[O] What the Heck?!

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Author: Dr Holly Bonfield

The Heck or Mizoroki-Heck reaction takes an alkene and an aryl halide or triflate, and, in the presence of palladium (0) and base, forms a more substituted alkene product. Since the initial publications on this reaction in 1971-72, many variants have also been reported. One example is the oxidative Heck. Here, an aryl boronic acid replaces the more traditional aryl halide or triflate. This requires the use of a palladium (II) catalyst and oxidant but forms similar types of products.

A more recent development in this area is the redox-relay Heck and oxidative Heck reaction, pioneered by Sigman and co-workers.¹ Here, reaction of an acyclic alkenol substrate leads to formation of an aldehyde containing a remotely located stereocentre, which is obtained in high enantioselectivity through use of a chiral PyrOx ligand. The palladium catalyst initially inserts into the alkene, analogous to a standard Heck reaction, but instead of eliminating, to form the traditional Heck product, a site selective syn-β-hydride elimination occurs. This reforms the alkene, but the alkene is now repositioned one carbon closer to the alcohol. A subsequent series of syn-migratory insertion/syn-β-hydride elimination steps, referred to as the relay, ultimately leads to the desired aldehyde product, with the alcohol acting as a terminal acceptor for the process. It was later shown that a secondary alcohol can also be used, generating the corresponding ketone.

It has since been shown that this migration can occur over long distances,² and through pre-existing stereocentres,³ delivering the desired products in high diastereoselectivity, with the particular diastereomer dictated by the enantiomer of ligand used.

Other terminal acceptors, beyond a primary or secondary alcohol, can be successfully used in the transformation, delivering the corresponding alpha, beta-unsaturated products.¹ Reaction success has also been reported with fluorinated alkenes, and the redox-relay can also be performed on enol ethers. In 2018, Sigman and co-workers reported the first example on a heterocyclic substrate, focusing on lactams.

1. E. Bonfield, D. Valette, D. M. Lindsay, M. Reid Chem Eur. J. 2021, 27, 158.
2. -S. Mei, E. W. Werner, A. J. Burckle, M. S. Sigman, J. Am. Chem. Soc. 2013, 135, 6830.
3. -S. Mei, H. H. Patel, M. S. Sigman, Nature 2014, 508, 340.