[clemi2310]

Hello everyone,

I am encountering a serious issue regarding the hydrolysis of an hindered ester.

The initial reaction that works is the BOC substrate in NaOH 10N at 120°C under microwave (see picture), quite harsh conditions but I manage to get the acid after 4 hours.

With the aim of simplifying my synthetic pathway, I wanted to hydrolyse in the same way the substrate already substituted (see picture second line). The reaction occurs but do not go till completion... I don't know why there is such a change between the boc version and the aromatic one.;.

I also tried the methyl ester instead of the ethyl as it should be more reactive, but it remains the same.

I tried conditions of a paper involving LiCl in DMF (anhydrous hydrolysis) but it didn't work.

My options now, are try to displace the equilibrium, test for other conditions (I saw thins with Toluene at 150°C and KOH under microwaves, or tBuOK in DMSO....)

I would like to know you suggestions if you can help me

Thanks by advance

Clémence

[Babcock_Hall]

I am not a specialist in synthetic organic chemistry.  However, I wonder whether or not iodotrimethylsilane under neutral conditions might give you the TMS ester, which could be treated with water, methanol, or other suitable alcohol, to give you the free acid.  I have used a reagent equivalent to TMSI in the presence of diisopropylethylamine for an ester that was a derivative of phosphoric acid.

[kamiyu]

I notice the only difference is the BOC and benzyl group attached to the nitrogen, all of which seem very distant from the reaction site. This causes me to wonder if it is the steric factor that matters

My personal experience of sterically hindered hydrolysis is the attempt of hydrolysis of 9-cyanoanthracene, which stops at amide. No acid is formed.

[kamiyu]

One further point, I am wondering if the solvent matters.

In the BOC case, which contains two carbonyl oxygen which can forms H-bond with water, may make the substrate more soluble/homogeneous

In the benzyl case, which obviously not soluble in water and you will have aggregate, which lowers the reaction rates (because OH ions prevented from reaching the reaction site due to aggregation)

[kriggy]

I suppose you could try methanolic NaOH because it seems that the water solubility is the main problem (had very similar problem while ago). What you could do is to run the reaction in two phase system using solvent that dissolves your compound and water with phase transfer catalyst. Or something like DMF+aq NaOH or DMSO+aq NaOH?
Also, maybe you could different ester? Benzyl ester might be removed by hydrogenation or trimethylsilyl ester that is removed by fluoride ions

[Guitarmaniac86]

When I had difficulty with an ester hydrolysis I used the following:

Anhydrous LiI in pyridine heated to 110 C for 24 hours.
Potassium trimethylsilanolate in THF at 80 C for 24 hours. Its a good reagent.
My favourite though the most nasty was:

10 equivalents of trimethyltin hydroxide heated to 80 C in 1,2-DCE over 96 hours. This always worked well but it always took an age to go to completion. However, that was on my compound. Literature for this is a few hours to 48 hours max.

[clemi2310]

First of all, thank you for all your answers !

I agree it seems to be a problem of solubility rather than steric hindrance because the benzyl is far away from the ester.

And sorry I haven't put all the solvent details in my scheme, but the original conditions are:

NaOH 10N (16eq) in THF/Isopropanol 1:1 120°C, µW so maybe THF is not appropriate enough

I also tried, LiOH 5N (16eq) in DMF/Isopropanol/THF 1:1:1 but didn't go to completion.

What I will try regarding your answers: DMSO, DMF/NaOH, and other reagents

[rolnor]

To use hydroxide with DMF is not good, the amide will be hydrolyzed, DMSO much better. Maby you can go even higher in temperature, the compound is not sensitive, maby KOH reflux in ethylenglycole or KOH in PEG, 250 degrees?

[kamiyu]

Agreed. DMF heated with base generates dimethylamine and carbon monoxide.

Therefore, DMF is not dried with CaH2 refluxing.

[clemi2310]

oooh right for the DMF incompatible with strong bases

I will first go with DMSO then 

Thank you !

[Babcock_Hall]

Here is a reference to TMSI under neutral conditions:  Olah, G. A.; Narang, S. C.; Salem, G. F.; Gupta, B. G. B. Synthesis 1981, 142.

[rolnor]

Sulfolane and potasium hydroxide, reflux, is another suggestion.

[clemi2310]

Hello everyone,

just to tell you that i've tried the hydrolysis in DMSO as the conditions mentionned above:

Ester (0,3mmol), NaOH 10N (0,45mL, 16 eq.), DMSO (1mL), 120°C µW, 4h

And according to the LCMS the conversion is around 50% after 4h .

I was able to get 16mg of the acid (17% yield..) maybe something went wrong with my work up. How do you usually treat reactions that occurs in DMSO?

are you sure it is just a problem of solubility? how about to displace the equilibrium?

I saw some papers with phase transfer catalyst, also.

Thank you for your *delete me*

[rolnor]

You can freezedry DMSO. I think higher temperature for your reaction would be good. If using Q-salt for phase-transfer you would get Hoffman elimination of the Q-salt I am afraid.

[clemi2310]

Thank you for your answer, I will go for 150°C as a second try !