Abstract

The Mannich reaction of ClCH₂CHO with indoles in the presence of NHR₃₂ gave gramines I (R = H, Me; NR₃₂ = NMe₂ morpholino; R₃ = H, MeO) which were reduced by NaBH₄ to the corresponding tryptamines II. Hydrolysis of I gave the amino alcs. which also rearranged to the a-hydroxytryptamines; dimerization during hydrolysis was also obsd. Treating II with addnl. ClCH₂CHO gave tetrahydrocarbolines III (Q = CHCH₂X, X = Cl, OH, H, SO₂C₆H₄Me-p) by a Pictet-Spengler condensation. Redn. with NaBH₄ gave the azepinoindole III (Q = CH₂CH₂).

Introduction:

The condensation of indole with chloroacetaldehyde and dimethylamine provided the alpha-chloro-methyl-gramine 1a isolated in the form of its chlorhydrate. The base of Mannich 1e of the methoxy-5-indole with chloroacetaldehyde and dimethylamine also has been prepared. The yields vary from 30 to 45%.

An interesting and simple reaction of those chloromethyl-gramines was the reduction in ionizing medium (6, 7). The reduction of the alpha-chloromethyl-gramine 1a by sodium tetrahydroborate in diglyme provided the dimethyl tryptamine (DMT) (yield 37%).

The methyl-1 and methoxy-5 dimethyl tryptamines 2b and 2e have also been prepared.

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Experimental:

alpha-chloro-methyl-gramine 1a, method A

Stir at RT, till dissolution, 2,75g of anhydrous sodium carbonate in a slurry of 50 mL of GAA and 25 mL of propionic acid. Add to this solution 11.7 g of indole (0.1 mol) and 8.8g (0.11mol) of dimethylamine-HCl in 5 mL of diglyme. Cool between -5°C and 0°C and add 11g of chloroacetaldehyde hydrate (containing 75% of the chloroacetaldehyde, 0.1 mol). Stir for 1 hour and keep the temp below 0°C then keep it for 5 days in the freezer at +5°C. Pour the reaction on some piece of ice. A white, snow-like precipitate form. This precipitate (the product of the indolic condensation) is essored. The acid filtrate is extracted with cold ether. The aqueous layer is then energically cooled and ether is added. With stiring this solution is neutralised with some aqueous NaOH. The following operations are then effectued rapidly: decant the ether layer, dry it on Na₂SO₄, and then with stirring and at low temperature add some hydrochloric ether.

The alpha-chloromethyl-gramine HCl (1a) fall as a viscous oil. The ether is decanted, and the oil is recrystallised with a little absolute EtOH. Add if necessary anhydrous Et₂O. The product may have a pink coloration.

Crude yield: 11.7 g (45%), mp=131°C. Recrystallise 3 times in Et₂O-EtOH or acetonitrile, final yield: 8.2g (32%), mp=138°C.

N,N-dimethyl tryptamine 2a

1 g of alpha-chloromethyl-gramine HCl is added to a suspension of 2,5 g of NaBH₄ in 75 mL of diglyme at 55°C with stirring. The slurry is warmed to 85-90°C and is kept at that temperature for 48h. The yellow coloration has disappeared. After 24h the mixture is cooled and poured on some ice. This is extracted with ethyl acetate and then the solvent is removed. The remaining oil has got a scatole stench and the TLC show two spot with Rf equal respectively to authentic sample of scatole and of DMT. These two products are separated by column chromatography (silice-celite 1/1). The scatole is eluted first with benzene and is identified by its mp and its picrate salt. The DMT is eluted with methanol (270 mg, 37%). After one recrystalisation with hexane, the product melt at 45°C, this mp is inchanged when authentic sample is mixed with it. The DMT is confirmed by its picrate salt, mp 166°C, and by its UV and IR spectra.

5-methoxy-N,N-dimethyl tryptamine

Same procedure. With 1g of the chloromethyl-amino-indole HCl we obtain an oil with only one spot on TLC. The picrate of this indolic base has got a correct analyse on C,H and N. It melt at 176°C. The freebase crystallise and its mp is 69°C. Yield: 28%, the HCl salt has a mp of 146°C.