Alkynes of Irony…

Bera, K.; Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. Iron-Catalyzed Synthesis of Functionalized 2H-Chromenes via Intramolecular Alkyne -Carbonyl Metathesis J. Org. Chem. ASAP March 18, 2011

So another week in the lab and things just keep getting better. My methodology is actually coming along quite nicely and I’ve been doing a few new reactions (my first Diels-Alder!) to begin preparing my substrate scope. My boss thinks it’s good enough for Angewandte Chemie so that kind of made my week. Also, I picked up a copy of the manual for our auto-column. I’m really not big on columns, I am more of a recrystallization and vacuum distillation sort of guy. But if I can get this thing up and running again, I’d be more than happy to start doing some more columns. I mean, don’t get me wrong, I do columns somewhat regularly, but if I can avoid them by another means, I will certainly go for that. As for the progress with my collaboration with Professor Tilley, that’s also going pretty well. Lastly, keep a look out in Org. Proc. Res. Dev. Our article has been accepted and should be published soon regarding some work I did last semester. And I should be hearing about that NSF anytime now…not that I’m worrying about it or anything :P…but let’s hit the lit!

So this article really grabbed my attention because of its stark similarity to some of the research I encountered when I was at Columbia. Prior to going down to NYC, I was given a good deal of literature that Dr. Dailbor Sames had published. One of the articles, detailing the research of one of the group’s best organic chemist Stefan Pastine, involved the formation of enantiopure chromenes using platinum-mediated C-H bond activation. The general idea was that the platinum (in their case, PtCl4) would coordinate to the alkyne making it electron-deficient (see below). It is electrophilic enough that EAS occurs to giving cyclization. After restoring the aromaticity and protonolysis of the platinum, the more favorable 6-endo product is formed. So when I saw this new method for forming chromenes using a much easier to work with and substantially less expensive catalyst (FeCl3) I had to take a peek.

So the article starts out by detailing how 2H-chromenes are important from both a biological standpoint and from an industrial perspective. They then discuss how these structures are currently constructed and they even refer to Pastine paper when mentioning Pt catalysis as a viable method. They point out, much the way I did, that using Pt or Au catalysts, while useful, is impractical due to their expensive and moisture-sensitive nature. So, as an alternative, they suggest alkyne-carbonyl metathesis would be of use in constructing these molecules. I had never really heard that term before but apparently it involves a 2+2 cycloaddition between the alkyne and the carbonyl group followed by a 2+2 cycloreversion to give a alpha, beta unsaturated carbonyl species (see below).

The authors then go into their desire to get this carbonyl-metathesis to occur under “environmentally-friendly” conditions and, since iron has been all the craze lately, they suggest that Lewis acidic iron complexes could be used for this purpose. Iron has the added bonus of being readily available and cheap. So to test their hypothesis, they decided to construct some propargylic ethers based on a salicylaldehyde core. They were pretty practical about it. They simply took salicylaldehyde, which is extremely cheap, and alkylated with propargyl bromide. They then took that compound and did a Sonogashira with an aryl halide to access a variety of substrates. If that didn’t work, they simply took the corresponding propargyl alcohol, treated it with PBr3 and then did a subsequent alkylation of salicylaldehyde. Using a phenyl substituted alkyne as their screening substrate, they ultimately found that FeCl3 was their optimal catalyst for this reaction and that the best solvent was in fact acetonitrile. Other solvents (which I would considered “non-coordinating”) such as DCE or toluene failed to give acceptable yields.

The authors really did do a good job of optimizing their reaction. Interestingly the iron (III) chloride had to be anhydrous or yields were diminished. Other Lewis acids, such as indium (III) chloride and aluminum (III) chloride either gave no product or very low yield. The only problem I had with their optimization was the fact that they didn’t really screen temperature (Okay okay, they did one room temperature run…but not in their optimized solvent!). They just assumed reflux was necessary. But I guess that’s just me being picky :P. Anyway, they went on to show that both the substituent off the alkyne and the substitution pattern of the salicylaldehyde moiety could be varied with little effect on the yield. The exception to that statement was when they attempted to but alkyl groups off the alkyne or leave it simply unsubstituted. While the alkyl compound did give acceptable yields, reaction times were a lot longer (3 times as long!). Moreover, the unsubstituted derivative failed to react completely! However, if you consider the mechanism, these results make sense:

The authors proposed that the iron is acting simply as a Lewis acid and coordinating to the oxygen. The alkyne then attacks to give a vinyl cation. That explains why the alkyl groups gave the authors such difficult while phenylated alkynes went without issue. That cation is then attacked by the carbonyl giving that oxetene-containing intermediate. The oxetene moiety then undergoes their desired cycloreversion to give the chromene. Congratulations to the Jana group for an excellent article and a job well done! That’s enough chemistry for tonight. I’ll be sure to update again soon! Ckellz…Signing off…


Leave a comment

No comments yet.

Comments RSS TrackBack Identifier URI

Leave a Reply

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

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

Google+ photo

You are commenting using your Google+ 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 )


Connecting to %s