Author Topic: The Eugenol Challenge - Demethylation of Eugenol or Derivitives (Read 641 times)

Vesp · « **on:** April 04, 2010, 04:42:30 AM »

While this may have been beat to death, I think we should work towards an easy, OTC method of demethylating eugenol or a derivative into a catechol of some sort. We already know of several methods, they are well documented in the rhodium archives, however they use hard to get items (AlCl3, AI3, etc) or are very inconvenient, such as requiring large amounts of pyridine*HCl.

So, we need to find away around the typical methods, or figure out how to make the known methods easier involving OTC chemicals. One way would be to produce AlCl3 more easily, from the talk I've seen on this -- it doesn't seem like it will ever be an easy task, perhaps other lewis acids can be used, that are more easily produced?

I'd love to hear more ideas on this, links from other sites discussing the same idea, or any references. I think a lot of people would like to learn more about a practical way to do this - hopefully we can get some good conversation that will actually produce something useful when it comes to the demethylation of eugenol.

Here are some links from this site that might spark up discussion or ideas...
AlCl3
DMSO-Lewis acid complexes. Anhydrous MgCl2, possible anhydrous trihalides
AlCl3
HBr. It's in the last ref
A methyl aryl ether demethylation review, and several thiol HSAB demethylations
Thiol demethylation @ SM

There are more related ones if you search eugenol, demethylation, AlCl3, etc... those are just some I found and think might be useful, or were already on this site.

I also remember reading something about graphite powder being used for either methyoxlation, or perhaps acylation on this forum.. but I cannot find a reference to it -- I have no idea how it works, or if I've just made this up, but maybe it has some potential for the demethylation? I doubt it, but might as well mention it anyways.

Ideas?

Enkidu · « **Reply #1 on:** April 04, 2010, 05:47:17 AM »

Vesp, I took the liberty of labeling the links.

I would hope that the thiol demethylations work when no electron withdrawing groups are present on the ring. Someone just needs to get to the lab. If it won't work, just isomerize, then make vanillin, and then the thiol demethylations should work.

Sedit · « **Reply #2 on:** April 04, 2010, 07:38:36 PM »

Lets make sure ring closure is added in this challenge as well along the lines of my studies early on.

Hydrogen removal from the methoxy moiety and the adjacent hydroxyl can in some cases lead to ring cloasure thru radical reactions blah blah...

someone with more skill then me needs to study this highly in depth.

Goldmember · « **Reply #3 on:** April 04, 2010, 08:32:09 PM »

Ive been meaning to try this out on vannilin for a while but havent gotten around to it.
Could you guys check it out.I know Ive posted it before but is there any reason why this shouldnt work for eugenol as well?
I was thinking of trying iodine to form this so-called complex also.

US2975214A Process for the manufacture of protocatechuic aldehyde

Please cite the reference instead of using a link that will soon be broken. - Enkidu

Vesp · « **Reply #4 on:** April 05, 2010, 01:39:46 AM »

Quote

Lets make sure ring closure is added in this challenge as well along the lines of my studies early on.

Sounds good to me!

Also there are these pages:
http://127.0.0.1/Douchermann/orgysynpages/4allylcatechol.html 4-allyl catechol
http://127.0.0.1/Douchermann/orgysynpages/isoeugenol.html Isoeugenol

Naf1 · « **Reply #5 on:** April 06, 2010, 12:44:56 AM »

"A mixture of 10.5 g 1-(3-Methoxy-4-methylphenyl)-2-propylamine-HCI and 60 ml 48% hydrobromic acid was refluxed for 5 h, the solution formed was evaporated in vacuo, the residue was made alkaline with NH4OH and the product was isolated by extraction with chloroform; 7.6 g (94%), mp. 134-138°C. Analytical sample mp. 137.5- 138.5°C (light petroleum)"
http://orgchembase.com/archive/Rhodium/chemistry/mma.html

One would just proceed to the phenylisopropylamine, then use the above proceedure in high yields.

"Hayashi and Namura[32] discuss demethylation during the pulping process and conducted experiments on individual components under such conditions. Eugenol and vanillin were both demethylated by cooking with either 5% NaOH or 5% Na2SO4, 1% NaHCO3 and H2O. The degree of demethylation is not given in the abstract but it is in the paper which luckily is in English if one cares to look it up. The reaction does proceed slowly."
http://orgchembase.com/archive/Rhodium/chemistry/tcboe/chapter5.html

Alkaline hydrolysis resulting in demethylation of the methoxy moiety is also another OTC route worthy of consideration. The availability and affordability of the precursors and reagents makes the lower yield more attractive? ie NaOH and Eugenol are cheap and easy to get therefore a cut in yield is not as important as Allylpyrocatechol is scheduled and watched (for good reasons!). So producing a 50% yield cheaply and easily maybe well worth considering and saving the harder to get reagents for later.

Enkidu · « **Reply #6 on:** April 06, 2010, 03:46:25 AM »

does 1-(4-hydroxy-3-methoxyphenyl)-2-bromopropane polymerize in the presence of base? I thought a lot of the schemes starting from eugenol failed because if its tendency to polymerize.

Naf1 · « **Reply #7 on:** April 06, 2010, 06:44:42 AM »

1-(4-hydroxy-3-methoxyphenyl)-2-bromopropane will have a tendency to polymerize in the presence of base. Also the use of hydrogen halides would be avoided in retrospect also, as you could easily halogenate the 4-hydroxy with a 48% HBr reflux. And hydrodehalogenation is not something one wants to add to the to do list. There was however a reference to the hydrolysis with NaOH;

Hayashi and Namura, Nippon Mokuzai Gakkaishi 13, 24-27 (1967) (In English);
Chemical Abstracts 67, 45000z (1967)

Thats all that was given...

Enkidu · « **Reply #8 on:** April 06, 2010, 06:52:00 AM »

Quote from: Naf1 on April 06, 2010, 06:44:42 AM

1-(4-hydroxy-3-methoxyphenyl)-2-bromopropane will have a tendency to polymerize in the presence of base. Also the use of hydrogen halides would be avoided in retrospect also, as you could easily halogenate the 4-hydroxy with a 48% HBr reflux.

You must be drinking the bong water or thinking of another substrate. 48% HBr will never brominate an aryl alcohol!

Naf1 · « **Reply #9 on:** April 06, 2010, 07:01:24 AM »

"You must be drinking the bong water or thinking of another substrate."

lol, I am known to have my moments

SOMA · « **Reply #10 on:** April 06, 2010, 10:56:44 AM »

An idea I tossed at another forum:

From eugenol to isosafrole in 4 "easy" steps

References:

1. On the alcohol hydration, here you have safrole to MDP2Pol: h++p://www.lycaeum.org/rhodium/chemistry/mdp2pol.html

2. On the demethylation, I think that the alcohol is stable enough, so here you have vanillin to protocatechuic acid: h++p://www.orgsynth.com/orgsyn/orgsyn/p ... p=cv3p0745

3. Formation of methylenedioxy ring: US Pat. 4082774

4. Dehydration to a propenylbenzene: h++p://designer-drugs.com/pte/12.162.18 ... ation.html

EDIT: If you don't like the NaOH demethylation, the one with high pressure and sodium acetate could be used instead (US Pat 4473713)

headstrong · « **Reply #11 on:** April 06, 2010, 11:51:28 AM »

I tried to do hydration and demethylation of Eugenol with H2SO4 and H3PO4, i can't give a good thing for you yet.
Some problems i found;
1. Eugenol is easily polymerized, in 50 % H2SO4 for hours or by heating will do, concentrated H3PO4 by heating.
2. Concentrated H2SO4 is worst, i ever tried addition 98% H2SO4 drop wise into 20 ml Eugenol by continuous stirring (without cooling), its highly exothermic, after about 10 drops solution become black, boiled, many smoke is produced, burning hot, and finally i got black solid plastic. Its tough to work with concentrated H2SO4 although by maintenance the temperature at 0c, just good on the paper.
3. seems like both H2SO4 and concentrated H3PO4 are strong enough to do demethylation, but i can't prove it yet, it's stating in text book.
4. the problem working with Eugenol are;
- in the C-C double bond, that cause polymerization
-solubility, not water soluble
-various substances are formed, sulfuric acid addition into double bond, hydrolyzed to alcohol, demethylated to 3-4-dihydroxy phenyl substances,....
I mean more reasonable working with Vanillin, if using H2SO4-H3PO4 as demethylation agent. I'll try vanillin+ H2SO4/H3PO4 soon.

Douchermann · « **Reply #12 on:** April 06, 2010, 04:39:39 PM »

One of the biggest issues I feel needs addressing is the stability of the demethylated molecule. The 4-allylcatechol polymerizes very quickly in open air, which is what gives the compound its smokey/diesel smell. When I experimented with preparing this material using pyr*HCl, there was a significant quantity produced, but would become polymerized and useless in a matter of hours. I had no real way to test the quantity without it being lost, so I used what I like to call a tomsheck test. Evap a small quantity in something like a petri dish, and after doing this a number of times, you get the feel for how much of the soln. is actually the chemical you desire. The more concentrated the material is that is left, the more you have dissolved (obviously) and you can guestimate the ratio of area covered with material vs. area not covered with material, factor in molecular attraction, and you're within 5-10%
Anyone know of any non-polar oxyphobic solvents?
Beware, the polymerized 4-allylcatechol is a bitch to clean up, it leaves your hands and glass sticky and stains everything black.

headstrong · « **Reply #13 on:** April 07, 2010, 05:08:07 AM »

Here the good one, taken from Hive;

Quote

Masquerade
(Stranger)
10-26-01 06:43
No 228897
                  Re: Cleavage of Alkoxy group to give Phenol
(Rated as: excellent)

Foxy the method you presented was good, but only good for 2-carbon alkyl groupes. The synthesis is only good for ethylvanillin or higher alkyl groups. SWIM found this...

Synthesis of Veratic Aldehyde from Vanillin
Heat 1,000 grams U.S.P. vanillin (7 moles) and 260 grams of water in a 5 liter reaction flask and heat to 70@C., to form a liquid mixture. Commence simultaneous addition of 1,030 cc. each of dimethyl sulfate and aqueous sodium hydroxide (34.9 percent by weight). The temperature rises to about 107@C. during the additions. Time of addition is about 100 minutes. Extract the resulting veratic aldehyde oil with ethylene dichloride, wash the extract with water until free of alkali, and remove the solvent by distillation. About 1,070 grams (98 percent) of crystalline veratic aldehyde is obtained.

Converting Veratic Aldehyde to Isovanillin (3-hydroxy-4-methoxy-benzaldehyde)
Add 1000 grams of the thus-obtained veratic aldehyde over a 15 minute period to 5500 grams of 66@ Be.sulfuric acid at 83@C. The temperature rises to 92@C. Hold at 92@C. +- 1@ for 120 minutes. Cool the acid solution to 15@C. and pour into 32 liters of water at 16@C. The temperature rises to 60@C. Extract the diluted acid with ethylene dichloride and wash the extract with 3.5 M sodium hydroxide. Distill the solvent from the washed extract to recover about 272 grams of unreacted veratic aldehyde. Lower the pH of the aqueous sodium hydroxide wash to 8.3 with 50 percent sulfuric acid. Wash the precipitate, filter and dry. 515 g. of isovanillin is obtained, a yield of 71 percent calculated on the veratic aldehyde which reacted.

Acide hydrolysis of veratic aldehyde into isovanillin is selective only at the 3 position. This is much of what SWIM was looking for. SWIM still likes to perform several reactions using HBr and lewis acid to cleave the alkoxy bond for some research. He/She will see what can do.

Thank you foxy. Finding this was becuase of your post. If you have ideas for synthesis of somethings, let SWIM know so maybe he/she can do research if you cannot. Thanks you again.

Rhodium you are the owner of the board? You have a impressive chemistry page.



        Osmium
(Stoni's sexual toy)
10-26-01 12:47
No 228994
                  Re: Cleavage of Alkoxy group to give Phenol

Holy shit! There is the proof! I told you years ago H2SO4 will work to hydrolyse phenolic ethers and nobody bought it! So there! Even if there are better yielding procedures I'd prefer using OTC H2SO4 on a cheap precursor like eugenol in the first or second reaction step over such nasty stuff like BF3 or other Lewis acids any day of the week! Fuck it, 30% would make me happy in that reaction since it is so cheap.

Antoncho
(Official Hive Translator)
10-27-01 00:47
No 229154
                  Re: Cleavage of Alkoxy group to give Phenol

Naturally, H2SO4 hydrolysis won't bee suitable for eugenol because of its double bond, will it? Whereas it should bee pretty stable to alkali in inert atmosphere - please, correct me if i'm wrong.

Respects,

Antoncho

This procedure isn't start from vanilin to get 3,4-dihydroxybenzaldehyde, but at least it show that H2SO4 can be used for ether cleavage/hydrolysis. I hope H3PO4 as well.

SOMA · « **Reply #14 on:** April 07, 2010, 10:23:01 PM »

Thanks for debunking the propossed procedure, back to the drawing board! BTW that vanillin demethylation procedure looks like a winner

Enkidu · « **Reply #15 on:** April 10, 2010, 12:31:03 AM »

A list of demethylations by CherrieBaby

===

Rapid microwave-assisted cleavage of methyl phenyl ethers: new method for synthesizing desmethyl precursors and for removing protecting groups
Anna Fredriksson, Sharon Stone-Elander
J. Label. Compd. Radiopharm. Volume 45 (2002), Issue 6 , Pages 529 - 538 DOI: 10.1002/jlcr.577

Abstract: A new microwave-enhanced method for rapid demethylation of methyl phenyl ethers using neat methanesulfonic acid (CH3SO3H) is presented. Using a monomodal microwave cavity, cleavage of anisole (1), used as model compound, to phenol (2) was achieved with high conversions (ca 80%) in very short reaction times (10-20 s). The feasibility of cleaving one or both of two methoxy groups was illustrated with 4-(3-bromoanilino)-6,7-dimethoxy-quinazoline (PD153035, 3). High conversions (82%) of 3 were attained with four different conditions (i.e. combination of input effect (35-125 W) and time (15 s-2 min)). 4-(3-Bromoanilino)-7-hydroxy-6-methoxyquinazoline (4), 4-(3-bromoanilino)-6-hydroxy-7-methoxyquinazoline (5) and 4-(3-bromoanilino)-6,7-dihydroxyquinazoline (6), the possible mono- or di-demethylated compounds, were obtained. Methods for rapid demethylations are of interest in radiochemistry for post-labeling deprotections of hydroxyl containing aromatic rings and also provide a more direct route for synthesizing precursor compounds for labeling by alkylation.

Sulfuro · « **Reply #16 on:** April 11, 2010, 05:36:31 AM »

I've always thought that one could react either chlorosafrole or bromosafrole with sodium acetate (via DMSO or PTC) to get the 2-acetyl intermediate and them react that with aqueous base to get the desired hydroxysafrole. It no doubt would be a simple reaction using very simple and readily available materials.

Btw, I'm working on a write-up that will review a synthesis (an old one) that to the best of my knowledge has not been discussed before -- ever -- either here at TheVespiary, Hive, Wetdreams, or ScienceMadness. It is for ring substituted propenyl benzenes via a facile reaction involving completely OTC materials.

I've thought about it and thought about it (hard) and it really is that good. The only thing is that neither I nor anyone I know has tried it. But, the literature is, hands down, totally solid.

Hope you enjoy reading it. By tomorrow evening, that is.

I'll give you a hint: DDT & transcoding (as in videos). (If you can guess, please don't say anything more than that. I want the write-up to be a surprise for at least some of the wasps at this site.)

Naf1 · « **Reply #17 on:** April 15, 2010, 12:10:21 AM »

Novel highly selective catalytic oxychlorination of phenols
Luciano Menini and Elena V. Gusevskaya
DOI: 10.1039/b513329g

The highly selective oxychlorination of various phenols
catalyzed by CuCl2 under mild conditions, in which chloride
ions are used as chlorinating agents and dioxygen as a final
oxidant, has been developed.

http://www.rsc.org/delivery/_ArticleLinking/DisplayArticleForFree.cfm?doi=b513329g&JournalCode=CC

82% yield in 6 hours for Eugenol, followed by cu mediated coupling (Ullmann coupling, if you had the Pd a Hiyama or Heck);

Yielding the dimethoxy compound, which could be converted to the corresponding trimethoxy with a methylating agent. I know some will not be impressed with this, but at least it is something!

pmic · « **Reply #18 on:** July 20, 2011, 06:48:35 PM »

im new to all these boards but i recently posted a request on WD for an explanation of the demethylation rxn,but i thought from reading that im much more likely to get a good answer from this forum(undouted).so my question is can some one explain to me how the demethylation rxn proceeds,and also why it is that certain reagents are able to function as these demethylation agents,what is the common denominator amoung these substances that allows them to do this and how do they do this p

akcom · « **Reply #19 on:** July 20, 2011, 08:28:00 PM »

http://lego.chemistry.tripod.com/various/demethylation.html

Quote

Conception, Characterization and Correlation of New Marine Odorants
Philip Kraft, Walter Eichenberger
Eur. J. Org. Chem., 2003, 19, 3745-3743
see also: Patent EP1136481

LiCl (292 g, 6.89 mol) was added to a solution of eugenol (354 mL, 2.30 mmol) in DMF (3.7 L), and the mixture was refluxed for 44 h, with additional portions of LiCl (292 g, 6.89 mol) being added after 4 h, 22 h and 29 h. The reaction mixture was allowed to cool down to room temp., and diluted with toluene (2 L). The formed precipitate was filtered off and washed with toluene, the washings were combined with the organic solution and concentrated in a rotary evaporator. Silicagel FC (Et2O/pentane, 1:1, Rf = 0.37) provided 4-allylpyrocatechol (173 g, 50%).

C-H activation at the mexothy position under acidic conditions could lead to nucleophilic attack. The second paper describes the first step. The issue is going to be that pd(2) hydride species will be hard to generate (and eliminate later) without the aryl iodide to generate the initial oxidative addition complex.

Palladium-Catalyzed C-H Activation at Methoxy Groups for Cross-Coupling Reactions: A New Approach to Substituted Benzo[\b]furans
Dyker, G. J. Org. Chem. 1993,58,6426-6428.

Quote

Palladium catalyzed C-H activation of methoxy groups as the key step in a cross-coupling reaction of o-iodomethoxybenzenes with bromo olefins is described. By this method, substituted benzofurans are synthesized in moderate to good yields

Author Topic: The Eugenol Challenge - Demethylation of Eugenol or Derivitives (Read 641 times)

Vesp

The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Enkidu

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Sedit

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Goldmember

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Vesp

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Naf1

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Enkidu

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Naf1

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Enkidu

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Naf1

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

SOMA

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

headstrong

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Douchermann

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

headstrong

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

SOMA

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Enkidu

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Sulfuro

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

Naf1

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives

pmic

explanation of demethylation

akcom

Re: The Eugenol Challenge - Demethylation of Eugenol or Derivitives