TMA-4 synthesis

This is classical synthesis method of TMA-4 was criated with help of experts from BB forum.

To a solution of 68 g 2,4-dimethoxybenzaldehyde (1) in 250 mL glacial acetic acid that had been warmed to 25 °C and well stirred, there was added, dropwise, 86 g of a 40% peracetic acid solution (in acetic acid). The reaction was exothermic, and the rate of addition was dictated by the need to maintain the internal temperature within a few degrees of 28 °C. External cooling was used as needed. The addition took 1 h, and when the reaction had clearly been completed (no further temperature rise) the entire reaction mixture was added to 3 volumes of H₂O. The excess acid was neutralized with solid K₂CO₃ (283 g were required). This was extracted with 3×100 mL Et₂O, the extracts pooled, and stripped of solvent under vacuum to give 66 g of crude 2,4-dimethoxyphenyl formate (2).

This (2) was suspended in 125 mL 10% NaOH, and the mixture heated on the steam bath for 1.5 h. On cooling, the reaction mixture set to a heavy black solid. This was removed by filtration, washed with H2O, and dissolved in 250 mL CH₂Cl₂. The organic phase was washed with dilute HCl, and then with aqueous NaHCO3, which removed much of the color. Removal of the solvent under vacuum gave a deep red goo that was dissolved in 200 mL anhydrous Et2O and filtered through paper. The resulting clear solution was stripped of solvent, yielding 34.4 g of 2,4-dimethoxyphenol (3) as a red oil that crystallized on cooling. A 1.0 g sample in 4 mL pyridine was treated with 0.9 g benzoyl chloride and heated on the steam bath for a few min. The addition of H2O gave a pasty solid that was isolated by pressing on a porous plate. The yield of crude 2,4-dimethoxyphenyl benzoate was 1.1 g. Recrystallization from cyclohexane gave a white product with a mp of 86-87 °C. A second recrystallization from cyclohexane raised this to 89-90 °C, which is in agreement with the literature value.

To a solution of 31.0 g crude 2,4-dimethoxyphenol (3) in 60 mL absolute EtOH there was added a solution of 11.25 g KOH in 90 mL boiling EtOH. To this, there was then added 28 g allyl bromide which produced an immediate white precipitate of KBr. The mixture was held at reflux for 2 h and then quenched in 3 volumes of H₂O. Sufficient 10% NaOH was added to make the reaction strongly basic, and this was extracted with 3×100 mL Et₂O. Removal of the solvent under vacuum gave 33.2 g of 1-allyloxy-2,4-dimethoxybenzene (4), shown to be free of phenol starting material by GC analysis. Analyses must be carried out at low column temperatures (below 180 °C) on an ethylene glycol succinate substrate. If a silicone column is used, even at these low temperatures, there is considerable Claisen rearrangement taking place on the column. Low temperature distillation can be used for further purification (107-110 °C at 1.0 mm/Hg).

A 31.0 g sample of 1-allyloxy-2,4-dimethoxybenzene (4) was gently heated with a soft flame until the internal temperature reached 215 °C. An exothermic reaction took place, with the temperature rising to 270 °C. The residue left in the flask was largely 2-allyl-4,6-dimethoxyphenol (5), that contained perhaps 10% of 2,4-dimethoxyphenol which resulted from the pyrolytic loss of the allyl group. This mixture was methylated without further purification.

To a solution of 30 g impure 2-allyl-4,6-dimethoxyphenol (5) in a little absolute EtOH there was added a boiling solution of 8.7 g KOH in 75 mL absolute EtOH followed, immediately, by 22.4 g methyl iodide in a little EtOH. The mixture was held at reflux for 3 h, then added to 4 volumes of H2O. Sufficient 10% NaOH was added to make the mixture strongly basic, and this was extracted with 4×100 mL Et₂O. Removal of the solvent gave 28 g of 1-allyl-2,3,5-trimethoxybenzene (6). GC analysis showed some 10% of the expected impurity, 1,2,4-trimethoxybenzene.

To a solution of 26 g crude 1-allyl-2,3,5-trimethoxybenzene (6) in an equal weight of absolute EtOH there was added 52 g of flaked KOH. The mixture was heated on the steam bath overnight, and then quenched with much H₂O. This was extracted with 3×100 mL Et₂O which, on removal under vacuum gave 24.6 g of product. This contained, by GC analysis, largely cis- and trans-1-propenyl-2,3,5-trimethoxybenzene and the expected 1,2,4-trimethoxybenzene. This mixture was dissolved in an equal volume of pentane, and cooled in dry ice. Quick filtration gave 9.2 g of an amber solid which had a melting point of 39-41.5 °C. Recrystallization from hexane provided pure trans-1-propenyl-2,3,5-trimethoxybenzene (7) with a m.p. of 44-45 °C. Evaporation of the original pentane mother liquor provided an impure sample of mixed cis- and trans- isomers.

A solution of 7.2 g trans-1-propenyl-2,3,5-trimethoxybenzene (7) in 41 g dry acetone was treated with 3.3 g dry pyridine and, with good stirring, cooled to 0 °C. There was then added 6.9 g of tetranitromethane over the course of 1 min, and the reaction mixture was allowed to stir for an additional 2 min. The reaction mixture was then quenched with a solution of 2.2 g KOH in 40 mL H2O. After the addition of more H2O, the product was extracted with 3×50 mL CH₂Cl₂. Removal of the solvent under vacuum yielded 7.0 g of an impure product which would not crystallize. This was distilled under vacuum to give four fractions, all of which crystallized spontaneously. Cuts #1 and #2 (b.p. 100-120 °C and 120-130 °C at 2 mm/Hg) were combined, weighed 0.8 g, and after crystallization from hexane yielded white crystals with a mp of 62-63 °C. The NMR spectrum (in CDCl3) was in agreement with 2,3,5-trimethoxybenzaldehyde, and the literature mp has been reported as being 62-63 °C. Cuts #3 and #4 (b.p. 130-170 °C and 170-175 °C at 2 mm/Hg with the bulk coming over in the latter fraction) were combined to give 3.0 g of yellow crystals. These were triturated under a little cold MeOH, and then recrystallized from MeOH to give 1.15 g of yellow crystals of 2-nitro-1-(2,3,5-trimethoxyphenyl)propene (8), with a m.p. of 87-88 °C. The forerun of the distillation contained considerable unreacted trans-1-propenyl-2,3,5-trimethoxybenzene and some 1,2,4-trimethoxybenzene, by GC analysis.

To a refluxing and stirred suspension of 1.1 g LAH in 150 mL anhydrous Et₂O and under Et2O, there was added a solution of 1.1 g 2-nitro-1-(2,3,5-trimethoxyphenyl)propene (8) in 50 mL anhydrous Et₂O. The creamy mixture was held at reflux for 4 h, cooled, and then the excess hydride cautiously destroyed by the addition of 1.5 N H₂SO₄. There was then added 20 g potassium sodium tartrate followed by sufficient aqueous NaOH to raise the pH to >9. The Et2O phase was separated, and the remaining aqueous phase extracted with 3×75 mL CH₂Cl₂. The organic phase and extracts were combined, and the solvent removed under vacuum yielding 0.9 g of a colorless oil. This was dissolved in 200 mL anhydrous Et₂O which was saturated with anhydrous HCl gas. There was generated a thick oil that did not crystallize. The Et₂O was decanted from this, and allowed to stand for several days in a sealed container at room temperature. There was the deposition of fine white needles of 2,3,5-trimethoxyamphetamine hydrochloride (TMA-4) (9) weighing, after Et₂O washing and air drying, 0.31 g. The m.p. was 118-119 °C. The residual oil was dissolved in H₂O, made basic with NaOH, and extracted with CH₂Cl₂. Evaporation of the solvent gave 0.40 of a white oil which was dissolved in a little MeOH containing 0.22 g oxalic acid. There was the immediate deposition of crystals of the oxalate salt of 2,3,5-trimethoxyamphetamine, with a m.p. of about 110 °C.