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Demethylation of 3,4,5-trimethoxybenzaldehyde

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Captain_America:
Here is an intersting preparation of syringaldehyde using piperidine:

Tetrahedron: Asymmetry 13 (2002) 1799–1804

A solution of 3,4,5-trimethoxybenzaldehyde 10 (3.48 g, 17.7 mmol) in piperidine (35 mL) and water (35 mL) was heated under reflux for 48 h and the cooled mixture was poured into 4N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with 2N hydrochloric acid, water, dried over Na2SO4. The solvent was distilled off and the residue was flash chromatographed using petroleum ether and ethyl acetate (4:1, v/v) as eluent to afford syringaldehyde as a white solid (2.58 g, 80%). Mp 113–114°C.

java:
Maybe this would be interesting in this thread......

Post 514141 (psyloxy: "3,4,5 precursors revisited", Chemistry Discourse)

armageddon:

moo:
Actually, I think isoproscaline sounds quite interesting.

Haven't seen anything demethylated this way before, or then it is because of my memory. I guess this produces N-methylpiperidine and needs a substrate that is prone to demethylation.

Captain_America:
Every good bee knows that vanillin (via syringaldehyde) is best precursor for the 3,4,5 substitution pattern (escaline, etc.), hence the bromination of vanillin ortho to -OH has been a subject of much discussion at the hive. From vanillin you can go to plenty places in Pihkal, even MDA compounds if you like. However, for the 2,4,5 substitution pattern (MEM, ORTHO-DOT*) it would be essential to put the Br  meta to OH in vanillin. It could bee done by first making the acethoxy ester, followed by bromination and treatment with HCl:

5-Bromo-4-formyl-2-methoxyphenol:

To the suspension of 4-acetoxy-3-methoxy-benzaldehyde (3.23 g, 16.7 mM) in KBr (6.67 g) and distilled water (80 mL) was added bromine (2.94 g, 18.4 mmol) dropwise. The reaction mixture was stirred for 10 h at room temperature and then subjected to filtration. The precipitate was suspended in 6 N HCl (80 mL) at 90 °C for 10 h. The reation mixture was then cooled and filtered and the resulting solid was dissolved in EtOAc and washed with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated. The residue was recrystallized from EtOA-hexane to give 5-Bromo-4-formyl-2-methoxyphenol (3.58 g, 93% yield) as a colorless solid. Mp 174-175 °C (from hexanes, lit. mp 174-175 °C)

* Notice how Shulgin tries 2-TOM from 60 + mg where it has the makings of a great compound, he tries ORTHO-DOT at only 25 mg and gets vague activity. At higher levels it might be as dark compound as TMA-2, don't you think so?

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