Selective dealkylation of aromatic alkoxylated compounds Selective de-ethylation of
2-ethoxyanisole is achieved by use of KOtBu as the reagent in the presence of 18-
crown-6 as the phase-transfer agent (PTA).

With addition of ethylene glycol (E.G.),
the selectivity is reversed and demethylation occurs (Eq. (61), Table 4.18). Although
involvement of microwaves is favorable in both examples, the second reaction was
shown to be more strongly accelerated than the first [147].
ð61Þ

Demethylation results from the SN2 reaction whereas de-ethylation occurred via
the E2 mechanism (Scheme 4.12).

The microwave-specific effect is more apparent in the demethylation (SN2). Microwave
acceleration clearly is more pronounced with the difficulty of the reaction,
Tab. 4.18. Reaction of KOtBu with 2-ethoxyanisole in the
presence of 18-crown-6 and, optionally, ethylene glycol.

thus constituting a clear example of an increased microwave effect with a more difficult
reaction, indicative of a later TS position along the reaction coordinates. The
microwave effect may also be connected to the more localized charge in the SN2
transition state (three centers) when compared with that of b-E2 (charge developed
over five centers).

the rxn runs 20 mins and yeilds 70% with a home microwave


I cant upload the ref it is too big..


demethylation... i gues it is always there when safrole runs out!

Searching this reaction, i found a link to erowid arrrgh. is there anything they havnt found!

http://www.erowid.org/archive/rhodium/pdf/microwave.chemistry.rationalization.pdf

its in a full document fairly hidden though maybe there is a chance someone missed it?

id like to know how far anyone got with this adventure.. did they see this ref? V16 says eugenol is dead.. hmm

they seemed to be stuck on aluminium trichloride for some reason


oh and one more thing, that NaBH4 of methylmans can be used to microwave reductivly aminate within minutes super high yeilds.. solvent free

i have another question, is there any reason we cant run the wolf kishner reduction on methcathinone to yeild MA?

No reason...but since ephedrine/pse is the main precursor to Methcathinone, kinda useless to oxidize it before reducing it back all the way to the alkane...Unless you can't get RP/I but wants to fuck around with hydrazine hydrate...Anyway, seems overcomplicated to me...


EDIT: Zinc amalgam isn't a Wolff–Kishner reduction and sure won't reduce the ketone tall the way to the alkane...Nobody would hunt for iodine and phosphorus if this worked

Much confusion...


Clemmensen reduction is what your talking about. Wolff–Kishner uses hydrazine to form the hydrazone which undergoes elimination and is protonated with water. I'm fairly sure either would work N-Methyl-Cathinone.

Quote

No reason...but since ephedrine/pse is the main precursor to Methcathinone, kinda useless to oxidize it before reducing it back all the way to the alkane...

Im very confused. It would not be useless it would be completely needed in order to perform the Clemmensen reduction or the Wolff–Kishner.

I'm sorry, I talked out of my ass, without even verifying anything about the zn almalgam reduction/clemmensen he was talking about...

Sorry for the confusion

As Sedit pointed out, you were talking about the Clemmensen reduction. Both reactions reduces a ketone function all the way to the alcane, but using differents reagents

Full PDF download here for those who want the 2006 second edition or won't put up with Scribd's Facebook account bullshit.

h**p://www.filefactory.com/file/42615d/n/MicrowOrgSynth.rar

ahh ok cool thanks heaps..

i guess that second one isnt looking so bad after all, if methanol could sub in for dmf that would be perfect! Either that, or i could add the lithium chloride to the 02 wacker in DMF or DMA run it for a couple days and kill 2 birds with 1 stone

@shake...since methanol is polar protic it would be better substituted with a polar aprotic solvent similar to DMF such as DMSO. the chloride anion formed from the conjugate acid acts as the nuc LiCl.  The lithium just kind of sits on the bottom like a NiOAc beckmann acting as an acid catalyst forming a better right side equalibrium. MeOH might work but DMSO def based on the mechanism.

There were numerous threads on the Hive on the subject, the last one before it went offline:

Chemistry Discourse     Thread:    
    

    All 21 posts           Subject: eugenol demethylation              
    

          
            Cadenza
(Stranger)
05-10-04 17:10
No 506283
                      eugenol demethylation          

The intermediate 4-allylcatechol has been obtained in good yield (75%+) from eugenol.  The process is easy, simple, and scalable; however, there are some issues that I would like to address before writing further on the topic.

1.  Melting point analysis indicates a range between 38-41 Celsius.
2.  IR spec is inconclusive- I can make out twin catechol peaks in the ~3400-3600 range but it is very messy- lots of static everywhere, especially in the upper range (absorbance).  There appears to be no upper limit to the IR spec- this is also a problem with eugenol (but at least eugenol has a clearly defined range > 2000).

In conclusion, does anyone know what might be causing this interference?  Do we even need an IR spec analysis? (Previous reports in literature have been analyzed only through M.P.- gotta love the old days when that was good enough...)

Note: Subsequent methylenation of 4-allylcatechol synthesized by this method has been shown to produce a water-white liquid with a strong root-beer smell.  So I know that there is at least some 4-allylcatechol in there, but the IR is an anomaly, to say the least...
Love is the most powerful force in the universe.      
          
 
          
            embezzler
(Hive Addict)
05-10-04 17:32
No 506289
                      have you got a scan of that ir            

spectrum that you can post?
chemically enhanced.      
          
 
          
            Cadenza
(Stranger)
05-10-04 17:42
No 506291
                      not yet            

It's still at the lab- I could it retrieve it, but I would be very embarrased to post it, as there are so many artifacts in it.   It sure isn't readable to me, but then again I am a very poor analytic chemist (actually not a chemist at all) and perhaps others might be able to shed some light on it.

Incidentally, I am not familiar with IR technique, but generally I don't encounter this sort of spectrum.  Even with the other demethylations that produced tar, severe dilution of the product with IR solvent would get rid of some of noise.  I have diluted the original IR mix at least 100^6 fold, and it is still pretty much producing the same spec.  Perhaps there is some sort of solvent contamination going on here.

Anyway, I will grab a copy of the spec soon and post it if there is interest.
Love is the most powerful force in the universe.      
          
 
          
            embezzler
(Hive Addict)
05-10-04 17:50
No 506294
                      i am no expert either        

but running the solvent as background  should remove any solvent signal, what solvent did you use?

it will certainly be interesting to see......
chemically enhanced.      
          
 
          
            _mu_
(Hive Bee)
05-10-04 18:10
No 506301
                      You (or somebody else) didn't make the IR...          

You (or somebody else) didn't make the IR machine dirty somehow, did you?      
          
 
          
            embezzler
(Hive Addict)
05-10-04 18:16
No 506304
                      thats definately a real problem          

especially in college where accountability is nil. the ionic disks are often in need of serious replacement.
chemically enhanced.      
          
 
          
            homeslice
(Hive Bee)
05-10-04 18:55
No 506311
                      a little off topic        

JW, but what demethylation method was chosen?

    The process is easy, simple, and scalable; however, there are some issues that I would like to address before writing further on the topic.


Im sure more than a few bees, including myself, are very interested in your future writings on the topic. A writeup of how it all went would be fantastic.
Never take a fox's word that the hens are safe.
    
          
 
          
            Cadenza
(Stranger)
05-10-04 20:09
No 506324
                      solvent, IR machine, etc            

embezzler and __mu__:

The background solvent used was CCl4.  I am not fond of working with such toxic reagents, but the catechol and eugenol IR specs from library references used CCl4, so CCl4 was used for the sake of consistency (background should be automagically filtered out, but CCl4 has an advantage in that it doesn't have much of a signature in the OH range).

The IR machine is/has been clean, and for the most part is well-behaved.  Perhaps I will try a different solvent (maybe toluene?)  Or maybe the product is inherently dirty with all sorts of polymerization (it looks OK to me, and the melting point range isn't that bad, but you never know).

With regards to the writeup, I will give more details soon, pending resolution of the IR issue.  For all I know, I've synthesized some crazy polymerized crap (although the subsequent methylenation into safrole appears to demonstrate that at least something is there).  Does anyone know how polymerization or rearrangement into the corresponding quinone will affect melting point range? (i.e. if the quinone is more stable/polar, I would expect the melting point to rise).

homeslice:

This was an amine-base method that I worked out a while ago.  For a while, based one extensive experimentation, I had concluded that triethylamine*HCl caused excessive decomposition of the product under microwave radiation.  More recently I discovered that using a biphasic aqueous layer w/conc. HCl and triethylamine, under long microwave irradiation, would result in demethylation without significant thermal degradation.  The yield of the reaction was largely unknown until Psychokitty gave me some pointers about purifying the allylcatechol (I have not yet found a way to crystallize the product).  It is unknown whether demethylation will proceed under traditional reflux conditions, but I doubt it because the reaction proceeds at the thermal boundary layer between the two phases.  The microwave method relies on the fact that eugenol heats up much faster than water/triethylamine/HCl- I am working out some rough heat transfer calculations right now.

The result is that finally I have a product that is can be ground up (i.e. not viscous at room temp).  I suspect that literature reports about 4-allylcatechol being a "red-yellow viscous solid" are due to eugenol contamination, as this is the type of product that was obtained pre-purification.

In addition, 4-allylcatechol (if this is indeed what I have) has some very interesting optical qualities that I will discuss later.
Love is the most powerful force in the universe.      
          
 
          
            Nicodem
(Hive Bee)
05-11-04 01:55
No 506370
                      If the product is a solid why didn't you ...        

If the product is a solid why didn't you simply make the KBr-pellets for the IR? If it is somewhat oily than you can just disolve it in some DCM and put a drop on a NaCl window, wait the DCM to evaporate an cover with the other NaCl monocrystalic window for the IR. That is the usual procedure for as much as I know. If the spectrum still isn't nice reduce the amount (even 0.5mg can sometimes still give you a nice spectrum).

background should be automagically filtered out, but CCl4 has an advantage in that it doesn't have much of a signature in the OH range

What do you mean by this? How can a bacground bee filtered off without runing it? And where did you hear CCl4 is a solvent for IR? I thought only nujol oil is a useful solvent, though avoided whenever possible. But then again I dont know anything more on making IR spectra than the rutine procedures.

Is the product completely colorless? No 4-allyl-orthoquinone present?
“The real drug-problem is that we need more and better drugs.” – J. Ott      
          
 
          
            Cadenza
(Newbee)
05-11-04 02:21
No 506373
                      depends on what kind of IR you use            

nicodem:

KBr/Nujol mull disks are the most common methods taught in organic chemistry labs (I have done my fair share) but the IR spec setup that I have uses a cuvette (it also does solid-phase scans but setting it up for that is more involved).

Of course the background was run before scanning the sample- you can use any solvent that you want (obviously some are better than others).  However I do not have Nujol on hand (neither do I have KBr discs), so CCl4 it was.  In my experience, liquid phase IR samples are even easier to prepare than KBr-- admittingly, it has been a long time since I have prepared a KBr disc.  If you look at IR databases, you'll see that CCl4 is used quite commonly (although not as common as Nujol/KBr).

The product is far from colorless- it is a characteristic tan color (think wet sand).  Why do you think that 4-allylcatechol is colorless?  Do you have a reference for this?- it has been described as everything from brilliant white to red-yellow to tan colored.  When I was running experiments with pyridine hydrochloride demethylations, the closest I got to a lighter colored substance was a yellow viscous solid (might have been eugenol contamination).

I personally believe that there might be some ortho-quinone present, but I cannot prove this.  If you have any information on the color/MP/properties of o-quinone-allyl, I would be very interested in seeing it, as this would help greatly in identifying contaminants.  In addition, if there is a way to reduce the quinone back to the o-catechol species, I would be interested in that too
Love is the most powerful force in the universe.      
          
 
          
            Nicodem
(Hive Bee)
05-11-04 03:22
No 506383
                      In addition, if there is a way to reduce the...            

In addition, if there is a way to reduce the quinone back to the o-catechol species, I would be interested in that too

That's the reason I ask about color.
The allylcatechol shouldn't bee coloured but the quinone counterpart surely is (probably from green, yelow, brown to red - who knows?). There are many ways to reduce orthoquinones and a suitable reducent could bee added at the work up stage too purify/recycle/discolour the product.
“The real drug-problem is that we need more and better drugs.” – J. Ott      
          
 
          
            embezzler
(Hive Addict)
05-11-04 07:53
No 506408
                      any chance that the ccl4            

was wet ?? water would throw some oh peaks in there...

swim doesnt like to suggest it but too large a particle size will scatter the beam, this problem is common in liquid samples?
chemically enhanced.      
          
 
          
            Cadenza
(Newbee)
05-11-04 11:19
No 506446
                      reducing quinones            

Nicodem:

In general quinones are darker than their phenolic counterparts, right?  I think that your assumption that pure allylcatechol is either colorless or white (like phenol) is probably correct, which is unfortunate considering that I have never come close to obtaining a colorless product sample.  I do wonder if the catechol oxidation is due to lack of inert atmosphere (easily fixed, even in the microwave reactor).

With regards to reducing the quinione contaminants back to o-catechol, do you have any suggestions off the top of your head?  I had always thought that this would be difficult but I have never looked into it.  It would be nice to clear up the color- brown is never a good sign in my opinion!

embezzler:

The CCl4 is (or at least is supposed to be) of very high purity, I doubt that much water gets in the bottle since carbon tetrachloride is so volatile (high vapor pressure).  Since the liquid phase IR always worked on eugenol (some crazy artifacts under 2000 but very clean above that range) I assume that it is an impurity problem with the product rather than the solvent system.
Love is the most powerful force in the universe.      
          
 
          
            lugh
(Moderator)
05-15-04 21:25
No 507407
                      Dictionary of Organic Compounds Entry
(Rated as: good read)          

According to the Dictionary of Organic Compounds, the easiest method for purification of 4-allylcatechol is crystallizaton:


Someone should retrieve and post Schopf's article, he synthesized 4-allylcatechol from eugenol using methylmagnesium iodide
Chemistry is our Covalent Bond                
 
          
            Cadenza
(Newbee)
05-15-04 23:47
No 507425
                      recrystallization          

Lugh:

Thank you for the reference, I will reattempt crystallization tomorrow.  I am not familiar with arcane chemistry notation-- does C6H6-petrol refer to benzene, a mixture of benzene and something another solvent, or petroleum ether, etc?
Love is the most powerful force in the universe.      
          
 
          
            lugh
(Moderator)
05-16-04 08:09
No 507469
                      Imperial System Terminology            

The Dictionary of Organic Compounds is a British publication, the definition from a chemical dictionary

Petrol: A name used in the British Empire (except Canada) to designate gasoline.

IMHO since many non organic polar solvents are fractions of crude petroleum, others may serve as well as gasoline without additives The naptha used by various bees for pill extraction is such a fraction, if that's available it would be a possible option
Chemistry is our Covalent Bond      
          
 
          
            Cadenza
(Newbee)
05-16-04 20:10
No 507575
                      solvents            

Lugh:

Thank you for the clarification (I was aware of the British name for petrol, but I didn't know that it applied here ).  Since I am accustomed to using laboratory reagents, I might try some sort of equivalent mix-- maybe hexanes or pentane.

Incidentally I think there might be some water in the mix (as embezzler noted a while ago) contributing to melting point depression.  This might also be the reason that the IR spec is going crazy-- hopefully slow recrystallization will clear this up.

Do you have more information on the Schopf reference that was alluded to earlier?  I can grab it from the library and scan it in if there is interest.
Love is the most powerful force in the universe.      
          
 
          
            Rhodium
(Chief Bee)
05-17-04 19:16
No 507775
                      Schöpf: MeMgI Demethylation of Eugenol
(Rated as: excellent)            

Here is the article containing the grignard demethylation of eugenol - The actual procedure is detailed on pages 49-50 and they say that their yield of pure 3,4-dihydroxyallylbenzene from methyleugenol after treatment with methylmagnesium iodide is 33%, and that both eugenol and safrole reacts just the same, but gives a slightly less pure product.

Die Synthese des 3-Oxy-4-methoxy-phenylacetaldehyds (Homoisovanillins) und des 3,4-Dioxyphenylacetaldehyds (Homoprotocatechualdehyds)
von Clemens Schöpf, Eva Brass, Ernst Jacobi, Walter Jorde, Walter Mocnik, Ludwig Neuroth und Walter Salzer
Ann. Chem. 544, 30-62 (1940) (https://www.rhodium.ws/djvu/schopf-ann.chem.544.30-62.1940.djvu)
The Hive - Clandestine Chemists Without Borders      
          
 
          
            L42L
(Newbee)
05-20-04 20:02
No 508504
                      questions        

Wow cadenza cool beans.

As others, can’t wait to hear about your method.

Would LOVE to hear about your experiments with pyridine-HCl as well.

“under long microwave irradiation”
Long as in time? Are you using a mono-modal or domestic-ish system.

Have you toyed with the methanesulfonic acid demethylation?
(post # No 379200)
Would love to see how that one works in a non mono-modal reflux.

You sound busy, thanks for your time and experimentation!      
          
 
          
            Cadenza
(Newbee)
05-21-04 22:20
No 508710
                      microwave type etc.          

Rhodium:

Thanks for the ref-- interesting info! (where do you find this stuff?  I thought that I had pretty much read everything in the literature concerning eugenol->4-allylcatechol)

L42L:

The microwave was a standard commercial model (i.e. multi-mode) with a hole drilled in the top to allow for a passage to a reflux condensor.  In fact, I got the idea for the microwave setup from one of Rhodium's posts.

Microwave reactors are very easy to construct from domestic microwaves.  I do not recall if anyone on this board has actually made one, but it took less than 2 hours to build, equip, and make the necessary modifications in order for the oven to work.  The entire cost of the project was on the order of $40 ($10 for the actual modification, $30 for the microwave detector).

In my experience, the microwave leakage is almost negligible.  Of course, it is always wise to check irradiation levels, but I noticed that within a five foot radius, there was essentially no radiation-- even without the pipe shielding the condensor.

The main reason that I like microwave experiments is that they are very fast and easy to conduct- far more convenient than traditional reflux, which is about as easy as you can get in terms of orthodox methods.  The irradiation time used in this particular instance was 90 minutes, but I think it was total overkill; I hypothesize that it could reduced to < 30 minutes without change in yield, and perhaps this would help reduce polymerization etc.

The two most important outcome of the experiments (thus far) were:

1)  The substitution of triethylamine for pyridine in an aqueous reaction matrix.  Hitherto, the type of amine-base used in microwave cleavage had been severly restricted by the melting point of the respective hydrochloride salt.  But since the reflux point is lowered with the addition of water, product composition does not appear to occur (it is true that the reaction probably also occurs much slower, but experimentation suggests that it doesn't impact the yield).

I would like to point out that there are a lot of amine-bases available, including variations of pyridine (i.e. picoline etc.) as well as other aromatic/non-aromatics.  Research into these could yield useful results not only for eugenol demethylation, but for ether cleavage in general (who really wants to mess with BBr3 or pyridine when deprotecting aryl ethers?)

2)  The mole ratio was bumped down from 5:1 all the way to 1.5:1 (triethylamine:eugenol) and triethylamine is still present in excess.

I haven't tried the methanesulfonic acid method-- it might be interesting for a future project, but I chose to stick with the amine-bases this time, mainly because there are so many of them.

I would suggest that if anyone is interested in the conversion of eugenol to safrole (or in methylenation reactions in general) that the second synthetic step (catechol -> benzodioxole) be first established.  I have tried many of the methods, including PTC w/TBAB/wide variety of surfactants as well as DMSO, with poor results.

The reason I say this is that the result from the first (and only) reaction that I ran from 4-allylcatechol -> safrole resulted in a yield of 20% safrole (overall).  This reaction was carried out with some no-name PTC that I had never heard of, but subsequent runs with established PTCs failed to improve the situation.  So until a reliable method is found to methylenate m-sterically hindered catechols (and I mean by experimentation, literature can fudge a lot ) there will be a lot of guesswork involved.

As a side-note, neither pyridine*HCl nor triethylamine*HCl/triethylamine*aqueous HCl demethylated vanillin at all under microwave irradiation.  But then again, if you want to synthesize protocatechualdehyde (isn't this available commercially?) you could always use amine-base/AlCl3 in ethyl acetate, etc.
Love is the most powerful force in the universe.      
          
 
          
            Rhodium
(Chief Bee)
05-21-04 22:26
No 508711
                      how to find the good stuff          

where do you find this stuff?

The Schöpf article was found in Post 507407 (lugh: "Dictionary of Organic Compounds Entry", Chemistry Discourse), but I usually find stuff by back-tracing the references from all articles of interest, as well as checking Beilstein to find new leads when searching.
The Hive - Clandestine Chemists Without Borders

The article by Schopf in pdf format is attached