A Green, Facile Method for Selective α-Bromination of Flavanones

Flavonoids, a broad class of polyphenolic secondary metabolites, possess diverse and potent biological activities, including anti-inflammatory, antioxidative, antiviral, and analgesic properties. Flavanones, a prominent flavonoid subclass, are especially notable for their therapeutic potential, with several derivatives exhibiting anticancer and antiviral effects. Bromination is a valuable strategy in drug development, as halogenation can enhance biological activity and provide synthetic handles for further molecular elaboration. While aromatic bromination of flavonoids is known, selective α-bromination of flavanones, particularly those bearing hydroxy and alkoxy substituents, remains underexplored due to electronic and oxidative challenges. In this study, we investigated the selective α-bromination of hydroxy- and alkoxy-substituted flavanones, generating novel brominated derivatives. We identified a mild, green protocol for α-bromination of a range of monosubstituted flavanones in good yields using copper-(II) bromide in ethyl acetate. The α-bromination of flavanones bearing multiple hydroxyl groups resulted in poor selectivity and competing nuclear bromination, underscoring the challenges posed by increased aromatic nucleophilicity. Novel products were characterized using a combination of nuclear magnetic resonance (NMR) spectroscopy, high-resolution mass spectrometry (HRMS), tandem electrospray ionization mass spectrometry (ESI-MS/MS), and X-ray crystallography. These findings expand the chemical space of flavanone derivatives and provide valuable intermediates for the synthesis of pharmacologically relevant heterocycles.