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Topic: Selective hydrolysis of methyl ester in presence of t- butyl ester  (Read 16722 times)

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Offline Lynda92

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 How do I selectively hydrolyse a methyl ester in the presence of a tert-butyl ester?
« Last Edit: November 28, 2013, 02:42:35 PM by Lynda92 »

Offline discodermolide

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #1 on: November 28, 2013, 02:40:55 PM »
Try NaOH/ water?
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Offline Lynda92

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #2 on: November 28, 2013, 02:48:18 PM »
Try NaOH/ water?

Hello, I've been using lithium hydroxide. I've been trying to monitor by tlc- until most starting material has been used up. I initially started with 1.5eq then after 3 days I used another 0.5eq coz there was still a lot of starting material left. After another day I worked it up with a little bit of starting material still present. the nmr revealed the peak where the tert butyl should be is present but it integrates to 2 protons instead of 9
« Last Edit: November 28, 2013, 02:58:31 PM by Lynda92 »

Offline discodermolide

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #3 on: November 28, 2013, 03:05:11 PM »
Try NaOH at RT.
Ot LiI at RT or warmed.
The tButyl ester should survive these conditions.
How did you work the reaction up? Or is your analysis based on the crude reaction mixture?

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Offline Lynda92

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #4 on: November 28, 2013, 03:27:29 PM »
Try NaOH at RT.
Ot LiI at RT or warmed.
The tButyl ester should survive these conditions.
How did you work the reaction up? Or is your analysis based on the crude reaction mixture?

I've been doing the reaction at room temperature with LiOH,so it shouldn't be any different in sodium hydroxide? I worked up the reaction mixture by acidifying in 1M HCL and extracted with DCM. The nmr was done on the worked up product.

Offline discodermolide

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #5 on: November 28, 2013, 10:29:28 PM »
Quite a big difference between LiOH and NaOH.
Perhaps you don't need to make it quite so acidic. What does the NMR of the crude product before acidification kook like?
You could also try a trans esterification reaction, catalytic in base, NaOMe/methanol and use acetic acid. Remove the methyl acetate as it forms by distillation.

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Offline spirochete

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #6 on: November 30, 2013, 12:27:43 AM »
Quite a big difference between LiOH and NaOH.
Perhaps you don't need to make it quite so acidic. What does the NMR of the crude product before acidification kook like?
You could also try a trans esterification reaction, catalytic in base, NaOMe/methanol and use acetic acid. Remove the methyl acetate as it forms by distillation.

Yup. I've been told LiOH is less reactive (or at least less nucleophilic) because the lithium ion is harder and forms a stronger ionic bond with the hydroxide ion.

Offline BobfromNC

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #7 on: December 18, 2013, 02:23:52 PM »
I cleave Me esters frequently without bothering tBu esters.   Use 1M LiOH (1-4 eq) in 1,4-dioxanes overnight at RT.   It should not touch the tBu ester.    Raising the temp much or leaving the reaction in strong acid for any time are both bad for tBu esters.

For example, for 100 mg of a diester (MW ~500) , I might use 1ml 1N LiOH, 2 ml 1,4-dioxanes, stir at RT for 16 hours, then concentrate to dryness, add ~2 ml H2O, 1 ml 1N HCl (should make pH about 5, might add one or two drops more than 1 ml, not much more), then extract with 2-5 ml DCM DCM and dry with NaSO4.   I normally get about 80-90% yield, no loss of tBu ester.   

Offline Lynda92

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #8 on: December 18, 2013, 04:52:15 PM »
I cleave Me esters frequently without bothering tBu esters.   Use 1M LiOH (1-4 eq) in 1,4-dioxanes overnight at RT.   It should not touch the tBu ester.    Raising the temp much or leaving the reaction in strong acid for any time are both bad for tBu esters.

For example, for 100 mg of a diester (MW ~500) , I might use 1ml 1N LiOH, 2 ml 1,4-dioxanes, stir at RT for 16 hours, then concentrate to dryness, add ~2 ml H2O, 1 ml 1N HCl (should make pH about 5, might add one or two drops more than 1 ml, not much more), then extract with 2-5 ml DCM DCM and dry with NaSO4.   I normally get about 80-90% yield, no loss of tBu ester.

okay thanks, i will try it.

Also have you ever tried hydrolysing using NaI. If so, what conditions did you use?

Offline TheUnassuming

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #9 on: December 28, 2013, 01:54:03 PM »
Hello. 
Thread is old but in case you are still working on this, I have selectively deprotected OMe in the presence of OtBu.  My substrate was a bit fussy so used 1.1 equiv LiOH in a MeOH/H2O solution (9:1, ~1M) at rt for about 12h.  I quenched with KHSO4, careful not to get the pH too low otherwise I observed a measurable increase in tBu deprotection (my ester was finicky) before extracting with EtoAc.  Depending on the purity of starting material (and a bit of luck) you can often continue onto the next step without having to run a column. 
When in doubt, avoid the Stille coupling.

Offline BobfromNC

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Re: Selective hydrolysis of methyl ester in presence of t- butyl ester
« Reply #10 on: January 02, 2014, 04:56:11 PM »
Also have you ever tried hydrolysing using NaI. If so, what conditions did you use?

I have used NaI or KI in pyridine, it works, I usually had to heat to reflux for several hours, but is miserable to work up, as you have to rotovap or distill off most of the pyridine, without overheating the product (remember most tBu esters are heat labile), then try to dissolve your product acid/ester into some solvent that you can wash the remaining pyridine from.   If you have a high vacuum pump, then it is much easier to remove the residual pyridine.  Usually use 1-3 eq of the NaI in pyridine, enough to be able to stir it, but not too much solvent.

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