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- Title
Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation.
- Authors
Monteiro, Júlia L.; Carneiro, Paula F.; Elsner, Petteri; Roberge, Dominique M.; Wuts, Peter G. M.; Kurjan, Katherine C.; Gutmann, Bernhard; Kappe, C. Oliver
- 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 FeII catalyst. 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.
- Subjects
BIOCHEMICAL substrates; HYDROGEN peroxide; ERGOTAMINE (Drug); REACTIVITY (Chemistry); BOND formation mechanism
- Publication
Chemistry - A European Journal, 2017, Vol 23, Issue 1, p176
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201604579