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. 2014 Aug 1;79(15):7122-31.
doi: 10.1021/jo501289v. Epub 2014 Jul 15.

Metal-free trifluoromethylation of aromatic and heteroaromatic aldehydes and ketones

Yupu Qiao  1 , Tuda Si, Ming-Hsiu Yang, Ryan A Altman
Affiliations

Metal-free trifluoromethylation of aromatic and heteroaromatic aldehydes and ketones

Yupu Qiao et al. J Org Chem. .

Abstract

The ability to convert simple and common substrates into fluoroalkyl derivatives under mild conditions remains an important goal for medicinal and agricultural chemists. One representative example of a desirable transformation involves the conversion of aromatic and heteroaromatic ketones and aldehydes into aryl and heteroaryl β,β,β-trifluoroethylarenes and -heteroarenes. The traditional approach for this net transformation involves stoichiometric metals and/or multistep reaction sequences that consume excessive time, material, and labor resources while providing low yields of products. To complement these traditional strategies, we report a one-pot metal-free decarboxylative procedure for accessing β,β,β-trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes. This method features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability.

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Figures

Scheme 1
Scheme 1. Trifluoromethylation of Aryl and Heteroaryl Aldehydes and Ketones Complements Existing Methods
Scheme 2
Scheme 2. Strategy for Troubleshooting Trifluoromethylation of Substituted Acetophenone
Scheme 3
Scheme 3. Improved Protocol for Trifluoromethylation of Heteroaromatic Aldehydes
Reagents and conditions: (a) Me3SiCF3, TBAF (cat.), THF, rt. (b) PhOCSCl, DMAP, PhMe, 50–60 °C. (c) Bu3SnH, AIBN (cat.), PhMe, 80 °C. (d) (i) Ph3P+CF2CO2–, DMF, 60 °C, 1 h; (ii) TBAF (1.0 M in THF), 6 h, 60 °C.
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