Structure of 103962-05-6
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CAS No. : | 103962-05-6 |
Formula : | C7H4F3IO |
M.W : | 288.01 |
SMILES Code : | FC(OC1=CC=C(C=C1)I)(F)F |
MDL No. : | MFCD00042411 |
InChI Key : | RTUDBROGOZBBIC-UHFFFAOYSA-N |
Pubchem ID : | 2777294 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 ? Topological Polar Surface Area: Calculated from |
9.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.36 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.75 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.45 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.17 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.35 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.42 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.23 |
Solubility | 0.0171 mg/ml ; 0.0000594 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.64 |
Solubility | 0.0665 mg/ml ; 0.000231 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.97 |
Solubility | 0.031 mg/ml ; 0.000108 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.39 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.24 |
* 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 |
---|---|---|
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 |
---|---|---|
56% | With copper(l) iodide; 8-quinolinol; caesium carbonate; In water; N,N-dimethyl-formamide; at 130℃; for 17h; | A round bottom flask was charged with 4-bromo-1H-imidazole (3.83 g, 26.0 mmol), copper(I) iodide (0.331 g, 1.736 mmol), quinolin-8-ol (0.252 g, 1.736 mmol), cesium carbonate (11.31 g, 34.7 mmol), and <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (2.72 mL, 17.36 mmol). A 10:1 mixture of DMF (50 mL) and water (5.0 mL) were added to the reaction mixture, and the solution was heated to 130C overnight. After stirring 17 h, LC-MS indicated reaction completion. The reaction mixture was cooled to room temperature, was diluted with EtOAc, and was transferred to a separatory funnel with the aid of water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated aqueous sodium bicarbonate and then ammonium chloride, were dried overNa2SO4/magnesium sulfate (MgSO4) and were concentrated in vacuo. Purification of the residue by normal-phase high-performance liquid chromatography, eluting with 0 - 10% methanol-DCM afforded the title compound as an off-white solid (3.01 g, 56%):1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 1.5 Hz, 1H);19F NMR (376 MHz, CDCl3) d - 58.05; ESIMS m/z 307 ([M+H]+). |
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 4-bromoimidazole (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 4-bromoimidazole (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 4-bromoimidazole (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℃; for 0.166667h;Inert atmosphere; Irradiation; | To a solution of <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (288 mg, 1.0 mmol) and 6-chloro-5-methylpyridin-3-ylboronic acid (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 |
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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 |
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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 <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (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) δ 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 <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (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) δ 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) δ 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 <strong>[103962-05-6]1-iodo-4-(trifluoromethoxy)benzene</strong> (15.0 g, 52.0 mmol) in dimethylformamide (90 mL) and water (10 mL) was added 3-(4-bromophenyl)-1H-1,2,4-triazole (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) δ 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) δ 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) δ -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 |
---|---|---|
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. |
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