Sciencemadness Discussion Board

Reductive monomethylation with NaBH4 and aq. Formaldehyde

Methansaeuretier - 9-11-2010 at 13:22

Hello
I'm searching for references and experiences for monomethylation of primary amines (in this case a 5-(sulfon-(N-methyl)amide-ethyl)tryptamine [I know this is not iupac]; target is the Naratriptane-derivate without the piperidyl-ring but with 3-ethyl-2-(N-Methyl)amine instead on the indole) with NaBH4 and aq. formaldehyde.
Is azeotropic destillation a way?

Has anyone ever performed something like that?

http://www.organic-chemistry.org/chemicals/reductions/sodium...

Naratriptane:




[Edited on 10-11-2010 by Methansaeuretier]

chemrox - 4-12-2010 at 22:36

NaCNBH3 and MeNH2.HCl or aq MeNH2. STAB might work too. A number of other ways are available as well.. in solution with Zn/Hg or Al/Hg and MeNH2 gas etc....etc....

Methansaeuretier - 6-12-2010 at 01:44

Quote: Originally posted by chemrox  
NaCNBH3 and MeNH2.HCl or aq MeNH2. STAB might work too. A number of other ways are available as well.. in solution with Zn/Hg or Al/Hg and MeNH2 gas etc....etc....

Its not as easy...
I have a tryptamine... MeNH2 does not work; Formaldyhde is the reagent of choice. And I think MeNH2*HCl does not work anyway, because I doesn't form imines. Also NaCNBH3 may not work because it leads to dialkylation in this case. STAB is known to reduce indoles to indolines very fast and does not work in aqueous solutions by the way because it's sensitive to moisture (aq. formaldehyde would not work). Al/Hg will overdo the job and should produce crappy yields (indoline formation). I have no idea about Zn/Hg but it sounds also very messy.

Anything would lead to a mess or major side products.

[Edited on 6-12-2010 by Methansaeuretier]

jon - 6-12-2010 at 10:23

yeah do this form a shiff's base with bulky benzaldehyde quaternize it with methy iodide and hydrolyse it.
that should'nt cyclize too bulky i went over this shit before just wiki baldwin's rules for cyclization.

madscientist - 6-12-2010 at 10:32

Only reductions that work under basic conditions are usable due to the Pictet-Spengler reaction, which is where tryptamines cyclize under acidic conditions and the presence of aldehydes or ketones to form beta-carbolines. I believe this may preclude the usage of Al/Hg.

Why would NaBH3CN lead to the dialkylated product while NaBH4 wouldn't?

NaBH3CN is preferred as it isn't as quick to reduce a carbonyl as NaBH4, leading to higher yields from reductive aminations. Triacetoxyborohydride also works well, is less toxic, and is simple to prepare from NaBH4.

Since we're already discussing potential alternative reductions, solo posted a paper earlier on the usage of zinc powder in 10% aq. NaOH to effect a variety of reductive aminations. No tests were done with tryptamines, though I see nothing to suggest it wouldn't work.

I like jon's idea, but you'd need a good fumehood or glovebox to work safely with alkyl halides (potent carcinogens). If you do have such things, it might be the best way.

[Edited on 6-12-2010 by madscientist]

Bolt - 6-12-2010 at 11:11

Err, nice try but check Chem. Rev., 1995, 95 (6), pp 1797–1842, scheme 2. Cyclization can occur when benzaldehyde is used.

madscientist, the pictet-spengler condensation can also occur under conditions other than what most people would think of as "acidic."

madscientist - 6-12-2010 at 11:17

It happens even in neutral conditions, I think - I should've specified that. I only have cursory background on that reaction. If there's more pitfalls please do elaborate!

Methansaeuretier - 6-12-2010 at 23:36

Quote: Originally posted by madscientist  

Why would NaBH3CN lead to the dialkylated product while NaBH4 wouldn't?

NaBH3CN is preferred as it isn't as quick to reduce a carbonyl as NaBH4, leading to higher yields from reductive aminations. Triacetoxyborohydride also works well, is less toxic, and is simple to prepare from NaBH4.

Since we're already discussing potential alternative reductions, solo posted a paper earlier on the usage of zinc powder in 10% aq. NaOH to effect a variety of reductive aminations. No tests were done with tryptamines, though I see nothing to suggest it wouldn't work.

I like jon's idea, but you'd need a good fumehood or glovebox to work safely with alkyl halides (potent carcinogens). If you do have such things, it might be the best way.

[Edited on 6-12-2010 by madscientist]

First of all I don't like to work with methyl iodide and I think methyl carbonate or dimethyl oxalate do not work here...

NaBH4 does not lead to dialkylation, because it does reduce carbonyl groups faster than imines. If the imine is made first, for example by azeotropic destillation and reduced with MeOH/NaBH4 any excess of aldehyde is removed by reduction and so no dialkylation can occur.

STAB does not work, because it does reduce indoles to indolines very fast and quantitative. See reference (first page): http://www.rsc.org/delivery/_ArticleLinking/DisplayArticleFo...
There is one refernce for a monoalkylation of a tryptamine with STAB anda very bulky aldehyde, but another problem of STAB that it is very sensitive to the water in aq. formaldehyde.

turd - 7-12-2010 at 15:33

Quote: Originally posted by Methansaeuretier  
STAB is known to reduce indoles to indolines very fast and does not work in aqueous solutions by the way because it's sensitive to moisture (aq. formaldehyde would not work).

Are you sure that the same applies to tryptamines? IIRC there are some postings saying that STAB is quite unpredictable. Also I figure that dialkylation is slower in Eschweiler-Clarke reactions, so the same might apply here. Therefore you might be able to obtain mono-methylated material. In any case, be prepared to do many small-scale experiments and to use preparative chromatography.

See:
http://www.erowid.org/archive/rhodium/chemistry/tryptamine2d...
http://www.erowid.org/experiences/exp.php?ID=61171
Of course these aren't the most reliable sources.

chemrox - 14-12-2010 at 15:52

So, I scanned the article and thanks for that, glad I checked back in. Now can't you do it with NaBH4/formic?

@turd- one thing about the Rhodium article. He doesn't mention using acid. NaCNBH3 works best at a pH of around 6. I like to drop in con HCl or ethereal HCl. Reax go a whole lot quicker.

[Edited on 15-12-2010 by chemrox]

chemrox - 18-12-2010 at 22:09

I'm trying to upload a 760 kb pdf that could be helpful.

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