* 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.
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: With sodium hydroxide; water In tetrahydrofuran
2- (2-Methoxy-phenyl)-ethanol; Lithium aluminum hydride (21 g, 0.55 mol) was added to a solution of (2-methoxy-phenyl) -acetic acid methyl ester (90 g, 0.50 mol) in anhydrous tetrahydrofuran (500 mL) at 0 °C. After stirred at 0 °C for 30 minutes, the mixture was treated with sodium hydroxide (5 percent aqueous solution, 180 g). The mixture was extracted three times with ethyl acetate (400 mL) and the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give 2- (2-methoxy-phenyl)-ethanol (43 g, 0.28 mol, 57 percent), which was used directly in the next step
Reference：
[1] Patent: WO2005/75435, 2005, A1, . Location in patent: Page/Page column 139
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735
2
[ 67-56-1 ]
[ 93-25-4 ]
[ 27798-60-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 50℃; for 0.333333 h; Sonication
General procedure: The carboxylic acid (0.271 mmol), TCT (0.050 g, 0.271 mmol), PS-Ph3P (0.009 g, 0.027 mmol, loading 3.0 mmol/g), and Na2CO3 (0.057 g, 0.542 mmol) were added to MeOH (0.5 mL). Then the mixture was sonicated in an ultrasonic bath (Elmasonic S 30H) at 50°C for the specified time. After completion, the crude mixture was filtered through a short pad of silica to obtain the product after solvent evaporation. Whenever necessary, the product was further purified by flash chromatography.
87%
Reflux
General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5percent NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils.
Reference：
[1] Helvetica Chimica Acta, 2003, vol. 86, # 2, p. 343 - 360
[2] Synlett, 2015, vol. 26, # 14, p. 2006 - 2008
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 2, p. 555 - 559[4] Angew. Chem., 2018, vol. 130, # 2, p. 564 - 568,5
[5] Tetrahedron Letters, 2003, vol. 44, # 2, p. 331 - 334
[6] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 117 - 124
[7] Tetrahedron Letters, 1994, vol. 35, # 40, p. 7307 - 7310
[8] Medicinal Chemistry Research, 1995, vol. 5, # 8, p. 618 - 630
[9] Journal of the Brazilian Chemical Society, 2012, vol. 23, # 5, p. 854 - 860
[10] Chemical Communications, 2012, vol. 48, # 79, p. 9936 - 9938
[11] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3885 - 3896
[12] Russian Journal of Bioorganic Chemistry, 2015, vol. 41, # 2, p. 170 - 177
[13] CrystEngComm, 2014, vol. 16, # 2, p. 164 - 174
[14] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735
3
[ 614-75-5 ]
[ 74-88-4 ]
[ 27798-60-3 ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate In acetonitrile for 15 h; Heating / reflux
Example 9:; (2-Methoxy-phenyl) -acetic acid methyl ester; A solution of methyl iodide (188 g, 1.33 mole) in acetonitrile (200 mL) was slowly added to a mixture of (2-hydroxy-phenyl) -acetic acid (80 g, 0.53 mol) and potassium carbonate (254 g, 1.84 mol) in acetonitrile (800 mL) under reflux. The reaction was heated to reflux for 15 hours. The reaction mixture was cooled and the precipitate was removed by filtration. The filtrate was evaporated to dryness to give the crude product (90. g, 0.50 mol, 94 percent)
89%
With potassium carbonate In acetone at 20℃; for 12 h;
To a stirred solution of 2-hydroxyphenylacetic acid (1.04 g, 6.8 mmol) in acetone (30 mL), K2CO3 (2.83 g, 20.5 mmol) and MeI (1.06 mL, 17.1 mmol) was added. The mixture was stirred at room temperature for 12 h and then acetone was removed at vacuum. Water (20 mL) was added to the mixture and extracted with ethyl acetate (2*30 mL). The organic layer was washed with water (2*20 mL), brine (20 mL), dried (Na2SO4) and concentrated. The crude product was purified by silica gel column chromatography to get 16 (1.10 g, 89percent) as colorless oil. Rf 0.5 (1:20 ethyl acetate:hexane); 1H NMR (CDCl3, 500 MHz) δ 7.24 (d, 1H, J=8.0Hz, C6′-H), 7.16 (d, 1H, J=8.0Hz, C3′-H), 6.92–6.85 (m, 2H, C4′-H & C5′-H), 3.80 (s, OCH3), 3.67 (s, 3H, CO2CH3), 3.62 (s, 2H, C2-H2).
With N-Bromosuccinimide In tetrachloromethane for 2 h; Heating / reflux
Methyl bromo-(2-methoxyphenyl)acetate; A mixture of 14.6 g (81.2 mmol) of methyl (2-methoxyphenyl)acetate, 15.2 g (85.3 mmol) of Λ/-bromosuccinimide and a catalytic amount of AIBN in tetrachloromethane (180 ml) was heated under reflux with stirring for 2h. The cooled reaction solution was filtered, and the solvent was removed in vacuo. Yield: 21.6 g (100percent) of yellow oil 1H-NMR (CDCI3): 3.78 (s, 3H), 3.87 (s, 3H), 5.90 (s, 1 H), 6.88 (d, 8.31 Hz, 1 H), 6.99 (t, 7.5 Hz, 1 H), 7.32 (dt, 7.6 Hz, 1.5 Hz, 1 H), 7.61 (dd, 7.6 Hz, 1.5 Hz). MS (API-ES,pos) m/z = 259 [M+H]+
To a stirred solution of methyl 2- (2-methoxyphenyl) acetate (5.0 g, 27.7 mmol) in 60 mL of THF was added LDA (15 mL, 2.0 M) at -78 C under N2. The resulting mixture was stirred for 30 min. MeI (12.0 g, 84.5 mmol) was added in drops. The reaction mixture was allowed to warm to rt and stirred for 5 hrs. The mixture was quenched with 50 mL of H2O, extracted with EA (50 mL x 3) . The organic extracts were combined, washed with brine (50 mL x 3) , dried over Na2SO4and concentrated. The residue was purified by column chromatography to give the title product (4.9 g, 91%) as a light yellow oil.1H NMR (400 MHz, CDCl3) delta 7.27 -7.16 (m, 2H) , 6.97 -6.91 (m, 1H) , 6.87 (d, J = 8.0 Hz, 1H) , 4.05 (q, J = 7.2 Hz, 1H) , 3.82 (s, 3H) , 3.65 (s, 3H) , 1.45 (d, J = 7.2 Hz, 3H) .
With 1,3,5-trichloro-2,4,6-triazine; sodium carbonate; at 50℃; for 0.333333h;Sonication;
General procedure: The carboxylic acid (0.271 mmol), TCT (0.050 g, 0.271 mmol), PS-Ph3P (0.009 g, 0.027 mmol, loading 3.0 mmol/g), and Na2CO3 (0.057 g, 0.542 mmol) were added to MeOH (0.5 mL). Then the mixture was sonicated in an ultrasonic bath (Elmasonic S 30H) at 50C for the specified time. After completion, the crude mixture was filtered through a short pad of silica to obtain the product after solvent evaporation. Whenever necessary, the product was further purified by flash chromatography.
87%
With sulfuric acid;Reflux;
General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5% NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils.
87%
With sulfuric acid; for 8h;Reflux;
(1) First install the three-necked flask on a magnetic stirrer with a heating device, install a temperature controller and a condenser tube, and mix 18g (0.15mol) methoxyphenylacetic acid, 50ml (1.23mol) methanol and 5ml concentrated sulfuric acid Add to a 100ml three-necked flask and reflux for 8h.Then add saturated sodium carbonate to neutralize the excess acid, and then extract with ethyl acetate, add anhydrous sodium sulfate to dry, rotary evaporation to obtain methyl ortho-methoxyphenyl acetate, light yellow liquid, yield 87%.
With thionyl chloride; at 0 - 20℃; for 3h;
General procedure: 5.1.57.1. Step 1. To a solution of 3-fluorophenylacetic acid (24.85 g,158 mmol) in MeOH (200 mL) was added SOCl2 (4.00 mL,52.2 mmol) at 0 C with silica gel blue tube. After stirring at rtfor 3 h, the reaction mixture was concentrated under reduced pressure.The residue was partitioned between 1 N NaOH (250 mL) andEtOAc (250 mL). The separable organic layer was washed withbrine (100 mL), dried over MgSO4, filtered, concentrated underreduced pressure to obtain methyl (3-fluorophenyl)acetate(25.81 g, 97%) as colorless oil.
With sulfuric acid; for 8h;Reflux;
General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a)
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 2h;Heating / reflux;
Methyl bromo-(2-methoxyphenyl)acetate; A mixture of 14.6 g (81.2 mmol) of <strong>[27798-60-3]methyl (2-methoxyphenyl)acetate</strong>, 15.2 g (85.3 mmol) of Lambda/-bromosuccinimide and a catalytic amount of AIBN in tetrachloromethane (180 ml) was heated under reflux with stirring for 2h. The cooled reaction solution was filtered, and the solvent was removed in vacuo. Yield: 21.6 g (100%) of yellow oil 1H-NMR (CDCI3): 3.78 (s, 3H), 3.87 (s, 3H), 5.90 (s, 1 H), 6.88 (d, 8.31 Hz, 1 H), 6.99 (t, 7.5 Hz, 1 H), 7.32 (dt, 7.6 Hz, 1.5 Hz, 1 H), 7.61 (dd, 7.6 Hz, 1.5 Hz). MS (API-ES,pos) m/z = 259 [M+H]+
With N-Bromosuccinimide; In tetrachloromethane; for 4h;Heating / reflux;
Bromo-(2-methoxyphenyl)acetic acid methyl ester (cas # 99552-78-0)The (2-methoxyphenyl)acetic acid methyl ester (20.0 g, 111 mmol) is dissolved in carbon tetrachloride (250 ml_) along with NBS (29.6 g, 166.5 mmol) and refluxed for 4.5 h. The solution is then allowed to cool to room temperature and is filtered. The filtrate is evaporated and the residue purified via flash column chromatography (10% EtOAc/hexa?es) to give bromo-(2-methoxyphenyl)acetic acid methyl ester as a yellow oil. MS (ESI) m/z 259.1, 261.1 (M+H)
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