GC_MS
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04-01-03 07:19
No 423031
      New, convenient route to erbstatin
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A new, convenient route to erbstatin and N-acetyl-1,2-didehydrodopamine

H Ishibashi e.a.
Chem Pharm Bull 37(8) (1989) 2214-2216

as req'd by Rh

Abstract - Erbstatin dimethyl ether (12) was synthesized by Friedel-Crafts reaction of chloro(methyl- or phenyl thio)acetonitrile (5a or 5b) with hydroquinone dimethyl ether, followed by reduction to the amine, formylation, and oxidative desulfenylation. By using a similar sequence of reactions, N-acetyl-1,2-didehydrodopamine dimethyl ether (13) was prepared from veratrole and 5a,b.

2,5-dimethoxyphenyl(methylthio)acetonitrile (6a) - TiCl4 (0.81 mL, 7.4 mmol) was added to a stirred solution of [3] (p-dimethoxybenzene, 1.02 g, 7.4 mmol) and [5a] (chloro(methylthio)acetonitrile, 0.9 g, 7.4 mmol) in DCM (15 mL at 0C, and stirring was continued at the same temperature for 1 h. The reaction was quenched by the addition of water, then the mixture was extracted with DCM and dried (MgSO4). The solvent was evaporated off and the residue was chromatographed on silica gel (hexane-EtOAc, 7:1) to give [6a] (1.17 g, 71%), mp 42.5-43C (from petroleum ether).

2,5-dimethoxyphenyl(phenylthio)acetonitrile (6b) - TiCl4 (0.5 mL, 3.6 mmol) was added to a stirred solution of [3] (0.6 g, 4.3 mmol) and [5b] (0.67 g, 3.6 mmol) in DCM (10 mL) at 0C, and the mixture was stirred at room temperature for 1.5 h. Work-up gave [6b] (0.81 g, 78%), mp 61.0-61.5C (from petroleum ether).

3,4-dimethoxyphenyl(methylthio)acetonitrile (7a) - SnCl4 (770 mg, 2.96 mmol) was added to a solution of [4] (o-dimethoxybenzene, 410 mg, 2.96 mmol) and [5a] (360 mg, 2.96 mmol) in DCM (50 mL) at 0C and the mixture was stirred at the same temperature for 1 h. Work-up gave [7a] (377 mg, 57%) as an oil.

3,4-dimethoxyphenyl(phenylthio)acetonitrile (7b) - In a manner similar to that described for 7a, the chloride [5b] (chloro(phenylthio)acetonitrile, 200 mg, 1.09 mmol) was allowed to react with [4] (151 mg, 1.09 mmol) to give [7b] (100 mg, 32%), mp 84C (from petroleum ether).

N-[2-(2,5-dimethoxyphenyl)-2-(methylthio)ethyl]formamide (10a) - AlCl3 (120 mg, 0.9 mmol) was added to a stirred suspension of LAH (34 mg, 0.9 mmol) in dry Et2O (2.3 mL) at 0C and stirring was continued at the same temperature for 5 min. A solution of [6a] (200 mg, 0.9 mmol) in dry diethyl ether (1.8 mL) was added to the above solution of alane at 0C, and the mixture was stirred at the same temperature for 1 h. Water (10 mL) was added to the reaction mixture and the whole was made alkaline with 10% NaOH solution, then extracted with Et2O. The extract was dried (NaOH) and the solvent was evaporated off to give the amine [8a] (214 mg, quantitative), which was used in the next step without further purification. This amine was dissolved in ethyl formate (1 mL) and the mixture was heated under reflux for 2 h. Excess ethyl formate was evaporated off and the residue was chromatographed on silica gel (hexane-ethyl acetate, 1:1) to give [10a] (192 mg, 84% from [6a]), mp 64-65C (from hexane-ethyl acetate). [8a = 2-(2,5-dimethoxyphenyl)-2-methylthio)ethylamine]

(E)-N-[2-(2,5-dimethoxyphenyl)ethenyl]formamide (12) - A solution of NaIO4 (161 mg, 0.75 mmol) in water (3.4 mL) was added dropwise to a solution of [10a] (192 mg, 0.75 mmol) in MeOH (2.3 mL), and the mixture was stirred at room temperature for 15 h. Water (10 mL) was added to the reaction mixture and the whole was extracted with DCM. The extract was dried (MgSO4) and the solvent evaporated off to give N-[2-(2,5-dimethoxyphenyl)-3-(methylsulfinyl)ethyl]formamide (202 mg, quantitative). This sulfoxide, without further purification, was dissolved in chlorobenzene (5 mL) and the mixture was heated under reflux for 4 h. The solvent was removed in vacuo and the residue was chromatographed on silica gel (benzene-EtOAc 5:1) to give [12] (105 mg, 63% from [10a]). mp 85C (from EtOAc).

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