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Topic: triisopropylsilane by-product after carbocation scavenging  (Read 662 times)

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Offline Babcock_Hall

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triisopropylsilane by-product after carbocation scavenging
« on: April 06, 2021, 05:23:09 PM »
We wish to deprotect a BOC-protected amine and a tert-butyl carboxylic ester.  When triisopropylsilane is used with TFA and a small amount of water, my understanding is that it can transfer a hydride ion to the carbocation.  When it does, I am not quite sure what happens to it, but one drawing I saw suggests that (iPr)3SiOH is formed.  Our product will have a positive charge and be hydrophilic.  This will limit what kinds of purifications that we can perform.

I was thinking that the unreacted triisopropyl silane might come off under high vacuum.  How do we remove the silicon-containing side product created after scavenging?
« Last Edit: April 06, 2021, 06:13:43 PM by Babcock_Hall »

Offline Babcock_Hall

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #1 on: April 07, 2021, 08:26:40 AM »
Pearson DA et al., Tetrahedron Letters 30(21):2739-2742,1989.

This reference discusses the use of Triethylsilane as a scavenger.  They write a side product as Et3SiO2CCF3.  They mention that Triisopropylsilane is more hindered, which is an advantage when working with tryptophan-containing peptides.  I am starting to think that extracting the side products into an organic phase while the product partitions into an aqueous phase might be what we need to do.
EDT
The trifluoroacetic acid (TFA) is the presumed source of the group attached to the silicon atom.
« Last Edit: April 07, 2021, 09:37:36 AM by Babcock_Hall »

Offline rolnor

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #2 on: April 07, 2021, 09:25:49 AM »
I would try high-vacuum first, maybe the freeze-dryer? Either method probably works.

Offline kriggy

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #3 on: April 14, 2021, 04:44:45 AM »
Did you try just TFA in DCM ? It worked well for me without any additional scavengers, might be worth trying.

Offline Babcock_Hall

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #4 on: April 14, 2021, 09:40:50 AM »
Not yet; I was just trying to plan ahead.  We still have one more step to complete in our synthesis before the deprotection.

Offline rolnor

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #5 on: April 15, 2021, 05:34:25 AM »
Is not the scavenger nessecary if you have cysteine och tyrosine in the molecule?

Offline Babcock_Hall

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #6 on: April 15, 2021, 08:54:07 AM »
We don't have cysteine or tyrosine present.  One reason that I was planning to use triisopropylsilane is that a similar molecule was deprotected in its presence.  That molecule had a free amino group (having been deprotected in the previous step), whereas in our case, we are deprotecting our amino group at the same time as the carboxylic acid.  They used 95:2.5:2.5 TFA/TIS/water.  The boiling point of TIS itself is 166 °C at atmospheric pressure and 84-86 °C/35 mmHg.  If none of it reacted, high vacuum might pull it off.
« Last Edit: April 15, 2021, 09:16:03 AM by Babcock_Hall »

Offline rolnor

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #7 on: April 16, 2021, 08:27:35 AM »
I would try without scavenger first.

Offline wildfyr

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #8 on: April 20, 2021, 08:39:39 PM »
Triisopropyl silane boils at 166C so a stout high vac will probably pull it off, maybe with gentle heat.

Its also pretty nonpolar, so putting the crude on a silica plug and running some hexane through will probably leave you product stuck on the top layer, and the silane will elute. The just push off the product with acetone or ethyl acetate.

Could do this as a full on gradient column too if you like.

Offline Babcock_Hall

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #9 on: April 21, 2021, 09:12:36 AM »
We just ran the column yesterday and will deprotect tomorrow.  There is at least one reference I found in which a tert-butylcarboxylate ester was deprotected in the presence of a vinyl sulfone, which our molecule also has.  For that reason, we think that this functional group is probably compatible with the deprotection we are planning.

The completely deprotected molecule is charged and presumably too polar for silica.  We will try without TIS.
« Last Edit: April 21, 2021, 10:02:38 AM by Babcock_Hall »

Offline Babcock_Hall

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #10 on: May 04, 2021, 05:27:08 PM »
The deprotection appears to have worked, based upon a preliminary analysis of the NMR spectra.  We are in the process of characterizing the product further.  The product is a bit gooey.  One of our summer projects will be to make more.  Thanks to everyone for the help that we received.

Offline rolnor

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Re: triisopropylsilane by-product after carbocation scavenging
« Reply #11 on: May 09, 2021, 04:21:51 AM »
Great! Maybe freezedrying a solution can make it more powder-like. Water or dioxane can be used.

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