A three-step diastereoselective synthesis of N-alkylated octahydroacridines has been
developed from inexpensive starting materials. Alkylation of cyclohexanone with 2-fluorobenzyl
bromide, followed by nitration para to the aromatic fluoro substituent provided the cyclization substrate in 61% yield.
Finally, a tandem reductive amination-SNAr cyclization with NaCNBH3 furnished the target compounds in 74–92% yields. X-ray and 1H NMR studies permitted assignment of the stereochemistry of the B–C ring junction.
The 3:1–10:1 preference for the cis-isomer was rationalized in terms of steric interactions in the imine reduction and
a chair-like conformation for the cyclization. Hydride would be delivered to the molecular
face opposite the fluoronitrobenzyl substituent at C-2 of the cyclohexanimine intermediate
and the resulting amine would be positioned for addition to the SNAr acceptor ring via a chair-like conformation.
Key words
octahydroacridines - tandem reductive amination-S
NAr reactions - diastereoselective synthesis - steric control - chair-like conformation
for ring closure
