musings on music and life

August 14, 2015

CBS catalysis…and trifluoromethylation shenanigans

Filed under: Chemistry, Classics in Organic Chemistry — Tags: — sankirnam @ 12:20 pm

In order to wash the previous paper from our minds, it is often good to step back and read some of the really important  manuscripts from decades past. One example is the classic 1987 JACS paper by Corey on the enantioselective reduction of ketones, which after this publication, came to be known as the “CBS” method, after the authors (Corey, Bakshi, Shibata).

In the introduction, Corey, Bakshi, and Shibata state that Itsuno had already discovered that mixtures of borane and chiral vicinal amino alcohols (derived from enantiopure amino acids) were very effective for the stereospecific reduction of ketones. However, Corey states that “reagent structure, scope, and mode of reduction has remained at a primitive level, limiting both application and further development“. Thus, they isolated the complex formed from borane and (R)-1-phenylethanol as well as borane and (S)-diphenylprolinol by vacuum sublimation.

CBS catalyst

The complex derived from prolinol and borane turned out to be extremely active, and Corey reports reductions of around 95% ee with >99% conversion at room temperature! The simplicity and practicality of this paper should be noted; according to Google, it has at least 1,200 citations! The catalyst derived from prolinol soon became commercially available from several vendors, and is now popularly known as the “CBS catalyst”. Interestingly enough, this can also be thought of as one of the early modes of organocatalysis, but the term does not appear even once in this paper. The use of prolinol here laid the foundation for the future development of the Hayashi-Jorgensen catalyst, which is now an exceedingly popular organocatalyst.

Upon typing this, I became reminded of a similar incident that occurred in the fluorine chemistry community while I was doing my PhD. One of the developments in trifluoromethylation chemistry that occurred during that time was the discovery of a copper-catalyzed trifluoromethylation of aryl iodides by Prof. Hideki Amii. The proposed mechanism involved the intermediacy of phenanthroline-ligated copper(I) complex [(phen)CuCF3], but that complex was not characterized or isolated. Prof. John Hartwig (UIUC, now at Cal) soon published a paper where all he did was synthesize the [(phen)CuCF3] complex and use that as a trifluoromethylating agent! In his talks, Hartwig claimed that using the pre-synthesized complex in this manner greatly expanded the substrate scope beyond what Amii reported, although he always skirted around the issue that he had taken a reaction that was previously catalytic in copper and made it stoichiometric in copper! Hartwig soon started a company based on this chemistry, selling the [(phen)CuCF3] complex, which is now known as “Trifluoromethylator“.

But really, is this any different than what E. J. Corey did in 1987 with Itsuno’s chemistry? I’m not trying to justify or defend Hartwig’s research, but there is a precedent for this kind of stuff, from a Nobel Laureate, no less. Having some distance from fluorine chemistry at this point gives me a valuable outsider’s perspective now, without which I would not have come to this realization.

1 Comment »

  1. […] and AgCF3 are also receiving increased interest now; I talked about CuCF3 earlier. Both of these complexes can be generated in situ from TMSCF3 and appropriate metal salts, and can […]

    Pingback by Classics in Organic Chemistry, Part VIII | musings on music and life — November 17, 2016 @ 3:46 pm

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