eugenol-->safrole in one step

[El_Zorro]

Alright, boys and girls, it's gone on waaayy, too long.  We need a big fat hairy synth of safrole that proceeds directly from eugenol, in one step.  They're just so fucking close, why does no one besides me go nearly insane trying to figure out ways to get eugenol to safrole in one high-yeilding step?

Ok, the only synth I've seen with any real promise is terb's alkali fusion synth.  terbium: "Eugenol demethylation via alkali fusion." (Methods Discourse) It doesn't look like it'll apply to vanillin for piperonal synths, because it oxidizes the aldehyde to a carboxylic acid.  But might very well be used for eugenol--> safrole synths.  Now, let's look at it.  This is all in reference to the Organic Synthesis article, by the way.

Ok, heating the substrate with NaOH and KOH is pretty obvious, it forms two KO-R groups, and cleaves the methoxy group in the process.  But is that high of a temp really necessary?  Can the methoxy group be cleaved at a lower temp?

Now, after that.  The mixture is cooled dow to 150–160°, and water is added, to dissolve the fused product.  Then SO2 is passed into it for a little bit, so as to "prevent the formation of a very dark-colored product when the reaction mixture is acidified with a strong acid."  Terbium made the suggestion that a bisulfite could be used instead of having to fuck with SO2 gas.  Thuis would definately be preferrable, but how much would need to be used?  Does anyone know, or is it just going to have to be trial and error?

Now, for the good part.  They say just to acidify the mix with HCl(aq), and you've got it.  Now, I see this as being HCl + KO-R --> KCl + HO-R.  Am I wrong?  If this is the correct reaction, what is stoppong someone from using this opportunity to go directly to methylation with DCM?  The medium is already basic, strongly, in fact.  The substrate has already been cleaved of its methoxy group, and is primed for the final step.  There is sulfur in the mix, which I'm assuming acts to prevent polymerization of the phenolic groups.

So could this final solution just be dripped into a refluxing solution of DMSO and DCM, as in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methylenation.html#DCM

, giving safrole in one big fat hairy reaction?

Thoughts?
Who is that masked man?

[Mountain_Girl]

They say just to acidify the mix with HCl(aq), and you've got it

I could be wrong, but I think the problem with eugenol is that strong acids will add to the double bond.

Mountain Boy

[SPISSHAK]

Hydrobromic acid wil easily add to a doulble bond but hydrochloric needs some persuasion to get it to add markovnikov to a double bond.
I think the Na2HSO3 is used because it forms a complex with the double bond and protects it from oxidation.
This is also done during morphine extraction, when the morpphine is made basic the sodium (or Alkali phenolate ion) makes the molecule more prone to oxidation (i.e. turning black) so sodium bisulfite is added to prevent this.
The fact that sodium bisulphite complexes with double bonds may also explain the conundrum of crude ketone precipitation with sodium bisuphite.
as the safrole is also complexing with the bisulpite ion.
This may be why Big daddy Osmium suggests using stoichiometric amounts of sodium bisuphite when forming it's complex with crude ketones?
Anybody like to comment?

[Osmium]

Bisulphite doesn't react with C=C double bonds. And I never said to use stoichometric amounts.
I'm not fat just horizontally disproportionate.

[GC_MS]

SWiM once thought of a one pot eugenol->isosafrole. Lewis acids are known to isomerize the double bond of the propenyl chain, so SWiM gave AlCl3 a shot. He ended up with alot of tar, no honey   . Found in an article afterwards that AlCl3 causes polymerization... boohoohoo   .
WOMAN.ZIP: Great Shareware, but be careful of viruses...

[El_Zorro]

Well, nobody seems to think it's impossible, so how about a theoretical procedure.

In a 3l flask, equipped with a thermometer and reflux condensor, are placed 2 moles of 97% sodium hydroxide  pellets, 5 moles of 85% potassium hydroxide  pellets, and 50 ml. of water. The mixture is stirred and heated. When the temperature of the fluid mixture reaches 160°, 1 mole of eugenol is added in portions over a period of 2.5–3 minutes. Stirring is continued, and heat is applied until the temperature reaches 240–245° . The temperature is maintained at 240–245° for 5 minutes. The hot plate is removed, and the mixture is allowed to cool with stirring. When the mixture has cooled to about 150–160°, 1L of water is added, and the mixture is stirred until all the fusion mixture is dissolved. Another 500 ml. of water is added, and X moles of sodium bisulfite is added.

(1).The mixture is then completely acidified with 1.5L of 6 N hydrochloric acid. The acidified mixture is cooled in an ice bath (5°) for 2 hours, and extracted to give 4-allylcatechol, in (hopefully) 89–99% yield.

(2).The mixture is then added over a 30 minute period to a refluxing solution of 120 ml of methylene dichloride in 300 ml of DMSO. Thereafter, the reaction mixture was stirred at reflux for 1.5 hours.  The mixture is then extracted, and washed with 5% NaOH to remove phenols, and distilled to give yeild of safrole.


The two alternate endings to the procedure are me taking into consideration that it might not be possible to directly methylate the fused product.

The X amount of bisulfite still needs to be figured out, but I'm guessing that it will need to be figured out through experimentation.

Thoughts on this?  Rhodium?
Who is that masked man?

[starlight]

An inert atmosphere may well be necessary with eugenol to prevent oxidation

Why does the procedure have water added - I thought that it was supposed to be fused alkali, not dissolved?

Wont fused alkali metal hydroxide at 245 degrees centigrade eat through the glass?

[weedar]

Fill a moisture protection tube with CaCl₂ as

Post 291881

(Rhodium: "allylpyrocatechol", Novel Discourse)

Probably not as good yields, but much more OTC/easy..

Weedar
My other signature is funny.

[El_Zorro]

Would the fused alkali eat through the glass?  I've heard of strong bases etching ground glass joints, but never bare glass.  That might have been why they used a stainless steel reactor in the article.
Who is that masked man?

[Rhodium]

It won't eat through the entire glass, but it will probably eat a millimeter or so.

[El_Zorro]

What are your thoughts on the proposed reaction, Rhod?
Who is that masked man?

[Rhodium]

I don't know. Either it works, or it polymerizes. Don't fill your flask more than 1/4:th full.

[El_Zorro]

Heh heh, you're a big help.

Is that what you think about the methylenation reaction, or just the fusion of eugenol in general?

And do you have any thoughts on how much bisulfite to use?  I would think no more than a few grams, considering how much SO₂ they used in the article.

But what I wanna know is, how do you take the temp of the reaction if it's gonna etch your glass thermometer?  I guess you could just go by the oil bath temp, and hope.

Who is that masked man?

[Rhodium]

There is no question about that the methylenation will work, I am just worried about the eugenol side-chain adding to the phenolic oxygens under very basic or acidic conditions. I am not sure that will happen though, you have to try if nobody else knows.

UTFSE on eugenol, I know of at least one posted article about basic eugenol demethylation. 

Take the temp in the ordinary fashion, the hydroxides won't etch the glass if you aren't leaving them in contact for a long time (many minutes). Just dip the thermometer into the solution from time to time, and wipe it off on a wet cloth inbetween.

[El_Zorro]

Thanks a shitload, Rhod.  If I ever get around to this, I'll have to post back at the Hive with my results.
Who is that masked man?

[starlight]

is the added water a good thing or a bad thing?