Hello there.
Are there any recipes/references on monomethylation or monoalkylation of tryptamines with NaBH4?

I interested in the synthesis of an 5-substituted N-Methyltryptamine.
Plan right now is azeotropic destillation of the tryptamine with aq. formaldehyde in toluene to get the imine and reduction of this with NaBH4, but the major problem is that tryptamines, NaBH4 and maybe the imine does not dissolve in toluene.  

Well, there are a few options...

The easiest is probably the use of caesium salts as a catalyst. In the presence of Cs+, a stoichiometric amount of methylating agent will form the secondary amine but no higher amines:

http://www.erowid.org/archive/rhodium/pdf/amine.alkylation.cesium-effect.pdf

The following method should not be for trypamines due to the formation of the iminium intermediate - Enkidu
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Another is through the benzaldehyde imine intermediate. This is described on Rhodium:

http://www.erowid.org/archive/rhodium/chemistry/amphetamine.methylation.html

p-Methoxyphenethylamine, generated from 100 g (0.536 mole) of the hydrochloride by stirring with conc. aq NaOH, was treated with 100 ml of benzene (toluene could be substituted) and 70 g (0.66 mole) of benzaldehyde. A mildly exothermic reaction began at once. The mixt was heated under reflux until no more H2O was present in the condensate (ca. 1 hr), then, without cooling, an attached Dean-Stark trap was removed and a soln of 82 g (0.65 mole) of Me2SO45 in 200 ml of benzene (toluene could be substituted) was added through the condenser at such a rate as to maintain reflux (15 min). The 2-phase mixt was heated for 90 min on the steam bath, cooled slightly, treated with 200 ml of H2O, and heated for an addn 20 min. After cooling in ice, the aqueous layer was washed twice with Et2O to remove unreacted benzaldehyde and made strongly basic with 50% aq NaOH. Two Et2O exts of the basic aqueous phase were added to the amine layer which separated, and the resulting solution was evacuated at the aspirator for 30 min, leaving 90 g (102%) of crude N-methyl-p-methoxyphenethylamine. This material was dissolved in 500 ml of 20% abs EtOH-Et2O and treated with 50 ml of conc HCl with swirling and cooling to yield the white, cryst hydrochloride, which was washed thoroughly with ice-cold 20% EtOH-Et2O and dried, mp 185.5-186.5°C. The yield was 83 g (77%).

I suspect, though I do not know, that vanillin may safely substitute for benzaldehyde in this instance -- it has all the right parts in all the right places. The major limitation of this method is that the intermediate imine is not very nucleophilic and so a stronger methylating agent must be used, or the methylation must be performed under reflux (dimethyl sulfate will alkylate amines at room temperature in minutes, but the tek requires a lengthy reflux. A weaker agent like methyl bromide would probably not work at all!).
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The third method is the formation of the N-formyl intermediate and the reduction thereof. Amide reduction is typically carried out with lithium aluminium hydride, a difficult-to-obtain and highly dangerous reagent, which is probably not an option for most bees. Amides can also be reduced by the combined action of phosphoroyl chloride and sodium borohydride, though phosphoroyl chloride is not much safer. POCl3 can be prepared OTC, at least.

I believe Tsathoggua is correct in saying that an attempt at reductive amination with formaldehyde will result largely in the beta-carboline rather than the desired N-methyl tryptamine.

^ This is also incorrect. The primary tryptamines cannot be methylated to the tertiary amine using reductive methylation (as with tryptamine to DMT), but they can be methylated to the secondary amine because the iminium ion is never formed. - Enkidu

I'm going to tentatively recommend caesium salts. I know of at least one Chinese chemical company that supplies caesium salts and would probably ship no questions asked. There are probably others as well.

the imine is going to be tricky to make. iirc klute from sciencemadness has posted a route for mono-methylation of amines with methyl tosylate, easily made from tosyl chloride and methanol i think. the post is here http://www.sciencemadness.org/talk/viewthread.php?tid=12542
prep of the methyl tosylate is here http://www.sciencemadness.org/talk/viewthread.php?tid=11004
his methodology calls for making the benzylideneamine (imine from benzaldehyde and amine), then methylation with methyl tosylate then hydrolysis of the bezylidene moiety to give the methylated amine. I think this is your best bet to get the n-methyltryptamine with ease.

Again, this method suffers from the same iminium intermediate drawback that atara's second method does. - Enkidu

I'm not sure about the benzaldehyde imine derivative, it might be liable to undergo pictet-spengler cyclisation. Is it possible that the iminium intermediate in the POCl3/NaBH4 might cyclise as well? But if I recall correctly the furfural imine does not (easily) (of either tryptamine or tryptophan). In that case it might be a useful trick for monomethylation; furfural itself is easily enough prepared. However it would be best to keep at higher pH and on the cooler side because it CAN cyclise http://www.relaquim.com/archive/2007/p2007353-58.pdf

First, the imine condensation product of benzaldehyde and tryptamine will not cyclicize on its own. Second, the analogous condensation product with furfural will work no better than with benzaldehyde when the goal is a monomethylated tryptamine. Yes, it's due to the iminium intermediate. - Enkidu

I haven't seen any reports of the cesium catalyst attempted in this context, but by all means it looks worth a try.

The last of my three cents, if a suitable PTC can be found (TBAB I think) microwaves will facilitate a direct alkylation of an amide, ahem, like an acetamide, and Me2CO3 ought to work swimmingly for that. Although as Jon pointed out, it may be somewhat difficult to hydrolyse. http://www.hsc.wvu.edu/sop/compchem/mdpi/molecules/papers/41100333.pdf

Hello there.
Are there any recipes/references on monomethylation or monoalkylation of tryptamines with NaBH4?

I interested in the synthesis of an 5-substituted N-Methyltryptamine.
Plan right now is azeotropic destillation of the tryptamine with aq. formaldehyde in toluene to get the imine and reduction of this with NaBH4, but the major problem is that tryptamines, NaBH4 and maybe the imine does not dissolve in toluene.  

Why not use methanol as the solvent?

The imine and NaBH4 are both soluble in methanol. I wasn't suggesting a solvent for the condensation of the aldehyde and the amine: I was suggesting a different solvent for the reduction.

Just use paraformaldehyde instead of aqueous formaldehyde.

A more practical reductant for amides is zinc borohydride, which is much easier to obtain and produce and far safer to handle than LiAlH4. It doesn't seem very well-known, so it's probably worth mentioning.

http://www.erowid.org/archive/rhodium/pdf/zinc.borohydride.pdf

Also, and I didn't think of this before, the use of the POCl3 reduction for a tryptamine amide will likely result in the same condensation that is problematic with the benzaldehyde route. The POCl3-amide complex is, after all, the active alkylating agent in the Vilsmeier-Haack reaction.

@Enkidu: the method you blocked out was the second method I suggested, not the first. The first method was the use of caesium salts as a catalyst.

Zn(BH4)2 is well known reduce amides but will also reduce the indol-core under usual conditions, as well as NaBH4 in acetic acid etc.
And lewis acids may also lead to cyclisation of tryptamines, so Zn(BH4)2 isn't a real option here I think.

But LiBH4 may work here... but I can't find any refs on LiBH4 used in reduction of amides

POCl3 is hard to obtain for me. But I would love to give it a try

How was your 5-subbed tryptamine prepared? Has it been characterized (MP test, spectroscopy, derivatives, etc)? According to this, tryptamine isn't soluble in benzene, so I doubt that it's soluble in toluene either.

The alien mass is definitely some type of polymerization (tar), but I don't have any good ideas about why it formed yet.

100ml IPA was added, a white precipitate formed!(? what is it)

That's something I really don't understand. What concentration was the isopropanol? Anhydrous?

Edit: You really need to do a MP test and develop a spot with TLC.

Maybe direct alkylation in MeOH (1,2 eq paraformaldehyde in MeOH, the tryptamine, ~3h RT and reduction with NaBH4) is tried next. Because it's hard to obtain paraformaldehyd here, the same with waterfree acetaldehyde might be tested first.
I made this many times for N-Benzylation of other primary amines and it worked well everytime in ~70%+ yields.
Hope it works as well with shorter aldehydes and maybe ketones .. but I can't find any refs for shorter aldehydes but many with bigger aldehydes... maybe no coincidence.

I assume that you're talking about driving amine + aldehyde <--> imine + water equilibrium to the right by removing the water using the properties of the toluene/water(/formaldehyde?) azeotrope. IIRC formaldehyde will distill over with the water as a maximum of 8% (i.e., if you were boil the formalin alone). I don't know for sure whether the toluene will break that azeotrope, but probably not.