This is just something I have been playing around with in my head for a while. I am curious as to what research has been done on phenethylamines containing hetrocyclic aromatic backbones. A number of active analogs have been created by altering the 5 membered methylenedioxy ring in MDA. These analogs such as 6-APB[1] and 5-API[2] have 5 membered rings containing both oxygen and nitrogen atoms, forming furan and pyrrole rings respectively. Both of these modifications have resulted in a similar or significant increase in potency.

My question is have any sulfur containing analogs of MDA been synthesised and if so have they any activity in humans? Shulgin et. al has synthesised a range of thiophenethylamines (2C-T's and ALEPH's) which have some unique characteristic. They also exhibit a much increased activity. For example 2C-O-4 (http://isomerdesign.com/PiHKAL/read.php?domain=pk&id=35) is inactive where as the thio analog is active at <10mg. From what I can see David E. Nichols theorizes that thiophenethylamines should be more active as they are easily subjected to oxidative metabolism.

The ability of a compound to produce hallucinatory disturbances may be lost when the 4-substituent is resistant to oxidation. The concept that facile oxidation of the 4-function might be involved in the production of hallucinations by psychotomimetic amphetamine derivatives may receive support through study of an amphetamine derivative with a 4-substituent that is unusually susceptible to oxidative metabolism.

The sulfur atom would appear to be an excellent choice for such a substituent. Metabolically, it should retain the chemical properties of oxygen in reactions such as S-demethylation but should allow the formation of sulfoxides and sulfones as products of oxidative metabolism12. The lipophilicity, electronic character, and size of sulfur also seem ideal.

David E. Nichols & Alexander T. Shulgin - Sulfur Analogs of Psychotomimetic Amines, J. Pharm. Sci. 65(10), 1554-1555 (1976)

An interesting first choice would be the 3,4-methylenedithioamphetamine where both oxygen atoms in MDA are substituted with sulfur atoms. benzene-1,2-dithiol (17534-15-5) appears to be commercial available. Pardon my naivety but I see know reason the desired 3,4-methylenedithiole could not be synthesised from this starting material analogously to the synthesis of MDA from catechol.

Proposed Synthesis:
I have no references for the methylation of thiols ATM, but I don't see why I can't be methylated with dibromomethane in the presence of a PTC as is possible with substituted catechol's^[3]. Please correct me if I am completely wrong. Either way it is possible to form the 1,3-benzodithiol by some means. Once benzodithiol has been obtained it should be possible to obtain the respective phenylpropan-2-one by Friedel-Crafts alkylation with 2-Nitropropene.^[4] Finally this P2P can be subjected to reductive amination by the known means to the desired amine. It should be possible to obtain 3,4-methyleneoxathioamphetamine by just starting with the 2-hydroxythiophenol instead and methylating to 1,3-benzoxothiole?? (Unsure of correct IUPAC name).

I'm not sure why more research hasn't been done into these sulfur based analogs considering the potency and effect of the 2C-T's.  These substances should also be legal, at least under the UK Misuse of Drugs Act. Please let me know what you think of this. Do you think these would be active and if so do they look worthwhile synthesizing?


3,4-methylenedithioamphetamine (MDTA?)


3,4-methyleneoxythioamphetamine


6-(2-aminopropyl)benzothiophene

Edit: It appears that 1,3-benzothiophene-5-carbaldehyde (CAS#: 10133-30-9) is commercially available. This should make this analog very easy to synthesize. Simply condense with nitroethane and then reduce as standard to the amine.


References:
[1] 6-APB - http://en.wikipedia.org/wiki/6-APB
[2] 5-API - http://en.wikipedia.org/wiki/5-%282-Aminopropyl%29indole
[3] PTC Methylenation of Catechol (Using Adogen 464) - http://www.erowid.org/archive/rhodium/chemistry/methylenation.html#PTC1
[4] Synthesis of MDP2P From 1,3-Benzodioxole by Friedel-Crafts Alkylation with 2-Nitropropene - http://www.erowid.org/archive/rhodium/chemistry/mdp2p.nitroalkylation.html

Okay, I'm going to propose a synthesis. Please let me know what you guys think. These analogs seem very interesting! If we got enough interest we could potentialy get someone to do a custom synthesis of these legal compounds.

I did a literature review regarding the synthesis of benzothiophene's and came across the following paper where 5-methoxy benzothiophene is synthesized in 2 steps from 4-methoxythiophenol. Here is an excerpt:

5-Hydroxybenzothiophene was prepared according to our reported procedure for the synthesis of 5-hydroxybenzofuran¹⁰(Scheme 2). Thus, 4-methoxythiophenol ¹⁶ was reacted with bromoacetaldehyde diethyl acetal and K₂CO₃ in dry DMF at reflux to furnish 17 in 86% yield which was directly used in the next reaction without further purification.
Compound 17 was converted to 5-methoxybenzothiophene ¹⁸ by treatment with polyphosphoric acid (PPA) in toluene at reflux in 24% yield. Demethylation of 18 with BBr₃.SMe₂ in dry chlorobenzene at reflux provided 5-hydroxybenzothiophene¹⁹ in 81% yield.



Synthesis and biological evaluation of novel small non-peptidic HIV-1 PIs: The benzothiophene ring as an effective moiety,
Lucia Chiummiento, Maria Funicello, Paolo Lupattelli, Francesco Tramutola, Federico Berti, Francesca Marino-Merlo,
Bioorganic &amp; Medicinal Chemistry Letters, Volume 22, Issue 8, 15 April 2012, Pages 2948-2950, ISSN 0960-894X,
DOI: 10.1016/j.bmcl.2012.02.046.

Proposed Synthesis:

I propose a similar synthesis could be employed. I am not sure if the activating p-methoxy is critical to this reaction as I cannot find the mechanism. If it is not critically it should be possible to start with 4-bromothiophenol. This is then refluxed with bromoacetaldehyde diethyl acetal ^[1] and K₂CO₃ in dry DMF as outline in the paper. bromoacetaldehyde diethyl acetal is easily prepared and its synthesis is outlined below. This compound is then cyclised by refluxing with polyphosphoric acid (PPA) in toluene.

It seems pretty straight forward to me. Once you have your 4-bromothiophene it should be possible to either substitute the bromine to the more reactive iodine or proceed directly with the SN1 substitution of a halogen of an enolate. This is outlined on the Rhodium Archives where bromobenzene is converted to P2P by reaction with an acetone enolate (Enolate phenylacetone synthesis FAQ 1.0. I'm not sure how well this reaction has been tested practically but it looks like there is the literature to back it up. Everyone knows we can get whatever amphetamine we like from here by the known methods.

In that paper, the benzothiophene analog showed significantly more activity although I'm not really sure what they were actually testing. Either way the thiophene hetrocycle should be more hydrophobic which should also increase any activity by being more lipophilic as a result??. Please correct me where I am making silly mistakes!

Alkylation at indole nitrogen leads to inactive compounds, most likely due to steric reasons, and the replacement of nitrogen with oxygen is not effective. However, the more hydrophobic ben-
zothiophene containing compound is significantly more active than the parent indole molecule, and the enhanced activity is consistent with a reduced desolvation penalty.

tl;dr

To summarize, it appears possible to synthesize 1,3-benzothiophene-5-(propan-2-one) from 4-bromothiophenol in 3 steps using relatively accessible reagents and techniques. There is defiantly loads here that is unknown here and need to be confirmed experimentally. Any ambitious chemist want to try and be the first to sample a brand new potential psychoactive?

Preparation of Bromoacetaldehyde diethyl acetal:
It is obtained by bromide, alcoholysis of vinyl acetate. Mixing vinyl acetate and ethanol at -10 °C. Slowly dropping bromine to maintain -5 °C under stirring. Gradually heated to 60 °C maintained for 1h, cooled to 10 °C, and 1 times the amount of ice water added. Add ammonia to make pH = 6 and double the amount of ice water to separate oil. Collect distillate under 71-76 °C (2.67kPa) by vacuum distillation to get the product.
http://www.lookchem.com/Bromoacetaldehyde-diethyl-acetal/

Apologies for the extra posts. Just found the following reference which describes the synthesis of 1,3-benzodioxole, 1,3-benzodithiole and 1,3-benzoxathiols from 1,2-benzodiol (catechol), 1,2-dimercaptobenzene and 2-Hydroxybenzenethiol respectively. The scheme involves heating the substrate at 110c with bromo-chloromethane in dry DMF with cesium carbonate as a catalyst.

This reaction is almost identical to the methylenation reactions on the Rhodium Archive. (http://www.erowid.org/archive/rhodium/chemistry/methylenation.html) The yield of the 1,3-benzodithiol in the paper was 98%. This seems very straightforward. Unfortunately the  1,3-benzoxathiols is only formed in approx. 30% yields. Either way this is a very accessible approach to these potentially active analogs.

A Re-examination of the Methylenation Reaction
Maria Grazia Cabiddu, Enzo Cadoni, Stefania De Montis, Claudia Fattuoni, Stefana Melis and Michele Usai
Tetrahedron Vol.59 (2003) pp.4383-4387
DOI: 10.1016/S0040-4020(03)00619-7

Abstract:
A re-examination of the methylenation reaction of 1-hydroxy-2-mercapto-, 1,2-dihydroxy- and 1,2-dimercapto substituted benzenes by bromochloromethane with cesium carbonate shows that these substrates give mixtures of five- and ten-membered benzocondensed heterocyclic compounds and in some cases even dibenzodioxines.

Relevent Excerpts:
We decided to apply this reaction protocol to 1,2-dimercaptobenzene (1h): 1,3-benzodithiole (2h) (98%) was obtained almost exclusively beside traces amount of unknown products.
The same reactions performed in acetonitrile and at different concentrations gave analogous results. At the end we can deduce that when the benzene ring bears two equally nucleophilic groups (benzodioles and dimercaptobenzenes) the main product is the one with a five-membered ring;
when the groups have a different nucleophilic power the main product is the ten-membered ring.

General method of methylenation of compounds
To a suspension of the starting compound 1a – h (50 mmol), cesium carbonate (24.4 g, 75 mmol) and anhydrous N,N-dimethylformamide (120 mL), was added dropwise bromo-chloromethane (9.6 g, 75 mmol) and the resulting mixture was vigorously stirred under a nitrogen atmosphere and then
heated at 107 – 1108C for 2 h. The mixture was poured into water, the organic layer separated and the aqueous layer extracted with ether and then with dichloromethane, because ether is able to extract only the monomeric product while the dimeric ones are extracted by dichloromethane.
The organic phases were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was analysed by HPLC.

Please let me know what you think guys!!

Sulfur doesn't act, electronically, very much like oxygen. It is more similar to carbon. I would expect the dithia analog of MDMA to behave much like IAP, if it is not extremely toxic. 4-thio substituted phenethylamines tend to be monoamine oxidase inhibitors, which is very dangerous, and a thioacetal does not act like an acetal (in particular, it is difficult to hydrolyse). The thioalkyl 2C's avoid this somewhat because the methoxy groups inhibit binding to MAO.

Benzothiophenes have serious hepatotoxicity concerns! This problem was encountered with BTCP, a really fun stimulant that causes serious liver damage.

http://pubs.acs.org/doi/abs/10.1021/tx0341409