2-氯-4-氟-3-碘苄腈

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Adapting a protocol by Uchiyama et al (J. Am. Chem. Soc., 2002, 124, 8514-8515), which reference is incorporated herein by reference in its entirety, 2-chloro-4-fluorobenzonitrile (311 mg, 2.0 mmol) in dry THF (1.0 mL) was added dropwise to lithium di-t-butyl(2,2,6,6-tetramethylpiperidino)zinncate (4.0 mmol in 10 mL THF, Uchiyama et al J. Am. Chem. Soc., 1999, 121, 3539-3540, which is incorporated herein by reference in its entirety) at 0° C. and stirred at 0° C. for 3.5 h. Iodine (5.08 g, 20.0 mmol) was then added and the reaction was stirred at r.t. overnight. Na2S2O3 (1.0 M, 50 mL) and saturated aqueous NH4Cl (100 mL) were added, followed by extraction with dichloromethane (3×100 mL), drying of the combined organic layers over Na2SO4, filtering, and removal of the solvents in vacuo. The residue was passed through a pad of silica gel eluting with EtOAc/n-heptane (1:40), affording 112 mg (0.40 mmol) of 2-chloro-4-fluoro-3-iodobenzonitrile. This material was combined with nortropine (114 mg, 0.90 mmol), K2CO3 (186 mg, 0.134 mol) and DMSO (2.0 mL), and stirred at 130° C. for 1.5 h. The crude mixture thus obtained was diluted with n-heptane (10 mL), passed through a pad of silica gel using EtOAc/n-heptane (1:2), concentrated and purified by preparative TLC (EtOAC/n-heptane, 1:1) to give 1.5 mg (1.7%) of 195JP18 as an off-white solid. at 0° C. the reaction was stirred at r.t. overnight followed by extraction with dichloromethane (3×100 mL) drying of the combined organic layers over Na2SO4 filtering removal of the solvents in vacuo

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A thick-walled glass pressure vessel was charged with 2-chloro-4-fluoro-3-iodobenzonitrile (2.815 g, 10.00 mmol), Pd(PPh3)2Cl2 (0.351 g, 0.500 mmol), and CuI (0.095 g, 0.500 mmol) and sealed with a rubber septum. Anhydrous THF (25 mL) and DIPA (4.22 mL, 30.0 mmol) were added via syringe and the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic cleaning bath. To the degassed mixture was added ethynyltrimethylsilane (4.24 mL, 30.0 mmol), the vessel was resealed with a PTFE bushing, and the mixture was stirred in a heating block at 50° C. After 41 h, the mixture was cooled and poured into half-satd NH4Cl. The whole was filtered through a pad of Celite and the filtrate was extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (2.29 g, 91% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=8.7, 5.4 Hz, 1H), 7.12 (dd, J=8.7, 7.9 Hz, 1H), 0.30 (s, 9H); MS (GCMS EI) m/z 251 ([M]+, 14%), 236 ([M-CH3]+, 100%). sealed with a rubber septum the mixture was degassed 10 min by sparging with N2 while immersed in an ultrasonic cleaning bath the mixture was cooled The whole was filtered through a pad of Celite the filtrate was extracted with EtOAc (×3) Combined organics were washed (water, brine) dried over Na2SO4 concentrated in vacuo The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Adapting a protocol by Uchiyama et al (J. Am. Chem. Soc., 2002, 124, 8514-8515), which reference is incorporated herein by reference in its entirety, 2-chloro-4-fluorobenzonitrile (311 mg, 2.0 mmol) in dry THF (1.0 mL) was added dropwise to lithium di-t-butyl(2,2,6,6-tetramethylpiperidino)zinncate (4.0 mmol in 10 mL THF, Uchiyama et al J. Am. Chem. Soc., 1999, 121, 3539-3540, which is incorporated herein by reference in its entirety) at 0° C. and stirred at 0° C. for 3.5 h. Iodine (5.08 g, 20.0 mmol) was then added and the reaction was stirred at r.t. overnight. Na2S2O3 (1.0 M, 50 mL) and saturated aqueous NH4Cl (100 mL) were added, followed by extraction with dichloromethane (3×100 mL), drying of the combined organic layers over Na2SO4, filtering, and removal of the solvents in vacuo. The residue was passed through a pad of silica gel eluting with EtOAc/n-heptane (1:40), affording 112 mg (0.40 mmol) of 2-chloro-4-fluoro-3-iodobenzonitrile. This material was combined with nortropine (114 mg, 0.90 mmol), K2CO3 (186 mg, 0.134 mol) and DMSO (2.0 mL), and stirred at 130° C. for 1.5 h. The crude mixture thus obtained was diluted with n-heptane (10 mL), passed through a pad of silica gel using EtOAc/n-heptane (1:2), concentrated and purified by preparative TLC (EtOAC/n-heptane, 1:1) to give 1.5 mg (1.7%) of 195JP18 as an off-white solid. at 0° C. the reaction was stirred at r.t. overnight followed by extraction with dichloromethane (3×100 mL) drying of the combined organic layers over Na2SO4 filtering removal of the solvents in vacuo