<3 trifluoromethyl…

Todd D. Senecal, Andrew T. Parsons, and Stephen L. Buchwald Room Temperature Aryl Trifluoromethylation via Copper-Mediated Oxidative Cross-Coupling Journal of Organic Chemsitry ASAP January 14, 2011

I have a soft spot in my heart for the trifluoromethyl group. It’s just so freaking cool. It enables drugs to cross the blood brain barrier, lowers boiling points (despite an increase in mass: compare hexafluoroacetone with acetone), and helped me in my undergrad research. And I love fluorinated compounds in general. I mean it enables us to havenon-stick pans! And not to mention the most common way to put a trifluoromethyl group involves another near and dear substituent, the trimethylsilyl group and an awesome mechanism (a CF3 nucleophile!). So it’s no surprise this article caught my attention in the JOC ASAPs.

Dr. Buchwald is renowned for his organometallic work and this article is no exception. Buchwald begins by giving a short history of fluorinated compounds in pharma and the current methods for preparing trifluoromethylated compounds. I was surprised to find out that making trifluoromethylated arenes isn’t that easy. Current methods rely on using trichloromethylbenzenes and treating them with HF or SbF5 (Swarts Reaction) which as you can guess is neither safe nor eco-friendly.  Buchwald, among others, has been looking to solve this problem and recently reported that he could use PdCl2 or Pd(dba)2  with aryl chlorides (cheap to make) with TESCF3 to effect trifluoromethylation. The drawback? Fancy ligands, high temperatures, and long reaction times. Not to mention the fact that, even if it’s only a catalyst, palladium is expensive. So from a pharma standpoint, this isn’t practical despite the excellent yields.
Therefore Buchwald needed to make it more economical and more eco-friendly. I always like reactions that are practical. And this particular reaction Buchwald discloses here is certainly practical. Instead of high temperatures and long reaction times and even using palladium, Buchwald therefore investigated the possibility of using phenyl boronic acids (somewhat more pricey than aryl chlorides but readily available) in a Chan-Lam-like reaction with the trifluoromethyl anion. Pretty sweet idea, not completely new (some lit precedence using a decarboxylative approach of TFA to generate the Cu-CF3 complex in the presence of copper to get aryl halides to become CF3 and a recent report by a group in china that was able to couple boronic acids via TMSCF3). However, the current methods are complicated to say the least and, again, not amendable to pharma.
Therefore Buchwald(‘s students) went out and tried to simplify it. They got their first hit using standard Chan-Lam conditions withp-phenyloxyphenyl boronic acid as a test substrate. Not surprising they chose a para compound; the spectras are just so much easier to read. I’m not particularly sure why they chose the a biphenyl arene to start but it was a good idea that it wasnt the phenol, otherwise they’d silylate the -OH and need excess TMSCF3 (NOT the cheapest reagent). By tossing in a popular ligand, 1,10 phenanthroline, they took their hit from 5% conversion to 45% (at room temperature no less!). However, here is where they encountered their first big issue: Protodeboronation. Now that just sounds badass. Water from the air was protonating their copper-aryl complex, killing their yields. So they solved it by using an atmosphere of dry O2 and putting in molecular sieves (a little overkill I think but effective). They also had issues with chloride formation (donated from the DCE solvent). When chlorination became an issue (which seemed substrate specific) they switched to i-Pr-CN as a solvent.
After solving all the preliminary issues, they moved to the scope of the reaction (which turned out to be rather large). They were able to take both activated and deactivated phenylboronic acids and get reasonable yields. They even threw in some nice heterocycles including pyridine, thiophene, pyridazine, indole and even a phenoxathiine. An acetophenone derivative was even used unprotected, showing the power of their methodology. Not only that but they even demonstrated that their method could be scaled up (10 mmol, see reaction below)

Buchwald concludes that this new method he developed will see widespead use in med. chem. because of its relative ease and the ablitity to conduct it on the benchtop. Hats off to the the grad students and Dr. Buchwald for an excellent article!


1 Comment

  1. […] 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 […]

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