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CAS No. : | 103962-05-6 | MDL No. : | MFCD00042411 |
Formula : | C7H4F3IO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RTUDBROGOZBBIC-UHFFFAOYSA-N |
M.W : | 288.01 | Pubchem ID : | 2777294 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.84 |
TPSA : | 9.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.39 cm/s |
Log Po/w (iLOGP) : | 2.36 |
Log Po/w (XLOGP3) : | 3.75 |
Log Po/w (WLOGP) : | 4.45 |
Log Po/w (MLOGP) : | 3.17 |
Log Po/w (SILICOS-IT) : | 3.35 |
Consensus Log Po/w : | 3.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.23 |
Solubility : | 0.0171 mg/ml ; 0.0000594 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -3.64 |
Solubility : | 0.0665 mg/ml ; 0.000231 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.97 |
Solubility : | 0.031 mg/ml ; 0.000108 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.24 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate;copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 100℃; for 5h; | A solution of 4-bromophenol (0.173 g) in 4 mL of 1-methyl-2-pyrrolidone under argon atmosphere was treated with 4-(trifluoromethoxy)iodobenzene (0.313 mL), 2,2,6,6-tetramethylheptane-3,5-dione (0.046 mL) and caesium carbonate (0.652 g). The slurry was degassed by bubbling argon for 15 min and copper(I) chloride (0.099 g) was added. The reaction mixture was degassed by bubbling argon for 15 min, then heated to 100 C under argon for 5 h. The reaction mixture was cooled to room temperature and added dropwise to 30 mL of tert-butyl-methyl-ether. The slurry was filtered and the solids washed with tert-butyl-methyl-ether (3x20 mL). The combined filtrates were washed subsequently with 1N NaOH (50 mL), water (50 mL), 2N HCl (50 mL), 1N HCl (50 mL), water (50 mL) and brine (50 mL). The resulting organic layer was dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography on silica gel eluting with hexane to afford 0.15 g of the title compound as a colourless liquid. 1H-NMR(d, ppm, CDCl3): 7.45(m, 2H); 7.20(m, 2H); 6.99(m, 2H); 6.90(m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium carbonate; copper(I) bromide; In N-methyl pyrrolidinone;Heating / reflux; | A mixture of 0.6 g (2.6 MMOL) 5- (4-TRIFLUOROMETHOXY-PHENYL)-1 H-INDOLE, 0.53 mL (2.8 MMOL) 4- (TRIFLUOROMETHOXY) iodobenzene, 0.075 g (0.52 MMOL) copper (L) bromide and 0.54 g (3.9 MMOL) K2CO3 in 10 mL anhydrous N-methyl PYRROLIDINONE was heated to reflux overnight with stirring. The reaction was allowed to cool and was then poured into 200 mL of water. The aqueous solution was shaken with 200 mL ethyl acetate, the combined aqueous and organic phases were filtered, and the organic phase was separated. The aqueous phase was extracted once more with 200 mL ethyl acetate and the combined organic phases were washed with brine and concentrated. The crude product was chromatographed on silica (5-7% EtOAc- hexane as lutant) to afford 0.505 g (44% yield) of 1, 5-bis- (4-trifluoromethoxy- phenyl)-1 H-indole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; triphenylphosphine; In DMF (N,N-dimethyl-formamide); at 140℃; for 24h;Product distribution / selectivity; | Step D': An alternative one step coupling reaction to prepare 2-methyl-5- (4-trifluoromethoxy-phenyl)-thiazole.; [00194] Following the procedure of intermediate 56, except substituting 1-iodo-4- trifluoromethoxy-benzene for 4-iodobiphenyl in step D'. 2-methyl-5-(4-trifluoromethoxy- phenyl) -thiazole is obtained. | |
With caesium carbonate;palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 140℃; for 24h; | Intermediate 97; 4-Bromo-2-bromomethyl-5-(4-trifluoromethoxy-phenyl)-thiazole; Step A; 4-Iodotrifluoromethoxyphenyl (49.5 g, 171.6 mmol) is dissolved in DMF (800 mL), then <strong>[3581-87-1]<strong>[3581-87-1]2-<strong>[3581-87-1]methylthiazol</strong></strong>e</strong> (8.50 g, 85.5 mmol), triphenylphosphine (3.6 g, 13.73 mmol), cesium carbonate (55.9 g, 171.6 mmol), palladium(II) acetate (3.01 g, 13.7 mmol) are added and the mixture is stirred at 1400C for 24 hours. The reaction mixture is subsequently filtered through Celite 545 and washed with sat. K2CO3 and EtOAc. The filtrate is diluted with EtOAc and washed with saturated NaHCO3, brine and water. The organic layer is dried (MgSO4), filtered and concentrated to give crude product, which is purified by silic gel chromatography (ether/hexane, gradient) to give 2-methyl-5-(4-trifluoromethoxy-phenyl)- thiazole 95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; pyridinium chlorochromate; In diethyl ether; hexane; dichloromethane; chloroform; acetic acid; ethyl acetate; | The 4-trifluoromethoxy-alpha-(1,2,4-triazol-1-yl)-acetophenone used as starting material in the above process, may be obtained as follows: A solution of 4-(trifluoromethoxy)iodobenzene (8.64 g.) in anhydrous diethyl ether (60 ml.) was added dropwise at -65° C. to n-butyl-lithium (21 ml. of a 1.6M solution in hexane) over 20 minutes. After stirring for a further 20 minutes, a solution of acetaldehyde (1.6 g.) in diethyl ether (15 ml.) was added, keeping the temperature below -60° C. Stirring was continued for 1 hour, after which time the temperature was allowed to rise to -30° C. and a mixture of glacial acetic acid (15 ml) and diethyl ether (20 ml.) was added. On reaching room temperature, the solution was poured into water, the organic layer was separated, washed with water and then sodium bicarbonate solution, dried over sodium sulphate and filtered, and the solvents were evaporated to give a pale yellow oil which was purified by column chromatography on silica and using chloroform, then chloroform/ethyl acetate (7:3 v/v) as eluent. Evaporation of the appropriate fractions gave a colourless oil which was dissolved in methylene dichloride (60 ml.) and treated with pyridinium chlorochromate (7.35 g.). After stirring for 3 hours, the reaction mixture was diluted with diethyl ether (100 ml.), and the suspension was filtered through a "Florosil" (trade mark) silica pad. Evaporation of the solvent gave 4-trifluoromethoxyacetophenone as a pale yellow oil. N.m.r. in deuteriochloroform gave signals at 2.59 (3H, singlet) and 7.7 (4H, quartet). | |
With n-butyllithium; pyridinium chlorochromate; In diethyl ether; hexane; dichloromethane; chloroform; acetic acid; ethyl acetate; | Example 2 The 4-trifluoromethoxy-alpha-(1,2,4-triazol-1-yl)-acetophenone used as starting material in the above process, may be obtained as follows:- A solution of 4-(trifluoromethoxy)iodobenzene (8.64g.) in anhydrous diethyl ether (60ml.) was added dropwise at -65°C to n-butyl-lithium (21ml. of a 1.6M solution in hexane) over 20 minutes. After stirring for a further 20 minutes, a solution of acetaldehyde (1.6g.) in diethyl ether (15ml.) was added, keeping the temperature below -60°C. Stirring was continued for 1 hour, after which time the temperature was allowed to rise to -30°C and a mixture of glacial acetic acid (15ml) and diethyl ether (20ml.) was added. On reaching room temperature, the solution was poured into water, the organic layer was separated, washed with water and then sodium bicarbonate solution, dried over sodium sulphate and filtered, and the solvents were evaporated to give a pale yellow oil which was purified by column chromatography on silica and using chloroform, then chloroform/ethyl acetate (7:3 v/v) as eluent. Evaporation of the appropriate fractions gave a colourless oil which was dissolved in methylene dichloride (60ml.) and treated with pyridinium chlorochromate (7.53g.). After stirring for 3 hours, the reaction mixture was diluted with diethyl ether (100ml.), and the suspension was filtered through a 'Florosil' (trade mark) silica pad. Evaporation of the solvent gave 4-trifluoromethoxyacetophenone as a pale yellow oil. N.m.r. in deuteriochloroform gave signals at 2.59 (3H, singlet) and 7.7 (4H, quartet). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate; In 1,4-dioxane; at 90℃; | EXAMPLE 11; Step 1; To a solution of 4-(trifluoromethoxy)iodobenzene (0.54 mL, 3.45 mmol), 4-methoxyphenol (0.28 g, 2.26 mmol) and cesium carbonate (1.54 g, 4.73 mmol) in dioxane (10 mL) was added N,N-dimethylglycine hydrochloride (0.03 g, 0.22 mmol). The vessel was purged with nitrogen before Cu(I) iodide (0.02 g, 0.08 mmol) was added. The brownish-green reaction mixture was heated to 90 C. overnight. The reaction mixture was diluted with water and ethyl acetate. The organic portion was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (0.8 g, 100%) as brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Preparation of (1S)-N-(2-amino-1-hydroxycarbamoyl-ethyl)-4-(4-trifluoromethoxy- phenylethynyl)-benzamide (5). Resin (3) (120 mg, 0.084 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 4-(trifiuoromethoxy)iodobenzene (4) (96.8 mg, 0.336 mmol) and Et3N (150 μL, 1.10 mmol) in DMF (2.0 mL) was purged with a stream of N2 bubbles for two minutes and added to the resin. After mixing for 5 min, PdCl2(PPh3 )2 (18.0 mg, 0.025 mmol) and CuI (8.0 mg, 0.042 mmol) were added and the mixture shaken for 24 h. The resin was drained, washed with DMF (3x2 mL), DCM (3x2 mL) and cleaved with 10% TFA/DCM (2.0 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (3.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue. Purification by RP-HPLC (C18 column, CH3CN gradient 5-55%, 0.1% TFA, UV analysis 300 nm, 28 min) and lyophilization of the collected fractions afforded 9.0 mg (25% yield) of (5) as a white solid. LRMS (ES+) m/z 408.0 (C19Hi6F3N3O4+H requires 408.11); RP-HPLC (300 nm, 28 min run) 18.0 min. | |
22% | Resin 3 (120 mg, 0.084 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 4-(trifluoromethoxy)iodobenzene 4 (96.8 mg, 0.336 mmol) and Et3N (150 mL, 1.10 mmol) in DMF (2.0 mL) was purged with a streamof N2 bubbles for two minutes and added to the resin. After mixing for 5 min, PdCl2(PPh3)2 (18.0 mg, 0.025 mmol) andCuI (8.0 mg, 0.042 mmol) were added and the mixture shaken for 24 h. The resin was drained, washed with DMF (3 32 mL), DCM (3 3 2 mL) and cleaved with 10% TFA/DCM (2.0 mL) for 20 min. The solution was collected and the resinwas rinsed with additional 10% TFA/DCM (10 mL). The cleavage fractions were combined, treated with neat TFA (3.0mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue. Purification by RP-HPLC(C18 column, CH3CN gradient 5-55%, 0.1% TFA, UV analysis 300 nm, 28 min) and lyophilization of the collected fractionsafforded 9.0 mg (25% yield) of (1S)-N-(2-amino-1-hydroxycarbamoyl-ethyl)-4-(4-trifluoromethoxy-phenylethynyl)-benzamideas a white solid. LRMS (ES+) m/z 408.0 (C19H16F3N3O4 + H requires 408.11); RP-HPLC (300 nm, 28 min run)18.0 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; 8-quinolinol; caesium carbonate; In water; N,N-dimethyl-formamide; at 130℃; for 4h; | Example 19; Preparation of 4-bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole A round bottom flask was charged with <strong>[2302-25-2]4-bromoimidazole</strong> (1.15 g, 7.81 mmol), CuI (0.07 g, 0.36 mmol), 8-hydroxyquinoline (0.05 g, 0.36 mmol), cesium carbonate (3.39 g, 10.4 mmol) and 4-trifluoromethoxyiodobenzene (1.50 g, 5.21 mmol). A 10:1 mixture of DMF (15 mL) and H2O (1.5 mL) were added to the reaction mixture, and the solution was heated to 130 C. for 4 h. The reaction mixture was then diluted with EtOAc and washed sequentially with water, ammonium chloride (saturated), water and sodium bicarbonate. The organics were dried over MgSO4, filtered and purified on a reverse phase column to give 820 mg of imidazole as a white solid. MS 308.0 (M+H); mp 139-141 C. | |
With copper(l) iodide; 8-quinolinol; caesium carbonate; In water; N,N-dimethyl-formamide; at 130℃; for 4h; | A round bottom flask was charged with <strong>[2302-25-2]4-bromoimidazole</strong> (1.15 g, 7.81 mmol), CuI (0.07 g, 0.36 mmol), 8-hydroxyquinoline (0.05 g, 0.36 mmol), cesium carbonate (3.39 g, 10.4 mmol) and 4-trifluoromethoxyiodobenzene (1.50 g, 5.21 mmol). A 10:1 mixture of DMF (15 mL) and H2O (1.5 mL) was added to the reaction mixture, and the solution was heated to 130 0C for 4 h. The reaction mixture was then diluted with EtOAc and washed sequentially with H2O, ammonium chloride (NH4Cl, saturated), H2O and sodium bicarbonate (NaHCO3). The organics were dried over MgSO4, filtered and purified by reverse phase column chromatography to give the imidazole (820 mg) as a white solid: mp 139-141 0C; ESIMS m/z 308.0 (M+H). | |
With 8-quinolinol; caesium carbonate;copper(l) iodide; In water; N,N-dimethyl-formamide; at 130℃; for 4h; | Example 12: Preparation of 4-bromo-l-(4-trifluoromethoxyphenyl)-lH-imidazole. A round bottom flask was charged with <strong>[2302-25-2]4-bromoimidazole</strong> (1.15 g, 7.81 mmol), CuI (0.07 g, 0.36 mmol), 8-hydroxyquinoline (0.05 g, 0.36 mmol), cesium carbonate (3.39 g, 10.4 mmol) and 4-trifluoromethoxyiodobenzene (1.50 g, 5.21 mmol). A 10:1 mixture of DMF (15 mL) and H2O (1.5 mL) was added to the reaction mixture, and the solution was heated to 130 0C for 4 h. The reaction mixture was then diluted with EtOAc and washed sequentially with water, ammonium chloride (saturated), water and sodium bicarbonate. The organics were dried over MgSO4, filtered and purified on a reverse phase column to give the imidazole (820 mg) as a white solid: mp 139-141 0C; ESIMS m/z 308.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel, Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes, Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. To a degassed (argon) solution of 178 mg (0.60 mmol) 1-iodo-4-trifluoromethoxy-benzene in 2 ml piperidine was added 29 mg (0.03 mmol) Pd(PPh3)4 and 5 mg (0.03 mmol) CuI. The reaction mixture was stirred at 50 C. for 10 min, then a solution of 152 mg (0.50 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]) in 2 ml piperidine was added dropwise within 1 h. During the addition the oil bath was slowly heated to 80 C. starting after 30 min. The reaction mixture was stirred at this temperature for 3 h and then extracted with chilled aqueous 10% KHSO4/Et2O (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (n-heptane/EtOAc 95:5 to 9:1) yielded 190 mg of the title compound as a light yellow viscous oil. MS: 464.3 (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; water; at 20℃; for 48h;Inert atmosphere; | M. Synthesis of (6S)-6-({1-methyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (11) by the method of Scheme 8 A solution of 2-(2-propynyloxy)tetrahydro-2H-pyran (69) (0.758 g, 5.41 mmol), CuI (17 mg, 0.09 mmol) and PdCl2(PPh3)2 (0.158 g, 0.023 mmol) in THF (15 mL) was purged with N2. 1-Iodo-4-(trifluoromethoxy)benzene (70) (1.30 g, 4.51 mmol) in THF (10 mL) was added, followed by a solution of methylhydrazine sulfate (1.95 g, 13.5 mmol) and NaHCO3 (2.27 g, 27 mmol) in water (25 mL). The mixture was flushed with carbon monoxide and then stirred at room temperature for 2 days under one atmosphere of carbon monoxide. The resulting mixture was partitioned between CH2Cl2 and water, the CH2Cl2 fraction was dried, and the solvent was evaporated. Column chromatography of the residue on silica gel (eluting with CH2Cl2) gave 1-methyl-5-[tetrahydro-2H-pyran-2-yloxy)methyl]-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (71) (1.034 g, 64%) as a brown solid: mp 40-42 C.; 1H NMR (CDCl3) δ 7.78 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.51 (s, 1H), 4.75 (d, J=12.8 Hz, 1H), 4.69 (t, J=3.3 Hz, 1H), 4.57 (d, J=12.8 Hz, 1H), 3.94 (s, 3H), 3.84-3.91 (m, 1H), 3.53-3.60 (m, 1H), 1.68-1.88 (m, 2H), 1.50-1.66 (m, 4H). APCI MS m/z 357 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 120.0℃; for 0.166667h;Inert atmosphere; Irradiation; | To a solution of 1-iodo-4-(trifluoromethoxy)benzene (288 mg, 1.0 mmol) and <strong>[1003043-40-0]6-chloro-5-methylpyridin-3-ylboronic acid</strong> (223 mg, 1.3 mmol) in DMF (2 mL) was added K2CO3 (552 mg, 4.0 mmol) and H2O (0.5 mL). The reaction mixture was stirred for 5 min under an atmosphere of dry N2. Pd(PPh3)4 (10 mg, 0.009 mmol) was added, and the resulting mixture was subjected to irradiation at 120 C. for 10 min. Cooled, diluted with EtOAc (20 mL), filtered through a layer of celite, washed with 10% DMF in EtOAc (50 mL), transferred to a separation funnel, organic phase was washed with 2N Na2CO3 (20 mL, 4.00 mmol), H2O (20 mL), 30% aqueous NH4Cl (50 mL) and brine (50 mL), and dried and concentrated. The crude mixture was subjected to preparative HPLC with a gradient MeCN/H2O (5% to 98%) containing 0.1% TFA to afford 2-chloro-3-methyl-5-(4-(trifluoromethoxy)phenyl)pyridine,MS m/z 288.0 (M+H), HPLC purity>97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With copper(l) iodide; sodium hydrogencarbonate;bis(triphenylphosphine)palladium(II) dichloride; In tetrahydrofuran; water; at 20℃; for 48h; | A solution of 2-(2-propynyloxy)tetrahydro-2/J-pyran (69) (0.758 g, 5.41 mmol), CuI (17 mg, 0.09 mmol) and PdCl2(PPh3)2 (0.158 g, 0.023 mmol) in THF (15 mL) was purged with N2. l-Iodo-4-(trifiuoromethoxy)benzene (70) (1.30 g, 4.51 mmol) in THF (10 mL) was added, followed by a solution of methylhydrazine sulfate (1.95 g, 13.5 mmol) and NaHCO3 (2.27 g, 27 mmol) in water (25 mL). The mixture was flushed with carbon monoxide and then stirred at room temperature for 2 days under one atmosphere of carbon monoxide. The resulting mixture was partitioned between CH2Cl2 and water, the CH2Cl2 fraction was dried, and the solvent was evaporated. Column chromatography of the residue on silica gel (eluting with CH2Cl2) gave 1 -methyl-5-[(tetrahydro-2//-pyran-2-yloxy)methyl]-3-[4-(trifluoromethoxy)phenyl]-lH-pyrazole (71) (1.034 g, 64%) as a brown solid: mp 40-42 0C; 1H NMR (CDCl3) δ 7.78 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.51 (s, 1 H), 4.75 (d, J = 12.8 Hz, 1 H), 4.69 (t, J= 3.3 Hz, 1 H), 4.57 (d, J- 12.8 Hz, 1 H), 3.94 (s, 3 H), 3.84-3.91 (m, 1 H), 3.53-3.60 (m, 1 H), 1.68-1.88 (m, 2 H), 1.50-1.66 (m, 4 H). APCI MS m/z 357 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With copper(l) iodide; triethylamine;bis(triphenylphosphine)palladium(II) dichloride; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | A mixture of alkyne 97 (0.075 g, 0.25 mmol), l-iodo-4- (trifluoromethoxy)benzene (70) (0.088 g, 0.30 mmol) and copper iodide (5 mg, 0.03 mmol) in DMF (2 mL) and Et3N (2 mL) was purged with N2. PdCl2(PPh3)2 (9 mg, 0.01 mmol) was added and the mixture was stirred at room temperature for 0.5 h, and then partitioned between EtOAc and water. Column chromatography of the organic portion on silica gel using gradient elution (0- 5% MeOH:EtOAc) gave 18 (0.084 g, 73%) as a white solid: mp 207-208 0C; 1H NMR [(CDs)2SO] δ 8.71 (d, J= 1.7 Hz, 1 H), 8.03 (s, 1 H), 7.99 (dd, J= 8.1, 2.2 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 2 H), 7.42-7.47 (m, 3 H), 4.81 (d, J= 13.9 Hz, 1 H), 4.77 (d, J= 13.9 Hz, 1 H), 4.71 (dt, J= 12.0, 2.5 Hz, 1 H), 4.51 (d, J= 1 1.9 Hz, 1 H), 4.31-4.37 (m, 2 H), 4.26 (dd, J= 13.7, 3.5 Hz, 1 H). Anal. (C2IH15F3N4O5) C, H, N. |
73% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | A mixture of alkyne 97 (0.075 g, 0.25 mmol), <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (70) (0.088 g, 0.30 mmol) and copper iodide (5 mg, 0.03 mmol) in DMF (2 mL) and Et3N (2 mL) was purged with N2. PdCl2(PPh3)2 (9 mg, 0.01 mmol) was added and the mixture was stirred at room temperature for 0.5 h, and then partitioned between EtOAc and water. Column chromatography of the organic portion on silica gel using gradient elution (0-5% MeOH:EtOAc) gave 18 (0.084 g, 73%) as a white solid: mp 207-208 C.; 1H NMR [(CD3)2SO] δ 8.71 (d, J=1.7 Hz, 1H), 8.03 (s, 1H), 7.99 (dd, J=8.1, 2.2 Hz, 1H), 7.73 (d, J=8.9 Hz, 2H), 7.42-7.47 (m, 3H), 4.81 (d, J=13.9 Hz, 1H), 4.77 (d, J=13.9 Hz, 1H), 4.71 (dt, J=12.0, 2.5 Hz, 1H), 4.51 (d, J=11.9 Hz, 1H), 4.31-4.37 (m, 2H), 4.26 (dd, J=13.7, 3.5 Hz, 1H). Anal. (C21H15F3N4O5) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With palladium diacetate; silver nitrate; at 110℃; for 24h;Inert atmosphere; | General procedure: Aryl iodides (0.5 mmol) and AgNO3 (85 mg, 0.5 mmol) and Pd(OAc)2 (11.2 mg, 0.05 mmol) were added to Schlenk tubes. Benzene (4 ml) was added to the tubes using a syringe. The mixture was then stirred in a sealed tube under argon atmosphere. Then the mixture was stirred at 110 C until complete consumption of the starting material was monitored by TLC. After completion of the reaction, the mixture was diluted with ethyl acetate, passed through a fritted glass filter to remove the inorganic salts and the solvent was removed with the aid of a rotary evaporator. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1A 2-(4-(trifluoromethoxy)phenyl)malononitrile To a suspension of sodium hydride (2.87 g, 114 mmol) in THF (15 mL), malononitrile (4.77 mL, 76 mmol) in 2 mL of THF was added dropwise at 0 C. After the gas evolution ceased, <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (5.92 mL, 37.8 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.797 g, 1.135 mmol) were added. This mixture was then heated at reflux under nitrogen overnight. The suspension was cooled to ambient temperature, treated with water, acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (0-30% ethyl acetate in hexanes) to give 8.2 g of product as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.48-7.65 (m, 2H) 7.37 (d, J=8.35 Hz, 2H) 5.09 (s, 1H). MS (ESI) m/z 225.1 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
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89% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 60℃; for 2h;Inert atmosphere; | To a stirred solution of <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (500 mg 1 eq.) in THF (5 ml) under nitrogen, triethylamine (3.5 ml, 3 eq.), trimethylsilyl acetylene (0.731 ml, 3 eq.), Cul (33 mg, 0.1 eq.) and PdCl2(PPh3)2 (122 mg, 0.1 eq.) were added and stirred at 60 C for 2 h. After TLC indicated completion of the reaction, the mixture was filtered through Celite and water (10 ml) was added. The organic phase was extracted by using ethyl acetate (3x 15 ml) and the combined organic phase was washed using brine and dried over sodium sulfate. The solvent was removed to obtain crude product, which was purified by column chromatography to obtain trimethyl-[2-[4-(trifluoromethoxy)phenyl]ethynyl]silane (400 mg, 89% yield). 1H NMR (500 MHz, CDCIs): d 7.29 (d, J = 8.00 Hz, 2H), 6.95 (d, J = 8.00 Hz, 2H), 0.06 (s, 9H). |
With copper(l) iodide; triethylamine;trans-bis(triphenylphosphine)palladium dichloride; In tetrahydrofuran; at 20℃; for 3h; | To a solution of l-iodo-4-(trifIuoromethoxy)benzene (1.087 mL, 6.94 mMol) and TMS- acetylene (1.166 ml, 8.33 mmol) in THF (30ml) were added Copper(I) iodide (0.066 g, 0.347 mMol), Trans-Bis(triphenylphosphine)palladium(II)chloride (0.244 g, 0.347 mmol) and triethylamine (2.90 ml, 20.83 mmol). After stirring for 3h at room temperature, the reaction mixture was concentrated. The residue was dissolved in heptane, filtered through a plug of silica gel and concentrated to give the desired product as oil. Mass Spectra (m/e): 259 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
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13% | With copper(l) iodide; 8-quinolinol; caesium carbonate; In water; N,N-dimethyl-formamide; at 150℃; for 0.5h;Microwave irradiation; | The triazole (70 mg, 0.41 mmol), l-iodo-4-trifluoromethoxybenzene (142 mg, 0.493 mmol), Cs2CO3 (535 mg, 1.644 mmol), CuI (3 mg, 0.012 mmol), 8-hydroxyquinoline (2 mg, 0.012 mmol), and DMF/Η2O (2 mL; 10:1 solution) were combined in a 10 mL CEM Microwave reaction vessel fitted with magnetic stir bar and subjected to microwave irradiation at 150 0C for 30 min. The contents were then filtered and concentrated to dryness affording the 1,3- diphenyl triazole intermediate (18 mg, 13%). |
13% | With 8-quinolinol; caesium carbonate;copper(l) iodide; In water; N,N-dimethyl-formamide; at 150℃; for 0.5h;Microwave irradiation; | Step 2. 4-[l-(4-Trifluoromethoxyphenyl)-lH-[l,2,4]triazol-3-yl]-benzonitrile.. The triazole (70 mg, 0.41 mmol), l-iodo-4-trifluoromethoxybenzene (142 mg, 0.493 mmol), Cs2CO3 (535 mg, 1.644 mmol), CuI (3 mg, 0.012 mmol), 8-hydroxyquinoline (2 mg, 0.012 mmol), and DMF/Η2O (2 mL; 10:1 solution) were combined in a 10 mL CEM Microwave reaction vessel fitted with magnetic stir bar and subjected to microwave irradiation at 150 0C for 30 min. The contents were then filtered and concentrated to dryness affording the 1,3- diphenyl triazole intermediate (18 mg, 13%). |
Yield | Reaction Conditions | Operation in experiment |
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Intermediate 8: (S)-N-((S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethoxy)- phenyl)methyl)-2-methylpropane-2-sulfinamidel-Iodo-4-(trifluoromethoxy)benzene (1.00 g, 3.47 mmol) was dissolved in dry THF (10 mL) and cooled in an ice bath. Isopropylmagnesium chloride, lithium chloride complex (14% solution in THF, Aldrich, 3.07 mL, 2.82 mmol) was added, and the mixture was stirred for 10 min. A solution of (S,E)-N-((3- fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.643 g, 2.82 mmol) in dry THF (10 mL) was added, and the reaction was stirred. After 50 minutes, the reaction was quenched by addition of saturated aqueous NH4C1 (10 mL). H20 (100 mL) and EtOAc (150 mL) were added, and the phases were mixed and separated. The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (S)-N-((S)-(3- fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-methylpropane-2- sulfinamide. | ||
Method C:Intermediate 5: (S)-N-((S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethoxy)- phenyl)methyl)-2-methylpropane-2-sulfinamidel-Iodo-4-(trifluoromethoxy)benzene (1.00 g, 3.47 mmol) was dissolved in dry THF (10 mL) and cooled in an ice bath. Isopropylmagnesium chloride, lithium chloride complex (14% solution in THF, Aldrich, 3.07 mL, 2.82 mmol) was added, and the mixture was stirred for 10 min. A solution of (S,E)-N-((3- fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.643 g, 2.82 mmol) in dry THF (10 mL) was added and the reaction was stirred. After 50 minutes, the reaction was quenched by addition of saturated aqueous NH4C1 (10 mL). H20 (100 mL) and EtOAc (150 mL) were added, and the phases were mixed and separated. The organic layer was dried with MgS04 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (S)-N-((S)-(3-fluoropyridin-2-yl)(4-(trifluoro- methoxy)phenyl)methyl)-2-methylpropane-2-sulfinamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 36h;Inert atmosphere; | A dry round bottom flask was charged with <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol), and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N2, then DMSO (33.8 mL) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 36 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through a plug of Celite® and further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash chromatography (silica/EtOAc/Hexanes) yielded 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole as an off white solid (3.78 g, 73percent yield): mp 67-69° C.; 1H NMR (400 MHz, CDCl3) delta 8.43 (s, 1H), 7.70 (m, 2H), 7.38 (m, 2H); 19F NMR (376 MHz, CDCl3) delta -58.02. |
73% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere; | To a 250 mL reaction flask was added <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol) and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with nitrogen gas, and then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 20 hours (h). The reaction was cooled to room temperature, diluted with EtOAc and filtered through a plug of Celite®. The Celite® was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography using EtOAc/hexanes as eluent to yield the title compound (3.78 g, 73percent): mp 69-70° C.; 1H NMR (400 MHz, CDCl3) delta 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta ?58.04; EIMS m/z 307 ([M]+). |
73% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere; | To a 250 mL reaction flask was added <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol) and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with nitrogen gas, and then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 20 hours (h). The reaction wascooled to room temperature (RT), diluted with EtOAc and filtered through a plug of Celite®. The Celite® was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography using EtOAc/hexanes as eluent provided the title compound as an off-white solid (3.78 g, 73percent): mp 69-70° C.; 1H NMR (400 MHz, CDCl3) delta 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta-58.04; EIMS m/z 307 ([M]+) |
72.6% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere; | Example 59. Preparation of 3-bromo-l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazole (B61) To a 250 mL reaction flask was added 3-bromo-lH-l,2,4-triazole (5 g, 33.8 mmol), copper(I) iodide (0.644 g, 3.38 mmol) and cesium carbonate (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N2, then DMSO (33.8 ml) and l-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100 °C for 20 h. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a plug of Celite. The Celite was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash chromatography (silica/EtO Ac/Hex) yielded 3-bromo-l-(4- (trifluoromethoxy)phenyl)-lH-l,2,4-triazole as an off white solid (3.78 g, 12.27 mmol, 72.6percent): mp 69-70 °C; ]H NMR (400 MHz, CDC13) delta 8.44 (s, 1H), 7.70 (d, / = 8.9 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H); 19F NMR (376 MHz, CDC13) delta -58.04; EIMS m/z 307. |
72.6% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere; | To a 250 mL reaction flask was added <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol) and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with nitrogen gas, and then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 20 hours (h). The reaction was cooled to room temperature (RT), diluted with EtOAc and filtered through a plug of Celite®. The Celite® was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash chromatography (silica/EtOAc/hexanes) yielded 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole as an off-white solid (3.78 g, 12.27 mmol, 72.6percent): mp 69-70° C.; 1H NMR (400 MHz, CDCl3) delta 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta ?58.04; EIMS m/z 307. |
72.6% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 36h;Inert atmosphere; | Example 6 Preparation of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole A dry round bottom flask was charged with <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol), and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N2, then DMSO (33.8 mL) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 36 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through a plug of Celite® and further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography (EtOAc/hexanes) yielded the title compound as an off white solid (3.78 g, 72.6percent): mp 67-69° C.; 1H NMR (400 MHz, CDCl3) delta 8.43 (s, 1H), 7.70 (m, 2H), 7.38 (m, 2H); 19F NMR (376 MHz, CDCl3) delta -58.02. Example 5 Preparation of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole A dry round bottom flask was charged with potassium phosphate (K3PO4, 7.74 g, 36.5 mmol), CuI (0.165 g, 0.868 mmol), and <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (2.83 g, 19.10 mmol). The flask was evacuated/backfilled with N2 (3*). DMF (34.7 mL) was added, followed by trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexane diamine (0.274 ml, 1.736 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (5.000 g, 17.36 mmol). The solution was heated to 110° C. After 48 h, the reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite®. The filtrate was washed with water (100 mL) containing HCl (1 M, 10 mL. The organics were separated, and the aqueous phase was further extracted with EtOAc (3*). The organics were combined, dried, and concentrated in vacuo. Purification via flash column chromatography (EtOAc/hexanes) yielded the title compound as a tan solid (1.86 g, 34percent): 1H NMR (400 MHz, CDCl3) delta 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta -58.04; EIMS m/z 307. |
54% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere; | To a 100 mL round bottomed flask, equipped with a stir bar, was added copper(I) iodide (0.397 g, 2.08 mmol), <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (4.62 g, 31.2 mmol), and cesium carbonate (6.79 g, 20.83 mmol), as solids. These solids were diluted with anhydrous dimethyl sulfoxide (34.7 mL). Then 1-iodo-4-(trifluoromethoxy)benzene (1.65 mL, 10.4 mmol) was added as a liquid. The flask was placed under nitrogen atmosphere, and the suspension was heated to an internal temperature of 100° C. for 20 hours. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®, washing with excess ethyl acetate (200 mL). The filtrate was poured into a brine solution (200 mL), and the layers were partitioned. The aqueous phase was extracted with additional ethyl acetate (2*100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified via flash column chromatography using 10-50percent ethyl acetate/hexanes as eluent to afford the title compound as a white solid (1.80 g, 54percent): 1H NMR (400 MHz, DMSO-d6) delta 9.35 (s, 1H), 7.97 (d, J=8.9 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) delta -57.06; ESIMS m/z 308, 310 ([M+H]+). |
34% | With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 110℃; for 48h;Inert atmosphere; | A dry round bottom flask was charged with potassium phosphate (K3PO4, 7.74 g, 36.5 mmol), CuI (0.165 g, 0.868 mmol), and <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (2.83 g, 19.10 mmol). The flask was evacuated/backfilled with N2 (3*). DMF (34.7 ml) was added, followed by trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexane diamine (0.274 ml, 1.736 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (5 g, 17.36 mmol). The solution was heated to 110° C. After 48 h, the reaction mixture was cooled to RT, diluted with EtOAc and filtered through Celite®. The filtrate was washed with water (100 mL) containing 10 mL 1 M HCl. The organics were separated, and the aqueous phase was further extracted with EtOAc (3*). The organics were combined, dried, and concentrated in vacuo. Purification via flash column chromatography (EtOAc/hexanes) yielded the title compound as a tan solid (1.86 g, 34percent): 1H NMR (400 MHz, CDCl3) delta 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta -58.04; EIMS m/z 307 ([M]+). |
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere; | To a 250 mL reaction flask was added 3-bromo-lH-l,2,4-triazole (5 g, 33.8 mmol), copper(I) iodide (0.644 g, 3.38 mmol) and cesium carbonate (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N2, then DMSO (33.8 ml) and l-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100 °C for 20 h. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a plug of Celite. The Celite was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo.Purification via flash chromatography (silica/EtO Ac/Hex) yielded 3-bromo-l-(4- (trifluoromethoxy)phenyl)-lH-l,2,4-triazole as an off white solid (3.78 g, 12.27 mmol,72.6percent): mp 69-70 °C; ]H NMR (400 MHz, CDC13) delta 8.44 (s, 1H), 7.70 (d, / = 8.9 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H); 19F NMR (376 MHz, CDC13) delta -58.04; EIMS m/z 307. | |
With caesium carbonate; In water; dimethyl sulfoxide; | Example 6 Preparation of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole A dry round bottom flask was charged with <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol), and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N2, then DMSO (33.8 mL) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 36 h. The reaction mixture was cooled to RT, diluted with EtOAc, filtered through a plug of Celite® and further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography EtOAc/hexanes yielded the title compound as an off white solid (3.78 g, 73percent): mp 67-69° C.; 1H NMR (400 MHz, CDCl3) delta 8.43 (s, 1H), 7.70 (m, 2H), 7.38 (m, 2H); 19F NMR (376 MHz, CDCl3) delta-58.02. | |
With caesium carbonate; In water; dimethyl sulfoxide; | Example 6 Preparation of 3-bromo-1-(4-(trifluoromethoxy)Phenyl)-1H-1,2,4-triazole A dry round bottom flask was charged with <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol), and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with N2, then DMSO (33.8 mL) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 36 h. The reaction mixture was cooled to RT, diluted with EtOAc, filtered through a plug of Celite® and further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography (EtOAc/Hexanes) yielded the title compound as an off white solid (3.78 g, 73percent): mp 67-69° C.; 1H NMR (400 MHz, CDCl3) delta 8.43 (s, 1H), 7.70 (m, 2H), 7.38 (m, 2H); 19F NMR (376 MHz, CDCl3) delta -58.02. | |
3 g | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 130℃; for 18h;Inert atmosphere; Sealed tube; | To a mixture of 1 -iodo-4-(trifluoromethoxy)benzene (3 g, 10.416 mmol) in methylsulfinylmethane (24 mL) was added 3-bromo-1 H-1 ,2,4-triazole (3.1 g) under nitrogen atmosphere followed by addition of cesium carbonate (6.7 g, 20.833 mmol) and copper iodide (0.4 g, 2.083 mmol). The reaction mass was stirred at 130°C for 18 hours in seal tube. The reaction mass was then diluted with water and extracted with ethylacetate (3 x 70 mL). The combined organic layers were then dried over sodium sulphate and concentrated under reduced pressure followed by column chromatography to obtain the title compound as solid (3 g). (0581) H NMR (400 MHz, (CD3)3SO): delta 9.38 - 9.25 (m, 1 H), 7.98 - 7.92 (m, 2H), 7.65 - 7.53 (m, 2H) LC/MS (method E) m/z: 308 [M + H]+, Rt = 0.94 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 21h;Inert atmosphere; | Synthesis of 2-oxo- 1 -(4-(trifluoromethoxy)phenyl)- 1 ,2-dihydropyridine-3 - carbaldehyde (2-2) 2-oxo- l,2-dihydropyridine-3-carbaldehyde (200 mg, 1.63 mmdl), 1-iodo- 4-(trifluoromethoxy)benzene 2 (562 mg, 1.95 mmol), 8-hydroxyquinoline (47.2 mg, 0.324 mmol), copper iodide (61.9 mg, 0.324 mmol), and potassium carbonate (303 mg, 2.19 mmol) were combined in a round bottom flask with DMSO (3.5 mL) under a nitrogen atmosphere and heated to 130 C for 21 h. The reaction was cooled to room temperature and poured into a mixture of 10% aq. ammonium hydroxide and ethyl acetate. The resultant mixture was filtered through a pad bf Celite and washed with ethyl acetate three times. The layers were separated with the aqueous portion being back extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Purification by flash column chromatography on silica gel (0 - 50% EtOAc in hexane) gave 92.0 mg (20%) of 2-2 as an off-white solid: 1H NMR (400 MHz, CDC13) δ 10.34 (1H, d, J= 0.8 Hz), 8.14 (1H, dd, J= 6.9, 2.3 Hz), 7.65 (1H, dd, J= 6.9, 2.3 Hz), 7.45 (2H, m), 7.38 (2H, m), 6.44 (1H, dt, J= 0.8, 6.9 Hz); ESI-MS m/z 284 [C13H8F3NO3 + H]+. |
20% | With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 21h;Inert atmosphere; | 2-oxo-1,2-dihydropyridine-3-carbaldehyde 1-1 (200 mg, 1.63 mmol), <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> 2-1 (562 mg, 1.95 mmol), 8-hydroxyquinoline (47.2 mg, 0.324 mmol), copper iodide (61.9 mg, 0.324 mmol), and potassium carbonate (303 mg, 2.19 mmol) were combined in a round bottom flask with DMSO (3.5 mL) under a nitrogen atmosphere and heated to 130 C for 21 h. The reaction was cooled to room temperature and poured into a mixture of 10% aq. ammonium hydroxide and ethyl acetate. The resultant mixture was filtered through a pad of Celite and washed with ethyl acetate three times. The layers were separated with the aqueous portion being back extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash column chromatography on silica gel (0 - 50% EtOAc in hexane) gave 92.0 mg (20%) of 2-2 as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.34 (1H, d, J = 0.8 Hz), 8.14 (1H, dd, J = 6.9, 2.3 Hz), 7.65 (1H, dd, J = 6.9, 2.3 Hz), 7.45 (2H, m), 7.38 (2H, m), 6.44 (1H, dt, J = 0.8, 6.9 Hz); ESI-MS m/z 284 [C13H8F3NO3 + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-Picolinic acid; copper(l) iodide; caesium carbonate; In 1,4-dioxane; at 20℃; for 48h;Inert atmosphere; | CuI (0.26 g, 1.378 mmol), 2-picolinic acid (0.24 g, 1.969 mmol), and cesium carbonate (19.24 g, 59.061 mmol) were combined, evacuated and filled with argon (3 times). 1,4-Dioxane was then added followed by diethylmalonate (6 mL, 39.374 mmol) and <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (3 mL, 19.687 mmol). The resulting yellow suspension was stirred at room temperature for 48 hours and quenched with saturated NH4Cl. The mixture was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide the title compound. | |
With 2-Picolinic acid; copper(l) iodide; caesium carbonate; In 1,4-dioxane; at 20℃; for 48h;Inert atmosphere; | CuI (0.26 g, 1.378 mmol), 2-picolinic acid (0.24 g, 1.969 mmol) and cesium carbonate (19.24 g, 59.061 mmol) were combined in a reaction vessel and the flask was evacuated and re-filled with argon (3 times). 1,4-Dioxane was then added followed by diethylmalonate (6 mL, 39.374 mmol) and <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (3 mL, 19.687 mmol). The resulting yellow suspension was stirred at room temperature for 48 hours and quenched with saturated NH4Cl. The mixture was extracted with EtOAc (2*). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide the title compound. | |
With 2-Picolinic acid; copper(l) iodide; caesium carbonate; In 1,4-dioxane; at 20℃; for 48h;Inert atmosphere; | intermediate 13: step adiethyl 2-(4-(trifluoromethoxy)phenyl)malonateCul (0.26 g, 1.378 mmol), 2-picolinic acid (0.24 g, 1.969 mmol) and cesium carbonate (19.24 g, 59.061 mmol) were combined in a reaction vessel and the flask was evacuated and re-filled with argon (3 times). 1,4-Dioxane was then added followed by diethylmaionate (6 mL, 39.374 mmol) and l-iodo-4-(trifluoromethoxy)benzene (3 mL, 19.687 mmol). The resulting yellow suspension was stirred at room temperature for 48 hours and quenched with saturated NH4CI. The mixture was extracted with EtOAc (2x). The combined organic extracts were dried over Na2SQ4, filtered, and concentrated to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In N,N-dimethyl-formamide; | Example 5 Preparation of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole A dry round bottom flask was charged with potassium phosphate (K3PO4, 7.74 g, 36.5 mmol), CuI (0.165 g, 0.868 mmol), and <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (2.83 g, 19.10 mmol). The flask was evacuated/backfilled with N2 (3*). DMF (34.7 ml) was added, followed by trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexane diamine (0.274 ml, 1.736 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (5 g, 17.36 mmol). The solution was heated to 110° C. After 48 h, the reaction mixture was cooled to RT, diluted with EtOAc and filtered through Celite®. The filtrate was washed with water (100 mL) containing HCl (1 M, 10 mL). The organics were separated, and the aqueous phase was further extracted with EtOAc (3*). The organics were combined, dried, and concentrated in vacuo. Purification via flash column chromatography EtOAc/hexanes yielded the title compound as a tan solid (1.86 g, 34percent): 1H NMR (400 MHz, CDCl3) delta 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta-58.04; EIMS m/z 307 ([M]+). | |
With hydrogenchloride; In N,N-dimethyl-formamide; | Example 5 Preparation of 3-bromo-1-(4-(trifluoromethoxy)Phenyl)-1H-1,2,4-triazole A dry round bottom flask was charged with potassium phosphate (K3PO4, 7.74 g, 36.5 mmol), CuI (0.165 g, 0.868 mmol), and <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (2.83 g, 19.10 mmol). The flask was evacuated/backfilled with N2 (3*). DMF (34.7 mL) was added, followed by trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexane diamine (0.274 mL, 1.736 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (5 g, 17.36 mmol). The solution was heated to 110° C. After 48 h, the reaction mixture was cooled to RT, diluted with EtOAc and filtered through Celite®. The filtrate was washed with water (100 mL) containing HCl (1 M, 10 mL). The organics were separated, and the aqueous phase was further extracted with EtOAc (3*). The organics were combined, dried with sodium sulfate, and concentrated in vacuo. Purification via flash column chromatography (EtOAc/hexanes) yielded the title compound as a tan solid (1.86 g, 34percent): 1H NMR (400 MHz, CDCl3) delta 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) delta-58.04; EIMS m/z 307 ([M]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With potassium phosphate; copper(l) iodide; In N,N-dimethyl-formamide; at 140℃; for 4h;Inert atmosphere; | Example 7 Preparation of methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate and 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid To a nitrogen purged flask was added <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (313 μl, 2.00 mmol), methyl 4-(1H-1,2,4-triazol-3-yl)benzoate (203 mg, 1 mmol), K3PO4 (531 mg, 2.50 mmol) that had been ground together with CuI (19.05 mg, 0.100 mmol) using a mortar and pestle and DMF (2 mL). The reaction was heated to 140 C. After 4 h, the reaction was allowed to coolto room temperature. The reaction was then diluted with water and EtOAc and the layers separated. The aqueous layer was extracted with EtOAc (3*10 mL) and the combined organic fractions were washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated to give a yellow oil. The oil was taken up in EtOAc, washed with NaOH (1 N, 3*5 mL) and water (5 mL), dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (0-70% EtOAc/hexanes) provided methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate as a pale brown solid (25 mg, 7%): mp 166-168 C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.34-8.25 (m, 2H), 8.20-8.11 (m, 2H), 7.87-7.77 (m, 2H), 7.46-7.35 (m, 2H), 3.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.76, 162.63, 148.57, 141.78, 135.42, 134.46, 131.04, 130.02, 126.47, 122.45, 121.32, 52.24, 31.59; ESIMS m/z 363 ([M+]). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Example 7 Preparation of methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate and 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid To a nitrogen purged flask was added <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (313 μl, 2.00 mmol), methyl 4-(1H-1,2,4-triazol-3-yl)benzoate (203 mg, 1 mmol), K3PO4 (531 mg, 2.50 mmol) that had been ground together with CuI (19.05 mg, 0.100 mmol) using a mortar and pestle and DMF (2 mL). The reaction was heated to 140 C. After 4 h, the reaction was allowed to coolto room temperature. The reaction was then diluted with water and EtOAc and the layers separated. The aqueous layer was extracted with EtOAc (3*10 mL) and the combined organic fractions were washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated to give a yellow oil. The oil was taken up in EtOAc, washed with NaOH (1 N, 3*5 mL) and water (5 mL), dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (0-70% EtOAc/hexanes) provided methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate as a pale brown solid (25 mg, 7%): mp 166-168 C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.34-8.25 (m, 2H), 8.20-8.11 (m, 2H), 7.87-7.77 (m, 2H), 7.46-7.35 (m, 2H), 3.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.76, 162.63, 148.57, 141.78, 135.42, 134.46, 131.04, 130.02, 126.47, 122.45, 121.32, 52.24, 31.59; ESIMS m/z 363 ([M+]). The combined aqueous layers were acidified to pH 2. The white solid was isolated on a fritted glass funnel to give 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid as a tan solid (169 mg, 48%): mp 222-228 C.; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 9.47 (s, 1H), 8.30-8.19 (m, 2H), 8.15-8.03 (m, 4H), 7.64 (d, J=8.5 Hz, 2H); ESIMS m/z 349 ([M+]). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 72h;Inert atmosphere; | Example 8 Preparation of 3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C5) (0174) (0175) 3-(4-Bromophenyl)-1H-1,2,4-triazole (C4) (10.9 g, 48.5 mmol), copper(I) iodide (2.38 g, 12.5 mmol), and cesium carbonate (30.3 g, 93.0 mmol) in a round-bottomed flask was flushed with nitrogen. Dimethylsulfoxide (85 mL) was added, followed by 1-iodo-4-(trifluoromethoxy)benzene (13.2 g, 45.8 mmol). The reaction was degassed for 5 minutes, then heated at 100 C. for 3 days. The reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through a plug of Celite rinsing with ethyl acetate. To the filtrate was added saturated ammonium chloride and stirred for 1.5 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated onto Celite. Purification by flash column chromatography using 0-40% EtOAc/hexanes as eluent provided the title compound as an off-white solid (9.65 g, 52%): mp 109-112 C.; 1H NMR (400 MHz, CDCl3) delta 8.56 (s, 1H), 8.10-8.03 (m, 2H), 7.83-7.75 (m, 2H), 7.64-7.57 (m, 2H), 7.42-7.35 (m, 2H); ESIMS m/z 386 ([M+21-1 ]+). |
52% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 72h;Inert atmosphere; | Example 15 Preparation of 3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C7) 3-(4-Bromophenyl)-1H-1,2,4-triazole (C6) (10.9 g, 48.5 mmol), copper(I) iodide (2.38 g, 12.5 mmol), and cesium carbonate (30.3 g, 93.0 mmol) in a round-bottomed flask was flushed with nitrogen. Dimethylsulfoxide (85 mL) was added, followed by 1-iodo-4-(trifluoromethoxy)benzene (13.2 g, 45.8 mmol). The reaction was degassed for 5 minutes, then heated at 100 C. for 3 days. The reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through a plug of Celite rinsing with ethyl acetate. To the filtrate was added saturated ammonium chloride and stirred for 1.5 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (3*). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated onto Celite. Purification by flash column chromatography using 0-40% EtOAc/hexanes as eluent provided the title compound as an off-white solid (9.65 g, 52%): mp 109-112 C.; 1H NMR (400 MHz, CDCl3) delta 8.56 (s, 1H), 8.10-8.03 (m, 2H), 7.83-7.75 (m, 2H), 7.64-7.57 (m, 2H), 7.42-7.35 (m, 2H); ESIMS m/z 386 ([M+2H]+). |
52% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 60h;Inert atmosphere; | A solution of 3-(4-bromophenyl)-lH-l,2,4-triazole (10.9 g, 48.5 mmol), l-iodo-4-(trifluoromethoxy)benzene (13.2 g, 45.8 mmol), copper(I) iodide (2.38 g, 12.5 mmol), and cesium carbonate (30.3 g, 93.0 mmol) in dimethylsulfoxide (85 mL) was degassed with nitrogen for 5 minutes. The mixture was heated at 100 C for 60 hours. After cooling, ethyl acetate (200 mL) was added and the mixture was filtered through Celite. The filtrate was added to a solution of saturated ammonium chloride (200 mL) and stirred for one and a half hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and adsorbed onto Celite. Purification by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent provided the title molecule as an off-white solid (9.65 g, 52%) : mp 109-112 C; XH NMR (400 MHz, CDCI3) delta 8.56 (s, 1H), 8.10-8.03 (m, 2H), 7.83-7.75 (m, 2H), 7.64-7.57 (m, 2H), 7.42-7.35 (m, 2H); ESIMS m/z 384 ([M + H]+). |
50% | With copper(l) iodide; 8-quinolinol; caesium carbonate; In water; N,N-dimethyl-formamide; at 140℃; for 8h; | To a solution of 1-iodo-4-(trifluoromethoxy)benzene (15.0 g, 52.0 mmol) in dimethylformamide (90 mL) and water (10 mL) was added <strong>[118863-62-0]3-(4-bromophenyl)-1H-1,2,4-triazole</strong> (C51) (11.0 g, 49.0 mmol), cesium carbonate (34.0 g, 104 mmol), copper(I) iodide (2.80 g, 14.7 mmol), and 8-hydroxyquinoline (2.20 g, 15.0 mmol), and the solution was heated at 140 C. for 8 hours. The cooled solution was decanted from a layer of solid, diluted with a ammonium hydroxide (1N, 100 mL) solution, and extracted with of diethyl ether (2*100 mL). The combined organic layer was dried and concentrated, and the brown solid was eluted through a short silica gel column using 20% ethyl acetate/hexanes as eluent to give the title compound as a light tan solid (9.50 g, 50%): mp 111-113 C., 1H NMR (400 MHz, CDCl3) delta 8.56 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H); ESIMS m/z 384 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.7 g | With potassium fluoride; silver nitrate; palladium dichloride; In dimethyl sulfoxide; at 100℃; for 5h;Inert atmosphere; | Into a 1000-ml glass reaction vessel equipped with a thermometer and a stirring apparatus were placed 3.0 g (4.3 mmol) of palladium chloride, 10 g (174 mmol) of potassium fluoride, 25 g (86.8 mmol) of 4-(trifluoromethoxy)iodobenzene, 17 g (104.2 mmol) of 2-bromothiophene, 14.2 g (86.8 mmol) of silver nitrate, and 500 ml of anhydrous dimethyl sulfoxide. The mixture was subjected to freeze-pump-thaw (cycle) twice. The mixture was heated at 100C for 5 hours in argon atmosphere, and then cooled to room temperature. Inorganic substances were removed by filtration with Celite, and then the solvent was distilled off using a vacuum pump. The crude product obtained was purified by column chromatography (silica gel : hexane), to provide 16.7 g of Compound (1-1) in the form of a light yellow solid. [0094] The properties of Compound (1-1) were as follows. 1H-NMR (300MHz; CDCl3); 8 (ppm) 7.01-7.04 (m, 2H), 7.20-7.24 (m, 2H), 7.49-7.54 (m, 2H) CI-MS; 324 (M+1) |
16.7 g | With potassium fluoride; silver nitrate; palladium dichloride; In dimethyl sulfoxide; at 100℃; for 5h;Inert atmosphere; | Into a 1000-ml glass reaction vessel equipped with a thermometer and a stirring apparatus were placed 3.0 g (4.3 mmol) of palladium chloride, lOg (174 mmol) of potassium fluoride, 25 g (86.8 mmol) of 4-(trifluoromethoxy)iodoben- zene, 17 g (104.2 mmol) of 2-bromothiophene, 14.2 g (86.8 mmol) of silver nitrate, and 500 ml of anhydrous dimethyl sulfoxide. The mixture was subjected to freeze-pump-thaw (cycle) twice. The mixture was heated at 1000 C. for 5 hours in argon atmosphere, and then cooled to room temperature. Inorganic substances were removed by filtration with Celite, and then the solvent was distilled off using a vacuum pump. The crude product obtained was purified by column chromatography (silica gel:hexane), to provide 16.7 g of Compound (1-1) in the form of a light yellow solid.The properties of Compound (1-1) were as follows.‘H-NMR (300 MHz; CDC13); ö (ppm) 7.01-7.04 (m, 2H), 7.20-7.24 (m, 2H), 7.49-7.54 (m, 2H)CI-MS; 324 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper diacetate; potassium carbonate; In dimethyl sulfoxide; at 160℃; | [1207] To a stuffed solution of Compound 715 (1.Oeq) in 9V DMSO at 25C was added K2C03 (3.Oeq) . Addition of 4-Trifluoromethoxy iodide(1.leq) and Cu(OAc)2 (0.3eq) was followed by warming of the reaction mixture to 160C with stirring for 5-7h. Then, the reaction mixture was cooled to 25C and diluted with water:dichloromethane(1:1). The resulting mixture was filtered and the layers separated. The aqueous phase was extracted with DCM and the organic layers combined. The organic phase was concentrated under vacuum and diluted with MTBE to produce a white suspension. The solid was filtered to afford Compound 716 as a white solid in 85% yield. MS (ES) m/z (M+H)+ 310.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 1h;Inert atmosphere; Microwave irradiation; | Step A: Preparation of 2-bromo-5-(4-(trifluoromethoxy)phenyl)pyridine. [00137] To a microwave vial equipped with a magnetic stir bar were added (6-bromopyridin-3- yl)boronic acid (1.37 g, 6.77 mmol), l-iodo-4-(trifluoromethoxy)benzene (1.5 g, 5.21 mmol) and DMF (11.9 mL), followed by K2C03 (2.52 g, 18.2 mmol) and water (2.98 mL). The reaction mixture was stirred under N2 for 5 min and treated with Pd(PPh )4 (16.05 mg, 0.014 mmol). The reaction vessel was capped, placed in a Biotage Initiator microwave reactor for 1 h at 120 C, with external IR-sensor temperature monitoring from the side of the vessel. The cooled reaction mixture was filtered through a pad of Celite rinsing with EtOAc (100 mL), and the filtrate was washed successively with saturated aqueous NaHC03 (50 mL), water (3 x 50 mL), and brine (50 mL). The organic phase was dried over MgS04, filtered, and concentrated. The residue was purified by column chromatography (Si02, 0-M0 EtOAc in hexanes) to give the title compound (1.07 g, 63%) as an off-white solid: IR (Thin Film) 3036, 1453, 1210, 1167 cm"1; 1H NMR (400 MHz, CDC13) delta 8.57 (dd, J = 2.6, 0.8 Hz, 1H), 7.71 (dd, J= 8.2, 2.6 Hz, 1H), 7.63 - 7.54 (m, 3H), 7.38 - 7.29 (m, 2H); 19F NMR (376 MHz, CDC13) delta -57.83; HRMS-ESI (m/z) [M+H]+ calcd for Ci2H8BrF3NO, 317.9736; found, 317.9735. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A mixture of 4-methylaniline (8 g, 74.77mmol) and water was stirred at 35 C, before 98% sulfuric acid was added gradually. The reaction mixture was continue stirring for 35 minutes and then cooled to 0 C. Sodium nitrite solution (5.42 g, 80 mmol) was added and stirred for 2 hours. Then, dichloromethane and potassium iodide solution (13.03 g, 78.50 mmol) were added to the diazonium salt. The mixture was stirred for 6 hours at 0C and kept stirring at room temperature for 10 hours. The organic phase was separated, washed with sodium bisulfate solution, saturated sodium chloride solution, saturation sodium solution and then were dried by sodium sulfate solution. The mixture was filtered and the filtrate was concentrated in vacuum to give crude product. The crude productwas purified by column chromatography of silica gel, eluted with petroleum ether /ethyl acetate (3:1, V/V) to give 5a-d as yellow solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 110℃; for 24h;Inert atmosphere; | General procedure: A mixture containing 5a-d (6.3 g, 28.9 mmol), methylparaben (6.59 g, 43.35 mmol), CuI (1.1 g, 5.78 mmol), N,N-dimethylglycine (0.89 g, 8.67 mmol) and Cs2CO3 (18.78 g, 57.8mmol) in 1,4-dioxane was vigorously stirred at 110C under nitrogen atmosphere for 24 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The combined organic layers was washed with saturation sodium solution, driedby sodium sulfate and concentrated in vacuum. The residue was chromatographed on a silica gel column, eluted with petroleum ether /ethyl acetate (20:1, V/V)to give 6a-d as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In Petroleum ether; | Example 43 Preparation of 3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C23) In a 500 mL flask, <strong>[118863-62-0]3-(4-bromophenyl)-1H-1,2,4-triazole</strong> (20.0 g, 89.6 mmol), 1-iodo-4-(trifluoromethoxy)benzene (39.0 g, 135 mmol) were diluted with N,N-dimethylformamide and water (4:1, 100 mL). Then copper(I) iodide (15.3 g, 80.6 mmol), 8-hydroxyquinoline (8.50 g, 58.2 mmol) and cesium carbonate (87.4 g, 269 mmol) were added. The reaction was heated to 150 C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. Brine solution was added to the filtrate and stirred for 15 minutes. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 15% ethyl acetate/petroleum ether as eluent to afford the title compound as a white solid (10.0 g, 29%): mp 100-103 C.; 1H NMR (300 MHz, DMSO-d6) delta 9.42 (s, 1H), 8.07 (d, J=9.0 Hz, 2H), 8.05 (d, J=9.0 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H); ES+ m/z 385 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With iron(II) chloride; In tetrahydrofuran; at 0 - 25℃; for 18h;Schlenk technique; Inert atmosphere; | General procedure: A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a rubberseptum, was charged with FeCl2 (10 mol%, 99.5% pure), the corresponding electrophile (1.0equiv) and freshly distilled THF. Thereupon, the benzylic manganese(II) chloride solution (1.05-1.10 euqiv) was dropwise added at 0 C. After the addition was complete, the reaction mixturewas stirred for a given time at the prior adjusted temperature and then allowed to warm toroom temperature. The reaction completion was monitored by GC-analysis of quenched aliquots.A saturated aqueous solution of NH4Cl was added and the aqueous layer was extracted threetimes with Et2O or EtOAc (3 × 50 mL). The combined organic layers were dried over MgSO4,filtered and concentrated under reduced pressure. Purification of the crude products by flashcolumn chromatography afforded the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; In isopropyl alcohol; at 85℃; for 36h;Reflux; Inert atmosphere; | General procedure: Copper(I) iodide (1.0 mmol, 0.1 equiv, 200 mg) and potassium phosphate (20.0 mmol, 2.0 equiv,4.25 g) were added to a well dried bottom flasks with two necks and then evacuated and backfilled with Argon. 2-Propanol (30 mL), ethylene glycol (20.0 mmol, 2.0 equiv, 1.2 mL), 1,2,3,4-tetrahydroisoquinoline (15 mmol, 1.5 equiv, 2 mL) and an aryl iodide (10 mmol, 1 equiv) wereadded at room temperature. The reaction mixture was heated at 85 and refluxed for 36 h.After complete the reaction, it was quenched with water and extracted with ethyl acetate. Thenpurification the crude by column chromatography using petroleum / ethyl acetate to afford pureproduct of 1a-1m, 1o. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With copper(l) iodide; N,N′-di-β-D-glucopyranosylethylenediamine; caesium carbonate; In water; at 100℃; for 24h; | General procedure: To a stirred solution of H2O (5 ml) were added CuI (0.1 mmol, 19 mg), aryl halides (1.0 mmol),nitrogen nucleophiles (1.2 mmol), Cs2CO3 (2 mmol, 651 mg) and L5 (0.1 mmol) were added tothe solution, subsequently the mixture was heated to 100 C under air and stirred for 24 h. Whenthe reaction was finished, the mixture was cooled and partitioned by adding the ethyl acetate (20ml) and water (20 ml). Then, the organic phase was separated and the aqueous phase wasextracted with ethyl acetate (20 ml) twice. The combined organic phases were washed withsaturated brine, dried over Na2SO4, and concentrated in vacuo. Then the crude product waspurified by column chromatography through silica gel, eluting with ethyl acetate/petroleum ethersolvent mixture, to give the pure product. |
75% | With potassium carbonate; In water; at 100℃; for 24h;High pressure; | General procedure: To a stirred solution of H2O (4 mL), aryl halide (1.0 mmol), nucleophile(1.2 mmol), Cu/HCS-MA-F127 and K2CO3 (2 mmol) wereadded at room temperature. Next, the reaction mixture was heated to100 C in air and stirred for 24 h. After cooling down to room temperature,the catalyst Cu(at)HCS-MA-F127 was separated by centrifugation.The reaction mixture was partitioned by adding ethyl acetate (20mL) and water (20 mL). Subsequently, the organic phase was separatedand the aqueous phase was extracted with ethyl acetate (20 mL) twice.The combined organic phases were washed with brine, dried overNa2SO4, and concentrated in vacuo. Finally, the crude product waspurified by column chromatography with silica gel, eluting with apetroleum ether/ethyl acetate solvent mixture, to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃;Inert atmosphere; | A dried vial was charged with methyl 1 H-indazole-5-carboxylate (1 .00 g, 5.68 mmol), copper(l) iodide (0.108 g, 0.568 mmol), cesium carbonate (1.85 g, 5.68 mmol) and 5.7 imL DMSO. The reaction mixture was evacuated and flushed with argon again. After addition of 1 -iodo-4-(trifluoromethoxy)benzene (0.843 g, 2.84 mmol), the reaction mixture was heated at 100C. After cooling, the reaction mixture was diluted with ethyl acetate. It was filtrated over celite and washed several times with ethyl acetate. The organic layer was extracted with water, brine, dried with anhydrous MgS04, filtered of and evaporated. The crude product was purified by flash-chromatography to give a mixture of methyl 1 -[4-(trifluoromethoxy)- phenyl]indazole-5-carboxylate and methyl 2-[4-(trifluoromethoxy)phenyl]indazole-5-carboxylate (610 mg) as a yellow solid. LC-MS: tR = 1 .15 min, m/z = 337 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 3.91 (s, 3 H) 7.63 (d, J=8.44 Hz, 2 H) 7.92 - 7.99 (m, 3 H) 8.07 (dd, J=8.80, 1 .47 Hz, 1 H) 8.61 (d, J=2.20 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A dried vial was charged with methyl 1 H-indazole-5-carboxylate (1 .00 g, 5.68 mmol), copper(l) iodide (0.108 g, 0.568 mmol), cesium carbonate (1.85 g, 5.68 mmol) and 5.7 imL DMSO. The reaction mixture was evacuated and flushed with argon again. After addition of 1 -iodo-4-(trifluoromethoxy)benzene (0.843 g, 2.84 mmol), the reaction mixture was heated at 100C. After cooling, the reaction mixture was diluted with ethyl acetate. It was filtrated over celite and washed several times with ethyl acetate. The organic layer was extracted with water, brine, dried with anhydrous MgS04, filtered of and evaporated. The crude product was purified by flash-chromatography to give a mixture of methyl 1 -[4-(trifluoromethoxy)- phenyl]indazole-5-carboxylate and methyl 2-[4-(trifluoromethoxy)phenyl]indazole-5-carboxylate (610 mg) as a yellow solid. LC-MS: tR = 1 .15 min, m/z = 337 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 3.91 (s, 3 H) 7.63 (d, J=8.44 Hz, 2 H) 7.92 - 7.99 (m, 3 H) 8.07 (dd, J=8.80, 1 .47 Hz, 1 H) 8.61 (d, J=2.20 Hz, 2 H). Step L-2: Preparation of [1 -[4-(trifluoromethoxy)phenyl]indazol-5-yl]methanol and [2-[4- (trifluoromethoxy)phenyl]indazol-5-yl]methanol A vial under argon was charged with a mixture of methyl 1 -[4-(trifluoromethoxy)phenyl]indazole-5- carboxylate and (methyl 2-[4-(trifluoromethoxy)phenyl]indazole-5-carboxylate (0.610 g, 1 .72 mmol) and with diethyl ether (8.62 mL). The reaction mixture was cooled to -70C and a solution of DIBAL-H in dichloromethane (1 N , 1 .7 mL, 1 .7 mmol) was added dropwise. After 1 h at this temperature, the reaction mixture was warmed to 0C and another 1 equivalent (1 .7 mL) DIBAL-H in dichloromethane was added. The reaction mixture was stirred at 0C for another 30 min. After quenching at 0C with Rochelle salt (10 mL), the mixture was extracted twice with dichloromethane, dried over anhydrous MgS04, filtered and evaporated to give a mixture of [1 -[4-(trifluoromethoxy)phenyl]indazol-5-yl]methanol and [2-[4-(trifluoro- methoxy)phenyl]indazol-5-yl]methanol (0.849 mg) as a yellow oil. LC-MS: tR = 0.97 min, m/z = 308 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 4.64 (d, J=5.50 Hz, 2 H) 7.49 (d, J=8.44 Hz, 1 H) 7.59 (d, J=8.80 Hz, 2 H) 7.81 - 7.88 (m, 2 H) 7.93 (d, J=8.80 Hz, 2H) 8.39 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.265 mg; 0.046 mg | A dried vial was charged with methyl 1 H-indazole-5-carboxylate (1 .00 g, 5.68 mmol), copper(l) iodide (0.108 g, 0.568 mmol), cesium carbonate (1.85 g, 5.68 mmol) and 5.7 imL DMSO. The reaction mixture was evacuated and flushed with argon again. After addition of 1 -iodo-4-(trifluoromethoxy)benzene (0.843 g, 2.84 mmol), the reaction mixture was heated at 100C. After cooling, the reaction mixture was diluted with ethyl acetate. It was filtrated over celite and washed several times with ethyl acetate. The organic layer was extracted with water, brine, dried with anhydrous MgS04, filtered of and evaporated. The crude product was purified by flash-chromatography to give a mixture of methyl 1 -[4-(trifluoromethoxy)- phenyl]indazole-5-carboxylate and methyl 2-[4-(trifluoromethoxy)phenyl]indazole-5-carboxylate (610 mg) as a yellow solid. LC-MS: tR = 1 .15 min, m/z = 337 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 3.91 (s, 3 H) 7.63 (d, J=8.44 Hz, 2 H) 7.92 - 7.99 (m, 3 H) 8.07 (dd, J=8.80, 1 .47 Hz, 1 H) 8.61 (d, J=2.20 Hz, 2 H). Step L-2: Preparation of [1 -[4-(trifluoromethoxy)phenyl]indazol-5-yl]methanol and [2-[4- (trifluoromethoxy)phenyl]indazol-5-yl]methanol A vial under argon was charged with a mixture of methyl 1 -[4-(trifluoromethoxy)phenyl]indazole-5- carboxylate and (methyl 2-[4-(trifluoromethoxy)phenyl]indazole-5-carboxylate (0.610 g, 1 .72 mmol) and with diethyl ether (8.62 mL). The reaction mixture was cooled to -70C and a solution of DIBAL-H in dichloromethane (1 N , 1 .7 mL, 1 .7 mmol) was added dropwise. After 1 h at this temperature, the reaction mixture was warmed to 0C and another 1 equivalent (1 .7 mL) DIBAL-H in dichloromethane was added. The reaction mixture was stirred at 0C for another 30 min. After quenching at 0C with Rochelle salt (10 mL), the mixture was extracted twice with dichloromethane, dried over anhydrous MgS04, filtered and evaporated to give a mixture of [1 -[4-(trifluoromethoxy)phenyl]indazol-5-yl]methanol and [2-[4-(trifluoro- methoxy)phenyl]indazol-5-yl]methanol (0.849 mg) as a yellow oil. LC-MS: tR = 0.97 min, m/z = 308 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 4.64 (d, J=5.50 Hz, 2 H) 7.49 (d, J=8.44 Hz, 1 H) 7.59 (d, J=8.80 Hz, 2 H) 7.81 - 7.88 (m, 2 H) 7.93 (d, J=8.80 Hz, 2H) 8.39 (s, 1 H). Step L-3: Preparation of 1 -[4-(trifluoromethoxy)phenyl]indazole-5-carbaldehyde and 2-[4- (trifluoromethoxy)phenyl]indazole-5-carbaldehyde. A 25 mL round bottom flask was set under argon and charged with Dess-Martin periodinane (0.707 g, 1 .67 mmol) suspended in dichloromethane (9.00 mL). A mixture of [1 -[4-(trifluoromethoxy)phenyl]indazol- 5-yl]methanol and [2-[4-(trifluoromethoxy)phenyl]indazol-5-yl]methanol (0.476 g, 1.39 mmol) in dichloromethane (4 mL) was added dropwise at room temperature. The reaction mixture was stirred at this temperature overnight. After dilution with 15 mL ethyl acetate, the mixture was poured into a mixture of saturated NaHC03 and saturated Na2S203 (-40 mL, 1 :1 ) and stirred for 10 min at 0C (pH~9). The solution was then extracted with ethyl acetate (100 mL), washed with saturated NaHC03 (80 mL), water (80 mL), brine (80 mL), dried over anhydrous MgS04, filtered and evaporated. The crude mixture was separated by flash-chromatography to give 1 -[4-(trifluoromethoxy)phenyl]indazole-5-carbaldehyde (0.265 mg) and 2-[4-(trifluoromethoxy)phenyl]indazole-5-carbaldehyde (0.046 mg). 1 -[4-(trifluoromethoxy)phenyl1indazole-5-carbaldehvde LC-MS: tR = 1 .07 min, m/z = 307 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 7.65 (d, J=8.44 Hz, 2 H) 7.94 - 8.07 (m, 4 H) 8.54 - 8.74 (m, 2 H) 10.07 - 10.16 (m, 1 H). 2-[4-(trifluoromethoxy)phenyl1indazole-5-carbaldehvde LC-MS: tR = 1 .05 min, m/z = 307 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 7.67 (d, J=8.80 Hz, 2 H) 7.74 - 7.79 (m, 1 H) 7.84 - 7.89 (m, 1 H) 8.29 (d, J=9.17 Hz, 2 H) 8.57 (s, 1 H) 9.52 (s, 1 H) 10.05 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With palladium diacetate; silver carbonate; In o-xylene;Inert atmosphere; | General procedure: A mixture of 8-aminoquinoline (0.4mmol), an appropriate carbonyl chloride (0.4mmol), an appropriate aryl iodide (0.16-0.24mmol, 4-6 equiv), Pd(OAc)2 (10mol %) and Ag2CO3 (0.6-0.8mmol, 1.5-2 equiv) was heated in o-xylene (2mL) at 110 C for an appropriate reaction period (12-36 h). Then, reaction mixture was cooled to rt and the solvent evaporated in vacuo to give the crude product, which was purified by chromatography to give the corresponding C-H arylated products (see the respective Tables 1-4/Scheme 2 for the specific entries and reaction conditions). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; XPhos; In 1,4-dioxane; at 110℃; for 1h;Microwave irradiation; Inert atmosphere; | Preparation of Compound 15 A solution of intermediate AN (15.0 mg, 0.0420 mmol), l-iodo-4-(trifluoromethoxy) benzene (CAS [103962-05-6], 12.1 mg, 0.042 mmol), Pd(dba)2 (3.66 mg, 6.37 umol), X-phos (3.81 mg, 8.00 mmol) and sodium tert-butoxide (16.1 mg, 0.168 mmol) in 1,4-dioxane (2 mL) was irradiated under microwave at 110C for 60 min under N2 atmosphere. The mixture was filtered and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/1) to give crude compound. It was further purified by high performance liquid chromatography over Gemini CI 8 150χ25ητηιχ10μ1 (eluent: ammonia in water/acetonitrile 30/70 to 0/100). The desired fractions were collected and lyophilized to give Compound 15 (2.30 mg, yield: 10%>). 1H NMR (400MHz, CDC13) δ = 9.47 (s, 1H), 7.54 (d, J=9.5 Hz, 1H), 7.29 (dd, J=2.0, 9.5 Hz, 1H), 7.08 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 5.80 (br. s., 1H), 3.57 (t, J=6.5 Hz, 2H), 3.17 - 3.09 (m, 2H), 3.09 - 3.03 (m, 2H), 3.00 (q, J=7.5 Hz, 2H), 2.61 (td, J=8.3, 16.1 Hz, 1H), 2.11 - 1.99 (m, 2H), 1.83 - 1.75 (m, 2H), 1.71 (d, J=5.5 Hz, 2H), 1.60 - 1.54 (m, 2H), 1.45 (t, J=7.7 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With copper(l) iodide; caesium carbonate; L-proline; In dimethyl sulfoxide; at 90℃; for 18h;Inert atmosphere; | Preparation of intermediate BE To a solution of l-iodo-4-(trifhioromethoxy)benzene (CAS [103962-05-6], 4.48 g, 15.54 mmol) in DMSO (50mL) was added intermediate BD (1.84 g, 10.36 mmol), cesium carbonate (8.44 g, 25.9 mmol), L-Proline (0.48 g, 4.14 mmol) and copper iodide (0.39 g, 2.07 mmol). The mixture was heated at 90 C for 18 h under argon atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mLx3). The organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/l) to give intermediate BE, 1.5 g, 48%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; XPhos; In 1,4-dioxane; at 110℃; for 1h;Microwave irradiation; Inert atmosphere; | Preparation of Compound 1 A solution of E (20 mg, 0.058 mmol), l-iodo-4-(trifluoromethoxy)benzene (CAS [103962-05-6], 16.7 mg, 0.058 mmol), Pd(dba)2 (3.34 mg, 0.006 mmol), Xphos (4.57 mg, 0.009 mmol) and t-BuONa (22.3 mg, 0.232 mmol) in 1 ,4-dioxane (5 mL) was irradiated under microwave at 110C for 1 hour under N2. The mixture was concentrated under vacuum. The residue was purified by high performance liquid chromatography over Gemini (eluent: NH3 water/acetonitrile 30/70 to 70/30). The desired fractions were collected and concentrated to give Compound 1 , 19.3 mg, 64% 1H NMR (400 MHz, CDC13) δ ppm 9.47 (s, 1 H) 7.54(d, J=9.29 Hz, 1 H) 7.30 (dd, J=9.41, 1.83 Hz, 1 H) 7.10 (d, J=8.80 Hz, 2 H) 6.91 (d, J=9.05 Hz, 2 H) 5.87 (br. s., 1 H) 3.51 - 3.60 (m, 2 H) 3.30 - 3.42 (m, 2 H) 3.08 -3.17 (m, 2 H) 3.02 (q, J=7.58 Hz, 2 H) 1.86 - 1.94 (m, 1 H) 1.73 - 1.82 (m, 1H) 1.64 - 1.69 (m, 1 H) 1.43 (t, J=7.58 Hz, 3 H) 1.36 (d, J=13.45 Hz, 1 H) 1.01 - 1.10 (m, 1 H) 0.70 (dd, J=8.44, 4.77 Hz, 1 H) 0.38(t, J=4.89 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; XPhos; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation; Inert atmosphere; | Preparation of intermediate H A solution of intermediate G (100 mg, 0.504 mmol), l-iodo-4-(trifluoromethoxy) benzene (CAS [103962-05-6], 145 mg, 0.504 mmol), X-Phos (28.8 mg, 0.06 mmol), Pd(dba)2 (17.4 mg, 0.03 mmol) and t-BuONa (194 mg, 2.02 mmol) in dioxane (4 mL) was irradiated under microwave at 100C for 1 hour under N2. The mixture was concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate / petroleum ether from 0 to 1/1). The desired fractions were collected and concentrated to give intermediate H (100 mg, yield: 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; XPhos; In 1,4-dioxane; at 110℃; for 1h;Microwave irradiation; Inert atmosphere; | Preparation of intermediate N A solution of <strong>[1041026-70-3]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate</strong> (CAS [1041026-70- 3], 500 mg, 2.52 mmol), l-iodo-4-(trifiuoromethoxy)benzene (CAS [103962-05-6], 726 mg, 2.52 mmol), X-phos (240 mg, 0.504 mmol), Pd(dba)2 (145 mg, 0.252 mmol) and t-BuONa (969 mg, 10.1 mmol) in dioxane (8 mL) was irradiated under microwave at 110C for 1 hour under N2. Water was added to the mixture and the mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were washed brine, dried over MgS04 and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate/hexane from 0 to 1/5). The desired fractions were collected and concentrated to give N, 500 mg, 50%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; XPhos; In 1,4-dioxane; at 110℃; for 1h;Microwave irradiation; Inert atmosphere; | Preparation of Compound 14 A solution of intermediate AJ (30.0 mg, 0.0770 mmol), l-iodo-4-(trifluoromethoxy) benzene (CAS [103962-05-6], 22.2 mg, 0.0770 mmol), Pd(dba)2 (4.60 mg, 8.00 μιηο, X-phos (7.63 mg, 16.0 μιηο) and sodium tert-butoxide (29.6 mg, 0.308 mmol) in dioxane (4 mL) was irradiated under microwave at 110C for 1 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, brine, dried over Na2S04, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether/ethyl acetate 10/1 to 0/1) to give crude compound. It was further purified by high performance liquid chromatography over Gemini C18 150χ25ιηηιχ10μ1 (eluent: 0.5% ammonia in water/acetonitrile 45/55 to 15/85). The desired fractions were collected and lyophilized to give Compound 14 (1.30 mg, yield: 3%). 1H NMR (400MHz, CDC13) δ = 9.50 (d, J=1.3 Hz, 1H), 7.54 (d, J=9.5 Hz, 1H), 7.29 (dd, J=2.1, 9.4 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.89 (d, J=9.3 Hz, 2H), 6.35 (br. s., 1H), 3.93 - 3.85 (m, 2H), 3.51 (br. s., 1H), 3.30 (m, 1H), 3.24 (d, J=11.3 Hz, 1H), 3.21 - 3.07 (m, 4H), 3.03 (q, J=7.5 Hz, 2H), 1.94 - 1.85 (m, 2H), 1.79 (d, J=7.0 Hz, 1H), 1.66 - 1.62 (m, 1H), 1.61 - 1.59 (m, 2H), 1.50 - 1.47 (m, 2H), 1.44 (t, J=7.5 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere; Sealed tube; | Example 14 Preparation of 3-(4-nitrophenethyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C41) To a 100 mL flask were added 3-(4-nitrophenethyl)-1H-1,2,4-triazole (C38) (6.50 g, 29.8 mmol), potassium carbonate (8.23 g, 59.6 mmol), and copper(I) chloride (0.590 g, 5.96 mmol). The flask was sealed and placed under inert atmosphere, then N,N-dimethylformamide (99 mL), N1,N2-dimethylethane-1,2-diamine (1.28 mL, 11.9 mmol), and <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (6.99 mL, 44.7 mmol) were added. The reaction mixture was stirred in a heating block warmed to 100 C., overnight. The reaction mixture was cooled to room temperature and poured into brine solution. The aqueous layer was extracted with ethyl acetate (3*100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography using 0-70% ethyl acetate/hexanes as eluent to provide the title compound (8.97 g, 79%): 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.21-8.07 (m, 2H), 7.99-7.87 (m, 2H), 7.55 (dd, J=8.8, 1.8 Hz, 4H), 3.20 (dd, J=8.2, 6.2 Hz, 2H), 3.15-3.04 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ -57.06; 13C NMR (101 MHz, DMSO-d6) δ 163.73, 149.34, 146.85, 145.93, 142.91, 135.61, 129.69, 123.81, 123.30, 122.46, 121.26, 120.76, 118.71, 116.14, 32.94, 28.62; ESIMS m/z 379 ([M+H]+). |
79% | With potassium carbonate; copper(l) chloride; N,N`-dimethylethylenediamine; at 100℃;Sealed tube; Inert atmosphere; | To a 100 mL flask were added 3-(4-nitrophenethyl)-l--l,2,4-triazole (C38) (6.50 g, 29.8 mmol), potassium carbonate (8.23 g, 59.6 mmol), and copper(I) chloride (0.590 g, 5.96 mmol). The flask was sealed and placed under inert atmosphere, then Λ/,/V-dimethylformamide (99 mL), /Vl,/V2-dimethylethane-l,2-diamine (1.28 mL, 11.9 mmol), and l-iodo-4-(trifluoromethoxy)benzene (6.99 mL, 44.7 mmol) were added. The reaction mixture was stirred in a heating block warmed to 100 C, overnight. The reaction mixture was cooled to room temperature and poured into brine solution. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography using 0-70% ethyl acetate/hexanes as eluent to provide the title compound (8.97 g, 79%): *H NMR (400 MHz, DMSO- 6) δ 9.23 (s, 1H), 8.21 - 8.07 (m, 2H), 7.99 - 7.87 (m, 2H), 7.55 (dd, J = 8.8, 1.8 Hz, 4H), 3.20 (dd, J = 8.2, 6.2 Hz, 2H), 3.15 - 3.04 (m, 2H); 19F NMR (376 MHz, DMSO- 6) δ -57.06; 13C NMR (101 MHz, DMSO- 6) δ 163.73, 149.34, 146.85, 145.93, 142.91, 135.61, 129.69, 123.81, 123.30, 122.46, 121.26, 120.76, 118.71, 116.14, 32.94, 28.62; ESIMS m/z 379 ([M + H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.36% | With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 110℃; for 18h;Inert atmosphere; | To a mixture of 6 (100.00mg, 542.77ij.mol) and (299.73mg, l.O9rninol) in toluene (5.OOmL) was added Pd(dba)2(31.2img, 54.28iimol), Cs2CO2 (353.69mg, i.O9mmol) and Xantphos (31.41mg, 54.28imol) in one portion at 11. under N2 atmosphere. The mixture was then heated to110C and stirred for 18 hours. LCMS showed the reaction was completed. The mixture was cooled to rt. and filtered. The filtrate was concentrated in reduced pressure at 60C. The residue was purified by prep-HPLC to afford the desired product Compound 3 (8.00 mg, yield: 4.36%).LCMS: m/z, 345 (M±H)1HNMR (400 MHz, CDCI3): ö 8.54 (d, J 4.85Hz, IH), 7.63 (td, J 7.72, 1.76Hz, 1H), 7.39(d, J 7.72Hz, IH), 7.20 (dd, J 7.06, 5.51Hz, IH), 7.07 (d, J= 8.60Hz, 2H), 6.51 (d, J=9.26Hz,2H), 3.76 (d, J= 8.82Hz. IH), 3.55 (d, J= 9.04Hz, IH), 3.32-3.46 (in, 2H), 2.10-2.19 (in, IH),1.36 (dd, J= 8.05, 4.52Hz, 1H), 1.05 (t, J= 4.63Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; | To a solution of <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong> (1.6 g, 8.7 mmol, 1.0 eq) and l -iodo-4-(trifluoromethoxy)benzene (2.5 g, 8.7 mmol, 1.0 eq) in toluene (100 mL) was added sodium fert-butoxide (2.5 g, 25 mmol, 3.0 eq), racemic 2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (0.54 g, 0.87 mmol, 0.10 eq), and lastly tris(dibenzylideneacetone)-dipalladium(0) (0.80 g, 0.87 mmol, 0.10 eq), and the reaction mixture heated to 100 °C overnight. The resulting dark reaction mixture was cooled, passed thru a pad of celite, and concentrated in vacuo. Silica gel column (40 g) was dry loaded and run using an increasing gradient of EtOAc (0-50percent) in hexanes over 25 min yielding tert-butyl l -[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylate 9a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With potassium phosphate; 1,10-Phenanthroline; silver carbonate; palladium dichloride; In N,N-dimethyl acetamide; at 150℃; for 12h;Inert atmosphere; | To a solution of compound 02-5-1 (1.00 g, 3.0 mmol, 1.0 eq) in DMA (5 mL) was added <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (1.73 g, 6.0 mmol, 939 µL, 2.0 eq), PdCl2 (10.6 mg, 60.0 µmol, 0.02 eq), 1,10-phenanthroline (10.8 mg, 60.0 µmol, 0.02 eq), Ag2CO3 (1.24 g, 4.50 mmol, 204 µL, 1.5 eq) and K3PO4 (1.27 g, 6.0 mmol, 2.0 eq). The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 150 C for 12 h. The reaction mixture was poured into H2O (100 mL), filtered through Celite, and washed with EtOAc (50 mL). The filtrate was extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give compound 02-5-2 (300.0 mg, 608 µmol, 20% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium phosphate; copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 110℃; for 12h;Inert atmosphere; | A mixture of compound 03-1-3 (2.50 g, 7.52 mmol, 1.0 eq), 1-iodo-4- (trifluoromethoxy)benzene (3.25 g, 11.3 mmol, 1.5 eq), CuI (143.2 mg, 752.1 µmol, 0.1 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (321.0 mg, 2.26 mmol, 0.3 eq) and K3PO4 (3.19 g, 15.0 mmol, 2.0 eq) in toluene (3.0 mL) was heated at 110 C for 12 h under N2. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (80 mL*4). The combined organic layers were washed with brine (20 mL*3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give compound 03-1-4 (3.00 g, 74%). M+H+ = 393.2 (LCMS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium phosphate; copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 110℃; for 18h;Inert atmosphere; | To a solution of compound 03-4-1 (5.30 g, 20.6 mmol, 1.0 eq) in toluene (150 mL) was added <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (7.12 g, 24.7 mmol, 3.87 mL, 1.2 eq), K3PO4 (10.9 g, 51.5 mmol, 2.5 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (879.0 mg, 6.18 mmol, 0.3 eq) and CuI (392.3 mg, 2.06 mmol, 0.1 eq) under N2 protection. The mixture was stirred at 110 C for 18 h, cooled to room temperature, quenched by addition of H2O (250 mL) at room temperature, and diluted with EtOAc (250 mL). The organic layer was separated, washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give compound 03-4-2 (7.00 g, 81% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With palladium diacetate; potassium hydroxide; In water; at 100℃; for 24h;Inert atmosphere; | General procedure: The mixture of 1 (0.1g), 2/2'/2"(1.5 equivalent), Pd(OAc)2 (5 mol%), KOH (3 equivalent) in 4 mL of nitrogen purged deionised water were stirred at 100 C. The reaction was carried out under nitrogen atmosphere. The progress of reaction was monitored using TLC. Upon completion of the reaction, silica gel was added and the mixture was evaporated under vacuum. The resulted mixture was purified by column chromatography using EtOAc:Petroleum ether (0.4:0.6 to 0.8:0.2, EtOAc:Petroleum ether) to afford pure 3-aryl imidazo[1,2-a]pyridines 3 and 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.08% | With caesium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; | To a solution of uSc g, 24O7mmol), CuCI (0238g. 24O7mmoi) and Cs2C03 (8.63g. 26.Smmoi) in 5mL of DMF was added 224(6.93g, 24.O7mmoi) and the resulting mixture was heated at130 C via MW irradiation for 30 minutes. The mixture was cooled to room temperature, and diluted with EA, washed with [120 (20 mLx3). The combined organic layer was washed with saturated NaCI and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford 230(lg, yield: 17.08%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With copper diacetate; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; | A mixture of 220( .613g, 9.Olmmol), Cs2C03 (4.40g. 13.5 Immol), 224(2Og, 9.Olmmoi) andCu(OAc)2 (0. 16g) in 20mL DMF. The mixture was heated at 120C for the appropriate time andsubsequent cooling, the reaction mixture was diluted with saturated aqueous ammonium chloride.Products were isolated by extraction with EA. The organic layer was dried over anhydrousNa2SO4, filtered, and concentrated. Products 225 were purified by silica gel columnchromatography (1 40g, yield: 68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 5h;Inert atmosphere; | To a solution of 50 (156g. 16.O6mmoi) in DMF (5OmL) was added 56 (5.09g, 1767mmol), CuT (306mg, 1 .6lmmoI), C52CO3 (I0.47g, 32.1 3rnmol). The mixture was stirred at 110C for 5 hoursunder N2 atmosphere, then the mixture was filtered and concentrated to give the crude product which was purified by silica gel chromatography to give product 57(800mg, 19%). LCMS: m/z, 259.1 (M÷H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tellurium; potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 10h;Inert atmosphere; Sealed tube; | General procedure: A sealed tube containing a magnetic stirring bar was charged with aryl iodide (1.0 mmol), Te (0.13 g, 1.0 mmol), KOH (0.11 g, 2.0 mmol) and DMSO (2 mL) under nitrogen. The reaction mixture was heated in an oil bath at 110 C and stirred at this temperature for 10 h. The progress of the reaction was monitored by TLC via syringe. After the reaction was complete, the reaction mixture was allowed to cool, and treated with CH2Cl2 and H2O. The organic layer was washed with sat. NH4Cl and brine solution, dried with Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel with an eluent consisting of hexanes and ethyl acetate to affording the corresponding diaryl tellurides in good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With selenium; copper diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 24h;Inert atmosphere; | in room temperature,4-Trifluoromethoxyiodobenzene (1.2 mmol, 3 equiv),Elemental selenium (1.2 mmol, 3 equiv),<strong>[825-56-9]5-phenyl-1,3,4-oxadiazole</strong> (0.4 mmol, 1 equiv),Cu (OAc) 2 (0.04 mmol),Potassium carbonate (1.2 mmol, 3 equiv) was added to the reaction tube,Then filled with nitrogen, and replaced three times, in the nitrogen reaction environment,Then, 2 mL of DMF was added to the reaction solvent and stirred at 140 C for 24 h.After the reaction was monitored by thin layer chromatography, the reaction mixture was cooled,Then diluted with ethyl acetate, and the diluted solution was transferred to a separatory funnel,Extracted with saturated brine, separated from the aqueous phase and organic phase, and then extracted with ethyl acetate 3 times,The organic phases were combined, 5 g of anhydrous sodium sulfate was added,Wash the filter cake with 5 mL of ethyl acetate each time 3 times, then spin off the solvent,The product was isolated by column chromatography (eluent: petroleum ether: ether = 98: 2)The product was a yellow solid in 57% yield and 88 mg of product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1,10-Phenanthroline; oxygen; copper diacetate; potassium carbonate; In toluene; at 100℃; for 24h; | At room temperature, <strong>[33844-21-2]2-nitro-4-methoxybenzoic acid</strong> (0.4 mmol, 1 equiv), elemental selenium (1.2mmol, 3equiv), 4- trifluoromethoxy-iodobenzene (1.2mmol, 3equiv), Cu (OAc) 2 (0.04mmol), 1,10- phenanthroline (0.04 mmol), potassium carbonate (1.2mmol, 3equiv) and 2mL of toluene was added to the reaction tube, then filled with oxygen, and substituted three times, the oxygen the reaction environment, the reaction was stirred at a temperature of 100 deg.] C 24h. By the end of the reaction was monitored by thin layer chromatography, the reaction mixture was cooled, filtered and then ethyl acetate was added, and then spin off the solvent, the product obtained was isolated by column chromatography (eluent: petroleum ether: diethyl ether = 98), the product is yellow liquid, yield 91%, by weight of the product is 143mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; for 8h;Inert atmosphere; Reflux; | General procedure: Under argon, imidazo[2,1-c][1,2,4]triazine 1 (100mg, 0.44mmol), (hetero)aryl iodide (0.46mmol) and cesium carbonate (216mg, 0.66mmol) were solubilized in 2mL of toluene. The mixture was evacuated and back-filled with dry argon twice and Xantphos (26mg, 0.044mmol), Palladium acetate (5mg, 0.022mmol) were added and the mixture was submitted to reflux with stirring for 8h. Then cooled to room temperature and the mixture was filtered through celite and the organic phase was extracted three times with ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica (EtOAc/EP 2:8 to 3:7) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With copper(l) iodide; caesium carbonate; L-proline; In dimethyl sulfoxide; at 90℃; for 18h;Inert atmosphere; | To a solution of l-iodo-4-(trifluoromethoxy)benzene (CAS [103962-05-6], 4.9 g, 17.01 mmol) in DMSO (30 mL) was added 3-azetidin-3-ol hydrogen chloride salt (1.24 g, 11.34 mmol), cesium carbonate (9.24 g, 28.36 mmol), Copper Iodide (434 mg, 2.27 mmol) and L-proline (522 mg, 4.54 mmol) and then the mixture was heated at 90 C for 18 h under argon atmosphere. The solution was diluted with ethyl acetate and water and the organic layer was washed with brine three times, concentrated under reduced pressure and purified by column chromatography over silica gel (petroleum ether/ethyl acetate =8: 1) to give intermediate C as a yellow solid, 2 g, 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With copper(II) acetate monohydrate; caesium carbonate; In N,N-dimethyl-formamide; at 20 - 110℃; for 24h;Inert atmosphere; Schlenk technique; | General procedure: An oven-dried Schlenk tube was charged with Cu(OAc)2·H2O (0.1 mmol, 0.01 equiv), Cs2CO3(20 mmol, 2 equiv), and aryl iodide (if solid, 12 mmol, 1.2 equiv). The tube was degassed with argon for three times. Then DMF (20 mL), pyrrole (10 mmol, 1 equiv), and aryl iodide (if liquid,12 mmol, 1.2 equiv) were added via syringe under room temperature. The mixture was stirred at110 C for 24 h, and then cooled down to room temperature. The reaction mixture was quenched with water (40 mL) and extracted with ethyl ether (20 mL) for three times. The combined organic layers were dried with Na2SO4, filtered and concentrated. The crude products were purified using flash column chromatography on silica gel to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium tert-butylate; copper(II) oxide; In dimethyl sulfoxide; at 80℃; for 18h;Sealed tube; Inert atmosphere; | Under an argon atmosphere, copper oxide (50 μmol), iminodibenzyl substrate (1 mmol), potassium tert-butoxide (2 mmol, 2.0 equiv), 4-trifluoromethoxy substituted aromatic hydrocarbon (2 mmol, 2.0 equiv) were successively The solvent (2 mL) was added to a 10 mL sealed tube and placed in an oil bath heated to 80 C. for 18 hours. After the reaction was completed, the reaction was exposed to air quenching, and the amine product was directly separated by column chromatography.According to the results of column chromatographic separation, when DMSO was used as the reaction solvent, the yields of 4-trifluoromethoxychlorobenzene, bromobenzene, and iodobenzene respectively reacted with the substrate were: 68%, 85%, and 79%; When DMF was used as the reaction solvent, the yields of reaction of 4-trifluoromethoxy chlorobenzene, bromobenzene, and iodobenzene with the substrate were 47%, 65%, and 62%, respectively |
69% | With nickel(II) oxide; potassium tert-butylate; triphenylphosphine; In tetrahydrofuran; at 100℃; for 24h;Inert atmosphere; Sealed tube; Green chemistry; | General procedure: Under an argon atmosphere, nickel oxide (0.1 mmol, 10 mol%), triphenylphosphine (0.2 mmol, 20 mol%), iminodibenzyl substrate (1 mmol), potassium tert-butoxide (2 mmol, 2.0 equiv) were sequentially 4-trifluoromethoxyhalogenated aromatic hydrocarbon (2 mmol, 2.0 equiv) and tetrahydrofuran (2 mL) were added to a 10 mL sealed tube and placed in a 100 C. oil bath with heating and stirring for 24 hours. The reaction was completed and the reaction was exposed to air quenching. , and then directly separated by column chromatography to obtain amine products.According to the results of column chromatographic separation, the yields of 4-trifluoromethoxybromobenzene and 4-trifluoromethoxy iodobenzene respectively reacted with the substrate were 78% and 69%, respectively; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 120℃; for 5h;Inert atmosphere; | A mixture of 5-Bromo-4,6-dimethyl-pyridin-2-amine (2 g), Cesium carbonate (6.46 g), 4- Trifluoromethoxy iodobenzene (4.29 g), Palladium (II) acetate (0.22 g, 0.99 minol) and 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (0.57 g) was taken up in Toleune (40 mL) and degassed with nitrogen gas and heated at 120 C for 5 h. The reaction was diluted with Water (50 mL) and extracted with Ethyl acetate (2 X 30 mL) and the combined organic extracts were driedover anhydrous Sodium sulphate and evaporated under reduced pressure. The residue was subjected to Silica gel flash column chromatography eluting with a gradient of Ethyl acetate and Heptane to obtain the title compound as an off white solid (2.7 g, 75 %). LCMS: Rt: 2.44 min; MS:mz = 363.2 (M+2) 1H NMR (300 MHz, CDCI3) 6 7.36 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 2.66 (5, 3H), 2.39 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Under an argon atmosphere, a suspension of lithium chloride (113 mg, 2.66 mmol) in THF (5.3 mL)A THF solution (2 M, 1.33 mL, 2.66 mmol) of isopropyl magnesium chloride and 1-iodo-4- (trifluoromethyloxy) benzene (0.425 mL, 2.76 mmol) were added at room temperature,And the mixture was stirred for 3 hours.A solution of 2-fluoro-N-methyl-N-methyloxy-2- (1,2,4-triazol-1-yl) acetamide (200 mg, 1.06 mmol) in THF (3.5 mL) In addition,And the mixture was stirred at that temperature for 10 minutes.Saturated ammonium chloride aqueous solution was added to the reaction solution,And extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The obtained crude product was purified by column chromatography (hexane: ethyl acetate = 10: 1 to 2: 1)2-fluoro-2- (1,2,4-triazol-1-yl) -1- [4- (trifluoromethyloxy) phenyl] ethanoneWhite solids(218 mg, yield: 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With 5-chloro-3-nitropyridin-2(1H)-one; 1,1,1,3',3',3'-hexafluoro-propanol; palladium diacetate; silver trifluoroacetate; at 100℃; for 20h; | General procedure: DG1-tetheredalcohol substrate (0.1 mmol), aryl iodide (0.3 mmol), palladium acetate(0.01 mmol), 3-nitro-5-chloro-pyridone (0.04 mmol) and silver trifluoroacetate(0.25 mmol) were added to a 10 ml reaction vial with a magnetic stir bar, themixture was dissolved with 1 ml of HFIP and then the vial was capped. Thereaction mixture was stirred at 100 C for 20 h. The mixture was cooled toroom temperature, diluted with 2 ml of ethyl acetate and filtered through a padof Celite, and then washed with another 2 ml of ethyl acetate. The filtrate wasconcentrated and redissolved with 5 ml of methanol, cooled with an ice bath,and then sulfonyl chloride (0.2 ml) was added slowly. The resulting mixture wasstirred at room temperature for 30 min and then concentrated, the residue waspurified by preparative thin-layer chromatography to get the arylation product.Full experimental details and characterization of compounds are given inthe Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 2-Picolinic acid; copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 100℃; for 24h;Schlenk technique; Inert atmosphere; | General procedure: A Schlenk tube was charged with a mixture of tetrahydroberberrubine (1, 228 mg,0.70 mmol), potassium carbonate (97 mg, 0.70 mmol), copper(I) iodide (13 mg,0.07 mmol), picolinic acid (17 mg, 0.14 mmol), aryl iodide (1.40 mmol, 2 equiv) andDMSO (6 mL) before it was evacuated and backfilled with N2 for three times. Thereaction mixture was stirred for 24 h at 100 C and the resulting mixture was subjectedto column chromatography (SiO2, CH2Cl2/MeOH 200:1-150:1) to give the respectiveproduct 2a-o as pale-yellow solids and 4 as yellow solid. Characterization data and theoriginal spectra are presented below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With C22H14ClN3O2Pd; cesium acetate; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 24h;Sealed tube; | General procedure: A tubular reactor was charged with Na2CO3 (0.0424 g,0.4 mmol), CsOAc (0.1152 g, 0.6 mmol), 2-iodobiphenyl (0.0560 g,0.2 mmol), iodobenzene (0.0816 g, 0.4 mmol), A1 (10 at%), and solvent(3 mL), sealed, and heated to 120 C in an oil bath for 24 h.Subsequently, the reaction mixture was cooled and quenched withbrine (20 mL) and ethyl acetate (40 mL). The organic layer wasretained, and the aqueous phase was extracted with ethyl acetate(2 40 mL). All organic phases were combined, dried over anhydrousMgSO4, and filtered. The desired product was separated viavacuum distillation and was further purified by silica gel thin layerchromatography using petroleum ether as an expansion agent. Theproduct-containing silica gel was scraped off and pulverised. Thepowderwas leached with ethyl acetate for 4 h, and the leachatewasfiltered and subjected to vacuum distillation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine; In acetonitrile; at 40℃; for 16h;Inert atmosphere; Sealed tube; | General procedure: To a solution of compound 6r (401.3 mg, 1 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol), P(O-Tolyl)3 (60.9 mg, 0.2 mmol), Et3N (303.6 mg, 417 μL, 3 mmol) in ACN (10 mL) was added a solution of R2X (heteroaryl or aryl halides, X=Br, I; 1.5 mmol) in ACN (5 mL) dropwise under an argon atmosphere in a sealed tube. The mixture was stirred under an argon atmosphere at 40 C for 16-48 h. The reaction mixture was then cooled, concentrated under vacuum and re-dissolved in CH2Cl2. After filtering, the filtrate was washed with saturated NaCl aqueous solution, dried with MgSO4 and concentrated under vacuum. The crude material was purified by column chromatography (PE/EA) on silica gel to afford compound 6ra-rt.This reaction showed high stereo- and regioselectivity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; 1,3-bis-(diphenylphosphino)propane; sodium carbonate; In 2-methyltetrahydrofuran; at 125℃; for 24h;Molecular sieve; Inert atmosphere; Sealed tube; | General procedure: Rh(cod)2BF4(6 mol%), DPPP (0.09 mmol), Na2CO3 (1 mmol) and 4A MS (SiO2,powder, 150 mg) were transferred into an oven-dried tube (15 mL), which was evacuated and backfilled with N2 (5x). 2-Methyltetrahydrofuran (2.5 mL), alkyl or aryl iodide (1 mmol),HMF (1.2 mmol) were added into the tube via syringe and sealed with Teflon plug. The reaction mixture was stirred at 125 C for24 h. After the reaction was complete, the mixture was concentrated by rotary evaporation. The crude product was purified by column chromatography (EA/PE = 1/20) on a silica gel to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With nickel(II) iodide; manganese; In N,N-dimethyl-formamide; at 40 - 60℃; for 18h;Inert atmosphere; Glovebox; | General procedure: In a N2-filled glovebox, to an oven-dried 5 mL vial equipped with a magnetic stir bar wereadded alkene substrate (0.1 mmol), aryl iodide (0.15 mmol), alkyl iodide or bromide (ifsolid, added at this time) (0.2 mmol), NiI2 (0.01 mmol) and Mn powder (0.25 mmol). Themixture was then dissolved in 0.3 mL dry DMF. The vial was tightly capped and removedfrom the glovebox. The alkyl iodide or bromide (if liquid, added at this time) was addedby a micro-syringe. The mixture was allowed to vigorously stir at 40 oC for 18 h (unlessotherwise stated). After 18 h, the alkene was almost fully consumed (monitored by GCMS).The mixture was directly subjected to flash silica gel column chromatography to afford thepure product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(1,5-cyclooctadiene)nickel (0); N-Methyldicyclohexylamine; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; (4S,4'S)-(4,4'-diheptan-4-yl)-4,4',5,5'-tetrahydro-2,2'-bioxazole; In N,N-dimethyl acetamide; at 25℃; for 48h;Inert atmosphere; Glovebox; Sealed tube; Irradiation; | In a glove box filled with argon, add the chiral ligand represented by formula III (4.0mg, 0.011mmol) and bis-(1,5-cyclooctadiene) nickel as nickel (2.8mg, 0.01mmol) Into 0.5mL N,N-dimethylacetamide, and then add 4-trifluoromethoxy iodobenzene (86.4mg, 0.3mmol),2-chloropropionic acid (2,3,3-trimethyl-2-butyl) ester (20.6mg, 0.1mmol),N,N-Dicyclohexylmethylamine (58.5mg, 64μL, 0.3mmol), 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (75.9mg, 0.3 mmol) and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (8 mg, 0.01 mmol). Put the lid on the reaction flask and seal it, take out the glove box,Place on a stirrer irradiated with blue light and react for 48 hours at room temperature 25 degrees.After the completion of the reaction, 10 mL of ethyl acetate was added to the reaction solution, a solid was deposited, and by-product 2 (white solid, 62% yield) was obtained by filtration. Then, the filtrate was washed with saturated brine (5 mL×5), and the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 50:1) to sequentially obtain the target product represented by formula IV (23.9 mg, 72% yield, 86% enantiomeric excess, specific rotation [α ] D20 = +11.87 (c0.716, CHCl3), the product ratio Rf = 0.3 (petroleum ether: ethyl acetate = 20:1)), by-product 1 (white solid, 100% yield), photocatalyst (Yellow solid, 93% yield, can be reused). The hydrogen spectrum and carbon spectrum of the target product are shown in Figure 17 and Figure 18, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 20℃; for 1h;Inert atmosphere; Flow reactor; Irradiation; | General procedure: The CF3O-reagent 1 (1 equiv, 45.3 mg, 0.0944 mmol), [Ru(bpy)3](PF6)2 (1 mol %, 0.9 mg) and solid substrate (10 equiv, 0.944 mmol) were added to a vial equipped with cap with septum and stirring bar. In case of liquid substrate, it was added after the solvent. Three vacuum-argon cycles were performed, and the vial was filled with argon. Dry acetonitrile (1.25 mL) was added via syringe. After 1 minute of vigorous sonification in ultrasonic bath, the solution was loaded into a 5 mL syringe. This syringe was then fitted to a syringe pump and connected to a 2.3 mL PFA microreactor coil (internal diameter of 750 μm), previously flushed with 5 mL of dry acetonitrile. The flowrate was set to 0.0383 mL/min to obtain a residence time of 1 h. When the syringe was fully empty, again dry acetonitrile was loaded into a syringe and injected to collect all product at the end of the reactor in a round bottom flask equipped with stirring bar and under argon atmosphere. 10 μL (11.9 mg, 0.0815 mmol) of benzotrifluoride (C6H5CF3) were then added to the mixture and stirred for 1 minute. For quantitative 19F NMR 0.3 mL of resulting solution was transferred to NMR tube and diluted with 0.3 mL of CDCl3. |
Tags: 103962-05-6 synthesis path| 103962-05-6 SDS| 103962-05-6 COA| 103962-05-6 purity| 103962-05-6 application| 103962-05-6 NMR| 103962-05-6 COA| 103962-05-6 structure
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P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
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 |
Sorry,this product has been discontinued.
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