Supporting Information

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1 Supporting Information Difluoromethylthiolation of Phenols and Related Compounds with an HF 2 CSO 2 Na/Ph 2 PCl/Me 3 SiCl System Zhongyan Huang, Okiya Matsubara, Shichong Jia, Etsuko Tokunaga, and Norio Shibata Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya , Japan Contents. Table S General Information Preparing substrates 3 and Difluoromethylthiolation of nucleophiles 3 and Copies of H, C and 9 F NMR spectra S

2 . Table S Table S. Optimization of Reaction Conditions a entry R 2 PCl add.(mol %) sol. temp. ( o C) (time) yield (%) b P - MeCN 25 (2 h) 2 P - MeCN 9 (2 h) 4 3 P AlCl 3 (2) MeCN 9 (2 h) < 5 4 P TsOH/H 2 O (2) MeCN 9 (24 h) 9 5 P TfOH () MeCN 9 (24 h) 8 6 P Me 3 SiOTf () MeCN 9 (24 h) 33 7 P Me 3 SiCl (5) MeCN 9 (24 h) 5 8 P Me 3 SiCl (5) DMF 9 (24 h) 26 9 P Me 3 SiCl (5) EtOAc 9 (24 h) trace P Me 3 SiCl (5) dioxane 9 (24 h) trace P Me 3 SiCl (5) toluene 9 (24 h) 4 2 P 2 Me 3 SiCl (5) MeCN 9 (24 h) 26 P 3 Me 3 SiCl (5) MeCN 9 (24 h) < 5 4 P 4 Me 3 SiCl (5) MeCN 9 (24 h) 5 P 5 Me 3 SiCl (5) MeCN 9 (24 h) 6 c P Me 3 SiCl (5) MeCN 9 (24 h) 62 7 d P Me 3 SiCl (5) MeCN 9 (2 h) 83 a Reaction conditions: HF 2 CSO 2 Na (.2 mmol) in.75 ml of solvent, Ph 2 PCl (.2 mmol) was added, stirred at room temperature for 3 min. Then, 2-naphthol (3a,. mmol) in.25 ml of solvent was added in the presence of additives. The reaction was conducted at room temperature, or heated. b Yields were determined by 9 F NMR spectroscopy with trifluoromethyl benzene as the internal standard. c 3. equivalents of HF 2 CSO 2 Na/Ph 2 PCl was used. d 4. equivalents of HF 2 CSO 2 Na/Ph 2 PCl was used. P : chlorodiphenylphosphane; P 2 : chlorodi-o-tolylphosphane; P 3 : chlorodicyclo-hexylphosphane; P 4 : chlorodi(furan-2-yl)phosphane; P 5 : di-tert-butylchloro-phosphane. S2

3 2. General Information All reagents were used as received from commercial sources, unless specified otherwise, or prepared as described in the literature. Reactions requiring anhydrous conditions were performed in flame-dried glassware under a positive pressure of nitrogen. Reaction mixtures were stirred magnetically. Solvents were transferred via syringe and were introduced into the reaction vessels though a rubber septum. All of the reactions were monitored by thin-layer chromatography (TLC) carried out on.25 mm Merck silica-gel (6-F254). The TLC plates were visualized with UV light and 7% phosphomolybdic acid or KMnO 4 in water/heat. Preparative thin-layer plates (PLC) carried out on 2. mm Merck silica gel (6- F254). Column chromatography was carried out on a column packed with silica-gel 6N spherical neutral size 63-2 μm. The H NMR (3 MHz) with TMS (δ =. ppm) as internal and 9 F NMR (282 MHz) spectra was recorded on a Varian Mercury 3 with Cl 3 CF (δ =. ppm) as internal. The C NMR (25 MHz) was recorded on a Bruker Avance 5. Chemical shifts (δ) are reported in parts per million and coupling constants (J) are in hertz. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. All the melting points are uncorrected. Mass spectra were recorded on SHIMAZU LCMS-2EV (ESI-MS). Infrared spectra were recorded on a JASCO FT/ IR-2 spectrometer. S3

4 3. Preparing substrates 3 and 5 Synthesis of chromane-5,7-diol (3m),3-Dibromopropane (.88 ml, 8.7 mmol,. equiv.) in ml ethanol was added dropwise to a mixture of phloroglucinol ( g, 7.9 mmol,. equiv.) in 2N NaOH ( ml). The mixture was stirring at room temperature for h. After that the reaction was acidified to PH 2 with N HCl under ice-bath. The mixture was extracted with ethyl acetate (3 2 ml). The combined organic solution was dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with acetone/dichloromethene (2/8, v/v) as eluent to afford chromane-5,7- diol (3m) (265 mg, 2%) as a white solid. H NMR (3 MHz, CDCl 3 ) δ: 8.5 (brs, H), 7.86 (brs, H), 5.96 (s, H), 5.79 (s, H), 4.3 (t, J = 5. Hz, 2H), 2.53 (t, J = 6.6 Hz, 2H), (m, 2H). The product was identified by comparison of the spectral data with the reported data. Reference: S. A. Belapure, Z. G. Beamer, J. E. Bartmess, S. R. Campagna, Tetrahedron 2, 67, Synthesis of iridol (3n) KOH ( mg,.8 mmol,.36 equiv.) was added to a mixture of 3,4,5-trimethoxybenzaldehyde (98 mg, 5 mmol,. equiv.) and N 2 H 4 H 2 O (.5 ml, mmol, 2. equiv.) in 3 ml ethane glycol, then the mixture was heated at 7 o C for 2 h, 2 o C for h, and 5 o C for 2 h. The mixture was poured into 5 ml H 2 O and extracted with Et 2 O (3 3 ml). The combine organic phase was washed by brine and dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/6, v/v) as eluent to afford,2,3- trimethoxy-5-methylbenzene as colorless liquid (758 mg, 83%). The above,2,3-trimethoxy-5-methylbenzene (364 mg, 2 mmol,. equiv.) and t BuONa (796 mg, 8 mmol, 4. equiv.) was added to sealed tube, then 5 ml DMSO was added under argon atmosphere, the tube was sealed and heated at 4 o C for 24 h. After cooling to room temperature, the mixture was poured into 5 ml H 2 O and acidified to PH 5-6 with 2N HCl. The solution was extracted with DCM (3 5 ml), the combine organic solution was washed with brine and dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/6, v/v) as eluent to afford iridol (3n) as white solid (22 mg, 37%). H NMR (3 MHz, CDCl 3 ) δ: 6.42 (s, H), 6.28 (s, H), 5.69 (s, H), 3.86 (s, 3H), 3.84 (s, 3H), 2.26 (s, 3H). The product was identified by comparison of the spectral data with the reported data. Reference: Zhang, M.- X.; Hu, X.-H.; Xu, Y.-H.; Loh, T.-P. Asian J. Org. Chem. 25, 4, 47. S4

5 Synthesis of 3-phenylisoxazol-5-amine (3r) To a mixture of benzoylacetonitrile (58 mg, 4 mmol,. equiv.), NaOH (328 mg, 8.2 mmol, 2.5 equiv.) in 4 ml H 2 O in sealed tube, NH 2 OH HCl (.9 ml, 3.62 mmol,.5 equiv.) was added, and the tube was sealed. The mixture was heated at 2 o C oil-bath for 3 h. After cooling to room temperature, the mixture extracted with DCM (2 5 ml), the combine organic solution was washed with brine and dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure to afford 3- phenylisoxazol-5-amine (3r) as white solid (45 mg, 7%). H NMR (3 MHz, CDCl 3 ) δ: (m, 2H), (m, 3H), 5.43 (s, H), 4.55 (brs, 2H). The product was identified by comparison of the spectral data with the reported data. Reference: Bourbeau, M. P.; Rider, J. T. Org. Lett. 26, 8, Synthesis of -methyl-3-phenyl-h-pyrazol-5-amine (3s) Benzoylacetonitrile (5 mg, 3.44 mmol,. equiv.), MeNHNH 2 (.9 ml, 3.62 mmol,.5 equiv.) was added to sealed tube, and the tube was sealed. The mixture was heated at 2 o C oil-bath for 3 h. After cooling to room temperature, the mixture was purified by column chromatography with ethyl acetate/hexane (/, v/v) as eluent to afford -methyl-3-phenyl-h-pyrazol-5-amine (3s) as white solid (46 mg, 77%). H NMR (3 MHz, CDCl 3 ) δ: 7.72 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, H), 5.85 (s, H), 3.7 (s, H), 3.53 (brs, 2H). The product was identified by comparison of the spectral data with the reported data. Reference: Bagley, M. C.; Davis, T.; Dix, M. C.; Widdowson, C. S.; Kipling, D. Org. Biomol. Chem. 26, 4, 458. Synthesis of 5,7-dihydroxy-4H-chromen-4-one (5a) BF 3 Et 2 O (.52 ml, 2 mmol, 4. equiv.) was added dropwise into a solution of -(2,4,6- trihydroxyphenyl)ethanone (56 mg, 3 mmol,. equiv.) in 5 ml DMF. The reaction was transferred to an oil bath at 9 o C, then a solution of MsCl (.7 ml, 9 mmol, 3 equiv.) in 2 ml DMF was added. The reaction was heated at 9 o C for 3 h, and then cooled and slowly poured into ml ice-water. The black solid was filtered off, and washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The organic mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexene (2/3, v/v) as eluent to afford 5,7-dihydroxy-4H-chromen-4- one (5a) (255 mg, 47%) as a yellow solid. H NMR (3 MHz, (CD 3 ) 2 CO) δ: 2.76 (brs, H), 9.64 (brs, H), 8.6 (d, J = 6.3 Hz, H), 6.39 (s, H), 6.26 (s, H), 6.22 (d, J = 6.3 Hz, H). The product was identified by comparison of the spectral data with the reported data. Reference: Wei, G.; Yu, B. Eur. J. Org. Chem. 28, 356. S5

6 Synthesis of 5,7-dihydroxy-2H-chromen-2-one (5b) Methyl propiolate (.67 ml, 7.5 mmol,.5 equiv.) was added to a ml flask containing phloroglucinol (63 mg, 5 mmol,. equiv.) and ZnCl 2 (68 mg, 5 mmol,. equiv.). The reaction was heated at o C for 5 h and quenched with 2N HCl ( ml). The mixture was extracted with ml ethyl acetate. The organic phase was washed with brine, and dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/2, v/v) as eluent to afford 5,7-dihydroxy-2H-chromen-2-one (5b) (579 mg, 65%) as a yellow solid. H NMR (3 MHz, DMSO-d 6 ) δ:.66 (brs, H),.38 (brs, H), 7.94 (d, J = 9.6 Hz, H), 6.25 (s, H), 6.7 (s, H), 6.2 (d, J = 9.6 Hz, H). The product was identified by comparison of the spectral data with the reported data. Reference: Kaufmann, K. D.; Kelly, R. C. J. Heterocycl. Chem. 965, 2, 9. Synthesis of 4-hydroxy-chromen-2-one (5c) '-Hydroxyacetophenone (953 mg, 7 mmol,. equiv.) was added portion-wise to a suspension of NaH (.43 g, 35 mmol, 5. equiv.) in 2 ml toluene. The reaction was stirred at room temperature for 3 min, and then diethyl carbonate (.7 ml,.5 mmol,.5 equiv.) in 4 ml toluene was added drop-wise, after that the reaction was heated to reflux for 3 h. The precipitate was filtered after cooling to room temperature and washed with 2N HCl, H 2 O and Et 2 O to give 4-hydroxy-chromen-2-one (5c) as white solid (765 mg, 68%). H NMR (3 MHz, DMSO-d 6 ) δ: 7.8 (d, J = 7.8 Hz, H), 7.62 (t, J = 7.8 Hz, H), 7.35 (d, J = 7.8 Hz, H), 7.33 (t, J = 7.8 Hz, H),5.57 (s, H). The product was identified by comparison of the spectral data with the reported data. Reference: Ogawa, A.; Kondo, K.; Murai, S.; Sonoda, N. J. Chem. Soc., Chem. Commun. 982, 283. Synthesis of 2-amino-chromen-4-one (5d) The solution of 3-(dimethylamino)--(2-hydroxyphenyl)prop-2-en--one (8 mg, 4.8 mmol,. equiv.) and NH 2 OH HCl (436 mg, 6.27 mmol,.5 equiv.) in 5 ml EtOH was heated to reflux for h. Ice-water (3 ml) was added after the solvent was removed under reduced pressure. The solid was filtered and washed with H 2 O, dried in the air overnight to provide 5-phenylisoxazole as white solid (52 mg, 86%). The product was used in the next step without any purification. The above 5-phenylisoxazole (322 mg, 2 mmol,. equiv.), Et 3 N (.56 ml, 4 mmol, 2. equiv.) was added to sealed tube, and the tube was sealed after 5 ml DMF was added. The mixture was heated at 45 o C oil-bath for 2 h. Ice-water (3 ml) was added after DMF was removed under reduced pressure. S6

7 The solid was filtered and washed with H 2 O, then recrystallized from MeOH to give 2-amino-chromen- 4-one (5d) as yellow solid (28 mg, 68%). H NMR (3 MHz, DMSO-d 6 ) δ: 7.9 (d, J = 7.5 Hz, H), 7.6 (t, J = 7.5 Hz, H), 7.52 (brs, 2H), 7.36 (d, J = 7.5 Hz, H), 7.34 (t, J = 7.5 Hz, H), 5.8 (s, H). The product was identified by comparison of the spectral data with the reported data. Reference: Ghosh, T.; Saha, S.; Bandyopadhyay, C. Synthesis 25, 845. Synthesis of 2-(3,4-dihydroxyphenethyl)isoindoline-,3-dione (5g) A suspension of phthalic anhydride (.96 g,.2 mmol) in 8 ml toluene in an oven dried round bottom flask fitted with Dean-Stark apparatus was heated to reflux until complete dissolution of the anhydride and no additional water was removed. To this solution was added appropriate phenethylamines (2.7 g, 2 mmol) and refluxing was continued for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was recrystallized from ethyl acetate/hexane to give 2-(3,4- dimethoxyphenethyl)isoindoline-,3-dione (3.25 g, 86%) as pale yellow solid. The above 2-(3,4-dimethoxyphenethyl)isoindoline-,3-dione (32 mg, mmol) in 2 ml DCM in an oven dried two neck round bottom flask bearing septum in side arm was cooled to -5 C. BBr 3 (3 ml, M soln. in DCM) was added dropwise under nitrogen atmosphere. After 2 h, the reaction mixture was quenched with water ( ml). The organic layer was separated and aqueous layer was extracted with dichloromethane (2 5 ml). The combined organic extract was washed with brine solution and dried over anhydrous Na 2 SO 4. The mixture was concentrated under reduced pressure. The residue was purified through column chromatography using ethyl acetate and hexane (5:) as eluent to afford 2-(3,4- dihydroxyphenethyl)isoindoline-,3-dione (5g) (52 mg, 54%) as yellow solid. H NMR (3 MHz, CD 3 OD): δ (m, 4H), 6.63 (s, H), 6.6 (d, J = 7.8 Hz, H), 6.49 (d, J = 7.8 Hz, H), 4.87 (brs, 2H), 3.8 (t, J = 7.2 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H). The product was identified by comparison of the spectral data with the reported data. Reference: Selvakumar, J.; Ramanathan, C. R. Org. Biomol. Chem. 2, 9, Difluoromethylthiolation of nucleophiles 3 and 5 -((Difluoromethyl)thio)naphthalen-2-ol (4a) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2-naphthol (29 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The S7

8 residue was purified by column chromatography with ethyl acetate/hexane (/9, v/v) as eluent to afford -((difluoromethyl)thio)naphthalen-2-ol as pale yellow solid (39.7 mg, 88%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 8.32 (d, J = 8.4 Hz, H), 7.9 (d, J = 9. Hz, H), 7.79 (d, J = 8. Hz, H), 7.6 (dd, J = 8.4, 8. Hz, H), 7.4 (dd, J = 8.4, 8. Hz, H), 7.29 (d, J = 9. Hz, H), 6.97 (brs, H), 6.67 (t, J = 57. Hz, H); C NMR (25 MHz, CDCl 3 ) δ 57.9, 5.8, 3.8, 29.3, 28.6, 28., 24.2, 24., 2.4 (t, J = Hz), 6.9, 2. (t, J = 2.5 Hz); 9 F NMR (282 MHz, CDCl 3 ) δ -9.6 (d, J = 56.9 Hz, 2F); IR (KBr) 3399, 35, 2958, 68, 595, 572, 459, 82, 92, 65, 42 cm - ; HRMS (ESI) calcd. for C H 7 F 2 OS [M-H] - : , Found: ((Difluoromethyl)thio)naphthalen--ol (4b) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then -naphthol (29 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/9, v/v) as eluent to afford 2-((difluoromethyl)thio)naphthalen--ol as brown solid (24.4 mg, 54%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 8.49 (d, J = 8.4 Hz, H), 8.25 (d, J = 8.4 Hz, H), 7.74 (d, J = 7.8 Hz, H), 7.65 (dd, J = 7.8, 7.2 Hz, H), 7.56 (dd, J = 7.8, 7.2 Hz, H), 6.8 (d, J = 7.8 Hz, H), 6.74 (t, J = 57. Hz, H); C NMR (25 MHz, CDCl 3 ) δ 54., 7.5, 6.5, 27.9, 25.9, 25.8, 25., 22.3, 2.3 (t, J = 275. Hz), 4. (t, J = 2.5 Hz), 8.5; 9 F NMR (282 MHz, CDCl 3 ) δ -92. (d, J = 57.2 Hz, 2F); IR (KBr) 3342, 355, 595, 5, 24, 263, 57 cm - ; HRMS (ESI) calcd. for C H 7 F 2 OS [M-H] - : , Found: ((Difluoromethyl)thio)-4-methoxynaphthalen--ol (4c) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 4-methoxynaphthalen--ol (34.8 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for.5 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/2, v/v) as eluent to afford 2-((difluoromethyl)thio)-4-methoxynaphthalen--ol as white solid (32 mg, 64%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 6.78 (s, H), 6.76 (t, J = 57. Hz, H), 6.63 (brs, H), 3.96 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 49.8, 49., 28.2, 27.7, 26.7, 24.3, 23., 22., 2.5 (t, J = Hz), 9.,.7 (t, J = 2.5 Hz), 56.8; 9 F NMR (282 S8

9 MHz, CDCl 3 ) δ -9.3 (d, J = 56.6 Hz, 2F); IR (KBr) 3426, 374, 324, 2942, 2834, 58, 459, 94, 24, 274, 255, 7, 57, 8 cm - ; HRMS (ESI) calcd. for C 2 H 9 F 2 O 2 S [M-H] - : , Found: ((Difluoromethyl)thio)-2,3-dimethylphenol (4d) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2,3-dimethylphenol (24.4 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/8, v/v) as eluent to afford 4-((difluoromethyl)thio)-2,3-dimethylphenol as colorless oil (3.8 mg, 78%). H NMR (3 MHz, CDCl 3 ) δ 7.37 (d, J = 8.4 Hz, H), 6.67 (t, J = 57. Hz, H), 6.65 (d, J = 8.4 Hz, H), 4.93 (brs, H), 2.48 (s, 3H), 2.2 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 55.3, 44., 6.2, 24.2, 2.3 (t, J = Hz), 6.3 (t, J = 2.5 Hz),.2, 8.4, 2.5; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56.9 Hz, 2F); IR (KBr) 3585, 3446, 38, 2965, 2923, 576, 47, 282, 53 cm - ; HRMS (ESI) calcd. for C 9 H 9 F 2 OS [M-H] - : , Found: ((Difluoromethyl)thio)-2,5-dimethylphenol (4e) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2,5-dimethylphenol (24.4 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/8, v/v) as eluent to afford 4-((difluoromethyl)thio)-2,5-dimethylphenol as pale yellow oil (22 mg, 54%). H NMR (3 MHz, CDCl 3 ) δ 7.34 (s, H), 6.7 (s, H), 6.67 (t, J = 57. Hz, H), 4.9 (brs, H), 2.4 (s, 3H), 2.2 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 55.6, 42.8, 4.3, 22.4, 2.3 (t, J = Hz), 7., 5.4 (t, J = 2.5 Hz), 2.9, 5.; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56.9 Hz, 2F); IR (KBr) 3593, 345, 2958, 2923, 65, 58, 499, 94, 294, 255, 69, cm - ; HRMS (ESI) calcd. for C 9 H 9 F 2 OS [M-H] - : , Found: ((Difluoromethyl)thio)-2,5,6-dimethylphenol (4f) S9

10 Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2,5,6-trimethylphenol (27.2 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/2, v/v) as eluent to afford 4-((difluoromethyl)thio)-2,5,6-trimethylphenol as pale yellow semi-solid (23.6 mg, 54%). H NMR (3 MHz, CDCl 3 ) δ 7.28 (s, H), 6.67 (t, J = 57.3 Hz, H), 4.79 (brs, H), 2.45 (s, 3H), 2.22 (s, 3H), 2.2 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 53.9, 4.2, 7.2, 23.3, 2.5 (t, J = Hz), 2., 5.4 (t, J = 2.5 Hz), 8.2, 5.5, 2.7; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56.9 Hz, 2F); IR (KBr) 36, 3392, 2989, 295, 2923, 2869, 463, 294, 29, 2, 69, 7 cm - ; HRMS (ESI) calcd. for C H F 2 OS [M-H] - : , Found: ((Difluoromethyl)thio)-2,3-dihydro-inden-5-ol (4g) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2,3-dihydro-inden-5-ol (26.8 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/9, v/v) as eluent to afford 6-((difluoromethyl)thio)-2,3-dihydro-inden-5-ol as pale yellow solid (5.2 mg, 35%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 7.33 (s, H), 6.92 (s, H), 6.67 (t, J = 57. Hz, H), 6.24 (brs, H), 2.89 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H), 2.7 (tt, J = 7.2, 7.2 Hz, 2H); C NMR (25 MHz, CDCl 3 ) δ 56.4, 5.8, 7., 2.7, 2.3 (t, J = 275. Hz),.5, 6.2 (t, J = 2.5 Hz), 33., 3.7, 25.7; 9 F NMR (282 MHz, CDCl 3 ) δ -92. (d, J = 56.9 Hz, 2F); IR (KBr) 3372, 2962, 2846, 6, 47, 32, 65, 46 cm - ; HRMS (ESI) calcd. for C H 9 F 2 OS [M-H] - : , Found: ((Difluoromethyl)thio)-4,5-dimethoxyphenol (4h) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 3,4-dimethoxyphenol (3.8 mg,.2 mmol,. equiv.) in.5 ml MeCN was S

11 added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/4, v/v) as eluent to afford 2-((difluoromethyl)thio)-4,5-dimethoxyphenol as white solid (36.5 mg, 78%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 6.94 (s, H), 6.66 (d, J = 57. Hz, H), 6.62 (s, H), 6. (brs, H), 3.88 (s, 3H), 3.84 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 53.5, 53.4, 43.3, 2.2 (t, J = Hz), 8.8, 99.5, 97.6 (t, J = 2.5 Hz), 56.5, 56.; 9 F NMR (282 MHz, CDCl 3 ) δ -92.2(d, J = 56.9 Hz, 2F); IR (KBr) 3338, 2962, 2935, 295, 285, 63, 522, 42, 263, 24, 73, 57, 23 cm - ; HRMS (ESI) calcd. for C 9 H 9 F 2 O 3 S [M-H] - : , Found: ((Difluoromethyl)thio)benzo[d][,3]dioxol-5-ol (4i) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then benzo[d][,3]dioxol-5-ol (27.6 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/4, v/v) as eluent to afford 6-((difluoromethyl)thio)benzo[d][,3]dioxol-5-ol as pale yellow solid (32.3 mg, 74%). M.p. 5-5 o C. H NMR (3 MHz, CDCl 3 ) δ 6.9 (s, H), 6.64 (t, J = 57. Hz, H), 6.58 (s, H), 6.22 (brs, H), 5.96 (s, 2H); C NMR (25 MHz, CDCl 3 ) δ 54.4, 5.9, 4.7, 2. (t, J = Hz), 5.,.8, 98.4 (t, J = 2.5 Hz), 97.5; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56.6 Hz, 2F); IR (KBr) 3438, 39, 355, 34, 2973, 299, 285, 626, 499, 47, 75, 278, 8, 57, 23 cm - ; HRMS (ESI) calcd. for C 8 H 5 F 2 O 3 S [M-H] - : , Found: ,6-Bis((difluoromethyl)thio)benzene-,3-diol (4j) Ph 2 PCl (25 μl,.2 mmol, 6. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na (65 mg,.2 mmol, 6. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then resorcinol (22 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/2.2, v/v) as eluent to afford 4,6-bis((difluoromethyl)thio)benzene-,3-diol as white solid (42 mg, 73%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 7.74 (s, H), 6.75 (s, H), 6.67 (t, J = 56.4 Hz, 2H), 6.58 (brs, 2H); C NMR (25 MHz, CDCl 3 ) δ 62.2, 47.2, 9.5 (t, J = Hz), 2.7, 2. (t, J = 2.5 Hz); 9 F NMR (282 MHz, S

12 CDCl 3 ) δ (d, J = 56.6 Hz, 2F); IR (KBr) 3423, 67, 568, 463, 4, 54, 57 cm - ; HRMS (ESI) calcd. for C 8 H 5 F 4 O 2 S 2 [M-H] - : , Found: ((Difluoromethyl)thio)-3-methoxyphenol (4k) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 3-methoxyphenol (24.8 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/6, v/v) as eluent to afford 4-((difluoromethyl)thio)-3-methoxyphenol as white solid (2.3 mg, 5%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 7.39 (d, J = 8. Hz, H), 6.79 (t, J = 57.9 Hz, H), 6.47 (s, H), 6.43 (d, J = 8. Hz, H), 5.37 (brs, H), 3.87 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 6.4, 59., 9., 2.6 (t, J = Hz), 8., 4.9 (t, J = 2.5 Hz), 99.7, 56.; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 58. Hz, 2F); IR (KBr) 348, 2973, 2946, 2838, 63, 584, 467, 425, 7, 92, 58, 46 cm - ; HRMS (ESI) calcd. for C 8 H 7 F 2 O 2 S [M-H] - : 25.5, Found: ((Difluoromethyl)thio)-5-methoxyphenol (4k ) as brown oil (2.5 mg, 3%). H NMR (3 MHz, CDCl 3 ) δ 7.4 (d, J = 8.4 Hz, H), 6.63 (t, J = 57. Hz, H), 6.59 (s, H), 6.53 (d, J = 8.4 Hz, H), 6.38 (brs, H), 3.8 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 63.9, 59.3, 8.6, 2. (t, J = 276. Hz), 8.4,.6,. (t, J = 2.5 Hz), 55.4; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56.9 Hz, 2F); IR (KBr) 346, 38, 2946, 299, 2842, 67, 572, 482,, 54, 69, 23 cm - ; HRMS (ESI) calcd. for C 8 H 7 F 2 O 2 S [M-H] - : 25.5, Found: ((Difluoromethyl)thio)-6-methylpyridine-2,4-diol (4l) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 6-methylpyridine-2,4-diol (25 mg,.2 mmol,. equiv.) was quickly added in one-pot with.75 ml MeCN washed, followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 6 h. The solvent was removed, and 3 ml HCl (N) was added. The suspension was filtered, and the solid was washed with ml HCl (N) and 3 ml H 2 O. The filtrate was S2

13 neutralized with Sat. NaHCO 3 (aq.) to PH 7-8. Removed water and the residue was extracted with 3 ml acetone. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane/acetone (//, v/v/v) as eluent to afford 5- ((difluoromethyl)thio)-6-methylpyridine-2,4-diol as white solid (2.4 mg, 49%). M.p o C. H NMR (3 MHz, CD 3 OD) δ 6.93 (t, J = 58.8 Hz, H), 5.95 (s, H), 4.89 (brs, 2H), 2.24 (s, 3H); C NMR (25 MHz, CD 3 OD) δ 72.7, 66.6, 49.8, 2.5 (t, J = Hz),.6, 94. (t, J = 3.7 Hz), 8.9; 9 F NMR (282 MHz, CD 3 OD) δ (d, J = 58.6 Hz, 2F); IR (KBr) 3244, 325, 324, 2935, 2823, 262, 256, 634, 59, 553, 455, 4, 57 cm - ; HRMS (ESI) calcd. for C 7 H 6 F 2 NO 2 S [M-H] - : 26.87, Found: ,8-Bis((difluoromethyl)thio)chromane-5,7-diol (4m) Ph 2 PCl (25 μl,.2 mmol, 6. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na (65 mg,.2 mmol, 6. equiv.) in.5 ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then chromane-5,7-diol (33.5 mg,.2 mmol,. equiv.) in.75 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with dichloromethene and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/5, v/v) as eluent to afford 6,8-bis((difluoromethyl)thio)chromane-5,7-diol as pale yellow solid (55 mg, 83%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 6.96 (brs, H), 6.9 (brs, H), 6.68 (t, J = 57.3 Hz, H), 6.65 (t, J = 57.3 Hz, H), 4.29 (t, J = 5. Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H), 2. (tt, J = 6.6, 5. Hz, 2H); C NMR (25 MHz, CDCl 3 ) δ 59.9, 59.6, 59.4, 9.7 (t, J = Hz), 9.6 (t, J = Hz),., 9. (t, J = 2.5 Hz), 88.2 (t, J = 2.5 Hz), 67.7, 2., 9.2; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 57.5 Hz, 2F), -93. (d, J = 57.5 Hz, 2F); IR (KBr) 3465, 343, 295, 2896, 584, 436, 7, 247, 96, 57, 23 cm - ; HRMS (ESI) calcd. for C H 9 F 4 O 3 S 2 [M-H] - : , Found: ((Difluoromethyl)thio)-2,3-dimethoxy-5-methylphenol (4n) and 2-((Difluoromethyl)thio)-5,6- dimethoxy-3-methylphenol (4n ) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then iridol (33.6 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/9, v/v) as eluent to afford a mixture of 4-((difluoromethyl)thio)-2,3-dimethoxy-5-methylphenol (4n) with 2-((difluoromethyl)thio)-5,6- S

14 dimethoxy-3-methylphenol (4n ) as pale yellow semi-solid (43.6 mg, 87%). 4n: H NMR (3 MHz, CDCl 3 ) δ 6.73 (t, J = 57.6 Hz, H), 6.69 (brs, H), 6.46 (s, H), 3.9 (s, 3H), 3.88 (s, 3H), 2.46 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 54.3, 5.6, 4.3, 3.8, 2.5 (t, J = 275. Hz), 6., 2.5 (t, J = 2.5 Hz), 6.9, 55.8, 2.6; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 57.2 Hz, 2F); 4n : H NMR (3 MHz, CDCl 3 ) δ 6.77 (t, J = 57.6 Hz, H), 6.39 (s, H), 5.9 (brs, H), 3.9 (s, 3H), 3.88 (s, 3H), 2.42 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 54.6, 5.2, 4.7, 8.2, 2.2 (t, J = 275. Hz), 2.6,. (t, J = 2.5 Hz), 6.8, 6.6, 2.5; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 57.8 Hz, 2F); IR (KBr) 3396, 34, 2973, 2942, 2846, 599, 576, 499, 459, 44, 242, 2, 9, 65 cm - ; HRMS (ESI) calcd. for C H F 2 O 3 S [M-H] - : , Found: (Difluoromethyl)(2,4-dimethoxyphenyl)sulfane (4o) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then,3-dimethoxybenzene (27.6 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/2, v/v) as eluent to afford (difluoromethyl)(2,4-dimethoxyphenyl)sulfane as colorless oil (28.6 mg, 65%). H NMR (3 MHz, CDCl 3 ) δ 7.46 (d, J = 9. Hz, H), 6.8 (t, J = 58.2 Hz, H), 6.5 (s, H), 6.49 (d, J = 9. Hz, H), 3.88 (s, 3H), 3.82 (s, 3H); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 58. Hz, 2F); MS (EI, m/z) 22 [M]. The product was identified by comparison of the spectral data with the reported data. Reference: Ismalaj, E.; Bars, D. L.; Billard, T. Angew. Chem. Int. Ed. 26, 55, ((Difluoromethyl)sulfinothioyl)-4-nitrobenzene (4p) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for min, then 4-nitrobenzene (3 mg,.2 mmol,. equiv.) was added as solid in onepot, and the reaction was heated at 9 o C for h. The solution was diluted with dichloromethene and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/5, v/v) as eluent to afford - ((difluoromethyl)sulfinothioyl)-4-nitrobenzene as yellow oil (4.6 mg, 3%). H NMR (3 MHz, CDCl 3 ) δ 8.22 (d, J = 9. Hz, 2H), 7.7 (d, J = 9. Hz, 2H), 6.8 (t, J = 56.4 Hz, H); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56.4 Hz, 2F); MS (EI, m/z) 237 [M]. The product was identified by comparison of the spectral data with the reported data. Reference: Zhu, D.; Gu, Y.; Lu, L.; Shen, Q. J. Am. Chem. Soc. 25, 7, 547. S4

15 2-((Difluoromethyl)thio)-3-(phenylamino)cyclohex-2-en--one (4q) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 3-(phenylamino)cyclohex-2-en--one (37.5 mg,.2 mmol,. equiv.) in. ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with dichloromethene and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/, v/v) as eluent to afford 2-((difluoromethyl)thio)-3-(phenylamino)cyclohex-2-en--one as colorless crystal (37.2 mg, 69%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 8.32 (brs, H), 7.42 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, H), 7.5 (d, J = 7.5 Hz, 2H), 6.75 (t, J = 58.8 Hz, H), 2.6 (t, J = 6.3 Hz, 2H), 2.54 (t, J = 6.3 Hz, 2H),.96 (tt, J = 6.3 Hz, 2H); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 58.9 Hz, 2F); MS (ESI, m/z) 268 [M-H] -. The product was identified by comparison of the spectral data with the reported data. Reference: Arimori, S.; Matsubara, O.; Takada, M.; Shiro, M.; Shibata, N. R. Soc. Open Sci. 26, 3, ((Difluoromethyl)thio)-3-phenylisoxazol-5-amine (4r) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 3-phenylisoxazol-5-amine (32 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with dichloromethene and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/3, v/v) as eluent to afford 4-((difluoromethyl)thio)-3-phenylisoxazol-5-amine as pale yellow solid (4 mg, 83%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ (m, 2H), (m, 3H), 6.54 (t, J = 57. Hz, H), 5.2 (brs, 2H); C NMR (25 MHz, CDCl 3 ) δ 72.5, 64.,., 28.5, 28.2, 28.2, 2.3 (t, J = Hz), 7.9 (t, J = 3.8 Hz); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56.6 Hz, 2F); IR (KBr) 348, 3388, 375, 3, 363, 2973, 63, 557, 486, 47, 46 cm - ; HRMS (ESI) calcd. for C H 7 F 2 N 2 OS [M-H] - : , Found: ((Difluoromethyl)thio)--methyl-3-phenyl-H-pyrazol-5-amine (4s) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room S5

16 temperature for 3 min, then -methyl-3-phenyl-h-pyrazol-5-amine (34.6 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with dichloromethene and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/, v/v) as eluent to afford 4-((difluoromethyl)thio)--methyl-3-phenyl-H-pyrazol-5-amine as pale yellow solid (38 mg, 74%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 7.88 (d, J = 6.9 Hz, 2H), (m, 3H), 6.5 (t, J = 57.6 Hz, H), 4.7 (brs, 2H), 3.72 (s, 3H); C NMR (25 MHz, CDCl 3 ) δ 52., 5.3, 2.4, 28.3, 28.2, 27.6, 2. (t, J = Hz), 8.2 (t, J = 3.7 Hz), 35.; 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 57.5 Hz, 2F); IR (KBr) 3399, 3288, 362, 32, 2946, 63, 557, 57, 82, 69, 23 cm - ; HRMS (ESI) calcd. for C H F 2 N 3 S [M-H] - : , Found: Methyl 2-((difluoromethyl)thio)-6-methyl--oxo-2,3-dihydro-H-indene-2-carboxylate (4t) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then methyl 6-methyl--oxo-2,3-dihydro-H-indene-2-carboxylate (38 mg,.2 mmol,. equiv.) in. ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with dichloromethene and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with dichloromethene/hexane (4/, v/v) as eluent to afford methyl 2-((difluoromethyl)thio)-6-methyl-- oxo-2,3-dihydro-h-indene-2-carboxylate as yellow oil (3.5 mg, 56%). H NMR (3 MHz, CDCl 3 ) δ 7.63 (s, H), 7.5 (d, J = 7.5 Hz, H), 7.49 (t, J = 69. Hz, H), 7.36 (d, J = 7.5 Hz, H), 3.98 (d, J = 7.7 Hz, H), 3.8 (s, 3H), 3.22 (d, J = 7.7 Hz, H), 2.43 (s, 3H); 9 F NMR (282 MHz, CDCl 3 ) δ -9.9 (dd, J = 25.7, 55.5 Hz, F), (dd, J = 25.7, 55.5 Hz, F); MS (ESI, m/z) 287 [M+H] +. The product was identified by comparison of the spectral data with the reported data. Reference: Arimori, S.; Matsubara, O.; Takada, M.; Shiro, M.; Shibata, N. R. Soc. Open Sci. 26, 3, ((Difluoromethyl)thio)--phenylethan--one (4u) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then acetophenone (24 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 6 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/25, v/v) as eluent to afford 2-((difluoromethyl)thio)--phenylethan--one as colorless oil (.2 mg, 28%). H NMR (3 MHz, CDCl 3 ) δ 7.97 (d, J = 6.9 Hz, 2H), 7.62 (t, J = 6.9 Hz, H), 7.5 (t, J = 6.9 Hz, 2H), 6.94 (t, J = 56. Hz, H), 4.32 (s, 2H); C NMR (25 MHz, CDCl 3 ) δ 93., 4.9, 3.9, 29., 28.4, 9.6 (t, J = S6

17 Hz), 34.4 (t, J = 3. Hz); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 56. Hz, 2F); IR (KBr) 363, 2962, 299, 285, 684, 58, 448, 2, 69, 26 cm - ; HRMS (ESI) calcd. for C 9 H 7 F 2 OS [M-H] - : 2.86, Found: ((Difluoromethyl)thio)-H-indole (4v) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml DMF under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then indole (23.5 mg,.2 mmol,. equiv.) with camphorsulfonic acid (9.2 mg,.4 mmol,.2 equiv.) in.75 ml DMF was added, and the reaction was heated at o C for 2 h. The solution was diluted with 4 ml Et 2 O and washed with H 2 O (2 2 ml), brine, dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/5, v/v) as eluent to afford 3-((difluoromethyl)thio)-Hindole as orange oil (37 mg, 92%). H NMR (3 MHz, CDCl 3 ) δ 8.42 (brs, H), 7.79 (d, J = 8.4 Hz, H), (m, 2H), (m, 2H), 6.67 (t, J = 57.6 Hz, H); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 57.5 Hz, 2F); MS (ESI, m/z) 98 [M-H] -. The product was identified by comparison of the spectral data with the reported data. Reference: Arimori, S.; Matsubara, O.; Takada, M.; Shiro, M.; Shibata, N. R. Soc. Open Sci. 26, 3, 62. -Benzyl-3-((difluoromethyl)thio)-H-indole (4w) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml DMF under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then -benzylindole (4.4 mg,.2 mmol,. equiv.) with camphorsulfonic acid (9.2 mg,.4 mmol,.2 equiv.) in.75 ml DMF was added, and the reaction was heated at o C for 2 h. The solution was diluted with 4 ml Et 2 O and washed with H 2 O (2 2 ml), brine, dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/5, v/v) as eluent to afford -benzyl-3- ((difluoromethyl)thio)-h-indole as yellow solid (57 mg, 98%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ (m, H), 7.38 (s, H), (m, 6H), 7. (d, J = 6.9 Hz, 2H), 6.66 (t, J = 57.6 Hz, H), 5.3 (s, 2H); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 57.5 Hz, 2F); MS (ESI, m/z) 29 [M+H] +. The product was identified by comparison of the spectral data with the reported data. Reference: Arimori, S.; Matsubara, O.; Takada, M.; Shiro, M.; Shibata, N. R. Soc. Open Sci. 26, 3, ((Difluoromethyl)thio)-3-methyl-H-indole (4x) S7

18 Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml DMF under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 3-methylindole (38.6 mg,.2 mmol,. equiv.) with camphorsulfonic acid (9.2 mg,.4 mmol,.2 equiv.) in.75 ml DMF was added, and the reaction was heated at o C for 2 h. The solution was diluted with 4 ml Et 2 O and washed with H 2 O (2 2 ml), brine, dried over Na 2 SO 4 anhydrous. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/5, v/v) as eluent to afford 2- ((difluoromethyl)thio)-3-methyl-h-indole as yellow solid (3. mg, 73%). M.p o C. H NMR (3 MHz, CDCl 3 ) δ 8.5 (brs, H), 7.58 (d, J = 7.8 Hz, H), (m, 2H), (m, H), 6.68 (t, J = 57. Hz, H), 2.4 (s, 3H); 9 F NMR (282 MHz, CDCl 3 ) δ -9.4 (d, J = 56.9 Hz, 2F); MS (ESI, m/z) 22 [M-H] -. The product was identified by comparison of the spectral data with the reported data. Reference: Arimori, S.; Matsubara, O.; Takada, M.; Shiro, M.; Shibata, N. R. Soc. Open Sci. 26, 3, ((difluoromethyl)thio)-5-phenyl-H-pyrrole (4y) Ph 2 PCl (72 μl,.4 mmol, 2. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na (56 mg,.4 mmol, 2. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2-phenyl-H-pyrrole (28.6 mg,.2 mmol,. equiv.) in.5 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for.5 h. The solution was diluted with Et 2 O and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/2, v/v) as eluent to afford 2-((difluoromethyl)thio)-5-phenyl-H-pyrrole as violet solid (3.5 mg, 7%). M.p. 3-3 o C. H NMR (3 MHz, CDCl 3 ) δ 8.55 (brs, H), 7.6 (d, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, H), 6.8 (d, J = 2.4 Hz, H), 6.7 (t, J = 57. Hz, H), 6.65 (t, J = 57. Hz, H); 9 F NMR (282 MHz, CDCl 3 ) δ (d, J = 57.5 Hz, 2F); MS (ESI, m/z) 224 [M-H] -. The product was identified by comparison of the spectral data with the reported data. Reference: Arimori, S.; Matsubara, O.; Takada, M.; Shiro, M.; Shibata, N. R. Soc. Open Sci. 26, 3, ((difluoromethyl)thio)-5,7-dihydroxy-4H-chromen-4-one (6a) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 5,7-dihydroxy-4H-chromen-4-one (35.6 mg,.2 mmol,. equiv.) was S8

19 quickly added in one-pot with.75 ml MeCN washed, followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/3, v/v) as eluent to afford 8-((difluoromethyl)thio)-5,7- dihydroxy-4h-chromen-4-one as white solid (.5 mg, 26%). M.p o C. H NMR (3 MHz, (CD 3 ) 2 CO) δ.23 (brs, H), 8.24 (d, J = 6. Hz, H), 7. (t, J = 57.3 Hz, H), 6.44 (s, H), 6.36 (d, J = 6. Hz, H); C NMR (25 MHz, (CD 3 ) 2 CO) δ 82.8, 66.8, 65.3, 6.4, 58., 2.6 (t, J = Hz), 2., 7.5, 99.8, 9. (t, J = 3.7 Hz); 9 F NMR (282 MHz, (CD 3 ) 2 CO) δ -94. (d, J = 57.2 Hz, 2F); IR (KBr) 394, 649, 564, 42, 58,, 42 cm - ; HRMS (ESI) calcd. for C H 5 F 2 O 4 S [M- H] - : , Found: ((Difluoromethyl)thio)-5,7-dihydroxy-2H-chromen-2-one (6b) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml DMF under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 5,7-dihydroxy-2H-chromen-2-one (35.6 mg,.2 mmol,. equiv.).75 ml DMF was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/3, v/v) as eluent to afford 8-((difluoromethyl)thio)-5,7-dihydroxy-2H-chromen-2-one as pale yellow solid (22.6 mg, 44%). M.p o C. H NMR (3 MHz, CD 3 OD) δ 8.8 (d, J = 9.6 Hz, H), 6.93 (t, J = 57.9 Hz, H), 6.4 (s, H), 6. (d, J = 9.6 Hz, H), 4.89 (brs, H); C NMR (25 MHz, CD 3 OD) δ 66.3, 63.2, 59.2, 58.9, 4., 2.6 (t, J = Hz),., 4.5, 98.8, 9.8 (t, J = 3.7 Hz); 9 F NMR (282 MHz, CD 3 OD) δ -95. (d, J = 57.8 Hz, 2F); IR (KBr) 3434, 3225, 35, 374, 2544, 244, 68, 595, 486, 436, 67, 239 cm - ; HRMS (ESI) calcd. for C H 5 F 2 O 4 S [M-H] - : , Found: ((Difluoromethyl)thio)-4-hydroxychromen-2-one (6c) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 4-hydroxychromen-2-one (32.4 mg,.2 mmol,. equiv.) was quickly added in one-pot with.75 ml MeCN washed, followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with acetone and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane/acetone (//, v/v/v) as eluent to afford 3-((difluoromethyl)thio)-4- hydroxychromen-2-one as white solid (27.2 mg, 56%). M.p o C. H NMR (3 MHz, CD 3 OD) S9

20 δ 7.98 (dd, J = 7.8,.5 Hz, H), 7.63 (td, J = 7.8,.5 Hz, H), 7.32 (td, J = 7.8,.5 Hz, H), 7.3 (d, J = 7.8 Hz, H), 7. (t, J = 58.5 Hz, H); C NMR (25 MHz, CD 3 OD) δ 73.8, 65.7, 54.8, 4.5, 25.9, 25.2, 2.9 (t, J = Hz), 8.7, 7.5, 88.7 (t, J = 2.5 Hz); 9 F NMR (282 MHz, CD 3 OD) δ (d, J = 58. Hz, 2F); IR (KBr) 344, 688, 63, 54, 42, cm - ; HRMS (ESI) calcd. for C H 5 F 2 O 3 S [M-H] - : , Found: Amino-3-((difluoromethyl)thio)chromen-4-one (6d) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2-aminochromen-4-one (32.2 mg,.2 mmol,. equiv.) was quickly added in one-pot with.75 ml MeCN washed, followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (2/3, v/v) as eluent to afford 2-amino-3-((difluoromethyl)thio)chromen-4-one as white solid (45.7 mg, 94%). M.p o C. H NMR (3 MHz, (CD 3 ) 2 CO) δ 8.5 (dd, J = 7.8,.5 Hz, H), 7.66 (td, J = 7.8,.5 Hz, H), 7.5 (brs, 2H), 7.4 (td, J = 7.8,.5 Hz, H), 7.36 (d, J = 7.8 Hz, H), 7. (t, J = 58.5 Hz, H); C NMR (25 MHz, (CD 3 ) 2 CO) δ 74., 68.2, 53.8, 3.8, 26.5, 25.8, 23., 2.8 (t, J = Hz), 7.4, 8.9 (t, J = 2.5 Hz); 9 F NMR (282 MHz, (CD 3 ) 2 CO) δ (d, J = 58.6 Hz, 2F); IR (KBr) 345, 32, 599, 572, 522, 69, cm - ; HRMS (ESI) calcd. for C H 6 F 2 NO 2 S [M-H] - : , Found: (2-((Difluoromethyl)thio)indol-3-yl)acetic acid (6e) Ph 2 PCl (43 μl,.8 mmol, 4. equiv.) was added drop-wise to a suspension of HF 2 SO 2 Na ( mg,.8 mmol, 4. equiv.) in ml MeCN under nitrogen atmosphere, and the reaction was stirred at room temperature for 3 min, then 2-(indol-3-yl)acetic acid (35 mg,.2 mmol,. equiv.) in.75 ml MeCN was added followed by TMSCl (26 μl,.3 mmol,.5 equiv.), and the reaction was heated at 9 o C for 2 h. The solution was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with ethyl acetate/hexane (/3, v/ v) as eluent to afford 2-(2-((difluoromethyl)thio)indol-3-yl)acetic acid as white solid (39.7 mg, 77%). M.p o C. H NMR (3 MHz, CD 3 OD) δ.6 (brs, H), 7.56 (d, J = 8. Hz, H), 7.37 (d, J = 8. Hz, H), 7.2 (dd, J = 8., 7.2 Hz, H), 7.6 (dd, J = 8., 7.2 Hz, H), 6.98 (t, J = 57.3 Hz, H), 4.89 (brs, H), 3.89 (s, 2H); C NMR (25 MHz, CD 3 OD) δ 75.2, 8.8, 28.4, 24.4, 22. (t, J = Hz), 2.4, 2., 8.4, 7.8 (t, J = 3.7 Hz), 2., 3.; 9 F NMR (282 MHz, CD 3 OD) δ (d, J = 57.2 Hz, 2F); IR (KBr) 34, 77, 432, 7, 9, 6 cm - ; HRMS (ESI) calcd. for C H 8 F 2 NO 2 S [M-H] - : , Found: S2