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Isomerisation of α-alkyl (Me, n-Pr, i-Pr, Bn) N,N-dimethylhydrazone derivatives of 8-methyl-8-azabicyclo-[3.2.1]octane (tropane) gave two isomers (E,exo Z,exo) while of 9-azabicyclo[3.3.1]nonane (granatane) three isomers (E,exo Z,exo and E,endo), excepting 2-isopropyl granatane. Relative free energies of isomeric hydrazones, at B3LYP/6-31G(d), provided satisfactory reproduction of isomer distributions for granatanes only. The thermodynamically preferred configuration for the 2-alkyl substituent was exo. The granatanone N,N-dimethylhydrazone was deuterated in D2O significantly faster than the tropinone analogue. The differences in two hydrazone series were rationalised using calculated ΔG's of tautomeric enhydrazines. Deuteration (Li-azaenolate or in D2O) led to exo (axial) α-deutero hydrazones of tropinone and granatanone. Crystal structures of tropane derived hydrazones, tropinone, 2-benzyltropinone and 3-granatanone salts were reported and used for assignment of configurations. Crystallization provided E,endo configured α-methyl, α-benzyl tropane hydrazones contrary to 2-isopropyltropane (remained E,exo). Crystallographic analysis, NMR and DFT calculations allowed configurational assignment to all experimentally accessible diastereomers of α-alkylated tropinone and granatanone hydrazones.

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.

Several chiral secondary N -benzhydrylamines were synthesized in good yields (68–92%) without racemization by the direct alkylation of amines with benzhydryl chloride under solvent-free conditions. Using the solvent-free conditions ( R )- N -benzhydryl-1-phenylethylamine was obtained with the highest yield (92%), purified on ion-exchange resin, and converted to its hydrochloride salt. The resulting chiral amine hydrochloride was transformed into lithium amide/lithium chloride mixture used in asymmetric deprotonations of N -benzyl analogues of tropinone and granatanone followed by aldol reactions giving products in high ­diastereomeric purities (up to 96%) and enantiomeric excesses of 77 to 96%.

The title compounds, C21H22BrNO2, are isomeric 8-benzyl-2-[(4-bromophenyl)(hydroxy)methyl]-8-azabicyclo[3.2.1]octan-3-ones. Compound (I), the (±)-exo,syn-(1RS,2SR,5SR,9SR) isomer, crystallizes in the hexagonal space groupR\overline{3}, while compounds (II) [the (+)-exo,anti-(1R,2S,5S,9R) isomer] and (III) [the (±)-exo,anti-(1RS,2SR,5SR,9RS) isomer] crystallize in the orthorhombic space groupsP212121andPna21, respectively. The absolute configuration was determined for enantiomerically pure (II). For the noncentrosymmetric crystal of (III), its absolute structure was established. In the crystal structures of (I) and (II), an intramolecular hydrogen bond is formed between the hydroxy group and the heterocyclic N atom. In the crystal structure of racemic (III), hydrogen-bonded chains of molecules are formedviaintermolecular O—H...O interactions. Additionally, face-to-edge π–π interactions are present in the crystal structures of (I) and (II). In all three structures, the piperidinone rings adopt chair conformations and theN-benzyl substituents occupy the equatorial positions.

(R)-N-benzhydryl-1-phenylethylamine is utilized as chiral auxiliary in asymmetric deprotonations of N-benzyl analogues of tropinone and granatanone.