Sometimes you just need to heat it…

Deb, I; Coiro; D. J.; Seidel, D. Decarboxylative formation of N-alkyl pyrroles from 4-hydroxyproline Chem. Comm. Advance Article April 18th, 2011

Honestly, there is nothing worse than being in a chemistry lab when you have a bad cold. You are constantly sneezing and coughing, you can’t get anything done, and you simply feel miserable. Not to mention the acetone fumes from cleaning make you cough even more. Needless to say this represented my experience in lab last week. I went to a concert Sunday (which I have some video from here and I must have picked up something cause I woke up the next morning quite ill. Not only that but I really needed to get more done last week than I did. I’m a lot better physically now, but I’m rushing to get things done. Tomorrow I have some flow stuff, a vac distill, a column, and a new reaction to test out, and two other reactions to carry out….yeah…but at least the chemistry itself is working. I think the thing that kills the most time is cleaning. I spend at least 5 hrs a week cleaning glassware (or more depending on how bad it gets). Not that I mind it because there’s nothing more beautiful (besides maybe clean white crystals from a recrystallization) than spotless glassware. And if I really can’t get it clean, the magic of the glass-eating base bath will take care of it. In terms of chemistry though (and not cleaning) things progress well. I hope to be done with our collaboration with Fenteany’s group in two weeks at maximum. I also came up with a new reaction based on a recent JOC article which could lead to a new project (hopefully). Otherwise our collaboration with Professor Tilley is going pretty well too. I plan on beginning to writing it up sometime this week to get an idea of what needs to be done and where the article will go. I’m thinking Org. Lett. but possibly J. Org Chem. considering all the information we will be putting in it.
I know I’ve been getting quite a few views lately (which makes me really excited!!!). I came up with an interesting idea the other night. If you want me to review an article or a topic etc. in organic chemistry I’d be all for it. So just send me a message either by leaving a comment or by e-mailing me at . And now, chemistry time….

So as you all may know, I’m a big fan of Dan Seidel’s work at Rutger’s. His work is pretty simple, but it’s usually elegantly presented and has good applications. And as I always say, the best kind of chemistry is simple. Seidel’s group has done quite a bit of work with C-H bond activation and redox isomerizations. Lately, he is very much interested in the formation of azomethine ylides in situ from relatively cheap materials such as pyrollidines and utilize them to form some complicated, difficult to synthesize materials. His other area of interest is in thiourea catalysis, but since this the former topic is the one involved in this paper, I’ll leave it to you to read more about this project and Seidel here.

Proline is a very interesting and very useful molecule. It’s very good for Diels-Alder reactions as a catalyst (particularly the methyl ester which for me worked like a charm). It’s also good at catalyzing aldol additions. It does so by forming the iminium species which tautomerizes to the enamine. However, Seidel likes to take advantage of the iminium tautomer for the formation of azomethine ylides. A while back, he published an article that I really liked where he took proline and benzaldehyde and a nucleophile (in their screening case, 2-naphthol) and did a three component reaction to give a highly substituted pyrrolidine:

He used a variety of “nucleophiles” to do the same including alkynes, indoles and nitro alkanes. All that’s really happening is the azomethine ylide is forming and the highly electrophilic iminium moiety (which rearranges to be inside the ring) is reacting with electron rich pi systems. Now you may be like, well who cares? Well this was a sort of precursor work to this next article and it also accessed difficult to synthesize compounds using relatively inexpensive materials.

So this follows suit on the theme of use simple starting materials to access complex products. The article starts out by describing the use of pyrroles in medicinal, material, and natural product chemistry. While there are a million ways to make them, being able to make theme relatively fast and in a cost effective manner would be useful. Hence Seidel’s group was interested in making this idea a reality.

They took some inspiration from an article by Tunge and coworkers (which caught my eye a while back). Tunge used 3-pyrrolines to make N-alkyl pyrroles. The problem I had (and apparently so did Seidel’s group) with this article is that 3-pyrrolines ain’t the cheapest compound to use. Moreover, as Seidel mentions, they have the annoying tendency to oxidize to pyrrole over time if exposed to atmospheric oxygen. So what Seidel thought to do was use 4-hydroxy proline as a surrogate for 3-pyrroline. Basically what he hoped to have happen mechanistically was as follows:

Note that the key is that dehydration step. That allows you to get at pyrroles. Initially though, this reaction failed hard. It seemed that they tried conventional approaches (refluxing in various solvents) but that simply didn’t give them much in the way of conversion. Switching over to microwave heating with the addition of a silicon carbide heating element, they reached temperatures of 240-250 oC. That’s pretty damn hot, especially since they are using toluene as the solvent which can be a pain to heat in the microwave. They found that it was necessary to have 20% mol of benzoic acid in there to catalyze enamine formation. Not surprisingly, the reaction was very fast (<15 min). And they found the scope was quite wide, in that a variety of aldehydes and even ketones could be used with moderate to good yields!
And that’s about it! Short, simple and to the point. I really enjoyed this article and look forward to more azomethine ylide chemistry by Seidel’s group!



  1. I think the structure of the product of the beta naphtol reaction must be different. Beta naphtol reacts with electrophiles exclusively to the 1 position (not the 3 position)

  2. yeah, thats what I get for staying up until 2 and doing a post. Thanks, all fixed up!

  3. […] interesting article I found was in my favorite journal Organic Letters. About half a year ago I posted on some work that the Seidel group over at Rutgers was doing, regarding the exploitation of […]

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