Carbene Size Guides Coupling

With the help of carbene ligands, chemists have found new ways of controlling cross-coupling reactions that lead to allylic alcohols. Choosing either large or small ligands for a nickel catalyst helps define which region of an alkyne will couple to an aldehyde to form the alcohol, a level of control synthetic chemists have traditionally found difficult to achieve.

Allylic alcohols are common motifs in antibiotics and other pharmaceuticals, and although chemists have developed catalytic and enantioselective couplings of aldehydes and alkynes, controlling the regiochemistry of such metal-catalyzed couplings is still not straightforward. To avoid getting mixtures of products, researchers must turn to alkynes that are highly biased toward one outcome or the other or that have directing groups. Such workarounds limit the overall utility of the reaction.

Now, John Montgomery and graduate students Hasnain A. Malik and Grant J. Sormunen of the University of Michigan, Ann Arbor, have found that the size of N-heterocyclic carbene ligands of a nickel catalyst dictates the regiochemical fate of the reactions (J. Am. Chem. Soc., DOI: 10.1021/ja102262v). Bulky ligands lead to bond formation at the more hindered end of the alkyne, whereas small ligands lead to the opposite outcome. No ligand is the single best choice for either scenario yet, Montgomery says. “We’re trying to tease out those rules now,” he says.

With their nickel-catalyzed method, the team was able to control regioselectivity with less biased alkynes and was also able to override the selectivity that would be expected of certain biased alkynes. Now, they are delving into a wider range of alkynes and aldehydes to test the reaction’s scope, as well as improving their ligands.

The Montgomery group’s work “solves a long-standing problem in chemical reactivity” and “provides a powerful example of the impact that diverse N-heterocyclic carbenes can have in control of catalytic reactions,” says Scripps Florida chemistry professor Glenn Micalizio, whose lab also develops regioselective cross-coupling reactions.