| 98% |
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; |
|
| 97% |
With lithium aluminium hydride In diethyl ether for 15h; Ambient temperature; |
|
| 97% |
With lithium aluminium hydride In tetrahydrofuran |
|
| 97% |
With lithium aluminium hydride In tetrahydrofuran at -20 - 20℃; for 12h; |
|
| 96% |
With lithium aluminium hydride In tetrahydrofuran |
|
| 95% |
With lithium aluminium hydride In tetrahydrofuran at 0℃; for 0.5h; |
|
| 95% |
Stage #1: 3,5-dimethoxybenzoic acid methyl ester With lithium aluminium hydride In tetrahydrofuran at 25℃; Cooling with ice;
Stage #2: With water monomer; sodium hydroxide In tetrahydrofuran at 20℃; for 8h; |
3,5-Dimethoxybenzyl alcohol (4)
A round-bottomed flask (3 L) equipped with magnetic stirring bar and reflux condenser was charged with LAH (19 g, 500 mmol, 1 equiv). An addition funnel (500 mL) with N2 bubbler was connected to the top of the condenser. The addition funnel was charged anhydrous THF (500 mL) which was slowly added to the LAH to make a slurry. The reaction flask was cooled in an ice bath and the addition funnel was next charged with a solution of 3 (98 g, 500 mmol) in anhydrous THF (500 mL). The addition was made in a gentle stream so that the internal temperature did not exceed 25 °C. After the addition, the mixture was stirred overnight at rt. The mixture was cooled once again and carefully quenched by the sequential addition of: 1) H2O (19 mL); 2) 15% aqueous NaOH (19 g); 3) H2O (57 mL). After stirring 8 h at rt, the mixture was filtered through a medium porosity glass frit. The mixture was diluted with H2O (2 L) and extracted with Et2O (3 X 500 mL). The extracts were collected and washed with H2O (500 mL) followed by brine (500 mL). After drying over anhydrous MgSO4, the solvent was rotary evaporated leaving compound 4 as an off-white solid that did not require further purification. (79 g, 95%) Mp 46-48 °C [lit.Mauthner 47-48 °C]. 1H NMR (CDCl3): δ 6.47 (d, J = 2.3 Hz, 2H), 6.34 (t, J = 2.3 Hz, 1H), 4.55 (s, 2H), 3.74 (s, 6H), 2.79 (s, OH); 13C NMR (CDCl3): δ 160.99, 143.61, 104.66, 99.64, 65.14, 55.39. Elemental analysis calculated for C9H12O3: C, 64.27; H, 7.19. Found: C, 64.41; H, 7.03. |
| 95% |
With lithium aluminium hydride In tetrahydrofuran at 25℃; for 4.5 - 5.5h; Reflux; |
|
| 93% |
With lithium aluminium hydride In diethyl ether at 20℃; for 6h; Inert atmosphere; |
|
| 93% |
With sodium tetrahydridoborate In tetrahydrofuran; methanol at 70℃; for 2.5h; |
|
| 92% |
With lithium aluminium hydride In tetrahydrofuran for 10h; Ambient temperature; |
|
| 92% |
With lithium aluminium hydride In diethyl ether |
|
| 92.3% |
With lithium aluminium hydride In diethyl ether for 4h; Heating; |
|
| 92.3% |
With lithium aluminium hydride In diethyl ether for 4h; Reflux; |
|
| 92% |
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 2.16667h; |
|
| 91% |
With lithium aluminium hydride In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; |
(2-bromo-3,5-dimethoxyphenyl) methanol (15)
To a 100 mL round bottom flask was added LAH (0.89 g, 23.45 mmol, 1.5 eq) in THF(55 mL). 14 (3.1 g, 15.8 mmol, 1.0 eq) in THF (10 mL) was added to solution by cannulaat 0 . The reaction mixture was stirred at room temperature for 6 hours. Aftercompletion of reaction (TLC), the reaction mixture was diluted with water (40 mL) andether (50 mL). The organic layer was separated and further extracted three times withethyl ether (30 mL x 3). The combined organic layer was washed with saturated NaClsolution (50 mL), dried over anhydrous MgSO4, and filtered, and the solvent was removedat reduced pressure to yield a product (3,5-dimethoxyphenyl) methanol (2.41 g, 14.33mmol, 91%, colorless liquid); 1H NMR (400 MHz, CDCl3) δ 6.55 - 6.50 (m, 2H), 6.39 (t, J =2.3 Hz, 1H), 4.64 (s, 2H), 3.79 (s, 6H). To a 250 mL round bottom flask was added (3,5-dimethoxyphenyl) methanol (2.41 g,14.33 mmol, 1.0 eq) in CHCl3 under argon atmosphere. N-bromosuccinimide (2.55 g,14.33 mmol, 1.0 eq) was added to solution at 0 . After stirring for 2 hours at ambienttemperature, add saturated NaHCO3/Na2S2O3 solutions (1:1, 100 mL in total) and dilutedwith water (40 mL) and methylene chloride (50 mL). The organic layer was separated andfurther extracted three times with methylene chloride (30 mL x 3). The combined organiclayer was washed with saturated NaCl solution (50 mL), dried over anhydrous MgSO4, andfiltered, and the solvent was removed at reduced pressure to yield a product 15 (3.15 g,12.75 mmol, 89 %, white solid); 1H NMR (400 MHz, CDCl3) δ 6.70 (d, J = 2.8 Hz, 1H), 6.44(d, J = 2.8 Hz, 1H), 4.73 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H) |
| 82% |
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 3h; |
3,5-Dimethoxy Benzylalcohol (304)
Ester 303 (25 g, 0.13 mol) in THF (50 mL) was added slowly to a dry stirred suspension of LiAlH4 (7.25 g 0.19 mol) in THF (550 mL) at 0° C., The reaction mixture was stirred for 3 h at rt at which time all the starting material had disappeared (TLC), The reaction mixture was quenched by addition of ice-cold H2O (1.0 eq), 10% act NaOH (3.0 eq), and H2O (1.0 eq), sequentially and then filtered through a Buchner funnel. The filtrate was diluted with brine (800 mL) and extracted with EtOAc (3*300 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuum. The crude oil was purified by FCC (20% ethylacetate in hexane) to afford a yellow oily alcohol 304 (17.5 g, 82%): 1H NMR (300 MHz, CDCl3) δ 6.53 (2H, d, J=6.0 Hz HAr), 6.35 (1H, t, J=2.4 Hz, HAr), 4.49 (214, s, H2COH), 3.80 (611, s, H3CO). |
| 81.1% |
With lithium aluminium hydride In tetrahydrofuran at 20℃; for 4h; Inert atmosphere; Cooling with ice; |
1 Synthesis of Intermediate 3,5-dimethoxyphenylmethanol 3
Under argon atmosphere and ice-cooling,Followed by lithium aluminum hydride was added 1.251g (0.033mol) in 100mL of anhydrous tetrahydrofuran and 20mL three-necked flask,Stirring,Dripped with a syringe 5.886g (0.03mol)Compound 2Tetrahydrofuran 20mL,The ice bath was removed,The reaction was continued at room temperature for 4h,TLC tracking and detection,And so the reaction was complete the reaction mixture was slowly poured into 200mL of ice water,Stirring,Flocculent precipitate,The precipitate was dissolved with dilute hydrochloric acid,Ethyl acetate,Dried over anhydrous sodium sulfate,Ethyl acetate was distilled off under reduced pressure,Dried to give compound 3,The yield was 81.1%, |
| 80% |
Stage #1: 3,5-dimethoxybenzoic acid methyl ester With phenylsilane; potassium hydroxide at 20℃; for 3h;
Stage #2: With hydrogenchloride; water monomer In tetrahydrofuran at 20℃; for 1h; |
|
| 75% |
Stage #1: 3,5-dimethoxybenzoic acid methyl ester With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
Stage #2: With water monomer In tetrahydrofuran; methanol; ethyl acetate at 0 - 20℃; Inert atmosphere; Molecular sieve; |
|
|
With lithium aluminium hydride In diethyl ether |
|
|
With lithium aluminium hydride |
|
| 4.58 g |
With lithium aluminium hydride In diethyl ether for 3h; Heating; |
|
|
With lithium tetrahydridoborate |
|
|
With lithium aluminium hydride |
|
| 100 % Chromat. |
With sodium tetrahydridoborate In methanol; 1,2-dimethoxyethane for 1h; Heating; |
|
|
With lithium aluminium hydride In tetrahydrofuran at 20℃; for 4h; |
|
|
With sodium tetrahydridoborate In tetrahydrofuran; methanol for 1.66667h; Reflux; |
|
|
With lithium aluminium hydride In diethyl ether for 6h; Reflux; Inert atmosphere; |
2 4.2. Synthesis of 3,5-dimethoxybenzyl chloride (2) [27]
To a suspension of AlLiH4 (0.6 g; 15.8 mmol) in dry ethyl eter (15 mL) under nitrogen atmosphere, a solution of commercial methyl-3,5-dimethoxybenzoate (1) (2 g; 10.0 mmol) in 10 mL of anhydrous ethyl eter was added dropwise with stirring. After 6 h of refluxing, the mixture was quenched with HCl 10% (20 mL). The organic layer was separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product (1.71 g, quantitative yield, 10.2 mmol) was dissolved in CH2Cl2 (48 mL) under nitrogen atmosphere and, with magnetic stirring, tionyl chloride freshly distilled (1.5 mL; 20.4 mmol) was added dropwise. The reaction mixture was heated to reflux and then a solution of triethylamine (6 mL) in CH2Cl2 (48 mL) was added during 2 h. The reaction mixture was quenched with saturated NaHCO3 (100 mL) and was extracted with ether (40 mL * 3). The organic layer was separated and dried over anhydrous MgSO4 and concentrated. The crude residue was purified by flash column chromatography with alumina and 3,5-dimethoxybenzyl chloride (2) eluted as a yellowish solid (1.8 g, 9.6 mmol, 94%, m.p.: 45-46 °C, lit. |
|
With sodium tetrahydridoborate In tetrahydrofuran; methanol for 1.66667h; |
To a mixture of methyl ester 3 (12.0 g, 61.2 mmol, 1 equiv.) andNaBH4 (12.7 g, 336 mmol, 5.5 equiv.) in THF (260 mL) was added MeOH(74 mL) dropwise under reflux over 1 h. After heating under reflux for 40 min,the reaction was cooled down to room temperature, and the pH was adjusted to 7by the dropwise addition of 1 M HCl. The reaction mixture was filtered througha Celite pad. The filtrate was extracted with EtOAc (4 x 30mL), and thecombined organic extracts were washed with brine (100 mL), dried over Na2SO4,and concentrated under reduced pressure to give alcohol 4 which was used for the subsequent reaction without purification.An analytical quantity may be further purified by recrystallization fromcyclohexene. Yield 92%, White crystalline solid; Mp 47-48 °C {lit. [i]47-48 °C}; TLC (EtOAc/Hexane, 1:4 v/v): Rf = 0.08; 1H-NMR[CDCl3, 600 MHz] δ: 6.52 (d, J= 2.2 Hz, 2H), 6.39 (t, J = 2.2 Hz,1H), 4.64 (s, 2H), 3.80 (s, 6H); 13C-NMR [CDCl3, 150 MHz]δ: 161.2, 143.5, 104.7, 99.8, 65.6, 55.5. |
|
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 11h; |
|
| 2.4 g |
With lithium aluminium hydride In diethyl ether at 0℃; |
|
| 1.4 g |
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 1h; |
3.5
To a solution of 3,5-dihydroxybenzoic acid (2.00 g, 13.0 mmol) in DMF were added K2CO3 (27.0 g, 0.195 mol), CH3I (20.2 ml, 0.325 mol) and the mixture was stirred under reflux for 1h. The mixture was filtered and the filtrated solvent was evaporated in vacuo. The residue was dissolved in CH2Cl2, and the organic layer was washed with H2O and then dried over MgSO4. The solvent was evaporated in vacuo and the resulting precipitate was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give methyl ester (2.11 g, 10.7 mmol). To a solution of methyl ester (2.11 g, 10.7 mmol) in THF was added to LiAlH4 (0.812 g, 21.4 mmol) at 0. After being stirred for 1h at room temperature, H2Oand 1M NaOH added to the solution. The mixture was filtered and the organic layer was evaporated in vacuo to yield alcohol (1.40 g, 8.32 mmol). To a solution of alcohol (1.40 g, 8.32 mmol) in CH2Cl2 was added PDC (4.96 g, 8.32 mmol) and the mixture was stirred at room temperature for 5h. The mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give benzaldehyde (1.25 g, 7.52 mmol). To a solution of benzaldehyde (1.25 g, 7.52 mmol) were added ethyldiethylphosphonoacetate (3.01 ml, 15.4 mmol) and NaH (0.330 g, 8.27 mmol) at 0. After being stirred for 1h at room temperature, AcOEt and H2O were added to the solution. The organic layer was evaporated in vacuo and the residue was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give unsaturated ethyl ester (0.540 g, 2.03 mmol). To a solution of unsaturated ethyl ester (0.540 g, 2.03 mmol) in MeOH was added LiOH-H2O (1.22 g, 29.1 mmol).After being stirred under reflux for 2h, 1M HCl aq. and AcOEt were added to the mixture. The organic layer was washed with H2O and brine. The solvent was evaporated in vacuo to yield unsaturated carboxyl acid (1.35 g, 6.48 mmol, 89 %) as a white powder. |
|
With lithium aluminium hydride In tetrahydrofuran at 0 - 80℃; for 4h; Inert atmosphere; |
|
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