4-[tert-butyl(dimethyl)silyl]oxybenzaldehyde

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:

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

Procedure: To a stirred solution of 10.4 grams (0.085 mole) of 4-hydroxybenzaldehyde in 36.5 mL of dimethylformamide was added 15.4 grams (0.102 mole) of (1,1-dimethylethyl)dimethylsilyl chloride and then 14.8 grams (0.218 mole) of imidazole. Upon completion of addition the reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for three hours. The reaction mixture was poured into a separatory funnel, and water was added. The mixture was extracted with diethyl ether. The ether layer was washed in turn with one portion of aqueous 10% sodium hydroxide, one portion of aqueous 10% hydrochloric acid, one portion of water, and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether and was stirred for 20 minutes with decolorizing carbon and neutral alumina. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to yield 19.4 grams of 4-[(1,1-dimethylethyl)dimethylsilyloxy]benzaldehyde. The nmr spectrum was consistent with the proposed structure. Upon completion of addition the reaction mixture The reaction mixture was poured into a separatory funnel The mixture was extracted with diethyl ether The ether layer was washed in turn with one portion of aqueous 10% sodium hydroxide, one portion of aqueous 10% hydrochloric acid, one portion of water, and one portion of an aqueous solution saturated with sodium chloride The organic layer was dried with sodium sulfate filtered The filtrate was concentrated under reduced pressure to a residue The residue was dissolved in diethyl ether was stirred for 20 minutes with decolorizing carbon and neutral alumina The mixture was filtered through diatomaceous earth the filtrate was concentrated under reduced pressure

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

Procedure: When the substituent R1 was methylsulfonyloxy or trifluoromethylsulfonyloxy, a number of additional synthesis steps were needed to obtain the hydrazone (I). The intermediate 4-hydroxybenzaldehyde was reacted with (1,1-dimethylethyl)dimethylsilyl chloride and imidazole in dimethylformamide to afford 4-[(I,1-dimethylethyl)dimethylsilyloxy]benzaldehyde. With the hydroxy substituent protected, the benzaldehyde was reacted by methods described above with the 5-bromo-2,2-difluoro-1,3-benzodioxole to afford the corresponding alcohol which was in turn converted to the ketone. Reaction of the resulting [[4-(1,1-dimethylethyl)dimethylsilyloxy]phenyl](2,2-difluoro-1,3-benzodioxol-5-yl) ketone with tetrabutylammonium fluoride in tetrahydrofuran cleaved the (1,1-dimethylethyl)dimethylsilyl substituent to yield (4-hydroxyphenyl)(2,2-difluoro-1,3-benzodiox-5-yl) ketone. The 4-hydroxy intermediate was reacted with methanesulfonyl chloride or trifluoromethanesulfonic anhydride by methods described above to yield the corresponding (4-methylsulfonyloxyphenyl)- or (4-trifluoromethylsulfonyloxyphenyl)(2,2-difluoro-1,3-benzodioxol-5yl) ketone. The ketone was then converted to the hydrazone (I) as described above. Example 4 illustrates this route. a number of additional synthesis steps

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

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

Procedure: (3) 4-Hydroxybenzaldehyde (20 g, 0.164 mol) was dissolved in DMF (60 ml) and stirred at RT as imidazole (22.3 g, 0.328 mol) and tert-butyldimethylsilyl chloride (32.1 g, 0.213 mol) were added. The reaction mixture was stirred for 16 h. The solution was diluted with EtOAc, washed with water, brine, then dried (MgSO4) and concentrated in-vacuo to afford 24 g of crude 4-(tert-butyldimethylsilanyloxy)benzaldehyde. were added washed with water, brine dried (MgSO4) concentrated in-vacuo

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

Procedure: (3) 4-Hydroxybenzaldehyde (20 g, 0.164 mol) was dissolved in DMF (60 ml) and stirred at RT as imidazole (22.3 g, 0.328 mol) and tert-butyldimethylsilyl chloride (32.1 g, 0.213 mol) were added. The reaction mixture was stirred for 16 h. The solution was diluted with EtOAc, washed with water, brine, then dried (MgSO4) and concentrated in-vacuo to afford 24 g of crude 4-(tert-butyldimethylsilanyloxy)benzaldehyde. were added washed with water, brine dried (MgSO4) concentrated in-vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 0.65 g (1.5 mmol) 4-(6-Iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid and 0.77 g (6.0 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.5 g (2.0 mmol) tert-Butyl-dimethyl-(4-prop-2-ynyl-phenoxy)-silane is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Purify by flash chromatography (EtOAc/hexane eluent) to cool to room temperature the mixture stirred 30 minutes Filter dry under reduced pressure Purify by flash chromatography (EtOAc/hexane eluent)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 0.65 g (1.5 mmol) 4-(6-Iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid and 0.77 g (6.0 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.5 g (2.0 mmol) tert-Butyl-dimethyl-(4-prop-2-ynyl-phenoxy)-silane is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Purify by flash chromatography (EtOAc/hexane eluent) to cool to room temperature the mixture stirred 30 minutes Filter dry under reduced pressure Purify by flash chromatography (EtOAc/hexane eluent)

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

Procedure: Triphenylphosphine (3.44 g, 13.1 mmol) was dissolved in dichloromethane (25 ml) in nitrogen atmosphere, carbon tetrabromide (2.18 g, 6.56 mmol) was added little by little under cooling with ice, and triethylamine (4.4 ml, 26.2 mmol) was dropwise added, followed by stirring for 10 minutes. Then, under cooling with ice, a dichloromethane solution (20 ml) of 4-(tert-butyldimethylsilyloxy)benzaldehyde (10.0 g, 73.4 mmol) prepared in 1) was dropwise added, followed by stirring for 1 hour. Silica gel (50 g) was added to the reaction solution, the reaction solution was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1, containing 0.1% v/v triethylamine) to give 1,1-dibromo-2-(tert-butyldimethylsilyloxyphenyl)ethylene (2.77 g, 81%) as a pale yellow oily substance. was added little by little was dropwise added Then, under cooling with ice was dropwise added by stirring for 1 hour Silica gel (50 g) was added to the reaction solution the reaction solution was concentrated under reduced pressure to dryness the resulting product was purified by silica gel column chromatography (hexane ethyl acetate=20:1, containing 0.1% v/v triethylamine)