My mental map of “standard organic chemistry transformations” keeps getting defaced, and I’m glad of it. That’s because I first developed it about forty years ago when I took my initial organic chemistry classes, elaborating it over the years with reactions that I’d read about and used in the lab, so it would frankly be discouraging if there hadn’t been some remodeling needed over that period. I think that the first big addition for me was Pd-coupling chemistry, which I started using around 1991 or 1992, wondering if it was actually going to work or not (it did). That of course turned into a gigantic addition to the organic chemistry landscape, and now undergraduates naturally build it into their own worldviews as they learn the field.
Here’s another example of a new reaction that plows shortcuts across several well-established lawns in that same landscape. In general, the standard way of thinking for a bench chemist is that you can turn some other groups into amines, but turning amines into other things in turn is not so easy. In the first category you have things like reductive amination of carbonyls, or substitution with a cyanide followed by reduction, or direct substitution via some of those Pd coupling reactions, or even simple nucleophilic displacement like the Gabriel synthesis. There are plenty of others.
But turning amines into something else is harder. Aromatic ones can be transformed by the classic Sandmeyer reaction (making a diazonium and substituting it with all kinds of nucleophiles, but aliphatic ones are a pain to convert to other groups (not least because the diazonium tends to just eliminate rather than get replaced). The paper under discussion says that “amines have remained one of the most challenging groups for functional group interconversion”, and notes that there are generally some sort of multistep activation procedures needed to soften the thing up before you can replace it (such as turning it into a pyridinium salt, for example). Directly ripping out a plain NH2 and turning it into some other functionality is just not something we tend to think about.
Maybe we will now, though. If you use a rather odd-looking N-O-pivaloyl-N-O-benzyl amide reagent and some sort of trapping agent, you can apparently convert both aryl and alkyl amines to bromides (with carbon tetrabromide), chlorides (with carbon tetrachloride), iodides (with isopropyl iodide), thioethers (with a disulfide), alcohols (with oxygen followed by triphenylphosphine, and phosphonates (with triethyl phosphite). It’s a radical reaction mechanism, with that reagent turning the target amine into a funky isodiazene species. The challenge was getting things to work with radical chain propagation while avoiding detouring off into reductive loss of the whole functionality, and the authors seem to have struck the balance pretty well. The bromination is absolutely the widest-ranging of the bunch, since the tribromocarbon radical seems to be an excellent chain carrier.
The paper demonstrates a long list of interesting transformations on primary and secondary aliphatic amines, aromatic amines, and heteroaryl ones as well. And I definitely appreciate the inclusion of numerous things that didn’t work, with likely reasons why they failed. When things do go right, which seems to be pretty often (especially with the bromination), a wide variety of other functional groups are tolerated (esters, nitros, amides, terminal acetylenes, sulfonamides, ketals and more). So now I’ll need to remember a new shortcut from amines to bromides, among other things, which does seem a bit weird to have all of a sudden. But welcome!
