5-Chloro-2-(trifluoromethyl)pyridine

Step B 5-chloro-2-(trifluoromethyl)pyridine Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a solution of KF (53 mg, 0.91 mmol, 1.10 equiv) in NMP (3 mL), CuI (175 mg, 0.92 mmol, 1.10 equiv), trimethyl(trifluoromethyl)silane (119 mg, 0.84 mmol, 1.00 equiv) and 5-chloro-2-iodopyridine (as prepared in the previous step, 200 mg, 0.84 mmol, 1.00 equiv). The reaction mixture was stirred overnight at 60 C. The reaction was then quenched by the addition of 20 mL of ammonia (12%). The resulting solution was extracted with 2*20 mL of ethyl acetate. The combined organic layers were washed with 50 ml of brine, dried (Na2SO4), and concentrated to yield 5-chloro-2-(trifluoromethyl)pyridine as a yellow oil.Step C 5-chloro-4-iodo-2-(trifluoromethyl)pyridine Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Step 1: LDA (lithium diisopropyl amide) preparation: To a solution of diisopropylamine (5.8 mL, 41.3 mmol) in THF (40 mL), at -78 C in a 250 mL 3 neck RBF, was added n-butyl lithium (1.6 M in hexane, 25.8 mL, 6.49 mmol) and the resulting solution was stirred at that temperature for 0.5 h. To a solution of iodine (8.37 g, 33.0 mmol) and 5-chloro-2-(trifluoromethyl) pyridine (10 g, 55.08 mmol) in THF (100 mL) at -78 C in a 500 mL 3 neck RBF, was added the above prepared LDA solution through a canula and the resulting solution was stirred at that temperature for 1 h.The reaction was stopped by the addition of saturated NH4C1 solution (50 mL) and extracted with MTBE (2 x 100 mL).The organic layer was washed with water (2 x 50 mL), dried over anhydrous Na2S04 and concentrated. The crude product was purified by column chromatography (2% EtOAc in petroleum ether) to yield 5-chloro-4-iodo-2- (trifiuoromethyl)pyridine. 1H NMR (300 MHz, DMSO-d6): 8.81(s, 1 H), 8.49 (s, 1H); GC-MS calc'd. for C6H2C1F3IN [M+H]+ 307.89, found 307.0.To a solution of 439 1) Mixing methyl ethyl sulfide, toluene, catalyst and ethylenediamine under nitrogen atmosphere, and heating to 110 C, The control pressure was 2 atm, and a mixture of 1 mol of General procedure: A mixture of methyl 1, 1-dimethyl-2, 3-dihydro-1H-isoindole-4-carboxylate (100 mg, 0.49 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (180 mg, 0.99 mmol), 2nd Generation RuPhos precatalyst (38 mg, 0.05 mmol), RuPhos (23 mg, 0.05 mmol) and cesium carbonate (477 mg, 1.46 mmol) in toluene (3 mL) was stirred for 12 h at 110 C. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 1:5 ethyl acetate/petroleum ether) to afford methyl 1, 1-dimethyl-2-(5-(trifluoromethyl)pyrazin-2-yl)isoindoline-4-carboxylate (150 mg, 88%) as a yellow solid.