Diastereoselective Synthesis of N-Alkylated Octahydroacridines via a Catalyst-Free S_NAr Approach

Abstract

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-S_NAr 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 S_NAr 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

• References

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