A Convenient and Stable Synthon for Ethyl Azide and Its Evaluation in a [3 + 2]-Cycloaddition Reaction under Continuous-Flow Conditions

Abstract

Azidoethyl phenyl sulfide, a readily accessible and reasonably stable synthon for ethyl azide with acceptable thermal safety properties, was investigated in a preliminary design space evaluation of a [3 + 2]-cycloaddition with cyanoacetamide under continuous-flow conditions in the Syrris AFRICA flow reactor.

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

“…The optimized conditions were applied to different plug sizes including 200, 300, 500, 1000, and 2000 μL volume yielding comparable conversions (60%) in nearly all experiments. An early demonstration of the benefits associated with flow chemistry and statistical tools towards the definition of safer synthetic routes is well exemplified by the preparation of 2-azidoethyl phenyl sulfide (6), a readily accessible and stable alternative for ethyl azide [15]. The usefulness of this synthon was demonstrated in a [3+2] cycloaddition design space evaluation aimed at developing a straightforward and scalable synthesis of N-alkylated 5-amino-1,2,3-triazole carboxamides (Scheme 2).…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…The use of flow and the inclusion of a phenylthio group allow its safe use in a cycloaddition approach to triazoles (Scheme 25). The thio group can be removed later by a Raney nickel reduction (98).…”

Continuous‐flow syntheses of heterocycles

“…In 2009, the synthesis of 5-amino-1-ethyl-1H-1,2,3-triazole-4-carboxamide from b-azidoethylphenyl azide was described under continuous-flow conditions [55]. Previous literature reports on the synthesis of this triazole suffered from low yields and considerable safety hazards because of the use of ethyl azide.…”