Author Topic: reductive amination w/ n-methyl benzylamine- help!  (Read 2115 times)

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Dope_Amine

  • Guest
reductive amination w/ n-methyl benzylamine- help!
« on: October 04, 2004, 12:02:00 AM »
Hi y'all.  I'm kinda embarrassed to ask about this, but it's been quite a while and I'm a bit rusty.  If someone had n-methyl benzylamine and a ketone, what would be the best way to get to home base?  As I remember, NaBH4 will not reduce off a benzyl group.  One general thing that I don't understand, but people claim (TFSE), is how n-methyl benzylamine can form an imine since it only has one H nd not the two H's that I would think would bee necessary to form the water + imine.  This theoretical understanding would bee greatly appreciated, but my main question is a recommended route.  I'd prefer not to deal with a pressurized rxn.  But, whaddya think: reduce the benzyl group first (by what means?) and then throw in the ketone to form the imine and reduce with NaBH4 -OR- form the imine with n-methyl benzylamine and ketone (I don't know how this can happen) and then reduce by a means that reduces both imine and benzyl group (?).  THANX BEES!!!


Barium

  • Guest
You are right when you question how
« Reply #1 on: October 04, 2004, 05:06:00 AM »
You are right when you question how a secondary amine such as N-methylbenzylamine can form a imine with a ketone - it can't! What does form is a enamine which, in some instances, can be rather trixy to reduce. This is because they are only reduced after they have been protonated and subsequently tautomerized to the iminium salt. Lithium aluminum hydride (LAH) does for example not reduce enamines in general. Borohydrides in alcoholic media does reduce them though, as does AlH3 in Et2O, NaBH4 in THF-AcOH and H2-Pd/Pt/Rh/Ni.

So, form the enamine by reacting equimolar amounts of the carbonyl compound with N-methylbenzylamine in toluene using mol sieves or potassium carbonate to remove the formed water. Then strip off the toluene, add MeOH, EtOH or IPA followed by sodium borohydride as when reducing any imine. Isolate the e.g. 4-fluoro-N-benzyl-N-methylamphetamine (if you started with 4-fluorophenylacetone) and remove the N-benzyl group by CTH with ammonium formate or potassium formate and Pd/C, which requires no pressure.


indole_amine

  • Guest
forming imines with n-benzylmethylamine
« Reply #2 on: October 04, 2004, 11:23:00 AM »
This article was just retrieved (requested by Rhodium), exactly what is discussed here...

Post 534361

(fogged: "For Rhodium", Novel Discourse)


indole_amine

Rhodium

  • Guest
N-(?-Phenethyl)-Ketimines to 2° Amines
« Reply #3 on: October 04, 2004, 01:32:00 PM »
Dope_Amine: You have already participated in such a dicussion, it was three years ago, but anyway:

Post 189454

(Dope_Amine: "Re: here it is: direct amination of allylbenzene", Chemistry Discourse)


Other related posts & articles:

Upon reading your post above, I went on and requested the following article in this thread:

Post 217986

(Rhodium: "Wanted references", Novel Discourse)
A few hours later, the article had already been retrieved by the user foggy (thanks!). The article deals exactly with your query.


Methamphetamine synthesis via reductive alkylation hydrogenolysis of phenyl-2-propanone with N-benzylmethylamine
Harry F. Skinner

Forensic Sci. Int. 60(3), 155-162 (1993)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/forensic/meth.redutive.amination-dealkylation.p2p-benzylmethylamine.pdf)

Abstract
Methamphetamine was synthesized by reductive alkylation hydrogenolysis of phenyl-2-propanone with N-benzylmethylamine. The expected product N-benzylmethamphetamine, once formed, undergoes hydrogenolysis to methamphetamine and toluene. The progress of the reaction, the intermediates formed during the reaction, and the products were analyzed by gas chromatography and mass spectrometry.



The following excerpt is written by Psychokitty, and is reposted from

Post 108804 (missing)

(dormouse: "Microwave-Assited Rapid and Simplified Hydrogenation  -psychokitty", Novel Discourse)


[If] the microwave leukart occurs in this system, it would give the disubtituted hydrazine, which is also an intermediate in the hydrogenation pathway, and would get reduced by the Pd/C/H2 to give the primary amine just the same, so it really wouldn't effect the final product . As an additional note of speculation, it may be possible to produce the N-methylated derivative through the following sequence:

A. Combine the ketone and N-methyl benzylamine(could easily be made from MeNH2 and benzyl bromide) in toluene or benzene. Reflux using a Dean-Stark trap until all water is removed. The product will be the N-benzyl-N-methyl enamine.

B. Use this enamine in lieu of the hydrazone in the hydrogenation procedure(microwave or otherwise). Pd catalysts should be able to reduce both the C-C double bond and the benzyl-N bond. If the carbon-carbon bond is reduced faster that the benzyl-N bond, the N-methylated amine should be the only product. I can think of reasons why either of these bonds may be reduced faster than each other, but I think it would go in the order we want.



The above excerpt is referring to the method published in this article:


Mentioned before, for example in:

Post 204286 (missing)

(obituary: "microwave hydrogenations", Chemistry Discourse)

Post 108804 (missing)

(dormouse: "Microwave-Assited Rapid and Simplified Hydrogenation  -psychokitty", Novel Discourse)


Microwave-Assisted Rapid and Simplified Hydrogenation
Bimal K. Banik, Khaled J. Barakat, Dilip R. Wagle, Maghar S. Manhas, and Ajay K. Bose

J. Org. Chem. 64, 5746-5753 (1999)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/mw.cth.pdf)

Abstract
Catalytic transfer hydrogenation has been conducted under microwave irradiation in open vessels using high-boiling solvents such as ethylene glycol (bp 198°C) as the microwave energy transfer agent. Reduction of double bonds and hydrogenolysis of several functional groups were carried out safely and rapidly (3-5 min) at about 110-130°C with 10% Pd/C as an efficient catalyst and ammonium formate as the hydrogen donor. Diverse types of ?-lactam synthons were prepared by the reduction of ring substituents containing alkene and alkylidene groups or conjugated unsaturated esters. Cleavage of the ?-lactam ring by hydrogenolysis of the N-C4 bond of 4-aryl-2-azetidinones was a facile reaction with 10% Pd/C as the catalyst; but no ring scission occurred when Raney nickel catalyst was employed. Dehalogenation of aromatic compounds was also successful with ammonium formate and Pd/C catalyst. Hydrogenolysis of phenylhydrazone of methyl benzoylformate gave the methyl ester of phenylglycine in excellent yield. The techniques described here for microwave assisted hydrogenation are safe, rapid, and efficient and are suitable for research investigation as well as for undergraduate and high school laboratory exercises.



Two other related articles follow here - one with and one without Leuckart technology:


Mentioned before, for example in:

Post 108374

(dormouse: "Ketone -> Honey w/ NaBH4 + Microwaves! (Page 1) -ReFlux", Novel Discourse)

Post 108523 (missing)

(dormouse: "NaBH4 Reductive amination using microwaves  -sparkle", Novel Discourse)

Post 166806 (missing)

(Nefertiti: "(pseudo)Ephedrine => Methamphetamine", Stimulants)


Sodium borohydride on wet clay: Solvent-free reductive amination of carbonyl compounds using microwaves
Rajender S. Varma, and Rajender Dahiya

Tetrahedron 54(23), 6293-6298 (1998)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/mw.red-amination.txt)

Abstract
A solvent-free reductive amination of carbonyl compounds by wet montmorillonite K 10 clay supported sodium borohydride is described; microwave irradiation facilitates the procedure.

latest addition (10-04-04):
Now also as PDF:


(thanks to indole_amine for retrieval and correction of the above *.txt URL)

____ ___ __ _

Mentioned before, for example in:

Post 61247

(6ULdv8: "Re: Leukard scaleable ?", Methods Discourse)

Post 108529 (missing)

(dormouse: "Son of Leuckart arises to battle the evil Narc hordes.  -Cherrie Baby", Novel Discourse)

Post 108861 (missing)

(dormouse: "Leucart amination via microwave.  -Chopper", Novel Discourse)


Towards the rehabilitation of the Leuckart reductive amination reaction using microwave technology
André Loupy, Daphné Monteux, Alain Petit, Jesús Ma Aizpurua, Esther Domínguez and Claudio Palomo

Tet. Lett. 37(45), 8177-8180 (1996)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/leuckart.microwave.rehab.pdf)

Abstract
Leuckart reductive amination of carbonyl compounds was dramatically enhanced with respect to conventional heating by a specific microwave effect when the reaction was performed, under solvent-free conditions, in a monomode microwave reactor. Excellent isolated yields (up to 97%) were attained within short reaction times (typically, 30 minutes).



Finally, in my opinion N-benzyl groups are most easily removed by Zinc/Ammonium formate, as most other available methods use rather expensive reagents, such as

Pd/C with a high catalyst load

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/debenzylation.pd-af.html).




Barium

  • Guest
Whoops! I wasn't aware that N-benzyl groups...
« Reply #4 on: October 04, 2004, 01:46:00 PM »
Whoops! I wasn't aware that N-benzyl groups were removed by Zn/ammonium formate. If that is the case then of course that is the preferred system for small scale runs. But I know that if potassium formate or triethylamine formate is used instead of ammonium formate as the hydrogen source the catalyst ratio can be cut back to 5-10% w/w of the substrate, as compared to the overloads needed when ammonium formate is used.


Dope_Amine

  • Guest
reduction & debenzylation
« Reply #5 on: October 05, 2004, 03:20:00 AM »
Rhodium: Yea, I read that old thread of mine over as well as the microwave/psychokitty one before posting.  Notice that Ritter calls it an imine.  I think this is good for clarification.  Thanks for your thorough follow-up.  I don't have access to a lot of my old work, but I do think the product of the hydroamination attempt was debenzylated either by atmospheric H2 or NaBH4.

1. That new methamphetamine article is very interesting.  I noticed that they didn't mention anything about removing the water b4 reducing.  Hmmm...  Alcohols, I believe, are known to sometimes azeotrope away water to drive a reaction (or is this folklore), so maybe the removal of water is unnecessary.  I'm a bit confused:  They say that the final product is methamphetamine, then they say in a different part that they also got some benzylmethylamine too.


2. In the experimental section of that microwave debenzylation paper (Synth. Commun. 34(10), 1831-1837 (2004)), they also have a non-microwave version with just MeOH, zinc dust, and ammonium formate.  Maybe the microwave wouldn't even bee necessary. 

3. In the synthesis of oxycodone from codeine, after the dichromate oxidation, I used to reduce the double bond with 5% Pd/C and an atmospheric presssure of H2.  It was confirmed by H-nMR to have worked.  Anybody want to argue why that shouldn't reduce the double bond in this case?

4. If CTH with potassium formate only requires 5-10% (w/w) of Pd/C, then that's not too bad and I think it ought to do both reductions which is what I'd really like to achieve.

Hmmm, I'd like to run a few trials (the above, zinc dust + potassium formate), just theorizing for now.

Thanks guys...


Barium

  • Guest
Here
« Reply #6 on: October 05, 2004, 11:12:00 AM »
Thanks to indole_amine we have two good refs from Forensic Sci. Int. 60(3), 155-162 (1993), originally posted by the chief, about N and O-debenzylations with H2/Pd. The refs are found in

Post 534414

(indole_amine: "for Barium...", Novel Discourse)
.