Au(I) Catalyzed HF Transfer: Tandem Alkyne Hydrofluorination and Perfluoroarene Functionalization

Abstract

HF transfer reactions between organic substrates are potentially useful transformations. Such reactions require the development of catalytic systems that can promote both defluorination and fluorination steps in a single reaction sequence. Herein, we report a catalytic protocol in which an equivalent of HF is generated from a perfluoroarene | nucleophile pair and transferred directly to an alkyne. The reaction is catalyzed by [Au(IPr)NⁱPr₂] (IPr = N,N'-1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). HF transfer generates two useful products in the form of functionalized fluoroarenes and fluoroalkenes. Mechanistic studies (rate laws, KIEs, density functional theory (DFT) calculations, competition experiments) are consistent with the Au(I) catalyst facilitating a catalytic network involving both concerted S_NAr and hydrofluorination steps. The nature of the nucleophile impacts the turnover-limiting step. The cS_NAr step is turnover-limiting for phenol-based nucleophiles, while protodeuaration likely becomes turnover-limiting for aniline-based nucleophiles. The approach removes the need for direct handling of HF reagents in hydrofluorination and offers possibilities to manipulate the fluorine content of organic molecules through catalysis.

Figure 1

(a) General reaction scheme for transition metal-catalyzed HX shuttling (X = Cl, Br, CN). (b) HF transfer catalysis. (c) This work.

Figure 2

HF transfer reaction scope catalyzed by [Au(IPr)NⁱPr₂]. [a] Reactions were performed with 0.1:1:1.2:3 equivalents of catalyst: fluoroarene (0.04 M): nucleophile: alkyne. Yields of fluoroarene (1a-1p) and fluoroalkene (2a-2d) were calculated from ¹⁹F NMR spectroscopy using a fluorobenzene internal standard. Reactions were performed in triplicate, and standard deviations are reported with a 99% confidence level. [b] Isolated yields were obtained from scale-up reactions and are shown in parenthesis. [c] Isolated yields of 2a are not reported due to this compound co-eluting with diphenylacetylene. [d] Due to the challenging isolation, this product was contaminated with ∼20% of unreacted alkyne. [e] Ratio of regioisomers β:α functionalization. Major isomer is shown.

Figure 3

KIEs determined by independent rates.

Figure 4

DFT calculated pathways for (a) cS_NAr and (b) hydrofluorination reaction pathways. (inset) Models of TS-1 and TS-4 showing geometries of key steps. Free energy values are calculated at 298.15 K.

Figure 5

Plots for the concentration of fluoroarene and fluoroalkene products and HF intermediate over time for the reaction of pentafluoropyridine and diphenylacetylene with (a) 4-methoxyphenol and (b) 4-methoxyaniline.

Figure 6

Plausible catalytic network for HF transfer.