Ethyl 4,4,4-trifluorocrotonate

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of N-(2-formyl-4-(trifluoromethylphenyl)-2,2-dimethyl propanamide (Step 2) (921 mg, 3.7 mol) and lithium hydride (115 mg, 14.5 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 4,4,4-trifluorocrotonate (2.83 g, 16.8 mmol) and the contents warmed to 30° C. for 4 hours. After the addition of ethyl acetate (50 mL), the reaction was washed with water (2×30 mL), saturated ammonium chloride solution (2×30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, eluant: ethyl acetate-hexanes, 1:9) to yield, upon concentration of the appropriate fractions, ethyl 6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (65 mg, 5%): mp 138-139° C. 1H NMR (CDCl3/300 MHz) 7.67 (s, 1H), 7.26 (s, 1H), 7.04 (d, 1H, J=6.6 Hz), 6.62 (m, 1H), 5.14 (m, 1H), 4.60 (brs, 1H), 4.32 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). ESHRMS m/z 338.0592 (M−H Calc'd 338.0616). Anal. Calc'd for C13H11F3NO2: C, 49.57; H, 3.27; N, 4.13; Found: C, 49.23; H, 2.81; N, 3.93. the reaction was washed with water (2×30 mL), saturated ammonium chloride solution (2×30 mL) dried over sodium sulfate filtered The filtrate was concentrated in vacuo to afford a yellow solid The product was purified by flash chromatography (silica gel, eluant: ethyl acetate-hexanes, 1:9)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol), diazbicyclo[2.2.2]-undec-7-ene (32.2 g, 212.0 mmol), and ethyl 4,4,4-trifluorocrotonate (35.7 g, 212.0 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (48 mL) was heated at 60° C. for 8 hours. The solution was cooled to room temperature and the solution poured into ethyl acetate-hexanes (1:1, 500 mL). The solution was extracted with 2.5 N aqueous hydrochloric acid (2×200 mL), saturated aqueous ammonium chloride (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexanes (100 mL) and fine yellow crystals formed upon standing. Vacuum filtration of this suspension yielded ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as fine yellow crystals (19.3 g, 50% yield): mp 137-138° C. 1H NMR (CDCl3, 300 MHz) 7.62 (s, 1H), 7.36-7.48 (m, 2H), 6.43 (d, J=8.2 Hz), 5.36 (brs, 1H), 5.11 (q, 1H, J=7.1 Hz), 4.25-4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz). ESHRMS m/z 395.9716 (M−H, Calc'd 395.9708). The solution was cooled to room temperature The solution was extracted with 2.5 N aqueous hydrochloric acid (2×200 mL), saturated aqueous ammonium chloride (2×200 mL) dried over sodium sulfate filtered concentrated in vacuo The resulting dark yellow oil was dissolved in hexanes (100 mL) fine yellow crystals formed Vacuum filtration of this suspension

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

Procedure: The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol), anhydrous potassium carbonate (27.6 g, 200 mmol), and ethyl 4,4,4-trifluorocrotonate (34 mL, 200 mmol) were mixed in anhydrous dimethyformamide (60 mL) and heated at 100° C. for 7 hours. The contents were allowed to cool and partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (1×100 mL). The ethyl acetate extracts were combined and washed with brine (1×200 mL), dried over MgSO4, and concentrated in vacuo leaving a dark oil which solidified upon standing. The solid was purified by flash chromatography (silica gel; ethyl acetate-hexanes, 1:9). Fractions containing the desired product were combined, concentrated in vacuo and the residue recrystallized from ethyl acetate-hexanes to afford the ethyl 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (16.36 g, 56%): mp 132.6-134.2° C. 1H NMR (CDCl, 300 MHz) 7.61 (s, 1H), 7.10 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.10 (q, 1H, J=6.0 Hz), 4.55 (brs, 1H), 4.23 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). FABHRMS m/z 306.0468 (M+H+, Calc'd 306.0509). Anal. Calc'd for C13H11NO2F3Cl: C, 51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72. to cool partitioned between ethyl acetate (200 mL) and water (200 mL) The aqueous layer was extracted with ethyl acetate (1×100 mL) washed with brine (1×200 mL) dried over MgSO4 concentrated in vacuo leaving a dark oil which The solid was purified by flash chromatography (silica gel; ethyl acetate-hexanes, 1:9) Fractions containing the desired product concentrated in vacuo the residue recrystallized from ethyl acetate-hexanes

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

Procedure: The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g, 21.3 mmol) was added to DMF (5 mL) and ethyl 4,4,4-trifluorocrotonate (4.32 g, 25.7 mmol). With stirring, K2CO3 (3.78 g, 27.3 mmol) was added causing the reaction to become a deep red. The reaction was stirred at room temperature for 20 hours, acidified with 3N HCl, diluted with ethyl acetate and washed with water, saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was crystallized from diethyl ether-petroleum ether to give ethyl 6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate as a light yellow solid (4.47 g, 69%): mp 93.1-94.7° C. 1H NMR (acetone-d6/300 MHz) 7.94 (s, 1H), 7.41 (s, 1H), 7.31 (d, 1H, J=7.9 Hz), 7.25 (d, 1H, J=7.9 Hz), 4.96 (q, 1H, J=8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 309 (M+Li). the reaction The reaction was stirred at room temperature for 20 hours washed with water, saturated NaHCO3 solution, brine dried over MgSO4 filtered concentrated in vacuo yielding an oil The oil was crystallized from diethyl ether-petroleum ether

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-iodosalicylaldehyde (16.2 g, 65.3 mmol), ethyl 4,4,4-trifluorocrotonate (22.4 g, 133 mmol) and triethylamine (50 ml, 395 mmol)were combined, stirred at 70° C. for 8 h and then heated at reflux for 48 h. The solution was poured into ethyl acetate (300 mL) and washed with 1N hydrochloric acid (3×200 mL). The aqueous layers were combined and extracted with ethyl acetate (1×100 mL). The combined ethyl acetate extracts were washed with saturated ammonium chloride (2×200 mL), dried over magnesium sulfate and concentrated in vacuo yielding a dark red oil. This oil was purified by flash chromatography using ethyl acetate-hexanes (3:7) yielding a red oil. Crystallization of this oil from hexanes yielded the title compound as light red crystals (8.3 g, 31%): mp 105-106° C. 1H NMR (CDCl3/300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H, J=8.6, J=2.1 Hz, 7.54 (d, 1H, J=2.1 Hz), 6.77 (d, 1H, J=8.6 Hz), 5.70 (q, 1H, J=6.7 Hz), 4.20-4.38 (m 2H), 1.35 (t, 3H, J=7.2 Hz). ESHRMS 415.9926 (M+NH4+ Calc'd 396.9746). heated at reflux for 48 h washed with 1N hydrochloric acid (3×200 mL) extracted with ethyl acetate (1×100 mL) The combined ethyl acetate extracts were washed with saturated ammonium chloride (2×200 mL) dried over magnesium sulfate concentrated in vacuo yielding a dark red oil This oil was purified by flash chromatography yielding a red oil Crystallization of this oil from hexanes

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of potassium t-butoxide (8.11 g, 0.075 mol) in tetrahydrofuran at -60° C. is treated dropwise with a mixture of ethyl 4,4,4-trifluorocrotonate (10.5 g, 0.063 mol) and p-tolylsulfonylmethylisocyanide (12.2 g, 0.063 mol) in tetrahydrofuran over a 1 hour period, stirred at -60° C. for 30 minutes, allowed to warm to room temperature and quenched with water. The reaction mixture is extracted with ether and ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to give a solid residue. Recrystallization from 1,2-dichloroethane affords the title compound as a tan solid, 7.3 g (56%), mp 163°-164° C. to warm to room temperature quenched with water The reaction mixture is extracted with ether and ethyl acetate The combined extracts are washed with brine dried (MgSO4) concentrated in vacuo to give a solid residue Recrystallization from 1,2-dichloroethane

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 115 mg (5 mmol) of sodium metal (cut into small pieces and washed with hexanes) in 5 ml of THF was added a solution of diethyl malonate (800 mg, 5 mmol) in 10 ml THF. The mixture was stirred at room temperature until all of the sodium metal was consumed (2-3 hours). A catalytic amount of tetrabutylammonium bromide was added, followed by a THF solution (10 ml) of ethyl 4,4,4-trifluorocrotonate (0.84 g, 5 mmol). This mixture was-warmed to 40° C. and stirred for 17 hours. After cooling to 10° C., glacial acetic acid (300 mg, 5 mmol) was added and the THF was removed in vacuo. The resulting residue was treated with a solution of 87.3% KOH (1.28 g, 20 mmol) in 10 ml water and refluxed for 4.5 hours. After cooling to 10° C., 2.5 ml (26 mmol) of conc. HCl was added dropwise via pipette and the mixture was again heated to reflux until CO2 evolution had ceased (ca. 1 hour). The solution was cooled to 15° C. and extracted with Et2O (3×10 ml). The combined organic phases were dried over Na2SO4 , filtered and concentrated in vacuo to afford 3-(trifluoromethyl)glutaric acid as a white solid in 95% yield (m.p. 100°-100.5° C.). was consumed (2-3 hours) A catalytic amount of tetrabutylammonium bromide was added After cooling to 10° C. the THF was removed in vacuo refluxed for 4.5 hours After cooling to 10° C. the mixture was again heated (ca. 1 hour) The solution was cooled to 15° C. extracted with Et2O (3×10 ml) The combined organic phases were dried over Na2SO4 filtered concentrated in vacuo

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 115 mg (5 mmol) of sodium metal (cut into small pieces and washed with hexanes) in 5 ml of THF was added a solution of diethyl malonate (800 mg, 5 mmol) in 10 ml THF. The mixture was stirred at room temperature until all of the sodium metal was consumed (2-3 hours). A catalytic amount of tetrabutylammonium bromide was added, followed by a THF solution (10 ml) of ethyl 4,4,4-trifluorocrotonate (0.84 g, 5 mmol). This mixture was-warmed to 40° C. and stirred for 17 hours. After cooling to 10° C., glacial acetic acid (300 mg, 5 mmol) was added and the THF was removed in vacuo. The resulting residue was treated with a solution of 87.3% KOH (1.28 g, 20 mmol) in 10 ml water and refluxed for 4.5 hours. After cooling to 10° C., 2.5 ml (26 mmol) of conc. HCl was added dropwise via pipette and the mixture was again heated to reflux until CO2 evolution had ceased (ca. 1 hour). The solution was cooled to 15° C. and extracted with Et2O (3×10 ml). The combined organic phases were dried over Na2SO4 , filtered and concentrated in vacuo to afford 3-(trifluoromethyl)glutaric acid as a white solid in 95% yield (m.p. 100°-100.5° C.). was consumed (2-3 hours) A catalytic amount of tetrabutylammonium bromide was added After cooling to 10° C. the THF was removed in vacuo refluxed for 4.5 hours After cooling to 10° C. the mixture was again heated (ca. 1 hour) The solution was cooled to 15° C. extracted with Et2O (3×10 ml) The combined organic phases were dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: A mixture of 4.203 g (25 mmol) of ethyl 4,4,4-trifluorocrotonate, 20 mL of nitromethane and ca 0.576 g (5 mmol) of tetramethyl guanidine were stirred for 13 hours at room temperature, and then diluted with water and acidified by the addition of 0.5 M sulfuric acid. The mixture was extracted three times with diethyl ether. The combined ether extracts were washed with water, and then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5.601 g (98%) of 4,4,4-trifluoro-3-nitromethyl-butyric acid ethyl ester as an amber oil. The mixture was extracted three times with diethyl ether The combined ether extracts were washed with water brine, dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

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

Procedure: A mixture of 4.203 g (25 mmol) of ethyl 4,4,4-trifluorocrotonate, 20 mL of nitromethane and ca 0.576 g (5 mmol) of tetramethyl guanidine were stirred for 13 hours at room temperature, and then diluted with water and acidified by the addition of 0.5 M sulfuric acid. The mixture was extracted three times with diethyl ether. The combined ether extracts were washed with water, and then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5.601 g (98%) of 4,4,4-trifluoro-3-nitromethyl-butyric acid ethyl ester as an amber oil. The mixture was extracted three times with diethyl ether The combined ether extracts were washed with water brine, dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

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

Procedure: A solution of ethyl 4,4,4-trifluorocrotonate (9.85g, 65.9 mmole) and 1N NaOH (92.3 mL, 92.3 mmole) in THF (24 mL) was stirred at room temperature for 3 hours. The pH was brought to 1 with conc. HCl and the mixture extracted with Et2O (3×). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound as an oil. NMR (CDCl3): δ 6.55 (d, 1H); 6.89 (dq, 1H). the mixture extracted with Et2O (3×) The combined extracts were dried (MgSO4) concentrated in vacuo

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

Procedure: A mixture of 8.7 g (62 mmole) of 2-fluoro-6-hydroxybenzaldehyde, 18.6 mL (20.9 g, 124 mmole) of ethyl trifluorocrotonate and 17.3 mL (12.6 g, 124 mmole) of triethylamine was heated to reflux. After 3 hrs an additional 18.6 mL of ethyl trifluorocrotonate and 2 g of potassium carbonate was added and the mixture heated for 3 days. The mixture was allowed to cool, concd in vacuo, diluted with 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with 1N HCl, brine, dried and concd to afford a dark oil. Kugelrohr distillation (0.2 torr, 50° C.) afforded 11.2 g (62%) of a white solid: mp 45.5-47.0° C.; 1H NMR (CDCl3/400 MHz) 1.33 (t, 3H, J=7.1 Hz), 4.30 (m, 2H), 5.68 (q, 1H, J=6.8 Hz), 6.70 (t, 1H, J=9.0 Hz), 6.76 (d, 1H, J=8.3 Hz), 7.24 (q, 1H, J=7.2 Hz), 7.92 (s, 1H); 19F NMR (CDCl3/ 400 MHz) −78.9 (d, 3F, J=7.7 Hz), −118.9 (m, 1F); 13C NMR (CDCl3/100 MHz) 14.2, 61.6, 70.7 (q, J=33.2 Hz), 108.7 (d, J=18.7 Hz), 109.2 (d, CH, J=20.6 Hz), 111.9 (d, CH, J=3.2 Hz), 117.0, 123.3 (q, J=287.5 Hz), 129.9 (d, CH, J=5.0 Hz), 133.2 (d, CH, J=10.3 Hz), 153.9, 158.5, 162.3 (d, J=253.5 Hz); MS(ES+) 291 (M+1, 100); MS(EI) 290 (M+, 13), 245 (18), 221 (100), 193 (99); HRMS (EI) m/z calcd for (C13H10O3F4) 290.0566, found 290.0589. was heated to reflux the mixture heated for 3 days to cool extracted three times with diethyl ether The combined extracts were washed with 1N HCl, brine dried to afford a dark oil Kugelrohr distillation (0.2 torr, 50° C.)