ethyl 3-amino-1H-pyrrole-2-carboxylate

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

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

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

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

Procedure: Into a 250-mL round-bottom flask was placed a solution of ethyl 3-amino-1H-pyrrole-2-carboxylate (10 g, 58.38 mmol, 1.00 equiv, 90%) in ethanol (150 mL) and formamidine acetate (10 g, 94.13 mmol, 1.61 equiv, 98%). The resulting solution was stirred at reflux for 16 h. The precipitates were collected by filtration, washed with ethanol and dried under reduced pressure to afford 5 g (61%) of 3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one as a gray solid Into a 250-mL round-bottom flask was placed at reflux for 16 h The precipitates were collected by filtration washed with ethanol dried under reduced pressure

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

Procedure: Into a 1000-mL round-bottom flask was placed a solution of diethyl 2-(2-cyanovinylamino)malonate (30 g, 119.3 mmol, 1.00 equiv, 90%) in ethanol (420 mL) and sodium ethanolate (80 mL, 21%). The resulting solution was stirred for 3 days at room temperature. After the addition of acetic acid (15 ml), the resulting mixture was concentrated under vacuum, dissolved in 200 mL of dichloromethane, washed with 2×100 mL of saturated aqueous sodium bicarbonate and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was dried in HV to afford 10 g (49%) of ethyl 3-amino-1H-pyrrole-2-carboxylate as an orange syrup. Into a 1000-mL round-bottom flask was placed the resulting mixture was concentrated under vacuum dissolved in 200 mL of dichloromethane washed with 2×100 mL of saturated aqueous sodium bicarbonate and 1×100 mL of brine dried over anhydrous sodium sulfate concentrated The residue was dried in HV

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

Procedure: Into a 1000-mL round-bottom flask was placed a solution of diethyl 2-(2-cyanovinylamino)malonate (30 g, 119.3 mmol, 1.00 equiv, 90%) in ethanol (420 mL) and sodium ethanolate (80 mL, 21%). The resulting solution was stirred for 3 days at room temperature. After the addition of acetic acid (15 ml), the resulting mixture was concentrated under vacuum, dissolved in 200 mL of dichloromethane, washed with 2×100 mL of saturated aqueous sodium bicarbonate and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was dried in HV to afford 10 g (49%) of ethyl 3-amino-1H-pyrrole-2-carboxylate as an orange syrup. Into a 1000-mL round-bottom flask was placed the resulting mixture was concentrated under vacuum dissolved in 200 mL of dichloromethane washed with 2×100 mL of saturated aqueous sodium bicarbonate and 1×100 mL of brine dried over anhydrous sodium sulfate concentrated The residue was dried in HV

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

Procedure: Formamidine acetate (20 g, 0.19 mol.) was added to a solution of crude 2-ethoxycarbonyl-3-aminopyrrole (14) (15.3 g, 0.1 mol.) in ethanol (150 ml) and the solution was heated under reflux for 16 h and then cooled. The solid formed was filtered, washed with ethanol and dried to give 3H, 5H-pyrrolo[3,2-d]pyrimidin-4-one (1) (11.5 g, 85.2 mmol.). Recrystallized from water it had mp >300° C. 1H NMR (d6-DMSO), was as reported3. 13C NMR δ 154.0, 145.0, 141.8, 127.7, 118.2, 103.3. the solution was heated under reflux for 16 h cooled The solid formed was filtered washed with ethanol dried

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

Procedure: Formamidine acetate (20 g, 0.19 mol.) was added to a solution of crude 2-ethoxycarbonyl-3-aminopyrrole (14) (15.3 g, 0.1 mol.) in ethanol (150 ml) and the solution was heated under reflux for 16 h and then cooled. The solid formed was filtered, washed with ethanol and dried to give 3H, 5H-pyrrolo[3,2-d]pyrimidin-4-one (1) (11.5 g, 85.2 mmol.). Recrystallized from water it had mp >300° C. 1H NMR (d6-DMSO), was as reported3. 13C NMR δ 154.0, 145.0, 141.8, 127.7, 118.2, 103.3. the solution was heated under reflux for 16 h cooled The solid formed was filtered washed with ethanol dried

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

Procedure: A solution of sodium ethoxide in ethanol (2M, 152 mL, 305 mmol) was added slowly to a stirred solution of isoxazole 18 (20 g, 290 mmol) in ethanol (80 mL) in an ice bath with the reaction temperature ≦8° C. After an additional 0.5 h with stirring, acetic acid (5.5 mL, 100 mmol), diethyl aminomalonate hydrochloride (40.9 g, 193 mmol) and sodium acetate (16.4 g, 200 mmol) were added and the mixture was stirred at room temperature for 2 days after which most of the ethanol was removed under vacuum. The residue was partitioned between chloroform and water and the organic phase was dried and filtered through a pad of silica gel. Evaporation afforded a syrup which was dissolved in a solution of sodium ethoxide in ethanol (0.5 M, 400 mL) and the solution was stirred at room temperature for 3 days. Acetic acid (12 mL, 210 mmol) was added and the ethanol removed under vacuum. The residue was dissolved in chloroform and washed with NaHCO3 (aq., pH kept ˜7) The organic phase was dried and filtered through a thick pad of silica gel to give crude syrupy 3-amino-2-ethoxycarbonylpyrrole (16.4 g, 106 mmol) with clean 1H and 13C NMR spectra that was suitable for synthetic use. A portion in ether was treated with HCl in dioxane to precipitate the corresponding hydrochloride salt. Recrystallized from ethyl acetate/ethanol it had mp 197-200° C.; 1H NMR (d6-DMSO), δ 7.02 (t, J=3.0 Hz, 1H), 6.34 (t, J=2.5 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.31 (t, J=7 Hz, 3H). 13C NMR δ 159.7, 123.2, 121.6, 114.7, 106.1, 60.6, 14.6. Anal. Calcd for C7H11ClN2O5: C, 44.10; H, 5.82; N, 14.70. Found: C, 44.02; H, 6.13; N, 14.55. was removed under vacuum The residue was partitioned between chloroform and water the organic phase was dried filtered through a pad of silica gel Evaporation afforded a syrup which the solution was stirred at room temperature for 3 days the ethanol removed under vacuum The residue was dissolved in chloroform washed with NaHCO3 (aq., pH kept ˜7) The organic phase was dried filtered through a thick pad of silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.20 g, 1.3 mmol), 3-bromochlorobenzene (0.30 g, 1.6 mmol), Pd2(dba)3 (0.048 g, 0.052 mmol), rac-BINAP (0.048 g, 0.078 mmol) and cesium carbonate (0.59 g, 1.8 mmol) was heated at 100° C. in a sealed microwave vial under nitrogen atmosphere overnight. Additional Pd2(dba)3 (0.10 g, 0.11 mmol) and R,S-BINAP (0.11 g, 0.18 mmol) were added and the reaction was continued stirring at 100° C. overnight. Additional 3-bromochlorobenzene (0.15 g), Pd2(dba)3 (0.098 g) and R,S-BINAP (0.098 g) were added and the reaction was continued stirring at 100° C. for three more days. The reaction mixture was poured into ethanol and the resulting solution was filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 30% ethyl acetate), obtaining 0.052 g (15%) of the title compound. the reaction was continued stirring at 100° C. for three more days the resulting solution was filtered The filtrate was evaporated in vacuo the residue was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 30% ethyl acetate)

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

Procedure: 3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077 g, 0.5 mmol), 4,5-dimethyl-1H-benzimidazole-2-carbaldehyde (0.130 g, 0.75 mmol) and HOAc (0.045 g, 0.75 mmol) were stirred in methanol (4 mL) followed by addition of NaCNBH3. The resulting mixture was stirred at r.t. for 16 h. The reaction mixture was neutralized with 2M NaOH and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate), obtaining a white solid, 0.043 g (27%) of the title compound, as a tautomeric mixture (1:1). the solvent was removed in vacuo The residue was dissolved in ethyl acetate extracted with water The organic layer was dried (Na2SO4) concentrated The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate)

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

Procedure: A reaction mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077 g, 0.5 mmol), NaCNBH3 (0.057 g, 0.9 mmol) and HOAc (0.030 g, 0.5 mmol) in methanol (4 mL) were stirred at r.t. fo 5 minutes before 5-chloro-1H-benzimidazole-2-carbaldehyde (0.144 g, 0.8 mmol) was added, followed by addition of CH2Cl2 (1 mL) and DMF (0.4 mL). The resulting mixture was allowed to stir for 16 h at r.t. under nitrogen atmosphere. Additional 5-chloro-1H-benzimidazole-2-carbaldehyde (0.030 g) and NaCNBH3 (0.015 g) were added and the reaction mixture was stirred at 4 h. The reaction mixture was neutralized with 2M NaOH and diluted with ethyl acetate. Extracted with water and the organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate), obtaining 0.074 g (46%) of the title product. was added to stir for 16 h at r.t. under nitrogen atmosphere the reaction mixture was stirred at 4 h Extracted with water the organic layer was dried (Na2SO4) concentrated The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate)