Chemists over the years have combined boron, carbon, nitrogen, and oxygen in various ways to create a variety of six-membered heterocyclic ring systems. One of the reasons they make these rings is to expand the array of available polycyclic aromatic materials used for making optoelectronic devices and used as organocatalysts. In particular, researchers have been looking at graphite-type materials based on six-membered ring core structures containing electron-deficient boron atoms. But incorporating both nitrogen and oxygen along with boron has remained elusive.
A research team at Japan’s Institute of Microbial Chemistry has now designed and synthesized oxaazaborinanes—molecules that contain a B3NO2 ring—that are a cross between previously known borazines (B3N3) and boroxines (B3O3). The new ring had been a missing link in the collection of six-membered ring compounds containing B, C, N, and O (Nat. Chem. 2017, DOI: 10.1038/nchem.2708).
The team led by Masakatsu Shibasaki and Naoya Kumagai prepared a set of the 1,3-dioxa-5-aza-2,4,6-triborinanes (DATBs) in a stepwise fashion starting from bromine-substituted aniline. The process required building a terphenyl template as a framework to support the B3NO2 ring. Kumagai says the peripheral architecture is important for the ring’s stability, explaining that the instability of the stand-alone B3NO2 ring is likely why chemists were not able to readily prepare it in the past.
The Japanese researchers realized the multiple Lewis acidic boron atoms in their DATBs should make the new molecules good catalysts. As a test case, they selected the direct amidation of carboxylic acids with amines, a key reaction for making pharmaceuticals. Chemists currently rely on boron-based acid organocatalysts with or without a supplemental metal to carry out this transformation.
The team found that its initial DATB molecule with a phenyl substituent produced modest results. But DATB derivatives with bulkier substituted phenyl groups containing a hydroxy azaborine moiety provide high yields for a broad range of amidations, in particular for sterically hindered substrates, outperforming previously known direct amidation catalysts.
“Accessing these compounds represents a significant achievement in heterocyclic chemistry,” says Jose M. Goicoechea of the University of Oxford, who focuses on the synthesis of new main-group-element molecules. “This report contributes to a burgeoning area of research aimed at developing catalysts from environmentally abundant main-group elements, which may ultimately provide an inexpensive and nontoxic alternative to compounds based on precious metals.”
“This paper illustrates wholly the state of the art and beauty of the chemical sciences,” adds Hansjörg Grützmacher of ETH Zurich, whose group recently reported the synthesis of another new heterocycle, triphosphabenzene. The work doesn’t just describe “a new and rather unusual boron heterocycle,” Grützmacher says, but also a remarkable application. “This represents a breakthrough in organocatalysis.”
“We believe that the substrate generality of DATB catalysis will convince chemists in academia and industry to replace reagent-based amidation with catalytic amidation,” Kumagai says. The Japanese researchers have a collaboration with a company to commercialize DATBs, he adds, and they continue to work on defining the catalytic mechanism as well as the synthesis of more active DATB derivatives.