|[3D .mol structure]|
The above crude 3,4-dimethoxyphenol was dissolved in 200 mL EtOH, and treated with a solution of 38.1 g KOH in 300 mL hot EtOH. The clear solution of the potassium salt was a deep red color, and was promptly treated with 94.3 g allyl bromide, at a rate commensurate with the exothermic reaction. The mixture was held at reflux for 2 h. This was then added to 1 L H2O and extracted with 5x100 mL Et2O. The extracts were pooled, and removal of the solvent under vacuum gave a residue of 98 g of a black oil. This was distilled at 104-108 °C at 0.7-1.0 mm/Hg to give 59.3 g 1-allyloxy-3,4-dimethoxybenzene as a pale yellow oil with a greenish cast.
A total of 59 g of the neat 1-allyloxy-3,4-dimethoxybenzene was provided with an internal thermometer, and heated with an open flame. The color quickly became purple, then lightened to a red at 70 °C, and finally to a pale pink by 210 °C. At 240 °C an exothermic reaction set in with the temperature going up to almost 290 °C. It was held in the 270-280 °C range for several min, then allowed to return to room temperature. GC analysis showed two peaks, the second and major one being the desired 1,2,4,5-isomer. A small sample was caught by prep-GC, and it successfully seeded the crude Claissen rearrangement product. The isolated 2-allyl-4,5-dimethoxyphenol, pressed on a porous plate, had a mp of 39.5-40.5 °C which was improved to 41.5-42 °C by recrystallization from hexane.
To a solution of 9.7 g 2-allyl-4,5-dimethoxyphenol in a few mL EtOH, there was added a solution of 2.8 g KOH in 25 mL boiling EtOH followed by 5.5 g ethyl bromide. The mixture was held at reflux for 3.5 h and then poured into 200 mL H2O and extracted with 3x100 mL CH2Cl2. Pooling the extracts and removal of the solvent under vacuum gave a residue of 10.4 g of 4,5-dimethoxy-2-ethoxy-1-allylbenzene as a clear, mobile oil. It was substantially a single component by GC and was used in the following isomerization step without further purification.
A solution of 9.4 g 4,5-dimethoxy-2-ethoxy-1-allylbenzene in 10 mL EtOH was treated with 20 g flaked KOH, and heated on the steam bath. The progress of the isomerization was followed by the assay of isolates by GC. After 5 h, the reaction mixture was poured into 250 mL H2O which immediately generated a pasty solid. This was sucked free of solvent and other liquids on a sintered funnel, giving 5.5 g of trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene as an amber solid with a mp of 65-67 °C. A small analytical sample from hexane had a mp of 68 °C.
A solution of 5.0 g trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene in 27 g acetone that contained 2.2 g pyridine was magnetically stirred and cooled to 0 °C. There was then added 4.5 g tetranitromethane and, after 2 minutes stirring at this temperature, the reaction mixture was quenched with a solution of 1.5 g KOH in 26 mL H2O. The reaction mixture remained a clear deep orange color, and additional H2O was required to institute crystallization. There was the slow deposition of bright yellow crystals of 1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitro-propene which weighed, after EtOH washing and air drying to constant weight of 4.4 g. The mp was 75-76 °C.
To a gently refluxing suspension of 3.5 g LAH in 250 mL anhydrous Et2O under a He atmosphere, there was added 3.9 g 1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet apparatus with the thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise; the nitrostyrene was very soluble in Et2O. Refluxing was maintained for 2.5 h and the reaction continued to stir at room temperature for an additional 3.5 h. The excess hydride was destroyed by the cautious addition of 225 mL 1.5 N H2SO4. When the aqeous and Et2O layers were finally clear, they were separated, and 75 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x100 mL CH2Cl2. Evaporation of the solvent under vacuum produced 2.8 g of a clear, almost colorless oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. This initially generated a solid that then oiled out. After a few minutes stirring, this began to solidify again and it finally transformed into a loose fine white solid. This was recrystallized by dissolution in 50 mL warm IPA followed by dilution with 300 mL Et2O. After a few minutes, crystals of 4,5-dimethoxy-2-ethoxyamphetamine hydrochloride (EMM) formed which were removed by filtration, Et2O washed, and air dried. These weighed 2.7 g and had a mp of 171-172 °C. Anal. (C13H22ClNO3) C,H,N.
DOSAGE: greater than 50 mg.
QUALITATIVE COMMENTS: (with 50 mg) There were no effects.
EXTENSIONS AND COMMENTARY: This was the first of the ethoxy homologues of TMA-2, and it was immediately (well, within a couple of months) run up from an initial dab to 25 milligrams. This was in early 1963, and the lack of activity of EMM was keenly disappointing. This was a level at which the prototype, TMA-2, was very active, and the conclusion was that maybe any change on the molecule would result in a loss of activity. So this approach was shelved for a while, and all efforts were directed into the relocation, rather than the elongation, of the methoxy groups. A few months later, the ethoxy question was addressed again, and the discovery of MEM rekindled full interest in this ethoxy question.
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