Programmed S → N Remote Cyano Migration: A Thiocyanate-Based Entry to Cyanamides and Selective Ferroptosis Inducers

Ferroptosis represents a promising strategy to overcome apoptosis-associated drug resistance, yet access to diverse and drug-like ferroptosis-inducing chemical space remains limited. Among potential scaffolds for populating this high-value space, cyanamide-bearing molecules are attractive but synthetically challenging due to the long-standing difficulty of constructing the N-CN bond. Here we disclose a thiocyanate-enabled cascade cyclization that leverages inexpensive, low-toxicity inorganic thiocyanate as an unconventional electrophilic CN surrogate. This transformation proceeds through a cascade sequence involving SCN installation, remote S → N cyano migration, and subsequent intramolecular thiazine annulation under mild, metal-free conditions. The resulting cyanamide 3,4-dihydro-2H-1,4-thiazines exhibited nanomolar ferroptosis-inducing potency; lead compounds 3b and 3c achieved IC50 values of 6.8 nM and 14 nM, respectively; and significantly suppressed tumor growth in a lung cancer PDX model.