Hydrazone performs cross-coupling twofer

Choose Your Own Adventure novels let readers send characters down divergent paths to different endings. The same can be true in chemical transformations: slight tweaks to reagents or conditions can lead to different products from the same starting material. Chemists now report that α,α-disubstituted alkenyl hydrazones are such reagents. The bench-stable compounds act as cyclopropylcarbinyl equivalents and can produce either skipped dienes or vinyl cyclopropanes in cross-coupling reactions (shown). The final product depends on the nature of the aryl halide coupling partner (J. Am. Chem. Soc. 2022, DOI: 10.1021/jacs.1c12881).

University of North Carolina at Chapel Hill chemists Sidney M. Wilkerson-Hill, Nina F. C. Ritchie, and Adam J. Zahara discovered α,α-disubstituted alkenyl hydrazones’ divergent reactivity, which is a boon to synthetic chemists. Skipped dienes (also known as 1,4-dienes) can be found in certain insect pheromones, and vinyl cyclopropanes are useful building blocks in organic synthesis.

Wilkerson-Hill says the chemists were initially surprised that they observed vinyl cyclopropanes as the major product in some cases because they are the more strained isomers. “We are currently trying to understand what subtle electronic and steric factors are at play here that dictate whether you get vinyl cyclopropane or whether you get skipped diene,” he says.

Martín Fañanás-Mastral, an organic chemist at the Center for Research in Biological Chemistry and Molecular Materials, who was not involved in the work, says it would be interesting to see if the catalyst, rather than the aryl halide coupling partner, could be used to control which product is made. “The most interesting part of this work is how the inspiration from biosynthesis meets organometallic catalysis,” he says in an email. The UNC team designed a reaction pathway that produces an organopalladium intermediate that mimics an intermediate in the biosynthesis of skipped dienes, Fañanás-Mastral says.

Wilkerson-Hill says the team is working on enantioselective versions of these reactions. “Ultimately, our goal is to build natural products using the strategies,” he says.