Cyclohexanone pyrrolidine

Toward this end, halo-spacers 41, 42, 45 and 46 were synthesized (Scheme 2), and the appropriate chromophores were attached [56, 57], Tweezers 27 and 28 are synthesized in only 7 and 8 steps, respectively, from bromobenzene and succinic anhydride. The synthesis of 29 required 13 steps from cyclohexanone, pyrrolidine, and acrylonitrile. Although this synthesis is two steps longer than an alternative... 

A mixture of cyclohexanone, pyrrolidine, and anhydrous benzene refluxed 3 hrs. under a Dean-Stark trap, evaporated to dryness under reduced pressure, 3-hydroxy-6-piperidinomethyl-2(lH)-pyridone and anhydrous dioxane added to the resulting... 

Enamines as nucleophiles react with butadiene, and a-octadienyl ketones or aldehydes are obtained after hydrolysis[57]. This is a good way of introducing an octadienyl group at the o-position of ketones or aldehydes, because butadiene does not react with ketones or aldehydes directly. The reaction of the pyrrolidine enamine of cyclohexanone gives, after hydrolysis, 2-(2,7-octadie-nyOcyclohe.xanone (58) as the main product, accompanied by a small amount of 2,6-di(2,7-octadienyl)cyclohexanone. The reaction of the optically active enamine 59 with butadiene gave 2-(2,7-octadienyl)cyclohexanone (60) in 72% ce[58]. 

In 1954 Stork et al. (i) reported that the alkylation of the pyrrolidine enamine of cyclohexanone (5) with methyl iodide followed by acid hydro-I ysis led to the monoalkylated ketone. It was thus obvious that the enamine (7) derived by the loss of proton from the intermediate methylated iminium cation (6) failed to undergo any further alkylation. 

Johnson and Whitehead have further shown that the reductive elimination of the pyrrolidine group from the pyrrolidine enamine of 2,4-dimethyl-cyclohexanone (16), which involved treating it with a mixture of lithium aluminum hydride and aluminum chloride (9), gave the trans isomer of 3,5-dimethyl-/l -cyclohexene (17) which on subsequent hydrogenation on a platinum catalyst led to the // onr-3,5-dimethylcyclohexane (18). 

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. 

Reaction of the pyrrolidine enamine of cyclohexanone with phenyl vinyl sulfone afforded a 9 1 mixture of the tri- and tetrasubstituted isomers (2(5). The preference of the less substituted isomer in this case is in keeping with the greater overlap requirement between the n electrons of the double bond and the electron pair on the nitrogen atom, since the double bond exo to the five-membered ring is much more favored than the double bond exo to the six-membered ring. It is, however, hard to explain the formation of largely the trisubstituted isomer with the piperidine enamine of cyclohexanone, where both of the rings involved are six-membered. 

It was, however, found 22) that when the pyrrolidine enamine of cyclohexanone was allowed to react with an excess of -nitrostyrene, a bis adduct (46), made up of one molecule of the enamine and two molecules of olefin, was obtained in addition to the monoadduct. That the bis adduct is not derived from the monoadduct was shown by the latter s failure to react with (9-nitrostyrene. Therefore, this adduct must be formed by the addition of the olefin to the dipolar intermediate (47), as shown in the following scheme. 

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). 

Stork and Borowitz (36) have reported that the reaction of the pyrrolidine enamine of cyclohexanone with aromatic sulfonyl chloride led to the tetrasubstituted isomer of the sulfonated enamine (63). 

Malhotra et al. (5pyrrolidine enamine of 3-methyl-cyclohexanone, prepared under equilibrating conditions, is a 3 7 mixture of A and A isomers (67 and 68) on the basis of NMR spectral data. The preponderance of the A isomer in the mixture was attributed to strain between the equatorial methyl group and the vinylic hydrogen atom... 

Other secondary amines such as pyrrolidine, di- -butylamine, tetrahydro-quinoline, n-benzylamine, and piperidine were also found to be capable of effecting this reduction. Interestingly, morpholine does not reduce enamines as readily (47) and its acid-catalyzed reaction with norbornanone was reported (45) to give only the corresponding enamine (93), although trace amounts of the reduction product were detected when cyclohexanone was treated with morpholine under these conditions (47a). The yield of morpholine reduction product was increased by using higher temperatures. 

The only kinetic data reported are in a Ph.D. thesis (41). Integral order kinetics were usually not obtained for the reaction of a number of ketones with piperidine and a number of secondary amines with cyclohexanone. A few of the combinations studied (cyclopentanone plus piperidine, pyrrolidine, and 4-methylpiperidine, and N-methylpiperazine plus cyclohexanone) gave reactions which were close to first-order in each reactant. Relative rates were based on the time at which a 50% yield of water was evolved. For the cyclohexanone-piperidine system the half-time (txn) for the 3 1 ratio was 124 min and for the 1 3 ratio 121 min. It appears that an... 

The piperidine, pyrrolidine, and morpholine enamines of cyclohexanone substituted in the 3-position by methyl, phenyl, and l-butyl have been prepared (49). The complexity of the NMR spectra in the ethylenic hydrogen region indicated a mixture of isomeric enamines. Estimation of the per cent of each isomer by examination of the NMR spectra was not possible, nor were the isomeric enamines separable by vapor-phase chromatography. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

With enamines of cyclic ketones direct C alkylation occurs with allyl and propargyl as well as alkyl halides. The reaction is again sensitive to the polarity of the solvent (29). The pyrrolidine enamine of cyclohexanone on reaction with ethyl iodide in dioxane gave 25% of 2-ethylcyclohexanone on hydrolysis, while in chloroform the yield was increased to 32%. 

The enamines derived from cyclic ketones give the normal alkylated products, although there is some evidence that unstable cycloadducts are initially formed (55b). Thus the enamine (28) derived from cyclohexanone and pyrrolidine on reaction with acrylonitrile, acrylate esters, or phenyl vinyl sulfone gave the 2-alkylated cyclohexanones (63) on hydrolysis of the intermediates (31,32,55,56). These additions are sensitive to the polarity of the solvent. Thus (28) in benzene or dioxane gave an 80% yield of the... 

Aryl halides with a halogen activated by electron-withdrawing groups react with pyrrolidine enamines of cyclic ketones (68) to give the a-arylated ketones after hydrolysis. The enamine (28) with 2,4-dinitrochlorobenzene gave an excellent yield of 2(2,4-dinitrophenyl)cyclohexanone (88). The... 

The pyrrolidine enamine of cyclohexanone (28) has been shown to react with 0-, m-, and p-nitrobenzenesulfenyl chlorides (105). A mixture of the 2-mono- and 2,6-bis(o-, m-, and p-nitrophenylsulfenyl)cyclohexanones is obtained on hydrolysis. Only the monosubstituted derivative (155) is... 

Acrolein (19), when allowed to react with an enamine such as the pyrrolidine enamine of cyclohexanone at room temperature followed by distillation, gives an interesting bicycioaminoketone (20) in a 75 % yield (27). This... 

The similarity between the reactions of alkenes and cyclopropanes is further demonstrated by the reactions of electrophilic cyclopropanes and cyclopropenes with enamines. Cyclopropylcyanoester74, when treated with the pyrrolidine enamine of cyclohexanone, undergoes what would be a 1,2 cycloaddition in the analogous alkene case, but is actually a 1,3 cycloaddition here, to form adduct 75 (90). A similar reaction between the... 

The reaction of methyl propiolate (82) with acyclic enamines produces acyclic dienamines (100), as was the case with dimethyl acetylenedicarboxylate, and the treatment of the pyrrolidine enamines of cycloheptanone, cyclooctanone, cycloundecanone, and cyclododecanone with methyl propiolate results in ring enlargement products (100,101). When the enamines of cyclohexanone are allowed to react with methyl propiolate, rather anomalous products are formed (100). The pyrrolidine enamine of cyclopentanone forms stable 1,2-cycloaddition adduct 83 with methyl propiolate (82). Adduct 83 rearranges to the simple alkylation product 84 upon standing at room temperature, and heating 83 to about 90° causes ring expansion to 85 (97,100). 

A pseudo 1,2 cycloaddition (actually a 1,3 cycloaddition, but may be considered a 1,2 type if a three-membered ring is considered analogous to an alkene) is observed when the pyrrolidine enamine of cyclohexanone is allowed to react with N-carbethoxyaziridine (129) to produce octahydro-indole 130 91). Octahydroindoles and pyrrolidines can also be produced through the intramolecular alkylation of the enamines of certain halo-ketourethanes 176a). 

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