Palladium-Catalyzed Cascade Sonogashira Cyclization for Synthesis of Fluorescent Benzofuran Amino Acids

The Sonogashira cross-coupling reaction is a Pd/Cu-catalyzed method that forms C–C bonds between aryl halides and terminal alkynes, providing a versatile tool for constructing conjugated aromatic scaffolds (1,2). Fluorescent non-canonical amino acids are valuable biophysical probes, since their site-selective incorporation into proteins enables imaging without disrupting native conformation, and substituent-dependent conjugation strongly modulates their emission efficiency (3,4). Building on these concepts, we developed a one-pot Sonogashira coupling/cyclization strategy converting 3-iodotyrosine methyl ester and terminal alkynes directly into benzofuran-fused tyrosine derivatives under mild Pd(II)/Cu(I) catalysis. The optimized protocol tolerated aromatic, heteroaromatic, and alkyl alkynes, affording benzofuran amino acids in 35–92% yield, with fluorescence quantum yields ranging from 11% to 35% and extended-conjugation aryl substituents giving the brightest emitters. These results establish a practical, scalable route to structurally rigid, fluorescent benzofuran amino acids with promising applications as biophysical probes for peptide-based optical imaging.