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Topic: Yield in a Horner Wadsworth Emmons reaction  (Read 998 times)

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Offline Babcock_Hall

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Yield in a Horner Wadsworth Emmons reaction
« on: June 19, 2019, 03:55:50 PM »
I am attempting to convert an aldehyde into a vinylsulfone using Horner-Wadsworth-Emmons chemistry with lithium hexamethyldisilazane as the base (28.7%).  The number in parentheses is the yield of a closely related, purified product, as reported in the paper I am following.  With respect to the HWE reaction, the protocol specified stirring for an hour at 0 °C  followed by two hours at room temperature.  The other reactant is a diethyl β-sulfonylphosphonate.

Although the important thing is just to get the product, I am somewhat concerned about the low yield in the HWE reaction, given that this is a multistep synthesis.  The only idea that I can think of as a possible improvement is to monitor the HWE reaction by TLC or by P-31 NMR (there should be a difference in chemical shifts of roughly 10 ppm).  I have previously found P-31 NMR to be useful in that it is relatively sensitive yet ideally there are only two molecules present, reactant and product.  However, I do not presently know whether or not incompleteness of the reaction was the reason for the relatively low yield in the step.  I have not yet surveyed other similar reactions for yield, although I have seen a variety of bases used.

Offline Babcock_Hall

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #1 on: June 20, 2019, 09:32:49 AM »
One thing I just thought about:  the paper I am following uses FMOC to protect nitrogen.  I wonder whether or not there might be some loss of the FMOC group during the HWE reaction.

Offline TheUnassuming

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #2 on: June 20, 2019, 11:00:04 AM »
If you have an FMOC group in HWE conditions I would guess you are getting relatively high levels deprotection of the amine since it can usually be done with much weaker amine bases.  Have you been able to shoot the crude through LCMS to go back and check?

Out of curiosity are you seeing full conversion of your starting material?
When in doubt, avoid the Stille coupling.

Offline Babcock_Hall

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #3 on: June 20, 2019, 11:14:00 AM »
Thank you.  I have not run the HWE reaction yet, but it is coming up the step after next.  I have a BOC-protected nitrogen, and I am hoping that this will work at least as well as FMOC, possibly better for the reason that you suggested.  For my purposes, BOC-protection is fine.

Offline pgk

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #4 on: June 20, 2019, 01:17:28 PM »
FmocN- is described to be incompatible with aldehydes but BocN- is described as compatible.
Anyway, the Horner-Wadsworth-Emmons reaction might have a higher yield by slow addition of diluted reagents (say 1 drop/sec) at -5oC (NaCl/ice), left to react at -5oC for 1 h, followed by reaction at 0oC for another 1 h and then at room temperature for 2 hours (or something else like that).

Offline Babcock_Hall

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #5 on: June 21, 2019, 11:23:48 AM »
I wonder if the deprotection conditions for FMOC cause self condensation of an aldehyde.  This would be useful to know in that I was contemplating working with the FMOC-version of the same compound later on.
« Last Edit: June 21, 2019, 11:46:13 AM by Babcock_Hall »

Offline pgk

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #6 on: June 21, 2019, 12:00:05 PM »
1). In general, aldol type reactions need heat under basic catalysis.
2). Contrary, the fluorene ring of FMOC can be deprotonated by bases forming the fluorenyl anion that can react with aldehydes (even at room temperature, in some cases), forming the corresponding 9-fluorenyl carbinol, which may further be dehydrated.
Condensation of Aldehydes with Fluorene and Nirofluorenes, J. Org. Chem., (1951), 16(11), 1690-1696
https://pubs.acs.org/doi/abs/10.1021/jo50005a005


Offline Babcock_Hall

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #7 on: July 01, 2019, 10:23:25 AM »
FmocN- is described to be incompatible with aldehydes but BocN- is described as compatible.
Anyway, the Horner-Wadsworth-Emmons reaction might have a higher yield by slow addition of diluted reagents (say 1 drop/sec) at -5oC (NaCl/ice), left to react at -5oC for 1 h, followed by reaction at 0oC for another 1 h and then at room temperature for 2 hours (or something else like that).

Thank you very much.  The protocol that I will follow first calls for drop-wise addition of the base to the phosphonate at 0 °C then stirring for 90 minutes, then drop-wise addition of the aldehyde, followed by stirring at zero, then room temperature.  This sounds similar to your suggestion.

If this is unsatisfactory in the presence of FMOC, I would consider trying different conditions for the Horner reaction, possibly similar to Blanchette M et al., (1984) Tetrahedron Letters 25(21) 2183-2186.  These authors use DBU or DIPEA as the base and lithium ions to chelate the intermediate and

Offline rolnor

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #8 on: July 02, 2019, 05:26:23 AM »
I dont think its neccesary to add the base so slow and the acid-base reaction is very rapid.

Offline pgk

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #9 on: July 02, 2019, 10:05:12 AM »
No!
The base must slowly be added at low temperature otherwise, uncontrolled exothermic (acid-base) reaction will occur that will favor side reactions, like self-condensation of diethyl β-sulfonylphosphonate.

Offline kriggy

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Re: Yield in a Horner Wadsworth Emmons reaction
« Reply #10 on: July 02, 2019, 02:29:13 PM »
I wonder if the deprotection conditions for FMOC cause self condensation of an aldehyde.  This would be useful to know in that I was contemplating working with the FMOC-version of the same compound later on.

You will very likely get de-fmocation which could easily account for low yield. The removal of fmoc with base like piperidine is super fast, the halflife of fmoc in presence of piperidine is like 10 seconds...
Loss of Fmoc group with molecular weight about 220 could easily account for the low yield, especially if you are using low. molecular weight aldehyde where the fmoc group is signigficant % of the mass of the compound.

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