title: 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 (H2O2) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeIIcatalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including.CF3,.C4F9,.CH2CN, and.CH2CO2Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3I and C4F9I 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.
authors: Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria.
authors: Júlia L
authors: JL
authors: Monteiro
authors: Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria.
authors: Paula F
authors: PF
authors: Carneiro
authors: Chemical Manufacturing Technologies, Lonza AG, 3930, Visp, Switzerland.
authors: Petteri
authors: P
authors: Elsner
authors: Chemical Manufacturing Technologies, Lonza AG, 3930, Visp, Switzerland.
authors: Dominique M
authors: DM
authors: Roberge
authors: Kalexsyn, Inc., 4502 Campus Drive, Kalamazoo, MI, 49008, USA.|Wuts Chemistry Consulting, 5287 Saddle Club Drive, Kalamazoo, MI, 49009, USA.
authors: Peter G M
authors: PG
authors: Wuts
authors: Allergan plc, 2525 Dupont Drive, Irvine, CA, 92612, USA.
authors: Katherine C
authors: KC
authors: Kurjan
authors: Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria.|Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010, Graz, Austria.
authors: Bernhard
authors: B
authors: Gutmann
authors: Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria.|Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010, Graz, Austria.
authors: C Oliver
authors: 0000-0003-2983-6007
authors: CO
authors: Kappe
keywords: Fenton reagent; Minisci reaction; flow chemistry; radical reactions; trifluoromethylation