Sciencemadness Discussion Board - problem of Diketoacid synthesis - starting material regeneration

problem of Diketoacid synthesis - starting material regeneration

clemi2310 - 9-2-2016 at 07:28

Hello everyone,

This is the first time I post here, thank you for what you do here. I hope you can help me. I am a french PhD student in 1st year and I already encounter troubles with chemistry !

Basically, I am trying to synthetize diverse diketoacids following the first synthetic scheme attached

The first step is ok I get my ester pure enough. But when it comes to the hydrolysis, I get the diketo acid but the methyl ketone (starting material) is regenerated... so my product isn't pure.

I made another test, is to leave the reaction during 24h, and I got full recovery of methylketone without any acid.
I also try the hydrolysis in acidic conditions (HCl 1M in water + dioxane, reflux), I still obtain the methyl ketone

my reactions conditions for the hydrolysis are in the 2nd attachement, maybe NaOH and MeOH play a role in the reapparition of the methylketone, the hydrogen between the 2 carbonyl is still enolisable so maybe that is why..

The thing is, my compounds are too polar to purify them by silica gel chromatography so i have to get them pure enough, or recrystallized (but depending on substrate it is difficult).

Could you help me to figure it out what is happening, in terms of mechanism maybe ? Do you have any solutions? For example changing the solvant...

Thanks a lot.

Clémence

clearly_not_atara - 9-2-2016 at 12:14

Your hydrolysis conditions cause a retro-aldol. The easiest solution IMO is to forgo hydrolysis and use a different protecting group such as benzyl or trityl which can be removed by selective catalytic hydrogenation.

Another alternative is to use an excess of oxalyl chloride and an enamine. In this case hydrolysis will occur rapidly at low temperature, so the cleavage will not interfere.

[Edited on 9-2-2016 by clearly_not_atara]

clemi2310 - 9-2-2016 at 23:55

Thank you for your help!

Unfortunately i dont have the material to proceed to catalytic hydrogenation in my lab, but I will consider the second alternative with oxalyl chloride and an enamine.

I am curious because to do my condensation to form the diketoester I use a stronger base than NaOH, tBuOLi, so I wonder why NaOH can reverse the reaction, maybe some methanolate is formed? Is there a way to change operating conditions such as solvant to prevent the retro aldol formation?

Curiously in all papers reporting diketoacids synthesis they dont mention this side reaction i wonder how they proceed!

Anyway, thank you again

Dr.Bob - 10-2-2016 at 07:41

If you are reacting the acid with an amine for the next step, you can often skip the methyl ester removal, and simply heat the ester and amine together to form the amide. Aldol type reactions tend to be equilibrium reactions, so they can go backwards, forwards, and make lots of side products. What is the next step, that will often determine the best route. If the 1, 3-diketones are to be reacted, like for making a pyrazole, often once that step is done, the ester will behave and deprotect easily.

clemi2310 - 10-2-2016 at 08:15

I see, but the formation of the diketo acid is unfortunately the last step because we want to keep it for its ability to bind divalent ions.

I will try to purify the salt through a dowex resin H+ to get the acid, hoping the methyl ketone will go in the dead volume. I don't know if it is a good idea

thank you!

Nicodem - 10-2-2016 at 09:13

Quote: Originally posted by clemi2310

I am curious because to do my condensation to form the diketoester I use a stronger base than NaOH, tBuOLi, so I wonder why NaOH can reverse the reaction, maybe some methanolate is formed? Is there a way to change operating conditions such as solvant to prevent the retro aldol formation?

It is not just about the strength of the base. The retro-Claisen reaction occurs when you have suitable nucleophiles in the reaction mixture, such as water, methanol, amines, etc. tert-Butoxide is not nucleophilic enough. Neither is sodium hydride or NaHMDS and similar. That's why they are used in the Claisen condensations.

You should try doing the hydrolysis with 1.1 eq. NaOH in water/THF. It's an alpha-ketoester, so it should hydrolyze relatively rapidly already at rt, though the acidic methylene will slow down the reaction by buffering the pH. Remove the acetophenone side product by washing the diluted reaction mixture prior to neutralisation. Some carboxylates tend to partition into the organic phase, so don't use dichloromethane or ethyl acetate. Use less solvating solvents such as toluene, MTBE, diethyl ether or isopropyl acetate.

If this does not work, then try a transesterification with acetic acid in the presence of a few mol% of some sulfonic acid. retro-Claisen reactions can occur also in acidic media, but hopefully in the absence of water this will be minimal.

clemi2310 - 11-2-2016 at 08:40

Hello! Thank you Nicodem.

I tried this afternoon what you said : 1.1eq NaOH in water/THF. Same behaviour for the formation of the methyl ketone, so MeOH is not the main driver!

Concerning the extraction before neutralization I already tried before, but obviously with the wrong solvent because I extracted with dcm and got full of methyl ketone..so thank you for your explanation, I tried with Diethylether, with 3 extraction I think I managed to remove the methyl ketone.

HPLC analysis tomorrow will tell me if it is pure enough. Thanks!!

I made and will make these reactions on various methyl ketone substrates and I noticed the huge variability of methyl ketone solubility in organic solvents. So, it seems to work for this pattern today, but what if another substrate is insoluble in Et2O? Well, I will try other solvents

Another question, I saw few procedures that uses LiOH instead of NaOH, what do you think?