4-bromo-N,N-bis(trimethylsilyl)aniline

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The general procedure described by J. R. Pratt et al, in the publication entitled "Organosilicon Compounds. XX. Synthesis of Aromatic Diamines via Trimethylsilyl-Protecting Aniline Intermediates," J. Org. Chem, Vol. 40, No. 8, 1975, pages 1090 to 1094, was followed with some modifications as described herein To a tetrahydrofuran (500 ml) solution of p-bromoaniline (106.0g, 0.62 mol) cooled to 0° C. there was added over a period of one hour n-butyllithium (825 ml, 1.3 mol). The reaction mixture turned brown but remained homogeneous The reaction mixture was refluxed for 2 hours to complete the metallation, cooled to ice temperature, and then chlorotrimethylsilane (180 ml, 1 4 mol) was added so as to not let the reaction temperature exceed 15° C.. The reaction mixture was allowed to warm to room temperature and was refluxed overnight Filtration was accomplished by the Schlenk technique, and a gas chromatogram (GC) was taken. The solvent was evaporated and the residue was distilled to give three fractions Fraction 1 - b.p. 25°-89° C./0.5 torr, 22.0g (this forerun was discarded); Fraction 2 - b.p. 90°-108° C./0 5 torr, 32g, 95% pure by was refluxed for 2 hours cooled to ice temperature exceed 15° C. to warm to room temperature was refluxed overnight Filtration The solvent was evaporated the residue was distilled to give three fractions Fraction 1 - b.p. 25°-89° C./0.5 torr, 22.0g (this forerun

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-(4-Bromophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (7 g, 22.12 mmol) in tetrahydrofuran (100 mL) was treated with a solution of n-BuLi (1M, 22 mL) at −78° C. The reaction mixture was stirred an additional hour at −78° C. and then treated with a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.97 g, 19.91 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature. The reaction was quenched by addition of saturated ammonium chloride solution (100 mL) and then was extracted with ethyl acetate. The combined organics were washed with water, brine, dried with magnesium sulfate, filtered and concentrated. The crude tert-butyl 4-(4-(bis(trimethylsilyl)amino)phenyl)-4-hydroxypiperidine-1-carboxylate was treated with a solution of tetrabutylammonium fluoride (1M THF, 40 mL) at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate, filtered and concentrated. Purification by normal phase chromatography provided the title compound. The reaction mixture was stirred at −78° C. for 30 minutes warmed to room temperature The reaction was quenched by addition of saturated ammonium chloride solution (100 mL) was extracted with ethyl acetate The combined organics were washed with water, brine dried with magnesium sulfate filtered concentrated The crude tert-butyl 4-(4-(bis(trimethylsilyl)amino)phenyl)-4-hydroxypiperidine-1-carboxylate was treated with a solution of tetrabutylammonium fluoride (1M THF, 40 mL) at room temperature for 1 hour The reaction mixture was diluted with water extracted with ethyl acetate The organics were washed with water and brine dried with magnesium sulfate filtered concentrated Purification by normal phase chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 2.2 g magnesium turnings (83.5 mmol) in 15 ml tetrahydrofuran were added 0.1 mL 1,2-dibromethane to start the Grignard reaction followed by slow addition of 13.0 g 2-(4-bromphenyl)-1,1,1,3,3,3-hexamethyldisilazane (41 mmol) in 70 mL tetrahydrofuran over a period of 20 minutes at room temperature with subsequent stirring for further 30 minutes. The resulting mixture was added dropwise at −78° C. to a solution of 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (5.6 g) in 70 mL tetrahydrofuran. The reaction mixture was slowly warmed to room temperature. Sulfuric acid (2 mL, 1 M) was added and the solvent was removed under reduced pressure. The residue was added carefully to 20 mL of 0.5 M sulfuric acid solution and the desired product started to precipitate and was extracted with ethyl acetate. Acidification of the water phase and extraction with ethyl acetate was continued until pH˜4-5 (at least three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and the solvent was subsequently evaporated under reduced pressure. Purification of the raw material by column chromatography with ethyl acetate/hexane 1:1 and subsequently 100% ethyl acetate resulted in the desired product. the Grignard reaction the solvent was removed under reduced pressure The residue was added carefully to 20 mL of 0.5 M sulfuric acid solution to precipitate was extracted with ethyl acetate Acidification of the water phase and extraction with ethyl acetate The combined organic phases were washed with brine dried over magnesium sulfate filtered the solvent was subsequently evaporated under reduced pressure Purification of the raw material by column chromatography with ethyl acetate/hexane 1:1 and subsequently 100% ethyl acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Aminophenylboronic acid by Grignard reaction on N,N-bis(trimethylsilyl)-4-bromoaniline 10.0 g (58.1 mmol) of 4-bromoaniline were dissolved in 200 ml of triethylamine and admixed with 25 ml (130 mmol) of trimethylsilyl trifluoromethanesulfonate. The mixture was heated to reflux for 8 h. The reaction mixture was concentrated and the crude product distilled under high vacuum. 11.9 g (37.8 mmol, 65%) of N,N-bis(trimethylsilyl)-4-bromoaniline were obtained. The mixture was heated to reflux for 8 h The reaction mixture was concentrated the crude product distilled under high vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-N,N-bis(trimethylsilyl)aniline (1.64 mL, 5.82 mmol) was dissolved in tetrahydrofuran (9 mL), and a 1.6 N n-butyllithium-hexane solution (3.23 mL, 5.33 mmol) was added at −78° C. A solution of tert-butyl {4-[methoxy(methyl)amino]-4-oxobutyl}methylcarbamate (1.26 g, 4.85 mmol) in tetrahydrofuran (9 mL) was further added at −78° C. The temperature was increased to room temperature, water (2 mL) was added, then 1 N tetrabutylammonium fluoride (10 mL, 10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added, then the mixture was extracted with dichloromethane and ethyl acetate, and the organic layers were combined and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvents, hexane:ethyl acetate=4:1→2:1, v/v) to give the title compound (1.32 g; yield, 71%). a 1.6 N n-butyllithium-hexane solution (3.23 mL, 5.33 mmol) was added at −78° C the mixture was extracted with dichloromethane and ethyl acetate dried with anhydrous sodium sulfate The solvent was evaporated under reduced pressure the resulting residue was purified by silica gel column chromatography ( elution solvents, hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-N,N-bis(trimethylsilyl)aniline (1.64 mL, 5.82 mmol) was dissolved in tetrahydrofuran (9 mL), and a 1.6 N n-butyllithium-hexane solution (3.23 mL, 5.33 mmol) was added at −78° C. A solution of tert-butyl {4-[methoxy(methyl)amino]-4-oxobutyl}methylcarbamate (1.26 g, 4.85 mmol) in tetrahydrofuran (9 mL) was further added at −78° C. The temperature was increased to room temperature, water (2 mL) was added, then 1 N tetrabutylammonium fluoride (10 mL, 10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added, then the mixture was extracted with dichloromethane and ethyl acetate, and the organic layers were combined and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvents, hexane:ethyl acetate=4:1→2:1, v/v) to give the title compound (1.32 g; yield, 71%). a 1.6 N n-butyllithium-hexane solution (3.23 mL, 5.33 mmol) was added at −78° C the mixture was extracted with dichloromethane and ethyl acetate dried with anhydrous sodium sulfate The solvent was evaporated under reduced pressure the resulting residue was purified by silica gel column chromatography ( elution solvents, hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: n-Butyl lithium (1 mL, 1.6 M in hexane, 1.6 mmol) was added dropwise to a solution of 2-(4-bromo-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (0.7 g, 2.20 mmol) in dry diethyl ether (10 mL) and stirred at room temperature for 15 min then cooled in an ice bath. A solution of 4′,6′-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyridinyl-4-one (0.3 g, 1.47 mmol) in dry tetrahydrofuran (15 mL) was added and the resulting mixture heated at 50° C. for 2.5 h. The reaction mixture was brought to room temperature and stirred overnight, then cooled to 0° C. and quenched into ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the crude compound, to which was added 2N HCl and the resulting mixture was stirred overnight at room temperature. The pH of the solution was adjusted to pH 10 with dilute sodium hydroxide then the mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a viscous red oil which was purified by washing with pentane (5×10 mL) to afford 4-(4-amino-phenyl)-4′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-ol (0.25 g, 57%). then cooled in an ice bath the resulting mixture heated at 50° C. for 2.5 h was brought to room temperature stirred overnight cooled to 0° C. quenched into ammonium chloride solution The mixture was extracted with ethyl acetate the organic phase was washed with water, brine dried over anhydrous sodium sulfate filtered concentrated in vacuo to yield the crude compound the resulting mixture was stirred overnight at room temperature the mixture was extracted with chloroform The organic phase was dried over anhydrous sodium sulfate filtered concentrated to dryness to give a viscous red oil which was purified by washing with pentane (5×10 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: n-Butyl lithium (1 mL, 1.6 M in hexane, 1.6 mmol) was added dropwise to a solution of 2-(4-bromo-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (0.7 g, 2.20 mmol) in dry diethyl ether (10 mL) and stirred at room temperature for 15 min then cooled in an ice bath. A solution of 4′,6′-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyridinyl-4-one (0.3 g, 1.47 mmol) in dry tetrahydrofuran (15 mL) was added and the resulting mixture heated at 50° C. for 2.5 h. The reaction mixture was brought to room temperature and stirred overnight, then cooled to 0° C. and quenched into ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the crude compound, to which was added 2N HCl and the resulting mixture was stirred overnight at room temperature. The pH of the solution was adjusted to pH 10 with dilute sodium hydroxide then the mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a viscous red oil which was purified by washing with pentane (5×10 mL) to afford 4-(4-amino-phenyl)-4′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-ol (0.25 g, 57%). then cooled in an ice bath the resulting mixture heated at 50° C. for 2.5 h was brought to room temperature stirred overnight cooled to 0° C. quenched into ammonium chloride solution The mixture was extracted with ethyl acetate the organic phase was washed with water, brine dried over anhydrous sodium sulfate filtered concentrated in vacuo to yield the crude compound the resulting mixture was stirred overnight at room temperature the mixture was extracted with chloroform The organic phase was dried over anhydrous sodium sulfate filtered concentrated to dryness to give a viscous red oil which was purified by washing with pentane (5×10 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: n-Butyl lithium (1 mL, 1.6 M in hexane, 1.6 mmol) was added dropwise to a solution of 2-(4-bromo-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (0.7 g, 2.20 mmol) in dry diethyl ether (10 mL) and stirred at room temperature for 15 min then cooled in an ice bath. A solution of 4′,6′-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyridinyl-4-one (0.3 g, 1.47 mmol) in dry tetrahydrofuran (15 mL) was added and the resulting mixture heated at 50° C. for 2.5 h. The reaction mixture was brought to room temperature and stirred overnight, then cooled to 0° C. and quenched into ammonium chloride solution. The organics were extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield the crude compound, to which was added 2N HCl and the resulting mixture was stirred overnight at room temperature. The pH of the solution was adjusted to pH 10 with dilute sodium hydroxide and the organics extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a red viscous oil which was purified by washing with pentane (5×10 mL) to afford 4-(4-amino-phenyl)-4′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-ol (0.25 g, 57.3%). then cooled in an ice bath the resulting mixture heated at 50° C. for 2.5 h was brought to room temperature stirred overnight cooled to 0° C. quenched into ammonium chloride solution The organics were extracted with ethyl acetate washed with water, brine dried over anhydrous sodium sulfate filtered evaporated in vacuo to yield the crude compound the resulting mixture was stirred overnight at room temperature the organics extracted with chloroform The extract was dried over anhydrous sodium sulfate filtered evaporated to dryness to give a red viscous oil which was purified by washing with pentane (5×10 mL)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of n-butyllithium in hexanes (1.65 M, 5.14 mL) was added dropwise to a solution of 4-bromo-N,N-bis(trimethylsilyl)aniline (2.52 mL) in THF (14 mL) at −78° C. The resulting mixture was stirred for 1 h at −78° C. before a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide in THF (2.8 mL) was added dropwise over the course of 15 minutes at −78° C. The reaction mixture was stirred for an additional 1 h at −78° C. then allowed to warm to room temperature. After being stirred for 18 h at room temperature, the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue was diluted with diisopropylether and extracted with 1 M citric acid solution. The aqueous extracts were combined and basified with sodium bicarbonate solid to pH>7. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by recrystallization with ethyl acetate and column chromatography (30-100% ethyl acetate in hexanes) gave the product (1.37 g, 90%). 400 M Hz 1H-NMR (DMSO-d6) δ: 7.07 (d, J=8.7 Hz, 2H), 5.56 (d, J=8.7 Hz, 2H), 6.05 (s, 1H), 5.10 (brs, 2H), 4.94 (dd, J=6.0 and 2.3 Hz, 2H), 4.83 (d, J=6.0 Hz, 1H), 4.60 (d, J=6.0 Hz, 1H), 1.08 (s, 9H). was added dropwise over the course of 15 minutes at −78° C to warm to room temperature After being stirred for 18 h at room temperature the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution The aqueous layer was extracted with ethyl acetate The combined organic layer was washed with saturated sodium bicarbonate solution and brine dried over anhydrous sodium sulfate The dried solution was filtered the filtrate was concentrated to dryness The residue was diluted with diisopropylether extracted with 1 M citric acid solution The basic aqueous layer was extracted with ethyl acetate the organic layer was washed with brine The organics were dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by recrystallization with ethyl acetate and column chromatography (30-100% ethyl acetate in hexanes)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of n-butyllithium in hexanes (1.65 M, 5.2 mL) was added dropwise to a solution of 4-bromo-N,N-bis(trimethylsilyl)aniline (2.55 mL) in THF (14 mL) at −78° C. The resulting mixture was stirred for 1.5 h at −78° C. before a solution of N-isopropylidene-2-methylpropane-2-sulfinamide in THF (2.8 mL) was added dropwise at −78° C. The reaction mixture was stirred for an additional 1 h at −78° C. then allowed to warm to room temperature. After being stirred for 18 h at room temperature, the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue was diluted with diisopropylether and extracted with 1 M citric acid solution. The aqueous extracts were combined and basified with sodium bicarbonate solid to pH>7. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate in hexanes) gave the product (173 mg, 12%). 400 M Hz 1H-NMR (CDCl3) δ: 7.26 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.7 Hz, 2H), 3.66 (brs, 1H), 3.31 (s, 1H), 1.67 (s, 3H), 1.64 (s, 3H), 1.20 (s, 9H). was added dropwise at −78° C to warm to room temperature After being stirred for 18 h at room temperature the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution The aqueous layer was extracted with ethyl acetate The combined organic layer was washed with saturated sodium bicarbonate solution and brine dried over anhydrous sodium sulfate The dried solution was filtered the filtrate was concentrated to dryness The residue was diluted with diisopropylether extracted with 1 M citric acid solution The basic aqueous layer was extracted with ethyl acetate the organic layer was washed with brine The organics were dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by column chromatography (50-100% ethyl acetate in hexanes)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The general procedure described by J. R. Pratt et al, in the publication entitled "Organosilicon Compounds. XX. Synthesis of Aromatic Diamines via Trimethylsilyl-Protecting Aniline Intermediates," J. Org. Chem, Vol. 40, No. 8, 1975, pages 1090 to 1094, was followed with some modifications as described herein To a tetrahydrofuran (500 ml) solution of p-bromoaniline (106.0g, 0.62 mol) cooled to 0° C. there was added over a period of one hour n-butyllithium (825 ml, 1.3 mol). The reaction mixture turned brown but remained homogeneous The reaction mixture was refluxed for 2 hours to complete the metallation, cooled to ice temperature, and then chlorotrimethylsilane (180 ml, 1 4 mol) was added so as to not let the reaction temperature exceed 15° C.. The reaction mixture was allowed to warm to room temperature and was refluxed overnight Filtration was accomplished by the Schlenk technique, and a gas chromatogram (GC) was taken. The solvent was evaporated and the residue was distilled to give three fractions Fraction 1 - b.p. 25°-89° C./0.5 torr, 22.0g (this forerun was discarded); Fraction 2 - b.p. 90°-108° C./0 5 torr, 32g, 95% pure by was refluxed for 2 hours cooled to ice temperature exceed 15° C. to warm to room temperature was refluxed overnight Filtration The solvent was evaporated the residue was distilled to give three fractions Fraction 1 - b.p. 25°-89° C./0.5 torr, 22.0g (this forerun