The acylation of enamines

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. 

In Chapter 26 we saw that reliable C-alkylation occurs with reactive allyl halides and a halo-carbonyl compounds, but that unwanted N-alkylation often competes with simple alkyl halides. 

Acylation with acid chlorides could follow the same two pathways, but with one big difference. The products of N-acylation are unstable salts and N-acylation is reversible. Acylation on carbon, on the other hand, is irreversible For this reason enamines end up acylated reliably on carbon. 

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. 

Combining the enamine with the acid chloride led to a clean acylation at carbon in 82% yield and eventually to a successful synthesis of the natural product longifolene. 

---

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). 

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 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. 

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-... 

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... 

Arens discussed the homovalent class with odd numbers of atoms, shown in equations (1) and (3). These he described with the operator (H—) C, in which s= 2, 3,4,... and C means that the last bond listed remains unchanged, i.e., constant. The pericyclic dipolar cycloaddition of nitrile oxides with acetylenes is shown and coded in Scheme 5, with the bonds labeled clockwise from the top and the constant N-O <7-bond coded as (1). Recognizing that reactions normally written linear, as in equation (1), may equally be presented as cyclic, like equation (3), he shows the acylation of enamines... 

Acylation of Enol Ethers, Ketene Acetals, and Enamines. Enol ethers, ketene acetals (eq 24), and enamines (eq 25) react with PhCOCI to provide the corresponding p-acylated products (eq 24). The acylation of enamines has been extensively studied (eq 25) the resulting P-acyl enamine is generally hydrolyzed to give p-diketones (eq 25). 

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

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). 

Hunig and Salzwedel (20) report that the acylation of the pyrrolidine enamine of 3-methylcyclohexanone with propionylchloride followed by the hydrolysis and the base cleavage of the resulting dione isomers (71) and (72) and subsequent reduction of the keto groups gave a 3 7 mixture of the carboxylic acids (73 and 74), respectively. Vig et al. (39), however, found o o o o... 

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... 

More recently the acylation of aldehyde enamines has been reinvestigated (75) and shown to proceed normally when the enamine is added to the acid chloride. The morpholine enamine of isobutyraldehyde (98), on being added to an ether solution of acetyl chloride, afforded the iminium salt (99), from which the ketoaldehyde (100) was obtained in 66% yield by hydrolysis (75). 

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 enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

The treatment of enamines with acid halides which possess no a hydrogens results in the simple acylation of the enamine (7,12,62-67). If the acid halide possesses an a hydrogen, however, ketenes are produced in situ through base-catalyzed elimination of hydrogen chloride from the acid halide. The base catalyst for this reaction may be the enamine itself or some other base introduced into the reaction mixture such as triethylamine. However, if the ketene is produced in situ instead of externally, there still remains the possibility of a side reaction between the acid halide and the enamine other than the production of ketene (67,84). 

This is illustrated by the reaction of enamine, 113 with sulfene to produce adduct 114 in an 80 % yield (146). The product 114 was also observed in an 18% yield from the reaction of diazomethane, sulfur dioxide, and enamine 113 (153). It was demonstrated that this cyclization reaction must involve sulfene adding to the enamine directly and not acylation of the enamine by... 

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

The reaction of enamines with ketenes can be conveniently carried out by generating the ketene in situ from an acyl halide and a tertiary amine. 

The nucleophilicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael addition. 

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... 

This product is then treated with acryloyl chloride. The initial step in this case probably involves the acylation of nitrogen on the enamine conjugate addition then completes the formation of the lactam ring (23-5). Treatment of that product with triethyl silane then reduces the ring unsaturation and cleaves the benzylic nitrogen bond on the auxiliary to yield (23-6) as the optically pure tmns isomer. Displacement of bromine with the mercapto benzthiazole (23-7) completes the synthesis of izonsteride (23-8) [25]. 

C(R)=NR group with a nitrilium salt RCssNR .222 The acylation of the enamine can take place by the same mechanism as alkylation, but another mechanism is also possible, if the acyl halide has an a hydrogen and if a tertiary amine is present, as it often is (it is added to neutralize the HX given off). In this mechanism, the acyl halide is dehydrohalogenated by the tertiary amine, producing a ketene (7-14) which adds to the enamine to give a cyclobutanone (5-49). This compound can be cleaved in the solution to form the same acylated imine salt (27) that would form by the more direct mechanism, or it can be isolated (in the case of enamines derived from aldehydes), or it may cleave in other ways.223... 

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,... 

Reaction of phosphorus pentasulfide with j3,8-triketones leads to l fiayS -trithiapentalenes.1,2-8> 52 This was the first synthesis of trithiapentalenes known, but its development was delayed until practical methods for preparing 3,8-triketones were available. One of these procedures is the acylation of ketones in the presence of sodium hydride.53 Another method begins with the diacylation of the enamine derived from a cyclanone.38... 

---