Direct Hydroxylation and Amination of Arenes via Deprotonative Cupration

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1 Supporting Information Direct Hydroxylation and Amination of Arenes via Deprotonative Cupration Noriyuki Tezuka,, Kohei Shimojo,, Keiichi Hirano,*, Shinsuke Komagawa,, Kengo Yoshida, Chao Wang, Kazunori Miyamoto, Tatsuo Saito, Ryo Takita, and Masanobu Uchiyama*,, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo , Japan Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama , Japan Present Address: Graduate School of Pharmaceutical Sciences, saka University Table of Contents 1 General 2 2 Experimental Details Preparation of Cuprates Preparation of Substrates ortho Hydroxylation of Aromatics (Table 2) ortho Amination of Aromatics (Table 3) Catalytic ortho Hydroxylation of Aromatics (Table 4) Catalytic ortho Amination of Aromatics (Table 4) 17 3 Computational Details xidation of Aryl-Cu-ate (Scheme 1) Transition of Natural Charge through xidation of the Aryl-Cu-ate 23 4 References References in Experimental Section 4.2. References in Computational Details 5 Copies of NMR Spectra 30 1

2 1. General Instrumentation. NMR spectra were obtained on a Bruker AVANCE III HD 500 spectrometer and a Bruker Ascend 400 spectrometer. Chemical shifts are expressed in δ (ppm) values, and coupling constants are expressed in hertz (Hz). 1 H and 13 C NMR spectra were referenced to tetramethylsilane as an internal standard. The following abbreviations are used: s = singlet, d = doublet, t = triplet, quint = quintet, sep = septet, m = multiplet, brs = broad singlet, and brd = broad doublet. Melting points were determined with a Yanaco micro melting point apparatus and uncorrected. IR spectra were obtained on a METLER TLED ReactIR 4000 and JASC FT/IR-4700 spectrophotometer. ESI mass spectra were measured on a Bruker micrtf-ii spectrometer. Materials. Unless otherwise noted, materials were purchased from Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co., Ltd., Sigma-Aldrich Co., LLC., and other commercial suppliers. n BuLi in n hexane and t BuLi in n pentane were obtained from Kanto Chemical Co., Inc. Anhydrous THF was purchased from Kanto Chemical Co., Inc. All chemicals were of reagent grade and used as received. Air- and moisture-sensitive manipulations were performed with standard Schlenk techniques under argon atmosphere. Normal-phase column chromatography was performed with silica gel 60 ( mesh) from Merck and thin-layer chromatography was carried out on 0.25 mm Merck silica gel plates (60F-254). 2

3 2. Experimental Details 2.1. Preparation of Cuprates Preparation of LiTMP in THF (1.0 mmol scale) To a solution of 2,2,6,6-tetramethylpiperidine (0.17 ml, 1.0 mmol) in 1 ml of anhydrous THF was added n BuLi (2.53 M n hexane solution, 0.40 ml, 1.0 mmol) at 78 C under Ar. The mixture was stirred for 30 min at 0 C to give the solution of LiTMP (lithium 2,2,6,6-tetramethylpiperidide) in THF. Preparation of (TMP) 2 Cu(CN)Li 2 in THF (1.0 mmol scale) To a suspension of copper cyanide (89.6 mg, 1.0 mmol) in 2 ml of anhydrous THF was added the prepared solution of LiTMP in THF (2.0 mmol) at 78 C under Ar. The mixture was stirred at 0 C for 30 min to give the solution of (TMP) 2 CuCNLi 2 in THF. Preparation of ( i Pr 2 N) 2 Cu(CN)Li 2 in THF (1.0 mmol scale) To a solution of diisopropylamine (0.28 ml, 2.0 mmol) in 2 ml of anhydrous THF was added n BuLi (2.53 M n hexane solution, 0.79 ml, 2.0 mmol) at 78 C under Ar. The mixture was stirred for 30 min at 0 C to give the solution of LDA in THF. To a suspension of copper cyanide (89.6 mg, 1.0 mmol) in 2 ml of anhydrous THF was added the solution of LDA in THF (2.0 mmol) at 78 C under Ar, and the reaction mixture was stirred at 0 C for 30 min to give the solution of ( i Pr 2 N) 2 Cu(CN)Li 2 in THF. Preparation of n BuCu(TMP)(CN)Li 2 in THF (1.0 mmol scale) To a suspension of copper cyanide (89.6 mg, 1.0 mmol) in 2 ml of anhydrous THF was added n BuLi (2.53 M n hexane solution, 0.40 ml, 1.0 mmol) at 78 C under Ar. The mixture was stirred at 0 C for 30 min to give a solution of n BuCu(CN)Li in THF. To the prepared n BuCu(CN)Li solution was added the LiTMP solution (1.0 mmol) at 78 C under Ar, and the reaction mixture was stirred at 0 C for 30 min to give the solution of n BuCu(TMP)(CN)Li 2 in THF. Preparation of t BuCu(TMP)(CN)Li 2 in THF Solution (1.0 mmol scale) To a suspension of copper cyanide (89.6 mg, 1.0 mmol) in 2 ml of anhydrous THF was added t BuLi (1.50 M n pentane solution, 0.67 ml, 1.0 mmol) at 78 C under Ar. The mixture was stirred at 0 C for 30 min to give the solution of t BuCu(CN)Li in THF. To the prepared t BuCu(CN)Li solution was added the LiTMP solution (1.0 mmol) at 78 C under Ar, and the reaction mixture was stirred at 0 C for 30 min to give the solution of t BuCu(TMP)(CN)Li 2 in THF. Preparation of (HMDS) 2 Cu(CN)Li 2 in THF (1.0 mmol scale) To a suspension of copper cyanide (89.6 mg, 1.0 mmol) in 2 ml of anhydrous THF was added LiHMDS (1.00 M in THF, 1.00 ml, 1.0 mmol) at 78 C under Ar. The mixture was stirred at 0 C for 30 min to give the solution of (HMDS) 2 Cu(CN)Li 2 in THF. Preparation of t Bu 2 Zn(TMP)Li in THF (1.0 mmol scale) To zinc chloride (0.5 M THF solution, 2.00 ml, 1.0 mmol) was added t BuLi (1.50 M n pentane solution,

4 ml, 2.0 mmol) at 78 C under Ar. The mixture was stirred at 0 C for 30 min to give the solution of di- t butylzinc in THF. To the prepared di- t butylzinc solution was added the LiTMP solution (1.0 mmol) at 78 C under Ar, and the reaction mixture was stirred at 0 C for 30 min to give the solution of t Bu 2 Zn(TMP)Li in THF. Preparation of (TMP) 3 ZnLi in THF (2.0 mmol scale) To zinc chloride (0.5 M THF solution, 2.00 ml, 1.0 mmol) was added the LiTMP solution (3.0 mmol) at 78 C under Ar, and the reaction mixture was stirred at 0 C for 30 min to give the solution of (TMP) 3 ZnLi in THF Preparation of Substrates N,N-Diisopropylbenzamide substrates were prepared from the corresponding acyl chlorides or acids using General Procedure A or B. General Procedure A To a solution of the amine (1.7 ml, 12 mmol) and Et 3 N (1.8 ml, 12.5 mmol) in 20 ml of CH 2 Cl 2 was added acyl chloride (10 mmol) in one portion at room temperature leading the mixture to self-reflux. The reaction mixture was stirred for 20 min at room temperature and then diluted with CH 2 Cl 2. The solution was transferred to a separation funnel and was washed with 1M HCl aq (3 20 ml). The organic layer was dried over Na 2 S 4, filtered, and concentrated under reduced pressure to give the diisopropylarylamide substrates. The substrates were used without further purification. General Procedure B Thionyl chloride (4.02 mg, 33.8 mmol) was added to a solution of carboxylic acid (6.8 mmol) and DMF (8 ml, 3.3 mmol) in 34 ml of CH 2 Cl 2 at room temperature. The mixture was heated under reflux for 5 h, and then the excess thionyl chloride and CH 2 Cl 2 were removed in vacuo. The resultant acyl chloride was dissolved in dry CH 2 Cl 2 and cooled to 0, then diisopropylamine (1.1 ml, 8.1 mmol) was added. After 5 min, Et 3 N (1.2 ml, 8.5 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The mixture was diluted with CH 2 Cl 2 and washed with 3 M HCl aq. (2 20mL), water(1 20 ml), and brine(1 20 ml). The organic layer was dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the crude residue by flash column chromatography on silica gel afforded the N,N-diisopropylbenzamide substrates. 4-Methoxymethoxybiphenyl (1l) was prepared using the following procedure; To a stirred suspension of NaH (0.80 mg, 20 mmol) in 20 ml of THF at 0 was added dropwise a solution of 4-hydroxybiphenyl (3.40 g, 20 mmol) in 30 ml THF. The reaction mixture was stirred for 15 min at room temperature, the ClCH 2 CH 3 (3 ml, 40 mmol) was added at 0, and stirring was continued for 1 h at room temperature. The mixture was quenched with aqueous NH 4 Cl (30 ml), followed by extraction with Et 2 (30 ml 3). The combined Et 2 layers were dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the crude residue by flash column chromatography on silica gel afforded the title compound. 4

5 2.3. ortho Hydroxylation of Aromatics (Table 2) General Procedure: 2-Hydroxy-N,N-diisopropylbenzamide (2a) H 1) (TMP) 2 Cu(CN)Li 2 (1.3 eq.) THF, 0 C, 2 h H 1a N i Pr 2 2) TBHP (2.0 eq.) 78 C, 30 min 2a N i Pr 2 N,N-Diisopropylbenzamide 1a (61.5 mg, 0.3 mmol) and dry THF (0.3 ml) were added to a heat gun-dried Schlenk tube. The mixture was added to a solution of (TMP) 2 Cu(CN)Li 2 (0.4 mmol) via cannular at 78 ºC, and the resulting solution was stirred for 2 h at 0 ºC. To the mixture was added t BuH (109 µl, 0.6 mmol; 5.5 M decane solution) at 78 C, then stirred for 30 min at the same temperature. The reaction was quenched with aqueous NH 4 Cl (10 ml) and aqueous Na 2 S 2 3 (10 ml), followed by extraction with AcEt (30 ml 3). The combined AcEt layers were dried over Na 2 S 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using AcEt/hexane (1/3) as an eluent to give the titled compound (2a) as a white solid in 94% yield (62.5 mg). 1 H and 13 C NMR were in agreement with the reference. 1 1 H NMR (500 MHz, CDCl 3 ): δ 1.39 (d, J = 7.0 Hz, 12H), 3.95 (brs, 2H), (m, 1H), 6.99 (dd, J = 1.0, 8.0 Hz, 1H), 7.17 (dd, J = 1.0, 8.0 Hz, 1H), (m, 1H), 9.25 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 21.0, 49.0 (br), 118.0, 118.5, 120.2, 126.8, 131.6, 158.1, EI-MS (% relative intensity): m/z: 221 (M+, 23), 178 (37), 121 (100), 93 (14), 86 (73), 65 (20), 58 (21). Larger Scale: Following the General Procedure, 1a (1.44 g, 7 mmol), TMP-H (3.1 ml, 18.5 mmol), n BuLi (2.58 M in n hexane, 7.2 ml, 18.5 mmol), CuCN (828 mg, 9.2 mmol), and TBHP (5.5 M in n decane, 2.55 ml, 14 mmol) were used. The reaction was quenched with aqueous NH 4 Cl (50 ml) and aqueous Na 2 S 2 3 (50 ml), followed by extraction with AcEt (30 ml 3). The combined AcEt layers were dried over Na 2 S 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using AcEt/hexane (1/3) as an eluent to give the titled compound (2a) as a white solid in 91% yield (1.41 g). Unless otherwise noted, the reaction was performed on 0.3 mmol scale. 4-Chloro-2-hydroxy-N,N-diisopropylbenzamide (2b) H Following the General Procedure (The THF solution of the substrate was added to the solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at N i Pr 2 78 C.; purification: AcEt/hexane = 1/4), the titled compound was obtained as a white solid Cl in 89% yield (68.0 mg). 1 H and 13 C NMR were in agreement with the reference. 1 1 H NMR (500 MHz, CDCl 3 ): δ 1.38 (d, J = 6.5 Hz, 12H), 3.88 (brs, 2H), 6.81 (dd, J = 2.0, 8.0 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 9.60 (brs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.9, 49.1 (br), 118.2, 118.9, 119.2, 127.6, 136.8, 158.7, EI-MS (% relative intensity): m/z: 255 (M+, 12), 212 (29), 155 (61), 86 (100), 58 (28). 5

6 4-Bromo-2-hydroxy-N,N-diisopropylbenzamide (2c) Br Following the General Procedure (The THF solution of the substrate was added to the solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at 78 ºC.; purification: AcEt/hexane = 1/4), the titled compound was obtained as a white solid in 88% yield (79.0 mg). 1 H and 13 C NMR were in agreement with the reference. 1 1 H NMR (500 MHz, CDCl 3 ): δ 1.36 (d, J = 6.5 Hz, 12H), 3.82 (brs, 2H), 6.94 (dd, J = 1.5, 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 9.56 (brs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.8, 49.0 (br), 120.8, 121.0, 121.9, 124.4, 127.5, 157.6, EI-MS (% relative intensity): m/z: 299 (M+, 6), 256 (13), 213 (9), 199 (30), 86 (100), 58 (30). 2-Hydroxy-4-iodo-N,N-diisopropylbenzamide (2d) I H H N i Pr 2 N i Pr 2 Following the General Procedure (The THF solution of the substrate was added to the solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at 78 ºC.; purification: AcEt/hexane = 1/4), the titled compound was obtained as colorless crystals in 92% yield (95.7 mg). 1 H and 13 C NMR spectra were in agreement with the reference. 1 1 H NMR (500 MHz, CDCl 3 ): δ 1.34 (d, J = 6.0 Hz, 12H), 3.78 (brs, 2H), 6.80 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 1.5, 8.0 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 9.48 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.8, 49.0 (br), 96.1, 122.2, 126.9, 127.5, 128.0, 156.7, EI-MS (% relative intensity): m/z: 347 (M+, 11), 320 (48), 304 (27), 261 (42), 247 (31), 86 (100), 58 (25). 2-Hydroxy-4-(trifluoromethyl)-N,N-diisopropylbenzamide (2e) H Following the General Procedure (purification: AcEt/hexane = 1/3), the titled compound was obtained as a white solid in 92% yield (79.9 mg). 1 H and 13 C NMR were in agreement N i Pr 2 with the reference. 1 1 H NMR (500 MHz, CDCl 3 ): δ 1.37 (d, J = 6.0 Hz, 12H), 3.81 (brs, F 3 C 2H), 7.06 (dd, J = 1.0, 8.0 Hz, 1H), 7.14 (d, J = 1.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 9.42 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.8, 49.1 (br), (q, J = 3.8 Hz), (q, J = 3.8 Hz), (q, J = Hz), 125.2, 126.9, (q, J = 32.5 Hz), 156.7, EI-MS (% relative intensity): m/z: 289 (M+, 9), 246 (20), 189 (60), 161 (16), 113 (9), 86 (100), 58 (36). 2-Hydroxy-4-vinyl-N,N-diisopropylbenzamide (2f) H Following the General Procedure (1 mmol scale, 1.2 mmol of TBHP was used.; purification: AcEt/hexane = 1/9), the titled compound was obtained as colorless crystals in N i Pr 2 71% yield (176.7 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.38 (d, J = 6.0 Hz, 12H), 3.93 (brs, 2H), 5.30 (dd, J = 0.5, 11.0 Hz, 1H), 5.77 (dd, J = 0.5, 17.5 Hz, 1H), 6.63 (dd, J = 11.0, 17.5 Hz, 1H), 6.88 (dd, J = 1.5, 8.0 Hz, 1H), 7.01 (d, J = 1.5 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 9.40 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 19.9, 47.9 (br), 114.2, 114.4, 115.6, 119.1, 125.9, 135.1, 139.7, 156.9, IR (ATR-IR): 3331, 2982, 1328, 1297, 1165, 1110, 1068, 843, 769, 676 cm -1. mp: ºC (recrystallized from EtH). EI-MS (% relative intensity): m/z: 247 (M+, 21), 204 (21), 147 (78), 86 (100), 65 (14), 58 (35). Anal.: Calcd for C 15 H 21 N 2 : C, 72.84; H, 8.56; N, Found: C, 72.83; H, 8.37; N, HRMS (pos. ESI): m/z: calcd for C 15 H 21 N 2 [M+H] , found

7 2-Hydroxy-N,N-diisopropyl-1-naphthamide (2g) H Following the General Procedure (The substrate was added as a solution in 1 ml of THF.; purification: AcEt/hexane = 2/3), the titled compound was obtained as a white solid in 89% N i Pr 2 yield (72.9 mg). 1 H NMR (500 MHz, DMS-d6): δ 1.02 (d, J = 6.5 Hz, 3H), 1.13 (d, J = 6.5 Hz, 3H), 1.52 (d, J = 6.5 Hz, 3H), 1.60 (d, J = 6.5 Hz, 3H), 3.60 (sep, J = 6.8 Hz, 2H), 7.17 (d, J = 9.0 Hz, 1H), 7.29 (ddd, J = 1.3, 6.8, 8.3 Hz, 1H), 7.44 (ddd, J = 1.3, 6.8, 8.3 Hz, 1H), 7.50 (brd, J = 8.3 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.80 (brd, J = 8.3 Hz, 1H), 9.80 (s, 1H). 13 C NMR (125 MHz, DMS-d6): δ 21.0, 21.0, 21.1, 21.3, 45.3, 51.1, 118.6, 119.3, 123.4, 123.5, 127.1, 128.0, 128.5, 129.4, 131.5, 150.6, IR (ATR-IR): 3053, 2999, 2973, 2932, 2873, 1623, 1579, 1509, 1470, 1348, 1307, 1275, 1249, 1208, 1161, 1122, 1051, 1021, 968, 821, 750, 714, 617 cm 1. mp: ºC (recrystallized from MeH). Anal.: Calcd: C, 75.25; H, 7.80; N, Found: C, 75.10; H, 7.94; N, HRMS (pos. ESI): m/z: calcd for C 17 H 21 N 2 [M+H] , found Hydroxy-N,N-diisopropyl-2-naphthamide (2h) H Following the General Procedure (The substrate was added as a solution in 1 ml of THF.; purification: AcEt/hexane = 1/3), the titled compound was obtained as a white solid in 76% N i Pr 2 yield (61.8 mg). 1 H and 13 C NMR were in agreement with the reference. 1 1 H NMR (500 MHz, CDCl 3 ): δ 1.43 (d, J = 6.5 Hz, 12H), 4.00 (brs, 2H), (m, 2H), 7.45 (ddd, J = 1.3, 7.0, 8.3 Hz, 1H), (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 8.60 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 21.0, 49.2, 112.2, 123.2, 123.9, 126.4, 126.7, 127.1, 127.6, 128.2, 135.3, 153.8, EI-MS (% relative intensity): m/z: 271 (M+, 45), 228 (25), 170 (100), 142 (38), 115 (48), 86 (26). 2-Hydroxy-3-methoxy-N,N-diisopropylbenzamide (2i) H Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 1/4), the Me titled compound was obtained as a white solid in 79% yield (198.9 mg). 1 H NMR (500 N i Pr 2 MHz, CDCl 3 ): δ 1.36 (d, J = 4.5 Hz, 12H), 3.76 (brs, 2H), 3.90 (s, 3H), 6.78 (dd, J = 1.9, 7.5 Hz, 1H), 6.78 (dd, J = 7.5, 8.0 Hz 1H), 6.86 (dd, J = 1.9, 8.0 Hz, 1H), 7.08 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.8, 48.6 (br), 56.1, 111.5, 118.8, 119.4, 123.8, 144.0, 147.5, IR (ATR-IR): 3153, 2999, 2966, 2931, 2845, 1736, 1599, 1487, 1439, 1369, 1344, 1290, 1265, 1231, 1124, 1065, 1035, 941, 841, 806, 776, 744, 607, 553, 511 cm 1. mp: ºC (recrystallized from EtH). EI-MS (% relative intensity): m/z: 251 (M+, 28), 208 (26), 151 (100), 122 (41), 108 (15), 86 (48). Anal.: Calcd: C, 66.91; H, 8.42; N, Found: C, 66.86; H, 8.24; N, HRMS (pos. ESI): m/z: calcd for C 14 H 21 N 3 [M+H] , found Hydroxy-N,N-diethylbenzamide (2j) Following the General Procedure (0.45 mmol of (TMP) 2 Cu(CN)Li 2 was used.; purification: H AcEt/hexane = 1/3), the titled compound was obtained as a colorless oil in 90% yield (56.1 NEt 2 mg). 1 H and 13 C NMR were in agreement with the reference. 1,2 1 H NMR (500 MHz, CDCl 3 ): δ 1.28 (t, J = 7.0 Hz, 6H), 3.78 (q, J = 7.0 Hz, 4H), 6.84 (ddd, J = 1.1, 7.2, 7.5 Hz, 1H), 7.00 (brd, J = 8.1 Hz, 1H), (m, 1H), (m, 1H) 9.75 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 13.4, 42.2 (br), 118.0, 118.1, 118.4, 127.3, 132.3, 158.8, EI-MS (% relative intensity): m/z: 192 (M+, 43), 121 (100), 93 (14), 72 (36), 65 (21), 58 (41). 4-tert-Butyl-2-hydroxybenzonitrile (2k) t Bu H CN Following the General Procedure (1 mmol scale. 1.5 mmol of (TMP) 2 Cu(CN)Li 2 and 1.4 mmol of TBHP were used.; purification: AcEt/hexane = 1/19), the titled compound was obtained as a white solid in 87% yield (152.8 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.30 (s, 9H), 5.88 (brs, 1H), 7.00 (d, J = 1.5 Hz, 1H), 7.03 (dd, J = 1.5, 8.2 Hz, 1H), 7.43 (d, J = 8.2 Hz, 7

8 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 30.8, 35.3, 96.4, 113.7, 116.5, 118.8, 132.2, 158.1, IR (ATR-IR): 3244, 2954, 2232, 1739, 1611, 1584, 1424, 1362, 1310, 1279, 1236, 1204, 1130, 1089, 1025, 939, 871, 819, 748, 739, 688, 655, 622, 526 cm 1. mp: ºC (recrystallized from CH 2 Cl 2 ). EI-MS (% relative intensity): m/z: 175 (M+, 30), 160 (100), 132 (44), 120 (16). Anal.: Calcd for C 11 H 13 N: C, 75.40; H, 7.48; N, Found: C, 75.35; H, 7.61; N, HRMS (pos. ESI): m/z: calcd for C 11 H 13 N [M+H] , found Hydroxy-4-methoxymethoxybiphenyl (2l) H Following the General Procedure (1 mmol scale, 1.5 mmol of (TMP) 2 Cu(CN)Li 2 and 1.4 MM mmol of TBHP were used.; purification: AcEt/hexane = 1/19), the titled compound was obtained as a colorless oil in 82% yield (188.6 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 3.55 (s, Ph 3H), 5.24 (s, 2H), (m, 1H), 7.07 (dd, J = 2.0, 8.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.41 (dd, J = 7.4, 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ): δ 56.5, 96.1, 114.2, 115.8, 119.0, 126.9, 127.0, 128.7, 136.6, 140.6, 144.0, IR (ATR-IR): 3404, 2951, 2902, 2849, 2827, 1737, 1591, 1573, 1519, 1487, 1299, 1287, 1247, 1191, 1152, 1126, 1077, 1043, 981, 922, 900, 872, 814, 757, 696, 586 cm 1. EI-MS (% relative intensity): m/z: 230 (M+, 100), 198 (56), 185 (30), 157 (43), 139 (26), 128 (45). HRMS (pos. ESI): m/z: calcd for C 14 H 14 3 [M+Na] , found Hydroxy-4-methoxybiphenyl (2m) H Following the General Procedure (1 mmol scale, 2.2 mmol of (TMP) 2 Cu(CN)Li 2 and 2.0 Me mmol of TBHP were used.; purification: AcEt/hexane = 1/19), the titled compound was obtained as a white solid in 83% yield (166.2 mg). 1 H NMR spectrum was in agreement with Ph the reference. 3 1 H NMR (500 MHz, CDCl 3 ): δ 3.92 (s, 3H), 5.65 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 7.09 (dd, J = 2.2, 8.5 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.30 (tt, J = 1.4, 7.5 Hz, 1H), (m, 2H), (m, 2H). 13 C NMR (125 MHz, CDCl 3 ): δ 56.1, 110.9, 113.4, 118.8, 126.8, 126.8, 128.7, 134.8, 140.8, 145.8, EI-MS (% relative intensity): m/z: 200 (M+, 100), 185 (93), 157 (79), 139 (9), 128 (39), 115 (9), 102 (11), 77 (10), 63 (8), 51 (10). Dicyclohexyl(2-hydroxyphenyl)phosphine oxide (2n) H P Cy Cy Following the General Procedure (0.45 mmol of (TMP) 2 Cu(CN)Li 2 was used.; purification: AcEt/hexane = 1/3), the titled compound was obtained as a white solid in 86% yield (78.9 mg). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 10H), (m, 4H), (m, 4H), (m, 4H), (m, 1H), 6.90 (dd, J = 3.9, 8.3 Hz, 1H), (m, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 24.1 (d, J C P = 2.9 Hz), 25.2 (d, J C P = 2.2 Hz), 25.7, 26.2 (d, J C P = 13.2 Hz), 26.3 (d, J C P = 13.2 Hz), 35.7 (d, J C P = 66.0 Hz), (d, J C P = 85.8 Hz), (d, J C P = 6.6 Hz), (d, J C P = 11.0 Hz), (d, J C P = 9.5 Hz), 133.7, IR (ATR-IR): 2927, 2852, 2690, 2660, 2588, 2549, 1591, 1444, 1391, 1297, 1123, 1070, 910, 889, 851, 757, 732, 573 cm -1. mp: C (recrystallized from EtH). HRMS (pos. ESI): m/z: calcd for C 18 H 27 2 P [M+Na] , found Anal.: Calcd: C, 70.56; H, Found: C, 70.30; H, tert-butyl 2-hydroxybenzoate (2o) H Following the General Procedure (1 mmol scale, 2.2 mmol of (TMP) 2 Cu(CN)Li 2 and 2.0 mmol of cumene hydroperoxide instead of TBHP were used.; purification: AcEt/hexane = 1/9), the t Bu titled compound was obtained as a brown oil in 82% yield (189.1 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.61 (s, 9H), (m, 1H), 6.94 (dd, J = 1.0, 8.5 Hz, 1H), 7.41 (ddd, J = 1.5, 7.3, 8.5 Hz, 1H), 7.78 (dd, J = 1.5, 8.0 Hz, 1H), (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 28.2, 82.8, 113.9, 117.5, 118.8, 130.1, 135.1, 161.8, EI-MS (% relative intensity): m/z: 194 (M+, 3), 138 (51), 120 (100), 92 (20), 65 (10), 57 (11). HRMS (pos. ESI): m/z: calcd for C 11 H 14 3 [M+H] , found

9 Isopropyl 2-hydroxybenzoate (2p) Following the General Procedure (1 mmol scale, 2.2 mmol of (TMP) 2 Cu(CN)Li 2 and 2.0 mmol H of cumene hydroperoxide instead of TBHP were used.; purification: AcEt/hexane = 1/9), the i Pr titled compound was obtained as a colorless oil in 82% yield (189.1 mg). 1 H NMR spectrum was in agreement with the reference. 4 1 H NMR (500 MHz, CDCl 3 ): δ 1.39 (d, J = 6.3 Hz, 6H), 5.29 (sep, J = 6.3 Hz, 1H), 6.87 (ddd, J = 1.0, 7.1, 8.0 Hz, 1H), 6.97 (dd, J = 1.0, 8.3 Hz, 1H), 7.44 (ddd, J = 1.7, 7.1, 8.3 Hz, 1H), 7.84 (dd, J = 1.7, 8.0 Hz, 1H), (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.8, 68.2, 111.9, 116.5, 118.0, 128.9, 134.4, 160.7, EI-MS (% relative intensity): m/z: 180 (M+, 14), 138 (26), 120 (100), 92 (30), 65 (9). 1(2H)-Isoquinolinone (2r) Following the General Procedure (1 mmol scale, 1.5 mmol of (TMP) 2 Cu(CN)Li 2 and 1.4 mmol NH of TBHP were used.; purification: AcEt/hexane = 1/4), the titled compound was obtained as a white solid in 86% yield (125.3 mg). 1 H NMR spectrum was in agreement with the reference. 5 1 H NMR (500 MHz, CDCl 3 ): δ 6.58 (d, J = 7.0 Hz, 1H), 7.20 (d, J = 7.0 Hz, 1H), 7.52 (ddd, J = 1.0, 7.0, 8.0 Hz, 1H), 7.57 (brd, J = 8.0 Hz, 1H), 7.68 (ddd, J = 1.4, 7.0, 8.1 Hz, 1H), 8.44 (m, 1H), (brs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 106.7, 126.1, 126.2, 126.8, 127.3, 127.7, 132.6, 138.2, EI-MS (% relative intensity): m/z: 145 (M+, 100), 118 (33), 90 (36), 63 (16). 2(3H)-Benzothiazolone (2s) Following the General Procedure (purification: AcEt/hexane = 1/3), the titled compound was HN S obtained as a white solid in 64% yield (29.0 mg). 1 H and 13 C NMR spectra were in agreement with the reference. 6 1 H NMR (500 MHz, CDCl 3 ): δ 7.11 (brd, J = 8.0 Hz, 1H), 7.16 (ddd, J = 1.0, 7.5, 8.0 Hz, 1H), (m, 1H), 7.40 (brd, J = 8.0 Hz, 1H), 8.81 (brs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 111.8, 122.6, 123.3, 123.9, 126.5, 135.4, EI-MS (% relative intensity): m/z: 151 (M+, 100), 123 (53), 96 (60), 69 (12), 63 (6). 5-Chloro-3-hydroxy-N,N-diisopropylthiophene-2-carboxamide (2t) H Cl S N i Pr 2 Following the General Procedure (The THF solution of the substrate was added to the solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at 78 ºC.; purification: AcEt/hexane = 1/10), the titled compound was obtained as a colorless oil in 81% (63.7 mg). 1 H NMR (400 MHz, CDCl 3 ): δ 1.40 (d, J = 5.4 Hz, 12H), 4.02 (brs, 2H), 6.66 (s, 1H), (s, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.0, 48.5 (br), 101.9, 119.7, 134.5, 165.6, IR (ATR-IR): 2972, 2931, 1584, 1550, 1458, 1369, 1343, 1253, 1145, 1083, 1026, 990, 874, 823, 748, 707, 657, 625, 580, 539 cm -1. HRMS (neg. ESI): m/z: calcd for C 11 H 16 ClN 2 S [M H] , found Anal.: Calcd: N, 5.06; C, 52.07; H, Found: N, 5.25; C, 50.49; H, Hydroxy-N,N-diisopropylbenzo[b]thiophene-2-carboxamide (2u) H S N i Pr 2 Following the General Proceedure (1 mmol scale; purification: AcEt/hexane = 1/49), the titled compound was obtained as a white solid in 81% (224.9 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.45 (d, J = 6.0 Hz, 12H), 4.25 (brs, 2H), 7.39 (ddd, J = 0.9, 7.0, 7.9 Hz, 1H), 7,46 (ddd, J = 1.2, 7.0, 8.2 Hz, 1H), 7.68 (ddd, J = 0.6, 0.9, 8.2 Hz, 1H), 7.97 (ddd, J = 0.9, 1.2, 9

10 7.9 Hz, 1H), (s, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 21.3, 48.5 (br), 101.3, 122.1, 122.9, 124.4, 128.3, 131.3, 137.1, 161.9, IR (ATR-IR): 3001, 2970, 2932, 2873, 1574, 1523, 1473, 1441, 1379, 1346, 1322, 1264, 1238, 1156, 1127, 1062, 1022, 930, 864, 784, 748, 734, 715, 638, 616, 546, 509 cm -1. mp: C (recrystallized from EtH). HRMS (pos. ESI): m/z: calcd for C 15 H 19 N 2 S [M+H] , found Anal.: Calcd: N, 5.05; C, 64.95; H, Found: N, 5.00; C, 64.89; H,

11 2.4. ortho Amination of Aromatics (Table 3) General Procedure: 2-Amino-N,N-diisopropylbenzamide (3a) H 1) (TMP) 2 Cu(CN)Li 2 (1.3 eq.) NH 2 THF, 0 C, 2 h N i Pr 2 2) BnNH 2 (2.0 eq.) rt, 1 h 1a 3a N i Pr 2 N,N-Diisopropylbenzamide 1a (205.5 mg, 1 mmol) and dry THF (1 ml) were added to a heat gun-dried Schlenk tube. The mixture was added to a solution of (TMP) 2 Cu(CN)Li 2 (1.3 mmol) via cannula at 78 ºC, and the resulting solution was stirred for 2 h at 0 ºC. To the mixture was added -benzylhydroxylamine (233 µl, 2.0 mmol) at 78 ºC, then stirred for 30 min at room temperature. The reaction was quenched with aqueous NH 4 Cl (10 ml) and aqueous Na 2 S 2 3 (10 ml), followed by extraction with AcEt (30 ml 3). The combined AcEt layers were dried over Na 2 S 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using AcEt/hexane (1/3) as an eluent to give the titled compound (3a) as a colorless solid in 93% yield (205.1 mg). 1 H and 13 C NMR spectra were in agreement with the reference. 7 1 H NMR (500 MHz, CDCl 3 ): δ 1.35 (brs, 12H), 3.74 (brs, 2H), 4.03 (brs, 2H), (m, 2H), 7.00 (dd, J = 1.5, 7.7 Hz, 1H), 7.12 (ddd, J = 1.5, 7.7, 7.8 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.9, 48.3 (br), 116.5, 117.6, 123.8, 125.9, 129.4, 144.4, EI-MS (% relative intensity): m/z: 220 (M+, 11), 120 (100), 100 (10), 92 (16), 65 (10). Unless otherwise noted, the reaction was performed on 0.3 mmol scale. 2-Amino-4-iodo-N,N-diisopropylbenzamide (3d) NH 2 Following the General Procedure (The THF solution of the substrate was added to the N i Pr 2 solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at 78 ºC.; purification: AcEt/hexane = 1/9), the titled compound was obtained as a white solid in I 84% yield (86.8 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.34 (brs, 12H), 3.71 (brs, 2H), ,06 (m, 2H), 6.70 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 1.5, 8.0 Hz, 1H), 7.08 (d, J = 1.5 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.9, 48.6 (br), 95.0, 123.1, 125.0, 126.6, 127.3, 145.7, IR (ATR-IR): 3422, 3332, 3231, 2971, 2929, 2869, 1737, 1717, 1594, 1581, 1561, 1455, 1406, 1378, 1369, 1345, 1210, 1187, 1154, 1135, 1033, 916, 863, 795, 619, 555, 542, 522 cm 1. mp: ºC (recrystallized from EtH). EI-MS (% relative intensity): m/z: 346 (M+, 8), 331 (4), 303 (7), 246 (100), 218 (7), 119 (8), 100 (11), 91 (8). HRMS (pos. ESI): m/z: calcd for C 13 H 20 IN 2 [M+H] , found Anal.: Calcd: C, 45.10; H, 5.53; N, Found: C, 45.40; H, 5.53; N, Amino-4-(trifluoromethyl)-N,N-diisopropylbenzamide (3e) F 3 C NH 2 N i Pr 2 Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 1/9 followed by further purification with a preparative TLC developed with toluene/acetone = 6/1), the titled compound was obtained as a white solid in 70% yield (203.1 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.35 (brs, 12H), 3.69 (brs, 2H), 4.20 (brs, 2H), 6.93 (s, 1H), 6.95 (d, 11

12 J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.8, 47.3 (br), 50.6 (br), (q, J = 3.8 Hz), 114.3, (q, J = Hz), 126.3, 126.6, (q, J = 31.3 Hz), 144.5, IR (ATR-IR): 3475, 3344, 3227, 2979, 2939, 2874, 1736, 1610, 1514, 1435, 1371, 1334, 1259, 1211, 1171, 1108, 1051, 1035, 928, 885, 804, 765, 744, 684, 666, 622, 563, 530 cm 1. mp: ºC (recrystallized from EtH). EI-MS (% relative intensity): m/z: 288 (M+, 7), 273 (4), 245 (6), 188 (100), 160 (18), 140 (5), 100 (6), 86 (14). HRMS (pos. ESI): m/z: calcd for C 14 H 20 F 3 N 2 3 [M+H] , found Anal.: Calcd: C, 58.32; H, 6.64; N, Found: C, 58.33; H, 6.63; N, Amino-N,N-diisopropyl-1-naphthamide (3g) NH 2 Following the General Procedure (1 mmol scale, the substrate was added as a solution in 5 ml N i Pr 2 of THF.; purification: AcEt/hexane = 1/3), the titled compound was obtained as a white solid in 76% yield (205.9 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.02 (d, J = 6.7 Hz 3H), 1.12 (d, J = 6.8 Hz 3H), 1.68 (d, J = 7.0 Hz 3H), 1.73 (d, J = 7.0 Hz 3H), 3.59 (sep, J = 6.8 Hz 1H), 3.69 (sep, J = 6.7 Hz 1H), 3.92 (brs, 2H), 6.93 (d, J = 8.5 Hz 1H), (m, 1H), 7.39 (ddd, J = 1.4, 6.9, 8.4 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 20.6, 20.9, 21.0, 21.6, 46.1, 51.3, 117.1, 118.5, 122.7, 122.9, 127.0, 127.6, 128.1, 129.1, 130.8, 140.2, IR (ATR-IR): 3432, 3323, 3221, 2969, 2932, 2872, 1739, 1594, 1513, 1447, 1371, 1334, 1286, 1263, 1211, 1122, 1047, 822, 746, 690, 616, 588, 532 cm 1. mp: ºC (recrystallized from EtH). EI-MS (% relative intensity): m/z: 270 (M+, 45), 170 (100), 143 (39), 115 (24), 100 (10). HRMS (pos. ESI): m/z: calcd for C 17 H 22 N 2 [M+H] , found Anal.: Calcd: C, 75.52; H, 8.20; N, Found: C, 75.59; H, 8.11; N, Amino-N,N-diethylbenzamide (3j) NH 2 Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 1/5), the titled NEt compound was obtained as a white solid in 92% yield (177.4 mg). 1 H and 13 2 C NMR were in agreement with the reference. 7 1 H NMR (500 MHz, CDCl 3 ): δ 1.19 (brs, 6H), 3.43 (brs, 4H), 4.16 (brs, 2H), (m, 2H), (m, 1H), 7.27 (ddd, J = 1.1, 7.1, 7.9 Hz 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 12.5 (br), 38.6 (br), 42.0 (br), 115.5, 116.5, 120.7, 125.9, 129.0, 143.8, EI-MS (% relative intensity): m/z: 192 (M+, 33), 121 (100), 92 (22), 72 (21), 65 (12). 2-Amino-4-tert-butylbenzonitrile (3k) t Bu NH 2 Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 2/9), the titled compound was obtained as a brown oil in 84% yield (146.1 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 1.27 (s, 9H), 4.34 (brs, 2H), 6.74 (d, J = 1.7 Hz, 1H), 6.79 (dd, J = 1.7, 8.5 Hz 1H), 7.20 (d, J = 8.5 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 30.8, 35.1, 93.3, 112.1, 116.0, 117.9, 132.0, 149.5, IR (ATR-IR): 3474, 3372, 3235, 2963, 2905, 2869, 2211, 1735, 1626, 1562, 1498, 1430, 1364, 1243, 1203, 1151, 1117, 1025, 942, 867, 807, 657, 523 cm 1. EI-MS (% relative intensity): m/z: 174 (M+, 43), 159 (100), 131 (40), 119 (26), 116 (6). HRMS (pos. ESI): m/z: calcd for C 11 H 14 N 2 [M+H] , found CN 3-Amino-4-methoxymethoxybiphenyl (3l) Ph NH 2 Following the General Procedure (1 mmol scale; purification: acetone/toluene = 1/50), the mixture of titled compound and 4-phenyl phenol (1 : ) was obtained as a yellow oil in 81% yield (189.6 mg). 1 H NMR (500 MHz, CDCl 3 ): δ 3.53 (s, 3H), 3.89 (brs, 2H), 12

13 5.24 (s, 2H), (m, 1H), 6.98 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.30 (m, 1H), (m, 2H), 7.53 (d, J = 8.0 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ): δ 56.2, 95.2, 114.3, 115.0, 117.4, 126.7, 126.9, 128.6, 135.8, 137.0, 141.2, IR (ATR-IR): 3461, 3371, 3031, 2951, 2899, 2825, 1738, 1614, 1520, 1488, 1422, 1315, 1241, 1188, 1141, 1075, 1041, 988, 920, 864, 808, 758, 697, 651, 586 cm 1. EI-MS (% relative intensity): m/z: 229 (M+, 39), 198 (56), 184 (71), 156 (54), 128 (16), 115 (7). HRMS (pos. ESI): m/z: calcd for C 14 H 15 N 2 [M+H] , found Amino-4-methoxybiphenyl (3m) NH 2 Me Ph Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 1/3), the titled compound was obtained as a brown solid in 86% yield (171.6 mg). 1 H NMR (500 MHz, CDCl 3 ): δ (m, 5H), 6.85 (dd, J = 2.2, 8.3 Hz, 1H), (m, 2H), 7.28 (tt, J = 1.3, 7.5 Hz, 1H), (m, 2H), 7.53 (dd, J = 1.3, 8.5 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ): δ 55.6, 110.6, 113.8, 117.2, 126.6, 126.8, 128.6, 134.4, 136.3, 141.3, IR (ATR-IR): 3438, 3350, 3061, 3035, 2995, 2967, 2946, 2838, 1736, 1608, 1520, 1488, 1460, 1424, 1373, 1364, 1298, 1243, 1212, 1179, 1158, 1045, 1017, 866, 809, 758, 696, 643, 599, 520 cm 1. mp: ºC (recrystallized from CH 2 Cl 2 ). 8 EI-MS (% relative intensity): m/z: 199 (M+, 74), 184 (100), 156 (65), 128 (16), 115 (7), 77 (6). HRMS (pos. ESI): m/z: calcd for C 13 H 13 N [M+H] , found (2-Aminophenyl)dicyclohexylphosphine oxide (3n) NH 2 P Cy Cy Following the General Procedure (0.45 mmol of (TMP) 2 Cu(CN)Li 2 was used.; purification: AcEt/hexane = 10/9), the titled compound was obtained as a white foam in 94% yield (86.3 mg). 1 H NMR (400 MHz, CDCl 3 ): δ (m, 10H), (m, 6H), (m, 2H), (m, 4H), 5.61 (brs, 2H), (m, 2H), 6.92 (ddd, J = 1.2, 7.7, 13.4 Hz, 1H), 7.20 (m, 1 H). 13 C NMR (100 MHz, CDCl 3 ): δ 24.4 (d, J C P = 2.9 Hz), 25.4 (d, J C P = 2.2 Hz), 25.9, 26.3 (d, J C P = 5.1 Hz), 26.5 (d, J C P = 5.9 Hz), 36.0 (d, J C P = 67.5 Hz), (d, J C P = 86.6 Hz), (d, J C P = 11.0 Hz), (d, J C P = 7.3 Hz), (d, J C P = 9.5 Hz), (d, J C P = 2.2 Hz), (d, J C P = 2.2 Hz). IR (ATR-IR): 3406, 3384, 3309, 3199, 2927, 2852, 1611, 1484, 1448, 1326, 1136, 1111, 747, 570, 533 cm -1. HRMS (pos. ESI): m/z: calcd for C 18 H 28 NP [M+H] , found Anal.: Calcd: N, 4.59; C, 70.79; H, Found: N, 4.44; C, 70.28; H, tert-butyl 2-aminobenzoate (3o) NH 2 t Bu Following the General Procedure (purification: CH 2 Cl 2 /hexane = 1/9), the titled compound was obtained as a brown oil in 79% yield (151.9 mg). 1 H and 13 C NMR spectra were in agreement with the reference. 9 1 H NMR (500 MHz, CDCl 3 ): δ 1.58 (s, 9H), 5.68 (brs, 2H), (m, 2H), 7.22 (ddd, J = 1.5, 7.0, 8.3 Hz, 1H), (m, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 28.4, 80.6, 112.6, 116.1, 116.7, 131.5, 133.6, 150.3, EI-MS (% relative intensity): m/z: 193 (M+, 15), 137 (62), 119 (100), 92 (23), 65 (12), 56 (5). 13

14 Isoquinolin-1-amine (3r) NH 2 N Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 5/1 with 1% Et 3 N), the titled compound was obtained as a yellow solid in 87% yield (126.4 mg). 1 H and 13 C NMR spectra were in agreement with the reference H NMR (500 MHz, CDCl 3 ): δ 5.12 (brs, 2H), 7.06 (d, J = 5.5 Hz, 1H), 7.50 (ddd, J = 1.3, 7.0, 8.3 Hz, 1H), 7.63 (ddd, J = 1.1, 7.0, 8.2 Hz, 1H), 7.72 (apparent brd, J = 8.2 Hz, 1H), 7.80 (m, 1H), 7.96 (m, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 112.7, 117.8, 122.6, 126.1, 127.1, 130.1, 137.4, 141.3, EI-MS (% relative intensity): m/z: 144 (M+, 100), 117 (47), 89 (18), 63 (7). 3-Amino-5-chloro-N,N-diisopropylthiophene-2-carboxamide (3t) NH 2 Cl S N i Pr 2 Following the General Procedure (The THF solution of the substrate was added to the solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at 78 ºC.; purification: AcEt/hexane = 1/3), the titled compound was obtained as a white solid in 68% yield (53.4 mg). 1 H NMR (400 MHz, CDCl 3 ): δ 1.37 (d, J = 6.9 Hz, 12H), 4.04 (brs, 2H), 5.24 (brd, 2H), 6.44 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.4, 48.4, 103.0, 120.4, 132.1, 151.2, IR (ATR-IR): 3446, 3341, 3230, 3083, 2968, 2932, 1582, 1538, 1441, 1419, 1368, 1334, 1213, 1162, 1114, 1068, 1028, 984, 823, 748, 707, 623, 548 cm -1. mp: C (recrystallized from CH 2 Cl 2 /hexane). HRMS (pos. ESI): m/z: calcd for C 11 H 17 ClN 2 S [M+Na] , found Anal.: Calcd: N, 10.74; C, 50.66; H, Found: N, 10.64; C, 50.65; H, Amino-N,N-diisopropyl-5-phenylfuran-2-carboxamide (3v) NH 2 Ph N i Pr 2 Following the General Procedure (The THF solution of the substrate was added to the solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at 78 ºC.; purification: AcEt/CH 2 Cl 2 = 1/30), the titled compound was obtained as a brown solid in 46% yield (39.7 mg). 1 H NMR (400 MHz, CDCl 3 ): δ 1.44 (d, J = 6.6 Hz, 12H), 4.26 (brs, 2H), 4.78 (brs, 2H), 6.38 (s, 1H), 7.31 (dd, J = 7.3, 7.6 Hz, 1H), 7.39 (dd, J = 7.3, 7.6 Hz, 2H), 7.61 (brd, J = 7.3 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.5, 47.4 (br), 100.7, 124.2, 128.4, 128.8, 128.9, 130.1, 144.3, 152.2, IR (ATR-IR): 3460, 3448, 3334, 2967, 2930, 2870, 1624, 1602, 1477, 1349, 1151, 1033, 930, 910, 828, 800, 763, 690, 643, 623 cm -1. mp: C (recrystallized from Et 2 /hexane). HRMS (pos. ESI): m/z: calcd for C 17 H 23 N 2 2 [M+H] , found Anal.: Calcd: N, 9.78; C, 71.30; H, Found: N, 9.74; C, 71.36; H, Amino-N,N-diisopropyl-1-methyl-1H-indole-2-carboxamide (3w) NH 2 N N i Pr 2 Following the General Procedure (purification: AcEt/hexane = 1/1), the titled compound was obtained as a brown solid in 69% yield (61.1 mg). 1 H NMR (400 MHz, CDCl 3 ): δ 1.40 (d, J = 6.6 Hz, 12H), 3.53 (s, 3H), 4.02 (sep, J = 6.6 Hz, 2H), 4.95 (brs, 2H), (m, 3H), (d, J = 7.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 22.0, 27.9, 47.8, 91.9, 107.9, 117.2, 118.8, 120.3, 125.8, 133.0, 149.1, IR (ATR-IR): 3422, 3309, 3208, 3050, 2965, 2931, 2875, 14

15 1579, 1473, 1438, 1364, 1308, 1247, 1207, 1154, 1132, 1098, 1040, 909, 838, 778, 732, 669, 615, 559 cm -1. mp: C (recrystallized from CH 2 Cl 2 /hexane). HRMS (pos. ESI): m/z: calcd for C 16 H 23 N 3 [M+Na] , found Anal.: Calcd: N, 15.37; C, 70.30; H, Found: N, 15.23; C, 70.21; H, Amino-N,N-diisopropyl-1-methyl-1H-indole-3-carboxamide (3x) N i Pr 2 NH 2 N Following the General Procedure (purification: AcEt/hexane = 1/1), the titled compound was obtained as a brown liquid in 69% yield (61.1 mg). 1 H NMR (400 MHz, CDCl 3 ): δ 1.36 (d, J = 6.4 Hz, 6H), 1.44 (d, J = 6.4 Hz, 6H), 3.29 (brs, 2H), 3.63 (s, 3H), 3.88 (sep, J = 6.6 Hz, 2H), (m, 1H), (m, 2H), 7.49 (d, J = 7.8 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.3, 30.7, 48.5, 109.4, 118.1, 118.5, 120.4, 120.9, 121.8, 123.0, 136.0, IR (ATR-IR): 3328, 2966, 2931, 2876, 1607, 1448, 1366, 1340, 1303, 1251, 1209, 1151, 1132, 1035, 923, 735, 611 cm -1. HRMS (pos. ESI): m/z: calcd for C 16 H 23 N 3 [M+H] , found Amino-N,N-diisopropyl-ferrocene-2-carboxamide (3y) N i Pr 2 NH 2 Fe Following the General Procedure (1 mmol scale, The THF solution of the substrate was added to the solution of (TMP) 2 Cu(CN)Li 2 at 78 C, and the resulting solution was stirred for 2 h at 78 ºC.; purification: AcEt/hexane = 3/4), the titled compound was obtained as a brown solid in 63% yield (206.3 mg). 1 H and 13 C NMR spectra were in agreement with the reference H NMR (400 MHz, CDCl 3 ): δ 1.42 (brs, 12H), 3.49 (brs, 1H), 3.75 (s, 2H), 3.90 (dd, J = 2.5, 2.7 Hz, 1H), 4.08 (m, 1H), 4.12 (m, 5H), 4.18 (m, 1H), 4.61 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.1, 21.5, 46.7 (br), 49.2 (br) 58.7, 62.4, 62.5, 67.0, 70.6, 111.2, IR (ATR-IR): 3427, 3378, 3326, 3095, 2997, 2964, 2933, 2874, 1575, 1458, 1430, 1367, 1332, 1268, 1200, 1161, 1136, 1101, 1034, 997, 813, 797, 766, 679, 619, 561, 524 cm -1. mp: C. HRMS (pos. ESI): m/z: calcd for C 17 H 24 FeN 2 [M] , found Anal.: Calcd: N, 8.57; C, 62.21; H, Found: N, 8.42; C, 61.92; H,

16 2.5. Catalytic ortho Hydroxylation of Aromatics (Table 4) General Procedure: 2-hydroxy-N,N-diisopropylbenzamide (3a) H 1) t Bu 2 Zn(TMP)Li (2.0 eq.) THF, rt, 3 h H 1a N i Pr 2 2) CuCN (10 mol%), TBHP (2.0 eq.) 40 C, 30 min 2a N i Pr 2 N,N-Diisopropylbenzamide 1a (205.3 mg, 1 mmol) and dry THF (1 ml) were added to a heat gun-dried Schlenk tube. The mixture was added to a solution of t Bu 2 Zn(TMP)Li (2.0 mmol) via cannula at room temperature, and the resulting solution was stirred for 3 h at room temperature. To the mixture was added CuCN (9.0 mg, 0.1 mmol) before addition of t BuH (364 µl, 2.0 mmol; 5.5 M decane solution) at room temperature, then the resultant mixture was stirred for 30 min at 40 C. The reaction was quenched with aqueous NH 4 Cl (10 ml) and aqueous Na 2 S 2 3 (10 ml), followed by extraction with AcEt (30 ml 3). The combined organic layer was dried over Na 2 S 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using AcEt/hexane (1/3) as an eluent to give the titled compound (3a) as a colorless solid in 66% yield (146.5 mg). 2-Hydroxy-4-(trifluoromethyl)-N,N-diisopropylbenzamide (2e) H Following the General Procedure (1 mmol scale; purification: MeH/CH 2 Cl 2 = 1/50), the N i Pr 2 titled compound was obtained as a white solid in 63% yield (182.9 mg). F 3 C 1(2H)-Isoquinolinone (2r) NH Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 2/1), the titled compound was obtained as a white solid in 66% yield (94.9 mg). 2(3H)-Benzothiazolone (2s) HN S Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 1/3), the titled compound was obtained as a white solid in 53% yield (77.9 mg). 16

17 2.6. Catalytic ortho Amination of Aromatics (Table 4) General Procedure: 2-Amino-N,N-diisopropylbenzamide (3a) H 1) t Bu 2 Zn(TMP)Li (2.0 eq.) THF, rt, 3 h N i Pr 2 NH 2 2) CuCN (10 mol%), 1a BnNH 2 (2.0 eq.) rt, 1 h 3a N i Pr 2 N,N-Diisopropylbenzamide 1a (205.4 mg, 1 mmol) and dry THF (1 ml) were added to a heat gun-dried Schlenk tube. The mixture was added to a solution of t Bu 2 Zn(TMP)Li (2.0 mmol) via cannula at room temperature, and the resulting solution was stirred for 3 h at room temperature. To the mixture was added CuCN (9.0 mg, 0.1 mmol) before -benzylhydroxylamine (233 µl, 2.0 mmol) at room temperature, then the resultant mixture was stirred for 1 h at room temperature. The reaction was quenched with aqueous NH 4 Cl (10 ml) and aqueous Na 2 S 2 3 (10 ml), followed by extraction with AcEt (30 ml 3). The combined organic layer was dried over Na 2 S 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using AcEt/hexane (1/3) as an eluent to give the titled compound (3a) as a colorless solid in 62% yield (136.5 mg). 2-Amino-4-(trifluoromethyl)-N,N-diisopropylbenzamide (3e) F 3 C NH 2 N i Pr 2 Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 1/9 followed by further purification with a preparative TLC by toluene/acetone = 6/1), the titled compound was obtained as a white solid in 67% yield (194.1 mg). Isoquinolin-1-amine (3r) NH 2 N Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 5/1 with 1% Et 3 N), the titled compound was obtained as a yellow solid in 71% yield (102.2 mg). Benzo[d]thiazol-2-amine (3s) NH 2 N S Following the General Procedure (1 mmol scale; purification: AcEt/hexane = 1/1, then triturated in hexane), the titled compound was obtained as a yellow solid in 56% yield (83.5 mg). 1 H and 13 C NMR spectra were in agreement with the reference H NMR (400 MHz, CDCl 3 ): δ 5.24 (brs, 2H), 7.14 (dd, J = 1.0, 7.8 Hz, 1H), 7.32 (dd, J = 1.0, 7.8 Hz, 1H), 7,56 (d, J =7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 119.4, 120.9, 122.4, 126.0, 131.7, 152.1, IR (ATR-IR): 3392, 3269, 3055, 3032, 2925, 2728, 1738, 1636, 1522, 1442, 1367, 1306, 1281, 1103, 919, 887, 740, 717, 685, 623, 561 cm -1. mp: C (recrystallized from AcEt/hexane). HRMS (pos. ESI): m/z: calcd for C 7 H 6 N 2 S [M+H] , found Anal.: Calcd: N, 18.65; C, 55.98; H, Found: N, 18.35; C, 56.09; H,

18 3. Computational Details All calculations were carried with the Gaussian 09 program package 1 with the help of the development version of the GRRM (The Global Reaction Route Mapping, version 1.22) program 2,3 utilizing the energies and energy derivatives from Gaussian 09. The molecular structures and harmonic vibrational frequencies were obtained using the hybrid density functional method based on M06 functional 4. We used Ahlrichs' SVP 5 all electron basis set for Cu atom and 6 31+G* for the other atoms. Geometry optimization and vibrational analysis were performed at the same level. All stationary points were optimized without any symmetry assumptions, and characterized by normal coordinate analysis at the same level of theory (number of imaginary frequencies, NIMAG, 0 for minima and 1 for TSs). The intrinsic reaction coordinate (IRC) method was used to track minimum energy paths from transition structures to the corresponding local minima xidation of Aryl-Cu-ate (Scheme 1) Energy Profile for xidation of Lipshutz-type Aryl-Cu-ate ArCu(CN)( t Bu)Li 2 (Ar = [2-[[dimethylamino]carbonyl]phenyl]-) with Methyl hydroperoxide (M06 / 6-31+G* & SVP (Cu); energy: kcal/mol) H NMe 2 (R 2 N) 2 Cu(CN)Li 2 R 2 N-H Li R 2 N Cu N C Li MeH R 2 N-H RT Directed ortho Cupration NMe 2 IM1 Ligand Exchange N N Li C Li C Me Li ΔE = 25.4 Li Me ΔE = 12.9 Me I Cu III ΔE = 6.8 Cu ΔE = 92.7 NMe 2 NMe 2 N Li C I Li Cu 0.78 NMe 2 IM2 xidative Addition IM3 Reductive Elimination IM4 IM2 Me Li Cu I N C Li NMe 2 Energy (RB3LYP) = A.U Li Li

19 C N Cu C C C C C C C N C C H H H H H H H H H H C H H H TS1 (between IM2 and IM3) Me Li Cu N C Li NMe 2 Energy (RB3LYP) = Li Li C N Cu C C C C C C C

20 N C C H H H H H H H H H H C H H H IM3 Me N Li C Li Cu III NMe 2 Energy (RB3LYP) = A.U Li Li C N Cu C C C C C C C N C C H H H H H H