N,N-dimethyltryptophan

[pHarmacist]

Thank you for those refs

Post 445304

(Vitus_Verdegast: "continued.", Tryptamine Chemistry)!

If your dream come true, you must say:

http://www.dailywav.com/1000/children.wav

[Rhodium]

If you add one equivalent of LiCl to a suspension of NaBH₄ in THF, the soluble LiBH₄ is formed in situ, and as it is a stronger reedicing agent than NaBH₄, the reduction is even more likely to happen.

[Lilienthal]

BTW, to get a good yield of the quaternary amine you have to add an equimolar amount of a more-basic, non-nucleophilic base (like di-isopropyl-ethyl-amine) as an acid scavenger.

[Vitus_Verdegast]

Found some disencouraging info on the pyrolysis of tryptophan :

http://www.healthplanning.gov.bc.ca/guildford/pdf/130/00013076.pdf

(BATCo document for Province of British Columbia, 8 November 1999)

Chemical Identity of Some of the Mutagenic Products of Protein Pyrolysis

The majority of work has centered on identifying the mutagens from the pyrolysed amino acid tryptophan, which represent some of the most powerful mutagens known to date (3, 4)   . From tryptophan pyrolysate, the mutagens 3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole and 3-amino-l-methyl-5 H-pyrido(4,3-b)indole have been isolated (4). These compounds are both gamma-carbolines (Figure 1) and have also been found in pyrolysis products of whole proteins (7).

Furthermore, it is well known that the co-mutagens harman and norharman (beta-carbolines) from tryptophan pyrolysis are also present in the [cigarette smoke] condensate (Figure 1). All these compounds have complex mutagenic activities. The amino-alpha-carbolines are themselves powerful mutagens and also act synergistically with other mutagens (9) whilst the beta-carbolines are well established co-mutagens*(4).

Figure 1




*Co-mutagens are not themselves mutagenic, but are able to enhance the mutagenicity of other compounds. (BATCo document for Province of British Columbia 8 November 1999)

3. Matsumoto, T., Yoshida, D., Mizusaki, S. and Okamoto, H. Mutagenic activity of amino acid pyrolysates in Salmonella typhimurium. TA98. Mut. Res. 48, 279-286, (1977).

4. Sugimura, T. and Naigo, M. Mutagenic factors in cooked foods. CRC Critical Reviews in Toxicology 6, 189-209, (1979).

7. Yoshida, D., Matsumoto, T and Nishigata, H. Effect of heating methods on mutagenic activity and yield of mutagenic compounds in pyrolysis products of protein. Agric. Biol. Chem. 44, 253-255, (1980).

9. Yoshida, D. and Matsum to, T. Amino-a-carbolines as mutagenic agents in cigarette smoke condensate. Cancer Letters 10, 141-149, (1980)

http://www.hplc1.com/shodex/english/dc010901.htm

Medline (PMID=9641497)

says:

Cooking meat creates heterocyclic amines (HCAs) through pyrolysis of amino acids and creatinine.

The question is: what will happen if pure tryptophan or N,N-dimethyltryptophan are subject to pyrolysis?

[Vitus_Verdegast]

Well, I heard that Hjalmar P., a Hungarian architect, performed this reaction a while ago   :

To a stirring solution of L-tryptophan (2 g, 10 mmol) and NaOH (0.42 g, 10.5 mmol) in 25 mL MeOH was added a 30% formaline solution (3 g, ~30 mmol). After 15 min of stirring at RT (~25°C), the mixture was cooled in an ice/salt bath and NaBH₄ (600 mg, 15 mmol) was added bit by bit, care was taken that the temperature did not rise above 5°C. After an hour, all ice was melted, and the solution was stirred overnight.

It was then carefully acidified with HCl, to the iso-electric point of tryptophan (pH 5.89), where a small amount of solid, unreacted L-tryptophan, precipitated. This was filtered off, and the MeOH was evaporated in vacuo. An attempt was done to wash the remaining solid with acetone, but after the acetone was evaporated it left nothing.

The precipitate was extracted with a small amount of hot ethanol, (what was presumed to be) NaCl remained undissolved and was filtered off, and the warm EtOH was allowed to come to RT. After sitting overnight in the freezer, a offwhite precipitate formed.
This was filtered and the precipitate was air-dried, it weighed 0.5 g. Evaporation of the alcohol left 0.7 g of yellow substance which was gummy at first, but quickly became a hard solid.

The Harvey, Miller and Robson test was employed according to J. Chem. Soc. (1940) p. 154-155:
A small amount of the substance was dropped in a test-tube containing sulphuric acid and a trace of oxidizing agent. The paper suggests to use FeCl₃ among others, but in this case 50% H2O2 was used. Tryptophan, its methyl ester and N-methyltryptophan gave a colour reaction within a couple of minutes from pale pink -> weak purple -> yellow with strong fluorescence, so does tryptamine.HCl but with a less marked fluorescence. Most beta-carboline-4-carboxylic acids give a blue colour

Both obtained substances were tested this way, together with pure L-tryptophan. All three gave the same colour reactions, ascribed to tryptophan.

The melting point still has to be obtained. These melting points were found in the literature: by Chimimanie, thanks  

L-tryptophan : 289°C
N-Methyltryptophan : mp ranges over 100° (!)
N,N-dimethyltryptophan : 239-243°C

2,3,4,5-tetrahydro-beta-carboline-4-carboxylic acid : 306°C
3-methyl-2,3,4,5-tetrahydro-beta-carboline-4-carboxylic acid : 208°C, after softening at 194°C

Also, most beta-carboline-4-carboxylic acids have a tendency to separate after recrystallisation as typical rod-like crystals, which makes identification easier.



Now after reading the above ref (digged up by Chimimanie, thanks again   ), I propose a somewhat different approach :

I.
p. 157
alpha-hydroxymethylamino-beta-3-indolylpropionic acid
l-Tryptophan (0.6 g) was dissolved in water (12 mL), formalin (2 mL) added and the mixture was incubated at 38°C for not more than 3-4 hours. The colourless, crystalline, but rather granular solid which had then separated was collected, washed with cold water, and dried in a vacuum.
Yield 60%.  mp 226-240°C

If the above mixture is incubated at 38° for 15 hours in presence of 10 mL 0.1 N NaOH, the beta-carboline is obtained in 80% yield. The beta-carboline is also formed when l-tryptophan is boiled in aqueous solution for 2 hours.
Also, the beta-carboline crystallises from an equimolar aqueous solution of tryptophan and acetaldehyde when kept overnight at RT, according to Harvey and Robson, J. Chem. Soc. (1938) 97.
 
II.
Reduction of this with NaBH₄ as described in the above post yields N-methyltryptophan.

III.
p.158
3-methyl-2,3,4,5-tetrahydro-beta-carboline-4-carboxylic acid
To a cool solution of r-alpha-methylamino-beta-3-indolylpropionic acid (0.5 g) in water (75 mL), a slight excess (0.4 mL; 2.3 mols.) of commercial formalin was added, the whole incubated at 38° for 15 hours. The "solid" which separated was collected (0.11 g), and the filtrate concentrated to a small volume on a boiling water bath. The bundles of stout rods which settled on cooling were collected, washed with absolute alcohol, and dried in a dessicator. Concentration of the mother-liquor gave another crop of the carboline-4-carboxylic acid.
Yield, 0.40 g (76%)

Now, there is a good chance that, if N-methyltryptophan and formaline are incubated for only 2-3 hours at 38° N-hydroxymethyl-N-methyltryptophan will be the main product.
If so, then this can be isolated and again reduced as described before.

[Vitus_Verdegast]

From: "beta-2,4,5-Trimethoxyphenylethylamine, an isomer of mescaline", by Max. P. J. M. Jansen.
Recueil des Travaux Chimiques des Pays-Bas et de la Belgique 50, 291-312 (1931). (Edit: Ref corrected by Chimimanie)

p 312:
D. beta-2,4,5-trimethoxyphenylethylamine from 2,4,5-trimethoxyphenylalanine
3 g 2,4,5-trimethoxyphenylalanine were heated rapidly in a small retort over a free flame. The solid sintered together, frothed up and the liquid, which was turbid at first, distilled over along with nauseous smelling fumes   . The liquid partly solidified in the reciever, due to absorption of CO₂ from the air.
The distillate and the contents of the flask were extracted with dilute HCl, the acid extract made strongly alkaline, extracted with ether, the ethereal solution dried with Na₂SO₄ and evaporated: yield 0.7 g.

Schaaf and Labouchere have obtained mescaline from 3,4,5-trimethoxyphenylalanine this way (Helv. Chim. Acta 7 (1924) 357)  

So, if this is applicable on substituted phenethylamines, I don't see why it shouldn't work for N,N-dimethyltryptophan, but they only got an ~28% yield   , so God knows what side-products are formed.

I sure hope, in case of DMTrp, these won't be powerful mutagenic pyrazines like the ones obtained from tryptophan pyrolysis, described earlier in this thread.


If I decide to 'pyrolyse' the DMTrp, y'all will be saying :

http://www.geocities.com/eric_vornoff/mad.wav

[Lilienthal]

The easiest test would be Ehrlich's reagent, which forms red to blue colors by reaction with the indole-2 (or indole-3 if free) position. In beta-carbolines the 2-position is blocked.

[Vitus_Verdegast]

I asked the author's opinion on this subject,

dr. G. Verardo, personal communication :

Your thoughts are correct, in fact granular NaBH4 is used in Method B because it is more reactive than pellets one so it is able to reduce faster excess aldehyde than the imine. In this way when once the N-monoalkylated compound was formed there was no further carbonyl compound present. With our methods we are not able to obtain the monoalkylation using formaldehyde and acetaldehyde.

Not only is this good news for the subject of this thread, there also could be hope for a tryptamine->DMT using HCHO/NaBH₄ synthesis as described in

Post 431982

(Lego: "Article on DMT derivate synths", Tryptamine Chemistry).

As I understand it normally NaBH₄ is undesirable because it tends to reduce the aldehyde faster than the imine. Now we know that using NaBH₄ pellets gives the carbonyl compound ample time to form the imine, so higher yields should be obtained.