2,3-Dibromomaleinimide

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4.12 g of 2-methylindole in 75 ml of benzene was treated with 9.2 ml of a 3M solution of methylmagnesium iodide in diethyl ether and the resulting solution was stirred under nitrogen for 0.5 hour. 2.0 g of dibromomaleimide were added and the mixture was heated to reflux for 14 hours. The cooled mixture was evaporated, dissolved in 200 ml of dichloromethane and acidified with 100 ml of 2M hydrochloric acid. The organic layer was separated, washed with 100 ml of water, dried and evaporated. The residue was triturated with dichloromethane and the obtained solid was recrystallized from acetone/water to give 1.1 g of 3,4-bis(2-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 311°-313° C. the mixture was heated to reflux for 14 hours The cooled mixture was evaporated dissolved in 200 ml of dichloromethane The organic layer was separated washed with 100 ml of water dried evaporated The residue was triturated with dichloromethane the obtained solid was recrystallized from acetone/water

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottomed flask was charged with di-dansyl cystamine (48 mg, 0.08 mmol), TCEP (23 mg, 1 eq), and MeOH (10 ml). The reaction mixture was stirred at ambient temperature under argon for 3 hrs. Dibromomaleimide (41 mg, 2 eq) in MeOH (10 ml), was added to the reaction mixture. After 16 hrs, the reaction mixture was concentrated in vacuo. The residue was worked up with DCM and brine. The organic layers were combined, dried (MgSO4) and purified by flash chromatography (silica gel, 0-15% EtOAC-DCM) to yield the desired compound (17 mg, 22%). 1HNMR (CDCl3, 600 MHz), δ8.5 (1H, d J 8.5 Hz aromatic H's), δ8.2 (2H, m aromatic H's), δ7.6 (1H, s CONH), δ7.53 (2H, m, aromatic H's), δ7.15 (1H, d, J=7.4 Hz aromatic H's), δ5.30 (1H, t, J 5.6 SO2NH), δ3.38 (2H, t, J 6.3 SCH2), δ3.26 (2H, q, J 6.3 NHCH2), δ2.88 (6H, s NCH3); 13CNMR (CDCl3, 150 MHz), δ165.5, 162.9, 152.2, 142.5, 134.5, 130.95, 129.94, 129.92, 129.5, 128.7, 123.3, 119.0, 118.5, 115.4, 45.5, 43.7, 30.5; IR (cm−1) 3295 (br) 1726 (s) MS (ES+) m/z relative intensity: 485 (M, 100); Exact mass calculated for [C18H19N3O4S2Br] requires m/z 484.0000. Found 783.9982. After 16 hrs the reaction mixture was concentrated in vacuo dried (MgSO4) purified by flash chromatography (silica gel, 0-15% EtOAC-DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottomed flask was charged with di-dansyl cystamine (48 mg, 0.08 mmol), TCEP (23 mg, 1 eq), and MeOH (10 ml). The reaction mixture was stirred at ambient temperature under argon for 3 hrs. Dibromomaleimide (41 mg, 2 eq) in MeOH (10 ml), was added to the reaction mixture. After 16 hrs, the reaction mixture was concentrated in vacuo. The residue was worked up with DCM and brine. The organic layers were combined, dried (MgSO4) and purified by flash chromatography (silica gel, 0-15% EtOAC-DCM) to yield the desired compound (17 mg, 22%). 1HNMR (CDCl3, 600 MHz), δ8.5 (1H, d J 8.5 Hz aromatic H's), δ8.2 (2H, m aromatic H's), δ7.6 (1H, s CONH), δ7.53 (2H, m, aromatic H's), δ7.15 (1H, d, J=7.4 Hz aromatic H's), δ5.30 (1H, t, J 5.6 SO2NH), δ3.38 (2H, t, J 6.3 SCH2), δ3.26 (2H, q, J 6.3 NHCH2), δ2.88 (6H, s NCH3); 13CNMR (CDCl3, 150 MHz), δ165.5, 162.9, 152.2, 142.5, 134.5, 130.95, 129.94, 129.92, 129.5, 128.7, 123.3, 119.0, 118.5, 115.4, 45.5, 43.7, 30.5; IR (cm−1) 3295 (br) 1726 (s) MS (ES+) m/z relative intensity: 485 (M, 100); Exact mass calculated for [C18H19N3O4S2Br] requires m/z 484.0000. Found 783.9982. After 16 hrs the reaction mixture was concentrated in vacuo dried (MgSO4) purified by flash chromatography (silica gel, 0-15% EtOAC-DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottomed flask was charged with di-dansyl cystamine (100 mg, 0.16 mmol), TCEP (46 mg, 1 eq) and MeOH (10 ml). The reaction mixture was stirred at ambient temperature under argon for 3 hrs. Dibromomaleimide (36 mg, 0.9 eq), in MeOH (5 ml) was then added to the reaction mixture. After 30 mins NaOAc (56 mg, 4 eq), was added to the reaction mixture and the solvent evaporated in vacuo. The residue was worked up with DCM and brine. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-20% EtOAc-DCM) afforded the desired compound as a yellow gum (40 mg, 40%). 1HNMR (CDCl3, 600 MHz), δ8.5 (2H, d J 8.5 Hz aromatic H's), δ8.2 (4H, m aromatic H's), δ7.53 (1H, s CONH), δ7.46 (4H, m, aromatic H's), δ7.1 (2H, d, J=7.4 Hz aromatic H's), δ5.65 (2H, t, J 6.27 SO2NH), δ3.3 (4H, t, J 6.0 SCH2), δ3.17 (4H, q, J 6.0 NHCH2), δ2.8 (12H, s NCH3); 13CNMR (CDCl3, 150 MHz), 6165.9, 152.0, 136.5, 134.7, 130.7, 129.94, 129.85, 129.62, 129.57, 128.63, 123.3, 118.8, 115.4, 45.5, 43.6, 31.8; IR (cm−1) 3288 (br) 1720 (s) MS (Na+) m/z relative intensity: 736 (M, 100); Exact mass calculated for [C32H35N5O6NaS4] requires m/z 736.1368. Found 736.1390 (Na+). was added to the reaction mixture the solvent evaporated in vacuo dried (MgSO4) filtered concentrated in vacuo Purification by flash chromatography (silica gel, 0-20% EtOAc-DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To dibromomaleimide (80.0 mg, 0.3 mmol) and sodium hydrogencarbonate (130.2 mg, 1.6 mmol) in methanol (6 ml) was slowly added benzenethiol (66.6 μl, 0.7 mmol) in methanol (1 ml). The reaction was stirred for 15 min at RT. The solvent was removed in vacuo and the residual material was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, gradient elution from 9:1 to 7:3) to afford the desired product as bright yellow crystals (73 mg, 75%). λmax (50 mM sodium phosphate, pH 6.2, 40% MeCN, 2.5% DMF)/412 nm (ε/dm3 mol−1 cm−1 2245); 1H NMR (500 MHz, MeOD): δ=7.27-7.22 (m, 6H, Ar—H), 7.16-7.14 (m, 4H, Ar—H); 13C NMR (125 MHz, MeOD): δ=169.3 (C), 137.6 (C), 135.4 (C), 132.4 (CH), 130.1 (CH), 129.1 (CH); IR (solid, cm−1): 3285 (m), 3059 (w), 2924 (w), 1774 (m), 1715 (s); MS (CI) m/z, (%): 314 (M+H, 100), 206 (13), 111 (12); Mass calc. for C16H11O2NS2[H]: 314.0231. Found: 314.0309; m.p. 102-104° C. (Literature: 123-126° C.). The solvent was removed in vacuo the residual material was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, gradient elution from 9:1 to 7:3)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 2-mercaptoethanol (683.8 μl, 9.8 mmol) in buffer (100 ml, 150 mM NaCl, 100 mM sodium phosphate, pH 8.0, 5.0% DMF) was added di-bromomaleimide (1 g, 3.9 mmol) in DMF (2.5 ml, final concentration DMF 7.5%). The reaction was stirred for 30 min at RT and lithium chloride (20 g) was added. The aqueous reaction mixture was extracted with ethyl acetate (7×150 ml). The organic layers were combined, the solvent removed in vacuo and the residual material was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, gradient elution from 1:1 to 1:9). Fractions containing the product were collected and the solvent were removed in vacuo. The still impure product was purified by flash chromatography on silica gel (methanol:dichloromethane, gradient elution from 0.5-10.0% methanol) to afford the desired compound as a yellow solid (518 mg, 53%). λmax (50 mM sodium phosphate, pH 6.2, 40% MeCN, 2.5% DMF)/318 nm (ε/dm3 mol−1 cm−1 1855); 1H NMR (500 MHz, MeOD): δ=3.74 (t, 4H, J=6.4, 2×HO—CH2), 3.41 (t, 4H, J=6.3, 2×S—CH2) 13C NMR (125 MHz, MeOD): δ=168.5 (C), 137.2 (C), 62.3 (CH2), 34.4 (CH2); IR (solid, cm−1): 3344 (s), 2500 (m), 2078 (w); MS (EI) m/z, (%): 250 (M, 43), 232 (100), 161 (37); Mass calc. for C8H11O4NS2: 250.02077. Found: 250.02126; m.p. 46-50° C. final concentration DMF 7.5%) lithium chloride (20 g) was added The aqueous reaction mixture was extracted with ethyl acetate (7×150 ml) the solvent removed in vacuo the residual material was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, gradient elution from 1:1 to 1:9) Fractions containing the product were collected the solvent were removed in vacuo The still impure product was purified by flash chromatography on silica gel (methanol:dichloromethane, gradient elution from 0.5-10.0% methanol)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethylmagnesium bromide is prepared from magnesium (12.7 mmol) suspended in bromoethane (12.7 mmol) and dry tetrahydrofuran (5 ml). The solution is stirred for 1 hour at ambient temperature and then 7-azaindole (12.7 mmol), dissolved in 40 ml of anhydrous toluene, is added dropwise. After 1 hour 30 minutes' stirring at ambient temperature, a solution of 2,3-dibromomaleimide (3.53 mmol) in 40 ml of anhydrous toluene is added dropwise. After 20 minutes, 60 ml of dry dichloromethane are added, and then the reaction mixture is stirred for 75 hours at 40° C. and subsequently hydrolysed with a saturated aqueous ammonium chloride solution. The organic product is extracted with ethyl acetate, and then the combined organic phases are dried over magnesium sulphate and filtered. After removal of the solvent by evaporation, and purification of the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated. is added dropwise After 1 hour 30 minutes' stirring at ambient temperature After 20 minutes The organic product is extracted with ethyl acetate the combined organic phases are dried over magnesium sulphate filtered After removal of the solvent by evaporation, and purification of the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6.44 g (40 mmol) 5,6-methylenedioxyindole are dissolved in 300 ml anhydrous toluene and mixed dropwise at 60° C. with 20 ml of a 2M solution of ethyl magnesium bromide in tetrahydrofuran (Aldrich). After completion of the addition, there is added dropwise thereto a solution of 1.7 g (6.67 mmol) dibromomaleinimide in 50 ml toluene, with the addition of the minimum amount of tetrahydrofuran required for solution, and then heated under reflux for 18 hours. After cooling, the reaction mixture is mixed with a saturated aqueous solution of ammonium chloride, the organic phase is separated off and the aqueous phase is extracted three times with toluene and once with ethyl acetate. The combined organic phases are dried, rotary evaporated and chromatographed in silica gel (elution agent: dichloromethane/ethyl acetate 30:1 v/v). There is obtained 1.27 g (56% of theory) 2-bromo-3-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide; m.p. about 185° C. (decomp.); RF=0.50 (dichloromethane/ethyl acetate 3:1 v/v); and 0.63 g (22.5% of theory) 2,3-bis-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide in the form of red crystals; m.p, about 270° C. (decomp.), after recrystallisation from propanol; RF=0.36 (dichloromethane/ethyl acetate 3:1 v/v). After completion of the addition, there is added dropwise heated under reflux for 18 hours After cooling the organic phase is separated off the aqueous phase is extracted three times with toluene The combined organic phases are dried rotary evaporated chromatographed in silica gel (elution agent: dichloromethane/ethyl acetate 30:1 v/v)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 22 mmol ethyl magnesium bromide in 30 ml tetrahydrofuran is mixed at ambient temperature with a solution of 2.8 g (19 mmol) 5-methoxyindole in 50 ml toluene and stirred for 1 hour at ambient temperature. Under an atmosphere of nitrogen, there is then added dropwise thereto a solution of 1.5 g (5.8 mmol) dibromomaleinimide in 20 ml tetrahydrofuran/50 ml toluene and heated under reflux for 20 hours. After cooling, the reaction mixture is decomposed with a saturated aqueous solution of ammonium chloride, the products are extracted with ethyl acetate and the organic phase is dried over anhydrous sodium sulphate. After evaporation, the red residue obtained is triturated with a little methanol and the precipitated red product is filtered off with suction and dried in a vacuum at 0.1 Torr and 100° C. There is obtained 0.9 g (36% of theory) of red crystals; m.p. 336° C. (decomp.); RF=0.30 (toluene/ethanol 10:2 v/v). Under an atmosphere of nitrogen, there is then added dropwise under reflux for 20 hours After cooling the products are extracted with ethyl acetate the organic phase is dried over anhydrous sodium sulphate After evaporation the red residue obtained is triturated with a little methanol the precipitated red product is filtered off with suction dried in a vacuum at 0.1 Torr and 100° C There is obtained 0.9 g (36% of theory) of red crystals

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 22 mmol ethyl magnesium bromide in 30 ml tetrahydrofuran is mixed at ambient temperature with a solution of 2.8 g (19 mmol) 5-methoxyindole in 50 ml toluene and stirred for 1 hour at ambient temperature. Under an atmosphere of nitrogen, there is then added dropwise thereto a solution of 1.5 g (5.8 mmol) dibromomaleinimide in 20 ml tetrahydrofuran/50 ml toluene and heated under reflux for 20 hours. After cooling, the reaction mixture is decomposed with a saturated aqueous solution of ammonium chloride, the products are extracted with ethyl acetate and the organic phase is dried over anhydrous sodium sulphate. After evaporation, the red residue obtained is triturated with a little methanol and the precipitated red product is filtered off with suction and dried in a vacuum at 0.1 Torr and 100° C. There is obtained 0.9 g (36% of theory) of red crystals; m.p. 336° C. (decomp.); RF=0.30 (toluene/ethanol 10:2 v/v). Under an atmosphere of nitrogen, there is then added dropwise under reflux for 20 hours After cooling the products are extracted with ethyl acetate the organic phase is dried over anhydrous sodium sulphate After evaporation the red residue obtained is triturated with a little methanol the precipitated red product is filtered off with suction dried in a vacuum at 0.1 Torr and 100° C There is obtained 0.9 g (36% of theory) of red crystals

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The 2-bromo-3-(1H-indol-3-yl)-maleinimide used as starting material is prepared as follows: A solution of 49.3 mmol ethyl magnesium bromide in 30 ml tetrahydrofuran is mixed with a solution of 5.8 g (49.5 mmol) indole in 50 ml toluene. The reaction mixture is stirred for 1 hour at ambient temperature, a solution of 2.5 g (9.8 mmol) dibromomaleinimide in 20 ml tetrahydrofuran/50 ml toluene is then slowly added dropwise thereto and heated under reflux for 30 hours. After cooling, the reaction mixture is decomposed with a saturated aqueous solution of ammonium chloride, the products are extracted with ethyl acetate and the organic phase is subsequently dried over anhydrous sodium sulphate. After evaporation, the red residue obtained is triturated with a little dichloromethane, filtered off with suction and dried in a vacuum at 0.1 Torr and 70° C. There are obtained 2.2 g (75% of theory) of orange-coloured product; m.p. 196° C.; RF=0.35 (hexane/ethyl acetate 1:1 v/v). is prepared heated under reflux for 30 hours After cooling the products are extracted with ethyl acetate the organic phase is subsequently dried over anhydrous sodium sulphate After evaporation the red residue obtained is triturated with a little dichloromethane filtered off with suction dried in a vacuum at 0.1 Torr and 70° C There are obtained 2.2 g (75% of theory) of orange-coloured product

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The 2-bromo-3-(1H-indol-3-yl)-maleinimide used as starting material is prepared as follows: A solution of 49.3 mmol ethyl magnesium bromide in 30 ml tetrahydrofuran is mixed with a solution of 5.8 g (49.5 mmol) indole in 50 ml toluene. The reaction mixture is stirred for 1 hour at ambient temperature, a solution of 2.5 g (9.8 mmol) dibromomaleinimide in 20 ml tetrahydrofuran/50 ml toluene is then slowly added dropwise thereto and heated under reflux for 30 hours. After cooling, the reaction mixture is decomposed with a saturated aqueous solution of ammonium chloride, the products are extracted with ethyl acetate and the organic phase is subsequently dried over anhydrous sodium sulphate. After evaporation, the red residue obtained is triturated with a little dichloromethane, filtered off with suction and dried in a vacuum at 0.1 Torr and 70° C. There are obtained 2.2 g (75% of theory) of orange-coloured product; m.p. 196° C.; RF=0.35 (hexane/ethyl acetate 1:1 v/v). is prepared heated under reflux for 30 hours After cooling the products are extracted with ethyl acetate the organic phase is subsequently dried over anhydrous sodium sulphate After evaporation the red residue obtained is triturated with a little dichloromethane filtered off with suction dried in a vacuum at 0.1 Torr and 70° C There are obtained 2.2 g (75% of theory) of orange-coloured product