Supplementary Figure F NMR of (TMEDA)Pd(4-MeOC 6 H 4 )(CF 2 H) Supplementary Figure 2. 1 H NMR of (TMEDA)Pd(4-MeOC 6 H 4 )(CF 2 H)

Transcription

1 Supplementary Figure F NMR of (TMEDA)Pd(4-MeOC 6 H 4 )(CF 2 H) Supplementary Figure 2. 1 H NMR of (TMEDA)Pd(4-MeOC 6 H 4 )(CF 2 H) S1

2 Supplementary Figure C NMR of (TMEDA)Pd(4-MeOC 6 H 4 )(CF 2 H) Supplementary Figure F NMR of (TMEDA)Pd(4- t BuC 6 H 4 )(CF 2 H) S2

3 Supplementary Figure 5. 1 H NMR of (TMEDA)Pd(4- t BuC 6 H 4 )(CF 2 H) Supplementary Figure C NMR of (TMEDA)Pd(4- t BuC 6 H 4 )(CF 2 H) S3

4 Supplementary Figure F NMR of (TMEDA)Pd(C 6 H 5 )(CF 2 H) Supplementary Figure 8. 1 H NMR of (TMEDA)Pd(C 6 H 5 )(CF 2 H) S4

5 Supplementary Figure C NMR of (TMEDA)Pd(C 6 H 5 )(CF 2 H) Supplementary Figure F NMR of (TMEDA)Pd(4-ClC 6 H 4 )(CF 2 H) S5

6 Supplementary Figure H NMR of (TMEDA)Pd(4-ClC 6 H 4 )(CF 2 H) Supplementary Figure C NMR of (TMEDA)Pd(4-ClC 6 H 4 )(CF 2 H) S6

7 Supplementary Figure F NMR of (TMEDA)Pd(4-CF 3 C 6 H 4 )(CF 2 H) Supplementary Figure H NMR of (TMEDA)Pd(4-CF 3 C 6 H 4 )(CF 2 H) S7

8 Supplementary Figure C NMR of (TMEDA)Pd(4-CF 3 C 6 H 4 )(CF 2 H) Supplementary Figure F NMR of (DPPF)Pd(4-OMeC 6 H 4 )(CF 2 H) S8

9 Supplementary Figure H NMR of (DPPF)Pd(4-OMeC 6 H 4 )(CF 2 H) Supplementary Figure P NMR of (DPPF)Pd(4-OMeC 6 H 4 )(CF 2 H) S9

10 Supplementary Figure F NMR of (DPPF)Pd(4- t BuC 6 H 4 )(CF 2 H) Supplementary Figure H NMR of (DPPF)Pd(4- t BuC 6 H 4 )(CF 2 H) S10

11 Supplementary Figure P NMR of (DPPF)Pd(4- t BuC 6 H 4 )(CF 2 H) Supplementary Figure F NMR of (DPPF)Pd(C 6 H 5 )(CF 2 H) S11

12 Supplementary Figure H NMR of (DPPF)Pd(C 6 H 5 )(CF 2 H) Supplementary Figure P NMR of (DPPF)Pd(C 6 H 5 )(CF 2 H) S12

13 Supplementary Figure F NMR of (DPPF)Pd(4-ClC 6 H 4 )(CF 2 H) Supplementary Figure H NMR of (DPPF)Pd(4-ClC 6 H 4 )(CF 2 H) S13

14 Supplementary Figure P NMR of (DPPF)Pd(4-ClC 6 H 4 )(CF 2 H) Supplementary Figure F NMR of (DPPF)Pd(4-CF 3 C 6 H 4 )(CF 2 H) S14

15 Supplementary Figure H NMR of (DPPF)Pd(4-CF 3 C 6 H 4 )(CF 2 H) Supplementary Figure P NMR of (DPPF)Pd(4-CF 3 C 6 H 4 )(CF 2 H) S15

16 Supplementary Figure F NMR of (1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl) (difluoromethyl)silver [(SIPr)AgCF 2 H] 6 (376 MHz, THF-d 8 ) Supplementary Figure H NMR of (1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl) (difluoromethyl)silver [(SIPr)AgCF 2 H] 6 (400 MHz, THF-d 8 ) S16

17 Supplementary Figure C NMR of (1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl) (difluoromethyl)silver [(SIPr)AgCF 2 H] 6 (101 MHz, CDCl 3 ) Supplementary Figure F NMR of 4-(difluoromethyl)-1,1'-biphenyl 9a S17

18 Supplementary Figure H NMR of 4-(difluoromethyl)-1,1'-biphenyl 9a Supplementary Figure C NMR of 4-(difluoromethyl)-1,1'-biphenyl 9a S18

19 Supplementary Figure F NMR of 1-(benzyloxy)-4-(difluoromethyl)benzene 9b Supplementary Figure H NMR of 1-(benzyloxy)-4-(difluoromethyl)benzene 9b S19

20 Supplementary Figure C NMR of 1-(benzyloxy)-4-(difluoromethyl)benzene 9b Supplementary Figure F NMR of 1-butyl-4-(difluoromethyl)benzene 9c S20

21 Supplementary Figure H NMR of 1-butyl-4-(difluoromethyl)benzene 9c Supplementary Figure C NMR of 1-butyl-4-(difluoromethyl)benzene 9c S21

22 Supplementary Figure F NMR of tert-butyl 4-(difluoromethyl)benzoate 9d Supplementary Figure H NMR of tert-butyl 4-(difluoromethyl)benzoate 9d S22

23 Supplementary Figure C NMR of tert-butyl 4-(difluoromethyl)benzoate 9d Supplementary Figure F NMR of 4-(difluoromethyl)-N,N-diethylbenzamide (e S23

24 Supplementary Figure H NMR of 4-(difluoromethyl)-N,N-diethylbenzamide (e Supplementary Figure C NMR of 4-(difluoromethyl)-N,N-diethylbenzamide 9e S24

25 Supplementary Figure F NMR of N-(4-(difluoromethyl)benzyl)-N-ethylethanamine 9f Supplementary Figure H NMR of N-(4-(difluoromethyl)benzyl)-N-ethylethanamine 9f S25

26 Supplementary Figure C NMR of N-(4-(difluoromethyl)benzyl)-N-ethylethanamine 9f Supplementary Figure F NMR of 1-(4-(difluoromethyl)phenyl)-1H-pyrrole 9g S26

27 Supplementary Figure H NMR of 1-(4-(difluoromethyl)phenyl)-1H-pyrrole 9g Supplementary Figure C NMR of 1-(4-(difluoromethyl)phenyl)-1H-pyrrole 9g S27

28 Supplementary Figure F NMR of 4-bromo-4'-(difluoromethyl)-1,1'-biphenyl 9h Supplementary Figure H NMR of 4-bromo-4'-(difluoromethyl)-1,1'-biphenyl 9h S28

29 Supplementary Figure C NMR of 4-bromo-4'-(difluoromethyl)-1,1'-biphenyl 9h Supplementary Figure F NMR of 1-(cyclopropylmethoxy)-4- (difluoromethyl)benzene 9i S29

30 Supplementary Figure H NMR of 1-(cyclopropylmethoxy)-4- (difluoromethyl)benzene 9i Supplementary Figure C NMR of 1-(cyclopropylmethoxy)-4- (difluoromethyl)benzene 9i S30

31 Supplementary Figure F NMR of 4-(3-(4-(difluoromethyl)phenoxy)propyl) morpholine 9j Supplementary Figure H NMR of 4-(3-(4-(difluoromethyl)phenoxy)propyl)morpholine 9j S31

32 Supplementary Figure C NMR of 4-(3-(4-(difluoromethyl)phenoxy)propyl) morpholine 9j Supplementary Figure F NMR of 5-(difluoromethyl)-1,2,3-trimethoxybenzene 9k S32

33 Supplementary Figure H NMR of 5-(difluoromethyl)-1,2,3-trimethoxybenzene 9k Supplementary Figure C NMR of 5-(difluoromethyl)-1,2,3-trimethoxybenzene 9k S33

34 Supplementary Figure F NMR of 1-(benzyloxy)-3-(difluoromethyl)benzene 9l Supplementary Figure H NMR of 1-(benzyloxy)-3-(difluoromethyl)benzene 9l S34

35 Supplementary Figure C NMR of 1-(benzyloxy)-3-(difluoromethyl)benzene 9l Supplementary Figure F NMR of 3-(difluoromethyl)-4-fluoro-1,1'-biphenyl 9m S35

36 Supplementary Figure H NMR of 3-(difluoromethyl)-4-fluoro-1,1'-biphenyl 9m Supplementary Figure C NMR of 3-(difluoromethyl)-4-fluoro-1,1'-biphenyl 9m S36

37 Supplementary Figure F NMR of 4-(difluoromethyl)-N,N-diphenylaniline 9n Supplementary Figure H NMR of 4-(difluoromethyl)-N,N-diphenylaniline 9n S37

38 Supplementary Figure C NMR of 4-(difluoromethyl)-N,N-diphenylaniline 9n Supplementary Figure F NMR of 1-(difluoromethyl)-4-octylbenzene 9o S38

39 Supplementary Figure H NMR of 1-(difluoromethyl)-4-octylbenzene 9o Supplementary Figure C NMR of 1-(difluoromethyl)-4-octylbenzene 9o S39

40 Supplementary Figure F NMR of 1-(difluoromethyl)-3-phenoxybenzene 9p Supplementary Figure H NMR of 1-(difluoromethyl)-3-phenoxybenzene 9p S40

41 Supplementary Figure C NMR of 1-(difluoromethyl)-3-phenoxybenzene 9p Supplementary Figure F NMR of 1-(difluoromethyl)naphthalene 9q S41

42 Supplementary Figure H NMR of 1-(difluoromethyl)naphthalene 9q Supplementary Figure C NMR of 1-(difluoromethyl)naphthalene 9q S42

43 Supplementary Figure F NMR of 2-(difluoromethyl)naphthalene 9r Supplementary Figure H NMR of 2-(difluoromethyl)naphthalene 9r S43

44 Supplementary Figure C NMR of 2-(difluoromethyl)naphthalene 9r Supplementary Figure F NMR of 2-(4-(difluoromethyl)phenyl) -2-methyl-1,3-dioxolane 9s S44

45 Supplementary Figure H NMR of 2-(4-(difluoromethyl)phenyl) -2-methyl-1,3-dioxolane 9s Supplementary Figure C NMR of 2-(4-(difluoromethyl)phenyl)-2-methyl-1,3-dioxolane 9s S45

46 Supplementary Figure F NMR of 2-(4-(difluoromethyl)phenyl)benzo[d]thiazole 9t Supplementary Figure H NMR of 2-(4-(difluoromethyl)phenyl)benzo[d]thiazole 9t S46

47 Supplementary Figure C NMR of 2-(4-(difluoromethyl)phenyl)benzo[d]thiazole 9t Supplementary Figure F NMR of 9-(4-(difluoromethyl)phenyl)-9H-carbazole 9u S47

48 Supplementary Figure H NMR of 9-(4-(difluoromethyl)phenyl)-9H-carbazole 9u Supplementary Figure C NMR of 9-(4-(difluoromethyl)phenyl)-9H-carbazole 9u S48

49 Supplementary Figure F NMR of 3-(benzyloxy)-5-(difluoromethyl)pyridine (v Supplementary Figure H NMR of 3-(benzyloxy)-5-(difluoromethyl)pyridine 9v S49

50 Supplementary Figure C NMR of 3-(benzyloxy)-5-(difluoromethyl)pyridine 9v Supplementary Figure F NMR of 4-(difluoromethyl)-N,N-diethyl-3-methoxybenzamide 9w S50

51 Supplementary Figure H NMR of 4-(difluoromethyl)-N,N-diethyl-3-methoxybenzamide 9w Supplementary Figure C NMR of 4-(difluoromethyl)-N,N-diethyl-3-methoxybenzamide 9w S51

52 Supplementary Figure F NMR of 8R,9S,13S,14S)-3-(difluoromethyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cycl openta[a]phenanthrene-17,2'-[1,3]dioxolane] (x Supplementary Figure H NMR of 8R,9S,13S,14S)-3-(difluoromethyl)-13-methyl- 6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane] 9x S52

53 Supplementary Figure C NMR of 8R,9S,13S,14S)-3-(difluoromethyl)-13-methyl- 6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane] 9x Supplementary Figure F NMR of (S)-6-(difluoromethyl)-3,8-dimethyl- 3-((4S,8S)- 4,8,12-trimethyltridecyl)chroman 9y S53

54 Supplementary Figure H NMR of (S)-6-(difluoromethyl)-3,8-dimethyl-3-((4S,8S)- 4,8,12-trimethyltridecyl)chroman 9y Supplementary Figure C NMR of (S)-6-(difluoromethyl)-3,8-dimethyl-3-((4S,8S)- 4,8,12-trimethyltridecyl)chroman 9y S54

55 Yield % Supplementary Figure 109. Representative decay of 3c in the presence of 1.0 equivalent of DPPF y = m2*exp(-t/k) + m1 R 2 = m m K time (s) S55

56 Supplementary Tables Supplementary Table 1. Effect of different ligands on cooperative pd/ag catalyzed difluoromethylation a Ph I 5 mol % Pd(dba) 2 10 mol % Ligand 20 mol% [(SIPr)AgCl] TMSCF 2 H (2.4 eq) Ph CF 2 H 2.0 eq NaO t Bu, Dioxane, 80 o C, 4 h entry Ligand Yield (%) a Yield (%) b P( t Bu) 3 HBF 4 DPPE BrettPhos Xantphos DPPF DPEPhos Q-Phos BANAP <2% <2% <2% 23% 92% 35% <2% 8% <2% <2% 15% <5% 40% <5% <2% 12% Reaction conditions: i) 5 mol% Pd(dba) 2, 10 mol% DPPF, 20 mol% [(SIPr)AgCl], 2.0 equiv NaO t Bu, 2.4 equiv TMSCF 2 H, dioxane, 80 o C, 4 h; a Yields were determined by 19 F NMR spectroscopy in the presence of (trifluoromethoxy)benzene as the internal standard; b Reactions were conducted in the absence of [(SIPr)AgCl]. S56

57 Supplementary Table 2. Effects of different silver salts on the copperative Pd/Ag catalyzed difluoromethylation. a Ph I 5 mol % Pd(dba) 2 10 mol % Ligand 20 mol% [(SIPr)AgCl] TMSCF 2 H (2.4 eq) 2.0 eq NaO t Bu, Dioxane, 80 o C, 4 h Ph CF 2 H entry [Ag] [(SIPr)AgCl] IPrAgCl SIMesAgCl IMesAgCl ICyAgCl AgOPiv AgOTf AgPF 6 AgSbF 6 Yield (%) 89% <5% 56% 41% 21% 49% 36% <5% 55% Reaction conditions: i) 5 mol% Pd(dba) 2, 10 mol% DPPF, 20 mol% [(SIPr)AgCl], 2.0 equiv NaO t Bu, 2.4 equiv TMSCF 2 H, dioxane, 80 o C, 4 h; a Yields were determined by 19 F NMR spectroscopy in the presence of (trifluoromethoxy)benzene as the internal standard. S57

58 Supplementary Methods General Information All manipulations were conducted under an inert atmosphere with an argon-filled glovebox unless otherwise noted. All reactions were conducted in oven-dried 4.0 ml or 20.0 ml vials fitted with a Teflon-lined screw cap under an atmosphere of Argon unless otherwise noted. [(SIPr)AgCl] 1, [(TMEDA)Pd(Ar)(I)] 2, ArX (8d 3, 8d' 3, 8e 4, 8e' 4, 8f 5, 8s 6, 8x 7, 8y 7 ) were synthesized following the procedure reported in the literature. All solvents were purified by standard methods. 1 H, 13 C, 19 F NMR spectra were acquired on 400 MHz, 100 MHz, 376 MHz spectrometer (400 or 300 MHz for 1 H; 100 MHz or 125 MHZ for 13 C; 282 or 376 MHz for 19 F). Chemical shifts are reported in ppm and referenced to residual solvent peaks and 19 F spectra were referenced to CFCl 3. Coupling constants are reported in hertz. The following abbreviations were used to explain the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad. Materials. All reagents were used as received from commercial sources, unless specified otherwise, or prepared as described in the literature. S58

59 Synthesis of the Difluoromethylated Palladium Complexes General procedure for the synthesis of [(TMEDA)Pd(Ar)(CF 2 H)] (2a-e) To a solution of [(TMEDA)Pd(Ar)(X)] (1a-e) ( 2.00 mmol) and NaO t Bu (384.4 mg, 4.00 mmol) in THF (40 ml) was added TMSCF 2 H (992 mg, 8.00 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature. The mixture was filtered through a short plug with Celite and the solvent was evaporated under vacuum to give an orange-red solid. The solid was dissolved in CH 2 Cl 2 (100 ml), filtered through a short plug with Celite and the solvent was evaporated under vacuum to obtain the desired complex as a yellow crystal. The solid was recrystallized from CH 2 Cl 2 /pentane to give 2a-e General procedure for the formation of [(DPPF)Pd(Ar)(CF 2 H)] (3a-e) To a solution of [(TMEDA)Pd(Ar)(CF 2 H)] (2a-e) ( 0.5 mmol) in THF (12.5 ml) was added DPPF (388 mg, 0.70 mmol). The resulting mixture was stirred for 4.0 h at ambient temperature. The mixture was filtered through a short plug with Celite and the solvent was evaporated under vacuum to give an orange-red solid. The solid was recrystallized from THF/Et 2 O to give 3a-e. Complex 2a N CF 2 H Pd N According to the general procedure, [(TMEDA)Pd(C 6 H 4-4-OMe)(I)] (913.4 mg, 2.0 mmol) was reacted with NaO t Bu (384.4 mg, 4.0 mmol) and TMSCF 2 H (992 mg, 8.0 mmol) in 40 ml THF to afford 538 mg (1.42 mmol, 71%) of the desired complex as a red-orange crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.40 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.31 (t, J = 52.4 Hz, 1H), 3.74 (s, 3H), 2.72 (s, 6H), 2.55~2.54 (br, 4H), 2.24 (s, 6H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 52.4 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ 48.63, 49.38, 55.09, 59.91, 60.27, , (t, J = Hz), , , ppm; analysis (calcd., found for C 14 H 24 F 2 N 2 OPd): C (44.16, 43.92), H (6.35, 6.33), N (7.36, 7.31). OMe Complex 2b S59

60 N CF 2 H Pd N According to the general procedure, [(TMEDA)Pd(C 6 H 4-4- t Bu)(I)] (965.4 mg, 2.0 mmol) was reacted with NaO t Bu (384.4 mg, 4.0 mmol) and TMSCF 2 H (992 mg, 8.0 mmol) in 40 ml THF to afford 382 mg (0.94 mmol, 47%) of the desired complex as a off-white crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.40 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.33 (t, J = 52.4 Hz, 1H), 2.72 (s, 6H), 2.56~2.55 (br, 4H), 2.26 (s, 6H), 1.26 (s, 9H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 52.4 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ 31.73, 34.02, 48.68, 49.36, 59.93, 60.20, , (t, J = Hz), , , ppm. Complex 2c t Bu N CF 2 H Pd N According to the general procedure, [(TMEDA)Pd(C 6 H 5 )(I)] (853.8 mg, 2.0 mmol) was reacted with NaO t Bu (384.4 mg, 4.0 mmol) and TMSCF 2 H (992 mg, 8.0 mmol) in 40 ml THF to afford 585 mg (1.67 mmol, 83%) of the desired complex as a off-white crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.53 (d, J = 6.8 Hz, 2H), 7.00 ( m, 2H), 6.90 (m, 1H), 6.31 (t, J = 52.0 Hz, 1H), 2.73 (s, 6H), 2.57~2.56 (br, 4H), 2.26 (s, 6H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 52.0 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 48.65, 49.33, 59.91, 60.21, , , (t, J = Hz), , ppm; analysis (calcd., found for C 13 H 22 F 2 N 2 Pd): C (44.52, 44.53), H (7.99, 7.65), N (6.32, 6.48). Complex 2d N CF 2 H Pd N According to the general procedure, [(TMEDA)Pd(C 6 H 4-4-Cl)(I)] (922.2 mg, 2.0 mmol) was reacted with NaO t Bu (384.4 mg, 4.0 mmol) and TMSCF 2 H (992 mg, 8.0 mmol) in 40 ml THF to afford 595 mg (1.55 mmol, 77%) of the desired complex as a red-orange crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.46 (d, J = 8.4 Hz, 2H), 6.99 ( d, J = 8.4 Hz, 2H), 6.22 (t, J = 52.4 Hz, 1H), 2.72 Cl S60

61 (s, 6H), 2.57~2.55 (br, 4H), 2.25 (s, 6H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 52.4 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ 48.62, 49.34, 59.84, 60.29, , , (t, J = Hz), , ppm; analysis (calcd., found for C 13 H 21 ClF 2 N 2 Pd): C (40.54, 40.82), H (5.50, 5.41), N (7.27, 6.88). Complex 2e N CF 2 H Pd N According to the general procedure, [(TMEDA)Pd(C 6 H 4-4-CF 3 )(I)] (989.2 mg, 2.0 mmol) was reacted with NaO t Bu (384.4 mg, 4.0 mmol) and TMSCF 2 H (992 mg, 8.0 mmol) in 40 ml THF to afford 512 mg (1.23 mmol, 62%) of the desired complex as a off-white crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.67 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 6.18 (t, J = 52.4 Hz, 1H), 2.72 (s, 6H), 2.58~2.56 (br, 4H), 2.24 (s, 6H); 19 F NMR (376 MHz, CDCl 3 ): δ (s, 3F), (d, J = 52.4 Hz, 2F); 13 C NMR (101 MHz, CDCl 3 ): δ 48.69, 49.36, 59.87, 60.34, , (t, J = 31.5 Hz), (t, J = Hz), (t, J = Hz), , ppm; analysis (calcd., found for C 14 H 21 F 5 N 2 Pd): C (40.16, 40.04), H (5.05, 5.03), N (6.69, 6.71). Complex 3a Fe Ph Ph P P Ph Ph Pd According to the general procedure, [(TMEDA)Pd(C 6 H 4-4-OMe)(CF 2 H)] (190.4 mg, 0.5 mmol) was reacted with DPPF (388 mg, 0.70 mmol) in 12.5 ml THF to afford 192 mg (0.23 mmol, 47%) of the desired complex as a brown-yellow crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.93 (br, 4H), 7.49 (m, 7H), 7.28 (m, 5H), 7.11 (m, 4H), 6.99 (m, 2H), 6.59~6.31 (m, 3H), 4.46 (s, 2H), 4.39 (s, 2H), 4.13 (s, 2H), 3.75 (s, 2H), 3.60 (s, 3 H); 19 F NMR (376 MHz, CDCl 3 ): δ (ddd, J = 56.6, 48.9, 38.4 Hz); 31 P NMR (162 MHz, CDCl 3 ): δ 19.41~18.78 (m), 18.01~17.54 (m) ppm; analysis CF 2 H CF 3 OMe (calcd., found for C 42 H 36 F 2 FeOP 2 Pd): C (61.60, 61.85), H (4.43, 4.71). Complex 3b S61

62 Ph Ph P Fe Pd P CF 2 H Ph Ph According to the general procedure, [(TMEDA)Pd(C 6 H 4-4- t Bu)(CF 2 H)] (203.4 mg, 0.5 mmol) was reacted with DPPF (388 mg, 0.70 mmol) in 12.5 ml THF to afford 154 mg (0.18 mmol, 37%) of the desired complex as a light-yellow crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.94 (br, 4H), 7.49 (m, 7H), 7.29 (m, 5H), 7.01 (m, 6H), 6.67~6.65 (m, 3H), 4.50 (s, 2H), 4.40 (s, 2H), 4.11 (s, 2H), 3.70 (s, 2H), 1.15 (s, 9H); 19 F NMR (376 MHz, CDCl 3 ): δ (ddd, J = 57.7, 48.5, 39.9 Hz); 31 P NMR (162 MHz, CDCl 3 ): δ 19.70~19.05 (m), 17.43~16.94 (m) ppm; analysis (calcd., found for C 45 H 42 F 2 FeP 2 Pd): C (63.96, 64.12), H (5.01, 5.31). Complex 3c Ph Ph P Fe Pd P CF 2 H Ph Ph According to the general procedure, [(TMEDA)Pd(C 6 H 5 )(CF 2 H)] (175 mg, 0.5 mmol) was reacted with DPPF (388 mg, 0.70 mmol) in 12.5 ml THF to afford 206 mg (0.26 mmol, 52%) of the desired complex as a brown-yellow crystal. Crystals suitable for X-ray analysis were obtained by layering a solution of 10 mg 3c in CH 2 Cl 2 (70 μl) with pentane (3.5 ml) at -30 o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (br, 4 H), 7.50 (m, 7 H), 7.30 (m, 5 H), 7.07 (m, 6 H), 6.62~6.30 (m, 4H), 4.47 (s, 2 H), 4.40 (s, 2 H), 4.13 (s, 2 H), 3.75 (s, 2 H); 19 F NMR (376 MHz, CDCl 3 ) δ (ddd, J = 57.2, 49.6, 39.1 Hz); 31 P NMR (162 MHz, CDCl 3 ) δ 19.41~18.78 (m), 18.01~17.54 (m) ppm. Anal. Calcd for C 41 H 34 F 2 FeP 2 Pd: C, 62.42; H, 4.34; Found: C, 62.15; H, Complex 3d Cl Ph Ph P Fe Pd P CF 2 H Ph Ph According to the general procedure, [(TMEDA)Pd(C 6 H 4-4-Cl)(CF 2 H)] (193 mg, 0.5 mmol) was reacted with DPPF (388 mg, 0.70 mmol) in 12.5 ml THF to afford 312 mg (0.38 mmol, 76%) of the desired complex as a brown-yellow crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.92 (br, 4H), 7.53 S62

63 (m, 6H), 7.22 (m, 8H), 7.07 (m, 4H), 8.15 (d, J = 7.6 Hz, 2H), 6.51~6.26 (m, 1H), 4.52 (s, 2H), 4.44 (s, 2H), 4.14 (s, 2H), 3.71 (s, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (s, 3F), (ddd, J = 54.0, 49.3, 36.8 Hz, 2F); 31 P NMR (162 MHz, CDCl 3 ): δ 19.55~18.93 (m), 18.59~18.15 (m) ppm; analysis (calcd., found for C 41 H 33 ClF 2 FeP 2 Pd): C (59.81, 59.45), H (4.04, 4.44). Complex 3e CF 3 Ph Ph P Fe Pd P CF 2 H Ph Ph According to the general procedure, [(TMEDA)Pd(C 6 H 4-4-Cl)(CF 2 H)] (209 mg, 0.5 mmol) was reacted with DPPF (388 mg, 0.70 mmol) in 12.5 ml THF to afford 292 mg (0.34 mmol, 68%) of the desired complex as a yellow crystal. 1 H NMR (400 MHz, CDCl 3 ): δ 7.90 (br, 4H), 7.52 (m, 6H), 7.28 (m, 6H), 7.05 (m, 6H), 6.62~6.26 (m, 3H), 4.49 (s, 2H), 4.42 (s, 2H), 4.14 (s, 2H), 3.74 (s, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (ddd, J = 52.6, 49.3, 36.1 Hz); 31 P NMR (162 MHz, CDCl 3 ): δ 20.13~19.52 (m), 18.67~18.26 (m) ppm; analysis (calcd., found for C 41 H 33 ClF 2 FeP 2 Pd 1/2THF): C (59.44,59.18), H (4.45, 4.18). S63

64 Preparation of [(SIPr)Ag(CF 2 H)] 6 i Pr i Pr N N Ag i Pr i Pr CF 2 H To a solution of [(SIPr)AgCl] (831 mg, 1.50 mmol) and NaO t Bu (285 mg, 3.00 mmol) in THF (30 ml) was added TMSCF 2 H (375 ul, 3.00 mmol). The resulting mixture was stirred for 1.5 h at ambient temperature. The mixture was filtered through a short plug with Celite and the solvent was evaporated under vacuum to give an off-white solid. The solid was recrystallized from CH 2 Cl 2 /pentane to give (1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl)(difluoromethyl)silver [(SIPr)Ag(CF 2 H)] 6 as a white solid (698 mg, 1.23 mmol, 82%). Crystals suitable for X-ray analysis were obtained by laying a solution of complex 6 in THF (70 μl) pentane (3.5 ml) at -30 o C. 1 H NMR (400 MHz, THF-d 8 ): 7.36 (t, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 4H), 5.90 (td, J = 43.6, 14.0 Hz, 1H), 4.04 (s, 4H), 3.15 (hept, J = 6.8 Hz, 4H), 1.34 (d, J = 7.2 Hz, 12H), 1.32 (d, J = 7.2 Hz, 12H); 19 F NMR (376 MHz,THF-d 8 ): (dd, J 109 Ag-F = 62.4 Hz, J 107 Ag-F = 54.5 Hz, J H-F = 43.6 Hz); 13 C NMR (101 MHz, CDCl 3 ): 24.11, 25.76, 28.96, , , , , (dt, J 109 Ag-C = Hz, J 107 Ag-C = Hz, J C-F = Hz), (d, J 109 Ag-C = Hz, J 109 Ag-C = Hz) ppm; analysis (calcd., found for C 28 H 39 AgF 2 N 2 ): C (61.20, 60.91), H (7.15, 6.87), N (5.10, 4.78). S64

65 X-Ray data collection and refinement X-ray data for complex 3c was recorded at 20 o C using a Bruker APEX CCD diffractometer with graphite-monochromated Mo-K radiation ( = Å). The SMART program package was used to determine the unit-cell parameters. A Semi-empirical from equivalents absorption correction was applied. The structure was solved in the monoclinic space group C2/c by direct methods and refined to a R 1 value of 6.6% on F 2 by full-matrix least squares techniques with anisotropic thermal parameters for non-hydrogen atoms. Hydrogen atoms were placed in calculated positions and refined using a riding model. X-ray data for complex 6 was recorded at 20 o C using a Bruker APEX CCD diffractometer with graphite-monochromated Mo-K radiation ( = Å). The SMART program package was used to determine the unit-cell parameters. A Semi-empirical from equivalents absorption correction was applied. The structure was solved in the orthorhombic space group by direct methods and refined to a R 1 value of 4.9% on F 2 by full-matrix least squares techniques with anisotropic thermal parameters for non-hydrogen atoms. Hydrogen atoms were placed in calculated positions and refined using a riding model. S65

66 Kinetic Study on Reductive Elimination of 3a-e In a argon-filled glovebox, ca mg of complex 3a-e was added to a screw-cap NMR tube. Dioxane (0.6 ml) and (trifluoromethoxy)benzene (1.6 mg) were then added. The NMR probe was heated to 47 o C. Decay of the complexes were monitored by 19 F NMR spectroscopy. Kinetic date were fit to the expression y = m1 + m2 exp -t/k, in which 1/K is the first-order rate constant k obs. All results were average of two runs (See supplementary Figure 109 for the representative decay of 3c in the presence of 1.0 equivalent of DPPF). Reductive elimination of 3a (OMe) in the presence of 1 equiv. DPPF y = *exp(-t/189.9)+176.6, R 2 = 0.997; y' = *exp(-t/188.2)+154.7, R 2 = k obs(ome) = 8.790*10-5 S -1, k' obs(ome) = 8.856*10-5 S -1, k average(ome) = 8.823*10-5 S -1 ; t 1/2(OMe) = 1/k averge(ome) *ln2= min. Reductive elimination of 3b ( t Bu) in the presence of 1 equiv. DPPF y = *exp(-t/174.3)+164.7, R 2 = 0.999; y' = *exp(-t/181.7)+151.2, R 2 t = k obs( Bu) = 9.562*10-5 S -1 t, k obs( Bu) ' = 9.173*10-5 S -1 t, k average( Bu) = 9.368*10-5 S -1 t ; t 1/2( Bu ) = 1/k average( t Bu)*ln2= min. Reductive elimination of 3c (H) in the presence of 1 equiv. DPPF y = *exp(-t/224.8)+184.8, R 2 = 0.997; y' = *exp(-t/237.8)+138.3, R 2 = k obs(h) = 7.414*10-5 S -1 ; k obs(h )' = 7.009*10-5 S -1 ; k average(h) = 7.207*10-5 S -1 ; t 1/2(H) = 1/ k average(h) *ln2= min. Reductive elimination of 3d (Cl) in the presence of 1 equiv. DPPF y = *exp(-t/505.1)+204.1, R 2 = 0.999; y' = *exp(-t/492.3)+176.6, R 2 = k obs(cl) = 3.300*10-5 S -1 ; k obs(cl) ' = 3.385*10-5 S -1 ; k average(cl) = 3.343*10-5 S -1 t 1/2(Cl) = 1/ k average(cl) *ln2= min. Reductive elimination of 3e (CF 3 ) in the presence of 1 equiv. DPPF y = *exp(-t/717.8)+245.5, R 2 = 0.998; y' = *exp(-t/683.2)+58.00, R 2 = k obs(cf3) = 2.322*10-5 S -1 ; k obs(cf3) ' = 2.440*10-5 S -1, k average(cf3) = 2.381*10-5 S -1 ; t 1/2(CF3) = 1/ k average(cf3) *ln2= min. Reductive elimination of 3c ( t Bu) in the presence of 4 equiv. DPPF y = *exp(-t/163.3)+158.1, R 2 = 0.999; y' = *exp(-t/170.6)+148.8, R 2 t = k obs( Bu)4 = 1.021*10-4 S -1 t ; k obs( Bu)4 ' = 9.769*10-5 S -1 t ; k average( Bu)4 = 9.990*10-5 S -1 t t ; t 1/2( Bu)4 = 1/ k average( Bu)4 *ln2= min. S66

67 General Procedure for the Difluoromethylation of ArI In a Argon-filled glove box, ArI (0.5 mmol, 1.0 equiv), Pd(dba) 2 (14.4 mg, mmol, 0.05 equiv), DPPF (27.7 mg, 0.05 mmol, 0.1 equiv), [(SIPr)AgCl] (53.4 mg, 0.1 mmol, 0.2 quiv), and NaO t Bu (96.1 mg, 1.0 mmol, 2 equiv) were combined in a 20 ml vial. To this vial was added 5.0 ml of anhydrous dioxane, followed by trimethyl(difluoromethyl)silane (148.8 mg, 1.2 mmol, 2.4 equiv). The vial was sealed and moved out from the glove box. The mixture was stirred at 80 o C for 4 hours. The dark solution was diluted with H 2 O (15 ml). The mixture was filtered through a short plug of Celite, washed with CH 2 Cl 2 (20 ml 3). The organic layer was combined, dried over NaSO 4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane/et 2 O or pentane/ea mixture as the eluent to give the product. General Procedure for the Difluoromethylation of ArBr In a Argon-filled glove box, ArBr (0.5 mmol, 1.0 equiv), Pd(dba) 2 (20.1 mg, mmol, 0.07 equiv), DPPF (38.8 mg, 0.07 mmol, 0.14 equiv), [(SIPr)AgCl] (53.4 mg, 0.1 mmol, 0.2 equiv), and NaO t Bu (96.1 mg, 1.0 mmol, 2 equiv) were combined in a 20 ml vial. To this vial was added 5.0 ml of anhydrous toluene, followed by trimethyl(difluoromethyl)silane (148.8 mg, 1.2 mmol, 2.4 equiv). The vial was sealed and moved out from the glove box. The mixture was stirred at 80 o C for 6 hours. The dark solution was diluted with H 2 O (15 ml). The mixture was filtered through a short plug of Celite, washed with CH 2 Cl 2 (20 ml 3). The organic layer was combined, dried over NaSO 4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane/et 2 O or pentane/ea mixture as the eluent to give the product. 4-(Difluoromethyl)-1,1'-biphenyl (9a) CF 2 H Ph The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (142 mg, 8a) or ArBr on a 0.5 mmol scale (116.6 mg, 8a'). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9a (88 mg, 86% yield on ArI; 92 mg, 90% yield on ArBr). 1 H NMR (400 MHz, CDCl 3 ): δ 7.70 (d, J = 8.4 Hz, 2H), 7.62 (m, 4H), 7.49 (m, 2H), 7.42 (m, 1H), 6.72 (t, J = 56.4 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ (t, J = S67

68 239.4 Hz), (t, J = 5.0 Hz), , , , , (t, J = 22.7 Hz), , (t, J = 2.5 Hz) ppm; GC-MS (EI, m/z): [M + ], 183.0, (Benzyloxy)-4-(difluoromethyl)benzene (9b) CF 2 H OBn The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (155.1 mg, 8b) or ArBr on a 0.5 mmol scale (131.6 mg, 8b'). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 80:20) to give 9b (98 mg, 84% yield on ArI; 82 mg, 70% yield on ArBr). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 7H), 7.03 (d, J = 8.4 Hz, 2H), 6.60 (t, J = 56.8 Hz, 1H), 5.10 (s, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.8 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ 70.20, , (t, J = Hz), (t, J = 5.8 Hz), , , , , , (t, J = 1.9 Hz) ppm; LRMS (EI, m/z): 234 [M + ], 210, Butyl-4-(difluoromethyl)benzene (9c) CF 2 H tbu The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (155.1 mg, 8c). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9c (68 mg, 74% yield). 1 H NMR (300 MHz, CDCl 3 ): δ (m, 4H), 6.64 (t, J = 57.0 Hz, 1H), 1.35 (s, 9H); 19 F NMR (282 MHz, CDCl 3 ): δ (d, J = 57.0 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ 31.35, 34.99, (t, J = Hz), (t, J = 6.3 Hz), , (t, J = 21.4 Hz), ppm; GC-MS (EI, m/z): [M + ], 169.1, tert-butyl 4-(difluoromethyl)benzoate (9d) CF 2 H t BuO The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (157.1 mg, 8d) or ArBr on a 0.5 mmol scale (128.6 mg, 8d'). The crude O S68

69 mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9d (86 mg, 76% yield on ArI; 83 mg, 73% yield on ArBr). Mp: o C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.05 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 6.66 (t, J = 56.0 Hz, 1H), 1.58 (s, 9H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.0 Hz); 13 C NMR (126 MHz, CDCl 3 ): δ 28.29, 81.77, (t, J = Hz), (t, J = 5.9 Hz), , , (t, J = 25.0 Hz), ppm; HRMS (EI, m/z) [M + ] calcd. for C 12 H 14 O 2 F 2, ; found: ; IR (thin film) 3012, 2980, 2935, 1952, 1912, 1582, 1511, 1480, 1462, 1413, 1396, 1371, 1314, 1296, 1257, 1222, 1188, 1172, 1127, 1111, 1067, 1045, 1016, 976, 891, 863, 850, 833, 765, 753, 713, 664, 576, 515 cm (Difluoromethyl)-N,N-diethylbenzamide (9e) Et 2 N O The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (151.6 mg, 8e) or ArBr on a 0.5 mmol scale (128.1 mg, 8e'). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 90:10 to 50:50) to give 9e (81 mg, 71% yield on ArI; 87 mg, 77% yield on ArBr). 1 H NMR (400 MHz, CDCl 3 ): δ 7.51 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.64 (t, J = 56.4 Hz, 1H), 3.52 (br, 2H), 3.19 (br, 2H), (br, 3H), 1.09~1.05 (br, 3H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ 12.82, 14.15, 39.29, 43.23, (t, J = Hz), (t, J = 6.2 Hz), , (t, J = 22.6 Hz), , ppm; HRMS (ESI, m/z) [M + ] calcd. for C 12 H 16 NOF 2 : , found: ; IR (thin film) 2977, 2937, 2242, 1628, 1578, 1474, 1460, 1433, 1382, 1349, 1289, 1221, 1161, 1098, 1072, 1033, 911, 877, 834, 733, 647 cm -1. N-(4-(difluoromethyl)benzyl)-N-ethylethanamine (9f) Et 2 N The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (144.6 mg, 8f). The crude mixture was purified by silica gel chromatography (pentane: ethyl acetate = 95:5 to 50:50) to give 9f (76 mg, 74% yield). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 4H), 6.63 (t, J = 56.4 Hz, 1H), 3.60 (s, 2H), 2.51 (q, J = 2.1 Hz, 4H), 1.05 (t, J = 2.3 Hz, 6H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz); 13 C CF 2 H CF 2 H S69

70 NMR (126 MHz, CDCl 3 ): δ 11.92, 46.99, 57.42, (t, J = Hz), (t, J = 6.3 Hz), , (t, J = 22.4 Hz), (t, J = 2.0 Hz) ppm. LCMS (ESI,m/z): [(M+H) + ]. 1-(4-(Difluoromethyl)phenyl)-1H-pyrrole(9g) CF 2 H N The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (134.5 mg, 8g). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9g (80 mg, 83% yield). mp: o C. 1 H NMR (400 MHz, CDCl 3 ): δ 7.56 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.11 (m, 2H), 6.66 (t, J = 56.8 Hz, 1H), 6.37 (m, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.8 Hz); 13 C NMR (126 MHz, CDCl 3 ): δ , (t, J = Hz), , , (t, J = 6.1 Hz), (t, J = 22.8 Hz), ppm; HRMS (EI, m/z) [M + ] calcd. for C 10 H 6 OF 2 S: ; found: ; IR (thin film) 3143, 3085, 2967, 1910, 1618, 1594, 1568, 1532, 1475, 1437, 1384, 1330, 1309, 1230, 1194, 1128, 1083, 1067, 1012, 949, 921, 855, 725, 610, 551, 441 cm Bromo-4'-(difluoromethyl)-1,1'-biphenyl (9h) CF 2 H Br The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (179.5 mg, 8h). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9h (135 mg, 96% yield). mp: 109~110 o C. 1 H NMR (400 MHz, CDCl 3 ): δ (m, 6 H), (m, 2H), 6.68 (t, J = 56.4 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz); 13 C NMR (126 MHz, CDCl 3 ): δ (t, J = Hz), , (t, J = 6.0 Hz), , , , (t, J = 22.4 Hz), , (t, J = 2.0 Hz) ppm; HRMS (EI, m/z) [M + ] calcd. for C 13 H 9 BrF 2 : S70

71 ; found: ; IR (thin film) 2959, 1908, 1614, 1587, 1483, 1419, 1389, 1366, 1311, 1282, 1220, 1188, 1070, 1002, 881, 842, 807, 759, 665, 626, 568, 543, 517, 451 cm (Cyclopropylmethoxy)-4-(difluoromethyl)benzene (9i) CF 2 H O The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (137.1 mg, 8j). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9j (61 mg, 61% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.42 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.59 (t, J = 56.8 Hz, 1H), 3.83 (d, J = 3.4 Hz, 2H), (m, 1H), (m, 2H), (m, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.8 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ 3.34, 10.29, 73.01, , (t, J = Hz), (t, J = 22.8 Hz), (t, J = 6.0 Hz), ppm. HRMS (EI, m/z) [M + ] calcd. for C 11 H 12 OF 2 : ; found: ; IR (thin film) 2924, 1616, 1588, 1519, 1471, 1408, 1384, 1307, 1250, 1173, 1071, 1011, 940, 913, 861, 833 cm (3-(4-(Difluoromethyl)phenoxy)propyl)morpholine (9j) CF 2 H N O The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (173.6 mg, 8j). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9j (103.1 mg, 61% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.40 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.70 (t, J = 56.8 Hz, 1H), 4.02 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 4.4 Hz, 4H), 2.52~2.44 (m, 6H), 1.99~1.92 (m, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.8 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ 26.39, 53.80, 55.45, 66.26, 67.03, , (t, J = Hz), (t, J = 22.8 Hz), (t, J = 5.9 Hz), (t, J = 1.8 Hz) ppm; HRMS (EI, m/z) [M + ] calcd. for C 14 H 19 NO 2 F 2 : ; found: ; IR (thin film) 2958, 2856, 2814, 2247, 1705, 1615, 1589, 1519, 1448, 1459, 1433, 1383, 1305, 1255, 1222, 1176, 1144, 1118, 1070, 1020, 961, 911, 864, 836, 734, 645, 627, 613, 554 cm (Difluoromethyl)-1,2,3-trimethoxybenzene (9k) O S71

72 MeO CF 2 H MeO OMe The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (147 mg, 8k). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9k (65 mg, 60% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 6.71 (s, 2H), 6.56 (t, J = 56.8 Hz, 1H), 3.87 (s, 6H), 3.85 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.8 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ): δ 56.25, 60.90, (t, J = 6.3 Hz), (t, J = Hz), (t, J = 22.6 Hz), , ppm; HRMS (EI) [M + ] calcd. for C 10 H 12 O 3 F 2 : ; found: ; IR (thin film) 2943, 2845, 2253, 1598, 1509, 1466, 1425, 1381, 1333, 1301, 1241, 1185, 1161, 1132, 1090, 1025, 976, 911, 843, 759, 731 cm (Benzyloxy)-3-(difluoromethyl)benzene (9l) CF 2 H OBn The reaction was performed according to the general procedure for difluoromethylation of ArI on a 0.5 mmol scale (155 mg, 9l). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9l (83 mg, 71% yield). mp: o C. 1 H NMR (400 MHz, CDCl 3 ): δ (m, 6H), 7.20~7.09 (m, 3H), 6.63 (t, J = 56.4 Hz, 1H), 5.11 (s, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J 1 = 56.4 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ , , (t, J = 22.3 Hz), , , , 127,66, (t, J = 6.3 Hz), (t, J = 1.9 Hz), (t, J = Hz), (t, J = 6.1 Hz), ppm; HRMS (EI, m/z) [M + ] calcd. for C 14 H 12 OF 2 : ; found: ; IR (thin film) 3250, 2972, 2932, 1604, 1497, 1456, 1385, 1258, 1180, 1057, 1019, 861, 795, 750, 831, 697 cm (Difluoromethyl)-4-fluoro-1,1'-biphenyl (9m) F CF 2 H S72

73 The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (125.6 mg, 8m). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 95:5) to give 9m (98 mg, 88% yield). 10 mmol scale reaction The reaction was performed according to the general procedure with ArBr (2.51g, 10 mmol), Pd(dba) 2 (402 mg, 0.7 mmol), DPPF (776 mg, 1.4 mmol), SIPrAgCl (1.08 g, 2 mmol), NaO t Bu (1.92 g, 20 mmol), and TMSCF 2 H (2.98 g, 24 mmol) in toluene (100 ml) at 80 for 6 h. The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 95:5) to give 9l (1.80 g, 81% yield). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), (m, 4H), 7.16 (m, 2H), 6.72 (t, J = 56.4 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz, 2 F), (m, 1 F); 13 C NMR (126 MHz, CDCl 3 ): δ (t, J = Hz), (t, J = Hz), (t, J = 6.0 Hz), (t, J = 6.0 Hz), (d, J = 8.2 Hz), (d, J = 3.8 Hz), , (t, J = 22.3 Hz), (t, J = 3.4 Hz), , (d, J = Hz) ppm; HRMS (EI, m/z) [M + ] calcd. for C 13 H 9 F 3 : ; found: ; IR (thin film) 3045, 2964, 1607, 1516, 1487, 1447, 1404, 1369, 1302, 1236, 1200, 1221, 1160, 1101, 1064, 1032, 908, 838, 817, 797, 736, 699, 562, 548 cm (Difluoromethyl)-N,N-diphenylaniline (9n) Ph N Ph The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (162.1 mg, 8n). The crude mixture was purified by silica gel chromatography (pentane: ethyl acetate = 90:10 to 50:50) to give 9n (103.4 mg, 70% yield). mp: o C. 1 H NMR (400 MHz, CDCl 3 ): δ (m, 6H), (m, 8H), 6.60 (t, J = 56.8 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.8 Hz); 13 C NMR (126 MHz, CDCl 3 ): δ (t, J = Hz), , , , (t, J = 5.9 Hz), (t, J = 22.6 Hz), , , ppm; HRMS (EI, m/z) [M + ] calcd. for C 19 H 15 NF 2 : ; found: ; IR (thin film) 3062, 3035, 2962, 1614, 1593, 1515, 1486, 1451, 1430, 1382, 1334, 1283, 1269, 1222, 1191, 1176, 1125, 1064, 1016, 948, 903, 839, 758, 734, 698, 633, 623, 528, 506 cm -1. CF 2 H S73

74 1-(Difluoromethyl)-4-octylbenzene (9o) CF 2 H n Oct The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (134.6 mg, 8o). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9o (110 mg, 92% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.44 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.64 (t, J = 56.8 Hz, 1H), 2.67 (t, J = 8.0 Hz, 2H), 1.65~1.61 (m, 2H), 1.31 (m, 10H), 0.92 (t, J = 6.7 Hz, 3H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.8 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ 14.24, 22.83, 29.41, 29.43, 29.61, 31.52, 32.05, 35.98, (t, J = Hz), (t, J = 6.1 Hz), , (t, J = 22.6 Hz), (t, J = 2.0 Hz) ppm; HRMS (EI, m/z) [M + ] calcd. for C 15 H 22 F 2 : ; found: ; IR (thin film) 2927, 2856, 1618, 1519, 1466, 1425, 1378, 1303, 1222, 1183, 1073, 1031, 909, 859, 831, 735, 649, 630, 568 cm (Difluoromethyl)-3-phenoxybenzene (9p) CF 2 H OPh The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (124.6 mg, 8p). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9p (87 mg, 78% yield). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 3H), (m, 6H), 6.60 (t, J = 56.4 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ , (t, J = Hz), (t, J = 6.3 Hz), , , (t, J = 6.3 Hz), (t, J = 1.9 Hz), , , , (t, J = 22.5 Hz), , ppm; HRMS (EI, m/z) [M + ] calcd. for C 13 H 10 OF 2 : ; found: ; IR (thin film) 3042, 3021, 2946, 1587, 1489, 1452, 1385, 1371, 1257, 1216, 1162, 1043, 878, 800, 753, 734, 693 cm (Difluoromethyl)naphthalene (9q) CF 2 H S74

75 The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (103.5 mg, 8q). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9q (73 mg, 83% yield). 1 H NMR (500 MHz, CDCl 3 ): δ 8.21 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.72 (dd, J = 7.5, 1.0 Hz, 1H), 7.60 (m, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 56.4 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ (t, J = Hz), (t, J = 1.3 Hz), , (t, J = 8.8 Hz), , , , (t, J = 21.4 Hz), (t, J = 1.2 Hz), (t, J = 2.5 Hz), ppm GC-MS (EI, m/z): [M + ], 157.0, (Difluoromethyl)naphthalene (9r) CF 2 H The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (103.6 mg, 8r). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9r (73.0 mg, 83% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.00 (s, 1H), (m, 3H), (m, 3H), 6.84 (t, J = 56.4 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz). 13 C NMR (101 MHz, CDCl 3 ): δ (t, J = 1.4 Hz), , (t, J = 22.3 Hz), , , , , , (t, J = 7.6 Hz), (t, J = 4.8 Hz), (t, J = Hz); LRMS (EI, m/z): 178 [M + ], 177, 128, (4-(Difluoromethyl)phenyl)-2-methyl-1,3-dioxolane (9s) CF 2 H O O The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (121.6 mg, 8s). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 90:10 to 80:20) to give 9s (73.0 mg, 68% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.58 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 6.64 (t, J = 56.5 Hz, 1H), 4.07~4.04 (m, 2H), 3.78~3.74 (m, 2H), 1.66 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.5 Hz); 13 C NMR (126 MHz, CDCl 3 ): δ (t, J = 1.9 Hz), (t, J = 22.3 Hz), , (t, J = 6.0 Hz), , (t, J = Hz), , 64.66, 27.68, ppm. HRMS (EI, m/z) [M + ] calcd. for C 10 H 9 O 2 F 2 : ; found: IR (thin film) 2990, S75

76 2891, 1930, 1618, 1418, 1375, 1253, 1220, 1201, 1123, 1071, 1038, 949, 874, 846, 762, 736, 682 cm (4-(Difluoromethyl)phenyl)benzo[d]thiazole (9t) S CF 2 H N The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (145.1 mg, 8t). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9t (100.1 mg, 77% yield). mp: o C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.16 (d, J = 8.0 Hz, 2H), 8.09 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 6.70 (t, J = 56.0 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.0 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ (t, J = Hz), , , , (t, J = 6.1 Hz), , , , , (t, J = 22.7 Hz), , ppm; HRMS (EI, m/z) [M + ] calcd. for C 14 H 9 NSF 2 : ; found: ; IR (thin film) 3055, 2972, 1918, 1484, 1457, 1436, 1418, 1376, 1315, 1253, 1219, 1185, 1121, 1073, 1016, 970, 817, 756, 730, 672, 620 cm (4-(Difluoromethyl)phenyl)-9H-carbazole (9u) N CF 2 H The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (161.1 mg, 8u). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9u (131.0 mg, 90% yield). mp: o C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.23 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.50~7.49 (m, 4H), 7.42~7.38 (m, 2H), 6.60 (t, J = 56.4 Hz, 1H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.4 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ , (t, J = Hz), , , , , , (t, J = 6.1 Hz), (t, J = 22.6 Hz), , ppm; HRMS (EI, m/z) [M + ] calcd. for C 19 H 13 NF 2 : ; found: ; IR (thin film) 3047, 2975, 1611, 1520, 1480, 1453, 1378, 1365, 1336, 1319, 1302, 1230, 1185, 1168, 1150, 1123, 1072, 1022, 916, 839, 750, 725, 625 cm (Benzyloxy)-5-(difluoromethyl)pyridine (9v) S76

77 BnO CF 2 H N The reaction was performed according to the general procedure for difluoromethylation of ArBr on a 0.5 mmol scale (132.1 mg, 8t). The crude mixture was purified by silica gel chromatography (pentane: Et 2 O = 100:0 to 90:10) to give 9t (70.2 mg, 58% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.49 (s, 1H), 8.35 (s, 1H), (m, 6H), 6.68 (t, J = 56.0 Hz, 1H), 5.12 (s, 2H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 56.0 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ (t, J = Hz), (t, J = 5.6 Hz), , , , (t, J = 23.1 Hz), , (t, J = 7.1 Hz), (t, J = 2.0 Hz), ppm; HRMS (EI, m/z) [M + ] calcd. for C 13 H 11 NOF 2 : ; found: ; IR (thin film) 3066, 3036, 2933, 2877, 1918, 1816, 1597, 1498, 1466, 1456, 1440, 1376, 1324, 1288, 1246, 1183, 1072, 1029, 952, 911, 879, 844, 790, 737, 698, 630, 552 cm (Difluoromethyl)-N,N-diethyl-3-methoxybenzamide (9w) OMe CF 2 H Et 2 N O In a Argon-filled glove box, ArBr (8w, 143 mg, 0.5 mmol, 1.0 equiv), Pd(dba) 2 (41 mg, mmol, 0.07 equiv), DPPF (71 mg, 0.14 mmol, 0.28 equiv), [(SIPr)AgCl] (113 mg, 0.2 mmol, 0.4 quiv), and NaO t Bu (96 mg, 1.0 mmol, 2.0 equiv) were combined in a 20 ml vial. To this vial was added 5.0 ml of anhydrous toluene, followed by trimethyl(difluoromethyl)silane (148.8 mg, 1.2 mmol, 2.4 equiv). The vial was sealed and moved out from the glove box. The mixture was stirred at 80 for 6 hours. The dark solution was diluted with H 2 O (15 ml). The mixture was filtered through a short plug of Celite, washed with CH 2 Cl 2 (20 ml 3). The organic layer was combined, dried over NaSO 4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane/ea mixture as the eluent (90:10 to 40:60) to give the product 9w (83 mg, yield 65%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.58 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.94 (t, J = 55.6 Hz, 1H), 3.89 (s, 3H), 3.55 (br, 2H), 3.24 (br, 2H), 1.25~1.13 (m, 6H); 19 F NMR (376 MHz, CDCl 3 ): δ (d, J = 55.6 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ , (t, J = 5.8 Hz), (t, J = 2.0 Hz), (t, J = 5.8 Hz), (t, J = 22.4 Hz), (t, J = Hz), , 55.86, 43.33, 39.40, 14.36, ppm; HRMS (EI, m/z) [M + ] calcd. for C 13 H 17 NO 2 F 2 : ; found: S77

78 ; IR (thin film) 3479, 2976, 2938, 2876, 2240, 1633, 1581, 1510, 1463, 1432, 1408, 1385, 1366, 1348, 1294, 1256, 1219, 1204, 1171, 1136, 1099, 1065, 1032, 948, 922, 868, 851, 819, 760, 734, 646, 602, 547 cm -1. (8R,9S,13S,14S)-3-(difluoromethyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro [cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane] (9x) O O HF 2 C In a Argon-filled glove box, ArBr (8x, mg, 0.44 mmol, 1.0 equiv), Pd(dba) 2 (36.1 mg, mmol, 0.14 equiv), DPPF (66.9 mg, 0.12 mmol, 0.28 equiv), [(SIPr)AgCl] (93.3 mg, 0.18 mmol, 0.4 quiv), and NaO t Bu (84.6 mg, 0.88 mmol, 2 equiv) were combined in a 20 ml vial. To this vial was added 2.2 ml of anhydrous toluene, followed by trimethyl(difluoromethyl)silane (132 mg, 1.06 mmol, 2.4 equiv). The vial was sealed and moved out from the glove box. The mixture was stirred at 80 for 48 hours. The dark solution was diluted with H 2 O (15 ml). The mixture was filtered through a short plug of Celite, washed with CH 2 Cl 2 (20 ml 3). The organic layer was combined, dried over NaSO 4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel with pentane/et 2 O mixture as the eluent (100:0 to 80:20) to give the product 9x (121.2 mg, yield 70%). mp: o C. 1 H NMR (400 MHz, CDCl 3 ): δ 7.38 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 6.58 (t, J = 56.8 Hz, 1H), (m, 4H), (m, 2H), (m, 2H), (m, 1H), (m, 4H), (m, 6H), 0.89 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ): δ (dd, J = 56.8, 7.1 Hz); 13 C NMR (101 MHz, CDCl 3 ): δ , , (t, J = 22.7 Hz), (t, J = 5.1 Hz), , (t, J = 5.0 Hz), (t, J = Hz), 65.39, 64.71, 49.55, 46.17, 44.25, 38.70, 34.31, 30.77, 29.57, 26.84, 26.00, 22.47, ppm; HRMS (EI, m/z) [M + ] calcd. for C 15 H 22 F 2 : ; found: ; IR (thin film) 3420, 2935, 2861, 1618, 1456, 1380, 1330, 1310, 1285, 1276, 1232, 1191, 1178, 1106, 1076, 1066, 1021, 953, 964, 897, 833, 786, 755, 671,622, 551 cm -1. (S)-6-(difluoromethyl)-3,8-dimethyl-3-((4S,8S)-4,8,12-trimethyltridecyl)chroman (9y) H H H S78