Shi shows hydroarylation with shimmying hydrogens

Citation: 

Wang, Z.; Gao, L.; Liu, S.; Wang, P.; Shi, S. Facile Access to Quaternary Carbon Centers via Ni-Catalyzed Arylation of Alkenes with Organoborons. J. Am. Chem. Soc. ASAP. 

https://pubs.acs.org/doi/10.1021/jacs.4c17313

Summary Figure:

Background:

The Shi lab has done a number of reactions that can loosely be considered cross-coupling, usually with nickel or palladium, and takes advantage of different ligand systems than the extremely common phosphine, pyridine, or bisoxazoline manifolds. 

Hydroarylation is the process of adding a hydrogen and an aryl group across a pi bond, and can be fairly challenging. For one, there often are selectivity issues- which way do the functional groups go? Sometimes you can rely on selectivity in the substrate (Markovnikov vs anti-Markovnikov), while many other reactions just get a mix. Second, you need two different coupling partners because the hydrogen and the aryl group need to come from different places. That makes this reaction a three-component coupling, which are notoriously difficult to manage. 

The bigger issue that the authors need to tackle in this reaction is the presence of the terminal alkene, which usually shuts down the reactivity of nickel catalysts. Pi bonds make excellent ligands for nickel, so in many reactions the nickel catalyst will bind to the substrate and sit inert until the reaction is quenched, returning only starting material.

How it works:

The Shi lab found that only diimine ligands are able to effect the transformation, as an assortment of other common ligands were all completely ineffective. Here's the list of ligands, which is provided in the SI: 

Only L14 is able to conduct the reaction, which is incredible. As much as this reaction looks fairly simple, I don't know how likely it is that someone would find the correct ligand. 

The mechanism would be straight forward, except for one weird twist (Below). 

Initial transmetalation with the arylboronic acid gives an aryl nickel species, which binds to the pi bond of the alkene. Then, the aryl group can do migratory insertion to give a nickel alkyl species. Normally, this nickel alkyl can undergo protodemetalation directly to give the product, but the Shi group provides strong evidence that the proton instead comes from the aryl group, giving the a different nickel aryl species. This then undergoes the protodemetalation to provide product. The nickel catalyst does not change oxidation state, as there is no oxidative addition or reductive elimination.

This mechanism is supported by some very nice deuterium incorporation studies. If the solvent is deuterated, the methyl group shows no deuterium incorporation, and the aryl group does. If the aryl group is deuterated, then the methyl group begins to show deuterium incorporation. 

Initial Questions and Key Findings:

1. Can quaternary centers be synthesized from 1,1-disubstituted alkenes using hydroarylation?

A: Yes, but not with the most commonly used ligands. Diimine ligands are necessary to enable the reaction. 

2. Can this reaction construct enantioenriched quaternary centers?

A: Yes, by making the diimine ligand chiral, enantioenriched products can be formed. 

3. How does this reaction work?

A: The reaction proceeds through a redox-neutral mechanism that involves migratory insertion onto the alkene and then a unique 1,4- or 1,5-hydride shift to protonate the nickel alkyl species. 

Takeaways

I really like this paper. It's a reaction that is simple on the surface, and not necessarily very sexy, but the authors did a lot of things right to flesh it out. Finding an enantioselective variant is top notch, and the deuterium experiments are great. The scope could have been condensed to a few key functional groups, but I do like showing the scale up reaction. The choice of ligand is very interesting, and now I really want to try it out on some other transformations. It's possible that this sort of ligand is good for all sorts of other situations, possibly ones where you need a very electron rich metal center. As easy as it is to keep a set of phosphines in a cabinet and then screen that cabinet every time you have a reaction, diversity in the number of ligand classes is just as (or more!) important than the number of ligands within a class. That message might be particularly relevant for people at smaller institutions, where instead of getting the latest sleekest CatPhosG99 test kit with 16 phosphines, it might be better to screen 1 aryl phosphine, 1 alkyl phosphine, 1 bipyridine, 1 oxazoline, 1 NHC, etc. Even if they aren't designer, that screens more chemical space.