New Route To Rare Heterocycles

Researchers have created a series of unexpectedly stable boryl-dicarbonyl compounds and have used them to synthesize heterocyclic molecules that were previously difficult or impossible to make.

According to conventional wisdom among chemists, because the boryl-dicarbonyls have multiple reactive groups in close proximity, they should break down quickly. In this new work, however, they are stable and can undergo double-condensation reactions that result in ring formation. The heterocyclic products of these reactions could be useful as building blocks for medicines and in other applications.

To make the borylated dicarbonyl intermediates, Andrei K. Yudin of the University of Toronto and coworkers used photoredox catalysis and organocatalysis to react brominated ketones with N-methyliminodiacetic acid (MIDA)-boryl aldehyde. The intermediates have an electron-rich carbon-boron bond and two electron-deficient carbonyl groups.

The carbonyl groups can participate in double-condensation reactions with a range of nucleophiles, forming MIDA-boryl pyrroles, furans, and pyridazines (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201504271). These borylated heterocycles have unusual and in some cases unprecedented structures, with boron in locations that have been difficult or impossible to access using other synthetic routes. And each one retains the starting material’s nucleophilic carbon-boron bond, which can participate in a subsequent reaction to create products of greater complexity.

“The surprising aspect of this work lies in the observed stability of dicarbonyls equipped with carbon-boron bonds,” Yudin tells C&EN. “Anyone trained in synthesis would recognize several elimination and rearrangement pathways that should render such molecules unstable, yet they are perfectly okay. Sigma-Aldrich is actively commercializing our new heterocycles, and we hope they will be available to the community very soon.” Asked what types of medicinally important compounds might be synthesized with the new approach, Yudin gives as examples the cholesterol-lowering agent atorvastatin, the heartburn drug ranitidine, and the antibiotic nitrofurantoin.

MIDA boronate expert Martin Burke of the University of Illinois, Urbana-Champaign, agrees that most chemists would have predicted that the dicarbonyl intermediates could not be isolated. Demonstrating that these reagents can provide access to a wide range of borylated heterocycle building blocks is “an important breakthrough,” Burke says.