We recently reported that 3-aminoacridine derivatives react with formaldehyde in acidic media [Tatibouët, A.; Fixler, N.; Demeunynck, M.; Lhomme, J. Tetrahedron 1997, 53, 2891-2898] Along with the Tröger's bases, the reaction may lead to a number of products including dihydrooxazine and tetrahydroquinazoline derivatives and new heptacyclic heterocycles [Tatibouët, A.; Hancock, R.; Demeunynck, M.; Lhomme, J. Angew. Chem, Int. Ed. Engl. 1997, 36,1190-1191]. The product distribution depends on the nature of the acid used and on the amine/formaldehyde ratio [Salez, H.; Wardani, A.; Tatibouet, A.; Demeunynck, M.; Lhomme, J. Tetrahedron Lett. 1995, 36, 1271-1274]. The best yields in Tröger's Base were obtained using 1.5 equivalents of formaldehyde and trifluoroacetic acid as solvent.

Synthesis of the Tröger's Base starting from 3,6-diaminoacridine required protection of one of the amino groups prior to reaction with formaldehyde to avoid side reactions. The acetamido group introduced at position 3 proved convenient as it is stable in trifluoroacetic acid and deactivates substitution at carbon C-4 leading to selective reaction at C-5 ortho to the free amino function. The heterocyclic Tröger's Base analogue was prepared in two steps starting from monoacetylated proflavine. Condensation of monoacetylproflavine with formaldehyde in trifluoroacetic acid gave the diacetamido Tröger's Base analogue in 76 % yield. Treatment in basic conditions (EtOH, NaOH) allowed cleavage of the two acetamido groups without degradation of the methano diazocine bridge. The new Tröger's Base analogue was obtained in 90 % yield.

[Summary] [Introduction] [Physico...] [Interaction...] [Enantioselective...] [Conclusion]