3-methyl-1-oxidoquinolin-1-ium

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

Procedure: To a solution of tert-butyl (+/−)-4-(3-methylbutanoyl)benzoate (527 mg, 2.00 mmol) and 3-methylquinoline N-oxide (318 mg, 2.00 mmol) in dichloromethane (8.0 mL) was added diisopropylethylamine (1.31 mL, 7.50 mmol) followed by bromotripyrrolidinophosphonium hexafluorophosphate (1.18 g, 2.50 mmol). The solution was stirred at room temperature for 18 hours then diluted with sat. aq sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave tert-butyl (+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoate as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.2 Hz, 2 H), 7.63 (d, J=8.2 Hz, 1 H), 7.59 (s, 1 H), 7.54-7.48 (m, 3 H), 7.47-7.41 (m, 1 H), 7.19-7.13 (m, 1 H), 5.56 (q, J=7.4 Hz, 1 H), 4.73 (d, J=7.0 Hz, 1 H), 2.28 (s, 3 H), 1.94-1.83 (m, 1 H), 1.81-1.70 (m, 1 H), 1.70-1.60 (m, 1 H), 1.57 (s, 9 H), 1.04 (d, J=6.6 Hz, 3 H), 0.97 (d, J=6.6 Hz, 3 H). The mixture was extracted with ethyl acetate (3×20 mL) The combined organics were dried over anhydrous Na2SO4 filtered the filtrate was concentrated Purification by silica gel flash chromatography (ethyl acetate/heptane)

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

Procedure: (+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (Intermediate 24) (45 mg, 0.17 mmol) was combined with 3-methylquinoline-N-oxide (27.4 mg, 0.172 mmol, Alfa Aesar, Ward Hill, Mass., USA) and dichloromethane (2 mL). Diisopropylethylamine (0.112 mL, 0.645 mmol) was added followed by bromotripyrrolidinophosphonium hexafluorophosphate (109 mg, 0.224 mmol). The solution was stirred at room temperature for 28 h before partitioning between ethyl acetate and aq. sat. NaHCO3. The separated aqueous layer was extracted with additional ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (44.0 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 2 H) 7.56-7.62 (m, 2 H) 7.46-7.53 (m, 3 H) 7.38-7.46 (m, 1 H) 7.12-7.20 (m, 1 H) 5.33 (dd, J=9.5, 6.7 Hz, 1 H) 4.77 (d, J=6.6 Hz, 1 H) 4.34 (q, J=7.2 Hz, 2 H) 2.67 (sxt, J=8.8 Hz, 1 H) 2.30 (s, 3 H) 1.97 (ddd, J=11.1, 8.1, 3.2 Hz, 1 H) 1.74-1.85 (m, 1 H) 1.66-1.73 (m, 2 H) 1.36 (t, J=7.1 Hz, 3 H) 1.16 (s, 3 H) 1.10 (s, 3 H); MS (M+1): 403.3. before partitioning between ethyl acetate and aq. sat. NaHCO3 The separated aqueous layer was extracted with additional ethyl acetate the combined organics dried over MgSO4 Purification by silica gel flash chromatography (ethyl acetate/heptane)

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

Procedure: Intermediate 2 (22.9 g, 104 mmol) was combined with 3-methylquinoline-N-oxide (Intermediate 3, 17.3 g, 109 mmol) and dichloromethane (414 mL). Diisopropylethylamine (68.0 mL, 389 mmol) was added, followed by bromotripyrrolidinophosphonium hexafluorophosphate (61.0 g, 130 mmol). The solution was stirred at room temperature for 12 h before diluting with sat. aq NaHCO3 (400 mL). The mixture was extracted with ethyl acetate (3×400 mL). The combined organics were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave ethyl (+/−)-4-(1-((3-methylquinolin-2-yl)amino)butyl)benzoate (Intermediate 4). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.2 Hz, 2 H), 7.65-7.58 (m, 2 H), 7.56-7.48 (m, 3 H), 7.43 (t, J=7.5 Hz, 1 H), 7.16 (t, J=7.4 Hz, 1 H), 5.50 (q, J=7.2 Hz, 1 H), 4.79 (d, J=7.0 Hz, 1 H), 4.35 (q, J=7.0 Hz, 2 H), 2.30 (s, 3 H), 2.04-1.83 (m, 2 H), 1.54-1.39 (m, 2 H), 1.37 (t, J=7.1 Hz, 3 H), 0.98 (t, J=7.4 Hz, 3 H). The mixture was extracted with ethyl acetate (3×400 mL) The combined organics were dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure Purification by silica gel flash chromatography (ethyl acetate/heptane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methylquinoline (30.0 mL, 224 mmol) was dissolved in acetic acid (85 mL), and 30% aqueous hydrogen peroxide (30.4 mL) was added. The reaction was stirred at 80° C. for 16 h before cooling in an ice bath. 10% aq Na2SO3 (199 mL, 0.5 equiv) was added followed by sodium iodide (2.358 g, 0.05 equiv). This mixture was stirred for 5 min. A peroxide test strip indicated no peroxide remaining. 5 N aq NaOH was then added, keeping the internal temperature below 24° C. A dark color formed, indicating that the solution was basic (tested as pH 10). The solution was extracted with four portions of dichloromethane. The combined organics were dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 3-methylquinoline 1-oxide (Intermediate 3, 32.09 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=8.8 Hz, 1 H), 8.42 (s, 1 H), 7.77 (d, J=8.2 Hz, 1 H), 7.68 (td, J=7.8, 1.1 Hz, 1 H), 7.56-7.63 (m, 1 H), 7.52 (s, 1 H), 2.45 (s, 3 H); MS (M+1): 160.2. before cooling in an ice bath This mixture was stirred for 5 min the internal temperature below 24° C A dark color formed The solution was extracted with four portions of dichloromethane The combined organics were dried over MgSO4 filtered the filtrate was concentrated under reduced pressure Purification by silica gel flash chromatography (methanol/ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methylquinoline (30.0 mL, 224 mmol) was dissolved in acetic acid (85 mL), and 30% aqueous hydrogen peroxide (30.4 mL) was added. The reaction was stirred at 80° C. for 16 h before cooling in an ice bath. 10% aq Na2SO3 (199 mL, 0.5 equiv) was added followed by sodium iodide (2.358 g, 0.05 equiv). This mixture was stirred for 5 min. A peroxide test strip indicated no peroxide remaining. 5 N aq NaOH was then added, keeping the internal temperature below 24° C. A dark color formed, indicating that the solution was basic (tested as pH 10). The solution was extracted with four portions of dichloromethane. The combined organics were dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 3-methylquinoline 1-oxide (Intermediate 3, 32.09 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=8.8 Hz, 1 H), 8.42 (s, 1 H), 7.77 (d, J=8.2 Hz, 1 H), 7.68 (td, J=7.8, 1.1 Hz, 1 H), 7.56-7.63 (m, 1 H), 7.52 (s, 1 H), 2.45 (s, 3 H); MS (M+1): 160.2. before cooling in an ice bath This mixture was stirred for 5 min the internal temperature below 24° C A dark color formed The solution was extracted with four portions of dichloromethane The combined organics were dried over MgSO4 filtered the filtrate was concentrated under reduced pressure Purification by silica gel flash chromatography (methanol/ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methylquinoline (30.0 mL, 224 mmol) was dissolved in acetic acid (85 mL), and 30% aqueous hydrogen peroxide (30.4 mL) was added. The reaction was stirred at 80° C. for 16 h before cooling in an ice bath. 10% aq Na2SO3 (199 mL, 0.5 equiv) was added followed by sodium iodide (2.358 g, 0.05 equiv). This mixture was stirred for 5 min. A peroxide test strip indicated no peroxide remaining. 5 N aq NaOH was then added, keeping the internal temperature below 24° C. A dark color formed, indicating that the solution was basic (tested as pH 10). The solution was extracted with four portions of dichloromethane. The combined organics were dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 3-methylquinoline 1-oxide (Intermediate 3, 32.09 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=8.8 Hz, 1 H), 8.42 (s, 1 H), 7.77 (d, J=8.2 Hz, 1 H), 7.68 (td, J=7.8, 1.1 Hz, 1 H), 7.56-7.63 (m, 1 H), 7.52 (s, 1 H), 2.45 (s, 3 H); MS (M+1): 160.2. before cooling in an ice bath This mixture was stirred for 5 min the internal temperature below 24° C A dark color formed The solution was extracted with four portions of dichloromethane The combined organics were dried over MgSO4 filtered the filtrate was concentrated under reduced pressure Purification by silica gel flash chromatography (methanol/ethyl acetate)

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

Procedure: To a solution of tert-butyl(+/−)-4-(3-methylbutanoyl)benzoate (527 mg, 2.00 mmol) and 3-methylquinoline N-oxide (318 mg, 2.00 mmol) in dichloromethane (8.0 mL) was added diisopropylethylamine (1.31 mL, 7.50 mmol) followed by bromotripyrrolidinophosphonium hexafluorophosphate (1.18 g, 2.50 mmol). The solution was stirred at room temperature for 18 hours then diluted with sat. aq sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave tert-butyl(+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoate as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.54-7.48 (m, 3H), 7.47-7.41 (m, 1H), 7.19-7.13 (m, 1H), 5.56 (q, J=7.4 Hz, 1H), 4.73 (d, J=7.0 Hz, 1H), 2.28 (s, 3H), 1.94-1.83 (m, 1H), 1.81-1.70 (m, 1H), 1.70-1.60 (m, 1H), 1.57 (s, 9H), 1.04 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H). The mixture was extracted with ethyl acetate (3×20 mL) The combined organics were dried over anhydrous Na2SO4 filtered the filtrate was concentrated Purification by silica gel flash chromatography (ethyl acetate/heptane)

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

Procedure: (+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (Intermediate 24) (45 mg, 0.17 mmol) was combined with 3-methylquinoline-N-oxide (27.4 mg, 0.172 mmol, Alfa Aesar, Ward Hill, Mass., USA) and dichloromethane (2 mL). Diisopropylethylamine (0.112 mL, 0.645 mmol) was added followed by bromotripyrrolidinophosphonium hexafluorophosphate (109 mg, 0.224 mmol). The solution was stirred at room temperature for 28 h before partitioning between ethyl acetate and aq. sat. NaHCO3. The separated aqueous layer was extracted with additional ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (44.0 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 2H) 7.56-7.62 (m, 2H) 7.46-7.53 (m, 3H) 7.38-7.46 (m, 1H) 7.12-7.20 (m, 1H) 5.33 (dd, J=9.5, 6.7 Hz, 1H) 4.77 (d, J=6.6 Hz, 1H) 4.34 (q, J=7.2 Hz, 2H) 2.67 (sxt, J=8.8 Hz, 1H) 2.30 (s, 3H) 1.97 (ddd, J=11.1, 8.1, 3.2 Hz, 1H) 1.74-1.85 (m, 1H) 1.66-1.73 (m, 2H) 1.36 (t, J=7.1 Hz, 3H) 1.16 (s, 3H) 1.10 (s, 3H); MS (M+1): 403.3. before partitioning between ethyl acetate and aq. sat. NaHCO3 The separated aqueous layer was extracted with additional ethyl acetate the combined organics dried over MgSO4 Purification by silica gel flash chromatography (ethyl acetate/heptane)

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

Procedure: Intermediate 2 (22.9 g, 104 mmol) was combined with 3-methylquinoline-N-oxide (Intermediate 3, 17.3 g, 109 mmol) and dichloromethane (414 mL). Diisopropylethylamine (68.0 mL, 389 mmol) was added, followed by bromotripyrrolidinophosphonium hexafluorophosphate (61.0 g, 130 mmol). The solution was stirred at room temperature for 12 h before diluting with sat. aq NaHCO3 (400 mL). The mixture was extracted with ethyl acetate (3×400 mL). The combined organics were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave ethyl(+/−)-4-(1-((3-methylquinolin-2-yl)amino)butyl)benzoate (Intermediate 4). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.2 Hz, 2H), 7.65-7.58 (m, 2H), 7.56-7.48 (m, 3H), 7.43 (t, J=7.5 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 5.50 (q, J=7.2 Hz, 1H), 4.79 (d, J=7.0 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 2.30 (s, 3H), 2.04-1.83 (m, 2H), 1.54-1.39 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H). The mixture was extracted with ethyl acetate (3×400 mL) The combined organics were dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure Purification by silica gel flash chromatography (ethyl acetate/heptane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methylquinoline (30.0 mL, 224 mmol) was dissolved in acetic acid (85 mL), and 30% aqueous hydrogen peroxide (30.4 mL) was added. The reaction was stirred at 80° C. for 16 h before cooling in an ice bath. 10% aq Na2SO3 (199 mL, 0.5 equiv) was added followed by sodium iodide (2.358 g, 0.05 equiv). This mixture was stirred for 5 min. A peroxide test strip indicated no peroxide remaining. 5N aq NaOH was then added, keeping the internal temperature below 24° C. A dark color formed, indicating that the solution was basic (tested as pH 10). The solution was extracted with four portions of dichloromethane. The combined organics were dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 3-methylquinoline 1-oxide (Intermediate 3, 32.09 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=8.8 Hz, 1H), 8.42 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.68 (td, J=7.8, 1.1 Hz, 1H), 7.56-7.63 (m, 1H), 7.52 (s, 1H), 2.45 (s, 3H); MS (M+1): 160.2. before cooling in an ice bath This mixture was stirred for 5 min the internal temperature below 24° C A dark color formed The solution was extracted with four portions of dichloromethane The combined organics were dried over MgSO4 filtered the filtrate was concentrated under reduced pressure Purification by silica gel flash chromatography (methanol/ethyl acetate)