ethyl 2-(trifluoromethyl)-2H-chromene-3-carboxylate

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

Procedure: A 500 mL three neck round bottom flask was fitted with stir bar, thermocouple and heating mantle, condenser, and nitrogen inlet and charged with dichloromethane (150 mL), ethyl 2-trifluoromethyl-2H-chromene-3-carboxylate (14.94 g, 54.882 mmole), and AlCl3 (18.29 g, 137.21 mmole). With stirring, the reaction was chilled to 0° C. followed by addition of acetyl chloride (5.85 mL, 6.46 g, 82.32 mmole). The reaction was stirred at RT for three days and then at reflux for six days. The reaction was poured over ice and was extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield a solid. This solid was triturated with hexanes to provide a slurry. Vacuum filtration of the slurry yielded the title compound as a white solid. (11.78 g, 68.3%): mp 101-103° C. 1H NMR (acetone-d6/300 MHz) 8.14(s, 1H), 8.04 (d d, 1H, J=8.7, 2.2 Hz), 7.98(s, 1H), 7.13 (d, 1H, J=8.6 Hz), 5.95 (q, 1H, J=6.8 Hz), 4.38-4.23 (m, 2 H), 2.57(s, 3H), 1.33(t, 3H, J=7.0 Hz). GCMS m/z 314 (M+). thermocouple and heating mantle, condenser, and nitrogen inlet With stirring The reaction was stirred at RT for three days at reflux for six days The reaction was poured over ice was extracted with dichloromethane The organic phase was dried over MgSO4 filtered concentrated in vacuo to yield a solid This solid was triturated with hexanes to provide a slurry Vacuum filtration of the slurry

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

Procedure: Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 10, Step 1)(1.59 g, 5.8 mmol) was dissolved in 1,2-dichloroethane (3 mL) and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol) in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g, 7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction was heated to 80° C. and stirred for 4 hours. The solution was poured onto 3 N HCl and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCl, saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to afford the ester as a white crystalline solid (0.26 g, 12%): mp 114.7–116.1° C. 1H NMR (CDCl3/300 MHz) 7.82 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7 Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz). added to a 0° C. extracted with ethyl acetate washed with 3N HCl, saturated sodium bicarbonate, brine dried over MgSO4 concentrated in vacuo The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant)

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chlorosulfonic acid (50.0 mL) was cooled to 15° C. and ethyl 2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 10, Step 2) (6.21 g, 22.83 mmol) was added. After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The solution was added dropwise onto ice (500 mL) with vigorous stirring and extracted with diethyl ether (2×250 mL). The ether layers were combined, washed with water (2×250 mL), saturated sodium bicarbonate (2×250 mL), and brine (2×250 mL). Hexanes (50 mL) were added and the solution was dried over sodium sulfate. The solvent was removed in vacuo to afford the ester as a yellow solid (7.41 g, 87%): mp 97.2–98.4° C. 1H NMR (CDCl3, 300 MHz) 7.97 (dd, 1H, J=8.6, 2.2. Hz), 7.92 (d, 1H, J=2.2 Hz), 7.73 (s, 1H), 7.17 (d, 1H, J=2.2 Hz), 5.82 (qH-F, 1H, J=7.2 Hz), 4.28–4.39 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 376 (M+Li+). the solution was warmed to room temperature stirred for 16 hours The solution was added dropwise onto ice (500 mL) with vigorous stirring extracted with diethyl ether (2×250 mL) washed with water (2×250 mL), saturated sodium bicarbonate (2×250 mL), and brine (2×250 mL) Hexanes (50 mL) were added the solution was dried over sodium sulfate The solvent was removed in vacuo

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

Procedure: Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 10, Step 1) (1.59 g, 5.8 mmol) was dissolved in; 1,2-dichloroethane (3 mL) and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol) in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g, 7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction was heated to 80° C. and stirred for 4 hours. The solution was poured onto 3 N HCl and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCl saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to afford the ester as a white crystalline solid (0.26 g, 12%): mp 114.7–116.1° C. 1H NMR (CDCl3/300 MHz) 7.82 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7 Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz). extracted with ethyl acetate washed with 3N HCl saturated sodium bicarbonate, brine dried over MgSO4 concentrated in vacuo The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant)

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

Procedure: Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 10, Step 1) (1.59 g, 5.8 mmol) was dissolved in; 1,2-dichloroethane (3 mL) and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol) in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g, 7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction was heated to 80° C. and stirred for 4 hours. The solution was poured onto 3 N HCl and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCl saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to afford the ester as a white crystalline solid (0.26 g, 12%): mp 114.7–116.1° C. 1H NMR (CDCl3/300 MHz) 7.82 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7 Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz). extracted with ethyl acetate washed with 3N HCl saturated sodium bicarbonate, brine dried over MgSO4 concentrated in vacuo The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant)

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chlorosulfonic acid (50.0 mL) was cooled to 15° C. and ethyl 2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 10, Step 2) (6.21 g, 22.83 mmol) was added. After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The solution was added dropwise onto ice (500 mL) with vigorous stirring and extracted with diethyl ether (2×250 mL). The ether layers were combined, washed with water (2×250 mL), saturated sodium bicarbonate (2×250 mL), and brine (2×250 mL). Hexanes (50 mL) were added and the solution was dried over sodium sulfate. The solvent was removed in vacuo to afford the ester as a yellow solid (7.41 g, 87%): mp 97.2–98.4° C. 1H NMR (CDCl3, 300 MHz) 7.97 (dd, 1H, J=8.6, 2.2. Hz), 7.92 (d, 1H, J=2.2 Hz), 7.73 (s, 1H), 7.17 (d, 1H, J=2.2 Hz), 5.82 (qH-F, 1H, J=7.2 Hz), 4.28–4.39 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 376 (M+Li+). the solution was warmed to room temperature stirred for 16 hours The solution was added dropwise onto ice (500 mL) with vigorous stirring extracted with diethyl ether (2×250 mL) washed with water (2×250 mL), saturated sodium bicarbonate (2×250 mL), and brine (2×250 mL) Hexanes (50 mL) were added the solution was dried over sodium sulfate The solvent was removed in vacuo