Determination of the N-invertomer stereochemistry in N-substituted nortropanones and norgranatanones using computational and NMR methods

Abstract

Several N -substituted nortropane and norgranatane derivatives were synthesised from tropinone and granatanone. The equilibrium distributions of the axial and equatorial N- invertomers of the free amine forms of the prepared products in methanol and their protonated forms (hydrochlorides) in water were studied by low-temperature and room-temperature NMR spectroscopy. Theoretical distributions in the gas phase, methanol and water solvents were calculated using DFT methods and compared with inverse gated 13 C NMR experiments. DFT calculations provided results in reasonable agreement with experimental data. Equatorial invertomers dominated in N-tert -butyl- and N- benzylnortropinone, and the equatorial/axial ratio for N- ethyl- and N- phenethylnortropinone was close to 1. The axial invertomers dominated in all of the granatanone derivatives and the N- isopropyl- and N- phenylnortropane. Our experiments indicated that nitrogen protonation shifted the invertomer equilibrium towards equatorial forms. DFT calculations reproduced this effect for tropanes.