Design and Synthesis of TY‐Phos and Application in Palladium‐Catalyzed Enantioselective Fluoroarylation ofgem‐Difluoroalkenes

Abstract

The first example of highly enantioselective fluoroarylation of gem-difluoroalkenes with aryl halides is presented by using a new chiral sulfinamide phosphine (Sadphos) type ligand TY-Phos. N-Me-TY-Phos can be easily synthesized on a gram scale from readily available starting materials in three steps. Salient features of this work including readily available starting materials, good yields, high enantioselectivities as well as broad substrate scope make this approach very practical and attractive. Notably, the asymmetric synthesis of an analogue of a biologically active molecule is also reported. The gem-difluoroalkenes are increasingly being exploited as versatile fluorinated building blocks in organofluorine synthesis [1] via mono-defluorinative [2] or fluorine retentive [3] functionalization reactions. Over the past decade, by taking advantage of easily available gem-difluoroalkenes as reliable trifluoromethyl (CF 3) precursors, many chemists reported a conceptually novel protocol for the expedient synthesis of CF 3-containing molecules through an additional fluorine source via a radical pathway or an anion/ cation mechanism (Scheme 1),which are supplement to the typical trifluoromethylation reaction. [4] In 2014, Hu and co-workers demonstrated the formation of a-trifluoromethylated benzylsilver species from the reaction of gem-difluoroalkene with AgF for the first time, and which undergoes rapid C-Ag I bond homolysis in situ to afforded the a-CF 3 benzyl radical. [5] Recently, Feng et al. [6] reported a photoredox-coupled Fnucleophilic addition induced allylic alkylation of gemdifluoroalkenes via the a-CF 3 benzyl radical intermediate (Scheme 1 a). In contrast, the Feng and Loh group [7] and Malcolmson et al. [8] realized palladium-catalyzed fluorinative allylation and arylation of gem-difluoroalkenes via a-CF 3 carbanion intermediate, and the first attempt to palladiumcatalyzed asymmetric fluoroallylation of gem-difluoroalkenes Scheme 1. Trifluoromethylation of gem-difluoroalkenes.

Simultaneous construction of axial and planar chirality by gold/TY-Phos-catalyzed asymmetric hydroarylation

“…2 ). The gold complexes derived from Ming-Phos 42 , 43 , 54 – 56 , Xu-Phos 57 – 61 , Xiang-Phos 62 – 65 , PC-Phos 41 , 66 – 68 and TY-Phos 69 could deliver (−)- 2aa in up to 83% yield with 85% ee. We found that enantioselectivity roughly correlates to the electrical properties of the Sadphos, with a more σ-donating ligand providing a higher enantioselectivity and catalytic activity.…”

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

“…5 This difference in solventbonding drove the selectivity of inter-and intramolecular decomposition of the hypoperoxy intermediate, which in turn generated the alcohol or ketone products, respectively. Further evidence for this mechanism was provided by 18…”

Design and Synthesis of TY‐Phos and Application in Palladium‐Catalyzed Enantioselective Fluoroarylation ofgem‐Difluoroalkenes

“…The absolute configuration of TY-Phos was unambiguously determined via X-ray crystallography analysis. [24] Further screening of the palladium salts, reaction temperatures and solvents failed to give better results either (Supporting Information, Table S1). The optimal reaction conditions are described as follows: [allylPdCl] 2 as the catalyst, N-Me-TY9 as the chiral ligand in cyclohexane at 70 8C for 16 h. Having the optimal reaction conditions in hand, we first investigated the generality of the aryl halides (Scheme 4).…”

“…The absolute configuration of (S)-4 ae was unambiguously determined via X-ray crystallography analysis. [24] Notably, the aryl bromides are also suitable for this reaction (4 ac, 4 ae, 4 ah, 4 ai, and 4 ak). The reaction showed a high chemoselectivity when the aryl halides contain both iodide and bromide (4 aj, 4 ar), in which the reaction selectively take place at the iodide position.…”