Here is a selection of PS reactions taken from the literature with some related info. There are condensations for both isoquinolines and beta-carbolines as the processes should be the same.
[NOTE: These are excerpts from the titles listed in yellow. If any Moderator feels that this post is in violation of Nexus rules, please feel free to delete this post. It is intended to help understand the reaction of ring closure/cyclization as it may be applicable to some substance testing procedures]
The Pictet-Spengler Synthesis of Tetrahydroisoquinolines and Related Compounds
Wilson M. Whaley, Tuticorin R. Govindachari
In the book: "Organic Reactions"
In 1934 Schöpf and Bayerle achieved a Pictet-Spengler type of reaction under conditions of temperature, concentration, and acidity comparable to those which exist in plants, and since then numerous applications have been recorded. For example,the previously mentioned reaction of tryptamine (-indolylethylamine) with acetaldehyde to yield tetrahydroharman may be carried out at pH 5–6 and 25° to give a 70% yield of product after three days.
It has been shown that the Pictet-Spengler reaction is one which is facilitated by increased electron density at the point of ring closure. Few phenethylamines lacking an alkoxyl or hydroxyl group para to the position of closure have been cyclized. Beta-Phenethylamine and phenylalanine were converted to the corresponding tetrahydroisoquinolines in approximately 35% yield by treatment with methylal and hydrochloric acid.
Good yields are usually obtained with formaldehyde, which is apparently the most effective of the aldehydes.
Tryptophan and formaldehyde at pH 6.5 and 38° for 15 hours yielded 80% of product XLII.
Hahn found that tryptamine condensed easily with acetaldehyde (70%) and phenylacetaldehyde (90%), but less easily with homopiperonal (15%), trimethoxyphenylacetaldehyde (16%), and benzaldehyde (48%).
The Pictet-Spengler reaction may be carried out by heating the amine with a slight excess of aldehyde and a considerable excess of 20–30% hydrochloric acid at 100° for one-half hour to six hours. Many amines and aldehydes have been heated together for an hour or so to form the azomethines, which were then heated at 100° with aqueous hydrochloric acid to effect cyclization. Some investigators have found the two-step method preferable. In rarer instances the Schiff base has been isolated and purified before being cyclized with aqueous or ethanolic hydrochloric acid.
For no obvious reason, aqueous sulfuric acid has enjoyed greater popularity in the synthesis of tetrahydro-2-carbolines.
In carrying out the Pictet-Spengler reaction under physiological conditions the amine and aldehyde may be dissolved in an appropriate buffer solution, or, alternatively, the amine hydrohalide and aldehyde may be dissolved in water and the pH adjusted by addition of alkali. The solution is then set aside at a moderate temperature (25–40° ) until the reaction has proceeded to maximum yield. The time allowed for reaction may vary from one day to several weeks, depending upon the reactivity of the system.
6-Methoxy-1,2,3,4-tetrahydroisoquinoline:
(Schiff base isolated and condensed with hydrochloric acid.) Twenty-five grams of 20% formaldehyde solution was added dropwise to 24.5 g. of -(m-methoxyphenyl)-ethylamine. The warm, clear solution soon deposited an oil and the reaction was completed by heating the mixture for one hour on the water bath. The oil was extracted with benzene, and the extract was washed with water. Distillation of the benzene left the azomethine, a viscous, colorless oil (100%), which was dissolved in 32 g. of 20% hydrochloric acid and evaporated to dryness on the water bath. The crystalline mass was dissolved in a little water, made alkaline with concentrated potassium hydroxide solution, and extracted with ether. Distillation of the extract yielded 21.3 g. (80%) of the pure tetrahydroisoquinoline, b.p. 143–144°/6 mm. [This is the 2 step process]
2,3-Methylenedioxy-10,11-dimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a,g]quinolizine:
(Cyclization with formaldehyde and concentrated hydrochloric acid.) A solution of 5 g. of 1-veratryl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline in 10 ml. of methanol was warmed for a few minutes with 10 ml. of 40% formaldehyde solution. The azomethine was freed of excess formaldehyde by washing several times with water, then dissolved in concentrated hydrochloric acid and heated a few minutes on the steam bath. Filtration of the cooled mixture yielded the sparingly soluble hydrochloride of the product; it was decomposed by treatment with sodium hydroxide, and the resulting base was recrystallized from ethanol. The product obtained in 60% yield melted at 177°. [one step process with formaldehyde]
1-Methyl-1,2,3,4-tetrahydro-2-carboline:
(Use of acetaldehyde in dilute sulfuric acid.) A solution of 5 g. of tryptamine in 100 ml. of water and 16 ml. of 2 N sulfuric acid was added to 100 ml. of a 10% acetaldehyde solution. The solution was gradually heated in an oil bath to 110° and maintained at that temperature for twenty minutes. The cooled solution was treated with excess sodium carbonate solution, which precipitated a crystalline solid. The solid was dissolved in dilute hydrochloric acid, filtered, and treated with sodium hydroxide; the precipitate was extracted with ether. Evaporation of the ether yielded the product as a crystalline residue weighing 5.0 g. (86%). After recrystallization from 50% ethanol, the carboline melted at 179–180°.
Human Alkaloid Biosynthesis: Chemical Inducers of Parkinson's Disease? Hatzios, 2005, BFA Thesis for MIT
1-Me-THBC was prepared by dissolving tryptamine (100mg, 0.625 mmol), acetaldehyde (70 MicroLiters, 1.25 mmol), and triflouroacetic acid (116 microLiters, 1.5 mmol) in DCM (1 ml) and stirring the reaction mixture at room temperature for 4 hours. A 4:1 DCM:MeOH TLC solvent system was used to monitor the progress of the reaction. The mixture was combined with an additional 10 ml of DCM and washed with 1 ml of saturated sodium bicarbonate solution. Solvent was evaporated from the organic layer to isolate the product, an orange solid.
Alkaloids in certain species of Virola and other South American plants of Ethnopharmacological interest.
Agurell, et al, Acta Chem Scand. 23 (1969) No.3
2Me-6MeOTHBC was synthesized from N-methy-5-methoxyltryptamine [5MeONMT] and formaldehyde by heating for 1/2h at 50 C in a weakly acid solution as described for tetrahydroharman. UV-spectrum (ethanol) max. 225, 275, 294, and 307 mu.
"Alkaloid 216" [2Me6MeOTHBC] ...gave a negative reaction with Ehrlich's Reagent, indicating that ... it was substituted in the 2 position.
2MeTHBC was prepared from N-metyltryptamine and formaldehyde in a similar manner.
Side reactions in the preparation of 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, Iterbeke et al 1998.
The cyclization of tryptophan is performed in H2SO4 (pH=1) as well as in NaOH (pH=9) in the presence of 37% formaldehyde in water at room temperature. During the reaction a precipitate is formed, which can be isolated by filtration after the reaction. HPLC analysis of this crude solid reveals 3 peaks... as THBC-3-carboxylic acid [the wanted product], N-hydroxymethyl-THBC-3-carboxlic acid, and a dimer. These compounds are formed in basic as well as acidic conditions. By adjusting the pH after the reaction to 6, storing overnight at 4 C, followed by filtration, most of the N-hydroxymethyl compound is removed. A decrease in the reaction time or of the amount of formaldehyde does not prevent dimer formation.
Microwave‐Assisted One‐Pot Preparation of
Tetrahydro‐β‐carboline Hydrochlorides under
Solvent‐Free Conditions
Fei Liu a & Qi‐Dong You
All of the experiments were carried out in the Discover microwave synthesizer
from CEM Corp. The maximum temperature was set to 1008C. To control the
temperature, the melting point of all of the aldehydes should be less than
1008C. A mixture of 1 mmol of tryptamine hydrochloride and 1.2 mmol of
aldehyde was heated in the microwave synthesizer at 100 W for 2 – 9 min.
The residue was recrystallized from ethanol (95%) to yield pure products.
The xanthydrol reaction for pyrroles and indoles in histochemistry: zymogen granules, lens, enterochromaffin and melanins. R.D. Lillie (1956) Its a print out of a PDF copy, not sure of the origin of publication
P.191: Effects of formaldehyde: 200mg tryptamine was dissolved in dH2O with 200mg calcium acetate, the volume brought to 18cc with water and 2cc 37% formaldehyde was added. Opalescence appeared in a few seconds and a copious white precipitate formed. Which remained quite well suspended. [It goes on to give how they seperated that out with a centrifuge and and test this in xanthydrol giving a "somewhat retarded purple black reaction". They don't specifically state what this reaction is checking for other than there naturally was formaldehyde in tissue samples.]
P.192: Barter and Pearse have explained the negative Ehrlich's reaction of enterochromaffin on the basis that 5-hydroxytryptamine, condensed with formaldehyde to 6-hydroxytetrahydroharman...
Indole-3-alkylamine Bases of Desmodium pulchellum. Ghasal and Mukherjee, J. Org. Chem. 31 (1966) 2284
Rearrangement of 5-MeoDMT Oxide with Ferrous Sulfate. -A solution of amine oxide (64mg) in aqueous acetic acid (5ml) ans ferrous sulfate heptahydrate (198mg) in H2O (10ml) was kept for 40 minutes over a steam bath (60-65 C) After which the mixture was cooled in ice.
...
Identification of the basic fragments. -To the major portion of the ferrous sulfate treated solution solid sodium hydroxide was added (pH brought to 12) and the liberated bases were extracted with chloroform. The CHCl3 solution was washed with little cold H2O and dryed and then the solvent removed. The viscous brown mass left (27mg) was chromatographed on brockmann alumina (18 X 1 cm). From the benzene-chloroform (80:20) elutates was obtained the least polar component (ca. 7mg), as an oil... All the aforementioned properties [omitted here] indicate that it is 6-MeO-2-Me-THBC
t-Amine Oxide Rearrangements. N,N-Dimethyltryptamine Oxide. Fish, Johnson, and Horning, J. Am. Chem. Soc., 78, 3670 (1956)
It has been found that N,N-Dimethyltryptamine oxide, a naturally occurring indole base from the seeds of Piptadenia macrocarpa Benth. will undergo a ferric ion induced rearrangement in aqueous solution to give N-methyltryptamine and formaldehyde or formic acid.
_______________________________________________________
End of references
The pathways to the Beta-Carbolines:
Tryptamine -> THBC
MMT -> 2MeTHBC
DMT -> DMT Oxide -> MMT -> 2MeTHBC