methyl 2-(1H-indol-3-yl)-2-oxoacetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The cis and trans isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared beginning with the reaction of (1H-indol-3-yl)-oxo-acetic acid methyl ester and (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetic acid methyl ester in the presence of a base such as LDA (lithium diisopropylamide) in a polar aprotic solvent such as THF to yield 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester. Alternatively, 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester may be prepared by reaction of (1H-indol-3-yl)-acetic acid methyl ester and (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester in the presence of a base (e.g., LDA) in THF. The 2-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester is reduced by catalytic hydrogenation over a noble metal catalyst (e.g., Pd on charcoal) to give 2-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-3-(1H-indol-3-yl)-succinic acid dimethyl ester, which is reacted with benzylamine (PhCH2NH2) to yield a mixture of cis and trans 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrolidine-2,5-dione. The mixture of cis and trans isomers may be deprotected by catalytic hydrogenation over Pd on charcoal (Pd—C) to give rise to a mixture of cis and trans 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione. The cis and trans isomers may be separated to give all four cis and trans isomers (e.g., by chromatography as in Examples 4 and 5). The deprotected mixture of cis and trans isomers may be treated with potassium tert-butoxide in tert-butanol (as in Example 3) or a mixture of THF and tert-butanol at 50° C. to yield a mixture with a predominance of the trans isomers. Alternatively, the 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-succinic acid dimethyl ester can be reacted with ammonia in methanol at elevated temperatures to yield predominantly the cis isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, which may be isomerized to yield predominately the trans isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione with potassium tert-butoxide in tert-butanol (as in Example 3) or a mixture of THF and tert-butanol at 50° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(5-dimethylaminomethyl-benzofuran-3-yl)-acetamide (91 mg, 0.39 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (119 mg, 0.59 mmol) in anhydrous THF (5.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (1.6 mL) under an argon atmosphere at 0° C. The resulting deep red reaction mixture is stirred for 5 min. at 0° C. and 30 min. at room temperature followed by partitioning between brine and EtOAc. The layers are separated and the aqueous layer is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 7:1:1) affords the title compound as an orange solid (91.4 mg, 0.237 mmol, 63%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=11.90 (bs, 1H), 11.06 (bs, 1H), 8.28 (s, 1H), 7.89 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.94 (t, J=8.2 Hz, 1H), 6.82 (d, J=8.1 Hz, 1 H), 6.63 (d, J=8.2 Hz, 1H), 6.60 (s, 1H), 2.98 (s, 2H), 1.69 (s, 6H). MS (ES+): 386 (M(C23H19N3O3)+H)+. The resulting deep red reaction mixture by partitioning between brine and EtOAc The layers are separated the aqueous layer is extracted twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 filtered concentrated at reduced pressure to afford an orange solid Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 7:1:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(5-dimethylaminomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetamide (59.2 mg, 0.198 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (60.3 mg, 0.297 mmol) in anhydrous THF (4.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (0.989 mL) under an argon atmosphere at 0° C., followed by the addition of DMF (1.0 mL). The resulting deep red reaction mixture is stirred for 1 h at room temperature, diluted with EtOAc, washed with a saturated aqueous NH4Cl solution and washed with brine. The aqueous layer is extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford a red solid. The crude product is dissolved in DMF (1.0 mL), DBU (300 μL) is added, and the thus obtained solution is heated for 5 min. at 100° C. After cooling, the reaction mixture is diluted with EtOAc and washed with brine. The aqueous layer is extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford a red solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 8:1:1) affords the title compound as an orange solid (11 mg, 0.024 mmol, 12%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=12.54 (bs, 1H), 11.78 (bs, 1H), 11.06 (bs, 1H), 7.95 (d, J=2.9 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (t, J=8.1 Hz, 1H), 6.84 (s, 1H), 6.51 (t, J=8.1 Hz, 1 H), 6.45 (d, J=8.4 Hz, 1H), 3.10 (AB-system: δA=3.24 (d, JAB=−12.4 Hz, 1H), δB=2.97 (d, JAB=−12.4 Hz, 1H), 1.70 (s, 6H). MS (ES+): 453 (M(C24H19F3N4O2)+H)+. The resulting deep red reaction mixture washed with a saturated aqueous NH4Cl solution washed with brine The aqueous layer is extracted with EtOAc the combined organic phases are dried over Na2SO4 filtered concentrated at reduced pressure to afford a red solid the thus obtained solution is heated for 5 min. at 100° C After cooling washed with brine The aqueous layer is extracted with EtOAc the combined organic phases are dried over Na2SO4 filtered concentrated at reduced pressure to afford a red solid Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 8:1:1)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium tert-butoxide (1.0 M in THF, 1.90 ml, 1.90 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-Indol-3-yl)-oxo-acetic acid methyl ester (192 mg, 0.93 mmol, 1.5 equiv) and of 2-[6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyridin-3-yl]-acetamide (300 mg, 0.62 mmol) in anhydrous tetrahydrofuran (5.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at 0° C., 30 minutes at room temperature and 1 hour at 45° C. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane/EtOAc 50:50 to 20:80) affords the title compound (180 mg, 45%). MS (ES+): 611 (M+H)+. After three extractions with EtOAc the combined organic layers are dried over Na2SO4 filtered concentrated in vacuo Purification of the residue via flash chromatography (gradient of hexane/EtOAc 50:50 to 20:80)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium tert-butoxide (1.0 M in THF, 0.55 ml, 0.55 mmol, 2.7 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-indol-3-yl)-oxo-acetic acid methyl ester (45 mg, 0.22 mmol, 1.1 equiv) and of 2-(6-dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-acetamide (50 mg, 0.20 mmol) in anhydrous tetrahydrofuran (5.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at 0° C. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (5 ml), treated with DBU (0.27 ml, 1.8 mmol, 8.9 equiv) and heated to 110° C. for 10 minutes. After cooling, the reaction mixture is diluted with water and extracted three times with CH2Cl2. The combined organic layers are ished with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC affords the title compound (34 mg, 43%) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ=12.11 (s, 1H), 11.27 (s, 1H), 9.47 (br s, 1H), 8.21 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 7.78-7.76 (m, 2H), 7.73 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.0/4.0 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.49 (t, J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 3.48-3.40 (m, 2H), 2.16 (s, 6H). MS (ES+): 386 (M+H)+. After three extractions with EtOAc the combined organic layers are dried over Na2SO4 filtered concentrated in vacuo The residue is dissolved in N,N-dimethylformamide (5 ml) heated to 110° C. for 10 minutes After cooling extracted three times with CH2Cl2 dried over Na2SO4 filtered concentrated in vacuo Purification of the residue via preparative HPLC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium tert-butoxide (1.0 M in THF, 0.24 ml, 0.24 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-indol-3-yl)-oxo-acetic acid methyl ester (19.2 mg, 0.090 mmol, 1.1 equiv) and of 2-(6-dimethylaminomethyl-2-methyl-indolizin-3-yl)-acetamide (20 mg, 0.08 mmol) in anhydrous tetrahydrofuran (1.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at room temperature. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC affords the title compound (2 mg, 6%) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ=11.78 (s, 1H), 10.91 (s, 1H), 9.51 (s, 1H), 8.33 (s, 1H), 7.99 (d, J=2.9 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 6.95 (dt, J=8.0/1.2 Hz, 1H), 6.61 (dd, J=9.3/1.3 Hz, 1H), 6.52 (dt, J=8.1/1.0 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 4.13 (s, 2H), 2.67 (s, 6H), 1.93 (s, 3H). MS (ES+): 399 (M+H)+. After three extractions with EtOAc the combined organic layers are dried over Na2SO4 filtered concentrated in vacuo Purification of the residue via preparative HPLC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The cis and trans isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared beginning with the reaction of (1H-indol-3-yl)-oxo-acetic acid methyl ester and (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetic acid methyl ester in the presence of a base such as LDA (lithium diisopropylamide) in a polar aprotic solvent such as THF to yield 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester. Alternatively, 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester may be prepared by reaction of (1H-indol-3-yl)-acetic acid methyl ester and (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester in the presence of a base (e.g., LDA) in THF. The 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-but-2-enedioic acid dimethyl ester is reduced by catalytic hydrogenation over a noble metal catalyst (e.g., Pd on charcoal) to give 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-succinic acid dimethyl ester, which is reacted with benzylamine (PhCH2NH2) to yield a mixture of cis and trans 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrolidine-2,5-dione. The mixture of cis and trans isomers may be deprotected by catalytic hydrogenation over Pd on charcoal (Pd—C) to give rise to a mixture of cis and trans 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione. The cis and trans isomers may be separated to give all four cis and trans isomers (e.g., by chromatography as in Examples 4 and 5). The deprotected mixture of cis and trans isomers may be treated with potassium tert-butoxide in tert-butanol (as in Example 3) or a mixture of THF and tert-butanol at 50° C. to yield a mixture with a predominance of the trans isomers. Alternatively, the 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-succinic acid dimethyl ester can be reacted with ammonia in methanol at elevated temperatures to yield predominantly the cis isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, which may be isomerized to yield predominately the trans isomers of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione with potassium tert-butoxide in tert-butanol (as in Example 3) or a mixture of THF and tert-butanol at 50° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of indole-3-acetamide (1.00 g, 5.74 mmol) and methyl indolyl-3-glyoxylate (1.28 g, 6.30 mmole) in THF (10 mL) was treated with a 1 molar solution of potassium tert-butoxide in THF (17.2 mL, 17.2 mmol) at room temperature under N2. The resultant dark reaction mixture was stirred 3 hrs. at room temperature and was then treated with concentrated (37%) HCl (8 mL) allowing the reaction to exotherm. The reaction was worked up extractively using EtOAc (125 mL), water (2×100 mL), brine (25 ml) and the organic layer dried (MgSO4) and solvent removed in vacuo to give a solid that was purified by flash chromatography using a gradient of 2:1 to 1:1 hexanes:EtOAc to give 2.04 g (100%) of arcyriarubin A [1.28 g (68%) when using glyoxylyl chloride]. 3,4-(3-indolyl-1H-pyrrole-2,5-dione could also be recrystallized from EtOH to give a stiochiometric ethanol monosolvate in high purity (>99%) and yield (88%). NMR. MS (FD) m/z=327 (M+, 100%). Analytical calculated for C22H19N3O3C, 70.76; H, 5.13; N, 11.25. Found C, 70.97; H, 5.22; N, 11.12. The resultant dark reaction mixture at room temperature and was then treated with concentrated (37%) HCl (8 mL) the reaction the organic layer dried (MgSO4) and solvent removed in vacuo to give a solid that was purified by flash chromatography

Conditions: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of indole (2.0 g, 1.70 mmol) in Et2O (20 mL) was cooled to 0°-5° C. under N2 and oxalyl chloride (1.5 mL 1.70 mmol) was added dropwise at <5° C. The resultant yellow slurry was stirred 30 min. in the ice bath and was then cooled to -65° C. and a 25% wt. solution of sodium methoxide (7.8 mL, 3.4 mmol) was slowly added at ≤58° C. The reaction was then allowed to warm to room temperature, water was added (10 mL), and the resultant mixture filtered. The solid was dried at room temperature to give 3.21 g (93%) of the titled compound. NMR. MS (FD) m/z=203 (M+, 100%). Analytical calculated for C11H9NO3C, 65.02; H, 4.46; N, 6.89. Found C, 64.93; H, 4.25; N, 7.03. to warm to room temperature the resultant mixture filtered The solid was dried at room temperature

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetyl chloride (0.7 mL, 9.8 mmol), acetic acid (1 mL), and ethylhydrazine (1.5 g, 9.8 mmol) were added sequentially to a suspension of methyl (1H-indol-3-yl)glyoxalate (1.0 g, 4.9 mmol) in ethanol (25 mL). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was combined with acetonitrile. A pink solid was isolated by filtration and then purified by automated flash chromatography (Biotage, eluted with a gradient of 0-30% CMA in chloroform) to provide a white solid. This material was recrystallized from acetonitrile to provide 360 mg of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as white crystals, mp>250° C. MS (APCI) m/z 214 (M+H)+; Anal. calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.52; H, 5.14; N, 19.90. The reaction mixture was heated at reflux for 18 hours concentrated under reduced pressure A pink solid was isolated by filtration purified by automated flash chromatography (Biotage eluted with a gradient of 0-30% CMA in chloroform) to provide a white solid This material was recrystallized from acetonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of indole-3-acetamide (1.00 g, 5.74 mmol) and methyl indolyl-3-glyoxylate (1.28 g, 6.30 mmole) in THF (10 mL) was treated with a 1 molar solution of potassium tert-butoxide in THF (17.2 mL, 17.2 mmol) at room temperature under N2. The resultant dark reaction mixture was stirred 3 hrs. at room temperature and was then treated with concentrated (37%) HCl (8 mL) allowing the reaction to exotherm. The reaction was worked up extractively using EtOAc (125 mL), water (2× 100 mL), brine (25 ml) and the organic layer dried (MgSO4) and solvent removed in vacuo to give a solid that was purified by flash chromatography using a gradient of 2:1 to 1:1 hexanes:EtOAc to give 2.04 g (100%) of arcyriarubin A [1.28 g (68%) when using glyoxylyl chloride]. 3,4-(3-indolyl-1H-pyrrole-2,5-dione could also be recrystallized from EtOH to give a stiochiometric ethanol monosolvate in high purity (>99%) and yield (88%). NMR. MS (FD) m/z=327 (M+, 100%). Analytical calculated for C22H19N3O3C, 70.76; H, 5.13; N, 11.25. Found C, 70.97; H, 5.22; N, 11.12. The resultant dark reaction mixture at room temperature and was then treated with concentrated (37%) HCl (8 mL) the reaction the organic layer dried (MgSO4) and solvent removed in vacuo to give a solid that was purified by flash chromatography