Supporting Information. Cobalt(II)-Catalyzed C H Amination of Arenes with Simple. Alkylamines

Transcription

1 Supporting Information Cobalt(II)-Catalyzed C H Amination of Arenes with Simple Alkylamines Lin-Bao Zhang, Shou-Kun Zhang, Donghui Wei, Xinju Zhu, Xin-Qi Hao, Jian-Hang Su, Jun-Long iu,* and Mao-Ping Song* The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou , P. R. China niujunlong@zzu.edu.cn or mpsong@zzu.edu.cn Contents General Information... 1 Experimental Section General Procedure for the Synthesis of Amides ptimization of Reaction Conditions X-ray Crystal Structure of 3aa... 9 Characterizations of Products... 9 Control Experiments Kinetic Isotope Effect Measurements Reaction System under Added TEMP or BQ Reaction System under Added BHT Co(III)-Catalyzed C-H Amination Co-catalyzed C-H amination without Ag Experimental EPR Spectrum of the Reaction System Computational Section Computational Details The Calculated Gibbs Free Energy Mechanistic Proposal Computed Structures, Cartesian Coordinates and Energies Removal of directing group References MR Spectra... 49

2 General Information 1 H MR, 13 C MR and 19 F MR spectra were recorded at 400 MHz or 600 MHz, 100 MHz or 151 MHz, and 565 MHz respectively on a Bruker DPX instrument using Me 4 Si as an internal standard. ew compounds for HRMS were tested on a Waters Q-Tof Micro MS/MS System ESI spectrometer. EPR spectrum was analyzed on a Bruker E500 spectrometer at room temperature. Melting points were measured on a WC-1 instrument and uncorrected. Chemical shift multiplicities are represented as follows: (s = singlet, d = doublet, m = multiplet, dd = double doublet). Unless otherwise mentioned, all materials were commercially obtained and used without further purification, and all procedures were performed under the inert atmosphere. Experimental Section The synthesis of 2-aminopyridine 1-oxide was previously described by Adams and Miyano. [1] The aromatic amides 1 were obtained from the reaction of corresponding benzoic acids with 2-aminopyridine 1-oxide (see the following Experimental Procedures). The same procedure was applied to synthesize the following amides: -(quinolin-8-yl)benzamide, -(pyridin-2-ylmethyl)benzamide, -(2-methoxyphenyl)benzamide, -methoxybenzamide, -phenylbenzamide, -(pyridin-2-yl)benzamide. 2-(-methylbenzamido)pyridine 1-oxide was synthesized as the previous method. [2a] (S)-2-benzamido-3-methylbutanoic acid, (S)-methyl 2-((S)-2-benzamido-3-methylbutanamido)-3-methylbutanoate and (S)-methyl 2-((S)-2-((S)-2-benzamido-3-methylbutanamido)-3-methylbutanamido)-3-methylbuta noate were obtained according to the synthetic method of Di-, Tri-, and tetracoordinated directing groups. [3] 1. General Procedure for the Synthesis of Amides Synthesis of 1a is representative. [2] A 100 ml two-necked round-bottom flask was equipped with a magnetic stirbar and charged with benzoic acid (6 mmol, 732 mg), 2-aminopyridine 1-oxide (6.2 mmol, 682 mg),,-dimethyl-4-aminopyridine (DMAP, 0.6 mmol, 73.3 mg) dissolved in 30 S1

3 ml anhydrous CH 2 Cl 2 at 0 o C. Then EDCI (1.14 g, 7.2 mmol) in CH 2 Cl 2 (20 ml) was dropwise added to the solution under an argon atmosphere. After the addition, the reaction was then warmed to room temperature, stirred for 10 h and quenched with water (30 ml). The reaction mixture was extracted with CH 2 Cl 2 (3 20 ml) and the combined organic solvent was dried over a 2 S 4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (CH 2 Cl 2 /Acetone = 5/1) to give pure 1a as a white solid (1.02 g, 79%), mp o C. 1 H MR (400 MHz, CDCl 3 ) δ (s, 1H), 8.62 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.31 (dd, J = 6.5 Hz, J = 1.2 Hz, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 1H). 13 C MR (100 MHz, CDCl 3 ) δ 165.3, 144.5, 137.1, 133.1, 132.9, 129.0, 128.3, 127.7, 118.7, HRMS (positive ESI) Calcd for C 12 H (M+H) , Found ptimization of Reaction Conditions General Procedure for the Co-catalyzed C-H Amination of Arenes A 10 ml dry two-necked Schlenk tube was equipped with a magnetic stir bar and charged with 2-benzamidopyridine 1-oxide 1a (0.2 mmol, 42.8 mg), morpholine 2a (0.4 mmol, 2.0 equiv., 36 ul), Co salts (20 mol%), oxidant (0.4 mmol, 2.0 equiv.), base (0.2 mmol, 2.0 equiv.), and solvent (1.0 ml). The vessel was heated at 85 o C for 12 h, and cooled down to room temperature. ext, the reaction mixture was diluted with 40 ml of CH 2 Cl 2, and filtered through a celite pad. The reaction solution was detected by TLC, and was then concentrated in vacuum. Product was purified by column chromatography (CH 2 Cl 2 /Acetone = 5/1). Table S1. ptimization of Temperature a Entry Temperature ( o C) Yield b (%) S2

4 a Reaction conditions: substrate 1a (0.2 mmol), 2a (2.0 equiv.), Co(Ac) 2 4H 2 (20 mol %), aac (2.0 equiv.), AgTFA (2.0 equiv.), p-xylene (1.0 ml), air atmosphere, 12 h. b Isolated Yield. Table S2. ptimization of xidants a Entry xidant Yield b (%) 1 AgTFA R. 3 Ag AgAc 18 5 AgTf 32 6 Ag 2 C AgSbF 6.R. 8 Ag AgBF AgPF PhI(Ac) 2 Trace 12 ai K 2 S Mn 2.R. 15 Mn(Ac) 3 2H Mn(Ac) 2 4H 2.R. 17 BQ.R. 18 M TBHP Trace 20 2.R. S3

5 a Reaction conditions: substrate 1a (0.2 mmol), 2a (2.0 equiv.), Co(Ac) 2 4H 2 (20 mol %), aac (2.0 equiv.), xidant (2.0 equiv.), p-xylene (1.0 ml), air, 85 o C, 12 h. b Isolated Yield. M = -methyl morpholine-n-oxide ; BQ = benzoquinone; TBHP = tert-butyl hydroperoxide solution (70% in H 2 ). Table S3. ptimization of Solvents a Entry Solvent Yield b (%) 1 p-xylene 50 2 m-xylene 46 3 o-xylene 47 4 PhMe 44 5 PhCF Mesitylene 44 7 MeC 76 8 DMF 12 9 MP Trace 10 DCE.R. 11 DMPU Trace 12 Dioxane THF MTBE THP t-amh HFIP CH i-prc t-buc 68 a Reaction conditions: substrate 1a (0.2 mmol), 2a (2.0 equiv.), Co(Ac) 2 4H 2 (20 mol %), aac (2.0 equiv.), Ag 3 (2.0 equiv.), Solvent (1.0 ml), air, 85 o C, 12 h. b Isolated Yield. MP = -methyl-2-pyrrolidone; DMPU = 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; MTBE = Methyl tert-butyl ether; THP = Tetrahydropyran. Table S4. ptimization of Catalysts a S4

6 Entry Catalyst Yield b (%) 1 Co(Ac) 2 4H R. 3 Co(acac) Co(acac) CoBr 2 6H CoCl 2 6H Co( 3 ) 3 3a CoF CoF Cp*Co(C)I CoC 2 4 4H CoC 3 H 2 Trace 13 CoS 4 H 2 Trace 14 CoLi 2.R. 15 Co.R. a Reaction conditions: substrate 1a (0.2 mmol), 2a (2.0 equiv.), [Co] (20 mol %), aac (2.0 equiv.), Ag 3 (2.0 equiv.), MeC (1.0 ml), air, 85 o C, 12 h. b Isolated Yield. Cp* = 1,2,3,4,5-Pentamethylcyclopentadienyl. Table S5. ptimization of Bases a Entry Base Yield b (%) 1 aac a 2 C HCa 20 5 atf 49 S5

7 6 PhCa 56 7 Li 2 C ahc Piva H CsAc K 2 HP 4 3H 2. R. 12 ah 2 P 4 12H 2. R. 13 K 3 P 4. R. 14 K 2 C a 2 C Cs 2 C LiAc 2H LiH H t-ama DABC Et DIPEA Trace a Reaction conditions: substrate 1a (0.2 mmol), 2a (2.0 equiv.), Co(Ac) 2 4H 2 (20 mol %), aac (2.0 equiv.), Ag 3 (2.0 equiv.), MeC (1.0 ml), air, 85 o C, 12 h. b Isolated Yield. DABC = triethylenediamine; DIPEA =,-Diisopropylethylamine. Table S6. ptimization of Dosages a Entry 2a (equiv.) Co(Ac) 2 4H 2 (mol%) Ag 3 (equiv.) aac (equiv.) Yield b (%) c S6

8 a Reaction conditions: substrate 1a (0.2 mmol), 2a ( equiv.), Co(Ac) 2 4H 2 (5-20 mol %), aac ( equiv.), Ag 3 ( equiv.), MeC (1.0 ml), air, 85 o C, 12 h. b Isolated Yield. c MeC (0.5 ml). Table S7. ptimization of Additives a Entry Additive Yield b (%) 1 4 Å (40 mg) 75 2 K 3 (0.5 equiv.) 82 3 a 3 (0.5 equiv.) 78 4 MgCl 2 (0.5 equiv.) 50 5 (0.5 equiv.) 74 6 K 3 (0.25 equiv.) 78 7 K 3 (1.0 equiv.) 82 a Reaction conditions: substrate 1a (0.2 mmol), 2a (1.2 equiv.), Co(Ac) 2 4H 2 (10 mol %), aac (2.0 equiv.), Ag 3 (2.5 equiv.), MeC (0.5 ml), air, 85 o C, 12 h. b Isolated Yield. Table S8. ptimization of the Directing Groups a,b ther bidentate coordinating groups (A-D) failed to facilitate the CDC-amination. Moreover, the tri- (E), and tetracoordinated (F) directing groups that were firstly employed by Yu and co-workers did not work at all. [3] The product was not detected in the structurally similar monodentate groups (G-J) either. S7

9 a Reaction conditions: substrate 1 (0.2 mmol), 2a (1.2 equiv.), Co(Ac) 2 4H 2 (10 mol %), aac (2.0 equiv.), Ag 3 (2.5 equiv.), K 3 (0.5 equiv.), MeC (0.5 ml), air, 85 o C, 12 h. b Isolated Yield. Table S9. The Electronic Effect of Substituted Pyridine -oxides a,b a Reaction conditions: substrate 1 (0.2 mmol), 2a (1.2 equiv.), Co(Ac) 2 4H 2 (10 mol %), aac (2.0 equiv.), Ag 3 (2.5 equiv.), K 3 (0.5 equiv.), MeC (0.5 ml), air, 85 o C, 12 h. b Isolated Yield. S8

10 3. X-ray Crystal Structure of 3aa Figure S1. X-ray Crystal Structure for 3aa Characterizations of Products 2-(2-morpholinobenzamido)pyridine 1-oxide (3aa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.28; white solid (49.2 mg, 82%), mp o C (dichloromethane). 1 H MR (400 MHz, CDCl 3 ) δ (s, 1H), 8.77 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.30 (dd, J = 6.5 Hz, J = 1.1 Hz, 1H), 8.24 (dd, J = 7.8 Hz, J = 1.6 Hz, 1H), (m, 1H), (m, 2H), 7.31 (t, J = 7.4 Hz,1H), (m, 1H), 4.13 (t, J = 4.5 Hz, 4H), 3.09 (t, J = 4.7 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.3, 152.0, 145.3, 137.5, 133.6, 132.2, 127.5, 127.3, 125.1, 120.9, 118.7, 116.1, 66.1, HRMS (positive ESI) Calcd. For C 16 H (M + H) , Found: fluoro-2-(2-morpholinobenzamido)pyridine 1-oxide (4aa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.66; white solid (37 mg, 58%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) S9

11 δ (s, 1H), 8.77 (dd, J = 9.5 Hz, J = 6.6 Hz, 1H), 8.25 (dd, J = 3.5 Hz, J = 3.0 Hz, 1H), 8.23 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H), (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), 4.10 (s, 4H), 3.06 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.0, (d, J C-F = Hz), 152.0, 142.8, 133.6, 132.2, (d, J C-F = 36.3 Hz), 127.1, 125.3, 121.1, (d, J C-F = 7.8 Hz), (d, J C-F = 20.0 Hz), 66.1, F MR (565 MHz, CDCl 3 ) δ HRMS (positive ESI) Calcd. For C 16 H 17 F 3 3 (M + H) , Found: chloro-2-(2-morpholinobenzamido)pyridine 1-oxide (5aa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.65; white solid (32.6 mg, 49%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.73 (d, J = 9.1 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), (m, 2H), 4.09 (s, 4H), 3.06 (t, J = 4.1 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.1, 152.0, 136.7, 133.8, 132.3, 127.7, 127.0, 125.3, 125.1, 121.1, 115.8, 66.1, HRMS (positive ESI) Calcd. For C 16 H 17 Cl 3 3 (M + H) , Found: (2-morpholinobenzamido)-5-(trifluoromethyl)pyridine 1-oxide (6aa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.73; white solid (39.8 mg, 54%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.88 (d, J = 8.9 Hz, 1H), 8.58 (s, 1H), 8.24 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 4.11 (s, 4H), 3.07 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.4, 152.1, 147.6, (q, J C-F = 4.1 Hz), 134.0, 132.4, 126.8, 125.4, (q, J C-F = 2.9 Hz), (q, J C-F = 35.3 Hz), (q, J C-F = Hz), 121.2, 115.6, 66.1, F MR (565 MHz, CDCl 3 ) δ HRMS (positive ESI) Calcd. For C 17 H 17 F (M + H) , Found: methoxy-2-(2-morpholinobenzamido)pyridine 1-oxide (7aa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:1) as an eluent R f = 0.2; light yellow solid (22.6 mg, 34%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.40 (d, J = 3.3 Hz, 1H), 8.20 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H), 8.15 (d, J = 7.3 Hz, 1H), (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), (m, S10

12 1H), 6.58 (dd, J = 7.3 Hz, J = 3.4 Hz, 1H), 4.11 (s, 4H), 3.93 (s, 3H), 3.07 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.6, 159.1, 152.1, 145.5, 137.9, 133.6, 132.2, 127.2, 125.0, 120.8, 106.7, 100.1, 66.1, 56.2, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (2-morpholinobenzamido)-4-(trifluoromethyl)pyridine 1-oxide (8aa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.71; white solid (15.6 mg, 21%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 8.37 (d, J = 6.8 Hz, 1H), 8.25 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H), (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.23 (dd, J = 6.8 Hz, J = 2.4 Hz, 1H), 4.11 (t, J = 4.0 Hz, 4H), 3.07 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.3, 152.1, 145.9, 137.9, 134.0, 132.3, (q, J C-F = 35.3 Hz), 126.8, 125.5, (q, J C-F = Hz), 121.2, (q, J C-F = 3.8 Hz), (q, J C-F = 3.7 Hz), 66.1, F MR (565 MHz, CDCl 3 ) δ HRMS (positive ESI) Calcd. For C 17 H 17 F (M + H) , Found: methyl-2-(2-morpholinobenzamido)pyridine 1-oxide (9aa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.21; light brown solid (43.7 mg, 70%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.20 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H), 8.16 (d, J = 6.6 Hz, 1H), (m, 1H), 7.34 (d, J = 8.1 Hz, 1H), (m, 1H), 6.82 (dd, J = 6.5 Hz, J = 2.1 Hz, 1H), 4.10 (s, 4H), 3.07 (t, J = 4.6 Hz, 4H), 2.41 (s, 3H). 13 C MR (151 MHz, CDCl 3 ) δ 165.4, 152.0, 144.4, 139.4, 136.7, 133.5, 132.2, 127.3, 125.0, 120.8, 119.6, 116.4, 66.1, 54.1, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (4-methoxy-2-morpholinobenzamido)pyridine 1-oxide (3ba): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.25; white solid (59.7 mg, 91%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 6.5 Hz, 1H), 8.20 (dd, J = 8.8 Hz, J = 1.9 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 4.11 (s, 4H), 3.88 (s, 3H), 3.05 (t, J = 3.6 Hz, 4H). 13 C MR (151 S11

13 MHz, CDCl 3 ) δ 165.0, 163.8, 154.0, 145.5, 137.5, 134.3, 127.6, 119.9, 118.4, 116.0, 109.6, 107.3, 66.1, 55.5, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (4-methyl-2-morpholinobenzamido)pyridine 1-oxide (3ca): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.29; white solid (47.1 mg, 75%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.75 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.28 (dd, J = 6.5 Hz, J = 0.7 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), (m, 1H), 7.15 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), (m, 1H), 4.11 (s, 4H), 3.06 (t, J = 4.5 Hz, 4H), 2.42 (s, 3H). 13 C MR (151 MHz, CDCl 3 ) δ 165.3, 152.0, 145.4, 144.4, 137.5, 132.3, 127.5, 126.0, 124.5, 121.6, 118.5, 116.1, 66.2, 54.2, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (4-(tert-butyl)-2-morpholinobenzamido)pyridine 1-oxide (3da): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.31; light brown solid (61 mg, 86%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.76 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.29 (dd, J = 6.5 Hz, J = 1.1 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), (m, 2H), (m, 1H), 4.13 (s, 4H), 3.09 (t, J = 4.6 Hz, 4H), 1.36 (s, 9H). 13 C MR (151 MHz, CDCl 3 ) δ 165.2, 157.5, 151.9, 145.4, 137.5, 132.0, 127.5, 124.5, 122.5, 118.5, 118.0, 116.1, 66.2, 54.2, 35.4, HRMS (positive ESI) Calcd. For C 20 H (M + H) , Found: (3-morpholino-[1,1'-biphenyl]-4-ylcarboxamido)pyridine 1-oxide (3ea): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.33; white solid (61.7 mg, 82%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.78 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), (m, 2H), 7.63 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 1.4 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 8.1 Hz, 2H), 7.42 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.01 (t, J = 6.6 Hz, 1H), 4.14 (s, 4H), 3.14 (t, J = 4.4 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.1, 152.4, 146.5, 145.4, 139.7, 137.6, 132.8, 129.0, 128.4, 127.5, 127.3, 125.9, 123.8, 119.7, 118.7, 116.1, 66.2, HRMS (positive ESI) Calcd. For C 22 H (M + H) S12

14 , Found: (4-fluoro-2-morpholinobenzamido)pyridine 1-oxide (3fa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.31; white solid (47.5 mg, 75%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.73 (dd, J = 8.5 Hz, J = 1.3 Hz, 1H), 8.29 (d, J = 6.3 Hz, 1H), (m, 1H), 7.35 (t, J = 7.9 Hz, 1H), (m, 2H), (m, 1H), 4.10 (s, 4H), 3.05 (t, J = 4.5 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ (d, J C-F = Hz), 164.3, (d, J C-F = 8.7 Hz), 145.2, 137.5, (d, J C-F = 10.1 Hz), 127.6, (d, J C-F = 2.7 Hz), 118.8, 116.0, (d, J C-F = 21.5 Hz), (d, J C-F = 22.9 Hz), 65.9, F MR (565 MHz, CDCl 3 ) δ HRMS (positive ESI) Calcd. For C 16 H 17 F 3 3 (M + H) , Found: (4-iodo-2-morpholinobenzamido)pyridine 1-oxide (3ga): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.35; white solid (38.5 mg, 45%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.71 (d, J = 8.5 Hz, J = 1.5 Hz, 1H), 8.30 (d, J = 6.3 Hz, 1H), (m, 1H), (m, 2H), 7.33 (t, J = 7.8 Hz, 1H), (m, 1H), 4.09 (s, 4H), 3.05 (t, J = 4.5 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 164.7, 152.6, 145.1, 137.6, 134.4, 133.5, 130.4, 127.7, 126.9, 118.9, 116.0, 100.6, 66.0, HRMS (positive ESI) Calcd. For C 16 H 17 I 3 3 (M + H) , Found: (4-(methoxycarbonyl)-2-morpholinobenzamido)pyridine 1-oxide (3ha): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.26; light brown solid (39.5 mg, 55%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.73 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.30 (dd, J = 6.4 Hz, J = 0.8 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.92 (dd, J = 8.2 Hz, J = 1.5 Hz, 1H), (m, 1H), (m, 1H), 4.11 (s, 4H), 3.97 (s, 3H), 3.11 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 166.0, 164.5, 151.9, 145.0, 137.6, 134.5, 132.4, 131.0, 127.6, 125.8, 122.0, 119.0, 116.1, 66.0, 54.1, HRMS (positive ESI) Calcd. For C 18 H (M + H) , Found: (5-methoxy-2-morpholinobenzamido)pyridine 1-oxide (3ia): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.26; white S13

15 solid (42.4 mg, 64%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.76 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.30 (dd, J = 6.5 Hz, J = 1.0 Hz, 1H), 7.82 (d, J = 3.2 Hz, 1H), (m, 2H), 7.11 (dd, J = 8.8 Hz, J = 3.2 Hz, 1H), (m, 1H), 4.13 (s, 4H), 3.87 (s, 3H), 3.02 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 164.8, 157.1, 145.5, 145.3, 137.6, 128.3, 127.4, 123.2, 120.3, 118.7, 116.3, 115.4, 66.3, 55.7, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (5-methyl-2-morpholinobenzamido)pyridine 1-oxide (3ja): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.24; white solid (50 mg, 78%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.75 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.29 (dd, J = 6.5 Hz, J = 1.2 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), 4.11 (s, 4H), 3.04 (t, J = 4.6 Hz, 4H), 2.39 (s, 3H). 13 C MR (151 MHz, CDCl 3 ) δ 165.4, 149.6, 145.4, 137.6, 135.0, 134.2, 132.5, 127.5, 126.9, 121.1, 118.6, 116.2, 66.2, 54.2, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (5-fluoro-2-morpholinobenzamido)pyridine 1-oxide (3ka): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.32; white solid (25.8 mg, 41%), mp o C (dichloromethane). 1 H MR (400 MHz, CDCl 3 ) δ (s, 1H), 8.75 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.31 (d, J = 5.9 Hz, 1H), 7.97 (dd, J = 9.5 Hz, J = 3.1 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), 4.14 (t, J = 4.3 Hz, 4H), 3.05 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 163.8, (d, J C-F = Hz), (d, J C-F = 2.7 Hz), 145.1, 137.6, (d, J C-F = 7.0 Hz), 127.5, (d, J C-F = 7.8 Hz), (d, J C-F = 22.8 Hz), 119.0, (d, J C-F = 24.9 Hz), 116.3, 66.1, F MR (565 MHz, CDCl 3 ) δ HRMS (positive ESI) Calcd. For C 16 H 17 F 3 3 (M + H) , Found: (5-chloro-2-morpholinobenzamido)pyridine 1-oxide (3la): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.24; white solid (34.9 mg, 52%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.72 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.29 (dd, J = 6.4 Hz, J = 0.7 Hz, S14

16 1H), 8.20 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 8.6 Hz, J = 2.6 Hz, 1H), (m, 1H), 7.30 (d, J = 8.6 Hz, 1H), (m, 1H), 4.10 (t, J = 4.0 Hz, 4H), 3.04 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 163.9, 150.4, 145.1, 137.6, 133.3, 132.0, 131.0, 128.8, 127.6, 122.5, 119.0, 116.1, 66.0, HRMS (positive ESI) Calcd. For C 16 H 17 Cl 3 3 (M + H) , Found: (5-bromo-2-morpholinobenzamido)pyridine 1-oxide (3ma): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.24; white solid (58.9 mg, 78%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), (m, 1H), 8.29 (d, J = 6.5 Hz, 1H), (m, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.03 (t, J = 6.6 Hz, 1H), 4.09 (s, 4H), 3.04 (t, J = 4.3 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 163.8, 150.9, 145.1, 137.6, 136.3, 135.0, 129.0, 127.6, 122.8, 118.9, 118.5, 116.1, 66.0, HRMS (positive ESI) Calcd. For C 16 H 17 Br 3 3 (M + H) , Found: (5-iodo-2-morpholinobenzamido)pyridine 1-oxide (3na): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.24; light brown solid (57.2 mg, 67%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), (m, 1H), 8.50 (dd, J = 6.2 Hz, J = 1.5 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 7.08 (dd, J = 8.5 Hz, J = 3.9 Hz, 1H), (m, 1H), 4.08 (d, J = 2.8 Hz, 4H), 3.04 (t, J = 4.8 Hz, 4H). 13 C MR (151 MHz, CDCl3) δ 163.8, 151.6, 145.0, 142.2, 140.9, 137.5, 129.1, 127.6, 122.9, 118.9, 116.1, 88.9, 66.0, HRMS (positive ESI) Calcd. For C 16 H 17 I 3 3 (M + H) , Found: (2-morpholino-5-(trifluoromethyl)benzamido)pyridine 1-oxide (3oa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:1) as an eluent R f = 0.5; green solid (27 mg, 37%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.44 (d, J = 1.1 Hz, 1H), 8.30 (d, J = 6.3 Hz, 1H), 7.79 (dd, J = 8.4 Hz, J = 1.7 Hz, 1H), (m, 2H), (m, 1H), 4.10 (t, J = 3.9 Hz, 4H), 3.12 (t, J = 4.5 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 164.1, 154.6, 144.8, 137.5, (q, J C-F = 3.2 Hz), (q, J C-F = 3.5 Hz), 127.8, 127.7, (q, J C-F = 33.4 Hz), (q, J C-F = Hz), 120.8, 119.1, 116.0, 65.9, S15

17 F MR (565 MHz, CDCl 3 ) δ HRMS (positive ESI) Calcd. For C 17 H 17 F (M + H) , Found: (2-methyl-6-morpholinobenzamido)pyridine 1-oxide (3pa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.34; white solid (50.6 mg, 81%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 6.4 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), (m, 3H), 3.76 (t, J = 4.3 Hz, 4H), 3.03 (t, J = 4.4 Hz, 4H), 2.44 (m, 3H). 13 C MR (151 MHz, CDCl 3 ) δ 168.0, 150.4, 144.6, 138.4, 137.4, 130.9, 130.4, 127.8, 126.4, 118.6, 117.0, 114.7, 66.8, 53.3, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (2-chloro-6-morpholinobenzamido)pyridine 1-oxide (3qa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.43; green solid (32.8 mg, 49%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.61 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 6.3 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), (m, 2H), 3.71 (t, J = 4.3 Hz, 4H), 3.04 (t, J = 4.4 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.3, 151.7, 144.3, 137.4, 132.6, 131.6, 130.9, 128.0, 125.2, 119.0, 118.4, 114.9, 66.9, HRMS (positive ESI) Calcd. For C 16 H 17 Cl 3 3 (M + H) , Found: (2,4-dimethyl-6-morpholinobenzamido)pyridine 1-oxide (3ra): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.41; light brown solid (48.6 mg, 74%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 8.26 (dd, J = 6.5 Hz, J = 1.0 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), (m, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 3.77 (t, J = 4.4 Hz, 4H), 3.02 (t, J = 4.5 Hz, 4H), 2.41 (m, 3H), 2.34 (m, 3H). 13 C MR (151 MHz, CDCl 3 ) δ 168.1, 150.6, 144.8, 141.3, 138.7, 137.4, 127.7, 127.3, 127.1, 118.4, 117.6, 114.8, 66.8, 53.4, 21.5, HRMS (positive ESI) Calcd. For C 18 H (M + H) , Found: (3,6-dimethyl-2-morpholinobenzamido)pyridine 1-oxide (3sa): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.44; light brown solid (45.9 mg, 70%), mp o C (dichloromethane). 1 H MR (600 MHz, S16

18 CDCl 3 ) δ (s, 1H), 8.63 (d, J = 7.5 Hz, 1H), 8.26 (dd, J = 6.5 Hz, J = 1.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), (m, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 3.78 (t, J = 4.4 Hz, 4H), 3.02 (t, J = 4.5 Hz, 4H), 2.41 (m, 3H), 2.34 (m, 3H). 13 C MR (151 MHz, CDCl 3 ) δ 168.0, 150.6, 144.8, 141.3, 138.7, 137.4, 127.7, 127.3, 127.1, 118.4, 117.6, 114.8, 66.8, 53.4, 21.5, HRMS (positive ESI) Calcd. For C 18 H (M + H) , Found: (2-morpholino-1-naphthamido)pyridine 1-oxide (3ta): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:1) as an eluent R f = 0.55; white solid (45.7 mg, 65%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 6.2 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), (m, 3H), 7.04 (t, J = 6.5 Hz, 1H), 3.80 (t, J = 4.1 Hz, 4H), 3.18 (t, J = 4.1 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 167.8, 148.2, 144.7, 137.4, 132.3, 131.3, 130.5, 128.2, 127.9, 127.8, 125.5, 125.3, 124.4, 118.8, 118.7, 114.8, 66.9, HRMS (positive ESI) Calcd. For C 20 H (M + H) , Found: (3-morpholinothiophene-2-carboxamido)pyridine 1-oxide (3ua): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:1) as an eluent R f = 0.43; white solid (42 mg, 69%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.67 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.29 (dd, J = 6.5 Hz, J = 1.1 Hz, 1H), 7.60 (d, J = 5.3 Hz, 1H), (m, 1H), 7.23 (d, J = 5.3 Hz, 1H), (m, 1H), 4.12 (s, 4H), 3.04 (t, J = 4.6 Hz, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 160.3, 153.8, 145.0, 137.5, 131.7, 128.8, 127.6, 122.7, 118.6, 115.9, 66.7, HRMS (positive ESI) Calcd. For C 14 H S (M + H) , Found: (2-(2,6-dimethylmorpholino)benzamido)pyridine 1-oxide (3ab): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.41; white solid (48.6 mg, 74%), mp o C (dichloromethane). 1 H MR (400 MHz, CDCl 3 ) δ (s, 1H), 8.77 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 6.2 Hz, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.3 Hz, 1H), (m, 3H), 7.01 (t, J = 6.3 Hz, 1H), 4.39 (t, J = 7.7 Hz, 2H), 3.05 (d, J = 11.1 Hz, 2H), 2.62 (t, J = 10.8 Hz, 2H), 1.22 (s, 3H), 1.20 (s, 3H). 13 C MR (100 MHz, CDCl 3 ) δ 165.3, 151.8, 145.3, 137.6, 133.6, 132.2, 127.6, S17

19 127.2, 125.1, 121.0, 118.7, 116.1, 70.6, 59.6, HRMS (positive ESI) Calcd. For C 18 H (M + H) , Found: (2-(piperidin-1-yl)benzamido)pyridine 1-oxide (3ac): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.54; white solid (22.1 mg, 37%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.77 (dd, J = 8.5 Hz, J = 1.3 Hz, 1H), 8.28 (d, J = 6.4 Hz, 1H), 8.18 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H), (m, 1H), (m, 2H), 7.23 (t, J = 7.4 Hz, 1H), (m, 1H), 3.00 (t, J = 5.0 Hz, 4H), 1.96 (t, J = 4.7 Hz, 4H), 1.63 (s, 2H). 13 C MR (151 MHz, CDCl 3 ) δ 165.8, 153.6, 145.5, 137.6, 133.2, 131.9, 127.3, 127.1, 124.3, 120.7, 118.5, 116.2, 55.7, 25.3, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (2-(4-cyanopiperidin-1-yl)benzamido)pyridine 1-oxide (3ad): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.46; white solid (47.2 mg, 73%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.77 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), (m, 2H), (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 3H), 2.52 (s, 2H), 2.18 (s, 2H). 13 C MR (151 MHz, CDCl 3 ) δ 165.1, 152.2, 145.3, 137.5, 133.6, 132.2, 127.8, 127.1, 125.5, 121.6, 121.3, 118.7, 116.2, 51.8, 27.7, HRMS (positive ESI) Calcd. For C 18 H (M + H) , Found: (2-(4-cyanopiperidin-1-yl)-4-methoxybenzamido) pyridine1-oxide (3bd): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.43; white solid (52.8 mg, 75%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.76 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.24 (dd, J = 6.4 Hz, J = 0.7 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), (m, 1H), (m, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.82 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 3.88 (s, 3H), (m, 2H), (m, 3H), 2.53 (s, 2H), 2.16 (s, 2H). 13 C MR (151 MHz, CDCl 3 ) δ 164.8, 163.8, 154.1, 145.5, 137.4, 134.2, 127.7, 121.6, 119.7, 118.4, 116.1, 110.1, 107.6, 55.6, 51.8, 27.6, HRMS (positive ESI) Calcd. For C 19 H (M + H) , Found: S18

20 2-(2-(4-hydroxypiperidin-1-yl)benzamido)pyridine 1-oxide (3ae): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:3) as an eluent R f = 0.6; white solid (42.6 mg, 68%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.80 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.26 (dd, J = 6.4 Hz, J = 0.8 Hz, 1H), 8.21 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H), (m, 1H), (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), 3.87 (s, 1H), (m, 2H), (m, 2H), 2.19 (s, 1H), (m, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.6, 152.8, 145.3, 137.5, 133.4, 132.1, 128.2, 127.0, 124.8, 120.8, 118.6, 116.4, 67.2, 52.3, HRMS (positive ESI) Calcd. For C 17 H (M + H) , Found: (2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)benzamido)pyridine 1-oxide (3af): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:1) as an eluent R f = 0.73; white solid (40.5 mg, 49%), mp o C (dichloromethane). 1 H MR (400 MHz, CDCl 3 ) δ (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 6.3 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), 4.85 (d, J = 7.5 Hz, 1H), 3.67 (s, 1H), (m, 2H), 2.92 (t, J = 11.4 Hz, 2H), (m, 2H), (m, 2H), 1.47 (s, 9H). 13 C MR (151 MHz, CDCl 3 ) δ 165.5, 155.5, 152.6, 145.3, 137.5, 133.4, 132.1, 127.9, 127.0, 124.8, 120.8, 118.6, 116.3, 79.0, 53.9, 47.4, 31.8, HRMS (positive ESI) Calcd. For C 22 H (M + H) , Found: (2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-4-methoxybenzamido)pyridi ne 1-oxide (3bf): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.41; white solid (54.1 mg, 61%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.79 (d, J = 6.6 Hz, 1H), 8.27 (d, J = 5.9 Hz, 1H), (m, 1H), (m, 1H), 6.99 (s, 1H), 6.81 (d, J = 2.4 Hz, 1H), (m, 1H), 5.41 (s, 1H), (m, 3H), 3.66 (s, 1H), 3.20 (d, J = 8.2 Hz, 2H), 2.85 (t, J = 11.2 Hz, 2H), 2.14 (d, J = 10.6 Hz, 2H), 2.00 (s, 2H), 1.44 (s, 9H). 13 C MR (151 MHz, CDCl 3 ) δ 165.2, 163.7, 155.5, 154.6, 145.7, 137.6, 134.1, 127.9, 119.7, 118.3, 116.2, 109.3, 107.3, 79.1, 55.5, 53.9, 47.4, 31.7, HRMS (positive ESI) Calcd. For C 23 H (M + H) , Found: S19

21 2-(4-methoxy-2-(4-(methoxycarbonyl)piperidin-1-yl)benzamido)pyridine 1-oxide (3bg): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:2) as an eluent R f = 0.83; white solid (38.6 mg, 50%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 6.4 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), (m, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 3H), 3.19 (t, J = 6.2 Hz, 2H), 2.89 (t, J = 9.4 Hz, 2H), (m, 1H), (m, 2H), (m, 2H). 13 C MR (151 MHz, CDCl 3 ) δ 175.1, 165.2, 163.6, 154.7, 145.5, 137.5, 134.0, 127.3, 119.9, 118.3, 115.9, 109.2, 107.2, 55.5, 53.6, 51.7, 39.9, HRMS (positive ESI) Calcd. For C 20 H (M + H) , Found: (2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzamido)pyridine 1-oxide (3ah): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.41; white solid (57.4 mg, 81%), mp o C (dichloromethane). 1 H MR (400 MHz, CDCl 3 ) δ (s, 1H), 8.75 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.32 (dd, J = 6.5 Hz, J = 1.1 Hz, 1H), 8.22 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 4.01 (s, 4H), 3.15 (t, J = 5.7 Hz, 4H), 2.20 (s, 4H). 13 C MR (100 MHz, CDCl 3 ) δ 165.4, 152.6, 145.4, 137.8, 133.3, 132.0, 127.2, 127.1, 124.9, 121.1, 118.5, 116.0, 106.9, 64.4, 52.6, HRMS (positive ESI) Calcd. For C 19 H (M + H) , Found: (2-thiomorpholinobenzamido)pyridine 1-oxide (3ai): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.58; white solid (10.8 mg, 17%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 6.3 Hz, 1H), 8.25 (dd, J = 7.8 Hz, J = 7.8 Hz, 1H), (m, 1H), (m, 3H), (m, 1H), 3.30 (t, J = 4.7 Hz, 4H), 3.12 (s, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 165.1, 153.1, 145.3, 137.7, 133.5, 132.2, 127.5, 127.2, 125.4, 121.9, 118.7, 116.2, 56.3, HRMS (positive ESI) Calcd. For C 16 H S (M + H) , Found: (4-methoxy-2-morpholinobenzamido)pyridine 1-oxide (3bi): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (3:1) as an eluent R f = 0.68; white S20

22 solid (35.0 mg, 51%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.75 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.31 (dd, J = 6.4 Hz, J = 0.8 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), (m, 1H), (m, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.8 Hz, J = 2.5 Hz, 1H), 3.88 (s, 3H), 3.27 (t, J = 4.6 Hz, 4H), 3.12 (s, 4H). 13 C MR (151 MHz, CDCl 3 ) δ 164.8, 163.7, 155.0, 145.5, 137.6, 134.1, 127.5, 119.8, 118.4, 116.1, 110.1, 108.3, 56.3, 55.6, HRMS (positive ESI) Calcd. For C 17 H S (M + H) , Found: (2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzamido)pyridine 1-oxide (3aj): purified by preparative TLC on silica gel with CH 2 Cl 2 /acetone (1:2) as an eluent R f = 0.72; white solid (66 mg, 83%), mp o C (dichloromethane). 1 H MR (400 MHz, CDCl 3 ) δ (s, 1H), 8.75 (dd, J = 8.6 Hz, J = 1.7 Hz, 1H), 8.26 (dd, J = 6.5 Hz, J = 1.2 Hz, 1H), 8.23 (dd, J = 7.5 Hz, J = 1.0 Hz, 1H), (m, 1H), (m, 1H), 7.31 (d, J = 7.6 Hz, 2H), (m, 1H), 3.86 (t, J = 4.6 Hz, 4H), 3.01 (t, J = 5.1 Hz, 4H), 1.48 (s, 9H). 13 C MR (100 MHz, CDCl 3 ) δ 165.2, 154.5, 152.0, 145.2, 137.5, 133.5, 132.2, 127.6, 127.2, 125.2, 121.0, 118.7, 116.1, 79.7, 54.2, 53.6, 43.6, 42.4, HRMS (positive ESI) Calcd. For C 21 H (M + H) , Found: (2-(benzyl(methyl)amino)benzamido)pyridine 1-oxide (3ak): purified by column chromatography with EA/PE (4:1) as an eluent R f = 0.45; light brown solid (9.5 mg, 14%), mp o C (dichloromethane). 1 H MR (600 MHz, CDCl 3 ) δ (s, 1H), 8.67 (dd, J = 8.5 Hz, J = 1.5 Hz, 1H), 8.32 (d, J = 6.1 Hz, 1H), 8.19 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H), (m, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), (m, 4H), (m, 2H), (m, 1H), 4.29 (s, 2H), 2.94 (s, 3H). 13 C MR (100 MHz, CDCl 3 ) δ 164.9, 150.6, 145.6, 137.3, 135.2, 132.8, 131.7, 129.9, 128.0, 127.9, 127.5, 127.4, 124.9, 123.3, 118.4, 116.0, 62.0, HRMS (positive ESI) Calcd. For C 20 H (M + H) , Found: S21

23 Control Experiments 1. Kinetic Isotope Effect Measurements A: Intermolecular competition KIE. A 10 ml two-necked Schlenk tube was equipped with a magnetic stir bar and charged with 2-benzamidopyridine 1-oxide 1a (0.1 mmol, 21.4 mg), 1a-d 5 (0.1 mmol, 21.9 mg), Co(Ac) 2 4H 2 (10 mol %, 0.02 mmol, 5.0 mg), Ag 3 (0.5 mmol, 2.5 equiv., 85.0 mg), aac (0.4 mmol, 2.0 equiv., 32.8 mg), K 3 (0.1 mmol, 0.5 equiv., 10.1 mg), and MeC (0.5 ml). Reaction mixture was heated with an oil bath at 85 o C for 2.5 h. Then the reaction mixture was cooled down to room temperature, filtered through a celite pad, washed with 40 ml CH 2 Cl 2. The solvent was concentrated in vacuum and the resulting residue was purified by column chromatography (CH 2 Cl 2 /acetone = 5/1) to afford the target products of 3aa and 3aa-d 4 in 33% total yield. 1 H MR (400 MHz, CDCl 3 ): δ (s, 2H), 8.76 (dd, J = 8.5 Hz, J = 1.8 Hz, 2H), 8.30 (dd, J = 6.5 Hz, J = 1.1 Hz, 2H), (m, 1H), (m, 1H), (m, 3H), (m, 1H), (m, 2H), 4.11 (t, J = 4.5 Hz, 8H), 3.08 (t, J = 4.6 Hz, 8H). The KIE value was calculated as k H /k D = 1.2. S22

24 B: Independent initial rate comparison k H /k D. Following general procedure A, without any particular precautions to extrude oxygen or moisture, 1a (0.2 mmol, 42.8 mg) or 1a-d 5 (0.2 mmol, 43.8 mg), Co(Ac) 2 4H 2 (10 mol %, 0.02 mmol, 5.0 mg), Ag 3 (0.5 mmol, 2.5 equiv., 85.0 mg), aac (0.4 mmol, 2.0 equiv., 32.8 mg), K 3 (0.1 mmol, 0.5 equiv., 10.1 mg), and MeC (0.5 ml) were submitted to the typical reaction condition A. After 1 h, an aliquot of 50 L was taken every 3.0 minutes for 15 minutes and immediately quenched separately with 1 M HCl aqueous solution (1 ml), washed with 5 ml of EtAc. The solvent was then removed under reduced pressure and 1 H MR was taken using Dichloromethane (1 L) as the internal standard. The concentration of product was shown below: entry Time (min) Yield of 3aa Yield of [D 4 ]-3aa % 33.04% % 35.36% % 37.72% % 40.67% % 42.31% S23

25 % 46.73% a: y = x D 5 1a: y = x The calculated k H /k D = / = Reaction System under Added TEMP or BQ A 10 ml two-necked Schlenk tube equipped with a magnetic stir bar was charged with 2-benzamidopyridine 1-oxide 1a (0.2 mmol, 42.8 mg), morpholine 2a (0.24 mmol, 1.2 equiv., 21.0 ul), TEMP (0.2 mmol, 1.0 equiv., 31.3 mg) or BQ (0.2 mmol, 1.0 equiv., 21.6 mg), Ag 3 (0.5 mmol, 2.5 equiv., 85.0 mg), aac (0.4 mmol, 2.0 equiv., 32.8 mg), Co(Ac) 2 4H 2 (0.02 mmol, 10 mol %, 5.0 mg), K 3 (0.1 mmol, 0.5 equiv., 10.2 mg), and MeC (0.5 ml). The vial was heated at 85 o C for 12 h, and cooled to room temperature. The reaction mixture was diluted with 25 ml of CH 2 Cl 2, and filtered through a celite pad, then detected by TLC. The result showed that 3aa was not obtained. 3. Reaction System under Added BHT S24

26 H + H Co(Ac) 2 4H 2 (10mol%) Ag 3 (2.5 equiv.) BHT (1.2 equiv.) aac (2.0 equiv.) K 3 (0.5 equiv.) tbu tbu H 1a 2a MeC (0.5 ml) 85 o C, air, 12 h 1A A 10 ml two-necked Schlenk tube equipped with a magnetic stir bar was charged with 2-benzamidopyridine 1-oxide 1a (0.2 mmol, 42.8 mg), morpholine 2a (0.24 mmol, 1.2 equiv., 21.0 ul), BHT (0.24 mmol, 1.2 equiv., 52.9 mg), Ag 3 (0.5 mmol, 2.5 equiv., 85.0 mg), aac (0.4 mmol, 2.0 equiv.,32.8 mg), Co(Ac) 2 4H 2 (0.02 mmol, 10 mol %, 5.0 mg), K 3 (0.1 mmol, 0.5 equiv., 10.2 mg), and MeC (0.5 ml). The vial was heated at 85 o C for 12 h, and cooled down to room temperature. The reaction mixture was diluted with 25 ml of CH 2 Cl 2, and filtered through a celite pad, then detected by TLC. The result showed that the corresponding product 3aa was not obtained, and the radical coupling product 1A of morpholine (2a) with 2,4-di-tert-butyl-4-methylphenol (BHT) was also not detected. 4. Co(III)-Catalyzed C-H Amination A 10 ml dry two-necked Schlenk tube was equipped with a magnetic stir bar and charged with 2-benzamidopyridine 1-oxide 1a (0.2 mmol, 42.8 mg), morpholine 2a (0.4 mmol, 1.2 equiv., 21.0 ul), Co (III) salts (10 mol %), Ag 3 (0.5 mmol, 2.5 equiv., 85.0 mg or 0 equiv.), aac (0.4 mmol, 2.0 equiv., 32.8 mg), K 3 (0.1 mmol, 0.5 equiv., 10.2 mg), and MeC (0.5 ml). The vessel was heated at 85 o C for 12 h, and cooled down to room temperature. ext, the reaction mixture was diluted with 40 ml of CH 2 Cl 2, and filtered through a celite pad. The reaction solution was detected by TLC, and was then concentrated in vacuum. Product was purified by S25

27 column chromatography (CH 2 Cl 2 /Acetone = 3/1). When the reaction system was added in 2.5 equivalent of Ag 3, 10 mol% of Co(acac) 3, Cp*Co(C)I 2 or CoF 3 afforded the corresponding product 3aa with an output of 23.5 mg (39%), 31.6 mg (53%), 40.9 mg (68%), respectively. However, the absence of Ag 3 prevented the reaction, and no product 3aa was observed. 5. Co-catalyzed C-H amination without Ag 3 A 10 ml dry two-necked Schlenk tube was equipped with a magnetic stir bar and charged with 2-benzamidopyridine 1-oxide 1a (0.2 mmol, 42.8 mg), morpholine 2a (0.4 mmol, 1.2 equiv., 21.0 ul), Co(Ac) 2 4H 2 (10 mol %), aac (0.4 mmol, 2.0 equiv., 32.8 mg), K 3 (0.1 mmol, 0.5 equiv., 10.2 mg), and MeC (0.5 ml). The vessel was heated at 85 o C for 12 h, and cooled down to room temperature. ext, the reaction mixture was diluted with 40 ml of CH 2 Cl 2, and filtered through a celite pad. The reaction solution was detected by TLC, and product 3aa was not obtained. 6. Experimental EPR Spectrum of the Reaction System A 10 ml two-necked Schlenk tube equipped with a magnetic stir bar was charged with aromatic amides 1a (0.2 mmol, 42.8 mg), 2a (1.2 equiv., 21.0 ul), Co(Ac) 2 4H 2 (0.22 mmol, 1.1 equiv., 55.0 mg), Ag 3 (0.5 mmol, 2.5 equiv., 85.0 mg), aac (0.4 mmol, 2.0 equiv., 32.8 mg), K 3 (0.1 mmol, 0.5 equiv., 10.1 mg), and MeC (0.5 ml). The Schlenk tube was stirred at room temperature for 24 h. Then, CH 2 Cl 2 (20 ml) was added to the reaction mixture, and the mixture subsequently filtered through a celite pad. The residue was evaporated under reduced pressure, and detected by a Bruker E500 spectrometer at room temperature. For the experimental EPR spectrum of the reaction system, instrument settings were modulation frequency: KHz; modulation amplitude: 2.00 G; sweep width: G; time constant: ms; conversion: ms; sweep time: s; S26

28 receiver gain, 5.02 x 103. The microwave power was mw, and the frequency was GHz. The g value is as shown in the following EPR spectrum. Computational Section 1. Computational Details All of the calculations were performed using Gaussian 09. [5] Computed structures are illustrated using CYL View. [6] The density functional theory calculations were carried out with the M06-L [7] functional in the presence of the SMD continuum solvation model with acetonitrile as the solvent. All the structures were completely optimized using a combined basis set: the LanL2DZ basis set [8] was used for Co, along with the 6-31+G (d, p) basis set for C,, H, and. The frequency calculations were performed at the same level at 298 K and 1 atm, and vibrational analysis was performed to confirm the optimized stationary points as true minima with no imaginary frequency, or transition states with one and only one imaginary frequency, on the potential energy surface and to obtain the thermodynamic data. n S27

29 the basis of the optimized structures at the M06-L/6-31+G (d, p)//lanl2dz level, the energies were then refined by M06-L/ G(2df, 2pd)//LanL2DZ single-point calculations with the same solvent effects. We checked the S 2 values of all the stationary points obtained above, and found that all the differences between the obtained S 2 value and the normal S 2 value are less than 7.5%, so spin contamination can safely be ignored. 2. The Calculated Gibbs Free Energy As depicted in Figure S2, the energy barriers for the four transition states TS1, TS2, TS3, and TS4 are 11.59, 23.63, 9.51, and 9.05 kcal/mol, indicating that the C-H activation is not the rate-determining step for the entire cycle, in consistence of the lack of KIE. The energy difference between transition sate TS4 and intermediate IT7 become a negative value (-0.05 kcal/mol) after the thermal correction. Although the tridentate chelate IT7 should be very stable, we think it can be dissociated directly, because the structural transformation from reactants to IT7 is a highly exothermic process, which can compensate the energy for the direct dissociation. S28

30 a 0.0 TS TS1 H Ac TS H C Co IT IT2 SET TS2 IT TS2 IT H Co II Ac TS TS IT TS3 TS3 IT Co II H Ac Ac TS TS4 H Ac Co II TS Ac IT7 Figure S2. The calculated Gibbs free energy profiles for the entire catalytic cycle. (energy in kcal/mol, distance in Å) 3. Mechanistic Proposal. A tentative pathway is proposed, as shown in Figure S3, the directing group 1a is transformed to anion intermediate IT1 through proton abstraction by base via transition state TS1 at first. Then, a radical intermediate IT2 can be formed through the intermolecular single-electron-transfer (SET) between intermediate IT1 and Co III catalyst, which can easily obtained via oxidation of precatalyst Co(Ac) 2 by using oxidant Ag salts. [9] Subsequently, intermediate IT2 coordinates with Co III catalyst (Cata) to generate intermediate IT3, which is transformed to intermediate IT4 by amination of ortho carbon via transition state TS2. In the following formation of intermediate IT5, Co II center is coordinated with a molecule of base Ac -, which then abstracts the proton of ortho carbon to generate intermediate IT6 S29

31 via transition state TS3. The last intermediate IT7 is formed via an intramolecular proton transfer transitionn state TS4. At last, product Co II I (Ac) 2 precatalyst to complete the entire cycle. 3aa is dissociated with Ag 0, 3- Co III Ac Cata Ag I 3 HAc H IT T2 H Co II (Ac) 2 SET 3aaa Co II - (Ac) 2, 3 Co III (Ac) 2 3 H Co III Ac IT3 TS2 H Ac Co II Ac IT7 TS4 H IT1 TS1 H H 1a HAc Ac - H Co II Ac IT4 Ac - Co II HAcAc IT6 Figure S3. Proposed mechanisms for the Co-catalyzed C-H amination TS3 H Co II Ac Ac IT5 4. Computed Structures, Cartesian Coordinates and Energies 1a IT2 Ac - Cata S30

32 HAc IT3 IT1 IT4 Co II II (Ac) 2 3 IT5 Co(Ac) 2 IT6 3 - IT7 Cartesian Coordinates and Energies 1a (Singlet) E= a.u. C S31

33 C C C C C C H C C H H H H H H C H C H C H Ac - (Singlet) E= a.u. C C H H H TS1 (Singlet) E= a.u. Imaginary Frequency C C C C C S32

34 C C C H C C H H H H H C H C H C H H C H H H HAc (Singlet) E= a.u. C H H H C H IT1 (Singlet) E= a.u. C C S33

35 C C C C C H C C H H H H H C H C H C H Co III (Ac) 2 3 (Singlet) E= a.u. Co C C C H H H C H H H S34

36 Co II (Ac) 2 (Doublet, S**2 after annihilation: ) E= a.u. Co C C C H H H C H H H (Singlet) E= a.u IT2 (Doublet, S**2 after annihilation: ) E= a.u. C C C C C C C H C C H H H S35

37 H H C H C H C H Cata (Singlet) E= a.u. Co C H H C H H C H H C H H C C H H H IT3 (Doublet, S**2 after annihilation: ) E= a.u. C C C C C S36

38 C C C H C C H H H H C H C H H Co H C H H C H H C H H C H H C C H H H TS2 (Doublet, S**2 after annihilation: ) E= a.u. S37

39 Imaginary Frequency C C C C C C C C H C C H H H H C H C H H Co H C H H C H H C H H C H H C S38

40 C H H H IT4 (Doublet, S**2 after annihilation: ) E= a.u. C C C C C C C C H C C H H H H C H C H H Co H C H H C H H C H H C H S39

41 H C C H H H IT5 (Doublet, S**2 after annihilation: ) E= a.u. C C C C C C C C H C C H H H H C H C H H Co C H C H S40

42 H H C H H C H H C H H C H H C C H H H TS3 (Doublet, S**2 after annihilation: ) E= a.u. Imaginary Frequency C C C C C C C C H C C H H H S41

43 H C H C H H Co C H C H H H C H H C H H C H H C H H C C H H H IT6 (Doublet, S**2 after annihilation: ) E= a.u. C C C C S42

44 C C C C H C C H H H H C H C H H Co C H C H H H C H H C H H C H H C H H S43

45 C C H H H TS4 (Doublet, S**2 after annihilation: ) E= a.u. Imaginary Frequency C C C C C C C C H C C H H H H C H C H H Co C H C H H H C S44

46 H H C H H C H H C H H C C H H H IT7 (Doublet, S**2 after annihilation: ) E= a.u. C C C C C C C C H C C H H H H C H S45

47 C H H Co C H C H H H C H H C H H C H H C H H C C H H H Removal of directing group To a 10 ml-sealed tube equipped with a magnetic stir bar was added 2-(4-(tert-butyl)-2-morpholinobenzamido)pyridine 1-oxide 3da (0.2 mmol, 71 mg), S46

48 ah (2 mmol, 10 equiv., 80 mg) and EtH (2.0 ml). This tube was stirred in an oil bath at 100 o C for 48 h. After completion, the resulting mixture was cooled to room temperature, quenched with 40 ml ethyl acetate, and then washed by HCl (2 mol/l, 15 ml 2). ext, the combined aqueous solution was extracted with 20 ml ethyl acetate for four times. Then, the organic layers were combined, dried over a 2 S 4. After concentration in vacuum, the known pure acid 1B [4] was obtained with a 94% yield (49.3 mg). 1 H MR (600 MHz, CDCl 3 ) δ 8.23 (d, J = 7.7 Hz, 1H), 8.45 (d = 7.7 Hz, 1H), 7.43 (s, 1H), 3.97 (s, 4H), 3.10 (s, 4H), 1.35 (s, 9H). References [1] Adams, R.; Miyano, S. J. Am. Chem. Soc. 1954, 76, [2] (a) Hao, X.-Q.; Chen, B. Ren, L.-J.; Li, L.-Y.; Yang, X.-Y.; Gong, J.-F.; iu, J.-L.; Song, M.-P. rg. Lett. 2014, 16, (b) Zhang, L.-B.; Hao, X.-Q.; Zhang, S.-K.; Liu, K.; Ren, B.; Gong, J.-F.; iu, J.-L.; Song, M.-P.; J. rg. Chem. 2014, 79, (c) Zhang, L.-B.; Hao, X.-Q.; Zhang, S.-K.; Liu, Z.-J.; Zheng, X.-X.; Gong, J.-F.; iu, J.-L.; Song, M.-P. Angew. Chem. Int. Ed. 2015, 54, [3] Gong,W.; Zhang, G; Liu, T; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, [4] (a) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, (b) Tran, L. D.; Roane, J.; Daugulis,. Angew. Chem. Int. Ed. 2013, 52, [5] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; akatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; akajima,t.; Honda, Y.; Kitao,.; akai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; gliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K..; Staroverov, V..; Kobayashi, R.; ormand, J.; S47

49 Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,.; Austin, A. J.; Cammi, R.; Pomelli, C.; chterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; rtiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02; Gaussian, Inc., Wallingford, CT, [6] Legault, C. Y. CYLview, 1.0b, Universite de Sherbrooke, 2009, [7] Zhao, Y.; Truhlar, D. G. J. Chem. Phys., 2006, 125, [8] Wadt, W. R.; Hay, P. J. J. Chem. Phys., 1985, 82, 284. [9] Guo, X.-K.; Zhang, L.-B.; Wei, D.; iu, J.-L. Chem. Sci. 2015, 6, Complete Literature in References (4) and (7) (4) For selected examples of metal-catalyzed amination: (a) Kim, J. Y. S.; Park, H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134, (b) Padwa, A.; Stengel, T. rg. Lett. 2002, 4, (c) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, (d) Sun, K.; Sachwani, R.; Richert, K. J.; Driver, T. G. rg. Lett. 2009, 11, (e) Caselli, A.; Gallo, E.; Ragaini, F.; Ricatto, F.; Abbiati, G.; Cenini, S. Inorg. Chim. Acta. 2006, 359,2924. (f) Liu, G.; Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47, (g) Matsuda,.; Hirano, K.; Satoh, T.; Miura, M. rg. Lett. 2011, 13, (h) Park, S. H.; Kwak, J.; Shin, K.; Ryu, J.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, (7) For selected examples on intramolecular C H amination: (a) eumann, J. J.; Rakshit, S.; Dröge, T.; Glorius, F. Angew Chem., Int. Ed. 2009, 48, (b) Wu, X.; Zhao, Y.; Ge, H. Chem. Eur. J. 2014, 20, (c) Wang, Z.; i, J.;Kuninobu, Y.; Kanai, M. Angew. Chem., Int. Ed. 2014, 53, (d) He, G.; Lu, C.; Zhao,Y.; ack, W. A.; Chen, G. rg. Lett. 2012, 14, (e) He, G.; Zhang, S.-Y.; ack, W.A.; Li, Q.; Chen, G. Angew. Chem.,Int. Ed. 2013, 52, (f) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. S48

50 Chem., Int. Ed. 2013, 52, (g) Sun, W.-W.; Cao, P.; Mei, R.-Q.; Li, Y.; Ma, Y.-L.; Wu, B. rg. Lett. 2014, 16, 480. MR Spectra S49

51 S50

52 S51

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54 S53

55 Me 7aa H Me 7aa H S54

56 CF 3 8aa H CF 3 8aa H S55

57 S56

58 S57

59 S58

60 S59

61 S60

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63 S62

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65 S64

66 S65

67 S66

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71 S70

72 S71

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74 S73

75 S74

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77 S H 3ua S76

78 S77

79 S78

80 S79

81 Me 3bd H C S80

82 S81

83 3af H HBoc 3af H HBoc S82

84 Me 3bf H HBoc Me 3bf H HBoc S83

85 3bg H CMe S84