| 94% |
With pyridinium hydrobromide perbromide In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; |
|
| 94% |
With N-Bromosuccinimide In acetonitrile at 20℃; Cooling; |
NBS (29 g, 0.16 mol) was added partially into a solution of 2-aminoacetophenone (22 g, 0.16 mol) in acetonitrile (80 mL) at 5 oC, then the reaction mixture was warmed to room temperature and stirred overnight. After the completion monitored by TLC, the mixture was filtered, concentrated and washed with water to afford 31 (32 g, 94%). 1H-NMR (400 MHz, CDCl3): δ ppm 2.58 (s, 3H), 6.37 (brs, 2H), 6.58 (d, J = 8.84 Hz, 1H), 7.35 (dd, J = 8.84, 2.32 Hz, 1H), 7.82 (d, J = 2.32 Hz, 1H). |
| 93% |
With Oxone; ammonium bromide In methanol at 20℃; for 1h; regioselective reaction; |
2. General procedure
General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3×25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data. |
| 92% |
With N-Bromosuccinimide In dichloromethane |
|
| 89% |
With N-Bromosuccinimide In acetonitrile at 0 - 20℃; Inert atmosphere; |
|
| 88% |
With tetrabutylammomium bromide; copper(ll) bromide In ethanol at 25℃; regioselective reaction; |
General procedure for the synthesis of 1b-14ba, 15b-44b
General procedure: A round bottom flask was charged with Bu4NBr (2 mmol, 0.64 g), EtOH (8 mL) and 2-methylaniline (2 mmol, 0.21 g) followed by CuBr2 (3 mmol, 0.67 g). The resulted mixture was stirred at 25 °C. After the completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure. To the residue was added ammonium hydroxide (5 mL, 25% w/v) and water (5 mL) with stirring, and the suspension was extracted with DCM(10 mL×4) The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The product 2b was obtained using flash chromatograph column eluted with PE : EA (5 : 1). |
| 86% |
With N-Bromosuccinimide In diethyl ether; acetonitrile at 20℃; for 0.5h; |
|
| 85% |
Stage #1: 2-aminoacetophenone With acetic anhydride for 2h;
Stage #2: With bromine In dichloromethane for 3h; |
|
| 83% |
With pyridinium hydrobromide perbromide In dichloromethane at 0 - 20℃; for 30h; Inert atmosphere; |
|
| 83% |
With hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide; potassium bromide In acetic acid at 20℃; |
|
| 80% |
With pyridinium hydrobromide perbromide In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; |
|
| 76% |
With pyridinium hydrobromide perbromide In dichloromethane at 0 - 20℃; for 3h; |
2 4.2. Synthesis of 2-amino-5-bromoacetophenone (2)
A stirred solution of 2-aminoacetophenone (5.00 g,36.99 mmol) in CH2Cl2 (500 mL) at 0 C was treated slowly withpyridinium tribromide (11.83 g, 36.99 mmol). The reaction mixturewas allowed to warm up to rt and then stirred for 3 h at this temperature. Cold water (200 mL) was added to the reaction mixtureand the organic phase was separated. The aqueous phase wasextracted with CH2Cl2 (3 50 mL) and the combined organic layerswere dried over Na2SO4, filtered and then concentrated underreduced pressure on a rotary evaporator to afford 2 as a yellowsolid (6.02 g, 76%), mp 79-81 C (lit.14 82-83 C); mmax (ATR)3453, 3316, 1653, 1609, 1563, 1540, 1464, 1360, 1287, 1217,1160, 956, 888, 822, 738, 671, 623, 517 cm1; 1H NMR (500 MHz,CDCl3) 2.65 (3H, s, CH3), 6.29 (2H, br s, NH2), 6.56 (1H, d, J8.5 Hz, H-3), 7.34 (1H, dd, J 2.5 and 8.5 Hz, H-4), 7.80 (1H, d, J2.5 Hz, H-6); 13C NMR (125 MHz, CDCl3) 27.7, 106.5, 118.9, 119.2,134.0, 136.9, 149.0, 199.6. |
| 64% |
With dimethyl sulfoxide; ethylene dibromide at 20℃; for 8h; |
|
|
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; |
|
|
Multi-step reaction with 3 steps
1: 100 percent / triethylamine / CH2Cl2 / 3 h / 20 °C
2: Br2; acetic acid / 1.25 h / 20 °C
3: HCl / H2O; tetrahydrofuran / 1 h / Heating |
|
|
With N-Bromosuccinimide; sulfonic acid functionalized silica |
|
|
With N-Bromosuccinimide In dichloromethane at -10℃; |
34.9
A flask charged with l-(2-aminophenyl)ethanone (135 mg) and DCM (2.5 rnL) was cooled to -100C and NBS (178mg) was added in several portions over 30min. The reaction mixture was diluted with 10 mL DCM, washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure, affording the title compound. MS (ES I+): m/z 215.06 (MH+). 1H NMR (400 MHz, CDCl3) : δ 7.79 (s, IH), 7.31 (d, J= 8.8 Hz, IH), 6.54 (d, J = 8.8 Hz, IH), 6.30 (br, 2H), 2.55 (s, 3H). |
|
With N-Bromosuccinimide In acetonitrile at 20℃; |
|
|
With N-Bromosuccinimide In acetonitrile for 3h; |
|
|
With N-Bromosuccinimide In acetonitrile at 0 - 20℃; for 3h; |
|
|
With N-Bromosuccinimide In N,N-dimethyl-formamide at -10 - 20℃; for 2h; |
25 Example 25: Synthesis of 6-(2-(l-cyclopropyl-lH-pyrazol-3-yl)-6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-3 -yl)quinazoline-4-carboxamide (95)
A solution of aniline lxvii (3 g, 17.5 mmol) in DMF (30 mL) is cooled to -10 °C, and /V-bromosuccinimide (3.12 g, 17.5 mmol) is added. The reaction is allowed to come to room temperature and is stirred for 2 hours, then quenched with 10% aqueous sodium bicarbonate. (0295) The mixture is stirred for 30 minutes, and the resultant solid is filtered, washed with water, and dried to give bromide lxvii is used without further purification. |
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