Taming Radical Intermediates for the Construction of Enantioenriched Trifluoromethylated Quaternary Carbon Centers

Abstract

Demonstrated herein is the construction of trifluoromethylated quaternary carbon centers by an asymmetric radical transformation. Enantioenriched trifluoromethylated oxindoles were accessed using ah ypervalent iodine-based trifluoromethyl transfer reagent in combination with amagnesium Lewis acid catalyst and PyBOX-type ligands to achieve up to 99 %eeand excellent chemical yields.Mechanistic studies were performed by experimental and computational methods and suggest as ingle-electron transfer induced S N 2-type mechanism. This example is thereby the first report on the construction of enantioenriched trifluoromethylated carbon centers using hypervalent iodine-based reagents proceeding through such ar eaction pathway. Scheme 1. Generally accepted mechanismso fCF 3 transfer from hypervalent iodine-based reagents 1 and 2 to nucleophilic substrates. a) Reductivee limination pathway.b)Radical pathway.c )Our work on the enantioselective radical trifluoromethylation of oxindoles by an SET-induced S N 2-type pathway.

Catalytic Asymmetric Homologation of 4‐Substituted Cyclohexanones with CF3CHN2: Enantioselective Synthesis of α‐Trifluoromethyl Cycloheptanones

“…While significant progress has been made in the construction of C−CF 3 bonds, the creation of C(sp 3 )−CF 3 bonds in an enantioselective manner is still a highly challenging topic in this arena [7, 8] . For the enantioselective introduction of a CF 3 group adjacent to a carbonyl group, the groups of MacMillan, [9, 10] Gade, [11] Melchiorre [12] and Katayev [13] have made significant contributions in the asymmetric trifluoromethylation of aldehydes, 1,3‐dicarbonyl compounds and amides. On the other hand, cycloalkanones are ubiquitous and have found widespread use as synthons for constructing complex structures.…”

Enantioenriched Quaternary α-Pentafluoroethyl Derivatives of Alkyl 1-Indanone-2-Carboxylates

“…Finally, we decided to try MgBr2•Et2O, a completely different Lewis acid that has been recently used by Katayev's group in combination with pybox-type ligands in the trifluoromethylation of oxindoles. 17 In our case we reached a 74% ee and a 76% yield. [a] ee [b] (major R) [a] Yields of isolated pure compound 5d.…”

“…13b Moreover, while important catalytic enantioselective trifluoromethylation methods of the alfa carbon in carbonyl compounds have been developped, 16 to date only one isolated asymmetric pentafluoroethylation of an oxindole has been reported (using MgBr2.Et2O/pybox and Togni's reagent 1) in a remarkable Katayev's work dedicated to the asymmetric trifluoromethylation of substituted oxindoles. 17 As far as we know, there are no examples regarding the enantioselective -pentafluoroethylation of alkyl 1-indanone-2-carboxylates. In the past, our group have previously reported the asymmetric introduction of different electrophiles in β-dicarbonyl systems though lanthanide-pybox catalysis, from α-amination 18 to the most recent fluorination 19 and trifluoromethylation 20 reactions.…”

Recent advances in electrochemical synthesis of diversely functionalized oxindole derivatives

“…The direct functionalization of the pre-existing oxindole skeleton has been proven effective, in which oxindole could serve as either a nucleophile or an electrophilic synthon. 4 The other pathway relies on the de novo synthesis of the oxindole framework from acyclic precursors, which could be driven by a radical addition/cyclization process or mediated by a transition-metal catalyst in a cross-coupling manner. 3 d ,5 Remarkably, diversified functionalization of oxindole derivatives, including fluorination, 4 a amination, 4 b alkynylation, 4 c nitration, 4 e azidation, 4 h arylation, 4 i trifluoromethylation, 4 j phosphorylation, 5 b sulfonylation, 5 e – f and so on, could be achieved by these strategies.…”