Isomerisation and configurational assignment of 2-alkyltropane and 2-alkylgranatane derived hydrazones

Abstract

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.