5-amino-2-tert-butylphenol

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

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

Procedure: To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd—C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 166.1 m/z (MH+). The reaction mixture was refluxed for additional 30 min filtered through a plug of Celite The filtrate was concentrated to dryness purified by column chromatography (20-30% EtOAc-Hexane)

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

Procedure: A solution of 3,4-dihydro-2H-1,4-benzothiazine-2-carboxylic acid (80 mg, 0.41 mmol) and 5-amino-2-tert-butyl-phenol (67 mg, 0.41 mmol) in dichloromethane (3 mL) was treated with propane phosphonic acid anhydride (610 μL of 50% w/w in ethyl acetate, 1.02 mmol) and pyridine (99 μL, 1.2 mmol) and stirred for 30 min at room temperature. The reaction was washed with water, dried over Na2SO4, and concentrated in vacuo. HPLC purification (20-99% CH3CN/0.05% TFA) provided N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (51 mg, 36% yield). LC/MS m/z 343.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.38 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.93 (dd, J=1.1, 7.7 Hz, 1H), 6.88-6.83 (m, 2H), 6.58 (d, J=7.5 Hz, 1H), 6.51-6.47 (t, J=7.5, 1H), 3.92 (dd, J=3.0, 8.0 Hz, 1H), 3.72 (dd, J=3.0, 12.3 Hz, 1H), 3.53 (dd, J=8.1, 12.3 Hz, 1H), 1.31 (s, 9H). The reaction was washed with water dried over Na2SO4 concentrated in vacuo HPLC purification (20-99% CH3CN/0.05% TFA)

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

Procedure: To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd—C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 166.1 m/z (MH+). The reaction mixture was refluxed for additional 30 min filtered through a plug of Celite The filtrate was concentrated to dryness purified by column chromatography (20-30% EtOAc-Hexane)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-amino-2-tert-butyl-phenol (300 mg, 1.82 mmol), isobenzofuran-1,3-dione (283 mg, 1.91 mmol), triethylamine (759 μL, 5.45 mmol) in toluene (5.0 mL) was stirred at 110° C. for 13 h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL), and washed with 10% aqueous NaHCO3(10 mL) and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(4-tert-butyl-3-hydroxyphenyl)isoindoline-1,3-dione (450 mg, 84% yield) as a light brown solid which was used for next reaction without further purification. 1H NMR (400.0 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.96 (m, 2H), 7.90 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.79 (dd, J=2.1, 8.3 Hz, 1H), 1.38 (s, 9H). The reaction mixture was cooled washed with 10% aqueous NaHCO3(10 mL) and water The organic layer was dried over Na2SO4 filtered concentrated in vacuo

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: A solution of 3,4-dihydro-2H-1,4-benzothiazine-2-carboxylic acid (80 mg, 0.41 mmol) and 5-amino-2-tert-butyl-phenol (67 mg, 0.41 mmol) in dichloromethane (3 mL) was treated with propane phosphonic acid anhydride (610 μl, of 50% w/w in ethyl acetate, 1.02 mmol) and pyridine (99 μL, 1.2 mmol) and stirred for 30 min at room temperature. The reaction was washed with water, dried over Na2SO4, and concentrated in vacuo. HPLC purification (20-99% CH3CN/0.05% TFA) provided N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (51 mg, 36% yield). LC/MS m/z 343.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.38 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.93 (dd, J=1.1, 7.7 Hz, 1H), 6.88-6.83 (m, 2H), 6.58 (d, J=7.5 Hz, 1H), 6.51-6.47 (t, J=7.5, 1H), 3.92 (dd, J=3.0, 8.0 Hz, 1H), 3.72 (dd, J=3.0, 12.3 Hz, 1H), 3.53 (dd, J=8.1, 12.3 Hz, 1H), 1.31 (s, 9H). The reaction was washed with water dried over Na2SO4 concentrated in vacuo HPLC purification (20-99% CH3CN/0.05% TFA)

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

Procedure: To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd—C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 166.1 m/z (MH+). The reaction mixture was refluxed for additional 30 min filtered through a plug of Celite The filtrate was concentrated to dryness purified by column chromatography (20-30% EtOAc-Hexane)

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

Procedure: To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd—C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 166.1 m/z (MH+). The reaction mixture was refluxed for additional 30 min filtered through a plug of Celite The filtrate was concentrated to dryness purified by column chromatography (20-30% EtOAc-Hexane)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-amino-2-tert-butyl-phenol (300 mg, 1.82 mmol), isobenzofuran-1,3-dione (283 mg, 1.91 mmol), triethylamine (759 μL, 5.45 mmol) in toluene (5.0 mL) was stirred at 110° C. for 13 h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL), and washed with 10% aqueous NaHCO3(10 mL) and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(4-tert-butyl-3-hydroxyphenyl)isoindoline-1,3-dione (450 mg, 84% yield) as a light brown solid which was used for next reaction without further purification. 1H NMR (400.0 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.96 (m, 2H), 7.90 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.79 (dd, J=2.1, 8.3 Hz, 1H), 1.38 (s, 9H). The reaction mixture was cooled washed with 10% aqueous NaHCO3(10 mL) and water The organic layer was dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd—C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc—Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 166.1 m/z (MH+). The reaction mixture was refluxed for additional 30 min filtered through a plug of Celite The filtrate was concentrated to dryness purified by column chromatography (20-30% EtOAc—Hexane)