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With phosphorus pentaoxide;methanesulfonic acid; at 80℃; for 0.05h;
Diphosphorus pentoxide (17.9 g) was added to methanesulfonic acid (82.0 mL), and the compound (15.4 g) obtained in (EXAMPLE 2) <Step 1> was then added to the mixture at 80C. After stirring for 3 minutes, the reaction solution was poured onto ice and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogencarbonate aqueous solution and brine, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluate; n-hexane : ethyl acetate = 100:0 to 75:25) to give a mixture (9.8 g) of the title compounds (2-2-a and 2-2-b) as a purple solid.
General procedure: To a 25 mL 2-necked round-bottomed flask, equipped with thermocouple and nitrogen inlet, was charged 3-aryloxypropanenitriles 2a-2j (12.6 mmol) in 5 equiv of TFA(4.86 mL, 63.0 mmol) solution. To the resulting solution was slowly added 1.5 equiv of TfOH (1.67 mL, 17.7 mmol) at 0-5 C. The resulting solution was stirred at 0 C for 5 h, and then at ambient temperature for 16-24 h until the conversion of the reaction was >99%. The reaction mixture was cooled to 0 C. Then, 2 equiv of water (0.41 mL, 25.2 mmol) was added dropwise at 0-10 C. The resulting solution was stirred at room temperature for 1-5 h. The reaction mixture was transferred to a separation funnel and diluted with toluene (20 mL) and water (10 mL). After phase separation, the aqueous layer was extracted with toluene (6 mL × 1). The combined organic layers were washed with water (9 mL × 1) and concentrated. The pure 4-chromanones 3a, 3b, 3d, 3f, 3h, and 3i obtained by crystallization of their corresponding crude products in isopropanol (IPA) and the pure chromanones 3c, 3-4e, 3g and 3j were obtained by Biotage chromatographic purification (EtOAc/hexanes from 10% to 80%).
With trifluorormethanesulfonic acid; trifluoroacetic acid at 0 - 20℃; for 21h; Inert atmosphere;
1.2 (2) Synthesis of 5-bromo-4-chromanone,
The compound (1) 3-(3-bromophenoxy)propanenitrile (109 g, 482 mmol, 1 eq) was dissolved in trifluoroacetic acid (144.8 g, 2410 mmol, 5 eq) under N2. Fluoromethanesulfonic acid (108.5 g, 723 mmol, 1.5 eq), reacted at 0 ° C for 5 h, then warmed to 20 ° C and stirred for 16 h.The completion degree of the reaction was monitored by thin layer chromatography (TLC) (petroleum ether: ethyl acetate = 10:1), and the temperature was lowered to 0 ° C after completion of the reaction.Pour the reaction solution into 500 mL of ice water and stir for 1 h.The pH was adjusted to 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate.Wash with saturated brine, dry over anhydrous sodium sulfate, spin dry,The crude product of (2) 5-bromo-4-chromanone was isolated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1% to 2% to 5%). 66.4g, yield 60.9%),
With methanol; sodium tetrahydroborate In tetrahydrofuran at 20℃; for 1h;
1.3 (3) Synthesis of 5-bromo-4-chromanol,
The crude compound (6) 5-bromo-4-chromanone (66 g, 290 mmol, 1 eq) was dissolved in 600 mL of methanol and 600 mL of anhydrous tetrahydrofuran, and cooled to 0 ° C,Sodium borohydride (22 g, 579 mmol, 2 eq) was added.After the temperature is increased to 20 ° C for 1 h,The completion of the reaction was monitored by thin layer chromatography (TLC).After the reaction was completed, the temperature was lowered to 0 ° C, and 10 mL of acetone was added to quench the reaction.The pH was adjusted to 5 with 10% acetic acid solution and extracted with ethyl acetate.Wash with saturated brine, dry, spin dry,Separation by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 2% to 5%) to give pale yellow liquid compound (3) 5-bromo-4-chromanol(28g, yield 42.04%),
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