t-BuOK mediated oxidative coupling amination of 1,4-naphthoquinone and related 3-indolylnaphthoquinones with amines

The transition-metal free amination of 1,4-naphthoquinone and related 3-indolylnaphthoquinones with amines, such as various (hetero)aromatic amine and aliphatic amine via t-BuOK-mediated oxidative coupling at room temperature has been developed. This reaction provides efficient access to the biologically important and synthetically useful 2-amino-1,4-naphthoquinones and 2-amino-3-indolylnaphthoquinones with good yields under mild conditions. The present protocol is simple, practical and shows good functional group tolerance. In addition, the obtained 2-amino-3-indolylnaphthoquinones were further transformed to synthesize polycyclic N-heterocycles.


General information
Chemicals and analytical grade solvents were purchased from commercial suppliers and used without further purification unless otherwise stated. All reagents were weighed and handled in air at room temperature. Analytical thin-layer chromatography was performed on glass plates of Silica Gel GF-254 with detection by UV light (254 and 365 nm). Column chromatography was carried out on silica gel (200-300 mesh). 1 H NMR spectra were recorded at 400 MHz and 13 C NMR spectra were recorded at 101 MHz by using Agilent 400 MHz NMR spectrometer. Chemical shifts were calibrated using residual undeuterated solvent as an internal reference ( 1 H NMR: CDCl 3 7.26 ppm, DMSO-d 6 2.50 ppm, 13 C NMR: CDCl 3 77.16 ppm, DMSO-d 6 39.52 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), Coupling constants (J) were reported in Hertz (Hz). HRMS were performed on a Thermo Scientific LTQ Orbitrap XL instrument. Melting points were measured with micro melting point apparatus.

General procedure for the synthesis of the compounds
To a solution of indolylnaphthoquinon 、 phenylnaphthoquinones or 1,4-naphthoquinone (0.3 mmol), t-BuOK (0.6 mmol, 2 equiv) in DMF (2 mL) was added amines 2 (0.6 mmol, 2 equiv). The reaction mixture was stirred at room temperature under air atmosphere for 2 h. After the completion of the reaction (monitored by TLC). The reaction was quenched with saturated salt water (8 ml) and the mixture was extracted with EtOAc (3 × 3 mL). The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography to give 3 or 5.
To a solution of the 2-amino-3-indolylnaphthoquinones derivatives 3 (0.3 mmol), t-BuOK (0.45 mmol, 1.5 equiv) in DMF (2 mL) was added CoCl 2 (0.009 mmol, 3 mol %), The reaction mixture was stirred at 120 o C under air atmosphere for 24 h. After the completion of the reaction (monitored by TLC), and cooled down to room temperature. The reaction was quenched with saturated salt water (8 ml) and the mixture was extracted with EtOAc (3 × 3 mL). The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography to give 6.

Procedure for gram-scale reaction
To a solution of indolylnaphthoquinone 1a (1.43 g), t-BuOK ( 1.12 g, 2.0 equiv) in DMF (33 mL) was added aniline 2a (0.93 g, 2.0 equiv). The reaction mixture was stirred at room temperature under air atmosphere for 2 h. After the completion of the reaction (monitored by TLC), The reaction was quenched with saturated salt water (120 ml) and the mixture was extracted with EtOAc (3 × 60 mL). The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography to give 3a in 83% yield.
To a solution of naphthoquinone 4a (0.79 g), t-BuOK ( 1.12 g, 2.0 equiv) in DMF (33 mL) was added aniline 2a (0.93 g, 2.0 equiv). The reaction mixture was stirred at room temperature under air atmosphere for 2 h. After the completion of the reaction (monitored by TLC), The reaction was quenched with saturated salt water (120 ml) and the mixture was extracted with EtOAc (3 × 60 mL). The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography to give 5a in 83% yield.