hexane-2,5-dione

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

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

Procedure: A 250-mL round-bottomed flask equipped with a magnetic stirrer and a Dean-Stark trap was charged with 150b (11.0 g, 1.0 eq., 64.7 mmol), hexane-2,5-dione (11.1 g, 1.5 eq., 97.2 mmol), p-toluenesulfonic acid monohydrate (558 mg, 0.05 eq., 3.24 mmol), and toluene (100 mL). The reaction mixture was refluxed overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 1:2 petroleum ether/ethyl acetate to afford 150c (10.4 g, 65%) as a white solid. MS-ESI: [M+H]+ 249.0 A 250-mL round-bottomed flask equipped with a magnetic stirrer The reaction mixture was refluxed overnight concentrated under reduced pressure The resulting residue was purified by silica-gel column chromatography eluting with 1:2 petroleum ether/ethyl acetate

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

Procedure: The mixture of ethyl 3-aminobenzoate (2.0 g), hexane-2,5-dione (1.8 ml) and acetic acid (0.7 ml) in benzene (10.0 ml) was heated under reflux for 5 hours, while water was removed in a Dean-Stark apparatus. To the mixture was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with a brine, dried over magnesium sulfate and evaporated in vacuo to give ethyl 3-(2,5-dimethylpyrrol-1-yl)benzoate (2.9 g) as an oil. was heated was removed in a Dean-Stark apparatus To the mixture was added a mixture of ethyl acetate and water The separated organic layer was washed with a brine dried over magnesium sulfate evaporated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromoethylamine hydrobromide (20.5 g, 0.1 mol) and acetonylacetone (12.5 ml, 0.1 mol) in acetic acid (10 ml) was added potassium acetate (10 g, 0.1 mol), and the mixture was stirred for 1 h at 20° C. and for 2 h at 80° C. The reaction mixture was diluted with water (150 ml) and extracted with diethyl ether (150 ml). The extract was washed with brine and concentrated in vacuo to afford an oily residue. The residue was distilled at 60-64° C./0.5 mm of mercury to afford the title compound as a colourless oil (9.45 g, 47%). extracted with diethyl ether (150 ml) The extract was washed with brine concentrated in vacuo to afford an oily residue The residue was distilled at 60-64° C./0.5 mm of mercury

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

Procedure: A mixture of 4-fluoro-2-(trifluoromethyl)aniline (4.4 g, 24.6 mmol), 2,5-hexanedione (2.8 g, 24.5 mmol) and acetic acid (0.28 mL) was heated to 100° C. After 3 h the reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex (0:100 to 10:90) to afford 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole as a yellow oil (3.19 g, 50%); 1H NMR (CDCl3): δ 7.52 (dd, J=8, 3 Hz, 1H), 7.35 (dt, J=3, 8 Hz, 1H), 7.25 (dd, J=5, 8 Hz, 1H), 5.90 (s, 2H), 1.91 (s, 6H); MS (ESI) m/z 258 [M+H]+. After 3 h the reaction mixture was cooled partitioned between EtOAc and water The organic layer was separated dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (SiO2) eluting with EtOAc/Hex (0:100 to 10:90)

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

Procedure: 4-Bromoaniline (56.0 g., 0.33 Mol.), 2,5-hexanedione (37.6 g., 0.33 Mol), and acetic acid (5 ml) were placed into Toluene (500 ml) and heated under reflux for 8 hours employing a dean stark trap to remove the water from the reaction. The reaction was cooled to room temperature and concentrated under reduced vacuum. The resulting oil was taken into ethyl acetate, washed one time each with 2N hydrochloric acid, 2N NaOH, and H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield a brown solid. Material was purified by silica gel flash chromatography eluting with hexane. Concentration of the appropriate fractions yielded 55.0 gm. of a light yellow solid. (68%) NMR was consistent with the proposed title structure. heated under reflux for 8 hours to remove the water from the reaction concentrated under reduced vacuum washed one time each with 2N hydrochloric acid, 2N NaOH, and H2O dried over Na2SO4 concentrated under reduced vacuum to yield a brown solid Material was purified by silica gel flash chromatography eluting with hexane Concentration of the appropriate fractions yielded 55.0 gm

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

Procedure: 5-(3-Aminopropyl)-2-thiophenecarboxamide is reacted with acetonylacetone to give 5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide, m.p. 144°-126° C. (see J. Chem. Soc. Chem. Commun. 800 [1982]). This is alkylated with n-butyl bromide to give N-butyl-5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide (see Synthesis 266 [1976]). The latter is cleaved with hydroxylamine hydrochloride to give 5-(3-aminopropyl)-N-butyl-2-thiophenecarboxamide.

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

Procedure: Thionyl chloride (25 mL, 0.34 mol) was added dropwise to ethanol (540 mL). The reaction was heated to reflux for 15 minutes and cooled. The solution was treated with 2-[4-aminosulfonylphenyl]-1-phenyl-ethan-1-one from Step 1 (20.0 g, 72.64 mmol) and acetonylacetone (12.8 mL, 108.96 mmol), and reheated to reflux for 30 minutes. After cooling to room temperature, the solution was poured into rapidly stirred saturated aqueous Na2CO3 and ice (1500 mL). The aqueous phase was extracted with ethyl acetate (2×700 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo, yielding a brown oil. The oil was diluted with ethyl acetate (200 mL) and hexane (2000 mL), dried with MgSO4, gravity filtered, then purified through a short silica gel column with hexane and ethyl acetate (1:1) as eluant. The material was concentrated in vacuo and crystallized from hexane/ethyl acetate. The solid was isolated by filtration and air dried to afford 2,5-dimethyl-1-[[4-(2-oxo-2-phenylethyl)phenyl]sulfonyl]-1H-pyrrole (12.2 g, 49%) as a brown solid: mp 94.6°-98.8° C. 1H NMR (DMSO-d6 /300 MHz) 8.05 (d, J=7.25 Hz, 2H), 7.76 (d, J=8.26 Hz, 2H), 7.65 (t, J=7.85 Hz, 1H), 7.54 (t, J=7.85 Hz, 1H), 7.44 (d, J=8.26 Hz, 2H), 7.30 (br s, 2H), 4.52 (s, 2H). Mass spectrum: M+H obs. at m/z=354. The reaction was heated to reflux for 15 minutes cooled to reflux for 30 minutes The aqueous phase was extracted with ethyl acetate (2×700 mL) The combined organics were washed with brine dried over MgSO4 filtered concentrated in vacuo yielding a brown oil dried with MgSO4, gravity filtered purified through a short silica gel column with hexane and ethyl acetate (1:1) as eluant The material was concentrated in vacuo crystallized from hexane/ethyl acetate The solid was isolated by filtration and air dried

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

Procedure: A mixture of 6-amino-1,2,3,4-tetrahydrodibenzofuran (230 mg), 2,5-hexanedione (145 mg) and conc. hydrochloric acid (1 drop) in ethanol (3 ml) was refluxed for 1 hour and poured into water. The mixture was neutralized with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethanol and water to give 6-(2,5-dimethylpyrol-1-yl)-1,2,3,4-tetrahydrodibenzofuran (235 mg). was refluxed for 1 hour extracted with ethyl acetate The extract was washed with brine dried over sodium sulfate evaporated in vacuo The residue was purified by column chromatography on silica gel the obtained oil was crystallized from a mixture of ethanol and water

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

Procedure: A stirred suspension of N-aminophthalimide (19.75 g), acetonylacetone (14.3 ml), p-toluenesulfonic acid (5mg), and toluene (406 ml) was heated at reflux for 1 hour and cooled to room temperature. The reaction mixture was combined with another reaction mixture and the entire mixture decolorized with activated charcoal. Filtration through a bed of celite gave a solution which upon partial concentration resulted in crystallization of the desired product as a solid (11.0 g), m.p. 182.5°-183.5° C. was heated at reflux for 1 hour Filtration through a bed of celite gave a solution which upon partial concentration

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

Procedure: A suspension of methyl 4-amino-2-cyclopropylimidazole-5-carboxylate (Example 40, 5.72 g, 0.032 mol) in ethanol (40 mL) was treated with acetic acid (25 mL) and the mixture refluxed to effect solution. To the hot solution was added acetonylacetone (5.41 g, 0.047 mol) and the whole stirred and refluxed for 18 hours. The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2 to afford 7.93 g of the title compound methyl 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole-5-carboxylate. 1H-NMR (CDCl3) 5.85 (s, 2H), 3.68 (s, 3H), 2.0 (s, 6H), 1.80-2.0 (m, 1H), 1.0-1.18 (m, 4H). the mixture refluxed refluxed for 18 hours The solvent was removed under reduced pressure the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2

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

Procedure: A suspension of methyl 4-amino-2-cyclopropylimidazole-5-carboxylate (Example 40, 5.72 g, 0.032 mol) in ethanol (40 mL) was treated with acetic acid (25 mL) and the mixture refluxed to effect solution. To the hot solution was added acetonylacetone (5.41 g, 0.047 mol) and the whole stirred and refluxed for 18 hours. The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2 to afford 7.93 g of the title compound methyl 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole-5-carboxylate. 1H-NMR (CDCl3) 5.85 (s, 2H), 3.68 (s, 3H), 2.0 (s, 6H), 1.80-2.0 (m, 1H), 1.0-1.18 (m, 4H). the mixture refluxed refluxed for 18 hours The solvent was removed under reduced pressure the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2