Difluorocarbene: We’re bringing it back



Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Synthesis of gem-Difluorinated Cyclopropanes and Cyclopropenes: Trifluoromethyltrimethylsilane as a Difluorocarbene Source Angew. Chem. Int. Ed. Early View, June 16th 2011.


There is nothing I like more (we’ll at least when it comes to life in lab) then a reaction that works. It makes you feel good about yourself and you abilities as a chemist. What’s even more rewarding is carefully examining a problem and solving it, even if that means staying in lab until 11 or 12 o’clock at night. That’s exactly what happened this week in the Leadbeater lab. After spending nearly half a week working on it, we finally found a way to purify a key intermediate in one of my many projects. And it was through what was my least favorite form of purification: column chromatography. Now I say what was. Over the past couple of weeks I’ve not only become proficient in doing flash columns, but I’m starting to enjoy them (gasp!)! I never really appreciated their capabilities and even simplicity until recently. While they don’t always lead to the best yields, they certainly do a bang up job of getting my products pure (and beautiful spectra to match).
I stumbled upon an old but interesting pair of posts (one from Org. Prep. Daily the other from In the Pipeline. Both discuss “lousy reactions” or reactions that are pretty well-known but rarely work in practice. There were some pretty good stories and a few that I would want to add to the list. However, I wanted to make (and my apologizes if this has already been done) a list of a few reactions I really enjoy and always, always work. The first is trifluoromethylation via the Prakash-Ruppert reagent (Me3SiCF3 or TMS-CF3). Honestly, I’ve done this reaction countless times as a undergrad. Yields are typically good (>75%) plus the reaction is simple, non-harazdous, and the starting materials are relatively inexpensive. Another one that is also great is using Weinreb amides to construct various types of ketones. Both putting on the amide and converting it into the ketone is extraordinary simple and very general. Another great reaction (and kind of a UConn Chem department specialty) is the oxidation of alcohols to carbonyls using oxoammonium salts. The yellow salt, 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (affectionately dubbed “Bobbitt’s salt”, after one of its pioneers and UConn emeritus Dr. James M. Bobbitt) is very easily synthesized from commercially available inexpensive 4-amino-2,2,6,6-tetramethyl piperidine. Of all the oxidation protocols I’ve seen (and in some cases done) this is by far the best. All you do is mix the salt with your alcohol and some silica gel at room temperature in DCM and within a day or so you have your oxidized species. Even better, you know the reaction is done when the solution turns white! Soooooo are there any reactions you enjoy doing?!?
Also in an unrelated note, quite a few people I know have begun blogging. My girlfriend just recently started up her nailpolish blog called Polish4Pennies where she reviews different sorts of nail polishes. It looks great and it’s well written so go take a look (especially if you are into nailpolish)! Another one was started by one of the undergrads doing summer research in the Leadbeater lab. It’s called No Kitchen, No Problem. It features some creative ways to prepare meals with just microwaves and crockpots, so go if you’re hungry go take a look!



Ironically, this week’s article features the Prakash-Ruppert reagent but with a slight twist. Prakash (whom I’ve met and is an amazing chemist along with being a nice guy) is closely associated with an organic chemistry legend and Nobel laureate, George A. Olah. Impart, this is because Prakash obtained his Ph.D. working under Olah. For those of you unfamiliar with Olah, he is up there with Woodward and Ingold in terms of impact on the field of organic chemistry. His main claim to fame (and what got him a Nobel) is close to my heart: the study and exploration of the carbocation. Olah even observed CH5+ via NMR in “superacids” (e.g. fluoroantimonic acid). He even got his wife hooked on chemistry and they have been working together for quite some time. In recent years, Prakash and Olah have been exploring new applications of TMS-CF3 in addition to new ways to introduce fluorine into organic molecules. In fact just about a year ago, Olah and Prakash developed a system of perfluoroalkylating imines using perfluoroalkyl sulfones. While they don’t necessarily pump out ten articles in a year on the introduction of fluorine in organic molecules, the articles that they do publish are of extraordinary quality and detail. This same detail is even reflected in their group (one of the best talks I’ve seen was by a member of the Prakash group).



Prakash and Olah decided to tackle a somewhat different problem in this latest article. A few posts back, I mentioned a reagent developed by the Dolbier group known as trimethylsilyl fluorosulfonyldifluoroacetate (TFDA). In the presence of the fluoride anion, it decomposes to yield difluorocarbene which can be used to effect cyclopropanation. However, the problem with this reagent is a) It’s not commercially available b) One of the starting materials, 2-fluorosulfonyl-2,2-difluoroacetic acid, is somewhat costly c) its synthesis, while only one step, is somewhat entailed. The authors mention that there are other methods for generating difluorocarbene, but they suffer from similar drawbacks. Hence if we wanted to access important and possibly biologically active difluorocyclopropanes (one of the major synthons that can be obtained from difluorocarbene) we had to either deal with toxic materials, costly reagents and/or low yielding reactions with limited substrate scopes.



Seeking to fix this dilemma, Prakash and Olah investigated the possibility of generating difluorocarbene from TMS-CF3. During the development of TMS-CF3 as a reagent for trifluoromethylation, Prakash noted that decomposition of the trifluoromethyl anion yielded F- and difluorocarbene (giving minor side reactions). Prakash decided to revisit this and attempt to optimize it so that this side reaction became the desired reaction. Olah and Prakash initially screened a variety of F- sources. The key was that they had to be anhydrous (hence the standard source, tetrabutylammonium fluoride (TBAF), was not an option). One of the more popular alternative to TBAF, tetrabutylammonium triphenyldi-fluorosilicate (TBAT), was found to be the best for generating the carbene at low temperatures. Interestingly (and probably a trade secret of Prakash’s) sodium iodide could be used (at elevated temperatures) to induce difluorocarbene formation.



With a set of optimized conditions in hand for each type of catalysis in hand, the authors moved onto screening a variety of alkene substrates. As one would expect, electron-rich alkenes reacted better than electron-poor alkenes. Interestingly, when the NaI methodology was used, even unreactive alkene reacted well. Prakash and Olah attributed this to thermal activation of difluorocarbene, facilitating the [2+1] reaction. With this success, Prakash and Olah moved onto alkynes as substrates. These moieties gave substantially higher yields, mostly likely due to the increased electron density in the pi system. What I found interesting was that the reaction was extremely sensitive. The TBAT methodology was not used here, rather the focus was on NaI/heat method. Temperatures lower than 110 oC as well as changing the solvent from THF lead to diminished yields. However, in a few cases lower temperatures were required to avoid decomposition of the cycloaddition product.





My favorite part of the article, however, came right at the end. Prakash and Olah combine the two roles of TMS-CF3 in a series of two reactions. By adjusting the conditions, they authors were able to first effect trifluoromethylation (via TBAF) and follow it up with difluoromethylenation of an alkyne (in 85% overall yield!). In two quick steps they introduced 5 fluorine atoms!
Well that’s enough fluorine chemistry for this week. I really enjoyed this article by Olah and Prakash and I hope you do too! I look forward to their next article! Ckellz….signing off…

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Diene to Get Some Olefins



Jacobsen, M. J.; Funder, E. D.; Cramer, J. R.; Gothelf, K. V. β-Olefination of 2-Alkynoates Leading to
Trisubstituted 1,3-Dienes Org. Lett. ASAP June 7th, 2011


So after nearly two weeks of reaction after reaction after reaction, I finally found time to write another review. Chemistry in the Leadbeater lab has been going pretty well. Our collaboration with the Fenteany group is drawing to a close while our collaboration with Professor Tilley seems to get more interesting with each day. As for our own research, we have a couple of flow projects going (one of which is mine which is getting close to completion) so I’ll keep you updated on those as well. Also we’ve got a few undergrads in our lab this past week. One is a former student of mine from organic lab while the other is a rising senior from Bard College. Both have been extremely helpful in the lab and are really adding to the exciting research we are doing!
One of the more interesting issues that has come up in the past couple of weeks is the concept of buying or synthesizing a reagent. I’ve seen a couple of commentaries or suggestions (one from Alison Frontiers site, another from Transition States. But I guess how I view it really depends on the situation. The first thing I consider is how long will it take me to make the target intermediate? I’d say I’m one who will more often than not make a compound just because I really enjoy running reactions. However, there are only so many hours in a day and if it’s more than let’s say 4 steps, I would more likely opt to buy it (cost-permitting). I would caveat that with the following:

1. Are the steps long?
2. Can I get to the reagent or intermediate in a week (or the amount of time it would take for it to ship and be received)?
3. Does it involve any toxic, highly dangerous, or very expensive compounds to make?
4. *IMPORTANT* Do I have the reagents and/or equipment for every step involved (either in-house or via loaning from other labs)?
5. What’s my source of procedures for the synthesis? Are they quality journals with detailed procedures?
6. How necessary is this compound to my project?
7. *IMPORTANT* How expensive is the chemical? Can I get an adequate supply for a reasonable price?

Based on my responses to those questions, I generally have a feel for what I should do about this chemical. Sometimes you aren’t luck enough to be able to order a chemical and you have to just run the synthesis. I’d be curious to hear about some experiences (good/bad) from some of you all. For me, making some chemicals lately has really expanded my named reaction checklist. I mean in the past six months I’ve probably done at least ten new named reactions! I can’t say that all of them have been, well…successful, but at least I have the experience. But let’s talk olefins!
So this week I stumbled across a somewhat different article about a methodology useful in the synthesis of our highly conjugated friend, the diene. There are quite a few ways to prepare these compounds, from the classical Wittig reaction to the Julia Olefination to the newer enyne metathesis reactions. However despite the numerous ways they can be prepared, having another method for accessing these useful compounds is always beneficial. Building off of a paper by Xu and co-workers in 2009, Gothelf was interested if alkynyl esters (instead of those reactive unstable allenes) could be used to synthesize dienes via a phosphine-mediated pathway.



Before the article gets into the actual chemistry, however; it does what I would call a mini review on reactions of alkynyl esters activated by phosphines. There are some pretty interesting reactions already known, from furan/pyrrole formation to gamma addition. The reason they did this review because they wanted to show that their route would give yet another application for these species (and stress the “novel”-ness of it). What bothered me a little about this article is its stark similarity to Xu’s. They even optimized using the same initial substrate (o-chlorobenzylaldehyde), phosphine catalyst (triphenylphosphine) and solvent (DCM). However, unlike Xu’s allenes, this only gave 10% of the diene product. After screening time, temperature, solvent, and the substituents attached to the phosphine, they finally found the ideal conditions. The only phosphine that really worked well was 1,3,5-triaza-7-phospha-adamantane (PTA). They found that since they were operating at elevated temperatures (100 oC), extended reaction times lead to product degradation.
With their desired optimized conditions in hand, they then screened a variety of aldehydes with somewhat mixed results. No discernable trend can explain their results because both electron-rich and electron-poor substrates gave comparable yields. They then screened alkynyl esters showing that really only the one that they chose as a starting ester (where R1 in the first graphic = phenyl) gave acceptable yields.



Unlike Xu’s work, Gothelf’s article decided to investigate the utility of these dienes by performing a cyclization reactions. First, they did an interesting cyclization (by inserting an aldehyde as part of the ester moiety) to give a lactone. That alone great increases the usefulness of this method. They also took one of their diene and reacted it withN-methylmaleimide in a Diels-Alder reaction to give bicyclic system in the endoconformation.



To explain this somewhat unusual reaction, they borrowed some mechanistic ideas from Xu. First, the phosphine adds to the alkyne in a Michael-sense. Next a series of proton transfers occur, resulting in a phosphonium ylide. That ylide then reacts with the aldehyde via a Wittig-like reaction to give the desired diene. Overall quite a well done job by Gothelf and co-workers. That’s enough for this week, Ckellz…Signing off…