Flow Chemistry for Cycloaddition Reactions

Abstract

Continuous flow reactors form part of a rapidly growing research area that has changed the way synthetic chemistry is performed not only in academia but also at the industrial level. This Review highlights the most recent advances in cycloaddition reactions performed in flow systems. Cycloadditions are atom-efficient transformations for the synthesis of carbo-and heterocycles, involved in the construction of challenging skeletons of complex molecules. The main advantages of translating these processes into flow include using intensified conditions, safer handling of hazardous reagents and gases, easy tuning of reaction conditions, and straightforward scaling up. These benefits are especially important in cycloadditions such as the copper(I)-catalyzed azide alkyne cycloaddition (CuAAC), Diels-Alder reaction, ozonolysis and [2 + 2] photocycloadditions. Some of these transformations are key reactions in the industrial synthesis of pharmaceuticals.

Scalable Synthesis of Norbornadienes via in situ Cracking of Dicyclopentadiene Using Continuous Flow Chemistry

“…[7b] With regards to cycloaddition reactions, several examples using flow techniques are reported in the literature. [8] A variety of different Diels-Alder reactions was investigated in flow. [9] Hornung et al reported on the investigation and up-scaling of the Diels-Alder reaction of myrcene with acrylic acid in two different types of flow reactors, a tubular and a plate-type, and compared it to a batch stirred tank, and achieved shorter reaction times as well as a more uniform reaction using the flow technique.…”

Understanding flow chemistry for the production of active pharmaceutical ingredients

“…(2021) ; Cambié et al. (2016) ; Sambiagio and Noël (2020) 22 Asymmetric synthesis Ötvös and Kappe (2021) 23 Cycloaddition reactions García-Lacuna et al. (2020) 24 Integration of flow chemistry with 3D-printing technologies Sans (2020) 25 Circular synthesis to material manufacturing Sivo et al.…”

An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry

“…One approach to developing safe 21 and readily scalable procedures for chemistries involving unstable intermediates and intense conditions is flow chemistry. [22][23][24][25][26] This approach has been successfully applied to heterocycle synthesis, 27-28 cycloadditions [29][30] and even to acyl ketene formation, 31 and recent developments continue to show the potential flexibility 32 and portability 33 of this approach. Flow chemistry is often greener 34 than batch chemistry, and sometimes allows access to transformations near impossible 35 under batch conditions.…”