Sciencemadness Discussion Board

preparation of alpha methylcinnamic acid

Nestea - 19-11-2023 at 11:05

Hello, i challenged myself with a new target - alpha methylcinnamic acid.

sadly i just found one paper in german an this is from 1915.

https://sci-hub.wf/10.1002/jlac.19154090105

Seems easy.

mixing 4 mol methylpropionate in 1 mol benzaldehyde and then adding 6,9g of sodium metal (what kind of reaction is this exactly?)

followed by extraction with ether, distillation of the methylcinnamic acid methyl ester and saponifaction with alcoholic NaOH to get the free acid. ca. 25g

But according to the paper you have to do multiple recrystallisations.

Looks doable but this procedure is over 100 years old.
Maybe there are new routes since then which are easy to do aswell.
Does somebody know a different way?

DraconicAcid - 19-11-2023 at 11:30

It's a form of Claison(I think- I get the names mixed up?) condensation. A strong base such as sodium methoxide deprotonates the alpha carbon of the ester, which then attacks the carbonyl of the aldehyde, giving methyl 3-hydroxy-2-methyl-3-phenylpropanoate. This eliminates water to give the methyl methylcinnamate ester.

The condensation of aromatic aldehydes with malonic acid to give cinnamic acids is fairly easy. If one had methylmalonic acid, that would give the methylcinnamic acid.

EF2000 - 19-11-2023 at 11:33

There's this one from 2005, gives you n-butyl ester via Heck reaction (literally), but requires Pd catalyst: doi.org/10.15227/orgsyn.081.0063
New, but definitely not easy

[Edited on 19-11-2023 by EF2000]

Nestea - 19-11-2023 at 12:28

Claisen Condensation, ah ok. And the sodium methoxide forms insitu with the methyl from the ester?
i looked for methylmalonic acid, but it is not cheap on sigma or merck.
I always wanted to work with Pd, but commercial catalyst is expensive as well. maybe in future i will try to make some Pd/C starting from a 1g Palladium bar.

Found a synthesis for ethyl cinnamate

http://www.orgsyn.org/demo.aspx?prep=CV1P0252

looks like its the same but with ethylacetate. I think i can follow this one with methylpropionate instead.

And on rhodium there is a procedure using sodium hydride (instead of the insitu sodium methoxide i think)

Well, it seems like the good old procedures are still working and are sometimes the cheapest and best solutions :)

EF2000 - 20-11-2023 at 00:56

Quote: Originally posted by Nestea  

i looked for methylmalonic acid, but it is not cheap on sigma or merck.

Well, it seems like the good old procedures are still working and are sometimes the cheapest and best solutions :)

I've found two-step synth of ethyl methylmalonate, first you do ethyl ethoxalylpropionate from two ethyl esters, oxalate and propionate: prep=cv2p0272, then just heat it to make ethyl methylmalonate and a lot of carbon monooxide: prep=CV2P0279. The first step is Claisen condensation, right? And the second is decarboxylation?
But worry not, you don't need to risk sharing fate of Seochi from Liar Satsuki (almost died from CO poisoning), in the same OrgSyn paper there's more convenient way: alkylation of ethyl malonate with methyl bromide. Authors say that with MeBr there's no di-alkylation (usual problem of other methylating agents), hence no problem of separating dimethylmalonate. Yield is lower, but that's the cost of safety, isn't it?

Of course, the method from 1915 is hard to beat, chemists were much more easy going then, without poshy reagents and catalysts. The only problem is sodium, right?

clearly_not_atara - 20-11-2023 at 12:12

Based on my understanding of similar reactions, dry alkoxides are good catalysts for this reaction, while solutions of an alkoxide in alcohol or protic solvents are effectively much weaker bases and don't work.

One thing I have to try at some point is see if there is any dissolution of tripotassium phosphate in anhydrous ethanol.

By "this reaction" I of course mean the condensation of benzaldehyde with propionate esters. I think trying to make methylmalonate would be unnecessary, and MeBr is no joke on the safety front.

EF2000 - 21-11-2023 at 02:10

I wasn't saying that methyl bromide is safe, just that since it's consumed in the reaction and has distinctive smell, it's a bit safer than vigorously evoluting odorless and more toxic gas. I too think that benzaldehyde route is better.
I think I have found something: benzaldehyde condenses with phenacyl chloride in presence of triethylamine. Giving alpha-phenylcinnamic acid. There's a link in WP article about phenylcinnamic acid: http://www.orgsyn.org/demo.aspx?prep=cv4p0777 (can't check it on mobile)
So, propionyl chloride condensing with benzaldehyde will give alpha-methylcinnamic acid, right? Don't know how practical this way is, though, guess I'm talking bullshit again
Update: I checked link (don't know why it wasn't working). It actually about phenyacetic acid, not phenylacyl chloride. So, if that works with acids, then propionic acid would condense with benzaldehyde. Without sodium, just with triethylamine. Sounds better, doesn't it?

[Edited on 21-11-2023 by EF2000]

[Edited on 21-11-2023 by EF2000]

DraconicAcid - 21-11-2023 at 07:56

Quote: Originally posted by EF2000  
So, if that works with acids, then propionic acid would condense with benzaldehyde. Without sodium, just with triethylamine. Sounds better, doesn't it?

No, it probably won't. Phenylacetic acid or its esters would be much more easily deprotonated at the alpha carbon than propanoic acid, since the hydrogen is also benzylic.

Nestea - 22-11-2023 at 05:31

i checked your link. and yes, this route should work too, but phenylacetic acid and acetic anhydride is restricted, so hard to optain.
Sodium is dirt cheap, and if not, one can always follow the nurd rage procedure with NaOH and Magnesium.
I tried this before and collected around 50g of sodium.
I will travel back in time to 1915 and give this a go when i have the time.
Thank you guys.

Grizli7 - 13-12-2023 at 09:48

benzaldehyde+propionic anhydryde+sodium propionate. Also naphta.