Synthesis of Heterocyclic Scaffolds from Nitrobenzyl Alcohols Using Reduction‐Generated Azaquinone Methides and Cyclization

Tetrahydroisoquinolines (THIQs) and related heterocycles, including thioisochromanes and tetrahydrobenzazepines, are prominent in scaffolds of biologically active molecules. The classical syntheses for these scaffolds can be harsh, substrate specific, and incompatible with the late‐stage addition of the heterocycle into a molecule, therefore new, relatively mild reaction conditions for installing these heterocycles are of interest to synthetic and medicinal chemists. Herein, a library of 2‐substituted 4‐nitrobenzyl alcohols were synthesized, and in one step, reduction of the 4‐nitrobenzyl alcohols and 11 THIQs with a variety of substituents (e.g., benzyl, alkyl, phenylalanine) at the nitrogen atom and the THIQ ring were synthesized, alongside examples of the seven‐membered nitrogen heterocycle (2,3,4,5‐tetrahydrobenzazepine) and a thioisochromane. The reaction proceeded via a mild Zn/H + −mediated reduction of the nitroaromatic and in situ azaquinone methide generation following loss of water from the benzyl alcohol group. The strategic placement of an appended nitrogen or sulfur nucleophile at the 2‐position of the 4‐nitrobenzyl alcohol led to a rapid quench of the azaquinone methide via an intramolecular 6‐endo‐trig or 7‐endo‐trig cyclization. The broad scope of substituents, nucleophiles, and ability to synthesize six‐ or seven‐membered ring heterocycles via a reduction‐generated azaquinone methide adds a selective and mild late‐stage heterocycle strategy to the synthetic chemistry toolbox.