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Author: Subject: Baclofen via cinnamic acid ester
Tsjerk
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[*] posted on 10-6-2019 at 11:02
Baclofen via cinnamic acid ester


So baclofen synthesis via this method worked (overall yield ~15%).

Now I would like to try this via this way.

I can get tetrabutylammonium hydroxide as a 40% solution in water and I can get hydrogen fluoride. I'm thinking about mixing the two with a small excess HF and drying the product over calcium chloride and sodium hydroxide. So TBAF shouldn't be a problem. I have a couple liters of THF.

I will keep you posted on the nickel/borohydride in methanol reduction. I never did that one before.
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[*] posted on 10-6-2019 at 11:22


Quote: Originally posted by Tsjerk  
l I'm thinking about mixing the two with a small excess HF and drying the product over calcium chloride

Think harder.
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karlos³
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[*] posted on 10-6-2019 at 12:38


Just use another PTC agent.
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Tsjerk
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[*] posted on 10-6-2019 at 12:38


Quote: Originally posted by unionised  
Quote: Originally posted by Tsjerk  
l I'm thinking about mixing the two with a small excess HF and drying the product over calcium chloride

Think harder.


Enlighten me because I don't get it

[Edited on 10-6-2019 by Tsjerk]
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[*] posted on 10-6-2019 at 13:10


https://www.ebay.co.uk/itm/Blue-John-Paperweight-10cm-x-7cm-...
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DraconicAcid
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[*] posted on 10-6-2019 at 13:11


Calcium fluoride is the mineral fluorite; exceedingly insoluble.



Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Tsjerk
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[*] posted on 10-6-2019 at 21:34


"drying over" as in drying in a exsiccator I meant.
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Tsjerk
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[*] posted on 11-6-2019 at 03:04


I will do the esterfication of cinnamic acid with ethanol, as I then can drive of the water as the azeotrope.
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karlos³
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[*] posted on 11-6-2019 at 08:52


You can likely esterify also cinnamaldehyde with ethanol under oxidative conditions using oxone.
I think then there shouldn't be any water if you use dry ethanol?
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Tsjerk
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[*] posted on 11-6-2019 at 09:31


The title of this topic is a bit wrong... as cinnamic acid esters would lead to phenibut, and not baclofen. I'm planning on making ethyl 4-chlorocinnamate via 4-chlorobenzaldehyde, acetone and bleach (url) and then esterfication with ethanol and sulfuric acid.

Quote: Originally posted by karlos³  
You can likely esterify also cinnamaldehyde with ethanol under oxidative conditions using oxone.
I think then there shouldn't be any water if you use dry ethanol?


The water would come from the esterfication, as a reaction product. Removing it drives the reaction to completion.

[Edited on 11-6-2019 by Tsjerk]
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[*] posted on 11-6-2019 at 13:08


I can't comment on most of the chemistry here, but I do know that esterification of cinnamic acid works quite well (in stark contrast to flippin' salicylates), and they can be purified by recrystallization from hexane or toluene at low temperature (methyl melts around 33 C, ethyl at 12 C). Far easier than trying to distill the brats at 250 C.

The methyl ester smells vaguely like strawberry when heated; I can't identify the smell of the ethyl ester.

[Edited on 11-6-2019 by DraconicAcid]




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karlos³
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[*] posted on 12-6-2019 at 09:14


Quote: Originally posted by Tsjerk  

Quote: Originally posted by karlos³  
You can likely esterify also cinnamaldehyde with ethanol under oxidative conditions using oxone.
I think then there shouldn't be any water if you use dry ethanol?


The water would come from the esterfication, as a reaction product. Removing it drives the reaction to completion.

[Edited on 11-6-2019 by Tsjerk]


Yes I know that, so I suggested this alternative path in which you go straight to the ester in anhydrous conditions where no water will be created.
I don't have the paper available right now though.
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[*] posted on 12-6-2019 at 09:40


Quote: Originally posted by karlos³  


Yes I know that, so I suggested this alternative path in which you go straight to the ester in anhydrous conditions where no water will be created.
I don't have the paper available right now though.


Cool, please let me know when you find it. I planned to oxidize benzalacetone with bleach, but you might have a better solution. Benzalacetone to cinnamic acid is done at 88% yield and the esterfication drops yield a bit further. Men, I love this forum.

Edit: bummer; I now see that benzalacetone is not the same as cinnamaldedyde.

Edit2: I could use acetaldehyde instead of acetone..

[Edited on 12-6-2019 by Tsjerk]
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karlos³
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[*] posted on 12-6-2019 at 11:15


Here it is: https://pubs.acs.org/doi/10.1021/ol0340078
A friend made ethyl benzoate successfully this way from benzaldehyde and ethanol in great yields.

Edit: it seems I have myself used "this" method, not in alcohol but DMF, to oxidise an aldehyde to its acid.

[Edited on 12-6-2019 by karlos³]
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[*] posted on 13-6-2019 at 10:21


Are you guys thinking about the potential for that double bond to epoxidize? I think it would get oxidized, but let's see what the literature has for us.

EDIT: just a cursory look at Google search results list several instances with cinnamaldehyde having its double bond opened up with oxone, leading to benzoic acid, phenylacetic acid, etc.

[Edited on 13-6-2019 by Loptr]




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