* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With calcium carbonate; In methanol; dichloromethane; at 20℃;
Example 310A 5-chloro-2-iodo-4-methylaniline 3-CHLORO-4-METHYLANILINE (1. 50G, 10.6 mmol) and benzyltrimethylammonium dichloroiodate (4.60g, 13.2 mmol) were dissolved in CH2C12 (50 mL) and MEOH (20 mL), then CACO3 (3.10g, 31. 0 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with Et20 (200 mL), filtered through CELITE and concentrated. The crude material was purified by column chromatography using 97. 5/2. 5 HEXANE/ETOAC, giving the product (1. 80g, 63%) as light tan solids. MS (DCI) m/e 268 and 270 (M+H) + ; IH NMR (300 MHz, CDC13) 8 7.48 (s, 1H), 6.76 (s, 1H), 4.00 (v br s, 2H), 2.22 (s, 3H).
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
INTERMEDIATE 15 - PREPARATION of 5-chloro-2-iodo-4-methylaniline. A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred 72 hours at room temperature filtrated and the solid dissolved in dichloromethane, washed with a saturated solution of sodium thiosulphate, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of 5-chloro-2-iodo-4-methylaniline as a brown solid.ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
INTERMEDIATE 45 - PREPARATION of 5-chloro-2-iodo-4-methylaniline. A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred for 72 hours at room temperature and filtered. The solid was dissolved in dichloromethane, washed with a saturated solution of sodium thiosulfate, and the organic layer was dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of the title compound as a brown solid.ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred for 72 hours at room temperature and filtered. The solid was dissolved in dichloromethane, washed with a saturated solution of sodium thiosulfate, and the organic layer was dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of the title compound as a brown solid. [0636] ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a suspension of 3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodium bicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred 72 hours at room temperature filtrated and the solid dissolved in dichloromethane, washed with a saturated solution of sodium thiosulphate, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of 5-chloro-2-iodo-4-methylaniline as a brown solid. [0541] ESI/APCI(+): 268 (M+H).
24%
With iodine; sodium hydrogencarbonate; potassium iodide; In water; at 20℃; for 72h;
INTERMEDIATE 137 - PREPARATION of 5-chloro-2-iodo-4-methylaniline; A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a mixture of 3-chloro-4-methylaniline (5.00 g; 35.31 g), sodium bicarbonate (4.75 g; 56.50 mmol) in water. The resulting mixture was stirred 72 hours at room temperature filtrated and the solid dissolved in dichloromethane, washed with a saturated solution of sodium thiosulphate dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of the title compound as a brown solid. ESI/APCI(+): 268 (M+H).
With Iodine monochloride; In methanol; dichloromethane; at 5 - 20℃; for 1h;Industrial scale;
A solution of iodine monochloride (87.6 g, 540 mmol) in dichloromethane (800 ml) was added dropwise to a solution of compound A (51 g, 360 mmol) in methanolControl the dropping rate, keep the reaction temperature stable below 5 .After the addition was completed, the reaction was carried out at room temperature for 1 hour. The TLC (PE / EA = 20/1) test material almost disappeared and a new main point was formed.The reaction solution with a mass percentage concentration of 40% NaOH solution to adjust PH to 8-9, and then washed to a yellow sodium sulfite solution.The methylene chloride phases were separated and the aqueous phase was extracted once more with DCM (600 ml). The organic phases were combined, washed once more with water, once with saturated brine and dried to dryness.40 g of compound B was beaten with petroleum ether, and the yield was 41%, which was directly used for the next reaction.
With sodium carbonate; lithium chloride In N,N-dimethyl-formamide at 100℃; for 15h;
A.46
INTERMEDIATE 46 - PREPARATION of 2-(6-Chloro-5-methyl-2-(triethylsilyl)-1 H-indol-3- yl)ethanol. 5-Chloro-2-iodo-4-methylaniline (1.50 g; 5.61 mmol), 4-(triethylsilyl)but-3-yn-1-ol (2.36 mL; 1 1.22 mmol), bis(diphenylphosphino)ferrocene]palladium(ll) chloride (0.229 g; 0.280 mmol), lithium chloride (0.237 g; 5.61 mmol) and sodium carbonate (1.19 g; 1 1.22 mmol) were suspended in DMF (14 mL) and the mixture was stirred at 100°C for 15 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20 % ethyl acetate in heptane) to afford 1.44 g (79%) of the title compound as a brown oil.ESI/APCI(+): 324 (M+H); ESI/APCI(-): 322 (M-H).
79%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; lithium chloride In N,N-dimethyl-formamide at 100℃; for 15h;
Intermediate 46 PREPARATION of 2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol
5-Chloro-2-iodo-4-methylaniline (1.50 g; 5.61 mmol), 4-(triethylsilyl)but-3-yn-1-ol (2.36 mL; 11.22 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.229 g; 0.280 mmol), lithium chloride (0.237 g; 5.61 mmol) and sodium carbonate (1.19 g; 11.22 mmol) were suspended in DMF (14 mL) and the mixture was stirred at 100° C. for 15 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 1.44 g (79%) of the title compound as a brown oil. [0638] ESI/APCI(+): 324 (M+H); ESI/APCI(-): 322 (M-H).
79%
With sodium carbonate; lithium chloride In N,N-dimethyl-formamide at 100℃; for 15h;
138
INTERMEDIATE 138 - PREPARATION of 2-(6-chloro-5-methyl-2-(triethylsilyl)-1 H-indol-3- yl)ethanol; 5-chloro-2-iodo-4-methylaniline (1.50 g; 5.61 mmol), 4-(triethylsilyl)but-3-yn-1-ol (2.36 ml 11.22 mmol), Bis(diphenylphosphino)ferrocene]palladium(ll) chloride (0.229 g; 0.280 mmol), lithium chloride (0.237 g; 5.61 mmol) and sodium carbonate (1.19 g; 11.22 mmol) were suspended in DMF (14 mL) and the mixture was stirred at 1000C for 15 hours. The mixture was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulphate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (eluent 2 to 20 % ethyl acetate in heptane) to afford1.44 g (79%) of the title compound as a brown oil. ESI/APCI(+): 324 (M+H). ESI/APCK-): 322 (M-H).
6-chloro-2-(4-methoxyphenyl)-7-methylquinoxaline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With copper(l) iodide; sodium azide; potassium carbonate; N,N`-dimethylethylenediamine In dimethyl sulfoxide at 80℃; for 20h; Sealed tube; regioselective reaction;
General procedure: 2-iodoaniline (54.8 mg, 0.25 mmol) 1a, sodium azide (19.5 mg, 0.3mmol) 3, CuI (4.8 mg, 0.025 mmol), K2CO3 (34.5 mg, 0.25 mmol),phenylacetaldehyde (58 μL, 0.5 mmol) 2a, (DMEDA) (3 μL, 0.025mmol) were taken in a round bottom flask equipped with stirrer in 1.0mL of DMSO. The reaction mixture was heated to 80 °C for 20 h.After cooling the room temperature, to the reaction mixture wasadded water (2 mL), and extracted with EtOAc (310 mL). Thecombined organic phases were washed with brine (25 mL), driedover anhydrous MgSO4 and concentrated in vacuo. The residue wassubjected to flash column chromatography with petroleum/ethylacetate (20/1) to afford the final product 4aa as light yellow solid