[TheUnassuming]

Hey all,
I'm trying to deprotect a final compound with two BOM protected, secondary benzyl alchohols (ortho to each other) using the standard Pd/C, H₂ conditions.  I've been trying to just use a H₂ balloon but it seems to stall out with only one being clipped (t=36h, mix of which is deprotected).  I've tried cycling H₂ as well as adding additional Pd but it doesn't seem to make a difference.  I think once one is clipped it changes the electronics of the ring enough to make it difficult for the second to come off. 
I'm going to try using a bomb to get the H₂ pressure up, but was wondering if anyone had suggestions as to the best way to scale the pressure increase.  This is very precious compound (15 steps in) so even on a test scale I don't want to roach my compound by going to high in pressure if it can be avoided.
Thank you for any *delete me*

[discodermolide]

Don't know your scale but try a normal Paar hydrogenator.

[TheUnassuming]

Hey Disco,
Thanks for the suggestion!  Unfortunately our parr set up is only able to run on the scale of 250+ ml reactions, and I was hoping to run on 2-3 mg scale (molecule is ~1100 g/mol right now).  I could still run it I suppose, just with more compound than I had planned and far more dilute.  If the compound is a hit (expected) I'll need to scale it up and that might pose some problems for the scale up run.

Ran the reaction overnight at 50psi with no observed improvement, increased to 100psi and rocking on.  Hopefully it pulls the BOM groups off before it starts doing "interesting" chemistry. 

[discodermolide]

Good luck
Let us know what happens to your 2-3 mg at 100 psi.

[Dan]

What solvent are you using?

I used to to a lot of hydrogenolysis and found THF tended to give the highest reactivity (though not necessarily the cleanest). Water, ethanol, aqueous ethanol or aqueous dioxane tended to give me the best results.

Am I right in thinking you are aiming to reduce Ar-CHR-OBOM  ArCHR-OH ArCH₂R twice?

I've had stalling problems when chelating groups are exposed that tie up the catalyst (particularly aliphatic amines). It doesn't look as though this is the case here, but maybe elsewhere in your molecule? This problem can usually be solved by adding HCl to the mixture. Though maybe you chose BOM to avoid that sort of thing.... 

[TheUnassuming]

@disco: haha... thanks, about to crack it open and see if there is progress.  Unfortunately it looks like the bomb has a little bit of a leak, so its lost about ~20psi in the past 4-5h. 

@dan: I'm using MeOH with ~5% NEt₃.  I've used this system on a very similar analogue to concurrently reduce an alkyne and a ketone, so I know it works in theory.  The TEA is necessary to keep the compound from reacting with the protic solvent over the extended reaction time (or the free alcohols once deprotected).  EtOH or dioxane might work in my case.  What ratio of water did you use in the mix for those two?
There is an adenine moiety on the scaffold, which has the C6-amino group free, but this was also the case with the other analogue and I was able to work around the chelation by using increased levels of catalyst (though technically still catalytic amounts ).
I've attached a pic of generally what I'm doing.  I'm hoping it won't dehydroxylate the compound!
Yes, acid is most certainly out.  In the last route I tried for this compound, I had MOM's on these OH's and every condition I could find roached it.
I might be forced to add a few steps in the middle of my synthesis to do protecting group swaps when I can hit the compound harder without worrying about killing it.

[Dan]

@dan: I'm using MeOH with ~5% NEt₃. 
EtOH or dioxane might work in my case.  What ratio of water did you use in the mix for those two?

Usually as much water as possible without the starting material precipitating - but it won't be much different to MeOH. I used MeOH once and it was absolutely fine, but my supervisor at the time was not happy and told me we shouldn't ever use MeOH in case traces of formaldehyde caused unwanted reductive amination, so I never did it again. Contaminant formaldehyde must once have ruined his day in the past - I have spoken to plenty of people who've used MeOH for hydrogenation or hydrogenolysis in the presence of amines and never noticed methylation - I expect it depends on the quality/age of your methanol.

Yes, acid is most certainly out.  In the last route I tried for this compound, I had MOM's on these OH's and every condition I could find roached it.

Hmmm... did you try BF₃·Et₂O in Ac₂O? You get acetolysis, in this case replacing BOM with Ac (or possibly CH₂OAc depending on the electronics of the acetal), which you can then remove with cat. methoxide. I used it a few times to crack open acetals with exceptional resistance to protic acids. It will acylate your adenine though, and I'm not sure how easy that would be to reverse.

[TheUnassuming]

I used MeOH once and it was absolutely fine, but my supervisor at the time was not happy and told me we shouldn't ever use MeOH in case traces of formaldehyde caused unwanted reductive amination, so I never did it again. Contaminant formaldehyde must once have ruined his day in the past - I have spoken to plenty of people who've used MeOH for hydrogenation or hydrogenolysis in the presence of amines and never noticed methylation - I expect it depends on the quality/age of your methanol.

Yeah, that must have been some old methanol!  I've never heard of that happening before, something to watch out for I suppose!

Hmmm... did you try BF₃·Et₂O in Ac₂O? You get acetolysis, in this case replacing BOM with Ac (or possibly CH₂OAc depending on the electronics of the acetal), which you can then remove with cat. methoxide. I used it a few times to crack open acetals with exceptional resistance to protic acids. It will acylate your adenine though, and I'm not sure how easy that would be to reverse.

I tried something similar in a last ditch effort to clip my MOM's, but it too roached my compound.  The main problem with this method even if it worked is that it racimizes the steriocenters if I understand the mechanism correctly.  My DR isn't amazing at this point, but completely loosing it and having to resolve by HPLC/chiral HPLC might kill something inside me.

Good luck
Let us know what happens to your 2-3 mg at 100 psi.

Just checked the reaction, no deprotection yet... so not better than balloon at this pressure.  Increased to 200psi and we will see what happens now!

[discodermolide]

Why stop at 200, go all the way.
Talking about methanol and hydrogenation, as Dan was. His supervisor was almost correct. We were running a large scale hydrogenation >100kg in methanol and the damm thing kept on stopping and we ended up adding ever more catalyst until it went to completion.
So investigating the problem, as one does, we found that the methanol was being oxidised to formaldehyde which was decomposing to CO and poisoning the catalyst. Don't ask me the mechanism.
Solution, use a different solvent!

[TheUnassuming]

Why stop at 200, go all the way.

The tank I trust has about 300psi in it, so I can and would have gone higher in truth.  I stopped at 200 because the pressure regulator started hissing and in the isolated and rarely visited tank room I lost my nerve.   I'll swap out the tank pressure regulator if I need to go higher. 

I'm going to start another run in dioxane/water and one in THF (balloons to start), and with any luck one of them will work!

[discodermolide]

Safety first, hissing is always usually a bad sign.

[Dan]

We were running a large scale hydrogenation >100kg in methanol and the damm thing kept on stopping and we ended up adding ever more catalyst until it went to completion.

That is a useful nugget of information. Thanks.

[TheUnassuming]

Quick update:
Tried EtOH/H₂O, dioxane/H₂O, THF, and MeOH with up to 1.5 equiv Pd (Pd/C or Pd(OH)₂) ramping up to 300psi H₂.  In no case was I able to get both BOM groups to come off. 
I've tried a few other methods from the greene book and random journals that roached my compound, so its back several steps to do a protecting group swap!
Thank you again Dan and Disco for all of your input!

[TheUnassuming]

Seeing Dans update reminded me to do the same in this thread.

In a last ditch/covering all my bases move, I tried doping the hydrogenation/deprotection with ~2 equiv of formic acid, acetic acid, or 1N HCl and got a very surprising result.

When I had MOM's instead of BOM's, acid deprotection of any sort caused complete decomposition of my material (even silica was a problem).  With BOM hydrogenation, the organic acids caused decomposition but the HCl reaction gave me complete deprotection with only ~15% decomposition! 

I have no rational for why this is the case and it has many in my group (PI included) scratching our heads.

[Dan]

Nice. Yeah, HCl has saved my skin in hydrogenolysis before (see reply #4). In my cases there were obvious chelating groups in the molecules which I suspected were poisoning the catalyst. If I had to bet, I'd put money on HCl freeing up an inactive Pd complex by protonolysis.

I have no good idea why the BOM analogue would have such greater acid stability compared to MOM though. Are the decomposition products identifiable?