Enamines of cyclohexanone

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. 

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

In a similar manner the addition of ethyl azodicarboxylate to the morpholine enamine of cyclohexanone furnished the less substituted isomer (34) with the substituent in the axial orientation (2, 26). 

However, when the bulky substituent is no longer present at the electrophilic carbon atom, the addition of the olefin to the morpholine enamine of cyclohexanone leads largely to the tetrasubstituted isomer. For instance the reaction of this enamine with phenyl vinyl sulfone gave a 1 3 mixture of... 

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. 

Risaliti et al. (2J) have also studied the addition of 2-nitropropene, which also lacks any substituent at the electrophilic carbon atom, to the morpholine enamine of cyclohexanone. The product, as expected, was the tetrasubstituted isomer, the formation of which may be envisioned via the transition state (42). 

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. 

The reaction of morpholine enamine of cyclohexanone with 1 mole of phenyl isocyanate has been reported (30,31) to give the monoadduet (49), consisting largely of the trisubstituted isomer, and with 2 moles of phenyl isocyanate, the bis adduct (50). That the bis adduct is a dicarboxyanilide rather than a urea derivative (32) such as 51 was shown by its mild hydrolysis to the ketone (52). Reaction of the morpholine enamine of 2-methylcyclo-... 

The reaction of the morpholine enamine of cyclohexanone with phenyl isothiocyanate led only to the tetrasubstituted isomer of the monoadduct (54), which failed to add any more of the phenyl isothiocyanate. The formation of only the tetrasubstituted isomer has been attributed by Hunig et al. (37) to the stronger conjugation of the C=S group with the enamine double bond than that of the C=0 group in the enamine (49). 

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). 

Campbell and Jung (34) have reported that the reaction of 2 moles of o-halo-substituted benzoyl chloride with the morpholine enamine of cyclohexanone gave the corresponding 2,2-dibenzoyI derivative (57). 

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). 

In the NMR spectrum of the N-methylaniline enamine of cyclohexanone (135), the vinylic proton appears at a much lower field, i.e., at 324 Hz (75). Here the electron pair on nitrogen tends to conjugate with the phenyl group thus exhibiting a very small degree of overlap with the enamine double bond. 

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. 

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 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... 

The first reported cyclization involving an enamine was the 1,4 cycloaddition of methyl vinyl ketone with the enamine of cyclohexanone to give. 

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... 

Nitroolefins also offer the possibilities of 1,2 cycloaddition (37,57) or simple alkylation (57-59) products when they are allowed to react with enamines. The reaction of nitroethylene with the morpholine enamine of cyclohexanone led primarily to a cyclobutane adduct in nonpolar solvents and to a simple alkylated product in polar solvents (57). These products are evidently formed from kinetically controlled reactions since they cannot be converted to the other product under the conditions in which the other... 

Cyanoallene, when treated with the morpholine enamine of cyclohexanone, undergoes a 1,3-cycloaddition reaction to form 72 (89). The reaction between cyanoallene and diendiamine 73a produces di-1,2-cycloaddition adduct 73 (i 9). The 4a-azonioanthracene ion (73b) readily undergoes a 1,4-cycloaddition reaction with nucleophilic dienophiles such as enamines (89a). The cycloaddition is stereoselective so that the a- and... 

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). 

Addition of dichlorocarbene (88) to the enamine of cyclohexanone gives a relatively stable adduct 89 n = 4) 103-105). Hydrolysis of this adduct... 

Adduct 100 is formed from the 1,4 cycloaddition of o-quinone (99) with the morpholine enamine of cyclohexanone (125). Treatment of styrene oxide with cyclic enamines at elevated temperatures (about 230°C) produces O.N-ketals possessing a furan nucleus (125a). 

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

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). 

The reaction of isobenzofuroxan (131) with the morpholine enamine of cyclohexanone results in a 1,4 cycloaddition to form quinoxaline-di-N-oxide 132 (777). Quinone dibenzenesulfonimide has been found to undergo... 

Nitrilimines can be produced by treating halogenated hydrazones with a base such as triethylamine. These nitrilimines undergo 1,3 cycloaddition with enamines to form pyrazoles (181-183). This is shown by the reaction of the pyrrolidine enamine of cyclohexanone with diphenyinitrilimine to... 

The illumination of enamines as general activa ting derivatives of ketones in alkylation reactions also threw light on their special usefulness for controlling alkylations (3), particularly in the formation of monosubstituted cyclohexanones. Thus 2-methylcyclohexanone could be obtained in 80% yield from the pyrrolidine enamine of cyclohexanone, and further alkylation, which required more drastic conditions, gave only 2,6-dimethylcyclo-hexanone (1,237). 

The procedure is the same as that described in Chapter 9, Section T for the preparation of the morpholine enamine of cyclohexanone. In place of morpholine, pyrrolidine (12.8 g, 0.18 mole) is used. The product is collected at 114-115715 mm, 1.5200. 

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

The reaction of the enamines of cyclohexanones with a,ft-unsaluraled sulfones gives mixtures resulting from attack of the enamine at the a- and /(-carbons of the oc,/ -unsaturated sulfone. The ratio of x- and /1-adducts is dependent upon the reaction solvent, the geometry and structure of the sulfone1 4. The diastereoselectivity of these reactions is also poor. The reaction of lithium enolates of cyclic ketones with ( )-[2-(methylsulfonyl)ethenyl]benzene, however, gives bicyclic alcohols, as single diastereomers, that result from initial -attack on the oc,/ -unsaturated sulfone5. 

The pyrrolidine enamine of cyclohexanone 675 react, with 746 in THF/acetoni-trile to form, via 760, the bicyclic ketoester 761 in, as yet, only ca 30-40% yield... 

Enamines also react with electrophilic alkenes to give conjugate addition products. The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction.319 This is anticipated on stereoelectronic grounds because the tt orbital of the enamine is the site of nucleophilicity. 

Treated with ZnBr2 followed by enamines, phenyl thioethers 829 derived from aryl aldehydes are converted to (l-(phenylthio)alkyl ketones or aldehydes 830 in moderate to good yields (Equation 19). Enamines used in these syntheses are (1) morpholine enamine derived from diethyl ketone, (2) diethylamine enamine of propiophenone, (3) piperidine enamine derived from isovaleraldehyde, and (4) pyrrolidine enamine of cyclohexanone <2000H(53)331>. 

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