2,4-dimethyl-1H-pyrrole

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

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

Procedure: 2-Chloronicotinoyl chloride (3.4 g, 20 mmol) (Aldrich, Milwaukee, Wis.) was added to a solution of aluminum chloride (2.7 g, 20 mmol) (Aldrich, Milwaukee, Wis.) in dichloromethane (100 mL) at 0° C., followed by a solution of 2,4-dimethylpyrrole (2.9 g, 30 mmol) in dichloromethane (20 mL). The mixture was then stirred at room temperature for one hour. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.9 g (62%) of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone. washed with brine dried concentrated The residue was purified on a silica gel column

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

Procedure: 2-Chloronicotinoyl chloride (3.4 g, 20 mmol) (Aldrich, Milwaukee, Wis.) was added to a solution of aluminum chloride (2.7 g, 20 mmol) (Aldrich, Milwaukee, Wis.) in dichloromethane (100 mL) at 0° C., followed by a solution of 2,4-dimethylpyrrole (2.9 g, 30 mmol) in dichloromethane (20 mL). The mixture was then stirred at room temperature for one hour. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.9 g (62%) of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone. washed with brine dried concentrated The residue was purified on a silica gel column

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

Procedure: To dimethylformamide (4.5 mL, 57.8 mmol) under argon at 0° C. was added phosphorus oxychloride (57.8 mmol) dropwise over 5 min. The cooling bath was removed and after 15 min. 1,2-dichloroethane (15 mL) was added. The reaction mixture was again cooled to 0° C. and a solution of 2,4-dimethylpyrrole (52.6 mmol) in 1,2-dichloroethane (15 mL) was added dropwise over 15 min. The reaction was heated to reflux for 15 min, and then cooled to rt. A solution of sodium acetate (24 g) in water (75 mL) was added slowly to the reaction mixture and the resulting mixture was again heated to reflux for 20 min. After the reaction mixture was cooled to rt it was diluted with CH2Cl2, and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic fractions were washed with saturated NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide 5.2 g (80%) of the desired compound 2-formyl-3,5-dimethylpyrrole. [M+H]+=124.1, [M−H]−=122.0 The cooling bath was removed and after 15 min 1,2-dichloroethane (15 mL) was added The reaction was heated to reflux for 15 min cooled to rt the resulting mixture was again heated to reflux for 20 min After the reaction mixture was cooled to rt it the aqueous phase was washed with CH2Cl2 (2×50 mL) The combined organic fractions were washed with saturated NaHCO3 dried (Na2SO4) concentrated in vacuo The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane

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

Procedure: To dimethylformamide (4.5 mL, 57.8 mmol) under argon at 0° C. was added phosphorus oxychloride (57.8 mmol) dropwise over 5 min. The cooling bath was removed and after 15 min. 1,2-dichloroethane (15 mL) was added. The reaction mixture was again cooled to 0° C. and a solution of 2,4-dimethylpyrrole (52.6 mmol) in 1,2-dichloroethane (15 mL) was added dropwise over 15 min. The reaction was heated to reflux for 15 min, and then cooled to rt. A solution of sodium acetate (24 g) in water (75 mL) was added slowly to the reaction mixture and the resulting mixture was again heated to reflux for 20 min. After the reaction mixture was cooled to rt it was diluted with CH2Cl2, and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic fractions were washed with saturated NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide 5.2 g (80%) of the desired compound 2-formyl-3,5-dimethylpyrrole. [M+H]+=124.1, [M−H]−=122.0 The cooling bath was removed and after 15 min 1,2-dichloroethane (15 mL) was added The reaction was heated to reflux for 15 min cooled to rt the resulting mixture was again heated to reflux for 20 min After the reaction mixture was cooled to rt it the aqueous phase was washed with CH2Cl2 (2×50 mL) The combined organic fractions were washed with saturated NaHCO3 dried (Na2SO4) concentrated in vacuo The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane

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

Procedure: Aluminum chloride (1.7 g, 12.75 mmol) in dichloromethane (100 mL) was added to the 3,4-dimethoxybenzoyl chloride (2.0 g, 10 mmol) at room temperature, followed by a solution of 2,4-dimethylpyrrole (1.5 g, 15.8 mmol) in dichloromethane (5 mL). The mixture was then stirred at room temperature for overnight. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was chromatographed eluting with ethyl acetate and hexane to give 1 g (39%) of (3,4-dimethoxy-phenyl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone as a solid. washed with brine dried concentrated The residue was chromatographed eluting with ethyl acetate and hexane

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

Procedure: To a solution dimethylformamide (80.4 g) and 1 L of dichloroethane at 0° C. was added phosphorous oxychoride (153.3 g) over a few minutes and the reaction stirred for 1-2 hr at 0° C. 2,4-Dimethylpyrrole (114.6 g) was added dropwise to the above solution at temperature below 5° C. After the addition was complete the reaction was heated and the aqueous layer isolated and saved. The organic layer was extracted again with 300 mL of water and the two aqueous layers combined. The aqueous phase was extracted with 200 mL of dichloroethane and the organic layer discarded. The aqueous phase was cooled to 10° C. and adjusted to pH 10 with 10% sodium hydroxide. The mixture was stirred at 10° C. for 2 hr. The yellow solid was collected by vacuum filtration and washed thoroughly with water. The solid was dried at room temperature under vacuum to give 110.8 g (90% yield of 2,4-dimethyl-5-formylpyrrole. After the addition was heated the aqueous layer isolated The organic layer was extracted again with 300 mL of water The aqueous phase was extracted with 200 mL of dichloroethane The aqueous phase was cooled to 10° C. The mixture was stirred at 10° C. for 2 hr The yellow solid was collected by vacuum filtration washed thoroughly with water The solid was dried at room temperature under vacuum

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

Procedure: To a solution of tert-butyl 2-chloro-5-(5-formyl-4-methoxy-1H-pyrrol-2-yl)-4H-thieno[3,2-b]pyrrole-4-carboxylate (11 mg) and 2,4-dimethyl-1H-pyrrole (3.5 mg) in 1 mL of MeOH was added 2 small drops of a solution of 2 N HCl in ether. The dark-red reaction solution was stirred at r.t. for 10 min and then quenched with 3 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×5 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 60% EtOAc/hexanes to give 10 mg of the title compound as a dark solid. quenched with 3 mL of pH 7 sodium phosphate buffer solution The product was extracted with 2×5 mL of EtOAc The combined extracts were dried over Na2SO4 filtered concentrated The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 60% EtOAc/hexanes

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

Procedure: To a solution of 3-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrrole-2-carbaldehyde (8 mg) and 2,4-dimethyl-1H-pyrrole (3.2 mg) in 1 mL of MeOH was added 2 small drops of a solution of 2 N HCl in ether. The dark-red reaction solution was stirred at r.t. for 1 h and then quenched with 3 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×5 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 80% EtOAc/hexanes to give 8 mg of the title compound as a dark solid. quenched with 3 mL of pH 7 sodium phosphate buffer solution The product was extracted with 2×5 mL of EtOAc The combined extracts were dried over Na2SO4 filtered concentrated The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 80% EtOAc/hexanes

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

Procedure: Conversion of α-pyrrolecarboxylate esters to α-unsubstituted pyrroles by treatment with phosphoric acid provided a convenient preparation of pyrrole 5b and was extended to 3-n-propyl, 3-n-butyl, and 3-isopropyl derivatives 5d-f of 2,4-dimethylpyrrole 5a. A similar conversion afforded 3-methyl-4,5,6,7-tetrahydroindole 5i from its 2-carboxylate ester derivative 4i. Unsuccessful attempts to extend the method to the preparation of 2,4-dimethyl-3-tert-butylpyrrole 5g led instead to the replacement of both the carboethoxy and tert-butyl groups with hydrogen to give 2,4-dimethylpyrrole 5a. The pyrroles 5g, j, k were obtained from ethyl 3',5'-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g, ethyl 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolecarboxylate 4j, and ethyl 3,4-diethyl-5-methylpyrrole-2-carboxylate 4k by saponification with potassium hydroxide followed by decarboxylation of the free acids in ethanolamine at 180° C.

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

Procedure: To dimethylformamide (4.5 mL, 57.8 mmol) under argon at 0° C. was added phosphorus oxychloride (57.8 mmol) dropwise over 5 min. The cooling bath was removed and after 15 min. 1,2-dichloroethane (15 mL) was added. The reaction mixture was again cooled to 0° C. and a solution of 2,4-dimethylpyrrole (52.6 mmol) in 1,2-dichloroethane (15 mL) was added dropwise over 15 min. The reaction was heated to reflux for 15 min, and then cooled to rt. A solution of sodium acetate (24 g) in water (75 mL) was added slowly to the reaction mixture and the resulting mixture was again heated to reflux for 20 min. After the reaction mixture was cooled to rt it was diluted with CH2Cl2, and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic fractions were washed with saturated NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide 5.2 g (80%) of the desired compound 2-formyl-3,5-dimethylpyrrole. [M+H]+=124.1, [M−H]−=122.0 The cooling bath was removed and after 15 min 1,2-dichloroethane (15 mL) was added The reaction was heated to reflux for 15 min cooled to rt the resulting mixture was again heated to reflux for 20 min After the reaction mixture was cooled to rt it the aqueous phase was washed with CH2Cl2 (2×50 mL) The combined organic fractions were washed with saturated NaHCO3 dried (Na2SO4) concentrated in vacuo The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane

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

Procedure: To dimethylformamide (4.5 mL, 57.8 mmol) under argon at 0° C. was added phosphorus oxychloride (57.8 mmol) dropwise over 5 min. The cooling bath was removed and after 15 min. 1,2-dichloroethane (15 mL) was added. The reaction mixture was again cooled to 0° C. and a solution of 2,4-dimethylpyrrole (52.6 mmol) in 1,2-dichloroethane (15 mL) was added dropwise over 15 min. The reaction was heated to reflux for 15 min, and then cooled to rt. A solution of sodium acetate (24 g) in water (75 mL) was added slowly to the reaction mixture and the resulting mixture was again heated to reflux for 20 min. After the reaction mixture was cooled to rt it was diluted with CH2Cl2, and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic fractions were washed with saturated NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide 5.2 g (80%) of the desired compound 2-formyl-3,5-dimethylpyrrole. [M+H]+=124.1, [M−H]−=122.0 The cooling bath was removed and after 15 min 1,2-dichloroethane (15 mL) was added The reaction was heated to reflux for 15 min cooled to rt the resulting mixture was again heated to reflux for 20 min After the reaction mixture was cooled to rt it the aqueous phase was washed with CH2Cl2 (2×50 mL) The combined organic fractions were washed with saturated NaHCO3 dried (Na2SO4) concentrated in vacuo The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane