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       Synthesis of DMT (and other dialkyltryptamines) from tryptamine
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Drone #342:

In a 500 mL RB flask, 6.38 g crushed NaOH, 0.3 g benzyl triethyl ammonium 
chloride, and 150 mL DCM are combined, and allowed to stir at room temperature 
for 15 minutes. 5 g of tryptamine are added, and the mixture is allowed to stir 
for 1 hour. 11 g MeI is added, and the solution is allowed to stir overnight. 
The next day, the solution is checked via TLC for completion, the inorganic 
material is filtered out, extracted with DCM, and discarded. The solution is 
combined with the DCM washing, and is washed with H2O. It is then dried over 
MgSO4, and the solvent is evaporated off, yielding the final product (DMT). 
Yield: 98%

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I hope that that wasn't too dumb of a question. I just don't get this. 
I calculate 0.031 moles tryptamine for 0.077 m MeI, so there is just a slight 
excess of MeI. I guess that this should hold down overalkylation, but I thought 
that some quaternization was pretty much inevitable in a reaction like this. 
Am I wrong? Have you actually applied this to tryptamine itself? This seems
like a ridiculously easy route to DMT.

- - - - -

Actually, its even better to use a larger excess, and no, quanternization is 
not a problem and yes, there are still two phases.

The two phases are the NaOH powder, and the DCM, the PTC interacts between 
these and the amine.

Quaternization is not a problem, since from my understanding of the mechanism, 
the amine is first deprotonated before its
alkylated. When all those silly amino protons are stripped, the reaction cannot 
continue. I can't remember for certain, I'm really tired, my notes on the 
mechanism aren't with me, and I'm barely awake enough to type. Essentially, the 
method I describe is a fancier, more refined version of the method Shulgin uses 
in TiHKAL for synthesizing several of the basic dialkyltryptamines.

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This reaction really trips me out. As I now understand it, the PTC carrys OH- 
into the organic phase, where it is a stronger base. The amine can now actually 
be deprotonated under these conditions? Or maybe the N-H bond is just polarized 
by the OH-, increasing electron density and thus basicity of the N, which does 
the nucleophilic substitution on the MeI. Pretty damn cool!

- - - - -

Your understanding of chemistry is quite impressive; without any hints, you got 
the mechanism down pat! Yes, deprotonation by the OH- taken up by the PTC is what
drives the alkylation, which is exactly the reason why quaternization isn't a 
significant problem -- once you have a tertiary amine, there's simply no way for 
it to be deprotonated.

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Lilienthal:

Voil, here are the PTC-killer-reactions for (di-)methylation of tryptamines:

These one-pot reactions utilize only cheap and (more or less) non-toxic chemicals 
(no carcinogenic and expensive methyl iodide!). Because of the aprotic, non acidic
reaction and work-up conditions no cyclization to beta-carbolines should occur. 
The yields after purification are good to excellent (phenylethylamine: 72%, 
diisopropylamine: 92%, holafbrine: 85%).

Synth. Comm. 25, 2061 1995. Sukanta Bhattacharyya

A mixture of prim. amine (5 mmol) or sec. amine (10 mmol), ZnCl2 (20 mmol) and 
paraformaldehyde (20 mmol) in 25 ml CH2Cl2 was stirred at RT for 1h under dry
atmosphere. NaBH4 20 mmol was then added and the resulting mixture was stirred 
for 9 h (sec. amines) or 12h (prim. amines). The reaction mixture was then 
quenched by addition of aqueous ammonia (40 ml, 2 N), stirred for 10 min. and 
the organic layer was separated. The aqueous part was extracted with CH2Cl2 
(1x25 ml) and the combined organic extracts were concentrated in vacuo after 
drying over anhydrous Na2CO3. Prim. amines were purified by distillation, 
crystallization or flash chromatography. The sec. amines afforded the pure tert
amines without any chromatographic separation.

Tet. Lett. 3, 261 1973. B. L. Sondengam 

Formaline (35%, 35 mmol) was added with stirring to a solution of holafbrine 
(prim. amine) 3 mmol in methanol (10 ml) and the solution was refluxed for 
30 min. After cooling 400 mg NaBH4 was added slowly. After 1 h the reaction was 
evaporated and the mixture was extracted with CHCl2. Evaporation yields irhine
(dimethyl-holafbrine, 85%).

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Hexane:

Guess what? I'm tripping on DET right now. Weird stuff. Anyway, to make a short
story long, I'm currently in the midst of a synthesis of DET. Unfortunatley, I
am currently deprived of Beilstein Crossfire and have been forced to consult
the hardback version (Yes, life is difficult). All I could find for 15 or 20
3-(2-Diethylaminoethyl) indole analouges was the same sorry-ass loser method
with diethylamine-LiAlH4 and the occasional amide reduction.

I know Shulgin used a sterically hinder non-nucleophilic base, Hnig's base
(EthylDiisopropylamine). It's a good method, unfortunatly, my copy of Tihkal
is over 6000 km away right now (on another continent) and I haven't been able
to consult it. All I could remember is that there was Ethyldiisopropylamine
as the base, tryptamine, and an ethyl halide (which I think was the iodide).

In my reaction, I used 2 equiv of DIPEA, 1 equiv of tryptamine and 2 equiv of
ethyl iodide. As solvent I used acetonitrile (alkylations are always fastest in
polar solvents). I then let it stir at room temp for 12 hours. (BTW, tryptamine
isn't very soluble in this stuff.)

After work-up, I got about 60%, which is not too bad, but it was contaminated
with monoethyl tryptamine and a small amount of tryptamine. On tlc, it ran just
barely faster than DMT (CH2Cl2:EtOH:aq NH3, 40:8:1), which is exactly what I
would expect. 60% is ok, but if I don't want an oil for product, I'll have to
run a column, which would suck a great deal.

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Drone #342:

I just read J. Med. Chem. 38, 3566 (1995), and it is juicy! A tour-de-force
of tryptamine pharmacological technology, touching on SAR's of damn near
everything, culminating every loose end into one impressive little paper.
Highly recommend it for any aspiring organic chemist, though I have to say
the experimental procedural portion was stylisticly a little rough and hard
to discern (there were a few glaring errors, where things were off by a
couple orders of magnitude, etc.)

Of course, setting all the fancy technology aside, the real reason for
reading this are the lovely N-methylating procedures. On page 3577,
you'll find two fairly flavorful chemoselective tryptamine alkylations:

1) MeI with K2CO3 in DMF (83% yields)
2) DMS with K2CO3 in DMF (81% yields)

Considering the price of dimethyl sulfate, I have to say this looks like this
may be my new favorite, provided the volume of solvent can be brought down.
Right now, the concentration is pretty low (around 0.05 M), and I'm betting it
probobly could be concentrated up to maybe 0.5 M without too many hang-ups. For
doing that, you'd simply use 16.5 mL rather than 165 mL of DMF. Here's a rough
procedure, liberally modified from the procedure given in the article:

"To a solution of tryptamine (1.312 g, 8.2 mmol) and potassium carbonate
(2.78 g, 20.02 mmol) in dimethylformamide (165 mL)was added dimethyl sulfate
(2.15 g, 1.61 mL, 16.9 mmol) and the reaction mixture stirred at room temp
for 4 h. The reaction mixture was poured onto water and extracted with ethyl
acetate. The extracts were washed with brine and dried (MgSO4). The solvent
was evaporated to give an oil..."

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DMT from reductive methylation of tryptamine (by KrZ)

Tryptophan (454g) was suspended in tetralin (1150 ml) containing acetone
(12.9 g) and the mixture was heated to reflux for 12 hours with vigorous
stirring until no more carbon dioxide was evolved and the reaction mixture
became clear. The solvent was removed under vacuum, and the residue was
distilled under reduced pressure to give a yellow crystalline solid. (from
rhodium). Next 30g of formaldehyde and 120g Tryptamine were disolved in 1800ml
of MeOH, to this was slowly added dropwise 50g of NaCNBH3 disolved in 550ml
MeOH. Then 14g Glacial Acetic Acid was added dropwise with stirring. The mixture
was then stirred for 60 hours. The majority of the MeOH was distilled off (2L
collected) to the distillation flask was added 1L of 5% Aq. Ammonia which was
extracted with 3x 250ml of DCM. The DCM was washed with a salt solution (not
saturated but still pretty strong) then the DCM seperated and dried with a large
portion of MgSO4 made by dehydrating epsom salts overnight in the oven at 450C
(the rock-solid mass had to be pounded into a powder with a hammer and the small
remaining clumps ground in a pestal, quickly so as not to allow H2O uptake from
the atmosphere). The DCM was distilled off at atmospheric and then the
distillation was continued (~1 torr now) until the dimethyltryptamine was
collected. Which was recrystalized from boiling hexane with a few mls of Ethyl
Acetate added (these were the 2 hardest things to get!) This afforded 48.8g of
DMT, a 35% yield. Not high but it was still a fun adventure. The DMT was
immediately mailed 3500 miles away.

Higher yield variation (also by KrZ)  

Tryptamine hydrochloride (10 g, 62.4 mmol) and sodium cyanoborohydride (6.28 g, 
100 mmol) in a mixture of methanol (400 mL) and glacial acetic acid (11.76 g, 
196 mmol) were cooled to 0C in an ice bath over a steady stream of nitrogen.  
A solution of 4.20 g formaldehyde (140 mmol, 11.05 mL of 38% Aq. CH2O) in 125 mL 
of Methanol was added dropwise to the solution over a period of one hour with 
mild stirring.  The flask was stoppered, the reaction allowed to return to room 
temperature slowly, and allowed to proceed for the next 60 hours. Upon completion 
the pH was adjusted to 8.0 by the dropwise addition of an aqueous solution of 
sodium bicarbonate.  The mixture was then extracted 4x with 50 mL of ethyl acetate.  
The combined extracts were washed once with 250mL of brine and dried over MgSO4 (15g) 
for 15 minutes.  The MgSO4 was washed clean with another 75 mL of ethyl acetate.  
The solvent was reduced to 100 mL on the rotary evaporator.  The hot solution was 
added to a 200mL beaker and covered with plastic wrap which was sealed on with a 
rubber band.  Upon cooling in the freezer overnight, the precipitated DMT was 
removed by filtration, and dried in the dessicator.  

Overall yield: 7.88g, 45 mmol, 67%. The mp is solid, right around 64-67C.

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Thoughtcrime23:

This is my first post here.  But I've been following this procedure a little and
am quite pleased to see this dug up from possible permanent deletion.  The
journal ref. for KrZ's method is as follows:

Journal of Medical Chemistry, 1994, vol. 37, No. 19 pg.3029
"Gen. for the preparation of n,n-dimethyltryptamines"

     To a cooled (-2 C) and stirred sol. of (substituted amine)(7.0mmol),
NaCNBH3(14.0mmol), and GAA(35.0mmol) in MeOH was added dropwise, over 17min., a
sol. of CH2O(38% w/v aq. sol.) in MeOH. After 20min. of stirring at 0Celsius and
2.5hrs. at roon temp., sat. aq. k2co3 was added and the MeOH was removed under
vac.. The residue was diluted w/ H2O and the product was extracted with EtOAc
twice, washed with salt sol. twice, dried, and concentrated. Yield of sub.
trypt= 83%.

   It is ironic that this is actually quite similar to a DMT proposed synth.
back at DMT world that was also "lost and forgotten" (ref. Tet. Letters 3, 261.
1973 B.L. Sondengam e. a.) with the only major difference being the catalyst
NaBH4 vs. the more selective NaCNBH3.  I recall it actually being discarded,
without much trial, as producing quarternary tryptamines (betacarbolines) rather
than the desired n,n-dimethyl because of a cerntian mechanism in the reaction
(Pickett-Spengler?).

   However, to my knowledge when our revolutionary bee KrZ first posted the
procedure of this thread's topic, Rhodium somewhat concluded that the combo of a
gentler catalyst AND the use ose GAA to regulate the pH of the reaction that
quarternary product formation would be reduced and/or eliminated!! WOW!

    I feel that if KrZ's method is what it seems to be, that this could be
potentially the most accessible hypothetical route to DMT thus present so far.
Sodium Cyano, albeit be no means OTC, is less hazadous than LAH or Red Al (not
to mention its varied applications in other realms)... and everthing else in the
process's 2nd half (from T to DMT) CAN be had in some relative OTC form, save
Ethyl Acetate.  I've always dreamed of open the Pandora's box of
dimethyltryptamine accessability via revolutionary synthesis, and I have to be
cautious in my enthusiasm so as to remain rational and wary of hard evidence.

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KrZ:

If you're worried about NMT/T contaminating your product just do the workup 
this way;

Basify the aq. reaction mix to 13-14 with NaOH.  Extract repeatedly with DCM.  
Rotovap off the DCM and add Petroleum Ether, heat to a boil and decant the Pet. 
Ether from any undissolved material.  Cool the Pet. Ether in the freezer and 
collect any precipitated solids.  This will remove any unreacted tryptamine.  
To remove NMT you can react this mixture with acetic anhydride and seperate.  
I know that's quite a hassle but it's a good way to cover all the bases as far 
as purity is concerned. 

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