One Of These Halogens (Is Not Like The Other)

John, J. P.; Colby, D. A. J. Org. Chem. ASAP October 13, 2011

What’s one way to relax after a somewhat stressful week in lab? Some good ol’ fashion blogging! That and a bit of sleep, food, range time (Yes, I am in fact an avid shooter), and pumpkin picking. As promised, I plan on delivering more updates. So let’s start with lab. While this week was somewhat overwhelming for me, all in all, the deity of organic chemistry must have been smiling on me. We have once again resumed out collaboration with Dr. Tilley, and things are going exceeding well. We were finally able to isolate a few key compounds, which were necessary to continue the project. Isolating these compounds (sorry I can’t be more descriptive) is unbelievable difficult, but we were able to obtain about 4.5 grams of them each! We owe this to a little luck and using very pure reagents. We found out really quickly early on that the reaction is very sensitive to impurities. Hence, me and Mike spent a good deal of time purifying our starting materials as well as the reagents going into the mix.
Our other projects are also coming to fruition. Barring any unforeseen problems, our next paper should be submitted shortly (we are just tying up a few loose ends). We’ve had some mixed results with a continuous flow project we’ve been working on (a project that seems to have many highs and lows unfortunately). I’ve also begun thinking a bit about the future and I have a few projects in mind, one of which may be more synthetically driven (and by that I mean I would like to attempt small molecule synthesis, possibly using methods developed by our lab). I think Mike is also is looking into doing the same (though with a different target molecule in mind).
I really have gained some valuable skills in the past few months: becoming pro at columns, developing much more concise and elaborate synthetic skills, and enhancing my skills as a scientific writer. While grad school isn’t the most exciting job (and yes I do say it’s a job) on the planet, it sure as hell is fun, challenging, and at the end of the day, I really couldn’t envision myself doing anything else right now. As for non-research related events, I successfully presented a few syntheses of the Welwitindolinones alkaloids to my synthesis class (the Wood, Baran, and Garg syntheses). I seriously love presenting. It’s a rush of adrenaline right before I start, but once I get into it, I’m very relaxed (and almost on autopilot). Plus, it time to talk about one of my favorite items to discuss: organic chemistry. Speaking of which, let’s get on with the organic!
So this week’s article comes from JOC and its more organofluorine chemistry (Sorry, I promise next time I’ll pick a fluorine-free article but this one was too good to pass up). So if you have been following me for a while, you clearly know why organofluorine chemistry is so popular right now: new ways of getting fluorine into synthetic targets is very appealing to Med Chem. And if you read my last post, you know that the introduction of the CF2 group is currently very difficult to do. The Colby group has recently become interested in tackling this problem. Not long ago they introduced an extraordinary strategy for the rapid formation of alpha, alpha difluoroenolates:

It appears as if Colby stumbled upon some findings by Ogden in the 1960s regarding the decomposition of hexafluoroacetone. Ogden found that, in the presence of metal hydroxides, hexafluoroacetone underwent a fragmentation to yield trifluormethylacetate and CF3-. Colby reasoned that a similar fragmentation could be achieved in 1,1,1-trifluoro-2,4-dione systems to yield trifluormethylacetate as well as the corresponding difluoroenolate. Colby and his group therefore set out to first prepared some 1,1,1-trifluoro-2,4-diones via trifluoroacetylation of various methyl ketones followed by alpha difluorination with Selectfluor. They then used conditions that can best describe as (very roughly) Krapcho-like (lithium salt to induce fragmentation). With conditions to facilitate trifluoroacetate-release in hand, he was successfully able to induce an Aldol between the other fragment, the difluoroenolate, and an aldehyde additive. Unfortunately, they really didn’t give a mechanistic rationale for why it worked, but it worked well (great yields, reactions completing in 3 minutes at room temp).

With that impressive work behind them, Colby and his group set out exploit their newly developed trifluoroacetate-release strategy by synthesizing alpha-halo difluoromethyl ketones (which aren’t at all easy to make). All Colby really needed to do was find the appropriate electrophilic source of each halogen and couple it with his lithium-salt induced trifluoroacetate-release strategy. While that may seem trivial, it wasn’t as easy as one may think. First they attempted bromination using Br2. While this simple approach worked, excess base was required (which they attributed to acidic impurities in the Br2). They then opted for NBS, a logical Br+ source. However this failed to react whatsoever. Finally, they switched back to utilizing Selectfluor to generate electrophilic bromine from LiBr (a modification pioneered by Shreeve . This proved provide a reliable source of electrophilic bromine without requiring excess base.

Next they targeted iodination. Attempting to capitalize on Selectfluor-mediated halogenation, they initially tried using lithium iodide (serving both as their lithium salt and as their iodine source) in the presence of Selectfluor. However, due to the fact that no sufficiently electrophilic iodine was present, self-coupling reactions occurred. Colby then made a slight tweet to his conditions: add I2 and exchange LiI with LiBr. That managed to do the trick and they were able to isolate alpha iododifluoroketones in excellent yields (though these species decomposed rapidly over times upon storage). With this in mind, they decided to demonstrate the power of their iodination method by synthesizing one of these ketones in situ followed by an immediate copper coupling to an alkene. Coupling proceed well and had the advantage of not having to isolate the somewhat sensitive iodoketone

Finally, to wrap things up, chlorination was examined. Unlike iodination and bromination, molecular chlorine was not examined due to its hazardous nature (a good call in my opinion). Instead, Colby opted straight for NCS/LiCl. Lucky this proved perfect for chlorination (though ketones with alpha hydrogen atoms were over chlorinated).
I really enjoyed this article quite a bit. While it may not have been as impact as Colby’s previous work, it certainly was interesting and very well done. I still am really curious on the exact mechanism of the trifluoroacetate-release, because it’s so unusual! Anyway, that’s all for now. Ckellz…Signing off…


1 Comment

  1. I believe that LiBr and Selectfluor react to give Br-F in situ and that acts as your Br+ source.

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