Sciencemadness Discussion Board

Homoanisic acid - Ideas?

aliced25 - 17-5-2013 at 04:07

I'm looking for a decent route to homoanisic acid (p-methoxyphenylacetic acid). Now, due to the extremely variable results from Basil oil (which ranges from virtually all estragole to no estragole) I'm looking at Anise oil. Epoxidation and so on gives a methyl ketone, but has anyone got a single viable reference to the oxidation of this ketone to the phenylacetic acid?

I thought Haloform, but having read the review on Haloform Reactions, I couldn't find a single reference to benzyl methyl ketones. Could it be that we'd end up with the hydroxyacid and then the anisic acid? Has anyone got any suggestions?

Otherwise there is the oxidation of the terminal olefin that is estragole, but I can only find one English reference to that and zero data on yield (acetic acid and permanganate). They cite a german article - has anyone got better reaction conditions?

Attachment: Miller.Mosely.The.Volatile.Oils.of.the.Genus.Solidago.pdf (693kB)
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Finnnicus - 17-5-2013 at 06:57

All I really can say is:
What do you need this for?

Bot0nist - 17-5-2013 at 11:06

@Fin

He asked a technical question, he avoided "lazy cook" lingo, and he provided a reference, kinda. This a chemistry forum, and his, a chemistry question. Why do you care what he needs p-methoxyphenylacetic acid for? Do you have any insights or help for the OP, other than scrutinizing his intentions?

P.S. Yes, we all know about phenylacetic acid's more nefarious uses... Just report it, if you have objections. No need to derail.

aliced25 - 17-5-2013 at 15:37

Well, theoretically at least, for the purpose of elucidating the steps to making a 4 ring heterocycle, namely levo- or dextro- methorphan. For the challenge of being the first home chemist to make a 4 ring heterocycle, and pretty much like Kenner Rice, to prove it is possible. Not for the purpose of selling it, but to prove it can be done, with basic equipment and simple chemistry.

I'm not asking how to scrape fucking matchboxes, or extract pseudoephedrine from pills, I'm asking a fairly serious question about some fairly serious chemistry. You can choose to participate or not, personally I think the challenge is all. Pretty much the same way the various groups sought the same challenge with morphine. It isn't viable economically, but is one hell of a challenge - total synthesis of a product similar to a natural product, I think they call that chemistry.

[Edited on 17-5-2013 by aliced25]

zed - 18-5-2013 at 11:30

So, you're going to make some serious narcotics, nod off...possibly forever; and stop asking strange questions?

Tyrosine looks like a good possible starting point. I gotta check an old research paper, then come back.

Yeah, I'm back. I couldn't find the reference I wanted, but here is the gist of it.

Purportedly, amino acids can be decarboxylated and converted to a corresponding nitrile via TCCA in basic solution. There will be procedures in the archives for preparation of phenylacetonitrile from phenylalanine.

I don't know if tyrosine will stand up to such treatment, but it might. Thus in one step, you could go from tyrosine to 4-Hydroxy-phenylacetonitrile. Upon hydrolysis, this should yield 4-Hydroxy-phenylacetic acid. Methylation then yields your desired product.

https://docs.google.com/viewer?a=v&q=cache:a514FLGr4D8J:...

[Edited on 18-5-2013 by zed]

[Edited on 18-5-2013 by zed]

[Edited on 18-5-2013 by zed]

[Edited on 18-5-2013 by zed]

killer_lapin - 20-5-2013 at 11:48

Zed, I can confirm that tyrosine can be dearboxylated. But after you would have to convert the p-hydroxyphenetylamine to the methy ether before the chloration, after what It is like an exemple in the article provided by Zed.

Here is the reference for decarboxylation:
Attachment: LaDecarbI(1).pdf (765kB)
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Yea it's in french... to resume tyrosine can be decarboxylated by heating it in acetophenone for 5h with 80% yield. with a ratio of 0,17 = Amino acid / ketone. in some situation the ketone can be in catalytic amount. If you're interested I'll translate it for you.

It's a standard procedure mostly knowed for tryptamine production

[Edited on 20-5-2013 by killer_lapin]

zed - 21-5-2013 at 12:45

Likewise, P-Anisaldehyde could be converted to the corresponding Phenylacetaldehyde via the Darzens Glycidic ester route. Thereafter, the aldehyde could be oxidized to the Phenylacetic Acid.

ScienceSquirrel - 22-5-2013 at 06:54

The discussion of routes to any compound is allowed.
What is not allowed is talking about match box scraping in connection with cooking and recipes for GHBA.
A home synthesis of dextromorphan would be an extraordinary challenge. I would say that it would be a pretty big challenge for a postgraduate organic chemist with a fully equipped laboratory and any chemicals they wanted.

https://docs.google.com/viewer?url=www.google.com/patents/US...

Nicodem - 22-5-2013 at 08:59

The simplest route from common reagents is by the Friedel-Crafts acetylation of anisole to give para-methoxyacetophenone (a common lab practice for students: one example here, but you can find plenty of similar instructions for students).
The para-methoxyacetophenone is then subjected to the Willgerodt-Kindler reaction (with sulfur and morpholine) and the thioamide hydrolysed (both steps are described in Vogel).

Anethole is not good starting material, if your goal is simplicity and effectiveness. But if you insist, anethole can be reductively ozonolyzed to anisaldehyde (itself about as cheap as anethole), anisaldehyde can be reduced to anisyl alcohol (itself about as cheap as anethole). Its application in the synthesis of para-methoxyphenylacetonitrile is nicely described in Organic syntheses. The nitrile is the hydrolyzed as described in the literature.

Tyrosine would have to be first O-methylated, otherwise the oxidative decarboxylation via N-chlorination would not give the desired results.

amazingchemistry - 22-5-2013 at 21:25

I thought ozonolysis was hard enough to perform in a research lab (the ozonide being energetic and unstable), how'd you go about carrying it out with equipment and reagents available to the home chemist?

Dr.Bob - 23-5-2013 at 06:23

You build an ozonolyzer at home. They are pretty simple, just an arc in a cooled tube. It is still not an easy experiment to do in a home lab, but some people here have done some amazing work. The nice part about O3 is that you don't store it, you only make it in small quantities, and the SM is easy to find. Air is a great OTC chemical. Using pure O2 is much better, but even that is easy to obtain. But I think that Nicodem did make it clear that the simplest route was to start with anisole, which avoids that step.

Crowfjord - 23-5-2013 at 14:48

If it were me, I would like to try with tyrosine, just because it is so cheap and readily available from practically any health food/supplement store. Either as stated above, or via Strecker degradation. But this would be quite a challenge, as well.

A more facile approach would probably be through anisole, as Nicodem and Dr. Bob said. Chloromethylate, then a grignard with carbon dioxide in the form of dry ice. Maybe not as elegant, but the reagents may be easier to acquire. If you can get your hands on p-methoxybenzyl alcohol, it would be that much simpler, as it can be chlorinated with concentrated hydrochloric acid (I think this is what Nicodem was hinting at above).

Nicodem - 24-5-2013 at 09:53

Quote: Originally posted by Crowfjord  
Chloromethylate, then a grignard with carbon dioxide in the form of dry ice.

I have yet to see a regioselective anisole chloromethylation that would give mainly the para-methoxybenzyl chloride. Most literature example report about a 1 : 1 ratio of the ortho vs. para isomers. Do you have any reference for a procedure giving a better ratio?

A preparation of para-methoxybenzyl chloride is described at the Synthetic pages, but you would only need to isolate it pure, if used for the Grignard reaction. By the way, forming the grignard with it is not trivial, because benzyl halides tend to undergo the competing Wurtz coupling with magnesium. For the synthesis of para-methoxyphenylacetonitrile, the instable chloride intermediate needs not to be purified, but is merely telescoped to the next stage as the crude product (as described in the Organic Syntheses example).

manimal - 24-5-2013 at 11:28

Probably easier to prepare by the action of TCCA on tyrosine to form the nitrile, followed by hydrolysis of said nitrile. There is probably an optimum stage at which to methylate the phenol.

edit: I see this was already mentioned. Probably p-methoxyphenylalanine would stand up to the reaction with TCCA. Here is a reference to it's preparation from tyrosine: http://pubs.acs.org/doi/abs/10.1021/ja01343a060

[Edited on 24-5-2013 by manimal]

aliced25 - 24-5-2013 at 17:05

Too many steps for a simple precursor - I'm looking at trying out OTC ethyl(methyl)dioxirane (aka butanone peroxide/MEK Peroxide) on the methyl styrene in a single phase in butanone (MEK). It has been used before instead of Dimethyldioxirane, but there is not a single reference of it being used for an epoxidation. The Phthalate might interfere, it should not. I've also attached a paper on the use of isolated dioxirane on B-methylstyrene to give the epoxide in good yield.

As far as I am concerned, whether the haloform works or it doesn't work, it will be a contribution to the knowledge base, the same as MEK Peroxide for epoxidations. Science, succeed or fail, either is noteworthy, gotta love that.

Attachment: Walton.Thesis.Oxidation.with.Dioxiranes.p147.Oxidation.of.Trans.B.Methylstyrene.pdf (68kB)
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Attachment: Kataoka.etal.EthylMethylDioxirane.as.an.Efficient.Reagent.for.the.Oxidation.of.Nucleoside.Phosphites.into.Phosphates.Und (53kB)
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Attachment: SolladieCavallo.Bouerat.Epoxidation.of.p.Methoxycinnamates.Using.Chiral.Dioxanes.Derived.from.New.Trisubstituted.Halogen (59kB)
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Quote: Originally posted by Nicodem  
The simplest route from common reagents is by the Friedel-Crafts acetylation of anisole to give para-methoxyacetophenone (a common lab practice for students: one example here, but you can find plenty of similar instructions for students).
The para-methoxyacetophenone is then subjected to the Willgerodt-Kindler reaction (with sulfur and morpholine) and the thioamide hydrolysed (both steps are described in Vogel).


You forgot the Fries reaction from acetylphenyl - it is supposed to give good yields of p-hydroxyacetophenone in polyphosphoric acid (so too GAA and phenol), in 60+% yield.


Attachment: Snyder.Elston.Polyphosphoric.Acid.as.a.Reagent.in.Organic.Chemistry.VII.Acylation.pdf (423kB)
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As far as the Grignard goes, if I were to oxidize the anethole to anisealdehyde (http://www.erowid.org/archive/rhodium/pdf/isosafrole2piperon...) and then to the benzyl alcohol, I'd form the grignard and use that directly on the isoquinoline from N-formylphenethylamine and avoid the preparation of homoanisic acid altogether. It is an entirely different procedure to what I'm trying to achieve, but it is an existing procedure.

[Edited on 25-5-2013 by aliced25]

Nicodem - 25-5-2013 at 04:14

Quote: Originally posted by aliced25  
Too many steps for a simple precursor - I'm looking at trying out OTC ethyl(methyl)dioxirane (aka butanone peroxide/MEK Peroxide) on the methyl styrene in a single phase in butanone (MEK). It has been used before instead of Dimethyldioxirane, but there is not a single reference of it being used for an epoxidation. The Phthalate might interfere, it should not. I've also attached a paper on the use of isolated dioxirane on B-methylstyrene to give the epoxide in good yield.

How is this connected to the topic? Are you talking about the epoxidation of anethole? If so, nearly any method will do. Acetic acid with H2O2 is just fine. Or oxone based epoxidations. Or H2O2 in acetonitrile with a base. Etc, etc. Formic acid with H2O2 gives a mixture of the epoxide, glycol and glycol formates, but this is irrelevant, because all of these rearrange equally well to the ketone. There are plenty of literature examples on this substrate.
Quote:
As far as I am concerned, whether the haloform works or it doesn't work, it will be a contribution to the knowledge base, the same as MEK Peroxide for epoxidations. Science, succeed or fail, either is noteworthy, gotta love that.

The mechanism of the haloform reaction is well known. If you evaluate it on para-methoxyphenylacetone it is immediately obvious that it could not yield para-methoxyphenylacetic acid. But I do agree that it would be very interesting to characterize the products from the haloform reactions on this substrate. I wonder, if it would give the anisic acid or the reaction could be stopped at the para-methoxybenzal halides or anisaldehyde stage. If there would be a way to control the end product by the choice of the halogenating reagent, basicity and other conditions, it would be an interesting achievement, especially if this could be modified into a preparative reaction. Though, I could always first check the literature.

aliced25 - 25-5-2013 at 05:55

I have a negative on the haloform on phenylacetones, it took a while to find it but here it is:

Synthesis of Olavicine
Wenkert & Dave
J. Am. Chem. Soc., 1962, 84 (1), pp 94–97
Quote:



In an attempt to degrade the acetone side-chain in VIIb to an acetic acid residue, the behavior of the ketone in a haloform reaction was studied. While exposure of an alkyl methyl ketone to hypo- halite solution leads to demethylation, this being the basis of the well-known qualitative test for methyl ketones,6 ketones with a-substituents which enhance enolization toward the alkyl side of the ketones may decompose by dealkylation rather than by demethylation. Indeed, phenyl- acetone, a simple model for VIIb, was converted to benzoic acid, instead of phenylacetic acid, on treatment with sodium hypoiodite solution (p.95)


Bugger

Attachment: Wenkert.Dave.Synthesis.of.Olivacine.pdf (583kB)
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Ok - so I may have to utilize a different synthesis route - or go via the p-methoxytyramine and then N,N-dichlorination, reaction with an amine and then hydrolysis of the nitrile. BUGGER.

What is the consensus, will p-methoxytyrosine (made by methylation of N-Acetyltyrosine) stand up to the benzophenone decarboxylation (per the attached paper)? That would be the easiest route I could imagine, it would save deprotection, then reprotection and methylation. Then dichlorination of the nitrogen, etc. to get to the acid. A lot of fucking around, but there you go.:mad:

[Edited on 26-5-2013 by aliced25]

[Edited on 26-5-2013 by aliced25]

zed - 26-5-2013 at 15:18

Well, considering the input of others.....P-Anisaldhyde might be the ideal starting material.

It appears to be cheap, unrestricted, and available. An E-bay seller is offering it for about 100 dollars a kilo, and I suspect you could acquire it somewhere for about $50.00.

Utilizing simple KOH, you could then obtain about a 50% yield of P-Anisic Alcohol Via the Cannizarro.

If the Meerwin- Pondorf-Verley Reduction can be successfully utilized on the benzaldehyde, a much higher yield of the alcohol could be obtained via a very simple procedure.



[Edited on 26-5-2013 by zed]

[Edited on 26-5-2013 by zed]

Prometheus23 - 27-5-2013 at 01:22

Personally I might try this route:

1. Condense p-anisaldehyde with nitromethane to yield the nitrostyrene
2. Reduce the nitrostyrene with SnCl2 or iron powder and acid to yield p-methoxyphenylacetaldehyde
3. Oxidize the aldehyde to the carboxylic acid by whatever method is most available to you

True that this method probably wouldn't be quite as cheap as starting from tyrosine. But it's not that much more expensive and avoids the need to protect and/or methylate the phenol.

aliced25 - 27-5-2013 at 16:21

In this paper (https://smartech.gatech.edu/bitstream/handle/1853/5564/jones...), alkaline hydrogen peroxide was used to oxidize p-methoxy- and other phenyl-2-propanones, with the results being a mixture of benzyl alcohols, benzaldehydes and benzoic acids.

They also investiaged the oxidation of a couple of phenylbutanones, 4-phenyl-2-butanone and 3-phenyl-3-butanone for instance. In the case of the 4-phenyl-2-butanone the only product was the phenethyl alcohol (and an unknown).

Now, 4-(4-hydroxyphenyl)-2-butanone (Raspberry Ketone) is readily available, I'll start on a literature search on peroxide oxidations of it, to see what the products are, I'll happily go with the phenethyl alcohol or the acid (the self-condensing bitch of a phenylacetaldehyde I don't want). If anyone has access to a better literature search engine than me (namely google scholar), feel free to pitch in;). There is a paper on the alkaline peroxide oxidation of the unsaturated 4-methoxyphenylbut-3-en-2-one (http://parazite.nn.fi/hiveboard/picproxie_docs/000451381-The...), but that gives the same products as the Phenyl-2-propanones through epoxidation of the unsaturated linkage.

Using deductive reasoning, I'm confident the p-methoxyphenylbutan-2-one will behave similarly to the phenylbutan-2-one in the paper, as did the various phenylpropan-2-ones. I would just like to find some literature support for the proposition.

[Edited on 28-5-2013 by aliced25]