Efficient Access to New Chemical Space Through Flow-Construction of Druglike Macrocycles Through Copper-Surface-Catalyzed Azide-Alkyne Cycloaddition Reactions

A series of 12- to 22-membered macrocycles, with druglike functionality and properties, have been generated by using a simple and efficient copper-catalyzed azide-acetylene cycloaddition reaction, conducted in flow in high-temperature copper tubing, under environmentally friendly conditions. The triazole-containing macrocycles have been generated in up to 90% yield in a 5 min reaction, without resorting to the high-dilution conditions typical of macrocyclization reactions. This approach represents a very efficient method for constructing this important class of molecules, in terms of yield, concentration, and environmental considerations.