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

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 (H 2 O 2 ) 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 . CF 3 , . C 4 F 9 , . CH 2 CN, and . CH 2 CO 2 Et. In contrast, electron‐poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF 3 I and C 4 F 9 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.