4-fluoro-2-iodoaniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 4-fluoro-2-iodoaniline (2 g, 8.4 mmol) in THF (15 mL) and cyclopropylacetylene (1.4 mL, 16.9 mmol) is treated with PdCl2(PPh3)4 (177 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) and triethylamine (3.5 mL, 25.2 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 0%-35% EtOAc in heptane to afford 2-cyclopropylethynyl-4-fluoro-phenylamine (1.1 g, 74%). MS: 176 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.93 (m, 1H), 6.81 (m, 1H), 6.59 (m, 1H), 4.00 (s, NH2, 2H), 1.49 (m, 1H), 0.82 (m, 4H). The mixture is filtered through Celite concentrated The residue is purified by silica gel chromatography eluting with 0%-35% EtOAc in heptane

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

Procedure: A solution of 4-fluoro-2-iodoaniline (2 g, 8.4 mmol) in THF (15 mL) and cyclopropylacetylene (1.4 mL, 16.9 mmol) is treated with PdCl2(PPh3)4 (177 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) and triethylamine (3.5 mL, 25.2 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 0%-35% EtOAc in heptane to afford 2-cyclopropylethynyl-4-fluoro-phenylamine (1.1 g, 74%). MS: 176 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.93 (m, 1H), 6.81 (m, 1H), 6.59 (m, 1H), 4.00 (s, NH2, 2H), 1.49 (m, 1H), 0.82 (m, 4H). The mixture is filtered through Celite concentrated The residue is purified by silica gel chromatography eluting with 0%-35% EtOAc in heptane

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ehtyl 2-(2-oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115° C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene to provide 5.36 g of the title compound as a yellow solid. After this time, the benzene was removed under distillation Then, 60 ml of DMF was added the solution was degassed before 19 ml of Hunig's base were added successively cooled to room temperature To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added the mixture was filtered through Celite The phases were separated the acidic phase was extracted twice with 200 ml of ethyl acetate washed with brine dried over anhydrous Na2SO4 filtered through Celite concentrated The crude material was further purified by flash chromatography eluting with 100% toluene

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ehtyl 2-(2-oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115° C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene to provide 5.36 g of the title compound as a yellow solid. After this time, the benzene was removed under distillation Then, 60 ml of DMF was added the solution was degassed before 19 ml of Hunig's base were added successively cooled to room temperature To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added the mixture was filtered through Celite The phases were separated the acidic phase was extracted twice with 200 ml of ethyl acetate washed with brine dried over anhydrous Na2SO4 filtered through Celite concentrated The crude material was further purified by flash chromatography eluting with 100% toluene

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ehtyl 2-(2-oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115° C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene to provide 5.36 g of the title compound as a yellow solid. After this time, the benzene was removed under distillation Then, 60 ml of DMF was added the solution was degassed before 19 ml of Hunig's base were added successively cooled to room temperature To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added the mixture was filtered through Celite The phases were separated the acidic phase was extracted twice with 200 ml of ethyl acetate washed with brine dried over anhydrous Na2SO4 filtered through Celite concentrated The crude material was further purified by flash chromatography eluting with 100% toluene

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-dimethylamino-4-phenyl-1-(5-triethylsilanyl-pent-4-inyl)cyclohexanol (525 mg, 1.31 mmol), 4-fluoro-2-iodoaniline (374 mg, 1.58 mmol), [1,3-bis-(2,6-diisopropyl-phenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI, 178 mg, 0.26 mmol) and sodium carbonate (694 mg, 6.6 mmol) was evacuated for 30 min (oil pump). It was then flushed with argon and absolute N,N-dimethylformamide (5 mL, previously flushed for 1 h with argon) was added by syringe via a Schlenk tube. The mixture was stirred for 18 h at 100° C. and changed colour to dark brown during this. The reaction mixture was then concentrated to low volume in a vacuum, the residue taken up several times in toluol (3×10 mL) and concentrated to low volume again in each case, distributed between water and ethyl acetate (20 mL each) and the phases separated again. The aqueous phase was extracted with ethyl acetate (2×30 mL), the combined organic phases were washed with 1 M sodium thiosulphate solution (30 mL) and saturated sodium chloride solution (50 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (1.10 g) was purified by means of flash chromatography (50 g, 20×3.0 cm) with chloroform/methanol (97:3). was evacuated for 30 min (oil pump) It was then flushed with argon and absolute N,N-dimethylformamide (5 mL previously flushed for 1 h with argon) was added by syringe via a Schlenk tube The reaction mixture was then concentrated to low volume in a vacuum concentrated to low volume again in each case the phases separated again The aqueous phase was extracted with ethyl acetate (2×30 mL) the combined organic phases were washed with 1 M sodium thiosulphate solution (30 mL) and saturated sodium chloride solution (50 mL) dried with sodium sulphate concentrated to low volume in a vacuum The raw product (1.10 g) was purified by means of flash chromatography (50 g, 20×3.0 cm) with chloroform/methanol (97:3)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of {4-[(diisopropylamino)carbonyl]-2-ethoxypyridin-3-yl}boronic acid (8.19 g, 27.8 mmol) in THF (45 mL), were added 2-iodo-4-fluoro-aniline (3 g, 12.7 mmol), sodium carbonate (2.0 M, 10 mL), and tetrakis(triphenylphosphine)palladium (2.93 g, 2.53 mmol). The solution was degassed by bubbling nitrogen through the flask and subsequently heated to 100° C. for 2 hr. The solution was cooled and worked up with EtOAc and water, dried over MgSO4, filtered, and concentrated. Column chromatography on silica gel (100% hexanes to 100% EtOAc) provided the title product. The solution was degassed by bubbling nitrogen through the flask The solution was cooled dried over MgSO4 filtered concentrated

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

Procedure: 80 ml of tetrahydrofuran is placed under argon. 5 g 4-fluoro-2-iodophenylamine, 0.74 g dichlorobis(triphenylphosphine) palladium(II), 0.2 g copper iodide and 8.8 ml triethylamine are added. 4 g gaseous 1-butyne are passed through the suspension. The reaction mixture is stirred under argon for 15 hours at ambient temperature, then filtered through Celite and evaporated to dryness. 3.4 g product are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 2.45 (2H, q); 1.18 (3H, t). filtered through Celite evaporated to dryness

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

Procedure: To a stirred solution of 4-fluoro-2-iodoaniline and (18 g) 4-oxo-cyclohexanecarboxylic acid ethyl ester (20 g) in DCM (200 ml) is added acetic acid (4.4 ml) and 4 Å molecular sieves (5 g). After 2 h at rt, sodium acetoxyborohydride (50 g) is added and the suspension stirred overnight. The reaction is made slightly alkaline with KHCO3/NaHCO3(aq) and extracted with DCM to give crude 4-(4-fluoro-2-iodo-phenylamino)-cyclohexanecarboxylic acid ethyl ester. extracted with DCM

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2-oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115° C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene to provide 5.36 g of the title compound as a yellow solid. After this time, the benzene was removed under distillation Then, 60 ml of DMF was added the solution was degassed before 19 ml of Hunig's base were added successively cooled to room temperature To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added the mixture was filtered through Celite The phases were separated the acidic phase was extracted twice with 200 ml of ethyl acetate washed with brine dried over anhydrous Na2SO4 filtered through Celite concentrated The crude material was further purified by flash chromatography eluting with 100% toluene