Flow Macrocyclization Using Copper Tubing

Significance

Flow macrocyclization with a ­copper surface catalyst via the azide-acetylene cycloaddition reaction was described. The flow macrocyclization of an azidealkyne 1 with TTTA and DIPEA was performed in copper tubing (3 m length, 0.75 mm inner diameter) to give the tri­azole-containing macrocycle 2 in 73% isolated yield within five minutes of residence time without addition of extraneous copper(I) salt in the reaction mixture. The structure of the 12-memberd macrocycle 2 was confirmed by X-ray crystallography.