Acylation of enamine

A 250-ml round-bottom flask is charged with a mixture of cyclohexanone (14.7 g, 0.15 mole), morpholine (15.7 g, 0.18 mole), and / -toluenesulfonic acid monohydrate (0.15 g) in 50 ml of toluene. The flask is fitted with a water separator and a condenser and is brought to reflux (mantle). The separation of water begins immediately and the theoretical amount (2.7 ml) is obtained in about 1 hour. Without further treatment, the reaction mixture may then be distilled. After removal of the toluene at atmospheric pressure, the product is obtained by distillation at reduced pressure, bp II8-I207IO mm, 1.5122-1.5129, in about 75% yield. 

For many reactions, the enamine may be used without distillation. The cooled toluene solution is washed with bicarbonate followed by water. After drying, toluene is removed (rotary evaporator) and the crude enamine employed directly. 

In general, enamines are sensitive to moisture, and this fact should be kept in mind if the enamine is not to be used immediately. If the enamine is to be stored for any length of time, refrigeration is recommended. Yellowing may occur on long storage, but this change appears to have little effect on the outcome of subsequent reactions. 

In the acylation of enamines, the weakly basic acylated enamine does not absorb the acid formed. Consequently, one must employ 2 equivalents of the enamine or use a second tertiary amine to absorb the acid liberated. In the procedure, triethylamine is employed to absorb the hydrochloric acid. 

In a 500-ml round-bottom flask is placed a solution of 25 g of the enamine and 20 ml of triethylamine in 175 ml of dry chloroform. Slowly, with swirling, a solution of 15 ml of acetyl chloride in 75 ml of dry chloroform is added, and the solution is refluxed for 2 hours (mantle). 

One of the most actively investigated aspects of enamine chemistry has been the acylation process (i). Initial intensive studies by Hiinig (373-375) showed the ease of preparing a variety of 9-diketones and particularly the synthetic potential of acylated cyclic ketones as intermediates in the preparation of aliphatic keto acids, keto dicarboxylic acids and diketo dicarboxylic acids (376-378). 

From the outset, the further O acylation of the initial ketonic products was recognized. Detailed studies have been made of the benzoylation of morpholinoeyclohexene (379-382) and of the effect of the amine moiety of cyclohexanone derived enamines on the ratio of produets (iS5) obtained from acylations. 

The benzoylation reaction was applied to cyclic enamines (384) and the synthesis of a heptazulene (385). 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

In the acylation of enamines derived from 3-substituted cyclohexanones, 6-acylated products were favored over 2-acylated products (398), thus revealing another selective enamine reaction sequence. The use of oxalyl bromide for the acylation of enamines has also been described (399). 

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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). 

There is some spectral evidence that acylation of enamines of cyclic ketones with acid chlorides having an a-hydrogen in the presence of triethylamine proceeds via the ketene and subsequent cycloaddition (84). The intermediate cyclobutanone is then opened to give the enamino ketone which is hydrolyzed to the 2-acyl cyclohexanone. In the case of enamines of larger cyclic ketones the alternate mode of the cyclobutanone opening predominates, with the formation of ring-expanded 1,3-diketones upon... 

The acylation of enamines derived from cyclic ketones, which can lead to the acyl ketone or ring expansion (692-694), was studied by NMR and mass spectroscopic analysis of the products (695,696). In a comparative study of the rates of diphenylketene addition to olefins, a pronounced activation was observed in enamines (697). Enamine N- and C-acylation products were obtained from reactions of Schiff s bases (698), vinylogous urethanes (699), cyanamides (699), amides (670,700), and 2-benzylidene-3-methylbenzothiazoline (672) with acid chlorides, anhydrides, and dithio-esters (699). 

Further variants of the acylation of enamines with subsequent cyclization are found in the use of thioacylisocyanates (578) and acylthiocyanates (579,580) in heterocyclic syntheses. 

Another important application is the acylation of enamines 1 with an acyl chloride 9 to give a 1,3-dicarbonyl compound as final product ... 

In general, alkylations as well as some acylations of enamines using halides as the leaving group occur predominantly on carbon (B-69MI20700). For example, treatment of A2-piperideine (115) with methyl bromoacetate followed by sodium borohydride reduction... 

Thioamides are suitable intermediates for the preparation of amidines, thiazoles, and thiophenes. Thioamides have mainly been prepared on insoluble supports by C-acylation of enamines or C,H-acidic compounds with isothiocyanates (Entries 1-3,... 

Acylation of enamines is to a great extent similar to alkylation, and usually occurs on the -carbon atom of the enamine. There are few reports about the acylation of enamines of the pyrroline and piperi-deine type. Acylation of l,3,3-trimethyl-2-methyleneindoline leads to l,3,3-trimethyl-2-acylmethyleneindoline (67).236 l,2-Dimethyl-3-... 

Q Show how alkylation and acylation of enamines and lithium enolates are used Problems 22-68, 73, and 74... 

In addition to the synthesis of /1-dicarbonyl compounds3,25, the acylation of enamines also gives access to a wide variety of acyclic, carbocyclic and heterocyclic systems. The course of the reaction is often critically dependent upon the type of enamine used, on the substituents present in the two reagents, and on the experimental conditions, such as temperature, solvent, presence of added tertiary amine, etc. In contrast to alkylation, A-acylation is readily reversible. Since enamines are stronger bases than the C-acylated enamines, half an equivalent of the enamine is lost by salt formation in their reaction with acid chlorides. This can be avoided by addition of a tertiary amine179, but this in... 

Mteto esters can be obtained by acylation of enamines of acyclic and cyclic ketones with ethyl chloroformate3. Surprisingly no /J-keto ester was obtained when the reaction was carried out in the presence of triethylamine and an extra mole of enamine or a tertiary aromatic amine must therefore be used to neutralize the acid liberated The intermediate enamino ester can be isolated and reduced by hydride donors225 (Scheme 92). 

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