* 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.
Stage #1: With sodium methylate In dimethyl sulfoxide; toluene at 13 - 16℃; for 0.75 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide; toluene
Dimethylsulfoxide (DMSO) (300 ml), toluene (300 ml) and paraformaldehyde (PF) (40 gram) were charged into a round bottom flask, mixed and cooled to a temperature of 13-15 °C. Subsequently, sodium methoxide 30 percent solution (26 gram) was added to this mixture.Gradually fluorene in powder form (100 gram, 0.6 mole) was added to above reaction mixture over a period of 15 minutes, while the temperature was maintained at 14-16 °C. It was observed that most of the paraformaldehyde dissolves instantly upon addition of the fluorene. The resulting mixture was stirred for 30 minutes while the temperature was maintained at 14-16 °C. The resulting mixture was a clear pale yellowsolution.Subsequently, concentrated HCI (8-10 ml) was added to the obtained solution until al neutral pH (pH 6-7) was reached in order to stop the reaction. To the reaction mass gradually water (1000 ml) is added and reaction mass is cooled to 10 °C for 3 hours.The solid product was obtained by filtration. The solid product was filtered and washed with chilled toluene (two times 25 ml). The solid product was kept under vacuum till the toluene was completely removed from the product. The wet weight of the solid product was 120 gram. The product is then dried at 60-70 °C and weighed again. The dry weight was 90-95 gram. The yield was 70percent. The purity of the product as determined by HPLC was >98 percent. The melting point was 139-144 00.
69%
With sodium methylate In dimethyl sulfoxide at 13 - 16℃; for 0.75 h;
Dimethylsulfoxide (DMSO) (400 ml) and paraformaldehyde (PF) (40 gram) werecharged into a round bottom flask, mixed and cooled to a temperature of 13-15 00.Subsequently, sodium methoxide 30 percent solution (26 gram) was added to this mixture.Gradually fluorene in powder form (100 gram) was added to above reaction mixture over a period of 15 minutes, while the temperature was maintained at 14-16 00 It was observed that most of the paraformaldehyde dissolves instantly upon addition of the fluorene. The resulting mixture was stirred for 30 minutes while the temperaturewas maintained at 14-16 00 The resulting mixture was a clear pale yellow solution.Subsequently, concentrated HCI (8-10 ml) was added to the obtained solution until al neutral pH (pH 6-7) was reached in order to stop the reaction. The following work up was carried out for the reaction mixture: a large 3-5 liter round bottom flask wascharged with water (1200 ml). The reaction mixture was slowed added to the water under stirring. The resulting mixture was stirred for 30 minutes at room temperature. The solid crude reaction product was obtained by filtration.To the crude product toluene (350 ml) was added. The mixture was heated to80-90 00 The heating was stopped and the mixture was allowed to return to roomtemperature. Then the mixture was further cooled to 10 00 and maintained at that temperature for 2 hours. The solid product was filtered and washed with chilled toluene (two times 25 ml). The solid product was kept under vacuum till the toluene was completely removed from the product. The wet weight of the solid product was150 gram. The product is then dried at 60-70 00 and weighed again. The dry weight was 85-93 gram. The yield was 69percent. The purity of the product as determined by HPLC was >98 percent. The melting point was 139-144 00
30%
With sodium methylate In dimethyl sulfoxide at 13 - 16℃; for 0.25 h;
Dimethylsulfoxide (DMSO) (300 ml) and paraformaldehyde (PF) (25 gram) were charged into a round bottom flask, mixed and cooled to a temperature of 13-15 °C. Subsequently, sodium methoxide 30 percent solution (3.5 gram) was added to this mixture. A solution of fluorene (50 gram) in DMSO (300 ml) was added to above reaction mixture over a period of 1 -2 minutes, while the temperature was maintained at 14- 16 °C. The resulting mixture was stirred for 15 minutes while the temperature was maintained at 14-16 °C. The resulting mixture was a clear pale yellow solution. Subsequently, concentrated HCI (5-10 ml) was added to the obtained solution until al neutral pH (pH 6-7) was reached in order to stop the reaction. The following work up was carried out for the reaction mixture: a large 3-5 liter round bottom flask was charged with water (1200 ml). The reaction mixture was slowed added to the water under stirring. The resulting mixture was stirred for 15-30 minutes at room temperature. The crude reaction product was obtained by extraction with ethyl acetate. The organic phase is dried and distilled under vacuum. The residue was crystallized in 200 ml toluene to get the product as off white crystals. The dry weight was 25 gram. The yield was 30percent. The purity of the product as determined by HPLC was >98 percent.
Reference：
[1] Patent: WO2018/42013, 2018, A1, . Location in patent: Page/Page column 17; 18
[2] Patent: WO2016/193215, 2016, A1, . Location in patent: Page/Page column 18; 19
[3] Patent: WO2016/193212, 2016, A1, . Location in patent: Page/Page column 17-18
[4] Journal of the American Chemical Society, 1959, vol. 81, p. 1172,1175
[5] Journal of the American Chemical Society, 1960, vol. 82, p. 4945 - 4952
[6] Synthesis, 1992, # 9, p. 819 - 820
[7] Chemistry - A European Journal, 2015, vol. 21, # 13, p. 5061 - 5073
2
[ 7471-93-4 ]
[ 4425-93-8 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 1172,1175
3
[ 1989-33-9 ]
[ 4425-93-8 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 1172,1175
4
[ 108971-75-1 ]
[ 4425-93-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1964, vol. 42, p. 1409 - 1417
5
[ 93876-07-4 ]
[ 4425-93-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1964, vol. 42, p. 1409 - 1417
6
[ 3002-30-0 ]
[ 4425-93-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1964, vol. 42, p. 1409 - 1417
7
[ 92873-01-3 ]
[ 4425-93-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1964, vol. 42, p. 1409 - 1417
Dimethylsulfoxide (DMSO) (300 ml), toluene (300 ml) and paraformaldehyde (PF) (40 gram) were charged into a round bottom flask, mixed and cooled to a temperature of 13-15 C. Subsequently, sodium methoxide 30 % solution (26 gram) was added to this mixture.Gradually fluorene in powder form (100 gram, 0.6 mole) was added to above reaction mixture over a period of 15 minutes, while the temperature was maintained at 14-16 C. It was observed that most of the paraformaldehyde dissolves instantly upon addition of the fluorene. The resulting mixture was stirred for 30 minutes while the temperature was maintained at 14-16 C. The resulting mixture was a clear pale yellowsolution.Subsequently, concentrated HCI (8-10 ml) was added to the obtained solution until al neutral pH (pH 6-7) was reached in order to stop the reaction. To the reaction mass gradually water (1000 ml) is added and reaction mass is cooled to 10 C for 3 hours.The solid product was obtained by filtration. The solid product was filtered and washed with chilled toluene (two times 25 ml). The solid product was kept under vacuum till the toluene was completely removed from the product. The wet weight of the solid product was 120 gram. The product is then dried at 60-70 C and weighed again. The dry weight was 90-95 gram. The yield was 70%. The purity of the product as determined by HPLC was >98 %. The melting point was 139-144 00.
69%
With sodium methylate; In dimethyl sulfoxide; at 13 - 16℃; for 0.75h;
Dimethylsulfoxide (DMSO) (400 ml) and paraformaldehyde (PF) (40 gram) werecharged into a round bottom flask, mixed and cooled to a temperature of 13-15 00.Subsequently, sodium methoxide 30 % solution (26 gram) was added to this mixture.Gradually fluorene in powder form (100 gram) was added to above reaction mixture over a period of 15 minutes, while the temperature was maintained at 14-16 00 It was observed that most of the paraformaldehyde dissolves instantly upon addition of the fluorene. The resulting mixture was stirred for 30 minutes while the temperaturewas maintained at 14-16 00 The resulting mixture was a clear pale yellow solution.Subsequently, concentrated HCI (8-10 ml) was added to the obtained solution until al neutral pH (pH 6-7) was reached in order to stop the reaction. The following work up was carried out for the reaction mixture: a large 3-5 liter round bottom flask wascharged with water (1200 ml). The reaction mixture was slowed added to the water under stirring. The resulting mixture was stirred for 30 minutes at room temperature. The solid crude reaction product was obtained by filtration.To the crude product toluene (350 ml) was added. The mixture was heated to80-90 00 The heating was stopped and the mixture was allowed to return to roomtemperature. Then the mixture was further cooled to 10 00 and maintained at that temperature for 2 hours. The solid product was filtered and washed with chilled toluene (two times 25 ml). The solid product was kept under vacuum till the toluene was completely removed from the product. The wet weight of the solid product was150 gram. The product is then dried at 60-70 00 and weighed again. The dry weight was 85-93 gram. The yield was 69%. The purity of the product as determined by HPLC was >98 %. The melting point was 139-144 00
30%
With sodium methylate; In dimethyl sulfoxide; at 13 - 16℃; for 0.25h;
Dimethylsulfoxide (DMSO) (300 ml) and paraformaldehyde (PF) (25 gram) were charged into a round bottom flask, mixed and cooled to a temperature of 13-15 C. Subsequently, sodium methoxide 30 % solution (3.5 gram) was added to this mixture. A solution of fluorene (50 gram) in DMSO (300 ml) was added to above reaction mixture over a period of 1 -2 minutes, while the temperature was maintained at 14- 16 C. The resulting mixture was stirred for 15 minutes while the temperature was maintained at 14-16 C. The resulting mixture was a clear pale yellow solution. Subsequently, concentrated HCI (5-10 ml) was added to the obtained solution until al neutral pH (pH 6-7) was reached in order to stop the reaction. The following work up was carried out for the reaction mixture: a large 3-5 liter round bottom flask was charged with water (1200 ml). The reaction mixture was slowed added to the water under stirring. The resulting mixture was stirred for 15-30 minutes at room temperature. The crude reaction product was obtained by extraction with ethyl acetate. The organic phase is dried and distilled under vacuum. The residue was crystallized in 200 ml toluene to get the product as off white crystals. The dry weight was 25 gram. The yield was 30%. The purity of the product as determined by HPLC was >98 %.
9H-Fluorene-9,9-diyldimethylene dimethanesulfonate was obtained by allowing 9H-fluorene-9,9-diyldimethanol to react with methanesulfonyl chloride and triethylamine at room temperature in methylene chloride. EI-MS: 382 (M)+.
With triethylamine; In dichloromethane; at 20℃;
9H-Fluorene-9,9-diyldimethylene dimethanesulfonate was obtained by allowing 9H-fluorene-9,9-diyldimethanol to react with methanesulfonyl chloride and triethylamine at room temperature in methylene chloride. EI-MS: 382 (M)+.
With triethylamine; In dichloromethane; at 20℃;
Reference Example 16-a 9H-Fluorene-9,9-diyldimethylene dimethanesulfonate was obtained by allowing 9H-fluorene-9,9-diyldimethanol to react with methanesulfonyl chloride and triethylamine at room temperature in methylene chloride. EI-MS: 382 (M)+.
9-methoxymethyl-9-hydroxymethyl-fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
Under nitrogen atmosphere and anhydrous condition, to a reactor were added in succession 80 ml of tetrahydrofuran, 22.6 g (0.1 mol) of <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> and 57 g (0.4 mol) of iodomethane. After the reaction mixture was admixed homogeneously by stirring, 4.6 g of 52 percent NaH in mineral oil (0.1 mol) was added batch-wise over 2 hours at room temperature, Upon completing the addition, the reaction mixture was stirred for further 2 hours. The unreacted iodomethane was recovered by distillation. The remainder was diluted with 100 ml of water, and extracted twice using 100 ml of diethyl ether for each time. The combined diethyl ether extract was dried over anhydrous sodium sulfat. After drying, the ether solution was evaporated to dry to give 22.8 g of crude. The crude was purified through column chromatography to give 14.9 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (yield 62 percent). 1H-NMR (CDCl3/TMS) delta (ppm): 1.70 (s, 1H, OH). 3.40 (s, 3H, OCH3), 3.71 (s, 2H, -CH2O-), 3.96 (s, 2H, -CH2O-), 7.31 (t, 2H, ArH), 7.41 (t, 2H, ArH), 7.65 (d, 2H, ArH), 7.75 (d, 2H, ArH)
With CH3I; NaH; In tetrahydrofuran; water; mineral oil;
Example 1 Synthesis of 9,9-bis(methoxymethyl)fluorene Into a 100 mL flask are introduced, in nitrogen atmosphere, in order: 30 mL of tetrahydrofuran (THF), 11.3 g of <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong>, and 31.1 mL of CH3I. While agitating the flask content and operating at ambient temperature, one adds, in a period of 2 hours and 30 minutes, 4 g of NaH at 60percent by weight in mineral oil, and the content is then allowed to react for 1 hour and 30 minutes. The nonreacted CH3I is recorded by distillation and the remaining content is diluted with 100 mL of water; the resulting floating solid is filtered and dried under vacuum at 40°C. After ethanol crystallization, 11.3 g of product (yield: 90percent) is obtained.
50%
With CH3I; NaH; In tetrahydrofuran; water; mineral oil;
Comparative Example 2 Synthesis of 9,9-bis(methoxymethyl)fluorene Into a 250 mL flask are introduced, in anhydrous atmosphere, 100 mL of THF and 10 g of <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong>. Then at ambient temperature 1.8 g of NaH at 60percent by weight in mineral oil is added portionwise over a period of 30 minutes, and immediately thereafter 2.3 mL of CH3I are added dropwise over a period of 30 minutes. The solution is allowed to react for 3 hours. A second addition is then made consisting of 1.8 g of NaH and 2.3 mL of CH3I in the same manner described above. After 3 hours of reaction time the content is diluted with 300 mL of water and then the floating solid is separated and crystallized. 5.6 g of product (yield: 50percent) is obtained.
28%
With sodium hydroxide; CH3I; tetra(n-butyl)ammonium hydrogen sulfate; In water; toluene;
Comparative Example 1 Synthesis of 9,9-bis(methoxymethyl)fluorene Into a 250 mL flask are introduced 36 mL of a 50percent aqueous solution of NaOH, 84 mL of toluene, 9.6 g of <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong>, and 0.24 g of tetrabutylammonium hydrogen sulfate. After heating the resulting mixture to 40°C, 8 mL of CH3I are added dropwise over a period of 1 hour; at the end of the addition the content is allowed to react for 4 hours at 40°C. It is then cooled to ambient temperature, diluted with 40 mL of water, and the organic phase is then separated. The aqueous phase is extracted with toluene, then the toluene extracts put together are rendered anhydrous with anhydrous Na2SO4and the solvent is flashed off. After an ethanol crystallization 3 g of product (yield: 28percent) is obtained.
9,9-bis(trimethylsilyloxymethyl)fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
1 g of 9,9 bis(hydroxymethyl)fluorene (4.4 mmol) was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, and 1.9 ml of triethyl amine (13.2 mmol) was added thereto. Then 1.4 ml of trimethylsilyl chloride (11 mmol) was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.14 g of concentrate (yield 88percent). MS (EI) m/e; 370 (M+). 1H-NMR (CDCl3/TMS) delta (ppm): 0.08 (s, 18H, CH3), 3.77 (s, 4H, -CH2O-), 7.26 (t, 2H, ArH), 7.38 (t, 2K, ArH), 7.62 (d, 2H, ArH), 7.72 (d, 2H, ArH)
9,9-bis((tert-butyl-dimethyl-silyl)oxymethyl)fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
<strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> (4.4 mmol) was admixed with 10 ml of N,N-dimethyl formamide, and 0.309 of imidazole (4.4 mmol) was added thereto. The mixture was cooled in ice-water bath, and 2.1 ml of triethyl amine (15 mmol) was added thereto. Aft r stirring for 5 minutes, 1.86 g of tert-butyldimethylsilyl chloride (12.4 mmol) in 10 ml of N,N-dimethyl formamide was added drop-wise, and the mixture was stirred in ice-water bath for further 4 hours. The reaction mixture was diluted with 10 ml of water, and extracted twice using 20 ml of dichloromethane for each time. The combined dichloromethane extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dry to give 1.73 g of concentrate (yield 86 percent). 1 g of white crystal was obtained by recrystallization from n-hexane. 1H NMR (CDCl3/TMS) delta (ppm): 0.00 (s, 12H, CH3), 0.92 (s, 18H, CH3) 3.82 (s, 4H, -CH2O-), 7.26 (t, 2H, ArH), 7.36 (t, 2H, ArH), 7.65 (d, 2H, ArH), 7.71 (d, 2H, ArH)
9,9-bis((triethylsilyl)oxymethyl)fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.1%
1 g of <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> (4.4 mmol) was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, and 1.9 ml of triethyl amine (13.3 mmol) was added thereto. Then 1.85 ml of triethylsilyl chloride (11.1 mmmol) was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.75 g of concentrate (yield 87.1 percent). 1H NMR (CDCl31/TMS) delta (ppm); 0.56 (q, 12H, CH2), 0.92 (t, 18H, CH3) 3.83 (s, 4H, -CH2O-), 7.24 (t, 2H, ArH), 7.36 (t, 2H, ArH), 7.63 (d, 2H, ArH), 7.71 (d, 2H, ArH)
9,9-bis((dimethyl-phenyl-silyl)oxymethyl)fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.2%
1 g of <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> (4.4 mmol) was admixed with 20 ml of dichloromethane. The mixture was cooled with ice-water bath, and 2.1 ml of triethyl amine (15 mmol) was added thereto. Then 2.1 ml of dimethylphenylsilyl chloride (13.3 mmol) was added dropwise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was vaporated to give 1.93 g of concentrate (yield 88.2 percent). 1H NMR (CDCl3/TMS) delta (ppm) 0.33 (s, 12H, CH3), 3.88 (S, 4H1, -CH2O-) 7.25 (t, 2H, ArH), 7.35 (m. 8H, ArH), 7.51 (d. 4H, ArH), 7.61 (d, 2H, ArH) 7.71 (d, 2H, ArH)
9,9-bis((ethyl-dimethyl-silyl)oxymethyl)fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
1 g of <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> (4.4 mmol) was dissolved in 20 ml of dichloromethane. The solution was cooled with ice-water bath, and 1.9 ml of triethyl amine (13.5 mmol) was added thereto. Then 1.6 ml of ethyldimethylsilyl chloride (11.4 mmol) was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.41 g of concentrate (yield 80 percent). 1H NMR (CDCl3/TMS) delta (ppm) 0.00 (s, 12H, CH3). 0.52 (q, 4H, CH2) 0.88 (t, 6H, CH3). 374 (s, 4H, -CH2O-), 7.21 (t, 2H, ArH), 7.32 (t, 2H, ArH), 7.59 (d, 2H1, ArH), 7.67 (d, 21H, ArH)
(3a“R,6a“S)-3a“,4“,6”,6a“-tetrahydro-1“H-dispiro[fluorene-9,5‘-[1,3]dioxane-2‘,2''-pentalen]-5“(3“H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With toluene-4-sulfonic acid; In toluene; for 2h;Reflux;
A mixture of (3a,6a)-tetrahydropentalene-2,5(1H,3H)-dione (8.3 g, 60 mmol), (9H- fluorene-9,9-diyl)dimethanol (14.0 g, 60 mmol) and p-toluensulfonic acid (0.060 g, 0.32 mmol) in toluene (75 ml) was refluxed for 2 hour with a water separator. The solvent was evaporated. The residue was partitioned between dichloromethane (300 ml) and 5percent aqueous sodiumbicarbonate solution (50 ml). The layers were separated. The organic layer was dried over magnesium sulfate, filtrated and concentrated in vacuo. Purification by flash chromatography with n-heptane/dichloromethane as eluent gave the mono-protected intermediate (10.5 g, 51percent).
Sodium hydroxide (NaOH) (100 gram) was dissolved in water (100 ml) in a 2 liter roundbottom flask under stirring. The reaction mixture was allowed to cool to roomtemperature. To this were added <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> (100 gram) obtained from either example 1 or comparative example 1, tetrabutylammonium bromide (2 gram) and toluene (500 ml). The resulting mixture was stirred at room temperature for 2-3 hours. At this stage the reaction mixture changed in nature and had become athick paste.The addition of the methylation agent, dimethyl sulfate (DMS) was carried out in four equal lots, each at a temperature of between 20-30 00. Each lot was added over a period of between 30-40 minutes in a drop wise manner. After each addition theresulting mass was stirred for 90 minutes before starting the addition of another lot. After all lots were added, the mass was stirred at the same temperature for another 20-24 hours. The solid paste dissolved and the color of the toluene layer became pale yellow.Water (250 ml) was then added and the mixture was stirred for 15 minutes. The organic layer was separated and washed with water (200 ml). Toluene was distilled and traces thereof were removed by vacuum. To the solid residue methanol (200 ml) was added and this was refluxed for 15-30 minutes. The heating was stopped and the reaction mixture was cooled to 10 00 and maintained at that temperature for2 hours. Theproduct was filtered and washed with chilled methanol (two times 25 ml). The wet weight was 85 gram. The product was then dried 50-60 00 under vacuum to give a dry weight of 75-80 gram for comparative example 1 and 80-85 gram for example 1. The purity observed by HPLC was >99 percent for comparative example 1 and >99 percent for example 1. The yield was 80percent for comparative example 1 and 85percent for example 1.
80%
Sodium hydroxide (NaOH) (100 gram) was dissolved in water (100 ml) in a 2 liter round bottom flask under stirring. The reaction mixture was allowed to cool to room temperature. To this were added <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> (100 gram), tetrabutylammonium bromide (2 gram) and toluene (500 ml). The resulting mixture was stirred at room temperature for 2-3 hours. At this stage the reaction mixture changed in nature and had become a thick paste. The addition of the methylation agent, dimethyl sulfate (DMS) was carried out in four equal lots, each at a temperature of between 20-30 °C. Each lot was added over a period of between 30-40 minutes in a drop wise manner. After each addition the resulting mass was stirred for 90 minutes before starting the addition of another lot. After all lots were added, the mass was stirred at the same temperature for another 20-24 hours. The solid paste dissolved and the color of the toluene layer became pale yellow. Water (250 ml) was then added and the mixture was stirred for 15 minutes. The organic layer was separated and washed with water (200 ml). Toluene was distilled and traces thereof were removed by vacuum. To the solid residue methanol (200 ml) was added and this was refluxed for 15-30 minutes. The heating was stopped and the reaction mixture was cooled to 10 °C and maintained at that temperature for 2 hours. The product was filtered and washed with chilled methanol (two times 25 ml). The wet weight was 85 gram. The product was then dried 50-60 °C under vacuum to give a dry weight of 75-80 gram. The purity observed by HPLC was >99 percent. The yield was 80percent.
80%
Sodium hydroxide (NaOH) (100 gram) was dissolved in water (100 ml) in a 2 liter round bottom flask under stirring. The reaction mixture was allowed to cool to room temperature. To this were added <strong>[4425-93-8]9,9-bis(hydroxymethyl)fluorene</strong> (100 gram), tetrabutylammonium bromide (2 gram) and toluene (500 ml). The resulting mixturewas stirred at room temperature for 2-3 hours. At this stage the reaction mixture changed in nature and had become a thick paste.The addition of the methylation agent, dimethyl sulfate (DMS) was carried out in four equal lots, each at a temperature of between 20-30 00 Each lot was added over aperiod of between 30-40 minutes in a drop wise manner. After each addition the resulting mass was stirred for 90 minutes before starting the addition of another lot. After all lots were added, the mass was stirred at the same temperature for another 20-24 hours. The solid paste dissolved and the color of the toluene layer became pale yellow.Water (250 ml) was then added and the mixture was stirred for 15 minutes. Theorganic layer was separated and washed with water (200 ml). Toluene was distilledand traces thereof were removed by vacuum. To the solid residue methanol (200 ml) was added and this was refluxed for 15-30 minutes. The heating was stopped and the reaction mixture was cooled to 10 00 and maintained at that temperature for 2 hours. The product was filtered and washed with chilled methanol (two times25 ml). The wet weight was 85 gram. The product was then dried 50-60 00 under vacuum to give a dry weight of 75-80 gram. The purity observed by HPLC was>99 percent. The yield was 80percent.
With triethylamine; In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere; Reflux;
a reaction flask, under nitrogen protection and anhydrous conditions, 9, 9-dimethylolfluorene (5. 7 g) was added, (2.3 g) and tetrahydrofuran (40 ml) was added dropwise over 1 hour under cooling with ice-water bath, triethylamine (5 ml) and tetrahydrofuran (80 ml) After the addition, the reaction was allowed to proceed at room temperature for 12 hours, and the reaction was heated to reflux for 3 hours. Saturated aqueous ammonium chloride was then added and the organic phase was separated by stirring. Extract three times with ether and combine the organic phases. Washed successively with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to give 1. 7 g of product 2, 2-diallyl-5,6,7,8-dibenzo-1,3,2-dioxaspirasilane
With sodium hydride; In tetrahydrofuran; at 20℃; for 6h;Inert atmosphere; Cooling;
In a reactor (such as a reaction bottle)Under nitrogen protection and anhydrous conditions, 9,9-dimethylolfluorene (5.8 g), trivinylchlorosilane (7.8 g) and tetrahydrofuran (150 mL) were added,Under cooling conditions, sodium hydride (1.2 g) was added in portions over 2 hours, and the reaction was carried out at room temperature for 4 hours.Adding saturated aqueous ammonium chloride solution,After stirring, the organic phase was separated,Extracted three times with ether,Combine the organic phase.Followed by washing with water, saturated sodium chloride solution,Dried over anhydrous sodium sulfate and the solvent was removed.The residue was purified by column chromatography to give the product 9,9-bis (trivinylsiloxymethyl) fluorene (3.8 g).
With triethylamine; In tetrahydrofuran; at 20℃; for 10h;Inert atmosphere; Reflux;
In a reaction bottle,Nitrogen protection and anhydrous conditions,Was added 9,9-dimethylolfluorene (2.9 g)Triethylamine (11 mL) and tetrahydrofuran (80 mL).Under cooling was added dropwise over 1 hour triallyl chlorosilane (5.6 g) and tetrahydrofuran (20mL) of the mixture, after the addition reaction at room temperature for 4 hours. Heated to reflux for 6 hours.After completion of the reaction, the solution was cooled, filtered, washed three times with diethyl ether,Combine organic phase,The dried solvent was dried over anhydrous sodium sulfate for 24 hours.
With potassium chloride; triethylamine In acetonitrile at 20℃; for 18h; Inert atmosphere; Reflux;
3 Example 3Compound 8,9,10,11-dibenzo [hj] -2,6-dioxa-4,9’-fluorenylundecyl-1,7-dione (FC-3)
In a 250ml three-necked bottle,After blowing nitrogen, add 4.52 g of 9,9-dimethylolfluorene,130 ml of acetonitrile,2.15 ml of triethylamine and 0.32 g of potassium chloride,Add 5.54 g dropwise at room temperature1,1′-biphenylDiformyl chlorideAnd mix well.After stirring for 4 hours, the reaction was heated to reflux for 14 hours.After concentration under reduced pressure, it was recrystallized with a mixed solution of ether / petroleum ether (1:50) to obtain yellow crystals.Vacuum drying gave 2.59 g of product (yield 30%).
With potassium chloride; triethylamine In acetonitrile at 20℃; for 12h; Inert atmosphere; Reflux;
1 Example 1Compound 8,9-benzo [h] -2,6-dioxa-4,9’-fluorenyl-1,7-cyclononanedione (FC-1)
In a 250ml three-necked bottle,After blowing nitrogen, add 4.52 g of 9,9-dimethylolfluorene,120 ml of acetonitrile,2.15 ml of triethylamine and 0.32 g of potassium chloride,4.02 g of phthaloyl chloride was added dropwise at room temperature,Stir well.The reaction was stirred for 4 hours and then heated to reflux for 8 hours.After concentration under reduced pressure, it was recrystallized with a mixed solution of ether / petroleum ether (1:50) to obtain pale yellow crystals.Vacuum drying gave 2.42 g of product (34% yield).
With potassium chloride; triethylamine In acetonitrile at 20℃; for 14h; Inert atmosphere; Reflux;
2 Example 2Compound 8,9,10-naphtho [1 ’, 8’-hi] -2,6-dioxa-4,9’-fluorenyl-1,7-cycloquinodione (FC-2)
In a 250ml three-necked bottle,After blowing nitrogen, add 4.52 g of 9,9-dimethylolfluorene,120 ml of acetonitrile,2.15 ml of triethylamine and 0.32 g of potassium chloride,Add 5.00 g dropwise at room temperature1,8-naphthalene dicarboxylic acid chloride,Stir well.After stirring for 4 hours, the reaction was heated to reflux for 10 hours.After concentration under reduced pressure, it was recrystallized with a mixed solution of ether / petroleum ether (1:50) to obtain yellow crystals.Vacuum drying gave 2.43 g of product (yield 30%)
9-methoxymethyl-9-hydroxymethyl-fluorene[ No CAS ]
9,9-bis(methoxymethyl)-9H-fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide In 1,4-dioxane; toluene at 15 - 20℃;
2; 3 Example 2:
Charge 10 mL dioxane, 10 mL toluene and 5 g (0.022 moles) 9,9- bis(hydroxymethyl)fluorine (BHMF) under stirring. To this mixture, 6.2 g (0.1 55 moles) sodium hydroxide added. (0091) The mixture is stirred for 30 minutes. Gradually 7.85 g (0.055 moles) iodomethane is added over the course of 30 min at a temperature of 15-20 °C. (0092) The reaction mixture is subsequently stirred at the same temperature and progress is checked using Thin Layer Chromatography (TLC) with a diluted sample of approximately 2-5%. (0093) For the TLC a mixture of 20% ethyl acetate and 80% heptane is used. (0094) The reaction was not complete after 24 hours stirring and shows about 20 % unreacted 9,9-bis(hydroxymethyl)fluorine, 9,9-bis(methoxymethyl)fluorine about 50 % as major and mono-O-alkylated 9,9-bis(hydroxymethyl)fluorine. (0095) The reaction was checked again but there was no further progress.
1
Take a 500mL three-necked flask and add the crude product from the previous step and 200mL of methanol, stir to dissolve, and then add sodium borohydride (6.8g, 0.18mol) in batches.The reaction was carried out at room temperature until TLC showed complete conversion of the starting material.Then, filter, collect the filtrate, evaporate the solvent,The remaining solid was purified by toluene recrystallization to obtain 18.3 g of 9,9-fluorenedimethanol (the total yield of the two-step reaction was 90%, and the purity of 9,9-fluorenedimethanol was 98%).
With iron(II) triflate at 100℃; for 24h; Sealed tube;
1
Take a dry 100mL sealed tube reaction flask equipped with a magnet, and add 9,9-fluorenedimethanol (8.5g, 0.04mol),trimethyl phosphate (14mL, 0.12mol) and ferrous trifluoromethanesulfonate (0.56g, 1.6mmol), the tube was sealed and heated to 100°C for 24 hours.After the reaction, it was cooled to room temperature, methanol was added to the reaction solution, the target product was precipitated, and the target product was obtained by filtrationThe filtrate is subjected to atmospheric distillation and vacuum distillation in sequence, after recovering methanol and trimethyl phosphate,Using methanol again for recrystallization, part of the product can be obtained again.Finally, 9.3g of the target product 9,9-bis(methoxymethyl)fluorene was obtained, and the reaction yield was 92% (after gas chromatography, the purity of 9,9-bis(methoxymethyl)fluorene was 98% ).
Stage #1: (9H-fluorene-9,9-diyl)dimethanol With hydrogen bromide In toluene at 20℃; for 2h;
Stage #2: With sodium hydrogen sulfide In toluene for 12h;
2.1 step one:
On a 500mL 2L three-necked flask, install a mechanical stirrer, dropping funnel and air tube. Under nitrogen protection, use ice-salt bath cooling, add 100mL DMSO, 16.0g paraformaldehyde, 3.4g sodium ethoxide, 12mL ethanol to the bottle in turn, start mechanical stirring to cool the reaction material to below 0 . Within 30s, 100mL of DMSO solution dissolved in 32.0g of fluorene was rapidly added to keep the reaction temperature at 12-14°C. After the reaction for 3min, 3mL of concentrated hydrochloric acid was used to terminate the reaction; distilled water was added to dilute, the stirring was stopped after 20min, and suction filtration was performed to obtain a solid crude oil. The product was first recrystallized with ethanol, then recrystallized with toluene, and the solvent was removed to obtain a white solid with a yield of 88%. Then, the obtained fluorene diol was dissolved in 50 mL of toluene, 5 mL of HBr was added thereto, and after stirring at room temperature for 2 hours, 2.8 g of sodium hydrosulfide was added to react for 12 hours. The solvent was drained, extracted with 3×50 mL of anhydrous ether, concentrated and recrystallized to obtain 9,9-(dimethylthiol)fluorene as white crystals in a yield of 87%.
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