Pyrrolidine enamines

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]. 

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

Androst-4-ene-3,l 1,17-trionehas been converted into several 3,17-dienamine derivatives which, on reduction with LiAlH4 followed by removal of the protecting groups, give 11 jS-hydroxyandrost-4-ene-3,17-dione. An unsaturated 3-ketone has also been protected as an enamine in the LiAlH4 reduction of a 21-ester group a further example is the conversion of 7-methylene-5a-an-drostane-3,17-dione into the 3-pyrrolidine enamine followed by reduction of the 17-ketone by Li[OC(CH3)3]3 AlH. ... 

The A -3-keto system (176) has been the subject of several deconjugation studies including the use of pyrrolidine enamine (see ref. 94 and references cited therein). 

Steroidal A -dienamines are formed with a high degree of selectivity in the presence of 17- or 20-ketones. Preparation of morpholine and pyrrolidine enamines is achieved by azeotropic removal of water with or without a catalyst. Pyrrolidine enamines are also formed efficiently by addition of the base to the hot solution of the ketone in methanol followed by immediate cooling. ... 

Cyanogen azide is a useful reagent for conversion of pyrrolidine enamines of 3-keto steroids to A-norsteroids. " Ring contractions can be carried out in the presence of 17j5-hydroxy, 17j -acetoxy, 20-keto groups and isolated double bonds. In a typical procedure, 17j -hydroxy-5a-androstan-3-one (partial formula 8) is converted into the enamine (9) by pyrrolidine in benzene... 

Pyrolysis of pyrazolines, 102, 103 Pyrrolidine enamines, 412 2a-(N-pyrrolidinylcyanomininomethy 1) -A-nor-5a-androstan-17ftol, 415... 

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. 

The pyrrolidine enamine of 2-methylcyclohexanone (7) was in fact found to be quite inert toward further alkylation and was shown to consist only of the trisubstituted isomer (4) on the basis of the NMR spectral data. The... 

That the methyl group in the pyrrolidine enamine of 2-methylcyclo-hexanone (7) is in fact axial was demonstrated by Johnson and Whitehead (8). They found that careful hydrolysis of the pyrrolidine enamine of the conformationally more stable system, i.e., 2-methyI-4-t-butylcyclohexanone (13), led to a 1 4 mixture of cis and trans isomers of the ketone (14 and 15), showing that the methyl group in the enamine is largely in the axial orientation. 

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). 

Karady et al. (72) report that the alkylation of the pyrrolidine enamine of 4-alkycyclohexanone was found to be subject to stereoelectronic control the product of hydrolysis under nonequilibrating conditions led largely to the tra i-2,4-dialkylcyclohexanone. 

The increase in the proportion of the tetrasubstituted isomer in the cases of the morpholine and piperidine enamines of 2-methylcyelohexanone has been ascribed to both steric and electronic factors. The authors propose that the overlap of the electron pair on the nitrogen atom and the v electrons of the double bond is much more important in the case of the pyrrolidine enamines and much less with the others. Support for this postulate was provided by the NMR spectra of these enamines, wherein the chemical shifts of the vinylic protons of the pyrrolidine enamines were at a higher field than those of the corresponding morpholine and piperidine enamines by 20-27 Hz. The greater amount of overlap or electron delocalization, in the case of pyrrolidine enamine, is in accord with the postulate of Brown et al. (7- ) that the double bond exo to the five-membered ring is more favored than the double bond exo to the six-membered ring. 

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. 

Kuehne and Foley (29) have found that the reaction of the pyrrolidine enamine of butyraldehyde with 2 equivalents of (8-nitrostyrene also led to a bis adduct with the structure as shown in 48. 

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. (5methyl-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... 

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... 

In the steroidal series Heyl and Herr (40) have reported that the pyrrolidine enamine of 5a-cholestan-3-one consisted of a mixture of and A isomers (78),... 

Interestingly the pyrrolidine enamine of 3-t-butylcyclohexanone (41) consists of a 3 2 mixture of A and A isomers (79 and 80). The preference for the A isomer in this case is due to the relief of two of the four skew butane interactions, which are present in the isomer. The A isomer, owever, contains two additional interactions, i.e., one modified skew utane interaction 0.4 kcal/mole (42) and one interaction between c C-2 vinylic hydrogen atom and the ethyl portion of the t-butyl group hich is pointed toward it. 

In the five-membered ring compounds, much less is known about the position of the double bond in the enamincs of 3-alkyl ketones. Demole and Stoll 43) carried out the alkylation of the pyrrolidine enamine of methyl 1 -oxo-3-cyclopentylacetate (81) with bromopentyne-2 to give a 4 5 mixture of C-2 and C-5 alkylated products (82 and 83). 

Lochte and Pitman (44) have reported the cyanoethylation of the pyrrolidine enamine of 3-methylcycIopentanone (84), the product being a mixture of C-2 and C-5 cyanoethylated ketones (85 and 86). Hunig and Salzwedel 20) have obtained a mixture of C2- and C5-acylated products from the reaction of morpholine enamine of 3-methylcyclopentanone with propionyl chloride. 

Another interesting fact to be noted is that the bicyclic enamine (87) and its pyrrolidine analogue failed to undergo reduction with 98% formic acid, whereas the pyrrolidine enamine of 2-bicyclo[2.2.1]hepten-5-carboxalde-hyde (94), which exists largely in the transoid form (49), was readily reduced to (95). However, the saturated amine-substituted norbornane can be obtained directly from norbornanone under the more vigorous conditions of the Leuckart reaction (49a). 

The pyrrolidine enamines of /l -3.]cetosteroids (111), on alkylation with methyl iodide, gave mainly the N-alkylated product (5,55) in nonpolar solvents such as benzene. The reaction in more polar solvents gave the 4-methylated product (5.S). The reaction of (111) with perchloryl fluoride involves attack at the C-4 atom to give, after acid hydrolysis, either 4-fluoro-zJ -3-ketone (119) or 4,4-difluoro-zJ -3-ketone 120), depending on the reaction conditions (59). 

The pyrrolidine enamine of cyclopentanone, in which the double bond is exocyclic to two five-membered rings, shows the vinylic proton at 237 Hz (7S). 

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

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%. 

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 basicity of the enamine has an overriding influence on the yield of product. Good yields are obtained from the pyrrolidine enamines, poor yields from the piperidine enamines, and the morpholine enamines fail to... 

Low yields of C-arylated ketones have also been obtained by reaction of pyrrolidine enamines with diaryl iodonium salts (68). 

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 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 pyrrolidine enamine of 2-tetralone (177) was converted to l-cyano-2-tetralone, which exists almost entirely in the enolic form (178), by reaction with cyanogen chloride (J23). Reaction of 177 with cyanogen bromide gave N-naphthylpyrrolidine (179), presumably via the unstable bromoenamine (180). The latter observation is in accord with the mode of reaction of the heterocyclic enamine (126) with cyanogen bromide, which resulted in the... 

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 reaction between the pyrrolidine enamine of butyraldehyde (52) and )3-nitrostyrene (53) provides cyclobutane adduct 54 quantitatively in either petroleum ether or acetonitrile solvent, but in the more polar ethanol solvent a 2 1 condensation product occurred. The structure of the product was shown to be 55 (57). 

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