[zarhym]

I got a tricky problem here. My molecule has a BnO protection on secondary alcohol on one side, a THP-N protection on the middle, and a NR3 plus BocNR2 on the other side. I was trying to remove BnO by using Pd/C and hydrogen.

Because of the aliphatic nitrogen is poisoning the Pd catalyst, I have to add acid to prevent the palladium poisoning. Too much acid will remove THP. Thus, I have to adjust the amount of acid to avoid catalyst poisoning and let the hydrogenation go, while prevent the deprotection of THP from happening. This approach was successful when I was doing it at about 0.4g scale.

The problem appeared again when the reaction was scaled up to 10 gram. About 20% of product was desired product. One major byproduct was the hydrogenation at NR3 according to HNMR and LCMS.Due to the long pair of aliphatic nitrogen bonding to Pd, C-N bond was broken by the hydrogenation.  Aliphatic nitrogen does not deactivate palladium completely. I can further adjust  the amount of acid and find a room for this reaction very carefully. But this just doesn't look very promising.

The only alternative approach, as far as I can find, is to oxidize BnO to PhCOO group and then hydrolysis the ester. I am wondering if anyone here have any first hand experience about the yield and functional group tolerance.

Thanks.

[zarhym]

This is a demonstration of my problem.

[Dan]

You can use acetic acid instead of HCl to protonate the problematic amine - this keeps your pH range more Boc/THP friendly. But it may not help with the problematic amine hydrogenolysis.

I have no personal experience with ROBn ROBz, try it and see.

What reagents are you planning to use?

[Guitarmaniac86]

Can't you use sodium in liquid ammonia to remove the OBn group? The THP and Boc groups are stable towards it, though I am unaware how your piperazine will act I suspect it might be labile.

I have used sodium in liquid ammonia to remove such groups with TBS groups present and I first allow the ammonia to evaporate then pass nitrogen or argon through the sample to push out any ammonia left behind. I also have a carboxylic acid present so I use 0.01N KHSO₄ solution to extract my compound but you wont need to do that.

[zarhym]

You can use acetic acid instead of HCl to protonate the problematic amine - this keeps your pH range more Boc/THP friendly. But it may not help with the problematic amine hydrogenolysis.

I have no personal experience with ROBn ROBz, try it and see.

What reagents are you planning to use?

I found several paper using ROBz approach. I'll give some detail about this idea tomorrow.

For Pd reduction, I am planing using excess amount of AcOH/AcONa buffer to keep the pH around 4 to 5. This condition was found friendly to THP, while Pd hydrogenation can also happen in HCl. Boc was not an issue.

[zarhym]

Can't you use sodium in liquid ammonia to remove the OBn group? The THP and Boc groups are stable towards it, though I am unaware how your piperazine will act I suspect it might be labile.

I have used sodium in liquid ammonia to remove such groups with TBS groups present and I first allow the ammonia to evaporate then pass nitrogen or argon through the sample to push out any ammonia left behind. I also have a carboxylic acid present so I use 0.01N KHSO₄ solution to extract my compound but you wont need to do that.

You are right. The only thing keeps me from using that method was brich reduction of the aromatic rings. I have to test the stability of my starting material in Na/NH₃ or Li/NH₃ before using that.

[zarhym]

You can use acetic acid instead of HCl to protonate the problematic amine - this keeps your pH range more Boc/THP friendly. But it may not help with the problematic amine hydrogenolysis.

I have no personal experience with ROBn ROBz, try it and see.

What reagents are you planning to use?

There are several oxydation methods. The first one uses NaIO₄/RuO₂. This method was first reported in Tetrahedron letter, Vol 24, No.36, pp 3829-3830,1983.

The second method  uses Iodine centered radicals, which is not commercially available.(J. Am. Chem. Soc. 1996, 118,7716-7730)

The third one uses DDQ with photoirradiation. It will be a pain in the ass when scale up the reaction. (Tetrahedron Letter, 46, 2005, 7307-7309)

There is another one converting BnO to AcO using AcBr. I assuming this reaction is kind of acidic and has to be water free.(J. Org. Chem., 2009, 74, 1367-1370)

I tried AcOH yesterday. The starting material is stable even in pure AcOH. However, AcOH is not acidic enough to free palladium from amine. There is a similar result reported in Tetrahedron 54(1998) 13981-13996.

One approach was successful yesterday in small scale. 1.1eq HCl was used to ionize the amine, while the volume of solvent was increased to higher the pH.  In this condition, the volume is 100mL/mmol. I will try this again in a little bit larger scale.

[Guitarmaniac86]

Have you tried Mg turnings ammonium formate in methanol. Selectively deprotects OBn SBn and NHBn groups. I will post a prep when I find it. If you want to do a search look up catalytic transfer hydrogenation. You can use Mg, Fe, Zn, Pb, Pd, Ru, Rh I think as well.

[zarhym]

The problem has been solved. The approach I choose was addition of HCl to break the nitrogen palladium, while expend the volume of the solvent. If the condition was right, the reaction only takes about 3 hours to complete. However, if palladium is still attached to amine, the reaction takes forever and formation of byproduct is favourable due to the lose of amine.