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              Musings on the Synthesis of Safrole from Eugenol
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Rev Drone, posted to the Hive 01-11-99

Strike,

I think I see where your cencern about the use of AlCl3 stems from, and I
wanted to clarify this issue, if I haven't already (sort of preliminary
notes on the forthcoming report.) In TSII, you describe how AlCl3 can
destroy safrole, and this is to be expected. However, that same phenomena
that will wreck safrole is precisely what is being taken advantage of in
the case of demethylating eugenol.

Anydrous AlCl3 is a relatively strong Lewis acid. It bonds with the lone
pairs of electrons on the oxygens in the ethers. When this complex is
hydrolyzed, the ether is cleaved. When you do this to safrole, you can
definately expect a mess, since the methylenedioxy ring gets cleaved, and
things can get even more out of hand from there. In the case of eugenol,
this cleavage is exactly what we're looking for.

The use of lewis acids to cleave aryl methoxy groups has a long history of
success. Its by far the most gentle, most widely appilcable procedure for
doing this. The following is a list of demethylations employing aluminum
chloride or boron tribromide on a wide variety of different compounds. Its
interesting to see that this reaction is so selective, that by carefully
measuring out the amount of Lewis acid, selective ether cleavages can be
undertaken successfully:

(demethoxylation of N-allyl norcodeine derivatives; can't get pickier than that)
J.Amer.Chem.Soc.; 75; 1953; 4963, 4966;

(cleavage of 3-methoxy allylbenzene)
Helv.Chim.Acta; GE; 61; 1978; 401-429;

(cleavage of allyl-containing heterocyclic opioid -related compound)
J.Med.Chem.; EN; 21; 1978; 423-427;

(another convoluted methoxylated polycyclic arene, with an allyl dangling
randomly from another ring)
J.Med.Chem.; EN; 29; 4; 1986; 531-537;

There are literally dozens more examples, but I'll leave those for a later date.


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Psychokitty, posted to the Hive 01-11-99

This is really weird, Drone, because I was just about to post why it is
that AlCl3 CAN'T be used to demethylate eugenol. But my reasoning was based
on a section that I read in a very prestigious organic chemistry textbook
wherein, as one example, tetralin was being synthesized using a
butylbenzene with a chlorine atom dangling from the very end of the butyl
aliphatic side chain. This reaction, according to the text, is applicable
to any situation where the starting compound has a similar structure (one
having a susceptible group at the end of the side chain, such another
halogen, an alcohol group, or, would you believe it, a double bond!). So
the AlCl3 catalyzes in Friedel-Crafts fashion the cyclization of the side
chain, which in this case, forms the desired tetralin. With this new
information, I was about to suggest that using AlCl3 to cleave eugenol's
methoxyl group would only actually serve to cyclize the allyl side chain to
form a substituted indan ring. This would be good if one could make use of
such a thing, but for the purposes of demethylating eugenol . . . no, I
don't think so. But as I'm very happy to see, I was wrong. After all,
what's with the 3-methoxyallylbenzene cleavage? If AlCl3 ether cleavage can
work effectively on that molecule, I see no reason why it can't work on
eugenol. Perhaps the reason AlCl3 does work in this case is because of the
3 carbon allyl side chain in eugenol in contrast to the 4 carbon butyl side
chain in the above tetralin synthesis example. Maybe the double-bond is not
the best candidate for strong effecient reactiveness in the aforementioned
cyclization reaction. Who knows and who cares, because all that matters is
that the damn thing works!

I've come up with a protocol that obviates the typical eugenol to
allylpyrocatechol route. I figure that the best way to go about tackling
this problem is to try to use a simple, readily available, easily
synthesized cleaving agent that is generally safe to use, is predictable,
that works in an efficient fast manner producing high yields of product
while having little or no need of various other chemicals or solvents, that
provides an easy work-up, and that can be applied in a manner that has
already been detailed in the literature. My method meets all of the above
criteria. As an added plus, it bypasses the use of any controlled
precursors (unless you want to invoke the analogues law, which won't apply,
I'll later explain). It makes use of all the good work that has been poured
into the hive by dedicated bees, and in turn, offers an easy-to-follow
scheme that is all-too likely to work. Pay close attention all you busy
bees who already have basic experience with the standard safrole to MD-P2P
to MDA route. This method is so straight-forward, that you can begin
experimenting with it as soon as possible, because unlike all other ether
cleavage reactions, this one is pretty hard to fuck up, unless, like Strike
says, you're a total fucking idiot.

Excited? I am. Now for the goods:

I decided that the first step of oxidizing eugenol to methylvanniyllketone
(MVK) should be an already established one. I have no doubt that using the
Wacker to effect this change would work better than well. It's just that
to give my method more credibility, I need to have a proceedure that has
already been proven to work.

First, eugenol needs to be isomerized to isoeugenol. I've read that the
standard EtOH/KOH method is not well-suited to eugenol in that the reaction
produces low yields of isoeugenol. If one were to just use the Wacker on
eugenol, then this step could be skipped, but for the sake of accurracy,
I'm going to have to include it.

This method was originally applied to synthesizing isosafrole from safrole.
It is a super method that I have no doubt will work equally well on eugenol
to make isoeugenol.

Eugenol (500g), iron pentacarbonyl (2.5g), sodium hydroxide (1.6g) were
mixed in a 1Lt flask equipped with stirrer, thermometer and condenser. The
well stirred reaction mixture was heated to 110degC at which temperature a
vigorous reaction commenced, causing the temperature to rise to 1890degC in
6 minutes. After cooling the mixture, 250 ml of 2N acetic acid were added.
The organic layer was separated from the aqueous phase and washed with brine
to neutrality. After drying and evaporation of the solvent the mixture was
distilled from a Claisen flask and gave 485g (~97%) of isoeugenol.

The next step uses Strike's sentimental favorite. There are two variations
presented, though: a.) the peroxidation of isoeugenol to form the intermedate
diol which is dehydrated to MVK; and b.) the reaction of peracetic acid with
isoeugenol to form the epoxide, which is then hydrolyzed to the diol, and
lastly dehydrated to MVK.

Taken from UK Patent 2,059,955 A.

MVK from isoeugenol (through process)
A solution of 30% aqueous hydrogen peroxide (9ml,85.5mm) and formic acid
(16ml,88%)is added to a solution of isoeugenol (8.1g,50mm) in formic acid
(4ml). The reaction mixture is stirred at 35-40degC under nitrogen atmosphere
for 3 hours. The resulting 1-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-
monoformate is treated with 10% aqueous sulfuric acid (125ml) and toluene
(125ml). After refluxing with mixing for 6 hours, the reaction mixture is
cooled to room temperature, and the toluene layer separated. The aqueous layer
is extracted with fresh toluene and the toluene layers are combined, washed
with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate and
concentrated to give MVK in 48% yield. Purification can be done one of two
ways. The MVK can either be distilled under reduced pressure or it can be
separated by stirring with 5%NaOH in which it forms the sodium phenolate which
is soluble in the aqueous phase. The solution is then extracted with solvent
to remove the non-phenolic compounds and then acidified to release the MVK.

This next method uses the through process also, and makes use of a buffer much
like the process described in CA (1975)82,72640.

MVK from acetyl isoeugenol
A mixture of isoeugenol (8.21g,50mm), acetic anhydride (5.62g,55m) (feel free
to substitute this very naughty chemical with the less proscribed
triflouroacetic anhydride), and anhydrous sodium acetate (0.41g,5mm) is heated
at 100-105degC under nitrogen atmosphere for 2.5 hours. The reaction mixture
is cooled and diluted with 65ml of toluene before a solution (11ml) of 38.6%
peracetic acid and 0.85g of sodium acetate in acetic acid is added slowly.
After heating at 50-60degC for 2-3 hours, the reaction mixture is cooled to
20degC and treated with aqueous sodium bisulfite (2.8g) to destroy excess
peracetic acid. The entire mixture is mixed with 8ml of toluene, 50ml of 14%
aqueous sulfuric acid, and is heated with stirring to reflux for 12.5 hours.
After cooling to ambient temperature, the toluene layer is separated, and the
aqueous layer extracted 3 tms 20ml toluene. The toluene layers are combined,
washed with saturated aqueous sodium sulfate, dried over anhydrous magnesium
sulfate and concentrated in vacuo to give MVK in 85.3% yield.

The next step is standard. There are many good various ways to get to the
amine. Personally, from the established list of methods, I'd pick the
reduction using sodium cyanoborohydride. But for the sake of novelty, I'm
going to include another more promising method that has yet to get much
attention, but which will eventually supplant sodium cyanoborohydride as the
#1 reagent used to get to MDA.

This next method is very clean and high yielding, and uses two cheap reagents
(sodium borohydride and titanium(IV)isopropoxide) which are unwatched, readily
available, and safe.

A mixture of MVK(10mm), titanium(IV)isopropoxide (5.7g,20mm), ammonium
chloride or methylamine (20mm), and triethylamine (2.5g,25mm) in absolute
ethanol (10ml) was stirred at room temperature for 20hr. Sodium Borohydride
(.95g,25mm)was then added and stirring was continued for a further period of
20hrs. The reaction mixture was quenched with 30ml,2N)of ammonium hydroxide,
the resulting inorganic precipitate was filtered and the aqueous solution was
extracted with dichloromethane (50ml tms 3) to separate the neutral materials.
The aqueous solution was then made alkaline by addition of 10%NaOH (pH=10) and
extracted with dichloromethane (50ml tms 3). The combined dichloromethane
extracts were dried (K2CO3) and concentrated in vacuo to give 2.2g (75%) of
3-methoxy-4-hydroxyamphetamine (MHA?) or 3-methoxy-4-hydroxymethamphetamine
(MHMA?).

Information for the above posts was taken from the following references:

JOC 1995, 60, 4928-4929 "Reductive Alkylations of Dimethylamine Using
Titanium(IV)Isopropoxide and Sodium Borohydride: An Efficient, Safe, and
Convenient Method for the Synthesis of N,N-Dimethylated Tertiary Amines"

SYNLETT, Oct. 1995, pp1089-1080 "An Efficient, Safe and Convenient One-Step
Synthesis of B-Phenethylamines via Reductive Amination Reactions Utilizing
Ti(OiPr)4 and NaBH4"

The next step is the most ground breaking of all. Strike, you're always
complaining about how HBr has always proven to be less than ideal when it
comes to ether cleavages forming low yields of product with the unfortunate
concommitant formation of loads and loads of tar. So naturally, you have
little expectations of HBr's efficiency and plenty of doubts that it will ever
be appied to any worthwhile degree to the formation of that oh-so-desirable
catechol species we're all after. Well, I think I've found exactly what you've
been looking for: A method whereby ether cleavage is effected rather cleanly,
in high yield, simply, using a readily available reagent, in a short amount of
time. Here we go:

One part of 3,4-MHA or 3,4-MHMA is refluxed for 1-2 hours in 5 part of 48% HBr
to yield 80-90% 3,4-dihydroxyamphetamine (DHA) or 3,4-dihydroxymethamphetamine
(DHMA). And that's it! The solution is completely homogenized and is low
enough in volume to make scaling up cheap and easy. And the HBr can even be
recycled too.

Next part:
The HBr solution is distilled at room temperature or under reduced pressure.
Care is taken that the heating bath never exceeds 150degC as the melting point
of the amphetamine salt will be somewhere above 150degC area (I don't have the
exact melting point yet). After all the acid has evaporated, there is left a
colored residue which is dissolved in alcohol, decolorized with Norit
(activated carbon), and precipitated by adding ether. The salt should be
sufficienty pure to use in the next step.

Information for the above post was taken from the following references:

Fred W. Hoover and Henry B. Hass. JOC, 1947, pp.501-505
"SYNTHESIS OF PAREDRINE AND RELATED COMPOUNDS"

G. Hildebrandt, US Patent #2,344,356
"CHEMICAL COMPOUNDS B-(META-HYDROXY-PHENOL)-ISOPROPYLAMINES"

JACS 54, p271 (1932) & 60, p465 (1938)

One that I haven't check out but is applicable is JCS 1951, pp.2248-52.
Someone get the article for me please so that I can know what the yield is of
3,4-DHA from 3,4-DMA hydrolyzed under reflux in HBr.

Now for the next step. The methylenation reaction. Admittedly, this is the one
step where I feel all of us are wading in the dark. It's not that performing
it would bee especially difficult. It's just that no one knows how effective,
in terms of yields and EXACT reaction conditions, it will be. My interest was
in choosing a methylenation reaction that would allow one to proceed smoothly
from the previous reaction into the next and last step towards the final
product. My needs have led me to the previously published hive proceedure
using a PTC, excess dichloromethane, water, NaOH and in this case, the
catechol-amine which is then reacted for cal. 5 hours at 70-80degC under 2.4
atm of pressure. Now before I move on, I'd like to comment on the concern that
many bees seem to have about the effectiveness of using an "unprotected" amine
in the methylenation reaction. In regard to this, I'm stumpted as to why
anyone is concerned at all. Perhaps they just don't understand the reaction
mechanism. Allow me to enlighten and elaborate. The methylenation reaction
with which all of us are so familiar is formally called the Williamson
Reaction. What is occuring at the molecular level when it is carried out is as
follows:

NaOH, a base, reacts with the catechol (an acid) forming the sodium
catecholate, a salt through a simple neutralization reaction. The halogens in
the dichloromethane react with the sodium catecholate by swapping
(substituting) their halogens with the Na atoms to form NaBr and the desired
methylenedioxy compound. And that's it! With PTCs, the reaction is made to go
faster and in higher yield. But the reaction mechanism remains the same. With
dipolar aprotic solvents, the SN2 reaction (don't ask) occurs faster, but
again, the reaction mechanism remains the same. In the methylenation reaction
using KF, the KF handles the task that the NaOH normally would, except it does
so better. Other than that, everything else stays the same. It is common
knowledge for those who understand the nature of this reaction that because of
the way it occurs, many functional groups are tolerated during the course of
the reaction . . .

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Psychokitty, posted to the Hive 01-12-99

Okay, sorry, sorry, sorry. The correct temperature in the isomerization step
is 180degC. In the reductive amination step, use methylamine HCl, not
methylamine base. And in regard to the explanation of the Williamson Reaction,
it should be NaCl and NOT NaBr that is formed as a byproduct. Sorry about the
little mistakes. If any of you happen to catch any more, I'll be happy to make
the corrections . . . Now back to where I left off yesterday.

Ah, yes! Regarding the feasibility of using the free base amine in the
methylenation reaction. Well, there's nothing more to write about beyond that
which I posted yesterday. By every rule in the book that I know of, a catechol
with an amino function incorporated into it should present no problems when
used in the Williamson Reaction. If I'm wrong and any of you bees out there
can explain why, then believe me, I'm all ears. But, again, I'm concerned
aboout my method not being as all-inclusive as everyone should expect it to
be, so for the sake of accuracy, I'm going to add one additional step before I
proceed to the actual methylenation: The protection of the amino group.

Okay, here we go!

First, isolation of the amine free base is in order. Catechol-amines, from
what I can tell, are pretty tricky when it comes to using standard basifying
techniques. Why? Well, in this case, if you just basify with NaOH as usual,
you won't get the expected free-base, but instead, will be left with an
homogenous base solution with the following dissolved in it: NaOH and the
sodium catecholate of 3,4-DHA or 3,4-DHMA. So then how does one go about
liberating the free base? Well, I've read time and again that phenols are
insoluble in sodium bicarbonate solutions. Why? I don't really know, actually.
But what I do know is that sodium phenolate is decomposed by atmospheric
carbon dioxide, so it's my guess that the carbon dioxide that is essentially
part of sodium bicarbonate is what contributes to the retardation of the
formation of the sodium phenolate, making phenol insoluble in sodium
bicarbonate solutions. Who knows? I sure don't. But I would appreciate any
comments from my fellow bees regarding this perplexing issue. Anyway, back to
the basification step: It seems to me that a sodium bicarbonate solution of
about 25% might be sufficient to neutralize the amine-hydrobromide, thus
liberating the free-base amine. I suppose this step could be used immediately
after the ether group has been hydrolyzed, simply by cooling the HBr solution
and then basifying right of the bat. However, I think it more prudent and
conservative to evaporate the acid first, and then basify. In the end, though,
its up to the experimentor.

Another alternative to basifying with NaOH would be to use concentrated
ammonium hydroxide. In this way, there would be no Na ions in the solution to
contribute to sodium catecholate formation. After basification, simply
extract, dry, and evaporate to get the desired free-base. Weigh the amount
thats there and then go on to the next step. . . .

The information contained in the next post was taken from the following
reference:

J. Med. Chem. 1993, 36, 3700-3706.
"Synthesis and Pharmacological Examination of Benzofuran, Indan, and Tetralin
Analogues of 3,4-(Methylenedioxy)amphetamine"

Synthesis of
N-(Triflouroacetyl)-1-(3,4-dihydroxyphenyl)-2-aminopropane. To an ice-cooled
solution of 16mm of 1-(3,4-dihydroxy)-2-aminopropane (your isolated free base
from the last step) dissolved in 100ml of dry CH2Cl2 was added 2.0g (19.7mm)
of triethylamine. The mixture was stirred for 10 min and 9.8 (49mm) of
triflouroacetic anhydride in 50ml of CH2Cl2 was introduced dropwise to the
reaction vessel over a 10-min period. The reaction was allowed to warm to room
temperature. After 1.5h the solvent was removed by rotary evaporation and the
oily, yellow residue was taken up in ether. The organic phase was washed with
H2O (2 tms 25ml), 2N HCl (25ml), 5% NaHCO3 (25ml), and brine and then dried
over MgSO4 and filtered through Celite. After complete removal of solvent in
vacuo, a quantitative yield of white solid was obtained (may not be a solid in
this case). This was recrystallized from ethyl acetate-petroleum ether to
afford ~89% of the desired product as fluffy white crystals.

For those interested, the above reaction is not vigorous enough nor at a high
enough temperature to create problems with attendant formation of the
3,4-triflouroacetyl ether through reaction of triflouroacetic anhydride and
the catechol. Just thought you'd like to know.

Anyway, so now we have our "protected amine".

On to the methylenation reaction.

Although the reference I got this from didn't indicate so, my impression is
that there should be stirring of the mixture throughout the course of the
reaction.

Using the unprotected amine:

100ml (1.56m) of methylene chloride, 0.02m of hexadecyltributylphosphonium
bromide (PTC) and 200ml of water were placed in an autoclave, and a total of
0.2m of 3,4-DHA-HBr or 3,4-DHMA-HBr and 33 or so grams of NaOH flakes (Note 1)
in 30ml of water were added in stages at a temperature of 70degC (Note 2). The
pressure increased to a maximum of 2.4 atm, and the reaction was continued for
4h. After this time the reaction mixture was cooled to ambient temperature,
the organic phase was separated and the excess methylene chloride was
recovered by distillation. Yield is ~70%.

Note 1: The original amount of NaOH was 27.6g [0.6m] but because of the amine
is in its HBr salt form, more NaOH will be needed in order to neutralize it.

Note 2: The reference I used indicated that the temp was 700degC. Naturally, I
assumed it was a typo.

Information for the above post was taken from Rhodium's site under the
guest.eugenol.txt. The original information came from the following British
patent spec.: 1,518,064.

So now where do we go? Well, first, let's determine where we stand.

If the unprotected catechol-amine is used directly, then through the course of
the reaction, the NaOH reacts with amine hydrobromide to first form the free
base, and then the free base reacts with the excess NaOH to form the
respective sodium catecholate. The sodium catecholate then reacts with the
methylene chloride to form the desired MDA or MDMA product.

Unlike typical methylenation reactions, this one takes place through the
heating and agitation of two immiscible phases. It is the presence of a PTC
which optimizes this reaction by carring the normally insoluble ions from the
polar phase down into the organic non-polar phase. This, of course, expedites
the rate of the reaction. At the reaction's end, there will be two immiscible
phases. The bottom is the methylene chloride layer having dissolved in it the
PTC salt, possibly some dimer, and hopefully, the desired MDA or MDMA. The
upper polar phase will contain NaOH and possibly some unreacted sodium
catecholate. The layers are separated and the methylene choride layer should
be washed several times. Crystallization can be commenced at this point, but
it would be best to back-extract the amine from the methylene choride with
either 15% HCl or 10% H2SO4, separate the organic layer, and then basify the
acid solution to liberate the amine. Reextraction with a suitable solvent and
subsequent crystallization may be the next way to go. Otherwise, reextraction,
then solvent separation, drying, and then evaporation, followed by vaccum
distillation of the product, is in order. Expected yield ~70%.

If the protected N-triflouroacetyl-catechol-amine is used, then do not
increase the amount of NaOH in the reaction; instead, use the original 27.6g
(0.6m). Proceed as instructed above. After the completion of the reaction,
isolate the N-triflouroacetyl -MDA or -MDMA through evaporation of the
methylene chloride and proceed to the following deprotection step:

A solution of 5.12mm of protected amine in 110ml of 2-propanol (IPA,
isopropylalcohol, rubbing alcohol)was vigorously stirred while 10ml of 2N KOH
was added, and the mixture was heated at relux for 5h. After cooling, the
solvent was removed by rotary evaporation. The residue was taken up into 150ml
of 3N NaOH and the aqueous solution was extracted with CH2Cl2 (4 tms 50ml).
The organic fractions were combined and then extracted with 4 tms 50ml of 3N
HCl. The acidic aqueous extracts were combined and then basified 5N NaOH to pH
11 (external damp pH paper) while cooling on an ice bath. The free amine was
extracted into CH2Cl2 (4 tms 25ml)and the organic phase dried (MgSO4),
filtered through Celite, and concentrated on the rotary evaporator. The
residual yellow oil was dissolved in 15ml of anhydrous ether, and the
hydrochloride salt was formed by the addition of 6ml of 1.0 N HCl in anhydrous
ethanol. After removal of the volatiles by rotary evaporation, the resulting
white solid was recrystallized from ethanol-hexane to yield ~78% of white
crystalline MDA or MDMA.

Information for the above process was taken from the aforementioned J. Med.
Chem., 1993, 36, 3700-3706.

A few final notes of worth:

1. During the hydrolysis of the vanniyllisopropylamine in the refluxing HBr
solution, there will be considerable MeBr evolved. Therefore, steps should be
taken to efficiently vent this poisonous by product. Those with the knack to
do so, can pump the MeBr gas into a cooled alcoholic solution for later
reaction with hexamine and NaI to form methylamine-HCl.

2. To the voters: During your deliberation on the merits of this method,
remember to remain focused on the efficiency of the ether cleavage. Strike
said he was mostly going to base his final decision about which method is best
by only generally considering the catechol-forming step. So it seems like all
other proceedures, such as those detailing the formation of the ketone and
amine, are to be considered as nothing more than window dressing. However,
they are included in my post to make the method complete. Remember, ether
cleavage of eugenol and MVK followed by methylenation to form safrole and
MD-P2P, are methods far from established and rife with guesstimations and
uncertainties as to the length of reaction time and the likely but
questionable yields. Those methods are, at best, far from established and
would require numerous tests to determine exact and accurate parameters. My
hydrolysis step, however, is quite established. And for all you gripers out
there, I know what you're thinking: None of the examples that I gave actually
use vanniyllisopropylamine in the hydrolysis step. Well, yes, that's true, but
I did find relevant experimental information that allows one to make a very
accurate educational guess as applicabilty of the HBr hydrolysis step. I mean,
come on! No one is going to tell me that because vanniyllisopropylamine isn't
4- or 2-methoxyamphetamine or 3,4-dimethoxyamphetamine, that it isn't going to
react in the same way! That instead, one is going to go from 80-90% yield,
down to 20% with the unfortunate concommitant formation of loads and loads of
tar! To suggest such a thing is ludicrous! Furthermore, if it were likely,
then I would say that we're all in a lot of trouble. Why? Well, if you think
MY example needs to be more substantiated, then consider how far off the mark
the other TOTALLY untested methods (such as the hydrolysis of eugenol using
god-knows-what historically unappied reagent) really are.

3. This is for those of you who think that refluxing the amine salt to form
the catechol-amine in concentrated HBr is nothing more than a recipe for the
formation of a butload of tar. I ask you this: What is presently the most
popular way of synthesizing d-meth from ephedrine? Answer: The red-P/HI
reduction! And how does this reduction occur? By refluxing the ephedrine in
concentrated HI! How long is this reaction? Fucking 24 hours! What are the
yields and purity of product typical of this reaction? High! So what's the
problem with refluxing the amine in concentrated HBr for just one hour? THERE
IS NO PROBLEM!

4. For those of you who would prefer to use the cheaper and more readily
available concentrated HCl to effect the ether hydrolysis, refer to the
following:

JACS 54, 271 (1932) & JACS 60, 465 (1938)

You'll have to carry out the reaction in an enclosed vessel under pressure.
Yields and reaction time are about the same. Don't know how you're going to
safely vent out all that MeCl byproduct, though.

5. One other interesting thing. It seems pretty clear now that it will be
unfeasible to sythesize ether substituted amphetamines through the HI
reduction of their ephedrine counterparts simply because ether cleavage is
going to occur much much faster than reduction of the beta-hydroxy group.
Wierd, huh?

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Psychokitty, posted to the Hive 01-14-99

Taken from JOC Vol.23, pp.1783-1784.

Looks like your idea about hydrolysing MVK to form the dihyroxyphenylacetone
was right on the mark, Mr. Drone. The following is a demethylation sythesis
using concentrated HI as the cleaving agent. Yields are a little low, but hey,
you wisely suggested using a PTC to avoid that problem. The following sythesis
uses 2,3-dimethoxypropiophenone as its starting material. It's not too
different from MVK, so using MVK in its place should proceed smoothly.

2,3-dimethoxypropiophenone (2.8g) was refluxed with hydriodic acid (11g) and
an equal volume of glacial acetic acid for 6 hr. The reaction mixture was then
poured onto ice and left over-night. The precipitated product was filtered
off, dissolved in benzene, and the dark solution treated with charcoal. To the
filtrate after concentration, a few drops of petroleum ether (40-60degC) were
added, whereby 2,3-dihydroxypropiophenone separated out. It was recrystallized
from petroleum ether (40-60degC) in pale yellow crystals, mp 53degC, yield
41%. It gave a green color with alcoholic ferric chloride solution which
changed to red on the addition of sodium carbonate solution.

As for the last part of the above scheme, I'm not sure that it would definitely
apply. Depends, I guess, on whether or not 3,4-dihydroxyphenylacetone is a
solid at room temperature.

Next on the hit list is another example where a lewis acid is employed - AlBr3 -
as the cleaving agent. According to a limited review I read recently, its even
better than AlCl3 for that purpose. Again, I don't know if there would any
side reactions due to eugenol's double-bond. But to me, it doesn't matter
because this method requires the use of way too much toxic solvent (acetonitrile
or carbon disulfide) for converting such a paltry amount of eugenol.

Somewhere in the article, the authors rambled on about how they were very
selective and careful about which demethylation they chose to employ. And,
although the method is not all that great, I enthusiastically applaud these
guys because in most of the other papers I've read, nothing more than basic
information is ever offered. You all know what I mean.

The final product on this one is a benzaldehyde called Atranol. Must have been a
much-needed compound back in 1948. Anyway, I guess this means that AlCl3
complexes with ketones but not with aldehydes. Who knows. Who cares. Here's the
goods on the proceedure:

To a solution of 5g of atranol dimethyl ether in 250ml of carbond disulfide in a
500ml round bottomed flask fitted with a mechanical stirrer, 22g of aluminum
bromide (3 moles per aldehyde) in 250 ml of carbon disulfide was added quickly
with stirring. The addition complex precipitated as a red gum. After stirring
for one hour the carbon disulfide was decanted into a separatory funnel and 100g
of crushed ice, 150ml of 3N hydrochloric acid and 200ml of ether was added to
the residual gum in the flask and stirred until it was completely dissolved (one
or two hours). The carbon disulfide in the separatory funnel was washed with 3N
hydrochloric acid, the carbon disulfide layer was discarded and the acid layer
added to the mixture in the flask. The ether layer was removed and the aqueous
layer extracted with two 200-ml portions of ether.

The combined ether solutions were extracted with three 50-ml portions of 1 N
aqueous sodium hydroxide. The atranol was precipitated from the alkaline
solution by addition of concentrated hydrochloric acid. The product was
filtered, washed with a little water and recrystallized from 125 ml of boiling
water (Norit). Yield (average of twelve runs), 2.9g (70%)of slightly yellow
product of adequate purity for the next step.

Information for the above post was taken from the following citation:

JACS Vol. 70, pp.2120-2122 (1948)

Now we come to the grand prize offering. I must say that I truly love the
potential the next method has to offer. The reaction is quick, the yields are
high, only one reagent is used to effect the cleavage which it seems can also be
recycled, no toxic by-product seems to be formed, and best of all, 4-hydroxy-
3-methoxy-propiophenone is used as the starting compound! Short of finding a
published proceedure detailing the ACTUAL ether cleavage of EUGENOL, things
can't get any better than this, folks! . . . Oh, what am I saying? Of course it
can!

The proceedure detailed in the following post was taken from several different
sources. For those that want mechanistic proof of the method, refer to Fieser
and Fieser's "Reagents for Organic Sythesis, Vol 1". I don't remember what the
page numbers were. Just look up "pyridine hydrochloride" in the index and turn
to the relevant pages. Easy enough. Let's proceed.

Preparation of 4-propionyl catechol. Taken from JOC Vol 26, pp.2401-2402 (1961)

A mixture of 5g of 4-hydroxy-3-methoxypropiophenone and 10g of redistilled
pyridine hydrochloride was gently refluxed (200-220degC) for 10 min; after
cooling and addition of dilute hydrochloric acid, the precipitate formed was
washed with water and recrystallized from aqueous ethanol, giving
4-proprionylcatechol in 80% yield.

Here's another way to proceed after the reflux step. Details to the process were
taken from JACS Vol. 79, pp.147-148 (1957).

After cooling, the fused mass was crushed in 15ml of 5% hydrochloric acid and
the mixture extracted with ether. The etherial solution was washed with water,
extracted with N potassium hydroxide, the combined basic extracts washed with
ether, then acidified with concentrated hydrochloric acid and stored over-night.
There was obtained the final product as colorless crystalline material.

And there's even another way to go.

Taken from JOC Vol. 27 pp.4660-4662 (1962).

After the flask has cooled, the reaction mixture was dissolved in ether and
diluted with water. After three extractions with ether, the combined extracts
were washed with dilute sodium chloride solution and dried over anhydrous sodium
sulfate. The solution was evaporated almost to dryness and the residue
crystallized from a benzene-petroleum ether mixture to give the purified desired
product.

I'm sure the pyridine can be recycled but I don't really know exactly how right
now. That's a proceedure I'll outline later.

Oh, I forgot to mention something! If it turns out that this reaction is
incompatible with eugenol, then what needs to be done first is the oxidation of
eugenol via the Wacker to form MVK. Then one can proceed to the above
demethylation step. MVK, I'm quite sure, can be used in place of
4-hyroxy-3-methoxypropiophenone as there is only one slight difference between
the two. Namely, where the carbonyl group is located on the propane side-chain.

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