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

Abstract

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.

Aminopropyl-silica-supported Cu nanoparticles: An efficient catalyst for continuous-flow Huisgen azide-alkyne cycloaddition (CuAAC)

“…The amount of copper present in the combined products from all the flow reactions (53 ppm) was much less than reported for other supported Cu systems [31][32][33][34][35][36][37][38]. Nonetheless, the leaching level in these initial experiments was still above the generally accepted Cu contamination in pharmaceuticals (15 mg kg À1 ) [35].…”

“…The combination of supported Cu-based catalysts and flow reactor technologies represents a step forward in terms of reliability, time, safety, and costs over traditional batch reaction conditions. Recently, considerable efforts in this direction have been devoted to the preparation of innovative Cu-based catalysts by using different strategies to perform CuAAC in flow [31][32][33][34][35][36][37][38]. However, the development of highly recyclable heterogeneous systems with a copper contamination content into the final product at the acceptable levels still remains a challenge [35].…”

Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities

“…The key reaction in the synthesis of the target compounds is the click chemistry between azides and terminal alkynes [27]. On the one hand, the indole bromide 1a-1c were reacted with NaN 3 to generate indole azides 2a-2c in MeCN solution.…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…The use of azides can be adapted to make macrocycles by a ring closing cycloaddition (Scheme 26) (99,100). The reaction is intramolecular rather the bimolecular reactions described above.…”