Moving along the pyridine ring

A couple of weeks ago, I finished teaching the synthesis of pyridine and its derivatives in my 4th year synthesis class. Whenever I present this material, I can’t help but appreciate the value of N-oxidation. While there are N-oxides of other heterocycles (thiazole N-oxide stands out for its interesting properties), nowhere else do I feel the same level of enthusiasm about N-oxidation than in the case of pyridine. And new applications attributed to the role of N-oxides keep coming out! The one that attracted my attention comes from the lab of Nuno Maulide. This chemistry, described in a recent Angewandte paper, documents thermal modification at the 3-position of pyridine. According to the authors, the reaction likely involves a series of [2,3]-sigmatropic rearrangements. I think this “merry-go-round” sort of activation is amusing. Given the value of 3-substituted pyridines in drug discovery, this simple reaction should find many applications.

2.jpg

http://onlinelibrary.wiley.com/doi/10.1002/anie.201607988/abstract

 

7 thoughts on “Moving along the pyridine ring

  1. Intermediate D is reminiscent of intermediates seen in the Buchner ring expansion. Given the highly reversible nature of the Buchner reaction, it would be interesting to see the computed energies of azepine intermediates.

  2. DMF gradually decomposes at reflux (154C) so heating a react mix in wet DMF to 200C, especially in microwave (known for local overheating effects) is a rather messy way of generating dimethylamine plus carbon monoxide and dimethylamine formate. It would be better if they had used propiolic ester with a thermolyzable ester group, i.e. tBu or PMB = in that way maybe they could use a less problematic solvent like chorobenzene, and decrease the ratio of propiolic ester from four equivs down to two equivs or less

  3. Pingback: Moving along the pyridine ring — amphoteros | ORGANIC CHEMISTRY SELECT

  4. Actually Dimethylacetamide is much, much better behaved at high temperature and its boiling point is not greatly different than DMF. I always use DMA instead of DMF at a reaction temperature above 120-130 C.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s