1-Bromo-3,5-dimethyl-4-iodobenzene

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

Procedure: To a solution of 4-bromo-2,6-dimethyl-1-iodobenzene (150 g, 0.48 mol) in tetrahydrofuran (1500 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 364 ml, 0.58 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 (302 g, 2.9 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 (3×1000 ml) and the organic extracts are combined, washed with brine, 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-2,6-dimethylphenylboronic acid (48 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 (3×1000 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-2,6-dimethylaniline (75 g, 0.37 mol) in distilled water (75 ml) is added concentrated sulphuric acid (75 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 (25.33 g, 0.36 mol) in distilled water (126 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 (187.6 g, 1.13 mol) in distilled water (190 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 (750 ml×3) and the organic phase is washed with 1M aqueous hydrochloric acid (200 ml) and aqueous sodium thiosulfate (2×200 ml). The organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-dimethyl-1-iodo benzene (75 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 (750 ml×3) the organic phase is washed with 1M aqueous hydrochloric acid (200 ml) and aqueous sodium thiosulfate (2×200 ml) The organic phase is dried over anhydrous sodium sulphate 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: 2.5 M n-Butyllithium, in tetrahydrofuran, (1.42 ml, 3.54 mmol, 1.1 equiv.) was added dropwise to a solution of bromobenzene (0.34 ml, 3.22 mmol, 1.0 equiv.) in dry tetrahydrofuran (18 ml), under nitrogen at −78° C. and the mixture stirred for 30 minutes. Zinc chloride (0.48 g, 3.54 mmol, 1.1 equiv.) was added and the mixture allowed to warm to room temperature while stirring for 2 hours. Palladium tetrakistriphenylphosphine (0.19 g, 0.16 mmol, 0.05 equiv.) and a solution of 5-bromo-2-iodo-1,3-dimethyl-benzene (1.00 g, 3.22 mmol, 1.0 equiv.) in tetrahydrofuran (2 ml) were added and the mixture stirred at room temperature for 16 hours. The tetrahydrofuran was evaporated under reduced pressure and the crude product purified by column chromatography (SiO2, heptane). The fractions were combined to afford 4-bromo-2,6-dimethylbiphenyl, 278 mg (33% yield) as a clear oil δH (400 MHz; d4-methanol) 7.28-7.39 (3H, m), 7.18 (2H, s), 7.03 (2H, d), 1.90 (6H, s). while stirring for 2 hours the mixture stirred at room temperature for 16 hours The tetrahydrofuran was evaporated under reduced pressure the crude product purified by column chromatography (SiO2, heptane)

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

Procedure: 2.5 M n-Butyllithium, in tetrahydrofuran, (1.42 ml, 3.54 mmol, 1.1 equiv.) was added dropwise to a solution of bromobenzene (0.34 ml, 3.22 mmol, 1.0 equiv.) in dry tetrahydrofuran (18 ml), under nitrogen at −78° C. and the mixture stirred for 30 minutes. Zinc chloride (0.48 g, 3.54 mmol, 1.1 equiv.) was added and the mixture allowed to warm to room temperature while stirring for 2 hours. Palladium tetrakistriphenylphosphine (0.19 g, 0.16 mmol, 0.05 equiv.) and a solution of 5-bromo-2-iodo-1,3-dimethyl-benzene (1.00 g, 3.22 mmol, 1.0 equiv.) in tetrahydrofuran (2 ml) were added and the mixture stirred at room temperature for 16 hours. The tetrahydrofuran was evaporated under reduced pressure and the crude product purified by column chromatography (SiO2, heptane). The fractions were combined to afford 4-bromo-2,6-dimethylbiphenyl, 278 mg (33% yield) as a clear oil δH (400 MHz; d4-methanol) 7.28-7.39 (3H, m), 7.18 (2H, s), 7.03 (2H, d), 1.90 (6H, s). while stirring for 2 hours the mixture stirred at room temperature for 16 hours The tetrahydrofuran was evaporated under reduced pressure the crude product purified by column chromatography (SiO2, heptane)

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

Procedure: 1,4-bis(4-n-Butylphenylethynyl)-2,6-dimethylbenzene is prepared from 4-n-butylphenylacetylene and 1-iodo-4-bromo-2,6-dimethylbenzene analogously to the synthesis described under 1A.

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

Procedure: Using a procedure analogous to that used to prepare 30A, 5-bromo-2-iodo-1,3-dimethylbenzene (15.6 g, 48 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 160° C. for 1 h to yield 32A (10.0 g, 94%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.26 (s, 6 H) 5.24 (dd, J=17.86, 1.92 Hz, 1 H) 5.55 (dd, J=11.54, 2.20 Hz, 1 H) 7.18 (s, 2 H).

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

Procedure: To a degassed solution of 5-bromo-2-iodo-1,3-dimethylbenzene (3.9 g, 12.54 mmol) and ethyl 2-bromo-2,2-difluoroacetate (3.22 ml, 25.08 mmol) in DMSO (30 ml) was added copper (3.19 g, 50.2 mmol). The reaction mixture was stirred at 60° C. for 3 h, then cooled to r.t. and filtered. The filtrate was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated. The crude product was purified by flash chromatography to give Intermediate 7A (3.4 g, 11.07 mmol, 88% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.32 (t, J=7.03 Hz, 3H) 2.44 (t, J=4.17 Hz, 6H) 4.32 (q, J=7.18 Hz, 2H) 7.23 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ ppm −95.28 (br. s., 2F). cooled to r.t. filtered The filtrate was diluted with EtOAc and water extracted with EtOAc (3×) The combined organic layer was washed with brine dried with MgSO4 filtered concentrated The crude product was purified by flash chromatography

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

Procedure: To a degassed solution of 5-bromo-2-iodo-1,3-dimethylbenzene (3.9 g, 12.54 mmol) and ethyl 2-bromo-2,2-difluoroacetate (3.22 ml, 25.08 mmol) in DMSO (30 ml) was added copper (3.19 g, 50.2 mmol). The reaction mixture was stirred at 60° C. for 3 h, then cooled to r.t. and filtered. The filtrate was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated. The crude product was purified by flash chromatography to give Intermediate 7A (3.4 g, 11.07 mmol, 88% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.32 (t, J=7.03 Hz, 3H) 2.44 (t, J=4.17 Hz, 6H) 4.32 (q, J=7.18 Hz, 2H) 7.23 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ ppm −95.28 (br. s., 2F). cooled to r.t. filtered The filtrate was diluted with EtOAc and water extracted with EtOAc (3×) The combined organic layer was washed with brine dried with MgSO4 filtered concentrated The crude product was purified by flash chromatography

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

Procedure: 2,6-Dimethyl-4-bromoiodobenzene (5.04 g, 16.2 mmol) was dissolved in diethyl ether (50 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (2.6 M, 6.5 ml) at −50° C. The mixture was then stirred at the same temperature for 45 minutes. To the mixture was then added dropwise trimethylsilyl trifluoromethanesulfonate (3.7 ml, 19.4 mmol). The mixture was then stirred at −30° C. for 30 minutes and at room temperature overnight. After the quenching of the reaction with water, the product was then extracted with diethyl ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then distilled under reduced pressure using a glass tube oven so that it was purified to obtain 3,5-dimethyl-4-trimethylsilylbromobenzene (3.54 g; yield: 85%). The mixture was then stirred at −30° C. for 30 minutes and at room temperature overnight After the quenching of the reaction with water the product was then extracted with diethyl ether The resulting organic phase was then dried over magnesium sulfate The solvent was then distilled off The crude product thus obtained was then distilled under reduced pressure was purified

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

Procedure: To a solution of 4-bromo-2,6-dimethyl-1-iodobenzene (150 g, 0.48 mol) in tetrahydrofuran (1500 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 364 ml, 0.58 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 (302 g, 2.9 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 (3×1000 ml) and the organic extracts are combined, washed with brine, 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-2,6-dimethylphenylboronic acid (48 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 (3×1000 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-2,6-dimethyl-1-iodobenzene (150 g, 0.48 mol) in tetrahydrofuran (1500 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 364 ml, 0.58 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 (302 g, 2.9 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 (3×1000 ml) and the organic extracts are combined, washed with brine, 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-2,6-dimethylphenylboronic acid (48 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 (3×1000 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-2,6-dimethylaniline (75 g, 0.37 mol) in distilled water (75 ml) is added concentrated sulphuric acid (75 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 (25.33 g, 0.36 mol) in distilled water (126 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 (187.6 g, 1.13 mol) in distilled water (190 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 (750 ml×3) and the organic phase is washed with 1M aqueous hydrochloric acid (200 ml) and aqueous sodium thiosulfate (2×200 ml). The organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-dimethyl-1-iodo benzene (75 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 (750 ml×3) the organic phase is washed with 1M aqueous hydrochloric acid (200 ml) and aqueous sodium thiosulfate (2×200 ml) The organic phase is dried over anhydrous sodium sulphate concentrated under reduced pressure The residue is purified by column chromatography on silica gel