Site‐Selective, Modular Diversification of Polyhalogenated Aryl Fluorosulfates (ArOSO2F) Enabled by an Air‐Stable PdI Dimer

Abstract Since 2014, the interest in aryl fluorosulfates (ArOSO2F) as well as their implementation in powerful applications has continuously grown. In this context, the enabling capability of ArOSO2F will strongly depend on the substitution pattern of the arene, which ultimately dictates its overall function as drug candidate, material, or bio‐linker. This report showcases the modular, substrate‐independent, and fully predictable, selective functionalization of polysubstituted arenes bearing C−OSO2F, C−Br, and C−Cl sites, which makes it possible to diversify the arene in the presence of OSO2F or utilize OSO2F as a triflate surrogate. Sequential and triply selective arylations and alkylations were realized within minutes at room temperature, using a single and air‐stable PdI dimer.


Reagents and Starting Material
All reagents and starting materials were commercially available and used as received. Pd (I) -iodo-dimer 1 was prepared according to the literature procedure. [1] Anhydrous solvents were dried using an Innovative Technology PS-MD-5 solvent purification system. Solvents used in work up and purification were received in technical grade and distilled prior to use. Thin layer chromatography (TLC) was performed on Merck Kieselgel 60 F254 aluminium plates with unmodified silica and visualized under UV light. Flash column chromatography was performed with Merck silica gel 60 (35 -70 mesh).

Experimental Techniques
The work-up of all reactions and the isolation of products were carried out in a fume hood using standard techniques. Whether a reaction was performed under an argon or air atmosphere is specified in the experimental procedure.

Characterization
All 1 H, 13 C and 19 F NMR spectra were recorded on Varian VNMRS 600, Varian VNMRS 400 or Varian Mercury 300 spectrometers at ambient temperature. Chemical shifts (δ) are reported in parts per million (ppm) and were referenced to residual solvent peak. Coupling constants (J) are given in Hertz (Hz) and coupling patterns are described as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.  Table S1: Application of previously reported strategies for the site-selective transformation of aryl fluorosulfates.

Investigation on a general Br vs. OFs vs. Cl selective strategy
Reactions were performed in accordance with the procedure reported by Sharpless and co-workers. [2] Reaction Conditions: Under inert atmosphere the aryl fluorosulfate (0.1 mmol) was placed together with the boronic acid (1.5 equiv, 0.15 mmol, 20.4 mg), Pd(PPh3)4 (10 mol %, 11.6 mg) and KF (3.0 equiv, 0.3 mmol, 17.4 mg) to a 4 mL vial equipped with a magnetic stirring bar. Subsequently, toluene (1 mL) was added and the reaction mixture was heated to reflux for 24 hours. The solvent was then removed in vacuo, the internal standard 4-(trifluoromethoxy)-anisole (0.5 equiv, 0.05 mmol, 9.6 mg) and CDCl3 were added and the mixture was filtered through a short plug of celite (3-4 cm in a Pasteur pipette). The reaction mixture was then analyzed using GC-MS and 1 H (and 19 F) NMR spectroscopy used to determine the extent of conversion to the products.
Next, chamber B was charged with the appropriate (hetero)aryl alcohol (5. Finally, trifluoroacetic acid (5 mL, 3.26 M) was added by injection through the septum in chamber A (Caution! Instant gas formation!). After 18 hours of stirring at room temperature, one of the caps was carefully removed inside a well ventilated fume hood to release the residual pressure. The reaction was stirred for another 15 min to ensure that all sulfuryl fluoride could evaporate. Chamber A was neutralized with aqueous NaHCO3 (sat.). Next, the content of chamber B was transferred to a 100 mL round-bottomed flask. Chamber B was rinsed five times with 2 mL of dichloromethane. The organic layers were combined and the solvent was removed under reduced pressure. The crude product was purified by solid-phase flash column chromatography on silica gel.

General Procedure A (C-Br Site-selective Arylation on Air)
The appropriate aryl fluorosulfate (0.2 mmol, 1.0 equiv.) and the Pd(I)-iodo-dimer 1 catalyst (4.4 mg, 0.005 mmol, 0.025 equiv.) were placed into a vial and solubilized in toluene (2 mL). No efforts were made to exclude air. Then, a freshly prepared solution of appropriate organozinc was added fast to the reaction mixture. It was stirred for 5 min, before it was quenched with pentane. Ammonium pyrrolidine-1dithiocarboxylic acid was added to precipitate palladium and the mixture was filtered through a plug of silica. [4] The filtrate was concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel.
The reaction mixture was stirred for additional 5 min, before it was quenched with pentane. Ammonium pyrrolidine-1-dithiocarboxylic acid was added to precipitate palladium and the mixture was filtered through a plug of silica. [4] The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography.
The reaction mixture was stirred for extra 10 min, before it was quenched with pentane. Ammonium pyrrolidine-1-dithiocarboxylic acid was added to precipitate palladium and the mixture was filtered through a plug of silica. [4] The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography.

General Procedure D (C-Br Site-selective Thiolation)
To an oven dried 8 mL vial equipped with a stirrer bar, the bromoaryl fluorosulfate (0.2 mmol, 1.0 equiv) and Pd(I)-iodo-dimer 1 catalyst (8.7 mg, 0.01 mmol, 0.05 equiv.) were placed. Then, the reaction vessel was introduced to the glovebox and the appropriate sodium thiolate (1.5 equiv) was added. The mixture was suspended in toluene (1 mL). Subsequently, ZnCl2 (1.6 equiv, 1M in THF) and LiCl (1.6 equiv, 0.5M in THF) were added. The vial was closed and sealed with teflon tape. In addition, it was stirred for 4-8 hours at 40 °C.
After the indicated time the reaction mixture was diluted with 2 mL pentane and ammonium pyrrolidine-1dithiocarboxylic acid was added to precipitate palladium. [4] The mixture was filtered through a plug of silica and solvent was concentrated under reduced pressure. The crude was then purified by column chromatography with indicated solvent.

General Procedure E (Double/Triple Sequential Coupling)
The appropriate aryl fluorosulfate (0.2 mmol, 1.0 equiv.) and Pd(I)-iodo-dimer 1 catalyst (4.4 mg, 0.005 mmol, 0.025 equiv.) were placed into a vial. It was flushed with argon and solubilized in toluene (2 mL). Then, a freshly prepared solution of appropriate organozinc was added slowly to the reaction mixture via syringe pump (over 10 min). The reaction mixture was stirred for additional 15 min to ensure full consumption of the organometallic reagent. During this time another organozinc reagent was prepared. Next, NMP (2 mL) was added to both the organozinc reagent and to the reaction mixture. Immediately, the diluted organozinc reagent was added fast to the reaction mixture and it was stirred for 10 min. The reaction was quenched with pentane and ammonium pyrrolidine-1-dithiocarboxylic acid was added to precipitate palladium. [4] The mixture was filtered through a plug of silica, the filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography giving the double sequential coupling products.* In accord with our group's previous work [5] the resulting aryl chloride was then placed together with Pd(I)iodo-dimer 1 catalyst (4.4 mg, 0.005 mmol, 0.025 equiv.) into a vial and flushed with argon. It was solubilized in NMP (2 mL) and placed in a sand bath at 80 °C. The appropriate organozinc reagent was added by syringe pump over 15 min. In addition, it was stirred for an extra 10 min. The mixture was allowed to cool to room temperature and was then quenched with pentane and ammonium pyrrolidine-1-dithiocarboxylic acid was added to precipitate palladium. [4] After filtration through a plug of silica, the filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography. *1 mmol scale: Additional aqueous work up was performed: Therefore, the reaction mixture was filtered through a plug of silica and transferred to a separating funnel using EtOAc (2x10 mL) to wash the reaction vial. To remove NMP the organic layer was extracted with water (5x50 mL). Then, it was dried over Na2SO4, filtered through cotton and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography with pentane.
Preparation of the ZnCl2 solution: [6] To an oven dried Schlenk tube equipped with a stir-bar was added anhydrous ZnCl2 (1.36 g, 10 mmol) under argon atmosphere. Upon melting under high vacuum using a Bunsen burner, the tube was allowed to cool to room temperature and refilled with argon. Subsequently, anhydrous THF (10 mL) was added and it was stirred vigorously until a clear solution resulted.

Synthesis of Sodium Aryl and Alkyl thiolates
Under argon atmosphere, NaH (0.98 equiv, 12.50 mmol, 300 mg) was placed into a round bottom flask and was suspended in dry THF (30 mL). Subsequently, a solution of thiol (1.0 equiv, 12.71 mmol) in THF (3 mL) was added slowly (Caution! H2 formation!). The mixture was stirred for 1 hour at room temperature. Then, the sodium thiolate was precipitated by addition of dry hexane (50 mL). The solid was collected by filtration and dried under vacuum. The corresponding thiolate was obtained in quantitative yield and was used without further purification.

Computational Studies
DFT calculations were performed using the Gaussian 16 software, Revision A.03. [10] Structural optimizations were performed in the gas phase at the ωB97XD/6-31G(d) level of theory using SDD as an ECP on Pd.