Heterocyclic compounds with privileged scaffolds are central to the development of novel bioactive molecules due to their ability to interact selectively with biological targets. Among them, flavenes stand out for their structural versatility. This work describes the stereoselective synthesis of 2H-flavenes using the ApDOS strategy (Aminocatalytic privileged Diversity-Oriented Synthesis). The key transformation involves an oxa-Michael cyclization between salicylaldehydes and an iminium ion intermediate formed in situ from cinnamaldehyde (or its derivatives) and the Hayashi–Jørgensen catalyst.

A systematic study of additives (PhCOOH, p-NO₂PhCOOH and NaOAc), solvents (toluene, acetonitrile, chloroform and dioxane) and temperatures (25 and 40 °C) was performed. Optimal conditions (PhCOOH, toluene, 40 °C, 18 h) afforded flavenes in up to 81% yield and 90% ee. The synthesized compounds were fully characterized by NMR, High-Resolution Mass Spectrometry (HRMS), and single-crystal X-ray analysis.

Subsequent functionalization of the flavenes with ethyl cyanoacetate under mild basic conditions resulted in Knoevenagel-type adducts rather than the expected Michael addition products. This unexpected chemoselectivity is attributed to the extended conjugation of the flavene core, HSAB (hard and soft acids and bases) principles, and both kinetic and thermodynamic factors. The resulting polycyclic products exhibit promising electronic features and may serve as valuable dienophiles in Diels–Alder-type pericyclic reactions, thus broadening the structural diversity of this class of compounds and paving the way for future bioactive molecule development.