A novel synthesis of (di)-benzazocinones via an endocyclic N-acyliminium ion cyclisation

Abstract

The triflic acid-mediated endocyclic N-acyliminium ion cyclisation provides a facile synthesis of (di)-benzazocinones. On reduction of the 10-phenyl derivative, an unusually non-polar tertiary alkylamine was obtained.

Scaffold Diversity from N-Acyliminium Ions

“…King and co-workers have described the synthesis of several polycyclic scaffolds through triflic acid-mediated NAI cyclization, with examples of the acyl group being either endocyclic or exocyclic to the cyclic NAI precursors. − The study was initiated with triflic acid-mediated cyclization of biphenylacetamide 176 , leading to the expected tricyclic compound 177 , as well as the tetracyclic compound 178 , which is a rare example of NAI cyclization of unactivated aromatic nucleophiles in the synthesis of eight-membered rings . A series of substituted phenylbutyramides 179 and their corresponding N -acyl-2-hydroxy-pyrrolidines 181 were examined in the reaction.…”

“…147 As a complement to this exocyclic NAI cyclization approach, an endocyclic approach for the synthesis of benzo-fused eightmembered benzazocinones and dibenzazocinones was reported by the same group. 149 Reduction of the succinimides 182 gave the corresponding hydroxylactams 183, which were applied in endocyclic NAI cyclization in the presence of 10 equiv of triflic acid in refluxing CHCl 3 , thereby generating pyrrolobenzazocin-5-ones 184 from mildly deactivated or activated phenyl substrates. The cyclization did not occur for the strongly deactivated nitro derivative 184i, but even more surprisingly, the reaction also did not occur for the 4-methoxy-substituted analogue 184g.…”

“…Succinimides 187 were subjected to the reduction/cyclization approach to give the "trans" isomers 188, with the R group oriented trans to the pyrrolidinone ring as the major product, together with minor amounts of the "cis" isomers 189 (Scheme 49). 149 Dai ch and co-workers investigated the use of sulfur nucleophiles in NAI cyclization in the late 1990s, 150,151 152 The formation of products resulting from direct π-cationic cyclization and heterocyclization/transposition/cyclization was observed. 154 4.2.…”

Synthesis and Spectral Characterization of Benzo-[6,7][1,5]diazocino[2,1-a]isoindol-12-(14H)-one Derivatives

“…Therefore, there is a need to introduce new and more efficient methods in order to develop the synthesis of medium-sized rings in the pharmaceutical industry. Interesting biological activities are shown by compounds containing five or six membered heterocyclic rings fused to diazocines [28,29,30,31,32,33,34]. Compound 3 , a potent and orally bioavailable Smac mimetic, inhibits cell growth and induces apoptosis in cancer cells and has been shown to be a potent antagonist of inhibitor of apoptosis proteins (IAPs).…”