Difluoromethanesulfonyl hypervalent iodonium ylides for electrophilic difluoromethylthiolation reactions under copper catalysis

Difluoromethanesulfonyl hypervalent iodonium ylides 2 were developed as electrophilic difluoromethylthiolation reagents for a wide range of nucleophiles. Enamines, indoles, β-keto esters, silyl enol ethers and pyrroles were effectively reacted with 2 affording desired difluoromethylthio (SCF2H)-substituted compounds in good to high yields under copper catalysis. The reaction of allyl alcohols with 2 under the same conditions provided difluoromethylsulfinyl (S(O)CF2H) products in good yields. The difluoromethylthiolation of enamines is particularly effective with wide generality, thus the enamine method was nicely extended to the synthesis of a series of difluoromethythiolated cyclic and acyclic β-keto esters, 1,3-diketones, pyrazole and pyrimidine derivatives by a consecutive, two-step one-pot reaction using 2.


General Information
All reactions were performed in oven-dried glassware under a positive pressure of nitrogen. Solvents were transferred via syringe and were introduced into the reaction vessels through a rubber septum. All solvents were purified by standard method. All of the reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica gel (60-F254). The TLC plates were visualized with UV light or KMnO 4 in water/heat. All of the reaction products were purified by Column chromatography. Column chromatography was carried out on a column packed with silica gel 60N spherical neutral size 63-210 mm. The 19 F NMR (282 MHz) and 1 H NMR (300 MHz) in CDCl 3 , (CD 3 ) 2 CO or (CD 3 ) 2 SO were recorded on a Varian Mercury 300. 13 C NMR (125 MHz) spectra for solution in CDCl 3 , CD 3 CN or (CD 3 ) 2 SO were recorded on a BRUKER Advance 500. Chemical shifts () are expressed in ppm downfield from internal TMS (= 0.00) or C 6 F 6 [= -162.2 (CDCl 3 ) or -163.5 ((CD 3 ) 2 CO)] as an internal standard. Coupling constants (J) are in Hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Mass spectra were recorded on a SHIMADZU GCMS-QP5050A (EI-MS) and SHIMAZU LCMS-2020 (ESI-MS and APCI-MS). Infrared spectra were recorded on JASCO FT/IR-200 or a JASCO FT/IR-4100 spectrometer.

Preparation of Reagent 2a-d and Starting Materials
Synthesis of Reagent 2a-d Scheme S1. Synthesis of reagent 2a-d

Synthesis of reagent 2a:
A mixture of 2-bromo-4'-nitoroacetophenone (2.00 g, 8.2 mmol) and sodium difluoromethanesulfinate (1.25 g, 9.1 mmol) in DMAc (70 mL) was stirred at 50 ºC for 20 h. Then water (50 mL) was added to the mixture at room temperature. The resulting mixture was extracted with Et 2 O and organic layer was washed with water 2 times, brine for once then dried over magnesium sulfate. The solvent was removed by rotary evaporation to give a crude product then the crude product was purified by frash column chromatography on silica gel (eluent: ethyl acetate/hexane =1/1, Rf = 0.5 -0.6). A yellow solid (1-(4-

Experimental Details (A) General procedure for difluoromethylthiolation of enamines 3, indoles 5 and pyrroles 7.
To a mixture of enamine 3, indole 5 or pyrrole 7 (0.2 mmol) and Cu(I)Br (0.04 mmol) in 1,4-dioxane (2.5 mL), reagent 2a (0.4 mmol) or 2d (0.4 mmol) was added at room temperature under N 2 . The resulting mixture was stirred at room temperature for 5 h and then filtered through a short plug of celite. The filtrate was concentrated under reduced pressure and purified through flash column chromatography on silica gel (ethyl acetate/hexane) to afforded the target product.

(B) General procedure for difluoromethylthiolation of -keto esters 9
To a mixture of -keto ester 9 (0.2 mmol) Cu(I)Br (0.04 mmol) and K 2 CO 3 (0.08 mmol) in 1,4-dioxane (2.5 mL), reagent 2d (0.4 mmol) was added at room temperature under N 2 . The resulting mixture was stirred at room temperature for 24 h and then filtered through a short plug of celite. The filtrate was concentrated under reduced pressure and purified through flash column chromatography on silica gel (ethyl acetate/hexane) to afforded the target product.
(C) General procedure for reaction of ally alcohols 11 with reagent 2.
To a mixture of ally alcohol (0.20 mmol) and CuF 2 (0.04 mmol) in DMAc (2.5 mL), reagent 2a (0.4 mmol) was added at room temperature under N 2 . After stirring at room temperature for 24 h, water (2.0 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate, the organic phase was washed with water 2 times and saturated sodium bicarbonate solution over 5 times to remove the starting material and brine once then dried over magnesium sulfate. The solvent was removed by rotary evaporation and purified through flash column chromatography on silica gel (ethyl acetate/hexane) to afforded the target product. After stirring at room temperature for 5 h, 1N-HCl aq (1.0 mL) was added to the reaction mixture. The resulting mixture was continuously stirred for 12 h (for 24 h when 3q or 3r was a starting material), then extracted with ethyl acetate, the organic phase was washed with water 2 times and brine once then dried over magnesium sulfate. The solvent was removed by rotary evaporation and purified through flash column chromatography on silica gel (ethyl acetate/hexane) to afforded the target product. To a mixture of -keto esters (0.2 mmol), CuF 2 (0.04 mmol) and Potassium carbonate (0.04 mmol) in DMAc (2.5 mL), reagent 2d (0.4 mmol) was added at room temperature under N 2 . After stirring at room temperature for 18 h or 16 h. The resulting mixture was then extracted with ethyl acetate, the organic phase was washed with water and brine once then dried over magnesium sulfate. The solvent was removed by rotary evaporation and purified through flash column chromatography on silica gel (DCM/hexane) to afforded the target product.
(F) General procedure for reaction of silyl enol ether 9d with reagent 2.
To a mixture of silyl enol ether (0.20 mmol) and CuBr (0.04 mmol) in 1,4-dioxane (2.5 mL), reagent 2d (0.4 mmol) was added at room temperature under N 2 . After stirring at room temperature for 18 h, 1 N HClaq (1.0 mL) was added to the mixture and stirring at room temperature for 30 min. The resulting mixture was extracted with ethyl acetate, the organic phase was washed with water 2 times and brine once then dried over magnesium sulfate. The solvent was removed by rotary evaporation and purified through flash column chromatography on silica gel (DCM/hexane) to afforded the target product. Reagent 2a-d (0.1 mmol, respectively) was put into a glass tube at room temperature in air atmosphere. After 1 h, 5 h, 10 h and 24 h respectively, CDCl 3 and PhF (0.2 mmol: an internal standard) were added to the resulting reagent. The residual rate of reagent was immediately analyzed by 19 F NMR spectroscopy.

Scheme S2. Reaction of 3m with Reagent 2a under Different conditions
(1): To a mixture of enamine 3m (0.1 mmol) and Cu(I)Br (2.9 mg, 0.02 mmol) in 1,4-dioxane (1.3 mL), reagent 2a (174.5 mg, 0.2 mmol) was added at room temperature under N 2 . The resulting mixture was stirred at room temperature for 5 h and then filtered through a short plug of celite. The filtrate was concentrated under reduced pressure then analyzed by 19 F NMR spectroscopy with PhF (18.4 L, 0.2 mmol) as an internal standard.
(2): The mixture of Cu(I)Br (2.9 mg, 0.02 mmol), 2a (174.5 mg, 0.2 mmol) and 1,4-dioxane (1.3 mL) was stirred at room temperature for 20 min under N 2 . 3m was added to the resulting mixture and then stirred for 5 h. The reaction mixture was filtered through a short plug of celite. The filtrate was concentrated under reduced pressure then analyzed by 19 F NMR spectroscopy with PhF (18.4 L, 0.2 mmol) as an internal standard.

Scheme S3. GCMS Analysis of Difluoromethylthiolation of 3m with 2d
To a mixture of enamine 3m (18.9 mg, 0.1 mmol) and Cu(I)Br (2.8 mg, 0.02 mmol) in 1,4-dioxane (1.3 mL), reagent 2d (104.7 mg, 0.2 mmol) was added at room temperature under N 2 . The resulting mixture was stirred at room temperature for 5 h and then filtered through a short plug of celite. The filtrate 0.1 mL was added into CH 2 Cl 2 1.5 mL then the resulting mixture 5 L was analyzed by GCMS.
GCMS analytical data of the reaction mixture of 3m, CuBr and reagent 2d. All peak data (Peak 1-3)   atmosphere. b 19 F NMR yields with PhF as an internal standard.

4-(Difluoromethyl)thio-3-phenyl-1H-pyrazole (13)
To a mixture of enamine 3z (35.2 mg, 0.2 mmol, 1.0 equiv) and Cu(I)Br (5.7 mg, 0.04 mmol, 20 mol%) in 1,4-dioxane (2.5 ml), reagent 2a (174.5 mg, 0.4 mmol, 2.0 equiv) was added at room temperature. After stirring at room temperature for 5 h, hydrazine monohydrate (48.6 L, 1.0 mmol, 5.0 equiv) was added to the reaction mixture. The resulting mixture was continuously stirred at 90 °C for 5 h, then 2 mL of water was added and extracted with ethyl acetate, the organic phase was washed with water 2 times and brine once then dried over magnesium sulfate. The solvent was removed by rotary evaporation and purified through flash column chromatography on silica gel