The following article has been requested by one of the more active Bees of this forum: D Lemaire, P Jacob III, AT Shulgin. Ring Substituted beta-methoxyphenethylamines: a New Class of Psychotomimetic Agents Active in Man. J Pharm Pharmacol 37 (1985) 575-577. It appeared to me that only the synthesis part was needed, so that will be the only part I'm presenting right now.
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2-methoxy-2-(2,5-dimethoxy-4-methylphenyl)-ethylamine - A suspension of 2,5-dimethoxy-4-methyl-beta-nitrostyrene (Ho et al 1970) (39 g) in warm methanol (300 mL) was treated with a solution of sodium methoxide (9 g sodium in 150 mL MeOH). After a few minutes (when the solution was complete and nearly colourless) aetic acid (75 mL) was added followed by water (2000 mL) and the reaction mixture was extracted with methylene chloride (3 x 200 mL). The extracts were pooled, and the solvent removed under vacuum to yield an oil which was diluted with a small amount of MeOH and held for 4 h at 0°C. They yellow crystals that formed were removed by filtration, and recrystallized from MeOH to yield 11.1 g of 2-methoxy-2-(2,5-dimethoxy-4-methylphenyl)-1-nitroethane, mp 78-79°C. This intermediate (in anhydrous THF) was added to an ice-cold solution of aluminium hydride (prepared from 96 mL of 1 M LiAlH4 in THF and 2.4 mL 100% sulphuric acid) and brought to reflux for 2h. The excess hydride was destroyed with IPA, and 15% aqueous NaOH was added untill all solids were white and filterable. The filtrate was evaporated to a residual amber oil which was dissolved in methylene chloride and extracted with dilute sulphuric acid. These aqueous extracts were pooled, made basic with 25% NaOH, and re-extracted with methylene dichloride. After removal of the solvent under vacuum, the residue was distilled (0.4 mmHg, 115-128°C) yielding 5.3 g of a colourless oil. This, in IPA (15 mL) was neutralized with concentrated HCl and treated with 70 mL diethyl ether to allow the spontaneous crystallization of the amine as the HCl salt, mp 171-172°C.
2-methoxy-2-(3,4,5-trimethoxyphenyl)-ethylamine - was prepared in a similar manner from 2-methoxy-2-(3,4,5-trimethoxyphenyl)-1-nitroethane (mp 143-144°C) and isolated as the HCl salt, mp 198.5-199.5°C.
2-methoxy-2-(3,4-methylenedioxyphenyl)-ethylamine - was prepared in a similar manner from 2-methoxy-2-(3,4-methylenedioxyphenyl)-1-nitroethane (mp 58-59°C) and isolated as the HCl salt, mp 152-153°C.
2-methoxy-2-(4-bromo-2,5-dimethoxyphenyl)-ethylamine - 4-Bromo-2,5-dimethoxy-beta-nitrostyrene was prepared from 4-bromo-2,5-dimethoxybenzaldehyde (Barfknecht & Nichols 1971) with ammonium acetate in nitromethane (yellow crystals, mp 157-158°C). This nitrostyrene was converted to 2-methoxy-2-(4-bromo-2,5-dimethoxyphenyl)-1-nitroethane (mp 119-120°C) and reduced to the amine as described above. HCl salt, mp 187-188°C.
References:
- CF Barfknecht, DE Nichols. J Med Chem 14 (1971) 370-372
- BT Ho, LW Tansey, RL Balster, R An, WM McIsaac, RT Harris. J Med Chem 13 (1970) 134-135