Synthesis of polysubstituted β-amino cyclohexane carboxylic acids via dielsalder reaction using 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: hliu@mail.shcnc.ac.cn
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
S1
(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
13
C 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.
S2
(B) Analytical and Spectral Characterization Data of Reaction Products
General procedures for the synthesis of 13 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 13.
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).
13
C 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): δ 163.6, 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.
S3
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).
13
C 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
S4
H), 2.04 - 1.99 (m, 2 H), 1.31 - 1.20 (m, 8 H), 0.85 (t, J = 6.8 Hz, 3 H).
13
C 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).
13
C 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).
13
C 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
S5
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).
C NMR (100MHz, CDCl3): δ 172.2, 169.3, 166.4, 152.6,
13
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-5carboxylic 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
S6
(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): δ 176.9, 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
S7
(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).
C NMR (100 MHz, CDCl3): δ 175.0, 145.3,
13
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;
1
H NMR (400MHz,
CDCl3): δ 8.54 (d, J = 8.4 Hz, 1 H), 8.11 (m, 1 H), 7.99 (d, J = 4.4 Hz, 2 H), 7.57 - 7.52 (m, 3
H), 7.50 - 7.30 (m, 3 H), 7.05 (d, J = 7.4 Hz, 1 H), 6.73 (d, J = 2.7 Hz, 2 H), 6.58 (m, 1 H), 4.35
(d, J = 1.7 Hz, 1 H), 3.52 - 3.39 (m, 3 H), 3.17 - 3.12 (m, 1 H), 2.77 (t, J = 7.7 Hz, 1 H), 1.78 1.48 (m, 6 H), 1.42 - 1.39 (m, 2 H), 1.39 - 1.07 (m, 2 H), 0.98 (t, J = 7.2 Hz, 3 H), 0.86 (t, J = 7.2
Hz, 3 H). ESI-MS: 663 [M+H]+.
13
C NMR (100 MHz, CDCl3): δ 175.0, 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): δ 8.53 (d, J = 8.7 Hz, 1 H), 8.14 (m, 1 H), 7.99 (d, J = 4.4 Hz, 2 H), 7.55 - 7.45 (m, 4
H), 7.42 (d, J = 4.0 Hz, 1 H), 7.27 - 7.38-7.27 (m, 1 H), 7.03 (d, J = 7.0 Hz, 1 H), 6.76-6.66 (m, 3
H), 4.29 (m, 1 H), 3.53 - 3.42 (m, 2 H), 3.13 (dd, J = 8.2, 5.2 Hz, 1 H), 2.82 (t, J = 7.9 Hz, 1 H),
1.75 (m, 2 H), 1.34 - 1.27 (m, 1 H), 0.99 (t, J = 7.0 Hz, 3 H), 0.74-.0.65 (m, 1 H), 0.61 (dd, J =
S8
7.9, 5.2 Hz, 2 H). 13C NMR (100MHz, CDCl3): δ 174.6, 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-isoindole5-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, 1 H), 8.14 (m, 1 H), 7.99 - 7.97 (m, 2 H), 7.56 - 7.40 (m, 5 H),
7.36 - 7.27 (m, 1 H), 7.06 (d, J = 7.4 Hz, 1 H), 6.73 - 6.64 (m, 3 H), 4.39 (m, 1 H), 3.46 - 3.38
(m, 2 H), 3.13 - 3.01 (m, 2 H), 2.14 (d, J = 11.4 Hz, 1 H), 1.92 - 1.80 (m, 3 H), 1.66 - 1.63 (m, 2
H), 1.34 - 1.20 (m, 2 H), 0.98 - 1.15 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H), 0.60 - 0.75 (m, 2 H). 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-isoindole5-carboxylic Acid Schiff Base Complex 17g. 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,
S9
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-5carboxylic
Acid Schiff Base Complex 19a. 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).
13
C NMR
(100MHz, CDCl3): δ 177.4, 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-5carboxylic 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;
1
H 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:
S10
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 NiCl 2 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.
S11
(C) Copies of 1H NMR and 13C NMR Spectra for the Products
Ni(II)-PBP/2-(Aminomethylene)-3-methylbut-3-enoic
Complex 13.
S12
Acid
Schiff
Base
S13
Ni(II)-PBP/ 2-(Aminomethylene)but-3-enoic Acid Schiff Base Complex 16a.
S14
S15
Ni(II)-PBP/ 2-(Aminomethylene)pent-3-enoic Acid Schiff Base Complex 16b.
S16
S17
Ni(II)-PBP/ 2-(Aminomethylene)hept-3-enoic Acid Schiff Base Complex 16c.
S18
S19
Ni(II)-PBP/ 2-(Aminomethylene)dec-3-enoic Acid Schiff Base Complex 16d.
S20
S21
Ni(II)-PBP/2-(Aminomethylene)-4-cyclopropylbut-3-enoic Acid Schiff Base
Complex 16e.
S22
S23
Ni(II)-PBP/2-(Aminomethylene)-4-cyclohexylbut-3-enoic Acid Schiff Base
Complex 16f.
S24
S25
Ni(II)-PBP/2-(Aminomethylene)-5,5-dimethylhex-3-enoic Acid Schiff Base
Complex 16g.
S26
S27
Ni(II)-PBP/4-Amino-2-ethyl-6-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1Hisoindole-5-carboxylic Acid Schiff Base Complex 15.
S28
S29
Ni(II)-PBP/ 4-Amino-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole5-carboxylic Acid Schiff Base Complex 17a.
S30
S31
Ni(II)-PBP/ 4-Amino-2-ethyl-7-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1Hisoindole-5-carboxylic Acid Schiff Base Complex 17b.
S32
S33
Ni(II)-PBP/ 4-Amino-2-ethyl-1,3-dioxo-7-propyl-2,3,3a,4,7,7a-hexahydro-1Hisoindole-5-carboxylic Acid Schiff Base Complex 17c.
S34
S35
Ni(II)-PBP/ 4-Amino-7- hexy-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1Hisoindole-5-carboxylic Acid Schiff Base Complex 17d .
S36
S37
Ni(II)-PBP/ 4-Amino-7-cyclopropyl-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro1H-isoindole-5-carboxylic Acid Schiff Base Complex 17e.
S38
S39
Ni(II)-PBP/ 4-Amino-7-cyclohexyl-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro1H-isoindole-5-carboxylic Acid Schiff Base Complex 17f.
S40
S41
Ni(II)-PBP/ 4-Amino-7-(tert-butyl)-2-ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro1H-isoindole-5-carboxylic Acid Schiff Base Complex 17g.
S42
S43
Ni(II)-PBP/4-Amino-2,6-dimethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1Hisoindole-5-carboxylic Acid Schiff Base Complex 19a.
S44
S45
Ni(II)-PBP/4-Amino-6-methyl-1,3-dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro1H-isoindole-5-carboxylic Acid Schiff Base Complex 19b.
S46
S47
Ni(II)-PBP/6-Amino-4,5-bis(methoxycarbonyl)-2-methylcyclohex-1-enecarboxylic Acid Schiff Base Complex 19d.
S48
S49
4-Amino-2-ethyl-1,3-dioxo-7-propyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5carboxylic Acid 20.
S50
S51