B–N Hyperconjugation Enables Site-Selective C–H Azidation of Alkyl and Benzyl N-Methyliminodiacetyl (MIDA) Boronates: Synthesis of α-Azido Boronates

Abstract

α-Azidoboronates, integrating both azido and boryl groups, are versatile intermediates for accessing α-aminoborons, α-triazolylborons, and bioorthogonal ligation handles. However, existing syntheses rely primarily on nucleophilic substitution of pre-functionalized α-haloboronates, which require multistep cryogenic Matteson homologation and involve unstable intermediates as well as hazardous azide reagents. Direct Cα–H azidation of alkyl boronates offers an appealing alternative but remains challenging due to competing radical addition to the sp²-boron center, leading to deborylation. Motivated by the unique stereoelectronic properties of B(MIDA) groups, which can stabilize α-radicals and promote boron-retentive transformations, we envisioned that selective radical C–H azidation of secondary B(MIDA)s could be feasible. Herein, we establish an iron-catalyzed protocol enabling efficient and site-selective Cα–H azidation of secondary MIDA boronates, leveraging σ(B–N) → p(C) hyperconjugation for α-radical stabilization. The protocol furnishes a broad range of α-azidoboronates in a single step. Preliminary studies further demonstrate their compatibility with click chemistry, underscoring their potential utility in functional molecule construction and bioorthogonal applications.

Keywords

α-Azidoboronates / C–H azidation / Hyperconjugation / Hypervalent iodine / Iron / Azides / Radicals / Click chemistry

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