Ⅲ. Chapter 3. Electrochemical C(sp 3 )-H Functionalization of ɣ-Lactams based on Hydrogen
3.10 Procedure for the electrolysis
For 0.1 mmol scales, the glassy carbon (GC) anode and carbon felt (CF) cathode with dimensions of 0.8 cm x 0.2 cm x 5.2 cm and 0.8 cm x 0.2 cm x 3.5 cm, respectively, were employed. For experiments for larger scales, the dimensions are specified in the relevant experimental section and it carried out in an undivided cell.
57
Graphical guide for electrochemical amination of ElectraSyn 2.0
a. b.
Figure 3-7. a: ElectraSyn 2.0. b: ElectraSyn vial (5 mL).
a. b.
Figure 3-8. a: Upper: ElectraSyn 2.0 vial cap; middle: electrodes (carbon felt and glassy carbon);
lower: electrode holders. b: The electrode holders were plugged into the vial cap.
General Procedure (A) for ElectraSyn and characterization of 3-substituted lactam
The reaction was carried out in an undivided cell. A 5 mL vial was charged with the lactam derivative 1/4 (0.1 mmol, 1.0 equiv.), alkene 2 (x equiv.), nBu4NN3 (0.3 M solution in MeCN) (0.1 ml, 30 mol%), MeCN (3.7 mL, 0.1 M nBu4NBF4) and a stir bar, and was closed with a cap attached with a glassy carbon anode and a carbon felt cathode. The solution was stirred at 900 rpm for 10 minutes at room
58
temperature before current was turned on. The electrolysis was performed at a constant current of 3 mA.
Upon full consumption of the lactam starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, the solvent was removed under reduced pressure. The product was purified by flash chromatography. Structural assignments were made with additional information from gHSQC and gHMBC experiments
General Procedure (B) for ElectraSyn and characterization of polycyclic compound (inter- intramolecular cyclization)
The reaction was carried out in an undivided cell. A 5 mL vial was charged with the 2-methylisoindolin- 1-one 1a (0.1 mmol, 1.0 equiv.), alkene 2 (1.5 equiv.), nBu4NN3 (0.3 M solution in MeCN) (0.1 ml, 30 mol%), MeCN (3.7 mL, 0.1 M nBu4NBF4) and a stir bar, and was closed with a cap attached with a glassy carbon anode and a carbon felt cathode. The solution was stirred at 900 rpm for 10 minutes at room temperature before current was turned on. The electrolysis was performed at a constant current of 3 mA. Upon full consumption of the isoindolinone starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, the solvent was removed under reduced pressure.
The product was purified by flash chromatography. Structural assignments were made with additional information from gHSQC, gHMBC and NOESY experiments
General Procedure (C) for ElectraSyn and characterization of polycyclic compound (intramolecular cyclization)
The reaction was carried out in an undivided cell. A 5 mL vial was charged with the isoindolinone derivative 6 (0.1 mmol, 1.0 equiv.), nBu4NN3 (0.3 M solution in MeCN) (0.1 ml, 30 mol%), MeCN (3.7 mL, 0.1 M nBu4NBF4) and a stir bar, and was closed with a cap attached with a glassy carbon anode and a carbon felt cathode. The solution was stirred at 900 rpm for 10 minutes at room temperature before current was turned on. The electrolysis was performed at a constant current of 3 mA. Upon full consumption of the isoindolinone starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, the solvent was removed under reduced pressure. The product was purified by flash chromatography.
General Procedure (D) for ElectraSyn and characterization of sulfonamide
The reaction was carried out in an undivided cell. A 5 mL vial was charged with the 2-methylisoindolin-
59
1-one 1a (0.4 mmol, 1.0 equiv.), aldimine 8 (1.5 equiv.), nBu4NN3 (0.3 M solution in MeCN) (0.4 ml, 30 mol%), MeCN (3.6 mL, 0.1 M nBu4NBF4) and a stir bar, and was closed with a cap attached with a glassy carbon anode and a carbon felt cathode. The solution was stirred at 900 rpm for 10 minutes at room temperature before current was turned on. The electrolysis was performed at a constant current of 9 mA. Upon full consumption of the aldimine starting material as determined by thin-layer chromatography analysis, additional aldimine 8 (1.5 equiv.) was added. Upon full consumption of the lactam starting material as determined by thin-layer chromatography analysis, electrolysis was terminated, the solvent was removed under reduced pressure. The product was purified by flash chromatography.
Synthesis of dihydroaristolactam and aristolactam derivatives
To a suspension of methyl 3-(2-bromophenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate 3ai (0.05 mmol, 1.0 equiv., d.r. = 4:1), Pd(OAc)2 (7 mol%), PCy3HBF4 (14 mol%), and K2CO3 (2.0 equiv.) in DMA (0.2 ml, 0.3 M) was microwave irradiated at X °C for 30 minutes (microwave). The reaction mixture was filtered through a pad of Celite®, and concentrated. The crude material was purified by flash chromatography.
Synthesis of tricyclic compound
Methyl 3-(2-(4-methoxybenzyl)-3-oxoisoindolin-1-yl)-3-phenylpropanoate 3ja (0.05 mmol, 1.0 equiv.) was dissolved in DCE (0.5 ml) and trifluoroacetic acid (0.5 ml). The mixture was stirred at 80 °C (oil bath). After the completion of the reaction, the solution was diluted with DCMand washed with saturated solution of NaHCO3. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography to afford desired product methyl 3-(3-oxoisoindolin-1-yl)-3-phenylpropanoate. This compound (0.04 mmol, 1.0 equiv.) was dissolved with p-toluenesulfonic acid monohydrate (1.0 equiv.) in o-xylene (0.1 M) and stirred at 150 °C (oil bath).
After the completion of the reaction, the solution was diluted with ethyl acetate and washed with water.
The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography to afford desired product 1-phenyl-1,9b-dihydro-3H-pyrrolo[2,1- a]isoindole-3,5(2H)-dione 8c. To a stirred solution of compound 8c (0.1 mmol, 1.0 equiv.) in THF (0.1
60
M) was added BH3-SMe2 (10.0 equiv.) dropwise at 0 °C, and then the mixture was stirred at room temperature. Once the reaction was determined to be completed by TLC, MeOH (0.05 M) was added, and the solvent was removed under reduced pressure. The product 8d was purified through the flash chromatography. Structural assignments were made with additional information from gHSQC, gHMBC and NOESY experiments