2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone

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:

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

Procedure: 2,2,2-Trichloro-1-(4-iodo-1H-pyrrol-2-yl)-ethanone 57c (47 g, 136 mmol) was dissolved in 265 mL of methanol followed by dropwise addition of a solution of sodium methoxide (17.23 g, 163 mmol) in 200 mL of methanol. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure. The residue was diluted with 20 mL of water and then extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester 57d (32.2 g, yield 92.5%) as a grey solid. The mixture was concentrated under reduced pressure The residue was diluted with 20 mL of water extracted with ethyl acetate (30 mL×3) The combined organic extracts were washed with saturated brine dried over anhydrous sodium sulfate filtered to remove the drying agent concentrated under reduced pressure

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

Procedure: 2,2,2-Trichloro-1-(1H-pyrrol-2-yl)-ethanone 57b (32 g, 151.8 mmol) was dissolved in 250 mL of dichloromethane followed by dropwise addition of a solution of iodine monochloride (25 g, 153 mmol) in 125 mL of dichloromethane. Upon completion of the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was washed with saturated aqueous sodium carbonate, aqueous sodium thiosulfate (2 M) and saturated brine successively, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-ethanone 57c (47 g, yield 92%) as a yellow solid. Upon completion of the addition The mixture was washed with saturated aqueous sodium carbonate, aqueous sodium thiosulfate (2 M) and saturated brine successively dried over anhydrous magnesium sulfate filtered to remove the drying agent concentrated under reduced pressure The residue was purified by silica gel column chromatography

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

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

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

Procedure: The title compound was prepared from 2-(trichloroacetyl)pyrrole according to the method of Bélanger, Tetrahedron Lett., 1979, 2505. Thus, iodine (12.0 g, 47.2 mmol) was added portionwise (approximately 1 g per portion) over 0.17 h to a magnetically stirred mixture of silver trifluoroacetate (11.0 g, 49.8 mmol) and 2-(trichloroacetyl)pyrrole (10.0 g, 47.1 mmol) in dry chloroform (70 ml) maintained at 0° C. (ice-bath). After addition was complete the reaction mixture was allowed to warm to 18° C. and stirred at this temperature for a further 2 h. The resultant suspension was filtered through a sintered glass funnel (No. 3 porosity) and the filtrate washed with Na2S2O5 (1×80 ml of 5% w/v aqueous solution) and water (2×80 ml) then dried (MgSO4), filtered and concentrated under reduced pressure. The solid residue thus obtained was treated with hexane/ether (50 ml of a 4:1 v/v mixture) and the resulting suspension stirred at 18° C. for 5 h then the solid was filtered off to give the title compound (13.1 g, 82%) as a cream solid, m.p. 129-130° C. (lit. m.p. 128-130° C.). 1H n.m.r. d 9.45, broad s, 1H; 7.44, dd, J 2.6 and 1.3 Hz, 1H; 7.19, dd, J 2.6 and 1.3 Hz, 1H. After addition to warm to 18° C. The resultant suspension was filtered through a sintered glass funnel (No 3 porosity) and the filtrate washed with Na2S2O5 (1×80 ml of 5% w/v aqueous solution) and water (2×80 ml) then dried (MgSO4) filtered concentrated under reduced pressure The solid residue thus obtained stirred at 18° C. for 5 h the solid was filtered off

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

Procedure: To a stirred solution of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (68 g, 201 mmol, 1.0 equivalent) in dry methanol (400 mL) under nitrogen, was added a solution of sodium methoxide in methanol (4.37 M, 54 mL, 235 mmol, 1.2 equivalents) over 10 minutes. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the crude was then partitioned between water and tert-butylmethyl ether. The organic phase was separated, washed two times with water, saturated sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (48 g, 96%) as a colorless solid, that was used directly without further purification. The volatiles were removed under reduced pressure the crude was then partitioned between water and tert-butylmethyl ether The organic phase was separated washed two times with water, saturated sodium chloride dried over sodium sulfate filtered concentrated under vacuum

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

Procedure: To a stirred solution of 50 g (235 mmol, 1.0 equiv.) of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone in dry dichloromethane (400 mL) under nitrogen, a solution of iodine monochloride (39 g, 240 mmol, 1.02 equivalents) in of dichloromethane (200 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The solution was washed with 10% potassium carbonate, water, 1.0 M sodium thiosulfate, saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was recrystallized from hexanes/methyl acetate to afford the title compound (68.5 g, 86%) as a colorless solid (86%). MS FIA: 335.8, 337.8 ES−. The solution was washed with 10% potassium carbonate, water, 1.0 M sodium thiosulfate, saturated sodium chloride dried over sodium sulfate filtered concentrated under reduced pressure The solid was recrystallized from hexanes/methyl acetate

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

Procedure: Ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) (0.97 g, 4 mmol) was added to a solution of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) (0.68 g, 2 mmol) and N,N-diisopropylethylamine (DIPEA) (2.7 mL, 16 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO2, hexane-EtOAc 1:1) to obtain compound ethyl (2E)-4-{[(4-iodo-1H-pyrrol-2-yl)carbonyl]amino}but-2-enoate (X, where R1=OCH2CH3) as an off-white solid (0.48 g, 68% yield). The solvent was evaporated under vacuum the residue purified by flash chromatography (SiO2, hexane-EtOAc 1:1)