Three-component aminofluorination of alkenes with electronically rich amino sources

The first intermolecular three-component aminofluorination of alkenes with electronically rich amino sources has been developed via an umpolung strategy. In this reaction, electrophilic N-bromo-dialkylamines are employed as amine electrophiles, whereas multifunctional AgF serves as both a nucleophilic fluoride source and a reductive catalyst, for the first time, to initiate a single-electron transfer with N-bromodialkylamines. The addition of hexafluoroisopropanol as a cosolvent is crucial to promote protonated alkylaminyl radical formation and maintain the nucleophilicity of fluoride ion. This protocol exhibits excellent functional-group tolerance toward various aryl and unactivated alkenes, furnishing the corresponding beta-fluoroamines with high regioselectivity. Mechanistic investigation reveals an aziridinium intermediate via a radical pathway. The synthetic utility of this transformation was demonstrated by the amino fluorination of several bioactive molecules, including an efficient route to a Rizatriptan analog. We anticipate that our finding holds promise for new discoveries in medicinal chemistry and the amination reactions.

Automated summary

A new three-component aminofluorination reaction using electronically rich amino sources has been developed through an umpolung strategy. This reaction utilizes electrophilic N-bromo-dialkylamines as amine electrophiles and multifunctional AgF as both a nucleophilic fluoride source and a reductive catalyst. The addition of a cosolvent, hexafluoroisopropanol, is crucial for the formation of alkylaminyl radicals and the maintenance of fluoride ion nucleophilicity. This protocol exhibits excellent functional-group tolerance and high regioselectivity towards various aryl and unactivated alkenes. Mechanistic investigation reveals the formation of an aziridinium intermediate via a radical pathway. The synthetic utility of this transformation has been demonstrated by the amino fluorination of several bioactive molecules.