The Pyrrolidine Group

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). 

Condensation of the pyrrolidine enamine of cyclohexanone with l,l-dicyano-2,2-dimethylcyclopropane proceeds smoothly in refluxing dry xylene and gives the expected adduct in 76% yield. Recrystallisation of the adduct from 95% ethanol, however, gave a 91% yield of a product which no longer contained the pyrrolidine group but whose spectral data clearly showed the presence of a ketone group and an enaminonitrile function. Hydrolysis of this latter product with phosphoric acid/acetic acid gave 5-(2-oxo-4,4-dimethylcyclopentyl)pentanoic acid in 83% yield. 

When allene derivatives are treated with aryl halides in the presence of Pd(0), the aryl group is introduced to the central carbon by insertion of one of the allenic bonds to form the 7r-allylpalladium intermediate 271, which is attacked further by amine to give the allylic amine 272. A good ligand for the reaction is dppe[182]. Intramolecular reaction of the 7-aminoallene 273 affords the pyrrolidine derivative 274[183]. 

Aldehydes take part in the cycloaddition to give the methylenetetrahydrofuran 178 by the co-catalysis of Pd and Sn compounds[115]. A similar product 180 is obtained by the reaction of the allyl acetate 179, which has a tributyltin group instead of a TMS group, with aldehydesfl 16]. The pyrrolidine derivative 182 is formed by the addition of the tosylimine 181 to 154[117]. 

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]. 

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. ... 

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. 

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... 

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... 

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. 

The general rule has been formulated (P) that the less substituted enamine is formed from unsymmetrical ketones such as the 2-alkylcyclohexanones. In enamine 21 the R, group and the N-alkyl groups would interfere with one another if overlap is to be maintained between the nitrogen unshared electrons and the double bond. There would be less repulsion if the isomeric enamine (22) were formed. 2-Phenylcyclohexanone and pyrrolidine with p-toluenesulfonic acid as catalyst in refluxing benzene gave enamine... 

Vinylogous amides, which have an enamine function in conjugation with a carbonyl group, constitute tridentate systems and thus open the possibility of alkylation on carbon, nitrogen, or oxygen. It has been found that the pyrrolidine enamine of acetylacetone gives rise to a carbon mcthylation but an oxygen ethylation product 41). The alkylation of cyclic 1,3-diketone-derived enamines has been studied 41,283). O Alkylation was found in alcohol solvents and predominant C alkylation in nonprotonic solvents. 

The selective bromination of a ketone in the presence of another susceptible functional group was achieved in a diterpene synthesis 240). A competing bromination of an anisole ring could be avoided here through the use of a pyrrolidine enamine derivative for activation of the methylene group adjacent to the carbonyl function. 

The phthalimido group is susceptible to basic reagents and thus must occasionally be protected. This is accomplished by treatment with pyrrolidine to open the ring (>90%), which can be closed by treatment with HE, B(0H)3, the, H2O, 73-99% yield. ... 

Ammonia treatment removes the TFA group, which then releases the phosphate and pyrrolidine through intramolecular cyclization. The analogous pentyl derivative was also prepared. ... 

Imines with an electron-withdrawing group at the nitrogen atom are excellent acceptors for the acetate (1) or the carbonate (13) [36]. Thus, N-tosylimines (84) gave very good yields of pyrrolidines (85) under typical conditions. The strained cyclic imine (86) and a,/ -unsaturated imine (87) both participated smoothly in the cydoadditions. The hindered nitrimine (88) also reacts well with (1) (but not with 13) to produce the pyrrolidine (89) with a 17 1 diastereoselectivity. However, the unhindered nitrimines from cyclohexanone and 2-nonanone failed to react presumably due to enolization (Scheme 2.24). 

Extension of the alkyl group on the carbon bearing the amine changes the pharmacologic profile. Reductive amination of 1-phenylbutanone-2 (60) with pyrrolidine in formic acid gives pro-litane (61), a central nervous system stimulant agent with antidepressant properties. 

Treatment of that intermediate with aluminum chloride leads to selective demethylation of that ether para to the carbonyl group (23). Cyclization by means of tosic acid gives the dihydronaphthalene nucleus (24). Alkylation of the phenol with N-(2-chloroethyl)pyrrolidine affords nafoxidine (25). ... 

Optically active 2-allylpiperidines and -pyrrolidines arc obtained by treating hydroxylactams containing the l-[(S)-l-arylethyl]substituent as an auxiliary (see Appendix) with tin(IV) chloride and trimethyl(2-propenyl)silane46. Interestingly, the moderate diastereoselection when the aryl group is phenyl decreases when 2-chlorophenyl is used, whereas the sense of the stereoselectivity reverses for 2,6-dichlorophenyl or pentachlorophcnyl. These results are rationalized by application of molecular orbital theory and substrate conformational preferences46. 

---