Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation

Abstract

We report an operationally simple and rapid continuous flow radical C-C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H₂ O₂ ) and dimethylsulfoxide (DMSO) as reagents in the presence of an Fe^II catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including ^. CF₃ , ^. C₄ F₉ , ^. CH₂ CN, and ^. CH₂ CO₂ Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF₃ I and C₄ F₉ I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.