Removing Neighboring Ring Influence in Monocyclic B-OH Diazaborines: Properties and Reactivity as Phenolic Bioisosteres with Dynamic Hydroxy Exchange.

The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. This challenge is compounded when emphasis is placed on the preparation of new chemotypes that have distinct and practical functions. To expand the structural diversity of boron-containing heterocycles, we report herein the preparation of novel monocyclic hemiboronic acids, diazaborines. These compounds have enabled the study of a pseudoaromatic boranol-containing (B-OH) ring free of influence from an appended aromatic system. Synthetic and spectroscopic studies have provided insight into the aromatic character, Lewis acidic nature, chemical reactivity, and unique ability of the exocyclic B-OH unit to participate in hydroxy exchange, suggesting their use in organocatalysis and as reversible covalent inhibitors. Moreover, density functional theory and nucleus-independent chemical shift calculations reveal that the aromatic character of the boroheterocyclic ring is increased significantly in comparison to known bicyclic benzodiazaborines (naphthoid congeners), consequently leading to attenuated Lewis acidity. Direct structural comparison to a well-established biaryl isostere, 2-phenylphenol, through X-ray crystallographic analysis reveals that N-aryl derivatives are strikingly similar in size and conformation, with attenuated logP values underscoring the value of the polar BNN unit. Their potential application as low-molecular-weight scaffolds in drug discovery is demonstrated through orthogonal diversification and preliminary antifungal evaluation (Candida albicans), which unveiled analogs with low micromolar inhibitory concentration.

Ferrocenium Boronic Acid Catalyzed Deoxygenative Coupling of Alcohols with Carbon- and Nitrogen-Based Borate and Silane Nucleophiles.

A boronic acid catalyzed carbon-carbon and carbon-nitrogen bond-forming reaction for the functionalization of various π-activated alcohols has been developed. Ferrocenium boronic acid hexafluoroantimonate salt was identified as an effective catalyst in the direct deoxygenative coupling of alcohols with a variety of potassium trifluoroborate and organosilane nucleophiles. In a comparison between these two classes of nucleophiles, the use of organosilanes leads to higher reaction yields, increased diversity of the alcohol substrate scope, and high E/Z selectivity. Furthermore, the reaction proceeds under mild conditions and yields up to 98%. Computational studies provide a rationalization for a mechanistic pathway for the retention of E/Z stereochemistry when E or Z alkenyl silanes are used as nucleophiles. This methodology is complementary to existing methodologies for deoxygenative coupling reactions involving organosilanes, and it is effective with a variety of organosilane nucleophile sub-types, including allylic, vinylic, and propargylic trimethylsilanes.