Triple Aryne-Tetrazine Reaction Enabling Rapid Access to a New Class of Polyaromatic Heterocycles

Abstract

One of the most challenging goals of modern synthetic chemistry is to develop multi-step reactions for rapid and efficient access to complex molecules. We report a triple aryne-tetrazine reaction that enables rapid access to a new class of polyaromatic heterocycles. This new reaction, which couples diverse reactivity modes between simple aryne and tetrazine starting materials, proceeds in a single operation and takes less than 5 minutes in air with no metal catalyst.

Fig. 1. Triple aryne–tetrazine reaction. Red bold lines represent new bonds formed during the course of the reaction.

Fig. 2. (A) Proposed mechanism of the reaction. DA, Diels-Alder; DA_inv, inverse electron demand Diels-Alder. (B) Reaction conditions trapping intermediate 6. (C) Resubjection of isolated intermediate 6 to the original reaction conditions. (D) Reaction of benzyne with diphenyltetrazine 1 to produce 9,10-diphenylanthracene 7.

Fig. 3. Structure of 5q. Solutions of 5q in CH₂Cl₂ (left) and in CH₂Cl₂/TFA (right) irradiated at 365 nm with a UV lamp (left).

Fig. 4. Emission spectra for the neutral and protonated forms of compounds 5b, 5d, 5i, and 5q.

Fig. 5. Live-cell imaging of HeLa cells in the presence of 5e. (A) Cultured HeLa cells were incubated with 5e for 2 hours and imaged using confocal microscopy. (B) Cells were incubated with 5e for 2 hours, then counterstained with Hoechst 33342 and MitoTracker Red FM. Extranuclear cyan corresponds to compound 5e. Using an excitation of 405 nm and emission from 450 to 500 nm allows for simultaneous visualization of 5e, nuclear localized Hoechst 33342, and mitochondrial localized MitoTracker Red FM.