Sciencemadness Discussion Board - Sythesis proposal for preparing 1,3-benzodioxole oxidation products using simple precursors

Sythesis proposal for preparing 1,3-benzodioxole oxidation products using simple precursors

Monoamine - 11-6-2021 at 21:11

1,3-benzodioxoles are a well-known class of substituted benzene derivatives. Perhaps the most useful of these is piperanol, which can serve as a building block for preparing many useful compounds.
Unfortunately, piperanol itself, as well as several other related compounds are difficult to obtain, because they are watched precursors because they can be used in the synthesis of the entactogen MDMA, which is a controlled substance.

Unfortunately this means that much legitimate chemistry with these compounds is difficult to perform. But unfortunately I doubt that the people drafting these rash laws care or even realize the wider consequences for science...

Anyway, I've attached a possible synthesis scheme to make oxidized 1,3-benzodioxoles from the readily available compound vanillin. I haven't tried this and since I'm a bit squeamish I'm probably not going to anyway (for the reasons I mentioned above), but I'd be curious to hear your thoughts about the feasibility of this synthesis. If you see any errors I made let me know and I'll fix it right away. Cheers

[Edited on 12-6-2021 by Monoamine]

Amos - 12-6-2021 at 07:14

I mean, I can appreciate that you worked hard on this, but a lot of the chemistry here isn't that simple, or is just incorrect. Demethylation of vanillin, your very first step, is often shown to be incredibly frustrating and low-yielding, and attempts made with hydrobromic acid as you suggest frequently don't demethylate it, and those that do show signs of hope often lead to brominated products as well.

A Williamson ether synthesis doesn't involve a carboxylic acid; it involves a deprotonated alcohol, such as a phenol or an alkoxide in anhydrous conditions. So one of your products in the second picture is incorrect. Dihalomethanes aren't going to react in any way with piperonylic acid, if one were to get that far in the first place.

I'm not sure why you propose carrying out a Cannizzaro reaction after demethylation of vanillin, when piperonal can be made directly from protocatechualdehyde and then someone could use piperonal itself as the substrate for cannizzaro, if they actually want piperonyl alcohol and piperonylic acid.

Monoamine - 12-6-2021 at 14:17

Quote: Originally posted by Amos

I mean, I can appreciate that you worked hard on this, but a lot of the chemistry here isn't that simple, or is just incorrect. Demethylation of vanillin, your very first step, is often shown to be incredibly frustrating and low-yielding, and attempts made with hydrobromic acid as you suggest frequently don't demethylate it, and those that do show signs of hope often lead to brominated products as well.

A Williamson ether synthesis doesn't involve a carboxylic acid; it involves a deprotonated alcohol, such as a phenol or an alkoxide in anhydrous conditions. So one of your products in the second picture is incorrect. Dihalomethanes aren't going to react in any way with piperonylic acid, if one were to get that far in the first place.

I'm not sure why you propose carrying out a Cannizzaro reaction after demethylation of vanillin, when piperonal can be made directly from protocatechualdehyde and then someone could use piperonal itself as the substrate for cannizzaro, if they actually want piperonyl alcohol and piperonylic acid.

Thank you for your insights and for pointing out these flaws. Is the demethylation step law yielding for vanillin specifically? The reason I'm asking is because I've successfully cleaved aromatic methyl ethers in the past using this approach (the nice thing is that the MeBr produced is a gas and so leaves the vessel, which should drive the reaction to completion). However, I tried this with indole as the aromatic ring (specifically with 5-methoxyserotonin) to form serotonin. So I suspect that it might work here too, unless there is something fundamentally different about this reaction when it is performed with vanillin.

Please excuse my lack of knowledge about the Cannizzaro reaction. As far as I can understand, threading and aldehyde with OH^- will cause this reaction to occur. But I don't know if this requires a high temperature or not. If you know, I would be grateful for your advice. Also, if there's a non RO^- base that is strong enough to deprotonate phenol (possibly an alkylamine, the pKa of phenol is about 10 and the pKa of methylamonium is about 10.63 refference), might this be an option?

Thanks also for pointing out that carboxylic acids don't form ethers via Williamson ether synthesis.

It looks overall this can be simplified somewhat: 1) If the Canizzaro reaction can be avoided, then we basically get piperonal as the sole product, right? 2) If then we can skip several steps and get right to the carboxylic acid.

If you think this is right let me know and I'll post an updated version.

Cheers!

clearly_not_atara - 12-6-2021 at 16:59

The Cannizzarro reaction is not really a useful preparative method. If you want an alcohol, you use a reduction. If you want an acid, you use an oxidation. You almost never want a 50/50 mixture of the two. It is more of a warning: do not combine aldehyde and alkali, or you will get this crap.

Also, you can absolutely esterify a carboxylate with an alkyl halide. You just can't do it with dibromomethane, because it isn't electrophilic enough. Unless you use the silver salt, because weird silver stuff.

zed - 13-6-2021 at 00:35

Go to the search engine... Search!

There have been many discussions on this subject.

Find out what is likely work. No point in trying to re-invent the wheel.

Errata

Monoamine - 13-6-2021 at 08:48

So for some reason, the system won't let me correct the original post, so consider this the errata to it.

Here is an updated synthesis proposal, which hopefully would give piperonol and two of its oxidized products.

I wrote it like this so that one can get all three products if needed. You're right, if you only want one of them there are more straightforward ways that could work. However, the ones that I know of suffer from the disadvantage that they use reagents which are harder to obtain or which are more dangerous and toxic to work with. But in any case, below are two schemes that should work.

Amos - 14-6-2021 at 05:42

Quote:

The Cannizzarro reaction is not really a useful preparative method. If you want an alcohol, you use a reduction. If you want an acid, you use an oxidation. You almost never want a 50/50 mixture of the two. It is more of a warning: do not combine aldehyde and alkali, or you will get this crap.

I wouldn't say it's entirely a bad idea; I've intentionally done the reaction of benzaldehyde to benzyl alcohol and benzoic acid merely as a test of my bench chemistry skills, and it was high-yielding enough that I would do it again on other aldehydes that are cheap and easy to obtain. I'll probably eventually do a bulk preparation of vanillyl alcohol and vanillic acid starting from vanillin someday. I'd love to see what kinds of delicious-smelling esters could be made from them.

Quote:

Also, you can absolutely esterify a carboxylate with an alkyl halide. You just can't do it with dibromomethane, because it isn't electrophilic enough. Unless you use the silver salt, because weird silver stuff.

That reaction wouldn't be a Williamson synthesis though. And I said that dihalomethanes wouldn't react, not all alkyl halides.

clearly_not_atara - 14-6-2021 at 05:54

Quote:

That reaction wouldn't be a Williamson synthesis though. And I said that dihalomethanes wouldn't react, not all alkyl halides.

I wasn't responding to you, I was trying to clarify an apparent misunderstanding of Monoamine. If we are going to be instructors, we need to get the right message across. But yes, it would be somebody else's esterification, I think.

So for another boring side point: if you are going to demethylate vanillin with HBr, you should probably be using HBr in dry acetic acid, not aqueous hydrobromic acid. The former system is much more active, and as others have mentioned, vanillin is a resistant substrate.

The 4-hydroxy on vanillin also inhibits the Cannizzarro reaction due to keto-enol tautomerism. The reaction is still possible, but takes a long time. However, heating solutions of catecholate dianion for a long time can lead to aerobic oxidation and consequent polymerization. This inhibition of the Cannizzarro happens to also be key to the prep of syringaldehyde and myristicinaldehyde from vanillin.

zed - 14-6-2021 at 07:02

Depending on substrate, yields on the Cannizzarro, may not be 100%. In some cases there are side reactions that decrease the yields of usable products substantially.

Aryl ethers other than methyl, are easier to cleave.

Seriously, if you are interested in this subject; utilize the Search Engine. Spend a day or so, reading-up on the subject of Heliotropin synthesis.

In my opinion, he yields that most folks have actually achieved, are disappointing, and were I hot to get myself into trouble... I would purchase a quantity of the 3,4-Methylenedioxyacetonitrile as a starting material.

Opylation - 14-6-2021 at 21:13

If you’re looking for a phenolic dealkylation procedure then take a look at this paper. The most OTC phenolic ether cleavage method that I’ve seen uses aluminum halides to form an aluminum phenolate intermediate that gets broken during acidic work up. Another way you might go about piperonal preparation is glyoxylic condensation with 1,3-benzodioxole. I’ll attach both papers here for you to scroll through.

Edit: issue with uploading files

Attachment: tian2018.pdf (463kB)
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[Edited on 15-6-2021 by Opylation]

Attachment: 1488-Bjorsvik.Liguori.Minisci.Synthesis.Vanillin.Isovanillin.Heliotropin160c.pdf (183kB)
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Monoamine - 22-6-2021 at 08:57

Quote: Originally posted by Opylation

If you’re looking for a phenolic dealkylation procedure then take a look at this paper. The most OTC phenolic ether cleavage method that I’ve seen uses aluminum halides to form an aluminum phenolate intermediate that gets broken during acidic work up. Another way you might go about piperonal preparation is glyoxylic condensation with 1,3-benzodioxole. I’ll attach both papers here for you to scroll through.

Edit: issue with uploading files

Thank you sir!

[Edited on 15-6-2021 by Opylation]