1,3-difluoro-2-iodobenzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%). (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7.08 (ddd, J=7.0, 1.0, 0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5, 8.3, 0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7.2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+). The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution the product was extracted with hexanes (3×50 mL) The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL) dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Roe, A. M.; Burton, R. A.; Willey, G. L.; Baines, M. W.; Rasmussen, A. C. J. Med. Chem. 1968, 11, 814-819. Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature, and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1-5 mm at −80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H). GCMS m/e 240 (M+). was maintained below −70° C The total addition time that maintained an internal temperature below −70° C After complete addition the mixture stirred The layers were separated the aqueous layer extracted with hexanes (2×250 mL) The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL) dried (Na2SO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated Chromatography on Silica gel provided product as an oil (1.5 g, 45%) (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7 08 (ddd, J=7 0, 1.0, 0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7 0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5, 8.3, 0.8 Hz, 1H), 4.25 (br s, 1 H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7 2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+). The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution the product was extracted with hexanes (3×50 mL) The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL) dried (MgSO4) filtered evaporated Chromatography on Silica gel provided product as an oil (1.5 g, 45%) (TLC hexanes Rf 0.55)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Roe, A. M.; Burton, R. A.: Willey, G. L., Baines, M W., Rasmussen, A. C. J. Med. Chem 1968, 11, 814-819. Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J., Sall, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature. and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL). saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1.5 mm at ˜80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H) GCMS m/e 240 (M+). was maintained below −70° C The total addition time that maintained an internal temperature below −70° C After complete addition the mixture stirred The layers were separated the aqueous layer extracted with hexanes (2×250 mL) The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL) saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Roe, A. M.; Burton, R. A.: Willey, G. L., Baines, M W., Rasmussen, A. C. J. Med. Chem 1968, 11, 814-819. Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J., Sall, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature. and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL). saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1.5 mm at ˜80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H) GCMS m/e 240 (M+). was maintained below −70° C The total addition time that maintained an internal temperature below −70° C After complete addition the mixture stirred The layers were separated the aqueous layer extracted with hexanes (2×250 mL) The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL) saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40–60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%). (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7.08 (ddd, J=7.0,1.0,0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5,8.3,0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7.2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+). The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution the product was extracted with hexanes (3×50 mL) The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL) dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%). (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7.08 (ddd, J=7.0, 1.0, 0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5, 8.3, 0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7.2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+). The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution the product was extracted with hexanes (3×50 mL) The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL) dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%). (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7.08 (ddd, J=7.0, 1.0, 0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5, 8.3, 0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7.2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+). The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution the product was extracted with hexanes (3×50 mL) The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL) dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Roe, A. M.; Burton, R. A.; Willey, G. L.; Baines, M. W.; Rasmussen, A. C. J. Med. Chem. 1968, 11, 814-819. Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature, and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1-5 mm at −80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H). GCMS m/e 240 (M+). was maintained below −70° C The total addition time that maintained an internal temperature below −70° C After complete addition the mixture stirred The layers were separated the aqueous layer extracted with hexanes (2×250 mL) The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL) dried (Na2SO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Roe, A. M.; Burton, R. A.; Willey, G. L.; Baines, M. W.; Rasmussen, A. C. J. Med. Chem. 1968, 11, 814-819. Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature, and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1-5 mm at −80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H). GCMS m/e 240 (M+). was maintained below −70° C The total addition time that maintained an internal temperature below −70° C After complete addition the mixture stirred The layers were separated the aqueous layer extracted with hexanes (2×250 mL) The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL) dried (Na2SO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P, ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%) (TLC hexanes Rf0.55). 1H NMR (400 Mhz, CDCl3) δ7.08 (ddd, J=7.0,1.0,0.8 Hz, 1H), 6.96 (ddd, J=8.5,8.3,7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5,8.3,0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2,1.7,1.7 Hz, 1H), 2.30 (ddd, J=7.2,1.7,1.5 Hz, 1H), GCMS m/e 160 (M+). The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution the product was extracted with hexanes (3×50 mL) The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL) dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%). (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7.08 (ddd, J=7.0, 1.0, 0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5, 8.3, 0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7.2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+). The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution the product was extracted with hexanes (3×50 mL) The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL) dried (MgSO4) filtered evaporated