Those of you who are fans of high-throughput reaction discovery have another paper to check out - and those who aren't have another reason to grit your teeth. (Previous examples here, here, and here). The authors, a collaboration between the Bellomo lab at Penn and the Merck process group at Rahway, have gotten the reaction screen size down to 20 microliters with 1 mg of compound, which allows you to go through 96-well plates pretty rapidly.
Their test bed was a pyrimidone synthesis reaction. They screened 475 reaction conditions (95 different additives/catalysts in 5 different solvents). Each of them got one hour at 60 C to show what it could do, and the entire analysis was completed in one day. A phenantholine/copper bromide catalyst in dioxane showed the best results from that run, so it was taken to a separate series of experiments, to see how low the loading could go, what similar solvents might work out, how low they could push the reaction temperature, and so on. As it turned out, 2-methyl THF at RT overnight with 5% catalyst gave an 84% yield, which already represented a significant improvement over the known conditions (which used no catalyst at 140 C).
Moving to different substrates, they found that these conditions gave product each time, but in varying yields. A further catalyst screen, with 112 phosphine ligands, gave another set of conditions that could also be applied to the diverse substrates. A re-screen of solvents together with the best phosphine gave (along with the initial optimization conditions) high-yielding reactions for each of the new substrates. There was no set of one-size-fits-all conditions, though, which certainly fits with organic synthesis as I know it.
With these in hand, they did some work on the mechanism. It appears that the copper is participating in a single-electron transfer reaction, but further details aren't clear. It's not the sort of thing that you would have been able to think your way to on a blackboard, which (to me) is the whole point of doing chemistry this way. As the authors put it:
We envision that similar, generally useful platform tools will soon become more widely available, thus dramatically impacting chemistry development and enabling increased access to chemical diversity and lower-cost synthesis. Most importantly, we believe that such platforms will lead to the discovery of new and potentially useful chemical reactivity and reaction mechanisms.
Exactly. We should be finding easier ways to make compounds, and new ways to make compounds we've never been able to prepare. I think that searching for them in this way is an efficient way to do that, and will also open up new areas of research as we stumble across things we never realized were even there. If there's a downside here, I'm not seeing it.