Saturday, December 1, 2012

Conjugate addition, aqueous edition

Organocopper chemistry is one of those fields that doesn't get the attention it deserves in advanced undergraduate and many graduate synthesis courses. Usually, we settle for writing "R2CuLi" and being done with it, but cuprates do some pretty neat things that plain old Grignards and organolithiums just aren't as good at. Just like pretty much any organometallic species, though, their reactivity is dependent on additives, solvent, aggregation state, etc., which all ties in to the method of generation as well. (For a good review, if you get Organic Reactions, see Lipshutz).

There's a bunch of flavors (Gilman homocuprates, mixed Gilman cuprates, controversial "higher-order" cuprates, cyano-Gilman cuprates, etc.) that people have argued over (especially the alleged higher-order variety). Organocuprate reactions are, of course, moisture-sensitive, which means fun with cannula transfer and good Schlenk technique when you need to use them (this is annoying, by the way, when adding one needs to add solids at various points of the reaction). Additionally, additives can make a big difference:

Thus, this JACS article came as a surprise: "C–C Bond Formation via Copper-Catalyzed Conjugate Addition Reactions to Enones in Water at Room Temperature." (Lipshutz, B. et al. JACS 2012, DOI: 10.1021/ja309409e). Note that it's from Bruce Lipshutz, who has been fairly influential in the cuprate field.

From the abstract (with Fig. 1 from the paper): (note typo from the abstract, red emphasis mine)
"Conjugate addition reactions to enones can now be done in water at room temperature with in situ generated organocopper reagents. Mixing an enone, zinc powder, TMEDA, and an alkyl halide in a micellar environemnt containing catalytic amounts of Cu(I), Ag(I), and Au(III) leads to 1,4-adducts in good isolated yields: no organometallic precursor need be formed."

Sounds pretty good, doesn't it? The development of aqueous conditions for organic reactions is challenging, of course, due to the sensitivity of many reagents to water as well as the utterly poor aqueous solubility of many (most?) substrates. Nevertheless, Lipshutz points out examples, including an aqueous conjugate addition by Luche that beat this paper by 26 years, and a more recent aqueous Negishi reaction by his own group.

The reaction:
Both the Negishi reaction and this new work are powered by "nanomicelles", tiny nonpolar environments formed by a catalytic amount of an expensive-looking detergent added to the reaction medium. The amphiphile is a vitamin E derivative (polyoxyethanyl-α-tocopheryl succinate; aka. TPGS-750-M), interestingly enough (other compounds were screened and didn't work). The authors include the structure in their paper (I've included the image from their manuscript rather than drawing it myself in order to point out a curiosity: is it weird to use "Me" and "CH3" in the same structure?)

Of course, you can read for yourself the details. A variety of conditions/additives were screened, and the reaction was found to be generalizable to primary/secondary alkyl iodides/bromides. The best loadings and rates were found for what was described as the "coinage metal triad" (copper acetate, AgBF4, and AuCl3) along with zinc metal.

It's probably worth noting that all the enones presented were relatively uncrowded; this isn't exactly surprising, since usually TMSCl, borane, or some other additive is needed in the normal, water-sensitive route in order to effect conjugate addition to highly substituted enones. It's a bit trickier to find additives like that here.

Still, this seems, at first read, to be pretty interesting. It's aqueous, it's catalytic, you can recycle the catalyst/medium, and you can buy all the reagents. Yields seem to be good (but that doesn't always mean anything). Most importantly, the reaction looks to be facile. Facile is nice. Though I would have called the nanomicelles "transient nanoroundbottoms".

1 comment:

  1. Hello! I was thrilled as soon as I loaded this web page of your resource. What was your aim at that moment when you took a decision to compose your first domain?