(Hive Bee)
10-18-02 15:19
No 369921
      Tryptamine from scratch
(Rated as: excellent)

Phenylhydrazone of 4-acetamido-4,4-diethoxycarbonylbutanal

Place 43.5 g (0.2 mol) of diethyl acetamidomalonate and 70 ml of benzene in a 250 ml three-necked flask fitted with a stirrer and dropping funnel and surrounded by a bath of water at room temperature.  Stir mechanically, add about 0.5 ml of a concentrated solution of sodium ethoxide in ethanol and then add slowly from the dropping funnel a solution of 12 g (14 ml, 0.215 mol) of acrylaldehyde in 14 ml of benzene; adjust the rate of addition so that the temperature of the reaction mixture does not exceed 35 C.  When the addition is complete, stir for 2 hours more and filter off any traces of insoluble material.  Add 5 ml of glacial acetic acid and 24 g (22 ml, 0.22 mol) of redistilled phenylhydrazine, warm to 50 C and leave the resulting orange solution at room temperature for 2 days.  Collect the crystalline phenylhydrazone by filtration and wash it thoroughly by trituration with two 40 ml portions of benzene.  The yield of off-white crystalls, m.p. 141 C, is 50 g (69 %).  If the yield is low, warm the filtrate to 50 C and set it aside for a further 2 days, when a further crop of product may be obtained.

Diethyl (3-indolylmethyl)acetamidomalonate

Add 47 g (0.13 mol) of the phenylhydrazone to 300 ml of water containing 14 ml of concentrated sulphuric acid in a 500 ml two-necked flask fitted with a sealed stirrer unit and a reflux condenser.  Boil the mixture under reflux with vigorous stirring for 4.5 hours; the suspended solid liquefies and then solidifies during this time.  Cool, filter off the resulting produst (in the form of hard nodules) and wash it thoroughly by grinding it with water and refiltering.  Recrystallise the product from 1:1 aqueous ethanol to obtain the purified malonate derivative: yield 32 g (71 %).  The product melts at 143 C, resolidifies and then melts at 159 C


Boil 31 g (0.09 mol) of diethyl (3-indolylmethyl)acetamidomalonate under reflux for 4 hours with a solution of 18 g (0.45 mol) of sodium hydroxide in 180 ml of water.  Add a little decolourising charcoal, filter and cool the filtrate in an ice-salt bath.  Acidify fhe filtrate by adding about 55 ml of concentrated hydrochloric acid slowly and with shaking, keeping the temperature below 20 C.  Cool the resulting suspension at 0 C for 4 hours and then collect the crude (indolmethyl)malonic acid, a pale buff solid, by filtration.  Boil the crude product under reflux with 130 ml of water for 3 hours; decarboxylation ensues and some N-acetyltryptophan separates.  Add a soltion of 16 g (0.4 mol) of sodium hydroxide in 30 ml of water, continue to boil under reflux for 20 hours and then add about 1 g of decolourising charcoal and filter.  Cool, acidify the filtrate by adding 24 g (23 ml, 0.4 mol) of glacial acetic acid and cool the mixture at 0C for 5 hours.  Collect the crude tryptophan by filtration, dissolve it in a solution of 5 g of sodium hydroxide in 200 ml of water and warm to 70 C.  Dilute the solution with 100 ml of ethanol at 70C and decant it from a little gummy precipitate which separates.  Acidify the hot solution with 7.5 ml of glacial acetic acid and allow to cool slowly.  When crystallisation is complete, filter off the purified DL-tryptophan and wash it successively with ice-cold water (2 x 40 ml), ethanol (2 x 40 ml) and ether (2 x 40 ml).  The yield of colorless plates is 15 g (82 %), m.p. 283 - 284 C (decomp.)

ref.: Vogel 's textbook of practical organic chemistry, 5 th ed., p 756


20 grams of DL-tryptophan was dissolved in 150 ml cyclohexanol containing 1.5 ml of 2-cyclohexen-1-one, and the temp of the solution was held at 154C for 1.5 hours. The tryptamine was isolated as the HCl salt, mp 256C. Yield 92.3%.

ref.: Chem. Lett. (1986) p 893

EDIT: The first step of this procedure is somewhat dangerous ...
* acrylaldehyde: the vapour is highly toxic and irritant.  An ampoule of acrolein should be cooled thoroughly before being opened with great care.  It has been reported that opened samples of acrolein stored in screw-cappped bottles may explode violently, presumably as the result of rapid exothermic polymerization.
* phenylhydrazine: highly poisonous and produces unplesant burns in contact with the skin.  Wear gloves!  If any liquid does come in contact with the skin, wash off immediately with 2 % acetic acid, then with soap and water.
* benzene: ... you all know about that one.

So, be carefull and use a fume cupboard.
(I'm Yust a Typo)
10-19-02 00:25
No 370036
      That last step is `a bit tricky'.  Bookmark   

That last step is `a bit tricky'. Plus that it's a bit on the short side wrt workup.

When all you've got is a nailgun, every problem looks like a messiah...
(Hive Bee)
10-19-02 02:21
No 370080
      If I had to perform the reaction, this is what I ...  Bookmark   

If I had to perform the reaction, this is what I would do to work it up:
* Evaporate the reaction mixture
* Make a NaOH (aq.) solution - say 10 % - and add this to the residue
* Extract with DCM
* Dry the combined DCM extracts over MgSO4
* Filter off the MgSO4
* Evaporate the DCM
* Vac. distill the tryptamine under reduced pressure
* Add ether to the distillate and gass the tryptamine with HCl
* Recrystalize the tryptamine.HCl with ... (who knows a good solvent for this?)

An alternative to the vac. distillation would be flash chromatography.

I don't know what would be the experimental work up.  I 've just found the ref. for the reaction and Rhodium was so kind to look it up (cfr. post Post 361428 (Cyrax: "Amino acid decarboxylation, need Chem Lett article", Tryptamine Chemistry) and the following).

Someone who has experience with the decarboxylation, feel free to post the prefered workup.