Fun with Fluorinated Furans!

Li, Y.; Wheeler, K.A.; Dembinski, R. Electrophilic Cyclizations of 2-Fluoroalk-3-yn-1-ones: Room-Temperature Synthesis of Diversely 2,5-Disubstituted 3,4-Fluorohalofurans Euro. J. Org. Chem. Early View Apr. 8th 2011

So the semester is finally winding down, and I’ve had a bit more time (like a few hours per week :P) to do some research. Things are still progressing well in our lab. In fact, just this week I put the finishing touches of the group’s new website. Check it out! Took me a while to learn all the proper coding but I’d say it came out fairly well. In other news I did not, unfortunately, get the NSF fellowship grant. It basically was the same story as last year. I got one really bad review (which it didn’t even seem like the reviewer even read my application) and it prevented me from getting it. You can tell there is a serious bias in that competition (if you look there are pages upon pages from places like Harvard, MIT, CIT etc. but little to none from other institutions). And I’m not saying people from those schools have bad ideas at all. I’m sure their applications are quite strong. What I believe occurs is that the name of their institution gives them an unfair advantage as the reviewer will give them more leeway/more of a in-depth review, then someone from a non-ivy institution. But, unfortunately, that is how the world works. Regardless, I plan on applying for future scholarships and fellowships such as the ACS Divisional Fellowship in due course. In terms of my own research, it goes well! I’m still at the making substrates stage in my multiple projects. But that just means I get to do more and more reactions! Also this week, I got to view the OPRD proofs, which look quite amazing! I’ll be sure to link you to the article as soon as it’s on the ASAPs for OPRD. And now, on with teh chemistry!
So I found this one early yesterday morning, after some of the Wiley journals came back online. I guess they were down for maintenance yesterday, but this article was well worth the wait. So as I mentioned earlier, I love the use of the trifluoromethyl group in organic synthesis mostly cause of its unique properties and medicinal applications. But as a whole, I find organofluorine chemistry fascinating, because it defies most of the normal rules of organic chemistry. Moreover, I love cascade reactions as it’s like the two for one deal of organic chemistry. So it’s no surprise this article attracted my attention.
So the article begins by outlining how furans are common moieties in drugs and natural products as well as in polymer science. However, preparing multi-substituted furans can be a pain. While they do your standard EAS sort of chemistry, adding substituents at the 3/4 (or beta) position in the ring can be difficult. Moreover, it’s hard to substitute all four carbons with unique substituents in good yield. These furans can be especially useful if they bare a halogen (as they can be stitched on to larger systems via organometallic chemistry i.e. via Suzuki coupling etc.). But what if you could not only prepare highly substituted, halogenated furans but also fluorinate them as well? Not only would you have a component of, let’s say, a natural product but you would also be able to prepare a more lipophilic and chemically resistant molecule as well! So that was the goal of this paper.

In a previous report, the Dembinski group has already developed a method for the preparation of tri-substituted furans. Seen above, they would take alkynyl silyl-enol ethers and transform them, via Selectfluor , into alpha fluoro-alkynyl-ketones. Treatment of these systems with a gold (I) catalyst and a silver co-catalyst facilitated cyclization to the tri-substituted furan. In fact, since such ketones are unstable species, they made this furan procedure a one-pot method. While neither this paper nor their previous publication gave a mechanism for this transformation, I’ve come up with my own (which may or may not be correct):

Now for this paper, they wanted to retain the ability to put a fourth substituent on furan. What better way then to put what is essentially a placeholder at that fourth position? But what place holder would be best? Well, as I mentioned early, Suzuki coupling reactions are excellent for stitching two molecules together and the best sort of halide for oxidative addition in this type of reaction is iodide.

Unfortunately incorporation of iodine wasn’t simple. They first tried to use a “more green” metal-free method to induce cyclization by just using NIS or N-iodosuccinimide a I+ source. attempting iodocyclization (which has been pretty popular lately and I even reviewed an article a while back). While the desired reaction did occur, yields were unacceptably low even after extended reaction times. The authors rationalized that the fluorine substituent was simply decreasing the nucleophilicity of the oxygen of the carbonyl, preventing cyclization in addition to decreasing the reactivity of the alkyne to electrophiles. Therefore they went back to the drawing board. If we consider the mechanism that I believe is in operation, the final step involve quenching the Au-C bond by protonlysis. However, if one intercepted that species with electrophilic iodine or I+, a C-I bond could be formed. Based on their previous work, they were essentially at the stage where all they had to do was combine their previous system with NIS to get their desired iodofluorofuran!
To further enhance their methodology, and improve yields, they tossed in a Lewis acid catalyst to magnify the electrophilicity of the iodide. Essentially, the Lewis acid (in their case Zn2+ from ZnBr2) would interact with the oxygen’s of the NIS causing further induction electron density from the iodine. Using this concept, they optimized their conditions and explored the scope which was reasonably wide. But they didn’t limit themselves to iodine. They also utilized NBS, or N-bromosuccinimide, to incorporate bromine at this position. What I think would have been really interesting (but outside the scope of this paper) would have been to use Selectfluor again, to get difluoro-substituted furans! Anyway, they ultimately showed the importance of their method by performing a Suzuki coupling to give the desired tetra-substituted furan

I must say I am really impressed in the level of depth of this article. It is one of the more thorough I’ve reviewed, and while it may not be as “impactful”, they really presented their story well, covering all bases. They even got a crystal structure to prove that they were indeed making their iodofluorofurans. Excellent work Dembinski and coworkers!!!


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