An efficient synthesis of halogenated 1,4,5,8-tetramethoxynaphthalenes

Naphthoquinones are bioactive natural products that have attracted considerable interests due to their potent anticancer, antimicrobial, and antiviral activities. Halogenated 1,4,5,8-tetramethoxynaphthalenes such as the 2-bromo and 2-iodo derivatives are key intermediates in synthesis of naphthoquinones, but existing methods for their preparation suffer from low yields and complicated procedures, limiting large-scale synthesis. Herein, we present a streamlined and efficient synthesis of 2-bromo-, 2-iodo-, and 2-chloro-1,4,5,8-tetramethoxynaphthalene from commercially available 1,5-dihydroxynaphthalene, with overall yields of 33.3%, 26.7%, and 8.1%, respectively. Structures of targeted compounds were confirmed by NMR, FT-IR, and HRMS. This method offers simple work-up procedures, uses readily available reagents, provides comparably high yields, and is amenable to scale-up, making it a practical and sustainable alternative for the synthesis of these valuable building blocks.