10-bromodec-1-ene

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

Procedure: Methyl 4-(dec-9-enyloxy)benzoate (3). Synthesized as described above for compound 1. Quantities: K2CO3 (18.2 g, 0.13 mol), methyl-4-hydroxy-benzoate (6.30 g, 41.4 mmol), 10-bromo-1-decene (8.6 mL, 42.8 mmol). Yield 12.0 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.23-1.51 (10 H, m, CH2), 1.77 (2 H, m, O—CH2—CH2), 2.03 (2 H, m, CH2═CH—CH2), 3.85 (3 H, s, OCH3), 3.95 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.79 (1 H, m, CH2═CH), 6.87 (2 H, d, 3J=9.0 Hz, Ar—H), 7.98 (2 H, d, 3J=9.0 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.9, 29.0, 29.1, 29.3, 29.4, 51.7, 68.1, 114.0, 114.2, 122.3, 131.5, 139.0, 162.9, 166.7. Synthesized

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

Procedure: Hydroquinone (37.65 g, 342 mmol) and dec-9-enyl bromide (25 g, 114 mmol) were dissolved in ethanol (150 ml) with warming under a nitrogen atmosphere. The solution was heated under reflux and a solution of potassium hydroxide (6.83 g, 121 mmol) in water (20 ml) was added dropwise over 1 h. The resulting suspension was heated under reflux (3 H) then poured on to water (500 ml) and extracted with ether (3×100 ml). The combined extracts were dried (MgSO4), evaporated in vacuo and the residue extracted with heptane (300 ml). On cooling, it afforded a first crop of the phenol (10.31 g). The remaining material was chromatographed (flash grade silica gel, petroleum ether 40-60° C./diethyl ether 3/2). 2 was isolated as white plates (Rf=0.57). Combined yield=15.61 g (55%). Mp=54° C. with warming under a nitrogen atmosphere The solution was heated under reflux The resulting suspension was heated under reflux (3 H) extracted with ether (3×100 ml) The combined extracts were dried (MgSO4) evaporated in vacuo the residue extracted with heptane (300 ml) On cooling

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

Procedure: Methyl 4-(dec-9-enyloxy)benzoate (3). Synthesized as described above for compound 1. Quantities: K2CO3 (18.2 g, 0.13 mol), methyl-4-hydroxy-benzoate (6.30 g, 41.4 mmol), 10-bromo-1-decene (8.6 mL, 42.8 mmol). Yield 12.0 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.23-1.51 (10 H, m, CH2), 1.77 (2 H, m, O—CH2—CH2), 2.03 (2 H, m, CH2═CH—CH2), 3.85 (3 H, s, OCH3), 3.95 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.79 (1 H, m, CH2═CH), 6.87 (2 H, d, 3J=9.0 Hz, Ar—H), 7.98 (2 H, d, 3J=9.0 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.9, 29.0, 29.1, 29.3, 29.4, 51.7, 68.1, 114.0, 114.2, 122.3, 131.5, 139.0, 162.9, 166.7. Synthesized

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

Procedure: Methyl 4-(dec-9-enyloxy)benzoate (3). Synthesized as described above for compound 1. Quantities: K2CO3 (18.2 g, 0.13 mol), methyl-4-hydroxy-benzoate (6.30 g, 41.4 mmol), 10-bromo-1-decene (8.6 mL, 42.8 mmol). Yield 12.0 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.23-1.51 (10 H, m, CH2), 1.77 (2 H, m, O—CH2—CH2), 2.03 (2 H, m, CH2═CH—CH2), 3.85 (3 H, s, OCH3), 3.95 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.79 (1 H, m, CH2═CH), 6.87 (2 H, d, 3J=9.0 Hz, Ar—H), 7.98 (2 H, d, 3J=9.0 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.9, 29.0, 29.1, 29.3, 29.4, 51.7, 68.1, 114.0, 114.2, 122.3, 131.5, 139.0, 162.9, 166.7. Synthesized

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 12.80 g (0.10 M) of 4-hydroxybenzyl alcohol (compound (8)) was dissolved in ethanol 190 mL, and 4.0 g (0.10 M) of sodium hydroxide was added thereto. The resulting mixture was heated to 65° C. After heating, 24.14 g (0.11 M) of 10-bromo-1-decene (compound (22)) prepared in Synthetic example 1-1 was added dropwise, and the resulting mixture was aged at a mixture temperature of 76° C. for 6 hours. Next, the generated salt was removed by decantation, and the reaction solution was concentrated. After concentration, the resulting solution was diluted with 350 mL of diethyl ether and washed twice with 100 mL of deionized water. After washing, the organic layer was concentrated to produce crude crystals. The crude crystals were recrystallized twice from 25 mL of hexane. The recrystallized crystals were washed with hexane and dried. Thereby, 16.88 g of 9-decenoxybenzyl alcohol (compound (23)) was produced (yield: 64.3%). After heating was added dropwise Next, the generated salt was removed by decantation the reaction solution was concentrated After concentration the resulting solution was diluted with 350 mL of diethyl ether washed twice with 100 mL of deionized water After washing the organic layer was concentrated to produce crude crystals The crude crystals were recrystallized twice from 25 mL of hexane The recrystallized crystals were washed with hexane dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 12.80 g (0.10 M) of 4-hydroxybenzyl alcohol (compound (6)) was dissolved in 190 mL of ethanol, and 4.0 g (0.10 M) of sodium hydroxide was added thereto. The resulting mixture was heated to 65° C. After heating, 24.14 g (0.11 M) of 10-bromo-1-decene (compound (22)) prepared in Synthetic example 1-1 was added dropwise, and the resulting mixture was aged at a mixture temperature of 760° C. for 6 hours. Next, the generated salt was removed by decantation, and the reaction solution was concentrated. After concentration, the resulting solution was diluted with 350 mL of diethyl ether and washed twice with 100 mL of deionized water. After washing, the organic layer was concentrated to produce crude crystals. The crude crystals were recrystallized twice from 25 mL of hexane. The recrystallized crystals were washed with hexane and dried. Thereby, 16.88 g of 9-decenoxybenzyl alcohol (compound (23)) was produced (yield: 64.3%). After heating was added dropwise Next, the generated salt was removed by decantation the reaction solution was concentrated After concentration the resulting solution was diluted with 350 mL of diethyl ether washed twice with 100 mL of deionized water After washing the organic layer was concentrated to produce crude crystals The crude crystals were recrystallized twice from 25 mL of hexane The recrystallized crystals were washed with hexane dried

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

Procedure: To a stirred solution of (S)-nicotine (0.52 g, 3.2 mmol) in AcOH (10 ml) was added 10-bromo-dec-1-ene (1.66 g, 7.58 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.74 g (61%) of (S)-1-dec-9-enyl-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide (NDNB-9e) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.65 (1H, d, J=5.1 Hz), 9.14 (1H, s), 8.41(1H, d, J=8.1 Hz), 8.09 (1H, dd, J=8.1, 5.1 Hz), 5.75 (1H, m), 4.88–5.10 (4H, m), 3.54 (1H, t, J=8.1 Hz), 3.23 (1H, m), 2.45 (2H, m), 2.22 (3H, s), 1.70–2.10 (6H, m), 1.61 (1H, m), 1.10–1.40 (10H, m); 13C NMR (75 MHz, CDCl3) δ 146.46, 144.39, 143.74, 142.97, 139.07, 128.50, 114.33, 67.17, 62.25, 56.92, 40.74, 36.11, 33.93, 32.35, 29.42, 29.24, 29.15, 29.03, 26.35, 23.41. The mixture was heated at reflux for 3 days AcOH was evaporated the residue was dissolved in CHCl3 The mixture was washed with saturated aqueous NaHCO3, water and brine successively dried Evaporation of the solvent

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of dec-9-en-1-ol (1.22 g, 7.82 mmol) in DMF (18 mL) was added triphenylphosphine (2.30 g, 8.77 mmol). The solution was cooled to 0° C. and NBS (1.52 g, 8.54 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.8 mL). The solution was diluted with ether (80 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 10-bromo-dec-1-ene (1.38 g, 81%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.80 (1H, m), 4.94 (2H, m), 3.38 (2H, t, J=6.9 Hz), 2.02 (2H, m), 1.83 (2H, m), 1.20–1.55 (10H, m); 13C NMR (75 MHz, CDCl3) δ 139.17, 114.30, 34.29, 34.02, 33.06, 29.53, 29.25, 29.12, 28.96, 28.40. the reaction was quenched with methanol (0.8 mL) The solution was diluted with ether (80 mL) washed with water, saturated aqueous NaHCO3 and brine successively The organic layer was dried concentrated The residue was purified by flash chromatography on silica gel eluting with hexane

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 12.80 g (0.10 M) of 4-hydroxybenzyl alcohol (compound (8)) was dissolved in ethanol 190 mL, and 4.0 g (0.10 M) of sodium hydroxide was added thereto. The resulting mixture was heated to 65° C. After heating, 24.14 g (0.11 M) of 10-bromo-1-decene (compound (22)) prepared in Synthetic example 1-1 was added dropwise, and the resulting mixture was aged at a mixture temperature of 76° C. for 6 hours. Next, the generated salt was removed by decantation, and the reaction solution was concentrated. After concentration, the resulting solution was diluted with 350 mL of diethyl ether and washed twice with 100 mL of deionized water. After washing, the organic layer was concentrated to produce crude crystals. The crude crystals were recrystallized twice from 25 mL of hexane. The recrystallized crystals were washed with hexane and dried. Thereby, 16.88 g of 9-decenoxybenzyl alcohol (compound (23)) was produced (yield: 64.3%). After heating was added dropwise Next, the generated salt was removed by decantation the reaction solution was concentrated After concentration the resulting solution was diluted with 350 mL of diethyl ether washed twice with 100 mL of deionized water After washing the organic layer was concentrated to produce crude crystals The crude crystals were recrystallized twice from 25 mL of hexane The recrystallized crystals were washed with hexane dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 12.80 g (0.10 M) of 4-hydroxybenzyl alcohol (compound (6)) was dissolved in 190 mL of ethanol, and 4.0 g (0.10 M) of sodium hydroxide was added thereto. The resulting mixture was heated to 65° C. After heating, 24.14 g (0.11 M) of 10-bromo-1-decene (compound (22)) prepared in Synthetic example 1-1 was added dropwise, and the resulting mixture was aged at a mixture temperature of 760° C. for 6 hours. Next, the generated salt was removed by decantation, and the reaction solution was concentrated. After concentration, the resulting solution was diluted with 350 mL of diethyl ether and washed twice with 100 mL of deionized water. After washing, the organic layer was concentrated to produce crude crystals. The crude crystals were recrystallized twice from 25 mL of hexane. The recrystallized crystals were washed with hexane and dried. Thereby, 16.88 g of 9-decenoxybenzyl alcohol (compound (23)) was produced (yield: 64.3%). After heating was added dropwise Next, the generated salt was removed by decantation the reaction solution was concentrated After concentration the resulting solution was diluted with 350 mL of diethyl ether washed twice with 100 mL of deionized water After washing the organic layer was concentrated to produce crude crystals The crude crystals were recrystallized twice from 25 mL of hexane The recrystallized crystals were washed with hexane dried

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

Procedure: To a stirred solution of (S)-nicotine (0.52 g, 3.2 mmol) in AcOH (10 ml) was added 10-bromo-dec-1-ene (1.66 g, 7.58 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.74 g (61%) of (S)-1-dec-9-enyl-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide (NDNB-9e) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.65 (1H, d, J=5.1 Hz), 9.14 (1H, s), 8.41(1H, d, J=8.1 Hz), 8.09 (1H, dd, J=8.1, 5.1 Hz), 5.75 (1H, m), 4.88–5.10 (4H, m), 3.54 (1H, t, J=8.1 Hz), 3.23 (1H, m), 2.45 (2H, m), 2.22 (3H, s), 1.70–2.10 (6H, m), 1.61 (1H, m), 1.10–1.40 (10H, m); 13C NMR (75 MHz, CDCl3) δ 146.46, 144.39, 143.74, 142.97, 139.07, 128.50, 114.33, 67.17, 62.25, 56.92, 40.74, 36.11, 33.93, 32.35, 29.42, 29.24, 29.15, 29.03, 26.35, 23.41. The mixture was heated at reflux for 3 days AcOH was evaporated the residue was dissolved in CHCl3 The mixture was washed with saturated aqueous NaHCO3, water and brine successively dried Evaporation of the solvent

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of dec-9-en-1-ol (1.22 g, 7.82 mmol) in DMF (18 mL) was added triphenylphosphine (2.30 g, 8.77 mmol). The solution was cooled to 0° C. and NBS (1.52 g, 8.54 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.8 mL). The solution was diluted with ether (80 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 10-bromo-dec-1-ene (1.38 g, 81%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.80 (1H, m), 4.94 (2H, m), 3.38 (2H, t, J=6.9 Hz), 2.02 (2H, m), 1.83 (2H, m), 1.20–1.55 (10H, m); 13C NMR (75 MHz, CDCl3) δ 139.17, 114.30, 34.29, 34.02, 33.06, 29.53, 29.25, 29.12, 28.96, 28.40. the reaction was quenched with methanol (0.8 mL) The solution was diluted with ether (80 mL) washed with water, saturated aqueous NaHCO3 and brine successively The organic layer was dried concentrated The residue was purified by flash chromatography on silica gel eluting with hexane