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CAS No. : | 205865-67-4 | MDL No. : | MFCD04973092 |
Formula : | C7H14F2O2Si | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DYAKYYSMROBYNG-UHFFFAOYSA-N |
M.W : | 196.27 | Pubchem ID : | 2758940 |
Synonyms : |
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Signal Word: | Danger | Class: | 3,8 |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | 2924 |
Hazard Statements: | H225-H315-H318-H335 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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 |
---|---|---|
62% | Stage #1: chloro-trimethyl-silane With magnesium; copper(l) chloride; lithium chloride In N,N-dimethylimidazolidinone at 25℃; for 0.25h; Inert atmosphere; Stage #2: ethyl trifluoroacetate, In N,N-dimethylimidazolidinone at 25℃; for 4h; Inert atmosphere; Stage #3: With hydrogenchloride In ethanol at 25℃; for 1.5h; Inert atmosphere; | 4.2.1. Synthesis of ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (2a) Mg powder (0.486 g, 20 mmol), copper(I) chloride (0.248 g, 2.5 mmol), and lithium chloride (1.7 g, 40 mmol) were stirred in DMI (10.0 ml) and TMS-Cl (5.0 ml, 40 mmol) for 15 min under an argon atmosphere at room temperature. Ethyl trifluoroacetate (5 mmol, 0.71 g) was added dropwise into the stirred suspension. The suspension was stirred for additional 4 h at room temperature. After removal of Mg-Cu by decantation, the DMI solution was extracted with Et2O. The Et2O layer was washed with 10% HCl aq and brine, dried over MgSO4. Then, solvent was removed under a reduced pressure. The mixture of difluoro-compound 2a and silyl ketal 3a was obtained. Procedure for removal of 3a from the mixture of 2a and 3a. Anhydrous HCl/EtOH was prepared from TMS-Cl (3.0 ml, 25 mmol) and ethanol (2 ml, 34 mmol). The prepared anhydrous HCl/EtOH was added dropwise into the mixture of difluoro-compound 2a and silyl ketal 3a. After stirring 90 min at room temperature, the solution was extracted with ether (5 ml×4). The combined organic layer was washed with brine. Organic layer was dried over MgSO4, then, was concentrated under a reduced pressure. Kugelrohr distillation (100 °C/32 mmHg, bath temperature) of the crude product gave ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (2a) in 62% (0.602 g) of isolated yield. Colorless oil. Bp=70 °C/20 mmHg (bath temperature). IR νmax (neat) 2980, 1760 cm-1. 1H NMR (400 MHz, CDCl3) δ 0.23 (s, 9H), 1.34 (t, J=7 Hz, 3H), 4.31 (q, J=7 Hz, 2H) ppm. [δ 0.16 (s, 9H), 1.27 (t, J=7 Hz, 3H), 4.24 (q, J=7 Hz 2H) ppm. (Ref. 2c)] 13C NMR (100 MHz, CDCl3) δ -5.2 (s), 13.9 (s), 62.2 (s), 121.0 (t, J=268 Hz), 166.3 (t, J=26 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ 38.4 (s, 2F) ppm. [δ 38.7 (s, 2F) ppm. (Ref. 2c)] EI-MS m/z (% relative intensity) 181 ([M]+-CH3, 1), 153 (4), 117 (5), 73 (100). |
47% | With tetrabutylammomium bromide; triethylamine In acetonitrile at 50℃; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 56% 2: 11 % Chromat. | With tetrabutylammomium bromide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide at -25℃; Electrochemical reaction; | |
1: 69 %Spectr. 2: 22 %Spectr. | Stage #1: chloro-trimethyl-silane With magnesium; copper(l) chloride; lithium chloride In N,N-dimethylimidazolidinone at 25℃; for 0.25h; Inert atmosphere; Stage #2: ethyl trifluoroacetate, In N,N-dimethylimidazolidinone at 25℃; for 4h; Inert atmosphere; | 4.2.1. Synthesis of ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (2a) Mg powder (0.486 g, 20 mmol), copper(I) chloride (0.248 g, 2.5 mmol), and lithium chloride (1.7 g, 40 mmol) were stirred in DMI (10.0 ml) and TMS-Cl (5.0 ml, 40 mmol) for 15 min under an argon atmosphere at room temperature. Ethyl trifluoroacetate (5 mmol, 0.71 g) was added dropwise into the stirred suspension. The suspension was stirred for additional 4 h at room temperature. After removal of Mg-Cu by decantation, the DMI solution was extracted with Et2O. The Et2O layer was washed with 10% HCl aq and brine, dried over MgSO4. Then, solvent was removed under a reduced pressure. The mixture of difluoro-compound 2a and silyl ketal 3a was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | |
29% | With potassium fluoride In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 3 Example 3Production of aromatic difluoroacetic acid ester According to the above-described scheme, 4-iodonitrobenzene (Compound 1b; 74.7 mg, 0.3 mmol), difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a; 70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) were put into a two-neck reaction tube, and the mixture was stirred under nitrogen atmosphere at 60° C. for 15 hours. After the reaction, when trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added thereto as an internal reference to conduct 19F NMR measurement, it was found that 2,2-difluoro-2-(4-nitrophenyl)acetic acid ethyl ester (Compound 2b) as a target product was produced with a yield of 41%. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2,2-difluoro-2-(4-nitrophenyl)acetic acid ethyl ester (Compound 2b) was obtained with a yield of 29%.The results of instrumental analysis of the product (Compound 2b) are shown below:1H-NMR (CDCl3, TMS) δ8.33 (2H, d, J=9.0 Hz), 7.82 (2H, d, J=9.0 Hz), 4.33 (2H, q, J=7.0 Hz), 1.32 (1H, t, J=7.0 Hz) 19F-NMR (CDCl3, C6F6) δ57.2 (2F, s) Mass m/e: (m/z) (%) 172 (100), 156 (16), 142 (16), 126 (42), 107 (5), 75 (4) |
29% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 2 Preparation of aromatic difluoroacetic acid ester Accordance with the above scheme, the 2-neck reaction tube 4-iodo-nitrobenzene (Compound 1b; 74.7 mg, 0.3mmol), difluoromethyltrimethylsilanyl ethyl ester (compound 3a; 70.7 mg, 0.36mmol), copper iodide (I) (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol), placed in DMSO (0.6 mL), under a nitrogen atmosphere and stirred for 15 hours at 60 °C. After the reaction, trifluoroethanol (30.0 mg, 21.9μL, 0.3 mmol) was added as an internal standard, the target compound was determined by 19 F NMR 2,2-difluoro-2-(4-nitrophenyl)ethyl acetate ester it was found that produced in 41% yield. The reaction mixture was extracted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure and purified by silica gel column chromatography to obtain 2,2-difluoro-2-(4-nitrophenyl)acetic acid ethyl ester (Compound 2b) in 29% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | |
75% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; Schlenk technique; | 6 <Preparation of Heteroaryldifluoroacetic Acid Ester Compound> 2,2-Difluoro-2- (quinolin-2-yl) acetic acid ethyl ester (Compound 3e) was prepared according to the following procedure.2-Iodoquinoline (76.5 mg, 0.3 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) are placed in a Schlenk tube. Finally, α- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (70.7 mg, 0.36 mmol) was added and stirred under a nitrogen atmosphere at 60 ° C. for 15 hours. After the reaction, trifluoroethanol (30.0 mg, 0.3 mmol) was added as an internal standard and measurement by 19 F-NMR revealed that 2,2-difluoro-2- (quinolin-2-yl) acetic acid ethyl ester 3e) was produced in a yield of 88%. The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (Hexane: EtOAc = 50: 1) gave 2,2-difluoro-2- (quinolin-2-yl) acetic acid ethyl ester (Compound 3e) (56.8 mg, 0.23 mmol, Yield: 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With magnesium; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Inert atmosphere; | According to the following procedure, alpha- (trimethylsilyl) difluoroacetic acid ethyl ester (also referred to as difluorotrimethylsilanylacetic acid ethyl ester) (compound 2a) was prepared. Under a nitrogen atmosphere in a two-neck reaction tube,Magnesium (972.4 mg, 40.0 mmol), chlorotrimethylsilane (8.691 g, 80.0 mmol) and DMF (60 mL) were injected.Ethyl chlorodifluoroacetate (793 mg, 20.0 mmol) was added thereto,And the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with diethyl ether,After washing with water, DMF was completely removed,The organic layer was dried over anhydrous sodium sulfate.Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by Kugel distillation (91 mmHg, 110 C.) to obtain alpha- (trimethylsilyl) difluoroacetic acid ethyl ester (Me 3 Si - CF 2 CO 2 Et; Compound 2a) (2.729 g, yield: 70%). |
43% | With magnesium; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Inert atmosphere; | Example 1Production of alpha-silyl difluoroacetic acid ester (1) According to the above-described scheme, magnesium (243 mg, 10.0 mmol), chlorotrimethylsilane (Me3SiCl; 2.17 g, 20.0 mmol) and DMF (15 mL) were put into a two-neck reaction tube under nitrogen atmosphere. Ethyl chlorodifluoroacetate (Compound 3; 793 mg, 624 muL, 5.0 mmol) was added thereto with the reaction container being cooled in water bath, and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with diethyl ether and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Diethyl ether was distilled away under reduced pressure, and by carrying out the production by silica gel column chromatography, difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a) was obtained with a yield of 43%.Note that in other working examples, as difluorotrimethylsilanylacetic acid ethyl ester (Me3Si-CF2CO2Et; Compound 3a), the product obtained in this working example was used.The results of instrumental analysis of the product (Compound 3a) are shown below:1H-NMR (CDCl3, TMS) delta4.32 (2H, q, J=7.0 Hz), 1.35 (3H, t, J=7.0 Hz), 0.237 (9H, s) 19F-NMR (CDCl3, C6F6) delta38.5 (2F, s) Mass m/e: (m/z) (%) 181 (6), 153 (10), 125 (6), 103 (8), 77 (26), 73 (100) |
43% | With magnesium; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Inert atmosphere; Cooling with ice; | In accordance with the above scheme, magnesium (243 mg, 10.0 mmol), chlorotrimethylsilane (Me 3 SiCl; 2.17 g, 20.0 mmol) and DMF (15 mL) are placed in a two-neck reaction tube under a nitrogen atmosphere. While cooling the reaction vessel with a water bath, <strong>[383-62-0]ethyl chlorodifluoroacetate</strong> (Compound 3; 793 mg, 624 muL, 5.0 mmol) was added, followed by stirring at room temperature for 1.5 hours. The reaction mixture was extracted with diethyl ether, washed with water, and the organic layer was dried over anhydrous sodium sulfate. Distilling off diethyl ether under reduced pressure and purifying by silica gel column chromatography yielded ethyl difluorotrimethylsilanylacetate in a yield of 43% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | |
40% | With potassium fluoride In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 1 Comparative Example 1 Production of aromatic difluoroacetic acid ester According to the above-described scheme, 4-iodobenzene (Compound 1h; 61.2 mg, 33.4 μL, 0.3 mmol), difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a; 70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) were put into a two-neck reaction tube, and the mixture was stirred under nitrogen atmosphere at 60° C. for 15 hours. After the reaction, when the mixture was analyzed by GC-Mass, it was found that 2-(phenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2h) as a target product was produced with a conversion rate of 76%. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(phenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2h) was obtained with a yield of 40%.The results of instrumental analysis of the product (Compound 2h) are shown below:1H-NMR (CDCl3, TMS) δ7.61 (2H, d, J=9.2 Hz) 7.44-7.52 (3H, m), 4.30 (2H, q, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz) 19F-NMR (CDCl3, C6F6) δ57.8 (2F, s) Mass m/e: (m/z) (%) 200 (M+, 8), 127 (100), 77 (6) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | |
54% | With potassium fluoride In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 7 Example 7Production of aromatic difluoroacetic acid ester According to the above-described scheme, 4-bromoiodobenzene (Compound 1f; 84.9 mg, 0.3 mmol), difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a; 70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) were put into a two-neck reaction tube, and the mixture was stirred under nitrogen atmosphere at 60° C. for 15 hours. After the reaction, when trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added thereto as an internal reference to conduct 19F NMR measurement, it was found that 2-(4-bromophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2f) as a target product was produced with a yield of 76%. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-bromophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2f) was obtained with a yield of 54%.The results of instrumental analysis of the product (Compound 2f) are shown below:1H-NMR (CDCl3, TMS) δ7.60 (2H, d, J=8.6 Hz), 7.48 (2H, d, J=8.6 Hz), 4.30 (2H, q, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz) 19F-NMR (CDCl3, C6F6) δ57.6 (2F, s) Mass m/e: (m/z) (%) 280 (M+2, 12), 278 (M+, 12), 207 (94), 205 (100), 126 (32), 75 (8) |
54% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 6 Preparation of aromatic difluoroacetic acid ester According to the above scheme, 4-bromoiodobenzene (Compound 1f; 84.9 mg, 0.3 mmol), difluorotrimethylsilanylacetate ethyl ester (70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL), and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere. After the reaction, trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added as an internal standard and measurement by 19 F NMR revealed that 2- (4-bromophenyl) -2,2-difluoroacetic acid ethyl ester It was found that it was produced in a yield of 76%. The reaction mixture was extracted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure and purified by silica gel column chromatography to obtain 2-(4-bromophenyl)-2,2-difluoroacetic acid ethyl ester (compound 2f) in 54% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | |
71% | With potassium fluoride In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 1 Production of aromatic difluoroacetic acid ester According to the above-described scheme, 4-iodobenzonitrile (Compound 1a; 68.7 mg, 0.3 mmol), difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a; 70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) were put into a two-neck reaction tube, and the mixture was stirred under nitrogen atmosphere at 60° C. for 15 hours. After the reaction, when trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added thereto as an internal reference to conduct 19F NMR measurement, it was found that 2-(4-cyanophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2a) as a target product was produced with a yield of 88%. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-cyanophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2a) was obtained with a yield of 71%.The results of instrumental analysis of the product (Compound 2a) are shown below:1H-NMR (CDCl3, TMS) δ7.78 (2H, d, J=8.8 Hz), 7.74 (2H, d, J=8.8 Hz), 4.34 (2H, q, J=7.0 Hz), 1.31 (3H, t, J=7.0 Hz) 19F-NMR (CDCl3, C6F6) δ56.8 (2F, s) Mass m/e: (m/z) (%) 225 (M+, 2), 181 (2), 152 (100), 126 (4), 102 (8), 75 (4) |
71% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 1 Preparation of aromatic difluoroacetic acid ester Accordance with the above scheme, the 2-neck reaction tube 4-iodo-benzonitrile (compound 1a; 68.7 mg, 0.3mmol), difluoromethyl trimethylsilanyl ethyl ester (compound 3a; 70.7 mg, 0.36mmol), copper iodide (I) ( 57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol), placed in DMSO (0.6 mL), under a nitrogen atmosphere and stirred for 15 hours at 60 ° C. After the reaction, trifluoroethanol (30.0 mg, 21.9μL, 0.3 mmol) was added as an internal standard, the target compound was determined by 19 F NMR 2-(4-cyanophenyl)-2,2-difluoroacetic acid ethyl ester ( compound 2a) was found to be produced in a yield of 88%. The reaction mixture was extracted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure and purified by silica gel column chromatography, 2- (4-cyanophenyl) -2,2-difluoro-acetic acid ethyl ester (Compound 2a) was obtained in 71% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium fluoride;copper(l) iodide; In dimethyl sulfoxide; at 60℃; for 15h;Inert atmosphere; | Comparative Example 2 Production of aromatic difluoroacetic acid ester According to the above-described scheme, 4-iodophenetole (Compound 1i; 74.7 mg, 0.3 mmol), difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a; 70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) were put into a two-neck reaction tube, and the mixture was stirred under nitrogen atmosphere at 60 C. for 15 hours. After the reaction, when trifluoroethanol (30.0 mg, 21.9 muL, 0.3 mmol) was added thereto as an internal reference to conduct 19F NMR measurement, it was found that 2-(4-ethoxyphenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2i) as a target product was produced with a yield of 78%. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-ethoxyphenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2i) was obtained with a yield of 72%.The results of instrumental analysis of the product (Compound 2i) are shown below:1H-NMR (CDCl3, TMS) delta7.52 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8 Hz),4.29 (2H, q, J=7.2 Hz), 4.06 (2H, q, J=7.0 Hz), 1.43 (3H, t, J=7.0 Hz), 1.30 (3H, t, J =7.2 Hz) 19F-NMR (CDCl3, C6F6) delta59.2 (2F, s) Mass m/e: (m/z) (%) 244 (M+, 12), 171 (98), 143 (100), 126 (4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | |
68% | With potassium fluoride In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 8 Example 8Production of aromatic difluoroacetic acid ester According to the above-described scheme, 4-iodobiphenyl (Compound 1g; 84.0 mg, 0.3 mmol), difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a; 70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) were put into a two-neck reaction tube, and the mixture was stirred under nitrogen atmosphere at 60° C. for 15 hours. After the reaction, when trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added thereto as an internal reference to conduct 19F NMR measurement, it was found that 2-(biphenyl-4-yl)-2,2-difluoroacetic acid ethyl ester (Compound 2g) as a target product was produced with a yield of 78%. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(biphenyl-4-yl)-2,2-difluoroacetic acid ethyl ester (Compound 2g) was obtained with a yield of 68%.The results of instrumental analysis of the product (Compound 2g) are shown below:1H-NMR (CDCl3, TMS) δ7.38-7.70 (9H, m), 4.35 (2H, q, J=7.2 Hz), 1.33 (3H, t, J=7.2 Hz) 19F-NMR (CDCl3, C6F6) δ58.3 (2F, s) Mass m/e: (m/z) (%) 276 (M+, 21), 203 (100), 183 (6), 152 (6) |
68% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 7 Preparation of aromatic difluoroacetic acid ester According to the above scheme, 4-iodobiphenyl (compound 1 g; 84.0 mg, 0.3 mmol), difluorotrimethylsilanylacetate ethyl ester (70.7 mg, 0.36 mmol), copper(I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL), and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere. After the reaction, trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added as an internal standard and measurement by 19 F NMR revealed that 2-(biphenyl-4-yl)-2,2-difluoroacetic acid ethyl ester Was produced in a yield of 78%. The reaction mixture was extracted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure and purified by silica gel column chromatography to obtain ethyl 2-(biphenyl-4-yl)-2,2-difluoroacetate(compound 2 g) in a yield of 68% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | |
73% | With potassium fluoride In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 5 Example 5Production of aromatic difluoroacetic acid ester According to the above-described scheme, ethyl 4-iodobenzoate (Compound 1d; 82.8 mg, 49.9 μL, 0.3 mmol), difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a; 70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL) were put into a two-neck reaction tube, and the mixture was stirred under nitrogen atmosphere at 60° C. for 15 hours. After the reaction, when trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added thereto as an internal reference to conduct 19F NMR measurement, it was found that 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoic acid ethyl ester (Compound 2d) as a target product was produced with a yield of 81%. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoic acid ethyl ester (Compound 2d) was obtained with a yield of 73%.The results of instrumental analysis of the product (Compound 2d) are shown below:1H-NMR (CDCl3, TMS) δ8.13 (2H, d, J=8.2 Hz), 7.68 (2H, d, J=8.2 Hz), 4.41 (2H, q, J=7.2 Hz), 4.30 (2H, q, J=7.2 Hz), 1.41 (3H, J=7.2 Hz), 1.30 (3H, J=7.2 Hz) 19F-NMR (CDCl3, C6F6) δ57.2 (2F, s) Mass m/e: (m/z) (%) 272 (M+, 2), 227 (15), 199 (100), 171 (34), 126 (14) |
73% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | 4 Preparation of aromatic difluoroacetic acid ester Accordance with the above scheme, the 2-neck reaction tube 4-iodo-benzoic acid ethyl ester (compound 1d; 82.8 mg, 49.9μL, 0.3 mmol), difluoromethyl trimethylsilanyl ethyl ester (70.7 mg, 0.36 mmol), copper (I) iodide (57.1 mg, 0.3 mmol), potassium fluoride (20.9 mg, 0.36 mmol) and DMSO (0.6 mL), and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere. After the reaction, trifluoroethanol (30.0 mg, 21.9 μL, 0.3 mmol) was added as an internal standard and measurement by 19 F NMR revealed that 4- (2-ethoxy-1,1-difluoro-2-oxoethyl) benzyl It was found that the acid ethyl ester was produced in a yield of 81%. The reaction mixture was extracted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure and purified by silica gel column chromatography to give 4- (2-ethoxy-1,1-difluoro-2-oxoethyl) benzoic acid ethyl ester (compound 2d) is 73% of the yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere; | General procedure: KF (291mg, 5mmol) was added to a solution of borane 2 (1.10g, 5mmol) and silane 3e or 3f (6mmol) in DMF (5mL), and the resulting suspension was stirred for 18h at room temperature. The mixture was extracted with hexane (2×12mL). More hexane (10mL) was added to the DMF layer, the two-phase mixture was shaken, water (5mL) was added, the mixture was again shaken, and the hexane layer was separated. The combined hexane phase was washed with water (3×3mL), dried (Na2SO4), concentrated under vacuum, and the residue was distilled under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With magnesium In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; Inert atmosphere; | 4.3 Ethyl difluoro(trimethylsilyl)acetate (3e) Ethyl bromodifluoroacetate (3.2mL, 25mmol) was added dropwise to a suspension of magnesium turnings (1.21mg, 50mmol) and chlorotrimethylsilane (9.6mL, 75mmol) in anhydrous DMF (40mL) at 0°C. The reaction mixture was stirred for 90min at room temperature and quenched with water (40mL). The aqueous layer was extracted with pentane (3×15mL), the combined organic phase was washed with water, dried over Na2SO4. The solvent was evaporated under vacuum, and the residue distilled (110-111°C/90Torr) furnishing product 3e as a pale yellow oil (2.71g, 55%). |
51% | With magnesium In N,N-dimethyl-formamide at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240 mg | With potassium fluoride In N,N-dimethyl-formamide at 20℃; for 0.5h; | 18 Iminium intermediate was dissolved in dimethylformamide (4.5 mL) and potassium fluoride (96 mg, 1.659 mmol) was added. A solution of ethyl 2,2-difluoro-2- (trimethylsilyl)acetate (0.217 g, 1.106 mmol) in dimethylformamide (3.0 mL) was added dropwise and the reaction stirred at rt for 30 min. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to afford product (240 mg, 81 % yield) as a brown oil. LC MS (m/z, MH+): 535.8. NMR (400 MHz, CHLOROFORM-^ δ 0.90 (t, J=7.33 Hz, 3 H), 2.62 (dt, J=15.66, 3.28 Hz, 1 H), 2.78 - 2.90 (m, 1 H), 2.94 (dt, J=12.00, 4.11 Hz, 1 H), 3.19 - 3.31 (m, 1 H), 3.63 (s, 3 H), 3.87 (qd, J=7.24, 2.02 Hz, 2 H), 6.49 - 6.58 (m, 6 H), 6.77 (dd, J=8.59, 4.55 Hz, 1 H), 6.96 (d, J=8.59 Hz, 2 H), 7.11 - 7.18 (m, 2 H). 19F NMR (376 MHz, CHLOROFORM-^ δ -117.02 (s, 1 F), -100.52 - -97.72 (m, 2 F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
516 mg | With potassium fluoride In N,N-dimethyl-formamide at 20℃; for 0.5h; | 101.1 Step 1 : Ethyl 2-(l-(4-bromophenyl)-2-(4-isobutylphenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate Iminium intermediate was dissolved in dimethylformamide (8.5 mL) and potassium fluoride (0.177 g, 3.05 mmol) was added. A solution of ethyl 2,2-difluoro-2- (trimethylsilyl)acetate (0.400 g, 2.036 mmol) in dimethylformamide (5.5 mL) was added dropwise and the reaction stirred at r.t. for 30 minutes. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel flash chromatography (0-10% ethyl acetate/heptanes) to afford product (516 mg,89 % yield) as a yellow oil. LC MS (m/z, MH+): 572.5. NMR (400 MHz, Chloroform-d) δ 7.28 - 7.20 (m, 2H), 7.16 - 7.09 (m, 2H), 6.90 (dd, J = 9.5, 4.4 Hz, 1H), 6.78 - 6.73 (m, 2H), 6.67 - 6.58 (m, 4H), 4.00 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 3.45 (ddd, J = 12.6, 9.7, 3.4 Hz, 1H), 3.22 (dt, J = 12.0, 4.5 Hz, 1H), 2.97 (ddd, J = 14.7, 9.6, 4.5 Hz, 1H), 2.80 (dt, J = 15.7, 3.8 Hz, 1H), 2.30 (dd, J = 7.2, 1.6 Hz, 2H), 1.72 (dp, J = 13.5, 6.7 Hz, 1H), 1.04 (t, J = 7.1 Hz, 3H), 0.80 (dd, J = 6.6, 2.9 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -97.62 (d, J = 246.9 Hz, 2F), -99.67 (d, J = 247.0 Hz, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With cesium fluoride; 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran at 20℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
74% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 6 Example 6: In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate, 0.217 g of methyl ketone methacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then 10 ml of N-N-methylpyrrolidone was added,Nitrogen, stirred at room temperature for 48 hours,After the reaction, the solvent was removed,Separation by silica gel column chromatography, eluent for pure methylene chloride,To give 0.251 g of a white solid in 74% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
89% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 1 Example 1: In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate,0.247 g of transesteryl methacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then 10 ml of N-N-methylpyrrolidone was added,Nitrogen protection,The mixture was stirred at room temperature for 48 hours,After the reaction, the solvent was removed,Separation by silica gel column chromatography, eluent for pure methylene chloride,To give 0.329 g of a white solid in 89% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 3 Example 3: In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate,0.205 g o-methoxymethacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then 10 ml of N-N-methylpyrrolidone was added,Nitrogen protection,The mixture was stirred at room temperature for 48 hours,After the reaction, the solvent was removed,Separation by silica gel column chromatography, eluent for pure methylene chloride,To give 0.291 g of a white solid in 89% yield. |
84% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
76% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 7 Example 7: In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate,0.254 g p-methyl ketone methacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then add 10 ml twoN-methylpyrrolidone,Nitrogen, stirred at room temperature for 48 hours,After the reaction, the solvent was removed,Separation by silica gel column chromatography, eluent for pure methylene chloride,To give 0.285 g of a white solid in 76% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
96% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 2 Example 2: In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate,0.247 g of ortho-methacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then 10 ml of N-N-methylpyrrolidone was added,Nitrogen, stirred at room temperature for 48 hours,After the completion of the reaction, the solvent was removed, separated by silica gel column chromatography,The eluent was pure methylene chloride to give 0.380 g of a white solid in 96% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
83% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 4 Example 4: In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate,0.235 g of 5,7-dimethoxymethylacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then 10 ml of N-N-methylpyrrolidone was added,Nitrogen, stirred at room temperature for 48 hours,After the reaction, the solvent was removed,Separation by silica gel column chromatography,The eluent was pure methylene chloride to give 0.296 g of a white solid in 83% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
77% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 5 Example 5: In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate,0.268 g of 5-methyl-7-bromomethylacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then 10 ml of N-N-methylpyrrolidone was added,Nitrogen protection,The mixture was stirred at room temperature for 48 hours,After the reaction, the solvent was removed,Separation by silica gel column chromatography,The eluent is pure methylene chloride,To give 0.300 g of a white solid, yield 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With [bis(acetoxy)iodo]benzene; sodium acetate; 2-isocyanobiphenyl; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Schlenk technique; Molecular sieve; Inert atmosphere; | |
100 %Spectr. | With [bis(acetoxy)iodo]benzene; N-methyl-N-phenylmethacrylamide; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
55 %Spectr. | With potassium fluoride; silver trifluoromethanesulfonate In dichloromethane at 20℃; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | |
82% | With [bis(acetoxy)iodo]benzene; sodium acetate; silver nitrate In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; | 8 Example 8: 2,2-difluoro-3- (5-iodo-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indole) -propionic acid ethyl esterStep:In a 25 ml reaction flask, 0.492 g of silver nitrate was added successively,0.644 g of iodobenzene diacetate,0.246 g of anhydrous sodium acetate,0.301 g p-methyl ketone methacrylamide,0.981 g of ethyl trimethylsilane ethyl fluoride,Then 10 ml of N-N-methylpyrrolidone was added,Nitrogen, stirred at room temperature for 48 hours,After the reaction, the solvent was removed,Separation by silica gel column chromatography, eluent for pure methylene chloride,To give 0.347 g of a white solid, yield 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Schlenk technique; Molecular sieve; Inert atmosphere; | |
39.6% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Inert atmosphere; | 3 Embodiment 3: Preparation (2,8-dimethyl-phenanthridine-6 -) difluoro ethyl acetate using the following steps: in 50 ml reaction flask are sequentially added 3.45 g silver carbonate, 3.22 g ACOH iodophenylamino, 2.07 g potassium carbonate, 1.23 g sodium acetate, 1.03 g 2- isocyano-D -2,8-dimethyl -1,1 '-biphenyl, nitrogen protection, then adding 4.91 g trimethylacetophenone silicon-based two fluorine ethyl acetate and 25 ml of 1,4-dioxane, stirring at room temperature for 24 hours, to remove the solvent after the reaction, separation with silica gel column chromatography, elution agent is 20:1 of the mixed solvent of petroleum ether and ethyl acetate, to obtain strawcoloured solid 0.65 g, yield 39.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.1% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Inert atmosphere; | 4 Embodiment 4 Preparation difluoro-(2-trifluoro-methyl-phenanthridine-6 -) ethyl acetate using the following steps: in 50 ml reaction flask are sequentially added 3.45 g silver carbonate, 3.22 g ACOH iodophenylamino, 2.07 g potassium carbonate, 1.23 g sodium acetate, 1.27 g 2- isocyano-D -5-trifluoromethyl -1,1 '-biphenyl, nitrogen protection, then adding 4.91 g trimethylacetophenone silicon-based two fluorine ethyl acetate and 25 ml of 1,4-dioxane, stirring at room temperature for 24 hours, to remove the solvent after the reaction, separation with silica gel column chromatography, elution agent is 50:1 of the mixed solvent of petroleum ether and ethyl acetate, to obtain red-brown solid 0.51 g, yield 28.1%. |
27% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Schlenk technique; Molecular sieve; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.7% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Inert atmosphere; | 1 Preparing di (8-methyl-phenanthridine-6 -) ethyl acetate using the following steps in 50 ml reaction flask are sequentially added 3.45 g silver carbonate, 3.22 g ACOH iodophenylamino, 2.07 g potassium carbonate, 1.23 g sodium acetate, 0.97 g 2- isocyano-D -4 '-methyl -1,1' -biphenyl, nitrogen protection, then adding 4.91 g trimethylacetophenone silicon-based two fluorine ethyl acetate and 25 ml of 1,4-dioxane, stirring at room temperature for 24 hours, to remove the solvent after the reaction, separation with silica gel column chromatography, elution agent is 20:1 of the mixed solvent of petroleum ether and ethyl acetate, to obtain light brown solid 0.83 g, yield 52.7%. Difluoro (8-methyl-phenanthridine-6 -) ethyl acetate, which is characterized in that the structure of this compound is: Molecular formula: C 18 H 15 F 2 NO 2 Chinese-named: difluoro (8-methyl-phenanthridine-6 -) acetic acid ethyl ester English-named: Difluoro-(8-methyl-phenanthridin-6-yl)-acetic acid ethyl ester Molecular weight: 315 Appearance: light brown solid |
50% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Schlenk technique; Molecular sieve; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Schlenk technique; Molecular sieve; Inert atmosphere; | |
51.2% | With [bis(acetoxy)iodo]benzene; sodium acetate; potassium carbonate; silver carbonate In 1,4-dioxane at 20℃; for 24h; Inert atmosphere; | 2 Embodiment 2: Preparation of (8-acetylprotoaescigenin phenanthridine-6 -) difluoro ethyl acetate using the following steps: in 50 ml reaction flask are sequentially added 3.45 g silver carbonate, 3.22 g ACOH iodophenylamino, 2.07 g potassium carbonate, 1.23 g sodium acetate, 1.11 g 2- isocyano-D -4 '-acetyl -1,1' -biphenyl, nitrogen protection, then adding 4.91 g trimethylacetophenone silicon-based two fluorine ethyl acetate and 25 ml of 1,4-dioxane, stirring at room temperature for 24 hours, to remove the solvent after the reaction, separation with silica gel column chromatography, elution agent is 5:1 of the mixed solvent of petroleum ether and ethyl acetate, to obtain light yellow solid 0.88 g, yield 51.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 70℃; for 18h; Inert atmosphere; | 97.3 ethyl 2,2-difluoro-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate To a vial was added 4-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (W-2) (2000mg, 5.329 mmol), copper(I)iodide (1220mg, 6.40 mmol) andpotassium fluoride (433 mg, 7.46 mmol). The vial was cappedand purged with nitrogen then DMSO (10.7 mE, c=0.5 M)and ethyl difluoro(trimethylsilyl)acetate (2160 mg, 10.7mmol, 1.74 mE) were added. The reaction was heated to 70°C. for 18 h then diluted with water (10 mE) and EtOAc (30mL). The mixture was filtered through a bed of Celite then the layers were separated and the organic phase was dried (MgSO4), filtered and concentrated. The crude residue was purified by column chromatography using the ISCO and a 24 g Si column with 0-70% EtOAc/Hep to give 975mg (49%) of ethyl 2,2-difluoro-2-(7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (W-3). ‘H NMR (400 MHz, DMSO-d6) ö ppm 8.96 (s, 1H), 8.01 (d, J=3.7 Hz, 1H), 6.93-6.72 (m, 1H), 5.70 (s, 2H), 4.36 (q, J=7.1 Hz, 2H),3.54 (t, J=7.9 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H), 0.82 (t, J=8.0 Hz, 2H), -0.11 (s, 9H); ECMS [M+1] 372. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium fluoride; 2-fluoropyridine; silver trifluoromethanesulfonate; lithium trifluoromethanesulfonate; Selectfluor In ethyl acetate at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. 4.2.1 Ethyl 3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropanoate (3a)15 Light yellow liquid; IR (KBr film): 1754, 1598, 1374, 1312, 1189, 1107, 1018, 1014, 852, 830, 778, 744, 672cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.46-7.36 (m, 4H), 5.17 (dd, J=15.3, 7.6Hz, 1H), 4.33 (q, J=7.1Hz, 2H), 2.80 (s, 1H), 1.33 (t, J=7.2Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.4 (dd, J=32.2, 30.6Hz), 135.2, 132.9, 129.1 (t, J=1.3Hz), 128.7, 113.5 (dd, J=259.7, 254.6Hz), 73.1 (dd, J=28.2, 24.6Hz), 63.3, 13.9; 19F NMR (376 MHz, Chloroform-d) δ-113.3 (d, J=264.2Hz),-120.5 (d, J=264.2Hz); GC-MS (EI): m/z 264.0 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 13h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; | 4.2 General procedure for the preparation of β-hydroxyl gem-difluoro esters General procedure: To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL) was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol, 88.2mg). Subsequently the reaction solution was stirred at room temperature until full consume of the starting aldehyde indicated by TLC, 1.0mL 1.0N HCl was added at this moment and the mixture was continuously stirred for 0.5 h, then the mixture was extracted by ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified through flash column chromatography (silica gel, PE/EtOAc) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
118.3 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
104.3 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
118.3 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
105.6 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
110.6 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
123.1 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
111.5 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.3 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
125.2 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
103.3mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.9 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
114.4 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
112.6 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.7 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.7 mg | With cesium fluoride In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.6 mg | With sodium acetate In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3 mg | With sodium acetate In N,N-dimethyl acetamide at 25℃; for 5h; | 4.1 General procedure for the synthesis of derivatives 3 or 5 General procedure: An oven-dried 20mL crimp cap vessel with Teflon-coated stirrer bar was charged with the bromid 1 or 4 (0.5mmol) and NaSCN (1.0mmol) in DMA (5mL), and the suspension was stirred at room temperature for 1h (for 3n-3s: 1 and NaSCN were firstly stirred at 60°C in DMA for 1h then cooled to room temperature). Then, ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (TMS-CF2CO2Et) (1.0mmol) was added to the reaction mixture followed by CsF (1.0mmol) or NaOAc (1.0mmol). The obtained reaction mixture was stirred at 25°C for 5h. The mixture was quenched with water (5mL) and extracted with EtOAc (3×5mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. After evaporation of the solvent, the residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate=100:1) to afford the desired products 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium fluoride In N,N-dimethyl-formamide at 25℃; for 16h; | 127.4; 128.4 ethyl 2-(6-(benzyloxy)-1-(4-bromophenyl)-2-(2-fluoro-2-methylpropyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-2,2-difluoroacetate To a mixture of 6-benzyloxy- 1- (4-bromophenyl)-2- (2-fluoro-2-methyl-propyl)-3 ,4-dihydroiso quinolin-2-ium (From step 2, 2.14 g, 4.58 mmol) in DMF (40 mL) was added KF(798 mg, 13.74 mmol). A solution of ethyl difluoro(trimethylsilyl)acetate (1.8 g, 9.16 mmol)in DMF (10 mL) was then added dropwise and the reaction mixture was stilTed at 25 °C for16 hours. Saturated aqueous NaHCO3 solution (150 mL) was added to the reaction mixtureand the mixture was extracted with DCM (150 mL x 2). The combined organic layers weredried over anhydrous Na2504, filtered and concentrated. The residue was purified by column chromatography (0-5% EtOAc in petroleum ether) to afford the title compound as a colorless oil (1.65 g, 61%). LCMS: 590.2 [M+H’i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium fluoride; copper(l) iodide; In dimethyl sulfoxide; at 60℃; for 15h;Schlenk technique; Inert atmosphere; | 2- (3-chloropyridin-4-yl) -2,2-difluoroacetic acid ethyl ester (compound 3c) was prepared according to the following procedure. In the Schlenk tube,3 - Chloro - 4 - iodopyridine (119.7 mg, 0.5 mmol), copper (I) iodide (190.5 mg, 1.0 mmol), potassium fluoride (58.1 mg, 1.0 mmol) and DMSO (2.0 mL).Finally, alpha- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (196.3 mg, 1.0 mmol) was added,Under a nitrogen atmosphere,And the mixture was stirred at 60 C. for 15 hours.After the reaction, trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard,As a result of measurement by 19 F-NMR, it was found that the objective product 2- (3-chloropyridin-4-yl) -2,2-difluoroacetic acid ethyl ester (compound 3c) was produced in 72% yield It was. The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: EtOAc = 30: 1, 20: 1, 20: 1) to give 2- (3-chloropyridin-4-yl) -2,2-difluoroacetic acid ethyl ester (Compound 3c) (70.8 mg, 0.30 mmol, yield: 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Schlenk technique; Inert atmosphere; | 4 Preparation of Heteroaryldifluoroacetic Acid Ester Compound 2,2-Difluoro-2- (pyridin-2-yl) acetic acid ethyl ester was prepared according to the following procedure.2-Bromopyridine (79.0 mg, 0.5 mmol), copper iodide (190.5 mg, 1.0 mmol), potassium fluoride (58.1 mg, 1.0 mmol) and DMSO (2.0 mL) were injected into a Schlenk tube. Finally, α- (trimethylsilyl) difluoroacetic acid ethyl ester (2a) (196.3 mg, 1.0 mmol) was added and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere. After the reaction, trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard and analyzed using 19 F-NMR, it was found that 2,2-difluoro-2- (pyridin-2-yl) acetic acid ethyl ester Was produced at a yield of 63%. The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: EtOAc = 50: 1, 30: 1, 20: 1, 10: 1)2,2-Difluoro-2- (pyridin-2-yl) acetic acid ethyl ester (53.2 mg, 0.26 mmol, yield: 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium fluoride; copper(l) iodide; In dimethyl sulfoxide; at 60℃; for 15h;Inert atmosphere; Schlenk technique; | 2,2-Difluoro-2- (pyrazin-2-yl) acetic acid ethyl ester (Compound 3d) was prepared according to the following procedure.Iodopyrazine (103.0 mg, 0.5 mmol), copper (I) iodide (190.5 mg, 1.0 mmol), potassium fluoride (58.1 mg, 1.0 mmol) and DMSO (2.0 mL) are placed in a Schlenk tube. Finally, alpha- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (196.3 mg, 1.0 mmol) was added and the mixture was stirred at 60 C. for 15 hours under a nitrogen atmosphere. After the reaction, trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard and measurement by 19 F-NMR revealed that 2,2-difluoro-2- (pyrazin-2-yl) acetic acid ethyl ester 3d) was produced in a yield of 70%. The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: EtOAc = 20: 1, 10: 1, 5: 1)) to give 2,2-difluoro-2- (pyrazin-2- yl) acetic acid ethyl ester 3d) (58.4 mg, 0.29 mmol, yield: 58%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Schlenk technique; Inert atmosphere; | 7 <Preparation of Heteroaryldifluoroacetic Acid Ester Compound> 2,2-Difluoro-2- (isoquinolin-1-yl) acetic acid ethyl ester (Compound 3f) was prepared according to the following procedure.In the Schlenk tube,1 - Iodoisoquinoline (127.5 mg, 0.5 mmol), copper (I) iodide (190.5 mg, 1.0 mmol), potassium fluoride (58.1 mg, 1.0 mmol) and DMSO (2.0 mL).Finally, α- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (196.3 mg, 1.0 mmol) was added and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere.After the reaction,Trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard,As a result of measurement by 19 F-NMR, it was found that 2,2-difluoro-2- (isoquinolin-1-yl) acetic acid ethyl ester (compound 3f) as an objective product was produced in a yield of 82%.The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: EtOAc = 30: 1, 20: 1)2,2-Difluoro-2- (isoquinolin-1-yl) acetic acid ethyl ester (Compound 3f) (96.7 mg, 0.38 mmol, yield: 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Schlenk technique; Inert atmosphere; | 8 <Preparation of Heteroaryldifluoroacetic Acid Ester Compound> According to the following procedure, 2,2-difluoro-2- (thiophen-2-yl) acetic acid ethyl ester (compound 3 g) was prepared.In the Schlenk tube,2-Iodothiophene (105.2 mg, 0.5 mmol), copper (I) iodide (190.5 mg, 1.0 mmol),Potassium fluoride (58.1 mg, 1.0 mmol) and DMSO (2.0 mL) are added.Finally, α- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (196.3 mg, 1.0 mmol) was added, and under nitrogen atmosphere,And the mixture was stirred at 60 ° C. for 15 hours. After the reaction,Trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard,As a result of measurement by 19 F-NMR, it was found that 2,2-difluoro-2- (thiophen-2-yl) acetic acid ethyl ester (compound 3 g) as a target product was produced in 49% yield.The reaction mixture was extracted with ethyl acetate,After washing with water, it was dried with anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: EtOAc = 50: 1, 30: 1, 20: 1) to give 2,2-difluoro-2- (thiophen-2-yl) acetic acid ethyl ester 3 g) (40.8 mg, 0.20 mmol, yield: 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium fluoride; copper (I) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; Schlenk technique; | 9 Preparation of Heteroaryldifluoroacetic Acid Ester Compound 2,2-Difluoro-2- (thiophen-3-yl) acetic acid ethyl ester (Compound 3h) was prepared according to the following procedure.In the Schlenk tube,3 - Iodothiophene (105.2 mg, 0.5 mmol), copper (I) iodide (190.5 mg, 1.0 mmol), potassium fluoride (58.1 mg, 1.0 mmol) and DMSO (2.0 mL). Finally, α- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (196.3 mg, 1.0 mmol) was added and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere. After the reaction, trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard and measurement by 19 F-NMR revealed that 2,2-difluoro-2- (thiophene-3-yl) acetic acid ethyl ester (compound 3 h) was produced in a yield of 77%. The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (Hexane: EtOAc = 50: 1) gave 2,2-difluoro-2- (thiophene-3-yl) acetic acid ethyl ester (Compound 3h) (76.5 mg, 0.37 mmol, Yield: 74%). |
With potassium fluoride; copper (I) iodide In dimethyl sulfoxide at 60℃; for 15h; Inert atmosphere; | A Step A: E-1 (6.42 g, 30.57 mmol) was added to dimethyl sulfoxide (50 mL) followed by potassium fluoride (3.55 g, 61.14 mmol) and cuprous iodide (11.64 g, 61.14 mmol) and finally ethyl (trimethylsilyl)difluoroacetate (12 g, 61.14 mmol) was added. The reaction mixture was stirred at 60 degrees Celsius for 15 hours under nitrogen protection. After natural cooling, tert-butyl methyl ether (200 mL) and water (300 mL) were added to dilute the reaction solution, and stirring was continued for 10 minutes, followed by filtration. The filter cake was washed with tert-butyl methyl ether (30 mL/time, washed 3 times). The filtrates were combined, and the organic phase was separated, washed with water (300 mL) and saturated brine (300 mL) in turn, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether) to obtain E-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium fluoride; copper(l) iodide; In dimethyl sulfoxide; at 60℃; for 15h;Schlenk technique; Inert atmosphere; | 2- (6-chloropyridin-3-yl) -2,2-difluoroacetic acid ethyl ester (compound 3b) was prepared according to the following procedure.In the Schlenk tube,<strong>[69045-79-0]2-Chloro-5-iodopyridine</strong> (119.7 mg, 0.5 mmol),Copper (I) iodide (190.5 mg, 1.0 mmol),Potassium fluoride (58.1 mg, 1.0 mmol),Place DMSO (2.0 mL).Finally, alpha- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (196.3 mg, 1.0 mmol) was added,Under a nitrogen atmosphere,And the mixture was stirred at 60 C. for 15 hours.After the reaction,Trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard,As a result of measurement by 19 F-NMR, it was found that 2- (6-chloropyridin-3-yl) -2,2-difluoroacetic acid ethyl ester (compound 3b) as a target product was produced in a yield of 80% It was. The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: EtOAc = 50: 1, 20: 1) to obtain ethyl 2- (6-chloropyridin-3-yl) -2,2-difluoroacetate (Compound 3b) (85.3 mg, 0.36 mmol, yield: 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium fluoride; copper(l) iodide In dimethyl sulfoxide at 60℃; for 15h; Schlenk technique; Inert atmosphere; | 1 Separately from the above, ethyl 2- (5-bromopyridin-2-yl) -2,2-difluoroacetate (Compound 3a) was prepared according to the following procedure. In a Schlenk tube, 5-bromo-2-iodopyridine (141.9 mg, 0.5 mmol), copper (I) iodide (190.5 mg, 1.0 mmol), potassium fluoride (58.1 mg, 1.0 mmol), DMSO (2.0 mL) . Finally, α- (trimethylsilyl) difluoroacetic acid ethyl ester (Compound 2a) (196.3 mg, 1.0 mmol) was added and the mixture was stirred at 60 ° C. for 15 hours under a nitrogen atmosphere. After the reaction, trifluoroethanol (50.0 mg, 0.5 mmol) was added as an internal standard and measurement by 19 F-NMR revealed that ethyl 2- (5-bromopyridin-2-yl) -2,2-difluoroacetate It was found that the ester (compound 3a) was produced in a yield of 74%. The reaction mixture was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: EtOAc = 100: 1, 50: 1) to give ethyl 2- (5-bromopyridin-2-yl) -2,2-difluoroacetate (Compound 3a) (100.6 mg, 0.36 mmol, yield: 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With silver nitrate; Selectfluor; cesium fluoride; bis-[(trifluoroacetoxy)iodo]benzene In acetonitrile at 25℃; for 18h; Inert atmosphere; | 1 Example 1 Take a dry reaction tube,Under nitrogen atmosphere, internal acetylene 1a (34.4mg, 0.2mmol) was added to the silver nitrate (68mg, 0.4mmol),Cesium fluoride (76mg, 0.5mmol),Bis (trifluoroacetoxy) iodobenzene (86mg, 0.2mmol),Fluorine reagent (1-chloromethyl-4-fluoro-1,4-diazobicyclo 2.2.2 octane bis(tetrafluoroborate) salt, 141.7mg, 0.4mmol),In a mixed system of ethyl trimethylsilyl difluoroacetate (98mg, 0.5mmol) in acetonitrile (2mL),A reaction system is formed.After the system was stirred for 18h at room temperature 25,It was quenched by adding 15 mL of water, and extracted three times with ethyl acetate (10 mL),After combining, the organic phase was washed with saturated edible water, and dried with anhydrous sodium sulfate.The organic phase was concentrated and separated by silica gel (300-400 mesh) column chromatography to obtain 48 mg of pale yellow liquid 2a.The yield was 76%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: α-(trimethylsilyl)difluoroacetic acid ethyl ester With diethylamino-sulfur trifluoride; N-ethyl-N,N-diisopropylamine at 25℃; for 1.5h; Stage #2: aniline at 25℃; for 16h; | ethyl 2,2-difluoro-2-[(phenylamino)sulfanyl)]acetate General procedure: The procedure was adapted from a previously reported procedure [8]. To a solution of DIPEA (3.4 mL, 19.8 mmol, 1.1 equiv.) in CH2Cl2 (36 mL), DAST (2.6 mL, 19.8 mmol, 1.1 equiv.) was slowly added under argon at 25 C during 20 min. Then, TMSCF2CO2Et (3.4 mL, 18 mmol, 1 equiv.) was slowly added and the reaction mixture was stirred for 1.5 h at 25 C. Once the aniline (1.6 mL, 18 mmol, 1 equiv.) was added, the reaction mixture was stirred at 25 C for 16 h. The mixture was diluted in 100 mL of water and the aqueous phase was extracted with CH2Cl2 (3 100 mL). The combined organic phases were washed with an aqueous saturated NaCl solution (100 mL), dried under Na2SO4, filtered and concentrated under reduce pressure. Purification of the crude reaction mixture by flash column chromatography on silica gel (height 15 cm, width 8 cm, pentane/diethyl ether 95:5) afforded the desired product I (2.3 g, 52%). |
Tags: 205865-67-4 synthesis path| 205865-67-4 SDS| 205865-67-4 COA| 205865-67-4 purity| 205865-67-4 application| 205865-67-4 NMR| 205865-67-4 COA| 205865-67-4 structure
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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