enima
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From Anise Star to Mescaline.
Anise star oil contains anethole. Anethole is a 4-methoxypropylbenzene. It a cheap essential oil (one can find it for around $40/kilo). Converting it
to mescaline can be done almost OTC.
Here is my proposed proceedure.
Anethole is distilled from the anise star oil to insure a pure precursor to work with.
1. The anethole is dibrominated using ammonium bromide, hydrogen peroxide in a glacial acetic acid solvent.
2. The chemical 3,5-dibromo,4-methoxypropylbenzene is then oxidatively cleaved (using KMnO4..etc) to yield the aldehyde.
3. Nucliophillic substitution with sodium methoxide will yield a 3,4,5-trimethoxybenzaldehyde.
4. Hendry Condensation
5. Al/Hg Reduction.
The biggest concerns is obtaining the sodium methoxide. Is it possible to make this OTC?
The dibromination might not give a high yield but I know it is possible.
Questions and(positive) criticism welcome.
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sparkgap
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synthesis critique
Just wanted to point out that the correct systematic name for anethole is 4-(1-propenyl)anisole.
Now, for a critique:
1) "Hendry" condensation? I suppose you mean condensing the resulting aldehyde with acetonitrile? How do you propose to get acetonitrile
OTC? Sorry, I'm not familiar with the name, but I assume that's what you were proposing since your last step was a reduction.
2) The bromination, I fear, will also mess with the side chains, thus interfering with your oxidative cleavage. In short, how selective is NH4Br/H2O2
as a brominating agent. Convince me.
3) I don't think replacing the bromine with methoxy will work. Substitutions at aromatic rings frequently are of the electrophilic kind, and, as
you know, methoxide is a nucleophile. Nucleophilic aromatic substitution can happen, but it usually requires harsh conditions.
Besides, you'll need sodium metal to produce sodium methoxide. 
sparky (^_^)
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Nicodem
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I find it impossible that you can doubly brominate anethole without brominating the double bond as well.
Bromination with excess bromine would produce 1-[4-methoxy-3,5-dibromophenyl]-1,2-dibromopropane. Essentially, this would not be a problem since you
don’t want that side chain anyway. But oxidizing this product with the methods known to oxidize double bonds into aldehydes (with CuO, KIO3 etc.)
would not give you the wanted aldehyde. Though by introducing one more step to your scheme, you can always debrominate the compound with activated
zinc in ether and this would give you the wanted 3,5-dibromo-anethole. You can then oxidize this with an OTC oxidant like CuO in order to get
4-methoxy-3,5-dibromo-bezaldehyde.
Sparkgap: I think Enima is reffering to some known procedures on the nucleophylic aromatic substitutions from the literature and published on The Hive
catalysed by Cu or Cu(I) salts. I don't remember if this specific example was covered but it works with phenolic benzaldehydes like
5-halogeno-vanillins and 4-hydroxy-3,5-bromo-benzaldehyde. For some reasons though, he does not mentions the references. With "Hendry" he
surely means the Henry condensation with nitromethane.
[Edited on 11-2-2005 by Nicodem]
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Sergei_Eisenstein
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| Quote: | | 1. The anethole is dibrominated using ammonium bromide, hydrogen peroxide in a glacial acetic acid solvent. |
It will first brominate the side chain and only when that is fully brominated, it will affect the arene nucleus.
Dibromination of 4-methoxybenzaldehyde is slow.
[Edited on 11-2-2005 by Sergei_Eisenstein]
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sparkgap
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Oh I forgot, Zn can dehalogenate side chains. Kudos to Nicodem for pointing that out.
But he must address my two other points...
(edit: bromination would be slow? shouldn't the CH3O- group be sufficiently activating?)
sparky (^_^)
[Edited on 11-2-2005 by sparkgap]
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Sergei_Eisenstein
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Monobromination of 4-methoxybenzaldehyde is OK, but dibromination runs much slower. It might be more adventageous to focus on 4-hydroxybenzaldehyde
(waste product of 2-hydroxybenzaldehyde  ). Dibromination runs smoothly and
syringaldehyde offers you more flexibility towards M analogs syntheses.
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Nicodem
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Sparkgap, I'm convinced that anethole can be brominated twice on the ring plus on the side chain. If I was to do this I would use ZnCl2 or Fe as
a catalyst though. The bromine on the benzylic position slightly deactivates the benzene ring but this effect is not so strong to prevent the double
bromination on 3 and 5 positions if a weak Lewis acid catalyst is used.
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sparkgap
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Double deactivation, eh, Comrade Sergei? Forgot about it, but then again, I didn't take into account that you will then have two deactivators
against one activator. Whopsee.
Nicodem, I mentioned the point regarding bromination selectivity in my first post. Lewis acids are always good for EAS halogenations. Point well
taken.
And please, call me sparky!!
(edit: clarified a few ambiguous lines)
sparky (^_^)
[Edited on 11-2-2005 by sparkgap]
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Kinetic
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Dibrominations
Once again I've been beaten to the answer of the original question because of my fondness for literature references.
Your best bet may be to oxidise anethole to 4-methoxybenzaldehyde, then try the dibromination according to a similar literature procedure.
I came across a paper which details the dibromination of 4-methoxyphenylacetic acid in almost quantitative yield. Of course this is more activated (or
less deactivated) than 4-methoxbenzaldehyde, but not by that much. The reference is Journal of Organic Chemistry,
49(11), 2061-2063 (1984), and the pertinent experimental follows; note it is pretty slow, as Sergei_Eisenstein says above. It should
be relatively easy to make the required bromine and ferrous bromide:
(3,5-Dibromo-4-methoxyphenyl)acetic Acid (3c).
To a solution of 20.09 g (120 mmol) of 3a in 220 mL of anhydrous CHCl3 was added 4.28 g (14.4 mmol) of FeBr2 A solution of 18.5 mL
(360 mmol) of Br2 in 30 mL of CHCl3, was added dropwise to the reaction vessel. After the mixture was stirred for 42 h at room temperature, an
additional 10 mL of Br2 (190 mmol) and 1.04 g (4.8 mmol) of FeBr2, were added. The solution was stirred for 18 h, then poured carefully into an excess
of 5% aqueous NaHSO3, and extracted with ether. The combined ethereal extracts were washed with H2O and brine and then dried (Na2S04). Removal of the
solvent afforded 37.76 g (96%) of dibromo 3c, in greater than 98% purity, as determined by 'H NMR. The crude solid was routinely
used directly. Recrystallization from toluene/ hexane gave 3c with the following: mp 132 134 "C [goes on to give NMR etc. data]
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enima
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ah fuck.
haha, I completely forgot about the bromination across the alkene.
I have though about 4-hydroxybenzaldehyde before but the problem is that it requires methylating agents that are not so easy to get.
hmmm...
I guess the oxidative cleavage could occur first and this would elimate the problem of brominating the side chain. Although, this seems to bring in
the problem of deactivation of the ring with the aldehyde group.
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