Azetidinyl-Tryptamine (Cool DMT analog)

[Rhodium]

"Azetidinyl-Tryptamine", or 3-(N-Azetidinyl-ethyl)-Indole is a DMT analog, where the two N-methyl groups are connected with a -CH₂- group to form a four-membered ring, an azetidine. The compound can be thought of as a conformationally restricted analog of DMT and a cyclic isomer of N-Methyl-N-Ethyl-Tryptamine (Why can I not find the latter in Tihkal?). It is most certainly active, and I find it to be a very worthwhile synthetic target. Who will be the first to prove that it is active (perhaps even orally so)?

4-(1-Azetidinyl)butanal dimethylacetal

A mixture of azetidine (2.0 g, 35.0 mmol), 4-chlorobutanal dimethylacetal (5.88 g, 39.0 mmol) and K2CO3 (5.38 g, 39.0 mmol), in anhydrous DMF (100ml), was stirred at room temperature for 72 h. Water (50 ml) was added and the mixture extracted with EtOAc (3x150 ml). The combined extracts were washed with 3x50ml H2O, dried (Na2SO4) and evaporated. The crude product was purified by distillation (1.2 g).

3-indolyl-ethylazetidine (Hydrogen Oxalate Hemihydrate)

A solution of substituted phenylhydrazine (4.1 mmol) and 4-(1-azetidinyl)butanal dimethylacetal (0.65 g, 3.8 mmol), in 4% H2SO4 (30 ml), was refluxed for 4.5 h. The solution was cooled to room temperature, basified with K2CO3 and extracted with EtOAc (4x100 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed on silica-gel eluting with CH2Cl2/MeOH/NH3 (40:8:1) to give the title indole. The hydrogen oxalate hemihydrate salt was prepared (30 mg).

Reference:

Patent US5567726

[Nemo_Tenetur]

Nice synthesis, but the precursor azetidine is EXTREMELY expensive. I've looked at this a few month ago as precursor for the theoretical AAP (alpha-azetidinylpropiophenone) but i abandoned the project. Azetidine is also sensitive to acids and may hydrolyze in aqueous solution .

[Lilienthal]

I don't want to dicourage you, but the 5-MeO-pyrrolidinyl analog is a really nasty stuff (probably due to high selectively for 5-HT₁ receptors). I heard it caused a long catatonic, unconcious state and / or extremely weird behaviour, without the slightest memory what happened.

[Rhodium]

Nemo: Buying Azetidine from a chem supplier in western europe is out of the question, but it can be synthesized relatively easy - I can dig up my references if you are seriously interested.

Lilienthal: I know that, but the azetidine analog is necessarily a closer analog of DMT than the pyrrolidine one, and my instincts tells me that its pharmacology doesn't follow the Pyr-T failure. A few years ago, I fantasized about the aziridine-tryptamine, as it is only two hydrogens less than DMT itself, but reading more about aziridines, I found out that they will at best give you cancer, not visionary experiences.

[anton_berg]

I've looked at this one before, and I thought I remembered something about some rather unfortunate toxicity involving arylethylazetidines, where the ring was prone to opening and reacting. I'll look it up this week and report back...

anton_berg

[Lilienthal]

The cancer-structure you are thinking of is probably the aziridine (three-membered ring). The four-membered ring should be stable (?).

[Nemo_Tenetur]

The azetidine ring is not particulary stable. There are recipes preparing this from 1,3-dibromopropane and primary amine followed by cleavage (Na/amyl alcohol) or cyclization of 3-chloropropylamine, but the yields are low. I doubt that there is an appropriate synthesis for the clandestine chemist. Additionaly, we don't know if the final product has pleasant effects. Rhodium, if you have a better azetidine synthesis than the two above mentioned, please let it me know. But please without expensive or exotic precursors (which I cannot reach or pay). I would like to synthesize the alpha-azetidinylpropiophenone and explore its effects.

[anton_berg]

Rh,

Where did you read that aziridines are prone to causng cancer? There are actually quite a few therapeutic drugs that contain aziridine-1-yl rings; alprazolam is the only one I can think of off the top of my head, but I know there are others.

[Rhodium]

Alprazolam structure:

http://www.biopsychiatry.com/alprazolam/index.html

Aziridine is a three-membered ring, Alprazolam has a five-membered heterohycle.

[anton_berg]

Rh,

I know what aziridine looks like, but I forgot what alprazolam looked like . What I meant was prazepam, but even that's not right: it just has a cyclopropane ring on it dangling conspicuously. Nevermind.

But aziridines are safely used in humans, e.g. azimexon, carboquone, and Imexon.

[anton_berg]

Incidentally, I did give some thought to azetidinyl tryptamine analog synthesis. I looked at some of what had previously been done, and at least from what I saw, it looks like the most sensible routes would be from azetidine; the first would be to condense it with indole-3-acetic acid, followed by reduction. The second method, and the one I found the most literature on, would be an Sn2 reaction of azetidine with an appropriate (indole-3-yl)-ethyl electrophile; the most commonly encountered ones in the literature are 1-(indole-3-yl)-ethylhalides, but I also found an example of the triflate ester of tryptophol being used in the exact same fashion.

General azetidine-derived tryptamines:

Patent WO9402477

Patent WO9743281

Sn2 additions of aryl ethyl halides to azetidines:

J.Med.Chem., (1991), 34(4), 1314-1328.
J.Med.Chem., (1989), 32(9), 2178-2199.


From tryptophol triflates:
Bioorg. Med. Chem. Lett., (2000) 10(24), 2697-2700.

A third method that looks interesting would be to start with tryptamine, and react it with 1,3-dibromopropane:

Patent US5856492