| 96% |
With potassium carbonate In acetonitrile for 24h; Reflux; |
3 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 N,N-dimethyl-formamide at 65℃; for 10h; Inert atmosphere; |
4.2 3,4-Bis(benzyloxy)benzaldehyde (22)
To a solution of 3,4-dihydroxybenzaldehyde (5.0g, 36.20mmol), potassium carbonate (20.1g, 144.80mmol) in DMF (100mL) was added benzyl bromide (17.19mL, 144.80mmol) at room temperature. The mixture was heated to 65°C for 10h. After cooling, the solvent was evaporated under vacuum. The residue was partitioned between EtOAc and water. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography [EtOAc: petroleum ether: CH2Cl2, 15 : 1: 1] to afford 22 as a white solid (11.10g, 96%). 1H NMR (600MHz, Chloroform-d) δ 9.83 (s, 1H, Ar-CHO), 7.51 (d, 1H, J=1.9Hz, Ar-H), 7.50-7.45 (m, 4H, Ar-H), 7.43 (dd, 1H, J=8.2, 1.9Hz, Ar-H), 7.42-7.38 (m, 4H, Ar-H), 7.37-7.32 (m, 2H, Ar-H), 7.04 (d, 1H, J=8.2Hz, Ar-H), 5.28, 5.23 (each s, each 2H, Ar-CH2-O); ESIMS: calcd for [M+H]+ m/z 319.1; found, 319.1. |
| 96% |
With potassium carbonate In ethanol at 60℃; for 8h; Inert atmosphere; |
1.2-2.2 (2) Preparation of 3,4-dibenzyloxybenzaldehyde:
200ml of absolute ethanol, 50g of 3.4-dihydroxybenzaldehyde, and 125.08g of potassium carbonate to the reaction flask under the protection of nitrogen. Slowly add 136.21 g of benzyl bromide. After the addition is completed, the temperature is raised to 60 degrees and the reaction is 8 hours. The solvent is recovered by concentration under reduced pressure. The residue is poured into 300 g of ice water, filtered and the filter cake is washed with 100 ml of water and dried to obtain 110g of 3,4-dibenzyloxybenzaldehyde, 96% yield. |
| 95% |
With potassium carbonate In N,N-dimethyl-formamide at 20 - 70℃; for 2.5h; |
|
| 95% |
With potassium carbonate In N,N-dimethyl-formamide at 20 - 70℃; for 2.5h; |
|
| 94% |
With potassium carbonate In acetone for 7h; Heating; |
|
| 94% |
With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone for 24h; Heating; |
|
| 94% |
Stage #1: 3,4-dihydroxybenzaldehyde With potassium carbonate In acetone for 0.5h;
Stage #2: benzyl bromide In acetone at 20℃; for 17.25h; |
1.1 Step 1: Preparation of 3,4-bis-benzyloxy-benzaldehyde
To a solution of 3,4-dihydroxy- benzaldehyde (10 g, 0.07 mole) in acetone (100 ml) was added K2C03 (30 g, 0.21739 M) and the mixture stirred for 30 min. Benzyl bromide 30.97 g, (0.181mole) was added drop wise at RT in 15 min. and the resulting mixture stirred further, at RT, for 17 hours. TLC showed absence of starting material (Ethyl acetate-Hexane, 10:90). The reaction mass was filtered and solid cake was washed with (2 X 25 ml) acetone. The filtrate was concentrated under reduced pressure at 40°C.To the residual solid mass 30 ml hexane was added and stirred for 30 minutes and the separated solid filtered under suction. The solid was dried under reduced pressure to obtain the product as a white solid, 21.5 gm, in 94% yield. |
| 94% |
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. |
| 93% |
With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 12h; |
3,4-Dibenzyloxybenzaldehyde
Benzyl bromide (2.58 mL, 21.72 mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (Compound 9) (1.0 g, 7.24 mmol) and K2CO3 (4.302 g, 31.13 mmol) in DMF (18 mL) One drop was added at room temperature. The mixture At 80 ° C Stir for 12 hours.After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite (R), and washed with ether (50 mL). H2O (20 mL) was added to the filtrate and the two layers were separated.The aqueous layer was extracted with ether (2 x 60 mL).The mixed organic solvent layer was washed with H2O (3 x 50 mL), Washed with brine (2x50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 1) to give pureCompound 10 (2.14 g, 93%) was obtained. Yield: 93%; |
| 93% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; |
|
| 92% |
With potassium carbonate In acetone for 15h; Heating; |
|
| 92% |
With potassium carbonate In acetone for 20h; Reflux; |
|
| 91% |
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; |
3,4-bis(benzyloxy)benzaldehyde (SI-2)
To a mixture of SI-1 (1.0 g, 7.2 mmol, 1.0 eq.) and Cs2CO3 (5.9 g, 18 mmol, 2.5 eq.) in DMF (11.1 mL) was added BnBr (2.2 mL, 18 mmol, 2.5 eq.) dropwise. The reaction mixture was stirred at RT for 18 h, then sat. aq. NaHCO3 was added and extractions with Et2O (4 x 10 mL) were performed. The combined organic layers were dried over Na2SO4 then evaporated in vacuo. The solid residue was taken back in a minimum volume of EtOAc and precipitated with petroleum ether. The solid was filtered, washed with additional petroleum ether to afford pure compound SI-2 as a white powder (2.0 g, 91 % yield). 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H, 1’-H), 7.54 - 7.27 (m, 2H + 2x5 H, 2-H, 6-H, Ph-H), 7.03 (d, J = 8.2 Hz, 1H, 5-H), 5.26 (s, 2Hm 4-O-CH2-Ph), 5.22 (s, 2H, 3-O-CH2-Ph). 13C NMR (100 MHz, CDCl3) δ 190.9 (C-1’), 154.3 (C-4), 149.3(C-3), 136.6 (i-CAr), 136.3 (i-CAr), 130.4 (C-1), 128.7 (m-CAr), 128.7 (m-CAr), 128.2 (p-CAr), 128.1 (p-CAr), 127.4 (o-CAr), 127.2 (o-CAr), 126.7 (C-6), 113.2 (C-5), 112.5 (C-2), 71.1 (4-O-CH2-Ph), 70.9 (3-O-CH2-Ph). NMR data were consistent with reported literature.[2] |
| 90% |
With potassium carbonate In acetone for 6.5h; Reflux; |
1 Example 1:
2g 3,4-dihydroxybenzaldehyde dissolved in 20mL acetone, 4.4g potassium carbonate by stirring, room temperature and a half smallAnd then 5.45 g of benzyl bromide was added thereto, followed by heating under reflux for 6 hours. After the reaction, 20 mL of distilled water and ethyl acetate were added(20 mL x 3). The combined organic layers were washed once with saturated brine and dried over anhydrous sodium sulfate. stress relieverThe ethyl acetate was distilled off and a small amount of precipitate was added to the precipitate. The filter cake was washed with a small amount of methanol to obtain a product4.06 g, 90% yield. |
| 90% |
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; |
1.1 Step 1) Preparation of 3,4-bis(benzyloxy)benzaldehyde (1101)
After 3,4-dihydroxybenzaldehyde (0.50 g, 3.62 mmol) was dissolved in anhydrous DMF (5 ml), potassiumcarbonate (K2CO3, 1.50 g, 10.86 mmol) was added and benzyl bromide (0.92 mL, 7.96 mmol) was then slowly addedto the reaction and stirred at 60°C for 4 hours. When the reaction was completed, the reaction mixture was cooled toroom temperature, diluted with purified water and extracted twice with diethyl ether (50 ml). The organic layer waswashed twice with purified water (50 ml) and then once again with saturated aqueous sodium chloride solution (50 ml).Then, anhydrous sodium sulfate was added to the organic layer and stirred, followed by filtration under reduced pressure.The filtered solution was concentrated and then purified by column chromatography to give 3,4-bis(benzyloxy)benzaldehyde(1101, 1.04 g, yield: 90%). 1H NMR (CDCl3, 300 MHz) δ 9.81 (s, 1H), 7.49-7.31 (m, 12H), 7.04 (d, J = 8.3 Hz,1H), 5.27 (s, 2 H), 5.22 (s, 2H); ESIMS m/z: 319.33 [M+H]+. |
| 89% |
With potassium carbonate In acetone for 4h; Heating; |
|
| 88.2% |
With potassium carbonate In N,N-dimethyl-formamide at 18.8 - 35.4℃; |
2
Example 2 - Preparation of 3,4-Bis(benzyloxy)benzaldehyde.; [0045] To a stirred suspension of commercially available 3,4- dihydroxybenzaldehyde (68 g, 0.492 mol, 1 eq), potassium carbonate (170 g, 1.23 mol, 2.5 eq) in N,N-dimethylformamide (400 ml_, ~ 5.9 vol., ~ 5.9 mL/g) was added slowly benzyl bromide (185.14 g, 1.08 mol, 2.2 eq) at RT with agitation under a nitrogen atmosphere. An exotherm was observed during the benzyl bromide addition as the internal temperature rose from 18.8° to 35.4°C. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with 200 mL of water and 125 mL of 50% aqueous hydrochloric acid. The reaction mixture was extracted with 500 mL of ethyl acetate and then with 200 mL of ethyl acetate. The combined organic layers were washed with 500 mL of water and 500 mL of a brine solution, dried over 200 g of sodium sulfate, and filtered. The solvent was removed in vacuum to give a beige-colored semi-solid which was dissolved in 150 mL of hot ethyl acetate. Then, 600 mL of heptane was slowly added with agitation. The mixture was cooled to RT and allowed to stir overnight. The solids were suction filtered and then washed twice with 200 mL of a mixture (v/v) of 10% ethyl acetate and 90% heptane and dried under high vacuum. The yield was 138.2 g (88.2%). HPLC purity was 100%. |
| 87% |
With potassium carbonate In acetone for 15h; Heating / reflux; |
Using the procedure reported by A. F. Barrero et al., Tetrahedron, 1998, 54, 5635. To a suspension of 3,4-dihydroxybenzaldehyde (6.9 g, 50 mmol) and potassium carbonate (14.5 g) in acetone (150 mL) was added benzyl bromide (11.96 mL, 101 mmol) and the mixture heated at reflux for 15 h. The reaction was cooled and the solvent removed in vacuo to give a light brown residue. The residue was redissolved in Et2O (200 mL), washed with water (3*200 mL) and dried (Na2SO4). Concetration in vacuo gave a pale yellow solid which was recrystallized from EtOH to give OBS01058 as a white powder (13.84 g, 87%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.7; m.p. 93-94° C. [Lit. (EtOH): 93-94° C.]; 1H-NMR (400 MHz, d6-DMSO) 5.22 (2H, s), 5.28 (2H, s), 7.29 (1H, d, J=8.4), 7.30-7.48 (10H, m), 7.51 (1H, d, J=2), 7.55 (1H, dd, J=2, 8.4), 9.81 (1H, s). |
| 86% |
With potassium carbonate In acetone for 6h; Reflux; |
|
| 86% |
With potassium carbonate In ethanol for 24h; Reflux; |
7 4.7 9 3,4-Dibenzyloxybenzaldehyde 2
Benzyl bromide (52mL, 434.6mmol), 53 K2CO3 (36g, 260.5mmol) were added to the solution of 54 3,4-dihydroxybenzaldehyde 1 (15g, 108.7mmol) in 10 ethanol (225mL). The reaction was stirred and heated for 24hat reflux. After cooling to the ambient temperature, the K2CO3 was filtered, washed with ethanol, and the residue was evaporated to dryness. The residue was crystallized from diethyl ether to afford a white solid; yield 29.8g (86%); m.p. 82-85°C; mp 88°C [16]; 1H NMR (CDCl3; 200MHz) δ 9.80 (s, 1H), 7.49-7.34 (m, 12H), 7.04 (d, 1H, J=8.4Hz), 5.25-5.21 (m, 4H); 13C NMR (CDCl3, 50MHz) δ 190.2, 153.6, 148.5, 135.9, 135.6, 129.6, 128.0, 127.9, 127.5, 127.4, 126.6, 126.4, 126.1, 112.4, 111.6, 99.9, 70.3, 70.2. |
| 85% |
With sodium hydride In N,N-dimethyl-formamide |
|
| 85% |
With potassium carbonate In acetone at 20℃; for 10h; |
|
| 84% |
With potassium carbonate In acetone for 4h; Heating; |
|
| 84% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; |
Synthesis ofcompound 27
General procedure: Benzylation of 3,4-dihydroxybenzaldehyde (15.06 g, 109.04 mmol) as describe for17gave compound27as white crystals (84%).1H NMR (500 MHz, CDCl3): δ (ppm) 5.23 (s, 2H), 5.27 (s, 2H), 7.03 (d, J = 8.2, 1H), 7.34 (m, 2H), 7.39 (m, 5H), 7.47 (m, 5H), 9.82 (s, 1H).13C NMR (500 MHz, CDCl3): δ (ppm) 31.1, 70.9, 71.1, 112.5, 113.2, 126.9, 127.2, 127.5, 128.2, 128.3, 128.8, 128.8, 130.5, 136.4, 136.7, 149.3, 154.4, 191.0. ESI-MS (m/z): 319.10 [M+H]+.; 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 %). |
| 84% |
With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; |
Synthesis of benzylated precursors
General procedure: To a solution of 2,3-dihydroxybenzaldehyde or3,4-dihydroxybenzaldehyde (1.00 g, 7.24 mmol) and K2CO3 (2.20 g, 15.9 mmol) in DMF(20 mL) at 0 °C, benzyl bromide (1.89 mL, 15.9 mmol) was added drop-by-drop, underN2 atmosphere. After stirring at 0 °C for 15 min, the reaction mixture was allowed towarm up to room temperature and the stirring was maintained for 4 h. After that time, thereaction mixture was precipitated into an ice/water mixture and neutralized using citricacid. The white solid obtained was filtered, washed with water, dissolved in chloroform,and crystallized in n-hexane to afford the respective products. |
| 78% |
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 4h; |
|
| 78% |
With potassium carbonate In acetone at 20℃; for 16h; |
|
| 78% |
With potassium carbonate In acetone at 0 - 20℃; Inert atmosphere; |
|
| 76% |
With potassium carbonate In acetone for 21h; Reflux; |
3 3,4-Bis(benzyloxy)benzaldehyde (S15)
General procedure: 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%). |
| 40% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; |
|
|
With potassium carbonate In N,N-dimethyl-formamide for 24h; Ambient temperature; |
|
|
With potassium carbonate In methanol Heating; |
|
|
In ethanol |
|
|
With potassium carbonate In acetone for 4h; Heating; |
|
| 104% |
With potassium carbonate In acetone |
22.a EXAMPLE 22
(a) Synthesis of 3,4-dibenzyloxy Benzaldehyde and Reaction with 7A to Form (trans)-8-[3,4-bis(benzyloxy)benzyl]-5-[4-(dimethylamino)-1-naphthyl]-2-(2-morpholin-4-ylethyl)hexahydro-1H-pyrrolo [3',4':2,3]pyrrolo[1,2-c]imidazole-1,3 (2H)-dione (52): In a round bottom flask under nitrogen was placed 3,4-Dihydroxybenzaldehyde (l.Og, 7.24 mmol) and acetone added (22 mL). To this solution was added potassium carbonate (2.1 g, 15.2 mmol) followed by benzyl bromide (1.72 mL, 14.48 mmol) and the mixture heated to reflux for sixteen hours and partitioned between ethyl acetate and water. Washed organics with brine, dried, and concentrated to yield 2.41 g of 3,4-dibenzyloxy benzaldehyde 51 as a brown solid (104%). |
|
With potassium carbonate; potassium hydrogencarbonate In water; N,N-dimethyl-formamide |
225 3,5-Trans-N-(2-fluorobenzyl)-5-(3-tert-butoxycarbonylaminomethylphenyl)-1-(3,4-dibenzyloxybenzyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,4-dibenzyloxybenzaldehyde
EXAMPLE 225 3,5-Trans-N-(2-fluorobenzyl)-5-(3-tert-butoxycarbonylaminomethylphenyl)-1-(3,4-dibenzyloxybenzyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,4-dibenzyloxybenzaldehyde A mixture of 3,4-dihydroxybenzaldehyde (5.0 g), benzyl bromide (14.8 g), potassium carbonate (13 g) and N,N-dimethylformamide (120 ml) was stirred for two hours at 60° C. To the reaction mixture was added cold water (200 ml), which was subjected to extraction with ethyl acetate (150 ml). The organic layer was washed with a 5% aqueous solution of potassium hydrogencarbonate, which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 3,4-dibenzyloxybenzaldehyde (10.5 g) as colorless crystals. m.p.: 87-88° C. |
|
With potassium carbonate In acetone |
40 3,4-Dibenzyloxy-benzaldehyde
EXAMPLE 40 3,4-Dibenzyloxy-benzaldehyde A mixture of 3,4-dihydroxy-benzaldehyde (2.76 g, 20 mmol) in dry acetone (50 ml), potassium carbonate (5.52 g, 40 mmol) and benzylbromide (5 ml, 42 mmol) was heated at reflux for 12 hours. The mixture was cooled to room temperature, potassium carbonate was removed by filtering the solution and the filtrate was concentrated to a powder which was recrystallized from acetone to yield (5.4 g, 81%) ether as prisms, mp 89-90° (lit. mp 90°) IRνmax1685, 1595, 1483, 1508, 1454, 1434, 1269, 1132, 695, 650 cmmin1; and 1H-NMR (90 MHz), 5.21 (2H, s, ArCH2O), 5.26 (2H, s, ArCH20), 7.02 (1H, d, J = 7.9 Hz), 7.30-7.50 (12H, ArH), 9.81 (1H, s, CHO). Anal. calcd for C21H18O3: C, 79.23; H, 5.70. Found: C, 79.26; H, 5.68. |
|
With potassium carbonate; potassium iodide In ethanol |
|
|
With potassium carbonate |
|
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; |
31 Reference Example 31
Reference Example 31 10.36 g of 3,4-dihydroxybenzaldehyde, 25.65 g of benzyl bromide, 22.8 g of potassium carbonate and 200 ml of N,N-dimethylformaldehyde were mixed and stirred at room temperature for 3 hours. Water was then added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was washed with hexane to obtain 23.27 g of 3,4-bis(benzyloxy)benzaldehyde. 1H-NMR (CDCl3, TMS) δ (ppm): 9.80 (1H, s), 7.27-7.49 (12H, m), 7.01 (1H, d, J = 8.1 Hz), 5.25 (2H, s), 5.21 (2H, s) |
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; |
Typical procedure for synthesis of compound 4a.
General procedure: To a mixture of 3-hydroxy-4-methoxybenzaldehyde (3.0 g, 19.7 mmol) and potassium carbonate (10.9 g, 78.8 mmol) in DMF (30 mL) was added benzyl bromide (4.7 mL, 39.4 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction solution was filtered to remove inorganic salts, and the filtrate was diluted with water (200 mL), extracted three times with ethyl acetate and washed with brine. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1) to give 4.7 g of benzylated compound. To a mixture of magnesium turnings (0.75 g, 0.031 mol) in THF (5 mL) at room temperature was slowly added a solution of 4-methoxybenzylchloride (1.6 g, 10.2 mmol) in THF (10 mL). The reaction solution was refluxed with heating for one hour and then cooled down in a 0 °C water bath. The ashy solution was extracted by using a syringe, which was used as a Grignard reagent. To a solution of the benzylated aldehyde (0.82 g, 3.4 mmol) in THF (15 mL) at 0 °C was added the Grignard reagent slowly, and the reaction mixture was stirred at room temperature for 1 h. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate threetimes and washed with brine. Combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1), to give 1.2 g of alcoholic compound. To a mixture of the alcoholic compound (1.2 g, 3.3 mmol), 4-methylmorpholine N-oxide (0.57 g, 4.9 mmol) and anhydrous powdered 4 Å molecular sieves (1.64 g) in dichloromethane (10 mL) was added tetrapropylammonium perruthenate (57 mg). The reaction mixture wasstirred for 30 min, passed through a short silica-gel pad by washing with ethyl acetate, and concentrated to give 1.1 g (88% in three-steps) of compound 2. To a solution of compound 2 (1.26 g, 3.5 mmol) in toluene (10 mL) was added dimethylformamide dimethylacetal (DMFDMA) (1.2 g, 10 mmol). The reaction mixture was refluxed for 16 h at 135 °C. The reaction solution was cooled to 0 °C, concentrated and purified by silica-gel column chromatography(hexane/ethyl acetate = 1:2) to give 1.35 g (93%) of compound 3. To a solution of compound 3 (1.12 g, 2.7 mmol) in methanol (35 mL) was added sodium carbonate (190 mg, 1.7 mmol) and NH2OH HCl (1.9 g, 27.0 mmol). The mixturewas adjusted to be pH 4-5 using acetic acid (1.0 mL) and then heated in a heavy-wall screw capped tube at 115 °C for 2 h. The reaction mixture was cooled to room temperature and methanol was removed under reducedpressure. The residue was extracted with methylene chloride and water, and the organic layer washed with brine, dried over Na2SO4, concentrated and purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1) to give 1.0 g (97%) of isoxazole compound 4a |
|
With potassium carbonate In dimethyl sulfoxide at 20℃; |
|
|
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide Inert atmosphere; |
|
|
With potassium carbonate |
|
|
With potassium carbonate |
|
|
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h; Inert atmosphere; |
|
|
Stage #1: 3,4-dihydroxybenzaldehyde With potassium carbonate In N,N-dimethyl-formamide for 0.166667h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide at 40℃; for 4h; |
4.1.2. General procedure for synthesis of benzyl-substitutedbenzaldehyde
General procedure: To a stirred solution of hydroxyl benzaldehyde 1a-c (5 mmol) indry DMF (10 mL) were added K2CO3 (10 mmol). After being stirredfor 10 min, benzyl bromide (5 mmol) were added at room temperature.The reaction was slowly heated to 40 °C, after beingstirred for 4 h, the solvent was removed on a rotary evaporator andthe residue was the reaction mixture. Cold water (10 mL) waspoured into the residue, and extracted with DCM (3 10 mL). Thecombined organic extracts were washed with brine (10 mL), driedover anhydrous Na2SO4 and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel(petroleum ether/EtOAc: 10/1) to afford powder of compounds 2a-c(Scheme S1) respectively. |
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; |
Preparation of 3,4-bis(benzyloxy)benzaldehyde 7
A 250-mL reaction vessel with a magnetic stirringbar was equipped with 3,4-dihydroxybenzaldehyde (5.13 g, 37.2 mmol), K2CO3 (25.70 g, 186.0 mmol),BnBr (19.0 g, 111.6 mmol), and DMF (100 mL). The mixture was stirred at room temperature for 4 h.After the reaction was completed, water (500 mL) was added, and the mixture was extracted withethyl acetate (500 mL). The organic layer was washed with water (250 mL 2) and brine (250 mL).After drying over MgSO4, the extracts were filtered and concentrated. The residue was firstly stirred inhexane (200 mL) overnight and then filtered to aord the intermediate 7 without any purification forthe next step. White solid; 10.17 g, 86% yield; melting point (m.p.) 89-90 C; Rf: 0.43 (EA:hexane = 1:4);IR (cm1): 3026, 2819, 2726, 1676, 1596, 1580, 1512, 1435, 1396, 1386, 1349, 1269, 1245, 1231, 1211,1135, 1021; 1H-NMR (CDCl3, 300 MHz): 5.24 (s, 2H), 5.28 (s, 2H), 7.05 (d, J = 8.1 Hz, 1H), 7.34-7.52(m, J = 12.0 Hz, 12 Hz), 9.84 (s, 1H); 13C-NMR (CDCl3, 75 MHz): 70.4, 70.5, 112.0, 112.7, 126.2, 126.6,126.8, 127.5, 127.6, 128.1, 128.2, 129.9, 135.8, 136.1, 148.8, 153.9, 190.3 ppm; HR-MS (ESI) calculated forC21H19O3 [M + H] 319.1334, found 319.1330. |
|
With potassium carbonate In N,N-dimethyl-formamide Reflux; |
GP-1: General Procedure for the Benzylation of Dihydroxybenzaldehydes
General procedure: A solution of hydroxybenzaldehyde (1 equiv.), anhydrous potassium carbonate (per hydroxylgroup, 1 equiv.) and benzyl bromide (per hydroxyl group, 1 equiv.) in anhydrous DMF (100 mL)was heated at reflux until TLC analysis showed consumption of the starting aldehyde (9 h). Uponcooling to room temperature, the reaction mixture was diluted with water (300 mL) and the resultingprecipitate was collected via filtration and washed with water (2 250 mL). Upon drying, the residuewas recrystallized from dichloromethane and n-hexane to give the title compound. |
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With potassium carbonate In N,N-dimethyl-formamide Reflux; |
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