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

Author(s)

Monteiro, Julia L. ; Carneiro, Paula F. ; Elsner, Petteri ; Roberge, Dominique M. ; Wuts, Peter G. M. ; Kurjan, Katherine C. ; Gutmann, Bernhard ; Kappe, C. Oliver

• Document type: Journal article
• Source: CHEMISTRY-A EUROPEAN JOURNAL; v. 23, n. 1, p. 176-186, JAN 1 2017.
• Web of Science Citations: 12

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 Fe-II catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including (CF3)-C-center dot, (C4F9)-C-center dot, (CH2CN)-C-center dot, and (CH2CO2Et)-C-center dot. 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. (AU)

• FAPESP's process: 14/21319-8 - Evaluation of a continuous flow reactor for the synthesis of hydantoin, imidazolidinone and oxazolidine derivatives
• Grantee: Júlia Lammoglia Monteiro
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)