New Avenues in Copper-Mediated Trifluoromethylation Reactions Using Fluoroform as the CF₃ Source

Dedicated to Professor Benjamin List on winning the Nobel Prize in Chemistry 2021

Abstract

Organic molecules containing the trifluoromethyl (CF₃) group play a vital role in pharmaceuticals, agrochemicals, and materials. New trifluoromethylation methods should encompass capabilities to address issues in efficiency, selectivity, and CF₃ source all at once. Fluoroform (CF₃H), an industrial byproduct, has emerged as an attractive CF₃ source. The reaction profile of the [CuCF₃] reagent derived from fluo­roform has surpassed its original applications in cross-coupling-type trifluoromethylation. We have discovered a host of unique copper-mediated trifluoromethylation reactions using [CuCF₃] from fluoroform, especially under oxidative conditions, to deliver efficient and selective synthesis of trifluoromethylated compounds.

1 Introduction

2 Construction of C–CF₃ Bonds for the Synthesis of Trifluoromethylated Building Blocks

2.1 C(sp)–CF₃ Bond Formation

2.2 C(sp²)–CF₃ Bond Formation

2.3 C(sp³)–CF₃ Bond Formation

3 Domino Synthesis of Trifluoromethylated Heterocycles

3.1 3-(Trifluoromethyl)indoles

3.2 3-(Trifluoromethyl)benzofurans

3.3 2-(Trifluoromethyl)indoles

4 Trifluoromethylative Difunctionalization of Arynes

4.1 Trifluoromethylation–Allylation of Arynes

4.2 1,2-Bis(trifluoromethylation) of Arynes

5 Pentafluoroethylation of Unactivated Alkenes

6 Conclusion

Key words

trifluoromethylation - fluoroform - copper - heterocycles - arynes

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