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CAS No. : | 1423-26-3 | MDL No. : | MFCD00151854 |
Formula : | C7H6BF3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WOAORAPRPVIATR-UHFFFAOYSA-N |
M.W : | 189.93 | Pubchem ID : | 2734388 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 41.27 |
TPSA : | 40.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.24 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.71 |
Log Po/w (WLOGP) : | 1.54 |
Log Po/w (MLOGP) : | 1.37 |
Log Po/w (SILICOS-IT) : | 0.29 |
Consensus Log Po/w : | 0.98 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.3 |
Solubility : | 0.942 mg/ml ; 0.00496 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.18 |
Solubility : | 1.27 mg/ml ; 0.00668 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.18 |
Solubility : | 1.26 mg/ml ; 0.00665 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.72 |
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 |
---|---|---|
94% | With potassium carbonate In water at 20℃; for 5 h; | General procedure: To a stirred solution of phenylboronic acid (1.0 mmol), aniline (1.0 mmol), and K2CO3 (2.0 mmol) in deionized H2O (10 mL) at room temperature was added an aqueous suspension of FePd nanowires (3.0 mol percent in 3 mL of H2O). The mixture was stirred at room temperature for 5h. After completion of the reaction (as monitored by TLC), 2 M HCl was added and the catalyst was separated by applying an external magnet. The catalyst was washed with EtOAc. The mixture was extracted with EtOAc (2 * 20 mL), dried, and concentrated. The residue was subjected to gel permeation chromatography to afford pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; ethanol at 80℃; for 2 h; Stage #2: With hydrogenchloride In water; ethyl acetate |
A portion of Pd(dppf)Cl2 (1.49 mmol, 1.09 g) was added to a suspension of 4-bromobenzoic acid 4a (14.9 mmol, 3.0 g), 3-trifluoromethylboronic acid 4b (17.9 mmol, 3.4 g), and Cs2CO3 (37.3 mmol, 12.2 g) in 30 mL of dioxane and 7.5 mL of EtOH. The mixture was stirred at 80° C. for 2 h. After cooling, the solid was collected by filtration and washed with MeOH. The filtrate was concentrated and partitioned between EtOAc and 1N aqueous HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated. CH2Cl2 was added to the residue and the resulting solid was collected by filtration, washed with CH2Cl2, and dried to give 3.58 g (86percent yield) of compound 4c, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: at 50℃; for 3 h; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran; 1,4-dioxane; water at 50℃; for 3 h; |
To a 10 mL reaction tube equipped with a magnet was added 76 mg (0.4 mmol) of 3-trifluoromethylphenylboronic acid, 0.4 mL (0.8 mmol) of trimethylsilyl diazomethane (2M n-hexane solution) 1 mL of toluene, stoppered with a rubber stopper and reacted on an electromagnetic heating stirrer at 50 ° C for 3 hours.Followed by addition of 71 mg (0.6 mmol) of pinacol (dissolved in 1 mL of 1,4-dioxane), 0.5 mL of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) and 200 uL of water at 50 ° C in an electromagnetic heating stirrer To continue for 3 hours.After completion of the reaction, the organic solvent was removed by a rotary evaporator and purified by column chromatography3-trifluoromethylbenzyl boronic acid pinacol ester, its structure is as follows:The compound was a colorless liquid in a yield of 72percent with the following NMR data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | A portion of Pd(dppf)Cl2 (1.49 mmol, 1.09 g) was added to a suspension of 4-bromobenzoic acid 4a (14.9 mmol, 3.0 g), 3-trifluoromethylboronic acid 4b (17.9 mmol, 3.4 g), and Cs2CO3 (37.3 mmol, 12.2 g) in 30 mL of dioxane and 7.5 mL of EtOH. The mixture was stirred at 80 C. for 2 h. After cooling, the solid was collected by filtration and washed with MeOH. The filtrate was concentrated and partitioned between EtOAc and 1N aqueous HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated. CH2Cl2 was added to the residue and the resulting solid was collected by filtration, washed with CH2Cl2, and dried to give 3.58 g (86% yield) of compound 4c, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | A 50 mL Schlenk tube was charged with <strong>[68449-30-9]5-bromo-3,4-dihydronaphthalen-1(2H)-one</strong> (<strong>[68449-30-9]5-bromo-1-tetralone</strong> [Aldrich], 488 mg, 2.17 mmol), which was dissolved in toluene (2.5 mL) under a nitrogen atmosphere. Tetrakis(triphenylphosphine) palladium (0) (70 mg, 0.06 mmol) was added to the flask followed by more toluene (2.5 mL). Aqueous sodium carbonate (2.0 M, 2 mL, 4 mmol) was added, followed by a solution of 3-trifluoromethylphenyl boronic acid (489 mg, 2.57 mmol) in ethanol (2.5 mL). A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3*), then the flask was sealed and heated in a 110 C. oil bath overnight. The resulting mixture was cooled to room temperature. Aqueous hydrogen peroxide solution (30%, 0.3 mL) was added and the mixture was stirred for 1 h. The reaction was then diluted with water (25 mL) and extracted with ethyl ether or EtOAc (3*75 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes?40% EtOAc/hexanes, gradient), to afford 628 mg (99%) of 5-(3-(trifluoromethyl)phenyl)-3,4-dihydronaphthalen-1(2H)-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In toluene; at 20℃; for 2h; | The title compound (47%, oil) was prepared from 3-trifluoromethylphenylboronic acid and pinacol. 1H NMR (300 MHz, CDCl3): delta 1.35 (s, 12H), 7.48 (t, 1H), 7.70 (d, 1H), 7.97 (d, 1H), 8.06 (bs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With 1,1'-bis-(diphenylphosphino)ferrocene; potassium carbonate;palladium diacetate; In water; toluene; at 110℃; for 16h; | A mixture of 5-Amino-2-chloro-pyrimidine (4.5 g, 34.9 mmol), 3- TRIFUOROMETHYLPHENYLBORONIC acid (9.9 g, 52.3 MMOL), Pd (OAc) 2 (390 MG, 1.74 MMOL), DPPF (963 mg, 1.74 MMOL), 2 M aqueous K2C03 (52 mL), and toluene (100 mL) were heated at 110 C for 16 h. The mixture was diluted with EtOAc (100 mL) and the organic layer washed with H20 (100 mL) and brine (100 mL). Drying (MgS04) and removal of the volatiles in-vacuo gave a dark brown solid. Chromatography of this material on silica gel using a Hexanes/EtOAc gradient (20% EtOAc to 80% EtOAc) gave 3 as a colorless solid (3.5 g, 14.6 MMOL, 41% yield, M/Z + = 240. 1). |
38% | With potassium carbonate;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 100℃; | Intermediate 4a: 2-(3-(trifluoromethyl phenyl pyrimidin-5-amine.; To 2- chloropyrimidin-5-amine (1.7 g, 13.18 mmol, 1.00 equiv) was added 3- (trifluoromethyl) phenylboronic acid (3.8 g, 20.00 mmol, 1.50 equiv), Pd(OAc)2 (0.15 g, 0.05 equiv), dppf (0.37 g, 0.05 equiv) and potassium carbonate (3.6 g, 26.09 mmol, 2.00 equiv) and the mixture was stirred overnight at 100C in an oil bath. The reaction was diluted with 300 mL of ethyl acetate and the solids were filtered out. The filtrate was was washed with water and the organic layer dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :15) to afford 1.2 g (38%) of 2-(3- (trifluoromethyl)phenyl)pyrimidin-5 -amine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 2.0h;Heating / reflux; | To a toluene (10 mL)-water (1 mL) mixed solution of <strong>[35265-82-8]2,4-dichloro-6-methylthieno[3,2-d]pyrimidine</strong> (1.00 g, 4.56 mmol) were added 3-(trifluoromethyl)benzeneboronic acid (0.87 g, 4.56 mmol), sodium carbonate (0.97 g, 9.13 mmol), and tetrakis(triphenylphosphine)palladium (0.10 g, 5 mol%), followed by heating under reflux under a nitrogen stream for 2 hours. After completion of the reaction, the reaction liquid was poured into water and extracted with ethyl acetate. The resulting extract solution was washed with water and brine and then the solvent was removed by evaporation. The residue was purified on a silica gel column (Kiesel gel 60 manufactured by MERCK, 10% AcOEt-Hex) to obtain 2-chloro-6-methyl-4-[3-(trifluoromethyl)phenyl]thieno[3,2-d]pyrimidine (1.33 g, 89%). 1H-NMR (400MHz, CDCl3): 2.75(d, 3H, J=1.2Hz), 7.26(d, 1H, J=1.2Hz), 7.72(t, 1H, J=8.0Hz), 7.85(d, 1H, J=8.0Hz), 8.36(d, 1H, J=8.0Hz), 8.43(s, 1H). mp: 174-176C (dec.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4 A molecular sieve; copper (I) acetate; triethylamine; In dichloromethane; for 78h; | 3-(trifluoromethyl)phenylboric acid (1.03g) and <strong>[348-27-6]2-fluoro-4-hydroxybenzaldehyde</strong> (760mg) were dissolved in methylene chloride (20mL). While the mixture was stirred, copper acetate (985mg), molecular sieve 4A (800mg) and triethylamine (3.76mL) were added to the mixture. An equal amount of copper acetate was added after 6 hours and after 24 hours. After 48 hours of stirring, the insoluble materials were removed by filtration and the filtrate was poured in water and was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified on a silica gel column chromatography (hexane: ethyl acetate = 7: 1 then 2: 1). This gave the desired product as a pale yellow oil (265mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B] 3'-Trifluoromethyl-biphenyl-4-carboxylic acid 3.0 g (12.1 mmol) of 4-iodo benzoic acid was dissolved in 40 ml of 1,2-dimethoxy-ethane, 20 ml of water was added, followed by 2.44 g (12.5 mmol) of 3-(trifluoromethyl)-benzeneboronic acid, 2.27 g (20.8 mmol) of sodium carbonate and 0.28 g (0.24 mmol) of tetrakis(triphenylphosphine)palladium. This mixture was stirred for 2 hours at 95 C., cooled down to RT and filtered. The pH of this solution was adjusted with HCl (1N) to pH 1-2, and it was then extracted twice with AcOEt. The organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated to give 3.58 g crude product, which was purified by chromatography over silica gel with a gradient of MeCl2 and MeOH to give 2.70 g of the title compound as light yellow solid. MS: 265.0 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tert-butyl methyl ether; | Example 139 (2S)-1-({1,1-Dimethyl-2-[6-(3-trifluoromethyl-phenyl)-pyridin-2-ylamino]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, Methansolfonic Acid Salt This compound was obtained in analogy to example 36, steps A1 to C] starting from 2,6-dibromopyridine, 1,2-diamino-2-methlypropane, 3-trifluoromethyl-phenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in tert-butyl methyl ether and precipitated by treatment with methanesulfonic acid yielding a white powder. MS (ISP): 446.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tert-butyl methyl ether; | Example 119 (2S)-1-({1,1-Dimethyl-2-[5-(3-trifluoromethyl-phenyl)-pyridin-2-ylamino]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, Methansolfonic Acid Salt This compound was obtained in analogy to example 36, steps A] to C] starting from 2,5-dibromopyridine, 1,2-diamino-2-methlypropane, 3-(trifluoromethyl)-phenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in tert-butyl methyl ether and precipitated by treatment with methanesulfonic acid yielding a white powder. MS (ISP): 446.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; for 10h;Heating / reflux;Product distribution / selectivity; | Example 11: 4-(3,3,4-Trimethyl-4-oxy-piperazin-1-yl)-6-(3-trifluoromethyl-phenyl)- pyrimidine-2-carbonitrile A: 2-Methylsulfanyl-6-(3-trifluoromethylphenyl)-pyrimidin-4-ylamine To a stirred solution of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> (3.5 g) in toluene (45 ml.) under a nitrogen atmosphere was added, sequentially, 3-(trifluoro- methyl)phenylboronic acid (4.15 g), potassium carbonate (25 ml_, 2M) and tetrakis- (triphenylphosphine)palladium(O) (1.16 g). The mixture was heated to reflux for ten hours. Ethyl acetate (15OmL) was added and the mixture washed with water (2 x 100 ml_). Organic layer was separated, washed with saturated sodium chloride (100 ml_), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methyl- sulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g) 1H NMR (CDCI3): delta 8.25 (s, 1 H), 8.19 (d, 1 H), 7.70 (d, 1 H), 7.58 (t, 1 H), 6.56 (s, 1 H), 4.92 (s, 2H), 2.61 (s, 3H). MS m/z: 286.3 (M+1 ). | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 20℃;Heating / reflux;Product distribution / selectivity; | To a stirred solution of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> (3.5 g) in toluene (45 mL) under a nitrogen atmosphere was added, sequentially, 3-(trifluoromethyl)phenylboronic acid (4.15 g), potassium carbonate (25 mL, 2M) and tetrakis(triphenylphosphine)palladium(0) (1.16 g). The mixture was heated to reflux for ten hours. Ethyl acetate (150 mL) was added and the mixture washed with water (2.x.100 mL). Organic layer was separated, washed with saturated sodium chloride (100 mL), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g) 1H NMR (CDCl3): delta 8.25 (s, 1H), 8.19 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 6.56 (s, 1H), 4.92 (s, 2H), 2.61 (s, 3H). MS m/z: 286.3 (M+1).; A: 2-Methylsulfanyl-6-(3-trifluoromethylphenyl)-pyrimidin-4-ylamine To a stirred solution of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> (3.5 g) in toluene (45 mL) under a nitrogen atmosphere was added, sequentially, (3-trifluoromethylphenyl)boronic acid (4.15 g), potassium carbonate (25 mL, 2M) and tetrakis(triphenylphosphine)palladium(0) (1.16 g). The mixture was heated to reflux for ten hours and stirred at room temperature over the weekend. Ethyl acetate (150 mL) was added and the mixture washed with water (2.x.100 mL). Organics were separated, washed with saturated sodium chloride (100 mL), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g) 1H NMR (CDCl3): 8.25 (s, 1H), 8.19 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 6.56 (s, 1H), 4.92 (s, 2H), 2.61 (s, 3H). MS m/z 286.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 4h;Combinatorial reaction / High throughput screening (HTS);Product distribution / selectivity; | EXAMPLE 36The Preparation of a series of compounds using multiple parallel synthetic techquires from 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as in Example 7 Combichem Procedure 1; In a 8 ml screw cap vial was added a solution of 9-Hydroxy-4-iodo-6H-pyrrolo[3,4-c]carbazole-1,3-dione, (0.1 mmol) prepared as in example 7 in dioxane (1 ml), a solution of Reagent 1 (see table) (0.1 mmol) in 1:1 dioxane/2.5 M K2CO3 (1 ml) and [1,1'Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.003 g, 0.0037 mmol). The vial was capped and the reaction mixture was shaken for 4 hours at 90 C. After cooling to room temperature, the solution was was removed under vacuum. Purification was carried out via reverse-phase HPLC (3% n-propanol in acetonitrile and 3% n-propanol in water as the eluent; C-18 column). The products were characterised by mass spectral analysis (See Table 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 20 - 50℃;Inert atmosphere; | Intermediate 13-Methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acidA) 3-Methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester; To a degassed solution of 8.35 g (36.3 mmol) of <strong>[213771-32-5]5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester</strong> [Wu, G. G.; Wong, Y.-S.; Poirier, M. Organic Letters (1999), 1(5), 745-747] in 180 ml of dioxane were added 13.79 g (72.6 mmol) of 3-(trifluoromethyl)phenyl boronic acid and 11.54 g (108.9 mmol) of sodium carbonate (dissolved in 55 ml of H2O). While stirring, 1.33 g (1.89 mmol) of (1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) was added and the reaction mixture was stirred at RT for 4 hours, then heated up to 50 C. After 90 min, it was cooled down to RT, poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 9:1 to 1:1) to give 9.35 g (87%) of the title compound as light yellow solid. MS: 296.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;Reflux; | General Procedure 4 (GP4): Suzuki Coupling; The 4-chloropyrimidine (1.0 eq.) is dissolved in DME/water (20:1 v/v), boronic acid (1.3 eq.), K2CO3 (2.0 eq.) and Pd(PPh3)4 (0.2 eq.) are added and the reaction mixture is stirred for 4 h under reflux. In case the conversion of the starting material is not complete, additional amounts of boronic acid and Pd-catalyst are added and the reaction is run over night under reflux. After cooling to RT water is added. The precipitate is filtered off. In cases where the product is not precipitated it is extracted with diethylether, the organic phase is dried, filtered off, and the solvent removed under reduced pressure. The obtained product can either be used without further purification or is purified by chromatography.; A-22) 4-Methyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-ylamine; The title compound is synthesized according to general procedure GP4 starting from 2.O g (14 mmol) <strong>[5600-21-5]2-amino-4-chloro-6-methyl pyrimidine</strong> and 3.4 g (18 mmol) 3-trifluoromethyl- phenyl boronic acid. Yield after extraction: 5.0 g (99 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 80.0℃; for 3.0h; | Step 3) Preparation of methyl 2-(3-(trifluoromethyl)phenyl)benzo[d]thiazole-4- carboxylate (31):A mixture containing <strong>[1208225-86-8]methyl 2-chlorobenzo[d]thiazole-4-carboxylate</strong> (29; 0.25 g, 1.1 mmol), 3-(trifluoromethyl)phenylboronic acid (30; 0.25 g, 1.3 mmol), Cs2CO3 (0.71 g, 2.2 mmol) and Pd[PPh3J4 (0.064 g, 0.055mmol) in Dioxane:water:EtOH (5OmL, 4:1:0.5 ratio) was stirred at 80 0C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The two layers were separated and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography afforded methyl 2-(3-(trifluoromethyl)phenyl)benzo[d]thiazole-4-carboxylate 31 (0.33g, 88%). MS (ESI) calcd for CI6HI0F3NO2S: 337.04; found: 338 [M+H]. Additional compounds shown in Table 1 were prepared by using the appropriate boronic acids according to the general procedure shown in this step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | <strong>[61047-43-6]8-bromo-2-methylquinoline</strong> (28; 5.0 g, 22 mmol) was taken up in dioxane(50 mL) and water (15mL) along with 3-(trifluoromethoxy)phenylboronic acid (4.7 g, 25 mmol), Cs2CO3 (22 g, 67 mmol) and Pd(dppf)Cl2 (938mg, lmmol). The reaction mixture was stirred at 800C under nitrogen atmosphere for 3 h. The solid was filtered. The filtration was then diluted with water and extracted with ethyl acetate The combined organic layers were washed with brine, dried over sodium sulfate then concentrated under reduced pressure. The residue was purified by column chromatography to afford 2-methyl-8-(3-(trifluoromethyl)phenyl)quinoline 84 (6.3 g , 97%). MS (ESI) calcd for Ci7Hi2F3N: 287.3; found: 288 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.166667h;microwave irradiation; | Methyl 2-bromoisonicotinate (2.71 g, 12.57 mmol), 3-(trifluoromethyl)phenylboronic acid (3.58 g, 18.85 mmol), potassium carbonate (2.61 g, 18.85 mmol) and PdCl2 (dppf) (0.162 g, 0.25 mmol) were mixed in methanol (30 mL) in two 20 mL microwave vials. The vials were capped and heated at 100 C. for 10 min in a single node microwave reactor. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH (1 CV each). The NH3/MeOH layer was evaporated yielding methyl 2-(3-(trifluoromethyl)phenyl)isonicotinate (2.6 g, 73%). MS m/z 282 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2A 2-Chloro-6-[3-(trifluoromethyl)phenyl]nicotinaldehyde The title compound is prepared and purified analogously to Example 1A. Additional purification is effected by chromatography on silica gel (eluent: 10:1, then 4:1 cyclohexane/ethyl acetate). 200 mg (1.14 mmol) of 2,6-dichloronicotinaldehyde and 216 mg (1.14 mmol) of 3-(trifluoromethyl)phenylboronic acid afford 202 mg (62% of theory) of the target compound. LC-MS (method 2): Rt=2.67 min; m/z=286 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 12h;Inert atmosphere; | ethyl 5-[3-(trifluoromethyl)phenyl]thiophene-2-carboxylate Under a nitrogen atmosphere, to a mixed solvent of <strong>[5751-83-7]ethyl 5-bromothiophene-2-carboxylate</strong> (2.4 g, 10 mmol), 3-(trifluoromethyl)phenylboronic acid (2.9 g, 15 mmol) and sodium carbonate (2.1 g, 20 mmol) in water/1,4-dioxane (v/v = 1/1, 10 mL) was added tetrakistriphenylphosphinepalladium (1.1 g, 1.0 mmol), and the mixture was stirred at 80C for 12 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (petroleum ether/ethyl acetate=60/1) to give the title compound (2.5 g, 83%) as colorless crystals. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.39 (3H, t, J=7.0 Hz), 4.36 (2 H, q, J=7.1 Hz), 7.33 (1 H, d, J=4.0 Hz), 7.52 (1H, t, J=7.8 Hz), 7.59 (1 H, d, J=4.8 Hz), 7.74-7.86 (2H, m), 7.85 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 50℃; | 6-bromo-3,4-dihydro-2H-pyrido[3,2-b] [l ,4]oxazine (5; 2.0 g, 9.30 mmol), 3-(trifluromethyl)- phenylboronic acid (2.65 g, 1 3.95 mmol), Pd(Ph3)4 (21 5 mg, 0. 186 mmol) and CsCO3 (6.0 g, 18.6 mmol) were all dissolved in dioxane:H20 mixture (45 mL: l mL) and heated to 50 C overnight. Product peak seen by LCMS, but some starting material remained, added more boronic acid and stirred at 50 C overnight. The starting material peak was unchanged, cooled to room temp and some precipitates started to crash out. Diluted with water (40 mL), extracted with EtOAc (3 x 40 mL), washed with brine, dried over MgS04, filtered, concentrated and purified through I SCO silica column (0 to 100% EtOAc/pentanes) to collect mixed fractions of 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][ l ,4]oxazine (6) M S (ESI) calcd for C 14H1 1 F3N2O (m/z) 280.08, found 281 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 120℃; for 12h;Inert atmosphere; sealed tube; | 2-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazine (68; 1.41 g, 8.22 mmol), 3- (trifluoromethyl)phenylboronic acid (1.87 g, 9.86 mmol), Pd(PPh3)4 (475 mg, 0.411 mmol), Na2C03 (2.09 g, 19.7 mmol) and dioxane/water(4:l, 35 ml) were added to a sealed tube and filled with nitrogen. Then the mixture was heated to 120 C for 12 hours. After cooling, CH2CI2 (100 mL) was added and the mixture was passed through a pad of Na2SO<i. The solvent was removed under vacuum and the residue was purified by column chromatography (1:15EtO Ac/petroleum ether) to afford 2-(3-(trifluoromethyl)phenyl)-7,8-dihydiO-6H-pyrimido[5,4- b][l,4]oxazine(69; 1.20 g, 52% yield). MS (ESI) calcd for C,3H|0F3N3O: 281.23; found 282[M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 90.0℃;Inert atmosphere; | Under a nitrogen atomosphere, 1 , 2, 3,4-tetrahydro- 1 ,8-naphthyridine (110; 1 .2g, 7. 12mmol) was dissolved in DME (40mL) along with , 3-(tri fluromethyl)-phenylboronic acid (2.03g, 1 0.68 mmol), Cs2C03 (4.64 g, 14.24 mmol) and Pd(dppf)Cl2 (297 mg, 0.356 mmol). The reaction mixture was stirred at 90 C overnight. The solid was filtrated. The filtration was then diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography to afford 7-(3-(trifluoromethyl)phenyl)- 1 ,2, 3 , 4-tetrahydro- 1 ,8-naphthyridine (111 ; 1.25g, 63%). MS (ESI) calcd for C sH nFs^ (m/z) 278.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 8h;Inert atmosphere; | General procedure: The reaction was carried out in a pressure tube. To a dioxane suspension (5 mL) of the <strong>[7657-09-2]1,4-dibromo-2-(trifluoromethyl)benzene</strong> (6), Pd(PPh3)4 (3-5 mol%) and of the arylboronic acid (2) was added an aqueous solution of K2CO3 (2 M, 1-2 mL). The mixture was heated at the indicated temperature (90 8C) under Argon atmosphere for the indicated period of time (8 h). The solution was cooled to 20 C, poured into H2O and CH2Cl2 (5 mL each), and the organic and the aqueous layers were separated. The latter was extracted with CH2Cl2 (3 15 mL). The combined organic layers were washed with H2O (3 10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes/EtOAc) to give 1,4-diaryl-3-(trifluoromethyl)benzene (8a-m) (79-95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine;copper diacetate; In 1,4-dioxane; | 6-bromo-3-r3-(trifluoromethyl)phenyl]-13-benzothiazol-2(3H)-one (15-1)To a round bottom flask was added 6-bromo-l ,3-benzothiazol-2(3H)-one (0.050 g, 0.217 mmol), copper(2+) diacetate (0.079 g, 0.435 mmol), [3-(trifluoromethyl)phenyl]boronic acid (0.124 g, 0.652 mmol), Dioxane (1 mL), and DIPEA (0.1 14 mL, 0.652 mmol). The reaction mixture was then permitted to stir open to the atmosphere for -17 hours (overnight). The crude reaction mixture was then diluted with methanol, filtered and concentrated. Purification of cmde reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 30% acetonitrile / 0.1 % trifluoroacetic acid / water -» 100% acetonitrile / 0.1% trifluoroacetic acid / water) gave 6- bromo-3-[3-(tnfluoromethyl)phenyl]-l ,3-beiizothiazol-2(3H)-one (15-1) as a white solid.HRMS (M+H)+: observed -373.9455, calculated =373.9457. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium fluoride;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In 1,4-dioxane; at 80℃; for 8h; | -Bromo-3-chlorophenol (518 mg, 2.5 mmol), 3-(trifluoromethyl)phenylboronic acid (617 mg, 3.25 mmol), potassium fluoride (435 mg, 7.5 mmol) palladium acetate (28 mg, 0.125 mmol) and S_phos (102 mg, 0.25 mmol) were stirred in dioxane (10 mL) at 80 C. for 4 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The EtOAc was dried over MgSO4 and evaporated. The residue was resubjected to the reaction conditions and was redissolved in dioxane (10 mL). 3-(trifluoromethyl)phenylboronic acid (380 mg, 2 mmol), potassium fluoride (348 mg, 6 mmol) palladium acetate (14 mg, 0.0625 mmol) and S_phos (51 mg, 0.125 mmol) were added and the reaction stirred at 80 C. for a further 4 hours. The reaction mixture was worked up as before and the crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 75:25. Fractions containing product were evaporated. The resulting material was chromatographed on silica eluting with a gradient of cyclohexane:triethylamine:isopropyl alcohol 95:5:0 to 95:5:10 to give the title compound (310 mg, 1.14 mmol, 45%) as a colourless gum.1HNMR (400 MHz, CDCl3): delta 6.75 (m, 1H), 6.94 (s, 1H), 7.15 (d, 1H), 7.49 (m, 1H), 7.56 (m, 2H), 7.60 (s, 1H).LCMS (5.0 min) Rt=3.41 minutes, MS m/z 271 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; methanol; water; at 135℃;Inert atmosphere; Sealed tube; | Intermediate 6a: 5-(3-(trifluoromethyl phenyl pyrazin-2-amine.; Into a 500-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromopyrazin-2-amine (4 g, 22.99 mmol, 1.00 equiv) in 1,4-dioxane (68 mL) and methanol (23 mL), 3-(trifluoromethyl)phenylboronic acid (4.46 g, 23.48 mmol, 1.02 equiv), a solution of sodium carbonate (4.88 g, 46.04 mmol, 2.00 equiv) in water (23 mL), and Pd(PPh3)4 (532 mg, 0.46 mmol, 0.02 equiv). The resulting solution was stirred overnight at 135C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :5). This resulted in 4.4 g (80%) of 5-(3- (trifluoromethyl)phenyl)pyrazin-2-amine as a yellow solid. |
80% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; methanol; at 135℃; | 5-bromo-piperazin-2-amine 4g, 22.99mmol, 1.00N was dissolved in 1,4-dioxane 68 mL and a mixed solution of 46mL ofanhydrous methanol, and then were added 3- (trifluoromethyl) phenylboronic acid 4.46g, 23.48mmol, 1.02N, sodium carbonate4.88g, 46.04mmol, 2.00N and Pd (PPh 3) 4 532mg, 0.46mmol, 0.02N, the whole system is heated to 135 C, stirred overnight,concentrated under reduced pressure Shrink, and finally by silica gel column chromatography, eluting with petroleum ether /ethyl acetate = 5: 1 to give yellow Colored solid of 5- (3- (trifluoromethyl) phenyl) piperazin-2-amine 4.4g, yield 80% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With pyridine; copper diacetate; In dichloromethane; at 30℃;Molecular sieve; | Intermediate 2a: 3-nitro- 1 -(3 -(trifluoromethyl phenyiy 1 H- 1 ,2,4-triazole. Into a 250- mL round bottom flask, was placed a solution of 3-nitro-lH-l,2,4-triazole (2 g, 17.54 mmol, 1.00 equiv) in dichloromethane (100 mL), 3-(trifluoromethyl)phenylboronic acid (6.66 g, 35.05 mmol, 2.00 equiv), Cu(OAc)2 (4.79 g, 26.32 mmol, 1.50 equiv), pyridine (2.77 g, 35.06 mmol, 2.00 equiv), and molecular sieves (5.2 g). The resulting solution was stirred overnight at 30C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :20-1:10) to give 2.2 g (49%) of product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine;copper diacetate; In tetrahydrofuran; for 42h; | Example 7(5S)-5-Amino-7-hvdroxy-2-[3-(trifluoromethyl)phenyll-2,4,5J-tetrahydro-6/-/-pyrazolo[3,4- iblPyridin-6-one, HCI salt (7) 7Step 1 . Synthesis of 4-bromo-3-nitro-1-[3-(trifluoromethyl)phenyll-1 /-/-pyrazole (C56). Pyridine (99%, 0.512 mL, 6.27 mmol) and [3-(trifluoromethyl)phenyl]boronic acid (649 mg, 3.42 mmol) were added to a solution of 4-bromo-3-nitro-1 /-/-pyrazole (596.6 mg, 3.108 mmol) in tetrahydrofuran (9 mL); copper(ll) acetate (99%, 855 mg, 4.66 mmol) was then added, and the reaction was stirred for 42 hours. The reaction mixture was filtered through Celite and concentrated in vacuo, then partitioned between EtOAc (5 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL), and the combined organic layers were washed with water (5 mL) and dried over sodium sulfate. After filtration and removal of solvent under reduced pressure, the residue was purified via silica gel chromatography (Gradient: 0% to 20% EtOAc in heptane) to provide C56. The regiochemistry of C56 was assigned based on NOE experiments. Yield: 779 mg, 2.32 mmol, 75%. GCMS m/z 335, 337 (M+). H NMR (400 MHz, CDCI3) delta 7.68-7.76 (m, 2H), 7.94-7.98 (m, 1 H), 7.99-8.01 (m, 1 H), 8.14 (s, 1 H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 75℃; for 4.0h;Inert atmosphere; | General procedure: A 1,4-Dioxane solution (8 mL) of 10 (1.0 mmol), arylboronic acid 2 (1.0 equiv.), K3PO4, and Pd(PPh3)4 (5 molpercent) was heated at 75 C for 4 h. After cooling to room temperature, H2O was added and the reaction mixture was extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (pure n-heptane).#10;#10;#10;#10;#10;#10;#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 6h;Inert atmosphere; | General procedure: A 1,4-dioxane solution (8 mL) of 1 (1.0 mmol), arylboronic acid 2 (1.3 equiv.), 2 M K2CO3 (1 mL per cross coupling), and Pd(PPh3)4 (5 mol%) was heated at 80 8C for 6 h. After cooling to room temperature, H2O was added and the reaction mixture was extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (pure n-heptane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With [Pd(N3)(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)(N,N'-dimethylbenzylamine(-H))]; caesium carbonate; In ethanol; at 80℃; for 1h;Inert atmosphere; Heating;Catalytic behavior; | General procedure: To a 13 x 90 mm test tube were added phenylboronic acid (0.18 mmol), CsCO3 (0.18 mmol), Pd catalyst (1E-3 mmol, 1 mol-%), and aryl halide (0.15 mmol) with a stirring bar. Ethanol (0.2 m) was added, and the resulting mixture was heated in an oil bath at 80 C. The reaction was monitored by TLC. After the aryl halide was totally consumed, the reaction mixture was cooled to room temperature and quenched with brine (1.0 mL), and then extracted with EtOAc (3 x 1.0 mL). The resulting organic solution was dried with MgSO4 and concentrated with a rotary evaporator. The crude product was purified by preparative TLC (0.5 mm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.26 g | With potassium phosphate; palladium diacetate; DavePhos; In toluene; | Intermediate 139: 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanoneA cloudy solution of 1 -(5-bromopyrimidin-2-yl)ethanone (300 mg, 1 .49 mmol), 3- (trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K3PO4 (950 mg, 4.48 mmol),DavePhos ligand [2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl] (59 mg, 0.15 mmol), and Pd(OAc)2 (17 mg, 0.075 mmol) in 6 mL toluene was heated at 100C for 1 h. The mixture was cooled to room temperature, and filtered through Celite. Filter cake was rinsed with 30 mL EtOAc. The filtrate was poured into 20 mL water. Layers were separated, and the aqueous was further extracted with EtOAc (20 mL). Combined organics were washed with water (20mL) and brine (20mL), dried over Na2S04, filtered and concentrated directly onto silica gel. Column chromatography (10 - 100% EtOAc/heptane) gave 0.26 g 1 -(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (V) as tan solid. MS m/z 267.1 (M + H)+. 1H NMR (400 MHz, CDCI3) delta 9.16 (s, 2H), 7.93 - 7.69 (m, 4H), 2.87 (s, 3H). |
0.26 g | With potassium phosphate; palladium diacetate; DavePhos; In toluene; at 100℃; for 1.0h; | A cloudy solution of <strong>[1189169-37-6]1-(5-bromopyrimidin-2-yl)ethanone</strong> (300 mg, 1.49 mmol), 3-(trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K3P04 (950 mg, 4.48 mmol),DavePhos ligand [2-dicyclohexylphosphino-2?-(N, N-dimethylamino)biphenyl] (59 mg, 0.15mmol), and Pd(OAc)2 (17 mg, 0.075 mmol) in 6 mL toluene was heated at 100C for 1 h. Themixture was cooled to room temperature, and filtered through Celite. Filter cake was rinsed with 30 mL EtOAc. The filtrate was poured into 20 mL water. Layers were separated, and the aqueous was further extracted with EtOAc (20 mL). Combined organics were washed with water (2OmL) and brine (2OmL), dried over Na2504, filtered and concentrated directly ontosilica gel. Column chromatography (10 - 100% EtOAc/heptane) gave 0.26 g 1-(5-(3- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone as tan solid. MS mlz 267.1 (M + H)+. 1H NMR (400 MHz, CDCI3) O 9.16 (5, 2H), 7.93-7.69 (m, 4H), 2.87 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; ethanol; water; at 100℃; for 2h; | A mixture containing <strong>[1150566-27-0]ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate</strong> (1.25 g, 5.55 mmol), 3-(trifluoromethyl)phenylboronic acid (5.55 mmol), CS2CO3 (3.62 g, 11.1 mmol) and Pd(PPh3)4 (0.32 g, 0.277 mmol) in 4:1:1 dioxane/water/ethanol (10 mL) was stirred at 100 C for 2 h. Upon cooling to room temp, the reaction mixture was concentrated under reduced pressure. Purification by chromatography afforded ethyl 6-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-3-carboxylate (1.5 g , 80%). MS (ESI) calcd for C16H12F3N302: 335.09; found: 336 [M+H] |
80% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; ethanol; water; at 100℃; for 2h; | A mixture containing <strong>[1150566-27-0]ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate</strong> (1.25 g, 5.55 mmol), 3-(trifluoromethyl)phenylboronic acid (5.55 mmol), Cs2CO3 (3.62 g, 11.1 mmol) and Pd(PPh3)4 (0.32 g, 0.277 mmol) in 4:1:1 dioxane/ water/ethanol (10 mL) was stirred at 100 C for 2 h. Upon cooling to room temp, the reaction mixture was concentrated under reduced pressure. Purification by chromatography afforded ethyl 6-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-3-carboxylate (1.5 g , 80%). MS (ESI) calcd for C16H12F3N3O2: 335.09; found: 336 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 5h; | General procedure: 4.1.1 Methyl 3-phenylthiophene-2-carboxylate (5) Tetrakis(triphenylphosphine)palladium (5.49 g, 4.75 mmol) and 2 M aqueous disodium carbonate (71 mL) were added to a mixture of methyl 3-bromothiophene-2-carboxylate (1, 21 g, 95.0 mmol), phenylboronic acid (13.9 g, 114 mmol) and 1,4-dioxane (210 mL), and the mixture was stirred for 5 h at 90 C. The reaction mixture was cooled to room temperature and then diluted with H2O and extracted with AcOEt. The organic layer was washed successively with H2O and saturated aqueous NaCl and then dried and concentrated in vacuo. The residue was chromatographed on silica gel with elution using hexane/AcOEt (9:1 to 4:1) to produce the desired compound 5 (14.4 g, 70%) as a colorless solid which was used in the next reaction without recrystallization. 4.1.7 Ethyl 5-(3-trifluoromethylphenyl)-1,3-thiazole-4-carboxylate (11) Compound 11 was prepared from 4 and (3-trifluoromethylphenyl)boronic acid in 84% yield as a yellow solid, using an approach similar to that described for 5, and was used in the next reaction without further purification. 1H NMR (DMSO-d6) delta 1.08 (3H, t, J = 7.2 Hz), 4.16 (2H, q, J = 7.2 Hz), 7.68-7.91 (5H, m), 9.21(1H, s); FAB MS m/e [M+H]+ 302. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tris-(dibenzylideneacetone)dipalladium(0); potassium phosphate; In toluene; at 100℃; for 22h;Inert atmosphere; Sealed tube; | General procedure: 4.2.8 2,3,5,6-Tetrakis(3-(trifluoromethyl)phenyl)pyridine (2h) Starting with <strong>[2402-79-1]2,3,5,6-<strong>[2402-79-1]tetrachloropyridine</strong></strong> 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.8 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 3-(trifluoromethyl)phenylboronic acid (333 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2h was isolated as a colorless solid (93 mg, 57%); mp=119-121 C. 1H NMR (300 MHz, CDCl3): delta=7.39-7.65 (m, 16H, CH), 7.85 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): delta=123.7 (q, 4JC-F=274.3 Hz, CF3), 123.7 (q, 4JC-F=272.3 Hz, CF3), 124.7 (q, 3JC-F=4.1 Hz, CH), 125.1 (q, 3JC-F=3.8 Hz, CH), 126.2 (q, 3JC-F=3.8 Hz, CH), 127.0 (q, 3JC-F=4.0 Hz, CH), 128.7 (CH), 129.3 (CH), 130.6 (q, 2JC-F=32.9 Hz, C), 131.3 (q, 2JC-F=32.9 Hz, C), 132.8 (CH), 133.2 (CH), 134.0 (C), 139.2 (C), 139.4 (C), 140.9 (CH), 154.8 (C). 19F NMR (282.4 MHz, CDCl3): delta=-62.5 (CF3), -62.6 (CF3). IR (ATR, cm-1): ?=1411 (m), 1374 (w), 1324 (s), 1276 (w), 1250 (m), 1213 (w), 1180 (m), 1214 (m), 1180 (m), 1162 (m), 1069 (s), 1001 (m), 899 (m), 836 (m), 802 (s), 727 (m), 700 (s), 536 (m), 465 (m), 436 (m), 416 (w), 399 (w). GC-MS (EI, 70 eV): m/z (%): 655 (M+, 61), 654 (100), 652 (2), 544 (12), 488 (4), 468 (4), 281 (2), 207 (3), 137 (2), 125 (3), 123 (3), 111 (5), 109 (5), 95 (6), 81 (6), 71 (8), 69 (10), 57 (15), 55 (10), 43 (11), 41 (11), 39 (5). HRMS (ESI, 70 eV): calcd for C33H18F12N ([M+H]+): 656.12421, found 656.12419. Anal. Calcd for C33H17F12N (655.48): C, 60.47; H, 2.61. Found: C, 60.67; H, 2.232. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In tetrahydrofuran; water; at 100.0℃; for 2.0h;Microwave irradiation; Inert atmosphere; Sealed tube; | General procedure: Aryl bromide (0.20g) and the appropriate boronic acid or boronate ester (1.5 eq) were dispersed in degassed THF (3mL) and degassed 1M Na2CO3(aq) (1mL) in a 10mL microwave vessel. A steady stream of nitrogen was bubbled through the mixture for 5min, before adding PdCl2(PPh3)2 (41mg, 0.1 eq), then immediately sealing the tube. The mixture was heated at 100C in an aluminium heating block for 2h, at which point LC-MS analysis indicated the reaction was complete. After cooling, the mixture was diluted with EtOAc (10mL) and water (10mL), and the aqueous layer discarded. The organic layer was filtered through a plug of cotton wool, before concentration and further purification by FCC (eluent DCM or MeOH/DCM 0:100 to 5:95 for more polar compounds). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere; | A solution of compound 1 (50.0 g, 0.248 mol, 1.0 equiv, F-chemicals), compound 2 (51.49 g, 0.265 mol, 1.1 equiv, combi-blocks) and potassium carbonate (100 g, 0.725 mol, 3.0 equiv) in 1,4-dioxane (1.0 L) and H2O (250 mL) was degassed with nitrogen for 15 min. Pd(PPh3)4 (14.0 g, 0.0294 mol, 0.05 equiv) was added and the mixture was again degassed with nitrogen for 5 min. The reaction mixture was heated at 90 C. for 3 h. The reaction mass was cooled to RT, diluted with ethyl acetate (1.0 L) and washed with brine (500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude material which was purified by column chromatography (silica gel 60-120 mesh, elution 1% EtOAc/Hexane) to get the pure compound 3 (55 g, 89%). TLC solvent system: Heptane, Product Rf: 0.5. 1H NMR (300 MHz, Chloroform-d) 7.62-7.53 (m, 4H), 7.27-7.19 (m, 1H), 6.88-6.78 (m, 2H), 3.82 (s, 3H), 2.19 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium phosphate; palladium bis(dibenzylideneacetone)palladium(0); catacxium A; In toluene; at 110℃; for 24h;Inert atmosphere; Sealed tube; | General procedure: An oven-dried and argon-flushed pressure tube was charged with <strong>[108-70-3]1,3,5-trichlorobenzene</strong>, 1,2,4-trichlorobenzene or 1,2,3-trichlorobenzene (0.25 mmol), Pd2(dba)2 (1.25 mol%), cataCXium A (5.0 mol%), boronic acid (1.5 mmol) and K3PO4 (1.5 mmol) followed by anhydrous toluene (4.0 mL). The tube was sealed with a Teflon valve and the reaction mixture was stirred at 110 C for 24 h. The cooled reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a 10 mL reaction tube equipped with a magnet was added 76 mg (0.4 mmol) of 3-trifluoromethylphenylboronic acid, 0.4 mL (0.8 mmol) of trimethylsilyl diazomethane (2M n-hexane solution) 1 mL of toluene, stoppered with a rubber stopper and reacted on an electromagnetic heating stirrer at 50 C for 3 hours.Followed by addition of 71 mg (0.6 mmol) of pinacol (dissolved in 1 mL of 1,4-dioxane), 0.5 mL of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) and 200 uL of water at 50 C in an electromagnetic heating stirrer To continue for 3 hours.After completion of the reaction, the organic solvent was removed by a rotary evaporator and purified by column chromatography3-trifluoromethylbenzyl boronic acid pinacol ester, its structure is as follows:The compound was a colorless liquid in a yield of 72% with the following NMR data: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | General procedure: A mixture of N-boc-2-(4-bromophenyl)ethylamine, the desiredarylboronic acid (a-m) (1.2 equiv), tetrakis(triphenylphosphine)-palladium(0) (0.04 equiv), Na2CO3 (5 equiv) in degassed toluene/H2O (5/2) was refluxed for 18 h. The reaction mixture was filteredthrough Celite and concentrated in vacuo. The resulting residuewas dissolved in in EtOAc (200 mL), washed with H2O (200 mL 2) and brine (200 mL). The organic layer was dried with anhydrousNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on SiO2.Using Method E, 13 (1.00?g, 3.3?mmol), 3-(trifluoromethyl)phenylboronic acid (0.76?g, 4.0?mmol), tetrakis(triphenylphosphine)palladium(0) (0.15?g, 0.1?mmol), Na2CO3 (1.77?g, 16.7?mmol) in toluene/H2O (33?ml/13.3?ml), followed by 4.0?M HCl in dioxane (2.50?ml, 10.0?mmol) gave 14a as a white solid (0.57?g, 56%): Rf?=?0.00 (EtOAc 9: acetone 1): 1H NMR (DMSO-d6, 400?MHz) delta 2.98-3.10 (m, NH3CH2CH2), 7.42 (d, J?=?8.2?Hz, 2 ArH), 7.69-7.74 (m, 4 ArH), 7.95-8.00 (m, 2 ArH), 8.31 (s, NH3); 13C NMR (DMSO-d6, 100?MHz) delta 33.0 (NCH2CH2), 123.4 (q, JC-F?=?3.9?Hz), 124.4 (q, JC-F?=?3.7?Hz), 124.7 (CF3, q, JC-F?=?270.9?Hz), 127.6, 129.9, 130.2 (q, JC-F?=?31.4?Hz), 130.5, 131.1, 137.4, 138.1, 141.4 (12 ArC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With oxygen; copper diacetate; triethylamine; In N,N-dimethyl-formamide; at 65℃; for 4h; | General procedure: To a solution of <strong>[461-89-2]6-azauracil</strong> (100 mg, 0.88 mmol) inDMF (10.0 mL) was added base (1.76 mmol) and Cu(OAc) 2(159 mg, 0.88 mmol) at room temperature. The resulting reationmixture was degassed with oxygen for 10 min and then addedarylboronic acids (0.96 mmol) at room temperature and stirredat appropriate temperature (Table-1) under oxygen atmosphere.The reaction mixture was diluted with water (15 mL) andextracted with dichloromethane (3 × 15 mL). The organic layerwashed with H 2 O (15 mL), brine solution (15 mL), dried overNa 2 SO 4 and concentrated. The obtained crude product waspurified by column chromatography (0 to 10 % CH 3 OH/CH 2 Cl 2 )to afford the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃;Inert atmosphere; | General procedure: In a dried MW flask under Ar were introduced arylbromide (1 eq.), Na2CO3 (3 eq.) and arylboronic acid (1.2 eq.) followed by the addition of toluene/ EtOH/H2O (4/1/1: C: 0.2 mmol/mL). The flask was purged three times with Ar before the addition of Pd(PPh3)4 (0.1 eq.). The flask was sealed and the reaction mixture was stirred overnight at 90 C. After removal of the solvent in vacuo, the crude product was purified by Combiflash silica gel chromatography. |
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