| 83% |
With lithium diisopropyl amide In tetrahydrofuran at -78℃; |
|
| 81% |
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate at 45 - 60℃; for 5h; |
|
| 81% |
Stage #1: 3,4-dimethoxyphenylacetonitrile With sodium amide In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: isopropyl bromide In tetrahydrofuran at 60℃; for 1h; |
1.1 Example 1; Synthesis of 2-(3',4'-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile; (1) Synthesis of 2-(3' ,4' -dimethoxyphenyl)-3-methylbutyronitrile
17.70g(100mmol) of 3,4-dimethoxyacetonitrile was dissolved in 100ml of anhydrous tetrahydrofuran, and 4.68g(120mmol) of sodium amide was added thereto in fractional amounts while being stirred and cooled with ice. After being stirred for 30 minutes, 14.76g(120mmol) of 2-bromopropane was dropwise added to the mixture and then stirred with heating at 60°C for 1 hour. After disappearance of the starting material was checked, a small amount of methanol was added to the mixture to decompose excess sodium amide, and the solvent was evaporated out under a vacuum. The residue was extracted with ethyl acetate and then washed with water until it became neutral. The organic layer was filtrated through IPS filter paper, and then the solvent was evaporated out. The residue was purified by silica gel column chromatography, to give 17.8g(81mmol, 81%) of 2-(3',4'-dimethoxyphenyl)-3-methylbtyronitrile. 1H-NMR (d, CDCl3):1.05 (6H, d, J=6.6Hz), 2.00-2.15 (1H, m), 3.59 (1H, d, J=6.6Hz), 3.89 (3H, s), 3.90 (3H, s), 6.76-6.86 (3H, m). |
| 81% |
Stage #1: 3,4-dimethoxyphenylacetonitrile With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; Inert atmosphere;
Stage #2: isopropyl bromide In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere; |
|
| 69% |
Stage #1: 3,4-dimethoxyphenylacetonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: isopropyl bromide In N,N-dimethyl-formamide at 20℃; for 15h; |
|
| 69% |
Stage #1: 3,4-dimethoxyphenylacetonitrile With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 0.5h; Inert atmosphere;
Stage #2: isopropyl bromide In tetrahydrofuran; hexane for 1h; Inert atmosphere; |
1.4 General procedure for the synthesis of (3,4-dimethoxyphenyl)-3-methylbutanenitrile(5)3
General procedure: To a stirred solution of 2-(3,4-dimethoxyphenyl)acetonitrile 4 (5g, 0.028 mol) in dry THF (80ml) at 0°C under a nitrogen atmosphere, 2.7 N n-BuLi in hexanes (11.4 ml, 0.03 mol) was introduced using a syringe. The reaction mixture was stirred at room temperature for 0.5 h after which reaction was again cooled to 0°C and 2-bromopropane (5.30 g, 0.042 mol) dissolved in dry THF (10 ml) was added to the reaction mixture. After completion of reaction (TLC, 1h), the reaction was quenched with saturated aqueous solution of NH4Cl (30 ml) at 0°C and extracted with ethyl acetate (3×30 ml). The extracts were dried over anhydrous magnesium sulphate and evaporated under reduced pressure. Purification by column chromatography afford product 5 was obtained as a white solid (4.3g, 69%). Rf (25% EtOAc-Hexane) 0.4; m.p. 50-52°C; 1H NMR (400MHz, CDCl3) δ 6.87 (dd, J = 8.0 and 2.0 Hz, 1H),6.86 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.59 (d, J = 6.4Hz, 1H), 2.10 (m, 1H), 1.05 (d, J = 6.8 Hz, 6H). |
| 57% |
With sodium hydroxide |
6 Isopropyl Veratryl Cyanide STR18
EXAMPLE 6 Isopropyl Veratryl Cyanide STR18 27.83 g of 50% NaOH solution, 5.84 g (145.95 mmol) of NaOH pellets and veratryl cyanide (8.9 g, 50.24 mmol) were placed in a 100 ml round-bottom flask. 2.05 g (9.02 mmol) of TEBAC was added and the mixture was stirred until homogenous while heating to 50° C. with a heating mantle. Isopropyl bromide (5.5 ml, 58.58 mmol) was added dropwise over 0.5 h at 50° C.+-5° to the above mixture which was stirred at 50° C.+-5° for 24 hours. The reactin mixture was partitioned between water and toluene and transferred to a separatory funnel. The aqueous layer was drawn off and extracted with ether. The toluene and ether fractions were combined and washed twice with water and dried over Na2 SO4. The mixture was filtered and solvent removed by rotary evaporation. The combined fractions, following evaporation and recrystallization from 70 percent methanol/water yielded 6.32 g of the title compound (57% yield). NMR (CDCl3): δ (ppm), 0.71-1.3(m, 6H), 1.9-2.3(m, 1H), 3.59(d, J=6 Hz, 1H), 3.87(s, 6H), 6.75-7.0(m, 3H). |
| 57% |
With sodium hydroxide |
6 Isopropyl Veratryl Cyanide STR18
EXAMPLE 6 Isopropyl Veratryl Cyanide STR18 27.83 g of 50% NaOH solution, 5.84 g (145.95 mmol) of NaOH pellets and veratryl cyanide (8.9 g, 50.24 mmol) were placed in a 100 ml round-bottom flask. 2.05 g (9.02 mmol) of TEBAC was added and the mixture was stirred until homogenous while heating to 50° C. with a heating mantle. Isopropyl bromide (5.5 ml, 58.58 mmol) was added dropwise over 0.5 h at 50° C.+-5° to the above mixture which was stirred at 50° C.+-5° for 24 hours. The reaction mixture was partitioned between water and toluene and transferred to a separatory funnel. The aqueous layer was drawn off and extracted with ether. The toluene and ether fractions were combined and washed twice with water and dried over Na2 SO4. The mixture was filtered and solvent removed by rotary evaporation. The combined fractions, following evaporation and recrystallization from 70 percent methanol/water yielded 6.32 g of the title compound (57% yield). NMR(CDCl3): δ(ppm), 0.71-1.3(m, 6H), 1.9-2.3(m, 1H), 3.59(d, J=6 Hz, 1H), 3.87(s, 6H), 6.75-7.0(m, 3H). |
| 47% |
Stage #1: 3,4-dimethoxyphenylacetonitrile With sodium hydride In N,N-dimethyl-formamide for 5h;
Stage #2: isopropyl bromide In N,N-dimethyl-formamide at 20℃; |
|
|
With sodium hydride 1.) DMF, RT, 5 h, 2.) RT, overnight; Yield given. Multistep reaction; |
|
|
With sodium amide 1.) THF, 0.5 h, room temp. 2.) THF, 4 h, room temp.; Yield given. Multistep reaction; |
|
|
Stage #1: 3,4-dimethoxyphenylacetonitrile With sodium hexamethyldisilazane In tetrahydrofuran at -30℃; for 0.166667h;
Stage #2: isopropyl bromide In tetrahydrofuran at 22℃; for 18h; Reflux; |
1.A.1
Method A Step 1 : To a solution of 9.99 g (56.4 mmol) of (3,4-Dimethoxyphenyl)acetonitrile in 141 mL of tetrahydrofuran (THF) at -30 ºC, was slowly added 56.4 mL (56.4 mmol) of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF). The mixture was stirred at -30 ºC for 10 minutes and 10.6 mL (113.0 mmol) of 2-bromopropane was added. The mixture was heated to reflux for 2 hours (h) then left at 22 ºC for about 16 h. A saturated aqueous solution OfNH4Cl was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil. |
|
Stage #1: 3,4-dimethoxyphenylacetonitrile With sodium hexamethyldisilazane In tetrahydrofuran at -30℃; for 0.166667h;
Stage #2: isopropyl bromide In tetrahydrofuran at -30℃; for 18h; Reflux; |
1.I.A.1
Method A, Step 1: To a solution of 9.99 g (56.4 mmol) of (3,4- Dimethoxyphenyl)acetonitrile in 141 mL of tetrahydrofuran (THF) at -30 °C, was slowly added 56.4 mL (56.4 mmol) of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF). The mixture was stirred at -30 °C for 10 minutes and 0.6 mL ( 1 13.0 mmol) of 2-bromopropane was added. The mixture was heated to reflux for 2 hours (h) then left at 22 °C for about 16 h. A saturated aqueous solution of NH4C1 was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2S04), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil. |
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