| 79% |
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; potassium-t-butoxide In toluene at 100℃; for 16h; Inert atmosphere; |
1 Preparation 1: 2-chloro-4-fluoro-N-(4-fluorophenyl)aniline
A round bottom flask was charged with 1-bromo-4-fluorobenzene (13.0 g, 74.3 mmol), 2-chloro-4-fluoroaniline (11.354 g, 78.0 mmol), anhydrous toluene (200 mL) and potassium tert-butoxide (10.003 g, 89.1 mmol). The mixture was degassed and back-filled with nitrogen, and then tris(dibenzylideneacetone)dipalladium(0) (2.041 g, 2.2 mmol) and tri-tert-butylphosphine (0.902 g, 4.5 mmol) were added and the reaction was stirred under nitrogen at 100° C. for 16 hours. After cooling, the mixture was treated with 6 M aqueous hydrochloric acid to acidic pH and then adjusted back to basic pH with solid sodium carbonate. The mixture was dried (anhydrous magnesium sulfate), filtered through Celite and the filter cake washed with ethyl acetate. The filtrate was concentrated and the residue purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to afford a yellowish oil (14 g, 79%). 1H NMR (300 MHz, CDCl3): δ 7.14 (dd, 1H, J=8.4, 3.0 Hz), 7.12-6.98 (m, 5H), 6.88 (td, 1H, J=8.7, 3.0 Hz), 5.80 (br s, 1H). |
| 76.2% |
With tri-tert-butylphosphonium tetrafluoroborate; palladium diacetate; sodium tertiary butoxide In toluene for 12h; Inert atmosphere; Reflux; |
1 Preparation of 3,6-difluorocarbazole
2-chloro-4-fluoroaniline (2g, 13.7 mmol) and 4-fluorobromobenzene (2.4 g, 13.7 mmol) were dissolved in 60 ml of toluene, and palladium acetate (157 mg, 0.7 mmol), tri-tert-butylphosphine tetrafluoroborate (297 mg, 1.028 mmol), sodium tert-butanol (6.6 g, 68.5 mmol) were added sequentially, and the reflux reaction was carried out for 12 hours under nitrogen protection. cooled to room temperature, inorganic salts removed by extraction filtration, concentrated the filtrate under reduced pressure to dry, the residue was washed with 30ml of dichloromethane dissolved in water, saturated brine was removed from water, the organic phase anhydrous sodium sulfate was dried, spin-dried, and the crude product column chromatography was purified to obtain a yellow oily product (2.5g, 76.2%), which was directly used for the next reaction |
| 68% |
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium tertiary butoxide In toluene at 100℃; for 16h; Inert atmosphere; |
38 Preparation 38
2-Chloro-4-fluoro-N-(4-fluorophenyl)aniline
Preparation 38 2-Chloro-4-fluoro-N-(4-fluorophenyl)aniline A round bottom flask was charged with 1-bromo-4-fluorobenzene (6.011 g, 34.4 mmol), 2-chloro-4-fluoroaniline (5.000 g, 34.3 mmol), Xantphos (0.795 g, 1.4 mmol), anhydrous toluene (200 mL), and sodium tert-butoxide (4.952 g, 51.5 mmol). The mixture was degassed and filled with nitrogen, and then tris(dibenzylideneacetone)dipalladium(0) (0.944 g, 1.0 mmol) was added and the reaction was stirred under nitrogen at 100° C. for 16 hrs. After cooling to room temperature, the mixture was filtered through Celite and the filter cake washed with methylene chloride. The filtrate was concentrated and the residue purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to afford a yellowish oil (5.63 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.14 (dd, 1H, J=8.4, 3.0 Hz), 7.12-6.98 (m, 5H), 6.88 (td, 1H, J=8.7, 3.0 Hz), 5.80 (br s, 1H). |
| 41% |
With palladium diacetate; sodium tertiary butoxide; tri-tert-butylphosphonium hydrogen tetrafluoroborate In toluene for 18h; Reflux; |
4.1 Step 1
Step 1: 2-Chloro-4-fluoroaniline (3.0 g, 20.6 mmol) and 4-fluoro-1-bromo benzene (3.6 g, 20.6 mmol) were added to NaOfBu (9.9 g, 103.0 mmol), Pd(OAc)2 (0.231 g, 1.03 mmol) and [HPtBu3][BF4] (0.42 g, 1.4 mmol) suspended in toluene (120 mL). The reaction was then heated to reflux for 18 h, allowed to cool and concentrated to remove toluene. The residue was extracted with dichloromethane (2 X 100 mL), dried (Na2S04), then filtered and the solvent removed under reduced pressure. The crude product was purified by column chromatography using silica gel 230-400 mesh to get the desired colorless product 2-chloro-4-fluoro-A-(4- fluorophenyl)aniline (2.0 g, 41%). GC MS: (Method B) 239.0 (M+H), RT- 4.73 min H NMR (400 MHz, DMSO-d6): δ 7.28 (s, 1H), 7.01-7.16 (m, 5H), 6.89-6.88 (m, 1 H), 5.84 (s, 1H). |
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Stage #1: 2-chloro-4-fluoroaniline; 1-Bromo-4-fluorobenzene With potassium-t-butoxide; tri-tert-butylphosphonium hydrogen tetrafluoroborate In toluene at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: With tris-(dibenzylideneacetone)dipalladium(0) In toluene at 18 - 55℃; for 3h; Inert atmosphere; |
Preparation of5: 3,6-difluoro-9H-carbazole
A 5L 3-necked round bottom flask was equipped with reflux condenser, thermometer, and overhead mechanical stirrer. The flask was purged with argon, charged with 1-bromo-4-fluorobenzene (280 g, 1.6 mol), 2-chloro-4-fluoroaniline (240 g, 1.64 mol), anhydrous toluene (1.5 L) and potassiumtert-butoxide (233 g, 2.08 mol), sequentially under argon. The well-stirred mixture was degassed under vacuum and purged with argon, and then tri-tert-butylphosphonium tetrafluoroborate (9.46 g, 32.6 mmol) was added. The mixture was stirred at ambient temperature for 10 min and tris(dibenzylideneacetone)dipalladium(0) (14.7 g, 16.0 mmol) was added. The reaction was degassed and purged with argon again.CAUTION: Following addition of the catalyst, the internal temperature increased from 18 °C to 55 °C over 20 min. The reaction was cooled with an external ice-water bath, adding ice as the temperature approached 50 C.The reaction was cooled to 40 °C, and the water bath removed. The internal temperature was kept at 40-45 C using external heating and the reaction stirred for 3 h. The reaction was filtered through a short silica gel/Celite plug and rinsed with toluene. The filtrate was concentrated under vacuum and directly used for the next reaction. When purified (column chromatography on silica gel eluting with 0-10% ethyl acetate/hexanes), purified product is a pale yellow liquid:1H NMR (300 MHz, CDCl3) δ 7.14 (dd, 1H,J= 8.4, 3.0 Hz), 7.12-6.98 (m, 5H), 6.87 (ddd, 1H,J= 9.3, 8.1, 3.0 Hz), 5.80 (br s, 1H). A 5L 3-necked round bottom flask was equipped with reflux condenser, thermometer, and overhead mechanical stirrer. The flask was charged with the crude 2-chloro-4-fluoro-N-(4-fluorophenyl)aniline (368 g, 1.536 mol) in anhydrous DMA (1.5 L) and potassium carbonate (425 g, 3.071 mol) was added. The mixture was degassed and purged with argon, and tricyclohexylphosphonium tetrafluoroborate (56.5 g, 154 mmol) and palladium diacetate (17.2 g, 77 mmol) were added. The reaction was degassed under vacuum and purged with argon again. The reaction mixture was heated, stirring under argon at 125-135 C for 7 h. After cooling, the reaction mixture was slowly poured into a mixture of hexanes (500 mL) and ice-cold water (6 L).After 1 h of stirring, the solids were collected by filtration and washed with water and then hexanes (2 times), and air-dried for 16 h. The solids were dissolved in warm toluene, dried (anhydrous magnesium sulfate), filtered through Celite, and the filter cake washed with toluene. The filtrate was concentrated under vacuum and the crude product crystallized from toluene. The solids were collected by filtration and washed with cold toluene and then hexanes to give the desired product as a light brown/grey powder (163 g, 52% yield). The mother liquor was concentrated under vacuum and additional product could be obtained either by crystallization from toluene, or passing through a short silica gel plug (eluting with 0-50% ethyl acetate/hexanes to collect the fractions containing product) followed by concentration under vacuum and crystallization from toluene to give additional product as a light brown solid (35 g, 12%). |
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With palladium diacetate; sodium tertiary butoxide; tri-tert-butylphosphonium hydrogen tetrafluoroborate In toluene at 110℃; for 4h; Inert atmosphere; |
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