[stinemarkussen]

Hey there.

Can anyone help me with the mechanism for debenzylation of amines using ammonium formate and Pd/C?

I have found that this reaction works fine for my compound, where as debenzylation using 55 bar of hydrogen atmosphere and Pd/C gave almost no debenzylation at al. I can't understand why the hydrogen formed in situ is so much more effective. Any ideas anyone?

Kind regards

[fledarmus]

Oh, the black art of catalytic amine debenzylation! I've read several papers that definitively describe the perfect set of conditions for debenzylating amines, they don't agree with each other, and they don't necessarily agree with what I get in my lab.

Have you tried the DeGussa type (wet) catalysts? I have had more success with them in debenzylations than the dry catalysts, and they are easier to handle and store. Is it possible that whatever effect the water is having in these catalysts can be partially replicated by the ammonium formate?

I've gotten to the point where I don't worry too much about why a debenzylation works or doesn't work - I just make sure to try each on a small batch before running my entire sample, and using the same bottle of catalyst on both the small and large batch.

[discodermolide]

Hey there.

Can anyone help me with the mechanism for debenzylation of amines using ammonium formate and Pd/C?

I have found that this reaction works fine for my compound, where as debenzylation using 55 bar of hydrogen atmosphere and Pd/C gave almost no debenzylation at al. I can't understand why the hydrogen formed in situ is so much more effective. Any ideas anyone?

Kind regards

Transfer hydrog?

[OC pro]

Can you provide structural information? Did you use methanol? From my experience, DMA (N,N-Dimethylacetamide) is one of the best solvents for debenzylation of amines. Some amines tend to deactivate the palladium catalyst via complexation. DMA will prevent this. 

[stinemarkussen]

Thank you all for your replies. Yes I've used the Degussa type of Palladium hydroxide in both reactions. The solvent was MeOH, so it might be an idea to try DMA instead.
The compound is a 3,9-diazaspiro[5.5]undecan which is boc-protected in one end and benzylprotected in the other end.
I have solved the problem of debenzylating using ammonium formate. But now it turns out I get the formylated amine as a product instead of the free amine. The amine apperently attacks CO2 during the reaction. I have reacted it for 30 min at 60 degrees at microwave irradiation. The formyl group should be possible to cleave of afterwards without losing the boc-group, but it would be easier if I can finetune the reaction so I can get the free amine in the first step. Any good ideas?

[Dan]

I've been in this position many times. The general problem with N-debenzylation is that aliphatic amines can poison Pd catalysts (the effect is well documented).

A solution that I have found 100% successful so far is to acidify the reaction medium with HCl, which protonates the amines and prevents poisoning. In my experience, reaction mixtures containing HCl at a total concentration of 0.1-0.3 M have always successfully debenzylated in 24 h with 10% Pd/C under hydrogen at atmospheric pressure, even in cases where <10% conversion was observed over several days with various more active catalysts in the absence of acid. My solvents of choice are ethanol, water, aqueous ethanol or aqueous 1,4-dioxane. It is important to properly purge the vessel and flush with hydrogen (I normally do 3 cycles).

The slight acidity of ammonium formate may be the reason it works for you. If you have acid sensitive groups in your molecule you can use weaker acids, like acetic acid.

[stinemarkussen]

Thanks!

Since I have a Boc-group in the compound I am affraid to cleave it of if i use acid. Ammonium formate decomposes into H2, CO2 and NH3 so the mixture is basic.

I just found out that I can attach the structure of the compound, so that is now done.

[OC pro]

I suspected a structure like this. Protected piperidines are nasty. At room temperature, acetic acid will not cleave the boc group.

[orgopete]

A point I often sought when asked about a reaction was, "What are you trying to do?" Obviously, you are trying to debenzylate the compound, but I am presuming this is not the final stage. In that spirit, what is the next step you wish to perform? Can this reaction be carried out simultaneously in the hydrogenolysis step? Rather than formylating your intermediate, can you replace the ammonium formate with your next reagent, add hydrogen gas, catalyst and do the two steps together?

[fledarmus]

I know this is a bad place in the synthesis to ask, but why not start with the CBZ protecting group instead of a benzyl protecting group? It still allows you to differentiate between the CBZ and the boc. Of course a perfectly legitimate answer is that this was the compound available...

[stinemarkussen]

I have synthesized the compound from 1-benzylpiperidone, because that was available and the steps were manageable. I just tried to use DMA as a solvent in a simple hydrogenation, and the TLC looks promissing, so maibe my problem is solved. The next step is to react the amine with either a carboxylic acid by the use of coupling agents, to react it with an isocyanate or a simple Sn2 reaction with the structure below.

[OC pro]

Nice to see your prob solved. The rest should be straight-forward.

[Mobius1988]

I've been in this position many times. The general problem with N-debenzylation is that aliphatic amines can poison Pd catalysts (the effect is well documented).

A solution that I have found 100% successful so far is to acidify the reaction medium with HCl, which protonates the amines and prevents poisoning. In my experience, reaction mixtures containing HCl at a total concentration of 0.1-0.3 M have always successfully debenzylated in 24 h with 10% Pd/C under hydrogen at atmospheric pressure, even in cases where <10% conversion was observed over several days with various more active catalysts in the absence of acid. My solvents of choice are ethanol, water, aqueous ethanol or aqueous 1,4-dioxane. It is important to properly purge the vessel and flush with hydrogen (I normally do 3 cycles).

The slight acidity of ammonium formate may be the reason it works for you. If you have acid sensitive groups in your molecule you can use weaker acids, like acetic acid.

In my molecule I have a BOM protecting group and an alkyne, both of which I tend to cleave/reduce using Pd/C and H2 in a H-Cube at 60 degrees C. Ive recently had to introdruce dibenzylamine onto a heteroaromatic ring in the same molecule which I will need to remove to give me the aromatic amine. Could I use your above suggestion in the H-Cube in an attempt to take out all three at the same time?

I would likely get the HCL salt since i have a basic amine in my molecule. I put my molecules through an MDAP at high pH which uses an ammonium carbonate modifier, would this remove the HCL salt and give me the free base i require?

Do you have any papers on the use of HCl for debenzylation? My supervisor is unlikely to let me try it without literature evidence.

[Dan]

In my molecule I have a BOM protecting group and an alkyne, ... dibenzylamine . which I will need to remove to give me the aromatic amine. Could I use your above suggestion in the H-Cube in an attempt to take out all three at the same time?

I don't see why not.

I would likely get the HCL salt since i have a basic amine in my molecule. I put my molecules through an MDAP at high pH which uses an ammonium carbonate modifier, would this remove the HCL salt and give me the free base i require?

I don't know what MDAP is, but if you want the free base you can probably just do an organic extraction from a basic aqueous layer. If the free base is water soluble, then I'd use ion exchange.

Do you have any papers on the use of HCl for debenzylation? My supervisor is unlikely to let me try it without literature evidence.

Look it up in one of the protecting group books - Green and Wuts or Kocienski for example, they will mention it - I didn't invent it, it is well known.

[discodermolide]

Try Na or Li/liq NH3 at -78°,
see the following

A. I. Meyers, L. Snyder, J. Org. Chem. 1993, 58, 36.