Copper‐Mediated Deoxygenative Trifluoromethylation of Benzylic Xanthates: Generation of a CCF₃ Bond from an O‐Based Electrophile

Abstract

The conversion of an alcohol-based functional group, into a trifluoromethyl analogue is a desirable transformation. However, few methods are capable of converting O-based electrophiles into trifluoromethanes. The copper-mediated trifluoromethylation of benzylic xanthates using Umemoto's reagent as the source of CF3 to form C-CF3 bonds is described. The method is compatible with an array of benzylic xanthates bearing useful functional groups. A preliminary mechanistic investigation suggests that the C-CF3 bond forms by reaction of the substrate with in situ generated CuCF3 and CuOTf. Further evidence suggests that the reaction could proceed via a radical cation intermediate.

Copper-Catalyzed Decarboxylative Trifluoromethylation of Allylic Bromodifluoroacetates

“…Most commonly, the conversion of alcohols into trifluoromethanes requires four-step sequences that: 1) involve undesirable manipulation of oxidation states; 2) require excess time and labor to conduct; 3) generate excess waste; 4) lead to diminished overall yields (eq 1). 5 Alternatively, alcohols can be converted to halides, 6 trifluoroacetates, 6b halodifluoroacetates, 7 fluorosulfonyldifluoroacetates, 6f,7a or xanthates, 8 which can be trifluoromethylated in the presence of stoichiometric quantities of transition metals (eq 2). However, for economic and environmental considerations, catalytic methods are desirable.…”

Palladium‐Catalyzed Fluoroarylation of gem‐Difluoroalkenes

“…Arguably, direct benzylic C−H trifluoromethylation should be the privileged strategy, however, the success of this method is quite substrate‐restricted, which severely limits its more general application . Whereas elegant studies from the groups of Fu, Molander, Moran, Hu, Altman, Nishibayashi, Prakash, and Olah have provided effective and orthogonal synthetic potential for access to 1,1,1‐trifluoro‐2‐arylalkane derivatives, disadvantages owing to the reliance on the use of sensitive coupling reagents, as well as substrate‐scope limitations, are still prominent, which reduces the diversity of molecular skeletons that can be accomplished (Scheme a–d). Of note, among the methods discovered, synthetic strategies based on the elaboration of α‐trifluoromethyl‐derived alkyl nucleophiles are appealing but far less well developed.…”

The Cyclopropane Ring as a Reporter of Radical Leaving-Group Reactivity for Ni-Catalyzed C(sp3)–O Arylation

“…2 To date, there are very few examples of redox-active leaving groups which have been directly functionalized by Ni without the aid of an external photocatalyst or reductant. 3,4,5 Thus, more general strategies which employ redox-active C(sp 3 )-O leaving groups in Ni catalysis may aid the rational design of future coupling partners.…”