| 77% |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h; |
1 Step 1: Preparation of 3-(4-bromophenoxy)propan-1-ol
To a solution of 4-bromophenol (3 g, 17.34 mmol, 1 eq) in N,N-dimethylformamide (100 mL) was added 3-bromopropan-1-ol (2.89 g, 20.81 mmol, 1.2 eq) and potassium carbonate (7.19 g, 52.02 mmol, 3 eq), and the mixture was stirred at 70°C for 2 hrs. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3) and washed with brine (300 mL). The organic phase was dried by anhydrous sodium sulfate, filtered and the filtrate was condensed to give crude product. The residue was purified by silica gel column chromatography (pure petroleum ether). The product 3-(4-bromophenoxy)propan-1-ol (3.10 g, 13.41 mmol, 77% yield) was obtained as colorless oil.1H-NMR (400MHz, CDCl3) d 7.41 - 7.30 (m, 2H), 6.84 - 6.69 (m, 2H), 4.16 - 3.95 (m, 2H), 3.83 (t, J=6.0 Hz, 2H), 2.23 - 1.90 (m, 4H). |
| 64.4% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
Synthesis of 3-(4-bromophenoxy)propan-1-ol. To a 250 mL round bottom flask was added 4-bromophenol (16.5 g, 95.3 mmol), 3-bromopropanol (15.9 g, 114.4 mmol), N,N-dimethylformamide (50 mL) and potassium carbonate (22.4 g, 162.0 mmol). The reaction was allowed to stir at room temperature while being monitored by TLC (CH2Cl2). Upon the disappearance of 4-bromophenol the mixture was poured into a separatory funnel containing 50 mL of water. The product was extracted in diethyl ether and the organic layer was washed with 3 x 25- mL portions of cold water. The solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel eluting with dichloro methane. The solvent was removed under reduced pressure. Residual solvent and remaining 3-bromopropanol were removed in vacuo (14.2 g, 64.4%). 1B NMR (300 MHz, CDCl3) δ 7.35 (d, 9.0 Hz), 6.77 (d, J = 9.0 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.84 (t, J = 6.0 Hz, 2H), 2.10 (q, J = 6.0 Hz, 2H), 1.65 (s, IH). |
| 64.4% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
Synthesis of 3-(4-bromophenoxy)propan-1-ol
To a 250 mL round bottom flask was added 4-bromophenol (16.5 g, 95.3 mmol), 3-bromopropanol (15.9 g, 114.4 mmol), N,N-dimethylformamide (50 mL) and potassium carbonate (22.4 g, 162.0 mmol). The reaction was allowed to stir at room temperature while being monitored by TLC (CH2Cl2). Upon the disappearance of 4-bromophenol the mixture was poured into a separatory funnel containing 50 mL of water. The product was extracted in diethyl ether and the organic layer was washed with 3×25-mL portions of cold water. The solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel eluting with dichloromethane. The solvent was removed under reduced pressure. Residual solvent and remaining 3-bromopropanol were removed in vacuo (14.2 g, 64.4%). |
| 56% |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; |
|
| 51% |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; |
Synthesis of Compound 2.
General procedure: Compound 2 was synthesized as describedpreviously.34 Briefly, to a suspension of 4-bromophenol (5.00 g,28.90 mmol) and K2CO3 (5.99 g, 43.35 mmol) in DMF (100 mL) wasadded 3-bromo-1-propanol (6.02 g, 43.35 mmol), and the reactionmixture was heated to 70 °C. After 12 h, the reaction mixture wascooled to room temperature, quenched with water and aqueous NH4Cl.The organic compound was extracted with ethyl acetate (3 × 100 mL).The combined organic layer was washed with brine (3 × 100 mL),dried over MgSO4, and then concentrated under reduced pressure. Theresidue was purified by flash column chromatography, eluting withethyl acetate/hexane (1:4, v/v) to afford 3-(4-bromophenoxy)propan-1-ol as a white solid (3.4 g, yield 51%). 1H NMR (400 MHz, CD3Cl): δ7.35 (2H, d), 6.76 (2H, d), 4.04 (2H, t), 3.81 (2H, t), 2.24 (1H, br),2.06-1.94 (2H, m) ppm. The 3-(4-bromophenoxy)propan-1-ol (1.00 g,4.33 mmol), sodium azide (563 mg, 8.66 mmol), sodium ascorbate(44 mg, 0.22 mmol), copper iodide (82 mg, 0.43 mmol), and N,N′-dimethylethylenediamine(DMEDA, 70 μL, 0.65 mmol) were placed in atwo-necked round bottom flask equipped with a reflux condenser, and13 mL of ethanol/water (7:3, v/v) was added under N2 atmosphere. Thereaction mixture was stirred at 80 °C for 6 h, and then cooled down toroom temperature, quenched with water, and organic compounds wereextracted with ethyl acetate (3 × 100 mL). The combined organic layerwas washed with brine (3 × 100 mL), dried over MgSO4 and concentratedunder reduced pressure. The residue was purified by flashcolumn chromatography, eluting with ethyl acetate/hexane (2:3, v/v)to afford compound 2 as yellow oil (669 mg, 80% yield). 1H NMR(400 MHz, CD3Cl): δ 6.95-6.84 (4H, m), 4.06 (2H, t), 3.82 (2H, t), 2.35(1H, br), 2.07-1.95 (2H, m) ppm. |
|
With potassium carbonate In water; N,N-dimethyl-formamide |
R.128 Reference Example 128
Reference Example 128 In DMF (150 ml) was dissolved 4-bromophenol (25 g). To the mixture was added potassium carbonate (30 g) and then was added dropwise 3-bromopropanol (26.1 g), and the mixture was stirred at 100° C. for 20 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 3-(4-bromophenoxy)-1-propanol (20.6 g). 1H-NMR (200 MHz, CDCl3) δ 1.76 (1H, br), 1.97-2.09 (2H, m), 3.80-3.91 (2H, m), 4.08 (2H, t, J=6.0 Hz), 6.76-6.81 (2H, m), 7.33-7.40 (2H, m). |
|
With potassium carbonate In water; N,N-dimethyl-formamide |
The Following Synthetic Procedures are in Reference to FIG. 17.
Synthesis of 3-(4-bromophenoxy)propan-1-ol. To a 250 mL round bottom flask was added 4-bromophenol (16.5 g, 95.3 mmol), 3-bromopropanol (15.9 g, 114.4 mmol), N,N-dimethylformamide (50 mL) and potassium carbonate (22.4 g, 162.0 mmol). The reaction was allowed to stir at room temperature while being monitored by TLC (CH2Cl2). Upon the disappearance of 4-bromophenol the mixture was poured into a separatory funnel containing 50 mL of water. The product was extracted in diethyl ether and the organic layer was washed with 3*25-mL portions of cold water. The solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel eluting with dichloromethane. The solvent was removed under reduced pressure. Residual solvent and remaining 3-bromopropanol were removed in vacuo (14.2 g, 64.4%). 1H NMR (300 MHz, CDCl3) δ 7.35 (d, 9.0 Hz), 6.77 (d, J=9.0 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.10 (q, J=6.0 Hz, 2H), 1.65 (s, 1H). |
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8.5h; |
5.23.1
(1) Potassium carbonate (12.0 g) and 3-bromo-1-propanol (5.1 mL) were added to a solution of 4-bromophenol (5.0 g) in N,N-dimethylformamide (200 mL) under ice-cooling, and the mixture was stirred at room temperature for 8.5 hours. The reaction solution was ice-cooled and a saturated ammonium chloride solution and water were added, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1→4:1→3:1) to give 3-(4-bromophenoxy)propan-1-ol as a crude product. |
|
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; |
Synthesis of Compound B. Compound B was synthesized as described (Tetrahedron Letters 48 (2007) 3953-3957). Briefly, to a suspension of 4-bromophenol (5.00 g, 28.90 mmol) and K2CO3 (5.99 g, 43.35 mmol) in DMF (100 mL) was added 3-bromo-l-propanol (6.02g, 43.35 mmol), and the reaction mixture was heated to 70 °C. After 12 h, the reaction mixture was cooled to room temperature, quenched with water and aqueous H4CI. The organic compound were extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2S04, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (20% Ethyl acetate/Hexane) to give 3-(4- bromophenoxy)propan-l-ol. NMR (400MHz, CD3CI): δ 7.35 (2H, d), 6.76 (2H, d), 4.04 (2H, t), 3.81 (2H, t), 2.24 (1H, br), 2.06-1.94 (2H, m) ppm. The purified 3-(4-bromophenoxy)propan-l-ol (1.00 g, 4.33 mmol), sodium azide (563 mg, 8.66 mmol), sodium ascorbate (44 mg, 0.22 mmol), copper iodide (82 mg, 0.43 mmol), and N, N'- dimethylehtylene amine (DMEDA, 70 μΕ, 0.65 mmol) were placed in a two-necked round bottom flask equipped with a reflux condenser, and 13 mL of Ethanol -water (7:3) was added under N2 atmosphere. The reaction mixture was stirred at 90 °C for 45 min., and then the reaction mixture was cooled to room temperature, quenched with water, and organic compounds were extracted with Ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash chromatography (40% Ethyl acetate/Hexane) to afford compound B. NMR (400MHz, CD3CI): δ 6.95-6.84 (4H, m), 4.06 (2H, t), 3.82 (2H, t), 2.35 (1H, br), 2.07-1.95 (2H, m) ppm. |
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