3,3,3-trifluoro-2,2-dimethylpropanoic acid

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: To a mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (10 g, 64.1 mmol) in CHCl3 (100 mL) cooled to 0° C. was added oxalyl chloride (7.29 mL, 83 mmol) dropwise. The mixture was stirred at 70° C. for 4 h. Then the mixture was concentrated. To a mixture of (E)-4-methoxybut-3-en-2-one (12.83 g, 128 mmol) in THF (100 mL) cooled to −78° C. was added LiHMDS (128 mL, 128 mmol) dropwise under N2. The mixture was stirred at −78° C. for 1 h. Then to the mixture was added a solution of 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride in THF (100 mL) at −78° C. The whole mixture was allowed to warm to rt over 2 h and quenched by NH4Cl (saturated aqueous, 30 mL). THF was removed under vacuum. To the mixture was added H2O (80 mL) and then extracted with EA (100 mL×3). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=2:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.5) were combined to yield an off-white oil of (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one (1 g, 3.36 mmol, 5.2% yield): 1H NMR (400 MHz, CDCl3): δ 15.90 (s, 1H), 7.65 (d, J=12.4 Hz, 1H), 5.63 (s, 1H), 5.33 (d, J=12.4 Hz, 1H), 3.74 (s, 3H), 1.38 (s, 6H). ES-LCMS m/z 239.1 (M+H). Then the mixture was concentrated cooled to −78° C. The mixture was stirred at −78° C. for 1 h to warm to rt over 2 h quenched by NH4Cl (saturated aqueous, 30 mL) THF was removed under vacuum To the mixture was added H2O (80 mL) extracted with EA (100 mL×3) The organic layer was washed with brine (80 mL) dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=2:1)

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

Procedure: A solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.5 g, 3.20 mmol) in DCM (5 mL) was treated with oxalyl chloride (0.350 mL, 4.00 mmol) and 1 drop of DMF, stirred at RT for 1 h, added drop-wise to a solution of NH4OH (˜15M, 5 mL, ˜75 mmol) in THF (5 mL) and stirred at RT overnight. Solids were removed via filtration through diatomaceous earth, rinsed well with 4:1 DCM/THF, the filtrate saturated with solid NaCl, extracted with 4:1 DCM/THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 3,3,3-trifluoro-2,2-dimethylpropanamide (370 mg, 74%). 1H NMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.35 (s, 1H), 1.29 (s, 6H). stirred at RT overnight Solids were removed via filtration through diatomaceous earth rinsed well with 4:1 DCM/THF the filtrate saturated with solid NaCl, extracted with 4:1 DCM/THF (3×) the combined organics were dried over Na2SO4 concentrated to dryness

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

Procedure: A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.96 g, 19.0 mmol), 2-(bromomethyl)naphthalene (4.19 g, 19.0 mmol), and potassium carbonate (7.86 g, 56.9 mmol) in 50 ml of anhydrous DMF was stirred at 30° C. overnight. Diluted with 150 ml of EtOAc, washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl, diced (Na2SO4) and concentrated to give an oil that was purified by ISCO using EtOAc in hexanes (5%) as eluents to provide the title compound as an oil. washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl concentrated to give an oil that was purified by ISCO

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

Procedure: A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.96 g, 19.0 mmol), 2-(bromomethyl)naphthalene (4.19 g, 19.0 mmol), and potassium carbonate (7.86 g, 56.9 mmol) in 50 ml of anhydrous DMF was stirred at 30° C. overnight. Diluted with 150 ml of EtOAc, washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl, diced (Na2SO4) and concentrated to give an oil that was purified by ISCO using EtOAc in hexanes (5%) as eluents to provide the title compound as an oil. washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl concentrated to give an oil that was purified by ISCO

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

Procedure: To a biphasic mixture of 1-methoxy-4-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene (10.0 g, 45.8 mmol) and sodium periodate (137 g, 642 mmol) in a mixture solvent of CCl4:CH3CN:H2O (2:2:3, 550 ml) was added slowly ruthenium(III) chloride hydrate (0.517 g, 2.29 mmol) (black powder) while the reaction flask was kept in an ice-water bath. The mixture turned yellow rapidly then red after 5 minutes, ans was stirred for 0.5 h. The ice-water bath was removed and the reaction mixture was stirred vigorously, via a mechanical stirrer, overnight. The solids were filtered off, washed with 100 ml of DCM, 100 ml of H2O. The filtrate (pH ˜1) was basified with 10 N NaOH to pH>11, and the layers were separated, and the aq. layer was extracted with 130 ml of DCM. The aq. layer was then acidified carefully with conc. HCl to pH ˜1, extracted with 3×150 ml of DCM. The org layers were combined, dried (Na2SO4), and concentrated to give the title compound as an oil, which became a semi-solid upon drying on the vac line. was kept in an ice-water bath The ice-water bath was removed the reaction mixture was stirred vigorously, via a mechanical stirrer, overnight The solids were filtered off washed with 100 ml of DCM, 100 ml of H2O the layers were separated the aq. layer was extracted with 130 ml of DCM extracted with 3×150 ml of DCM dried (Na2SO4) concentrated

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

Procedure: Reaction was carried out in two separate batches, employing 3.85 g of methyl 3,3,3-trifluoro-2,2-dimethylpropanoate in each batch. To a stirred refluxing suspension of sodium hydride (1.41 g of a 60% dispersion in mineral oil, 35 mmol) in dry THF (30 mL) (under an argon atmosphere) was added a mixture of crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (3.85 g) and dry acetonitrile (1.85 mL, 35 mmol), dropwise over the course of 45 mins. The resulting pale yellow suspension was heated at 70° C. for a further 15 h. After cooling to rt, both reaction batches were combined whereupon the solvent was removed in vacuo. The resulting orange foam was redissolved in water (200 mL) and washed with diethyl ether (2×200 mL), to remove residual mineral oil. The aqueous layer was separated, acidified to pH 2 with aqueous 2N hydrochloric acid and extracted with diethyl ether (3×200 mL). The combined ether layers were dried over MgSO4, filtered, then concentrated under reduced pressure to afford 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (4.27 g, 37% from 3,3,3-trifluoro-2,2-dimethylpropionic acid) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.77 (s, 2H), 1.43 (s, 6H). Reaction separate batches To a stirred refluxing suspension of sodium hydride (1.41 g of a 60% dispersion in mineral oil, 35 mmol) in dry THF (30 mL) (under an argon atmosphere) was added dropwise over the course of 45 mins After cooling to rt both reaction batches was removed in vacuo The resulting orange foam was redissolved in water (200 mL) washed with diethyl ether (2×200 mL) to remove residual mineral oil The aqueous layer was separated extracted with diethyl ether (3×200 mL) The combined ether layers were dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: Reaction was carried out in two separate batches, employing 3.85 g of methyl 3,3,3-trifluoro-2,2-dimethylpropanoate in each batch. To a stirred refluxing suspension of sodium hydride (1.41 g of a 60% dispersion in mineral oil, 35 mmol) in dry THF (30 mL) (under an argon atmosphere) was added a mixture of crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (3.85 g) and dry acetonitrile (1.85 mL, 35 mmol), dropwise over the course of 45 mins. The resulting pale yellow suspension was heated at 70° C. for a further 15 h. After cooling to rt, both reaction batches were combined whereupon the solvent was removed in vacuo. The resulting orange foam was redissolved in water (200 mL) and washed with diethyl ether (2×200 mL), to remove residual mineral oil. The aqueous layer was separated, acidified to pH 2 with aqueous 2N hydrochloric acid and extracted with diethyl ether (3×200 mL). The combined ether layers were dried over MgSO4, filtered, then concentrated under reduced pressure to afford 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (4.27 g, 37% from 3,3,3-trifluoro-2,2-dimethylpropionic acid) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.77 (s, 2H), 1.43 (s, 6H). Reaction separate batches To a stirred refluxing suspension of sodium hydride (1.41 g of a 60% dispersion in mineral oil, 35 mmol) in dry THF (30 mL) (under an argon atmosphere) was added dropwise over the course of 45 mins After cooling to rt both reaction batches was removed in vacuo The resulting orange foam was redissolved in water (200 mL) washed with diethyl ether (2×200 mL) to remove residual mineral oil The aqueous layer was separated extracted with diethyl ether (3×200 mL) The combined ether layers were dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: Reaction was carried out in two separate batches, employing 5 g of 3,3,3-trifluoro-2,2-dimethylpropionic acid in each batch. To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (5 g, 32 mmol) in anhydrous dichloromethane (20 mL) at 0° C. (under an argon atmosphere), was added dropwise a solution of (trimethylsilyl)diazomethane (18 mL of a 2M solution in diethyl ether, 35 mmol) (gas evolution observed). The resulting yellow solution was allowed to warm to rt and stirred for a further 48 h. An additional 5 mL of 2M (trimethylsilyl)diazomethane solution (10 mmol) was added, and stirring continued for a further 5 h whereupon a further 6 mL of 2 M (trimethylsilyl)diazomethane solution (12 mmol) was added. After stirring for a further 15 h, the reaction mixture was concentrated in vacuo (keeping bath temperature below 30° C.). The resulting oil was redissolved in diethyl ether (200 mL), washed with saturated sodium hydrogencarbonate solution (100 mL), separated, and dried over MgSO4. Filtration followed by concentration in vacuo (keeping bath temperature below 30° C.) gave crude product. Crude product from both batches were combined to afford crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (7.69 g) as a yellow oil which was taken on without further purification. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 1.40 (s, 6H). Reaction separate batches stirring was added After stirring for a further 15 h the reaction mixture was concentrated in vacuo (keeping bath temperature below 30° C.) The resulting oil was redissolved in diethyl ether (200 mL) washed with saturated sodium hydrogencarbonate solution (100 mL) separated dried over MgSO4 Filtration followed by concentration in vacuo (keeping bath temperature below 30° C.) gave crude product

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

Procedure: Commercially available, 3,3,3-trifluoro-2,2-dimethylpropanoic acid (Matrix), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 212 (M+H)+.

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

Procedure: Commercially available, 3,3,3-trifluoro-2,2-dimethylpropanoic acid (Matrix), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 212 (M+H)+.