4-bromo-2-ethyl-1-iodobenzene

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-ethyl-1-iodobenzene (75 g, 0.24 mol) in tetrahydrofuran (375 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 196 ml, 0.31 mol) dropwise, maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then N,N-dimethylformamide (70.7 g, 0.97 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 2 hours, then allowed to warm to room temperature for 2 hours. The mixture is cooled in an ice bath and acidified with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, and dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylbenzaldehyde (48 g) as an oil. maintaining the temperature of the reaction mixture below −70° C When the addition After the addition is stirred at −75° C. for 2 hours to warm to room temperature for 2 hours The mixture is cooled in an ice bath The mixture is extracted with ethyl acetate (3×500 ml) washed with brine dried over anhydrous sodium sulphate The mixture is filtered the filtrate is evaporated under reduced pressure The residue is purified by column chromatography on silica gel

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-ethyl-1-iodobenzene (80 g, 0.25 mol) in tetrahydrofuran (800 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 188 ml, 0.3 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (153.7 g, 1.48 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, then dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylphenylboronic acid (26 g) as a white solid. dropwise maintaining the temperature of the reaction mixture below −70° C When the addition After the addition is stirred at −75° C. for 1 hour to come to room temperature stirred for 2 hours by cooling in an ice bath The mixture is extracted with ethyl acetate (3×500 ml) washed with brine dried over anhydrous sodium sulphate The mixture is filtered the filtrate is evaporated under reduced pressure The residue is purified by column chromatography on silica gel

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 4-bromo-2-ethylaniline (80 g, 0.4 mol) in distilled water (400 ml) is added concentrated sulphuric acid (80 ml), followed by brief heating to 60° C. for 1 hour until dissolution is complete. The mixture is allowed to cool to room temperature then further cooled to approximately 0° C. in an ice/salt bath. To this slurry is added an aqueous solution of sodium nitrite (28 g, 0.4 mol) in distilled water (140 ml) dropwise over 15 minutes, maintaining the temperature below 5° C., followed by additional stirring for 30 minutes. The reaction mixture is allowed to come to room temperature and then a solution of aqueous potassium iodide (199 g, 1.2 mol) in distilled water (200 ml) is added dropwise at room temperature. After the addition is complete the solution is briefly heated to 80° C. then allowed to cool to room temperature again. The reaction mixture is extracted with ethyl acetate (1000 ml×3) and the organic phase is washed with 1M aqueous hydrochloric acid (500 ml) and aqueous sodium thiosulfate (2×250 ml). The organic phase is dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethyl-1-iodobenzene (84.6 g) as an orange liquid. to cool to room temperature then further cooled to approximately 0° C. in an ice/salt bath maintaining the temperature below 5° C. to come to room temperature After the addition is briefly heated to 80° C. to cool to room temperature again The reaction mixture is extracted with ethyl acetate (1000 ml×3) the organic phase is washed with 1M aqueous hydrochloric acid (500 ml) and aqueous sodium thiosulfate (2×250 ml) The organic phase is dried over anhydrous sodium sulphate filtered the filtrate is concentrated under reduced pressure The residue is purified by column chromatography on silica gel

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

Procedure: Using a procedure analogous to that used to prepare 30A, 4-bromo-2-ethyl-1-iodobenzene (2.1 g, 6.9 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 175° C. for 45 min to yield 36A (1.1 g, 77%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.03 (t, J=7.58 Hz, 3 H) 2.51 (q, J=7.66 Hz, 2 H) 5.15 (dd, J=10.99, 1.14 Hz, 1 H) 5.47 (dd, J=17.31, 1.14 Hz, 1 H) 6.74 (dd, J=17.43, 11.12 Hz, 1 H) 7.08-7.20 (m, 3 H).

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

Procedure: Using a procedure analogous to that used to prepare 30A, 4-bromo-2-ethyl-1-iodobenzene (2.1 g, 6.9 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 175° C. for 45 min to yield 36A (1.1 g, 77%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.03 (t, J=7.58 Hz, 3 H) 2.51 (q, J=7.66 Hz, 2 H) 5.15 (dd, J=10.99, 1.14 Hz, 1 H) 5.47 (dd, J=17.31, 1.14 Hz, 1 H) 6.74 (dd, J=17.43, 11.12 Hz, 1 H) 7.08-7.20 (m, 3 H).

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

Procedure: Using a procedure analogous to that used to prepare 8A, benzyl but-3-enoate (3.63 g, 0.020 mmol, reference for preparation: Cardillo, G.; De Simone, A.; Mingardi, A.; Tomasini, C. Synlett 1995, 11, 1131-2) was reacted with 4-bromo-2-ethyl-iodobenzene (6.23 g, 0.020 mmol) to give 21A (1.5 g, 21%). 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (t, J=7.69 Hz, 3 H) 1.84-1.94 (m, 2 H) 2.41 (t, J=7.25 Hz, 2 H) 2.55-2.62 (m, 4 H) 5.12 (s, 1 H) 6.96 (d, J=7.91 Hz, 1 H) 7.22 (dd, J=7.91, 2.20 Hz, 1 H) 7.29 (d, J=2.20 Hz, 1 H) 7.30-7.40 (m, 5 H). for preparation

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

Procedure: 20 g (64.3 mmol) of 1-iodo-2-ethyl-4-bromobenzene and 12 g (64.3 mmol) of 4-n-hexylphenylacetylene are initially introduced in 300 ml of triethylamine, 250 mg (1.3 mmol) of copper(I) iodide and 900 mg (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and the mixture is stirred at RT for 3 h and subsequently refluxed for 1 h. The batch is cooled, water and heptane are added, and the phases are separated. The organic phase is washed with saturated sodium chloride soln., dried over sodium sulfate, filtered and evaporated in a rotary evaporator. The residue is purified by column chromatography (SiO2, heptane); the product is obtained as a colourless oil. subsequently refluxed for 1 h The batch is cooled the phases are separated The organic phase is washed with saturated sodium chloride soln , dried over sodium sulfate filtered evaporated in a rotary evaporator The residue is purified by column chromatography (SiO2, heptane) the product is obtained as a colourless oil

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-ethyl-1-iodobenzene (75 g, 0.24 mol) in tetrahydrofuran (375 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 196 ml, 0.31 mol) dropwise, maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then N,N-dimethylformamide (70.7 g, 0.97 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 2 hours, then allowed to warm to room temperature for 2 hours. The mixture is cooled in an ice bath and acidified with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, and dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylbenzaldehyde (48 g) as an oil. maintaining the temperature of the reaction mixture below −70° C When the addition After the addition is stirred at −75° C. for 2 hours to warm to room temperature for 2 hours The mixture is cooled in an ice bath The mixture is extracted with ethyl acetate (3×500 ml) washed with brine dried over anhydrous sodium sulphate The mixture is filtered the filtrate is evaporated under reduced pressure The residue is purified by column chromatography on silica gel

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-ethyl-1-iodobenzene (80 g, 0.25 mol) in tetrahydrofuran (800 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 188 ml, 0.3 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (153.7 g, 1.48 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, then dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylphenylboronic acid (26 g) as a white solid. dropwise maintaining the temperature of the reaction mixture below −70° C When the addition After the addition is stirred at −75° C. for 1 hour to come to room temperature stirred for 2 hours by cooling in an ice bath The mixture is extracted with ethyl acetate (3×500 ml) washed with brine dried over anhydrous sodium sulphate The mixture is filtered the filtrate is evaporated under reduced pressure The residue is purified by column chromatography on silica gel

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-ethyl-1-iodobenzene (80 g, 0.25 mol) in tetrahydrofuran (800 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 188 ml, 0.3 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (153.7 g, 1.48 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, then dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylphenylboronic acid (26 g) as a white solid. dropwise maintaining the temperature of the reaction mixture below −70° C When the addition After the addition is stirred at −75° C. for 1 hour to come to room temperature stirred for 2 hours by cooling in an ice bath The mixture is extracted with ethyl acetate (3×500 ml) washed with brine dried over anhydrous sodium sulphate The mixture is filtered the filtrate is evaporated under reduced pressure The residue is purified by column chromatography on silica gel

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 4-bromo-2-ethylaniline (80 g, 0.4 mol) in distilled water (400 ml) is added concentrated sulphuric acid (80 ml), followed by brief heating to 60° C. for 1 hour until dissolution is complete. The mixture is allowed to cool to room temperature then further cooled to approximately 0° C. in an ice/salt bath. To this slurry is added an aqueous solution of sodium nitrite (28 g, 0.4 mol) in distilled water (140 ml) dropwise over 15 minutes, maintaining the temperature below 5° C., followed by additional stirring for 30 minutes. The reaction mixture is allowed to come to room temperature and then a solution of aqueous potassium iodide (199 g, 1.2 mol) in distilled water (200 ml) is added dropwise at room temperature. After the addition is complete the solution is briefly heated to 80° C. then allowed to cool to room temperature again. The reaction mixture is extracted with ethyl acetate (1000 ml×3) and the organic phase is washed with 1M aqueous hydrochloric acid (500 ml) and aqueous sodium thiosulfate (2×250 ml). The organic phase is dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethyl-1-iodobenzene (84.6 g) as an orange liquid. to cool to room temperature then further cooled to approximately 0° C. in an ice/salt bath maintaining the temperature below 5° C. to come to room temperature After the addition is briefly heated to 80° C. to cool to room temperature again The reaction mixture is extracted with ethyl acetate (1000 ml×3) the organic phase is washed with 1M aqueous hydrochloric acid (500 ml) and aqueous sodium thiosulfate (2×250 ml) The organic phase is dried over anhydrous sodium sulphate filtered the filtrate is concentrated under reduced pressure The residue is purified by column chromatography on silica gel

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

Procedure: Magnesium turnings (1.16 g, 0.048 mol) are stirred under a nitrogen atmosphere for 30 minutes, followed by dropwise addition of 4-bromo-2-ethyl-1-iodobenzene (15.0 g, 0.048 mol) as a solution in anhydrous tetrahydrofuran (40 ml), until the magnesium is just covered. A crystal of iodine is added and the reaction heated to reflux. After initiation begins external heating is stopped and the remaining aryl halide solution is added at such a rate as to maintain a controlled reflux. Once addition is complete the reaction is heated at reflux for 1 hour and the mixture is then cooled to room temperature. A solution of furan-2-carbaldehyde (4.0 ml, 0.048 mol) in anhydrous tetrahydrofuran (10 ml) is then added dropwise, and the suspension is then stirred at room temperature for 20 hours. The reaction is quenched with saturated ammonium chloride (200 ml) and extracted with ethyl acetate (200 ml). The organic phase is separated, dried over anhydrous magnesium sulfate then evaporated under reduced pressure. The crude product is purified by flash column chromatography (1:4 ethyl acetate/hexane eluant) to afford (4-bromo-2-ethyl-phenyl)furan-2-yl methanol as a brown oil. the reaction heated to reflux After initiation begins external heating to maintain a controlled reflux Once addition is heated at reflux for 1 hour The reaction is quenched with saturated ammonium chloride (200 ml) extracted with ethyl acetate (200 ml) The organic phase is separated dried over anhydrous magnesium sulfate then evaporated under reduced pressure The crude product is purified by flash column chromatography (1:4 ethyl acetate/hexane eluant)