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

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 SNAr and hydrofluorination steps. The nature of the nucleophile impacts the turnover-limiting step. The cSNAr 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.


Experimental Methods
All manipulations were carried out using standard Schlenk-line and glovebox techniques under an inert atmosphere of dinitrogen. An MBraun Labmaster glovebox was employed, operating at <0.1 ppm O 2 and <0.1 ppm H2O. Solvents were dried over alumina from an SPS (solvent purification system) and degassed before use. Glassware was dried for 12 h at 120 °C prior to use. Benzene-d6 was stored over 3 Å molecular sieves and distilled prior to use. NMR scale reactions were conducted in J. Young's tap tubes and prepared in a glovebox. Scaled-up reactions were conducted in a PTFE lined 30 ml reaction vessel, containing a PTFE-coated magnetic stirrer bar and sealed with electrical tape. Heating of NMR scale reactions was done using silicone oil baths and heating of scaled-up reactions was done using a sand bath. 1 H, 13 C, and 19 F NMR spectra were obtained on BRUKER 400 MHz or 500 MHz machines, unless otherwise stated, and referenced against SiMe4 ( 1 H, 13 C) or CFCl3 ( 19 F). All peak intensities are derived against an internal standard peak ( 1 H m-xylene; δH = 2.30 ppm, 19 F fluorobenzene; δF = -110.7 ppm). NMR data was processed using MestReNova software. Multiplicity assignments for NMR spectra are labelled as follows: "s" = singlet, "d" = doublet, "t" = triplet, "q" = quartet, "hept" = heptet, "m" = multiplet. Some ipso-and fluorocarbon environments on arene rings are not observed by 13 C NMR and this is indicated in the product characterisation in each case.
Phenols and anilines were sublimed or distilled prior to use. LiN i Pr2 was sublimed prior to use.
Fluoroarenes and fluoroalkanes were dried over activated 3 Å molecular sieves and freeze-pump-thaw degassed before use. 1,2-bis(4-fluorophenyl)ethylene and 1,2-bis(4-methoxyphenol)ethylene were synthesised according to the literature report by Grieco and co-workers. [S1] (Cyclohexylethynyl)benzene was synthesised according to the literature report by Tsuhi and coworkers. [S2] All other chemicals were purchased from Sigma Aldrich and used without purification unless stated. S3

Synthesis of [Au( t BuXantphos)Cl]
According to the literature procedure reported by Zhang and co-workers, the gold catalyst 1 was synthesised. [S3] In a glovebox under an inert atmosphere, t BuXantPhos (68.2 mg, 0.14 mmol) was dissolved in toluene (3 ml) and [AuCl(SMe2)] (40.3 mg, 0.14 mmol) was added. This reaction mixture was then stirred for 16 hours at room temperature in darkness and filtered through a celite plug. The solvent was then removed in vacuo to afford catalyst 1 as an off-white solid (85.0 mg, 0.12 mmol, 85 %).

Optimisation of Reaction Conditions.
Initial optimisation of the reaction conditions were conducted with 0.1:1:1:3 equiv. of catalyst : pentafluoropyridine : 4-methoxyphenol : diphenylacetylene. Reactions were run in PTFE tubes. 4-Methoxyphenol was used as the nucleophile of choice due to higher conversion to product 2a than with phenol in a preliminary screening. Three equivalents of diphenylacetylene were added to maintain an excess of diphenylacetylene throughout the reaction, as prior studies had demonstrated that an excess of alkyne is necessary to achieve the fluoroauration of the alkyne and that addition of [Au(IPr)F] to diphenylacetylene is reversible. [ Table S1. Percentage production of products 1a and 2a with a variety of homogeneous Au(I) catalysts. Reactions run with 1:1:3 equivalents of pentafluoropyridine (0.036 mmol, 0.04 M) : paramethoxyphenol : diphenylacetylene in 1.0 ml C6D6. Reactions were run in PTFE inserts inside J-Young's NMR tubes. Production of 1a and 2a was monitored by 19 F NMR spectroscopy using fluorobenzene as an internal standard.
Multiple side-products were observed in the 19 F NMR spectrum of Entry 4 which were attributed to 4hydroxy-2,3,5,6-tetrafluoropyridine ( = -92.8 and -164.2 ppm at 6 % conversion), and 4-(tert-butoxy)-2,3,5,6-tetrafluoropyridine ( = --91.2 and -152.9 ppm at 8 % conversion). Owing to this unwanted side reactivity, further optimisations were conducted with [Au(IPr)N i Pr2], which did not display these sideproducts. S12  which was placed inside a J-Young's NMR tube and sealed. The reaction was heated for 16 hours at 120 °C in a silicone oil bath, ensuring that the tube is immersed in the heating medium up to the solvent line. Quantitative 19 F NMR spectroscopy integration was performed using the fluorobenzene singlet resonance at δF -112.7 ppm as an internal standard.

Conditions
Preparative Scale: In a glovebox, [Au(IPr)N i Pr2] (25 mg, 10 mol %), alkyne (1.08 mmol), nucleophile (0.43 mmol) and fluoroarene (0.36 mmol) were added to a PTFE lined 15 ml vial with a PTFE covered stirrer bar. 10 ml of toluene was added, and the solution was stirred until homogeneous. The vial was sealed and heated in a sand bath for 16 h at 120 °C. After the 16 hours, the vial was removed and allowed to cool. Once cooled, the vial was opened, and the reaction solution was transferred to a Schlenk and the toluene solvent was removed under reduced pressure. The resulting solid was purified by column chromatography on silica gel (tech grades, 60 Å, 230-400 mesh, 40-63 µm particle size, 200 : 1 silica gel : crude mixture loading) to provide the isolated products. The eluent system for each separation is listed in the product characterisation below.

DFT Studies
DFT calculations were run using Gaussian 09 (Revision D.01) using the PBE0, B3PW91 and wB97X-D density functionals. The 6-31G** basis set was used for all atoms except Au. Geometry optimisation calculations were performed without symmetry constraints. The pseudo potential SDDAll was applied for Au only. Frequency analyses for all stationary points were performed to confirm the nature of the structures as either minima (no imaginary frequency) or transition states (only one imaginary frequency). Intrinsic reaction coordinate (IRC) calculations followed by full geometry optimisations on final points were used to connect transition states and minima located on the potential energy surface allowing a full energy profile (calculated at 298.15 K, 1 atm) of the reaction to be constructed.   Table S4. Calculated energies for the intermediates and transition states shown in Figure S3. a Values calculated with empirical dispersion = GD3-BJ and solvent interaction scrf=(pcm, solvent=toluene) included in the optimisation. b Values calculated with single point solvent and dispersion after structure optimisation. c The 6-311G** basis set was applied as a single point energy correction to 6-31G** / PBE0 values.  Table S5. Optimised structures of transition states and intermediates of the reaction energy profile detailed in Figure S3. Selected bond lengths and angles are provided below each structure. Full reaction coordinates for each structure can be found under XYZ coordinates. Protons and IPr ligand removed for clarity.   Table S6. Calculated energies for the intermediates and transition states shown in Figure S4. a Values calculated with empirical dispersion = GD3-BJ and solvent interaction scrf=(pcm, solvent=toluene) included in the optimisation. b Values calculated with single point solvent and dispersion after structure optimisation. c The 6-311G** basis set was applied as a single point energy correction to 6-31G** / PBE0 values.  Table S7. Optimised structures of transition states and intermediates of the reaction energy profile detailed in Figure S4. Selected bond lengths and angles are provided below each structure. Full reaction coordinates for each structure can be found under XYZ coordinates. Protons and IPr-ligand removed for clarity.

Uncatalyzed SNAr Energy Barriers
The energy barrier to the SNAr reaction of both 4-methoxyphenol, 4-methoxyaniline and their {Au(IPr)} bound analogues was computationally modelled, as shown in Figure S5. S52

Kinetic Studies
Kinetic data was used to determine the catalyst and reagent order for both the Au (I) catalysed reactions of pentafluoropyridine, diphenylacetylene and 4-methoxyphenol, or 4-methoxyaniline.
Catalyst order was determined by initial rates experiments, monitoring the initial consumption of 4methoxyphenol or 4-methoxyaniline through 1 H NMR spectroscopy. Three non-zero time points were taken at 5 minutes, 10 minutes, and 15 minutes. Initial reaction rates were recorded for a range of catalyst concentrations, measured against an internal standard (mesitylene). Order in 4methoxyphenol (or aniline) and pentafluoropyridine was determined by pseudo-first-order reactions.
Pseudo-first-order reactions were performed in-situ in a Bruker 500 MHz machine. 1 H NMR spectra were recorded with a scan range of 0 to 12 ppm. An FID was collected every 15 minutes over a period of 10 hours. The reactions were conducted at 120 °C. Conversions were calculated from reagent and product concentrations, based on proton integration value, relative to an internal standard (mesitylene). Reactions were performed in J. Young's NMR Tubes. In each case, a time-zero 1 H NMR spectrum was taken of the reaction mixture at room temperature, in the absence of pentafluoropyridine. The NMR tube was then taken into a glovebox and the reaction mixture was transferred into a PTFE liner and placed back in the NMR tube and re-submitted into the Bruker machine thermostated at 120 °C.

S53
As shown in Figure S7, the proposed reaction mechanism, which is supported by computational studies, suggests the non-trivial rate equations (1), (2). In the case of HX = 4-methoxyphenol, it is expected that K2 > K1 and the rate law can therefore be approximated as shown in equation (3). In this case, the order in reagent and catalyst can be determined through either consumption of A, or formation of B or C. In the case of HX = 4-methoxyaniline, k2 > k1 and the rate equation remains nontrivial. Rates data has been provided for both cases however rate orders have not been extracted for the case of HX = 4-methoxyaniline.

Product Formation Plots
The relative rates of fluoroarene (1a, 1h), and fluoroalkene (2a) product formation are plotted over time for the Au(I) catalysed reaction of pentafluoropyridine with diphenylacetylene and either 4methoxyphenol or 4-methoxyaniline. Figure S14. Plots of the formation of both products (1a and 2a, or 1h and 2a), along with HF, for the reaction of pentafluoropyridine with diphenylacetylene and 4-methoxyphenol (A) or 4-methoxyaniline (B). Reactions were monitored by in-situ 1 H NMR kinetics at 120 °C. 1a and 1d product formations were monitored by the product methoxy environments at δ 3.21 and 3.30 ppm respectively. 2a formation was monitored by the product doublet at δ 6.1 ppm. HF concentration was monitored by 19 F NMR environment at δ = 150.5 -152.5 ppm.

Kinetic Isotope Effect: Competition Experiments
Deuterated analogues of 4-methoxyphenol and 4-methoxyaniline were synthesised by dissolving 50 mg of each nucleophile in 3 ml of hot D2O. Recrystallization of the deuterated nucleophiles occurred by cooling the solution to 5 °C over 2 hours. The crystals were filtered, redissolved in dichloromethane and dried over activated 3Å mol sieves, before being freeze-pump-thawed. The reaction mixture was then filtered, and the solvent was removed in vacuo. The reactions were then set up in J. Young's NMR tubes as outlined in the general experimental. Deuterium incorporation was measured by 1 H NMR and high-resolution mass spectrometry and was shown to be >95 % in each case.  S62