J’-Pyrrolines

The reactivity of the methylene group adjacent to the lactam group affords the possibility of a Claisen condensation. Thus, treatment of 2-pyrrolidone or 2-piperidone with ethyl oxalate leads to the J -pyrroline-carboxylic (70) and, d -piperideine-2-carboxylic acids (71), respectively. N-methyl lactams furnish N-methyl derivatives (72,73) (Scheme 3). 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

A -Pyrroline-N-oxides when unsubstituted in the 2 position readily add hydrogen cyanide. The 1 -hydroxy-2-cyanopyrrolidines thus formed undergo oxidation to 2-cyano-J -pyrroline-N-oxides. 

The dimer of 1-methyl- -pyrroline (39) was obtained by reduction of N-methylpyrrole with zinc and hydrochloric acid (132) and, together with the trimer, by mercuric acetate dehydrogenation of N-methylpyrrolidine (131). J -Pyrroline-N-oxides form dimers in a similar manner (302). Treatment of 1,2-dimethyl-zl -piperideine with formaldehyde, producing l-methyl-3-acetylpiperidine (603), serves as an example of a mixed aldol reaction (Scheme 18). 

If the amino group forms part of the ketone, as it does with y-87, 88 and 8-amino-ketones,89,90 heterocyclic enamines are obtained. 1,2-Dialkyl-J2-pyrrolines and 1,2-dialkyl-J2-piperideines (15) are formed from secondary amino groups, whereas primary amino groups 91 lead to 2-alkyl-J pyrrolines and 2-alkyl-J -piperideines. Gabriel90 used the suitably substituted phthalimidoketone for the synthesis of the alkaloid y-coniceine (15 R = H, R = n-Pr, n = 2). 

The Hofmann degradation of 8-benzoylpropionamide takes a similar course and leads to the formation of 2-phenyl-J -pyrroline.90... 

By contrast, addition of hydrogen cyanide to J -pyrrolines yields stable nitriles, which are reduced by lithium aluminum hydride to diamines and can be saponified to acids318 (Scheme 14). 

The simplest compounds, J -pyrroline and A 1-piperideine, are similar both exist as trimers. Various products of the auto-condensa-tion of A 1-piperideine (114) have been described by Schopf et aZ.,339 including two geometric isomers, a and / , of the trimer 113. An equilibrium has been found to exist between A 1-piperideine and the trimer which, therefore, reacts as a typical aldehyde-ammonia. The trimer rearranges spontaneously at pH 9-10 and 26° C in an almost quantitative yield to isotripiperideine (115)340,341 which, in turn, is in equilibrium with tetrahydroanabasine (116) and bond formed by an aldol... 

In contrast to proline, 3,4-dehydro-DL-proline (167) does not give a color with isatin. The reaction proceeds to give 168 and the mechanism of formation has been discussed. Both cis- and react with isatin to give 168. A... 

The carbapenems are mechanism-based inhibitors which involve acylation of the active-site residue and subsequent rearrangement to a more stable acyl-enzyme species. Knowles and co-workers [32, 33] have demonstrated that the progressive inhibition of the TEM S-lactamase by the olivanic acids is due to the rearrangement of the J -pyrroline intermediate (15) to the tautomeric and thermodynamically more stable zl -pyrroline (16) Scheme 6.3). The resultant acyl-enzyme complex is believed to be stable to subsequent hydrolytic breakdown, thereby disrupting the catalytic activity of the enzyme. 

Diphenylmethylene)-2,2,3-trimethyl-l-phenyl-J -pyrroline (25, R = R =Me) Typical Procedure ... 

An ethereal soln. of N-sulfinylaniline added dropwise during 0.5 hr. to a Dry Ice-acetone-cooled ethereal soln. of 4,5,5-trimethyl-/d -pyrroline 1-oxide, and allowed to stand 1 hr. at room temp. 2-anilino-4,5,5-trimethyl-J -pyrroline. Y 74%. F. e. and limitations s. O. Tsuge, M. Tashiro, and S. Mataka, Tetrah. Let. 1968, 3877. 

A soln. of phenylazirene in excess methyl acrylate irradiated under N, with Vycor-filtered light from a 450 w. Hg-arc -> 2-phenyl-4-carbomethoxy-J pyrroline. Y 80%. F. e. s. A. Padwa and J. Smolanoff, Am. Soc. 93, 548 (1971). 

Potassium tert-butanol Pyrrole-2-carboxylic acid esters from tosylglycine esters via 3-hydroxypyrrolidine- and J -pyrroline-carboxylic acid esters... 

Oxazolincs and J -pyrroline-3,4-diols from 2 a-hydroxyketonc molecules... 

J -pyrroline-2-carboxamides quinaldoamides N-a-siloxycarboxylic acid amides... 

J -Pyrroline-2-carboxylic acid can be separated from J -pyrroline-5-carboxylic acid on silica gel G layers, using chloroform-methanol-concentrated ammonium hydroxide (50 + 25 + 25) [51]. 

The orientation of the groups in the J -pyrrolines obtained from the photoaddition process is essentially identical to that observed by Huisgen in... 

Whereas the cycloaddition of arylazirines to electron-deficient olefins produces J -pyrrolines, a rearranged isomer is formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This intramolecular electrocyclization reaction was first observed by Padwa and Smolanoff using 2-vinyl-substituted 2/f-azirines. Irradiation of 2i/-azirine 107 afforded a 2,3-disubstituted pyrrole (108), while thermolysis gave a 2,5-disubstituted pyrrole (109). Photolysis of azirine 110 proceeded similarly and gave 1,2-diphenylimidazole (111) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of 110 which afforded l,3-diphenylp3nrazole... 

Pyrrolecarboxylie acids. A heterogeneous mixture of l,3-dicarbethoxy-4-methoxy-J -pyrroline and aq. Ba-hydroxide boiled 4 hrs. pyrrole-3-carboxylic acid. Y 60%. F. e. s. H. Rapoport and G. D. Willson, J. Org. Ghem. 26, 1102 (1961). 

Equimolar mixtures of allyl isocyanide and benzaldehyde in toluene heated 12 hrs. at 80° under Ng in the presence of a catalytic amount of CU2O -> product. Y 95%. F. e., also J -pyrrolines from ethylene derivs. and isonitriles, s. T. Sae-gusa, I. Murase, and Y. Ito, Bull. Chem. Soc. Japan 45, 830 (1972). 

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