And suddenly fluorine…all of it!



Methyl 2,2-Difluoro-2-(fluorosulfonyl)acetate, a Difluorocarbene Reagent with Reactivity Comparable to That of Trimethylsilyl 2,2-Difluoro-2-(fluorosulfonyl)acetate (TFDA) Eusterwiemann, S.; Martinez, H.; Dolbier, W. R., Jr. JOC ASAP May 21, 2012.

Direct Electrophilic N-Trifluoromethylation of Azoles by a Hypervalent Iodine Reagent Niedermann, K.; Früh, N.; Senn, R.; Czarniecki, B.; Verel, R.; Togni, A. Angew. Chem. Int. Ed. Early View May 22, 2012


After a long hiatus, I have finally returned to the world of chemistry blogging. These past two months have been some of the busiest of my graduate career thus far. After my tetrahedrane guest post on BRSM, I really stepped-up my chemistry game trying to finish up the three project that I am currently involved in. Two of these three should be ready for submission very soon and the remaining one should be complete by summer’s end (at least that’s my expectation right now). We manage to get another publication, a flow paper in OPRD in April. It was more technically oriented so it fit better in OPRD than in a more organic journal like Org. Lett. With the semester ending, I am finally officially done with class for the rest of my life (at least for required class, I presume I will take classes of my own volition in the near future *cough* pistol permit safety class *cough*). With this complete, I will have even more time to do research in the fall. Speaking of the fall, rumor has it we may have an exciting speaker coming to UConn to give a talk next semester, Dr. G. K. S. Prakash! I would be very happy to get a chance to talk with the guy whose lab helped develop one of the most powerful trifluoromethylating reagents known, TMS-CF3. Speaking of TMS-CF3, I’ve put up a bunch of procedures (including one using TMS-CF3) up on Chem Spider Synthetic Pages (Paal-Knorr Pyrrole, KBH4 Reduction, [2+2] Cyclobutanone Synthesis, Finkelstein TMS-CF3) so go check them out!
The graduate student conference in Buffalo, the CGSS, went quite well. The Leadbeater group all had great posters and presentations. It was my first time to Buffalo and I ended up really liking it there. We all meet some cool people (including DiAndra’s former boss at Niagara University, Dr. Ronney Priefer) and saw some excellent presentations (especially by one of the key note speakers, Corey Stephenson from BU). I’m really looking forward to our next conference, the ACS meeting in Philly in August. All of the talks and posters submitted by our group have been approved so we will all be going.
With the end of classes and the beginning of the summer, I’ve had far more time for research. Its also nice to get out of work feeling like I accomplished light AND its not pitch black out. We have several students in our lab for the summer, one from CCSU, one from UConn, and a Stonehill Student that was sent by Dr. Tilley. They all seem excited to start doing research but they all require a bit of training. Everyone in the lab has been pitching in to get them trained up. Unfortunately though, while gaining some people, we are also losing DiAndra. She is off to Boehringer Ingelheim (BI) for the next part of her Master’s in synthetic organic chemistry. Her internship at BI could possible lead to a job there. I hope she really enjoys it there and I know she will own. She won’t be all that far away either…the BI research plant is in Ridgefield Connecticut and after she’s done there she will return in the fall to finish her thesis and defend. Considering that I have no experience with industry, I am currently looking into the possibility of getting an internship there for the summer of my third year. BI and UConn have a great relationship and many students have done that sort of thing in the past. An internship like that may swing me towards industry or academia but I think you’ve heard enough about my life now though :P, let’s get to the chemistry.

While I wasn’t blogging, I was still trying to keep up with the latest literature. However, to keep things current, I found a number of good articles in past few weeks that have been interesting and have had great chemistry in them:

  • Intramolecular σ-Bond Metathesis Between Carbon- Carbon and Silicon- Silicon Bonds from the
    Murakami Group details a interesting strained-ring expansion strategy to access silaindanes (see my previous post about another awesome method to access this sort of motif)
  • Palladium-Catalyzed Substitution and Cross-Coupling of Benzylic Fluorides by Brown and Gouverneur detailing a remarkable C-F bond-breaking method (a transformation which is not very common, although benzylic fluorides are somewhat reactive). This article was also featured on Synthetic Remarks!
  • Synthesis of Indolines, Indoles, and Benzopyrrolizidinones from Simple Aryl Azides from the Renaud group which demonstrates how a radical cleavage of a C-I bond mediated by Et3B and O2 in the presence of an alkenyl azide can induce cyclization.
  • Today’s special double feature, however, will be two rather different ways of introducing fluorine into organic molecules. The first is very reminiscent of two articles I’ve reviewed in the past (link 1, link 2) The author? None other than William R. Dolbier, Jr., one of the premier organofluorine chemists. Dolbier has put out a continuous stream of articles within the past year or so dealing with strained fluorinated small ring systems. In a sort of response, Prakash and some former students of his developed a method to form difluorocarbene from TMS-CF3 via TBAT and/or NaI. Dolbier’s “reagent” or the one he tend to employ/market is TFDA or trimethylsilyl fluorosulfonyldifluoroacetate. One detail that didn’t really surprise me with Prakash’s method was that electron-deficient alkenes were a no-go. Difluorocarbene generated by this method (which is likely not a “naked” carbene) is simply not reactive enough to give successful cyclization. As Dolbier notes, the only reagent capable of getting a truly naked carbene is in fact TFDA because all of the byproducts are gaseous under atmospheric conditions. However, TFDA isn’t the most friendly reagent: it has a short shelf life (because of its instability), moisture-sensitive (meaning rigorously dried solvents are required) and its very expensive (meaning if you waste it, your PI will be displeased to say the least). Therefore, to mitigate these drawbacks but still promote this system as a viable and practical difluorocarbene source
    In that vein, Dolbier and his group looked into an analogous compound, Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, MDFA. They hoped to exploit it in a similar manner to TFDA by a demethylation strategy:



    The fluoride byproduct, which would likely interfere with free carbene formation, can be trapped with TMS-Cl. Initial runs using this system did in fact give promising results. However, high temperatures and minimal solvent were necessary. As Dolbier notes, this temperature requirement is very similar to both Prakash’s method and the TFDA method. Solvent, while minimal, needed to be somewhat good at dissociating the KI (used as the I- source). Hence a mixture of dioxane and diglyme was chosen. This was also advantageous because it provided a good thermal cushion. It was later found that 2 equiv of MDFA was required as compared to the substrate. After the tedious process of optimization was accomplished, Dolbier demonstrated that this system, while somewhat harsh, enable difficult-to-react alkenes to undergo cyclopropanation in good yield. In fact, it was later revealed that a much less Lewis-acidic trapping agent hexamethyldisiloxane could be used as an alternative trapping agent, though this required extended reaction times.



    While this article was short and many of the yields are solely by NMR, I still really enjoyed this article because of the complexity of the transformation. There’s a lot going on in the reaction flask so I’m kind of surprised how well the reaction does in fact work.

    In a sort of up-and-coming field, we have article featuring electrophilic trifluoromethylation. The two leading reagents have kind of set the standard for electrophilic trifluoromethylation. Togni’s reagent(s), which uses a Dess-Martin-like hypervalent iodine architecture, is commercially available (though it is expensive) and have become quite popular even though they are less than 10 years old. The other older reagent system, whose popularity is increasing, is those based off of Umemoto reagent. These are O-(trifluoromethyl)dibenzofuranium, (Trifluoromethyl)dibenzothio-, seleno- and telluro-phenium salts. They rely on the principle of attaching the CF3 group to a formally positive heteroatom to make it electrophilic. I personally am a fan of the Togni system mostly because I like hypervalent iodine. How often do you see a halogen with that many bonds to it that has some synthetic utility? With the exception of the Dess-Martin reagent itself and a few other chlorine examples, there pretty much are none. In this latest paper, Togni at ETH Zürich reports on a method to trifluoromethylate azoles using his 2nd generation reagent. As you probably know by now from reading the various post on my blog, adding fluorine into a molecule (whether it be via a CF3 group or a simple fluorine atom) is pretty popular in medicinal chemistry. Not only does it (usually) increase the ability of a molecule to penetrate cellular membranes but it can serve as a bioisostere. Bioisosterism is the capacity of substituent with similar sizes or shapes to be interchanged with others without substantially altering biological behavior, i.e. binding affinity.



    Many drugs have exploited this principle and Togni acknowledges this by citing the powerful antibacterial agent norfloxacin and Ciprofloxacin as an examples. The paper Togni cites, by Asahina of Kyorin Pharmaceutical Co., states that the N-CF3 compound is comparable to that of a simple methyl group with respect to the antibacterial properties and on par with the with activity of norfloxacin for most species of bacteria.



    With that in mind, this paper is kind of a follow up work which I really like. Basically Togni’s group observed the formation of a N-CF3 triazole compound attempting to make trifluoromethyl imines from azoles by way of a Ritter-type reaction. While only a side product, knowing that there were limited methods for accessing this class of compounds, Togni decided to optimize the reaction to yield this as the major product.



    Now here’s another interesting part about this article: the discussion of the results from their study (yields, how they characterized their products by some fancy 19F-NMR techniques) came before their optimization of reaction conditions. I think this was something that a reviewer may have wanted them to add in after the fact but its quite extensive. Much of the focus was on solvent, temperature, Lewis acid catalyst choice, and concentration. In fact they did a good deal of reaction monitoring to assist in some finer details of the conditions (i.e. silylating the nitrogen just prior to conducting the reaction rather than storing it and adding LiNTf2 into the mix as a “less Lewis acidic fluoride scavenger”. Overall, work was done quite thoroughly and didn’t leave me with much in the way of questions, which is something I love see.

    Well that’s it for this post. I will hopefully be posting again soon about some more interesting methods now that my schedule is somewhat less hectic! Hats off to the Togni and Dolbier group for some excellent work!! Ckellz…Signing off…

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