Having trouble closing the ring in your imidazolium salt synthesis?

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Discussion Overview

The discussion revolves around challenges in synthesizing imidazolium salts, particularly focusing on the closing of the ring in the final steps of the synthesis process. Participants explore various methods, catalysts, and functional groups involved in the reactions, as well as troubleshooting specific issues encountered during the synthesis.

Discussion Character

  • Exploratory
  • Technical explanation
  • Debate/contested
  • Homework-related

Main Points Raised

  • One participant reports difficulties in synthesizing imidazolium salts using a vinyl amino pyridine and questions whether the presence of a pyridine ring is problematic.
  • Another participant suggests that functional groups like amines and pyridines may hinder the effectiveness of Grubbs catalysts, referencing literature that discusses successful metathesis with specific amine structures.
  • A third participant shares a relevant article that describes a method involving a substituted pyridine N-oxide and tert-butylamine, proposing that this approach may be suitable for the Grubbs catalyst.
  • A later reply indicates success in overcoming the initial problem by using a different reaction pathway involving a boronic acid and a rhodium catalyst, noting specific conditions and reagents used.
  • One participant shifts the discussion to their ongoing work in medicinal chemistry, expressing concerns about the future of their company and the status of a specific drug candidate.
  • Another participant shares a job opportunity, indicating a potential shift in focus from the current synthesis challenges.
  • A new participant describes their own difficulties in closing the ring in the synthesis of asymmetric imidazolium chlorides, detailing the steps taken and the issues faced during the reaction.

Areas of Agreement / Disagreement

Participants express a range of experiences and challenges related to the synthesis of imidazolium salts, with no clear consensus on the best approach or resolution to the issues raised. Multiple competing views and methods are presented, indicating ongoing debate and exploration of the topic.

Contextual Notes

Some participants reference specific literature and methodologies, but there are unresolved questions regarding the effectiveness of various catalysts and functional groups in the reactions discussed. The discussion includes a mix of personal experiences and theoretical considerations without definitive conclusions.

Who May Find This Useful

Researchers and practitioners in organic chemistry, particularly those focused on synthesis and catalysis, may find the insights and shared experiences relevant to their work.

gravenewworld
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Anyone ever try it with an amine moiety present? It doesn't seem to be working for me. I basically have a vinyl amino pyridine that I am trying to react with another olefin. I have tried the 1st and 2nd generation catalysts with no luck. I also have tried a Schrock rxn. I have searched the literature and there really isn't any precedent for what I am trying to do. Could it be the pyridine ring that is giving me the problem?

I really don't want to have to spend $500 for 500 mg of the 3rd generation catalyst if it won't work.
 
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Substrates that contain functional groups that are good ligands for Grubbs catalysts are generally not successful. Your example contains both amine and pyridine which are very good ligands. The chiral Grubbs catalyst actually contains a couple of pyridines as ligands as you are probably aware. Allyl amines have been sucessfully metathesized using Grubbs chiral catalyst when the amine was secondary and had an adjacent bulky aryl group. (Toste, F.D., et al, Pure Appl. Chem., Vol 74, No. 1, pp 7-10, 2002.) They note that Fmoc and boc-protected amines only produced enamines so amino protection with those groups may not work. Amides are usually OK with the catalyst, so you might consider protection as an amide. This will still leave you with the pyridine functionality but it may work if the pyridine is 2,6-disubstituted with bulky enough groups (2,4-substituted thiazoles have been used successfully as well.). You may also consider using a vinyl-substituted nitropyridine N-oxide for the metathesis followed by conversion to the aminopyridine. I believe that refluxing with iron and acid will accomplish the reduction.
 
I just found this article over on OrgPrepDaily (thanks, Milkshake!):

Yin, J., Xiang, B. JOC 72(2007),4554-4557.
http://orgprepdaily.wordpress.com/

In this article, a substituted pyridine N-oxide is treated with tert-butylamine and [tex]Ts_2O[/tex] in [tex]PhCF_3[/tex]. Deprotection with TFA gives a 2-aminopyridine (or a 6-amino if that side is available). This protection may be suitable for the Grubbs catalyst since the substitution on the amine is very sterically blocked and the pyridine is in the N-oxide form. Deprotection/reduction appears to be trivial (TFA in solvent at 70C). The reported yields were in the range of 70%-90% for the N-oxide to aminopyridine step.
 
Totally forgot about this post. Thanks for the info though. I was able to get around the problem by reacting the vinyl amino pyridine with a suitable boronic acid via a rhodium cyclooctene chloride dimer catalyzed reaction. I had to use an exotic ligand, something called tppds that I ordered from STREM. The reaction actually also took place in water and toluene and SDS was used as the phase transfer catalyst. Stirred at room temperature for a couple of hours. Worked like a charm.


I will keep your reference though. It will definitely be useful in the future.
 
You still doing medicinal chemistry?
 
chemisttree said:
You still doing medicinal chemistry?

For the time being. We will submit a response to the FDA (3Q) very soon which would trigger a 6 month period before we get a response. Based on the facts, I'd say there is about 0.5% chance of getting approval. Word has it that our CSO/VP is looking to bail which tells you pretty much what the outlooks is for our company.

The only thing that we have going for us right now is our delta opioid agonist which is the first of its kind. It has been generating a lot of buzz in the industry. It is only in phase II right now and is years away from getting approval. The company won't be able to last that long IMO. The only way to stay afloat, that I can reasonably see, is to sell our delta compound to big pharma.I'd say I have another 6-10 months left. Even if I didn't get laid off, who would want to work for a company that is on the very brink? They will just unload all the work from the people that they will lay off on the people that they keep. So far we have had about 1-2 people leave every week for about the past two months.
 
See here.

http://www.swri.org/hr/ViewJob.asp?JobID=963&Type=Exempt

The winters are nice. There is a medical school in town.


August sucks!
 
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Hi! I'm working on synthesis of assimetric imidazolium chlorides but I'm having problems in the last step. I'm following exactly the steps in the general procedure of Waltman and Grubbs (Organometallics, 23, 2004, 3105). I'm trying to synthesize the imidazolium salts combining mesityl with methyl and cyclohexyl group. The reduction of the oxalamides with BH3.THF is complete but in the last step I never get to close the ring with HC(EtO)3. After leaving the reaction mixture heating at 120 ºC and refluxing overnight, the next day I always find some very dark solution (almost black, like carbonized) and when I filtered the solid that appeared once in that solution I only could see in H-NMR and C-NMR that no peak of carbon at about 160 ppm was present (the one closing the ring, linked to two N). I also distilated EtOH formed during the reaction to force it to the right side and added more HCl to increase acidic conditions...

Could someone help me, please?

Thanx a lot in advance,

Cheers,

Ana
 

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