Methylenedioxy isosteres?

[Greensnake]

While recently skimming through certain journals in library some guy noticed approximately the following thesis: thiadiazole ring is a very close isostere for methylenedioxy group (we are talking about benzo-2,1,3-thiadiazole here)

Now, whaddya think about possible certain derivatives of said thiadiazole? Maybe some diligent guy already prepared these?

Some prelim info on benzo-2,1,3-thiadiazole chemistry - made from ortho diamine, reacting it with SOCl2 or S2Cl2, may not be stable against heavy reducing agents (LAH?)

[Rhodium]

Is it an electronic isostere, or a bioisostere? It sounds good, except that I'm worried that the pkA of trhe nitrogens would make the compound partially positively charged, which may be a problem, but then again, it may not. Entactogenic serotonin releasers like MDMA does not have the same structural requirements as the 4-substituted PEA's.

[foxy2]

Better yet, put a sulfur(1,3-Benzoxathiole) or two(1,3-Benzodithiole) in place of the oxygens in the methylenedioxy ring.

Or how about replaceing one oxygen with a carbon(2,3-Dihydrobenzofuran) or both with carbons (indan) been done already.

Stay Informed

(http://www.mapinc.org/)

[slappy]

Benzo-[2,1,3]-thiadiazole is an electronic isostere of Benzo-[1,3]-dioxolane. However, it is very air sensitive and decomposes rapidly upon contact with air.

[Greensnake]

Huh, are you sure about instability? My preliminary lookup did not revealed such a problem, if fact it left an impression that benzo-(2,1,3)-thiadiazole is reasonably "hard" and stable electron deficient heterocycle. And J. Med. Chem. guys usually are not interested in unstable things too.

Could you please give the source of your information? Thanks.

[Rhodium]

foxy2: I have looked into the synthesis of benzodithioles, and it seems almost impossible. It is extremely oxidation-sensitive and is easily oxidized in the 2-position on the hetero-ring, and it has to be made by pyrolysis, or by strange diazonium reactions. Phew.

On a side note; alkoxy substituents on a benzene ring is ortho-para drecting, while trifluoromethane substituents are meta-directing. What about trifluoromethoxy? In what manner does that group direct? I have not been able to find the information using Google.

[slappy]

Yes, I am sure that they are sensitive to oxidation. You haven't given any ref for this article, and although JMC is a good journal, you can't always believe what is published.

The synthesis of these compounds is not practically feasible anyway. You have to start with a o-Diaminobenzene, which are incredibly toxic and carcinogenic, and react that in Et₂O with Piperidinyl Sulphur Chloride. Here is the ref:

J. Chem. Soc., Perkin Trans. 1, (11), 2591-3;  1984

[Lilienthal]

There are a lot other and better ways to that particular compound. And I doubt it's very oxygen sensitive because thiadiazoles are a common protecting group for diamino-benzenes. And yes, LAH reduces them back to the diamine. Did you know that benzothiadiazoles are aromatic over both rings?

Hey bees, come on, the only proof of the honey is in the eating. There are so many isosters, none of them has been synthesized and tested.

[cheeseboy]

Let us know how it went Lilienthal