactions proceeding via enamines as intermediates. A DFT study at the B3LYP/6-31H-G(2df,p)//B3LYP/6-31G(d) level of the proline-catalysed Michael addition of ketones (via enamines) to nitroalkenes has revealed that the added benzoic acids play two major roles, namely assisting the proton transfer and activating the nitro group. °... 

Potassium iodideldimethylformamide Preferential alkylation of ketones via enamines Synthesis of ketones... 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and applied synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One reason is that aldehydes are rapidly converted to aldol addition products by base. (See Chapter 2 for a discussion of this reaction.) Only when the enolate can be rapidly and quantitatively formed is aldol formation avoided. Success has been reported using potassium amide in liquid ammonia67 and potassium hydride in tetrahydrofuran.68 Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions are discussed in Section 1.3. 

Secondary amines react with aldehydes and ketones via addition reactions, but instead of forming imines, produce compounds known as enamines. Initially, there is the same type of nucleophilic attack of the amine onto the carbonyl system, followed by acid-catalysed dehydration but, since the amine is secondary, the product of dehydration is an iminium... 

Abstract The reversible reaction of primary or secondary amines with enolizable aldehydes or ketones affords nncleophilic intermediates, enamines. With chiral amines, catalytic enantioselective reactions via enamine intermediates become possible. In this review, structure-activity relationships and the scope as well as cnrrent limitations of enamine catalysis are discnssed. 

Recently [52] it was reported that enamines derived from 2-substituted ketones exist as a mixture of the more and less substituted double-bond isomers. The isomer ratio is dependent on the various steric and electronic factors of the overlap of the lone pair of electrons on the nitrogen and the double bond of the enamine. On the other hand, alkylation of ketones via their anions affords substitution on the most substituted carbon position [51]. 

Small chiral organic molecules may catalyze the asymmetric addition of ketones, and aldehydes to electron-deficient olefins, such as vinylidene acetones, nitroole-fins, enones, and vinyl sulfones. In this chapter we will describe the inter- and intramolecular reactions in which activation of the carbonyl compound takes place via enamine formation. 

Returning again to pyrroles, probably the most widely-used method for their preparation is the Knorr pyrrole synthesis, which is the condensation of a ketone 2.22 with an a-aminoketone 2.23 to give pyrrole 2.13, via enamine 2.24. A reasonable mechanism is shown below, although none of the intermediates is isolated. 

It is of great interest to compare this last value with the keto-enol equilibrium constant obtained similarly for acetone = 0.35 x 10-8). Indeed, in many enzyme-catalysed reactions, aldolisation for example, enamine formation is not rate-limiting, and the rate is usually controlled by subsequent electrophilic additions. Consequently, the rate depends on enamine reactivity and on the enamine concentration at equilibrium. Therefore, if one wants to compare the two processes, via enol and via enamine, in order to explain why the enamine route is usually preferred, the difference in equilibrium constants for enol and enamine formation must be taken into account. Data on ketone to enol and ketone to enamine equilibrium constants show that the enamine and enol concentrations are of similar magnitude even for relatively small concentrations of primary amine. Thereafter, since the enamine is much more reactive than the enol for reactions with electrophilic reagents (in a ratio of 4-6 powers of ten for proton addition), it can be easily understood why the amine-catalysed pathway is energetically more favourable. 

Enamines are made from secondary amines and aldehydes or ketones via the iminium salt you met them in Chapter 14 and have seen them in action in Chapters 21,26, and 27. 

Both chiral amines42 and chiral protonating agents43 have been used for the enantioselective deracemisation of a-substituted aldehydes and ketones via the derived enamine. However, the enantiomeric excesses achieved were usually not very high and there have been no new developments reported in this area41. 

Enamines react with ethoxycarbonylnitrene to give N-substituted a-amino ketones via an aziridine intermediate362" (Scheme 186). Using chiral enamines the a-amino ketone can be obtained in relatively high optical yield (77% ee) but low chemical yield (18%)362. ... 

Pyrrolizine derivatives 86 or polyhydropyrrolo[l,2-intermediate enamines (equation 38)59. 

Intramolecular cyclizations. Cyclizations of a>azido-/3-ketoesters, such as 138 (obtained by a multistep reaction starting from cyclohexanone), produced eight-membered enamines 139 (Scheme 57 <2004JOC997>). Preparations of 138 are based on a method developed from the formal ring expansion of cyclic ketones via retro-Reformatsky fragmentation <2004JOC997>. 

Several cyclic a-fluoro ketones 8 have been obtained from the corresponding cyclic ketones via the enamines 7, using difluorodiazene as the fluorinating agent. 

Enamines like enolates are alkylated when treated with reactive alkylating agent, a-Substituted enamines can be converted into aldehydes and ketones by acid-catalyzed hydrolysis. Thus, in the three-step process, alkylation of aldehydes and ketones may be carried out via enamines (Stork enamine synthesis) (Scheme 3.19). 

Archer and co-workers (84) have used the original Stillwell ellipticine synthesis (87), as later exploited by Gouyette et al. (88) to prepare the simple 9-hydroxy-6//-pyrido[4,3-fe]carbazole (158) (Scheme 27). V-Benzyl-4-piperidone was converted via enamine 154 to the enone 155. Hydrogenation gave a mixture of cis- and trawj-ketones 156 which were separately converted to indole 157 by Fischer indolization. Some of the nonlinear pyrido[3,4-c]carbazole (17%) was formed from the cis-ketone. Dehydrogenation and demethylation gave the desired 158. 

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