[The Walrus]

Hi I'm new to the forum (if you can't already tell by my post count). I'll do my best to help around here.

I've been told to provide an answer (this is not school work) to this but it's different than what I have learned so far in ochem 1 and 2. This is different than the usual synthesis I'm used to, and I definitely need a little help with this one.

Since these rings are aromatic I suspect you may be able to use some form of electromagnetic substitution (in the manner it is done with benzene)


(I had to draw this in paint since I don't have a program)

[Jorriss]

Electrophilic substitution.

Can you still do friedel crafts or add a nitro group to that?

[nj_bartel]

Maybe with extra LA to tie up the sulfur lone pair?

[Jorriss]

I can't think of what LA stands for at all lol. Any help ?

[nj_bartel]

lewis acid

[Jorriss]

Ahhh... Yeah I totally was thinking that >.>

But anyways! That would make sense, although, I don't know if sulfur is powerful enough to deactivate the catalyst for friedel-crafts, I'm more curious about where it will be directed.

[cundi]

Here you are my idea.
I think it is possible to bromide both 2 posiition. (NBS)
Then, Br-Li exchange (only in one position), trap the organolithium formed with CO2.
Finally the other Br was displaced in a Nucleofilic subtutions.

See attached pdf.

[The Walrus]

Here you are my idea.
I think it is possible to bromide both 2 posiition. (NBS)
Then, Br-Li exchange (only in one position), trap the organolithium formed with CO2.
Finally the other Br was displaced in a Nucleofilic subtutions.

See attached pdf.

Would the Br add to that position with NBS? I thought it added to an allylic or benzyllic position (one carbon away from the double bond) and not actually in the double bond itself.

[OC pro]

@ The Walrus:  
NBS gives a Br+ in solution leading to an electrophilic aromatic substitution at both the carbons next to the sulfur atoms (see also cundi´s idea). It is a widely used bromination agent. Milder and less toxic than bromine itself.

@cundi: the last step of your synthesis will be difficult. I strongly doubt that a nucleophilic substitution will take place onto the electron-rich thiophene ring.

[g-bones]

Here you are my idea.
I think it is possible to bromide both 2 posiition. (NBS)
Then, Br-Li exchange (only in one position), trap the organolithium formed with CO2.
Finally the other Br was displaced in a Nucleofilic subtutions.

See attached pdf.

no need to brominate first.  i believe you can directly lithiate these types of compounds with nBuLi.  try lithiating (1 equiv of nBuli to get mono-lithiation) and quenching with methyl chloroformate.  this will provide the ester where your acid needs to be (easy to transform in last step).  treat the corresponding aryl-ester with nBuLi again (typically more basic than nucleophilic) with a source of Cl+ (like NCS).  this will place a chlorine where you need the methoxy group.  treat this compound with NaOMe to perform an SNAr reaction in which you attack the position of the Chlorine and push electrons into your ester.  pushing them back to kick out chlorine over methoxide will be favorable.  finally, saponify your ester with LiOH or any hydroxide base. 

Hope this helps

[cundi]

Do you want to treat the aryl-ester with BuLi? I don't know if it is a good idea!!

[g-bones]

Do you want to treat the aryl-ester with BuLi? I don't know if it is a good idea!!

Should be alright, perhaps a better choice of alkyl lithium would be tBuLi, definitely NOT nucleophilic and should lithiate much much more selectively than add into the ester

[cundi]

I agree.
Anycase, I'd prefer lithiated without an ester in the molecule.