Metal-Free Trifluoromethylation of Aromatic and Heteroaromatic Aldehydes and Ketones

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.

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

“…This strategy benefits from a reversible equilibrium as the addition of Freaction generates an ,,-trifluoromethyl anion 15, from which -fluoride elimination simply regenerates the gemdifluoroalkene, thus preventing the loss of substrate. [7][8][9][10][11][12][13][14][15] When using AgF, the metalated intermediate 17 can participate in Ag-or Pd-catalyzed processes in difunctionalization reactions (Scheme 2B). [16][17][18][19] Moreover, the use of electrophilic sources of fluorine, such as Selectfluor and NFSI can avoid anionic intermediates entirely (Scheme 2C).…”

BBDFA: A Practical Reagent for Trifluoromethylation of Allylic and Benzylic Alcohols on Preparative Scale

“…Current methods to convert alcohols into trifluoromethanes unfortunately require four-step synthetic sequences that lead to low overall yields and generate large quantities of waste. Further, the sequences require the use of strong nucleophilic reagents (TMS–CF 3 ), oxidants, and reductants that limit the scope of accessible molecules (Figure a). , Thus, despite the potential significance of this reaction, the efficient conversion of alcohols to trifluoromethanes on large scale remains challenging.…”

“…Further, the sequences require the use of strong nucleophilic reagents (TMS−CF 3 ), oxidants, and reductants that limit the scope of accessible molecules (Figure 1a). 5,6 Thus, despite the potential significance of this reaction, the efficient conversion of alcohols to trifluoromethanes on large scale remains challenging.…”

Nickel‐Catalyzed Direct Trifluoroethylation of Aryl Iodides with 1,1,1‐Trifluoro‐2‐Iodoethane via Reductive Coupling

“…[2] Among all the fluorine-containing motifs, (2,2,2-trifluoroethyl)arenes have received considerable attention due to their favourable properties over the non-fluorinated analogues, such as lipophilicity, metabolic stability and bioavailability. [3] The traditional synthesis methods towards trifluoroethyl arenes have been developed by the late-stage construction of trifluoroethyl groups on the functional arenes, including trifluorination from aldehydes, [4] hydrofluorination from difluorostyrenes [5] and nucleophilic substitution on benzylic compounds with "CuCF 3 ". [6] While multistep prefunctionalization was normally required for the synthesis of such starting materials, the direct introduction of trifluoroethyl group into arenes have been established as an efficient and convenient alternative approach to make trifluoroethyl arenes.…”