"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 (http://l2.espacenet.com/dips/viewer?PN=US5567726&CY=gb&LG=en&DB=EPD)
Alprazolam structure: http://www.biopsychiatry.com/alprazolam/index.html (http://www.biopsychiatry.com/alprazolam/index.html)
Aziridine is a three-membered ring, Alprazolam has a five-membered heterohycle.
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 (http://l2.espacenet.com/dips/viewer?PN=WO9402477&CY=gb&LG=en&DB=EPD)
Patent WO9743281 (http://l2.espacenet.com/dips/viewer?PN=WO9743281&CY=gb&LG=en&DB=EPD)
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 (http://l2.espacenet.com/dips/viewer?PN=US5856492&CY=gb&LG=en&DB=EPD)