Alkyne–Azide Cycloadditions with Copper Powder in a High‐Pressure Continuous‐Flow Reactor: High‐Temperature Conditions versus the Role of Additives

Abstract

A safe and efficient flow-chemistry-based procedure is presented for 1,3-dipolar cycloaddition reactions between organic azides and acetylenes. This simple and inexpensive technique eliminates the need for costly special apparatus and utilizes Cu powder as a plausible Cu(I) source. To maximize the reaction rates, high-pressure/high-temperature conditions are utilized; alternatively, the harsh reaction conditions can be moderated at room temperature by the joint application of basic and acidic additives. A comparison of the performance of these two approaches in a series of model reactions has resulted in the formation of useful 1,4-disubstituted 1,2,3-triazoles in excellent yields. The risks that are associated with the handling of azides are lowered, thanks to the benefits of flow processing, and gram-scale production has been safely implemented. The synthetic capability of this continuous-flow technique is demonstrated by the efficient syntheses of some highly functionalized derivatives of the antifungal cispentacin.

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].…”

“…As a consequence, the total productivity obtained with Cu/APSiO 2 (0.55 wt.%) in flow (P n = 1689) was more than two times larger of that achieved with Cu/APSiO 2 (1.0 wt.%) under comparable conditions (vide supra) [71]. Most importantly, ICP-OES data for all the flow reactions showed now very low copper leaching in the reaction mixture (8.1 ppm) [72], which is below the maximum allowed limit for pharmaceuticals and demonstrates the unique features of the nanostructured MVS system described in this work with respect to bulk copper catalysts and devices reported to date [31,[34][35][36][37].…”

“…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].…”

New click-chemistry methods for 1,2,3-triazoles synthesis: recent advances and applications

“…Two different conditions were compared for the conversion of benzyl azide and phenylacetylene to 1,4-disubstituted-1,2,3-triazoles using copper powder. 36 The first set of reaction conditions used high pressure and high temperatures (100 bar, 50 to 100°C) and the authors showed that conversion increases with increased temperature and pressure. The second set uses acetic acid and diisopropylamine as additives at room temperature.…”

High Pressure Effects on 1,3-Dipolar Cycloaddition of Azides with Alkynes

“…또한, 1,2,3-트리아 졸은 신약개발에 있어서도 매우 중요한 역할을 담당 [7] 하는데, 1,2,3-트리아졸은 수소결합과 이중극자 상호작 용을 통해 생체 표적 물질에 쉽게 결합하여 핵심적인 역할을 하기 때문이다. 1,2,3-트리아졸 유도체들은 항 바이러스, 항균, 항진균, 그리고 항암 작용을 보인다 [8] .…”