Phil Baran’s group has (yet another) good synthetic methods paper out, this one on metal-catalyzed cross-coupling. Now, there are an awful lot of metal-catalyzed cross coupling reactions out there, so if you’re going to propose a new one, it has to have some advantages over the back catalog. The group’s Open Flask blog has some back story on this one, and you can tell that they were thinking along these lines.
What this one does is create a bond between an aryl carbon and an aliphatic carbon. The aryl group comes in as an arylzinc reagent – you can buy quite a few of these, since they’re quite stable, and (thanks to Paul Knochel‘s group, among others) methods for making them are well optimized. That side of the reaction is not particularly surprising; there have been plenty of organozinc couplings, and the number of aryl organometallics used in such reactions is beyond counting. That’s not to discount the amount of work that went into this part – as the blog post mentions, the reaction was first realized using a preformed arylnickel reagent, which is a much less attractive beast.
But it’s the aliphatic partner that’s really unusual: your R group comes in from an R-carboxylic acid derivative. The blog post goes into some of the details behind this. Originally, they were using Barton esters, but those (although interesting compounds) can be rather painful to work with, because they’re light-sensitive. The team went on a search for more practical esters, and N-hydroxyphthalimide turned out to work well. Pushing things along even further, it turns out that you can do the condensation to make this intermediate from the carboxylic acid, followed by the Ni-catalyzed arylzinc coupling in the same pot. You can make and keep a solution of your favorite arylzinc around, which makes the rest of the reactions (as the blog puts it) basically dump-and-stir jobs, room temperature, done overnight. You don’t have to be wildly anhydrous, either – the nickel source is nickel chloride hydrate, which has the advantages of being cheaper than some kinds of dirt, as well as having one of the most intense green colors in all of chemistry. Jacob Edwards, who wrote the Open Flask post, specifically mentions enjoying the way that the reactions go from green to orange on completion, and I assume that he’s also the reason that there’s a St. Louis Cardinals logo at the bottom of the page (I approve!)
The only place to object to these reactions is in atom efficiency – you’re tossing quite a bit of stuff off your R group to couple it to the aryl ring. But for high-value products, which is what I’m used to while working on drug optimization, that’s not as big a concern. There are an awful lot of carboxylic acids out there in the world, and being able to one-pot-couple them to a variety of aryl and heteroaryl systems is a good ability to have!