Structure of 444915-76-8
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| CAS No. : | 444915-76-8 |
| Formula : | C9H8F2O2 |
| M.W : | 186.16 |
| SMILES Code : | O=C(OC)C1=CC=C(C(F)F)C=C1 |
| English Name : | Methyl 4-(difluoromethyl)benzoate |
| MDL No. : | MFCD12922540 |
| InChI Key : | CTUNEFJJWFAGEP-UHFFFAOYSA-N |
| Pubchem ID : | 22262108 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With potassium fluoride; formic acid; tetramethylammonium fluoride; N,N`-sulfuryldiimidazole In N,N-dimethyl-formamide at 25℃; for 4h; Inert atmosphere; | |
| 96% | With diethylamino-sulfur trifluoride at 20℃; | 14.1 (1) A solution of methyl 4-formylbenzoate (j-1) (0.90 g, 5.5 mmol) in (diethylamino)sulfate trifluoride (DAST) (3.6 mL, 27 mmol) was stirred overnight at room temperature. The reaction mixture was cooled to 0° C. and water was added dropwise. Extraction was conducted with ethyl acetate and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvents in the organic layer were distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give methyl 4-(difluoromethyl)benzoate (j-2) (amount, 0.98 g; yield, 96%). |
| 96% | With diethylamino-sulfur trifluoride at 20℃; | 14.1 A solution of methyl 4-formylbenzoate (j-1) (0.90 g, 5.5 mmol) in (diethylamino)sulfate trifluoride (DAST) (3.6 mL, 27 mmol) was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and water was added dropwise. Extraction was conducted with ethyl acetate and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvents in the organic layer were distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to give methyl 4-(difluoromethyl)benzoate (j-2) (amount, 0.98 g; yield, 96%). |
| 89% | With diethylamino-sulfur trifluoride at 23℃; for 24h; | |
| 85% | With triethylamine tris(hydrogen fluoride); N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine at 180℃; for 0.333333h; microwave irradiation; | |
| 84% | With diethylamino-sulfur trifluoride at 23℃; for 24h; Inert atmosphere; | |
| 82% | With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane for 16h; | 47 Methyl 4-(difluoromethyl)benzoate Dissolve p-carbomethoxybenzaldehyde (3.103 g, 18.713 mmol) in DCM (50 mL). Add bis(2-methoxyethyl)aminosulfur trifluoride (9.079 mL, 46.783 mmol), and stir 16 hours. Slowly pour the reaction mixture into a saturated aqueous NaHCO3 aqueous solution (300 mL). Stir until gas evolution is complete (about 2 hours). Extract with DCM (2*100 mL). Dry the organic extracts over Na2SO4; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify by silica gel chromatography (Analogix 80 g 55 mL/min) eluting with a gradient of hexanes to 20% ethyl acetate/hexanes over 30 minutes to give the title compound as a white solid (2.863 g, 82% yield). 1H NMR (400.15 MHz, d6-DMSO) δ 8.08-8.06 (m, 2H), 7.70 (ddd, J=8.7, 1.1, 0.6 Hz, 2H), 7.26-6.98 (t, J=55.2 Hz, 1H), 3.86 (s, 3H). |
| 81% | With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃; | 1.11.1 Step 1: methyl 4-(difluoromethyl)benzoate Step 1: methyl 4-(difluoromethyl)benzoate [0217] To a stirred solution of methyl 4-formylbenzoate (10.0 g, 61 mmol) in DCM (300 mL) was added DAST (16 mL, 121 mmol) dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature and quenched by addition of saturated sodium bicarbonate solution. The mixture was extracted with DCM. The combined organic phases were washed with water, brine, dried over Na2S04 and concentrated. The concentrate was purified by column chromatography over silica gel (eluent: hexane/EtOAc = 10:1) to afford the title compound as a yellow powder (9.26 g, 81%). 1H NMR (400 MHz, CDCI3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 56.4 Hz, 1H), 3.95 (s, 3H). |
| 79% | With diethylamino-sulfur trifluoride In ethanol; dichloromethane at 20℃; | General Procedure I (Synthesis of difluoromethylarenes from arene carbaldehydes) General procedure: To a flame dried flask containing a solution of aryl aldehyde (1.0 eq.) in DCM (1.0 M) at room temperature was added EtOH (5-100 μL) and DAST (1.7 eq.). The reaction was stirred over night at room temperature before it was quenched with aq. NaHCO3 (sat.) and extracted with DCM. The combined organic fractions were washed with brine, dried over MgSO4, evaporated to dryness and loaded onto a silica gel column for purification. |
| 69% | With diethylamino-sulfur trifluoride at 20℃; Inert atmosphere; | 34.A [00226] Step A: A mixture of methyl 4-formylbenzoate (1.4 g, 8.5 mmol) and DAST (6 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM, the organic layer was concentrated. The residue was purified by column to give methyl 4-(difluoromethyl)benzoate (1.1 g, 69.0% yield). 1H NMR (CDC13, 400 MHz) δ 8.13- 8.11 (m, 2H), 7.59-7.57 (m, 2H), 6.82 (t, J = 56 Hz, 1H), 3.94 (s, 3H). |
| With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃; for 24h; | 5a Example 5a Preparation of methyl 4-(difluoromethyl)benzoate To a cooled (0 °C) solution of methyl 4-formylbenzoate (9.0 g, 55 mmol) in CH2CI2 (250 mL) was added DAST (11 mL, 84 mmol) dropwise. After stirring for 2 hrs, the cooling bath was removed and the reaction mixture was allowed to warm to rt. After 6 hrs at rt, the reaction was incomplete as judged by GC/MS analysis. The reaction mixture was treated with additional DAST (4.4 mL, 33 mmol). After stirring for 16 hrs at rt, the reaction was quenched by pouring the mixture onto ice. The aqueous layer was made basic by careful addition of solid Na2C03, with vigorous stirring.. The layers were separated and the basic aqueous solution was further extracted with CH2CI2 (3 x) The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound as a brown solid. The material was carried on to the next step without further purification. 1H NMR (400 MHz, CDCI3) δ ppm 8.13 (d, J= 8.0 Hz, 2H), 7.59 (d, J= 8.2 Hz, 2H), 6.69 (t, J(H_F) = 56.1 Hz, 1H), 3.95 (s, 3H). | |
| 619 mg | With diethylamino-sulfur trifluoride In toluene at 10 - 35℃; for 20h; | 85.A A) methyl 4-(difluoromethyl)benzoate A) methyl 4-(difluoromethyl)benzoate To a solution of methyl 4-formylbenzoate (821 mg) in toluene (25 mL) was added N,N-diethylaminosulfur trifluoride (1.98 mL). The reaction mixture was stirred at room temperature for 20 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (619 mg). 1H NMR (300 MHz, CDCl3) δ 3.95 (3H, s), 6.46-6.92 (1H, m), 7.59 (2H, d, J = 8.3 Hz), 8.13 (2H, d, J = 8.7 Hz). |
| Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / 3 h / 20 °C / Inert atmosphere 2: 4-(difluoroiodo)toluene; titanium(III) fluoride / dichloromethane / Inert atmosphere; Reflux | ||
| With diethylamino-sulfur trifluoride In dichloromethane at 0 - 40℃; for 4h; | 3B.3.1 Step 1: methyl 4-(difluorometh l)benzoate To a solution of methyl 4-formylbenzoate (79.50 g, 0.48 mol) in DCM (800 mL) was added diethylaminosulfur trifluoride (96 mL, 0.73 mol) dropwise at 0-5 °C. The reaction mixture was then allowed to warm to 40 °C and stirred at 40 °C for 4 hours. The mixture was poured into ice-water and diluted with ethyl acetate. The organic layer was washed with saturated NaHC03, brine, dried over Na2S04and concentrated under reduced pressure to afford the crude title compound as an off-white solid (98.00 g). The crude product was used in the next step without further purification. | |
| With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 12h; | ||
| With diethylamino-sulfur trifluoride In ethanol; dichloromethane at 80℃; for 12h; Inert atmosphere; | ||
| With (bis-(2-methoxyethyl)amino)sulfur trufluoride In ethanol; dichloromethane at 20 - 65℃; for 24h; Inert atmosphere; Schlenk technique; | ||
| 84 % | With triethylamine tris(hydrogen fluoride); xtalfluor-E In neat (no solvent) at 20℃; Inert atmosphere; | |
| 82 % | With diethylamino-sulfur trifluoride In dichloromethane at 80℃; Sealed tube; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With hydrogenchloride In water for 24h; Heating / reflux; | G.38A A solution of 4-(difluoromethyl)benzoic acid (5.47 g, 31.8 mmol) in MeOH (100 mL) was treated with concentrated aq HCl (0.5 mL, 6.0 mmol), and the reaction mixture was heated to reflux. After 24 hr the solution was cooled to ambient temperature and concentrated in vacuo. The residue was taken up in Et2O and washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated in vacuo. The result was 5.82 g (98%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.06 (m, 2H), 7.76-7.69 (m, 2H), 7.14 (t, J=55.5, 1H), 3.89 (s, 3H). |
| 92% | With thionyl chloride at 0 - 50℃; for 2h; | 29 Preparation of 2: General procedure: To a solution of 4-(trifluoromethoxy)benzoic acid (3.00 g, 14.6 mmol, 1.00 eq)in methanol (30.0 mL)was added thionyl chloride (2.60 g, 21.8 mmol, 1.58 mL, 1.50 eq)at 0 °C. The mixture was stirred at 60 °C for 3 h. The mixture was concentrated under reduced pressure to give methyl 4-(trifluoromethoxy)benzoate (2.6 g, crude)as a white solid. |
| With thionyl chloride at 0℃; for 2h; Reflux; | 1 Thionyl chloride (0.83 ml_, 7.26 mmol, 5.0 equiv.), was added dropwise to a solution of 4-(difluoromethyl)benzoic acid (250 mg, 1.45 mmol, 1.0 equiv.) in methanol (8 ml.) at 0 °C (external). The reaction mixture was heated to reflux for 2 hours, cooled to room temperature and concentrated under reduced pressure. The crude residue was then passed through a short pad of silica (0-20% ethyl acetate in cyclohexane) to provide crude methyl 4-(difluoromethyl)benzoate, which was used without further purification. |
| With thionyl chloride at 0℃; for 2h; Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With lithium borohydride In tetrahydrofuran at 0 - 60℃; for 4h; | 3B.3.2 Step 2: (4-(difluoromethyl)phenyl)methanol To a stirred suspension of lithium borohydride (21.10 g, 0.97 mol) in THF (900 mL) was added methyl 4-(difluoromethyl)benzoate (98.00 g, 0.48 mol) in THF (200 mL) dropwise at 0-5 °C. The reaction mixture was then warmed to 60 °C and stirred at 60 °C for 4 hours. After the reaction was completed, the mixture was quenched with 2 M aqueous HC1 and diluted with ethyl acetate. The organic layer was washed with saturated NaHC03, brine, dried over Na2S04, and concentrated under reduced pressure to afford the crude product, which was purified by distillation under reduced pressure pump to afford the title compound as a colorless oil (65.50 g, 85%). 1H MR (400 MHz, CDC13) δ 7.51 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.65 (t, J = 56.4 Hz, 1H), 4.76 (d, J = 5.2 Hz, 2H), 1.74 (t, J = 5.8 Hz, 1H) |
| 81% | Stage #1: methyl 4-(difluoromethyl)benzoate With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1h; Stage #2: With water; sodium sulfate In tetrahydrofuran at 0 - 20℃; for 0.5h; | G.38B A solution of LAH (1.0 M in THF, 31 mL, 31 mmol) was added dropwise to a solution of Example 38A (5.82 g, 31.3 mmol) in THF (100 mL) at 0° C. The reaction was stirred for 1 hr, then quenched by careful addition of solid Na2SO4.10H2O. The mixture was warmed to ambient temperature and stirred 30 min. Celite filter aid was added and the mixture was filtered. The filtrate was concentrated in vacuo to yield 4.02 g (81%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.52 (d, J=8.2, 2H), 7.48-7.41 (m, 2H), 7.00 (t, J=56.0, 1H), 5.30 (t, J=5.7, 1H), 4.55 (d, J=5.4, 2H). |
| 77% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | 1.11.2 Step 2. (4-(difluoromethyl)phenyl)methanol Step 2. (4-(difluoromethyl)phenyl)methanol [0218] A solution of methyl 4-(difluoromethyl)benzoate (1.00 g, 5.37 mmol) in THF (dried) was added dropwise to a stirred suspension of LiAIH4 in dry THF (25 mL) at 0 °C under N2 atmosphere. The reaction mixture was stirred for 1 h, then quenched by addition of Na2SO4.10H2O under ice-water bath cooling. The mixture was stirred at rt for 30 min and filtered through celite. The filter mass was washed with EtOAc. The combined organic phases were dried over Na2S04, and concentrated in vacuo to afford the title compound as a white solid (650 mg, 77%). 1H NM (400 MHz, CDCI3) δ 7.51 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 56.4 Hz, 1H), 4.75 (d, J = 6.0 Hz, 2H), 1.78 (t, J=6.0 hz, 1H). |
| 70% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; | 14.2 (2) A solution of the foregoing compound (j-2) (1.0 g, 5.4 mmol) in THF (27 mL) was cooled to 0° C. To the cooled solution, lithium aluminum hydride (0.20 g, 5.4 mmol) was added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, anhydrous sodium sulfate was added, followed by filtration through Celite. The solvent in the filtrate was distilled off under reduced pressure to give [4-(difluoromethyl)phenyl]methanol (j-3) (amount, 0.60 g; yield, 70%). |
| 70% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; | 14.2 A solution of the foregoing compound (j-2) (1.0 g, 5.4 mmol) in THF (27 mL) was cooled to 0°C. To the cooled solution, lithium aluminum hydride (0.20 g, 5.4 mmol) was added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, anhydrous sodium sulfate was added, followed by filtration through Celite. The solvent in the filtrate was distilled off under reduced pressure to give [4-(difluoromethyl)phenyl]methanol (j-3) (amount, 0.60 g; yield, 70%). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1: potassium trimethylsilonate / diethyl ether / 12 h / 23 °C / Inert atmosphere 2: thionyl chloride / 1,2-dichloro-ethane; N,N-dimethyl-formamide / 0 - 100 °C / Inert atmosphere 3: sodium azide / water; acetone / 1 h / 0 °C / Inert atmosphere 4: toluene / 1 h / 100 °C / Inert atmosphere 5: toluene / 3 h / 100 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1: potassium trimethylsilonate / diethyl ether / 12 h / 23 °C / Inert atmosphere 2: thionyl chloride / 1,2-dichloro-ethane; N,N-dimethyl-formamide / 0 - 100 °C / Inert atmosphere 3: sodium azide / water; acetone / 1 h / 0 °C / Inert atmosphere 4: toluene / 1 h / 100 °C / Inert atmosphere 5: toluene / 3 h / 95 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With potassium trimethylsilonate In diethyl ether at 23℃; for 12h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: potassium trimethylsilonate / diethyl ether / 12 h / 23 °C / Inert atmosphere 2: thionyl chloride / 1,2-dichloro-ethane; N,N-dimethyl-formamide / 0 - 100 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 0 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: potassium trimethylsilonate / diethyl ether / 12 h / 23 °C / Inert atmosphere 2: thionyl chloride / 1,2-dichloro-ethane; N,N-dimethyl-formamide / 0 - 100 °C / Inert atmosphere 3: sodium azide / water; acetone / 1 h / 0 °C / Inert atmosphere | ||
| Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 0 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C 3: sodium azide / water; acetone / 0 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1: potassium trimethylsilonate / diethyl ether / 12 h / 23 °C / Inert atmosphere 2: thionyl chloride / 1,2-dichloro-ethane; N,N-dimethyl-formamide / 0 - 100 °C / Inert atmosphere 3: sodium azide / water; acetone / 1 h / 0 °C / Inert atmosphere 4: toluene / 1 h / 100 °C / Inert atmosphere 5: toluene / 3 h / 95 °C / Inert atmosphere 6: pyridine; trifuran-2-yl-phosphane; water / methanol / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1: potassium trimethylsilonate / diethyl ether / 12 h / 23 °C / Inert atmosphere 2: thionyl chloride / 1,2-dichloro-ethane; N,N-dimethyl-formamide / 0 - 100 °C / Inert atmosphere 3: sodium azide / water; acetone / 1 h / 0 °C / Inert atmosphere 4: toluene / 1 h / 100 °C / Inert atmosphere 5: toluene / 1 h / 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: potassium trimethylsilonate / diethyl ether / 12 h / 23 °C / Inert atmosphere 2: thionyl chloride / 1,2-dichloro-ethane; N,N-dimethyl-formamide / 0 - 100 °C / Inert atmosphere 3: sodium azide / water; acetone / 1 h / 0 °C / Inert atmosphere 4: toluene / 1 h / 100 °C / Inert atmosphere | ||
| Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 0 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C 3: sodium azide / water; acetone / 0 °C 4: toluene / 1.5 h / 110 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 0 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C 3: sodium azide / water; acetone / 0 °C 4: toluene / 1.5 h / 110 °C 5: dichloromethane; toluene / 20 - 80 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 0 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C 3: sodium azide / water; acetone / 0 °C 4: toluene / 1.5 h / 110 °C 5: dichloromethane; toluene / 20 - 80 °C 6: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 0 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; | 34.B [00227] Step B: A mixture of methyl 4-(difluoromethyl)benzoate (1.1 g, 5.9 mmol) and LiOH H20 (1.24 g, 29.5 mmol) in THF/H20 (30/10 mL) was stirred at room temperature for 3 hours. The mixture was acidified by IN HC1 to a pH of 2 and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated to give 4-(difluoromethyl)benzoic acid (1.0 g, 98.0% yield). |
| 96% | Stage #1: methyl 4-(difluoromethyl)benzoate With potassium hydroxide In methanol for 16h; Stage #2: With hydrogenchloride In water; ethyl acetate for 0.5h; | 48 4-(Difluoromethyl)benzoic acid Dissolve methyl 4-(difluoromethyl)benzoate (2.855 g, 15.336 mmol) in MeOH (30 mL). Add potassium hydroxide (8.41 mL 2 equivalents, 30.7 mmol), and stir the mixture for 16 hours. Concentrate the reaction mixture under reduced pressure, and add EtOAc (100 mL) and 1 N HCl (50 mL). Stir for 30 minutes. Separate the layers. Dry the organics over Na2SO4; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the titled compound as a white solid (2.541 g, 96% yield). 1H NMR (399.83 MHz, d6-DMSO) δ 13.29-13.28 (m, 1H), 8.04 (d, J=7.8 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.24-6.97 (t, J=55.6, 1H). |
| 68% | With lithium hydroxide monohydrate In tetrahydrofuran; methanol at 0℃; |
| With water; sodium hydroxide In tetrahydrofuran at 10 - 35℃; for 3h; | 85.B B) B) 4-(difluoromethyl)-N-methoxy-N-methylbenzamide To a solution of methyl 4-(difluoromethyl)benzoate (615 mg) in a mixed solvent of tetrahydrofuran (15 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the obtained residue, N,O-dimethylhydroxylamine hydrochloride (387 mg), triethylamine (0.921 mL), 1-hydroxybenzotriazole monohydrate (607 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (760 mg) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (540 mg). 1H NMR (300 MHz, CDCl3) δ 3.38 (3H, s), 3.54 (3H, s), 6.47-6.89 (1H, m), 7.56 (2H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.7 Hz). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With BrF3*K(1+)*F2H(1-) In dichloromethane at 20℃; for 0.25h; | 4.3. Desulfurizing difluorination of benzylic sulfides 1 with BrF3-KHF24.3.1. 2,2-Difluoro-1,2-diphenylethanone (2a) General procedure: To a suspension of BrF3-KHF2 (129 mg) in CH2Cl2 (2.4 mL) inTeflonTM bottle, 1a (101 mg, 0.3 mmol) in CH2Cl2 (1.0 mL) wasadded at room temperature, and the mixture was stirred at roomtemperature for 15 min. Then, H2O (5 mL) was added to thereaction mixture and the resulting product was extracted withCH2Cl2 (5 mL X 3). The combined organic layer was washed withsaturated aqueous NaHCO3 (5 mL) and saturated aqueous Na2S2O3(5 mL), and dried over MgSO4. After concentration under reducedpressure, 2a was isolated by column chromatography (silica gel,hexane-ether) in 89% yield. IR (neat) 1703 (C55O), 1450, 1256, 1135 cm1; 1H NMR (400 MHz, CDCl3) d 7.43-7.61 (m, 8H), 8.02-8.04 (m, 2H); 19F NMR (376 MHz, CDCl3) d 98.12 (s, 2F); 13C NMR(100 MHz, CDCl3) d 188.9 (t, 2JC-F = 30.7 Hz), 134.2, 133.1 (t, 2JCF= 24.9 Hz), 132.1, 130.9, 130.3 (t, 4JC-F = 2.9 Hz, 2C), 128.8 (2C),128.6 (2C), 125.6 (t, 3JC-F = 5.8 Hz, 2C), 116.9 (t, 1JC-F = 253.9 Hz);HRMS (EI) calcd for C14H10F2O 232.0700, found 232.0683. |
| 91% | With BrF3*2FH*F2K2 In dichloromethane at 20℃; for 0.25h; | 17 Example 16 to 18 Desulfurization-Fluorination Reaction The BrF3-2KHF2 complex (193 mg, 0.66 mmol) obtained in Example 1 and CH2Cl2 (2.4 mL) were placed in a Teflon (registered trademark) container. Then, compound 1a (100 mg, 0.3 mmol) shown in Table 1 below was added thereto at room temperature and stirred for 1 hour while the temperature was maintained. After the completion of the reaction, the resulting product was quenched with the addition of water, and after separation, the washing was performed with a saturated aqueous NaHCO3 solution and a saturated aqueous Na2S2O3 solution. The organic layer was dried over MgSO4 and concentrated, followed by purification by silica column chromatography. In this manner, compound 2a (57 mg, 84%) shown in Table 1 below was obtained.The desulfurization fluorination reaction was performed as in Example 3, except that compounds 1o to 1q shown in Table 9 below were used as the starting material in place of compound 1a used in Example 3, and that the molar ratio of the fluorinating agent to the starting material, the reaction temperature, and the reaction time were changed to the values shown in Table 9. Table 9 shows the resulting products and their yields. |
| 75% | With iodine pentafluoride-pyridine-hydrogen fluoride In dichloromethane at 20℃; for 24h; | 3 Desulfurizing-fluorination of dithioacetal with IF5-pyridine-HF General procedure: To a CH2Cl2 solution (1.0 mL) of naphthaldehyde diphenyl dithioacetal (19) (179 mg, 0.5 mmol) was added at room temperature IF5-pyridine-HF (321 mg, 1 mmol) and the mixture was stirred at room temperature for 24 h. The resulting dark red solution was poured into water (20 mL) and extracted with ether (20 mL*3). The combined organic layer was washed with aq NaHCO3 and aq Na2S2O3, and dried over MgSO4. After concentration under reduced pressure, 20 was isolated by column chromatography (silica gel/hexane/CH2Cl2) in 74% yield |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With potassium fluoride; copper(l) iodide In N,N-dimethyl acetamide at 100℃; for 24h; Inert atmosphere; Glovebox; Darkness; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate; water / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0 - 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate; water / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0 - 20 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / methanol / 1.5 h / Reflux; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | Stage #1: 4-methoxycarbonyl aniline With tetrafluoroboric acid; tert.-butylnitrite In ethanol; water at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: difluoromethyl copper In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere; |