| 90% |
With potassium carbonate In acetone for 48h; Heating; |
|
| 88% |
With potassium carbonate In acetonitrile at 90℃; for 24h; |
|
| 86% |
With potassium carbonate In acetone at 60℃; for 36h; Inert atmosphere; |
6. General synthetic procedure for intermediate 22
To a solution of 3,4-dihydroxybenzaldehyde (20, 10 g, 72.40 mmol) in acetone (100 mL) was added K2CO3 (20 g, 144.92 mmol), then 1,2-dibromoethane (19 g, 101.44 mmol) was added dropwise under N2 atmosphere. The mixture was stirred for 36 h at 60. The resulting reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/petroleum ether (1:4, v/v) to provide the intermediate (21, 10.5 g, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.43 (dd, J = 8.3, 1.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.36-4.34 (m, 2H), 4.31-4.29 (m 2H). 13C NMR (101 MHz, DMSO-d6) δ 191.26 (s), 149.04 (s), 143.73 (s), 130.24 (s), 123.68 (s), 117.78 (s), 117.70 (s), 64.59 (s), 63.89 (s). |
| 81% |
With potassium carbonate In N,N-dimethyl-formamide at 10℃; for 1h; Reflux; |
Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (3)
2.00g (14.5mmol) of 3,4-dihydroxybenzaldehyde 1 was dissolved in DMF (30 mL), after which 4.00g (29mmol) of K2CO3was added and stirred for 1 hour. At 10 oC 3.2ml (17.38 mmol) of 1,2-dibromoethane was added dropwise. The reaction was refluxed, while being stirred, until the starting materials were consumed. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature; the crude product was dumped in ice cold water, solid was separated and filtered out to achieve 2,3-dihydro[1,4]benzodioxin-6- carbaldehyde 3 (1.54 g, 81% yield, m.p-50-520C (reported)). |
| 74% |
With potassium carbonate In N,N-dimethyl-formamide at 60 - 90℃; for 8h; |
123 Example 123: Preparation of 1,4-benzodioxane-7-carbaldehyde (Intermediate IX).
138 mg of 3,4-dihydroxybenzaldehyde was dissolved in 5 ml of N,N-dimethylformamide.Add 100 mg of 1,2-dibromoethane and 300 mg of potassium carbonate,60-90°C reaction for 8 hours. After the reaction is over, the system is quenched with water.Extract three times with 30 ml of ethyl acetate and wash with saturated saline.Dry over anhydrous magnesium sulfate, filter, and concentrate to obtain intermediate 120 mg1,4-benzodioxane-7-carbaldehyde, yield 74%, untreated,Used directly for the next reaction. |
| 73% |
With potassium carbonate In acetone at 50 - 60℃; Industry scale; |
5
SYNTHETIC PREPARATION 5 Synthesis of 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Compound of formula (11) A 2000 L reactor was charged with acetone (404.5 kg), followed by potassium carbonate (256 kg, 1852 mol) and 1,2-dibromoethane (241.5 kg, 1298 mol). The mixture was heated at reflux. A 500 L reactor was charged with acetone (606 kg) and 3,4-dihydroxybenzalhdehyde (128 kg, 926 mol). The contents of the 500 L reactor were added to the 2000 L reactor at a rate of 150-180 kg/h while the reaction temperature was maintained at 50-60° C. The reaction mixture was stirred at 54-60° C. for 12 h, was cooled to 20° C. and was filtered through a 500 L Nutsche filter. The filter cake was washed with acetone (2*202 kg). The filtrate and acetone washes were combined in a 2000 L reactor and the resultant solution was concentrated to dryness under reduced pressure at a temperature <40° C. To the residue was added ethyl acetate (683 kg) and the resultant solution was washed with a 5% by weight aqueous solution of potassium carbonate (256 kg). The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed. This washing procedure was repeated three times in total. The organic phase was temporarily set aside into drums. A 2000 L reactor was charged with the combined aqueous washes, followed by ethyl acetate (113.9 kg). The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed. The organic phase from the drums was added to the reactor followed by a 28% by weight aqueous solution of sodium chloride (192 kg). The mixture was stirred for 0.5 h, allowed to settle for 0.5 h and the aqueous phase was removed. The organic phase was concentrated under reduced pressure at a temperature <45° C. until the mixture's ethyl acetate content was below 10% (as determined by gas chromatography). Petroleum ether (268.8 kg) was added to the residue at a rate of 80-90 kg/h while the mixture was maintained at a temperature of 35-45° C. The mixture was cooled to 5° C. over 3 h and held at this temperature for a further 1 h, during which time a precipitate was deposited. The resultant slurry was filtered through a centrifugal filter and dried to afford 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (111.4 kg, 73%) as an off-white solid: purity (HPLC-UV at 230 nm) 99.3%. |
| 73% |
With potassium carbonate In N,N-dimethyl-formamide at 50℃; |
6-Formyl-1,4-benzodioxane (1)
3,4-Dihydroxybenzaldehyde (3.0 g, 22 mmol) was dissolved in 14 mL of DMF, 1,2-dibromoethane (4.9 g, 26 mmol) and K2CO3 (7.2 g, 52 mmol) were added, and the mixture was stirred at 50 ° C. overnight. .The reaction solution was extracted with EtOAc, and the organic layer was washed with 1N NaOHaq. And saturated saline, dehydrated with Na2SO4,After concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: EtOAc = 3: 1) to obtain compound (1) (2.7 g, 73%). |
| 67% |
With potassium carbonate In acetone for 25h; Reflux; |
Synthesis of 2,3-dihydro-1,4-benzodioxane-6-carbaldehyde (1)
Anhydrous potassium carbonate (21 g) was added in portions to a stirred solution of 27.6 g of 3,4-dihydroxy benzaldehyde in 100 ml of dry acetone followed by the dropwise addition of 4.3 ml of ethylene dibromide. Another 21 g of potassium carbonate and 4.3 ml of ethylene dibromide were added similarly and this was repeated twice more using a total of 84 g of potassium carbonate and 17.2 g of ethylene dibromide. Stirring and refluxing was continued for another 25 h. The reaction mixture was then filtered by sintered glass funnel and the solid residue was washed several times with acetone. The combined filtrate was concentrated to about 25 ml and the residue was poured onto crushed ice, asolid was separated which was filtered, dried and crystallized with methanol to give a low melting solid; mp 35-37 °C; 67% yield; 1H NMR (300 MHz, DMSOd6): δ 4.30 (2H, d, J = 8.7 Hz, CH2-2), 4.33 (2H, d, J = 8.7, CH2-3), 7.03 (1H, d,J = 8.4 Hz, ArH-8), 7.36 (1H, d, J = 2.5 Hz, ArH-5), 7.43 (1H, dd, J = 8.4, 2.5 Hz, ArH-7), 9.79 (1H, s, Ar-CHO). |
| 63% |
With potassium carbonate In N,N-dimethyl-formamide at 100 - 110℃; |
General procedure for the synthesis of 1,4-benzodioxanes 16 and 17
General procedure: 43.80 g potassium carbonate (0.32 mol) and 15.1 cm3 1,2-dibromoethane (32.90 g, 0.18 mol) were added to a solutionof 22.00 g 13 (0.16 mol) or 26.70 g 15 (0.16 mol) in250 cm3 DMF. The reaction mixture was stirred at100-110 C for 4-8 h. After cooling to rt, the precipitatedinorganic salts were filtered and the reaction mixture wasevaporated to 80 cm3 in vacuo. The residue was pouredinto 670 cm3 water. The product was isolated as specified.2,3-Dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (16) Theaqueous phase was extracted with ethyl acetate(4 9 200 cm3), and the combined organic layer waswashed with brine and dried over Na2SO4. The crudeproduct was purified by distillation in vacuo to afford 16.Yield: 63%; white solid; m.p.: 48-49 C (Ref. [63] 49.5-50.5 C); b.p.: 105-108 C (0.3 mbar); 1H NMR(300 MHz, CDCl3): d = 9.82 (s, 1H, CHO), 7.42-7.38 (m,2H, 5-HAr and 7-HAr), 6.98 (d, J = 8.7 Hz, 1H, 8-HAr),4.35-4.28 (m, 4H, OCH2CH2O) ppm; 13C NMR (75 MHz,CDCl3): d = 64.0 (OCH2CH2O), 64.7 (OCH2CH2O), 117.8(5-CAr or 8-CAr), 118.4 (5-CAr or 8-CAr), 124.2 (7-CAr),130.7 (6-CAr), 143.9 (4a-CAr), 149.1 (8a-CAr), 190.7(CHO) ppm; IR (KBr): m = 3001, 2883, 1687, 1581, 1506,1458, 1394, 1291, 1156, 1062, 887, 777 cm-1. |
| 50% |
With sodium hydroxide In water for 1h; Heating; |
|
| 48% |
With sodium methylate In methanol for 24h; Heating; |
|
|
With potassium hydroxide |
|
|
With sodium ethanolate |
|
|
With caesium carbonate; N,N-dimethyl-formamide at 70℃; for 16h; |
8.70.3
A (5 0 g, 36 2 mmol), cesium carbonate (26 g. 72 4 mmol), 1, 2- dibromoethane (7 0 mL. 72 4 mmol) and anhydrous DMF (50 mL) were stirred at 700C for 16 h After cooling, the solvent was evaporated under reduced pressure and the residue was submitted to flash chromatography (S1O2 column eluted with CH2CI2), resulting in the isolation of 5 8 g of B. |
|
With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 16h; |
2.33
33. Preparation of Compound 115; A→B; A (5.0 g, 36.2 mmol), cesium carbonate (26 g, 72.4 mmol), 1,2-dibromoethane (7.0 mL, 72.4 mmol) and anhydrous DMF (50 mL) were stirred at 70° C. for 16 h. After cooling, the solvent was evaporated under reduced pressure and the residue was submitted to flash chromatography (SiO2 column eluted with CH2Cl2), resulting in the isolation of 5.8 g of B. |
|
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; |
18
Intermediate- 18 : 2,3-Dihydrobenzo[&] [ 1 ,4]dioxine-6-carbaldehyde:To a stirred solution of 3,4-dihydroxybenzaldehyde (55.24 g, 40.0 mmol) and K2C03 (82.65 g, 44.0 mmol) in dry DMF (250 ml) at 0 °C was added dibromoethane ( 138.2 g, 100.0 mmol) over a period of 1 h. The reaction mixture was stirred at room temperature for over night. The course of reaction was monitored with TLC. The reaction mixture was quenched with addition of ice water, the phases were separated. The reaction mixture was extracted with EtOAc (2 x 500 ml). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude brown color liquid compound was washed with NaOH solution and water to get free from the starting material. The crude liquid compound was obtained (50 g) in 76 % yield. NMR (400 MHz, CDC13): δ 9.78 (s, 1H), 7.40-7.36 (m, 2H), 6.95 (d, J = 8.8 Hz, 1H), 4.38 (m, 4H); MS (ES+) m/z 165.0 (M+l). |
|
With potassium carbonate In acetone at 70 - 80℃; for 20h; |
Synthesis of compounds with dioxygenated rings 7-10
General procedure: According to the method, 1716 we had improved this strategy. As to 8, 9, and 10, the corresponding liquid of dibromoalkane (1,2-Dibromomethane for 8, 1,3-Dibromopropane for 9, 1,4-Dibromobutane for 10; 10 mmol, 1.0 equiv) was added to 3,4-dihydroxy benazaldehyde (12mmol, 1.2 equiv) and potassium carbonate (2 g) in acetone (60 ml) with stirring at 70-80 ℃. After 20 h reflux, the reaction mixture was cooled and evaporated in reduced pressure, then poured into water and extracted with EtOAc three times. The extraction liquid was purified by a flash chromatography with EtOAc/petroleum ether. As to 7, 3,4-dihydroxy benzaldehyde (12 mmol, 1.2 equiv) dissolved in N’N-dimethylformamide (40 ml) containing potassium carbonate (2 g) and dibromomethane (10 mmol, 1.0 equiv) were heated under reflux at 70-80 ℃ overnight. The mixture was pour into ice water (160 ml) and extracted with EtOAc three times. The organic phase was purified by a flash chromatography with EtOAc/petroleum ether to give the intermediate 7. Due to a number of studies referred to the intermediate compounds 7, 8, 9, and 10, we could identify these compounds by their melting points. |
|
With potassium carbonate In acetonitrile for 24h; Reflux; |
1 4.2.1. General synthetic procedure of benzodioxole compounds (benzo[d][1,3]dioxole-5-carbaldehyde and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde)
General procedure: Equimolar portions of the appropriately protocatechuic aldehydes (50 mmol, 1 equiv) and dibromomethane or 1, 2-dibromoethane (50 mmol, 1 equiv) were dissolved in acetonitrile. The mixture was allowed to stir for several minutes at 90 °C to let dissolve. Then potassium carbonate (20.7 g, 3 equiv) was slowly added to the reaction as acid binding agent. The reaction solution was refluxed approximately 24 h. Most commonly, filtered and removed the precipitation, spin dry the solvent, extraction and recrystallization, then you will get benzodioxole compounds as reaction raw materials. |
|
With potassium carbonate In acetone for 24h; Inert atmosphere; Reflux; |
General procedure for synthesis of compounds 1-3
General procedure: In the three-necked flask under a nitrogen atmosphere, 3, 4-dihydroxybenzaldehyde (0.828 g, 6 mmol) was dissolved in dry acetone (10 ml), then added anhydrous potassium carbonate (2.5 g). After that, the acetone solution containing dibromomethane or 1,2-dibromoethane or 1,3- dibromopropane (6 mmol) was added dropwise then refluxed for 24 h. The reaction solution was evaporated reduced pressure distillation. The appropriate amount of water was added in the residue, and extracted with ethyl acetate (3×40 ml). Combined organic layer and dried with anhydrous magnesium sulfate. Then the solvent was removed by reduced pressure steam to give the crude product The crude product is purified by column chromatography [eluent: V (petroleum ether) : V (ethyl acetate) = 4: 1] to give white solid (compounds 1-3). |
|
With potassium carbonate In acetone for 24h; Inert atmosphere; Reflux; |
|
|
With sulfuric acid In acetone |
|
| 25 g |
With tetrabutylammomium bromide; sodium hydroxide In water for 5h; Reflux; |
1 Example 1 Synthesis of the compound 2,3-dihydro-1,4-benzodioxane-6-carbaldehyde.
In this step, 3,4-dihydroxybenzaldehyde was used as a starting material,And 1,2-dibromoethane in the alkaline environment for the reduction reaction, the synthesis of intermediate 2,3-dihydro-1,4-benzodioxane-6-carbaldehyde. The base used in the present reaction includes: potassium hydroxide, The condensing agent is an ammonium bromide compound such as tetrabutylammonium bromide; The molar ratio used was 3,4-dihydroxybenzaldehyde: 1,2-dibromoethane = 1: 5; The use of sodium hydroxide in excess of 5 times, under strong alkaline conditions for testing. The temperature used was the reflux temperature. |
|
With potassium carbonate at 60℃; |
4.1.2 General procedure for the preparation of 2a-2d
General procedure: A mixture of 3,4-dihydroxybenzaldehyde (3.04g, 22mM) and acetone or DMF (100mL) was stirred at room temperature until clear, and then dibromoalkane (26.4mM) and K2CO3 (3.64g, 26.4mM) were added. The mixture was heated at reflux about 60°C for 4-5h. After completion of the reaction as indicated by TLC, the solution was evaporated under reduced pressure. Then the resulting solid was poured into H2O (50mL) and extracted with ethyl acetate for column chromatography. Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether to give 2a-2d (Yield: 50-60%). |
|
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; |
3.2.1. General Procedure for the Synthesis of Compound 2a,2b
General procedure: The protocatechuic aldehyde 1a (1 mmol) was dissolved in anhydrous DMF (5 mL), anhydrouspotassium carbonate (0.5 mmol) added. The solution was then heated to 70 °Cand then dibromomethaneor 1,2-dibromoethane was added dropwise. The reaction was stirred for 4 h and poured into icewater. A white precipitate (compound 2a, 2b) was formed which was filtered and recrystallized fromethanol [33]. |
|
With potassium carbonate Reflux; |
|
|
With copper(II) oxide In dichloromethane Reflux; |
4.2. General procedure for the synthesis of benzo[d][1,3]dioxole-5-carbaldehyde (2a) or2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde(2b)
General procedure: 3,4-dihydroxybenzaldehyde (1.0 equiv) as the starting material andcopper oxide (0.1 equiv) were added into DCM. Subsequently, dibromomethane(1.5 equiv) or dibromomethane (1.5 equiv) was continuouslyadded to the mixed solution. The solution was heated to refluxfor 40 min. After the reaction was completed, the mixed solutionwas filtered, and the solvent was removed by vacuum evaporation. Theresulting product was dried to give the desired compound (2a, 2b). |
| 5.8 g |
With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 16h; |
8.70.3 (3) Preparation of Compound 115
[00298] A (5.0 g, 36.2 mmol), cesium carbonate (26 g, 72.4 mmol), 1, 2- dibromoethane (7.0 mL, 72.4 mmol) and anhydrous DMF (50 mL) were stirred at 70 °C for 16 h. After cooling, the solvent was evaporated under reduced pressure and the residue was submitted to flash chromatography (S1O2 column eluted with CH2CI2), resulting in the isolation of 5.8 g of B. |
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