Supporting Information

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1 Supporting Information Copper-Catalyzed Reductive Trifluoromethylation of Alkyl Iodides with Togni s Reagent Yanchi Chen, Guobin Ma* and Hegui Gong* School of Materials Science and Engineering, Center for Supramolecular Materials and Catalysis, and Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai , China hegui_gong@shu.edu.cn, ma_guobin@shu.edu.cn Table of Contents I. Experimental Section....S2-S33 Part 1. General Information...S2 Part 2. Details of Optimization and Control Experiments.S3-S4 Part 3. Mechanistic consideration. S5-S8 Part 4. Preparation of ligands.s9-s10 Part 5. Preparation of Alkyl Halides..S11-S19 Part 6. Reductive Trifluoromethylation of Alkyl Halides with Togni s Reagent..S20-S33 References S34 II. Spectral Data for New Compounds... S35-S89 S1

2 I. Experimental Section Part 1. General Information 1. Chemicals and Reagents All manipulations were carried out under an atmosphere of nitrogen using standard Schlenk or glove box techniques. THF, diethyl ether and toluene were distilled from sodium/benzophenone ketyl prior to use. The following anhydrous solvents were purchased from INFI, DMF (N, N-dimethylformamide, 99.8%), 1, 4-Dioxane (99.5%), NMP (N-methylpyrrolidinone, 99.5%). Deuterated solvents were used as received (CDCl 3 from J&K Co., China). The following reagents, Cu(MeCN) 4 PF 6 (Alfa Aesar), Trifluoromethyl(1,10- phenanthroline)copper(i) (Strem Chemicals, Inc.), CuCl (Alfa Aesar), CuBr (Sigma Aldrich), CuI (Alfa Aesa), CuOAc (Acros), NiCl 2 dme (Strem), 4,4',4''-Tri-tert-butyl-[2,2';6',2'']terpyridine (Sigma Aldrich), [2,2';6',2'']Terpyridine (Sigma Aldrich), (pin)b B(pin) (Aladdin, China), (nep)b B(nep) (Aladdin, China), LiOMe (J&K) were purchased, and used as received. Unless otherwise noted, all other reagents and starting materials were purchased from commercial sources and used without further purification. Procedures for the synthesis of alkyl iodides have been reported in our previous publications. 1 Togni s reagent II 2 and ligands L1~L4, L8 3 and L11~L14 4 were synthesized according to the literature procedures. 2. Physical method Column chromatography was performed using silica gel mesh (purchased from Accela ChemBio Co., Ltd. China) as the solid support. Nuclear magnetic resonance (NMR) spectra were recorded on a JNM- ECZ400s/L or Bruker Avance 500 MHz or a Bruker Avance 600 MHz. 1 H NMR and 13 C NMR chemical shifts are reported in δ units, parts per million (ppm) relative to the chemical shift of residual solvent. Reference peaks for chloroform in 1 H NMR and 13 C NMR spectra were set at 7.26 ppm and 77.0 ppm, respectively. Reference peaks for dimethyl sulfoxide in 1 H NMR and 13 C NMR spectra were set at 2.50 ppm and ppm, respectively. High-resolution mass spectra (HRMS) were obtained using an AB-SCIEX Triple TOF Melting point was recorded on a micro melting point apparatus (X-4, YUHUA Co., Ltd, Gongyi, China). S2

3 Part 2. Details of Optimization and Control Experiments A typical procedure for optimization of the reaction conditions: To a flame-dried Schlenk tube equipped with a stir bar was added alkyl halide, ligand, additives and Togni s reagent II, followed by addition of Cu and (or) Ni catalyst, reductant in glove-box under N 2 atmosphere. The tube was capped with a rubber septum and moved out of glove-box. Solvent was then added via a syringe. After the reaction mixture was allowed to stir for 8 hours under N 2 atmosphere at room temperature, it was directly loaded onto a silica gel column without work-up. The residue in the reaction vessel was rinsed with small amount of DCM or eluent. Flash column chromatography provided a mixture containing the product. Yields were determined by 19 F NMR using benzotrifluoride (Ph-CF 3 ) as internal standard. Table S1. Control experiments for the reaction of 1a with Togni s reagent II. a Ts N I + O I 1a CF mmol 0.36 mmol entry CuCl (mol %) O NiCl2(dme) (mol %) Standard method: CuCl (20 mol % ) NiCl 2 dme (15 mol %) L1 (35 mol % ) B 2 (nep) 2 (200 mol %) LiOMe (250 mol %) 2-pyrrolidinone (50 mol %) DMF (2.0 ml) rt, 6 h Recovered 1a (%) ~16 79 b not Ts N CF 3 2a Ts + Ts N N 2a' 6 O B O 2a (%) 2a (%) 2a (%) 6 (%) applicable not applicable ~10 ~2 ~ not detected + Ts N 2a'' not applicable 21 not applicable not detected ~16 not applicable ~ ~18 not applicable 35 a Unless otherwise noted, the yields were referred to as 1 H NMR yield using 2,5-dimethylfuran as the internal standard. b Isolated yield. Table S2: Catalyst screening for trifluoromethylation of 1a with Togni s reagent II. Ts N I + 1a (0.15 mmol) 3 20 mol % Cu(I) 15 mol % NiCl 2 (glyme) O 35 mol % t-bu-terpy 200 mol % B 2 (Pin) 2 O 250 mol % MeOLi ICF Ts N CF ml NMP 2.0 equiv 25 o C, 6 h 2a Entry Catalyst 2a (%) a 1 CuI 11 2 CuCl 40 (32) b 3 CuOAc 37 4 CuTC < 10 S3

4 5 CuOTf 11 6 CuBr CH3SCH CuCl2 < 10 8 Cu(MeCN) 4 PF 6 23 a Yields were determined by 19 F NMR using benzotrifluoride as internal standard. b Isolated yield. Table S3: Optimization for trifluoromethylation of 1a with Togni s reagent II. Ts N I + O I 1a (X equiv) CF 3 Y equiv O 20 mol % CuCl 15 mol % NiCl 2 (glyme) 35 mol % t-bu-terpy 200 mol % Reductant 250 mol % MeOLi 1.0 ml DMF 25 o C, 6 h Ts N CF 3 Entry X/Y Reductant 2a (%) a 1 1/2 B2(pin) /1 B2(pin) /1 B2(pin) /1 B2(nep)2 70 (61) b 5 2/1 Bis(hexylene glycolato) diboron /1 Bis(2, 4-dimethylpentane-2, 4-glycolato) diboron 43 a Yields were determined by 19 F NMR using benzotrifluoride as internal standard. b Isolated yield. 2a S4

5 Part 3. Mechanistic consideration 1. Reaction of (iodomethyl)cyclopropane with Togni s reagent II. The reaction of (iodomethyl)cyclopropane with Togni s reagent II was performed under the Standard Method (Page S20) except DMF-d7 was used as the solvent. After 6 hours, about 24% of ring-opened product 5, 5, 5-trifluoro-pent-1-ene was detected by 19 F NMR using benzotrifluoride as internal standard. The reaction mixture was added deuterochloroform, which was subjected to distillation at ambient pressure in an oil bath at 100 o C. The liquid fraction containing the trifluoromethyl product was collected and confirmed by 1 H NMR and 19 F NMR. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 2H), (m, 2H), (m, 2H). 19 F NMR (376 MHz, CDCl 3 ) δ (t, J = 10.5 Hz). 2. Coupling reaction in the presence of TEMPO. The reaction of 1a with the Togni s reagent II was performed using the Standard Method (Page S20). The trifluoromethylation was totally shut down. No target product 2a was detected, wherein TEMPO-CF 3 was formed in 27% yield as estimated by 19 F NMR and GCMS. 5 N O O 0.36 mmol Ts N I 1a 0.15 mmol mmol O I CF 3 standard method Ts N CF 3 2a not detected + N O F 3 C TEMPO-CF 3 1a ~50% recovered 27% ( 19 F NMR yield) 3. Reaction of alkylboronic ester 6 with Togni s reagent II. Preparation of 4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1-(toluene-4-sulfonyl)-piperidine (6): This compound was prepared according to a literature procedure. 6 To a flame-dried Schlenk tube equipped with a stir bar was added 1a (330 mg, 0.9 mmol), B 2 (nep) 2 (407 mg, 1.8 mmol), CuI (26.6 mg, 0.14 mmol), PPh 3 (47.2 mg, 0.18 mmol) and LiOMe (85.4 mg, 2.3 mmol). The vessel was evacuated and back-filled with N 2 (three times). DMF (5 ml) was added by a syringe. The resulting reaction mixture was stirred vigorously S5

6 at room temperature for 12 h. The reaction mixture was then diluted with EtOAc, washed with water. The organic phase was concentrated and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc = 5/1) to afford a white solid (152 mg, 0.43 mmol, 48% yield). 1 H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 7.4 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 3.52 (s, 4H), (m, 2H), 2.41 (s, 3H), 2.35 (t, J = 10.7 Hz, 2H), (m, 2H), 1.57 (td, J = 13.9, 3.3 Hz, 2H), 0.87 (s, 6H), (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 143.1, 133.2, 129.4, 127.7, 71.9, 47.3, 31.5, 26.6, 21.6, HRMS calcd for C 17 H 27 BNO 4 S [M+H]: Found M.p ºC. Reaction of 6 with Togni s reagent II: The reaction was performed using the Standard Method (page S20). After a flash column (eluent: 40% EtOAc in petroleum ether), the mixture was subjected to 19 F NMR study, no detectable 2a was observed. 1 H NMR study using 2, 5-dimethylfuran as the internal standard indicated that 6 was primarily recovered. Ts N Bnep + O standard method O Ts N CF 3 I 6 CF 3 2a 0.3 mmol 0.36 mmol not detected Ts N Bnep 6 ~100% (recovered) 4. Reaction of 1a with (phen)cu I CF 3 : 1a (0.15 mmol) N N Cu I CF mmol B 2 (nep) 2 (0 or 200 mol %) LiOMe (0 or 250 mol %) 4-pyrrolidinone (50 mol %) DMF (1 ml) w/o B 2 (nep) 2 & LiOMe: TsN 2a nd CF 3 + 1a 96% (recovered) TsN not available Bnep TsN 6 2a' not available w/ B 2 (nep) 2 & LiOMe: nd not available 20% 25% To a flame-dried Schlenk tube equipped with a stir bar was added 4-iodo-1-(toluene-4-sulfonyl)-piperidine (1a) (54.8 mg, 0.15 mmol), (phen)cu I CF 3 (48.0 mg, 0.15 mmol), B 2 (nep) 2 (67.8 mg, 0.3 mmol) and LiOMe (14.3 mg, mmol) (or in the absence of B 2 (nep) 2 and LiOMe) in glove-box. The tube was capped with a rubber septum and moved out of the glove-box. DMF (1.0 ml) and 2-pyrrolidinone (6.4 μl) were added via syringes. The reaction mixture was stirred vigorously at room temperature for 6 hours. The reaction mixture was directly loaded onto a silica gel column without work-up. The residue in the reaction vessel was rinsed with small amount of DCM or eluent. Flash column chromatography provided the products. S6

7 Results: While in the absence of both B 2 (nep) 2 and LiOMe, no trifluoromethylation product was detected by 19 F NMR. Instead, 52.4 mg (0.14 mmol, 96% yield) of 1a was recovered. While in the presence of B 2 (nep) 2 and LiOMe, no trifluoromethylation product was detected by 19 F NMR. Wherein 8.8 mg (0.038 mmol, 25% yield) of hydrodehalogenation product 2a and 10.4 mg (0.030 mmol, 20% yield) of borylation product 6 were isolated. 5. Reaction of 1a with (phen)cu III (CF 3 ) 3 : The preparation of (phen)cu III (CF 3 ) 3 complex was performed according to a literature procedures F NMR (565 MHz, CDCl 3 ) δ (quintet, J = 5.65, Hz), (q, J = 9.7 Hz). 1 H NMR (600 MHz, CDCl 3 ) δ 9.45 (dd, J = 4.8, 1.2 Hz, 2H), 8.58 (dd, J = 8.1, 1.3 Hz, 2H), 8.02 (s, 2H), 7.99 (dd, J = 8.1, 4.8 Hz, 2H). 1a (0.15 mmol) F 3 C N N Cu III CF 3 CF mmol B 2 (nep) 2 (0 or 200 mol %) LiOMe (0 or 250 mol %) 4-pyrrolidinone (50 mol %) DMF (1 ml) w/o B 2 (nep) 2 & LiOMe: TsN 2a nd CF 3 + 1a 95% (recovered) w/ B 2 (nep) 2 & LiOMe: nd substantial amount To a flame-dried Schlenk tube equipped with a stir bar was added 4-iodo-1-(toluene-4-sulfonyl)-piperidine (1a) (54.8 mg, 0.15 mmol), (phen)cu III (CF 3 ) 3 (67.6 mg, 0.15 mmol), B 2 (nep) 2 (67.8 mg, 0.3 mmol) and LiOMe (14.3 mg, mmol) (or in the absence of both B 2 (nep) 2 and LiOMe) in a glove box. The tube was capped with a rubber septum and moved out of the glove-box. DMF (1.0 ml) and 2-pyrrolidinone (6.4μL) were then added via syringes. The reaction mixture was stirred vigorously at room temperature for 6 hours. The reaction mixture was directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of DCM or eluent. Flash column chromatography (25% of EtOAc in petroleum ether, v/v) provided mixtures of compounds for analysis. Results: No trifluoromethylation product was detected by 19 F NMR in the presence or absence of B 2 (nep) 2 and LiOMe. 6. Reaction of 4a with B 2 (nep) 2. S7

8 CuCl (20 mol %) L1 (20 mol %) I B 2 (nep) 2 (200 mol %) N Ts LiOMe (250 mol %) Ts N 4a 4-pyrrolidinone (50 mol %) mmol DMF (1 ml) 74% B(nep) + Ts N 8 20% To a flame-dried Schlenk tube equipped with a stir bar was added 4a (109.6 mg, 0.3 mmol), L1 (29.1 mg, 0.06 mmol), B 2 (nep) 2 (135.6 mg, 0.6 mmol) and LiOMe (28.6 mg, 0.75 mmol) followed by addition of CuCl (5.8 mg, 0.06 mmol) in a glove-box under N 2 atmosphere. The tube was capped with a rubber septum and moved out of the glove-box. DMF (1.0 ml) and 2-pyrrolidinone (12.8 μl) were then added via syringes. The reaction mixture was stirred vigorously at room temperature for another 8 hours at room temperature. The reaction mixture was directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of DCM or eluent. Flash column chromatography provided 3-methyl-1- (toluene-4-sulfonyl)-pyrrolidine (8) (14.6 mg, mmol, 20% yield) and the borylation product (7) (79.0 mg, 0.22 mmol, 74% yield). NMR data for compound 7: 1 H NMR (600 MHz, CDCl 3 ) δ 7.69 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 3.53 (s, 4H), 3.48 (dd, J = 9.4, 7.4 Hz, 1H), 3.31 (td, J = 9.6, 3.3 Hz, 1H), 3.16 (dd, J = 16.6, 9.3 Hz, 1H), 2.69 (t, J = 9.1 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 0.91 (s, 6H), 0.67 (d, J = 7.4 Hz, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 143.0, 134.0, 129.5, 127.4, 71.8, 55.0, 47.7, 34.8, 33.7, 31.5, 21.7, NiCl 2 (dme) (15 mol %) L1 (15 mol %) I B 2 (nep) 2 (200 mol %) B(nep) N Ts N Ts + LiOMe (250 mol %) Ts N Ts N + 4a 4-pyrrolidinone (50 mol %) 7 DMF (1 ml) 0.3 mmol not detected 30% ( 1 H NMR) unknown materials A similar procedure was applied to 4a but only with NiCl 2 (dme) as the catalyst, no detectable 7 was isolated. S8

9 Part 4. Preparation of ligands Preparation of 2, 4, 7, 9-tetraphenyl-1, 10-phenanthroline (L1): 3 To a solution of bathophenanthroline (8.3 g, 25 mmol) in toluene (100 ml) was added phenyl lithium (1.0 M, ethyl ether solution, 100 ml, 100 mmol) dropwise at 0, while the reaction mixture was stirred vigorously. After completion of the addition, the reaction mixture was stirred at room temperature for another 18 hours. At which point, the resulting reaction mixture was quenched with 50 ml of iced water. The organic layer was separated, and collected. The aqueous layer was extracted three times with chloroform, and the resultant organic layer was collected. After 100 g of manganese dioxide (activated) was added to the organic solution, the mixture was stirred for 30 minutes. Following this, 100 g of sodium sulfate was added. The resultant mixture was stirred for additional 30 minutes. At which point, the mixture was filtered and concentrated. The residue was purified through silica gel column chromatography (eluent: n-hexane/dcm = 5:1), followed by recrystallization (solvent for recrystallization: DCM/EtOAc = 1:3) to afford a pale solid (5.3 g, 10.9 mmol, 44% yield over two steps). 1 H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 7.7 Hz, 4H), 8.11 (s, 2H), 7.83 (s, 2H), (m, 8H), 7.57 (t, J = 7.4 Hz, 4H), 7.52 (t, J = 7.3 Hz, 4H). 13 C NMR (151 MHz, CDCl3) δ 156.1, 149.2, 146.8, 139.5, 138.4, 129.7, 129.4, 128.8, 128.6, 128.4, 127.7, 125.8, 123.6, HRMS calcd for C 36 H 25 N 2 [M+H]: Found Preparation of 2, 9-Bis-(2, 6-dimethyl-phenyl)-4, 7-diphenyl-[1, 10]phenanthroline (L8): S9

10 Following the procedure for L1, L8 was obtained as a light yellow solid (5.4 g, 10.0 mmol, 40% yield over two steps). 1 H NMR (600 MHz, CDCl3) δ 7.97 (s, 2H), (m, 6H), 7.55 (t, J = 7.4 Hz, 4H), (m, 2H), (m, 2H), 7.13 (d, J = 7.6 Hz, 4H), 2.28 (s, 12H). 13 C NMR (151 MHz, CDCl3) δ 159.4, 148.0, 146.9, 140.7, 138.2, 136.4, 129.7, 128.6, 128.4, 127.9, 127.8, 125.3, 125.0, 123.7, HRMS calcd for C 40 H 33 N 2 [M+H]: Found S10

11 Part 5. Preparation of Alkyl Halides. Preparation of (R)-2-(2-iodo-1-phenylethyl)isoindoline-1,3-dione. O O O H 2 N Ph OH O O N Ph OH (1) MsCl (2) NaI To a flame-dried flask equipped with a stir bar was added (R)-(-)-2-phenylglycinol (2.74 g, 20 mmol), phthalic anhydride (2.96 g, 20 mmol) and 100 ml of anhydrous toluene. The resulting mixture was heated to reflux and stirred for 6 hours. The solvent was removed under reduced pressure to afford the crude product as a white solid (5.1 g, 19.1 mmol, 95% yield). The crude product was used in next step without purification. 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 7.47 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.1 Hz, 2H), 7.29 (t, J = 6.5 Hz, 1H), 5.48 (dd, J = 9.3, 5.1 Hz, 1H), 4.69 (dd, J = 11.7, 9.4 Hz, 1H), 4.22 (ddd, J = 11.7, 5.0, 1.8 Hz, 1H), 3.09 (s, 1H). O O N Ph I To a solution of (R)-2-(2-hydroxy-1-phenyl-ethyl)-isoindole-1,3-dione (4.5 g, 16.8 mmol) and Et 3 N (1.9 g, 18.5 mmol) in DCM (100 ml) was added methanesulfonyl chloride (2.1 g, 18.5 mmol) at 0. The resulting mixture was warmed to room temperature and stirred for another 4 hours. The reaction mixture was washed with water, dried over anhydrous MgSO 4, filtered, evaporated under reduced pressure to afford a white solid (6.0 g). To a 250 ml of thick wall pressure tube equipped with a stir bar was added the obtained solid (6.0 g), NaI (12.8 g, 85 mmol) and 150 ml of acetone. The resulting suspension was heated to 100 and stirred for 18 hours. The solvent was removed under reduced pressure. The solid residue was dissolved in ethyl acetate, washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (eluent: ethyl acetate / petroleum ether = 1/ 5) to afford a white solid (5.6 g, 14.8 mmol, 88% overall yield). 1 H NMR (600 MHz, CDCl3) δ (m, 2H), (m, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.35 Hz, 1H), 5.56 (dd, J = 11.5, 5.2 Hz, 1H), 4.53 (t, J = 10.9 Hz, 1H), 3.83 (dd, J = 10.3, 5.3 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 167.8, 137.7, 134.2, 131.5, 128.9, 128.6, 127.7, 123.5, 57.5, 4.6. HRMS calcd for C 16 H 13 INO 2 [M+H]: Found M.p ºC. Preparation of 6-iodo-hexanoic acid benzyl ester. To a solution of 6-bromo-hexanoic acid (4.0 g, 20.5 mmol) in 50 ml of DCM was added DMF (0.1 ml) and oxalyl chloride (3.4 g, 26.6 mmol) in 0. The resulting mixture was slowly warmed to room temperature and stirred vigorously for 18 hours. The volatile materials were removed under reduced pressure. The residue was dissolved in 30 ml of DCM. Then benzyl alcohol (2.1 g, 19.0 mmol) in 10 ml of DCM was added in 0 while stirring vigorously, followed 3.0 ml of Et 3 N. The resulting mixture was stirred at room S11

12 temperature for 4 hours. The reaction mixture was washed with water, then brine, dried over Na 2 SO 4, concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate / petroleum ether = 1/ 20) to afford a colorless oil (3.8 g, 13.3 mmol, 65% yield). 1 H NMR (600 MHz, CDCl 3 ) δ (m, 5H), 5.13 (s, 2H), 3.39 (t, J = 6.7 Hz, 2H), 2.39 (t, J = 7.5 Hz, 2H), (m, 2H), (m, 2H), (m, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 173.1, 135.9, 128.4, 128.1, 66.1, 33.9, 33.4, 32.2, 27.5, A mixture of 6-bromo-hexanoic acid benzyl ester (3.6 g, 12.6 mmol) and NaI (5.7 g, 37.8 mmol) in 120 ml of acetone was reflux for 12 hours. The solvent was removed under reduced pressure. The solid residue was dissolved in ethyl acetate, washed with water, dried over Na 2 SO 4, concentrated under reduced pressure. The obtained residue was purified by flash chromatography (eluent: ethyl acetate / petroleum ether = 1/ 20) to afford a colorless oil (3.2 g, 9.6 mmol, 76% yield). 1 H NMR (600 MHz, CDCl3) δ (m, 5H), 5.12 (s, 2H), 3.17 (t, J = 7.0 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), (m, 2H), (m, 2H), (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 173.2, 135.9, 128.5, 128.2, 66.1, 34.0, 33.0, 29.9, 23.8, 6.6. HRMS calcd for C 13 H 18 IO 2 [M+H]: Found The following compounds were prepared from their alcohol precursors by treating with I 2 /PPh 3 /1H-Imidazol in DCM according to the literature procedure. 1 4-Iodo-1-(toluene-4-sulfonyl)-piperidine (1a) 1 H NMR (600 MHz, CDCl 3 ): δ 7.63 (d, J = 8.22 Hz, 2H), 7.33 (d, J = 7.98 Hz, 2H), (m, 1H), (m, 2H), (m, 2H), 2.43 (s, 3H), (m, 4H). 13 C NMR (151 MHz, CDCl 3): δ 143.7, 133.1, 129.7, 127.5, 45.6, 36.4, 25.5, HRMS calcd for C 12 H 17 INO 2 S [M+H]: Found M.p ºC. 4-Iodo-piperidine-1-carboxylic acid benzyl ester (1b) 1 H NMR (600 MHz, CDCl 3 ): δ (m, 5H), 5.30 (s, 2H), (m, 1H), (m, 2H), (m, 2H), 2.02 (br s, 4H). 13 C NMR (151 MHz, CDCl 3 ): δ 155.1, 136.5, 128.4, 128.0, 127.8, 67.2, 43.8, 37.0, HRMS calcd for C 13 H 17 INO 2 [M+H]: Found Iodo-piperidine-1-carboxylic acid tert-butyl ester (1c) S12

13 1 H NMR (600 MHz, CDCl 3 ): δ (m, 1H), 3.55 (dt, J = Hz, 2H), 3.25 (dt, J = Hz, 2H), 1.99 (dd, J = 5.3, 5.76 Hz, 4H), 1.42 (s, 9H). 13 C NMR (151 MHz, CDCl 3 ): δ 154.6, 79.7, 43.8, 37.2, 28.3, HRMS calcd for C 6 H 11 INO 2 [M t-bu + 2H]: Found (4-Iodo-piperidin-1-yl)-(4-methoxy-phenyl)-methanone (1d) 1 H NMR (600 MHz, CDCl 3): δ (m, 2H), (m, 2H), (m, 1H), 3.81 (s, 3H), 3.74 (br s, 2H), 3.47 (br s, 2H), 2.06 (br s, 4H). 13 C NMR (151 MHz, CDCl 3 ): δ 170.4, 160.7, 128.9, 127.5, 113.7, 55.3, 46.9 (br), 42.5 (br), 37.4 (br), HRMS calcd for C 13 H 17 INO 2 [M+H]: Found M.p ºC. 1-(2-Bromo-benzyl)-4-iodo-piperidine (1e) 1 H NMR (600 MHz, CDCl3) δ 7.53 (dd, J = 8.0, 1.0 Hz, 1H), 7.45 (dd, J = 7.6, 1.3 Hz, 1H), (m, 1H), 7.11 (td, J = 7.8, 1.6 Hz, 1H), 4.31 (br s, 1H), 3.57 (s, 2H), (m, 2H), 2.33 (br s, 2H), (m, 4H). 13 C NMR (151 MHz, CDCl3) δ 137.6, 132.7, 130.5, 128.3, 127.2, 124.5, 61.8, 53.8 (br), 38.3 (br), 28.3 (br). HRMS calcd for C 12 H 16 BrIN [M+H]: and Found and M.p ºC. Cis-(4-iodo-cyclohexyl)-carbamic acid benzyl ester (1f) 1 H NMR (600 MHz, CDCl3) δ (m, 5H), 5.09 (s, 2H), 4.88 (d, J = 5.4 Hz, 1H), 4.66 (br s, 1H), 3.64 (br s, 1H), (m, 2H), (m, 6H). 13 C NMR (151 MHz, CDCl3) δ 155.5, 136.4, 128.5, 128.0, 66.5, 48.5, 35.2, 32.8, HRMS calcd for C 14 H 19 INO 2 [M+H]: Found M.p ºC. 8-Iodo-1, 4-dioxa-spiro[4.5]decane (1h) 1 H NMR (600 MHz, CDCl3) δ 4.40 (s, 1H), (m, 2H), (m, 2H), (m, 4H), S13

14 (m, 2H), (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 107.4, 64.3, 64.2, 36.2, 34.7, EIMS: m/z 268 (M + ), 141, 99, Iodo-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid benzyl ester (1i) Cbz N I 1 H NMR (600 MHz, CDCl 3 ): δ (m, 5H), 5.16 (d, J = 3.2 Hz, 2H), (m, 1H), 4.16 (d, J = 31.8 Hz, 2H), (m, 2H), 2.21 (d, J = 9.8 Hz, 2H), (m, 2H), 1.67 (q, J = 7.3 Hz, 2H). 13 C NMR (151 MHz, CDCl 3 ): δ 153.3, 136.6, 128.5, 128.0, 127.8, 66.8, 56.0, 45.3, 44.5, 27.8, 27.0, HRMS calcd for C 15 H 19 INO 2 [M+H]: Found M.p ºC. 3-Iodo-1-(toluene-4-sulfonyl)-pyrrolidine (1j) 1 H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), (m, 1H), 3.88 (dd, J = 11.7, 5.9 Hz, 1H), 3.55 (dd, J = 11.7, 4.7 Hz, 1H), (m, 2H), 2.42 (s, 3H), (m, 1H), (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 143.7, 133.7, 129.7, 127.5, 58.6, 46.9, 38.0, 21.5, HRMS calcd for C 11 H 15 INO 2 S [M+H]: Found M.p ºC. 2-(2-Iodo-propyl)-isoindole-1, 3-dione (1l) 1 H NMR (600 MHz, CDCl3) δ 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), (m, 1H), 4.12 (dd, J = 14.1, 8.0 Hz, 1H), 3.85 (dd, J = 14.2, 7.4 Hz, 1H), 1.91 (d, J = 6.9 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 167.8, 134.2, 131.7, 123.5, 47.5, 25.5, HRMS calcd for C 11 H 11 INO 2 [M+H]: Found M.p ºC. Tert - Butyl-(3-iodo-butoxy)-diphenyl-silane (1n) 1 H NMR (600 MHz, CDCl3) δ (m, 4H), (m, 6H), (m, 1H), (m, 2H), (m, 1H), 1.97 (d, J = 6.9 Hz, 3H), (m, 1H), 1.08 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 135.6, 135.5, 133.6, 133.5, 129.7, 129.6, 127.7, 63.3, 45.3, 29.1, 26.8, 26.4, S14

15 19.2. Thiophene-2-carboxylic acid 3-iodo-butyl ester (1o) 1 H NMR (600 MHz, CDCl 3 ): δ 7.79 (dd, J = 1.24, 3.73 Hz, 1H), 7.55 (dd, J = 1.24, 4.98 Hz, 1H), 7.09 (dd, J = 3.76, 4.95 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), 1.99 (d, J = 6.89 Hz, 3H). 13 C NMR (151 MHz, CDCl 3 ): δ 161.9, 133.5, 133.4, 132.5, 127.7, 64.7, 41.3, 28.9, HRMS calcd for C 9 H 12 IO 2 S [M+H]: Found Furan-2-carboxylic acid 3-iodo-butyl ester (1p) 1 H NMR (600 MHz, CDCl 3 ): δ 7.56 (dd, J = 0.72, 1.56 Hz, 1H), 7.15 (dd, J = 0.58, 3.53 Hz, 1H), 6.49 (dd, J = 1.77, 3.53 Hz, 1H), (m 1H), (m, 2H), (m, 1H), (m, 1H), 1.96 (d, J = 7.06 Hz, 3H). 13 C NMR (151 MHz, CDCl 3 ): δ 158.3, 146.3, 144.3, 118.0, 111.8, 64.5, 41.2, 28.9, HRMS calcd for C 9 H 12 IO 3 [M+H]: Found (3-Iodo-butyl)-4-methoxy-benzene (1q) 1 H NMR (600 MHz, CDCl3) δ 7.13 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), (m, 1H), 3.80 (s, 3H), (m, 1H), (m, 1H), (m, 1H), 1.95 (d, J = 6.8 Hz, 3H), (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 157.9, 132.7, 129.4, 113.8, 55.2, 44.6, 34.9, 29.8, HRMS calcd for C 11 H 16 IO [M+H]: Found (3-Iodo-butyl)-benzo[1,3] dioxole (1r) 1 H NMR (600 MHz, CDCl 3 ): δ (m, 2H), 6.66 (dd, J = 1.56, 7.86 Hz, 1H), 5.92 (s, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 1.94 (d, J = 6.93 Hz, 3H), (m, 1H). 13 C NMR (151 MHz, CDCl 3 ): δ 147.6, 145.7, 134.4, 121.2, 108.8, 108.1, 100.7, 44.5, 35.5, 29.5, HRMS calcd for C 11 H 14 IO 2 [M+H]: Found S15

16 4-Methoxy-benzoic acid 3-iodo-propyl ester (1a ) 1 H NMR (600 MHz, CDCl3) δ (m, 2H), (m, 2H), 4.35 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.29 (t, J = 6.9 Hz, 3H), (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 166.0, 163.4, 131.5, 122.3, 113.6, 64.2, 55.4, 32.5, 1.6. HRMS calcd for C 11 H 14 IO 3 [M+H]: Found M.p ºC. 1-(3-Iodo-propoxy)-naphthalene (1b ) 1 H NMR (600 MHz, CDCl3) δ (m, 1H), 7.83 (dd, J = 7.2, 1.9 Hz, 1H), (m, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.23 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 6.8 Hz, 2H), (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 154.2, 134.4, 127.5, 126.4, 125.8, 125.5, 125.2, 121.8, 120.4, 104.7, 67.3, 33.0, 2.6. HRMS calcd for C 13 H 14 IO [M+H]: Found M.p ºC. (3-Iodo-propoxy)-benzene (1c ) 1 H NMR (600 MHz, CDCl3) δ (m, 2H), 6.98 (t, J = 7.3 Hz, 1H), (m, 2H), 4.05 (t, J = 5.8 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H), (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 158.6, 129.4, 120.9, 114.5, 67.1, 33.0, 2.6. HRMS calcd for C 9H 12IO [M+H]: Found Amino-benzoic acid 8-iodo-octyl ester (1d ) 1 H NMR (600 MHz, DMSO) δ 7.63 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 5.78 (br s, 2H), 4.13 (t, J = 6.5 Hz, 2H), 3.26 (t, J = 6.9 Hz, 2H), (m, 2H), (m, 2H), (m, 8H). 13 C NMR (151 MHz, DMSO) δ 165.9, 153.1, 131.0, 116.3, 112.8, 63.5, 32.9, 29.8, 28.5, 28.3, 27.8, 25.5, 9.1. HRMS calcd for C 15 H 23 INO 2 [M+H]: Found M.p ºC. S16

17 Tert-butyl-(5-iodo-pentyloxy)-diphenyl-silane (1e ) 1 H NMR (600 MHz, CDCl3) δ (m, 4H), (m, 6H), 3.71 (t, J = 6.3 Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), 1.10 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 135.5, 133.9, 129.5, 127.6, 63.5, 33.2, 31.4, 26.9, 26.8, 19.2, 7.1. Trans-3-bromo-2-(3-iodo-propoxy)-tetrahydro-furan (1g ) 1 Br I O O 1 H NMR (600 MHz, CDCl3) δ 5.18 (s, 1H), 4.18 (d, J = 5.7 Hz, 1H), 4.13 (dd, J = 15.7, 8.1 Hz, 1H), 4.03 (td, J = 8.5, 3.3 Hz, 1H), 3.69 (dt, J = 10.2, 5.8 Hz, 1H), 3.44 (dt, J = 10.1, 5.8 Hz, 1H), 3.19 (t, J = 6.8 Hz, 2H), (m, 1H), (m, 1H), (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 108.4, 66.7, 66.4, 49.8, 33.7, 33.0, 2.9. HRMS calcd for C 7 H 13 BrIO 2 [M+H]: Found N-(3-Iodo-propyl)-4-methyl-benzenesulfonamide (1h ) 1 H NMR (600 MHz, CDCl 3 ): δ 7.76 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.02 (s, 1H), 3.16 (t, J = 6.7 Hz, 2H), 3.02 (q, J = 6.3 Hz, 2H), 2.43 (s, 3H), (m, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 143.6, 136.6, 129.8, 127.0, 43.4, 32.9, 21.5, 2.5. HRMS calcd C 10 H 15 INO 2 S for [M+H]: Found M.p ºC. 3-(3-Iodo-propyl)-indole-1-carboxylic acid tert - butyl ester (1i ) 1 H NMR (600 MHz, CDCl3) δ 8.18 (br s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.45 (br s, 1H), (m, 1H), (m, 1H), 3.25 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H), (m, 2H), 1.71 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 149.6, 135.4, 130.3, 124.3, 122.7, 122.3, 118.9, 118.8, 115.2, 83.3, 32.6, 28.1, 25.4, 6.5. HRMS calcd for C 16 H 21 INO 2 [M+H]: Found M.p ºC. N-(2-Iodo-ethyl)-4-methyl-N-phenyl-benzenesulfonamide (1j ) S17

18 1 H NMR (600 MHz, CDCl3) δ 7.47 (d, J = 8.2 Hz, 2H), (m, 3H), 7.25 (d, J = 8.1 Hz, 2H), (m, 2H), 3.86 (t, J = 7.64 Hz, 2H), 3.17 (t, J = 7.91Hz, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 143.7, 138.7, 135.0, 129.5, 129.3, 128.9, 128.4, 127.6, 53.4, 21.6, 1.5. HRMS calcd for C 15 H 17 INO 2 S [M+H]: Found M.p ºC. 2-(3-Iodo-propyl)-isoindole-1, 3-dione (1k ) 1 H NMR (600 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 3.76 (t, J = 6.80 Hz, 2H), 3.15 (t, J = 7.13 Hz, 2H), (m, 2H). 13 C NMR (150 MHz, CDCl 3 ): δ 168.2, 134.0, 131.9, 123.3, 38.6, 32.5, 1.2. HRMS calcd for C 11 H 11 INO 2 [M+H]: Found M.p ºC. (R)-(1-iodomethyl-2-phenyl-ethyl)-carbamic acid benzyl ester (1m ) I NHCbz 1 H NMR (600 MHz, CDCl3) δ (m, 7H), (m, 3H), 5.01 (s, 2H), 4.92 (d, J = 8.1 Hz, 1H), 3.61 (d, J = 4.8 Hz, 1H), 3.31 (dd, J = 10.2, 4.4 Hz, 1H), 3.08 (dd, J = 10.2, 3.6 Hz, 1H), 2.83 (dd, J = 13.6, 5.9 Hz, 1H), 2.71 (dd, J = 13.6, 8.1 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 155.3, 136.7, 136.2, 129.1, 128.7, 128.5, 128.2, 128.0, 126.9, 66.8, 51.5, 40.5, HRMS calcd for C 17H 19INO 2 [M+H]: Found M.p ºC. (S)-2-iodomethyl-pyrrolidine-1-carboxylic acid benzyl ester (1n ) 1 H NMR (600 MHz, CDCl3) δ (m, 5H), (m, 2H), (m, 1H), (m, 4H), (m, 1H), (m, 2H), (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 154.6, 154.4, 136.6, 136.4, 128.4, 128.3, 127.9, 127.8, 127.7, 66.9, 66.6, 58.2, 57.9, 47.5, 47.2, 31.5, 31.0, 23.4, 22.7, 10.4, S18

19 HRMS calcd for C 13 H 17 INO 2 [M+H]: Found N-allyl-N-(2-iodo-ethyl)-4-methyl-benzenesulfonamide (4a) 1 H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), (m, 1H), 5.18 (t, J = 8.82 Hz, 2H), 3.78 (d, J = 6.4 Hz, 2H), 3.41 (t, J = 7.68 Hz, 2H), 3.22 (t, J = 8.52 Hz, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 143.6, 136.3, 132.8, 129.8, 127.1, 119.6, 51.6, 50.1, 21.5, 2.0. HRMS calcd for C 12 H 17 INO 2 S [M+H]: Found M.p ºC. S19

20 Part 6. Copper-catalyzed Trifluoromethylation of Alkyl Halides General procedures for trifluoromethylation of alkyl halides with Togni s reagent II (GP): To a flame-dried Schlenk tube was added CuCl (5.9 mg, mmol, 20 mol %), NiCl 2 glyme (9.9 mg, mmol, 15 mol %), 2,4,7,9-tetraphenyl-1,10-phenanthroline (50.9 mg, mmol, 35 mol %), B 2 (nep) 2 (135.5 mg, mmol, 200 mol %), LiOMe (28.6 mg, 0.75mmol, 250 mol %) and alkyl iodide (0.300 mmol, 100 mol %, if the alkyl halide is solid ). The tube was capped with a rubber septum. After evacuated and backfilled nitrogen three times, 2-pyrrolidinone (12 µl, mmol, 50 mol %), alkyl iodide (0.300 mmol, 100 mol %, if the alkyl halide is liquid ) and DMF (1 ml) were added via a syringe. A solution of Togni s reagent II (113.8 mg, 0.36 mmol, 120 mol %) in 1 ml of DMF was added drop-wise via a microinject syringe pump within 40 min. After completion of the addition, the reaction mixture was allowed to stir for another 6 hours at room temperature. The mixture was added 30 ml of ethyl acetate and washed with saturated aqueous NH 4 Cl and then brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated under vacuum. The residue was purified by silica gel column chromatography to provide the target product. 1-(Toluene-4-sulfonyl)-4-trifluoromethyl-piperidine (2a) This compound was prepared according to the GP. After purification by column chromatography (SiO 2 : 20% ethyl acetate in petroleum ether), the title compound was isolated as a white solid containing trace amount of starting material 1a, which was removed by preparative thin layer column chromatography offering the target product as white solid (72.4 mg; mmol, 79% yield). 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 3.89 (d, J = 12.0 Hz, 2H), 2.44 (s, 3H), 2.25 (td, J = 12.2, 2.3 Hz, 2H), (m, 3H), (m, 2H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 7.8 Hz). 13 C NMR (151 MHz, CDCl3) δ 143.8, 132.9, 129.8, 127.7, (q, J = Hz), 45.0, 39.7 (q, J = Hz), 24.0(d, J = 2.09 Hz), HRMS calcd for C 13 H 17 F 3 NO 2 S [M+H]: Found M.p ºC. To further demonstrate the utility of this trifluoromethylation protocol, the reaction was also amplified to 1.5 mmol scale. To a 50 ml flame-dried Schlenk flask was added CuCl (29.4 mg, 0.3 mmol, 20 mol %), NiCl 2 glyme (49.4 mg, mmol, 15 mol %), L1 (254.4 mg, mmol, 35 mol %), B 2 (nep) 2 (677.5 mg, 3.0 mmol, 200 mol %), LiOMe (143.0 mg, 3.75mmol, 250 mol %) and 1a (547.8 mg, 1.5 mmol, 100 mol %). The flask was capped with a rubber septum. After evacuated and backfilled nitrogen three times, 2- pyrrolidinone (60 µl, 0.75 mmol, 50 mol %) and DMF (5 ml) were added via a syringe. A solution of Togni s reagent II (568.8 mg, 1.8 mmol, 120 mol %) in 5 ml of DMF was added drop-wise via a microinject syringe pump within 40 min. After completion of the addition, the reaction mixture was allowed to stir for another 6 hours at room temperature. The mixture was added 30 ml of ethyl acetate and washed with saturated aqueous NH 4 Cl and then brine. The organic phase was dried over Na 2 SO 4, filtered, and evaporated S20

21 under vacuum. The residue was purified by silica gel column chromatography (eluent: 20% ethyl acetate in petroleum ether) to provide mg white solid. A handful of impurities were further removed by preparative thin layer column chromatography offering the target product (338.6 mg, 1.10 mmol, 73% yield). 4-Trifluoromethyl-piperidine-1-carboxylic acid benzyl ester (2b) This compound was prepared according to the GP. After purification by column chromatography (SiO 2 : 20% ethyl acetate in petroleum ether), the title compound was isolated as an oil containing trace amount of starting material 1b, which was removed by preparative thin layer column chromatography offering the product (55.6 mg, mmol, 64% yield). 1 H NMR (600 MHz, CDCl3) δ (m, 5H), 5.14 (s, 2H), 4.31 (d, J = 38.5 Hz, 2H), 2.77 (br s, 2H), (m, 1H), 1.86 (br s, 2H), 1.51 (br s, 2H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.2 Hz). 13 C NMR (151 MHz, CDCl3) δ 155.0, 136.5, 128.5, 128.0, 127.9, (q, J = Hz), 67.2, 42.7, 40.4 (q, J = Hz), 24.3 (br). HRMS calcd for C 14 H 17 F 3 NO 2 [M+H]: Found Trifluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (2c) This compound was prepared according to the GP. After purification by column chromatography (SiO 2 : 20% ethyl acetate in petroleum ether), trace inseparable starting material 1c was further converted into a dimerization product according to a literature procedure. 8 Following this, the trace impurity was removed by column chromatography offering a high quality of NMR sample (53.9 mg, mmol, 70% yield). 1 H NMR (600 MHz, CDCl3) δ 4.20 (br s, 2H), 2.67 (br s, 2H), (m, 1H), 1.82 (d, J = 13.1 Hz, 2H), (m, 11H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.2 Hz). 13 C NMR (151 MHz, CDCl3) δ 154.5, (q, J = Hz), 79.8, 42.6 (br), 40.5 (q, J =27.5 Hz), 28.3, HRMS calcd for C 11 H 19 F 3 NO 2 [M+H]: Found M.p ºC. (4-Methoxy-phenyl)-(4-trifluoromethyl-piperidin-1-yl)-methanone (2d) This compound was prepared according to the GP. After purification by column chromatography (SiO 2 : 20% ethyl acetate in petroleum ether), the title compound was isolated as a solid containing trace amounts of S21

22 starting material 1d and E2 elimination product from the iodo substrate. The trace impurities were removed by preparative thin layer chromatography offering the title product (60.1 mg, mmol, 70% yield). 1 H NMR (600 MHz, CDCl3) δ (m, 2H), (m, 2H), (m, 5H), 2.88 (br s, 2H), (m, 1H), 1.91 (br s, 2H), (m, 2H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.1 Hz). 13 C NMR (151 MHz, CDCl3) δ 170.4, 160.8, 128.9, 127.6, (q, J = Hz), 113.7, 55.3, 46.3 (br), 41.4 (br), 40.5 (q, J = 27.6 Hz), 24.7 (br). HRMS calcd for C 14 H 17 F 3 NO 2 [M+H]: Found M.p ºC. 1-(2-Bromo-benzyl)-4-trifluoromethyl-piperidine (2e) This compound was prepared according to the GP. After purification by column chromatography (SiO 2 : 15% ethyl acetate in petroleum ether), the title compound was isolated as an oil (58.4 mg, mmol, 60% yield). 1 H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), (m, 1H), 3.59 (s, 2H), 2.99 (d, J = 11.6 Hz, 2H), (m, 3H), 1.83 (d, J = 12.9 Hz, 2H), (m, 2H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.2 Hz). 13 C NMR (151 MHz, CDCl3) δ 137.6, 132.7, 130.5, 128.4, (q, J = Hz), 127.2, 124.5, 61.7, 52.4, 40.3 (q, J = 27.2 Hz), 24.7 (d, J = 2.5 Hz). HRMS calcd for C 13 H 16 BrF 3 N [M+H]: and Found and (4-Trifluoromethyl-cyclohexyl)-carbamic acid benzyl ester (2f) This compound was prepared according to the GP. After purification by column chromatography (SiO 2 : 10% ethyl acetate in petroleum ether), the title compound was isolated as a mixture of two isomers containing trace amounts of L1, E2 elimination and hydrodehalogenation of the iodo substrate. The ratio of isomers (isomer I : isomer II = 5:7) was estimated by 19 F NMR. The trace impurities were removed by preparative thin layer chromatography offering isomer I as an oil (24.2 mg, mmol, 27% yield) and isomer II as a solid (29.1 mg, mmol, 32% yield). Isomer I: 1 H NMR (600 MHz, CDCl3) δ (m, 5H), 5.10 (s, 2H), 4.89 (s, 1H), (m, 1H), (m, 1H), (m, 4H), (m, 4H). Isomer II: 1 H NMR (600 MHz, CDCl3) δ (m, 5H), 5.09 (s, 2H), 4.64 (s, 1H), (m, 1H), 2.13 (d, J = 11.8 Hz, 2H), (m, 3H), (m, 2H), (m, 2H). 19 F NMR (565 MHz, CDCl3) Isomer I: δ (s); Isomer II: δ (d, J = 5.7 Hz). Isomer I: 13 C NMR (151 MHz, CDCl3) δ 155.6, 136.3, 128.6, 128.2, (q, J = Hz), 66.8, 45.5, 40.5 (q, J = 26.7 Hz), 28.7, Isomer II: 13 C NMR (151 MHz, CDCl3) δ 155.5, 136.4, 128.5, 128.1, (q, J = Hz), 66.6, 49.4, 41.0 (q, J = 26.8 Hz), 31.7, 23.9 (d, J = 2.0 Hz). S22

23 HRMS calcd for C 15 H 19 F 3 NO 2 [M+H]: Found Tert-butyl-diphenyl-(4-trifluoromethyl-cyclohexyloxy)-silane (2g) After a flash column chromatography, an inseparable mixture containing the title compound, and trace amounts of E2 elimination, hydrodehalogenation and chloro-substitution of the iodo substrate was isolated. The ratio of trans/cis isomers (trans: cis = 1 : 1) was estimated by 19 F NMR. The yield was estimated based on 19 F NMR using benzotrifluoride as the internal standard (57% nmr yield). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.5 Hz), (d, J = 6.9 Hz). 8-Trifluoromethyl-1, 4-dioxa-spiro[4.5]decane (2h) This compound was prepared according to the GP. After purification by column chromatography (SiO 2 : 5% ethyl acetate in petroleum ether), an inseparable mixture containing the title compound, and trace amounts of E2 elimination product and chloro-substituted product was isolated as a colorless oil (45.4 mg). 1 H NMR (600 MHz, CDCl3) δ 3.95 (s, 4H), (m, 1H), 1.91 (d, J = 11.2 Hz, 2H), 1.82 (d, J = 12.4 Hz, 2H), (m, 2H), 1.53 (td, J = 13.5, 3.9 Hz, 2H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.2 Hz). EIMS: m/z 210 (M + ), 147, 141, 99, Trifluoromethyl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzyl ester (2i) Cbz N CF 3 This compound was prepared according to the GP. After a flash column chromatography(sio 2: 10% ethyl acetate in petroleum ether), a handful of inseparable starting alkyl iodide was converted into dimerization product according to the literature procedure. 8 The trace impurities were removed by preparative thin layer chromatography offering the title product (70.9 mg, 0.22 mmol, 75% yield). 1 H NMR (600 MHz, CDCl3) δ (m, 5H), 5.16 (d, J = 3.7 Hz, 2H), 4.41 (d, J = 33.6 Hz, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 5H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.2 Hz). 13 C NMR (151 MHz, CDCl3) δ 153.3, 136.7, 128.5, 128.0, 127.8, (q, J = Hz), 66.8, 52.3, 34.0 (q, J = 27.6 Hz), 30.1, 29.4, 28.2, HRMS calcd for C 16 H 19 F 3 NO 2 [M+H]: Found (Toluene-4-sulfonyl)-3-trifluoromethyl-pyrrolidine (2j) S23

24 This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 15% ethyl acetate in petroleum ether), the inseparable E2 elimination product was further converted into an alcohol according to a literature procedure. 9 Preparative thin layer chromatography offers the title product as a white solid (44.7 mg, mmol, 51% yield). 1 H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 3.52 (dd, J = 10.7, 8.7 Hz, 1H), (m, 2H), 3.23 (dd, J = 10.8, 7.0 Hz, 1H), (m, 1H), 2.44 (s, 3H), (m, 1H), (m, 1H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.8 Hz). 13 C NMR (151 MHz, CDCl3) δ 144.0, 132.7, 129.8, 127.6, (q, J = Hz), 47.2, 46.8 (q, J = 2.9 Hz), 42.0 (q, J = 28.9 Hz), 25.1, HRMS calcd for C 12 H 15 F 3 NO 2 S [M+H]: Found M.p ºC. 3-Trifluoromethyl-azetidine-1-carboxylic acid tert-butyl ester (2k) This compound was prepared according to the GP. After a flash column chromatography(sio 2 : 5% ethyl acetate in petroleum ether), the inseparable alkyl iodide was converted into the dimerization product according to the literature procedure. 8 Trace impurities were removed by preparative thin layer chromatography offering the title product as an oil (34.1 mg, mmol, 50% yield). 1 H NMR (400 MHz, CDCl3) δ 4.07 (t, J = 9.0 Hz, 2H), 3.98 (dd, J = 9.2, 5.7 Hz, 2H), (m, 1H), 1.44 (s, 9H). 19 F NMR (376 MHz, CDCl3) δ (d, J = 7.5 Hz). 13 C NMR (101 MHz, CDCl3) δ155.8, (q, J = Hz), 80.2, 48.6 (br s), 31.8 (q, J = 32.1 Hz), EIMS: m/z 225 (M + ), 210, 170, (3, 3, 3-Trifluoro-2-methyl-propyl)-isoindole-1, 3-dione (2l) This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 5% ethyl acetate in petroleum ether), the title compound was isolated as a solid containing trace amounts of E2 elimination and chloro-substitution products of the iodo substrate. The trace impurities were removed by preparative thin layer column chromatography offering the product (39.6 mg, mmol, 51% yield). 1 H NMR (600 MHz, CDCl3) δ 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.74 (dd, J = 5.4, 3.0 Hz, 2H), 3.96 (dd, J = 14.1, 6.5 Hz, 1H), 3.71 (dd, J = 14.0, 8.2 Hz, 1H), (m, 1H), 1.15 (d, J = 7.1 Hz, 3H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.6 Hz). S24

25 13 C NMR (151 MHz, CDCl3) δ 167.9, 134.2, 131.8, (q, J = Hz), 123.5, 37.5 (d, J = 3.0 Hz), 37.1 (q, J = 26.5 Hz), 11.2(d, J = 3.0 Hz). HRMS calcd for C 12 H 11 F3NO 2 [M+H]: Found M.p ºC. 4-Methoxy-benzoic acid 4, 4, 4-trifluoro-3-methyl-butyl ester (2m) This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 10% ethyl acetate in petroleum ether), the title compound was isolated as an oil containing trace amounts of hydrodehalogenation and chloro-substitution products of the iodo substrate. The trace impurities were removed by preparative thin layer chromatography offering the product (43.7 mg, mmol, 53% yield). 1 H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), (m, 2H), 3.86 (s, 3H), (m, 1H), (m, 1H), (m, 1H), 1.20 (d, J = 7.0 Hz, 3H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.9 Hz). 13 C NMR (151 MHz, CDCl3) δ 166.1, 163.5, 131.6, (q, J = Hz), 122.3, 113.7, 61.4, 55.4, 35.2 (q, J = 27.0 Hz), 28.7 (d, J = 2.3 Hz), 12.6 (q, J = 2.9 Hz). HRMS calcd for C 13 H 16 F 3 O 3 [M+H]: Found Tert-butyl-diphenyl-(4, 4, 4-trifluoro-3-methyl-butoxy)-silane (2n) This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 5% ethyl acetate in petroleum ether), which contains the inseparable unreacted alkyl iodide. The alkyl iodide was further converted into a dimerization product according to the literature procedure. 8 The remaining impurities were removed by preparative thin layer chromatography offering the product as an oil (51.9 mg, mmol, 45% yield). 1 H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 4H), 7.45 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.3 Hz, 4H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 1.07 (s, 12H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 9.3 Hz). 13 C NMR (151 MHz, CDCl3) δ 135.5, 133.6, 133.5, 129.7, (q, J = Hz), 127.7, 60.5, 34.5 (q, J = 26.6 Hz), 32.1 (d, J = 1.8 Hz), 26.8, 19.2, 12.3 (q, J = 3.1 Hz) HRMS calcd for C 21 H 28 F 3 OSi [M+H]: Found Thiophene-2-carboxylic acid 4, 4, 4-trifluoro-3-methyl-butyl ester (2o) S25

26 This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 10% ethyl acetate in petroleum ether), the title compound was isolated as an oil containing trace amounts of hydrodehalogenation, E2 elimination and chloro-substitution products of the iodo substrate. The impurities were removed by preparative thin layer chromatography offering the title product (41.2 mg, mmol, 54% yield). 1 H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 4.9 Hz, 1H), 7.11 (t, J = 4.3 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), 1.20 (d, J = 7.0 Hz, 3H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 8.9 Hz). 13 C NMR (151 MHz, CDCl3) δ 162.0, 133.6, 133.4, 132.6, (q, J = 279.4Hz), 127.8, 61.9, 35.2 (q, J = 27.0 Hz), 28.7 (d, J = 2.4 Hz), 12.6 (q, J = 2.9 Hz). HRMS calcd for C 10 H 12 F 3 O 2 S [M+H]: Found Furan-2-carboxylic acid 4, 4, 4-trifluoro-3-methyl-butyl ester (2p) This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 10% ethyl acetate in petroleum ether), the title compound was isolated as an oil containing trace amounts of hydrodehalogenation, E2 elimination and chloro-substitution products of the iodo substrate. The impurities were removed by preparative thin layer chromatography offering the title product (37.3 mg, mmol, 53% yield). 1 H NMR (600 MHz, CDCl3) δ (m, 1H), 7.14 (d, J = 3.5 Hz, 1H), 6.48 (dd, J = 3.1, 1.4 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), 1.14 (d, J = 7.0 Hz, 3H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 9.0 Hz). 13 C NMR (151 MHz, CDCl3) δ 158.3, 146.4, 144.3, (q, J = Hz), 118.0, 111.8, 61.6, 35.0 (q, J = 27.0 Hz), 28.5 (d, J = 2.3 Hz), 12.4 (q, J = 3.0 Hz). HRMS calcd for C 10 H 12 F 3 O 3 [M+H]: Found Methoxy-4-(4, 4, 4-trifluoro-3-methyl-butyl)-benzene (2q) This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 5% ethyl acetate in petroleum ether), the title compound was isolated as an oil containing trace amounts of hydrodehalogenation, E2 elimination and chloro-substitution products of the iodo substrate. The impurities were removed by preparative thin layer chromatography offering the product (36.6 mg, mmol, 52% yield). 1 H NMR (600 MHz, CDCl3) δ 7.11 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 3.80 (s, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 1.15 (d, J = 6.9 Hz, 3H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 9.0 Hz). S26

27 13 C NMR (151 MHz, CDCl3) δ 158.0, 133.0, 129.2, (q, J = Hz), 113.9, 55.2, (q, J = 26.3 Hz), 31.7, 31.2 (d, J = 2.1 Hz), 12.5 (q, J = 3.1 Hz). HRMS calcd for C 12 H 16 F 3 O [M+H]: Found (4, 4, 4-Trifluoro-3-methyl-butyl)-benzo[1,3]dioxole (2r) This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 10% ethyl acetate in petroleum ether), the title compound was isolated as an oil containing trace amonts of hydrodehalogenation, E2 elimination and chloro-substitution products of the iodo substrate. The impurities were removed by preparative thin layer chromatography offering the product (44.5 mg, mmol, 60% yield). 1 H NMR (600 MHz, CDCl3) δ 6.74 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 1.3 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 5.93 (s, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 1.14 (d, J = 6.9 Hz, 3H). 19 F NMR (565 MHz, CDCl3) δ (d, J = 9.1 Hz). 13 C NMR (151 MHz, CDCl3) δ 147.7, 145.9, 134.8, (q, J = Hz), 121.1, 108.7, 108.2, 100.8, 37.0 (q, J = 26.3 Hz), 32.4, 31.3, 12.6 (q, J = 3.0 Hz). HRMS calcd for C 12 H 14 F 3 O 2 [M+H]: Found Trifluoromethyl-heptadecane (2s) The title compound was isolated after a column chromatography, which was contaminated with inseparable E2 elimination and hydrodehalogenation products of the iodo substrate. The yield was estimated based on 19 F NMR using (trifluoromethyl)benzene as the internal standard (26% nmr yield). 19 F NMR (376 MHz, CDCl3) δ (d, J = 9.3 Hz). EIMS: m/z 308 (M + ), 288, 268, Methoxy-benzoic acid 4, 4, 4-trifluoro-butyl ester (3a) This compound was prepared according to the GP. After a flash column chromatography (SiO 2 : 10% ethyl acetate in petroleum ether), the title compound was isolated as an oil containing trace amount of unreacted alkyl iodide, hydrodehalogenation and chloro-substitution products of the iodo substrate. The impurities were removed by preparative thin layer chromatography offering the title product (50.1 mg, mmol, 61% yield). 1 H NMR (600 MHz, CDCl3) δ (m, 2H), (m, 2H), 4.35 (t, J = 6.3 Hz, 2H), 3.87 (s, S27