| 89% |
With tripotassium phosphate tribasic; copper (I) iodide; N-Methyl-L-proline Methyl Ester In dimethyl sulfoxide at 110℃; for 5h; Inert atmosphere; |
|
| 87% |
With copper (I) iodide; potassium-t-butoxide; N<SUP>1</SUP>,N<SUP>2</SUP>-bis(pyridin-2-ylmethyl)oxalamide In dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere; Sealed tube; Schlenk technique; chemoselective reaction; |
|
| 85% |
With Cs2CO3 In dimethyl sulfoxide at 20℃; for 22h; |
|
| 81% |
With tripotassium phosphate monohydrate; 3,4,7,8-tetramethyl-1,10-phenanthroline; copper (II) acetate In dimethyl sulfoxide at 80℃; for 8h; Inert atmosphere; |
|
| 80% |
With copper (I) iodide; potassium carbonate; N,N'-dimethylethane-1,2-diamine In toluene for 6h; Reflux; |
1.1 1-(4-bromophenyl)pyrrolidin-2-one
To a two-necked flask was added 1-bromo-4-iodobenzene (1.10 g, 3.77 mmol) 2-pyrrolidone (488 mg, 5.74 mmol) potassium carbonate (1.05 g, 7.52 mmol), cuprous iodide (0.072 g, 0.38 mmol), N,N'-dimethylethylenediamine (0.068 g, 0.76 mmol) and anhydrous toluene (20 mL), the mixture was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), stirred, extracted with ethyl acetate (50 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate / dichloromethane (v / v) = 1/7) to give the title compound (0.73 g, 80%) as a pale yellow oil. |
| 75% |
With copper (I) iodide; (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine; Cs2CO3 In dimethyl sulfoxide at 110℃; for 16h; |
|
| 65% |
With copper (I) iodide; Cs2CO3; N,N'-dimethylethane-1,2-diamine In acetonitrile at 80℃; for 16h; |
35.1 Synthesis of Bromine 82
CuI (12 mg, 0.282 mmol, 20 mol %) was added to a degassed solution of iodine derivative 81 (200 mg, 0.707 mmol, 1.0 eq.), amine 83 (0.056 ml, 0.742 mmol, 1.5 eq.), N,N-dimethylethylenediamine (0.026 ml, 0.282 mmol, 20% mol) and CsCO3 (459 mg, 1.41 mmol, 2.0 eq) in 3.0 ml of CH3CN. The mixture was stirred at 80° C. for 16 h under argon. Then the mixture was cooled and filtered through Celite. The filtrate is evaporated under reduced pressure before being purified by flash column chromatography on silicagel with eluting agent (ethyl acetate/petroleum ether=25/75) to give 110 mg of the bromine 82 as a colorless oil with the yield of 65%. 1H NMR (250 MHz, CDCl3, 20° C.) δ 7.57-7.37 (m, 4H), 3.81 (t, J=7.0 Hz, 2H), 2.58 (t, J=8.1 Hz, 2H), 2.14 (m, 2H). CAS Number: 7661-32-7. |
| 46% |
With copper (I) iodide; caesium fluoride; N,N'-dimethylethane-1,2-diamine In 1,4-dioxane at 20℃; for 48h; Inert atmosphere; |
64.1 1-(4-bromophenyl)pyrrolidin-2-one
The mixture of pyrrolidin-2-one (1.3 g, 15 mmol), 1-bromo-4-iodobenzene (2.8 g, 9.8 mmol), copper iodide (0.19 g, 0.98 mmol), cesium fluoride (3.7 g, 25 mmol) and N,N'-dimethylethylenediamine (186 mg, 0.196 mmol) in 1,4-dioxane (100 mL) was evacuated and back-filled with nitrogen three times. The reaction mixture was stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated to give a white solid. The solid was purified by combi flash silica gel chromatography to give the title compound (1.1 g, 46% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.52 (d, 2H), 7.48 (d, 2H), 3.83 (t, 2H), 2.59 (t, 2H), 2.18 (m, 2H). |
| 1.6 g |
With copper (I) iodide; caesium fluoride; N,N'-dimethylethane-1,2-diamine In ethyl acetate at 20℃; for 30h; |
35
pyrrolidin-2-one (3.0 g, 35.2 mmol, 1.0 equiv), 1-bromo-4-iodobenzene (9.95 g, 35.2 mmol, 1.0 equiv), DMEDA (0.37 ml, 3.5 mmol, 0.1 equiv) , CsF (13.36 g, 88.0 mmol, 2.5 equiv) and Cul (0.335 g, 1.8 mmol, 0.05 equiv) were taken in EtOAc (100 ml) and stirred for 30h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3 x 100mL). Combined organic layers were washed with water and brine solution and dried over Na2S04, filtered and concentrated to get crude product. The crude product was purified by flash chromatography to give 1-(4-bromophenyl) pyrrolidin-2-one as white solid, yield (1.6g, 19%). LC-MS (ES) m/z = 240.0, 242.0 [M+H]+. 1H NMR (400 MHz, DMSOd6) δ ppm 2.00 - 2.08 (m, 2 H), 2.48 - 2.50 (m, 2 H), 3.80 (t, J=6.8 Hz, 2 H), 7.53 (d, J=9.2 Hz, 2 H), 7.62 (d, J=9.2 Hz, 2 H). |
|
With tripotassium phosphate tribasic In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; |
|
|
With Cs2CO3; Ethyl 2-oxocyclohexanecarboxylate; copper(II) bromide In dimethyl sulfoxide at 30℃; Inert atmosphere; |
42.42.1 Compound 1-(4-Bromophenyl)pyrrolidin-2-onePreparation of (L042-1)
p-Bromoiodobenzene (2.0 g, 7.1 mmol) and 2-pyrrolidone (0.65 mL, 8.5 mmol)A solution of dimethyl sulfoxide (40 mL) was added to ethyl 2-cyclohexanonecarboxylate (0.24 g, 1.4 mmol),copper bromide (0.1 g, 0.7 mmol),In a mixture of cesium carbonate (4.9 g, 14.9 mmol) and dimethyl sulfoxide (20 mL).The mixture was stirred at 30°C overnight under nitrogen protection.After the reaction, the reaction solution was filtered, the filtrate was collected, and quenched with ice water (200 mL),Extraction with ethyl acetate (50mL*3), followed by saturated brine (100mL)Washed and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product.After purification by column chromatography (petroleum ether/ethyl acetate=2/1), compound L042-1 was obtained. |
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