The first Metal-Free Cross-Coupling

The article opens with the line "Reactions that couple two aromatic rings to make biaryls are among the most widely used processes in the pharmaceutical industry" and brings us to the problem that whereas metal-catalyzed cross coupling has found wide success in constructing biaryl rings, it has not been that successful in heterobiaryl construction. So, the authors established to do the same, get this, by avoiding metals all together.

Now, personally for me, this is a hell lot exciting because I want to see more synthetic chemistry that exclude metals. It is very true that metals, especially transition metals still dominates both academics and especially industry in cross-coupling, metathesis and asymmetric catalysis reactions. But that does not diminish the facts that they still posses a threat to the environment (heavy metals), they are costly and they are rare, making them going against a green, economic development in chemistry. But. only one property tricks these crucial issues and it is still helping the metals surviving, hell ! dominating the market till today. That property is the ability to be used in catalytic amounts. If you develop an extraordinary, holy-grail transformation that uses stoichiometric amount of an Ir compound, sorry to break it to you, you probably won't get the attention that you think you deserve just because of the problems associated with these kind of metals I mentioned above; and your next aim should be to develop a catalytic version of the same process to make it practical.

The authors of this paper have thus solved two problems in one shot. Firstly, they solved the problem of making heterobiaryls by cross-coupling where metal-catalysis was not working so well; and secondly, they developed the first successful metal-free cross coupling of heterobiaryls. 

Using only three steps, with phosphine 1 as the phosphorous source they have synthesized various heterobiaryls including complex drug-like structures. 

The mechanism of the reaction is extremely interesting and adds to the beauty of this one-of-a-kind transformation. It got featured as the mechanism of the month in the Cell Press journal Trends in Chemistry, June 2019, Vol. 1, No. 3. It will be little too complicated to describe it here fully let's have a quick look. 

The first step just puts a triflate group on the nitrogen of the pyridine and makes it ready for the nucleophilic attack by the phosphine, and DBU then does the rest and we get the phosphine 2a. Mechanistically same steps occurs in the second step with the other heteroaryl system and the crucial phosphonium (V) intermediate is obtained. Finally, in an acidic medium, the ethanol adds to the P(V) intermediate to give a trigonal bipyramidal intermediate that induces what seems like a concerted axial-equatorial reductive elimination to give the product. But, although common in transition metals, this type of R.E. is symmetry forbidden in trigonal bipyramidal geometries and the it actually proceeds through the migration of the axial heteroaryl group which acts as a nucleophile and attacks the π* orbital of the equatorial heteroaryl group followed by a pseudo-nucleophilic aromatic substitution to generate the product. Pretty cool !

However, this is only the begining, and we need more metal-free cross-coupling reactions. Who knows maybe one day there will be a Nobel prize for it too.