Sciencemadness Discussion Board

Preparation of propargyl alcohol (2-propyn-1-ol)

Morue - 28-9-2020 at 15:13

Hello all,

I'm starting to plan a somewhat lengthy project to synthesize R-Rasagiline, a drug used to treat Parkinson's disease. The idea is to build the molecule using easily sourced chemicals, starting from malonic acid and propargyl alcohol (2-propyn-1-ol). Malonic acid can easily be purchased online, but propargyl alcohol is problematic, so I might need to prepare it myself if I ever go ahead with this projet...

The only viable route for a home lab appears to be the "textbook" one, from the reaction between sodium acetylide with formaldehyde. However, based on some old papers on the subject, it seems that this reaction is in practice quite complex and requires a lot a finesse... And the yields are reported to always be terrible (which is anyway not the end of the world if that's the case since the reagents for this reaction are cheap). Another method I found is based on a patent that mentions production of propargyl alcohol from the reaction of acetylene with formaldehyde over a copper acetylide catalyst at high temperature and high pressure (US3218362A). They say in the patent that this reaction do not proceed easily under atmospheric pressure, so it pretty much removes this option as a potential route.

Anyway, I was wondering if someone had already attempted to react formaldehyde with sodium acetylide to form propargyl alcohol? It seems that paraformaldehyde do not react readily with sodium acetylide (J. Am. Chem. Soc. 1943, 65, 10, 1847–1848) and I believe that bubbling gaseous formaldehyde would likely transform the reaction mixture into a giant polimerized mess or generate an explosion... The general synthesis plan I came up with would be as follows.

1. Form sodium amide from the reaction of sodium with liquid ammonia in a dry ice/toluene cooling bath
2. Bubble previously washed and dried acetylene into the solution.
3. Remove cooling bath and add 1,4-dioxane after allowing most of the ammonia to evaporate.
4. In an addition funnel, dissolve the paraformaldehyde in 1,4-dioxane and add a little bit to the reaction mixture. Heat the reaction. Once the reaction has started, slowly add the rest of the paraformaldehyde and let stir for a few hours.
5. Cool the reaction mixture with an ice bath and acidify with slow addition of ammonium chloride
6. Work-up to isolate propargyl alcohol.

Would this be feasible? Any comment or recommendation regarding the procedure is welcomed :)

Here's also a thesis for a Bachelor of science on this subject (different times ...) : https://dspace.mit.edu/bitstream/handle/1721.1/49600/3437667...)

Cou - 28-9-2020 at 20:03

Sorry, I don't have any experience with any of these reactions.

Morue - 29-9-2020 at 11:27

That's fine, thanks Cou.

I had a quick look on Reaxys today and it appears that propargyl alcohol could be made from the reaction of paraformaldehyde and acetylene in a KOH-DMSO superbase medium under normal temperature and atmospheric pressure (Trofimov, B. A.; Gusarova, N. K.. Russian Chemical Reviews 2007, pp 507–527) and the yields are supposedly good. The experimental procedure appears to be described in one Russian paper (Trofimov, B. A.; Sobenina, L. N.; Mikhaleva, A. I.; Nesterenko, R. N.; Voronkov, M. G., Journal of Organic Chemistry USSR , 1989, vol. 25, 5.2, p. 999), to which I unfortunately do not have access :(

This seems a more promising route...

Heptylene - 30-9-2020 at 01:59

If you have the DOI for the article, there is a chance you can find the PDF on sci-hub. I would love to have a read if you find it.

CuReUS - 30-9-2020 at 08:55

Instead of trying to make propargyl alcohol,why don't you take 2-chloroacrylonitrile and dehydrohalogenate that with NaNH2 ,followed by reduction with Na/Ethanol to get propargylamine.Then you could reductive aminate that with indanone followed by resolution to get R-rasagiline.(If you can't get 2-chloroacrylonitrile,you can take acrylonitrile,react that with Br2 and then double dehydrohalogenate it)

Morue - 30-9-2020 at 13:03

Quote: Originally posted by Heptylene  
If you have the DOI for the article, there is a chance you can find the PDF on sci-hub. I would love to have a read if you find it.


The article I mentionned is somewhat old and appears to be available only in printed form. I wasn't able to find it anywhere (or sci-hub). However, I was able to find a printed copy of another article from the same authors (Moiseev, V K Stankevich, G K Balakhchi, A I Mikhaleva,R N Nesterenko, B A Trofimov. Dokl. Akad. Nauk SSSR, 321, 524 (1991)) which describes in detail the reaction conditions which would favour the formation of propargyl alcohol. I can send you the paper by U2U if you want. It's in Russian, which I can't read. But Google translates gives me the following :

"Optimization of equation (2) by numerical methods predicts, and control experiment confirms the 95% yield of the target product with the following values ​​of the factors taken into account: synthesis temperature 15 ° C; synthesis time 4 h; paraform amount 0.05 mol; stirrer rotation speed 350 rpm. The calculations were performed on an IBM XT personal computer. The synthesis of propargyl alcohol was carried out under the conditions described above at atmospheric pressure in a three-necked flask with a reflux condenser, stirrer and bubbler. At the end of the synthesis, the reaction mixture was diluted with water (1:2) and extracted with methylene chloride".

They obtained a 89 % in one of their experiments with the following parameters : temperature 15C, reaction time 4 hours, 0.05 mol of paraformaldehyde and 1000 rpm stirring. They are not very specific about the amount of acetylene, but it seems that they just bubbled the gaz into the solution at a constant rate. They don't say anything unfortunately about the molar ratio between the DMSO-KOH superbase and paraformaldehyde, but from what I understand dilute conditions favours the formation of propargyl alcohol and concentrated conditions favours the formation of but-2-yne-1,4-diol.

Anyway, this seems very promising, hopefully I'll get the chance to try this soon enough!
Quote: Originally posted by CuReUS  
Instead of trying to make propargyl alcohol,why don't you take 2-chloroacrylonitrile and dehydrohalogenate that with NaNH2 ,followed by reduction with Na/Ethanol to get propargylamine.Then you could reductive aminate that with indanone followed by resolution to get R-rasagiline.


My plan was as follows :
(1) Preparation of 1-indanamine by reductive ammination of 1-indanone (Leuckart reaction)
(2) Preparation of propargyl tosylate from tosyl chloride and propargyl alcohol
(3) Preparation of (R/S)-Rasagiline via Sn2 between propargyl tosylate and 1-indanamine
(4) Resolution to (R)-Rasagiline using (R,R)-tartaric acid.

Starting with propargylamine is interesting, but your route isn't really an option for me. I don't have access to a fumehood and a safe way to store/use/dispose acrylonitrile.