good decarboxylation results in DMF

[Z_Hound]

Hello! My first post here,
need feedback on this decasrboxylation/methylation (fictional).

10 g of L-tryptophan (0.05 mol) were mixed with 35 ml of DMF
under argon flow. With vigorous stirring the mixture was brought to reflux
(~155 C) after approximately 20 minutes solution became clear-yellow.
After total 50 min of refluxing, the reaction was stopped;
DMF was removed at  ~10 mm Hg (??) (boiled around 45 C)
Dark - yellow - orange residue was dissolved CH2CL2 (dissolves completely)
resulted solution has dark-orange color.  This was washed in sequence with 2% NH4HCO3
and distilled water, CH2CL2 was dried over sodium sulfate overnight.
solvent was rotor-vaped out, orange-yellow crystalline solid was formed. (m.p. 112 C)
This was recrystallized from hot benzene, yellow-light-orange crystalls m.p. 117 C -  6.9 g ( 86%)

different catalysts in dmf were tried:
With 0.3g of methyl-ethylketone - yeild was only 70%
with 0.2 g of acetone - yeild was only 60%
with 0.5 g of benzyl-methyl ketone - 74% (this is the best keton ever! and ... still not good.)
with 0.5 g of cylcoxenanone -                62%

Seems that in DMF one does not need catalyst.
Also it seems, less product forms if you do it without inert gas flow, or reflux for more than 1.5 hr
(then mixture becomes dark - red; it seems you need to stop it when it is bright-yellow).
------

Methylation attempt:

2 g of tryptamine (~0.012 mol)  is dissolved in 15 mL of MeOH, 5 mL of 38% formaldehyde (~0.06 mol) was added, the mixture was stirred in the argon flow, at room temperature for ~2 hrs.
The mixture was placed in the cold bath (CHCL3/liquid-N2 ~220 K) and 2 g (~0.05 mol) of solid CaH2 was added in small portions. Reaction was left to stir untill all liquid N2 in the bath was gone. Then it was placed in the ice bath and was stirred for 24 more hrs (ice was allowed to melt).
The resulted mixture wasdiluted with large amount of CH2CL2
(100 mL) which was in turn washed with 2% (NH4)2CO3, distilled water; followed by drying over sodium sulfate
for 6 hrs. sodium sulfate was filtered off, CH2CL2 removed on rotor vap;
dark-brown residue was distilled under vacuum with oil pump.  (2 fractions collected)
low-t boiling fraction - 0.7 g (formed yellow crystalls - dimethyl form, ~30% yeild, m.p. 68-70 C)
high-t boiling fraction       was discarded      (seems it was unreacted tryp or monomethyl form)
 ----
I believe that low yeild was the result of the overheat during vacuum distillation.
However, I still have faith in the CaH2 method and will think how to optimize it.
did anyone try : NaH; or just bubble hydrogen through?

-------

Z_hound




Any Possession is a Demonic Possession!

[Ritter]

Hello,

I have never heard of CaH2 being used as a reductive amination catalyst.  Do you have a ref for this or is this something you thought of on your own?  If the latter is the case and you really did get active product, CONGRATULATIONS!!

[cilliersb]

I think the bad yeild can be attributed to water in the reaction mixture during the Dimethylation of your TRP.

I assume you used 38%Aq. Formaldehyde, the water in this solution will definitely react with a big portion of your CaH2 and render it useless.

Try using a rather large excess of Reducing Agent and see if this improves yeilds. (maybe 50% or more)

Was the product tested / bioassayed. If so, please report on your results. This could be the synth of choice for swim if we can boost yeilds to the 50%+ region.

Bee Well

[foxy2]

Anhydrous formaldehyde would probably work better.
Here is what you need.

Patent GB1301533

Foxy

Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[Lilienthal]

Where are the reducing agents? CaH₂ and NaH are strong bases but not reducing agents. The second step of your syntheses doesn't make sense to me.
And the boiling point of DMF of 45°C at 10 mm seems a bit low.

[Z_Hound]

Apparently, it is hydrogen, which is generated in the mix when a hydrid
reacts with alkohol or water. It is as the same as for NaBH4 or LiALH4, i suppose,
e.g. : NaBH4+MeOH -> MeONa +1/2 H2 + 1/2 B2H6; or just BH3*THF;
BH3+MeOH -> B(OMe)x + H2; borohydrid is pretty strong reductunt, and very often reduces 2,3- double
bond in the indole ring, so, i decided to try something else - CaH2
which is base only in the same sense, as NaBH4 is base (i.e. reacts wiith "acidic" protons)
Any Possession is a Demonic Possession!

[Rhodium]

What was the DMT boiling point, and with how strong a vacuum?

[foxy2]

I'll admit my initial reaction was the same as Lili.  I did some searching and CaH2 is used very little in organic chemistry, the only common use is to dechlorinate various chlorine containing aryl and alkyl hydrocarbons.  It has many uses in inoganic chemistry, chiefly as a reducing agent.

Ok now the big question.
Can this work for methylateing tryptamine to DMT?
I think it MIGHT, i'll post some references later.





Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[Lilienthal]

NaBH₄ or LiAlH₄ don't reduce carbonyls because they can develop hydrogen on reaction with acidic protons   .

The low bp product may be simply formyltryptamine. Have you tried an acid /  base extraction, TLC, or some other tests, to find out if it is an amine?

[Z_Hound]

Formyl-tryptamine is a possibility.

The product was bioassayed with inconclusive results.
~100 mg in the evaporator on a hot plate. - definetely not
as strong as dmt; or if dmt not as pure as it should be.
Increased heart beat, and slight shake in the surroundings, with "oohooh"
sort of sound - whole thing lasted couple minutes.
--------
I read about methylation with dimethyl-sulfate and K2CO3 somewhere on this forum.
Is there good method of making dimethyl-sulfate from methanol and sulfuric acid?
I browsed web for dimethylsulfate a little, all I learned that it is extremely cancirogenic.
-----
about Al, B hydrides:;
 as far as I understand, the  mechanism as  addition, say to some shiff's base, for example, would be:
RR'C=NR'' + MH ---> RR'CH-N(M)R'' (M- 'metal', Al, or B)
RR'CH-N(M)R' + ROH ---> RR'CH-NH-R'' + ROM
In the case of Al, and B, M-H bond is of rather covalent character;
while in the case of Ca, or Na, it is  ionic. So, in the latter case,
it seems, it rather evolves H2 when reacts with alcohol.
-----
Thanks for the feedback!
-----
Z_hound
Any Possession is a Demonic Possession!

[slothrop]

Most attempts of reductive alkylation of tryptamine with formaldehyde I've seen has not given that high yields. How about an approach with Ti(iv)isopropoxide and NaBH4 in diglyme? I remember seeing dimethylation done in quite good yields of various amines. Anyone tried it on tryptamine?

//Tyrone Slothrop

[Sunlight]

Inspired by your post, I've beeing trying the same DMF decarboxylation of glycine to recover methylamine. It seems to work very little, a smell of methylamine appears but there is not a consistent bubbling in the receiveing flask and in one hour the rxn was almost like in the beginning. The addition of a bit of cyclohexanone helped rxn a bit, but not enough.
Forgive me, but I have doubt about your procedure so I've put a bit of tryptophan in DMF, and yes, it works like you say, exactly the same. I won't make the workup this time for this small quantity, but I don't doubt you got really tryptamine if you report that mp. And by the way, it seems for me the best decarboxylation method of tryptophan that has been posted here, including the serious references, 1 hour, very good yields and uses only the easy to get DMF.
Congratulations, and thanks.

[Z_Hound]

Disclaimer: procedure below is *entirely* theoretical.

I. Formulation and principle.
   a) Methyl-tosylate is prepared from tosyl-chloride (chlor-anhydride of para-toluene-sulfonic acid)under basic conditions with sodium-methylate.
   b) ... is added to the solution of tryptamine in dichloromethane, stoichiometrically, 2:1
------------
Actual methylation attempt.

MeO-Na : to 20 ml of freshly distilled MeOH was added several small chunks of sodium metal. - small quantity of white precipitate was formed on the bottom of the beaker.
After the gas evolution stopped, the resulted solution of MeOH/MeONa was placed into an addition funnel with a piece of cotton near the valve (to filter).
Note: handling sodium. Sodium was stored in the xylol; must
be handled with extreme care(!!!) one takes it from the flask with forceps, cuts with a knife  and makes strips out of it with a glass tube. Important is to wash utensils after, with isopropanol first, and only then water. Excess sodium can be thrown into isopropanol for deactivation.

2. Meanwhile:
   In the 2-neck small flask: 2 g of tryptamine is dissolved in ~20 mL of freshly distilled CH2CL2 and is stirred with magnetic stirrer at room temperature under argon flow.

The addition funnel with MeOH/MeONa is attached.

3. To the addition funnel is added 2.5 g solid Tosyl-Cl
and is mixed in with a glass rod.

The whole thing is left to stand like that under urgon flow
for ~0.5 hr. Then addition drop by drop starts on the course of 5 min.

Monitoring with TLC
Personal Note: really need help on TLC with tryptamine derivatives.

Solvent used : MeOH:AcOEt (4:1)  and some, undefined (several drops), quantity of diethyl amine.

Tryptamine Rf here was 0.8 (measured from center of the spot)
On the course of the reaction above
spots with Rf )0.7;0.6 and 0.42 were noticed
0.42 was tentatively ascribed to dmt.
spot that barely moved was attributed to fully methylated
salt.

[How do you develop your TLC for tryptamines? what I did:
drop into iodine-filled closed beaker, then dump into water to make them visible]

Reaction stopped after 3 hrs of stirring at room temperature.
Diluted with large amount of CH2CL2 (70 mL) washed with
water solution of diethyl amine, 4% tetramethylammonium salt, and distilled water.
Dried over sodium sulfate, reduced significantly in volume;

and chromatographed on ~15cmx1cm silicagel (100 mesh) column
(Eluted with MeOH, monitored by TLC)

desired fraction after rotor-vaping solvent formed lightly yellow crystalline solid, ~2 g (~80%).
m.p 56 C (huh ??)

WARNING: POISON: TARGET ORGANS: CNS (Yes!)

addressing Rhodium question: sublimes/melts/ at 60-70 C under ~ 1 mm Hg ( small quantity was wasted on that in the
aldritch-micro-scale boiling point apparatus)
{Do not have Mcleod gauge, will borrow from a friend,
and then will report more precisely)

Z_hound










Any Possession is a Demonic Possession!

[Rhodium]

The boiling point is way too low. The bp of DMT freebase is 130-140°C at 0.1 mm/Hg.

Ref:

http://www.erowid.org/library/books_online/tihkal/tihkal06.shtml

[Sunlight]

mp is correct, may be it's better to smoke it to see what happens... But you could make the chlorhydrate and make that mp too.

[Student]

In your first post you concluded that the low boiling fraction of product was DMT based on its melting range of 68-70°C. The Merck lists 44.6-46.8°C for DMT. Maybe I've missed something, but that seems like quite a difference, especially since your higher mp suggests greater purity than the sample reported in the Merck. On the other hand, if what you analyzed was impure, recovered tryptamine, the melting range could be depressed below the normal 118°C. For example, the crude tryptamine obtained from decarboxylation in xylene using spearmint oil catalyst had a melting range of 104-105°C. Impurities, unless they are the majority of the sample, tend to lower and broaden the melting range. The bioassay you reported sounds like what would be expected of tryptamine (see TIHKAL).

To reduce the likelihood of misidentifying a product, use an acid-base workup preceeded by treatment with acetic anhydride. Then neither tryptamine nor formyltryptamine would be mistaken for DMT.

I've been surprised how polar tryptamine is on TLC. Even pure isopropanol barely moves it. I would have expected DMT to be less polar, but it is more basic than tryptamine and maybe it is what you have. You seem quite skilled at TLC, even using diethylamine to prevent streaking! Having a reference would make your life easier - perhaps a small extract of one of the plant material rich in your desired product.

If you don't have a nice NMR spectrometer handy, you can always make the picrate derivative and check its melting point (Merck 216-217°C).

[Lilienthal]

See

Post 126957

(Lilienthal: "Breath of Hoax? / PTC tryptamine alkylation on the test bench", Tryptamine Chemistry) for a tryptamine alkylation. It's NOT possible to get more than trace amounts of dimethyltryptamine from tryptamine alkylation.

UTFSE to find help about TLC.
I would suggest you to use methanol with an small open vial of conc. ammonium hydroxide in the chamber, alkylamines usually give a front. Use Ehrlich's reagent as a coloring reagent.

[Rhodium]

Perhaps a suggestion from 'Hexane' could help you with the TLC solvent system: "On tlc, DET ran just barely faster than DMT (CH2Cl2:EtOH:aq NH3, 40:8:1), which is exactly what I would expect."

[Z_Hound]

thanks for the tips.
Very educating.  Would 4-amino-bezaldehyde work for staining instead?

Z_Hound
Any Possession is a Demonic Possession!

[Rhodium]

I only know of 4-(dimethylamino)benzaldehyde plus a lewis acid - Erlich's reagent. It should work all right, and you may find a lot of info on it in THFSE and on google.com.

Here for example:

http://www.erowid.org/plants/mushrooms/mushrooms_article2-2.shtml

[Lilienthal]

You can't use or buy p-amino-benzaldehyde because it's not stable.

[hypo]

the decarboxylation procedure sounds very cool, but a friend of mine simply has no luck with trp decarboxylation  

2g trp were refluxed in 30ml DMF with vivid bubling of H2 (from Al suspended in water + NaOH(aq)). the mixture never became clear and bright yellow, but clear and red. after about 45min the reaction was cooled in a water bath and once cool the H2 bubbling removed. the DMF was removed under aspirator vacuum leaving a dark red oil, on the edge of crystalizing (it didn't even after 30min in the freezer). so DCM was added, and first it looked like the oil would dissolve, but suddenly the little pieces floating arround clumped together forming an totally ugly chewing gum like sticky mass. the mess was tried to be partitioned between DCM and water with the result of red tar sticking all over the wall of the separatory funnel. the DCM extracts were washed three times with water giving an orange organic phase, which was dried over MgSO4. out of frustration, they were ignored for one week when the chemist noticed crystals on the bottom of the DCM layer. happily he filtered the brown crystals of, dried them and did an mp -> result: they did not melt even though the chemist went up to 200°C. the chemist is short of kicking his trp out of the window    i will report back when the DCM is evaporated - but am not very confident.

[Sunlight]

Why the hell did you bubble H2 ? H2 is not argon, and you have not to bubble, just if you can, make the rxn in an inert atmosphere, not bubble any gas in it.

[hypo]

well, the idea was that oxygen is bad, so replace it with something different. argon was not available, so H2 was the next candidate.

as for bubbling it, this was probably stupid. but it shouldnt have interfered, should it?

did you get the clear yellow solution? were you using an inert gas? would CO2 be suitable as inert gas?

[foxy2]

Hypo
Is it possible you had a tryptamine salt?

I wonder if the addition of a tiny amount of acid or base would dramatically affect the decarboxylation?  CO2 is slightly acidic, could a tiny amount of base help push the decarboxylation?  Just an idea.

Another idea is to add a little copper(II) salt to catalyze the reaction.  You could choose the salt based on its solubility in DMF.
Foxy
Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[cilliersb]

Just use the Decarboxylation in Tatralin with Ketone Catalyst.

Swim did this (with Acetone as catalyst).

10g Tryptophan, 45ml Tetralin (this is one of the small tweaks) and 0.5ml Acetone.

Refluxed at 162C - 168C for 6 1/2 Hours with very good stirring. Added .5ml more Acetone at the 3 hour mark. When the reaction contents (Dark yellow/Orange/reddish liquid) was still hot (125C - 140C) I poured it in to a beaker and sealed the beaker with cling wrap. This was put in the fridge at 5-8C over night and in the morning the beaker had a yellow crystalline solid in the bottom of the beaker. The tetralin (now almost colorless with a slight hint of yellow) was decanted from the crystals.

I got 8.5g of pure Tryptamine after A/B with MP of 113C.

This is by far the simplest way to obtain your TRP.  

Swim is now Considering the following:
 A suspension of 1.0 g tryptamine in 50 mL ethyl formate was held at reflux for 15 h during which time the mixture became homogeneous. The volatiles were removed under vacuum, yielding an oily residue of the formamide. This may be purified by distillation but this unpurified product can serve satisfactorily in the following reaction. This residue was dissolved in 50 mL anhydrous THF and added, dropwise, to a solution of 1.0 M LAH in THF (40 mL, 40 mmole) which had been diluted with another 50 mL THF. After the addition was complete the reaction mixture was heated under reflux for 15 hours. Reflux was continued as a solution of 40 mL 1.0 M freshly distilled ethyl formate in THF was added dropwise over the course of 2 h. Heating was discontinued and the reaction mixture was quenched by the addition of excess solid sodium sulfate decahydrate at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum to yield 1.15 g pure N,N-dimethyltryptamine as an oil which solidified upon storage in the freezer. The material can be recrystallized from hexane to give white crystals with a mp 67 °C.

Rhodium, any thoughts on this procedure..... Does it even work?

[foxy2]

cilliersb
Tryptophan to tryptamine.
That post is either total bullshit or your tryptamine is very very very dirty.  Either way those decarboxylation results are no good as is.

You are saying you got a 108% yeild.
Thats impossible  

[Lilienthal]

Reduction of formyltryptamine with LiAlH₄ has been reported to give shitty yields. But maybe you have luck and get comparable yields to your decarboxylation reaction (108%).

[Lilienthal]

Oops, Foxy was a bit faster...    

The reported melting point is 114 - 119°C, so the tryptamine can't be very dirty (or a hydrochloride).

Anyway, the literature is full of statements that lithium aluminum hydride reduction of formyltryptamines or monomethyl-indolyl-glyoxylamides gives bad yields.

[cilliersb]

It appears that you're all right about my decarbox...

Swim was a little too when weighing goods. Forgot to Tare the @#$ scale.

I publically apologise for the misinformation. Upon weighing the TRP again I got only 5.7g

Why does The writeup in Phikal report 90%+ yeilds for this RXN if it is low yeilding, did the chemist make the same mistake I did or was he just being full of shit?

What literature are you referring to Lili?

[foxy2]

cill
Perhaps you should check lili's webpage, its chock full of references.
5.7g is not that bad of a yeild, its 73%, considering the small scale your working at there will probably bee considerable mechanical losses in the work-up/purification.  If I was you I would bee extremely happy considering the lack of success some have had. I'll bet that at the 100g scale the yeilds could climb considerably.
Foxy
Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[cilliersb]

Thanks for the tips lili

It would seem that this procedure does indeed produce a very pure product.

Upon extracting the yellow crystals / red residue with Aq. HCL there was very little insoluble material left and washing this with Cloroform hardly introduced any impurities to the cloroform.

I'd say the Tetralin Decarb is a winner!! Swim will try it with one of the other ketones mentioned to see if that 2-pentanone 86.2% yield is reproducable like the Acetone one.

It is important for the beez to note that when using acetone it is essential to add more later in the reaction as quite a bit of it decomposes after some time at 165C. You'll see little pufs of smoke as the acetone hits the reaction during reflux.

Is KRZ's method with NaCNBH3 better than the LAH route?

[Sunlight]

May be smoke is the water released in the imine formation...

[cilliersb]

Sunlight, you may have a point there.

Judging by the smell and also the fact that it looks similar to Safrole decomposing when distilled without Vac, I say it's decomposing acetone. The pufs of smoke also don't get condensed by the condenser, they just waft slowly out of the flask. This is smoke, not H2O vapour(steam).

Prior runs where acetone was not replaced during the reaction resulted in a reaction time that was 10.5 hours instead of 6.5 hours (at 10g Levels). There was also quite a bit more of the impurities and a less pure post reaction product. This made the A/B difficult.

Lili. Did you ever try the NaBH4/Paraformaldehyde/ZnCl2 dimethylation of Tryptamine or any prim. amine for that matter. If so, what were the yeilds? You posted this procedure at some stage and it ended up @ Rhodium.

Here it is, so we're all on the same page:

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%, holafébrine: 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.

Hoping this will work as NaCNBH3 is 8X more expensive than NaBH4 in swim's country.

[Sunlight]

If it doesn't condense, it's not water.

[Lilienthal]

I currently believe that it is absolutely impossible to get reasonable yields (everything above 30%) with any procedure involving tryptamines and formaldehyde because of beta-carboline formation! This was the main product even in triethylamine as a solvent (in a reaction with triethylammonium formate, Pd/C, and formaline).

There were serious doubts about the yields for the NaCNBH3 route posted to the Hive...

Your smoke is probably acetone vapor - just compare the boiling points