[3 + 2] Cycloaddition of Nitrile Ylides with Diazonium Salts: Copper-Catalyzed One-Pot Synthesis of Fully Substituted 1,2,4-Triazoles

Abstract

A novel [3 + 2] cycloaddition between nitrile ylides and diazonium salts was well-established. This copper-catalyzed three-component reaction was distinguished by mild conditions, ready availability, and operational simplicity, thus opening access to 1,2,4-triazoles with a diverse set of substitution patterns.

Cu‐Catalysed Three‐Component Reaction of Aryldiazonium Salts with Fluorinated Diazo Reagents and Nitriles: Access to Difluoro‐ and Trifluoromethylated N1‐Aryl‐1,2,4‐triazoles

“…Among them, we reported a copper‐catalysed three‐component transformation to CF 3 ‐oxazolines in 2015 by harnessing the reactivity of nitrile ylides in situ generated from trifluorodiazoethane and nitriles . Subsequently, Wan and Bao developed a [3+2] annulation reaction of ester‐derived nitrile ylides with aryldiazonium salts to form N 1 ‐aryl‐5‐carboxylic‐1,2,4‐triazoles . Inspired by these studies and as part of our continuing interest in fluoroalkyl heterocycles, here we present the synthesis of both difluoro‐ and trifluoromethylated N 1 ‐aryl‐1,2,4‐triazoles enabled by a novel multicomponent reaction of aryldiazonium salts with fluorinated diazo reagents and nitriles (Scheme b) .…”

“…The observed difference in regioselectivity profile of trifluorodiazoethane compared with phenylsulfone difluorodiazoethane might be attributed to the increased steric effect in the case of trifluoromethyl-substituted nitrile ylide intermediate. [8] The operational simplicity and broad compatibility of this multicomponent reaction promoted us to further explore the preparation of divergent difluoromethyl and trifluoromethyl analogues of P2X3 receptor antagonists (Scheme 7). [18] By operating aryldiazonium salt 9 with respective fluorinated diazo reagent in acetonitrile under standard copper catalysis conditions, four fluoroalkyl N 1 -aryl-1,2,4-triazoles 10 a, 10 b, 12 a, and 12 b were all routinely obtained.…”

“…[7] Subsequently, Wan and Bao developed a [3 + 2] annulation reaction of ester-derived nitrile ylides with aryldiazonium salts to form N 1 -aryl-5-carboxylic-1,2,4triazoles. [8] Inspired by these studies and as part of our continuing interest in fluoroalkyl heterocycles, [9] here we present the synthesis of both difluoro-and trifluoromethylated N 1 -aryl-1,2,4-triazoles enabled by a novel multicomponent reaction of aryldiazonium salts with fluorinated diazo reagents and nitriles (Scheme 1b). [10][11][12] The regioselectivity is controlled by a copper-catalysed [3 + 2] annulation process of in situ formed nitrile ylide intermediate with aryldiazonium salt.…”

Recent Advances in the Synthesis of Nitrogen Heterocycles Using Arenediazonium Salts as Nitrogen Sources

“…A simple and efficient strategy for the synthesis of structurally diverse 1,2,4-triazoles via copper-catalyzed three-component reaction was disclosed by Wan and co-workers (Scheme 27). [39] In their reactions, the aryldiazonium salts undergo [3 + 2] cycloaddition with nitrile ylides generated in situ from nitriles and diazo compounds to deliver the desired 1,2,4-triazoles in a one-step fashion under mild reaction conditions. A wide range of functional groups were well tolerated in this transformation.…”

Aryl DiazoniumSalt‐TriggeredCyclization and Cycloaddition Reactions: Past, Present, and Future

“…In 2018, Wan and co‐workers reported the catalytic construction of 1,2,4‐triazoles 110 via the three‐component reaction of alkyl 2‐diazoacetates 78 , aryl diazonium salts 30 , and nitrile solvents (Scheme 27). [ 155 ] Mechanistic study suggested that Cu catalyst could react with alkyl 2‐diazoacetate to form a Cu‐alkylidene species 107 , which further coupled with nitrile to generate a nitrile ylide intermediate 108 . Nitrile ylide 108 then underwent [3 + 2] cycloaddition with aryl diazonium ion 30 to give a five‐membered aza‐cycle 109 , which finally isomerized in the presence of base to produce a series of tri‐substituted 1‐aryl‐1,2,4‐triazole‐ 3‐carboxylate products 110 .…”