Ketone enamino ketones

If a molecule contains both a ketonic and aldehydic carbonyl group, a secondary amine will react with the aldehydic carbonyl group to give a -enamino ketone (15). This has been shown not only for 2-formylcyclo-hexanone (14) (32,33) but also in steroidal systems when the aldehyde and ketone groups are in five- or six-membered rings (34). 

The above considerations presuppose that two important conditions are fulfilled. First the nitrogen must be tertiary, as primary and secondary vinylamines are generally more stable in the imine form (5). Only in the case of enamino ketones and esters are the enamine more stable than the imine forms (7). Secondly, the atoms comprising the tt system must be able... 

Enamino ketones can protonate not only on nitrogen or carbon but also on oxygen to give 12,13, and 14, respectively. Enamino ketones form stable perchlorates, chlorides, bromides, and iodides, and examination of their infrared (21,22), ultraviolet (23), and nuclear magnetic resonance (24,25) spectra show these salts to be O protonated. The salts of 4-dialkylamino-... 

Alkylation of enamino ketones occurs on oxygen, as would be expected from the site of protonation. Thus 4-N-pyrrolidino-3-penten-2-one (47) gave N-(2-ethoxy-2-penten-4-ylidene)-pyrrolidinium iodide (48) on alkylation with ethyl iodide (22), and the enamino ketones derived from 5,5-... 

Even 5,5-dimethyl-3-cyclohexylaminocyclohex-2-en-l-one (52), the mono-Schiff s base derived from the 1,3-diketone which is stable in the enamino ketone form (7) and theoretically could alkylate on nitrogen, gave the O-alkylated product (53) (23). 

In a similar manner it was shown (47) that the enamino ketone (54) on treatment with ethyl iodide gave an intermediate hydroiodide from which 7-ethoxy-2,3,4,5,6,10-hexahydroquinoline (55) was obtained on treatment with base. The corresponding N-alkylated product was obtained by alkylation of (54) in the presence of sodium hydride. 

Enamino ketones and esters also react with dimethyl acetylenedicarboxylate (67). Again cycloaddition appears to occur and the unstable cyclobutene intermediates rearrange to give insertion of two carbon atoms. 

The enamino ketone 5,5-dimethyl-l-pyrrolidinocyclohex-l-en-3-one (49) on treatment with dimethyl acetylenedicarboxylate and subsequent hydrolysis yielded 2,3-dicarbomethoxy-7,7-dimethyl- 1-hydroxy-5-oxo-1,3-cyclooctadiene (79). 

A particularly interesting case is the reaction of the enamino ketone (47), which under similar conditions gives the intermediate product (80), which then undergoes cyclization to the benzene derivative dimethyl 3-pyrrolidino-5-methyl phthalate (81). 

Much less work has been done on the arylation of enamino ketones. The enamino ketone (49) has been allowed to react with 2,4,6-trinitrochloro-benzene. In this instance the latter reacts as the acid chloride of an acid the anion of which is a good leaving group (46). This type of reaction will be discussed in Section IV.A. 

Reactions of quinones with enamino ketones have not been reported, but ethyl (S-anilinocrotonate (94), an enamino ester, has been shown to condense (71) with p-benzoquinone to give l-phenyl-2-methyl-3-carbethoxy-5-hydroxyindole (95). 

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 reaction of ketene with the enamine (113) is reported (88) to give l-morpholino-2-acetyl-l-cyclohexene i.e., the enamino ketone expected from acylation of (113). The pyrrolidine enamine (28), however, has been shown to react (73) with excess ketene to give the a-pyrone (124). On the... 

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]. 

Acylation with aromatic acid chlorides was believed to occur on carbon 91). The dibenzoylation of the enamine (113) with benzoyl chloride in the presence of triethylamine has, however, been shown to give a mixture of three products (92). The major components are the cis and Irons isomers of the O-acylated enamino ketone (Ola and b) and the minor isomer is the 2,6-diacylated enamine (132). 

It would thus appear that O acylation is the normal course of the acylation of enamino ketones. Surprisingly the enamino ketones 49 and 50 undergo reaction with acid chlorides not having an a-hydrogen (e.g., benzoyl and pivalyl chlorides) to give the products of C acylation (133). 

It is of interest to note that 2,4,6-trinitrochlorobenzene reacts similarly with 49 to give the cation of 138 isolated as the perchlorate. In the reaction of the enamino ketone (50) with trichloroacetyl chloride (77) the chloro-... 

Methanesulfonyl chloride reacts with enamino ketones (104), (e.g., 151) to give good yields of the enol sulfones (e.g., 152). The analogy with ketene addition to form a-pyrones (Section IV.A) is obvious. 

In the reaction with enamino ketones derived from dimedone (e.g., 49) p-toluenesulfonyl chloride gives the chloroiminium cation (138) isolated as the perchlorate. This indicates that initial O sulfonation is followed by addition of chloride ion and subsequent expulsion of tosylate (42) in a manner similar to the trichloroacetyl chloride reaction with 49 (Section IV.A). 

The enamino ketone 49 has also been found to react with o-nitrobenzene-sulfenyl chloride to give the derivative 156, having the o-nitrophenylthio group substituted in the 2 position (93), i.e., the same position at which normal acylation with acid chlorides takes place. 

The reaction of enamino ketones with isocyanates and isothiocyanates has not been studied extensively. The enamino ketone (162) has been shown to react with phenyl isothiocyanate to give 163, the product of C acylation 114). Enamino ester derivatives of acetoacetic ester react similarly with isothiocyanates, also giving the C-acylated products 115). 

The enamino ketone (49) was reported to give no identifiable products on reaction with N,N-dimethyl carbamoyl chloride 63). However, reaction of (49) with N,N-diethyl carbamoyl chloride in refluxing chlorobenzene gave the N-(3-diethyl-amino-5,5-dimethylcyclohex-2-en-1 -ylidene)pyrrolidinium salt, isolated as the perchlorate. The latter must have been formed as outlined in Scheme I, involving initial O carbamoylation followed by an addition-elimination reaction to give 138 cation which can react with diethylamino anion by a further addition-elimination displacement to give the product 46). 

Zl -Pyrrolines have been isolated from the hydrogenation products of y-ketonitriles (23-26) and in a large number of reactions during which enamino ketones are formed as intermediates. The preparation of pyrrolines from anhydro-5-hydroxyoxazolinium hydroxides (13, R, R" = Ph, R = Me) is also important (27). By the reaction of 13 with styrene, l-methyl-2,3,5-triphenyl-/l -pyrroline (14) is formed. 

The general method for preparation of heterocyclic enamino ketones, amide vinylogs, consists of a cyclization reaction (Scheme 6). The most convenient technique involves heating the starting substance in acetonitrile in the presence of silver perchlorate 137-139). 

Secondary enamino ketones such as - -octahydro-7-quinolone (64) furnish a mixture of N- and C-alkylated bases, 120 and 121, respectively, on treatment with ethyliodide (168). Alkylation of tertiary enamino ketones as, for example, 101 proceeds exclusively on the oxygen-atom, forming product 122 (206). 

Reaction of organometallic compounds with enamine salts have been successfully used for the synthesis of some natural products (256). Thus reaction of the immonium salt of 0-alkylated enamino ketone 122 with isobutyllithium affords the compound 169. 

Reactions of enamines with selenium dioxide gave low yields of enamino ketones (J8). Aromatization of cyclohexanone derived enamines eould be largely prevented by the use of aeetonitrile as solvent for the reaction. Even then, yields were eonsiderably below the limit of 50%, imposed by the generation of an equivalent of water. 

Conditions were also arrived at whereby one could obtain without rearrangement the cyclization product 31 from enamino-ketone 30. ... 

The condensation of nitro ilkenes with enamino- ketones or enamino-esters CGrob-Camenisch reacdoni has been v/idely used for pyrrole synthesis fEq. 10.4. This process is now carried out v/ith resin-boiind enamino-ketones for combinatoriM syntheses of pyrroles. ... 

Intermolecular befera-Diels-Alder reactions of enamino ketones with highly substituted vinyl ethers. Effect of high pressure on the kinetics and diastereoselectivity [77]... 

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). 

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