OK, so SWIM is about to get back to his lab, and he's been been strongly considering making some mescaline with all the vanillin and nitromethane he has. I haven't done all the calculations, but here's the basic game plan, together with a few questions:
(1) Take vanillin and brominate via in situ bromine generation (H2O2/GAA/H2SO4/NaBr), a la uemura (Post 297806 (https://www.thevespiary.org/talk/index.php?topic=9683.msg29780600#msg29780600)
(uemura: "How to prepare hydroxyvanillin", Methods Discourse)). The sodium bromide should be able to replace the potassium bromide without any problem (I think).
(2) Place magnesium turnings into methanol with a crystal of iodine; and reflux until all the magnesium has reacted. This should create at best an 8% solution. Then much of the methanol is distilled off, so as to create the equivalent of a 5M solution (in terms of the methoxide ions). Some of the Mg(OMe)2 will crystalize out of solution, but hopefully will disolve back in as the reaction progresses and heat is added. The workup will then be as on https://www.thevespiary.org/rhodium/Rhodium/chemistry/mmda.mescaline.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/mmda.mescaline.html)
to make syringaldehyde; just replacing the sodium methoxide solution with a magnesium methoxide solution.
(3) The syringaldehyde is then methylated either via DMS or methyl iodide. SWIM is leaning towards methyl iodide, since it is much less toxic and also easier to make. The workup in Vogel with RP/I/MeOH should be fine, though SWIM's also considering generating HI in an iodine/turpentine/methanol solution, and then distilling off the MeI. Methanol and turpentine seem to be miscible, so this should work fine. Trimethyl phosphate would be optimal, but SWIM can't seem to find any phosphorus pentoxide needed to make it. :P
(4) The 3,4,5 trimethoxy benzaldehyde is then condensed with nitromethane in GAA with an ammonium acetate catalyst in an ultrasonic cleaner, as in https://www.thevespiary.org/rhodium/Rhodium/chemistry/nitrostyrene.ultrasound.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/nitrostyrene.ultrasound.html)
(5) Reduce with Urushibara nickel as in https://www.thevespiary.org/rhodium/Rhodium/chemistry/amph.urushibara.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/amph.urushibara.html)
Questions:
(1) Comments on step 2 would be much appreciated. Is MgBr2 soluble in methanol/EtOAc?
(2) Is P2O5 available at all? SWIM hasn't been able to find a chemical company which sells to individuals who sells it, nor has he been able to find any OTC sources. Should he bother to keep looking?
(3) Is there any problem with using Urushibara nickel to reduce nitrostyrenes? I've only seen it used with nitropropenes, though I don't know of a reason why it wouldn't work.
Thanks in advance,
MethyMouse
I was also interested in mesc. at one time and found what I thought was the most feasible route.
1. Iodovanillin here: Post 303014 (https://www.thevespiary.org/talk/index.php?topic=9871.msg30301400#msg30301400)
(cesium: "5-iodovanillin (Chloramine T + NaI)", Methods Discourse)
2. Hydroxyvanillin here (from Rhodium):
"2.8g 5-Iodovanillin, 1.6g hydrated CuSO4 and 76mL 4N NaOH were refluxed(105°) for 4.5h with continuous stirring under N2. After cooling to 60-70°, the mixture was filtered under suction and the residue washed with 3x10mL hot water. The alkaline solution was cooled to 10° and acidified to pH 3-4, by the dropwise addition of concentrated HCl. During this addition the mixture was stirred continuously and the tmperature maintained below 25°C. The resulting mixture, which contained a small amount of percipitate, was extracted continuously with ether for 16h. After being dried over anhydrous MgSO4, the ether was removed (60-65°) to leave 1.5g dark gray product. All but 0.10g was dissolved in hot benzene, from which, after concentration to 75mL, 1.15g 5-hydroxyvanillin crystallized, yield 68%, mp 128-129°. Recrystallization from benzene, with charcoaling, gave a chromatographically pure product......"
3. 3,4,5 TMB here (from Rhodium):
"Into a 1-l. round-bottomed flask equipped with a magnetic stirrer and a reflux condenser were placed: 50 g (0.298 mol) 5-hydroxyvanillin, 500 ml acetone, 91.0 g (0.716 mol) dimethylsulfate, 100 g (0.806 mol) finely ground Na2CO3.H2O, 10 ml of 10% KOH in methanol. Of course equimolar amounts of anhydrous Na2CO3 or K2CO3 can be used.
The heterogenous mixture was stirred under vigorous reflux for 24 hours, after which the reflux condenser was replaced with a descending condenser. The solvent was distilled at a bath temp. of ca. 100° until the distillation ceased. To the solid residue was added 400 ml of water and the heterogenous mixture was stirred VIGOROUSLY for 2 hours at room temperature followed by one hour at 0-5° (ice-cooling). The light brown crystals were filtered by suction, washed with 3*150 ml of ice water and air dried to constant weight. Yield 55.1g (94%), m.p. 72.5-74°. After distillation at 0.5mm/130°, there was obtained a 90% yield of 3,4,5-trimethoxybenzaldehyde, m.p. 73.5-75, VPC purity 99.3%."
4. 3,4,5 TMbNS from here: https://www.thevespiary.org/rhodium/Rhodium/chemistry/mescaline.cathyd.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/mescaline.cathyd.html)
5. Mescaline from here: https://www.thevespiary.org/rhodium/Rhodium/chemistry/leminger.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/leminger.html)
Your only real hitch should be the dimethylsulfate..but it CAN be bought and worked with safely.
Antoncho and Vitus seem to have already solved all MeI problems one could have in Post 301629 (https://www.thevespiary.org/talk/index.php?topic=7607.msg30162900#msg30162900)
(Antoncho: "Two tried-and-true ways to make MeI !", Chemistry Discourse) :) :) :) , so I think SWIM won't be doing anything with DMS.
As for NaI vs. NaBr, SWIM can get NaBr at a hardware store in the swimming pool section for something like $5/pound. He's never seen NaI OTC. Online, the lowest price he's seen was something like $12/100g. $/mole, NaBr wins out.
I definitely should have read Rhodium's page on 5-OH-vanillin more carefully. There are a couple of neat tricks there, as you say--toluene extraction and the bisulfite aduct.
And yes, I know that helium is an inert gas, though running it for several hours is not very cheap--my main concern.
Thanks a lot, everybody! :) SWIM can't wait to get back to his lab and start trying some of this stuff out.