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Author: Subject: 5-hydroxyvanillin methylation?
monolithic
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[*] posted on 5-9-2021 at 14:36
5-hydroxyvanillin methylation?


Has anyone ever tried to methylate both hydroxy groups of 5-hydroxyvanillin (3,4-dihydroxy-5-methoxybenzaldehyde) to yield 3,4,5-trimethoxybenzaldehyde with one of the "safer" methylating agents? The classical one-pot method is to use dimethyl sulfate but I would like to avoid this for obvious reasons.

I have personally done syringaldehyde --> 3,4,5-TMBA with dimethyl carbonate in DMF with TBAB and it worked quite well. Does anyone know if dimethyl carbonate, dimethyl oxalate, or something similarly "safe" would work on 5-hydroxyvanillin to 3,4,5-TMBA in a one-pot fashion?

I am aware of the benefits of the Ullmann-type reaction of 5-bromovanillin --> syringaldehyde. I plan on carrying out this reaction too. :)
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Triflic Acid
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[*] posted on 5-9-2021 at 16:45


Maybe deprotonate the phenol and then react with methyl iodide.



Hope is not a reagent
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monolithic
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[*] posted on 7-9-2021 at 12:17


Any ideas on how much excess is required? Methyl iodide isn't too difficult to prepare as long as it's not something crazy like a 3x molar excess.
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[*] posted on 8-9-2021 at 01:19


Nope! My old-time buddy Dr. Death, methylated 5-hydroxy-vanillin, but he did it the straightforward way.

Dimethyl-Sulfate. Very poisonous, but it works well, and I suppose it is easy to make.

Methyl-Iodide isn't especially healthful either.

Dimethyl carbonate worked for Syringaldehyde? Seems like it should work for 5-hydroxy-vanillin.

Worth a try. Let us know!
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njl
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[*] posted on 8-9-2021 at 07:43


Vanillin will undergo a Cannizarro reaction with base.



Reflux condenser?? I barely know her!
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[*] posted on 8-9-2021 at 08:47


Post by "Flasky Mountain Flask" next door:
https://www.thevespiary.org/talk/index.php?topic=16804.msg54...

Quote:

0.03152m 5-OH-Vanillin (5.3g re-x from toluene), 0.09456m K2CO3 (13.07g, finely powdered), 0.03152M TBAB (10.16g), and 1.00864M Dimethyl Carbonate (90.96g) was placed in a 500ml RBF and stirred in an oil bath under reflux at 88-93C for 5 hours.

Workup: diluted room-temp reaction mixture with water, based with a few grams KOH, extracted reaction mixture with ethyl acetate until satisfied (don't know how many mls), then acidified reaction mixture with dilute H2SO4 and again extracted with ethyl acetate until satisfied. Each ethyl acetate solution was washed with a bit of water, dried with Na2SO4, and vapped off under vacuum to yield a residue. Each residue was then extracted with several changes of cyclohexane, then each cyclohexane solution was simply evaporated rather than crystallizing. Yields were poor, in the 3-5% range for the trimethoxy compound.

The reason I wanted to post this at all was that in previous experiments using methyl bromide on the same substrate, it appeared to be very effective with step-wise methylation. Poor yields (5-10%) of the fully methylated compound on the first round, but decent yields (50-60%) of mono-methylated product (syringaldehyde structural isomers). Then, taking the mono-methylated product and running it through again resulted in about 50% yield of trimethoxy compound. I noticed working this reaction up resulted in a lot of unchanged product, the dihydroxy compound but almost none of the monomethylated compound. Also ethyl acetate will extract 5-oh-vanillin from aqueous solution and DCM will not, so it could be that sequential extraction of the acidified reaction mixture, first with DCM to remove syringaldehyde/isomers then with ethyl acetate to remove unchanged starting material would be effective for separating the 3 compounds.

I know that the temp could be much higher and the TBAB use was not economical. Just wanted to report that the monomethyl compound is produced in much less amount relative to the dimethyl compound compared to other tried methylating agents.
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monolithic
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[*] posted on 8-9-2021 at 11:43


Quote: Originally posted by xdragon  
Post by "Flasky Mountain Flask" next door:
https://www.thevespiary.org/talk/index.php?topic=16804.msg54...

Quote:

0.03152m 5-OH-Vanillin (5.3g re-x from toluene), 0.09456m K2CO3 (13.07g, finely powdered), 0.03152M TBAB (10.16g), and 1.00864M Dimethyl Carbonate (90.96g) was placed in a 500ml RBF and stirred in an oil bath under reflux at 88-93C for 5 hours.

Workup: diluted room-temp reaction mixture with water, based with a few grams KOH, extracted reaction mixture with ethyl acetate until satisfied (don't know how many mls), then acidified reaction mixture with dilute H2SO4 and again extracted with ethyl acetate until satisfied. Each ethyl acetate solution was washed with a bit of water, dried with Na2SO4, and vapped off under vacuum to yield a residue. Each residue was then extracted with several changes of cyclohexane, then each cyclohexane solution was simply evaporated rather than crystallizing. Yields were poor, in the 3-5% range for the trimethoxy compound.

The reason I wanted to post this at all was that in previous experiments using methyl bromide on the same substrate, it appeared to be very effective with step-wise methylation. Poor yields (5-10%) of the fully methylated compound on the first round, but decent yields (50-60%) of mono-methylated product (syringaldehyde structural isomers). Then, taking the mono-methylated product and running it through again resulted in about 50% yield of trimethoxy compound. I noticed working this reaction up resulted in a lot of unchanged product, the dihydroxy compound but almost none of the monomethylated compound. Also ethyl acetate will extract 5-oh-vanillin from aqueous solution and DCM will not, so it could be that sequential extraction of the acidified reaction mixture, first with DCM to remove syringaldehyde/isomers then with ethyl acetate to remove unchanged starting material would be effective for separating the 3 compounds.

I know that the temp could be much higher and the TBAB use was not economical. Just wanted to report that the monomethyl compound is produced in much less amount relative to the dimethyl compound compared to other tried methylating agents.


Nice find. When methylating syringaldehyde I did a ~16 hour reflux at 125 C with 24 g syringaldehyde, 120 ml DMF, 14 g K2CO3, 7 g TBAB, and 55 ml dimethyl carbonate. His stated 3-5% is terrible... I wonder if 48 hours reflux would help any. I guess that's a good starting point. If only I had TLC plates.

[Edited on 9-8-2021 by monolithic]
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[*] posted on 9-9-2021 at 09:11


Quote: Originally posted by monolithic  

If only I had TLC plates.


They are pretty cheap to buy and easy to make. If you've got silica gel or alumina, plaster or corn starch, and some microscope slides or even alu foil.

https://www.youtube.com/watch?v=pNDQkM3jasA

I wonder if paper chromatography would work.

Edit: apparently paper chromatography should work.

Quote:

Paper Chromatography

5-Hydroxyvanillin, vanillin and 5-iodovanillin were separated by descending chromatography using Whatman No.1 paper and the solvent system of n-butanol saturated with 2% ammonia. A saturated solution 2,4-dinitrophenylhydrazine in 1N HCl was the spay reagent. For these compounds the Rf values were 0.38, 0.50 and 0.48 respectively.

Canadian Journal of Chemistry, Volume 40 (1962), 2175-2177, S.K.Banerjee, M.Manolopoulo and J.M.Pepper


[Edited on 9/9/2021 by Zelot]




So... what did you do over the weekend?
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