Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation
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- 作者：Jú ; lia L. Monteiro ; Dr. Paula F. Carneiro ; Dr. Petteri Elsner ; Dr. Dominique M. Roberge ; Dr. Peter G. M. Wuts ; Katherine C. Kurjan ; Dr. Bernhard Gutmann and Prof. Dr. C. Oliver Kappe
- 刊名：Chemistry - A European Journal
- 出版年：2017
- 出版时间：January 1, 2017
- 年：2017
- 卷：23
- 期：1
- 页码：176-186
- 全文大小：1858K
- ISSN：1521-3765
文摘
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<sub>2sub>O<sub>2sub>) and dimethylsulfoxide (DMSO) as reagents in the presence of an Fe<sup>IIsup> catalyst. For electron-rich aromatic and heteroaromatic substrates, C−C bond formation proceeds satisfactorily with electrophilic radicals including <sup>.sup>CF<sub>3sub>, <sup>.sup>C<sub>4sub>F<sub>9sub>, <sup>.sup>CH<sub>2sub>CN, and <sup>.sup>CH<sub>2sub>CO<sub>2sub>Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF<sub>3sub>I and C<sub>4sub>F<sub>9sub>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.