Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: uglepik on May 25, 2011, 09:20:38 AM
-
I'm attempting to protect secondary amines on solid-phase using Boc2O (4 eq in DCM) and a reaction time of 2 days.
After that I have attempted to cleave my compound from a 2-chlorotrityl resin using 5% TFA in DCM, which I think should NOT take off the bocs.
However, it doesn't seem to work very well, as my MS-peaks make very little sense.
Does anyone have any experience with boc-protection of secondary amines? And with subsequent mild cleavage where the bocs are supposed to stay on? How do you go about this?
Thanks!
-
What type of ionization are you using? BOC is also thermally labile (comes of at ~100°) and ESI usually has a hot enough source temp to remove it. Every time I've done an LC-MS on a BOC protected amine (BOC is there by NMR) I always see the -BOC species as the major peak, frequently there is no +BOC peak observed.
Modification: If you're doing LC-MS on a BOC protected species, check for an m/z = 57 (t-butyl cation) peak that coelutes with the -BOC peak. Its indirect evidence that the BOC was there, but fell off during ionization.
-
What type of ionization are you using? BOC is also thermally labile (comes of at ~100°) and ESI usually has a hot enough source temp to remove it. Every time I've done an LC-MS on a BOC protected amine (BOC is there by NMR) I always see the -BOC species as the major peak, frequently there is no +BOC peak observed.
We're using ESI and as you say, usually boc-groups come off to some extent. However, my experience is that it is only a fraction that falls off and that the "complete" molecule is usually seen with -boc peaks lagging behind it. With these experiements, the peaks I do get, usually make very little sense and cannot be attributed to anything rational.
-
I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....
-
I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....
I was thinking this too, but wanted to get the MS thing out of the way
-
I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....
To remove boc from at least a primary amine you usually employ relatively large concentrations of TFA (95%) while what I use is 5%. I believe that it should be possible to cleave the still protected compound from a 2-chlorotrityl resin using mild cleavage conditions. I have done this before with tBu protection groups (on glutamic acids) and they stayed on after mild cleavage wheras they are removed by 95% TFA. I would expect at least primary boc's to behave the same way - however with secondary bocs I am not sure.
Which conditions did you use to remove your secondary bocs with TFA/DCM?
-
I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....
To remove boc from at least a primary amine you usually employ relatively large concentrations of TFA (95%) while what I use is 5%. I believe that it should be possible to cleave the still protected compound from a 2-chlorotrityl resin using mild cleavage conditions. I have done this before with tBu protection groups (on glutamic acids) and they stayed on after mild cleavage wheras they are removed by 95% TFA. I would expect at least primary boc's to behave the same way - however with secondary bocs I am not sure.
Which conditions did you use to remove your secondary bocs with TFA/DCM?
15%. ~12 grams of product went to completion in less then 20 minutes.
-
I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....
To remove boc from at least a primary amine you usually employ relatively large concentrations of TFA (95%) while what I use is 5%. I believe that it should be possible to cleave the still protected compound from a 2-chlorotrityl resin using mild cleavage conditions. I have done this before with tBu protection groups (on glutamic acids) and they stayed on after mild cleavage wheras they are removed by 95% TFA. I would expect at least primary boc's to behave the same way - however with secondary bocs I am not sure.
Which conditions did you use to remove your secondary bocs with TFA/DCM?
15%. ~12 grams of product went to completion in less then 20 minutes.
Ouch!
-
I see this thread is almost a year old now, however I will share my thoughts/experience anyway...
I am a graduate student who works in the field of peptidomimetics and has a lot of experience working with Boc protected proline-type derivatives on solid support.
In my experience, there is no way around cleaving Boc protecting groups when cleaving from 2-Cl-Trt resin. tBu esters are more sluggish and can sometimes be retained when cleaving from this resin though it is essentially a race.
I suggest two possible solutions to this issue:
The first should be obvious in that a more acid-stable protecting group such as CBz may be able to be used in place of the Boc group.
The second is a little less obvious - use a more acid-labile resin! I suggest Sieber Amide resin (sold by Novabiochem and a few other companies) which is cleaved by only 1% TFA in DCM. I have personally used this resin to successfully cleave a molecule with Boc protecting groups intact.
Best,
CPfeif