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Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 22, p. 6801 - 6805
3
[ 618-32-6 ]
[ 866633-25-2 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 22, p. 6801 - 6805
[2] Journal of the American Chemical Society, 2018, vol. 140, # 22, p. 6801 - 6805
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; pyridine hydrogenfluoride; In dichloromethane; at -78 - 20℃;
A solution of the xanthate (1g) (from Step 1 above) in CH2C12 (10 mL) was added to HF/pyridine (4.4M, 4mL) placed in a 250ml plastic bottle. The bottle was cooled to-78C and 1,3-dibromo- 5,5-dimethyl hydantoin (5.1g) was added in portion while stirring. The reaction mixture was allowed to warm up to room temperature; the progress of the reaction was monitored by NMR. The reaction mixture was carefully neutralized by pouring into a mixture of 15g NaOH/ 100g ice. The resulting mixture was filtered through a pad of celite and washed with ether. The filtrate was separated, the organic layer was washed with 10% KOH and IN HCI, dried over Na2S04, purified by column chromatography on silica gel (using hexane) to give the desired aryl bromide as a colorless oil. ¹H NMR (CDC13): 7.42 (m, 1H), 7.33 (m, 1H), 7.38 (m, 1H), 7.09 (m, 1H). MS (ESI): m/e 192 (M+1)+
To a solution of the aryl bromide (from Step 2 above) (5g) in THF (25 mL) was added Isopropylmagnesium chloride (15 mL, 2.0M in THF) at room temperature. After stirring at the ambient for 2 h, B (OiPr)3 added to the reaction and stirred overnight. The reaction was quenched with IN HCl, stirred at room temperature for 30min and extracted with EtOAc. The residue obtained after removal of the solvent in vacuo, was dissolved in 10% KOH, extracted with ether. The aqueous phase was acidified with concentrated HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the aryl boronic acid as a white solid. ¹H NMR (CDCl3) : 7.28-7.32 (m, 1H), 7.17-7.22 (m, 2H) MS (ESI): m/e 225 (M+1)+
A solution of isopropylmagnesium bromide (2M solution in tetrahydrofuran) (83 ml, 0.166 mol) was added drop-wise to a stirred solution of 2-(trifluoromethoxy)-5-fluoro- 1 -bromobenzene (Preparation 49, 27.6 g, 0.107 mol) in anhydrous tetrahydrofuran (125 ml) at -1O0C under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2 hours. Tri/sopropyl borate (26.1 g, 0.139 mol) was then added drop-wise at -100C and the resulting mixture was stirred at room temperature for 16 hours. Hydrochloric acid (1 N aqueous solution) (100 ml) was added drop-wise at O0C and the mixture stirred at room temperature for 30 minutes. Ethyl acetate (150 ml) was added and the layers were separated, the aqueous layer was further extracted with ethyl acetate (2 x 150 ml). The organic extracts were combined and concentrated in vacuo. The residue was dissolved in potassium hydroxide (10% aqueous solution) (50 ml) and extracted with diethyl ether (2 x 150 ml). The separated aqueous layer was acidified to pH~4 by addition of hydrochloric acid (1 N aqueous solution) (100 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give an off white solid. Purification by preparative HPLC gave the title compound as an off white solid (5.82 g, 24%).1HNMR (cfe-DMSO): 7.23-7.32 (m, 3H), 7.53-7.55 (m, 1 H), 8.36 (br s, 1 H).MS m/z 223 [MH]-
Preparation 17 f2-(Trifluoromethoxy)- 5-fluoro-1 -bromolbenzeneTo a stirred solution of 3-bromo-4-trifluoromethoxyaniline (30 g, 0.12 mol) in hydrochloric acid (6N aqueous solution) (300 ml) was added drop-wise a solution of sodium nitrite (9.7 g, 0.14 mol) in water (30 ml) at O0C. The resulting mixture was stirred at 0-50C for 1 hour until the reaction system became clear. Tetrafluoroboronic acid (40% aqueous solution) (90 ml) was then added drop-wise over 15 minutes. The resulting mixture was again stirred at 0-50C for 1 hour then filtered. The filter cake was washed with cold water (100 ml) and diethyl ether (100 ml), then dried in vacuo to give the hydrazinium tetrafluoroborate salt as a white solid (35 g, 84%). This solid (8.5 g,0.024 mol) was then slowly heated to 14O0C and maintained at this temperature for 1 hour under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and distilled under reduced pressure to afford the title compound as a colourless oil (4.86 g, 78%).1HNMR (CDCI3): 7.02-7.09 (m, 1 H), 7.26-7.29 (m, 1 H), 7.33-7.38 (m, 1 H). LCMS (30 min) Rt= 6.9 mins;MS m/z 258 [MH]+
78%
at 140℃; for 1h;
To a stirred solution of 3-bromo-4-trifluoromethoxyaniline (3Og, 0.12 mol) in hydrochloric acid (6N aqueous solution) (300 ml) was added drop-wise a solution of sodium nitrite (9.7 g, 0.14 mol) in water (30 ml) at O0C. The resulting mixture was stirred at 0-50C for 1 hour until the reaction system became clear. Tetrafluoroboronic acid (40% aqueous solution) (90 ml) was then added drop-wise over 15 minutes. The resulting mixture was again stirred at 0-50C for 1 hour then filtered. The filter cake was washed with cold water (100 ml) and diethyl ether (100 ml), then dried in vacuo to give the hydrazinium tetrafluoroborate salt as a white solid (35 g, 84%). This solid (8.5 g, 0.024 mol) was then slowly heated to 14O0C and maintained at this temperature for 1 hour under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and distilled under reduced pressure to afford the title compound as a colourless oil (4.86 g, 78%). 1HNMR (CDCI3): 7.02-7.09 (m, 1 H), 7.26-7.29 (m, 1 H), 7.33-7.38 (m, 1 H). <n="170"/>LCMS (30 min) Rt=6.9min MS m/z 258 [MH+]
Preparation 18 r2-(Trifluoromethoxy)-5-fluorophenyllboronic acid <n="65"/>A solution of isopropylmagnesium bromide (2M solution in tetrahydrofuran) (83 ml, 0.166 mol) was added drop-wise to a stirred solution of 2-(trifluoromethoxy)-5-fluoro- 1-bromobenzene (Preparation 17, 27.6 g, 0.107 mol) in anhydrous tetrahydrofuran (125 ml) at -1 O0C under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2 hours. Triisopropyl borate (26.1 g, 0.139 mol) was then added drop-wise at -100C and the resulting mixture was stirred at room temperature for 16 hours. Hydrochloric acid (1 N aqueous solution) (100 ml) was added drop-wise at O0C and the mixture stirred at room temperature for 30 minutes. Ethyl acetate (150 ml) was added and the layers were separated, the aqueous layer was further extracted with ethyl acetate (2 x 150 ml). The organic extracts were combined and concentrated in vacuo. The residue was dissolved in potassium hydroxide (10% aqueous solution) (50 ml) and extracted with diethyl ether (2 x 150 ml). The separated aqueous layer was acidified to pH~4 by addition of hydrochloric acid (1 N aqueous solution) (100 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give an off white solid. Purification by preparative HPLC gave the title compound as an off white solid (5.82 g, 24%).1HNMR (de-DMSO): 7.23-7.32 (m, 3H), 7.53-7.55 (m, 1 H), 8.36 (br s, 1 H).MS m/z 223 [MH]-
With perhydrodibenzo-18-crown-6; potassium fluoride; bromopentafluorobenzene; 1-Bromo-2-phenylacetylene; In ethyl acetate; at 20℃; for 12h;Glovebox; Sealed tube;
General procedure: In the glove box, add KF (78.4mg, 1.35mmol, 4.5equiv) to cis- in 20mL plastic tube (PE).Dicyclohexano-18-crown-6 (503 mg, 1.35 mmol, 4.5 equiv) and 6 mL ethyl acetate.Then a phenylene precursor (0.3 mmol, 1.0 equiv), 1-bromophenylacetylene (218 mg, 1.2 mmol. 4.0 equiv) or perfluorohexyl bromide (479 mg,1.2 mmol. 4.0 equiv) or pentafluorophenyl bromide (296 mg, 1.2 mmol. 4.0 equiv) and trifluoromethyl benzoate (171 mg, 0.9 mmol, 3 equiv) were capped and allowed to react at room temperature for 12 hours.After the end of the reaction, the F-spectrum yield was first calculated by 19F NMR.After completion of the reaction, the mixture was filtered, dried, and directly subjected to column chromatography.
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