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CAS No. : | 14548-39-1 | MDL No. : | MFCD02179286 |
Formula : | C9H7BrO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SEQHEDQNODAFIU-UHFFFAOYSA-N |
M.W : | 211.06 | Pubchem ID : | 139778 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 47.19 |
TPSA : | 17.07 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) : | -5.91 cm/s |
Log Po/w (iLOGP) : | 2.05 |
Log Po/w (XLOGP3) : | 2.36 |
Log Po/w (WLOGP) : | 2.58 |
Log Po/w (MLOGP) : | 2.42 |
Log Po/w (SILICOS-IT) : | 3.44 |
Consensus Log Po/w : | 2.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.04 |
Solubility : | 0.193 mg/ml ; 0.000914 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.36 |
Solubility : | 0.924 mg/ml ; 0.00438 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.98 |
Solubility : | 0.0224 mg/ml ; 0.000106 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.72 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium azide; methanesulfonic acid In chloroform for 3 h; Reflux | The compound 6-bromo-2,3-dihydro-1H-inden-1-one (2.0 g, 9.5 mmol) was dissolved in chloroform (30 mL)Methanesulfonic acid (6 mL) was then added dropwise to the reaction system,Finally, sodium azide (1.90 g, 9.5 mmol) was added portionwise to the reaction system,Reflux for three hours.After completion of the reaction, the mixture was cooled to room temperature, and then the reaction solution was poured into ice water. The mixture was separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by column chromatography (Petroleum ether / ethyl acetate: 2/1) to give 7-bromo-3,4-dihydroquinolin-2 (1H) -one(0.90 g) in 42percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tetrahydroborate In ethanol at 10 - 20℃; for 3 h; | 168.8g compd. 6 and 650 ml of ethanol is added during the reaction of the bottle. Next, the water temperature is lower than 10 °C, NaBH445g of small amounts of added. Next, raised in temperature to room temperature, the reaction solution is a 3-hour continuous agitation. After the reaction is completed, ethanol is removed, then the hydrolysis of 10percent HCl 450 ml is added is in order. The mixture is extracted by dichlomethane, thereafter is washed with water, dried and then, the solvent is removed, 170g compd. 7 in which yield 100percent (corallite solid). The reaction of the pathway of the following relationships. |
99% | With sodium borohydrid In methanol | Example 10 Part A, 6-Bromo-2,3-dihydro-1H-inden-1-ol To a solution of 6-bromo-1-indanone (prepared as described by Cornelius, Lyndon A. M. and Combs, Donald W. Synth. Commun. (1994), 24(19), 2777-88) (1.4 g, 6.57 mmol) in 20 mL of methanol was added sodium borohydride (0.087 g, 2.3 mmol) over a period of five minutes at room temperature. The reaction mixture was stirred for two hours at room temperature, concentrated under pressure and partitioned between ethyl acetate (50 mL) and 1N HCl (20 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a solid (1.4 g, 99percent). 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 5.2 (t, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.4 (m, 1H), 1.9 (m, 2H). |
99% | at 20℃; for 2 h; Inert atmosphere | To a solution of 6-bromo-2,3-dihydro-1 H-inden-1 -one (5 g, 23.69 mmol) in methanol (50 mL) was added sodium borohydride (0.896 g, 23.69 mmol) under N2 protection. The reaction mixture was stirred for 2 h at ambient temperature. Then the solvent was removed by reduced pressure. The residue was dissolved inlOO mL of ethyl acetate and 20 mL of 1 N HCI. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). Thecombined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound 6-bromo-2,3-dihydro-1 H-inden-1 -ol (5.0 g, 23.47 mmol, 99percent). LC-MS m/z 195.0 (M-OH), 1.46 mm (ret. time). |
99% | at 20℃; for 2 h; Inert atmosphere | To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.69 mmol) in methanol (50 mL) was added sodium borohydride (0.896 g, 23.69 mmol) under N2 protection. The reaction mixture was stirred for 2 h at ambient temperature. Then the solvent was removed by reduced pressure. The residue was dissolved in100 mL of ethyl acetate and 20 mL of 1 N HCl. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound 6-bromo-2,3-dihydro-1H-inden-1-ol (5.0 g, 23.47 mmol, 99percent). LC-MS m/z 195.0 (M-OH)+, 1.46 min (ret. time). |
97% | at 20℃; for 2 h; Inert atmosphere | To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.69 mmol) in methanol (100 mL) was added sodium borohydride (0.986 g, 26.1 mmol) under N2. The reaction mixturewas stirred at ambient temperature for 2 hrs. The solvent was removed by reducedpressure. The residue was re-dissolved in 100 mL of ethyl acetate and 20 mL of iN HCI.The organic layer was separated and the aqueous layer was extracted with ethyl acetate(3x). The combined organic layer was washed with brine and dried over anhydrous Na2SO4.After filtration and concentration, the title compound 6-bromo-2,3-dihydro-1 H-inden-1 -ol (4.9g, 23.0 mmol, 97percent) was obtained and was carried over to next step without furtherpurification. LC-MS mlz 197.0 (M+H-18), 1.80 mm (ret. time) |
96% | for 0.5 h; Inert atmosphere | Under N2 atmosphere, 6-bromo-1-indanone (1 mmol) was dissolved in MeOH (2.25 mL) and NaBH4 (1 mmol) was added in 3 portions, every 10 min. After 30 min, the solvent was evaporated and crude was dissolved in EtOAc (1 mL) and H2O (3 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were dried and concentrated to dryness to give pure alcohol in 96percent yield. 1H-NMR (400MHz, CDCl3) δ ppm: 7.3-7.2 (m, 2H), 7.14 (dd, , J=8 and 2 Hz, 1H), 5.26 (t, J=6 Hz, 1H,), 3.09-3.01 (m, 1H), 2.87-2.80 (m, 1H), 2.62-2.54 (m, 1H), 2.03-1.96 (m, 1H). |
96% | for 0.5 h; Inert atmosphere | Under N2 atmosphere, 6-bromo-1 -indanone (1 mmol) was dissolved in MeOH (2.25 mL) and NaBH4 (1 mmol) was added in 3 portions, every 10 min. After 30 min, the solvent was evaporated and crude was dissolved in EtOAc (1 mL) and H20 (3 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were dried and concentrated to dryness to give pure alcohol in 96percent yield.1 H-NMR (400MHz, CDCI3) δ Dppm: 7.3-7.2 (m, 2H), 7.14 (dd, , J=8 and 2 Hz, 1 H), 5.26 (t, J=6 Hz, 1 H,), 3.09-3.01 (m, 1 H), 2.87-2.80 (m, 1 H), 2.62-2.54 (m, 1 H), 2.03- 1 .96 (m, 1 H). |
95% | With sodium tetrahydroborate In methanol at 20℃; for 2 h; | To a solution of 6-bromoindan-1-one (Aldrich, cat No.597147: 250 mg, 1.2 mmol) in methanol (3 mL) was added sodium tetrahydroborate (49 mg, 1.3 mmol) in 2 portions. The reaction mixture was stirred at room temperature for 2 h leading to complete conversion. The solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried over sodium sulfate, and the solvent was removed to obtain 6-bromoindan-1-ol (racemic, 240 mg, 95percent) which was used in the next step without further purification. LC-MS calculated for C9H8Br (M+H-H2O)+: m/z=195.0. found 195.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium azide; methanesulfonic acid In dichloromethane at 0 - 20℃; | Intermediate 23-1Preparation of 7-bromo-3,4-dihydroisoquinolin-1(2H)-one Sodium azide (0.431 g, 6.63 mmol) was added slowly to a mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1 g, 4.74 mmol) and methanesulfonic acid (15 mL, 231 mmol) in DCM (30 mL) at 0° C. The mixture was stirred at rt for 15 hrs, then was carefully quenched with 1 M aqueous sodium hydroxide (50 mL). The aqueous layer was extracted with DCM (3.x.50 mL), and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 hexane-EtOAc to EtOAc) to give 7-bromo-3,4-dihydroisoquinolin-1(2H)-one as white solid (650 mg, 61percent). 1H NMR (400 MHz, chloroform-d) δ 8.35 (1H, br. s.), 7.08-7.17 (1 H, m), 6.98-7.06 (1H, m), 6.95 (1H, d, J=1.98 Hz), 2.93 (2H, t, J=7.59 Hz), 2.49-2.68 (2H, m). Mass spectrum m/z 226, 228 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trifluorormethanesulfonic acid; In dichloromethane; at 80℃; for 1h;High pressure; Inert atmosphere; Green chemistry; | 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. |
80% | With aluminum (III) chloride; In dichloromethane; for 3h;Reflux; | 229g of 4-bromo-phenylpropionic acid (Compound 5) and 357g of aluminum chlorideHexafluorophosphate (AlCl3) was added to the 2L three-necked flask, and heated under reflux for 3 hours. Then, excess AlCl3 was removed and dichloromethane 1.2L were added. Then, the temperature is lowered to 5 , AlCl3 of 3200g was added. The reaction solution was refluxed for 5 hours and poured into a mixture of HCl and ice for hydrolysis. The product is extracted, and is purified by flash chromatography to give compound 6 (pale yellow solid) of 168.8g was obtained in 80% yield. Synthetic route of the reaction is as follows. |
With chlorosulfonic acid; for 2h;Cooling with ice; | Step 1-1; To chlorosulfuric acid (1.19 L) was added 3- (4-bromophenyl) propanoic acid (91.1 g) under ice cooling and the mixture was stirred for 2 hours. To H2O (2.00 L), the reaction mixture was slowly added under ice cooling, and extracted 6 times with CHCl3. The combined organic layers were washed with a saturated aqueous NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. To the resultant residue, MeOH was added and the mixture was heated to reflux for 30 minutes. A solid substance was obtained by filtration to give solid A. The filtrate was concentrated under reduced pressure and solid B was obtained in the same manner. Thereafter, the filtrate was again concentrated under reduced pressure and solid C was obtained in the same manner. Solids A, B and C were combined to obtain 6-bromo-2, 3-dihydro-lH-inden-l- one (59.3 g, a light yellow solid) .1H NMR (600 MHz, CDCl3, delta) : 2.66-2.75 (m, 2H), 3.04-3.12 (m, 2H), 7.36 (d, J = 8.3 Hz, IH), 7.67 (dd, J = 8.0, 2.1 Hz, IH), 7.86 (d, J = 1.8 Hz, IH); ESI/APCI MS m/z 210 [M+H]+. |
With hydrogenchloride; thionyl chloride;aluminium trichloride; In dichloromethane; | 6-Bromo-1-indanone. 3 3-(4-Bromophenyl)propionic acid (162 g, 706 mmol) and thionyl chloride (155 mL, 2120 mmol) were refluxed for 90 minutes. The thionyl chloride was then removed under vacuum to yield an amber oil. This oil, aluminum chloride (109 g, 816 mmol), and dichloromethane (1000 mL) were refluxed for 90 minutes and then poured onto ice. Dilute hydrochloric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate, water, and brine. The product was flash chromatographed on a 25*7 cm silica gel column and eluted with ethyl acetate/dichloromethane (5:95) to obtain a pale brown solid after removing solvent under vacuum, (142 g, 95%), 107-109 C. m.p. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tetrahydroborate; In ethanol; at 10 - 20℃; for 3h; | 168.8g compd. 6 and 650 ml of ethanol is added during the reaction of the bottle. Next, the water temperature is lower than 10 C, NaBH445g of small amounts of added. Next, raised in temperature to room temperature, the reaction solution is a 3-hour continuous agitation. After the reaction is completed, ethanol is removed, then the hydrolysis of 10% HCl 450 ml is added is in order. The mixture is extracted by dichlomethane, thereafter is washed with water, dried and then, the solvent is removed, 170g compd. 7 in which yield 100% (corallite solid). The reaction of the pathway of the following relationships. |
99% | With sodium borohydrid; In methanol; | Example 10 Part A, 6-Bromo-2,3-dihydro-1H-inden-1-ol To a solution of 6-bromo-1-indanone (prepared as described by Cornelius, Lyndon A. M. and Combs, Donald W. Synth. Commun. (1994), 24(19), 2777-88) (1.4 g, 6.57 mmol) in 20 mL of methanol was added sodium borohydride (0.087 g, 2.3 mmol) over a period of five minutes at room temperature. The reaction mixture was stirred for two hours at room temperature, concentrated under pressure and partitioned between ethyl acetate (50 mL) and 1N HCl (20 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a solid (1.4 g, 99%). 1H NMR (CDCl3): delta 7.45 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 5.2 (t, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.4 (m, 1H), 1.9 (m, 2H). |
99% | With methanol; sodium tetrahydroborate; at 20℃; for 2h;Inert atmosphere; | To a solution of 6-bromo-2,3-dihydro-1 H-inden-1 -one (5 g, 23.69 mmol) in methanol (50 mL) was added sodium borohydride (0.896 g, 23.69 mmol) under N2 protection. The reaction mixture was stirred for 2 h at ambient temperature. Then the solvent was removed by reduced pressure. The residue was dissolved inlOO mL of ethyl acetate and 20 mL of 1 N HCI. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). Thecombined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound 6-bromo-2,3-dihydro-1 H-inden-1 -ol (5.0 g, 23.47 mmol, 99%). LC-MS m/z 195.0 (M-OH), 1.46 mm (ret. time). |
99% | With methanol; sodium tetrahydroborate; at 20℃; for 2h;Inert atmosphere; | To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.69 mmol) in methanol (50 mL) was added sodium borohydride (0.896 g, 23.69 mmol) under N2 protection. The reaction mixture was stirred for 2 h at ambient temperature. Then the solvent was removed by reduced pressure. The residue was dissolved in100 mL of ethyl acetate and 20 mL of 1 N HCl. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound 6-bromo-2,3-dihydro-1H-inden-1-ol (5.0 g, 23.47 mmol, 99%). LC-MS m/z 195.0 (M-OH)+, 1.46 min (ret. time). |
97% | With methanol; sodium tetrahydroborate; at 20℃; for 2h;Inert atmosphere; | To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.69 mmol) in methanol (100 mL) was added sodium borohydride (0.986 g, 26.1 mmol) under N2. The reaction mixturewas stirred at ambient temperature for 2 hrs. The solvent was removed by reducedpressure. The residue was re-dissolved in 100 mL of ethyl acetate and 20 mL of iN HCI.The organic layer was separated and the aqueous layer was extracted with ethyl acetate(3x). The combined organic layer was washed with brine and dried over anhydrous Na2SO4.After filtration and concentration, the title compound 6-bromo-2,3-dihydro-1 H-inden-1 -ol (4.9g, 23.0 mmol, 97%) was obtained and was carried over to next step without furtherpurification. LC-MS mlz 197.0 (M+H-18), 1.80 mm (ret. time) |
96% | With methanol; sodium tetrahydroborate; for 0.5h;Inert atmosphere; | Under N2 atmosphere, 6-bromo-1-indanone (1 mmol) was dissolved in MeOH (2.25 mL) and NaBH4 (1 mmol) was added in 3 portions, every 10 min. After 30 min, the solvent was evaporated and crude was dissolved in EtOAc (1 mL) and H2O (3 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were dried and concentrated to dryness to give pure alcohol in 96% yield. 1H-NMR (400MHz, CDCl3) delta ppm: 7.3-7.2 (m, 2H), 7.14 (dd, , J=8 and 2 Hz, 1H), 5.26 (t, J=6 Hz, 1H,), 3.09-3.01 (m, 1H), 2.87-2.80 (m, 1H), 2.62-2.54 (m, 1H), 2.03-1.96 (m, 1H). |
96% | With methanol; sodium tetrahydroborate; for 0.5h;Inert atmosphere; | Under N2 atmosphere, 6-bromo-1 -indanone (1 mmol) was dissolved in MeOH (2.25 mL) and NaBH4 (1 mmol) was added in 3 portions, every 10 min. After 30 min, the solvent was evaporated and crude was dissolved in EtOAc (1 mL) and H20 (3 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were dried and concentrated to dryness to give pure alcohol in 96% yield.1 H-NMR (400MHz, CDCI3) delta Dppm: 7.3-7.2 (m, 2H), 7.14 (dd, , J=8 and 2 Hz, 1 H), 5.26 (t, J=6 Hz, 1 H,), 3.09-3.01 (m, 1 H), 2.87-2.80 (m, 1 H), 2.62-2.54 (m, 1 H), 2.03- 1 .96 (m, 1 H). |
96% | With sodium tetrahydroborate; ethanol; at 20℃; for 12h; | EtOH (250 mL) containing indanone compound 12 (5.00 g, 23.7 mmol) NaBH4 (806 mg, 21.3 mmol) was added to the solution at ambient temperature.at ambient temperature.After stirring for 12 hours at the same temperature,The reaction mixture was quenched with saturated NH 4 Cl and then concentrated in vacuo. The residue was extracted with EtOAc.The combined organic layers were dried over MgSO 4 and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1: 4) to afford 4.86 g (96%) of compound 18 as a white solid. |
95% | With sodium tetrahydroborate; In methanol; at 20℃; for 2h; | To a solution of 6-bromoindan-1-one (Aldrich, cat No.597147: 250 mg, 1.2 mmol) in methanol (3 mL) was added sodium tetrahydroborate (49 mg, 1.3 mmol) in 2 portions. The reaction mixture was stirred at room temperature for 2 h leading to complete conversion. The solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried over sodium sulfate, and the solvent was removed to obtain 6-bromoindan-1-ol (racemic, 240 mg, 95%) which was used in the next step without further purification. LC-MS calculated for C9H8Br (M+H-H2O)+: m/z=195.0. found 195.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum (III) chloride; In dichloromethane; at 20℃; for 5.0h;Heating / reflux; | 6-Bromo-indan-1-one (Compound 10) Thionyl chloride (15.6 g, 131. 1 mmol) was added slowly to a solution of 3- (4- bromo-phenyl) -propionic acid (available from Transworld Chemicals, 10.0 g, 43.7 mmol) in 100 mL of dichloromethane at room temperature. The mixture was then heated at reflux for 14 h. After cooling to room temperature, the solvent and excess thionyl chloride were removed under reduced pressure to afford a yellow crude oil. The crude product was then dissolved in 100 mL of dichloromethane and aluminum chloride (17.5 g, 131. 1 mmol) was added portionwise at room temperature. After heating at reflux for 5 h, the mixture was then slowly poured into ice-water, extracted with dichloromethane (3 x 50 mL), washed with brine (1 x 50 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (95: 5 hexane/ethyl acetate) yielded the title compound (8.94 g, 97 % yield) as a light yellow solid: 1H NMR (CDC13, 300 MHz) 6 7. 88 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 2.1, 8.1 Hz, 1H), 7.36 (d, J= 8.1 Hz, 1H), 3.12-3. 08 (m, 2H), 2.75-2. 71 (m, 2H). | |
With aluminum (III) chloride; In 1,2-dichloro-ethane; at 5 - 20℃; for 1.0h; | A suspension of Example 1 (23.5 g, 91 mmol) in toluene (10 mL) was treated thionyl chloride (10 mL, 137 mmol) and the mixture was stirred at about 60 C for about 1 hour. The mixture was concentrated under reduced pressure and was slowly added to a mixture of aluminum chloride (13.4 g, 100 mmol) in 1,2-dichloroethane (90 mL) at about 5 C. The reaction mixture was stirred at room temperature for about 1 hour, poured into ice water and was extracted with dichloromethane. The combined organic extracts were washed successively with water, 5% aqueous sodium bicarbonate and brine, dried (MgS04), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2: 1) as eluent to present the desired product. MS (DCI-NH3) : m/z 228,230 (M+NH4) +. | |
With aluminum (III) chloride; In dichloromethane; at 20℃; | A mixture of 3-(4-bromophenyl)propanoic acid (26 g, 12 mmol) in SOCI2 (50 mL) was refluxed overnight, the mixture was concentrated, then added to AlCl; (80 g, 61 mmol) in DCM (100 mL), the mixture was stirred at room temperature overnight. The mixture was quenched with HCl aqueous, extracted with DCM, washed with brine, dried over Na2SO4, concentrated to give 6-bromo-indan-l-one (12 g, 48%). H-NMR (CD3OD): 2.65 (m, 2H), 3.06 (m, 2H), 7.31 (m, IH), 7.62 (m, IH), 7.80 (m, IH). |
Step 1 6-Bromo-indan-1-one; To a 250 mL of flask was added 3-(4-bromo-phenyl)-propionic acid 38a (20.6 g, 90 mmol, ABCR) and dried in vacuo for 20 minutes followed by addition of 110 mL of anhydrous dichloromethane under nitrogen atmosphere, and then thionyl chloride (20 mL, 276 mmol) was added. The reaction mixture was heated to reflux overnight. The mixture was concentrated under reduced pressure to remove most solvent followed by addition of 100 mL of dichloromethane, and then aluminium trichloride (24.5 g, 25.8 mmol) was added. The generated gas was released. The mixture was warmed up to reflux and stirred overnight. The mixture was poured into 200 g of ice to form a copious amount of precipitates and filtered through silica gel. The filtrate was separated and the aqueous layer was extracted with 30 mL of dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound 6-bromo-indan-1-one 38b (18.34 g, yield 96.6%) as a yellow solid. MS m/z (ESI): 210 [M-1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride; bromine 1.) 10 min, 2.) 80 deg C, 5 min; Yield given. Multistep reaction. Yields of byproduct given; | ||
With hydrogenchloride; bromine In tetrahydrofuran; hexane; water | 6-Bromoindan-1-one (VIIb)and 4-bromoindan-1-one (VIIa). 6-Bromoindan-1-one (VIIb)and 4-bromoindan-1-one (VIIa). A 250 mL three-necked round bottom flask was equipped with a water cooled Liebig condenser, a mechanical stirrer and a pressure-equalized addition funnel protected by means of drying tubes. The flask was charged with anhydrous aluminum chloride (16.6 g, 0.125 moles) and stirred while 1-Indanone (VI) (6.60 g, 0.05 moles), which had been ground to a fine powder with a mortar and pestle was added in two portions over 3 minutes. Copious evolution of HCl gas was accompanied by a moderate exotherm and the mixture rapidly became a dark brown, homogenous slurry which was stirred for an additional 10 minutes. Bromine (3.1 ml, 0.06 moles) was added dropwise to the well stirred mixture over a 10 minute period. After all the bromine had been added, the molten mixture was heated in a water bath to 80° C. for 5 minutes. While still hot, the mixture was poured into 100 g of crushed ice and 20 ml of concentrated hydrochloric acid. The ice mixture was then stirred for 10 minutes, diluted with 100 ml of water and extracted with ether (2*200 mL). The combined ether extracts were washed with water (2*100 mL) and dried over anhydrous sodium sulfate and concentrated to give 10.6 g of a red oil which crystallized on standing at room temperature. Product analysis by GC-MS showed a 1:1 mixture of monobromo isomers. The material was chromatographed on a silica gel column (45*10 cm) using n-hexane/THF (8:1) thereby separating the isomers. The separated isomers were each recrystallized from hexane to give 3.8 g of 6-bromoindan-1-one (VIIa) and 4.0 g of 4-bromoindan-1-one (VIIb). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; 2,2-dimethoxy-propane for 64h; Heating; | ||
With toluene-4-sulfonic acid In 2,2-dimethoxy-propane | 11.a EXAMPLE 11 a) A solution of 10.0 g of 6-bromo-1-indanone, 9.79 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 71 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 1:1). In addition to 3.07 g of educt, there were obtained 9.86 g (78%) of (RS)-2-(2-buten-1-yl)-6-bromo-1-indanone as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With toluene-4-sulfonic acid; propionic acid In 1,2-dichloro-benzene at 105℃; for 16h; | |
84% | With toluene-4-sulfonic acid; propionic acid In 1,2-dichloro-benzene at 105℃; for 16h; | 2 Synthesis of compound 5: Compound 4 (3.28 g, 15.6 mmol), p-toluenesulfonic acid monohydrate (12.7 g, 66.6 mmol), and propionic acid (3.69 g, 49.7 mmol) were dissolved in 15 mL of o-dichlorobenzene.The reaction solution was heated to 105 ° C. and stirred for 16 h. Cool to room temperature,The reaction solution was poured into methanol, neutralized with sodium hydroxide, and the solid was collected by filtration.The obtained solid was washed with methanol and ethanol,And recrystallized from tetrachloroethane to obtain product 5 (2.54 g, yield: 84%) as a pale yellow solid. |
84% | With toluene-4-sulfonic acid; propionic acid In 1,2-dichloro-benzene at 135℃; | 1 The preparation process is as follows Dissolve 6-bromoindanone (3.0g, 14.2mmol) and p-toluenesulfonic acid monohydrate (9.5g, 49.9mmol) in dry o-dichlorobenzene (45mL), add propionic acid (3.7mL) with stirring at room temperature ), the system was heated to 135°C and refluxed for 72 hours. After the reaction is over, cool to room temperature, pour the reaction solution into 100 mL methanol, adjust the pH of the system to neutral with 1M NaOH aqueous solution, at this time a large amount of precipitation will precipitate out, filter, and wash the filter cake with methanol and ethanol successively to obtainIntermediate Y-M, light yellow solid 2.3g, yield 84%. |
24% | With PPA at 120℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 47% 2: 21% 3: 3% 4: 2% | With aluminium trichloride; bromine at 110℃; for 0.5h; Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With toluene-4-sulfonic acid In benzene at 115℃; for 48h; Dean-Stark; Inert atmosphere; | 1.A A. 6'-bromo-2',3'-dihydrospiro[[1,3]dioxolane-2,1'-indene] (2) To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one 1 (5 g, 23.69 mmol) in benzene (158 mL) were added ethane-1,2-diol (26.4 mL, 474 mmol) and tosic acid (0.045 g, 0.237 mmol). The flask was fitted with a Dean-Stark apparatus pre-filled with benzene and a reflux condenser and heated to 115 C over 48 h. The reaction mixture was diluted with EtOAc and neutralized with sat. aq. NaHCO3. Layers were separated and the resulting aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. Flash column chromatography (SiO2, 95:5 hexanes/EtOAc) afforded 2 as a clear, pale yellow oil (5.73 g, 95%). 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 1.8 Hz, 1 H), 7.84 (dd, J = 8.0, 1.8 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 4.15-4.20 (m, 2 H), 4.06-4.11 (m, 2 H), 2.89 (t, J = 7.0 Hz, 2 H), 2.30 (t, J = 7.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 144.5, 142.7, 132.7, 126.9, 126.6, 120.6, 116.9, 65.5, 37.5, 28.3; HRMS (ES+) m/z = 253.9947 ([M]+; calcd for C11H11BrO2: 253.9942). |
95% | With toluene-4-sulfonic acid In benzene at 115℃; for 48h; Dean-Stark; Inert atmosphere; | |
With toluene-4-sulfonic acid In benzene Heating; |
With toluene-4-sulfonic acid In benzene for 24h; Heating / reflux; | 20 A mixture of Example 3 (13.0 g, 61.8 mmol), p-toluenesulfonic acid (23 mg, 0.12 mmol) and ethylene glycol (27.6 mL, 494.6 mmol) in benzene (140 mL) was heated to reflux for about 24 hours, using a Dean-Stark trap to separate the forming water. The mixture was cooled, poured into excess 5% aqueous sodium bicarbonate and was extracted with toluene. The combined organic extracts were washed with brine, dried (MgS04), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane as the mobile phase to provide the desired product. MS (DCI-NH3) : m/z 254,256 (M) +. | |
10.5 g | With toluene-4-sulfonic acid In toluene at 125℃; | 183.1 Step 1: 6-Bromoindanone (182-1, 10.0 g, 47.38 mmol), ethylene glycol (30.0 g, 483.3 mmol) and p-toluenesulfonic acid (80 mg, 0.46 mmol) were dissolved in toluene (300 mL), heated to reflux (125°C) to separate water overnight. The water separation was complete. TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, concentrated to remove the solvent, neutralized with saturated sodium carbonate aqueous solution, and extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography to obtain 182-2 (10.5 g) as a yellow oil. 1H-NMR: (CDCl3, 400 MHz): δ 2.31 (t, J =7.2 Hz, 2H), 2.90 (t, J =7.2 Hz, 2H), 4.07-4.11(m, 2H), 4.18-4.22 (m, 2H), 7.12(d, J = 8.0 Hz, 1H), 7.43(dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: With dimethyl zinc(II); titanium tetrachloride In dichloromethane; toluene at -40℃; for 0.333333h; Stage #2: 6-bromoindan-1-one In dichloromethane; toluene at -40 - 20℃; for 18h; | 11 6-Bromo-l, l-dimethyl-indan (Compound 11) To a solution of 24.6 mL of 1 M titanium chloride (24.6 mmol) in 20 mL of dichloromethane at-40 °C was slowly added 17.6 mL of 2 M dimethyl zinc in toluene (35.1 mmol). After stirring at-40 °C for 20 min, the mixture was added a solution of 6-bromo-indan-1-one (Compound 10,2. 46 g, 11.7 mmol) in 20 mL of dichloromethane through cannulation. The reaction was then slowly warmed to room temperature for 18 h. After quenching with methanol at 0 °C, the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with brine (1 x 10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chormatography (hexane) yielded the title compound (2.45 g, 94 % yield) as a colorless oil: 1H NMR (CDC13, 300 MHz) 8 7.25-7. 22 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 2.82 (t, J = 6.9 Hz, 2H), 1.92 (t, J = 6.9 Hz, 2H), 1.24 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-bromoindan-1-one With nitric acid at 0 - 10℃; for 0.5h; Stage #2: With sodium hydroxide In water | 4 Fuming nitric acid (20 mL, 476 mmol) was cooled to about 0 °C and treated slowly with Example 3 (4 g, 18.95 mmol) over a period of about 30 minutes. The reaction mixture was allowed to warm to about 10 °C over about 30 minutes and then the mixture was poured into ice water (100 mL). The white precipitate was collected by filtration and was washed with water. The solid was dissolved in dichloromethane and the solution was washed with 5% aqueous sodium hydroxide and water. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (2: 1) as the mobile phase to provide the desired product. MS (ESI) : m/z 254,256 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With acetic acid In ethanol for 0.5h; Heating / reflux; | 1.1.1B Preparation of N-(6-Bromo-indan-1-ylidene)-N'-(4-chloro-phenyl)-hydrazine To a mixture of 6-Bromo-indan-1-one (0.58 g, 2.7 mmole) in ethyl alcohol (5 mL) was added (4-Chloro-phenyl)-hydrazine (0.492 g, 2.7 mmole) and 5 drops of acetic acid. The reaction mixture was refluxed for 30 minutes then cooled to room temperature. The resulting solid precipitate was filtered and washed with ice cold methanol to give N-(6-Bromo-indan-1-ylidene)-N'-(4-chloro-phenyl)-hydrazine (0.92 gm, 100%). HPLC Rt=4.69 min. m/z=335 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | Stage #1: inden-1-one With aluminum (III) chloride for 0.216667h; Stage #2: With bromine at 0 - 80℃; for 0.25h; | 1.1.1A Preparation of 6-Bromo-indan-1-one To a 3-neck 250 mL round bottom flask equipped with a mechanical stirrer and charged with anhydrous aluminum chloride (16.6 gm, 0.125 mole) was added indanone (6.6 gm, 0.05 mole) in-two portions over 3 minutes. The reaction mixture was stirred for 10 minutes before bromine (9.7 g, 0.06 mole) was added dropwise over 10 minutes. The reaction mixture was heated to 80° C. for 5 minutes. The resulting mixture was poured into a mixture of ice (100 g) and concentrated HCl (20 mL). The resulting mixture was extracted with ether. The ether layer was separated, washed with water, dried (Na2SO4), filtered and concentrated. The crude material was purified by flash chromatography over silica gel eluting with 15% ether/hexanes to afford 6-Bromo-indan-1-one(2.0g, 19%). 1HNMR(CDCl3) δ 7.81 (d, 1H, J=1.76 Hz),7.62 (dd, 1H, J=8.36, 2.20 Hz), 7.30 (d, 1H, J=8.30 Hz), 3.03 (t, 2H, J=6.16 Hz), 2.65 (t, 2H, J=6.20 Hz). HPLC Rt=3.09 min. |
Multi-step reaction with 3 steps 1.1: potassium nitrate; sulfuric acid / 1.5 h / 0 - 5 °C 2.1: iron; ammonium chloride / water; ethanol / 80 °C 3.1: sodium nitrite; hydrogenchloride / water / 0 °C 3.2: 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: dimethyl zinc(II) With titanium tetrachloride In dichloromethane; toluene at -30 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 6-bromoindan-1-one In dichloromethane; toluene at -10℃; for 4h; | |
94% | Stage #1: dimethyl zinc(II) With titanium(III) chloride In dichloromethane; toluene at 40℃; for 0.333333h; Stage #2: 6-bromoindan-1-one In dichloromethane; toluene at 20℃; for 18h; | 6-1 Synthesis Example 6-1. 6-bromo-2,3 -1h, 1- dimethyl -1H- inden synthesis Into a 1M titanium chloride, 246 mL (246 mmol) and a mixture of dichloromethane 200 mL 2 M to the reactor at 40 The dimethylzinc / toluene solution 176 mL (351 mmol) was added dropwise slowly. After stirring for about 20 minutes, 6-Bromo-indan-1-one 460 g, 117mmol) and the die is put a mixed solution of 200 mL dichloromethane. Reaction proceeds for about 18 hours at room temperature. The end of the reactionAfter that, after quenching from 0 with methanol, and extracted with dichloromethane. The organic layer was concentrated and treated with magnesium sulfate under reduced pressure. Hexane to remove column chromatography to give a colorless oil (24 g, yield 94%). |
94% | Stage #1: dimethyl zinc(II) With titanium tetrachloride In dichloromethane; toluene at 40℃; for 0.333333h; Stage #2: 6-bromoindan-1-one In dichloromethane; toluene at 20℃; for 18h; | 6.6-1 Synthesis Example 6-1. Synthesis of 6-bromo-2,3-dihydro-1,1-dimethyl-1H-indene To the reactor is added a mixed solution of 246 mL (246 mmol) of 1 M titanium chloride and 200 mL of dichloromethane and 176 mL (351 mmol) of 2 M dimethyl zinc / toluene solution is slowly added dropwise at 40 ° C. After stirring for about 20 minutes, a mixed solution of 460 g (117 mmol) of 6-bromo-indan-1-one and 200 mL of dichloromethane is added. The reaction proceeds at room temperature for about 18 hours. After completion of the reaction, quenching with methanol at 0 and extraction with dichloromethane. The organic layer was treated with magnesium sulfate and then concentrated under reduced pressureCongratulations. Column chromatography with hexane gave a colorless oil (24 g, 94% yield). |
78% | Stage #1: dimethyl zinc(II) With titanium tetrachloride In dichloromethane; toluene at -40℃; for 0.333333h; Stage #2: 6-bromoindan-1-one In dichloromethane; toluene at -40 - 20℃; | 6.35 A 1.0 M solution of TiCl4 in DCM (50 mL, 49.8 mmol) was added to a reaction vessel containing DCM (40 mL) cooled to -40° C. Then, a 2.0 M solution of dimethyl zinc in toluene (35.5 ml, 71.1 mmol) was added slowly and the solution was stirred for 20 minutes at -40° C. To this mixture was added a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5.0 g, 23.7 mmol) in DCM (40 ml) and the reaction was allowed to warm gradually to room temperature overnight. At completion, the reaction was cooled to 0° C. and quenched with MeOH (10 mL), then diluted with water (50 mL) and DCM (50 mL). The layers were separated and the organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. 6-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (4.14 g, 78% yield) was isolated as a clear oil after purification by flash chromatography over silica gel (hexane eluent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.33 (m, 2H), 7.07 (d, J=8.5 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 1.95 (t, J=7.3 Hz, 2H), 1.28 (s, 6H); MS (EI) m/z=226.2 [M+1]+. |
53% | Stage #1: 6-bromoindan-1-one; dimethyl zinc(II) With titanium tetrachloride In dichloromethane; toluene at -78 - 10℃; for 2h; Stage #2: With water In dichloromethane; toluene at 0℃; | A; 2114.A To a solution of TiCl4 (3.54 g) in dichloromethane (20 ml) was added dimethyl zinc (1.3M in toluene, 15.5 mL) at -78° C. After 10 min at this temperature, commercially available 6-bromo-indan-1-one (3.58 g), dissolved in dichloromethane (20 mL) was added. After 2 h at -78° C. to -10° C. the mixture was poured onto ice and the aqueous layer was extracted with diethyl ether. The organic layer was dried (MgSO4), concentrated and purified by column chromatography (silica, cyclohexane/EtOAc, 9:1) to afford the title compound (2.04 g; 53%) as a yellow oil. 1H-NMR (CDCl3) δ=1.25 (s, 6 H), 1.94 (t, 2 H), 2.82 (t, 2 H), 7.05 (d, 1 H), 7.20-7.30 (m, 3 H). |
Stage #1: dimethyl zinc(II) With titanium tetrachloride In tetrahydrofuran; dichloromethane at -78℃; Inert atmosphere; Stage #2: 6-bromoindan-1-one In tetrahydrofuran; dichloromethane at -75 - 20℃; Stage #3: With methanol In tetrahydrofuran; dichloromethane | I.FS1022.a 5.75 ml (52.10 mmol) of titanium(IV) chloride are dissolved in 50 ml of DCM under argon, cooled to -78° C. A 2 M dimethylzinc solution in THF is added dropwise at this temperature (37.22 ml, 74.43 mmol). The mixture is stirred for a further 30 min. A solution of 5.24 g (24.81 mmol) of 6-bromo-1-indanone in 50 ml of DCM is added dropwise at -75° C. The reaction mixture is stirred for a further 45 min, then allowed to come slowly to room temperature, subsequently stirred at room temperature overnight, cooled to 0° C., quenched using MeOH, diluted with water and extracted 3 times with DCM. The org. phase is dried over sodium sulfate, filtered and evaporated. The residue is purified by means of RP flash chromatography on C18 silica gel and subsequently distilled off under reduced pressure.3.14 g, colourless oil, Rt.=3.64 min (method B) | |
2.84 g | Stage #1: dimethyl zinc(II) With titanium tetrachloride In hexane; dichloromethane at -40℃; for 0.333333h; Stage #2: 6-bromoindan-1-one In hexane; dichloromethane at 20℃; | 29 6-bromo-1,1-dimethylindane To titanium(IV) chloride (29.8 mL, a 1 M dichloromethane solution), dimethylzinc (42.6 mL, a 1 M hexane solution) was added at -40 °C, followed by stirring for 20 minutes. Thereafter, a dichloromethane (24 mL) solution of 6-bromo-1-indanone () (3.00 g) was added thereto, followed by stirring overnight at room temperature. To the reaction mixture, a small amount of methanol was added under ice-cooling, followed by dilution with water, and then extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 90:10), whereby the title compound having the following physical property values was obtained (2.84 g). TLC: Rf 0.78 (hexane:ethyl acetate = 1:1); 1H-NMR (DMSO-d6): δ 1.21, 1.84-1.89, 2.78-2.83, 7.14, 7.28, 7.34. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; ethyl acetate n-hexane; dichloromethane; water; | Stage A: 1-oxo-6-indanecarbonitrile 2 g of 6-bromo-indanone, 10 ml of dimethylformamide and 3 g of copper cyanide are taken to reflux for 20 hours. At 20 C. the reaction mixture is poured into 40 ml of water and 30 ml of methylene chloride, agitated for 15 minutes and filtered on celite. The filtrate is decanted and re-extracted with methylene chloride. The organic phase is washed with water, dried, brought to dryness under reduced pressure and the residue is chromatographed on silica in a hexane-ethyl acetate mixture as eluant (7-3). 1.03 g of expected product is obtained, M.p.=109 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.628 g (86%) | In ethanol; water; | Step 1) Preparation of o-[(2,3-dihydro-6-bromoinden-3-ylidene)hydrazino]-benzoic acid To a solution of 6-bromoindanone (0.447 g, 2.12 mmol) [Adamczyk, M. et al. J. Org. Chem. 1984, 49, 4226-4237] in ethanol (100 mL) was added a solution of <strong>[33906-30-8]2-hydrazinobenzoic acid hydrochloride</strong> (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for 1 h then cooled to 0 C. The precipitated hydrazone was vacuum filtered and dried in vacuo to afford 0.628 g (86%) of the title compound as a yellow solid: mp 186 C. (dec). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In 1,4-dioxane at 160℃; for 0.5h; Microwave irradiation; | 33 Example 33: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-l3-r(2-methylpropyl)aminol-2,3- dihvdro-1 H-inden-5-ylH H-indole-7-carboxamide trifluoroacetate; To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /-/-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 6-bromo-2,3-dihydro-1 /-/-inden-1 -one (274 mg, 1.30 mmol), and potassium carbonate (360 mg, 2.60 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before the addition of tetrakis (triphenylphosphosphine) palladium (0) (50 mg, 0.043 mmol). The reaction was then heated in the microwave for EPO 30 min at 160s C. The reaction was then filtered and the solid was dissolved in EtOAc and H2O. The organic layer was separated and concentrated. The crude residue was purified by Gilson Preparatory HPLC to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo- 2,3-dihydro-1 H-inden-5-yl)-1 H-indole-7-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydroxyamino hydrochloride; potassium hydroxide In methanol; water monomer for 3h; Reflux; | |
With hydroxyamino hydrochloride In methanol for 1h; Heating; | ||
With pyridine; hydroxyamino hydrochloride In ethanol at 20℃; for 2h; |
With pyridine; hydroxyamino hydrochloride In methanol at 70℃; for 2h; Inert atmosphere; | 11.1 Step 1: To a solution of 6-bromoindan-1-one (2.5 g, 1 eq.) in 25 ml_ methanol, under argon at at about 25 °C pyridine (1.87 ml_, 2 eq.) was added in one portion. Hydroxylamine hydrochloride (1.64 g, 2 eq.) was and the reaction mixture was heated at 70 °C for 2 hours. After cooling to about 25 °C, the reaction mixture was concentrated by removing solvent. Then 100 ml_ ethyl acetate was added. The organic phase was washed with water (3 x 50 ml_) and with brine (1 x 20 ml_), dried with sodium sulfate and concentrated to obtain crude 6-bromoindan-1-one oxime as white solid (2.47 g, 92% yield).1H NMR (400 MHz, DMSO-d6) d 11.08 (s, 1 H), 7.64 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.1, 2.0 Hz, 1 H), 7.44 - 7.25 (m, 1 H), 3.04 - 2.87 (m, 2H), 2.88 - 2.72 (m, 2H). | |
With pyridine; hydroxyamino hydrochloride In methanol at 70℃; for 2h; Inert atmosphere; | 11.1 Step 1: To a solution of 6-bromoindan-1-one (2.5 g, 1 eq.) in 25 ml_ methanol, under argon at at about 25 °C pyridine (1.87 ml_, 2 eq.) was added in one portion. Hydroxylamine hydrochloride (1.64 g, 2 eq.) was and the reaction mixture was heated at 70 °C for 2 hours. After cooling to about 25 °C, the reaction mixture was concentrated by removing solvent. Then 100 ml_ ethyl acetate was added. The organic phase was washed with water (3 x 50 ml_) and with brine (1 x 20 ml_), dried with sodium sulfate and concentrated to obtain crude 6-bromoindan-1-one oxime as white solid (2.47 g, 92% yield).1H NMR (400 MHz, DMSO-d6) d 11.08 (s, 1 H), 7.64 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.1, 2.0 Hz, 1 H), 7.44 - 7.25 (m, 1 H), 3.04 - 2.87 (m, 2H), 2.88 - 2.72 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 120℃; for 0.0833333h; Microwave irradiation; | A (6-Bromo-indan-1-yl)-dimethyl-amine Example A (6-Bromo-indan-1-yl)-dimethyl-amine 6-Bromo-indan-1-one (0.23 mmol) and dimethyl-amine (0.71 mmol) were mixed in 3 ml of 1,2-dichloroethane in a process vial, which was sealed with a septum. Sodium triacetoxyborohydride (0.47 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover equipped with a CEM Explorer automated reaction handling module). The reaction mixture was heated for 5 min at 120°C and then cooled. The crude was evaporated to dryness and then suspended in aqueous NaHCO3. The product was extracted with CH2Cl2 and washed with aqueous NaHCO3. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product (6-bromo-indan-1-yl)-dimethyl-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion system to yield the title compound (85%). MS [MH]+= 240. |
85% | With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 120℃; for 0.0833333h; Inert atmosphere; Microwave irradiation; | b 6-Bromo-indan-1-one (0.23 mmol) and dimethyl-amine (0.71 mmol) were mixed in 3 ml of 1,2-dichloroethane in a process vial, which was sealed with a septum. Sodium triacetoxyborohydride (0.47 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover equipped with a CEM Explorer automated reaction handling module). The reaction mixture was heated for 5 min at 120°C and then cooled. The crude was evaporated to dryness and then suspended in aqueous NaHCO3. The product was extracted with CH2Cl2 and washed with aqueous NaHCO3. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product 6-bromo-2,3-dihydro-N,N-dimethyl-1H-inden-1-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion system to yield the title compound (85%). |
85% | Stage #1: 6-bromoindan-1-one; dimethyl amine In 1,2-dichloro-ethane Sealed tube; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 120℃; for 0.0833333h; Inert atmosphere; Microwave irradiation; | b (b) 6-Bromo-indan-1 -one (0.23 mmol) and dimethyl-amine (0.71 mmol) were mixed in 3 ml of 1 ,2-dichloroethane in a process vial, which was sealed with a septum. Sodium triacetoxyborohydride (0.47 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover equipped with a CEM Explorer automated reaction handling module). The reaction mixture was heated for 5 min at 1205C and then cooled. The crude was evaporated to dryness and then suspended in aqueous NaHC03. The product was extracted with CH2CI2 and washed with aqueous NaHC03. The CH2CI2 extract was dried with anhydrous Na2S04, filtered and evaporated to dryness to give the crude product 6- bromo-2,3-dihydro-/V,/V-dimethyl-1 H-inden-1 -amine. The crude was purified by flash column chromatography (CH2CI2-MeOH as eluents) by using a CombiFlashCompanion system to yield the title compound (85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 3h; | Example B 6-(1,3,5-Trimethyl-1 H-pyrazol-4-yl)-indan-1-one 6-Bromo-indan-1-one (0.94 mmol) was dissolved in DME/H2O 1/1 (10 mL) under argon atmosphere. 1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (1.42 mmol), K2CO3 (2.82 mmol), and tetrakis-(triphenylphosphine)palladium (5 mol%, 0.047 mmol) were added and the reaction mixture was stirred at 100C for 3h. The reaction mixture was evaporated to dryness, then dissolved in CHCl3 and filtered through Celite to give the crude product 6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-one. The crude was purified by flash column chromatography (AcOEt-Cyclohexane as eluents) by using a CombiFlash Companion system to yield the title compound (84%). MS [MH]+= 240 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In toluene at 90℃; for 12h; Inert atmosphere; | |
96% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In toluene at 90℃; for 12h; Inert atmosphere; | Intermediate A2. 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one 6-Bromo-2,3-dihydro-1H-inden-1-one (2.0 g, 9.5 mmol), bis(pinacolato)diborane (3.1 g, 12.3 mmol), PdCl2(dppf).CH2Cl2 (390 mg, 0.47 mmol) and potassium acetate (2.8 g, 28 mmol) were taken in toluene (40 mL) under an inert atmosphere and heated to 90° C. for 12 h. The cooled mixture was diluted with EtOAc and filtered through Celite, washing with further EtOAc. The filtrate was washed with water, sat. aq. NaCl and concentrated under reduced pressure. Purification by flash column chromatography (80 g silica, 0-20% EtOAc in hexanes) afforded a pale yellow solid (2.35 g, 9.10 mmol, 96%): 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, 1H, J=7.5), 7.89 (s, 1H), 7.60 (d, 1H, J=7.5), 3.14-3.11 (m, 2H), 2.66-2.62 (m, 2H), 1.21 (s, 12H); LC-MS >95% (215, 254 nm). |
95% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 100℃; for 1h; Microwave irradiation; | 41 6-(4,4,5,5-Tetramethyl-i ,3,2-d ioxaborolan-2-yI)-2,3-d ihydro-i H-inden-i -one To the solution of 6-bromo-2,3-dihydro-1 H-inden-1 -one (1 .688 g, 8 mmol) in N,Ndimethylformamide (16 mL) was added bis(pinacolato)diboron (3.05 g, 12.00 mmol), KOAc(1 .570 g,1 6.00 mmol) and PdCI2(dppf) (0.293 g, 0.400 mmol). The resulting reaction mixtue was heated with microwave at 100 00 for 1 h. The reaction mixture was diluted with H20 (20 mL) and EtOAc (40 mL), stirred and filtered. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (40 mL), dried over MgSO4, filtered, evaporated down under vacuum, purified with flashchromatographyy to afford desired product 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2,3- dihydro-1 H-inden-1 -one (1 .9623 g, 7.60 mmol, 95 % yield). LC-MS m/z 259.1 (M+H), 1 .03 mm (ret. time). |
95% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 100℃; for 1h; Microwave irradiation; | 41 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol ihydro-1H-inden-1-one To the solution of 6-bromo-2,3-dihydro-1H-inden-1-one (1.688 g, 8 mmol) in N,N- dimethylformamide (16 mL) was added bis(pinacolato)diboron (3.05 g, 12.00 mmol), KOAc (1.570 g,16.00 mmol) and PdCl2(dppf) (0.293 g, 0.400 mmol). The resulting reaction mixtue was heated with microwave at 100 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and EtOAc (40 mL), stirred and filtered. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (40 mL), dried over MgSO4, filtered, evaporated down under vacuum, purified with flash chromatographyy to afford desired product 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3- dihydro-1H-inden-1-one (1.9623 g, 7.60 mmol, 95 % yield). LC-MS m/z 259.1 (M+H)+, 1.03 min (ret. time). |
91% | With potassium acetate In 1,2-dimethoxyethane at 110℃; for 2h; | 8 A mixture of 6-bromo-2,3-dihydro-lH-inden-l-one (4.60 g, 21.8 mmol), potassium acetate (6.42 g, 65.4 mmol), bis(pinacolato)diboron (6.64 g, 26.2 mmol), dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (690 mg, 0.943 mmol) in DME (100 mL) was heated at 110 0C. After 2 h, water was added and the mixture extracted with ethyl acetate twice. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. Purification by column chromatography (3/1, Pet ether/ethyl acetate) yielded the product (5.13 g, 91%) as an off-white solid. [00294 ] IH NMR (400 MHz, DMSO): 1.31 (12H, s), 2.65 (2H, t), 3.14 (2H, t),7.62 (IH, d), 7.90-7.93 (2H, m). |
90% | With potassium acetate In N,N-dimethyl-formamide at 95℃; for 18h; Inert atmosphere; Sealed flask; | 129 6-bromo-2,3-dihydro-1 H-inden-1 -one (0.422 g; 2 mmol), potassium acetate (0.687 g; 7.0 mmol) and bis[pinacolato]diborane (0.762 g; 3.0 mmol) were placed in a 20 mL microwave vial, dissolved in dry DMF (13 mL) and the flask was purged with nitrogen. The catalyst [1 ,1 '- Bis(diphenylphosphino)ferrocene]palladium(ll) chloride, complex with dichloromethane (0.169 g; 0.20 mmol) was added, the flask was again purged with argon, sealed and the reaction was heated at 950C for 18 h. The reaction mixture was diluted with water and the suspension was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (10 - 80 %) in heptane furnished 0.467 g (90 %) of the title compound. |
78% | With potassium acetate In N,N-dimethyl-formamide at 80℃; for 3h; | 165.1 EXAMPLE 165 6-[2-tert-Butyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazol-4-yl]indan-1-one (Compound 165) Step 1; 6-Bromoindan-1-one (300 mg, 1.42 mmol), bis(pinacolate) diboron (433 mg, 1.70 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium-methylene chloride complex (116 mg, 0.142 mmol), and potassium acetate (417 mg, 4.26 mmol) were dissolved in DMF (3.0 mL), and the mixture was stirred at 80°C for 3 hours. After the mixture was left to cool to room temperature, water was added thereto, and the mixture was filtered through Celite. To the filtrate, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1 to 2/1) to give 6-(4,4,5,5-tetramethyl [1,3,2]dioxaboran-2-yl)indan-1-one (286 mg, 1.11 mmol, yield: 78%). 1H-NMR (dppm, CDCl3): 8.24 (s, 1H), 7.99 (d, J = 7.3 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1 H), 3.19-3.12 (m, 2H), 2.71-2.67 (m, 2H), 1.34 (s, 12H). Mass (m/e): 259 (M+H)+. |
60.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 100℃; for 1h; Microwave irradiation; | 258 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1 -one 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1 -oneTo a solution of 6-bromo-2,3-dihydro-1 H-inden-1-one (1.688 g, 8 mmol) in DMF (16 ml_) was added bis(pinacolato)diboron (3.05 g, 12.00 mmol), KOAc (1.570 g, 16.00 mmol) and PdCI2(dppf) (0.293 g, 0.400 mmol) and the mixture heated with microwave irradiation at 100 °C for 1 h. The reaction mixture was evaporated down under vacuum, and purified by flash chromatography to afford desired product 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-inden-1-one (1.5529 g, 4.81 mmol, 60.2 % yield). LC-MS m/z 259.0 (M+H)+, 1.00 min (ret. time). |
23% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In methanol at 60℃; for 10h; Inert atmosphere; | |
22% | With potassium acetate In methanol at 60℃; for 14h; | 34.a a) Preparation of boronic ester6-bromo-l-indanone (183mg, 0.87 mmol), bis(pinacolato)diboron (286mg, 1.12 mmol), potassium acetate (186mg, 1.72 mmol) and [l,l '-bis(diphenylphosphino)ferrocene]- dichloropalladium (16mg, 0.022 mmol) were dissolved in 4 mL methanol and the solution was stirred at 6O0C for 14 hours. The reaction was allowed to cool, filtered over celite and concentrated to give a dark oil. The crude product was purified by flash chromatography on silica, using a 7:3 and then 9:1 ratio of petroleum hydrocarbons and ethyl acetate as eluent to give the boronic ester (50 mg, 22%). 1H NMR (d-chloroform) δ (ppm):1.36 (s, 12H); 2.69 (m, 2H); 3.16 (m, 2H); 7.48 (d, IH); 8.00 (s, IH), 8.25 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: 6-bromoindan-1-one; 3-Carboxyphenylboronic acid With potassium carbonate In 1,4-dioxane; water at 100℃; for 1h; Microwave irradiation; Stage #2: With hydrogenchloride; water | 31.a a) Suzuki coupling3-acetylphenylboronic acid (802mg, 4.89 mmol), 6-bromopicolinic acid (764mg, 3.80 mmol), tetrabutylammoniumbromide (l l lmg, 0.38 mmol), potassium carbonate (1.42g, 10.3 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) (134mg, 0.19 mmol) were dissolved in a mixture of dioxane (15 mL) and water (8 mL). Under microwave conditions (120W) the solution was heated at 1000C for 1 hour. After cooling the reaction mixture was poured into a water/ethyl acetate mixture. After extraction, the aqueous layer was acidified with 2N hydrochloric acid (pH ~3) to give a white precipitate which was collected by filtration to give the desired product (731mg, 80%). 1H-NMR (d6DMSO) δ (ppm):2.67 (s, 3H); 7.66 (t, IH); 8.05 (t, IH); 8.11 (t, IH); 8.30 (dd, IH); 8.44 (d, IH); 8.69 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 1h; Inert atmosphere of nitrogen; | To a solution of 6-bromoindan-l-one (1 eq.) and 4,4,5,5-tetramethyl-2-[(l£>3- (methyloxy)-l-propen-l-yl]-l,3,2-dioxaborolane (1.3 eq.) in DMF (0.1 M) was added trans- bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and10 back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 1000C for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO^ filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex -> 1 : 1 (v/v) Hex: EtOAc) afforded the title compound as a beige solid. | |
With sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 1h; Inert atmosphere; | 85.1 To a solution of 6-bromoindan-l-one (1 eq.) and 4,4,5, 5-tetramethyl-2-[(lE)-3- (methyloxy)-l -propen-1 -yl]-l ,3,2-dioxaborolane (1.3 eq.) in DMF (0.1 M) was added trans- bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 1000C for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex -> 1 :1 (v/v) Hex: EtOAc) afforded the title compound as a beige solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 6-bromoindan-1-one; phenylmagnesium bromide In tetrahydrofuran; diethyl ether at 20℃; for 6h; Inert atmosphere; Stage #2: With sulfuric acid In tetrahydrofuran; diethyl ether at 20℃; for 3h; | |
Stage #1: 6-bromoindan-1-one; phenylmagnesium bromide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: With toluene-4-sulfonic acid In tetrahydrofuran at 20℃; for 6h; | 8.1 5-bromo-3-phenyl-l H-indene To 6-bromo-2,3-dihydro-lH-inden-l -one (2.80 g, 13.27 mmol) in THF (10 mL) was added dropwise to a cooled (0 °C) solution of phenylmagnesium bromide (1 M in THF, 19.90 mL, 19.90 mmol), under argon atmosphere, in THF (26 mL). The reaction was allowed to stir overnight at room temperature and was the quenched with IN HCl (200 mL), The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure to afford the tertiary alcohol, which was dissolved in THF (50 mL) and treated with 4-methylbenzenesulfonic acid (0.46 g, 2.65 mmol). This reaction was allowed to stir at room temperature for 6 h, and was then diluted with water (200 mL). The mixture was extracted with dichloromethane (3 x 100 mL) and the combined extracts were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes/ethyl acetate 20: 1) to afford 5-bromo-3-phenyl- 1 H-indene (300 mg, 1 1%) as a colorless oil. This material was used in the next step without further purification. LCMS M Z (M+H) 271 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium azide; methanesulfonic acid; In chloroform; for 3.0h;Reflux; | The compound 6-bromo-2,3-dihydro-1H-inden-1-one (2.0 g, 9.5 mmol) was dissolved in chloroform (30 mL)Methanesulfonic acid (6 mL) was then added dropwise to the reaction system,Finally, sodium azide (1.90 g, 9.5 mmol) was added portionwise to the reaction system,Reflux for three hours.After completion of the reaction, the mixture was cooled to room temperature, and then the reaction solution was poured into ice water. The mixture was separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by column chromatography (Petroleum ether / ethyl acetate: 2/1) to give 7-bromo-3,4-dihydroquinolin-2 (1H) -one(0.90 g) in 42% yield. |
Step 1-2: To the CHCl3 solution (560 mL) of the compound (39.5 g) obtained in Step 1-1 and methanesulfonic acid (122 mL) , sodium azide (36.5 g) was added separately in parts under ice cooling, and then the mixture was heated to reflux for 2.5 hours. To H2O (400 mL) , the reaction mixture was added under ice cooling, adjusted to pH 9 with 28% ammonia water and extracted with CHCl3 three times. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Thereafter, the residue was purified by column chromatography (silica gel 60 N, mobile phase: EtOAc/hexane = 50/50 to 75/25; v/v) . The solid substance obtained was suspended in a solution of EtOAc/hexane (1/1; v/v) and the mixture was stirred at room temperature for one hour. A solid substance was obtained by filtration to give 7-bromo-3,4- dihydroquinolin-2 (IH) -one (15.5 g, a light yellow solid) . 1H NMR (200 MHz, CDCl3, delta) : 2.59-2.68 (m, 2H),2.88-2.97 (m, 2H), 6.91-7.16 (m, 3H), 8.27 (brs, IH); ESI/APCI MS m/z 226 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium azide; methanesulfonic acid; In dichloromethane; at 0 - 20℃; | Intermediate 23-1Preparation of 7-bromo-3,4-dihydroisoquinolin-1(2H)-one Sodium azide (0.431 g, 6.63 mmol) was added slowly to a mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1 g, 4.74 mmol) and methanesulfonic acid (15 mL, 231 mmol) in DCM (30 mL) at 0 C. The mixture was stirred at rt for 15 hrs, then was carefully quenched with 1 M aqueous sodium hydroxide (50 mL). The aqueous layer was extracted with DCM (3×50 mL), and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 hexane-EtOAc to EtOAc) to give 7-bromo-3,4-dihydroisoquinolin-1(2H)-one as white solid (650 mg, 61%). 1H NMR (400 MHz, chloroform-d) delta 8.35 (1H, br. s.), 7.08-7.17 (1 H, m), 6.98-7.06 (1H, m), 6.95 (1H, d, J=1.98 Hz), 2.93 (2H, t, J=7.59 Hz), 2.49-2.68 (2H, m). Mass spectrum m/z 226, 228 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydride In tetrahydrofuran; mineral oil at 23℃; for 16h; Inert atmosphere; | |
84% | Stage #1: 6-bromoindan-1-one; methyl iodide In tetrahydrofuran for 0.25h; Stage #2: With sodium hydride In tetrahydrofuran; water for 2.5h; | 9.1 Step 1: 6-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.69 mmol) in dry THF(150 mL) was added iodomethane (3.70 mL, 59.23 mmol) and the mixture was stirred for 15min. Sodium hydride (2.369 g, 59.23 mmol) was added in portions and stirring continued. After 2.5 h, water (100 mL) was added slowly and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by column chromatography using a gradient of 0-8% EtOAc in heptane as eluent afforded 4.74 g (84 %)of the title compound. 1HNMR (500 MHz, CHLOROFORM-d) δ 1.24 (s, 6 H), 2.95 (s, 2 H), 7.32 (d, 1 H), 7.70 (dd, 1 H), 7.89 (d, 1 H). MS (El) m/z 238, 240 [M]+. |
78.6% | Stage #1: 6-bromoindan-1-one; methyl iodide In tetrahydrofuran at 20℃; for 0.25h; Stage #2: With sodium hydride In tetrahydrofuran for 2h; | 45.1 Step 1 6-Bromo-2,2-dimethyl-indan-1-one; 6-Bromo-indan-1-one 38b (6.02 g, 28.5 mmol) and iodomethane (4.4 mL, 70 mmol) were dissolved in 200 mL of dry tetrahydrofuran. After the mixture was stirred at room temperature for 15 minutes, sodium hydride (2.73 g, 68.2 mmol) was added. The reaction mixture was stirred for another 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction was quenched with 150 mL of water and then extracted with ethyl acetate (150 mL×2). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-2,2-dimethyl-indan-1-one 45a (5.36 g, yield 78.6%) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.918 (d, J = 1.6 Hz, 1H), 7.725 (dd, J1 = 8 Hz, J2 = 2 Hz, 1H), 7.352 (d, J = 8 Hz, 1H), 2.979 (s, 2H), 1.273 (s, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium hydride; In tetrahydrofuran; at 20.0℃;Reflux; | A mixture of 6-bromo-indan-l-one (3.57 g, 17 mmol), l-(2-bromo-ethyl)-2- bromomethyl-benzene (4.7 g, 17 mmol) in THF (50 mL) was added NaH (816 mg, 34 mmol) at room temperature, the mixture was refluxed for 2 hours. The mixture was quenched with water, concentrated, then extracted with DCM, washed with brine, dried over Na2SO4, concentrated to 6-bromo-3',4'-dihydro-lEta-spiro[indene-2,2'-naphthalen]- l(3No.)-one (1.8 g, 33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 6-bromoindan-1-one In tetrahydrofuran at 20℃; Inert atmosphere; | |
93.4% | Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.583333h; Stage #2: 6-bromoindan-1-one In tetrahydrofuran at 20℃; for 1h; Stage #3: With water In tetrahydrofuran | 38.2 Step 2 6-Bromo-1 -methylene-indan; Methytriphenyl phosphonium bromide (4.56 g, 12.76 mmol) was dissolved in 25 mL of tetrahydrofuran followed by addition of potassium tert-butoxide (1.5g, 13.4 mmol). Upon completion of the addition, the mixture was stirred at room temperature for 35 minutes and used in the following reaction. 6-Bromo-indan-1-one 38b (898 mg, 4.25 mmol) was dissolved in 5 mL of tetrahydrofuran under stirring followed by addition of above mentioned mixture. The reaction mixture was stirred at room temperature for 1 hour prior to quenching by addition of 25 mL of water. The mixture was extracted with dichloromethane (25 mL×4). The combined organic extracts were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-methylene-indan 38c (830 mg, yield 93.4%) as a yellow oil. MS m/z (ESI): 208 [M-1] |
62% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexanes at 0℃; for 1h; Stage #2: 6-bromoindan-1-one In tetrahydrofuran; hexanes | 6.36 A 2.5 M solution of n-BuLi in hexanes (23.6 mL, 59 mmol) was added dropwise to a 0° C. slurry of methyltriphenylphosphonium bromide (16.8 g, 47.0 mmol) in THF (200 mL). After 1 h, a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (10.0 g, 47.0 mmol) in THF (50 mL) was added to the resulting solution and the reaction cold bath was removed. Upon completion, the reaction was quenched with water (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×40 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford 6-bromo-1-methylene-2,3-dihydro-1H-indene (6.06 g, 62% yield) as a clear oil after purification by flash chromatography over silica gel (hexane eluent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.0, 1.8 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 5.45 (t, J=2.5 Hz, 1H), 5.08 (t, J=2.1 Hz, 1H), 2.88-2.98 (m, 2H), 2.78-2.86 (m, 2H); MS (EI) m/z=210.1 [M+1]+. |
60% | Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran for 1h; Inert atmosphere; Cooling with ice; Stage #2: 6-bromoindan-1-one In tetrahydrofuran for 0.5h; Cooling with ice; | 97 Intermediate 6-bromo-1-methylenyl-2,3-dihydro-1H-indene(Int 97-1) Synthesis Dissolve methyltriphenylphosphanium bromide (35.6g, 100mmol) in THF (300mL), under nitrogen protection, add t-BuOK (11.2g, 100mmol) in batches under ice-water bath conditions,After the addition, react at this temperature for one hour,Get this solution and set aside. Dissolve SM 29 (21g, 100mmol) in THF (300mL),After cooling in an ice-water bath, drip the standby solution into the SM 29 THF solution, and continue the reaction for half an hour after the dripping in the ice-water bath. The reaction solution was poured into water (1L), extracted with ethyl acetate 3 times, and the organic phase was washed with saturated brine,Concentrate to obtain a crude product, column chromatography to obtain Int 97-1 (12g),The yield is 60% |
60% | Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at -5℃; for 1h; Stage #2: 6-bromoindan-1-one In tetrahydrofuran at -5℃; for 2h; | 6-Bromo-1-methylene-2,3-dihydro-1H-indene (23): A solution of methyltriphenylphosphonium bromide (28.4 g, 79.6 mmol) in dry THF (100 mL) was stirredunder -5 °C for 5 minutes. A solution of t-BuOK (10.4 g, 92.7 mmol) in dry THF wasadded dropwise and stirred for 1 hour at -5 °C. A solution of 22 (14 g, 66.4 mmol) indry THF was added dropwise. After stirred for 2 h at -5 °C, the reaction was quenchedwith water (100 mL), warmed to room temperature, and extracted with ethyl acetate.The organic layers were concentrated. The residue was purified by silica gel columnchromatography (PE) to afford 23 (10g, 60%). |
Yield | Reaction Conditions | Operation in experiment |
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74% | Stage #1: ethyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h; Stage #2: 6-bromoindan-1-one In tetrahydrofuran for 1h; Stage #3: With water In tetrahydrofuran | 41.1 Step 1 6-Bromo-1-ethylidene-indan; (Ethyl)triphenylphosphonium bromide (14.5 g, 39.1 mmol) was dissolved in 75 mL of tetrahydrofuran followed by addition of potassium tert-butoxide (5.29 g, 47.3 mmol) at room temperature. Upon completion of the addition, the reaction mixture was stirred for 1 hour. A solution of 6-bromo-indan-1-one 38b (3.39 g, 18.6 mmol) in 25 mL of tetrahydrofuran was added to above mixture and the mixture was stirred for another 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction was quenched with 150 mL of water and then the mixture was extracted with dichloromethane (50 mL×4). The combined organic extracts were washed with saturated brine (45 mL×2), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-ethylidene-indan 41a ( 3.07 g, 74%) as a yellow oil. MS m/z (ESI): 221.8 [M-1] |
Yield | Reaction Conditions | Operation in experiment |
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75% | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium 2-methylbutan-2-olate In 2-methyltetrahydrofuran; toluene at 25 - 43℃; for 0.5h; Stage #2: With potassium hydroxide In 2-methyltetrahydrofuran; water; toluene for 4h; Reflux; | 5.B.1 Method BStep 1: 6'-Bromospiro[cyclohexane-1,2'-indene]-1',4(3'H)-dione; 6-Bromo-2,3-dihydro-1H-inden-1-one (800 g, 3.79 mol) and methyl acrylate (787 mL, 8.72 mol) in 2-methyl-tetrahydrofuran (4 L) were stirred at 28° C. Potassium tent-pentoxide solution in toluene (1.7 M, 2.68 L, 4.55 mol) was added dropwise keeping the temperature between 30° C. and 43° C. The mixture was stirred for 0.5 h at 25° C. Water (4 L) was added and after 10 min were KOH (383 g, 6.82 mol) added. The mixture was heated to reflux and the organic solvent was distilled off during 4 h. The mixture was cooled to 10° C., and the formed precipitate was filtered off and dried in vacuo to give the title compound (837 g, 75% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.74-1.85 (m, 2H), 1.94 (m, 2H), 2.34 (m, 2H), 2.52-2.60 (m, 2H), 3.27 (s, 2H), 7.60 (d, 1H), 7.79-7.83 (m, 1H), 7.89 (m, 1H); MS (ES+) m/z 293 [M+H]+. |
75% | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium 2-methylbutan-2-olate In 2-methyltetrahydrofuran; toluene at 25 - 43℃; Stage #2: With water; potassium hydroxide In 2-methyltetrahydrofuran; toluene for 4h; Reflux; | 2.B Intermediate 2 6'-Bromospiro[cyclohexane-1,2'-indene]-1',4(3'H)-dione Method B 6-Bromo-2,3-dihydro-lH-inden-l-one (800 g, 3.79 mol) and methyl acrylate (787 mL, 8.72 mol) in 2-Me THF (4 L) were stirred at 28 °C. Potassium tert-pentoxide solution in toluene (1.7 M, 2.68 L, 4.55 mol) was added dropwise keeping the temperature between 30 °C and 43 °C. The mixture was stirred for 0.5 h at 25 °C. Water (4 L) was added and after 10 min were KOH (383 g, 6.82 mol) added. The mixture was heated to reflux and the organic solvent was distilled off during 4 h. The mixture was cooled to 10 °C, and the formed precipitate was filtered off and dried in vacuo to give the title compound (837 g, 75% yield). 1H MR (500 MHz, DMSO-6) ppm 1.74 - 1.85 (m, 2 H), 1.94 (m, 2 H), 2.34 (m, 2 H), 2.52 - 2.60 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.79 - 7.83 (m, 1 H), 7.89 (m, 1 H); MS (ES+) m/z 293 [M+H]+. |
75% | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In 2-methyltetrahydrofuran; toluene at 25 - 43℃; Stage #2: With water; potassium hydroxide In 2-methyltetrahydrofuran; toluene for 4h; Reflux; | 2.B Intermediate 2 6'-Bromospiro[cyclohexane-l,2'-indene]-l',4(3'H)-dione 6-Bromo-2,3-dihydro-lH-inden-l-one (800 g, 3.79 mol) and methyl acrylate (787 mL, 8.72 mol) in 2-Me THF (4 L) were stirred at 28 °C. Potassium tert-pentoxide solution in toluene (1.7 M, 2.68 L, 4.55 mol) was added dropwise keeping the temperature between 30 °C and 43 °C. The mixture was stirred for 0.5 h at 25 °C. Water (4 L) was added and after 10 min were KOH (383 g, 6.82 mol) added. The mixture was heated to reflux and the organic solvent was distilled off during 4 h. The mixture was cooled to 10 °C, and the formed precipitate was filtered off and dried in vacuo to give the title compound (837 g, 75% yield). 1H NMR (500 MHz, DMSO-6) δ ppm 1.74 - 1.85 (m, 2 H), 1.94 (m, 2 H), 2.34 (m, 2 H), 2.52 - 2.60 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.79 - 7.83 (m, 1 H), 7.89 (m, 1 H); MS (ES+) m/z 293 [M+H]+. |
72% | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran at 20 - 25℃; for 1.5h; Cooling with ice; Stage #2: With water; potassium hydroxide In tetrahydrofuran at 60 - 75℃; | 6,-bromo-4H-spiro[cyclohexane-1,2'-indene]-1,,4(3,H)-dione Potassium tert-butoxide (7.50 g, 66.81 mmol) was added in portions to 6-bromo-2,3- dihydro-1H-inden-1-one (1 1.75 g, 55.67 mmol) and methyl acrylate (1 1.05 mL, 122.5 mmol) in THF (55 mL) cooled in an ice-bath. The mixture was stirred for 1.5 h at r.t. Water (80 mL) and potassium hydroxide (3.12 g, 55.7 mmol) was added and the mixture was heated to 75 °C and then at 60 °C overnight. The mixture was cooled to 0 °C, and the formed precipitate was filtered off and dried in vacuo to give the title compound (1 1.69 g, 72% yield). 1H NMR (500 MHz, CDCI3) δ ppm 1.83 - 1.92 (m, 2 H), 2.15 - 2.27 (m, 2 H), 2.40 - 2.50 (m, 2 H), 2.71 (dt, 2 H), 3.17 (s, 2 H), 7.39 (d, 1 H), 7.75 (dd, 1 H), 7.92 (d, 1 H); MS (ES+) m/z 293, 295 [M+H]+. |
72% | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran at 25℃; for 1.5h; Cooling with ice; Stage #2: With potassium hydroxide In tetrahydrofuran; water at 60 - 75℃; | 1 Step 1: 6’-Bromo-4H-spiro [cyclohexane-1,2’-indenej-l ‘,4(3 ‘H)-dione) Potassium tert-butoxide (7.50 g, 66.8 mmol) was added in portions to 6- bromo-2,3-dihydro-1H-inden-1-one (11.75 g, 55.67 mmol) and methyl acrylate (11.05 mL, 122.5 mmol) in THF (55 mL) cooled in an ice-bath. The mixture was stirred for 1.5 hat r.t. Water (80 mL) and potassium hydroxide (3.12 g, 55.7 mmol) was added and the mixture was heated to 75 °C and then at 60 °C overnight. The mixture wascooled to 0 °C, and the formed precipitate was filtered off and dried in vacuo to givethe title compound (11.69 g, 72% yield). ‘H NMR (500 MHz, CDC13) ö ppm 1.83 -1.92 (m, 2 H), 2.15 - 2.27 (m, 2 H), 2.40 - 2.50 (m, 2 H), 2.71 (dt, 2 H), 3.17 (s, 2 H),7.39 (d, 1 H), 7.75 (dd, 1 H), 7.92 (d, 1 H); MS (ES+) mlz 293, 295 [M + H]. |
Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h; Stage #2: With water; potassium hydroxide In tetrahydrofuran Reflux; Stage #3: With hydrogenchloride In tetrahydrofuran; water | I.2 Alternative method for synthesis of 6'-bromospiro[cyclohexane-l,2'-indene]- l',4(3'H)-dione1 A To a solution of compound 1 (20 g, 95 mmol) and methyl acrylate (18 g, 201 mmol) in anhydrous THF (200 mL) was added t-BuOK (16 g, 114 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Water (400 mL) and KOH (5.32 g, 95 mmol) were added. The resulting mixture was heated to reflux overnight. 3 N HC1 (150 mL) was added and extracted with CH2CI2 (500 mL*2). The organic layers were washed with NaHC03 (150 mL), brine (150 mL) and dried over Na2S04, concentrated in vacuo to give compound A as a grey solid (23 g, 83% yield), which was used for next step without purification. 1H NMR (300 MHz, CDC13) δ 7.84 (s, 1H), 7.60-7.71 (d, 1H), 7.25-7.36 (d, 1H), 3.11 (s, 2H), 2.60-2.71 (m, 2H), 2.35-2.46 (m, 2H), 2.10-2.23 (m, 2H), 1.75-1.87 (m, 2H) | |
7.78 kg | With potassium <i>tert</i>-butylate In tetrahydrofuran at 20 - 65℃; for 1.91667h; Large scale; | 1 6'-Bromospiro[cyclohexane-1,2'-indene]-1' ,4(3'H)-dione Potassium tert-butoxide (223 g, 1.99 mol) was charged to a 100 reactor containing a stirred mixture of 6-bromo-1-indanone (8.38 kg, 39.7 mol) in THF (16.75 ) at 20-30 °c. Methyl acrylate (2.33 , 25.8 mol) was then charged to the mixture during 15 minutes keeping the temperature between 20-30°c. A solution of potassium tert-butoxide (89.1 g, 0.79 mol) dissolyed in THF (400 m) was added were after methyl acrylate (2.33 , 25.8 mol) was added during 20 minutes at 20-30 °c. A third portion ofpotassium tert-butoxide (90 g, 0.80 mol) dissolyed in THF (400 m) was then added, followed by a third addition of methyl acrylate (2.33 , 25.8 mol) during 20 minutes at 20-30 °c. Potassium tert-butoxide (4.86 kg,43.3 mol) dissolyed in THF (21.9 ) was charged to the reactor during 1 hour at 20-30 °c. The reaction was heated to approximately 65 °c and 23 of solyent was distilled oli Reaction temperature was lowered to 60 °c and 50% aqueous potassium hydroxide (2.42, 31.7 mol) dissolved in water (5 1.1 ) was added to the mixture during 30 minutes at 55-60 °c were after the mixture was stirred for 6 hours at 60 °C, cooled to 20 °C during 2 hours. After stirring for12 hours at 20 °C the solid material was filtered off, washed twice with a mixture of water (8.4 ) and THF (4.2 ) and then dried at 50 °C under vacuum to yield 6'-bromospiro[cyclohexane-1,2'-indene]-1',4(3'H)-dione (7.78 kg; 26.6 mol). 1H NMR (500 MHz, DMSO-d6) ppm 1.78 - 1.84 (m, 2 H), 1.95 (td, 2 H), 2.32 - 2.38 (m, 2 H), 2.51 - 2.59(m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.81 (m, 1 H), 7.89 (m, 1 H). |
7.78 kg | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran at 20 - 65℃; for 1.91667h; Large scale; Stage #2: With potassium hydroxide In water at 20 - 60℃; for 20.5h; Large scale; | 6 Example 6: 6’-Bromospirocyclohexane-12’-indene-1’4(3’H)-dione Potassium tert-butoxide (223 g, 1.99 mol) was charged to a 100 L reactor containing a stirred mixture of 6-bromo-1-indanone (8.38 kg, 39.7 mol) in THF (16.75 L) at 20-30 °C. Methylacrylate (2.33 L, 25.8 mol) was then charged to the mixture during 15 minutes keeping the temperature between 20-30 °C. A solution of potassium tert-butoxide (89.1 g, 0.79 mol) dissolved in THF (400 mL) was added were after methyl acrylate (2.33 L, 25.8 mol) was added during 20 minutes at 20-30 °C. A third portion of potassium tert-butoxide (90 g, 0.80 mol) dissolved in THF (400 mL) was then added, followed by a third addition of methyl acrylate (2.33L, 25.8 mol) during 20 minutes at 20-30 °C. Potassium tert-butoxide (4.86 kg, 43.3 mol) dissolved in THF (21.9 L) was charged to the reactor during 1 hour at 20-30 °C. The reaction was heated to approximately 65 °C and 23 L of solvent was distilled off. Reaction temperature was lowered to 60 °C and 50% aqueous potassium hydroxide (2.42 L, 31.7 mol) dissolved in water (51.1 L) was added to the mixture during 30 minutes at 5 5-60 °C were after the mixturewas stirred for 6 hours at 60 °C, cooled to 20 °C during 2 hours, After stirring for 12 hours at20 °C the solid material was filtered off washed twice with a mixture of water (8.4 L) and THF(4.2 L) and then dried at 50 °C under vacuum to yield 6’-bromospiro[cyclohexane-1,2-indene]-1’,4(3’H)-dione (7.78 kg; 26.6 mol). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.78 - 1.84 (m, 2 H),1.95 (td, 2 H), 2.32 -2.38 (m, 2 H), 2.51 - 2.59 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.81 (m, 1H), 7.89 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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83% | Stage #1: 6-bromoindan-1-one With N-benzyl-trimethylammonium hydroxide In methanol; toluene at 50℃; for 0.166667h; Inert atmosphere; Stage #2: acrylic acid methyl ester In methanol; toluene at 50℃; Inert atmosphere; | I.2.1 Step 1. Synthesis of dimethyl 3,3'-(6-bromo-l-oxo-2,3-dihydro-lH-indene-2,2- diyl) dipropanoateUnder N2, triton B (benzyl(tri-methyl)-ammonium hydroxide, 40% in MeOH, 2.48 mL) was added to a solution of 6-bromo-indan-l-one (26.1 g, 0.124 mol) in toluene (200 mL), and the mixture was stirred at 50°C for 10 minutes. Acrylic methyl ester (31 mL, 0.286 mol) was added at 50°C, and the mixture was stirred at 50°C overnight. After being cooled to room temperature, the mixture was poured into water (150 mL), and extracted with DCM (100 mLx4). The combined organic phases were dried over Na2S04, and evaporated, and purified by column chromatography on silica gel (PE/EA=10: 1) to give the compound 2 (39 g, 83%) as a yellow oil. 1H NMR (G000044883 692-154-1A CDC13 400MHz): δ 7.75-7.81 (s, IH), 7.55-7.58 (d, IH), 7.22-7.28 (d, IH), 3.51-3.55 (s, 3H), 2.85-2.99 (s, 2H), 2.10-2.25 (m, 4H), 1.80- 1.95 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
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4% | With sodium hydride In tetrahydrofuran at 20℃; for 3h; Reflux; | I.1.2 Step 2. Synthesis of 6,-bromo-4-methoxyspiro[cyclohexane-l,2'-inden]-l,(3,H)- oneA mixture of 6-bromo-2,3-dihydro-lH-inden-l-one (1.037 g, 4.94 mmol) and 1,5- dibromo-3-methoxypentane (1.2 g, 4.94 mmol) in THF (16 mL) was added NaH (237.12 mg, 60%, 9.88 mmol) at room temperature. The mixture was refluxes for 3 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give the residue, which was purified by column chromatography to give 6'-bromo-4-methoxyspiro[cyclohexane-l,2'-inden]- (3'H)- one (60 mg, 4%). |
Yield | Reaction Conditions | Operation in experiment |
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77% | General procedure: To a suspension of benzyltriphenylphosphonium bromide (1.63 g, 3.76 mmol) in THF (40 mL) was dropwise added n-BuLi (2.35 mL, 1.6 M in hexanes). After the system was stirred at room temperature for 2 h, indanone (7a, 0.25 g, 1.89 mmol) or its derivative (8a-17a, 1.89 mmol) in THF (10 mL) was added. The reaction mixture was stirred at reflux for 24 h, then, cooled to room temperature, quenched with water (20 mL), and extracted with n-hexane (3 × 30 mL). The organic layers were combined, washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane) to give the corresponding products (7b-17b). |
Yield | Reaction Conditions | Operation in experiment |
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24% | Stage #1: 6-bromoindan-1-one With potassium <i>tert</i>-butylate In 2-methyltetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; for 0.25h; Inert atmosphere; Stage #2: 1,1'-oxybis(2-bromo-ethane) In 2-methyltetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; | 10 Intermediate 106-Bromo-2',3',5',6'-tetrahydrospiro[indene-2,4'-pyran]-1(3H)-one; A solution of potassium tert-butoxide (3.94 g, 35.1 mmol) in t-BuOH (35 mL) was added dropwise over 15 min to a solution of 6-bromo-1-indanone (3.53 g, 16.73 mmol) in 2-methyl-tetrahydrofuran (350 mL) at r.t. under a nitrogen atmosphere. After 15 min bis(2-bromoethyl)ether (2.102 mL, 16.73 mmol) was added and the resulting mixture was stirred at r.t. for 5 h. Potassium tert-butoxide (0.938 g, 8.36 mmol) was added and the mixture was stirred at r.t. overnight. The mixture was quenched with saturated aq. NH4Cl (150 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×50 mL) and Et2O (50 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and concentrated. The resulting residue was taken up in DCM, concentrated onto silica gel and purified on a silica gel column eluted with 0-40% EtOAc in heptane to give 1.14 g (24% yield) of the title compound; MS (ES+) m/z 281 [M+H]1. |
7.2% | With potassium <i>tert</i>-butylate In toluene at 0 - 110℃; for 2.5h; | 78.I Step I 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1-(3H)-one 78b The compound t-BuOK (3.99 g, 35.54 mmol) was added to toluene (40 mL) in a reaction flask and cooled to 0° C. Then the compound 78a (5 g, 3.69 mmol) and 2,2′-dibromodiethyl ether (6.04 g, 6.06 mmol) were added to toluene to obtain a mixed solution, which was added to the reaction flask dropwise. The mixture was heated to 110° C. and refluxed for 2.5 hours under stirring. A little residue of raw materials was determined by TLC monitoring. The reaction solution was poured to ice water, extracted with EA, dried with anhydrous sodium sulfate, spin-dried, and purified by flash column chromatography (petroleum ether:ethyl acetate=10:1) to obtain 500 mg of a relatively pure orange-yellow solid of compound 78b (500 mg, 1.78 mmol) with a yield of 7.2%. MS m/z (ESI): 281 [M+H]+. |
7.2% | With potassium <i>tert</i>-butylate In toluene at 0 - 110℃; for 2.5h; | 78.I Step I 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1-(3H)-one 78b The compound t-BuOK (3.99 g, 35.54 mmol) was added to toluene (40 mL) in a reaction flask and cooled to 0° C. Then the compound 78a (5 g, 3.69 mmol) and 2,2′-dibromodiethyl ether (6.04 g, 6.06 mmol) were added to toluene to obtain a mixed solution, which was added to the reaction flask dropwise. The mixture was heated to 110° C. and refluxed for 2.5 hours under stirring. A little residue of raw materials was determined by TLC monitoring. The reaction solution was poured to ice water, extracted with EA, dried with anhydrous sodium sulfate, spin-dried, and purified by flash column chromatography (petroleum ether:ethyl acetate=10:1) to obtain 500 mg of a relatively pure orange-yellow solid of compound 78b (500 mg, 1.78 mmol) with a yield of 7.2%. MS m/z (ESI): 281 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; ruphos In water; toluene at 100℃; Inert atmosphere; Sealed vial; | 9 In an open ChemGlass vial with pressure -release top, a stirred mixture of 6- bromo-l-indanone (Aldrich, St. Louis, MO) (53 mg, 0.25 mmol), palladium(II) acetate (5.5 mg, 0.025 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (23 mg, 0.05 mmol), K2C03 (138 mg, 1.0 mmol) and ira/i5,-2-(trifluoromethyl)cyclopropylboronic acid MIDA ester (99 mg, 0.38 mmol) in toluene (2.5 mL) and H20 (0.5 mL) was de-gassed with N2 for 15 minutes, then the reaction mixture placed under nitrogen, sealed and heated to 100 °C and stirred overnight. After allowing to cool, the reaction mixture was diluted with H20 (15 mL) and EtOAc (20 mL), filtered through Celite and the filter cake washed with EtOAc (2 x 20 mL). The filtrate was partitioned and the aqueous layer extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by preparative thin-layer chromatography (3 prep TLC plates used) using EtOAc / hexane (1:4) as eluent to give the product (53.8 mg, 90%) as an oil.[00219] 1H NMR (CDC13, 300MHz): δ 7.46 (s, IH), 7.43 (m, 2H), 3.14-3.10 (m, 2H), 2.73-2.68 (m, 2H), 2.45-2.38 (m, IH), 1.87-1.76 (m, IH), 1.45-1.38 (m, IH), 1.25-1.18 (m, IH). 13C NMR (CDCI3, 75MHz): 5 207.0, 154.1, 139.0, 137.8, 134.2, 127.8 (q, 7 = 271 Hz), 127.2, 121.0, 36.9, 25.8, 23.7 (q, / = 36.8 Hz), 19.5 (q, J = 2.1 Hz), 11.1 (q, J = 2.6 Hz). 19F NMR (CDC13, 282 MHz): -66.9 (d, / = 5.9 Hz), m/z = 282.05 [M+MeCN+H]+ HRMS (EI): [M+MeCN+H]+ calc'd for Ci3HnF30+MeCN m/z 282.1106, found 282.1100. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water | 12.2 12.2 6-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]indanone 12.2 6-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]indanone The procedure described in Example 3 is followed. Starting from 0.2 g (0.56 mmol) of 2-(4-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine, obtained in stage 12.1, 0.24 mg (1.14 mmol) of 6-bromo-1-indanone, 0.55 g (1.69 mmol) of caesium carbonate, 0.046 g (0.06 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and 5 ml of a THF/water (9/1) mixture and after chromatographing on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.127 g (62%) of the expected product is obtained in the form of a yellow powder. LC-MS: M+H=359 1H NMR (d6-DMSO) δ (ppm): 2.72 (m, 2H); 3.20 (m, 2H); 7.15 (s, 1H); 7.35 (dd, 1H); 7.55 (m, 2H); 7.75 (m, 1H); from 8.05 to 8.20 (m, 5H); 8.80 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 16h; | 7; 12 Scheme 6.4 To a stirred suspension of NaH (0.86 g, 60% in mineral oil, 20 mmol) in 20 mL dimethyl carbonate was added dropwise a solution of Compound 1 (6- bromoindanone) (1.0 g, 4.73 mmol) in 30 mL dimethyl carbonate and DMF 1 mL. The mixture was refluxed at 80°C for 16 hours. After cooling to room temperature, and then H20 (80 mL) was added. The aqueous phase was separated and extracted with CH2CI2 (3 x 50 mL). The combined organic extracts were dried (MgS04) and concentrated under reduced pressure. The crude oil thus obtained was subjected to chromatography (silica gel, 2:1 hcxane/CI I2CI2) to yield 1.06 g (83%) of Compound 59a (methyl 6-bromo-l-oxo-2,3-dihydro-lH-indene-2-carboxylate). |
Stage #1: 6-bromoindan-1-one With sodium hydride In tetrahydrofuran for 0.333333h; Inert atmosphere; Stage #2: carbonic acid dimethyl ester In tetrahydrofuran Inert atmosphere; Reflux; | ||
With sodium hydride In tetrahydrofuran; mineral oil at 50℃; for 0.5h; Inert atmosphere; | methyl 6-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate Into a 50-mi. round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (1.00 g, 4.74 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). Sodium hydride (0.38 g, 60% in mineral oil, 9.48 mmol) was added followed by dimethyl carbonate (0.90 g, 10.00 mmol). The resulting mixture wasstirred for 30 mm at 50 °C then quenched by the addition of hydrochloric acid (20 mL, 1 M). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford compound I-80a. LRMS (ESI) calc’d for C11H10BrO3 [M + H]: 269, 271(1:1), found 269, 271 (1:1). |
With sodium hydride In mineral oil at 80℃; Inert atmosphere; Schlenk technique; | ||
With sodium hydride In mineral oil at 80℃; for 2h; | 6-Bromo-1 -oxo-indan-2-carboxylic acid methyl ester 6-Bromo-1 -oxo-indan-2-carboxylic acid methyl ester To a mixture of 6-bromo-indan-1 -one (10.0 g) and dimethylcarbonate (107 g) was added NaH (4.17 g, 60% in mineral oil). After heating at 80°C for 2 hours the mixture was allowed to cool to rt, quenched by addition of ammonium chloride solution and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to provide the title compound. MS ESI+: m/z = 269 [M+H]+. | |
With potassium <i>tert</i>-butylate; sodium hydride at 0℃; Inert atmosphere; | ||
at 80℃; for 1h; | ||
With potassium <i>tert</i>-butylate; sodium hydride at 0℃; | ||
With sodium hydride In mineral oil for 4h; Reflux; | ||
With sodium hydride In tetrahydrofuran; mineral oil at 30℃; for 1h; | 242.1 Step 1. To a 250 mL round-bottom flask '.vas added 6-bromo-2,3-dihydro-1H-inden-1-one5 313a (5 g, 23.69 mmoL 1.00 equiv.), sodium hydride (1.84 g, 60% dispersed in mineral oil,76.67 mmoL 2.00 equiv.), tetrahydrofuran (20 mL), and dimethyl carbonate (3.2 g, 35.52mmol, 1.50 equiv.). The resulting mixture was stirred at 30°C for 1h. The reaction wasquenched by the addition of 50 mL of water. The aqueous mixture was extracted with ethylacetate 0 00 mL x 2), and the combined organic extracts ·were washed ·with brine (1 00 mL xl 0 2), dried, and concentrated under reduced pressure. The residue was purified by silica gelcolumn chromatography eluting with ethyl acetate/hexane (2:1) to atiord methyl6-bromo-1-oxo-2,3-dihydro-1H-indene-2-ca.rboxy late 313b (7.1 g, Q) a | |
With sodium hydride In mineral oil at 90℃; | ||
With sodium hydride In mineral oil for 0.5h; Inert atmosphere; Schlenk technique; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With toluene-4-sulfonic acid In methanol for 10h; Reflux; | 6-Bromo-1-indanone thiosemicarbazone (34) 6-Bromo-1-indanone (0.301 g, 1.42 mmol) was dissolved in anhydrous methanol (10mL). The solution was heated at reflux for 15 min, and thiosemicarbazide (0.155 g, 1.71 mmol)and a catalytic amount of p-toluenesulfonic acid (0.024 g, 0.142 mmol) were added. After 10 h atreflux, the resulting precipitate was collected by filtration and washed with methanol. Afterdrying under high vacuum, thiosemicarbazone was obtained as a white solid (0.304 g, 1.07mmol, 76 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | (5-Bromo-1H-inden-3-yl)oxy)trimethylsilane (35) To a solution of the indanone (1.0 g, 5 mmol) in dry dichloromethane (50 mL) at 0 °Cunder N2 was added successively Et3N (0.79 mL) and TMSOTf (0.9 mL). The mixture waswarmed to room temperature and stirred for 10 min. The reaction mixture was again cooled to 0°C and diluted with Ether and NaHCO3 solution. The layers were separated and the aqueousphase was extracted with Ether. The combined organic layers were washed with brine, then driedover Na2SO4, filtered and evaporated under reduced pressure to afford the silylenol ether as lightyellow oil (1.02 g, 3.73 mmol, 74 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With water; palladium diacetate; potassium carbonate; ruphos In toluene at 100℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 2.16667h; Stage #2: ethyl iodide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; | 1.1 Step 1: Synthesis of interemdiate 3 A mixture of compound 1 (50.0 g, 236 mmol) and methyl acrylate (42.0 g, 472 mmol) in anhydrous THF (900 mL) was pre-cooled at 0°C and i-BuOK (31.8 g, 284 mmol, 1.1 eq) was added in equal portion over 30 min, the mixture was then warmed up to rt over 1 h and was stirred for 40 min at rt. DMF (200mL) and Etl (74 g, 472 mmol) were added to this reaction mixture, and stirred at rt overnight. THF was removed under reduced pressure. The residue was diluted with H20 (300 mL) and extracted with EtOAc, concentrated to afford the crude compound 2 (120.0 g). This product was used as is for next step. A mixture of compound 2 (120.0 g, 310 mmol) and LiCl (130.0 g, 3100 mmol) in DMSO (900 mL) was refluxed overnight. The mixture was quenched with water (3L) and extracted with EtOAc (3 x 400 mL). The separated organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc = 20: 1) to give intermediate 3 (15 g, 20%). | |
120 g | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 2.16667h; Stage #2: ethyl iodide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; | 9.1 A mixture of 6-bromo-indan-1-one 1 (50.0 g, 236 mmol) and methyl acrylate (42.0 g, 472 mmol) in anhydrous THF (900 mL) was pre-cooled to 0° C. and t-BuOK (31.8 g, 284 mmol, 1.1 eq) was added portion wise over 30 min. The mixture was warmed to rt over 1 h and stirred for an additional 40 min at rt. DMF (200 mL) and EtI (74 g, 472 mmol) were added to this reaction mixture, and the mixture was stirred at rt overnight. THF was removed under reduced pressure. The residue was diluted with H2O (300 mL) and extracted with EtOAc (300 mL). The organic layer was concentrated under reduced pressure to afford the crude intermediate 63 (120.0 g). This product was used as is for the next step.A mixture of intermediate 63 (120.0 g, 310 mmol) and LiCl (130.0 g, 3100 mmol) in DMSO (900 mL) was refluxed overnight. The mixture was quenched with water (3 L) and extracted with EtOAc (3×400 mL). The combined organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc; 20:1) to give intermediate 64 (15 g).1H NMR: (CDCl3): δ 7.91 (s, 1H), 7.74 (dd, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 3.80 (s, 2H), 2.48-2.53 (m, 2H), 2.33-2.49 (m, 1H), 2.15-2.23 (m, 1H), 1.75-1.95 (m, 4H), 1.21-1.40 (m, 1H), 0.88 (t, J=8.0 Hz, 3H) |
146 g | Stage #1: 6-bromoindan-1-one; acrylic acid methyl ester With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 25℃; for 2h; Stage #2: ethyl iodide In N,N-dimethyl-formamide at 20 - 25℃; for 12h; | 1 Step 1: methyl (5R)-6 ‘-bromo- 1-ethyl-i ‘,2-dioxo-spiro [cyclohexane-5,2 ‘-indanej -1-carboxylate A mixture of 6-bromoindan-1-one (75.0 g, 355 mmol) and methyl acrylate (64 mL, 710 mmol) in THF (1.35 L) was cooled at 0 °C and treated with potassium tertbutoxide (58 mL, 426 mmol in equal portion over 30 mm. The mixture was warmed up to r.t. over 1 h, stirred for 40 mm at r.t., treated with DMF (300 mL) andiodoethane (57 mL, 711 mmol) and stirred at r.t. for 12 h. The solvent was evaporated and the residue diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL), dried (Na2SO4) filtered and concentrated in vacuo to give a brown oil (146 g) which was used for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: 6-bromoindan-1-one With potassium <i>tert</i>-butylate In tetrahydrofuran at -5 - 10℃; for 0.333333h; Stage #2: methacrylic acid methyl ester In tetrahydrofuran for 2h; Stage #3: acrylic acid methyl ester; methyl iodide Further stages; | |
50 g | Stage #1: 6-bromoindan-1-one With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: methacrylic acid methyl ester In tetrahydrofuran at 20℃; for 2h; Stage #3: acrylic acid methyl ester; methyl iodide | 1.1 To a mixture of 6-bromo-indan-1-one (100.00 g, 473.8 mmol) in anhydrous THF (1 L) at 0° C. was added t-BuOK (58.5 g, 521.2 mmol). After 5 minutes, the mixture was warmed to rt and was stirred for another 10 min before methyl methacrylate (49.8 g, 53.2 mL, 497.5 mmol, 1.05 eq) was added in one portion. After 2 h, methyl acrylate (49.0 g, 51.2 mL, 568.6 mmol, 1.2 eq) was added to the reaction mixture. After 3 h of stirring at rt, MeI (101 g, 44.3 mL, 710.7 mmol, 1.5 eq) was added to the reaction mixture, and the mixture was further stirred for 16 h. H2O (1 L) was added followed by LiOH*H2O (79.5 g, 1895 mmol, 4.0 eq). The mixture was stirred for 28 h at rt. THF was removed under reduced pressure. The residue was diluted with H2O (1 L), filtered, and washed with H2O until the filtrate was neutral. The product was washed with MeOH to afford 50 g of intermediate 3. |
50 g | Stage #1: 6-bromoindan-1-one With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 0.2h; Stage #2: methacrylic acid methyl ester In tetrahydrofuran for 2h; Stage #3: acrylic acid methyl ester; methyl iodide Further stages; | 14.A.1 Step 1 : Synthesis of intermediate 29a Step 1 : Synthesis of intermediate 29a To a mixture of 6-bromo-indan-l-one (100.00 g, 473.8 mmol) in anhydrous THF (1 L) at 0°C was added i-BuOK (58.5 g, 521.2 mmol, 1.1 eq), 2 min later the mixture was warmed up to room temperature and was stirred for another 10 min before methyl methacrylate (49.8 g, 53.2 mL, 497.5 mmol, 1.05 eq) was added in one portion. After 2h, methyl acrylate (49.0 g, 51.2 mL, 568.6 mmol, 1.2 eq) was added to the reaction mixture. After 3 h at room temperature, Mel (101 g, 44.3 mL, 710.7 mmol, 1.5 eq) was added to the reaction mixture, and it was stirred for 16 hours. H20 (1 L) was added followed by LiOH H20 (79.5 g, 1895.2 mmol, 4.0 eq), the mixture was stirred for 28 h at room temperature. THF was removed under reduced pressure. The residue was diluted with H20 (1 L) and filtered, washed with H20 until the filtrate was neutral. The product was washed with to afford 50 g of intermediate 29a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; | 1.1-01 Preparation of Examples 1 Example 1-01 (Typical Procedure 1) Preparation of Examples 1 Example 1-01 (Typical Procedure 1) [0265] To a solution of 6-bromo-indan-1-one (70 mg) and 3-[4-(3-methyl-butoxy)-phenoxy]-pyrrolidin-2-one (70 mg) in 1,4-dioxane (2 mL) was added N,N′-dimethyl-ethane-1,2-diamine (0.325 mL) and cesium carbonate (141 mg). The mixture was purged for 5 minutes with a flow of argon and CuI (3.2 mg) was added. The mixture was heated at 100° C. for 1 hour. After cooling to r.t. insoluble material was removed by filtration and the filtrate concentrated. The residue was purified by preparative HPLC to provide example 1-01. | |
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; | 1.01 Example 1 -01 (Typical Procedure 1 ) To a solution of 6-bromo-indan-1 -one (70 mg) and 3-[4-(3-methyl-butoxy)-phenoxy]- pyrrolidin-2-one (70 mg) in 1 ,4-dioxane (2 ml_) was added W,/V-dimethyl-ethane-1 ,2-diamine (0.325 mL) and cesium carbonate (141 mg). The mixture was purged for 5 minutes with a flow of argon and Cul (3.2 mg) was added. The mixture was heated at 100°C for 1 hour. After cooling to r.t. insoluble material was removed by filtration and the filtrate concentrated. The residue was purified by preparative HPLC to provide example 1 -01 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8%; 70% | General procedure: A solutionof carboxylic acid (1 mmol), ketone (1 mmol, if required) and TFAA (0.85 mL, 6 mmol) in dichloromethane (1 mL) was stirred for 15 min at rt. The required quantity of triflic acid (usually 44 muL, 0.5 mmol) was then added, and the resulting solution was stirred at rt for 1-4 h (24 h for 3v and 3w) under the conditions indicated in Scheme 1, Scheme 2, Table 1, and Table 2 (TLC monitoring). The reaction mixture was evaporated under reduced pressure, and after quenching with water, the residue was redissolved in dichloromethane (10 mL), washed with 5% NaHCO3 (2 × 3 mL), water (2 × 3 mL), and dried over MgSO4. The solvent was removed in vacuum, andthe crude reaction mixture was purified by silica gel chromatography (n-hexane/CH2Cl2/MeOH). | |
62% | General procedure: A solutionof carboxylic acid (1 mmol), ketone (1 mmol, if required) and TFAA (0.85 mL, 6 mmol) in dichloromethane (1 mL) was stirred for 15 min at rt. The required quantity of triflic acid (usually 44 muL, 0.5 mmol) was then added, and the resulting solution was stirred at rt for 1-4 h (24 h for 3v and 3w) under the conditions indicated in Scheme 1, Scheme 2, Table 1, and Table 2 (TLC monitoring). The reaction mixture was evaporated under reduced pressure, and after quenching with water, the residue was redissolved in dichloromethane (10 mL), washed with 5% NaHCO3 (2 × 3 mL), water (2 × 3 mL), and dried over MgSO4. The solvent was removed in vacuum, andthe crude reaction mixture was purified by silica gel chromatography (n-hexane/CH2Cl2/MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; Sealed tube; | 1.1 Step 1. 6-(3-Fluorophenyl)-2,3-dihydro-1H-inden-1-one Step 1. 6-(3-Fluorophenyl)-2,3-dihydro-1H-inden-1-one Cesium carbonate (618 mg, 1.90 mmol) was added to a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (200 mg, 0.948 mmol), (3-fluorophenyl)boronic acid (265 mg, 1.90 mmol) and toluene (20 mL) in a 50 mL Schlenk tube at room temperature. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3*), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.001 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated in vacuo. The resulting crude residue was purified on a Teledyne-Isco combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 174 mg (81%) of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium etoxide In ethanol at 60 - 120℃; Inert atmosphere; | 5 Add 500ml of ethanol, 6-bromoindanone (40g, 0.19mol) to the 1000ML reactor, after replacing nitrogen with o-phthalaldehyde (25.4g, 0.19mol), add sodium ethoxide (25.8g, 0.38mol) under nitrogen protection, warmed up to 60~120 °C and start stirring, the system is gradually dissolved and clear, react for 3 to 6 hours, monitor with liquid phase, when 6-bromoindanone is less than 2%, begin to cool down, cool down to below 60 , import 500ml water to quench , after filtration under reduced pressure, the crude product was obtained, and the crude product was washed with 500 ml of ethanol and heated at 40 °C to 70 °C. After filtration under reduced pressure, a yellow solid intermediate 2-bromo-11H-benzo[b]fluorenone was obtained, 54.5g, HPLC = 99.2%, yield 93%. |
64% | In ethanol for 3h; Reflux; | 1 Preparation of compound 1-1[158]After introducing 6-bromoindanone (50g, 237mmol), phthal aldehyde (35g, 261mmol) and ethanol 600mL into a reaction vessel, the mixture was under reflux for 3 hours. The reaction mixture was cooled to 0°C. The crystalized solid was filtered, and washed with cool methanol to obtain compound 1-1 (47g, 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.3% | With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; | 6 Methyl 2-(6-bromo-1 -oxo-2,3-d ihydro-1 H-i nden-2-yl)acetate To a solution of 6-bromo-2,3-dihydro-1 H-inden-1 -one (15 g, 71 .1 mmol) in THE (300 mL), LiHMDS (85 mL, 85 mmol) was added dropwise at -78 00. Then the reaction mixture was allowed to warm up to 0 00 and was cooled to -78 00 again. Methyl 2-bromoacetate (7.38 mL, 78 mmol) was added dropwise at -78 00. The reaction mixture was warmed to ambienttemperature. Water was added and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried with MgSO4 and concentrated to give crude product which waspurified through silica gel column chromatography (petroleum ether : ethyl acetate=1 0:1) toafford methyl 2-(6-bromo-1 -oxo-2,3-dihydro-1 H-inden-2-yl)acetate (8.1 g, 28.6 mmol, 40.3 %yield). LC-MS m/z 285.0 (M+H), 1 .68 mm (ret. time). |
40.3% | Stage #1: 6-bromoindan-1-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; Stage #2: bromoacetic acid methyl ester In tetrahydrofuran at -78 - 20℃; | 6 Methyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (15 g, 71.1 mmol) in THF (300 mL), LiHMDS (85 mL, 85 mmol) was added dropwise at -78 °C. Then the reaction mixture was allowed to warm up to 0 °C and was cooled to -78 °C again. Methyl 2-bromoacetate (7.38 mL, 78 mmol) was added dropwise at -78 °C. The reaction mixture was warmed to ambient temperature. Water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried with MgSO4 and concentrated to give crude product which was purified through silica gel column chromatography (petroleum ether : ethyl acetate=10:1) to afford methyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate (8.1g, 28.6 mmol, 40.3 % yield). LC-MS m/z 285.0 (M+H)+, 1.68 min (ret. time). |
Stage #1: 6-bromoindan-1-one With lithium diisopropyl amide In tetrahydrofuran at -78 - 0℃; for 0.333333h; Stage #2: bromoacetic acid methyl ester In tetrahydrofuran at -78 - 20℃; for 3h; | Methyl 2-(6-bromo-1 -oxo-2,3-dihydro-1 H-inden-2-yl)acetate Methyl 2-(6-bromo-1 -oxo-2,3-dihydro-1 H-inden-2-yl)acetate To a solution of 6-bromo-2,3-dihydroinden-1 -one (3.0 g) in THF (80 mL) was added LDA (8.5 mL, 2 M solution) dropwise at -78°C and the mixture was allowed to warm to 0°C with stirring for 20 minutes. The mixture was cooled to -78°C and methyl 2- bromoacetate (4.35 g) was added. The mixture was allowed to warm to RT with stirring for 3 hours. The mixture was poured into water and then extracted with EA (100 mL x 3). The organic phase was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation under reduced pressure and the residue was purified by preparative HPLC to provide the title compound. MS ESI+: m/z = 283 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.462 g | With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 150℃; for 1h; Microwave irradiation; | Reference Example 1-1-6-Cyclopropylindan-1-one (0335) To a suspension of 6-bromoindan-1-one (0.60 g), cyclopropylboronic acid monohydrate (0.47 g), tricyclohexylphosphine (0.081 g) and tripotassium phosphate (2.11 g) in toluene (10 mL) and distilled water (0.5 mL) was added palladium(II) acetate (0.064 g), and the mixture was stirred for 1 hour at 150° C. under microwave irradiation. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/n-hexane=0/100 to 20/80) to afford the title compound (0.462 g). (0336) 1H-NMR (CDCl3) δ: 0.68-0.75 (2H, m), 0.95-1.05 (2H, m), 1.90-2.00 (1H, m), 2.64-2.73 (2H, m), 3.05-3.13 (2H, m), 7.34-7.38 (2H, m), 7.40-7.43 (1H, m). |
0.462 g | With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 150℃; for 1h; Microwave irradiation; | 1-1 6-Cyclopropylindan-1-one To a suspension of 6-bromoindan-1-one (0.60 g), cyclopropylboronic acid monohydrate (0.47 g), tricyclohexylphosphine (0.081 g) and tripotassium phosphate (2.11 g) in toluene (10 mL) and distilled water (0.5 mL) was added palladium(II) acetate (0.064 g), and the mixture was stirred for 1 hour at 150° C. under microwave irradiation. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/n-hexane=0/100 to 20/80) to afford the title compound (0.462 g). Read more: http://www.patentsencyclopedia.com/app/20160115119ixzz49dhpDzEA |
0.462 g | With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 0.99℃; for 1h; Microwave irradiation; | 1-1 6-cyclopropylindan-1-one 6 bromoindan-1-one (0.60g), cyclopropyl boronic acid monohydrate (0.47g), tricyclohexylphosphine (0.081g) and toluene of tripotassium phosphate(2.11g) (10mL ), palladium acetate (II) (0.064g) was added to distilled water (0.5 mL) suspension, and the mixture was stirred for 1 hour at microwaveirradiation under 0.99 ° C.. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent ethyl acetate / n-hexane = 0 /100-20 / 80) to give the title compound (0.462 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With acetic acid In tetrahydrofuran; methanol for 16h; Reflux; | 1 Step 1: 2-(6-bromo-2,3-dihydro- 1H-inden- 1-ylidene)-1 , 1-dimethyihydrazine A suspension of 6-bromoindan-1-one (5.00 g, 23 mmol) in MeOH (35 mL)and THF (35 mL) was treated with 1,1 -dimethyihydrazine (2.7 mL, 35 mmol) and acetic acid (0.7 mL, 12 mmol) and stirred under reflux for 16 h. The mixture wascooled to r.t., evaporated and the residue dissolved in DCM, washed by aq. sat. NaHCO3 and extracted with DCM. The layers were separated and the aqueous phase extracted with DCM. The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated. Purification by column chromatography (0 - 25% EtOAc in hexane) afforded the title compound (4.1 g, 68%). ‘H NMR (400 MHz, CDC13) ö ppm2.66 (6H, s), 2.87 - 2.91 (2H, m), 2.97 - 3.01 (2H, m), 7.15 - 7.17 (1H, m), 7.41 - 7.44 (1H, m), 7.88 (1H, s). MS: m/z = 252.8 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
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9.5 mg | With hydrogen bromide; bromine; acetic acid In water at 20 - 25℃; for 4h; | 1 Step 1: 2,6-dibromo-2,3-dihydro-1H-inden-1-one A stirred suspension of 6-bromoindan-1-one (20 g, 94.7 mmol) in acetic acid (250 mL) was treated dropwise with a solution of hydrobromic acid (48 wt.% in H20,1.0 mL, 18 mmol) and bromine (4.86 mL, 94.7 mmol) in acetic acid (50 mL) atambient temperature. After 4 h, the solution was added in small portions to a stirringice-water (800 mL). The mixture was diluted with EtOAc (1L) and filtered. Theorganic phase was separated, washed with H20 (2 x 500 mL), dried (Na2SO4) andevaporated to give a brown semi-solid. This material was suspended in hexane/Et20 (1:1, 150 mL) and heated at 60 °C for 20 mm. The hot suspension was filtered and the filtrate was cooled and concentrated in vacuo to give an orange solid. The material was stirred in Et20 (45 mL) for 30 mm to give a fine precipitate. The solids werecolleted by filtration and washed with Et20 to afford the desired product as an off-white solid (9.5 g). ‘H NMR (400 MHz, CDC13) ö ppm 3.35 (1H, dd), 3.77 (1H, dd),4.65 (1H, dd), 7.34 (1H, dd), 7.75 (1H, dd), 7.94 (1H, s). LCMS: rt = 3.25 mi m/z =291 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
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52.1% | Stage #1: 6-bromoindan-1-one With potassium hydroxide In methanol at 0℃; for 0.166667h; Stage #2: [bis(acetoxy)iodo]benzene In methanol at 0 - 20℃; for 3h; | 20 6-Bromo-1 ,1 -dimethoxy-2,3-dihydro-1 H-inden-2-ol A solution of 6-bromo-2,3-dihydro-1 H-inden-1 -one (1 .055 g, 5 mmol) and KOH (3.09 g, 55.0 mmol) in methanol (25 mL) was stirred for 10 mm at 0 00 after which time (diacetoxyiodo)benzene (1 .933 g, 6.00 mmol) was added. The resulting solution was stirred at 0 00 for 1 h and at ambient temperature for 2 h. The reaction mixture was then concentrated under reduced pressure and purified via silica gel chromatography to afford the title compound (0.7734 g, 2.61 mmol, 52.1 % yield) as a dark red gum. LC-MS m/z 273.0 (M+H), 0.84 mm (ret. time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sulfuric acid In 1,4-dioxane at 100℃; for 4h; Inert atmosphere; | 2-(6-Bromo-1 -oxo-1 H-inden-2(3H)-yI idene)acetic acid To a solution of 6-bromo-2,3-dihydro-1 H-inden-1 -one (5 g, 23.69 mmol) in 1 ,4-dioxane (20 mL)was added 2-oxoacetic acid (35.1 g, 237 mmol), H2S04 (5 mL, 94 mmol) slowly under nitrogenat ambient temperature. The reaction mixture was stirred at 100 00 for 4 h. The reaction wascooled to ambient temperature and water (100 mL) was added to the reaction. The reaction wasfiltered and the white solid was dried on high vacuum to afford the title compound (5.6 g, 84 %yield). LC-MS m/z 268 (M+H), 1 .56 mm (ret. time). |
84% | With sulfuric acid In 1,4-dioxane at 100℃; for 4h; Inert atmosphere; | Intermediate 15 (0466) 2-(6-Bromo-1-oxo-1H-inden-2(3H)-ylidene)acetic acid To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.69 mmol) in 1,4-dioxane (20 mL) was added 2-oxoacetic acid (35.1 g, 237 mmol), H2SO4 (5 mL, 94 mmol) slowly under nitrogen at ambient temperature. The reaction mixture was stirred at 100 °C for 4 h. The reaction was cooled to ambient temperature and water (100 mL) was added to the reaction. The reaction was filtered and the white solid was dried on high vacuum to afford the title compound (5.6 g, 84 % yield). LC-MS m/z 268 (M+H)+, 1.56 min (ret. time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.56% | Stage #1: 6-bromoindan-1-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 8h; Inert atmosphere; Stage #2: Benzyl bromoacetate In tetrahydrofuran for 0.5h; | 1 Benzyl 2-(6-bromo-1 -oxo-2,3-d ihydro-1 H-inden-2-yI)acetate To a solution of 6-bromo-2,3-dihydro-1 H-inden-1 -one (2.Og, 9.48 mmol) in THE (10 mL) under N2 atmosphere was added LiHMDS (11 .37 mL, 11 .37 mmol) dropwise at -78 00. After the addition, the reaction mixure was allowed to slowly warm up to 0 00 and stirred for 8 h at thistemperature. The mixture was recooled to -78 00 and benzyl 2-bromoacetate (1 .651 mL, 10.42 mmol) was added dropwise. The reaction mixture was stirred for 30 mm and slowly allowed to warm to ambient temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The crude residue was purified by flash chromatographyy eluting with petroleum ether:EtOAc (10:1) toafford the title compound (700 mg, 20.56% yield). LC-MS m/z359 (M+H), 1.78 mm (ret. time). |
20.56% | Stage #1: 6-bromoindan-1-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 8h; Inert atmosphere; Stage #2: Benzyl bromoacetate In tetrahydrofuran at -78℃; for 0.5h; | 1 Intermediate 26 (0495) Benzyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate To a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (2.0g, 9.48 mmol) in THF (10 mL) under N2 atmosphere was added LiHMDS (11.37 mL, 11.37 mmol) dropwise at -78 °C. After the addition, the reaction mixure was allowed to slowly warm up to 0 oC and stirred for 8 h at this temperature. The mixture was recooled to -78 °C and benzyl 2-bromoacetate (1.651 mL, 10.42 mmol) was added dropwise. The reaction mixture was stirred for 30 min and slowly allowed to warm to ambient temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The crude residue was purified by flash chromatographyy eluting with petroleum ether:EtOAc (10:1) to afford the title compound (700 mg, 20.56 % yield). LC-MS m/z 359 (M+H)+, 1.78 min (ret. time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.1% | Stage #1: methanol; 6-bromoindan-1-one With potassium hydroxide at 0℃; for 0.166667h; Stage #2: With [bis(acetoxy)iodo]benzene at 0 - 20℃; for 3h; | 20 6-Bromo-1,1-dimethoxy-2,3-dihydro-1H-inden-2-ol A solution of 6-bromo-2,3-dihydro-1H-inden-1-one (1.055 g, 5 mmol) and KOH (3.09 g, 55.0 mmol) in methanol (25 mL) was stirred for 10 min at 0 °C after which time (diacetoxyiodo) benzene (1.933 g, 6.00 mmol) was added. The resulting solution was stirred at 0 °C for 1 h and at ambient temperature for 2 h. The reaction mixture was then concentrated under reduced pressure and purified via silica gel chromatography to afford the title compound (0.7734 g, 2.61 mmol, 52.1 % yield) as a dark red gum. LC-MS m/z 273.0 (M+H)+, 0.84 min (ret. time). |
With [bis(acetoxy)iodo]benzene; potassium hydroxide at 0 - 20℃; for 1.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 6h; Inert atmosphere; | 1.2 Step 2: Preparation of the compound trans-6-(4-(4-ethylphenyl)butenyl)-2,3-dihydro-1-indanone Under the protection of argon, 6-bromo-1-indanone (112 mg, 0.53 mmol) was weighed separately.Compound 1 (140 mg, 0.80 mmol), palladium acetate (6 mg, 0.027 mmol),Tris(o-methylphenyl)phosphine (16 mg, 0.053 mmol) was added to a 25 mL three-necked flask.Triethylamine (1.5 mL), N,N-dimethylformamide (1.5 mL) was added.The reaction system was heated to 100 ° C in an oil bath, stirred for 6 hours, and the reaction was monitored by thin layer chromatography.After cooling to room temperature, the reaction was quenched by adding 5 mL of water and stirring for 10 minutes, and extracted three times with 15 mL of ethyl acetate.The organic phases are combined, then the organic phase is washed with water and the organic phase washed with saturated sodium chloride.Dry over anhydrous sodium sulfate, filter and concentrate, and then purified by column chromatography (mobile phase: ethyl acetate:Petroleum ether = 1:5) purified. 70 mg (44%) of a yellow solid were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 6-bromoindan-1-one With sodium hydride In N,N-dimethyl-formamide at 4 - 23℃; for 1h; Stage #2: p-methoxybenzyl chloride In N,N-dimethyl-formamide at 10 - 23℃; for 14h; | 87 6-Bromo-1-((4-methoxybenzyl)oxy)-2,3-dihydro-1H-indene 6-Bromo-2,3-dihydro-1H-inden-1-ol (8.6 g, 40.4 mmol) was dissolved in DMF (50 mL) and cooled to 4°C and 60% sodium hydride (3.23 g, 81 mmol) was added in one portion. Stirr at 23 °C for 1 h and then cooled again to 10 °C with the ice bath and 1-(chloromethyl)-4- methoxybenzene (9.48 g, 60.5 mmol) was added. Stirred at 23 °C for 14 h. The reaction was quenched with water 25 mL stirred 3 min and then diluted with EtOAc (200 mL) and more water (25 mL). Phases were separated and the aq was extracted with an additional 2 X 75 mL EtOAc. The combined EtOAc was washed with water (75 mL) and then satd aq NaCl (50 mL), dried (Na2SO4), concentrated and the residual amber oil was purified on an ISCO silica cartridge (120 g) with a Combiflash Companion, eluting at 85 mL/min with a gradient running from hexanes to 10% EtOAc/hexanes over 30 min. The desired fractions were pooled to afford 6-bromo-1-((4- methoxybenzyl)oxy)-2,3-dihydro-1H-indene (11.76 g, 35.3 mmol, 87 % yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) d 7.46-7.61 (m, 1H), 7.23-7.44 (m, 3H), 7.06-7.18 (m, 1H), 6.81-7.00 (m, 2H), 4.89-5.08 (m, 1H),4.38-4.74 (m, 2H), 3.84 (s, 3H), 2.95-3.18 (m, 1H), 2.92- 3.15 (m, 1H), 2.65-2.89 (m, 1H), 2.30-2.50 (m, 1H), 2.05-2.22 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 6-bromoindan-1-one; acetoacetic acid methyl ester In toluene for 0.25h; Inert atmosphere; Stage #2: With 2-(di-tert-butylphosphino)-2',4',6'-trimethylbiphenyl; palladium diacetate In toluene at 120℃; | 1a.1 Step 1 6-bromo-2,3-dihydroinden-1 -one (500 mg, 2.37 mmol), methylacetoacetate (767 pL, 7.11 mmol) and potassium phosphate (2.01 g, 9.48mmol) were diluted with toluene (15 mL). The solution was degassed with N2 for15 mi Pd(OAc)2 (27 mg, 0.12 mmol) followed by di-tert-butyl XPhos (101 mg,0.24 mmol). The reaction mixture was heated overnight at 120°C. Thesuspension was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated to dryness and purified by silica gel columnchromatography using Cyclohexane/EtOAc (70:30) as eluent. The desiredfractions were combined and concentrated under reduced pressure to obtainmethyl 2-(1-oxo-2,3-dihydro-1H-inden-6-yl)acetate Ex.51a (361 mg, 75%) aspale brown solid. 1H NMR (300 MHz, DMSO-d6, d in ppm): 2.62 (t, 2H,J=5.8Hz), 3.07 (t, 2H, J=6.2Hz), 3.61 (s, 3H), 3.79 (s, 2H), 7.54-7.55 (m, 2H),7.59 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 6-bromoindan-1-one; methylamine In methanol at 20℃; for 3.5h; Stage #2: With sodium tetrahydroborate In methanol at 20℃; | Scheme 1.1 6-bromoindanole (4.3 g/20.3 mmole) (Compound 1) and methylamine (20 mL, 9.8 M in MeOH), in methanol (50 mL) were charged into a round bottom flask and stirred for about 3.5 hours at room temperature to form a solution. Sodium borohydride (1.2 g) was slowly added to the solution at room temperature to form a mixture, and then the mixture is stirred and maintained for completion of the reaction overnight. After that, the solvent and excess methylamine in the mixture was removed under vacuum to produce a residue. Ice-water was added to the residue and then a brown black solid was found, filtered, collected and washed by NaHC03 (aq). Next, the solid was dried under vacuum to afford a product (4.04 g, 87% yield). The product was Compound 2 (6-bromo- -mcthyl-2, 3-dihydro- 1 //-inden- 1 -amine). The product was used in the next step without further purification. |
Stage #1: 6-bromoindan-1-one; methylamine In methanol at 20℃; for 3.5h; Stage #2: With methanol; sodium tetrahydroborate at 20℃; | I Synthesis of Compound 64 Compound 15a (5-bromo-2,3-dihydro-lH-inden-l-one) (4.3 g, 20.3 mmol) and methylamine (20 mL, 9.8 M in MeOH), in methanol (50 mL) were charged into a round bottom flask and stirred for about 3.5 hours at room temperature to form a solution. Sodium borohydride (1.2 g) was slowly added to the solution at room temperature to form a mixture, and then the mixture is stirred and maintained for completion of the reaction overnight. After that, the solvent and excess methylamine in the mixture was removed under vacuum to produce a residue. Ice-water was added to the residue and then a brown black solid was found, filtered, collected and washed by NaHC03 (aq). Next, the solid was dried under vacuum to afford a product Compound 64a (5-bromo-N-methyl-2,3-dihydro-lH-inden-l-amine) (3.21 g, 14.20 mmol, yield 70%). The product Compound 64a was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In toluene at 0 - 20℃; for 16h; | 6-bromo- l-ethyl-2, 3-dihydro- lH-inden- l-ol To a stirred solution of 6-bromo-2,3 -dihydro- l/7-inden-l -one (5.0 g, 23.68 mmol) in toluene (50 mL) was added EtMgBr (23.70 mL, 71.07 mmol) drop-wise at 0 °C. The ice bath was removed and the reaction was stirred at rt for 16 h. The reaction was quenched with sat. aq. NH4Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2S04) and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (Si02, 20 % EtOAc/pet. ether) to afford Intermediate 27 (4 g, 70%) as a colorless liquid. MS (ESI) 223.1 [M+H-H20]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: methyllithium With cerium(III) chloride In tetrahydrofuran; diethyl ether at -78 - 20℃; for 1.5h; Stage #2: 6-bromoindan-1-one In tetrahydrofuran; diethyl ether at -78 - 20℃; for 2h; | 6-bromo- 1 -methyl-2,3 -dihydro- lH-inden- 1 -ol A suspension of anhydrous CeCl3 (17.5 g, 71.08 mmol) in THF (100 mL) was stirred at rt for 1 h and cooled down to -78 °C. 1.6 M MeLi in DEE (44 mL, 71.08 mmol) was added at -78 °C and the reaction was stirred for 30 min. To this, was added a solution of 6-bromo-2,3-dihydro- 1 /7-indcn- 1 -one (10 g, 47.39 mmol) in THF (100 mL) at - 78 °C. The ice bath was removed and the reaction was stirred at rt for 2 h. After completion by TLC, the reaction was quenched with aq. NH4Cl (200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (S1O2, 30 % EtOAc/pet. ether) to afford Intermediate 25 (6 g, 55%) as a colorless oil. 1H NMR (400 MHz, DMSO-76) d 7.43 (d, 7=2.0 Hz, 1H), 7.35 (dd, 7=8.0, 2.0 Hz, 1H), 7.16 (d, 7=8.0 Hz, 1H), 5.14 (s, 1H) 2.89-2.81 (m, 1H), 2.75-2.66 (m, 1H), 2.07 (t, 7=4.4 Hz, 2H), 1.40 (s, 3H). |
55% | Stage #1: methyllithium With cerium(III) chloride In tetrahydrofuran; diethyl ether at -78℃; for 0.5h; Inert atmosphere; Stage #2: 6-bromoindan-1-one In tetrahydrofuran; diethyl ether at -78 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 2,6-dimethylpyridine; nickel(II) bromide dimethoxyethane; 2.9-dimethyl-1,10-phenanthroline; carbon nitride In N,N-dimethyl-formamide at 25℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: 6-bromoindan-1-one; S-tert-butylsulfinimide With titanium(IV) tetraethanolate In tetrahydrofuran at 70℃; for 3h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran at -48℃; for 0.833333h; | |
16% | Stage #1: 6-bromoindan-1-one; S-tert-butylsulfinimide With titanium(IV) isopropylate In tetrahydrofuran at 70℃; for 3h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran at -48℃; for 0.666667h; | 2 (±)-N-(5-Bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide Ketone 75 (0.422 g, 2.00 mmol) was diluted in anhydrous THF (10 mL) and Ti(OEt)4 (1.048 mL, 4 mmol) was added, followed by (RS)-t-butanesulfinamide (0.242 g, 2.00 mmol), as a solution in 2 mL of anhydrous THF. The reaction mixture (a suspension) was heated to 70 °C for 3 h, and was cooled to r.t. and then to -48 °C. NaBH4 (0.304 g, 8.00 mmol) was added in one portion. After 40 mm at -48 °C, the reaction was quenched by addition of MeOH until gas evolution ceased. The mixture was then warmed to r.t. and an equal volume of sat. aq. NaC1 was added to precipitate titanium salts. After stirring for 5 mm, the suspension was filtered through Celite and the filter cake was washed with EtOAc (100 mL). The organic layers were separated, and the aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to yield a residue that was purified by flash column chromatography, eluting with a gradient of hexanes to 50% EtOAc in hexanes, to afford the title compound (presumably the RR and SS diasteromers) as a white wax (0.103 g, 16%). The compound was used immediately in the next step without further characterization. ‘HNIVIR (500 IVIHz; CDC13): 7.45 (d, J 8.0 Hz, 1 H), 7.37-7.34 (m, 2 H), 4.84 (q, J 6.9 Hz, 1 H), 3.40 (d, J= 6.3 Hz, 1 H), 2.97 (ddd, J 16.0, 8.5, 4.4 Hz, 1 H), 2.81 (dt, J 16.0, 7.9 Hz, 1 H), 2.52-2.45 (m, 1 H), 2.04-1.96 (m, 1 H), 1.23 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With sodium azide In dichloromethane at 0 - 20℃; | S-51.1 Step 1 : Synthesis of 7-bromo-3,4-dihydroisoquinolin-l(2H)-one. Sodium azide (0.924 g, 14.218 mmol, 1.0 equiv) was added slowly to a mixture of 6-bromo-2,3-dihydro-lH- inden-l-one (2.0 g, 9.478 mmol, 1.0 equiv) and methanesulfonic acid ( 18.1 g, 189.5 mmol, 20.0 equiv) in DCM (60 niL) at 0° C. The mixture was stirred at RT for overnight. The reaction mixture was carefully quenched with 1 M aqueous sodium hydroxide (80 tuL). The aqueous layer was extracted with DCM (3 x 100 mL), and the combined organic layers were washed with water (2 c 100 mL) and brine (100 mL), dried anhydrous NarSCL and concentrated. Hie residue was purified by flash chromatography (0-20 % ethyl acetate in hexane as an eluent) to obtain 7- bromo-3,4-dihydroisoquinolin- 1 (2H)-one (0.250 g, 12 % Yield) as a white solid. LCMS 225.9 | M i | Tf NMR (400 MHz, CHLOROFORM-7) d 8.20 (d, 7= 1.75 Hz, 1 H) 7.56 (dd, 7= 7.89, 2.19 Hz, 1 H) 7.26 (s, 1 H) 7.11 (d, ./ 7.H9 Hz, 1 H) 6.35 (br. s., 1 H) 3.57 (id. 7= 6.69, 2 85 Hz, 2 H) 2.96 (t, .7=6.58 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In methanol for 16h; Reflux; | |
10% | With 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In methanol at 50℃; for 7h; | 91.1 Step 1: Synthesis of 6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one: 6-bromo-indanone (2 g, 9.5 mmol) was dissolved in anhydrous MeOH (80 ml). Selectfluor(4 g, 11 mmol) was added. The reaction mixture was stirred for 7 h at 50°C. The solventwas evaporated at reduced pressure. DCM was added and insoluble material was filtered.The organic layer was washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered and concentrated at reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / DCM 100/0 to 92/8) to obtain220 mg of 6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one as a white solid, yield 10%. |
10% | With 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In methanol at 50℃; for 7h; | 91.1 Step 1: Synthesis of 6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one: 6-bromo-indanone (2 g, 9.5 mmol) was dissolved in anhydrous MeOH (80 ml). Selectfluor(4 g, 11 mmol) was added. The reaction mixture was stirred for 7 h at 50°C. The solventwas evaporated at reduced pressure. DCM was added and insoluble material was filtered.The organic layer was washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered and concentrated at reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / DCM 100/0 to 92/8) to obtain220 mg of 6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one as a white solid, yield 10%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; ethanol at 0 - 25℃; for 16h; | 98.1 To a solution of 6-bromoindan-1-one (50 g, 236.91 mmol) and 1-(isocyanomethylsulfonyl)-4- methyl-benzene (69.38 g, 355.36 mmol) in DME (2500 mL) and EtOH (100 mL) was added f-BuOK (53.17 g, 473.81 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture becomes muddy. The reaction mixture (each batch) was poured into water (2000 mL) and extracted with EA (2000 mL_ *2). The combined organic layer (contained water) was concentrated in vacuum to removed DME&EtOH. Then diluted with EA (500 mL) , washed with brine (500 mL) , dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica gel chromatography column (1000 g of 100 silica gel, PE~PE/EA=20/1 , desired spot collected from PE/EA=30/1). The fraction was concentrated in vacuum and triturated with MTBE (100 mL) to give Intermediate B (58 g, 55% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.58 (s, 1 H), 7.42 - 7.40 (m, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 4.12 - 4.08 (m, 1 H), 3.10 - 3.00 (m, 1 H), 2.97 - 2.86 (m, 1 H), 2.65 - 2.55 (m, 1 H), 2.43 - 2.37 (m, 1 H) ppm. |
28% | Stage #1: 6-bromoindan-1-one; [(p-methylphenyl)sulfonylmethyl]isonitrile In tetrahydrofuran at 30℃; for 0.166667h; Stage #2: With sodium t-butanolate In tetrahydrofuran at 30℃; | 28.1; 29.1 Step 1: 6-Bromo-2,3-dihydro-1H-indene-1-carbonitrile (racemate compound 26b) To a solution of compound 26a (3.0 g, 14.2 mmol) in dry tetrahydrofuran (3.0 mL) was added TosMIC (4.16 g, 21.3 mmol). After the reaction was stirred at 30°C for 10 minutes, a solution of sodium tert-butoxide (2.0M) in tetrahydrofuran (14.2 mL) was added. The mixture was fully reacted at 30°C.Dilute with water (100 mL), extract with ethyl acetate (100 mL×4), wash the combined organic phase with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.The crude product was obtained and purified by silica gel column chromatography (eluent: 2% ethyl acetate in petroleum ether) to obtain racemate compound 26b (878.0 mg, yield 28%). |
29 g | With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; ethanol at 0 - 25℃; for 16h; | 1.1 Step 1. 6-Bromoindane-1-carbonitrile Potassium tert-butoxide (53.2 g, 474 mmol) was added to a solution of 6-bromoindan-1-one (50 g, 237 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (69.4 g, 356 mmol) in DME (2.5 L) and EtOH (100 ml_) at 0 °C. The reaction mixture was stirred at 25°C for 16 hrs. The reaction mixture was poured into water (2 L) and extracted with EA (2 L x 2). The combined organic layer was concentrated in vacuo. The crude product was diluted with EA (500 ml_), washed with brine (500 ml_), dried over anhydrous Na2SC>4, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA = 20:1). The desired fractions were collected and concentrated in vacuo. The solid was then triturated with MTBE (100 ml_) affording the title compound (29 g, 130 mmol) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) d = 7.58 (s, 1 H), 7.42 - 7.40 (m, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 4.12 - 4.08 (m, 1 H), 3.10 - 3.00 (m, 1 H), 2.97 - 2.86 (m, 1 H), 2.65 - 2.55 (m, 1 H), 2.43 - 2.37 (m, 1 H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With palladium diacetate; potassium carbonate; triphenylphosphine In tetrahydrofuran; methanol at 20℃; for 12h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With palladium diacetate; potassium carbonate; triphenylphosphine In tetrahydrofuran; methanol at 20℃; for 12h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: trimethyl phosphonoacetate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 6-bromoindan-1-one In tetrahydrofuran at 20℃; | 20.1; 21.1 Step 1: Methyl 2-(6-bromo-2,3-dihydro-1H-inden-1-ylidene) acetate (Compound 18c) Sodium hydride (1.9g, 47.38mmol, 60%) was dispersed in tetrahydrofuran (200mL) and cooled to 0°C, and then compound 18b (8.2mL, 56.86mmol) was added. The mixture was stirred at 0°C for 30 minutes and then a solution of compound 18a (5 g, 23.69 mmol) in tetrahydrofuran (50 mL) was added. The mixture was fully reacted at room temperature. It was quenched with saturated ammonium chloride solution (300 mL), extracted with ethyl acetate (100×2 mL), and the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product . Purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in petroleum ether) to obtain compound 18c (2.4 g, yield 38%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium <i>tert</i>-butylate; ammonium chloride; ethanolamine; Selectfluor In water at 120℃; for 24h; Sealed tube; Green chemistry; | |
61% | With potassium <i>tert</i>-butylate; ammonium chloride; ethanolamine; Selectfluor In water at 120℃; for 24h; | 5 Example 5 Preparation of 3,7-dibromo-10,12-dihydroindeno[1,2-b:2',1'-e]pyridine The first step: add 6-bromo-1-indanone (42.2mg, 0.2mmol) to a 50mL reaction tube with a ground branch pipe,NH4Cl (53.5mg, 1.0mmol), fluorine reagent (70.9mg, 0.2mmol), potassium tert-butoxide (22.4mg, 0.2mmol),Ethanolamine (1 mL) and water (2 mL).The second step: replace the air in the reaction tube with carbon dioxide gas at one atmospheric pressure, heat to 120°C and stir for 24 hours.The third step: cooling to room temperature, adding 5 mL of water to dilute the reaction solution, extracting the aqueous phase three times with 10 mL dichloromethane, and mixing the dichloromethane phases obtained by the three extractions and draining.The remaining crude product was separated by column chromatography (petroleum ether/ethyl acetate=7:1) to obtain a white solid product (Product 5) in 61% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With (R)-AntPhos; potassium carbonate; Palladium(0) bis(dibenzylideneacetone) In tert-Amyl alcohol; ethyl acetate at 80℃; for 40h; Sealed tube; Inert atmosphere; enantioselective reaction; |
Tags: 14548-39-1 synthesis path| 14548-39-1 SDS| 14548-39-1 COA| 14548-39-1 purity| 14548-39-1 application| 14548-39-1 NMR| 14548-39-1 COA| 14548-39-1 structure
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