5-Formylpyrrole-2-carboxylic acid methyl ester

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

Procedure: Preparation of methyl 5-(aminomethyl)pyrrole-2-carboxylate hydrochloride (X) can be accomplished by the approach shown in Scheme 11. A three-step conversion of pyrrole into methyl 5-formylpyrrole-2-carboxylate has been described (Org. Syn., Coll Vol. 4, 1963, p831). Alternatively, Muchowski (Tetrahedron Lett., 1988, 29, 777) has described the bis(dimethylamino)azafulvene dimer resulting from treatment of 2-formylpyrrole with dimethylamine. Such species may be lithiated at low temperatures and captured with a variety of electrophiles, including methyl chloroformate, to also give methyl 5-formylpyrrole-2-carboxylate. The aldehyde group is then converted to the oxime under standard conditions and finally reduced by catalytic hydrogenation in the presence of hydrochloric acid to give the target linker (X). ##STR44##

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

Procedure: To a suspension of NaH (5.74 g, 143.5 mmol; 60% in oil) in THF (200 mL) at 0° C. was added (tert-butoxycarbonylmethyl)triphenylphosphonium bromide (66 g, 143.5 mmol) as a solid in three portions. Cooling was removed and the mixture was stirred at rt for 30 min. It was then cooled to 0° C. and methyl 5-formyl-1H-pyrrole-2-carboxylate (16.9 g, 110.4 mmol) in THF (60 mL) was added dropwise over 40 min. The reaction mixture was allowed to warm to rt and was stirred overnight. Silica was added and the solvent was removed. The crude product was purified by flash chromatography (0-20% EtOAc/Heptane) to afford two isomeric compounds: Cooling was removed It was then cooled to 0° C. to warm to rt was stirred overnight Silica was added the solvent was removed The crude product was purified by flash chromatography (0-20% EtOAc/Heptane) to afford two isomeric compounds

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

Procedure: To 1,2-dichloroethane (40 mL) was added DMF (13.6 mL, 176 mmol). The mixture was cooled to 0° C. and phosphorus oxychloride (16.4 mL, 176 mmol) was added dropwise over 5 min. The resulting solution was stirred for 15 min. To the solution at 0° C. was added dropwise methyl 1H-pyrrole-2-carboxylate (20 g, 160 mmol) in dichloroethane (80 mL) (about 1 h). The cooling bath was removed, and the reaction mixture was heated to reflux for about 1 h and was then cooled to rt. EtOAc (250 mL) in ice water (400 mL) was added and the organic layer was separated. The aqueous layer was neutralized with NaHCO3 solution, and then extracted with EtOAc (4×100 mL). The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine, dried (Na2SO4) and filtered. Silica gel was added, the solvent removed and the silica gel-imbedded material was purified by flash chromatography (0-50% EtOAc/Heptane) to afford a major product, methyl 5-formyl-1H-pyrrole-2-carboxylate (16.3 g) and a minor product, methyl 4-formyl-1H-pyrrole-2-carboxylate (6.94 g). Combined yield: 23.3 g (95%). The cooling bath was removed the reaction mixture was heated to reflux for about 1 h was then cooled to rt EtOAc (250 mL) in ice water (400 mL) was added the organic layer was separated extracted with EtOAc (4×100 mL) The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine dried (Na2SO4) filtered Silica gel was added the solvent removed the silica gel-imbedded material was purified by flash chromatography (0-50% EtOAc/Heptane)

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

Procedure: Both formyl-pyrrole derivatives were prepared adopting a procedure described by C. Schmuck, Tetrahedron 2001, 57, 3063: To DMF (1.61 g) was added POCl3 (3.37 g) dropwise under Ar at 0° C. The mixture was allowed to warm to RT after which it was diluted with DCM (11 mL). A solution of 1H-pyrrole-2-carboxylic acid methyl ester (2.51 g) in DCM (11 mL) was added dropwise. The mixture was refluxed for 30 min whereupon it was cooled to 10° C. and quenched with a solution of potassium acetate (10.8 g) in water (28 mL). The phases were separated and the aqueous layer was extracted with MTBE. The combined organic phases were washed with saturated aqueous K2CO3 solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica (ethyl acetate/heptane 1:5) to yield 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester (1.60 g) as solids. The mixture was refluxed for 30 min whereupon it was cooled to 10° C. quenched with a solution of potassium acetate (10.8 g) in water (28 mL) The phases were separated the aqueous layer was extracted with MTBE The combined organic phases were washed with saturated aqueous K2CO3 solution concentrated in vacuo The residue was purified by flash column chromatography on silica (ethyl acetate/heptane 1:5)

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

Procedure: Both formyl-pyrrole derivatives were prepared adopting a procedure described by C. Schmuck, Tetrahedron 2001, 57, 3063: To DMF (1.61 g) was added POCl3 (3.37 g) dropwise under Ar at 0° C. The mixture was allowed to warm to RT after which it was diluted with DCM (11 mL). A solution of 1H-pyrrole-2-carboxylic acid methyl ester (2.51 g) in DCM (11 mL) was added dropwise. The mixture was refluxed for 30 min whereupon it was cooled to 10° C. and quenched with a solution of potassium acetate (10.8 g) in water (28 mL). The phases were separated and the aqueous layer was extracted with MTBE. The combined organic phases were washed with saturated aqueous K2CO3 solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica (ethyl acetate/heptane 1:5) to yield 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester (1.60 g) as solids. The mixture was refluxed for 30 min whereupon it was cooled to 10° C. quenched with a solution of potassium acetate (10.8 g) in water (28 mL) The phases were separated the aqueous layer was extracted with MTBE The combined organic phases were washed with saturated aqueous K2CO3 solution concentrated in vacuo The residue was purified by flash column chromatography on silica (ethyl acetate/heptane 1:5)

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

Procedure: Both formyl-pyrrole derivatives were prepared adopting a procedure described by C. Schmuck, Tetrahedron 2001, 57, 3063: To DMF (1.61 g) was added POCl3 (3.37 g) dropwise under Ar at 0° C. The mixture was allowed to warm to RT after which it was diluted with DCM (11 mL). A solution of 1H-pyrrole-2-carboxylic acid methyl ester (2.51 g) in DCM (11 mL) was added dropwise. The mixture was refluxed for 30 min whereupon it was cooled to 10° C. and quenched with a solution of potassium acetate (10.8 g) in water (28 mL). The phases were separated and the aqueous layer was extracted with MTBE. The combined organic phases were washed with saturated aqueous K2CO3 solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica (ethyl acetate/heptane 1:5) to yield 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester (1.60 g) as solids. The mixture was refluxed for 30 min whereupon it was cooled to 10° C. quenched with a solution of potassium acetate (10.8 g) in water (28 mL) The phases were separated the aqueous layer was extracted with MTBE The combined organic phases were washed with saturated aqueous K2CO3 solution concentrated in vacuo The residue was purified by flash column chromatography on silica (ethyl acetate/heptane 1:5)

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

Procedure: Anhydrous DMF (7.0 mL, 90.4 mmol) was cooled to 5-10 degrees Centigrade under nitrogen. POCl3 (7.8 mL, 83.7 mmol) was added dropwise to the cooled DMF over a couple of minutes. Dry 1,2-dichloroethane (25 mL) was then added and the solution was cooled to 0-5 degrees Centigrade during the addition of 2 (9.46 g, 75.6 mmol) in dry 1,2-dichloroethane (25 mL). The mixture was then heated to reflux for 15 minutes. The reaction was cooled to room temperature, treated with a mixture of ethyl acetate (60 mL) and water (75 mL), poured into saturated NaHCO3 (350 mL), and separated. The aqueous layer was washed three times with ether, and the combined organic extracts were washed twice with aqueous saturated Na2CO3, dried over Na2SO4, and evaporated under vacuum. The resulting solid was sublimed under reduced pressure (20×10−3 torr) at 60 degrees Centigrade in 3-hour intervals to yield compound 3 (7.79 g, 50.1 mmol, 66%). 1H-NMR (CDCl3): δ 10.57 (br s, 1H), 9.70 (s, 1H), 6.95 (m, 2H), 3.94 (s, 3H). The mixture was then heated to reflux for 15 minutes separated The aqueous layer was washed three times with ether the combined organic extracts were washed twice with aqueous saturated Na2CO3 dried over Na2SO4 evaporated under vacuum The resulting solid was sublimed under reduced pressure (20×10−3 torr) at 60 degrees Centigrade in 3-hour

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

Procedure: Preparation of methyl 5-(aminomethyl)pyrrole-2-carboxylate hydrochloride (X) can be accomplished by the approach shown in Scheme 11. A three-step conversion of pyrrole into methyl 5-formylpyrrole-2-carboxylate has been described (Org. Syn., Coll Vol. 4, 1963, p831). Alternatively, Muchowski (Tetrahedron Lett., 1988, 29, 777) has described the bis(dimethylamino)azafulvene dimer resulting from treatment of 2-formylpyrrole with dimethylamine. Such species may be lithiated at low temperatures and captured with a variety of electrophiles, including methyl chloroformate, to also give methyl 5-formylpyrrole-2-carboxylate. The aldehyde group is then converted to the oxime under standard conditions and finally reduced by catalytic hydrogenation in the presence of hydrochloric acid to give the target linker (X). ##STR44##

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

Procedure: Preparation of methyl 5-(aminomethyl)pyrrole-2-carboxylate hydrochloride (X) can be accomplished by the approach shown in Scheme 11. A three-step conversion of pyrrole into methyl 5-formylpyrrole-2-carboxylate has been described (Org. Syn., Coll Vol. 4, 1963, p831). Alternatively, Muchowski (Tetrahedron Lett., 1988, 29, 777) has described the bis(dimethylamino)azafulvene dimer resulting from treatment of 2-formylpyrrole with dimethylamine. Such species may be lithiated at low temperatures and captured with a variety of electrophiles, including methyl chloroformate, to also give methyl 5-formylpyrrole-2-carboxylate. The aldehyde group is then converted to the oxime under standard conditions and finally reduced by catalytic hydrogenation in the presence of hydrochloric acid to give the target linker (X). ##STR44##

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

Procedure: To a suspension of NaH (5.74 g, 143.5 mmol; 60% in oil) in THF (200 mL) at 0° C. was added (tert-butoxycarbonylmethyl)triphenylphosphonium bromide (66 g, 143.5 mmol) as a solid in three portions. Cooling was removed and the mixture was stirred at rt for 30 min. It was then cooled to 0° C. and methyl 5-formyl-1H-pyrrole-2-carboxylate (16.9 g, 110.4 mmol) in THF (60 mL) was added dropwise over 40 min. The reaction mixture was allowed to warm to rt and was stirred overnight. Silica was added and the solvent was removed. The crude product was purified by flash chromatography (0-20% EtOAc/Heptane) to afford two isomeric compounds: Cooling was removed It was then cooled to 0° C. to warm to rt was stirred overnight Silica was added the solvent was removed The crude product was purified by flash chromatography (0-20% EtOAc/Heptane) to afford two isomeric compounds

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

Procedure: To 1,2-dichloroethane (40 mL) was added DMF (13.6 mL, 176 mmol). The mixture was cooled to 0° C. and phosphorus oxychloride (16.4 mL, 176 mmol) was added dropwise over 5 min. The resulting solution was stirred for 15 min. To the solution at 0° C. was added dropwise methyl 1H-pyrrole-2-carboxylate (20 g, 160 mmol) in dichloroethane (80 mL) (about 1 h). The cooling bath was removed, and the reaction mixture was heated to reflux for about 1 h and was then cooled to rt. EtOAc (250 mL) in ice water (400 mL) was added and the organic layer was separated. The aqueous layer was neutralized with NaHCO3 solution, and then extracted with EtOAc (4×100 mL). The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine, dried (Na2SO4) and filtered. Silica gel was added, the solvent removed and the silica gel-imbedded material was purified by flash chromatography (0-50% EtOAc/Heptane) to afford a major product, methyl 5-formyl-1H-pyrrole-2-carboxylate (16.3 g) and a minor product, methyl 4-formyl-1H-pyrrole-2-carboxylate (6.94 g). Combined yield: 23.3 g (95%). The cooling bath was removed the reaction mixture was heated to reflux for about 1 h was then cooled to rt EtOAc (250 mL) in ice water (400 mL) was added the organic layer was separated extracted with EtOAc (4×100 mL) The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine dried (Na2SO4) filtered Silica gel was added the solvent removed the silica gel-imbedded material was purified by flash chromatography (0-50% EtOAc/Heptane)