Lactams. VII. Stereochemical Characterization and Cis-Trans Isomerization of 5-Ethyl-2-oxo-4-piperidineacetic Acid and Related Compounds

The stereochemistry of pairs of isomers found for 5-ethyl-2-oxo-4-piperidineacetic acid (I) and its derivatives [methyl ester (II), ethyl ester (III), and 1-benzyl derivative (IX)] has been established by interrelation of I with cincholoipon ethyl ester [(+)-VIIb], derived from the alkaloid cinchonine, through 3-ethyl-4-piperidineethanol (IV). trans-Acid IXa has been prepared by benzylation of trans-lactam ester IIIa and subsequent alkaline hydrolysis of the N-benzylated product (XIa) ; cis-acid IXb, by the alkaline hydrolysis of lactam ester Xb obtained from lactim ether VIIIb by the reaction with benzyl bromide. The lactim ether (VIIIb) has been synthesized from cis-lactam ester IIb the methylation with dimethyl sulfate in boiling benzene. It has been found that on thermal treatment at 180° either cis-acid IXb or trans-acid IXa is partially isomerized to give an equilibrated 67 : 33 mixture of IXa and IXb in 50 min. Under the same conditions the N-unsubstituted trans-acid (Ia) attains to an equilibrium faster than IXa, resulting in 33% conversion into Ib in 8 min. At 210° cis-acid Ib undergoes isomerization very rapidly to produce an equilibrated mixture of the same composition. In boiling 6 N hydrochloric acid either IXa or IXb gives an equilibrated 57 : 28 : 15 mixture of IXa, IXb, and the ring-opened product (XIII, R=C6H5CH2) within 28 hr. In contrast, the methyl esters (IIa, b, Xa, b) of these acids have been found not to suffer such a cis-trans isomerization at 180° over a period of at least 1 hr. On the basis of these findings, mechanisms of the observed isomerizations are discussed.