Since I mentioned a new Mitsunobu-type reaction yesterday, I should note that a new route to hindered ethers has come out this summer from the Baran group at Scripps. Here’s the ChemRxiv version, and here’s the Nature paper that just appeared. And there are more details at the group’s blog here. It’s an electrochemical reaction that involves decarboxylation to give very reactive carbocations that are then trapped by oxygen nucleophiles. You can make ethers, or use the reaction as a way to prepare alcohols if you just let water trap the cation, and if you really are into it, you can even trap with things like fluoride (albeit in lower yields).
These kinds of hindered products are totally unavailable through Mitsunobu chemistry, or through the classic Williamson ether synthesis, or basically anything that involves Sn2 nucleophilic attack. And the paper shows some dramatic examples of this, with compounds that were either unknown or only prepared by all-the-way-around-the-barn methods that can now be made directly. If you read the paper, you’ll see that this took a lot of experimentation. There are numerous variables and side reactions, and you cannot figure out how to solve them from first principles. The Kolbe electrolysis reaction is the 19th-century forerunner (1847!) to this work and the related Hofer-Moest reaction (1902) is an even more direct ancestor. But that uses the alcohol partner as the solvent, which is not a practical solution:
It became immediately apparent that limiting the amount of alcohol posed several considerable challenges: the decomposition of the carbocation due to the low nucleophilicity of alcohols; the competitive trapping of the carbocation by water; the consumption of alcohols by anodic oxidation; and the necessity of an external electron-acceptor in order to balance electrons. Figure 1c summarizes the results of around 1,000 experiments (see Supplementary Information for an extensive sampling) that were undertaken in order to solve these problems.
Adjusting the solvent, the electron acceptor, the anode material, and the addition of small amounts of base were all crucial, but the resulting reaction looks pretty robust (and naturally can be realized with the Baran-developed ElectraSyn device). Olefins, esters, acetals, Boc- and Cbz-amines, heterocycles, alkyl and aryl halides, and boronic esters are all compatible with the conditions. As the blog post linked above notes, though, you’ll do best if your acid (and the resulting carbocation) is tertiary, given the well-known stability order of carbocations.
So this could open up a number of compounds that normally you wouldn’t even think about, because ether synthesis is just synonymous in most synthetic chemists’ minds with nucleophilic displacement, and hindered things Just Don’t Work. We’ve all pushed the boundaries of such reactions. When I first started out in the lab in grad school, I had some tetrahydropyran derivatives to make, and a suggested synthetic route had been mapped out for me. I plunged in, but pretty quickly came up against the step to form the ring, which was an arrow with “Mitsunobu” written across the top. My first Mitsunobu! And it was hopeless; the starting material was just too hindered, as I shortly realized. I’ve told the story of how I got around that problem here, which was a valuable lesson in taking people’s word for stuff.
I would assume that intramolecular variants of this new electrochemical route would be a nice way to prepare crowded cyclic ethers as well. I’m always glad to see things come up that demolish the classic synthetic routes and disconnections that we all have in our heads!