Site-Selective C–H Functionalization–Sulfination Sequence to Access Aryl Sulfonamides

Aryl sulfinates are precursors to a diverse number of sulfonyl-derived arenes, which are common motifs in pharmaceuticals and agrochemicals. Here, we report a site-selective two-step C–H sulfination sequence via aryl sulfonium salts to access aryl sulfonamides. Combined with site-selective aromatic thianthrenation, an operationally simple one-pot palladium-catalyzed protocol introduces the sulfonyl group using sodium hydroxymethylsulfinate (Rongalite) as a source of SO22–. The hydroxymethyl sulfone intermediate generated from the catalytic process can be employed as a synthetic handle to deliver a variety of sulfonyl-containing compounds.


Solvents
Anhydrous isopropanol was purchased from Sigma Aldrich (278475). Anhydrous MeCN and THF were obtained from a Phoenix Solvent Drying System from JC Meyer. All deuterated solvents were purchased from Euriso-Top.

Chromatography
Thin layer chromatography (TLC) was performed using EMD TLC plates pre-coated with 250 m thickness silica gel 60 F254 plates. Compound visualization was achieved by fluorescence quenching under 254 nm UV light, permanganate stain, cerium ammonium molybdate stain, or phosphomolybdic acid stain. Flash chromatography was performed using silica gel (40-63 m particle size) purchased from Geduran.

Spectroscopy and instruments
NMR spectra were recorded on a Bruker Ascend TM spectrometer operating at 500 MHz and 400 MHz for 1  Data is reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants are reported in Hz.

Starting materials
All reagents were used as received from commercial suppliers unless otherwise stated. For convenient operation, Pd(dppf)Cl2 was stored in a N2-filled glovebox after being dried for more than 24 h under highvacuum. Arylthianthrenium salts TT-5 to TT-20 and thianthrene-S-oxide (S2) were prepared according to our previous reports. 1-5 S10 EXPERIMENTAL DATA

General procedure for thianthrenation of arenes
Under ambient atmosphere, a 20 mL glass-vial was charged with arene (0.50 mmol, 1.0 equiv) and dry MeCN 3.0 equiv) was added in one portion at 0 °C, resulting in a color change to deep purple. The vial was sealed with a screw-cap. The mixture was stirred at 0 °C for 1 h, subsequently, the reaction mixture was warmed to 25 °C and stirred until all solid dissolved and the intensity of the purple color decreased. The solution was diluted with 5 mL DCM and poured onto a mixture of 30 mL DCM, 20 mL saturated aqueous Na2CO3 solution, and 10 ml water. After stirring for 5 min at 25 °C, the mixture was poured into a separatory funnel, and the layers were separated. The DCM layer was washed with aqueous NaBF4 solution (2 × ca. 20 ml, 5 % w/w) and with water (2 × ca. 20 mL). Washing with NaBF4 solution is only required if it is of interest that the product contains only one type of counterion, solutions containing other ions, like triflate or hexafluorophosphate may be used as well. The DCM layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. In order to obtain analytically pure samples of thiantrhenium salts, the residue was purified by chromatography on silica gel eluting with DCM / i-PrOH, subsequently, the product was dissolved in 2 mL DCM and precipitated with 20 mL Et2O. The solid was dried in vacuo to afford the thianthrenium salt.

General procedure for sulfonamidation
An oven dried borosilicate 4 mL reaction vial equipped with a magnetic stir bar was charged with an aryl thianthrenium salt (0.100 mmol, 1.00 equiv), Pd(dppf)Cl2 (4 mg, 5 µmol, 5 mol %), Rongalite (17 mg, 0.15 mmol S11 1.5 equiv) and sealed with a septum cap. The vial was evacuated and flushed with argon three times. Under positive pressure of argon, anhydrous isopropanol (0.5 mL, c = 0.2 M) was added through the septum and the reaction mixture was placed in a preheated metal heating block at 60 °C for 12 h. After cooling to 25 °C, triethylamine (28 µL, 20 mg, 0.20 mmol, 2.0 equiv), the corresponding amine (0.20 mmol, 2.0 equiv), and a solution of N-chlorosuccinimide (26.7 mg, 0.200 mmol, 2.00 equiv) in THF (0.5 mL) were added sequentially through the septum. After stirring the reaction mixture at 25 °C for 1 h, the solvent was removed under reduced pressure, and the crude product was purified by chromatography on silica gel to afford the sulfonamide product.
NOTE: For convenience, we have stored and weighted the Pd(dppf)Cl2, Rongalite, and TT salts in a N2-filled glovebox.

2-Phenylethyl acetate-derived thianthrenium tetrafluoroborate TT-2
Under ambient atmosphere, a 100 mL round bottom flask equipped with a magnetic stir bar was charged with 2-phenylethylacetate (1.64 g, 10.0 mmol, 1.00 equiv) and MeCN (40 mL, c = 0.25 M). Trifluoroacetic anhydride (4.17 mL, 6.30 g, 30.0 mmol, 3.00 equiv) was added at ambient temperature while stirring. After cooling to 0 °C, thianthrene-S-oxide (S2) (2.56 g, 11.0 mmol, 1.10 equiv) was added in one portion, followed by the addition of HBF4•OEt2 (2.04 mL, 2.43 g, 15.0 mmol, 1.50 equiv). The vial was sealed with a screw-cap, and the mixture was stirred at 0 °C for 1 h, followed by stirring at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure and subsequently diluted with DCM (50 mL). The solution was poured onto a saturated aqueous NaHCO3 solution (50 mL), and the layers were separated. The organic phase was washed with aqueous NaBF4 solution (2 × 50 mL, 10%). The organic phase was dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with DCM / MeOH (1:0-20:1 (v/v)) to afford 3.54 g (76%) of TT-2 as a yellow foam.

Bifonazole morpholine sulfonamide derivative (19)
In an argon-filled glovebox, an oven dried borosilicate 4 mL reaction vial equipped with a magnetic stir bar was
The resulting mixture was stirred for 1 h. After stirring the reaction mixture at 25 °C for 1 h, the solvent was removed under reduced pressure, and the crude product was purified by chromatography on silica gel eluting with hexanes / EtOAc (1:0-5:1 (v/v)) to afford 21 mg (66%) of 39 as a white solid. Rf = 0.51 (hexanes / ethyl acetate, 1:1 (v/v)).
The resulting mixture was heated at 90 °C and stirred at this temperature for 12 h. After cooling to 25 °C, sat.