N-(3-bromopropyl)-N-methylaniline

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

Procedure: To a solution of 23a (0.20 g, 0.88 mmol) and phenol (0.75 g, 0.79 mmol) in DMF (5.0 mL) was added K2CO3 (0.24 g, 1.75 mmol). The reaction was then stirred at 80° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 23 as a colorless oil (0.12 g, 0.49 mmol, 56.7% yield). MS (ESI, positive) m/z calcd. for C16H20NO [M+H]+: 242.15, found: 241.93. 1H NMR (CDCl3, 400 MHz) δ7.22-7.33 (m, 4H), 6.92-6.99 (m, 3H), 6.69-6.77 (m, 3H), 4.04 (t, J=6.0 Hz, 2H), 3.58 (t, J=6.8 Hz, 2H), 2.97 (s, 3H), 2.06-2.12 (m, 2H). The reaction mixture was concentrated purified by column chromatography

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

Procedure: N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 23a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H). The solvent was evaporated the residue was purified by silica gel column chromatography

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

Procedure: A mixture of compound 9a (500 mg, 2.7 mmol), K2CO3 (740 mg, 5.4 mmol), and KI (445 mg, 2.7 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (589 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hours. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mLs water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound 9 (170 mg, 0.66 mmol, 24% yield) as a white solid. HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.14886, found: 258.14888. 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.27 (m, 2H), 6.94-6.70 (m, 7H), 5.94 (broad s, 1H), 4.00 (t, J=5.9 Hz, 2H), 3.60 (t, J=7.0 Hz, 2H), 3.01 (s, 3H), 2.09 (p, J=6.2 Hz, 2H). was added to the mixture under argon The reaction mixture was heated After cooling to room temperature the solvent was evaporated the residue was quenched with 100 mLs water The mixture was then extracted with CH2Cl2 the combined organic layer was washed with water brine and was dried over Na2SO4 The solvent was evaporated the residue was purified by silica gel column chromatography with hexane/EtOAc

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

Procedure: A mixture of compound 9a (500 mg, 2.7 mmol), K2CO3 (740 mg, 5.4 mmol), and KI (445 mg, 2.7 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (589 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hours. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mLs water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound 9 (170 mg, 0.66 mmol, 24% yield) as a white solid. HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.14886, found: 258.14888. 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.27 (m, 2H), 6.94-6.70 (m, 7H), 5.94 (broad s, 1H), 4.00 (t, J=5.9 Hz, 2H), 3.60 (t, J=7.0 Hz, 2H), 3.01 (s, 3H), 2.09 (p, J=6.2 Hz, 2H). was added to the mixture under argon The reaction mixture was heated After cooling to room temperature the solvent was evaporated the residue was quenched with 100 mLs water The mixture was then extracted with CH2Cl2 the combined organic layer was washed with water brine and was dried over Na2SO4 The solvent was evaporated the residue was purified by silica gel column chromatography with hexane/EtOAc

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

Procedure: N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 9a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H). The solvent was evaporated the residue was purified by silica gel column chromatography

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-methyl-3-methoxyaniline (1.0 g, 7.294 mmol) was dissolved in anhydrous DMF (20 mL), to which 1,3-dibromopropane (1.48 mL, 14.589 mmol), K2CO3 (3.018 g, 21.884 mmol) and 18-crown-6 (0.24 g, 1.458 mmol) were added at room temperature, and reaction mixture stirred at 35° C. for 24 hours. The remaining procedure was followed as described for compound 14 to obtain compound 15. Yield: 0.760 g (75%). 1H NMR (500 MHz, CDCl3): δ 2.16 (tt, 2H, J=6.5, 13.5 Hz, Hc), 2.98 (s, 3H, NCH3, Ha), 3.46-3.54 (m, 4H, Hb and Hd), 3.83 (s, 3H, OMe), 6.32-6.66 (m, 2H, Hg and Hi), 6.38-6.42 (m, 1H, Ha), 7.16-7.21 (m, 1H, Hf); 13C NMR (125 MHz, CDCl3): δ 29.90 (Cc), 31.34 (Cd), 38.65 (Ca), 50.79 (Cb), 55.02 (OCH3), 98.77 (Ci), 101.26 (Ce), 105.31 (Cg), 129.81 (Cf), 150.32 (Cj), 160.72 (Ch). EI-MS: [M+H]+ C11H7BrNO calcd 258.05, obsd 258.04. were added at room temperature reaction mixture

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-methylaniline (300 mg, 2.80 mmol), 1,3-dibromopropane (0.568 mL, 5.6 mmol), K2CO3 (1.16 g, 8.40 mmol) and 18-crown-6 (49.8 mg, 0.30 mmol) were dissolved in 20 mL of anhydrous DMF and mixture stirred for 24 hours at 35° C. The reaction mixture was filtered and washed with DCM, and filtrate dissolved in DCM (100 mL) before extraction in water. The organic layer was washed with water (2×50 ml), brine (50 ml), and dried over Na2SO4, followed by evaporation of solvents under reduced pressure and the residue purified by silica gel column chromatography (EtOAc:n-hexane 1:20 to 1:10) to obtain compound 14. Yield: 0.260 g (74%). 1H NMR (500 MHz, CDCl3): δ 2.16 (tt, 2H, J=6.5 and 13.5 Hz, Hc), 2.99 (s, 3H, NCH3, Ha), 3.46-3.55 (m, 4H, Hb and Hd), 6.71-6.79 (m, 2H, He and Hg), 7.24-7.29 (m, 2H, Hf). EI-MS: [M+H]+ C10H15BrN calcd 228.03, obsd 228.04. The reaction mixture was filtered washed with DCM, and filtrate dissolved in DCM (100 mL) before extraction in water The organic layer was washed with water (2×50 ml), brine (50 ml) dried over Na2SO4 followed by evaporation of solvents under reduced pressure the residue purified by silica gel column chromatography (EtOAc:n-hexane 1:20 to 1:10)

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

Procedure: To a solution of 23a (0.20 g, 0.88 mmol) and phenol (0.75 g, 0.79 mmol) in DMF (5.0 mL) was added K2CO3 (0.24 g, 1.75 mmol). The reaction was then stirred at 80° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 23 as a colorless oil (0.12 g, 0.49 mmol, 56.7% yield). MS (ESI, positive) m/z calcd. for C16H20NO [M+H]+: 242.15, found: 241.93. 1H NMR (CDCl3, 400 MHz) δ7.22-7.33 (m, 4H), 6.92-6.99 (m, 3H), 6.69-6.77 (m, 3H), 4.04 (t, J=6.0 Hz, 2H), 3.58 (t, J=6.8 Hz, 2H), 2.97 (s, 3H), 2.06-2.12 (m, 2H). The reaction mixture was concentrated purified by column chromatography

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

Procedure: N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 23a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H). The solvent was evaporated the residue was purified by silica gel column chromatography

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

Procedure: A mixture of compound 9a (500 mg, 2.7 mmol), K2CO3 (740 mg, 5.4 mmol), and KI (445 mg, 2.7 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (589 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hours. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mLs water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound 9 (170 mg, 0.66 mmol, 24% yield) as a white solid. HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.14886, found: 258.14888. 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.27 (m, 2H), 6.94-6.70 (m, 7H), 5.94 (broad s, 1H), 4.00 (t, J=5.9 Hz, 2H), 3.60 (t, J=7.0 Hz, 2H), 3.01 (s, 3H), 2.09 (p, J=6.2 Hz, 2H). was added to the mixture under argon The reaction mixture was heated After cooling to room temperature the solvent was evaporated the residue was quenched with 100 mLs water The mixture was then extracted with CH2Cl2 the combined organic layer was washed with water brine and was dried over Na2SO4 The solvent was evaporated the residue was purified by silica gel column chromatography with hexane/EtOAc

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

Procedure: N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 9a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H). The solvent was evaporated the residue was purified by silica gel column chromatography

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-methyl-3-methoxyaniline (1.0 g, 7.294 mmol) was dissolved in anhydrous DMF (20 mL), to which 1,3-dibromopropane (1.48 mL, 14.589 mmol), K2CO3 (3.018 g, 21.884 mmol) and 18-crown-6 (0.24 g, 1.458 mmol) were added at room temperature, and reaction mixture stirred at 35° C. for 24 hours. The remaining procedure was followed as described for compound 14 to obtain compound 15. Yield: 0.760 g (75%). 1H NMR (500 MHz, CDCl3): δ 2.16 (tt, 2H, J=6.5, 13.5 Hz, Hc), 2.98 (s, 3H, NCH3, Ha), 3.46-3.54 (m, 4H, Hb and Hd), 3.83 (s, 3H, OMe), 6.32-6.66 (m, 2H, Hg and Hi), 6.38-6.42 (m, 1H, Ha), 7.16-7.21 (m, 1H, Hf); 13C NMR (125 MHz, CDCl3): δ 29.90 (Cc), 31.34 (Cd), 38.65 (Ca), 50.79 (Cb), 55.02 (OCH3), 98.77 (Ci), 101.26 (Ce), 105.31 (Cg), 129.81 (Cf), 150.32 (Cj), 160.72 (Ch). EI-MS: [M+H]+ C11H7BrNO calcd 258.05, obsd 258.04. were added at room temperature reaction mixture