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To benzofura?-5-carbonitrile (500 mg, 3.49 mmol) in THF (9.98 mL) at -78 0C was added nBuLi 1.6M in hexanes (2.401 ml, 3.84 mmol) dropwise. The mixture was stirred for 30min at this temperature, and then trimethyt borate (0.858 mL, 7.68 mmoi) was added dropwise. The mixture was stirred for 20min, and then HC. 2N (11.52 mL, 23.05 mmol) was added. The bath was removed, and stirring continued for 30min. The mixture was diluted with water and extracted with EtOAc three times, dried over magnesium sulfate, filtered, concentrated. Crude 5-cyanobenzofuran-2-ylboronic acid (623 mg, 87%) was then dried and used as is for the next step.
Example 7: Synthesis of 2-(5-fluoro-4-(1-hydroxyethyl)pyridin-3-yl)benzofuran-5- carbonitrile (17)Step 1: 5-cyanobenzofuran-2-ylboronic acid (7a) To <strong>[79002-39-4]benzofuran-5-carbonitrile</strong> (500 mg, 3.49 mmol) in THF (9.98 mL) at -78 C was added n- BuLi 1 6M in hexanes (2.401 mL, 3.84 mmol) dropwise. The mixture was stirred for 30min at this temperature, and then trimethy. borate (0.858 mL, 7.68 mmol) was added dropwise. The mixture was stirred for 20 min, and then HCI (2M, 1 1.52 mL, 23.05 mmol) was added. The bath was removed, and then stirred for 30min. To the mixture was added more water and extracted with EtOAc three times, dried over magnesium sulfate, filtered, concentrated, crude 7a (623 mg, 87%) was then dried and used as is for next step.
Tert-butyl 4-(4-((4-(5-cyanobenzofuran-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 160℃; for 1h;Microwave irradiation;
To a 10 mL microwave vessel charged with a solution of 3c (0.308 g, 1.65 mmol), 7a (0.500 g, 1.1 mmol) and Pd(PPh3)4(0.064 g, 0.055 mmol) in DMF (4 mL) was added Na2CO3 (0.233 g, 2.2 mmol). The mixture was stirred at 160C for 1 h at automatic CEM microwave reactor. The reaction mixture was cooled to room temperature, filtered through Celite, diluted with water (30 mL), extracted with EtOAc (30 mL 3), washed with brine(50 mL 2), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography to give compound 5g as a yellow solid (0.350 g, 56%).
2-(2-chloro-5-methylpyrimidin-4-yl)benzofuran-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; for 12h;Inert atmosphere; Reflux;
General procedure: To a mixture of compound 3a (6.40 g, 39.5 mmol) and 2,4-dichloro-5-methyl pyrimidine (6.44 g, 39.5 mmol) in dioxane(50 mL) was added Pd(PPh3)4 (2.31 g, 2.0 mmol) and K2CO3 (16.40 g, 118.5 mmol) under nitrogen. The reaction mixture was stirred at reflux for 12 h before cooling to room temperature and filtered to remove any solid. The filtrate was concentrated and purified by flash chromatography to give the desired products.
4-Chloro-N-(4-(3,5-dimethylpiperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine[ No CAS ]
[ 331833-83-1 ]
2-(2-((4-(3,5-Dimethylpiperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)benzofuran-6-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 160℃; for 1h;Microwave irradiation;
General procedure: To a 10 mL microwave vessel charged with a solution of 3c (0.308 g, 1.65 mmol), 7a (0.500 g, 1.1 mmol) and Pd(PPh3)4(0.064 g, 0.055 mmol) in DMF (4 mL) was added Na2CO3 (0.233 g, 2.2 mmol). The mixture was stirred at 160C for 1 h at automatic CEM microwave reactor. The reaction mixture was cooled to room temperature, filtered through Celite, diluted with water (30 mL), extracted with EtOAc (30 mL 3), washed with brine(50 mL 2), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography to give compound 5g as a yellow solid (0.350 g, 56%).
methyl 3,5-diamino-6-(5-cyanobenzofuran-2-yl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; toluene;Inert atmosphere; Reflux;
General procedure: <strong>[1458-01-1]Methyl 3,5-diamino-6-chloropyrazine-2-carboxylate</strong> 2 (1 eq.) was combined with K2CO3 (10 eq.), the appropriate (het)aryl boronic acid (1.5 eq.) and Pd(PPh3)4 (5 mol%) in a two-neck round bottom flask. The flask was connected to a condenser and purged with nitrogen. A 4:1 mixture of anhydrous toluene: MeOH (60 mL) was added via syringe and the reaction mixture was heated at reflux for 0.5-18 h. The mixture was allowed to cool to room temperature and filtered through Celite (10 x 3 cm, eluting with 3 x 20 mL EtOAc). The filtrate was evaporated to dryness and the residue purified by silica gel flash column chromatography using EtOAc/pet spirit.