Practical olefin hydroamination with nitroarenes

A new, powerful method to generate quaternary amines without using expensive catalysts.

Baran has done it again. He is without discussion one of the most brilliant chemists around, touching many different topics from total synthesis to new reagents. Just check the entries in this blog and see by yourself. Very recently Chemistry World published a biographical sketch of Baran and it is simply amazing. You get an Ozymandias feeling: “Look on my works, ye Mighty, and despair!”

This time it is a new method for the preparation of amines catalyzed by… Iron. No Palladium, Platinum, Rhodium or whatever. A cheap iron catalyst. But the method is revolutionary not only by this. The raw materials of the reaction are nitroarenes and alkenes. Nitroarenes are widely available and cheap, coming from one of the oldest industrial processes, nitration. And alkenes, boy, we have plenty of those. Want more than a price reduction? The reaction yields quaternary amines. And those are pretty hard to hit by any other synthetic method. Just think in how you would prepare some of those building blocks. The authors include a drug discovery case in the second page of the paper (scheme A).

In the usual protocol, the nitrocompound is reacted with the alkene (3 equiv) in the presence of Fe(acac)3 and PhSiH3 as reducing agent in EtOH at 60 °C. To avoid the formation of a N,O-dialkylated product, coming from the intermediate hydroxylamine formed by partial reduction of the nitro, Zn and HCl are also used in a second ‘cleaning’ step. The results? Check the tables in the paper (more than 90 examples, and 350 pages of supporting information!) and you will see that you can run the reaction with almost everything in the aromatic ring: triflates, boronics, fluorides, chlorides, iodides, esters, ethers and thioeters… a long list. The reaction works also with heteroarenes. Examples include pyrroles, indoles, pyrazoles, thiophenes, pyridines and others.

Finally, some remarks about the methodology. This is one of the finest articles I have seen in a long time, speaking from the point of view of a company which is usually tasked with the preparation of challenging substrates. Not only the reaction has a broad scope; the authors include a section entitled “Substrate limitations”, where you can find some of the things that DO NOT work: free thiols, 2-nitropyridines, nitroalkanes (low yields, but workable), ortho-esters
, etc. Also, the experimental design (i.e., which substrates are selected to probe a point) is pretty good. And they have scaled up the reaction on a decagram scale.

So this paper has my vote for the Best Paper of the Year.

Olefin hydroamination

Science 2015348(6237) pp 886-891.
See: 10.1126/science.aab0245