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With iodine; sodium hydrogencarbonate In water at 20℃; for 0.5 h;
3,4-Difluoroaniline (645mg, 5mmol) was suspended in water (25 mL). Sodium bicarbonate (630 mg, 7.5 mmol) was added and then iodine (1.65 g, 6.5 mmol). The reaction mixture was stirred vigorously at ambient temperature for 30min and then poured into saturated sodium thiosulphate solution (50 mL) and extracted with ethyl acetate (2x25 mL). The combined extracts were washed with sodium thiosulphate (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to give the title compound as a dark oil. (1.24g, 97percent).
69%
With N-iodo-succinimide In dichloromethane at 20℃; Inert atmosphere
At room temperature, a solution of 3,4-difluoroaniline (100 μL, 1 mmol) and N-iodosuccinimide (225 mg, 1 mmol) in anhydrous dichloromethane (4 mL) was stirred overnight under argon atmosphere. Then an aqueous solution of sodium sulfite was added and the reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 1/0 to 8/2) to afford 4,5-difluoro-2-iodoaniline (175 mg, 69percent) as a red oil. ESI-MS m/z 255.9 (M+H)+.
12 g
With iodine; sodium hydrogencarbonate In water at 20℃; for 1 h;
Reference Example 3a 2-methyl-5,6-fluoro-2,3-dihydro-1H-indole Step 1a:4,5-Difluoro-2-iodoaniline 16.5 g of iodine and 6.3 g of sodium bicarbonate are added, at ambient temperature, to a suspension of 6.45 g of 3,4-difluoroaniline in 250 ml of water. The reaction medium is stirred at ambient temperature for 1 hour.A saturated sodium thiosulfate solution is added and then the resulting mixture is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give 12 g of 4,5-difluoro-2-iodoainiline, the characteristics of which are the following:Mass spectrometry: method ARetention time Tr (min)=0.90; [M+H]+: m/z 256; base peak: m/z 297
With calcium oxide;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 1,1'-bis(diphenylphosphino)ferrocene; In acetonitrile; at 60℃;Inert atmosphere;
Representative procedure for the palladium catalyzed synthesis of (1,3-thiazol-2-yl)methylamine compounds A solution of 4,5-difluoro-2-iodoaniline (167 mg, 0.65 mmol) in anhydrous acetonitrile (0.7 mL) was added to the reaction mixture containing tris(dibenzylidene acetone)dipalladium(0) (13.8 mg, 0.015 mmol), dppf (33 mg, 0.06 mmol), calcium (II) oxide (56.1 mg, 1 mmol) and tert-butyl-2-amino-2-thioxoethylcarbamate (150 mg, 0.79 mmol) in degassed anhydrous acetonitrile (0.3 mL). Then the reaction mixture was degassed, placed under argon atmosphere and stirred at 60C overnight. The solution was filtered over a pad of celite, rinsed with dichloromethane, methanol, ethyl acetate, and evaporated. Purification by preparative TLC (silica gel, dichloromethane/methanol 95/5) led to tert-butyl (5,6-difluoro-1,3-benzothiazol-2-yl)methylcarbamate (19.2 mg). The latter compound was dissolved in ethyl acetate (0.9 mL) and hydrochloric acid (37%, 0.3 mL) was slowly added at 0C. The reaction mixture was vigorously stirred for 20 minutes at 0C and then 15 minutes at room temperature. Water and ethyl acetate were added, extraction with diethyl ether and ethyl acetate gave organic layers which were discarded. The aqueous layer was basified with aqueous sodium hydroxide to pH = 10, then extracted with diethyl ether and ethyl acetate. Combined organic extracts were dried over sodium sulfate, filtered and evaporated to give crude (5,6-difluoro-1,3-benzothiazol-2-yl)methylamine (8.5 mg, 6%) as a red solid. ESI-MS m/z 201 (M+H)+.
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