Mechanistic Insights for Acid-catalyzed Rearrangement of Quinoxalin-2-one with Diamine and Enamine

Benzimidazoles and benzimidazolones can be efficiently synthesized via acid-catalyzed rearrangements of 3-aroylquinoxalin-2-ones with various nucleophiles. The detailed mechanisms of typical rearrangements of 3-benzoylquinoxalin-2-one (1 Q) with 1,2-benzendiamine (1 a, Type I) and with methyl 3-aminocrotonate (1 b, Type II) in acetic acid solution are explored by extensive DFT calculations. Acetic acid acts as proton source and efficient proton shuttle during the catalysis. The former rearrangement is initiated by site-selective N...C condensation at protonated benzoyl site of 1 Q, while the latter is initiated by two competing C...C nucleophilic additions at protonated imine and benzoyl sites of 1 Q that eventually leads to two isomeric products. Both rearrangements proceed via intramolecular S-N(ANRORC) mechanism (sequential Addition of Nucleophile, Ring-Opening and Ring-Closing) involving spiro-quinoxalinone intermediates, but with fundamentally different RORC steps via ring-opening anilide cation and isocyanate cation species, respectively. A simple energetic rule is suggested to determine the type of rearrangement by counting the conjugated pi-electrons within the spiro-forming ring that may stabilize the ring-opening anilide cation species, which may enable further rational design of novel spiro-quinoxalinone based rearrangements.

Automated summary

This study investigated the detailed synthesis mechanisms of benzimidazoles and benzimidazolones through extensive DFT calculations, revealing two different types of rearrangement reactions. A simple energetic rule was proposed to determine the type of rearrangement, which may aid in the rational design of novel rearrangements based on spiro-quinoxalinone.