6-BROMO-1,1,4,4,7-PENTAMETHYL-1,2,3,4-TETRAHYDRONAPHTHALENE

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

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: 2-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene 33 (620 mg, 2.2 mmol) and the acetylpyridineamide 36a (500 mg, 2 mmol) were converted by a similar method as described above to obtain the intermediate 34 in over 80% yield. To a solution of the pyridine amide 34 (432 mg, 1 mmol) in 5 mL of THF at −78° C. was added 1.5 M DIBAL toluene solution (0.7 mL, 1.05 mmol) and the resulting yellow clear solution was warmed up to −20° C. slowly in 60 min. and then was quenched with water. Removal of solvent and chromatography of the crude mixture afforded the pyridinealdehyde 35 in 83% yield as a white solid. 1H-NMR (CDCl3) δ 1.25 (s, 2(CH3)), 1.29 (s, 2(CH3)), 1.70 (s, 2(CH2)), 1.96 (s, CH3), 5.47 (s, ═CH), 5.92 (s, ═CH), 7.10 (s, Ar—CH), 7.11 (s, Ar—CH), 7.70 (d, J=8.0 Hz, Pyr-CH), 7.88 (d, J=8.0 Hz, Pyr-CH), 8.72 (s, Pyr-CH), 10.06 (s, CHO).

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

Procedure: Following General Procedure A, 5-[(trimethylsilyl)ethynyl]thiophen-2-ylmethyl tert-butyldiphenylsilyl ether (Compound 13, 0.75 g, 1.8 mmol) and 2-bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (0.45 g, 1.67 mmol) were coupled to give the title compound.

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

Procedure: A mixture of 2-methoxy-5-formylphenylboronic acid (2.3 g, 12.80 mmol), 6-bromo-1,1,4,4,7pentamethyl1,2,3,4-tetrahydronaphthalene (3.0 g, 10.66 mmol) and potassium carbonate (5.89 g, 42.64 mmol) in 1,2-dimethoxyethane (100 mL) and water (5 mL) was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.13 mmol) was added and the mixture heated at reflux under argon for 8 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: 0% to 25% ethyl acetate in hexane) to give 3.43 g (95%) of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde. 1H NMR (500 MHz; CDCl3): δ1.26 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 3.89 (s, 3H); 7.06 (d, J=8.5 Hz, 1H); 7.09 (s, 1H); 7.16 (s, 1H); 7.71 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=8.5 Hz, J2=2.0 Hz 1H), 9.91 (s, 1H). was degassed with argon for 15 minutes the mixture heated at reflux under argon for 8 hours washed successively with water and brine dried over anhydrous magnesium sulfate filtered evaporated The residue was chromatographed on silica gel (eluent: 0% to 25% ethyl acetate in hexane)

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

Procedure: 18.31 g (100.0 mmol) of 2,5-dichloro-2,5-dimethylhexane, 17.10 g (100.0 mmol) of 2-bromotoluene and 200 ml of 1,2-dichloroethane are introduced into a three-necked flask under an argon atmosphere. 1.33 g (10.0 mmol) of aluminium chloride are added rapidly in a single portion and the reaction medium is stirred for thirty minutes at room temperature. The reaction medium is poured into water, extracted with dichloromethane and washed with water, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. After recrystallization of the residue from methanol, 17.78 g (63%) of the expected compound are collected in the form of fine white crystals with a melting point of 73° C. extracted with dichloromethane washed with water the organic phase is separated out after settling dried over magnesium sulphate evaporated After recrystallization of the residue from methanol, 17.78 g (63%) of the expected compound are collected in the form of fine white crystals with a melting point of 73° C.

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

Procedure: 30 ml of 2-bromotoluene and 14 g (0.11 mol) of AlCl3 were introduced into a three-necked flask, cooling was carried out to 0° C. and a solution of 50 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane in 100 ml of 2-bromotoluene was added dropwise, and the reaction mixture was permitted to heat to room temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was separated by settling, washed with an aqueous sodium bicarbonate solution and evaporated. The product crystallized on stirring in methanol. After filtration, 56.9 g (75%) of 2-bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene, with a melting-point of 92°-93° C., were recovered. cooling was carried out to 0° C. extracted with dichloromethane The organic phase was separated washed with an aqueous sodium bicarbonate solution evaporated The product crystallized After filtration, 56.9 g (75%) of 2-bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene a melting-point of 92°-93° C. were recovered

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

Procedure: 30 ml of 2-bromotoluene and 14 g (0.11 mol) of AlCl3 were introduced into a three-necked flask, cooling was carried out to 0° C. and a solution of 50 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane in 100 ml of 2-bromotoluene was added dropwise, and the reaction mixture was permitted to heat to room temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was separated by settling, washed with an aqueous sodium bicarbonate solution and evaporated. The product crystallized on stirring in methanol. After filtration, 56.9 g (75%) of 2-bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene, with a melting-point of 92°-93° C., were recovered. cooling was carried out to 0° C. extracted with dichloromethane The organic phase was separated washed with an aqueous sodium bicarbonate solution evaporated The product crystallized After filtration, 56.9 g (75%) of 2-bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene a melting-point of 92°-93° C. were recovered

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

Procedure: The mixture of 6-bromo-7-methyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.20 g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2′-azobisisobutyronitrile (0.3 g, 1.8 mmol) and CCl4 (120 mL) was heated at reflux for 16 hours. The mixture was concentrated under reduced pressure to about 50 mL. The reaction was then filtered, and the solid was washed with Et2O (20 mL). The combined organic solution was then concentrated under vacuum to generate crude product. Crude 91.2 was generated as a brown oil and used directly in the next step without further purification. was heated at reflux for 16 hours The mixture was concentrated under reduced pressure to about 50 mL The reaction was then filtered the solid was washed with Et2O (20 mL) The combined organic solution was then concentrated under vacuum used directly in the next step without further purification

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

Procedure: The mixture of 6-bromo-7-methyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.20 g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2′-azobisisobutyronitrile (0.3 g, 1.8 mmol) and CCl4 (120 mL) was heated at reflux for 16 hours. The mixture was concentrated under reduced pressure to about 50 mL. The reaction was then filtered, and the solid was washed with Et2O (20 mL). The combined organic solution was then concentrated under vacuum to generate crude product. Crude 91.2 was generated as a brown oil and used directly in the next step without further purification. was heated at reflux for 16 hours The mixture was concentrated under reduced pressure to about 50 mL The reaction was then filtered the solid was washed with Et2O (20 mL) The combined organic solution was then concentrated under vacuum used directly in the next step without further purification

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

Procedure: 2-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene 33 (620 mg, 2.2 mmol) and the acetylpyridineamide 36a (500 mg, 2 mmol) were converted by a similar method as described above to obtain the intermediate 34 in over 80% yield. To a solution of the pyridine amide 34 (432 mg, 1 mmol) in 5 mL of THF at −78° C. was added 1.5 M DIBAL toluene solution (0.7 mL, 1.05 mmol) and the resulting yellow clear solution was warmed up to −20° C. slowly in 60 min. and then was quenched with water. Removal of solvent and chromatography of the crude mixture afforded the pyridinealdehyde 35 in 83% yield as a white solid. 1H-NMR (CDCl3) δ1.25 (s,2(CH3)), 1.29 (s,2(CH3)), 1.70 (s,2(CH2)), 1.96 (s,CH3), 5.47 (s,═CH), 5.92 (s,═CH), 7.10 (s,Ar—CH), 7.11 (s,Ar—CH), 7.70 (d,J=8.0 Hz,Pyr—CH), 7.88 (d,J=8.0 Hz,Pyr—CH), 8.72 (s, Pyr—CH), 10.06 (s,CHO).