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CAS No. : | 2426-87-1 | MDL No. : | MFCD00003365 |
Formula : | C15H14O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JSHLOPGSDZTEGQ-UHFFFAOYSA-N |
M.W : | 242.27 | Pubchem ID : | 75506 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.13 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 69.3 |
TPSA : | 35.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.85 cm/s |
Log Po/w (iLOGP) : | 2.48 |
Log Po/w (XLOGP3) : | 2.71 |
Log Po/w (WLOGP) : | 2.93 |
Log Po/w (MLOGP) : | 2.24 |
Log Po/w (SILICOS-IT) : | 3.59 |
Consensus Log Po/w : | 2.79 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.21 |
Solubility : | 0.148 mg/ml ; 0.000613 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.11 |
Solubility : | 0.188 mg/ml ; 0.000777 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.14 |
Solubility : | 0.00175 mg/ml ; 0.00000721 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.93 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane; water at 0℃; for 7.5 h; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere |
Under an argon atmosphere, m-chloroperbenzoic acid (contains ca 30percent water, purity >65percent, 41.7 g, ca. 157 mmol) was addedportionwise to a solution of S6 (25.3 g, 105 mmol) in dichloromethane (160 mL) at 0 °C.After stirring for 7.5 h, the reaction mixture was quenched with saturated aqueousNaHCO3. The mixture was diluted with water and the organic layer was separated. The aqueouslayer was extracted with dichloromethane. The combined extracts were washed with saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, and evaporated. The residue was dissolvedin methanol (300 mL) and K2CO3 (72.3 g, 523 mmol) was added portionwise to the solution atroom temperature. After stirring for 1 h, the mixture was evaporated under reduced pressure. Waterwas added to the residue and the product was extracted with diethyl ether. The extract was washedwith water and brine, dried over Na2SO4, and evaporated. The residue was recrystallized fromdiethyl ether-hexane to give S7 as pale yellow granules (14.7 g, 61percent). The mother liquor from theabove recrystallization was evaporated and the residue was chromatographed over silica gel 60N (hexane–ethyl acetate = 3:1) to give an additional S7 as pale yellow solid (3.14 g, 13percent). The totalyield of S7 was 17.8 g (74percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | for 4 h; Reflux; Inert atmosphere | General procedure: Ethyl(triphenylphosphoranylidene)acetate (1.55 g, 4.46 mmol) was added to a stirred solution of 3,4,5-trimethoxy benzaldehyde 13a (0.73 g, 3.72 mmol) in benzene (10 mL). Then the reaction mixture was refluxed for 4 h. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (EtOAc/pet-ether, 1:19) to afford the pure compound 25a (0.89 g, 90percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With ammonium acetate In acetic acid at 90℃; for 19h; | 4.6. 1-(Benzyloxy)-2-methoxy-4-[(E)-2-nitroethenyl]benzene(27) 4.6. 1-(Benzyloxy)-2-methoxy-4-[(E)-2-nitroethenyl]benzene(27) 4-Benzyloxy-3-methoxybenzaldehyde 26 (1.00 g, 4.13 mmol)was dissolved in AcOH (5 mL), and NH4OAc (477 mg, 6.20 mmol)and MeNO2 (756 mg, 12.4 mmol) were added successively. Theresulting mixture was heated to 90 C for 19 h. After this time, thereaction mixture was cooled to rt, quenched with H2O (20 mL) and ltered. The ltrate was extracted with ethyl acetate (320 mL),and the organic extracts combined with the ltrant, dried (MgSO4)and concentrated in vacuo to afford the title compound 27 whichwas used without further purication (1.17 g, 99%). Mp 119e120 C(lit.13a 119e121 C); dH (400 MHz, CDCl3) 7.95 (d, J13.6 Hz,1H), 7.51(d, J13.6 Hz, 1H), 7.45e7.30 (m, 5H), 7.10 (dd, J8.3, 2.0 Hz, 1H),7.02 (d, J2.0 Hz, 1H), 6.92 (d, J8.3 Hz, 1H), 5.22 (s, 2H), 3.93 (s, 3HdC (100 MHz, CDCl3) 152.0, 150.1, 139.4, 136.2, 135.4, 128.9, 128.3,127.3, 124.5, 123.2, 113.5, 110.9, 71.0, 56.2. |
96% | With acetic acid; ethylenediamine at 20℃; | |
95% | With ammonium acetate at 55 - 80℃; |
90% | With ammonium acetate In acetic acid for 1.5h; Heating; | |
90% | With ammonium acetate; acetic acid at 80℃; for 2h; | 1 (E)-1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene (a3) Compound a2 (26.32 g, 106.47 mmol) was dissolved in nitromethane (129.98 g, 2129.4 mmol), and ammoniumacetate (16.41 g, 212.94 mmol) and acetic acid (59.86 g, 997.82 mmol) were added at room temperature, and stirredat 80°C for 2 hours. After the reaction completed (TLC monitoring and UV development), the mixture was concentratedby distillation under reduced pressure, and the obtained concentrate was poured into a saturated NaHCO3 solution withstirring to give a yellow solid suspension. The suspension was suction-filtrated under reduced pressure with a Buchnerfunnel. The obtained cake was added to isopropanol, and suction-filtered with a Buchner funnel. This operation wasrepeated twice, and the filter cake was collected and dried to obtain purified product a3 (27.34 g, 95.82 mmol), yield 90 %.1H NMR (400 MHz, Chloroform-d) δ 8.16 - 8.14 (d, 1H), 7.98 - 7.96 (d, 1H), 7.47 - 6.94 (m, 8H), 5.16 (s, 2H), 3.83 (s, 3H);LRMS (ESI, m/z): 286 [M+H]+. |
68% | With ammonium acetate In acetic acid for 3h; Heating; | |
68% | With ammonium acetate; acetic acid at 20 - 120℃; | |
68% | With ammonium acetate; acetic acid for 5h; Reflux; | S (E)-1-(Benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene 4-Benzyloxy-3-methoxyphenethylamine was prepared according to Schrittweieser. J. H, et, J.O.C. 2011, 76, 6703-6714. A solution of 4-(benzyloxy)-3-methoxybenzaldehyde (25 g, 103.2 mmol), nitromethane (18 mL, 333.2 mmol) and NH4OAc (20.23 g, 262.5 mmol) in AcOH (220 mL) was refluxed for 5 hr. After cooling it was poured into ice-water (300 mL), followed by addition CH2Cl2 (200 mL) stirred at room temperature until the phases were separated. The aqueous phase was extracted with the CH2Cl2 (3*100 mL). The combined organics were washed with water (200 mL), saturated NaHCO3 (200 mL), brine (200 mL), dried (Na2SO4), filtered and concentrated to afford a brownish solid which was recrystallized from ethanol to afford the desired compound in 68% yield. |
60% | With ammonium acetate; acetic acid for 3h; Reflux; | |
With sodium hydroxide | ||
With potassium hydroxide | ||
With ethanol; methylamine hydrochloride; sodium carbonate | ||
With ammonium acetate; nitromethane; acetic acid at 20℃; for 3h; sonication; | ||
With ammonium acetate; acetic acid Heating; | ||
With ammonium acetate; acetic acid at 22 - 25℃; Sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With ammonia; hydrogen In <i>tert</i>-butyl alcohol at 120℃; for 15h; | |
With ammonia; nickel at 50 - 60℃; Hydrogenation; | ||
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / methanol / 3 h / 20 °C 2.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 1 h / 0 - 20 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 6 h / 120 °C 4.1: hydrazine hydrate / ethanol / 4 h / Reflux; Inert atmosphere |
Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With hydroxylamine hydrochloride; sodium acetate In ethanol at 20℃; for 12h; Stage #2: With hydrogenchloride; zinc In ethanol; water at 70℃; for 2h; | 4.4.2. Procedure for synthesis of compounds 5a-5f General procedure: To a solution of corresponding aldehydes (1 mmol), hydroxylaminehydrochloride (140.0 mg, 2 mmol), NaOAc (164.1 mg, 2 mmol) inEtOH (5 mL) were stirred for 12 h at room temperature. The resultingmixture was concentrated by reduced pressure and suspension in icewater, the precipitates was then filtrated and washed by ice water.Following, the precipitates were mixed with activated zinc dust(500 mg) in EtOH (5 mL), then 0.2 mL 37% HCl(aq) was added into themixture slowly under ice bath and stirred for 2 h under 70 . The pHvalue of resulting mixture was adjusted to 8-9 by concentrated NaHCO3solution, then filtrated by a short pad of celite. The solution was driedover anhydrous MgSO4, filtered, and concentrated under reducedpressure to give target amines 5a-5f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide In water; acetonitrile at 20℃; for 1.5h; | |
99% | With sodium chlorite; sodium dihydrogenphosphate dihydrate; dihydrogen peroxide In water; acetonitrile at 10 - 20℃; Inert atmosphere; | 4-(Benzyloxy)-3-methoxybenzoic acid (16) To a stirred solution of aldehyde 15 (2.5 g, 10.33 mmol, 1.0 equiv), NaH2PO4·2H2O (0.483 g, 3.10 mmol, 0.3 equiv) and H2O2 (60 %, 0.31 mL, 10.84 mmol, 1.04 equiv) in MeCN/H2O (60 mL, 5:1, v/v) was added a solution of NaClO2 (1.64 g, 14.46 mmol, 1.4 eq) in H2O (15 mL) dropwise while keeping the temperature of the mixture below 10 °C with a water bath. The mixture was stirred at room temperature for 90 min, before solid Na2S2O3 (0.254 g, 1.6 mmol) was added followed by stirring of the mixture at room temperature for 5 min to decompose excess H2O2. The mixture was diluted with saturated NaCl solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated NaCl solution (2 × 20 mL) and with saturated NaHCO3 solution (3 × 20 mL). The organic layers were discarded. The combined aqueous layers were acidified with concentrated HCl until pH 4 followed by extraction with EtOAc (3 × 20 mL). These organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the crude acid (2.55 g, 99 %) as white solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): d = 3.94 (s,3H, OMe), 5.23 (s, 2H, CH2Ph), 6.92 (d, J = 8.6 Hz, 1H, 5-H), 7.28-7.34 (m, 1H, Ar), 7.35-7.40 (m, 2H, Ar),7.41-7.46 (m, 2H, Ar), 7.61(d, J =2.0 Hz, 2-H), 7.70 (dd, J = 2.0, 8.3Hz, 1H, 6-H); 13C NMR (100 MHz, CDCl3): d = 56.0 (OMe), 70.7 (CH2Ph),112.3 (C-5), 112.7 (C-2), 121.9 (C-6), 124.4 (Ar), 127.2 (Ar), 128.1 (Ar),128.7 (Ar), 136.2 (Ar), 149.1 (Ar), 152.8 (Ar), 172.0 (CO2H). |
96% | With sodium chlorite; sulfur trioxide * ammonia In water at 20℃; for 12h; |
89% | With potassium permanganate In water; acetone for 1h; Reflux; | 4.1.3 3-methoxy-4-benzyloxybenzoic acid (3) The above benzaldehyde (6.05g, 25mmol) was dissolved in a mixture of acetone: H2O (75: 62.5mL) and to it KMnO4 (4.74g, 30mmol) was added and the mixture was stirred for 1hat reflux. The reaction mixture was filtered while hot. The filtrate was made alkaline (40% NaOH solution) to PH 10-11 and filtered. Then the filtrate was acidified with HCl until no further precipitate formed (PH 2-3). The resulting white precipitate was filtered, washed with water and dried to afford 5.7g of the product as a white solid with a yield of 89%. Mp: 173-175°C; 1H NMR (CDCl3, 300MHz): δ (ppm) 3.94 (s, 3H), 5.22 (s, 2H), 6.90-6.92 (d, J=8.4Hz, 1H), 7.31-7.44 (m, 5H), 7.60 (s, 1H), 7.65-7.68 (m, 1H). |
89% | With potassium permanganate In water; acetone for 1h; Reflux; | 11 Example 11 3-Methoxy-4-benzyloxybenzoic acid Methoxy-4-benzyloxybenzaldehyde (25 mmol, 6.05 g) was added to a 250-ml round-bottomed flask, and then a mixed solvent of acetone: water (V: V = 75: 62.5 ml) was added, Will KMnO4(30 mmol, 4.74 g) was slowly added to the reaction flask and heated under reflux for 1 hour.After the reaction was complete, the residue was filtered off and the filtrate was adjusted to pH = 10-11 with 40% sodium hydroxide solution. The solution was clarified and a small amount of insoluble residue was filtered off and the residue was filtered off. The filtrate was then adjusted to pH 6N HCl = 2-3, a lot of white solid was precipitated, with stirring, suction filtered, the filter cake was washed with water, and drying give 5.7 g of a white solid, 3-methoxy-4-benzyloxy benzoic acid yield% 89, |
85% | With chromium(VI) oxide; acetic acid for 1h; Ambient temperature; | |
79% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With potassium permanganate In acetone at 0 - 20℃; for 1 - 2h; Stage #2: With hydrogenchloride; ethanol; water In acetone | 8.A Example 8A4-(benzyloxy)-3-methoxybenzoic acid; 8.83 g (36.4 mmol) 4-benzyloxy-3-methoxybenzaldehyde are dissolved in 150 ml acetone and cooled to 00C. 5.76 g (36.4 mmol) potassium permanganate are added at 00C in portions. The rapidly stirred mixture is allowed to warm slowly to rt. After 1 to 2 h the reaction is terminated by addition of ethanol (50 ml). After excess of potassium permanganate is destroyed the mixture is treated with IN hydrochloric acid and filtered over celite. The residual solid is washed with ethanol. All filtrates are combined and concentrated, the residual solution is poured onto water. The precipitate is collected by filtration and washed three times with water. Additional crops of product can be obtained: the filter cake is washed with dichloromethane / methanol mixtures or ethanol, concentration to remove the bulk of the solvent and precipitation by addition of water. In total 7.48 g (79% of th.) of the title compound can be obtained.LC-MS (method 5): R, = 2.09 min; m/z = 259 (M+H)+1H-NMR (400 MHz, DMSO-(I6): δ = 12.68 (bs, IH) 7.54 (dd, IH), 7.51-7.31 (m, 6H), 7.14 (d, IH), 5.18 (s, 2H), 3.81 (s, 3H). |
With potassium permanganate; acetone | ||
With sodium hydroxide; silver(l) oxide | ||
With silver(l) oxide | ||
With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide In water; acetonitrile at 0 - 10℃; | ||
With sodium hypochlorite; disodium hydrogenphosphate; dihydrogen peroxide In tetrahydrofuran; water | 4.2 Prepared compound 3-methoxy-4-benzyloxybenzoic acid (11) 7.27g (30mmol) of 3-Methoxy-4-benzyloxybenzaldehyde (10) dissolved in 100mL of Anhydrous tetrahydrofen, then added the 40mL of distilled water and 2.16g (18mmol) of disodium hydrogen phosphate, under the ice condition added the drops of 8.96g (99mmol) sodium hypochlorite and 6.80mL (66mmol) of a 30% aqueous solution of hydrogen peroxide, after dripping at room temperature for 3 h; after completion of the reaction, tetrahydrofuran was recovered under reduced pressure, then extracted with 160 mL of ethyl acetate, washed with 2 mol / L NaOH solution to the organic phase without absorption. The combined aqueous phases were collected and acidified to pH 3~4 with concentrated hydrochloric acid to precipitate a white solid, after filtered and dried obtained white 7.05g of3-Methoxy-4-benzyloxybenzoic acid (11) , yield 91%. | |
With potassium hydroxide; oxygen In 1,2-dimethoxyethane | 3.ii (ii) Synthesis of 4-benzyloxy)-3-methoxybenzoicacid (3) A mixture of 1,2-dimethoxyethane and potassium hydroxide (5 to 20 eq.) is purged with oxygen and the calculated amount of isolated product 2 (1.0 eq.) is added. After the absorption of oxygen ceases, the mixture is diluted with distilled water and neutral organic products are extracted with an appropriate solvent. The aqueous layer is acidified and the acidic organic products are extracted with an appropriate solvent. Product 3 is isolated from the organic layer. | |
With oxygen; potassium hydroxide In 1,2-dimethoxyethane | 3.ii (ii) Synthesis of 4-(benzyloxy)-3-methoxybenzoic acid (3): A mixture of 1 ,2-dimethoxyethane and potassium hydroxide (5 to 20 eq.) is purged with oxygen and the calculated amount of isolated product 2 (1 .0 eq.) is added. After the absorption of oxygen ceases, the mixture is diluted with distilled water and neutral organic products are extracted with an appropriate solvent. The aqueous layer is acidified and the acidic organic products are extracted with an appropriate solvent. Product 3 is isolated from the organic layer. | |
With potassium permanganate In water; acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium iodide In acetonitrile | |
96% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 1h; | |
96% | Stage #1: vanillin With potassium carbonate In N,N-dimethyl-formamide for 0.25h; Stage #2: benzyl chloride In N,N-dimethyl-formamide Reflux; | 3 A solution of 6.25 g (41 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 11.3 g of potassium carbonate was placed in a three-necked flask, 50 ml of N, N-dimethylformamide (DMF) was added, stirred for 15 min to form a suspension, Add 5.7 g (45 mmol) of benzyl chloride, heat to reflux, continue to reaction 3-4h, TLC follow the end of the reaction, pour into the ice water mixture immediately precipitate a large number of solid, filter, washed with water several times, dry that white 9.52 g of solid 3-methoxy-4-benzyloxybenzaldehyde (5) (yield: 96%) |
96% | With potassium carbonate; potassium iodide In acetonitrile for 6h; Reflux; | |
95.7% | With potassium carbonate In ethanol for 6h; Reflux; | 4.1.2 3-methoxy-4-benzyloxybenzaldehyde (2) To a solution of vanillin (1) (11.4g, 75mmol) in ethanol (100mL), were added the benzyl chloride (13mL, 112.5mmol) and K2CO3 (13.5g, 97.6mmol). After 6hat reflux, the mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the residue crystallization from EtOH gave pure 2 (17.3g) as a light yellow solid with a yield of 95.7%. Mp: 58-60°C; 1H NMR (CDCl3, 300MHz): δ (ppm) 3.94 (s, 3H), 5.24 (s, 2H), 6.97-6.99 (d, J=8.2Hz, 1H), 7.25 (s, 1H), 7.29-7.45 (m, 6H), 9.83 (s, 1H). |
95.7% | With potassium carbonate In ethanol for 6h; Reflux; | 10 Example 10 3-Methoxy-4-benzyloxybenzaldehyde Vanillin (75 mmol, 11.4 g) was added to a 250 ml reaction flask and 100 ml of ethanol was added and dissolved with stirring. K2CO3(97.6 mmol, 13.5 g) and benzyl chloride (112.5 mmol, 13 ml) were added thereto, followed by heating under reflux for 6 hours.The reaction solution was cooled to room temperature, filtered and filtered2CO3The filtrate was concentrated and crystallized in ethanol to give a pale yellow crystal. The filter cake was washed with ethanol and dried to give 17.3 g of 3-methoxy-4-benzyloxybenzaldehyde as a pale yellow solid in a yield of 95.7% , |
95% | Stage #1: vanillin With potassium carbonate In propan-2-one for 0.25h; Stage #2: benzyl chloride With sodium iodide In propan-2-one Inert atmosphere; Reflux; | |
94% | With 4-dimethylaminopyridine; potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | |
93% | ||
93% | With potassium carbonate In N,N-dimethyl-formamide; acetonitrile Reflux; | Aldehydes 9-12 (general procedure). General procedure: A mixture of the corresponding halide (0.010 mol), hydroxybenzaldehyde (0.011 mol), and potassium carbonate (2.00 g, 0.0145 mol) in a mixture of acetonitrile-DMF (20 mL, 8 : 2, v/v) was refluxed for 5-7 h with stirring (TLC monitoring). After evaporation of the solvents, the residue was treated with water, a precipitate formed was filtered off, washed with 30% aqueous methanol, and dried in air. Yields and physicochemical characteristics of aldehydes 9-12 are given in Table 4. |
93.8% | With potassium carbonate In methanol at 20℃; for 8h; | 1 Example 1: To a solution of vanillin (50 g, 0.33 mol)K2CO3 (68.1 g, 0.50 mol)Of methanol (200 mL)Was added dropwise benzyl chloride (49.2 mL, 0.43 mol)After the addition of 8 minutes,After the TLC test reaction was complete,The solvent was removed by distillation under reduced pressure,Then add water (100mL), respectively,Extracted with ethyl acetate (3 x 100 L)The organic phase was washed twice with 15% sodium hydroxide and water,Anhydrous magnesium sulfate, filtered,Concentration gave white solid benzyl ether (75 g. 93.8%).4-Benzyloxy-3-methoxy vanillin (50 g, 0.21 mol)And ammonium acetate (32.4 g, 0.42 mol)Were added to nitromethane (23 ml, 0.42 mol)Then stirred at 80 ° C for 1.5 h.After the TLC detection reaction was completed,Cooled to room temperature,Add ice water mixture, a large amount of yellow solid precipitation, filtration, solid water and ethanol washing,Dried to give yellow solid 2 (54.5 g, yield 90.8%). |
92% | With potassium carbonate In ethanol for 4h; Reflux; | |
92% | With potassium carbonate In ethanol Reflux; | |
92% | With potassium carbonate In ethanol for 4h; Reflux; | |
92% | With potassium carbonate In ethanol for 4h; Reflux; | Synthesis and structural characterization of oxadiazole derivatives The compound 1 can be prepared by the reaction between vanillin and benzyl chloride. Briefly, a mixture of vanillin (1.52 g, 10 mmol) and benzyl chloride (1.39 g, 11 mmol) was added to a well-stirred ethanolic solution of K2CO3 and refluxed for 4 h. The mixture was then concentrated in vacuum. The residue was dissolved in CH3COOC2H5, filtered, and washed with 10% aqueous NaOH and saturated NaCl solution for three times. The organic layer was dried over MgSO4 and concentrated in vacuum. The solids were recrystallized with ethanol to yield compound 1 as a colorless crystal (2.23 g, 92%). m.p. 62-63 °C. |
92% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h; | 5 Example 5 2- (3'-Methoxy-4'-benzyloxybenzeneacryloyl) -estradiol(I-10)Preparation Vanillin (200 mg, 1.32 mmol) was taken,Dissolved in 5 ml of DMF,1.1 eq of potassium carbonate was added,After the system was warmed to 60 ,1.1 eq of benzyl chloride was added,Reaction three hours, point plate, the reaction is complete,After the system temperature is lowered,Ice bath,Add pure water and stir,Suction filtration,dry,4-benzyl vanillin 293mg,The yield is 92% |
92% | With pyridine at 5℃; for 0.5h; | |
91% | With potassium carbonate In dimethyl sulfoxide at 90℃; for 15h; Inert atmosphere; | |
91% | With potassium carbonate In ethanol at 0℃; Reflux; Inert atmosphere; | 4-benzyloxy-3-methoxybenzaldehyde (S2) To a well stirred solution of vanillin (20 g, 131 mmol) in absolute ethanol (115 mL),K2CO3 (20 g, 144 mmol, 1.1 equiv.) and benzyl chloride (16.6 mL, 131 mmol, 1 equiv.)were added drop wise at 0 °C. The reaction was heated to reflux and maintained undernitrogen atmosphere overnight. The reaction was quenched with 30 mL of distilledwater, which was added dropwise. The mixture was dissolved in EtOAc (250 mL),filtered and washed with 10% NaOH (3 × 75 mL) and brine (3 × 90 mL) and dried usingMgSO4. The solvent was evaporated under reduced pressure to produce pure S2(28.85 g, 91%). |
90% | With potassium hydroxide Heating; | |
90% | With potassium carbonate; sodium iodide In ethanol | |
90% | With potassium carbonate In ethanol Reflux; | |
90% | With potassium carbonate | 4.1.13. Synthesis of 4-(benzyloxy)-3-methoxybenzaldehyde (13) Benzyl chloride (36 mmol) was slowly added to a solution of compound 6 (30 mmol), K2CO3 (36mmol) and 4-fluorobenzyl bromide (2.4 mmol) in ethyl alcohol. The mixture was refluxed overnightuntil compound 6 was depleted, as determined by TLC analysis. Then, the mixture was cooled to r.t.After filtration, the residue was purified using silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to produce a faint yellow solid at 90% yield. |
89% | With potassium carbonate; sodium iodide In acetonitrile Heating; | |
87% | With potassium carbonate; potassium iodide In propan-2-one | |
86% | With potassium carbonate In propan-2-one for 8h; Heating; | |
86.7% | With potassium carbonate In ethanol at 80℃; for 15h; | 29 To a mixture of compound 1 (15 g, 100 mmol) in EtOH (100 mL) was added BnCl (12.6 g, 100 mmol) and K2CO3 (27.6 g, 200 mmol). The mixture was heated to 80° C. for 15 h and concentrated. The residue was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1) to give the desired product (21 g, 86.7 mmol, 86.7%) as a white solid. |
84.8% | With potassium carbonate In <i>N</i>-methyl-acetamide; n-heptane; toluene | 4 (Production of 3-Methoxy-4-benzyloxybenzaldehyde) (Production of 3-Methoxy-4-benzyloxybenzaldehyde) 76 g (0.5 mol) of 3-methoxy-4-hydroxybenzaldehyde were placed in a four-necked flask together with 228 g of dimethylformamide and 82.8 g (0.6 mol) of potassium carbonate. 66.4 g (0.525 mol) of benzyl chloride was added dropwise at a temperature of 60° C. for one hour. After the addition, the mixture was stirred at a temperature of 60° C. for five hours. The resulting reaction mixture was washed with 190 g of toluene and 330 g of water. 270 g of the solvent were removed by distillation under reduced pressure of 70 mmHg and then 265 g of n-heptane and 80 g of toluene were added to the distillation residue and the separated crystals were collected by filtration to provide 102.6 g of 3-methoxy-4-benzyloxybenzaldehyde as white crystals in a yield of 84.8%. |
83% | With sodium hydride 1) DMF, 2) 125 deg C, 4 h; | |
80% | With potassium carbonate In N,N-dimethyl-formamide for 6h; Reflux; | Preparation of 4-benzyloxy-3-methoxybenzaldehyde The 4-hydroxy-3-methoxybenzaldehyde (4.56g, 30mmol) dissolved in DMF (45 ml), then potassium carbonate (4.56g, 33mmol) and benzyl chloride (4.18g, 33mmol) was added and heated reflux for 6 hours. The degree of reaction was monitored by TLC monitoring. After the end of reaction , cooling to room temperature, filtering off the solid insoluble materials, while fast stirring slowly added water (150 ml), allowed to stand for a moment for white solid precipitation. Filtering, drying to obtain the white solid (5.8g), yield 80%. |
79.1% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 2 Synthesis of 4-(benzyloxy)-3-methoxybenzaldehyde Vanillin (10 g, 0.065 mol) was added in turn to a 100 mL three-neck flask.DMF (50mL),K2CO3 (13.7 g, 0.099 mol), benzyl chloride (10 g, 0.079 mol) was added dropwise, and the mixture was stirred overnight at room temperature.Add 50mL of water to quench,Dichloromethane extraction (30mL x 3), combined organic phase, washed with water (25mL x 3), dried over anhydrous sodium sulfate,Filter, concentrate,Cyclohexane was recrystallized to give 12.45 g,The yield was 79.1%. |
72% | With tetrabutylammonium bromide; sodium chloride; sodium hydroxide In lithium hydroxide monohydrate; toluene at 90℃; for 2h; Reflux; | |
70% | In sodium hydroxide; dichloromethane Heating; | |
67.3% | With potassium iodide; sodium hydroxide In isopropanol at 20 - 70℃; for 8h; | 3.10 (10) Preparation of Compound 13 To a 2 L three-necked flask, 76 g of vanillin, 7.6 g of potassium iodide, 48 g of sodium hydroxide and 600 g of isopropanol were added, and 100 g of benzyl chloride was added dropwise at room temperature. After the completion of the dropwise addition, the reaction was heated to 70 ° C for 8 hours, and the reaction of the starting materials was completed. After cooling to room temperature, 150 g of water was added, and pH was adjusted to about 2 with 10% dilute hydrochloric acid to precipitate a large amount of solid. Filter, filter cake twice with water, dry at 60 oC, get white solid The body was 81.4 g, which was the compound 13, and the yield was 67.3%. |
66% | With sodium hydroxide; diphenylether; tetrabutylammonium bromide In lithium hydroxide monohydrate; toluene at 90℃; for 3h; low energy microwave irradiation; | |
36% | Stage #1: vanillin With sodium hydride In N,N-dimethyl-formamide for 1h; Cooling with ice; Stage #2: benzyl chloride In N,N-dimethyl-formamide at 125℃; for 0.25h; Cooling with ice; Microwave irradiation; | General procedure for the synthesis of arylaldehydes 3e and 3f General procedure: A mixture of 4-hydroxy-3-methoxybenzaldehyde or 3-hydroxy-4-methoxybenzaldehyde (0.5 g, 3.28 mmol) and sodium hydride (0.1 g, 4.1 mmol) in anhydrous DMF (5 ml) was stirred on an ice bath for 1 h. Then, benzyl chloride (0.42 g, 3.28 mmol) was added and the mixture was irradiated with microwaves for 15 minutes (125°C, max 200 psi, max 300W). The crude mixture was diluted with H2O and acidified (pH 4-5) with glacial AcOH. Then the mixture was extracted with ethyl acetate. The organic layer was washed with H2O (3×100ml), dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. The solid residue was recrystallized from a methanol/water mixture to give pure aldehyde 3e or 3f. |
With potassium hydroxide at 110 - 120℃; | ||
With ethanol; potassium etoxide; sodium iodide | ||
With ethanol; potassium carbonate | ||
With potassium etoxide | ||
With sodium hydroxide | ||
With potassium hydroxide In ethanol Heating; | ||
With potassium hydroxide | ||
With potassium hydroxide In ethanol | ||
With potassium carbonate; sodium iodide In ethanol Heating; Yield given; | ||
With hydroxide In lithium hydroxide monohydrate | ||
With potassium carbonate; potassium iodide In propan-2-one Heating; | ||
With potassium carbonate; sodium iodide In ethanol | ||
at 70℃; for 12h; | ||
With potassium carbonate In ethanol Heating; | ||
With potassium carbonate In propan-2-one | ||
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80 - 90℃; for 1h; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | ||
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 2h; | ||
With anhydrous sodium carbonate | ||
With potassium carbonate In ethanol for 5h; Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide for 6h; Reflux; | ||
With anhydrous sodium carbonate | ||
With potassium carbonate In ethanol | ||
Stage #1: vanillin With potassium carbonate In ethanol for 0.5h; Reflux; Stage #2: benzyl chloride In ethanol for 6h; Reflux; | General procedure: The hydroxyl group in aldehyde A was protected by etherizing with benzyl chloride before used in the following synthesis. Briefly, hydroxyl-substituted benzaldehyde (10mmol) and K2CO3 (2.07g, 15mmol) were refluxed in 10mL of 95% ethanol for 0.5h, then, benzyl chloride (1.55g, 12mmol) was added and refluxed for 6h. The reaction mixture was cooled to room temperature and filtered to remove inorganic salt. The organic solvent was removed under vacuum to yield benzoxyl-substituted benzaldehyde (>90%). | |
With N,N,N-tributyl-1-butanaminium iodide; potassium carbonate In acetonitrile at 85℃; for 12h; | Methyl 4-(4-(chloromethyl)-2-methoxyphenoxy)butanoate (1) General procedure: Ethyl bromo-4-butyrate (201.2mmol), tetrabutylammonium iodide (19.7 mmol) and potassium carbonate (361 mmol) weresuccessively added to a solution of vanillin (30 g, 197.2 mmol) in acetonitrile (900 ml). The mixturewas refluxed for 4 h and then allowed to return to room temperature. The solvent was evaporatedand the residue was diluted with water (500 ml) and then extracted with diethyl ether (3 x 300 ml).The recovered organic phase was dried with magnesium sulfate and evaporated to give a viscous oil which rapidly turned to a slightly yellow solid when triturated with petroleum ether. The precipitatewas filtered on a glass-sintered funnel and further dried under vacuum. The crude alkylated vanillinwas subsequently dissolved in methanol (500 ml) and cooled to 0°C, before adding sodiumborohydride (98.6 mmol) in 4 portions. The mixture was allowed to warm to room temperature andcontinued stirring for an additional hour, until the complete consumption of the starting material. Thereaction was quenched by addition of water (300 ml) and hydrochloric acid (1N aqueous solution)until a neutral pH. The methanol was evaporated and the aqueous residue extracted with ethylacetate (3 x 300 ml). The combined organic layers were dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a crude product which was subsequently used withoutfurther purification. To a solution of the previously obtained alcohol in chloroform (400 ml), thionylchloride (256.4 mmol) was added slowly at 0°C. The mixture was allowed to return to roomtemperature and continued stirring for 3 hours, before pouring onto 400 ml of water. Solid sodiumbicarbonate was slowly added to the biphasic mixture until saturation of the aqueous phase and thenthe organic layer separated. The residual aqueous layer was further extracted with dichloromethane(3 x 200 ml) and the combined organic layers were dried with magnesium sulfate, filtrated and thesolvent evaporated. The obtained crude oil was triturated in petroleum ether (boiling range: 40-60°C), filtrated and dried under vacuum to conduct to the desired compound which was used withoutfurther purification in the next step. | |
With potassium carbonate In N,N-dimethyl-formamide Reflux; | ||
Stage #1: vanillin With potassium carbonate In ethanol; lithium hydroxide monohydrate for 0.5h; Reflux; Stage #2: benzyl chloride In ethanol; lithium hydroxide monohydrate for 6h; Reflux; | 4.2.4. Protection of hydroxyl group in benzaldehyde General procedure: In brief, the preparation of 2-phenylmethoxylbenzaldehyde was taken as an example. 2-Hydroxybenzaldehyde (1.22 g, 10 mmol) and K2CO3 (2.07 g, 15 mmol) were refluxed in 10 mL of 95% ethanol for 0.5 h, then benzyl chloride (1.55 g, 12 mmol) was added and refluxed for 6 h. The reaction mixture was cooled to room temperature and filtered to remove inorganic salt. The organic solvent was removed under vacuum to yield 2-phenylmethoxylbenzaldehyde. The yields of this reaction were generally >90%. | |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | Protection (if necessary) General procedure: Asolution of benzaldehyde (10 mmol), benzyl chloride (12mmol) and potassiumcarbonate (15mmol) in DMF (30 mL) was stirred at 80 °C for3 h. The suspension was poured into water (150 mL) and extracted with ethylacetate (3 * 100 mL). The combined organic layer was concentrated and theresidue was recrystallized with ethyl acetate to give benzyl-protectedbenzaldehyde. | |
Stage #1: vanillin With potassium carbonate In ethanol at 20℃; for 0.166667h; Stage #2: benzyl chloride In ethanol for 5h; Reflux; | 4.1 Prepared compound 3-methoxy-4-benzyloxybenzaldehyde 4.56g (30mmol) 3-methoxy-4-Hydroxybenzaldehyde (9) dissolved in 120mL of anhydrous ethanol, then added the 12.44g (90mmol) Anhydrous potassium carbonate, after stirring at room temperature for 10 minutes, added the 5.20 mL(45 mmol) of benzyl chloride and the reaction is heated under reflux for 5 hours. After completion of the reaction, the mixture is cooled at room temperature and the filtrate has been decompressed to recover ethanol, and then extracted with 140 mL of ethyl acetate. The organic phase has washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, the final organic phase has been dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtained light yellow 3-Methoxy-4-benzyloxybenzaldehyde (10) crude 6.69g, yield 92%. | |
With potassium carbonate; potassium iodide In propan-2-one Reflux; | 4.2 General procedure for the synthesis of 9h-9t General procedure: To the solution of 4-hydroxy benzaldehydes, vanillin or iso-vanillin (1 equivalent) in acetone was added potassium carbonate (2 equivalents). Then, corresponding substituted benzyl chlorides or acetamide was added followed by addition of potassium iodide (1.5 equivalents). Reaction mixture was refluxed for 8-10h. After completion of reaction, the resultant mixture was concentrated and was diluted with water. Product was extracted with ethyl acetate (3×20ml). The organic layers were combined and treated with brine and dried over sodium sulfate and concentrated. The crude mixture was purified over gel silica gel column (60-120 mesh) using petroleum ether: ethyl acetate (9:1). | |
With potassium carbonate In propan-2-one | General procedure for the preparation of compounds 5a-f and 9a-l General procedure: To a solution consisting of hydroxyl benzaldehyde (10 mmol), vanillin or 6-hydroxy-2-naphthaldehyde (10 mmol) and K2CO3 (10 mmol) in dry DMF (20 mL), the corresponding substituted benzyl chloride (10 mmol) was added to the stirred solution 8-12h at 60 oC. After the reaction is completed, the mixture was poured into ice water. The resulting precipitate was filtered, recrystallized with ethanol to obtain crude products which purified by column chromatography (dichloromethane : petroleum ether = 10 : 1). | |
With potassium carbonate In acetonitrile Reflux; | 1.1 (1) Synthesis of 4- (benzyloxy) -3-methoxybenzaldehyde A mixture of vanillin (1.52 g, 10 mmol) and benzyl chloride (1.26 g, 10 mmol) was added to 100 mL three-necked flask and add 40 mL of acetonitrile to dissolve the solid. Anhydrous K2CO3 (2.76 g, 20 mmol) was added. The reaction system was pale yellow turbidity (K2CO3 not dissolved), reflux stirring,TLC followed the reaction process (in which the developing solvent was petroleum ether: ethyl acetate = 3: 1, v/v). After the disappearance of the starting point, the reaction was stopped and the solvent was dried. Add 50 mL of H2O to stir at room temperature to precipitate a white solid. Crystallization to give a white solid; | |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60 - 120℃; | 3.i (i) Synthesis of 4-(benzyloxy)-3-methoxybenzaldehyde (2) Vanillin (1) (1.0 eq.) and benzyl chloride (1.2 eq.) are dissolved in N,N-dimethylformamide and potassium iodine (0.5 mol %) is added. Afterwards potassium carbonate is added and the reaction is stirred above 60° C., preferably between 60 to 120° C. for at least 1 h, preferably 1 to 8 h. After completion of the reaction, the solution is diluted with distilled water and extracted with an appropriate solvent. The organic phase is washed with brine and the product is then isolated from the organic phase. | |
With potassium carbonate In propan-2-one for 4h; Reflux; | 5.2. General procedure for the synthesis of 7-10 General procedure: Compound 6 was synthesized as previously reported [36].A mixture of hydroxyaromatic aldehydes (1.0 mmol), appropriatebenzyl chlorides (1.2 mmol), and anhydrous sodium carbonatewas stirred for 4 h in refluxing acetone. The solvent wasevaporated under reduced pressure and the residue was dissolvedin dichloromethane, washed using water and brine, dried overanhydrous MgSO4, and the solvent was removed under reducedpressure. The resulting residue was purified through silica gel columnchromatography (dichloromethane/PE, 5:1 v/v) to affordcompounds 2-5 as white solids. To a solution of each of compounds2-5 (1.0 mmol) and compound 6 (1.0 mmol) in absoluteethanol (5 mL), was added drops of glacial acetic acid and piperidine.The reaction mixture was stirred at 80° C for 2-6 h, until thecompletion of the reaction as evidenced through TLC. The resultingreaction mixture was concentrated to dryness, and purifiedthrough silica gel column chromatography (dichloromethane/methanol/acetic acid, 100:1:1) to afford the pure products 7-10.The yield, melting point and spectral data of each compound aregiven below. | |
With potassium carbonate In acetonitrile Reflux; | 13.2 (2) vanillin (5.0 mmol), potassium carbonate (20.0 mmol), and benzyl chloride (6.0 mmol), 30 mL of acetonitrile as a solvent.Add to a 100mL three-necked bottle and reflux for 3-5h.The progress of the reaction was followed by TLC. After the reaction was completed, the reaction was stopped and washed with ice water.The solid intermediate 4-(benzyloxy)-3-methoxybenzaldehyde was then collected by filtration; | |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60 - 120℃; | 3.i (i) Synthesis of 4-(benzyloxy)-3-methoxybenzaldehyde (2): Vanillin (1 ) (1 .0 eq.) and benzyl chloride (1 .2 eq.) are dissolved in L/,/V-dimethylformamide and potassium iodine (0.5 mol%) is added. Afterwards potassium carbonate is added and the reaction is stirred above 60°C, preferably between 60 to 120 °C for at least 1 h, preferably 1 to 8 h. After completion of the reaction, the solution is diluted with distilled water and extracted with an appropriate solvent. The organic phase is washed with brine and the product is then isolated from the organic phase. | |
With potassium carbonate In acetonitrile Reflux; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; | ||
With potassium carbonate In N,N-dimethyl-formamide for 5h; Reflux; | Procedure for the synthesis of 2a-l [19]. General procedure: To the solution of aldehyde1a-d (2.2 mmol) in DMF (5 mL), K2CO3 (1.216 g, 8.8 mmol for 1a-c;0.608 g, 4.4 mmol for 1d) was added, followed by the correspondingalkyl halide (MeI, nPrBr, nBuBr, iBuBr or BnCl) (for 1a-c 5.07 mmol; for1d 2.53 mmol). The resulting mixture was then refluxed for 5 h. Aftercompletion, the suspension was filtrated, the precipitate was discarded,and 25 mL of cold water was added to the filtrate. The pH of the solutionwas adjusted to 4 with HCl aqueous solution (2 M), upon which a precipitatewas formed in the case of compounds 2a-d, 2g, and 2h. Theformed suspension was then stirred for 1 h at the room temperature,filtrated, washed with a small amount of cold water, and dried overCaCl2. In the case of compounds 2e, 2f, 2i and 2j-l, the solution wasextracted with ethyl acetate (2 × 30 mL) after acidification, and theorganic portion was dried over Na2SO4. Afterward, the solvent wasevaporated under reduced pressure, and the obtained compounds 2e, 2f,2i, and 2j-l were dried over CaCl2. The aldehydes 2f-h, 2j-l were purifiedby column chromatography (stationary phase: silica gel, eluent: chloroform),while the other compounds 2a-e and 2i were obtained with satisfactory purity and were used for further synthesis without purification. | |
With potassium carbonate In propan-2-one | ||
With potassium carbonate In N,N-dimethyl-formamide for 8h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydroxylamine hydrochloride; sodium acetate; acetic acid at 130℃; for 18h; | |
100% | With hydroxylamine hydrochloride; sodium acetate In acetic acid | 199 4-benzyloxy-3-methoxybenzonitrile 4-benzyloxy-3-methoxybenzonitrile 4-benzyloxy-3-methoxybenzaldehyde (4.84 g, 20 mmol) in acetic acid (25 ml) and sodium acetate (3.3 g, 40 mmol) was reacted with hydroxylamine hydrochloride (2.8 g, 40 mmol) at reflux for 6 hours. The mixture was cooled, diluted with water, extracted with methylene chloride, dried over MgSO4, concentrated to give title compound (4.8 g, 100%). 1H-NMR (DMSOd6): 3.83 (s, 3H); 5.20 (s, 2H); 7.21 (d, 1H); 7.40 (m, 7H). |
95% | With phthalic anhydride; hydroxylamine hydrochloride; triethylamine In acetonitrile for 7h; Heating; |
95% | With ammonia; iodine In tetrahydrofuran; water at 20℃; for 12h; | Synthesis and structural characterization of oxadiazole derivatives The compound 2 was derived from compound 1 treated by I2 in NH3 aqueous solution. A tetrahydrofuran (15 mL) solution of compound 1 (2.42 g, 10 mmol) was mixed with I2 (2.79 g, 11 mmol) in 28% aqueous solution of NH3 (90 mL). The mixture was stirred for 12 h at room temperature and extracted with CHCl3 (3 × 15 mL). The organic solution was washed with water, 10% aqueous solution of Na2S2O3, and brine, then dried over MgSO4. The organic solution was removed in vacuum. The residue was recrystallized with ethanol to yield compound 2 as a colorless crystal (2.27 g, 95%). m.p. 89-90 °C. |
80% | With hydroxylamine hydrochloride; sodium acetate In acetic acid for 21h; Heating / reflux; | 1.a a) A mixture of 4-benzyloxy-3-methoxybenzaldehyde (157 g, 649 mmol), sodium acetate (106 g, 1.29 mol), hydroxylamine hydrochloride (90 g, 1.29 mol) and acetic acid (500 ml) was refluxed for 21 hours. The solvent was evaporated and ice/water (1000 ml) was added to the residue forming a sticky solid. The mixture was neutralised with aqueous sodium hydroxide solution then extracted with dichloromethane (2 x 500 ml). The organic solution was washed with 1.0 N sodium hydroxide (100 ml), brine (100 ml) and then dried over magnesium sulphate. Solvent evaporation, trituration of the residue with hexane: ethyl acetate (3: 1) and collection of the solid by vacuum filtration yielded 4-benzyloxy-3- METHOXYBENZONITRILE (123 g, 80 % yield) as a brown solid: 1H-NMR (DMSO d6): 7.38 (M, 7H), 7.19 (M, 1H), 5.18 (s, 2H), 3.80 (s, 3H): MS (-ve ESI): 238 (M-H)-. |
80% | With hydroxylamine hydrochloride; sodium acetate In acetic acid for 21h; Heating / reflux; | 1.a A mixture OF 4-BENZYLOXY-3-METHOXYBENZALDEHYDE (157 g, 649 mmol), sodium acetate (106 g, 1.29 mol), hydroxylamine hydrochloride (90 g, 1.29 mol) and acetic acid (500 ml) was heated at reflux for 21 hours. The solvent was evaporated in vacuo and ICE/WATER (1000 ml) was added to the residue, forming a sticky solid. The mixture was neutralised by addition of aqueous sodium hydroxide solution then extracted with dichloromethane (2 x 500 ml). The organic solution was washed with 1.0 N sodium hydroxide (100 ml) and brine (100 ml) and then dried over magnesium sulphate. Solvent evaporation in vacuo, followed by trituration of the residue with hexane: ethyl acetate (3: 1) and collection of the solid by suction filtration yielded 4-benzyloxy-3-methoxybenzonitrile (123 g, 80 % yield) as a brown solid: 'H-NMR (DMSO d6): 7.38 (M, 7H), 7.19 (m, 1H), 5.18 (s, 2H), 3.80 (s, 3H): MS (-ve ESI): 238 (M-H)&APOS |
(i) NH2OH*HCl, Py, (ii) DCC, CuSO4*5H2O, Et3N; Multistep reaction; | ||
With pyridine; oxygen; copper; ammonium chloride at 60℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium hydroxide In ethanol at 20℃; for 72h; | |
70% | With potassium hydroxide In methanol at 20℃; for 36h; | preparation of (E)-3-(4-(benzyloxy)-3-methoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)propan-2-en-1-one The intermediate 4,6-dimethoxy-2-hydroxy - acetophenone (2g, 10.2mmol) and Intermediate 4-benzyloxy-3-methoxybenzaldehyde (2.5g, 10.2mmol) was dissolved in methanol (50ml), the stirring was slowly added dropwise a 50% aqueous potassium hydroxide solution (6 ml of), yellow color of the solution gradually, dropwise, stirred for 36 hours at room temperature, the extent of reaction is monitored by TLC.After completion of the reaction, stirring was added dropwise 1mol / L hydrochloric acid solution, adjusted to PH = 5, standing for a while, to give a yellow oily solid was filtered, washed with methanol (30ml), filtered, and dried to give a yellow solid (3.0 g), yield about 70%. |
With potassium hydroxide In ethanol at 35 - 40℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.8% | With ammonium acetate at 80℃; for 1.5h; | 1 Example 1: 1-Benzyl-2-methoxy-4- (2-nitrovinyl) benzene (2) To a solution of vanillin (50 g, 0.33 mol)K2CO3 (68.1 g, 0.50 mol)Of methanol (200 mL)Was added dropwise benzyl chloride (49.2 mL, 0.43 mol)After the addition of 8 minutes,After the TLC test reaction was complete,The solvent was removed by distillation under reduced pressure,Then add water (100mL), respectively,Extracted with ethyl acetate (3 x 100 L)The organic phase was washed twice with 15% sodium hydroxide and water,Anhydrous magnesium sulfate, filtered,Concentration gave white solid benzyl ether (75 g. 93.8%).4-Benzyloxy-3-methoxy vanillin (50 g, 0.21 mol)And ammonium acetate (32.4 g, 0.42 mol)Were added to nitromethane (23 ml, 0.42 mol)Then stirred at 80 ° C for 1.5 h.After the TLC detection reaction was completed,Cooled to room temperature,Add ice water mixture, a large amount of yellow solid precipitation, filtration, solid water and ethanol washing,Dried to give yellow solid 2 (54.5 g, yield 90.8%). |
86% | With ammonium acetate; acetic acid at 90℃; for 4h; | 6.2.1. 1-(Benzyloxy)-2-methoxy-4-(2-nitroethenyl)benzene (12a) General procedure: To a solution of 10a (8.5 g, 35 mmol) in glacial acetic acid (30 mL) was added CH3NO2 (6.4 g, 105 mmol) and ammonium acetate (2.70 g, 35 mmol), the mixture was heated to 90 °C for 4 h, then cooled to room temperature and poured to water (200 mL) to favor the precipitation as a solid, which was subsequently filtered and washed with cold water and methanol. The crude product was purified by column chromatography (PE/EA = 6/1) to yield 12a (8.58 g, 86%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 7.94 (d, J = 13.5 Hz, 1H), 7.52 (d, J = 13.2 Hz, 1H), 7.44-7.30 (m, 5H), 7.10 (dd, J = 8.4, 1.8 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.22 (s, 2H), 3.93 (s, 3H); ESI-MS m/z 284 [M-H]-. |
86.5% | With triethylamine In ethanol for 12h; Reflux; | 1.11; 2.11 (11) Preparation of Compound 14 To a 2 L three-necked flask, 109 g of compound 13, 68 g of triethylamine, 110 g of nitromethane and 545 g of absolute ethanol were added, and the mixture was heated to reflux for 12 hours, and the starting material was completely reacted. The reaction solution was cooled to room temperature, and 545 g of water was added to precipitate a large amount of solid. Filtration, the filter cake was stirred twice with water, isopropyl alcohol twice, dried at 60 ° C to give a yellow solid 111 g, which is compound 14, yield86.5%. |
83% | With ammonium acetate In acetic acid for 5h; Inert atmosphere; Reflux; | |
83% | With ammonium acetate; acetic acid | |
82% | With ammonium acetate; acetic acid for 4h; Reflux; | |
75% | With ammonium acetate; acetic acid at 40 - 130℃; for 2h; | |
73% | With ammonium acetate for 1.5h; Heating; | |
72% | With potassium hydroxide In ethanol at 0℃; for 2h; | |
70% | With ammonium acetate; acetic acid at 100℃; | 1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl) benzene (3c) General procedure: To the solution of 2c (11.5g, 49.5 mmol) in acetic acid (50 mL) was added ammonium acetate (3.82 g, 49.5 mmol ) and nitromethane (9.2 g, 150 mmol), and the mixture was reflux overnight, then the reaction mixture was cooled to room temperature and the product was obtained by filtered. (9.88 g; yellow solid, 70%) |
70% | With ammonium acetate; acetic acid at 90℃; | 1.5 5.1.5. 1-(Benzyloxy)-2-methoxy-4-(2-nitrovinyl) benzene (17) To the solution of 16 (11.5 g, 49.5 mmol) in acetic acid (50 mL)was added ammonium acetate (3.82 g, 1 equiv) and nitro methane(9.2 g, 3 equiv), and the mixture was reflux overnight, then thereaction mixture was cooled to room temperature and the productwas obtained by filtration (9.88 g; yellow solid, 70%). 1H NMR(CDCl3, 300 MHz): d 7.95 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.2 Hz,1H), 7.42-7.32 (m, 5H), 7.10 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 7.02(d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.22 (s, 2H), 3.92 (s,3H). LRMS (ESI) m/z: 286.1 (M+H). |
68% | With ammonium acetate In acetic acid for 4h; Heating; | |
68% | With ammonium acetate In acetic acid for 5h; Reflux; | |
With potassium hydroxide | ||
With ammonium acetate In acetic acid Heating; | ||
With ammonium acetate; acetic acid | ||
With methylamine hydrochloride; sodium carbonate In ethanol | ||
With ammonium acetate In acetic acid | ||
With ammonium acetate; acetic acid | ||
With ammonium acetate; acetic acid for 1.5h; Heating; | ||
With N-butylamine In acetic acid for 2h; Heating / reflux; | 4 Reference Production Example 4; [0212] 15.2 g (0.1 mol) of vanilline, 20.5 g (0.12 mol) of benzyl bromide, 17.9 g (0.13 mol) of potassium carbonate and 150 ml of N,N-dimethylformamide were mixed and stirred at 50[deg.] C. for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and then saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 23.1 g of 4-benzyloxy-3-methoxybenzaldehyde. [0213] <1>H-NMR(CDCl3, TMS) [delta](ppm): 9.83(1H,s), 7.5-7.3(7H,m), 6.98(1H,d, J=8.2Hz), 5.24(2H,s), 3.95(3H,s) [0214] 23.1 g (95.7 mmol) of 4-benzyloxy-3-methoxybenzaldehyde, 8.76 g (143 mmol) of nitromethane and 250 ml of acetic acid were mixed and 7.07 g (96.7 mmol) of butylamine was added dropwise thereto. The mixture was refluxed for 2 hours by heating, and then cooled and poured into ice-water. The precipitated crystals were dissolved with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 17.0 g of 1-benzyloxy-2-methoxy-4-(2-nitrovinyl)benzene. [0215] <1>H-NMR(CDCl3, TMS) [delta](ppm): 7.95(1H,d,J=13.5Hz), 7.51(1H,d,J=14.7Hz), 7.3-7.5(5H,m), 5.24(2H,s), 3.95(3H,s) [0216] 6.78 g (178.8 mmol) of lithium aluminum hydride and 200 ml of anhydrous tetrahydrofuran were mixed and an anhydrous tetrahydrofuran solution of 17.0 g (59.6 mmol) of 1-benzyloxy-2-methoxy-4-(2-nitrovinyl)benzene was added dropwise thereto over about 90 minutes under vigorous stirring. The mixture was refluxed for 2 hours by heating, and then cooled and aqueous sodium hydroxide solution was added to the mixture. The precipitates were filtered off with celite-precoated glass filter and the solvent was distilled off from the filtrate under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, dried over potassium carbonate and the solvent was distilled off under reduced pressure to give 13.67 g of crude 2-(3-methoxy-4-benzyloxyphenyl) ethylamine. [0217] <1>H-NMR(CDCl3, TMS) [delta](ppm): 7.2-7.5(5H,m), 6.6-6.9(3H,m), 5.10(2H,s), 3.85(3H,s), 2.90(2H,t,J=6.7Hz), 2.66(2H,t,J=6.8Hz), 2.0-2.4(2H,br) [0218] 8.01 g (31.2 mmol) of crude 2-(3-methoxy-4-benzyloxyphenyl)ethylamine, 3.78 g (37.4 mmol) of triethylamine and 80 ml of tetrahydrofuran were mixed and cooled to 0[deg.] C. and then (5,6,7,8-tetrahydronaphthalen-2-yl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0[deg.] C. for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and then saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate =1:1) to give 8.3 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2 -yl)acetamide. [0219] <1>H-NMR(CDCl3, TMS) [delta](ppm): 7.1-7.2(4H,m), 6.72(1H,d,J=8.2Hz), 6.5-6.6(2H,m), 5.4(1H,s), 3.86(3H,s), 3.82(3H,s), 3.49(2H,s), 3.3-3.4(2H,m), 2.67(2H,t,J=6.9Hz), 2.34(3H,s) [0220] 8.8 g (13.6 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, 8.9 g (51.1 mmol) of t-butoxybis (dimethylamino)methane and 100 ml of N,N-dimethylformamide were mixed and stirred at 100[deg.] C. for 6 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue, 50 ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate =2:1) and dried to give 4.20 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide. [0221] <1>H-NMR(CDCl3, TMS) [delta](ppm): 13.61(1H,d,J=11.3Hz), 7.2-7.5(5H,m), 7.04(1H,d, J=11.0Hz), 6.97(1H,d,J=8.2Hz), 6.7-6.9(3H,m), 6.66(1H,d,J=2.0Hz), 6.59(1H,dd,J=8.3, 1.9Hz), 5.55(1H,br), 5.11(2H,s), 3.83(3H,s), 3.4-3.6(2H,m), 2.6-2.9(6H,m), 1.7-1.9(4H,m) | |
With methylamine In methanol for 4h; | ||
With ammonium acetate; acetic acid Reflux; | 1 Scheme 1 (FIG. 1): Protection of the hydroxyl group in vanillin with benzyl bromide yielded aldehyde 1 is shown in Scheme 1. Henry reaction between aldehyde 1 and nitromethane gave nitrostyrene 2. Reduction of compound 2 with lithium aluminum hydride in tetrahydrofuran (THF) afforded amine 3. The reaction of amine 3 with an excess amount of methyl formate provided formamide 4. Cyclization of amide 4 using phosphorus oxychloride (POCl3) via Bischler-Napieralski reaction obtained 3,4-dihydroisoquinoline 5. Alkylation of compound 5 with iodopropane followed by NaBH4 reduction produced tetrahydroisoquinoline 6 in high yield. Catalytic hydrogenation over Pd/C removed the protective groups of 6 to afford 1,2,3,4-tetrahydroisoquinolin-7-ol 7 in quantitative yield. Treatment of compound 7 with Pb(OAc)4 in acetic acid followed by acid-catalyzed aromatic substitution with 1,3-dimethoxybenzene using trifluoroacetic acid (TFA) furnished 8-phenyl-tetrahydroisoquinolin-7-ol 8. | |
With ammonium acetate; acetic acid Reflux; | 1.1.1 1.1 Preparation of 3-methoxy-4-benzyloxy-ω-nitrostyrolene (Compound 2) The preparation was conducted with reference to org. Lett., 2008, 8(8), 1525-1528. Firstly, the hydroxyl of vanillin (purchased from Alfa Aesar company) was protected with benzyl. And then protected vanillin and nitromethane were refluxed in ammonium acetate and acetic acid to obtain the target product. Two-step yield: 75%; melting point: 117-118° C. 1H NMR (CDCl3): 1H NMR (CDCl3, 300 MHz): δ 7.95 (d, J=13.2 Hz, 1H), 7.51 (d, J=13.2 Hz, 1H), 7.42-7.32 (m, 5H), 7.10 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 5.22 (s, 2H), 3.92 (s, 3H); ESI-MS m/z 251 [M+H]+. |
|
With ammonium acetate; acetic acid | ||
With zirconium(IV) chloride at 0 - 20℃; for 3h; | ||
With methylamine In methanol at 50℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃; for 0.5h; | |
98% | With methanol; sodium tetrahydroborate at 0 - 20℃; for 0.5h; | |
98% | With methanol; sodium tetrahydroborate at 0 - 20℃; for 0.5h; | (4-(benzyloxy)-3-methoxyphenyl)methanol (Compound 26) General procedure: To a stirred solution of the aromatic aldehyde (1.00 mmol) in MeOH (3 mL) was added sodium borohydride (0.05 g, 1.20 mmol, 1.2 eq.) At a constant rate at 0 ° C.After completion of the reaction, the reaction temperature was raised to room temperature and stirred for 30 minutes.After completion of the reaction,To the excess sodium borohydride was added water (1 mL), cooled, stirred for 15 minutes, and the solvent was removed under reduced pressure. EtOAc (20 mL) and H2O (10 mL) were added to the crude compound and the two layers were separated.The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic solvent layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc / Hexane = 1/3 - 1/1) to give pure benzyl alcohol. |
97% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With sodium tetrahydroborate In methanol; dichloromethane at 20℃; for 18h; Stage #2: With water In methanol; dichloromethane | Using the procedure reported by A. van Oeveran et al., J. Org. Chem., 1994, 59 (20), 5999. To a solution of OBS01056 (5.0 g, 20.64 mmol) in anhydrous DCM (25 mL) was added a suspension of sodium borohydride (0.97 g, 25.59 mmol) in MeOH (12 mL) and the mixture stirred at room temperature for 18 h. The reaction was poured into water (50 mL) (CARE !!) and extracted with DCM (3*50 mL) and dried (MgSO4). Concentration in vacuo gave a white residue. Recrystallisation from Et2O-petroleum ether gave OBS01063 as colorless needles (4.91 g, 97%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.49; m.p. 72-74° C. [Lit. (Et2O-Pet. ether): 72-73° C.]; 1H-NMR (400 MHz, d6-DMSO) 3.74 (3H, s), 4.39 (2H, d, J=5.7), 5.05 (2H, s), 5.08 (1H, t, J=5.7, OH), 6.84 (1H, dd, J=2, 8.2), 6.91 (1H, d, J=8.2), 7.01 (1H, d, J=2), 7.31-7.46 (5H, m). |
97% | With sodium tetrahydroborate In methanol at 0 - 20℃; | |
97% | With sodium tetrahydroborate In methanol; dichloromethane at 20℃; for 1h; | |
97% | With sodium tetrahydroborate In methanol | |
96.6% | With sodium tetrahydroborate In methanol for 3h; | |
93.4% | With sodium tetrahydroborate In methanol at 20℃; for 3h; | General procedures for the synthesis of compounds 4a-4h General procedure: Sodium borohydride (5.4 mmol) was added portion-wise to the solution of compound 3 (5.4 mmol) in methanol (40 ml) and the mixture was stirred at room temperature for 3 h. After evaporation of methanol, the resulting residue was neutralized with a solution of hydrochloric acid (1 M) to pH 6-8. The mixture was extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, concentrated to produce the white solid. |
91% | With sodium tetrahydroborate In tetrahydrofuran; ethanol at 20℃; for 2h; | |
84% | With sodium tetrahydroborate | |
84% | With sodium tetrahydroborate In methanol at 0 - 20℃; for 2h; Inert atmosphere; | |
82% | With sodium tetrahydroborate In isopropyl alcohol for 4h; | |
70% | With sodium tetrahydroborate In methanol at 0℃; for 2h; | |
62% | With sodium tetrahydroborate In methanol at 0℃; | |
42.9% | With phenylselenomagnesium bromide In tetrahydrofuran for 13h; Ambient temperature; | |
With sodium tetrahydroborate In methanol | ||
With sodium tetrahydroborate | ||
With sodium tetrahydroborate In methanol; dichloromethane for 1h; | ||
With sodium tetrahydroborate In isopropyl alcohol | ||
With sodium tetrahydroborate In methanol at 20℃; | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1h; | ||
With sodium tetrahydroborate In tetrahydrofuran; ethanol at 0 - 20℃; | ||
With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃; for 2h; | ||
With sodium tetrahydroborate In isopropyl alcohol at 20℃; | ||
With sodium tetrahydroborate In methanol at 0℃; Inert atmosphere; | ||
With sodium tetrahydroborate In methanol at 0 - 25℃; for 2h; | Methyl 4-(4-(chloromethyl)-2-methoxyphenoxy)butanoate (1) General procedure: Ethyl bromo-4-butyrate (201.2mmol), tetrabutylammonium iodide (19.7 mmol) and potassium carbonate (361 mmol) weresuccessively added to a solution of vanillin (30 g, 197.2 mmol) in acetonitrile (900 ml). The mixturewas refluxed for 4 h and then allowed to return to room temperature. The solvent was evaporatedand the residue was diluted with water (500 ml) and then extracted with diethyl ether (3 x 300 ml).The recovered organic phase was dried with magnesium sulfate and evaporated to give a viscous oil which rapidly turned to a slightly yellow solid when triturated with petroleum ether. The precipitatewas filtered on a glass-sintered funnel and further dried under vacuum. The crude alkylated vanillinwas subsequently dissolved in methanol (500 ml) and cooled to 0°C, before adding sodiumborohydride (98.6 mmol) in 4 portions. The mixture was allowed to warm to room temperature andcontinued stirring for an additional hour, until the complete consumption of the starting material. Thereaction was quenched by addition of water (300 ml) and hydrochloric acid (1N aqueous solution)until a neutral pH. The methanol was evaporated and the aqueous residue extracted with ethylacetate (3 x 300 ml). The combined organic layers were dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a crude product which was subsequently used withoutfurther purification. To a solution of the previously obtained alcohol in chloroform (400 ml), thionylchloride (256.4 mmol) was added slowly at 0°C. The mixture was allowed to return to roomtemperature and continued stirring for 3 hours, before pouring onto 400 ml of water. Solid sodiumbicarbonate was slowly added to the biphasic mixture until saturation of the aqueous phase and thenthe organic layer separated. The residual aqueous layer was further extracted with dichloromethane(3 x 200 ml) and the combined organic layers were dried with magnesium sulfate, filtrated and thesolvent evaporated. The obtained crude oil was triturated in petroleum ether (boiling range: 40-60°C), filtrated and dried under vacuum to conduct to the desired compound which was used withoutfurther purification in the next step. C14H19ClO4; yield 72%; light-beige solid; | |
With sodium tetrahydroborate | ||
With sodium tetrahydroborate | ||
10 %Chromat. | With methanol; nickel(II) oxide at 200℃; for 3h; Autoclave; | 2.2. Catalytic tests General procedure: 20 mg catalysts were introduced in each of six120 ml autoclavescontaining 20 ml of 5 mM solution of 4-benzyloxy-3-methoxybenzaldehyde(BMBA) in anhydrous methanol. The autoclaves were connectedto a Parr 5000 system and deoxygenated by bubbling N2 in successivecycles of pressurization and depressurization. The closed autoclaveswere heated at 5 C/min and maintained 3 h at 200 C under stirring at500 rpm. At an autogenous pressure of 40 atm with 17 % autoclavefilling, nearly 70 % of methanol is in the liquid phase. The liquidproducts recovered after cooling were identified by GC-MS (ShimadzuGCMS-QP 2010, low polarity polyimide Zebron ZB-5HT column) andquantified by a GC-FID equipped with the same column. Yields ofproducts were calculated as ratios between carbon atoms of eachproduct and carbon atoms of BMBA reagent. |
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium nitrate; trifluoroacetic acid at 20℃; for 1h; | 35 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde (32) A solution of potassium nitrate (5.4 g, 53 mmol) in trifluoroacetic acid (25 mL) was added dropwise to a solution of 4-(benzyloxy)-3-methoxybenzaldehyde (31) (12.5 g, 42 mmol) in trifluoroacetic acid (25 mL) at room temperature. The reaction mixture was stirred for 1 h. It was then concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL). The organic layer was successively washed with brine (3 x 50 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 x 40 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound (14.4 g, 100%) as a yellow solid. The product was used in the next step without further purification. NMR (400 MHz, DMSO-d6) 10.21 (s, lH), 7.84 (s, lH), 7-50-7-38 (m, 6H), 5.33 (s, 2H), 3.96 (s, 3H); FontWeight="Bold" FontSize="10" SC NMR (100 MHz, CDC13) £188.6, 152.8, 150.8, 135-6, 128.6, 128.5, 128.3, 128.1, 124.9, 110.2, 108.7, 70.7, 56.5; MS (ES+): m/z = 288 (M+H)+, MS (ES-): m/z = 286 (M-i)-; LCMS (Method B): tR= 3.98 min, LCMS (Method A): tR= 7.67 min |
98% | With potassium nitrate; trifluoroacetic acid at 0℃; | |
97% | With nitric acid at 0℃; for 1h; | 7.2 Step 2: 4-(benzyloxy)-5-methoxy-2-nitro-benzaldehyde To concentrated nitric acid (3 mL) was added 4-(benzyloxy)-3-methoxy benzaldehyde (242 mg, 1.0 mmol).The mixture was stirred at 0 °C for 1 h and then filtered. The filter cake was washed with water and dried to give the title compound (280 mg, 97 %). 1H NMR (CDCl3): δ 10.45 (1H, s), 7.68 (1H, s), 7.48-7.35 (7H, m), 5.28 (2H, s), 4.03 (3H, s) |
97% | With nitric acid at 0℃; for 1h; | 7.2 4-(benzyloxy)-5-methoxy-2-nitro-benzaldehyde To concentrated nitric acid (3 mL) was added 4-(benzyloxy)-3-methoxy benzaldehyde (242 mg, 1.0 mmol).The mixture was stirred at 0° C. for 1 h and then filtered. The filter cake was washed with water and dried to give the title compound (280 mg, 97%). 1H NMR (CDCl3): δ10.45 (1H, s), 7.68 (1H, s), 7.48-7.35 (7H, m), 5.28 (2H, s), 4.03 (3H, s) |
96% | With nitric acid at 0℃; for 1h; | |
95% | With nitric acid In water at 12℃; for 1h; | |
87% | With nitric acid at 0 - 20℃; for 2h; | 44.1 Nitric acid (100 mL) was cooled to 0°C, 4-benzyloxy-3-methoxybenzaldehyde (20g, 82.55mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added thereto and the mixture was stirred for 30 min, followed by filtration of the solid to obtain the title compound (20.52g, 87%). NMR(300 MHz, CDC13):< 10.43(s, 1H), 7.66(s, 1H), 7.47-7.34(m, 6H), 5.26(s, 2H), 4.01 (s, 3H).MS(ESI+, m/z): 288 [M+H]+ |
84% | With nitric acid Cooling with ice; | 1.2 The second step, Compound 1 prepared in the first step(8g, 33mmol) ground into a powder,Slowly add to a round bottom flask containing 30 mL of nitric acid.When a reddish brown gas is emitted from the reaction,Add an ice bath to the reaction,Dot board monitoring. After the reaction,Pour the reaction solution into 1.5 L of ice water and stir.Filter the filter cake,Recrystallization of ethanol,8g yellow crystal compound 2,The yield was 84%. |
83% | With potassium nitrate; trifluoroacetic acid at 0℃; for 1h; | 4-(Benzyloxy)-5-methoxy-2-nitrobenzaldehyde (2) A solution of 4-(benzyloxy)-3-methoxybenzalclehycle (i) (65.00 g, 268.3 mmol) in trifluoroacetic acid (300.0 mL) was charged with a solution of potassium nitrate (32.55 g, 322.0 mmol), in trifluoroacetic acid (300 mL) clropwise at 0°C. The reaction mixturewas stirred for 1 h and then diluted with water (1.2 L). The resulting precipitate wasfiltered and washed with cold water (so mL x 2) to afford the title compound (64.0 g,83%) as a yellow solid. 1H NMR (400 MHz, CDC13) 6 10.43 (s, 1H), 7.67 (s, 1H), 7.46-7.40 (m, H), 5.27 (s, 2H), 4.02 (s, 3H). |
82.7% | With nitric acid In acetonitrile at 15℃; for 0.833333h; Cooling with ice; | 1.2 (2) Synthesis of Compound 2 Add 40 mL of concentrated nitric acid to a 250 mL round bottom flask and stir for 5 min under ice bath to give compound 1 (5 g,0.02mol) was slowly added to concentrated nitric acid to prevent violent reaction, the ice bath was removed, the reaction was stirred for 20 min, and the reaction was moved to 15 °C.Stir the reaction for 30 min, take a small amount of the reaction solution, dilute with ethyl acetate, extract with water, and use DCM to carry out organic phase TLC detection reaction.The extent of the line. After the reaction is completed, the reaction solution is poured into cold water to reprecipitate, suction filtration, and the filter cake is rinsed with water until the pH of the water is in the middle.The crude product was dried, the crude product was crystallized from 95% ethanol, filtered, dried,Compound 2, the yield was 82.7%. |
82% | With nitric acid; acetic anhydride at 20℃; for 0.5h; | 88.2 (2) Synthesis of Compound 112: Compound 111 (10g, 41.3mmol) was dissolved in 50mL of acetic anhydride, and then gradually added dropwise 50mL of nitric acid (65%) under ice-cooling.After the dropwise addition, the ice bath removed, the reaction at room temperature for 30min, after the completion of the reaction, the reaction system was then slowly poured into 600mL ice water, the precipitated yellow solid was filtered under reduced pressure to give a yellow solid was then recrystallized from ethanol to give yellow needles, compound 112 (9.72g, 82%). |
81% | With potassium nitrate In trifluoroacetic acid at 0℃; for 1h; | ii 4-(Benzyloxy)-5-methoxy-2-nitrobenzaldehyde (15) A solution of 4-(benzyloxy)-3-methoxybenzaldehyde (14) (130 g, 537 mmol) in trifluoroacetic acid (600 mL) was charged with a solution of potassium nitrate (65 g, 644 mmol), in trifluoroacetic acid (600 mL) dropwise at o°C. The reaction mixture was stirred for 1 h and then diluted with water (2.40 L). The resulting precipitate was filtered and washed with cold water (500 mL x 2) to afford the title compound (125 g, 81%) as a yellow solid.NMR (400 MHz, CDCI3) d 10.43 (s, lH), 7.67 (s, lH), 7.46-7.30 (m, 6H), 5.27 (s, 2H), 4-02 (s, 3H); 13C NMR (100 MHz, CDC13) d 187.8, 153.7, 151-4, 134-85, 129-0,128.9, 128.7, 127-6, 125.7, no.o, 108.9, 71-6, 56.7; MS (ES-): m/z = 286 (M-H) q LCMS (Method A): tR = 7.87 min. |
80.1% | With nitric acid at 0℃; for 1h; Inert atmosphere; | |
80% | With potassium nitrate; trifluoroacetic acid at 0℃; for 1h; | 4-(Benzyloxy)-5-methoxy-2-nitrobenzaldehyde (18) To a stirred solution of 4-(benzyloxy)-3-methoxybenzaldehyde (17) (130 g, 536.6 mmol) in trifluoroacetic acid (600 mL) was added potassium nitrate (65.1 g, 643.9 mmol, in 600 mL of trifluoroacetic acid) dropwise at o °C. The reaction mixture was stirred for another hour. The reaction mixture was diluted with water (2.4 L). The precipitate was hltered and washed with cold water (2 x 500 mL) to give the title compound (125 g, 81%) as a yellow solid. The product was carried through to the next step without any further purification. NMR (400 MHz, CDCl3) d 10.42 (s, 1 H), 7.66 (s, 1 H), 7.34-7.46 (m, 6 H), 5.26 (s, 2 H), 4.0 (s, 3 H); C NMR (lOO MHz, CDCl3) d 187-8, 153-7, 151-4, 134-85, 129-0, 128.9, 128.7, 127-6, 125.7, no.o, 108.9, 71-6, 56.73; MS (ES+): m/z = 286 (M-H) LCMS (Method A): tR = 7.87 min |
78% | With sulfuric acid; nitric acid; acetic acid at 20℃; for 1h; | |
76% | With nitric acid; acetic acid at 25℃; Cooling with ice; | |
75% | With nitric acid at 0℃; for 1h; | 29 Compound 2 (21 g, 86.7 mmol) was added to HNO3 (30 mL) at 0° C. and stirred for 1 h. The reaction mixture was poured into the ice water and extracted with EtOAc. The combined extracts were washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1) to give the desired product (18.7 g, 65.1 mmol, 75.0%) as a yellow solid. |
75% | With nitric acid In water; acetic acid at 22℃; for 2h; Large scale; | |
66% | With nitric acid; acetic anhydride at 0℃; for 3.5h; | 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde (S3) A solution of 4-benzyloxy-3-methoxybenzaldehyde S2 (28 g, 0.118 mol) in aceticanhydride (100 mL) was added dropwise over a 30-minute period to a solution of 70%nitric acid (445 mL) in acetic anhydride (100 mL) at 0 °C. The mixture was stirred for3.5 hours at 0 °C. Then, the reaction mixture was poured into ice-water (2 L) to producea yellow precipitate which was filtered and washed with distilled water. The yellow solidwas then dried in an oven overnight at 40 °C to give pure S3 as a yellow powder (22.4g, 66%); |
60% | With nitric acid at 0 - 20℃; for 0.5h; | |
52% | With nitric acid at 0℃; for 1.25h; | |
50% | With nitric acid In 1,2-dichloro-ethane at -20 - 25℃; for 16h; | |
32.5% | In water | 79 5-Methoxy-2-nitro-4-(phenylmethoxy)benzaldehyde PREPARATION 79 5-Methoxy-2-nitro-4-(phenylmethoxy)benzaldehyde Reference: J. Med. Chem. 1977, Vol. 20, No. 1, p. 147. 3-Methoxy-4-(phenylmethyloxy)benzaldehyde (48.0 g, 0.198 mole) was added in small portions over 0.5 hour to 200 ml of concentrated nitric acid cooled to 0° C. in an acetone-dry ice bath. The temperature was maintained at 0°-1° C. for ten minutes. The temperature was allowed next to reach 15° C. and suddenly but briefly allowed to rise to 45° C. The temperature was cooled to 20° C. and then the reaction mixture was poured in ice/water. A yellow solid was obtained and filtered and washed with ethyl ether. A two gram sample was recrystallized from isopropanol. The light yellow solid isolated was dried in vacuo overnight at 80° C. to give 0.92 g (32.5% yield) of light yellow solid, mp 122°-124° C. Analysis: Calculated for C15 H13 NO5: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.42; H, 4.57; N, 5.17. |
With nitric acid; Nitrogen dioxide In acetic acid | ||
With nitric acid In 1,2-dichloro-ethane at -15℃; for 3h; | ||
With nitric acid at 40℃; for 5h; | ||
With nitric acid at 40℃; for 5h; | ||
With nitric acid at 20℃; for 2h; | 42 4-Benzyloxy-3-methoxybenzaldehyde (4.85 g) was added to nitric acid (d=1.42, 20 mL) in a dropwise manner over 1 hour at room temperature, and this mixture was stirred for 1 hour. This reaction mixture was poured into ice water and the precipitated solid was collected by filtration. This solid was washed with water, dried under reduced pressure at 50°C to give 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde (4.99 g). | |
With nitric acid In 1,2-dichloro-ethane at -30 - -15℃; for 3h; | 1.A [000167] Step A: To a solution of 4-(benzyloxy)-3-methoxybenzaldehyde (2.00 g, 8.090 mmol) in 1 ,2-dichloroethane (8 mL) at -30°C was slowly added fuming nitric acid (4.00 ml, 88.21 mmol) while maintaining the temperature at -15°C for 3 hours. The reaction mixture was poured into water and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to give the crude material that was triturated with a mixture solvents of EtOAc and hexanes to afford 1.81 g (78%) of 4- (benzyloxy)-5-methoxy-2-nitrobenzaldehyde. The filtrate was concentrated again under reduced pressure to give additional 615 mg (24% based on 91 ) purity) of the desired product. A total of 2.37 g of the product was obtained after consideration of the purity. The product appeared to be a mixture of the desired product and the over-nitrated product on the O-benzyl group. Both batches were used directly without further purification. | |
34.2 g | With nitric acid at 0 - 20℃; for 1h; | |
With nitric acid for 0.5h; | 1.3 (3) Synthesis of compound a5 Under ice bath conditions, add 30 mL of concentrated nitric acid to a 250 mL single-neck round bottom flask and stir magnetically for 15 minutes.Compound a4 (8g, 0.033mol) was slowly added to the reaction flask in batches, stirring was continued, and the progress of the reaction was monitored by TLC.After about 0.5 hours of reaction, the reaction mixture was poured into 500 mL cold water, filtered with suction, and the filter cake was washed with cold water until the filtrate in the funnel became neutral, and the filter cake was dried to obtain a yellow crude product.Ethanol recrystallization and purification yielded yellow needle-like crystal compound a5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 12h; Stage #2: With sodium hydroxide In methanol; water for 3h; Further stages.; | |
90% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With 3-chloro-benzenecarboperoxoic acid In dichloromethane Stage #2: With lithium hydroxide In tetrahydrofuran; methanol; water | |
85% | With AMCPB In dichloromethane |
85% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With 3-chloro-benzenecarboperoxoic acid for 0.0833333h; Stage #2: With sodium hydroxide for 0.0833333h; Further stages.; | |
74% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde With 3-chloro-benzenecarboperoxoic acid In dichloromethane; water at 0℃; for 7.5h; Inert atmosphere; Stage #2: With methanol; potassium carbonate at 20℃; for 1h; Inert atmosphere; | 7 4-Benzyloxy-3-methoxyphenol (S7) Under an argon atmosphere, m-chloroperbenzoic acid (contains ca 30% water, purity >65%, 41.7 g, ca. 157 mmol) was addedportionwise to a solution of S6 (25.3 g, 105 mmol) in dichloromethane (160 mL) at 0 °C.After stirring for 7.5 h, the reaction mixture was quenched with saturated aqueousNaHCO3. The mixture was diluted with water and the organic layer was separated. The aqueouslayer was extracted with dichloromethane. The combined extracts were washed with saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, and evaporated. The residue was dissolvedin methanol (300 mL) and K2CO3 (72.3 g, 523 mmol) was added portionwise to the solution atroom temperature. After stirring for 1 h, the mixture was evaporated under reduced pressure. Waterwas added to the residue and the product was extracted with diethyl ether. The extract was washedwith water and brine, dried over Na2SO4, and evaporated. The residue was recrystallized fromdiethyl ether-hexane to give S7 as pale yellow granules (14.7 g, 61%). The mother liquor from theabove recrystallization was evaporated and the residue was chromatographed over silica gel 60N (hexane-ethyl acetate = 3:1) to give an additional S7 as pale yellow solid (3.14 g, 13%). The totalyield of S7 was 17.8 g (74%). |
59% | With dihydrogen peroxide; boric acid In tetrahydrofuran; sulfuric acid; water at 20℃; for 5h; | |
(i) AcOOH, (ii) aq. KOH; Multistep reaction; | ||
With Peroxyformic acid Ambient temperature; | ||
61.2 g | With formic acid; dihydrogen peroxide at 0℃; for 3h; | |
Multi-step reaction with 2 steps 1: 60 percent / MCPBA / CH2Cl2 / 3 h / 20 °C 2: 85 percent / K2CO3; water / methanol / 0.5 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 30percent aq. H2O2 / 2,4-(NO2)2C6H3SeSeC6H3(NO2)2-2,4 / CH2Cl2 / 49 h / Ambient temperature 2: KOH / methanol / 1 h / Ambient temperature | ||
With peracetic acid In acetic acid | 24.A STEP A: STEP A: 4-benzyloxy-3-methoxyphenol 24.2 g of 4-benzyloxy-3-methoxy benzaldehyde (Beilst. Vol. 8, II p 283) were dissolved in 100 ml of acetic acid and a mixture of 25 ml of peracetic acid and 50 ml of acetic acid was added without exceeding 45° C. The mixture was stirred for 18 hours at +40° C. and after concentration to dryness, the residue was chromatographed on silica (eluant: hexane-ethyl acetate 8-2) to obtain 9.1 g of the expected product melting at 84° C. | |
Multi-step reaction with 2 steps 1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 20 °C 2: water; potassium carbonate / methanol / 0.5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 18 - 20℃; for 5h; | |
100% | With potassium carbonate In acetone for 12h; Heating; | |
100% | With potassium carbonate In methanol for 4h; Reflux; | 3-benzyloxy-4-methoxybenzaldehyde 5: General procedure: The mixture of aldehyde 4 (10 g, 65.8 mmol), benzyl bromide (9.38 mL, 79.0 mmol), and potassium carbonate (10.9 g, 79.0 mmol) in methanol (40 mL) was refluxed for 4 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. Chloroform (80 mL) was added to the residue, and the solution was washed with water (2 × 30 mL), the organic layer was filtered using a Biotage ISOLUTE phase separator and then evaporated to afford a white powder (15 g, yield: 100%). |
100% | With potassium carbonate In methanol for 2h; Reflux; | 10 General procedure (A) to obtain benzylated products General procedure: Unprotected starting material (1 Eq), benzyl bromide (1.2 Eq) and dipotassic carbonate (1,2 Eq) in MeOH (5 mL mmol1) were stirred at reflux for 2 h. The reaction mixture was filtered and evaporated to vacuo, taken up with DCM (15 mL mmol1) and washed by water (3 1 mL mmol1). Organic layer was dried overMgSO4 and evaporated in vacuo to give the expected protected product. |
99% | With potassium carbonate; sodium iodide In acetonitrile Heating; | |
99% | With potassium carbonate In N,N-dimethyl-formamide at 23℃; for 2h; | |
99% | With potassium carbonate In acetone Reflux; | 7.1 Step 1: 4-(benzyloxy)-3-methoxy benzaldehyde 4-Hydroxy-3-methoxy benzaldehyde (2.0 g, 12.8 mmol), benzyl bromide (2.2 g, 12.8 mmol) and potassium carbonate (880 mg, 6.4 mmol) were added to acetone (30 mL), and the mixture was refluxed overnight. Water was added , and the mixture was filtered. The filter cake was washed by water, and recystallized in ethanol to give the title compound (3.1 g, 99 %). 1H NMR (CDCl3): δ 9.84 (1H, s), 7.45-7.31 (7H, m), 6.99 (1H, d, J = 8.4 Hz), 5.25 (2H, s), 3.95 (3H, s). |
99% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; | 9 Benzylvanillin Benzyl bromide (5.90 g, 34.5 mmol) was added to a solution of vanillin 59 (5.00 g, 32.9 mmol) in DMF (50 mL), followed by the addition of K2C03 (9.08 g, 65.7 mmol). The yellow mixture was stirred at room temperature for 2 h, and then poured into a solution of Et20- H20 (200 mL, 1:1) and stirred for 5 min. The ethereal layer was separated. The aqueous layer was extracted with Et20 (50 mL x 2). The combined organic extract was washed with H20 (50 mL x 3) and brine (50 mL), and dried over anhydrous Na2S04, filtered and concentrated to obtain a crude residue, which was washed with hexane to furnish the pure product 60as a white solid (7.91 g, 99%): mp 49-51 °C (lit. (Guthrie, et &.,Can. J. Chem. 1955,33, 729-742),61 °C). *H NMR (300 MHz, CDC13) .84 (s, 1 H), 7.44-7.36 (m, 7 H), 7.00 (d, / = 8.2 Hz, 1 H), 5.25 (s, 2 H), 3.95 (s, 3 H). |
99% | With potassium carbonate In acetone Reflux; | 7.1 4-(benzyloxy)-3-methoxy benzaldehyde 4-Hydroxy-3-methoxy benzaldehyde (2.0 g, 12.8 mmol), benzyl bromide (2.2 g, 12.8 mmol) and potassium carbonate (880 mg, 6.4 mmol) were added to acetone (30 mL), and the mixture was refluxed overnight. Water was added, and the mixture was filtered. The filter cake was washed by water, and recystallized in ethanol to give the title compound (3.1 g, 99%). 1H NMR (CDCl3): δ9.84 (1H, s), 7.45-7.31 (7H, m), 6.99 (1H, d, J=8.4 Hz), 5.25 (2H, s), 3.95 (3H, s). |
99% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; | |
98% | With potassium carbonate In acetone for 5h; Heating; | |
98% | With potassium carbonate In acetonitrile for 1h; Heating / reflux; | 7.1 Benzylation of vanillin (1) was achieved by using one equivalent of potassium carbonate and one equivalent of benzyl bromide in refluxing acetonitrile, was complete within one hour to give a quantitative yield of the benzyl vanillin (2) . |
97% | With potassium carbonate | |
97% | With potassium carbonate In ethanol at 0 - 70℃; for 12h; | |
97% | With potassium carbonate In acetone for 12h; Inert atmosphere; Reflux; | |
97% | Stage #1: vanillin With potassium carbonate In methanol at 20℃; for 0.166667h; Stage #2: benzyl bromide In methanol for 48h; Reflux; | 6 7.3.6 4-(Benzyloxy)-3-methoxybenzaldehyde (9) The title compound was prepared according to a procedure of Shen and Sun. 41 To a solution of vanillin (8, 10.0 g, 65.8 mmol, 1.0 eq.) in methanol (40 mL), K2CO3 (10.9 g, 79.0 mmol, 1.2 eq.) was added and the resulting suspension was stirred for 10 min at room temperature. Benzyl bromide (9.38 mL, 79.0 mmol, 1.2 eq.) was added dropwise and the reaction mixture was heated to reflux for 48 h. The suspension was filtered with suction the filtrate was concentrated under reduced pressure and diluted with DCM (80 mL). The solution was washed with (2 * 30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure. The remaining solid was dried in vacuo. The product was obtained as a colourless solid (15.3 g, 63.6 mmol, 97%). Rf = 0.45 (cyclohexane/ethyl acetate, 3:2). Mp: 60-61 °C. 1H NMR (300 MHz, CDCl3): δ = 9.84 (s, 1H, CHO), 7.45-7.31 (m, 7H, Ar), 6.99 (d, 3J = 8.2 Hz, 1H, 5-H), 5.25 (s, 2H, OCH2Ph), 3.95 (s, 3H, OCH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 191.0 (CHO), 153.7, 150.2, 136.2 (Cq-1, Ph), 130.5 (Cq-1), 128.9 (CH-3, CH-5, Ph), 128.4 (CH-4, Ph), 127.3 (CH-2, CH-6, Ph), 126.7, 112.6, 109.5, 71.0 (OCH2Ph), 56.2 (OCH3) ppm. The spectroscopic data matched those reported in the literature. 41 |
97% | With potassium carbonate In acetonitrile for 24h; Reflux; | 5 4.1.1 General procedure for the synthesis of compounds 25-29 [57] General procedure: Benzaldehydes 20-24 (5.00g), benzyl bromide (1.0 equiv.), potassium carbonate (1.0 equiv.) and acetonitrile (50mL) were added to a 250mL round-bottom flask and the reaction mixture was refluxed for 24h. Acetonitrile was evaporated on completion of the reaction and the residues were partitioned between dichloromethane and water. The dichloromethane layer was dried with anhydrous MgSO4 and evaporated in vacuo to give benzyl-protected benzaldehydes 25-29 as a white or grey solid in yields of 95-97%. |
97% | With potassium carbonate In acetonitrile for 24h; Reflux; | 5 4.1.1. General procedure for the preparation of compounds 16-20 General procedure: Benzaldehydes 11-15 (5.00 g), benzyl bromide (1.0 equiv.), potassiumcarbonate (1.0 equiv.) and acetonitrile (50 mL) were added to a250 mL round-bottom flask and the reaction mixture was refluxed for24 h. Acetonitrile was evaporated on completion of the reaction and theresulting residues were partitioned between dichloromethane andwater. The dichloromethane layer was dried with MgSO4, filtered, andevaporated under reduced pressure to give the products 16-20 as awhite or grey solid in yields of 95 - 97%. |
97% | With potassium carbonate In acetonitrile for 24h; Reflux; | 5 4.1.1. General procedure for the synthesis of compounds 26 - 30 General procedure: Benzaldehyde 21 - 25 (5.00 g), benzyl bromide (1.0 equiv.), potassiumcarbonate (1.0 equiv.) and acetonitrile (50 mL) were added to a250 mL round-bottom flask and the reaction mixture was refluxed for24 h. Volatiles were evaporated on completion of the reaction and the resultant residues were partitioned between dichloromethane andwater. The organic layer was dried with anhydrous MgSO4 and evaporatedin vacuo to provide the products 26-30 as a white solid in yieldsof 95 - 97%. Spectroscopic data can be found in SI. |
96% | With potassium carbonate In methanol; chloroform for 4h; Heating; | |
96% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; | |
96% | With potassium carbonate In acetone for 8h; Reflux; | |
96.7% | With potassium carbonate In acetone Reflux; Inert atmosphere; | General procedures for the synthesis of compounds 3a-3h General procedure: A mixture of hydroxybenzaldehyde (6 mmol), substituted benzyl bromide (6 mmol) and potassium carbonate (9 mmol) in acetone (40 ml) was refluxed for 5 h under N2 atmosphere, cooled to room temperature. After evaporation of acetone, the resulting residue was alkalized with a solution of sodium hydroxide (1 M) and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, concentrated to produce the white or light yellow solid. |
96% | Stage #1: vanillin With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil for 2h; | |
96% | With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 8h; Inert atmosphere; | 4.1.1 4.1.1. 4-(Benzyloxy)-3-methoxybenzaldehyde (19) To a solution of compound 18 (25 g, 0.16 mol) in dry DMF(100 mL) was added K2CO3 (33 g, 0.24 mol) and benzyl bromide (25 mL, 0.22 mol), which was then heated at 65° C under argon. After stirred for 8 h, the mixture was filtrated and concentrated in vacuo. The dried residue was dissolved in 500 mL of EtOAc andthen washed with H2O (200 mL 2), saturated aqueous NaHCO3 (200 mL 2), and brine (200 mL 2), dried over Na2SO4, and concentrated to dryness. The residue was purified by silica gel column chromatography (5:1, V:V, petroleum ether-EtOAc) to yield 19 as a white solid (38 g, 96%); 1H NMR (CDCl3): d 9.84 (s, 1H, CHO), 7.45(dd, 3H, J = 7.8, 1.8 Hz, Ar-H), 7.39-7.41 (m, 3H, Ar-H), 7.34 (t, 1H,J = 7.3 Hz, Ar-H), 7.00 (d, 1H, J = 8.2 Hz, Ar-H), 5.26 (s, 2H, Ar-OCH2),3.96 (s, 3H, OCH3); 13C NMR (CDCl3): d 190.9, 153.6, 150.0, 136.0,130.3, 128.7 (two), 128.2, 127.2, 126.5, 112.4, 109.3, 70.8, 56.0;ESIMS: calcd for [M+H]+ m/z 243.1; found, 243.2. |
96% | With potassium carbonate In acetone at 20℃; for 10h; | 4.2.1 4-(Benzyloxy)benzaldehyde (11a) General procedure: To a solution of 4-hydroxybenzaldehyde 10 (2.0g, 16.38mmol) in acetone (60mL) was added benzylbromide (2.14mL, 18.02mmol, 1.1 equiv), followed by anhydrous K2CO3 (3.4g, 24.58mmol, 1.5 equiv). The mixture was stirred at room temperature for 10h. This was then concentrated and the residue dissolved in EtOAc and water. The organic layer was separated and the aqueous layer extracted with EtOAc (3×40mL). The combined organic layers were washed with water (2×40mL), brine (50mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (9:1) as eluent to give 11a (3.34g, 96%) as a white solid. |
95% | With potassium carbonate In acetone for 4h; Heating; | |
95% | With potassium carbonate In acetone at 0 - 20℃; | |
95% | With potassium carbonate In acetone at 20℃; | |
95% | Stage #1: vanillin With potassium carbonate; sodium hydroxide In water Inert atmosphere; Reflux; Stage #2: benzyl bromide In water for 1h; Inert atmosphere; Reflux; | |
95% | With potassium carbonate In acetone at 20℃; | |
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2.3h; | |
95% | With potassium carbonate In acetone for 4h; Reflux; | 3-methoxy-4-benyloxybenzaldehde (2c) To a solution of 1 (7.6 g, 50 mmol) in acetone (150 mL) was added K2CO3 (10.4 g, 75 mmol) and BnBr (9.41 g, 55 mmol), and the mixture was heated at reflux for 4 h before it was cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure to get a yellow oil, which was purified by flash chromatography (ethyl acetate/petroleum ether = 1:6) to yield 2c (11.5 g, 95 %) as white solid. |
95% | With potassium carbonate In acetone Reflux; | 1.4 5.1.4. 4-(Benzyloxy)-3-methoxybenzaldehyde (16) To a solution of 4-hydroxy-3-methoxybenzaldehyde (15, 7.6 g,50 mmol) in acetone (150 mL) was added K2CO3 (10.4 g, 1.5 equiv)and BnBr (9.41 g, 1.05 equiv), and the mixture was heated at reflux for 4 h before it was cooled to room temperature. The solid was filteredoff, and the filtrate was concentrated under reduced pressureto get yellow oil, which was purified by flash chromatography(ethyl acetate/petroleum ether = 1:6) to yield 4-(benzyloxy)-3-methoxybenzaldehyde (16, 11.5 g, 95%) as white solid. 1H NMR(CDCl3, 300 MHz): d 9.85 (s, 1H), 7.44-7.34 (m, 7H), 6.99 (d,J = 8.1 Hz, 1H), 5.26 (s, 2H), 3.96 (s, 3H). LRMS (ESI) m/z: 243.1(M+H). |
95% | With potassium carbonate In acetone for 6h; Reflux; | 78.2 78.2 Preparation of 3-methoxy-4-benzyloxybenzaldehyde 78.2 Preparation of 3-methoxy-4-benzyloxybenzaldehyde 10g of 3-methoxy-4-hydroxybenzaldehyde was dissolved in 100mL of acetone, added with anhydrous K2CO3 (3eq), followed by dropwise addition of benzylbromide (1.1eq) under agitating. Then, the mixture was placed in an oil bath and refluxed for 6 hours. After the reaction was completed, the reaction mixture was vacuum filtered and the filtrate was evaporated to dyness. Saturated NaHCO3 aqueous solution was added, and the resultant mixture was extracted with dichloromethane. The organic phase was evaporated to dryness to give the product. Yield, 95%. 1H NMR (CDCl3, 400 MHz): δ 7.50-7.40 (m, 5H), 7.25 (s, 1H), 7.10 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H). ESI-MS m/z: 243.0 [M+H]+. |
95% | With potassium carbonate In acetone for 6h; Reflux; | 78.2 78.2 Preparation of 3-methoxy-4-benzyloxybenzaldehyde 10 g of 3-methoxy-4-hydroxybenzaldehyde was dissolved in 100 mL of acetone, added with anhydrous K2CO3 (3 eq), followed by dropwise addition of benzylbromide (1.1 eq) under agitating. Then, the mixture was placed in an oil bath and refluxed for 6 hours. After the reaction was completed, the reaction mixture was vacuum filtered and the filtrate was evaporated to dryness. Saturated NaHCO3 aqueous solution was added, and the resultant mixture was extracted with dichloromethane. The organic phase was evaporated to dryness to give the product. Yield, 95%. 1H NMR (CDCl3, 400 MHz): δ7.50-7.40 (m, 5H), 7.25 (s, 1H), 7.10 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H). ESI-MS m/z: 243.0 [M+H]+. |
95% | With potassium carbonate In ethanol for 6h; Reflux; | |
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 4.2 4-(Benzyloxy)-3-methoxybenzaldehyde(3a) A stirring solution of vanillin (2, 1 g, 5 mmol) in 20 mLDMF was charged with solid K2CO3 (8 g) at room temperature.To the resulting suspension benzyl bromide (1 mL)was added drop wise and further stirred for 1 h. After completionof the reaction (TLC control) water was added andthe product extracted with dichloromethane (10 mL) threetimes. The organic layer was dried with anhydrous sodiumsulfate and the solvent removed at low pressure to yield a light brown solid. After recrystallization in methanol, thetitle compound 3a was obtained as a white crystal in 95%yield (1.15 g). Spectroscopic data matched with the previouslyreported values [26]. |
95% | With potassium carbonate In methanol for 8h; Reflux; | 1.1.2 (2) 50 mmol of 3-methoxy-4-hydroxybenzaldehyde and 70 mmol of potassium carbonate were dissolved in 30 mL of methanol, and Benzyl bromide 80 mmol was slowly added dropwise with stirring. Heated in an oil bath, slowly warmed to reflux, and continue stirring for 8 h. It was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give crude material. The crude product was separated by column chromatography to give 3-methoxy-4- benzyloxy benzaldehyde (yield: 95%). |
95% | Stage #1: vanillin With potassium carbonate In acetone for 0.166667h; Stage #2: benzyl bromide In acetone at 20℃; for 10h; | |
95% | With potassium carbonate In ethanol for 3h; Reflux; | |
94% | With potassium carbonate In acetone for 6h; Heating; | |
94% | With potassium carbonate In acetonitrile for 4h; Reflux; | |
94% | With potassium carbonate In acetonitrile at 40 - 50℃; Inert atmosphere; | |
94% | With potassium carbonate In methanol for 4h; Reflux; | 4-(Benzyloxy)-3-methoxybenzaldehyde (1) A mixture of compound vanillin (50.0 g, 328.6 mmol), benzyl bromide (59.0 g, 345.1 mmol) and potassium carbonate (136.3 g, 985.9 mmol) in methanol (300 mL) wasrefluxecl for 4 h. The reaction mixture was filtered, and the filtrate evaporated under reduced pressure to afford the title compound (75.0 g, 94%) as a pale yellow solid.1H NMR (400 MHz, CDC13) 6 9.83 (s, 1H), 7.47-7.35 (m, 6H), 7.33 (ci, J=7.2 Hz, 1H),6.98 (ci, J=8.2 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H). |
94% | With potassium carbonate In acetonitrile at 100℃; for 8h; Industrial scale; | 1-2 Preparation of Compound 6 In a 5 L reactor, add compound 5 (1.0 kg, 6.6 mol, 1.0 eq.),Acetonitrile (3 L), benzyl bromide (1.1 kg, 6.6 mol, 1.0 eq.) And anhydrous potassium carbonate (1.4 kg, 9.9 mol, 1.5 eq.).After the addition is completed, the temperature is raised to 100 , stirring is continued for 8 h, TLC detection, the reaction is completed, the above reaction solution is filtered, and the filtrate is collected.The resulting filtrate was distilled under reduced pressure to recover the solvent to obtain a yellow oily residue, and the obtained residue was dissolved in ethyl acetate (3 L),It was washed with water (2L × 3) and saturated sodium chloride (1 L) in this order, and the resulting organic phase was dried over anhydrous sodium sulfate,After filtration and concentration, the crude product was obtained, which was recrystallized from absolute ethanol (W / V = 1/2) to obtain a white crystalline solid 1.5 kg, with a yield of 94%. |
94.1% | With potassium carbonate In methanol for 2h; Reflux; | |
94% | With potassium carbonate In methanol Inert atmosphere; | 4-benzyloxy-3-methoxybenzaldehyde (S1) A dry flask, purged with argon for 5 minutes, was charged with vanillin (10 g, 65.8 mmol) and K2CO3 (10.9 g, 79 mmol) before being dissolved in dry methanol (40 mL). Benzyl bromide (9.4 mL, 79 mmol) was added dropwise to the mixture and the reaction was stirred overnight. Once complete, the reaction was quenched with H2O (50 mL). The resulting solution was extracted with CHCl3 (3 × 40 mL) and the combined organic layers were washed with brine (2 × 30 mL), dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified via silica gel column chromatography using a mobile phase of hexane:EtOAc (19:1 v:v) to afford off-white crystals as the pure product (15.02 g, 62 mmol, 94%). 1H NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.51 - 7.29 (m, 7H), 6.99 (d, J = 8.2 Hz, 1H), 5.25 (s, 2H), 3.95 (s, 3H). HRMS (ESI, M+H) Calc’d for C15H15O3 243.1021, found 243.1038. |
93% | With potassium carbonate In acetone for 2h; Heating; | |
93% | With potassium carbonate In acetone for 2h; Reflux; | 6.1.1. 4-(Benzyloxy)-3-methoxybenzaldehyde (10a) General procedure: To a solution of commercial available compound 3-methoxy-4-hydroxybenzaldehyde 9a (6.08 g, 40 mmol) in dry acetone (100 mL) was added BnBr (7.18 g, 42 mmol) and K2CO3 (11.04 g, 80 mmol). The mixture was stirred for 2 h in reflux. Then the reaction solution was filtered after cooled to room temperature. The filtrate was concentrated, and purified by column chromatography (PE/EA = 4/1) to give 10a (9 g, 93%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 9.85 (s, 1H), 7.44-7.34 (m, 7H), 6.99 (d, J = 8.1 Hz, 1H), 5.26 (s, 2H), 3.96 (s, 3H). ESI-MS m/z 243 [M+H]+. |
93% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2.33333h; Inert atmosphere; | Preparation of 3-hydroxy-5-benzyloxybenzoic acid methyl ester (3a) General procedure: To the suspension of sodium hydride (60% dispersion in mineral oil, 1.98 g, 49.5 mmol) in anhydrous N,N-dimethylformamide (100 mL) at 0°C under nitrogen was added a solution of 2 (10 g, 59.5 mmol) in anhydrous N,N-dimethylformamide (30 mL) followed by benzyl bromide (6 mL, 50.5 mmol) was added dropwise via a syringe over 20 min25. The reaction mixture was stirred at room temperature for 2 hours, monitored by TLC, quenched with cold distilled water (50 mL), acidified with cold 1 M hydrochloric acid (20 mL) and extracted with diethyl ether (3 × 50 mL). The combined organic layers was washed with distilled water (2 × 50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The product residue was purified on silica gel using chloroform/ethanol (19:1) as mobile phase affording 3a as an off-white powder (6.5 g, 42%), mp 97-98°C (lit.[34] mp 98°C). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (1H, s, OH), 7.43-7.33 (5H, m, benzyl Ph), 7.24 (1H, dd, J=2.0, 1.2 Hz, H-2), 7.20 (1H, dd, J=2.0, 1.2 Hz, H-6), 6.70 (1H, t, J=2.0 Hz, H-4), 5.07 (2H, s, benzyl CH2), 3.90 (3H, s, COOCH3). The 1H NMR spectrum was in good agreement with previously reported data[35, 36]. |
93% | With potassium carbonate In 1-methyl-pyrrolidin-2-one at 60℃; for 1h; Large scale; | |
92% | With potassium carbonate In acetone for 24h; Heating; | |
92% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; | |
92.6% | With potassium carbonate In acetonitrile | 78 3-Methoxy-4-(phenylmethyloxy)benzaldehyde PREPARATION 78 3-Methoxy-4-(phenylmethyloxy)benzaldehyde A mixture of 4-hydroxy-3-methoxybenzaldehyde (100.0 g, 0.657 mole), benzyl bromide (112.4 g, 0.657 mole), and potassium carbonate (90.8 g, 0.657 mole) was heated overnight at reflux in 600 ml of dry acetonitrile (dried over 4A molecular sieves). The reaction mixture was stripped to dryness on a rotary evaporator. A white solid was obtained which was recrystallized form ethanol and dried in vacuo overnight at 80° C., to give 147.45 g (92.6% yield) of white crystalline product, mp 58°-63° C. Analysis: Calculated for C15 H14 O3: C, 74.36; H, 5.83. Found: C, 74.36; H, 5.78. |
92% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 4h; Inert atmosphere; | B.7 7. Preparation of 3-methoxy-4-benzyloxybenzaldehyde (7); To a suspension of NaH (60% dispersion in mineral oil, 1.6g, 66.6 mmol) in anhydrous DMF (50 mL) at 0°C under N2 was added vanillin (4-hydroxy-3-methoxy benzaldehyde, 4 g, 26.3 mmol) in anhydrous DMF (20 mL) slowly via syringe, followed by the dropwise addition of benzyl bromide (3 mL, 25.2 mmol). The mixture was stirred-at room temperature for-4 hours^ quenched with co Id water (30 mL) acidified with cold 1 M HCl (15 mL) and extracted with diethyl-ether (3 x 40 mL). The combined organic extracts were washed with water (2 x 30 mL), dried over sodium sulphate and dried under reduced pressure to afford 7 as a colourless solid (6 g, 92%): mp 60-62°C (lit.6 mp 61-62°C); C,5H14C>3 NMR (400 MHz, CDCI3) δ 9.84 (s, 1H)), 7.43-7.31 (m, 7H)), 7.00 (d, J= 8.4 Hz, 1H)), 5.25 (s, 2H)), 3.95 (s, 3H)). |
92% | With potassium carbonate In acetone at 60℃; for 2h; | |
92% | With potassium carbonate In acetone for 24h; Reflux; | |
91% | With potassium carbonate In ethanol at 20℃; | Using the procedure reported by A. I. Meyers et al., Heterocycles, 1989, 295. To a solution of vanillin (7.7 g, 50.67 mmol) in EtOH (40 mL) was added potassium carbonate (7.9 g, 57.35 mmol) and benzyl bromide (6.0 mL, 50.67 mmol) and the mixture stirred at room temperature overnight. The reaction was filtered through Celite and the filtrates concentrated in vacuo. The residue was redissolved in DCM (250 mL), washed with aqueous NaOH (5% w/v, 2×100 mL) and the organic layer dried (Na2SO4). Concentration in vacuo and recrystallisation of the residue obtained from EtOH gave OBS01056 as a white powder (11.16 g, 91%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.8; m.p. 63-64° C. [Lit. (MeOH): 63-64° C.]; 1H-NMR (400 MHz, CDCl3) 3.95 (3H, s), 5.25 (2H, s), 6.99 (1H, m), 7.33-7.45 (7H, m), 9.84 (1H, s) |
91% | With potassium carbonate In ethanol at 20℃; | |
91% | With potassium hydroxide In methanol; water for 2h; Reflux; | |
91% | With potassium carbonate In acetone at 90℃; for 8h; | 88.1 (1) Synthesis of Compound 111: vanillin (25g, 165mmol), and potassium carbonate (11.4g, 83mmol) was dissolved in 200mL of acetone, benzyl bromide (21.2 g, 181 mmol) was added dropwise, under conditions at 90 °C reflux 8h. After completion of the reaction, the reaction system was cooled to room temperature, acetone was distilled off under reduced pressure, 100mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the organic solvent is spin-dried to give a colorless liquid.100mL was then recrystallized from ethanol to give white needles, compound 111 (36.2g, 91%). |
90% | With sodium carbonate | |
90% | With potassium carbonate In acetone Heating; | |
90% | With potassium carbonate In acetone for 24h; Inert atmosphere; Reflux; | 4-Benzyloxy-3-methoxybenzaldehyde (9) Vanilin 7 (1.97mmol, 0.300 g) was dissolved in anhydrous acetone (10 mL) in an oven-dried three-neck flask under argon. K2CO3 (3.35 mmol, 0.463 g) was then added and the mixture was stirred for 5 minutes before the addition of benzyl bromide (3.35 mmol, 0.399 mL). The reaction was refluxed for 24 h or until completion was shown by TLC (EtOAc/hexanes 30:70). The reaction mixture was allowed to warm at room temperature, poured into saturated K2CO3 and extracted three times with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4, concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexanes 30:70) yielding 0.431 g (90 %) of 9 as a white solid. mp= 62-65oC. 1H-NMR(500 MHz, dmso-d6): δH 9.83 (1H, s), 7.46 - 7.42 (3H, m), 7.41 - 7.36 (3H, m), 7.33 (1H, m), 6.99 (1H, dd, J = 8.2, 1.5), 5.24 (2H, s), 3.94 (3H, s). 13C-NMR(125 MHz, dmso-d6): δC 190.9, 153.6, 150.0, 136.0, 130.3, 128.7, 128.2, 127.2, 126.6, 112.4, 109.3, 70.8, 56.0. IR (ZnSe): νmax 1672, 1582, 1504, 1259, 1235, 1159, 988, 865, 747, 697 cm-1. HRMS (ESI-TOF, m/z): calcd for C15H15O3(M+H)+ = 243.1016, found 243.1140. This compound has been also previously reported.3 |
90% | With triethylamine; sodium iodide In tetrahydrofuran at 0 - 20℃; for 14h; | 15 4-Hydroxy-3-methoxybenzaldehyde (1.52 mL, 10 mmol) was dissolved in tetrahydrofuran (30 mL), then triethylamine (1.53 mL, 11 mmol), benzyl bromide (1.19 mL, 10 mmol), and sodium iodide (99 mg, 0.5 mmol) were added at 0°C or less, and this was stirred at room temperature for 14 hours. Thereafter, while cooling on ice, 1 M hydrochloric acid (10 mL) was added to the reaction mixture solution, this was extracted with ethyl acetate, dried over magnesium sulfate, and filtered through filter paper. Then, the solvent was distilled off, and purified by silica gel column chromatography (elude: hexane: ethyl acetate = 3:1) which resulted in a pale yellow solid (2.18 g, 90% yield). 1H NMR (300 MHz, CDCl3) δ: 9.84 (1H, s), 7.33-7.46 (7H, m), 7.98 (1H, d, J=8.21Hz), 5.25 (2H, s), 8.95 (3H, s). |
89% | With potassium carbonate In ethanol at 20℃; for 20h; Inert atmosphere; | |
89% | With potassium carbonate In ethanol at 80℃; for 12h; | |
88% | With potassium carbonate In ethanol | |
88% | With potassium carbonate In acetone for 1h; Reflux; | 4.2.6.13. 4-(Benzyloxy)-3-methoxybenzaldehyde (98) A solution of vanillin (1.52 g, 10.0 mmol), K2CO3 (5 g, 36.2 mmol) and benzylbromide (2.5 ml, 21.0 mmol) in acetone (20 ml) was refluxed for 1 h. After cooling to room temperature and addition of water the emerging oil was extracted with hexane and separated. After removal of the solvent and drying compound 98 was obtained as a pale yellow solid (2.14 g, 88%). 1H NMR (300 MHz, CDCl3): δ = 3.94 (s, 3H), 5.24 (s, 2H), 6.98 (d, J = 8.2 Hz, 1H), 7.78-7.46 (m, 7H), 9.83 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ = 56.1, 70.9, 109.3, 112.4, 126.6, 127.2, 128.2, 128.7, 130.3, 136.0, 150.1, 153.6, 190.9 ppm; MS (MALDI-TOF): m/z: 243.1 [M+H]+. |
88% | With potassium carbonate In acetone for 3h; Inert atmosphere; Reflux; | 4.1.8. 1-(Benzyloxy)-2-methoxy-4-vinylbenzene 5 Benzylbromide (0.42 mL, 3.54 mmol) was added to a mixture of 4-hydroxy-3-methoxy benzaldehyde (0.6 g, 3.94 mmol) and potassium carbonate (1.08 g, 7.88 mmol) in acetone (15 mL). The mixture was stirred for 3 h at reflux condition. TLC indicated the consumption of the starting material. The mixture was filtered through Celite and the filter cake was washed well with acetone. The filtrate was concentrated under vacuo. The resulting residue was redissolved in ethyl acetate, transferred to a separatory funnel, washed with sodium carbonate (satd), HCl (3 M) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude aldehyde was purified by column chromatography on silica gel (eluent: PE-EtOAc, 8:2) to afford 17 (0.84 g, 88%) as a colorless solid. |
88% | With potassium carbonate In acetone at 0 - 40℃; for 12h; Inert atmosphere; | |
88% | With potassium carbonate In acetone at 0 - 40℃; for 12h; Inert atmosphere; | 4-(benzyloxy)-3-methoxybenzaldehyde (Compound 16) General procedure: To the stirred solution of phenolic aldehyde (2.00 mmol) in anhydrous acetone (10 mL) was added K2CO3 (3.00 mmol, 1.5 eq.) In a nitrogen atmosphere0 And cooled.Benzyl bromide (2.4 mmol, 1.2 eq.) Was slowly added,The mixture temperature was raised to 40 ,Stir for 12 hours.After completion of the reaction, the reaction mixture was cooled to room temperature,Filter through a Celite pad and concentrate in vacuo.The crude compound was purified by column chromatography (EtOAc / Hexane = 1/3) to give the pure aromatic aldehyde in which the benzyl group was protected [note: two equivalents of K2CO3 were used in the synthesis of compound 18, 2.4 equivalents of benzyl bromide and 4.0 equivalents of K2CO3 was used for the synthesis of Compound 19). |
88.2% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 14h; | |
87% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 47℃; for 24h; | |
87% | With potassium carbonate In ethanol Inert atmosphere; | |
85% | With potassium carbonate In methanol for 4h; Reflux; Inert atmosphere; | |
85% | With potassium carbonate In methanol for 5h; Reflux; | 4-(Benzyloxy)-3-methoxybenzaldehyde (17) A mixture of 4-hydroxy-3-methoxybenzaldehyde (200 g, 1.31 mol), benzyl bromide (236 g, 1.38 mol) and potassium carbonate (545 g, 3.94 mol) in methanol (1.2 L) was refluxed for 5 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (271 g, 85%) as a light yellow solid. The product was carried through to the next step without any further purification. NMR (400 MHz, CDCI3) d 9.83 (s, 1 H), 7.29-7.46 (m, 7 H), 6.98 (d, J = 8.1 Hz, 1 H), 5.25 (s, 2 H), 3.94 (s, 3 H); C NMR (too MHz, CDCl3) 6191.0, 153.6, 150.1, 136.0, 130.3, 128.7, 128.2, 127.2, 126.6, 112.3, 109.3, 70.9, 56.1; MS (ES+): m/z = 243 (M+H) +; LCMS (Method A): tR = 7.53 min |
85% | With potassium carbonate In methanol at 0 - 70℃; for 2h; | 1.3 (3) Preparation of 4-(benzyloxy)-3-methoxybenzaldehyde [4-(benzyloxy)-3-methoxybenzaldehyde] (step: b-1-1) After mixing 4-hydroxy-3-methoxybenzaldehyde (456 mg, 3 mmol) and potassium carbonate (497 mg, 3.6 mmol) using methanol (15 mL) as a solvent in a 25 mL round bottom flask, at 0 °C And benzyl bromide (615 mg, 3.6 mmol) were added dropwise. After the dropping was completed, the mixture was heated to 70° C. and after 2 hours, when the reaction was terminated, the salt was removed with water and extracted with ethyl acetate. After removing the solvent, separation was performed by column chromatography to obtain the title compound, 4-(benzyloxy)-3-methoxybenzaldehyde (626 mg, 85%). |
84% | Stage #1: vanillin With sodium hydride In tetrahydrofuran; mineral oil at 10 - 20℃; Inert atmosphere; Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; mineral oil for 18h; Reflux; Inert atmosphere; | |
84% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h; | |
84% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h; | |
84% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h; | 2h 'rytftro-l-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)-l,3- propanediol (2h): (0183) (0184) 2h (0185) Scheme 9. Synthesis of £'r_yi zro-l-(4-hydroxy-3-methoxyphenyl)-2-(2- methoxyphenoxy)-- 1 ,3-propanediol (2h). (0186) This compound was prepared according to the same literature procedure as for compound 2g. Spectral data were consistent with those reported in the literature. JH NMR (400 MHz, CDC13) δ 7.16 (dd, J = 8.2, 1.6 Hz, 1H), 7.04-6.86 (m, 5H), 6.86 (d, J = 8.2 Hz, 1H), 5.71 (b s 1H), 4.96 (d, J = 7.9 Hz, 1H), 4.06-3.97 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.73-3.58 (m, 2H), 3.48 (ddd, J = 12.0, 7.8 and 3.6 Hz, 1H), 2.78-2.73 (m, 1H). HRMS (ESI) calculated for CnHzoOeNa [M + Na]+ 343.1158, found 343.1154. |
84% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; | Synthesis of compound 17 Vanillin (10 g, 65.72 mmol)and K2CO3 (13.7g, 98.58 mmol) were stirred in DMF (60 ml)under nitrogen atmosphere at room temperature. Benzyl bromide (9.4 ml, 78.86mmol) was slowly added via syringe with agitation. The mixture was stirred atrt for 1 h. The reaction mixture was diluted with water (27 ml), neutralizedwith 50% HCl (20 ml) and extracted with EtOAC (67 ml, 20 ml ×2). The combinedEtOAc extract was wash with water, brine (67 ml each) and dried with MgSO4.The solvent was evaporated in vacuoto give orange solid which after recrystallization from heptane-EtOAc (9:1)gave white crystals (84 %). 1H NMR (500 MHz, CDCl3): δ(ppm) 3.95 (s, 3H), 5.25 (s, 2H), 6.99 (d, J = 8.2, 1H), 7.33 (t, J = 7.3, 1H),7.39 (m, 3H), 7.44 (d, J = 7.3), 9.84 (s, 1H). 13C NMR (500 MHz,CDCl3): δ (ppm) 56.1, 70.9, 109.3, 112.4, 126.6, 127.2, 128.2,129.0, 130.3, 136.0, 150.1, 153.6. ESI-MS (m/z)= 243.1 [M+H]+ |
84% | With potassium carbonate In acetone Reflux; | |
84% | With potassium carbonate In acetonitrile at 80℃; for 9h; | 1.1 Example 1 First step, vanillin(50g, 328mmol), potassium carbonate (82.8g, 600mmol) and benzyl bromide (76.9g,450mmol) dissolved in 1000ml of acetonitrile,80 ° C reflux9h,Point board monitoring (TLC monitoring reaction),When the reaction is over,Filter the filtrate,Spin dry to remove solvent,A pale yellow viscous liquid. Dissolve the liquid in ethanol,Heat to clear and transparent,Add a small amount of petroleum ether,Cool to room temperature,Recrystallization overnight,Precipitating white crystals,Filter the filter cake,67g of white crystals are obtained as compound 1,The yield was 84%. |
83% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | |
83.9% | With potassium carbonate; potassium iodide In acetonitrile at 90℃; Inert atmosphere; | 1.1 Synthesis of Compound 1 Vanillin (15 g, 0.1 mol) was added to a 500 mL one-neck round bottom flask, dissolved in 300 mL of acetonitrile, and potassium carbonate (16.35 g, 1.2 mol) and potassium iodide (19.62 g, 1.2 mol) were slowly added to the flask under stirring. To prevent agitation, heat to 90 ° C reflux, and react under argon atmosphere overnight. The degree of reaction was detected by TLC (PE: EA = 1:1). After the reaction was completed, the system was cooled to room temperature, suction filtered, and the filtrate was dried.Ethyl acetate dissolves the solid and is washed with water to remove soluble salts.The solid was recrystallized from 95% ethanol by spin-drying. After cooling to complete crystallization, suction filtration.Obtained a white solid and dried in an oven.20.3 g of a solid, Compound 1, was obtained in a yield of 83.9%. |
82% | With potassium carbonate In ethanol | |
82% | With potassium carbonate In acetone at 20℃; for 48h; | |
82% | With potassium carbonate In acetone for 10h; Inert atmosphere; Reflux; | 4-(Benzyloxy)-3-methoxybenzaldehyde (15) To a suspension of vanillin (5.0 g, 32.9 mmol, 1.0 equiv) and K2CO3 (11.4 g, 82.2 mmol, 2.5 equiv) in acetone (50 mL), benzyl bromide (4.3 mL, 36.1 mmol, 1.1 equiv) was added and the resulting mixture was refluxed for 10 h. After being cooled to room temperature, the suspension was filtered through a sintered funnel. The filtrate was evaporated to dryness and treated with (50 mL) water and extracted with ethyl actate (3 ×20 mL). The combined organic layers were washed with (20 mL) saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether, 1:20) to afford the pure benzyl ether 15 (6.66 g, 82 %) as a yellow solid. 1HNMR (400 MHz, CDCl3): d =3.95 (s, 3H, OMe), 5.25 (s, 2H, OCH2Ph), 6.98 (d, J = 8.1Hz, 1H, 5-H), 7.30-7.36 (m, 1H,2-H), 7.36-7.42 (m, 3H, Ar), 7.42-7.48 (m, 3H, Ar), 9.84 (s, 1H, CHO); 13CNMR (100 MHz, CDCl3): d =56.0 (OMe), 70.8 (CH2Ph), 109.3 (C-2), 112.3 (C-5), 126.5 (Ar),127.2 (Ar), 128.2 (Ar), 128.7 (Ar), 130.2 (Ar), 136.0 (Ar), 150.0 (Ar), 153.5(Ar), 190.9 (CHO). |
81% | With potassium carbonate In acetone at 65℃; for 6h; | 1 3-methoxy-4-hydroxy-benzaldehyde (a2) 3-methoxy-4-hydroxy-benzaldehyde a1-2 (20.00 g, 131.45 mmol) and benzylbromide (26.98 g, 157.74 mmol)were dissolved in acetone solution, and potassium carbonate (36.33 g, 262.90 mmol) was added in two portions, andthe mixture was stirred at 65 °C for 6 hours after the addition. After the reaction was completed (TLC monitoring, UVdevelopment), the reaction solution was suction-filtrated, and the filtrate was collected and concentrated by distillationunder reduced pressure. The concentrated crude product was purified by silica gel column chromatography (petroleumether/ethyl acetate=8/1) to give compound a2 (26.32 g, 106.47 mmol), yield 81%.1H NMR (400 MHz, Chloroform-d) δ 9.61 (s, 1H), 7.47 - 7.18 (m, 8H), 5.16 (s, 2H), 3.83 (s, 3H);LRMS (ESI, m/z): 243 [M+H]+. |
80% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 30℃; | |
80% | With potassium carbonate In acetone Reflux; Inert atmosphere; | |
79% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 20℃; for 18h; | 1; 19 NaOH (16 g, 400 mmol) in water (400 raL) was added to a solution of vanillin (1) (40 g, 260 mmol) , benzyl bromide (45 g, 31 mL, 260 mmol) and Bu4NBr (8.4 g, 260 mmol) in dichloromethane (400 mL) . The reaction mixture was stirred at high speed for 18 hours at room temperature. The organic layer was then separated and the aqueous portion extracted with dichloromethane (2 x 100 mL) . The combined organics were washed with water (2 x 100 mL) then evaporated to give an orange coloured oil . This was recrystallised from methanol to yield (6) as a white crystalline material (50 g, 79%) . The remaining material in the mother liquors was discarded. |
79% | With potassium carbonate In acetone for 4h; Reflux; Inert atmosphere; | |
77% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; | |
77% | With potassium carbonate In acetone for 12h; Reflux; | 6 4-Benzyloxy-3-methoxybenzaldehyde (S6) A neat liquid of benzyl bromide (43.2 mL,361 mmol) was added to a suspension of vanillin (50.0 g, 329 mmol) and K2CO3 (50.0 g,361 mmol) in acetone (500 mL) at room temperature and the mixture was refluxed for12 h. The reaction mixture was cooled to room temperature and then filtered. The filtrate was evaporated and the residue was diluted with diethyl ether. The mixture was washedwith with 10% aqueous NaOH, water, and brine, dried over Na2SO4, and evaporated. The residuewas recrystallized from diethyl ether-hexane to give S6 as pale yellow granules (52.8 g, 66%). Themother liquor from the above recrystallization was evaporated and the residue was purified bybulb-to-bulb distillation (175-185 °C, 0.7 mmHg) to give an additional S6 as pale yellow solid(8.49 g, 11%). The total yield of S6 was 61.3 g (77%). |
75% | With potassium carbonate In acetonitrile at 90℃; for 12h; | |
71.2% | With potassium carbonate; potassium iodide In dichloromethane at 20℃; for 8h; Reflux; | 1.10; 2.10 (10) Preparation of Compound 13 To a 1 L three-necked flask, 90 g of vanillin, 9 g of potassium iodide, 90 g of potassium carbonate and 450 g of dichloromethane were added, and 112 g of benzyl bromide was added dropwise at room temperature. After the dropwise addition, the mixture was heated to reflux for 8 hours, and the starting material was completely reacted. The temperature was lowered to room temperature, filtered, and the filtrate was washed twice with 400 g of a 5% sodium hydroxide solution, once with 200 g of water and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated to dryness under reduced pressure to give yellow The color oil was crystallized from 180 g of petroleum ether to give a white solid, 102 g, which was compound 13 in a yield of 71.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde; malonic acid With piperidine; pyridine at 90℃; Reflux; Stage #2: With water for 1h; Cooling with ice; | |
77% | With pyridine at 110℃; for 14h; Inert atmosphere; | 4-benzyloxy-3-methoxycinnamic acid (S2) A dry flask containing S1 (10.23 g, 42 mmol) was purged with argon for 10 minutes, then dissolved in pyridine (7.8 mL, 97 mmol). Malonic acid (7 g, 67.2 mmol) was added and the mixture was refluxed at 110C. After 14 hrs, the reaction was placed in an ice bath and acidified with aqueous HCl (6 M). The resulting solid was vacuum filtered and washed with cold water to yield the crude product. This was recrystallized twice from EtOH to afford the pure product as a white powder (9.21 g, 32.3 mmol, 77%). 1H NMR (500 MHz, DMSO-d6) δ 12.21 (br, 1H), 7.52 (d, J = 15.9 Hz, 1H), 7.46 - 7.32 (m, 6H), 7.22 - 7.14 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 15.9 Hz, 1H), 5.13 (s, 2H), 3.82 (s, 3H). HRMS (ESI, M+H) Calc’d for C17H17O4 285.1127, found 285.1162. Purity by HPLC: 99.9 % (tR = 10.91 min). |
With piperidine In pyridine |
Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde; malonic acid With piperidine; pyridine Reflux; Stage #2: With hydrogenchloride In water at 25℃; | ||
With piperidine for 3h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bromine In methanol at 20℃; for 3h; | |
85% | With pyridinium hydrobromide perbromide In methanol at 20℃; for 3h; | |
69% | With bromine; sodium acetate In acetic acid at 40℃; for 11h; |
43% | With bromine; sodium acetate In water; acetic acid at 20℃; | 208.a Example 208; 4-[2-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5-hydroxy-4-methoxy-phenoxy]-benzoic acid; Step a To a mixture of 4-benzyloxy-3-methoxybenzaldehyde (10.0 g, 41 mmol; compound 10, scheme 7) and NaOAc.3H2O (11.2 g, 82 mmol) of in 25 mL of acetic acid and 2.5 mL of water was added dropwise bromine (2.6 mL, 49 mmol). The mixture was stirred at room temperature overnight and quenched with water. After stirring at room temperature for ca. 15 min, the precipitate was collected via filtration and chromatographed (20% ethyl acetate-hexane) to give 5.7 g of 4-benzyloxy-2-bromo-3-methoxybenzaldehyde (43%; compound 11, scheme 7). |
(bromination); | ||
With bromine; sodium acetate In acetic acid at 40℃; | ||
With bromine In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 45% 2: 44% | With potassium hydroxide In methanol at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 150℃; for 6h; | Reference Example 17 30 g of 4-benzyloxy-3-methoxybenzaidehyde, 12 g of sodium propionate and 24 g of propionic anhydride were mixed and stirred at 150C for 6 hours. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 5% hydrochloric acid and then with an aqueous saturated sodium chloride solution twice, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was washed with toluene and hexane to obtain 28 g of 3-(3-methoxy-4-benzyloxyphenyl)-2-methylacrylic acid. 1H-NMR (CDCl3, TMS) delta (ppm): 7.74 (1H, br.s), 7. 29-7. 45 (5H, m), 6.99-7.04 (2H, m), 6.91 (1H, d, J = 8.9 Hz), 5.20 (2H, s), 3.91 (3H, s), 2.16 (3H, d, J = 1.3 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
218 mg (41%) | With hydrogenchloride; triethylamine; In water; isopropyl alcohol; | EXAMPLE 1 At room temperature, 1 mmol of <strong>[2498-50-2]4-aminobenzamidine dihydrochloride</strong> (208 mg), 1 mmol of triethylamine (101 mg), 1 mmol of benzylisonitrile (117 mg) and 1 mmol of 4-benzyloxy-3-methoxybenzaldehyde (260 mg) was stirred in a solvent mixture of 1.2 ml of isopropanol and 0.8 ml of water for 5 days. The mixture was then admixed with 0.5 ml of 25% strength hydrochloric acid and stirred at room temperature for 1 hour. The precipitated crystals was filtered off and washed with 5 ml of water. This yielded 218 mg (41%) of (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide hydrochloride as colorless crystals. ISP-MS: 495.5 ([M+H]+, 100). |
1.6 g (30%) | With hydrogenchloride; trifluoroborane diethyl ether; triethylamine; In methanol; dichloromethane; water; | EXAMPLE 3 10 mmol of <strong>[2498-50-2]4-aminobenzamidine dihydrochloride</strong> (2.8 g), 10 mmol of triethylamine (1.01 g), 0.5 ml of water, 10 mmol of 4-benzyloxy-3-methoxybenzaldehyde (2.6 g) and 10 mmol of benzylisonitrile (1.2 ml) were initially charged in 40 ml of methanol, and 3.8 ml of boron trifluoride etherate (30 mmol) are then added dropwise with ice-bath cooling over a period of 2 hours. The mixture was stirred at room temperature for a further hour, the solvent was then removed under reduced pressure and the crude product was chromatographed over an RP-18 column using water/methanol as mobile phase. Alternatively, the crude product was, with ice-cooling, admixed with 5 ml of 25% strength hydrochloric acid, 10 ml of dichloromethane and 10 ml of water were added and the precipitated crystals were filtered off with suction after 5 hours. This gave 1.6 g (30%) of (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide hydrochloride as colorless crystals. ISP-MS: 495.5 ([M+H]+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde; N-BOC-1,2-diaminoethane In methanol at 20℃; for 2h; Stage #2: With sodium tetrahydroborate In methanol at 0℃; Stage #3: With water In methanol | 1A Example IA tert-buty] (2-[4-(benzyloxy)-3-methoxybenzyl]amino}ethyl)carbamate; 33.8 g (139.6 mmol) 4-benzyloxy-3-methoxybenzaldehyde are dissolved in 160 ml methanol, 24.6 g (153.5 mmol) tert-butyl(2-aminoethyl)carbamate are added and the resulting suspension is stirred for 2 h at rt. The mixture is cooled to O0C and 26.4 g (697.9 mmol) sodium borohydride is added in portions. After stirring over night the solution is diluted with water and extracted three times with dichloromethane (aq. layer is saturated with sodium chloride). The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by' chromatography on silica gel (gradient dichloromethane / methanol 100:1, 50:1, 20:1.) to yield47.68 g (88% of th.) of the title compound.LC-MS (method 1): R4 = 1.50 min, m/z = 387 (M+H)+1H-NMR (300 MHz, DMSO-d6): δ = 7.50-7.25 (m, 5H), 6.90 (m, 2H), 6.80-6.70 (m, 2H), 5.05 (s, 2H), 3.75 (s, 3H), 3.60 (s, 2H), 3.00 (m, 2H), 2.50 (m, 2H), 1.40 (s, 9H). |
69% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde; N-BOC-1,2-diaminoethane In dichloromethane at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 0 - 20℃; Stage #3: With sodium hydroxide; water In dichloromethane | 1-1A Example 1-lA; tert-butyl (2- { [4-(benzyloxy)-3 -methoxybenzyl] amino}ethyl)carbamate; 1.45 g (5.98 mmol) 4-benzyloxy-3-methoxybenzaldehyde and 1.01 g (6.58 mmol) tert-butyl (2- aminoethyl)carbamate are dissolved in 20 ml dichloromethane and stirred for Ih at room temperature. The solution is cooled to 00C and 1.96 g (8.98 mmol) sodium triacetoxyborohydride are carefully added and the mixture is warmed to room temperature and stirred overnight. The reaction is quenched with water and the organic materials are washed with IN sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated under vacuum to yield 1.60 g (69% of th.) of the title compound of sufficient purity to be used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde; N-Boc-1,3-diaminopropane In methanol at 20℃; for 2h; Stage #2: With sodium tetrahydroborate In methanol at 0℃; Stage #3: With water In methanol | 2A Example 2A tert-buty l-(3 - { [4-(benzy loxy)-3 -methoxybenzy 1] amino } propy l)carbamate; 6.31 g (26.04 mmol) 4-benzyloxy-3-methoxybenzaldehyde are dissolved in 30 ml methanol, 4.99 g (28.64 mmol) ter?-butyl(3-aminopropyl)carbamate are added and the resulting suspension is stirred for 2 h at rt. The mixture is cooled to O0C and 4.93 g (130.2 mmol) sodium borohydride is added in EPO portions. After stirring over night the solution is diluted with water and extracted three times with dichloromethane (aq. layer is saturated with sodium chloride). The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel (gradient dichloromethane / methanol 100:1, 50:1, 20:1.) to yield 9.7 g (93% of th.) of the title compound.HPLC (method 2): R1 = 3.37 min,MS: m/z = 401 (M+H)+1H-NMR (300 MHz, DMSO-d6): δ = 7.47-7.27 (m, 5H), 6.90-6.95 (m, 2H), 6.81-6.70 (m, 2H), 5.04 (s, 2H), 3.75 (s, 3H), 3.58 (s, 2H), 3.00-2.90 (m, 2H), 2.47-2.40 (m, 2H), 1.58-1.48 (m, IH), 1.45 (s, 9H). EPO |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisopropylamine In tetrahydrofuran; diethyl ether; hexane; cyclohexane | 11.A 3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionic Acid Step A 3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionic Acid A stirred solution of LDA in cyclohexane (1.5 M) was cooled to -20° C., to which a solution of 2-phenoxypropionic acid (10 g, 60.2 mmol) in THF (80.3 mL) was slowly added, keeping the temperature below -10° C. The resulting dianion solution was stirred for 15 min, then a solution of 4-benzyloxy-3-methoxybenzaldehyde (14.58 g, 60.2 mmol) in THF (80.3 mL) was added over 1 h, maintaining temperature below -10° C. Fifteen minutes after completion of aldehyde addition, the reaction mixture was poured onto ice water (200 mL), and extracted using 1:2 Et2O:hexane (500 mL). The aqueous layer was isolated, extracted again with 1:2 Et2O:hexane (240 mL), then acidified with concentrated HCl until pH=3. The product acid was extracted into EtOAc (2*165 mL), which was dried over Na2SO4 and concentrated to an orange paste (16.5 g crude, 67%): MS (EI) 426.2 (M+NH4)+, 407.2 (M-H)-. | |
With diisopropylamine In tetrahydrofuran; diethyl ether; hexane; cyclohexane | 7.A A. A. 3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionic acid A stirred solution of LDA in cyclohexane (1.5 M) was cooled to -20° C., to which a solution of 2-phenoxypropionic acid (10 g, 60.2 mmol) in TBF (80.3 mL) was slowly added, keeping the temperature below -10° C. The resulting dianion solution was stirred for 15 min, then a solution of 4-benzyloxy-3-methoxybenzaldehyde (14.58 g, 60.2 mmol) in THF (80.3 mL) was added over 1 h, maintaining temperature below -10° C. Fifteen minutes after completion of aldehyde addition, the reaction mixture was poured onto ice water (200 mL), and extracted using 1:2 Et2O:hexane (500 mL). The aqueous layer was isolated, extracted again with 1:2 Et2O:hexane (240 mL), then acidified with concentrated HCl until pH=3. The product acid was extracted into ethyl acetate (2*165 mL), which was dried over Na2SO4 and concentrated to an orange paste (16.5 g crude, 67%): MS (EI) 426.2 (M+NH4)+, 407.2 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With toluene-4-sulfonic acid In acetonitrile at 20℃; for 1.2h; | |
92% | With acetic acid at 20℃; | 7 General procedure for the preparation of compounds 1a-n General procedure: In a flask containing 5ml of glacial acetic acid and 2mmol of indole (0.234gm) or 5-chloroindole 0.303 gm or 6-chloroindole 0.303 gm was added under stirring until all the indole was dissolved. Then 1mmol of the appropriate aromatic or heterocyclic aldehyde was added under vigorous stirring. The reaction mixture was allowed to stir over 4-6h, where the reaction solution turned from light yellow to light pink to dark red colour. The product was detected by TLC (100% CH2Cl2), and when the reaction was finished 10ml of water were added and the solution was extracted with ethylacetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The product was purified by passing over a column and eluted with dichloromethane. |
92% | With acetic acid at 20℃; for 5h; | 2.1. General Procedure for the Preparation of Compounds 1-26 General procedure: In a flask containing 5 ml of glacial acetic acid and 2 mmol of indole (0.234 gm) or 5-chloroindole 0.303 gm or 6-chloroindole 0.303 gm was added under stirring until all the indole was dissolved. Then 1 mmol of the appropriate aromatic or heterocyclic aldehyde was added under vigorous stirring. The reaction mixture was allowed to stir over 4 to 6 h, where the reaction solution turned from light yellow to light pink to dark red colour. The product was detected by TLC (100 % CH2Cl2), and when the reaction was finished 10 ml of water were added and the solution was extracted with ethyl acetate, washed with water and 100 ml brine, driedover anhydrous sodium sulphate and concentrated in vacuum.The product was purified by passing over a column and eluted with dichloromethane. |
With acetic acid at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | 4-Benzyloxy-3-methoxybenzaldehyde (5Og, 206 mmol) and amino acetaldehyde diethyl acetal (31.6 mL, 217 mmol) were heated up to 650C for 6 hours then cooled to rt. The resulting yellow oil was stirred in ethanol (25OmL), cooled to O0C and NaBH4 (8.3g5 220 mmol) was added portion wise. The mixture was refluxed for 4 hours then cooled to O0C and water added. The solution was stirred for 30 minutes, extracted with ethyl acetate and the organic layer was washed with water, brine, dried and concentrated to yield 72g (97%) of a yellow oil, 1H NMR (270 MHz, CDCl3) delta 1.19 (6H5 X, J=7.2Hz)5 1.51 (IH5 br s), 2.72 (2H5 d5 J= 5.5Hz)5 3.51 (2H5 dq, J= 7.2 and 1.9 Hz)5 3.67 (2H5 dq5 J= 7.2 and 1.9 Hz), 3.72 (2H, s), 3.88 (3H, s), 4.60 (IH5 t, J= 5.5 Hz), 5.13 (2H5 s), 6.75 (lH5dd5 J= 8.3 and 1.4Hz), 6.81 (IH5 d5 J= 8.3Hz)5 6.89 (IH5 d, J= 1.4Hz)5 7.27-7.44 (5H5 m). HRMS (ES) calcd. for C21H30NO4 (MH+), 360.2169 found 360.2161; HPLC: tr= 3.92 (99.2%) CH3CNZH2O 90/10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Working examples; Example 1. [(4-Benzyloxy-3-methoxyphenyl)(4-carbamimidoylphenylamino)methyl]phosphonic acid dimethyl ester hydrochloride; To a mixture of <strong>[2498-50-2]4-aminobenzamidine dihydrochloride</strong> (104 mg, 0.5 mmol), AcOH (2 ml), and 4-benzyloxy-3-methoxybenzaldehyde (124 mg, 0.5 mmol) was added trimethylphosphite (0.18 ml, 1.5 mmol). The mixture was stirred at room temperature for two days, and then diluted with aqueous 1N HCl (10 ml). The resulting solution was kept overnight at 4 C, and the precipitated solid was isolated by filtration. Drying under reduced pressure yielded 146 mg (58%) of the title compound as colorless solid. LCMS: MH+ = 470. 94% pure by ELS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | At room temperature, 1-Benzyloxy-4-bromo-2-methoxybenzene 10 (1.70 mmol, 0.50 g) was dissolved in freshly distilled THF (7 mL) in an oven-dried three-neck flask under argon. The temperature was cooled down to -78 oC and n-BuLi (1.6M in hexane, 1.96 mmol, 1.22 mL) was added dropwise. The reaction mixture was stirred for 1 h at this temperature and a solution of 4-benzyloxy-3-methoxybenzaldehyde 9 (1.70 mmol, 0.412 g) in THF (4mL) was added dropwise. The reaction mixture was stirred at -78 oC for 1.5 h, allowed to warm at room temperature and stirred for another 2 h. Water (24 mL) was slowly added to the mixture which was then extracted three times with EtOAc. The organic layers were dried with MgSO4 and concentrated in vacuo. The crude product was dissolved in a minimum of EtOAc and 100 mL of hexanes were added to precipitate the desired product. After 12 h at 0 oC, the precipitate was filtered, lightly washed with cold EtOAc and dried in vacuo, yielding 0.618 g (79 %) of 11 as a white solid. mp = 94-100oC. 1H-NMR (500 MHz, CDCl3): deltaH7.46-7.29 (10H,m), 6.96-6.79 (6H,m), 5.72 (1H, s), 5.13 (4H, s), 3.86 (6H, s). 13C-NMR (125 MHz, CDCl3): deltaC 149.7, 149.5, 147.6, 137.2, 135.4, 128.6, 127.9, 127.3, 119.7, 119.7, 118.9, 113.7, 113.5, 111.0, 110.3, 75.7, 71.0, 56.0. IR (ZnSe): numax 1511, 1251, 1226, 1132, 1019, 1006, 754, 741, 696 cm-1. HRMS (ESI-TOF,m/z): calcd for C29H27O4 (M-H2O+H)+= 439.1904, found 439.1923. This compound has been also previously reported.4 | |
55% | To a stirred solution of <strong>[63057-72-7]1-(benzyloxy)-4-bromo-2-methoxybenzene</strong> (1) (10.23 mmol) in THF (25 ml_) at -78 C slowly is added n-butyllithium (n-BuLi, 10.74 mmol, 1.6 M solution in hexane) under N2. The mixture is stirred for 30 min at the same temperature. 4-(Benzyloxy)-3-methoxybenzaldehyde (2, 11.26 mmol) in THF (25 ml_) is slowly added to the solution over a period of 5 min. Then the solution is stirred for 30 min at -78 C. TLC indicated complete conversion of 1 to the product. The reaction mixture is allowed to reach 0 C, quenched with saturated NH4CI solution, and extracted with ethyl acetate. The organic layer is dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude compound is purified by column chromatography (ethyl acetate:hexane 35/65 v/v) to afford 3 as a white solid (yield 55%). Figs. 4A and B show 1H NMR spectrum and MS spectrum for compound 3, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triphenylphosphine In dichloromethane at 0℃; for 0.5h; | |
90% | With triphenylphosphine In dichloromethane at 0 - 20℃; for 0.5h; Inert atmosphere; | |
88% | With triphenylphosphine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; |
80% | With triphenylphosphine In dichloromethane at 0℃; Inert atmosphere; | |
80% | Stage #1: carbon tetrabromide With triphenylphosphine In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In dichloromethane at 0 - 20℃; for 15h; | l-(Benzyloxy)-4-(2,2-dibromoethene)-2-methoxybenzene. l-(Benzyloxy)-4-(2,2-dibromoethene)-2-methoxybenzene. To a solution of triphenylphosphine (3 equiv, 61.8 mmol, 16.2 g) in methylene chloride (0.2 M, 100 mL) cooled to 0 °C under argon gas, was added carbon tetrabromide (1.5 equiv, 30.9 mmol, 10.24 g) and stirring continued for 15 min. To the solution was added 4- (benzyloxy)-3-methoxybenzaldehyde (5 g, 20.6 mmol) in methylene chloride (2 M, 11 mL). The resultant mixture was stirred at rt for 15 hr. The mixture was concentrated and triturated with cold hexanes (60 mL) and filtered (paper cone) to remove excess triphenylphosphine. The filtrate was concentrated and subjected to silica gel chromatography (10 % EtOAc/hexanes) to obtain the dibromoolefin product (80 %, 6.2 g) as a yellow solid: Rf 0.80 (20 % EtOAc/hexanes), NMR (300 MHz, CDC13) δ 7.40 (m, 5H), 7.33 (m, 1H), 7.22 (s, 1H), 7.02 (d, J= 4 Hz, 1H), 6.83 (d, J= 4 Hz, 1H), 5.18 (s, 2H), 3.94 (s, 3H). |
59% | With triphenylphosphine In dichloromethane at 0 - 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure for the preparation of intermediates of the General Formula (9)Intermediate (9) A mixture of benzaldehyde derivative (1.0 equiv.) and 2-aminobenzoxazole or 2- aminobenzothiazole (1.0 equiv.) in ^-xylene was stirred at reflux temperature for 18 h. The mixture containing the imino derivative was cooled to room temperature and sodium cyanoborohydride (1.2 equiv.) was added over 5 min. The reaction mixture was then further stirred at room temperature for 48 h. The mixture was diluted with ethyl acetate and washed twice with water. The organic layer was dried and evaporated to give a viscous residue, which was purified by silica gel column chromatography to yield the compound of general formula (9) as off-white to yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: (S)-4-benzyl-3-propionyl-2-oxazolidinone With dibutylboron triflate; triethylamine In dichloromethane at -78 - -40℃; for 0.5h; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In dichloromethane at -78℃; for 11h; Stage #3: With dihydrogen peroxide In methanol; dichloromethane at 0℃; for 1h; aq. phosphate buffer; optical yield given as %de; diastereoselective reaction; | aldol 5 To a solution of (+)-(S)-4-benzyl-3-propyl-2-oxazolidinone (3.00 g, 12.9 mmol) in DCM (70.0 mL) was added 1.0 M dibutylboron triflate in DCM (14.2 mL, 14.2 mmol) and Et3N (2.69 mL, 19.3 mmol) at -78 oC, and then stirring was continued for 30 min at -40 oC. To the reaction mixture cooled to -78 oC was added a solution of 4-benzyloxy-3-methoxybenzaldehyde (3.40 g, 14.2 mmol) in DCM (60.0 mL). After stirring for 11 h, the reaction was quenched by addition of phosphoric buffer (15.4 mL), methanol (51.5 mL), and 30% H2O2 (15.4 mL) at 0 oC. The mixture was stirred for 1 h. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt = 2:1) to afford 5 (4.88 g, 80%, 98% de) as colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.40-7.43 (2H, m), 7.24-7.35 (6H, m), 7.17-7.19 (2H, m), 6.92 (1H, d, J = 1.7 Hz), 6.83 (1H, d, J = 8.0 Hz), 6.80 (1H, dd, J = 8.0, 1.7 Hz), 5.14 (2H, s), 4.97 (1H, d, J = 4.7 Hz), 4.49 (1H, dddd, J = 9.6, 8.4, 3.4, 2.4 Hz), 4.11 (1H, qd, J = 6.8, 4.7 Hz), 4.08 (1H, dd, J = 9.0, 2.4 Hz), 3.94 (1H, dd, J = 9.0, 8.4 Hz), 3.86 (3H, s), 3.22 (1H, dd, J = 13.3, 3.4 Hz), 2.74 (1H, dd, J = 13.3, 9.6 Hz), 1.25 (3H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 176.5, 152.9, 149.5, 147.4, 137.1, 135.0, 134.5, 129.4, 129.0, 128.5, 127.8, 127.4, 127.3, 118.3, 113.5, 109.7, 74.0, 70.9, 66.1, 56.0, 55.3, 44.6, 37.8, 11.4; IR (ATR) 3509, 1775, 1695 cm-1; EIMS (rel. int.) m/z 475 [M]+(1), 91 (100); HREIMS calcd 475.1995 for C28H29O6N, found 475.1979; [α]D20 +58.9 (c 1.00, CHCl3); m.p. 117.0 oC. |
80% | Stage #1: (S)-4-benzyl-3-propionyl-2-oxazolidinone With di-n-butylboryl trifluoromethanesulfonate; triethylamine In dichloromethane at -78 - -40℃; for 0.5h; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In dichloromethane at -78℃; for 11h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With piperidine In ethanol Reflux; | |
72% | Stage #1: 2,4-imidazolidinedione With sodium hydrogencarbonate; ethanolamine In water at 70 - 90℃; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In ethanol; water at 120℃; for 12h; | 4.1.1. 5-(4-Benzyloxy-3-methoxybenzylidene)-imidazolidine-2,4-dione (13) Hydantoin (3.07 g, 30.6 mmol) was dissolved in 40 mL of water at 70 °C with stirring. After complete dissolution, the pH of the mixture was adjusted to 7.0 with satd NaHCO3 aq Ethanolamine (3.0 mL, 49.7 mmol) was added and the temperature of the reaction mixture was increased to 90 °C. After aldehyde 12 was heated with EtOH (50 mL) until complete dissolution, it was added to the reaction mixture. The temperature was raised to 120 °C and the reaction mixture was refluxed at that temperature for 12 h. After cooling to room temperature, the precipitate was filtered. The residue was washed with H2O/EtOH (5:1) to give 13 (5.03 g, 72%) as a colorless powder. This product was used without further purification. Mp: 251-253 °C. IR (ATR, cm-1): 3143, 1754, 1710. 1H NMR (400 MHz, DMSO) δ: 3.82 (3H, s), 5.11 (2H, s), 6.37 (1H, s), 7.03 (1H, d, J=8.0 Hz), 7.14 (1H, d, J=1.6 Hz), 7.15 (1H, dd, J=8.0, 1.6 Hz), 7.32 (1H, t, J=7.2 Hz), 7.35 (2H, t, J=7.2 Hz), 7.43 (2H, d, J=7.2 Hz), 10.48 (1H, s). 13C NMR (100 MHz, DMSO) δ: 56.2, 70.2, 109.6, 113.3, 113.9, 123.3, 126.4, 126.7, 128.3, 128.4, 128.9, 137.3, 148.7, 149.5, 156.2, 166.1. HRESIMS: m/z 347.1012 (calcd for C18H16N2NaO4: 347.1002). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In tetrahydrofuran for 2h; | B.9 9. Preparation of 4-ethenyl-2-methoxy-l-benzyIoxybenzene (9).; To a suspension of methyltriphenylphosphonium bromide (6.5 g, 18.2 mmol) in anhydrous tetrahydrofuran (THF) (15 mL) under N2 at 0°C was added potassium tert- butoxide (2.3 g, 20.5 mmol) and the reaction mixture was warmed to room temperature. A solution of benzyl vanillin (7) (4 g, 16.5 mmol) in anhydrous THF (15 mL) was added dropwise and stirred for 2 hours, then quenched with cold water (20 mL), acidified with 0.1 M HC1 (20 mL), and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with 20% aq. sodium chloride (20 mL) then dried under reduced pressure. The product was purified using NPSCC using a step-wise mobile phase consisting of hexane/ethyl acetate to afford 9 as a colourless solid (3.37 g, 85%); mp 53-54°C (lit.8 mp 50-51°C); C,6H1602 NMR (400 MHz, CDC13) δ 7.45- 7.28 (m, 5H), 6.99 (d, J= 2 Hz, IH), 6.90 (dd, J= 4, 1 Hz, 1H), 6.83 (d, J= 4 Hz, 1H), 6.68 (dd, J= 17, 1 Hz, 1H), 5.64 (dd, J= 17, 1 Hz, 1H), 5.17 (s, 2H), 5.14 (d, J= 1 Hz, 1H), 3.92 (s, 3H). |
85% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | Preparation of 4-benzyloxy-3-methoxy-1-ethenylbenzene (10a) General procedure: To a suspension of methyltriphenylphosphonium bromide (6.5 g, 18.2 mmol) in freshly distilled anhydrous tetrahydrofuran (15 mL) was added potassium tert-butoxide (2.3 g, 20.5 mmol) under nitrogen at 0°C. The mixture was allowed to warm up to room temperature then added dropwise a solution of 9a (4 g, 16.5 mmol) in anhydrous tetrahydrofuran (15 mL). The resulting solution was stirred for 1-2 hours at room temperature and monitored by TLC. The reaction mixture was quenched with cold distilled water (20 mL), acidified with 0.1 M hydrochloric acid (20 mL), and extracted with ethyl acetate (3 × 40 mL). The combined organic layers was washed with 20% aqueous sodium chloride (20 mL), dried over sodium sulfate and evaporated under reduced pressure to remove solvent. The residue was purified on silica gel using hexane/ethyl acetate (3:1) as mobile phase to afford 10a as colorless solid (3.37 g, 85%), mp 53-54°C (lit.[41] mp 50-51°C). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.45-7.28 (5H, m, benzyl Ph), 6.99 (1H, d, J=1.8 Hz, H-2), 6.90-6.87 (1H, dd, J=4.4, 1.8 Hz, H-6), 6.83 (1H, d, J=4.4 Hz, H-5), 6.68-6.61 (1H, dd, J=17.6, 10.8 Hz, H-olefinic), 5.64-6.59 (1H, dd, J=17.6, 0.8 Hz, H-olefinic), 5.17 (2H, s, benzyl CH2), 5.14 (1H, dd, J=17.6, 0.8 Hz, H-olefinic), 3.92 (3H, s, OCH3). The 1H NMR spectrum was in good agreement with previously reported data[43]. |
78% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexanes at 0℃; for 1h; Inert atmosphere; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In tetrahydrofuran; hexanes at 0℃; for 3h; Inert atmosphere; | 4.1.8. 1-(Benzyloxy)-2-methoxy-4-vinylbenzene 5 To a mixture of methyltriphenylphosphonium bromide (2.47 g, 6.60 mmol) in 20 mL of anhydrous THF was added 1.6 M solution of n-BuLi in hexanes (2.5 mL, 3.96 mmol) at 0 °C. After stirring for 1 h at 0 °C, a solution of 17 (0.8 g, 3.30 mmol) in 10 mL of anhydrous THF was added. After stirring for 3 h at 0 °C, the reaction mixture was quenched with saturated aqueous NH4Cl, extracted with ether, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by Column Chromatography on silica gel (eluent: PE-EtOAc, 9:1) to afford the desired product 5 (0.61 g, 78%) as a white solid. mp = 59-60 °C; IR (KBr): 3063, 3034, 2936, 2873, 1580, 1511, 1458, 1330, 1264, 1139, 1028 cm-1; 1H NMR: (CDCl3, 300 MHz): δ 7.42-7.22 (m, 5H), 6.92 (d, 1H, J = 1.7 Hz), 6.84-6.75 (m, 2H), 6.58 (dd, 1H, J = 10.7, 17.5 Hz), 5.55 (d, 1H, J = 17.5 Hz), 5.13-5.07 (m, 1H), 5.11 (s, 2H), 3.89 (s, 3H); ESI-MS: 263 [M+Na]+. |
Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In tetrahydrofuran Inert atmosphere; | Synthesis of Terminal Alkene Substrates; General Procedure A General procedure: A solution of KOtBu dissolved in THF (1.25 equiv) was added dropwiseat rt to a solution of methyltriphenylphosphonium bromide (1.25equiv) in anhyd THF under a N2 atmosphere. The mixture was allowedto stir for 0.5 h at rt. The corresponding aldehyde or ketone dissolvedin THF (1.0 equiv) was subsequently added dropwise. The mixturewas then allowed to stir for 3-18 h. After completion, the reactionwas quenched with sat. aq NH4Cl (25-30 mL) and H2O (20 mL). Themixture was extracted with EtOAc (2 × 30 mL). The combined organicphases were dried over anhyd Na2SO4 and concentrated in vacuo. Theresulting crude product was purified by flash column chromatography(silica gel, hexanes/EtOAc 100:0 to 95:5) to afford the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium hydroxide; In methanol; at 20℃; for 24h; | General procedure: The chalcones were prepared through an aldol condensation reaction between acetophenones (1.0 mmol) and the corresponding aldehydes (1.0 mmol), in methanol (15 mL), KOH (50 % v/v), at room temperature with magnetic stirring for 24 h.14 Distilled water and 10% hydrochloric acid were added to the reaction for total precipitation of the compounds, which were then obtained by vacuum filtration and later recrystallized from hot ethanol. The purity of the synthesized compounds was analyzed by thin-layer chromatography (TLC) using Merck silica pre-coated aluminum plates of 200 mum thickness, with several solvent systems of different polarities. Compounds were visualized with ultraviolet light (l = 254 and 360 nm) and using sulfuric anisaldehyde solution followed by heat application as the developing agent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In methanol at 20℃; for 24h; | Preparation of chalcones General procedure: The chalcones were prepared through an aldol condensation reaction between acetophenones (1.0 mmol) and the corresponding aldehydes (1.0 mmol), in methanol (15 mL), KOH (50 % v/v), at room temperature with magnetic stirring for 24 h.14 Distilled water and 10% hydrochloric acid were added to the reaction for total precipitation of the compounds, which were then obtained by vacuum filtration and later recrystallized from hot ethanol. The purity of the synthesized compounds was analyzed by thin-layer chromatography (TLC) using Merck silica pre-coated aluminum plates of 200 μm thickness, with several solvent systems of different polarities. Compounds were visualized with ultraviolet light (l = 254 and 360 nm) and using sulfuric anisaldehyde solution followed by heat application as the developing agent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium hydroxide In methanol; water at 20℃; for 12h; | (E)-5-(4-(benzyloxy)-3-methoxyphenyl)-1,1-bis (methylthio)penta-1,4-dien-3-one (6f) General procedure: To a solution of 1,1-dithiomethyl-1-en-3-butenone (5) (1.62 gm, 10 mmol) in methanol (40 ml), substituted benzaldehydes (4) (10 mmol) were added, followed by aqueous KOH solution (1.12 gm, 20 mmol, in 10 ml of water), the resulting reaction mixture was stirred at room temperature for 12 hr. It was concentrated in vacuo, poured into water (100 ml) and extracted with dichloromethane (50 ml x 3). The combined extract was washed with water (100 ml x 2), brine solution (50 ml x 2), and dried(Na2SO4). The solvent was removed in vacuo and the resulting crude product was column chromatographed (SiO2, 60-120 mesh). Elution with mixture of ethylacetate in hexane furnished compounds 6a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium sulfate; triethylamine In chloroform at 20℃; for 44h; | |
100% | With sodium sulfate; triethylamine In chloroform at 23℃; for 16h; | |
100% | With sodium sulfate; triethylamine In chloroform at 20℃; for 16h; | 10 N-[4'-(Benzyloxy)-3'-methoxybenzylidene]-3-bromopropan-l-amine 3-Bromopropylamine hydrobromide (3.12 g, 14.2 mmol) was diluted in CHCI3 (10 mL). Benzylvanillin 60 (3.00 g, 12.4 mmol) was dissolved in CHCI3 (10 mL) and added slowly to the amine solution. Upon the addition of Et3N (1.39 g, 13.6 mmol), the mixture turned clear. Na2S04 (3.52 g, 24.8 mmol) was added, and the mixture was stirred at room temperature for 16 h, and then diluted to 50 mL with CHCI3 and washed with H20 (100 mL x 3) and brine (100 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated to provide the product 61as a yellow syrup (4.49 g, 100% + residual solvent). IR (film) 2937, 2841, 1646, 1602, 1587, 1512, 1456, 1415, 1270, 1233, 743 cm"1; *H NMR (300 MHz, CDC13) 8.22 (s, 1 H), 7.45-7.30 (m, 6 H), 7.10 (dd, / = 1.7 and 6.4 Hz, 1 H), 6.90 (d, / = 8.2 Hz, 1 H), 5.20 (s, 2 H), 3.95 (s, 3 H), 3.74 (t, / = 6.1 Hz, 2 H), 3.51 (t, / = 6.5 Hz, 2 H), 2.27 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 1-(2-(benzyloxy)-6-hydroxy-4-(methoxymethoxy)phenyl)ethan-1-one With sodium hydride In n-heptane; N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In n-heptane; N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2.16667h; Inert atmosphere; | 4.16 Preparation of (E)-1-(2-benzyloxy-6-hydroxy-4-methoxymethoxy-phenyl)-3-(4-benzyloxy-3-methoxy-phenyl)-propenone 5g A dried 250 mL 3-necked round-bottomed flask was charged with NaH (2.21 g, 55.31 mmol, 60% dispersion in mineral oil) under nitrogen. Heptane (5 ml) was then added and the mixture was stirred for 5 min. Next, DMF (60 mL) was added and the white suspension was cooled in an ice-water bath for 10 min. A solution of the acetophenone 6b (7.60 g, 25.14 mmol) in DMF (30 mL) was added slowly via a syringe. The mixture was stirred for 30 min while cooling in an ice-water bath. A solution of the 3-O-methyl 4-O-benzyl benzaldehyde 7d (6.39 g, 26.39 mmol) in DMF (30 mL) was added via syringe. The resultant orange mixture was stirred for an additional 10 min at 0 °C and at room temperature for 2 h. The reaction was then poured onto crushed ice (350 g). The mixture was stirred vigorously to obtain a yellow suspension. The solution pH was adjusted to neutral with 1 M HCl. The mixture was stirred until no sticky droplets were visible and a homogenous yellow suspension was obtained (ca 2 h). The yellow solid was collected by suction filtration, rinsed with water (2 × 30 mL), and suction dried to afford the title compound 5g (13.44 g, 100% yield): mp 138-139 °C; LC/MS m/z 527 [M+H], 1H NMR (CDCl3, 400 MHz) δ 3.52 (s, 3H), 3.69 (s, 3H), 5.11 (s, 2H), 5.02 (s, 4H), 6.22 (s, 1H), 6.32 (s, 1H), 6.66 (ABq, JAB = 8.2, ΔνAB = 25.7, 2H), 7.21-7.51 (m, 10H), 7.75 (ABq, JAB = 15.7, ΔνAB = 27.3, 2H), 14.32 (s, 1H, OH); 13C NMR (CDCl3, 100 MHz) δ 56.0, 56.6, 71.0, 71.4, 92.8, 94.2, 97.1, 107.2, 112.0, 113.8, 121.9, 125.9, 127.2, 128.1, 128.5, 128.75, 128.79, 128.9, 135.7, 136.9, 143.0, 149.6, 150.1, 161.8, 163.6, 168.1, 192.8. Anal. Calcd for C32H30O7: C, 72.99; H, 5.74. Found: C, 72.88; H, 5.90. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | General procedure: n-BuLi (10.7 mmol, 1.6 M solution in hexanes) was slowly added at -78 C under N2 atm to a stirred solution of 1a (10.2 mmol) in THF (25 mL) then stirred for 30 min at the same temperature. Aldehyde 2a (11.3 mmol) in THF (25 mL) was added dropwise over a period of 5 min then the reaction mixture was stirred for 30 min at -78 C. The reaction mixture was allowed to warm to 0 C, quenched with saturated NH4Cl solution, and extracted into ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and the solvents were evaporated. The crude compound was purified by column chromatography (35% EtOAc/hexane) to get alcohol 3a as off-white solid (yield 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With cerium impregnated on MCM-41 In neat (no solvent) at 80℃; for 0.833333h; | General procedure for the synthesis of benzoxanthenone General procedure: In a 25 mL round-bottom flask, aldehyde (1 mmol), naphthol (1 mmol), 1,3 diketone (1 mmol) and Ce-MCM-41 (1.7 mol %) were taken. The reaction mixture was stirred at 80 °C under solvent-free conditions for 30-50 min. The reaction was monitored by TLC and on completion of the reaction, the reaction mixture was cooled to room temperature and ethyl acetate was added to dissolve all organic components and filtered to remove catalyst. The filtrate was concentrated and purified by silica gel column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: To the suspension of amino acid esterhydrochloride (1.2 equiv., 12 mmol) and MgSO4 (1.25 equiv., 12.5 mmol) in DCM (15 mL)was added Et3N (1.2 equiv., 12 mmol). The mixture was stirred at ambient temperature for1h. Then the corresponding aldehyde (1 equiv., 10 mmol) was added and the mixture wasallowed to stir at ambient temperature overnight. The precipitate was removed by filtration and the filtrate was washed with water (15 mL). The aqueous phase was extracted two timeswith DCM (10 mL) and the combined organic layer was washed once with brine (15 mL),dried over MgSO4 and concentrated. Solids were purified by crystallisation from ethyl acetate/ n-pentane. Oils were used for 1,3-dipolar cycloadditions without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; | 'rytftro-l-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)-l,3- propanediol (2h): (0183) (0184) 2h (0185) Scheme 9. Synthesis of £'r_yi zro-l-(4-hydroxy-3-methoxyphenyl)-2-(2- methoxyphenoxy)-- 1 ,3-propanediol (2h). (0186) This compound was prepared according to the same literature procedure as for compound 2g. Spectral data were consistent with those reported in the literature. JH NMR (400 MHz, CDC13) delta 7.16 (dd, J = 8.2, 1.6 Hz, 1H), 7.04-6.86 (m, 5H), 6.86 (d, J = 8.2 Hz, 1H), 5.71 (b s 1H), 4.96 (d, J = 7.9 Hz, 1H), 4.06-3.97 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.73-3.58 (m, 2H), 3.48 (ddd, J = 12.0, 7.8 and 3.6 Hz, 1H), 2.78-2.73 (m, 1H). HRMS (ESI) calculated for CnHzoOeNa [M + Na]+ 343.1158, found 343.1154. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide In methanol; water at 60℃; for 1.5h; | 22 General procedure (E) for aldolisation General procedure: Phenylpyrrolizinone (1 Eq) and appropriated aldehyde (1 Eq) were suspended in a mixture of MeOH (8 mL mmol1) and 5N aqueous NaOH (2Eq) and heated at 60 C for 1.5 h. After return to room temperature, the mixture was evaporated in vacuo, taken up with DCM (8 mL mmol1) and washed by HCl 2 M(3 1 mL mmol1). Organic layer was dried under MgSO4 and evaporated in vacuo. The crude was purified on silica gel column (cyclohexane/EtOAc; 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide In methanol; water at 60℃; for 1.5h; | 19 General procedure (E) for aldolisation General procedure: Phenylpyrrolizinone (1 Eq) and appropriated aldehyde (1 Eq) were suspended in a mixture of MeOH (8 mL mmol1) and 5N aqueous NaOH (2Eq) and heated at 60 C for 1.5 h. After return to room temperature, the mixture was evaporated in vacuo, taken up with DCM (8 mL mmol1) and washed by HCl 2 M(3 1 mL mmol1). Organic layer was dried under MgSO4 and evaporated in vacuo. The crude was purified on silica gel column (cyclohexane/EtOAc; 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: acetylferrocene; 3-methoxy-4-(phenylmethoxy)benzaldehyde In ethanol for 0.166667h; Stage #2: With sodium hydroxide In ethanol at 50℃; | General procedure for synthesis of chalcones General procedure: The corresponding vanillin aldehyde 2a-f (10 mmol) and acetylferrocene (10 mmol) were dissolved in 20 mL of warm ethanol, and the mixture was stirred for 10 min and1 mL of 40% NaOH was added slowly. The reaction mixture was stirred overnight at 50°C. Crushed ice, 100 g, was placed in a beaker and the reaction mixture was poured onto it with stirring. The product in some cases could be isolated by filtration, if not it was necessary to extract with toluene or dichloromethane (3 ×50 mL). The organic layerwas washed with water (2 ×50 mL), brine (2 ×50 mL), and dried over anhydrous Na2SO4. The main part of the solvent was evaporated at reduced pressure and crude concentrated solution was filtered through a short column of silica gel. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel column using toluene-ethyl acetate (8:2) mixture as eluent for separation of reaction products 3a-f. |
With sodium hydroxide In ethanol at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.3% | Stage #1: anthranilic acid amide With sodium acetate In N,N-dimethyl-formamide for 0.166667h; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde With iodine In N,N-dimethyl-formamide at 70 - 80℃; for 24h; | 14 General procedure for the synthesis of 5a-t General procedure: To the stirring solution of 2-aminobenzamide (1 equivalent) in DMF, sodium acetate (2 equivalents) was added. After stirring for- 10min, substituted benzaldehydes (1 equivalent, 7a-g and 9h-t) and iodine (2 equivalents) were added. The reaction mixture was stirred at 70-80°C for 20-24h. Then the reaction mixture was poured on to crushed ice. The resulting mixture was treated with sodium thiosulphate (10% w/v in water) to reduce the remaining iodine. The precipitate was filtered off and washed with petroleum ether (40:60): ethyl acetate in 1:1 ratio. |
Stage #1: anthranilic acid amide With sodium acetate In N,N-dimethyl-formamide for 0.166667h; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde With iodine In N,N-dimethyl-formamide Heating; | 4.3. General procedure for the synthesis of the newly synthesizedcompounds 35-72 General procedure: To the stirring solution of antranilamide (4.1 equivalents) indimethylformamide, sodium acetate (2 equivalents) was added.After stirring for 10 min appropriate benzaldehyde derivative (1equivalent) and iodine (2 equivalents) were added. The reactionmixture was heated at 70-80 °C for 20-24 h. Then reactionmixture was poured on to crushed-ice. The resulting mixture wastreated with sodium thiosulphate (10% w/v in water) to reduce theremaining iodine. The precipitate was filtered off and washed withn-hexane: ethyl acetate (50:50). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With acetic acid;Reflux; | General procedure: Synthesized intermediate compounds (1 mmol) and Moroxydine hydrochloride or Metformin hydrochloride (1 mmol) were refluxed in glacial acetic acid (10 mL) at 120 oCfor 4?6 h. The whole processes of the reactions were traced by TLC, then removed solvent under reduced pressure. The crude products were purified by column chromatography (dichloromethane : methanol = 20 : 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With acetic acid;Reflux; | General procedure: Synthesized intermediate compounds (1 mmol) and Moroxydine hydrochloride or Metformin hydrochloride (1 mmol) were refluxed in glacial acetic acid (10 mL) at 120 oCfor 4-6 h. The whole processes of the reactions were traced by TLC, then removed solvent under reduced pressure. The crude products were purified by column chromatography (dichloromethane : methanol = 20 : 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogen In water; <i>tert</i>-butyl alcohol at 120℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydroxide In ethanol; water at 20℃; | 2 4.1.1 General procedure for the synthesis of chalcones (3a-3h) General procedure: A mixture of the acetophenone (5-10mmol, 1equiv) and the corresponding aldehyde (1equiv) in EtOH (20-40mL) was stirred at room temperature and a 50% aqueous solution of NaOH (5-8mL) was added. The reaction mixture was stirred at room temperature until aldehyde consumption. After that, HCl (10%) was added until neutrality. Precipitated chalcones were generally filtered and crystallized from MeOH, although in some cases the product was purified using column chromatography. Chalcones 3a, 3c, 3e and 3f have been previously described. |
36% | With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70%; 20% | With sodium ethanolate; In ethanol; at 20 - 55℃; | To a stirred solution of PPh3 (1.7 g, 6.7 mmol) in ethylacetate, a solution of methyl 2-bromoacetate (0.62 muL,6.5 mmol) in ethyl acetate was added at room temperature.After 17 h, a white precipitate was collectedby filtration, washed three times with ether and driedin air to furnish (2-methoxy-2-oxoethyl)triphenylphosphoniumbromide (4, 2.49 g) as a white solid in almostquantitative yield. The phosphonium bromide 4 (2.0 g,4.81 mmol) was added to a suspension of sodium ethoxide(340 mg) in ethanol (10 mL) followed by the additionof 3a (1.15 g, 4.75 mmol) at room temperature for 25 min.The mixture was stirred at 50-55C for 1 h. The progressof the reaction was monitored via TLC. After completionof the reaction, water (10 mL) was added to the reactionmixture, and the product was extracted four timeswith diethyl ether (20 mL). The organic layers were combined,dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to furnish a solid residue.Further purification by column chromatography (ethylacetate : hexane 3 : 7) afforded two methyl cinnamatederivatives as a 3.5 : 1 mixture of E- and Z-isomers,respectively. 4.3.1 Methyl (E)-3-(4-(benzyloxy)-3-methoxyphenyl)acrylate (6a) Yield: 990 mg (70%). -M.p. 56-58C. - IR (powder):nu = 2922, 1716 (C=O), 1380, 1227, 920 cm- 1. - 1H NMR(300.132 MHz, [D6]DMSO): delta = 7.60 (d, J = 16.0 Hz, 1 H,olefinic proton), 7.46-7.33 (m, 6 H, Ph), 7.22 (dd, J = 1.6,8.3 Hz, 1 H, Ph-H), 7.05 (d, J = 8.3 Hz, 1 H, Ph-H), 6.56 (d,J = 16 Hz, 1 H, olefinic proton), 5.13 (s, 2 H, Ph-CH2-), 3.77(s, 3 H, CH3), 3.67 (s, 3 H, CH3). - C18H18O4 (298.34): calcd.C 72.47, H 6.08; found C 72.59, H 6.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 3-methoxy-4-(phenylmethoxy)benzaldehyde; ethylmagnesium bromide In tetrahydrofuran at 0℃; for 16h; Stage #2: With Dess-Martin periodane In dichloromethane for 12h; | 4.1.7 4.1.7 1-(4-Benzyloxy-3-methoxyphenyl)propan-1-one (4a) To a solution of 4-benyloxy-3-methoxybenzaldehyde (3, 5.00 g, 20.6 mmol) in THF (206 mL) was added EtMgBr (30.0 mL, 1.0 M solution in THF) at 0 °C. After being stirred for 16 h, the reaction was quenched with saturated NH4Cl. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. To the residue was added Dess-Martin periodinane (11.3 g, 30.1 mmol) in DCM (103 mL). After being stirred for 12 h, the mixture was added to excess ether and filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (hexane:EtOAc = 3:1) to afford 4a (5.51 g, 99%) as a colorless oil. 1H NMR (200 MHz, CDCl3) δ 7.56-7.33 (7H, m), 6.89 (1H, d, J = 8.4 Hz), 5.23 (2H, s), 3.94 (3H, s), 2.94 (2H, q, J = 7.3 Hz), 1.21 (3H, t, J = 7.3 Hz). 13C NMR (75 MHz, CDCl3) δ 199.5, 152.1, 149.4, 136.3, 130.3, 128.6, 128.1, 127.1, 122.3, 112.1, 110.5, 70.7, 56.0, 31.3, 8.6. IR (ATR) 2972, 2935, 1671, 1584, 1510, 1453, 1416, 1340 cm-1. HRMS (EI) m/z: calcd. for C17H18O3 [M]+ 270.1256, found 270.1252. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide In ethanol; water at 20℃; for 7h; | 2.3 4.2.3 2-Hydroxy-4,6-bis(methoxymethoxy)acetophenone (6) A mixture of compound 4 (90.1 g, 0.35 mol) and 4-benzyloxy-3-methoxybenzaldehyde 5 (85.1 g, 0.35 mol) was dissolved in ethanol (900.0 ml). To this solution was added 20% NaOH aqueous solution (540.0 ml). After being stirred under room temperature overnight, the solution was adjusted to pH 6 with 20% HCl aqueous solution and filtrated to get the crude product 6. The crude product was dried in vacuum at 50 °C for 2 h and recrystallized by ethanol (1200.0 ml) to afford yellow solid 6 (143.4 g, 85%). 1H NMR (600 MHz, CDCl3) δ: 13.89 (s, 1H, OH), 7.83 (d, J = 15.5 Hz, 1H, β-CH=), 7.75 (d, J = 15.5 Hz, 1H, α-CH=), 7.44 (d, J = 7.4 Hz, 2H, ArH), 7.38 (t, J = 7.5 Hz, 2H, ArH), 7.32 (t, J = 7.3 Hz, 1H, ArH), 7.16 (d, J = 1.8 Hz,1H, ArH), 7.14 (dd, J = 8.3, 1.9 Hz, 1H, ArH), 6.90 (d, J = 8.3 Hz, 1H, ArH), 6.32 (d, J = 2.3 Hz, 1H, ArH), 6.22 (d, J = 2.3Hz, 1H, ArH), 5.28 (s, 2H, O-CH2-O), 5.21 (s, 2H, O-CH2-O), 5.19 (s, 2H, O-CH2-Ar), 3.93 (s, 3H, OCH3), 3.53 (s, 3H, OCH3), 3.48 (s, 3H, OCH3); 13C NMR (150 MHz, CDCl3) δ: 192.74, 167.34, 163.34, 159.79, 150.37, 149.80,142.81, 136.62, 128.89, 128.66, 128.05, 127.22, 125.40, 122.60, 97.60, 95.33, 94.75, 94.10, 70.93, 56.97, 56.47, 55.96. HRMS calcd for C27H28O8 m/z [M+H]+: 480.1857, found 480.1856. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 2-bromo-3,5-dibenzyloxyacetophenone With sodium hydroxide In methanol; lithium hydroxide monohydrate for 0.166667h; Stage #2: 3-methoxy-4-benzyloxybenzaldehyde In methanol; lithium hydroxide monohydrate at 70℃; for 10h; Darkness; | |
87% | Stage #1: 2-bromo-3,5-dibenzyloxyacetophenone With sodium hydroxide In methanol; lithium hydroxide monohydrate at 20℃; for 0.166667h; Stage #2: 3-methoxy-4-benzyloxybenzaldehyde In methanol; lithium hydroxide monohydrate at 20℃; for 10h; | 11 1-(2-Bromo-3,5-diphenylmethoxyphenyl)-3-(3-methoxy-4-benzyloxyphenyl)-(2E)-2-propen-1-one(11) 2-Bromo-3,5-dibenzyloxyacetophenone 20 g (48.8 mmol) was dissolved in a mixed solvent of 2000 ml of methanol and water (methanol: water = 2:1, v/v), and NaOH solids 20 g (48.8 mmol) were added. Stir at room temperature for 10 minutes, then add 3-methoxy-4-benzyloxybenzaldehyde 14.2g (58.6mmol), continue the reaction for 10h, TLC detection shows that the reaction is complete. The reaction liquid diatomaceous earth filtered out yellow solid compound 11 (27.5g, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.4% | With sodium hydroxide In 1,4-dioxane; methanol at 20℃; | 3.3.1. Method I (Compounds 1-6, 10-18) General procedure: In a round bottomed flask 0.24 g (6.00 mmol) of sodium hydroxide was dissolved in 10 mLmethanol and 10 mL dioxane. After that, an appropriate aminoacetophenone (3.67 mmol) and thecorresponding benzaldehyde (3.67 mmol) were added. Reactions were performed in room temperatureon a magnetic stirrer until complete conversion of the substrates. After that, the reaction mixtureswere poured into ice water. Precipitated crystals were collected and purified by liquid columnchromatography on silica gel using mixtures of hexane-acetone, hexane-ethyl acetate or hexane-ethylacetate-methylene chloride as eluents. Compounds 4 and 6 were synthesized at 2.5 times smaller scale. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.4% | With sodium hydroxide In 1,4-dioxane; methanol at 20℃; | 3.3.1. Method I (Compounds 1-6, 10-18) General procedure: In a round bottomed flask 0.24 g (6.00 mmol) of sodium hydroxide was dissolved in 10 mLmethanol and 10 mL dioxane. After that, an appropriate aminoacetophenone (3.67 mmol) and thecorresponding benzaldehyde (3.67 mmol) were added. Reactions were performed in room temperatureon a magnetic stirrer until complete conversion of the substrates. After that, the reaction mixtureswere poured into ice water. Precipitated crystals were collected and purified by liquid columnchromatography on silica gel using mixtures of hexane-acetone, hexane-ethyl acetate or hexane-ethylacetate-methylene chloride as eluents. Compounds 4 and 6 were synthesized at 2.5 times smaller scale. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In ethanol at 25℃; | Synthesis of compound 10: One eq A and one eq B were dissolved in ethanol. A total of 1.2 eqpotassium hydroxide solution (15%, w/v) were added dropwise under constant cooling over 5 min.After stirring at 25 C overnight, the mixture was cooled down to 0-5 C and stirred for another 1.5 h.The mixture was then acidified with 2 eq glacial acetic acid and precipitated with H2O by stirring at0-5 C for 1 h. The precipitate was filtered, washed 3 times with ethanol (50%), and dried at 80 C. Thedried precipitate was then dissolved in a mixture (1:1) of tetrahydrofuran and ethanolic potassiumhydroxid solution (10%, w/v) and refluxed for 18 h. After cooling, the mixture was again acidifiedwith glacial acetic acid and precipitated with H2O by stirring at 0-5 C for 1 h. The crude precipitatewas then recrystallized from acetone. The rened product was then dissolved in ethyl acetate/ethanol(2:1, v/v), hydrogenated using Pd/C 5% (for approximately 6 h). After the removal of the catalyst via filtration over SiO2, the solvent was evaporated, and the crude product was recrystallized fromhexane/ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 26℃; for 16h; | AcOH (15.0 μL, 0.27 mmol, 1.2 eq) and NaBH(OAc)3 (52.8 mg, 0.25 mmol, 1.1 eq) were added to a solution of 5-(tert-butyl)-2-methoxyaniline (44.3 mg, 0.25 mmol, 1.1 eq) and 4-(benzyloxy)-3-methoxybenzaldehyde (53.6 mg, 0.22 mmol, 1.0 eq) in dicholoroethane (1.5 mL) and the mixture was stirred at 25 C. for 16 h. Upon completion, the reaction was concentrated under a stream of nitrogen and the resulting residue was re-dissolved in saturated aqueous NaHCO3 solution (2 mL) and extracted with ethyl acetate (3*2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Mg2SO4, filtered and concentrated under a stream of nitrogen. The resulting residue was re-dissolved in DCM and purified by silica gel chromatography (15-25% EtOAc/hexanes) to afford SI-47 (59.7 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With iodosylbenzene In dichloromethane at 20℃; for 0.75h; | General procedure for the deprotection process. General procedure: To a solution of 1,3-dithiolane/dithiane (2.0 mmol) in DCM (5.0 mL) was added the well ground PhIO (2.4 mmol) powder with stirring. The mixture was stirred at room temperature until TLC revealed a complete consumption of the substrates. Then the reaction solution was concentrated to afford the crude product, which was further purified by silica gel column chromatography to give the parent aldehyde/ketone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sulphur In dimethyl sulfoxide at 100℃; for 1h; | 4.1. General procedure for the synthesis of aryl(4-phenylpiperazin-1-yl)methanethione derivatives 4a-n General procedure: A mixture of 1-phenylpiperazine 1 (1 mmol), sulfur 2 (2 mmol), and different benzaldehyde derivatives 3a-n (1 mmol) in DMSO (10 mL) was stirred at 100 °C for 1 h. Then, the mixture reaction was allowed to cool at room temperature and diluted with wa- ter and obtained participate were purified by recrystallization in ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: Diethyl allylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: 3-methoxy-4-(phenylmethoxy)benzaldehyde In tetrahydrofuran at 0℃; for 14h; Inert atmosphere; |
Tags: 2426-87-1 synthesis path| 2426-87-1 SDS| 2426-87-1 COA| 2426-87-1 purity| 2426-87-1 application| 2426-87-1 NMR| 2426-87-1 COA| 2426-87-1 structure
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Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
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Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
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P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
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P243 | Take precautionary measures against static discharge. |
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
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P283 | Wear fire/flame resistant/retardant clothing. |
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P285 | In case of inadequate ventilation wear respiratory protection. |
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Code | Phrase |
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P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
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P314 | Get medical advice/attention if you feel unwell. |
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P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
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P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
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P362 | Take off contaminated clothing and wash before reuse. |
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P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
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P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
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P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
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P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
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P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
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P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
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Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
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H220 | Extremely flammable gas |
H221 | Flammable gas |
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H223 | Flammable aerosol |
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H225 | Highly flammable liquid and vapour |
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H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
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H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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