Stereochemistry of nitrogen heterocycles. 68. Stereochemistry of 2,5-dimethyl-4-piperidone, 2,5-dimethyl-4-piperidol, and their N-benzoyl derivatives

Abstract

The isomers of 1-benzoyl-2,5-dimethyl-4-piperidone were obtained and equilibrated (89.8% cis ⇄ 10.2% trans isomer, preferred conformations 2a, 5e, and 2a, 5a). The position of the equilibrium between the isomers of 2,5-dimethyl-4-piperidone was determined by two independent methods (89.5% trans ⇄ 10.5% cis isomer). The differences in the free energies of the isomers, the conformational energy of the Β-CH3 group, and the energy of syn-axial 1,3-interaction between the CH and the unshared electron pair were calculated; the decrease in the conformational energy of the Β-methyl group in the series of piperidine (1.6), 4-piperidone (1.47), and N-acyl-4-piperidone (1.28 kcal/mole) was explained by the successive weakening of the repulsive interaction between the Β-CH3 group and the n-pair of the nitrogen as a result of the flattening of the ring and of the conjugation between the free electron pair of the nitrogen and the π electrons of the acyl carbonyl group. The last previously unknown fourth isomer of 2,5-dimethyl-4-piperidol, which exists in the 2e,4a,5a conformation, was obtained by the reduction of cis-1-benzoyl-2,5-dimethyl-4-piperidone followed by debenzoylation. In contrast to the secondary amine, its N-benzoyl- and N-benzyl-substituted derivatives exist in the alternative 2a,4e,5e conformation. The configurations and conformations of the isomers were determined by means of the IR and NMR spectra.