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CAS No. : | 327-54-8 | MDL No. : | MFCD00000307 |
Formula : | C6H2F4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SDXUIOOHCIQXRP-UHFFFAOYSA-N |
M.W : | 150.07 | Pubchem ID : | 9474 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 26.27 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.57 cm/s |
Log Po/w (iLOGP) : | 1.84 |
Log Po/w (XLOGP3) : | 2.32 |
Log Po/w (WLOGP) : | 3.92 |
Log Po/w (MLOGP) : | 4.01 |
Log Po/w (SILICOS-IT) : | 3.54 |
Consensus Log Po/w : | 3.13 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.68 |
Solubility : | 0.316 mg/ml ; 0.00211 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.96 |
Solubility : | 1.65 mg/ml ; 0.011 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.5 |
Solubility : | 0.048 mg/ml ; 0.00032 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.23 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P261-P305+P351+P338 | UN#: | 1993 |
Hazard Statements: | H225-H315-H319-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 |
---|---|---|
95% | With iodine; lithium tert-butylate In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere; | |
88% | Stage #1: 1,2,4,5-Tetrafluorobenzene With [(dioxane)0.5*NaFe{N(SiMe3)2}3] In benzene at 20℃; for 16h; Inert atmosphere; Schlenk technique; Glovebox; Stage #2: With iodine at 20℃; for 1h; Inert atmosphere; Schlenk technique; Glovebox; regioselective reaction; | |
78% | With sulfuric acid; periodic acid; potassium iodide at 0 - 70℃; for 4h; |
68% | With sulfuric acid; iodine; fluorine In 1,1,2-Trichloro-1,2,2-trifluoroethane Ambient temperature; | |
68% | With iodine | 5 1,2,4,5-Tetrafluoro-3,6-diiodobenzene EXAMPLE 5 1,2,4,5-Tetrafluoro-3,6-diiodobenzene 1,2,4,5-Tetrafluorobenzene(11.3 g, 75 mmol) and iodine(21.9 g, 86 mmol) gave 3,6-diiodo-1,2,4,5-tetrafluorobenzene (20.5 g, 68%); m.p. 109°-111° C. (lit;2 109°-111° C.); (Found: C. 17.59; H, 0; N, 0. C6 F4 I2 requires C, 17.93; H, 0; N, 0%); δF -118.0 (4F, s,1-F, 2-F, 3-F, 4-F); δC 72.9 (2C, t, 2 JC-F 27.9, 3C, 6-C) and 146.6 (4C, m, 1 JC-F 250.4, 1-C, 2C, 4-C, 5-C); m/z (EI+) 402 (M+, 46.7%). |
With sulfuric acid; iodine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1-methyl-pyrrolidin-2-one at 20℃; for 24h; Inert atmosphere; | |
58% | In N,N-dimethyl-formamide for 0.5h; ratio RS(1-):substrate 6:1; | |
In N,N-dimethyl-formamide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 79% 2: 21% | With [Ru(IMe4)4H2]; HSiPh3 In benzene at 120℃; for 740h; regioselective reaction; | |
1: 71% 2: 3% | With ammonium hydroxide; ammonia hydrochloride; zinc powder at 20℃; for 24h; | |
1: 65% 2: 20% | With sodium tetrahydridoborate; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) In N,N-dimethyl-formamide at 20℃; for 18h; | Catalytic hydrodehalogenation experiments General procedure: All reactions were carriedout in air at room temperature. A 50 mL round-bottom flask equippedwith a magnetic stir bar was charged with 280.8 mg (0.90 mmol) of 4,4′ -dibromobiphenyl (or 0.90 mmol of another aryl halide), 0.09 mmol ofcatalyst (10 mole%), 68.1 mg (0.18 mmol, 2.0 eq) of NaBH4 and 6 mL ofDMF (or other solvents) in room temperature. The reaction mixture wasleft to stir overnight for 18 h. Thereafter, 6 mL of deionised water wasadded to stop the reaction by deactivating the excess NaBH4 in themixture. |
1: 62% 2: 10% | With triethylsilane; [((1,2-bis(diisopropylphosphino)ethane))Ni(μ-H)]2; triphenylphosphine In 1,4-dioxane at 120℃; for 72h; | |
1: 38% 2: 8% | With lithium hydroxide monohydrate; triphenylphosphine In 1,4-dioxane Schlenk technique; Inert atmosphere; Glovebox; | |
With (PMe3)3RhC6F5; hydrogen; triethylamine at 95 - 100℃; for 17h; other rhodium catalyst, also pentafluorobenzene; | ||
With zirconocene dichloride; [{((2,6-dimethylphenyl)NC(methyl))2CH}AlH2] In hexadeuterobenzene at 80℃; for 24h; Inert atmosphere; Overall yield = 90 %; | ||
With [Cp*Rh(bpy)]; hydrogen; diethylamine In acetonitrile at 25℃; for 24h; Inert atmosphere; | ||
With [Cp*Rh(bpy)]; hydrogen; diethylamine In tetrahydrofuran at 25℃; for 24h; | A reaction test for the defluorination of hexafluorobenzene was carried out using the Rh 1 valent catalyst prepared above. 58 μL (0.5 mmol) of hexafluorobenzene and diethylamine were added to a solution of Rh 1 -valent catalyst in 2.34 mL of THF as a reaction solvent. This solution was reacted by stirring in a hydrogen atmosphere (0.1 MPa) at a temperature of 25 ° C. for 24 hours. Next, 29 μL of 1-fluoropentane was added to the reaction solution for constitution analysis of the reaction solution, 0.2 mL of the reaction solution was collected, 0.4 mL of deuterated benzene (C 6 D 6) was added thereto, Samples were prepared for NMR measurements (1 H and 19 F). Then, NMR analysis was performed to determine the turnover number (TON: mol number of reaction product / mol number of catalyst) and conversion from the components of the reaction solution. In this reaction test, two kinds of fluorobenzenes, pentafluorobenzene (C 6 F 5 H) and 1,2,4,5-tetrafluorobenzene (C 6 F 4 H 2) were confirmed, and TON for each was determined. | |
1: 25 %Chromat. 2: 50 %Chromat. | With N,N,N',N'-tetramethyl-para-phenylenediamine; N-ethyl-N,N-diisopropylamine In acetonitrile at 24.84℃; for 24h; UV-irradiation; Inert atmosphere; | |
With C19H23Cl2N4Ni(1+)*Br(1-); zinc powder In lithium hydroxide monohydrate at 70℃; for 6h; Ionic liquid; Inert atmosphere; Sealed tube; | 5.3 General method of catalytic hydrodefluorination of hexafluorobenzene In a 5ml vial, 0.01mmol of the corresponding complex and 196mg (3mmol) of zinc dust were placed. The vial was evacuated, then filled with argon. In a dry box, 1g of dry IL was added. The vial was closed, supplied with argon, heated to 70 °C, 200 μL of water was added, and the mixture was stirred until the mixture turned black (~ 10min). Then 116 μl (1mmol) of hexafluorobenzene was added and stirred for 6h. The qualitative and quantitative composition of the products was determined by 19F-NMR (CD3CN) and GCMS. A typical view of 19F NMR spectrum of the reaction mixture is given in the Supplementary data (Fig. S5). | |
1: 74 %Spectr. 2: 16 %Spectr. | With H2SiEt2; C17H21BiN2O3 In tetrahydrofuran at 60℃; for 20h; Inert atmosphere; Sealed tube; | |
With phenylsilane; 2-H-1,3-di-tert-butyl-2,3-dihydro-1H-1,3,2-diazaphosphole In toluene at 100℃; for 9h; Inert atmosphere; Schlenk technique; Overall yield = 84 percentSpectr.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Schlenk technique; Stage #2: formic acid ethyl ester In tetrahydrofuran Inert atmosphere; Schlenk technique; | |
Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium In tetrahydrofuran at -50℃; for 1h; Stage #2: formic acid ethyl ester In tetrahydrofuran at -50 - 20℃; | ||
Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium Stage #2: formic acid ethyl ester |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 79% 2: 20% | With di-tert-butyl(methyl)phosphonium tetrafluoroborate salt; potassium carbonate In N,N-dimethyl acetamide at 120℃; | |
1: 49% 2: 5% | With palladium diacetate; caesium carbonate; tricyclohexylphosphine In toluene at 80℃; for 19h; Sealed tube; | |
41% | With palladium 10% on activated carbon; potassium acetate In N,N-dimethyl acetamide at 150℃; for 16h; Inert atmosphere; regioselective reaction; |
1: 29 mg 2: 9 mg | With C27H32N6Pd(2+)*2CF3O3S(1-); potassium carbonate In N,N-dimethyl acetamide at 120℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.9% | With potassium hydroxide; water; at 90 - 95℃; for 3.25h; | In einem Glaskolben mit Rueckflusskuehler, Ruehrer und Thermometer werden 76 g (0,610 mol) waessrige KOH-Loesung (45 %ig) unter Argon auf 90 bis 95C erwaermt. Unter Ruehren werden 42 g (0,204 mol) Tetrafluorterephthalaldehyd innerhalb von 3 Stunden in kleinen Portionen (jeweils ca. 2 g) zugegeben. Nach Beendigung der Zugabe wird 15 min bei 95C nachgeruehrt und auf Raumtemperatur abgekuehlt. Gaschromatographisch wird nach Extraktion einer Probe des Reaktionsgemischs mit Diethylether vollstaendiger Umsatz an Tetrafluorterephthalaldehyd detektiert. Nach Extraktion mit Diethylether, Trocknung der organischen Phase ueber Na2SO4 und fraktionierter Destillation werden 25,1 g (0,167 mol) 1,2,4,5-Tetrafluorbenzol (Ausbeute 81,9 %) erhalten. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; hexane; water; | EXAMPLE 7 This Example illustrates the preparation of 2,3,5,6-tetrafluorobenzoic acid. n-Butyllithium (2.7M solution in n-hexane, 148 cm3) was added dropwise over a period of one hour to a stirred solution of 2,3,5,6-tetrafluorobenzene (60 g) in dry tetrahydrofuran (200 cm3) maintained at -70 C. under a nitrogen atmosphere, after which the mixture was stirred at -70 C. for a further one hour. Carbon dioxide gas was passed into the mixture over a period of 4 hours during which time the temperature was allowed to warm up to the ambient value (ca. 22 C.). After adding water and acidifying with dilute hydrochloric acid, the mixture was extracted with diethyl ether and the extracts dried over anhydrous magnesium sulphate. The product was obtained by removal of the solvent by evaporation under reduced pressure to give 2,3,5,6-tetrafluorobenzoic acid (42.5 g), mp. 152-154 C. 90 MHz N.m.r. (CDCl3 +DMSO): 7.3-7.7 (m, 1H); 10.75 (broad s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; hexane; water; | EXAMPLE 7 This Example illustrates the preparation of 2,3,5,6-tetrafluorobenzoic acid. n -Butyllithium (2.7M solution in n -hexane, 148cm3) was added dropwise over a period of one hour to a stirred solution of 2,3,5,6-tetrafluorobenzene (60g) in dry tetrahydrofuran (200cm3) maintained at -70C under a nitrogen atmosphere, after which the mixture was stirred at -70C for a further one hour. Carbon dioxide gas was passed into the mixture over a period of 4 hours during which time the temperature was allowed to warm up to the ambient value (ca. 22C). After adding water and acidifying with dilute hydrochloric acid, the mixture was extracted with diethyl ether and the extracts dried over anhydrous magnesium sulphate. The product was obtained by removal of the solvent by evaporation under reduced pressure to give 2,3,5,6-tetrafluorobenzoic acid (42.5g), mp. 152-154C. 90 MHz N.m.r (CDCl3+DMSO): 7.3-7.7 (m, 1H); 10.75 (broad s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[Example 1]; In a conical flask, 20.6 g of 95% sulfuric acid was slowly added dropwise to 70 g (2.2 mol) of methanol with ice cooling. Then, into a 300-ml glass autoclave, the resulting sulfuric acid/methanol solution and a 5% Rh/C catalyst (available from NE Chemcat Corporation, hydrous product) in an amount of 0.25 g on a dry weight basis were charged. The system was purged with hydrogen to make a hydrogen pressure 0.1 MPa at room temperature. Heating of the autoclave and stirring of the contents in the EPO <DP n="20"/>autoclave were started, and the temperature was increased to 400C and was held constant for 1 hour. After the autoclave was cooled, 10 g (50 mmol) of tetrafluoroterephthalonitrile (available from Tokyo Kasei Kogyo Co., Ltd.) was fed to the autoclave, and the temperature was raised to 700C in a nitrogen atmosphere. At 700C, introduction of hydrogen was started. The reaction pressure was controlled so that the hydrogen absorption rate should become not more than 10 ml/min. After a lapse of 6 hours and 30 minutes, absorption of hydrogen ceased. The quantity of hydrogen absorbed was 119% of the theoretical quantity of hydrogen absorbed. The reaction solution was filtered to separate the catalyst, and methanol was distilled off at atmospheric pressure. Thereafter, 100 g of water was added to the residue, and the mixture was refluxed by heating at an internal temperature of 1000C for 60 minutes. Then, methanol formed by hydrolysis of acetal was distilled off at atmospheric pressure. When the top temperature of the distillation reached 99C, the distillation was finished, and the resulting solution was cooled to room temperature. Then, the solution was extracted 3 times each with 30 g of toluene . EPO <DP n="21"/>From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, the amount of tetrafluoroterephthalaldehyde was 92.0 mol%, the amount of 2, 3, 5, 6-tetrafluorobenzene was 0.94 mol%, and the amount of 2, 3, 5, 6-tetrafluorobenzonitrile was 0.79 mol%. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 3.39 mol% of 2, 3, 5, 6-tetrafluorobenzylamine was confirmed. The results are set forth in Table 1. [Example 2]The same operations as in Example 1 were carried out, except that as a catalyst a 5% Pd/C catalyst (available from NE Chemcat Corporation, hydrous product) was charged in an amount of 0.25 g on a dry weight basis. After a lapse of 3.3 hours, absorption of hydrogen ceased. The quantity of hydrogen absorbed was 117% of the theoretical quantity of hydrogen absorbed. Treatment of the reaction solution was carried out in the same manner as in Example 1.From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a EPO <DP n="22"/>result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, and the amount of tetrafluoroterephthalaldehyde was 68.9 mol%. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of14.8 mo1% of 2, 3, 5, 6-tetrafluorobenzylamine was confirmed.The results are set forth in Table 1. [Example 2]; The same operations as in Example 1 were carried out, except that as a catalyst a 5% Pd/C catalyst (available from NE Chemcat Corporation, hydrous product) was charged in an amount of 0.25 g on a dry weight basis. After a lapse of 3.3 hours, absorption of hydrogen ceased. The quantity of hydrogen absorbed was 117% of the theoretical quantity of hydrogen absorbed. Treatment of the reaction solution was carried out in the same manner as in Example 1.From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a EPO <DP n="22"/>result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, and the amount of tetrafluoroterephthalaldehyde was 68.9 mol%. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of14.8 mo1% of 2, 3, 5, 6-tetrafluorobenzylamine was confirmed.The results are set forth in Table 1.; [Example 3] The same operations as in Example 1 were carried out, except that the temperature of the pretreatment of the catalyst with hydrogen was changed from 400C to 500C.After a lapse of 5.5 hours, absorption of hydrogen ceased.The quantity of hydrogen absorbed was 106% of the theoretical quantity of hydrogen absorbed. Treatment of the reaction solution was carried out in the same manner as in Example 1.From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was ... | ||
[Example 7]; The same operations as in Example 1 were carried out, except that the catalyst used was changed from the 5% Rh/C catalyst (available from NE Chemcat Corporation, hydrous product) to a 2% Rh/C catalyst (available from NE Chemcat EPO <DP n="26"/>Corporation, hydrous product) . After a lapse of 7.3 hours, absorption of hydrogen ceased. The quantity of hydrogen absorbed was 114% of the theoretical quantity of hydrogen absorbed. Treatment of the reaction solution was carried out in the same manner as in Example 1.From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, the amount of tetrafluoroterephthalaldehyde was 88.6 mol%, the amount of 2, 3, 5, 6-tetrafluorobenzene was 1.15 mol%, and the amount of 2, 3, 5, 6-tetrafluorobenzonitrile was 2.63 ralphaol%. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 2.36 mol% of 2, 3, 5, 6-tetrafluorobenzylamine was confirmed. The results are set forth in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[Comparative Example 1]; The same operations as in Example 1 were carried out, except that the amount of the catalyst used was changed from 0.25 g to 0.05 g on a dry weight basis. After a lapse of 7.0 hours, absorption of hydrogen ceased. The quantity of hydrogen absorbed was 83% of the theoretical quantity of hydrogen absorbed. Treatment of the reaction solution was carried out in the same manner as in Example 1. EPO <DP n="28"/>From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, the tetrafluoroterephthalonitrile as a raw material remained in an amount of 21.0 mol%, and tetrafluoroterephthalaldehyde was obtained in an amount of only 5.0 mol%. The amount of 2, 3, 5, 6-tetrafluorobenzene was 0.65 mol%, the amount of 2,3,5,6- tetrafluorobenzonitrile was 0.53 mol%, and 1-cyano- 2, 3, 5, 6-tetrafluorobenzaldehyde wherein a nitrile group on only one side had reacted was obtained in an amount of 63.1 mol%. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 2.88 mol% of 2,3,5,6- tetrafluorobenzylamine was confirmed. The results are set forth in Table 2.; [Comparative Example 3]; The same operations as in Example 1 were carried out, except that the amount of sulfuric acid used was changed from 20.6 g to 5.15 g (50 mmol). After a lapse of 4.2 hours, absorption of hydrogen ceased. The quantity of hydrogen absorbed was 47% of the theoretical quantity of hydrogen absorbed. Treatment of the reaction solution was carried out in the same manner as in Example 1.From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below EPO <DP n="30"/>the detection limit, and tetrafluoroterephthalaldehyde was obtained in an amount of only 14.5 mol%. The amount of 2, 3, 5, 6-tetrafluorobenzene was 0.81 mol%, the amount of 2, 3, 5, 6-tetrafluorobenzonitrile was 0.67 mol%, and 1- cyano-2, 3, 5, 6-tetrafluorobenzaldehyde wherein a nitrile group on only one side had reacted was obtained in an amount of 54.0 mol%. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 0.04 mol% of 2,3,5,6- tetrafluorobenzylamine was confirmed. The results are set forth in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[Comparative Example 4]; The same operations as in Example 1 were carried out, except that the reaction temperature was changed from 7O0C to 12O0C. After a lapse of 8.0 hours, absorption of hydrogen ceased. The quantity of hydrogen absorbed was 103% of the theoretical quantity of hydrogen absorbed. Treatment of the reaction solution was carried out in the same manner as in Example 1. From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, and tetrafluoroterephthalaldehyde was EPO <DP n="31"/>obtained in an amount of only 2.6 mol%. The amount of 2, 3, 5, beta-tetrafluorobenzene was 1.08 mol%, the amount of 2, 3, 5, 6-tetrafluorobenzonitrile was 0.87 mol%, and 1- cyano-2, 3, 5, 6-tetrafluorobenzaldehyde wherein a nitrile group on only one side had reacted was obtained in an amount of 42.2 mol%. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, the amount of 2,3,5,6- tetrafluorobenzylamine was below the detection limit. The results are set forth in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 77% 2: 15% | With potassium phosphate In N,N-dimethyl-formamide at 130℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydroxide In sodium hydroxide with 3 N NaOH soln.; stirring and refluxing; | |
90% | With NaOH In sodium hydroxide aq. NaOH; with 3 N NaOH soln.; stirring and refluxing; | |
With tin(ll) chloride In water in concd. HCl; |
With C2H5ONa In ethanol at 30°C; | ||
With SnCl2 In water in concd. HCl; | ||
With sodium ethanolate In ethanol at 30°C; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 99% 2: 5% | With bis(1,5-cyclooctadiene)nickel (0); tricyclopentylphosphine In toluene at 80℃; for 10h; | |
1: 53% 2: 7% | With bis(1,5-cyclooctadiene)nickel (0); tricyclopentylphosphine In toluene at 80℃; for 1h; | |
1: 53% 2: 7% | With bis(1,5-cyclooctadiene)nickel (0); tricyclopentylphosphine In toluene at 80℃; for 1h; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 66% 2: 8% | With palladium diacetate; silver carbonate; Trimethylacetic acid In N,N-dimethyl-formamide at 120℃; for 21h; Inert atmosphere; regioselective reaction; | |
1: 41% 2: 9% | With methyl-phenyl-thioether; oxygen; palladium diacetate; silver carbonate In N,N-dimethyl acetamide at 120℃; for 8h; Sealed tube; Green chemistry; | General Procedure for the Alkenylation of Polyfluorobenzene General procedure: To a 25 mL sealed tube were added Pd(OAc)2 (10 mol%) and Ag2CO3 (0.1 equiv), After the sealed tube was refilled with O2 three times, DMA (1.0 mL), PhSCH3 (70 L), Fluoroarene 1 (0.3 mmol, 1.0 equiv) and alkene 2 (1.0equiv) were added subsequently. The sealed tube was screw capped and heated to 120 oC (oil bath).After stirring for 8 h, the reaction mixture was cooled to room temperature and diluted with ethylacetate, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography to provide product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With palladium diacetate; potassium carbonate; silver carbonate; 2-(dicyclohexylphosphino)-2'-methylbiphenyl In water; ethyl acetate at 23℃; for 16h; Inert atmosphere; | |
83% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); lithium tert-butoxide In N,N-dimethyl-formamide at 120℃; for 24h; Inert atmosphere; Schlenk technique; | General procedure for the arylation of polyfluoroarenes General procedure: Aryl iodides (0:5 mmol), polyfluoroarenes (1.5 equiv.), CuI (20 mol-%), Pd(PPh3)4 (5 mol-%) and tBuOLi (2.0 equiv.) were weighed into a 25 mL Schlenk round bottom flask under nitrogen atmosphere. The system was degassed four times by an oil pump, and then 3 mL DMF was added by a syringe. The resulting solution was stirred at 120 °C under nitrogen. The reaction progress was monitored by GCMS. After the completion of the reaction, the solution was extracted with ethyl acetate (310 mL), the extract was washed with H2O and brine, dried (MgSO4), and concentrated to dryness. Purification on silica gel (petroleum ether-EtOAc, 10 : 1 ~ 30 : 1) gave the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With palladium diacetate; acetic acid; silver carbonate In dimethyl sulfoxide; N,N-dimethyl-formamide for 4h; Inert atmosphere; Sealed tube; Heating; | |
50% | With palladium diacetate; acetic acid; silver carbonate In dimethyl sulfoxide; N,N-dimethyl-formamide at 140℃; for 4h; Inert atmosphere; regioselective reaction; | |
48% | With oxygen; palladium diacetate; silver(l) oxide; Trimethylacetic acid In dimethyl sulfoxide; N,N-dimethyl-formamide at 120℃; for 9h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 93% 2: 7% | at 80℃; for 0.2h; | In a first example process, a single-step catalytic stannylation of a fluorinated arene compound was achieved using Bu3Sn(CHCH2) or Me3Sn(CHCH2) as a first organometallic compound in the presence of Ni(COD)2 with at least one of MeNC5H4NiPr and PiPr3 as a catalyst as follows: The preferred reaction advantageously shows quantitative functionalization and may be performed using as little as 1 mol % of Ni(COD)2 and MeNC5H4NiPr to go to completion. Test reactions were run at room temperature and yielded ethylene as a by-product. The reaction may further be performed without addition of solvent.In test samples the above reaction has been demonstrated to work with a number of different fluorinated arene compounds yielding resulting functionalized products in excess of 90%.Table 1 below illustrates example single-step reactions of the present invention involving use of fluorinated arene compounds having 2 to 5 fluorine substituents, the catalyst Ni(COD)2 and the ancillary ligand MeNC5H4NiPr and/or PiPr3. The yield percent marked with the superscript a provides NMR yield from integration of 19F[1H] NMR spectra, and yield percent marked with the superscript b provides isolated yield after chromatography. The condition hours marked with the superscript c and d denote that the reaction was carried out using 2.5 molar amount of Bu3Sn(CHCH2) and 10 fold excess of the fluorinated arene compound, respectively. |
With Ni(C8H12)2; P(CH(CH3)2)3 In benzene-d6 byproducts: CH2CH2; heating mixt. of tin compd., excess of tetrafluorobenzene, nickel compd.and phosphine deriv. in C6D6 at 80°C for 0.2 h; detected by NMR as 93:7 mixt. of mono- and distannylated derivs.; | ||
With Ni(C8H12)2; (CH3)2CHNC5H4NCH3 In benzene-d6 byproducts: CH2CH2; heating tin compd., C6F4H2, nickel compd. and iminopyridone deriv. in C6D6; using excess of C6F4H2 at 35°C for 0.5 h results in monostannylated deriv. mainly, using excess of tin compd. at 45°C for 6 h gives distannylated deriv. mainly; NMR; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In N,N-dimethyl-formamide at 125℃; for 24h; Inert atmosphere; | |
84% | With copper(l) iodide; 1,10-Phenanthroline; lithium tert-butoxide In N,N-dimethyl-formamide at 125℃; for 24h; Inert atmosphere; Glovebox; Sealed tube; | |
80% | With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In N,N-dimethyl-formamide at 125℃; for 24h; Glovebox; |
55% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; acetic acid at 75℃; for 12h; Inert atmosphere; Ionic liquid; | Procedure for kinetic isotopic effect measurement 1,2,4,5-Tetrafluorobenzene (1 mmol) was introduced at r.t. into an oven-dried Schlenk tube charged with fresh (bmim)BF4 ionic liquid (~4 mL) under a nitrogen atmosphere. After efficient magnetic stirring (for 10-20 min) Pd(OAc)2 (20 mol%) was introduced and was dissolved in the IL following efficient magnetic stirring (for 10-20 min). The reaction mixture was then charged with a 1:1 mixture of arenes (benzene + benzene-d6) (4 mmol) and AcOH (1-2 mol%) under nitrogen and was stirred at 75oC under nitrogen while monitoring the progress of the reaction by GC-MS. The brown-colored reaction mass was cooled to r.t. and the products were extracted with dry diethyl ether (4-5 times). Removal of solvent under vacuum furnished the crude products which were chromatographed with hexane-ethyl acetate mixture (75:25) to afford the pure cross-coupling products that were characterized by GC-MS, 1H, and 19F NMR. The KH/KD value was calculated based on integral ratios in the 1H and 19F NMR spectra. The 19F NMR spectrum of a mixture of benzene and benzene-d6 coupled to 1,2,4,5-tetrafluorobenzene displayed three multiplets at δF -139.36, δF -143.73 and δF -143.99 with relative integral values 2.44, 0.38 and 2 respectively [1 integral unit per F versus 0.205 per F (for deuterated analog)] which gave a KH/KD ratio of 2/0.41 = 4.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (1,3-diisopropylimidazolin-2-ylidene)*AlH3 In 5,5-dimethyl-1,3-cyclohexadiene at 135℃; for 72h; | |
98% | With [((1,2-bis(diisopropylphosphino)ethane))Ni(μ-H)]2; triethylphosphine In 1,4-dioxane at 120℃; for 72h; | |
81% | With zirconocene dichloride; [{((2,6-dimethylphenyl)NC(methyl))2CH}AlH2] In hexadeuterobenzene at 80℃; for 24h; Inert atmosphere; |
72% | With sodium tetrahydridoborate; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) In N,N-dimethyl-formamide at 20℃; for 18h; | Catalytic hydrodehalogenation experiments General procedure: All reactions were carriedout in air at room temperature. A 50 mL round-bottom flask equippedwith a magnetic stir bar was charged with 280.8 mg (0.90 mmol) of 4,4′ -dibromobiphenyl (or 0.90 mmol of another aryl halide), 0.09 mmol ofcatalyst (10 mole%), 68.1 mg (0.18 mmol, 2.0 eq) of NaBH4 and 6 mL ofDMF (or other solvents) in room temperature. The reaction mixture wasleft to stir overnight for 18 h. Thereafter, 6 mL of deionised water wasadded to stop the reaction by deactivating the excess NaBH4 in themixture. |
30 %Spectr. | With 4,5-bis(di-tert-butyl phosphino)-9,9-dimethylxanthene; [t-BuXantphosAu]+[Cl-Au-Cl]-; diphenylsilane; glacial acetic acid In 1,2-dichloro-ethane at 80℃; for 24h; Inert atmosphere; | |
100 %Spectr. | With Dimethylphenylsilane; 1,2-bis(diphenylphosphanyl)benzene; potassium-t-butoxide; copper chloride (I) In tetrahydrofuran for 12h; Inert atmosphere; Reflux; regioselective reaction; | |
With tetrakis(trimethylphosphine)cobalt(0); anhydrous sodium formate In dimethyl sulfoxide for 3h; Inert atmosphere; | ||
With [Cp*Rh(bpy)]; hydrogen; diethylamine In acetonitrile at 25℃; for 24h; | ||
80 %Spectr. | With 1,3,6,8-tetrakis(3,5-dimethylphenyl)pyrene; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 45℃; for 24h; Inert atmosphere; Sealed tube; Irradiation; | |
45 %Spectr. | With H2SiEt2; C17H21BiN2O3 In tetrahydrofuran at 60℃; for 72h; Inert atmosphere; Sealed tube; | |
92 %Spectr. | With phenylsilane; 2-H-1,3-di-tert-butyl-2,3-dihydro-1H-1,3,2-diazaphosphole In acetonitrile at 100℃; for 5h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 2h; Stage #2: formic acid ethyl ester In tetrahydrofuran; hexane at -78℃; for 3h; Stage #3: With ethanol; iodine; potassium carbonate In hexane at -78 - 20℃; for 40h; | 4.2. Typical procedure for one-pot conversion of aromatic bromides into aromatic ethyl esters with ethyl formate General procedure: n-BuLi (1.67 M solution in hexane, 1.32 mL, 2.2 mmol) was added dropwise into a solution of p-bromochlorobenzene (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, ethyl formate (1.6 mL, 20 mmol) was added to the mixture and the obtained mixture was stirred at -78 °C. After 3 h at the same temperature, I2 (1523 mg, 6 mmol), K2CO3 (1382 mg, 10 mmol) and EtOH (3 mL) were added at -78 °C and the mixture was stirred for 14 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide ethyl 4-chlorobenzoate in 77% yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure ethyl 4-chloro-1-benzoate as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline; tetra-(n-butyl)ammonium iodide In dimethyl sulfoxide; acetonitrile at 130℃; for 24h; Inert atmosphere; Schlenk technique; | General procedure for coupling of Arenediazonium salts with polyfluorobenzenes General procedure: A 25mL schlenk flask was charged under nitrogen with arenediazonium salt (1.0 mmol), n-Bu4NI (1.5 mmol), CuI (0.2 mmol), Phen (0.2 mmol), potassium orthophosphate (3.0 mmol), polyfluorobenzenes (3.0 mmol) and a mixture (1/1) of anhydrous DMSO and MeCN (3.0 mL). The flask was sealed and stirred at 130 oC for a period of time. Then, the reaction mixture was diluted with EtOAc (20mL) and washed with a saturated NaCl solution(20mL) for there times. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography eluting with a petroleum ether/ethyl acetate mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In 1-methyl-pyrrolidin-2-one at 220℃; for 1.5h; Microwave irradiation; Sealed tube; | 9 4-(2,4,5-Trifluorophenyl)morpholine (10) General procedure: Fluorobenzenes (3eq, 30 mmol), amines (1 eq, 10 mmol), K2CO3 (2 eq) and NMP (15 mL) were charged to a 20 mL microwave vial equipped with a magnetic stir bar. The vial was capped and heated in the Biotage Initiator microwave reactor (with following setting: prestir = 20 s; absorption level = very high; fixed hold time = on) for 1-6 h at 190-250 °C as indicated. After cooling to 50 °C, the vial was opened and the contents were transferred to a separatory funnel containing water (60 mL) and extracted with ethyl acetate (15 mL × 4). The combined organic extracts were washed with water, and dried over anhydrous Na2SO4. After removal of the solvent, the residues were purified by the column chromatography on silica gel to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In 1-methyl-pyrrolidin-2-one at 190℃; for 1h; Microwave irradiation; Sealed tube; | 12 1-(2,4,5-Trifluorophenyl)piperazine (15) General procedure: Fluorobenzenes (3eq, 30 mmol), amines (1 eq, 10 mmol), K2CO3 (2 eq) and NMP (15 mL) were charged to a 20 mL microwave vial equipped with a magnetic stir bar. The vial was capped and heated in the Biotage Initiator microwave reactor (with following setting: prestir = 20 s; absorption level = very high; fixed hold time = on) for 1-6 h at 190-250 °C as indicated. After cooling to 50 °C, the vial was opened and the contents were transferred to a separatory funnel containing water (60 mL) and extracted with ethyl acetate (15 mL × 4). The combined organic extracts were washed with water, and dried over anhydrous Na2SO4. After removal of the solvent, the residues were purified by the column chromatography on silica gel to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In 1-methyl-pyrrolidin-2-one at 220℃; for 1h; Microwave irradiation; Sealed tube; | 4 1-(2,4,5-Trifluorophenyl)-4-methylpiperazine (5) General procedure: Fluorobenzenes (3eq, 30 mmol), amines (1 eq, 10 mmol), K2CO3 (2 eq) and NMP (15 mL) were charged to a 20 mL microwave vial equipped with a magnetic stir bar. The vial was capped and heated in the Biotage Initiator microwave reactor (with following setting: prestir = 20 s; absorption level = very high; fixed hold time = on) for 1-6 h at 190-250 °C as indicated. After cooling to 50 °C, the vial was opened and the contents were transferred to a separatory funnel containing water (60 mL) and extracted with ethyl acetate (15 mL × 4). The combined organic extracts were washed with water, and dried over anhydrous Na2SO4. After removal of the solvent, the residues were purified by the column chromatography on silica gel to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In toluene at 80℃; for 24h; | Reactivity of Gold (1) Hydroxide Complexes Protonolysis reactions involving the fluoroarenes 10 (a-b) [Table 1 below] led to complete conversion of the starting material and conversions into corresponding complexes 11a and 11b in 86 and 93% isolated yields, respectively. In the case of trifluorobenzene 10c, this is however not the case as no reaction was observed and 2 was recovered unchanged. From these reactivity results and the known pKa (a measure of the acidity of the proton on the substrate) values of the protons on 10, it is estimated that protonolysis reactions involving protons with a pKa value of up to 29-31 should be successful. (11). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 62% 2: 13% | With palladium diacetate; silver(l) oxide In 1-methyl-pyrrolidin-2-one at 100℃; for 15h; Glovebox; Schlenk technique; | 4.2 General procedure for Pd-catalyzed direct cross-coupling of polyfluoroarenes with aryltrifluoroborates General procedure: In a glovebox, Pd(OAc)2 (9.0 mg, 0.040 mmol), Ag2O (138.0 mg, 0.60 mmol) and aryltrifluoroborates (0.40 mmol) were added to a Schlenk tube that was equipped with a stirring bar. Freshly distilled solvent NMP (3.0 mL) was added into this tube, polyfluoroarene (0.40 mmol) were added in turn to the Schlenk tube through the rubber septum via syringe. The tube was capped with a septum and taken out. The reaction mixture was stirred at 100 °C for 15 h. After cooling down, the reaction mixture was diluted with 10 mL of ethyl ether, filtered through a pad of silica gel, followed by washing the pad of the silica gel with the same solvent (10 mL). The filtrate was washed with water (3 × 10 mL). The organic phase was dried over MgSO4, filtered, concentrated in vacuo. The residue was then purified by flash chromatography on silica gel to provide the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In benzene-d6; at 50℃; for 96h;Inert atmosphere; | General procedure: To a solution of [Rh(mu-H)(dippp)]2 (1) (0.1 M) in benzene-d6 in a PFA tube fluoroarene (0.22 M) was added and alpha,alpha,alpha-tri-fluorotoluene or alpha,alpha,alpha-trifluorotoluene (1-2 muL) as internal standard. The PFA tube was closed by a Teflon plug and inserted into a NMR tube. An initial 19F{1H} NMR spectrum was recorded at room temperature and the reaction mixture was then heated to 50 C. After a set period of time complete conversion of 1 to 2 was observed by 31P{1H} NMR spectroscopy. Hydrodefluorination products were identified by 19F NMR and 1H NMR spectroscopy by comparison with literature data [23]. A reaction of 1 with pentafluoropyridine gave 2,3,5,6- and 2,3,4,5-tetrafluoropyridine (ratio 3:1) after 48 h. A reaction of 1 with 2,3,5,6-tetrafluoropyridine gave 2,3,6- and 2,3,5-trifluoropyridine (ratio 21:1) after 48 h. A reaction of 1 with hexafluorobenzene gave pentafluorobenzene, 1,2,3,4- and 1,2,4,5 tetrafluorobenzene (ratio 11:2:1) after 96 h. A reaction of 1 with pentafluorobenzene gave 1,2,3,4- and 1,2,4,5-tetrafluorobenzene (ratio 32:1) after 72 h. Ratios of the organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In benzene-d6; at 50℃; for 72h;Inert atmosphere; | General procedure: To a solution of [Rh(mu-H)(dippp)]2 (1) (0.1 M) in benzene-d6 in a PFA tube fluoroarene (0.22 M) was added and alpha,alpha,alpha-tri-fluorotoluene or alpha,alpha,alpha-trifluorotoluene (1-2 muL) as internal standard. The PFA tube was closed by a Teflon plug and inserted into a NMR tube. An initial 19F{1H} NMR spectrum was recorded at room temperature and the reaction mixture was then heated to 50 C. After a set period of time complete conversion of 1 to 2 was observed by 31P{1H} NMR spectroscopy. Hydrodefluorination products were identified by 19F NMR and 1H NMR spectroscopy by comparison with literature data [23]. A reaction of 1 with pentafluoropyridine gave 2,3,5,6- and 2,3,4,5-tetrafluoropyridine (ratio 3:1) after 48 h. A reaction of 1 with 2,3,5,6-tetrafluoropyridine gave 2,3,6- and 2,3,5-trifluoropyridine (ratio 21:1) after 48 h. A reaction of 1 with hexafluorobenzene gave pentafluorobenzene, 1,2,3,4- and 1,2,4,5 tetrafluorobenzene (ratio 11:2:1) after 96 h. A reaction of 1 with pentafluorobenzene gave 1,2,3,4- and 1,2,4,5-tetrafluorobenzene (ratio 32:1) after 72 h. Ratios of the organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium phosphate dodecahydrate; silver carbonate; palladium dichloride In water; dimethyl sulfoxide at 100℃; for 18h; Schlenk technique; | |
48% | With bis(η3-allyl-μ-chloropalladium(II)); silver(l) oxide; XPhos In water; N,N-dimethyl-formamide at 110℃; for 20h; Schlenk technique; | 4.2. General procedure for direct Pd-catalyzed cross-coupling ofpolyfluoroarenes with sodium arylsulfinate General procedure: [PdCl(allyl)]2 (36.6mg, 0.10mmol), Xphos (47.6mg, 0.10mmol), Ag2O (236.0mg, 1.0mmol) and sodium arylsulfinate (0.50mmol) were added to a Schlenk tube that was equipped with a stirring bar. Wet DMF (5.0mL, containing 1vol% of H2O) was added into this tube, polyfluoroarene (1.0mmol) were added in turn to the Schlenk tube through the rubber septum via syringe. The tube was capped with a septum and taken out. The reaction mixture was stirred at 110°C for 20h. After cooling down, the reaction mixture was diluted with 10mL of ethyl ether, filtered through a pad of silica gel, followed by washing the pad of the silica gel with the same solvent (10mL). The filtrate was washed with water (3× 10mL). The organic phase was dried over MgSO4, filtered, concentrated in vacuo. The residue was then purified by flash chromatography on silica gel to provide the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium phosphate dodecahydrate; silver carbonate; palladium dichloride In water; dimethyl sulfoxide at 100℃; for 18h; Schlenk technique; | |
42% | With bis(η3-allyl-μ-chloropalladium(II)); silver(l) oxide; XPhos In water; N,N-dimethyl-formamide at 110℃; for 20h; Schlenk technique; | 4.2. General procedure for direct Pd-catalyzed cross-coupling ofpolyfluoroarenes with sodium arylsulfinate General procedure: [PdCl(allyl)]2 (36.6mg, 0.10mmol), Xphos (47.6mg, 0.10mmol), Ag2O (236.0mg, 1.0mmol) and sodium arylsulfinate (0.50mmol) were added to a Schlenk tube that was equipped with a stirring bar. Wet DMF (5.0mL, containing 1vol% of H2O) was added into this tube, polyfluoroarene (1.0mmol) were added in turn to the Schlenk tube through the rubber septum via syringe. The tube was capped with a septum and taken out. The reaction mixture was stirred at 110°C for 20h. After cooling down, the reaction mixture was diluted with 10mL of ethyl ether, filtered through a pad of silica gel, followed by washing the pad of the silica gel with the same solvent (10mL). The filtrate was washed with water (3× 10mL). The organic phase was dried over MgSO4, filtered, concentrated in vacuo. The residue was then purified by flash chromatography on silica gel to provide the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With bis(η3-allyl-μ-chloropalladium(II)); silver(l) oxide; XPhos In water; N,N-dimethyl-formamide at 110℃; for 20h; Schlenk technique; | 4.2. General procedure for direct Pd-catalyzed cross-coupling ofpolyfluoroarenes with sodium arylsulfinate General procedure: [PdCl(allyl)]2 (36.6mg, 0.10mmol), Xphos (47.6mg, 0.10mmol), Ag2O (236.0mg, 1.0mmol) and sodium arylsulfinate (0.50mmol) were added to a Schlenk tube that was equipped with a stirring bar. Wet DMF (5.0mL, containing 1vol% of H2O) was added into this tube, polyfluoroarene (1.0mmol) were added in turn to the Schlenk tube through the rubber septum via syringe. The tube was capped with a septum and taken out. The reaction mixture was stirred at 110°C for 20h. After cooling down, the reaction mixture was diluted with 10mL of ethyl ether, filtered through a pad of silica gel, followed by washing the pad of the silica gel with the same solvent (10mL). The filtrate was washed with water (3× 10mL). The organic phase was dried over MgSO4, filtered, concentrated in vacuo. The residue was then purified by flash chromatography on silica gel to provide the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With bis(η3-allyl-μ-chloropalladium(II)); silver(l) oxide; XPhos; In water; N,N-dimethyl-formamide; at 110℃; for 20h;Schlenk technique; | General procedure: [PdCl(allyl)]2 (36.6mg, 0.10mmol), Xphos (47.6mg, 0.10mmol), Ag2O (236.0mg, 1.0mmol) and sodium arylsulfinate (0.50mmol) were added to a Schlenk tube that was equipped with a stirring bar. Wet DMF (5.0mL, containing 1vol% of H2O) was added into this tube, polyfluoroarene (1.0mmol) were added in turn to the Schlenk tube through the rubber septum via syringe. The tube was capped with a septum and taken out. The reaction mixture was stirred at 110C for 20h. After cooling down, the reaction mixture was diluted with 10mL of ethyl ether, filtered through a pad of silica gel, followed by washing the pad of the silica gel with the same solvent (10mL). The filtrate was washed with water (3× 10mL). The organic phase was dried over MgSO4, filtered, concentrated in vacuo. The residue was then purified by flash chromatography on silica gel to provide the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With palladium diacetate; silver carbonate; silver(l) oxide In dimethyl sulfoxide at 120℃; for 24h; | Synthesis of 3a-v General procedure: Synthesis of 3a-v A mixture of 1 (0.2 mmol), 2 (0.6 mmol), DMSO (3 mL),Pd(OAc)2 (5 mol%), and Ag2CO3 and Ag2O (1.5 equiv, 1:1) was stirred at 120 °C under air atmosphere for 24 h. To the reaction mixture was added H2O and EtOAc, and the aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the corresponding products(3a,12 3g,13 3h,14 3i-l,9 3m,16 3n,17 3p,q,s-v9 according to the literature). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium phosphate; chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II); Trimethylacetic acid In N,N-dimethyl acetamide at 80℃; for 2 - 4h; | |
66% | With sodium carbonate; acetic acid In N,N-dimethyl acetamide; N,N-dimethyl-formamide at 140℃; for 24h; Sealed tube; | 2.4. General catalytic procedure and analyzes General procedure: A mixture of pentafluorobenzene (1.5 mmol, 1.5 equiv.), aryl halides (1.0 mmol, 1.0 equiv.), sodium carbonate (2 mmol, 2 equiv.), acetic acid (2 mmol, 2 equiv.) and the as-prepared Pd NCs catalyst (1 mol%) was added into a 35 mL pressure tube. Then, 2 mL mixed solvent solution of DMA/DMF (0.6/1.4) was added. The reaction mixture was stirred at 140 °C for 24 h under ambient atmosphere. After the reaction was completed, the solid catalyst was separated by filtration, and the filtrate was diluted with water followed by extraction with ethyl acetate (3 x 10 mL), and dried over anhydrous Na2SO4. The solvent was removed by vacuum rotary evaporation, and the crude product was directly analyzed by GC-MS with n-dodecane as an internal standard. The product was further purified by column chromatography (silica gel, ethyl acetate/hexane gradient) for NMR. |
30% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium carbonate; acetic acid In N,N-dimethyl acetamide; N,N-dimethyl-formamide at 140℃; for 24h; Sealed tube; | 2.4. General catalytic procedure and analyzes General procedure: A mixture of pentafluorobenzene (1.5 mmol, 1.5 equiv.), aryl halides (1.0 mmol, 1.0 equiv.), sodium carbonate (2 mmol, 2 equiv.), acetic acid (2 mmol, 2 equiv.) and the as-prepared Pd NCs catalyst (1 mol%) was added into a 35 mL pressure tube. Then, 2 mL mixed solvent solution of DMA/DMF (0.6/1.4) was added. The reaction mixture was stirred at 140 °C for 24 h under ambient atmosphere. After the reaction was completed, the solid catalyst was separated by filtration, and the filtrate was diluted with water followed by extraction with ethyl acetate (3 x 10 mL), and dried over anhydrous Na2SO4. The solvent was removed by vacuum rotary evaporation, and the crude product was directly analyzed by GC-MS with n-dodecane as an internal standard. The product was further purified by column chromatography (silica gel, ethyl acetate/hexane gradient) for NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.5% | With hydrogenchloride In water; acetonitrile at 140℃; for 0.75h; Microwave irradiation; | 1.1 1 .1 : 1 -carbamimidoyl-3-(2,3,5,6-tetrafluorophenyl)guanidine Aq. HCI (38% w/w, 1.5 mL) was added, with stirring, to a solution of 2,3,5,6- Tetrafluoropyridine (2.00 g, 12.1 mmol) and 1 -cyanoguanidine (1.22 g, 14,5 mmol) in acetonitrile (50 mL) and the mixture was heated under microwave radiation (45 min, 140 °C, 15 bar). The reaction mixture was cooled to room temperature and aq. NaOH (2M) was added until pH 12. Ethyl acetate was added and the phases were separated. The organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to yield the desired product (2.19 g, 72,5% yield), which was directly used in the next step without any further purification. MS (ESI) m/z 250 [M+H+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium In diethyl ether; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: boron trifluoride diethyl etherate In diethyl ether; hexane at -78 - 0℃; for 0.416667h; Inert atmosphere; Stage #3: potassium phosphate In diethyl ether; hexane; water at 20℃; Inert atmosphere; | 10 4.7 Potassium organotrifluoroborates General procedure: To a solution of RH (2.6 mmol) in Et2O was added n-BuLi (1.0 mL, 2.5 M in hexane) at -78 °C under N2. After stirring for 1 h, BF3·OEt2 (0.25 mL, 2.0 mmol) was added, and the mixture was stirred for 10 min, followed by stirring at 0 °C for additional 15 min. Saturated aqueous K3PO4 (0.63 mL, 4.2 M) was added to the mixture. Subsequently, the reaction mixture was dried under high vacuum at rt with stirring. The residue was extracted with acetone, filtered through cotton and concentrated. The resulting residue was filtered through a filter paper, concentrated and precipitated with CH2Cl2. The solid was filtered and washed with CH2Cl2 to obtain potassium organotrifluoroborates (If needed, the solid mixture was washed with Et2O to remove Ar2BF2K). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.6% | Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium In tetrahydrofuran; hexane at -80 - -70℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyl isocyanide In tetrahydrofuran; hexane at -80 - -70℃; for 0.5h; Inert atmosphere; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexane for 0.5h; Reflux; Inert atmosphere; | 1 Example 1 Example 1 Equipped with a stirrer, a thermometer and a dropping funnel 250ml four-necked round flask was charged with 15g of 1,2,4,5-tetrafluorobenzene (0.1mol) and 80ml of tetrahydrofuran, the solution frozen in liquid nitrogen acetone frozen to -70~-80 . With vigorous stirring at -70~-80 , 42ml hexane was added dropwise in a solution of n-butyllithium (0.105mol), stirring was continued for 30min. With vigorous stirring at -70~-80 , 13.6g of tert-butylcarbonitrile and 20ml of tetrahydrofuran was dubbed in, stirring was continued for 30min, warmed to room temperature slowly. At room temperature the reaction was transferred to another 500ml round bottom flask and stirred and a 5% diluted hydrochloric acid was added 75ml (1.1mol), was heated at reflux for 30min then cooled to room temperature. Was allowed to stand at room temperature stratification, the organic phase was added 20g of anhydrous magnesium sulfate and stirred for 1h, filtered to remove inorganic salts, the filtrate was distilled to remove the solvent, the crystalline solid occurred when heating was stopped, cooling and crystallization was added 40ml of heptane, filtered and dried to give a white crystalline solid 18.3 g. GC area percentage of 99.2%, a yield of 77.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | 1, 360 mg (2.4 mmol) of 1,2,4,5-tetrafluorobenzene was dissolved in tetrahydrofuran (1 mL) under anhydrous anaerobic conditions, and then 1 mL of 2 mol / L isopropylmagnesium chloride in tetrahydrofuran was added. 12 hours, and then 2.2 mL of a 1 mol / L solution of zinc chloride in tetrahydrofuran was added, and the stirring was continued at room temperature for 2 hours. 2. To a tetrahydrofuran (1 mL) was added 20.6 g (0.08 mmol) of bis (1,5-cyclooctadiene) nickel and 53.9 mg (0.1 mmol) of bis (2-diphenylphosphino) benzene under anhydrous anaerobic conditions Ether, and the mixture was stirred at room temperature for 30 minutes. 3. The reaction mixture obtained in Step 1 and Step 2 was mixed under anhydrous anaerobic conditions and 224 mg (1.0 mmol) of <strong>[16494-36-3]2-methyl-5-iodothiophene</strong> was added and stirred at room temperature for 12 hours. The reaction was complete by TLC. ML methanol for 10 minutes. After the reaction was quenched completely, the reaction solution was washed with 0.1 mol / L hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, column chromatography to give 2-methyl-5- (2 ', 3', 5 ', 6'-tetrafluoro-phenyl) thiophene in a yield of 92%, | |
91% | 1,In the absence of anaerobic conditions,360 mg (2.4 mmol) of 1,2,4,5-tetrafluorobenzene was dissolved in 1 mL of tetrahydrofuran,Then, 1 mL of a 2 mol / L solution of isopropylmagnesium chloride in tetrahydrofuran was added,The reaction was stirred at room temperature for 12 hours,To the reaction solution was added 3 mL of 1,4-dioxane,0.6 mL of ethylene glycol dimethyl ether and 26.4 mg (0.10 mmol) of 18-crown ether-6,Stir for 30 minutes at room temperature.2, in the anhydrous anaerobic conditions,To 0.4 mL of tetrahydrofuran and 0.6 mL of 1,4-dioxane was added 20.6 g(0.08 mmol)Bis (1,5-cyclooctadiene) nickel,77 mg (0.1 mmol) of bis (2-bis (3,5-dimethyl-4-methoxyphenyl)phosphine)Phenyl ether,Stir for 30 minutes at room temperature.3, in the anhydrous anaerobic conditions,The reaction solution obtained in Step 1 and Step 2 was mixed,And 224 mg (1.0 mmol) of <strong>[16494-36-3]2-methyl-5-iodothiophene</strong> was added,Stirring at room temperature for 6 hours,TLC detection reaction is complete,Add 0.5 mL of methanol for 10 min,After the reaction is quenched completely,The reaction solution was washed with 0.1 mol / L hydrochloric acid,And extracted with ethyl acetate,The ethyl acetate extract was dried over anhydrous sodium sulfate,Evaporated under reduced pressure,And then separated by silica gel column chromatography,To give the product 2-methyl-5- (2',3',5',6'-tetrafluorophenyl) thiophene,Its yield was 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With PdCl(1,4-bis(diphenylphosphino)butane)(C<SUB>3</SUB>H<SUB>5</SUB>); potassium pivalate In N,N-dimethyl acetamide at 150℃; for 16h; Inert atmosphere; Schlenk technique; | 4.3. Arylated Products General procedure: As a typical experiment, the reaction of the N-protected 5-(2-bromophenyl)tetrazole (0.5 mmol), (hetero)arene (0.75 mmol),and PivOK (140 mg, 1 mmol) at 150 °C over 16 h in 2 mL of DMA in the presence of PdCl(C3H5)(dppb) (6.1 mg, 0.01 mmol), under argon affords the coupling product after evaporation of the solvent and purification on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With PdCl(1,4-bis(diphenylphosphino)butane)(C<SUB>3</SUB>H<SUB>5</SUB>); potassium pivalate In N,N-dimethyl acetamide at 150℃; for 16h; Inert atmosphere; Schlenk technique; | 4.3. Arylated Products General procedure: As a typical experiment, the reaction of the N-protected 5-(2-bromophenyl)tetrazole (0.5 mmol), (hetero)arene (0.75 mmol),and PivOK (140 mg, 1 mmol) at 150 °C over 16 h in 2 mL of DMA in the presence of PdCl(C3H5)(dppb) (6.1 mg, 0.01 mmol), under argon affords the coupling product after evaporation of the solvent and purification on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 1,2,4,5-Tetrafluorobenzene With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 12h; Stage #2: With 18-crown-6 ether In 1,4-dioxane; 1,2-dimethoxyethane at 20℃; for 0.5h; Stage #3: acetophenone With bis(1,5-cyclooctadiene)nickel (0); bis[2-(di(2-naphthyl)phosphino)phenyl]ether In tetrahydrofuran; 1,4-dioxane at 10℃; for 6h; | 2 4-(2',3',5',6'-tetrafluorophenyl)acetophenone 1,In the absence of anaerobic conditions,360 mg (2.4 mmol) of 1,2,4,5-tetrafluorobenzene was dissolved in 1 mL of tetrahydrofuran,Then, 1 mL of a 2 mol / L solution of isopropylmagnesium chloride in tetrahydrofuran was added,The reaction was stirred at room temperature for 12 hours,To the reaction solution was added 3 mL of 1,4-dioxane,0.6 mL of ethylene glycol dimethyl ether and 26.4 mg (0.10 mmol) of 18-crown ether-6,Stir for 30 minutes at room temperature.2, in the anhydrous anaerobic conditions,To 0.4 mL of tetrahydrofuran and 0.6 mL of 1,4-dioxane was added 20.6 g(0.08 mmol)Bis (1,5-cyclooctadiene) nickel,77 mg (0.1 mmol) of bis (2-bis (3,5-dimethyl-4-methoxyphenyl)phosphine)Phenyl ether,Stir for 30 minutes at room temperature.3, in the anhydrous anaerobic conditions,The reaction solution obtained in Step 1 and Step 2 was mixed,And 224 mg (1.0 mmol) of 2-methyl-5-iodothiophene was added,Stirring at room temperature for 6 hours,TLC detection reaction is complete,Add 0.5 mL of methanol for 10 min,After the reaction is quenched completely,The reaction solution was washed with 0.1 mol / L hydrochloric acid,And extracted with ethyl acetate,The ethyl acetate extract was dried over anhydrous sodium sulfate,Evaporated under reduced pressure,And then separated by silica gel column chromatography,To give the product 2-methyl-5- (2 ', 3', 5 ', 6'-tetrafluorophenyl) thiophene,Its yield was 91%. In step 2 of Example 1,Bis (2-bis (3,5-dimethyl-4-methoxyphenyl) phosphine) phenylene was equimolar Of bis (2-bis (2-naphthyl) phosphine) phenylene, in step 3,2-methyl-5-iodothiophene was used in equimolar amounts of p-acetylbenzene Based trifluoromethanesulfonate,The reaction temperature was lowered to 10 ° C,The other steps were the same as in Example 1,To give 4-(2',3',5',6'-tetrafluorophenyl) acetophenone,The yield was 85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; | |
81% | Stage #1: 1,2,4,5-Tetrafluorobenzene With isopropylmagnesium chloride at 20℃; for 12h; Stage #2: With 18-crown-6 ether In 1,4-dioxane; 1,2-dimethoxyethane at 20℃; for 0.5h; Stage #3: p-(ethoxycarbonyl)phenyl triflate With bis(1,5-cyclooctadiene)nickel (0); bis[2-(di(3,4-dimethoxyphenyl)phosphino)phenyl]ether In tetrahydrofuran; 1,4-dioxane at 10℃; for 6h; | 13 4-(2',3',5',6'-tetrafluorophenyl)-benzoic acid ethyl ester 1,In the absence of anaerobic conditions,360 mg (2.4 mmol) of 1,2,4,5-tetrafluorobenzene was dissolved in 1 mL of tetrahydrofuran,Then, 1 mL of a 2 mol / L solution of isopropylmagnesium chloride in tetrahydrofuran was added,The reaction was stirred at room temperature for 12 hours,To the reaction solution was added 3 mL of 1,4-dioxane,0.6 mL of ethylene glycol dimethyl ether and 26.4 mg (0.10 mmol) of 18-crown ether-6,Stir for 30 minutes at room temperature.2, in the anhydrous anaerobic conditions,To 0.4 mL of tetrahydrofuran and 0.6 mL of 1,4-dioxane was added 20.6 g(0.08 mmol)Bis (1,5-cyclooctadiene) nickel,77 mg (0.1 mmol) of bis (2-bis (3,5-dimethyl-4-methoxyphenyl)phosphine)Phenyl ether,Stir for 30 minutes at room temperature.3, in the anhydrous anaerobic conditions,The reaction solution obtained in Step 1 and Step 2 was mixed,And 224 mg (1.0 mmol) of 2-methyl-5-iodothiophene was added,Stirring at room temperature for 6 hours,TLC detection reaction is complete,Add 0.5 mL of methanol for 10 min,After the reaction is quenched completely,The reaction solution was washed with 0.1 mol / L hydrochloric acid,And extracted with ethyl acetate,The ethyl acetate extract was dried over anhydrous sodium sulfate,Evaporated under reduced pressure,And then separated by silica gel column chromatography,To give the product 2-methyl-5- (2 ', 3', 5 ', 6'-tetrafluorophenyl) thiophene,Its yield was 91%. In step 2 of Example 1,Bis (2-bis (3,5-dimethyl-4-methoxyphenyl) phosphine) phenylene was equimolar Of bis (2-bis (3,4-dimethoxyphenyl) phosphine) phenyl ether;In step 3,2-methyl-5-iodothiophene was replaced with equimolar p-ethoxycarbonylphenyl trifluoromethanesulfonate,The reaction temperature was lowered to 10 ° C,The other steps were the same as in Example 1,To give ethyl 4- (2 ', 3', 5 ', 6'-tetrafluorophenyl) -benzoic acid ethyl ester,Its yield was 93% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; | |
91% | Stage #1: 1,2,4,5-Tetrafluorobenzene With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 12h; Stage #2: With 18-crown-6 ether In 1,4-dioxane; 1,2-dimethoxyethane at 20℃; for 0.5h; Stage #3: Phenyl triflate With bis(1,5-cyclooctadiene)nickel (0); 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether In tetrahydrofuran; 1,4-dioxane at 40℃; for 6h; | 3 2,3,5,6-tetrafluoro-1,1'-biphenyl 1,In the absence of anaerobic conditions,360 mg (2.4 mmol) of 1,2,4,5-tetrafluorobenzene was dissolved in 1 mL of tetrahydrofuran,Then, 1 mL of a 2 mol / L solution of isopropylmagnesium chloride in tetrahydrofuran was added,The reaction was stirred at room temperature for 12 hours,To the reaction solution was added 3 mL of 1,4-dioxane,0.6 mL of ethylene glycol dimethyl ether and 26.4 mg (0.10 mmol) of 18-crown ether-6,Stir for 30 minutes at room temperature.2, in the anhydrous anaerobic conditions,To 0.4 mL of tetrahydrofuran and 0.6 mL of 1,4-dioxane was added 20.6 g(0.08 mmol)Bis (1,5-cyclooctadiene) nickel,77 mg (0.1 mmol) of bis (2-bis (3,5-dimethyl-4-methoxyphenyl)phosphine)Phenyl ether,Stir for 30 minutes at room temperature.3, in the anhydrous anaerobic conditions,The reaction solution obtained in Step 1 and Step 2 was mixed,And 224 mg (1.0 mmol) of 2-methyl-5-iodothiophene was added,Stirring at room temperature for 6 hours,TLC detection reaction is complete,Add 0.5 mL of methanol for 10 min,After the reaction is quenched completely,The reaction solution was washed with 0.1 mol / L hydrochloric acid,And extracted with ethyl acetate,The ethyl acetate extract was dried over anhydrous sodium sulfate,Evaporated under reduced pressure,And then separated by silica gel column chromatography,To give the product 2-methyl-5- (2 ', 3', 5 ', 6'-tetrafluorophenyl) thiophene,Its yield was 91%.In step 3 of Example 1,2-methyl-5-iodothiophene was replaced with equimolar phenyl trifluoromethanesulfonate,The reaction temperature was raised to 40 ° C,The other steps were the same as in Example 1,2,3,5,6-tetrafluoro-1,1'-biphenyl was obtained in a yield of 91% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium In tetrahydrofuran at -75 - -70℃; for 0.5h; Inert atmosphere; Stage #2: dibromodifluoromethane In tetrahydrofuran at -60℃; for 0.5h; | 1.1 Example 1: Preparation of diamine (Formula 1): (0.2 mol) of 1,2,4,5-tetrafluorobenzene and 600 ml of tetrahydrofuran were charged with stirring, cold bath, dropping and nitrogen protection, and the mixture was stirred and allowed to cool under nitrogen protection. -75 ° C, dropwise 220 mlButyl lithium solution(0.44 mol, 2 mol / L),After dripping,The mixture was stirred at -70 ° C for 30 minutes,Then, a solution of difluorodibromomethane (0.52 mol, containing 110 g of difluorodibromomethane) was added dropwise and kept at -60 ° C or lower. After completion of the dropwise addition, stirring was continued for 30 minutesHydrolyzed with 10% dilute hydrochloric acid, and further subjected to a post-treatment to obtain 70 g of a reddish brown oil in a yield of 86%Step forward, directly to the next reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With C31H47ClNRu; hydrogen In hexane at 25℃; for 24h; Molecular sieve; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With palladium diacetate; potassium carbonate In N,N-dimethyl acetamide at 150℃; for 12h; Inert atmosphere; | 1.3 (3) 8, 8 - (four-fluorophenyl) - b (6 - (2 - ethyl-hexyl) indole and quinoxaline 8-bromo-6-(2-ethylhexyl)indoloquinoxaline and quinoxaline (0.82g, 2mmol), tetrafluorobenzene (0.21g, 1.4mmol), palladium acetate (0.023g, 0.1mmol), PtBu2Me-HBF4 (0.494g, 0.2mmol) and potassium carbonate (0.691g, 5mmol) mixture into a flask containing DMA 20mL. The reaction system under the environment of nitrogen heated to 150 °C, reaction 12h. After the reaction by adding a proper amount of dichloromethane and excess saturated salt water extraction, the obtained organic phase with anhydrous magnesium sulfate drying. Ethyl acetate/petroleum ether=30:1 as eluant to silica gel column chromatography to obtain a yellow solid 0.53g (65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With bis(1,5-cyclooctadiene)nickel (0); 18-crown-6 ether; 2-[bis((3,5-dimethyl-4-methoxyphenyl)phosphino)phenyl]ether; isopropylmagnesium chloride In tetrahydrofuran; 1,4-dioxane; 1,2-dimethoxyethane at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With C32H46N2Ru; anhydrous sodium carbonate; isopropanol at 70℃; for 6h; Inert atmosphere; Schlenk technique; Glovebox; | |
18% | With H2SiEt2; tetra-n-butylammonium triphenyldifluorosilicate In tetrahydrofuran; hexadeuterobenzene at 100℃; for 40h; Inert atmosphere; Sealed tube; | |
8% | With sodium tetrahydridoborate; [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) In N,N-dimethyl-formamide at 20℃; for 18h; | Catalytic hydrodehalogenation experiments General procedure: All reactions were carriedout in air at room temperature. A 50 mL round-bottom flask equippedwith a magnetic stir bar was charged with 280.8 mg (0.90 mmol) of 4,4′ -dibromobiphenyl (or 0.90 mmol of another aryl halide), 0.09 mmol ofcatalyst (10 mole%), 68.1 mg (0.18 mmol, 2.0 eq) of NaBH4 and 6 mL ofDMF (or other solvents) in room temperature. The reaction mixture wasleft to stir overnight for 18 h. Thereafter, 6 mL of deionised water wasadded to stop the reaction by deactivating the excess NaBH4 in themixture. |
11 %Spectr. | With phenylsilane; 2-H-1,3-di-tert-butyl-2,3-dihydro-1H-1,3,2-diazaphosphole In acetonitrile at 100℃; for 12h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With caesium carbonate In dimethyl sulfoxide at 160℃; for 24h; Inert atmosphere; | 4 Example 4: Synthesis of compound o-4Cbz of formula (4) (i): CBz, cesium carbonate (Cs2CO3) and dimethyl sulfoxide under argon at 160 ° C. Under the argon system, cesium carbonate (11.70g; 35.90mmol), carbazole (4.21 g; 25.17 mmol) and 1,2,4,5-tetrafluorobenzene (0.9 g; 6.00 mmol) were mixed in dimethyl sulfoxide (15 ml; 0.4 M), and heated to 160 ° C for 24 hours. After the reaction, it was diluted with 300 mL of water and filtered to give a crude yellow product. Yellow crude solids in sequential order with methanol, Rinse with ethyl acetate and acetone. The white powder o-4Cbz (3.98 g, 97%) was obtained. |
With caesium carbonate In dimethyl sulfoxide at 160℃; for 24h; Inert atmosphere; | 4 Synthesis Example 4: Synthesis of compound o-4Cbz of formula (4) (i): CBz, cesium carbonate (Cs2CO3) and dimethylarsine under argon at 160°CUnder an argon atmosphere, cesium carbonate (11.70 g; 35.90 mmol), carbazole (4.21 g; 25.17 mmol), and 1,2,4,5-tetraflurobenzene (0.9 g; 6.00 mmol) were mixed in dimethyl sulfoxide ( 15 ml; 0.4 M), heated to 160°C for 24 hours. After the reaction, it was diluted with 300 mL of water and filtered to give a yellow crude product. The yellow crude solid was washed sequentially with methanol, ethyl acetate and acetone to give white powder o-4Cbz (3.98 g, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With caesium carbonate In dimethyl sulfoxide at 160℃; for 24h; Inert atmosphere; | 4 Synthesis Example 4: Synthesis of Compound o-4Cbz of Chemical Formula (4) (i): CBz, cesium carbonate (Cs2CO3) and dimethyl hydrazine at 160 ° C under argonUnder the argon system, cesium carbonate(11.70g; 35.90mmol), carbazole (4.21 g; 25.17 mmol)And 1,2,4,5-tetraflurobenzene (0.9 g; 6.00 mmol)Were mixed in dimethyl sulfoxide (15ml; 0.4M),The reaction was heated to 160 ° C for 24 hours. After the reaction,It was diluted with 300 mL of water and filtered to give a crude yellow product.Yellow crude solids in sequential order with methanol,Ethyl acetate was washed with acetone to give a white powder o-4 Cbz (3.98 g, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1h; | 1 Example 1 (0123) To a flame-dried 100 mL flask containing THF (30 mL) was added diisopropylamine (0.774 mL, 5.49 mmol, 2.60 equiv). This flask was then cooled to 0° C. at which point nBuLi (2.5 M in hexanes, 1.94 mL, 4.85 mmol, 2.30 equiv.) was added dropwise. After stirring for 10 minutes at 0° C., the flask was then was then cooled to -78° C. over 45 minutes. To this flask was then added 1,2,4,5-tetrafluorobenzene (neat) (240 uL, 2.11 mmol, 1.00 equiv) followed by 302 (as a solution in 3 mL THF) (2.0 g, 5.27 mmol, 2.5 equiv) resulting in a bright yellow solution that slowly became brown/orange over the course of 1 h. After 1 hour of stirring, the reaction was slowly quenched with a 20% acetic acid/methanol solution (5 mL), resulting in a colorless solution which was then brought to room temperature. The organic solvents were then removed via rotary evaporation and the remaining slightly yellow aqueous layer was extracted with ethyl acetate (3×75 mL). The combined organic phases were washed with H2O (3×100 mL), and brine (1×100 mL), and dried over sodium sulfate. The solvent was removed under reduced pressure to afford a faint yellow oil. Chromatography (0 to 10% EtOAc/Hexanes) of this oil yielded 305 as a colorless oil (1.41 g, 74%). 1H NMR (500 MHz, Chloroform-d) δ 7.41 (d, J=8.7 Hz, 4H), 7.21 (d, J=8.5 Hz, 4H), 6.30 (d, J=10.2 Hz, 4H), 6.01 (d, J=10.1 Hz, 4H), 2.55 (s, 2H), 0.99 (t, J=7.9 Hz, 18H), 0.69 (q, J=7.9 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 143.96, 134.16, 131.48, 127.64, 127.41, 121.43, 71.06, 68.02, 7.18, 6.58. 19F NMR (471 MHz, Chloroform-d) δ -138.00 (s). δ HRMS (TOF, ES+) (m/z): [M+2Na]+ calculated for C42H47O4Na2Br2F4Si2, 951.1111; found, 951.1354. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 1,2,4,5-Tetrafluorobenzene With n-butyllithium In diethyl ether; hexane at -78℃; Inert atmosphere; Schlenk technique; Stage #2: 1-phenyl-2-(trichlorosilyl)ethane In diethyl ether; hexane at -78 - 20℃; Inert atmosphere; Schlenk technique; | Introduction of Arenes by Lithiation; General Procedure General procedure: The corresponding HAr/BrAr was dissolved in diethyl ether and cooled to -78 °C. A syringe was used to slowly add n-butyllithium (1.6 M in n-hexane, 1 equiv). After complete addition, the reaction mixture was stirred for 1 h. The respective trichlorosilane was then added at -78 °C by using a syringe and the solution was slowly heated to r.t. overnight. After hydrolyzing with water and extraction of the aqueous layer with CH2Cl2, the combined organic phases were dried with Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel and subsequent crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With aluminum (III) chloride In tetrachloromethane at 70℃; for 2h; | 1.1; 2.1; 3.1; 4.1; 5.1 (1) Synthesis of 2,3,5,6-tetrafluorotrichloromethylbenzene With stirring rod, reflux condenser,In a 500mL four-necked flask with a thermometer and a constant pressure dropping funnel,Load 92.4g (0.6mol) of carbon tetrachloride,Aluminum chloride 20.2g (0.15mol) and zeolite 5.0g,After heating to 70°C,Slowly add 9g (0.06mol) of 2,3,5,6-tetrafluorobenzene dropwise, and finish the dropwise addition in 1h.After the dripping is completed, continue the constant temperature reaction for 1h,After cooling, 300 mL of ice water was added to the reaction system.After filtering out the solids, separate the organic layer,After extracting the water layer three times with 50 mL of carbon tetrachloride,Combine the organic layers, wash the organic layers with 5% sodium bicarbonate aqueous solution,The organic layer was washed with water, and the organic solvent was evaporated under reduced pressure to obtain 14.1 g of 2,3,5,6-tetrafluorotrichloromethylbenzene (yield 88.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: aluminum (III) chloride / tetrachloromethane / 2 h / 70 °C 2: iron(III) chloride / 2 h / 70 °C 3: thiourea; hydrogen; 5% Pd-CaCO3 / 6 h / 60 °C 4: hydrogen; Pt/MgAl2O4 / ethanol; water / 9 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: aluminum (III) chloride / tetrachloromethane / 2 h / 70 °C 2: iron(III) chloride / 2 h / 70 °C 3: thiourea; hydrogen; 5% Pd-CaCO3 / 6 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With [1,1′-biphenyl]-2-yldiphenylphosphane; palladium diacetate; potassium carbonate; Trimethylacetic acid In toluene at 120℃; for 12h; Inert atmosphere; | Compound 3 In a nitrogen-filled glove box, Pd(OAc)2 (336 mg, 1.5 mmol, 10 mol%), L (609 mg, 1.8 mmol, 12 mol%), anhydrous K2CO3 (4.98 g, 36 mmol, 2.4 equiv), and anhydrous toluene (225 mL) were added to a 350 mL glass heavy-wall pressure vessel (Beijing Synthware P170006) equipped with a stir bar. The mixture was stirred in the glove box at room temperature for 15 min. Then, tetrafluorobenzene 1 (13.0 mL, 123 mmol, 8.2 equiv), benzyl bromide 2 (3.23 g, 15 mmol, 1.0 equiv, prepared according to Org. Lett. 2007, 9, 1187), and pivalic acid (1.84 g, 18 mmol, 1.2 equiv) were sequentially added to the mixture. The vessel was capped, transferred out of the glove box, and stirred at 120 °C for 12 h. The mixture was cooled to room temperature and filtered through a short pad of celite with the aid of ethyl acetate (250 mL). The solvents were removed under reduced pressure. Purification using silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) afforded compound 3 (2.80 g, 66% yield) as a white solid. Compound 3 Rf = 0.5 (petroleum ether: ethyl acetate = 20:1); 1H NMR (400 MHz, acetone-d6) δ 7.46-7.37 (m, 1H), 7.32-7.22 (m, 4H), 4.39 (s, 2H), 4.13 (s, 2H), 3.30 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ 147.1 (dm, J = 247 Hz), 145.9 (dm, J = 244 Hz), 138.6, 138.0, 129.2, 129.0, 121.6 (t, J = 18.2 Hz), 105.6 (t, J = 23.2 Hz), 74.8, 58.3, 29.0 (t, J = 2.0 Hz); 19F NMR (376 MHz, CDCl3) δ -139.4 (m, 2F), -143.8 (m, 2F); IR (film): 3089, 2976, 2927, 2881, 1498, 1382, 1253, 1171, 1102, 984, 849 cm-1; HRMS (EI): [M]+ C15H12OF4, calcd 284.0819, found 284.0818.. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With [1,1′-biphenyl]-2-yldiphenylphosphane; palladium diacetate; potassium carbonate; Trimethylacetic acid In toluene at 120℃; for 12h; Inert atmosphere; | Compound 6 In a nitrogen-filled glove box, Pd(OAc)2 (152 mg, 0.68 mmol, 10 mol %), L (271 mg, 0.80 mmol, 12 mol %), anhydrous K2CO3 (2.19 g, 15.9 mmol, 2.4 equiv), and anhydrous toluene (100 mL) were added to a 150 mL glass heavy-wall pressure vessel (Beijing Synthware P170004) equipped with a stir bar. The mixture was stirred in the glove box at room temperature for 15 min. Then, compound 4 (2.20 g, 6.6 mmol, 1.0 equiv), tetrafluorobenzene 1 (4.4 mL, 41 mmol, 6.2 equiv), and pivalic acid (812 mg, 8.0 mmol, 1.2 equiv) were added to the mixture. The vessel was capped, transferred out of the glove box, and stirred at 120 °C for 12 h. The mixture was cooled to room temperature and filtered through a short pad of celite with the aid of ethyl acetate (250 mL). The solvents were removed under reduced pressure. Purification using silica gel column chromatography (petroleum ether) afforded compound 6 (1.30 g, 49 % yield) as a white solid. Compound 6. Rf = 0.3 (petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 4H), 6.97-6.88 (m, 2H), 4.02 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 146.0 (dm, J = 248 Hz), 144.8 (dm, J = 245 Hz), 136.4, 129.0, 120.4 (t, J = 18.2 Hz), 104.3 (t, J = 22.3 Hz), 28.5 (t, J = 2.0 Hz); 19F NMR (376 MHz, CDCl3) δ -139.4 (m, 4F), -143.8 (m, 4F); IR (film): 3090, 1612, 1501, 1253, 1172, 977, 851 cm-1; HRMS (EI): [M]+ C20H10F8, calcd 402.0649, found 402.0642. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In tetrahydrofuran at 20℃; for 1h; | Organozinc Compound Synthesis via TMPZnOPiv·Mg(OPiv)Cl·LiCl;General Procedure GPZn-1 General procedure: To a dried 50 mL round-bottom flask, anhydrous THF (5 mL per mmolof fluoroarenes) and the corresponding fluoroarene (1 equiv) wereadded. Then TMPZnOPiv·Mg(OPiv)Cl·LiCl (1.1 equiv) was added at r.t.and the solution was stirred for 1 h. The solvent was then removed invacuo (10-2 mbar) and heated at 120 °C to dryness, resulting in a white to yellow foam, depending on the used fluorobenzene. Aftercooling to r.t., the foam was redissolved in THF (usually 1 mL per 0.3mmol of fluorobenzene used was added but concentrations up to 1 Mare feasible). An aliquot of the solution (0.1 mL) was taken andquenched with iodine, then two aliquots of 25 L and 50 L weretransferred to an NMR tube, 1 L of trifluorotoluene was added andthe tube was filled with deuterated chloroform. The concentration ofthe solution was then determined by 19F NMR spectroscopic analysis.The solution was then used in couplings without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; | Organozinc Compound Synthesis via n-BuLi and Zn(OPiv)2; GeneralProcedure GPZn-2 General procedure: A dried 50 mL round-bottom flask was charged with anhydrous THF(10 mL per mmol of fluoroarene), then fluorobenzene (1 equiv) wasadded and the solution was cooled to -78 °C. n-BuLi (1.05 equiv) wasadded and the solution stirred at -78 °C for 1 h. Zinc pivalate was addedas a solid with argon counterflow in one batch and the suspensionwas taken out of the ice bath to warm up and become a clear solution.Once at r.t., the solvent was removed in vacuo (10-2 mbar) and heatedat 120 °C to dryness, resulting in a white to yellow foam depending onthe used fluorobenzene. After cooling to r.t., the foam was redissolvedin THF (usually 1 mL per 0.3 mmol of fluorobenzene used was added,but concentrations up to 1 M are feasible). An aliquot of the solution(0.1 mL) was taken and quenched with iodine. Then two aliquots of25 L and 50 L were transferred to an NMR tube, 1 L of trifluorotoluenewas added and the tube was filled with deuterated chloroform.The concentration of the solution was then determined by 19F NMR.The solution was then used in couplings without further purification |
Tags: 327-54-8 synthesis path| 327-54-8 SDS| 327-54-8 COA| 327-54-8 purity| 327-54-8 application| 327-54-8 NMR| 327-54-8 COA| 327-54-8 structure
[ 138526-69-9 ]
1-Bromo-3,4,5-trifluorobenzene
Similarity: 0.65
[ 138526-69-9 ]
1-Bromo-3,4,5-trifluorobenzene
Similarity: 0.65
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