Metal-Free Amination of (Hetero)aryl Boronic Acids

Keywords

amination - metal-free synthesis - heterocycles

Significance

(Hetero)aryl amines are an important class of functional group in medicinal chemistry, both for their biological properties and their utility as synthetic handles for further elaboration. Thus, many innovative strategies have been developed for (hetero)aryl C–N bond formation. Traditionally these methods rely on precious metal catalysts like palladium, or involve electrophilic nitration followed by reduction. The financial, environmental, and safety implications of these established protocols have driven the search for new, milder, metal-free methods. Recently, groups have had success with the metal-free synthesis of anilines from aryl boronic acids. However, achieving high conversion for sterically hindered and electron-deficient substrates remains a challenge. This report describes the rapid and mild amination of (hetero)aryl boronic acids using O-(diphenylphosphinyl)hydroxylamine (DPPH).

Comment

This reaction was exemplified on many sterically and electronically differentiated substrates. Importantly, several different electron-deficient aryl boronic acids were high-yielding. These substrates were challenging for previously established metal-free protocols. Good functional group tolerance was also demonstrated. Heteroaryl boronic acids, including pyridine- and indole-derived substrates, were also viable. (Hetero)aryl boron pinacol esters can undergo the transformation directly as well. Results from a Hammet study (ρ= –0.14) support the insensitivity of this method to the electronics of the substrate. This contrasts with another hydroxylamine-derived amination reagent, HOSA, that has a large negative ρ value of –1.9.

Publication History

Article published online:
25 February 2025