Iron or Palladium: You Decide

Prakash, G. K. S.; Krishnan, H. S.; Jog, P. V.; Iyer, A. P.; Olah, G. A. A Domino Approach of Heck Coupling for the Synthesis of β-Trifluoromethylstyrenes Org. Lett., 2012, 14, 1146.

Iron(II)-Catalyzed Trifluoromethylation of Potassium Vinyltrifluoroborates Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem. Int. Ed. Early View Feb 10th 2012

After a bout with a nasty cold and a presentation in front of the department, there is nothing better than returning to blogging. It has been a long while since my last post, which unfortunately (or fortunately?) has been due to all the stuff going on in the Leadbeater lab. While we don’t have any new papers to report on yet, we are certainly getting very close! Over the past couple of weeks we’ve made a lot of headway on our collaboration with Dr. Tilley. We’ve certainly hit a few roadblocks along the way but we’ve found some clever ways around them. DiAndra and I are wrapping up the project she has been focusing on for the past couple of months which we likely will be submitting to either JOC or Org. Lett. In fact, DiAndra also presented this work this week at a departmental seminar and did an excellent job! Both DiAndra and I presented on the same day though on different projects (I focused on some other work I’ve done along with our collaboration with Dr. Tilley). We (and the rest of the Leadbeater group) plan on giving more talks at the CGSS in Buffalo as well as at the fall ACS meeting in Philly. Other than that I don’t think there is much more to report so let’s get to the lit!
This week we have two interesting (if not somewhat related) articles disclosing methods to access trifluomethylated olefins. The first was a article released a few weeks ago by Prakash/Olah and co-workers detailing a clever way to access trifluoromethylated styrenes. Prakash and Olah are, in my opinion, the current leaders in organofluorine chemistry and have been featured before on New Reactions. Prakash is one of the pioneers of making trifluoromethylation practical thanks to his investigations with TMS-CF3. Prakash is a former student of Olah and hence they often work together on projects particularly ones involving fluorine or carbocations. This article is no exception. As part of a broad program to access trifluoromethylated synthons, Prakash and Olah became interested in accessing vinyl trifluoromethylated compounds.

The current methods available rely on two disconnects, at the CF3 group and at the C-C double bond. Neither is very effective for synthesizing these sorts of olefins and have many drawbacks (the former being complicated by the synthesizing the appropriate olefin precursor and the latter requiring the preparation of a trifluoromethylated ylide. Prakash decided to take a somewhat different approach. His disconnect was at the C-C=C of the olefin. Rather than forming the double bond or adding in the CF3 group, he wanted to attach 3,3,3-trifluoropropene to arenes in a Heck-like manner. Now Prakash was not the first to attempt this strategy. Fuchikami and co-workers used 3,3,3-trifluoropropene to prepare trifluoromethylstyrenes. However not only did this require one to work with 3,3,3-trifluoropropene (a gas at room temperature), a autoclave was also needed and the scope of the reaction was very limited. Prakash’s solution was rather simple but ingenious: generate 3,3,3-trifluoropropene in situ and couple it to a iodobenzene derivative via a Heck-reaction. In fact, his group had experience in these sort of domino elimination-heck reaction in the preparation of styrene sulfonate salts. The idea is that under the basic conditions of the reaction, a dehydrohalogenation occurs generating the olefin in situ which can subsequently be coupled by Pd(0).

Prakash and Olah therefore began their investigation using commercially available (and relatively inexpensive) 1-iodo-3,3,3-trifluoropropane as their 3,3,3-trifluoropropene precursor. Rather than using a autoclave for heating and pressure, they opted for something our group is familiar with: microwave irradiation. Prakash and Olah believed that this would dramatically shorten reaction times making this far more practical than Fuchikami approach. Unfortunately they hit a rough start. Their test substrate, 2-iodoanisole, proved to be slow to react under their initial conditions. The authors only got, at maximum, 40 % yield which they attributed to the steric bulk of the methoxy group. They then switched to 3-iodotoluene and were pleased to get far better yield and conversion (83% conversion, 63 % yield). They screened a variety of variables in the process: Pd source, base, solvent, and temperature.

After optimizing, they explored the scope (and it turned out to be quite wide). Many were pretty standard (iodonaphthalene, p-iodofluorobenzene, p-iodoanisole etc.). There were some odd balls though. Surprisingly, o-iodoaniline reacted quite well while o-iodobenzoic acid failed to react. They also screened heterocycles, though most attempts were meet with low yields or a complete lack of reactivity. While somewhat of a short article, it was very to the point and thorough and I really enjoyed it.

Only a couple of weeks later, Dr. Steven Buchwald at MIT published a article detailing a somewhat different approach to the synthesis of trifluoromethylated olefins. As with Prakash and Olah, Buchwald and his group have been <a href="; title="featured once before on New Reactions. Buchwald has really become interested in organofluorine chemistry lately, publishing several new methods for the synthesis of some elusive trifluoromethylated moieties. In fact, Buchwald recently disclosed a method to access allyl trifluoromethylated compounds from terminal olefins and Togni’s reagent (a relatively new electrophilic trifluoromethylating reagent). In the processes they encountered a bothersome intermediate, namely the alpha chlorination product. Rather than simply ignoring this side product, Buchwald and his group hoped to capitalize on it as vinyltrifluoromethyl precursor. With that in mind, they decided that vinyltrifluoroborates would make suitable olefins for addition followed by spontaneous elimination.

After a bit of screening, they found that Iron (II) chloride was the most effective catalyst for their desired transformation and gave excellent E/Z selectivity. They found that a variety of vinyltrifluoroborates could be transformed into vinyltrifluoromethylated olefins under their conditions, and most gave fair to excellent yields. In an effort to explain the selectivity of their reaction, they reacted both Z and E vinyltrifluoroborates and obtained near idential E:Z ratios. This seemed to indicate an alternative more traditional pathway (radical or carbocationic) rather than a organometallic reaction. With that in mind, they investigated whether a Lewis acid was a suitable alternative catalyst. Indeed, they found that tin triflate also successfully catalyzed their trifluoromethylation reaction, indicating the reaction is likely proceeding through a carbocation. And that’s exactly where Buchwald leaves you hanging. I bet we will be seeing more of this sort of reaction in the near future.

Well there you have it, two excellent articles detailing new methods to access trifluoromethylated olefins. Hats off to both Prakash’s group and Buchwald’s group for excellent, through jobs! That’s it for now, Ckellz…Signing off…

Organic Chemistry Memes

Hi All,

Just made this facebook group today, hope you all like it. Feel free to like it and post some of your own memes…also new post coming soon!!!