Friedel–Crafts Chemistry. Part 63. Syntheses of some condensed N-heterocyclic systems via combined Darzens and Friedel-Crafts approaches

An efficient protocol for the synthesis of novel fused N-heteropolycycles 10a-f (tetracyclic-fused and bridged dibenzo-azepinone, -azocinones, -azoninone, benzo[b]pyrido[3,2-f]azocinone and benzo[c]pyrido[3,2g]azoninones) via combined Darzens and Friedel-Crafts methodologies is described.The starting ketones 5a,b were conveniently obtained via cyanoethylation of aminoxylenes 1a,b followed by hydrolysis of the resulting nitriles 3a,b to the corresponding carboxylic acids 4a,b and were finally cycloacylated by intramolecular Friedel-Crafts reaction.The key acetylated intermediates 7a,b were obtained by Darzens condensation.Subsequently, two steps led to substituted heterocyclic acids 9a-f which successfully underwent Friedel-Crafts cycloacylations mediated by AlCl3/CH3NO2, TfOH or P2O5 catalysts.The method offers readily access to diverse drug-like 10a-f scaffolds in moderate to good yields.a: n = 0, x = 0, Y = CH; b: n = 0, x = 1, Y = CH; c: n = 0, x = 1, Y = N; d: n = 1, x = 0, Y = CH; e: n = 1, x = 1, Y = CH; f: n = 1, x =1, Y = N N n Y x n = 0 or 1 O -Wide starting scope -Expedient synthesis -Mild reaction condition -High regioselectivity