dimethyl 1H-indole-2,3-dicarboxylate

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

Procedure: Using general procedure B, 1H-indole-2,3-dicarboxylic acid dimethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 344.3 ([M−H]−). the product obtained

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An ice cold solution of dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol) in N,N-dimethylformamide (DMF) (31.5 ml) was treated with NaH (0.617 g, 15.44 mmol) and methyl iodide (0.881 ml, 14.15 mmol) and warmed to 75° C. After 8 h, the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The combined organics were washed with water (3×), brine, dried (MgSO4), filtered and concentrated. The residue was treated with a solution of KOH (8.66 g, 154 mmol) in EtOH (200 mL) and heated to reflux (95° C. bath temp). After 8 h, the reaction mixture was cooled to ambient temperature, diluted with EtOAc and the layers partitioned. The aqueous layer was extracted with EtOAc (2×) and acidified with 1 M HCl to pH 3. The aqueous layer was then extracted with EtOAc and the organics were washed with brine, dried (MgSO4), filtered and concentrated to afford 1-methyl-1H-indole-2,3-dicarboxylic acid (2.82 g, 12.87 mmol, 100% yield) as a white solid. The acid was suspended in DCM (30 mL) and treated dropwise with TFAA (4.39 ml, 32.2 mmol). After 2 h, the reaction mixture was concentrated in vacuo to afford 4-methyl-1H-furo[3,4-b]indole-1,3(4H)-dione as a purple solid. The anhydride was suspended in MeOH (100 mL) and stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo to afford 3-(methoxycarbonyl)-1-methyl-1H-indole-2-carboxylic acid (2.95 g, 12.65 mmol, 98% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ=8.00 (s, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.40-7.33 (m, 1 H), 7.28 (s, 1 H), 3.82 (d, J=5.7 Hz, 6 H); LCMS (m/z) ES+=234 (M+1). the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl The combined organics were washed with water (3×), brine dried (MgSO4) filtered concentrated heated to reflux (95° C. bath temp) After 8 h the reaction mixture was cooled to ambient temperature the layers partitioned The aqueous layer was extracted with EtOAc (2×) The aqueous layer was then extracted with EtOAc the organics were washed with brine dried (MgSO4) filtered concentrated

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of aniline (3.91 ml, 43.0 mmol) and dimethyl but-2-ynedioate (5.28 ml, 43.0 mmol) in N,N-dimethylacetamide (DMA) (194 ml)/acetic acid (64.8 ml) was degassed with O2 for 5 min and treated with Pd(OAc)2 (0.964 g, 4.30 mmol). The reaction mixture was heated to 115° C. and placed under and atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of Celite™, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 220 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (5.5 g, 23.58 mmol, 54.9% yield) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ=9.32 (br. s., 1 H), 8.08 (d, J=8.2 Hz, 1 H), 7.48-7.44 (m, 1 H), 7.42-7.37 (m, 1 H), 7.29 (s, 1 H), 4.01 (d, J=2.0 Hz, 6 H); LCMS (m/z) ES+=234 (M+1). the reaction was cooled to ambient temperature filtered through a pad of Celite™ diluted with EtOAc washed with H2O The organic was washed with brine dried (MgSO4) filtered concentrated The residue was purified by ISCO (0-50% EtOAc-hexanes: 220 g SiO2)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1). the reaction mixture was cooled to ambient temperature partitioned between EtOAc and sat. aq. NH4Cl The organic layer was washed with water (5×), brine dried (MgSO4) filtered concentrated in vacuo The residue was purified on ISCO (0-100% EtOAc-hexanes)

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1). was degassed with O2 for 5 min the reaction was cooled to ambient temperature filtered through a pad of celite diluted with EtOAc washed with H2O The organic was washed with brine dried (MgSO4) filtered concentrated The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2)

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

Procedure: Using general procedure B, 1H-indole-2,3-dicarboxylic acid dimethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 344.3 ([M−H]−). the product obtained