Can Water Trigger Room‐Temperature Formation of Benzofuran‐2(3H)‐one Scaffolds From Vinyldiazene Derivatives? Computational Insights Into an Unusual Cyclization

ABSTRACT

Access to benzofuran‐2(3H)‐one derivatives from readily available substrates under mild conditions is crucial in the pharmaceutical and plastics industries. We identified (Z)‐3‐(2‐phenylhydrazineylidene)benzofuran‐2(3H)‐one (P) during the recrystallization of (E)‐2‐(2,2‐dichloro‐1‐(phenyldiazenyl)vinyl)phenol using a 96% ethanol solution. The mechanism of the unexpected substrate conversion leading to P is investigated using density functional calculations. The computations revealed that ethanol is required to initiate the reaction via TS1E, which involves a concerted deprotonation of ethanol by the basic diaza group of the substrate and an ethoxy group attacking the electrophilic center (Cl₂C), with an energy barrier of 28.3 kcal/mol. The resulting intermediate (I1E) is calculated to be unstable and can yield a cyclic chloroacetal adduct with a lower energy barrier of 2.2 kcal/mol via the ring‐closure transition state (TS2E). In the absence of water, the next steps are impossible because water is required to cleave the ether bond, yielding P. A small amount of water (4% of the recrystallization solvent) can promote further transformation of I2E via the transition states TS3E (∆G^‡ = 11.1 kcal/mol) and TS4E (∆G^‡ = 10.5 kcal/mol). A comparison of the ethanol/water‐ and only water‐promoted free energy profiles shows that the presence of ethanol is crucial for lowering the energy barriers (by about 5 kcal/mol) for the initial two steps leading to the cyclic chloroacetal (I2E), whereas water is then required to initiate product formation.