Supporting Information

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1 Supporting Information Iron-Catalyzed Difluoromethylation of Arylzincs with Difluoromethyl 2-Pyridyl Sulfone Wenjun Miao, Yanchuan Zhao, Chuanfa Ni, Bing Gao, Wei Zhang, and Jinbo Hu* Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai , China * S1

2 Table of Contents 1. General Information... S3 2. General Procedure for Preparation of Aryl Grignard Reagents... S4 3. Preparation of Ph 2 Zn... S4 4. Screening of Reaction Conditions for Iron-Catalyzed Difluoromethylation of Phenylmagenesium Bromide with Difluoromethyl 2-Pyridyl Sulfone... S5 4.1 General Procedure... S5 4.2 Survey of Metal Salts as Catalysts... S6 4.3 Evaluation of Reaction Solvents... S7 4.4 Evaluation of Ligands... S8 5. Screening of Reaction Conditions for Iron-Catalyzed Cross-Coupling of Ph 2 Zn Generated in situ with Difluoromethyl 2-Pyridyl Sulfone... S9 5.1 General Procedure... S9 5.2 Evaluation of Reaction Temperature... S Survey of Iron Salts as Catalysts... S Survey of Difluoromethyl Reagents... S Survey of the Amounts of TMEDA and Reaction Time... S12 6. General Procedure for Iron-Catalyzed Difluoromethylation of Difluoromethyl 2-Pyridyl Sulfone with Diarylzinc Reagnets Generated in situ... S12 7. Synthesis of Compounds 2q... S23 8. Scaling up the Difluoromethylation Reaction... S24 9. Synthesis of Compounds 1b... S Mechanistic Investigation... S Control Experiments with Additives... S Radical Cyclization... S Iron-Catalyzed Difluoromethylation of 2-PySO 2 CF 2 D with Ph 2 Zn... S Other Experiments... S References... S NMR Spectra... S33 S2

3 1. General Information Unless otherwise mentioned, reagents were purchased from commercial sources and used without further purification. THF (tetrahydrofuran), CPME (cyclopentyl methyl ether), DME (dimethoxyethane), t-buome (methyl tert-butyl ether), diethyl ether, and toluene were freshly distilled over sodium with the use of diphenyl ketone as an indicator. Anisole was distilled over sodium with the use of diphenyl ketone as an indicator and stored over activated 4Å molecular sieve. TMEDA (N,N,N,N -tetramethylethane-1, 2-diamine) and TMBDA (N,N,N,N -tetramethylbutane-1,4-diamine) were distilled over CaH 2, and stored over activated 4Å molecular sieve. Fe(acac) 3 were purchased from Aldrich. Anhydrous ZnBr 2 was purchased from Aldrich and stored in the glove-box. Lithium chloride (ultra dry, %) was purchased from Alfa Aesar and stored in the glove-box. PhMgBr (1.0 M in THF) was purchased from Aldrich. i-prmgcl-licl (1.3 M in THF) was purchased from Aldrich. NMR spectra were obtained on a Bruker AV400 or Agilent MR400 (400 MHz for 1 H NMR; 376 MHz for 19 F NMR; 100 MHz for 13 C NMR), or a Agilent MR500 (500 MHz for 1 H NMR; 125 MHz for 13 C NMR) spectrometer. 1 H NMR chemical shifts were determined relative to internal (CH 3 ) 4 Si (TMS) at δ 0.00 ppm or to the signal of a residual protonated solvent: CDCl 3 δ 7.26 ppm. 13 C NMR chemical shifts were determined relative to internal CDCl 3 at δ 77.0 ppm. 1 H, 13 C and 19 F multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), triplet of quartets (tq), multiplet (m), and broad resonance (br). Flash chromatography was performed using mesh SiliaFlash P60 (Silicycle Inc.). All the melting points were uncorrected. High-resolution mass data were recorded on a high-resolution mass spectrometer in the EI or ESI mode. S3

4 2. General Procedure for Preparation of Aryl Grignard Reagents An oven-dried 25-mL Schlenk round-bottom flask equipped with a reflux condenser and a stir bar was sealed and heated under vacuum for 2 minutes with the help of a heat gun. After cooling down, the Schlenk flask was back-filled with Ar. Mg turnings were added under a positive pressure of Ar. The Schlenk flask was then sealed, evacuated and back-filled with Ar (this process was repeated 3 times). A solution of the aryl bromide (2.0 mmol) in THF (3 ml) was added at room temperature. The reaction was initiated by gently heating the flask with a heat gun. Once the reaction had initiated, a solution of the aryl bromide (6.0 mmol) in THF (5 ml) was added dropwise over 10 minutes. The resulting mixture was stirred at 80 o C for 30 minutes, and then it was allowed to cool it to room temperature. 1 The Gignard reagent was titrated with I Preparation of Ph 2 Zn In an oven-dried Schlenk tube equipped with a stir bar, ZnBr 2 (270 mg, 1.2 mmol, 1.0 equiv) and LiCl (51 mg, 1.2 mmol, 1.0 equiv) were weighed in glove-box and the tube was heated under vaccum for 2 minutes with the help of a heat gun. After cooling down, the Schlenk tube was back-filled with Ar. THF (2 ml) was added and the mixture was allowed to stir at room S4

5 temperature for 5 minutes. Then PhMgBr (2.4 mmol, 2.0 equiv, 2.4 ml, 1.0 M in THF) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. A dense-grey solution was formed and used without further titration. 3 Left: ZnBr 2 and LiCl dried under vacuum with a heatgun. Center: Addition of THF after cooling down. Right: Addition of PhMgBr. 4. Screening of Reaction Conditions for Iron-Catalyzed Difluoromethylation of Phenylmagenesium Bromide with Difluoromethyl 2-Pyridyl Sulfone 4.1 General Procedure In an oven-dried Schlenk tube equipped with a stir bar, Fe(acac) 3 (21 mg, 0.06 mmol, 0.2 equiv) and 2-PySO 2 CF 2 H (58 mg, 0.3 mmol, 1.0 equiv) were weighed in glove-box, then the tube was sealed with a rubber septum and removed from the box. Outside of the glove-box, the Schlenk tube was then S5

6 evacuated and back-filled with Ar (this process was repeated 3 times). Then CPME (2.5 ml) was added to form a red solution. TMEDA (90 L, 0.6 mmol, 2.0 equiv) was added via syringe to the Schlenk tube. The mixture was then cooled to 40 ºC, followed by the addition of phenylmagenesium bromide (0.45 mmol, 1.5 equiv, 0.45 ml, 1.0 M in THF) via syringe dropwise over 10 min minutes. The mixture was allowed to warm to room temperature and stirred for 8 h at room temperature. After stirring for 8 h at room temperature, PhCF 3 was added as an internal standard, the reaction was monitored by 19 F NMR. 4.2 Survey of Metal Salts as Catalysts entry a catalyst (20 mol%) 2a, yield (%) b 1 Ni(acac) Cu(acac) Fe(acac) CoCl Pd(OAc) 2 0 a Reaction conditions: 1 (0.3 mmol), PhMgBr (0.45 mmol), catalyst (20 mol%), CPME (cyclopentyl methyl ether) (2.0 ml), 40 o C to rt, 8 h. b Yields are determined by 19 F NMR analysis of the crude reaction mixture using PhCF 3 as an internal standard. S6

7 4.3 Evaluation of Reaction Solvents entry a Ligand Solvent T 2a, yield (%) b 1 TMBDA (2.0 equiv) CPME 40 o C to rt 19 2 TMBDA (2.0 equiv) CPME 40 o C to 50 o C 27 3 TMBDA (2.0 equiv) Et 2 O 40 o C to rt 20 4 TMBDA (2.0 equiv) t-buome 40 o C to rt 13 5 TMBDA (2.0 equiv) DME 40 o C to rt 17 6 TMBDA (2.0 equiv) toluene 40 o C to rt trace 7 TMBDA (2.0 equiv) anisole 40 o C to rt 44 8 TMBDA (40 mol%) anisole 40 o C to rt 44 9 TMEDA (2.0 equiv) THF 40 o C to rt 9 10 TMEDA (40 mol%) THF 40 o C to rt 18 a Reaction conditions: 1 (0.3 mmol), PhMgBr (0.45 mmol), Fe(acac) 3 (20 mol%), solvent(2.0 ml), 40 o C to rt, 8 h. b Yields are determined by 19 F NMR analysis of the crude reaction mixture using PhCF 3 as an internal standard. S7

8 4.4 Evaluation of Ligands S8

9 5. Screening of Reaction Conditions for Iron-Catalyzed Cross-Coupling of Ph 2 Zn Generated in situ with Difluoromethyl 2-Pyridyl Sulfone 5.1 General Procedure In an oven-dried Schlenk tube equipped with a stir bar, ZnBr 2 (101 mg, 0.45 mmol, 1.5 equiv) and LiCl (19 mg, 0.45 mmol, 1.5 equiv) were weighed in glove-box, then the tube was heated under vaccum for 2 minutes with the help of a heat gun outside of the glove-box. After cooling down, the Schlenk tube was evacuated and back-filled with Ar (this process was repeated 3 times). THF (2.0 ml) was added and the mixture was allowed to stir at room temperature for 5 minutes. Then PhMgBr (0.9 mmol, 0.9 ml, 1.0 M in THF) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. A dense-grey solution was formed and used without further titration. The mixture was then cooled to 40 ºC. Under a positive pressure of Ar, the tube was opened, Fe(acac) 3 (21.2 mg, 0.06 mmol, 20 mol%) was added. Then the tube was sealed again and cooled to 40 ºC. TMEDA (90 L, 0.6 mmol, 2.0 equiv) was added to the mixture at 40 ºC, followed by the addition of a solution of 2-PySO 2 CF 2 H (0.3 mmol, 58 mg, 1.0 equiv.) in THF (1.5 ml) via syringe in one portion. The mixture was allowed to warm to room temperature and stirred for 8 h at room temperature. PhCF 3 was added as an internal standard, the reaction was monitored by 19 F NMR. S9

10 5.2 Evaluation of Reaction Temperature entry a catalyst ligand (equiv) T 2a, yield (%) b 1 Fe(acac) 3 TMEDA (2.0) 78 o C to rt 81 2 Fe(acac) 3 TMEDA (2.0) 20 o C to rt 90 3 Fe(acac) 3 TMEDA (2.0) 40 o C to rt 94 4 Fe(acac) 3 TMEDA (2.0) 0 o C to rt 86 5 Fe(acac) 3 TMEDA (2.0) rt 13 a Reaction condition: 1 (0.3 mmol), Ph 2 Zn (0.45 mmol), Fe(acac) 3 (20 mol%), TMEDA (2.0 equiv), THF,, 8 h. b Yields are determined by 19 F NMR analysis of the crude reaction mixture using PhCF 3 as an internal standard. 5.3 Survey of Iron Salts as Catalysts entry a catalyst ligand (equiv) T 2a, yield (%) b 1 FeCl 2 TMEDA (2.0) 40 o C to rt 72 2 FeBr 2 TMEDA (2.0) 40 o C to rt 84 3 Fe(acac) 2 TMEDA (2.0) 40 o C to rt 53 4 FeCl 3 TMEDA (2.0) 40 o C to rt 80 5 FeBr 3 TMEDA (2.0) 40 o C to rt 85 6 Fe(OTf) 3 TMEDA (2.0) 40 o C to rt 70 7 Fe(acac) 3 TMEDA (2.0) 40 o C to rt 94 a Reaction conditions: 1 (0.3 mmol), Ph 2 Zn (0.45 mmol), catalyst (20 mol%), TMEDA (2.0 equiv), THF, 40 o C to rt, 8 h. b Yields are determined by 19 F NMR analysis of the crude reaction mixture using PhCF 3 as an internal standard. S10

11 5.4 Survey of Difluoromethyl Reagents entry R CF 2 H 2a, yield (%) a a 0 3 4b 0 4 4c d 9 6 4e 6 7 4f 0 8 4g 0 9 4h 0 S11

12 5.5 Survey of the Amounts of TMEDA and Reaction Time entry catalyst ligand (equiv) 2a, yield (%) b 1 Fe(acac) 3 TMEDA (0) 0 2 Fe(acac) 3 TMEDA (0.4) 21 3 Fe(acac) 3 TMEDA (1.0) 48 4 Fe(acac) 3 TMEDA (1.5) 61 5 Fe(acac) 3 TMEDA (2.0) 94 6 c Fe(acac) 3 TMEDA (2.0) 95 a Reaction conditions: 1 (0.3 mmol), Ph 2 Zn (0.45 mmol), catalyst (20 mol%), THF (2.0 ml), 40 o C to rt, 8 h. b Yields were determined by 19 F NMR with PhCF 3 as an internal standard. c 2 h. 6. General Procedure for Iron-Catalyzed Difluoromethylation of Difluoromethyl 2-Pyridyl Sulfone with Diarylzinc Reagnets Generated in situ In an oven-dried Schlenk tube equipped with a stir bar, ZnBr 2 (270 mg, 1.2 mmol, 1.5 equiv) and LiCl (51 mg, 1.2 mmol, 1.5 equiv) were weighed in glove-box and the tube was heated under vaccum for 2 minutes with the help of a heat gun. After cooling down, the Schlenk tube was back-filled with Ar. THF (2 ml) was added and the mixture was allowed to stir at room temperature for 5 minutes. Then aryl Grignard reagents (2.4 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. A dense-grey solution was formed and used without further titration. The mixture was then cooled to 40 ºC. Under a positive pressure of Ar, S12

13 the tube was opened, Fe(acac) 3 (56.5 mg, 0.16 mmol, 20 mol%) was added. Then the tube was sealed again and cooled to 40 ºC. TMEDA (240 L, 1.6 mmol, 2.0 equiv) was added to the mixture at 40 ºC, followed by the addition of a solution of 2-PySO 2 CF 2 H (155 mg, 0.8 mmol, 1.0 equiv) in THF (1.5 ml) via syringe in one portion. The mixture was allowed to warm to room temperature and stirred for 2 h at room temperature. Then the mixture was quenched with saturated NH 4 Cl aqueous solution (1.0 ml) and diluted with diethyl ether. The organic layer was separated and dried over Na 2 SO 4 anhydrous, filtered and evaporated to dryness (for volatile compounds the solvent was carefully evaporated under rotary evaporation at 150 Torr at 25 ºC). Pure products were obtained after column chromatography. Left: Diarylzinc reagent was cooled to 40 o C. Center: Fe(acac) 3 weight. Right: Reaction mixture after addition of Fe(acac) 3. Left: Addition of TMEDA. Center: Addition of 2-PySO 2 CF 2 H. Right: Reaction mixture after addition of 2-PySO 2 CF 2 H at 40 o C. S13

14 Left: The Schlenk tube was taken out from cold bath after addition of 2-PySO 2 CF 2 H immediately. Center: Color change after 5 minutes. Right: The reaction mixture was stirred at rt for 2 h. 1-(difluoromethyl)naphthalene (2e, cas: ) 4, 6 Colorless oil (77.8 mg, 55% yield). This compound is known. 4, 6 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J = 8.2 Hz, 1H), (m, 2H), 7.65 (dd, J = 7.1, 0.9 Hz, 1H), (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.09 (t, J = 55.2 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 55.2 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ 133.7, (t, J = 1.6 Hz), (t, J = 2.5 Hz), (t, J = 20.8 Hz), 128.7, 127.1, 126.3, (t, J = 8.7 Hz), 124.6, (t, J = 1.1 Hz), (t, J = Hz). MS (EI, m/z): 178 (M + ), 178 (100.0). HRMS (EI): m/z Calcd for C 11 H 8 F ; found Spectral data are in accordance with those reported in the literature. 4, 6 2-(difluoromethyl)naphthalene (2f, cas: ) 4a-4f White solid (115.8 mg, 81%), m.p o C. This compound is known. 4a-4f 1 H S14

15 NMR (400 MHz, CDCl 3 ) δ (m, 7H), 6.77 (t, J = 56.4 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.4 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ (t, J = 1.4 Hz), 132.6, (t, J = 22.2 Hz), 128.9, 128.5, 127.9, 127.4, 126.8, (t, J = 7.6 Hz), (t, J = 4.8 Hz), (t, J = Hz). MS (EI, m/z): 178 (M + ), 178 (100.0). HRMS (EI): m/z Calcd for C 11 H 8 F ; found Spectral data are in accordance with those reported in the literature. 4a-4f 3-(difluoromethyl)-1,1'-biphenyl (2g, cas: ) 4d, 5 Colorless oil (147.2 mg, 90% yield). This compound is known. 4d, 5 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (s, 1H), 7.65 (d, J = 6.6 Hz, 1H), 7.55 (d, J = 7.4 Hz, 2H), (m, 4H), 7.34 (t, J = 7.3 Hz, 1H), 6.65 (t, J = 56.5 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ 141.8, 140.1, (t, J = 22.2 Hz), (t, J = 1.7 Hz), 129.1, 128.9, 127.8, 127.1, (t, J = 5.8 Hz), (t, J = 5.9 Hz), (t, J = Hz). MS (EI, m/z): 204 (M + ), 204 (100.0). HRMS (EI): m/z Calcd for C 13 H 10 F ; found Spectral data are in accordance with those reported in the literature. 4d, 5 4-(difluoromethyl)-1,1'-biphenyl (2h, cas: ) 4 White solid (152.2 mg, 93%), m.p o C. This compound is known. 4 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 8.1 Hz, 2H), 7.58 (t, J = 7.5 Hz, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 6.68 (t, J = 56.5 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ (t, J = 2.0 Hz), 140.2, (t, J = 22.5 Hz), 128.9, 127.9, 127.4, 127.3, (t, J = 6.0 Hz), (t, J = Hz). MS (EI, m/z): 204 S15

16 (M + ), 204 (100.0). HRMS (EI): m/z Calcd for C 13 H 10 F ; found Spectral data are in accordance with those reported in the literature. 4 4-(tert-butyl)-4'-(difluoromethyl)-1,1'-biphenyl (2i) White solid ( mg, 87%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 8.2 Hz, 2H), (m, 6H), 6.70 (t, J = 56.6 Hz, 1H), 1.38 (s, 9H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.6 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 151.0, 143.5, 137.2, (t, J = 22.4 Hz), 127.2, 126.9, (t, J = 6.0 Hz), 125.9, (t, J = Hz), 34.6, GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 17 H 18 F ; found (4-(difluoromethyl)phenoxy)triisopropylsilane (2k) Colorless oil (156.6 mg, 65% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.60 (t, J = 56.8 Hz, 1H), (m, 3H), 1.14 (d, J = 7.3 Hz, 18H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.8 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ (t, J = 1.8 Hz), (t, J = 5.9 Hz), (t, J = 22.7 Hz), 120.0, (t, J = Hz), 17.8, MS (EI, m/z): 300 (M + ), 201 (100.0), 300 (12.2). HRMS (EI): m/z Calcd for C 16 H 26 F 2 OSi ; found (difluoromethyl)-4'-methoxy-1,1'-biphenyl (2l, cas: ) White solid (168.8 mg, 90%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 (d, J = 8.4 Hz, 2H), (m, 4H), 7.00 (dt, J = 8.8 Hz, 2.5 Hz, 2H), 6.69 (t, J = 56.6 Hz, 1H), 3.87 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, S16

17 J = 56.6 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 159.6, 143.2, , (t, J = 22.5 Hz), 128.2, 126.9, (t, J = 6.0 Hz), (t, J = Hz), 114.3, GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 14 H 12 F 2 O ; found (difluoromethyl)-6-methoxynaphthalene (2m, cas: ) 4e White solid (148.5 mg, 89%), m.p o C. This compound is known. 4e 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H), 7.73 (dd, J = 11.1, 9.0 Hz, 2H), 7.52 (d, J = 8.5 Hz, 1H), (m, 2H), 6.73 (t, J = 56.5 Hz, 1H), 3.88 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.6 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ 158.8, 135.8, 130.0, (t, J = 22.3 Hz), 127.9, 127.6, (t, J = 7.5 Hz), (t, J = 4.8 Hz), 119.7, (t, J = Hz), 105.8, MS (EI, m/z): 208 (M + ), 208 (100.0). HRMS (EI): m/z Calcd for C 12 H 10 F 2 O ; found Spectral data are in accordance with those reported in the literature. 4e 4'-(difluoromethyl)-3-fluoro-5-methoxy-1,1'-biphenyl (2n) White solid (141.9 mg, 70%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (dd, J = 21.9, 8.3 Hz, 4H), (m, 2H), 6.70 (t, J = 56.4 Hz, 1H), 6.65 (dt, J = 10.5, 2.2 Hz, 1H), 3.86 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.4 Hz, 2F), (t, J = 9.8 Hz, 1F). 13 C NMR (125 MHz, CDCl 3 ) δ (d, J = Hz), (d, J = 11.6 Hz), (d, J = 10.0 Hz), 142.4, (t, J = 22.5 Hz), 127.3, (t, J = 6.0 Hz), (t, J = Hz), (d, J = 2.6 Hz), (d, J = 22.6 Hz), (d, J = 25.2 Hz), GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 14 H 11 F 3 O ; found S17

18 (difluoromethyl)-4'-fluoro-1,1'-biphenyl (2r) White solid (151.8 mg, 85%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (d, J = 8.3 Hz, 2H), (m, 4H), 7.15 (t, J = 8.6 Hz, 2H), 6.70 (t, J = 56.5 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F), (tt, J = 8.6, 5.3 Hz, 1F). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = Hz), (t, J = 2.0 Hz), (d, J = 3.2 Hz), (t, J = 22.4 Hz), (d, J = 8.1 Hz), 127.2, (t, J = 6.0 Hz), (d, J = 21.5 Hz), (t, J = Hz). GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 13 H 9 F ; found '-(difluoromethyl)-3-(trifluoromethyl)-1,1'-biphenyl (2s) Colorless oil (202.8 mg, 93% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.63 (ddd, J = 25.9, 17.9, 8.0 Hz, 6H), 6.72 (t, J = 56.4 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ 62.7 (s, 3F), (d, J = 56.4 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ (t, J = 1.9 Hz), 140.9, (t, J = 22.5 Hz), (q, J = 32.3 Hz), 130.5, 129.4, 127.5, (t, J = 6.0 Hz), (q, J = 3.7 Hz), (q, J = Hz), (q, J = 3.8 Hz), (t, J = Hz). GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 14 H 9 F ; found (4-(difluoromethyl)-2-fluorophenyl)-1,3-dioxane (2t) Colorless oil (79.1 mg, 42%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (t, J = 7.4 Hz, S18

19 1H), 7.23 (dd, J = 37.4, 9.0 Hz, 2H), 6.59 (t, J = 56.2 Hz, 1H), 5.79 (s, 1H), 4.24 (dd, J = 10.9, 4.9 Hz, 2H), 3.98 (td, J = 12.5, 2.4 Hz, 2H), (m, 1H), 1.42 (d, J = 13.6 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.2 Hz, 2F), (dd, J = 10.1, 6.9 Hz, 1F). 13 C NMR (125 MHz, CDCl 3 ) δ (d, J = Hz), (td, J = 22.9, 7.6 Hz), , , (dd, J = 9.7, 6.1 Hz), (t, J = Hz), (dt, J = 23.7, 6.1 Hz), 95.8 (d, J = 4.1 Hz), 67.5, MS (EI, m/z): 232 (M + ), 173 (100.0), 232 (16.1). HRMS (EI): m/z Calcd for C 11 H 11 F 3 O ; found (E)-1-(difluoromethyl)-4-styrylbenzene (2u) White solid (166.4 mg, 90%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 14.2, 7.7 Hz, 4H), 7.37 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.17 (d, J = 16.4 Hz, 1H), 7.10 (d, J = 16.4 Hz, 1H), 6.64 (t, J = 56.5 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ (t, J = 2.1 Hz), 136.8, (t, J = 22.3 Hz), , 128.7, 128.1, (t, J = 1.0 Hz), 126.7, 126.6, (t, J = 6.1 Hz), (t, J = Hz). GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 15 H 12 F ; found (4-(difluoromethyl)phenyl)pyridine (2v, cas: ) White solid ( mg, 75%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (d, J = 4.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 2H), (m, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.22 (ddd, J = 6.7, 4.9, 2.2 Hz, 1H), 6.68 (t, J = 56.4 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 156.1, 149.7, (t, J = 2.0 Hz), 136.8, (t, J = 22.4 Hz), 127.0, (t, J = 6.0 Hz), 122.6, 120.6, (t, J = Hz). GC-MS (EI, S19

20 m/z): HRMS (EI): m/z Calcd for C 12 H 9 F 2 N ; found (4-(difluoromethyl)phenyl)-6-fluoropyridine (2w) White solid (99.8 mg, 56%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (d, J = 8.2 Hz, 2H), 7.87 (dd, J = 8.0, 8.0 Hz, 1H), 7.65 (dd, J = 7.6, 2.4 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 6.91 (dd, J = 8.1, 3.0 Hz, 1H), 6.70 (t, J = 56.4 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ 66.3 (d, J = 7.4 Hz, 1F), (d, J = 56.4 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ (d, J = Hz), (d, J = 13.5 Hz), (d, J = 7.7 Hz), (t, J = 1.9 Hz), (t, J = 22.4 Hz), 127.2, (t, J = 6.1 Hz), (d, J = 4.0 Hz), (t, J = Hz), (d, J = 37.6 Hz). GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 12 H 8 F 3 N ; found (6-(4-(difluoromethyl)phenyl)pyridin-2-yl)morpholine (2x) White solid (211.6 mg, 91%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J = 8.1 Hz, 2H), (m, 3H), 7.16 (d, J = 7.5 Hz, 1H), 6.69 (t, J = 56.6 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.61 (t, J = 4.8 Hz, 4H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 159.1, 154.0, (t, J = 2.0 Hz), 138.3, (t, J = 22.3 Hz), 126.9, (t, J = 6.0 Hz), (t, J = Hz), 110.3, 105.9, 66.7, GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 16 H 16 F 2 N 2 O ; found S20

21 2-(4-(difluoromethyl)phenyl)benzofuran (2y) White solid (168.2 mg, 86%), m.p o C. 1 H NMR (400 MHz, Acetone) δ 8.06 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 7.7 Hz, 1H), 7.58 (dd, J = 8.2, 0.7 Hz, 1H), 7.42 (s, 1H), 7.35 (td, J = 7.8, 1.2 Hz, 1H), 7.27 (td, J = 7.7, 0.8 Hz, 1H), 6.95 (t, J = 56.1 Hz, 1H). 19 F NMR (376 MHz, Acetone) δ (d, J = 56.1 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 155.0, 154.7, (t, J = 22.4 Hz), (t, J = 2.1 Hz), 128.9, (t, J = 6.2 Hz), 125.0, 124.8, 123.1, 121.2, (t, J = Hz), 111.3, GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 15 H 10 F 2 O ; found (4-(difluoromethyl)phenyl)thiophene (2z) White solid (117.8 mg, 70%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 3.6, 0.9 Hz, 1H), 7.32 (dd, J = 5.1, 1.0 Hz, 1H), 7.09 (dd, J = 5.1, 3.6 Hz, 1H), 6.64 (t, J = 56.5 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 143.1, (t, J = 2.1 Hz), (t, J = 22.5 Hz), 128.2, (t, J = 6.1 Hz), 126.0, 125.7, 124.0, (t, J = Hz). GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 11 H 8 F 2 S ; found (difluoromethyl)-9-methyl-9H-carbazole (2aa) White solid (96.6 mg, 52%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (t, J = 7.3 Hz, 2H), (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 6.83 (t, J = 56.8 Hz, 1H), 3.83 (s, 3H). 19 F S21

22 NMR (376 MHz, CDCl 3 ) δ (d, J = 56.8 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 141.6, 140.4, (t, J = 21.9 Hz), 126.5, (t, J = 1.7 Hz), 122.0, 120.7, 120.4, 119.3, (t, J = 6.1 Hz), (t, J = Hz), 108.6, (t, J = 6.5 Hz), GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 14 H 11 F 2 N ; found (4-(difluoromethyl)-2-fluorophenyl)-1-methyl-1H-indole (2ab) White solid (202.6 mg, 92%), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (s, 1H), 7.58 (t, J = 7.8 Hz, 1H), (m, 2H), 7.32 (t, J = 9.1 Hz, 2H), 7.09 (d, J = 2.9 Hz, 1H), 6.66 (t, J = 56.4 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 3.81 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.4 Hz, 2F), (dd, J = 9.6, 8.4 Hz, 1F). 13 C NMR (125 MHz, CDCl 3 ) δ (d, J = Hz), 136.4, (td, J = 22.9, 7.6 Hz), (dt, J = 13.5, 1.8 Hz), (d, J = 3.9 Hz), 129.6, 128.6, 125.9, (d, J = 2.9 Hz), (d, J = 2.8 Hz), (td, J = 6.1, 3.7 Hz), (td, J = 239.2, 1.8 Hz), (dt, J = 25.4, 6.2 Hz), 109.2, 101.5, GC-MS (EI, m/z): HRMS (EI): m/z Calcd for C 16 H 12 F 3 N ; found (difluoromethyl)-4-((((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)methyl) benzene (2ac) White solid (189.8 mg, 80% yield), m.p o C. 1 H NMR (500 MHz, CDCl 3 ) δ 7.48 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 6.64 (t, J = 56.5 Hz, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.44 (d, J = 11.9 Hz, 1H), 3.19 (td, J = 10.6, 4.2 Hz, S22

23 1H), 2.29 (dtd, J = 14.0, 7.0, 2.7 Hz, 1H), 2.19 (dtd, J = 12.1, 3.8, 2.0 Hz, 1H), (m, 2H), (m, 2H), (m, 9H), 0.74 (d, J = 7.0 Hz, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ (d, J = 56.5 Hz, 2F). 13 C NMR (125 MHz, CDCl 3 ) δ 142.1, (t, J = 22.4 Hz), 127.8, (t, J = 6.1 Hz), (t, J = Hz), 79.1, 69.8, 48.3, 40.3, 34.5, 31.6, 25.6, 23.3, 22.4, 21.0, MS (EI, m/z): 296 (M +, 0.31), 141 (100.0), 81 (48.8), 138 (40.7), 69 (34.9), 91 (31.7), 95 (29.6), 55 (26.2), 57 (13.2). HRMS (EI): m/z Calcd for C 18 H 26 F 2 O , found Synthesis of Compounds 2q Typical procedure for an iodine-magnesium exchange reaction: To an oven-dried 50 ml Schlenk flask equipped with a stir bar were added 4-iodobenzonitrile (6.0 mmol, 1.37 g). Under Ar, 8.0 ml THF was added. The reaction mixture was stirred and cooled to 20 o C, and i-prmgcl-licl (4.7 ml, 1.3 M in THF) in THF was added. After 1 h at 20 o C, the Gignard reagent was titrated with I 2. 2 In an oven-dried Schlenk tube equipped with a stir bar, ZnBr 2 (225.2 mg, 1.0 mmol, 2.0 equiv) and LiCl (42.4 mg, 1.0 mmol, 2.0 equiv) were weighed in glove-box, then the tube was heated under vaccum for 2 minutes with the help of a heat gun outside of the glove-box. After cooling down, the Schlenk tube was evacuated and back-filled with Ar (this process was repeated 3 times). THF (2 ml) was added and the mixture was allowed to stir at room temperature for 5 minutes. Then the mixture was added to S23

24 (4-cyanophenyl)magnesium bromide prepared in-situ (2.0 mmol) dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then cooled to 40 ºC. Under a positive pressure of Ar, the tube was opened, Fe(acac) 3 (35.3 mg, 0.1 mmol, 20 mol%) was added. Then the tube was sealed again and cooled to 40 ºC. TMEDA (149 L, 1.0 mmol, 2.0 equiv) was added to the mixture at 40 ºC, followed by the addition of a solution of 2-PySO 2 CF 2 H (0.5 mmol, 96.6 mg, 1.0 equiv.) in THF (1.5 ml) via syringe in one portion. The mixture was allowed to warm to room temperature and stirred for 2 h at room temperature. PhCF 3 was added as an internal standard, the reaction was monitored by 19 F NMR. 8. Scaling up the Difluoromethylation Reaction In an oven-dried 100 ml Schlenk tube equipped with a stir bar, ZnBr 2 (2.7 g, 12 mmol, 1.5 equiv) and LiCl (510 mg, 12 mmol, 1.5 equiv) were weighed in glove-box and the tube was heated under vaccum for 2 minutes with the help of a heat gun. After cooling down, the Schlenk tube was back-filled with Ar. THF (10 ml) was added and the mixture was allowed to stir at room temperature for 5 minutes. Then aryl Grignard reagents (24 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then cooled to 40 ºC. Under a positive pressure of Ar, the tube was opened, Fe(acac) 3 (565 mg, 1.6 mmol, 20 mol%) was added. Then the tube was sealed again and cooled to 40 ºC. TMEDA (2.40 ml, 16 mmol, 2.0 equiv) was added to the mixture at 40 ºC, followed by the addition of a solution of 2-PySO 2 CF 2 H (1.55 g, 8.0 mmol, 1.0 equiv) in THF (8.0 ml) via syringe in one portion. The mixture was allowed to warm to room temperature and stirred for 2 h at room temperature. Then the mixture was quenched with S24

25 saturated NH 4 Cl aqueous solution (8.0 ml) and diluted with diethyl ether. The organic layer was separated and dried over Na 2 SO 4 anhydrous, filtered and evaporated to dryness. Pure products were obtained after column chromatography. 9. Synthesis of Compounds 1b To an oven-dried 100 ml Schlenk flask equipped with a stir bar were added difluoromethyl 2-pyridyl sulfone (1, 2-PySO 2 CF 2 H, 3.9 mmol, 754 mg, 1.3 equiv) and 5-iodopent-1-ene (588 mg, 3.0 mmol, 1.0 equiv,) under Ar, THF/HMPA (v/v, 30.0 ml / 3.0 ml) was added. The reaction mixture was stirred and cooled to 98 o C with CH 3 OH/liquid N 2 cold bath. A hexane (4.5 ml) solution of (TMS) 2 NLi (LiHMDS, 1.0 M in hexanes, 4.5 mmol, 1.5 equiv) was added slowly in 5 minutes. Then the reaction mixture was immediately quenched with saturated NH 4 Cl aqueous solution (3.0 ml) at the same temperature. After the mixture was warmed to room temperature, water was added. The mixture was extracted with EtOAc, the combined organic phase was dried over Na 2 SO 4. After the solution was filtered and the solvent was evaporated under vacuum, the crude product was purified by flash column chromatography using petroleum ether and ethyl acetate as eluent to give product 1b. 7 2-((1,1-difluorohex-5-en-1-yl)sulfonyl)pyridine (1b) S25

26 Pale yellow oil (533.6 mg, 68% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.84 (ddd, J = 4.7, 1.6, 0.8 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 8.02 (td, J = 7.8, 1.7 Hz, 1H), 7.65 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 5.74 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), (m, 2H), (m, 2H), 2.14 (q, J = 7.1 Hz, 2H), (m, 2H),). 19 F NMR (376 MHz, CDCl 3 ) δ (t, J = 18.7 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ 152.0, 150.7, 138.2, 136.6, 128.6, 126.1, (t, J = Hz), 115.8, 32.5, 29.2 (t, J = 19.9 Hz), 19.7 (t, J = 3.2 Hz). MS (ESI, m/z): [M+H] +. HRMS (ESI): Calcd for C 11 H 14 F 2 NO 2 S + [M+H] + : ; found: Mechanistic Investigation 10.1 Control Experiments with Additives In an oven-dried Schlenk tube equipped with a stir bar, ZnBr 2 (101 mg, 0.45 mmol, 1.5 equiv) and LiCl (19 mg, 0.45 mmol, 1.5 equiv) were weighed in glove-box, then the tube was heated under vaccum for 2 minutes with the help of a heat gun outside of the glove-box. After cooling down, the Schlenk tube evacuated and back-filled with Ar (this process was repeated 3 times). THF (2 ml) was added and the mixture was allowed to stir at room temperature for 5 minutes. Then PhMgBr (0.9 mmol, 0.9 ml, 1.0 M in THF) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. A dense-grey solution was formed and used without further titration. S26

27 The mixture was then cooled to 40 ºC. Under a positive pressure of Ar, the tube was opened, Fe(acac) 3 (21.2 mg, 0.06 mmol, 20 mol%) was added. Then the tube was sealed again and cooled to 40 ºC. TMEDA (90 L, 0.6 mmol, 2.0 equiv) was added to the mixture at 40 ºC, followed by the addition of a solution of 2-PySO 2 CF 2 H (0.3 mmol, 58 mg, 1.0 equiv.) in THF (1.5 ml) via syringe in one portion. Next, a solution of additive (0.3 mmol, 1.0 equiv) in 1.0 ml THF was added to the mixture. The mixture was allowed to warm to room temperature and stirred for 2 h at room temperature. PhCF 3 was added as an internal standard, the reaction was monitored by 19 F NMR Radical Cyclization In an oven-dried Schlenk tube equipped with a stir bar, ZnBr 2 (270 mg, 1.2 mmol, 1.5 equiv) and LiCl (51 mg, 1.2 mmol, 1.5 equiv) were weighed in glove-box and the tube was heated under vaccum for 2 minutes with the help of a heat gun. After cooling down, the Schlenk tube was back-filled with argon. THF (2 ml) was added and the mixture was allowed to stir at room temperature for 5 minutes. Then aryl Grignard reagents (2.4 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. A dense-grey solution was formed and used without further titration. The mixture was then cooled to 40 ºC. Under a positive pressure of argon, the tube was opened, Fe(acac) 3 (56.5 mg, 0.16 mmol, 20 mol%) was added. Then the tube was sealed again and cooled to 40 ºC. TMEDA (240 L, 1.6 mmol, 2.0 equiv) was added to the mixture at 40 ºC, followed by the addition of a solution of 1b (0.8 mmol, 209 mg, 1.0 equiv) in THF (1.5 ml) via S27

28 syringe in one portion. The mixture was allowed to warm to room temperature and stirred for 2 h at room temperature. Then the mixture was quenched with saturated NH 4 Cl aqueous solution (1.0 ml) and diluted with diethyl ether. The organic layer was separated and dried over Na 2 SO 4 anhydrous, filtered and evaporated to dryness. Pure products were obtained after column chromatography. 4-((2,2-difluorocyclopentyl)methyl)-1,1'-biphenyl (3b) White solid (102.5 mg, 47% yield), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (dd, J = 7.2, 1.0 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), 7.30 (d, J = 7.2 Hz, 2H), 3.12 (dd, J = 13.8, 4.4 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 4H). 19 F NMR (376 MHz, CDCl 3 ) δ 98.7 (ddd, J = 226.2, 22.2, 12.2 Hz, 1F), (ddd, J = 226.2, 36.7, 18.7 Hz, 1F). 13 C NMR (100 MHz, CDCl 3 ) δ 140.9, 139.1, 138.9, (dd, J = 252.2, Hz), (d, J = 51.6 Hz), 127.0, 126.9, 47.9 (t, J = 22.6 Hz), 34.8 (t, J = 24.9 Hz), 33.3 (d, J = 6.9 Hz), 28.9 (d, J = 6.9 Hz), 19.8 (dd, J = 5.7, 3.3 Hz). MS (GCMS-EI): (M + ). HRMS (EI): m/z Calcd for C 18 H 18 F ; found When we added diallyl ether in the model reaction, no cyclized product was obtained. S28

29 10.3 Iron-Catalyzed Difluoromethylation of 2-PySO 2 CF 2 D with Ph 2 Zn Na 2 S 2 O 4 (3.5 mg, 0.02 mmol) was added into a mixture of 2-((difluoroiodomethyl)sulfonyl)pyridine (2-PySO 2 CF 2 I, 64 mg, 0.2 mmol), NaHCO 3 (2 mg, 0.02 mmol), acetonitrile-d 3 (1.0 ml) and deuterium oxide (1.0 ml) at 0 o C. The reaction mixture was then stirred at room temperature for 8 h. Additional Na 2 S 2 O 4 (3.5 mg, 0.02 mmol) and NaHCO 3 (2 mg, 0.02 mmol) was added for every 20 minnutes. After 19 F NMR spectroscopy indicated the complete conversion of 2-PySO 2 CF 2 I, water was then added into the reaction mixture, followed by extraction with Et 2 O. The combined organic phase was washed with brine, and then dried over anhydrous Na 2 SO 4. After filtration and solvent removal, the crude product was purified by silica gel chromatography. 2-((difluoromethyl-d)sulfonyl)pyridine (5) White solid (23.6 mg, 60% yield), m.p o C. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.09 (td, J = 7.8, 1.6 Hz, 1H), 7.72 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ (t, J = 8.2 Hz, 2F). 13 C NMR (100 MHz, CDCl 3 ) δ 152.4, 150.9, 138.6, 128.9, 125.0, (tt, J = 284.4, 31.9 Hz). MS (ESI, m/z): [M+H] +. HRMS (ESI): exact mass calcd for C 6 H 5 DF 2 NO 2 S + [M+H] + : ; found: S29

30 92.6% deuterated In an oven-dried Schlenk tube equipped with a stir bar, ZnBr 2 (101 mg, 0.45 mmol, 1.5 equiv) and LiCl (19 mg, 0.45 mmol, 1.5 equiv) were weighed in glove-box, then the tube was heated under vaccum for 2 minutes with the help of a heat gun outside of the glove-box. After cooling down, the Schlenk tube evacuated and back-filled with Ar (this process was repeated 3 times). THF (2 ml) was added and the mixture was allowed to stir at room temperature for 5 minutes. Then PhMgBr (0.9 mmol, 0.9 ml, 1.0 M in THF) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. A dense-grey solution was formed and used without further titration. The mixture was then cooled to 40 ºC. Under a positive pressure of argon, the tube was opened, Fe(acac) 3 (21.2 mg, 0.06 mmol, 20 mol%) was added. Then the tube was sealed again and cooled to 40 ºC. TMEDA (90 L, 0.6 mmol, 2.0 equiv) was added to the mixture at 40 ºC, followed by the S30

31 addition of a solution of 2-PySO 2 CF 2 D (0.3 mmol, 59 mg, 1.0 equiv) in THF (1.5 ml) via syringe in one portion. The mixture was allowed to warm to room temperature and stirred for 2 h at room temperature. PhCF 3 was added as an internal standard, the reaction was monitored by 19 F NMR. Internal standard 92.6% deuterated 10.4 Other Experiments S31

32 11. References 1. Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, Krasovskiy, A.; Knochel, P. Synthesis 2006, 2006, Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T.-G.; Dixon, D. D.; Creech, G.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, (a) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, (b) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, (c) Matheis, C.; Jouvin, K.; Goossen, L. J. Org. Lett. 2014, 16, (c) Gu, Y.; Leng, X.; Shen, Q. Nat. Commun. 2014, 5, (d) Feng, Z.; Min, Q.-Q.; Zhang, X. Org. Lett. 2016, 18, 44. (e) Deng, X.-Y.; Lin, J.-H.; Xiao, J.-C. Org. Lett. 2016, 18, (f) Xu, L.; Vicic, D. A. J. Am. Chem. Soc. 2016, 138, (g) Aikawa, K.; Serizawa, H.; Ishii, K.; Mikami, K. Org. Lett. 2016, 18, Fuchibe, K.; Ohshima, Y.; Mitomi, K.; Akiyama, T. Org. Lett. 2007, 9, Serizawa, H.; Ishii, K.; Aikawa, K.; Mikami, K. Org. Lett. 2016, 18, Prakash, G. K. S.; Ni, C.; Wang, F.; Hu, J.; Olah, G. A. Angew. Chem., Int. Ed. 2011, 50, S32

33 12. NMR Spectra 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S33

34 13 C NMR (100 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S34

35 19 F NMR (376 MHz, CDCl 3) 13 C NMR (100 MHz, CDCl 3) S35

36 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S36

37 13 C NMR (100 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S37

38 19 F NMR (376 MHz, CDCl 3) 13 C NMR (100 MHz, CDCl 3) S38

39 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S39

40 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S40

41 19 F NMR (376 MHz, CDCl 3) 13 C NMR (100 MHz, CDCl 3) S41

42 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S42

43 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S43

44 19 F NMR (376 MHz, CDCl 3) 13 C NMR (100 MHz, CDCl 3) S44

45 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S45

46 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S46

47 19 F NMR (376 MHz, CDCl 3) 13 C NMR (100 MHz, CDCl 3) S47

48 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S48

49 13 C NMR (100 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S49

50 19 F NMR (376 MHz, CDCl 3) 13 C NMR (125 MHz, CDCl 3) S50

51 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S51

52 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S52

53 19 F NMR (376 MHz, CDCl 3) 13 C NMR (125 MHz, CDCl 3) S53

54 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S54

55 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S55

56 19 F NMR (376 MHz, CDCl 3) 13 C NMR (125 MHz, CDCl 3) S56

57 1 H NMR (400 MHz, Acetone) 19 F NMR (376 MHz, Acetone) S57

58 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S58

59 19 F NMR (376 MHz, CDCl 3) 13 C NMR (125 MHz, CDCl 3) S59

60 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S60

61 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S61

62 19 F NMR (376 MHz, CDCl 3) 13 C NMR (125 MHz, CDCl 3) S62

63 1 H NMR (500 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S63

64 13 C NMR (125 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S64

65 19 F NMR (376 MHz, CDCl 3) 13 C NMR (100 MHz, CDCl 3) S65

66 1 H NMR (400 MHz, CDCl 3) 19 F NMR (376 MHz, CDCl 3) S66

67 13 C NMR (100 MHz, CDCl 3) 1 H NMR (400 MHz, CDCl 3) S67

68 19 F NMR (376 MHz, CDCl 3) 13 C NMR (100 MHz, CDCl 3) S68