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

作者：Muddala Nagendra Prasad; Nammalwar Baskar; Selvaraju Subhashini; Bunce Richard A^*

来源：Synthesis (Germany), 2015, 47(20): 3198-3206.

DOI：10.1055/s-0034-1381033

• octahydroacridines
• tandem reductive amination-SNAr reactions
• diastereoselective synthesis
• steric control
• chair-like conformation for ring closure

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 H-1 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.

• 出版日期2015-10