Help with debenzylation of N-Benzyl

Hello,

i have some problem with debenzylation of N-benzyl protected amine.

I wanted to use a "Catalytic Hydrogenation" using 5% Pd/C + H2 in 50 C MeOH, but this requires 2 atm pressure, so to do this it's not a good option in a simple glass flask.
I tried to do this using baloon but it takes very long... Already 24 hours passed and still not finished...

When i tried to search for good ideas in google i found this one:
https://www.erowid.org/archive/rhodium/chemistry/debenzylati...

I already tried this procedure:

A suspension of substrate (10 mmol), ammonium formate (20 mmol), and zinc dust (2 mmol) in methanol (15 mL) was stirred at room temperature, under nitrogen until the completion of the reaction. After the completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite pad, washed with solvent and then the combined filtrate and washings were evaporated under vacuum. The residue was taken into chloroform or ether, washed twice with saturated brine solution and finally with water. The organic layer was dried over anhydrous sodium sulphate, filtered and evaporation of the organic layer followed by purification either by preparative TLC or by column chromatography.

The yield i got after 5 hours of stirring was ~10%. So seems that this procedure works.
So i wanted to ask, maybe someone already have experience with such deprotection procedure? It looks like something is wrong with the Zinc ammount used for this procedure (2 mmol)? I think i really need more as in my reaction 1 gr substrate need 100 mg Zinc, sounds to good to be true

Any good ideas about this procedure?

From reading another topics i started to understand that it's better don't trust to much Indian postings, but in my case seems that it works (only yield is very poor).

P.S. sorry for my poor English. Also it's my first post in this forum, so please be liberal for amateur chemist


[Edited on 8-5-2014 by ChemistryAddictive]

Quote: Originally posted by ChemistryAddictive

I wanted to use a Transfer hydrogenation using 5% Pd/C + H2 in 50 C MeOH, but this requires 2 atm pressure, so to do this it's not a good option in a simple glass flask.

First of all, thank you for your fast answer.


Well, if you use hydrogen then it is not transfer hydrogenation.
---- Sorry here must be "Catalytic Hydrogenation". To much readings today... I fixed this mistake.

I tried to do this using baloon but it takes very long... Already 24 hours passed and still not finished...
----- Any recomendations for this? At the moment i just have 5 % Pd/C... Now i use 5% by weight to substrate.

Also i have an article for Tranfer hydrogenation, but it using 10% Pd/C and Ammonium Formate, but the problem is as this procedure uses 25% catalyst by weight to the substrate. And Pd/C isn't cheap...

The yield i got after 5 hours of stirring was ~10%. So seems that this procedure works.
---- I don't have TLC plates at the moment, so i just titrated debenzylated product with HCL and checked the melting point (it can be that i can lost some product when i done all work-up) Also i checked starting product, it don't react with HCl to make salt. It makes an orange oil instead (I got three layers when i performed titration: Organic solvent --- Water --- Orange oil. I seperated water layer and evaporated it and got HCl salt of deprotected amine)

I doubt that anybody would ever check that procedure as it does not make any sense (even if I ignored the fact that these authors published a number of known BS articles, all based on the same template).
----- But this procedure works and it uses cheap Zn instead of Pd/C But as i said i think it needs more Zn... As in this procedure they use less Zn than they use Pd/C in this article ( General procedure for selective mono debenzylation of dibenbenzylamines: The substrate dibenzyl compounds (1 mmol), ammonium formate (3 mmol), 10% Pd/C (100 mg) and methanol (20 mL) were charged in to a 50 ml reactor. Reaction was stirred for 15- 20 min at room temperature under nitrogen. After completion of the reaction (monitored by TLC) catalyst was removed by filtration, catalyst was washed with 5ml of methanol. The combined filtrate was concentrated to dryness.... )

Forget about it. An Indian article in Synthetic communications is just as suspicious as an Iranian article in Tetrahedron letters.
---- Really good advice But it looks so attractive... No pressure, cheap Zn instead of expensive Pd/C...


[Edited on 8-5-2014 by ChemistryAddictive]

Quote: Originally posted by ChemistryAddictive

At the moment i just have 5 % Pd/C... Now i use 5% by weight to substrate.

I don't know the MW of your substrate, but 5% by weight does not sound enough for an atmospheric pressure N-debenzylation. I would go with at least 10 mol% Pd-C. Even at 5 bar pressure or more, I generally use a couple of mol% Pd-C. Though, the ease of N-debenzylations is quite substrate specific, so it is a pretty much try-and-optimize issue.
---- If MW means Molecular weight, than my substrate MW is 267 gr/mol. I was adviced to use 5% by weight loading of 5% Pd/C, 2 Atm (~2 Bar) pressure and 50 C (I was advised by the friend who deprotected this product succesfully in Industrial scale). So seems that this product isn't very complicated to deprotect As for "try-and-optimize", this why i will try to do it with ballon, to check the conversation on such pressure.

Also one more interested thing is that this product itself is "N-benzyl protected amine Phopshate salt". And i was advised to use it directly (disolve in methanol and perform catalytical hydrogenation and only later to basify it to release a "free amine"). Last days i tried to find any information how this can impact reaction yield and catalyst itself. Any comments about this? But when i done Zinc/Ammonium formate reaction, i first made this material basic with NaOH.

What can I say? Like I told you, don't be to cheap on palladium. You can try with less catalyst and a longer reaction time. Maybe you will be lucky.
---- thank you for an advice, this is what i am doing right now Only the problem that i don't have a TLC plates to check the conversation.

That's not enough to convince me.
---- I will send it tommorow to make analysis of this sample. I will write you results But by the all characteristics (physical properties, appearance, smell, MP) it's really deprotected amine HCl.

Dr.Bob and AvBaeyer, thank you for sharing your experience and your advices.

Now i sttired my product for 36 hours, so i am going to check the results. I asked for your help to late, as my sttiring wasn't very vigorous, becouse i made a mistake when choosed to long magnetic stir bar And if i add to much Rpm it start to "fly" in a flask

Only good sign is that balloon was shrinking, so i hope that this was an indication that my reaction consumed some H2 and not an indication that it was leaking I had to add some H2 from time to time. Also i wanted to ask, in theory this reaction must use 1 mol H2 to 1 mol substrate to deprotect it?

Next question is, as i said in my previous post, my substrate is N-benzyl protected amine phosphate salt. And i use it in this form directly (without basify, to release the free amine).
So it's still good idea to add Acetic acid?


As for Acetic acid itself, at the moment i have 60%. It's good? Water don't have any influence in such reactions?
My prefered solvent is MeOH, as it dissolves my substrate very well.
Also it's good idea to reuse same MeOH for further hydrogenations?


[Edited on 9-5-2014 by ChemistryAddictive]

Quote: Originally posted by ChemistryAddictive

Only good sign is that balloon was shrinking, so i hope that this was an indication that my reaction consumed some H2 and not an indication that it was leaking

Hello,

after 32 hours of stirring under baloon, the product was deprotected succesfully (no starting intermediate recovered). I used 5% by weight Pd/C (50% wet) to starting substrate. So next time i will try to use double of Pd/C and more vigorious stirring. And try 24 hours...

Also i wanted to ask, maybe you can advice how to reuse Pd/C? Any good procedure? I was adviced just to add 20% fresh Pd/C and use it as it is, without any washings with acid/or base.


As for methanol:

The only volatile side product is toluene which does not affect much the reaction at low amounts, but can change the solvent properties at higher compositions. So, if you plan a solvent recovery as part of a production process, you better fractionate to separate the toluene/methanol azeotrope from the methanol. Even assuming an efficient column, you will loose significant part of methanol after each run due to the unfavourable azeotrope composition. But who wants to recover a solvent like methanol? It is one of the cheapest (after water), costs less than an EUR per kg.------

I asked this not becouse of the price, but i had to evaporate Methanol in my process, so i was thinking if the Methanol is pure enough to use again - why not? But you answered to my question. For such cheap solvent i don't going to do any additional steps to recycle it.


But i still want to try CTH for this deprotection: as i have Ammonium formate, Pd/C and Nitrogen.
I was addviced to use such procedure: 10% by weight 5% Pd/C, 5 eq Ammonium formate and 50 C and stirr overnight.
But all such procedures i can find requires Nitrogen atmpshere. So i think i will do this under Nitrogen. Or this is not necessary?
Also i was advised to use very low ammount of Pd/C comparing to another such procedures. Is longer reaction time will help to use less Pd/C? As in another procedures, they deprotecting N-benzyl in max 30 minutes (but with huge ammounts of Pd/C, about 30% by weight 10% Pd/C).

Thank you in advance for your answers

N-debenzylation options?