Design of Ni(II)-Complex Stabilized -Alanine Derived Dienes; Generalized Approach For

Synthesis of polysubstituted β-amino cyclohexane carboxylic acids via diels-alder reactionusing Ni(II)-complex stabilized β-Alanine derived dienes

Xiao Ding†+, Hengshuai Wang†+, Jiang Wang†, Sinan Wang†,Daizong Lin†, Li Lv†, Yu Zhou†, Xiaomin Luo†,Hualiang Jiang†, José Luis Aceña§, Vadim A. Soloshonok‡,§, and Hong Liu†,*

† State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People’s Republic of China

‡University of the Basque Country UPV/EHU, San Sebastian, Spain

§IKERBASQUE, Basque Foundation for Science, 48011, Bilbao

+Authors equally contributed to this work.

Email:hl

Contents:

(A) General Method...... …………………………………………..S2

(B) Analytical and Spectral Characterization Data of Reaction Products……………………………………………………….S3

(C) Copies of 1H NMR and 13C NMR Spectra………….…...S12

(A) General Methods

The reagents (chemicals) were purchased from commercial sources, and used without further purification. Analytical thin layer chromatography (TLC) was HSGF 254 (0.15-0.2 mm thickness). All products were characterized by their NMR and MS spectra. 1H and 13C NMR spectra were recorded in deuterochloroform (CDCl3) on a 400MHz or 500MHz instrument. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low- and high-resolution mass spectra (LRMS and HRMS) were measured on spectrometer.

(B) Analytical and Spectral Characterization Data of Reaction Products

General procedures for the synthesis of 13a and 16a-16g. To a solution of 12(1 mmol)in PhCH3 (2.5 mL) and water (1 mL) was added boronic acid (2 mmol), followed by Na2CO3 (3 mmol)and Pd(PPh3)4 (0.05 mmol) in a sealed tube. The mixture was stirred at 80 oC for 40 min under microwave irradiation. Solvent was evaporated and the residue was dissolved in CH2Cl2 and extracted with NaHCO3 solution, brine and water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified via automated chromatography (CH2Cl2: CH3OH = 20:1, v/v) to give the corresponding product as red solids.

Ni(II)-PBP/2-(Aminomethylene)-3-methylbut-3-enoic Acid Schiff Base Complex 13a. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 82%. 1H NMR (400MHz, CDCl3):δ 8.53 - 8.51 (m, 1 H), 8.25 - 8.24 (m, 1 H), 8.02-8.00 (m, 1 H), 7.98 - 7.96 (m, 1 H), 7.56 - 7.46 (m, 6 H), 7.35 (dd, J = 3.0, 5.8 Hz, 1 H), 7.14 - 7.11 (m, 2 H), 6.82 - 6.81 (m, 2 H), 6.46 (s, 1 H), 1.71 (s, 3 H).13C NMR (100MHz, CDCl3):δ 172.9, 168.7, 165.6, 152.0, 145.2, 143.1, 140.1, 139.1, 138.3, 134.7, 133.9,133.1,130.6, 129.6, 129.0, 128.5, 123.5, 122.8, 120.9, 118.5, 24.3. ESI-MS: 468 [M+H]+. HRMS (ESI) m/z calcd for C25H19N3O3NaNi([M+Na]+): 490.0678, found: 490.0692.

Ni(II)-PBP/2-(Aminomethylene)but-3-enoic Acid Schiff Base Complex 16a. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 73%.1H NMR (400MHz,CDCl3):δ 8.28 (m, 1 H), 8.03-8.02 (m, 2 H), 8.01 (m, 1 H), 7.57 - 7.50 (m, 5 H), 7.40 - 7.34 (m, 2 H), 7.24 - 7.21 (m, 1 H), 7.16 - 7.14 (m, 2 H), 6.82 (m, 1 H), 6.69 (d, J = 1.5 Hz, 1 H), 6.54 (m, 1 H).13C NMR (125MHz, CDCl3):δ163.6, 150.2, 148.7, 139.8, 138.8, 137.4, 134.0, 133.5, 132.5, 130.1, 128.3, 126.5, 124.8, 122.7, 122.5, 121.7. ESI-MS: 454 [M+H]+. HRMS (ESI) m/z calcd for C24H17N3O3NaNi([M+Na]+): 476.0521, found: 476.0545.

Ni(II)-PBP/2-(Aminomethylene)pent-3-enoic Acid Schiff Base Complex 16b. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield 84%. 1H NMR (400MHz, CDCl3): δ 8.49 (d, J = 8.7 Hz, 1 H), 8.20 (d, J = 5.0 Hz, 1 H), 7.99 - 7.95 (m, 1 H), 7.88 (d, J = 7.5 Hz, 1 H), 7.57 - 7.54 (m, 1 H), 7.53 - 7.42 (m, 3 H), 7.35 - 7.31 (m, 1 H), 7.11 (d, J = 7.3 Hz, 2 H), 6.81 - 6.75 (m, 2 H), 6.46 (s, 1 H), 6.17 - 6.08 (m, 1 H), 5.95 (d, J = 15.5 Hz, 1 H), 1.69 (d, J = 6.4 Hz, 3 H). 13C NMR (100MHz, CDCl3): δ 172.4, 169.3, 166.3, 152.6, 145.7, 143.5, 140.7, 138.4, 136.3, 135.2, 134.3, 131.8, 131.1, 129.7, 129.1, 128.5, 126.9, 126.9, 124.1, 123.4, 121.5, 19.3. EI-MS: 467 [M]+. HRMS (EI) m/z calcd for C25H19N3NiO3 ([M]+): 467.0780, found: 467.0779.

Ni(II)-PBP/2-(Aminomethylene)hept-3-enoic Acid Schiff Base Complex 16c.Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield 91%. 1H NMR (400MHz, CDCl3):δ 8.51 (d, J = 8.6 Hz, 1 H), 8.21 (d, J = 4.8 Hz, 1 H), 8.00 - 7.96 (m, 1 H), 7.89 (d, J = 7.4 Hz, 1 H), 7.59 - 7.55 (m, 1 H), 7.52 - 7.44 (m, 3 H), 7.38 - 7.33 (m, 1 H), 7.14 (d, J = 7.1 Hz, 2 H), 6.83 - 6.78 (m, 2 H), 6.49 (s, 1 H), 6.18 - 6.10 (m, 1 H), 5.97 (d, J = 15.5 Hz, 1 H), 2.03 - 1.98 (m, 2 H), 1.38 - 1.32 (m, 2 H), 0.83 (t, J = 7.4 Hz, 3 H). 13C NMR (125MHz, CDCl3):δ 172.4, 169.5, 166.6, 152.7, 145.8, 143.5, 140.7, 138.3, 136.9, 136.3, 135.3, 134.3, 131.1, 129.8, 129.1, 128.6, 126.9, 125.7, 124.1, 123.4, 121.5, 35.7, 22.3, 13.8. EI-MS: 495 [M]+. HRMS (EI) m/z calcd for C27H23N3NiO3 ([M]+): 495.1093, found: 495.1088.

Ni(II)-PBP/2-(Aminomethylene)dec-3-enoic Acid Schiff Base Complex 16d.Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 93%. 1H NMR (400MHz, CDCl3):δ 8.50 (d, J = 8.7 Hz, 1 H), 8.24 (d, J = 4.6 Hz, 1 H), 7.96 - 8.00 (m, 1 H), 7.89 (d, J = 7.5 Hz, 1 H), 7.58 - 7.54 (m, 1 H), 7.52 - 7.45 (m, 3 H), 7.37 - 7.33 (m, 1 H), 7.13 (d, J = 7.3 Hz, 2 H), 6.83 - 6.75 (m, 2 H), 6.42 (s, 1 H), 6.16 - 6.08 (m, 1 H), 5.94 (d, J = 15.8 Hz, 1 H), 2.04 - 1.99 (m, 2 H), 1.31 - 1.20 (m, 8 H), 0.85 (t, J = 6.8 Hz, 3 H). 13C NMR (125MHz, CDCl3):δ 172.4, 169.5, 166.6, 152.8, 145.9, 143.6, 140.7, 138.3, 137.2, 136.4, 135.3, 134.4, 131.1, 129.8, 129.2, 128.6, 126.9, 125.6, 124.1, 123.5, 121.6, 77.5, 77.2, 77.0, 33.7, 31.9, 29.1, 29.1, 22.8, 14.3. EI-MS: 537 [M]+. HRMS (EI) m/z calcd for C30H29N3NiO3 ([M]+): 537.1562, found: 537.1564.

Ni(II)-PBP/2-(Aminomethylene)-4-cyclopropylbut-3-enoic Acid Schiff Base Complex 16e. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 90%. 1H NMR (400MHz, CDCl3):δ 8.50 (d, J = 9.2 Hz, 1 H), 8.22 (d, J = 5.6 Hz, 1 H), 8.00 - 7.96 (m, 1 H), 7.90 - 7.88 (m, 1 H), 7.58 - 7.54 (m, 1 H), 7.52 - 7.44 (m, 3 H), 7.37 - 7.33 (m, 1 H), 7.12 (d, J = 6.8 Hz, 2 H), 6.83 - 6.76 (m, 2 H), 6.37 (s, 1 H), 5.97 (d, J = 5.6 Hz, 1 H), 5.84 - 5.78 (m, 1 H), 1.43 - 1.34 (m, 1 H), 0.77 - 0.72 (m, 2 H), 0.46 - 0.42 (m, 2 H). 13C NMR (100MHz, CDCl3):δ 171.9, 169.5, 166.5, 152.8, 145.9, 143.5, 142.2, 140.7, 138.1, 136.4, 135.3, 134.3, 131.1, 129.9, 129.2, 128.6, 126.9, 124.1, 123.4, 123.2, 121.6, 15.8, 8.1. ESI-MS: 494 [M+H]+. HRMS (ESI) m/z calcd for C27H21N3NiO3 ([M+H]+): 494.0936, found: 494.1041.

Ni(II)-PBP/2-(Aminomethylene)-4-cyclohexylbut-3-enoic Acid Schiff Base Complex 16f. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 87%. 1H NMR (400MHz, CDCl3):δ 8.49 (d, J = 8.4 Hz, 1 H), 8.23 (d, J = 8.8 Hz, 1 H), 8.00 - 7. 96 (m, 1 H), 7.89 - 7.87 (m, 1 H), 7.58 - 7.54 (m, 1 H), 7.52 - 7.44 (m, 3 H), 7.37 - 7.32 (m, 1 H), 7.12 (d, J = 6.8 Hz, 2 H), 6.83 - 6.77 (m, 2 H), 6.41 (s, 1 H), 6.11 - 1.05 (m, 1 H), 5.89 (d, J = 6.0 Hz, 1 H), 1.97 - 1.89 (m, 1 H), 1.68 - 1.58 (m, 5 H), 1.27 - 1.17 (m, 2 H), 1.05 - 1.10 (m, 1 H), 1.06 - 0.96 (m, 2 H). 13C NMR (100MHz, CDCl3):δ 172.3, 1695, 166.5, 152.7, 145.8, 143.5, 142.5, 140.7, 138.3, 136.3, 135.3, 134.3, 131.1, 130.1, 129.8, 129.1, 128.5, 126.9, 124.1, 123.4, 123.3, 121.6, 41.8, 32.6, 26.2, 26.0. ESI-MS: 536 [M+H]+. HRMS (ESI) m/z calcd for C30H27N3NiO3 ([M+H]+): 536.1406, found: 536.1460.

Ni(II)-PBP/2-(Aminomethylene)-5,5-dimethylhex-3-enoic Acid Schiff Base Complex 16g. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 76%. 1H NMR (400MHz, CDCl3):δ 8.51 (d, J = 8.4 Hz, 1 H), 8.23 (d, J = 5.2 Hz, 1 H), 8.00 - 7.96 (m, 1 H), 7.90 - 7.88 (m, 1 H), 7.59 - 7.55 (m, 1 H), 7.53 - 7.44 (m, 3 H), 7.38 - 7.33 (m, 1 H), 7.14 (d, J = 6.8 Hz, 2 H), 6.84 - 6.79 (m, 2 H), 6.43 (s, 1 H), 6.12 (d, J = 6.0 Hz, 1 H), 5.89 (d, J = 6.0 Hz, 1 H), 0.96 (s, 9 H). 13C NMR (100MHz, CDCl3):δ 172.2, 169.3, 166.4, 152.6, 146.8, 145.7, 143.4, 140.4, 137.9, 136.2, 135.1, 134.1, 130.9, 129.7, 128.9, 128.4, 126.7, 126.8, 123.9, 123.2, 121.4, 120.5, 33.8, 29.2. ESI-MS: 510 [M+H]+. HRMS (ESI) m/z calcd for C28H25N3NiO3 ([M+H]+): 509.1249, found: 510.1353.

General procedures of Diels-Alder reaction for the synthesis of 15, 17a-17g and 19a-19g. To a solution of 13a or 16a-16g(1 mmol)in PhCH3 was added dienophiles (3 mmol). The mixture was stirred at 120 oC for 24 hours. Solvent was evaporated and the residue was purified via automated chromatography (CH2Cl2: CH3OH = 20:1, v/v) to give corresponding products as red solids.

Ni(II)-PBP/4-Amino-2-ethyl-6-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 15. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 92%.Mp 87-89ºC;1H NMR (400MHz, CDCl3):δ 8.59 - 8.55 (m, 1 H), 8.01 (m, 3 H), 7.55 - 7.34 (m, 6 H), 7.20 - 7.18 (m, 1 H), 7.11 - 7.03 (m, 1 H), 6.75 (d, J = 9.6 Hz, 2 H), 4.47 (m, 1 H), 3.57 - 3.48 (m, 3 H), 3.13 (m, 1 H), 2.90 - 2.86 (m, 1 H), 2.07 (s, 3 H), 1.00 - 0.96 (m, 3 H). 13C NMR (100MHz, CDCl3):δ 177.5, 141.9, 140.6, 139.9, 134.8, 133.9, 131.0, 130.2, 129.5, 129.3, 129.1, 128.5, 126.7, 121.5, 120.9, 63.7, 47.6, 39.5, 32.4, 29.7, 25.3, 21.8. ESI-MS: 593 [M+H]+. HRMS (ESI) m/z calcd for C31H26N4O5NaNi([M+Na]+): 615.1154, found: 615.1176.

Ni(II)-PBP/4-Amino-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17a. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 93%. Mp 79-81ºC;1H NMR (400MHz, CDCl3):δ 8.58 - 8.56 (m, 1 H), 8.07 - 7.99 (m, 3 H), 7.58 - 7.51 (m, 3 H), 7.30 - 7.15 (m, 3 H), 7.06 - 7.04 (m, 1 H), 6.76 - 6.74 (m, 3 H), 4.30 (m, 1 H), 3.51 - 3.48 (m, 2 H), 3.17 (dd, J = 5.2, 8.5 Hz, 1 H), 2.86 - 2.73 (m, 2 H), 1.58 - 1.52 (m, 1 H), 1.01 (t, 3 H).13C NMR (100MHz, CDCl3):δ176.9, 176.1, 175.7, 144.9, 139.5, 134.3, 133.5, 132.5, 129.8, 129.1, 128.8, 126.7, 126.1, 123.5, 120.4, 47.2, 38.9, 33.8, 24.7, 12.6. ESI-MS: 579 [M+H]+. HRMS (ESI) m/z calcd for C30H24N4O5NaNi([M+Na]+): 601.0998, found: 601.1013.

Ni(II)-PBP/4-Amino-2-ethyl-7-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17b. Obtained as a red solid by flash column chromatography (CH2Cl2:CH3OH = 20:1, v/v), yield: 90%.Mp 82-83ºC;1H NMR (400MHz, CDCl3):δ 8.60 - 8.50 (m, 1 H), 8.10 (m, 1 H), 8.01-8.00 (m, 2 H), 7.61 - 7.48 (m, 3 H), 7.42 (m, 1 H), 7.35 (ddd, J = 2.0, 6.6, 8.6 Hz, 1 H), 7.31 - 7.28 (m, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.76 - 6.73 (m, 2 H), 6.55 (dd, J = 2.3, 3.8 Hz, 1 H), 4.34 (m, 1 H), 3.51 - 3.47 (m, 2 H), 3.19 - 3.15 (m, 1 H), 2.71 - 2.69 (m, 1 H), 1.77-1.74 (m, 1 H), 1.36 (d, J = 7.1 Hz, 3 H), 1.01 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3):δ 175.0, 140.0, 139.4, 134.0, 133.6, 130.3, 129.6, 129.3, 129.2, 129.1, 127.1, 126.5, 121.2, 121.0, 61.4, 48.8, 44.0, 34.0, 32.0, 16.1, 13.1. ESI-MS: 593 [M+H]+. HRMS (ESI) m/z calcd for C31H26N4O5NaNi([M+Na]+): 615.1154, found: 615.1172.

Ni(II)-PBP/4-Amino-2-ethyl-1,3-dioxo-7-propyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17c. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 88%.Mp 75-77ºC;1H NMR (400MHz, CDCl3):δ 8.57 - 8.55 (m, 1 H), 8.10 (m, 1 H), 8.01-7.99 (m, 2 H), 7.58 - 7.56 (m, 3 H), 7.42 (td, J = 3.0, 5.7 Hz, 1 H), 7.35 - 7.28 (m, 2 H), 7.10 - 7.02 (m, 1 H), 6.77 - 6.75 (m, 2 H), 6.60 (dd, J = 2.4, 3.9 Hz, 1 H), 4.32 (br. s., 1 H), 3.50 - 3.46 (m, 2 H), 3.16 (dd, J = 5.1, 8.3 Hz, 1 H), 2.78 (t, J = 7.8 Hz, 1 H), 1.70 - 1.68 (m, 1 H), 1.66 - 1.64 (m, 1 H), 1.54 - 1.46 (m, 1 H), 1.39 - 1.36 (m, 2 H), 1.00 (t, J = 7.2 Hz, 3 H), 0.88 (t, 3 H). 13C NMR (100 MHz, CDCl3):δ 175.0, 145.3, 143.7, 140.0, 138.7, 134.7, 134.0, 133.8, 130.2, 129.6, 129.3, 127.2, 126.6, 126.2, 124.0, 123.4, 120.9, 61.6, 48.5, 42.7, 37.5, 34.0, 32.4, 21.2, 13.8, 13.1. ESI-MS: 621 [M+H]+. HRMS (ESI) m/z calcd for C33H30N4O5NaNi([M+Na]+): 643.1467, found: 643.1491.

Ni(II)-PBP/4-Amino-7-hexy-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17d. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 85%.Mp 77-79ºC; 1H NMR (400MHz, CDCl3):δ 8.54 (d, J = 8.4 Hz, 1H), 8.11 (m, 1H), 7.99 (d, J = 4.4 Hz, 2H), 7.57 - 7.52 (m, 3H), 7.50 - 7.30 (m, 3H), 7.05 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 2.7 Hz, 2H), 6.58 (m, 1H), 4.35 (d, J = 1.7 Hz, 1H), 3.52 - 3.39 (m, 3H), 3.17 - 3.12 (m, 1H), 2.77 (t, J = 7.7 Hz, 1H), 1.78 - 1.48 (m, 6H), 1.42 - 1.39 (m, 2H), 1.39 - 1.07 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). ESI-MS: 663 [M+H]+.13C NMR (100 MHz, CDCl3): δ175.0, 145.4, 140.0, 138.8, 134.7, 134.0, 130.2, 129.6, 129.3, 129.3, 127.1, 126.5, 124.0, 120.9, 61.7, 48.5, 42.8, 37.8, 34.0, 31.6, 30.3, 29.0, 28.1, 22.6, 14.1, 13.1. ESI-MS: 663 [M+H]+.HRMS (ESI) m/z calcd for C36H36N4O5NaNi([M+Na]+): 685.1937, found: 685.1976.

Ni(II)-PBP/4-Amino-7-cyclopropyl-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17e. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 90%.Mp 80-81ºC; 1H NMR (400MHz, CDCl3):δ8.53 (d, J = 8.7 Hz, 1H), 8.14 (m, 1H), 7.99 (d, J = 4.4 Hz, 2H), 7.55 - 7.45 (m, 4H), 7.42 (d, J = 4.0 Hz, 1H), 7.27 - 7.38-7.27 (m, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.76-6.66 (m, 3H), 4.29 (m, 1H), 3.53 - 3.42 (m, 2H), 3.13 (dd, J = 8.2, 5.2 Hz, 1H), 2.82 (t, J = 7.9 Hz, 1H), 1.75 (m, 2H), 1.34 - 1.27 (m, 1H), 0.99 (t, J = 7.0 Hz, 3H), 0.74-.0.65 (m, 1H), 0.61 (dd, J = 7.9, 5.2 Hz, 2H). 13C NMR (100MHz, CDCl3):δ174.6, 145.0, 139.6, 137.5, 134.2, 133.5, 129.8, 129.1, 128.8, 126.7, 126.0, 123.6, 120.4, 60.9, 48.0, 43.0, 42.9, 33.6, 29.2, 12.6, 10.9. ESI-MS: 619 [M+H]+. HRMS (ESI) m/z calcd for C33H28N4O5NaNi([M+Na]+): 641.1311, found: 641.1341.

Ni(II)-PBP/4-Amino-7-cyclohexyl-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17f. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 82%.Mp 75-76ºC; 1H NMR (400MHz, CDCl3):δ 8.51 (d, J = 8.7 Hz, 1H), 8.14 (m, 1H), 7.99-7.97 (m, 2H), 7.56 - 7.40 (m, 5H), 7.36 - 7.27 (m, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.73 - 6.64 (m, 3H), 4.39 (m, 1H), 3.46 - 3.38 (m, 2H), 3.13 - 3.01 (m, 2H), 2.14 (d, J = 11.4 Hz, 1H), 1.92 - 1.80 (m, 3H), 1.66 - 1.63 (m, 2H), 1.34 - 1.20 (m, 2H), 0.98 - 1.15 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H), 0.60 - 0.75 (m, 2H).13C NMR (100MHz, CDCl3):δ 175.1, 145.3, 140.1, 138.0, 134.8, 134.0, 133.5, 130.2, 129.6, 129.2, 127.2, 126.6, 123.9, 120.6, 62.0, 48.0, 44.2, 40.4, 38.7, 34.0, 32.7, 31.0, 28.3, 25.8, 25.8, 13.1. ESI-MS: 661 [M+H]+. HRMS (ESI) m/z calcd for C36H34N4O5NaNi([M+Na]+): 683.1780, found: 683.1812.

Ni(II)-PBP/4-Amino-7-(tert-butyl)-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex17g. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 76%.Mp 72-74ºC; 1H NMR (400MHz, CDCl3):δ 8.57 - 8.55 (m, 1 H), 8.28 - 8.10 (m, 1 H), 8.01 - 7.99 (m, 2 H), 7.59 - 7.57 (m, 3 H), 7.47 - 7.40 (m, 1 H), 7.37 - 7.33 (m, 2 H), 7.05 (m, 1 H), 6.89 - 6.83 (m, 1 H), 6.76 (d, J = 4.0 Hz, 2 H), 4.37 (br. s., 1 H), 3.50 - 3.45 (m, 2 H), 3.18 (dd, J = 4.8, 8.3 Hz, 1 H), 2.96 (t, J = 7.8 Hz, 1 H), 1.74 (m, 1 H), 1.04-1.00 (m, 12 H).13C NMR (100MHz,CDCl3): δ 175.4, 145.3, 139.5, 135.2, 134.1, 133.4, 129.7, 129.1, 128.8, 126.5, 126.1, 123.6, 120.5, 60.7, 49.6, 48.8, 41.4, 33.7, 31.6, 28.1, 12.6. ESI-MS: 635 [M+H]+. HRMS (ESI) m/z calcd for C34H32N4O5NaNi([M+Na]+): 657.1624, found: 657.1638.

Ni(II)-PBP/4-Amino-2,6-dimethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5- carboxylic Acid Schiff Base Complex19a. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 92%. Mp 83-85ºC; 1H NMR (400MHz, CDCl3):δ 8.55 - 8.53 (m, 1 H), 8.20 (m, 2 H), 8.10 - 7.99 (m, 1 H), 7.52 - 7.40 (m, 4 H), 7.40 (m, 2 H), 7.09 - 6.98 (m, 1 H), 6.82 - 6.73 (m, 3 H), 4.46 - 4.38 (m, 1 H), 3.42 - 3.16(m, 1 H), 2.92 (s, 3 H), 2.89 - 2.86 (m, 1 H), 2.53 (dd, J = 1.6, 15.0 Hz, 1 H), 2.09 (s, 3 H).13C NMR (100MHz, CDCl3): δ177.4, 177.1, 145.5, 145.4, 142.2, 141.9, 140.6, 139.9, 135.6, 134.9, 134.8, 133.9, 131.0, 130.2, 129.5, 129.3, 129.2, 129.1, 127.0, 126.8, 126.7, 124.0, 123.9, 121.4, 120.9, 119.5, 63.7, 47.6, 39.5, 32.4, 29.7, 25.3, 21.8. ESI-MS: 579 [M+H]+. HRMS (ESI) m/z calcd for C30H24N4O5NaNi([M+Na]+): 601.0998, found: 601.1010.

Ni(II)-PBP/4-Amino-6-methyl-1,3-dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 19b. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 72%. Mp 88-90ºC; 1H NMR (400MHz,CDCl3): δ 8.53 - 8.51 (m, 1 H), 8.00 (m, 1 H), 7.88 - 7.87 (m, 2 H), 7.60 - 7.56 (m, 5 H), 7.33 - 7.28 (m, 5 H), 7.11 - 7.09 (m, 3 H), 6.75 - 6.74 (m, 2 H), 4.56 - 4.41 (m, 1 H), 3.32 - 3.29 (m, 1 H), 3.11 (t, J = 6.6 Hz, 1 H), 2.68 - 2.64 (m, 1 H), 2.14 (s, 3 H). 13C NMR (100MHz, CDCl3):δ 176.0, 175.7, 144.7, 143.2, 141.5, 139.2, 134.4, 133.5, 131.2, 129.7, 129.1, 128.9, 128.4, 128.2, 126.6, 126.3, 125.9, 123.4, 120.4, 64.0, 46.8, 39.4, 31.9, 21.3. ESI-MS: 641 [M+H]+. HRMS (ESI) m/z calcd for C35H26N4O5NaNi([M+Na]+): 663.1154, found: 663.1171.

Ni(II)-PBP/6-Amino-4,5-bis(methoxycarbonyl)-2-methylcyclohex-1-enecarboxylic Acid Schiff Base Complex 19d. Obtained as a red solid by flash column chromatography (CH2Cl2: CH3OH = 20:1, v/v), yield: 58%. Mp 70-71ºC; 1H NMR (400MHz, CDCl3):δ 8.65 - 8.58 (m, 1 H), 8.30 - 8.12 (m, 1 H), 8.04 - 7.92 (m, 2 H), 7.53 - 7.51 (m, 5 H), 7.44 - 7.28 (m, 1 H), 7.02 - 6.95 (m, 1 H), 6.87 (m, 1 H), 6.80 - 6.77 (m, 1 H), 5.00 (m, 1 H), 3.67 (s, 3 H), 3.58 (d, J = 7.1 Hz, 2 H), 3.52 (m, 1 H), 3.44 (m, 1 H), 3.27 (s, 3 H), 2.00 - 1.95 (m, 3 H).13C NMR (100MHz, CDCl3):δ 172.2, 170.1, 168.7, 145.4, 145.3, 140.0, 139.9, 134.1, 134.1, 134.0, 133.9, 130.2, 130.0, 129.3, 129.3, 128.1, 127.9, 124.5, 120.8, 51.8, 51.7, 51.5, 44.6, 36.4, 32.3, 29.4. ESI-MS: 612 [M+H]+. HRMS (ESI) m/z calcd for C31H27N3O7NaNi([M+Na]+): 634.1100, found: 634.1151.

Procedures for the synthesis of 4-Amino-2-ethyl-1,3-dioxo-7-propyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid 20. The complex 17c(300mg) was decomposed by refluxing a suspension in a mixture of aqueous 1N HCl (1 mL) and CH3OH (15 mL) for 30 min, until the red color of the solution disappeared. The reaction was cooled to room temperature and then evaporated to dryness. Water (20 mL) was added to the residue to form a clear solution, and this solution was then separated by column chromatography on C18-reversed phase (230-400 mesh) silica gel. Pure water as an eluent was employed to remove the green NiCl2 and excess HCl; CH3CN/Water (1/1, 0.1%HCl) was then used to obtain the product as a white solid.1H NMR (400MHz,CD3OD):δ 6.95 - 6.93 (m, 1 H), 4.25 - 4.24 (m, 1 H), 3.59 (dd, J = 5.6, 8.6 Hz, 1 H), 3.46 - 3.44 (m, 3 H), 2.54 (dd, J = 4.2, 7.2 Hz, 1 H), 1.97 - 1.96 (m, 1 H), 1.81 (m, 1 H), 1.59 - 1.55 (m, 2 H), 1.08 - 1.02 (m, 6 H). 13C NMR (100MHz, CD3OD):δ 178.0, 174.9, 45.6, 42.6, 41.4, 34.1, 32.5, 21.1, 18.6, 13.9, 12.8. ESI-MS: 281 [M+H]+. HRMS (ESI) m/z calcd for C14H21N2O4 ([M+H]+): 281.1501, found: 281.1534.

(C) Copies of 1H NMR and13CNMR Spectra for the Products

Ni(II)-PBP/2-(Aminomethylene)-3-methylbut-3-enoic Acid Schiff Base Complex 13a.

Ni(II)-PBP/2-(Aminomethylene)but-3-enoicAcid Schiff Base Complex 16a.

Ni(II)-PBP/2-(Aminomethylene)pent-3-enoic Acid Schiff Base Complex 16b.

Ni(II)-PBP/2-(Aminomethylene)hept-3-enoic Acid Schiff Base Complex16c.

Ni(II)-PBP/2-(Aminomethylene)dec-3-enoic Acid Schiff Base Complex 16d.

Ni(II)-PBP/2-(Aminomethylene)-4-cyclopropylbut-3-enoic Acid Schiff Base Complex 16e.

Ni(II)-PBP/2-(Aminomethylene)-4-cyclohexylbut-3-enoic Acid Schiff Base Complex16f.

Ni(II)-PBP/2-(Aminomethylene)-5,5-dimethylhex-3-enoic Acid Schiff Base Complex16g.

Ni(II)-PBP/4-Amino-2-ethyl-6-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex15.

Ni(II)-PBP/4-Amino-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex17a.

Ni(II)-PBP/4-Amino-2-ethyl-7-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex17b.

Ni(II)-PBP/4-Amino-2-ethyl-1,3-dioxo-7-propyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex17c.

Ni(II)-PBP/4-Amino-7-hexy-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17d .

Ni(II)-PBP/4-Amino-7-cyclopropyl-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 17e.

Ni(II)-PBP/4-Amino-7-cyclohexyl-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex17f.

Ni(II)-PBP/4-Amino-7-(tert-butyl)-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex17g.

Ni(II)-PBP/4-Amino-2,6-dimethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylicAcid Schiff Base Complex19a.

Ni(II)-PBP/4-Amino-6-methyl-1,3-dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid Schiff Base Complex 19b.

Ni(II)-PBP/6-Amino-4,5-bis(methoxycarbonyl)-2-methylcyclohex-1-enecarbo- xylic Acid Schiff Base Complex 19d.

4-Amino-2-ethyl-1,3-dioxo-7-propyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carboxylic Acid 20.

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