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CAS No. : | 2107-69-9 | MDL No. : | MFCD00003790 |
Formula : | C11H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IHMQOBPGHZFGLC-UHFFFAOYSA-N |
M.W : | 192.21 | Pubchem ID : | 75018 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 52.47 |
TPSA : | 35.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.33 cm/s |
Log Po/w (iLOGP) : | 2.21 |
Log Po/w (XLOGP3) : | 1.61 |
Log Po/w (WLOGP) : | 1.83 |
Log Po/w (MLOGP) : | 1.03 |
Log Po/w (SILICOS-IT) : | 2.73 |
Consensus Log Po/w : | 1.88 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.23 |
Solubility : | 1.13 mg/ml ; 0.00587 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.97 |
Solubility : | 2.07 mg/ml ; 0.0108 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.37 |
Solubility : | 0.0812 mg/ml ; 0.000423 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.84 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
100% | With boron tribromide In chloroform at -78℃; for 4 h; | The global demethylation of the commercially available starting material, 5,6- dimethoxyindanone is accomplished with an excess of BBr3 in CH2CI2 to give crude 1 in 100percent yield (Scheme 1 ); this material requires no further purification to be used in the next step. |
98% | With boron tribromide In dichloromethane at -78 - 20℃; for 1 h; | To A solution OF 5, 6-DIMETHOXY-INDAN-1-ONE (40.0 g, 0.208 mol) in CH2C12 (800 mL) at- 78 C WAS added BBR3 (59.0 mL, 0.624 mol) dropwise. The dry ice bath was removed after the addition. The mixture was stirred at room temperature for 1 hour and poured into a large amount of ice/water and stirred vigorously. The pink solid was filtered, washed with water, and vacuum oven dried to give 33.3 g (98percent) of the desired product. MS (DCI/NH3) M/Z : 165.0 (M+H)+ ; IH NMR (300 MHZ, CD30D) 8 ppm 2.58-2. 61 (m, 2 H) 2.98 (t, J=5.55 Hz, 2 H) 6. 85 (s, 1 H) 7.04 (s, 1 H). |
77% | Stage #1: With boron tribromide In dichloromethane at -40 - 20℃; Stage #2: With water In dichloromethaneCooling with ice |
At about -40° C., a solution of tribromoborane (22.5 g, 89.81 mmol, 3.00 equiv.) in dichloromethane (50 mL) was added dropwise to a stirred solution of 5,6-dimethoxy-indan-1-one (5.76 g, 29.97 mmol, 1.00 equiv.) in dichloromethane (100 mL). After warming the solution to ambient temperature, the solution was stirred for about 2 hours, and then water/ice (100 mL) was added. Standard extractive workup with dichloromethane (2*30 mL) gave the title product as a red solid (3.8 g; yield=77percent). LC-MS: m/z=165 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium hydroxide In water at 25 - 30℃; for 3 h; | Example 1: Process for preparation of 5,6-dimethoxy-2-(4-pyridylmethylene)-l- indanone of formula IVTo a 1 liter round bottom flask equipped with a mechanical stirrer, thermometer pocket, addition funnel and a condenser, charged demineralized water (250ml), 5,6- dimethoxy-l-indanone (25g) and pyridine-4-carboxaldehyde (19.5g). The reaction mixture was stirred for 5 minutes at a temperature of 25°C to 30°C. To the reaction mixture then charged a solution of potassium hydroxide (5.2g) dissolved in demineralized water (125ml) slowly over period of 2 hours at a temperature of 25 °C to 30°C. The reaction mixture was further maintained at a temperature of 25°C to 30°C for 1 hour to obtain the product, 5,6-dimethoxy-2-(4-pyridylmethylene)-l- indanone. The product obtained was then filtered and washed with demineralized water. Dry the product under vacuum at a temperature of 50°C to 55°C for 10 hours. Yield: 98percentPurity: 99.71percent |
95.8% | Stage #1: With toluene-4-sulfonic acid In toluene for 6 h; Heating / reflux Stage #2: With sodium carbonate In water for 0.5 - 1 h; |
5, 6 Dimethoxy indanone (100 grams), Pyridine-4-carboxaldehyde (78.0 grams) and p-toluene sulfonic acid (138.4 grams) were suspended in toluene (1250 ml) and heated to reflux using water separator for 6 hours. The resulting mass was cooled to 25-40° C. and the solid was filtered off under suction. Further the wet solid was suspended in aqueous 10percent sodium carbonate solution (1200 ml) and stirred for 30-60 minutes. The resulting pale yellow precipitate solid was filtered off under suction, washed with water (1000 ml) and dried at a temperature of 80° C. to afford 5,6 Dimethoxy-2-(pyridin-4yl)-methylene-indan-lone (Weight: 140 grams, 95.8percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium hydroxide In water; toluene at 20℃; Inert atmosphere; Reflux | Example 4; 5,6-Dimethoxyindan-1-one (60.0 g), 1-benzylpiperidine-4-carbaldehyde (70.5 g), potassium hydroxide (13.6 g) and benzyltriethylammonium chloride (3.56 g) were suspended in a mixture of toluene (380 mL) and water (42 mL) at room temperature. Nitrogen was bubbled through the suspension for 30 minutes, and the mixture was then heated to reflux temperature. After stirring at reflux temperature for 8 hours, water was added (380 mL), and the toluene was removed from the reaction mixture by distillation. The resulting crystals were isolated by filtration to yield 140 g of Compound 1. (Yield: Quantitative; Loss on Drying: 13.3percent, 121 g). |
93.4% | With sodium methylate In methanol; ethanol at 79℃; for 1.58333 h; Heating / reflux | Example 8 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using ethanol and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of ethanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (79°C). After completion of the pouring, stirring was continued with refluxing for 1 hour and 35 minutes to complete the reaction, whereby crystals were precipitated. The crystals were precipitated during the refluxing. Then, the reaction solution was cooled to 5°C (cooling rate: 32°C/hour). The crystals precipitated at 5°C or higher were collected by filtration, washed with water (30 mL) and 6 mL of methanol and then dried at 50°C (drying time: 2 hours) to obtain 3.67 g of the crystals of the title compound (yield: 93.4percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
93.9% | With sodium methylate In methanol at 66℃; for 1 h; Heating / reflux | Example 3 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using methanol and sodium methoxide and adopting method B Into a 100-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of methanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (66°C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated (precipitation temperature: 66°C) 2 minutes after the pouring. The reaction solution was cooled to 5°C (cooling rate: 26°C/hour) with ice water and the crystals precipitated at 5°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50°C (drying time: 1 hour and 30 minutes) to obtain 3.69 g of the crystals of the title compound (yield: 93.9percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
92.9% | With sodium ethanolate In ethanol at 75 - 79℃; for 1.2 h; Heating / reflux | Example 18 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using ethanol and sodium ethoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of ethanol. After the air in the system was replaced with nitrogen, a solution of 0.85 g (12.5 mmol, 1.2 equivalents) of sodium ethoxide in 4.5 mL of ethanol was poured into the reaction solution with refluxing (75°C). After completion of the pouring, stirring was continued with refluxing (76-79°C) for 1 hour and 12 minutes to complete the reaction, whereby crystals were precipitated. The crystals were precipitated during the refluxing. Then, the reaction solution was cooled (cooling rate: 35°C/hour) and the crystals precipitated at 5°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 1 hour) to obtain 3.65 g of the crystals of the title compound (yield: 92.9percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
87.6% | With sodium methylate In tetrahydrofuran; methanol at 17 - 43℃; for 1 h; | Comparative Example 1 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine by the process described in Example 1 in patent document 3 Into a 100-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of tetrahydrofuran. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was added dropwise at 17 to 23°C. After completion of the dropwise addition, the resulting mixture was continuously stirred as it was for 1 hour. After 40 mL of water was added to the reaction solution, the resulting mixture was cooled with ice water, and the crystals precipitated were collected by filtration. The crystals collected by filtration were washed with water (50 mL) and methanol (3 mL x 2) and dried at 24-25°C for 13 hours and 40 minutes to obtain 3.46 g of the crystals of the title compound (yield: 88.10). 1H-NMR data of these crystals agreed with those obtained in Example 1. Comparative Example 2 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine by the process described in Example 2 in patent document 3 Into a 100-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of tetrahydrofuran, and 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was added dropwise thereto at 37 to 43°C. After completion of the dropwise addition, the resulting mixture was continuously stirred as it was for 1 hour. After 40 mL of water was added to the reaction solution, the resulting mixture was cooled with ice water, and the crystals precipitated were collected by filtration. The crystals collected by filtration were washed with water (50 mL) and methanol (3 mL x 2) and dried at 24-25°C for 13 hours and 40 minutes to obtain 3.44 g of the crystals of the title compound (yield: 87.6percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
84.3% | With sodium hydroxide In methanol; toluene at 65℃; for 1 h; Heating / reflux | Example 20 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium hydroxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 0.5 g (12.5 mmol, 1.2 equivalents) of sodium hydroxide was added to the reaction solution with refluxing (65°C). After completion of the addition, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was air-cooled until crystals were precipitated. After the precipitation, the reaction solution was further cooled (cooling rate: 36°C/hour) and the crystals precipitated at 4°C or higher were collected by filtration. The crystals began to be precipitated at 49°C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 2 hours and 35 minutes) to obtain 3.31 g of the crystals of the title compound (yield: 84.3percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
84% | With sodium hydroxide In methanol at 20℃; for 3 h; Inert atmosphere | A solution of 5,6-dimethoxy-indanone (5, 19 g, 0.10 mol) in methanol (8 mL) is stirred under inert atmosphere at room temperature. Slowly add NaOH flakes (12.8 g, 0.32 mol) followed by N-benzyl-piperidine-4-carboxaldehyde (4, 20.2 g, 0.10 mol) to the reaction mixture. The mixture was stirred at room temperature for 3 h and progress of the reaction was monitored by TLC (hexane:ethyl acetate; 1:1). Once the reaction is complete, the solid formed was filtered, washed with 5 percent acetic acid and then with methanol and dried. The obtained solid (34 g) was taken into a round bottom flask and refluxed with DMF (50 mL). Gradually cooled to room temperature and stirred for 2 h, filtered the solid formed, wash with chilled methanol to afford a pale yellow crystalline solid 6 (32.0 g, 84 percent); m.p.: 175-177°C. |
82.5% | With sodium methylate In methanol; ethanol; toluene at 79℃; for 1 h; Heating / reflux | Example 9 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of ethanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (ethanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (79°C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled to 3°C (cooling rate: 25°C/hour). Crystals began to be precipitated at 46°C. The crystals were collected by filtration, washed with water (30 mL) and 6 mL of methanol and then dried at 50°C (drying time: 2 hours) to obtain 3.24 g of the crystals of the title compound (yield: 82.5percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
79.9% | With sodium methylate In methanol; propan-1-ol at 71 - 90℃; for 1 h; Heating / reflux | Example 12 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using 1-propanol and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of 1-propanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at an internal temperature of 71°C. After completion of the pouring, stirring was continued with refluxing (about 90°C) for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated before the refluxing. Then, the reaction solution was cooled (cooling rate: 38°C/hour) and the crystals precipitated at 7°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 2 hours) to obtain 3.14 g of the crystals of the title compound (yield: 79.90). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
78.2% | With sodium methylate In methanol; isopropyl alcohol at 60 - 80℃; for 1 h; Heating / reflux | Example 10 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using 2-propanol and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of 2-propanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at an internal temperature of 60°C. After completion of the pouring, stirring was continued with refluxing (about 80°C) for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated (precipitation temperature: 70°C) before the refluxing. Then, the reaction solution was cooled (cooling rate: 33°C/hour) and the crystals precipitated at 7°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50°C (drying time: 2 hours) to obtain 3.07 g of the crystals of the title compound (yield: 78.20). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
76.4% | With sodium methylate In tetrahydrofuran; methanol; toluene at 79℃; for 1 h; Heating / reflux | Example 15 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of tetrahydrofuran and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (tetrahydrofuran: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (79°C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 30°C/hour) and the crystals precipitated at 4°C or higher were collected by filtration. The crystals began to be precipitated at 44°C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 2 hours and 25 minutes) to obtain 3.00 g of the crystals of the title compound (yield: 76.4percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
75.4% | With sodium methylate In methanol; toluene at 23 - 64℃; for 1 - 4.51667 h; | Example 1 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 ml of a mixed solvent (methanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 64°C. After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was air-cooled until crystals were precipitated (precipitation temperature: 45°C). After the precipitation, the reaction solution was cooled (cooling rate: 18°C/hour) and the crystals precipitated at 5°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50°C (1 hour and 20 minutes) and then at 110°C (1 hour and 10 minutes) to obtain 3.53 g of the crystals of the title compound (yield: 89.9percent). 1H-NMR (400MHz,CDCl3) δ(ppm)=1.60-1.72(4H, m), 2.03-2.09(2H, m), 2.29-2.37(1H, m), 2.92-2.95(2H, m), 3.53 (2H, s), 3.60(2H, d, J=2Hz), 3.93 (3H, s), 3.98(3H, s), 6.67(1H, dt, J=10, 2Hz), 6.90(1H, s), 7.25-7.34(6H, m) Example 2 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine 1/2 toluene solvate using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A The process of Example 1 was repeated except for conducting the drying of crystals at 50°C (1 hour and 20 minutes) only. 1 H-NMR (400MHz, CDCl3) 6 (ppm) =1 . 58-1.72 (4H, m), 2.03-2.09(2H, m), 2.28-2.38(2.5H, m), 2.91-2.94(2H, m), 3.53(2H, s), 3.59(2H, d, J=2Hz), 3.93(3H, s), 3.97(3H, s), 6.67(1H, dt, J=10, 2Hz), 6.90(1H, s), 7.13-7.33(8.5H, m) In TG-DTA (Thermogravimetry Differential Thermal Analysis) of the dried crystals, a weight loss corresponding to 1/2 toluene was recognized together with a heat absorption peak at about 100°C. In addition, these crystals and crystals obtained by further drying them at 110°C (1 hour and 10 minutes) showed different patterns, respectively, in powder X-ray diffraction.; Example 4 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 ml of a mixed solvent (methanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 61°C. After completion of the pouring, stirring was continued at 54-63°C for 1 hour to complete the reaction. Then, the reaction solution was air-cooled until crystals were precipitated (precipitation temperature: 50°C). After the precipitation of the crystals, the reaction solution was cooled (cooling rate: 25°C/hour) and the crystals precipitated at 6°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50°C (drying time: 3 hours and 10 minutes) to obtain 3.24 g of the crystals of the title compound (yield: 82.5percent). 1H-NMR data of these crystals agreed with those obtained in Example 1.; Example 5 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol : toluene = 16 : 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 50°C. After the pouring, stirring was continued at 45-53°C for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated (precipitation temperature: 48°C) 47 minutes after the pouring. After the continuous stirring at 45-53°C for 1 hour, the reaction solution was cooled (cooling rate: 22°C/hour) and the crystals precipitated at 3°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 3 hours and 10 minutes) to obtain 3.17 g of the crystals of the title compound (yield: 80.70). 1H-NMR data of these crystals agreed with those obtained in Example 1; Example 6 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 ml of a mixed solvent (methanol : toluene = 16 : 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 28°C. After completion of the pouring, stirring was continued at 23-30°C for 4 hours and 31 minutes to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated (precipitation temperature: 26°C) 1 hour after the pouring. After the continuous stirring at 23-30°C for 4 hours and 31 minutes, the reaction solution was ice-cooled (cooling rate: 18°C/hour) and the crystals precipitated at 7°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50°C (drying time: 1 hour and 23 minutes) to obtain 2.96 g of the crystals of the title compound (yield: 75.4percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
75.9% | With sodium methylate In methanol; ethyl acetate at 65 - 71℃; for 1.08333 h; Heating / reflux | Example 19 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using ethyl acetate and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of ethyl acetate. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 65°C. After completion of the pouring, stirring was continued with refluxing (about 71°C) for 1 hour and 5 minutes to complete the reaction. Crystals were precipitated during the refluxing. Then, the reaction solution was cooled (cooling rate: 31°C/hour) and the crystals precipitated at 5°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 1 hour) to obtain 2.98 g of the crystals of the title compound (yield: 75.9percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
73.1% | With sodium methylate In methanol; isopropyl alcohol; toluene at 83℃; for 1.03333 h; Heating / reflux | Example 11 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of 2-propanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (2-propanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (83°C). After completion of the pouring, stirring was continued with refluxing for 1 hour and 2 minutes to complete the reaction. Then, the reaction solution was cooled to 7°C (cooling rate: 33°C/hour). Crystals began to be precipitated at 42°C. The crystals were collected by filtration, washed with water (30 ml) and 6 mL of methanol and then dried at 50°C (drying time: 1 hour and 20 minutes) to obtain 2.87 g of the crystals of the title compound (yield: 73.1percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
72.6% | With sodium methylate In methanol; toluene at 60 - 85℃; for 1 h; Heating / reflux | Example 14 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of toluene. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 66°C. After completion of the pouring, stirring was continued with refluxing (85°C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 31°C/hour) and the crystals precipitated at 5°C or higher were collected by filtration. The crystals began to be precipitated at 37°C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 2 hours and 25 minutes) to obtain 2.85 g of the crystals of the title compound (yield: 72.60). 1H-NMR data of these crystals agreed with those obtained in Example 1.; Example 16 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol: toluene = 12: 18). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 60°C. After completion of the pouring, stirring was continued with refluxing (67°C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 26°C/hour) and the crystals precipitated at 5°C or higher were collected by filtration. The crystals began to be precipitated at 42°C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (1 hour and 20 minutes) and then at 110°C (1 hour and 5 minutes) to obtain 3.49 g of the crystals of the title compound (yield: 88.9percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. Example 17 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol : toluene = 6 : 24). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 62°C. After completion of the pouring, stirring was continued with refluxing (about 71°C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 29°C/hour) and the crystals precipitated at 7°C or higher were collected by filtration. The crystals began to be precipitated at 60°C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (1 hour and 20 minutes) and then at 100°C (1 hour and 5 minutes) to obtain 3.44 g of the crystals of the title compound (yield: 87.6percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
70% | With sodium hydroxide In methanol at 20 - 66℃; for 6 h; | Preparation of l-Benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyIlinethyl piperidine. Sodium hydroxide (1.46g) was added to methanol (150ml) followed by addition of 5,6-dimethoxy-l-indanone (5g) and l-benzylρiρeridene-4-carboxaldehyde (6.8g) at 20-30°C.The temperature of the reaction mass was gradually raised to 62-660C and was stirred for 6 hours. The reaction mass was concentrated under vacuum and 2/3 volume of the reaction mass was recovered. The remaining slurry was filtered and the product was washed with water followed by methanol to give 6.9 g of l-benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=70percent), having purity 98.5percent by HPLC. |
69.3% | With sodium methylate In tetrahydrofuran; methanol at 63℃; for 1 h; Heating / reflux | Example 7 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using tetrahydrofuran and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of tetrahydrofuran. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (63°C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled to 4°C (cooling rate: 30°C/hour). Crystals began to be precipitated at 28°C. The crystals precipitated at 4°C or higher were collected by filtration, washed with water (30 ml) and 6 mL of methanol and then dried at 50°C (drying time: 2 hours and 40 minutes) to obtain 2.72 g of the crystals of the title compound (yield: 69.3percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
63.9% | With sodium methylate In methanol; propan-1-ol; toluene at 95℃; for 1 h; Heating / reflux | Example 13 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of 1-propanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (1-propanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (95°C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled to 5°C (cooling rate: 38°C/hour). Crystals began to be precipitated at 40°C. The crystals were collected by filtration, washed with water (30 mL) and 6 mL of methanol and then dried at 50°C (drying time: 2 hours and 40 minutes) to obtain 2.51 g of the crystals of the title compound (yield: 63.9percent). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
62.9% | With sodium methylate In methanol; 1,2-dimethoxyethane at 60 - 80℃; for 1 h; Heating / reflux | Example 21 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using 1,2-dimethoxyethane and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of 1,2-dimethoxyethane. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 63°C. After completion of the pouring, stirring was continued with refluxing (80°C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 52°C/hour) and the crystals precipitated at 5°C or higher were collected by filtration. The crystals began to be precipitated at 48°C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (drying time: 2 hours and 35 minutes) to obtain 2.47 g of the crystals of the title compound (yield: 62.90). 1H-NMR data of these crystals agreed with those obtained in Example 1. Example 22 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and 1,2-dimethoxyethane and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol: 1,2-dimethoxyethane = 16 : 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28percent-sodium methoxide/methanol solution was poured into the reaction solution at 60°C. After completion of the pouring, stirring was continued with refluxing (about 68°C) for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals were precipitated during the refluxing. Then, the reaction solution was cooled (cooling rate: 26°C/hour) and the crystals precipitated at 8°C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50°C (1 hour and 20 minutes) and then at 110°C (1 hour and 30 minutes) to obtain 3.67 g of the crystals of the title compound (yield: 93.40). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
60% | With sodium methylate In methanol at 20 - 65℃; for 2 h; | Preparation of Benzyl-4-f(5, 6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine. A solution 9.8 g of sodium methoxide in 60 ml of methanol was added to a stirred solution of 25 g of 5,6-dimethoxy-l-indanone and 36.75 g 1-benzyl piperidene-4- carboxaldehyde in methanol (690ml) at 20-3 O0C. The temperature of the reaction mass was gradually raised to 60-650C and stirred for 2 hours. The precipitated solid was filtered and the product was washed with water followed by methanol to give crude product which was converted to its hydrochloride salt using methanol. The hydrochloride salt was basified using sodium hydroxide to obtain 26.9 g of 1-benzyl-4- [5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=60percent) having purity 99.92percent by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With bromine In ethyl acetate at 10 - 20℃; for 0.5h; | 1.1 Synthesis of Intermediate 12 A mixture of 96.1g compound 11 (0.5mol) was dissolved in 500ml of ethyl acetate, and slowly added dropwise bromine 80g (0.5mol) at below 10 , dropping was completed, stirring was continued holding at 20 30 Fenzhong, TLC monitoring until complete reaction, 1000ml water was added dropwise to quench the layers were separated and the organic phase was washed with saturated brine once 1000ml, dried over anhydrous sodium sulfate and concentrated to dryness to give a yellow oily liquid 135.5g (yield 98%), i.e. intermediate 12. |
84% | With bromine In methanol at 20℃; for 0.5h; | 6.1.7. 2-Bromo-5,6-dimethoxy-1-indanone 30 To a stirring solution of 5,6-dimethoxy-1-indanone 12 (10.00 g,52.03 mmol, 1 eq.) in methanol (100 mL), was added bromine(2.82 mL, 54.63 mmol, 1.05 eq.) drop-wise. After addition ofbromine the product precipitated out of solution. The mixture wasleft to stir for 30 min after which time the precipitate was filteredoff, washed with ice cold methanol (50 mL), and dried in vacuo toafford 2-bromo-5,6-dimethoxy-1-indanone 30 as a light-yellowpowder (84%) which was used as is without any further purification;Rf 0.72 (3:1 ethyl acetate: hexane); mp 162e163 C [15]; nmax(neat)/cm1 2959, 2688, 1687, 1583, 1497, 1309, 1261, 1218, 1107,1015, 727; 1H NMR (300 MHz, CDCl3); d 7.19 (s, 1H, ArH), 6.82 (s, 1H,ArH), 4.61 (dd, 1H, J 2.9 &7.3 Hz, CHBr), 3.95 (s, 3H, OCH3), 3.88 (s,3H, OCH3), 3.72 (dd, 1H, J 7.2 & 17.9 Hz, CH2aCHBr), 3.30 (dd, 1H,J 2.98 & 17.9 Hz, CH2bCHBr); 13C NMR (75 MHz, CDCl3); d 198.17,156.75, 150.19, 146.73, 126.44, 107.27, 105.24, 56.49, 56.46, 56.28,56.25, 44.70, 37.86. |
81% | With copper(ll) bromide In ethyl acetate Reflux; |
79% | With copper(I) bromide; copper(ll) bromide In chloroform; ethyl acetate Reflux; | |
79% | With copper(ll) bromide In chloroform; ethyl acetate for 3h; Reflux; | |
79% | With copper(ll) bromide In chloroform; ethyl acetate for 3h; Reflux; Inert atmosphere; Schlenk technique; | 2-Bromo-5,6-dimethoxy-1-indanone: A stirring solution of5,6-dimethoxy-1-indanone (20.0 g, 104.6 mmol, 1.0 equiv.)in an ethyl acetate/chloroform solution (50:50, 600 mL) wasBr heated to reflux. Copper (II) bromide (46.7 g, 209.2 mmol,2.0 equiv.) was added in three portions (28.0 g, 14.0 g, 4.730 g) and the mixture was stirred vigorously. Each portion wasadded after the black copper(ll) bromide changed to white copper(l) bromide. Following the final addition, the reaction solution was refluxed for a further 3 h. The resultant mixture was filtered through a plug of Celite, decolorized with activated charcoal and filtered again. The solvent was removed in vacuo and the crude product wasrecrystallized from methanol to yield 2-bromo-5,6-dimethoxy-1-indanone as an off-white solid (22.4 g, 79%). 1H NMR (400 MHz, 0D013)6: 3.27 (dd, J= 18.0, 2.8 Hz, 1H), 3.70 (dd, J= 18.0, 7.2 Hz, 1H), 3.86 (s, 3H), 3.93 (s, 3H), 4.59 (dd, J= 7.2, 2.8 Hz, 1H), 6.80 (s, 1H), 7.15 (s, 1H); 130 NMR (100 MHz, 0D013) 6: 37.7, 44.7, 56.2, 56.4, 105.0, 107.2, 126.3, 146.7, 150.0, 156.6, 198.2.MeG |
77% | With copper(ll) bromide In ethyl acetate Heating; | |
74% | With bromine In diethyl ether for 3h; Ambient temperature; | |
46% | With oxone; potassium bromide In methanol at 20℃; for 2h; | |
46% | With bromine In diethyl ether at 20℃; | |
With tetrachloromethane; bromine | ||
1.85 g | With bromine In 1,4-dioxane at 50 - 60℃; for 2h; | |
With tetra-N-butylammonium tribromide In methanol; dichloromethane at 20℃; | ||
With copper(ll) bromide In chloroform; ethyl acetate Reflux; | ||
With bromine In methanol for 0.166667h; | 6.1.20. 2-Bromo-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one 64 To a stirring solution of 5,6-dimethoxy-1-indanone 108 (2.02 g,10.49 mmol, 1.0 eq.) in methanol (25 ml) was added bromine(1.76 g, 0.57 ml, 28.8 mmol, 1.05 eq.) in a drop-wise fashion. Halfwaythrough the bromine addition, the product started precipitatingout. Upon addition of all the bromine to the reaction mixture,the slurry was left to stir for 10 min after which time the productwas filtered off andwashed with minimum cold methanol to obtainthe product, 2-bromo-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one170 (2.29 g, 81%) as a light yellow powder. The product was usedwithout any further purification. Rf 0.72 (1:3 ethyl acetate: hexane);mp 162-163 °C (literature [39] 161-162 °C); νmax (neat)/cm-1 2959, 1688, 1588, 1498, 1309, 1261, 1218; 1H NMR (300 MHz,CDCl3); δ 7.19 (s, 1H, ArH), 6.82 (s, 1H, ArH), 4.61 (dd, 1H, J 2.9 &7.3 Hz, CHBr), 3.95 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.72 (dd, 1H,J 7.2 & 17.9 Hz, CH2aCHBr), 3.30 (dd, 1H, J 2.98 & 17.9 Hz,CH2bCHBr); 13C NMR (75 MHz, CDCl3); δ 198.17, 156.75, 150.19,146.73, 126.44, 107.27, 105.24, 56.49, 56.46, 56.28, 56.25, 44.70,37.86. | |
With copper(ll) bromide In chloroform; ethyl acetate Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium tetrahydroborate In methanol at 0 - 25℃; for 3h; | |
87% | With sodium tetrahydroborate; ethanol | |
With lithium aluminium tetrahydride |
With sodium tetrahydroborate | ||
Stage #1: 5,6-dimethoxy-1-indanone With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Stage #2: With water; sodium hydrogencarbonate; ammonium chloride In tetrahydrofuran; diethyl ether | 1 Comparative Example 1; Synthesis of 5,6-diniethoxyindene [5]; [Show Image] 5,6-dimethoxyindanone (12.88 g, 67 mmol) in THF (100 ml) was added slowly to a slurry of LiAlH4 (25.9 mmol, 0.983 g) in THF (100 ml) at 0 °C. Let to warm to room temperature overnight to result in a grey suspension. Cooled to 0°C and added 0.5 g of LiAlH4. After 20 minutes water was added to the suspension dropwise very slowly to result in an exothermic reaction with bubbling and foaming. Let to stir overnight. Diluted with Et2O (200 ml) and filtered the cloudy organic phase through P4 glass filter. Extracted the inorganic phase with some extra Et2O and filtered. The combined organic phases were washed with aqueous NH4Cl (2 x 150 ml), aqueous NaHCO3 (100 ml), brine (100 ml), dried over Na2 SO4 and evaporated to leave yellow oil. Distilled and collected the fraction boiling at 155°C-165°C/~10 mmHg, 6.75g (57%) as white crystalline solid. 1H NMR (250 MHz, CDCl3): δ 3.24 - 3.42 (m, 2 H) 3.90 (s, 3 H) 3.91 (s, 3 H) 6.42 - 6.49 (m, 1 H) 6.76 - 6.83 (m, 1 H) 6.97 (s, 1 H) 7.08 (s, 1 H). | |
With sodium tetrahydroborate In methanol at 0 - 25℃; for 2h; Inert atmosphere; | ||
With sodium tetrahydroborate In methanol at 20℃; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trifluorormethanesulfonic acid In dichloromethane at 80℃; for 1h; High pressure; Inert atmosphere; Green chemistry; | 3.4. General Q-tube-Assisted Procedure General procedure: Trifluoromethane sulfonic acid (3 eq.) was gently added to a cooled (0 °C) solution of a 3-Phenylpropionic acid (0.5 mmol) in dry CH2Cl2 (1.0 mL) in a 12 mL Q-tube pressure tube, furnished by QLabtech. The temperature was raised to room temperature. A Teflon septum was placed on the top of the tube and the appropriate cap and pressure adapter were used. The mixture was heated in an oil bath at 80 °C. The reaction was monitored by TLC and GC/MS until the reactant disappeared. The mixture was poured into ice and extracted three times with CH2Cl2. The organic phase collected was dried on Na2SO4, filtered and concentrated under vacuum. The desired pure product was separated from the crude by flash chromatography. |
100% | With trifluorormethanesulfonic acid In dichloromethane at 0 - 80℃; | |
96% | With trifluorormethanesulfonic acid In dichloromethane at 0 - 80℃; for 1.5h; Sealed tube; |
95% | With methanesulfonic acid; phosphorus pentoxide at 100℃; for 0.05h; | |
87% | With phosphorus pentoxide; phosphoric acid at 40 - 60℃; Inert atmosphere; | 1 [Example 1] To a 2L 4-necked flask having a condenser, a calcium chloride tube, a nitrogen-introducing tube, a mechanical stirrer, and a thermometer, 450 g of 85% phosphoric acid was added under a nitrogen stream and stirring was initiated. To this flask, 550 g of phosphorus pentoxide was gradually added, and the mixture was stirred at 120°C to prepare 1000 g of polyphosphoric acid. After stirring for one hour, the polyphosphoric acid was cooled to 40°C and 200 g of 3-(3,4-dimethoxyphenyl)propionic acid (manufactured by Tokyo Chemical Industry, Co., Ltd.) was added, followed by stirring at 60°C. After stirring for two hours, the mixture was cooled to 40°C, and 435 g of toluene was added, and the mixture was further cooled to 30°C. Subsequently, 282 g of water and 657 g of a 25% aqueous solution of sodium hydroxide were added dropwise while maintaining the temperature at 70°C or lower, and extraction was performed while the condensing agent is decomposed, thereby the organic layer was separated. Into the separated aqueous layer, 435 g of toluene was added and the mixture was heated to 50°C and extraction was repeated. The organic layer was separated and transferred to another 2L 4-necked flask. The two organic layers thus obtained were combined and washed with 210 g of a 5% aqueous solution of sodium hydroxide. The organic layer was further washed with 10% saline and water. A crude product of 5,6-dimethoxy-1-indanone was sampled from the washed organic layer and analyzed by HPLC. As a result, the purity was 99.55% and the content of the self-condensed dimer was 0.01%. The organic layer thus obtained was subjected to distillation under reduced pressure, and toluene was distilled off until the amount of the liquid was approximately 730 mL. In the concentrated liquid thus obtained, 2g of activated carbon was added. The liquid was heated to 65°C and stirred for 30 minutes. Subsequently, the liquid was filtrated to remove the activated carbon. Further, the obtained filtrate was subjected to distillation, and toluene was distilled off until the amount of the liquid was approximately 370 mL, whereby 5,6-dimethoxy-1-indanone was crystallized out. Further, 5,6-dimethoxy-1-indanone was crystallized out by cooling the liquid to 5°C in an ice water bath. The liquid was filtrated and the crystal thus obtained was dried. As a result, 159.5 g (yield 87%) of purified crystal of 5,6-dimethoxy-1-indanone was obtained as light yellow crystalline powder. The purified product of 5,6-dimethoxy-1-indanone thus obtained was analyzed by HPLC, and it was found that the purity was 99.99% or higher and the amount of the self-condensed dimer contained was 0.01% or less. Conditions of HPLC: detector: ultraviolet absorption spectrometer (measurement wavelength: 242 nm), column: Inertsil ODS-3 (diameter of 4.6 mm x 250 mm), mobile phase: acetonitrile/methanol = 4/6), flow rate: 1.0 mL/min, column temperature: 40°C. |
87% | With phosphorus pentoxide; toluene-4-sulfonic acid at 120℃; for 0.0833333h; | 5,6-Dimethoxy-2,3-dihydro-1H-inden-1-one (4) In a round bottom flask, P2O5 (6.85 g, 36 mmol) andtoluenesulfonic acid (5.11 g, 36 mmol) was warmed to120 °C and stirred for 30 min. To the clear homogeneoussolution was added the 3-(3,4-dimethoxyphenyl)propanoicacid (0.630 g, 3.0 mmol) in one portion and the solutionwas stirred at 120 °C for 5 min. Then, ice water wasadded to the deep purple solution formed and the resultingmixture was extracted three times with dichloromethane(CH2Cl2). The combined organic layers were washedwith saturated solution of sodium bicarbonate (NaHCO3),dried with magnesium sulfate (MgSO4), filtered andconcentrated under reduced pressure. The resulting brownsolid was purified by chromatography column eluted withethylacetate/hexane (1:1, v:v) yielding 4 as a yellow solid(0.51 g) in 87% yield; mp 118-119 °C (Lit.46 116-118 °C);IR (attenuated total reflection (ATR)) ν/ cm-1 3001, 2923,2853, 1688, 1604, 1590, 1500, 1457, 1440, 1423, 1364,1309, 1264, 1245, 1211, 1188, 1175, 1156, 1118, 1074,1038, 985, 962, 847, 816, 780, 710; 1H NMR (400 MHz,CDCl3) δ 2.56-2.59 (m, 2H), 2.96 (t, 2H, 3J = 5.6 Hz), 3.82(s, 3H), 3.88 (s, 3H), 6.81 (s, 1H), 7.08 (s, 1H); 13C NMR(100 MHz, CDCl3) δ 25.6, 36.6, 56.3, 56.1, 104.3, 107.6,130.0, 149.5, 150.5, 155.5, 205.7; HRMS (ESI) m/z,observed: 193.0863 for C11H12O3 [M + H]+; required:193.0864. |
85% | Stage #1: 3,4-methoxycinnamic acid With thionyl chloride; N,N-dimethyl-formamide In dichloromethane Reflux; Stage #2: With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 1.5h; | |
80% | Stage #1: 3,4-methoxycinnamic acid With trifluoroacetic anhydride In acetonitrile at 25℃; for 0.166667h; Stage #2: With 3,4-dimethoxy-benzaldehyde In acetonitrile at 25℃; for 10h; | |
78% | With trifluorormethanesulfonic acid In dichloromethane at 80℃; for 1h; | 5,6-dimethoxyindan-1-one (S6) To a solution of S5 (2 g, 96.2 mmol) in DCM (20 ml) cooled to 0 °C in an Ace pressure flask was added TfOH (0.29 mol, 5.26 g, 3 ml), then the flask was sealed and immersed into the oil bath preheated to 80 °C. The reaction mixture was stirred vigorously at this temperature for 1 h, then cooled to RT and poured into ice water, then stirred for 20 min, and the organic phase was separated. The water phase was extracted with DCM (325 ml), combined organic extract was washed with water (50 ml), saturated NaHCO3 solution (20 ml), dried over Na2SO4 and evaporated in vacuo. The residue was recrystallized from PE 40-70 (40 ml) with an addition of DCM. The formed crystals were washed twice with 3:1 PE-EtOAc mixture (24 ml) and dried in air. Brownish-red solid, yield 78% (1.43 g). Mp 113-5 °C (lit.4 113-5 °C). 1H NMR (CDCl3, 400 MHz) δ, ppm: 2.64-2.69 m (2H), 3.02-3.07 m (2H), 3.90 s (3H, OMe), 3.96 s (3H, OMe), 6.89 s (1H), 7.18 s (1H). |
74% | With methanesulfonic acid; phosphorus pentoxide at 100℃; for 0.0833333h; | |
55% | With phosphorus pentoxide; phosphoric acid at 120℃; for 6h; | |
34% | Stage #1: 3,4-methoxycinnamic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 18h; Stage #2: With aluminum (III) chloride In dichloromethane at 20℃; for 2h; | |
With phosphorus pentachloride Behandeln des Reaktionsprodukts in Petrolaether mit AlCl3; | ||
With phosphorus pentoxide; benzene | ||
With hydrogen fluoride | ||
With water; phosphorus pentoxide; benzene | ||
With phosphoric acid; phosphorus pentoxide | ||
With PPA | ||
With phosphorus pentaoxide In benzene | 2 α-Bromo-2-carboxy-4,5-dimethoxyphenylacetic Acid Diethyl Ester (III: R5 =H, R18 and R19 =OMe and Alk=Et) EXAMPLE 2 α-Bromo-2-carboxy-4,5-dimethoxyphenylacetic Acid Diethyl Ester (III: R5 =H, R18 and R19 =OMe and Alk=Et) Phosphorus pentoxide (500 g, 3.5 mol) is added portionwise to a mechanically stirred solution of 3-(3,4-dimethoxyphenyl)propionic acid (100 g, 0.67 mol) in benzene (2500 ml) and the mixture is refluxed for 8 hr. The reaction is slowly poured into ice-water, and the benzene layer is separated and washed with 10% sodium hydroxide and water, dried and evaporated to give 5,6-dimethoxyindan-1-one (60 g), mp 100° C., described by W. H. | |
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 20 °C 2: aluminum (III) chloride / dichloromethane / 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C / Inert atmosphere 2: aluminum (III) chloride / dichloromethane / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 °C / Inert atmosphere 2: aluminum (III) chloride / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere | ||
With polyphosphoric acid at 20 - 100℃; for 2h; | ||
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 8 h / 20 °C 2: aluminum (III) chloride / dichloromethane / 3.5 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 8 h / 20 °C 2: aluminum (III) chloride / dichloromethane / 3.5 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 12 h / 20 °C 2: aluminum (III) chloride / dichloromethane / 2.5 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydroxide In ethanol; water at 20℃; | |
With potassium hydroxide; ethanol | ||
With sodium hydroxide In methanol at 20℃; |
With sodium hydroxide In methanol at 20℃; for 4h; | Compound (4c): General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (1.92 g, 0.001 mole) with 4-fluorobenzaldehyde (1.24 g, 0.001 mole) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h giving the (2E)-2-(4-fluorobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one which was then refluxed with 4-fluorophenyl semicarbazides in glacial acetic acid for 12 h furnished N,3-bis(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c). | |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In ethanol; water; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; | ||
With sodium hydroxide In ethanol at 20℃; for 5h; | General Procedure for Synthesis of Substituted 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone General procedure: An equimolar mixture of 1-indanone and various aromatic aldehydes were dissolved in ethanol (10 mL) and 30% of sodium hydroxide solution (5 mL) was added and stirred at room temperature for 5 hours. The mixture was then poured on to crushed ice and neutralized with concentrated HCl. The precipitated solid was filtered, washed with water and recrystallized from methanol to reveal the titled compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; ethanol | ||
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In methanol at 20℃; for 4h; | Compound (4c): General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (1.92 g, 0.001 mole) with 4-fluorobenzaldehyde (1.24 g, 0.001 mole) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h giving the (2E)-2-(4-fluorobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one which was then refluxed with 4-fluorophenyl semicarbazides in glacial acetic acid for 12 h furnished N,3-bis(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c). |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In ethanol; water; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; | ||
With sodium hydroxide In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium cyanide In dimethyl sulfoxide at 100℃; for 16h; | |
70% | With piperidine In water at 140℃; for 192h; | |
53% | With sodium cyanide In dimethyl sulfoxide at 145℃; |
49% | With sodium cyanide In dimethyl sulfoxide at 100℃; | |
With lithium chloride In DMF (N,N-dimethyl-formamide) at 160℃; for 60h; | 1 A mixture of 5,6dimethoxyindan-1-one Compound 1a (25 g, 0.13mol),LiCI (20 g, 0.47 mol) in DMF (200 mL) was stirred at 160 C for 60 h. Water (400 mL) was added and the mixture washed with EtOAc. The aqueous layer was acidified with 2NHCI and extracted with EtOAc (2 x 300 mL). The organic layer was washed with brine and the solvent was removed in vacuo. The crude material was purified (silica gel, DCM/MeOH, 97/3). The solvent was removed in vacuo to yield Compound1b as a light yellow solid. MS m/z 179 (M+H) +. | |
Stage #1: 5,6-dimethoxy-1-indanone With sodium cyanide In dimethyl sulfoxide at 100℃; for 48h; Stage #2: With hydrogenchloride; water | 172A Example 172 3- (4-BROMOPHENYL)-7-METHOXY-1. 4-DIHVDROINDENO F 1, 2-C1PYRAZOL-6-OL; Example 172A 5-hydroxy-6-methoxyindan-1-one 5, 6-DIMETHOXY-L-INDANONE (1 g, 5.20 mmol) and NaCN (2.55g, 52 mmol) were combined in DMSO (10 ML). The reaction was stirred at 100oC for two days, cooled, diluted with water and extracted with dichloromethane. The aqueous solution was acidified with concentrated HC1, and extracted with dichloromethane. The organic layer was dried over MGSO4 and evaporated to give the title compound (500 mg). MS (DCI/NH3) m/z: 178. 99 (M+H) +.'H NMR (500 MHz, CD2C12) 8 ppm 2.59 (t, J=5.62 Hz, 2 H) 3.01 (t, J=5.62 Hz, 2 H) 3.93 (s, 3 H) 6.33 (s, 1 H) 6.95 (s, 1 H) 7.17 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogenchloride; n-Butyl nitrite In methanol at 40℃; for 0.5h; | |
93% | With hydrogenchloride; n-Butyl nitrite In methanol; water at 40℃; for 2.5h; | 1.a a. Preparation of Compound; To a solution of 5,6-dimethoxy-l-indanone (2 g) in 40 mL MeOH was added concentrated HCl (1.04 mL). Butyl nitrite (1.34 mL, 1.1 eq.) in 10 mL MeOH was then added at 40°C and reaction mixture was allowed to stir for 2.5 hours. Reaction mixture was then cooled to room temperature and precipitate was filtered out and dried yielding a pale yellow solid (2.14 g, 93% yield). *H NMR (400MHz) (DMSO-d6) δ 12.44 (s, 1H), 7.18 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.66 (s, 2H). 13C NMR (100MHz) (DMSO-d6) δ 187.54, 155.96, 154.66, 149.29, 142.46, 130.48, 108.56, 104.49, 55.87, 55.67, 27.79. MP: 221-223°C. |
92% | With hydrogenchloride; n-Butyl nitrite In methanol at 40℃; for 0.5h; |
89% | With hydrogenchloride; n-Butyl nitrite In methanol; water at 0℃; for 0.25h; | |
81% | With hydrogenchloride; isopentyl nitrite In methanol; water at 40℃; for 0.5h; | 6.1.5. 2-Oximino-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one 13 To a solution of 5,6-dimethoxy-1-indanone 12 (1.50 g,7.82 mmol, 1.0 eq.) in methanol (25 mL) at 40 C was added 96%isopentyl nitrite (1.31 mL, 9.38 mmol, 1.2 eq.) followed by concentratedaqueous hydrochloric acid (0.78 mL, 9.38 mmol, 1.2 eq.). Thesolution was stirred for 30 min during which time a precipitateformed. The precipitatewas collected and dried to yield 2-oximino-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one 13 as a yellow solid(81%) which was used as is without any further purification; Rf 0.45(3:1 ethyl acetate: hexane); mp240 C (literature [18] 227e228 C);nmax (neat)/cm1 3189, 1694, 1579, 1498, 1449, 1304, 1233, 1119,1029, 978, 915, 801, 746; 1H NMR (300 MHz, DMSO); d 12.41 (s, 1H,NOH), 7.17 (s, 1H, ArH), 7.16 (s, 1H, ArH), 3.89 (s, 3H, OCH3), 3.82 (s,3H, OCH3), 3.64 (s, 2H, CH2); 13C NMR (75 MHz, DMSO); d 187.57,155.98, 154.71, 149.32, 142.48, 130.54, 108.57, 104.51, 56.15, 56.13,55.72, 55.69, 27.85; HRMS m/z (ESI) 292.1558 ([M H] requires292.0761). |
78% | With hydrogenchloride; isopentyl nitrite In methanol; water at 40 - 60℃; for 1h; | 2.1 (1) Synthesis of 2-hydroxyindole-1-indanone (Compound II-2) 60 g of 5,6-diethyl-1-indanone and 191 mL of methanol were added to the reaction flask.Adjust the temperature of the system to 40-60 ° C, and slowly add 37.4 g of isoamyl nitrite.After the completion of the dropwise addition, 15 mL of concentrated hydrochloric acid was slowly added, and stirring was continued for 1 hour, and the reaction was completed.The reaction is cooled to 0-10 ° C,After filtration and drying, 54 g of a gray solid was obtained in a yield of 78%. |
71% | With hydrogenchloride; isopentyl nitrite In methanol; water at 20 - 45℃; for 1h; | General synthetic procedures and characteristic data General procedure: A. General synthetic procedure for the synthesis of oxime derivatives 2, 7b-13b, and 15: To solution of 1-indanone (1, 1.32 g, 10 mmol for synthesis of 2), 3,3-dimethyl-2-indanone (7a, 1.60 g, 10 mmol for synthesis of 7b), 4-methyl-2-indanone (8a, 1.46 g, 10 mmol for synthesis of 8b), 5-methoxy-2-indanone (9a, 1.62 g, 10 mmol for synthesis of 9b), 6-methoxy-2-indanone (10a, 1.62 g, 10 mmol for synthesis of 10b), 5,6-dimethoxy-2-indanone (11a, 1.92 g, 10 mmol for synthesis of 11b), 4,5,6-trimethoxy-2-indanone (12a, 2.22 g, 10 mmol for synthesis of 12b), or 5,6-difluoro-2-indanone (13a, 1.68 g, 10 mmol for synthesis of 13b), and 2-indanone (14, 1.32 g, 10 mmol for synthesis of 15) in methanol (30 mL) was added isoamyl nitrite (1.52 g, 13 mmol) and conc. HCl (1.3 mL) at room temperature. The reaction mixture was stirred for 1-3 h at 45°C and concentrated under reduced pressure to remove the methanol. The residue was diluted with H2O, repeatedly extracted with dichloromethane (3 x 30 mL or 3 x 40 mL) and the combined extract was dried with anhydrous MgSO4 and filtered. The filtrate was evaporated to give the crude product under reduced pressure. The crude product was purified by short column chromatography using ethyl acetate/n-hexane (1:1) or recrystallized with methanol and n-hexane to obtain pure oxime derivatives 2, 7b-13b, and 15. |
49% | With hydrogenchloride; 1-nitrobutane In methanol at 40℃; for 3h; | 168 To a solution of compound (245) (6.55 g, 0.034 mol) in MeOH (50 mL) was added HC1 (3.5 mL), 1 -nitro-butane (4.68 g, 0.04 mol) in MeOH (10 mL) and the mixture was stirred at 40 °C for 3 hours. The mixture was cooled to room temperature and filtered to give compound (246) (3.65 g, 49%) as yellow solid. |
With hydrogenchloride; ethyl nitrite In tetrahydrofuran; ethanol | ||
With hydrogenchloride; n-Butyl nitrite In diethyl ether | ||
With hydrogenchloride; n-Butyl nitrite 1.) methanol, 40 deg C; 2.) methanol, 40 deg C, 0.5 h; Yield given. Multistep reaction; | ||
With hydrogenchloride; isopentyl nitrite In methanol; water at 40℃; for 1h; | ||
With hydrogenchloride; butyl nitrate In methanol; water at 40℃; for 0.5h; | ||
With hydrogenchloride; isopentyl nitrite In methanol at 40℃; for 2h; | ||
With hydrogenchloride; isopentyl nitrite In methanol at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride; sodium cyanoborohydride In tetrahydrofuran; water at 20℃; for 5h; | |
94% | With hydrogenchloride; mercury; zinc In water; toluene for 6h; Heating; | |
71% | With amalgamated zinc |
With hydrogenchloride; mercury; zinc |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In tetrahydrofuran; mineral oil Reflux; Inert atmosphere; | 3. General procedure for the acylation reactions General procedure: In a round-bottomed flask NaH 60% in grease (3 eq.) was placed. Then, it wasdissolved in dry THF (0.2 mL/mmol NaH) while stirring under argon atmosphere,forming a white suspension. Next, dimethyl carbonate (3 eq.) was added (methyl 1Himidazole-1-carboxylate in case 1i) to the suspension and the corresponding ketone (1eq.) was dissolved with dry THF (1 mL/mol ketone) in an addition funnel. The ketonesolution was added to the reaction mixture dropwise in a period of 3-5 minutes. Thereaction mixture was heated to reflux until total conversion of the reagent was observedby TLC (3-5 h). Afterwards, 1 M HCl was added to the mixture until pH = 2-3. Theaqueous mixture was then extracted with dichloromethane. The organic fraction wasdried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, the product was purified by column chromatography on silica-gel whennecessary. |
92% | With sodium hydride In paraffin oil at 90℃; | |
92% | With sodium hydride In paraffin oil at 90℃; Inert atmosphere; |
91% | With sodium hydride In tetrahydrofuran; mineral oil for 4h; Reflux; Inert atmosphere; | |
86% | With sodium methylate for 8h; Heating; | |
84% | With sodium hydride In tetrahydrofuran at 66℃; for 12h; | |
81% | With sodium hydride In tetrahydrofuran; mineral oil for 1h; Reflux; | 6.1.18. Methyl 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate 64 To a mixture of 5,6-dimethoxy-1-indanone 5 (3.00 g,15.61 mmol, 1.0 eq.) and dimethyl carbonate (14.06 g, 13.14 cm3,156.1 mmol, 10 eq.) in dry tetrahydrofuran (30 mL) was added sodium hydride (2.50 g, 62.5 mmol, 4.0 eq., 60% wt in mineral oil) at rt. The slurry obtained was refluxed for 1 h after which time the mixturewas left to cool to rt. Ethyl acetate (100 mL)was then addedand the reaction mixture was quenched with 3 M aqueous hydrochloric acid. The reaction mixture was diluted with water (50 mL).The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The organic layers werethen combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product as an orange clay. The crude clay was then re-crystallised from minimumvolume of ethanol to afford the product, rac-methyl 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate 64 (3.15 g, 12.6 mmol, 81%) as light yellow needle-like crystals. The product was then used without any further purification. Rf 0.52(3:1 ethyl acetate: hexane); mp 160 °C (literature157 161-162 °C);νmax (neat)/cm-1 2952, 1719, 1689, 1581, 1501, 1429, 1306, 1254,1189, 1019, 871, 796; 1H NMR (300 MHz, CDCl3) 7.15 (s, 1H, ArH),6.89 (s, 1H, ArH), 3.96 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.77 (s, 3H,CO2CH3), 3.71 (dd, 1H, J 3.6 & 7.9 Hz, COCHCO2Me), 3.44 (dd, 1H,J 3.5 & 17.1 Hz, CH2aCH), 3.26 (dd, 1H, J 7.9 & 17.1 Hz, CH2bCH);13C NMR (75 MHz, CDCl3) 198.02, 170.00, 156.23, 149.90, 149.35,128.04, 107.37, 104.95, 56.38, 56.23, 53.51, 52.82, 30.13; HRMS m/z(ESI) 273.0705 ([M + Na]+ requires 273.0733). |
60% | With sodium hydride In mineral oil at 90℃; | Synthesis procedure of5,6-Dimethoxy-1-oxo-indan-2-carboxylic acid methyl ester NaH (2.4 g, 60 mmol, 60% in mineral oil) was added slowly to the solutionof 5,6-dimethoxy-indane-1-one (4 g, 20 mmol) in dimethylcarbonate (22 mL). Andthe suspension was refluxed at 90 °C for 2-3 h. The resulting solid was cooledto 0 oC with an ice bath. After cooling, cold water (80mL) was added carefully. The aqueus layer was extracted with CH2Cl2(3x80 mL). The combined organic extracts were dried overNa2SO4 and concentrated. The desired product (whitesolid, % 60 yield) were obtained by recrystallizationfrom ethanol. |
50% | With sodium hydride; sodium t-butanolate In tetrahydrofuran; mineral oil at 20℃; for 16h; | |
2 g | With sodium hydride In paraffin oil at 88℃; for 2h; | Synthesis ofmethyl ester 13 To a solution of 5, 6-dimethoxy-1-indanone 11 (1.54 g, 8.0 mmol) in dimethyl carbonate (8.5mL) was added NaH (960 mg, 24.0 mmol, 60% in paraffin) at room temperature, and the mixture was stirred at 88 °C for 2 h. The resulting solid was cooled to room temperature and dichloromethane (40 mL) was added, then, neutralized by aqueous solution of 3M HCl. The organic phase was separated, and the aqueous layer was extracted with CH2Cl2(3×100 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. Recrystallization from ethanol provided methyl ester 12 (2.0 g) as pale yellow solid. The product was used directly in the next step |
With potassium <i>tert</i>-butylate; sodium hydride at 20℃; for 1h; Inert atmosphere; | General procedure for the synthesis of 2a-g. General procedure: In an ice bath, anhydrous dimethyl carbonate (30 mL) was added to a mixture of 95% NaH (3.03 g, 120 mmol) and potassiumtert-butoxide (4.2 g, 37.5 mmol). And then, a solution of indenone (30 mmol) in anhydrous dimethyl carbonate (70 mL) was added dropwise under argon. The mixture was stirred at room temperature for 1 h and adjusted pH to 2-3 with diluted HCl. The organic layers were collected and washed with brine (2 × 100 mL), dried over MgSO4, filtered and concentrated in vacuum to obtain the corresponding crude compounds 2a-g. The crude products were used in the next reaction without further purification. | |
With sodium hydride In mineral oil at 90℃; Reflux; | ||
With potassium <i>tert</i>-butylate; sodium hydride at 0℃; Inert atmosphere; | ||
With sodium hydride In tetrahydrofuran; mineral oil Inert atmosphere; Reflux; | 3. General procedures for the preparation of 1,3-dicarbonyls. General procedure: Procedure D: A round-bottom flask was charged with NaH (60% in mineral oil, 1.00 g, 25 mmol) and THF (10 mL) with vigorous stirring at 0 C. Then the corresponding ester (11 mmol) and ketone (10 mmol) were added. The suspension was heated at reflux for 16 h, cooled to room temperature, acidified with 1.0 M aqueous HCl solution, and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using petroleum ether / ethyl acetate = 10 : 1 (v / v) as eluents to give the desired product. | |
With sodium hydride In mineral oil at 90℃; | ||
With sodium hydride In mineral oil for 12h; Reflux; | ||
With sodium hydride In tetrahydrofuran; mineral oil Reflux; | 1. β-keto amides General procedure: β-keto methyl esters were prepared according to the literature procedures (Eur. J. Org. Chem.-6530;).2010, 34, 6525NaH (50 mmol, 2.5 g, 2.5 equiv., 60% dispersion in mineral oil) andanhydrous dimethyl carbonate (DMC, 5 mL)andanhydrous THF (100 mL) were addedsequentially to a dry three-necked flask equipped with a septum, condenser, argon inlet, and alarge stirring egg. The 1-indanone (20 mmol, 1 eq), solubilized in anhydrous THF (20 mL),was added via a dropping funnel for the course of 30 minutes. The heterogeneous mixturewas brought to reflux, and heated for 6 h at this temperature. The reaction was allowed to cooland cautiously quenched at 0 C with H2O (10 mL). The mixture was transferred to aseparative funnel with EtOAc while adding additional 50 mL of 1M HCl. The reaction wasextracted with EtOAc (50 mL x 3) and the combined organic layers washed with a saturatedbrine solution before being dried over solid anhydrous magnesium sulfate and the crudemethyl esters was purified by column chromatography. -keto amides 1a-1v were prepared745).according to the literature procedure (Adv. Synth. Catal. 2016, 358, 737-To a flask equipped with a reflux condenser was added -keto methyl ester (1 mmol), correspondingmmol).amidesR4NH(1.5The mixture was refluxed until complete conversion wasobserved by TLC, then concentrated under reduced pressure and the crude residue waspurified by column chromatography and recrystallization. The 1-indanone derivates werepurchased from Energy-Chemical, Aladdin and Adamas |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With rhenium(I) pentacarbonyl bromide In 1,2-dichloro-ethane for 2h; Heating; | |
40.2 g | With aluminium trichloride In dichloromethane at 20℃; for 3h; | |
With aluminum (III) chloride In dichloromethane at 20℃; for 2h; |
18.6 g | With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | |
With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 3.5h; | Synthesis procedure of 5,6-dimethoxy-indane-1-one To synthesis of 5,6-dimethoxy-indane-1-one, a solution of 3-(3,4-dimethoxy-phenyl)-propionic acid(4.98 g, 23.7 mmol) in dry dichloromethane (72.5 mL), N,N-dimethylformamide(1.39 mmol) and oxalyl chloride (8.03 mL, 95 mmol) was stirred at roomtemperature for 8 hours. The reaction mixture was concentrated byrotary evaporation. A solutionof crude 3-(3,4-dimethoxy-phenyl)-propionyl chloride in anhydrousdichloromethane (82 mL) was cooled with an icebath to 0 oC and a powder of AlCl3 (5.73 g, 43 mmol) wasadded portionwise over 30 min. The reaction was then stirred at room temperaturefor 3 h and cooled to 0 oC. Ice-water (85 mL) was added slowly in reactionmedium to quench the excess AlCl3. The layers were separated, andthe aqueous phase was extracted with four portions ofCH2Cl2 (4×85 mL). The combined organic phases were dried overNa2SO4, filtered andconcentrated by rotary evaporation. The crude solid was dissolved in ethylacetate and treated with activatedcarbon, and stirred overnight. The mixture was filtered, and the filtrate wasconcentrated. And the target compound (5,6-dimethoxy-indane-1-one)was recrystallized from ethyl acetate and obtained as yellow solid in % 75yield. | |
With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 3.5h; | ||
With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium hydroxide;N-benzyl-N,N,N-triethylammonium chloride; In water; toluene; at 20℃;Inert atmosphere; Reflux;Product distribution / selectivity; | Example 4; 5,6-Dimethoxyindan-1-one (60.0 g), 1-benzylpiperidine-4-carbaldehyde (70.5 g), potassium hydroxide (13.6 g) and benzyltriethylammonium chloride (3.56 g) were suspended in a mixture of toluene (380 mL) and water (42 mL) at room temperature. Nitrogen was bubbled through the suspension for 30 minutes, and the mixture was then heated to reflux temperature. After stirring at reflux temperature for 8 hours, water was added (380 mL), and the toluene was removed from the reaction mixture by distillation. The resulting crystals were isolated by filtration to yield 140 g of Compound 1. (Yield: Quantitative; Loss on Drying: 13.3%, 121 g). |
93.4% | With sodium methylate; In methanol; ethanol; at 79℃; for 1.58333h;Heating / reflux;Product distribution / selectivity; | Example 8 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using ethanol and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of ethanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (79C). After completion of the pouring, stirring was continued with refluxing for 1 hour and 35 minutes to complete the reaction, whereby crystals were precipitated. The crystals were precipitated during the refluxing. Then, the reaction solution was cooled to 5C (cooling rate: 32C/hour). The crystals precipitated at 5C or higher were collected by filtration, washed with water (30 mL) and 6 mL of methanol and then dried at 50C (drying time: 2 hours) to obtain 3.67 g of the crystals of the title compound (yield: 93.4%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
93.9% | With sodium methylate; In methanol; at 66℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 3 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using methanol and sodium methoxide and adopting method B Into a 100-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of methanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (66C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated (precipitation temperature: 66C) 2 minutes after the pouring. The reaction solution was cooled to 5C (cooling rate: 26C/hour) with ice water and the crystals precipitated at 5C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50C (drying time: 1 hour and 30 minutes) to obtain 3.69 g of the crystals of the title compound (yield: 93.9%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
92.9% | With sodium ethanolate; In ethanol; at 75 - 79℃; for 1.2h;Heating / reflux;Product distribution / selectivity; | Example 18 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using ethanol and sodium ethoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of ethanol. After the air in the system was replaced with nitrogen, a solution of 0.85 g (12.5 mmol, 1.2 equivalents) of sodium ethoxide in 4.5 mL of ethanol was poured into the reaction solution with refluxing (75C). After completion of the pouring, stirring was continued with refluxing (76-79C) for 1 hour and 12 minutes to complete the reaction, whereby crystals were precipitated. The crystals were precipitated during the refluxing. Then, the reaction solution was cooled (cooling rate: 35C/hour) and the crystals precipitated at 5C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 1 hour) to obtain 3.65 g of the crystals of the title compound (yield: 92.9%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
87.6 - 88.1% | With sodium methylate; In tetrahydrofuran; methanol; at 17 - 43℃; for 1h;Product distribution / selectivity; | Comparative Example 1 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine by the process described in Example 1 in patent document 3 Into a 100-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of tetrahydrofuran. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was added dropwise at 17 to 23C. After completion of the dropwise addition, the resulting mixture was continuously stirred as it was for 1 hour. After 40 mL of water was added to the reaction solution, the resulting mixture was cooled with ice water, and the crystals precipitated were collected by filtration. The crystals collected by filtration were washed with water (50 mL) and methanol (3 mL x 2) and dried at 24-25C for 13 hours and 40 minutes to obtain 3.46 g of the crystals of the title compound (yield: 88.10). 1H-NMR data of these crystals agreed with those obtained in Example 1. Comparative Example 2 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine by the process described in Example 2 in patent document 3 Into a 100-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of tetrahydrofuran, and 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was added dropwise thereto at 37 to 43C. After completion of the dropwise addition, the resulting mixture was continuously stirred as it was for 1 hour. After 40 mL of water was added to the reaction solution, the resulting mixture was cooled with ice water, and the crystals precipitated were collected by filtration. The crystals collected by filtration were washed with water (50 mL) and methanol (3 mL x 2) and dried at 24-25C for 13 hours and 40 minutes to obtain 3.44 g of the crystals of the title compound (yield: 87.6%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
84.3% | With sodium hydroxide; In methanol; toluene; at 65℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 20 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium hydroxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 0.5 g (12.5 mmol, 1.2 equivalents) of sodium hydroxide was added to the reaction solution with refluxing (65C). After completion of the addition, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was air-cooled until crystals were precipitated. After the precipitation, the reaction solution was further cooled (cooling rate: 36C/hour) and the crystals precipitated at 4C or higher were collected by filtration. The crystals began to be precipitated at 49C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 2 hours and 35 minutes) to obtain 3.31 g of the crystals of the title compound (yield: 84.3%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
84% | With sodium hydroxide; In methanol; at 20℃; for 3h;Inert atmosphere; | A solution of 5,6-dimethoxy-indanone (5, 19 g, 0.10 mol) in methanol (8 mL) is stirred under inert atmosphere at room temperature. Slowly add NaOH flakes (12.8 g, 0.32 mol) followed by N-benzyl-piperidine-4-carboxaldehyde (4, 20.2 g, 0.10 mol) to the reaction mixture. The mixture was stirred at room temperature for 3 h and progress of the reaction was monitored by TLC (hexane:ethyl acetate; 1:1). Once the reaction is complete, the solid formed was filtered, washed with 5 % acetic acid and then with methanol and dried. The obtained solid (34 g) was taken into a round bottom flask and refluxed with DMF (50 mL). Gradually cooled to room temperature and stirred for 2 h, filtered the solid formed, wash with chilled methanol to afford a pale yellow crystalline solid 6 (32.0 g, 84 %); m.p.: 175-177C. |
82.5% | With sodium methylate; In methanol; ethanol; toluene; at 79℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 9 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of ethanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (ethanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (79C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled to 3C (cooling rate: 25C/hour). Crystals began to be precipitated at 46C. The crystals were collected by filtration, washed with water (30 mL) and 6 mL of methanol and then dried at 50C (drying time: 2 hours) to obtain 3.24 g of the crystals of the title compound (yield: 82.5%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
79.9% | With sodium methylate; In methanol; propan-1-ol; at 71 - 90℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 12 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using 1-propanol and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of 1-propanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at an internal temperature of 71C. After completion of the pouring, stirring was continued with refluxing (about 90C) for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated before the refluxing. Then, the reaction solution was cooled (cooling rate: 38C/hour) and the crystals precipitated at 7C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 2 hours) to obtain 3.14 g of the crystals of the title compound (yield: 79.90). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
78.20% | With sodium methylate; In methanol; isopropyl alcohol; at 60 - 80℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 10 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using 2-propanol and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of 2-propanol. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at an internal temperature of 60C. After completion of the pouring, stirring was continued with refluxing (about 80C) for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated (precipitation temperature: 70C) before the refluxing. Then, the reaction solution was cooled (cooling rate: 33C/hour) and the crystals precipitated at 7C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50C (drying time: 2 hours) to obtain 3.07 g of the crystals of the title compound (yield: 78.20). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
76.4% | With sodium methylate; In tetrahydrofuran; methanol; toluene; at 79℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 15 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of tetrahydrofuran and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (tetrahydrofuran: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (79C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 30C/hour) and the crystals precipitated at 4C or higher were collected by filtration. The crystals began to be precipitated at 44C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 2 hours and 25 minutes) to obtain 3.00 g of the crystals of the title compound (yield: 76.4%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
75.4 - 89.9% | With sodium methylate; In methanol; toluene; at 23 - 64℃; for 1 - 4.51667h;Product distribution / selectivity; | Example 1 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 ml of a mixed solvent (methanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 64C. After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was air-cooled until crystals were precipitated (precipitation temperature: 45C). After the precipitation, the reaction solution was cooled (cooling rate: 18C/hour) and the crystals precipitated at 5C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50C (1 hour and 20 minutes) and then at 110C (1 hour and 10 minutes) to obtain 3.53 g of the crystals of the title compound (yield: 89.9%). 1H-NMR (400MHz,CDCl3) delta(ppm)=1.60-1.72(4H, m), 2.03-2.09(2H, m), 2.29-2.37(1H, m), 2.92-2.95(2H, m), 3.53 (2H, s), 3.60(2H, d, J=2Hz), 3.93 (3H, s), 3.98(3H, s), 6.67(1H, dt, J=10, 2Hz), 6.90(1H, s), 7.25-7.34(6H, m) Example 2 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine 1/2 toluene solvate using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A The process of Example 1 was repeated except for conducting the drying of crystals at 50C (1 hour and 20 minutes) only. 1 H-NMR (400MHz, CDCl3) 6 (ppm) =1 . 58-1.72 (4H, m), 2.03-2.09(2H, m), 2.28-2.38(2.5H, m), 2.91-2.94(2H, m), 3.53(2H, s), 3.59(2H, d, J=2Hz), 3.93(3H, s), 3.97(3H, s), 6.67(1H, dt, J=10, 2Hz), 6.90(1H, s), 7.13-7.33(8.5H, m) In TG-DTA (Thermogravimetry Differential Thermal Analysis) of the dried crystals, a weight loss corresponding to 1/2 toluene was recognized together with a heat absorption peak at about 100C. In addition, these crystals and crystals obtained by further drying them at 110C (1 hour and 10 minutes) showed different patterns, respectively, in powder X-ray diffraction.; Example 4 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 ml of a mixed solvent (methanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 61C. After completion of the pouring, stirring was continued at 54-63C for 1 hour to complete the reaction. Then, the reaction solution was air-cooled until crystals were precipitated (precipitation temperature: 50C). After the precipitation of the crystals, the reaction solution was cooled (cooling rate: 25C/hour) and the crystals precipitated at 6C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 ml) and 6 mL of methanol and dried at 50C (drying time: 3 hours and 10 minutes) to obtain 3.24 g of the crystals of the title compound (yield: 82.5%). 1H-NMR data of these crystals agreed with those obtained in Example 1.; Example 5 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol : toluene = 16 : 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 50C. After the pouring, stirring was continued at 45-53C for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals began to be precipitated (precipitation temperature: 48C) 47 minutes after the pouring. After the continuous stirring at 45-53C for 1 hour, the reaction solution was cooled (cooling rate: 22C/hour) and the crystals precipitated at 3C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 3 hours and 10 minutes) to obtain 3.17 g of the crystals of the title compound (yield: 80.70). 1H-NMR data of these crystals agreed with those obtained in Example 1; Example 6 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium me... |
75.9% | With sodium methylate; In methanol; ethyl acetate; at 65 - 71℃; for 1.08333h;Heating / reflux;Product distribution / selectivity; | Example 19 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using ethyl acetate and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of ethyl acetate. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 65C. After completion of the pouring, stirring was continued with refluxing (about 71C) for 1 hour and 5 minutes to complete the reaction. Crystals were precipitated during the refluxing. Then, the reaction solution was cooled (cooling rate: 31C/hour) and the crystals precipitated at 5C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 1 hour) to obtain 2.98 g of the crystals of the title compound (yield: 75.9%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
73.1% | With sodium methylate; In methanol; isopropyl alcohol; toluene; at 83℃; for 1.03333h;Heating / reflux;Product distribution / selectivity; | Example 11 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of 2-propanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (2-propanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (83C). After completion of the pouring, stirring was continued with refluxing for 1 hour and 2 minutes to complete the reaction. Then, the reaction solution was cooled to 7C (cooling rate: 33C/hour). Crystals began to be precipitated at 42C. The crystals were collected by filtration, washed with water (30 ml) and 6 mL of methanol and then dried at 50C (drying time: 1 hour and 20 minutes) to obtain 2.87 g of the crystals of the title compound (yield: 73.1%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
72.6 - 88.9% | With sodium methylate; In methanol; toluene; at 60 - 85℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 14 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of toluene. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 66C. After completion of the pouring, stirring was continued with refluxing (85C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 31C/hour) and the crystals precipitated at 5C or higher were collected by filtration. The crystals began to be precipitated at 37C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 2 hours and 25 minutes) to obtain 2.85 g of the crystals of the title compound (yield: 72.60). 1H-NMR data of these crystals agreed with those obtained in Example 1.; Example 16 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol: toluene = 12: 18). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 60C. After completion of the pouring, stirring was continued with refluxing (67C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 26C/hour) and the crystals precipitated at 5C or higher were collected by filtration. The crystals began to be precipitated at 42C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (1 hour and 20 minutes) and then at 110C (1 hour and 5 minutes) to obtain 3.49 g of the crystals of the title compound (yield: 88.9%). 1H-NMR data of these crystals agreed with those obtained in Example 1. Example 17 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol : toluene = 6 : 24). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 62C. After completion of the pouring, stirring was continued with refluxing (about 71C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 29C/hour) and the crystals precipitated at 7C or higher were collected by filtration. The crystals began to be precipitated at 60C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (1 hour and 20 minutes) and then at 100C (1 hour and 5 minutes) to obtain 3.44 g of the crystals of the title compound (yield: 87.6%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
70% | With sodium hydroxide; In methanol; at 20 - 66℃; for 6h;Product distribution / selectivity; | Preparation of l-Benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyIlinethyl piperidine. Sodium hydroxide (1.46g) was added to methanol (150ml) followed by addition of 5,6-dimethoxy-l-indanone (5g) and l-benzylrhoirhoeridene-4-carboxaldehyde (6.8g) at 20-30C.The temperature of the reaction mass was gradually raised to 62-660C and was stirred for 6 hours. The reaction mass was concentrated under vacuum and 2/3 volume of the reaction mass was recovered. The remaining slurry was filtered and the product was washed with water followed by methanol to give 6.9 g of l-benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=70%), having purity 98.5% by HPLC. |
69.3% | With sodium methylate; In tetrahydrofuran; methanol; at 63℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 7 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using tetrahydrofuran and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of tetrahydrofuran. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (63C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled to 4C (cooling rate: 30C/hour). Crystals began to be precipitated at 28C. The crystals precipitated at 4C or higher were collected by filtration, washed with water (30 ml) and 6 mL of methanol and then dried at 50C (drying time: 2 hours and 40 minutes) to obtain 2.72 g of the crystals of the title compound (yield: 69.3%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
63.9% | With sodium methylate; In methanol; propan-1-ol; toluene; at 95℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 13 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of 1-propanol and toluene and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (1-propanol: toluene = 16: 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution with refluxing (95C). After completion of the pouring, stirring was continued with refluxing for 1 hour to complete the reaction. Then, the reaction solution was cooled to 5C (cooling rate: 38C/hour). Crystals began to be precipitated at 40C. The crystals were collected by filtration, washed with water (30 mL) and 6 mL of methanol and then dried at 50C (drying time: 2 hours and 40 minutes) to obtain 2.51 g of the crystals of the title compound (yield: 63.9%). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
62.9 - 93.4% | With sodium methylate; In methanol; 1,2-dimethoxyethane; at 60 - 80℃; for 1h;Heating / reflux;Product distribution / selectivity; | Example 21 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using 1,2-dimethoxyethane and sodium methoxide and adopting method A Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 30 mL of 1,2-dimethoxyethane. After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 63C. After completion of the pouring, stirring was continued with refluxing (80C) for 1 hour to complete the reaction. Then, the reaction solution was cooled (cooling rate: 52C/hour) and the crystals precipitated at 5C or higher were collected by filtration. The crystals began to be precipitated at 48C. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (drying time: 2 hours and 35 minutes) to obtain 2.47 g of the crystals of the title compound (yield: 62.90). 1H-NMR data of these crystals agreed with those obtained in Example 1. Example 22 Production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methylpiperidine using a mixed solvent of methanol and 1,2-dimethoxyethane and sodium methoxide and adopting method B Into a 50-mL four-necked flask were charged 2.0 g (10.4 mmol) of 5,6-dimethoxy-1-indanone, 2.5 g (12.3 mmol, 1.2 equivalents) of 1-benzyl-4-formylpiperidine and 24 mL of a mixed solvent (methanol: 1,2-dimethoxyethane = 16 : 14). After the air in the system was replaced with nitrogen, 2.4 g (12.4 mmol, 1.2 equivalents) of a 28%-sodium methoxide/methanol solution was poured into the reaction solution at 60C. After completion of the pouring, stirring was continued with refluxing (about 68C) for 1 hour to complete the reaction, whereby crystals were precipitated. The crystals were precipitated during the refluxing. Then, the reaction solution was cooled (cooling rate: 26C/hour) and the crystals precipitated at 8C or higher were collected by filtration. The crystals collected by filtration were washed with water (30 mL) and 6 mL of methanol and dried at 50C (1 hour and 20 minutes) and then at 110C (1 hour and 30 minutes) to obtain 3.67 g of the crystals of the title compound (yield: 93.40). 1H-NMR data of these crystals agreed with those obtained in Example 1. |
60% | With sodium methylate; In methanol; at 20 - 65℃; for 2h;Product distribution / selectivity; | Preparation of Benzyl-4-f(5, 6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine. A solution 9.8 g of sodium methoxide in 60 ml of methanol was added to a stirred solution of 25 g of 5,6-dimethoxy-l-indanone and 36.75 g 1-benzyl piperidene-4- carboxaldehyde in methanol (690ml) at 20-3 O0C. The temperature of the reaction mass was gradually raised to 60-650C and stirred for 2 hours. The precipitated solid was filtered and the product was washed with water followed by methanol to give crude product which was converted to its hydrochloride salt using methanol. The hydrochloride salt was basified using sodium hydroxide to obtain 26.9 g of 1-benzyl-4- [5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=60%) having purity 99.92% by HPLC. |
This reaction took place in argon atmosphere. 2.05 ml diisopropylamine was added to 10 ml anhydrous THF and 9.12 ml 1.6M n-butyllithium hexane solution was further added at 0 C. The resultant was stirred at 0 C. for 10 minutes, cooled to -78 C., and added with 2.55 g 5,6-dimethoxy-1-indanone in 30 ml anhydrous THF solution and 2.31 ml hexamethyl phosphoramide. The resultant was stirred at -78 C. for 15 minutes, added with 2.70 g 1-benzyl-4-piperidinecarboaldehyde obtained in (a) in 30 ml anhydrous THF solution, and gradually heated to room temperature. Again stirring at room temperature for another 2 hours, 1% ammonium chloride solution was added to separate the organic layer. Next, the aqueous layer was extracted with ethyl acetate, combined with the organic layer separated above, and washed with saturated saline. The solution was dried with magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified through a silica gel column (methylene chloride:methanol=500:1 to 100:1). After concentrating the eluate under reduced pressure, the resultant was dissolved in methylene chloride, added with 10% hydrochloric acid-ethyl acetate solution, and further concentrated under reduced pressure to obtain a crystal. This was recrystallized from methylene chloride-IPE to obtain 3.40 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine hydrochloride (yield 62%) having the following properties: Melting point ( C.); 237-238 (dec.) Elementary analysis; as C24H27NO3 HCl, CHN calculated (%): 69.64 6.82 3.38, found (%): 69.51 6.78 3.30. | ||
With sodium methylate; hydroquinone; In methanol; toluene; at 55 - 70℃; for 0.5h; | EXAMPLE Step A: Preparation 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl] Methylpiperidine Toluene Solvate (Dehydrodonepezil Toluene Solvate) 5,6-Dimethoxy-1-indanone (100 g, 0.52 mol) and hydroquinone (0.5 g) were suspended in toluene (500 ml) and heated to 55-60 C. under nitrogen atmosphere. 1-Benzyl-4-piperidinecarboxaldehyde (130 g, 0.64 mol) was added followed by methanolic sodium methoxide solution [prepared by dissolving sodium methoxide (57 g, 1.06 mol) in methanol (200 ml)] to the reaction mass at 55-60 C. After stirring at 66-70 C. for 30 minutes, the reaction mass was cooled to 5 C. and water (500 ml) was added. The pH of the reaction was adjusted to 7.8 with concentrated hydrochloric acid under cooling. The resulting product was filtered and washed with water (250 ml) followed by methanol (200 ml) to obtain dehydrodonepezezil (203 g) as a toluene solvate with a HPLC purity of 99.5%. [Toluene content: 10% w/w as determined by its LOD on 1 g of sample at 105 C.]. 1H NMR (300 MHz, CDCl3) 1.57-1.72 (m, 4 H), 2.02-2.10 (m, 2H), 2.28-2.35 (m, 1 H) 2.91-2.95 (brd, 2H), 3.53 (S, 2H), 3.59 (S, 2H), 3.93 (S, 3H), 3.98 (S, 3H) 6.66 (dt, 1H, 9.6 Hz, 1.92 Hz), 6.90 (S, 1H), 7.29 (S, 1H), 7.13-7.34 (m, 5H) [Signals due to toluene are observed at 2.35 (S), 7.17 (m) and 7.25 (m)] | |
With sodium hydroxide; In tetrahydrofuran; at 20 - 70℃; for 3h; | Example-1; Preparation of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (II).6.5 gm of sodium hydroxide was added to 50 ml of tetrahydrofuran at room temperature. The mixture was stirred at room temperature for 30 minutes and then 5.0 gm of 5,6-dimethoxy-l- indanone & 6.5 gm of 1 -benzyl-4-piperidine carboxaldehyde were added thereto. The mixture was heated to reflux and stirred at reflux temperature (65 C- 70 C) for 3 hours. The tetrahydrofuran was completely distilled off from resulting mass under vacuum below 50 C. Isopropyl alcohol was added to the residue at 45 C- 50 Cand the content were then cooled to 25 C- 30 C and stirred for 1 hour at 25 C- 30 C. Solution is further cooled to 0-50C and stirred for 3 hours at 0-50C. The separated solid was filtered off under suction, washed with chilled isopropyl alcohol (25 ml) and dried the material at 30 C- 35 C for 5 hours to afford l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2- ylidenyl] methyl piperidine (II) ( weight: 8.0 gm) and purity is 97.04%. | |
At about 0 C. and under an atmosphere of argon, a solution of n-butyllithium in hexane (2.5 M, 3.7 mL, 1.12 equiv.) was added dropwise to a solution of diisopropylamine (930 mg, 9.19 mmol, 1.12 equiv.) in tetrahydrofuran (10 mL). The resulting solution was stirred at about 0 C. for about 10 minutes. After cooling the solution to about -78 C., a solution of 5,6-dimethoxyindan-1-one (1.58 g, 8.22 mmol, 1.00 equiv.) and hexamethylphosphoramide (1.47 g, 8.20 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL) was added dropwise. The solution was stirred at about -78 C. for about 15 minutes, and then a solution of 1-benzyl-piperidine-4-carbaldehyde (1 g, 4.92 mmol, 0.60 equiv.) in tetrahydrofuran (10 mL) was added. After warming the solution to ambient temperature, the solution was stirred at ambient temperature for about 2 hours and then an aqueous solution of ammonium chloride (1%) was added. The resulting precipitant was collected by filtration, and then dried in an oven in vacuo to afford the tittle product as a solid (2 g), which was used in the next step without further purification. LC-MS: m/z=378 (MH)+. | ||
This reaction took place in argon atmosphere. 2.05 ml diisopropylamine was added to 10 ml anhydrous THF and 9.12 ml 1.6M n-butyllithium hexane solution was further added at 0 C. The resultant was stirred at 0 C. for 10 minutes, cooled to -78 C., and added with 2.55 g 5,6-dimethoxy-1-indanone in 30 ml anhydrous THF solution and 2.31 ml hexamethyl phosphoramide. The resultant was stirred at -78 C. for 15 minutes, added with 2.70 g 1-benzyl-4-piperidinecarboaldehyde obtained in (a) in 30 ml anhydrous THF solution, and gradually heated to room temperature. Again stirring at room temperature for another 2 hours, 1% ammonium chloride solution was added to separate the organic layer. Next, the aqueous layer was extracted with ethyl acetate, combined with the organic layer separated above, and washed with saturated saline. The solution was dried with magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified through a silica gel column (methylene chloride: methanol 500:1 to 100:1). After concentrating the eluate under reduced pressure, the resultant was dissolved in methylene chloride, added with 10% hydrochloric acid-ethyl acetate solution, and further concentrated under reduced pressure to obtain a crystal. This was recrystallized from methylene chloride-IPE to obtain 3.40 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine hydrochloride (yield 62%) having the following properties: Melting point ( C.); 237-238 (dec.) Elementary analysis; as C24H27NO3 HCl, CHN calculated (%): 69.64 6.82 3.38, found (%): 69.51 6.78 3.30. | ||
This reaction took place in argon atmosphere. 2.05 ml diisopropylamine was added to 10 ml anhydrous THF and 9.12 ml 1.6M n-butyllithium hexane solution was further added at 0C. The resultant was stirred at 0C for 10 minutes, cooled to -78C, and added with 2.55 g 5,6-dimethoxy-1-indanone in 30 ml anhydrous THF solution and 2.31 ml hexamethyl phosphoramide. The resultant was stirred at -78C for 15 minutes, added with 2.70 g 1-benzyl-4-piperidinecarboaldehyde obtained in (a) in 30 ml anhydrous THF solution, and gradually heated to room temperature. Again stirring at room temperature for another 2 hours, 1% aqueous ammonium chloride solution was added to separate the organic layer. Next, the aqueous layer was extracted with ethyl acetate, combined with the organic layer separated above, and washed with saturated saline. The solution was dried with magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified through a silica gel column (methylene chloride: methanol = 500:1 to 100:1). After concentrating the eluate under reduced pressure, the resultant was dissolved in methylene chloride, added with 10% hydrochloric acid-ethyl acetate solution, and further concentrated under reduced pressure to obtain a crystal. This was recrystallized from methylene chloride-IPE to obtain 3.40 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine hydrochloride (yield 62%) having the following properties: Melting point (C); 237-238 (dec.)Elementary analysis; as C24H27NO3 HCl, CHN calculated (%): 69.64 6.82 3.38, found (%): 69.51 6.78 3.30. | ||
Example 1: Preparation of l-Benzyl-4-(5,6-Dimethoxy-l-indanone)-2- ylidenyl) methyl piperidine hydrochloride1 -Benzyl piperidine-4-carboxaldehyde (150.0 g) was added to 5, 6-dimethoxy- l - indanone (l OOg) dissolved in methylene chloride (1000 mL) and the reaction mixture was stirred for 15 minutes at 25-30C for dissolution. The reaction mixture was cooled to 0-5C, potassium hydroxide dissolved in methanol solution (48.0 g in 200 ml methanol) was added to it over a period of 30-60 minutes and stirred for 30 minutes at 0-5C. The temperature of the reaction mass was raised to 25-30C and the stirring was continued for 2 hours. After the completion of the reaction, purified water (300mL) was added and the mixture was stirred for 15 minutes. The pH of the reaction mass was adjusted to 6.5-7.5 with concentrated hydrochloric acid at 25-30C and stirred for 30 minutes. The layers were separated and the organic layer was extracted with methylene chloride. The methylene chloride layer was washed with purified water, treated with activated carbon ( l Og) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloric acid. The organic layer was distilled under vacuum, methanol (200 mL) was added to the residue and stirred for 15 minutes followed by the addition of acetone (1000 mL) and the stirring was continued for 3 hours at 25-30C. The compound was filtered and washed with acetone to obtain a wet cake, which was dissolved in methanol (200 mL), followed by the addition of acetone (600 mL) and stirring was continued for 3 hours. The mixture was filtered, washed with acetone (200 mL) and dried at 60-65C to obtain the title compound/ Dry weight: 195.g)(% Yield: 91.3%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With zinc In benzene for 4h; Heating; | |
64% | With zinc In tetrahydrofuran at 70℃; for 1h; Sealed tube; | 2 Example 2: Preparation of compound of formula (VI-64) In a sealed vial, known compound of formula (VII-64) (WO2008073452) (1.5 g, 7.8 mmol) was dissolved in tetrahydrofuran (15 mL) and ethyl 2-bromoacetate (2.6 g, 16 mmol) follow by Zinc (1.5 g, 23 mmol) was added. The resulting brown suspension was then heated to 70°C, stirred for 1 hour and quenched with a saturated aqueous NhUCI solution. 5 imL of an aqueous HCI (4N) solution was added and the reaction mixture was stirred for 5 minutes at room temperature. The phases were then separated follow by extraction with ethyl acetate and the combined organic fractions were dried over sodium sulfate and concentrated under vacuum. The resulting crude residue was purify by flash chromatography on silica gel and compound of formula (VI-64) was isolated in 64% yield (1.3 g, 5.0 mmol). LCMS: RT 1.01 min; ES+ 263 (M+H+); NMR (400 MHz, CDCIs): δ ppm 7.00 (s, 1 H), 6.85 (s, 1 H), 6.12 (m, 1 H), 4.22 (q, 2H), 3.88 (s, 3H), 3.92 (s, 3H), 3.30 (m, 2H), 3.02 (m, 2H), 1.33 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine; palladium diacetate; tetrabutyl-ammonium chloride In N,N-dimethyl-formamide at 100℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 65% 2: 5% | With terbium(III) trifluoromethanesulfonate In chlorobenzene at 250℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid In toluene for 6h; Reflux; | 2.1. (E)-5,6-Dimethoxy-2-[(4-pyridyl)methylene]-1-indanone A solution of 5,6-dimethoxy-1-indanone (20.0 g, 104 mmol) in toluene (250 mL) was treated withpyridine-4-carboxaldehyde (13.7 mL, 15.4 g, 144 mmol) and p-TsOH·H2O (30.4 g, 160 mmol).The reaction mixture was heated under reflux for 6 h, allowed to cool to r.t. and filtered. The solidwas washed with 10% aq. NaHCO3 (400 mL) and H2O (400 mL) and dried at 50 °C/20 Torr to give 8(28.5 g, 98% yield) as a yellow solid, whose IR, 1H- and 13C-NMR data coincided with thosepreviously reported [4]. |
95.6% | With toluene-4-sulfonic acid In toluene for 6h; Heating; | |
90% | With toluene-4-sulfonic acid In toluene for 6h; Reflux; | 4.1.1. (E)-5, 6-dimethoxy-2-(pyridin-4-ylmethylene)-2, 3-dihydro-1H-inden-1-one (3) A mixture of 5, 6-dimethoxy-indan-1-one (10 g), pyridine-4-carboxaldehyde (7.8 g), p-toluenesulphonic acid (13.8 g) intoluene (120 ml) was refluxed for 6 h. The reaction mixture wascooled to room temperature and filtered. The wet solid so obtainedwas stirred with 10% aqueous sodium carbonate solution. The solidwas filtered, washed with acetone and then dried to get the titlecompound as a yellow solid. Yield 90%; ESI/MS m/z: 282.3 [MH]1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 8.69(d, J 6.0 Hz, 2H), 7.68 (d, J 6.0 Hz, 2H), 7.38 (s, 1H), 7.24 (s, 1H),7.21 (s, 1H), 4.05 (s, 2H), 3.92 (s, 3H), 3.84 (s, 3H). |
76% | With toluene-4-sulfonic acid In toluene for 4h; Reflux; Dean-Stark; | |
75% | With sodium hydroxide In ethanol; water at 0℃; | General procedure A (Aldolic condensation) General procedure: Benzaldehyde (3.0 mmol) was added to a well-stirred solution of benzocycloalkan-1-one (3.0 mmol) and NaOH/H2O 10% (1.6 mL) in ethanol (1.6 mL). After the mixture was stirred at ice bath or room temperature for 2-4 h, the solid was filtered and washed with water. 2-Arylidenebenzocycloalkan-1-ones 7a, 7b, 8, 12a, 16a, 17a, and 17b were prepared as per the mentioned procedure and identified by m.p. and 1H NMR spectra. |
69% | With sodium ethanolate In tetrahydrofuran at 20℃; for 16h; | |
With toluene-4-sulfonic acid In toluene for 6h; Heating / reflux; | 1 A mixture of 5,6-dimethoxy-indan-l-one (1Og), pyridine-4-carboxaldehyde (7.8g), p- toluenesulphonic acid (13.8g) in toluene (120ml) was refluxed azeotropically for 6 hours. The reaction mixture was cooled to room temperature and filtered. The wet solid so obtained was stirred with 10% aqueous sodium carbonate solution. The solid was filtered, washed with acetone and then dried to get the title compound (13.2g). | |
With sodium hydroxide In methanol at 20℃; for 4h; | Compound (4c): General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (1.92 g, 0.001 mole) with 4-fluorobenzaldehyde (1.24 g, 0.001 mole) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h giving the (2E)-2-(4-fluorobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one which was then refluxed with 4-fluorophenyl semicarbazides in glacial acetic acid for 12 h furnished N,3-bis(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c). | |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In methanol; Petroleum ether at 20℃; for 4h; | ||
With toluene-4-sulfonic acid In toluene Reflux; | ||
With sodium hydroxide In ethanol | ||
With sodium hydroxide In ethanol at 20℃; for 5h; | General Procedure for Synthesis of Substituted 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone General procedure: An equimolar mixture of 1-indanone and various aromatic aldehydes were dissolved in ethanol (10 mL) and 30% of sodium hydroxide solution (5 mL) was added and stirred at room temperature for 5 hours. The mixture was then poured on to crushed ice and neutralized with concentrated HCl. The precipitated solid was filtered, washed with water and recrystallized from methanol to reveal the titled compounds. | |
7.39 g | With toluene-4-sulfonic acid In toluene for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With boron tribromide; In chloroform; at -78℃; for 4.0h; | The global demethylation of the commercially available starting material, 5,6- dimethoxyindanone is accomplished with an excess of BBr3 in CH2CI2 to give crude 1 in 100% yield (Scheme 1 ); this material requires no further purification to be used in the next step. |
98% | With boron tribromide; In dichloromethane; at -78 - 20℃; for 1.0h; | To A solution OF 5, 6-DIMETHOXY-INDAN-1-ONE (40.0 g, 0.208 mol) in CH2C12 (800 mL) at- 78 C WAS added BBR3 (59.0 mL, 0.624 mol) dropwise. The dry ice bath was removed after the addition. The mixture was stirred at room temperature for 1 hour and poured into a large amount of ice/water and stirred vigorously. The pink solid was filtered, washed with water, and vacuum oven dried to give 33.3 g (98%) of the desired product. MS (DCI/NH3) M/Z : 165.0 (M+H)+ ; IH NMR (300 MHZ, CD30D) 8 ppm 2.58-2. 61 (m, 2 H) 2.98 (t, J=5.55 Hz, 2 H) 6. 85 (s, 1 H) 7.04 (s, 1 H). |
77% | At about -40 C., a solution of tribromoborane (22.5 g, 89.81 mmol, 3.00 equiv.) in dichloromethane (50 mL) was added dropwise to a stirred solution of 5,6-dimethoxy-indan-1-one (5.76 g, 29.97 mmol, 1.00 equiv.) in dichloromethane (100 mL). After warming the solution to ambient temperature, the solution was stirred for about 2 hours, and then water/ice (100 mL) was added. Standard extractive workup with dichloromethane (2*30 mL) gave the title product as a red solid (3.8 g; yield=77%). LC-MS: m/z=165 (MH)+. |
With boron tribromide; In dichloromethane; at -78 - 0℃; for 2.0h; | A solution of Compound1a (19 g, 0.094 mol) in 200 mL of methylene chloride wascooled to-78 C using a dry ice/i-PrOH bath. A solution ofBBr3 inCH2CI2 (200 mL, 0.2 mol) was added dropwise. The resulting solution was stirredat-78 C for 1 h, at which time the temperature was allowed to warm to0 C with stirring for an additional 1 h. The mixture was then cooled backto-78 C and quenched withMeOH (50 mL). The solution was concentrated under reduced pressure to dryness. The resulting solid was dissolved inMeOH (50 mL) and concentrated under reduced pressure two more times. The red solid, Compound 5a, was used in the subsequent reaction without further purification. MS m/z 165(M+H) + | |
With boron tribromide; In dichloromethane; at -78℃; for 1.0h; | A solution of 5, 6-dimethoxy-indan-1-one (6.1 g, 31.7 mmol) in dichloromethane (150 mL) was cooled to about-78 C and boron tribromide (7.1 mL, 75.1 mmol) was added dropwise. After the addition, the reaction was stirred for about 1 hour while being allowed to warm to room temperature. The mixture was poured into ice water under vigorous stirring. The pink precipitate was collected by filtration, washed with water, and dried under high vacuum to provide the desired product. MS (APCI): m/z 165 (M+H) +. | |
With boron tribromide; In dichloromethane; at 0℃; for 4.0h;Inert atmosphere; | A, the 5, 6-dimethoxy -2, 3-dihydro -1H-inden-1-one dissolved in dichloromethane solvent, stir, to obtain 5, 6-dimethoxy -2, 3-dihydro -1H-inden-1-one concentration is 2mol/L a clear solution;Second, under the condition of the protection of nitrogen, a solution of the step a by stirring, and the ice water bath cooling to 0 C, then adding boron tribromide, to the solution from light yellow to red, then remain 4h, the reaction liquid obtained; wherein the boron tribromide and 5, 6-dimethoxy -2, 3-dihydro -1H-inden-1-one in the molar ratio of 1 [...] 2.8;Three, under the condition of room temperature, saturated sodium bicarbonate solution is added into the from the reaction solution obtained in the second step, until the solution turned from red pink, solution streamed bubble and produce a large amount of precipitation, the obtained solid product;Four, step c to obtain the solid product with ethyl acetate is dissolved, the organic layer is obtained, then the spin vaporization, the pink solid 5, 6-dihydroxy -2, 3-dihydro -1H-inden-1-one;Wherein four steps when using ethyl acetate to dissolve the solid product, specific operating as: ethyl acetate to dissolve the solid product is used, the un-dissolved solid product is washed with water, then dissolved with ethyl acetate, the organic layer, multiple operations ethyl acetate is dissolved and water washing process, to the solid product completely dissolved in ethyl acetate, then the organic layer obtained by merging a plurality of times |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydroxide In ethanol; water at 25℃; | General procedure A (Aldolic condensation) General procedure: Benzaldehyde (3.0 mmol) was added to a well-stirred solution of benzocycloalkan-1-one (3.0 mmol) and NaOH/H2O 10% (1.6 mL) in ethanol (1.6 mL). After the mixture was stirred at ice bath or room temperature for 2-4 h, the solid was filtered and washed with water. 2-Arylidenebenzocycloalkan-1-ones 7a, 7b, 8, 12a, 16a, 17a, and 17b were prepared as per the mentioned procedure and identified by m.p. and 1H NMR spectra. |
88% | With sodium ethanolate In tetrahydrofuran at 20℃; for 16h; | |
86% | With sodium hydroxide In ethanol; water at 20℃; |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In methanol at 20℃; for 4h; | Compound (4c): General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (1.92 g, 0.001 mole) with 4-fluorobenzaldehyde (1.24 g, 0.001 mole) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h giving the (2E)-2-(4-fluorobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one which was then refluxed with 4-fluorophenyl semicarbazides in glacial acetic acid for 12 h furnished N,3-bis(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c). | |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In ethanol; water; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; | ||
With sodium hydroxide In ethanol | ||
With sodium hydroxide In ethanol at 20℃; for 5h; | General Procedure for Synthesis of Substituted 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone General procedure: An equimolar mixture of 1-indanone and various aromatic aldehydes were dissolved in ethanol (10 mL) and 30% of sodium hydroxide solution (5 mL) was added and stirred at room temperature for 5 hours. The mixture was then poured on to crushed ice and neutralized with concentrated HCl. The precipitated solid was filtered, washed with water and recrystallized from methanol to reveal the titled compounds. | |
100 %Spectr. | With A26 basic resin In ethanol; toluene at 60℃; Flow reactor; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.2% | With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 0 - 25℃; for 1.25h; | 4 Example 4: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -5,6-dimethoxy-l-indanone compound[74] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of t-butanol, and 14.01 g of potassium t-butoxide was added drop wise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 1 hour. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.2 g of a target compound (yield: 92.2%). |
92.5% | With sodium methylate In isopropyl alcohol at 0 - 25℃; for 3.25h; | 5 Example 5: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -5,6-dimethoxy-l-indanone compound[78] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of isopropanol, and 6.75 g of sodium methoxide was added drop wise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.33 g of a target compound (yield: 92.5%). |
90% | With tetrabutylammomium bromide; potassium hydroxide In dichloromethane; water at 38℃; for 1.5h; | 1 1. 11.11 grams or 0.0535 mol of N-benzylpiperidine-4-carboxyaldehyde having a structure as shown in Formula 3, and 10 grams or 0.051 mol of 5,6-Dimethoxy-1-indanone having a structure as shown in Formula 4 were prepared. 13.46 grams or 0.2039 mol of potassium hydroxide (KOH), 100 ml of water, 8.39 grams or 0.0255 mol of tetrabutylammonium bromide, and 80 ml of dichloromethane were prepared, wherein the mole ratio of aforementioned compounds was: N-benzylpiperidine-4-carboxyaldehyde: 5,6-Dimethoxy-1-indanone: potassium hydroxide: tetrabutylammonium bromide=1.05:1:4:0.5.In a container potassium hydroxide was dissolved in water, added with tetrabutylammonium bromide, dichloromethane, N-benzylpiperidine-4-carboxyaldehyde and 5,6-Dimethoxy-1-indanone to form a mixture, and then the mixture was stirred and heated to allow reacting at 38 degrees Celsius for 1.5 hours to obtain a heated potassium hydroxide mixture solution, wherein the tetrabutylammonium bromide was employed as a phase transfer catalyst. 2. An organic layer was separated from an aqueous layer of the heated potassium hydroxide mixture solution, washed with 80 ml of water, dehydrated with anhydrous magnesium sulfate, and condensed and dried. 3. 100 ml of methylbenzene was added to the organic layer to obtain a mixture. The mixture was stirred and heated to 78 degrees Celsius to allow dissolution and clearance. Gradually the temperature was lowered to 68 degrees Celsius to allow generation of crystals. Stirring of the mixture was continued for 30 minutes and the temperature was further lowered to room temperature. The mixture was ice-bathed for 2 hours and filtered and a powderwas obtained. |
90% | With tetrabutylammomium bromide; potassium hydroxide In dichloromethane; water at 38℃; for 1.5h; | 1 In this example a method for preparing E2M, the precursor for making donepezil, is demonstrated. The method for preparing E2M comprises the following steps:[0017]1. Obtaining a potassium hydroxide aqueous solution by dissolving sodium hydroxide in water;[0018]2. Adding 1) tetrabutylammonium bromide, 2) 5,6-Dimethoxy-1-indanone, 3) dichloromethane, and 4) N-benzylpiperidine-4-carboxyaldehyde into the aforementioned potassium hydroxide aqueous solution to obtain a potassium hydroxide mixture solution;[0019]3. Heating the potassium hydroxide mixture solution while stirring to allow reaction for obtaining a heated potassium hydroxide mixture solution that has an organic layer; and[0020]4. Extracting the organic layer of the heated potassium hydroxide mixture solution with methylbenzene (toluene) to obtain a product and crystallizing and filtering the product to obtain E2M.[0021]In the instant example, the foregoing steps were specifically performed as follows.[0022]1. 11.11 grams or 0.0535 mol of N-benzylpiperidine-4-carboxyaldehyde having a structure as shown in Formula 3, and 10 grams or 0.051 mol of 5,6-Dimethoxy-1-indanone having a structure as shown in Formula 4 were prepared.[0023]13.46 grams or 0.2039 mol of potassium hydroxide (KOH), 100 ml of water, 8.39 grams or 0.0255 mol of tetrabutylammonium bromide, and 80 ml of dichloromethane were prepared, wherein the mole ratio of aforementioned compounds was:[0024]N-benzylpiperidine-4-carboxyaldehyde:5,6-Dimethoxy-1-indanone:potassium hydroxide: tetrabutylammoniumbromide=1.05:1:4:0.5.[0025]In a container potassium hydroxide was dissolved in water, added with tetrabutylammonium bromide, dichloromethane, N-benzylpiperidine-4-carboxyaldehyde and 5,6-Dimethoxy-1-indanone to form a mixture, and then the mixture was stirred and heated to allow reacting at 38 degrees Celsius for 1.5 hours to obtain a heated potassium hydroxide mixture solution, wherein the tetrabutylammonium bromide was employed as a phase transfer catalyst.[0026]2. An organic layer was separated from an aqueous layer of the heated potassium hydroxide mixture solution, washed with 80 ml of water, dehydrated with anhydrous magnesium sulfate, and condensed and dried.[0027]3. 100 ml of methylbenzene was added to the organic layer to obtain a mixture. The mixture was stirred and heated to 78 degrees Celsius to allow dissolution and clearance. Gradually the temperature was lowered to 68 degrees Celsius to allow generation of crystals. Stirring of the mixture was continued for 30 minutes and the temperature was further lowered to room temperature. The mixture was ice-bathed for 2 hours and filtered and a powder was obtained.[0028]With reference to FIG. 1, by hydrogen-1 NMR analysis the powder is identified as E2M. With the method as demonstrated in the instant example, the molecular weight of E2M is 377.5 and the yield of E2M is more than 90% while the purity thereof reaches 98.551%. |
89.5% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 25℃; for 1.25h; | 3 Example 3: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -5,6-dimethoxy-l-indanone compound[71] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 14.01 g of potassium t-butoxide was added dropwise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 1 hour. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 35.15 g of a target compound (yield: 89. f [72] [73] |
86.2% | With sodium methylate In tetrahydrofuran at 0 - 25℃; for 3.25h; | 1; 2 Example 1: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -5,6-dimethoxy-l-indanone compound[62] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 6.75 g of sodium methoxide was added dropwise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.53 g of a target compound (yield: 93.0%).[63] m.p. 175-1770C;[64] m/e 377.5 (parent ion);[65] 1U NMR (CDCl ) δl.62~1.83 (m, 4H), 2.08-2.26 (m, 2H), 2.27-2.42 (m, IH),2.92-3.03 (m, 2H), 3.55-3.67 (m, 4H), 3.92 (s, 3H), 3.97 (s, 3H), 6.65 (d, IH), 6.89 (s, IH), 7.28 (s, IH), 7.30-7.39 (m, 5H) Example 2: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -5,6-dimethoxy-l-indanone compound[68] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 8.50 g of sodium methoxide was added dropwise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 33.86 g of a target compound (yield: 86.2%). |
86% | With sodium methylate In ethanol at 0 - 25℃; for 3.25h; | 6 Example 6: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -5,6-dimethoxy-l-indanone compound[81] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of ethanol, and 6.75 g of sodium methoxide was added drop wise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 33.78 g of a target compound (yield: 86.0%). |
77% | Stage #1: 5,6-dimethoxy-1-indanone With potassium carbonate In methanol; water Heating; Stage #2: N-benzyl-4-formylpiperidine In methanol; water at 75℃; for 2.5h; Further stages.; | |
56% | With Amberlyst A-26 In methanol at 20 - 50℃; for 2h; Irradiation; Green chemistry; regioselective reaction; | |
95 %Spectr. | With water In tetrahydrofuran; isopropyl alcohol at 55℃; for 3h; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium carbonate / methanol; H2O / Heating 1.2: 77 percent / methanol; H2O / 2.5 h / 75 °C 2.1: 31 g / H2 / palladium carbon / methanol / 2 h / 20 °C / 760.05 Torr | ||
Multi-step reaction with 3 steps 1: 95.6 percent / p-toluenesulfonic acid / toluene / 6 h / Heating 2: 90 percent / hydrogen; acetic acid / palladium on activated charcoal / methanol / 7 h / 60 - 65 °C 3: sodium carbonate / methanol; propan-2-ol / 11 h / 60 - 65 °C | ||
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / water; dichloromethane / 1.5 h / 38 °C 2: tetrabutylammomium bromide; sodium hydrogencarbonate; sodium dithionite / water; ethyl acetate |
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / dichloromethane; water / 1.5 h / 38 °C 2: tetrabutylammomium bromide; sodium hydrogencarbonate; sodium dithionite; water / ethyl acetate / 0.5 h / 65 °C | ||
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / toluene / 24 h / Reflux 2: hydrogen / neat (no solvent) / 144 h / 50 °C / 760.05 Torr 3: sodium carbonate / isopropyl alcohol / 12 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 5,6-dimethoxy-1-indanone With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2.5h; Reflux; Stage #2: With triethylamine In tetrachloromethane at 0℃; | Representative experimental procedure for the Synthesis of benzo[c]fluorenone General procedure: NBS (195 mg, 1.1 mmol) and AIBN (2 mg, 0.01 mmol) were added to a CCl4 solution (4 ml) of the 6-methoxyindanone (162 mg, 1 mmol). The resulting mixture was stirred at reflux temperature for 2.5 h, then cooled and filtered through Celite, which was then washed with CCl4. The filtrate was cooled to 0 °C and treated with triethylamine (0.28 mL, 2.0 mmol) overnight, then concentrated in vacuuo. Chromatography of the residue (1 : 9~1 : 4 EtOAc/hexanes) afforded 97 mg (60%) of enone 1a as the pink oil which solidified as light red solid in refrigerator. |
63% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2.5h; Reflux; | General procedure: NBS (195 mg, 1.1 mmol) and AIBN (2 mg, 0.01 mmol) were added to a CCl4 solution (4 ml) of the 6-methoxyindanone (162 mg, 1 mmol).The resulting mixture was stirred at reflux temperature for 2.5 h, then cooledand filtered through Celite, which was then washed with CCl4. The filtrate was cooled to 0 °C and treated with triethylamine (0.28 mL, 2.0 mmol)overnight, then concentrated in vacuuo. Chromatography of the residue (19~14 EtOAc/hexanes) afforded 97 mg (60%) of enone 1a as the pink oil which solidified as light red solid in refrigerator. |
Multi-step reaction with 2 steps 1: 97 percent / NBS; AIBN / CCl4 / 2.5 h / Heating 2: EtAlCl2 / toluene / 0.5 h / 20 °C |
Multi-step reaction with 2 steps 1: Et3N / benzene / 0 - 20 °C 2: Pd(OAc)2 / CH2Cl2; acetonitrile / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.3% | With ammonia; hydrogen In ethanol at 100℃; Autoclave; | 1.1 Example 11) Preparation of 5,6-dimethoxy-1-aminoindan Autoclave, 96 g of 5,6-dimethoxy-1-aminoindanone, 500 ml of absolute ethanol,16g catalyst SN-6000P, sealed reactor, with a vacuum pump to remove the air inside the kettle,And then filled with nitrogen to 0.5MPa, and then vacuum pump vacuum; negative pressure conditions filled with 42g ammonia,After the ammonia was charged, the autoclave was charged with hydrogen to 4.5 MPa and heated to 100 ° C to carry out the reaction.Reaction to no longer absorb hydrogen, then stop the reaction. When the temperature of the system is reduced to room temperature, the reaction solution is filtered,Concentrated 5,6-dimethoxy-1-aminoindane crude. The crude product in the case of mixing,Added to dilute hydrochloric acid solution, allowed to react to produce 5,6-dimethoxy-1-amino-indane salt,And dissolved in aqueous solution, and ethyl acetate extract water to remove organic impurities, after separation, to retain the water phase,Water phase and then ethyl acetate to take two times, with sodium hydroxide to adjust the pH to alkaline,And then ethyl acetate extract 3 times, then adjust the PH value after extraction of ethyl acetate phase, dried and concentrated,5,0-dimethoxy-1-aminoindan was obtained in 90.03 g yield, the yield was 93.3%, and the purity was 99.4% by HPLC. |
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride, NaOH, H2O / ethanol / 0.33 h / Heating 2: Raney nickel, NaOH, H2O / ethanol / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium hydroxide; In water; at 25 - 30℃; for 3h;Product distribution / selectivity; | Example 1: Process for preparation of 5,6-dimethoxy-2-(4-pyridylmethylene)-l- indanone of formula IVTo a 1 liter round bottom flask equipped with a mechanical stirrer, thermometer pocket, addition funnel and a condenser, charged demineralized water (250ml), 5,6- dimethoxy-l-indanone (25g) and pyridine-4-carboxaldehyde (19.5g). The reaction mixture was stirred for 5 minutes at a temperature of 25C to 30C. To the reaction mixture then charged a solution of potassium hydroxide (5.2g) dissolved in demineralized water (125ml) slowly over period of 2 hours at a temperature of 25 C to 30C. The reaction mixture was further maintained at a temperature of 25C to 30C for 1 hour to obtain the product, 5,6-dimethoxy-2-(4-pyridylmethylene)-l- indanone. The product obtained was then filtered and washed with demineralized water. Dry the product under vacuum at a temperature of 50C to 55C for 10 hours. Yield: 98%Purity: 99.71% |
95.8% | 5, 6 Dimethoxy indanone (100 grams), Pyridine-4-carboxaldehyde (78.0 grams) and p-toluene sulfonic acid (138.4 grams) were suspended in toluene (1250 ml) and heated to reflux using water separator for 6 hours. The resulting mass was cooled to 25-40 C. and the solid was filtered off under suction. Further the wet solid was suspended in aqueous 10% sodium carbonate solution (1200 ml) and stirred for 30-60 minutes. The resulting pale yellow precipitate solid was filtered off under suction, washed with water (1000 ml) and dried at a temperature of 80 C. to afford 5,6 Dimethoxy-2-(pyridin-4yl)-methylene-indan-lone (Weight: 140 grams, 95.8%). | |
92.2% | With potassium iodide; calcium chloride; In acetone; at 40 - 50℃; for 4h; | In a three-necked flask equipped with a condenser and a stirrer, acetone 60 mL, 5,6-dimethoxy-1-indanone was sequentially added.9.6g, anhydrous calcium chloride 5.55g (0.05mol), 4-pyridine formaldehyde 5.89g, potassium iodide 0.96g, stirred at 40 ~ 50 CAfter mixing for 4 h, the basic reaction was completely monitored by HPLC, cooled to room temperature, filtered, and the filtrate was concentrated.Filtration and drying under vacuum gave Compound III 12.96 g, yield 92.2%, HPLC, purity 99.7%. |
67% | With sodium hydroxide; In ethanol; water; at 20℃;Inert atmosphere; | To a solution of 1 mmol of 4-pyridinecarboxaldehyde and 1 mmol of 5,6-dimethoxy-1-indanone in 10 ml EtOH, aqueous solution of NaOH (10%) was added dropwise. The reaction mixture was stirred overnight at room temperature. The obtained solid was fltered and recrystallized from EtOH to give 3 as an of-white solid [22]; yield 67%; mp: 118-120 C; FTIR (KBr) nu3008, 2937, 1691, 1600, 1465, 1315, 1268, 1029 cm-1; 1H NMR (400 MHz, CDCl3): 3.82 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.03 (2H, s, CH2), 7.17 (1H, s, Ar), 7.22 (1H, s, Ar), 7.42 (1H, s, =CH), 7.67 (2H, d, 3JH-H = 5.36, pyridine-H), 8.64 (2H, d, 3JH-H = 5.46, pyridine-H). |
With toluene-4-sulfonic acid; In toluene; for 6h;Heating / reflux; | Preparation 1 Preparation of 5, 6-dimethoxy-2- (pyridine-4-yl) methylene-indan-1-one A mixture OF 5, 6-DIMETHOXY-INDAN-1-ONE (100G), pyridine-4-carboxaldehyde (67g), p- toluene sulfonic acid (118G) in toluene (1200ML) was refluxed azeotropically for 6 hours. The reaction mixture was cooled to room temperature and filtered. The wet solid so obtained was stirred with 10% aqueous sodium carbonate solution. The solid was filtered, washed with acetone and then dried to get the title compound (130G). HPLC Purity: 99.5% | |
With sodium hydroxide; In methanol; at 20℃; for 4h; | General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (0.001 mol) with appropriate aldehyde (0.001 mol) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h. The resulting solution was allowed to stand overnight and then the reaction mixture was poured into cold water and neutralized with dilute HCl. The solid was filtered, dried and recrystallized with ethanol furnished the 2-substituted-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 5,6-dimethoxy-1-indanone; formic acid ethyl ester With sodium hydride In benzene at 20℃; Stage #2: With acetic acid; hydrazine In ethanol for 3h; Heating / reflux; | 243A Example 243 6, 7-DIMETHOXY-3-PYRIDIN-3-YL-1, 4-dihydroindeno[1,2-c]pyrazole; Example 243A 6, 7-dimethoxy-1, 4-dihydroindeno 1 L, 2-CLPYRAZOLE A mixture of 5,6-dimethoxyindanone (6.0 g, 31 mmol), formic acid ethyl ester (5.04 mL, 62 mmol), 95% NaH (2.35 g, 93 mmol) and benzene (100 mL) was stirred at room temperature overnight. The solvent was removed. To the residue was added slowly ethanol (200 mL), acetic acid (20 ML) and hydrazine monohydrate (20 mL). The mixture was heated to reflux for 3 hours and cooled. The solvents were removed. The residue was suspended in water (100 mL), and the solid was collected by filtration, washed with water (100 ML) and CC4 (100 mL), and dried to give the desired product as light yellow solid powder (5.80 g, 87%). MS (ESI) m/z 217 (M+H) +. 1H NMR (300 MHz, DMSO-D6) 5 ppm 3.51 (s, 2 H) 3.79 (s, 3 H) 3.82 (s, 3 H) 7.17 (s, 1 H) 7.20 (s, 1 H) 7.56 (s, 1 H) 12. 51 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 6 6,7-Dimethoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-2,4-dihydroindeno[1,2-c]pyrazole 5,6-Dimethoxy-1-indanone (1.92 g, 10 mmol) in tetrahydrofuran (10 ml) was added dropwise to a solution of lithium diisopropylamide (10 mmol) in tetrahydrofuran (10 ml) at -78 C. and stirred for 0.5 h. 5-Methyl-3-phenylisoxazole-4-carboxylic acid (1.02 g, 5 mmol) was stirred with N,N'-carbonyldiimidazole (810 mg, 5 mmol) in tetrahydrofuran (5 ml) for 1 h and then added to the dimethoxyindanone solution with 4-dimethylaminopyridine (610 mg, 5 mmol).This was stirred at -78 C. for 1.5 h and warmed to RT over 2 h then diluted with EtOAc, washed with citric acid solution, brine, dried (MgSO4) and evaporated.The resulting yellow oil was dissolved in ethanol (5 ml), saturated copper acetate solution (10 ml) was added and the precipitate formed was filtered off and washed with H2O, methanol, diethyl ether, dried (MgSO4) and evaporated.The residue was dissolved in ethanol, hydrazine hydrochloride (500 mg) and sodium acetate (1 g) and H2O were added and heated to reflux for 24 h.The solvent was evaporated, the residue dissolved in EtOAc, washed with brine, dried (MgSO4) and evaporated.Purified by prep HPLC to give the title compound (7 mg).1H NMR (360 MHz, CDCl3) delta7.52 (d, J=6.8 Hz, 2H), 7.43-7.33 (m, 5H), 3.94 (s, 3H), 3.91 (s, 3H), 3.28 (s, 2H), 2.57 (s, 3H), m/z (ES+) 374 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: Diethyl carbonate With sodium hydride In tetrahydrofuran; oil for 1.5h; Heating / reflux; Stage #2: 5,6-dimethoxy-1-indanone In tetrahydrofuran; oil for 3h; Heating / reflux; | 1 2-ethoxycarbonyl-5,6-dimethoxyindan-1-one Reference Example 1 2-ethoxycarbonyl-5,6-dimethoxyindan-1-one This compound is prepared according to the procedure disclosed in EP 534859. To a suspension of sodium hydride (50% dispersion in oil, 20 g) in 240 mL of THF, diethyl carbonate was added and the mixture was stirred and refluxed for 90 min. A solution of 5,6-Dimethoxyindan-1-one (40 g) in THF (440 mL) was added, the mixture was heated under reflux for 3 h, then cooled and concentrated. Ethyl acetate (200 mL) was added, the organic layer was washed with water. The organic layer was dried over MgSO4, filtered and the ethyl acetate was removed under reduced pressure. The title product was obtained in 98% yield. |
98% | Stage #1: Diethyl carbonate With sodium hydride In tetrahydrofuran for 1.5h; Heating / reflux; Stage #2: 5,6-dimethoxy-1-indanone In tetrahydrofuran for 3h; Heating / reflux; | 1 This compound is prepared according to the procedure disclosed in EP 534859. To a suspension of sodium hydride (50% dispersion in oil, 20g) in 240mL of THF, diethyl carbonate was added and the mixture was stirred and refluxed for 90 min. A solution of 5,6-Dimethoxyindan-1-one (40g) in THF (440mL) was added, the mixture was heated under reflux for 3h, then cooled and concentrated. Ethyl acetate (200mL) was added, the organic layer was washed with water. The organic layer was dried over MgSO4, filtered and the ethyl acetate was removed under reduced pressure. The title product was obtained in 98% yield. |
85% | With sodium hydride In toluene; mineral oil for 6h; Reflux; | 1 4.1.1 5,6-Dimethoxy-1-oxo-indan-2-carboxylic acid ethyl ester (14) To a solution of diethyl carbonate (1.89 mL, 15.6 mmol), NaH (0.46 g, 15.6 mmol, 80% dispersion in mineral oil) in toluene (10 mL), a solution of 5,6-dimethoxy-indan-1-one 13 (1.50 g, 7.8 mmol) in toluene (20 mL) was added dropwise over a 1 h period, and the mixture was stirred at reflux for 5 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and acetic acid (1.5 mL). The resulting mixture was extracted with dichloromethane (3 x 30 mL), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash column chromatography (silica gel, EtOAc/PE, 3/7) generated the title compound (1.76 g, 85%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.18 (s, 1H), 6.92 (s, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 3.69-3.72 (m, 1H), 3.45 (dd, J = 17.0, 3.5 Hz, 1H), 3.28 (dd, J = 17.0, 7.9 Hz, 1H), 1.31 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 198.1, 169.5, 156.0, 149.8, 149.3, 128.0, 107.3, 104.8, 61.7, 56.3, 56.1, 53.6, 30.1, 14.2. |
85% | With sodium hydride In toluene for 2h; Reflux; | |
85% | With sodium hydride In mineral oil at 80℃; for 2h; Inert atmosphere; Reflux; | Synthesis of Ethyl 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2): To a stirred suspension of NaH (5.0 g, 60% in mineral oil, 125 mmol) in diethyl carbonate(20 mL) was added drop wise a solution of 5,6-dimethoxy-1-indanone (10 g, 52 mmol) in diethyl carbonate (70 mL). The mixture was then refluxed at 80 0°C for 2 h, cooled to rt, and diluted with H2O (200 mL). The aqueous phase was separated and extracted with CH2Cl2 (3 x50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The oily residue was subjected to purification by column chromatography to yield 11.68 g (85%) of 2 as a white crystalline solid. Physical characteristics are matching with literature report. |
78% | Stage #1: Diethyl carbonate With sodium hydride In tetrahydrofuran; mineral oil for 1.5h; Reflux; Stage #2: 5,6-dimethoxy-1-indanone In tetrahydrofuran; mineral oil at 20℃; for 3h; Reflux; Inert atmosphere; | 1 Example 1-Synthesis of 2-carbethoxy-5,6-dimethoxyindanone To a suspension of NaH 60 % (1.37 g, 34.2 mmol) in TI-IF (50 mL) was added diethylcarbonate (4.15 mL, 34.2 mmol). The mixture was stirred at reflux for 1h30 before indanone (3.29 g, 17.1 mmol) in THF (100 mL) was added at room temperature. The reaction was further stirred at reflux under argon for 3 h. At room temperature, ethyl acetate was then added, and the mixture was washed with a solution of acetic acid. The oganic layer was dried over Na2SO4. Filtration and evaporation of the solvent under reduced pressure gave a residue, which was purified by flash silica chromatography (CH2C12/MeOH: 99.5/0.5). Evaporation of the solvent gave compound as a white solid (3.5 g, 78%).NMR (CDC13, 300 MHz, 298 K, S ppm): 7.17 (s, 1 H), 6.90 (s, 1 H), 4.23 (q,J 7.2 Hz, 2 H), 3,97 (s, 3 H), 3.89 (s, 3 H), 3.69 (m, 1 H), 3.48-3.22 (m, 2H), 1.3 (t, J = 7.2 Hz, 3H).13C NMR (CDC13, 75.5 MHz, 298 K, S ppm): 198.26, 169.62, 156.17, 149.87, 149.42, 128.14,107.38, 104.94, 61.83, 56.47, 56.28, 53.73, 30.19, 14.36. |
62% | With sodium hydride In toluene; mineral oil for 5h; Inert atmosphere; Reflux; | Preparation of intermediate IV: ethyl 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-carboxylate 2.3 g (78 mmol) of 80% sodium hydride dispersed in oil,And 9.5 mL (78 mmol) of diethyl carbonate were added to 200 mL of toluene,Under an argon atmosphere was added dropwise 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one 7.5g (39mmol) in toluene solution was heated to refluxThe reaction continued at reflux for 5 hours,cool down,The reaction was quenched by the addition of 200 mL of water and 10 mL of glacial acetic acid,Dichloromethane 200 mL x 3,The organic layers were combined,Saturated sodium chloride solution,Dried over anhydrous sodium sulfate,After filtration, silica gel column chromatography,The eluent was petroleum ether: ethyl acetate = 3: 1,To give 6.3 g of a pale yellow solid (IV)Yield 62%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | Stage #1: 5,6-dimethoxy-1-indanone; N-benzyl-4-formylpiperidine In dichloromethane at 25 - 30℃; Stage #2: With potassium hydroxide In methanol; dichloromethane at 0 - 30℃; | 1 To 5,6-dimethoxy-l- indanone (10Og) in methylene chloride (1000ml) was added 1-benzyl piperidine-4-carboxaldehyde (150.0 g) and the reaction mixture was stirred for 15 minutes at 25- 30°C for dissolution. The reaction mixture was cooled to 0-50C and to it was added potassium hydroxide dissolved in methanol solution (48.0 g in 200 ml methanol) in a period of 30-60 minutes and stirred for 30 minutes at 0-50C. The temperature of the reaction mass was raised to 25-300C and the stirring continued for 2 hours. The reaction was monitored by thin layer chromatography for absence of 5, 6-dimethoxy-l -indanone. After the completion of the reaction purified water (30OmL) was added and the mixture was stirred for 15 minutes. The pH of the reaction mass was adjusted to 6.5-7.5 with concentrated hydrochloric acid at 25-300C and stirred for 30 minutes. The layers were separated and the organic layer was extracted with methylene chloride. The methylene chloride layer was washed with purified water, treated with activated carbon (5g) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloride. The organic layer was distilled under vacuum, methanol (200.OmL) was added to the residue and stirred for 15 minutes followed by the addition of acetone (100OmL) and the stirring was continued for 3 hours at 25- 30°C. The compound was filtered and washed with acetone, to the wet cake was added methanol (200.OmL) and the mixture was stirred for 15 minutes followed by the addition of acetone (600.OmL) and stirring was continued for 3 hours. The mixture was filtered, washed with acetone (200.OmL) and dried at 60-650C to obtain the title compound, f Dry weight: 195.g)(% Yield: 91.3%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In methanol at 20℃; for 4h; | Compound (4c): General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (1.92 g, 0.001 mole) with 4-fluorobenzaldehyde (1.24 g, 0.001 mole) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h giving the (2E)-2-(4-fluorobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one which was then refluxed with 4-fluorophenyl semicarbazides in glacial acetic acid for 12 h furnished N,3-bis(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c). | |
With sodium hydroxide In methanol at 20℃; for 4h; | Compound (4o) 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (1.92 g, 0.001 mol) with 4-fluorobenzaldehyde (1.24 g, 0.001 mol) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h. The reaction mixture was then poured in crushed ice neutralized with diluted HCl, giving the (2E)-2-(4-fluorobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one which was then refluxed with thiosemicarbazide in glacial acetic acid for 12 h. Excess of solvent was removed and the reaction mixture was poured in crushed ice then filtered and washed furnished 3-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carbothioamide (4o). |
With sodium hydroxide In ethanol; water; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; | ||
With sodium hydroxide In ethanol | ||
With sodium hydroxide In ethanol at 20℃; for 5h; | General Procedure for Synthesis of Substituted 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone General procedure: An equimolar mixture of 1-indanone and various aromatic aldehydes were dissolved in ethanol (10 mL) and 30% of sodium hydroxide solution (5 mL) was added and stirred at room temperature for 5 hours. The mixture was then poured on to crushed ice and neutralized with concentrated HCl. The precipitated solid was filtered, washed with water and recrystallized from methanol to reveal the titled compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In methanol at 20℃; for 4h; | Compound (4c): General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (1.92 g, 0.001 mole) with 4-fluorobenzaldehyde (1.24 g, 0.001 mole) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h giving the (2E)-2-(4-fluorobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one which was then refluxed with 4-fluorophenyl semicarbazides in glacial acetic acid for 12 h furnished N,3-bis(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c). | |
With sodium hydroxide In methanol at 20℃; |
With sodium hydroxide In ethanol; water; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; for 4h; | ||
With sodium hydroxide In ethanol; Petroleum ether at 20℃; | ||
With sodium hydroxide In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydroxide In ethanol; water at 20℃; | |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In ethanol; water; Petroleum ether at 20℃; for 4h; |
With sodium hydroxide In ethanol; Petroleum ether at 20℃; | ||
With sodium hydroxide In ethanol at 20℃; for 5h; | General Procedure for Synthesis of Substituted 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone General procedure: An equimolar mixture of 1-indanone and various aromatic aldehydes were dissolved in ethanol (10 mL) and 30% of sodium hydroxide solution (5 mL) was added and stirred at room temperature for 5 hours. The mixture was then poured on to crushed ice and neutralized with concentrated HCl. The precipitated solid was filtered, washed with water and recrystallized from methanol to reveal the titled compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 5,6-dimethoxy-1-indanone With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; | 3.3 4-(5,6-Dimethoxy-1-oxo-indan-2-ylidenemethyl)-piperidine-1-carboxylic acid tent-butyl ester: At about 0° C. and under an atmosphere of argon, a solution of n-butyllithium in hexane (2.5 M, 3.7 mL, 1.12 equiv.) was added dropwise to a solution of diisopropylamine (930 mg, 9.19 mmol, 1.12 equiv.) in tetrahydrofuran (10 mL). The resulting solution was stirred at about 0° C. for about 10 minutes. After cooling the solution to about -78° C., a solution of 5,6-dimethoxyindan-1-one (1.5 g, 7.80 mmol, 1.00 equiv.) and hexamethylphosphoramide (1.6 g, 7.50 mmol, 1.12 equiv.) in tetrahydrofuran (10 mL) was added dropwise. The resulting solution was stirred at about -78° C. for about 15 minutes, and then a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 7.50 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL) was added. After warming the solution to ambient temperature, the solution was stirred at ambient temperature for about 2 hours and then an aqueous solution of ammonium chloride (1%, 50 mL) was added. Standard extractive workup with ethyl acetate (2×50 mL), gave the title product as a yellow solid (2.0 g; yield=67%), which was used in the next step without further purification. LC-MS: m/z=388 (MH)+. |
3.3 g | Stage #1: 5,6-dimethoxy-1-indanone With tetrabutylammomium bromide; sodium hydroxide In dichloromethane; water at 20℃; for 0.5h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 50℃; for 5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol; water at 20℃; | |
85% | With sodium hydroxide In ethanol; water at 20℃; for 24h; Inert atmosphere; | General procedure for the synthesis of compound (3) General procedure: To a stirred solution of 4-halobenzaldehyde (1 mmol) and indanone (1 mmol) in EtOH (10 mL), an aqueous solution of NaOH (10%) was added dropwise. The reaction mixture was stirred overnight at room temperature. The obtained solid was collected by filtration and purified by recrystallization from EtOH to give desired product as a pure solid. 2-(4-Fluorobenzylidene)-5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-one (3c)Pale yellow solid; Yield 85%; mp: 198-200 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.63-7.65 (2 H, d, J = 8.6 Hz, Ar-H), 7.61(1 H, s, methine-H), 7.13-7.15 (2 H, d, J = 8.6 Hz, Ar-H), 7.11(1 H, s, Ar-H), 6.97 (1 H, s, Ar-H), 3.99 (3 H, s, O-CH3), 3.94 (3 H, s, O-CH3), 3.93 (2 H, s, -inden-CH2); FT-IR (KBr): 2958, 1691, 1591, 1490, 1302, 1224, 1085 cm-1. |
85.8% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
With sodium hydroxide In methanol at 20℃; for 4h; | 5.2. General method for the synthesis of 2-substituted-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one derivatives (3a-f) General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (0.001 mol) with appropriate aldehyde (0.001 mol) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h. The resulting solution was allowed to stand overnight and then the reaction mixture was poured into cold water and neutralized with dilute HCl. The solid was filtered, dried and recrystallized with ethanol furnished the 2-substituted-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one. | |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In methanol at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 5,6-dimethoxy-1-indanone With potassium hydroxide In methanol at 0℃; Stage #2: 4-methoxy-benzaldehyde In methanol at 0 - 40℃; Stage #3: With hydrogenchloride | |
80.5% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
With sodium hydroxide In methanol at 20℃; for 4h; | 5.2. General method for the synthesis of 2-substituted-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one derivatives (3a-f) General procedure: 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (0.001 mol) with appropriate aldehyde (0.001 mol) in diluted methanolic sodium hydroxide solution was stirred under room temperature for 4 h. The resulting solution was allowed to stand overnight and then the reaction mixture was poured into cold water and neutralized with dilute HCl. The solid was filtered, dried and recrystallized with ethanol furnished the 2-substituted-5,6-dimethoxy-2,3-dihydro-1H-indene-1-one. |
With sodium hydroxide In methanol at 20℃; | ||
With sodium hydroxide In methanol at 20℃; for 4h; | ||
With sodium hydroxide In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With hydrazine hydrate; acetic acid In ethanol at 90℃; for 0.25h; Microwave irradiation; | 4.1.5. General procedure for the synthesis of N4-TSCs (19-24) General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), hydrazine hydrate 85% (21 μL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 μL) and ethanol (0.5 mL) in a glass tube equipped with a screw cap and magnetic agitation, was placed in a microwave synthesizer at 90 °C (30 W, 2.5 bar). After completion of the reaction, monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recystallized from ethanol. |
With hydrazine hydrate; acetic acid In isopropyl alcohol at 90℃; Microwave irradiation; | General procedure for the synthesis of N4-TSCs General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), 85% hydrazine hydrate (21 mL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 mL) and isopropanol (0.5 mL) contained in a glass tube equipped with a screw cap and magnetic agitation was placed in a microwave synthesis reactor (Microwave 300 Anton Paar) at 90 C (30 W, 2.5 bar). Once the reaction was completed, as monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With hydrazine hydrate; acetic acid In ethanol at 90℃; for 0.333333h; Microwave irradiation; | 4.1.5. General procedure for the synthesis of N4-TSCs (19-24) General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), hydrazine hydrate 85% (21 μL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 μL) and ethanol (0.5 mL) in a glass tube equipped with a screw cap and magnetic agitation, was placed in a microwave synthesizer at 90 °C (30 W, 2.5 bar). After completion of the reaction, monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recystallized from ethanol. |
With hydrazine hydrate; acetic acid In isopropyl alcohol at 90℃; Microwave irradiation; | General procedure for the synthesis of N4-TSCs General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), 85% hydrazine hydrate (21 mL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 mL) and isopropanol (0.5 mL) contained in a glass tube equipped with a screw cap and magnetic agitation was placed in a microwave synthesis reactor (Microwave 300 Anton Paar) at 90 C (30 W, 2.5 bar). Once the reaction was completed, as monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With hydrazine hydrate; acetic acid In ethanol at 90℃; for 0.333333h; Microwave irradiation; | 4.1.5. General procedure for the synthesis of N4-TSCs (19-24) General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), hydrazine hydrate 85% (21 μL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 μL) and ethanol (0.5 mL) in a glass tube equipped with a screw cap and magnetic agitation, was placed in a microwave synthesizer at 90 °C (30 W, 2.5 bar). After completion of the reaction, monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recystallized from ethanol. |
With hydrazine hydrate; acetic acid In isopropyl alcohol at 90℃; Microwave irradiation; | General procedure for the synthesis of N4-TSCs General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), 85% hydrazine hydrate (21 mL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 mL) and isopropanol (0.5 mL) contained in a glass tube equipped with a screw cap and magnetic agitation was placed in a microwave synthesis reactor (Microwave 300 Anton Paar) at 90 C (30 W, 2.5 bar). Once the reaction was completed, as monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium hydroxide In ethanol at 20℃; | |
83.1% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
57% | Stage #1: 5,6-dimethoxy-1-indanone With sodium hydroxide In ethanol at 20℃; for 0.5h; Stage #2: 4-dimethylamino-benzaldehyde In ethanol at 20℃; | 2.1.2 General Synthesis Procedure for Compounds 3-23 General procedure: A solution of the 2.5 mmol of the appropriate acetophenone, indanone, tetralone derivative or 1,3-diacteylbenzene and 2mL 50% NaOH in 10mL ethanol was stirred at room temperature for 30min. Then, 2.5mmol (or 5mmol with 1,3-diacetylbenzene) of the corresponding benzaldehyde or cinnamaldehyde derivative, dissolved in 1mL ethanol, were added and stirred at room temperature After conversion of the starting compounds was completed as monitored by TLC, the reaction mixture was poured into ice water and acidified with 10% HCl to pH 6. The so-formed solid was filtered off and the crude product was further purified by recrystallization in ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With aluminum oxide; Pt/Al<SUB>2</SUB>O<SUB>3</SUB> In tetrahydrofuran; ethanol; water; isopropyl alcohol at 45 - 55℃; for 7h; | 1-21 100 g of strong basic styrene-based anion exchange resin Amberlyst A26 (Sigma-Aldrich, 542571-1KG) (hereinafter, "Anion exchange resin A26") in water 170 mL x 3, Ethanol 170mL x 3, Tetrahydrofuran: 2-propanol: distilled water = 88:10: 2 mixed solvent 170 mL × 3 was washed in this order. As a first reactor for continuously performing the aldol condensation step by the flow method Stainless steel column with a diameter of 23 mm and a length of 300 mm (Tokyo Rika Kikai) was filled with 100 g of the anion exchange resin A26, the lid was closed, and the lid was closed. It was installed in a column oven (Tokyo Rika Kikai). This is the first column Liquid transfer pump 1 (made by Fromm, UI-22-410D) Connect the polytetrafluoroethylene (PTFE) tube connected to the lower part of the first column, The upper part of the first column is a second reactor for continuously performing the next hydrogenation step of the solution after the aldol condensation reaction by the flow method. A tube for inducing the column to carry out the hydrogenation reaction was attached. 12.47 g of 5% platinum alumina (N.E. Chemcat, AA1501) and 90.52 g of activated alumina (Fujifilm Wako Pure Chemical Industries, Ltd., for column chromatographs, 019-08295, about 75 μm) After mixing uniformly, diameter 23 mm, Stainless steel column with a length of 300 mm Fill (Tokyo Rika Kikai), close the lid, It was installed in a column oven (Tokyo Rika Kikai). This was designated as the second column. The upper part of the second column is The shape is such that two flow paths can be connected. One flow path is connected to the outlet side of the tube connected to the upper part of the first column. To the other flow path, a tube in which the hydrogen flow path was previously merged with the tube connected to the liquid feed pump 2 (manufactured by Fromm, U1-22-110D) was connected. A tube was connected to the lower part of the second column, and the tip of the tube was introduced into a container for storing the reaction solution. After that, the column oven of the first column was heated to 55 ° C. The column oven of the second column was set to 45 ° C. and heated. Tetrahydrofuran from liquid feed pump 1: 2-propanol: distilled water = 88:10: 2 Mix solvent at a flow rate of 2.4 mL / min Tetrahydrofuran was pumped from the liquid feed pump 2 at a flow rate of 1.4 mL / min for 1 hour. After sending liquid for 1 hour, Hydrogen was supplied at 0.95 cm / sec (240 mL / min) for 1 hour while continuing the liquid supply. Hydrogen is supplied from a hydrogen cylinder, The supply amount was controlled by a regulator and a mass flow controller (Brooks, SLA5850S / H2 type) connected to a hydrogen cylinder. 19.22 g of 5,6-dimethoxy-1-indanone (100 mmol) and 21.98 g of 1-benzyl-4-formylpiperidin (108 mmol) in tetrahydrofuran: 2-propanol: distilled water = 88:10: 2 mixed solvent 1000 mL Completely dissolved in 0.1M to prepare a solution, Liquid was sent from the liquid feed pump 1 at a flow rate of 2.4 mL per minute. This liquid feeding start time was defined as the reaction start time. Sampling was performed for a certain period of time from 2 hours after the start of the reaction. Purity was measured by HPLC. Samples for HPLC measurements Collect the flow solution in a container for 5 minutes Extract 500 μL from there, It was prepared by making up to 25 mL with a diluted solution (0.1% aqueous trifluoroacetic acid solution: acetonitrile = 1: 1). The purity of donepezil 7 hours after the start of the reaction was 93.9%. The total amount of the obtained reaction solution was quantified by HPLC. 33.6 g of donepezil was obtained (yield: 88%). |
Multi-step reaction with 2 steps 1: sodium methylate / tetrahydrofuran 2: palladium 10% on activated carbon; hydrogenchloride / ethanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With hydrogenchloride; sodium azide; In water; at 0 - 20℃; | General procedure: To a solution of the appropriate indan-1-one (1.5 mmol) in 37% HCl (5 mL) at 0 C NaN3 (0.2 g, 3.0 mmol) was cautiously added. The mixture was stirred overnight at room temperature. The mixture was poured into ice and made basic with Na2CO3. The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The collected organic phases were dried over Na2SO4 and concentrated under reduced pressure to give a crude residue which was purified by column chromatography with CH2Cl2/AcOEt (9:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 5,6-dimethoxy-1-indanone With sodium hydroxide In ethanol at 20℃; for 0.5h; Stage #2: 3-(3',4',5'-trimethoxyphenyl)-prop-2-en-1-al In ethanol at 20℃; | 2.1.2 General Synthesis Procedure for Compounds 3-23 General procedure: A solution of the 2.5 mmol of the appropriate acetophenone, indanone, tetralone derivative or 1,3-diacteylbenzene and 2mL 50% NaOH in 10mL ethanol was stirred at room temperature for 30min. Then, 2.5mmol (or 5mmol with 1,3-diacetylbenzene) of the corresponding benzaldehyde or cinnamaldehyde derivative, dissolved in 1mL ethanol, were added and stirred at room temperature After conversion of the starting compounds was completed as monitored by TLC, the reaction mixture was poured into ice water and acidified with 10% HCl to pH 6. The so-formed solid was filtered off and the crude product was further purified by recrystallization in ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.4% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
With hydrogenchloride In water; butan-1-ol for 1h; Reflux; | (E/Z) 2-(3/4-Hydroxybenzylidene)-6-substituted-2,3-dihydro-1H-inden-1-one (1) General procedure: The synthetic route for obtaining 2-(3/4-hydroxybenzylidene)-6-substituted-2,3-dihydro-1H-inden-1-one derivatives was depicted in (Scheme 2). Concentrated hydrochloric acid (1 mL) was added to a mixture of suitable ketone compound (100 mmol) and 3- or 4-hydroxy-benzaldehyde (110 mmol) in 1-butanol (5 mL). The mixture was refluxed for 1 hour. The precipitate formed upon cooling was filtered and crystallised from ethanol. | |
With potassium hydroxide In ethanol at 25℃; for 72h; | 1.A A. 2.0 mmol of the corresponding ketone compound (1),3.0 mmol of the corresponding hydroxybenzaldehyde compound (2) andAdd 20 mL of ethanol to the reaction flask and mix well.Add 50% aqueous KOH solution (where KOH 5mmol),Stir at 25 ° C for 72 h (the progress of the reaction was followed by TLC), after the reaction was completed,The solvent was evaporated to dryness under reduced pressure, and 30 mL of deionized water was added to the residue.Adjust the pH to strong acid with 10% HCl,Adjust the pH to a weak alkaline with saturated sodium bicarbonate solution.Extracted in three portions with 120 mL of dichloromethane.The organic layer was combined and washed with aq.Petroleum ether: acetone = 100:1v/v),Corresponding hydroxychalcone compounds (3); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.4% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
With hydrogenchloride In water; butan-1-ol for 1h; Reflux; | (E/Z) 2-(3/4-Hydroxybenzylidene)-6-substituted-2,3-dihydro-1H-inden-1-one (1) General procedure: The synthetic route for obtaining 2-(3/4-hydroxybenzylidene)-6-substituted-2,3-dihydro-1H-inden-1-one derivatives was depicted in (Scheme 2). Concentrated hydrochloric acid (1 mL) was added to a mixture of suitable ketone compound (100 mmol) and 3- or 4-hydroxy-benzaldehyde (110 mmol) in 1-butanol (5 mL). The mixture was refluxed for 1 hour. The precipitate formed upon cooling was filtered and crystallised from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With titanium tetrachloride In toluene at -10 - 20℃; Inert atmosphere; | 4.1.1. General procedure for the synthesis of (inden-3-yl)piperidines (1a-4a) General procedure: A solution of 1-indanone (1-4, 0.52 mmol) in dry toluene (10 mL) was stirred under nitrogen atmosphere at room temperature. Then, 0.31 mL of piperidine (3.1 mmol) was added and the mixture was cooled to -10 °C on an ice bath. The mixture was treated with TiCl4 (0.32 mL, 0.31 mmol) and stirred at -10 °C for one additional hour. Then, the ice bath was removed and stirring was continued at room temperature for 3 days. The resulting suspension was filtered through Celite, which was washed with AcOEt, dried over Na2SO4 and concentrated to dryness. The enamines 1a-4a were used in the following step with no further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.6% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
With sodium hydroxide In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.7% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. (Z)-5,6-Dimethoxy-2-(4-methylbenzylidene)-2,3-dihydro-1Hinden-1-one (TM-1) Light yellow solid, m.p.: 98.6-99.9 °C, 86.7% yield, 98.9% HPLC purity. 1H NMR (400MHz,DMSO-d6): δ = 7.64 (d, J = 8.0 Hz, 2H, 2 × Ar-H), 7.40 (s,1H, C=CH), 7.31 (d, J = 8.0 Hz, 2H, 2 × Ar-H), 7.22 (s,2H, 2 × Ar-H), 3.97 (s, 2H, phCH2), 3.90 (s, 3H, OCH3),3.84 (s, 3H, OCH3), 2.36 (s, 3H, CH3). 13C NMR(100 MHz, DMSO-d6), 193.3 (C-13), 155.7 (C-2), 149.8(C-1), 145.5 (C-5), 139.9 (C-4), 135.4 (C-15), 132.8 (C-19),131.5 (C-12), 131.0 (C-18, 20), 130.5 (C-16), 130.1 (C-17,21), 108.5 (C-3), 105.0 (C-6), 56.5, 56.1 (C-8, 10), 32.1 (C-11), 21.5 (C-22). IR(cm-1): 3100-2900 (-CH3, -CH), 1683(C=O), 1363 (-CH3), 1253, 1087 (C-O-C). MS (ESI) m/z295.1 [M + H]+. |
With sodium hydroxide In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol; water at 20℃; | |
79% | With sodium hydroxide In ethanol; water at 20℃; for 24h; Inert atmosphere; | General procedure for the synthesis of compound (3) General procedure: To a stirred solution of 4-halobenzaldehyde (1 mmol) and indanone (1 mmol) in EtOH (10 mL), an aqueous solution of NaOH (10%) was added dropwise. The reaction mixture was stirred overnight at room temperature. The obtained solid was collected by filtration and purified by recrystallization from EtOH to give desired product as a pure solid. |
With sodium hydroxide In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol; water at 20℃; | General procedure for the synthesis of compound 5c To a stirred solution of 4-bromobenzaldehyde (1 mmol) and indanone (1 mmol) in EtOH (10 cc) the aqueous solution of NaOH (10 %) was added dropwise. The reaction mixture was stirred overnight at room temperature. The obtained solid was collected by filtration and purified by recrystallization from EtOH to give 5c as a pure solid. 2-(4-bromobenzilidine)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (5c) Pale yellow solid; Yield 86 %; mp: 178-180 C; FT-IR (KBr) m 2961, 1687, 1630, 1497, 1304, 1252, 1087 cm-1; 1HNMR (400 MHz, CDCl3): δ 3.90 (2H, s, -inden-CH2), 3.94 (3H, s, O-CH3), 3.99 (3H, s, O-CH3), 6.96 (1H, s, Ar-H), 7.31 (1H,s, Ar-H), 7.47-7.50 (2H, d, J = 8.4 Hz, Ar-H), 7.50 (1H, s, methine-H), 7.55-7.57 (2H, d, J = 8.4, Ar-H). |
86% | With sodium hydroxide In ethanol; water at 20℃; for 24h; Inert atmosphere; | General procedure for the synthesis of compound (3) General procedure: To a stirred solution of 4-halobenzaldehyde (1 mmol) and indanone (1 mmol) in EtOH (10 mL), an aqueous solution of NaOH (10%) was added dropwise. The reaction mixture was stirred overnight at room temperature. The obtained solid was collected by filtration and purified by recrystallization from EtOH to give desired product as a pure solid. |
60.8% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With [Ir(dpyx-N,C,N)Cl(i-Cl)]2; caesium carbonate; In tert-Amyl alcohol; at 130℃; for 2h; | 5,6-dimethoxyindanone (284 mg, 1 mmol),<strong>[67686-01-5]1-benzyl-4-piperidinemethanol</strong> (284 mg, 1 mmol), [Ir(dpyx-N,C,N)Cl(i-Cl)]2 (10.8 mg, 0.01 mmol, 0.5 mol%),After adding cesium carbonate (98 mg, 0.3 mmol, 0.3 equiv.) and t-amyl alcohol (1 mL) to the dried 25 mL reaction mixture at 130 C for 2 hours,Cool to room temperature. The solvent was removed by rotary evaporation and then purified by column chromatography (developer: petroleum ether/ethyl acetate) to give the pure target compound in a yield of 85%. |
83% | With C39H32Cl2N5PRu; potassium tert-butylate; In tert-Amyl alcohol; at 120℃; for 12h;Inert atmosphere; Schlenk technique; | In a 15 ml Schlenk tube, add 76.88 mg (0.4 mmol) of 5,6-dimethoxyindanone,90.33 mg (0.44 mmol) of <strong>[67686-01-5]1-benzyl-4-piperidinemethanol</strong>, 1.55 mg (0.5 mol %) of a clamp metal ruthenium (II) compound,22.44 mg (0.5 equiv) Potassium tert-butoxide, 0.5 ml t-amyl alcohol, magnetic stirring under argon atmosphere, reaction at 120 C for 12 h.According to TLC analysis, the starting material has been completely reacted. After rotary evaporation in vacuum and thin layer chromatography, the quality of the finished product was 126.65 mg and the yield was 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium hydroxide In ethanol at 20℃; | 4.1.2. General procedure for the synthesis of (E)-2-(4-(4-(substituted) piperazin-1-yl) benzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (32-46) General procedure: Equimolar ratio (1 M each) of 5,6-dimethoxyindanone andrespective piperazine aldehyde was reacted in anhydrous ethanolin the presence of 5 ml ethanolic solution of KOH (4 g KOH in100 ml). The reaction mixture was stirred overnight, then, on thenext day the appeared solid product was filtered and washed twicewith ethanol and water. The crude products were dried in oven andpurified by column chromatography using chloroform/methanol(97:03) as eluent. The compounds were fully characterized by using1H NMR, 13C NMR and Mass spectroscopy. The spectral characterizationof all final compounds except 40, 44 and 46 are given in thesupplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium hydroxide In ethanol at 20℃; | 4.1.2. General procedure for the synthesis of (E)-2-(4-(4-(substituted) piperazin-1-yl) benzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (32-46) General procedure: Equimolar ratio (1 M each) of 5,6-dimethoxyindanone andrespective piperazine aldehyde was reacted in anhydrous ethanolin the presence of 5 ml ethanolic solution of KOH (4 g KOH in100 ml). The reaction mixture was stirred overnight, then, on thenext day the appeared solid product was filtered and washed twicewith ethanol and water. The crude products were dried in oven andpurified by column chromatography using chloroform/methanol(97:03) as eluent. The compounds were fully characterized by using1H NMR, 13C NMR and Mass spectroscopy. The spectral characterizationof all final compounds except 40, 44 and 46 are given in thesupplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium hydroxide In ethanol at 20℃; | 4.1.2. General procedure for the synthesis of (E)-2-(4-(4-(substituted) piperazin-1-yl) benzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (32-46) General procedure: Equimolar ratio (1 M each) of 5,6-dimethoxyindanone andrespective piperazine aldehyde was reacted in anhydrous ethanolin the presence of 5 ml ethanolic solution of KOH (4 g KOH in100 ml). The reaction mixture was stirred overnight, then, on thenext day the appeared solid product was filtered and washed twicewith ethanol and water. The crude products were dried in oven andpurified by column chromatography using chloroform/methanol(97:03) as eluent. The compounds were fully characterized by using1H NMR, 13C NMR and Mass spectroscopy. The spectral characterizationof all final compounds except 40, 44 and 46 are given in thesupplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium hydroxide In ethanol at 20℃; | 4.1.2. General procedure for the synthesis of (E)-2-(4-(4-(substituted) piperazin-1-yl) benzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (32-46) General procedure: Equimolar ratio (1 M each) of 5,6-dimethoxyindanone andrespective piperazine aldehyde was reacted in anhydrous ethanolin the presence of 5 ml ethanolic solution of KOH (4 g KOH in100 ml). The reaction mixture was stirred overnight, then, on thenext day the appeared solid product was filtered and washed twicewith ethanol and water. The crude products were dried in oven andpurified by column chromatography using chloroform/methanol(97:03) as eluent. The compounds were fully characterized by using1H NMR, 13C NMR and Mass spectroscopy. The spectral characterizationof all final compounds except 40, 44 and 46 are given in thesupplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium hydroxide In ethanol at 20℃; | 4.1.2. General procedure for the synthesis of (E)-2-(4-(4-(substituted) piperazin-1-yl) benzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (32-46) General procedure: Equimolar ratio (1 M each) of 5,6-dimethoxyindanone andrespective piperazine aldehyde was reacted in anhydrous ethanolin the presence of 5 ml ethanolic solution of KOH (4 g KOH in100 ml). The reaction mixture was stirred overnight, then, on thenext day the appeared solid product was filtered and washed twicewith ethanol and water. The crude products were dried in oven andpurified by column chromatography using chloroform/methanol(97:03) as eluent. The compounds were fully characterized by using1H NMR, 13C NMR and Mass spectroscopy. The spectral characterizationof all final compounds except 40, 44 and 46 are given in thesupplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium hydroxide In ethanol at 20℃; | 4.1.2. General procedure for the synthesis of (E)-2-(4-(4-(substituted) piperazin-1-yl) benzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (32-46) General procedure: Equimolar ratio (1 M each) of 5,6-dimethoxyindanone andrespective piperazine aldehyde was reacted in anhydrous ethanolin the presence of 5 ml ethanolic solution of KOH (4 g KOH in100 ml). The reaction mixture was stirred overnight, then, on thenext day the appeared solid product was filtered and washed twicewith ethanol and water. The crude products were dried in oven andpurified by column chromatography using chloroform/methanol(97:03) as eluent. The compounds were fully characterized by using1H NMR, 13C NMR and Mass spectroscopy. The spectral characterizationof all final compounds except 40, 44 and 46 are given in thesupplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium hydroxide In ethanol at 20℃; | 4.1.2. General procedure for the synthesis of (E)-2-(4-(4-(substituted) piperazin-1-yl) benzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (32-46) General procedure: Equimolar ratio (1 M each) of 5,6-dimethoxyindanone andrespective piperazine aldehyde was reacted in anhydrous ethanolin the presence of 5 ml ethanolic solution of KOH (4 g KOH in100 ml). The reaction mixture was stirred overnight, then, on thenext day the appeared solid product was filtered and washed twicewith ethanol and water. The crude products were dried in oven andpurified by column chromatography using chloroform/methanol(97:03) as eluent. The compounds were fully characterized by using1H NMR, 13C NMR and Mass spectroscopy. The spectral characterizationof all final compounds except 40, 44 and 46 are given in thesupplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide In ethanol; water at 20℃; for 48h; | 4.4. General procedure for the synthesis of compounds 8 and 9a-b General procedure: 2,3-Dihydro-5,6-dimethoxy-1H-inden-1-one (7) (1 g, 5.2 mmol)and benzaldehyde derivatives 3 or 6a-b (5.2 mmol) were dissolvedin ethanol (30 ml). Aqueous NaOH solution (10% W/W, 10 ml) wasadded to this solution dropwise with stirring. The reaction mixturewas stirred for 48 h at room temperature. The precipitate was filtered and washed with aqueous ethanol solution (50% V/V) andthen the solid product was dried under vacuum and used withoutfurther purification. |
88% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium hydroxide; In methanol; at 20℃; for 48h; | General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium hydroxide In methanol at 20℃; for 48h; | 4.1.1.4. 5-Methoxy, 6-methoxy or 5,6-dimethoxy-2-(4-substituedbenzilidene)-2,3-dihydro-1H-inden-1-one derivatives(15-38). General procedure: A mixture of appropriate indan-1-one derivative(2 mmol), benzaldehyde derivative (2 mmol) and potassium hydroxide(2 mmol, 0.112 g) in methanol (10 mL) was stirred at roomtemperature for 48 h. The resulting colored solid was filtered, driedand crystallized from EtOH [63]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With hydrazine hydrate; acetic acid In isopropyl alcohol at 90℃; for 0.5h; Microwave irradiation; | General procedure for the synthesis of N4-TSCs General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), 85% hydrazine hydrate (21 mL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 mL) and isopropanol (0.5 mL) contained in a glass tube equipped with a screw cap and magnetic agitation was placed in a microwave synthesis reactor (Microwave 300 Anton Paar) at 90 C (30 W, 2.5 bar). Once the reaction was completed, as monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrazine hydrate; acetic acid In isopropyl alcohol at 90℃; for 1.08333h; Microwave irradiation; | General procedure for the synthesis of N4-TSCs General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), 85% hydrazine hydrate (21 mL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 mL) and isopropanol (0.5 mL) contained in a glass tube equipped with a screw cap and magnetic agitation was placed in a microwave synthesis reactor (Microwave 300 Anton Paar) at 90 C (30 W, 2.5 bar). Once the reaction was completed, as monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With hydrazine hydrate; acetic acid In isopropyl alcohol at 90℃; for 0.75h; Microwave irradiation; | General procedure for the synthesis of N4-TSCs General procedure: Method B: A mixture of 1-indanone or 5,6-dimethoxy-1-indanone (0.38 mmol), 85% hydrazine hydrate (21 mL), the corresponding isothiocyanate (0.43 mmol), acetic acid (20 mL) and isopropanol (0.5 mL) contained in a glass tube equipped with a screw cap and magnetic agitation was placed in a microwave synthesis reactor (Microwave 300 Anton Paar) at 90 C (30 W, 2.5 bar). Once the reaction was completed, as monitored by TLC, the obtained mixture was suspended in water (5 mL), filtered and washed with ethanol (2 mL). N4-TSCs were recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydroxide In ethanol at 20℃; | 5.6. Synthesis of (E)-1-substitutedphenyl-3-(3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-yl)prop-2-en-1-one 18(a-f) General procedure: To the 3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazole-5-carbaldehyde (12b) prepared in the previous step was added correspondingsubstituted acetophenones and catalytic amount ofsodium hydroxide in ethanol. The reaction mixture was stirred atroom temperature for 3-4 h and progress of the reaction wasmonitored by TLC. After completion, ethanol was evopouratedunder vacuum and the residue was neutralised with dilute HClsolution. Finally the chalcones were extracted with ethyl acetatefollowed by purification was done by using column chromatographyto obtain pure compounds of 18a-f with good yields(60-75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 5,6-dimethoxy-1-indanone With sodium ethanolate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: C16H17ClN2O In tetrahydrofuran for 20h; Inert atmosphere; | (E) 2-((1-((4-Chloroquinolin-2-yl)methyl)piperidin-4-yl) methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (12) To a mixture of 5,6-dimethoxy-1-indanone (10) (0.0445g; 0.2316mmol) in anhydrous THF (1.5mL) under argon protection was added EtONa 95% (0.0266g; 0.3910mmol), and stirred at room temperature for 30min. After, was dropwise added a solution of aldehyde 8 (0,080g; 0,2770mmol) in THF (1,5mL), and stirred for 20h. The mixture was partitioned with dichloromethane and NaCl sat, the organic phase was concentrated under reduced pressure and the crude material was purified by flash chromatography with dichloromethane:ethyl acetate gradient. Yields: 86% (0,092g); mp:189-191°C. IR: 1688,1656cm-1. 1H NMR (400MHz, CDCl3) δ: 8.22 (1H, d, J=9.3Hz, H-9), 8.08 (1H, d, J=8.4Hz, H-6), 7.80 (1H, s, H-3), 7.75 (1H, ddd, J=8.4; 7.0; 1.4Hz, H-8), 7.62 (1H, ddd, J=8.2; 7.0; 1.0 H-7), 7.30 (1H, s, H-23), 6.91 (1H, s, H-26), 6.69 (1H, dd, J=8.0; 1.7, H-17), 3.97 (3H, s, H-27), 3.93 (3H, s, H-28), 3.83 (2H, s, H-11), 3.61 (2H, d, J=1.3Hz, H-19), 2.94-3.02 (2H, m, H-16eq, H-12eq), 2.32-2.42 (2H, m, H-13eq, H-14), 2.25 (2H, td, J=11.2; 3.4Hz, H-12ax, H-16ax), 1.67-1.78 (3H, m, H-13ax, H-15ax, H-15eq). 13C NMR (400MHz, CDCl3) δ: 29.5 (C19), 31.2 (C13 e C15), 37.1 (C14), 53.5 (C12 e C16), 56.2 (C27), 56.3 (C28), 65.2 (C11), 105.0 (C23), 107.2 (C26), 121.0 (C3), 124.0 (C9), 125.6 (C4), 127.1 (C7), 129.3 (C6), 130.3 (C8), 131.8 (C21), 135.8 (C18), 139.6 (C17), 143.1(C5), 144.5 (C20), 148.4 (C10), 149.5 (C25), 155.3 (C24), 160.0 (C2), 192.6 (C22). HRMS (ESI): m/z [M+H+] calcd for C27H27ClN2O3 463.1783, found m/z [M+H+] 463.1782. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With manganese(IV) oxide; ammonium hydroxide; oxygen; chlorobenzene In N,N-dimethyl-formamide at 100℃; for 24h; Autoclave; Green chemistry; | 6; 28 Example 28: General procedure: 0.01g of MnO2 catalyst, 0.5mmol of 1-indanone, 0.2g of ammonia water (25wt%) and 2g of chlorobenzene were added to a stainless steel autoclave with a polytetrafluoroethylene inner liner.The temperature was raised to 110 by automatic temperature controller, 0.6MPa oxygen was added and the reaction was continued for 4h. The pressure was kept constant during the reaction.The reaction product was analyzed using GC-MS with a phthalamide yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydroxide In ethanol; water at 25℃; | General procedure C (Michael addition) General procedure: 2-Arylideneindan-1-one (3.0 mmol) was added to a well-stirred solution of 1-indanones(3.0 mmol) and NaOH/H2O 10% (1.6 mL) in ethanol (1.6 mL). After the mixture wasstirred at ice bath or room temperature for 3-5 h, the solid was filtered and washed withwater. The product was purified by preparative TLC. The compounds 9a, 9a*, 9b 18a, 19a,20a, and 20b were prepared as per the mentioned procedure. The structure of reactionproducts were established by spectroscopic data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.8% | With potassium hydroxide In ethanol; water monomer at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
With sodium hydroxide In ethanol; water monomer at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.3% | With potassium hydroxide In ethanol; water at 50℃; for 72h; | General procedure for the preparation of indanone-chalcone hybrid compounds TM-1-TM-12 General procedure: To a mixture of 5,6-dimethoxy-1-indanone (1 mmol) in EtOH (3 mL) was added the appropriate benzaldehyde(1 mmol). An amount of a 30% aqueous KOH (4 mmol)solution was then slowly added dropwise to the reaction.The mixture was stirred for 72 h at 50 °C. After cooling to room temperature, 10% HCl was added dropwise to the mixture making pH = 2, overnight, a yellow precipitate formed and filtrated, the residue was recrystallized with 80% ethanol to give yellow solid TM-1-TM-12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydroxide In ethanol; water at 20℃; for 48h; | 4.4. General procedure for the synthesis of compounds 8 and 9a-b General procedure: 2,3-Dihydro-5,6-dimethoxy-1H-inden-1-one (7) (1 g, 5.2 mmol)and benzaldehyde derivatives 3 or 6a-b (5.2 mmol) were dissolvedin ethanol (30 ml). Aqueous NaOH solution (10% W/W, 10 ml) wasadded to this solution dropwise with stirring. The reaction mixturewas stirred for 48 h at room temperature. The precipitate was filtered and washed with aqueous ethanol solution (50% V/V) andthen the solid product was dried under vacuum and used withoutfurther purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydroxide; In ethanol; water; at 20℃; for 48h; | General procedure: 2,3-Dihydro-5,6-dimethoxy-1H-inden-1-one (7) (1 g, 5.2 mmol)and benzaldehyde derivatives 3 or 6a-b (5.2 mmol) were dissolvedin ethanol (30 ml). Aqueous NaOH solution (10% W/W, 10 ml) wasadded to this solution dropwise with stirring. The reaction mixturewas stirred for 48 h at room temperature. The precipitate was filtered and washed with aqueous ethanol solution (50% V/V) andthen the solid product was dried under vacuum and used withoutfurther purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With hydrogenchloride; In methanol; water; at 60 - 80℃; for 6h; | General procedure: To a solution of (7) 1-(<strong>[4649-09-6]1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde</strong> (0.300g, 2.053mmol) in 32% aqueous HCl/methanol (1.5:1 v/v) (4.5ml/3 ml) was added a selected bicyclic scaffold (tetralone, indanone, 3-coumaranone, 4-chromanone and thiochroman-4-one) (2.053mmol) and the reaction was refluxed for at least 6h at 60-80C. The progress of the reaction was monitored by silica gel TLC with ethyl acetate as mobile phase. When the reaction reached completion, the target products were isolated by precipitation with ice-cold water, after which they were purified by recrystallisation with ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With hydrogenchloride In ethanol; water at 79℃; | 3.1. General procedure for synthesis of thiosemicarbazones (3a-v) General procedure: Aldehydes and ketones (5 mmol) 2a-d and thiosemicarbazides (5mmol) 1a-k were dissolved in ethanol solvent in the presence of catalyticamount of dilute HCl (2-3 drops). The reaction mixture wasallowed to reflux for 2-3 h and reaction progression was monitored byTLC. Upon consumption of the starting material, the reaction mixturewas evaporated under vacuum. The resulting crude product was filteredand washed with hot alcohol. Thiosemicarbazones (3a-v) were obtainedin good yields (Table 1). The products were crystallized fromchloroform-ethanol (1:1) mixture. For X-ray measurements, singlecrystal of 3g was mounted on a MiTeGen loop with grease and examinedon a Bruker D8 Venture APEX diffractometer equipped with Photon 100CCD area detector and Oxford Cryostream cooler at 296 (2) K usinggraphite-monochromated Mo-Kα radiation(λ = 0.71073 Å). Data wascollected using the APEX-II software [49], integrated using SAINT [50]and corrected for absorption using a multi-scan approach (SADABS)[51]. The structure was solved using intrinsic phasing (SHELXT) [52].Final cell constants were determined from full least squares refinementof all observed reflections. All non-H atoms were located in subsequentdifference maps and refined anisotropically with SHELXL-2016 [52]using full least squares refinement against F2. H-atoms were added atcalculated positions and refined with a riding model. N-H atoms werelocated in the difference map and refined isotropically with U(iso) ridingon the N with DFIX constraints applied. The structure has been depositedwith the CCDC (CSD deposition number = 1984391). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride In ethanol; water at 79℃; | 3.1. General procedure for synthesis of thiosemicarbazones (3a-v) General procedure: Aldehydes and ketones (5 mmol) 2a-d and thiosemicarbazides (5mmol) 1a-k were dissolved in ethanol solvent in the presence of catalyticamount of dilute HCl (2-3 drops). The reaction mixture wasallowed to reflux for 2-3 h and reaction progression was monitored byTLC. Upon consumption of the starting material, the reaction mixturewas evaporated under vacuum. The resulting crude product was filteredand washed with hot alcohol. Thiosemicarbazones (3a-v) were obtainedin good yields (Table 1). The products were crystallized fromchloroform-ethanol (1:1) mixture. For X-ray measurements, singlecrystal of 3g was mounted on a MiTeGen loop with grease and examinedon a Bruker D8 Venture APEX diffractometer equipped with Photon 100CCD area detector and Oxford Cryostream cooler at 296 (2) K usinggraphite-monochromated Mo-Kα radiation(λ = 0.71073 Å). Data wascollected using the APEX-II software [49], integrated using SAINT [50]and corrected for absorption using a multi-scan approach (SADABS)[51]. The structure was solved using intrinsic phasing (SHELXT) [52].Final cell constants were determined from full least squares refinementof all observed reflections. All non-H atoms were located in subsequentdifference maps and refined anisotropically with SHELXL-2016 [52]using full least squares refinement against F2. H-atoms were added atcalculated positions and refined with a riding model. N-H atoms werelocated in the difference map and refined isotropically with U(iso) ridingon the N with DFIX constraints applied. The structure has been depositedwith the CCDC (CSD deposition number = 1984391). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride In ethanol; water at 79℃; | 3.1. General procedure for synthesis of thiosemicarbazones (3a-v) General procedure: Aldehydes and ketones (5 mmol) 2a-d and thiosemicarbazides (5mmol) 1a-k were dissolved in ethanol solvent in the presence of catalyticamount of dilute HCl (2-3 drops). The reaction mixture wasallowed to reflux for 2-3 h and reaction progression was monitored byTLC. Upon consumption of the starting material, the reaction mixturewas evaporated under vacuum. The resulting crude product was filteredand washed with hot alcohol. Thiosemicarbazones (3a-v) were obtainedin good yields (Table 1). The products were crystallized fromchloroform-ethanol (1:1) mixture. For X-ray measurements, singlecrystal of 3g was mounted on a MiTeGen loop with grease and examinedon a Bruker D8 Venture APEX diffractometer equipped with Photon 100CCD area detector and Oxford Cryostream cooler at 296 (2) K usinggraphite-monochromated Mo-Kα radiation(λ = 0.71073 Å). Data wascollected using the APEX-II software [49], integrated using SAINT [50]and corrected for absorption using a multi-scan approach (SADABS)[51]. The structure was solved using intrinsic phasing (SHELXT) [52].Final cell constants were determined from full least squares refinementof all observed reflections. All non-H atoms were located in subsequentdifference maps and refined anisotropically with SHELXL-2016 [52]using full least squares refinement against F2. H-atoms were added atcalculated positions and refined with a riding model. N-H atoms werelocated in the difference map and refined isotropically with U(iso) ridingon the N with DFIX constraints applied. The structure has been depositedwith the CCDC (CSD deposition number = 1984391). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride In ethanol; water at 79℃; | 3.1. General procedure for synthesis of thiosemicarbazones (3a-v) General procedure: Aldehydes and ketones (5 mmol) 2a-d and thiosemicarbazides (5mmol) 1a-k were dissolved in ethanol solvent in the presence of catalyticamount of dilute HCl (2-3 drops). The reaction mixture wasallowed to reflux for 2-3 h and reaction progression was monitored byTLC. Upon consumption of the starting material, the reaction mixturewas evaporated under vacuum. The resulting crude product was filteredand washed with hot alcohol. Thiosemicarbazones (3a-v) were obtainedin good yields (Table 1). The products were crystallized fromchloroform-ethanol (1:1) mixture. For X-ray measurements, singlecrystal of 3g was mounted on a MiTeGen loop with grease and examinedon a Bruker D8 Venture APEX diffractometer equipped with Photon 100CCD area detector and Oxford Cryostream cooler at 296 (2) K usinggraphite-monochromated Mo-Kα radiation(λ = 0.71073 Å). Data wascollected using the APEX-II software [49], integrated using SAINT [50]and corrected for absorption using a multi-scan approach (SADABS)[51]. The structure was solved using intrinsic phasing (SHELXT) [52].Final cell constants were determined from full least squares refinementof all observed reflections. All non-H atoms were located in subsequentdifference maps and refined anisotropically with SHELXL-2016 [52]using full least squares refinement against F2. H-atoms were added atcalculated positions and refined with a riding model. N-H atoms werelocated in the difference map and refined isotropically with U(iso) ridingon the N with DFIX constraints applied. The structure has been depositedwith the CCDC (CSD deposition number = 1984391). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride In ethanol; water at 79℃; | 3.1. General procedure for synthesis of thiosemicarbazones (3a-v) General procedure: Aldehydes and ketones (5 mmol) 2a-d and thiosemicarbazides (5mmol) 1a-k were dissolved in ethanol solvent in the presence of catalyticamount of dilute HCl (2-3 drops). The reaction mixture wasallowed to reflux for 2-3 h and reaction progression was monitored byTLC. Upon consumption of the starting material, the reaction mixturewas evaporated under vacuum. The resulting crude product was filteredand washed with hot alcohol. Thiosemicarbazones (3a-v) were obtainedin good yields (Table 1). The products were crystallized fromchloroform-ethanol (1:1) mixture. For X-ray measurements, singlecrystal of 3g was mounted on a MiTeGen loop with grease and examinedon a Bruker D8 Venture APEX diffractometer equipped with Photon 100CCD area detector and Oxford Cryostream cooler at 296 (2) K usinggraphite-monochromated Mo-Kα radiation(λ = 0.71073 Å). Data wascollected using the APEX-II software [49], integrated using SAINT [50]and corrected for absorption using a multi-scan approach (SADABS)[51]. The structure was solved using intrinsic phasing (SHELXT) [52].Final cell constants were determined from full least squares refinementof all observed reflections. All non-H atoms were located in subsequentdifference maps and refined anisotropically with SHELXL-2016 [52]using full least squares refinement against F2. H-atoms were added atcalculated positions and refined with a riding model. N-H atoms werelocated in the difference map and refined isotropically with U(iso) ridingon the N with DFIX constraints applied. The structure has been depositedwith the CCDC (CSD deposition number = 1984391). |
Tags: 2107-69-9 synthesis path| 2107-69-9 SDS| 2107-69-9 COA| 2107-69-9 purity| 2107-69-9 application| 2107-69-9 NMR| 2107-69-9 COA| 2107-69-9 structure
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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 |
Sorry,this product has been discontinued.
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