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

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 -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 -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 -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 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.For Communication 67, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 953–961, July, 1989.