A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

Abstract

The reported flow-batch approach enables the easy preparation of 2H-azirines and their stereoselective transformation into highly functionalized NH-aziridines, starting from vinyl azides and organolithium compounds. The protocol has been developed using cyclopentyl methyl ether (CPME) as an environmentally benign solvent, resulting into a sustainable, safe and potentially automatable method for the synthesis of interesting strained compounds.

Advances in the Continuous Flow Synthesis of 3‐ and 4‐Membered Ring Systems

“…In 2021, Luisi, Degannaro and Andresini used this approach to access a range of azirines which could then be transformed into functionalised aziridines in a subsequent telescoped batch step. [18] By heating solutions of vinyl azides to 130 °C using cyclopentyl methyl ether (CPME, b.p.106 °C) as the solvent, the corresponding azirine is quickly generated. The use of a BPR does not only facilitate superheating of the reaction mixture, but also ensures the steady release of nitrogen gas giving full conversion of the substrate in 16 min compared to 45 min in batch.…”

Recent advances in the accessibility, synthetic utility, and biological applications of aziridines

“…Review coordination is present, the limiting step of the reaction concerns the formation of the carbon-nitrene bond (39). In case the chlorine atom is not present, the highest barrier corresponds to the formation of the copper-nitrene intermediate (40). Chen and co-workers selected bis( pyrazolyl)borate Cu(I) complexes (43) as catalysts for the aziridination of olefins (Scheme 7path b).…”

“…Afterwards, the 2H-azirine ( 110) solution from the microfluidic system was collected in a round bottom flask, cooled to −78 °C and reacted with various lithiated species (e.g., phenyllithium, hexyllithium, n-butyllithium, and i-butyllithium, 111), affording the desired NHaziridines (112) (Scheme 22). 40 Gnanaprakasam et al described a mixed continuous flow/ batch approach for the preparation of spiro-aziridines (116). In the first step of the reaction, a variety of spirooxindole 2H-azirines (114) were synthesized via intramolecular oxidative cyclization of 3-(amino( phenyl)methylene)-indolin-2-one derivatives (113) in the presence of I 2 and Cs 2 CO 3 .…”

“…, phenyllithium, hexyllithium, n -butyllithium, and i-butyllithium, 111 ), affording the desired NH-aziridines ( 112 ) (Scheme 22). 40…”

Sustainable continuous flow synthesis of β-aminocarbonyls via acid-catalyzed hydration of N-Boc-2-azetines

“…Relying on our experience in the field of flow technology, [16][17][18][19][20][21][22] we have recently developed a sustainable continuous flow protocol to access either C3-functionalized azetidines or C2functionalized 2-azetines by using 3-iodo N-Boc-2-azetidine as common starting material. 23 This synthetic protocol was proved to be highly efficient and robust for the preparation of several C2-functionalized 2-azetines.…”