ethyl 4,4,4-trifluoro-3-oxobutanoate

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:

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: In a 100-mL flask a solution of 4-bromoaniline (20 g, 116 mmol) and ethyl-4,4,4-trifluoroacetoacetate (25.5 mL, 175 mmol, 1.5 equiv) in toluene (5 mL) is heated to reflux for 5 h, cooled and excess solvent removed to provide N-(4-bromophenyl)-4,4,4-trifluoroacetoacetamide (Structure 15 of Scheme XX). The crude reaction mixture is then dissolved in CH2Cl2 (40 mL) and water (10 mL) and then treated with N-fluorobenzenesulfonimide (1.1 equiv) at room temperature overnight. The reaction mixture is then diluted with water (30 mL) and partitioned. The aqueous layer is extracted with CH2Cl2 (3×75 mL), the combined organic layers are then washed with sat NaHCO3 (25 mL), saturated NH4Cl (2×25 mL), water (25 mL), Brine (25 mL), dried (MgSO4), filtered and concentrated to afford N-(4-bromophenyl)-2,4,4,4-tetrafluoroacetoacetamide (Structure 15a of Scheme XX). The crude product was then dissolved in concentrated H2SO4 (10 mL) and heated to 80° C. for 3-4 h, cooled to room temperature, and poured over NaOH pellets/ice. The cold aqueous solution was then filtered, the white precipitate was then redissolved in EtOAc (200 mL), washed with water (2×20 mL), Brine (25 mL), dried (MgSO4), filtered and concentrated to yield Compound 634 as a white powder: 1H NMR (400 MHz, DMSO-d6) 12.92 (bs, 1H), 7.83 (dd, J=8.0, 1.2, 1H), 7.77 (s, 1H), 7.41 (d, J=7.9, 1H). to reflux for 5 h cooled excess solvent removed

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

Procedure: Scheme VIII describes the synthesis of 6-alkylaminocoumarins, as demonstrated by Structure 45, from phenol through a similar route as that described in Schemes I and II. A mixture of a phenol compound and a 3-ketoester such as ethyl 4,4,4-trifluoroacetoacetate are heated in refluxing toluene in the presence of TsOH to afford a coumarin compound e.g., Structure 43. Nitration of coumarin compounds (e.g., Structure 43) followed by hydrogenation give aminocoumarin compounds such as Structure 44. Sequential reductive alkylation provides dialkylamino-coumarin compounds as shown in Structure 45. Hydrogenation of a dialkylamino-coumarin compound (e.g., Structure 45) affords compounds Structure 46.

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-methyl-3-phenyl-1H-pyrazol-5-amine (1.7 g, 9.815 mmol) and 4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (2.168 g, 11.776 mmol) in acetic acid (3.0 mL) was heated at 150° C. for 10 h in a sealed tube under constant stirring. The reaction mixture was cooled to rt and poured into rapidly stirred ice-cold water to obtain the crude product as a solid. The product was collected by filtration and dried under vacuum. The product was purified by flash-chromatography (eluent: 35% EtOAc in hexane) to yield the title compound as a white solid (0.7 g, 24%). [1H-NMR (CDCl3, 300 MHz) δ 13.65 (s, 1H), 7.52-7.37 (m, 5H), 6.78 (s, 1H), 4.20 (s, 3H); LCMS RtC=1.430 min; [M+H]+=294.0] The reaction mixture was cooled to rt poured into rapidly stirred ice-cold water to obtain the crude product as a solid The product was collected by filtration dried under vacuum The product was purified by flash-chromatography (eluent: 35% EtOAc in hexane)