Regioselective Pd-Catalyzed Aerobic Aza-Wacker Cyclization for. Preparation of Isoindolinones and Isoquinolin-1(2H)-ones

Transcription

1 Supporting Information Regioselective Pd-Catalyzed Aerobic Aza-Wacker Cyclization for Preparation of Isoindolinones and Isoquinolin-1(2H)-ones Guoqiang Yang and Wanbin Zhang* School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai , P. R. China. Fax: ; Tel: ; Table of Contents 1 General Details p. S2 2 Preparation of Starting Materials p. S2 3 Palladium Catalyzed Aza-Wacker Cyclizations p. S16 4 References p. S30 5 Spectra of ew Products p. S31 1

2 1. General Details All reactions were performed in flame-dried glassware under an atmosphere of dry nitrogen, and the workup was carried out in air, unless otherwise noted. thanol was dried and distilled from metal magnesium. Toluene, dichloromethane (CH 2 Cl 2 ), diisopropylamine (DIPA), triethylamine (Et 3 ) and,-dimethylformamide (DMF) were dried and distilled from calcium hydride. Tetrahydrofuran (THF) and 1.4-dioxane were dried and distilled from metal sodium and benzophenone. Column chromatographic purification of products was carried out using silica gel 60 (200~300 mesh). The reagents were used without further purification. The MR spectra were recorded on a Varian MERCURY plus-400 (400 MHz, 1 H; 100 MHz, 13 C) spectrometer with chemical shifts reported in ppm relative to the residual deuterated solvent, the internal standard tetramethylsilane. Mass spectrometry analysis was carried out using an electrospray spectrometer Waters 4 micro quadrupole. lting points were measured with SGW X-4 micro melting point apparatus. 2. Preparation of Starting Materials General Procedure A: Preparation of,-diisopropylbenzamide derivatives (According to the method of Faigla and Volk 1 ) 4-thyl-,-diisopropylbenzamide (S1). 2 A mixture of diisopropylamine (13.4 ml, 9.68 g, 96.0 mmol, 1.5 equiv) and triethylamine (13.4 ml, 9.72 g, 96.0 mmol, 1.5 equiv) was added to a solution of 4-methylbenzoyl chloride (9.89 g, 64.0 mmol, 1.0 equiv) (prepared from 4-methylbenzoic acid) in dry toluene (120 ml). After stirring for 24 h at ambient temperature, toluene (25 ml) and water (40 ml) were added. The organic layer was separated, washed with an aq HCl solution (1, 30 ml) and brine (30 ml), dried over MgS 4, and evaporated. The residue was triturated with hexane (20 ml), and the crystalline product was collected by filtration to give 4-methyl-,-diisopropylbenzamide (11.2 g, 80%) as colorless crystals. 1 H MR (400 MHz, CDCl 3 ): δ = 7.21~7.15 (m, 4H), 3.69 (br, 2H), 2.36 (s, 3H), 1.35 (br, 12H); 13 C MR (100 MHz, CDCl 3 ): δ = 171.4, 138.7, 136.3, 129.2, 125.8, 50.8 (br), 46.3 (br), 21.5,

3 S2 3-thyl-,-diisopropylbenzamide (S2). 77% yield, colorless crystals. Mp: 59~60 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.25 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 3.83 (br, 1H), 3.51 (br, 1H), 2.35 (s, 3H), 1.50 (br, 6H), 1.13 (br, 6H); 13 C MR (100 MHz, CDCl 3 ): δ = 171.4, 139.1, 138.4, 129.5, 128.4, 126.4, 122.6, 51.0 (br), 46.0 (br), 21.6, 20.9; HRMS (ESI) calcd for C 14 H 22 [M+H] , found General Procedure B: Preparation of,-diisopropyl-2-formylbenzamide derivatives (According to the method of Faigla and Volk 1 ) 4-thyl-,-diisopropyl-2-formylbenzamide (S3). Butyllithium (15.0 ml of a 2.5 M solution in hexane, 37.5 mmol, 1.2 equiv) was added to a solution of S1 (6.80 g, 31.0 mmol, 1.0 equiv) in THF (72 ml) at -78 C. After stirring for 1 h at -78 C, DMF (3.1 ml, 2.95 g, 40.3 mmol, 1.3 equiv) was added, while the temperature of the mixture rose to -50 C. After warming to ambient temperature, the reaction mixture was diluted with a saturated aq H 4 Cl (70 ml) and extracted with ethyl acetate (70 ml and 2 30 ml). The organic layer was washed with brine (50 ml), dried over MgS 4, and evaporated. The residue was triturated with a mixture of hexane (24 ml) and ethyl acetate (2 ml). The crystalline product was collected by filtration to give 6.21 g (85%) of S3 as colorless crystals. Mp: 85~86 o C; 1 H MR (400 MHz, CDCl 3 ): δ = (s, 1H), 7.73 (d, J = 0.8 Hz, 1H), 7.43~7.41 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 3.64~3.54 (m, 1H), 3.58~3.48 (m, 1H), 2.43 (s, 3H), 1.59 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H); 13 C MR (100 MHz, CDCl 3 ): δ = 190.9, 168.7, , 138.8, 135.1, 132.4, 130.0, 126.1, 51.4, 46.3, 21.2, 20.7, 20.6; HRMS (ESI) calcd for C 16 H 22 2 [M+H] , found S4 S5 3

4 5-thyl-,-diisopropyl-2-formylbenzamide (S4) and 3-thyl-,-diisopropyl-2-formylbenzamide (S5). (S5:S4 = 1.0:0.3). From S2, total 81% yield, a white solid. Since these two compounds could not be separated by column chromatography, the mixture was used for the next step. S4: 1 H MR (400 MHz, CDCl 3 ): δ = (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 3.65~3.48 (m, 2H), 2.43 (s, 3H), 1.59 (d, J = 7.6 Hz, 6H), 1.09 (d, J = 6.4 Hz, 6H); 13 C MR (100 MHz, CDCl 3 ): δ = 190.4, 168.7, 141.4, 130.4, 130.1, 130.1, 129.7, 126.7, 51.4, 46.3, 22.1, 20.6, S5: 1 H MR (400 MHz, CDCl 3 ): δ = (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 3.65~3.48 (m, 2H), 2.66 (s, 3H), 1.59 (d, J = 7.6 Hz, 6H), 1.10 (d, J = 6.4 Hz, 6H); 13 C MR (100 MHz, CDCl 3 ): δ = 191.8, 169.4, 145.8, 142.9, 141.5, 133.6, 131.9, 123.9, 51.4, 46.2, 20.8, 20.6, HRMS (ESI) calcd for C 16 H 22 2 [M+H] , found General Procedure C: Preparation of 3-hydroxyisobenzofuran-1(3H)-one derivatives (According to the method of Snider 3 ) S6 H 3-Hydroxy-5-methylisobenzofuran-1(3H)-one (S6). 4 A solution of S3 (2.00 g, 8.09 mmol) in 17 ml of 4.0 M aq HCl solution and 17 ml of AcH was stirred at reflux for 1 d and cooled to room temperature. Removal of the solvent under vacuum gave a brown residue that was extracted with EtAc (3 15 ml). The combined EtAc layers were extracted with saturated aqueous ahc 3 solution (3 10 ml). The combined base phase was acidified by concentrated HCl forming a white precipitate. Removal of the solvent by filtration gave crude S6 (1.07 g, 80%) as a white solid which was used directly for the next step. S7 H + H S8 3-Hydroxy-6-methylisobenzofuran-1(3H)-one (S7) and 3-hydroxy-4-methylisobenzofuran-1(3H)-one (S8). From S4 and S5, total 62% yield, a white solid. The mixture was used directly for the next step. 3-Hydroxy-5-chloroisobenzofuran-1(3H)-one (S9). 5 From 4-chloro-,-diisopropyl-2-formylbenzamide 1, 70% 4

5 yield, a white solid. S9 was used directly for the next step. General Procedure D: Preparation of 2-vinylbenzoic acid derivatives H S10 2-(Prop-1-enyl)benzoic acid (S10). 6 To a suspension of potassium t-butoxide (4.15 g, 37.0 mmol, 3.7 equiv) in THF (50 ml) was added EtPPh 3 Br (13.7 g, 37.0 mmol, 3.7 equiv) and the mixture was stirred at 0 C for 10 min. The resulting orange suspension was warmed to room temperature and stirred for an additional 2 h. The reaction mixture was cooled to 0 C and subjected to add 3-hydroxyisobenzofuran-1(3H)-one in one portion (1.50 g, 10.0 mmol, 1.0 equiv). The mixture was warmed to room temperature and stirred for 1 d, then quenched with saturated aq H 4 Cl (50 ml). The organic layer was separated and the aqueous layer was extracted with EtAc (2 50 ml). The combined organic layers were dried over a 2 S 4, filtered, and concentrated in vacuo. Then purification by flash column chromatography on silica gel (petroleum ether/ethyl acetate 10/1) afforded the 2-(prop-1-enyl)benzoic acid (E:Z = 10:1) as colorless crystals (1.34 g, 83% yield). 4-thyl-2-(prop-1-enyl)benzoic acid (S11). From S6, 99% yield, colorless crystals (E:Z = 5:1). Mp: 121~123 o C; 1 H MR (400 MHz, CDCl 3 ): (E): δ = 7.92 (d, J = 7.6 Hz, 1H), 7.35 (s, 1H), 7.28 (dq, J = 8.0, 2.0 Hz, 1H), 7.10 (dd, J = 8.0, 0.8 Hz, 1H), 6.16 (dq, J = 15.8, 6.8 Hz, 1H), 2.39 (s, 3H), 1.93 (dd, J = 6.8, 2.0 Hz, 3H); (Z): δ = 8.00 (d, J = 8.4 Hz, 1H), 7.17~7.13 (m, 2H), 6.94 (dq, J = 11.6, 1.6 Hz, 1H), 5.85 (dq, J = 11.6, 7.2 Hz, 1H), 2.41 (s, 3H), 1.76 (dd, J = 7.2, 1.6 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): (E): δ = 173.4, 143.8, 141.1, 131.8, 130.3, 128.9, 128.4, 127.7, 124.1, 21.8, (Z): δ = 173.5, 143.4, 140.1, 132.0, 131.9, 130.2, 127.7, 126.2, 125.4, 21.9, 14.6; HRMS (ESI) calcd for C 11 H 11 2 [M H] , found thyl-2-(prop-1-enyl)benzoic acid (S12) and 3-thyl-2-(prop-1-enyl)benzoic acid (S13). Form S7 and S8, total 76% yield (S12:S13 = 1:3). S12 and S13 were separated by column chromatography on silica gel (petroleum 5

6 ether/ethyl acetate 50/1 to 20/1). S12: colorless crystals (E:Z = 11:4). Mp: 56~58 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.91 (Z)(d, J = 1.2 Hz, 1H), 7.81 (E)(d, J = 1.2 Hz, 1H), 7.45 (E)(d, J = 8.4 Hz, 1H), 7.34 (Z)(dd, J = 8.4, 1.2 Hz, 1H), 7.30 (E)(dd, J = 8.4, 1.2 Hz, 1H), 7.26~7.20 (E)(m, 1H), 7.26~7.20 (Z)(m, 1H), 6.91 (Z)(dd, J = 11.2, 1.6 Hz, 1H ), 6.14 (E)(dq, J = 15.4, 6.8 Hz, 1H), 5.84 (Z)(dq, J = 11.2, 7.0 Hz, 1H), 2.40 (Z)(s, 3H), 2.37 (E)(s, 3H), 1.92 (E)(dd, J = 6.8, 1.8 Hz, 3H), 1.76 (Z)(dd, J = 7.0, 1.8 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 173.9, 173.5, 138.1, 136.9, 136.7, 136.6, 134.0, 133.4, 132.1, 131.8, 131.3, 129.8, 129.8, 128.3, 128.1, 127.6, 126.7, 126.2, 21.2, 21.1, 19.0, 14.6; HRMS (ESI) calcd for C 11 H 11 2 [M H] , found S13: 7 a white solid (E:Z = 5:1). H Cl S14 4-Chloro-2-(prop-1-enyl)benzoic acid (S14). From S9, 89% yield, a white solid. Mp: 124~126 o C; 1 H MR (400 MHz, CDCl 3 ): (E): δ = 7.96 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.0, 2.0 Hz, 1H), 7.24 (dq, J = 15.6, 1.6 Hz, 1H), 6.21 (dq, J = 15.6, 6.8 Hz, 1H), 1.56 (dd, J = 6.8, 2.0 Hz, 3H); (Z): δ = 7.96 (d, J = 9.2 Hz, 1H), 7.34~7.31 (m, 2H), 6.89 (dq, J = 11.6, 1.6 Hz, 1H), 5.91 (dq, J = 11.6, 7.2 Hz, 1H), 1.78 (dd, J = 7.2, 1.6 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): (E): δ = 172.8, 142.8, 139.6, 133.1, 130.8, 129.0, 127.7, 126.9, 125.0, 19.0; (Z): δ = 172.4, 141.7, 139.1, 133.2, 131.2, 128.9, 127.1, 126.5, 120.8, 14.5; HRMS (ESI) calcd for C 10 H 8 Cl 2 [M H] , found (E)-4-thoxy-2-(prop-1-enyl)benzoic acid (S15). A solution of the (E)-1-bromo-4-methoxy-2-(prop-1- enyl)benzene 8 (611 mg, 2.69 mmol, 1.0 equiv) in anhydrous Et 2 (2 ml) was treated dropwise with n-buli (2.5 M in hexane, 1.40 ml, 3.50 mmol, 1.3 equiv) at 0 C. After 30 min, the lithiated mixture was poured onto dry ice and stirred for 30 min. The mixture was allowed to warm to room temperature and stirred for an additional 1 h. The reaction was quenched with saturated aq ahc 3 (20 ml) and washed with Et 2 (2 20 ml). The aqueous layer was then acidified with 2 HCl to ph 1 and extracted with Et 2 (3 20 ml). The combined organic layers were dried over a 2 S 4, filtered, and concentrated under reduced pressure to furnish S14 as a white solid (320 mg, 62% 6

7 yield). Mp: 139~140 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.03 (d, J = 8.8 Hz, 1H), 7.34 (dq, J = 15.6, 1.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 6.15 (dq, J = 16.0, 6.8 Hz, 1H), 3.88 (s, 3H), 1.94 (dd, J = 6.8, 1.6 Hz, 3H); 13 C MR (100 MHz, D 6 -Acetone): δ = 167.8, 162.8, 142.5, 133.3, 130.4, 128.1, 120.5, 112.4, 111.9, 55.1, 18.2; HRMS (ESI) calcd for C 11 H 11 3 [M H] , found (E)-4-Chloro-2-(prop-1-enyl)benzoic acid (S16). According to a similar method of Kaufman, 8 (E)-2-bromo-4-chloro-1-(prop-1-enyl)benzene was prepared from 2-bromo-4-chlorobenzaldehyde 9 in 85% yield, as a colorless oil. 1 H MR (400 MHz, CDCl 3 ): 7.53 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H), 6.66 (dq, J = 16.0, 1.6 Hz, 1H), 6.17 (dq, J = 11.6, 6.8 Hz, 1H), 1.92 (dd, J = 6.8, 2.0 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 136.5, 133.0, 132.5, 129.7, 129.1, 127.9, 127.6, 123.2, Then S16 was prepared analogously to S14 starting from (E)-2-bromo-4-chloro-1-(prop-1-enyl)benzene. 73% yield, a white solid. Mp: 82~84 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.98 (d, J = 2.4 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.20 (dt, J = 8.0, 1.6 Hz, 1H), 6.18 (dt, J = 8.0, 6.6 Hz, 1H), 1.94 (dd, J = 6.6, 1.6 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): δ = 172.4, 139.4, 133.2, 132.7, 132.6, 131.2, 130.2, 129.1, 128.9, 19.1; HRMS (ESI) calcd for C 10 H 8 Cl 2 [M H] , found H (E)-S10 (E)-2-(Prop-1-enyl)benzoic acid ((E)-S10). 6 (E)-S10 could be prepared analogously to S14 starting from (E)-2-bromo-1-(prop-1-enyl)benzene 10 in 76% yield. H S17 Bn (E)-2-(3-Phenylprop-1-enyl)benzoic acid (S17). From phenethyltriphenylphosphonium bromide and 3-hydroxyisobenzofuran-1(3H)-one, S17 could be obtained according to general procedure D after recrystallization from EtAc/hexane. 64% yield, a white solid. Mp: 75~77 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.03 (dd, J = 8.0, 1.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (td, J = 7.6, 1.2 Hz, 1H), 7.38~7.28 (m, 6H), 7.24~7.20 (m, 1H),

8 (dt, J = 15.6, 7.2 Hz, 1H), 3.62 (d, J = 7.2 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): δ = 173.2, 140.6, 140.3, 133.2, 132.6, 131.6, 130.3, 129.0, 127.9, 127.2, 127.1, 126.4, 39.8; HRMS (ESI) calcd for C 16 H 13 2 [M H] , found General Procedure E: Preparation of 1a~1p and 1r. HPh 1a (E)--Phenyl-2-(prop-1-enyl)benzamide (1a). Thionyl chloride (2.24 ml, 30.8 mmol, 5.0 equiv) was added to a solution of (E)-S10 (1.00 g, 6.17 mmol, 1.0 equiv) and DMF (5 μl, cat.) in 10 ml of dry CH 2 Cl 2 under 0 o C. The mixture was heated at reflux for 5 h after which the excess thionyl chloride and CH 2 Cl 2 were removed in vacuo. The (E)-2-(prop-1-enyl)benzoyl chloride formed was dissolved in 20 ml of dry CH 2 Cl 2, cooled to 0 o C and then added aniline (0.68 ml, g, 7.40 mmol, 1.2 equiv). After 5 min, triethylamine (2.58 ml, 1.87 g, 18.5 mmol, 3.0 equiv) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The mixture was diluted with 20 ml of CH 2 Cl 2 and extracted with 3 M HCl (3 15 ml), water (1 15 ml), brine (1 15 ml) and the organic layer was dried over anhydrous MgS 4. The solvent was removed by rotary evaporation. Then purification by flash column chromatography on silica gel (petroleum ether/ethyl acetate 30/1 to 15/1) afforded the (E)--phenyl-2-(prop-1-enyl)benzamide (1a) as a white solid (1.35 g, 92%). When a mixture of (Z+E)-2-vinylbenzoic acid derivative was used, the pure (E) product was obtained by recrystallization from EtAc/Hexane after the flash column chromatography. Mp: 109~110 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.63 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.53 (br, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 15.6 Hz, 1H), 6.26 (dq, J = 15.6, 6.8 Hz, 1H), 1.90 (dd, J = 6.8, 1.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 168.1, 138.4, 136.4, 130.6, 129.5, 129.2, 128.6, 127.8, 127.0, 126.7, 124.7, 120.2, 120.0, 19.0; HRMS (ESI) calcd for C 16 H 16 [M+H] , found (E)-3-thyl--phenyl-2-(prop-1-enyl)benzamide (1b). 45% yield, a white solid from S13. Mp: 105~106 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.56 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.45 (br, 1H), 7.35 (t, J = 7.2 Hz, 8

9 2H), 7.31~7.19 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 15.6 Hz, 1H), 5.95 (dq, J = 15.6, 6.4 Hz, 1H), 2.35 (s, 3H), 1.86 (dd, J = 6.4, 2.0 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 169.0, 138.4, 136.9, 136.4, 135.5, 132.7, 132.0, 129.2, 127.3, 126.8, 126.1, 124.5, 120.2, 20.85, 19.3; HRMS (ESI) calcd for C 17 H 18 [M+H] , found (E)-4-thyl--phenyl-2-(prop-1-enyl)benzamide (1c). 44% yield, a white solid from S11. Mp: 137~138 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.60 (d, J = 7.6 Hz, 2H), 7.53 (br, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.32 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 15.6 Hz, 1H), 6.23 (dq, J = 15.6, 6.6 Hz, 1H), 2.38 (s, 3H), 1.90 (dd, J = 6.6, 1.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 168.0, 140.7, 138.5, 136.5, 132.1, 129.3, 129.2, 128.8, 128.1, 127.9, 127.5, 124.5, 120.1, 21.7, 19.0; HRMS (ESI) calcd for C 17 H 18 [M+H] , found (E)-5-thyl--phenyl-2-(prop-1-enyl)benzamide (1d). 31% yield, a white solid from S12. Mp: 156~157 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.69 (br, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.34 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H), 6.18 (dq, J = 15.6, 6.8 Hz, 1H), 2.33 (s, 3H), 1.88 (dd, J = 6.8, 1.6 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 168.0, 138.3, 137.0, 134.7, 133.6, 131.5, 129.3, 128.8, 128.4, 126.9, 124.7, 120.0, 21.2, 19.0; HRMS (ESI) calcd for C 17 H 17 a [M+a] , found (E)-4-thoxy--phenyl-2-(prop-1-enyl)benzamide (13). 87% yield, a white solid from S15. Mp: 143~144 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.71 (br, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 2H), 7.13 (tt, J = 7.6, 1.2 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.79 (dq, J = 15.6, 1.6 Hz, 1H), 6.77 (dd, J = 8.8, 2.4 Hz, 1H), 6.23 (dq, J = 15.6, 6.8 Hz, 1H), 3.83 (s, 3H), 1.90 (dd, J = 6.8, 1.6 Hz, 3H); 13 C MR (100 MHz, 9

10 CDCl 3 ): δ = 167.5, 161.4, 138.7, 138.4, 130.0, , 129.3, 129.0, 127.4, 124.5, 120.0, 112.7, 112.2, 55.6, 18.9; HRMS (ESI) calcd for C 17 H 17 2 a [M+a] , found HPh Cl 1f (E)-4-Chloro--phenyl-2-(prop-1-enyl)benzamide (1f). 41% yield, a white solid from S14. Mp: 134~135 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.60 (d, J = 8.0 Hz, 2H), 7.53 (br, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 2H), 7.24 (dd, J = 8.4, 1.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.72 (dd, J = 15.8, 1.4 Hz, 1H), 6.27 (dq, J = 15.8, 6.8 Hz, 1H), 1.90 (dd, J = 6.8, 1.6 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.2, 138.2, 136.5, 133.0, 130.8, 130.2, 129.3, 129.2, 127.4, 126.9, 126.5, 124.9, 120.3, 18.9; HRMS (ESI) calcd for C 16 H 14 Cla [M+a] , found (E)-5-Chloro--phenyl-2-(prop-1-enyl)benzamide (1g). 95% yield, a white solid from S16. Mp: 136~138 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.61 (s, 1H), 7.59 (s, 1H), 7.57~7.53 (m, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.40~7.34 (m, 3H), 7.17 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 15.6 Hz, 1H), 6.24 (dq, J = 15.6, 6.8 Hz, 1H), 1.89 (dd, J = 6.8, 1.8 Hz, 3H); 13 C MR (100 MHz, D 6 -Acetone): δ = 166.4, 139.5, 137.4, 134.9, 131.7, 129.9, 129.0, 129.0, 127.6, 127.4, 127.3, 124.2, 120.0, 18.3; HRMS (ESI) calcd for C 16 H 15 Cl [M+H] , found H 1h (E)-2-(Prop-1-enyl)--p-tolylbenzamide (1h). 81% yield, colorless crystals from (E)-S10 and p-toluidine. Mp: 128~129 o C; 1 H MR (400 MHz, CDCl3): δ = 7.56 (d, J = 7.2 Hz, 1H), 7.52~7.49 (m, 3H), 7.46 (br, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.77 (dd, J = 16.0, 1.4 Hz, 1H), 6.25 (dq, J = 15.6, 6.6 Hz, 1H), 2.34 (s, 3H), 1.90 (dd, J = 6.6, 1.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.8, 136.4, 135.8, , 134.3, 130.6, 129.8, 129.5, 128.6, 127.9, 127.1, 126.8, 120.2, 21.1, 19.0; HRMS (ESI) calcd for C 17 H 18 [M+H] , found

11 H 1i (E)--(3,4-Dimethylphenyl)-2-(prop-1-enyl)benzamide (1i). 86% yield, a white solid from (E)-S10 and 3,4-dimethylaniline. Mp: 121~122 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.56 (br, 1H), 7.53~7.49 (m, 2H), 7.43 (s, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.32 (dd, J = 8.0, 1.8 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 15.6 Hz, 1H), 6.23 (dq, J = 15.6, 6.8 Hz, 1H), 2,28 (s, 3H), 2.25 (s, 3H), 1.90 (d, J = 6.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.7, 137.6, 136.4, 136.0, 135.1, 133.1, 130.6, 130.3, 129.6, 128.6, 127.8, 127.1, 126.8, 121.4, 117.6, 20.2, 19.5, 19.0; HRMS (ESI) calcd for C 18 H 20 [M+H] , found H 1j (E)--(2,4-Dimethylphenyl)-2-(prop-1-enyl)benzamide (1j). 89% yield, a white solid from (E)-S10 and 2,4-dimethylaniline. Mp: 108~109 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.87 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.36 (br, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.84 (d, J = 15.6 Hz, 1H), 6.25 (dq, J = 15.6, 6.8 Hz, 1H), 2,32 (s, 3H), 2.25 (s, 3H), 1.91 (dd, J = 6.8, 1.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.8, 136.4, 135.2, 135.1, 133.5, 133.5, 131.4, 130.6, 129.7, 128.9, 128.1, 127.6, 127.3, 127.1, 123.2, 21.1, 19.0, 18.1; HRMS (ESI) calcd for C 18 H 20 [M+H] , found (E)--(4-Chlorophenyl)-2-(prop-1-enyl)benzamide (1k). 77% yield, colorless, needle crystals from (E)-S10 and 4-chloroaniline. Mp: 141~142 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.58~7.51 (m, 5H), 7.42 (td, J = 7.6, 1.2 Hz, 1H), 7.34~7.28 (m, 3H), 6.75 (d, J = 15.2 Hz, 1H), 6.25 (dq, J = 15.2, 6.6 Hz, 1H), 1.91 (dd, J = 6.6, 1.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 168.0, 136.8, 136.4, 134.4, 130.8, 129.8, 129.6, 129.2, 128.4, 127.8, 127.1, 126.9, 121.4, 19.0; HRMS (ESI) calcd for C 16 H 15 Cl [M+H] , found

12 (E)--Benzyl-2-(prop-1-enyl)benzamide (1l). 87% yield, a white solid from (E)-S10 and benzylamine. Mp: 1115~116 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.48~7.45 (m, 2H), 7.38~5.28 (m, 6H), 7.23 (td, J = 7.6, 1.2 Hz, 1H), 6.69 (dq, J = 15.6, 1.6 Hz, 1H), 6.25 (dq, J = 15.6, 6.8 Hz, 1H), 6.05 (br, 1H), 4.64 (d, J = 6.0 Hz, 2H), 1.84 (dd, J = 6.8, 2.0 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 169.7, 138.4, 136.2, 134.8, 130.3, 129.0, 129.0, 128.8, 128.1, 127.7, 127.7, 127.0, 126.6, 44.2, 18.9; HRMS (ESI) calcd for C 17 H 17 a [M+a] , found (E)--Butyl-2-(prop-1-enyl)benzamide (1m). 90% yield, colorless crystals from (E)-S10 and butylamine. Mp: 85~86 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.45 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4, Hz, 1H), 6.67 (d, J = 15.6 Hz, 1H), 6.17 (dq, J = 15.6, 6.8 Hz, 1H), 5.85 (br, 1H), 3.41 (q, J = 6.8 Hz, 2H), 1.88 (dd, J = 6.8, 1,0 Hz, 3H), 1.56 (quint, J = 7.2 Hz, 2H), 1.40 (sext, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 169.8, 136.0, 135.3, 130.1, 128.9, 128.7, 127.6, 127.0, 126.5, 39.9, 31.9, 20.3, 18.9, 14.0; HRMS (ESI) calcd for C 14 H 20 [M+H] , found (E)-2-(But-1-enyl)--phenylbenzamide (1n). 93% yield, a white solid from (E)-2-(but-1-enyl)benzoic acid. 11 Mp: 80~81 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.62~7.51 (m, 5H), 7.43~7.27 (m, 4H), 7.15 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 16.0 Hz, 1H), 6.28 (dt, J = 16.0, 6.8 Hz, 1H), 2.25 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 166.1, 138.4, 136.4, 135.0, 130.6, 129.2, 129.1, 128.0, 127.1, 126.9, 126.5, 124.7, 120.2, 26.5, 13.9; HRMS (ESI) calcd for C 17 H 18 [M+H] , found

13 (E)-2-(3-thylbut-1-enyl)--phenylbenzamide (1o). 63% yield, a white solid from (E)-2-(3-methylbut-1-enyl) benzoic acid. 11 Mp: 97~98 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.08 (br, 1H), 7.83 (d, J = 6.8, Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.6, 1.2 Hz, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 2H), 6.59 (d, J = 11.2 Hz, 1H), 5.73 (t, J = 11.2 Hz, 1H), 2.73 (m, 1H), 1.05 (d, J = 6.4 Hz, 6H); 13 C MR (100 MHz, CDCl 3 ): δ = 166.8, 142.7, 138.3, 135.5, 134.9, 130.8, 130.3, 129.3, 129.2, 127.6, 125.5, 124.6, 119.9, 27.6, 23.2; HRMS (ESI) calcd for C 18 H 20 [M+H] , found (E)--Phenyl-2-(3-phenylprop-1-enyl)benzamide (1p). 81% yield, a white solid from (E)-S17. Mp: 109~110 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.60~7.14 (m, 14H), 6.85 (d, J = 16.0 Hz, 1H), 6.38 (dt, J = 16.0, 7.2 Hz, 1H), 3.55 (d, J = 7.2 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.8, 140.0, 138.2, 136.0, 135.2, 133.3, 130.7, 129.3, 128.9, 128.8, 128.6, 128.0, 127.5, 127.0, 126.5, 124.8, 120.2, 39.78; HRMS (ESI) calcd for C 22 H 20 [M+H] , found HPh 1r (E)-2-(But-2-en-2-yl)--phenylbenzamide (1r). 46% yield, a white solid from 2-(but-2-en-2-yl)benzoic acid. 12 Mp: 102~103 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.40 (br, 1H), 8.02 (dd, J = 7.6, 0.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.48 (td, J = 7.4, 1.6 Hz, 1H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.36 (m, 2H), 7.14 (m, 2H), 5.84 (qq, J = 6.8, 1.6 Hz, 1H), 2.04 (quint, J = 1.6 Hz, 3H), 1.59 (dq, J = 6.8, 1.6 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 166.2, 140.0, 138.5, 133.6, 131.4, 131.3, 130.1, 129.8, 129.3, 129.2, 127.8, 124.6, 120.0, 26.0, 18.9, 15.2; HRMS (ESI) calcd for C 17 H 17 a [M+a] , found

14 thyl 2,2-dimethylhex-4-enoate (S18). A 2.5 M solution of n-buli in hexane (9.4 ml, 23.5 mmol, 1.2 equiv) was added dropwise to a solution of diisopropylamine (3.3 ml, 2.38 g, 23.5 mmol, 1.2 equiv) in anhydrous THF (40 ml) at 0 C under 2 atmosphere and stirred 30 min at 0 C. Ethyl isobutyrate (2.00 g, 19.6 mmol, 1.0 equiv) was then added dropwise at 78 C and stirred 1 h. Finally, 1-chlorobut-2-ene (2.13 g, 23.5 mmol, 1.2 equiv) was added dropwise at 78 C and the mixture was slowly warmed to room temperature. After stirring for 12 h, the reaction mixture was cooled to 0 C, and quenched by the addition of saturated aq H 4 Cl (20 ml) and water (20 ml), then extracted with Et 2 (3 40 ml). The combined organic extracts were dried over MgS 4, filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (petroleum ether) yielded S18 (E:Z = 3.7:1, 2.21 g, 72%) as a pale yellow oil. 1 H MR (400 MHz, D 6 -Acetone): δ = 5.58~5.28 (m, 2H), 3.62 (Z)(s, 3H), 3.62 (E)(s, 3H), 2.27 (Z)(dq, J = 7.2, 0.8 Hz, 2H), 2.18 (Z)(dp, J = 7.2, 0.8 Hz, 2H), 1.61 (E)(dq, J = 6.0, 1.2 Hz, 3H), 1.59 (Z)(m, 3H), 1.15 (Z)(s, 6H), 1.11 (E)(s, 6H); 13 C MR (100 MHz, D 6 -Acetone): δ = 177.2, (E), (E), (Z), (Z), 51.1, 43.6 (E), 42.4 (Z), 37.3, 24.4, 21.4 (Z), (E). (E)-2,2-Dimethyl--phenylhex-4-enamide (1q). A 2.5 M solution of n-buli in hexane (1.8 ml, 4.51 mmol, 2.35 equiv) was added dropwise to a solution of aniline (0.40 ml, g, 4.42 mmol, 2.3 equiv) in anhydrous THF (15 ml) at 0 C under 2 atmosphere and stirred 1 h at room temperature. S18 (0.300 g, 1.92 mmol, 1.0 equiv) was then added dropwise at 0 C and stirred 12 h. The reaction mixture was cooled to 0 C, and quenched by the addition of saturated aq H 4 Cl (10 ml) and water (10 ml), then extracted with Et 2 (3 20 ml). The combined organic extracts were dried over MgS 4, filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (petroleum ether/etac) and recrystallization (EtAc/hexane) yielded 1q (0.103 g, 25%) as a white solid. Mp: 75~76 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.49 (dd, J = 8.4, 1.2 Hz, 1H), 7.35 (br, 1H), 7.33~7.29 (m, 2H), 7.10 (tt, J = 7.6, 1.2 Hz, 1H), 5.61~5.42 (m, 2H), 2.29 (dd, J = 6.8, 1.2 Hz, 2H), 1.68 (dd, J = 6.0, 1.2 Hz, 3H), 1.27 (s, 6H); 13 C MR (100 MHz, CDCl 3 ): δ = 176.1, 138.3, 129.3, 129.1, 126.9, 124.4, 120.5, 44.2, 43.2, 25.5, 18.3; HRMS (ESI) calcd for C 12 H 19 a [M+a] , found

15 HPh 4 2-Allyl--phenylbenzamide (4). In a dry two-neck flask, 2-iodo--phenylbenzamide 13 (0.500 g, 1.55 mmol, 1.0 equiv), allyltributyltin (0.539 g, 1.70 mmol, 1.1 equiv), Pd(PPh 3 ) 4 (89.4 mg, mmol, 0.05 equiv), and dioxane (10 ml) were combined. The reaction mixture was degassed and then heated at reflux. After 12 h, the reaction was cooled to room temperature and quenched by the addition of 2 aq ah (10 ml) and water (10 ml), then extracted with EtAc (3 20 ml). The combined organic extracts were dried over MgS 4, filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (petroleum ether/etac 50/1 to 15/1) yielded 4 (0.351 g, 96%) as a white solid. Mp: 1114~115 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.61~7.54 (m, 4H), 7.42 (td, J = 7.6, 1.6 Hz, 3H), 7.39~7.29 (m, 4H), 7.15 (tt, J = 7.6, 1.2 Hz, 1H), 6.14~6.04 (m, 1H), 5.13 (dq, J = 10.2, 1.6 Hz, 1H), 5.02 (dq, J = 17.2, 1.6 Hz, 1H), 3.62 (d, J = 6.4 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): δ = 168.3, 138.3, 137.8, 137.8, 136.8, 130.8, 130.6, 129.2, 127.7, 126.7, 124.7, 120.3, 116.6, 37.8; HRMS (ESI) calcd for C 16 H 16 [M+H] , found

16 3. Palladium Catalyzed Aza-Wacker Cyclizations Table 1'. Reaction Conditions Screening a, b entry Pd source L c solvent yield yield (2a) (3a) 1 Pd(Ac) 2 pyridine toluene 68% D 2 Pd(Ac) 2 quinoline toluene 61% 5% 3 Pd(Ac) 2 Phen e toluene R 4 Pd(Ac) 2 quinoline f THF 51% 6% 5 Pd(Ac) 2 Phen e THF R 6 Pd(Ac) 2 quinoline H R 7 Pd(Ac) 2 Phen H 85% D 8 d Pd(Ac) 2 -- H D 9% 9 d g Pd(Ac) 2 -- H D 42% 10 d g (C) 2 PdCl 2 -- H D 85% 11 d, g (C) 2 PdCl 2 -- DME D 74% 12 d g (C) 2 PdCl 2 -- THF D 84% 13 d g (C) 2 PdCl 2 Et 3 H D 98% 14 d -- g -- H R 15 Pd(Ac) 2 Phen h H 42% D 16 d g (C) 2 PdCl 2 -- h H D 85% 17 d (C) 2 PdCl 2 Phen e H R 18 d g (C) 2 PdCl 2 Phen e H R 19 d i Pd(Ac) 2 -- H 5% 32% 20 d j Pd(Ac) 2 -- H D 69% 21 Pd(Ac) 2 Bpy H 84% D 22 d Pd(Ac) 2 C H D 9% 23 k Pd(Ac) 2 ipr-pyox H 46 l D 24 d Pd(Ac) 2 ipr-quinox H D 10% 25 k Pd(Ac) 2 ipr-quinox H D 19% 26 (C) 2 PdCl 2 quinoline e H R 27 d g (C) 2 PdCl 2 quinoline e, m H R 28 (C) 2 PdCl 2 C e H R 29 d n Pd(Ac) 2 Phen H R a Unless otherwise stated, reactions were carried out on a 0.20 mmol scale using 10 mol % Pd salt, with or without added 20 mol % ligand in solvent (2.0 ml) under 1 atm dioxygen at 60 o C for 12 h. When the solvent was toluene, the reaction temperature was 80 o C. b Isolated yield. R = o reaction. D = trace, not detected. c Phen = 1,10-phenanthroline. C = neocuproine. Bpy = 2,2'-bipyridine. ipr-pyox = (S)-4-isopropyl-2-(pyridin-2-yl)-4,5-16

17 dihydrooxazole. ipr-quinox = (S)-4-isopropyl-2-(quinolin-2-yl)-4,5-dihydrooxazole. d The reaction time was 15 h. e The corresponding complex showed poor solubility in the solvent. f The solubility of the corresponding comlex in the solvent was not good. g CuCl 2 (10 mol %) was added. h PhC 2 H (30 mol % for entry 15, 20 mol % for entry 16) was added. i Cu(Ac) 2 (10 mol %) was added. j Cu(Tf) 2 (10 mol %) was added. k The reaction time was 48 h. l With 49% yield of the olefin isomers of 2a obtained. m 40 mol % of quinoline was used. n LiCl (400 mol %) was added after stirring the mixture of Phen and Pd(Ac) 2 for 10 min. Then a white precipitate was formed and the yellow color of the solvent faded. Condition A: The flame dried Schlenk tube was charged with Pd(Ac) 2 (4.6 mg, mmol, 0.1 equiv) and 1,10-phenanthroline (7.2 mg, mmol, 0.2 equiv) under a 2 atmosphere and then the mixture was dissolved in dry H (2.0 ml). The solution was stirred at room temperature for 10 min, then substrate 1a (47.5 mg, 0.20 mmol, 1.0 equiv) was added. The reaction was cooled by liquid nitrogen, then degassed and recharged with 2 three times. The mixture was allowed to warm to room temperature and heated to 60 o C. After stirred 12 h, the reaction mixture was cooled to room temperature, and the H was removed by rotary evaporation. The residue was purified by flash column chromatography on silica gel (petroleum ether/etac = 20/1 to 10/1) to afford the 2-phenyl-3-vinylisoindolin-1-one (2a) as a white solid (40 mg, 85%). Condition B: The flame dried Schlenk tube was charged with PdCl 2 (C) 2 (5.2 mg, mmol, 0.1 equiv) and CuCl 2 (2.6 mg, mmol, 0.1 equiv) under a 2 atmosphere and then the mixture was added dry H (2.0 ml) and Et 3 (5.8 μl, mmol, 0.2 equiv) sequentially. The mixture was stirred at room temperature for 10 min, then substrate 1a (47.5 mg, 0.20 mmol, 1.0 equiv) was added. The reaction was cooled by liquid nitrogen, then degassed and recharged with 2 three times. The mixture was allowed to warm to room temperature and heated to 60 o C. After stirred 15 h, the reaction mixture was cooled to room temperature, and the H was removed by rotary evaporation. The residue was purified by flash column chromatography on silica gel (petroleum ether/etac = 15/1 to 7/1) to afford the 3-methylene-2-phenyl-3,4-dihydroisoquinolin-1(2H)-one (3a) as a white solid (46 mg, 98%). 17

18 2a 2-Phenyl-3-vinylisoindolin-1-one (2a). Condition A: 85% yield, a white solid. Mp: 110~111 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.93 (dt, J = 7.6, 1.0 Hz, 1H), 7.65~7.59 (m, 3H), 7.52 (t, J = 7.4 Hz, 1H), 7.45~7.40 (m, 3H), 7.20 (tt, J = 7.2, 1.2 Hz, 1H), 5.59~5.53 (m, 3H), 5.36~5.33 (m, 1H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.5, 143.7, 137.8, 135.4, 132.5, 132.0, 129.1, 129.0, 125.4, 124.3, 123.3, 123.2, 120.5, 65.0; HRMS (ESI) calcd for C 16 H 13 a [M+a] , found a 3-thylene-2-phenyl-3,4-dihydroisoquinolin-1(2H)-one (3a). Condition B: 98% yield, a white solid. Mp: 133~134 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.37 (d, J = 7.6 Hz, 1H), 7.63 (td, J = 7.4, 1.2 Hz, 1H), 7.54~7.40 (m, 5H), 7.25 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 2.00 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.7, 139.7, 139.4, 137.3, 132.8, 129.8, 128.7, 128.7, 128.4, 126.3, 125.4, 125.0, 105.7, 21.8; HRMS (ESI) calcd for C 16 H 14 [M+H] , found b 4-thyl-2-phenyl-3-vinylisoindolin-1-one (2b). Condition A: 76% yield, a white solid. Mp: 66~67 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.79 (d, J = 7.6 Hz, 1H), 7.63~7.60 (m, 2H), 7.46~7.36 (m, 3H), 7.20 (tt, J = 7.6, 1.2 Hz, 1H), 5.53~5.35 (m, 4H), 2.39 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.6, 141.6, 137.6, 134.1, 133.7, 132.1, 129.2, 129.1, 125.5, 123.6, 121.9, 121.7, 64.7, 18.2; HRMS (ESI) calcd for C 17 H 16 [M+H] , found ,5-Dimethyl-2-phenylisoquinolin-1(2H)-one (3b). Condition B: 86% yield, a white solid. Mp: 116~117 o C; 1 H 18

19 MR (400 MHz, CDCl 3 ): δ = 8.25 (dd, J = 8.6, 0.6 Hz, 1H), 7.55~7.50 (m, 2H), 7.48~7.43 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.26~7.23 (m, 2H), 6.54 (t, J = 0.8 Hz, 1H), 2.54 (s, 3H), 2.04 (d, J = 0.8 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 164.0, 139.5, 139.3, 136.2, 133.6, 132.5, 129.8, 128.8, 128.7, 126.4, 125.9, 125.2, 102.4, 22.2, 19.2; HRMS (ESI) calcd for C 17 H 16 [M+H] , found c 5-thyl-2-phenyl-3-vinylisoindolin-1-one (2c). Condition A: 77% yield, a white solid. Mp: 132~133 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.81 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.19 (t, J = 7.8 Hz, 1H), 5.62~5.55 (m, 3H), 5.34~5.32 (m, 1H), 2.48 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.6, 144.1, 143.3, 138.0, 135.7, 130.0, 129.4, 129.0, 125.2, 124.1, 123.7, 123.0, 120.3, 64.9, 22.2; HRMS (ESI) calcd for C 17 H 16 [M+H] , found ,6-Dimethyl-2-phenylisoquinolin-1(2H)-one (3c). Condition B: 88% yield, colorless crystals. Mp: 131~132 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.25 (d, J = 8.4 Hz, 1H), 7.54~7.50 (m, 2H), 7.44 (tt, J = 7.4, 1.2 Hz, 1H), 7.26~7.23 (m, 4H), 6.36 (s, 1H), 2.48 (s, 3H), 1.99 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.7, 143.3, 139.6, 139.5, 137.5, 129.8, 128.8, 128.7, 128.3, 127.9, 125.1, 122.9, 105.5, 22.1, 21.9; HRMS (ESI) calcd for C 17 H 16 [M+H] , found d 6-thyl-2-phenyl-3-vinylisoindolin-1-one (2d). Condition A: 97% yield, a white solid. Mp: 122~123 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.73 (s, 1H), 7.65~7.62 (m, 2H), 7.43~7.39 (m, 3H), 7.32 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 5.62~5.49 (m, 3H), 5.31 (dd, J = 8.6, 2.2 Hz, 1H), 2.47 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.6, 141.0, 139.1, 138.0, 135.7, 133.5, 132.1, 129.1, 129.0, 125.3, 124.4, 123.1, 123.0, 120.2, 64.8, 21.6; HRMS (ESI) calcd for C 17 H 16 [M+H] , found

20 3,7-Dimethyl-2-phenylisoquinolin-1(2H)-one (3d). Condition B: 99% yield, a white solid. Mp: 103~104 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.17 (d, J = 1.2 Hz, 1H), 7.54~7.50 (m, 2H), 7.45 (t, J = 7.4, 1.2 Hz, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.26~7.23 (m, 2H), 6.40 (s, 1H), 2.47 (s, 3H), 1.98 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.7, 139.5, 138.6, 136.3, 135.1, 134.3, 129.2, 128.7, 127.9, 125.3, 124.9, 105.7, 21.8, 21.7; HRMS (ESI) calcd for C 17 H 16 [M+H] , found e 5-thoxy-2-phenyl-3-vinylisoindolin-1-one (2e). Condition A: 80% yield, a white solid. Mp: 84~85 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.84 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.2, 1.2 Hz, 2H), 7.40 (t, J = 8.2 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.65~5.52 (m, 2H), 5.48 (d, J = 7.6Hz, 1H), 5.35~5.33 (m, 1H), 3.89 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.6, 163.6, 146.1, 138.1, 135.6, 129.0, 125.7, 125.1, 124.5, 122.9, 120.5, 115.9, 107.8, 64.7, 55.9; HRMS (ESI) calcd for C 17 H 16 2 [M+H] , found thoxy-3-methyl-2-phenylisoquinolin-1(2H)-one (3e). Condition B: 99% yield, colorless crystals. Mp: 169~170 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.28 (d, J = 9.2 Hz, 1H), 7.53~7.49 (m, 2H), 7.44 (tt, J = 7.4, 1.6 Hz, 1H), 7.26~7.22 (m, 2H), 7.00 (dd, J = 8.8, 2.8 Hz, 1H), 6.82 (d, J = 2.8 Hz, 1H), 6.36 (s, 1H), 3.92 (s, 3H), 1.98 (d, J = 0.8 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.4, 163.3, 140.4, 139.4, 130.4, 129.8, 128.8, 128.7, 118.9, 115.7, 106.3, 105.5, 55.7, 21.9; HRMS (ESI) calcd for C 17 H 16 2 [M+H] , found Cl 2f 20

21 5-Chloro-2-phenyl-3-vinylisoindolin-1-one (2f). Condition A: 58% yield, a white solid. Mp: 118~119 o C; When reaction time was 48 h under condition A, the yield of 2f was 77% with 19% 3f separated. 1 H MR (400 MHz, CDCl 3 ): δ = 7.86 (d, J = 8.0 Hz, 1H), 7.62~7.59 (m, 2H), 7.50 (dd, J = 7.8, 1.8 Hz, 1H), 7.44~7.39 (m, 3H), 7.21 (td, J = 7.4, 1.2 Hz, 1H), 5.58~5.50 (m, 3H), 5.38~5.36 (m, 1H); 13 C MR (100 MHz, CDCl 3 ): δ = 166.4, 145.3, 138.9, 137.5, 134.7, 130.5, 129.7, 129.2, 125.7, 125.6, 123.7, 123.2, 121.2, 64.7; HRMS (ESI) calcd for C 16 H 13 Cl [M+H] , found Chloro-3-methyl-2-phenylisoquinolin-1(2H)-one (3f). Condition B: 49% yield, a white solid. Mp: 150~151 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.29 (d, J = 8.4 Hz, 1H), 7.55~7.51 (m, 2H), 7.49~7.44 (m, 2H), 7.36 (dd, J = 8.4 Hz, 1H), 7.26~7.23 (m, 2H), 6.35 (s, 1H), 2.00 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.1, 141.4, 139.2, 139.0, 138.6, 130.2, 129.9, 129.0, 128.6, 126.8, 124.6, 123.3, 104.7, 21.9; HRMS (ESI) calcd for C 16 H 13 Cl [M+H] , found Cl 2g 6-Chloro-2-phenyl-3-vinylisoindolin-1-one (2g). Condition A (48 h): 40% yield, a white solid. Mp: 136~137 o C; With 8% 3g separated. 1 H MR (400 MHz, CDCl 3 ): δ = 7.89 (d, J = 2.0 Hz, 1H), 7.61~7.59 (m, 2H), 7.56 (dd, J = 7.8, 1.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 5.57~5.50 (m, 3H), 5.37~5.34 (m, 1H); 13 C MR (100 MHz, CDCl 3 ): δ = 166.1, 141.9, 137.5, 135.4, 134.9, 132.7, 129.3, 129.2, 125.7, 124.6, 124.4, 123.2, 121.0, 64.8; HRMS (ESI) calcd for C 16 H 13 Cl [M+H] , found Chloro-3-methyl-2-phenylisoquinolin-1(2H)-one (3f). Condition B (48 h): 37% yield, a white solid. Mp: 122~123 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.33 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 2.2 Hz, 1H), 7.55~7.51 (m, 2H), 7.47 (tt, J = 7.2, 1.6 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.25~7.23 (m, 2H), 6.41 (s, 1H), 1.99 (d, J = 0.8 Hz 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 162.7, 140.2, 139.0, 135.7, 133.3, 132.1, 129.9, 129.0, 128.5, 127.8, 127.0, 21

22 126.1, 105.1, 21.9; HRMS (ESI) calcd for C 16 H 13 Cl [M+H] , found h 2-p-Tolyl-3-vinylisoindolin-1-one (2h). Condition A: 65% yield, a white solid. Mp: 82~83 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.92 (d, J = 7.2 Hz, 1H), 7.59 (td, J = 7.6, 0.8 Hz, 1H), 7.53~7.48 (m, 3H), 7.42 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 5.61~5.45 (m, 3H), 5.34~5.31 (m, 1H), 2.35 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.4, 143.8, 135.5, 135.2, 135.2, 132.4, 132.1, 129.7, 129.0, 124.2, 123.4, 123.2, 120.4, 65.2, 21.2; HRMS (ESI) calcd for C 17 H 16 [M+H] , found thyl-2-p-tolylisoquinolin-1(2H)-one (3h). Condition B: 91% yield, colorless crystals. Mp: 124~125 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.37 (d, J = 8.4 Hz, 1H), 7.62 (td, J = 7.4, 1.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.42 (td, J = 7.4, 0.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.12 (m, 2H), 6.42 (s, 1H), 2.43 (s, 3H), 2.01 (d, J = 0.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.8, 139.9, 138.6, 137.4, 136.7, 132.7, 130.5, 128.4, 128.4, 126.2, 125.3, 125.1, 105.6, 21.9, 21.5; HRMS (ESI) calcd for C 17 H 16 [M+H] , found i 2-(3,4-Dimethylphenyl)-3-vinylisoindolin-1-one (2i). Condition A: 62% yield, a clear, viscous oil. 1 H MR (400 MHz, CDCl ): δ = 7.92 (dt, J = 7.6, 1.0 Hz, 1H), 7.59 (td, J = 7.6, 1.2 Hz, 1H), 7.51 (td, J = 7.6, 1.2 Hz, 1H), ~7.41 (m, 2H), 7.25 (dd, J = 7.6, 2.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.62~5.45 (m, 3H), 5.34~5.31 (m, 1H), 2.29 (s, 3H), 2.25 (s, 3H); 13 C MR (100 MHz, CDCl ): δ = 167.5, 143.8, 137.4, 135.5, 135.3, 134.2, 132.3, 132.1, , 128.9, 125.0, 124., 123.2, 121.0, 120.4, 65.4, 20.3, 19.5; HRMS (ESI) calcd for C H [M+H] , found

23 2-(3,4-Dimethylphenyl)-3-methylisoquinolin-1(2H)-one (3i). Condition B: 85% yield, a white solid. Mp: 109~110 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.37 (d, J = 7.2 Hz, 1H), 7.62 (td, J = 7.6, 1.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 1.2 Hz, 1H), 6.97 (dd, J = 8.0, 2.4 Hz, 1H), 6.41 (s, 1H), 2.32 (s, 3H), 2.30 (s, 3H), 2.02 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.9, 140.0, 138.3, 137.4, 137.3, 136.9, 132.7, 130.9, 129.4, 128.4, 126.1, 125.7, 125.3, 125.1, 105.5, 21.9, 20.1, 19.8; HRMS (ESI) calcd for C 18 H 18 [M+H] , found j 2-(2,4-Dimethylphenyl)-3-vinylisoindolin-1-one (2j). Condition A: 61% yield, a light yellow, viscous oil. 1 H MR (400 MHz, CDCl 3 ): δ = 7.94 (dt, J = 7.6, 0.8 Hz, 1H), 7.60 (td, J = 7.6, 1.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.42 (dd, J = 7.6, 0.8 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J = 1.2 Hz, 2H), 5.64~5.56 (m, 1H), 5.37 (d, J = 17.2 Hz, 1H), 5.26 (d, J = 9.6 Hz, 1H), 2.34 (s, 3H), 2.20 (br, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = (br), 144.7, (br), (br), (br), (br), 133.1, 132.1, 132.0, 131.9, 128.9, 127.5, 124.3, 123.4, 121.1, 67.4 (br), 21.3, 18.5 (br). Because it is a mixture of two diastereomers, there are some broad peaks in the 1 H MR and 13 C MR. HRMS (ESI) calcd for C 18 H 18 [M+H] , found (2,4-Dimethylphenyl)-3-methylisoquinolin-1(2H)-one (3j). Condition B: 57% yield, a white solid. Mp: 139~140 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.38 (dd, J = 7.6, 0.8 Hz, 1H), 7.63 (td, J = 7.6, 1.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41 (td, J = 7.6, 1.6 Hz, 1H), 7.17 (d, J = 0.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 2.39 (s, 3H), 2.05 (s, 3H), 1.95 (d, J = 0.8 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.2, 139.8, 138.9, 137.5, 135.8, 135.5, 132.7, 132.1, 128.5, 128.2, 128.2, 126.1, 125.4, 125.9, 105.6, 21.9, 21.4, 17.6; 23

24 HRMS (ESI) calcd for C 18 H 18 [M+H] , found Cl 2k 2-(4-Chlorophenyl)-3-vinylisoindolin-1-one (2k). Condition A: 87% yield, a white solid. Mp: 75~77 o C; 1 H MR (400 MHz, CDCl ): δ = 7.89 (dt, J = 7.6, 1.0 Hz, 1H), 7.63~7.58 (m, 3H), 7.50 (t, J = 7.4 Hz, 3H), 7.42 (dd, 3 J = 7.8, 0.8 Hz, 1H), 7.37~7.33 (m, 2H), 5.59~5.47 (m, 3H), 5.37~5.34 (m, 1H); 13 C MR (100 MHz, CDCl ): δ = 167.5, 143.6, 136.5, 135.2, 132.7, 131.6, 130.6, 129.2, 129.1, 124.3, 124.0, 123.3, 120.8, 64.9; HRMS (ESI) calcd 3 for C H Cl [M+H] , found Cl 3k 2-(4-Chlorophenyl)-3-methylisoquinolin-1(2H)-one (3k). Condition B: 95% yield, a white solid. Mp: 128~129 o C; 1 H MR (400 MHz, CDCl ): δ = 8.35 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.50~7.42 (m, 4H), 7.19 (d, 3 J = 8.8 Hz, 2H), 6.44 (s, 1H), 2.43 (s, 3H), 2.01 (s, 3H); 13 C MR (100 MHz, CDCl ): δ = 163.6, 139.2, 137.8, 137.3, 134.7, 133.0, 130.2, 130.1, 128.3, 126.5, 125.5, 12 0, 106.0, 21.8; HRMS (ESI) calcd for C H Cl [M+H] , found Bn 2l 2-Benzyl-3-vinylisoindolin-1-one (2l). Condition A: 22% yield, a colorless oil. 1 H MR (400 MHz, CDCl 3 ): δ = 7.89 (d, J = 6.8 Hz, 1H), 7.52 (td, J = 7.2, 1.2 Hz, 1H), 7.48~7.45 (m, 1H), 7.32~7.26 (m, 6H), 5.51~5.43 (m, 3H), 5.34 (d, J = 14.4 Hz, 1H), 4.72~4.70 (m, 1H), 4.14 (d, J = 14.8 Hz, 1H); 13 C MR (100 MHz, CDCl ): δ = 168.3, 144.5, 137.5, 135.0, 132.0, 131.9, 128.9, 128.7, , 128.5, 127.9, 127.7, 126.5, 125.3, 124.0, 123.3, 121.4, 63.4, 44.1; HRMS (ESI) calcd for C H a [M+a] , found

25 2-Benzyl-3-methylisoquinolin-1(2H)-one (3l). Condition B: 84% yield, colorless crystals. Mp: 96~97 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.43 (dd, J = 8.0, 0.8 Hz, 1H), 7.62 (td, J = 7.4, 1.2 Hz, 1H), 7.45~7.42 (m, 2H), 7.31~7.27 (m, 3H), 7.23 (t, J = 7.2 Hz, 1H), 7.16 (d, J = 6.8 Hz, 2H), 6.37 (s, 1H), 5.43 (s, 2H), 2.34 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.7, 139.8, 137.4, 137.1, 132.6, 129.0, 128.5, 127.4, 126.5, 126.2, 125.3, 124.6, 106.4, 47.3, 20.9; HRMS (ESI) calcd for C 17 H 16 [M+H] , found Bu 2m 2-Butyl-3-vinylisoindolin-1-one (2m). Condition A (20 mol % Pd(Ac) 2, 40 mol % Phen, 48 h): 41% yield, a colorless oil. 1 H MR (400 MHz, CDCl 3 ): δ = 7.82 (d, J = 7.2 Hz, 1H), 7.51 (td, J = 7.6, 1.6 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 5.63~5.41 (m, 3H), 4.86 (d, J = 7.6 Hz, 1H), 3.87 (dt, J = 13.6, 8.0 Hz, 1H), 3.18 (ddd, J = 13.6, 8.0, 5.6 Hz, 1H), 1.67~1.51 (m, 2H), 1.34 (sext, J = 7.6 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H); C MR (100 MHz, CDCl 3 ): δ = 168.3, , 135.5, 132.4, 131.6, 128.7, 123.7, 123.6, 123.1, 120.8, 64.3, 40.2, 30.7, 20.3, 14.0; HRMS (ESI) calcd for C 14 H 18 [M+H] , found m Bu 2-Butyl-3-methylisoquinolin-1(2H)-one (3m). Condition B (18 h): 87% yield, a colorless oil. 1 H MR (400 MHz, CDCl 3 ): δ = 8.36 (d, J = 8.0 Hz, 1H), 7.62 (td, J = 7.6, 1.6 Hz, 1H), 7.41~7.38 (m, 2H), 6.33 (s, 1H), 4.08 (t, J = 8.0 Hz, 2H), 2.43 (s, 3H), 1.70 (quint, J = 8.0 Hz, 2H), 1.45 (sext, J = 7.4 Hz, 2H), 0.98 (t, J = 0.74 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.1, 139.2, 136.9, 132.2, 128.0, 125.9, 125.1, 124.7, 106.1, 44.3, 31.1, 20.7, 20.6, 14.0; HRMS (ESI) calcd for C 14 H 18 [M+H] , found Ph Ph 2n 2n' (E)-2-Phenyl-3-(prop-1-enyl)isoindolin-1-one (2n) and 3-allyl-2-phenylisoindolin-1-one (2n'). Condition A: 2n: 41% yield (separated), a white solid; 2n': 35% yield (separated), a white solid. 2n: Mp: 111~112 o C; 1 H MR (400 25

26 MHz, CDCl 3 ): δ = 7.91 (m, 1H), 7.64~7.61 (m, 2H), 7.58 (dd, J = 7.2, 1.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.43~7.39 (m, 3H), 7.19 (tt, J = 7.2, 1.0 Hz, 1H), 5.99 (dqd, J = 15.2, 6.6, 0.8 Hz, 1H), 5.50 (d, J = 9.2 Hz, 1H), 5.19 (ddq, J = 15.2, 8.4, 1.6 Hz, 1H), 1.69 (dd, J = 6.6, 1.6 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.5, 144.5, 137.9, 132.4, 132.0, 131.9, 129.3, 129.0, 128.8, 128.1, , 124.2, 123.3, 64.5, 18.0; HRMS (ESI) calcd for C 17 H 16 [M+H] , found n': Mp: 112~113 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.92 (m, 1H), 7.62 (dd, J = 7.2, 1.2 Hz, 1H), 7.59~7.55 (m, 2H), 7.54~7.50 (m, 2H), 7.49~7.42 (m, 2H), 7.24 (tt, J = 7.2, 1.0 Hz, 1H), 5.41~5.29 (m, 1H), 5.28 (dd, J = 7.0, 3.2 Hz, 1H), 4.93 (d, J = 10.0 Hz, 1H), 4.84 (dq, J = 16.8, 1.2 Hz, 1H), 2.74 (m, 1H), 2.56 (m, 1H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.4, 144.4, 137.2, 132.7, 132.1, 131.0, 129.3, 128.7, 125.8, 124.3, 124.0, 122.6, 119.8, 60.3, 36.7; HRMS (ESI) calcd for C 17 H 16 [M+H] , found n Ph Et 3-Ethyl-2-phenylisoquinolin-1(2 H)-one (3n). Condition B: 87% yield, a white solid. Mp: 93~95 o C; 1 H MR (400 MHz, CDCl ): δ = 8.43 (dd, J = 8.0, 0.8 Hz, 1H), 7.64 (td, J = 7.4, 1.2 Hz, 1H), 7.54~7.50 (m, 3H), 7.48~ (m, 2H), 7.26~7.24 (m, 2H), 6.43 (s, 1H), 2.26 (qd, J = 7.4, 0.8 Hz, 2H), 1.13 (t, J = 7.4 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.8, 145.1, 138.9, 137.4, 132.8, 129.7, 129.0, 128.8, 128.3, 126.4, 125.7, 125.0, 103.7, 27.0, 12.5; HRMS (ESI) calcd for C 17 H 16 [M+H] , found o Ph Pr i 3-Isopropyl-2-phenylisoquinolin-1(2H)-one (3o). Condition A (92 h): 40% yield; Condition B (48 h): 9% yield. A white solid. Mp: 120~121 o C; 1 H MR (400 MHz, CDCl ): δ = 8.37 (d, J = 7.6 Hz, 1H), 7.66~7.61 (m, 1H), 7.55~7.50 (m, 3H), 7.49~7.45 (m, 1H), 7.45~7. 40 (m, 1H), 7.28~7.25 (m, 2H), 6.49 (s, 1H), 2.57 (hept, J = 6.8 Hz, 1H), 1.15 (t, J = 7.2 Hz, 6H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.9, 150.4, 138.9, 137.4, 132.8, 129.7, 129.2, 128.7, 128.3, 126.4, 125.8, 124.9, 102.1, 30.3, 23.1; HRMS (ESI) calcd for C 18 H 18 [M+H] , found

27 Ph 2p Ph (E)-2-Phenyl-3-styrylisoindolin-1-one (2p). Condition A: 80% yield, a white solid Mp: 157~158 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.96 (d, J = 7.6 Hz, 1H), 7.69~7.67 (m, 2H), 7.54 (t, J = 7.0 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.42~7.37 (m, 2H), 7.33~7.22 (m, 4H), 7.17 (tt, J = 7.4, 0.8 Hz, 1H), 6.87 (d, J = 16.0 Hz, 1H), 5.92 (dd, J = 16.0, 9.0 Hz, 1H), 5.71 (d, J = 9.0 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.6, 144.0, 138.0, 136.0, 135.1, 132.6, 132.1, 129.2, 129.1, 128.9, 128.6, 126.9, 126.5, 125.4, 124.4, 123.5, 123.2, 64.7; HRMS (ESI) calcd for C 22 H 17 a [M+a] , found p Ph Bn 3-Benzyl-2-phenylisoquinolin-1(2H)-one (3p). Condition B: 32% yield, a white solid. With 44% 2p separated. Mp: 121~122 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 8.39 (dd, J = 8.6, 0.8 Hz, 1H), 7.64 (td, J = 7.4, 1.4 Hz, 1H), 7.48~7.43 (m, 2H), 7.39~7.37 (m, 3H), 7.21~7.18 (m, 3H), 7.05~7.03 (m, 2H), 6.90~6.88 (m, 2H), 6.34 (s, 1H), 3.64 (s, 2H); 13 C MR (100 MHz, CDCl 3 ): δ = 163.8, 142.2, , 137.0, 137.0, 132.8, 129.4, 129.2, 129.1, 128.7, 128.6, 128.4, 127.0, 126.7, 125.8, 123.4, 107.1, 40.6; HRMS (ESI) calcd for C 22 H 18 [M+H] , found ,3-Dimethyl-1-phenyl-5-vinylpyrrolidin-2-one (2q). Condition A: R. Condition: 10 mo% Pd(Ac) 2, 20 mol % pyridine, toluene, 48 h. 16% yield, a colorless oil. 1 H MR (400 MHz, CDCl 3 ): δ = 7.41~7.37 (m, 2H), 7.36~7.31 (m, 2H), 7.15 (tt, J = 7.2, 1.2 Hz, 1H), 5.64 (ddd, J = 17.8, 10.0, 7.6 Hz, 1H), 5.22 (dt, J = 17.2, 1.0 Hz, 1H), 5.13 (dt, J = 10.0, 0.8 Hz, 1H), 4.61 (q, J = 7.6 Hz, 1H), ( dd, J = 12.6, 7.6 Hz, 1H), 1.78 (dd, J = 12.8, 7.6 Hz, 1H), 1.31 (s, 3H), 1.22 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 179.3, 138.8, 138.2, 128.8, 125.4, 123.7, 118.1, 59.4, 41.9, 41.2, 25.9, 25.1; HRMS (ESI) calcd for C 14 H 18 [M+H] , found

28 Ph 2r 3-thyl-2-phenyl-3-vinylisoindolin-1-one (2r). Condition A: 99% yield. Condition B: 27% yield. Colorless crystals. Mp: 126~1270 o C; 1 H MR (400 MHz, CDCl 3 ): δ = 7.93 (d, J = 7.6 Hz, 1H), 7.59 (td, J = 7.6, 1.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.45~7.30 (m, 6H), 5.92 (dd, J = 17.4, 10.6 Hz, 1H), 5.32 (d, J = 17.2 Hz, 1H), 5.29 (d, J = 10.4 Hz, 1H), 1.60 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 167.9, 149.6, 140.7, 136.6, 132.5, 131.1, 129.2, 128.7, 128.3, 127.7, 124.4, 122.4, 116.3, 68.4, 22.2; HRMS (ESI) calcd for C 17 H 16 [M+H] , found a (20 mol %) Ph + Ph (1) Pd(Ac) 2 (10 mol %) 2,H,60 o C, 2 d 2a: 46% (18% ee) S19: 49%(E:Z = 3.1:1) 1 HMRyields 3-Ethylidene-2-phenylisoindolin-1-one (S19). Reaction conditions were similar to Condition A. The flame dried Schlenk tube was charged with Pd(Ac) 2 (4.6 mg, mmol, 0.1 equiv) and (S)-i-Pr-Pyox (7.6 mg, mmol, 0.2 equiv) under a 2 atmosphere and then the mixture was dissolved in dry H (2.0 m L). The solution was stirred at room temperature for 30 min, then substrate 1a (47.5 mg, 0.20 mmol, 1.0 equiv) was added. The reaction was cooled by liquid nitrogen, then degassed and recharged with 2 three times. The mixture was allowed to warm to room temperature and heated to 60 o C. After stirred 48 h, the reaction mixture was cooled to room temperature, and the H was removed by rotary evaporation. The residue was purified by flash column chromatography on silica gel (petroleum ether/etac = 20/1 to 10/1) to afford a mixture of 2a and S19 (44.7 mg, 95% yield). 1 H MR spectrum showed that 2a/(E)-S19/(Z)-S19 was 3.8/3.1/1. Chiral HPLC (AD-H column) showed that the ee of 2a was 18%. (E)-3-Ethylidene-2-phenylisoindolin-1-one ((E)-S19). (E)-S19 was also prepared as following procedure. The flame dried flask was charged with 2-phenylisoindoline-1,3-dione 14 (1.50 g, 6.72 mmol, 1.0 equiv) and freshly 28

29 distilled THF (50 ml). Ethylmagnesium bromide (3 in Et 2, 4.48 ml, 13.4 mmol, 2.0 equiv) was added dropwise to the mixture under -5 o C. After 1.5 h at -5 o C, the reaction was quenched by the addition of saturated aq H 4 Cl (20 ml), then extracted with EtAc (2 20 ml). The combined organic extracts were dried over MgS 4, filtered, and concentrated by rotary evaporation. A mixture of the res idue and TsH H 2 (0.128 g, mmol, 0.1 equiv) in toluene (50 ml) was refluxed using a Dean Stark apparatus for 6 h. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (CH 2 Cl 2 / petroleum ether = 1/1) to give (E)-S19 as a colorless oil (0.757 g, 48%). 1 H MR (400 MHz, CDCl 3 ): δ = 7.98 (dt, J = 7.6, 0.8 Hz, 1H), 7.93 (d, J = 7.6 Hz, 3H), 7.66 (td, J = 7.6, 1.2 Hz, 1H), 7.55 (td, J = 7.6, 0.8 Hz, 1H), 7.51 (m, 2H), 7.42 (td, J = 7.4, 1.6 Hz, 1H), 7.31 (m, 2H), 5.38 (q, J = 7.6 Hz, 1H), 2.17 (d, J = 7.6 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): δ = 166.2, 137.9, 135.7, 135.2, 132.3, 130.3, 129.6, 129.1, 129.0, 128.4, 124.0, 123.6, 108.0, 13.1; HRMS (ESI) calcd for C 16 H 14 [M+H] , found The configuration was detected by E. Although we could not isolate or prepare the pure (Z)-19, we still can provide some characteristic peaks in 1 H MR spectrum. δ = 5.75 (q, J = 8.0 Hz, 1H), 1.37 (d, J = 8.0 Hz, 3H). Scheme 1. 29

30 Some discussions: This result gave us some information about the aminopalladation step of the aza-wacker-type mechanism. Under condition A, syn-aminopalladation/ -H elimination of 1a would give products 2a and (E)-S19 (Scheme 1, path I), while anti-aminopalladation/ -H elimination of the same substrate would result in the formation of products 2a and (Z)-S19 (Scheme 1, path II). Thus, both types of aminopalladation are possible for five-membered ring forming reactions. However, since the (E)-S19 is thermodynamic stable, it might also be produced from 2a and (Z)-S19 under the catalysis of the L n PdH species. Therefore, the issue of cis- vs. trans-aminopalladation cannot be straightforwardly discerned from these results above. The mechanism of the six-membered ring construction reaction may be anti-aminopalladation/ -H elimination (Scheme 1, path III) because the syn-aminopalladation intermediate cannot -H eliminate to produce 3a (Scheme 1, path IV). ne of the reviewers suggested that these two intermediates could be transferred to each other via a π-benzyl interaction. Thus, we still cannot exclude the possibility completely that the 3a was formed through the syn-aminopalladation. 4. References (1) Faigl, F.; Thurner, A.; Molnár, B.; Simig, G.; Volk, B. rg. Process Res. Dev. 2010, 14, 617. (2) Fleming, P.; Shea, D. F. J. Am. Chem. Soc. 2011, 133, (3) Snider, B. B.; Gao, X. J. rg. Chem. 2005, 70, (4) eudeck, H. K. Monatsh. Chem. 1996, 127, 201. (5) W A (6) Shahzad, S. A.; Vivant,C.; Wirth, T. rg. Lett. 2010, 12, (7) W A (8) Bianchi, D. A.; Cipulli, M. A.; Kaufman, T. S. Eur. J. rg. Chem. 2003, (9) Capkova, K.; Yoneda, Y.; Dickerson, T. J.; Janda, K. D. Bioorg. d. Chem. Lett. 2007, 17, (10) Padwa, A.; Rieker, W. F.; Rosenthal, R. J. J. Am. Chem. Soc. 1985, 107, (11) Mali, R. S.; Patil, S. R.; Kulkarni, B. K.; Yeola, S.. Indian J. Chem., Sect. B 1990, 29, 319. (12) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, (13) Jithunsa, M.; Ueda, M.; Miyata,. rg. Lett. 2011, 13, 518. (14) Takebayashi, S.; John, J. M.; Bergens, S. H. J. Am. Chem. Soc. 2010, 132,

31 5. Spectra of ew Products S1 S1 31

32 S2 S2 32

33 S3 S3 33

34 + S5 S4 + S5 S4 34

35 C 2 H S11 C 2 H S11 35

36 C 2 H S12 C 2 H S12 36

37 C 2 H Cl S14 C 2 H Cl S14 37

38 C 2 H S15 C 2 H S15 38

39 Cl Br Cl Br 39

40 Cl C 2 H S16 Cl C 2 H S16 40

41 C 2 H S17 C 2 H S17 41

42 C 2 S18 C 2 S18 42

43 43

44 44

45 45

46 46

47 47

48 48

49 49

50 50

51 51

52 52

53 53

54 54

55 55

56 56

57 57

58 58

59 H 1q H 1q 59

60 H 1r H 1r 60

61 H 4 H 4 61

62 2a 2a 62

63 2b 2b 63

64 2c 2c 64

65 2d 2d 65

66 2e 2e 66

67 Cl 2f Cl 2f 67

68 Cl 2g Cl 2g 68

69 2h 2h 69

70 2i 2i 70

71 2j 2j 71

72 Cl 2k Cl 2k 72

73 2l 2l 73

74 2m 2m 74

75 2n 2n 75

76 2n' 2n' 76

77 2p 2p 77

78 2q 2q 78

79 2r 2r 79

80 3a 3a 80